Pearson's Thoracic Esophageal Surgery 3rd Ed [PDF][tahir99] VRG.pdf

THIRD EDITION

PEARSON’S THORACIC & ESOPHAGEAL SURGERY pe 9 rs - V ia R ns G s. ir

G. Alexander Patterson, MD, FRCSC Evarts A. Graham Professor of Surgery Chief, Division of Cardiothoracic Surgery Washington University School of Medicine St. Louis, Missouri

Joel D. Cooper, MD, FRCS

r9

Antoon (Toni) E. M. R. Lerut, MD, PhD

vi

ta

hi

Jean Deslauriers, MD, FRCSC

p.

Professor of Surgery Chief, Division of Thoracic Surgery University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Professor, Department of Surgery Laval University Faculty of Medicine Chief, Thoracic Surgery Division Center of Pneumology, Laval Hospital Quebec City, Quebec, Canada

Professor of Surgery, Catholic University Leuven Chairman, Department of Thoracic Surgery University Hospital Gasthuisberg Leuven, Belgium

James D. Luketich, MD

Henry T. Bahnson Professor of Cardiothoracic Surgery Director, Heart, Lung, and Esophageal Surgery Institute Chief, Division of Thoracic and Foregut Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Thomas W. Rice, MD

Daniel and Karen Lee Chair in Thoracic Surgery Head, Section of General Thoracic Surgery Cleveland Clinic Professor of Surgery, Cleveland Clinic Lerner College of Medicine Cleveland, Ohio

Honorary Editor:

F. Griffith Pearson, MD

Professor, Division of Thoracic Surgery Department of Surgery University of Toronto Faculty of Medicine Senior Surgeon, Division of Thoracic Surgery The Toronto General Hospital Toronto, Ontario, Canada

tahir99-VRG vip.persianss.ir

1600 John F. Kennedy Boulevard Suite 1800 Philadelphia, PA 19103-2899

PEARSON’S THORACIC AND ESOPHAGEAL SURGERY

ISBN: 978-0-443-06861-4

Copyright © 2008, 2002, 1995 by Churchill Livingstone, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editor/Authors assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Library of Congress Cataloging-in-Publication Data Pearson’s thoracic and esophageal surgery.—3rd ed. / [edited by] G. Alexander Patterson . . . [et al.]. p. ; cm. Rev. and combined ed. of: Esophageal surgery / edited by F. Griffith Pearson . . . [et al.]. 2nd ed. c2002 and Thoracic surgery / edited by F. Griffith Pearson . . . [et al.]. 2nd ed. c2002. Includes bibliographical references and index. ISBN 978-0-443-06861-4 (set) 1. Esophagus–Surgery. 2. Chest–Surgery. I. Pearson, F. Griffith. II. Patterson, G. Alexander. III. Esophageal surgery. IV. Thoracic surgery. V. Title: Thoracic and esophageal surgery. [DNLM: 1. Esophagus—surgery. 2. Esophageal Diseases—surgery. 3. Thoracic Surgical Procedures—methods. WI 250 P362 2008] RD539.5.E87 2008 617.5′48–dc22 2007006456

Associate Acquisitions Editor: Scott Scheidt Developmental Editor: Dee Simpson Publishing Services Manager: Tina Rebane Senior Project Manager: Amy L. Cannon Design Director: Steven Stave

Working together to grow libraries in developing countries Printed in China Last digit is the print number:

www.elsevier.com | www.bookaid.org | www.sabre.org

9

8

7

6

5

4

3

2

1

Volume 2 Esophageal cover image: Reprinted with permission of The Cleveland Clinic Center for Medical Art & Photography © 2007. All Rights Reserved.

tahir99-VRG vip.persianss.ir

Dedication

I would like to acknowledge the loving support of my wife Susan, a brilliant surgeon-scientist, and our four wonderful children Lachlan, Megan, Brendan, and Caitlan. I also would like to thank the many thoracic surgery trainees I have had the honor of working with over the years. These outstanding young surgeons are the future of our specialty and make our work so very rewarding. G. Alexander Patterson To my wife Janet, for her “old fashioned” devotion, support, and sacrifice to myself and our family. To our four sons for their understanding and tolerance. To my teachers, mentors, partners, and trainees who have inspired, taught, and encouraged me. Joel D. Cooper I wish to express my gratitude to all of those who helped and encouraged me in co-editing this third edition of Pearson’s Thoracic and Esophageal Surgery. Of particular importance are my wife Debbie, my five sons Daniel, David, Andre, Philippe, and Patrick, and my secretaries Ann Julien, Lucie Gosselin, and MarieHelene Lavoie. Jean Deslauriers I dedicate this book to my teachers and my mentors who were so influential in the development of my career. Without them my name would not be on the cover of this magnificent book. I dedicate this book to my wife Gertji, and my three children Katja, Philip, and Bob. They are the sunshine and the shining stars of my universe. I thank them for all their understanding. I finally would like to dedicate this book to all thoracic surgeons who, through their daily commitment to and care for their patients, are carrying forward the legacy of the great pioneers of thoracic surgery. Antoon (Toni) E. M. R. Lerut To my mentor in thoracic surgery Robert Ginsberg; I feel blessed to have been one of your students. My inclusion in this book was made possible by all of the other editors of this text and I would like to thank each one of them for their camaraderie and mentorship during this long process. A special thanks to my assistants at Pitt, including Arjun Pennathur, Kathy Lovas, and Theresa Krupka. I would like to dedicate my contributions to this textbook of thoracic surgery to my family: my wife Christine, Jim, Jr., Derek, Bobby, Patty, and our most recent addition to the family, dearest Sam, who is the light of his daddy’s life. James D. Luketich To my wife Janet, my children Matthew, Jonathan, Carolyn, and Andrea, and my grandson Nathan. Thomas W. Rice

v tahir99-VRG vip.persianss.ir

Preface

The current edition of these two volumes is substantially changed from the previous two editions. One important change is the title. The previous editions were entitled Thoracic Surgery and Esophageal Surgery. The current volumes are renamed Pearson’s Thoracic and Esophageal Surgery. This change acknowledges the enormous impact Dr. Pearson has had on developing, practicing, teaching, and research in the discipline we have come to know as general thoracic surgery. Dr. Pearson was the senior editor of the first two editions of this text, and, with his appointment as honorary editor to this edition, the editors decided the change in name was timely. It should be noted that virtually all of the authors of the previous and current editions have been students, partners, or colleagues of Dr. Pearson or were themselves trained by one of Dr. Pearson’s trainees. This edition was developed and executed by a new editorial board. With the untimely death of Dr. Robert Ginsberg and the retirement of Drs. Harold Urschel and Clem Hiebert from the editorial board, we were given an opportunity to add illustrious new members. Dr. James Luketich brings an international reputation for the development of minimally invasive surgery and other innovative techniques in thoracic surgery. Drs. Tom Rice and Toni Lerut have both made major contributions to the field of esophageal surgery. They shared principal responsibility for editing the esophageal volume. Of course, Dr. Lerut also brings an important international perspective to this edition and was able to recruit a number of international experts as authors. As in prior editions, Drs. Joel Cooper and Jean Deslauriers continue to make important contributions to the thoracic volume. It has been my privilege to serve as senior editor of this edition.

The editorial board has reflected on the recent passing of two outstanding thoracic surgeons, both of whom were influential in the evolution of this textbook. In recognition of their contributions, the thoracic volume is dedicated to Dr. Robert Ginsberg and the esophageal volume is dedicated to Mr. Ronald Belsey. These volumes have not previously been dedicated, but the appropriateness of these dedications is evident by the tributes to these great surgeons that follow on subsequent pages. The content of these two volumes has changed dramatically to reflect developments in the 6 years since the last edition. The vast majority of chapters are new additions or prior topics rewritten by new authors. The authorship represents an excellent collection of expertise from North American and international contributors. These thoracic and esophageal volumes embody the enthusiasm and exciting developments that characterize general thoracic surgery internationally. The biology of diseases we confront is being clarified by outstanding basic and clinical research. Clinical staging of thoracic malignancies, although still not perfect, is much more accurate than only a few years ago. Innovative surgeons have developed and refined minimally invasive techniques for many operative procedures we perform routinely. National and international societies as well as an increasing number of institutions continue to commit to the development of general thoracic surgery. Postgraduate training and curriculum requirements demand attention to and focus on general thoracic surgery. Although we as practicing thoracic surgeons benefit from this progress, the ultimate beneficiaries are the young surgeons attracted to this exciting field and, of course, our patients. G. Alexander Patterson, MD, FRCSC

vii tahir99-VRG vip.persianss.ir

FM-F06861.indd vii

1/21/2008 3:22:40 PM

Dedication for Dr. Robert Jason Ginsberg (1940-2003)

Robert J. Ginsberg was a Canadian thoracic surgeon who became one of the most recognized world leaders in thoracic oncology. His success was the result of great leadership capability, drive, and innovative initiative, combined with his exceptional talent for obtaining loyal, enthusiastic support from colleagues from every level of status and experience. These leadership and organizational talents were exemplified by his coordination of the University of Toronto Thoracic Surgery Group and their highly successful role in the U.S. National Institutes of Health (NIH)–sponsored Lung Cancer Study Group (LCSG) trials. Bob was born, raised, and largely educated in Toronto. He graduated with honors (Alpha Omega Alpha) from the University of Toronto Medical School in 1963, and he obtained his Canadian certificate in general surgery in 1968. He then became the first Chief Resident in the newly created Division of General Thoracic Surgery at Toronto General Hospital (TGH) at the University of Toronto. He subsequently spent 1 year as a Fellow at Baylor University School of Medicine in Dallas, Texas, on the Cardiothoracic Service of Drs. Donald Paulson and Harold Urschel. At that time, Donald Paulson was a world leader in the surgical staging and operative management of lung cancer. Bob spent the following year as Senior Registrar at the University of Birmingham in England. There he acquired further knowledge of thoracic surgery and met Dr. Gordon Cummings, who stimulated his lifelong interest in pulmonary function studies and their practical application for the management of Robert Jason Ginsberg resectable lung cancer. Bob died on March 1, 2003. He was a founding editor of this textbook, and the thoracic surgery volume of this third edition is appropriately dedicated in his name. He is greatly missed by his friends, colleagues, and students.

QUALITIES A gruff, sometimes forbidding, demeanor camouflaged a vibrant, warm personality and a willingness to give his all for colleagues, students, or patients. Astonishingly unselfish behavior was happily combined with unusual foresight. As his mentor Harold Urschel frequently observed, “Bob Ginsberg could see the big picture.” Bob’s selflessness recruited enthusiastic and loyal support from everyone. These qualities were exemplified on the occasion of the appointment of a new Chief of General Thoracic Surgery at TGH and the University of Toronto in 1978. Many expected Bob to be appointed the new Chief of General Thoracic Surgery, but he did have competition. Dr. Joel D. Cooper, who had been on staff in the TGH Division of General Thoracic Division since migrating from the Massachusetts General Hospital in 1972, had previously indicated his wish to stay in Canada for about 5 years and then return to his native United States. But Joel changed his mind and threw his hat into the ring for the Chief of General Thoracic Surgery position. When doing so, he stated that, if appointed, he was prepared to remain in Toronto for the next 10 years. About 2 weeks after Joel’s declaration of interest, Bob appeared in Dr. F. Griffith Pearson’s office stating that he wanted to withdraw his name for consideration. When asked why, Bob replied, “If I take the job, Joel Cooper will leave, and that would be a great loss for Toronto.” This was a selfless act but, in the end, a great judgment by Bob. Within 1 year, Joel recruited Bob to the staff of TGH and appointed Bob Director of Thoracic Oncology. These two individualistic and exceptionally able men complemented one another, and the Division of Thoracic Surgery undoubtedly became stronger for their dual presence. Bob was a very skilled technical surgeon, remaining cool and innovative under duress. For trainees at all levels, he was a consummate teacher. Some found him unduly frank and outspoken with his judgments, but this was always aimed at the best interest of the student. ix tahir99-VRG vip.persianss.ir

FM-F06861.indd ix

1/21/2008 3:22:40 PM

x

Dedication

Finally, he was a compassionate man. Inevitably, he became much loved and appreciated by his colleagues and was generally revered by his patients.

ACCOMPLISHMENTS Bob’s contributions to the Toronto Thoracic Surgery Group and this group’s participation in the NIH-sponsored LCSG multicenter North American randomized trials (1977-1989) has already been mentioned. It is notable, however, that Bob and a medical oncologist colleague, Dr. Michael Baker, wrote and submitted the successful Request for Proposal to the NIH from their home hospital—the Toronto Western Hospital—not TGH. Bob subsequently became Principle Investigator (PI) for Toronto and remained so between 1979 and 1989. The Toronto Thoracic Surgery Group was one of the seven original participating North American Centers. Toronto accrued almost half of the total number of patients in the LCSG trials. This remarkable productivity was the result of Bob’s success in recruiting thoracic surgeons and their patients from the University of Toronto–affiliated hospitals. Bob himself was a leader among the PIs from other participating American centers. He was the originator of the much quoted study on mortality rates for some 2500 lung cancer resections entered in LCSG trials during the first 3 years of study. Bob proposed and wrote the protocol for the trial comparing lobectomy with lesser resection for stage 1, non–small cell tumors. In 1990, Bob became Head of Thoracic Surgery at Memorial Sloan-Kettering Cancer Center in New York City. He considerably broadened and strengthened their already notable clinical program, as well as the thoracic residency experience. His curriculum vitae listed some 260 publications, many editorial appointments, and countless invitations throughout the world as visiting professor. He was an indefatigable worker.

AVOCATIONS Undoubtedly, his greatest pleasure was time spent with his family: his wife Charlotte and their three children Karen (a pediatrician in New York City), Jordan (a secondary school teacher in New York City), and David (a restaurateur in Toronto). Many weekends and holidays were spent at the family cottage on Lake Simcoe, where Bob was constantly adding or fixing up something. It was here that Charlotte and Bob had planned to retire. Bob and his wife were both experienced and enthusiastic world travelers. Bob was widely known for his love of good food, odd food, and fine restaurants. He was a formidable amateur chef. F. Griffith Pearson, MD G. Alexander Patterson, MD, FRCSC

tahir99-VRG vip.persianss.ir

FM-F06861.indd x

1/21/2008 3:22:40 PM

Contributors

Ghulam Abbas, MD

Michael J. Andritsos, MD

Director of Image-Guided Thoracic Surgery and Assistant Professor, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Clinical Assistant Professor, Department of Anesthesiology, Ohio State University School of Medicine, Columbus, Ohio

THORACIC: Alternatives to Surgical Resection for Non–Small Cell Lung Cancer

David J. Adelstein, MD Professor of Medicine, Department of Solid Tumor Oncology, Taussig Cancer Center, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio THORACIC: Definitive Management of Inoperable Non–Small Cell Lung Cancer

THORACIC: Anesthesia for Airway Surgery

M. Janine Arruda, MD Staff, Pediatric Cardiology, Cleveland Clinic, Cleveland; Fairview Hospital, Cleveland; Medina General Hospital, Medina; Parma Community Hospital, Parma, Ohio ESOPHAGEAL: Vascular Tracheoesophageal Compression: Vascular Rings, Pulmonary Artery Sling, and Innominate Artery Compression of the Trachea

Simon K. Ashiku, MD Clemens Aigner, MD Department of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria THORACIC: Bronchiectasis; Evaluation and Management of Elevated Diaphragm

Marco Alifano, MD Surgeon, Department of Thoracic Surgery, Hôtel Dieu, Hospital of Paris, Paris, France THORACIC: Plication of the Diaphragm

Surgeon, Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts THORACIC: Tracheomalacia

Ahmad S. Ashrafi, MD, FRCSC Thoracic Surgeon, Niagara Health System, St. Catherines, Ontario, Canada ESOPHAGEAL: Open Toupet and Fundoplications THORACIC: Unusual Mediastinal Tumors

Dor

Partial

Mark S. Allen, MD

Carl Lewis Backer, MD

Chair, Division of General Thoracic Surgery and Professor of Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota

Professor of Surgery, Northwestern University Feinberg School of Medicine; A. C. Buehler Professor of Cardiovascular-Thoracic Surgery, Division of CardiovascularThoracic Surgery, Children’s Memorial Hospital, Chicago, Illinois

THORACIC: Radionecrosis and Infection of the Chest Wall and Sternum

THORACIC: Congenital Anomalies: Vascular Rings

Nasser K. Altorki, MD, MBBCh Professor and Chief of Thoracic Surgery and Director, Center of Thoracic Surgical Oncology, Department of Cardiothoracic Surgery, Weill-Cornell Medical College, New York, New York ESOPHAGEAL: Primary Surgery for Adenocarcinoma of the Esophagus; Three-Field Lymph Node Dissection for Cancer of the Esophagus THORACIC: Early Detection and Screening of Lung Cancer

Rafael S. Andrade, MD Assistant Professor of Surgery, University of Minnesota Medical School; Thoracic Surgeon, Fairview University Medical Center, Minneapolis, Minnesota ESOPHAGEAL: Peptic Esophagitis, Peptic Stricture, and Short Esophagus

Majit S. Bains, MD Attending Surgeon, Memorial Sloan-Kettering Cancer Center; Professor of Surgery, Cornell University Medical College, New York, New York ESOPHAGEAL: Unusual Malignancies

Mark E. Baker, MD Staff, Diagnostic Radiology and Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio ESOPHAGEAL: Radiology, Computed Tomography, and Magnetic Resonance Imaging

Farzaneh Banki, MD Cardiothoracic Fellow, Department of Surgery, Division of Cardiothoracic Surgery, University of Washington, Seattle, Washington THORACIC: Inflammatory Conditions of the Airway

xi tahir99-VRG vip.persianss.ir

FM-F06861.indd xi

1/21/2008 3:22:40 PM

xii

Contributors

Nancy L. Bartlett, MD

Costas Bizekis, MD

Associate Professor, Department of Medicine, Oncology Division, Medical Oncology Section, Washington University, St. Louis, Missouri

Assistant Professor of Cardiothoracic Surgery; Director, Esophageal Surgery Program; Director, General Thoracic Surgery, Bellevue Hospital, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York University Medical Center, New York, New York

THORACIC: Lymphoma of the Mediastinum

Richard J. Battafarano, MD, PhD Chief, Division of Thoracic Surgery, University of Maryland Medical Center; Associate Professor, University of Maryland School of Medicine, Baltimore, Maryland ESOPHAGEAL: Complications of Esophageal Resection THORACIC: Open Drainage of Thoracic Infections; Diagnostic Strategies for a Chest Wall Mass

Gilles Beauchamp, MD Professor of Surgery, Department of Surgery, University of Montreal; Division of Thoracic Surgery, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada THORACIC: Spontaneous Pneumothorax and Pneumomediastinum

Ricardo A. Bello, MD Clinical Instructor of Cardiothoracic Surgery, Albert Einstein College of Medicine; Instructor of Cardiothoracic Surgery, Montefiore Medical Center, Bronx, New York THORACIC: Mediastinal Lymph Node Dissection

ESOPHAGEAL: Esophageal Diverticula

Brendan J. Boland, MD Resident in General Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California ESOPHAGEAL: En-Bloc Resection of the Esophagus

Michael Bousamra, II, MD Associate Professor of Surgery, University of Louisville; Director of Lung Transplantation, Jewish Hospital; Head of Thoracic Surgery, James Graham Brown Cancer Center, Louisville, Kentucky THORACIC: Neurogenic Tumors of the Mediastinum

Jeffrey D. Bradley, MD Associate Professor, Department of Radiation Oncology, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Missouri THORACIC: Induction and Adjuvant Therapy for Operable Non–Small Cell Lung Cancer

W. Fred Bennett, MD, FRCSC

Mario Brandolino, MD

Assistant Professor, Division of Thoracic Surgery, Department of Surgery, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Former Head, Department of Thoracic Surgery, Saint Bois Hospital; Former Head, Department of Thoracic Surgery, Asociacion Española, Montevideo, Uruguay

THORACIC: Management of Malignant Pleural Effusions

THORACIC: Rare Infections of the Pleural Space

Michel G. Bergeron, MD, FRCPC

Carl E. Bredenberg, MD

Director, Division of Microbiology, Laval University and Research Center for Infectious Diseases, Quebec City, Quebec, Canada

Professor of Surgery, University of Vermont College of Medicine, Burlington, Vermont; Surgeon-in-Chief Emeritus, Maine Medical Center, Portland, Maine

THORACIC: Pulmonary Infections in the Immunocompromised Host

Yves Bergeron, PhD Adjunct Professor, Laval University; Project Leader, Research Center for Infectious Diseases, Quebec City, Quebec, Canada THORACIC: Pulmonary Infections in the Immunocompromised Host

Sanjeev Bhalla, MD Assistant Professor of Radiology, Division of Diagnostic Radiology, Thoracic Imaging Section; Chief, Thoracic Imaging Section; Co-Chief, Body Computed Tomography; Assistant Radiology Residency Program Director, Mallinckrodt Institute of Radiology, St. Louis, Missouri THORACIC: Imaging of the Upper Airway

ESOPHAGEAL: Selection and Placement of Conduits

Ross M. Bremner, MD, PhD Chief, General Thoracic Surgery and Director, Center for Thoracic Diseases, Heart and Lung Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona THORACIC: Tracheoesophageal Fistula

Mary P. Bronner, MD Section Head, Morphologic Molecular Pathology; Director, Gastrointestinal Pathology, Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio ESOPHAGEAL: Histopathology of Gastroesophageal Disease and Barrett’s Esophagus

Ayesha Bryant, MSPH, MD Assistant Professor, Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, Alabama THORACIC: Anatomy and Physiology of the Chest Wall and Sternum With Surgical Implications

tahir99-VRG vip.persianss.ir

FM-F06861.indd xii

1/21/2008 3:22:40 PM

Contributors

Joshua H. Burack, MD

Robert James Cerfolio, MD

Clinical Associate Professor, Department of Surgery, Division of Cardiothoracic Surgery, State University of New York– Downstate, Brooklyn, New York

Professor of Surgery, Department of Surgery; Chief of Thoracic Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, Alabama

THORACIC: Pathophysiology and Initial Management of Thoracic Trauma

THORACIC: Early Postoperative Complications; Closed Drainage and Suction Systems

Raul Burgos, MD

Ibrahim Bulent Cetindag, MD

Professor of Thoracic and Cardiovascular Surgery, University Autonoma of Madrid; Staff, Thoracic and Cardiovascular Surgery, Puerta de Mierro University Hospital, Madrid, Spain

General Surgery, Southern Illinois University School of Medicine, Springfield, Illinois

THORACIC: Parasitic Diseases of the Lung and Pleura

Jean S. Bussières, MD Associate Professor, Laval University; Anesthesiologist, University Heart and Lung Institute, Laval Hospital, Quebec City, Quebec, Canada THORACIC: Anesthesia for General Thoracic Surgery

Javier H. Campos, MD Professor of Anesthesia; Vice Chair of Clinical Affairs; Medical Director, Operating Rooms; Director of Cardiothoracic Anesthesia, Department of Anesthesia, University of Iowa Health Care, Roy J. and Lucille A. Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa THORACIC: Anesthesia for General Thoracic Surgery

Mieke Cannie, MD Department of Radiology, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Stephen D. Cassivi, MD, MSc, FRCSC Associate Professor of Surgery, Division of General Thoracic Surgery, Mayo Clinic College of Medicine; Consultant Surgeon and Surgical Director of Lung Transplantation, Department of Surgery, Mayo Clinic, Rochester, Minnesota THORACIC: Mycotic Infections of the Lung

Alan G. Casson, MB, ChB, MSc, FRCSC Professor of Surgery, University of Saskatchewan; Head, Department of Surgery, Saskatoon Health Region, Saskatoon, Saskatchewan, Canada ESOPHAGEAL: Biology and Epidemiology of Malignant Esophageal Carcinoma

Evaristo Castedo, MD Professor of Cardiovascular Surgery, University Autonoma of Madrid; Staff, Thoracic and Cardiovascular Surgery, Puerta de Mierro University Hospital, Madrid, Spain THORACIC: Parasitic Diseases of the Lung and Pleura

xiii

THORACIC: Thoracoscopy

Jacques E. Chelly, MD, PhD, MBA Professor of Anesthesiology and Vice Chair of Clinical Research, Department of Anesthesiology, University of Pittsburgh Physicians, Pittsburgh, Pennsylvania THORACIC: Perioperative Pain Management

Priscilla Chiu, MD, PhD Staff Pediatric Surgeon, Division of General Surgery, Hospital for Sick Children; Assistant Professor, Department of Surgery, University of Toronto, Toronto, Ontario, Canada THORACIC: Mediastinal Cysts and Duplications in Infants and Children

Neil A. Christie, MD Assistant Professor of Surgery, Heart, Lung, and Esophageal Surgery Institute and Director, LIFE Bronchoscopy and Early Lung Cancer Detection Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania ESOPHAGEAL: Palliation of Esophageal Cancer

Andy T. A. Chung, MD Instructor of Otolaryngology, Head and Neck Surgery, Washington University School of Medicine; Instructor, BarnesJewish Hospital, St. Louis, Missouri ESOPHAGEAL: Free Vascularized Grafts in Esophageal Reconstruction

R. Brannon Claytor, MD Clinical Instructor, Division of Plastic Surgery, Lahey Clinic, Burlington, Massachusetts; Clinical Instructor, Maine Medical Center for the University of Vermont College of Medicine, Portland; Plastic and Hand Surgical Associates, South Portland, Maine THORACIC: Surgery of the Phrenic Nerve

Joel D. Cooper, MD Professor of Surgery and Chief, Division of Thoracic Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania THORACIC: Investigation and Management of the Indeterminate Pulmonary Nodule; Transcervical Thymectomy for Nonthymomatous Myasthenia Gravis

Mario Costantini, MD Department of Medical and Surgical Sciences, Clinica Chirurgica III, University of Padova School of Medicine, Padova, Italy ESOPHAGEAL: Function Tests

tahir99-VRG vip.persianss.ir

FM-F06861.indd xiii

1/21/2008 3:22:40 PM

xiv

Contributors

Anita P. Courcoulas, MD, MPH

Farrokh Dehdashti, MD

Chief, Minimally Invasive Bariatric and General Surgery, Associate Professor of Surgery, University of Pittsburgh School of Medicine; University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Professor, Department of Radiology, Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, St. Louis, Missouri ESOPHAGEAL: Nuclear Imaging

ESOPHAGEAL: Reflux in the Morbidly Obese

Steven R. DeMeester, MD Thomas A. D’Amico, MD Professor of Surgery, Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina THORACIC: Diagnosis and Staging of Lung Cancer

Associate Professor of Cardiothoracic Surgery, University of Southern California; Chief, Section of Foregut and Thoracic Surgery, Los Angeles County/University of Southern California Medical Center, Los Angeles, California ESOPHAGEAL: Colon Interposition

Gail Darling, MD, FRCSC Associate Professor and Residency Program Director, Department of Surgery, Division of Thoracic Surgery, University of Toronto; Consultant, Thoracic Surgery, Department of Surgical Oncology, Toronto General Hospital and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada THORACIC: Bacterial Infections of the Lung

Tom R. DeMeester, MD Jeffrey P. Smith Professor of General and Thoracic Surgery; Chairman, Department of Surgery, Keck School of Medicine, University of Southern California; Chief of Surgery, Department of Surgery, University of Southern California University Hospital, Los Angeles, California ESOPHAGEAL: Function Tests

Philippe Dartevelle, MD

Jan Deprest, MD

Professor of Thoracic Surgery, University Paris-Sud, Paris; Chairman, Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Hospital MarieLannelongue, Les Plessis Robinson, France

Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium

THORACIC: Carinal Resection

Alberto de Hoyos, MD Director, Center for Robotic and Minimally Invasive Thoracic Surgery, Department of Surgery, Division of Cardiothoracic Surgery; Assistant Professor of Surgery, Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois THORACIC: Principles of Airway Surgery: Management of Acute Airway Obstruction

Marc de Perrot, MD, MSc Department of Surgery, Division of Thoracic Surgery, Toronto General Hospital, Toronto, Ontario, Canada THORACIC: Carinal Resection

Charl J. De Wet, MBChB Associate Professor, Departments of Anesthesiology and Surgery, Washington University School of Medicine; Medical Director, Cardiothoracic Intensive Care Unit, Barnes-Jewish Hospital, St. Louis, Missouri THORACIC: Critical Care of the Thoracic Surgical Patient

Anne Debeer, MD Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Malcolm M. DeCamp, Jr., MD

THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Claude Deschamps, MD Professor of Surgery, Department of Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota THORACIC: Fibrothorax and Decortication

Jean Deslauriers, MD, FRCSC Professor, Department of Surgery, Laval University Faculty of Medicine; Chief, Thoracic Surgery Division, Center of Pulmonology, Laval Hospital, Quebec City, Quebec, Canada THORACIC: Tuberculosis and Atypical Mycobacterial Diseases; Bronchoplasty; Anatomy and Physiology of the Pleural Space; Management of Malignant Pleural Effusions; Thoracoplasty; Fibrothorax and Decortication; Anatomy and Physiology of the Chest Wall and Sternum With Surgical Implications; Congenital Diaphragmatic Malformations

Frank C. Detterbeck, MD Professor and Chief, Thoracic Surgery; Associate Director, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut THORACIC: Thymic Tumors: A Review of Current Diagnosis, Classification, and Treatment

Ismael A. Conti Díaz, MD Former Professor and Chairman, Department of Parasitology and Mycology, School of Medicine, University of the Republic, Montevideo, Uruguay THORACIC: Rare Infections of the Pleural Space

Associate Professor of Surgery, Harvard Medical School; Chief, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts THORACIC: Role of Lung Biopsy in Interstitial Lung Disease

tahir99-VRG vip.persianss.ir

FM-F06861.indd xiv

1/21/2008 3:22:40 PM

Contributors

Elise Doné, MD

David M. Einstein, MD

Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium

Staff, Diagnostic Radiology, Cleveland Clinic, Cleveland, Ohio

THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

ESOPHAGEAL: Radiology, Computed Tomography, and Magnetic Resonance Imaging

Daniel P. Doody, MD

F. Henry Ellis, Jr., MD, PhD

Surgery Service, Massachusetts General Hospital, Boston, Massachusetts

Clinical Professor of Surgery Emeritus, Harvard Medical School; Chief Emeritus, Division of Cardiothoracic Surgery, New England Deaconess Hospital, Boston, Massachusetts

ESOPHAGEAL: Congenital Anomalies

xv

ESOPHAGEAL: Open Nissen Fundoplication

Gregory P. Downey, MD, FRCPC Vice Chair, Department of Medicine, University of Toronto, Toronto, Ontario, Canada THORACIC: Bacterial Infections of the Lung

Robert J. Downey, MD Associate Professor of Surgery, Department of Surgery, Thoracic Service, Memorial Sloan-Kettering Cancer Center, New York, New York THORACIC: Rare Primary Malignant Neoplasms of the Lung

Christopher T. Ducko, MD Instructor in Surgery, Department of Surgery, Harvard Medical School; Associate Surgeon, Division of Thoracic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts

Elie Fadel, MD Professor of Thoracic Surgery, University Paris-Sud, Paris; Thoracic Surgeon, Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Hospital MarieLannelongue, Le Plessis Robinson, France THORACIC: Carinal Resection

Stanley C. Fell, MD Professor of Cardiothoracic Surgery, Albert Einstein College of Medicine, Bronx, New York; Chief Emeritus, Division of Cardiothoracic Surgery, New England Deaconess Hospital, Boston, Massachusetts ESOPHAGEAL: Gastric Tubes: Reversed and Nonreversed; Esophageal Perforation THORACIC: History and Development of General Thoracic Surgery; Segmental Resection

THORACIC: Pleural Tumors

Timothy S. Fenske, MD, MS John A. Dumot, DO Vice Chairman, Clinical Practice, Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio ESOPHAGEAL: Flexible Endoscopy

Assistant Professor of Medicine, Neoplastic Diseases and Related Disorders, Medical College of Wisconsin, Milwaukee, Wisconsin THORACIC: Lymphoma of the Mediastinum

Brian W. Duncan, MD

Mark K. Ferguson, MD

Staff, Pediatric and Congenital Heart Surgery, Cleveland Clinic, Cleveland, Ohio

Professor, Department of Surgery, University of Chicago; Head, Thoracic Surgery Service, University of Chicago Medical Center, Chicago, Illinois

ESOPHAGEAL: Vascular Tracheoesophageal Compression: Vascular Rings, Pulmonary Artery Sling, and Innominate Artery Compression of the Trachea

THORACIC: Preoperative Assessment of the Thoracic Surgical Patient

André Duranceau, MD, FRCSC

Felix G. Fernandez, MD

Professor of Surgery, Department of Surgery, Division of Thoracic Surgery, Esophageal Surgery Section, University of Montreal; Thoracic Surgeon, Centre Hospitalier de l’Université de Montreal, Division of Thoracic Surgery, Montreal, Quebec, Canada

Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri

ESOPHAGEAL: Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities; Pharyngeal and Cricopharyngeal Disorders

Steven A. Edmundowicz, MD Professor of Medicine, Washington University; Chief of Endoscopy, Barnes-Jewish Hospital, St. Louis, Missouri

THORACIC: Extended Pulmonary Resections

Hiran C. Fernando, MD, FRCS Associate Professor, Cardiothoracic Surgery, Boston University; Director, Minimally Invasive Thoracic Surgery, Boston Medical Center, Boston, Massachusetts THORACIC: Alternatives to Surgical Resection for Non–Small Cell Lung Cancer

ESOPHAGEAL: Endoscopic Management of Reflux

tahir99-VRG vip.persianss.ir

FM-F06861.indd xv

1/21/2008 3:22:40 PM

xvi

Contributors

Pasquale Ferraro, MD, FRCSC

Éric Fréchette, MD

Associate Professor, Department of Surgery, Division of Thoracic Surgery and Lung Transplantation, University of Montreal; Chief, Division of Thoracic Surgery, Centre Hospitalier de l’Université de Montreal, Montreal, Quebec, Canada

Clinical Teacher of Surgery, Laval University; Staff Surgeon, Thoracic Surgery, Laval Hospital, Quebec City, Quebec, Canada

ESOPHAGEAL: Pharyngeal and Cricopharyngeal Disorders

Lorenzo E. Ferri, MD, FRCSC Assistant Professor of Surgery, McGill University; Thoracic and Esophageal Surgeon, McGill University Health Centre, Montreal, Quebec, Canada ESOPHAGEAL: Reconstruction After Pharyngolaryngectomy

Peter F. Ferson, MD Professor of Surgery, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania THORACIC: Late Sequelae of Thoracic Injury

Jonathan F. Finks, MD Assistant Professor of Surgery, Department of General Surgery, University of Michigan, Ann Arbor, Michigan ESOPHAGEAL: Laparoscopic Nissen Fundoplication

THORACIC: Congenital Diaphragmatic Malformations

Henning A. Gaissert, MD Associate Professor of Surgery, Harvard Medical School; Associate Visiting Surgeon, Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts THORACIC: Primary Tumors of the Trachea; Tracheostomy

Ziv Gamliel, MD, MSc Chief, Thoracic Surgery, St. Joseph Medical Center, Towson, Maryland ESOPHAGEAL: Induction and Adjuvant Therapy for Cancer of the Esophagus

Sanjiv K. Gandhi, MD Associate Professor of Surgery, Department of Surgery, Washington University; Associate Professor of Surgery, Department of Surgery, Division of Pediatric Cardiothoracic Surgery, St. Louis Children’s Hospital, St. Louis, Missouri THORACIC: Pediatric Mediastinal Tumors

Richard J. Finley, MD

Mario C. Ghefter, MD

Professor and Head, Division of Thoracic Surgery, Department of Surgery, University of British Columbia, Vancouver General Hospital, Vancouver, British Columbia, Canada

Director, General Thoracic Surgery, Hospital Do Servidor Publico Estadual, Sao Paulo, Brazil

ESOPHAGEAL: Rings and Webs; Surgical Approaches for Primary Motor Disorders of the Esophagus

Raja M. Flores, MD Assistant Professor of Cardiothoracic Surgery, Department of Surgery, Cornell University Medical College; Assistant Attending Surgeon, Thoracic Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York THORACIC: Robotic-Assisted Surgery Lobectomy

Video-Assisted

Thoracic

THORACIC: Penetrating Thoracic Trauma

David S. Gierada, MD Associate Professor, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri THORACIC: Pleura Imaging; Chest Wall and Sternum Imaging; Imaging of the Diaphragm

Sebastien Gilbert, MD Assistant Professor of Surgery, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania THORACIC: Late Sequelae of Thoracic Injury

Alexander A. Fokin, MD, PhD Associate Director and Director of Surgical Research, Heineman Medical Research Laboratories, Department of Cardiovascular and Thoracic Surgery, Carolinas Medical Center, Charlotte, North Carolina THORACIC: Complications of Midline Sternotomy; Complications of Pectus Deformity Repair

Dalilah Fortin, MD, FRCSC Assistant Professor of Surgery, Division of Thoracic Surgery, University of Western Ontario, London Health Sciences Centre, Victoria Hospital, London, Ontario, Canada

Allan M. Goldstein, MD Surgery Service, Massachusetts General Hospital, Boston, Massachusetts ESOPHAGEAL: Congenital Anomalies

Ramaswamy Govindan, MD Associate Professor of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri THORACIC: Induction and Adjuvant Therapy for Operable Non–Small Cell Lung Cancer

THORACIC: The Thoracic Duct and Chylothorax

tahir99-VRG vip.persianss.ir

FM-F06861.indd xvi

1/21/2008 3:22:41 PM

Contributors

Geoffrey M. Graeber, MD

Charles Hantler, MD

Professor of Surgery, Section of Thoracic and Cardiovascular Surgery; Chief, General Thoracic Surgery Service, Department of Surgery, West Virginia School of Medicine, Morgantown, West Virginia

Professor, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri

THORACIC: Neoplasms of the Chest Wall; Chest Wall and Sternum Resection and Reconstruction

Jocelyn Grégoire, MD Clinical Instructor and Professor, Department of Surgery, Laval University School of Medicine; Thoracic Surgeon and Consultant, Center of Pneumology, Laval Hospital, Quebec City, Quebec, Canada THORACIC: Bronchoplasty; Thoracoplasty

xvii

THORACIC: Anesthesia for Airway Surgery

David H. Harpole, Jr., MD Vice Chair, Faculty Affairs, Department of Surgery, Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina THORACIC: Bronchial Gland Tumors

Karen Harrison-Phipps, MD Fellow, Division of General Thoracic Surgery, Mayo Clinic, Rochester, Minnesota THORACIC: Mediastinal Cysts and Duplications in Adults

Noreen Griffin, CNP Certified Nurse Practitioner, Thoracic Surgery, Metrohealth Medical Center, Cleveland, Ohio THORACIC: Late Postoperative Complications

Hermes C. Grillo, MD† Former Thoracic Surgeon, Massachusetts General Hospital, Boston, Massachusetts THORACIC: Idiopathic Laryngotracheal Stenosis

Bruce H. Haughey, MBChB, MS, FRACS Kimbrough Professor of Otolaryngology, Head and Neck Surgery, Washington University School of Medicine; Director, Division of Head and Neck Surgical Oncology, Department of Otolaryngology, Head and Neck Surgery, Barnes-Jewish Hospital, St. Louis, Missouri ESOPHAGEAL: Free Vascularized Grafts in Esophageal Reconstruction

Dominique Grunenwald, MD

Karin Haustermans, MD, PhD

Director, Thoracic Surgery, Hospital Tenon, Paris, France

Professor, Radiation Oncology, Catholic University Leuven; Clinical Head, Department of Radiation Oncology, Leuven Cancer Institute, Leuven, Belgium

THORACIC: Surgical Resection of Pulmonary Metastases

Leonardo Gucciardo, MD Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Patrick J. Gullane, MD, FRCSC Professor and Chair, Department of Otolaryngology–Head and Neck Surgery, University of Toronto; Otolaryngologistin-Chief and Wharton Chair, Head and Neck Surgery, University Health Network, Toronto, Ontario, Canada THORACIC: Laryngoscopy

Jeffrey A. Hagen, MD Associate Professor of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California ESOPHAGEAL: En-Bloc Resection of the Esophagus

Bruce Lee Hall, MD, PhD, MBA Associate Professor of Surgery and Assistant Professor of Business Administration, Washington University; BarnesJewish Hospital, St. Louis, Missouri THORACIC: Mediastinal Thyroid Tumors; Mediastinal Parathyroid Tumors

ESOPHAGEAL: Principles of Radiotherapy

Stephen R. Hazelrigg, MD Professor and Chairman, Division of Cardiothoracic Surgery, Department of Surgery, Southern Illinois University School of Medicine, Springfield, Illinois THORACIC: Thoracoscopy

Claudia I. Henschke, MD, PhD Professor of Radiology in Cardiothoracic Surgery, Department of Radiology, Weill-Cornell Medical College, New York, New York THORACIC: Early Detection and Screening of Lung Cancer

Margaret S. Herridge, MD, MPH Associate Professor, Department of Medicine, Division of Respirology, Interdepartmental Division of Critical Care Medicine, University of Toronto; Consultant, Respiratory and Critical Care Medicine, Department of Medicine, University Health Network, Toronto, Ontario, Canada THORACIC: Bacterial Infections of the Lung

Clement A. Hiebert, MD Clinical Professor of Surgery, University of Vermont College of Medicine, Burlington, Vermont; Chairman Emeritus, Department of Surgery, Maine Medical Center, Portland, Maine ESOPHAGEAL: Selection and Placement of Conduits

†

Deceased.

tahir99-VRG vip.persianss.ir

FM-F06861.indd xvii

1/21/2008 3:22:41 PM

xviii

Contributors

Lauren Holinger, MD

Kashif Irshad, MD

Professor of Otolaryngology, Head and Neck Surgery, Northwestern University Feinberg School of Medicine; Head, Pediatric Otolaryngology, Children’s Memorial Hospital, Chicago, Illinois

Attending Surgeon, Division of Thoracic Surgery, William Osler Health Centre, Etobicoke, Ontario, Canada

THORACIC: Congenital Anomalies: Vascular Rings

ESOPHAGEAL: Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux; Caustic Injuries to the Esophagus

Arnulf H. Hölscher, MD

Eric Jacobsohn, MBChB, MHPE, FRCPC

Chairman, Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany

Professor and Chairman, Department of Anesthesia, University of Manitoba; Medical Director, Winnipeg Regional Health Authority Anesthesia Program, Winnipeg, Manitoba, Canada

ESOPHAGEAL: Adenocarcinoma of the Cardia

Susan J. Hoover, MD Director, Breast Diagnostic Center, Lifetime Cancer Screening Center; Medical Director of Diversity Affairs; and Assistant Professor of Surgery, Comprehensive Breast Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida THORACIC: Chronic Mediastinitis

Jasmine Huang, MD Resident, Department of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa ESOPHAGEAL: Hill Repair

THORACIC: Critical Care of the Thoracic Surgical Patient

Jacques Jani, MD Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Cylen Javidan-Nejad, MD Assistant Professor, Department of Radiology, Division of Diagnostic Radiology, Section of Cardiopulmonary Imaging, Washington University School of Medicine, St. Louis, Missouri THORACIC: Imaging of the Upper Airway

Charles B. Huddleston, MD Professor of Surgery and Chief, Pediatric Cardiothoracic Surgery, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, Missouri THORACIC: Congenital Abnormalities of the Lung; Chest Wall Deformities

John G. Hunter, MD Mackenzie Professor and Chairman, Surgery Department, Oregon Health and Science University, Portland, Oregon ESOPHAGEAL: Laparoscopic Nissen Fundoplication

David R. Jones, MD Professor of Surgery; Division Chief, Thoracic and Cardiovascular Surgery; Chief, General Thoracic Surgery, University of Virginia, Charlottesville, Virginia THORACIC: Biology and Epidemiology of Lung Cancer; Neoplasms of the Chest Wall

William G. Jones, II, MD Attending Cardiothoracic Surgeon, Doctor’s Hospital; Texas Cardiothoracic Surgery Associates, Dallas, Texas THORACIC: Pericardial Disease

Mark D. Iannettoni, MD Head, Department of Cardiothoracic Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa THORACIC: Acute Necrotizing Mediastinitis

David H. Ilson, MD, PhD Associate Professor, Weill-Cornell Medical College; Associate Attending Physician and Associate Member, Memorial Sloan-Kettering Cancer Center, New York, New York ESOPHAGEAL: Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

Richard I. Inculet, MD Associate Professor of Surgery, Division of Thoracic Surgery, Schulich School of Medicine; Chair, Division of Thoracic Surgery, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada THORACIC: The Thoracic Duct and Chylothorax

Gregory Jurkovich, MD Professor of Surgery, University of Washington; Chief of Trauma, Harborview Medical Center, Seattle, Washington THORACIC: Management of Blunt Chest and Diaphragmatic Injuries

Larry R. Kaiser, MD The John Rhea Barton Professor and Chairman, Department of Surgery, University of Pennsylvania School of Medicine; Surgeon-in-Chief, University of Pennsylvania Health System, Philadelphia, Pennsylvania THORACIC: Benign Lung Tumors; Surgery of Pectus Deformities; Surgery for Myasthenia Gravis

Riyad Karmy-Jones, MD, FRCSC Medical Director, Thoracic and Vascular Surgery, Southwest Washington Medical Center, Vancouver, Washington THORACIC: Tracheobronchial Trauma; Management of Blunt Chest and Diaphragmatic Injuries

tahir99-VRG vip.persianss.ir

FM-F06861.indd xviii

1/21/2008 3:22:41 PM

Contributors

Steven M. Keller, MD

Mark J. Krasna, MD

Professor of Cardiothoracic Surgery, Albert Einstein College of Medicine; Chief, Division of Thoracic Surgery, Montefiore Medical Center, Bronx, New York

Medical Director, Cancer Institute, St. Joseph Medical Center, Towson, Maryland

THORACIC: Mediastinal Lymph Node Dissection

Michael S. Kent, MD Instructor in Surgery, Harvard Medical School; Attending Surgeon, Division of Thoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts ESOPHAGEAL: Caustic Injuries to the Esophagus THORACIC: Interventional Bronchoscopy for the Management of Airway Obstruction

xix

ESOPHAGEAL: Induction and Adjuvant Therapy for Cancer of the Esophagus THORACIC: Dorsal Sympathectomy for Hyperhidrosis

Daniel Kreisel, MD, PhD Assistant Professor of Surgery and of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri THORACIC: Lung Transplantation

Priya D. Krishna, MD Shaf Keshavjee, MD, MSc, FRCSC Professor of Surgery, University of Toronto; Chair, Division of Thoracic Surgery; Director, Toronto Lung Transplant Program; Director, Thoracic Surgery Research Laboratory, Toronto General Hospital, Toronto, Ontario, Canada ESOPHAGEAL: Reconstruction After Pharyngolaryngectomy THORACIC: Upper Airway Tumors: Secondary Tumors

Kenneth A. Kesler, MD Professor of Surgery, Indiana University School of Medicine, Thoracic Surgery Division, Department of Cardiothoracic Surgery, Indianapolis, Indiana THORACIC: Germ Cell Tumors of the Mediastinum

Walter Klepetko, MD Professor of Special Thoracic Surgery and Director, Vienna Lung Transplant Program, Department of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria THORACIC: Bronchiectasis; Evaluation and Management of Elevated Diaphragm

Anastasios Konstantakos, MD Associate Surgeon, Division of Cardiothoracic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard University, Boston, Massachusetts THORACIC: Last Postoperative Complications

Robert J. Korst, MD Medical Director, Daniel and Gloria Blumenthal Cancer Center and Director, Thoracic Surgery, Valley Health System, Paramus, New Jersey THORACIC: Early Detection and Screening of Lung Cancer

Assistant Professor, Division of Laryngology, Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania THORACIC: Management of Vocal Fold Paralysis

Alexander S. Krupnick, MD Assistant Professor of Surgery, Department of Surgery, Division of Cardiothoracic Surgery, Washington University, St. Louis, Missouri THORACIC: Lung Transplantation; Surgery of the Phrenic Nerve

John C. Kucharczuk, MD Assistant Professor of Surgery, Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania THORACIC: Surgery of Pectus Deformities; Transcervical Thymectomy for Nonthymomatous Myasthenia Gravis

King F. Kwong, MD Investigator, Thoracic Oncology Section, Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, Maryland THORACIC: Dorsal Sympathectomy for Hyperhidrosis

Rodney J. Landreneau, MD Professor of Surgery and Director, Comprehensive Lung Center, University of Pittsburgh Medical Center Shadyside; Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania THORACIC: Role of Sublobar Resection (Segmentectomy and Wedge Resection) in the Surgical Management of Non–Small Cell Lung Cancer

Benjamin D. Kozower, MD Assistant Professor of Surgery, General Thoracic Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia THORACIC: Surgical Management of Non–Small Cell Lung Cancer; Anterior Approach to Superior Sulcus Tumors

Paul Krakovitz, MD Staff, Pediatric Otolaryngology, Cleveland Clinic, Cleveland, Ohio

Florian Lang, MD Associate Professor, University of Lausanne; Faculty of Medicine, Department of Otorhinolaryngology, Head and Neck Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ESOPHAGEAL: Esophageal Foreign Bodies in Adults THORACIC: Subglottic Resection: Infants and Children; Laryngeal Trauma

ESOPHAGEAL: Vascular Tracheoesophageal Compression: Vascular Rings, Pulmonary Artery Sling, and Innominate Artery Compression of the Trachea

FM-F06861.indd xix

1/21/2008 3:22:41 PM

xx

Contributors

Jacob C. Langer, MD

Philip A. Linden, MD

Professor of Surgery, University of Toronto and Chief, Division of Pediatric General Surgery, Hospital for Sick Children, Toronto, Ontario, Canada

Assistant Professor, Harvard Medical School; Staff Surgeon, Brigham and Women’s Hospital, Boston, Massachusetts

THORACIC: Mediastinal Cysts and Duplications in Infants and Children

Humberto Lara-Guerra, MD Research Fellow, Division of Thoracic Surgery, University of Toronto, Toronto, Ontario, Canada

ESOPHAGEAL: Esophagectomy Via Right Thoracotomy

Virginia R. Litle, MD Assistant Professor of Surgery, Department of Cardiothoracic Surgery, Mount Sinai Medical Center, New York, New York ESOPHAGEAL: Palliation of Esophageal Cancer

THORACIC: Principles of Postoperative Care

Sherard Little, MD Didier Lardinois, MD Chief, Division of Thoracic Surgery, University Hospital, Basel, Switzerland THORACIC: Diagnostic Strategies in the Mediastinal Mass

Simon Law, MS, MBBChir, FRCSEd Professor, Department of Surgery, University of Hong Kong Medical Centre; Honorary Consultant, Queen Mary Hospital, Hong Kong, China ESOPHAGEAL: Surgical Management of Squamous Cell Carcinoma

Stephen S. Lefrak, MD Professor of Medicine, Division of Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, Missouri THORACIC: Medical Management of Chronic Obstructive Pulmonary Disease

Natasha B. Leighl, MD Assistant Professor, Department of Medicine, University of Toronto; Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada

Fellow, Cleveland Clinic Foundation, Cleveland, Ohio ESOPHAGEAL: Open Reoperative Antireflux Surgery

Mirjam Locadia, PhD Department of Medical Psychology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ESOPHAGEAL: Quality of Life in Esophageal Cancer Patients

Luis C. Losso, MD, PhD Professor of Surgery, General Thoracic Surgery Department, ABC Foundation, School of Medicine; Head, General Thoracic Surgery and Respiratory Diseases Department, Edmundo Vasconcelos Hospital, Sao Paulo, Brazil THORACIC: Penetrating Thoracic Trauma

Brian E. Louie, MD, MPH, FRCSC Director, Education, Thoracic and Esophageal Surgery, Swedish Medical Center and Cancer Institute, Seattle, Washington ESOPHAGEAL: Colon Interposition THORACIC: Diagnostic Procedures for Pleural Diseases

THORACIC: Small Cell Lung Cancer

Donald E. Low, MD Francesco Leo, MD Surgeon, Department of Thoracic Surgery, European Institute of Oncology, Milan, Italy THORACIC: Plication of the Diaphragm

Antoon (Toni) E. M. R. Lerut, MD, PhD Professor of Surgery, Catholic University Leuven; Chairman, Department of Thoracic Surgery, University Hospital Gasthuisberg, Leuven, Belgium ESOPHAGEAL: Belsey Mark IV Repair; Surgical Therapy for the Columnar-Lined Esophagus: Barrett’s Carcinoma; Three-Field Lymph Node Dissection for Cancer of the Esophagus; Esophageal Diverticula THORACIC: History and Development of General Thoracic Surgery; Mediastinoscopy; Prenatal Intervention for Congenital Diaphragmatic Hernia

Dorothea Liebermann-Meffert, MD Professor of General and Visceral Surgery, University of Munich; Department of Surgery, Surgical Clinic and Polyclinic, Technical University, Munich, Germany ESOPHAGEAL: Clinically Oriented Anatomy, Embryology, and Histology

FM-F06861.indd xx

Virginia Mason Medical Center, Seattle, Washington ESOPHAGEAL: Hill Repair

James D. Luketich, MD Henry T. Bahnson Professor of Cardiothoracic Surgery, Department of Surgery; Director, Heart, Lung, and Esophageal Surgery Institute; Chief, Division of Thoracic and Foregut Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania ESOPHAGEAL: History and Development of Esophageal Surgery; Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux; Open Toupet and Dor Partial Fundoplications; Laparoscopic Gastroplasty; Laparoscopic Techniques in Reoperation for Failed Antireflux Repairs; Minimally Invasive Esophagectomy; Esophageal Diverticula; Caustic Injuries to the Esophagus THORACIC: Interventional Bronchoscopy for the Management of Airway Obstruction

Lars Lundell, MD, PhD Professor, Department of Surgery, Karolinska University Hospital, Stockholm, Sweden ESOPHAGEAL: Quality of Life After Antireflux Surgery

1/21/2008 3:22:41 PM

Contributors

Barbara A. Lutey, MD

Sandro Mattioli, MD

Fellow, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri

Associate Professor, Alma Mater Studiorum University of Bologna; Chairman, Division of Esophageal and Pulmonary Surgery, Department of Surgery, Intensive Care, and Organ Transplantation, University of Bologna, Bologna, Italy

THORACIC: Medical Management of Chronic Obstructive Pulmonary Disease

Paolo Macchiarini, MD, PhD Professor of General Thoracic Surgery, Department of Surgery, University of Barcelona Faculty of Medicine; Senior Consultant and Chief of Service, General Thoracic Surgery Service, Institut Clinic del Tòrax, Hospital Clinic, Barcelona, Spain THORACIC: Superior Vena Cava Obstruction

xxi

ESOPHAGEAL: Pathophysiology of Gastroesophageal Reflux Disease and Hiatal Hernia; Open Toupet and Dor Partial Fundoplications

Constantine Mavroudis, MD Professor of Surgery, Northwestern University Feinberg School of Medicine; Willis J. Potts Professor of Surgery, Division of Cardiovascular-Thoracic Surgery; Surgeon-inChief, Children’s Memorial Hospital, Chicago, Illinois THORACIC: Congenital Anomalies: Vascular Rings

Susan E. Mackinnon, MD, FRCSC Sydney M. Jr. and Robert H. Shoenberg Professor of Surgery and Chief, Division of Plastic Surgery, Washington University School of Medicine, St. Louis, Missouri THORACIC: Thoracic Outlet Syndromes; Supraclavicular Approach for Thoracic Outlet Syndrome; Surgery of the Phrenic Nerve

Donna E. Maziak, MDCM, MSc, FRCSC Associate Professor, University of Ottawa; Program Director and Director of Research, Division of Thoracic Surgery, Ottawa Hospital–General Campus, Ottawa, Ontario, Canada ESOPHAGEAL: Massive (Paraesophageal) Hiatal Hernia

Michael A. Maddaus, MD, MSc

Paul Mazur, MD

Professor and Vice Chair of Education; Chief, Division of Thoracic and Foregut Surgery; Program Director, General Surgery; Garamella Lynch Jensen Chair in Thoracic Cardiovascular Surgery; Co-Director, University of Minnesota Medical School; Thoracic Surgeon, Fairview University Medical Center, Minneapolis, Minnesota

Chief Resident, Department of Cardiothoracic Surgery, University of Southern California, Los Angeles, California

ESOPHAGEAL: Peptic Esophagitis, Peptic Stricture, and Short Esophagus; Laparoscopic Gastroplasty THORACIC: Postintubation Injury; Tracheomalacia; Subglottic Resection: Adults

THORACIC: Tracheoesophageal Fistula

Theresa McLoud, MD Professor of Radiology, Harvard Medical School; Associate Radiologist in Chief, Massachusetts General Hospital, Boston, Massachusetts THORACIC: Imaging the Lungs

Karen M. McRae, MD Richard A. Malthaner, MD, MSc Associate Professor, Department of Surgery, Biostatistics, and Epidemiology, Division of Thoracic Surgery, Schulich School of Medicine, University of Western Ontario; Thoracic Surgeon and Director of Thoracic Surgery Research, Department of Surgery, London Health Sciences Centre, London, Ontario, Canada THORACIC: The Thoracic Duct and Chylothorax

David P. Mason, MD Staff Surgeon, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland, Ohio ESOPHAGEAL: Open Reoperative Antireflux Surgery THORACIC: Lobectomy

Douglas J. Mathisen, MD Hermes Grillo Professor of Thoracic Surgery, Harvard Medical School; Chief, General Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts THORACIC: Primary Tumors of the Trachea; Tracheal Resection

Department of Anesthesia and Pain Management, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada THORACIC: Anesthesia for General Thoracic Surgery

Reza John Mehran, MD Associate Professor of Surgery, Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas THORACIC: Tuberculosis and Atypical Mycobacterial Diseases; Anatomy and Physiology of the Pleural Space

Tarek Mekhail, MD, MSc, FRCSI, FRCSEd Director, Lung Cancer Medical Oncology Program, Cleveland Clinic Foundation, Cleveland, Ohio THORACIC: Definitive Management of Inoperable Non–Small Cell Lung Cancer

Robert E. Merritt, MD Clinical Fellow in Surgery, Harvard Medical School; Chief Resident, Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts THORACIC: Tracheal Resection

FM-F06861.indd xxi

1/21/2008 3:22:41 PM

xxii

Contributors

Bryan F. Meyers, MD

Rachel Montano

Professor of Surgery and Chief, Section of General Thoracic Surgery, Washington University School of Medicine; Barnes-Jewish Hospital, St. Louis, Missouri

Research Director, Department of Cardiovascular and Thoracic Surgical Research, Baylor University Medical Center, Dallas, Texas

ESOPHAGEAL: Complications of Surgery for Gastroesophageal Reflux THORACIC: Mediastinoscopy; Lung Volume Reduction Surgery; Surgery for Bullous Disease

Shari L. Meyerson, MD Assistant Professor of Surgery and Program Director, Thoracic Surgery, University of Arizona, University Medical Center, Tucson, Arizona THORACIC: Bronchial Gland Tumors

Daniel L. Miller, MD Chief, General Thoracic Surgery, Emory University Healthcare; Kamal A. Mansour Professor of Surgery, Emory University School of Medicine, Atlanta, Georgia

THORACIC: Chronic Mediastinitis

Andre L. Moreira, MD, PhD Assistant Attending, Department of Pathology, Thoracic and Cytology Services, Memorial Sloan-Kettering Cancer Center, New York, New York THORACIC: Rare Primary Malignant Neoplasms of the Lung

Christopher R. Morse, MD Instructor in Surgery, Harvard Medical School; Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts ESOPHAGEAL: Laparoscopic Techniques in Reoperation for Failed Antireflux Repairs

THORACIC: Empyema and Bronchopleural Fistula

Jérôme Mouroux, MD Joseph I. Miller, Jr., MD Professor of Surgery, Emory Clinic; Chief, General Thoracic Surgery, Emory Healthcare, Atlanta, Georgia THORACIC: Anatomy and Physiology of the Chest Wall and Sternum With Surgical Implications

Tommaso C. Mineo, MD Cattedra di Chirurgia Toracica, Policlinico Tor Vergata, Rome, Italy THORACIC: Surgical Approaches to the Diaphragm

Bruce D. Minsky, MD Associate Dean and Chief Quality Officer, Professor of Radiation and Cellular Oncology, University of Chicago Medical Center, Chicago, Illinois ESOPHAGEAL: Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

Professor, Department of Thoracic Surgery, University of Nice, Faculty of Medicine; Chief, Department of Thoracic Surgery, Pasteur Hospital of Nice, Nice, France THORACIC: Plication of the Diaphragm

Nestor L. Müller, MD, PhD, FRCPC Professor and Chairman, Department of Radiology, University of British Columbia; Head and Medical Director, Department of Radiology, Vancouver General Hospital, Vancouver, British Columbia, Canada THORACIC: Imaging of the Mediastinum

Michael Mulligan, MD Surgeon, University of Washington Medical Center, Seattle, Washington THORACIC: Surgical Management of Chronic Pulmonary Thromboembolic Pulmonary Hypertension

Jeffrey Moley, MD

Sudish C. Murthy, MD, PhD

Professor of Surgery; Chief, Endocrine and Oncologic Surgery; Associate Director, Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri

Staff Surgeon and Surgical Director, Center for Major Airway Disease, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio

THORACIC: Mediastinal Thyroid Tumors; Mediastinal Parathyroid Tumors

ESOPHAGEAL: Left Thoracoabdominal Esophagectomy; Secondary Esophageal Motor Disorders THORACIC: Thoracic Incisions

Philippe Monnier, MD Professor, University of Lausanne Faculty of Medicine; Head, Department of Otorhinolaryngology, Head and Neck Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ESOPHAGEAL: Esophageal Foreign Bodies in Adults THORACIC: Subglottic Resection: Infants and Children; Laryngeal Trauma

Keith Naunheim, MD Vallee and Melba Willman Professor of Surgery and Chief of Thoracic Surgery, St. Louis University School of Medicine, St. Louis, Missouri THORACIC: Thoracoscopic Mediastinal Surgery

Bill Nelems, MD Emeritus Professor, Department of Surgery, University of British Columbia, Vancouver; Thoracic Surgeon, British Columbia Provincial Thoracic Surgery Programme, Kelowna, British Columbia, Canada THORACIC: Thoracic Surgery: A Palliative Care Specialty

FM-F06861.indd xxii

1/21/2008 3:22:41 PM

Contributors

Calvin S. H. Ng, MBBS, MRCSE

Mark B. Orringer, MD

Senior Resident, Department of Surgery, Chinese University of Hong Kong, Hong Kong, China

Professor and Head, Section of General Thoracic Surgery, University of Michigan Medical School, Ann Arbor, Michigan

THORACIC: Thoracoscopic Thymectomy for Myasthenia Gravis

xxiii

ESOPHAGEAL: Esophagectomy for Benign Disease; Transhiatal Esophagectomy

Ninh T. Nguyen, MD Associate Professor, Department of Surgery, University of California–Irvine, Medical Center, Orange, California ESOPHAGEAL: Minimally Invasive Esophagectomy

Francis C. Nichols, III, MD Assistant Professor of Surgery and Consultant, Division of General Thoracic Surgery, Mayo Clinic, Rochester, Minnesota THORACIC: Mediastinal Cysts and Duplications in Adults

Denise Ouellette, MD Associate Professor of Surgery, Department of Surgery, University of Montreal; Division of Thoracic Surgery, Hospital Maisonneuve–Rosemont, Montreal, Quebec, Canada THORACIC: Spontaneous Pneumomediastinum

Pneumothorax

and

Peter C. Pairolero, MD Professor of Surgery, Mayo Clinic, Rochester, Minnesota THORACIC: Neoplasms of the Chest Wall

Christine B. Novak, PT, MS Research Associate, Wharton Head and Neck Centre, University Health Network, Toronto, Ontario, Canada THORACIC: Laryngoscopy; Thoracic Outlet Syndromes

Michael J. Odell, MD Assistant Professor and Director of Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, St. Louis University School of Medicine, St. Louis, Missouri THORACIC: Laryngoscopy

Jean-Baptiste Ollyo, MD Department of Gastroenterology, Centre Hospitalier Universitaire, Lausanne, Switzerland ESOPHAGEAL: Esophageal Foreign Bodies in Adults

Mark W. Onaitis, MD Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Duke University Medical Center, Durham, North Carolina THORACIC: Diagnosis and Staging of Lung Cancer

Raymond P. Onders, MD Associate Professor of Surgery, Case Western Reserve University School of Medicine; Director of Minimally Invasive Surgery, University Hospitals Case Medical Center, Cleveland, Ohio THORACIC: Phrenic Nerve and Diaphragm Motor Point Pacing

Sharon Ong, MD, FRCS Resident, Department of Thoracic Surgery, University of British Columbia, Vancouver, British Columbia, Canada ESOPHAGEAL: Rings and Webs

Blake C. Papsin, MD Director, Cochlear Implant Program, Department of Otolaryngology, Hospital for Sick Children; Associate Scientist, Neurosciences and Mental Health, Research Institute; Associate Professor, Otolaryngology, University of Toronto, Toronto, Ontario, Canada ESOPHAGEAL: Esophageal Foreign Bodies in Infants and Children

Bernard J. Park, MD Assistant Professor of Surgery, Department of Surgery, Cornell University Medical College; Assistant Attending Surgeon, Thoracic Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York THORACIC: Robotic-Assisted Surgery Lobectomy

Video-Assisted

Thoracic

Alden M. Parsons, MD Cardiothoracic Resident, Department of Surgery, University of North Carolina Hospitals, Chapel Hill, North Carolina THORACIC: Thymic Tumors: A Review of Current Diagnosis, Classification, and Treatment

David A. Partrick, MD Associate Professor of Surgery, University of Colorado Health Sciences Center; Director of Surgical Endoscopy for Infants and Children, Children’s Hospital, Denver, Colorado ESOPHAGEAL: Gastroesophageal Reflux in Infants and Children

Philippe Pasche, MD Associate Professor, University of Lausanne Faculty of Medicine; Department of Otorhinolaryngology, Head and Neck Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ESOPHAGEAL: Esophageal Foreign Bodies in Adults THORACIC: Laryngeal Trauma

FM-F06861.indd xxiii

1/21/2008 3:22:41 PM

xxiv

Contributors

Ugo Pastorino, MD

Alberto Peracchia, MD

Director, Thoracic Surgery, Istituto Nazionale Tumori, Milan, Italy

Emeritus Professor of Surgery, University of Milan, Milan; Senior Consultant, General and Minimally Invasive Surgery, Istituto Clinico Humanitas, Rozzano, Italy

THORACIC: Surgical Resection of Pulmonary Metastases

Amit N. Patel, MD Assistant Professor of Surgery, Department of Thoracic Surgery, University of Pittsburgh Medical School; Director of Clinical Cardiac Cellular Therapy, McGowan Institute of Regenerative Medicine, Pittsburgh, Pennsylvania THORACIC: Transaxillary First Rib Resection for Thoracic Outlet Syndrome (With Dorsal Sympathectomy); Reoperation for Recurrent Thoracic Outlet Syndrome Through the Posterior Thoracoplasty Approach With Dorsal Sympathectomy; Chronic Mediastinitis

G. Alexander Patterson, MD, FRCSC Evarts A. Graham Professor of Surgery and Chief, Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri ESOPHAGEAL: Complications of Esophageal Resection THORACIC: Principals of Airway Surgery: Management of Acute Airway Obstruction; Lung Transplantation; Surgical Management of Non–Small Cell Lung Cancer; Anterior Approach to Superior Sulcus Tumors; Extended Pulmonary Resections; Thoracic Outlet Syndromes; Supraclavicular Approach for Thoracic Outlet Syndrome

F. Griffith Pearson, MD Professor, Division of Thoracic Surgery, Department of Surgery, University of Toronto Faculty of Medicine; Senior Surgeon, Division of Thoracic Surgery, The Toronto General Hospital, Toronto, Ontario, Canada ESOPHAGEAL: Massive (Paraesophageal) Hiatal Hernia; Open Gastroplasty THORACIC: History and Development of General Thoracic Surgery; Postintubation Injury; Tracheomalacia; Subglottic Resection: Adults

Andrew B. Peitzman, MD Professor of Surgery, Department of Surgery, University of Pittsburgh; Pittsburgh, Pennsylvania

ESOPHAGEAL: Total Reconstruction

Gastrectomy

and

Roux-en-Y

Sérgio Tadeu L. F. Pereira, MD Assistant Professor, Department of Surgery, Escola Bahiana de Medicina e Saúde Pública; Head, Department of General Thoracic Surgery, Hospital Santa Izabel da Santa Casa de Misericórdia da Bahia, Salvadore, Bahia, Brazil THORACIC: Tuberculous Pleural Disease

Jeffrey H. Peters, MD Professor and Chairman, Department of Surgery, University of Rochester, Rochester, New York ESOPHAGEAL: Clinical Features of Esophageal Disease

Brian Pettiford, MD Clinical Assistant Professor of Surgery, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania THORACIC: Role of Sublobar Resection (Segmentectomy and Wedge Resection) in the Surgical Management of Non–Small Cell Lung Cancer

Kacy Phillips, MD Formerly of MD Anderson Cancer Center, Houston, Texas THORACIC: Posterior Approach to Superior Sulcus Tumors

Andrew F. Pierre, MD, MSc Assistant Professor, Division of Thoracic Surgery, University of Toronto; Staff Surgeon, Toronto General Hospital, Toronto, Ontario, Canada ESOPHAGEAL: Benign Esophageal Tumors THORACIC: Bronchoscopy

Eugenio Pompeo, MD Thoracic Surgery Division, Tor Vergata University School of Medicine, Rome, Italy THORACIC: Surgical Approaches to the Diaphragm

THORACIC: Late Sequelae of Thoracic Injury

Arjun Pennathur, MD Assistant Professor of Surgery, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania ESOPHAGEAL: Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux; Laparoscopic Techniques in Reoperation for Failed Antireflux Repairs

Manuel Pera, MD, PhD Associate Professor of Surgery, Univeritat Autònoma de Barcelona; Head, Section of Gastrointestinal Surgery, Hospital Universitario del Mar, Barcelona, Spain ESOPHAGEAL: Columnar-Lined Esophagus: Epidemiology and Pathophysiology

Daniel Pop, MD Surgeon, Department of Thoracic Surgery, Pasteur Hospital of Nice, Nice, France THORACIC: Plication of the Diaphragm

Vitaliy Poylin, MD Senior Resident, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts THORACIC: Role of Lung Biopsy in Interstitial Lung Disease

Evan J. Propst, MD Department of Otolaryngology, Head and Neck Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada ESOPHAGEAL: Esophageal Foreign Bodies in Infants and Children

tahir99-VRG vip.persianss.ir

FM-F06861.indd xxiv

1/21/2008 3:22:41 PM

Contributors

Joe B. Putnam, Jr., MD

Joel E. Richter, MD

Ingram Professor of Surgery and Chairman, Department of Thoracic Surgery; Professor, Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee

Professor of Medicine, The Richard L. Evans Chair, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania

THORACIC: Postresection Follow-Up for Non–Small Cell Lung Cancer

xxv

ESOPHAGEAL: Medical Treatment of Gastroesophageal Reflux Disease

Jon H. Ritter, MD Mohammed A. Qadeer, MD Fellow, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio

Associate Professor of Pathology, Washington University Medical Center, St. Louis, Missouri THORACIC: Pathologic Features of Carcinoma of the Lung

ESOPHAGEAL: Esophageal Motility Disorders

Nabil P. Rizk, MD Ganesh Raghu, MD Professor of Medicine and Adjunct Professor, Laboratory Medicine, Division of Pulmonary and Critical Care Medicine; Chief, Chest Clinic, University of Washington Medical Center; Director, Interstitial Lung Disease, Sarcoid and Pulmonary Fibrosis Program; Medical Director, Lung Transplant Program, University of Washington Medical Center, Seattle, Washington THORACIC: Interstitial Lung Disease

Maissa Rayyan, MD Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Linda M. Razzuk Research Coordinator, Department of Cardiovascular and Thoracic Surgical Research, Baylor University, Dallas, Texas THORACIC: Chronic Mediastinitis

Maruf A. Razzuk, MD† Former Professor of Cardiothoracic Surgery, University of Texas Southwestern Medical School, Dallas, Texas THORACIC: Chronic Mediastinitis

Erino A. Rendina, MD Professor and Chief of Thoracic Surgery, University La Sapienza; Chief, Division of Thoracic Surgery, Ospedale Sant’Andrea, Rome, Italy THORACIC: Emerging Surgical Technologies for Emphysema; Reconstruction of the Pulmonary Artery; Diaphragm: Anatomy, Embryology, Pathophysiology

Thomas W. Rice, MD Daniel and Karen Lee Chair in Thoracic Surgery; Head, Section of General Thoracic Surgery; Professor of Surgery, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio ESOPHAGEAL: Endoscopic Ultrasonography; Dilation of Peptic Esophageal Strictures; Surgical Therapy for the Columnar-Lined Esophagus: Non-Neoplastic Barrett’s Esophagus; Diagnosis and Staging of Esophageal Cancer THORACIC: Anatomy of the Lung †

Deceased.

Assistant Attending Surgeon, Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center; Assistant Professor of Surgery, Cornell University Medical College, New York, New York ESOPHAGEAL: Unusual Malignancies

Francis Robicsek, MD, PhD Clinical Professor of Surgery, University of North Carolina; Chairman, Department of Thoracic and Cardiovascular Surgery, Carolinas Medical Center, Charlotte, North Carolina THORACIC: Complications of Midline Sternotomy; Complications of Pectus Deformity Repair

Gaetano Rocco, MD Chief, Division of Thoracic Surgery, National Cancer Institute, Naples, Italy THORACIC: Fibrothorax and Decortication

Riccardo Rosati, MD Professor of Surgery, University of Milan, Milan; Director, General and Minimally Invasive Surgery, Istituto Clinico Humanitas, Rozzano, Italy ESOPHAGEAL: Total Reconstruction

Gastrectomy

and

Roux-en-Y

Clark A. Rosen, MD Associate Professor of Otolaryngology, Department of Otolaryngology, University of Pittsburgh School of Medicine; Associate Professor, Department of Communication Science and Disorders, University of Pittsburgh School of Health and Rehabilitation Sciences; Director, University of Pittsburgh Voice Center, University of Pittsburgh Physicians, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania THORACIC: Management of Vocal Fold Paralysis

Valerie W. Rusch, MD Professor of Surgery, Department of Surgery, Cornell University Medical College; Attending Surgeon and Chief, Thoracic Service, Department of Surgery and William G. Cahan Chair of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York THORACIC: Robotic-Assisted Video-Assisted Thoracic Surgery Lobectomy; Pleural Effusion: Benign and Malignant; Technique of Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

tahir99-VRG vip.persianss.ir

FM-F06861.indd xxv

1/21/2008 3:22:41 PM

xxvi

Contributors

Steve H. Salzman, MD

Joseph B. Shrager, MD

Professor of Clinical Medicine and Division Chief and Director, Pulmonary Function Laboratory, Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Medical Center, New York, New York

Associate Professor of Surgery, Division of Thoracic Surgery, University of Pennsylvania School of Medicine; Chief, Thoracic Surgery, Hospital of the University of Pennsylvania and Pennsylvania Hospital; Staff Surgeon, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania

THORACIC: Pulmonary Physiologic Testing

Richard E. Sampliner, MD Gastrointestinal Section, University of Arizona Health Sciences Center, Tucson, Arizona ESOPHAGEAL: Medical Therapy for Barrett’s Esophagus

Marcel Savary, MD Honorary Professor, Department of Otolaryngology, Head and Neck Surgery, University of Lausanne Medical School; Centre Hospitaliér Universitaír Vaudois, Lausanne, Switzerland ESOPHAGEAL: Esophageal Foreign Bodies in Adults THORACIC: Subglottic Resection: Infants and Children

Lourenço Sbragia, MD Centre for Surgical Technologies, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Paul H. Schipper, MD Assistant Professor, Oregon Health and Science University, Portland, Oregon THORACIC: Surgery for Bullous Disease

David S. Schrump, MD Senior Investigator and Head, Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland ESOPHAGEAL: Biology and Epidemiology of Malignant Esophageal Carcinoma

THORACIC: Investigation and Management of the Indeterminate Pulmonary Nodule; Benign Lung Tumors

Barry A. Siegel, MD Professor of Radiology, Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri ESOPHAGEAL: Nuclear Imaging

Alan D. L. Sihoe, FRCSEd(CTh) Associate Consultant, Division of Cardiothoracic Surgery, Department of Surgery, University of Hong Kong, Hong Kong, China THORACIC: Video-Assisted Pulmonary Resections

Sunil Singhal, MD Assistant Professor of Surgery, Department of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia THORACIC: Surgery for Myasthenia Gravis

Peter D. Slinger, MD Department of Anesthesia, Toronto General Hospital, Toronto, Ontario, Canada THORACIC: Anesthesia for General Thoracic Surgery

Philip W. Smith, MD Surgery Resident, Department of Surgery, University of Virginia, Charlottesville, Virginia THORACIC: Biology and Epidemiology of Lung Cancer

Frank C. Sciurba, MD

Nathaniel J. Soper, MD

Associate Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine; Director of Pulmonary Function and Exercise Physiology Laboratory; Director of Emphysema/Chronic Obstructive Pulmonary Disease Research Center, University of Pittsburgh School of Medicine and School of Education, Pittsburgh, Pennsylvania

Professor of Surgery and Chief of Gastrointestinal and Endocrine Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois

THORACIC: Pulmonary Physiologic Testing

Frances A. Shepherd, MD Professor of Medicine, University of Toronto; Scott Taylor Chair of Lung Cancer Research and Treatment, Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada THORACIC: Small Cell Lung Cancer

ESOPHAGEAL: Complications of Surgery for Gastroesophageal Reflux

Carolina A. Souza, MD, PhD Fellow in Thoracic Imaging, Department of Radiology, University of British Columbia; Clinical Fellow, Department of Radiology, Vancouver, British Columbia, Canada THORACIC: Imaging of the Mediastinum

Mirjam A. G. Sprangers, PhD Professor of Medical Psychology, Department of Medical Psychology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ESOPHAGEAL: Quality of Life in Esophageal Cancer Patients

tahir99-VRG vip.persianss.ir

FM-F06861.indd xxvi

1/21/2008 3:22:41 PM

Contributors

Robert D. Stewart, MD

Harold C. Urschel, Jr., MD

Assistant Professor of Surgery, Northwestern University Feinberg School of Medicine; Attending Surgeon, Division of Cardiovascular-Thoracic Surgery, Children’s Memorial Hospital, Chicago, Illinois

Chair of Cardiovascular and Thoracic Surgical Research, Education, and Clinical Excellence, Baylor University Medical Center; Professor of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical School, Dallas, Texas

THORACIC: Congenital Anomalies: Vascular Rings

Sigrid G. Stroobants, MD, PhD Department of Nuclear Medicine, University Hospitals of Leuven, Leuven, Belgium THORACIC: Nuclear Imaging of the Lung

David J. Sugarbaker, MD Richard E. Wilson Professor of Surgical Oncology, Department of Surgery, Harvard Medical School; Chief, Division of Thoracic Surgery, Brigham and Women’s Hospital; Phillip E. Lowe Senior Surgeon, Dana Farber Cancer Institute, Boston, Massachusetts ESOPHAGEAL: Esophagectomy Via Right Thoracotomy THORACIC: Pleural Tumors

Erin A. Sullivan, MD Associate Professor of Anesthesiology and Director of Cardiothoracic Anesthesiology, University of Pittsburgh Physicians, Department of Anesthesiology, Pittsburgh, Pennsylvania THORACIC: Perioperative Pain Management

Sudhir R. Sundaresan, MD, FRCSC Professor of Surgery and Chair, Division of Thoracic Surgery, University of Ottawa; Chief, Division of Thoracic Surgery, Ottawa Hospital, Ottawa, Ontario, Canada THORACIC: Unusual Mediastinal Tumors

Lee L. Swanström, MD Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic; Good Samaritan Medical Center, Portland, Oregon ESOPHAGEAL: Laparoscopic Toupet Fundoplication

R. Thomas Temes, MD, MBA Staff Physician, Thoracic and Cardiothoracic Surgery, Cleveland Clinic, Cleveland, Ohio THORACIC: Late Postoperative Complications

François Tronc, MD Clinical Fellow, Department of Surgery, Laval University; Clinical Fellow, Thoracic Surgery Division, Center of Pneumology, Laval Hospital, Quebec City, Quebec, Canada THORACIC: Bronchoplasty

Paula A. Ugalde, MD Assistant Professor and Instructor in Surgery, Department of Surgery, Division of Thoracic Surgery, Santa Casa da Misericordia Hospital, Salvador, Bahia, Brazil; Clinical Fellow, Thoracic Surgery Department, Laval Hospital, Quebec City, Quebec, Canada THORACIC: Tuberculous Pleural Disease; Management of Malignant Pleural Effusions

xxvii

THORACIC: Thoracic Outlet Syndromes; Approach for Thoracic Outlet Syndrome; Transaxillary First Rib Resection for Thoracic Outlet Syndrome (With Dorsal Sympathectomy); Reoperation for Recurrent Thoracic Outlet Syndrome Through the Posterior Thoracoplasty Approach With Dorsal Sympathectomy; Chronic Mediastinitis

Michael F. Vaezi, MD, PhD, MSc Professor of Medicine and Clinical Director, Division of Gastroenterology, Vanderbilt University, Nashville, Tennessee ESOPHAGEAL: Esophageal Motility Disorders

Eric Vallières, MD, FRCSC Surgical Director, Lung Cancer Program, Swedish Cancer Institute, Seattle, Washington THORACIC: Diagnostic Procedures for Pleural Diseases

Mark I. van Berge Henegouwen, MD, PhD Surgeon, Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ESOPHAGEAL: Quality of Life in Esophageal Cancer Patients

Marc Van de Velde, MD Department of Anesthesiology, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Jan J. B. van Lanschot, MD, PhD Professor of Surgery and Chairman, Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands ESOPHAGEAL: Quality of Life in Esophageal Cancer Patients

Tim Van Mieghem, MD Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

Timothy L. Van Natta, MD Associate Professor of Surgery, Divisions of Trauma and Critical Care and Cardiothoracic Surgery, Department of Surgery, Harbor–University of California–Los Angeles Medical Center, Los Angeles, California THORACIC: Acute Necrotizing Mediastinitis

Dominique Van Schoubroeck, MD Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium THORACIC: Prenatal Intervention for Congenital Diaphragmatic Hernia

tahir99-VRG vip.persianss.ir

FM-F06861.indd xxvii

1/21/2008 3:22:42 PM

xxviii

Contributors

Andrés Varela, MD

Paul F. Waters, MD

Professor of Thoracic Surgery, University Autonoma of Madrid; Chief of General Thoracic Surgery and Lung Transplantation, Puerta de Hierro University Hospital, Madrid, Spain

Director of Surgical Oncology, Greenwich Hospital, Yale New Haven Health, Greenwich, Connecticut

THORACIC: Parasitic Diseases of the Lung and Pleura

Nirmal K. Veeramachaneni, MD Cardiothoracic Surgery Resident, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri THORACIC: Lung Volume Reduction Surgery; Open Drainage of Thoracic Infections; Diagnostic Strategies for a Chest Wall Mass

Nicolas Venissac, MD Surgeon, Department of Thoracic Surgery, Pasteur Hospital of Nice, Nice, France THORACIC: Plication of the Diaphragm

Federico Venuta, MD Associate Professor of Thoracic Surgery, University La Spaienze; Division of Thoracic Surgery, Policlinico Umberto I, Rome, Italy THORACIC: Emerging Surgical Technologies for Emphysema; Reconstruction of the Pulmonary Artery; Diaphragm: Anatomy, Embryology, Pathophysiology

Gregory M. M. Videtic, MD, CM, FRCPC Staff Physician, Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, Ohio THORACIC: Definitive Management of Inoperable Non–Small Cell Lung Cancer

Jorge Nin Vivó, MD Associate Professor of Anatomy, Faculty of Medicine of Montevideo, Montevideo, Uruguay

THORACIC: Pneumonectomy

Thomas J. Watson, MD Associate Professor, Thoracic Surgery, University of Rochester, Rochester, New York ESOPHAGEAL: Clinical Features of Esophageal Disease

Larry T. Watts, MD Adjunct Professor of Surgery, University of North Carolina Chapel Hill, Chapel Hill; Director, Pediatric Cardiac Surgery, Levine Children’s Hospital, Carolinas Medical Center, Charlotte, North Carolina THORACIC: Complications of Pectus Deformity Repair

Walter Weder, MD Professor of Surgery, Department of Surgery, Division of Thoracic Surgery, University of Zurich, Zurich, Switzerland THORACIC: Diagnostic Strategies in the Mediastinal Mass

Mark R. Wick, MD Department of Pathology, Division of Surgical Pathology and Cytopathology, University of Virginia Medical Center; Associate Director of Surgical Pathology, University of Virginia Health System, Charlottesville, Virginia THORACIC: Pathologic Features of Carcinoma of the Lung

Dennis A. Wigle, MD, PhD Consultant, Division of General Thoracic Surgery and Assistant Professor of Surgery, Mayo Clinic, Rochester, Minnesota THORACIC: Upper Airway Tumors: Secondary Tumors; Investigation and Management of Massive Hemoptysis

THORACIC: Rare Infections of the Pleural Space

Thomas K. Waddell, MD, MSc, PhD, FRCSC R. Fraser Elliott Chair in Transplantation Research and Associate Professor of Surgery, Division of Thoracic Surgery, University of Toronto; Staff Surgeon, Division of Thoracic Surgery, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada THORACIC: Principles of Postoperative Care; Investigation and Management of Massive Hemoptysis

Garrett L. Walsh, MD Head, Perioperative Enterprise; Professor of Surgery, Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas THORACIC: Posterior Approach to Superior Sulcus Tumors

William H. Warren, MD Director, Division of General Thoracic Surgery, Department of Cardiovascular-Thoracic Surgery, Rush University Medical Center, Chicago, Illinois

Troy S. Wildes, MD Instructor, Department of Anesthesiology, Division of Cardiothoracic Anesthesiology, Washington University School of Medicine, St. Louis, Missouri THORACIC: Anesthesia for Airway Surgery

Earl Wayne Wilkins, Jr., MD Clinical Professor of Surgery Emeritus, Harvard Medical School; Senior Surgeon, Massachusetts General Hospital, Boston, Massachusetts ESOPHAGEAL: History and Development of Esophageal Surgery

H. Rodney Withers, MD, DSc American Cancer Society Clinical Research Professor and Chair, Department of Radiation Oncology, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California ESOPHAGEAL: Principles of Radiotherapy

THORACIC: Anatomy of the Mediastinum With Special Reference to Surgical Access

tahir99-VRG vip.persianss.ir

FM-F06861.indd xxviii

1/21/2008 3:22:42 PM

Contributors

Ian Witterick, MD, MSc, FRCSC

Manoel Ximenes-Netto, MD

Department of Otolaryngology–Head and Neck Surgery, University of Toronto; Mt. Sinai Hospital, Toronto, Ontario, Canada

Professor and Head, Thoracic Surgery Unit, Hospital de Base do Distrito Federal; Head, Thoracic Surgery, Hospital Santa Lucia, Brasilia, Brazil

THORACIC: Laryngoscopy

xxix

ESOPHAGEAL: Gastric Tubes: Reversed and Nonreversed; Chagas’ Disease

Joseph J. Wizorek, MD Clinical Instructor, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania THORACIC: Interventional Bronchoscopy for the Management of Airway Obstruction

Steve Yang, MBBS, MRCP, FCCP Consultant, Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore THORACIC: Interstitial Lung Disease

David F. Yankelevitz, MD John Wong, MD, PhD Professor and Head, Department of Surgery, University of Hong Kong Medical Centre; Chief of Service, Queen Mary Hospital, Hong Kong, China ESOPHAGEAL: Surgical Management of Squamous Cell Carcinoma

Douglas E. Wood, MD Professor and Chief, General Thoracic Surgery and Endowed Chair in Lung Cancer Research, University of Washington, Seattle, Washington THORACIC: Inflammatory Conditions of the Airway; Tracheobronchial Trauma

Cameron D. Wright, MD Associate Professor of Surgery, Harvard Medical School; Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts THORACIC: Anatomy, Physiology, and Embryology of the Upper Airway; Complications of Airway Surgery

Professor of Radiology and Cardiothoracic Surgery, Department of Radiology, Weill-Cornell Medical College, New York, New York THORACIC: Early Detection and Screening of Lung Cancer

Salam Yazbeck, MD Professor of Surgery, University of Montreal; Staff Surgeon, Pediatric Surgery, Ste-Justine Hospital, Montreal, Quebec, Canada THORACIC: Congenital Diaphragmatic Malformations

Anthony P. C. Yim, DM, FRCS, FRCSE Professor of Surgery, Department of Surgery, Chinese University of Hong Kong, Hong Kong, China THORACIC: Video-Assisted Pulmonary Resections; Thoracoscopic Thymectomy for Myasthenia Gravis

Maureen Zakowski, MD Associate Professor of Pathology and Laboratory Medicine, Weill-Cornell Medical College, New York, New York THORACIC: Rare Primary Malignant Neoplasms of the Lung

William Wrightson, MD Clinical Faculty, Department of Thoracic and Cardiovascular Surgery, University of Louisville; Chief, Thoracic Surgery, Veterans Administration Medical Center, Louisville, Kentucky THORACIC: Neurogenic Tumors of the Mediastinum

Gregory Zuccaro, Jr., MD Vice Chairman of Quality and Innovations, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio ESOPHAGEAL: Endoscopic Ultrasonography

tahir99-VRG vip.persianss.ir

FM-F06861.indd xxix

1/21/2008 3:22:42 PM

chapter

1

HISTORY AND DEVELOPMENT OF GENERAL THORACIC SURGERY F. Griffith Pearson Stanley C. Fell Toni E. M. R. Lerut

There is no exact date or specific event that marks the birth of chest surgery. It did not arise de novo in a particular country, or in one school of surgery. It appears that after the public demonstration of ether anesthesia by Warren in 1846, and the early understanding of sepsis following Semmelweiss’ work in 1847, physicians in a number of countries began to explore the possible application of surgical techniques to the relief of diseases of the thorax. Wilkins and Urschel1(p1)

HISTORICAL HIGHLIGHTS Anesthesia and Control of Ventilation Intrathoracic surgery only became possible after the introduction of controlled ventilation in the presence of an open thoracic cavity. Following his early and reported experience with the use of a negative-pressure chamber for control of the open thorax, Meyer, of New York, stated, “It is the danger of an acute pneumothorax that has been the stumbling block in the development of intrathoracic surgery, and nothing else!”2 He offered these comments at the first and founding meeting of the American Association for Thoracic Surgery (AATS). The “negative-pressure chamber” was, in fact, the invention of Johann von Mikulicz and his pupil Ferdinand Sauerbruch in Poland.3 The “chamber,” however, was large, cumbersome, and awkward. It was ultimately replaced by the much simpler and more practical application of a cuffed endotracheal tube for provision of anesthesia and ventilation. Successful animal experiments with a cuffed orotracheal tube were reported by Tuffier, of France, in 1896.4 In 1909, Meltzer and Auer, of New York City, reported the first clinical application of a cuffed endotracheal tube for the provision of anesthesia and ventilation.5

The Impetus for Development of Thoracic Surgery Following the development of general anesthesia and control of ventilation in the presence of an open thorax, a number of diseases and circumstances created powerful stimuli for the development of intrathoracic surgical interventions. First were the pleural and pulmonary complications of tuberculosis in the late 19th century and first half of the 20th century. This destructive and highly transmissible infection was epidemic and worldwide in distribution, and there were

no effective available therapeutic drugs. Various methods of “lung collapse” therapy were developed, including techniques of thoracoplasty. Tuberculous empyemas were aspirated, drained, and decorticated. Early attempts at removal of parts of a destroyed lung led to the earliest and ultimately successful attempts at wedge resection, lobectomy, segmentectomy, and pneumonectomy. This stage in the history of thoracic surgery is very well covered in Meade’s textbook (Meade, 1961).6 Extensive experience with open chest injuries occurred in World Wars I and II. World War I provided experience and progress in the management of an open thoracic space, lung injuries with hemorrhage, traumatic pneumothorax, and the late sequelae of empyema and pneumonia. World War II resulted in a significantly greater number of thoracic, cardiac, and vascular injuries and provided the background for the relatively rapid development of thoracic and cardiovascular surgery as it is practiced today. Progress included recognition of the physiology and management of shock syndromes, blood loss, and transfusion; intensive care facilities; techniques of safe anesthesia and ventilation; the management of intrathoracic sepsis coincident with the introduction of antibiotics; pulmonary repair and resection; management of the unstable chest wall; and the repair of vascular and cardiac injuries. The impact of World War II on the practice of thoracic surgery is well documented.7,8 The scourge of tuberculosis began to diminish rapidly in the 1950s after the introduction of streptomycin (by injection) and the subsequent arrival of safer and more effective antibiotics. Indeed, in 1958, Dr. F. G. Kergin, then professor of surgery at the University of Toronto, offered the senior author (F. G. P.) a position in the Division of General Surgery at Toronto General Hospital to be one of three general surgeons on staff who would also do general thoracic surgery. He stated that he was uncertain about the future and importance of general thoracic surgery. Dr. Kergin’s own surgical practice at the local “TB” sanatorium was rapidly contracting. I (F. G. P.) do not believe anyone at that time anticipated the epidemic of primary lung cancer that was already on the horizon. Surgical experience with lung cancer rapidly escalated during the 1960s and provided a major stimulus to development of every aspect of pulmonary surgery practiced today. Some personal features of this early experience are recorded in my (F. G. P.) presidential address to the AATS in 1990.9 The steady and significant increase in both blunt and penetrating trauma (motor vehicle accidents, urban knife and 3

Ch001-F06861.indd 3

1/21/2008 10:17:52 AM

4

Section 1 Introduction

gunshot wounds, and industrial accidents) has further augmented the general thoracic surgical volume.

Endoscopy Endoscopy has been a critically important part of the practice of thoracic surgery since its beginnings. It remains of key importance today, indeed, probably more so than ever. Endoscopy provides access for both diagnosis and treatment of surgical diseases of the larynx, trachea, and bronchi; the pharynx, esophagus, and stomach; the mediastinum (mediastinoscopy); and the pleural spaces. Rigid endoscopy of the airways and upper gastrointestinal tract evolved at the end of the 18th and early decades of the 19th centuries. Jacobeus was the first to describe the design and use of a rigid metal thoracoscope in 1912.10 Flexible endoscopy, including the addition of a magnified and televised image, was developed during the 1960s (largely in Japan) and enjoyed widespread adoption during the early 1970s. The flexible instruments may be used with little or no anesthesia or sedation and are now extensively employed by pulmonologists and gastroenterologists for both diagnostic and interventional procedures. The imaging technology developed for flexible endoscopy undoubtedly contributed to the recent, dramatic advances in minimally invasive video-assisted thoracoscopic surgery (VATS).

Pulmonary Resection Tuffier, of Paris, is credited with the first successful pulmonary resection. In 1891, during the era before control of ventilation during open thoracotomy, Tuffier removed the diseased, tuberculous apex of the left upper lobe using an extrapleural access and exposure.11

Lobectomy Pioneering efforts for pulmonary lobectomy were designed as two-stage operations, managed by mass ligation of the bronchial and vascular structures in the hilum of the lobe. Lilienthal, in New York City, reported his experience with 14 patients undergoing such a two-stage lobectomy for bronchiectasis. There were six postoperative deaths.12 But it must be recalled that these early operations were done in difficult patients, with grossly expanded bronchial arterial circulation and pleural adhesions and pulmonary sepsis and without antibiotics! Brunn was the first surgeon to report doing a single-stage lobectomy, with anatomic ligation of the hilar vessels and oversewing the stump of the lobar hilum, which had been secured with a Wertheim hysterectomy clamp. He reported one postoperative death in six consecutive patients.13 Churchill, of Boston, reported the first successful, onestage dissection lobectomy in 1931. The lobar vessels were individually ligated, and the bronchus was separately closed with a continuous layer of catgut suture.14 A number of innovations of simple lobectomy have since been developed. The first sleeve lobectomy was done in 1946 by Price Thomas of London, England, for removal of a right upper lobe adenoma.15 Many years later, Price Thomas,

Ch001-F06861.indd 4

himself, underwent a successful right upper lobe sleeve resection for lung cancer! The first sleeve lobectomy for primary lung cancer was reported by Shaw and Paulson in 1952.16,17 Minimally invasive, video-assisted pulmonary lobectomy was reported in 1993 by Walker and associates in Edinburgh,18 Roviaro and colleagues in Milan,19 and Kirby and coworkers in the United States.20 In 1992, Lewis, in New Jersey, reported on his original technique of video-assisted “cis-lobectomy,” with “mass stapling” of the pulmonary hilum.21 Naruke, of Tokyo, reported a detailed description of his technique of “thoracoscopic lobectomy with mediastinal lymph node dissection or sampling” in 199622 and in 2000.23 At the present time, thoracoscopic lobectomy for earlystage primary lung cancer is rapidly gaining in popularity in many thoracic centers throughout the world. Evidence is accumulating that in early-stage lung cancer, thoracoscopic lobectomy patients realize a comparable (if not slightly better) long-term survival, a similar low operative mortality, and less morbidity (shorter hospital stay) than comparable early-stage patients managed by traditional thoracotomy.23,24

Pneumonectomy Prior to 1931, all attempts at pneumonectomy in humans proved fatal. Deaths were the result of uncontrolled sepsis, hemorrhage, and failure to secure a durable closure of the main bronchus. Seven of the early attempts failed between 1895 and 1922.25,26 For a concise, well-written account of these historical events, see “A Brief History of Pneumonectomy.”27 The prevention of hemorrhage was facilitated by introduction of the “lung tourniquet” designed for lobectomy by Shenstone and Janes, of Toronto, and reported in 1932.28 In 1933, Graham and Singer, of St. Louis, recorded the first successful one-stage pneumonectomy for a physician with lung cancer. The Shenstone-Janes lung tourniquet was used in this patient, and a seven-rib thoracoplasty added (ribs 3-9) because of concern for infection in the postpneumonectomy space.29 This patient survived for the next 30 years, dying at the then ripe old age of 78! Archibald, of Montreal, was the first surgeon to report a successful one-stage pneumonectomy, using a dissection technique, with individual ligation of the pulmonary vessels, and the main bronchus.26 This operation was done within 3 months of the operation performed by Graham and Singer. Also, in 1933, Rienhoff, of Baltimore, described a dissection pneumonectomy that included a description of his definitive technique of bronchial closure.29 Various and subsequent modifications include sleeve pneumonectomy and pulmonary resection combined with concomitant removal of a section of chest wall, diaphragm, or contiguous mediastinal structures. Resection of superior sulcus, or Pancoast, tumors is included in this grouping. Detailed description of these procedures, including historical references, are provided elsewhere in this text.

Segmental and Lesser Resections Segmental resection of the lung was first reported by Churchill and Belsey in 1939.14 At that time, Ronald Belsey was working

1/21/2008 10:17:52 AM

Chapter 1 History and Development of General Thoracic Surgery

as a fellow with Churchill in Boston. The technique of individual dissection of the vessel(s) and segmental bronchus was used. The early experience with segmental resection was in patients with bronchiectasis, which frequently involved the lingular segment but not the remainder of the left upper lobe. Subsequently, however, this “limited” resection was increasingly selected in patients with lung cancer and compromised pulmonary reserve who were deemed unable to tolerate lobectomy. Later still, segmental resection was considered effective in selected, uncompromised patients with small early primary tumors (T1 N0). A prospective randomized trial comparing lobectomy with lesser resections (wedge or segment) for peripheral, non–small cell T1 N0 tumors was conducted by the North American Lung Cancer Study Group (LCSG). This study was sponsored by the National Institutes of Health in Washington, DC, and involved multiple prominent North American Centers. Initiated in 1982, the LCSG 821 was completed and reported on by Ginsberg and colleagues in 1987. This trial demonstrated less favorable outcomes in the “lesser resection” group and established lobectomy as the operation of choice in uncompromised patients.30 Recently, however, a number of centers speculated that a lesser resection may be as effective as lobectomy for the smaller T1 N0 tumors. The most persuasive, published evidence for this proposal is reported by Okada and colleagues from Japan.31 They have evaluated the role of extended segmentectomy in the management of non–small cell T1 N0 tumors of less than 2 cm in diameter. In this prospective study, reported in 2004, they concluded that segmentectomy may well provide comparable outcomes to those reported for lobectomy. They have designed an ingenious technique of segmentectomy in which the lung on the operated side remains collapsed and the segment to be removed remains inflated. The intersegmental plane is dissected under direct vision with fine cautery (like the original segmentectomies) and without the use of staplers. In 2004, this same Japanese group described and reported experience with their new technique of sleeve segmentectomy32 and minimally invasive hybrid VATS segmentectomy in 2007.33

Lung Transplantation Successful human lung transplantation was not accomplished until decades after successful transplantation of the kidneys, heart, and liver. The first attempt at single-lung transplantation in humans (for lung cancer) was reported by James Hardy, in Mississippi, in 1963. Some 40 unsuccessful attempts at human lung transplantation were done between 1963 and 1983. The first successful single-lung transplant (for idiopathic pulmonary fibrosis, with the patient surviving 6.5 years) was done by Cooper and his partners in Toronto in 1983.34 This same Toronto group had experience with two prior, failed single-lung transplants in 1978 and 1981.35,36 The availability of cyclosporine for immune suppression was undoubtedly an important factor in this success. Reitz and associates37 reported successful human heart-lung transplantation in 1981 with cyclosporine as part of the drug regimen.

Ch001-F06861.indd 5

5

Patterson, a partner in this same Toronto group, reported the first successful instance of double-lung transplantation (for α1-antitrypsin deficiency) in 1986.38 This patient survived 15 years!

Lung Volume Reduction Surgery Experience with lung transplantation greatly magnified the exposure and clinical experience in patients with pulmonary emphysema and hyperinflation. This became of particular interest to Joel Cooper and Alec Patterson, who had moved from Toronto to Washington University in St. Louis at the end of the 1980s. They quickly established an International Registry for Lung Transplantation and developed one of the busiest and sophisticated lung transplant programs in the world. Cooper became interested in problems that specifically beset the large numbers of patients with advanced emphysema referred for consideration of lung transplantation. He was stimulated by the early (1950s) reports of surgery for emphysema by Brantigan of Chicago.39 In 1995, Cooper and colleagues reported a favorable experience with lung volume reduction surgery in selected patients with emphysema and severe hyperinflation resulting in disabling failure of the mechanics of breathing.40 The recently reported results of a multicenter, randomized North American trial have confirmed the benefits of such lung volume reduction surgery in appropriately selected patients.41

Tracheal Surgery Significant developments in surgery of the trachea largely took place after the introduction of mechanical ventilators and intubation with cuffed tracheotomy or cuffed translaryngeal tubes. The first mechanical ventilators were designed in Denmark during the worldwide epidemic of poliomyelitis in 1952. This ventilator was a simple volume-cycled unit. Within a few years, Swedish engineers and physicians created the much more sophisticated Engstrom ventilator, which possessed both volume and pressure controls. By the late 1950s, these Engstrom units were in common use in Swedish Regional Thoracic Surgical Units in Stockholm, Uppsala, and Goteborg. The rest of Europe and North America followed these practices in the 1960s. The plethora of postintubation tracheal injuries that were recognized in busy respiratory units provided a huge experience with the resection and reconstruction of damaged and stenotic tracheal lesions. In 1960, it was widely accepted that the surgeon could safely remove no more than two or three tracheal rings (little more than 1 inch) and reconstruct the trachea by primary anastomosis. By 1968, however, advances in knowledge of the anatomy and blood supply of the trachea, the design of tension-reducing release procedures at the top and bottom ends of the trachea, and improved imaging of the upper airway had revolutionized our capability: in the adult patient, about half of the tracheal length could be circumferentially resected and restored by primary end-to-end anastomosis. The most prominent contributor in this field was Dr. Hermes C. Grillo of Boston. His classic textbook Surgery of the Trachea and Bronchi was published in 2004.42 I (F. G. P.), from my long personal acquaintance and friendship with Dr.

1/21/2008 10:17:52 AM

6

Section 1 Introduction

Grillo, know that he worked methodically at the collection of material for this masterwork during the 40 years before its publication. This book is meticulously researched and beautifully written and illustrated. A comprehensive historical review is presented in the introduction to Grillo’s textbook.42

Mediastinal Surgery Shield’s textbook Surgery of the Mediastinum is another excellent and comprehensive text that contains all pertinent history for this region.43

TRAINING AND ACCREDITATION IN GENERAL THORACIC SURGERY The facilities for training and accreditation in general thoracic surgery have never been uniform or standardized across the developed world. Indeed, they have evolved at different times and with differing patterns, in various countries and continents. As our world “contracts,” owing to the ongoing explosion in communication and information technology, there is a rapidly developing interest in evaluating and identifying standards and objectives aimed at improving such training and accreditation. Most new initiatives have arisen within the past 3 decades. In this section, we propose providing an outline of the development, and a resume of the current status of training and accreditation, in the three largest geographic regions with thoracic surgery training programs today: the United States of America, Canada, and the United Kingdom and the European Union.

was thoracic surgery officially sanctioned as an affiliate of the American Board of Surgery and labeled the American Board of Thoracic Surgery (ABTS). In 1971, the ABTS became an independent board. Although still restricted to Thoracic in its title, certification by the ABTS included accreditation in both thoracic and cardiovascular surgery. The AMA subsequently developed the Accreditation Council for Graduate Medical Education (ACGME), which constituted a broad base for purposes of accreditation of medical specialties. Under the auspices of the ACGME, the Residency Review Committee (RRC) for thoracic surgery was established. The RRC reviews each of the residency training programs in thoracic surgery at 5-year intervals. The RRC may cancel programs or place them on probation if standards are deemed inadequate. They do not review programs outside the United States and there is, therefore, no reciprocity for accreditation of training programs outside the borders of the United States. Although certification by the ABTS confers privileges in both general thoracic and cardiac surgery, recent decades have witnessed an increasing concentration of training interest in one or the other of these two main subspecialties. Residency programs increasingly provide options for “streaming,” or concentrating the residency exposure in either general thoracic or cardiac surgery. A few of the large U.S. teaching programs have actually separated the subspecialties into autonomous and independent divisions. The decrease in aortocoronary bypass surgery seen during the past decade has also influenced resident selection for one or the other of these “streamed” subspecialties.

Canada United States of America General thoracic surgery became an increasingly prominent and challenging component of general surgery after both world wars coincident with the intrathoracic complications seen in the worldwide pandemic of tuberculosis, followed in the 1940s and 1950s by the onset of the still persisting “epidemic” of primary lung cancer. The increase in blunt and penetrating thoracic trauma seen during these same years added further to the experience. Thus, the volume and complexity of general thoracic surgery resulted in the development of a “subspecialty” within general surgery and, ultimately, a separate section or specialty. In the United States, earliest developments saw the formation of thoracic surgical societies. The first of these was the New York Thoracic Surgical Society founded in New York City in 1917. The following year, with approval of the American Medical Association, the American Association for Thoracic Surgery was founded. Membership initially included interested members from the specialties of anesthesia, radiology, and endoscopy. Proceedings of the annual meetings were initially published in 1921 in the Archives of Surgery. The Journal of Thoracic Surgery became the official organ in 1931. After the birth and dramatic growth of both cardiac and vascular surgery in the 1950s, its name was changed to the Journal of Thoracic and Cardiovascular Surgery. Efforts to create a certifying mechanism for thoracic surgery were initiated by the AATS in 1937, but only in 1948

Ch001-F06861.indd 6

Early Canadian pioneers in pulmonary surgery include Archibald and Bethune of Montreal, and Shenstone, Janes, Kergin, and Delarue in Toronto. Kergin and Delarue returned to Toronto after World War II, whereas Shenstone and Janes “held the fort” during the war years. Most of their surgery through the 1940s and 1950s was focused on pleural and pulmonary sepsis, including the surgery of tuberculosis. The local sanatorium—the “Weston San”—included the care of aboriginal Canadians, including North American Indians and the Inuit (Eskimos) in the far north of the country. The aboriginal population were decimated by tuberculosis. The Weston Sanatorium had its own operating rooms and was equipped for major thoracic surgery and for functioning electively 5 days a week. Similar conditions prevailed in Montreal, Halifax, and Vancouver. All of the surgeons involved in this work began as general surgeons but became increasingly occupied with general thoracic surgery. In 1946, the Canadian Royal College of Physicians and Surgeons established certification in the subspecialty of thoracic surgery. With few exceptions, early endeavor in cardiac surgery was undertaken by thoracic surgeons. As the specialty of cardiac surgery matured, most training programs evolved in the combined subspecialties of cardiovascular and general thoracic surgery. This pattern prevails in almost all centers in North America, the United Kingdom, and much of Europe. The evolution of training in Thoracic Surgery in Toronto, however, was at variance with this pattern. After his return

1/21/2008 10:17:53 AM

Chapter 1 History and Development of General Thoracic Surgery

from World War II, W. G. Bigelow was a young general surgeon with no background or training in thoracic surgery. He developed an interest in vascular injury and repair during the war and subsequently spent 1 year in Baltimore with Alfred Blalock. By 1958, Bigelow had established a residency training program in the exciting new subspecialty of cardiovascular surgery at the University of Toronto. At this same time, general thoracic surgery remained a subspecialty within the Division of General Surgery and was the responsibility of four members of the general surgical staff, situated in three separate divisions of general surgery. Concentrated training in general thoracic surgery was difficult to impossible under these circumstances. In 1968, for purposes of residency training, the University of Toronto established a separate (and autonomous) Division of General Thoracic Surgery at the Toronto General Hospital. The founding surgeons in this new division were Drs. Delarue, Pearson, and Henderson. The new division became a busy clinical and residency training program within the next 5 years: five full-time staff surgeons, three residents, a 30-bed nursing unit with step-down facilities on the floor, dedicated operating room time, laboratory space, and research fellows. Most importantly, divisional status conferred unencumbered access to hospital and university resources. In 1970, Pearson sent a memorandum to the Committee for Thoracic and Cardiovascular Surgery in the College of Physicians and Surgeons of Canada. To quote from the introduction to this memorandum, Pearson stated, “It is increasingly evident that the present training programs and criteria for certification in (General) Thoracic Surgery are unsatisfactory. This memorandum is intended to define inadequacies which exist presently, and suggest modification in both training requirements and method of certification, which should produce graduates who are better qualified to provide the health care requirements in this area (General Thoracic Surgery) today.” In response, a number of meetings of the Royal College Nucleus Committee for Thoracic and Cardiovascular Surgery were held and the Canadian membership was canvassed with a questionnaire. In 1976, the Royal College of Physicians and Surgeons of Canada (RCPSC) established a certificate of special competence in general thoracic surgery, separate from the Canadian Royal College certification in thoracic and cardiovascular surgery. With the appropriate residency training in general thoracic surgery, trainees certified in general surgery could obtain this certificate of special competence. These trainees were not licensed to practice cardiovascular surgery. In contrast to developments in the United States, cardiac surgery in Canada remained limited to a relatively small number of centers, almost exclusively within Canadian university hospitals. In this environment, many Canadian communities required thoracic surgeons who would never have an opportunity to practice cardiac surgery. Many of the details described in this chapter can be found in Pearson’s 1990 Presidential address to the AATS “Adventures in Surgery.”9 It soon became apparent that aside from a few training programs like that in Toronto, general thoracic surgery was suffering the neglect of a “poor relation” in many combined

Ch001-F06861.indd 7

7

departments of thoracic and cardiovascular surgery. The certificate of special competence in general thoracic surgery, established by the Canadian Royal College in 1976, was designed to address these difficulties. Without doubt, this “special certificate” upgraded the quality of training and practice in general thoracic surgery. Many Canadian communities soon obtained the services of much needed and well-trained certified thoracic surgeons. In 1997, this model was adopted throughout all of Canada. General thoracic surgery and cardiac surgery were identified as separate specialty divisions by the Canadian Royal College of Physicians and Surgeons. Similar changes are currently under review in a number of American programs. Canada’s health care budget is administered provincially, under regulations laid down by the Federal Ministry of Health. In 2004, the Provincial Ministry of Health in British Columbia introduced “regionalization” of the specialty of general thoracic surgery: five centers (1 thoracic surgeon per 300,000 population); a minimum of two, and preferably three, full-time, certified thoracic surgeons in each center; guaranteed provision of adequate physical facilities; and ancillary services for such concentrated, specialty practice. The new model contained an alternate funding plan, with a salary and abolition of “fee for service.” This regionalized program was reviewed by the British Columbia Ministry of Health in 2007 and found to be uniformly and highly satisfactory for the surgeons and economically advantageous for the Provincial Ministry. The Association of General Thoracic Surgeons in Ontario is currently considering a similar arrangement with the Ontario Ministry of Health.

Europe At the beginning of the 20th century, pioneering contributions mainly in the treatment of tuberculosis originated from different European countries. Between the two World Wars, further advancement was spearheaded by icons such as Sauerbruch and Kirschner in Germany and Tudor Edwards and Roberts in the United Kingdom. Until World War II, thoracic surgery was usually performed by general surgeons. It was only after the war that thoracic surgery, as in North America, became established as a surgical speciality in its own right. This was reflected by the publication of textbooks focusing on thoracic surgery. In many European countries, thoracic surgery developed in the former sanatoria for tuberculosis. After the almost complete disappearance of this disease, these sanatoria were converted into centers for chest diseases with an increasing focus on lung cancer and its surgical treatment. This evolution is at the basis of the fact that, until today, in some countries thoracic surgery grew predominantly outside of academic environment. In addition, the rapid development of cardiac surgery, in particular coronary bypass surgery, required accelerated training of thoracic surgeons with a focus on cardiac surgery to remediate the equally rapidly growing waiting lists for cardiac surgery. Moreover, given the lack of a uniform approach throughout European countries, general thoracic surgery remained within the influence of general surgery.

1/21/2008 10:17:53 AM

8

Section 1 Introduction

It was only in 1986 that the European Association for Cardiothoracic Surgery (EACTS) was founded, followed in 1993 by the European Society for Thoracic Surgeons (ESTS). Thus, it is not surprising that almost every European country has a different definition and scope of thoracic surgery, the training required, and the certification needed. The uncertain specialty position of general thoracic surgery has meant problems for surgeons dedicating themselves to it and for patients needing it. One consequence is that the number of patients that a unit may handle each year may range from only a few interventions to well over 1000 patients each year. The surgeons’ experience levels vary considerably. To improve this situation, a joint EACTS/ESTS task force was created in order to define the structure of general thoracic surgery in Europe, and it was published in 2001.44 Another major joint effort was the creation of the School for Cardio-Thoracic Surgery in Bergamo, Italy. Each year, at this school, courses are organized for trainees in general thoracic surgery to allow them to prepare for the European Board examinations in thoracic surgery. Indeed, in 1996, after a number of preparative negotiations between the EACTS, ESTS, and European Society for Cardiovascular Surgery (ESJVS), a European Board examination was created in an effort to obtain a minimum level of quality throughout the European Community. In 2004, the Board entered into the Union Européenne de Medecins Specialistes (UEMS), an organization that was created in 1958 in parallel with the efforts to create the European Community. Within this organization the Board has the potential to gain more clout. This UEMS Board of Thoracic Surgery functions as a joint Board representing tho-

Ch001-F06861.indd 8

racic surgery in both the section of cardiothoracic and the section of general surgery within UEMS. Currently, however, the certificates issued by the UEMS Board do not have a legal value, and the key prerequisite for eligibility to participate in the examinations remains the national certificate of completion of specialist training (CCST) issued by each member state or affiliated state of the European Community. It is hoped that over time, as was the case for some other specialities (e.g., ophthalmology, anesthesiology), the UEMS Board examinations and certification will replace the national examinations and certification and will be a major step forward in harmonizing training and quality of training throughout Europe. KEY REFERENCES Delarue NC: Thoracic Surgery in Canada: A Story of People, Places, and Events: The Evolution of a Specialty. Hamilton, Ontario, BC Decker, 1989. ■ This detailed account identifies the history of thoracic surgical practice from all 10 Canadian provinces, including details of the evolution of training programs and credentialing of this specialty in Canada. Meade RH: A History of Thoracic Surgery. Springfield, IL, Charles C Thomas, 1961. ■ An encyclopedic review of thoracic surgery from earliest times until 1960. Naef AP: The Story of Thoracic Surgery: Milestones and Pioneers. Bern, Hogrefe & Huber, 1990. ■ A thorough and enthusiastically presented history, covering the span of significant, reported experience until 1990. Dr. Naef is a retired thoracic surgeon who practiced in Europe from the 1940s until the end of the 20th century. He knew and met many of the pioneers in this field and provides a spirited, complete, and knowledgeable report of historical events in Europe and the United Kingdom.

1/21/2008 10:17:53 AM

PREOPERATIVE ASSESSMENT OF THE THORACIC SURGICAL PATIENT

chapter

2

Mark K. Ferguson

Key Points ■ Most risk factors for complications after major lung resection and

esophagectomy are well known. ■ Comorbidity substantially increases the risk of major thoracic

surgery. ■ Assess risk factors before major thoracic surgery. ■ Consider intervention for comorbid factors if it will reduce the risk

of surgery. ■ Consider expected long-term quality of life when making recom-

mendations regarding thoracic surgery. ■ The values, concerns, and goals that a patient has might not be

similar to those of the surgeon.

Preoperative evaluation of patients who are candidates for thoracic surgery is a complex process that is essential in fulfilling a variety of objectives. The surgeon requires such assessment to plan the operative approach, anticipate potential operative and postoperative complications, decide on the necessary level of postoperative care, and determine what resources might be required to support the patient until full recovery takes place. The patient requires such assessment so that he or she can ask relevant questions about the recommended procedure, gain an understanding of the short- and long-term consequences of having surgery, and make an informed decision about whether to proceed. The preoperative evaluation of candidates for thoracic surgery is an art as much as it is a science. Despite the plethora of noninvasive and invasive tests that is available for assessing operative risks and predicting outcomes, the final decision ultimately is based on the surgeon’s impression of the likelihood of success of the planned operation. Success can be identified in a number of ways, such as absence of complications, survival until hospital discharge, correction of an underlying disorder, cure of a cancer, or improved longterm quality of life (QOL). This chapter focuses on the physiologic evaluation of patients and on the associations among surgery and perioperative complications, operative mortality, long-term survival, and postoperative QOL.

GENERAL STATUS Age Given the continued growth of the advanced age sector of the population, is it no surprise that surgeons are being referred a higher percentage of elderly patients for consideration for surgery. Seventy-five years was once considered a prohibitive age for aggressive intervention for intrathoracic

problems, but it is now commonplace to recommend major surgery to such patients. In 1975, the average U.S. white male barely lived into his early 70s; in 2005, the life expectancy of a 75-year-old U.S. white male was more than 10 years. The realization that the aging population needs and desires continued aggressive surgical care for selected problems has resulted in a substantial increase in the percentage of elderly patients in an overall surgical practice. For example, in 2001, the percentage of patients older than 70 years of age undergoing major lung resection was in excess of 43%,1 a 25% increase over the percentage of elderly in such a cohort only 2 decades earlier.2 In the 1970s and 1980s, advanced age was associated with a substantial increase in morbidity and mortality from thoracic surgery.2 In most reports, age continues to be an important and independent determinant of operative mortality and morbidity for lung resection, although the relative increased risk of surgery-related death associated with advanced age has substantially decreased owing to improvements in patient selection and surgical and postoperative management (Berrisford et al, 2005; Ferguson et al, 1995).3,4 In fact, some reports suggest that age is no longer an independent determinant of operative mortality.5,6 In contrast, advanced age universally remains an independent and strong factor associated with increased risk of mortality and morbidity after esophagectomy (Atkins et al, 2004).7-9 Advanced age by itself is not an absolute contraindication to major thoracic surgery. For example, disease-specific survival is unrelated to the patient’s age at the time of resection for lung cancer.10 However, a patient’s age must be considered carefully in deciding on major surgical intervention, particularly in light of other comorbid conditions. Age interacts with other factors to increase the risk of operative morbidity and mortality. For example, diffusing capacity and age have been shown to be independent predictors of morbidity and mortality after major lung resection.3 Whereas the presence of a high risk value for only one parameter moderately increases operative risk, mortality increases exponentially if both parameters are in the high risk zone. Similarly, combined increased risk values for age and renal function, or for age and cardiovascular function, substantially elevate the risk of postoperative morbidity and mortality.11 For this reason, never consider such values independently; rather, evaluate them collectively in the overall context of a patient’s medical condition.

Performance Status Performance status is a general measure of a patient’s overall ability to participate in activities of daily life. It is useful to 9

Ch002-F06861.indd 9

1/21/2008 10:18:49 AM

10

Section 1 Introduction

routinely assess performance status as part of the overview of a patient’s physiologic and psychological condition. Several scales have been developed for scoring performance status that are easy to use and are reproducible. The most commonly used scales are the Karnofsky score and the Zubrod (Eastern Cooperative Oncology Group [ECOG]) scale (Table 2-1). In the absence of specific risk factors, patients with an ECOG score of 0 to 1 or a Karnofsky score of 80% to 100% have a normal risk of complications and mortality after major thoracic surgery. Progressively worse performance status levels are associated with incremental operative risk. Performance status has been shown in a few studies to be an independent determinant of operative outcomes. For example, mortality after esophagectomy has been shown to be predicted by age and performance status.7 Similarly, poor performance status is associated with an increase in the risk of operative mortality after resection for lung cancer in elderly patients.12 However, most studies assessing operative risk associated with thoracic surgery have not specifically evaluated performance status as a potential risk factor. In addition, specific risk factors that contribute to poor performance status are more likely to be statistically linked to adverse outcomes than is performance status itself.

PULMONARY FUNCTION A general assessment of pulmonary function is appropriate in every patient undergoing thoracic surgery. The risk of pulmonary complications after major thoracic surgery is as high as 25%, and preoperative pulmonary function is an important predictor of such complications. Many patients who are can-

didates for thoracic surgery have had extensive exposure to tobacco smoke, putting them at high risk for emphysema and other forms of chronic obstructive lung disease. Assess the patient’s smoking status during the initial evaluation, and provide smoking cessation advice as part of the initial encounter. It is often appropriate to remind patients of the substantial increase in risk of pulmonary complications for those patients who are unable or unwilling to stop smoking before major thoracic surgery. Initial screening consists of taking a history focused on the patient’s respiratory status, including symptoms such as shortness of breath, dyspnea on exertion, the presence of a cough, whether the cough is productive, hemoptysis, and limitations in exercise capacity related to breathlessness. Additional informal evaluation in an outpatient clinic setting might include measurement of oxygen saturation during exercise, such as walking for a measured distance on flat ground or climbing a specified number of stairs. Failure to maintain adequate oxygen saturation during such maneuvers may indicate the need for more formal testing of pulmonary function.13,14 Formal pulmonary function testing is appropriate in patients undergoing certain types of thoracic surgery in whom surgical recommendations would be altered based on the results of such testing. The finding of poor spirometry values may not influence the decision to perform limited wedge resection for diagnosis of diffuse pulmonary disease or thoracoscopic excision of a small, peripheral lung nodule. In contrast, elective major lung resection should virtually always be preceded by a formal assessment of pulmonary function to help determine operative risks and enable the surgeon to hold an

TABLE 2-1 Scales for Assessing Individual Performance Status Grade

ECOG1

Score

Karnofsky2

0

Fully active, able to carry on all predisease performance without restriction

100 90

Normal, no complaints; no evidence of disease Able to carry on normal activity; minor signs or symptoms of disease

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work)

80

Normal activity with effort; some signs or symptoms of disease

2

Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours

70

Cares for self; unable to carry on normal activity or to do active work Requires occasional assistance, but is able to care for most personal needs

60

3

Capable of only limited self-care; confined to bed or chair more than 50% of waking hours

50

Requires considerable assistance and frequent medical care

4

Completely disabled; cannot carry on any self-care; totally confined to bed or chair

40 30

Disabled; requires special care and assistance Severely disabled; hospital admission is indicated although death is not imminent Very sick; hospital admission necessary; active supportive treatment necessary Moribund; fatal processes progressing rapidly

20 10 5

Dead

0

Dead

1

Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 2 Hollen PJ, Gralla RJ, Kris MG, et al: Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Cancer 73:2087-2098, 1994.

Ch002-F06861.indd 10

1/21/2008 10:18:49 AM

Chapter 2 Preoperative Assessment of the Thoracic Surgical Patient

informed discussion with the patient. Assessment of pulmonary function is also appropriate in many instances for preoperative evaluation before nonpulmonary surgery. For example, the risk of pulmonary complications is predicted by spirometry in patients undergoing esophagectomy,15-17 and operative mortality after esophagectomy may similarly be related to preoperative pulmonary disease.18

Risk Factors Specific risk factors for major thoracic surgery related to pulmonary function include chronic pulmonary disease (emphysema, chronic bronchitis, asthma) and any condition that limits lung volume, including a large pleural effusion, a large diaphragmatic hernia, and prior major lung resection. Interstitial lung disease that interferes with gas exchange may be associated with hypoxia. Induction chemotherapy and radiotherapy result in measurable decrements in lung function. Similarly, distant prior radiotherapy to the lung or mediastinum can cause considerable impairment of pulmonary function as well as decreasing chest wall mobility and limiting mediastinal motion. In addition to these conditions, many of which cause chronic changes in lung function, performance of a thoracotomy has acute detrimental effects on spirometry that persist for up to 8 to 12 weeks postoperatively. Functional residual capacity drops by 35% on the first postoperative day. Sixty percent decreases in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) also occur during this period.19,20 The addition of a major lung resection substantially further decreases spirometric values and gas exchange parameters to an extent directly correlated with the amount of functional lung tissue that is resected. Furthermore, these reductions persist because of permanent loss of lung volume and are sometimes associated with impaired exercise capacity, particularly in patients who have undergone pneumonectomy. At 6 to 12 months postoperatively, patients who have undergone lobectomy have a 5% to 15% reduction in FVC and a 10% to 25% reduction in FEV1. Corresponding values for pneumonectomy are a 35% to 40% reduction in FVC and a 35% to 50% decrease in FEV1.21,22 Interestingly, in highly selected patients with severe heterogeneous emphysema who undergo major lung resection, it is possible to demonstrate an improvement in spirometric function that is similar to that seen in patients undergoing lung volume reduction surgery (LVRS) (Baldi et al, 2005).23-25 Standard calculation of expected postoperative function in such patients may substantially underestimate their actual postoperative function. In order to properly select patients who can be shepherded through the acute recovery period after major lung resection and some other types of thoracic surgery, a careful preoperative assessment of lung function and estimation of expected postoperative function is essential in the evaluation of the lung resection candidate.

Spirometry Spirometry has been used to assess operative risk in lung resection candidates for more than 5 decades. FVC was

Ch002-F06861.indd 11

11

initially used to assess risk, and subsequently FEV1 was considered the optimal parameter for assessing the likelihood of postoperative respiratory complications (Table 2-2). Calculation of a predicted postoperative value for FEV1 (ppoFEV1) has proved to be very useful in estimating a patient’s postoperative risk.26 Patients with normal risk have a ppoFEV1 of 800 to 1000 mL or greater. Maximum voluntary ventilation (MVV) has also been used as a measure of risk associated with major lung resection; patients with an MVV less than 50% of predicted are at increased risk for postoperative complications after major lung resection. However, this parameter is strongly dependent on patient effort and therefore is subject to tremendous variability. Traditional cutoff values for FVC and FEV1 that are used to differentiate between low and high risk for major pulmonary resection are relatively inaccurate at the extremes of the body mass spectrum. In consideration of this fact, spirometric values expressed as a percentage of the predicted value based on age, gender, and height have more commonly been used to assess operative risk.13,26,27 In general, patients with a preoperative FEV1 of at least 60% of predicted have a normal risk profile for major lung resection excluding pneumonectomy. Further refinement has included calculation of a ppoFEV1; values of 40% or greater are generally thought to indicate normal operative risk for major lung resection. The calculation of predicted postoperative values is sometimes challenging. In patients with normal lung function (who do not often need major lung resection), the simplest method is to multiply the preoperative spirometric value by the fraction of functional lung segments expected to remain postoperatively. For example, assuming 19 functional lung segments, a patient who is undergoing right upper lobectomy (losing 3 segments) would be expected to retain 16/19 of original lung function. Another simple method of estimation is to subtract 5% from original lung function for each functioning segment that is to be removed. The calculation becomes more important in patients with marginal lung function, especially those who have areas of functional heterogeneity, and in patients who have undergone prior lung resection. Lung segments that are obstructed are eliminated from calculations in order to more accurately

TABLE 2-2 Preoperative Values for Assessing Risk Before Major Lung Resection Test

Value for Low-Risk Patients

FEV1%

>60%

DLCO%

>60%

ppoFEV1

>800 mL

ppoFEV1%

>40%

ppoDLCO% . VO2max during exercise

>40% >15 mL/kg/min

DLco, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in 1 second; ppo, predicted postoperative . value; V O2 max, maximum oxygen consumption.

1/21/2008 10:18:49 AM

12

Section 1 Introduction

assess predicted postoperative lung function. Lobes that are affected by emphysema to a greater extent than the remaining lung are not considered fully functional for purposes of calculating estimated postoperative function. Several techniques are available that enable refinement of the calculation of estimated postoperative function. Quantitative pulmonary scintigraphy, using the perfusion phase of the examination as the best estimate of regional function, effectively estimates regional lung function assessed per quadrant or per lung. A newer method, quantitative computed tomography (CT), provides similar or greater accuracy through measurement of relative lung density as an estimate of pulmonary vasculature (Bolliger et al, 2002).28 By using one or more of these techniques for estimating regional lung function, and thus the amount of functional lung expected to remain after major lung resection, one can calculate a ppoFEV1 that closely parallels the measured postoperative function. In addition to the utility of spirometry in estimating postoperative risk after major lung resection, it is also effective in predicting the risk of pulmonary complications after esophagectomy.17,29,30 Pulmonary complications are more than four times more likely to occur in patients with abnormal spirometry results than in those with normal spirometry.31 These findings do not suggest that spirometry be performed in all patients undergoing esophagectomy. Rather, spirometry may be appropriate to perform in patients who have clinical evidence of underlying lung dysfunction as a means to estimate the risk of postoperative pulmonary complications. If that risk is high, interventions such as preoperative cardiopulmonary rehabilitation may be appropriate, and a more accurate informed discussion can take place with the patient.

Diffusing Capacity Until the late 1980s, the only reliable method of assessing lung function as a means for predicting complications in patients undergoing thoracic surgery was spirometry. The measured and postoperative estimated values failed to predict most pulmonary complications and postoperative mortality, particularly in patients undergoing major lung resection. Subsequent studies identified diffusing capacity as an independent and important predictor of incremental risk of postoperative pulmonary morbidity and overall mortality after major lung resection.32-34 The highest risk group initially was identified as having a preoperative carbon monoxide diffusing capacity (DLCO) of less than 60% of predicted. The identification of high-risk patients is more accurately achieved by calculating the ppoDLCO based on the amount of lung to be resected; the highest risk group includes those patients with ppoDLCO less than 40% of predicted.3 In addition to predicting perioperative complications, DLCO also predicts longterm outcomes after major lung resection. Patients with a preoperative DLCO less than 50% of predicted who underwent lobectomy or less than 60% of predicted who underwent pneumonectomy had a worse QOL, an increased need for supplemental oxygen, and a greater frequency of hospital readmission during the first postoperative year after resection, compared to patients with normal DLCO.35

Ch002-F06861.indd 12

DLCO is also an important predictor of outcomes in patients undergoing LVRS for emphysema. DLCO is one of the components that helps identify patients who belong to the socalled prohibitive risk category for LVRS, which is characterized by an FEV1 of less than 20% of predicted and either a diffusing capacity less than 20% of predicted or homogenous distribution of emphysema.36 DLCO also predicts the likelihood of pulmonary morbidity after LVRS in the lower-risk groups.37 The data are sufficiently compelling that diffusing capacity be measured routinely in candidates for major lung resection or LVRS. In the absence of severe pulmonary dysfunction, DLCO assessment in patients undergoing lesser lung operations is of questionable value; DLCO measurement in patients with severely compromised lung function may assist the physician in having an informed discussion with the patient about potential risks and outcomes. In addition to its utility in assessing risk related to major lung resection and LVRS, the DLCO predicts the incremental risk of pulmonary complications in patients undergoing esophagectomy. In the predictive model that was developed from this analysis, patients with a DLCO less than 80% of predicted had a 1.7-fold increased risk of pulmonary complications, compared to patients with a DLCO of 100% of predicted or better.38 The predictive capacity of this value, although strong, is probably overshadowed by several other physiologic predictors in candidates for esophagectomy. Therefore, routine measurement of DLCO is not generally indicated in this patient population.

Exercise Capacity and Oxygen Consumption Another method of assessing operative risk for major lung resection is measurement of exercise capacity. This is accomplished with simple techniques such as the 6-minute walk distance, stair climbing ability, and assessment of arterial oxygen saturation (PaO2) during walking on flat ground or during stair climbing.39,40 Patients with a very limited ability to exercise and those who experience a substantial drop in PaO2 during exercise are considered to be at high risk for postoperative complications.41 These techniques are inexpensive and are reasonably reliable for estimating whether a patient’s risk is normal or substantially increased. However, incremental risk is difficult to establish using these semiquantitative methods. It is often appropriate to further evaluate patients who are deemed to be at substantially increased risk for complications after major lung. resection by measuring maximum oxygen consumption (VO2max) during exercise. This technique is expensive and labor intensive, and its accuracy depends to some extent on the patient’s willingness to exercise to capacity and on the ability of the physician who is supervising the test to determine when the point of maximum exercise has been achieved. With these caveats in mind, the objective data that result from this test provide estimates of risk that are similar or greater in accuracy to those provided by more standard measurements such as spirometry and DLCO.42 The . limiting value of VO2max for prohibitive risk is 10 mL/kg/ min; values in excess of 15 to 20 mL/kg/min are indicative

1/21/2008 10:18:49 AM

Chapter 2 Preoperative Assessment of the Thoracic Surgical Patient

of normal risk. Values between 10 and 15 mL/kg/min must be interpreted clinically because the risk level associated with this range of oxygen consumption is variable and often is not prohibitive. Efforts have been made to correlate risk with . VO2max expressed as a percentage of the predicted value; the results suggest that values less than 50% to 60% of predicted are indicative of much higher than average risk, although the accuracy of such predictions is poor at the extremes of the functional spectrum (Win et al, 2005).43-46 An algorithm for the stepwise pulmonary assessment of candidates for major lung resection is presented in Figure 2-1.

Lung Function and Long-Term Outcomes In addition to the immediate postoperative risk of morbidity and mortality after major thoracic surgery, long-term QOL and overall survival must be considered when making surgical recommendations to patients. The influence of pulmonary function on long-term outcomes has been best defined for patients undergoing major lung resection and often reflects processes that are characteristic of a general population. Impaired short- and intermediate-term QOL is related to reduced DLCO after major lung resection (Hardy et al, 2002).47,48 Spirometric values do not appear to have an important influence on QOL in this time frame. It has been known for centuries that life expectancy in the general population is inversely related to FVC, and insurance companies have recently begun to use spirometry as part of their actuarial analyses in setting life insurance rates. Similarly, long-term survival in patients with lung cancer is related to the severity of chronic obstructive pulmonary disease (LopezEncuentra et al, 2005).49 In patients who undergo major lung

resection, long-term survival is inversely related to FEV1, with incremental mortality occurring as a result of intercurrent disease rather than recurrent cancer.50-53 In patients with severely impaired spirometry results, give careful consideration to the impact of major lung resection on QOL and long-term survival. Weight this factor against the relative risk of death from recurrent cancer based on the type of lung resection performed.

CARDIOVASCULAR STATUS Patients who have disease requiring major thoracic surgery frequently have risk factors for pulmonary disease, as described earlier, and many of those risk factors are also associated with cardiovascular disease. As part of the initial evaluation of such patients, a careful history and a thorough physical examination are vitally important in identifying problems that portend an increased risk of postoperative cardiovascular complications, including stroke, myocardial infarction, and arrhythmia. It is estimated that between one quarter and one third of patients undergoing general anesthesia have known cardiac disease or known risk factors (Box 2-1) and that almost 5% of all patients will experience a postoperative cardiac complication.54 The risk of possible neurovascular and peripheral vascular complications is also substantial. In general, the risk of cardiovascular complications is much higher in patients undergoing major thoracic surgery than in those undergoing less stressful types of general surgical procedures.

Coronary Artery Disease Risk factors for postoperative coronary artery complications include ischemic heart disease, congestive heart failure, dia-

History Physical exam Pulmonary function tests

ppoFEV1% >40 and ppoDLCO% >40

ppoFEV1% <40 or ppoDLCO% <40

Resect

ppoFEV1% <40 or ppoDLCO% <40

Quantitative perfusion scan Recalculate predicted values

VO2max >10

Exercise test

ppoFEV1% <20 or ppoDLCO% <20

VO2max <10

No resection

Average risk: ppoFEV1% >40 ppoDLCO% >40 VO2max >15

Ch002-F06861.indd 13

High risk: ppoFEV1% 20-40 ppoDLCO% 20-40 VO2max 10-15

13

FIGURE 2-1 An algorithm for assessing risk of mortality and postoperative complications based on pulmonary function in patients who are candidates for major lung resection. DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in 1. second; ppo, predicted postoperative value; VO2max, maximum oxygen consumption.

Prohibitive risk: ppoFEV1% <20 ppoDLCO% <20 VO2max <10

1/21/2008 10:18:50 AM

14

Section 1 Introduction

Box 2-1 Factors Associated With Increased Risk of Cardiovascular Complications After Major Thoracic Surgery Major Unstable coronary syndromes Recent myocardial infarction with ongoing ischemic risk Unstable or severe angina Decompensated congestive heart failure Significant arrhythmia Severe valvular disease Pulmonary hypertension Intermediate Mild angina pectoris Prior myocardial infarction by history or pathologic Q waves Compensated or prior congestive heart failure Diabetes mellitus Advanced age Low functional capacity (e.g., inability to climb stairs) Uncontrolled systemic hypertension Minor Abnormal electrocardiogram (left ventricular hypertrophy, left bundlebranch block, ST-T abnormalities) Rhythm other than sinus rhythm History of stroke Cerebrovascular occlusive disease Peripheral arterial occlusive disease Modified from Beckles MA, Spiro SG, Colice GL, Rudd RM; American College of Chest Physicians: The physiologic evaluation of patients with lung cancer being considered for resectional surgery. Chest 123:105S114S, 2003.

betes mellitus, renal insufficiency, and poor overall functional status (Fleisher and Eagle, 2001).54 In the absence of any such risk factors, patients proceed directly to surgery without any specific evaluation of their coronary arterial anatomy. Patients who have unstable angina or recent myocardial infarction must undergo a thorough evaluation, and any elective surgery is postponed until such conditions are stabilized. An algorithm for managing patients with one or more risk factors is outlined in Figure 2-2. Specific testing is performed when the clinical situation indicates that changes in management would occur if the test returned positive, suggesting that the algorithm is cost-effective. Further testing is not performed if the results would not influence a patient’s overall management strategy. The likelihood of perioperative complications in patients with these risk factors may be reduced through revasculariza-

Ch002-F06861.indd 14

tion for coronary artery disease, including use of such techniques as angioplasty, stenting, and coronary artery bypass grafting (CABG). Stenting requires administration of antiplatelet agents, including aspirin and clopidogrel, for a period of at least 4 to 12 weeks after stent placement and aspirin indefinitely afterward. Performance of major surgery before the end of the 4- to 12-week period leads to unacceptable risks of bleeding if antithrombotic agents are not discontinued or to myocardial infarction in those patients in whom antithrombotic agents are stopped preoperatively. Some newer drug-eluting stents require intensive antithrombotic therapy for even longer periods before the risk of stent thrombosis is sufficiently small to permit discontinuation of these medications preoperatively. Both aspirin and clopidogrel must be discontinued for 5 to 7 days before major surgical intervention to reduce the risk of surgical bleeding. CABG before thoracic surgical intervention is appropriate in patients in whom important coronary artery disease is not amenable to percutaneous revascularization techniques. There is no specified interval that must be observed between successful coronary artery surgery and subsequent major thoracic surgery. The surgeon’s clinical judgment about the patient’s condition and ability to withstand further major surgery is the best means for determining suitable timing. It remains to be seen whether the routine use of minimally invasive approaches to off-pump coronary artery bypass surgery can meaningfully decrease the necessary time interval between operations. Of note, there is rarely an imperative to perform a major thoracic procedure under the same anesthesia used for CABG. Extensive operations for lung resection are usually performed less thoroughly through a median sternotomy than they are through a transthoracic approach, which may potentially compromise the therapeutic efficacy of interventions for oncologic problems. In addition, manipulations of tumor tissue before or during periods when patients are on cardiopulmonary bypass theoretically increase the risk of bloodborne distant metastatic disease. Finally, the use of anticoagulation, which is frequently necessary for performing coronary artery bypass, increases the risk of bleeding from the thoracic surgical sites, and these sites may not be easy to identify or control if such bleeding occurs. Additional medical management suitable for most patients with at least one risk factor includes administration of βblockers in the perioperative period. The medication is begun 2 to 7 days preoperatively and is continued for at least 1 week postoperatively. The dose is titrated to reduce resting heart rate to about 60 beats per minute. Patients with risk factors for coronary artery disease treated within these guidelines experience a reduction of up to 90% in the incidence of myocardial infarction or cardiac death after major noncardiac surgery.55 β-Blockers must be administered carefully in patients with important lung disease such as reactive airways disease or emphysema; however, use of highly selective βblockers is appropriate in most patients in this group.

Risk Factors for Postoperative Arrhythmias Cardiac arrhythmias, particularly supraventricular arrhythmias, occur commonly after major thoracic surgery. Often

1/21/2008 10:18:50 AM

Chapter 2 Preoperative Assessment of the Thoracic Surgical Patient

Risk factors • Ischemic heart disease • Congestive heart failure • Diabetes mellitus • Renal insufficiency • Poor performance status

No risk factors

No further testing needed

15

More than two risk factors

One or two risk factors

No

Suspected coronary artery disease

Noninvasive testing

Yes

Negative test

Positive test

Cardiac catheterization

Negative test

Perioperative beta-blocker therapy

Left main or severe threevessel disease

Possible CABG

One- or twovessel disease

Possible percutaneous revascularization

FIGURE 2-2 An algorithm for evaluating and minimizing the risk of cardiovascular complications in patients undergoing thoracic surgical procedures. CABG, coronary artery bypass grafting.

they are transient, but frequently they are persistent and difficult to manage. In efforts to prevent such complications, which develop most frequently after pneumonectomy and esophagectomy, prophylactic regimens are sometimes recommended for patients at increased risk. Elevated risk is associated with advanced age, greater extent of lung resection, mediastinal surgery (thymus, mediastinal tumor, esophagectomy), and possibly a low DLCO (Vaporciyan et al, 2004).56,57 One regimen used after major lung resection that has been shown to reduce the risk of supraventricular arrhythmias (including atrial fibrillation) by 50% is diltiazem given intravenously (IV) on arrival in the postanesthetic care unit and continued thereafter IV or orally for a period of 2 weeks.58

Systemic Anticoagulation in the Perioperative Period Conditions requiring preoperative anticoagulation are not uncommon among thoracic surgical patients. Anticoagulation is necessitated most commonly by acute conditions, including venous thrombosis and pulmonary embolism, and by chronic conditions such as recurrent venous thrombosis, a mechanical heart valve, or atrial fibrillation. In the setting of chronic conditions such as prior venous thrombosis, atrial fibrillation, or distant prior pulmonary embolism, anticoagulation is

Ch002-F06861.indd 15

usually safely discontinued 1 week preoperatively and is resumed after the risk of postoperative bleeding is normal. In contrast, patients with mechanical artificial valves or more acute thrombotic problems require anticoagulation until the day of the operation. This is most easily achieved by using either IV heparin in an inpatient setting or enoxaparin injections until 8 to 12 hours before the planned incision time. Anticoagulation therapy is resumed as soon as the risk of bleeding is substantially reduced, typically not until the day after surgery.

PREOPERATIVE EVALUATION OF OTHER SYSTEMS Patients undergoing major thoracic surgery who have underlying diabetes mellitus are at increased risk for a variety of complications, including myocardial infarction (see earlier discussion), wound infection, bronchial stump leak, and a variety of other wound healing complications.59,60 In patients undergoing cardiac surgery, assiduous control of blood glucose levels perioperatively appears to improve overall outcomes.61,62 Similar benefits may occur in general thoracic surgical patients, although this has not yet been established. In any case, assessment of the increased risks associated with diabetes enables the surgeon to have an informed discussion

1/21/2008 10:18:50 AM

16

Section 1 Introduction

with the patient regarding surgical outcomes and to prepare necessary resources to permit optimal perioperative management. Impaired renal function poses important challenges during the preoperative evaluation of thoracic surgical patients. Use of contrast material as part of staging studies is often contraindicated, reducing the accuracy of such studies and adding potential uncertainty to the outcome of any operation. Perioperative management in such patients requires a careful review of medications to be used, with appropriate dose reduction or altered dose scheduling based on the degree of functional renal impairment. For patients who are undergoing hemodialysis, arrangements must be made for this to be performed on the day before surgery, so that dialysis on the day of surgery is avoided, reducing the risk of bleeding associated with heparin needed for hemodialysis. Patients who are receiving peritoneal dialysis and who require a laparotomy must be converted for the short term to hemodialysis, usually through a temporary venous catheter rather than a shunt or fistula. The presence of renal failure is associated with poorer outcomes for most important general thoracic procedures, including major lung resection,63,64 and it is appropriate that this be discussed as part of the informed consent process. Hepatic insufficiency presents considerable challenges for performing thoracic surgery, including increased risks of bleeding from coagulopathy, hemorrhage from esophageal varices, hepatic encephalopathy, and uncontrollable ascites. Patients with suspected cirrhosis are evaluated according to standard systems such as the Child classification, which requires assessment of serum bilirubin and albumin, prothrombin time, degree of encephalopathy, and amount of ascites. Carefully selected patients in Child’s group A or possibly group B may be candidates for major lung resection or esophagectomy, with the anticipation that their risks of operative complications are considerably increased.65 The finding of cirrhosis also portends a reduced long-term survival after potentially curative oncologic thoracic surgery because of the increased risk of death from intercurrent causes. General physical limitations sometimes become important in the preoperative evaluation of the thoracic surgery patient. Patients with lower extremity amputations (e.g., for sarcoma) sometimes develop a need for thoracotomy or sternotomy, often for resection of pulmonary metastases. Patients who cannot ambulate independently using a limb prosthesis must be assessed with regard to their ability to ambulate as part of their recovery from surgery. This may not be an important issue if a muscle-sparing thoracotomy is performed because this procedure preserves shoulder girdle musculature and function and does not affect the use of walking aids. However, it may be a complicating factor if a sternotomy or transverse sternothoracotomy is performed because ambulation using a walker or crutches places unusual stresses on the reapproximated sternum, possibly leading to dehiscence and infection or simple malunion. Airway issues affect any patient who requires lung isolation as part of a thoracic surgical procedure. Lung and esophageal cancers share common risk factors with head and neck cancer, and it is not uncommon for a patient to require surgery for more than one of these conditions over time. Patients who

Ch002-F06861.indd 16

have undergone laryngectomy for head and neck cancer present unique challenges for obtaining lung isolation. This must be considered before major thoracic surgery is recommended. The collective effect of comorbidities has an important influence on both short-term and long-term outcomes after thoracic surgery. Higher comorbidity scores are associated with an increased risk of postoperative complications after major lung resection.66,67 In addition, elevated comorbidity scores are linked to increased long-term mortality after lung cancer resection.68,69

RISK ASSESSMENT An important focus of clinical research is the development of organized methods of assessing preoperative risks for surgical procedures. Risk assessment tools in thoracic surgery are in their infancy, compared with the robust tools available for risk assessment in adult cardiac surgery. The use of such algorithms is potentially important in informing individual patients about risk levels, in determining the potential utility of preoperative interventions for lowering risk, and in assessing the need for enhanced resources during the postoperative care of such patients. Various scoring systems have been used to provide a reasonably accurate quantitative estimate of risk for patient populations undergoing major lung resection and other operations. These systems include the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM), the Cardiopulmonary Risk Index (CPRI), the Predictive Respiratory Quotient (PRQ), the Predicted Postoperative Product (PPP), APACHE II (adapted from a trauma scoring system), the Estimation of Physiologic Ability and Surgical Stress (E-PASS), and evaluation of the three most important predictors of outcomes (expiratory volume, age, and diffusing capacity: EVAD).70-75 Unfortunately, such systems have not been adequately assessed with regard to their utility in estimating risk for individual patients. They are currently most useful for estimating outcomes in populations undergoing major lung resection that are stratified according to standard risk profiles.

DECISION-MAKING PROCESS After completing the preoperative evaluation of candidates for thoracic surgery, the surgeon offers recommendations regarding possible operative intervention. In making such recommendations, the goals of the surgeon and of the patient must be explicitly expressed and assessed; they are not always similar, and in many cases they are quite disparate. Patients tend to follow their self-interest by seeking procedures and outcomes that minimize discomfort and optimize QOL; death as an outcome of surgery does not pose nearly as great a concern as does permanent postoperative disability (Cykert et al, 2000).76 Surgeons, serving in part their own self-interest, tend to focus on minimizing postoperative complications and maximizing long-term survival, especially for oncologic conditions. Most risk factors described in this chapter are well understood and are indelibly etched into the minds of surgeons who deal with these patients on a daily basis. The scoring

1/21/2008 10:18:50 AM

Chapter 2 Preoperative Assessment of the Thoracic Surgical Patient

systems mentioned assess only short-term risk for groups of patients; none purports to assess risk for an individual patient. Potential methods to do this include the use of artificial intelligence software to train a neural network based on actual outcomes.77,78 As large quantities of data are entered, the neural network identifies risk patterns and modifies these patterns as new outcomes are included in the database. After sufficient learning and validation have taken place, the accuracy of neural network prediction of complications can exceed 95%. However, at present, a trained neural network is site specific, making its use feasible only in high-volume centers in which infrastructure is available to manage the network. No current scoring or artificial learning systems can provide insight into long-term outcomes, including QOL and longterm survival. In fact, the necessary tools to measure QOL in the specific context of thoracic surgical procedures have not yet been devised or validated. Generic QOL tools have been applied to outcomes for lung resection, esophagectomy, and LVRS. Examples of tools that assess overall QOL include the Short-Form 36 (SF-36) derived from the Medical Outcomes Study, the Health Related Quality of Life Measure (HRQOL-14) of the Centers for Disease Control and Prevention, the Sickness Impact Profile, and the Nottingham Health Profile.79 There are numerous QOL measures for chronic lung disease, including those that measure baseline function, function during exercise, general fatigue, and responsiveness to interventions.80 No measure to date has sought to incorporate issues such as QOL during the postoperative recovery period, postoperative and chronic incisional pain, swallowing impairment after esophageal surgery, maintenance of normal body weight, or the impact of surgery on specific vocational and avocational activities. Until such measures are developed, surgeons and their patients will not have the ability to make truly informed decisions about the utility of surgery. Decision analysis models are being developed as methods to appropriately weigh risks and benefits for patients undergoing thoracic surgery. Some issues that have been assessed include the utility of various treatments (surgical and nonsurgical) for achalasia, whether to perform routine mediastinoscopy for staging of surgical candidates for lung cancer resection, and the choice between sleeve lobectomy or pneumonectomy for centrally located lung cancers.81-83 Future possibilities for similar models include the selection of optimal therapy for medically marginal candidates for lung resection and esophagectomy. Such models, using data relevant to individual patients, may prove very useful in providing patientspecific risk estimates and guidelines for recommendations. Despite the promising work that is being done on risk analysis and decision-making algorithms, the evaluation of potential thoracic surgical patients currently remains an art that ultimately is dependent on the experience and judgment of the surgeon. The assessments outlined in this chapter provide useful algorithms for consideration of risks and outcomes in patient populations and in individual patients. Use of these algorithms must be tempered by the surgeon’s knowledge of an individual patient’s risks, needs, and desires. It is unlikely that this vital judgment function will ever be completely subsumed by technological advances.

Ch002-F06861.indd 17

17

COMMENTS AND CONTROVERSIES As pointed out by Doctor Ferguson, the preoperative evaluation of potential candidates for major thoracic procedures is a complex but important process that must be done for every patient. One must try to establish a reliable patient profile (low risk, high risk, prohibitive risk) to ensure that no individual is denied surgery while minimizing postoperative morbidity. Most importantly, the appreciation of such considerations allows the surgeon and other members of the team (anesthetist, intensivist) to use a number of prophylactic measures intended to decrease morbidity in high-risk patients. Where indicated, pulmonary rehabilitation, smoking cessation, optimization of medical treatment of chronic obstructive pulmonary disease, and treatment of cardiac disease decrease the risks associated with pulmonary or esophageal resection. Although scoring systems are available to predict operative risk, numbers do not tell everything, and nothing replaces good clinical judgment. Moreover, none of those systems has been validated with large numbers of patients, and none provides insight into long-term outcomes such as QOL and cardiorespiratory function 5 years after surgery. In this excellent chapter by Doctor Ferguson, a number of risk factors for operative morbidity and mortality are analyzed. In general, advanced age (70 years or older) and comorbidities are intimately related and act as dependent variables in increasing the risk of postoperative events, especially in patients undergoing pneumonectomy or esophagectomy. Indeed, older patients are more likely to lose their ability to cooperate postoperatively (increased risk of delirium), a feature that may add significantly to the operative risk. No patient should have pulmonary surgery, no matter how limited, without preoperative pulmonary function testing. In many cases, a simple spirometric test provides enough information to determine that the pulmonary function is normal and that the patient can tolerate pneumonectomy if necessary. Exercise testing (measurements . of VO2max, PaO2, and PaCO2, both at rest and during exercise) measures the ability of the whole organism to perform well because it assesses the interaction of pulmonary function, hemodynamic performance, and peripheral tissue oxygen use. A PaCO2 that rises on minimal exercise, for example, is a strong indicator of inadequate reserve, and such patients must be looked at very carefully before surgery. Indeed, several authors have shown that exercise testing is the only objective measurement of cardiopulmonary reserve to demonstrate a statistically significant difference between patients with benign postoperative courses and those with cardiorespiratory complications. For most patients undergoing thoracotomy, the greatest cardiac risk arises from the presence of coronary artery disease. Operations performed within 3 months after a myocardial infarction, for instance, result in a 27% incidence of recurrent infarction. This incidence decreases to about 15% if the infarction occurred 4 to 6 months previously and to 6% if the operation is delayed for 6 months or longer. Similar risks have been identified for patients with angina. For these reasons, an accurate cardiac history and evaluation are of utmost importance. A screening exercise test is recommended for all patients who are smokers and older than 45 years of age, and for those with significant other risk factors for coronary artery disease. Overall, it is important to remember that, in the practice of thoracic surgery, technical misadventures do occur but seldom account for significant postoperative morbidity. On the other hand, the majority

1/21/2008 10:18:50 AM

18

Section 1 Introduction

of postoperative complications and deaths are related to cardiopulmonary events, most of which could have been prevented if the problem had been identified preoperatively. J. D.

KEY REFERENCES Atkins BZ, Shah AS, Hutcheson KA, et al: Reducing hospital morbidity and mortality following esophagectomy. Ann Thorac Surg 78:11701176, 2004. Baldi S, Ruffini E, Harari S, et al: Does lobectomy for lung cancer in patients with chronic obstructive pulmonary disease affect lung function? A multicenter national study. J Thorac Cardiovasc Surg 130:1616-1622, 2005. Berrisford R, Brunelli A, Rocco G, et al: Audit and Guidelines Committee of the European Society of Thoracic Surgeons; European Association of Cardiothoracic Surgeons: The European Thoracic Surgery Database project: Modeling the risk of in-hospital death following lung resection. Eur J Cardiothorac Surg 28:306-311, 2005. Bolliger CT, Guckel C, Engel H, et al: Prediction of functional reserves after lung resection: comparison between quantitative computed

Ch002-F06861.indd 18

tomography, scintigraphy, and anatomy. Respiration 69:482-489, 2002. Cykert S, Kissling G, Hansen CJ: Patient preferences regarding possible outcomes of lung resection: What outcomes should preoperative evaluations target? Chest 117:1551-1559, 2000. Ferguson MK, Reeder LB, Mick R: Optimizing selection of patients for major lung resection. J Thorac Cardiovasc Surg 109:275-283, 1995. Fleisher LA, Eagle KA: Clinical practice: Lowering cardiac risk in noncardiac surgery. N Engl J Med 345:1677-1682, 2001. Handy JR Jr, Asaph JW, Skokan L, et al: What happens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after surgery. Chest 122:21-30, 2002. Lopez-Encuentra A, Astudillo J, Cerezal J, et al: Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S): Prognostic value of chronic obstructive pulmonary disease in 2994 cases of lung cancer. Eur J Cardiothorac Surg 27:8-13, 2005. Vaporciyan AA, Correa AM, Rice DC, et al: Risk factors associated with atrial fibrillation after noncardiac thoracic surgery: Analysis of 2588 patients. J Thorac Cardiovasc Surg 127:779-786, 2004. Win T, Jackson A, Sharples L, et al: Cardiopulmonary exercise tests and lung cancer surgical outcome. Chest 127:1159-1165, 2005.

1/21/2008 10:18:50 AM

chapter

3

PULMONARY PHYSIOLOGIC TESTING Frank C. Sciurba Steve H. Salzman Key Points

■ Spirometry is the most commonly performed and standardized

measurement of pulmonary function; it measures the volume and flow rate of air that leaves the lungs (how much and how fast). ■ Two separate methodologies are used to quantitate RV, FRC, and TLC: body plethysmography and gas dilution. ■ Other pulmonary function tests include maximal voluntary ventilation, maximal respiratory pressures, and lung compliance. ■ Cardiopulmonary exercise testing not only delineates the reserve of each of the contributing subcomponents of the process of respiration but also allows us to integrate the effects of a myriad of measurable and unmeasurable system subcomponents to assess functional status through measurements of maximal power output and oxygen consumption.

The physiologic role of the lung is to maintain homeostasis of the arterial pH, PCO2, and PO2 under varying conditions of oxygen consumption and carbon dioxide production, a goal that is dependent on the lung’s properties both as a mechanical structure and as a gas-exchanging surface. Clinical pulmonary function tests (PFTs) provide practical assessment of the integrity of the components of the respiratory system. Such testing provides a key ingredient in the diagnosis and assessment of severity of lung disease and is critical in the determination of perioperative risk. Cardiopulmonary exercise testing (CPET) may offer further diagnostic and prognostic advantages over resting assessment of the respiratory system because it measures physiologic reserve and integrated functional capacity that can only be inferred from resting measurements. It is imperative that the thoracic surgeon be competent not only in the application of lung function indices but also in the assessment of the techniques and quality of the data provided. In this chapter we offer a practical approach to the assessment of lung function and exercise physiology.

INDICATIONS FOR PULMONARY FUNCTION TESTING Pulmonary function tests (PFTs) have a central role in the evaluation of the thoracic surgery patient. The role of these tests in preoperative risk assessment is discussed in Chapter 2. Other indications are highlighted in Table 3-1. PFTs, although essential to the proper assessment of the respiratory system, rarely provide a specific diagnosis in the absence of complementary clinical and radiographic data. Tests of lung function can be broadly separated into those that evaluate the mechanical properties (volumes, flows,

compliance, resistance, respiratory pressures, airway hyperreactivity, or bronchodilator reversibility) and those that focus on gas exchange: arterial oxygen and carbon dioxide partial pressures (PaO2 and PaCO2) and saturations (SaO2 and SaCO2), alveolar-arterial oxygen pressure difference (P[A − a]O2), diffusing (DLCO), and physiologic dead . capacity . space ventilation (VD/VT). Various lung diseases, or individual variation within a given disease, may result in discordant impairment between various mechanical properties or between mechanical and gas exchange properties. Thus, a combination of tests to evaluate lung mechanics and gas exchange will provide the most comprehensive understanding.

SPIROMETRY Spirometry is the most commonly performed and standardized measurement of pulmonary function. This test measures the volume and flow rate of air that leaves the lungs (how much and how fast). Traditionally, exhaled volume is measured as a function of time using a volume-displacement spirometer with flow rates calculated by dividing volume into timed segments. It is now more common for systems to primarily measure flow, with real-time integration of flow over time to obtain volume, owing to the development of less expensive and more compact and accurate flow-sensing devices and fast microprocessors. The total volume exhaled from a full inspiration (total lung capacity [TLC]) to a full expiration (residual volume [RV]) is termed the vital capacity (VC). The maneuver can be performed using a forced complete exhalation, referred to as forced vital capacity (FVC), or during a slow complete exhalation, defined as slow vital capacity (SVC). Forced exhalation is necessary to assess expiratory flow rates, including peak expiratory flow (PEF) and the volume exhaled in the first second (FEV1) as well as other less commonly used timed volumes (e.g., FEV0.5, FEV3.0 [volumes exhaled in the first half second and the first 3 seconds, respectively]) and forced expiratory flows (FEF50%, FEF25-75% [forced expiratory flow at 50% of the FVC, and forced expiratory flow between 25% and 75% of the FVC, respectively]). The parameter FEV1 is the most reproducible and validated measure derived from the forced expiratory maneuver and, with its ratio FEV1/FVC, provides the foundation for lung disease classification, discussed later (Fig. 3-1). Slow vital capacity maneuvers are used to assess other static lung volumes and capacities such as inspiratory capacity (IC) and expiratory reserve volume (ERV) and, because spirometry cannot measure the air remaining in the lung after a complete exhalation, are often linked to tests of lung volume (Fig. 3-2). 19

Ch003-F06861.indd 19

1/21/2008 10:19:55 AM

20

Section 1 Introduction

8.0

8.0

6.0

7.0 TLC 6.0

4.0

RV

TLC

–2.0

FVC

3.0

FIF50

–4.0

2.0

–6.0

1.0

RV

0.0

–8.0 7.0

A

4.0

5%

FVC

FEV1

25–7

0.0

FEF

Flow (L/s)

5.0 Volume (L)

FEF50

2.0

FEV1

6.0

5.0

2.0 3.0 Volume (L)

2.0

0.0

1.0

1.0

2.0

3.0

4.0

Time (sec)

B

FIGURE 3-1 Flow and time curves. A, Good duration of effort is seen on the volume-time curve by the plateau of volume change over time. In a normal flow-volume loop, good early effort is shown by the rapid upstroke to a slightly rounded “sharp” peak flow. Good duration of effort is illustrated by the upward concavity at the end of exhalation, indicating slowing of airflow near residual volume. Patients with obstructive lung disease have deeper, upward concavity throughout exhalation on the flow-volume loop. FEF50, forced expiratory flow at 50% of the forced vital capacity (FVC); FEV1, volume exhaled in the first second; FIF50, forced inspiratory flow at 50% of FVC; RV, reserve volume; TLC, total lung capacity. TABLE 3-1 Common Indications for Pulmonary Function Testing Categorization of the type and severity of physiologic perturbation ■ Restrictive versus obstructive categorization ■ Asthma versus emphysema

Lung volumes and capacities

IC

Objective assessment of pulmonary symptoms ■ Documentation of abnormality ■ Disability assessment Documentation of progression of disease ■ Chronic obstructive pulmonary disease ■ Neuromuscular disease Documentation of the patient’s response to therapy ■ Asthma control ■ Lung volume reduction surgery ■ Sarcoidosis Preoperative assessment ■ Lung cancer resection operability ■ Nonthoracic surgery ■ Timing of lung transplantation Screening for subclinical disease ■ Emphysema (in a tobacco smoker) ■ Occupational risk ■ Diseases associated with pulmonary abnormalities

Technique and Specific Methodology The forced maneuver consists of three distinct phases (Miller et al, 2005)1: 1. Maximal inspiration 2. A “blast” of exhalation 3. Continued complete exhalation to the end of test (until no more air can be exhaled but maintaining an upright posture)

Ch003-F06861.indd 20

IC

IRV

TLC

SVC TV ERV ERV FRC RV

RV

RV

FIGURE 3-2 Subvolumes. ERV, expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capacity; IRV, inspiratory reserve volume; RV, residual volume; SVC, slow vital capacity; TLC, total lung capacity; TV, tidal volume.

It is then followed by a rapid inhalation back to full inspiration. This effort can be shown graphically as a flow-volume loop (FVL) or volume-time curve (V-t curve), both representing the same FVC maneuver (see Fig. 3-1). Enthusiastic coaching by the technician, including appropriate body language and phrases, is necessary to get full effort from the patient. The technician first explains and demonstrates the technique, instructs the patient to inhale rapidly and completely with minimal pause at full inspiration (only 1-2 s), then instructs the subject to “blast” the air from the lung and “keep going, keep going, keep going” until the patient has fully exhaled. An unacceptable pause (e.g., 4-6 s) at TLC, delaying the start of exhalation, has been shown to be associated with reductions in FEV1 and peak expiratory flow (PEF).

1/21/2008 10:19:55 AM

Chapter 3 Pulmonary Physiologic Testing

Patients can be standing or sitting during the test, and this is recorded on the report. Sitting is generally preferred over standing for safety reasons because equivalent results are obtained in normal-weight individuals for either position. Obese subjects will frequently obtain a deeper inspiration in the standing position, resulting in higher expiratory volumes and flows (Miller et al, 2005b).2 It is important to use the same position for longitudinal studies.

Acceptability and Repeatability Criteria Clinicians using parameters derived from these maneuvers need to become familiar with acceptable quality control standards, particularly when one is faced with deciding whether to utilize results provided from unfamiliar laboratories. Examination of numerical data as well as the expiratory flow and volume curves is important to determine when an individual FVC measurement or trial has met the American Thoracic Society (ATS) and European Respiratory Society’s (ERS) acceptability criteria for adequate effort (Table 3-2) (Miller et al, 2005a).1 Large variability among maneuvers can be due to incomplete inhalation before the expiratory blow or submaximal or variable expiratory force and duration. In general, acceptable inspiratory and expiratory efforts are also reproducible. Ideally, both the FVL and V-t curve are reviewed when assessing test quality. The FVL graphs flow versus volume, resulting in relative expansion of the graphic data for the first second, whereas the V-t curve gives equal spacing for each second and allows better resolution of the events marking the end of the test. Coughing or glottic closure is more easily recognized on the FVL because the rapid transients of flow result in large up and down spikes in the curve (Fig. 3-3). Submaximal effort is recognized graphically on the FVL by a slow rise to the peak flow or by a rounding and broadening of the normal shape at the peak flow. Submaximal early effort, resulting in a slow upswing in the V-t curve, is

21

TABLE 3-2 2005 American Thoracic Society–European Respiratory Society Acceptability Criteria for Spirometry* Within Maneuver Smooth continuous curve (free from artifacts, e.g., cough in the first second, early termination or cutoff, effort that is not maximal throughout, leak) Good start of test (“blast” it out) Extrapolated volume <5% of FVC or 150 mL, whichever is larger No hesitant start; flow-volume curve with a sharp rise to peak flow Note: FEV1 can be over- or under-measured with submaximal effort Satisfactory end of test (“keep going, keep going”) Plateau of 1 second on volume-time curve (no further volume exhaled despite continued expiratory effort) —or— “Reasonable” duration of effort: ≥6 seconds in subjects >10 years ≥3 seconds in subjects <10 years “Exhalation times >15 seconds will rarely change clinical decisions” —or— Subject cannot or should not continue further exhalation Between Maneuver After three acceptable maneuvers, if the largest and second largest FEV1 and FVC values are within 150 mL of each other, the session is completed If not, continue spirometry until criteria are met; or a total of eight trials have been done; or the patient cannot or should not continue testing Final report FEV1 and FVC reported as the largest values from any acceptable trial “Best test” curve from trial with largest sum of FVC + FEV1 Other flow parameters from best test curve FEV1, volume exhaled in the first second; FVC, forced vital capacity. *Modified from Miller MR, Hankinson J, Brusasco V, et al: Standardisation of spirometry. Eur Respir J 26:319-338, 2005.

10.0 Sharp peak 8.0 Plateau 6.0 Continuous curve

4.0

Artifacts (glottic closure)

Rapid rise (blast)

4.0 Good start

Gradual return to 0 flow

0.0 –2.0

Slow rise

Abrupt end flow

Incomplete inhalation

Smooth inhalation

–4.0

Hesitant start

–0.0 0.0

1.0

2.0 3.0 Acceptable loop

4.0

4.0 Inadequate loop

FIGURE 3-3 Characteristics of an acceptable and technically inadequate flow-volume loop.

Ch003-F06861.indd 21

1/21/2008 10:19:56 AM

22

Section 1 Introduction

expressed quantitatively as extrapolated volume and often printed in the numerical section of the report. The ATS-ERS criteria for spirometry apply withinmaneuver acceptability criteria to individual FVC efforts (see Table 3-2). The spirometry standards have been met when three acceptable FVC efforts have been obtained, with the best and second best meeting between-maneuver acceptability criteria, also referred to as repeatiblilty (Miller et al, 2005a).1 The difference between the largest and second largest FEV1 or FVC ideally is less than or equal to 150 mL, and in patients with an FVC less than 1.0 L it is less than or equal to 100 mL. With the exceptions of maneuvers that contain a cough or glottic closure in the first second or excessive volume of extrapolation, the use of data from maneuvers with poor repeatability or that fail to meet end-of-test criteria is left to the discretion of the interpreter (Miller et al, 2005a).1

Final Report Data The report comments on the test quality, referring to the test components that were not reliable. A suboptimal test can be reported at the discretion of the interpreting physician in an appropriate clinical context as long as the report is specific in describing the likely direction and magnitude of errors (Miller et al, 2005a).1-3 For example, the FEV1 may be useful and can be reported from maneuvers with early termination of exhalation, as long as there is an acceptable start of exhalation and no cough in the first second (“usable” curves), although the confidence in these data would be lower than a better performed FVC that met all acceptability criteria (Miller et al, 2005a).1 The FEV1 and FVC that are reported are the largest values from any acceptable trial, not necessarily from the same maneuver. The “best test” curve comes from the trial with the largest sum of FVC + FEV1. Other flow parameters come from this same curve.

LUNG VOLUME MEASUREMENTS As discussed earlier, spirometry only measures the air exiting the lungs and thus does not allow assessment of air remaining after a full expiration, which is necessary to calculate residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC). Two separate methodologies used to quantitate these volumes—body plethysmography and gas dilution—are discussed.

Definitions The 2005 ATS-ERS standards on lung volumes employed the following definitions.4 A lung volume parameter is termed a volume if it cannot be broken down into smaller subcomponents (see Fig. 3-2): Tidal volume (VT or TV) is the volume of gas inhaled or exhaled during the respiratory cycle. Inspiratory reserve volume (IRV) is the maximum volume of gas that can be inhaled from the end-inspiratory level during tidal breathing. Residual volume (RV) refers to the volume of gas remaining in the lung after maximal exhalation (regardless of the lung volume at which exhalation was started).

Ch003-F06861.indd 22

Expiratory reserve volume (ERV) is the volume of gas that can be maximally exhaled from the end-expiratory level during tidal breathing (i.e., from the FRC). Lung volumes that are made up of the addition of multiple lung “volumes” are termed capacities: Functional residual capacity (FRC) is the volume of gas present in the lung at end-expiration during tidal breathing; thus, FRC = RV + ERV. Inspiratory capacity (IC) is the maximum volume of gas that can be inspired from FRC; thus, IC = VT + IRV. Vital capacity (VC) is the volume change at the mouth between the positions of full inspiration and complete expiration. It can be measured in one of three ways: VC = ERV + IC or VC = IRV + VT + ERV or VC = TLC − RV Total lung capacity (TLC) refers to the volume of gas in the lungs after maximal inspiration or the sum of all volume compartments: TLC = RV + ERV + VT + IRV or TLC = VC + RV or TLC = FRC + IC. Thoracic gas volume (TGV or VTG), a term that still appears on many pulmonary function reports, is the absolute volume of gas in the thorax at any point and a term often used in body plethysmography when measuring FRC. It is too nonspecific and is replaced with more specific terminology, such as FRC by body plethysmography or TGV at FRC (FRCpleth).

Body Plethysmography Plethysmographic techniques have become the gold standard for measurement of lung volumes. The patient sits in a large, air-tight, glass-enclosed box and breathes through a mouthpiece (Fig. 3-4). During the test an electronic shutter temporarily occludes the mouthpiece and the patient continues to “pant” against the closed shutter. FRC is chosen as the starting point because the chest wall is in a relaxed state and it thus tends to be a very reproducible value. During an inspiratory pant against the closed airway the chest expands slightly, creating a negative pressure swing at the alveolus that can be measured at the mouth. Plethysmographic technique assumes that mouth and alveolar pressures are equal, whereas there is no flow as the subject pants against a closed shutter. The test employs Boyle’s law, which states that the product of the pressure and the volume of a gas at a given temperature remains constant (P1 × V1 = P2 × V2). If the pant begins as the shutter is closed at FRC, then (Patm × FRC) = (Patm + ∆Pmouth) × (FRC + ∆V) where ∆Pmouth is the pressure swing at the mouth and ∆V is the volume change of the thorax. ∆V is determined by applying Boyle’s law for a second time whereby the pressure change in the air-tight box ∆Pbox is proportionate to the ∆V of the chest wall. Intuitively, an individual with a small amount of air left in the lungs at end-expiration (small FRC) will have a higher mouth pressure change, when panting against a closed shutter, for a given change in thoracic volume (reflected in ∆Pbox).

1/21/2008 10:19:56 AM

Chapter 3 Pulmonary Physiologic Testing

FIGURE 3-4 Body plethysmography.

Body Plethysmograph Method for Determination of FRC –

23

+

Mouth pressure (Pm) Change in mouth pressure (Pm) reflects change in alveolar pressure

Electrically controlled shutter, closed at end-expiration –

FRC

+

Box pressure (Pm) Change in box pressure (Pm) reflects change in lung volume

Patient makes panting efforts against closed shutter

In contrast, an individual with a large FRC will have a smaller mouth pressure change than a patient with a low FRC for a similar change in thoracic volume or ∆Pbox. Pitfalls in the measurement of lung volumes and its subcomponents related to improperly timed shutter closure are demonstrated in Figure 3-5.

Gas Dilution The helium dilution technique is a closed-circuit technique. A spirometer is filled with a mixture of helium and oxygen. The amount of helium in the spirometer (helium concentration (C1) × volume of spirometer [V1]) is known at the beginning of the test. As the patient exhales to FRC, a valve switches the patient into a closed circuit breathing from the spirometer. Because the breathing circuit is closed (assuming no leaks) the total volume of helium in the system remains constant during the test. By measurement of the final helium concentration in the circuit after the patient has equilibrated with the mixture (C2), FRC can be solved from the equation: (C1 × V1 = C2 × (V1 + FRC)). Nitrogen washout technique involves collection of exhaled gas as the lung is washed out with a 100% oxygen mixture. The total volume of nitrogen collected after complete washout is then in proportion to the FRC.

Ch003-F06861.indd 23

Technique and Specific Methodology In normal subjects, the same values for FRC and TLC will be obtained whether measured by gas dilution (He dilution or N2 wash-out), plethysmography, or planimetry (geometric) measurement from a chest posteroanterior and lateral radiograph. On the other hand, gas dilution and wash-out techniques will underestimate FRC (and therefore RV and TLC) in patients who have severe inequality of the distribution of ventilation, such as those with severe airways disease. Regions of lung with long-time constants (directly proportional to resistance and compliance) will equilibrate much more slowly than the length of a typical gas dilution test and so will not be “seen” by these techniques. Conversely, plethysmographic techniques measure all intrathoracic gas, whether it communicates with the airways or not. Bullae are an extreme example of this poorly communicating lung. This difference between plethysmographic and gas dilution measurements of lung volume may have independent clinical meaning as “trapped gas” and has been shown to decrease after lung volume reduction surgery. Recent data indicate that FRC (and therefore RV and TLC) can be inaccurately “overmeasured” using plethysmographic techniques in patients with severe airflow limitation. In these cases, severe airflow obstruction may result in phase

1/21/2008 10:19:56 AM

24

Section 1 Introduction

BODY PLETHYSMOGRAPHY TECHNIQUE TLC Shutter closure a

IC ERV

Mid-rest position RV True FRC

False high FRC by amount a

O FIGURE 3-5 Body plethysmography technique: box error. Linked FRC and SVC maneuver performed suboptimally. The SVC portion was well performed as demonstrated by the slowing of flow near full lung inflation and near full exhalation demonstrating full inspiratory effort and full expiratory effort. The quiet tidal breathing portion (left side of curve) did not settle down a stable end-expiratory baseline for establishing FRC. When the shutter closes in the body plethysmograph, the measurement of VLpleth (thoracic gas volume during body box) may be correct but the lack of a prior stable end-expiratory point to define FRC will also result in incorrect values for FRC, and also ERV and IC, which are referenced to the point of FRC. This will also result in incorrect values for TLC and RV, when derived from arithmetic use of FRC, IC, or ERV.

lag between alveolar and mouth pressures, resulting in slow to-and-fro flow during panting, such that mouth pressure lags behind alveolar pressure, resulting in a falsely high measurement of FRCpleth. Fortunately, this small error is in the direction that enhances the ability to recognize the underlying disease (i.e., the degree of hyperinflation is exaggerated). As discussed earlier, plethysmographic measurements are combined with measurements derived from a VC maneuver, from which IC and ERV are also measured. Combinations of the data from these two separate measurements are used to obtain the other lung volumes (see Fig. 3-2). The 2005 ATSERS standards have recommended that the preferred testing sequence is a linked measurement (patient remains on the mouthpiece in the box throughout the sequence) of FRC followed by ERV, followed by IVC.4 With this approach, FRC is reported as the mean of technically satisfactory measurements linked to the technically satisfactory ERV and IVC maneuvers used for calculating the RV and TLC. The reported value for RV is the reported FRC minus the mean of the technically acceptable ERV measurements, linked to technically acceptable FRC measurements. The reported TLC is the reported value for RV plus the largest of the technically acceptable IVCs. A second recommended method, although not the preferred approach, utilizes a separate IC maneuver immediately after the FRC measurement to measure TLC. This approach may be easier for some dyspneic patients. The TLC is determined as the mean of the three largest sums of technically acceptable FRC values and linked IC maneuvers. RV may be calculated as the mean TLC minus the largest VC measured.

Diffusing Capacity The single-breath DLCO measures the capacity of the lung to transfer gas, using the test gas carbon monoxide (CO). Known as the transfer factor (TLCO) in Europe, it is measured in

Ch003-F06861.indd 24

milliliters per minute per millimeter of mercury (mL/min/ mm Hg), thus it can be thought of as the flow rate (mL/min) of CO gas per millimeter of mercury of CO pressure gradient from alveolus to capillary blood. CO is so avidly bound to hemoglobin that, unlike oxygen, little back-pressure develops in the capillary to slow its transfer from alveolus to blood as a given volume of capillary blood makes its transit through the capillary bed. CO is diffusion limited rather than perfusion limited and is thus ideal for assessing the lung’s capacity to transfer gas. Consequently, its transfer is not dependent on cardiac output. It is dependent on the volume of the capillary bed exposed to alveolar surface and to the hemoglobin concentration because each increases the available mass of hemoglobin available for CO binding. The transfer of CO also depends on the properties of the alveolar-capillary interstitium (surface area and thickness). In addition, because little back-pressure of CO develops in the capillaries as a result of its transfer, the driving pressure for CO transfer can be measured from alveolar CO concentration alone without the measurement of blood CO (except in the tobacco user).

Technique and Specific Methodology The widely accepted technique used to measure DLCO, utilized in virtually all clinical laboratories, is the single-breath methodology, whereas historically, and still in research settings, other steady-state techniques are utilized. In the singlebreath method, the subject exhales to RV and then rapidly inhales a gas mixture containing a minute concentration of CO (commonly 0.3%) and an inert tracer gas (usually 10% helium or 0.3% methane), which is used to adjust for dilutional effects. After a 10-second breath-hold at TLC, the patient rapidly exhales and, after a 0.75- to 1.0-L discarded sample (to exclude dead space collection), the exhaled gas (reflecting an alveolar sample) is collected and analyzed. Measurement of the initial (inspired) and final concentration

1/21/2008 10:19:56 AM

Chapter 3 Pulmonary Physiologic Testing

(exhaled) of CO adjusted for gas dilution and breath-hold time determines DLCO.

OTHER PULMONARY FUNCTION TESTS

Acceptability, Repeatability, and Number of Tests

To test maximal voluntary ventilation (MVV) the patient is instructed to breathe in and out as rapidly as possible for 12 seconds. The result is extrapolated to 1 minute and is expressed in liters per minute. Disadvantages of this test are that results depend on motivation, and it is tiring for patients. In the past the MVV was recommended to assess respiratory muscle weakness; however, in general it has no advantages over VC. MVV remains a common tool used in assisting the interpretation of ventilatory reserve during CPET. In subjects who achieve a ventilatory limitation, such as patients with severe chronic obstructive pulmonary disease (COPD) or respiratory muscle weakness, maximal exercise ventilation (VEmax) often approaches or exceeds MVV (VEmax/MVV > 0.75). MVV is commonly estimated from simple spirometric measures (40 × FEV1).

Acceptable maneuvers have an inspired volume (VI) greater than 85% of largest measured VC in less than 4 seconds; a breath-hold of 10 ± 2 seconds without Valsalva or Mueller maneuvers; expiration in less than 4 seconds (and sample collection less than 3 seconds); and graphic evidence that dead space has been cleared and an accurate alveolar sample has been obtained.5 Repeatability is within 3 mL/min/mm Hg or within 10% of the highest value. The mean of at least two acceptable tests that meet this repeatability requirement is reported. No more than five tests are performed because the resultant elevated carboxyhemoglobin (COHb) will affect the measurements.

Hemoglobin and Carboxyhemoglobin Adjustments of Measured DLCO Be wary of DLCO values that are reported without adjustment for hemoglobin. Patients with anemia have a lower measured DLCO, and patients with erythrocytosis have an elevated DLCO. Report the measured DLCO and “adjusted” or “corrected” DLCO, but base interpretation and trending on the adjusted values. The absolute adjustment, and the adjustment per gram per deciliter of hemoglobin deviation from normal (14.6 g/dL for men and 13.4 for women) increases with increasing anemia. When standard formulas are used, a hemoglobin concentration of 12 results in an 8% adjustment in the measured value; a hemoglobin of 10, an 18% adjustment; and a hemoglobin of 7, a 45% adjustment (ATS, 1995).5,6 Patients are instructed not to use tobacco before testing to minimize the effect of elevated capillary CO resulting in a lower measured DLCO. Although the ATS statement considers it optional, an acceptable adjustment of 1% of the measured DLCO per %COHb is appropriate. No adjustment is required for COHb under 2% because reference equations already account for this.5 It is not uncommon for a smoker who does not comply with instructions to abstain from tobacco use before testing to have a COHb of 5% to 10%.

Diffusing Capacity per Unit Lung Volume It is commonly incorrectly inferred that a normal DLCO per unit lung volume (DLCO/VA) rules out an intrinsic lung problem even when unadjusted DLCO is decreased. In patients with restrictive defects on PFTs and a low DLCO, a low DLCO/VA does, in fact, suggest parenchymal lung disease (e.g., interstitial lung disease, emphysema, or pulmonary vascular disease). In general, normal or high values for DLCO/VA occur in patients with an extrapulmonary cause of restriction, such as chest wall (obesity, kyphoscoliosis), pleural, or neuromuscular diseases. On the other hand, a normal DLCO/VA does not rule out interstitial lung disease. It is more useful to think of the DLCO/VA as a ratio that discriminates the presence of matched defects in mechanics and gas exchange (normal DLCO/VA) from discordant defects resulting in disproportionately greater abnormality in gas exchange (low DLCO/VA).7

Ch003-F06861.indd 25

25

Maximal Voluntary Ventilation

Maximal Respiratory Pressures The most specific tests to identify neuromuscular weakness as the cause of restriction are the maximal inspiratory pressure (MIP) and the maximal expiratory pressure (MEP). These parameters are also referred to as inspiratory pressure maximum (PImax) and expiratory pressure maximum (PEmax). The MIP assesses the lowest pressure a patient can sustain for 1 to 2 seconds when inhaling from an occluded mouthpiece connected to a manometer (Mueller maneuver). The most negative pressure is obtained when the test is performed at or near RV because the diaphragm is at its longest precontraction length, the optimal position for force generation. Conversely, the MEP is measured as an expiratory effort (Valsalva maneuver) after inhaling to or near TLC. Although simple tests, they are very effort dependent (patient and tester). A small leak is introduced to eliminate glottic and buccal occlusion and inadvertent measure of mouth pressures rather than intrathoracic pressures. Because of a learning curve, several trials are needed and careful instruction and encouragement are required. The reported value is the largest value that is reproducible and sustained for 1 second. The maximal value of three maneuvers that vary less than 20% is reported. Because they are very effortdependent tests, the MIP and MEP are better at ruling out respiratory muscle weakness than making a diagnosis. A low result may be due to lack of full effort. The lower limit of normal for MIP measured at RV is 75 cm H2O in men and 50 cm H2O in women. The lower limit of normal for MEP measured at TLC is 100 cm H2O in men and 80 cm H2O in women. A normal MEP with a low MIP suggests isolated diaphragmatic weakness. MIP can be decreased in emphysema associated with lung hyperinflation and suboptimal respiratory muscle configurations. In this setting the low inspiratory pressures are independent of intrinsic muscle weakness. As such, measurements of MIP have been shown to improve after lung volume reduction surgery in concert with improvements in resting lung hyperinflation.

1/21/2008 10:19:57 AM

26

Section 1 Introduction

Lung Compliance Although not a routine test in most laboratories, a more direct way of distinguishing parenchymal lung disease from chest wall disorders as a cause of restriction or low DLCO is to measure lung compliance. These measurements require placement of esophageal (balloon) catheters to measure esophageal pressure, which reflects pleural pressure across a compliant esophagus. Patients are asked to relax against a closed shutter attached to a manometer that measures mouth pressure at various lung volumes. The difference between mouth and esophageal pressure represents the elastic recoil pressure of the lung, abbreviated PEL(L). Figure 3-6 represents typical volume-pressure curves in diseases associated with decreased compliance (∆V/∆P), such as pulmonary fibrosis (right shift), normal compliance as is also present in chest wall abnormalities, and increased compliance such as with emphysema (left shift). PEL(L) at TLC, also represented as the ratio of PEL(L)/TLC and termed coefficient of retraction, is a useful representative parameter derived during this testing. Interstitial lung disease will have a high PEL(L) at TLC and high PEL(L)/TLC, whereas chest wall restriction will present as a low PEL(L) but a normal PEL(L)/TLC. This low PEL(L) in chest wall restriction (e.g., due to pleural restriction, kyphoscoliosis, neuromuscular weakness) is due to underexpansion of a normal lung, held to low lung volumes by the extrapulmonary process. By contrast, the very low PEL(L) at TLC resulting in low PEL(L)/TLC seen in emphysema is a reflection of the intrinsic loss of elasticity. The normal range for PEL(L)/TLC is 2 to 8 cm H2O/L.

CARDIOPULMONARY EXERCISE TESTING Parameters traditionally considered to be the gold standards of cardiopulmonary function such as FEV1 and cardiac ejection fraction often correlate poorly with symptoms or exercise capacity, and changes in these resting parameters after an intervention often do not reflect functional improve-

ments.8,9 Exercise testing not only delineates the reserve of each of the contributing subcomponents of the process of respiration but also allows us to integrate the effects of myriad measurable and unmeasurable system subcomponents to assess functional status through measurements of maximal power output and oxygen consumption (ATS, 2003).10

Assessment of Maximal Exercise Capacity In normal individuals and patients with cardiac abnormalities, exercise termination occurs at the maximal oxygen consumption (VO2max) due to overwhelming symptoms associated with metabolic demands at the limits of oxygen delivery and muscle oxidative capacity. Oxygen consumption is commonly represented through the Fick equation: VO2 = cardiac output × (A − V)O2 diff

Another way of representing this value allows better recognition of the physiologic components that contribute to maximal oxygen delivery and oxygen extraction. VO2max = heart rate(max) × stroke volume(max) × 1.34 × Hgb × SaO2 × muscle extraction rate(max)

where (A − V)O2 is the arteriovenous oxygen gradient, SaO2 is the arterial oxygen saturation, and Hgb is hemoblobin; “max” implies the parameter is at its maximal physiologic capacity. The maximal values for each of these parameters depend on genetics, the level of conditioning, and the presence of disease. At rest, humans are capable of maintaining homeostasis under all but the most severe internal disease conditions or in the most extremes of physical environments, but abnormal reserves in any of the above physiologic attributes will commonly be exposed during exertion when the increased metabolic demands delineate the limits to the response. VO2max is reported as a percentage of predicted normal or adjusted simply for weight in milliliters per kilogram per minute.

5

Heart Rate Response to Exertion Emphysema

Volume (L)

4

Although there is considerable variability in the heart rate response to exertion in normal individuals, heart rate normally has a predictable slope relative to the increase in oxygen consumption (see Fig. 3-13A). At maximal exertion the normal heart rate response can be estimated simply as (220 − age in years).

Normal

3 Fibrosis 2

Ventilatory Response During Exercise

. Increases in minute ventilation (VE) during exertion are necessary to maintain systemic blood gas and acid-base homeostasis. The formula describing the effect of changes in various factors on minute ventilation requirements is:

1

0 0

10 20 30 Distending pressure (cm H2O)

40

FIGURE 3-6 Static pressure-volume curves for patients with normal lungs, pulmonary fibrosis, and emphysema. Compliance represents the slope of the pressure-volume curve. (ADAPTED FROM MURRAY JF: THE NORMAL LUNG, 2ND ED. PHILADELPHIA, WB SAUNDERS, 1986, P 87.)

Ch003-F06861.indd 26

. VE = 0.86 × VCO2/(PaCO2 × [1 − VD/VT])

The level of minute ventilation required will depend on the central set point for PaCO2, which is influenced by central drive, vagal afferents, and humoral input (including pH and PaO2), the CO2 production, and the dead space proportion.

1/21/2008 10:19:57 AM

Chapter 3 Pulmonary Physiologic Testing

. Therefore, the rate of increase in VE is positively correlated with the level of exertional metabolism or carbon dioxide production (VCO2); inversely related to the arterial partial pressure of carbon dioxide central set point (PaCO2); and inversely associated with the proportion of tidal volume (VT) consisting of dead space (VD) identified as the ratio VD/VT. Lactic acidosis associated with increasing exertion .in both normal and cardiac-impaired individuals can drive VE both by increasing CO2 production associated with bicarbonate buffering and through direct effects on carotid body and central chemoreceptors. VD/VT abnormalities are associated with most pulmonary parenchymal and vascular disease processes due to regions of excessive ventilation-perfusion ratio. Whereas absolute dead space rises normally during exertion, the VD/VT falls from 0.35 at rest to less than 0.20 at maximal exertion. An arterial blood sample is necessary to accurately calculate the dead space proportion using the equation: VD/VT = (PaCO2 − PECO2)/PaCO2

where PECO2 represents the mixed expired CO2 concentration. . Maximal values of VE achieved during exertion are normally less than 75% of a normal individual’s ventilatory capacity or MVV (Fig. 3-7); thus, ventilatory capacity is almost never the . cause of exercise limitation in a normal individual. The VE is commonly compared. with the MVV to assess the ventilatory reserve, expressing VE as a percentage . of MVV. A VE/MVV of greater than 80% is supportive of ventilatory mechanical limitations to exertion, in contrast to the usual oxygen delivery/utilization mechanism for exercise limitation described earlier in normal and cardiac patients.

Exercise Inspiratory Capacity and End-Expiratory Lung Volume The end-expiratory lung volume (EELV) in normal individuals decreases with exertion, but COPD patients experience dynamic hyperinflation during exertion due to an

Normal

27

inability to increase expiratory flow as expiratory time decreases and is characterized by increases in their EELV, resulting in further impingement on their IC (Fig. 3-8). This measure has been found to be a sensitive indicator of early disease, and dyspnea has been found to correlate closely with measurements of exercise EELV. The maneuver is based on the validated assumption that TLC, measured at rest, does not change during exertion. Multiple IC maneuvers can then be performed throughout exertion, and EELV is then calculated as the difference between TLC and IC. Improvement in dynamic hyperinflation has been documented after bronchodilator therapy and lung volume reduction surgery.

Impact of Exercise Protocol on Outcome It is important for laboratories performing exercise studies to understand the impact of variations in exercise protocol on exercise-derived indices. Incremental bicycle studies involve stepwise or ramped increases in workload (watts) until symptom limitation occurs. The protocol often involves a period of pedaling with no added workload followed by incrementation at a predefined workload per minute. Treadmill studies can involve incrementation using any number of speed and grade combinations. Treadmill exercise protocols result in maximal oxygen consumption values approximately 10% higher than those achieved using cycle ergometry. Protocol durations that are too short or too long may affect maximal achieved values as well. Maximal exercise power output (watts) during incremental bicycle testing can vary dramatically with other seemingly subtle changes in exercise protocol. For example, the exercise protocol defined by the National Emphysema Treatment Trial (NETT) to stratify patients into high and low exercise categories (cutoff 25 W for women and 40 W for men) in assessing candidacy for lung volume reduction surgery is very specifically defined as using 3 minutes of unloaded pedaling followed by a 5 W/ min ramp if the resting MVV is less than 40 L/min and a 10 W/min ramp if MVV is greater than or equal to 40 L/ min (NETT, 1999).11,12

COPD With Ventilatory Limitation

FIGURE 3-7 Ventilatory limit.

(MVV)

·

·

VE

VE

Ventilatory reserve (MVV)

Work Rate or VCO2

·

Work Rate or VCO2

Ch003-F06861.indd 27

Alveolar ventilation

VE = Minute ventilation

Dead space

MVV = Maximal voluntary ventilation

1/21/2008 10:19:57 AM

28

Section 1 Introduction

HEALTHY NORMAL 6 5

Predicted Rest Exercise

4

6 4

2

Flow (L/s)

Flow (L/s)

3

1 0

FIGURE 3-8 Left, Tidal flow volume loops at rest and with exertion (small loops) superimposed on the maximal flow volume loop. Note IC increases during normal exertion. Right, The dynamic hyperinflation during exercise in patients with COPD.

COPD PATIENT 8

TLC

2 0

RV

–1

–2

–2 –4 –3 –4

–6 5

4 3 Volume (L)

2

7

6

5 4 Volume (L)

rest IC

exercise

Safety Issues Standard safety criteria for exercise termination that have been reported include the following13: ■ ■ ■ ■

■ ■ ■ ■ ■ ■ ■

Chest pain suggestive of angina Evolving mental confusion or lack of coordination Evolving lightheadedness Electrocardiographic evidence of ischemia or serious arrhythmia or conduction system abnormality (evolving complex ventricular ectopy, sustained supraventricular tachyarrhythmia, new left bundle branch block, secondor third-degree heart block) Systolic blood pressure greater than 250 mm Hg Diastolic blood pressure greater than 120 mm Hg Fall in systolic blood pressure greater than 20 mm Hg Chronotropic insufficiency in absence of β blockers Saturation of oxygen (SpO2) less than 80% Cadence cannot be sustained above 40 rpm Subject requests to stop despite encouragement owing to symptoms of dyspnea or leg or global fatigue or otherwise

After a maximal exercise maneuver it is essential that the patient continue to pedal with unloaded or low resistance on the bicycle to maintain venous return, particularly in patients with primary or secondary pulmonary hypertension who are particularly prone to postexercise hypotension and syncope. A rule in our laboratory is that you are either pedaling or you are rapidly assisted off the bicycle into a reclining chair with a capability for leg elevation if necessary.

INTERPRETATION Normal Reference Values Once a test has been reviewed for quality, the next step is to decide if individual test parameters fall within or outside

Ch003-F06861.indd 28

3

2

rest IC

exercise

the normal range. This step involves comparison of results to reference values derived in healthy subjects (“normal” values), a difficult problem in the interpretation of PFTs (Miller et al, 2005a; 2005b).1-3,14,15 Unlike blood pH, which has a narrow range of normal, PFT parameters vary greatly in normal people and are, in part, dependent on anthropometric values such as height, age, gender, and racial and ethnic background. It is best to use a reference equation derived from subjects with anthropometric values and ethnic and racial background that matches the patient being tested. Height and weight are measured at the time of testing (shoes removed), not reported by the patient. The reference values used are stated in the PFT report, citing the author’s last name (or organization) and year of publication.3 Because subjects of extreme height or age are more sparsely represented in the published reference cohorts, normal values in this range may be particularly suspect; and a statement needs to be included in the interpretation stating so. The significant variation in published normal prediction equations is generally underappreciated, particularly with respect to measures of lung volume and DLCO.16 The lack of attention to the specific normal reference equation can be particularly problematic with respect to cross-center validity in predicting outcome or perioperative risk. For example, the NETT determined that a DLCO of less than 20% predicted in the setting of an FEV1 less than 20% of predicted using Crapo normal equations determined a patient at excessively high risk for lung volume reduction surgery. Use of normal reference values other than Crapo’s set may result in significantly different values that may have different implications with respect to risk. For example, a 5-foot, 9-inch 50-yearold man undergoing preoperative assessment for lung volume reduction surgery who had a measured DLCO of 6.3 mL/min/ mm Hg would have a value calculated as 18% of predicted using Crapo’s normal value (35.0 mL/min/mm Hg) for an

1/21/2008 10:19:57 AM

Chapter 3 Pulmonary Physiologic Testing

individual of similar age, height and weight, suggesting a potentially excessive risk. On the other hand, false reassurance would be achieved using Miller’s (30.5 mL/min/mm Hg) or Burrow’s (24.5 mL/min/mm Hg) published equations, resulting in the value reported at 21% and 24% predicted, respectively. Similar attention also needs to be paid to specific normal equations cited when translating prognostic results from literature defining risk assessment in other potentially high-risk populations.

Determination of “Normal” Range The time-honored approach has been to consider a fixed percentage above and below a predicted value to be the normal range. In general, 80% to 120% of predicted has been the standard used for FVC and FEV1, although wider ranges are commonly used for other parameters (Table 3-3). This approach, although much more easily applied in a basic interpretation scheme, has been criticized as being statistically unsound.14 Recent guidelines suggest the assessment of the confidence interval describing a range between the 5th and 95th percentiles of the reference population as being within the “normal range.”3 The time-honored approach, of using percent of predicted for determining the normal range, most approximates the results using the confidence interval approach in middle-aged individuals of typical height. However, even adhering to the statistically more sound confidence interval approach to interpretation in patients at the extremes of height or age, available normal reference values may be unreliable because such individuals may not be well represented in the population from which the prediction equation was derived. Regardless of the approach, test parameters in patients with mild disease are likely to overlap the values found in

TABLE 3-3 Normal Predicted Ranges of Selected Pulmonary Function Variables, as Percentage of Predicted* Parameter

Normal Range, % Predicted

FEV1

80-120

FVC

80-120

FEV1/FVC

>0.70†

FEF25-75%

>65 of predicted or FEF25-75%/FVC >0.66

TLC

80-120

FRC

75-120

RV

75-120

DLCO

75-120

*Upper and lower limits are approximate; lower and upper fifth percentile or 95% confidence intervals for these variables are primarily used for deciding if a parameter is outside the normal range, with only a secondary role for percent of predicted. † Note: absolute ratio of 0.70 not 70% of predicted ratio. The use of a fixed ratio for the lower limit is less useful than one which is based on age, height, and sex. DLCO, diffusing capacity; FEF, forced expiratory flow; FEV1, volume exhaled in the first second; FVC, forced vital capacity; FRC, functional residual capacity; RV, residual volume; TLC, total lung capacity.

Ch003-F06861.indd 29

29

normal individuals. Thus, clinical context is necessary when interpreting values near the low or high range of normal. It is appropriate under these circumstances to express the uncertainty in the report, consider ordering additional tests (e.g., lung volumes or bronchoprovocation for borderline obstructive cases), or start empirical therapy with serial PFT assessment.

Ethnic and Racial Differences in Normal Values Subjects being tested need to identify their own race or ethnic group. Studies in populations of African or Asian ancestry find lower predicted values for a given age or height compared with equations derived in populations of European ancestry (resulting in a given African or Asian measurement being reported as a higher percentage of predicted when using these race-specific reference equations compared with use of unadjusted European ancestry–derived equations).3,15,17 On average, factors accounting for such differences appear to be related to shorter torsos for a given height, but socioeconomic factors and body mass index may contribute. To avoid these errors, race- and ethnic-specific reference equations are used whenever possible and indicated in the report.3 Spirometric reference values from the National Health and Nutrition Examination Survey (NHANES III),18 the recommended reference set of the 2005 ATS-ERS guidelines for interpretation of PFTs, provide different reference equations for male and female Americans of European-American, AfricanAmerican, and Mexican-American populations. An alternative to race-specific equations is to use adjustments to the most widely used prediction equations derived in populations of European ancestry. When using prediction equations from a European ancestry population, the following adjustments can be made for patients of African ancestry: FEV1, FVC, and TLC, 12% lower; FRC and RV, 7% lower; FEV1/FVC, no change; DLCO, 2 mL/min/mm Hg or 7% lower.3,4,14 Individuals of mixed racial ancestry have intermediate values. A race and ethnic adjustment factor of 6% for Asian Americans has been suggested.17,19 These adjustments may not be appropriate for those of Asian ancestry raised in the United States on “Western” diets.

Height Assessment in the Setting of Spinal Deformity or Leg Amputation With spinal deformities such as kyphoscoliosis, or in the setting of leg amputation, arm span from fingertip to fingertip measured with the subject standing against a wall can be used as an estimate of height. Although ratios such as height = arm span/1.06 perform reasonably well, there are more accurate regression equations using arm span, race, sex, and age (Miller et al, 2005b).2,20 The use of knee height is an option for those who cannot stand.2,21,22

Age and PFT Values The lung grows throughout childhood, and PFT parameters increase in parallel, reaching a peak in late adolescence or in the third decade of life. Female subjects attain peak PFT values earlier than male subjects, but these are numerically smaller even when adjusted for height. After the peak, most

1/21/2008 10:19:58 AM

30

Section 1 Introduction

test values decline steadily with age. The exception is RV, which increases with aging. As RV increases and VC decreases, TLC remains relatively constant. The FEV1/FVC ratio declines with age, being highest in young children and decreasing through adolescence and beyond as lung elastic recoil declines.

Patterns of Abnormality Figure 3-9 offers a simplified algorithm for classifying PFT patterns derived from the 2005 ATS-ERS standards.3

Obstructive Pattern The distinction between obstruction and restriction is based on the FEV1/FVC ratio (or the FEV1/VC ratio) (Figs. 3-1 and 3-10). In the 2005 ATS-ERS standards for interpretation

FEV1/VC ≥ LLN

Yes

No

VC ≥ LLN

VC ≥ LLN

Yes

No

No Yes

TLC ≥ LLN

Yes

TLC ≥ LLN

No

Yes

Normal

Restriction

DLCO ≥ LLN

DLCO ≥ LLN

Yes

No PV disorders

Normal

Yes

Obstruction

No

CW and NM disorders

No

ILD pneumonitis

Mixed defect

DLCO ≥ LLN Yes

No

Asthma CB

Emphysema

FIGURE 3-9 Interpretation chart. Simplified algorithm for interpretation of pulmonary function tests in clinical practice. It presents classic patterns for various pulmonary disorders. Many factors may cause an individual patient’s studies to fail to conform to this scheme. LLN, lower limits of normal; PV, pulmonary vascular disease; CW, chest wall; NM, neuromuscular; ILD, interstitial lung disease; CB, chronic bronchitis. (FROM PELLEGRINO R, ET AL: INTERPRETATIVE STRATEGIES FOR LUNG FUNCTION TESTS. EUR RESPIR J 26:948-68, 2005.)

of pulmonary function tests, an obstructive defect is defined by an FEV1/VC ratio below the 5th percentile of the predicted value.3 The three ethnic-racial NHANES III equations include an explicit formula for the lower limit of normal for FEV1/FVC.3 Using this method, a normal ratio will be age dependent because the FEV1/FVC ratio declines with age. The VC is defined as the largest recorded from an IVC, EVC, or FVC maneuver. The FVC may be less than the SVC in patients with obstructive dysfunction because the forced maneuver causes dynamic compression of the airways and premature closure during expiration. For this reason, some areas of Western Europe have used the Tiffeneau index (FEV1/inspiratory VC) as the preferred marker for airflow obstruction. Other guidelines have chosen to define obstruction based on values below an absolute ratio. The National Institutes of Health/World Health Organization GOLD Guidelines for COPD management recommends using a ratio below 0.70 for the diagnosis of COPD, citing the simplicity of this approach and the lack of an internationally accepted set of reference equations.23 The second National Asthma Education Program Guidelines (1997)24 sponsored by the National Institutes of Health recommends the use of 0.65 as the lower limit of normal for FEV1/FVC. The 2005 ATS-ERS discourages the use of a fixed FEV1/FVC ratio to define the lower limit of normal, citing a high rate of “false positive” diagnoses of obstructive defects in older patients.3 On the other hand, an argument can be made using the analogy that the presence of a decreased FEV1/FVC in 80-year-olds is no less reflective of age-related “disease” than the common presence of coronary artery plaques in this population. Caution is needed when a reduced FEV1/FVC ratio is found in a patient with an FEV1 in the normal range. In this situation, particularly when the FEV1 is above 100% of predicted, the low ratio may be a normal variant.3,15 In these cases, the lung volume measurements can be helpful in identifying the presence of hyperinflation associated with obstructive patterns. Recently, the forced expiratory volume in 6 seconds (FEV6) has been proposed as an acceptable surrogate to the FVC for

6

6

5

5 Flow (L/second)

c Volume (L)

4 c 3 b 2

4 3

b

2

a 1

1

1

A

2

3 4 5 Time (seconds)

6

7

8

a

1

B

2

3

4 5 Volume (L)

6

7

8

FIGURE 3-10 Volume-time curves (A) and flow-volume curves (B) in normal (c), obstructed (a), and restricted (b) ventilation.

Ch003-F06861.indd 30

1/21/2008 10:19:58 AM

Chapter 3 Pulmonary Physiologic Testing

the assessment of airflow obstruction because serial measurements of FVC requiring repeated forceful exhalations to RV can be difficult and time consuming to obtain. The ATS-ERS guidelines have suggested that 6 seconds is a minimum criterion for acceptable exhalation duration (Miller et al, 2005a).1 The NHANES III reference equations have provided predicted values for FEV6 and FEV1/FEV6 in addition to FVC and FEV1/FVC.4 One study has found the sensitivity of FEV1/FEV6 for diagnosing airway obstruction defined by FEV1/FVC was 95.0% and the specificity was 97.4%.25 When interpretations differed, the measured values were near the lower limits of the reference range. Potential advantages of the FEV6 include better reproducibility than the FVC, more explicit definition of the end of test point, and less physical demand on the subject.

Restrictive Pattern A restrictive ventilatory defect is defined as a reduction in TLC below the 5th percentile of the predicted value, accompanied by a normal FEV1/VC. A restrictive defect may be suspected when spirometry shows a decreased VC, the FEV1/VC is increased (>85%-90%), and the flow-volume curve shows a convex pattern.3 A normal or elevated FEV1/ FVC ratio with a low FEV1 or FVC suggests “restriction,” although lung volumes are needed to confirm true restrictive dysfunction. This is recommended because some with this spirometric pattern have underlying obstructive lung disease.3,14,26,27 This “pseudorestriction” in patients with asthma or COPD is recognized by hyperinflation on lung volume testing or bronchodilator responsiveness of the “restriction.” By contrast, those with true restriction have reduced lung volumes (TLC, and often also RV and FRC). As such, VC is very sensitive for restriction but less specific.26 When examining spirometric results, the likelihood of true restriction increases as FVC decreases and FEV1/FVC increases.26 A normal VC is very good at ruling out restriction.

Mixed Obstructive and Restrictive Defects This pattern is defined by the coexistence of both an FEV1/ VC and TLC below the 5th percentile of their predicted values. Both obstructive and restrictive diseases can result in a reduction in VC; therefore, restriction is not diagnosed from spirometry alone without measurement of full lung volumes, including TLC.

Use of Other Flow Parameters in Classification of Patterns The just-stated approach to classification into normal versus obstructive versus restrictive versus mixed defect uses only the parameters VC (or FVC), FEV1, FEV1/VC, and TLC.3 In general, other flow parameters reflecting flows at low lung volumes, such as FEF25-75%, FEF50%, and FEF75% have wide ranges of normal and are misleading for classifying a patient as having abnormal or obstructive function on the basis of these parameters alone.3 It is acceptable to classify isolated defects in FEF25-75% (<65% predicted) as “minimal airflow obstruction” in a subject with normal or borderline low values

Ch003-F06861.indd 31

31

of FEV1/VC and FEV1.3 It is no longer unacceptable, however, to use FEF25-75% as an indicator of “small airways disease” because this parameter can be affected by any pathologic process resulting in airflow obstruction. In the setting of upper airway obstruction, typically the FEV1, FVC, and VC are normal but peak expiratory flow (PEF) may be reduced. Some specific measurements are helpful in identifying upper airway obstruction (UAO). These include an FEF50%/FIF50% (forced inspiratory flow at 50% of FVC) ratio greater than 1 in the diagnosis of extrathoracic UAO (normally the mid-inspiratory flow is higher than the mid-expiratory flow) and a PEF/FEV1 ratio less than 8 in intrathoracic UAO and fixed UAO. However, assessing the overall shape of the FVL (see later) is currently the best method to identify these disorders.

Use of Flow-Volume Loops Although visual appearance of FVLs often provides interesting academic insights into the subpatterns of disease presentation, their clinical utility beyond quantitative spirometric assessment is largely unproven beyond their value in quality assessment described earlier (see Fig. 3-3) and in the assessment of patterns of upper airway obstruction (Figs. 3-11 and 3-12) Although uncommon, a high index of suspicion must be maintained for the FVL patterns seen in UAO, defined as obstruction in airflow in regions originating from the hypopharynx to the tracheal bifurcation at the main carina. The range of mechanisms associated with patterns of UAO includes extrinsic compression (e.g., goiter or mediastinal masses), intrinsic structural narrowing (e.g., tracheal stenosis or tumor), and functional disorders of airway tone (e.g., vocal cord dysfunction syndrome or functional stridor). In contrast to obstructive diseases of the lower airways such as asthma or COPD, which demonstrate a characteristic “scooped upward” concavity (National Asthma Education, 1997),22-26,28 UAO causes a distinct flattening of the inspiratory and/or expiratory limb of the FVL. When the obstruction is “fixed,” both inspiratory and expiratory limbs have a plateau-like flattening. Neck position can affect the observed pattern and severity of UAO with thyroid enlargement. Neck flexion worsens UAO as the thyroid slides into the root of the neck/upper thorax (“thyroid cork” effect), whereas neck extension reduces the degree of airflow obstruction. Other upper airway lesions are “variable” in severity as transmural pressures across the airway vary from inspiration to expiration. When the obstruction is above the suprasternal notch (variable extrathoracic UAO), these lesions demonstrate flattened inspiratory limbs but relatively normal expiratory loops as the negative intraluminal pressure during inspiration accentuates the narrowing (see Fig. 3-11). Thyroid masses without retrosternal extension may show a typical variable extrathoracic UAO pattern. When the UAO is within the thoracic cavity, below the suprasternal notch (variable intrathoracic UAO), the obstruction worsens on expiration because of compressive transmural forces, whereas the negative extraluminal pressures associ-

1/21/2008 10:19:58 AM

32

Section 1 Introduction

identified in patients with neuromuscular disease (due to weak upper airway muscles, particularly in extrapyramidal disorders). The fluttering is likely due to vibration of redundant or hypotonic tissues in the upper airway or is caused by resonance generated downstream from a narrowed section of airway. Expiratory flow limitation during tidal breathing is a marker of severe obstructive or restrictive defects. Such a pattern is recognized when a tidal breathing loop, viewed within the maximal effort FVL, manifests as tidal expiratory flow impinging on the maximal expiratory flow curve.

14 12 10 Flow (L/s)

8 6 4 2

–2 –4

Rating of Severity

–6

1

2

A Expiration

Ptr > Patm

3

4 5 6 Volume (L)

7

8

9

Inspiration

Ptr < Patm

B FIGURE 3-11 A, Variable extrathoracic UAO caused by vocal cord dysfunction syndrome is evident on this flow-volume loop. The inspiratory limb of the loop shows flattening and flow rates much below the expiratory limb. This functional disorder of vocal cord adduction is also known as functional stridor, factitious asthma, or laryngeal dyskinesia. Some patients have concomitant asthma, but when vocal cord dysfunction is an asthma mimic only inspiratory stridor is present. The flow-volume loop or laryngoscopy establishes the diagnosis. B, Variable extrathoracic UAO. During expiration, the transmural pressure gradient acting across the tracheal wall distends the airway, lessening the obstruction to airflow. On inspiration, the transmural gradient causes critical narrowing and a flow plateau develops. (FROM CLIN CHEST MED 1994; 15:35-53, 1994; ADAPTED FROM AM J MED 61:85, 1976.)

ated with inspiration result in more normal-appearing inspiratory loops (see Fig. 3-12). Because diseases causing UAO patterns are uncommon, many suggestive loops will be due to poor effort or can represent a normal variant. Such poor effort is generally associated with lack of repeatability, whereas true abnormalities are repeatable. High-frequency “flutter” waves (“sawtoothing”) are sometimes superimposed on otherwise normal FVLs in patients with upper airway pathology. This was first reported in patients with obstructive sleep apnea and initially was thought to be specific to that condition. Subsequently, it was also

Once the pattern of abnormalities is defined (obstruction versus restriction), the severity is rated. The 2005 ATS-ERS standards for interpretive strategies for lung function tests outline a rating of severity based on FEV1% predicted for both obstructive and restrictive defects (Table 3-4).3 In general, because VC is reduced proportionate to severity in restrictive defects, FEV1 is appropriate to rate the severity in a similar manner. The GOLD Guidelines for COPD23 introduced a combined severity rating system for educational purposes that differs from the system described earlier by being much more liberal in their ratings of severity. Although commonly employed in clinical practice, such a system is not recommended in the laboratory interpretation of PFTs. The DLCO has an important independent role in assessing severity in both emphysema and interstitial lung disease (see Table 3-4). Recently, many researchers have suggested that physiologic measures of hyperinflation (RV, TLC) or its indirect effects (reduced IC or increased IC/TLC) are independently associated with symptoms and may further complement other physiologic measures in assessing severity in COPD, although specific categories based on these parameters have not been described.

Bronchodilator Response ATS-ERS criteria for defining bronchodilator response considers a significant intra-session bronchodilator response to be an increase from baseline FEV1 or FVC greater than 12% and 200 mL.3 Testing is performed before and 10 to 15 minutes after use of a rapid-onset bronchodilator (typically albuterol), delivered as four puffs via a spacer device (Miller et al, 2005a).1,3 When bronchodilator responsiveness is to be assessed, short-acting bronchodilators are stopped for 4 hours and long-acting bronchodilators stopped for 12 to 24 hours before the testing session. If testing is performed to assess the patient’s maintenance medical regimen, bronchodilators are not withheld. Typically, measurement of DLCO, if ordered, will be performed during the 15-minute window after βagonist administration because results are generally not affected by the bronchodilator (Miller et al, 2005b).2,3 Bronchodilator reversibility has some clinical utility in determining lability of lung function and confirming the presence of a fixed obstructive impairment. This testing, however, is neither highly sensitive nor specific in distinguishing asthma from COPD, does not represent a fixed characteristic in an individual patient (because reversibility status commonly

tahir99-VRG vip.persianss.ir

Ch003-F06861.indd 32

1/21/2008 10:19:58 AM

10

10

8

8

6

6

4

4 Flow (L/s)

Flow (L/s)

Chapter 3 Pulmonary Physiologic Testing

2

–2

2

–2

–4

–4

–6

–6

–8

A

0

1

2

3

4

–8

0

Volume (L) a Expiration

Ptr < Ppl

1

2

3

Volume (L) b

4

33

FIGURE 3-12 A, Left (a), Variable intrathoracic UAO in this flowvolume loop was caused by a rare granular cell tumor of the distal trachea. Because the patient presented with wheezing, asthma was suspected. The plateau and abrupt concave-down shoulder at the right end are typical and contrast to the scooped-upward concavity typical of COPD or asthma. The small “squeak” of a peak flow before the plateau is sometimes seen and does not rule out UAO if a plateau of flow is present. Right (b), A normal flow-volume loop is shown after tumor resection. B, Variable intrathoracic UAO. The transmural pressure gradient during expiration results in compression of the intrathoracic trachea, as it does in the lower airways in asthma and COPD. This narrowing in the trachea results in a flow ceiling (plateau) during expiration. During inspiration, the gradient across the tracheal wall distends the airway and flow limitation at this site does not occur. (MODIFIED FROM CLIN CHEST MED 15:35-53, 1994; ADAPTED FROM AM J MED 61:85, 1976.)

Inspiration

Ptr > Ppl

B changes from month to month), and is not fully reflective of the clinical utility of a given inhaled agent.29,30 Pre- and postbronchodilator lung volume testing may demonstrate significant decreases in hyperinflation (reduced FRC, RV) such that significant improvement in flow at the same lung volume, associated with symptomatic improvements, may be observed despite an unchanged FEV1 and FVC.31 Quantitative comparison of flow at the same lung volumes may be a method of integrating these concepts and is termed isovolume flow assessment. A less well-accepted test of bronchodilator responsiveness is improvement in flow at low lung volumes such as FEF25-75%. Because the midflow section is always defined by the VC in which it resides, comparisons before and after use of a bronchodilator need to be adjusted to reflect flow through the same range of volumes (isoFEF25-75%), rather than from an unadjusted FEF25-75%. Improvement in isoFEF25-75% of 35% or more is suggestive of bronchodilator responsiveness when taken from a study with excellent repeatability.

Assessing Significant Change in Lung Function Over Time Repeated measurements may change for technical, statistical, or biologic reasons. The FEV1 is the most tightly repeatable PFT value and the best at tracking changes in both obstructive and restrictive disease. For short-term follow-up, differences in FEV1 above 12% and 200 mL are significant and not

TABLE 3-4 Rating of Severity of Pulmonary Function Tests Using the Method in the 2005 American Thoracic Society/ European Thoracic Society Standards* and Gold Guidelines for COPD

Rating

ATS/ERS FEV1 (%)

GOLD FEV1 (%)

Predicted DLCO* (%)

Mild

>70

>79 (FEV1/FVC <0.7)

>60 and
Moderate

60-69

50-79

40-60

<40

Moderately severe

50-59

Severe

35-49

30-49

Very severe

<34

<30

*The rating of severity is appropriate to use after the test has been determined to be abnormal based on a FEV1, VC, FEV1/VC, TLC, or DLCO outside the normal range. Rating of severity of obstruction or restriction is based on the FEV1. ATS, American Thoracic Society; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity; ERS, European Respiratory Society; FEV1, volume exhaled in the first second; LLN, lower limit of normal. Modified from Eur Respir J 26:948–968, 2005; and www.goldcopd.org.

coincidentally the same value used to determine a significant intra-session bronchodilator effect.3 For year-to-year assessment, significant changes ideally exceed 15%. Other parameters including VC, IC, TLC, and DLCO can be useful for tracking change in COPD or interstitial lung disease. For

tahir99-VRG vip.persianss.ir

Ch003-F06861.indd 33

1/21/2008 10:19:58 AM

34

Section 1 Introduction

DLCO, significant year-to-year changes of 15% or more are likely meaningful. For idiopathic pulmonary fibrosis, it has been suggested that a significant change in DLCO is 15% or more or greater than or equal to 3 mL/min/mm Hg and that for TLC or VC is 10% or more (or ≥200 mL).32 With these principles in mind, the treating pulmonologist can best interpret a series of PFT measurements by integrating the clinical scenario. Stable PFTs in a disease expected to be progressive could be interpreted as a sign of effectiveness of therapy. Lack of significant improvement in a disease expected to respond well to medication might be interpreted as a failure of therapy. A significant change in PFT measurements may not be clinically meaningful to a given patient. Serial follow-up demonstrating consistent trends, focusing on the major parameters listed earlier, is likely to be most useful.

Patterns Helpful With Specific Disease Classification True Restrictive Disorders These conditions include the intraparenchymal disorders (interstitial and infiltrative lung disease, diffuse alveolar disease) and chest wall restriction (pleural, skeletal). These processes have the classic findings of reduced TLC, FRC, RV, and VC and normal to high FEV1/FVC ratio. A spirometric diagnosis of “restriction,” defined by a low FVC and an FEV1/ FVC ratio greater than 70%, was found to have a sensitivity of 93% but a specificity of only 82% when compared with a plethysmograpy lung volume gold standard.33 This study noted that 10% of pure obstructive defects had “restrictive” spirometry and thus supports the ATS-ERS recommendation that an interpretation of restriction from spirometry requires confirmation by full lung volume measurements. A more cautious term for such spirometric patterns when full lung volumes have not been measured is a “nonspecific” defect.

Neuromuscular Disease These patients generally have a normal lung and chest wall but weakness of the inspiratory muscles (mainly the diaphragm) and the expiratory muscles (mainly the abdominal muscles), which limits inspiratory and expiratory deviation from the resting lung volume (FRC). Consequently, the characteristic abnormality is a reduction in VC caused by reduction in both IC and ERV. The reduced IC, with a normal FRC, results in a reduced TLC (and hence is “restrictive”). The reduced ERV, with a normal FRC, results in an increased RV in those with more severe weakness. This elevation of RV in the setting of decreased VC and increased RV distinguishes the “restriction” of neuromuscular disease from true restrictive disorders. Patients with isolated or disproportionate bilateral diaphragmatic weakness or paralysis show a marked fall in VC in the supine compared with the erect posture. This reflects the effects of gravitational forces on abdominal contents in the two positions. In the normal subjects the VC falls 5% to 10% in the supine position. A fall of 30% or more is associated with severe diaphragmatic weakness, and the postural fall may exceed 50% in some subjects.

Although the MIP and MEP are the more specific and sensitive tests for muscle weakness, the simpler and more accessible VC is most often followed in neuromuscular disease patients. VC is also sensitive for assessing the progression from moderate to severe respiratory muscle weakness. The rate of decline in VC predicts survival in both amyotrophic lateral sclerosis and Duchenne muscular dystrophy. Although, in general, MVV has no advantages over VC, in some patients with Parkinson’s disease the MVV may be reduced disproportionately to VC.

Pseudorestriction Associated With Obesity and Asthma Patients with obesity or asthma may have spirometric findings that may be confused with those associated with true restrictive disorders. FVC may be low with a normal or elevated FEV1/FVC ratio. With obesity, the associated reduction in chest wall and abdominal compliance also results in a mild fall in VC as well as FRC and TLC.34 In contrast to true restriction, however, abdominal compression of the lower lung leads to early airway closure and a low ERV with elevated RV and reduced midexpiratory flow (FEF25-75%).35 Clues to distinguish a pseudorestrictive pattern in asthma from true restriction and from the pseudorestriction of obesity include the following: ■ ■ ■ ■ ■ ■

Significant improvement of FEV1 or FVC before and after bronchodilator spirometry Elevated FRC and TLC (RV can be low or high in obesity) Improved “restriction” with asthma therapy Very low ERV, forced ERV Positive bronchoprovocation test Elevated DLCO and DLCO/VA

Causes of pseudorestrictive spirometry in asthma may be related to complete airway occlusions due to mucus plugging or dynamic premature airway closure such that FVC is reduced proportionate to FEV1, resulting in a normal FEV1/ FVC ratio. In addition, incomplete expiratory effort on the FVC or failure to inspire completely to TLC before the expiratory blast will result in undermeasurement of the FVC. Although the low FEV1 and FVC and normal ratio may be mistaken for restriction, the short expiratory time, lack of an expiratory plateau, hyperinflation on lung volume measurements, and scooped-out FVL indicate that the true disorder is obstructive.

Diseases With Mixed Obstructive and Restrictive Defects Diffuse interstitial or infiltrative lung disease typically causes restrictive patterns with normal or high FEV1/FVC and reduced lung volumes (TLC, FRC, RV). Obstructive ventilatory defects can be seen in traditionally restrictive processes such as sarcoidosis, rheumatoid lung disease, and advanced idiopathic pulmonary fibrosis. This may be due to granulomatous airways disease (e.g., sarcoidosis), bronchiolitis (e.g., rheumatoid lung), or airway distortion from severe parenchy-

tahir99-VRG vip.persianss.ir

Ch003-F06861.indd 34

1/21/2008 10:19:59 AM

Chapter 3 Pulmonary Physiologic Testing

mal fibrosis or cystic spaces with honeycombing in any advanced interstitial lung disease. Bronchiectasis causes reduced expiratory flow rates as a result of total obliteration of some airways and increased collapsibility of dilated, patent airways. However, reduced TLC (restriction) is often present due to fibrosis of parenchyma in the bronchiectatic lung segments. Certain diffuse infiltrative diseases (e.g., eosinophilic granuloma and lymphangioleiomyomatosis) are typically associated with airflow obstruction and increased volumes. Although bronchiolitis is an “airway” disease, proliferative bronchiolitis, such as bronchiolitis obliterans organizing pneumonia, usually has a restrictive pattern. Mixed patterns can be seen in smokers. In contrast, constrictive bronchiolitis, such as transplant-associated bronchiolitis and diffuse panbronchiolitis, usually has an obstructive pattern with hyperinflation.

Disease Processes Causing Abnormalities of Diffusing Capacity The DLCO is decreased in conditions that disrupt the alveolar-capillary surface for gas transfer. This can occur due to loss of surface area (pulmonary resection, pulmonary fibrosis, emphysema, pneumonia); reduced lung capillary volume (pulmonary vascular disease including vasculitis, pulmonary thromboembolism, and primary pulmonary hypertension and also in emphysema and interstitial lung disease); or increased diffusion distance (pulmonary alveolar proteinosis, Pneumocystis carinii pneumonia). The most sensitive tests for demonstrating abnormalities in early or mild interstitial lung disease include DLCO and P(A − a)O2 during exercise, both of which may be abnormal when spirometry, lung volumes, and blood gases at rest are normal.36 Other causes of an isolated reduction in DLCO include disease of the pulmonary vascular compartment (primary or thromboembolic pulmonary hypertension, or pulmonary vasculitis). Recent data indicate that we also need to consider emphysema in this setting.37 In contrast to the low DLCO seen in emphysema, asthmatics tend to have elevated values.38 DLCO can be increased by conditions that lead to recruitment of the pulmonary vascular bed and an increase in capillary blood volume (exercise, mild congestive heart failure, left-to-right shunt, asthma) or by an increased amount of hemoglobin, which binds CO (pulmonary hemorrhage, erythrocytosis). The increased DLCO in asthma is most likely due to increased capillary blood volume induced by the single breath maneuver when the asthmatic takes a forced inspiratory VC against high airway resistance before performing the breath-hold.

Cardiac Effects on PFTs The relationship between lung function and cardiac events has been documented in the Framingham longitudinal studies, which found that reduced FVC is an independent predictor of cardiac events even in people without established cardiac disease. In patients with congestive heart failure, the PFT findings are well explained by the mechanisms and stages of

35

pulmonary congestion. In mild stages, with vascular congestion but without frank pulmonary edema, the increased capillary blood volume will result in an increased DLCO. With more blood volume (and hemoglobin) to accept CO and nothing interfering with the transfer of gas from alveolus to capillary, uptake of CO is enhanced. As congestion worsens with the development of interstitial and alveolar edema, a restrictive process with a reduced DLCO develops.39 In chronic congestive heart failure, pericapillary hemosiderosis and fibrosis can result in a stable drop in DLCO.40 Amiodarone pulmonary toxicity is a difficult diagnosis to establish. Although serial PFTs, including the measurement of DLCO, have not proven useful in screening for early disease, otherwise unexplained restriction and low DLCO is part of the clinical pattern suggesting toxicity from this drug.

Bronchoprovocation FEV1 and PEF rate are good measures of asthma severity and measure the degree of airflow obstruction. A related but distinct aspect of asthma is the degree of twitchiness of the airways, known as airway hyperresponsiveness. This tendency to bronchoconstriction can be assessed for specific antigens, although it is more common to assess nonspecific hyperresponsiveness in the laboratory with pharmacologic agents (methacholine or histamine), exercise (exercise-induced bronchospasm), or cold dry air inhalation (which is often combined with exercise). Although these techniques are complementary in yield, the pharmacologic agent methacholine is most frequently used.

Methacholine Challenge Testing Clinically, this test is most commonly used to diagnose asthma in patients who have had normal results of routine PFT studies yet have symptoms that may suggest asthma. When symptoms are typical, an empirical course of treatment for asthma is a reasonable alternative. Cough-variant asthma frequently presents as monosymptomatic cough without wheeze and with normal routine PFT results. Patients inhale concentrations of methacholine, doubling from 0.05 mg/mL up to 25 mg/mL, with measurement of FEV1 after each concentration. The results are graphed as the percent reduction in FEV1 from baseline versus inhaled concentration. The concentration of inhaled agent that causes a 20% reduction in FEV1 (PC20-FEV1) is interpolated from the graph. The ATS guidelines have suggested cutoff points for interpretation that vary relative to the ordering physician’s pretest probability (Crapo et al, 2000).41 Assuming a pretest probability of asthma of 30% to 70%, a PC20-FEV1 greater than 16 mg/mL is normal; 4.0 to 16 mg/mL is borderline bronchial hyperresponsiveness (BHR); 1.0 to 4.0 is mild BHR (positive test); less than 1.0 mg/mL is considered moderate to severe BHR. The threshold below which a test is considered positive shifts to higher concentrations when the pretest likelihood of asthma is higher. Conversely, a lower concentration is required to designate a test positive when the pretest suspicion of asthma is lower, such as in population screening. The test is also sometimes performed using the body plethysmograph to measure airways resistance (Raw) and its

tahir99-VRG vip.persianss.ir

Ch003-F06861.indd 35

1/21/2008 10:19:59 AM

36

Section 1 Introduction

reciprocal, conductance (Gaw). This is usually expressed as specific airway conductance, G/TGV (conductance divided by the thoracic gas volume at which it is measured). A 45% reduction in Gaw is considered positive due to greater variability in this measurement than for FEV1. Most consider bronchoprovocation highly sensitive for asthma but nonspecific. Consequently, a negative test is a strong argument against the diagnosis of asthma. Falsenegative findings can be due to currently inactive or adequately treated asthma. Bronchoprovocation is not useful in distinguishing asthma from COPD because there is a high prevalence of airway hyperresponsiveness in tobacco-related COPD. The lower the PC20, however, the more likely it is that the patient has asthma. A negative methacholine study can be used as supportive evidence for vocal cord dysfunction mimicking asthma, especially if a flattened inspiratory limb of the FVL is present.

Exercise Bronchoprovocation Assessment for exercise-induced bronchospasm can be performed as an add-on to CPET or as a separate diagnostic maneuver. Testing for EIA in the laboratory is only moderately sensitive because conditions may not mimic the cold and dry air conditions or the pattern of ventilation present under field conditions. Therefore, methacholine challenge testing always needs to be the first bronchoprovocation study, even in subjects with suspected exercise-induced bronchospasm, because it is also simpler to perform and more sensitive for the diagnosis. Some patients will demonstrate hyperresponsiveness to exercise or cold air challenge testing who do not react to methacholine. Exercise bronchoprovocation is best performed on the treadmill, with a target heart rate of 80% to 90% of predicted maximum (220 − age in years) maintained for 4 to 6 minutes, with a total exercise duration of 6 to 8 minutes. Spirometry measurements are made before and then every 5 minutes for 20 minutes after the exercise maneuver.42 A drop in FEV1 of greater than 15%

is considered diagnostic. Having the patient inhale cold, dry air during the study increases the yield of this test.

CLINICAL UTILITY OF CARDIOPULMONARY EXERCISE TESTING Unexplained or Disproportionate Dyspnea Cardiopulmonary exercise testing can be useful in documenting impairment and distinguishing abnormal cardiopulmonary physiologic responses from inorganic causes associated with anxiety or even malingering when routine history, physical, basic PFTs, and laboratory tests fail to determine a cause of dyspnea (Fig. 3-13).36,43 A normal study can serve to reassure the patient and avoid expensive and invasive testing. An abnormal study may direct the workup toward more invasive testing, such as right- or left-sided heart catheterization, pulmonary angiography, lung biopsy, or muscle biopsy or indicate specific therapy such as exercise training, bronchodilators, or angiotensin converting-enzyme inhibitors. Because of the wide variation of normal values, serial tests in the setting of persistent or progressive symptoms may be necessary to document progression of an abnormal physiologic response. CPET can be useful in determining relative contributions of cardiovascular and ventilatory abnormalities to exercise impairment in patients with known disease. Such determinations can direct therapy to the appropriate organ system.

Assessment of Intervention Cardiopulmonary exercise testing has shown promise in the research and clinical arenas in the assessment of physiologic and functional change associated with an intervention. CPET not only offers greater insight into specific physiologic changes than resting testing but also allows assessment of the integrated response of varying effects of the intervention on the system. For example, in the assessment of exercise response to lung volume reduction surgery, a given individual may demonstrate increased tidal volume and lower respiratory

FIGURE 3-13 A to D, Patterns of cardiovascular and ventilatory response during exertion. AT % VO2 pred, anaerobic threshold as a percentage of predicted maximal oxygen consumption; ∆BE, change in base excess; HR %pred, heart rate response as a percentage of predicted; O2 pulse, oxygen consumption/heart rate; VD/VT, dead space to tidal volume ratio; VE-max/MVV, maximal exercise ventilation as a proportion of maximal voluntary ventilation; VO2 max %, maximal oxygen consumption as a percentage of predicted.

NORMAL RESPONSE

VO2 max %

71%

HR %pred

95%

VE-max/MVV

0.62

AT % VO2 pred

50%

O2 pulse

92

⌬BE

–5

PCO2

34

VD/VT

0.21

180

100 HR 1/min

98%

140

60 100

20 60 1000

A

VE L/min

FEV1 %pred

2000

3000

VO2 mL/min

tahir99-VRG vip.persianss.ir

Ch003-F06861.indd 36

1/21/2008 10:19:59 AM

Chapter 3 Pulmonary Physiologic Testing

FIGURE 3-13, cont’d

PURE CARDIOVASCULAR LIMITATION

VO2 max %

66%

HR %pred

102%

VE-max/MVV

0.47

AT % VO2 pred

39%

O2 pulse

58

⌬BE

–7

PCO2

32

VD/VT

0.24

180

100 140 HR 1/min

87%

VE L/min

FEV1 %pred

37

60 100

20 60 1000

B

2000

3000

VO2 mL/min PURE VENTILATORY LIMITATION 47%

VO2 max %

62%

HR %pred

77%

VE-max/MVV

0.92 NA

O2 pulse

81

⌬BE

–2

PCO2

48

VD/VT

0.47

100 140

60 100

VE L/min

AT % VO2 pred

180

HR 1/min

FEV1 %pred

20 60 1000

2000

3000

VO2 mL/min

C

PULMONARY VASCULAR DISEASE

VO2 max %

72%

HR %pred

98%

VE-max/MVV

0.53

AT % VO2 pred

36%

O2 pulse

62

⌬BE

–5

PCO2

26

VD/VT

0.42

180

100 140 HR 1/min

97%

60 100

20 60 1000

D

VE L/min

FEV1 %pred

2000

3000

VO2 mL/min

tahir99-VRG vip.persianss.ir

Ch003-F06861.indd 37

1/21/2008 10:19:59 AM

38

Section 1 Introduction

rates, lower VD/VT, and increased IC associated with less dynamic hyperinflation; however, an earlier-onset lactic acidosis and elevated heart rate/oxygen consumption relationship due to simultaneous excision of the pulmonary vascular bed may balance the beneficial pulmonary. mechanical effects and result in no change or deterioration in VO2max or maximal watts. Exercise testing has been used to document the effects of bronchodilators in COPD,44,45 immunosuppressive therapy in idiopathic pulmonary fibrosis,46 lung transplantation in COPD,47 lung volume reduction surgery,48 and prostacyclin therapy in primary pulmonary hypertension.49

DETERMINATION OF PROGNOSIS Measurements of maximal oxygen consumption are predictive of survival in individuals with cystic fibrosis, congestive heart failure, and COPD.50 Patients with cystic fibrosis with . VO2peak less than 59% predicted were more than three times as likely to die as those with values greater than 82% of predicted, whereas measures of resting pulmonary function did not independently correlate with survival.51 Individuals with cardiomyopathy awaiting heart transplantation who have . VO2peak greater than 14 mL/min/kg demonstrate a 94% oneyear survival compared with 70% of those individuals with 52 values less than 14 mL/min/kg. Based on these data, indi. viduals with values for VO2peak less than 14 are prioritized in consideration for heart transplantation. The National Emphysema Treatment Trial stratified severe emphysema patients into subgroups, based on patterns of exercise response. Patients who had a high mortality rate in the control group based on low incremental cycle ergometry watts (defined earlier) experienced a greater than 50% reduction in mortality rate if they had upper lobe dominant disease, whereas patients in the high-exercise category were not likely to experience a survival benefit. The high-exercise responders, however, still experienced improved exercise tolerance and quality of life if they had upper lobe dominant disease. The role for CPET measurements in the assessment of preoperative risk before thoracotomy are . discussed in Chapter 2, and in this situation low maximal VO2 measures can define subgroups of . patients at excessively high risk for surgery, and higher VO2 measures define subgroups at acceptable risk despite traditionally unacceptable FEV1 levels.53-55

Disability Assessment Although clear guidelines for determination of disability are lacking, it is clear that resting pulmonary function measurements do not adequately predict functional status. In a group of subjects studied who met ATS guidelines for respiratory disability, 48% had slight or no disability measured using CPET.56 One standard commonly used in determination of disability is to compare oxygen consumption measurements in the laboratory to published energy requirements for

Ch003-F06861.indd 38

different jobs57; the average energy requirement on the job does not exceed 50% of an individual’s maximal work capacity.

Pulmonary Rehabilitation The use of CPET before pulmonary rehabilitation is recommended to define safety and determine exercise prescription. CPET allows supervised observation of potential ischemia, arrhythmia, and desaturation before training sessions.58-60

COMMENTS AND CONTROVERSIES It is critical that thoracic surgeons understand clearly the measurement of pulmonary physiology (both mechanical properties and gas exchange). Interpretation of results and integration of data into a treatment plan is impossible without this knowledge. Drs. Sciurba and Salzman have produced an excellent review with practicality in mind. Spirometric evaluation of FEV1 and FVC and pitfalls in their measurement are discussed. The definitions of lung volume and capacities are essential information. The techniques of their measurement (plethysmography and gas dilution) are described, and pitfalls are noted. It is important for thoracic surgeons to note that gas dilution and wash-out techniques underestimate FRC, RV, and TLC in patients with severe inequality in distribution of ventilation (e.g., airway disease or COPD). The potentially confusing measurement of DLCO is discussed, and the importance of hemoglobin level and current smoking on the measurement of DLCO is emphasized. Considerable attention is devoted to cardiopulmonary exercise testing and its limited role in the evaluation of thoracic surgical patients. Of course, the interpretation of results requires knowledge of the predicted “normal” values used for comparison. An informative discussion of normal reference values is included. Also of particular help is the excellent review of patterns of abnormality. The text and accompanying figures are excellent source materials for the practicing thoracic surgeon. G. A. P.

KEY REFERENCES American Thoracic Society: Single-breath carbon monoxide diffusing capacity. Recommendations for a standard technique; 1995 update. Am J Respir Crit Care Med 152(6 pt 1):2185-2198, 1995. American Thoracic Society/American College of Chest Physicians: ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167:211-277, 2003. Crapo RO, Casaburi R, Coodes AL, et al: Guideline for methacholine and exercise challenge testing—1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 161:309-329, 2000. Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force: Standardisation of spirometry. Eur Respir J 26:319-338, 2005a. Miller M, Crapo R, Hankinson J, et al; ATS/ERS Task Force: General considerations for lung function testing. ATS/ERS Task Force. Eur Respir J 26:153-161, 2005b.

1/21/2008 10:20:00 AM

chapter

4

ANESTHESIA FOR GENERAL THORACIC SURGERY Karen M. McRae Jean S. Bussières Javier H. Campos Peter D. Slinger

Key Points ■ Anesthetic management is guided by preoperative assessment of

the perioperative risk. ■ Primary differences between thoracic anesthesia and other types

■ ■

■

■

■

■ ■ ■

■

of anesthesia are the requirement for lung isolation and the management of one-lung anesthesia. There are two basic methods of lung isolation: double-lumen endobronchial tubes and bronchial blockers. Anesthetic management for specific procedures is determined by the patient’s underlying disease and by the physiologic effects of the surgery. Lung isolation is mandatory for complex surgeries to avoid soiling of the lung, tension pneumothorax, or air leak through a bronchopleural fistula. Patients with large, anterior mediastinal masses may experience life-threatening lower airway obstruction or cardiovascular collapse with the induction of general anesthesia. Patients with myasthenia gravis are very sensitive to nondepolarizing muscle relaxants, and their use must be avoided; optimization and maintenance of the patient’s medical regimen perioperatively is crucial. Patients having esophageal surgery may be prone to reflux of gastric contents and aspiration. Patients with severe emphysema are prone to gas trapping and cardiovascular instability during positive-pressure ventilation. In patients undergoing lung transplantation, the patient’s underlying lung condition influences the ventilation parameters required during surgery and the need for cardiopulmonary bypass (CPB). Patients with pulmonary alveolar proteinosis have restrictive disease and are hypoxic.

General thoracic surgery encompasses a wide breadth of varied procedures; we have had the privilege of practicing anesthesiology at institutions where these procedures are performed with regularity. The practice of thoracic anesthesia requires a firm understanding of pulmonary anatomy and physiology, in addition to technical knowledge and experience. A vast literature describing the care of the patient undergoing thoracotomy for pulmonary resection exists. The bulk of this chapter, which describes our experiences in patient assessment, airway management, and lung separation, draws on this literature. The chapter ends with a brief overview of some of the particular anesthetic considerations germane to other procedures performed by general thoracic

surgeons. Management issues discussed include those related to complex pulmonary resections, mediastinal surgery, esophageal surgery, whole lung lavage, and surgical procedures to improve the quality of life of patients with end-stage lung disease through lung volume reduction and pulmonary transplantation.

HISTORICAL NOTE Until the early 20th century, attempts at thoracic surgery without anesthesia were usually disastrous. Spontaneous ventilation with an open thorax is hampered by lung collapse, mediastinal and diaphragmatic shift, and paradoxical respiratory movement, all of which hinder operating conditions for all but the simplest procedures. In 1904, Ferdinand Sauerbruch, a pioneering thoracic surgeon from Breslau, Germany, successfully performed chest surgery with the surgical team working inside a chamber held at a pressure of −7 to −8 mm Hg while the patient’s head, and the anesthesiologist, remained outside. At the same time, his colleague Brauer in Marburg tried a reverse method, the so-called plus or positive pressure approach, whereby the patient’s head was isolated in a positive-pressure chamber.1 Until 1907, endotracheal anesthesia was inhalational; patients breathed spontaneously through a mask or a largebore tube. Barthélemy and Dufour proposed an insufflation method for surgery on the face, whereby a continuous flow of air and chloroform entered the trachea via a catheter advanced to just above the carina.2 It was recommended that the catheter not occupy more than half of the glottis; expired gases escaped through the space between the tube and the trachea. The modest positive airway pressure provided by this technique was soon hailed as the solution to the problem of preventing pulmonary collapse in surgical pneumothorax. For casualties of the First World War, chest surgery was performed using insufflation, or the administration of nitrous oxide and oxygen via a tight-fitting face mask with a continuous positive pressure of approximately 5 mm Hg to promote lung inflation. IV morphine was administered for analgesia. Magill and Rowbotham in Britain, and Guedel and Waters and Flagg in the United States, soon realized that insufflation anesthesia provided inadequate carbon dioxide elimination and offered no protection against pulmonary aspiration. After World War I, Ivan W. Magill and Stanley Rowbotham played a prominent role in the development of endotracheal intubation. Guedel and Waters described “a new intratra39

40

Section 1 Introduction

cheal catheter” with an inflatable cuff in 1928,3 and Magill reported his experience at about the same time.4 Positivepressure ventilation was now much simplified. The introduction of the tracheal tube was facilitated by the newly popularized laryngoscope. In 1931, separate ventilation of one lung was achieved first by Gale and Waters, who used a standard rubber tube molded in hot water to obtain a lateral curve toward the bevel tip.5 The tube was advanced toward the bronchus until resistance was met. Graham and Singer described the first pneumonectomy using endobronchial anesthesia in 1933. Ether and cyclopropane were most often used during this era. Cyclopropane was popular in thoracic surgery as a powerful respiratory depressant, making positive-pressure ventilation feasible. The introduction of muscle relaxants into clinical practice in the 1940s greatly facilitated the use of positive-pressure ventilation. Despite the innovation of endobronchial intubation and the use of automatic ventilators for rhythmic ventilation of the lungs as early as the late 1930s, these devices and the personnel skilled in their use were not available outside highly specialized centers. Open chest surgery continued to be performed in spontaneously breathing patients well into the 1950s. The first double-lumen endobronchial tubes (DLTs) were adapted for surgery by Björk and Carlens in 1950. Over the past 25 years, anesthesia for noncardiac thoracic surgical procedures has evolved substantially. The introduction of “disposable” DLTs associated with the use of the small fiberoptic bronchoscope in the early 1980s is a good example of how new technology has made “one-lung anesthesia” much safer. Similarly, the introduction of epidural catheters in the mid-1980s not only changed the conduct of postoperative analgesia but also allowed the anesthesiologist to reduce the “depth” of anesthesia during lung resectional procedures. During the 1990s, the use of potent new, “short-acting” drugs allowed a more controlled anesthesia with rapid emergence. In conclusion, the first era of thoracic surgery was primarily for treatment of infectious disease, tuberculosis, and empyema. Methods to effectively remove secretions and prevent their movement into healthy lung segments were sought. Since that time, advances in anesthetic agents, pain control techniques, and monitoring have led us through the second era, defined by surgery for bronchogenic cancer, and into the current, third era, in which surgery for respiratory failure is successfully performed.6 HISTORICAL READINGS Archibald EJ: A consideration of the dangers of lobectomy. J Thorac Surg 4:335, 1935. Barthélemy et Dufour: L’anaesthésie dans la chirurgie de la face. Presse Méd 15:475, 1907. Björk VO, Carlens E: The prevention of spread during pulmonary resection by the use of a double lumen catheter. J Thorac Surg 20:151, 1950. Björk VO, Carlens E, Friberg O: Endobronchial anesthesia. Anesthesiology 14:60, 1953. Flagg PJ: Intratracheal inhalation: Preliminary report of a simplified method of intratracheal anesthesia developed under the supervision of Dr. Chevalier Jackson. Arch Otolaryngol 5:394, 1927.

Gale JW, Waters RM: Closed endobronchial anesthesia in thoracic surgery: Preliminary report. J Thorac Surg 1:432, 1932. Graham AE, Singer JJ: Successful removal of the entire lung for carcinoma of the bronchus. JAMA 101:1371, 1933. Guedel AE, Waters RM: A new intratracheal catheter. Anesth Analg 7:238, 1928. Guedel AE, Waters RM: Endotracheal anesthesia: A new technic. Ann Otol (St. Louis) 40:1139, 1931. Magill IW: Anaesthesia in thoracic surgery with special reference to lobectomy. Proc R Soc Med 29:643, 1936. Magill IW: Endotracheal anaesthesia. Proc R Soc Med 22:1, 1928. Rowbotham S, Magill IW: Anaesthetics in plastic surgery of the face and jaws. Proc R Soc Med (Section of Anaesthetics) 14:17, 1921. Sauerbruch EF: Present status of surgery of the thorax. JAMA 51:808, 1908. White GMJ: Evolution of endotracheal and endobronchial intubation. Br J Anaesth 32:235, 1960.

PREOPERATIVE ASSESSMENT Preoperative anesthetic assessment before chest surgery is a continually evolving science and art. An overview of the preanesthetic assessment for pulmonary resection is presented in Table 4-1. This section concentrates on preoperative assessment for pulmonary resection surgery in cancer patients. The principles described here apply to all other types of nonmalignant pulmonary resection, and to other chest surgery as well. The major difference in their application is that, in patients with malignancy, the risk/benefit ratio of cancelling or delaying surgery for each individual patient pending other investigation or therapy is always complicated by the risk of further spread of cancer during any extended interval before resection. This is never completely “elective” surgery. Several general points need to be appreciated in the assessment of patients for pulmonary resection. 1. Anesthesiologists are not gatekeepers. It is rarely the anesthesiologist’s role to decide which patient is or is not an operative candidate. Indeed, with recent anesthetic and surgical advances, almost any patient, given a full under-

TABLE 4-1 Preanesthetic Assessment for Pulmonary Resection Initial Assessment All patients: Exercise tolerance, ppoFEV1, ? postoperative analgesia, discontinue smoking . . . Patients with ppoFEV1 <40%: DLCO, V/Q scan, VO2max Cancer patients: The 4 Ms—mass effects, metabolic effects, metastases, medications Patients with COPD: Arterial blood gas, physiotherapy, bronchodilators Patients with increased renal risk: Creatinine, BUN Final Assessment Review initial assessment and test results. Assess risk of hypoxemia during one-lung ventilation. Assess difficulty of lung isolation: chest radiograph, computed tomography scan. BUN, blood urea nitrogen; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity of the lung for carbon monoxide; ppoFEV1, . predicted postoperative forced expiratory . .volume in 1 second; V O2 max, maximum oxygen consumption; V /Q, ventilationperfusion.

Chapter 4 Anesthesia for General Thoracic Surgery

standing of the risks and appropriate investigation, can be considered “operable.”7 The preoperative anesthetic assessment is used primarily to identify those patients who are at increased anesthetic risk. Risk assessment is then used to stratify perioperative management and to focus resources on high-risk patients, with the goal of improving their outcome. 2. Preoperative evaluation comprises two disjoint phases. Until very recently, the preanesthesia evaluation was part of a continuum whereby a patient was admitted preoperatively for testing and the management plan evolved as test results were received. Currently, the reality of practice patterns in anesthesia has changed: a patient is commonly assessed initially in an outpatient clinic, and often not by the members of the anesthesia staff who will actually administer the anesthesia. The actual contact with the responsible anesthesiologist may occur for only 10 to 15 minutes of communication before induction takes place. Therefore, it is necessary for the anesthesiologist to organize and standardize the approach to preoperative evaluation into two temporally “disjoint” phases: the initial (clinic) assessment and the final (hallway) assessment. Elements vital to each assessment are described in this chapter. 3. Thoracic surgery involves specific perioperative complications. To assess patients for thoracic anesthesia, one must have an understanding of the risks specific to this type of surgery. The anesthesiologist must also understand that the major causes of perioperative morbidity and mortality in these patients are cardiorespiratory in nature. Surgery and anesthesia alter respiratory function, beginning with the induction of anesthesia and often lasting well into the convalescent period. Atelectasis occurs within minutes after induction, causing reductions in functional residual capacity (FRC) and lung compliance.8 Postoperative changes in respiratory function are in part due to the direct effect of the surgical procedure on respiratory muscles.9 Major respiratory complications of persistent atelectasis, pneumonia, and respiratory failure occur in

15% to 20% of patients and account for most of the reported 3% to 4% mortality rate.10 Cardiac complications (e.g., arrhythmia, ischemia) occur in 10% to 15% of the thoracic surgical population.11

ASSESSMENT OF RESPIRATORY FUNCTION Much scientific effort has been spent in the search for a single test of respiratory function that would have sufficient sensitivity and specificity to predict outcome for all patients undergoing pulmonary resection. It is now clear that no single test will ever accomplish this goal because there are many factors that determine overall respiratory performance. For anesthesiologists, it is useful to think of respiratory function in three related but somewhat independent areas: respiratory mechanics, gas exchange, and cardiorespiratory interaction. These three factors form the “three-legged stool” of prethoracotomy respiratory assessment (Fig. 4-1).

Respiratory Mechanics (Spirometry) Several tests that measure respiratory mechanics and lung volumes have demonstrated a correlation with postthoracotomy outcome. Of these, perhaps the most valued single test for post-thoracotomy respiratory complications is the predicted postoperative forced expiratory volume in 1 second (ppoFEV1), which is expressed as a percentage of the predicted value for a patient of similar age, gender, and height and is calculated as follows: ppoFEV1 = preoperative FEV1 × (1 − % functional lung tissue removed/100)

In 1988, for instance, Nakahara and associates10 showed that patients with a ppoFEV1 greater than 40% of predicted had no or only minor postresection respiratory complications. Major respiratory complications were seen only in the subgroup with a ppoFEV1 of less than 40% of predicted (although not all patients in this subgroup developed respiratory complications), and 10 of 10 patients with a ppoFEV1 less than 30% of predicted required postoperative mechanical ventilatory support.

Three-Legged Stool of Pre-Thoracotomy Respiratory Assessment

Respiratory mechanics FEV1 (ppo >40%)

Cardiopulmonary reserve VO2 max (>15 mL/kg/min)

MVV (>50%) RV/TLC (<40%) FVC

Lung parenchymal function DLCO (ppo >40%) PaO2 <60 mm Hg

Exercise oximetry (decrease SpO2 <4%) Stair climbing (≥3 flights) 6-min walk test

PaCO2 >45 mm Hg

FIGURE 4-1 Three separate but interrelated aspects of respiratory function are used for preanesthesia assessment for thoracic surgery. DLCO, carbon monoxide diffusing capacity of the lung; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; MVV, maximal voluntary ventilation; Paco2, partial pressure of carbon dioxide in arterial blood; PaO2, partial pressure of oxygen in arterial blood; ppo, predicted postoperative value; RV/TLC, residual volume/total lung. capacity; SpO2, oxygen saturation by pulse oximetry; VO2max, maximum oxygen consumption.

41

42

Section 1 Introduction

Although modern anesthetic management, particularly the use of thoracic epidural analgesia, has decreased the incidence of respiratory complications (Licker et al, 1999),12 the ppoFEV1 has shown continued validity to predict postresection lung function.13

Lung Parenchymal Function (Gas Exchange) Traditionally, measurements obtained from arterial blood gas (ABG) analysis, such as an arterial partial pressure of oxygen (PaO2) lower than 60 mm Hg or a PaCO2 greater than 45 mm Hg, have been used as cutoff values for pulmonary resection. Another useful measurement of the gas exchange capacity of the lung is the diffusing capacity for carbon monoxide (DLCO), which not only reflects the diffusion but also correlates with the total functioning surface area of the alveolocapillary interface. The corrected DLCO can be used to determine a postresection (ppo) value using the same calculation as for the FEV1. A ppoDLCO less than 40% of predicted correlates with increased respiratory and cardiac complications and is to a large degree independent of the FEV1.14

Cardiopulmonary Function and Exercise Testing All patients must have some assessment of their cardiopulmonary reserves. Formal laboratory exercise testing has now become standardized and is routinely used for the assessment of cardiopulmonary function. Among the many cardiac and respiratory factors tested, the maximum oxygen consump. tion (VO2max) is the most useful predictor of postthoracotomy outcome. The. 6-minute walk test shows an excellent correlation with VO2max and requires little or no laboratory equipment. A 6-minute . walk test distance of less than 2000 ft correlates with a VO2max of less than 15 mL/ kg/min and also correlates with a fall in oxygen saturation by oximetry (Spo2) during exercise.

Ventilation-Perfusion Scintigraphy Prediction of postresection pulmonary function can be further refined by assessment of the preoperative contribution of. the . lung or lobe to be resected, using ventilation-perfusion (V/Q) lung scanning.15 If the lung region to be resected is nonfunctional or is minimally functional, the prediction of postoperative function can be modifi . . ed accordingly. For the anesthesiologist, the result of V/Q lung scanning may help to

predict the level of oxygenation during one-lung ventilation (OLV).

Importance of Respiratory Function for the Anesthesiologist Before thoracic procedures, make an estimate of respiratory function in all three areas for each patient. Then use the data to plan anesthetic management (see Fig. 4-1) and to alter these plans if intraoperative surgical factors necessitate a resection that is more extensive than had been foreseen. The management schema outlined in Figure 4-2 is conservative. If a patient has a ppoFEV1 greater than 40%, it is probably possible for that patient to be extubated in the operating room at the conclusion of surgery, assuming that the patient is alert, warm, and comfortable (AWaC). If the ppoFEV1 is greater than 30% and exercise tolerance and lung parenchymal function exceed the increased-risk thresholds, then extubation in the operating room is probably possible, depending on the status of associated diseases (see later discussion). Consider patients in this subgroup who do not meet the minimal criteria for cardiopulmonary and parenchymal function for staged weaning from mechanical ventilation postoperatively, so that the effect of the increased oxygen consumption associated with spontaneous ventilation can be assessed. Patients with a ppoFEV1 of 20% to 30% and favorable predicted cardiorespiratory and parenchymal function can be considered for early extubation if thoracic epidural analgesia is used. Otherwise, these patients have a postoperative staged weaning from mechanical ventilation. In the borderline group (ppoFEV1 30%-40%), the presence of several associated factors and diseases, which are documented during the preoperative assessment, enters into the considerations for postoperative management. The National Emphysema Treatment Trial showed that patients with a preoperative ppoFEV1 or DLCO of less than 20% had an unacceptably high perioperative mortality rate (2003).16 These can be considered as the absolute minimum values compatible with successful outcome.

ASSESSMENT OF COMORBIDITIES Age, cardiac disease, and renal dysfunction are important to the anesthesiologist because they are predictors of perioperative morbidity. FIGURE 4-2 The preanesthesia assessment is used to guide initial postoperative ventilatory management (see text). (DLCO, carbon monoxide diffusing capacity of. the . lung; FEV1, forced expiratory volume in 1 second; V/Q, ventilation/perfusion.)

Predicted postoperative FEV1 (ppoFEV1%)

>40% Extubate in operating room if: • Patient AWaC (alert, warm, and comfortable)

30%-40%

<30%

Consider extubation based on: • Exercise tolerance • DLCO • V/Q scan • Associated diseases

Staged weaning from mechanical ventilation. Consider extubation if >20% plus: • Thoracic epidural analgesia

Chapter 4 Anesthesia for General Thoracic Surgery

Elderly patient (age >70 yr)

Transthoracic echocardiography Rule out pulmonary hypertension (major increase in risk for pneumonectomy with pulmonary hypertension)

Moderate/poor exercise tolerance or history of coronary artery disease or diabetes or congestive failure

Excellent exercise tolerance and no history of coronary artery disease or diabetes or congestive failure

Myocardial perfusion imaging • Dobutamine-stress echocardiography, or • Persantine-thallium scan

Low risk

Lung resection surgery

Increased risk Coronary angiography

Candidate for surgical revascularization

Cardiac surgery not indicated

Case-specific management FIGURE 4-3 Algorithm for the preoperative cardiac assessment of elderly patients for thoracic (noncardiac) surgery.

Age In the elderly, consider thoracotomy a high-risk procedure for cardiac complications, and in these individuals, the evaluation of cardiopulmonary function is the most important part of the preoperative assessment.17 An algorithm for cardiac assessment of the elderly for thoracic surgery is presented in Figure 4-3.

Intermediate clinical predictors of cardiac disease • Mild stable angina, previous myocardial infarction • Diabetes • Compensated/previous congestive heart failure

Poor functional capacity

Adequate functional capacity

Cardiac Disease Cardiac complications are the second most common cause of perioperative morbidity and mortality among the thoracic surgical population, after respiratory complications. Because most patients undergoing pulmonary resection have a smoking history, they already have one risk factor for coronary artery disease.18 Beyond the standard history, physical examination, and electrocardiogram, routine exercise testing appears not to be cost-effective for all prethoracotomy patients. Noninvasive testing is specially indicated in patients with major clinical predictors (unstable ischemia, recent infarction, severe valvular disease, significant arrhythmia) or intermediate clinical predictors (stable angina, remote infarction, previous congestive failure, diabetes) of myocardial risk. An algorithm for investigation of these patients, based on the recommendations of the American College of Cardiology/ American Heart Association,19 is presented in Figure 4-4. Therapeutic options to be considered in patients with significant coronary artery disease include optimization of medical therapy and the use of coronary angioplasty or coro-

Low risk Noninvasive testing

Surgery

High risk Angiography

Case-specific management FIGURE 4-4 Algorithm for the preoperative cardiac assessment of patients with intermediate-risk factors for cardiac disease for thoracic surgery. Based on the recommendations of the American College of Cardiology/American Heart Association (see text). (ADAPTED FROM FLEISCHER LH, EAGLE KA: ACC/AHA GUIDELINE UPDATE FOR PERIOPERATIVE CARDIOVASCULAR EXAMINATION FOR NONCARDIAC SURGERY: EXECUTIVE SUMMARY. ANESTH ANALG 94:1378, 2002.)

43

44

Section 1 Introduction

nary artery bypass, before or at the time of lung resection.20 Timing of lung resection surgery after a myocardial infarction is always a difficult decision. Based on the data of Rao and coworkers,21 and generally confirmed by clinical practice, limiting the delay to 4 to 6 weeks after myocardial infarction in a medically stable and fully investigated and optimized patient is acceptable. After coronary stenting, recommendations22 strongly support completion of combination antiplatelet therapy for a period varying from 2 weeks to 6 months, depending on the type of stent used (bare metal stent or different types of drug-eluting stent).23 After this period, one of the two agents, aspirin or clopidogrel, is continued and never stopped in a patient with a coronary stent. The recommendation also suggests delaying noncardiac elective surgery until the end of this treatment period. This recommendation is based on the occurrence of acute thrombosis of stents when antiplatelet drugs are stopped for the perioperative period.24-26 If urgent surgery is needed during the prescribed duration of dual antiplatelet treatment, evaluate stopping one of the two antiplatelet drugs against the risk of stent thrombosis and surgical bleeding. If it is necessary to stop one of the drugs before a surgery, early postoperative reinstitution is recommended. Finally, if a patient needs coronary angioplasty shortly before planned surgery, it would be better to avoid any coronary stent, if possible, and to use only balloon angioplasty. Dysrhythmias, particularly atrial fibrillation, are a wellrecognized complication of all pulmonary resection surgery. Prophylactic therapy with digoxin or other drugs has not been shown to prevent these arrhythmias. However, prophylactic verapamil may offer better efficacy with fewest side effects in patients at high risk for post-thoracotomy supraventricular arrhythmias.27

Renal Dysfunction Renal dysfunction after pulmonary resection surgery is associated with increased incidence of operative mortality. Golledge and Goldstraw28 reported a perioperative mortality rate of 19% (6/31) in patients who developed any significant elevation of serum creatinine during the post-thoracotomy period, compared with 0% (0/99) in those who did not show any renal dysfunction. Factors that were highly associated (P < .001) with an elevated risk of renal impairment in their study are listed in Table 4-2. Other factors that were statistically significant, but less strongly associated with renal impairment, included preoperative hypertension, chemotherapy, ischemic heart disease, and postoperative oliguria (<33 mL/hr). The use of nonsteroidal anti-inflammatory TABLE 4-2 Factors Associated With an Increased Risk of Post-Thoracotomy Renal Impairment Previous history of renal impairment Diuretic therapy Pneumonectomy Postoperative infection Blood loss requiring transfusion

agents (NSAIDs) was not associated with renal impairment, although it is a concern in any thoracotomy patient with a preexisting renal dysfunction.

Lung Cancer At the time of initial assessment, assess cancer patients for the “4 M’s” associated with malignancy: mass effects, metabolic abnormalities, metastases, and medications. The use of induction therapies with chemotherapeutic agents such as bleomycin29 or of medications such as amiodarone30 is particularly important to the anesthesiologist because these drugs can exacerbate oxygen-induced pulmonary toxicity.

PREMEDICATION Discuss and order premedication at the time of the initial preoperative visit. The most important aspect of preoperative medication is to avoid inadvertent withdrawal of those drugs that are taken for concurrent medical conditions (e.g., bronchodilators, antihypertensives, β-blockers). For some types of thoracic procedures, such as esophageal reflux surgery, oral antacids and histamine 2 (H2)-blockers are routinely ordered preoperatively. Currently, we do not routinely order preoperative sedation or analgesia for patients undergoing pulmonary resection. Mild sedation, such as an IV short-acting benzodiazepine, is often given immediately before placement of invasive monitoring lines and catheters. In patients with copious secretions, an antisialagogue (e.g., glycopyrrolate) is useful to facilitate fiberoptic bronchoscopy for positioning of a DLT or bronchial blocker. To avoid an intramuscular injection, this can be given orally or IV immediately after placement of the IV catheter. It is common practice to use short-term IV antibacterial prophylaxis such as a cephalosporin in thoracic surgical patients. If it is the local practice to administer these drugs before admission to the operating room, then they will have to be ordered preoperatively. Patients who are allergic to cephalosporin or penicillin are considered at the time of the initial preoperative visit. Recently, our practice has changed from using vancomycin to giving clindamycin to these patients.

POSTOPERATIVE ANALGESIA Develop and discuss the strategy for postoperative analgesia with the patient during the initial preoperative assessment. At this time explain the risks and benefits of the various forms of post-thoracotomy analgesia to the patient. Determine potential contraindications to specific methods of analgesia, such as coagulation problems, anticoagulant therapy, sepsis, or neurologic disorders. If the patient is to receive prophylactic anticoagulants and epidural analgesia has been selected, then appropriate timing of anticoagulant administration and neuraxial catheter placement needs to be arranged. A common practice is to administer prophylactic anticoagulants after the epidural catheter has been put in place.

FINAL PREOPERATIVE ASSESSMENT The final preoperative anesthetic assessment for most thoracic surgical patients is carried out immediately before

Chapter 4 Anesthesia for General Thoracic Surgery

TABLE 4-3 Factors That Correlate With an Increased Risk of Desaturation During One-Lung Ventilation High percentage . . of ventilation or perfusion to the operative lung on preoperative V/Q scan Poor PaO2 during two-lung ventilation, particularly in the lateral position intraoperatively Right-sided surgery Good preoperative spirometry (FEV1 or FVC) FEV1, forced expiratory volume in 1 second; FVC, . . forced vital capacity; PaO2, arterial partial pressure of oxygen; V /Q, ventilationperfusion.

admission of the patient to the operating room. At that time, too, the anesthesiologist reviews the data from the prethoracotomy assessment and estimates the potential for difficult lung isolation as well as the risk of desaturation during OLV (Table 4-3). The anesthesiologist must evaluate the upper airway to make sure that there are no problems that could preclude the introduction of a DLT. In a similar fashion, each patient must be assessed for ease of endobronchial intubation. Historical factors or physical findings such as previous radiotherapy, infection, or prior pulmonary or airway surgery may lead to suspicion of difficult endobronchial intubation. There may also be a written bronchoscopy report with a description of particular anatomic features. Often, the single most useful predictor of difficult endobronchial intubation is the plain chest radiograph (Fig. 4-5) or CT scan. For the anesthesiologist, the major factors in successful lower airway management are anticipation of problems and preparation based on the preoperative assessment and prophylaxis. In most cases, it is possible to predict preoperatively which patients are at risk of desaturation during OLV for thoracic surgery (see Table 4-3). Prophylactic measures such as continuous positive airway pressure (CPAP), with 2 to 5 cm H2O of oxygen to the nonventilated lung,31 can be used during OLV in high-risk patients to decrease this risk. To minimize the impact on surgical exposure during video-assisted thoracic surgery (VATS), it is important to apply the CPAP at the start of OLV. The most important predictor of PaO2 during OLV is the PaO2 during two-lung ventilation. Although the preoperative PaO2 correlates with the intraoperative OLV PaO2, the strongest correlation is with the intraoperative PaO2 during twolung ventilation in the lateral position, before OLV. The proportion of perfusion . . or ventilation to the nonoperated lung on preoperative V/Q scans also correlates with the PaO2 during OLV.32 If the operative lung has little perfusion preoperatively as a result of unilateral disease, the patient is unlikely to desaturate during OLV. The side of the thoracotomy has an effect on PaO2 during OLV. Because the left lung is 10% smaller than the right, there is less shunt when the left lung is collapsed. In a series of patients, the mean PaO2 during left thoracotomy was approximately 70 mm Hg higher than during right thoracotomy.33 The degree of obstructive lung disease correlates in

FIGURE 4-5 Preoperative chest radiograph of a 50-year-old woman presenting with hemoptysis for a right thoracotomy and possible completion pneumonectomy. The radiologist’s report mentions a mass in the right apex and old scarring in the left apex. No verbal or written report can easily describe the obvious potential problem this woman has for placement of a left-sided, double-lumen endobronchial tube, which can readily be appreciated by examination of the actual radiograph.

an inverse fashion with PaO2 during OLV. Other factors being equal, patients with more severe airflow limitation on preoperative spirometry tend to have better PaO2 during OLV than do patients with normal spirometry. The cause of this seemingly paradoxical finding is related to the development of self-controlled positive end-expiratory pressure (auto-PEEP) during OLV in patients with obstructive lung disease.34

INTRAOPERATIVE MANAGEMENT Monitoring Monitoring General to All Pulmonary Resections The majority of pulmonary resections are major procedures lasting 2 to 4 hours; most are performed with the patient in the lateral position with the hemithorax open. Therefore, give consideration for monitoring and maintenance of body temperature and fluid volume in all cases. Monitors are initially placed while the patient is in the supine position, but they must be rechecked and often repositioned after the patient is turned on one side. It is often very difficult to add additional monitoring equipment, particularly for invasive vascular monitoring, after the operation is started if complications arise. For this reason, the risk/benefit ratio tends to favor overly invasive procedures at the outset. Several intraoperative complications that can occur during all types of surgery are more prone to occur during thoracotomy. The choice of monitoring is guided by knowledge of the anticipated incidence of specific complications.

45

46

Section 1 Introduction

Monitoring Specific to Certain Types of Operation Some complications are more likely to occur with certain types of procedures, such as hemorrhage from an extrapleural pneumonectomy, contralateral lung soiling with resection of a cyst or bronchiectasis, or air-leak hypoventilation or tension pneumothorax with a bronchopleural fistula. Monitoring in these specific types of operation is directed in part by the intraoperative complications that may arise due to the underlying disease.

Monitoring of Ventilation Significant desaturation (<90%) during OLV is much less common than in the past and now occurs in approximately 1% of patients.35 Indeed, the risk of hypoxemia during OLV was one of the major factors that created the demand for on-line monitoring of intraoperative oxygenation. Pulse oximetry (SpO2) is useful but for several reasons has not negated the need for direct measurement of arterial PaO2 via intermittent ABG determinations in most patients undergoing thoracotomy. The PaO2 value offers a more useful estimate than the SpO2 of the margin of safety above desaturation. A patient whose two-lung ventilation PaO2 is greater than 400 mm Hg with a fraction of inspired oxygen (FIO2) of 1.0 (or an equivalent PaO2/FIO2 ratio) is unlikely to desaturate during OLV, whereas a patient with a PaO2 of 200 mm Hg is prone to desaturate, although both may have SpO2 values of 98% to 100%. The rapidity of the fall in PaO2 after the onset of OLV is also an indicator of the risk of subsequent desaturation. For this reason, it is useful to measure PaO2 via ABGs before OLV and 20 minutes after the start of OLV. The delay time for detection of falls in SpO2 in the supranormal ranges of oxygenation used in thoracic surgery is generally much longer than with continuous PaO2 monitoring systems. However, on-line monitoring systems using optode or similar technology continue to be plagued by problems of reliability and intravascular positioning “wall effect” and are not in widespread clinical use at present. There also are significant manufacturer-related differences in the accuracy of SpO2. Although the trends are reliable, before a specific cutoff SpO2 value is used as a guideline for treatment of hypoxemia, intraoperatively verify the accuracy of the oximeter model used with ABG measurements. It has been shown that the end-tidal carbon dioxide pressure (PETCO2) is a less reliable indicator of PaCO2 during OLV than during two-lung ventilation, and this PaCO2-PETCO2 difference tends to increase during OLV. Although the PETCO2 is less directly correlated with alveolar minute ventilation during OLV because the PETCO2 also reflects lung perfusion and cardiac output, it gives an indication of the relative changes in perfusion of the two lungs, independently, during position changes and during OLV. The recent development of side-stream spirometry has made it possible for inspiratory and expiratory pressure, volume, and flow interactions to be continuously monitored during anesthesia. This monitoring is particularly useful during pulmonary resection. An early indicator of accidental changes in the intraoperative position of a DLT can be

detected on-line by observation of changes in the ventilation pressure-volume loops.36 The development of a persistent end-expiratory flow during OLV, which correlates with the development of auto-PEEP, can be seen on the flow-volume loop. Also, the ability to accurately assess changes in inspiratory and expiratory tidal volumes is extremely useful in the assessment and management of pulmonary air leaks.

Hemodynamic Monitoring A significant incidence of transient severe hypotension results from surgical compression of the heart or great vessels during intrathoracic procedures. For this reason, and because of the helpfulness of intermittent ABG sampling, it is useful to have beat-to-beat assessment of systemic blood pressure during most thoracic surgery cases. For most thoracotomies, a radial artery catheter is inserted in either the dependent or the nondependent arm. Central venous pressure (CVP) monitoring and central venous access is routine for most thoracic procedures, even though CVP readings with the patient in the lateral position and chest open may not be completely reliable. CVP monitoring is useful postoperatively, particularly in cases for which fluid management is critical (e.g., pneumonectomies). We recommend routine insertion of CVP lines for patients undergoing pneumonectomy, but not for lesser resections unless there are significant other comorbidities. For lobectomies that unforeseeably become pneumonectomies during the course of the surgery, a CVP catheter is placed at the end of the operation. CVP readings are not reliable in patients with superior vena cava obstruction. Similar to CVP readings, intraoperative pulmonary artery pressure measurements are less accurate indicators of true left heart preload when the patient is in the lateral position with the chest open than in other clinical situations. This is partly because it is often not known initially whether the catheter tip lies in the dependent or the nondependent lung. It is also possible that thermodilution cardiac output data may be unreliable if there are significant transient unilateral differences in perfusion between the lungs, as can occur during OLV and positive pressure. There is, at present, no consensus on the reliability of thermodilution cardiac output data during OLV. If left-sided placement of a pulmonary artery catheter (PAC) is required, it can be achieved in 50% of patients (compared with the usual 10%) by floating the catheter into the pulmonary artery when the patient is in the right lateral position.37 It is usually possible for the surgeon to confirm the placement of the PAC once the chest is open. It is important to remember that a PAC placed ipsilateral to the side of surgery must be withdrawn before vascular clamping to avoid transection. Also, if a PAC lies in the nonventilated lung, it can become accidentally wedged, even without balloon inflation, as the lung collapses. The risk/benefit ratio for the routine use of PACs for pulmonary resection surgery favors their use only in certain specific cases, such as in patients with major coexisting disease (e.g., cardiac, renal) or in those undergoing particularly extensive procedures (e.g., extrapleural pneumonectomy).

Chapter 4 Anesthesia for General Thoracic Surgery

Placement of CVP lines and PACs may lead to complications such as sepsis, dysrhythmias, and air embolus. Pneumothorax and hemothorax are managed with the assistance of a thoracic surgeon. Accidental arterial puncture, dilation, or cannulation during central venous cannulation and pulmonary artery rupture are catastrophic events. Central venous cannulation for CVP or PAC insertion carries the risk of accidental arterial puncture and dilation. The incidence of carotid artery puncture with internal jugular vein cannulation varies from 1.9% to 9.4%.38 Accidental subclavian arterial puncture occurs in up to 3.7% of cases.39 The commonly used catheters and sheaths are 7 Fr for single-lumen or triple-lumen catheters and 8.5 Fr for PAC introducers. Incorrect arterial sheath placement is a particularly dangerous vascular complication. The risks associated with accidental arterial puncture include arterial occlusion, embolism, stroke, pseudoaneurysm, arteriovenous fistula, and respiratory obstruction from hematoma.40 There are two management options: removal of the cannula followed by application of local pressure or surgical exploration with removal of the cannula under direct vision and repair of the artery. Usually, when the catheter or the sheath has been removed by surgical exploration, there have been no new complications related to surgery.41 Although misplaced catheters have been removed with direct compression, the compression itself induces the risk of prolonged vessel occlusion and subsequent ischemia, distal thrombosis, and thromboembolism. Most strokes reported in the literature were attributed to the application of direct pressure after carotid artery injury during attempted cannulation of the internal jugular vein.42 Some arterial sites, such as the subclavian artery, are not compressible because of their anatomic location. Surgical exploration and closure may require partial removal of the first rib or thoracotomy, sometimes with high morbidity in very ill patients. Alternatives to surgery have been developed. Percutaneous balloon tamponade43 can be successful, and the insertion of stent-grafts44 allows major complications to be treated percutaneously, avoiding the increased risk associated with open surgery. The recent introduction of percutaneous vascular closure suture devices (Perclose, Abbot Laboratories, Redwood, CA, or Angio-Seal, St. Jude Medical, St. Paul, MN) permits quick, effective, and relatively cheap treatment, precluding the development of complications if the catheter is left in situ and not removed from the subclavian artery.45 It consists of a collagen plug-based device that seals an arterial puncture. All endovascular modalities require an angiogram before they are used. After any injury to a central artery, treated by any modality, close monitoring for neurologic and airway sequelae for up to 48 hours is suggested. Carotid ultrasonography may be a useful, noninvasive method of assessment in these cases. Doppler and two-dimensional ultrasound have been developed as technical aids to central venous catheterization. The use of ultrasound-guided cannulation of the internal jugular vein has been shown to reduce the complication rate, compared with the external landmark-guided technique.46

Transesophageal Echocardiography The clinical usefulness of transesophageal echocardiography (TEE) for pulmonary resection surgery is currently under investigation. In addition to the well-developed usefulness of TEE as an intraoperative monitor of ischemia and cardiac valvular function, several specific areas of pulmonary resection surgery seem to offer potential applications for TEE, such as diagnosis of cardiac compression from a mediastinal tumor or of the presence of a pericardial effusion. TEE has been shown to be capable of monitoring intraoperative changes in right ventricular function induced by changes in right ventricular afterload.47 Intraoperative TEE for major pulmonary resection may offer a more accurate and less invasive method of assessing the effects of pulmonary resection on the right side of the heart. Because it is possible to measure flow velocities in the pulmonary veins by TEE, it may soon be possible to make useful clinical measurements of the blood flow through each lung independently. This will allow monitoring of physiologic changes in blood flow redistribution during OLV; it also may be useful for guiding therapy such as PEEP to improve oxygenation during OLV. A rare cause of hypoxemia associated with thoracic surgery is reversal of shunt flow through an undiagnosed patent foramen ovale.48 When PEEP (to 15 cm H2O) was applied during controlled ventilation for nonthoracic surgery, 9% of patients developed a right-to-left intracardiac shunt.49 TEE should be capable of detecting the potential population of patients who might develop a right-to-left interatrial shunt during OLV for thoracic surgery.

Positioning Most thoracic procedures are performed with the patient in the lateral position, most often the lateral decubitus position; however, depending on the surgical technique, a semisupine or semiprone lateral position may be used. These positions have specific implications.

Position Changes Because it is awkward to induce anesthesia with the patient in the lateral position, monitors are placed and anesthesia is induced with the patient in the supine position. Induction of anesthesia with the patient in the lateral position can be indicated with unilateral lung disease, such as bronchiectasis or hemoptysis, until lung isolation can be achieved. Owing to the loss of venous vascular tone in the anesthetized patient, it is not uncommon to see hypotension when the patient is turned to or from the lateral position. This can occur at the beginning or at the end of the procedure and is generally more severe in patients who have a degree of intravascular volume depletion and in those with sympathetic blockade from epidural local anesthesia. All lines and monitors must be secured during position changes, and their function must be reassessed after repositioning. It is useful to make an initial “head-to-toe” survey of the patient after induction and intubation to check oxygenation, ventilation, hemodynamics, lines, monitors, and potential nerve injuries.

47

48

Section 1 Introduction

This survey then must be repeated after repositioning. It is almost impossible to avoid some movement of a DLT or bronchial blocker during repositioning.50 Certainly, turn the patient’s head, neck, and endobronchial tube en bloc with the patient’s thoracolumbar spine. However, the margin of error in positioning of endobronchial tubes or blockers is often so narrow that even very small movements can have significant clinical implications. The carina and mediastinum may shift independently with repositioning, and this can lead to distal displacement of a previously well-positioned tube. Endobronchial tube or blocker position and the adequacy of ventilation must be rechecked by auscultation and fiberoptic bronchoscopy after the patient has been repositioned. Access for additional intravascular lines is more difficult to attain after the patient has been repositioned; therefore, place all lines, whenever possible, with the patient supine.

Neurovascular Complications Associated With the Lateral Position There is a specific set of nerve and vascular injuries related to the lateral position that must be understood and appreciated. The brachial plexus is the site of most of the intraoperative nerve injuries related to the lateral position. Most of these are compression injuries to the brachial plexus of the dependent arm, but there is also significant risk of stretch injury to the brachial plexus of the nondependent arm. The brachial plexus is fixed at two points—proximally by the transverse process of the cervical vertebrae, and distally by the axillary fascia. This two-point fixation, plus the extreme mobility of neighboring skeletal and muscular structures, makes the brachial plexus exceptionally prone to injury. Position the patient with padding under the dependent thorax to keep the weight of the upper body off the dependent arm brachial plexus. However, this padding will exacerbate the pressure on the brachial plexus if it migrates rostrally into the axilla. The brachial plexus of the nondependent arm is most at risk if it is suspended from an arm support or “ether screen.” Traction on the brachial plexus in these situations is particularly likely to occur if the patient’s trunk accidentally slips toward a semiprone or semisupine position after fixation of the nondependent arm. Vascular compression of the nondependent arm in this situation is also possible, and it is useful to monitor pulse oximetry in the nondependent hand to observe for this problem. Do not abduct the arm beyond 90 degrees, do not extend it posteriorly beyond the neutral position, and do not flex it anteriorly more than 90 degrees. Anterior flexion of the arm at the shoulder (circumduction) across the chest, or lateral flexion of the neck toward the opposite side can cause a traction injury of the suprascapular nerve. This causes a deep, poorly circumscribed pain in the posterior and lateral aspects of the shoulder and may be responsible for some cases of post-thoracotomy shoulder pain. It is very easy, after the patient has been repositioned in the lateral decubitus position, to cause excessive lateral flexion of the cervical spine because of improper positioning of the patient’s head. This malpositioning, which exacerbates

brachial plexus traction, can cause a “whiplash” syndrome and can be difficult to appreciate after the surgical drapes have been placed. It is useful to survey the patient from the side of the table immediately after turning, to ensure that the entire vertebral column is aligned properly. Slightly flex the dependent leg, and position padding under the knee to protect the peroneal nerve lateral to the proximal head of the fibula. Place the nondependent leg in a neutral extended position, and position padding between it and the dependent leg. The dependent leg must be observed for vascular compression. Excessively tight strapping at the hip level can compress the sciatic nerve of the nondependent leg. Other sites particularly prone to neurovascular injury in the lateral position are the dependent ear pinna and eye.

Physiologic Changes in the Lateral Position Significant changes in ventilation develop between the lungs when the patient is placed in the lateral position. This is explained by the fact that the lungs move up and down a common compliance curve, with the dependent lung becoming less compliant and the nondependent lung more compliant. However, the reality is more complex.51 The compliance curves of the two lungs are different because of their difference in size. The lateral position, use of anesthesia, paralysis, and opening of the thorax all combine to magnify these differences between the lungs. The compliance curve (change in volume versus change in pressure) of a lung depends on the balance of two “springs”— the chest wall (which normally distends the lung) and the elastic recoil of the lung itself. Any factor that changes the mechanics of either of these springs places the lung on a different compliance curve.52 Because of the decrease in FRC and the compliance of the nondependent lung in the lateral position, selective application of PEEP to only this lung improves gas exchange.53 This is different from the effect of nonselective application of PEEP to both lungs in the lateral position, in which PEEP tends to go preferentially to the most compliant lung regions and to hyperinflate the nondependent lung without causing any improvement in gas exchange.54 Atelectasis develops in an average of 6% of the lung parenchyma after induction of anesthesia in the supine position. This atelectasis is evenly distributed in the dependent portions of both lungs in the supine position.55 Turning the patient to the lateral position results in a slight decrease of total atelectasis to 5% of lung volume, but this is now concentrated totally in the dependent lung. Traditional information shows that turning the patient from the supine to the lateral position is likely to decrease, by approximately 10%, the pulmonary blood flow56 to the nondependent lung, owing to gravity. However, more recent animal work has led to some question about the effect of gravity on pulmonary blood flow distribution.57 The distribution of pulmonary blood flow in various positions may be more related to inherent pulmonary vascular anatomic factors than to gravity. The matching of ventilation and perfusion is usually decreased in the lateral compared with the supine position. The pulmonary arteriovenous shunt usually increases

Chapter 4 Anesthesia for General Thoracic Surgery

from approximately 5% in the supine position to 10% to 15% in the lateral position.58

Anesthetic Technique Essentially, any anesthetic technique that provides safe and stable general anesthesia for major surgery can be, and has been, used for lung resection. There is currently a trend toward the use of combined thoracic epidural and general anesthesia for thoracic surgery. In one survey, 10 of 12 Australian hospitals reported that thoracic epidural analgesia (TEA) was the standard method of postoperative pain control. Midthoracic epidurals were used in more than 90% of cases; continuous infusions of local anesthetics and opioids were used in more than 90%, and these were continued for longer than 2 days postoperatively in more than 80% of patients.59 Epidural analgesia has been shown to decrease the incidence of respiratory complications after major surgery.60 Because of the high incidence of coexisting reactive airways disease in the thoracic surgical population, it is generally advisable to use an anesthetic technique that decreases bronchial irritability. This is particularly important because the added airway manipulation caused by placement of a DLT or a bronchial blocker is a potent trigger for bronchoconstriction. The principles of anesthetic management are the same as for any asthmatic patient: Avoid manipulation of the airway in a lightly anesthetized patient, use bronchodilating anesthetics, and avoid drugs that release histamine. For IV induction of anesthesia, either propofol or ketamine can be expected to diminish bronchospasm. This benefit is not seen with barbiturate, narcotic, benzodiazepine, or etomidate IV induction. For maintenance of anesthesia, propofol or any of the volatile anesthetics diminishes bronchial reactivity. Sevoflurane may be the most potent bronchodilator of the volatile anesthetics.61 Because the lung resection population largely comprises elderly patients and smokers, there is a high coincidence of coronary artery disease. This consideration is a major factor in the choice of anesthetic technique for most thoracic patients. The anesthetic technique needs to optimize the myocardial oxygen supply/demand ratio by maintaining arterial oxygenation and diastolic blood pressure while avoiding unnecessary increases in cardiac output and heart rate. Thoracic epidural anesthesia or analgesia may be of help.62

Lung Separation There are two aspects of anesthetic management that are essentially unique to thoracic surgery: lung separation and management of one-lung anesthesia. Methods to achieve lung separation have been available since the introduction of the red rubber Robert-Shaw DLT, based on the principle from Björk and Carlens.63 OLV can be accomplished with two different methods. The first method involves a bifurcated DLT that can be used independently to block either the right or the left lung. The second method involves blockade of a main stem bronchus with bronchial blockers to allow lung collapse distal to the occlusion. In addition, bronchial blockers can be used to block a secondary bronchus to achieve selective lobar collapse.

There are a number of recognized indications for OLV, including better exposure for surgery of the lung, heart, great vessels, esophagus, and mediastinum; management of secretions (abscess, hemoptysis, bronchiectasis, and bronchopulmonary lavage); control of the airway (bronchopleural fistula and sleeve resection); and differential lung ventilation (PEEP and CPAP ventilation) in the intraoperative period or in the intensive care unit.

Fiberoptic Bronchoscopy Scientific evidence strongly suggests that auscultation alone is unreliable for confirmation of proper DLT placement. One study involving 200 patients who were intubated with the blind technique followed by confirmation with a fiberoptic bronchoscope found that more than one third of the DLTs required repositioning by at least 0.5 cm. This represents a malposition rate of more than 30%.50 A second study by Brodsky and Lemmens reported clinical experience with the use of left-sided DLTs in 1170 patients.35 Using auscultation and clinical signs, they found 71 patients (6.2%) in whom the DLT was not in a satisfactory position and required readjustment after initial placement. In 56 patients, the DLT was considered too deep into the left bronchus, and, indirectly, this was a cause of hypoxemia in 21 of 56 patients who had a malpositioned tube. This complication could be avoided with the use of fiberoptic bronchoscopy to demonstrate optimal placement of a DLT when the patient is in the most optimal position before surgery (i.e., the lateral decubitus position with the operating room table flexed). Significant malpositioning of left- or right-sided DLTs, which can lead to desaturation during OLV, is often not detected by auscultation or other traditional methods of confirming tube placement. Confirm positioning of DLTs or bronchial blockers whenever possible after the patient is placed in the surgical position because these tubes or blockers frequently migrate during patient repositioning. A fiberoptic bronchoscope must be available in the operating room at all times while surgery is in process to correct any malposition of a DLT that may occur.

Double-Lumen Endobronchial Tube Technology The DLT is a bifurcated tube with both an endotracheal and an endobronchial lumen; it can be used to achieve isolation of either the right or the left lung. There are two versions, a left- and a right-sided DLT, which are designed to accommodate the unique anatomy of each main stem bronchus. In North America, only DLTs made of disposable, plastic polyvinyl chloride material are available. Selection of the proper size of DLT remains a challenge. A properly sized DLT is one in which the main body of the tube passes without resistance through the glottis and advances easily within the trachea and in which the bronchial component passes into the intended bronchus without difficulty. A properly sized DLT needs to have a bronchial tip 1 to 2 mm smaller than the patient’s bronchus diameter to allow for the space occupied by the deflated cuff. One of the advantages of using a larger-sized DLT (i.e., 39 or 41 Fr) is that there is

49

50

Section 1 Introduction

A

B

C

FIGURE 4-6 Blind technique for placing a left-sided double-lumen tube (DLT). A, The DLT is passed with direct laryngoscopy beyond the vocal cords. B, The DLT is rotated 90 degrees to the left. C, The DLT is advanced until moderate resistance is felt, indicating that the endobronchial lumen of the DLT has entered the bronchus.

less resistance to gas flow and less intrinsic auto-PEEP during OLV. A DLT that is too small requires a large endobronchial cuff volume, which might increase the incidence of malposition. Also, a small DLT does not readily allow fiberoptic bronchoscope placement and can make suction difficult. A number of methods have been proposed for determining proper DLT size.64-66 Two techniques can be used to insert and properly position a DLT. The first one is known as the blind technique. The DLT is passed with direct laryngoscopy and then turned 90 degrees, either left for a left-sided DLT or right for a rightsided DLT, after the endobronchial cuff has passed beyond the vocal cords. The DLT is advanced until moderate resistance is felt, which usually indicates that the endobronchial lumen of the DLT has entered the bronchus; alternatively, the tube is advanced until the depth of insertion at the teeth is approximately 29 cm for either men or women if their height is at least 170 cm. Figure 4-6 displays the blind technique for insertion and placement of a left-sided DLT. With the second technique, known as the fiberoptic bronchoscopy guidance technique, the tip of the endobronchial lumen is guided after the DLT is through the vocal cords with the aid of a flexible fiberoptic bronchoscope. In a study by Boucek and colleagues67 comparing this method with the blind technique, it was shown that both methods achieved greater than 90% success. Although both methods resulted in successful left main stem bronchus placement in most patients, slightly more time was required when the fiberoptic bronchoscopy guidance technique was used. In addition, two patients in each group required an alternative method for tube placement. Either method may fail when used alone. Figure 4-7 displays the fiberoptic bronchoscopy guidance technique while placing a left-sided DLT. The left-sided DLT is simpler to use than the right-sided DLT because it has a greater margin of safety.68 In addition, the left-sided DLT can be used for operation on either lung or for bilateral sequential lung collapse. For left pneumonectomies, we recommend the use of a right-sided DLT.

A

B

C

FIGURE 4-7 Fiberoptic bronchoscopy guidance technique for placing a left-sided double-lumen tube (DLT). A, The DLT is passed with direct laryngoscopy beyond the vocal cords. B, The fiberoptic bronchoscope is advanced through the endobronchial lumen. The tracheal carina and the left main stem bronchus are visualized. C, The DLT is rotated 90 degrees to the left, and, with the aid of the fiberoptic bronchoscope, the tube is advanced to the optimal position in the left main stem bronchus.

A

A

B B

FIGURE 4-8 Fiberoptic bronchoscopic examination for a left-sided double-lumen tube (DLT). A, The edge of the endobronchial cuff around the entrance of the left main stem bronchus when the bronchoscope is passed through the tracheal lumen. B, Clear view of the bronchial bifurcation (left upper and lower bronchi) when the leftsided DLT is in the optimal position and the fiberoptic bronchoscope is being advanced through the endobronchial lumen. (FROM CAMPOS JH: PROGRESS IN LUNG SEPARATION. THORAC SURG CLIN 15:71, 2005; WITH PERMISSION. COPYRIGHT ELSEVIER 2005.)

Regardless of the insertion and placement technique used for a left-sided DLT, the optimal position as seen with the fiberoptic bronchoscope is the one that allows, from the endotracheal view, observation of a fully inflated endobronchial cuff (no more than 3 mL of air) located approximately 5 to 10 mm below the tracheal carina inside the left main stem bronchus.

Chapter 4 Anesthesia for General Thoracic Surgery

A

D

B A

D B

B

A

C

C

FIGURE 4-9 Fiberoptic bronchoscopy guidance technique for a rightsided double-lumen tube (DLT) when the fiberoptic bronchoscope is advanced through the endobronchial lumen. A, Fiberoptic view of the tracheal carina. B, Fiberoptic view of the takeoff of the right upper lobe bronchus.

The second view is through the endobronchial lumen, where the fiberoptic bronchoscope is advanced to determine the patency of the lumen. The second view is at the distal end of the endobronchial tip of the tube, where a clear and unobstructed view of the left upper and lower lobe bronchus entrance orifices can be visualized. This view determines the margin of safety of the DLT, which is an unobstructed secondary airway by the tip of the DLT. Figure 4-8 shows the optimal position of a left-sided DLT when seen with a fiberoptic bronchoscope. Indications for the use of a right-sided DLT include the following: 1. Distorted anatomy of the origin of the left main stem bronchus due to external or intraluminal tumor compression or descending thoracic aortic aneurysm. 2. A site of surgery involving the left main stem bronchus, such as left lung transplantation, left proximal pneumonectomy, or left-sided sleeve resection. The right-sided DLT incorporates a modified cuff and a slot on the endobronchial side that allows ventilation for the right upper lobe. Figures 4-9 and 4-10 depict the fiberoptic bronchoscopy guidance technique and bronchoscopic examination for a right-sided DLT.

Problems With Double-Lumen Endobronchial Tubes Although left-sided DLTs are the most commonly used devices for lung isolation, there are some issues related to their use. For example, selection of the proper size of DLT

FIGURE 4-10 Fiberoptic bronchoscopic examination for a right-sided double-lumen tube (DLT). A, The white line marker when the bronchoscope is passed through the endobronchial lumen. B, Slot of the endobronchial lumen properly aligned within the entrance of the right upper bronchus. C, Part of the bronchus intermedius when the bronchoscope is advanced through the distal portion of the endobronchial lumen. D, Edge of the endobronchial cuff around the entrance of the right main stem bronchus when the bronchoscope is passed through the tracheal lumen. (FROM CAMPOS JH: CURRENT TECHNIQUES FOR PERIOPERATIVE LUNG ISOLATION IN ADULTS. ANESTHESIOLOGY 97:1295-1301, 2002; WITH PERMISSION.)

continues to be a problem in female patients of shorter stature; this has led to the overuse of small-sized DLTs in women and a consequent increase in airway-related complications (e.g., tracheobronchial rupture, bronchial rupture, tension pneumothorax).69 At the present time, the recommended methods for selecting a properly sized DLT are inconsistent. Airway trauma and rupture of the membranous part of the trachea continue to be an isolated problem with the use of DLTs. This problem can occur during insertion and placement, while the case is in progress, or during extubation. Airway damage during the use of DLTs can manifest as an unexpected air leak, subcutaneous emphysema, massive airway bleeding into the lumen of the DLT, or protrusion of the endotracheal or endobronchial cuff into the surgical field, with visualization of this condition by the surgeon. If any of these problems occur, perform a bronchoscopic examination, followed by surgical repair if needed.

Bronchial Blocker Technology An alternative method to achieve lung isolation involves blockade of a bronchus to obtain total lung collapse or, if used selectively, to achieve selective lobar collapse. Currently, several devices are available to facilitate lung collapse (Campos, 2005).70 Independent bronchial blockers can be used over a single-lumen endotracheal tube or outside the endotracheal tube. Table 4-4 describes various devices for lung separation. Although bronchial blockers are indicated when lung separation is needed, there are also some unique situations in

51

52

Section 1 Introduction

TABLE 4-4 Devices for Lung Separation Techniques Double-Lumen Tube Technology Left-sided DLT (used more frequently) Right-sided DLT (limited margin of safety) Bronchial Blocker Technology Independent bronchial blockers Fogarty catheter Arndt wire-guided endobronchial blocker Cohen tip-deflecting endobronchial blocker Attached to a single-lumen endotracheal tube Univent torque control blocker

which independent bronchial blockers may be more advantageous than the DLT. These include patients who: 1. Are already tracheally intubated 2. Present with a difficult airway and require an awake oral or nasotracheal intubation and OLV 3. Have airway abnormalities 4. Had previous tracheostomy requiring OLV71 5. Require postoperative mechanical ventilation after OLV 6. Require a selective lobar blockade72 Arndt Wire-Guided Endobronchial Blocker. The Arndt blocker is an independent blocker that is attached to a 5 Fr (for pediatric use), 7 Fr, or 9 Fr catheter with an inner lumen that measures 1.4 mm in diameter. A unique feature of the Arndt blocker is that the inner lumen contains a flexible nylon wire that passes through the proximal end of the catheter, extends to the distal end, and exits as a small, flexible wire loop. The wire loop of the Arndt blocker is coupled with the fiberoptic bronchoscope and serves as a guidewire to introduce the blocker into a bronchus. Figure 4-11 shows the proper position of the Arndt blocker in the right or left main stem bronchus. Cohen Tip-Deflecting Endobronchial Blocker. The Cohen blocker is an independent endobronchial blocker that is available in size 9 Fr with an inner lumen measuring 1.4 mm in diameter. The Cohen blocker relies on a wheel-twisting device located in the most proximal part of the unit that allows the anesthesiologist to deflect the tip of the distal part of the blocker into the desired bronchus. This device has been purposely preangled at the distal tip to facilitate insertion into a target bronchus. Also, there is a torque grip located at the 55-cm mark to allow rotation of the blocker. In the distal tip above the balloon, there is an arrow that, when seen with the fiberoptic bronchoscope, indicates in which direction the tip deflects. Confirmation of optimal position is identical to that sought with the Arndt blocker (see Fig. 4-11). Univent Torque Control Blocker. The Univent torque control blocker relies on a single-lumen endotracheal tube made of silicon material that encloses a movable, torquecontrolled bronchial blocker. This movable blocker can be used to block the left or right main stem or any specific secondary bronchus. The bronchial blocker has a 2-mm diameter lumen that can be used for suctioning or for oxygen administration. Placement of the Univent torque control blocker is quite simple; it relies on inserting the endotracheal

A

B

FIGURE 4-11 Wire-guided endobronchial blocker (Arndt blocker). The optimal position of the Arndt blocker in the right (A) and the left (B) main stem bronchus. (FROM CAMPOS JH: PROGRESS IN LUNG SEPARATION. THORAC SURG CLIN 15:71, 2005; WITH PERMISSION. COPYRIGHT ELSEVIER 2005.)

tube in a conventional fashion after its bronchial blocker has been fully retracted. A fiberoptic bronchoscope is then passed and the enclosed bronchial blocker is advanced under direct vision into the targeted bronchus. Figure 4-12 shows the optimal position of the Univent torque control blocker in the left or right main stem bronchus. Complications of Bronchial Blockers. A common problem with the bronchial blockers is malposition and dislodgment of the blocker when the patient is turned from the supine to the lateral decubitus position. Our recommendation to avoid this problem is to deflate the cuff of the blocker after the original placement, turn the patient into a lateral decubitus position, and then reinflate the bronchial blocker. Inclusion of the bronchial blocker into the stapling line can be a potential problem; therefore, communication with the surgical team regarding the presence of a bronchial blocker is crucial. A potential and dangerous complication with the Univent bronchial blocker cuff has been reported: the cuff of the bronchial blocker was inflated mistakenly near the tracheal lumen, precluding all airflow and producing respiratory arrest.73 Another reported complication is the development of a negative-pressure pulmonary edema after continuous suctioning of the nondependent lung by a bronchial blocker.74

Chapter 4 Anesthesia for General Thoracic Surgery

chial blocker). The blocker’s position is confirmed with the fiberoptic bronchoscope. If the indication for lung separation is an absolute indication, then a tube exchanger technique with a Cook exchanger or a double-diameter, coaxial tube exchanger technique can be used to exchange the single-lumen endotracheal tube for a DLT or a Univent tube.75 In patients with an existing tracheostomy who require OLV, an easy approach is to replace the metallic cannula with a disposable Shiley tracheostomy tube and then pass an Arndt blocker with the tracheostomy tube to establish OLV.71

MANAGEMENT OF ONE-LUNG VENTILATION

A

B

FIGURE 4-12 Univent torque control blocker. The optimal position of the Univent torque control blocker in the right (A) and the left (B) main stem bronchus. (FROM CAMPOS JH: AN UPDATE ON BRONCHIAL BLOCKERS DURING LUNG SEPARATION TECHNIQUES IN ADULTS. ANESTH ANALG 97:1269, 2003; WITH PERMISSION.)

Difficult Airways and One-Lung Ventilation OLV in patients with difficult airways represents a challenge. It has been estimated that between 5% and 8% of patients with lung carcinoma present with a carcinoma of the upper airway (pharynx, tongue, or epiglottis). Many of them have had previous surgery, such as hemimandibulectomy or glossectomy, or have a frozen jaw, making the placement of the DLT difficult. In addition, some patients also present with lower airway abnormalities requiring OLV. These patients have a tracheostomy in place, which also makes lung separation techniques challenging. In addition, many patients have distorted anatomy of the neck after radiation. A complete assessment of the airway anatomy, complemented with chest radiographs and CT scans, is mandatory to determine the best device to achieve lung separation. In every patient who requires OLV and presents with a difficult airway, the first priority is to establish an airway with a single-lumen endotracheal tube via an awake, oral intubation or nasotracheal intubation with the aid of a fiberoptic bronchoscope. Once the airway is secured with a singlelumen endotracheal tube, the second priority is to select a bronchial blocker that can be advanced through the singlelumen endotracheal tube (Arndt blocker or Cohen endobron-

A unique problem that influences anesthetic management for thoracic surgery is the occurrence of hypoxemia during OLV. Reports for the period 1950 to 1980 describe an incidence of hypoxemia (arterial saturation <90%) of 20% to 25%.76 In the past 25 years, anesthetic management has decreased the incidence to levels approaching 1%.35 This improvement is due to several factors, including improved lung isolation techniques such as routine fiberoscopy to prevent lobar obstruction from DLTs, a better understanding of the pathophysiology of OLV, and improved anesthetic techniques. The pathophysiology of OLV involves the body’s ability to redistribute pulmonary blood flow from the nonventilated to the ventilated lung. Several factors can aid or impede this redistribution, and these are under the control of the anesthesiologist to a variable degree.

Intraoperative Position Most thoracic surgery is performed with the patient in the lateral position, and gravity is thought to increase proportional blood flow to the dependent lung by approximately 10%. A comparison between groups of patients having OLV for surgery in the supine versus the lateral position showed a significantly different mean PaO2 of 80 mm Hg after 30 minutes of OLV in the supine group, versus 175 mm Hg in the lateral group.77 In another study, six of eight patients with chronic obstructive pulmonary disease (COPD) showed an improvement in PaO2 after being turned from the supine to the lateral position during OLV.78 This has important implications for bilateral thoracoscopic procedures, which are increasingly done in the supine position.

Bilateral Pulmonary Surgery Owing to mechanical trauma to the operative lung, the gas exchange in this lung is always temporarily impaired after OLV. Therefore, desaturation during bilateral lung procedures is a particular problem during the second period of OLV (i.e., during OLV of the lung that has already had surgery).79 In such a situation, it is recommended to operate first on the lung that has better gas exchange and less propensity to desaturate during the initial OLV.

Hypoxic Pulmonary Vasoconstriction Many authors consider hypoxic pulmonary vasoconstriction (HPV) to be the most important factor governing the redis-

53

54

Section 1 Introduction

tribution of blood flow during OLV. HPV is thought to be able to decrease the blood flow to the nonventilated lung by 50%. The stimulus for HPV is primarily the alveolar oxygen tension (PAO2), which stimulates precapillary vasoconstriction, redistributing pulmonary blood flow away from hypoxemic lung regions via a pathway involving inhibition of nitric oxide or cyclo-oxygenase synthesis.80 The mixed venous partial pressure of oxygen (Pv¯O2) is also a stimulus, although it is considerably weaker than the PAO2.81 HPV has a biphasic effect, with a rapid onset phase during the first 30 minutes and a slow onset phase that is maximal at 2 hours. HPV seems to be a response that can be induced by preconditioning, with a more rapid response during re-exposure.82 Surgical trauma to the lung can affect pulmonary blood flow redistribution. Surgery may oppose HPV by release of vasoactive metabolites locally in the lung, or it may cause autonomic effects from trauma to the perihilar plexus. Conversely, surgery can dramatically decrease blood flow to the nonventilated lung by deliberate, or accidental, mechanical interference with either the unilateral pulmonary arterial or the venous blood flow. It is not clear what the mechanical effects of lung collapse are on the pulmonary flow through the nonventilated lung. Some authors have described a local reduction in pulmonary blood flow caused by the mechanical effects of collapse. Pulmonary vascular resistance is increased at low lung volumes.83 Whether this is a mechanical effect, is related to HPV, or both, is unclear.

Choice of Anesthetic All of the volatile anesthetics inhibit HPV. This inhibition is dose dependent. Animal studies suggest that this inhibition is also dependent on the agent: halothane > enflurane > isoflurane. There has been some animal evidence that sevoflurane and desflurane may cause less inhibition. In general, human studies have tended to confirm observations from the animal models, except that no benefit has been shown for sevoflurane or desflurane over isoflurane.84 Also, no clinical benefit has been shown for total IV anesthesia beyond that seen with the usual clinical concentrations of isoflurane, even though IV agents are well documented not to interfere with HPV. The inability of clinical studies to demonstrate superior oxygenation when vasodilating, volatile anesthetics are avoided during OLV is not easy to explain. It may be related in part to the fact that the distribution of PaO2 values in a group of patients during stable OLV is very wide; the standard deviation approaches 100 mm Hg in most studies. Also, the inhibition of HPV by a volatile agent such as isoflurane is only about 20%. This could account for a net difference of only 4% in total shunt during OLV, which is a difference too small to be detected in most clinical studies. In addition, volatile anesthetics cause less inhibition of HPV when they are delivered to the active site of vasoconstriction via the pulmonary arterial blood than when delivered via the alveolus. This pattern is similar to the HPV inhibitory characteristics of oxygen. During established OLV, the volatile agent reaches the hypoxic lung alveoli only via the pulmonary

blood. Because the inhibition of HPV is dose dependent, the lower incidence of hypoxemia during OLV in the past decade may be related to the use of lower concentrations of volatile anesthetic agents. Many of the studies from the 1970s used relatively high doses of halothane.

Cardiac Output The effects of alterations of cardiac output during OLV are complex. Increasing cardiac output tends to cause increased pulmonary artery pressures and passive dilation of the pulmonary vascular bed, which in turn opposes HPV and has been shown to be associated with increased shunting during OLV. However, in patients with a relatively fixed oxygen consumption, as is seen during stable anesthesia, the effect of an increase in cardiac output is to increase mixed venous oxygen content. Therefore, increasing cardiac output during OLV tends to increase both shunt and venous oxygen, which have opposing effects on PaO2. The net effects of major increases or decreases in cardiac output during OLV tend to favor a decrease in PaO2.85 HPV is decreased by all vasodilators such as nitroglycerin and nitroprusside.86 In general, vasodilators can be expected to cause a deterioration in PaO2 during OLV.

Ventilation Strategies The strategy used to ventilate the ventilated lung during OLV plays an important part in the distribution of pulmonary blood flow between the lungs. It has been the practice of many anesthesiologists to use the same tidal volume during OLV as during two-lung ventilation. Although this strategy is adequate for most cases, it is clearly possible to improve gas exchange for selected patients by altering the ventilatory variables that are under the control of the anesthesiologist: tidal volume, rate, inspiratory/expiratory ratio, PaCO2, peak and plateau airway pressures, and PEEP.

Respiratory Acid/Base Status The efficacy of HPV in a hypoxic lung region is increased in the presence of respiratory acidosis and is inhibited by respiratory alkalosis. However, there is no net benefit to gas exchange during OLV from hypoventilation because the respiratory acidosis preferentially increases the pulmonary vascular tone of the well-oxygenated lung, and this opposes any clinically useful pulmonary blood flow redistribution. Overall, the effects of hyperventilation tend to decrease pulmonary pressures.

Positive End-Expiratory Pressure It is generally accepted that resistance to blood flow through the lung is related to lung volume in a biphasic pattern: it is lowest when the lung is at its FRC. For this reason, it is theorized that keeping the ventilated lung as close as possible to its normal FRC should favorably encourage pulmonary blood flow to that lung. Several intraoperative factors that are known to alter FRC tend to cause the FRC of the ventilated lung to fall below its normal level; these include lateral position, paralysis, and opening of the nondependent hemi-

Chapter 4 Anesthesia for General Thoracic Surgery

thorax, which allows the weight of the mediastinum to compress the dependent lung. Attempts to measure FRC in human patients during OLV have been complicated by the presence of a persistent end-expiratory airflow in most patients. Further investigation has shown that most patients do not actually reach their end-expiratory equilibrium FRC lung volume because of this delayed expiration as they try to exhale a relatively large tidal volume through one lumen of a DLT. These patients develop an occult positive endexpiratory pressure (auto-PEEP).87 PEEP tends to benefit patients with normal lung mechanics (patients without COPD) and those with increased elastic recoil (restrictive lung disease) during OLV.88

Auto-PEEP Auto-PEEP is most prone to occur in patients with decreased lung elastic recoil, including the elderly and those with emphysema. Auto-PEEP increases as the inspiratory/expiratory ratio increases (i.e., as the time of expiration decreases). This auto-PEEP, which averages 4 to 6 cm H2O in most series of patients studied, opposes factors that tend to diminish dependent-lung FRC during OLV. The effects of applying external PEEP through the ventilator circuit to the lung, in the presence of auto-PEEP, are complex. There tends to be a nonarithmetic additive effect. For most patients with an auto-PEEP of 4 to 6 cm H2O, the addition of 5 cm external PEEP to the ventilator circuit results in a net total PEEP to the patient of 7 to 8 cm. Patients with a very low auto-PEEP (<2 cm H2O) experience a greater increase in total PEEP from a moderate (5 cm H2O) external PEEP than do those with a high level of auto-PEEP (>10 cm H2O). Whether the application of PEEP during OLV will improve a patient’s gas exchange depends more on the individual’s lung mechanics (as demonstrated by the static lung compliance curve) than on the presence or absence of auto-PEEP.34 If the application of PEEP tends to shift the expiratory equilibration position on the compliance curve toward the lower inflection point of the curve (i.e., toward the FRC), then external PEEP is of benefit. However, if the application of PEEP raises the equilibration point such that it is farther from the inflection point, then gas exchange deteriorates. The fall in oxygenation as mean airway pressure increases is caused by the transmission of airway pressure to the pulmonary vasculature and redistribution of blood flow away from the ventilated lung because the airway pressure in the nonventilated hemithorax is atmospheric. Auto-PEEP is difficult to detect and measure using currently available anesthetic ventilators because these ventilators are open to the atmosphere during expiration. For auto-PEEP to be detected, the respiratory circuit must be held closed at the end of a normal expiration until an equilibrium appears in the airway pressure. Most current intensive care ventilators can be used to measure auto-PEEP. Many patients show surprisingly high levels of auto-PEEP, often greater than 10 cm H2O, during OLV using standard ventilatory parameters. Auto-PEEP is dependent on the time of expiration; therefore, the use of higher inspiratory/expiratory ratios or the addition of an end-inspiratory pause tends to increase auto-PEEP.

Tidal Volume There is without doubt an optimal combination of tidal volume, respiratory rate, inspiratory/expiratory ratio, and pressure- or volume-controlled ventilation for each individual patient during OLV. Traditionally, anesthesiologists have tended to use the same tidal volume for OLV as for two-lung ventilation (e.g., 10 mL/kg). Because of the presumed decrease in FRC with the nondependent thorax open, this was thought to decrease the risk of atelectasis formation in the dependent lung. However, certain individuals have better oxygenation with larger (14 mL/kg) or smaller (8 mL/kg) tidal volumes.89 At present, the benefits of alterations in tidal volume are unpredictable. This may be due in part to the interaction of tidal volume with auto-PEEP. The use of 10mL/kg tidal volumes initially for most patients seems a logical starting point during OLV. Decrease tidal volume so that peak airway pressures do not exceed 35 cm H2O. This corresponds to a plateau airway pressure of approximately 25 cm H2O. Peak airway pressures exceeding 40 cm H2O may contribute to hyperinflation damage to the ventilated lung during OLV. Turning the patient to the lateral position increases respiratory dead space and the arterial-to-end-tidal carbon dioxide tension gradient. This usually requires a 20% increase in minute ventilation to maintain the same PaCO2.

Volume-Controlled Versus Pressure-Controlled Ventilation Traditionally, volume-controlled ventilation has been used in the operating room for all types of surgery. The recent availability of anesthesia ventilators with optional pressure-control modes has made it possible for this form of ventilation to be studied and used during thoracic surgery. In a series of patients, pressure-controlled ventilation resulted in a statistically significant but small improvement in oxygenation.90 This improvement is most marked (for the same tidal volume) in patients with COPD. Pressure-controlled OLV is very useful in patients with severe obstructive disease, such as those undergoing lung volume reduction.

Increasing the Collapse of the Nonventilated Lung In certain clinical situations, increasing the speed of collapse of the lung on the side of surgery during one-lung anesthesia is useful. These situations include thoracoscopic surgery and surgery in patients with emphysema (who tend to have delayed collapse of the nonventilated lung). Avoiding the use of air in the ventilating gas mixture during the initial period of two-lung ventilation, by ventilating with either oxygen or a mixture of oxygen and nitrous oxide, leads to more rapid collapse of the nonventilated lung after the initiation of OLV.91 This is a result of the increased blood solubility and uptake of oxygen and nitrous oxide compared with the low solubility of nitrogen, the major constituent of air.

Treatment of Hypoxemia During One-Lung Ventilation Hypoxemia during OLV responds readily to treatment in most cases. Potential therapies are described in the following paragraphs.

55

56

Section 1 Introduction

Increased Fraction of Inspired Oxygen. The purpose of first-line therapy is normally to increase the FIO2; this is an option in essentially all patients except those who have received bleomycin or similar therapy that potentiates pulmonary oxygen toxicity. Continuous Positive Airway Pressure. CPAP with oxygen to the nonventilated lung is the most reliable ventilatory intervention,92 apart from augmenting the FIO2, and has proved to be consistently more reliable at improving oxygenation than other ventilatory maneuvers such as oxygen insufflation to the nonventilated lung or PEEP to the ventilated lung. There is an important caveat to be observed when CPAP is applied to the nonventilated lung, however: CPAP must be applied to a fully inflated lung to be effective. The opening pressure of atelectatic lung regions is greater than 20 cm H2O, and these units will not be recruited by CPAP levels of 5 to 10 cm H2O. Even a period as short as 5 minutes of collapse before CPAP application can have deleterious effects on oxygenation during OLV. When CPAP is properly applied to a fully inflated lung, levels of CPAP as low as 2 to 3 cm H2O can be used. Because the normal transpulmonary pressure of the lung at FRC is approximately 5 cm H2O, levels of 5 to 10 cm H2O CPAP result in a large-volume nonventilated lung, which impedes surgery. Because surgical exposure is the most common indication for OLV, it is preferable to use lower levels of CPAP. Owing to lung elastic recoil, this results in a nonventilated lung that is one third to one half of its resting FRC volume; also, during open thoracotomy, it does not interfere with surgical access into the operative hemithorax. CPAP levels lower than 10 cm H2O do not interfere with hemodynamics. The beneficial effects of low levels of CPAP are primarily due to oxygen uptake from the nonventilated lung and not to blood flow diversion to the ventilated lung. CPAP is most effective when oxygen (FIO2 1.0) is applied to the nonventilated lung. Lower FIO2 levels of CPAP are of clinical benefit and can be used along with decreased FIO2 to the ventilated lung in patients who are at risk for oxygen toxicity. Numerous anesthetic systems to apply CPAP to the nonventilated lung have been described.84 Essentially all that is required is a CPAP valve and an oxygen source. Ideally, the circuit permits variation of the CPAP level and includes a reservoir bag to allow easy reinflation of the nonventilated lung and a manometer to measure the actual CPAP supplied. Such circuits are commercially available or can be readily constructed from standard anesthetic equipment. However, CPAP, even when properly administered, is not completely reliable to improve oxygenation during OLV. If the bronchus of the operative lung is obstructed or is open to the atmosphere (as in a bronchopleural fistula or during endobronchial surgery), CPAP will not improve oxygenation. Also, in certain situations, particularly during thoracoscopic surgery in which surgical access to the operative hemithorax is limited, CPAP can interfere with surgery by preventing complete lung collapse. Positive End-Expiratory Pressure. PEEP to the ventilated, dependent lung has often been used to improve oxygenation during OLV. During two-lung ventilation in the

lateral position, the selective administration of PEEP to the dependent lung can be expected to improve dependent lung mechanics and gas exchange. However, studies of groups of patients consistently show a fall in mean PaO2 levels when PEEP is applied to the dependent lung during OLV. A small minority (<25%) of patients benefit from PEEP during OLV. Fortunately, these are often the patients with the lowest PaO2 levels.93 The unreliability of PEEP for improving PaO2 during OLV is probably due in part to the interaction of PEEP with autoPEEP and in part to the changes that develop in individual lung mechanics during OLV in the lateral position with an open hemithorax. It is possible to identify the subgroup of patients who will benefit from 5 cm H2O PEEP to the ventilated lung during OLV. These are patients who have both relatively low PaO2 values during two-lung ventilation in the lateral position (i.e., PaO2/FIO2 <160) and lower than mean auto-PEEP (4 cm H2O) during OLV. Tidal volume manipulations benefit certain individuals during OLV, but at present it is not possible to predict which patients, or at what volumes. This is undoubtedly due to complex interactions involving altered lung mechanics and auto-PEEP during OLV. It should be possible with better respiratory monitoring to choose an optimal tidal volume for an individual patient. Alternative Ventilation Methods. Several alternative methods of OLV, all involving partial ventilation of the nonventilated lung, have been described and improve oxygenation during OLV. These techniques are useful in patients who are particularly at risk of desaturation, such as those who have had previous pulmonary resection of the contralateral lung. 1. Selective lobar collapse of only the operative lobe in the open hemithorax. This is accomplished by placement of a blocker in the appropriate lobar bronchus of the ipsilateral operative lung.72 2. Differential lung ventilation. This is done by only partially occluding the lumen of the DLT to the operative lung.94 3. Intermittent reinflation of the nonventilated lung. This can be performed by regular re-expansion of the operative lung via an attached CPAP circuit.95 4. Two-lung high-frequency positive-pressure ventilation (HFPPV). The use of very small tidal volume at high rates permits ongoing ventilation of the operative lung with minimal movement of the surgical field.96 5. Conventional OLV of the nonoperative lung and high-frequency jet ventilation (HFJV) of the operative lung. These have both been shown during thoracic surgery to provide oxygenation superior to conventional OLV, or to conventional OLV plus CPAP to the nonventilated lung.97 Highfrequency ventilation strategies tend to increase the diameters of the central airways in the operative lung and make pulmonary resection surgically more difficult.98 It seems that these methods are most useful for improving oxygenation during intrathoracic, nonpulmonary surgery, such as esophageal or aortic surgery. It has been suggested that avoidance of total intraoperative collapse of the operative lung may improve postoperative pulmonary function

Chapter 4 Anesthesia for General Thoracic Surgery

and decrease morbidity.99 High-frequency ventilation techniques are also useful because they can be delivered through a catheter in cases involving surgery on the main bronchi, such as sleeve resection.100 Mechanical Restriction of Pulmonary Blood Flow. It is possible for the surgeon to directly compress or clamp the blood flow to the nonventilated lung. This can be done temporarily in emergency desaturation situations or definitively in cases of pneumonectomy or lung transplantation. Another technique of mechanical limitation of blood flow to the nonventilated lung is inflation of a pulmonary artery catheter balloon in the main pulmonary artery of the operative lung. The pulmonary artery catheter can be positioned at induction with fluoroscopic guidance and inflated as needed intraoperatively. This has been shown to be a useful technique for resection of large pulmonary arteriovenous fistulas.101 Pharmacologic Manipulations. Because patients tend to have a large intrapulmonary shunt (30%-40%) and fixed oxygen consumption during stable one-lung anesthesia, increasing the cardiac output results in a small but clinically useful increase in both Pv¯O2 and PaO2. In a similar sense, eliminating known potent vasodilators such as nitroglycerin and halothane improves oxygenation during OLV. The use of selective pulmonary vasoactive agents in an attempt to improve oxygenation during thoracotomy has recently been the subject of much interest. The selective administration of the vasodilator prostaglandin E1 to the ventilated lung102 or a nitric oxide synthase inhibitor (L-NAME)103 to a hypoxic lobe has been shown to result in improved redistribution of pulmonary blood flow in animal models. Selective administration of nitric oxide alone to the ventilated lung was not shown to be of benefit in humans. The combination of nitric oxide (20 ppm) to the nonventilated lung and an IV infusion of almitrine, which enhances HPV, was shown to restore PaO2 values during OLV in humans to essentially the same levels as during two-lung ventilation.104 It is unlikely that almitrine, which was previously available in North America as a respiratory stimulant, will be reintroduced to this market owing to adverse effects such as hepatic enzyme changes and lactic acidosis. However, the combination of nitric oxide and other pulmonary vasoconstrictors such as phenylephrine has been shown to improve oxygenation in ventilated patients with adult respiratory distress syndrome in intensive care units and may have applications in OLV. All treatments outlined as therapy for hypoxemia can be used prophylactically to prevent hypoxemia in patients who are at high risk of desaturation during OLV. These patients can be identified, as described earlier, based on data available before the onset of OLV. The advantage of prophylactic therapy for hypoxemia, in addition to the obvious patient safety benefit, is that maneuvers involving CPAP or alternative ventilation patterns of the operative lung can be instituted at the onset of OLV in a controlled fashion and do not require interruption of surgery and emergent reinflation of the nonventilated lung at a time when it may be extremely disadvantageous to do so.

Ventilation strategies must prioritize the avoidance of hypoxemia and barotrauma over concerns about hypercapnia. PaCO2 of up to 100 mm Hg is well tolerated during OLV for limited periods.105

Fluid Management Because of hydrostatic effects, excessive administration of IV fluids can cause increased shunting, leading to pulmonary edema of the dependent lung.106 Because the dependent lung is the lung that must carry on gas exchange during OLV, it is best to be as judicious as possible with fluid administration. IV fluids are administered during lung resection anesthesia only to replace volume deficits and for maintenance. No volume is given for theoretical third-space losses during thoracotomy. There is no good evidence that such third-space losses occur during lung resection as they do during abdominal or other types of major surgery.

Temperature Maintenance of body temperature can be a problem during thoracic surgery because of heat loss from the open hemithorax. This is a particular problem at the extremes of the age spectrum. Most of the body’s physiologic functions, including HPV, are inhibited during hypothermia. Increasing the ambient room temperature and using a lower-limb forced-air patient warmer are the best methods for preventing inadvertent intraoperative hypothermia.

ANESTHETIC CONSIDERATIONS FOR SPECIFIC THORACIC SURGICAL PROCEDURES Mediastinoscopy Paratracheal lymph nodes can be sampled during mediastinoscopy through a small suprasternal incision. General anesthesia is almost universally used during insertion of the mediastinoscope, with muscle relaxation to prevent coughing and avoid the resulting trauma to surrounding structures. Minimal surgical trespass and the use of short-acting general anesthetic agents have resulted in this procedure’s being routinely performed on an outpatient basis in many institutions, even on patients with significant chronic pulmonary disease. During mediastinoscopy, the patient’s neck is hyperextended by placement of a roll under the shoulders. Extensive cervical fusion or ankylosing spondylitis may preclude adequate positioning. Preoperatively, symptoms of cervical spine pathology prompt lateral neck radiographs in flexion and extension, as does a history of congenital or acquired disease that predisposes the patient to cervical spine instability. Down syndrome and certain forms of dwarfism can cause hypoplasia of the odontoid process of the second cervical vertebra (C2) or laxity of the atlantoaxial ligament, with implications for both intubation and surgical positioning.107,108 Patients with rheumatoid arthritis may develop atlantoaxial (C1-C2) subluxation from the inflammatory erosion of the joints and ligaments that stabilize the odontoid. Atlantoaxial subluxation can result from neck flexion, extension, and rotation, depending on the distribution of joint destruction; less frequently, subaxial (below C2) subluxation may occur.

57

58

Section 1 Introduction

Cervical involvement in rheumatoid arthritis is common (up to 86% of patients with long-standing disease) and may occur in the absence of signs or symptoms.109 In the worst case scenario, acute subluxation can result in spinal cord and vertebral artery compression, causing quadriparesis or sudden death. Continuous assessment of right arm perfusion is warranted during manipulation of the mediastinoscope because the innominate artery can be compressed, leading to total cessation of flow to the right upper extremity and right carotid artery. This is particularly important in patients with cerebrovascular disease, in whom transient neurologic deficit has been reported.110 If the patient’s underlying medical condition warrants an arterial line, this is placed on the right side, with an automatic, noninvasive blood pressure cuff on the left side as a second site for assessing blood pressure. Most patients do not require an arterial line; the pulse oximeter on the right hand, in combination with a second, hand-operated blood pressure cuff, ensures continuous flow monitoring on the right and pressure monitoring on both sides. Torrential hemorrhage may rarely occur from vascular injury at the biopsy site, requiring immediate thoracotomy. Resuscitation fluids administered IV in the upper body may spill into the mediastinum. If venous vascular injury occurs, packing is typically placed in the mediastinum. IV access in the lower limbs is sought. Sternotomy or thoracotomy may be required to locate the site of bleeding, and placement of a DLT may be possible if the patient’s hemodynamic status allows. In a rapidly deteriorating patient or a patient who is difficult to intubate, single-lung ventilation may be achieved with a bronchial blocker or by advancement of the singlelumen tube into one bronchus, if the endotracheal tube is left uncut. After uncomplicated mediastinoscopy, patients are observed in the postanesthetic care unit for signs of stridor or respiratory compromise indicative of vocal cord dysfunction from recurrent laryngeal injury, diaphragmatic dysfunction from phrenic nerve injury, or clinical manifestations of pneumothorax or airway disruption. A chest radiograph is usually performed before the patient is discharged.

Complex Operations Bronchopleural Fistula Whichever surgical procedure is used, there are three specific anesthetic goals in all patients with a bronchopleural fistula. First, healthy lung regions must be protected from soiling by extrapleural fluid from the affected hemithorax. Second, the ventilation technique must avoid development of a tension pneumothorax in the affected hemithorax. And third, the anesthetic technique must ensure adequate alveolar gas exchange in the presence of a low-resistance air leak. To achieve these three goals, there are two management principles that are used in essentially all cases. First, a functioning chest drain is placed before induction of anesthesia and connected to an underwater seal without suction. Second, some method of lung separation is placed so that the fistula can be isolated intraoperatively as necessary.

After placement of a chest drain, there are three options for induction of anesthesia. First, a DLT can be placed in an awake patient with topical anesthesia and its position checked fiberoptically before induction. This may be the safest option in some patients because it secures the airway and protects the lung before anesthesia and positive-pressure ventilation are instituted. However, awake double-lumen intubation is often not simple for either the anesthesiologist or the patient, and most patients can be safely managed using one of the other options. Also, this is often not the best choice in a patient with severely compromised gas exchange because maintaining adequate oxygenation in an already hypoxemic patient can be a problem during awake double-lumen intubation. The second option for airway management is induction of anesthesia while maintaining spontaneous ventilation until lung isolation is secured. This avoids the risk of tension pneumothorax and permits favorable matching of ventilation to perfusion. However, a spontaneous ventilation induction may not be desirable if there is a risk of aspiration. Patients with compromised hemodynamics may not tolerate it. A third option is IV induction of general anesthesia and muscle relaxation after meticulous preoxygenation and manual ventilation, using small tidal volumes and low airway pressures until the airway isolation is confirmed. The efficiency of this technique can be improved by using a bronchoscope to guide the DLT placement during intubation. The air leak through a bronchopleural fistula is dependent on the pressure gradient between the mean airway pressure at the site of the fistula and the interpleural space. A wide variety of differential methods of ventilation and chest drain management have been used to try to improve the ventilation in patients with bronchopleural fistula, both in the operating room and in the intensive care unit. High-frequency ventilation,111 with and without lung or lobar blockade, has been used in certain cases. The lack of agreement on a single best technique for these patients is probably a reflection of the fact that the individual mechanical properties of air leaks vary widely from patient to patient. Similarly, the centralperipheral gradient of mean airway pressures depends on the type of ventilation. High-frequency techniques may permit relatively lower proximal mean airway pressures than does conventional mechanical ventilation, and they may be more useful in larger, central air leaks.

Bullae and Blebs Whenever positive-pressure ventilation is applied to the airway of a patient with a bulla or a bleb, there is risk of rupturing the lesion and causing the development of a tension pneumothorax and bronchopleural fistula. The anesthetic considerations are similar to those for a patient with a bronchopleural fistula, with the exception that it is best not to place a prophylactic chest drain because it could enter the bulla and create a fistula. There is no risk of soiling healthy lung regions with extrapleural fluid, such as exists with fistulas. For induction of anesthesia, it is usually optimal to maintain spontaneous ventilation until the lung or lobe with the

Chapter 4 Anesthesia for General Thoracic Surgery

bulla or bleb is isolated. If there is risk of aspiration, or if it is believed that the patient’s gas exchange or hemodynamics may not permit spontaneous ventilation for induction, the anesthesiologist must use small tidal volumes and low airway pressures during positive-pressure ventilation until the airway is isolated.112

Abscesses, Bronchiectasis, Cysts, and Empyema Chronic infectious lung processes can arise after acute pulmonary infection or after surgery or trauma. Failure of conservative management with antibiotics or closed drainage may lead to the need for surgical intervention. As with bronchopleural fistulas, there is the risk of soiling healthy lung regions with uncontrolled spillage from the lesion. Lung isolation is a primary requirement for anesthesia, and the anesthetic principles and management are similar to those described for fistulas. Also, when an intrathoracic space-occupying lesion is removed, there is the potential for development of re-expansion pulmonary edema after reinflation of the ipsilateral lung. A slow and gradual reinflation may decrease the severity of this complication.113

Mediastinal Mass Lesions of the mediastinum may be approached via sternotomy or thoracotomy. The anesthetic approach to small lesions does not vary from that of other thoracic procedures. The anesthesiologist is, however, influenced by the presence of a large mediastinal mass in an anterior position (Fig. 4-13). Both complete tracheobronchial obstruction and cardiovascular collapse have occurred when a patient was placed in the supine position at induction of general anesthesia or in the

FIGURE 4-13 Chest radiograph of a patient with an anterior mediastinal mass, in this case a retrosternal goiter.

postoperative period.114,115 Positive-pressure ventilation and the use of muscle relaxants contribute to the compressive effects of the mass, thereby compromising vital structures. Under such circumstances, a change to lateral or prone positioning can be life-saving. Rigid bronchoscopy may alternatively bypass the compressed airway. During preoperative assessment, symptoms of concern include positional dyspnea (airway compression) and presyncope during Valsalva’s maneuver (pericardial or pulmonary arterial involvement). Superior vena cava obstruction may impair venous return, diminish the utility of upper body IV access, and promote edema of the upper airway. Among various diagnostic tools, upright and supine flow-volume loops are proposed for the evaluation of compressive airway lesions; however, there are no specific criteria to predict life-threatening complications. CT and magnetic resonance imaging (MRI) will delineate impingement on the airway, and contrast enhancement will reveal any vascular involvement, but not the dynamic effects of a change from the awake to the anesthetized or paralyzed state (Fig. 4-14). Surgical intervention is often necessary to ensure an accurate histologic diagnosis; however, every effort is made to avoid high-risk general anesthesia. It may be possible to sample superficial nodes under local anesthesia with sedation, or the anterior mass itself through a small intercostal incision. Limited preoperative administration of steroid or radiotherapy may rapidly decrease the size of the mass, and therefore the risk of general anesthesia; discuss this option with the oncology team. If surgery must proceed under general anesthesia in a symptomatic patient, a spontaneously breathing, inhalation induction of anesthesia with intubation without muscle relaxation is frequently chosen. Awake fiberoptic intubation followed by general anesthesia with spontaneous ventilation has been proposed to better maintain airway patency.116 With the airway secured, a test of positivepressure ventilation, with careful monitoring of delivered tidal volumes, peak airway pressure, and cardiovascular

FIGURE 4-14 CT scan showing airway compression at the carina from a large anterior mediastinal mass.

59

60

Section 1 Introduction

effects using beat-to-beat blood pressure monitoring with an arterial line, is possible. A rigid bronchoscope must be immediately available, as well as a stretcher for prone positioning of the patient. Some authors have suggested that all patients in whom imaging reveals more than 50% compression of the airway at the level of the lower trachea or main bronchi should undergo cannulation of their femoral vessels under local anesthesia before induction of general anesthesia, in readiness for CPB.117 This recommendation may be most relevant to pediatric patients, particularly young children with rapidly growing lymphomas, in whom there are reports of severe airway obstruction in minimally symptomatic patients.118 In adults with this degree of obstruction, the clinical picture must clearly be taken into account when considering the need for extracorporeal cardiorespiratory support. In addition to CPB, extracorporeal membrane oxygenation (ECMO) is an option increasingly used, particularly in pediatric centers, and it has been used to support patients who are at risk for airway obstruction and pulmonary vascular compression during surgery for mediastinal mass.119 The difficulty of awake placement of a femoral cannula in pediatric patients, or in any patient who is in respiratory distress and very dyspneic when lying flat, must not be underestimated. Anticoagulation with heparin is required for both CPB and ECMO, which can cause bleeding complications at the surgical site. To proceed with general anesthesia in a very high-risk patient without cannulation and with extracorporeal bypass available on a “standby” basis is fraught with risk because the patient will already be deteriorating from hypoxia or cardiovascular collapse, and timely rescue from end-organ ischemia is uncertain. In many cases, surgery for mediastinal masses is for tissue biopsy rather than resection, and the patient will emerge from anesthesia with the original degree of airway or vascular compression. Patients who are extubated ideally are wide awake and maintained in a comfortable sitting position. Careful postoperative monitoring is required. Recently, a report of anesthetic management of adults with large anterior mediastinal masses revealed that intraoperative airway obstruction was rare and was correctable in all cases. Both pleural and pericardial effusion on CT were predictive of intraoperative complications. Seven of 105 patients experienced life-threatening postoperative respiratory complications. Patients at high risk were those who were symptomatic at presentation and also had CT findings of tracheal compression greater than 50%. Additionally, the finding of combined obstructive and restrictive defects on pulmonary function testing was associated with a greater incidence of postoperative problems.120 Other patients may remain intubated, to receive urgent chemotherapy or radiotherapy to shrink the mass. In very high-risk patients, the decision to proceed must be made jointly by all specialties involved, including anesthesiology, surgery, and oncology, and must examine all factors in the case, including any possibility of the avoidance of general anesthesia, the availability of rigid bronchoscopy and an expert bronchoscopist, and extracorporeal perfusion techniques. If extracorporeal perfusion is contemplated, cannula-

tion is accomplished before induction of anesthesia, after appropriate risk counseling and consent of the patient.

Thymectomy for Myasthenia Gravis Myasthenia gravis is a disease of the neuromuscular junction; affected patients have a decreased number of acetylcholine receptors at the motor end plate. Thymectomy is frequently performed to induce clinical remission. The effects of muscle relaxants are modified by this disease; myasthenic patients are resistant to succinylcholine, so a greater-than-normal dose is required. The use of succinylcholine is associated with the early onset of phase II block, which can be prolonged. Nondepolarizing muscle relaxants have increased potency and duration, with incomplete antagonism by the IV anticholinesterase neostigmine.121 Myasthenic patients are more sensitive to the neuromuscular effects of the halogenated agents and to systemic narcotics. Monitoring for postoperative airway obstruction and hypoventilation is therefore of particular importance. Thymectomy may be performed via full or partial sternotomy, or a minimally invasive approach via cervicotomy or thoracoscopy may be used. Ideally, the use of neuromuscular relaxation is avoided. Induction of anesthesia with propofol facilitates intubation without the use of muscle relaxants.122 Alternatively, inhalational induction with a halogenated agent such as sevoflurane may be performed. Most patients are taking pyridostigmine, an oral anticholinesterase, and many patients are taking immunosuppressive medication. On the day of surgery, pyridostigmine dosing must ensure that the patient’s usual regimen is provided during the immediate perioperative period. A few patients require IV dosing with neostigmine until they are able to resume oral intake of pyridostigmine. A scoring system was devised for prediction of the need for prolonged mechanical ventilation after thymectomy via sternotomy. A predictive accuracy of 80% was initially described.123 Among the criteria that contributed to the predicted need for support were disease duration longer than 6 years, chronic respiratory illness, pyridostigmine dosage greater than 750 mg/day, and vital capacity less than 2.9 L. The relevance of this score has diminished with the advent of transcervical thymectomy, which, when applied to these patients, reduced the predictive accuracy to 13%.124 Referral for surgery early in the course of the disease and stabilization of symptoms with medication and plasmapheresis, combined with increased use of the transcervical approach, have made the need for postoperative ventilation infrequent. In optimized patients, mean hospital length of stay can been reduced to 1 day after transcervical and 3 days after transsternal thymectomy.125 Patients remain on their full medical regimen postoperatively; the remission from myasthenia gravis occurs over months to years.

Esophageal Surgery Esophageal surgery may be performed for resection of malignant or benign lesions or for correction of a functional abnormality. The potential for esophageal reflux and pulmonary aspiration of gastric contents must be considered at the time

Chapter 4 Anesthesia for General Thoracic Surgery

of induction and at emergence from anesthesia, and appropriate antireflux precautions must be taken. This may include rapid sequence intubation, maintenance of the patient in a semi-sitting position, nasogastric drainage, and the use of chemoprophylaxis to decrease the volume and increase the pH of gastric fluid. The value of antacids, gastric acid secretion blockers, antiemetics, and gastric propulsants remains unproven in the prevention of the secondary lung injury of acid aspiration. If aspiration has occurred, treatment is supportive; bronchoscopy is used for removal of particulate matter, and ventilation with PEEP is administered if respiratory failure occurs. The esophagus may be approached via an abdominal incision or thoracotomy or both, with or without an additional cervical incision, depending on the site of the cancer. Regardless of whether the chest is opened, the diaphragmatic dysfunction that accompanies an upper abdominal incision, combined with trauma to intrathoracic structures, results in a greater degree of respiratory compromise than the extent of the incision would suggest.126 Pneumonia occurs in as many as 15% of esophagogastrectomy patients, including those treated in high-volume centers, and is associated with a 20% mortality rate. Patients who develop pneumonia have significantly worse deglutition after surgery.127 Consider the potential for reduced ability to mobilize secretions and increased tendency to aspirate when these patients are extubated, during the early postoperative course, and if early reoperation is required. Superior analgesic regimens most likely have contributed to the improved outcomes reported in recent surgical series. Patients benefit from regional analgesia to optimize postoperative pulmonary function and to facilitate return of spontaneous ventilation. Early extubation after esophagectomy is associated with reduced morbidity and decreased length of stay in high-dependency units. Reductions in hospital stay have been reported by some authors when patients received epidural analgesia including local anesthetics rather than IV morphine,128 whereas others have reported only better pain control and less narcotic-related confusion and sedation.129,130 The inclusion of regional analgesia as part of a multimodal therapy allows reduced narcotic dosing, which may contribute to less postoperative ileus. A significant amount of fluid enters the interstitial space in the abdomen during major esophageal surgery; therefore, fluid administration is liberalized, compared with thoracotomy for pulmonary resection. Some intravascular volume loading is required to retain intravascular volume; however, there is increasing evidence of earlier return of bowel function in abdominal surgery if intraoperative fluid is restricted and lower urine output is tolerated.131 Fluid restriction was credited for a reduction of pulmonary complications, compared with historical controls, in two recent reports of esophagectomy.132,133 Accurate monitoring of intravascular volume status is desirable. The placement of a central venous catheter is justified, but there are questions as to how accurately CVP or pulmonary capillary wedge pressure measurement reflects circulating blood volume during and after esophagectomy.134 This is a particular problem during surgery when the patient is in the

lateral position with an open chest. Monitoring of the trends in CVP and urine output, as well as general clinical status of the patient, is an approach taken by many clinicians. Postoperative fluid management after esophagectomy presents some unique challenges. If stomach or jejunum is pulled up through the chest to replace the esophagus, this neoesophagus may retain a tenuous blood supply. Adequate circulating blood volume and systemic blood pressure is required to maintain perfusion, whereas fluid overloading must be avoided because it could lead to increased tissue edema or pulmonary compromise requiring reintubation and positivepressure ventilation. Thoracic epidural analgesia improved the microcirculation and increased gastric and intestinal motility in an experimental model of gastric pullup.135 In the postoperative period, the epidural infusion must be carefully titrated, as must the fluid replacement, to provide the benefits of epidural analgesia while optimizing the hemodynamic profile. Frequent reassessment is required. Increasingly, esophageal procedures are being performed using a laparoscopic approach, thus minimizing tissue trespass, postoperative pain, and pulmonary dysfunction. However, laparoscopic upper abdominal surgery is not without respiratory complications, including the occurrence of intraoperative subcutaneous emphysema, pneumothorax, and intravascular carbon dioxide embolism.136

Lung Volume Reduction Selected patients with severe, heterogeneous obstructive airway disease may derive benefit from the resection of 20% to 30% of their lung volume. If hyperinflated, poorly perfused areas of the lungs are removed, better ventilation of wellperfused lung may follow, and the improvement in pulmonary mechanics may be observed immediately—as early as on emergence from anesthesia. Patients referred for lung volume reduction surgery have extremely reduced FEV1, often less than 25% of predicted, and greatly increased residual volumes. They are severely dyspneic and frequently oxygen dependent. When positive-pressure ventilation is initiated, they are prone to dynamic hyperinflation; gas trapping causes increased mean intrathoracic pressure, which can lead to decreased venous return and circulatory compromise. Use low peak airway pressure and increased expiratory time to avoid gas trapping, and avoid extrinsic PEEP. Pay scrupulous attention to the mechanical ventilation parameters in order to minimize the occurrence of pneumothorax in the intact chest or exacerbation of air leaks from surgical sites, both of which are serious, potentially life-threatening complications. Permissive hypercapnia and moderate respiratory acidosis must be tolerated, particularly during OLV. Hypotension is frequently encountered after induction of anesthesia and during positive-pressure ventilation, with need for inotropic support.137 Early cases were performed via sternotomy, and a few centers continue to use this approach. Currently, bilateral volume reduction via a thoracoscopic approach is planned for most patients. If thoracotomy is required on the first side owing to widespread adhesions, surgery on the other side is postponed. Preferably, a left DLT is placed rather than a

61

62

Section 1 Introduction

bronchial blocker because sequential deflation of both sides is usually required, and collapse of the operative lung is slow due to reduced elastic recoil of emphysematous lungs. A DLT allows scrupulous suctioning of secretions to optimize lung collapse. Schedule lung volume reduction only in medically optimized patients who are stable on bronchodilators and steroids (inhaled or systemic) and free of active infection. A combined general anesthetic with regional analgesia is the typical approach for transthoracic lung volume reduction. The prompt return of spontaneous ventilation is paramount. Emphasis is placed on the use of short-acting general anesthetic agents with minimal residual respiratory depression. The use of IV and inhaled agents has been described. IV infusion of propofol, with or without remifentanil infusion in the latter part of the surgery, avoids the emergence . prolonged . from inhaled agents caused by poor V/Q matching. The use of nitrous oxide is avoided because of the potential for enlargement and rupture of noncommunicating bullae. Residual weakness from muscle relaxants is not tolerated; carefully timed doses of neuromuscular blocking drugs of short or intermediate duration allow full reversal at the end of surgery. An epidural catheter is placed in all patients to optimize analgesia from surgical port and chest tube site or from a larger incision should a thoracotomy be required. Excellent analgesia is sought to optimize conditions for sustained spontaneous ventilation, using local anesthesia via the epidural and modest doses of parenteral or epidural opioid. At the end of the procedure, the operating table is placed in a sitting position to minimize the weight of the abdominal contents on the diaphragm. When a consistent spontaneous respiratory pattern is observed, the trachea is extubated. Every effort is made to remove the endotracheal tube before the onset of coughing, which can significantly increase air leaks from the lung parenchyma and suture lines. The patient may require ventilatory assistance via a face mask or laryngeal mask. During recovery from anesthesia, which may be prolonged, constant verbal contact is maintained with the patient. Progressive somnolence is an early sign of hypercapnic respiratory failure. Secure, large-bore IV and arterial catheters are placed before surgery. Neither CVP nor pulmonary artery pressure monitoring is routinely used in our center; readings are greatly distorted by pulmonary hyperinflation during positive-pressure ventilation and are of limited use in the postoperative patient who remains in a sitting position much of the time. The role of intraoperative TEE is unclear, but it is likely to be of greater value than a pulmonary artery catheter in the evaluation of right-sided heart dysfunction or myocardial ischemia. Continuous TEE probably does not contribute to patient management in cases uncomplicated by cardiac disease.138 Patients initially are nursed in a high-dependency unit where serial ABG determinations may be made and expert physiotherapy and liberal use of bronchodilator therapy are available. Analgesia is maintained with an epidural infusion of a local anesthetic agent, with or without low-dose opioid and adjunctive analgesia with an NSAID or acetaminophen or both.

Recent clinical trials have explored bronchoscopic interventions to accomplish the same physiologic alteration of the hyperinflated emphysematous lungs without thoracic incision or routine need for chest tubes. Airway bypass involving the creation of stented air channels between the pulmonary parenchyma and large airways has been described in experimental lung models and shown to increase expiratory flow.139 Feasibility of airway bypass is being tested in patients.140 Another approach is the placement of one-way expiratory valves in the segmental airways identified on CT scan to lead to ventilated but poorly perfused lung, allowing these areas to collapse. Both procedures are accomplished under general anesthesia via a single-lumen endotracheal tube. The procedures are brief compared with transthoracic lung volume reduction, usually approximately 1 hour. The cardiorespiratory effects of positive-pressure ventilation in severe emphysema are similar to those in transthoracic cases, requiring the same level of monitoring and immediately available inotropic support. Although one center has reported performing bronchoscopic lung volume reduction with one-way valves using IV anesthesia and spontaneous assisted anesthesia,141 at other centers, including ours, the use of a muscle relaxant of intermediate duration is preferred, to avoid coughing during the surgery.142 The muscle relaxant must be fully reversed to ensure a smooth transition before positive-pressure and spontaneous ventilation. A bronchoscopic approach eliminates the need for narcotic analgesia and the attendant respiratory depression.

Lung Transplantation Anesthetic techniques for pulmonary transplantation vary with the recipient’s underlying lung disease, the procedure performed, and regional practices. Care of these patients incorporates principles from both cardiac and thoracic anesthesia. Noninvasive monitors and an arterial line are placed. At our institution, a PAC is inserted routinely and is left in place throughout surgery. Palpate the pulmonary artery for the presence of the catheter before division of each pulmonary artery; rarely, the catheter must be withdrawn and floated on the other side. We have found that the pulmonary artery pressure data obtained, even from the operative side, are clinically useful. TEE is increasingly used for routine monitoring of left- and right-sided heart function and left ventricular filling, or it may be required for a specific diagnosis, such as presence of a patent foramen ovale, or assessment of pulmonary vascular anastomoses.143 Despite unpredictable end-tidal-to-arterial carbon dioxide gradients, capnography can be useful in monitoring the progress of pulmonary blood flow to a newly reperfused lung, particularly when capnography from each lung is monitored independently. A variety of induction agents have been described; management is guided by the underlying disease, airway anatomy, and fasting status. Nitrous oxide is avoided in lung transplantation because it may increase pulmonary vascular resistance and will expand any gas emboli entrapped in the graft. Although potent inhaled anesthetics may be used, frequently air leaks develop during native lung dissection, which result in leakage of anesthetic gas into the surgical field. A narcotic-

Chapter 4 Anesthesia for General Thoracic Surgery

based anesthetic is frequently used, with a combination of benzodiazepines and propofol infusion to ensure amnesia. Ventilation strategy must be adapted to the underlying disease. Patients with obstructive airway disease are prone to hyperinflation and bronchospasm and are at risk for lifethreatening gas trapping with positive-pressure ventilation. Clearance of secretions is important. Patients with pulmonary fibrosis have decreased lung volumes, a relatively small chest cavity, and reduced gas exchange capability. Surgical manipulation of the mediastinum is hemodynamically poorly tolerated. High airway pressures, inotropic support, and permissive hypercapnia may be required during one-lung anesthesia of the native lung to avoid CPB. Patients with pulmonary hypertension have near-systemic pulmonary artery pressures and severe right-sided heart dysfunction, with little tolerance for any increase in pulmonary vascular resistance. Both atelectasis and lung hyperinflation therefore must be avoided. OLV is not attempted. All such patients require CPB. In our center, lung transplantation is performed using CPB only if indicated. Approximately 35% of cases require CPB; in 45%, the use of CPB is anticipated for pulmonary hypertension or concomitant cardiac repair; in 55%, CPB is unanticipated and is initiated for hemodynamic instability or inadequate gas exchange. During CPB for cardiac repair, the heart is arrested and the patient is moderately cooled. When lung transplantation alone is performed, the heart remains warm and beating. The use of CPB decreases afterload to the right side of the heart, possibly resulting in less right-sided heart dysfunction. There is less hemodynamic instability caused by interruption of venous return by surgical manipulation. Disadvantages in the use of CPB include the obligate infusion of large quantities of crystalloid solution, heparinization with resultant bleeding from raw surfaces, and the occurrence of coagulopathy and fibrinolysis. CPB is associated with activation of neutrophils and platelets, activation of complement, and increased circulating levels of cytokines such as endotoxin, interleukins, and tumor necrosis factor, all of which may contribute to increased reperfusion injury in the allograft.144 Neurologic deficits and renal dysfunction are common after CPB. The routine use of high-dose steroids in transplantation may attenuate the systemic release of proinflammatory cytokines during transplantation procedures should CPB be used, more so if they are administered well before initiation of CPB. Methylprednisolone, 500 to 1000 mg, is best administered at induction of anesthesia of the recipient, rather than immediately before graft reperfusion. The extent to which CPB contributes to morbidity in human lung transplantation is controversial.145,146 ECMO is emerging as an alternative to CPB for lung transplantation with less requirement for heparin. Femoral arterial ECMO using a heparin-bonded circuit may be initiated to support a patient with pulmonary hypertension throughout the surgery, and then weaned as tolerated.147 During bilateral sequential lung transplantation without CPB or ECMO, both lungs are initially dissected from the chest wall and .from . the hila. The native lung with the least blood flow on V/Q scan is the first to be removed, followed by engraftment of the first allograft. The allograft is gently

reinflated, then ventilated with an FIO2 of less than 0.5, PEEP of 5 cm H2O, and peak airway pressures of less than 25 cm H2O. Slow reperfusion of the allograft is accomplished by removal of the pulmonary artery clamp over 10 minutes. This modified reperfusion technique promotes vascular recruitment and avoids the shear-stress injury of high-flow reperfusion demonstrated in experimental models.148 The new allograft is then ventilated with an FIO2 of 1.0, and removal of the second native lung commences. A period of particular risk of hypoxemia ensues: Ventilation may go preferentially to the compliant allograft, whereas perfusion may be predominantly to the diseased native lung, the vasculature in the allograft being relatively vasoconstricted. Rapid . . clamping of the native pulmonary artery improves the V/Q mismatch. The entire cardiac output is forced through the allograft, which may amplify pulmonary edema if reperfusion injury has occurred. After hemodynamic and ventilatory equilibrium are achieved, the FIO2 is titrated to the resulting PaO2. Separate ventilation of each lung is required in almost all cases, including those using CPB, and placement of a leftsided DLT is preferred. The transplanted lung is unique among solid organ transplants in that its primary blood supply, the bronchial circulation, is not surgically re-established. Lung tissue is therefore dependent on collateral flow from the pulmonary circulation to maintain oxygen supply. Thus, when bilateral sequential transplantation is performed using CPB, ventilation and perfusion must be provided to the newly reperfused first allograft during engraftment of the second. This is accomplished by reducing the CPB flow to 75% of predicted cardiac output, permitting some ejection of blood into the pulmonary artery (the heart remains warm and beating), and by maintaining ventilation once the allograft is reperfused. Inotropic support is frequently required during lung transplantation, and vasodilatory hypotension frequently develops, most likely due to the inflammatory response to extensive surgery and to reperfusion injury. Norepinephrine is a particularly useful drug to treat hypotension due to low systemic vascular resistance. Ischemia-reperfusion injury is an important cause of morbidity and mortality after lung transplantation. The injury is characterized by endothelial dysfunction, increased vascular permeability, and sequestration of neutrophils. Clinical features include progressive increases in pulmonary vascular resistance, decreased pulmonary compliance, and impaired gas exchange. Radiographic findings include reticular interstitial infiltrates and air space disease; however, appearance is not related to functional impairment. A spectrum of injury is produced in transplanted lungs, from mild and self-limited dysfunction to fulminant pulmonary edema occurring in the operating room. Injury may be progressive over hours or days. Treatment consists of optimizing gas exchange while avoiding injurious ventilation settings, with increased PEEP and limiting of tidal volumes and peak airway pressures as much as possible. Hemodynamic support is always required with severe injury. Hypoxia is routinely treated with inhaled nitric oxide, an endothelium-derived vasodilator that improves gas exchange, allowing reduction of potentially harmful high FIO2. As a result of rapid hemoglobin-mediated inactivation in the pulmonary vasculature, inhaled nitric oxide is a selec-

63

64

Section 1 Introduction

tive pulmonary vasodilator causing no systemic hypotension.149 Despite a decrease in endogenous nitric oxide activity after lung transplantation, the prophylactic use of inhaled nitric oxide to prevent injury cannot be justified. A randomized, placebo-controlled trial of 84 patients, in whom inhaled nitric oxide was initiated 10 minutes after reperfusion and continued for a minimum of 6 hours, demonstrated no benefit in oxygenation, time to extubation, or mortality at 30 days.150 IV prostaglandin (epoprostenol or prostaglandin I2) may also be used as a pulmonary vasodilator, but it causes significant systemic hypotension and can worsen oxygenation in lung injury. The effects of inhaled nebulized epoprostenol (PGI2) on oxygenation and hemodynamics are similar to those of inhaled nitric oxide, and in lung transplantation the effects of the two drugs seem to be additive.151 Nebulized epoprostenol is likely to be more widely used to improve gas exchange in patients with ischemia-reperfusion injury, although no benefit on outcome has yet been demonstrated. In severe pulmonary dysfunction, ECMO is increasingly used as a respiratory support. Frequent complications including renal failure, hemorrhage, and neurologic dysfunction contribute to high patient mortality; however, a recent report suggests that venovenous femoral cannulation for posttransplantation ECMO may reduce the incidence of serious events.152 The pulmonary allograft is vulnerable to mechanical and biochemical injury throughout the harvesting, preservation, and engraftment procedures. An understanding of the mechanisms of allograft injury permits the incorporation of strategies for minimizing allograft injury in clinical practice.

Iatrogenic Pulmonary Artery Rupture The use of the PAC is becoming less frequent in the operating room since TEE has come into general use. Nevertheless, the PAC remains a useful tool for diagnosis and management of many cardiac and lung diseases. Sicker patients may need to have a PAC inserted, and these sicker patients are usually those most at risk for catheter-induced pulmonary artery rupture. Prevention is the first attitude to develop when confronted with an iatrogenic complication. The first step in prevention is judicious selection of the patient. The second one is appropriate use and management of the PAC. But when a catheter-induced pulmonary artery rupture occurs, the physician needs to have a clear scheme of intervention to deal with this severe complication. The incidence of rupture is not very high, averaging 0.01% to 0.47%. In a large retrospective study of patients with a Swan-Ganz catheter, Kearney and Shabot153 found an incidence of pulmonary artery rupture of 0.031%, with a consequent mortality rate of 70%. The mortality rate of pulmonary artery rupture averages 50% but can be as high as 75% in anticoagulated patients. Death occurs most often secondary to asphyxia. Any delay before appropriate management is instituted contributes to a higher mortality rate. Risk factors for catheter-induced pulmonary artery rupture include female gender, age older than 60 years, improper catheter placement, and preexisting pulmonary hypertension.

The initial presentation may be as obvious as massive pulmonary hemorrhage or as subtle as a minor hemoptysis associated with cough, or the rupture may be totally asymptomatic.154 Hemothorax is a mode of presentation when blood enters the pleural space instead of the airway. Moreover, any hemoptysis in the presence of a PAC must be investigated because of the high suspicion of pulmonary artery rupture or false aneurysm formation. The proposed mechanisms for catheter-induced pulmonary artery rupture include lodging of the catheter tip in the vessel wall when the PAC advances while the balloon is not inflated, or when eccentric balloon inflation exposes the catheter tip and guides it into the arterial wall, and migration of the PAC into a smaller arteriole, with subsequent rupture caused by balloon inflation. Primary management of catheterinduced pulmonary artery rupture focuses on the prevention of asphyxia. Hypoxia secondary to lung spillage or blood clots is the main factor leading to death. Prevention of contamination of the unaffected lung is essential. Blood loss is rarely massive enough to cause a great threat in hemodynamics, and slight hypotension may be treated with volume replacement. The three goals that must be achieved in appropriate management are derived from the basic “ABC” principles of resuscitation: airway, breathing, and circulation. The goals are lung isolation (A), maintaining appropriate gas exchange and oxygen delivery (B), and volume resuscitation (C). The decision to leave the PAC in place may be critical at that time for the next steps in the radiologic management of this complication. It is essential not to inflate the balloon without radiologic imaging support (see later discussion). Management differs depending on the clinical presentation, mainly in which setting it is presenting—intensive care unit, operating room, or radiology suite.

Intensive Care Unit Setting When a PAC is in place and there is a pulmonary hemorrhage, whether it is massive or negligible, a chest radiograph is usually obtained and shows infiltration around the catheter tip or pleural effusion. The side of PAC may serve as a guide to determine which side hemorrhage may be coming from. Because most PACs are located in the right lung (90%), mainly in the right lower lobe, it can be assumed that hemorrhage comes from the right side if the situation is critical.120 While diagnostic procedures are being performed, administer 100% oxygen to the patient. If the lungs are not separated, place the patient with the bleeding lung on the dependent (inferior) side to prevent spillage to the unaffected side. If the situation is not critical, a quick trial of fiberoptic bronchoscopy can be performed to determine the origin of bleeding. The patient must undergo selective intubation to obtain lung isolation. Lung isolation can be performed with various techniques, including selective intubation with a standard endotracheal tube, bronchial blocker, or DLT. It is our opinion that the best strategy is to place a DLT. A bronchial blocker can be used for lung separation if a DLT is not immediately available or is difficult to insert. Bronchial blockers can be

Chapter 4 Anesthesia for General Thoracic Surgery

used to tamponade the bleeding side while waiting for diagnostic and therapeutic interventions. Bronchial blockers are a useful but temporary measure for bleeding control. It provides time to proceed with a therapeutic and more definitive intervention. Once adequate lung isolation is achieved, the patient can be placed in the lateral decubitus position with the bleeding lung on the nondependent (superior) side. The dependent lung will receive most of the pulmonary blood flow, and this . . will help control the hemorrhage, as well as improve V/Q matching. The patient needs to be ventilated with 100% oxygen; PEEP or CPAP can be added on the bleeding lung to help control hemorrhage.155 Appropriate venous access must be in place, and blood needs to be available from the blood bank. If it is possible to reverse anticoagulation, do it. After lung isolation, fiberoptic bronchoscopic examination can be useful to confirm the good positioning of the device used for the lung isolation and to identify the bleeding site. It is frequently difficult to get a good view of the structures because the blood in the tracheobronchial tree highly absorbs the light of the fiberoptic bronchoscope. It has been suggested that the PAC could be deflated, withdrawn a few centimeters, and left in the pulmonary artery. The balloon may be inflated to compress the bleeding vessel or to temporarily obstruct the feeding artery.156 We recommend that this technique be used only with the aid of fluoroscopy to finely adjust the position of the balloon, in order to avoid malpositioning of the balloon. Improper positioning may augment the bleeding by increasing the vascular laceration or by diverting the pulmonary blood flow to the injured vessel. Injection of contrast medium via the distal port of the PAC left in place allows performance of a wedge angiogram.157 The angiogram generated through a PAC will show extravasation of contrast medium from the vessel into the lung but sometimes may not be accurate enough to proceed to a therapeutic intervention. With a stable patient, or if the diagnosis remains unclear, a contrast-enhanced CT scan may be performed and is a valuable diagnostic tool. It can confirm the possibility of pulmonary artery false aneurysm (PAFA) but also exclude any other causes of hemoptysis. CT scanning is usually followed by angiography with embolization, if indicated and feasible.

Operating Room Setting If hemorrhage happens during surgery, lung isolation can be rapidly achieved and the diagnostic and therapeutic procedures started while the patient is under anesthesia. If the pulmonary artery rupture happens before the principal period of the surgery, postpone elective surgery until the rupture is investigated and stabilized. During cardiac surgery, if hemorrhage happens after CPB but before heparin reversal, reinstitute CPB to bypass the lung circulation and stop the bleeding. This gives the anesthesiologist time to isolate the lungs and maximize oxygenation. If the hemoptysis begins after protamine administration, the best conduct is to finish the surgery as quickly as possible and proceed to a definitive investigation and treatment of the pulmonary artery rupture.

Radiology Setting During cardiac catheterization, the PAC can be used to evaluate pulmonary vascular resistance and the wedge pressure. If catheter-induced pulmonary artery rupture happens in this setting, it is relatively easy to pull the PAC back a few centimeters and reinflate the balloon under direct vision. Thus, it may be possible to stop the bleeding pending further radiologic intervention. However, this measure does not always enable containment of the hemorrhage.158 For this reason, we recommend the use of fluoroscopy and contrast injection to confirm that the PAC is still proximal to the injured vessel and that balloon inflation obliterates flow through the lacerated vessel. Diagnostic angiography and embolization can easily be performed at that point. In this way, intubation, lung isolation, and postprocedure ventilation may be avoided.159

Pulmonary Artery False Aneurysm Formation of a PAFA occurs secondary to the accumulation of blood in an aneurysmal sac compressed by lung parenchyma; there is no intact vessel wall lining containing the bleeding, but the lung parenchyma may prevent further extravasation. The presence of a PAFA requires intervention because one can never be certain that spontaneous healing will occur. Delayed pulmonary hemorrhage occurs in 30% to 40% of cases of PAFA caused by a previous catheter-induced pulmonary artery rupture. The patient may have initially bled a very small amount, and this hemorrhage may not have been noticed. Rebleeding can occur as late as 2 weeks to 7 months after the initial event.160 If there is suspicion of a PAFA on the CT scan, do an angiogram. If the clinical suspicion of pulmonary artery rupture is high or the patient is unstable, angiography remains the procedure of choice because it allows both diagnostic and therapeutic interventions.161 If PAFA diagnosis is confirmed, a selective embolization helps to reduce morbidity and mortality. Embolization is successful in 75% of cases, with a rebleeding rate of about 20%. Sometimes, it is deleterious to embolize the PAFA in regard to global lung function. In such cases, conservative treatment may be tried. Follow-up with repeat contrast CT scanning is required. With radiologic intervention, there is less place for surgery in the context of catheter-induced pulmonary artery rupture. Surgery, including pulmonary artery ligature, segmentectomy, lobectomy, or pneumonectomy, is reserved for extreme cases because it is technically challenging and carries a high morbidity.160 Because the morbidity and mortality of radiologic intervention offers advantages over traditional surgery, try it first.162 However, a proximal vascular injury may be an indication for performing lung surgery primarily.157

Whole Lung Lavage This part of the chapter reviews whole lung lavage (WLL), its indications, a few details of the technique, its complications, and its benefits. It is important to differentiate WLL from the bronchoalveolar lavage. Bronchoalveolar lavage is a diagnostic tool performed under local anesthesia, using only

65

66

Section 1 Introduction

300 mL of liquid in one segment of the lung, with the aid of the fiberoptic bronchoscope. WLL is a treatment modality that requires more than 10 L of normal saline instilled through a DLT in one whole lung while the patient is under general anesthesia. WLL is the most effective treatment modality for symptomatic pulmonary alveolar proteinosis. This lung disease is caused by alveolar accumulation of a lipoproteic material that has the aspect of a surfactant.163 Primary pulmonary alveolar proteinosis is a rare disorder of unknown cause and variable natural history.164 Supposedly a nonspecific pulmonary reaction to several insults, it creates a true alveolocapillary blockade. The patient presents with dyspnea and hypoxemia, aggravated by exercise. The usual goal of WLL is improvement in the clinical, physiologic, and radiologic aspects of the case. The prognosis of pulmonary alveolar proteinosis has greatly improved8 since the introduction of WLL in 1965.165 Recent data suggest that abnormality in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor may be an etiologic factor for pulmonary alveolar proteinosis. The use of GM-CSF represents a novel alternative to repeated WLL in treating the disease.166 Various pathologic states have been treated by WLL, with variable success, including cystic fibrosis, asthma, chronic obstructive lung disease, radioactive dust inhalation, alveolar microlithiasis, lipoid pneumonitis or exogenous lipoid pneumonia, and silicosis.167 Typically, in pulmonary alveolar proteinosis, the pulmonary function test reveals a restrictive pattern. The DLCO is usually reduced by an order of magnitude similar to the severity of the hypoxemia. Radiologic imaging findings are characteristic. Definitive diagnosis may be confirmed by bronchoalveolar lavage and the typical histologic picture. If there is any doubt about the diagnosis, an open lung biopsy can be performed. WLL is performed under general anesthesia with basic monitoring and supplemental respiratory monitoring. Lung separation is obtained by the use of a left-sided DLT. The patient is kept in the supine position during instillation of aliquots of approximately 1 L of warm normal saline (at 37ºC). The irrigating liquid is suspended 30 cm above the patient’s midchest level. After instillation via one lumen of the DLT, the saline is rapidly drained into a container positioned 60 cm below, with the assistance of a small amount of suction (<20 cm H2O). This process is repeated for 10 times or more, as necessary, to obtain clear effluent lavage fluid. Strict input and output balances of lavage liquid must be recorded. The main complication is a decrease in arterial oxygen saturation,168 mainly during the drainage phase. Some liquid spillage from the lavaged lung to the nonlavaged lung may occur. Other complications, such as pneumothorax and hydrothorax, are rare but require drainage and postponement of the procedure. When the effluent lavage fluid is clear, the procedure is finished. Usually, between 10 and 15 L is instilled (up to 50 L), and more than 90% is recovered. Alveolar infiltrates seen on the chest radiograph immediately after WLL nor-

mally clear within 24 hours. Observation in the intensive care unit for 24 hours is part of the routine procedure. WLL is usually performed on one lung; then, at least 1 week later, WLL of the contralateral lung is performed. At that time, oxygenation usually is not a problem because the treated and now near-normal lung is used to support gas exchange during the procedure. Recently, some centers have begun to safely perform bilateral WLL during the same anesthesia with good results. After WLL, patients usually have marked subjective improvement that correlates with increases in PaO2 (at rest and exercise), vital capacity, diffusing capacity, and clearing of the chest roentgenogram. Some patients require lavage every few months, whereas others remain in remission for several years. The disease may eventually show a late recurrence. In our experience, fewer than 50% of patients need more than the initial bilateral WLL. In pulmonary alveolar proteinosis, WLL is successful because the lavage removes the enormous accumulation of alveolar lipoproteinaceous material and also because it interrupts the pathogenic loop and temporarily restores the activity and function of the macrophages.

COMMENTS AND CONTROVERSIES As shown in this excellent and thorough chapter, anesthesia for noncardiac thoracic surgical procedures has evolved substantially over the past 20 years. The “disposable” DLT introduced in the early 1980s is a good example of new technology that has made “onelung anesthesia” much safer. Similarly, the introduction of epidural catheters in the mid-1980s not only changed the conduct of postoperative analgesia but also allowed the anesthetist to reduce the “depth” of anesthesia during lung resectional procedures. During the 1990s, potent new short-acting drugs allowed a more controlled anesthesia with rapid emergence. To be safe and reliable, thoracic anesthesia must be given by anesthetists who are well trained and have gained experience in this field. They also must have good knowledge of the anatomy and physiology of the respiratory system, and, most importantly, they must be able to work in conjunction with the surgeon with whom they will share the airway. Indeed, good communication and teamwork between the surgeon and the anesthetist are prerequisites for successful outcomes. OLV is used in almost all cases of pulmonary resection because it improves surgical exposure while preventing excessive retraction of the lung, which can cause parenchymal hemorrhage and contusion. OLV also prevents soiling of the contralateral lung by purulent bronchial secretion in patients being operated upon for bronchiectasis or lung abscess (absolute indications for DLT). Most often, OLV is carried out through a DLT. Alternatively, endobronchial blockers may be used. In general, however, endobronchial brokers are considered less versatile and less easy to manage than DLTs. Most patients undergoing pulmonary surgery should be extubated either in the operating room or shortly after their arrival in the recovery room. This early extubation is recommended to prevent continuous positive pressure from putting undue stress on parenchymal or bronchial suture lines. J. D.

Chapter 4 Anesthesia for General Thoracic Surgery

KEY REFERENCES British Thoracic Society: Guidelines on the selection of patients with lung cancer for surgery. Thorax 56:89-108, 2001. ■ A comprehensive discussion of preoperative evaluation.

National Emphysema Treatment Trial Research Group: A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 348:2059, 2003. ■ A landmark study of the indications and outcomes for lung volume reduction surgery.

Campos JH: Progress in lung separation. Thorac Surg Clin 15:71, 2005. ■ A comprehensive review of the issues relating to separation of the lung for thoracic surgery.

Slinger P (ed): Progress in Thoracic Anesthesia. Society of Cardiovascular Anesthesiologists Monograph. Baltimore, Lippincott Williams & Wilkins, 2004. ■ A current look at progress in selected topics in the field of thoracic anesthesia.

Kaplan, J, Slinger P (eds): Thoracic Anesthesia, 3rd ed. Philadelphia, Churchill Livingstone, 2003. ■ This text is a cohesive review of all aspects of thoracic anesthesia.

Warner DO: Helping surgical patients stop smoking: Why, when and how. Anesth Analg 101:481, 2005. ■ A practical guide to aiding patients to stop smoking.

Licker M, de Perrot M, Hohn L, et al: Perioperative mortality and major cardiopulmonary complications after lung surgery for non-small cell carcinoma. Eur J Cardiothorac Surg 15:314, 1999. ■ A useful survey of perioperative complications in pulmonary resection surgery.

67

chapter

5

PERIOPERATIVE PAIN MANAGEMENT Erin A. Sullivan Jacques E. Chelly

Key Points ■ Lower morbidity and mortality rates in thoracic surgery have been

attributed, in part, to more effective management of perioperative pain. ■ Thoracic epidural catheters, paravertebral nerve catheters, or intercostal nerve catheters may be used to provide safe and effective perioperative analgesia. Local anesthetic agents may be delivered through these catheters via a continuous infusion. Thoracic epidural catheters may also be used to administer neuraxial opioids combined with the local anesthetic. ■ Multimodal analgesia combines neuronal blockade, opioids, nonsteroidal anti-inflammatory agents, and other adjuvant medications (e.g., clonidine, dexmedetomidine) and directs therapy at multiple anatomic and pharmacologic sites of action to provide the best analgesia possible with minimal adverse side effects.

The suboptimal treatment of perioperative pain is widely recognized among medical practitioners, and the pain associated with a surgical procedure remains a significant concern for patients.1 Thoracic surgery in particular can elicit intense postoperative pain, which, if inadequately treated, may lead to the development of chronic pain syndromes.2-4 The trend toward lower morbidity and mortality rates in thoracic surgery has paralleled the improvement in postoperative analgesic techniques, and evidence supports the concept that at least a part of the reported improvement can be attributed to more effective management of postoperative pain (Table 5-1).5-8 Pain may be classified as acute, chronic, cancer, or palliative pain. The pain experienced by patients undergoing thoracic surgery is often a complex combination of noxious stimuli associated with the surgical trauma, the presence of a chest tube, and a history of chronic and/or cancer pain. The neurobiologic basis of acute pain and the subsequent development of chronic pain syndromes have been partially elucidated (Kelly, 2001).9 It is essential to understand that multiple sites and multiple receptors collectively contribute to the perception of pain and that the nervous system is sensitized by a painful stimulus that initiates a cascade of events whereby subsequent noxious stimuli are perceived with greater intensity (hyperalgesia) and previous nonpainful stimuli may become painful (allodynia). This is the scientific basis for the development of effective preemptive multimodal perioperative pain management regimens that are designed to attenuate the undesired consequences that result from surgical pain. Preemptive multimodal analgesia uses a variety of pharmaco-

logic agents and techniques that produce an additive (if not synergistic) effect that is initiated before the onset of noxious stimuli and is maintained throughout the patient’s hospital course. This chapter reviews the pathophysiologic impact of thoracic surgery and research on current pain treatment regimens that serve as the basis for effective preemptive multimodal perioperative analgesia.

PHYSIOLOGIC BASIS OF ACUTE PAIN IN THORACIC SURGERY A painful stimulus begins with mechanical, thermal, or chemical stimulation of peripheral nociceptors that may be classified into two categories: (1) fast-conducting myelinated A-delta nerve fibers and (2) slow-conducting unmyelinated C nerve fibers. The pain mediated by the A-delta nerve fibers is early onset, sharp, and short in duration, whereas pain mediated by the C nerve fibers is delayed onset, dull, and longer in duration. The sensitivity of the peripheral nervous system can be enhanced, as in peripheral sensitization, and the sensitivity of the dorsal horn of the spinal cord can be increased, as in windup or central sensitization. In peripheral sensitization, the repeated application of a noxious stimulus enhances the intensity and duration of the nociceptor response to subsequent applications of the same stimulus. Tissue injury results in the release of mediators that are linked with the inflammatory response, and they may either activate or enhance nociceptor activities. These mediators include potassium, bradykinin, kallidin, histamine, substance P, calcitonin gene-related peptide (CGRP), prostaglandins, leukotrienes, and hydroxy acids.10-15 This leads to the development of local inflammatory reactions coupled with the activation of efferent nerve terminal conduction of the stimulus to the spinal cord and brain. In central sensitization, peripheral nociceptor activity increases the sensitivity of the dorsal horn that results in transmission of a noxious stimulus to this region of the spinal cord. At this level, cyclooxygenase (COX-1 and COX-2), N-methyl-Daspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and µ and δ opioid receptors are implicated. Stimulation of COX-1, COX-2, NMDA, and APMA receptors amplifies pain signals, whereas stimulation of the opioid receptors blocks transmission of pain signals. These pain signals trigger the release of glutamate into the synaptic cleft between nociceptors and dorsal horn cells. In the case of acute pain, glutamate activates AMPA receptors, but not NMDA receptors because they are blocked by magnesium. The pain signals are transmitted to the brain via two pathways: (1) the lateral system (neospinothalamic tract,

68

Ch005-F06861.indd 68

1/21/2008 10:33:22 AM

Chapter 5 Perioperative Pain Management

TABLE 5-1 Recent Trends in Perioperative Mortality After Lung Cancer Surgery

PAIN

Author (Year)

Patients

Mortality (%)

Analgesic Technique

Nakahara, et al6 (1988)

All risks

6.4

IV/IM

Licker, et al (1999)

All risks

4.8

IV/IM/LEA

Cerfolio, et al7 (1996)

High-risk

2.4

LEA/TEA

Licker, et al8 (1999)

All risks

2.1

TEA

8

IM, intramuscular; IV, intravenous; LEA, lumbar epidural analgesia; TEA, thoracic epidural analgesia. From Conacher ID, Slinger PD: Pain management. In Kaplan J, Slinger P (eds): Thoracic Anesthesia, 3rd ed. New York, Churchill Livingstone, 2003.

neotrigeminothalamic tract, and medial lemniscus tract), which rapidly transmits a signal (onset, location, and intensity of injury) to trigger rapid release of analgesic from the brain, and (2) the medial system (paleospinothalamic tract, spinomesencephalic tract, spinoreticular tract, and reticular formation), which conducts signals more slowly and conducts those signals related to the extent of the injury and modulation of the body’s responses. The pain signal is integrated into the brain, which transmits pain-relieving signals via the thalamus, periaqueductal gray matter, nucleus raphe magnus, corticospinal tract, dorsal horn, and substantia gelatinosa. Presynaptic activity at the level of the dorsal horn end terminal is regulated by γ-aminobutyric acid type B (GABAB) receptors, endorphins (µ and δ), and α2-adrenergic and serotonin (5-HT3) receptors. During prolonged stimulation/sensitization of the dorsal horn, the dorsal horn neurons cause antidromic firing of nociceptors and manifest as allodynia, a phenomenon that occurs when a typically nonpainful stimulus causes pain. This is the physiologic basis of central sensitization—a signal travels in a retrograde fashion, causing the cell to release substance P and CGRP into peripheral tissues,10 resulting in the following: ■ ■ ■ ■

Tissue edema Increased excitability of nociceptors Provoking and potentiating transmission of pain signals from the periphery Minor stimuli that cause pain at unpredictable sites

Central sensitization can also lead to deregulation of pain modulation at the level of the spinal cord. This is also known as windup, in which the magnitude of the response to any stimulus is exaggerated (hyperalgesia). The activation of the NMDA receptors is also observed in conjunction with the development of opioid resistance, neuronal remodeling, and violation of dermatomal boundaries. Analgesic regimens that intervene at one or more sites along the pain pathway (Fig. 5-1) before the onset of noxious stimuli may minimize sensitization. This concept has been supported by several studies in which the preemptive administration of epidural analgesia reduced or prevented postthoracotomy pain (Gottschalk, 2002; Senturk, 2002).16-19

Ch005-F06861.indd 69

69

• Opioids • ␣2-Agonists

Descending modulation

Ascending input

Dorsal horn

Spinothalamic tract

• Local anesthetics • Opioids • NMDA antagonists • ␣2-Agonists • NSAIDs Nerve root • Local anesthetics

Peripheral nerve (A␦ and C fibers)

TRAUMA Peripheral nociceptors

• Local anesthetics • NSAIDs/Steroids • Opioids • NMDA antagonists • ␣2-Agonists

FIGURE 5-1 Conduction of a painful stimulus from a peripheral site to the central nervous system. Pharmacologic agents exert their specific effects at variable sites along the pain pathway. NMDA, Nmethyl-D-aspartate; NSAIDs, nonsteroidal anti-inflammatory drugs. (FROM KEHLET H: THE VALUE OF “MULTIMODAL” OR “BALANCED ANALGESIA” IN POSTOPERATIVE PAIN TREATMENT. ANESTH ANALG 77:1048-1056, 1993.)

PHYSIOLOGIC IMPACT OF ACUTE PAIN IN THORACIC SURGERY The posterolateral thoracotomy incision is reported to be among the most intense pain experienced.2,3,20 Chest wall nociception, whether generated by surgery or by traumatic injury, is conducted via the intercostal nerves to the dorsal horn in the spinal cord, the autonomic nervous system, and the vagus nerve. Skin incision, dissection of the skeletal muscle, rib and intercostal space retraction, and dissection of the parietal pleura is mediated via the intercostal nerves to the dorsal horn in the spinal cord.21 Stimuli generated by dissection of the visceral pleura are primarily conducted via the autonomic nervous system; however, the vagus nerve conducts noxious stimuli caused by retraction of the lung. Noxious stimuli originating from manipulation of the diaphragm, mediastinum, and pericardial pleura are relayed via the phrenic nerve (Hazelrigg, 2002).22 Stretching of the brachial plexus and distraction of the shoulder is postulated to be mediated by the sympathetic nervous system.31 Each of these pain pathways produces a characteristic perception of pain. Pain mediated via the intercostal nerves is primarily sharp in nature. Intercostal nerves may be targeted with analgesics and/or local anesthetics individually or in multiples in the epidural or paravertebral space. The advantage of the multiple and central neuraxial analgesic techniques is that the posterior ramus of the intercostal nerve is

1/21/2008 10:33:23 AM

70

Section 1 Introduction

TABLE 5-2 Post-Thoracotomy Pain Pathways Pain Source

Afferent Conduction

Incision

Intercostal nerves (4-6)

Chest drains

Intercostal nerves (5-8)

Mediastinal pleura

Vagus nerve

Central diaphragmatic pleura

Phrenic nerve

Ipsilateral shoulder

Phrenic nerve ± brachial plexus

From Conacher ID, Slinger PD: Pain management. In Kaplan J, Slinger P (eds): Thoracic Anesthesia, 3rd ed. New York, Churchill Livingstone, 2003.

also blocked. This is very important for patients undergoing a posterolateral thoracotomy incision and of lesser importance for patients undergoing thoracoscopy. Pain that results from dissection of the mediastinal and diaphragmatic pleura is primarily conducted via the vagus nerve and the phrenic nerve, respectively. The characteristic pain produced is that of nonincisional, deep-seated, illdefined, nonlocalizable discomfort. Patients may also complain of shoulder pain that is caused by diaphragmatic irritation. Chest drains produce both incisional and nonincisional pain profiles. An understanding of these multiple afferent pathways involved in the etiology of post-thoracotomy pain (Table 5-2) leads to an appreciation of why no single analgesic technique is completely satisfactory and why postthoracotomy analgesia should be multimodal. The impact of thoracotomy pain on postoperative pulmonary function is significant and can impair a patient’s ability to generate an effective cough to clear the airways of secretions. This may lead to further deterioration of a patient’s pulmonary function and increase the length of hospital stay and health care costs, as well as cause an increase in patient morbidity and mortality. Other contributing factors to postoperative pulmonary impairment after thoracic surgery include loss of functional lung units, atelectasis, loss of function of incised or retracted intercostal muscles, rib dislocation, exacerbation of preexisting lung disease, and diaphragmatic dysfunction (Table 5-3) (Sabanathan, 1990).23,24 Impairment of pulmonary function during thoracic surgery begins with the induction of general anesthesia. General anesthesia causes a reduction in functional residual capacity (FRC) of approximately 20% (Sabanathan, 1990).23,24 This condition is exacerbated by positioning of the patient in the lateral decubitus position. Mechanical ventilator pressures to preserve FRC, high inspired oxygen concentrations, and alternation of single and double lung ventilation exert consequences on the pulmonary vasculature and right ventricular function. The surgical manipulation and resection of the lungs combined with the physiologic alterations of general anesthesia reduce lung compliance through a mechanism of retained interstitial and intra-alveolar water. These negative effects coupled with the pain and trauma of incision and disruption of the intercostal muscles along with diaphragmatic splinting can explain why patients develop a restrictive ventilation pattern with dysfunctional respiratory activity (Sabanathan,

Ch005-F06861.indd 70

TABLE 5-3 Mechanisms of Pulmonary Dysfunction After Thoracotomy Pulmonary resection Pulmonary edema and hemorrhage Distortion of segmental bronchi with resulting lobar collapse Gastric and abdominal distention Increased airways resistance Impaired mucociliary clearance Residual anesthetic effects Pain-related alteration of pulmonary function Diaphragmatic dysfunction Adapted from Pennefather SH, Russell GN: Postthoracotomy analgesia: Recent advances and future directions. In Slinger PD (ed): Progress in Thoracic Anesthesia. Baltimore, Lippincott Williams & Wilkins, 2004.

1990).23 As the FRC diminishes, ventilation-perfusion mismatch resulting from atelectasis and accumulation of lung water leads to hypoxemia and predisposes the patient to the development of pneumonia and other infective processes. Carbon dioxide retention results from ineffective gas exchange, a process that may be exacerbated by the overzealous administration of opioids to treat pain. Thoracotomy also stimulates the stress response, which adversely affects circulating catecholamine levels, glucose homeostasis, nitrogen balance, coagulation, and sodium balance.25,26 The stress response leads to increased levels of adrenocorticotropic hormone (ACTH), cortisol, catecholamines, and interleukins; decreased insulin release; and decreased fibrinolysis. These hormonal changes increase myocardial oxygen consumption as well as the risk of myocardial ischemia and infarct. They may cause hypertension, development of coagulopathy, and a decrease in regional blood flow, and they increase the risks for infection, depression, and insomnia. Therefore, one of the goals for effective postoperative pain management is to suppress the development of the acute postoperative stress syndrome. In this regard, opioids have been shown to be ineffective in preventing the changes associated with stress, even when used as a patientcontrolled analgesia (PCA) technique. Adverse side effects from opioids, including pruritus, nausea and vomiting, respiratory depression, urinary retention, constipation, and immunosuppression, represent serious limitations to their use. The modern approach to postoperative pain management is based on the use of a multimodal regimen that includes both pharmacologic and nonpharmacologic techniques. In addition to being multimodal, the approach to acute pain management is also multidisciplinary, being focused not only on the patient’s pain but on his or her entire recovery. This is a team approach, involving the surgeon, the anesthesiologist, nurses, respiratory therapists, and, most importantly, the patient. Preoperative education of the patient is essential and includes the following: 1. Informing the patient of his or her options 2. Setting realistic expectations (e.g., minimization of postoperative pain but not its complete elimination)

1/21/2008 10:33:23 AM

Chapter 5 Perioperative Pain Management

3. Reassuring the patient that there is an acute pain specialist available to respond to the patient at all times 4. Educating the patient as to the critical importance of his or her own motivation, involvement, and effort in recovery (Kehlet, 2002; Lewis, 1994; Moraca, 2003)27-30

ANALGESIA FOR THORACIC SURGERY Minimally invasive approaches to thoracic surgery that employ video-assisted thoracic surgery (VATS) techniques are considered to elicit less pain than the conventional posterolateral thoracotomy,32 but less pain does not mean that these patients do not experience any pain. Therefore, even in patients undergoing VATS, effective postoperative pain management is essential, especially when the expectation of many patients is to be completely free of pain after minimally invasive surgery. Patients of the contemporary era are empowered with knowledge from a variety of sources, including the Internet, consumer organizations, and patient organizations. In order to make informed and contributory decisions, it is necessary that patients be informed about the risk of morbidity from inadequately treated perioperative pain, compared with that due to the inherent risks of the analgesic regimens. Likewise, patients have the expectation to opt out of a specific therapy should it fail to meet their expectations or if the therapy’s complications are deemed worse than the discomfort involved. Analgesic options are as diverse as thoracic surgical techniques. In general, two strategical approaches to perioperative pain management for thoracic surgery have evolved, and a combination of both is frequently used. The first strategy, injection of local anesthetic agents into the surgical site, targets and decreases afferent transmission of noxious stimuli caused by incisional pain. The second strategy employs a multimodal pain management approach using regional anesthetic techniques and local anesthetic agents to attenuate incisional pain, opioids for nonincisional pain, and nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenases and decrease mediators of pain such as prostaglandins in both the peripheral and the central nervous system.33,34 Adjunctive therapy with NSAIDs has been demonstrated to have an opioid-sparing effect.35 The population of patients who present for thoracic surgery is at risk for adverse side effects due to age, preexisting comorbidities, and the type of surgical resection being performed. For this reason, a combination of the best of both strategies is generally sought in order to minimize the side effects of any single approach. The combined use of low-dose local anesthetics and neuraxial opioids is key to reducing the incidence of motor blocks, sympatholysis, and the nondiscriminant effects of systemic opioids.36 In addition, gabapentin37 and pregabalin, both blockers of the α2 subunit of the N-type calcium channel, have been shown to be effective in reducing postoperative pain, either alone or in combination with a COX-2 inhibitor (Reuben, 2006).38 The following sections address the primary modalities of analgesia for thoracic surgery, including systemic opioids and PCA, blockade of peripheral nerves with local anesthetics, central neuraxial blockade, and adjuvant medications.

Ch005-F06861.indd 71

71

OPIOIDS AND INTRAVENOUS PATIENT-CONTROLLED ANALGESIA Systemically administered opioids (intravenous [IV], intramuscular, and subcutaneous) have been the mainstay for perioperative analgesia. This technique has the disadvantage of a narrow therapeutic window that may be associated with undesired side effects such as nausea, vomiting, somnolence, and respiratory depression. Postoperative pain is a constant background pain that is exacerbated acutely during deep breathing, coughing, and ambulation. Systemic opioids alone are effective in controlling background pain; however, the plasma levels required to provide effective analgesia frequently result in oversedation and hypoventilation in most patients.39 It has been shown that opioids administered by an asneeded technique fail to achieve adequate analgesia greater than 60% of the time.40 IV PCA attenuates the peak and trough effects and individualizes analgesia to the patient’s requirements. In order for PCA to be an effective technique, however, the patient must understand the concept and be able to operate the device. Interruption of sleep patterns occurs when serum opioid levels fall below the therapeutic range because patients must awaken to activate the device (Kavanaugh, 1994).41 Basal infusions of opioids are used infrequently because of the increased incidence of respiratory depression, particularly in elderly patients and in those patients who are also receiving sedatives.42 Block and colleagues43 published a meta-analysis including 30 clinical trials demonstrating that IV PCA opioids were inferior to epidurally administered (lumbar or thoracic) opioids and/or local anesthetics for the treatment of postthoracotomy pain in terms of higher pain scores, increased time to patient ambulation, and increased length of hospital stay. Visual analogue pain scores were significantly lower in the epidural group (P < .002), and the incidence of nausea and vomiting was lower in the patients receiving lumbar epidural opioids, compared with those receiving PCA.

PERIPHERAL NERVE BLOCKS Local anesthetic agents may be used to block conduction of the afferent impulse of painful stimuli along intercostal nerves. Single-injection techniques are limited by the duration of action of the local anesthetic used. To maintain efficacy with this technique, repeated injections are required which can be painful and labor intensive. Intercostal nerve catheters and paravertebral catheters offer the advantage of a continuous delivery system for local anesthetics and allow for prolonged analgesia. There is, however, a concern of local anesthetic toxicity due to systemic drug accumulation with this technique.

Intercostal Nerve Blocks Intercostal nerve blockade has been shown to be an effective but short duration method to provide post-thoracotomy analgesia (Savage, 2002).44,45 Intercostal nerve blocks may be performed percutaneously or under direct vision during thoracotomy or VATS. As previously stated, the duration of the

1/21/2008 10:33:23 AM

72

Section 1 Introduction

Posterior cutaneous Posterior branch

Anterior branch Anterior cutaneous FIGURE 5-2 The anatomy of an intercostal nerve. There are three cutaneous nerves (anterior, lateral, posterior) derived from the dorsal nerve ramus. (FROM THOMPSON GE: INTERCOSTAL NERVE BLOCK. IN WALDMAN SD, WINNIE AP [EDS]: INTERVENTIONAL PAIN MANAGEMENT. PHILADELPHIA, WB SAUNDERS, 1996.)

analgesia is relatively short (up to 6-8 hours with bupivacaine), and the blocks need to be repeated to achieve any long-term benefit.46 To appreciate the usefulness and limitations of intercostal nerve blockade, one must understand the anatomy involved (Fig. 5-2). There are three sensory divisions of the intercostal nerve: the posterior, lateral, and anterior cutaneous nerves. An intercostal block must be placed at or posterior to the posterior axillary line to block the posterior branch of the lateral cutaneous nerve. The posterior cutaneous nerve, which supplies the innervation for the posterior end of a traditional posterolateral thoracotomy incision, cannot be blocked with a conventional intercostal nerve block. Intercostal nerve blocks can be used effectively for lateral or anterolateral thoracotomy incisions, insertion of chest drains, and awake thoracoscopy.

Intercostal Nerve Catheters Intercostal nerve catheters are an alternative to conventional intercostal nerve blockade and may be used for continuous infusions and boluses of local anesthetic agents. The major disadvantage of this technique is that, when placed percutaneously, the catheter is difficult to position and difficult to secure in place47; however, the intercostal nerve catheters may be placed under direct vision by the surgeon during thoracotomy or during VATS. A recent study conducted by Luketich and associates (Luketich, 2005)48 compared the use of intercostal nerve catheters plus PCA versus thoracic epi-

Ch005-F06861.indd 72

dural analgesia (TEA) using bupivacaine and morphine. A total of 124 patients with matched demographic data were enrolled into the study, and 91 patients had sufficient data for analysis. Of these, 47 patients were in the PCA arm, and 44 received TEA. The primary end point was measurement of pain using a visual analogue scale, numerical rating, and categorical rating. Secondary end points included the success rate (completion) of the analgesia delivery method, antibiotic use, intensive care unit (ICU) and hospital days, Foley catheter days, and the use of non-narcotic and narcotic pain medications. Pulmonary function tests were also obtained preoperatively and in the early postoperative period (days 2 through 6). The average postoperative composite pain score was 2.4 (scale of 0-10, with 10 being the worst score). No differences in pain scores were detected between the treatment arms or between male and female patients. With respect to the secondary end points, there were no differences in number of days on which antibiotics were required, blood transfusions, development of arrhythmias or pneumonias, ICU days, and length of hospital stay. There was no difference in postoperative pulmonary function between the groups. There was no morbidity related to the method of analgesia used, and in particular no bupivacaine toxicity from the extrapleural infusion. The number of days on which supplemental narcotic medications (beyond the planned randomized treatments) were used was significantly lower (P = .0316) in the group with intercostal nerve blockade plus PCA (248 days total), compared with the group receiving TEA (286 days total). The other positive finding in this study was the lower number of Foley catheter days (P = .002) in the PCA group (mean 81 ± 1.7, versus 108 ± 2.5 for the TEA group). This study demonstrated that intercostal nerve catheters can be placed safely and efficiently by the surgeon. There were no adverse effects from continuous bupivacaine infusion, and pain control was as effective as with TEA. There were some advantages, such as decreased Foley catheter and supplemental narcotic requirements. Intercostal nerve blockade plus PCA may be used after thoracotomy in those patients for whom epidural placement is not feasible due to anatomic abnormalities and the presence of anticoagulation, and it perhaps should be considered for all cases in which there is no disruption of the parietal pleura.

Cryoanalgesia Cryoanalgesia is a technique that achieves an extremely longlasting intercostal nerve block by freezing the intercostal nerve. Direct application of a −60ºC probe to the exposed nerve in the open thorax intraoperatively causes degeneration of nerve axons without damage to the support structure of the nerve, thus reversibly disrupting nerve activity. The anesthesia obtained by this technique occurs along the dermatomes treated, and the block can last as long as 6 months. Cryoanalgesia has been deemed moderately efficient49 for decreasing postoperative pain, but it is associated with an incidence of chronic neuralgia that has led many centers to abandon the procedure.50,51 Nevertheless, cryoanalgesia has been shown to be useful to treat thoracic pain that is expected to last for a prolonged period (e.g., pain due to chest trauma)

1/21/2008 10:33:23 AM

Chapter 5 Perioperative Pain Management

73

and in patients for whom epidural and paravertebral analgesia is not feasible. Pleura

Interpleural Catheters The insertion of interpleural catheters was described by Reiestad and Strømskag in 1986 as a potential means of providing analgesia for patients who experience chest trauma or undergo thoracotomy. Interpleural injections of local anesthetics were used as an alternative to multiple intercostal nerve injections.52-54 This technique compares unfavorably with other catheter techniques in terms of pain relief and improvement in pulmonary function.55 This finding may be due to the loss of local anesthetic through chest drains, wide dispersal of local anesthetic throughout the hemithorax,54,56 and pooling of local anesthetic in the costophrenic angle.

Sympathetic chain Dorsal root ganglion Intercostal nerve Superior costotransverse ligament Rib

Paravertebral Nerve Block Paravertebral nerve blocks are multiple-level intercostal nerve blocks that have replaced the direct and multiple applications of local anesthetics to intercostal nerves, cryotherapy, and interpleural local anesthetics.57 Paravertebral nerve blocks may be performed either by administering multiple injections or by inserting a catheter into the paravertebral space for use with a continuous infusion of local anesthetic (Hill, 2006).58,59 The levels of analgesia and restoration of pulmonary function seen with TEA can also be achieved with paravertebral nerve blockade when a multimodal analgesic regimen including the use of IV opioids and NSAIDs is used. Outcome studies of the effect of paravertebral nerve blocks on morbidity and mortality rates after thoracic surgery have yet to be performed. It is widely accepted that the use of multimodal analgesia in conjunction with paravertebral nerve block is an excellent alternative to TEA. Paravertebral catheters may be inserted either percutaneously or under direct vision during thoracotomy. This technique is particularly useful in patients for whom placement of TEA is difficult or contraindicated. Paravertebral nerve blockade is a concept that dates back to 1906 and is attributed to Sellheim. In 1912, the technique was first used by Kappis, and Laewen dubbed it paravertebral conduction anesthesia.60 It was used during the early 20th century to treat conditions ranging from angina pectoris to abdominal surgery.61 After World War II, paravertebral nerve blockade continued to be practiced in veterinary medicine yet all but disappeared in human medicine. It was not until a paper was published by Eason and Wyatt in 1979 that the technique was resurrected.62 They suggested that, with a different approach to percutaneous access, paravertebral nerve blockade lent itself both to detection of loss of resistance and easier catheter insertion, and that it was suitable for treating post-thoracotomy pain.61 Sabanathan and colleagues described a direct open technique for the placement of paravertebral catheters.63 The paravertebral space is continuous along the entire length of the vertebral column, extending laterally from the vertebral column and merging into the intercostal space (Fig 5-3). It is continuous medially with the epidural space via the intervertebral foramen.64 The paravertebral space contains the sympathetic chain, the rami communicans, the dorsal

Ch005-F06861.indd 73

FIGURE 5-3 Percutaneous approach to paravertebral nerve blockade. The thoracic somatic nerve enters a triangular space formed by the vertebral body, the transverse process and the pleura as it exits the intervertebral foramen. (FROM MULROY MF: PERIPHERAL NERVE BLOCKADE. IN BARASH PG, CULLEN BF, STOELTING RK [EDS]: CLINICAL ANESTHESIA, 3RD ED. PHILADELPHIA, LIPPINCOTT-RAVEN, 1997.)

ramus, and the intercostal nerves.62 Within the paravertebral space, the intercostal nerves are void of a fascial sheath, which means that they are easily blocked by local anesthetic agents.65 Richardson and Lonnqvist described the anatomy and the spread of injectate into the thoracic paravertebral space,66 stating that the injectate takes the route of least resistance. This route varies in each patient; the usual paths for spread are as follows: 1. Cephalad and caudad within the space for a variable number of adjacent spaces 2. Contiguous to the intercostal space 3. Lateral border of the vertebral body 4. Adjacent to the intervertebral foramen Some evidence suggests that the route of least resistance is also dependent on the presence of local factors such as pleural effusions, rib trauma, epidural venous dynamics, pathologic condition, and intrathoracic pressure. The single most important factor with regard to the use of paravertebral nerve blocks, however, is the proximity of the neuraxis for the deposition of local anesthetics. Paravertebral nerve blockade offers several advantages, particularly when a catheter is used to provide a continuous infusion of local anesthetic. Once a physician becomes comfortable with the technique, it may be implemented rapidly and can be effective at blunting the noxious stimuli resulting from the initiation of surgical skin incision and rib retraction. Paravertebral nerve catheters can be used as an adjuvant to general anesthesia for patients undergoing major thoracic

1/21/2008 10:33:23 AM

74

Section 1 Introduction

Skin

Pleura

Skin

Pleura

Transverse process Transverse process Superior costotransverse ligament

Rib

Rib Spinal nerve

B Spinal nerve A

Paravertebral space

Inferior costotransverse ligament

Superior costotransverse ligament

C

D

Paravertebral space

Inferior costotransverse ligament

FIGURE 5-4 Two approaches to paravertebral nerve blockade. The conventional percutaneous approach to the paravertebral space is seen on the left, walking the needle off the superior border of the transverse process, continuing through the costotransverse ligament, and then seeking a loss of resistance. Some authors advocate the technique on the right, walking the needle off the inferior border of the transverse process. The margin of safety to avoid puncturing the pleura, however, is larger when the technique on the left is used (the distance A to B) than when the technique on the right is used (the distance C to D). (FROM CHAN VWS, FERRANTE MF: CONTINUOUS THORACIC PARAVERTEBRAL BLOCK. IN FERRANTE MF, VADEBONCOEUR TR [EDS]: POSTOPERATIVE PAIN MANAGEMENT. NEW YORK, CHURCHILL LIVINGSTONE, 1993).

surgery via thoracotomy or VATS to provide either unilateral or bilateral analgesia. They may be inserted either percutaneously or with an open technique that allows the surgeon to directly visualize the position of the catheter. The technique has very few adverse effects, which are primarily minor and easily corrected. For the percutaneous placement of a paravertebral nerve block or catheter, the initial point of reference is the midline upper border of the spinous process. The needle is placed 2 to 3 cm lateral to the spinous process and advanced at right angles to the skin in all planes until contact with the transverse process is made. Using the conventional technique, the needle is walked off of the superior border of the transverse process, through the costotransverse ligament until a loss of resistance is encountered. Alternatively, the needle may be walked off the inferior border of the transverse process until a loss of resistance is achieved (Fig. 5-4). A more medial approach with the needle increases the risk of entry into the epidural space, whereas a more lateral approach increases the risk of pneumothorax. When placing a paravertebral nerve catheter, a Tuohy needle and an epidural catheter are used. The open technique to place a paravertebral catheter may also be used. This is achieved by using a Tuohy needle to pass an epidural catheter into the open hemithorax through an intercostal space in the lateral chest wall. A small incision is made in the parietal pleura covering the paravertebral gutter, and a blunt dissection is performed in order to thread the tip of the catheter close to the neurovascular bundle of the next cephalad space (Figs. 5-5 and 5-6). A thoracoscopic technique of placing the catheter has been described in which blunt dissection is used and saline is injected through the catheter as it is advanced.67

Ch005-F06861.indd 74

Adverse effects of paravertebral nerve blockade are generally minor and are easily corrected. They may be technique related, due to technique failure, or agent related. There is a 3.8% incidence of vascular puncture, skin hamartoma, and pain at the site of injection. Percutaneous placement of paravertebral nerve blocks and catheters is not advised in circumstances in which intercostal vessels may be enlarged (e.g., coarctation of the aorta, thoracic aortic aneurysm), predisposing the patient to major vascular injury. Pleural puncture with associated pneumothorax (1.1% incidence) or lung parenchyma penetration (0.5% incidence) has been reported, and there is an eightfold increase in risk when a bilateral block is attempted.68,69 The failure rate has been reported to be as high as 6% to 10% even in the most experienced of hands.70 This complication may be reduced by employing techniques such as ultrasonography, use of a nerve stimulator, and direct catheter insertion during surgery. Lastly, hypotension resulting from sympathetic blockade has an incidence of 4%.70 Concern has been expressed regarding the potential for continuous infusion of local anesthetic agents to cause toxicity due to the vascularity of the thoracic paravertebral space. The proximity of the neuraxis should always make the physician aware of the risk of a total spinal block should the dura be punctured during the procedure. As previously stated, only local anesthetics are suitable for injection or infusion into the paravertebral space. A variety of local agents with varying concentrations are used, most commonly, 0.25% or 0.5% bupivacaine or 0.2% ropivacaine. The advantage of ropivacaine over bupivacaine is that the potential to cause cardiotoxicity is much less. For catheter techniques, an infusion of the local anesthetic is provided at a rate of 0.5 to 1.0 mL per segment to be blocked, or

1/21/2008 10:33:24 AM

Chapter 5 Perioperative Pain Management

FIGURE 5-5 Open placement of a paravertebral catheter intraoperatively. This approach involves stripping the parietal pleura from the posterior chest wall and inserting an epidural catheter through a small incision created in the extrapleural fascia. Using a Tuohy needle, the proximal end of the catheter is brought through the chest wall via an intercostal space near the chest drain. (FROM BERRISFORD RG, SABANATHAN SS: DIRECT ACCESS TO THE PARAVERTEBRAL SPACE AT THORACOTOMY. ANN THORAC SURG 49:854, 1990. COPYRIGHT ELSEVIER 1990.)

0.1 mL/kg/hr for most adult patients. This dose is decreased in smaller adults, the elderly, and the chronically ill (Marret, 2005).66,71

CENTRAL NEURAXIAL BLOCKADE Thoracic Epidural Analgesia TEA only recently made its debut as a mode of pain management for patients undergoing thoracic surgery. In 1957, Crawford and coworkers reported a series of 2172 operations that were conducted with so-called peridural anesthesia.72 They described early postoperative improvements in patients receiving this analgesia compared with those who received only general anesthesia. It was not until the 1970s that TEA became widely used for postoperative analgesia in thoracic surgery, and it was initially used only for high-risk patients.73,74 TEA became the gold standard for post-thoracotomy analgesia with the introduction of neuraxial opioids. A classic study by Bromage and colleagues75 demonstrated the advantages of epidural opioids for postoperative analgesia in comparison with local anesthetics alone for thoracotomy and upper abdominal surgery. The use of continuous infusion techniques and the development of ambulatory and PCA systems enabled TEA to become accepted as a safe and beneficial way to manage perioperative pain.76,77 A review published by Cook and Riley78 determined that, by 1997, 80%

Ch005-F06861.indd 75

75

FIGURE 5-6 The optimal position of a paravertebral catheter. An extrapleural pocket at the posterior end of the surgical incision is created. The catheter is introduced percutaneously into this pocket under direct vision by a needle placed through an intercostal space directly into the pocket. This “extrapleural” block could function more as a multilevel intercostal block if the pocket is not developed medially to the paravertebral space. (FROM WATSON DS, PANIAN S, KENDALL V, ET AL: PAIN CONTROL AFTER THORACOTOMY: BUPIVACAINE VERSUS LIDOCAINE IN CONTINUOUS EXTRAPLEURAL INTERCOSTAL NERVE BLOCKADE. ANN THORAC SURG 67:825, 1999. COPYRIGHT ELSEVIER 1990.)

of all institutions performing more than 100 thoracotomies annually used midthoracic epidural techniques and opioid/ local anesthetic combinations as standard practice to provide perioperative analgesia. The anatomy of the thoracic spine and the oblique angle of the spinous processes (Fig. 5-7) determine the percutaneous approach to the epidural space. The spinous processes are most oblique, and the interspinous space is most vertical in the midthoracic region (T4-T7). There are two approaches to the thoracic epidural space: the midline approach and the paramedian approach (Fig. 5-8). The midline approach requires an oblique cephalad direction of the needle, which is then walked off of the superior surface of the spinous process of the vertebra just below the desired interspinous space. The paramedian approach is favored by many anesthesiologists for its ease in placement of epidural catheters due to the oblique angle of the spinous processes in the midthoracic region. The needle is inserted 1 cm lateral to the superior tip of the spinous process at the desired level and then advanced perpendicular to all planes to contact the lamina of the vertebral body immediately below. The needle is then walked up the lamina at an angle rostrally (45 degrees) and medially (20 degrees) until the rostral edge of the lamina is felt. The needle is advanced over the edge of the lamina until a loss of resistance is obtained when penetrating the ligamentum flavum and entering the epidural space. The tip of the epidural catheter needs to be close to the dermatomes involved in the surgical procedure. In thoracic surgery, this means that thoracic epidural catheters are most often inserted at the T3 to T6 interspinous level, particularly

1/21/2008 10:33:24 AM

76

Section 1 Introduction

C1 2 3 Cervical 4 5 6 7 T1 2 3 4 5 6 7 8

Thoracic

9

45°

10 11 12

A 15°–

20°

B

L1 Paramedian approach

2 3

Lumbar

4

5

Sacrum (5)

Midline approach

FIGURE 5-8 Most anesthesiologists favor the paramedian (A) approach to the epidural space at the midthoracic levels. The needle is inserted 1 cm lateral to the superior tip of the spinous process and then advanced perpendicular to all planes to contact the lamina of the vertebral body immediately below. The needle is then “walked” up the lamina at an angle rostrally (45 degrees) and medially (20 degrees) until the rostral edge of the lamina is felt. The needle is next advanced over the edge of the lamina seeking a loss of resistance on entering the epidural space after transversing the ligamentum flavum. Some practitioners favor the midline approach (B). The needle is inserted right next to the rostral edge of the spinous process and advanced straight, without any angle from the midline. (FROM RAMAMURTHY S: THORACIC EPIDURAL NERVE BLOCK. IN WALDMAN SD, WINNIE AP [EDS]: INTERVENTIONAL PAIN MANAGEMENT. PHILADELPHIA, WB SAUNDERS, 1996.)

Coccyx (4) FIGURE 5-7 The anatomy of the thoracic spine. Note the steep oblique angle of the spinous processes in the midthoracic region (T4T7), which is the most common site for insertion of thoracic epidural catheters for post-thoracotomy analgesia. (FROM RAMAMURTHY S: THORACIC EPIDURAL NERVE BLOCK. IN WALDMAN SD, WINNIE AP [EDS]: INTERVENTIONAL PAIN MANAGEMENT. PHILADELPHIA, WB SAUNDERS, 1996.)

if the TEA is used as an adjunct to general anesthesia for posterolateral thoracotomy. Local anesthetics and/or opioids may be injected through the catheter to obtain segmental dermatome analgesia. The spread of local anesthetics within the thoracic epidural space tends to be more caudal than rostral; however, this is highly dependent on the level at which the injection occurs. Injections of local anesthetics at higher thoracic levels (above T3) tend to result in limited rostral spread, whereas injections at lower thoracic levels tend to have equal spread in the rostral and caudad directions.79

Ch005-F06861.indd 76

TEA is a safe way to provide excellent analgesia,80 and it offers several advantages over other analgesic techniques. Experimental evidence demonstrates that TEA is superior in terms of its effects on perioperative pulmonary function, reduction of the neurohumoral stress response to anesthesia and surgery, myocardial function, oxygen delivery, reduction of myocardial irritability, restoration of gastrointestinal function, and postoperative patient mobility.81-85 It has been demonstrated that the benefits of epidural analgesia are greatest when TEA is used in high-risk patients86 and include reduced ICU stay, quicker recovery, and greater overall hospital cost savings. As with other regional anesthetic techniques, TEA may have undesirable technique- and agent-related side effects. The overall incidence of complications related to technique is approximately 3%. These complications include technical failure, inadvertent dural puncture, postoperative radicular pain, transient peripheral nerve lesions, and inadvertent epidural venous puncture. Spinal cord damage as a result of

1/21/2008 10:33:25 AM

Chapter 5 Perioperative Pain Management

needle trauma or epidural hematoma formation occurs rarely, with an estimated incidence of 0.07%. The technical failure rate for TEA has been reported to be less than 10% on average and can be further reduced with experience and by using fluoroscopy and radiocontrast for catheter placement, obtaining a reliable sensory level with local anesthetic administration, and securing the catheter properly to reduce the incidence of catheter dislodgement.80 Most of the adverse effects seen with TEA are related to the analgesic agents, primarily local anesthetics and opioids. Common adverse effects related to local anesthetics include motor blockade (muscle weakness) and sympathetic blockade (hypotension secondary to peripheral vasodilation). Bradycardia may occur as a result of blockade of the cardiac sympathetic accelerator fibers (T1 through T6), particularly when catheters are placed in the high thoracic region. Hemodynamic changes may be minimized through the use of continuous infusions of local anesthetics rather than intermittent bolusing techniques and by using lower concentrations of local anesthetics combined with an opioid. All clinically available opioids have been used for TEA (Conacher, 2001).80,87 Adverse effects of neuraxial opioids result from systemic absorption and are also related to the opioid’s lipophilicity or hydrophilicity. Common systemic side effects include sedation, nausea, vomiting, inhibition of gastrointestinal motility, pruritus, and respiratory depression. When an opioid is used in combination with a local anesthetic, the opioid requirement is often minimized. The use of a combination of local anesthetics and opioids for TEA is standard practice. Local anesthetics or opioids may be delivered via a continuous infusion alone or in combination with patient-controlled epidural analgesia (PCEA). The combination of local anesthetics with opioids seems to exert a synergistic analgesic effect that is thought to be due in part to facilitation of transfer of the opioid into the cerebrospinal fluid by the local anesthetic and to an increase in the affinity of the opioid receptor for the opioid that is caused by the local anesthetic. These mechanisms are independent of the dose of the local anesthetic.88 This makes it possible to use low doses of local anesthetics in combination with opioids to minimize the sympathetic block side effects (hypotension) that can be a drawback to TEA.

77

commonly as bowel or bladder dysfunction, and rarely as severe radicular back pain.91 Symptoms of a profound motor block that is disproportionate to the concentration of local anesthetic being used for TEA should result in an immediate computed tomographic (CT) or magnetic resonance imaging (MRI) scan and an emergency consultation with a neurosurgeon. Neurologic sequelae can be minimized in patients who develop epidural hematoma with spinal cord compression if a decompression laminectomy is performed within 8 hours after the onset of symptoms.90 Specific practice guidelines for the use of regional anesthesia in anticoagulated patients were outlined by the American Society for Regional Anesthesia in 2003.91 The primary message is that an epidural catheter must not be placed or removed while the patient is significantly anticoagulated. This is defined by the class of the anticoagulant that is being used. Do not initiate anticoagulation or resume it for 2 hours after catheter placement or removal, particularly if blood is noted in the epidural space or catheter placement was technically difficult. Do not administer unfractionated heparin IV for at least 1 hour after epidural placement, and make sure the activated partial thromboplastin time (APTT) is within normal range at the time of catheter removal. Delay heparinization for 2 hours after catheter removal. There are presently no contraindications for subcutaneous administration of 5000 U of unfractionated heparin. Catheter guidelines for lowmolecular-weight heparin state that there needs to be a 12hour delay for the placement or removal of a catheter when thromboprophylactic doses are administered. Observe a 24hour delay for placement or removal of a catheter when systemic anticoagulation is achieved. For patients receiving chronic anticoagulation therapy with warfarin, withhold the dose for 24 hours before catheter placement or removal, and make sure the international normalized ratio (INR) is less than 1.5. Aspirin and NSAIDs alone are not a contraindication to the placement or removal of an epidural catheter; however, the risk is increased when these medications are combined with other anticoagulants. Withhold abciximab (ReoPro), a platelet glycoprotein IIb/IIIa inhibitor, for 24 hours, and withhold eptifibatide (Integrilin) and tirofiban (Aggrastat) for 4 to 8 hours. Stop ticlopidine (Ticlid) 14 days before surgery, and stop clopidogrel (Plavix) within 7 days of surgery.

Anticoagulation and Central Neuraxial Blockade Many thoracic surgeons administer perioperative antithrombus prophylaxis to decrease the incidence of postoperative pulmonary emboli. This may generate concern with regard to the placement and removal of epidural catheters for thoracic surgery. The occurrence of spinal and epidural hematoma after placement of epidural catheters is rare. It has been estimated that the incidence of epidural hematoma with neurologic compromise is 1/150, 000 for epidural anesthetics and 1/220,000 for spinal anesthetics.89,90 This condition is a medical emergency and requires immediate treatment. Neurologic compromise from hematoma manifests most commonly as a progressive motor or sensory blockade, less

ADJUVANT MEDICATIONS Nonsteroidal Anti-inflammatory Drugs NSAIDs are an integral component of multimodal analgesia, and they have been shown to reduce the requirement for opioids after thoracotomy.92-94 Indomethacin, diclofenac, ketorolac, and ketoprofen are among the most popular agents.95,96 These medications can be useful for a variety of thoracic surgery procedures, including thoracoscopic sympathectomy, lung biopsy, and pleurodesis. These procedures usually produce only a mild amount of incisional pain. NSAIDs are generally ineffective when administered as the

tahir99-VRG vip.persianss.ir

Ch005-F06861.indd 77

1/21/2008 10:33:25 AM

78

Section 1 Introduction

sole analgesic for major thoracic surgery, but they are very useful for treating the poorly defined pain of diaphragmatic and pleural irritation that commonly occurs. Despite the potential benefits of NSAIDs, many physicians are concerned about the adverse effects that may be associated with these drugs. Adverse side effects may include renal failure, bleeding at the surgical site, and gastrointestinal hemorrhage.97 Use NSAIDs cautiously in patients of advanced age. Patients who have normal renal function preoperatively are probably not at risk for renal failure due to NSAID administration in the perioperative period. Lee and colleagues98 conducted a Cochrane Database System review of 14 studies and found that NSAIDs caused a minimal and clinically unimportant reduction in creatinine clearance postoperatively, compared with placebo. No incidents of acute renal failure were reported. The authors concluded, “NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.”98 Although thoracic surgical patients may be at a slightly increased risk for NSAID-induced renal dysfunction due to patients’ advanced age and fluid restriction, there have not been any clinical trials of NSAIDs in this population that have confirmed this hypothesis.92,99,100 Bleeding from the surgical site as a result of NSAID inhibition of platelet function does not seem to be of significance. Moiniche and associates101 performed a meta-analysis of 1800 patients who underwent tonsillectomy and found no effect of NSAIDs on perioperative bleeding. The clinical studies involving NSAIDs in thoracic surgery have been too small to reach a statistically significant conclusion. In general, the riskto-benefit ratio of renal failure and bleeding, compared with the benefit gained from attenuation of pain and decreased risk for hypoventilation, favors the use of NSAIDs in appropriate circumstances.

a2-Agonists α2-Adrenergic receptors are present in both the central and peripheral nervous systems at the autonomic ganglia and presynaptic and postsynaptic nerve terminals. α2-Agonists inhibit sympathetic activity in the central nervous system by binding to the postsynaptic α2-adrenergic receptors. The result is a decrease in blood pressure and heart rate, sedation, and minimal respiratory depression.102 In the spinal cord, activation of α2-agonists produces analgesia. Epidural clonidine is the only α2-agonist approved for use as an analgesic for treatment of cancer and neuropathic pain. Therefore, the majority of α2-agonists used for the purpose of analgesia are used either off-label or for clinical research. Clonidine is an effective analgesic when it is administered epidurally, either alone or in combination with local anesthetics or opioids.103-105 Epidural clonidine may produce a greater degree of hypotension than local anesthetics alone.102,105 Dexmedetomidine is a newer α2-agonist that has been approved for ICU sedation in intubated patients. The main advantages of dexmedetomidine over clonidine are a shorter half-life and a greater specificity for the α2-receptor.106 When used intraoperatively and postoperatively, it significantly decreases opioid requirements after major surgery.107

MULTIMODAL ANALGESIA Multimodal analgesia is the concept of directing therapy at multiple anatomic and pharmacologic sites of action to provide the best analgesia possible with minimal adverse side effects (Jin, 2001).108 The essential elements of multimodal analgesia are the following: 1. Neuronal blockade by local anesthetics that may be administered via epidural anesthesia, spinal anesthesia, peripheral nerve blockade, skin infiltration before surgical incision, or wound infiltration before surgical closure. 2. Infusion of opioids via the IV, intrathecal, or epidural route before surgical incision and throughout the perioperative period. 3. Administration of NSAIDs before surgical incision, throughout the intraoperative period, and postoperatively. 4. Administration of other adjuvant medications, such as α2-agonists, clonidine, and dexmedetomidine. Current perioperative pain management practice for thoracic surgery patients tends to follow this approach.

ACUTE POST-THORACOTOMY NEURALGIA Acute post-thoracotomy neuralgia is manifested as intractable pain that occurs in 5% of patients undergoing thoracotomy or VATS. It can occur within hours after surgery and is characterized by vague localization, allodynia, and dysesthesia. Acute post-thoracotomy neuralgia is generally resistant to conventional analgesic regimens, including local anesthetics, NSAIDs, and opioids. Intercostal nerve blockade and paravertebral nerve blockade with local anesthetics may be used in conjunction with medications commonly used to treat chronic pain syndromes (e.g., diazepam, amitriptyline, carbamazepine, gabapentin).109 Development of acute post-thoracotomy neuralgia almost certainly leads to the development of chronic post-thoracotomy neuralgia or neuritis.110

CHRONIC POST-THORACOTOMY PAIN SYNDROME Chronic post-thoracotomy pain has been declared by some authors to be the most common complication after thoracotomy. It is defined as pain that recurs or persists along a thoracotomy scar for at least 2 months after the surgical procedure, and it has a reported incidence of 44% to 67%.111 Chronic post-thoracotomy pain can be severe and disabling in 5% to 10% of patients who develop the syndrome. Preemptive analgesia, the administration of analgesia before surgical insult to reduce the sensitization that might be produced by a nociceptive impulse to the nervous system, has not been shown to decrease the incidence of the development of this syndrome. Several factors may contribute to the development of chronic post-thoracotomy pain syndrome: intercostal neuroma, rib fracture, local infection, costochondritis/costochondral dislocation, local tumor recurrence, and psychological overlay.112 There does not seem to be any difference in the incidence of chronic pain with a conventional thora-

tahir99-VRG vip.persianss.ir

Ch005-F06861.indd 78

1/21/2008 10:33:25 AM

Chapter 5 Perioperative Pain Management

cotomy incision versus a minimally invasive (VATS) approach.113

MANAGEMENT OF OPIOID TOLERANCE Opioid tolerance in patients who present for thoracic surgery can be very challenging when it comes to providing satisfactory perioperative analgesia. Patients may develop opioid tolerance for a variety of reasons, including treatment of cancer pain, treatment of other chronic pain syndromes, and chemical dependence. Opioid tolerance develops as a result of downregulation of active receptor sites from chronic exposure to agonist. Both a decrease in the number of receptors and desensitization to agonist binding are implicated. Opioid doses required to produce satisfactory levels of perioperative analgesia in these patients are increased. Multimodal analgesic regimens that employ regional anesthesia techniques combined with NSAIDs are frequently the optimal choice to control perioperative pain. Withdrawal from opioids during the perioperative period can be problematic. Systemic IV administration (e.g., PCA) or epidural administration may be effective in preventing opioid withdrawal in patients with chronic dependency. An alternative route for dosing opioids is in the form of a transdermal fentanyl patch. All opioid-tolerant patients require frequent adjustment of analgesic doses. Despite appropriate adjustment, pain scores of 2 to 4 (on a scale of 10) with movement are often the lowest achievable. The increased analgesic requirements remain longer postoperatively in opioid-tolerant patients than in opioid-naïve patients.

79

Which analgesic technique is best? Effective pain relief may be achieved in a number of ways. TEA has been the gold standard of perioperative pain management for thoracic surgery. Multimodal analgesic therapy seems to hold the most promise for the future. The issue of which technique is best is one of continuing discussion that is likely to be settled on pragmatic rather than scientific grounds.78,87,115

COMMENTS AND CONTROVERSIES The authors have provided us with a very complete review of the pathophysiology of post-thoracotomy pain and the approaches to pain control. It is apparent that a number of approaches available to thoracic surgeons and their patients can deliver very good pain control. The use of IV narcotics alone is likely to be suboptimal for many patients after open thoracotomy, and in this group a regional approach to analgesia, such as TEA or continuous intercostal nerve catheters with IV PCA, work well. Pain control after thoracoscopy needs to be individualized based on the size and number of ports and the extent of the surgical procedure. For example, simple thoracoscopic procedures with small, 5-mm port entry, such as VATS sympathectomies, may easily be managed with oral analgesics, and many centers perform these as outpatient procedures. On the other hand, more extensive VATS procedures, such as lobectomies or esophageal procedures, may require multiple ports and access incisions and may require an approach similar to that of open thoracotomy. In summary, thoracic surgeons need to be aware of the available options for pain control and to work closely with their colleagues in anesthesiology to produce algorithms for their patients that deliver optimal pain control after thoracic surgical procedures. J. D. L.

KEY REFERENCES

SUMMARY Immense changes and progress in pain management have occurred during the past 20 years. Patient outcomes in thoracic surgery that have been considered to be a direct function of pain include postoperative mobility; duration of hospital stay; atelectasis, pneumonia, and respiratory failure; and the development of chronic pain syndromes. Of these factors, the respiratory components are regarded as most critical and reflect the morbidity and potential for mortality (Warner, 2000).114 Postoperative epidural analgesia is currently the only pain management technique that has achieved a level 1 evidence base for decreasing the incidence of adverse pulmonary outcomes after thoracic surgery. The use of combined epidural local anesthesia and opioid therapy produces a superior analgesic effect, compared with either agent used alone, and provides a lower incidence of adverse effects. NSAIDs may be used alone for treatment of minor incisional pain; however, they are useful for treating severe pain only as a component of a multimodal analgesic regimen. There is no supportive evidence for preemptive analgesia and the prevention of chronic post-thoracotomy pain syndrome through the treatment of acute pain. One might suggest that acute pain that fails to be treated with what is generally considered adequate analgesia may be an indicator of something more serious (e.g., nerve damage).

Conacher ID: Post-thoracotomy analgesia. Anesth Clin North Am 19:611-625, 2001. Gottschalk A, Wu CL, Ochroch EA: Current treatment options for acute pain. Expert Opin Pharmacother 3:1599-1611, 2002. Hazelrigg SR, Cetindag IB, Fullerton J: Acute and chronic pain syndromes after thoracic surgery. Surg Clin North Am 82:849-865, 2002. Hill SE, Keller RA, Stafford-Smith M, et al: Efficacy of single-dose, multilevel paravertebral nerve blockade for analgesia after thoracoscopic procedures. Anesthesiology 104:1047-1053, 2006. Jin F, Chung F: Multimodal analgesia for postoperative pain control. J Clin Anesth 13:524-539, 2001. Kavanagh BP, Katz J, Sandler AN: Pain control after thoracic surgery: A review of current techniques. Anesthesiology 81:737-759, 1994. Kehlet H, Wilmore DW: Multimodal strategies to improve surgical outcome. Am J Surg 183:630-641, 2002. Kelly DJ, Ahmad M, Brull SJ: Preemptive analgesia: I. Physiological pathways and pharmacological modalities. Can J Anaesth 48:10001010, 2001. Lewis KS, Whipple JK, Michael KA, Quebbeman EJ: Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm 51:1539-1554, 1994. Luketich JD, Land SR, Sullivan EA, et al: Thoracic epidural versus intercostal nerve catheter plus patient-controlled analgesia: A randomized study. Ann Thor Surg 79:1849-1850, 2005. Marret E, Bazelly B, Taylor G, et al: Paravertebral block with ropivacaine 0.5% versus systemic analgesia for pain relief after thoracotomy. Ann Thorac Surg 79:2109-2113, 2005.

tahir99-VRG vip.persianss.ir

Ch005-F06861.indd 79

1/21/2008 10:33:25 AM

80

Section 1 Introduction

Moraca RJ, Sheldon DG, Thirlby RC: The role of epidural anesthesia and analgesia in surgical practice. Ann Surg 238:663-673, 2003. Reuben SS, Raghunathan K, Ekman E: Preoperative administration of pregabalin, celecoxib and their combination following spinal fusion surgery. Anesth Analg 102:S228, 2006. Sabanathan S, Eng J, Mearns AJ: Alterations in respiratory mechanisms following thoracotomy. J R Coll Surg Edinb 35:144-150, 1990.

Savage C, McQuitty C, Wang D, Zwischenberger JB: Postthoracotomy Pain management. Chest Surg Clin North Am 12:251-263, 2002. Senturk M, Ozcan PE, Talu GK, et al: The effects of three different analgesia techniques on long-term post-thoracotomy pain. Anesth Analg 94:11-15, 2002. Warner DO: Preventing postoperative pulmonary complications: The role of the anesthesiologist. Anesthesiology 92:1467-1472, 2000.

tahir99-VRG vip.persianss.ir

Ch005-F06861.indd 80

1/21/2008 10:33:26 AM

chapter

6

LARYNGOSCOPY Patrick J. Gullane Ian Witterick Christine B. Novak Michael J. Odell

Key Points ■ The use of the operating microscope during laryngoscopy under

■

■

■

■

■

anesthesia allows for precise assessment and treatment of many benign and malignant laryngeal lesions. However, because of the size and axis of vision, the operating microscope has some distinct limitations in its capacity to visualize certain regions. With the advancement of fiberoptic technology, rigid endoscopes have assumed a greater diagnostic and therapeutic role. Excellent optical resolution, combined with the ability to magnify and digitally record the images, has resulted in increasing reliance on this technology in sinonasal surgery, otology, neurotology, and facial plastic and reconstructive surgery. Rigid endoscopes offer multiple viewing angles and allow for accurate visualization of areas that can be difficult to assess with standard techniques. Evaluation of the laryngeal surface of the epiglottis, the anterior commissure, the laryngeal ventricle, and the subglottic region is greatly facilitated by the use of rigid endoscopes. Rigid endoscopes that are most commonly used for laryngeal assessment are 24 cm long and 5 mm in diameter, with angles of vision of 0, 30, 70, and 120 degrees. Zero- and 30-degree scopes offer excellent magnified views of the superior laryngeal surfaces, whereas the more angled scopes offer excellent views of those areas typically hidden from view by overlying structures. Treatment strategies for benign lesions of the laryngeal mucosa that have failed previous medical or conservative measures typically involve removal of involved pathologic tissue with maximal preservation of normal tissues. The improved ability to identify the exact extent of disease can minimize removal of normal tissue, ensure a complete resection, and thus minimize patient morbidity by preserving voice function. Endoscopic transoral laser resection, partial laryngeal surgery, and nonsurgical radiation- and chemotherapy-based protocols are all designed to avoid total laryngectomy in appropriate patients and thus maintain normal voice production. Rigid endoscopic assessment of the extent of malignancy allows for more accurate stratification of patients and better assessment of suspected recurrences, resulting in more appropriate treatment selection.

Laryngoscopy is an important component of the complete examination of the upper aerodigestive tract: 1. To identify benign and malignant disease 2. To evaluate vocal cord mobility 3. To assess laryngeal trauma and stenosis

Direct laryngoscopy implies that the larynx is seen in a direct line from the examiner’s eye to the area of interest. It usually requires placement of a hollow metal scope through the patient’s mouth to evaluate for pathologic conditions. Indirect laryngoscopy uses various devices, including mirrors and fiberoptic endoscopes (flexible or rigid), to direct an image of the larynx and pharynx to the examiner’s eye.

INDIRECT LARYNGOSCOPY Indications Indirect laryngoscopy is a routine part of the examination of the head and neck. It is particularly important in patients with a history of smoking and alcohol abuse because of the known risk of upper aerodigestive tract malignancies associated with these habits. It is advisable to perform indirect laryngoscopy in any patient who complains of dysphagia, odynophagia, or hoarseness lasting longer than 2 to 3 weeks. It can also be used with appropriate instrumentation to obtain a biopsy of lesions in the larynx, remove foreign bodies, and augment the vocal cords with temporary (Gelfoam, glycerin) or permanent (Teflon) materials. Indirect laryngoscopy performed in a cooperative patient provides a good view of the base of the tongue, vallecula, supraglottic and glottic larynx, and posterior pharyngeal wall. However, it may be difficult to fully assess the piriform sinuses, the laryngeal surface of the epiglottis, and the subglottis with this technique, and the postcricoid area usually cannot be completely visualized. One contraindication to indirect laryngoscopy is a suspected case of supraglottitis or epiglottitis in a child. Traction on the tongue and insertion of a laryngeal mirror may precipitate an acute airway obstruction. If the diagnosis is in question, it may be possible to examine these patients with a flexible scope inserted transnasally. Alternatively, the patient can be taken to the operating room for inhalational induction, direct laryngoscopy, and intubation.

Instruments The larynx may be examined indirectly with a mirror or with a flexible or rigid fiberoptic scope. A mirror is adequate for the examination of most patients, although good illumination is necessary. Either a head mirror and appropriate light source or a head light with its own built-in light source is required. Flexible and rigid scopes have revolutionized the examination of the larynx and pharynx. In patients who are difficult to 81 tahir99-VRG vip.persianss.ir

Ch006-F06861.indd 81

1/21/2008 10:34:40 AM

82

Section 1 Introduction

examine with a mirror or rigid scope because of gagging or an overhanging epiglottis, the flexible scope is superior. This type of scope does not trigger the pharyngeal gag reflex and can be manipulated posterior to the epiglottis. Rigid scopes come in a variety of designs, but basically they are like a 90-degree periscope (Fig. 6-1). The light is conducted along fiberoptic cables to the end of the instrument and directed at the target. Some scopes have built-in zoom lenses to magnify the larynx and give an excellent view of pathologic conditions of the vocal cord. Rigid scopes may be ineffective in patients with a prominent gag reflex or in those in whom the epiglottis is displaced posteriorly. Flexible laryngoscopes are similar to bronchoscopes except that they are shorter, have a smaller diameter, and usually are not equipped with suction (Fig. 6-2). A lever mechanism manipulates the end forward or backward but not from side to side. Therefore, orientation of the end of the scope before insertion is important. Transnasal insertion does not trigger the pharyngeal gag reflex in most patients. Flexible bronchoscopes can be substituted, but the diameter of some bronchoscopes may be too large to fit comfortably through the nasal passage. Pediatric bronchoscopes are of similar caliber but are more difficult to manipulate because of added length, and they do not give as wide or as bright a view as a flexible laryngoscope. Another advantage of the fiberoptic systems is the ability to connect them to camera and video devices. High-quality still and motion pictures can be produced for documentation, discussion with colleagues, or teaching. A strobe light can be connected to slow laryngeal vocal cord vibrations perceptively and allow an assessment of subtle laryngeal pathologic conditions.1

Anesthesia Most patients can be examined without anesthesia. If the patient has a prominent gag reflex, the anterior tonsillar pillars, base of tongue, and posterior oropharyngeal wall can be sprayed with a topical anesthetic (e.g., 10% lidocaine spray). Having the patient gargle with a topical anesthetic (e.g., 2%-5% lidocaine) is also effective. Rarely is a superior laryngeal nerve block required; it is accomplished by subcutaneous infiltration of a local anesthetic 1 cm anterior to the superior thyroid cornua and 1 cm superior to the thyroid cartilage. When a flexible laryngoscope is passed transnasally, the procedure is much more comfortable for the patient if a topical anesthetic agent is used. Topical cocaine (4%) is particularly effective because it can act as a decongestant and anesthetic agent at the same time. Attention to the maximum dose of the anesthetic per kilogram of weight must be observed, particularly in children and in patients with cardiac disease.

Technique Mirror Laryngeal mirrors are readily available and inexpensive, but they require some practice to use them effectively. The examiner and patient are seated comfortably at eye level (Fig. 6-3). A head mirror or head light is used to focus light on the soft palate and posterior pharyngeal wall. The mirror is warmed with hot water, heated beads, or a flame in order to prevent the patient’s respirations from fogging the mirror during the examination. Test the temperature on your hand before inserting the instrument in order to avoid burning the patient. Alternatively, a defogging solution may be used on

FIGURE 6-1 Rigid fiberoptic scope for examination of the pharynx and larynx.

FIGURE 6-2 Flexible fiberoptic scope for examination of the pharynx and larynx.

FIGURE 6-3 Indirect mirror laryngoscopy. Note the examiner’s hand retracting the tongue with a folded gauze while the contralateral hand positions the mirror.

tahir99-VRG vip.persianss.ir

Ch006-F06861.indd 82

1/21/2008 10:34:41 AM

Chapter 6 Laryngoscopy

the mirror. If the examiner is right handed, the left hand is used to hold the protruded tongue with a folded gauze pad. If the examiner needs both hands free, the patient may be asked to hold out his or her own tongue. The right hand directs the mirror towards the posterior oropharyngeal wall and angles it so that a view of the base of the tongue, vallecula, hypopharynx and larynx is obtained. It is helpful to have the patient pant, and it is often necessary to touch and elevate the soft palate to gain an adequate view. The patient attempts to vocalize “eee” so that vocal cord mobility may be assessed and also to rotate the larynx anteriorly for improved visualization. Examination of the larynx and pharynx in a systematic fashion may require several trials. It is important to remember that, with a mirror, the anterior and posterior relationships of the larynx are reversed but right and left remain the same when the examiner looks at the reflected image. An easy way to understand and visualize this concept is to draw two labeled vocal cords on a piece of paper and position them so that the anterior commissure is facing the examiner (i.e., the patient is facing the examiner). When the mirror is held over the paper, it will be noted that the right and left cords remain on the same side, but the anterior and posterior dimensions are reversed. This reversal makes instrumentation of the larynx with a mirror confusing. An advantage of both the rigid and flexible telescopes is that there is no reversal and a true image of the larynx is obtained.

Rigid Telescope Examination with the rigid scope is similar to that with the mirror. The tongue is held protruded with one hand while the telescope is inserted through the mouth toward the posterior oropharyngeal wall. It often touches the wall. The telescope can be rotated to view the entire larynx and pharynx while the patient pants or attempts to vocalize “eee.” If the telescope is equipped with a zoom lens, specific areas can be examined with magnification.

FIGURE 6-4 Flexible laryngoscopy.

1990, 1993, 2003; Kleinsasser, 1991).2-6 The extent of any disease process can be precisely characterized, and appropriate biopsies can be taken. Areas that are not amenable to examination with indirect methods can be evaluated, such as the laryngeal ventricles, subglottis, postcricoid area, and piriform sinuses. The vocal cords and arytenoid processes may be palpated to ascertain whether the vocal cord immobility is due to paralysis or ankylosis. The vocal cords may be augmented with Gelfoam, fat, or Teflon. Laryngeal lesions may be removed using either cold microlaryngeal instrumentation or various types of lasers.

Contraindications and Precautions

Indications

General anesthesia is contraindicated if the patient has a laryngeal obstruction (e.g., neoplasm, foreign body, edema). If the pharyngeal tone is lost, a marginal airway could result in total obstruction. There are several options in this situation, including awake intubation (often with the aid of a flexible bronchoscope7) and tracheotomy under local anesthesia. Unfavorable patient anatomy or comorbidities may create impossible or dangerous situations for direct laryngoscopy; examples include ankylosing spondylitis, rheumatoid arthritis, and cervical spine fractures or dislocation. Other anatomic features that may make laryngoscopy difficult include a small mandible, trismus, long central incisors, a short neck, and inability to extend the neck. There are still cases of unanticipated difficult laryngoscopic intubation. Several preoperative airway assessment tests have been proposed in the anesthesia literature to predict difficulty with intubation. These include measurements of mouth opening (interincisal gap), hyomental distance, length of mandibular ramus, and atlanto-occipital extension and assessments of the oropharyngeal view. These last assessments are graded according to the Mallampati classification, as modified by Samsoon and Young (Samsoon, 1987)8:

Direct laryngoscopy is the preferred technique for detailed evaluation of laryngeal tumors, stenosis, and trauma (Benjamin,

Class 1: Good visualization of the soft palate and tonsillar pillars

Flexible Telescope The patient is asked if one nasal passage is more patent, or, preferably, patency is assessed by anterior rhinoscopy. After topical anesthesia is administered, the scope is directed along the floor of the nose adjacent to the inferior turbinate or between the inferior and middle turbinates. In the nasopharynx, the scope is directed posterior to the soft palate, and a panoramic view of the base of the tongue, larynx, and pharynx is obtained. The scope is then directed toward the areas of interest for a closer examination of both the subglottis and trachea in a systematic fashion. The access to areas that are otherwise difficult to examine is superb, although the illumination and clarity may not always be as good as with a mirror or rigid scope (Fig. 6-4).

DIRECT LARYNGOSCOPY

Ch006-F06861.indd 83

83

1/21/2008 10:34:41 AM

84

Section 1 Introduction

FIGURE 6-5 Anterior commissure scope.

FIGURE 6-6 Two examples illustrate the different luminal sizes of direct laryngoscopes: anterior commissure scope (left) and Dedo scope (right).

Class 2: Pillars obscured by the soft palate but posterior oropharyngeal wall visible Class 3: Soft palate and base of uvula visible Class 4: Soft palate not visible Although these measures may be somewhat helpful, they are not foolproof because interobserver reliability is often poor (Karkouti, 1996).9

Preoperative Preparation The patient is placed in the supine position on a head support that raises the head approximately 10 cm above the operating room table. This flexes the neck on the chest and places the patient in the Boyce or so-called sniffing position, which is optimal for endoscopic visualization of the larynx. Secretions can be minimized if the patient is given a drying agent preoperatively, such as atropine or glycopyrrolate.

Anesthesia Direct laryngoscopy can be performed under local or general anesthesia. General anesthesia is preferred for patient comfort and muscle relaxation. Local anesthesia is used in circumstances in which vocal cord mobility or assessment of the voice is important (e.g., Teflon augmentation). Ventilation may be carried out with or without the use of an endotracheal tube during direct laryngoscopy. Techniques of ventilation using an endotracheal tube may be divided into large tube and small tube techniques. With the large tube technique, a standard 7 to 9 Fr endotracheal tube is used. This presents a significant obstruction to the surgeon’s view, especially of the posterior commissure. This can be overcome to some extent by moving the tube into the anterior glottis. The small tube technique involves the use of an endotracheal tube ranging from 5 to 6 mm in interior diameter. The primary difficulty with such tubes arises if adequate time is not given for expiration, resulting in a raised intrathoracic pressure and possible hypotension, pneumothorax, or pneumomediastinum. Positive-pressure ventilation may be provided for up to 1 hour with a small tube. In most cases,

Ch006-F06861.indd 84

FIGURE 6-7 Lindholm laryngoscope.

however, the tube lies posterior to the laryngoscope and is taped to the patient’s face or held by the anesthetist at the left oral commissure to remove it from the path of entry of the laryngoscope through the right side of the oropharynx. Care must also be taken when lasers are used to avoid puncture of the tube and initiation of an endotracheal tube fire. This risk can be reduced using an endotracheal tube, placing wet cottonoids around the tube to act as a heat sink, and using blue dye in the endotracheal tube cuff to warn of laser puncture. Nonintubation techniques in current use entail some form of jet ventilation. This involves the entrainment of room air by a jet stream of gas based on the principles elucidated by Daniel Bernoulli in 1730 and Giovanni Venturi in 1797. This, in essence, means that the faster moving stream of gas gives up some of its velocity to the slowly moving room air such that the entrained room air is dragged into the moving stream. Jet ventilation may be divided into supraglottic, subglottic,

1/21/2008 10:34:41 AM

Chapter 6 Laryngoscopy

85

FIGURE 6-8 The Weerda bivalved laryngoscope with adjustable blades to distend structures in the larynx and hypopharynx, improving exposure.

transtracheal, and high-frequency ventilation techniques. Supraglottic jet ventilation is the most commonly used method, but it has some disadvantages, including soiling of the trachea with blood and debris, inefficient ventilation due to turbulence, and gastric distention. Subglottic ventilation does not have these problems but does have an increased risk of barotrauma. Transtracheal jet ventilation is rarely used. High-frequency jet ventilation uses respiratory rates at 1 Hz and at relatively low volumes. This enhances diffusion and inter-regional mixing within the lungs and may have a place in patients with chronic obstructive pulmonary disease, poor compliance, or obesity.10,11 The increased use of the laryngeal mask has helped to further minimize trauma to the laryngeal structures.12 However, it visually occludes the laryngeal anatomy, and therefore its use with this examination is limited. At the end of the procedure, with reversal of anesthesia, the laryngeal mask may be useful to oxygenate the patient and thereby avoid intubation.

Protection of Teeth The patient’s upper dentition is at risk for damage during direct laryngoscopy. It is important to note dental work and to identify loose teeth before the procedure is performed and to inform the patient. Gauze or a prefabricated plastic dental guard are most useful to prevent dental abrasion. A guard may help to distribute pressure, but it does not allow the upper teeth to be used as a fulcrum during exposure of the larynx in a difficult patient. In patients who require frequent endoscopies and in those with precarious dentition, a customized acrylic or plastic plate of the upper dentition is useful to reduce dental trauma. It is much easier to position the scope in patients who do not have teeth or who have large gaps in their upper teeth.

Instruments There are many laryngoscopes that can be used to carry out direct laryngoscopy. To examine the entire larynx, the Holinger anterior commissure laryngoscope is excellent

Ch006-F06861.indd 85

FIGURE 6-9 Kantor-Berci video microlaryngoscope.

because the hourglass shape allows it to reach most sites (Figs. 6-5 and 6-6). Unfortunately, the panoramic view is lost, and each site must be sequentially examined; in addition, binocular visualization is not possible. For delicate laryngeal surgery, it is preferable to select the widest scope that can be inserted to expose the anterior commissure. A variety of shapes and sizes of laryngoscopes is required to meet the needs of the entire spectrum of patients (see Fig. 6-6). The Dedo laryngoscope is a good standard laryngoscope because it allows for a panoramic view of the endolarynx and can be used in most patients. The Lindholm laryngoscope6 (Fig. 6-7) is designed so that its anterior aspect sits in the vallecula. This allows for visualization of both the supraglottis and the glottis. For further access to the supraglottis, a bivalve laryngoscope may be used (Zeitels, 1990).13 The Weerda laryngoscope (Fig. 6-8) is a bivalve scope that has two adjustable blades, allowing for the diameter of the scope to be enlarged after insertion into the larynx. The subglottis is an area that can be difficult to access with a conventional laryngoscope. A subglottoscope with an elongated tube and a diameter large enough to allow binocular visualization is available for this purpose (Ossoff, 1991).14 Laryngoscopes have one or two ports for fiberoptic light carriers. The KantorBerci video microlaryngoscope (Fig. 6-9) has a port for the insertion of a rigid telescope for both illumination and magnification. Ports may also be present to allow for jet ventilation or smoke evacuation. The use of these ports for jet ventilation is less efficient than holding the jet in the middle of the laryngoscope lumen, which allows for more efficient entrainment of room air. The laryngoscope may be held with one hand, or it may be suspended to allow both hands to be used. Two commonly used suspension devices are the Lewy and Boston systems. The Lewy suspension device is light, is easy to attach and detach, and provides excellent stabilization of the laryngoscope within the larynx (Fig. 6-10). However, the Lewy system may exert unacceptable pressure on the upper denti-

1/21/2008 10:34:42 AM

86

Section 1 Introduction

FIGURE 6-10 Lewy suspension system with jet Venturi. This system is placed on a Mayo stand over the patient’s upper chest and attached to the laryngoscope.

FIGURE 6-11 Boston suspension system.

tion if exposure of the larynx is difficult. The Boston suspension system is favored in such cases because it allows for proper positioning of the head and neck, and pressure on the maxillary teeth is minimized (Fig. 6-11). This system does take longer to set up and position accurately. Magnification of the larynx can be accomplished with an operating microscope (Fig. 6-12). The axis of the microscope is aligned with the axis of the laryngoscope. A 400-mm objective lens has a focal length long enough to allow instrumentation of the larynx without the instrument hitting the microscope. It usually is not possible to get binocular vision through narrow scopes, and hence there is a need for the widest scope possible that will expose the area of interest. For microlaryngeal surgery, a support stand such as a Mayo stand may be placed at the patient’s head to rest one’s elbows.

Ch006-F06861.indd 86

Intraoperative Assessment of the Larynx With Rigid Fiberoptic Endoscopy The use of the operating microscope during laryngoscopy with the patient under anesthesia has allowed for precise assessment and treatment of benign and malignant laryngeal lesions. Because of its size and axis of vision, however, the operating microscope has some distinct limitations in its ability to visualize certain areas. As fiberoptic technology has improved, rigid endoscopes have assumed a greater diagnostic and therapeutic role in otolaryngology and head and neck surgery. Excellent optical resolution, combined with the ability to magnify and digitally record the images, has resulted in an increasing reliance on this technology in sinonasal surgery, otology, neurotology, and facial plastic and reconstructive surgery.

1/21/2008 10:34:43 AM

Chapter 6 Laryngoscopy

87

FIGURE 6-12 Direct microlaryngoscopy.

The use of rigid endoscopes to improve the accuracy of laryngeal assessment is well documented. The ability of rigid endoscopes to offer multiple viewing angles allows for accurate visualization of some areas that can be difficult to assess with standard techniques. Evaluation of the laryngeal surface of the epiglottis, the anterior commissure, the laryngeal ventricle, and the subglottic region is greatly facilitated by the use of rigid endoscopes. Rigid endoscopes that are 24 cm long and 5 mm in diameter are most commonly used for laryngeal assessment, and the angles of vision include 0, 30, 70, and 120 degrees. Zeroand 30-degree scopes offer excellent magnified views of the superior laryngeal surfaces, whereas the more angled scopes offer excellent visualization of those areas typically hidden from view by overlying structures. Treatment strategies for benign lesions of the laryngeal mucosa, after medical or conservative measures have failed, typically involve removal of abnormal tissue with maximal preservation of normal tissues, in an effort to minimize the detrimental effects of surgery on the voice. The improved ability to assess the exact extent of disease can help avoid the removal of normal tissue while ensuring a complete resection. In cases of malignant diseases of the larynx, efforts are being increasingly directed toward treatments that provide more natural voice production by avoiding unnecessary total laryngectomies. Endoscopic transoral laser resection, partial laryngeal surgery, and nonsurgical radiation and chemotherapy-based protocols are all designed to avoid total laryngectomy in appropriate patients. Rigid endoscopic assessment of the extent of malignancy allows for more accurate stratification of patients and better assessment of suspected recurrences, allowing for more appropriate treatment selection.

Contact Endoscopy The epithelium of the vocal cords can be further evaluated with the use of contact endoscopy. This technique involves

Ch006-F06861.indd 87

the staining of the vocal cords with methylene blue, followed by visualization with a contact endoscope. This allows for the examination of cellular detail of the vocal cord epithelium.15-17

LASER LARYNGEAL SURGERY Lasers can be used for selected purposes in the larynx, such as excision of laryngeal cancer or papillomata. The most common method is to use a carbon laser by attaching a micromanipulator to the operating microscope, with the surgeon aiming the laser with a joystick. Because the carbon dioxide laser is invisible, a coaxial red helium-neon beam is required for aiming. This technique can be used for ablation or excision of the lesion.

Technique To ensure an uneventful endoscopic examination, the airway must be stable, and the patient must be relaxed. This is best provided through close collaboration between surgeon and anesthesiologist. In most cases, induction is carried out with an intravenous agent after preoxygenation. Do not administer general anesthesia if there is a concern regarding airway patency. The procedure is carried out with neuromuscular paralysis to allow for easy insertion of the laryngoscope. Anesthesia is maintained with volatile agents such as nitrous oxide, halothane, or enflurane. Propofol is an intravenous agent that can provide complete anesthesia by itself. The patient’s eyes are taped shut to prevent corneal abrasion. Ventilation is achieved by intubation or jet ventilation, as discussed previously. The surgeon is positioned at the head of the table and introduces the laryngoscope with his or her left hand, through the patient’s mouth to the epiglottis. It is important to minimize trauma to the lips or tongue during manipulation of the laryngoscope. The tip of the laryngoscope is passed under the epiglottis, which is displaced anteriorly. The scope is advanced to the laryngeal inlet as far as necessary to expose the internal surface of

1/21/2008 10:34:43 AM

88

Section 1 Introduction

the larynx, and, at that point, it can be suspended or held in the hand to systematically examine various parts of the larynx, including the true and false vocal cords, anterior and posterior commissures, ventricles, subglottis, epiglottis, piriform sinus, vallecula, and postcricoid area. It is often necessary to push on the thyroid or cricoid cartilage externally to bring structures into view through the scope. Fine dissecting instruments are required for microsurgery of the larynx. Local anesthesia is commonly applied topically to the larynx at the conclusion of the laryngoscopy to prevent postoperative laryngospasm. Most patients have minimal pain after the procedure and can return to a normal diet. Depending on the amount of instrumentation, the patient’s voice may be hoarse after the procedure, and instruct him or her to speak softly for short periods and to avoid whispering, shouting, or long conversations.

SUMMARY The technique of endoscopic evaluation of the larynx has expanded and revolutionized the examination of the larynx and the identification of pathology and has maximized out-

Ch006-F06861.indd 88

comes previously unattainable. The future directions utilizing robotics18,19 may further enhance patient care. KEY REFERENCES Benjamin B: Diagnostic Laryngology: Adults and Children. Philadelphia, WB Saunders, 1990. Benjamin B: Prolonged intubation injuries of the larynx: Endoscopic diagnosis, classification and treatment. Ann Otol Rhinol Laryngol 160(Suppl):1, 1993. Benjamin B, Lindholm C-E: Systematic direct laryngoscopy: The Lindholm laryngoscopes. Ann Otol Rhinol Laryngol 112:787, 2003. Karkouti K, Rose D, Ferris L, et al: Interobserver reliability of ten tests used for predicting difficult tracheal intubation. Can J Anaesth 43:554, 1996. Kleinsasser O: Microlaryngoscopy and Endolaryngeal Microsurgery. Techniques and Typical Findings. St Louis, Mosby-Year Book, 1991. Ossoff R, Duncavage I, Dere H: Microsubglottiscopy: An expansion of operative microlaryngoscopy. Otolaryngol Head Neck Surg 104:842, 1991. Samsoon GL, Young JR: Difficult tracheal intubation: A retrospective study. Anaesthesia 42:487, 1987. Zeitels S, Vaughn C: The adjustable supraglottiscope. Otolaryngol Head Neck Surg 103:487, 1990.

1/21/2008 10:34:44 AM

chapter

7

BRONCHOSCOPY Andrew F. Pierre

Key Points ■ Flexible and rigid bronchoscopy are important skills that the tho-

racic surgeon should master. ■ The decision as to which technique to use depends on the condi-

tion of the patient and the pathology at hand.

FLEXIBLE BRONCHOSCOPY Until the 1970s, the airway could be examined only by using a rigid bronchoscope. In 1968, Ikeda from Japan introduced the first flexible fiberoptic bronchoscope (Ikeda et al, 1968).1 Since then, the flexible scope has become an invaluable tool in the diagnosis and management of tracheobronchial and pulmonary diseases. Although the flexible bronchoscope enhances the capabilities of the endoscopist, it does not replace the rigid scope. The rigid bronchoscope is still the optimal instrument for control of airway hemorrhage, placement of Silastic stents, removal of foreign bodies, and management of airway obstruction. The flexible and rigid bronchoscopes are complementary instruments and should be used as such. Flexible bronchoscopy has its greatest utility in diagnostic procedures. It is relatively easy to learn to use; it can be used with topical anesthesia and minimal sedation; and serious complications are rare. Specimens may be obtained by direct forceps biopsy, washings, needle biopsies, protected brushings, or transbronchial biopsies—all at relatively low risk to the patient. The flexible scope is an important tool used by thoracic surgeons, pulmonologists, intensivists, anesthesiologists, and otolaryngologists. The flexible bronchoscope may also be used to deliver laser therapy, photodynamic therapy, and brachytherapy to the airways.

INDICATIONS Flexible fiberoptic bronchoscopy is now widely used in the diagnosis and management of inflammatory, infectious, and neoplastic diseases of the lungs. In well-trained hands, the application of the flexible instrument is safe and effective, but experience and sound clinical judgment determine the ultimate indications and utility of flexible bronchoscopy. No list of indications can accurately reflect the changing state of medical technology and capabilities. New instrumentation and techniques will continue to expand the role of flexible bronchoscopy. Also, details of how and when a particular physician decides to perform the procedure for the various indications depend on several factors related to the disease,

the condition of the patient, and the risks and benefits of the procedure in each instance. All patients undergo a thorough history and physical examination, and medical problems are addressed before the procedure is performed. Obtain a coagulation profile if biopsies are planned or if the history is suggestive of a coagulopathy. Note, in particular, that asthma can be triggered and worsened by bronchoscopy, and bronchial edema and bronchospasm can result from the procedure. If asthma is adequately treated and controlled, asthmatic patients can be examined safely. Table 7-1 lists the general indications and contraindications for flexible bronchoscopy. This section provides a brief discussion of some of the common indications for which a thoracic surgeon might use the flexible bronchoscope.

Pulmonary Lesions or Infiltrates Indications for flexible bronchoscopy commonly include an abnormal mass or nodule detected on chest radiography that is suspected of being a lung cancer. The exact location of the lesion can be identified, and the mass may be biopsied. The remaining airways are examined carefully for other lesions that might represent metastatic disease or other primary cancers. Other frequent indications include recurrent pulmonary infiltrates, an unresolving infiltrate, and persistent atelectasis (collapse of a segment, a lobe, or a lung); a mediastinal or hilar mass; or persistent pleural effusions. Bronchoscopy may help in the diagnosis of diffuse parenchymal lung disease when the differential diagnosis includes neoplastic, infectious, or inflammatory lung diseases. Flexible bronchoscopy can be a very useful diagnostic tool in immunocompromised patients with new pulmonary infiltrates. In this population, bronchoalveolar lavage with or without transbronchial lung biopsies frequently helps to define an infectious cause for the new pulmonary infiltrate.2 The yield from these procedures is high and has reduced the need for openlung biopsy in these immunocompromised patients.

Planning a Lung Cancer Operation Information gathered with the bronchoscopic examination is crucial to planning resection of a lung cancer. The decision to perform a lobectomy, sleeve resection, pneumonectomy, or carinal pneumonectomy depends on determination of the exact location of the tumor in the airway and evaluation of the length of airway involved. For example, a tumor of the right upper lobe extending into the right main stem bronchus may be resected by pneumonectomy or by a right upper lobe sleeve resection with preservation of the right middle and 89

Ch007-F06861.indd 89

1/21/2008 10:36:03 AM

90

Section 1 Introduction

TABLE 7-1 American Thoracic Society Guidelines for Flexible Fiberoptic Bronchoscopy Diagnostic Uses To evaluate lung lesions of unknown etiology that appear on the chest radiograph To assess airway patency To investigate unexplained hemoptysis, unexplained cough, localized wheeze, or stridor To search for the origin of suspicious or positive sputum cytology To investigate the cause of unexplained paralysis of a vocal cord or hemidiaphragm, superior vena cava syndrome, chylothorax, or unexplained pleural effusion To evaluate problems associated with endotracheal tubes, such as tracheal damage, airway obstruction, or tube placement To stage lung cancer preoperatively and, when appropriate, to evaluate the response to therapy To obtain material for microbiologic studies in suspected pulmonary infections To evaluate the airways for suspected bronchial tear or other injury after thoracic trauma To evaluate a suspected tracheoesophageal fistula To determine the location and extent of respiratory tract injury after acute inhalation of noxious fumes or aspiration of gastric contents To obtain material for study from the lungs of patients with diffuse or focal lung disease Therapeutic Uses To remove retained secretions or mucous plugs not mobilized by conventional noninvasive techniques To remove foreign bodies To remove abnormal endobronchial tissue or foreign material by use of forceps or laser techniques To perform difficult intubations To aid in the delivery of brachytherapy To aid in the deployment of expandable wire stents Conditions Involving Increased Risk Lack of patient cooperation Recent myocardial infarction or unstable angina Partial tracheal obstruction Unstable bronchial asthma Respiratory insufficiency associated with moderate to severe hypoxemia or any degree of hypercarbia Uremia and pulmonary hypertension (possibility of serious hemorrhage after biopsy) Lung abscess (danger of flooding the airway with purulent material) Obstruction of the superior vena cava (possibility of bleeding and laryngeal edema) Debility, advanced age, malnutrition Unstable cardiac arrhythmia Respiratory failure requiring mechanical ventilation Disorders requiring laser therapy, biopsy of lesions obstructing large airways, or multiple transbronchial lung biopsies The danger of a serious complication is especially high in the following conditions: Malignant arrhythmia Profound refractory hypoxemia Severe bleeding diathesis that cannot be corrected when biopsy is anticipated Contraindications Absence of consent from the patient or his or her representative Bronchoscopy by an inexperienced person without direct supervision Bronchoscopy without adequate facilities and personnel to care for emergencies such as cardiopulmonary arrest, pneumothorax, or bleeding Inability to adequately oxygenate the patient during the procedure Adapted with permission from the guidelines for fiberoptic bronchoscopy in adults. Accepted as official position paper by the American Thoracic Society Board of Directors, November 1986; from Sokolowski RW, Burgher LW, Jones FL, et al: Guidelines for fiberoptic bronchoscopy in adults. Am Rev Respir Dis 136:1066, 1987.

lower lobes. Information obtained at bronchoscopy is vital to planning this resection and making this decision.

Pulmonary Toilet The clearing of secretions is very important after a thoracic operation, but it is especially important after a tracheal resection. The flexible scope can be used at the bedside to achieve this goal of pulmonary toilet in the thoracic patient. Topical anesthesia and minimal sedation are required. This technique is used liberally if patients, for whatever reason, are unable to clear their secretions with chest physiotherapy and more conservative measures.

Ch007-F06861.indd 90

Endotracheal Intubation and the Intubated Patient The flexible bronchoscope that is advanced through a standard single-lumen endotracheal tube can be used for difficult intubations that cannot be accomplished by standard techniques. The awake patient is topically anesthetized. The flexible bronchoscope is passed through an endotracheal tube. The bronchoscope is guided into the distal airway, and the endotracheal tube is advanced down the bronchoscope to ensure accurate placement in the trachea. Finally, the position of the endotracheal tube is checked, using the scope as it is removed. The

1/21/2008 10:36:03 AM

Chapter 7 Bronchoscopy

patient is then anesthetized and connected to the ventilator. After endotracheal intubation with a double-lumen tube, the flexible bronchoscope is used to confirm proper positioning of the bronchial arm and the bronchial balloon. Flexible scopes are also useful for positioning bronchial blockers or Univent tubes for single-lung ventilation. In the intubated patient, the flexible bronchoscope may be used to evaluate the position and patency of the endotracheal tube, to evaluate hemoptysis, to obtain samples for microbiologic examination, and to clear secretions. These indications commonly arise in the intensive care unit but may also occur in the operating room.

Bronchopleural Fistula The bronchoscope may help in the diagnosis and management of a bronchopleural fistula. Examination of the bronchial stump may reveal the fistula, and bronchoscopic evaluation can be used to determine whether further intervention is required. The scope can be used to help position bronchial blockers or long endotracheal tubes for single-lung ventilation, if such instruments are required for management of ventilation.

rigid bronchoscope. Continuous visualization in this fashion ensures that the stent is optimally deployed.

Airway Trauma After blunt or penetrating chest trauma, perform bronchoscopy if the patient’s lung fails to re-expand after adequate chest tube drainage or if the suspicion of a tracheobronchial injury is high. Such patients may present with high-volume air leaks, persistent pneumothorax, pneumomediastinum, or hemoptysis. Signs and symptoms of a tracheobronchial injury may, however, be subtle in some patients.

Foreign Bodies The flexible bronchoscope may be used to identify foreign bodies and, on occasion, to remove them. However, the rigid bronchoscope is the preferred tool for the removal of foreign bodies because it facilitates safe and rapid removal and simultaneously provides excellent airway control for ventilation.

Inhalation Injury Perform bronchoscopy for a patient with an inhalation injury to determine the extent of injury. The flexible scope may also be used to facilitate endotracheal intubation of these patients if there is significant airway edema.

Airway Obstruction

Laser Therapy

A patient with a persistent lung abscess or pneumonia may have an endobronchial obstruction and should undergo bronchoscopy. In this situation, bronchoscopy may reveal a foreign body, a tumor, or an extrinsic compression. Occasionally, flexible bronchoscopy can help establish drainage from the affected area of the lung, or a tumor, if present, can be biopsied. Stridor or localized wheezing may be caused by a structural narrowing of the upper airway and trachea; evaluate by bronchoscopy. Lesions may include laryngeal abnormalities, vocal cord paralysis, benign and malignant tumors, extrinsic compression, tracheal stricture caused by mucosal pathology, or tracheomalacia. Suspicious lesions can be biopsied. Management depends on the cause. If tracheal obstruction is suspected, perform the bronchoscopic examination in an operating room, where rigid bronchoscopy can be performed first to ensure control of the airway. The flexible bronchoscope may be used through the rigid bronchoscope to examine the distal airway in detail (see later discussion of Rigid Bronchoscopy). Bronchial obstruction by tumor is best managed with the rigid bronchoscope, but the flexible scope can aid in many of the maneuvers that are necessary to open the airway. Débridement by laser is slow, but the laser can be used to help achieve hemostasis after manual forceps débridement via the rigid bronchoscope. The airway may then be stented if required.3 If an expandable metal stent is selected, the stent and delivery device are advanced into the trachea along the rigid scope. The flexible scope is then placed through the rigid scope and used to visualize the stent as it is positioned accurately into the bronchus across the stricture or obstruction. Ventilation is maintained through the side arm of the

The flexible bronchoscope facilitates use of the neodymium : yttrium-aluminum-garnet (Nd : YAG) laser by directing the laser fiber into locations that are difficult to reach with the rigid bronchoscope.4 This laser may then be used in the management of bronchial obstruction secondary to tumor once distal luminal patency is confirmed. However, the management of bronchial obstruction is best and most safely carried out with the use of a rigid bronchoscope. The flexible scope is used in conjunction with the rigid scope by simply passing it through the lumen of the rigid scope to deliver laser therapy. With this technique, the obstructed airway may be effectively opened using a combination of manual forceps débridement and laser débridement.

Ch007-F06861.indd 91

91

Mediastinal Adenopathy In certain circumstances, the flexible scope and a Wang needle can be used to perform transbronchial biopsies of mediastinal nodes. However, mediastinal nodes are more commonly sampled by cervical mediastinoscopy.

Lung Transplantation The flexible bronchoscope is used extensively in the management of lung transplantation. Bronchoscopy is an important part of donor assessment and may identify donors who have aspirated, have infections, or have abnormal airway anatomy. The recipient is intubated with a double-lumen endotracheal tube, the position of which is confirmed with the flexible bronchoscope. After completion of the bronchial anastomoses, they are examined endobronchially with the flexible scope, and the distal airways are cleared of blood and secretions. Pulmonary toilet is very important in the postoperative

1/21/2008 10:36:03 AM

92

Section 1 Introduction

period, and the scope may be used for this purpose at the bedside or in the intensive care unit. Finally, the diagnosis of infection or rejection is heavily dependent on flexible bronchoscopy. The patient undergoes transbronchial lung biopsies under fluoroscopic guidance to diagnose rejection, and bronchoalveolar lavage is used to help diagnose various pulmonary infections.

EQUIPMENT

FIGURE 7-1 A selection of flexible biopsy forceps for use through the flexible bronchoscope.

FIGURE 7-2 Bronchial brushes in protective plastic catheter sheaths can be used to obtain protected samples from the distal airways for culture.

The basic setup consists of a flexible fiberoptic bronchoscope, light source, biopsy forceps, and suction apparatus (Figs. 7-1 and 7-2). The video bronchoscope has become standard equipment. It provides excellent visualization and is ideal for teaching. Flexible bronchoscopes are classified according to the size (diameter) of their distal ends (Fig. 7-3). Standard adult scopes are 5 to 6 mm in outside diameter, with a 2.2- to 2.8-mm working channel. Pediatric scopes are typically 3.5 to 3.6 mm with a smaller (1.2-mm) working channel. With technological advances, smaller-caliber video bronchoscopes of high quality are becoming available. Consider the intended

FIGURE 7-3 Distal tips of various size bronchoscopes and their working channels.

Ch007-F06861.indd 92

1/21/2008 10:36:03 AM

Chapter 7 Bronchoscopy

use of the scope. The suctioning and clearing of secretions is best accomplished through larger scopes with wider working channels, but the ability to reach very distal airways to obtain direct biopsies is greater with smaller scopes. Having two sizes of adult scope and a pediatric scope on hand offers the endoscopist the greatest flexibility. The endoscopy suite needs to be equipped with supplemental oxygen, a cardiac monitor, an oxygen saturation monitor, and supplies for cardiopulmonary resuscitation. In addition, the necessary drugs for sedation and topical anesthesia as well as appropriate solutions and containers for cytology, microbiology, and pathology specimens must be present. Table 7-2 lists some of the more common items found in the endoscopy suite. Special equipment such as lasers and brachytherapy equipment are discussed in other chapters of this book; they are not typically used in the generic endoscopy suite.

TECHNIQUE Flexible bronchoscopy can be performed with the patient in either the seated or the supine position. Patients may be premedicated with intravenous (IV) midazolam, 1 to 2 mg, and fentanyl, 50 to 100 µg. The patient gargles with lidocaine (2% aqueous Xylocaine) before insertion of the bronchoscope, and additional topical Xylocaine spray is administered. The scope may be inserted either through the anesthetized naris or orally through a bite-block. In the intubated patient, the scope is inserted through a connector to the endotracheal tube. Xylocaine 2% is then injected through the bronchoscope to anesthetize the hypopharynx, the larynx, the vocal cords, and the tracheobronchial tree in a progressive fashion as the bronchoscope is advanced. In the very cooperative patient, there is no need for sedation, and the procedure can be performed with topical anesthesia alone. However, in the uncooperative patient or in situations in which the airway or respiratory function is compromised, bronchoscopy may be best performed in the operating room with IV sedation or general anesthesia. At bronchoscopy systematically evaluate the entire tracheobronchial tree, including the vocal cords. Several addiTABLE 7-2 Bronchoscopy Equipment Essential Bronchoscopes Suction tubing, connectors, wall suction Biopsy forceps Syringes (non–Luer-Lok) Specimen containers Lidocaine Pulse oximeter Cardiac monitor Oxygen source Advanced Cardiac Life Support (ACLS) equipment for resuscitation (e.g., endotracheal tubes, medications) Desirable Cytology brushes Protected catheter brushes Video camera and photographic equipment

Ch007-F06861.indd 93

93

tional procedures may be carried out after inspection of the airways. These include washings, bronchoalveolar lavage, protected brushings, biopsies, and transbronchial biopsies. Ideally, transbronchial biopsies are performed with the aid of fluoroscopy to reduce the incidence of pneumothorax. Management of the specimens depends on the practices of the various laboratories and of the institution involved. A solution of epinephrine 0.2 to 1 mg in 500 mL normal saline is useful for hemostasis via instillation down the working channel of the bronchoscope when mild to moderate bleeding occurs during bronchoscopy or after a biopsy. Aliquots of 2 to 5 mL are typically used. If epinephrine is administered in the operating room, make the anesthetist aware of its use because it may affect heart rate and blood pressure. The reader may refer to later discussions of tracheobronchial stents, endoscopic laser therapy, photodynamic therapy, and brachytherapy for more detailed information on the use of flexible bronchoscopy with these techniques and modalities.

LIMITATIONS AND COMPLICATIONS The best visualization is obtained with the larger adult scope and the video camera. Smaller scopes also do not allow for easy clearing of secretions and mucus, and visualization is consequently impaired. Adult scopes usually fit through a No. 7.5 endotracheal tube, but it may be necessary to use a pediatric bronchoscope in smaller endotracheal tubes or in double-lumen endotracheal tubes. Flexible bronchoscopy performed by experienced endoscopists is a safe procedure. The complications have been well summarized by Pereira and colleagues.5 The overall mortality in their study was 0.1%. Major complications (respiratory arrest, pneumonia, pneumothorax, and airway obstruction) occurred in 1.7% of the patients. Minor complications, which included vasovagal reaction, fever, cardiac arrhythmia, nausea and vomiting, and psychotic reactions, occurred in 6.5% of patients. Pneumothorax occurred in 5% of transbronchial biopsies. Complications such as pneumothorax are more likely in patients receiving transbronchial lung biopsies, and bleeding is more likely in patients having biopsies of airway lesions. Postbronchoscopy respiratory failure may be anticipated in patients who are already verging on the need for intubation and mechanical ventilation. The relative risks and benefits must always be carefully weighed in each patient who is being considered for a bronchoscopic procedure.

ENDOBRONCHIAL ULTRASOUND Endobronchial ultrasound (EBUS) is an innovative technique that involves use of an ultrasound probe mounted on the end of a flexible bronchoscope.6 Usually, a transbronchial needle device is also part of the distal end of the scope. The outer diameter of these composite scopes is 6.9 mm. Mediastinal and hilar lymph nodes can be identified and biopsied fairly accurately by fine-needle aspiration under real-time ultrasound guidance. Preliminary reports have been favorable,7 but, at present, mediastinoscopy remains the gold standard for mediastinal staging.

1/21/2008 10:36:04 AM

94

Section 1 Introduction

RIGID BRONCHOSCOPY Historical Note Until 1970, the only access to the tracheobronchial tree was provided by the rigid bronchoscope, initially designed by Jackson (Boyd, 1994; Jackson, Jackson, 1950).8,9 Although the rigid bronchoscope provided a limited view, the operator could usually visualize the pulmonary segmental orifices of most lobes. However, the rigidity of the instruments limited the ability to obtain biopsy specimens distal to the major bronchi. The development of rigid telescopes with highquality optics enhanced the ability to examine the subsegmental bronchi and lesions of the central airway in detail. The introduction of flexible bronchoscopic equipment has enhanced the ability to view the distal segmental bronchi and has simplified the procedure considerably. Both techniques of bronchoscopy—rigid and flexible—have evolved to define their own diagnostic and therapeutic indications. Each system has its strengths and limitations, and the thoracic surgeon must be competent in the use of both modalities to manage the spectrum of thoracic disease that may be confronted.

Indications Indications for rigid bronchoscopy are presented in Table 7-3.

Hemoptysis Although many common respiratory symptoms can be investigated by flexible bronchoscopy, one specific indication for the use of rigid equipment is massive hemoptysis.10 A rigid endoscope provides the operator with immediate control of the airway. In addition, it permits the use of large-bore suction equipment to keep the airway clear of blood and clots, which allows improved ventilation and oxygenation. Although occlusive balloon catheters or packing (to tamponade bleeding) may be placed in certain circumstances with flexible equipment, they can be positioned with greater speed, control, and accuracy under direct vision with the rigid scope, especially when there is significant bleeding that requires efficient suctioning.

TABLE 7-3 Indications for Rigid Bronchoscopy Massive hemoptysis Airway obstruction: diagnostic and therapeutic Foreign body Tumor: endobronchial, extrinsic compression Benign stricture Laser therapy Endobronchial stenting Tracheobronchial toilet Pediatric bronchoscopy Miscellaneous

Ch007-F06861.indd 94

Airway Obstruction In conditions that cause obstruction of the airway (larynx, trachea, or main bronchi), the rigid bronchoscope is the safest modality for obtaining a diagnosis because it enables secure control of the airway should a problem arise. In many instances, its use is both diagnostic and therapeutic.

Foreign Bodies The need for a rigid bronchoscope for the extraction of foreign bodies is self-evident. In fact, this was the initial indication for which Jackson developed the instrument (Boyd, 1994).8 With the varied forceps available and working through the scope, the operator can manipulate and extract a foreign body directly.11,12

Malignant Disease In cases of malignant obstruction, the first priority is establishment of a safe airway. This is readily achieved with a rigid bronchoscope. Endobronchial tumors may be débrided directly with biopsy forceps, electrocautery, or a laser to establish an improved airway. Such débridement is often impossible with flexible equipment.13 Such cases are handled in an operating room, where problems with airway control can be readily dealt with if necessary. In cases of obstruction caused by endobronchial pathologic conditions or extrinsic compression, it is safer to keep the patient breathing spontaneously until a secure airway is established. Once an airway is established, the obstructing lesion can be dilated as the first step. Dilation may be carried out by the surgeon, who first passes the smallest scope that will fit through the stricture and then uses sequentially larger scopes for dilation in a stepwise fashion. Gum-tipped Jackson bougies inserted under direct vision through the bronchoscope can be used in selected cases of tumor obstruction to define the lumen before the laser is used.

Benign Stricture Rigid bronchoscopy is often the first step in the management of a benign stricture. Tracheal or main stem bronchial stenoses are often readily dilated with sequential passage of bronchoscopes of increasing diameter. Narrow, tight strictures that will not easily admit the tip of a scope may be initially dilated with gum-tipped Jackson bougies that are passed under direct vision through the bronchoscope. Rigid equipment allows accurate assessment of the location, caliber, length, and rigidity of the stricture and the status of the distal airway. This detailed examination is essential in the preoperative assessment and planning for subglottic or tracheal resection (see Chapters 30 through 32).

Laser Therapy Laser therapy of the airway is dealt with in detail in Chapter 18. It is apparent that the use of rigid equipment enhances the surgeon’s ability to remove a tumor more rapidly in combination with laser coagulation. The bulk of the endobronchial tumor is directly débrided with large biopsy forceps. The flexible bronchoscope is then passed through the rigid

1/21/2008 10:36:04 AM

Chapter 7 Bronchoscopy

scope to permit use of the Nd : YAG laser to complete the débridement and obtain hemostasis. The carbon dioxide laser, which cannot be used with a fiberoptic system, mandates the use of rigid equipment. Once again, in cases of airway obstruction, the rigid bronchoscope enables the surgeon to obtain immediate control of the airway safely. The tumor can then be managed by dilation or débridement before application of the laser. In many such cases, the laser is not required because gross tumor can be adequately débrided with the biopsy forceps, and bleeding can be controlled with epinephrine solution or electrocautery.

cardiography) throughout the procedure. Additional details on the anesthetic management of rigid bronchoscopy are found in Chapter 4.

Endobronchial Stents

The classic technique of ventilation through the bronchoscope involves intermittent ventilation through either a side port or the proximal end of the bronchoscope to ventilate, oxygenate, and maintain anesthesia. This is carried out simply by the examiner’s inserting an endotracheal tube, attached to the ventilating system, into either the side port or the open end of the bronchoscope. The endoscopist may need to occlude the upper airway with packing or occlude the nose and mouth by hand if there is a large air leak. This technique is cumbersome and does not allow for continuous viewing through the scope.

The placement of endobronchial stents frequently requires the use of the rigid bronchoscope.14 Stents are used in the palliation of obstructing tumors and in stenting the airway for benign stenoses. The indications and techniques for stent placement are described in detail in Chapter 18.

Tracheobronchial Toilet In rare instances, the tracheobronchial toilet of thick secretions cannot be managed adequately with a flexible bronchoscope. Rigid equipment allows the use of larger-bore suction equipment and facilitates rapid removal of viscid secretions.

Pediatric Bronchoscopy In children with tiny airways, rigid bronchoscopy is the only option available to inspect the airway because tiny endotracheal tubes do not permit the passage of flexible equipment.

Miscellaneous Indications Proponents of rigid endoscopy maintain that the assessment of airway invasion by surrounding or extrinsic tumors (e.g., esophageal carcinoma) can be done better with a rigid instrument than with flexible bronchoscopy. The rigidity of the airway is best felt with a rigid scope, and the larger biopsy specimens obtained improve accuracy in the assessment of microscopic submucosal invasion. However, the advent of EBUS techniques (see earlier discussion) has provided a much more accurate way of determining airway invasion by surrounding tumors.6

METHODS OF ANESTHESIA AND VENTILATION General Anesthesia When bronchoscopy is performed under general anesthesia, the patient is supine, usually on an operating table. IV or inhalation general anesthesia, or a combination of both, may be used. The induction is rapid if IV agents are used. This is the preferred technique because 10 to 20 minutes can be required to “breathe down” the patient with inhalational agents. Once suitable induction has occurred and a muscle relaxant has been administered, the lower jaw should be loose and mobile. This indicates a suitable depth of anesthesia and muscle relaxation for the procedure. The patient is fully monitored (oxygen saturation, blood pressure, and electro-

Ch007-F06861.indd 95

95

Techniques of Ventilation For rigid bronchoscopic examination, four techniques of ventilation are available: intermittent insufflation, continuous insufflation, Venturi (jet) ventilation, and spontaneous inhalation ventilation.

Intermittent Insufflation

Continuous Insufflation With continuous insufflation, the end of the bronchoscope is fitted with a lens, and a side port is used to ventilate the patient continually while the endoscopist proceeds with the bronchoscopy. This practice provides the advantages of allowing uninterrupted bronchoscopy and using inhalational agents throughout the procedure, thus minimizing the need for IV anesthesia. One simply slides the lens open for biopsy sampling or suctioning. This technique is simple and reliable in that it provides relatively continuous viewing and continuous ventilation. The middle bronchoscope in Figure 7-4 is shown fitted with the viewing lens. With the use of rigid telescopes, this ventilation technique provides excellent conditions for continuous, detailed viewing. The lower bronchoscope in Figure 7-4 is shown with the ventilation tubing attached and a Hopkins telescope in place.

Jet Ventilation The most common form of ventilation used during rigid bronchoscopy is the Venturi technique (Fig. 7-5). This is based on the principle of air entrainment. With a side port or the open proximal end of the scope, a high-pressure (2530 psi) jet of oxygen (delivered at 10-20 breaths per minute through an 18-gauge catheter) entrains surrounding ambient air, thus ventilating the patient throughout the procedure. The modified Sanders ventilating system (see Fig. 7-5) and a reducing valve are required.15,16 With this technique, it is essential that the surgeon wear eye protection because droplets of secretions or blood can be blown out of the open end of the bronchoscope. Anesthesia is maintained with IV agents and muscle relaxants. The advantage of this technique is that ventilation is better maintained while instrumentation or débridement is taking place.

1/21/2008 10:36:04 AM

96

Section 1 Introduction

FIGURE 7-4 Basic equipment for rigid bronchoscopy. From top to bottom: biopsy forceps, ruler, rigid suction cannula, three rigid bronchoscopes of varying sizes, and two rigid Hopkins telescopes. The middle bronchoscope is shown with the viewing lens fitted. The lower bronchoscope is illustrated with the ventilation tubing attached to the side port and a zero-degree telescope inserted as it would be during use. The light source and fiberoptic cable are not shown.

25 50 0

Pressureadjusting knob O2 50 psi

Adjustable reducing valve

FIGURE 7-5 A schematic diagram illustrating the modified Sanders jet ventilation technique for ventilation through a rigid bronchoscope. The wall oxygen supply at 50 psi is connected to a reducing valve that allows the pressure to be adjusted from 0 to 50 psi. The side port of the bronchoscope is used as the Venturi injector site, and the open end can be used for continuous viewing by the endoscopist. (FROM EHRENWERTH J, BRULL S: ANESTHESIA FOR THORACIC DIAGNOSTIC PROCEDURES. IN KAPLAN JA [ED]: ANESTHESIA, 2ND ED. NEW YORK, CHURCHILL LIVINGSTONE, 1991.)

Spontaneous Inhalation Ventilation The technique of spontaneous inhalation ventilation demands a nonapneic patient. Inhalational agents are administered through the side port, and the anesthesia is kept light enough to maintain spontaneous respiration. The major disadvantages

Ch007-F06861.indd 96

are lack of relaxation and exposure of the operator to the anesthetic gases. This technique is useful for induction in a patient with an obstructive lesion of the airway when the surgeon anticipates that airway control is precarious. With this technique, it is not catastrophic if an airway is not

1/21/2008 10:36:05 AM

Chapter 7 Bronchoscopy

obtained immediately because patients continue to breathe on their own.

Local Anesthesia Rigid bronchoscopy can be carried out under local anesthesia; however, this technique is mostly of historical interest; general anesthesia is now the usual and preferred technique. The technique of local anesthesia is similar to that used with flexible bronchoscopy and includes adequate topical anesthesia of the mouth, pharynx, and vocal cords and IV sedation as required. The use of atropine to decrease secretions and inhibit vagal reflexes is helpful. My own technique is as follows: I administer a local spray anesthetic to the pharynx and larynx, a transcricoid injection of 3 mL of 1% lidocaine, and premedication with an IV narcotic analgesic (e.g., fentanyl 100-200 µg IV). IV sedation with midazolam is then titrated to the patient’s needs. The need for an adequately sedated and reasonably comfortable patient cannot be overemphasized because intubation of the airway under local anesthesia requires the patient’s cooperation. This can be enhanced with moderate sedation and effective local anesthesia, as described earlier. The procedure may be performed with the patient in a chair (preferably a dental-type chair) or supine on an operating table. If necessary in an emergency, intubation can be carried out on a stretcher or hospital bed. The technique for intubation under local anesthesia is identical to that for general anesthesia (described later).

TECHNIQUE OF RIGID BRONCHOSCOPY Before the induction of anesthesia, the equipment and light source are checked for proper function. The basic setup includes at least two sizes of bronchoscopes, appropriate suctioning cannulas, a variety of biopsy forceps, and a variety of telescopes (see Fig. 7-4 and later discussion). Care must be taken to protect the patient’s eyes, usually with adhesive tape. At all times, the operator must protect the lips and teeth or gums of the patient from injury. A commercial rubber tooth guard is available, but a saline-soaked gauze sponge is adequate. The largest bronchoscope sufficient for the needs of the operator is chosen. In most instances an 8- or 9-mm (outer diameter) scope is used for men, and a 7- or 8-mm scope is used for women (see Fig. 7-5). Largerdiameter scopes may damage the larynx and may preclude intubation of the smaller distal bronchi. Much smaller equipment is required for infants and children; the selection of the size depends on the size of the child. Scopes as small as 2.5 to 3 mm are required for patients who weigh less than 10 kg. Placement of the patient’s head on a pillow and then extension of the patient’s neck so that the chin points vertically (the so-called sniffing or intubating position) facilitate introduction of the bronchoscope. With the examiner’s thumb always protecting the patient’s upper teeth from injury from the rigid bronchoscope, the scope is inserted through one side of the mouth (usually the right side for right-handed operators) or in the midline in edentulous patients. Under direct vision, it is advanced to the posterior median groove of the tongue (Fig. 7-6A). The upper teeth must never serve as a

Ch007-F06861.indd 97

97

fulcrum to lever the bronchoscope into place; the operator’s left thumb bears this pressure and supports the scope at all times. The scope is first introduced almost vertically; the proximal end is then brought smoothly downward as the tip follows the contour of the tongue until the instrument is almost horizontal. By gently elevating the tongue and slowly advancing the scope, the operator can identify the epiglottis (see Fig. 7-6B,C). If the epiglottis is not seen (usually because the instrument was advanced too rapidly past it), the scope is partially withdrawn and the maneuver repeated. The tip of the bronchoscope is insinuated a short distance beyond and posterior to the epiglottis, just far enough to raise it without having it slip off the end of the instrument (see Fig. 7-6D). Once the epiglottis is lifted anteriorly with the tip of the bronchoscope, the posterior part of the laryngeal inlet, the arytenoids, and the vocal cords are identified (see Fig. 7-6E,F). Occasionally, external pressure on the larynx by an assistant, to displace it posteriorly, is required to visualize the cords. In difficult cases, the glottis can be displayed with a laryngoscope held in the left hand, and the bronchoscope is then inserted with the right hand. Once the glottis is visualized, the bronchoscope is advanced toward the cords (see Fig. 7-6G-I). As the cords are approached, the scope is turned 90 degrees to align the vertical orifice of the glottic chink with the tip of the scope (see Fig. 7-6J-L). The scope is then gently advanced through the larynx into the upper airway. With a gentle twisting motion, the scope is rotated back to the original orientation. No force must be used at this stage. If the examiner advances the scope gently, injuries will not occur. If significant resistance is met, a smaller-sized bronchoscope is used. Also, the surgeon ensures that the lips and pharyngeal tissues are not being inadvertently compressed and injured by the advancing scope. After intubation, the pillow is removed and the patient’s head is extended; care is taken to prevent injury to the cervical spine. The operator is advised to sit on a mobile stool and to raise the operating table to a comfortable position before beginning the examination. The scope is then slowly advanced, and the glottis, trachea, and carina are examined. To inspect the left or right side, the patient’s head is turned in the opposite direction so that a straight line is developed between the oropharynx, the trachea, and the main stem bronchus to be examined. To examine the left side, the examiner places the bronchoscope in the right corner of the patient’s mouth and turns the patient’s head to the right. The scope is then gently advanced down the left main bronchus. The lingular and lower lobe bronchi are easily seen. To visualize the segmental and subsegmental bronchi clearly, a telescope (see Fig. 7-4) may be used, or, more commonly, a flexible scope is passed through the rigid scope. The presence of an aortic arch aneurysm is a contraindication to the passing of a rigid instrument down the left main stem bronchus. To examine the right bronchial tree, the examiner turns the patient’s head to the left and moves the bronchoscope the left corner of the patient’s mouth. The right main bronchus and the bronchus intermedius are easily examined. The lower lobe is relatively easily visualized. To examine

1/21/2008 10:36:05 AM

98

Section 1 Introduction

A

B

Bronchoscope Epiglottis

Adherent secretion Posterior pharyngeal wall

C

D

Left vocal cord

Left corniculate tubercle

E

Right aryepiglottic fold

Anterior pharyngeal wall

F

FIGURE 7-6 A-C, Visualization of the epiglottis. The tip of the bronchoscope has followed the contour of the tongue toward its root (A), and the epiglottis has been located and centered in the field of vision (B and C). D-F, The epiglottis is elevated with the tip of the scope (D), and the scope is advanced just beyond to demonstrate the glottis. The posterior larynx and vocal cords are clearly visualized (E and F).

Ch007-F06861.indd 98

1/21/2008 10:36:05 AM

Chapter 7 Bronchoscopy

G

99

H

Left vocal cord

Right vestibular fold

Glottis

Right vocal cord

J

I

Left vocal cord centered in field of vision

Vestibular fold

Trachea

Tip of bronchoscope tube entering glottis

L K FIGURE 7-6, cont’d G, The bronchoscope is advanced a little further and its axis is carefully aligned with that of the glottis and trachea (H and I). J-L, The bronchoscope is turned 90 degrees and gently advanced between the cords into the trachea (J); the tracheal cartilages are seen in the distance (K and L). Once the bronchoscope is in the trachea, it is rotated back to its original orientation for comfortable manipulation, and the pillow behind the patient’s head is removed. (FROM STRADLING P: DIAGNOSTIC BRONCHOSCOPY: AN INTRODUCTION, 2ND ED. BALTIMORE, WILLIAMS & WILKINS, 1973.)

Ch007-F06861.indd 99

1/21/2008 10:36:06 AM

100

Section 1 Introduction

the middle lobe orifice, the patient’s head may have to be extended further to allow the operator an adequate angle to view the anteriorly placed middle lobe orifice. A flexible bronchoscope facilitates this task. Removal of the rigid bronchoscope is performed as carefully as its insertion. The opportunity is taken to examine the entire airway carefully on the way out. This is especially important for the proximal trachea and the subglottic, glottic, and supraglottic areas, which may not have been visualized in detail on the way in. Furthermore, if the patient is starting to so-called lighten from the anesthetic, this will provide an opportunity to assess the function of the vocal cords.

EQUIPMENT The performance of rigid bronchoscopy requires several essential pieces of equipment (see Fig. 7-4). Additional components or modifications are available for specialized procedures or are based on operator preference. The basic components are discussed under the categories of bronchoscopes and light sources, suction devices, forceps, and enhanced visualization.

Bronchoscopes A variety of rigid bronchoscopes is available; all are variations of the original design by Jackson (Boyd, 1994; Jackson, Jackson, 1950).8,9 Several standard rigid bronchoscopes are illustrated in Figure 7-4. The most commonly used sizes in adult practice are in the range of 6 to 9 mm in external diameter and 40 cm in length. For pediatric use, a range of smaller (3-6 mm) and shorter scopes is available. A cold halogen light source is connected by a fiberoptic cable to the bronchoscope. The light is transmitted down a fiberoptic bundle along the sidewall of the tube, so that the light is emitted from a point just inside the distal tip of the scope.

Suction Devices One of the major advantages of rigid bronchoscopy is the ability to suction out the airway effectively, especially in cases of massive hemoptysis. An effective (operating room–type) suction source is required. The rigid suction cannula (see Fig. 7-4) must be long enough to protrude from the distal end of the scope that is being used. An insulated suction tube is useful for the application of electrocautery to deal with bleeding after tumor débridement or biopsy.

Forceps A wide variety of forceps is available for use in varying circumstances. Some of these are illustrated in Figure 7-4. Tissue biopsy forceps are available in several sizes. The large biopsy forceps allow deeper biopsy specimens to be sampled than are generally obtainable with the flexible bronchoscope, but caution must be used to avoid hemorrhage. Aggressive, deep biopsy sampling can remove the full thickness of airway cartilage and lead to troublesome bronchial arterial bleeding or perforation. The larger forceps can be used to débride an obstructing tumor or to extract a clot from the airway. A number of forceps are also available that can be used to

Ch007-F06861.indd 100

manipulate, grasp, and extract foreign bodies in the airway. These are stronger than biopsy forceps and are more suitably designed for grasping and removing objects.

Enhanced Visualization: Telescopes and Video Display Rigid Hopkins rod-type telescopes have been developed to examine distal segmental orifices and improve the image.17 These solid-rod telescopes produce the best image available, far superior to that seen with fiberoptic equipment. Zero (forward)-, 30-, 60-, and 90-degree telescopes are available (see Fig. 7-4). Some telescopes are also equipped with malleable forceps so that biopsy specimens can be taken when this equipment is used. However, in most instances, the need to examine segmental and subsegmental orifices is best handled by insertion of the flexible bronchoscope through the rigid scope to examine the distal structures. Specimens can be taken in the usual fashion with flexible equipment. For this examination, a 7- or 8-mm bronchoscope is necessary to allow passage of the adult flexible scopes, although flexible pediatric bronchoscopes are available for use through smaller rigid scopes. Because of the nature of the examination, it can be difficult to teach the fine points of rigid bronchoscopy.18 However, cameras are available that mount on the end of the telescope and allow display of the image on a video monitor. This is of obvious value in the teaching environment and to obtain permanent video or photographic records of the surgeon’s observations.

LIMITATIONS AND COMPLICATIONS There are many potential complications of rigid bronchoscopy, but most can be avoided with careful technique. The major disadvantages of rigid endoscopy are the limitation of view necessitated by the rigid equipment and the need for general anesthesia during this procedure. Because of the rigid nature of the equipment, injury to the upper aerodigestive tract is also a potential complication. The unique complications of rigid endoscopy are injuries to the mouth, pharynx, and upper airway as a result of poor application of the technique. Injuries to the lips, gums, and incisor teeth are avoided with care in the insertion and manipulation of the instrument. Lacerations of the peripharyngeal tissues and injuries to the glottis (e.g., dislocation of the arytenoids) are rare but can occur with forceful manipulation of the scope. A traumatic bronchoscopic examination can result in laryngeal edema, especially in small adults or children, in whom the bronchoscope may be larger than the laryngeal orifice. Rigid bronchoscopy may be difficult or impossible in patients with certain physical disabilities (e.g., temporomandibular joint fixation, cervical spondylosis) because of restriction in opening the mouth or extending the neck. Major hemorrhage can occur if excessive or ill-advised biopsy specimens are taken. The examiner must always remember that the biopsy forceps are large, that bronchial vessels lie in the submucosa, and that certain tumors (e.g., carcinoid) can be highly vascular. If sudden hemorrhage does occur, the main bronchus on the side of bleeding is intubated

1/21/2008 10:36:07 AM

Chapter 7 Bronchoscopy

with the bronchoscope to diminish spillage into the contralateral lung. Working through the bronchoscope lumen, the surgeon can deal directly with the bleeding site. The topical application of epinephrine solutions (0.2 mg of epinephrine in 500 mL of Ringer’s lactate) for vasoconstriction is helpful in some instances. Ventilation of the contralateral lung is maintained through the side ports of the bronchoscope (see Fig. 7-4), which by design will always be in the tracheal lumen. Cauterization, tamponade with epinephrine-soaked gauze, or selective balloon catheterization can be performed through the bronchoscope. The major anesthetic complication occurs with misuse of the Venturi technique. High-pressure jets can produce surgical emphysema, especially if the airway is injured during the procedure. This is extremely rare and is totally avoidable. On occasion, rupture of peripheral pulmonary blebs or bullae can result in a pneumothorax. This complication can occur with any positive-pressure ventilation technique. All patients need to have a chest radiograph after the procedure when the Venturi technique is used.

SUMMARY The rigid bronchoscope remains an extremely valuable tool for the diagnosis and management of many thoracic conditions. In certain instances of upper airway obstruction, it may be the only modality that can save a patient’s life. It has specific advantages but requires expertise to avoid unnecessary complications. Flexible and rigid bronchoscopy are complementary, rather than mutually exclusive, tools to be used in the diagnosis and therapy of thoracic disease. Although there is some overlap of indications, each modality has its unique indications and limitations, and the thoracic surgeon needs to be experienced with both techniques to diagnose and treat the spectrum of thoracic disease that may be encountered effectively.

COMMENTS AND CONTROVERSIES Bronchoscopy is invaluable to all physicians involved in the diagnosis and treatment of diseases of the respiratory tract. Although more and more bronchoscopies are performed by chest physicians, anesthetists, and intensivists, all thoracic surgeons must have a clear understanding of the procedure, including indications and contraindications; instrumentation; basic techniques of airway examination, such as biopsy, washing, and brushing; and possible complications. As pointed out by Doctor Pierre, the use of flexible bronchoscopy is now safe and effective in well-trained hands. Possible contraindications are all relative and do not necessarily preclude a carefully performed examination. These include bleeding disorders, severe

Ch007-F06861.indd 101

101

hypoxemia, cardiovascular instability, and severe bronchospasm. The most common indication for diagnostic flexible bronchoscopy is an abnormal finding on chest radiography, such as a lung mass, atelectasis, or diffuse infiltrates, and two of the most common indications for therapeutic flexible bronchoscopy are positioning of endobronchial double-lumen tubes (done by the anesthetist) and suctioning of retained secretions or mucous plugs in the postoperative patient. In this setting, flexible bronchoscopy is always done at bedside and with the video camera, so that the intensivist, chest physician, and surgeon can all see the bronchial stump and the remaining bronchi (spatial reorientation, kinking, narrowing), as well as the amount of mucus being aspirated. Rigid bronchoscopy is preferable in cases of massive hemoptysis. In patients with life-threatening hemoptysis (150 mL/hr or greater), the rigid bronchoscope provides the operator with immediate control of the airway in addition to permitting the use of large-bore suction equipment to keep the airway clear of blood or clots. The rigid bronchoscope is also the instrument of choice and the safest modality for diagnosis of conditions that produce significant airway obstruction. One of its major drawbacks, however, is the fact that it must be done under general anesthesia and by an operator familiar with the technique. Unfortunately, most people attempting to do rigid bronchoscopy are untrained with the technique, and indeed, most young chest physicians or thoracic surgeons have never seen, let alone performed, a rigid bronchoscopy. Virtual bronchoscopy uses thin-section spiral computed tomographic and three-dimensional image data processing techniques as a diagnostic method for depicting endoluminal airway disease. The advantage of virtual bronchoscopy over flexible bronchoscopy is that it is less invasive and better tolerated by patients. Another advantage is that it allows simultaneous visualization of airways and adjacent mediastinal structures, thus potentially providing a more accurate assessment of the surgical implications of the lesion being studied. The main disadvantage of virtual bronchoscopy is that biopsy specimens cannot be obtained. In my opinion, every resident in thoracic surgery training programs and every thoracic surgeon must be comfortable with the use of both the rigid and the flexible bronchoscope under local or general anesthesia, and this level of comfort can only be achieved through proper training. The current availability of computerized training modes may help achieve these goals. J. D.

KEY REFERENCES Boyd AD: Chevalier Jackson: The father of American bronchoesophagoscopy. Ann Thorac Surg 57:502-505, 1994. Ikeda S, Yanai N, Ishikawa S: Flexible bronchofiberscope. Keio J Med 17:1-16, 1968. Jackson C, Jackson C: Bronchoesophagology. Philadelphia, WB Saunders, 1950.

1/21/2008 10:36:07 AM

chapter

8

MEDIASTINOSCOPY Bryan F. Meyers Toni E. M. R. Lerut

Key Points ■ There are several indications for mediastinoscopy, including

■

■

■

■

screening for unsuspected mediastinal metastases, verifying metastases suggested by radiological testing, and diagnosing mediastinal adenopathy of uncertain etiology. The main techniques have been remarkably stable in the past 50 years, although technology has improved, especially with the addition of video-mediastinoscopy. Complications are uncommon but can be quite dramatic, especially with inadvertent biospy of the aorta, innominate artery, right main pulmonary artery, or right upper lobe pulmonary artery. False negative rates are 5.5% to 8% when screening patients with known lung cancer, and this low rate makes mediastinoscopy the gold standard against which other modalities must be compared. Novel techniques, such as EUS and EBUS, rival mediastinoscopy, but cervical mediastinoscopy is still an essential tool for the thoracic surgeon to master.

Mediastinoscopy now has a history associated with it that is 50 years old. Harken and associates first described the techniques of mediastinoscopy in 1954.1 The procedure was modified and transformed into the techniques that are still familiar to thoracic surgeons now. The development of the procedure into its current iteration is credited to Carlens.2 It is generally agreed that Dr. F. G. Pearson popularized mediastinoscopy in North America. The need for review and additional study of mediastinoscopy is exemplified by the paper presented by Little and colleagues at the Society of Thoracic Surgeons (STS) in 2005, which documented that a minority of patients undergoing surgical resection for lung cancer with data in a national database underwent mediastinoscopy, and fewer than half of those having the procedure actually had nodes biopsied (Little et al, 2005).3 There has been a tendency to accept the results of noninvasive staging modalities such as computed tomography (CT) and positron emission tomography (PET), and the result is misclassification of patients and possibly a systematic application of inappropriate therapy. If falsely positive noninvasive staging is accepted without verification through mediastinal nodal sampling, many patients without N2 disease will be subjected inappropriately to induction chemotherapy or chemoradiation, while others are assigned to definitive nonsurgical therapy and prevented from having surgery altogether. At the other extreme, falsely negative noninvasive staging can prevent patients from being offered induction therapy when it may be appropriate.

There are several distinct indications for mediastinoscopy. Most common is screening for N2 lung cancer in patients with known or suspected clinical stage I-III lung cancer. An additional indication is the desire to get a tissue diagnosis for patients with bulky stage IIIA, IIIB, and IV lung cancer. Tissue diagnosis is essential to facilitate nonsurgical therapy for these patients. Next is the evaluation of patients with mediastinal adenopathy in the absence of lung lesions. In the case of a carcinoma of uncertain origin with metastasis to the mediastinal lymph nodes, it is possible that a fine-needle aspiration via bronchoscopy or endoscopic ultrasonography from the esophagus could make the diagnosis. On the other hand, if lymphoma is suspected, larger tissue biopsies are often necessary to allow histopathology and flow cytometry. If lymphoma is suspected, mediastinoscopy is most appropriate. An additional indication is the need to ensure comparable stage among patients enrolled in clinical trials for lung cancer: this may lead to mediastinoscopy even in some instances in which clinical practice would not employ it. Finally, there are uncommon instances in which mediastinoscopy might be useful to diagnose or treat other masses of the mediastinum. For instance, there are some who view drainage via a mediastinoscopy as appropriate and minimally invasive therapy for subcarinal mediastinal cysts.4,5 Although the techniques of mediastinoscopy are fairly safe and straightforward, there are a number of relative and absolute contraindications to its use. Extreme kyphosis, neck injury, and severe degenerative joint disease of the neck all make hyperextension of the neck dangerous. In these cases, if mediastinal lymph node biopsies are believed to be important, consider video-assisted thoracic surgery (VATS) as a technique to obtain the nodal biopsies. Other contraindications include the presence of a tracheostomy after laryngectomy, the concurrent diagnosis of a superior vena cava syndrome, a large goiter, and a previous mediastinoscopy. Most practitioners agree that a repeat mediastinoscopy can be accomplished but must be avoided if possible. With appropriate planning, a patient who needs two mediastinal assessments, such as a patient with N2 disease who is undergoing induction therapy, can have one mediastinoscopy and one additional evaluation with endoscopic ultrasound (EUS), endobronchial ultrasound (EBS), or VATS. The primary indication for mediastinoscopy, screening for N2 disease in lung cancer patients, is based on a large series of work that shows poor outcomes for patients undergoing resection when known N2 disease is present. In a paper now of historic importance, Pearson and colleagues found 64% resectability and 9% survival at 5 years in a favorable, selected

102

Ch008-F06861.indd 102

1/21/2008 10:36:58 AM

Chapter 8 Mediastinoscopy

subgroup of patients with N2 discovered at mediastinoscopy.6 The poor resectability rate and the dismal long-term cure rate have led to the generally accepted belief that patients with N2 disease ought not to undergo resection. This was underscored by the work of Funatsu and colleagues, who operated on 117 patients with positive mediastinoscopy.7 A resection was performed in 91 of the 117 patients but was believed to be curative resection in only 13. The 5-year survival rate in resected patients was 6%, a figure very similar to that reported by Pearson and ample evidence to omit resection from that group of patients. There has been recent reconsideration of this notion. The widespread use of PET probably reduces the risk of occult M1 disease in such patients, and this in itself would improve the 5-year survival rate by selecting a more favorable subset of patients. In addition, adjuvant chemotherapy has been shown to be effective in patients with stage IIIA disease, and the argument can be made that no modern trial has compared resection and adjuvant therapy to induction therapy plus surgery. Finally, several articles have shown that patients with minimal (single-station) N2 disease have better survival than those described earlier, with median survival times of 36 months.8,9 One observation can be made: the harder it is to prove the existence of N2, the more likely the patient has a minimal burden of N2 disease, with a reasonable and acceptable prognosis after surgery and additional induction or adjuvant therapy. Mediastinoscopy does no service to the patient if no lymph nodes are biopsied. This was the case in more than half of the patients who underwent mediastinoscopy in a national cohort of patients reported by Little and colleagues (Little et al, 2005).3 The bare minimum biopsies are two or more lymph nodes from the ipsilateral side in a patient with lung cancer, as well as subcarinal biopsies and possibly contralateral biopsies if preoperative imaging suggests some increased risk of metastases to these nodes. Obviously, the more lymph nodes that are biopsied, the more sensitive this tool will be as a whole to detect occult metastases. There are no widely accepted figures for a minimal or ideal number of individual biopsies to perform during a mediastinoscopy procedure. If the biopsies are being done for mediastinal adenopathy in the absence of a lung mass, it is worthwhile to acquire frozen sections to ensure that diagnostic material has been obtained. One does not want to biopsy any more nodes than necessary, but the prospect of a return trip to the operating room for additional biopsies in the event of nondiagnostic material is reason enough to get frozen sections and wait for the answer before waking the patient up and leaving the operating room.

103

Cervical mediastinoscopy begins with the patient asleep under a general anesthetic. The anesthetist is asked to tape the endotracheal tube off to the side, to prevent its getting in the way of the surgeon. Our usual practice is to have the patient positioned at a right angle to the anesthesiologist, with the patient’s left side toward the anesthesiologist. The occiput is cradled in a padded foam “donut,” and a shoulder roll or inflatable thyroid bag is placed behind the shoulders to allow hyperextension of the neck. A simple roll of blankets or sheets could easily replace the inflatable thyroid bag. As the thyroid bag is inflated, it is important to check to make sure that the occiput is still in contact with the bed (i.e., the patient’s head is not “floating”) (Fig. 8-1). In general, younger patients are quite able to tolerate hyperextension, but older patients with arthritis and kyphosis have a tendency to float with far less hyperextension. The extreme example of this variability is the severe kyphoscoliotic patient, for whom mediastinoscopy is contraindicated. Once the patient is positioned, preparation and draping is accomplished to include the neck and chest from the chin to the subxiphoid region. Although an urgent median sternotomy is an unlikely consequence of mediastinoscopy, it is always possible, and the patient must be prepared accordingly. Other preparations for such a contingency include the presence of a sternal saw and retractor in the room at the time a mediastinoscopy is taking place. The incision is usually a horizontal incision 2 cm long and 2 cm above the sternal notch. Dissection is continued down through the platysma toward the trachea (Fig. 8-2). It is better to take the incision directly to the trachea, rather than angling the incision into the mediastinum. As the trachea passes into the mediastinum, it gets increasingly posterior and harder to reach. If the incision is taken directly to the trachea in the neck, the correct plane of dissection can be quickly identified and then maintained for the rest of the procedure. Once the trachea is identified, the surgeon’s index finger can be passed gently down in the mediastinum, with the nail bed on the trachea and the palpating tip of the finger developing

TECHNIQUES OF MEDIASTINOSCOPY The techniques of mediastinoscopy are fairly well accepted because the procedure has undergone little change in the past 40 to 50 years. The techniques described here include the standard cervical mediastinoscopy, the extended cervical mediastinoscopy, the anterior mediastinotomy or Chamberlain procedure, repeat mediastinoscopy, and the increasingly common variant of video-mediastinoscopy.

Ch008-F06861.indd 103

FIGURE 8-1 The patient is positioned with the neck gently hyperextended and a pillow or thyroid bag behind the shoulders. The occiput should still maintain contact with the bed or with a circular donut pillow, to avoid having the head float.

1/21/2008 10:36:59 AM

104

Section 1 Introduction

FIGURE 8-2 The incision is made 2 cm above the sternal notch and is typically 2 cm long. The incision is brought straight down to the airway, specifically avoiding an angled path into the mediastinum.

the mediastinoscopy plane and feeling for the mediastinal structures. Usually, the aortic arch can be felt to the patient’s left and the innominate artery can be felt passing across the top of the mediastinoscopy space (Fig. 8-3). Once this plane has been developed down to the carina, the mediastinoscope is introduced. The best way to introduce the scope is to place the beveled opening at the end of the scope onto the trachea and gently tilt it upward; this allows the leading tip of the scope to lift up the anterior tissue and show the way into the mediastinum. Safety is maintained if the trachea or the main stem bronchi are kept in view at all times. Wandering off the airway is an invitation to vascular injury and must be avoided. With the mediastinoscope in the mediastinum, dissection is performed with the use of a rigid mediastinoscopy suction device (Fig. 8-4). We use two different versions of this instrument: one that is made entirely of steel, and another that is plastic with a metal interior. In the former, electrocautery can be used by an assistant placing a standard electrocautery pen on the suction device outside the patient. The other device has a cautery attachment and allows the use of a cautery foot pedal activated by the surgeon. Most of the dissection is blunt and is performed with the suction device, with and without cautery (Fig. 8-5). A typical strategy is to use blunt dissection to identify the right and left main stem bronchi, and then to systematically dissect in the subcarinal space, the ipsilateral paratracheal space, and the contralateral paratracheal space. A particularly motivated or daring surgeon might also biopsy level 10 hilar nodes via this route, but such a feat would be the exception rather than the rule. To maintain safety with the mediastinal node biopsies, dissect the nodes out as thoroughly as possible before performing a biopsy. This thorough, blunt dissection of the nodes makes it far less likely that a vascular structure will be misidentified and biopsied. Another strategy that reduces the likelihood of a vascular complication is the routine use of an aspirating needle to aspirate the nodes before biopsy (Fig. 8-6). With these two strategies in use, the inadvertent biopsy of an azygos vein or a pulmonary artery branch is extremely rare.

Ch008-F06861.indd 104

FIGURE 8-3 Once the airway is met, an examining finger can dissect the pretracheal plane to make room for the mediastinoscope and to palpate for the location of hard lymph nodes to be sought and biopsied.

FIGURE 8-4 The mediastinoscope is inserted, and the plane created by the finger is extended using the suction device as a blunt dissector. The view and the dissection are always kept on the airway, to avoid wandering off and encountering the mediastinal vessels.

A common source of bleeding during mediastinoscopy is branches of the bronchial arteries that run through the subcarinal space. In many instances, these arteries can be seen and avoided rather than biopsied. If they are biopsied or torn with the biopsy of an adjacent lymph node, there are a few steps that can be followed to obtain hemostasis and continue on with biopsies elsewhere. First, the suction device itself can be used to apply gentle pressure to the bleeding site and put a stop to the bleeding while the surgeon determines the next step. The pressure can be released slightly to allow the bleeding to resume, with cautery then applied to the area source of the bleeding. If the bleeding is still difficult, we usually pack the mediastinum with a long, narrow gauze pad that is commonly used for vaginal packing. This gauze usually stops the bleeding and must be left in place for 5 to 10 minutes to allow the offending bleeder to clot. Usually, the gauze

1/21/2008 10:36:59 AM

Chapter 8 Mediastinoscopy

Innominate artery

105

Station 4 lymph node

Station 2 lymph node

Needle aspirator Suction cautery

FIGURE 8-5 This detail shows the suction device dissecting a node from the surrounding mediastinal fat. Care is taken to thoroughly dissect these nodes before biopsy, to prevent mistaking an artery or a vein for a lymph node.

FIGURE 8-6 Additional protection against a vascular biopsy can be obtained by aspirating lymph nodes with a long mediastinoscopy aspirating needle before biopsy. With careful dissection and routine use of the needle, vascular biopsy should occur very infrequently.

can then be removed and the site cauterized additionally to secure a durable hemostasis. Once all the desired biopsies have been obtained, the scope is removed and the wound is closed with absorbable suture. An extended cervical mediastinoscopy has been reported, though we have no personal experience with its use.10 In this procedure, the mediastinoscope is angled anterior and to the left, to allow the tip to pass over the aortic arch and into the aortopulmonary window. Biopsies in the pleural space and left hilum can be obtained. Although this is possible, it appears that the procedure has not caught on with any great following of surgeons, and it is likely that most surgeons who desire left hilar and pleural biopsies are using anterior mediastinoscopy or VATS.11 Left anterior mediastinotomy, also known at the Chamberlain procedure, can allow safe access to level 5 aortopulmonary window lymph nodes.12 In this procedure, a transverse incision is made at the level of the second or third interspace, just lateral to the sternum. The incision is carried down through the intercostal muscles, and the internal mammary artery is encountered. Although it is possible to do this procedure without disrupting the mammary artery, it is usually ligated twice and divided to allow free access into the pleural space at that location. Once the mammary is divided, the pleural space is entered, and an examining finger can be passed in to palpate the level 5 and level 10 lymph nodes in the left hilum and mediastinum. Dissection is carried out much in the same way as described previously for standard mediastinoscopy. Extra care must be taken to identify and avoid injury to the left phrenic nerve as it passes along the mediastinal pleura just anterior to the hilum. A special subset of mediastinoscopy is the repeat mediastinoscopy procedure. Depending on the extent of dissection and biopsies, this can be a difficult and potentially hazardous endeavor. The natural plane that exists anterior to the trachea is absent due to scarring from the original procedure. The right pulmonary artery can be stuck down to the central main bronchi and the upper subcarinal space. If this procedure is

being done to assess a specific lymph node that is suspicious based on imaging, then a focused approach is recommended to limit the chances of complications resulting from the scarring. If this is a screening repeat mediastinoscopy, consideration must be given to the alternatives of EUS, EBS, or VATS. A final special subset of mediastinoscopy from a technical point of view is that of video-mediastinoscopy. The equipment used for this procedure is very similar in size and configuration to the standard mediastinoscope that requires one to peer through the opening. In addition to that same hollow center for direct visualization, the video-mediastinoscope has a port for the insertion of a 5-mm camera that allows display of the images onto a large monitor screen for the operating surgeon and everyone else in the operating suite to see (Fig. 8-7). This is a great improvement in visibility and also greatly increases the ability to teach and supervise a trainee as he or she performs the dissection and biopsies. There has been no head-to-head comparison between a video-mediastinoscopy and standard mediastinoscopy, but there are many surgeons who have adopted the approach who would be quite unwilling to return to earlier systems. Credit must go to Dr. Anton Lerut for developing and popularizing the videomediastinoscope (De Leyn and Lerut, 2007).13,14

Ch008-F06861.indd 105

COMPLICATIONS Any procedure eventually gets characterized by the complications associated with it. In the case of mediastinoscopy, the complications are rare and usually not life-threatening, but because of the vital structures in the mediastinum there remains a potential for severe and life-threatening injuries. The most readily discussed complication after mediastinoscopy is bleeding. As described previously, this problem most typically results from injury to one of the bronchial artery branches that pass through the subcarinal space. If bleeding is encountered, gentle pressure with the tip of the scope or the end of the suction cannula is usually sufficient to control

1/21/2008 10:36:59 AM

106

Section 1 Introduction

Monitor

FIGURE 8-7 The typical operating room setup for a videomediastinoscopy. The magnification and the ability to have multiple simultaneous viewers make this method ideal for teaching and for standardization of the procedure.

the bleeding and allow clotting of the vessel to occur. The group at Duke University recently reported on a large series of mediastinoscopy procedures and mentioned a modern technical fix for the problem of bleeding (Lemaire et al, 2006).15 In some circumstances, it was beneficial in their experience to pass an endo-clipper down the scope to directly clip the offending bronchial artery. Other vessels may be injured, most commonly the azygos vein and the branch of the pulmonary artery to the right upper lobe. Depending on the size of the injury to these vessels, hemostasis may or may not be possible with pressure alone. Packing the mediastinoscopy space with gauze might provide tamponade, and such a strategy has been successful in the management of an azygos injury, but it is likely that a pulmonary artery injury would need direct repair. If the planned pulmonary resection was to be on the right, the most straightforward approach is to pack the mediastinum and close the mediastinoscopy wound completely, then proceed to a thoracotomy and repair of the injured vessel. After hemostasis is secured, the pulmonary resection can take place as indicated. If the primary lesion is on the left and the pulmonary artery injury is on the right, the best management is less clear. A median sternotomy may allow for access to the right pulmonary artery injury and the left lung for a subsequent resection, but the exposure for either of these problems is suboptimal via a sternotomy, and consideration must be made for separate incisions to handle the repair and the resection. A less dramatic but equally important injury incurred at the time of mediastinoscopy is an injury to the left recurrent

Ch008-F06861.indd 106

laryngeal nerve. The hoarseness and poor cough that result from this injury could lead to poor pulmonary toilet and thereby compound the initial problem with additional subsequent problems such as atelectasis, retention of secretions, and pneumonia. If the patient’s cough is at all compromised by the injury to the nerve, consultation with colleagues in otolaryngology is advised because they can assist with temporary or permanent medialization of the injured left vocal cord. A temporary injection of Gelfoam or other biologic material can medialize the cord and allow spontaneous recovery if the injury to the recurrent nerve is a mild one. On the other hand, if a major injury to the nerve is suspected, such as when the pathology report from the mediastinoscopy describes normal peripheral nerve, a permanent thyroplasty may be the best approach. This problem is best avoided altogether, and steps to avoid it include taking extreme care with biopsies performed at the left tracheobronchial angle and stubborn avoidance of cautery in that location. If these steps are taken, the problem of recurrent nerve injury will be quite rare. In the Duke study, it occurred in 0.5% of cases (Lemaire et al, 2006).15 Injury to the airway itself is possible with mediastinoscopy. In some cases, the airway may tear when inflamed or scarred lymph nodes are pulled away from it. In other instances, the bronchus may be mistaken for a lymph node and injured when cautery is applied. Management of this unusual complication is often accomplished by the simple act of draining the mediastinum with a soft, flat drain left in place after biopsies are taken. A small cautery injury heals rapidly and would very rarely require additional surgery, either at the time of discovery or at a later date. Conservative management might not be as appropriate for injuries to the esophagus. The esophagus is most commonly injured in the subcarinal space or in the left paratracheal location. Such an injury might be indicated by an unexpected result from the pathologist on a subcarinal biopsy: normal squamous epithelium. Other presentations include immediate postoperative pain and mediastinal emphysema. The surgeon must have a level of suspicion guided by the difficulty of the dissection and the ease with which the lymph nodes were identified during the case. A confirmatory swallow with Gastrografin is useful, although a CT scan with water-soluble oral contrast would also help to secure the diagnosis. Management is straightforward: a right thoracotomy and repair of the injured esophagus. It has been reported, however, that a small subcarinal injury to the esophagus can be managed with drainage provided through the mediastinoscopy incision. There are other injuries that occur rarely. Vascular injury to the aorta or innominate artery has been encountered. The key point here is avoidance and emphasis on the concept that it is unlikely that such an injury could take place as long as the trachea or main stem bronchus is kept in sight. These injuries are most common when the mediastinum is filled with tumor and are made even more likely when previous radiation therapy has obliterated the natural tissue planes. The use of the aspirating needle before biopsies in such a setting greatly reduces the chances of an arterial injury. Keeping the number of biopsies to the minimum required to

1/21/2008 10:37:00 AM

Chapter 8 Mediastinoscopy

make the diagnosis also reduces the chances of complications. Even if such a strategy lengthens the procedure by causing more than one round of frozen sections to be necessary, it may still be beneficial in the long run by avoiding mischief.

RESULTS OF MEDIASTINOSCOPY The results of a screening procedure or a test are often presented with the following statistics: sensitivity, specificity, and accuracy. In the case of mediastinoscopy, it is difficult to offer up such statistics because there are many discrete settings in which mediastinoscopy is performed, and the characteristics of its use are different in each setting. For instance, if a lung cancer patient has a large primary tumor and there are multiple bulky mediastinal lymph nodes, the sensitivity of the test will be almost 100%. On the other hand, if a patient presents with a small peripheral tumor and no obvious abnormalities of the mediastinal nodes on CT or PET, the prevalence of N2 disease will be much lower (5%10%), and the sensitivity will be less than 50%. With regard to specificity, if a mediastinoscopy is positive, it is considered a gold standard, and the specificity of such a designation is 100%. One way to characterize the accuracy of mediastinoscopy in the setting of staging lung cancer is to look at the rate of false-negative findings. If a mediastinoscopy is performed in an otherwise resectable patient, a negative mediastinoscopy result allows the patient to go on to resection. If a thorough lymph node dissection or sampling of the mediastinum is performed, any positive lymph nodes in the resected mediastinal nodes would represent false-negative findings for the mediastinoscopy screen. These false-negative rates have been estimated to be between 5.5% and 8% in large retrospective series (Lemaire et al, 2006).15,16 Factors that influence the false-negative rate include the overall prevalence of N2 nodes in the patients screened and the thoroughness of the mediastinal evaluation after the mediastinoscopy. The use of PET screening before mediastinoscopy is also a factor because one of the additional values of PET is the role it plays in identifying suspicious lymph nodes which can be sought out with additional zeal at the time of mediastinoscopy. Several current controversial issues are debated with regard to the screening function of mediastinoscopy in the staging of patients with lung cancer. First, the fundamental value of mediastinoscopy is to avoid operating on patients with N2 disease, but there are subsets of patients with minimal N2 disease (microscopic metastasis in one or two nodes) who do reasonably well with resection and adjuvant chemotherapy. It has not been proven that identifying the minimal N2 before resection and offering induction therapy carries a survival advantage over a complete resection and nodal dissection followed by postoperative adjuvant therapy (Meyers et al, 2006).17,18 On the other hand, it makes little sense to do a mediastinoscopy if a positive result does not trigger some change in management. Some have argued that the value of mediastinoscopy is low in patients with clinical stage I disease. A paper by Choi and colleagues challenged that assertion in a group of 291 patients with clinical stage I disease who underwent mediastinoscopy before thoracotomy.19 Twenty (6.9%) of the 291 patients had

Ch008-F06861.indd 107

107

a positive mediastinoscopy, and 25 of the remaining 271 had positive N2 nodes at thoracotomy. Overall prevalence of N2/ N3 in the stage I group was 45/291, and the sensitivity for mediastinoscopy was 20/45 (44%). These data seem to support the notion that, in the absence of PET, mediastinoscopy is still important and necessary in clinical stage I lung cancer. It also underscores the association between the prevalence of N2 disease in the screened population and the sensitivity of mediastinoscopy. As the prevalence decreases, so too does the sensitivity of the procedure. If there is acceptable evidence of the value of mediastinoscopy in patients clinically staged with CT scanning alone, there is less certain value in patients who are deemed to be in clinical stage I after both PET and CT scanning. The use of PET decreases the prevalence of N2 disease and the sensitivity of mediastinoscopy to the point that it may no longer be indicated. In one paper, the prevalence of N2 disease was 5.6%, and the sensitivity of mediastinoscopy was 40%, leading to a rate of positive mediastinoscopy of less than 3% (Meyers et al, 2006).17 Work from the American College of Surgeons Oncology Group trial Z0050 examining the use of PET for screening of lung cancer patients reported a prevalence of N2 disease of 5% in T1 N0 clinically staged patients and a rate of 14% in T2 N0 patients. The authors concluded that mediastinoscopy may not be useful in the T1 N0 group after CT and PET but may still be helpful for T2 N0 patients (Lemaire et al, 2006).15 Rivals to mediastinoscopy for staging the mediastinum are EUS and, more recently, EBUS. Both of these staging modalities use ultrasound probes that include a linear array of sensors that allow real-time visualization of the lymph node in question as the needle passes through it. The probes also have Doppler sensors to enhance the ability to distinguish a lymph node from a blood vessel. EUS has been shown to have a high rate of success when applied to patients with a high degree of suspicion based on CT or PET. Less is known about the value of EUS or EBUS when the dose of N2 disease is low. The advantages of EUS/EBUS staging are several. First, if an accurate answer is obtained without the need for general anesthesia or a surgical procedure, the patients may benefit. If the negative predictive value of EUS/EBUS is high enough to omit mediastinoscopy altogether, then the efficiency might improve in the operating room because a thoracotomy would be performed in all cases, and such procedures as an epidural or use of a double-lumen endotracheal tube can be performed without concern that they might not be necessary. In addition, another benefit of EUS/EBUS is that re-assessing the mediastinum after induction therapy does not present the same dilemma as does repeat mediastinoscopy. A postinduction repeat EUS would carry no additional risks or difficulties compared with a standard procedure, and a mediastinoscopy after a previous EUS should likewise present no increased difficulty. A final question addresses the timing of mediastinoscopy with regard to the planned surgical resection. Some centers do the mediastinoscopy as a stand-alone procedure, with the thoracotomy to follow at a later date if the mediastinoscopy is negative. The advantages of this strategy include lack of reliance on frozen sections, no unanticipated gaps in the

1/21/2008 10:37:00 AM

108

Section 1 Introduction

operative schedule due to positive mediastinoscopies, no unnecessary epidurals, and other consequences. The disadvantages are the need for two distinct anesthesias and hospital visits for most patients. This decision was studied in detail by the team from Cleveland Clinic, who reported that the combined strategy is safe and efficient but may not be as financially rewarding to the institution as the staged strategy.20

SUMMARY Mediastinoscopy remains an integral part of the staging process in many lung cancer patients more than 50 years after its introduction. It was certainly a pioneer procedure in the minimally invasive surgical movement, and it is now being challenged on many fronts for the role of the dominant procedure for staging the mediastinum and diagnosing mediastinal masses and adenopathy. Video-mediastinoscopy has made the procedure safer and easier to teach to trainees and deserves a role in every thoracic surgeon’s armamentarium. Time and careful study will tell the extent to which EUS, EBUS, and VATS will render this 50-year-old procedure obsolete.

COMMENTS AND CONTROVERSIES Mediastinoscopy was first described in 1959 by Doctor Eric Carlens (an ear, nose, and throat surgeon) as a method for palpation, inspection, and biopsy of mediastinal lymph nodes in patients with primary lung cancer. It is done through a small transverse incision just above the suprasternal notch; once the pretracheal fascia has been elevated, the surgeon has access to the entire superior mediastinum, where nodes can be palpated, seen, and biopsied. For an experienced surgeon, mediastinoscopy can be done quite safely even in patients with superior vena cava syndrome or as a repeat procedure. As well stated by the authors, lymph nodes must be biopsied in every case, and it is our policy to routinely obtain nodal tissue from at least three nodal stations, usually right and left lower paratracheal regions and the subcarinal space. From our perspective, a negative mediastinoscopy provides just as much information as a positive one; for a given patient, this information is most useful to determine the best course of action. Mediastinoscopy is often done on an outpatient basis. For reasons mentioned by the authors

Ch008-F06861.indd 108

(e.g., no need to rely on frozen sections, no unanticipated gap in the operating room schedule), we prefer to do mediastinoscopy as a stand-alone procedure, with the thoracotomy being carried out a few days later. Should mediastinoscopy be done in every patient with presumed operable lung cancer, or should it be performed only by indication? Although all thoracic surgeons agree with the need for preoperative clinical nodal staging, their views on the role of mediastinoscopy are often very different and based on where they trained and where they live, the availability of imaging techniques, and their personal opinion about the value of the test. In Canada, for instance, most surgeons still do mediastinoscopies in most lung cancer cases because they believe that the operation is cost-effective and associated with minimal morbidity, while providing the most objective and reliable information concerning the clinical nodal status. In the United States, mediastinoscopy is often done by indication in cases of large central tumors, enlarged nodes on CT scanning, or positive PET imaging. Some interventional respirologists even think that mediastinoscopy is never indicated, based on the high diagnostic accuracy of EUS techniques. For the author of this commentary, the most important message is that the operability of lung cancer must depend on objective information obtained preoperatively. Therefore, every surgeon must have a clear strategy as to what must be done to determine the clinical nodal stage of any patient with presumed operable lung cancer. J. D.

KEY REFERENCES De Leyn P, Lerut T: Cervical videomediastinoscopy for staging of lung cancer. Epublication World Electronic Book of Surgery, 2003. Available at: http://www.websurg.com/ref/doi-ot02en245.htm (accessed January 11, 2007). Lemaire A, Nikolic I, Petersen T, et al: Nine-year single center experience with cervical mediastinoscopy: Complications and false negative rate. Ann Thorac Surg 82:1185-1190, 2006. Little AG, Rusch VW, Bonner JA, et al: Patterns of surgical care of lung cancer patients. Ann Thorac Surg 80:2051-2056, 2005. Meyers BF, Haddad F, Siegel B, et al: Cost-effectiveness of routine mediastinoscopy in CT- and PET-screened patients with stage I lung cancer. J Thorac Cardiovasc Surg 131:822-829, 2006.

1/21/2008 10:37:00 AM

chapter

9

THORACOSCOPY Ibrahim Bulent Cetindag Stephen R. Hazelrigg

Key Points ■ Video-assisted thoracic surgery (VATS) is useful for undiagnosed

exudative pleural effusions to rule out malignancy. ■ VATS is very effective for empyema before the chronic fibrous

phase, which occurs after 3 to 4 weeks. ■ VATS wedge resection for peripheral nodules provides definitive

diagnosis. ■ VATS lobectomy appears safe and comparable to open lobectomy

when done by experienced thoracic surgeons. ■ Lung volume reduction surgery may be done by VATS or ster-

notomy with comparative outcome results in regard to lung function, 6-minute walk, and oxygen requirements. ■ VATS sympathectomy approaches 100% success for palmar hyperhidrosis. ■ VATS pericardectomy may provide advantages over a subxiphoid approach when the cause is benign; for malignant sources, the subxiphoid route is typically preferred.

Thoracoscopy has emerged as a frequently used surgical technique over the past 15 years. Before 1990, it was largely a diagnostic procedure that was mostly reserved for the evaluation of pleural disease. The emergence of better scopes and instruments has allowed thoracoscopy to evolve into a therapeutic modality. As evidence of its renewed popularity, a literature search of the word thoracoscopy yields 200 articles before 1990 and more than 1700 articles since. Thoracoscopic procedures using modified small incisions with scopes are referred to as video-assisted thoracic surgery, or VATS. This term is probably more appropriate now than thoracoscopy, which simply suggests the use of a scope to look inside the thoracic cavity. In this chapter, indications, techniques, and complications of VATS for both diagnostic and therapeutic procedures are reviewed. For some procedures, VATS has replaced open approaches due to reduced morbidity, shortened hospital stay, better cosmetics, or better exposure,1-10 whereas in other procedures the advantages are not as clear.

HISTORICAL PERSPECTIVE A brief review of the evolution of VATS reveals the use of scopes for various purposes dating back to the 1800s. In 1882, Koch found the tuberculosis bacillus, and it was soon discovered that the tubercular cavities could be healed by collapse therapy. Therapeutic pneumothorax became a surgical treatment in the early 1900s, and Hans Christian Jacobaeus from Stockholm, Sweden, is credited with the first thoraco-

scopic intrapleural pneumolysis to allow pneumothorax, in 1910. His technique involved adding a light to a cystoscope, and he reported success rates as high as 62%.11-14 Thoracoscopy was subsequently used for pleural procedures and biopsies, but its use diminished after effective drug treatments for tuberculosis were developed in 1945.15-20 Enthusiasm was renewed in the late 1980s with the development of laparoscopic procedures. It became apparent to early adopters that the same scope could provide visualization in the chest cavity, with results far superior to those of other techniques.21 Gradually, improved instrumentation evolved to allow lung resection, which dramatically increased the number of potential procedures. By 1992, we published an experience of almost 500 cases performed at three institutions.22 The endoscopic stapling device was the single most important advancement, allowing rapid and safe wedge resection, which opened the door to many thoracic procedures. The VATS approach offered advantages for many procedures, and the next few years witnessed a flurry of publications attesting to this fact. By 1993, a VATS study group was formed from multiple institutions and published a review of more than 1700 cases (Hazelrigg et al, 1993).23 VATS soon became an accepted, mainstream procedure, and over the past 10 years, its precise role has been better defined.

THORACOSCOPY: GENERALITIES AND TECHNICAL POINTS Thoracoscopy, or VATS, is performed through small access incisions. Because of the rigid chest wall, the use of single lung ventilation allows the ipsilateral lung to become atelectatic, which creates the necessary space to work in. In contrast to laparoscopy, carbon dioxide insufflation is not required, although it may be used if desired. Without the use of carbon dioxide, we usually make skin incisions and, except for the site of the scope, often simply introduce instruments directly through these small incisions. If carbon dioxide is used, then a seal must be maintained and trocars used at each incision (Fig. 9-1). For a high percentage of procedures, we use three incisions. We are often moving the site of the scope and instruments between these three sites to maximize visualization and instrument angles (Fig. 9-2). We try to avoid trocar sites posteriorly because the interspaces narrow, increasing the chance for intercostal nerve injury. Similarly, we try to minimize extreme angles with the instruments that might crush the intercostal nerves (Fig. 9-3). When planning our VATS approach, we try to avoid prior incisions or chest tube sites because the likelihood of 109

Ch009-F06861.indd 109

1/21/2008 10:37:48 AM

110

Section 1 Introduction

adherent lung in this area is high. After the first trocar is placed and the camera is introduced, the other port sites can be selected under direct vision. There are few general contraindications for VATS (Table 9-1). For patients already on the ventilator, we generally do not desire to change endotracheal tubes and usually will not achieve the advantages of VATS, such as early mobilization and discharge. Adhesions, although problematic, are not an absolute contraindication. In most cases we can take down adhesions to satisfactorily perform the planned procedure. However, prior decortication or pleurodesis is a contraindication. Of interest

0°

180°

3rd base

1st base

FIGURE 9-1 Patient in the left lateral decubitus position; digital exploration of the proposed initial trocar site is performed to confirm that a free pleural space is present. (MODIFIED WITH PERMISSION FROM

FIGURE 9-2 So-called baseball diamond concept for triangulation of the instruments and the thoracoscope for strategic visibility and manipulation of the target pathology. (MODIFIED WITH PERMISSION

THE SOCIETY OF THORACIC SURGEONS. FROM LANDRENEAU RJ, HAZELRIGG SR, MACK MJ, ET AL: VIDEO-ASSISTED SURGERY: BASIC TECHNICAL CONCEPTS AND INTERCOSTAL APPROACH STRATEGIES. ANN THORAC SURG 54:800, 1992. COPYRIGHT ELSEVIER 1992.)

FROM THE SOCIETY OF THORACIC SURGEONS. FROM LANDRENEAU RJ, HAZELRIGG SR, MACK MJ, ET AL: VIDEO-ASSISTED SURGERY: BASIC TECHNICAL CONCEPTS AND APPROACH STRATEGIES. ANN THORAC SURG 54:800, 1992. COPYRIGHT ELSEVIER 1992.)

FIGURE 9-3 A, Narrow intercostal space prevents use of standard open instruments. B-D, Coaxial thoracoscopic instruments allow use of small port incisions but retain instrument feel of standard open instruments. (MODIFIED WITH PERMISSION FROM ELSEVIER. FROM LIN JC, LANDRENEAU RJ: STRATEGIC PLANNING FOR VIDEO-ASSISTED THORACIC SURGERY IN MINIMAL ACCESS CARDIOTHORACIC SURGERY. IN YIM AP, HAZELRIGG SR, LANDRENEAU RJ, ET AL [EDS]: MINIMAL ACCESS CARDIOTHORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 1999, PP 28-35.)

Ch009-F06861.indd 110

A

B

C

D

1/21/2008 10:37:48 AM

Chapter 9 Thoracoscopy

TABLE 9-1 Contraindications for Video-Assisted Thoracic Surgery Absolute Contraindications Inability to tolerate single-lung ventilation Ventilator dependency Extremely poor lung functions Previous pneumonectomy General contraindications for general anesthesia (e.g., recent myocardial infarction, poor pulmonary function test results, coagulopathy) Extensive pleural adhesions or known previous pleurodesis Relative Contraindications Deep central small lesions Previous intrathoracic surgery Upper posterior mediastinal mass Wide chest wall involvement Thoracic anatomic deformity Sleeve resection

is the published use of ultrasound for preoperative assessment of adhesions. The authors measured pleural movement at seven locations and compared the findings with surgical observations. Ultrasound had a 97% negative predictive value and may be a consideration for the future.24 Superficial nodules are the easiest to resect with VATS, and, obviously, the small, deep nodules are the toughest. Many techniques have been tried to facilitate resection of these lesions, including methylene blue injections, hook-wire placement, ultrasound, 99mTc radionuclide injection with VATS gamma probes, and preoperative computed tomographic (CT) localization (Hazelrigg et al, 1998).25-30 In truth, with experience, we have not found any of these to be of much help. Our approach is to make one trocar site near where we expect the nodule to be, based on CT scans. Through this trocar, a finger is inserted and used to palpate the lung while a ring forceps is used to move the underlying lung. We have been successful at finding nodules smaller than 5 mm routinely; however, if this fails, then thoracotomy may be required.31,32 All nodules with suspicion of malignancy are removed in sterile bags to prevent seeding, which has occurred on several occasions. The procedures for which VATS can be used are listed in Table 9-2. For some of these procedures, VATS would be considered standard. It would be difficult today to be a general thoracic surgeon and not employ VATS for some of these procedures. Clearly, some of the VATS procedures require advanced skills and experience, and some have not demonstrated clear advantages. The remaining discussion focuses on VATS by area of procedure.

PLEURAL DISEASE Pleural diseases are among the oldest of the major indications for VATS. Conditions discussed here include pleural malignancy, chylothorax, empyema, and hemothorax. Thoracentesis and cytology, as well as with pleural biopsies, have a lower yield than thoracoscopy in terms of identification of undiagnosed pleural effusions. This does not mean that VATS is the first choice for identifying nonemergent undiagnosed pleural effusions. VATS allows surgeons to

Ch009-F06861.indd 111

111

TABLE 9-2 Published Applications of the Video-Assisted Thoracic Surgery Approach Pleural Diseases Undetermined pleural effusions Pleurodesis Chylothorax Treatment of empyema Drainage of hemothorax after trauma Pulmonary Parenchymal Diseases Diagnosis of undetermined pulmonary nodule Minor and major pulmonary resection for lung cancer Resection of pulmonary metastasis Bleb and bulla resection for spontaneous pneumothorax and persistent air leak Lung volume reduction surgery, giant bullectomy Interstitial lung disease Mediastinal Diseases Biopsy of mediastinal masses and lymph nodes for staging of intrathoracic malignancy Thymectomy Excision of benign cysts and masses Splanchnicectomy for chronic pain Sympathectomy for hyperhidrosis Posterior mediastinal and neurogenic tumors Esophageal Disease Myotomy Antireflux procedures Staging and resection of esophageal cancer Cardiac Diseases Pericardial effusions, pericardial window Internal epicardial pacemaker implantation Closure of patent ductus arteriosis Other Indications Spine surgery

directly visualize and biopsy the undetermined pathology in malignant effusions. The procedure is well tolerated, requires a short period of anesthesia, and is widely accepted. Because of the simplicity, excellent visualization, and 100% pathologic yield of this procedure, blind pleural biopsies have been made almost obsolete. In addition, VATS provides more effective drainage of pleural effusions by allowing direct visualization and breaking down of loculations. Numerous publications have shown the superiority of the VATS approach in the diagnosis of undetermined pleural effusions. Thoracentesis and cytology have 60% to 80% accuracy, compared with 90% to 100% for VATS.33-35 The Video-Assisted Thoracic Surgery Study Group data published in 1992 included 1820 initial VATS procedures in 40 institutions. In this study, the most common procedures were pleural procedures and wedge resections. VATS revealed a 63% malignancy rate among the 274 pleural effusions that were not diagnosed with previous interventions (Hazelrigg et al, 1993).23 When the results of thoracentesis and cytology are inconclusive or suggest a malignant effusion, VATS is indicated for identification or biopsy of the pathologic lesion. Malignant pleural effusion is the result of several etiologic events, which are listed in Table 9-3. Pleurodesis is indicated if the recurrence of the fluid is likely. Pleurodesis is also

1/21/2008 10:37:50 AM

112

Section 1 Introduction

TABLE 9-3 Causes of Malignant Effusions Obstruction of subpleural lymphatics and visceral pleural capillaries Obstruction of lymphatic outflow with nodal involvement Release of vasoactive amines by tumor cells, resulting in changes in capillary permeability Hypoalbuminemia, pericardial involvement and right heart tamponade, superior caval obstruction, irradiation

used for recurrent pneumothoraces and prolonged air leaks. Pleurodesis is indicated if a malignant effusion is diagnosed during a VATS procedure. Yim and colleagues36 reported on 69 VATS procedures for pleural effusions. Pleurodesis with talc was 94% successful at 6 months. More recently, Marrazzo and coworkers reported a 96% success rate with 2.6% morbidity.37 The success of VATS pleurodesis ranges from 88% to 100%.36-41 Pleurodesis can be performed by using several different chemicals or mechanical abrasion of parietal pleura. Chemical pleurodesis has been performed with talc, doxycycline, fibrin glue, bleomycin, tetracycline, kaolin derivatives, and silver nitrate. Talc has been superior to antibiotics in achieving pleurodesis,41-43 and its cost is low. A few studies have shown that VATS pleurodesis is more effective than closed pleurodesis.41,42 The difference may not be enough, however, to justify the risk of anesthesia, the cost, and poor healing of severely ill, debilitated patients with a limited lifespan. The advantage of VATS for pleurodesis is the ability to perform adhesiolysis, break down loculations, and achieve a homogeneous distribution of the chemical agent with a single intervention. We use VATS for all undiagnosed pleural effusions and obtain consent from our patients for possible pleural biopsy and pleurodesis at the same time, unless the patient’s general condition is too poor to tolerate the procedure and there is known incurable malignancy. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), acid pH, and early removal of chest tubes adversely affect the success of pleurodesis.44,45 Adjunctive placement of pleuroperitoneal shunts or Pleurex catheters for continuous drainage until adhesions are formed may be beneficial to diminish the duration of chest tube drainage in the hospital. Chylothorax is an uncommon condition. Chylous pleural effusion occurs as a result of disruption of large lymphatics or the thoracic duct. A wide variety of causes are described for chylothorax. Traumatic chylothorax often requires surgical correction and occurs after 0.2% to 0.4% of intrathoracic procedures.46,47 The diagnosis is based on detection of triglycerides in the pleural fluid. If the triglyceride level is greater than 110 mg/dL, then a chylothorax exists. If the level is less than 50 mg/dL, a chylothorax does not exist. If the triglyceride level is between 50 and 100 mg/dL, then the existence of chylomicrons on lipid electrophoresis confirms the diagnosis. Initial management is conservative and includes draining of the chyle with a large chest tube, total parenteral nutrition or, in less severe cases, a medium-chain triglyceride diet. Pleurodesis through the chest tube has been described,48 but this may lead to nonhomogenous pleural adhesions and complicate a subsequent operation should one become necessary.

Ch009-F06861.indd 112

Cerfolio and colleagues,46 in their retrospective review of 11,315 general thoracic surgery cases, found that the rate of chylothorax was 0.42%. Among 47 patients with a postoperative chylothorax, only 13 responded to conservative measures. The average enteral feeding time was 7 days (range, 2-15 days) among those successes. The factor that predicted reoperation was greater than 1000 mL/day drainage for 7 days.46 The patient’s general condition and the amount of drainage are factors in the decision for surgery. Drainage of more than 500 mL/day for 1 week or increasing drainage indicates a need for intervention. Early intervention is important in patients who have a poor nutritional status. Surgical options are pleurodesis, pleural shunts, and ligation of the thoracic duct, all of which can be achieved with VATS. Graham published a 10-case experience, in which 8 patients had talc pleurodesis alone. One had talc along with clipping of the thoracic duct. In two cases, a malfunctioning pleuroperitoneal shunt was repositioned and adhesions were lysed for more effective drainage. The success rate was 100%.49 It is not clear whether VATS or thoracotomy is optimal for the treatment of chylothorax, but most published material indicates a high success rate with VATS, which suggests that it is the preferred initial approach.47,49-51 Empyema is the most common benign condition of the pleura that is treated with VATS. Empyema and parapneumonic effusions accompany 1% to 5% of antibiotic-treated pneumonias. Outcomes and the incidence of empyema significantly changed in the 20th century with advances in both surgery and antibiotics. In the 1920s, closed drainage of the thorax was recommended by Evarts Graham and reduced the mortality rate from 30% to 10%.52 Before then, open drainage had been the treatment of choice since the time of Hippocrates. Empyemas consist of three phases: Exudative Phase: Initially, the exudative effusion remains fluid and the pleura is edematous. Chest tubes are indicated if the condition is diagnosed in this phase. Fibrinopurulent Phase: As infection progresses, more thickened fluid accumulates within the pleura, and fibrin deposits start to form over the lung. Simple chest tubes have not been very successful during this phase. VATS is indicated in this phase for effective decortication. The peel is loose and the chance of lung injury is minimal during the procedure. Early decortication is associated with lower morbidity (Landreneau et al, 1996).53 After approximately 3 weeks, the fibrinous (chronic) organized empyema phase starts. Fibrous Phase: After 3 weeks, the fibrinous peel becomes thick and adherent to the chest wall and lung, along with loculated fluid. At this time, the VATS approach is technically challenging, and thoracotomy is required in most patients. The treatment of empyema has three goals; evacuation of infectious material, full expansion of the lung, and correction of the cause of the infection. The first two goals are achieved surgically with either chest tubes or débridement. Because of the heterogeneity of the disease process, there is no single initial treatment. Properly placed chest tubes are the initial and best therapy for early empyema. If there is no improve-

1/21/2008 10:37:50 AM

Chapter 9 Thoracoscopy

ment in the clinical picture after placement of chest tubes, a CT scan must be obtained for determination of loculated effusion. Loculated collections on CT represent an indication for thoracoscopy. Definitive drainage of fluid with placement of chest tubes in strategic locations under direct vision may prevent progression of the disease.54 Catheter-directed fibrinolytic agents have been used, but comparative studies favor VATS in the fibrinopurulent phase.55,56 Wait and associates55 reported a randomized, prospective study on patients in the fibrinopurulent phase of empyema. VATS was associated with a higher efficacy, shorter hospital stay, and lower cost than catheter-directed fibrinolytic therapy.55 As an empyema becomes chronic, the conversion rate to thoracotomy increases. After 3 weeks, the rate of conversion has been reported to be 46% because of the adherent fibrinous peel (Landreneau et al, 1996).53 The same principles hold for débridement of an undrained hemothorax with VATS. Early intervention is more likely to be successful and is associated with a low morbidity. As blood remains in the chest cavity, it causes an adherent fibrin peel to form on the parietal and visceral pleura. With a hemothorax, the safe window for VATS appears to be shorter than with empyema. Successful VATS has been achieved uniformly when performed within 1 week after the event.57 Fibrinolytic therapy has also been suggested in late cases, but VATS has again been a superior approach to this problem.58 VATS has been used as the initial approach in the diagnosis and treatment of bleeding, for both penetrating and blunt thoracic trauma in stable patients.59 Thoracoscopy provides a thorough assessment of the thoracic cavity in the trauma setting. Diaphragmatic defects can be identified and repaired, clots can be removed, tears in the lung parenchyma can be stapled, and the effective placement of drainage tubes under direct vision can be achieved with the VATS approach.60-63 Available data suggest that VATS can provide results comparable to those of open surgery in subacute and elective indications related to thoracic trauma.61

PULMONARY PARENCHYMAL DISEASE This section discusses the use of VATS in cases of solitary pulmonary nodules, wedge resection, lobectomy, metastasectomy, pneumothorax, lung volume reduction surgery, and lung biopsy. The diagnosis of a solitary pulmonary nodule has been one of the more common indications for VATS (Hazelrigg et al, 1993).23 A solitary pulmonary nodule is defined as a pulmonary opacity that is less than 3 cm in size without any signs of atelectasis or lymphadenopathy. The increased use of chest radiography and CT in clinical practice has contributed to the frequent finding of asymptomatic nodules, and the incidence of malignancy is approximately 40% to 50% among these newly diagnosed nodules.25,64-68 Establishing a diagnosis and minimizing false-negative results remains the goal. Many modalities are available to evaluate lung nodules, and the choice of how best to investigate these new nodules is influenced by many factors. The estimated risk of malignancy is the most significant consideration regarding how aggressively to pursue a tissue diagnosis.

Ch009-F06861.indd 113

113

The risk of malignancy is determined by many factors, including the size of the mass, the patient’s age, smoking history, existence of the mass in earlier radiographs, evidence or suspicion of lymphadenopathy, change in size, calcification patterns of the mass, and the shape of the borders.25 Spiculated borders, no central calcification, older age, nodule growth, lymphadenopathy, long history of smoking, and size greater than 3 cm are factors that favor malignancy in pulmonary masses. Masses larger than 3 cm have a 95% risk of being cancer.69,70 Most solitary pulmonary nodules fall into a diagnostic grey zone and require further investigation. A high-resolution spiral CT scan with contrast enhancement, a positron emission tomographic (PET) scan, and fine-needle biopsy may precede surgery for the diagnosis of these indeterminate pulmonary nodules. CT with contrast enhancement is obtained by injecting contrast material at a fixed rate with a 3-mm-cut magnified view of the nodule at specified intervals after injection. The enhancement of a nodule from baseline by more than 15 Hounsfield units (HU) indicates an increased likelihood of malignancy, and less than 15 HU usually indicates benign pathology. In a multicenter, prospective study, a sensitivity of 98%, specificity of 58%, and overall accuracy rate of 77% were found with this technique. The authors of the study concluded that enhancement of less than 15 HU is a strong predictor of benign pathology, but higher enhancement is an indication for further investigation because of the high false-positive malignancy rate.71 This technique may be a good screening tool. Nodules with low enhancement can be observed with CT scans every 3 months until it is stable for 2 years or disappears. Any size increase leads to reconsideration for surgical biopsy. Positron emission tomography scanning with fluorodeoxyglucose (FDG-PET) has very good sensitivity but a moderate specificity.72,73 With active granulomatous or other inflammatory disease, the FDG-PET may be falsely positive. Smaller nodules (<1 cm) have not been reliably monitored with PET scan.73 Fine-needle biopsy has sensitivity greater than 90% for malignancy.25,70,74 A nonspecific benign diagnosis is common, although a specific benign diagnosis occurs in only about 15% of cases.25 Computer-aided volumetric nodule measurements with CT have recently emerged as a more sensitive method to detect growth in small nodules. Growth can be detected in a shorter time interval, and removal of the growing mass can be achieved earlier.75 The emergence of VATS has significantly altered the complex algorithm for evaluation of the solitary pulmonary nodule. Wedge excision has a 100% yield and minimal morbidity and mortality compared with thoracotomy. The ideal location for VATS resection is in the periphery of the lung or fissure. In our experience, the conversion to thoracotomy is only about 1% for wedge biopsy of a solitary pulmonary nodule, and the length of stay for wedge resection is short, with a mortality rate close to zero.25 Lesions are sent for frozen sectioning; if cancer is diagnosed, the appropriate pulmonary resection is performed at the same time. This may require thoracotomy. VATS lobectomy has been well described in the literature. Several studies have demonstrated results comparable to

1/21/2008 10:37:50 AM

114

Section 1 Introduction

those of thoracotomy in the treatment of lung cancer (Lendreneau et al, 1998; McKenna et al, 1998; Walker et al, 2003).76-88 Most of the studies were for stage I disease, but comparable results also have been shown for other resectable stages (McKenna et al, 1998; Walker et al, 2003).77,78 The size cutoff for thoracoscopic removal is about 4 to 5 cm to avoid rib spreading. McKenna, in his 1100-case series, reported a 2.5% conversion rate, 0.8% mortality, 0.57% local recurrence, and a mean length of hospital stay of 4.78 days.86 VATS lobectomy clearly requires more technical skill than wedge resection does. Anatomic lung resections with VATS have not been a routine part of most thoracic surgical training programs, but the number of surgeons performing this procedure is increasing. Quicker physical recovery and less immune compromise have been suggested as advantages of the VATS approach for lobectomy.84,86,89-91 Wedge resection of small lung cancers (i.e., those classified T1 N0) with VATS is indicated for patients with poor lung functions and poor health status who cannot tolerate lobectomy. Linden and colleagues92 performed VATS wedge resections in patients with a mean forced expiratory volume in 1 second (FEV1) of 26% and reported a 1% mortality rate. An analysis of 1400 stage I and II non–small cell lung cancers concluded that the better survival rate after lobectomy versus wedge resection disappeared in patients older than 71 years of age (after adjustment for significant comorbidities).93 Local recurrence remains a problem with sublobar nonanatomic resections. Thoracoscopic placement of radioactive seeds at the stapled margin has been suggested as an adjunct to wedge resection along with external beam irradiation.94-96 Santos and coworkers95 reported reduction of local recurrences from 18% to 2% with the use of 125I brachytherapy at the time of wedge resection in high-risk patients. VATS has also been used for resection of pulmonary metastases. The generally accepted indications for metastasectomy are listed in Table 9-4. Options for surgical resection include thoracotomy, median sternotomy, a subxiphoid approach, and VATS. In 1993, McCormack and colleagues97 reported that the CT and radiographic studies were often inconsistent with the findings during thoracotomy for pulmonary metastasis. They postulated that careful palpation of the entire lung was necessary for therapeutic metastasectomy. Since 1993, CT imaging has significantly improved, and in 2000, the spiral CT was shown to have better sensitivity and specificity in preoperative localization of pulmonary metastases. A report from Memorial Sloan-Kettering Institute in 1993 demonstrated that an open surgical approach identified additional metastases over VATS.97 VATS metastasectomy

TABLE 9-4 Selection Criteria for Pulmonary Metastasectomy Primary tumor is controlled or controllable No extrapulmonary metastases exist Medical status and pulmonary function test results are adequate for resection Complete resection for limited number of metastases is possible based on preoperative imaging

Ch009-F06861.indd 114

has been shown to be effective in many series, but its exact role for lung metastases remains an area of debate. Part of this debate includes tumor biology. The natural history of small metastases that are not identified during a VATS procedure is unknown. Whether a delayed resection (when later growth of these small nodules is noted) increases the patient’s failure rate is unknown. Spontaneous pneumothorax affects about 5 to 9 of every 100,00 people per year. It is caused by ruptured blebs and bullae. Blebs are defined as small air-filled areas that are less than 1 cm in diameter; they are the etiologic factor in spontaneous pneumothorax in young patients (<40 years of age), who are said to have primary spontaneous pneumothorax. These blebs are located on the surface of the lung, predominantly on the upper lobes and on the apical aspect of the lower lobe. Spontaneous pneumothorax at older ages is usually the result of ruptured bullae and emphysema. Bullae are larger (>1 cm) and are caused by emphysematous changes of the lung. These pneumothoraces are termed secondary spontaneous pneumothorax, indicating the presence of known underlying lung disease. Other causes of secondary spontaneous pneumothorax are AIDS (i.e., Pneumocystis jiroveci infection [formerly Pneumocystis carinii pneumonia or PCP]), malignancy, catamenial pneumothorax, and lymphangioleiomyomatosis. For patients with AIDS and PCP, spontaneous pneumothorax represents a sign of terminal disease, and treatment is tailored appropriately. Catamenial pneumothorax is caused by diaphragmatic or pulmonary endometriosis and most commonly occurs on the right side. Surgical resection and/or pleurodesis can be achieved with VATS.98-102 Surgical indications for spontaneous pneumothorax include recurrent pneumothorax, complications (e.g., hypoxia with secondary spontaneous pneumothorax, hemothorax, giant bulla); prolonged leaks; and patients who are pilots, divers, or living in remote areas. The risk of recurrence is 20% to 30% after a first episode of spontaneous pneumothorax and rises to 50% with a second episode (Naunheim et al, 1995).103-105 Definitive intervention tends to be recommended after the second episode. The surgical options include bleb (or bullae) resection with or without pleurodesis. Although the preoperative CT scan may be helpful in determining bullae locations, it is not required. Finding a visible bulla or bleb during surgery is associated with a low recurrence (Naunheim et al, 1995).105 A comparison of axillary thoracotomy with VATS for the treatment of spontaneous pneumothorax showed comparable recurrence but favored VATS with regard to less analgesic use and shorter length of hospital stay.104 VATS is currently a preferred approach for the resection of bullae and blebs with spontaneous pneumothorax, and the recurrence rate is 2% to 6% (Naunheim et al, 1995).105-107 Emphysema is a progressive disabling disease that affects more than 2 million people in the United States. Many different surgical techniques have been suggested for the treatment of this disease over the past 100 years. Most recently, lung volume reduction surgery (LVRS) has gained popularity, with reproducible successful results. Based on prior studies and, most recently, results from the National Emphysema

1/21/2008 10:37:50 AM

Chapter 9 Thoracoscopy

Treatment Trial (NETT), subgroups of patients that are appropriate for surgery have been defined. Favorable candidates are younger than 75 years of age; have no other comorbid disease; are not active smokers; have had no previous thoracic surgery; have an FEV1 between 20% and 45%; have a diffusing capacity for carbon monoxide (DLCO) greater than 20%; have no chest wall deformity; have upper lobe– dominant, heterogeneous bullous disease; have a postrehabilitation 6-minute walk distance greater than 140 m; have severe dyspnea with maximal medical treatment; and have a partial pressure of carbon dioxide (PCO2) of less than 60 mm Hg.108 The NETT trial was a prospective, randomized trial that was sponsored by the Health Care Finance Administration and the National Heart, Lung and Blood Institute to define the indications of LVRS. In this trial, having an FEV1 of less than 20% and either a DLCO less than 20% of predicted or homogenous disease was associated with a higher mortality rate; the subset of patients with these characteristics was recommended for medical therapy.108-110 Staged thoracotomy, median sternotomy, and bilateral VATS have all been suggested as possible surgical approaches for LVRS. A recent survey in Japan found that median sternotomy was the most common approach for bilateral LVRS, and VATS was the most common for unilateral LVRS, among their surgeons. Bilateral VATS was second to median sternotomy for bilateral LVRS.111 The outcome benefits of LVRS are comparable for either approach.5,112-113 Staged VATS has no demonstrated benefit over simultaneous bilateral VATS.113 A recent subanalysis on NETT trial results showed that the VATS approach was associated with earlier recovery and lower cost compared to median sternotomy.5 The VATS approach is preferred for unilateral disease. Surgeon’s and patient’s preference plays a role in choosing a surgical approach. Under ordinary circumstances, thoracotomy is not commonly used for LVRS.114 Median sternotomy and VATS both seem to be appropriate approaches, and VATS may be preferred for patients who take steroids (to avoid sternal healing problems) and have posterior-inferior nodules. The use of lung biopsy for interstitial lung disease has been an increasing trend to obtain a definitive diagnosis. Results of biopsies may lead to a change in therapy or give clues to the response to therapy and prognosis. Surgical biopsy is indicated when there is a worsening clinical picture with unknown etiology and maximal medical therapy. Lee and associates115 reviewed 196 consecutive surgical lung biopsies and found that the results changed the therapy in 84% of the patients and that 63% of the patients benefited from this change. Lung biopsies have been performed via thoracotomy and VATS. There is equal success in terms of determination of pathology. However, VATS has been demonstrated to have lower morbidity, less pain, better functional recovery, and a shorter hospital stay, compared with minithoracotomy, in nonrandomized series.116-120 More recently, two randomized controlled studies have produced conflicting results. Whereas Ayed and Raghunathan120 found that VATS was associated with less narcotic use, shorter length of hospital stay, and shorter operating time, Miller and coworkers121 found no difference between the two approaches. The VATS approach will have little advantage in ventilator-dependent hospital

Ch009-F06861.indd 115

115

patients. These patients poorly tolerate single-lung ventilation, and functional recovery is not a priority in the short term. They are better candidates for a limited anterior thoracotomy approach. We usually offer the VATS approach to our ambulatory and in-hospital patients who can tolerate single-lung ventilation because our experience has been favorable.118 VATS provides a full view of the thorax, all lobes of the lung are accessible for biopsy, and it is more cosmetically appealing.

MEDIASTINAL DISEASE The use of VATS in mediastinal disease includes mediastinal masses, staging of lung cancer, and sympathectomy. Diagnosis of mediastinal masses has been a challenge for surgeons for years. The location of the lesion may provide a clue (Table 9-5) as to the pathology, but in most situations, tissue must be obtained. VATS has offered excellent exposure with minimal surgical trauma for the biopsy of mediastinal masses. Alternatives to VATS for diagnostic purposes include mediastinoscopy, video-mediastinoscopy, and a Chamberlain approach. The Chamberlain approach is used for reaching aortopulmonary window masses, and mediastinoscopy is used for paratracheal masses. Rendina and colleagues, in their 55-patient series, found VATS to be the most favorable approach for the diagnosis of mediastinal masses. In their series, mediastinoscopy misdiagnosed lymphoma in three cases.122 Often, the diagnosis of lymphoma requires large samples, and VATS is an excellent approach to obtain sufficient amounts of tissue. It also allows access to the ipsilateral thoracic cavity for biopsy or treatment of any other pathologic lesions or effusions. VATS may also be used for the staging of intrathoracic malignancies. This approach is well defined for malignant effusions, as was discussed earlier. Thoracoscopy may be considered if there are questions of chest wall, great vessel, or mediastinal involvement. It allows biopsy of extrapleural mediastinal lymph nodes that may not be accessible via medi-

TABLE 9-5 Common Tumors of the Mediastinum Anterior Mediastinum Thymic neoplasms and cysts Lymphoma Germ cell tumors Ectopic thyroid Parathyroid adenoma Mesenchymal tumors Vascular masses Middle Mediastinum Lymphoma Enteric cysts Mesothelial cysts Metastatic or granulomatous tumors Lymphadenopathy Posterior Mediastinum Neurogenic tumors Enteric cysts Lymphoma Mesenchymal tumors

1/21/2008 10:37:50 AM

116

Section 1 Introduction

astinoscopy. All patients are assessed individually, and all noninvasive and less invasive diagnostic methods (fine-needle aspiration, transbronchial biopsy, and bronchoscopy) may be tried before a decision to use VATS is made. In most situations, a staging VATS procedure can be done at the time of a planned curative resection.123-125 Even when thoracotomy is planned for resection, starting with VATS may be strategically important for those who have the indications. In this way, positive N2 lymph nodes or large unresectable T3 tumors are identified, and appropriate cancer treatment may be started earlier by avoiding the thoracotomy. Thymectomy has two main indications: thymic neoplasms and some immune diseases, especially myasthenia gravis. Buckingham and colleagues126 demonstrated a 35% complete remission with thymectomy in myasthenia patients in 1976, compared with an 8% remission rate in those medically treated. Some authors have advocated indications for thymectomy in ocular forms because 30% to 70% of those patients advance to generalized myasthenia. It was well documented in a 2062-patient study that patients with milder symptoms had a higher rate of remission than patients with severe symptoms and advanced disease.127 Indicators of a good outcome after thymectomy are age younger than 45 years127; female sex126,127; and earlier stage of disease.126,127 The presence of thymoma is prognostic of a worse outcome. All patients should be in a controlled state, with either medications or plasmapheresis, before the surgery, and particular attention must be given to pulmonary functions and steroid use (especially in patients for whom a sternotomy approach is planned). Partial sternotomy, sternotomy, sternotomy with cervical extension (maximal thymectomy), transcervical approach, VATS, and, more recently, robotic VATS have been suggested as approaches for thymectomy. The ideal surgical approach remains controversial because of similar remission rates (Mack et al, 1996).128-131 Only the robotic approach has no clear data to compare with the others. Complete excision of the gland is the goal in every approach, and surgeons must choose the approach that will allow this goal to be achieved based on their own expertise. VATS and the transcervical approach have a longer learning curve than sternotomy. VATS provides better visualization than a transcervical approach, but both approaches provide excellent preservation of lung functions. Patients with large thymomas, with or without myasthenia, are probably better served with sternotomy because use of VATS for thymomas is reserved for small encapsulated lesions.132 Overall, patients with myasthenia achieve a 46% complete remission rate and a 50% rate of improvement on therapy after thymectomy.133 Mediastinal cysts are relatively uncommon and may arise from numerous sources, including lymphangioma (cystic hygroma); meningocele; and thymic, hydatid, thoracic duct, teratomatous, bronchogenic, pericardial, enteric, parathyroid, thyroid, and pancreatic cysts. Cysts represent 18% to 25% of primary mediastinal mass lesions. The most common are bronchogenic, pericardial, enteric, thymic, and parathyroid cysts. If the cyst is incidentally found and the diagnosis is certain, careful follow-up is advised if there are no symptoms. Intervention is reserved for suspicion of malignancy, symp-

Ch009-F06861.indd 116

toms, or an increase in size on follow-up. Mediastinal cysts represent ideal lesions for a minimally invasive approach, and results have demonstrated VATS to be safe and effective.134 In adults, the majority of posterior mediastinal masses are neurogenic in origin. The history and physical examination can help eliminate some of the differential diagnoses and may focus the diagnostic workup. For example, a history of hypertension with tachycardia leads to suspicion of pheochromocytoma. Pheochromocytoma is diagnosed with a metaiodobenzylguanidine (MIBG) scan and determination of metabolites of catecholamines in the urine. It is necessary to prepare patients with an α-blocker before surgery, to avoid a hypertensive crisis. All posterior tumors near the spine are worked up with a magnetic resonance imaging (MRI) study to rule out intraspinal extension (dumbbell lesion). If a dumbbell lesion is identified with MRI, surgical excision can be accomplished as a joint effort of the neurosurgeon and the thoracic surgeon. Resection of neurogenic posterior mediastinal tumors is generally indicated and is easily performed thoracoscopically. Care is taken near the intercostal bundles and for apical masses to avoid the brachial plexus and vascular structures. Thoracic sympathectomy and splanchnicectomy have been beneficial and are among the procedures that can now be performed with the VATS approach. Thoracic sympathectomy is indicated in palmar hyperhidrosis, Raynaud’s phenomenon, causalgia, and reflex sympathetic dystrophy. Splanchnicectomy is indicated in intractable upper abdominal pain most commonly related to chronic pancreatitis. Thoracic sympathectomy has a high incidence of satisfactory results for palmar, facial, and axillary hyperhidrosis. Although palmar hyperhidrosis is not a life-threatening problem, it does markedly affect a patient’s social and professional life. It may interfere with activities such as hand shaking, writing, typing, and using electronic equipment. The success rate for thoracic sympathectomy for palmar hyperhidrosis approaches 100%. More than 50% of patients develop compensatory sweating; however, almost all are pleased with the tradeoff. Horner’s syndrome occurs in fewer than 1% of the patients.135-137 The indications for vasomotor disorders are reserved for diseases that cannot be controlled with other measures and that cause necrosis and nonhealing ulcers. The success rate of thoracic sympathectomy for the vasomotor upper extremity disorders has been 70%, and the effects last for approximately 2 years. The success rate of splanchnicectomy has been between 50% and 60% in patients with chronic pancreatitis.138 Sympathectomy and splanchnicectomy procedures are simple and can be performed with VATS, with the use of small ports, on an outpatient basis.135-141

ESOPHAGEAL DISEASE The majority of minimally invasive esophageal surgery is done laparoscopically. Thoracoscopy may be used for myotomy, esophageal benign neoplasms, staging of esophageal carcinoma, antireflux procedures, and by a few centers for esophagectomy. Achalasia of the esophagus is a disease characterized by high basal pressure of the lower esophageal sphincter and

1/21/2008 10:37:51 AM

Chapter 9 Thoracoscopy

absence of peristalsis of the lower esophagus. All patients with achalasia need to be evaluated with esophagography, manometry, and/or endoscopy. The treatment has been a subject of controversy for years, and the options include pneumatic dilation, injection of botulinum toxin to the lower esophageal sphincter, laparoscopic myotomy, and thoracoscopic myotomy. Laparoscopic myotomy allows for an antireflux procedure, and most laparoscopic myotomies are done in conjunction with a partial wrap.142-144 Raftopoulos and colleagues,145 in a recent study, reviewed the quality of life in 105 patients who underwent a laparoscopic myotomy with fundoplication and thoracoscopic myotomy without an antireflux procedure. They found that, with the exception of patients who had undergone a prior nonoperative treatment, all of those who underwent myotomy had a significant improvement in their quality of life, regardless of concomitant antireflux procedure or approach. Bloomston and associates146 found that experience does play a role in the postoperative relief of symptoms. His first 20 patients had significantly less improvement than later cases having a videoscopic Heller myotomy.146 Thoracoscopy is preferred in patients with previous abdominal operations, and surgery is expected to be more successful in patients with no previous botulinum injections or pneumatic dilations.145 Antireflux procedures via thoracoscopy are more difficult than the laparoscopic procedures. Nguyen and colleagues147 published their experience with a thoracoscopic Belsey-Mark IV in 15 patients. They concluded that this approach should remain an option when the abdominal approach is not desired for patients with motility disorders like achalasia.147 Thoracoscopic/laparoscopic esophagectomy is performed in specialized centers and has a steep learning curve. Indications are similar to those for open esophagectomy. The procedure was shown to be technically feasible and safe for the treatment of benign and malignant esophageal disease by Luketich and coworkers in a series of 222 patients, with a mortality rate of only 1.4%.148 Nguyen and colleagues published similar oncologic results with a mean follow-up period of 26 months for esophageal cancer.149 Another area of use of thoracoscopy has been in staging of esophageal cancer. In a prospective, multi-institutional trial sponsored by the National Cancer Institute, Krasna and associates150 demonstrated in 134 patients that staging thoracoscopy and laparoscopy revealed twice the number of positive lymph nodes as preoperative imaging studies, including CT, MRI, and endoscopic ultrasound. The role of laparoscopy and thoracoscopy is not clearly established in the algorithm of staging of esophageal cancer, but it is definitely a tool for diagnosing suspicious mediastinal nodes that could change the algorithm of treatment.

PERICARDIAL DISEASE VATS has been used for pericardial biopsies and effusions. The alternative to VATS has been the subxiphoid route. VATS allows the resection of a segment of the pericardium, and chronic effusions can be drained. VATS also allows biopsy during the procedure to identify the cause of the effusion if malignancy is suspected.

Ch009-F06861.indd 117

117

VATS has been used for epicardial pacemaker lead implantation for patients who have occlusion of upper extremity veins and, more recently, for cardiac resynchronization therapy.151-154 There have been anecdotal reports of thoracoscopic ablation methods for the treatment of atrial fibrillation, but these have not yet become established indications.155-158

SPINE SURGERY Over the years, the thoracic surgeon’s role in thoracic spinal surgery has been to provide exposure. The new technology and superior optics have allowed spine surgeons to correct scoliosis of less than 50 to 70 degrees, to provide fixation of thoracic vertebral fractures, to correct kyphotic deformities of less than 70 degrees, and to drain abscesses thoracoscopically.

SUMMARY Thoracoscopy, or VATS, has now become a central part of the thoracic surgeon’s practice. Continued improvements in technology allow more advanced procedures to be done safely. The debate is no longer whether VATS has a role but, rather, just how extensive that role should be in advanced procedures. If comparable procedures can be performed thoracoscopically, then thoracoscopy is likely to offer advantages over open techniques.

COMMENTS AND CONTROVERSIES The authors have presented an exhaustive review of the VATS literature for a variety of indications. It is apparent that essentially all operations of the thoracic cavity have been performed to some degree with minimally invasive approaches. In some cases, such as VATS wedge resections of the lung, this represents a new standard of care. However, although extension of this application to VATS lobectomy has been reported to be safe and effective in several large single-institution series, a recent estimate in the United States suggests that more than 90% of lobectomies are still done through open thoracotomy. Therefore, advancing the clinical application of more complex VATS operation to the general thoracic surgical community at large is still a work in progress. Some diseases traditionally approached through an open thoracotomy by thoracic surgeons, such as achalasia and giant paraesophageal hernias, are now almost uniformly done through a laparoscopic approach by general surgeons, and it is unlikely that thoracic surgeons will regain any of these patients if they persist with a thoracic approach. Therefore, although it is essential that thoracic surgeons continue to evaluate minimally invasive thoracic procedures, it is equally imperative that thoracic surgical residency training strive to include the standard and more complex laparoscopic approaches to complex esophageal disorders such as achalasia and giant paraesophageal hernia. J. D. L.

KEY REFERENCES Hazelrigg SR, Magee MJ, Cetindag IB: Video-assisted thoracic surgery for diagnosis of the solitary lung nodule. Chest Surg Clin North Am 8:763-774, 1998.

1/21/2008 10:37:51 AM

118

Section 1 Introduction

Hazelrigg SR, Nunchuck SK, LoCicero J 3rd: Video Assisted Thoracic Surgery Study Group data. Ann Thorac Surg 56:1039-1043; discussion 1043-1044, 1993. Landreneau RJ, Keenan RJ, Hazelrigg SR, et al: Thoracoscopy for empyema and hemothorax. Chest 109:18-24, 1996. Landreneau RJ, Mack MJ, Dowling RD, et al: The role of thoracoscopy in lung cancer management. Chest 113(1 Suppl):6S-12S, 1998. Mack MJ, Landreneau RJ, Yim AP, et al: Results of video-assisted thymectomy in patients with myasthenia gravis. J Thorac Cardiovasc Surg 112:1352-1359; discussion 1359-1360, 1996.

Ch009-F06861.indd 118

McKenna RJ Jr, Wolf RK, Brenner M, et al: Is lobectomy by videoassisted thoracic surgery an adequate cancer operation? Ann Thorac Surg 66:1903-1908, 1998. Naunheim KS, Mack MJ, Hazelrigg SR, et al: Safety and efficacy of video-assisted thoracic surgical techniques for the treatment of spontaneous pneumothorax. J Thorac Cardiovasc Surg 109:1198-1203; discussion 1203-1204, 1995. Walker WS, Codispoti M, Soon SY, et al: Long-term outcomes following VATS lobectomy for non-small cell bronchogenic carcinoma. Eur J Cardiothorac Surg 23:397-402, 2003.

1/21/2008 10:37:51 AM

chapter

10

THORACIC INCISIONS Sudish C. Murthy

Key Points ■ Numerous incisions are used in thoracic surgery. ■ The goal of each approach is to optimize exposure of the affected

tissues. ■ The surgeon must have a thorough understanding of the muscu-

loskeletal anatomy of the chest wall.

The history of thoracic surgery is replete with vivid descriptions of morbid, often gruesome, surgical approaches to the chest. The rigidity of the chest wall and the relative lack of mobility of thoracic viscera magnify the importance of a wellconceived incision to facilitate exposure for procedures. A century of experience and technologic advancement has afforded the modern thoracic surgeon the luxury of choosing from a variety of surgical approaches to the chest that are aimed not only to optimize exposure but also to limit morbidity and expedite recovery. However, to successfully utilize this information, the surgeon must be facile with the surgical anatomy of the chest wall and contents and must understand the advantages and limitations of each incision.

GENERAL CONSIDERATIONS Regardless of size, the incision is always positioned to allow for the best possible exposure to the necessary area, and to facilitate technically challenging parts of the operation. For example, for standard pulmonary resections, incisions expose the hilum of the lung. Also, the location of the incision must permit rapid extension should circumstances dictate. This mandates a wide sterile prep for most thoracic procedures. Options to widen an existing incision need not be restricted to the linear axis because counterincisions or perpendicular incisions can be used for greater surgical exposure if needed. Retractors have been developed to improve exposure from otherwise less than adequate incisions,1 and more videoassisted procedures are being performed, thus greatly reducing the size of incisions and resulting in chest surgeries without clear “line-of-sight” access. Although thoracotomies can be safely performed in octogenarians,2 physical condition and body habitus of the patient need to be considered when planning the surgical approach. A cachectic, bedridden patient will be more likely to develop wound complications from a posteriorly placed thoracotomy incision versus a lateral one. Similarly, muscular individuals require much larger subcutaneous dissection and soft tissue mobilization for muscle-sparing thoracotomy approaches and may subsequently be at greater risk for incisional seroma. Tall

individuals with narrow costal flares who require pericardial drainage may be more easily treated from an anterior left minithoracotomy or video-assisted thoracoscopic ( VATS) approach than from a subxiphoid exposure. Standard risk factors for wound complications (e.g., obesity, diabetes, corticosteroid use) are considered preoperatively and incisions planned accordingly. Meticulous surgical technique, gentle tissue handling, and excellent hemostasis will minimize local wound problems. Optimizing medical comorbid disease (i.e., tight blood glucose control for a diabetic) will also expedite healing and recovery. Ancillary services at an institution can greatly impact the surgical plan. If reliable single-lung isolation is available, incision size can be drastically reduced and postoperative recovery may be enhanced by epidural analgesia (Lubenow et al, 1994).3 Expert intensive and respiratory care similarly impacts outcome. Preoperative imaging studies are useful to define the pathology and may also help direct the location of the incision.4 Finally, as postoperative survival progressively improves, the long-term sequelae of thoracic incisions must be considered. A muscle-sparing thoracotomy may be less painful and preserve arm function better than the classic posterolateral approach (Kittle, 1988),5,6 although objective data are insufficient to support this theory.7,8 Post-thoracotomy neuralgia remains a problem without a definitive solution, although avoiding crush injury to intercostal nerves may be of some benefit. Finally, excessive abduction of the arm during thoracotomy, or spreading of the sternum after sternotomy, can lead to a brachial plexopathy, which then serves as an intractable source of protracted morbidity. With this background in mind, the chest can be accessed from a variety of locations (anterior, lateral, or posterior) for a vast number of intentions. A fundamental understanding of the regional musculoskeletal anatomy is valuable in reconstructing the wound and in predicting postoperative problems that might result.

ANTERIOR CHEST INCISIONS The musculoskeletal anatomy of the anterior neck, chest, and abdomen are represented in Figure 10-1. Important skeletal landmarks include the thyroid cartilage, suprasternal notch, sternal angle of Louis, and xiphoid process. The suprasternal notch lies over the inferior aspect of the second thoracic vertebra (T2), the angle of Louis superimposes onto T4, and the xiphoid approximates T9. When mediastinal structures are projected through the anterior skeleton (Fig. 10-2), the left innominate vein/superior vena cava confluence lies 119

120

Section 1 Introduction

FIGURE 10-1 Musculoskeletal structures encountered with anterior approaches. Important muscle groups include sternocleidomastoid, pectoralis major, serratus anterior, and rectus abdominis.

FIGURE 10-2 Anterior projection of major mediastinal structures through the chest wall. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

(REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

beneath the junction of the first right rib and manubrium, the aortic arch is situated under the midportion of the manubrium, and the hila are located deep to the proximal third ribs. Major anterior muscles include the platysma, sternocleidomastoid (SCM), pectoralis major, serratus anterior, and rectus abdominis. The direction of muscle fibers is noted to permit muscle-splitting, rather than muscle-dividing, incisions, if possible. The vascular supply to the pectoralis major is both medial, from internal mammary perforators, and lateral, from the thoracoacromial trunk and intercostal artery perforators. This becomes relevant when mobilizing this muscle for reconstructive efforts.

Transverse Cervical Incision The transverse cervical incision is the most common approach to access the thyroid, cervical trachea, proximal esophagus, and superior mediastinum. This is a complicated space, and one needs to be familiar with the major anatomic landmarks within the region (Fig. 10-3). Patients are placed in a supine position and arms are tucked at the sides (Fig. 10-4). Ulnar nerve compression is avoided by appropriate padding, and cervical exposure is augmented by neck hyperextension. This is not possible in patients with significant cervical spine disease. For some tracheal procedures, the ability to both flex

FIGURE 10-3 Exposure of the neck. With the platysma cut away, the relationship of the deeper cervical muscles is understood. Exposure to the trachea mandates lateral mobilization of the strap muscles and elevation (or division) of the thyroid isthmus. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

and extend the neck intraoperatively is required. Both surgeon and anesthesiologist must ensure that proper head support is provided before the placement of the drapes. Preoperative placement of a central venous line (if necessary) must be done with the operative plan in mind.

Chapter 10 Thoracic Incisions

FIGURE 10-4 Standard position for midline cervical incisions. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 10-5 Variety of common cervical incisions. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

The neck is cleansed with alcohol, and a standard iodinebased gel is used to prepare the skin. It is customary to consider the entire neck (to the jaw angle) and the anterior chest (to the costal margins) as part of the operative field, although after the sterile preparation these regions may be covered and exposed only if needed. Examination with the patient under anesthesia will help the surgeon identify anatomic landmarks (e.g., thyroid cartilage, suprasternal notch, SCM) before beginning the procedure. Depending on the patient’s anatomy and indication, a standard transverse cervical incision (Fig. 10-5) is usually made midway between the thyroid cartilage and the suprasternal notch in a convenient skin crease. This location is consistent with the lines of Langer. Sharp dissection is used to carry the incision through the platysma. This allows for easier identification of the muscle when closing. The incision is easily

extended laterally across the boundary of the SCM or superolaterally toward the mastoid process for additional exposure. Myocutaneous flaps are raised because dissection subadjacent to the platysma is relatively bloodless and can be done with a scalpel. In the midline, the strap muscles are then easily identified and bluntly mobilized laterally to expose the isthmus of the thyroid gland. To expose the cervical trachea, the thyroid is elevated superiorly (or the thyroid isthmus divided) and pretracheal (thymic) fat is mobilized laterally. This approach is recommended for tracheotomy or tracheal resection.9 Elevation of the pretracheal fascia off the trachea permits access to the middle mediastinum (for mediastinoscopy). A transcervical approach to the superior and anterior mediastinum has been used for thymectomy1 and is occasionally helpful in reoperative parathyroid surgery10 and for substernal goiter. There are numerous variations of this incision (see Fig. 10-5). With the neck extended and turned to the contralateral side, a transverse incision started at the lateral border of the SCM and carried laterally across the supraclavicular fossa facilitates scalene lymph node biopsy. The platysma is incised sharply, and the ipsilateral external jugular vein is ligated. The SCM can be mobilized medially with cautery to expose the internal jugular vein. The omohyoid muscle courses obliquely in the field and can be mobilized or divided without consequence. The supraclavicular fat pad can then be harvested off the scalene anticus muscle (medially and posteriorly) after the phrenic nerve has been identified and preserved. The subclavian artery courses at the inferior aspect of the field, and the thyrocervical trunk can be skeletonized. A mirror-image left-sided approach may bring the thoracic duct in the field, and this must be appreciated, mandating when the medial aspect of the fat pad is mobilized. The cervical esophagus is exposed with an oblique incision along the anterior border of the SCM. After the SCM is mobilized laterally, the omohyoid is divided if necessary. To properly mobilize the carotid sheath requires division of the middle thyroid vein and, often, the inferior thyroid artery. As the thyroid, trachea, and strap muscles are gently retracted medially and the carotid sheath and SCM moved laterally, the esophagus is approached. Blunt dissection posteriorly along the anterior border of the cervical spine provides the safest route to control the cervical esophagus. The anterior transcervical approach to superior sulcus tumors permits controlled cervical mobilization for anterior/ apical non–small cell lung cancers (Dartevelle et al, 1993).11,12 After appropriate positioning (neck extension and contralateral head rotation), intersecting incisions are made along (1) the anterior border of the SCM and (2) transversely across to the inferior edge of the clavicle (see Fig. 10-5). Much of the dissection is similar to that discussed previously. Notable differences include division of the SCM and the scalenus anticus. A nerve stimulator may be of some assistance in identification of the phrenic nerve. After removal of the scalene fat pad, the tumor is carefully assessed. If deemed resectable, the medial half of the clavicle is resected and proximal vascular control can be obtained (Fig. 10-6). Division of the scalenus anticus muscle also exposes the stellate

121

122

Section 1 Introduction

FIGURE 10-6 Anterior transcervical approach to superior sulcus tumors. Schematic represents a right-sided approach. The medial portion of the clavicle (bottom of the picture) has been resected. A retractor (left) distracts platysma and the cut end of the sternocleidomastoid muscle, exposing the scalene anticus. The phrenic nerve is mobilized medially to permit safe division of the scalene muscle. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

ganglia, and, historically, this approach was used for dorsal sympathectomy.13 Closure entails repair of divided muscle with interrupted absorbable suture. A closed suction drain is temporarily employed for most complex neck procedures because only a small amount of retained fluid or blood may cause airway compromise. Consequently, meticulous hemostasis is required and close postoperative observation is warranted for large neck dissections. The drain is placed deep to the platysma closure. A fine, absorbable, subcuticular suture is used for skin closure. Wound infection is very rare unless a viscus (e.g., esophagus) has been opened or tissues have been previously irradiated. Postoperative hoarseness heralds a recurrent nerve injury, and ipsilateral diaphragm elevation suggests phrenic nerve palsy. Familiarity with the surgical anatomy of the region greatly reduces complications.

Anterior Mediastinotomy The original description of anterior mediastinotomy detailed a 6-cm incision at the left second intercostal space and removal of the entire cartilaginous portion of the second rib.14 The internal mammary pedicle was ligated and divided, and the retrosternal (extrapleural) space was entered by blunt dissection. The procedure was devised to identify patients with unresectable cancer (mediastinal spread) and prevent unnecessary thoracotomy. Current indications for the procedure are considerably narrower because accurate radiographic staging and alternative surgical approaches (mediastinoscopy and VATS) have largely supplanted the technique. Nonetheless, it is still used for staging patients with left upper lobe

FIGURE 10-7 Modified Chamberlain procedure for access to the superior-anterior mediastinum. A mediastinoscope is used to facilitate exposure and minimize the incision length and morbidity. The scope is inserted medial to the internal mammary pedicle for most applications. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

bronchogenic cancer but is more commonly required to diagnose primary mediastinal masses not amenable to percutaneous procedures (e.g., fine-needle aspiration). A preoperative chest CT scan can help place the incision directly over the pathology, simplifying the procedure. The entire ipsilateral thorax is prepped in the event the incision needs to be extended to improve exposure or control hemorrhage. If a mediastinoscope is used to assist in the exposure, seldom is more than a 3-cm incision required. The selected interspace may be wide enough to accommodate the mediastinoscope without rib resection (Fig. 10-7). Once the skin is incised, the pectoralis major muscle can be separated bluntly in the direction of its fibers to expose the interspace or rib head. For an extrapleural approach, once the intercostal muscle fibers are divided, sharp dissection is used to identify the internal mammary pedicle, which is then gently retracted laterally. The mediastinum is then entered and dissected bluntly, and a mediastinoscope can be inserted. The cartilaginous rib head can be removed to provide extra room to maneuver the mediastinoscope. Rarely, the internal mammary artery will need to be sacrificed. If an intrapleural approach is preferred, the pleural cavity is entered lateral to the mammary pedicle. When a mediastinoscope is used, lung isolation is generally not needed. The surgeon must be careful not to mistake hilar lymph nodes (N1) for mediastinal lymph nodes (N2) because both may be sampled through this approach. Moreover, care must be

tahir99-VRG vip.persianss.ir

Chapter 10 Thoracic Incisions

FIGURE 10-8 Position for anterior thoracotomy. A roll is used to elevate the patient on the ipsilateral side. The ipsilateral arm can be positioned at the side (as shown) or elevated across the body. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC

123

FIGURE 10-9 The pleural cavity is commonly entered at interspace 4. Resection of the sternocostal junction at rib 4 allows sufficient exposure for single-lung transplantation (not shown). (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FOUNDATION.)

taken to avoid injury to the ipsilateral phrenic nerve. At the conclusion of the procedure, air is evacuated through a soft catheter left in the pleural space. Suction is applied to the catheter as pectoralis muscle is tightly closed around it with absorbable suture. The catheter is pulled out during a deep breath-hold, and the muscle layer is cinched tight. If a parenchymal lung injury was incurred, a chest tube is warranted.

Anterior Thoracotomy Anterior thoracotomy has both general thoracic and cardiac surgical applications. The right middle lobe is easily approached anteriorly, and bilateral anterior thoracotomy is gaining popularity for double-lung transplantation.15,16 Moreover, open-lung biopsy on critically ill patients can be conducted through anterior exposure, as can partial pericardectomy. Similarly, reoperative cardiac surgeries are often approached via anterior thoracotomy.17,18 Because the posterior hilum and the esophagus are poorly exposed, the anterior approach is infrequently used for most other pulmonary or esophageal resections. The patient is placed supine with a paraspinal roll elevating the ipsilateral chest by 20 to 30 degrees (Fig. 10-8). Arms are tucked at the sides and elbows padded. The ipsilateral elbow is elevated if excessive stretch on the shoulder girdle is noted. After a standard sterile prep and drape, the angle of Louis is identified because this reliable landmark identifies the second rib and interspace. For entrance into the chest at the fourth interspace (middle lobectomy or transplant incision), the incision is made along the inframammary crease from sternal edge to anterior axillary line (Fig. 10-9). The pectoralis major muscle is divided slightly more cephalad than the skin incision, preventing suture line overlap. Breast tissues are mobilized off the pectoralis fascia, with cautery used to control perforating vessels. The cephalad portion of the pectoralis muscle is mobilized off the ribs until the desired interspace is reached. In large-breasted women or patients with significant thoracic obesity, landmarks are more difficult to identify and extensive dissection of soft

tissues may be required. Alternative incisions need to be considered for these patients. Cautery is used to incise the intercostal muscles from the superior aspect of the rib below the interspace. Laterally, serratus muscle is split along the course of its fibers. Slips of pectoralis minor muscle are divided. The pleura is entered bluntly to prevent thermal injury to lung. Once the lung is collapsed, or retracted, the rest of the interspace is opened with cautery posteriorly toward the sympathetic chain. The intercostal neurovascular pedicle courses more toward the middle of the interspace posteriorly, and troublesome bleeding from cautery injury to the pedicle often results from attempting to open the interspace back to the rib/transverse process articulation. If additional exposure is necessary, the internal mammary pedicle can be divided anteriorly and the rib cartilage shingled to allow for further rib distraction. For closure, after chest drains are placed, ribs are reapproximated with large-gauge absorbable suture. Sutures are placed to incorporate intercostal muscle from the interspace below to cushion the neurovascular bundle, and excessive force is avoided when sutures are tied down. Anteriorly, it is seldom possible to obtain rib-to-rib apposition, and trying to do so predisposes to neurovascular bundle compression. Instead, pay attention to meticulous soft tissue apposition over the interspace. When an anterior rib cartilage defect exists, identify and reapproximate the perichondrium and anchor the anterior rib to the sternum with heavy, nonabsorbable monofilament suture, if necessary. Repair the pectoralis major muscle with either continuous or interrupted absorbable suture technique. Close deep dermal tissues and skin with absorbable suture also. Place subcutaneous drains if extensive soft tissue mobilization was required.

Upper Midline The upper midline abdominal incision has wide applications in thoracic and general surgery. In addition to providing access to the upper alimentary tract, the inferior pericardium can be accessed and the omentum can be harvested for tissue

tahir99-VRG vip.persianss.ir

124

Section 1 Introduction

FIGURE 10-10 Location of the incision for a subxiphoid approach to the pericardium. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 10-11 Subxiphoid pericardial exposure. When the xiphisternum is elevated and the diaphragm depressed, the inferior pericardium is brought into the operative field. The pericardium is then incised sharply to create the window. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

transfer. Moreover, the incision is routinely coupled with other incisions during two- or three-field approaches for esophagectomy. Contraindications are few, although a previous laparotomy incision may deter a subxiphoid approach to the pericardium. Although there remains some disagreement as to the best surgical strategy to manage effusive pericardial disease (Hankins et al, 1980),19-21 the subxiphoid approach to the pericardium is rapid, is effective, and, if needed, can be performed without general anesthesia.22 In obese or tall patients with narrow costal arches, subxiphoid exposure of the pericardium can be difficult23 and perhaps needs to be avoided. For a subxiphoid window, patients with compromising effusive disease (pericardial tamponade) must be hemodynamically stabilized (often with percutaneous drainage) before surgery. This is done the day before, and pericardial drains are left in place. If, for some reason, preoperative drainage cannot be effected, induction of anesthesia must be carefully controlled and the operating room team be ready for hemodynamic collapse. In these cases, the patient’s abdomen and chest are sterilized and draped before induction of anesthesia. If the patient’s condition is too unstable, the procedure can be done with local anesthesia and conscious sedation. The patient is placed supine on the operating table. A roll can be placed behind the lumbar spine so that a lordotic posture is created. A midline incision is made from the xiphisternal junction to 8 to 10 cm below the tip of the xiphoid (Fig. 10-10). The linea alba is divided, and division of the

peritoneum is avoided. The soft tissue plane behind the xiphoid is developed bluntly; the xiphoid can be dislocated from the xiphisternal joint after being freed from its fascial and muscular attachments, if necessary. The preperitoneal fat and peritoneum are bluntly dissected off the diaphragm with a sponge stick until the diaphragm/inferior pericardium interface is encountered. A hand-held retractor can be used to elevate the sternum for optimal exposure. If a preoperative pericardial catheter was placed, the pericardial space can be filled with 100 to 200 mL of body-temperature, sterile saline to facilitate its identification and permit safe entrance. However, more often, there is ample redundancy within the pericardial sac to permit safe entry regardless of preoperative drainage. Once identified, the pericardium is grasped and sharply incised (Fig. 10-11). Blunt deloculation is prudent to ensure complete evacuation of the space. A mediastinoscope can be used to identify and sample pericardial implants.24 A generous segment of pericardium is resected (16-25 cm2) to decrease recurrence rate.20,21,24 A chest tube or closed suction drain is left in the pericardial space and tunneled out of a separate stab incision for postoperative drainage. Complications, although rare, can be catastrophic. If the preoperative diagnosis was incorrect and an obliterative pericardial process exists, a coronary artery or ventricle can be lacerated when the pericardium is incised.23 Real-time transesophageal echocardiography is a valuable modality to use for complicated cases.

tahir99-VRG vip.persianss.ir

Chapter 10 Thoracic Incisions

FIGURE 10-12 Placement of upper midline incision for distal esophageal and diaphragm exposure. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Proper reapproximation of the linea alba with heavy nonabsorbable suture prevents postoperative ventral hernia. Patients tolerate the incision well and can be mobilized early. Heterotopic ossification is cited as an uncommon late sequela of midline incisions.25 Although a follow-up echocardiogram is not imperative, it is recommended before chest tube removal. When the upper midline incision is extended down to the umbilicus (Fig. 10-12) and self-retaining retractors are properly placed, the esophageal hiatus can be exposed. After the left lobe of the liver is mobilized from the diaphragm and gently retracted to the right, the hiatus is brought into full view (Fig. 10-13). Access to the posterior mediastinum can be achieved by incising the diaphragm anteriorly from the hiatus or through a transverse semicircular incision in the central tendon that spares the hiatus.26 When dividing the diaphragm, attention is paid to controlling the inferior phrenic vessels and preserving phrenic nerve branches.

Sternotomy Median sternotomy was originally described for the management of mediastinal tuberculosis.27 Median sternotomy has now become the most common thoracic incision, owing to its use in heart surgery. By virtue of its midline and anterior location, it has broad applications for noncardiac chest operations as well. The transsternal route is the most direct for thymectomy and resection of other anterior mediastinal tumors. Tracheal9,28 and upper esophageal exposure29 is

FIGURE 10-13 After the left lateral segments of the liver are mobilized toward the midline, the esophageal hiatus is brought into full view. An upper-hand retractor greatly improves exposure. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

enhanced when cervical incisions are combined with full or partial sternal split. Bilateral pulmonary metastasectomy30,31 and lung volume reduction surgery32 are facilitated through sternotomy. Anatomic pulmonary resections,33-35 repair of postpneumonectomy bronchopleural fistula,36 and pulmonary transplantation can also be performed transsternally. The sternotomy incision is performed with the patient supine. Arms are tucked and elbows padded. Regardless of the indication, the sterile drape includes the entire neck and abdomen. The groins are sterilized for cardiac operations. A double-lumen endotracheal tube is preferable for most pulmonary operations except tracheal resection. The standard sternotomy incision is from the suprasternal notch to a point just beyond the xiphoid process. The incision is generally carried to the pectoral fascia and linea alba with the scalpel. Cautery can then be applied to control superficial bleeders, score the periosteum, and divide the linea alba. The superior end of the skin incision is retracted in a cephalad manner to expose the top of the manubrium and allow for identification of crossing jugular tributaries in the space of Burns. The interclavicular ligament can be divided sharply or with cautery; care must be taken to avoid an anterior coursing innominate artery or vein. Blunt dissection is used to open the retrosternal space both superiorly and inferiorly.

125

126

Section 1 Introduction

FIGURE 10-14 Location of incision for median sternotomy. A sternal saw can be applied either superiorly or inferiorly. It is critical to ensure a midline division of the bone. (REPRINTED WITH THE

FIGURE 10-15 The sternal spreader is applied at the inferior aspect of the incision to reduce the incidence of brachial plexus injury.

PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

(REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Deliberate palpation of the interspaces allows for an accurate assessment of the true midline. The angle of Louis serves as a useful guide. If necessary, the midline can be re-marked with cautery. A reciprocating saw is used to divide the sternum either from top down or bottom up (Fig. 10-14). Before splitting the sternum, the lungs are transiently deflated to prevent unintentional entry into a pleural space. Bone and periosteal bleeding is immediately controlled with gauze packing; and after sternal edges are distracted, periosteal bleeders are selectively cauterized. Marrow bleeding can be controlled with judicious use of bone wax without increasing infectious complications.37 Biologic sealants are now available for this purpose.38 Any one of a number of sternal spreaders can be used to distract the sternal edges (Fig. 10-15). A more inferior (caudad) placement of the retractor seems less frequently associated with rib fracture or brachial plexus injury.39 Sternal edges are spread only far enough to permit adequate exposure for safe completion of the operation. Anterior diaphragm fibers may prematurely restrict sternal spreading and can be sacrificed. In addition to brachial plexus, rib, and sternal injury, excessive traction on the innominate vein often limits the degree of sternal distraction. Multiple modifications of the skin incision have been made to improve cosmesis yet provide for complete sternotomy. Common to all is extensive soft tissue mobilization; and because of this, high-dose corticosteroid use is a relative contraindication. A limited 10- to 12-cm skin-sparing incision can be made beginning below the angle of Louis. This keeps the scar below

the neckline. Subcutaneous flaps are raised laterally off the pectoralis fascia and rectus sheath. Internal mammary perforators are encountered as the flaps are raised. Depending on the size of the incision it may be necessary to undermine the subcutaneous flaps laterally to the midclavicular line. Superiorly, the soft tissue is universally more lax, requiring less dissection for adequate mobilization; nonetheless, flaps must be raised above the clavicles. The incision needs to be able to be mobilized to provide exposure from the suprasternal notch to the xiphoid. Because the decreased length of the incision limits the view of operative field, intraoperative repositioning of the sternal retractor is frequently necessary. Subcutaneous drains and compressive dressings are used postoperatively. A limited Y incision has also been described.40 The submammary exposure of the sternum is popular for use in young women.41,42 Patients are positioned supine with elbows slightly flexed at the patient’s side to expose the anterior axillary line (Fig. 10-16). The submammary folds can be marked preoperatively. Beginning just lateral to the nipple, the transthoracic incision is made in the submammary creases and elevated to a point level with the nipples in the midline. Cautery dissection is used to elevate the breasts and soft tissues, in a triangular fashion, toward both the suprasternal notch and the xiphoid (see Fig. 10-16). The lateral extent of the dissection does not interrupt the lateral perforating branches of the intercostal arteries that perfuse the flap and breasts. After completion of the dissection and exposure of the sternum, the superior and inferior flaps are handled gently and retracted with sutures. A standard sternotomy is then

Chapter 10 Thoracic Incisions

FIGURE 10-16 Submammary incision for sternotomy. Subcutaneous tissue flaps are raised as depicted by the shaded areas in the diagram. The lateral extent of the soft tissue dissection is not beyond the midclavicular line. (REPRINTED WITH THE PERMISSION OF THE

FIGURE 10-17 Conventional sternal reapproximation with No. 6 stainless steel. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

CLEVELAND CLINIC FOUNDATION.)

performed. When closing, the flaps can be loosely tacked down to the pectoral fascia and closed over vacuum drains. The deep dermis and skin are reapproximated with fine absorbable suture. Compressive dressings are applied to the wound, and breast support is provided with an elastic bra. Subcutaneous drains are often required for 7 to 10 days to reduce the chance of seroma. Wound hematoma and skin necrosis in the central connecting portion of the incision are observed in 5% to 10% of cases. A linear horizontal (versus elevated curvilinear) connecting incision across the sternum surprisingly has a higher incidence of wound breakdown.43 Healing by secondary intention in these cases still results in an acceptable cosmetic outcome. Hypertrophic scarring has been noted in 10% to 20% of patients.42,44 Intralesional triamcinolone injection seems effective in these cases.42 Decreased areolar sensitivity is reported in 30% of patients.44 No long-term interference with breast-feeding is reported.45 Regardless of skin incision, rigid reapproximation of the sternum is the single most important factor in preventing sternal dehiscence and deep infection.46 A variety of strategies have been devised to reapproximate the sternum (Robicsek et al, 1977).46-50 For uncomplicated cases, a stainless steel wire reapproximation is appropriate (Fig. 10-17). Six to eight No. 6 stainless steel wires are used. Depending on patient size, two or three wires are placed in the body of the manubrium. The remaining wires are placed parasternally beginning at the second interspace. If an osteoporotic or fractured sternum is encountered, the wire-reinforced closure

suggested by Robicsek and associates48 is used (Fig. 10-18). This technique is also useful to help salvage a paramedian sternal split. Mersilene tape, steel bands, and large-gauge absorbable suture have all been successfully used to close sternotomy incisions. For patients with preoperative and operative risk factors for sternal wound complications,51,52 the interlocking figure-of-eight closure reported by DiMarco and associates46 needs to be considered. The incidence of mediastinitis after sternotomy is reported at 1% to 2%. Interestingly, sternal wound complications do predict a slight long-term survival disadvantage for patients after cardiac surgery.53 In addition to appropriate patient selection, intraoperative hemostasis, proper sternal closure, and early extubation are important factors preventing mediastinitis.51 Delayed chest wall complications of median sternotomy include costochondral separation, occult rib fracture, chronic osteomyelitis of the sternum, rib cartilage necrosis, sternal nonunion, and sternal wire erosion.54

Partial Sternotomy Partial sternotomy is a useful adjunct for a variety of incisions when additional exposure is necessary. It has been combined with a low, collar incision to facilitate tracheal reconstruction,28 with an oblique cervical incision for upper esophageal29 and great vessel exposure, with anterior thoracotomy (“hemiclamshell”), and with parallel supraclavicular and infraclavicular incisions (“open book” incision). Moreover, when extended in an intercostal space, partial (hemi-) sternotomy can serve as the principal incision for resection of mediastinal

127

128

Section 1 Introduction

FIGURE 10-18 Sternal closure as proposed by Robicsek. The transverse wires must be placed outside the parasternal weave. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 10-19 Skin incision and position of sternal division for a hemisternotomy. Soft tissue flaps are elevated to expose the upper sternum. The sternum is “T’d” off to the appropriate side. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

tumors, thymectomy, substernal goiter, or ectopic parathyroid adenoma. The patient is positioned supine as for a standard sternotomy. The neck is included in the drape. Flexion and extension of the neck is generally possible for tracheal cases. When used as the only incision, an 8- to 10-cm incision can be made beginning at the angle of Louis (Fig. 10-19). Soft tissue flaps are raised as previously described, and the sternum is exposed. A reciprocating saw divides the sternum to the chosen interspace (usually the third or fourth). Given the location of the mass, the saw is used to “T-off” one side of the sternum toward the mass. A small sternal spreader is used to distract the tissues. The internal mammary pedicle may be divided to improve exposure. Lung isolation is preferable. After the operation is completed, stainless steel wire is used to reapproximate the sternum. An anchoring wire is used to firmly fix the divided bone to the main body of the sternum at the base of the incision (Fig. 10-20). Suction drains can be placed under large subcutaneous flaps.

Thoracosternotomy (Clamshell) Incision The clamshell incision offers superior exposure of the heart, great vessels, mediastinum, and pulmonary hila. It has applications in the management of life-threatening traumatic injury, pulmonary metastastectomy,55 and bilateral sequential double-lung transplantation.56 Rarely, the incision has been used for coronary surgery.57 After a double-lumen endotracheal tube is placed, the patient is positioned supine on the operating table with both

FIGURE 10-20 Wire closure for the partial sternal split is similar to the standard closure with the exception of an inferior anchoring wire placed through the body of the undivided sternum. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Chapter 10 Thoracic Incisions

FIGURE 10-21 Patient position for thoracosternotomy (clamshell) incision. Alternatively, arms may be positioned laterally. (REPRINTED

FIGURE 10-22 Excellent exposure is obtained for anterior and middle mediastinal structures. (REPRINTED WITH THE PERMISSION OF THE

WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

CLEVELAND CLINIC FOUNDATION.)

arms either tucked or flexed at the elbows and extended (and suspended) over the face (Fig. 10-21). The patient may be elevated from the table by placement of a roll along the spine and parallel rolls across the scapulae and pelvis. This allows for better exposure should the incision need to be carried more posteriorly. The skin incision is identical to that used for the submammary exposure of the sternum (see Fig. 10-16). Bilateral anterior thoracotomies are performed as previously described; however, rib cartilage is not divided. The fourth interspace is the entrance into the thorax for most cases. Internal mammary pedicles are divided and oversewn. The sternum conjoining the two thoracotomies is divided with the Gigli saw after the retrosternal space is dissected bluntly. Bone wax may be applied to the cut ends of the sternum. Rib spreaders are placed bilaterally to open the incision (Fig. 10-22). Closure is time consuming. Attention to proper surgical technique is warranted, especially for lung transplant recipients because more than 10% of these patients develop wound complications.56 In addition to a sturdy thoracotomy closure, the sternum is reapproximated with two interrupted No. 6 stainless steel wires. Epidural analgesia usually permits early postoperative extubation.

ficulty to enter the thorax. The two most common lateral chest incisions are the “axillary thoracotomy” and the lateral “muscle-sparing” thoracotomy.

LATERAL CHEST INCISIONS The boundaries of the lateral chest stretch from the nipple anteriorly to the scapular tip posteriorly. Incisions contained within these arbitrary limits are classified as lateral chest incisions. Because there is a relative paucity of large muscles that span this area (pectoralis major lies anterior and latissimus dorsi lies posterior), most exposures in this location can be done using muscle-sparing techniques. The fibers of the serratus muscle, the only muscle in the space, run in a similar direction as the rib interspaces and can be split without dif-

Axillary Thoracotomy Because of the widespread use of VATS, no longer are sympathectomy,58 apical bullous disease,59 or cosmetic concerns60 considered indications for axillary thoracotomy. Instead, the incision is now largely considered a utility incision applicable if problems are encountered in VATS procedures. The transaxillary approach to first rib resection61 shares the same incision, although the dissection is carried much more superiorly. Classically, an axillary thoracotomy provides exposure through the axilla. The patient is placed in the lateral position on the operating table with the ipsilateral arm flexed and abducted 90 degrees (Fig. 10-23). A contralateral subaxillary roll is also placed. The entire hemithorax is included in the sterile field. If first rib resection is planned, the entire ipsilateral arm is included in the sterile preparation. A curvilinear incision is made at the base of the hairline from pectoralis major anteriorly to latissimus dorsi posteriorly. After subcutaneous fascia is divided, the axillary fat pad is bluntly dissected superiorly. With the pectoralis major retracted anteriorly and the latissimus dorsi posteriorly, the second intercostal interspace is identified by locating the intercostal brachial nerve. The third interspace is entered anteriorly to the long thoracic nerve by dividing intercostal muscle. The third rib may be resected for additional exposure. The long thoracic nerve is gently mobilized posteriorly to allow rib distraction and prevent nerve injury.62 The interspace can be opened widely under both pectoralis major and latissimus dorsi muscles to further improve access to the chest. Superior slips of the serratus anterior muscle may be encountered if the interspace

129

130

Section 1 Introduction

FIGURE 10-23 Patient position and location of the axillary thoracotomy incision. (REPRINTED WITH THE PERMISSION OF THE

FIGURE 10-24 Common locations of incisions used for lateral thoracotomy. Most of each incision is anterior to the latissimus dorsi allowing for easy posterior mobilization of the muscle. As incisions are placed more posteriorly, muscle-sparing approaches require greater mobilization of the latissimus muscle. (REPRINTED WITH THE

CLEVELAND CLINIC FOUNDATION.)

PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

is opened beneath the pectoralis major muscle. These slips can be divided with cautery. Exposure for first rib resection is discussed elsewhere. Closure entails rib reapproximation with heavy absorbable suture and repositioning of the axillary fat pad. The superficial fascia is closed over a suction drain in obese individuals to reduce the likelihood of axillary seroma.

Several variations of the lateral thoracotomy exist. Cosmetically, they differ only in the location of the skin incision (Fig. 10-24). Technically, all involve posterior mobilization and preservation of the latissimus dorsi muscle. Serratus anterior is usually divided in the direction of its fibers for more cephalad and anterior chest entry or mobilized anteriorly for lower and more posterior approaches. Functionally, there are slight differences in mediastinal exposure afforded by the various lateral approaches. Some argue that the more anterior approaches need to be avoided if extensive chest wall, posterior hilar, or posterior mediastinal pathology exists.67 The “French” incision67 is a cosmetic, muscle-sparing anterolateral thoracotomy. This approach provides excellent access for anatomic pulmonary resection. The patient is positioned laterally on the operating table and rotated slightly posteriorly. Either deflatable beanbag or cloth rolls can be used to fix the position. The axilla is opened as the arm is flexed and abducted 90 degrees. The sterile drape extends posteriorly to the spine to allow prompt extension of the thoracotomy if needed. The incision is made from the submammary crease (below the nipple) toward a point 1 to 2 cm below the scapular tip. Alternatively, the incision can be carried up toward the axilla in a “lazy-S” manner (see Fig. 10-24),68 although this incision is more difficult to extend if needed. The latissimus dorsi is carefully dissected off the

Lateral (Muscle-Sparing) Thoracotomy Muscle-sparing entry of the chest was initially greeted with enthusiasm. There were improvements in postoperative forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC),63 better shoulder function,64 and decreased pain7 compared with the standard muscle-dividing, posterolateral thoracotomy. In addition, involuntary muscular spasm was reported as a late complication of latissimus dorsi division during posterolateral thoracotomy.65 These reports have led some to recommend muscle-sparing lateral thoracotomy be used for routine anatomic pulmonary resection.5,6,66 Unfortunately, no controlled studies have documented faster recovery, or better long-term function, when comparing muscle-sparing and muscle-dividing techniques. In fact, Landreneau and colleagues64 concluded that the only advantage of muscle-sparing thoracotomy is preservation of chest wall musculature in the event that rotational muscle flaps would be needed (e.g., bronchopleural fistula closure).

Chapter 10 Thoracic Incisions

is placed between the legs. A skin incision is extended from the anterior axillary (or midaxillary) line to below the scapular tip. Soft tissue flaps are raised with cautery, and the latissimus dorsi muscle is fully mobilized. The serratus anterior muscle is usually elevated anteriorly without division. A closed-suction drain is tunneled subcutaneously at the conclusion of the procedure.

POSTERIOR INCISIONS Although some consider the classic posterolateral thoracotomy outdated, the utility of this incision cannot be underscored. One might argue that this incision has experienced a renaissance as larger, more complicated pulmonary and esophageal resections have become more common.69 Current indications include extrapleural pneumonectomy, superior sulcus tumors, tracheal surgery, and resection of advanced malignancy after induction therapy. Often, the serratus anterior can be spared during the thoracotomy, limiting postoperative disability. This is a common approach for single lung transplantation. The posterolateral thoracotomy can also be performed in a muscle-sparing manner.70 Because the latissimus dorsi is mobilized anteriorly, contrary to lateral thoracotomy approaches, the muscle is not stretched against the maximum convexity of the chest. This may result in less muscle stress and quicker recovery.70 FIGURE 10-25 Standard location of the posterolateral thoracotomy. The incision can be extended posteriorly (and superiorly) to the base of the neck and anteriorly (and inferiorly) to the costal margin. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

serratus anterior and mobilized posteriorly. The long thoracic neurovascular bundle is exposed on the serratus muscle as the latissimus dorsi is dissected. The serratus anterior is divided along its fibers over the chosen interspace (fourth or fifth), staying anterior to the nerve pedicle. The interspace is entered in the standard fashion, and intercostal muscles well beyond the confines of the skin incision can be divided to allow maximal spreading of ribs. A second retractor, placed perpendicular to the rib spreader, is used to distract the latissimus dorsi posteriorly. For closure, ribs are coapted in the standard fashion and the serratus muscle is repaired with absorbable monofilament or braided suture. The latissimus dorsi is repositioned anatomically, and the subcutaneous tissue and skin are closed with absorbable running sutures. If posterior mediastinal exposure is desired, the French incision may be inadequate. A more posterior incision, however, centers the latissimus dorsi in the operative field (see Fig. 10-24). Consequently, more lateral muscle-sparing approaches require that the latissimus be mobilized more completely. As expected, postoperative seroma complicates these approaches. For the lateral thoracotomy, the patient is placed in a lateral position and the ipsilateral arm positioned in front of the patient (see Fig. 10-24). The patient may be slightly elevated off the operating table and the table slightly flexed under the torso. This widens the ipsilateral interspaces. The dependent leg is slightly flexed at the hip and knee; a pillow

Posterolateral Thoracotomy The patient is placed in the same position as that described for lateral thoracotomy. The incision is started at the anterior axillary line and continued posteriorly for 2 to 3 cm below the scapular tip. The incision then follows the contour of the posterior border of the scapula superiorly along a line midway between the posterior border of the scapula and the spine (Fig. 10-25). The dissection is carried down to the latissimus muscle, which is divided with cautery. Vascular pedicles within the muscle are easily identified by their investing areolar tissue. The serratus muscle can often be spared. If this muscle is to be divided, division of the serratus slips close to rib insertions ensures that the majority of the muscle will remain innervated. If additional scapular mobility is necessary (e.g., superior sulcus tumor), trapezius and rhomboid muscles can be divided between the scapula and spine. Ribs are then counted posteriorly, and the appropriate interspace (fourth or fifth) is entered. For extended resections, it is often necessary to resect or “shingle” a rib to enhance exposure. For rib resection, the periosteum is first scored longitudinally along the rib. A periosteal elevator is used to reflect the periosteum off the anterior surface of the rib. Once the intercostal neurovascular bundle is separated from a portion of the underside of the rib, sharp elevators can be used to separate the remaining periosteum off the underside of the rib. The rib is then resected with shears, and the periosteum and pleura are opened to permit access into the pleural cavity. If the intercostal muscles are left attached to the vascular pedicle and periosteum, the resulting muscle flap can be used for tissue coverage (of a bronchial stump) providing the pedicle was harvested without injury to the vascular structures.

131

132

Section 1 Introduction

FIGURE 10-26 For the muscle-sparing posterolateral thoracotomy, the latissimus dorsi is disconnected from the thoracolumbar fascia with cautery (dashed line). (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

When a rib is resected, the closure becomes more complicated. Simply reapproximating the ribs above and below the resected rib bed leaves a defect in the chest wall through which the lung may herniate. This defect can be particularly troubling if a pneumonectomy has been performed because a subcutaneous seroma may result from extravasated pleural fluid. To prevent this complication, slips of serratus muscle can be used to buttress the defect.

FIGURE 10-27 After complete mobilization, both latissimus and serratus muscles can be moved anteriorly and spared. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

muscle (Fig. 10-27). After the serratus is moved anteriorly under the latissimus, the interspace is approached and opened.

Muscle-Sparing Posterolateral Thoracotomy To spare the latissimus dorsi from a posterolateral approach requires extensive anterior mobilization of the muscle. This is achieved by disconnecting the latissimus muscle posteriorly from the thoracolumbar fascia (Fig. 10-26). This incision is used for the majority of our pulmonary resections. It offers excellent posterior exposure for complicated hilar dissections and lymphadenectomy. Limited postoperative disability has been encountered with this approach. After standard posterolateral incision, subcutaneous flaps are raised over the latissimus dorsi superiorly and inferiorly. The plane between the latissimus and trapezius muscles is developed with cautery. The posterior aspect of the latissimus muscle is then freed from the thoracolumbar fascia with cautery. After this maneuver, the latissimus dorsi can be reflected anteriorly several centimeters, exposing the serratus

Posterior Thoracotomy Before the development of lung isolation, pneumonectomy for suppurative disease was often performed from a posterior approach. This permitted early division of the bronchus and lung collapse. With the bronchus controlled, purulent secretions would not escape from the ipsilateral lung and contaminate the other side. Few indications remain for this approach. The patient is placed in a prone position on a specially designed table that allows anterior access to the chest if necessary (Fig. 10-28). An incision is extended from the anterior axillary line to the base of the neck, midway between the posterior edge of the scapula and the spine. Rhomboid, trapezius, latissimus, and serratus muscles are divided. The selected interspace may then be entered.

Chapter 10 Thoracic Incisions

FIGURE 10-28 Location of the posterior thoracotomy incision. With the patient placed prone on the operating table, the posterior thoracotomy incision begins at the base of the neck and is carried inferiorly and anteriorly. The scapula is disconnected from trapezius, rhomboid, and teres muscle groups. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 10-30 Through the left thoracoabdominal approach, superior exposure to the posterior mediastinum and gastroesophageal junction is obtained. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 10-29 Incision for thoracoabdominal approach. The patient’s hips are rotated back 45 degrees to facilitate the abdominal dissection. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Thoracoabdominal Incision The thoracoabdominal incision permits simultaneous dissection in pleural and abdominal cavities. The left-sided approach is particularly attractive for esophageal surgeons. This exposure facilitates esophageal, gastric, splenic, and retroperitoneal surgeries. The closure can be formidable and time consuming. Postoperative recovery has been greatly improved because of epidural analgesia. Left lung isolation is necessary. The patient is placed in a lateral position with the hips rotated back toward the operating table by 10 to 20 degrees (Figs. 10-29 and 10-30). The sterile field includes the left arm and neck if a cervical esophagogastric anastomosis is anticipated. In cases of esophageal malignancy, the abdominal portion of the incision is made first to determine operability. An oblique incision from the midline to the left costal margin is utilized. If manual exploration of the abdominal cavity is unremarkable, the incision is

continued obliquely across the costal margin and extended upward as a posterolateral thoracotomy incision. Latissimus and serratus muscles are divided, and the chest is entered in either the sixth or seventh interspace. The costal margin is cut sharply. A short segment of rib cartilage is not routinely resected as advocated by others (Heitmiller, 1988).71 The exposure is completed by division of the diaphragm. Although the diaphragm can be incised circumferentially, a radial incision can be made if anterior branches of the phrenic nerve are identified and carefully avoided. The closure must not be underestimated and assumed to simply be the end of a long procedure but rather considered as an entire operation on its own. The diaphragm is reconstructed with nonabsorbable suture, and the paracostal sutures are spaced by 2 to 3 cm. The costal margin is repaired with a heavy, absorbable, figure-of-eight suture. This suture is passed through the diaphragm to buttress the costal margin and prevent herniation. Each muscle layer is carefully closed with running absorbable suture. Superficial tissues are closed in the standard fashion. Understanding that improper closure of this incision can serve as a source of important morbidity is critical.

VIDEO-ASSISTED THORACIC SURGERY The cylindrical geometry of the hemithoraces makes port placement for thorascopy more challenging than for laparoscopy. It is advantageous to position all operating ports within the same 180-degree arc as the primacy viewing port

133

134

Section 1 Introduction

FIGURE 10-31 Placement of thoracoports for video-assisted thoracic surgery. Ports are placed within the same 180-degree arc as the camera. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC

FIGURE 10-32 Incision for video-assisted lobectomy. The utility incision is positioned over the hilum. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FOUNDATION.)

(Fig. 10-31). This decreases the time operating against the camera (i.e., on the mirror image). As experience has been accrued, more advanced resections are being attempted thoracoscopically. Specifically, VATS lobectomy is rapidly gaining popularity (Demmy et al, 2005)72 and has been shown to be a reasonable alternative to “open” lobectomy but with less morbidity and expedited patient recovery.73 The locations of incisions used for VATS lobectomy will vary according to surgeon preference, although most will be some variation of the setup presented in Figure 10-32. Critical components include an inferoanterior axillary line port (the primary viewing port), an inferoposterior axillary line port (for retraction and stapler access), and an anterolateral utility incision (usually at approximately the fourth interspace) for dissection of the hilum. An additional port may be placed posteriorly, directly below the scapular tip, to facilitate a subcarinal lymph node dissection. The utility incision is usually only large enough to permit the specimen to be delivered and is generally 6 to 8 cm in length. For true VATS cases, rib distraction is not performed.

SUMMARY Since the times of Hippocrates, surgeons have been incising the chest with curative intent. As knowledge has been accumulated and techniques refined, the thoracic surgeon is now armed with a vast array of incisions from which to choose.

The difficulty lies in choosing the right one. To this end, careful consideration of the goals of the operation and individual patient characteristics must be kept in mind before laying scalpel to skin.

COMMENTS AND CONTROVERSIES The selection of the surgical incision is the responsibility of the surgeon who needs the best possible exposure to complete the proposed operation. In the case of pulmonary resection, for instance, the incision must provide exposure of the hilum so that mobilization of pulmonary vessels can be done safely or a proposed lobectomy can be converted to a pneumonectomy should circumstances dictate. Indeed, a poorly planned incision is likely to lead to a difficult and frustrating operation, increasing the chances of technical misadventures. The selection of the surgical incision also is based on the surgeon’s experience and familiarity with the exposure that a particular incision provides. For example, anatomic pulmonary resection through a midline sternotomy incision can be safely performed, but for the surgeon unfamiliar with the anatomy seen from the front, this can turn out to be a nightmare. Finally, the incision must be acceptable to the patient, who will have postoperative pain or may suffer from long-term muscular, neurologic, or even cosmetic disabilities. As discussed by Dr. Murthy, a clear understanding of proper positioning of the patient is also important if one is to achieve maximum use of the incision. A recent radiograph must also be available in the operating room to ensure that the patient is positioned on the proper side. Although the surgeon does not neces-

Chapter 10 Thoracic Incisions

sarily have to be in the operating room while the patient is being positioned, it is important that the personnel who actually position the patient be familiar with the technique. Fortunately, there are few complications related to thoracic incisions and most can be prevented. Wound infection, for instance, is rare; and when it occurs one must always suspect that the problem is related to an undiagnosed empyema draining spontaneously through the wound. Wound seromas are common with musclesparing incisions, but most can be avoided by preventing dead spaces and using soft drains. Rib fractures need to be avoided because they create wound instability, which increases the amount of pain and makes effective coughing more difficult. Preventive measures include a skin incision properly placed and entrance in the pleural cavity through the appropriate intercostal space. Other prophylactic measures include gradual (rather than forceful) spreading of the intercostal space and, in some cases, resection of a 1-cm segment of the lower rib (posteriorly). J. D.

KEY REFERENCES Dartevelle FG, Chapelier AR, Macchiarini P, et al: Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet. J Thorac Cardiovasc Surg 105:1025, 1993. Demmy TL, James TA, Swanson SJ, et al: Troubleshooting videoassisted thoracic surgery lobectomy. Ann Thorac Surg 79:1744, 2005. Hankins JR, Satterfield JR, Aisner J, et al: Pericardial window for malignant pericardial effusion. Ann Thorac Surg 30:465, 1980. Heitmiller RF: The left thoracoabdominal incision. Ann Thorac Surg 46:250, 1988. Kittle CF: Which way in? The thoracotomy incision. Ann Thorac Surg 45:234, 1988. Lubenow TR, Faber LP, McCarthy RJ, et al: Post-thoracotomy pain management using continuous epidural analgesia in 1324 patients. Ann Thorac Surg 58:924, 1994. Robicsek F, Daugherty HK, Cook JW: The prevention and treatment of sternum separation following open-heart surgery. J Thorac Cardiovasc Surg 73:267, 1977.

135

chapter

11

PRINCIPLES OF POSTOPERATIVE CARE Humberto Lara-Guerra Thomas K. Waddell

Key Points ■ Monitoring ■ ■ ■ ■

must be appropriate to the patient and the procedure. Maintenance of homeostasis includes temperature, fluid balance, and oxygen saturation. Pain control is important. Early return of nutrition and mobility are postoperative goals. Prevention of specific complications includes respiratory and cardiovascular complications, as well as venous thromboembolism.

Excellent surgical, anesthetic, physiotherapeutic, and nursing care are all required for optimal postoperative results after any thoracic surgical procedure. Each of these teams involved in patient care is important to reach the general goals of the postoperative period: 1. Recovery from both the specific physiologic changes and the general inflammatory response due to the surgical procedure 2. Decreased pain, early mobilization, and prompt return to normal function 3. Prevention and early detection of complications Physicians involved in the patient’s preoperative care and assessment must carefully assess the risks and benefits of surgery. The balance of risks and benefits plays an important role in the selection of appropriate candidates for surgical resection. Preoperative assessment is specifically discussed in Chapter 2, but it is important to state here that excellent postoperative care begins with seasoned judgment regarding risk assessment. Overall perioperative mortality of thoracic surgical procedures ranges from less than 1% for low-risk lobectomy to 10% for high-risk esophagectomy. This mortality is mainly caused by major respiratory complications, such as atelectasis, pneumonia, and respiratory failure, which can occur in up to 15% to 20% of these patients.1 Cardiac complications occur in 10% to 15%.2 Specific respiratory evaluation of both mechanics and gas exchange, as well as other special considerations, must be performed in addition to standard preoperative assessments.3 This chapter discusses the general postoperative care of patients undergoing major thoracic procedures. Additional considerations regarding specific operations may be found in their respective chapters.

PREOPERATIVE PREPARATION Optimal postoperative care requires active cooperation and compliance of the patient. Preoperative education and orien-

tation are important as background.4 In particular, smoking cessation is highly encouraged, although the duration of smoking cessation to ensure decreased complications is controversial. The patient and family need to be prepared for hospital procedures and advised of potential complications and their warning signs. In particular, the use of various pain control techniques controlled by the patient must be clarified. Similarly, the medications taken by the patient need to be reviewed by the nursing staff and brought to the hospital by the patient at the time of admission. Most hospitals have preadmission clinics to meet these goals in a cost-effective manner. Development of written patient education material is also very important, and such material can be translated into other languages as required. The role of preoperative pulmonary rehabilitation is more controversial. Certainly for high-risk individuals, a brief period of smoking cessation, optimization of bronchodilators, chest physiotherapy, and supervised exercise may demonstrate changes in objective pulmonary function. This is definitely advisable for truly elective operations such as lung volume reduction surgery; however, it must be balanced against a risk of progression in patients with malignancy if surgical treatment is delayed.

MONITORING In patients who require large-volume fluid resuscitation, undergo prolonged anesthesia, or have hemodynamic instability, myocardial ischemia, or potential problematic lung reexpansion due to a reduction in pulmonary compliance, a short period of elective postoperative mechanical ventilation may provide a margin of safety. Detailed discussion of critical care medicine is beyond the scope of this chapter, however, and the remaining sections describe postoperative care of the non–mechanically ventilated patient. All patients who have undergone a major thoracic procedure must be cared for on a specialized postsurgical care unit until they are stabilized. There is tremendous variability in practice regarding intensive care unit (ICU), step-down, or ward monitoring of such patients. However, it is clear that optimal results emerge from units with significant experience. Our practice is to use a step-down unit with 1 : 2 nurseto-patient ratio for all patients immediately after surgery unless postoperative ventilation is required. Patients who have undergone pulmonary resection usually transfer to the ward on the first postoperative day, whereas esophagectomy patients usually spend 48 hours with this level of monitoring. Monitoring of respiratory rate, heart rhythm, systemic blood pressure, body temperature, urine output, and pulse

136

Ch011-F06861.indd 136

1/21/2008 10:43:50 AM

Chapter 11 Principles of Postoperative Care

oximetry is advisable during both critical care and hospital ward periods. In the thoracic step-down unit at Toronto General Hospital, these parameters are monitored continuously; on the ward, they are measured intermittently, no less than every 8 hours. Some patients may need more invasive monitoring approaches, depending on their physiology and medical condition (Table 11-1). Measurement and calculation of fluid balance, routine on most surgical wards, is very important in thoracic surgical care. Similarly, daily weight measurement is extremely helpful, although considerable attention must be given to nursing education to ensure reliable results. Wide swings in weight are often the result of variation in patient’s level of dress, use of different scales, or incorrect tare (zeroing) procedures. After a general thoracic surgical procedure, cardiorespiratory monitoring is essential; this is particularly important during the initial few postoperative days because the majority of both cardiac (e.g., arrhythmias) and respiratory (e.g., respiratory failure) complications occur during this period. Atrial fibrillation and supraventricular tachycardia are the most common cardiac arrhythmias. In addition, approximately 3% of patients undergoing noncardiac surgery suffer a myocardial infarction.5 The majority of myocardial infarctions occur during the first 3 days after surgery.6 During this period, symptoms of myocardial infarction may be more difficult to recognize due to analgesic effects, intubation, or other complications with similar symptoms. Clinically unrecognized myocardial infarction in the perioperative setting is not uncommon. Among noncardiac surgical patients who develop myocardial infarction, half present with signs or symptoms suspicious for myocardial infarction, but only 14% complain of chest pain.5 Diagnosis of perioperative arrhythmias and myocardial infarction in patients undergoing noncardiac surgery is not standardized. Our practice is to use continuous monitoring in the step-down unit, although telemetry can be obtained on ward patients who are at high risk, have suggestive symptoms, or have arrhythmias in the step-down unit. Daily electrocardiograms (ECGs) are obtained in high-risk patients, but troponin levels are monitored only in response to specific concerns. Oxygen saturation can be measured via invasive or noninvasive approaches. Pulse oximetry, a popular noninvasive approach, detects variations in arterial blood oxygen saturation by estimating the difference in absorption of light

137

between oxygenated and deoxygenated blood in the red region of the spectrum. However, because this approach depends on the detection of an arterial pulse, patients with physiologic, pharmacologic, or pathologic alterations of peripheral circulation may have inaccurate pulse oximetry readings. Patients with elevated carboxyhemoglobin concentrations have falsely elevated saturation readings as well because carboxyhemoglobin absorbs light at the same wavelength as oxygenated hemoglobin. Obtain arterial blood gas measurements initially after surgery to assess postoperative ventilatory status via carbon dioxide partial pressure (PaCO2), particularly in patients requiring ventilatory support, in order to establish baseline values. After initial PaCO2 measurement, blood oxygen saturation can be monitored by pulse oximetry. In the critically ill, another option is intravascular electrodes, which have been used to provide continuous measurements of oxygen partial pressure (PO2) and PaCO2. Excessive analgesia, inadequate reversal of anesthesia, and carbon dioxide retention can cause hypoventilation and further PaCO2 elevation. For high-risk patients, preoperative assessment of PaCO2 is helpful to identify those with carbon dioxide retention and hypoxemic respiratory drive. In these patients, an intra-arterial catheter, placed in the operating room, is left in place for several days to monitor trends in PaCO2. Standard postoperative blood tests include complete blood count, serum electrolytes including calcium and magnesium, glucose concentration, and renal function tests. These are probably required only for the first 1 or 2 days after routine surgery. More complex procedures, such as esophagectomy and lung volume reduction, require more prolonged monitoring of blood tests. Chest radiographs are part of the standard routine for most thoracic surgical units. The value of obtaining them on a daily basis has been questioned.7 Examination in the recovery room and after any significant change in pleural drainage is probably warranted.

MAINTENANCE OF NORMOTHERMIA Maintenance of normothermia during surgical procedures is important. If no additional active warming techniques are used, patients can develop hypothermia because of multiple factors, including exposure, evaporative loss, and peripheral

TABLE 11-1 Types and Indications for Advanced Monitoring Approaches During the Postoperative Period Device

Indications

Positioning

Arterial catheterization

Constant blood pressure monitoring Ventilatory support Inotropic support

Radial artery

Central venous catheter

When central venous pressure as a measurement of volume status is necessary in patients without valvular disease or pulmonary hypertension

Subclavian vein, internal jugular vein

Pulmonary artery catheter

Patients with inaccurate central venous pressure measurement or necessity of monitoring cardiac output

Via central venous catheter

Esophageal Doppler monitor

Cardiac output, stroke volume, flow time; more accurate than pulmonary artery catheter in patients with valvular lesion, septal defect, or pulmonary hypertension

Esophagus

Ch011-F06861.indd 137

1/21/2008 10:43:50 AM

138

Section 1 Introduction

vasodilation caused by general anesthesia. Hypothermia has various impacts, including metabolic, cardiovascular, endocrine, renal, hematologic, gastrointestinal, immunologic, neurologic, and pharmacologic effects. It contributes to coagulopathy, hypovolemia, insulin resistance, electrolyte imbalances, and increased risk of surgical site infection.8-10 It activates the sympathetic nervous system, leading to myocardial ischemia10,11 and increased risk of death.12 To keep patients warm, warming systems are used routinely, and ambient temperature can be rapidly adjusted in most modern operating rooms. Infused fluids can be warmed by dry heat, a water bath, or countercurrent heat exchange. However, the efficiency of fluid warming systems in maintaining normothermia depends on the speed of fluid infused, which makes air-flow systems more advantageous. Several models of forced-air warming systems exist; they effectively prevent hypothermia, even when limited skin surface is available.13,14 Forced-air warming systems can increase skin temperature by up to 2ºC, improve thermal comfort, diminish oxygen consumption, and reduce the intensity but not the duration of shivering.15 Evidence is not available for thoracic surgery, but the only randomized trial of perioperative warming suggested that cardiac events occurred less frequently in the normothermic group (1.4% versus 6.3%; P = .02). This study examined 300 patients undergoing major abdominal or vascular surgery and found that hypothermia was a risk factor for cardiac events (relative risk, 2.2; 95% confidence interval, 1.1-4.7).16 Measuring and maintaining body temperature is an essential part of postoperative care as well. Hypothermia is less problematic because patients can be more completely covered and fluid intake is decreased. Hyperthermia is also common in the postoperative setting and can result in an increased metabolic rate and increased insensible fluid losses. Most fevers in the immediate postoperative setting are inflammatory in nature. Hyperthermia that persists beyond the third postoperative day is suspicious for infection and calls for further evaluation. Mild hyperthermia is tolerable, but significant temperature elevation must be treated with topical cooling and pharmacologic measures.

INTRAVENOUS FLUIDS The goals of intravenous (IV) fluid replacement are to correct deficits, to cover basal requirements, and to replace ongoing abnormal losses. Intraoperative fluid management has recently been reviewed.17 Pulmonary, thymic, or benign esophageal surgery is not associated with large postoperative fluid shifts, but losses after esophageal, chest wall, or spinal resection procedures can be substantial. Lung manipulation and collapse may impair pulmonary lymphatic drainage and increase extravascular lung water due to disruption of the alveolarcapillary membrane. Because of this, patients undergoing pulmonary resections should not receive excessive fluid replacement, and standard fluid management used in other types of surgical patients needs to be moderated. Excessive fluids can result in pulmonary edema, decreased alveolar gas permeability, decreased pulmonary compliance, atelectasis, and hypoxia. On the other hand, esophagectomy patients in

Ch011-F06861.indd 138

particular may require large amounts of perioperative fluid, due to large third-space accumulation. An adult should receive not less than 1000 mL of fluids per day. If there are no previous deficits or current complications, the typical amount of liquid ingested by an adult is 2 to 3.5 L/day. Two liters per day should maintain an adequate diuretic range (1000 mL) and cover requirements for Na+, K+, and Cl− (70, 40, and 70 mEq, respectively). The minimal diuresis expected in a patient with normal renal function is 0.5 mL/kg/hr. It is necessary to remember that, in patients with renal failure and in those who have had large blood losses or fluid resuscitation, close monitoring of serum electrolytes (including Ca2+ and Mg2+), blood urea nitrogen, and creatinine is recommended. In special circumstances, such as after pneumonectomy or lung volume reduction surgery, more extreme fluid restriction (<1.5 L) may be advised. Attention needs to be given to how much fluid is provided with medications. Urine output and serum creatinine must be monitored very carefully, and medications need to be reviewed to reduce or eliminate other nephrotoxins, such as nonsteroidal anti-inflammatory agents (NSAIDs) or angiotensinconverting enzyme inhibitors.

POSTOPERATIVE NUTRITION For patients who have been fasting or may require fasting for more than 7 days (less in patients with nutritional deficiencies), nutritional support also must be considered. Enteral support may be started in the first 12 hours after surgery, but hemodynamic stability must be achieved first, to avoid intestinal ischemia.18 Most patients tolerate inadequate postoperative nutrition for a week, so the routine use of parenteral nutrition in thoracic surgical patients is uncommon. In esophageal resections, jejunal feeding tubes are commonly inserted and can be used almost immediately. IV nutrition is rarely required in routine general thoracic surgery and is outside the scope of the current chapter. Enteral nutrition supplemented with L-arginine, ribonucleic acids, and ω-3 fatty acids (immunonutrition) has been shown to improve perioperative immune suppression and reduce postoperative complications but is not in widespread clinical use.19 An often overlooked issue is the early use of laxatives and stool softeners. Constipation is a common cause of readmission to hospital. Reduction in narcotics as tolerated, adequate oral hydration, and early ambulation all help.

RESPIRATORY CARE The published evidence regarding all interventions thought to affect postoperative complications was recently reviewed for noncardiothoracic surgical patients (Lawrence et al, 2006).20 Although the evidence base applies to a different group of patients, the principles are sound and need to be applied to general thoracic surgical patients as well (Box 11-1). Incentive spirometry is standard, and training with the device begins in the preadmission clinic. Oxygen is administered as needed during the postoperative period. However, do not forget that chest physiotherapy has been demonstrated to be effective in preventing postoperative pulmonary

1/21/2008 10:43:50 AM

Chapter 11 Principles of Postoperative Care

Box 11-1 Respiratory Care Preoperative preparation Cessation of smoking Bronchodilators Steroids Rehabilitation Incentive spirometry Chest physiotherapy Titrated oxygen Bronchodilators Steroids Bronchoscopy

complications and is considered routine postoperative care for patients undergoing thoracotomy.21 It has been shown to be highly cost-effective.22 Many patients with hypoxemia benefit more from physiotherapy to increase functional residual capacity than from further increases in the fraction of inspired oxygen (FIO2). If necessary, supplemental oxygen is administered by nasal cannulae, with the lowest flow possible to sustain oxygenation saturation greater than 92%. Excessive oxygen administration has potential drawbacks despite the short-term margin of safety it can provide. Increased alveolar oxygen tension promotes atelectasis as the oxygen is rapidly absorbed. Drying of secretions, even by humidified gases, can increase difficulty with coughing and clearance of mucus. Nasal cannulae allow natural humidification of inhaled gas when flow rates are minimal to moderate. If higher levels are required, face mask administration of humidified oxygen is appropriate. Short-term supplemental oxygen (FIO2 0.8 for 2 hours postoperatively) prevents cardiac stress and increases the arterial and subcutaneous partial pressure of oxygen, which is important in preventing wound infections,23,24 without modifying the incidence of atelectasis.25 Patients with chronic obstructive pulmonary disease (COPD) may have chronic carbon dioxide retention and a hypoxic respiratory drive. Removal of their chronic hypoxemia can lead to respiratory depression and progressive carbon dioxide retention, with subsequent respiratory acidosis. Therefore, in patients who have an elevated PaCO2 preoperatively, oxygen saturation is maintained at 90% or less, preserving the hypoxic drive to breathe. Early application of continuous positive airway pressure (CPAP) may prevent the need for intubation and mechanical ventilation in patients with hypoxemia by reducing atelectasis and, therefore, improving oxygenation. In non-COPD patients without a history of respiratory imbalance who underwent major abdominal surgery and developed hypoxemia during the initial first postoperative hour, CPAP at 7.5 cm H2O for 6 hours, in addition to the standard oxygen treatment, lowered the intubation rate within the first week after surgery.26 The rate of infectious complications and the number of days spent in the ICU were also decreased. Pulmonary morbidity and length of stay can be reduced by CPAP after thoracic aortic surgery, but similar trials have not been performed after general thoracic surgery.27 We have limited experience with noninvasive ventilation or CPAP.

Ch011-F06861.indd 139

139

We have little experience with preemptive tracheostomy or minitracheostomy but liberally use bronchoscopy and have a small bronchoscopy suite available on the thoracic surgery ward 24 hours/day. Patients can be cleared of secretions daily if their cough is ineffective.

DRAINAGE OF THE PLEURAL CAVITY The goal of a pleural drainage is to evacuate the accumulated substance (e.g., liquid, air) and to promote pulmonary reexpansion. Pleural drainage systems are evaluated regularly for drainage and air leakage. Respiratory and water seal movements are synchronous. If the column of water does not move with the respiratory movements, an obstruction in the system must be sought. The external tube system must be examined first, looking for inadvertent clamping and external obstructions. The chest tube may be disconnected and the distal drainage tubing irrigated or replaced to correct obstructions from purulent material, blood, or fibrin organized in the chest tube lumen. All staff keep the system empty of fluid whenever possible, including so-called milking or stripping of the tubes (squeezing soft tubing together to occlude and then pulling distally a short distance) if necessary. Bubbling in the drainage system indicates the presence of an air leak, but leaks in the system must first be ruled out. Clamping of the chest tube immediately after it leaves the chest cavity causes the bubbling to stop if the leak is in the system itself. The leak site can be found by sequential clamping along the drainage system. Bubbling disappears once the clamp is positioned distal to the leak. Chest tubes are removed once there is minimal drainage (<200 mL/24 hr), the air leak has stopped, and the lung is judged to be completely expanded by auscultation and chest radiographic evaluation. The chest tube must be removed quickly during a Valsalva maneuver at the end of expiration. The wound borders are brought together, and a wound dressing is applied. We routinely use a preplaced U stitch to approximate the wound edges. A chest radiograph must be obtained during the next 3 hours to evaluate for adequate pulmonary re-expansion. A few special considerations with respect to chest drainage after pneumonectomy are discussed here. Traditional water seal devices allow egress of air out from the pleural cavity but not for its return. This can lead to progressive mediastinal shift after pneumonectomy. There are several possible solutions. A chest drain need not be left at all. The mediastinum can be balanced by removing a few hundred milliliters of air as the thoracotomy is being closed, by means of a red rubber catheter. As well, a needle thoracentesis can be performed in the recovery room after the postoperative chest radiograph is reviewed. If bleeding is sufficiently worrisome as to require drainage, a balanced pneumonectomy chest drainage system is available; this device allows air both in and out, to keep the pleural space within a preset range. Alternatively, a traditional system may be used but clamped and only intermittently opened, although this approach is vulnerable to missteps by inexperienced staff. Traditional approaches have suggested that suction be applied to chest drains to maximize pleural apposition.

1/21/2008 10:43:51 AM

140

Section 1 Introduction

However, in patients with significant emphysema, especially when pleural apposition is not realistically achievable, such an approach merely serves to prolong the air leak. Cerfolio’s group has convincingly demonstrated more rapid resolution of air leak when water seal drainage is used, provided that the lung remains well expanded.28 Our current approach is to use the minimal amount of suction to allow full expansion of the lung, beginning with −20 cm H2O but decreasing as soon as possible to no suction at all. There are several possible approaches to management of a prolonged air leak. As mentioned earlier, if pleural apposition is not judged to be achievable, minimal or no suction and patience are important. Indeed, Heimlich valves can be used to discharge patients who still have a minimal air leak without any other medical complication and who live close to a medical center. If this approach is not feasible, reoperation may be required. We have not found identification or correction of an air leak at thoracoscopy to be particularly easy, and thoracotomy is often required. If pleural apposition is achievable in the face of an ongoing air leak, a computed tomographic (CT) scan is often helpful to indicate remaining pockets where intrapleural air is preventing the lung from touching the ribs. This can guide placement of additional chest drains, including soft pigtail catheters. Once full pleural apposition is achieved, the air leak may immediately cease. If not, pleurodesis may be achieved by instillation of agents to inflame the pleura, such as doxycycline, the patient’s own blood (IV drawn), or talc. Finally, if the leak persists for more than 10 days, or perhaps earlier depending on the degree of intraoperative irritation of the pleura (e.g., at repeat thoracotomy), the suction can be gradually reduced with radiographic monitoring of the chest. If the lung remains inflated, the chest tube can be converted to water seal and even subsequently clamped, despite an ongoing air leak. Occasionally, a loculated pneumothorax results, but, as long as it is stable over several days, the patient may be discharged, and the space usually resolves gradually over the next few weeks.

MEDICATIONS With most medications, patients can and should resume their preoperative regimens as soon as possible. After pulmonary resection, most patients resume oral intake the same day and can certainly eat the following morning. It is our practice to use jejunal feeding tubes after esophageal or other major gastrointestinal resections, so most medications can be delivered enterally. For other medications, IV formulations may be substituted (e.g., steroids, antihypertensives) or other alternatives employed (e.g., nitroglycerin patch, sublingual anxiolytics). Although prophylactic antibiotics can diminish the risk of infection, their use is limited based on available evidence (Bratzler and Houck, 2005).29 Endocarditis prophylaxis guidelines must not be overlooked.30 Prophylactic antibiotics must be started before the surgical procedure, and they should not be administered for longer than 48 hours (Table 11-2). The usual prophylactic antibiotic used at our institution is IV cefazolin to cover skin flora. It is our practice to

Ch011-F06861.indd 140

TABLE 11-2 Principles of Antimicrobial Prophylaxis Timing

Infusion of the first dose should begin within 60 min before the surgical incision.

Duration

Prophylactic antimicrobials should be discontinued within 24 hr after the end of surgery.

Screening for βlactam allergy

Where cephalosporins represent the most appropriate antimicrobials for prophylaxis, the medical history should be adequate to determine whether the patient has a history of allergy or serious adverse antibiotic reaction.

Dose

The initial antimicrobial dose should be adequate based on the patient’s body weight, adjusted dosing weight, or body mass index. An additional antimicrobial dose should be provided intraoperatively if the operation is still continuing 2 half-lives after the initial dose.

Drug of choice

Cefazolin or cefuroxime is recommended for thoracic surgery.

continue antibiotics only for 24 hours, despite chest tubes remaining in place. Glucose levels must be monitored closely and treated in the postoperative period in both diabetic patients and those with newly elevated blood glucose levels. High blood levels have negative effects on the metabolic state, the immune system, and wound healing. In cardiac surgery patients, tight postoperative glycemic control has been shown to reduce the incidence of wound infections.31,32 Insulin can be used for uncontrolled postoperative elevated glucose levels. In fact, use of intensive IV insulin infusions to maintain postoperative blood glucose levels lower than 200 mg/dL reduces the incidence of mediastinitis by 66%31-33 and decreases mortality.34 Patients with hyperthyroidism, including subclinical hyperthyroidism, are at higher risk for development of tachycardia and atrial fibrillation during the postoperative period. Even without surgery, a low serum thyrotropin concentration is associated with more than fivefold greater likelihood of atrial fibrillation, without differences between subclinical and overt hyperthyroidism.35 In addition, patients with hyperthyroidism can present with a wide pulse pressure, increased cardiac output, increased left ventricular mass, and reduction in peripheral vascular resistance and can develop congestive heart failure.36 Therefore, it is important to maintain these patients in the euthyroid state and to control manifestations with β-blockers. Patients with hypothyroidism can develop bradycardia, systemic hypertension, narrow pulse pressure, reduced cardiac output, angina, and an abnormal ECG and are at risk for other postoperative cardiac events, such as ventricular arrythmias.36,37 Patients who are currently taking thyroid hormone replacements should restart them as soon as oral intake is re-established. Patients with preexisting peptic ulcer disease require resumption of their previous medications. However, in routine postoperative use, the majority of recently published

1/21/2008 10:43:51 AM

Chapter 11 Principles of Postoperative Care

prospective studies and a meta-analysis have been unable to demonstrate a reduction in clinically important bleeding due to stress ulcers with pharmacologic agents.38 Critically ill patients requiring ventilatory support often undergo stress ulcer prophylaxis, most commonly with histamine receptor 2 (H2) blockers, although the choice of drug for individual patients remains controversial.39

PAIN CONTROL Pain and the immobility it causes result in decreased cough and clearance of secretions and lead to an inability to recruit alveoli. Atelectasis and hypoxemia develop, and susceptibility to pneumonia increases. Adequate pain control after thoracotomy improves lung function.40 It also improves oxygenation and diminishes pulmonary complications.41 In addition, adequate pain control has been related to a reduction in the frequency of supraventricular arrhythmias.42 Pain is influenced by several factors which determine the final quality of analgesia obtained (Gottschalk et al, 2006).43 However, it must also be stated that overall results of surgery are affected by other factors, such as avoidance of undue sedation to ensure good cough, adequate blood pressure to ensure adequate tissue perfusion pressure at healing anastomoses, and quick return of normal bowel function. Therefore, surgical and anesthetic teams need to work closely together to ensure that postoperative pain is optimally controlled while keeping other goals also in mind. The standard of care in controlling pain after thoracic surgical procedures includes placement of an epidural catheter in the operating room to provide preemptive analgesia and adequate pain control immediately after the operation. Pain is controlled usually by a combination of local analgesics (bupivacaine, ropivacaine) and opiates (fentanyl, hydromorphone), blocking the specific opiate receptors on the dorsal columns of the spinal cord. Adding epinephrine recently has been reported to improve pain control.44,45 The usual infusion is 4 to 6 mL/hr, with boluses of 2 to 4 mL every 10 minutes, as controlled by the patient. Epidural catheters are accompanied by urinary catheter insertion for fluid balance monitoring and bladder weakness, but recently this approach has generated controversy. It is probably feasible to remove urinary catheters once patients are stabilized from a fluid balance point of view and walking, especially in women. Epidural analgesia is generally maintained until chest tubes are removed. Possible complications of epidural analgesia that are monitored include epidural hematoma, respiratory depression, and hypotension. An adequate epidural catheter allows excellent analgesia without impairment of motor function. Motor weakness immediately triggers concern for hematoma. Motor weakness should respond to discontinuation of the infusion, as should hypotension. Respiratory depression can often be improved by removing the narcotic completely from the infusion. With the recent development of video-assisted thoracic procedures as well as new analgesic approaches, epidural analgesia may become less necessary, but it still must be considered, particularly in patients who are at risk of pulmonary dysfunction.

Ch011-F06861.indd 141

141

Local anesthesia, combined with some IV narcotic, is also an acceptable option for pain control by a variety of routes of administration. Paravertebral thoracic catheter infusion of lidocaine to cover two dermatomes above and below the incision is an acceptable alternative to epidural analgesia when supplemented with patient-controlled IV narcotic administration.46 For minor surgical procedures or videoassisted thoracic surgery (VATS), or if coagulopathy is a concern, intercostal blockade with longer-acting bupivacaine, with adrenalin to delay absorption, is another option.47,48 IV administration of opioid compounds, either hourly or by patient-controlled analgesia (PCA), provides an acceptable minimum level of comfort. Continuous IV infusion of tramadol is another option, although we have no experience with this approach.49 Oral narcotics, such as oxycodone or codeine, are usually required after withdrawal of epidural or IV administration. These are usually required after discharge from hospital as well, for a few days to a few weeks, depending on patient factors. Caution is required with the use of narcotics because they can induce respiratory depression that can be especially worrisome in patients with COPD, who often have minimal respiratory drive. Liberal use of NSAIDs and acetaminophen is beneficial and safe and allows reduction of narcotic dose.50 Cyclooxygenase type 2 inhibitors must be avoided because of concerns about their cardiovascular safety.51 Narcotics also cause significant constipation problems, which often are regarded as a mere inconvenience but occasionally lead to obstipation, perforation, and even mortality. Constipation is a frequent cause of readmission after thoracic surgery. Stool softeners, early mobilization, and a progressive laxative regimen to ensure bowel function early after surgery make prevention of constipation far easier than treatment once it is established.

PREVENTION OF CARDIAC ARRHYTHMIAS Atrial tachyarrhythmias, predominantly atrial fibrillation, are the most common cardiac complications after general thoracic surgical procedures.52 Atrial fibrillation can lead to palpitations, fatigue, hypotension, congestive heart failure, angina or infarction, stroke, prolonged hospitalization, and increased costs. Several medications have been used to prevent atrial tachyarrhythmias (Sedrakyan et al, 2005).53,54 Blocking of β-adrenergic receptors has been shown to be important in the prevention of atrial fibrillation because reducing the sympathetic tone reduces the susceptibility to postoperative dysrhythmias. Agents with β-blocking effect are effective, with a reduction to less than half the normal incidence of atrial fibrillation.55 In several randomized trials,53,56 the use of β-blockers in patients undergoing surgical procedures reduced morbidity and mortality significantly. βBlockers are started before induction of anesthesia in the operating room and continued during the entire hospitalization. Those patients who are already being treated with βblockers before surgery need to continue them postoperatively unless absolutely contraindicated because their suspension can increase the incidence of postoperative atrial fibrillation.

1/21/2008 10:43:51 AM

142

Section 1 Introduction

Sotalol, a dual β-blocking and potassium channel–blocking agent, and amiodarone, which inhibits potassium and calcium channels and has α- and β-blocking properties, have also been demonstrated to be effective in preventing postoperative atrial fibrillation, and they may be more effective than pure β-receptor antagonists.57 Unfortunately, sotalol can also lead to hypotension and bradycardia and needs close monitoring, particularly in patients with renal insufficiency. For effective prophylaxis, amiodarone needs to be started at least 1 week before surgery but this can be planned for patients in whom β-blockers are contraindicated. In contrast to their lack of potency in preventing atrial arrhythmias after cardiac surgery,53 calcium channel blockers (verapamil, diltiazem) seem to be effective in general thoracic surgery,54,58 with less risk of congestive heart failure. Do not use digitalis because it actually increases the risk of tachyarrhythmia. Magnesium has been tested only in an unblinded trial. In patients with a permanent implanted cardiac rhythm management device (CRMD), such as a pacemaker, implantable cardioverter-defibrillator, or cardiac resynchronization device for management of bradyarrhythmia, tachyarrhythmia, or heart failure, additional considerations must be taken into account.59 During the immediate postoperative period, CRMD function must be assessed and restored, and cardiac rate and rhythm must be continuously monitored. If CRMD settings are inappropriate, the device must be reprogrammed. In the case of implantable cardioverter-defibrillators, antitachyarrhythmic drugs must be restarted, if they were discontinued in the preoperative preparation. Special equipment for cardiac resuscitation (e.g., pacing, cardioversion, defibrillation) must be immediately available at all times.

PREVENTION OF MYOCARDIAL INFARCTION Some perioperative interventions (e.g., β-blockers, α2adrenergic agonists, statins) may prevent major cardiac ischemic events, but they have not yet shown a definitive advantage in reducing the number of perioperative myocardial infarctions. Most of the available best evidence does not come specifically from studies of general thoracic surgical patients, but the general principles probably apply (Fleisher and Eagle, 2001).60 β-Blockers moderate the effects of catecholamines and therefore may prevent perioperative cardiac events. In vascular surgery trials, β-blockers as cardiac prophylaxis agents on a short-term follow-up were initially reported to be beneficial, with a reduction of 90% of deaths due to cardiac events or myocardial infarction at 30 days after surgery.61 However, a more recent meta-analysis did not find a significant advantage and showed an increased risk of significant bradycardia.62 An outcomes study using administrative data from 700,000 patients suggested that perioperative βblockade provided a protective benefit only in higher-risk patients. In those at lower risk, treatment increased the risk for complications.63 Therefore, current recommendations focus on patients with intermediate to high risk and who have one or more risk factors (Box 11-2). These simple risk factors have recently been validated.64 Low-risk patients have very low rates of cardiac events, probably derive little benefit from

Ch011-F06861.indd 142

Box 11-2 Perioperative Cardiac Risk Factors Ischemic heart disease Congestive heart failure Cerebrovascular disease Renal insufficiency Diabetes

Box 11-3 Cardiac Medications Perioperative adrenergic agents β-Blockers or α-agonists acceptable No benefit in low-risk patients Antiarrhythmics Amiodarone, sotalol, β-blockers, diltiazem all helpful Digitalis increases risk Aspirin No benefit Statins Benefit suspected but not proven Nitrates Continue preoperative regimen No benefit for perioperative prophylaxis

perioperative therapy, and may even experience more complications. Intermediate-risk patients derive the most benefit from β-blocker therapy.65 Adrenergic agents must be started and/or titrated to a target heart rate of 60 to 65 beats per minute before anesthesia is begun. Patients without a longterm indication must have their agent continued for at least 7 days, and optimally for 30 days.66 Other medications have also been suggested to decrease the perioperative cardiovascular risk. α-Adrenergic agonists also suppress the release of catecholamines. In the early postoperative period, the use of α-agonists reduced total mortality and the number of myocardial infarctions in vascular surgery patients, but this was not observed in nonvascular, noncardiac surgical cases.67 A simple strategy of 4 days of transdermal and oral clonidine reduced perioperative ischemia and mortality in a recent placebo-controlled, randomized trial.68 Calcium channel blockers increase coronary blood flow by dilation of coronary vessels and therefore may reduce the risk of myocardial infarction. However, a meta-analysis of 11 randomized trials did not find any advantage to the use of calcium channel blockers in terms of mortality or myocardial infarction in short-term postoperative follow-up.69 Statins stabilize the plaque and therefore prevent thrombosis. Observational studies have reported that statins reduce the risk of perioperative death in patients undergoing noncardiac surgery,70-72 but the only controlled trial that has been reported was very small.73 No data support the use of aspirin to reduce perioperative cardiac risk. These recommendations are generally summarized in Box 11-3.

1/21/2008 10:43:51 AM

Chapter 11 Principles of Postoperative Care

TABLE 11-3 Risk Categories for Thromboembolism Low risk

Uncomplicated surgery <3 hr, <40 years old, with minimal immobility and no risk factors (see Box 11-2)

Moderate risk

Any surgery if 40-60 years old If <40 years old, major surgery with no other risk factors, or minor surgery with 1 or more risk factors

High risk

Any surgery if >60 years old If 40-60 years old, major surgery with 1 or more risk factors

Very high risk

Major surgery in patients aged >40 years with previous venous thromboembolism, cancer, or known hypercoagulable state

Box 11-4 Risk Factors for Deep Venous Thrombosis Associated With Thoracic Surgery Malignancy Cancer therapy (hormonal therapy, chemotherapy, radiotherapy) Previous venous thromboembolism Advanced age Estrogen-containing oral contraception or hormone replacement therapy Selective estrogen receptor modulators Heart or respiratory failure Obesity Smoking Varicose veins Central venous catheterization

PREVENTION OF DEEP VENOUS THROMBOSIS AND PULMONARY THROMBOEMBOLISM All patients undergoing a major surgical procedure are at moderate or high risk and need to have prophylaxis to prevent deep venous thrombosis (DVT) and pulmonary embolism (PE).74 The risk of developing PE can be evaluated for each individual patient (Table 11-3 and Box 11-4). Generally, thoracic surgical patients fall into the moderate to high risk category. In all patients, apply elastic compression stockings before surgery, and patients need to resume walking as early as possible after surgery, usually the same day or the next morning at the latest. In low-risk patients, unfractionated subcutaneous heparin in low doses (5000 U, administered 2 hours before surgery and every 12 hours after surgery) is used. In patients at high risk, in fact in most patients, we use elastic compression stockings, unfractionated subcutaneous heparin, and intermittent pneumatic compression devices. Others have recommended higher levels of anticoagulation with various regimens of low-molecular-weight heparin subcutaneously, but we have not found this to be necessary (Geerts et al, 2004),75 because we are quite liberal with the use of intermittent pneumatic compression devices. Patients taking anticoagulants before surgery generally can resume IV heparin, without bolus infusion, 6 to 12 hours after surgery, depending on intraoperative blood loss and

Ch011-F06861.indd 143

143

the urgency for anticoagulation. Low-risk patients, such as those with atrial fibrillation without prior stroke or cardiomyopathy without atrial fibrillation, have an annual thrombotic risk without anticoagulation of less than 4% and can resume anticoagulation after hospital discharge. Moderaterisk patients with a mechanical aortic valve have a risk between 4% and 7% and must be restarted on anticoagulation therapy before discharge. High-risk patients (e.g., mechanical mitral valve, atrial fibrillation with prior stroke) have an annual risk of greater than 7% and must be anticoagulated with IV heparin as soon as possible after surgery.76,77 Paravertebral catheters may offer a safety advantage over epidural catheters for pain control in patients requiring anticoagulation. High-risk patients who are not candidates for pharmacologic prophylaxis and patients who bleed while taking anticoagulants can be considered for implantation of inferior vena cava filters. We have generally reserved these for patients with documented recent DVT or PE.

NEUROLOGIC ISSUES Many thoracic surgical patients are older and have other risk factors for postoperative delirium. The incidence is approximately 10% with sensitive measures; in practice, it is a significant concern in only a few pulmonary patients but more common after esophagectomy. Older data identified age greater than 70 years, alcohol abuse, poor cognitive status, poor functional status, and markedly abnormal preoperative serum sodium, potassium, or glucose level as risk factors.78 Noncardiac thoracic surgery was itself a risk factor. Patients with delirium had more major complications, longer lengths of stay, and less chance of discharge directly to their homes. Alcohol withdrawal is also an occasional management issue; again, it is more common after esophagectomy. Medical therapy includes benzodiazepines or alcohol ingestion as requested by the patient, haloperidol for management of agitation, and clonidine or β-blockers for management of adrenergic symptoms. For patients at risk, we allow brandy or beer even via J-tube to prevent sudden onset of withdrawal. There is evidence that standardized approaches improve care.79 Tobacco addiction is often associated, so management with nicotine patch is also often helpful and usually can be used prophylactically without symptoms.

SUMMARY Excellent postoperative care begins with careful consideration of the risk-to-benefit ratio of surgery. Preoperative preparation of the patient and assessment for, and mitigation of, risk factors must be completed before surgery. Intraoperative technique must be meticulous, and an experienced team of surgeons, anesthesiologists, and nurses must work in a coordinated fashion. Similarly, postoperative care, whether in an ICU, a step-down unit, or a general ward bed, must be efficient and organized. Specific prophylactic measures that have been tested and are of proven benefit include perioperative antibiotics, anticoagulation strategies, and perhaps β-blockers. These are used in accordance with established principles. Other aspects of care may be tailored to

1/21/2008 10:43:51 AM

144

Section 1 Introduction

local practice, keeping the general goals of early mobility, excellent pain control, and rapid return to normal function in mind.

COMMENTS AND CONTROVERSIES Thoracic surgery and especially pulmonary surgery have well-defined indications and operative techniques. Unfortunately, this type of work often involves significant removal of lung parenchyma in individuals whose cardiopulmonary function is already compromised by comorbidities such as emphysema, coronary artery disease, and other physiologic derangements related to smoking. In all specialized services that treat thoracic surgical patients on a daily basis, the entire medical team—from nurses to anesthetists, thoracic surgeons, ICU specialists, physiotherapists, chest physicians, and others—knows and understands the indications for surgery and, most importantly, how to prepare the patient for the intervention. The medical team also knows how to forecast possible complications, how to prevent them, how to diagnose them early, and how to heat them efficiently, so that a minor event does not progress to a major morbidity. Although better knowledge of cardiopulmonary physiology, improvements in anesthesia and postoperative analgesia, and introduction of postoperative monitoring have aided postoperative management in thoracic surgical patients, the modern approach to this type of work must be multidisciplinary. The primary benefit of this approach will be improving patient care. As indicated by the authors of this chapter, the rationale for active monitoring of thoracic surgical patients is the prevention, early identification, and early treatment of cardiopulmonary complications. Because such events are more likely to occur during the first three postoperative days, this time interval needs to be the period of most intensive monitoring. Whether monitoring is done in an ICU environment or in an intermediate care facility does not seem to be of great importance, as long as the unit allows close and reliable observation

Ch011-F06861.indd 144

of clinical, hemodynamic, respiratory, radiographic, and biologic parameters. J. D.

KEY REFERENCES Bratzler DW, Houck PM: Antimicrobial prophylaxis for surgery: An advisory statement from the National Surgical Infection Prevention Project. Am J Surg 189:395-404, 2005. ■ The most recent and widely endorsed group of recommendations. Fleisher LA, Eagle KA: Clinical practice: Lowering cardiac risk in noncardiac surgery. N Engl J Med 345:1677-1682, 2001. ■ An older paper, well-written, widely read, and still useful. Geerts WH, Pineo GF, Heit JA, et al: Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:338S-400S, 2004. ■ An excellent, recent, evidence-based review with consensus recommendations which unfortunately does not discuss thoracic surgical patients specifically. Gottschalk A, Cohen SP, Yang S, Ochroch EA: Preventing and treating pain after thoracic surgery. Anesthesiology 104:594-600, 2006. ■ An outstanding state-of-the-art review. Lawrence VA, Cornell JE, Smetana GW: Strategies to reduce postoperative pulmonary complications after noncardiothoracic surgery: Systematic review for the American College of Physicians. Ann Intern Med 144:596-608, 2006. ■ Very up-to-date recommendations, primarily based on data from nonthoracic surgical patients but highly useful nonetheless. Sedrakyan A, Treasure T, Browne J, et al: Pharmacologic prophylaxis for postoperative atrial tachyarrhythmia in general thoracic surgery: Evidence from randomized clinical trials. J Thorac Cardiovasc Surg 129:997-1005, 2005. ■ Prevention of atrial fibrillation is one of the few areas where there is sufficient evidence to build proper metasummaries in general thoracic surgery. A useful compendium of large numbers of studies.

1/21/2008 10:43:51 AM

chapter

12

CRITICAL CARE OF THE THORACIC SURGICAL PATIENT Eric Jacobsohn Charl J. De Wet

Key Points ■ Critically ill patients, when cared for in ICUs that have a multi-

■ ■ ■

■

■ ■

■

■

disciplinary, intensivist-led team, have reduced morbidity and mortality. Sepsis remains a cause of mortality among patients treated in ICU; early diagnosis, source control, and treatment are essential. Appropriate fluid management is important in critically ill patients and remains a controversial field. RBC transfusions are administered to increase oxygen carrying capacity, but it remains uncertain what constitutes an acceptable trigger level of Hb. Atrial arrhythmia is a common problem after thoracic surgery despite pharmacologic prophylaxis. There are currently no consensus guidelines for the primary prevention of AF that are specific to thoracic or cardiac surgical patients. ALI and ARDS are common complications of sepsis and carry a mortality rate of almost 50%. Inappropriate use of sedation and paralysis significantly increases morbidity. Routine use of neuromuscular blockade must be discouraged and should be used only if all other means have been tried without success. The use of a PAC in the care of critically ill patients is increasingly being questioned. It has been associated with an increased risk of death. The risk factors for stress ulcer that have been identified include surgical patients requiring mechanical ventilation for more than 48 hours, coagulopathy or anticoagulant use, and corticosteroids.

The critical care of the complicated postoperative thoracic surgical patient has undergone significant developments over the last decade. As critical care outcomes research has flourished, so has the application of evidence-based principles to critical care. This has led to improved patient care, with reduced morbidity and mortality. This chapter reviews many of these new developments that have affected the care of those thoracic surgical patients who require care in intensive care units (ICUs).

THE INTENSIVIST-LED MULTIDISCIPLINARY ICU TEAM IMPROVES OUTCOMES IN THE ICU There are now substantial data to show that critically ill patients, when cared for in ICUs that have a multidisciplinary, intensivist-led team, have reduced morbidity and mortality.1 The intensivist-model ICU, when compared with the older, traditional open unit, has a reduction in hospital mortality in the range of 30% to 40%. In the most recent

study examining the risk of death after traumatic injuries, the relative risk (RR) of death in an intensivist-model ICU was 0.78 when compared with an open ICU model. The effect was greatest in the elderly (RR, 0.55) and in units led by surgical intensivists,2 as well as in designated trauma centers (RR, 0.64 [range, 0.46-0.88]).2 It would not be unreasonable to expect similar beneficial effects in thoracic ICUs when the care is delivered by experts in thoracic critical care. However, there are few data available on the current staffing practices in thoracic ICUs per se. The rationale for improved morbidity and mortality with intensivist staffing is multifactorial. The intensivist-led team has the skills and knowledge to treat critically ill patients and is immediately available to diagnose and treat problems. The intensivist-staffing model may also yield benefits through a leadership role at the ICU organizational level. The improved and ongoing communication with patients and families may also lead to improved patient and family satisfaction. Intensivist-staffed ICUs may also realize decreased resource use because these physicians may be better at reducing inappropriate admissions, preventing complications that prolong length of stay, and recognizing opportunities for prompt discharge.3 As a result of these data, the Leapfrog Group, a large coalition of public and private U.S. organizations that provide health care benefits to more than 30 million persons, has made the ICU physician model an important quality indicator for its beneficiaries. They have defined these standards of care and the definitions of an intensivist (Table 12-1).4 Despite the reported benefits of intensivist staffing, only 24% of U.S. hospitals surveyed had intensivists, and only 4% of U.S. ICUs fully met this physician-staffing standard. There are potentially major barriers to implementing the standard, including how the cost savings are to be shifted into the staffing model, serious medical staff politics, and the current lack of intensivists.

DIAGNOSIS AND MANAGEMENT OF SEPSIS Sepsis remains an important cause of mortality among patients treated in intensive care units. Delays in the diagnosis of sepsis are common, particularly in some populations of patients who do not present with the classic findings of sepsis. The early diagnosis of sepsis is often missed on postoperative units because the early signs are nonspecific and frequently include only tachypnea and/or confusion. Early diagnosis, source control, and treatment form the cornerstones of current management. There have been many important developments in the treatment of sepsis in the past 5 years, and these were addressed in a recent paper endorsed by 145

Ch012-F06861.indd 145

1/21/2008 10:44:43 AM

146

Section 1 Introduction

TABLE 12-1 Proposed Standards for ICU Physician Staffing Standard 1. ICUs are managed or co-managed by intensivists. 2. Intensivists are present during daytime hours and provide clinical care exclusively in the ICU; at other times, intensivists can, at least 95% of the time: 1. Return ICU pages within 5 min 2. Arrange for an FCCS-certified nonphysician provider to reach the ICU within 5 min Intensivist Definition 1. Board-certified physicians who are additionally certified in the subspecialty of critical care medicine or 2. Physicians board-certified in emergency medicine who have completed a critical care fellowship in an ACGME-accredited program or 3. Physicians board-certified in medicine, anesthesiology, pediatrics, or surgery who completed training before the availability of subspecialty certification in critical care and who have provided at least 6 weeks of full-time ICU care annually since 1987 ACGME, Accreditation Council for Graduate Medical Education; FCCS, fundamental critical care support; ICU, intensive care unit.

several international critical care and other professional societies.5

Antibiotic Therapy and Source Control Delays in diagnosis and delays in instituting appropriate, broad-spectrum antimicrobial coverage increase mortality.6 Gram-positive bacteria and fungal organisms are now recognized as increasingly common causes of sepsis.7 Obvious sources of infection need to be drained or removed as soon as possible, including vascular access catheters such as tunneled or surgically implanted catheters. Blood cultures are obtained, preferably before administering appropriate antibiotic coverage. Two or more blood cultures are recommended and are obtained peripherally. Cultures from other body fluids are obtained based on the clinical scenario. The sensitivity and benefits of imaging studies to search for a source of the infection need to be weighed against the risk of transporting a hemodynamically unstable patient and the potential interruption of other therapies. Jimenez and Marshall showed that hospital mortality from sepsis with inadequate initial choice of antibiotics is double that observed when the initial antibiotic choice is adequate.8 Appropriate doses of broad-spectrum antibiotics, including loading doses if appropriate, are administered within 60 minutes after the diagnosis of sepsis.5 The actual choice of antibiotics is dictated by the clinical scenario and by unitand/or hospital-specific antibiograms. Neutropenic patients receive broad-spectrum antibiotics for the entire course of their neutropenia. As more resistant ICU pathogens continue to emerge, it is crucial to involve infectious disease physicians in the management of complex cases. Hospital- and ICUspecific antibiograms must be used in selecting antibiotic coverage for patients. Ideally, protocols need to be estab-

Ch012-F06861.indd 146

lished for managing infections and for deciding on discontinuation of antibiotic therapy. The duration of antibiotic coverage remains controversial and is guided by clinical response and culture results. However, the initial broad-spectrum choice needs to be reviewed at least every 48 hours. All efforts must be made to restrict the antibiotic spectrum as soon as possible to limit the appearance of drug-resistant organisms (e.g., resistant gram-negative organisms, vancomycin-resistant enterococcus) and other antibiotic-associated complications (e.g., fungal superinfections, Clostridium difficile colitis). In a recent study, Chastre and colleagues showed that, for patients with microbiologically proven ventilator-associated pneumonia who had received appropriate initial empiric therapy (with the possible exception of those with nonfermenting gram-negative bacillus infections), there was comparable effectiveness with 8 versus 15 days of antibiotic treatment.9 The 8-day group had less antibiotic use, and, among those patients who developed recurrent infections, multiresistant pathogens emerged less frequently in those who had received 8 days of antibiotics. Although the appropriate use of limited-duration prophylactic antibiotics after many thoracic surgical procedures has been shown to decrease surgical site infections,10 surgical site infections are a major contributor to patient injury and subsequent sepsis syndromes, resulting in morbidity and mortality and increased health care costs. Despite evidence of the effectiveness of antimicrobials to prevent these infections, studies continue to demonstrate inappropriate timing, selection, and duration of administration of antimicrobial prophylaxis.11 Selective digestive decontamination (SDD) can reduce the occurrence of nosocomial pneumonia among ventilated patients in the ICU setting, but it has also been demonstrated to increase subsequent patient colonization and infection and to increase infections with resistant bacteria, particularly gram-positive cocci.12 Therefore, the routine use of SDD cannot be advocated at the present time. The mortality benefit of SDD appears to occur in surgical/trauma patients and to be associated primarily with the administration of parenteral antibiotics. This is already an accepted practice in most patients during the perioperative period. Prolonged decontamination of the aerodigestive tract with topical antimicrobials does not appear to influence outcome and should not be routinely employed.

Goal-Directed Resuscitation and Use of Vasopressors Resuscitation needs to begin as soon as the syndrome of sepsis is recognized. A recent study by Rivers and associates showed that early goal-directed therapy (EGDT) in sepsis, which strives to detect patients at high risk for hemodynamic compromise using variables other than traditional vital signs, improves the likelihood of survival. EGDT strives to normalize oxygen delivery and to minimize oxygen consumption in patients with severe sepsis and septic shock.13 Rivers and associates used infusions of fluids and transfusions of red cells to increase oxygen delivery. Resuscitation end points chosen for assessment of the adequacy of oxygen delivery were the

1/21/2008 10:44:43 AM

Chapter 12 Critical Care of the Thoracic Surgical Patient

normalization of mixed venous oxygen saturation, lactate, base deficit, and pH values. Patients in the EGDT group received more fluid, inotropic support, and blood transfusions during the first 6 hours based on hemodynamic data that also included central venous oxygen saturation and lactate measurements than did control patients, who received standard resuscitation therapy based on traditional signs of adequate perfusion, such as urine output, blood pressure, and central venous pressure. During the interval from 7 to 72 hours, patients in the EGDT group had a higher central venous oxygen concentration, a lower mean lactate concentration, a lower mean base deficit, and a higher mean pH than the control group. Mortality was 30.5% in the EGDT group and 46.5% in the control group (P = .009). Based on this work, Dellinger proposed a decision tree to initiate monitoring based on traditional end points such as blood pressure, with subsequent titration based on central venous pressures and pulmonary artery pressures for management decisions in septic shock (Dellinger, 2003).14 This approach was criticized by the authors of the EGDT study, who pointed out that the key difference between the two groups was in the timing and physiologic titration of therapy, which was based on central venous oxygen saturation, and not in the global management of these patients: over the first 6 hours, the EGDT group received more inotropic support, but over the total 72-hour period, the mean difference in total red cell transfusion was only 72 mL, the total fluid given essentially equalized, and there was no difference in dobutamine use. Furthermore, they pointed out that the EGDT group required significantly less vasopressors, pulmonary artery catheterization, and mechanical ventilation over the total 72 hours. In a subset analysis, they also found that, among patients who had a lactate concentration greater than 4 mmol/L despite a mean arterial pressure of greater than 110 mm Hg, those in the control group had a 40% higher mortality rate.15 However, their study has been criticized for the fact that almost 10% of patients did not receive antibiotics within 6 hours after the initial diagnosis of sepsis.16 Although some controversy still remains, the end points used in the EGDT protocol, the outcome results, and the

147

cost-effectiveness findings have subsequently been validated with similar or even better results than in the original clinical trial.17 Although EGDT is faced with challenges, it is crucial to the effective management of sepsis in ICUs. The choice of vasoactive agents remains controversial. There has been renewed interest regarding the use of vasopressin in vasodilated shock states.18-20 Many septic patients have been shown to have relative vasopressor deficiency, and replacement doses of vasopressin have been shown to significantly reduce the requirement for catecholamine support. Although high endogenous levels of vasopressin in nonshock states do not produce hypertension, in shock states vasopressin stimulation of vascular V1 receptors appears to be an important mechanism of blood pressure augmentation. Recent literature supports vasopressin as an option to raise blood pressure in septic shock and to wean more traditional vasopressors (norepinephrine) already in place. Septic shock– associated exhaustion of neurohypophyseal stores due to intense and prolonged stimulation, as well as impairment of baroreflex-mediated stimulation of vasopressin release, may lead to inappropriately low levels of serum vasopressin. Low doses of vasopressin, targeted to achieve serum vasopressin levels similar to those present in cardiogenic shock, have been demonstrated to produce a significant rise in mean arterial pressure in septic shock, often leading to the discontinuation of traditional vasopressors. The effect of this strategy on clinical outcome is unknown because no randomized, prospective clinical outcome trials exist. However, more evidence is developing that late-stage shock of all kinds may represent a vasoplegic, vasopressin-responsive state. The potential use of vasopressin in critical care units is summarized in Table 12-2.21 If vasopressin is used, it seems most appropriate for patients who require moderate- to high-dose vasopressors, especially if blood pressure remains inadequate. Dosing is limited to 0.01 to 0.04 U/min, because higher doses put the patient at a greater risk for splanchnic and coronary artery ischemia, as well as decreased cardiac output. However, any vasopressor support, especially vasopressin therapy, must be judiciously started, ideally with some assessment of cardiac output. Vaso-

TABLE 12-2 Potential Uses of Vasopressin in Critical Care Type

Rationale

Indication

Dose

Notes

Cardiac arrest

↑ CPP ↑ ROSC

VF, PEA, asystole

2 × 40 U bolus with epinephrine

Combination likely beneficial

Cardiogenic shock

VP depletion

Refractory hypotension

2-4 IU/hr

Only refractory state

Septic shock

Pathologic low SVR VP depletion

Refractory to norepinephrine

2-4 IU/hr

Beware if low CO Not as single agent (use with agent with β-adrenergic activity)

Anaphylaxis

↑ Pathologic low SVR

Refractory to standard therapy

2-10 IU bolus 2-4 IU/hr

Only case reports in humans

Late hemorrhagic shock

↑ Perfusion to vital organs until bleeding is controlled VP depletion

Unresponsive to standard therapy

2-10 IU bolus 2-4 IU/min

Not standard therapy yet

CO, cardiac output; CPP, coronary perfusion pressure; PEA, pulseless electrical activity; ROSC, return of spontaneous circulation; SVR, systemic vascular resistance; IU, international units; VF, ventricular fibrillation; VP, vasopressin.

Ch012-F06861.indd 147

1/21/2008 10:44:43 AM

148

Section 1 Introduction

pressin has no inotropic effects, and there is a potential for cardiac output to decrease. Escalating doses of vasopressin can have serious deleterious effects in the presence of low or inadequately increased cardiac output. It is important to recognize those patients who do not have an appropriate cardiac output response in sepsis, to establish the cause of the inappropriate cardiac output response, and to start dobutamine therapy if appropriate. The aim of dobutamine is not to increase cardiac output to some predefined, elevated level because two large prospective trials failed to demonstrate a benefit from increasing oxygen delivery to supranormal levels.22,23 Rather, dobutamine is titrated to normalize cardiac output and ensure adequacy of peripheral perfusion as evidenced by lack of acidosis. There is currently no evidencebased rationale to choose colloids over crystalloids for purposes of resuscitation.

Activated Protein C The current understanding of the pathophysiology of sepsis encompasses a triad of abnormal coagulation, inflammation, and reduced fibrinolysis, leading to microvascular thrombosis and end-organ dysfunction.24 Extreme clinical manifestations of disseminated intravascular coagulation, such as purpura fulminans or digital ischemia, have long been identified as a poor prognostic sign of septic shock. However, subclinical manifestations of disseminated intravascular coagulation are present in essentially all patients with septic shock (some combination of increased D-dimers, decreased protein C, thrombocytopenia, and increased prothrombin time), and consumptive coagulopathy is most likely an important facet of pathophysiology in septic shock. The activation of protein C from its inactive form is an important mechanism for modulating sepsis-induced consumptive coagulopathy and the resultant microvascular occlusion and end-organ dysfunction (Fig. 12-1).25 In order for protein C to be activated, thrombin has to bind to its endothelial receptor, thrombo-

FIGURE 12-1 The pathophysiology of sepsis and its relation to increased intravascular coagulation and inflammation. A, Perivascular inflammation. B, Intravascular inflammation. C, Inflammation around a nonthrombosed blood vessel. D, Normal staining of thrombomodulin in a healthy patient. E, Depleted thrombomodulin in the vessel wall in a patient with meningococcemia. (MODIFIED FROM FAUST SN, LEVIN M, HARRISON OB, ET AL: DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS. N ENGL J MED 345:408-416, 2001. COPYRIGHT 2001, MASSACHUSETTS MEDICAL SOCIETY. ALL RIGHTS RESERVED.)

Ch012-F06861.indd 148

modulin. The activation of protein C can then occur via the thrombin-thrombomodulin complex. However, because of the endothelial damage in sepsis, thrombomodulin is released from the endothelium, and, hence, thrombin cannot bind to the endothelium. Protein C cannot be activated, and this potentially leads to severe intravascular coagulation. Recombinant human activated protein C (APC) is an anticoagulant that has anti-inflammatory effects and promotes fibrinolysis. It has proved effective in the treatment of sepsis (Bernard et al, 2001).26 In patients with severe sepsis (PROWESS study), the administration of APC resulted in a 19.4% reduction in the RR of death and an absolute risk reduction of 6.1% (Bernard et al, 2001).26 APC inactivates factors Va and VIIIa, thereby preventing the generation of thrombin. The efficacy of an anticoagulant agent in patients with sepsis has been attributed to feedback between the coagulation system and the inflammatory cascade. Inhibition of thrombin generation by APC decreases inflammation by inhibiting platelet activation, neutrophil recruitment, and mast-cell degranulation. APC has direct anti-inflammatory properties, including blocking of the production of cytokines by monocytes and blocking of cell adhesion. APC has also been shown to modulate the abnormal fibrinolytic response during severe sepsis. However, the role of APC remains controversial in severe sepsis, and there is controversy about its potential role or efficacy in less severe forms of sepsis. As a result of analysis of the subgroup with less severe sepsis in the PROWESS study, the U.S. Food and Drug Administration (FDA) required a phase IIIB study to assess the use of the drug in less severe sepsis (Bernard et al, 2004).27 There was a planned enrollment of 11,000 patients, making this the largest sepsis drug study ever performed. However, at the first interim analysis, and after enrolling only 25% of the planned patients, the trial was discontinued by the company on the basis of futility (communication to investigators, Feb 2004). A concerning issue that remains is why APC was successful whereas two

A

D

E B

C

1/21/2008 10:44:43 AM

Chapter 12 Critical Care of the Thoracic Surgical Patient

other anticoagulants—antithrombin III and tissue factorpathway inhibitor—failed as treatments of sepsis in large, well-designed studies. A possible explanation for the failure of these two anticoagulant agents is that they work at different sites in the coagulation cascade. Also, APC has antiapoptotic actions that may contribute to its efficacy. However, some scientists believe that the PROWESS study had significant methodologic issues, that the study should not have been prematurely discontinued, and that the use of APC in severe sepsis is not justified based on this study alone. A major risk associated with APC is hemorrhage (Bernard et al, 2001)26,28,29: 3.5% of patients in the PROWESS study had serious bleeding (intracranial hemorrhage, a life-threatening bleeding episode, or a requirement for 3 or more units of blood), compared with 2% of patients who received placebo (P < .06). With open-label use of APC after the trial, 13 of 520 patients (2.5%) had intracranial hemorrhage. Caution is advised in the use of APC in patients with an international normalized ratio (INR) greater than 3.0 or a platelet count of less than 30,000 per cubic millimeter. Currently, APC is approved only for use in patients with sepsis who have severe organ compromise and the highest likelihood of death. Use of APC is restricted in many hospitals to the more seriously ill patients who meet the criteria for sepsis specified by the Acute Physiology and Chronic Health Evaluation (APACHE II) scoring system (Apache Score >25). The ultimate fate remains to be determined.

Role of Corticosteroids in Critical Care Administration of high doses of corticosteroids does not improve survival in patients with sepsis. It may actually worsen outcomes by increasing the frequency of secondary infections. In the late 1990s, several single-center studies of septic shock using stress (low) doses of steroids showed promising results.30 In 2000, a prospective observational study used the response to a high-dose corticotropin (ACTH) stimulation test to characterize the status of patients in septic shock.31 The highest value of the two poststimulation cortisol measurements was compared with the baseline level and suggested that the inability to raise cortisol after ACTH stimulation was more predictive of a poor outcome than the basal level itself. This group of patients was called nonresponders and was identified as having “relative adrenal insufficiency.” Based on these findings, a multicenter, prospective, randomized, blinded study of stress-dose (low-dose) steroid therapy targeting this group of nonresponders was performed.32 Patients with septic shock were randomized to receive either 50 mg of intravenous (IV) hydrocortisone every 6 hours plus 50 µg by mouth of the mineralocorticoid fludrocortisone every day or placebo. Treatment continued for 7 days. The primary analysis group was nonresponders to ATCH, defined as those who failed to increase serum cortisol levels by at least 10 µg/dL or greater after ACTH stimulation. Use of stress-dose steroids in nonresponders was associated with decreased mortality and decreased vasopressor usage. There was no benefit of steroids in responders. There was no statistically significant difference in the 28-day mortality rate, but statistical significance was reached when logistic regres-

Ch012-F06861.indd 149

149

sion adjustment was done. Another somewhat worrisome aspect was the fact that patients who did not have adrenal insufficiency and who received corticosteroids had a slight, albeit not statistically significant, trend toward increased mortality. A second issue that has been raised is the high mortality rate in the population of patients—63% in the placebo group. Although validation of this study is needed (and is being done in Europe), in the interim, it is reasonable to consider stress-dose steroids in patients who are requiring high doses of vasopressor therapy. In those patients, a reasonable approach would be to give dexamethasone, 4 mg IV every 6 hours (this does not interfere with cortisol assay), until the high-dose ACTH stimulation test can be performed. Hydrocortisone and fludrocortisone would then be started and continued or discontinued based on the results of the ACTH stimulation test. If the ACTH stimulation test is not available, then empiric stress-dose steroids need to be considered. Some investigators question the choice of the 250-µg ACTH stimulation test for the evaluation of adrenal reserve in critically ill patients and judge it to be supraphysiologic and potentially overestimating of adrenal reserve. They recommend a 1- to 2-µg ACTH dose. The proposed explanation for the physiologic response to corticosteroids (despite normal or elevated plasma cortisol levels) is desensitization of corticosteroid responsiveness with downregulation of adrenergic receptors. Catecholamines increase arterial pressure through effects on adrenergic receptors of the vasculature; corticosteroids increase the expression of adrenergic receptors. Testing involving stimulation by adrenocorticotropic hormones may not be useful in identifying patients with relative adrenal insufficiency. Such patients may have markedly elevated baseline plasma cortisol levels and a blunted response to stimulation by adrenocorticotropic hormones. However, another very recent publication examining the role of free cortisol levels in critically ill patients further complicates the issue of stress-dose steroids in this patient group. Because more than 90% of circulating cortisol is protein bound, changes in the binding proteins can alter measured serum total cortisol concentrations without influencing free concentrations. The 10% that is free cortisol is the bioactive component. Of the 90% protein-bound cortisol, 20% is loosely bound to albumin, and 70% is tightly bound to cortisol-binding globulin. The binding to cortisol-binding globulin is almost saturated at plasma cortisol levels in the range of 15 to 18 µg/dL (Fig. 12-2). With stress and hypoalbuminemia, the maximal total cortisol measurement will fall below that level in persons with a normal albumin concentration and may often fall below the traditional cutoff for the ACTH stimulation test, even though the level of free, bioactive cortisol is appropriate for the clinical situation.33 In a recent study, Hamrahian and colleagues investigated the effect of decreased amounts of cortisol-binding proteins on total and free cortisol concentrations during critical illness.34 They compared baseline serum total cortisol, ACTHstimulated serum total cortisol, aldosterone, and free cortisol concentrations in critically ill patients and healthy volunteers. They found that the baseline and ACTH-stimulated total cortisol concentrations were lower in patients with hypopro-

1/21/2008 10:44:45 AM

Section 1 Introduction

Plasma cortisol level (␮g/dL)

150

24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

Bound to corticosteroidbinding globulin Bound to albumin Free

Cutoff for cosyntropin stimulation test

Metabolic Effects of Fluid Therapy Normal

Stressed

Stressed with hypoalbuminemia

FIGURE 12-2 Total cortisol and free cortisol levels in sepsis. The free cortisol could be normal even though total cortisol is reduced, leading to the unnecessary use of corticosteroids. (DATA FROM HAMRAHIAN AH, OSENI TS, ARAFAH BM: MEASUREMENTS OF SERUM-FREE CORTISOL IN CRITICALLY ILL PATIENTS. N ENGL J MED 350:1629-1638, 2004.)

teinemia than in those with near-normal serum albumin concentrations, but that baseline serum free cortisol concentrations were similar. However, the values in both of these patient groups were several times higher than the values in healthy volunteers. ACTH-stimulated total cortisol concentrations were subnormal in several patients, all of whom had hypoproteinemia. In all the critically ill patients, including those with hypoproteinemia, the baseline ACTH-stimulated serum free cortisol concentrations were high-normal or elevated. In this study, almost 40% of critically ill patients with hypoproteinemia had subnormal total cortisol levels, even though their adrenal function was normal. The authors concluded that glucocorticoid secretion increases during critical illness, but the increase is not discernible if only total cortisol concentration is measured. However, free cortisol measurements are not currently widely available. Until further studies of free cortisol in critically ill patients are done, the risks and benefits of cortisol therapy based on total cortisol levels must be individualized but need to be critically evaluated in light of these important new findings. If corticosteroids are used, they are discontinued as soon as possible; that is, the 7-day course is not required in many and may be harmful in some patients.

FLUID THERAPY IN CRITICAL CARE What Is New in the Crystalloid Versus Colloid Debate? Appropriate fluid management is important in critically ill patients and remains a controversial field. The Cochrane Injuries Group meta-analysis of randomized control trials examined the effect of albumin on mortality compared with crystalloid, no albumin, or a low dose of albumin and found that the mortality rate was higher with albumin therapy.35

Ch012-F06861.indd 150

Finfer and colleagues addressed some of the methodologic concerns of the Cochrane reviews and found no effect of albumin on mortality. In an effort to address the albumin controversy, a large Australian/NZ randomized controlled trial (SAFE study) enrolled patients who required ICU admission to receive either albumin or normal saline (Finfer et al, 2004).36 The outcomes at 28 days were similar, including death, number of organ system failures, time in ICU/hospital, duration of mechanical ventilation, and days of dialysis. In the trauma subgroup, albumin was associated with increased morbidity, and in the severe sepsis subgroup, albumin was associated with a trend toward reduced mortality. Another interesting finding was that the commonly accepted rule of 3:1 crystalloid-to-colloid resuscitation did not hold up, and the actual ratio was 1.4:1.

It has also become clear that the choice of resuscitation fluid in the ICU has important metabolic consequences. Fluids that have high chloride concentrations cause hyperchloremic, non–anion gap metabolic acidosis. Although they were historically believed to be benign, there is now increasing evidence that such fluids impair cellular mechanisms; decrease renal blood flow, gastric motility, and perfusion; and increase pulmonary artery pressure.37 The effect of a non–anion gap metabolic acidosis on pulmonary artery pressures is particularly important in many postoperative thoracic surgical patients who already have abnormal pulmonary vascular resistance. However, a big problem with this type of metabolic acidosis is the reaction of clinicians, who may not recognize it or may confuse it with other dangerous conditions such as anion gap acidosis, and respiratory acidosis. In patients with compromised respiratory function and in those receiving narcotics, both common situations after thoracic surgery, there is an impaired ability for compensatory hyperventilation, and severe acidemia may ensue.

Immunologic Effects of Fluid Therapy Fluid management may also have an effect on immune function.38 Isotonic crystalloids cause immune activation, the effect being greatest with lactated Ringer’s solution. Of the colloids studied, dextran and Hespan caused the most pronounced neutrophil activation and cellular injury.39,40 Efforts are being made to develop resuscitation fluids that eliminate D-lactate and substitute pyruvate as the base. Activation of the immune system has not been demonstrated with plasma and albumin.

Coagulation and Fluid Therapy Fluid choice in the ICU can also affect the coagulation system. Non-protein colloids are associated with impaired hemostasis, platelet dysfunction, and excessive bleeding.41-43 Of the colloids, albumin has minimal effects on coagulation, although procoagulatory and anticoagulatory effects (e.g., inhibiting platelet aggregation, enhancing the inhibition of factor Xa by antithrombin III) have been described. Dextrans affect hemostasis by decreasing both VIIIR:Ag and VIIIR:RCo levels, leading to reduced binding to the platelet

1/21/2008 10:44:46 AM

Chapter 12 Critical Care of the Thoracic Surgical Patient

membrane receptor proteins glycoprotein (GP) Ib and GP IIb/IIIa and decreased platelet adhesion. Gelatin-based plasma expanders (Gelofusine) have minimal negative effect on coagulation, although gelatin has recently been shown to significantly impair thrombin generation in healthy volunteers.44 Changes in coagulation have most often been reported with hydroxyethyl starches (HES), the magnitude of the effect depending on the physiochemical properties of the HES preparation used. These properties include concentration, degree of substitution, mean molecular weight, and the ratio of hydroxyethylation.45 Several HES preparations are available in Europe. In the United States, only the firstgeneration HMW-HES (Hetastarch 6%; 450/0.7) is approved. In Canada, only MMW-HES (HES 270/0.5; Pentastarch) is available. HES has been associated with increased bleeding complications in cardiac surgery, but the effect is dependent on the type of HES.46 The HMW-HES diminishes factors VIIIR:Ag and VIIIR:RCo more than a LMW-HES. Platelet aggregation abnormalities occur with HMW-HES, and fibrinolysis is accelerated. All artificial colloids in large volumes can potentially cause increased bleeding, especially in patients with mild von Willebrand disease. In contrast, crystalloids have been shown in some studies to induce a hypercoagulable state. They may increase the risk of deep venous thrombosis,47 the postulated mechanism being hemodilution of antithrombin III.48

Third Space Fluids and Edema The volume of fluids used in ICU patients has also come under increasing scrutiny. In the 1960s, it was postulated that large volumes of fluid were required after some surgeries due to third space losses.49 This is still common practice after esophageal surgery. Because of difficulties in measuring the fluid compartments, it is hard to accurately define the amount of fluid needed. However, there is accumulating evidence that the magnitude of extracellular fluid shifts may not be as large as previously thought. Studies on stress hormones show that they generally cause fluid retention. Multiple abnormalities are induced in the normal Starling equation after major surgery, including changes in oncotic pressures and tissue capillary permeability. Large amounts of crystalloid cause deleterious tissue oxygenation and poor wound healing.50 In a recent trial, patients undergoing colon surgery were randomized to receive either standard therapy (which included replacement of third space fluids) or restricted fluids (third space fluid not replaced).51 Although there were some methodologic issues of concern, the restricted group had significantly fewer complications and had a trend toward fewer deaths. The results of this study of restricted fluid were duplicated in another Israeli study.52 Similar results also were demonstrated when fluids were restricted after esophagectomy,53 but that study was methodologically less rigorous than the previous studies. The development of postoperative intestinal edema and ileus has been associated with excessive crystalloid therapy and hypoalbuminemia, and abdominal compartment syndrome may be more likely with massive crystalloid fluid resuscitation. Excess fluid is emerging as a

Ch012-F06861.indd 151

Inadequate fluid

Excess fluid

End-organ hypoperfusion

Widespread tissue edema and end-organ system dysfunction

↑ Morbidity ↑ Mortality

151

↑ Morbidity ↑ Mortality

FIGURE 12-3 The balance between inadequate fluid and excess fluid.

causative agent for poor outcome, just as inadequate fluid is established as a cause of poor outcomes (Fig. 12-3).

Effect of Fluid Therapy on Pulmonary Function Another significant problem of excess fluid therapy is that of pulmonary edema. A large fluid bolus has been shown to acutely decrease pulmonary function even in healthy patients, and this effect can be corrected with furosemide.54,55 Arieff studied the incidence and morbidity of postoperative pulmonary edema in the United States and reported on 13 patients who died of postoperative pulmonary edema. The autopsies showed no pathology other than pulmonary edema, and all patients had received high-volume fluid replacement.56 Of 8195 patients undergoing major operations, 7.6% developed pulmonary edema, with a mortality rate of 11.9%. There may be special consideration for choice of fluids in patients with acute respiratory distress syndrome (ARDS).57,58 Hypoproteinemia is common in ARDS. Given Starling’s law, it would seem logical to manipulate the forces to try and reverse fluid flux in the lungs. Mangialardi and coworkers found an independent association between hypoproteinemia and ARDS development and outcome, suggesting that colloid oncotic pressure may play a pathophysiologic role.59 In a randomized controlled trial comparing albumin and furosemide versus standard therapy in patients with ARDS, diuresis and weight loss were better, as were the improvements in arterial partial pressure of oxygen compared with the fraction of inspired oxygen (PaO2/FIO2 ratio).60 However, in the recent SAFE study, the subgroup with ARDS who received albumin did not do better.36 In a recent trial examining fluid therapy in acute lung injury (ALI) that compared liberal versus conservative fluid strategy, the latter strategy improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing non–pulmonaryorgan failures.61 There is also new understanding developing in the field of reabsorption of pulmonary edema fluid. In contrast to the previous understanding, alveolar fluid resorption is not affected by manipulation of Starling forces but via active transport of sodium from the alveolar air spaces, across the alveolar epithelium, and into the pulmonary circulation (Fig. 12-4).62 This creates an osmotic gradient that is responsible for the clearance of lung edema from the alveolar spaces. The sodium (Na+) uptake occurs on the apical surface of alveolar epithelial cells through an amiloride-sensitive Na+ channel

1/21/2008 10:44:46 AM

152

Section 1 Introduction

H2O Alveolar space

Na+ Na+

Na+

H2O

H+ Apical

Na+

K+

Na+

Basolateral

FIGURE 12-4 The important role of the sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) transport pump in lung water reabsorption. (REDRAWN FROM CRITICAL CARE MEDICINE.)

(amiloride is a specific Na+-channel inhibitor). Sodium is then actively extruded from the basolateral surface into the lung interstitium by the sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) pump; water follows because of the osmotic gradient. In many patients with ARDS, there appears to be a reduced ability to clear fluid accumulation from the alveoli. In a study of 79 ARDS patients, Ware and Matthay showed that most had reduced maximal fluid clearing capacity.63 Certain drugs may stimulate the channels (e.g., β-stimulants), whereas others block the channel (e.g., amiloride), which may eventually have therapeutic implications for patients who have or are at risk for increased lung water. Ware and colleagues also showed that therapeutic levels of inhaled albuterol can be reached in the lung fluid of patients with ARDS.64

Sepsis and the Choice of Fluids The fluid choice in sepsis is also controversial, and prospective studies of choice of fluid resuscitation in septic shock are lacking. Meta-analysis of clinical studies comparing crystalloids and colloids in both general and surgical patients indicate no clinical outcome difference; these findings would appear to be generalizable to septic patients.65,66 The volume required is much larger for crystalloids; more fluid causes more edema, which may be deleterious for wound healing, gastrointestinal function, and tissue oxygen delivery. The SAFE study subgroup analysis suggested that albumin might be beneficial in patients with sepsis. Albumin may have beneficial effects other than its volume effects, including its oncotic effects, transport functions, and free radical scavenging effects. In septic patients, resuscitation with both HES and gelatin improves hemodynamics without increasing lung water or worsening oxygenation.67 However, in a study of resuscitation in patients with septic shock, early goal-directed resuscitation resulted in a large mortality reduction; all patients in the study were resuscitated with crystalloids.13

BLOOD TRANSFUSION STRATEGIES IN THE ICU Minimum Acceptable Hemoglobin Red blood cell (RBC) transfusions are administered to increase oxygen carrying capacity, but it remains uncertain

Ch012-F06861.indd 152

what constitutes an acceptable trigger level of hemoglobin (Hb). Healthy animals can endure Hb levels of 3.0 to 5.0 g/dL, but in the presence of coronary stenoses, only levels of 7.0 to 10 g/dL can be tolerated before ischemia ensues. This is less well established in humans. Healthy volunteers undergoing isovolemic hemodilution develop ischemia at a Hb of 5.0 g/dL. However, there are reports of humans tolerating Hb levels as low as 4.5 g/dL. Among patients who are Jehovah’s Witnesses, healthy adults have been shown to survive without transfusion to an Hb of 5.0 g/dL.68 Older patients with comorbidities are thought to tolerate anemia less well. Two retrospective studies, one in the perioperative period and one involving critically ill patients, showed that severe anemia was associated with increased mortality in patients with cardiac disease.69,70 In assessing transfusion in patients with cardiac disease, Hébert and coworkers showed that patients with cardiovascular and respiratory disease may have increased mortality when Hb levels are less than 9.5 g/ dL, and that transfusion may result in significantly lower mortality rates.70 Similarly, in a large study of patients with acute myocardial infarction, transfusion was associated with a lower short-term mortality rate if the hematocrit (Hct) on admission was 30.0% or lower; transfusion was possibly effective in patients with Hct as high as 33.0%, but mortality was increased with a Hct greater than 36%.71 On the other hand, elderly patients with hip fractures and comorbidities tolerated a Hb level as low as 8.0 g/dL.72 In a European ICU study, the mean pretransfusion Hb was 8.4 ± 1.3 g/dL, and transfusion was associated with a 33% increased risk of death.73

Transfusion and Outcomes in ICU The recent study of anemia and blood transfusion in the critically ill (CRIT) evaluated transfusion practice in 284 ICUs.74 The authors found that 44% of ICU patients still received blood, and that transfusion practice had changed little during the last 10 years. The mean pretransfusion Hb was 8.5 ± 1.5 g/ dL. Only 30% of patients had a transfusion trigger lower than 8 g/dL, and in only 7.5% was the trigger lower than 7 g/dL. Several large cohort studies in England,75 Europe,73 and Australia76 have shown similar transfusion triggers. These findings are surprising, considering the results of the Transfusion Requirements in Critical Care (TRICC) trial.77 This randomized controlled trial assigned patients to either a liberal (Hb 10.0-12.0 g/dL) or restrictive (Hb 7.0-9.0 g/dL) transfusion strategy. The restrictive group received 54% less blood and had a lower in-hospital mortality rate. Among the less severely ill patients and among patients younger than 55 years of age, those in the restrictive group were half as likely to die within 30 days. In these two patient populations, one more death occurred for every 13 to 14 patients treated with the liberal strategy. In a follow-up study of patients in the TRICC trial who had cardiorespiratory disease, overall mortality rates were shown to be similar with restrictive versus liberal transfusion strategies, and the changes in multiple organ dysfunction scores were significantly less in the restrictive group.78 However, in the subgroup of patients with severe ischemic heart disease, the restrictive group had a lower (but nonsignificant) absolute survival rate. The authors concluded that a

1/21/2008 10:44:46 AM

Chapter 12 Critical Care of the Thoracic Surgical Patient

restrictive strategy is safe in most critically ill patients with cardiovascular disease, with the exception of patients with acute myocardial infarction or unstable angina. For those requiring mechanical ventilation, Hb levels did not affect duration of ventilation; however, after adjustment for comorbidities, transfusion was associated with increased duration of mechanical ventilation and increased incidence of pulmonary edema and ARDS. Why is liberal transfusion not associated with improved outcomes? Either anemia has beneficial effects or transfusion has adverse effects, or both (Table 12-3).79 The adverse effects of transfusion include infections (both known and yet undiscovered agents), hemolytic reactions, contamination, allergic reactions, anaphylaxis, transfusion-related ALI, fluidoverload pulmonary edema, and immune modulation. These all increase morbidity and mortality. The issue of transfusionassociated immune modulation has gained increasing attention. It is thought that transfused allogeneic leukocytes trigger an immune response, leading to an increased risk of infection, earlier recurrence of malignancy, and increased mortality. A significant association between the number of RBCs transfused and the risk of nosocomial infections has been reported.80 A recent study showed that the adoption of a universal leukoreduction pathway decreased hospital mortality.81 However, nosocomial infections did not decrease, but the frequency of post-transfusion fevers decreased significantly, as did antibiotic use. Other studies have not shown similar benefits, but many have been limited by methodologic issues.82 Universal leukoreduction is performed in Canada and many European countries, but it remains voluntary in the United States. The only arguments against it are cost and the loss of 4% to 19% of RBCs. Given that society has demanded other policies that possibly increase blood safety, universal leukoreduction needs to become standard.83 However, the studies that have shown an increased mortality among trans-

TABLE 12-3 Hazards of Blood Transfusion Risk Factor

Frequency

Deaths/Million

Infectious Hazards Have Decreased by a Factor of 10,000 Since the 1960s Infection: Viral Hepatitis A 1/1,000,000 0 Hepatitis B 1/30,000-1/250,000 0.14 Hepatitis C 1/30,000-1/150,000 0.5-17 HIV 1/200,000-1/2,000,000 0.5-5 HTLV I and II 1/250,000-1/2,000,000 0 Infection: Bacterial Red cells 1/500,000 0.1-0.25 Platelets 1/12,000 2 NISHOT Have Changed Little Since the 1960s Acute hemolytic 1/250,000-1/1,000,000 Delayed hemolytic 1/1,000 Storage lesions: ? ↓ tissue O2 TRALI 1/5,000 Immune modulation ??

0.67 0.4 ?? 0.2 ??

HIV, human immunodeficiency virus; HTLV, human T-cell lymphotropic virus; NISHOT, noninfectious serious hazards of transfusion; TRALI, transfusion-associated lung injury.

Ch012-F06861.indd 153

153

fused ICU patients have all been done using non–universally leukoreduced blood. The question remains whether similar deleterious effects could be shown if universally leukoreduced blood was used. There is an increasing awareness that certain ischemic syndromes may not benefit from a restricted transfusion threshold. This includes severe coronary artery disease, heart failure, and acute coronary syndromes.84 The effect of transfusion on outcomes in patients with other ischemic syndromes, such as acute neurologic insults, acute tubular necrosis, and acute respiratory failure, is not well established. Another controversial area is the transfusion of old blood. Blood storage lesion refers to the depletion of 2,3-diphosphoglyceric acid and adenosine triphosphate (ATP), with subsequent changes to the cell membrane that reduce deformability. This may impair O2 delivery to tissues by reducing both capillary flow and O2 unloading from Hb. One study supporting this view was an O2 kinetics study that found a correlation between the transfusion of RBCs stored for longer than 15 days and a deterioration in gastric intramucosal pH.85 In the CRIT study, the mean age of blood was 21 days, and in the European study, it was 16 days. In the CRIT study, there was a trend toward worse clinical outcomes in patients who received relatively old blood. However, in a more recent study, the transfusion of stored, leukodepleted RBCs to anemic, critically ill patients had no adverse effects on gastric tonometry or global indexes of tissue O2 delivery.86

POSTOPERATIVE ARRHYTHMIAS Atrial arrhythmias remain a common problem after thoracic surgery despite pharmacologic prophylaxis. The incidence of atrial tachyarrhythmias ranges from 10% to 30% after thoracic surgery,87 with atrial fibrillation (AF) being the most common arrhythmia. A recent analysis of more than 2500 patients undergoing noncardiac thoracic surgery over a 5-year period revealed a 12.3% incidence of AF,88 which is consistent with previous reports in this patient population.87 There are currently no consensus guidelines for the primary prevention of AF that are specific to thoracic or cardiac surgical patients. Digoxin, despite widespread use, has not been proven to reduce the incidence of postoperative AF and may be proarrhythmic.89 Prophylactic oral amiodarone, when given before cardiac surgery, was shown to be cost-effective and safe90 and might be a reasonable preventive strategy in thoracic or other noncardiac surgical patients. The routine use of postoperative IV amiodarone may not be justified because of high cost and associated toxicities, including its proarrhythmic effects and the potential for pulmonary toxicity. It may be cost-effective in selected patient groups only if there is a high predicted incidence of postoperative AF, such as in patients undergoing combined coronary artery surgery and valvular surgery, who have a predicted incidence of AF of greater than 30%.91 However, consensus practice guidelines for the management of new-onset or established AF, from the American College of Cardiology, the American Heart Association, and the European Society of Cardiology, recommend the use of β-blockers for treatment of AF, unless contraindicated.92 Consideration for amiodarone and sotalol is given, but their

1/21/2008 10:44:46 AM

154

Section 1 Introduction

use is supported only by a limited number of randomized trials, with conflicting evidence and/or divergence of opinion about the usefulness or efficacy of the treatment among the task force members. Most recent evidence supports the concept of heart rate control in AF, rather than rhythm control.92 Immediate electrical cardioversion is still indicated whenever hemodynamic instability is present. Left atrial appendage thrombus needs to be excluded with transesophageal echocardiography (TEE) before elective cardioversion is used. However, anticoagulation is recommended for 3 to 4 weeks before and after cardioversion for patients with AF of unknown duration or with AF lasting longer than 48 hours.92 There is no solid clinical evidence that cardioversion followed by prolonged maintenance of sinus rhythm effectively reduces thromboembolism in patients with AF. It is therefore unclear at present whether efforts to restore and maintain sinus rhythm are justified for the specific purpose of preventing stroke. Recovery of mechanical function may be delayed for several weeks. This could explain why some patients with no demonstrable left atrial thrombus on TEE before cardioversion subsequently experience thromboembolic events. Presumably, thrombus forms during the period of stunning and is expelled after the return of mechanical function.92 Ventricular arrhythmias are much less common than atrial arrhythmias after thoracic surgery. Prophylactic suppression of nonsustained ventricular arrhythmias after cardiac surgery with lidocaine has not been shown to improve outcome. A detailed discussion of ventricular arrhythmias is beyond the scope of this section.

MANAGEMENT OF RESPIRATORY FAILURE AFTER THORACIC SURGERY Lung-Protective Ventilation Strategies ALI and ARDS are common complications of sepsis and carry a mortality rate of almost 50%.93 Lung-protective ventilatory strategies that use lower tidal volumes and reduced airway pressures have been shown to reduce morbidity and mortality. Over the past decade, several large multicenter trials have been conducted to evaluate the effect of limiting ventilatory pressures by limiting tidal volumes.94-97 There has not been consistent benefit shown in the studies, and this has been postulated to be due to the differences in airway pressures between the studies.97 In the largest trial, the ARDS Network enrolled patients with ALI in a multicenter, randomized trial. It compared traditional ventilation treatment, with initial tidal volume of 12 mL/kg of predicted body weight and a plateau pressure (measured after a 0.5-second pause at the end of inspiration) of 50 cm H2O or less, with ventilation with a lower tidal volume (initial tidal volume, 6 mL/kg) and a plateau pressure of 30 cm H2O or less. The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0% versus 39.8%; P = .007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group.98 There has been some controversy

Ch012-F06861.indd 154

surrounding this study, including a contention that 12 mL/kg could not be construed as standard therapy in view of what was known about volutrauma and barotrauma at the time the trial was conducted. It also is important to note that other elements were part of the protective ventilator strategy, such as permissive hypercapnia, variable levels of positive end-expiratory pressure (PEEP), and low plateau airway pressures. Permissive hypercapnia as part of a lung-protective strategy has been shown to be safe in small, nonrandomized series.99,100 A recent Cochrane collaborative systematic review of the literature concluded that the comparison between small and conventional tidal volume ventilation was not significantly different if a plateau pressure of 31 cm H2O or less in the control group was used. Mortality at day 28 was significantly reduced by lung-protective ventilation, whereas a beneficial effect on long-term mortality was uncertain.101 The impact from the possible adverse effects of smaller tidal volume ventilation—acidosis and hypercapnia—on the development of organ failure and outcome remains unclear. In a recent meta-analysis of low tidal volumes and outcome in ARDS, Eichacker and colleagues showed that the two trials demonstrating benefit had an odds ratio (OR) of survival varying from 1.57 to 3.97 (the 95% confidence interval [CI] varied from 1.28-7.7), whereas the OR for surviving from the three nonbeneficial trials varied from 0.7 to 0.85 (95% CI, 0.48-1.28).102

Prone Ventilation The role of the prone position in treating refractory hypoxemia is controversial. Patients improve their oxygenation in the prone position,103-105 but this position is labor intensive and can have serious complications, including loss of endotracheal tube and venous catheters, hemodynamic consequences from incorrect position, and pressure necrosis. In a study of prone positioning by Gattinoni and associates, there was no improvement in mortality rate, although there was a suggestion of improved mortality in a post-hoc analysis of the most critically ill patients.106 Until the effect of prone positioning on mortality is further elucidated, the benefit of improved oxygenation must be carefully weighed against the risk, particularly in light of the potential role of selective pulmonary artery vasodilators in treating refractory hypoxemia (see later discussion).

High-Frequency Oscillatory Ventilation The postoperative management of patients with high-output bronchopleural fistulas remains a challenge in ventilatory and oxygenation management. Conventional positive-pressure ventilation (volume or pressure limited) often fails in these patients because of associated disease processes such as decreased pulmonary compliance and bilateral diffuse airspace disease (ARDS) and persistent increased peak and plateau airway pressures. Applying PEEP in an effort to improve oxygenation invariably results in an increase in the bronchopleural fistula leak. High-frequency ventilation was first introduced 30 years ago as a method for reducing intrathoracic pressure during

1/21/2008 10:44:46 AM

Chapter 12 Critical Care of the Thoracic Surgical Patient

thoracic and laryngeal surgery. High-frequency oscillation was developed in the 1970s for the treatment of lung disease of prematurity, but it is now used for acute hypoxemic respiratory failure in all ages—but mostly as rescue therapy.107,108 It has been described in the management of ARDS and bronchopleural fistulas.109,110 The simultaneous use of nitric oxide and high-frequency jet ventilation has also been used safely and effectively in this setting.111

Extracorporeal Membrane Oxygenation Extracorporeal membrane oxygenation (ECMO) was first introduced into clinical practice in the 1970s. Clinical trials to date have failed to show a mortality benefit in adult patients with ARDS. However, several case reports have described successful outcomes in patients for whom ECMO was used as rescue therapy.93,112 Several advances have been made in ECMO technology, including heparin-coated membranes and circuits and the use of centrifugal as opposed to roller pumps, as well as a better understanding of anticoagulation management. Some are now reporting improved mortality rates in adult patients with refractory respiratory failure managed on ECMO.113 There has been no published randomized clinical trial comparing current ventilatory treatment of ARDS with ECMO therapy.93

Selective Pulmonary Arterial Vasodilators Pulmonary hypertension, right ventricular dysfunction, and perioperative hypoxemia are common problems after thoracic surgical procedures requiring treatment in a cardiothoracic ICU. Inhaled nitric oxide (iNO) was the first agent shown to be a selective pulmonary artery vasodilator, and it has also been shown to improve oxygenation in patients with ALI and ARDS.114,115 In a recent Cochrane Review116 and in a systematic review by Kaisers and coworkers,117 the role of iNO in ARDS was addressed. Both studies concluded that the use of iNO does not alter mortality or other clinically relevant end points (e.g., ventilator-free days, ICU stay), but that it does temporarily improve oxygenation and hemodynamics in the acute phase. The investigators proposed that iNO has a role only as rescue therapy in refractory hypoxemia associated with ARDS. However, iNO has become prohibitively expensive and has several associated toxicities that require monitoring, which further increases cost.118 As a result of these issues, there has been an ongoing search for other selective pulmonary artery vasodilators, both as an alternative and possibly as a complement to iNO. Several drugs administered via the inhalational route have been described in animal models and humans. These include inhaled sodium nitroprusside, nitroglycerin, class 5 phosphodiesterase inhibitors (e.g., zaprinast, sildenafil), milrinone, prostaglandin E1 (PGE1, or alprostadil), PGI2 (prostacyclin), and iloprost (the stable analogue of PGI2).119 The use of IV PGI2 was first described in 1978.120 As opposed to PGE1, PGI2 was shown not to have any pulmonary inactivation and therefore to be 10 times more potent as a systemic vasodilator, even though its metabolite, 6-keto-prostaglandin F1α, had little systemic vasodilator properties. However, IV PGI2, as opposed to IV PGE1, became an important pulmonary

Ch012-F06861.indd 155

155

vasodilator in the treatment of pulmonary hypertension.121 Systemic hypotension is a problem in patients with severe pulmonary hypertension because large doses of prostaglandins are required to effectively lower the pulmonary arterial pressures. In 1993, Welte and colleagues reported that inhaled rather than IV PGI2 resulted in selective pulmonary artery vasodilation in dogs.122 It was later shown to be as effective as iNO in reducing pulmonary vascular resistance in candidates for heart transplantation,123,124 in lowering pulmonary artery pressures in primary and secondary pulmonary hypertension,125 and in improving right ventricular function in animals with hypoxic pulmonary vasoconstriction126; as a selective pulmonary artery vasodilator, iPGI2 led to improvement in oxygenation in patients with ARDS127-129 and in those with refractory hypoxemia after cardiothoracic surgery.130 In patients with poor oxygenation, iPGI2 not only improves oxygenation but is also effective as a pulmonary vasodilator while maintaining mean arterial pressure and cardiac output. It appears that there is no appreciable tolerance to any of the beneficial effects of iPGI2 after 4 to 6 hours of administration. Despite a theoretical concern about the potential antiplatelet effects of iPGI2, several studies have now attested to its safety, with no increased risk of bleeding.130,131 Compared to iNO, it is less expensive, is easier to administer, is relatively free of side effects, and requires no special toxicity monitoring.130

Postpneumonectomy Pulmonary Edema Zeldin and colleagues brought attention to the syndrome of postpneumonectomy pulmonary edema (PPPE) in 1984. Using a dog study as corroboration, they concluded that the risk factors for this complication are right pneumonectomy, large perioperative fluid load, and high intraoperative and postoperative urine outputs.132 However, 20 years later, the exact definition and pathophysiology of the syndrome remain unclear. It probably remains underdiagnosed. PPPE develops in approximately 5% of patients undergoing pneumonectomy or lobectomy, and it has a high associated mortality rate (>50%).133 Histologically, it is indistinguishable from ARDS or ALI. It is characterized by dyspnea, hypoxemia, diffuse infiltrates on chest radiography, and rapid evolution often unresponsive to current conventional therapy. ALI occurs almost exclusively after pneumonectomy, usually within 3 days and without a preceding cause. Since the first description by Zeldin and colleagues many other factors have been implicated in its pathogenesis, including excessive fluid administration,134 perioperative administration of fresh-frozen plasma,135 alveolar injury during single-lung ventilation, pulmonary hypertension, impaired lymph drainage and trauma caused by surgical manipulation, right ventricular dysfunction, postoperative hyperinflation related to intercostal tube drainage modes, and possibly occult microaspiration. Bigatello and associates136 and Alvarez137 recently reviewed this subject. Despite the initial emphasis on fluid overload, it is clear that simple fluid overload is not entirely responsible for the syndrome because diuresis is often unsuccessful in correcting the hypoxemia. Jordan and coworkers investigated the role

1/21/2008 10:44:46 AM

156

Section 1 Introduction

of endothelial injury in the development of PPPE.133 They concluded that PPPE more likely represents the pulmonary manifestation of a panendothelial injury consequent to inflammatory processes induced by the surgical procedure, which involves collapse and re-expansion of the operative lung to permit hilar dissection and pulmonary resection. Animal studies have shown that pulmonary ischemia-reperfusion can result in edema formation, possibly from the generation of pro-oxidant forces. Such evidence suggests that PPPE may be modulated by the high inspired oxygen concentrations associated with single-lung ventilation or by ischemia-reperfusion injury. Tamura and associates showed that rats that underwent pneumonectomy had higher plasma and lung concentrations of atrial natriuretic peptide (ANP) as well as a higher expression of ANP receptor-C.138 Similarly, Tayami and Takamori and their colleagues showed that ANP and Btype (brain) natriuretic peptide (BNP) are elevated after lobectomy and after pneumonectomy and that their concentrations correlate with the total pulmonary vasculature resistance after pneumonectomy. ANP and BNP therefore correlate with the amount of lung tissue resected.139 Nesiritide is the recombinant form of endogenous human BNP. It is not dependent on endothelial function, cyclic adenosine monophosphate (cAMP), or β-adrenergic receptors. It is currently used for decompensated heart failure and is a balanced arterial, coronary, and venous vasodilator with beneficial effects on the neurohormonal system, where it counteracts the effects of aldosterone, norepinephrine, and endothelin.140 It remains to be seen whether it has a role to play in PPPE. There is still no specific therapy for this syndrome. Suggested measures in the perioperative setting include the meticulous maintenance of physiologic stability, judicious fluid restriction, and the limitation of ventilatory volumes and pressures.136 Emphasis is also placed on a balanced underwater thoracostomy drainage system that prevents hyperinflation of the remaining lung. Recently Cerfolio and colleagues showed, in a prospective nonrandomized trial that used historical controls, that the use of 250 mg of methylprednisolone before pulmonary artery ligation prevented PPPE, decreased hospital length of stay, and yet did not increase the incidence of bronchopleural fistulas.141 Inhaled pulmonary vasodilators may ameliorate the hypoxemia by improving ventilation-perfusion matching.119,130

USE OF SEDATION AND PARALYSIS IN CRITICAL CARE Inappropriate use of sedation and paralysis significantly increases morbidity. There are no randomized controlled trials supporting the benefit of neuromuscular blockade over that of adequate sedation in patients with respiratory failure requiring mechanical ventilation. Neuromuscular blockade is often used in place of excellent sedation, analgesics, and antidelirium therapy. Its routine use must be discouraged. Neuromuscular blocking agents are used in the ICU to facilitate ventilation, manage increased intracranial pressure, treat muscle spasms, and decrease oxygen consumption only if all other means have been tried without success. Practice guidelines have now been established for the use of sedation and

Ch012-F06861.indd 156

neuromuscular blockade in the ICU.142-144 Rational-use guidelines in the provision of continuous analgesia, sedation, and neuromuscular blockade to critically ill patients requiring ventilator management have been shown to be safe and costeffective when compared with baseline prescribing strategies. Direct drug costs, ventilator time, and length of stay are reduced, as is the use of neuromuscular blockade.145 In a study by Kress and coauthors, the daily interruption of sedation in the ICU reduced costs and decreased time on mechanical ventilation.146 In a recent study, the same group showed that this strategy also reduced the incidence of complications such as ventilator-associated pneumonia, upper gastrointestinal hemorrhage, bacteremia, barotrauma, venous thromboembolic disease, and cholestasis or sinusitis requiring surgical intervention.147 Propofol and midazolam are now commonly used to achieve sedation in the ICU. Both drugs have been shown to achieve optimal sedation in a large fraction of patients when administered by specified dosing protocols. Propofol has a faster, more reliable wake-up time and provides for a more objective and reproducible assessment of time-to-awaken, compared with midazolam.148 Propofol infusion syndrome is a rare and often fatal syndrome that occurs in critically ill patients undergoing high-dose propofol infusion. The syndrome consists of cardiac failure, rhabdomyolysis, severe metabolic acidosis, and renal failure. To date, 21 pediatric and 14 adult cases have been described. The latter were mostly patients with acute neurologic illnesses or acute inflammatory diseases complicated by severe infection or even sepsis, and they were receiving catecholamines and/or steroids in addition to propofol. Central nervous system activation with production of catecholamines and glucocorticoids, and systemic inflammation with cytokine production, are priming factors for cardiac and peripheral muscle dysfunction. High-dose propofol and supportive treatments with catecholamines and corticosteroids act as triggering factors. The syndrome can be lethal, and caution is suggested when using prolonged (>48 hours) propofol sedation at doses higher than 5 mg/kg/hour.149 Although it is still a common practice in the ICU, being intubated is not an indication for automatic sedation. However, many of the ICU sedation studies still rely on this premise. Each patient’s treatment needs to be individualized, and, with the appropriate nursing ratios, some patients will require no psychoactive medications. Some may require only intermittent patient-requested analgesia, and the needs of others may vary from a nocturnal sleep aid to anxiolysis, deep sedation, continuous analgesia, and treatment for delirium.

GLUCOSE CONTROL IN CRITICALLY ILL PATIENTS Diabetes mellitus has long been associated with significant morbidity and mortality and with adverse outcome in critically ill patients. Hyperglycemia is associated with morbidity and mortality in a wide array of intensive care patients. In patients with severe brain injury, hyperglycemia is associated with a worse neurologic outcome and reduced survival. In children with severe burns, the incidence of bacteremia and fungemia, the number of skin grafting procedures, and the

1/21/2008 10:44:47 AM

Chapter 12 Critical Care of the Thoracic Surgical Patient

risk for death were higher in hyperglycemic than in normoglycemic patients. In trauma patients, elevated glucose levels early after injury have been associated with infectious morbidity, a lengthier ICU and hospital stay, and increased mortality. In patients with myocardial infarction, there is an increased risk for congestive heart failure or cardiogenic shock and in-hospital mortality. Similarly, in patients with acute stroke, hyperglycemia is associated with a higher risk of death and a poor functional recovery.150 There is increasing evidence that maintaining normoglycemia and treatment with insulin-based regimens are beneficial in limiting organ damage and significantly reduce both morbidity and mortality in critically ill patients who require intensive care therapy.151 In the first conclusive clinical study, Van den Berghe and colleagues demonstrated that intensive insulin therapy that maintained the blood glucose level at 80 to 110 mg/dL (4.4-6.1 mmol/L) resulted in lower morbidity and mortality among critically ill patients than did conventional therapy that maintained the blood glucose level at 180 to 200 mg/dL (10.0-11.1 mmol/L) (Van den Berghe, 2002).152,153 Intensive insulin therapy reduced the frequency of episodes of sepsis by 46%. Patients with bacteremia who were treated with intensive insulin therapy had lower mortality than those who received conventional therapy (12.5% versus 29.5%). Insulin therapy reduced the rate of death from multiple-organ failure among patients with sepsis, regardless of whether they had a history of diabetes. The protective mechanism of insulin in sepsis is unknown. The phagocytic function of neutrophils is impaired in patients with hyperglycemia, and correcting hyperglycemia may improve bacterial phagocytosis. Another potential mechanism involves the anti-apoptotic effect of insulin. Insulin prevents apoptotic cell death from numerous stimuli by activating the phosphatidylinositol 3-kinase-Akt pathway.154 Recently, however, Mesotten and coworkers showed that the beneficial effects of insulin therapy on lipids, rather than on glucose control, independently accounted for the beneficial effects on morbidity and mortality.155 Insulin therapy increased both low-density lipoprotein and high-density lipoprotein but suppressed elevated triglycerides. Regardless of mechanism, it seems reasonable to control blood glucose more tightly in critically ill patients. Clinicians must prevent hypoglycemic brain injury in attempting to maintain the blood glucose level at 80 to 110 mg/dL. Frequent monitoring of blood glucose is imperative, and studies are needed to determine whether less tight control of blood glucose—for example, a blood glucose level of 120 to 160 mg/dL (6.78.9 mmol/L)—provides similar benefits. There is now emerging data that even one episode of hypoglycemia in ICU can increase mortality. More controlled trials are needed to define the effects of tight glucose control on the outcome in subgroups of patients, to determine the target range of glycemic control for different patient populations, and to define the treatment standards with which to facilitate intensive insulin therapy without compromising patient safety. Institutional insulin infusion protocols must be developed, with special emphasis on efficiency, safety, and nursing workload and including the use of computer-assisted algorithms.

Ch012-F06861.indd 157

157

HEMODYNAMIC MONITORING IN CRITICAL CARE The Role of the Pulmonary Artery Catheter The use of a pulmonary artery catheter (PAC) in the care of critically ill patients is increasingly being questioned. In an important but controversial publication in 1996, the use of a PAC was associated with an increased risk of death (OR, 1.24).156 In an accompanying editorial, the question was raised whether there should be a moratorium on the use of the PAC.157 In 2000, the National Heart, Lung and Blood Institute published a report on the role of the PAC which maintained that there was no compelling evidence that it improved outcomes and that its use was associated with significant risks and cost. The report concluded that a state of clinical equipoise existed regarding the use of the PAC in critically ill patients, and that randomized studies on its utility need to be conducted. Richard and associates examined the use of the PAC in patients with shock and ARDS and found no effect on mortality, morbidity, or resource utilization.158 In a recent study comparing the central venous catheter (CVC) with the PAC in the management of ALI, PAC-guided therapy did not improve survival or organ function but was associated with more complications than CVC-guided therapy. These results, when considered with those of previous studies, suggest that the PAC should not be routinely used for management of ALI.159 Sandham and coworkers examined the use of the PAC in patients after high-risk, noncardiac surgery.160 They found that there was no significant effect on mortality and that there was possibly increased morbidity with its use. Yu and colleagues examined the effect of the PAC in patients with severe sepsis and found no beneficial effect on mortality or resource use.6

Alternatives to the Pulmonary Artery Catheter to Measure Cardiac Output It is possible that mortality after major surgery could be significantly reduced by the adoption of certain goal-directed approaches to perioperative hemodynamic management. One of the cornerstones of goal-directed resuscitation is adequate perfusion. There are now several techniques available to noninvasively measure cardiac output, but few or limited outcome studies have examined their use.161-164 We briefly review these methods. Lithium dilution is a new indicator dilution technique that is relatively minimally invasive and requires a venous line and an arterial catheter. The indicator is lithium chloride, which is injected as a bolus via the venous line (central or peripheral); the arterial plasma concentration is measured with the use of a lithium sensor. The change in lithium concentration with time is dependent on cardiac output. Lithium dilution has been shown to be at least as accurate as bolus thermodilution, and it has the added benefit of being simple to perform and safe. It does not elicit any of the hemodynamic changes that are sometimes seen with injections of cold saline. Partial carbon dioxide rebreathing requires a patient to be intubated. Based on Fick’s principle, cardiac output is measured by a device that uses partial CO2 rebreathing to deter-

1/21/2008 10:44:47 AM

158

Section 1 Introduction

mine cardiac output noninvasively. Rebreathing measurements are made every 3 minutes for 35 seconds. Cardiac output is proportional to the change in CO2 elimination divided by the change in end-tidal CO2 resulting from a brief rebreathing period. These measurements are accomplished and measured by the proprietary sensor, which periodically adds the rebreathing volume into the breathing circuit. The method is affected by lung function, including dead space and the alveolar-arterial oxygen gradient. Esophageal Doppler measures blood flow velocity in the descending thoracic aorta. This measurement is then combined with an estimate of the cross-sectional area of the aorta, which is derived from the patient’s age, height, and weight. The method allows hemodynamic variables, including stroke volume, cardiac output, and cardiac index, to be calculated. TEE can be used to calculate stroke volume, which can then be multiplied by heart rate to give a measurement of cardiac output. However, the method is limited to sedated patients. Thoracic bioimpedance uses pulsatile changes in resistance that occur during ventricular systole and diastole to measure cardiac output. Electrodes are applied to the neck and thorax, and a small electric current is passed across the thorax. The changes in impedance correlate with stroke volume and allow stroke volume to be calculated. However, the method has significant measurement-associated problems (e.g., electrode placement) and therefore has not gained wide acceptance. In pulse contour analysis, analysis of an arterial pulse pressure waveform can be used to measure beat-to-beat cardiac output. This involves measuring the area under the arterial pulse wave from the end of diastole to the end of the ejection phase, together with an individual calibration factor to account for individual vascular impedance. An arterial indicator dilution technique is used for calibration of the device. Pulse pressure analysis, when used in conjunction with the lithium dilution technique for calibrating the system, is a continuous noninvasive cardiac output measurement that is reliable and precise. It is a useful way to determine cardiac output, stroke volume, and systemic vascular resistance.

STRESS ULCER PROPHYLAXIS The incidence of significant stress-related bleeding seems to be decreasing in ICU patients for many reasons, including improved overall patient care, better treatment of shock states, earlier feeding, and earlier recognition of potential complications. The incidence of stress ulcer is likely much lower than was believed to be the case in the 1970s; at present, gastrointestinal bleeding occurs in about 1% of ICU patients. The risk factors that have been identified include surgical patients requiring mechanical ventilation for more than 48 hours, coagulopathy or anticoagulant use, and corticosteroids. The widespread use of prophylaxis seems to be limited even in high-risk patients, and there is little evidence of a mortality decrease or even a reduced length of stay in the ICU. The relative effectiveness of various classes of pharmacologic prophylaxis (H2 receptor antagonists, proton pump inhibitors, and sucralfate) is therefore controversial in light of the bigger issue of the effectiveness (or lack thereof) of

Ch012-F06861.indd 158

stress ulcer prophylaxis. A large, placebo-controlled trial with multiple intervention groups is needed to resolve the issue, but the incidence of clinically significant stress ulcer bleeding is now so low that a definitive study to settle this issue will be very difficult.165 There are significant associated side effects with stress ulcer prophylaxis. H2 receptor antagonists and proton pump inhibitors raise the gastric pH, thus eliminating one of the defense mechanisms against bacterial colonization in the upper gastrointestinal tract. There is concern that use of these agents might result in a greater risk of ventilatorassociated pneumonia as a result of microaspiration of heavily colonized gastric secretions. There is also growing concern that the widespread change in the pH of the gastrointestinal tract increases the overgrowth of C. difficile and the emergence of resistant forms of this organism. C. difficile is now associated with significant hospital morbidity and mortality.166 Given the available evidence, H2 receptor antagonist therapy is recommended over sucralfate in patients meeting high-risk criteria for stress ulcer bleeding. Stress ulcer prophylaxis must be discontinued as soon as possible, and especially once patients are receiving enteral feedings, unless they are receiving steroids or remain coagulopathic.

COMMENTS AND CONTROVERSIES Intensive care is an integral part of thoracic surgical practice. Drs. Jacobsohn and De Wet have provided an extensive review of major issues in thoracic surgical critical care. Sepsis and antibiotic therapy, APC, vasopressors, corticosteroid therapy, fluid management, blood transfusion, postoperative arrhythmia, strategies for management of respiratory failure, use of sedation and paralysis, glucose control, and the role of the pulmonary artery catheter are all reviewed from an evidence-based perspective. In each of these areas, new data are emerging, some from large clinical trials, which challenge the notions and dogmas we have considered unassailable for years. Evidence-based protocols and treatment algorithms improve outcomes in the intensive care setting. These protocols need to be in use in every ICU caring for thoracic surgical patients. Finally, the authors emphasize the importance of an intensivist-led multidisciplinary ICU team. I have had the pleasure and education of working with Dr. Jacobsohn as he developed such a team in our cardiothoracic ICU at Washington University Barnes-Jewish Hospital. Patient care, teaching, clinical research, and the efficiency of our unit improved dramatically as the intensive care group, appointed to our surgical division, assumed primary management for our patients in the ICU. As surgeons, we have not lost control of patient management. In fact, the opposite is true: we have gained greater control of the patients’ overall health by having the collaboration of knowledgeable colleagues available full time in the ICU. G. A. P.

KEY REFERENCES Bernard GR, Margolis BD, Shanies HM, et al: Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): A single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 125:2206-2216, 2004.

1/21/2008 10:44:47 AM

Chapter 12 Critical Care of the Thoracic Surgical Patient

Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699-709, 2001. Dellinger RP: Cardiovascular management of septic shock. Crit Care Med 31:946-955, 2003.

Ch012-F06861.indd 159

159

Finfer S, Bellomo R, Boyce N, et al: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247-2256, 2004. Van den Berghe G: Beyond diabetes: Saving lives with insulin in the ICU. Int J Obes Relat Metab Disord 26(Suppl 3):S3-S8, 2002.

1/21/2008 10:44:47 AM

chapter

13

EARLY POSTOPERATIVE COMPLICATIONS Robert James Cerfolio

Key Points ■ Careful patient selection, intraoperative techniques, and aggres-

sive postoperative care are essential to minimizing postoperative complications. ■ Despite careful selection, air leaks and pulmonary complications are common.

The postoperative care of a patient who is to undergo pulmonary resection starts long before the incision is made. Smoking cessation, pulmonary rehabilitation, incentive spirometry teaching, and patient education are all critical factors that help minimize some of the more common early postoperative complications described in this chapter. Additionally, careful patient selection based on pulmonary function tests, comorbidities, cardiopulmonary reserve, and the patient’s motivation to recover are also important factors. These preoperative factors must be followed by a meticulous operation that is efficient but not hurried and has minimal blood loss. The postoperative team is comprised of experienced and vigilant nurses, pain specialists, respiratory therapists, and physical therapists. Ideally, this team works on a hospital unit that allows continuous telemetry to monitor cardiac rhythm and pulse oximetry to monitor oxygen saturation of postoperative patients. However, despite maximization of all of these factors and adherence to the motto, “The best treatment of postoperative complications is prevention,” early complications occur nonetheless. The mortality rate from elective pulmonary resection is on the decline according to recent reports,1 but it remains significantly high. In most large studies, it is two to four times greater than that of elective coronary artery bypass surgery.2,3 The incidence of major morbidity in several large series is also high, ranging from 10% to 70%, with most series reporting approximately 30% to 40%.4,5 As the population continues to age, as more patients receive neoadjuvant chemotherapy and/or radiotherapy, and as more patients are immunocompromised, complications will continue to be an unavoidable and humbling part of the practice of thoracic surgery. This chapter provides a brief overview and describes the incidence, risk factors, and management of the some of the common early postoperative complications occurring after pulmonary resection, beginning with the most common.

AIR LEAK OR ALVEOLAR-PLEURAL FISTULA An alveolar-pleural fistula (APF), more commonly known as an air leak, is probably the most common complication after

elective pulmonary resection. It is defined as a communication between the pulmonary parenchyma distal to a segmental bronchus and the pleural space.6 Until recently, there were few scientific studies on this very common complication. However, several prospective studies have now been performed. In addition, the RDC (Robert David Cerfolio) classification system has been developed and shown to be accurate and reproducible. The RDC system describes the qualitative and quantitative aspects of air leaks that affect their natural history and, consequently, their treatment.7 The incidence of air leak varies according to the postoperative day on which it is accounted for. My colleagues and I have reported, in two separate prospective studies, an incidence of 25% on postoperative day 1 (1 in 4 patients who underwent elective pulmonary resection) and 20% on postoperative day 2 (1 in 5 patients).8,9 Some studies report the incidence of prolonged air leaks, which is the presence of an air leak on an arbitrary postoperative day. We believe that a prolonged leak is best defined as any leak that delays hospital discharge. Because most patients can be discharged by postoperative day 3 or 4 (Cerfolio et al, 2001),10 we choose to define a prolonged air leak as one that is present on postoperative day 4. The incidence of a prolonged leak, defined in this way, is about 5% in most published reports. Factors that increase the incidence of air leak include emphysema, bilobectomy compared to lobectomy, poor chest tube placement, and operative approaches that do not employ techniques that help prevent air leaks. These techniques include pleural tents,11 pericardial-buttressed stapled lines,12 fissureless surgery,13 and checking for air leaks before closing. The treatment for air leaks has recently been investigated with scientific rigor. Our group (Cerfolio et al, 2001)10 and that of Marshall14 showed, in two different prospective randomized studies, that air leaks are best treated by placing chest tubes on water seal instead of suction in the postoperative setting. However, Brunelli and colleagues did not find a statistical advantage for water seal, although they did identify a trend in patients who did not undergo pleural tenting favoring water seal over suction.15 Therefore, the best treatment of most air leaks appears to be water seal. Chest tubes are best placed on water seal unless a patient has a large leak (an expiratory of 3 or greater on the RDC classification system).7 In a recent study, our group showed that water seal is safe even for an air leak and a concomitant pneumothorax.16 However, if the patient develops an increasing pneumothorax with increasing hypoxia and/or subcutaneous emphysema, then suction (we prefer the least amount needed, usually −10 cm H2O) is appropriate. If the leak

160

Ch013-F06861.indd 160

1/21/2008 10:45:38 AM

Chapter 13 Early Postoperative Complications

continues after postoperative day 4, then the patient may be discharged home with a Heimlich valve or a similar device such as an Atrium Express (Atrium USA, Hudson, NH). The chest tube may be removed after 2 weeks even if the air leak remains (Cerfolio et al, 2002).17

ATRIAL FIBRILLATION Atrial fibrillation is another very common complication after pulmonary resection. The incidence varies due to inconsistent definitions (duration and postoperative day on which it is detected). Its incidence ranged from 12% to 20% in several large series with more than 500 patients each, with a peak onset on postoperative day 2.18,19 Risk factors for postoperative atrial fibrillation include advanced age (greatest for those older than 70 years),20 amount of lung resected,21 clamshell incision, history of congestive heart failure,21 and type of pulmonary resection (right-sided pneumonectomy20). The incidence is also dependent on the type of pulmonary resection performed. Other identified risk factors for the development of postoperative atrial fibrillation include male gender, previous cardiac arrhythmia, and intraoperative blood transfusions. The ideal treatment of atrial fibrillation is prevention. A prospective randomized trial from the Sloan-Kettering Institute showed that prophylactic diltiazem reduced the overall incidence of atrial fibrillation after standard and intrapericardial pneumonectomy.21 The treatment of postoperative atrial fibrillation depends on the patient’s ventricular rate and hemodynamic status. If the patient is unstable, transfer to the intensive care unit (ICU) and urgent cardiology consultation are suggested. Electrical cardioversion may be needed. However, most patients are hemodynamically stable despite a rapid ventricular rate. These patients are best treated with a calcium channel blocker. Often, a drip can be used while the blood pressure is carefully monitored. The use of digitalis has fallen out of favor, but this safe and timetested drug will slow the ventricular rate; however, it may not restore normal sinus rhythm. More recently, amiodarone has been shown to be effective in the treatment of supraventricular arrhythmias and safe even in elderly patients, and it often restores normal sinus rhythm.22

patient with adequate pulmonary reserve. However, atelectasis that is segmental or greater may cause clinical demise and usually requires bronchoscopy. Risk factors for this type of atelectasis are poor cough, impaired pulmonary function, inadequate pain control, diaphragmatic dysfunction, chest wall instability, and sleeve resection.25 The clinical sequela of this type of atelectasis is ventilation/perfusion mismatch that leads to hypoxemia, impaired alveolar macrophage function, and, often, pneumonia. Again, prevention is the best treatment. Chest physiotherapy with vibratory percussion, frequent spirometry exercises, ambulation at least three to four times daily, and secretion control are the mainstays of prevention. Ambulation not only decreases the risk of deep venous thrombosis but helps rehabilitate the patient. It changes pulmonary blood flow and helps improve areas of ventilation/perfusion mismatch. Respiratory treatments entail mist inhalation to loosen secretions, inhaled nebulized bronchodilator therapy, and chest percussion with postural drainage. Pain control allows for deep cough and facilitates adequate mobilization of secretions. Despite these preventive techniques, however, a new infiltrate sometimes develops. Sputum cultures are obtained and broad-spectrum antibiotics started. Although Tobin and Grenvik26 showed in 1984 that up to 30% of new infiltrates in the ICU prove not to be pneumonia, a missed pneumonia in a postoperative patient carries a high morbidity. Once the culture results and sensitivity panel are available, the antibiotics are narrowed to treat the offending organism. This will help prevent the selection of fungal or other resistant organisms. Often there is no evidence of an infiltrate but the patient develops a productive cough, fever, and/or elevated white count. Because the radiologic findings of an infiltrate often lag behind a clinical pneumonia, especially in the dehydrated patient, broad-spectrum antibiotics with fungal prophylaxis are started. If all the cultures are negative, then the antibiotics can be stopped. However, if the infiltrate worsens or the patient’s clinical course deteriorates, bronchoalveolar lavage is performed to help identify the pathogen and direct antibiotic coverage.

PNEUMONIA

POSTOPERATIVE SOMNOLENCE FROM EPIDURAL ANALGESIA

Pneumonia remains a vexing problem after pulmonary resection. Although the incidence at our institution has been as low as 2.2% in one series,11 other series, such as those from Deslauriers and associates in 1994 (Deslauriers et al, 1994)23 and Duque and colleagues in 1997,24 have reported incidences ranging up to 6%. When pneumonia occurs, it wreaks significant morbidity. Risk factors include preoperative hospital stay, immunocompromised state, procedure type (pneumonectomy > lobectomy), compromised pulmonary reserve, smoking, and atelectasis. Atelectasis, a risk factor for the development of pneumonia, is a common complication after pulmonary surgery itself, as shown by Deslauriers3 and Ginsberg2 and their associates. Fortunately, most atelectasis is plate-like, discoid, or linear; is subsegmental; and has little clinical consequence in the

Epidural analgesia has been one of the most important advances in general thoracic surgery in the past decade. It reduces respiratory complications by allowing patients to breathe deeper, walk sooner, and better mobilize secretions. These advantageous effects, however, have resulted in a dualedged sword. By enabling us to safely operate on older, sicker, and weaker patients with less cardiopulmonary reserve, it has raised the bar to such heights that there are now few, if any, patients who cannot tolerate a thoracotomy, a wedge resection, or segmentectomy. Complications from epidural analgesia include accidental entry into the subarachnoid space, hematoma, urinary retention, itching, nausea, and respiratory depression. A so-called wet tap can occur if the needle or catheter accidentally enters the subarachnoid space. The former is immediately recog-

Ch013-F06861.indd 161

161

1/21/2008 10:45:38 AM

162

Section 1 Introduction

nized by the physician placing the epidural. The latter is recognized when the test dose given after insertion results in numbness in the chest area. The most significant and most common complication from epidural analgesia is the overnarcotized patient. This is not uncommon and needs to be swiftly recognized and treated. New-onset somnolence can have several causes (e.g., stroke, intracranial abnormalities, electrolyte imbalances, sundowning), but the epidural as a potential cause must not be overlooked. Often, patients’ family members aggressively deliver their analgesia; clinical staff need to discourage this practice. If patients cannot deliver their own pain medicines or do not understand how to use the machine, they are poor candidates for a PCA unit and should not have one. They should have traditional pain medicines delivered by the nursing staff. If the patient is somnolent from excessive narcotic analgesia, we prefer to arouse the patient with external stimuli. A chest rub or aggressive bedside maneuvers can quickly wake up a patient; this helps establish the diagnosis and can eliminate other potential causes. A reliable, calm family member in the room can also be helpful, and often one-on-one nursing is needed. If external stimulation fails, if the patient’s oxygen saturation remains low, or if arterial blood gas measurements continue to show hypercapnia despite aggressive pulmonary toilet and incentive spirometry, then we prefer to give intravenous Narcan (naloxone hydrochloride; Endo Labs, Chadds Ford, PA). A higher dose can result in too much rebound pain. If the patient does not awaken, a higher dose can be administered after other causes of the new-onset somnolence have been ruled out. Such patients are best transferred to the ICU. If the patient arouses after the administration of Narcan, we eliminate the epidural basal rate and/or remove the epidural altogether, depending on the situation and postoperative day.

ASPIRATION Aspiration is a devastating complication after pulmonary surgery. The incidence is often underestimated because pneumonia frequently occurs secondary to silent aspiration, masking the true cause. Risk factors for an acute aspiratory event include age (incidence is greater in elderly patients), altered mental status, and a weak and/or sleepy patient. It is not uncommon for aspiration to occur when the patient is in the computed tomographic scanner because patients are often sick and must lay flat for considerable lengths of time. It can also occur in a healthy patient who is preparing to go home after an uncomplicated postoperative course, resulting, within a few days, in sepsis, multiorgan system failure, and death. Therefore, aspiration needs to be aggressively avoided. Patients are instructed to eat only when wide awake and when sitting upright at 90 degrees in bed or in a chair. Family members are discouraged from helping to feed the patient, especially if the patient is sleepy. Once aspiration occurs, patients quickly desaturate. Continuous pulse oximetry monitoring until discharge helps signal this event and leads to a quick diagnosis. The diagnosis can be made by history if the patient is still alert or a family

Ch013-F06861.indd 162

member was present at the time of the aspiration event. Treatment depends on the patient’s clinical status. Most patients have a nasogastric tube placed, a chest radiograph, an arterial blood gas sample drawn, and other laboratory work sent. If the patient is in extreme respiratory distress, immediate intubation and bronchoscopy with lavage and cultures are performed. Broad-spectrum antibiotics are started immediately; hemodynamics are maximized to help perfuse and protect end organs; and the patient is transferred to the ICU.

STATES WITH HIGH CHEST TUBE OUTPUT The true incidence of this complication is unknown. High chest tube output from a sympathetic effusion after pulmonary resection is common. It delays patient discharge, despite the fact that there are no data to support this practice. The minimum amount of drainage that precludes removal of a chest tube after an elective pulmonary resection is not known. We have studied this issue and have shown that it is safe to remove tubes with volumes of at least 450 mL/day without having patients coming back to the hospital with symptomatic effusions.11 Therefore, removal with at least this amount of drainage is safe, possibly secondary to the absorptive reactivity of the pleura after pulmonary resection. Although the volume of drainage is important, the color and character of the effluent as well as the rate of change in effluent volume are also important. However, before removing a tube with a high output (>450 mL/day), there are three conditions that must be ruled out. The first and most obvious is bleeding. The second is chylothorax, and the third is a subarachnoid-pleural fistula.

CHYLOTHORAX AND SUBARACHNOIDPLEURAL FISTULA A chylothorax is diagnosed when a milky white chylous effusion is discharged through the chest tube after enteral intake. It consists of intestinal lymphatic fluid (lymphocytes, immunoglobulins, and enzymes) and fat (fat-soluble vitamins, chylomicrons, and triglycerides).27 Once the patient starts to eat, the diagnosis is obvious. However, the diagnosis is suspected in a patient who is not eating, who has a stable hemoglobin and hematocrit, and whose chest tube output is high for unknown reasons. The diagnosis is made by sending the effluent for analysis. A triglyceride level greater than 110 mg/dL28 or a positive Sudan fat stain helps secure the diagnosis.29 The incidence of a chylothorax has been reported to be between 0.04% and 2% (Cerfolio et al, 2001) 10,30-32 after lobectomy, and 0.7% to 1% after pneumonectomy.33 The incidence of a subarachnoid-pleural fistula after thoracic surgery is very low, but several cases have been reported.34,35 Treatment depends on the level of the injury. Most commonly after pulmonary resection, a chylothorax occurs due to engorged lymphatics in patients who have positive N2 nodal disease, have received neoadjuvant therapy for N2 nodal disease, and have undergone a complete thoracic lymphadenectomy. The best treatment for most patients is to give nothing by mouth (NPO) and ensure that the chest

1/21/2008 10:45:38 AM

Chapter 13 Early Postoperative Complications

tube volume decreases. A medium-chain triglyceride (MCT) diet is then instituted for 2 weeks. The patient may be discharged home with the tube in place on the MCT diet for 2 weeks. Then, we challenge the patient with fatty meals for 2 days. If chest tube output is decreased, the chest tube is removed. However, if the output volume remains high despite compliance on an MCT diet, then complete cessation of all oral intake is needed, and total parental nutrition is required. Nutritional parameters are tested and the white blood cell count monitored. Persistent chylothorax can lead to neutropenia, infection, and malnutrition. Less frequently, a chylothorax occurs after pulmonary resection due to injury to the main thoracic duct (best determined from a lymphangiogram). If such an injury has occurred, reoperation with duct ligation and pleurodesis is best.

PULMONARY EDEMA One of the biggest obstacles facing the surgeon who has performed a pulmonary resection is convincing inexperienced anesthesiologists, nurses, residents, and fellows that patients do not require and should not have the traditional amount of fluids that most other postsurgical patients need. Pulmonary surgery does not cause large amounts of fluid shifts, as intraperitoneal surgery does. Moreover, expansion and deflation of the lung secondary to double-lumen tube anesthesia, intraoperative barotrauma and volutrauma to the alveoli, and surgical manipulation of the lung all lead to pulmonary damage and edema. Therefore, once again, the guiding principle to treat pulmonary edema is prevention. The true incidence is difficult to gauge because of varying causes and definitions. The tendency to give patients large volumes of fluids after epidural placement because of hypotension from the sympathectomy effect must be avoided. This difficult task is accomplished only by continued communication between the surgeons, the rest of the surgical service, and the pain, anesthesia, nursing, and residential staff who continually rotate through these services. We prefer the use of α-agonists such as phenylephrine if mean arterial blood pressure falls after epidural dosing in a patient who is to undergo pulmonary resection, after one 250-mL bolus of fluids. However, despite running the patient dry, some patients still develop pulmonary edema. Obviously, one needs to ensure that the cause is not cardiac insufficiency. Diuretics remain the mainstay of treatment, and the sodium level can be used as an indication of the patient’s fluid status. Other factors that need to be considered are weight gain since surgery, chloride level, and urinary osmolarity if diuretics have not yet been given. The more commonly used central venous pressure and/or pulmonary capillary pressure are not needed in most patients unless they are wet on chest roentgenogram, hypoxic, hypotensive, and oliguric. If the patient continues to deteriorate, echocardiography is performed to assess both right and left ventricular function, and the patient is transferred to the ICU for placement of a Swan-Ganz catheter. Blood cultures and appropriate scans are performed to rule out occult infection and leaking capillary membranes from sepsis. If high-dose diuretics are not successful, the

Ch013-F06861.indd 163

163

patient may have adult respiratory distress syndrome (ARDS). Management of this complication is discussed elsewhere in this textbook.

EARLY BRONCHOPLEURAL FISTULA A bronchopleural fistula (BPF) is defined as a communication between a lobar or segmental pulmonary bronchus and the pleural space.36 It is different from an alveolar-pleural fistula. This difference not only is one of semantics but also impacts treatment because an alveolar-pleural fistula almost never requires a reoperation, whereas a BPF almost always does. A BPF can manifest as an early complication, but more commonly it is a late one. The incidence of BPF has been reported to be 4.5% to 7% after a pneumonectomy37,38 (8.6% for right pneumonectomy and 2.3% for left pneumonectomy),39 about 1% after a lobectomy,38,39 and 0.3% after a segmentectomy.38 However, a BPF after lobectomy performed for cancer is very rare. Risk factors for BPF are divided into patient characteristics and intraoperative techniques. The former include infectious etiology, preoperative irradiation, type of procedure (the greatest incidence is with right pneumonectomy), immunocompromised state (e.g., history of solid organ transplantation), and comorbidities such as diabetes. Intraoperative risk factors include surgeon inexperience, a long stump, leaving lymph nodes on the bronchus, and injuring the arterial blood supply to the bronchus. When a BPF manifests as an early complication, patients developed a new large air leak that they did not have before. It usually is a continuous leak as described by the RDC classification system of air leaks. Treatment begins with immediate recognition, which requires a high index of suspicion at any time air leak suddenly increases. BPF can usually be confirmed with bronchoscopy, but this test can be falsely negative, and a small BPF can be missed. If the diagnosis remains in question, a xenon ventilation scan can be performed (this is difficult if the patient is intubated). Visualization of the xenon gas escaping the airway, traversing the pleural space, and going into the chest tube and drainage system secures the diagnosis. Once diagnosed, the BPF is treated with reoperation, using muscle flaps or omentum as described elsewhere in this textbook.

EMPYEMA Empyema is an uncommon complication after pulmonary resection. It is most often seen in patients who have undergone a pneumonectomy, in whom the estimated incidence is between 2% and 16%.41 In a study by Varela and coworkers (Varela et al, 2004),40 empyema was the most common cause of readmission after pulmonary resection, in 2.5% (18/727) of patients. The primary risk factor has been cited to be pneumonectomy with an associated BPF.41-43 Less commonly cited risk factors include anatomic extent of disease (no association with stage I cancer, some association with stage II and III cancer), degree of surgical manipulation, and an immunologically compromised host.42 The treatment is control of the pleural space. This can be established by chest tube placement, VATS, or, most commonly, repeat thoracotomy with a muscle flap. If there is any

1/21/2008 10:45:38 AM

164

Section 1 Introduction

question of an early BPF that is the cause of the early empyema, then repeat thoracotomy with muscle or omental harvesting is mandatory, not only to drain the empyema and decorticate the lung but also to buttress the open bronchus.

PULMONARY INSUFFICIENCY Despite the use of preoperative tests and techniques to preserve pulmonary function, pulmonary insufficiency can still occur after pulmonary resection.44 Inability to extubate a patient immediately after the operation, which is extremely rare, is a poor prognostic sign. The difficulty usually arises on postoperative day 2 or 3 secondary to pneumonia, poor cough effort, or pulmonary edema. The patient often begins to develop signs of respiratory distress before an infiltrate is seen on the chest roentgenogram. Sputum cultures are obtained, after which broadspectrum antibiotics are started immediately. These drugs need to be tailored to the cultures and sensitivities reported later. Pulmonary mechanics must be maximized, and this includes minimal intravenous fluids, aggressive chest physiotherapy, continuous respiratory treatments with bronchodilators, incentive spirometry, frequent ambulation with physical therapy, control of secretions, and nutritional support. If the patient cannot clear his or her own secretions, nasal tracheal suction is used to encourage coughing. Nasal tracheal suctioning via a nasal trumpet or even minitracheostomy affords the surgeon other methods to help clear the airway and avoid recurrent atelectasis and pneumonia. The somnolent patient needs to be aroused and treated as described earlier. Arterial blood gas measurements are performed to rule out hypercapnia. If this fails, minitracheostomy can be performed to manually suction the upper airways, and bronchoalveolar lavage is used to obtain sputum samples to identify the offending organisms.

POSTOPERATIVE HEMORRHAGE The incidence of postoperative hemorrhage after elective general thoracic surgical procedures in a noncoagulopathic patient is extremely low. The incidence of hemorrhage in our practice, after more than 5000 pulmonary resections, is 0.06%. This very low incidence is obtained by having the attending senior surgeon present during the entire opening and closing of the chest. The pulmonary artery must be handled with meticulous care, and it needs to be dissected carefully. We prefer double ligation or stapling. Before chest closure, re-examine the major vascular structures as well as all other sites of surgical dissection to ensure hemostasis. Check the inferior pulmonary ligament, which usually contains a small artery. We perform a complete lymph node resection in all patients with bronchogenic carcinoma, and therefore all lymph node stations need to be evaluated, especially the seventh, the subcarinal area. There always is a large artery that comes off of the carina and feeds the subcarinal lymph nodes. It must be visualized and ligated, and this is often difficult to do, especially on the left side. Excessive cauterization is avoided, especially in the aorta–pulmonary window lymph node area on the left and the paratracheal

Ch013-F06861.indd 164

area on the right, to avoid injury to the recurrent laryngeal nerves. Bleeding can also occur from the pulmonary parenchyma, especially after wedge resection. Re-evaluate this area before chest closure. Also, carefully examine the surface of the undercut rib, both anteriorly and posteriorly. Finally, examine the chest tube sites and the sites of pericostal sutures (if used instead of the preferred intracostal sutures) from inside the chest before closure. Identify and clip or tie, if dissected, the branches of the bronchial artery, which can be in spasm and later bleed. If a patient is having excessive bleeding postoperatively, defined as greater than 200 mL/hr of blood loss alone (not chyle, cerebral spinal fluid, or transudative effusion) for 2 to 4 consecutive hours, perform a coagulogram. This panel of blood work includes an international normalized ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT), and platelet count. Correct any abnormalities. If the mediastinum and pleural space do not have retained clots and the coagulogram is abnormal, reoperation can be avoided if the underlying problem is corrected and the bleeding slows down. However, residual clot in either space often leads to a local consumptive coagulopathy, and the patient will continue to hemorrhage until the clot is fully evacuated, either via the chest tubes or usually by reoperation.

SUMMARY The key to the management of postoperative complications is prevention. Despite careful patient selection, a meticulous operation, and hypervigilant postoperative care, these complications are not uncommon. Early recognition and prompt treatment can lead to minimization of the morbidity.

COMMENTS AND CONTROVERSIES Although prolonged air leaks as defined by Dr. Cerfolio are those persisting beyond a normal hospital stay, most surgeons consider that air leaks lasting longer than 7 days are significant because they delay hospital discharge, increase the possibility of other morbidities such as empyemas, and increase costs. After lobectomy, approximately 10% to 15% of patients have an air leak lasting longer than 7 days, and 5% have it for longer than 14 days. As discussed by Dr. Cerfolio, several options are available to manage prolonged air leaks, but often the treatment has to be individualized to a given patient. Overall, patience is the golden rule, not only for the patient and his or her relatives but also for the surgeon. Postoperative supraventricular arrhythmias are common after all types of thoracic surgical procedures. Their cause is unclear, but several risk factors, such as older age, preexisting cardiac disease, and pneumonectomy, have been identified. Prevention of these arrhythmias is potentially attractive, but several studies using flecainide, amiodarone, and diltiazem have resulted in lower incidence of clinically significant arrhythmias but no difference in overall morbidity or length of stay. In the postoperative setting, the triggering factor for the arrhythmia must always be sought and corrected. This would apply, for instance, to patients with severe hypoxemia, electrolyte imbalance (hypokalemia), or a low hemoglobin concentration. Similarly, if the chest radiograph shows evidence of atelectasis or pneumonia, this must be actively treated.

1/21/2008 10:45:38 AM

Chapter 13 Early Postoperative Complications

Atelectasis is one of the most common respiratory complications observed after pulmonary resection. Although most patients only have platelike atelectasis in lung bases, approximately 5% to 10% of resected patients develop significant lobar collapse due to retained secretions. Chest physiotherapy and pain control are the mainstay of all regimens intended to prevent atelectasis and physically aid in the expectoration of secretions. If the patient is unable or unwilling to raise sputum, treatment must be more aggressive, often involving bedside flexible bronchoscopy. If clinical or radiologic findings suggest that a pneumonia is developing, obtain a sputum sample and start antibiotics. Chylothorax is seldom seen after elective lung surgery, and its incidence is estimated to be only 0.05%. Extensive pleural adhesions, significant local tumor extension, and, most important, radical mediastinal lymphoidectomy are risk factors for the complication. Once the diagnosis of chylothorax is confirmed, a trial of conservative management is recommended, with the objective of adequately draining the pleural space, re-expanding the lung, preventing dehydration, maintaining nutrition, and minimizing chyle formation. Although options to minimize chyle formation include enteral feed-

Ch013-F06861.indd 165

165

ings with low-fat and MCT diets, early implementation of parenteral feeding is most likely to achieve resolution of the chylothorax. It is generally agreed that a continuous chyle leak in excess of 1000 mL/ day for 7 days in a patient with complete cessation of oral intake is an absolute indication for reoperation. Consider reoperation if there is a chyle leak of greater than 500 mL/day for longer than 2 weeks. J. D.

KEY REFERENCES Cerfolio RJ, Bass CS, Pask AH, et al: Predictors and treatment of persistent air leaks. Ann Thorac Surg 73:1727-1730, 2002. Cerfolio RJ, Pickens A, Bass C, et al: Fast-tracking pulmonary resections. J Thorac Cardiovasc Surg 122:318-324, 2001. Deslauriers J, Ginsberg RJ, Piantadosi S, et al: Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest 106:329S-330S, 1994. Varela G, Aranda JL, Jimenez MF, et al: Emergency hospital readmission after major lung resection: Prevalence and related variables. Eur J Cardiothorac Surg 26:494-497, 2004.

1/21/2008 10:45:38 AM

chapter

14

LATE POSTOPERATIVE COMPLICATIONS R. Thomas Temes Noreen Griffin Anastasios Konstantakos

Key Points ■ Late complications of thoracic surgery are sometimes preventable

with care, patience, and proper technique. ■ Late complications create medicolegal liability and can result in

unfavorable malpractice judgments. ■ There is increasing scientific analysis and public scrutiny of adverse

results. ■ Centers of excellence will be established for complex or expensive

procedures. Eligibility as a center of excellence will require low complication rates. ■ Excessive late complications may ultimately result in denial of governmental reimbursement to surgeons and hospitals.

Meticulously performed surgery in appropriately selected patients is the best prophylaxis against late postoperative surgical complications and their detrimental consequences. When late complications arise, they require an astute and diligent surgeon for identification and correction. This chapter describes some of the common late complications, their diagnosis, and techniques for their prevention and management. In-depth discussions are cited in the full and selected references.

LATE COMPLICATIONS OF THORACIC INCISIONS Most thoracic operations are done through posterolateral thoracotomy or thoracoscopy incisions. Other, less commonly used approaches are thoracotomy variations (anterolateral, muscle-sparing, axillary), sternotomy, and incisions spanning more than one anatomic cavity (thoracoabdominal, clamshell, hemiclamshell). Pain is the most common late complication associated with thoracoscopy and thoracotomy. Causes include injuries to intercostal nerves, rib fractures, and excessive tissue trauma or retraction. Preventive techniques include gentle manipulation of the thoracoscope, minimal rib spreading, avoidance of rib fractures, protection of intercostal nerves, stabilization or excision of rib fractures, and early and effective postoperative pain control. Muscle-sparing techniques create less shortterm pain but have the same rate of chronic postoperative pain as muscle-dividing techniques (Little, 2004; Wolfe, 1992).1,2 Other potential late complications of thoracotomy include neurologic injury, seroma formation, and wound infection. Spinal cord injury may result from cautery, loss of arterial

blood supply, epidural hematoma, metastatic cancer, or hypotension.3-5 Peripheral nerve injuries develop after improper positioning, with compression or stretch at the brachial plexus, the elbow, the hip, and the knee. Seromas occur after muscle-sparing techniques but are generally selflimited. Wound infections are rare after thoracoscopy or thoracotomy and are managed like wound infections elsewhere. Sternotomy is commonly used for operations on the heart, mediastinum, and great vessels. It is also sometimes used for operations on the lung and other thoracic organs. Sternotomy produces less pain and less respiratory compromise than thoracotomy. Complications associated with sternotomy occur in fewer than 5% of patients. Of these, wound infection is most common. Preoperative risk factors for wound infection include diabetes mellitus, obesity, chronic obstructive pulmonary disease (COPD), irradiation, immunosuppression, malnutrition, renal failure, and other comorbidities.1,6-8 Contributing technical factors include timing of antibiotic administration, intraoperative contamination, paramedian incision, excess electrocautery, foreign bodies (bone wax), excessive retraction, fractures or dislocations of the sternum or ribs, misaligned closure, prolonged operative time, wound re-exploration, transfusion, and inadequate hemostasis. Sternal rewiring can be used to repair dehiscence without infection. Superficial infections are managed with antibiotics, drainage, and local wound care. Deep sternal infections produce bone destruction, osteomyelitis, and mediastinitis. Management options include sternal débridement or sternectomy, prolonged open wound care or irrigation, muscle flap reconstruction, or some combination of these.6,8,9 The associated mortality rate is 5% to 25%. Ventral hernia is a potential late complication of sternotomy. It occurs in fewer than 5% of sternotomies. Risk factors are wound infection, closure with absorbable suture, obesity, and pulmonary disease. Management includes correction of underlying pathology along with surgical repair. Late complications of two-cavity incisions are relatively common. Thoracoabdominal incisions are prone to cartilage and diaphragm problems. Preservation of the vascular supply to the cartilage is essential. Infections are treated by resection of all or part of the cartilaginous arch. Diaphragmatic hernias require repair. Pain and sternal misalignment are not infrequent late complications of the clamshell incision. Wiring of the sternum is usually sufficient for correction of misalignment; additional internal fixation is occasionally required. Sternal complications after hemiclamshell incisions are uncommon.

166

Ch014-F06861.indd 166

1/21/2008 2:10:56 PM

Chapter 14 Late Postoperative Complications

Incisional recurrence is a late risk of any biopsy or operation for malignancy. Diagnostic fine-needle biopsies are rarely associated with chest wall seeding. With core needle biopsies, the risk is higher. Implantation rates are highest in open procedures if there is tumor manipulation or a positive surgical margin. During minimally invasive resections, specimens must be removed through ports or in bags. An unusual late complication after thoracic trauma or surgery is lung herniation (Fig. 14-1). Risk factors include COPD, obesity, medications or comorbidities that inhibit wound healing, wound infection, hematoma, inadequate tissue reapproximation, and tissue loss. Observation is acceptable in patients with small hernias and minimal symptoms. Hernias that are large or symptomatic are considered for repair. Prosthetics may be required to correct intercostal defects.1

LATE COMPLICATIONS AFTER PLEURAL PROCEDURES Most pleural operations are for diagnosis or management of pleural effusion or pneumothorax. Surgically managed pleural effusions are usually caused by malignancy, infection, or bleeding. Pneumothorax is usually iatrogenic, but it can be spontaneous or catamenial. Incision implantation and recurrent effusion are potential late complications of treatment of malignant pleural effusions. Chest wall seeding is uncommon and results from contact between the specimen and the incision. The use of ports for biopsy removal minimizes this risk. Mesothelioma has a predilection for incisional implantation. Biopsies are done along the line of a posterolateral thoracotomy. Local recurrences may be resected in patients undergoing radical pleural-pneumonectomy. Management with local excision or radiation is possible in medically treated patients. Recurrent malignant pleural effusion after sclerosis is usually caused by a trapped lung and inadequate pleural apposition. Complete lung expansion is less likely in patients with a long duration of effusion before drainage. Recurrence is

167

often predictable when there is incomplete lung re-expansion after thoracentesis. Effusions also recur after inadequate sclerosis or early tube removal. If the lung is not trapped, resclerosis may be attempted. Other management options for recurrent malignant effusions include observation, serial thoracentesis, chronic external drainage, pleuroperitoneal shunting, and chemotherapy or radiation therapy. Recurrence is also a late complication of empyema. Most empyemas are parapneumonic. All patients undergo bronchoscopy to exclude obstructing malignancy and postobstructive pneumonia. Initial management with antibiotics and large-bore chest tubes may be adequate for exudative empyemas. Fibropurulent or organized empyemas may also require radiologic catheter drainage of loculations, intrapleural fibrinolytic therapy, surgical pneumolysis, and/or decortication. Late recurrences are often caused by incomplete lung reexpansion or incomplete drainage of infected fluid. Tubes must remain in place until chest computed tomographic (CT) scans confirm both complete drainage and complete lung reexpansion. Infected foreign bodies can cause recurrence and must be removed. Empyema necessitatis is a potential late complication of chronic empyema (Fig. 14-2). Hemothorax develops from trauma, from iatrogenic misadventures, and, increasingly, from anticoagulation. Inadequate treatment produces late fibrothorax or empyema or both (Fig. 14-3). Management is with drainage, decortication, and permanent discontinuation of anticoagulation (as indicated). Treatment of recurrent primary spontaneous pneumothorax is with thoracoscopy, wedge resection, and apical pleural scarification. Late recurrence is caused by new blebs or by blebs missed during the initial operation. Management consists of CT scanning for surgical planning, reoperation, and repeated bleb resection with apical pleural procedures. In young women, recurrent spontaneous pneumothorax may be caused by undiagnosed catamenial pneumothorax. Look for a relationship between pneumothoraces and the patient’s menstrual cycle. Management is with medical suppression of menses or with surgical repair of the culpable diaphragmatic pores (Fig. 14-4). Initial management of secondary spontaneous pneumothorax is with bedside or thoracoscopic sclerosis. If possible, the leaking bulla can be surgically resected. Underlying emphysema and other comorbidities result in higher rates of both early and late complications. Late recurrence may require resclerosis or long-term drainage with a chest tube and Heimlich valve.

LATE COMPLICATIONS AFTER PULMONARY PROCEDURES Late Postpneumonectomy Bronchopleural Fistula

FIGURE 14-1 Lung herniation through a thoracoscopy incision.

Ch014-F06861.indd 167

Late postpneumonectomy bronchopleural fistula (BPF) is an uncommon and difficult-to-manage complication of pneumonectomy. Causes include technical factors such as bronchial devascularization, excessive or inadequate stump length, and tumor at the bronchus resection margin. Other variables

1/21/2008 2:10:56 PM

168

Section 1 Introduction

A

C

FIGURE 14-3 Large hemothorax months after a motor vehicle accident. The patient was taking Coumadin anticoagulation for atrial fibrillation.

Ch014-F06861.indd 168

B

FIGURE 14-2 A, Empyema necessitatis decades after plombage for treatment of tuberculosis. B, CT scan showing infected fluid extending through the chest wall. C, Resected Lucite balls.

FIGURE 14-4 Diaphragmatic pore (patient with hepatic hydrothorax).

1/21/2008 2:10:56 PM

Chapter 14 Late Postoperative Complications

protection of the remaining lung from aspiration, and institution of antibiotics. Patients are initially positioned with their operated side down. Urgent tube drainage of the pleural collection is performed. The functioning lung is elevated during tube insertion to prevent aspiration of pleural fluid. The mediastinum is mobile in early postpneumonectomy BPF. Use of a balanced chest tube drainage system prevents mediastinal shift. The mediastinum is fixed in late BPF. In these cases, chest tubes may be connected to standard water seal. In either case, avoid suction on the tube to minimize mediastinal shift and prevent loss of oxygen from the airway. There are several options for repair of the bronchus. Long stumps can be resected and closed primarily in patients with early postpneumonectomy BPF (Fig. 14-8). In many instances,

predisposing to late postpneumonectomy BPF include mechanical ventilation with barotrauma, poor bronchus healing due to comorbidities, irradiation, poor pulmonary function, and right pneumonectomy.10,11 Prevention by mitigation of these factors is ideal. BPF often occurs in the early postoperative period, but it can manifest months after surgery. Symptoms and signs include fever, productive cough with purulent or serosanguineous fluid, large new air leak, and loss of fluid seen on chest radiographs (Fig. 14-5). Definitive diagnosis is by bronchoscopy (Fig. 14-6). Management is determined by the timing between surgery and BPF, the condition of the patient, and the presence or absence of empyema. An organized approach to management of BPF is undertaken (Fig. 14-7). Initial goals are stabilization of the patient,

A

169

B

FIGURE 14-5 Postpneumonectomy bronchial stump leak after 1 month of mechanical ventilation for respiratory failure. A, Pneumonectomy space filled with fluid before stump leak. B, Loss of fluid indicating bronchial leak.

A

B

FIGURE 14-6 BRONCHOSCOPIC APPEARANCES OF A RIGHT MAIN STEM STUMP LEAK. A, Bronchoscopic view of right main stem stump suggesting possibility of leak. B, Bubbles emanating from confirmed leak.

Ch014-F06861.indd 169

1/21/2008 2:10:58 PM

170

Section 1 Introduction

At diagnosis—Elevate lung, drain pneumonectomy space

Early—Balanced drainage, urgent repair, tissue buttressing

Empyema present—Continued tube drainage

Late—Tube drainage, urgent repair, tissue buttressing

No empyema present— Antibiotic plombage, closure

Empyema present—Continued tube drainage

Eventual empyma tube or Clagett window

Early empyma tube or Clagett window

Late attempt at antibiotic plombage and closure

Late attempt at antibiotic plombage and closure

Repeat attempts above, permanent drainage, other

Repeat attempts above, permanent drainage, other

No empyema present— Antibiotic plombage, closure

FIGURE 14-7 An algorithm for managing postpneumonectomy bronchopleural fistula.

A

B

FIGURE 14-8 A, Normal filling of a left postpneumonectomy space. B, Loss of fluid indicating bronchial leak. The patient had a long bronchial stump (white dots), which was resected during repair. Permanent open drainage of the pleural space was created with the use of a Clagett window.

the repair can be accomplished through the original posterolateral thoracotomy incision. Sternotomy allows access to the bronchus through a transpericardial approach.1,12-14 Access to the left hilar structures is more difficult. Reinforce bronchial closures with a healthy tissue flap.15-18 In some cases, primary closure of postpneumonectomy BPF may not be tenable. Identification and control of the bronchial and vascular stumps can be hazardous because of inflammation and granulation in the mediastinum. In these situations, the bronchial leak can be sealed with a vascularized

Ch014-F06861.indd 170

flap. Options for flaps include intercostal muscle, omentum, pericardium or thymus, pectoralis major, latissimus dorsi, serratus anterior, rectus abdominus, and diaphragm. After repair of the airway, the pleural space is assessed. Sterile or minimally contaminated cavities can be irrigated, filled with antibiotic solution, and closed. Infected early postpneumonectomy BPF is managed with balanced drainage until the mediastinum is fixed. Eventually, the chest tube is converted to an empyema tube. Late infected BPF can be drained with empyema tubes or open drainage.

1/21/2008 2:11:00 PM

Chapter 14 Late Postoperative Complications

Clagett windows or Eloesser flaps are ideal for long-term open drainage and irrigation (Fig. 14-9). Open drainage may be continued indefinitely. Alternatively, after the pleural cavity is granulating and healthy, it is filled with antibiotic solution and closed. Successful resolution of the empyema is accomplished in up to 80% of cases.1,19 Daily povidone-iodine packing in the operating room is also an option. The chest is filled with antibiotic solution and closed after the space is clean. This approach accelerates closure of the chest but requires inpatient hospitalization and multiple operations.20 Minimally invasive approaches to pleural irrigation are also possible.21,22 If closure fails, repeated drainage and subsequent attempts at reclosure can be made. Manage persistent failures with permanent open drainage, vascularized tissue obliteration of the space, and/or thoracoplasty. Rarely, BPFs have been managed nonoperatively with endoscopic techniques combined with antibiotics.1,23-26

FIGURE 14-9 Same patient as in Figure 14-8 several years later. The space has resolved, and the Clagett window has epithelialized.

171

Late Bronchopleural Fistula Associated With a Residual Pleural Cavity BPF is a late complication of pulmonary resections in approximately 5% of cases. Residual pleural cavities are often present. In addition to surgery, BPFs also arise after spontaneous pneumothorax, trauma, and mechanical ventilation. Risk factors for BPF include advanced age, malnutrition, steroids, preoperative chemotherapy or radiation, lung disease, bronchial margins positive for infection or malignancy, and numerous other comorbidities. Intraoperative maneuvers can reduce the risk of BPF. These include protection of the bronchial blood supply, stumps of proper length, and the use of vascularized tissue for reinforcement of bilobectomies, pneumonectomies, and other vulnerable bronchial closures. Symptoms and signs of BPF include fever, productive cough with purulent or serosanguineous expectorant, new large air leak, new pleural loculation, and new pleural air-fluid level. Management is determined by the patient’s condition, location of the fistula, size of the residual space, and presence or absence of empyema. Apply an organized approach to management of BPF (Fig. 14-10). The initial management consists of water seal drainage of the pleural space, institution of antibiotics, and bronchoscopy. Repair the leak in stable patients with bronchial anastomotic disruptions. Primary closure is ideal but is not always possible. Other alternatives are application of a vascularized flap, bronchoplastic reconstruction, and completion pneumonectomy. Reinforce the bronchus with healthy tissues. Consider reoperation in stable patients with BPF and large residual pleural cavities, even if a major bronchial disruption is not identified. Options for obliteration of the space include decortication, pleural tent, muscle or omental transfer, phrenic nerve crush, thoracoplasty, and pneumoperitoneum. Alternatively, after the pleural space is clean and the air leak has resolved, a modification of the Clagett procedure can be tried by filling the space with antibiotic solution.

BPF—Chest tube, bronchoscopy, review of Op note

Surgical candidate, not critically iII

Not surgical candidate, critically iII

BPF visible or large space

BPF not visible, small or no space

Unable to ventilate

Repair with tissue buttress

Conservative—Tube drainage

Attempts at lung isolation or nonsurgical closure

Decort., pleural tent, tissue plombage, other if space large

Able to ventilate—Tube or open drainage until surgical candidate

Forced to operate, see surgical candidate arm FIGURE 14-10 An approach to management of bronchopleural fistula (BPF).

Ch014-F06861.indd 171

1/21/2008 2:11:00 PM

172

Section 1 Introduction

B A

FIGURE 14-11 Bronchopleural fistula and space after bilobectomy in a patient with severe restrictive disease. The space was managed with chronic open drainage. A, Chest radiograph. B, Stoma appearance. C, Close-up view of residual cavity.

Persistent spaces and persistent leaks in high-risk patients can be managed with chronic chest tube drainage or chronic open drainage (Fig. 14-11). The BPF and the space sometimes resolve with time. Continue open drainage until there is no leak and no space. Critically ill and mechanically ventilated patients pose the greatest challenge. If oxygenation and ventilation can be maintained, continued tube drainage without operation is preferable (Fig. 14-12). Patients may have low returned tidal volumes on the ventilator, subcutaneous emphysema, and/or incomplete lung expansion despite properly positioned chest tubes. If these problems are not life-threatening, they are not in themselves indications for operation. If oxygenation and ventilation are compromised, the prognosis is poor. Poor healing, mechanical ventilation, and barotrauma make successful surgical closure unlikely. Double-lumen tubes with dual ventilators, endobronchial gluing, or balloon occlusion of the fistula can be attempted but are also of dubious benefit.

Prolonged Air Leak Without Residual Cavity The incidence of prolonged air leak after pulmonary resection is approximately 10%. Prevention or repair of parenchymal air leaks during operation minimizes this complication. Techniques include suturing, stapling with or without but-

Ch014-F06861.indd 172

C

tressing, pleural pedicles or tents, pericardial patches, and tissue sealants. In the absence of bronchial disruption or residual spaces, postoperative air leaks will resolve spontaneously. Mechanical ventilation and chest tube suction slow healing and must be discontinued if possible. Patients with prolonged leaks can be discharged with Heimlich valve drainage. They are checked with chest radiographs during weekly clinic visits. The tubes can be removed after the leak has resolved and the lung is fully inflated.

Pleural Cavities Without Air Leak After lobectomy there is usually hyperexpansion of the remaining lung, mediastinal shift, diaphragm elevation, and narrowing of the intercostal spaces. This prevents residual pleural cavities in most patients. However, intrapleural cavities develop after pulmonary resections in approximately 20% of cases. In most cases, these spaces fill with sterile fluid and then gradually resolve. A minority of these spaces become infected. Patients with restrictive pulmonary disease are at increased risk for pleural space problems. Intraoperative maneuvers to lessen the risk for space problems include pleural tents, phrenic nerve crush, muscle or omental transposition, thoracoplasty, and pneumoperitoneum. Postoperative

1/21/2008 2:11:01 PM

Chapter 14 Late Postoperative Complications

A

173

B

FIGURE 14-12 A, Bronchopleural fistula and space in a critically ill, mechanically ventilated trauma patient with adult respiratory distress syndrome. B, Resolution of space and bronchopleural fistula after discontinuation of mechanical ventilation and prolonged empyema tube drainage.

techniques consist of mobilizing pulmonary secretions, maximizing respiratory hygiene, and increasing chest tube suction. In most patients with a residual space, the tubes can be removed after the air leak has resolved. Antibiotics are administered, and the cavity is managed expectantly. As the space gradually fills with fluid, an air-fluid level will become visible on the radiograph. If the level is rising and the patient is clinically well, continued observation and antibiotics are appropriate while the space fills. In many cases, both the fluid and the space eventually resolve.

Late Pleural Effusion A late pleural effusion after pulmonary resection is sometimes caused by filling of a residual space. Early postoperative films may demonstrate the space and the gradually rising airfluid level. Incompletely drained early effusions may also produce late pleural effusions. Effusions may be observed when they are small, asymptomatic, sterile, and stable. Tube drainage is indicated if infection is suspected. These patients may also have a pleural peel with resultant trapped lung. Thoracoscopic or open decortication may be required for lung re-expansion and to prevent recurrence. Pleural effusions may also develop late after pulmonary resection when a residual space was not present. Evaluate these effusions for empyema or recurrent malignancy. Postresection empyemas are managed like other empyemas. Malignant effusions may be difficult to diagnose. Thoracoscopy can be beneficial both for diagnosis and management.

Late Postoperative Pulmonary Torsion or Vascular Occlusion Postoperative, nonembolic pulmonary infarction is rare. It can involve a lobe or the entire lung. Careful intraoperative dissection and identification of vessels prevent infarction due to surgical ligation. Torsion most commonly affects the right middle lobe and occurs after right upper lobectomy. Other

Ch014-F06861.indd 173

torsions are infrequent. In patients with complete major fissures, affixing the right middle lobe to the lower lobe prevents right middle lobe torsion. Visual confirmation of anatomic position and proper lung inflation allows detection of twisted or ischemic lung before closure. Late symptoms and signs of torsion are caused by infection. Fever, purulent sputum, and large air leaks may develop. Radiographs may show bronchial cutoff, opacification of the lobe or lung, atelectasis, or pulmonary destruction. Chest CT, ventilation-perfusion scans, and angiography may be helpful. Bronchoscopy shows a compressed and twisted bronchus. The lung may be salvageable if torsion is recognized early, before infarction occurs. Usually the diagnosis is late. Resection is required and is associated with a significant mortality rate.

Late Airway Complications Late postoperative airway problems include postpneumonectomy syndrome, stricture, bronchovascular fistula, tracheoesophageal fistula, tracheo-innominate artery fistula, and complications of stents. Late airway problems can result from vocal cord paralysis and aspiration, recurrent or primary malignancy, extrinsic airway compression, strictures, bronchomalacia, and other problems. Chest CT and bronchoscopy are helpful in diagnosing most of these processes. Occasionally, pulmonary function testing or other procedures are useful. Unilateral vocal cord paralysis can be managed with local procedures. Tracheostomy is indicated in bilateral vocal cord paralysis. Recurrent malignancy may be resectable in selected patients. Stenting, external-beam irradiation, brachytherapy, chemotherapy, or other modalities are also options for managing local recurrence. Postpneumonectomy syndrome is caused by displacement and rotation of the mediastinum into the operated chest. The remaining main stem bronchus is stretched and compressed over the spine or aorta. Repositioning of the mediastinum with intrathoracic prosthetic implants relieves the airway compromise.27,28

1/21/2008 2:11:02 PM

174

Section 1 Introduction

FIGURE 14-13 Stenting of the entire trachea and bilateral main stem bronchi (arrows) for diffuse tracheomalacia and bronchomalacia.

Sleeve lobectomy or other bronchoplastic procedures may result in late airway complications in up to 20% of cases.29-31 The underlying causes include technical factors such as compromised blood supply, suture line dehiscence, and tension. Disease-specific factors such as nodal metastasis or positive margins are also significant predictors of anastomotic complications. Patients with significant underlying comorbidities are also at increased risk. During operation, preserve the vascular supply to the bronchus, gently handle the bronchus, and judiciously do the node dissection. Healthy tissue reinforcement of anastomoses facilitates healing, seals small leaks, and minimizes the risk of stricture formation. Avoid tension after extensive airway resections by using hilar and/or other release maneuvers. Repeated dilations sometimes stabilize strictures but usually only relieve the stenoses temporarily. Insufficient distal bronchus may preclude stenting. In some patients,

reoperation with completion pneumonectomy may be necessary. Tracheal strictures or tracheomalacia usually arises after prolonged intubation. These complications are created by pressure necrosis of the tracheal wall from the endotracheal tube or tracheostomy cuffs. Inadequate support of ventilator tubing can also create torsion and traction of the airway with resultant strictures. These may extend proximally as far as the tracheostomy stoma or the glottis. Other causes include tumor, previous tracheal resection, tracheoesophageal fistula, and idiopathic laryngotracheal stenosis. Patients usually have dyspnea or stridor or both. Radiographs and CT scans may demonstrate the stricture. Flow-volume loops reveal obstruction. Bronchoscopy facilitates diagnosis, measurement, and dilation. The patient’s condition needs to be medically optimized and the patient should be breathing spontaneously before attempts at definitive management of late strictures are made. A tracheostomy through the stricture (with the balloon uninflated) can be used for temporary or permanent relief. Tracheal dilation with a rigid bronchoscope is also sometimes useful. Laser therapy is usually unsuccessful for long-term management. Definitive options include resection, stenting, and permanent tracheostomy. Tracheal resection can be performed in low-risk patients. Technical risk factors for anastomotic complications include reoperation, long segment resection, laryngotracheal resection, compromised blood supply, tension, localized dehiscence, and granulation. Patient risk factors include diabetes, youth, and preoperative tracheostomy.1,32 The operative technique depends on the location of the stricture. Most resections can be done through cervical or cervicomediastinal incisions. Laryngeal and/or hilar releases decrease tension and the risk for recurrence. Results are good to excellent in more than 90% of cases.32,33 Custom and flexible tracheostomies allow management of long or low strictures. These are reasonable options in highrisk patients. Stenting also produces a stable airway for inop-

FIGURE 14-14 A, Close-up view of postintubation tracheal stricture. B, Expandable plastic stent for management of benign tracheal strictures.

A

Ch014-F06861.indd 174

B

1/21/2008 2:11:03 PM

Chapter 14 Late Postoperative Complications

A

175

B

FIGURE 14-15 A, Expandable plastic stent (arrows) in a patient with postintubation tracheal stricture. B, Stent dislodgement (arrows) after intubation for unrelated reasons.

A

C

Ch014-F06861.indd 175

B

FIGURE 14-16 A, CT scan showing late tracheal stricture after prolonged intubation. B, CT at same level, and in same patient, after dilation and insertion of expandable tracheal stent. C, CT at same level, and in same patient, several months after stent removal.

1/21/2008 2:11:05 PM

176

Section 1 Introduction

erable patients.34-36 Although metal stents are avoided in benign disease, newer plastic stents allow management of complex benign airway problems (Figs. 14-13 and 14-14). Stents are associated with potential risks of migration, occlusion, granulation, and erosion (Fig. 14-15). Give humidification and mucolytics to minimize secretions. Surveillance pulmonary function tests, CT scans, and/or bronchoscopy are also indicated. After several months, the stents can be removed (Fig. 14-16). After bronchoplasty or tracheal resection, late fistulas between the airway and pulmonary artery occur in fewer than 2% of patients.32,33 They are caused by airway dehiscence, infection, and erosion of the pulmonary artery or a vascular suture line. Wrap all airway anastomoses with healthy tissue flaps to aid healing and to separate bronchial and vascular suture lines. Fistulas usually manifest with a sentinel bleed. In stable patients, emergency bronchoscopy and/or pulmonary angiography can be done. However, do not delay emergency surgery if a fistula is apparent. The mortality rate of bronchovascular fistulas is high. Tracheo-innominate artery fistulas result from pressure necrosis of the tracheal and arterial walls. They are usually caused by tracheostomy tubes. The risk is minimized with good tracheostomy insertion technique, low cuff inflation pressures, and proper support of ventilator tubing. Most patients have a sentinel bleed that is later followed by massive hemorrhage. Bronchoscopy, aortography, and chest CT can be attempted in stable patients. False-negative studies occur, and a presumptive clinical diagnosis may be required (Fig. 14-17). Intubation and compression of the innominate artery against the manubrium (using the airway cuff or finger pressure) allows emergency transport to the operating room. Attempt ligation of the innominate artery, muscle patch closure or segmental resection of the trachea, and strap muscle interposition between suture lines. Although the stroke rate is low, the overall mortality rate is high.

Tracheoesophageal fistula is another late complication of prolonged intubation and mechanical ventilation. Simultaneous tracheal and esophageal tubes produce compression and necrosis of the posterior trachea and the anterior esophagus. Patients develop abdominal distention, aspiration pneumonia, and low returned ventilator tidal volumes. Bronchoscopy and esophagoscopy are diagnostic (Fig. 14-18). The airway can be temporarily protected by passing the endotracheal or tracheostomy tube beyond the fistula. Remove esophageal tubes and establish alimentation with the use of gastrostomy or jejunostomy feedings. Attempt surgical repair after the patient’s condition is optimized and he or she is breathing spontaneously. Through a cervical incision, a segmental tracheal resection, primary esophageal closure, and muscle interposition between suture lines are performed.37-39 In medically inoperable patients, permanent tracheostomy, stents, and esophageal isolation can be attempted. The prognosis is poor. Malignant tracheoesophageal fistula is a late complication of esophageal or bronchogenic carcinoma. Patients present with dysphagia and aspiration pneumonia. Fistulas may occur spontaneously or after chemoradiation therapy. Bronchoscopy, esophagoscopy, or contrast radiography demonstrates the communication. Esophageal stents seal the fistula and relieve dysphagia in approximately 80% of patients (Fig. 14-19).40,41 An airway stent may also be required.

Late Local Recurrence of Lung Cancer or Second Primary Lung Cancer Any patient with resected lung cancer is at risk for local recurrence, metachronous primary lung cancer, and other primary aerodigestive malignancies.42-46 Patients with positive bronchial margins or residual disease after initial resection have an additional risk for local recurrence.47-51 Routine chest CT and close clinical examinations sometimes allow early

B

A

Ch014-F06861.indd 176

FIGURE 14-17 A, Negative angiogram of the innominate artery in a patient proven to have tracheo-innominate artery fistula. B, Negative contrast-enhanced chest CT scan in the same patient.

1/21/2008 2:11:06 PM

Chapter 14 Late Postoperative Complications

A

177

B

FIGURE 14-18 A, Bronchoscopic view of a large, benign tracheoesophageal fistula at the level of the carina. The nasogastric tube (arrow) is visible through the fistula. B, The appearance during esophagoscopy. The tracheostomy tube is passing beyond the fistula and is visible through the defect.

FIGURE 14-19 A, Barium swallow in a patient with malignant tracheoesophageal fistula (arrow). B, Sealing of the fistula by placement of an expandable metal stent.

A

B

detection.52 Surveillance bronchoscopy is also appropriate after bronchoplastic procedures or previous positive surgical margins. Recurrent and second primary malignancies may sometimes be resected with reasonable long-term survival.53-59 Patients who are not candidates for resection may benefit from stenting, radiation, chemotherapy, or other treatment (Fig. 14-20). Late recurrence at port sites is a potential complication after thoracoscopic procedures. Mesothelioma is associated with the highest port implantation rates. To prevent port

Ch014-F06861.indd 177

seeding, biopsies and specimens must be removed with the use of trocars or bag retrieval devices. Port implantation can be managed with local resection or irradiation.

LATE COMPLICATIONS OF OPERATIONS INVOLVING THE CHEST WALL Chest wall resection, with or without skeletal reconstruction, is often performed for lung cancer with rib invasion.60,61 Other indications are primary chest wall tumors, locally

1/21/2008 2:11:06 PM

178

Section 1 Introduction

A

B

FIGURE 14-20 A, Tumor occluding the right main stem bronchus. B, Right main stem bronchus after rigid bronchoscopy, debulking, and deployment of an expandable metal stent.

recurrent or metastatic malignancies, and chest wall infections. Survival is influenced by stage, extent of chest wall involvement, gender, and differentiation of tumor. Late complications of chest wall resection without reconstruction include respiratory compromise, chest wall instability, upper extremity dysfunction, scapula tip entrapment, cosmetic deformity, and lung herniation. Graft infection is a late complication after chest wall resection with reconstruction. Even after prosthetic removal, patients generally do well. Vicryl mesh provides the early benefits of chest wall repair without the risk of late foreign body infection. It is an option during initial chest wall resection or during management of late complications. Local tissues are preferable for closure of soft tissue defects. Vascularized muscle or myocutaneous flaps can be used initially or during treatment of late wound complications. The choice of flap is determined by the location of the defect, available muscles, and the flap’s arc of rotation.62 Commonly used flaps are latissimus dorsi, pectoralis major, serratus anterior, external oblique, rectus abdominus, omentum, trapezius, and internal oblique. Soft tissue flap support may be sufficient to obviate skeletal reconstruction. Potential late complications of flaps are seroma, infection, and necrosis. Late local recurrence is also a complication after chest wall resection for malignancy. The incidence is as high as 25% in some situations.

LATE COMPLICATIONS OF VOLUME REDUCTION SURGERY Volume reduction surgery provides improvement in respiratory mechanics, dyspnea symptoms, and quality of life in selected patients.63,64 In some patients, it can serve as a bridge to lung transplantation. Early complications are common and include prolonged air leak, pneumonia, and respiratory failure.

Ch014-F06861.indd 178

Patients who have both a 1-second forced expiratory volume (FEV1) of less than 20% of predicted and a diffusion capacity of less than 20% of predicted may be at increased risk of respiratory failure and death.65,66 Respiratory failure may be caused by pneumonia or worsening emphysema. Although most survivors experience a gradual decline in pulmonary function after surgery, the benefits of volume reduction procedures appear to persist at least 5 years after operation.64,67

LATE COMPLICATIONS OF LUNG TRANSPLANTATION Late death after lung transplantation arises from bronchiolitis obliterans syndrome, infection, and respiratory failure.68 Other late complications arise from the airway anastomosis, rejection, and graft failure. Bronchiolitis obliterans is a progressive fibrosis of the small airways of unknown etiology. Possible causes include chronic inflammation due to rejection or infection. There are associations with acute rejection episodes, human leukocyte antigen mismatching, reperfusion injury, and viral infections.69-71 The clinical course is marked by progressively declining pulmonary function. No successful treatment is known, although macrolide antibiotics are under evaluation.72,73 Retransplantation is sometimes possible in selected patients. Differentiating infection from rejection may require sputum culture, serum titer assays, bronchoscopy, needle biopsy, transbronchial biopsy, or open lung biopsy. Bronchial complications may be related to mechanical ventilation, loss of bronchial circulation, ischemic time, and rejection.74 Late airway problems include bronchial strictures, bronchomalacia, granuloma, and dehiscence. Many of these complications can be managed with interventional bronchoscopy and stenting.75-78

1/21/2008 2:11:09 PM

Chapter 14 Late Postoperative Complications

SELECTED LATE COMPLICATIONS AFTER ESOPHAGEAL OPERATIONS Late Postresection Esophageal Stricture The leak rate after cervical esophagogastric anastomosis has been approximately 20% (Fig. 14-21). Newer techniques

FIGURE 14-21 Cervical anastomotic leak (arrow) after esophagectomy with gastric reconstruction.

179

using stapled anastomoses may decrease this incidence. The rate of intrathoracic anastomotic leaks is approximately 10%. Survivors of leaks in the chest or neck are prone to late anastomotic strictures. Other causes of late postoperative esophageal strictures include gastroesophageal reflux, Barrett’s esophagus, and recurrent malignancy. The initial evaluation of an esophageal stricture is with barium swallow, endoscopy, and chest and neck CT scans. Most benign strictures can be managed with dilation. The goal is a stable lumen of approximately 45 Fr. Gradual, controlled, and frequent dilations over a guidewire are preferable to forceful balloon dilation. Patients with recalcitrant strictures may be managed with self-dilation or revision (Fig. 14-22). Expandable plastic stents are also available for management of benign esophageal strictures (Fig. 14-23).

FIGURE 14-23 Expandable plastic stents for management of benign esophageal strictures.

FIGURE 14-22 A, Tight esophageal stricture after caustic ingestion. B, Resolution after gradual physician-performed dilations followed by maintenance self-dilation.

A

B tahir99-VRG vip.persianss.ir

Ch014-F06861.indd 179

1/21/2008 2:11:11 PM

180

Section 1 Introduction

Late Chylothorax The overall incidence of chylothorax after general thoracic surgical procedures is less than 0.5%. After esophagectomy, the risk rises to as high as 3%. Patients with large tumors or previous induction therapy may be at an even greater risk for postoperative chylothorax. In these patients, prophylactic thoracic duct ligation has been advocated. The diagnosis is occasionally made intraoperatively by observation of the leakage of large amounts of clear lymphatic fluid. Do the repair immediately. More commonly, the diagnosis is made after an oral diet is resumed. Rarely, patients are discharged and present with late chylothorax. Patients with chylothorax usually have high chest tube output. The drainage has a milky or peach-colored appearance. Measure the pleural fluid triglyceride level; a level greater than 110 mg/100 mL is diagnostic. A cell count with differential may also be helpful by demonstrating a predominance of lymphocytes. Nonoperative management consists of chest tube drainage, nothing by mouth, and total parental nutrition. Enteral nutrition with medium-chain triglycerides may also be used. Recently, etilefrine, a sympathomimetic drug that promotes smooth muscle contraction of the thoracic duct, has been used in management of chylothorax. The success of nonoperative therapy is between 25% and 75%. This rate is lower in chylothorax after esophagectomy. Surgical management is often necessary when the chylothorax occurs secondary to esophagectomy, tube drainage is greater than 1 L/day, chest tube output on postoperative day 5 is greater than 10 mL/kg, or medical therapy has failed after fewer than 2 weeks. A right thoracotomy and mass ligation of the thoracic duct is successful in more than 90% of cases. Preoperative or intraoperative administration of cream allows

the identification of persistent leakage. Patients for whom thoracic mass ligation has failed may benefit from direct suture of the leak, mass ligation in the abdomen, tube drainage and sclerosis, tissue sealants, and/or pleuroperitoneal shunting.

Late Complications After Esophageal Stenting Stenting is indicated for relief of benign or malignant strictures of the esophagus. Expandable stents are used in almost all cases. Potential late complications are tumor overgrowth, migration, stricture, food impaction, and erosion. Tumor overgrowth develops in up to one third of cases. Insertion of stents 1 to 2 cm longer than the tumor at each end minimizes this risk. Overgrowth can be managed with another overlapping stent, laser therapy, or photodynamic therapy. Migration of esophageal expandable stents occurs in approximately 25% of cases (Fig. 14-24). The risk is higher with the use of smaller-diameter stents, with placement across the gastroesophageal junction, and after chemotherapy or radiation therapy. Migrated stents can produce bowel obstruction or perforation and therefore need to be removed. Stents can also erode into the aorta, pericardium, or airway. Angulation and chemoradiation therapy increases the risk for erosion.

LATE COMPLICATIONS OF MEDIASTINAL PROCEDURES Late Complications Associated With Mediastinal Node Dissection or Sampling Mediastinal node dissection or sampling is performed routinely during resections for lung cancer. It is also applied during resections of other malignancies. Staging accuracy is

A

FIGURE 14-24 A, Migrated metal stent (arrows) in a patient with an extensive esophageal cancer. B, Nested esophageal stents (arrows) in same patient after retrieval of the migrated stent and insertion of new stents.

B

tahir99-VRG vip.persianss.ir

Ch014-F06861.indd 180

1/21/2008 2:11:12 PM

Chapter 14 Late Postoperative Complications

improved, and there may be an associated survival advantage. Complications that may manifest in the early or late postoperative period involve injury to surrounding structures, including the esophagus, vagus and recurrent nerves, great vessels, airway, and thoracic duct. Careful surgical technique prevents most injuries. Whether mediastinal node dissection contributes to other late complications, such as postpneumonectomy respiratory failure, is unknown.

181

Late Complications After Pericardial Window Pericardial window is frequently performed for management of benign and malignant pericardial effusions. Causes include carcinoma, recent cardiac surgery, renal failure, trauma, collagen vascular disease, Dressler’s syndrome, infections (including tuberculosis and viral pathogens), and nonspecific causes.79,80 Percutaneous echocardiography-guided catheter drainage can be performed safely and successfully.79-81 Surgical drainage using a transthoracic, subxiphoid, or thoracoscopic approach is also efficacious.82,83 Potential late complications include recurrent effusion, constrictive pericarditis, cardiac herniation, and other unusual complications such as pneumopericardium (Fig. 14-25). Late recurrence of pericardial effusions occurs in fewer than 10% of patients.80,84,85 Constriction develops in fewer than 5%.84 Other late complications are more uncommon. The prognosis depends primarily on the underlying cause.85 Hemodynamically significant recurrent effusions can be managed with catheter drainage or reoperation.

Late Complications After Mediastinoscopy The majority of complications from mediastinoscopy are acute. These include injury to major vessels, airway, esophagus, pleura, and left recurrent nerve. The most commonly injured vascular structure is the azygos vein. However, the innominate artery, aorta, pulmonary artery, superior vena cava, and left atrium are also vulnerable. Potential late complications include mediastinitis from an esophageal injury and tumor implantation at the skin incision. Esophageal injuries are identified using barium esophagogram, esophagoscopy, and chest CT scan. Most occur at the level of the carina and can be corrected through a right thoracotomy. Even after delayed diagnosis, a two-layer esophageal repair with wide drainage and intercostal muscle flap buttressing is usually possible. Metastases to the incision are rare. They may be caused by direct tumor implantation, lymphatic spread, or hematogenous seeding. Management is by excision or irradiation.

Late Complications After Mediastinal Resection Malignant mediastinal masses include thymomas, lymphomas, germ cell tumors, and thyroid tumors. Benign neoplasms include neurogenic tumors, germ cell tumors, and cysts. Many of these lesions are treated with resection as primary therapy. Others may require surgery for biopsy or for man-

B

A

FIGURE 14-25 Large pneumopericardium 1 month after pericardial window and talc sclerosis of the right pleural space. The patient had a previous right spontaneous pneumothorax, metastatic lung cancer, and pericardial effusion. A, Chest radiograph. B, CT scan.

tahir99-VRG vip.persianss.ir

Ch014-F06861.indd 181

1/21/2008 2:11:12 PM

182

Section 1 Introduction

agement of recurrent or residual disease. In addition, thymectomy is frequently performed for treatment of myasthenia gravis. A potential late complication of mediastinal resections is local recurrence. The risk is highest in patients with malignancy and positive surgical margins. Some patients may benefit from reoperation. In the remaining patients, clip placement at the resection margins during the initial operation facilitates adjuvant treatment. A late complication of thymectomy is new or recurrent myasthenia gravis. Incomplete thymectomy or development of thymoma may be responsible. Residual thymus and resectable thymomas need to be removed if technically possible.

LATE COMPLICATIONS ASSOCIATED WITH CHEMOTHERAPY AND RADIATION THERAPY Radiation therapy in patients with early-stage lung cancer produces 5-year survival rates of 15% to 20%.86 In patients with locally advanced non–small cell lung cancer, combined chemotherapy and radiation therapy results in 5-year survival rates of 25% to 30%.87 These encouraging results have led to the use of neoadjuvant chemotherapy, or combined chemoradiation therapy, followed by surgery for locally advanced non–small cell lung cancer.88,89 These regimens are associated with good compliance, high resection rates, and a possible survival advantage compared to surgery alone. Whether preoperative chemotherapy or preoperative chemoradiation therapy increases the risk of surgical complications is controversial. Some series have reported increased complication rates.90-92 In other reports, the complication rate was higher only after right pneumonectomy.93 Several other reports concluded that neoadjuvant therapy does not increase surgical risk.94-98 Some chemotherapeutic agents have pulmonary toxicity (Table 14-1).99 Risk factors for chemotherapy-induced respiratory insufficiency include age, total chemotherapy dose, preexisting pulmonary disease, high inspired oxygen concentrations, and radiation. Lung damage can arise from reactive oxygen derivatives, direct injury, altered homeostasis, activation of inflammatory cascades, and other pathways. In addition to pulmonary toxicity, chemotherapy may also be associated with late complications involving the heart, kidneys, nervous system, and other organ systems. Radiation therapy is also associated with potential late complications due to altered tissue healing. Although up to

TABLE 14-1 Chemotherapeutic Agents Associated With Pulmonary Toxicity Alkylating Agents Busulfan Chlorambucil Cyclophosphamide Melphalan Uracil mustard Antibiotics Bleomycin Mitomycin C

Antimetabolites Methotrexate Cytosine arabinoside Nitrosoureas Carmustine Lomustine Semustine Chlorozotocin

70 Gy of radiation may be given with curative intent to nonsurgical patients, induction radiation regimens are typically limited to 45 Gy. Newer three-dimensional treatments, multileaf collimators, and electronic portal devices may allow precise conformal irradiation and dose escalations in the future.

LATE THORACIC COMPLICATIONS DUE TO OPERATIONS OR DISEASE PROCESSES AT OTHER SITES Thoracic surgical management is often required for late complications unrelated to prior thoracic surgery. These include interventions by radiology, anesthesia, critical care, cardiac surgery, general surgery, orthopedic surgery, oncology, transplantation, or other services. Most thoracic complications of radiology and anesthesia occur early. These include pneumothorax or hemothorax after needle puncture. Rarely, these conditions progress to late complications such as BPF or chronic pleural effusion. Thoracic complications of critical care may also result in late complications requiring thoracic intervention. These include hemothorax, empyema, BPF, tracheoesophageal fistula, tracheo-innominate artery fistula, and tracheal stenosis. Common late thoracic complications of cardiac surgery are pleural or pericardial effusions. Pleural effusions may develop as a result of heart failure, undrained blood, pneumonia, or other causes. Small effusions without signs of infection may be simply observed; large or symptomatic effusions require intervention. Early effusions can be managed with thoracentesis or chest tube drainage. Late effusions usually require decortication for management of trapped lung and pleural peel. Management can be complex in patients with anticoagulation or other comorbidities. Late pericardial effusions may develop after cardiac surgery. Infected or hemodynamically significant effusions require drainage. Pericardial window may be difficult due to scarring, anticoagulation, or presence of coronary grafts. Patients with extrathoracic malignancies may develop late thoracic complications due to chemoradiation therapy or progression of their tumors. Tracheoesophageal fistulas, esophageal strictures, malignant pleural or pericardial effusions, chylothorax, and other complications are possible. Neurosurgical or orthopedic management of spine disease can result in complications involving the esophagus, pleural space, or other thoracic structures. These may present late and may require thoracic surgical intervention (Fig. 14-26).

LATE COMPLICATIONS COMMON TO ALL THORACIC PROCEDURES Wound Infection The incidence of wound infection after thoracotomy is less than 2%. Underlying patient risk factors include immunosuppression, diabetes, obesity, malnutrition, and other comorbidities. Surgical risk factors include wound contamination, hematoma, dead space, tissue trauma, prosthetics, and prolonged operative times. Perioperative prophylactic antibiotics

tahir99-VRG vip.persianss.ir

Ch014-F06861.indd 182

1/21/2008 2:11:13 PM

Chapter 14 Late Postoperative Complications

183

A

FIGURE 14-26 A patient with a previous cervical spine fracture treated with fibula graft and cervical fusion 1 year previously. A, CT scan demonstrates erosion of the fibula graft into the esophagus. B, Endoscopic view.

B

A

FIGURE 14-27 A, CT scan of a massive pulmonary embolism. B, Autopsy photographs of a patient who died of pulmonary embolism. A large clot is present in the main pulmonary artery.

lower infection rates. If wound infection develops, an underlying deep infection must also be excluded. Superficial wound infections resolve with antibiotics and local wound care. Infected prosthetic grafts and deep infections may require reoperation.

B

Deep Venous Thrombosis and Pulmonary Embolism

for surgical patients is determined by the type of operation performed and by individual patient characteristics.100 In the highest-risk groups, deep venous thrombosis can occur in up to 80% of patients.101 This group has a pulmonary embolism rate of up to 10% and a fatal embolic rate of up to 5% (Fig. 14-27).101 The Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy recommended the following prophylactic treatment:

Deep venous thrombosis and thromboembolism are potential long-term complications in any hospitalized patient. The risk

Unfractionated heparin (UFH), 5000 U subcutaneously (SQ) twice a day, or low-molecular-weight heparin

tahir99-VRG vip.persianss.ir

Ch014-F06861.indd 183

1/21/2008 2:11:13 PM

184

Section 1 Introduction

(LMWH), up to 3400 U SQ once a day, for moderate-risk general surgery patients. UFH 5000 U SQ three times daily, or LMWH 3400 U SQ once a day, for higher-risk general surgery patients. UFH 5000 U SQ three times daily or LMWH more than 3400 U SQ once a day, combined with compression devices, for high-risk general surgery patients.102 Prophylactic LMWH may be more effective than UFH without increasing bleeding risk.103,104 Because the risk for venous thromboembolism persists for up to 3 months postoperatively, high-risk patients may also benefit from extended prophylaxis.105 Thoracic surgical patients often have multiple risk factors for development of venous thromboembolism. Consequently, a combination of early ambulation, subcutaneous heparin, and pneumatic compression stockings appears optimal. Management choices for deep vein thrombosis include systemic anticoagulation and/or inferior vena cava filters. Therapeutic LMWH is associated with less bleeding risk than is UFH.106 Options for treatment of pulmonary emboli after thoracic surgery include anticoagulation, inferior vena cava filters, thrombolysis, and/or surgical thrombectomy.107-109

Cardiac Complications—Tachyarrhythmias, Myocardial Infarction The most common complication after general thoracic operations is atrial fibrillation.110,111 The incidence is approximately 20% (range, 10%-50%).111,112 Most episodes occur within 3 days after surgery, and more than 95% resolve in the first week.111 Risk factors are related to patient factors (age, baseline heart rate, cardiac disease, COPD), surgical procedure (major operation, intrapericardial dissection), and treatment (irradiation).111-115 Atrial fibrillation produces increased morbidity, longer hospital stays, higher hospital costs, and possibly higher mortality rates.110,114,115 Consequently, many studies have evaluated medical prophylaxis of general thoracic patients. The evidence supports the following conclusions110,111: Calcium channel blockers and β-blockers reduce the risk of atrial tachyarrhythmias. β-Blockers increase the risk of pulmonary edema. Magnesium appears to reduce the risk of atrial fibrillation. Digoxin increases the incidence of atrial fibrillation. The efficacy of flecainide is unknown. Amiodarone may result in high rates of respiratory failure. The risk of stroke is increased in patients with chronic atrial fibrillation. Management after surgery requires consideration of both the benefits of anticoagulation prophylaxis and the risk for postoperative bleeding. In medical patients (without antecedent thoracic surgery), the following guidelines for anticoagulation have been established.116 For patients with intermittent atrial fibrillation and a high risk for stroke (e.g., prior stroke, transient ischemic attacks, age older than 75 years, systemic embolus, congestive failure): Coumadin anticoagulation with a goal international normalized ratio (INR) between 2.0 and 3.0.

Ch014-F06861.indd 184

For patients with persistent atrial fibrillation, age 65 to 75 years, no other risk factors, and intermediate risk for stroke: Coumadin as described earlier or aspirin 325 mg/ day. For patients with persistent atrial fibrillation or paroxysmal atrial fibrillation, age younger than 65 years, and no risk factors: aspirin 325 mg/day. For patients with atrial fibrillation of less than 48 hours’ duration: cardioversion. Ventricular arrhythmias after general thoracic surgery occur in approximately 15% of patients, but sustained ventricular tachycardia or hemodynamic compromise is rare.111,117 Preoperative left bundle branch block is a risk factor. Other risk factors are postoperative atrial premature contractions, ventricular premature contractions, ventricular couplets, and atrial fibrillation.111,117 Despite the high prevalence, complications or poor outcome after ventricular arrhythmia are rare.117 The incidence of perioperative myocardial infarction is 1.2%, and that of perioperative cardiac ischemia is 3.8%.111 The risk of infarction increases from 0.13% in patients without a previous cardiac history to between 3% and 17% in patients with previous infarction.111 The American Heart Association guidelines for preoperative cardiac evaluation are as follows111: Coronary angiography for high-risk patients (unstable angina, uncompensated congestive heart failure, significant arrhythmias, severe valvular disease) Dobutamine stress echocardiography for patients at intermittent risk Delay in surgery of 2 to 4 weeks after angioplasty and stenting Perioperative monitoring and maintenance of preoperative β-blockers and other cardiac medications are recommended for patients who are at risk for postoperative cardiac complications. The mortality rate of perioperative myocardial infarction is between 30% and 70%.111

Late Respiratory Failure Postoperative respiratory insufficiency results from diseases affecting the pulmonary parenchyma, airways, pulmonary vasculature, or heart. Obtain pulse oximetry and pulmonary embolism protocol chest CT in all patients. Pulmonary function testing, bronchoscopy, pulmonary angiography, cardiac evaluation, or other diagnostic studies are helpful in selected cases. Pulmonary parenchymal causes of late postoperative respiratory insufficiency include preexisting conditions (lung disease, preoperative chemotherapy), pneumonia, and adult respiratory distress syndrome (ARDS). Chronic obstructive lung disease and pulmonary fibrosis have increased rates of respiratory insufficiency and death after lung resections.118,119 Concomitant volume reduction and pulmonary resections are being done in patients with marginal respiratory reserve.120 The likelihood of respiratory insufficiency may be increased in these patients.120,121

1/21/2008 2:11:16 PM

Chapter 14 Late Postoperative Complications

Pneumonia is a frequent cause of respiratory insufficiency after thoracic procedures. Clinical signs include fever, leukocytosis, purulent sputum, rising oxygen requirements, and radiographic infiltrates. Early empiric antibiotics and respiratory hygiene are used initially. After a specific organism is isolated, the antibiotic spectrum can be narrowed. Respiratory insufficiency can also be caused by ARDS. Management includes oxygen, mechanical support with lung protective strategies, and medications (possibly nitric oxide and low-dose steroids).111,122 The mortality rate of postoperative ARDS is high.111,123 Cardiac causes of late respiratory insufficiency include pericardial effusion, left- or right-sided congestive heart failure, pulmonary hypertension, and patent foramen ovale. Pericardial effusion may arise from induction or adjuvant therapy, malignancy, Dressler’s syndrome, infection, or other causes as described earlier. Pericardiocentesis or pericardial window achieves drainage and yields samples for analysis. Left-sided congestive heart failure may be caused by rightsided heart failure, preexisting disease, chemotherapy, perioperative infarction, or cardiac herniation.111 Acute right-sided heart failure from pulmonary hypertension may be reversible with vasodilators or inhaled nitric oxide (Fig. 14-28). Right-to-left cardiac shunting through a patent foramen ovale can produce late dyspnea. Patients present several months after surgery with dyspnea which may be postural or related to hydration.111 Treatment is with surgical or percutaneous closure.

Other Late Organ Insufficiency Renal failure results from prerenal ischemia, nephrotoxic drugs, or postrenal obstruction. Patients with preexisting renal insufficiency are at increased risk for development of chronic renal failure. Management is by maintaining renal perfusion and providing hemofiltration or dialysis as needed.

FIGURE 14-28 Severe right-sided heart failure with massive dilation of the right ventricle and displacement of the ventricular septum into the left ventricle. The patient had acute respiratory failure following pneumonectomy. Management with inhaled nitric oxide was successful.

Ch014-F06861.indd 185

185

Patients with underlying liver disease are at increased risk for postoperative complications, liver failure, and death. This is most common in the perioperative period but can also occur late in the postoperative course. The most accurate predictor of liver failure and mortality is the Child-PughTurcotte classification.

SUMMARY Late complications have significant health, moral, legal, political, and financial implications. To varying degrees, the occurrence and severity of late complications can be limited by carefully performed operations, early recognition, and proper management. This chapter provides an overview of the more common late complications after thoracic surgical procedures.

COMMENTS AND CONTROVERSIES Late complications after thoracic surgical procedures are uncommon and seldom life-threatening. However, they usually lead to chronicity and prolonged disabilities. As pointed out by the authors, chronic pain is the most common late complication associated with thoracotomy, but it is seen in fewer than 5% of patients. It is important to remember that, when pain occurs after resection of a lung cancer, it may be caused by recurrent tumor, which must be ruled out by appropriate imaging techniques. Late wound infections are also uncommon, and most are related to an undiagnosed empyema draining spontaneously through the wound (empyema necessitatis). Management must therefore include adequate drainage of the pleural cavity and of the infected space. Late BPFs occur after the second postoperative month, and most are the direct consequence of an empyema draining through the bronchial stump. This is the reason why such dehiscences are usually small and why spontaneous closure may occur once the empyema is properly evacuated. Patients are often debilitated, and, in general, factors such as the size of empyema and the bacteria involved, rather than size of the BPF, determine the extent of symptoms. In all such patients, do bronchoscopy, not only to document the BPF but also to rule out residual or recurrent cancer in the bronchial stump. Management of late BPF differs considerably from that of early BPF because conservative therapy is often successful in late BPF, and spontaneous closure of the BPF might occur. Late-onset postpneumonectomy empyemas are those that are diagnosed 6 months or more after surgery in patients who had an otherwise normal postoperative course. In the absence of a BPF, the most likely mechanism is that the pleural space was contaminated during the initial surgery with bacteria laying dormant in small pockets or loculations of fluid. Late esophagopleural fistulas are uncommon events that are difficult to diagnose and are often overlooked. They occur predominantly on the right side, most commonly immediately below the carina. Etiologic factors include cancer recurrence, esophageal wall necrosis due to radiotherapy, and an esophagus made vulnerable by devascularization or trauma during the initial operation. Management must be individualized, taking into account the patient’s medical condition, the oncologic status, and the specific characteristics of the fistula.

1/21/2008 2:11:16 PM

186

Section 1 Introduction

Late respiratory failure is seen almost exclusively after pneumonectomy. This complication is difficult to predict and manage, and ultimately it is an important cause of death. Common causes include progressive lung disease (COPD and pulmonary hypertension); mechanical syndromes such as the postpneumonectomy syndrome and the platypnea-ortho-deoxia syndrome; or recurrent cancer with pleural effusion, lymphangitic carcinomatosis, or airway obstruction. J. D.

Ch014-F06861.indd 186

KEY REFERENCES Little A (ed): Complications in Cardiothoracic Surgery: Avoidance and Treatment. Elmsford, NY, Futura, 2004. Wolfe W (ed): Complications in Thoracic Surgery: Recognition and Management. St. Louis, Mosby, 1992.

1/21/2008 2:11:16 PM

chapter

15

ANATOMY, PHYSIOLOGY, AND EMBRYOLOGY OF THE UPPER AIRWAY Cameron D. Wright

Key Points ■ The length of the adult trachea is about 11 cm, and its width is

about 2.3 cm. ■ The trachea grows steadily throughout childhood, and published

data are available to predict length and width. ■ The tracheal blood supply comes from two primary sources: tra-

cheoesophageal branches from the inferior thyroid artery and ascending branches from the bronchial arteries. ■ The trachea is enveloped in a connective tissue sheath, a fact that has surgical and pathologic implications.

EMBRYOLOGY Trachea The development of the respiratory system begins at 4 weeks of gestation with the development of an endodermal bud growing into the splanchnic mesenchyme.1 The endodermal components become the epithelium and glands, whereas the mesenchyme becomes cartilage, connective tissue, and muscular components. The primordial lung appears and bulges anteriorly from the primitive foregut. Separation of the trachea from the esophagus occurs by the sixth week. The tracheal bifurcation gradually moves down to the level of the fourth vertebra. Cartilage appears in the trachea at 10 weeks. Increases in the circumference of the trachea occur by the simultaneous processes of uniform growth of the convex side of the trachea and remodeling by resorption along the concave surface. In this manner, the whole cartilage grows as a unit. Although the growth of each segment is uniform, the different levels grow to different extents, so that the trachea is funnel shaped, being larger at the larynx than at the carina. This funnel shape is especially evident in the perinatal period. Failure of separation of the trachea from the esophagus is the most common congenital tracheal defect and produces tracheoesophageal fistula. Other congenital lesions include laryngotracheoesophageal cleft, tracheal webs, tracheal agenesis, tracheomalacia, and tracheal stenosis.

Tracheal Glands Tracheal glands develop from the endodermal layer of the developing embryo, development generally occurring after that of the cartilage, between 10 and 25 weeks of gestation. Glandular development after this stage occurs by an increase in the acinar components, thus increasing the mass but not the number of glands. After birth, the density of glands gradually decreases.

Cilia The cilia of the trachea develop within the first half of gestation, and by 24 weeks their development is complete. There is differentiation from columnar undifferentiated epithelium through primitive ciliated cells to the final form.

Blood Supply During prenatal life, the blood supply of the trachea is segmental. Multiple pairs of arteries arise in segmental fashion from the aorta to supply both trachea and esophagus. With time, the segmental distribution disappears, and branches that originate from the thyroid artery and aorta (via bronchial vessels) become the major sources of blood supply.

ANATOMY Trachea Length The trachea is a cartilaginous and membranous tube that connects the larynx with the bronchi. It is continuous with the larynx at the level of the cricoid cartilage. Inexperienced endoscopists often mistake the cricoid for the trachea, but careful examination of the posterior wall of the cricoid confirms the presence of circumferential cartilaginous ring, as opposed to the membranous wall of the trachea. The upper trachea is normally found at the level of the sixth or seventh cervical vertebra, and the lower end lies at the fourth or fifth thoracic vertebra in young people. On full inspiration, the distal end of the trachea may descend to the level of the sixth vertebra. Surface landmarks are often a poor way to localize tracheal pathology because the position of a tracheal lesion relative to adjacent structures varies considerably with neck flexion and extension, age, kyphoscoliosis, and body build. The location of a tracheal lesion is best described with reference to the cricoid or the carina, two fixed landmarks. In the resting state in an adult, the total length of the trachea is 11 to 13 cm, with approximately 5 cm lying superior to the suprasternal notch. The noncartilaginous portions of the trachea between rings are elastic and allow lengthening or shortening of the trachea during respiration (or neck flexion or extension). Projected anteriorly, the tracheal bifurcation, or carina, lies at the level of the manubriosternal junction, or the second costal cartilage. In children, the carina lies at the level of the third costal cartilage.

Shape The cross-sectional shape of the trachea is determined by the horseshoe-shaped cartilage anteriorly and the membranous 189

Ch015-F06861.indd 189

1/21/2008 10:47:44 AM

190

Section 2 Upper Airway

TABLE 15-1 Tracheal Size in Children and Adolescents Age (yr)

Length* (cm)

Anterior-Posterior Diameter (cm)

Transverse Diameter (cm)

Area (cm2)

0-2

5.4

0.53

0.64

0.28

2-4

6.4

0.74

0.81

0.48

4-6

7.2

0.80

0.90

0.58

6-8

8.2

0.92

0.93

0.69

8-10

8.8

1.03

1.07

0.89

10-12

10.0

1.16

1.18

1.1

12-14

10.8

1.3

1.33

1.39

14-16

11.6

1.42

1.44

1.62

16-18

12.3

1.47

1.50

1.76

18-20

12.4

1.58

1.52

1.94

*Tracheal length is from vocal cords to carina. Data from Griscom NT, Wohl MEB: Dimensions of the growing trachea related to body height. Am Rev Respir Dis 131:840, 1985; Griscom NT, Wohl MEB: Dimensions of the growing trachea related to age and gender. AJR Am J Roentgenol 146:233, 1986; Griscom NT, Wohl MEB: Dimensions of the trachea to age 6 years related to height. Pediatr Pulmonol 6:186, 1989.

portion posteriorly. The most common cross-sectional configuration of the cartilaginous trachea is elliptical (larger in the transverse than the anteroposterior diameter) in 33% of cases.2 A C shape (equal transverse and anteroposterior diameters) is found in 26% of cases, and a U shape in 21%. A triangular shape occurs in less than 10% of the population. The length and diameter of the trachea are proportional to the size of the person. The average transverse diameter of the adult male trachea is 2.3 cm, and that of the female is 2.0 cm. Griscom and Wohl published data on the size of the trachea in children and adolescents based on computed tomographic measurements (Table 15-1).3-5 The adult trachea has an almost constant dimension for its entire length, but the pediatric trachea does not. Wailoo and Emery6 studied humans from 28 weeks of gestation to 4 years of age and found that the trachea is a funnel-shaped structure that is larger at the larynx than at the carina. This shape is most pronounced in the prenatal and neonatal stages. With growth, the difference in size between larynx and carina decreases until it is negligible, creating a cylindrical rather than a funnel-shaped trachea.

Tracheal Rings There are between 12 and 16 tracheal rings, which are composed of hyaline cartilage. There is variation in size and shape, and the average ring in an adult is approximately 4 mm wide and 1 mm thick. Some rings are fused over variable circumferential distances, and there is great variability among individuals in this respect. Although the cartilaginous rings are resilient and compliant in childhood and early adulthood, they tend to calcify with age. This gradual calcification and resultant loss of compliance with age has clinical implications. Higher compliance means that blunt trauma may be better

Ch015-F06861.indd 190

Inferior thyroid artery

Lateral tracheal artery

Esophageal artery

Bronchial artery

FIGURE 15-1 The blood supply of the trachea. The inferior thyroid and bronchial arteries anastomose to supply a lateral arcade which supplies the trachea and esophagus in a segmental fashion.

tolerated by young compared with elderly patients. During tracheal resections, mobilization of a compliant trachea may allow a greater extent of resection without the anastomotic tension that is possible in the elderly patient with a rigid, calcified trachea. Each cartilage is enveloped by perichondrium, which is continuous with a sheet of dense connective tissue made up primarily of collagen with some elastin. The collagen and elastin are diagonally apposed, allowing both for changes in diameter of the airway and for some elastic recoil when the distending stress is removed. The connective tissue is continuous with the posterior or membranous trachea. External to the fibrous sheath and perichondrium of the trachea is an envelope of fascia, which is called the pretracheal fascia anterior to the trachea.

Membranous Trachea The membranous trachea consists of an enveloping fibrous sheath, smooth muscle, epithelium, and glands. The smooth muscle component consists mostly of transverse fibers, with some vertical elements external to the transverse layer. The cartilaginous part of the trachea also contains small amounts of muscle between the rings of cartilage. It is the soft, distensible, membranous trachea that allows most of the moment-to moment changes in size of the tracheal lumen.

Glands The luminal surface of the trachea consists of pseudostratified columnar cells, some goblet cells, and many glandular openings. The glands are situated in the membranous trachea and in the intercartilaginous components of the cartilaginous trachea. They are layered in the submucosa, with ducts extending through the mucosa and opening into the lumen.

1/21/2008 10:47:45 AM

Chapter 15 Anatomy, Physiology, and Embryology of the Upper Airway

FIGURE 15-2 Left anterior view of the tracheal blood supply. The inferior thyroid artery usually has three tracheoesophageal branches that supply the cervical trachea. An anterior branch of the superior bronchial artery usually courses over the left main bronchus to the carina. There may be a variable branch from the internal thoracic artery. (FROM SALASSA JR, PEARSON BW, PAYNE WS: GROSS AND

FIGURE 15-3 Right anterior view of the tracheal blood supply. The inferior thyroid artery in this case has two tracheoesophageal branches that supply the cervical trachea. Branches from the internal thoracic artery and subclavian also contribute in a variable fashion. The bronchial arteries anastomose around the carina in a variable fashion and ascend to anastomose with the lateral arcade. (FROM

MICROSCOPICAL BLOOD SUPPLY OF THE TRACHEA. ANN THORAC SURG 24:100, 1977.)

SALASSA JR, PEARSON BW, PAYNE WS: GROSS AND MICROSCOPICAL BLOOD SUPPLY OF THE TRACHEA. ANN THORAC SURG 24:100, 1977.)

Blood Supply Macroscopic

the trachea on the way to the thyroid gland. Typically, there are three tracheoesophageal branches, with one of the three dominant, most commonly the inferior one. Occasionally, a vessel arises directly from the subclavian artery, usually on the right side. When this occurs, two rather than three tracheoesophageal branches of the inferior thyroid artery are present. These branches, regardless of origin, anastomose with the bronchial vessels and also provide blood supply to the esophagus (Figs. 15-2 and 15-3). The superior thyroid artery has anastomotic connections with the inferior thyroid artery and therefore supplies the trachea (and esophagus) only indirectly. From the work of Cauldwell and colleagues8 and Salassa and associates (Salassa et al, 1977),9 it is known that bronchial vessels are the major blood supply to the lower trachea. There may be some variation in the origin and number of bronchial vessels, but the most common arrangement (∼40% of cases) is to have two left and one right bronchial

The blood supply of the trachea and esophagus are similar and closely linked. That of the trachea is segmental prenatally; however, there are primarily two sources after birth. The cervical trachea receives its arterial blood supply from the inferior thyroid artery and its tracheoesophageal branches. There are rich anastomotic connections among the branches of the inferior thyroid vessels. The bronchial arteries provide blood supply to the lower trachea, carina, and bronchi. Figure 15-1 demonstrates the anastomotic network of the trachea and the major origins from the inferior thyroid and bronchial vessels. Miura and Grillo7 studied the blood supply of the cervical trachea and found that the inferior thyroid artery gives rise to branches that serve not only the esophagus but also the trachea. They found that a variable number of vessels pass to

Ch015-F06861.indd 191

191

1/21/2008 10:47:45 AM

192

Section 2 Upper Airway

Type I (40.6%)

Type V (4.0%)

Type III (20.6%)

Type II (21.3%)

Type VI (2.0%)

Type VII (0.6%)

Type VIII (0.6%)

Type IV (9.7%)

Type IX (0.6%)

FIGURE 15-4 Patterns of variation of bronchial artery supply to the main bronchi. The view shown is posterior, with the aorta on the left and the esophagus between the aorta and trachea. (FROM CAULDWELL EW, SICKERT RG, LINIGER RS, ET AL: THE BRONCHIAL ARTERIES, AN ANATOMIC STUDY OF 150 HUMAN CADAVERS. SURG GYNECOL OBSTET 86:395, 1948.)

vessel originating directly from the aorta (Fig. 15-4). Approximately 50% of such bronchial arteries arise at the level of the sixth thoracic vertebra, and a smaller number (35%) arise at the level of the fifth vertebra. Occasionally there is only one left bronchial vessel (20% of cases), and occasionally there are two right vessels (20%). Two thirds of all right lungs are supplied by a single bronchial vessel, whereas only one third of all left lungs are singly supplied. The trachea is also supplied by branches that originate from the subclavian artery, the internal mammary artery, or the brachiocephalic (innominate) artery. The bronchial vessels usually arise from the aorta (the right from the lateral or posterolateral part, and the left from the anterior surface or the convex surface of the aortic arch), but they can and frequently do originate from a common trunk with an intercostal artery. This is found more commonly on the right side. More recently, Schreinemakers and colleagues10 studied the tracheal and bronchial vasculature in humans to better evaluate the role of the bronchial circulation in human lung trans-

Ch015-F06861.indd 192

plantation. Their findings confirmed the observations of Cauldwell and associates8 and Salassa and colleagues (Salassa et al, 1977).9 They also documented the importance of the right first intercostal artery, noting that many bronchial trunks arise from the right but not the left first intercostal artery. Cauldwell and coworkers8 found that 90% of the intercostobronchial arteries arose from the right first intercostal artery, and only 6% arose from the left.

Microcirculation Once the arteries reach the tracheoesophageal groove, they divide into primary tracheal and primary esophageal branches (Fig. 15-5). Tracheal vessels enter the trachea in its lateral wall, 0.7 to 1.5 cm anterior to the tracheoesophageal groove. After entering the trachea, lateral longitudinal and transverse intercartilaginous arteries are formed that connect the superior to the inferior vessels and supply blood in a circumferential manner to the trachea. The lateral longitudinal arteries

1/21/2008 10:47:46 AM

Chapter 15 Anatomy, Physiology, and Embryology of the Upper Airway

193

FIGURE 15-5 Tracheal microcirculation. Vessels enter on the lateral aspect and form a rich submucosal plexus. Tracheal cartilage is nourished from the submucosal circulation only. (FROM SALASSA JR, PEARSON BW, PAYNE WS: GROSS AND MICROSCOPICAL BLOOD SUPPLY OF THE TRACHEA. ANN THORAC SURG 24:100, 1977.)

can be large—up to 1 to 2 mm in diameter—and form an important anastomotic connection for the entire trachea. To safely preserve blood supply, minimize circumferential mobilization of long segments of trachea, especially along the posterolateral aspects, during tracheal surgery. Throughout the length of the trachea is an extensive submucosal plexus, fed by transverse intercartilaginous arteries, each of which penetrates the soft tissue space between the cartilaginous rings and runs anteriorly. As they reach the midline, they dive more deeply and terminate in the submucosal plexus. Conversely, there is no blood supply external to the cartilages. Therefore, the cartilages receive their nutrient supply from the submucosal arterial plexus. As a consequence, the tracheal rings may be damaged by ischemic injury caused by overinflation of endotracheal tube cuffs. The membranous trachea is not supplied by the transverse intercartilaginous arteries. Small twigs from these vessels pass posteriorly, but they tend to stop at the cartilage-membrane junction. The membranous portion is supplied by secondary tracheal twigs, which arise from primary esophageal branches of the tracheoesophageal arteries. These secondary tracheal twigs enter the membranous portion of the trachea and feed the submucosal plexus of the posterior wall of the trachea. These secondary arteries are well developed and form longitudinal arcades that span several segments. After subtotal esophagectomy, the blood supply of the membranous trachea

Ch015-F06861.indd 193

depends on small collateral channels from the remaining tracheal blood supply. If this microcirculation has been damaged by prior radiation, removal of the adjacent esophagus can have disastrous consequences on the viability of the membranous trachea.

Carina The most inferior portion of the trachea, the bifurcation, is called the carina. It normally lies slightly to the right of the midline and is at the level of the fourth or fifth vertebra posteriorly and the sternomanubrial junction anteriorly. In normal individuals, the left main stem bronchus lies under the aortic arch, and, for this reason, the carina, proximal left main stem bronchus, and distal trachea are difficult to access through a left thoracotomy. Exposure is excellent through a high (fourth interspace) right thoracotomy. The angle between the two main stem bronchi varies among individuals and is typically greater in children than in adults. The configuration of the cartilages at the carina is variable. Most often, there is a symmetrical contribution from each side, with or without fusion at the carinal bifurcation. The blood supply at the carina is robust and comes primarily from bronchial vessels, which branch to supply both the trachea and the bronchi. There is an abundance of lymph nodes in the crotch of the carina (subcarinal nodes), which drain each side of the tracheobronchial tree and the lungs.

1/21/2008 10:47:47 AM

194

Section 2 Upper Airway

Right vagus nerve Right subclavian artery Right recurrent laryngeal nerve Right and left brachiocephalic veins Brachiocephalic artery Superior vena cava

Left common carotid artery Vagus nerve

Left subclavian artery

Inferior cornu of thyroid cartilage

Right common carotid artery

Right carotid artery

Left vagus nerve Aorta

Cricoid cartilage Thyroid gland Brachiocephalic artery

Right subclavian artery

Arch of aorta

Right recurrent laryngeal nerve Trachea

Left recurrent laryngeal nerve Pulmonary trunk

1

Azygos vein

Carina 2

RMB

Superior vena cava

FIGURE 15-6 Anatomic relationship of the trachea and surrounding structures. Anterior view demonstrates close apposition of numerous structures to the trachea. (COURTESY OF EDITH TAGRIN.)

LMB Pulmonary veins

Lymphatics Lymphatic vessels are present in the trachea beneath the mucosa. Lymph from the anterior wall tends to flow laterally, whereas that from the lateral wall flows to the membranous wall. Lymph vessels course freely up and down the membranous wall. Lymph vessels freely exit the tracheal wall and become perivascular lymphatics, which are closely associated with peritracheal lymph nodes. Lymph nodes are commonly found anterior to, lateral to, and at the bifurcation of the trachea. They are not commonly found posteriorly, between the esophagus and trachea.

Anatomic Relationships The upper trachea is commonly covered by the closely applied thyroid gland with its two lobes and isthmus (Fig. 15-6). The recurrent laryngeal nerves are closely applied to the trachea and commonly lie in the tracheoesophageal groove. The left nerve lies along the tracheoesophageal groove for its entire course, due to its distal origin beneath the aortic arch. The right nerve originates from beneath the right subclavian artery and therefore courses to the trachea from a more lateral position. The right nerve usually is intermixed with the inferior thyroid artery branches, whereas the left usually lies posterior to the artery. The esophagus is usually directly posterior to the trachea; less commonly, it may lie partially to the left of the trachea. There is often relative fusion of the anterior wall of the esophagus with the membranous wall of the trachea with loose areolar connective tissue. The brachiocephalic artery lies anteriorly, in close apposition to the trachea. Connective tissue envelops this artery and separates it from the trachea.

Ch015-F06861.indd 194

Phrenic nerve

Pulmonary artery FIGURE 15-7 Anatomic relationship of the trachea and its surrounding structures from the right side. LMB, left main bronchus; RMB, right main bronchus. (COURTESY OF EDITH TAGRIN.)

The lower trachea is abutted and tethered by the aortic arch on the left because the left main bronchus courses under the arch (Fig. 15-7). The azygos vein on the right side is closely applied at the tracheobronchial angle but does not tether the trachea. The esophagus is adjacent to the membranous wall of the trachea from the inferior border of the cricoid cartilage down to the carina and then crosses behind the proximal part of the left main bronchus. The trachea (and esophagus) is enveloped in a dense fibrous connective tissue which is the deep layer of the deep cervical fascia. This sheath descends into the mediastinum and merges with the pericardium and visceral pleura. This sheath has surgical significance because it allows infections to descend from the neck and air to ascend to the neck from the tracheobronchial tree or lung. Anteriorly, this sheath is called the pretracheal fascia, and it has only a very loose areolar connection to the trachea, with no significant arteries traversing this plane. This allows entry into the mediastinum from the neck for mediastinoscopy, and it permits extensive mobilization of the anterior portion of the trachea for resection without fear of injuring its blood supply. The trachea is usually an almost vertical structure in young people but often becomes more horizontal with increasing age. Kyphosis makes this tendency even worse. In addition, the larynx descends toward the sternal notch with increasing

1/21/2008 10:47:48 AM

Chapter 15 Anatomy, Physiology, and Embryology of the Upper Airway

age, which limits the amount of cervical trachea present. As such, the sternal notch is a poor landmark to denote a tracheal lesion. When young people extend their neck, as much as one half of the trachea may be elevated into the neck. In contrast, older individuals start with less cervical trachea and elevate less into the neck with extension. As a result, tracheal reconstruction for proximal lesions is less complicated in the young than in older adults.

PHYSIOLOGY Airway Size Alterations in tracheal diameter and length occur with each respiration. During inspiration, both the length and the diameter increase. The airway resistance is markedly decreased (it is inversely related to the fourth power of the radius) as the diameter increases. The tracheal lumen markedly narrows during coughing, which increases air flow velocity and thus helps clear secretions.

195

cilia at a rate of 160 to 1500 times per minute and moves debris at a rate of about 166 mm/min.11

Tracheobronchial Secretions Tracheobronchial secretions consist of the output of the mucous glands under vagal and parasympathetic drug stimulation and of the goblet cells under the influence of local irritants. The sympathetic nervous system plays no known role in the production of these secretions. The total volume of the secretions is difficult to measure but under normal circumstances varies from 10 to 100 mL/day. The mucus layer forms a coat on the surface of the airway, which not only moistens the inspired air but also may limit evaporation from the trachea and bronchi. This mucus coat, which is about 5 µm in thickness, also carries foreign debris out of the airway. These secretions contain immunoglobulins, lysozymes, and other bacteriostatic and bacteriocidal components; they are 95% water, with carbohydrates, proteins, and lipids making up most of the remaining 5%.12

Ciliary Action The epithelium of the trachea consists of pseudostratified ciliated columnar epithelium with interspersed goblet cells. Ciliary action gently wafts debris proximally from more distal airways, and the mucoid material is then either expectorated or swallowed. This occurs by a rhythmic contraction of the

Ch015-F06861.indd 195

KEY REFERENCES Salassa JR, Pearson BW, Payne WS: Gross and microscopical blood supply of the trachea. Ann Thorac Surg 24:100, 1977. ■ The classic anatomic study of tracheal blood supply.

1/21/2008 10:47:49 AM

chapter

16

IMAGING OF THE UPPER AIRWAY Cylen Javidan-Nejad Sanjeev Bhalla

Key Points ■ Tracheal and bronchial imaging can effectively be done by mag-

netic resonance imaging (MRI) or computed tomography (CT). ■ Multidetector CT (MDCT) is faster than MRI. ■ MDCT does not require intravenous (IV) contrast. ■ Multiplanar and three-dimensional reconstructions may enhance

diagnostic certainty by better delineating the craniocaudal extent of disease. ■ The craniocaudal extent of disease defines the differential diagnosis on imaging.

Diseases of the trachea and main bronchi are uncommon. As with other respiratory conditions, initial imaging evaluation begins with chest radiography. The entire trachea (from vocal cords to carina) may not be clearly seen on a single radiographic examination because of overlapping mediastinal structures.1 In the era of digital radiography, the radiograph can be rewindowed to better delineate the trachea and separate it from adjacent structures. This can be a helpful way to detect suspected tracheal abnormalities, but it is not practical for routine evaluation of the chest because it requires extra steps that can be time-consuming.

and was relatively fast and noninvasive. It was also a preferred technique because of its depiction of the airway in a coronal plane, which was akin to a chest radiograph and easily understood by radiologists and nonradiologists. Because it was so readily employed and so well received, the tomogram would require that its replacement be able to depict the upper airway in a coronal plane. Because of the adjacent mediastinum, the trachea has some inherent contrast that the bronchi (air-filled structures surrounded by air) do not. Modifications were required to delineate the bronchi if a bronchial lesion or bronchiectasis was suspected. One such adaptation of bringing out the contrast of the bronchi was bronchography (Fig. 16-2). In this fairly invasive technique, positive contrast material was placed into the airway, and radiographs were obtained. Sometimes this was done via a small catheter placed into the airway; at other times, it was done by creating a cricothyroidotomy. Clearly, this would result in coughing and patient discomfort because the patient would be asked to essentially aspirate contrast material. The legacy of this technique would center on the exquisite radiographs that could be obtained in the ideal situation. Because of its invasive nature, bronchography readily gave way to axial imaging by CT but with the requirement that CT reconstructions duplicate the quality of images obtained by bronchography.

COMPUTED TOMOGRAPHY HISTORY OF TRACHEAL IMAGING The inherent desire to increase tracheal contrast led to modifications of conventional radiography that would serve as the basis for dedicated tracheobronchial CT and establish some of the conventions used today for displaying CT reconstructions. These techniques are no longer routinely used. Perhaps the simplest of the techniques for imaging of the upper airway centered on modifying the radiograph to make the tracheal air column more conspicuous compared with the adjacent mediastinum. This technique required modification of dose (decreased kilovolt peak [kVp]) and a coned-down radiograph to bring out the trachea. In another plain-film modification, a linear tomogram was employed to image the tracheobronchial tree (Fig. 16-1). This method used an x-ray source that moved while the object to be imaged remained stationary. The net effect was that the undesired part of the image would be blurred and the plane of interest (thickness based on width of the arc of x-ray motion) would be the sole part of the radiograph in focus. With three to four planes, the entire trachea could be imaged. This technique was used frequently for imaging the upper airway because it provided excellent tracheal depiction

In the 1980s, CT imaging became routinely used for evaluation of the upper airway. At that time, sequential imaging was used for imaging of the upper airway. Early sequential CT required the patient to breathe consistently as the entire trachea was imaged over a succession of breath-holds. With each breath-hold, one to three scans (i.e., 1-3 cm) could be obtained. The sequential technique did not allow for adequate multiplanar reconstructions because the patients, who were often dyspneic or stridulous, could not reliably breathe consistently with reproducible breath-holding. Another drawback to sequential imaging was the need to use thicker images (usually 1 cm) because of the limited craniocaudal (z-axis) coverage with each breath-hold. The net effect was that CT was seen as complementary to linear tomography but not as a substitute for it. In the late 1980s, the use of slip-ring technology brought forth spiral or helical CT. This technological advance allowed for coverage of the entire tracheobronchial tree in one breathhold. The slice thickness could be reduced, and overlapping reconstruction intervals could be used to minimize stair-step reconstruction artifacts. CT reconstructions were now able to challenge linear tomography and bronchography for coronal

196

Ch016-F06861.indd 196

1/21/2008 10:48:52 AM

Chapter 16 Imaging of the Upper Airway

FIGURE 16-1 Coronal linear tomogram of the trachea in a 50-yearold man with shortness of breath shows diffuse nodularity (arrows) of the distal tracheal wall and right main stem bronchus caused by tracheobronchopathia osteochondroplastica.

FIGURE 16-2 Bronchogram in a 65-year-old male smoker with chronic bronchitis shows the dilated mucosal glands in the left main and left lower lobe bronchi (open arrowheads).

display of the airways, and these latter techniques began to disappear. Advances in helical CT allowed for greater z-axis coverage in one breath-hold and thinner slice thicknesses. The net effect was improved reconstructions. In the mid-1990s, advances in computer processing and networking allowed for great advances in reconstruction techniques. What formerly had remained a two-dimensional (2D) technique (multiplanar reconstructions) could now be displayed in a variety of threedimensional (3D) and volume-rendered images. Simulated bronchoscopy was now possible (Fig. 16-3). The late 1990s saw the introduction of multidetector or multislice CT (MDCT). First 4-row, then 8-, 16-, and now 64-row multidetector scanners are being used. This technological escalation made it possible to routinely image the tracheobronchial tree with slices 1- to 2-mm thick and allowed for volumetric reconstructions that could be displayed in many ways. In the era of MDCT, comprehensive upper airway imaging is possible routinely with minimal patient discomfort. The patient simply needs to lie supine for the 10- to 20-second examination. No IV contrast agent is used.2 The main drawbacks of the use of MDCT for airway imaging center on its use of ionizing radiation, though the dose is low (relative to other types of CT). As with other CT techniques, MDCT of the upper airway is still prone to artifacts from metal and motion. This can be particularly problematic in the patient with a metallic tracheostomy. In these patients, we routinely ask that the tracheostomy be removed

before imaging, if possible. Motion can also degrade image quality. This is important to consider in the mechanically ventilated patient, in whom ventilation may be suspended for the 10- to 20-second examination.

Ch016-F06861.indd 197

197

MAGNETIC RESONANCE IMAGING MRI is another noninvasive way of imaging the upper airway. Whether conventional sequences (spin-echo, fast spin-echo) or newer, faster sequences (half-Fourier acquisition singleshot turbospin-echo [HASTE], single-shot fast spin-echo) are used, MRI has the ability to acquire tracheobronchial images in any plane (Fig. 16-4). This has theoretical advantages over CT, in which images are acquired in a transaxial plane but are reconstructed in other planes. However, in the era of MDCT, with its near-isotropic resolution, reconstructions are comparable to direct nonaxial acquisitions. Another advantage of MRI over CT is its lack of ionizing radiation. Given that CT uses a low-dose technique, if imaging is performed in children and needs to be frequently repeated, consideration of MRI is warranted. Despite its advantages, MRI possesses many features that have prevented it from replacing MDCT as the principal imaging modality used to evaluate the upper airway in the adult population. Specifically, MRI relies on generation of a magnetic field in a small imaging chamber. For this reason, it is not feasible to image large patients, who may be wider than the MRI tube; in addition, many patients become claustro-

1/21/2008 10:48:53 AM

198

Section 2 Upper Airway

A

B

C

D

E

F

FIGURE 16-3 Subglottic tracheal stenosis in a 52-year-old man who had undergone kidney and liver transplantations with prolonged intubation. A, Chest radiograph shows focal narrowing of the upper tracheal lumen (arrow). Axial CT images of the trachea show a normal caliber of the tracheal lumen above the level of stenosis (B); a collapsed tracheal ring at the site of previous tracheostomy, with a narrowed lumen and mild tracheal wall thickening at the level of stenosis (C); and normal shape and caliber of the trachea below the level of stenosis (D). The focal stenosis and its craniocaudal extent can be underestimated on axial images. Coronal (E) and sagittal (F) multiplanar reconstructions (MPR) of the trachea better demonstrate the extent of the narrowing and its distance from the vocal cords and carina. Other display techniques include minimum intensity projection (MinIP) images in the coronal

Ch016-F06861.indd 198

1/21/2008 10:48:53 AM

Chapter 16 Imaging of the Upper Airway

G

H

I

J

K

L

199

FIGURE 16-3, cont’d (G) and sagittal (H) planes and external volume-rendered images of the trachea in the coronal (I) and sagittal (J) planes. Finally, internal volume-rendered (virtual bronchoscopic) images of the trachea can be constructed, looking at the stenosis from above (K) and looking at the carina (L).

Ch016-F06861.indd 199

1/21/2008 10:48:54 AM

200

Section 2 Upper Airway

A

B

C FIGURE 16-4 This 48-year-old woman with a history of IV contrast allergy and dyspnea had a questionable mediastinal mass on chest radiograph. MRI in the coronal (A), sagittal (B), and axial (C) planes revealed no mediastinal or tracheal abnormality.

phobic when placed in such a small space. Furthermore, the magnet itself may not be compatible with certain metallic devices, such as pacemakers. Longer examination times (up to 1 hour) and therefore fewer schedule openings, make MRI imaging more problematic for a patient with respiratory symptoms. The remainder of this chapter focuses on CT techniques and differential diagnoses.

COMPUTED TOMOGRAPHY TECHNIQUES Image Acquisition Tracheobronchial MDCT can be performed fairly easily. Images are obtained with thin collimation (1-2 mm) and with overlapping reconstruction. The examination is carried from

Ch016-F06861.indd 200

the vocal cords to 2 cm below the carina, so that the main stem bronchi are included. With most MDCT machines, the entire scan can be completed in less than 20 seconds. The study is performed at suspended inspiration after the patient is instructed to take in a deep breath and stop breathing. A second examination is taken in some phase of expiration. Some authors have advocated full expiration, whereas others have advocated dynamic expiration to uncover tracheomalacia (Fig. 16-5).2-4 Newer software may allow for respiratorygated imaging so that the trachea can be imaged throughout the respiratory cycle. Images usually are taken with the patient supine, unless symptoms are worse in the prone position. Arms are routinely placed by the side to minimize streak artifact. Occasionally, patients report shortness of breath with abduction of the arms. In these rare instances, imaging can be performed with

1/21/2008 10:48:56 AM

Chapter 16 Imaging of the Upper Airway

A

201

B

FIGURE 16-5 A 31-year-old woman who had undergone lung transplantation presented with newly developed pulmonary aspergillosis. A, Axial CT image of the main bronchi at the level of the carina during inspiration shows an open lumen. A cavitary mass in the right upper lobe of the lung represents angio-invasive pulmonary aspergillosis (arrow). B, Axial CT image at the same level during expiration shows that the airway lumen collapses, indicating the presence of tracheomalacia.

elevation of the arms to highlight any anatomic explanation for the patient’s symptoms. IV contrast is not used routinely for airway CT, but it may be useful in evaluating some lesions, such as carcinoid tumors, paragangliomas, and paratracheal lymphadenopathy, and it is particularly useful for detecting a central obstructing endobronchial lesion in lobar atelectasis (Rosado de Christenson et al, 1999).4-6 Image acquisition usually takes only a few minutes.

Box 16-1 Standard Images in Tracheobronchial Multidetector Computed Tomography (MDCT) Axial images (1 mm) in lung and soft tissue windows Coronal and sagittal multiplanar reconstruction (MPR) Curved coronal and curved sagittal MPR Volume-rendered bronchogram (frontal and lateral view) Volume-rendered bronchoscopy (above and below abnormality)

Image Reconstruction Axial images provide a detailed depiction of the shape of the trachea, its thickness, and its relationship to adjacent structures. They are somewhat limited in demonstrating the craniocaudal extension of disease and in detecting subtle stenoses. In one study of 47 patients with tracheobronchial stenoses, 3D images provided more information in one third of patients regarding the length and extent of airway narrowing than did axial views (Remy-Jardin et al, 1998).4,7 Axial images also tend to be limited for evaluation of airways, such as the bronchi, that travel obliquely to the axial plane. For these reasons, we have also come to rely on 2D and 3D reconstructions of the CT data set in the evaluation of tracheobronchial imaging.

Two- and Three-Dimensional Rendering Techniques A number of 3D reconstruction techniques are available to reconstruct the volume data. Box 16-1 lists the standard reconstructions during evaluation of the trachea and main bronchi when using an MDCT scanner. A detailed description of the various rendering techniques is beyond the scope of this chapter. However, a brief review of reconstruction techniques is presented in the following sections.

Ch016-F06861.indd 201

Coronal oblique minimum intensity projection (MinIP)

Multiplanar Reformatting Multiplanar reconstruction (MPR), which is the simplest reformatting technique and is readily available at most workstations, is used to assess the extent of disease processes in the craniocaudal direction. Its advantages are that it is fast, it can be easily performed at the CT scanner, and it uses all of the pixels in the data set regardless of attenuation. Images can be reviewed in orthogonal to axial and oblique planes. The major disadvantage of this technique is that it provides only a 2D display of data; thus, it lacks depth (see Fig. 16-3C and D). Curved MPR is a variation of this technique in which a reference line is drawn through the center of the airway on the sagittal image set. The result is a coronal image set that parallels the long axis of the trachea. The true-coronal images can then be used to generate a curved sagittal data set. The curved MPR images allow for an accurate depiction of the long axis of the trachea. Measurements obtained orthogonal to these images are then true measurements of tracheal area and are invaluable in quantifying stenoses and planning for

1/21/2008 10:48:56 AM

202

Section 2 Upper Airway

FIGURE 16-6 Sagittal (A) and coronal (B) views show how curved multiplanar reconstruction (MPR) images are created by determining the center of the airway lumen of the trachea in one plane (A) and obtaining a straightened MPR image in the opposite plane (B).

A

stents. Curved MPR images serve as the workhorse for tracheal imaging (Fig. 16-6A and B).

Volume Rendering Volume rendering, which uses the entire volume of data to generate images in any desired plane, has become the preferred 3D imaging technique. Usually, an additional 3D workstation is required. With volume rendering, the user can scroll through images in any plane and can alter the opacity to display as much of the data as desired. The net effect is a 3D image with depth perception. We rely on two methods of 3D imaging: virtual bronchography, a variation on external rendering, and virtual bronchoscopy, a variation on internal rendering. The former produces a transparent depiction of the airways that allows the entire central airway to be shown on one image. The algorithm closely resembles contrast bronchography and is useful in delineating pathology for those not used to thinking about airway pathology in the axial plane. The latter technique simulates bronchoscopy and allows the observer to navigate through the airways. Its use is limited for diagnosis but can be quite helpful for reviewing studies, especially when optical bronchoscopy is planned (Ferretti et al, 2000)8 (see Fig. 16-3E-G).

Minimum Intensity Projections Minimum intensity projections (MinIPs) create images in which the lowest-attenuation pixels for a given volume are depicted on a single image. The images can be displayed in any plane and can be of any thickness (Cody, 2002).9 On

Ch016-F06861.indd 202

B

MinIPs, the airways are clearly seen as the darkest structures. Oblique coronal MinIPs allow for delineation of the entire central tracheobronchial tree on one image (see Fig. 16-3H).

Interpretation Hints Axial images are mandatory for assessing extraluminal disease, including the lung parenchyma and mediastinal structures. They are also helpful for recognizing motion artifacts and mucus or retained secretions. If only reconstructions are used, focal mucus can simulate an area of stenosis, and distinction of stenosis from tumor may be difficult (Fig. 16-7). 2D and 3D reconstructions are used to localize the pathology in terms of its relationship to the vocal cords and carina and to quantify the length of disease should resection be considered. These renderings are invaluable for understanding the pathology, but they may not affect the ability to detect the pathology. Radiologic differential diagnosis for tracheobronchial imaging depends on the length of the disease process, which is best displayed with reconstructions.

NORMAL TRACHEA On CT, the tracheal wall is a 1- to 3-mm thick, soft tissue stripe, which is delineated internally by air and externally by mediastinal fat or lung.10 Occasionally, tracheobronchial cartilage may calcify (Meyer and White, 1998).11 The posterior membranous tracheal wall is thin, and it can be flat, concave, or even convex. During forced exhalation, the posterior membrane of the trachea bulges anteriorly, decreasing the mean anteroposterior diameter. The net result is that the

1/21/2008 10:48:57 AM

Chapter 16 Imaging of the Upper Airway

203

B

A FIGURE 16-7 A, Sagittal multiplanar reconstruction image of the trachea shows a focal soft tissue density (arrow) arising from the anterior wall of the trachea at the level of the tracheostomy tip. This was originally thought to be intimal hyperplasia and focal stenosis. B, Axial CT image using lung windows reveals air within this density, so it represents mucus, rather than a true tracheal wall lesion.

trachea changes from an O configuration to a rotated D configuration. This change is normal and can be useful in differentiating inspiratory versus expiratory scans. During exhalation, the lateral walls change very little in shape.10 The percent of change between expiration and inspiration of the tracheal cross-sectional area and the change in anteroposterior diameter (sagittal dimension) can be useful for diagnosing tracheomalacia on CT (Aquino et al, 2001).12

Box 16-2 Causes of Focal Tracheal Narrowing

DISEASES OF THE CENTRAL AIRWAYS

Carcinoid tumor

Diseases of the central airways can be classified into two main groups based on the length of the abnormality (focal or diffuse). Such grouping is somewhat arbitrary because certain disease entities, particularly infection, can cause either focal or diffuse involvement of the airways. In some classification schemes, the effect on the tracheal lumen is included (narrowing or widening) to generate four categories of disease. Because tracheal widening is rarely treated surgically, we have not included it in the following discussion.

Metastases

Masses Causes of focal narrowing are shown in Box 16-2. The most common cause of focal narrowing encountered in daily practice is mucus. Occasionally, air bubbles within the mucus can allow for distinction of this pseudopolyp from a true lesion. Having the patient cough and repeating the scan or the observation of a change in morphology between inspiration and expiration can also be helpful in distinguishing mucus from a tumor.13

Ch016-F06861.indd 203

Malignant Masses Squamous cell carcinoma Minor salivary gland tumors Adenoid cystic carcinoma Mucoepidermoid carcinoma

Benign Masses Papilloma Hamartoma Paraganglioma Inflammatory myofibroblastic pseudotumor Acquired Stenoses Trauma Intubation Tracheostomy

1/21/2008 10:48:58 AM

204

Section 2 Upper Airway

In adults, 90% of the tumors of the central airways are malignant; the most common are squamous cell carcinoma and adenoid cystic carcinoma.13 Imaging provides little information on the histology of the lesion because many of the tracheal and bronchial neoplasms have overlapping imaging features. The main goal of imaging is to define the longitudinal length of the mass so as to determine resection length and to delineate any extra-airway spread of disease. Squamous cell carcinoma grows slowly, both exophytically and endobronchially, and often extends into the mediastinum. On CT, the tracheal or bronchial wall is usually seen to be irregular and focally thickened, and the tumor is visualized as a large, irregular mass. Only rarely do these lesions grow circumferentially within the trachea. If the squamous cell cancer extends into a bronchus, it usually is accompanied by lobar or segmental collapse (Fig. 16-8).13 Adenoid cystic carcinoma is a tumor of the minor salivary glands that usually arises from the mucus glands of the trachea and bronchi. It occurs with equal frequency in the trachea and main bronchi. Adenoid cystic carcinoma typically manifests as a focal, polypoid, intraluminal mass, arising posterolaterally at the site of the tracheobronchial mucus glands. This neoplasm grows slowly, and it characteristically spreads in the submucosal plane. Extraluminal growth is fairly common and may best be appreciated on the axial images. CT demonstrates smooth or nodular tracheal wall thickening and extension into the mediastinum. CT may also show metastases to mediastinal and cervical lymph nodes, lungs, liver, and bone.14,15 Mucoepidermoid carcinoma is another minor salivary gland tumor with a predisposition for the bronchi. When it is found in the trachea, it tends to be close to the carina. On CT, mucoepidermoid carcinoma appears as an oblong, nodular lesion that conforms to the shape of the airway.16 The spectrum of tracheobronchial neuroendocrine tumors includes typical and atypical carcinoid tumors and small cell lung carcinoma. The imaging features of typical and atypical carcinoid tumors tend to overlap.14,17 Typical carcinoid tumors occur most commonly within central bronchi, and on CT they appear as a focal nodule within or abutting a central bronchus.13 They are usually associated with postobstructive collapse, and they tend to be slow growing, frequently exhibiting large, dilated mucoceles at presentation. Because they are quite vascular, they may show intense enhancement after administration of IV contrast, differentiating them from mucoepidermoid carcinomas, which are relatively avascular. Imaging does not reliably exclude metastasis and does not reliably distinguish typical from atypical carcinoid tumors (Fig. 16-9). Occasionally, metastatic disease manifests within the trachea or bronchi. Direct invasion from adjacent malignancy may be seen with thyroid cancer, laryngeal carcinoma, lung cancer, and esophageal carcinoma. Endoluminal metastases may be seen with melanoma, breast, colon, genitourinary malignancies (including renal cell carcinoma), and hematologic malignancies (including chloroma or granulocytic sarcoma). Imaging features may overlap those of adenoid cystic carcinoma and tracheal squamous cell carcinoma. Metastatic lesions are usually solitary, but they may be mul-

Ch016-F06861.indd 204

tiple (Kwong et al, 1992).18 The most helpful distinguishing feature is an antecedent history of extratracheal malignancy. Benign neoplasms manifest as focal, well-defined, intraluminal, smooth or lobulated masses without tracheal or mediastinal invasion (Kwong et al, 1992; McCarthy et al, 1995).14,18,19 They are much less common in adults than their malignant counterparts and include papilloma, hamartoma, hemangioma, paraganglioma, and inflammatory myofibroblastic tumor. The main goal of imaging of these lesions is to demonstrate the lack of mediastinal invasion. CT cannot reliably distinguish benign from malignant lesions and cannot reliably distinguish among the benign lesions. Certain CT features, such as fat (as seen with hamartoma) or vigorous enhancement (as seen with hemangiomas), may suggest the correct diagnosis.

Acquired Tracheobronchial Stenosis Post-traumatic and iatrogenic tracheal stenoses appear the same on imaging studies and can be difficult to distinguish clinically because most patients with trauma significant enough to cause tracheal injury get intubated. Postintubation and post-tracheostomy stenoses represent the most common cause of focal tracheal narrowing. These stenoses may occur at the level of a tracheostomy stoma or at the level of an overinflated endotracheal tube balloon.20 CT images of postintubation strictures usually show somewhat irregular, concentric airway narrowing in an hourglass configuration and may show mass-like opacities of adjacent granulation tissue within the tracheal lumen. Post-tracheostomy stomal strictures, on the other hand, tend to result in greater loss of area due to right-to-left rather than anteroposterior narrowing. This may result from the disruption of the anterior trachea (akin to disruption of the keystone of an arch). In reporting these strictures, multiplanar and 3D imaging can be important in defining their relationship to the vocal cords and carina (see Fig. 16-3). Focal tracheomalacia may be primary, resulting in congenital deficiency of the cartilage, or acquired, usually secondary to intubation. Dynamic evaluation of airway caliber in the axial plane is possible with helical CT. The diagnosis of tracheomalacia can be made by CT if there is 50% or greater reduction in transluminal diameter during expiration (Fig. 16-10).2

DIFFUSE NARROWING The causes of diffuse narrowing of the trachea and main bronchi are shown in Box 16-3. It should be noted that many of these conditions can result in either focal or diffuse narrowing. If focal, they may simulate conditions described previously. CT features of diffuse tracheal narrowing tend to overlap. Some of the more distinctive entities are described in the following sections.

Saber-Sheath Trachea Saber-sheath trachea, also known as horseshoe trachea, refers to a diffuse decrease in coronal diameter (right-to-left dimension) of the intrathoracic trachea in association with obstructive pulmonary disease.10,21 The extrathoracic trachea

1/21/2008 10:48:59 AM

Chapter 16 Imaging of the Upper Airway

A

B

C

D

E

F

205

FIGURE 16-8 This 72-year-old male patient, who quit smoking 20 years ago, had recent weight loss and a nonresolving consolidation in the right lung. CT revealed a mass arising from the right upper lobe bronchus, and bronchoscopy and biopsy revealed squamous cell carcinoma. A and B, Contrast-enhanced axial CT images show a consolidation in the right upper lobe, with mediastinal and right hilar lymphadenopathy creating a confluent mass in the right hilum (arrow). Mild narrowing of the right main stem bronchus near this confluent mass is visible in B. Coronal multiplanar reconstruction CT image (C) shows a mass arising from and obstructing the right upper lobe bronchus and extending into the lumen of the right main stem bronchus (arrow). Note the better demonstration of the extent and size of this lesion on the MPR image (C) compared with the axial images (A and B). Axial CT images of the upper lobes show extensive bronchiectasis (D, arrowheads) and mucoceles (E, arrows), as well as surrounding consolidation of the lung parenchyma, caused by long-standing obstruction of the right upper lobe bronchus. F, The mucoceles (arrows) and extent of disease are well demonstrated by a coronal thick MIP image.

Ch016-F06861.indd 205

1/21/2008 10:48:59 AM

206

Section 2 Upper Airway

A

B

C

D

FIGURE 16-9 This 46-year-old woman was found to have an abnormal preoperative chest radiograph during preparation for hysterectomy. A and B, Posteroanterior and lateral chest radiographs show a right hilar mass (arrow). C and D, Axial CT images show an endoluminal mass occluding the bronchus intermedius. The mass shows moderate enhancement and represents a carcinoid tumor (arrow).

Ch016-F06861.indd 206

1/21/2008 10:49:00 AM

Chapter 16 Imaging of the Upper Airway

E

F

G

H

207

FIGURE 16-9, cont’d E, Coronal multiplanar reconstruction image shows the large size of this mass, with only a small part of the lesion protruding into the lumen (arrow). Coronal minimal intensity projection (MinIP, F) and external volume-rendered (G) images show the sudden cutoff of the bronchus intermedius (arrows). H, Virtual bronchoscopic view shows the tip of the carcinoid tumor protruding into the bronchus intermedius (arrow).

has a normal caliber. The coronal diameter of the intrathoracic trachea is less than one half to one third of the sagittal diameter. On CT, inward bowing or displacement of the lateral tracheal walls is seen. The thickness of the tracheal wall is normal. There may be associated tracheomalacia (Fig. 16-11).

Fibrosing Mediastinitis Fibrosing mediastinitis, also known as mediastinal fibrosis or sclerosing mediastinitis, is an uncommon disorder in which

Ch016-F06861.indd 207

there is a proliferation of dense fibrous tissue throughout the mediastinum.22 Two radiologic patterns have been described. In the first, a more focal fibrosis is observed, usually in the right paratracheal and subcarinal regions. In the second, a more diffuse form is noted. The former variation has been associated with stippled calcifications and prior granulomatous infection. The latter has no clear association with either calcified lymph nodes or prior infection.23 Most reports combine both forms of this disorder. This fibrosis can be seen on CT or MRI as confluent soft tissue extending beyond lymph nodes and, over time, encasing mediastinal vessels,

1/21/2008 10:49:01 AM

208

Section 2 Upper Airway

A

B

C

D

FIGURE 16-10 This 39-year-old man presented with new shortness of breath after sustaining multiple fractures in a motor vehicle accident. A CT scan was ordered to exclude a pulmonary embolism. Axial CT (A) and coronal multiplanar reconstruction (B) images show a small polyp arising from the left lateral wall of the distal trachea (arrows). Internal (C) and external (D) volume-rendered images show the distance of this polyp (arrows) from the carina.

airways, and esophagus. Although vascular involvement is more commonly seen (veins more often than arteries), tracheal involvement may be encountered in 15% to 30% of cases, resulting in long-segment tracheal narrowing. Isolated tracheal narrowing or tracheal fistulas have been described but are rare.

Ch016-F06861.indd 208

Tracheopathia Osteochondroplastica Tracheopathia osteochondroplastica (TOP) is a rare, benign, idiopathic disease characterized by multiple submucosal osteocartilaginous and hematopoietic nodules.24 These typically arise from the cartilage of the trachea and main bronchi;

1/21/2008 10:49:02 AM

Chapter 16 Imaging of the Upper Airway

the posterior wall of the trachea is usually spared. Subglottic involvement is rare. The wall irregularities are larger and more polypoid than the wall changes that occur with benign cartilage calcifications seen in the elderly. CT demonstrates thickened cartilage and multiple calcified nodules, usually 3 to 8 mm in diameter, along the anterolateral inner trachea and bronchi, resulting in undulating narrowing of the lumen. There is no associated malacia (Fig. 16-12).25

209

Relapsing Polychondritis Relapsing polychondritis is an autoimmune disorder characterized by recurrent inflammation of the cartilage, which results in fragmentation of the cartilage and its replacement by fibrosis.26 On CT, wall thickening tends to be limited to the anterior and lateral walls and spares the posterior membrane, similar to TOP.25 The wall thickening may be calcified,

Box 16-3 Causes of Diffuse Tracheal Narrowing Saber-sheath trachea (right-to-left narrowing) Fibrosing mediastinitis Tracheopathia osteochondroplastica (TOP) Relapsing polychondritis Amyloidosis Sarcoid Wegener’s granulomatosis Inhalational injury Infection

FIGURE 16-11 Axial CT scan of the chest of a 60-year-old man with emphysema shows narrowing of the coronal diameter of the trachea, representing a saber-sheath trachea.

A

B FIGURE 16-12 This 49-year-old man presented with occasional coughing. A, Axial CT scan of the trachea shows calcified nodules arising from the tracheal wall (arrows), sparing the posterior membrane. These nodules protrude into the tracheal lumen, resulting in luminal narrowing. This represents tracheobronchopathia osteochondroplastica. B, Coronal multiplanar reconstruction shows that a long segment of the distal trachea and both bronchi are involved (arrows).

Ch016-F06861.indd 209

1/21/2008 10:49:04 AM

210

Section 2 Upper Airway

as in TOP, but it tends to be smooth. Loss of cartilage results in tracheomalacia (Meyer and White, 1998).11,25,26

Wegener’s Granulomatosis Wegener’s granulomatosis is a granulomatous necrotizing vasculitis that involves the sinuses, lungs, and kidneys. CT depicts diffuse or focal stenoses with circumferential wall thickening, which results in narrowing of the tracheal lumen. Skip lesions may be seen. The cartilaginous tracheal rings can occasionally calcify. Isolated involvement of the airway is uncommon (Meyer and White, 1998).10,11,25-28

Amyloidosis Although it represents the most common manifestation of primary pulmonary amyloidosis, tracheobronchial amyloidosis is rare.10 It usually is not associated with systemic amyloidosis or pulmonary-parenchymal amyloidosis; however, parenchymal findings may be caused by the bronchial stenoses, including atelectasis, lobar collapse, and pneumonia.29 CT shows smooth or nodular submucosal tracheal wall thickening with soft tissue attenuation, or higher attenuation if it calcifies (Fig. 16-13). Unlike TOP and relapsing polychondritis, which only rarely involve the posterior membranous portion of the trachea, tracheobronchial amyloid is more likely to involve the entire trachea and to result in circumferential tracheal narrowing (Meyer and White, 1998).11,26

Tracheobronchial Infections The trachea and bronchi may be involved in viral, bacterial, mycobacterial, and fungal infection. In North America, most tracheobronchial infections are viral and manifest acutely with subglottic edema and no need for cross-sectional imaging.18 Two infections worth noting in the adult population are tuberculosis and rhinoscleroma. Each can manifest with concentric tracheobronchial thickening that can mimic amyloid.26,30

FIGURE 16-13 CT scan of the trachea in a 39-year-old woman with cough, dyspnea, and repeated pneumonias shows diffuse tracheal wall thickening with linear areas of calcification, representing tracheal amyloidosis. Note that the posterior membrane is also thickened (arrowhead).

inspiration and expiration for evaluation of dynamic changes in airway configuration. When planning either a resection or endoscopic dilation and stenting of a tracheal or bronchial lesion, 3D reconstructions help define the precise location, length, and direction of the involved segment and its relationship to anatomic landmarks such as the vocal cords, carina, and lobar orifices. This is especially true when the stenotic lesion is too tight to permit passage of a flexible bronchoscope through it before operative or endoscopic intervention. Now, more than ever, the expert thoracic radiologist is an essential member of the thoracic surgical team. J. D. C.

SUMMARY

KEY REFERENCES

Tracheobronchial imaging has undergone a major revolution from the days of bronchography and linear tomography to MDCT with 3D capabilities. The increased temporal resolution of MDCT has allowed for a variety of display techniques that can enhance the comprehension of a disease process before surgery or bronchoscopy. Understanding of the basics of the imaging protocol and the CT features assists the surgeon in selecting the most appropriate imaging techniques for the diagnosis, staging, and treatment of conditions affecting the upper airways.

Aquino SL, Shepard JA, Ginns LC, et al: Acquired tracheomalacia: Detection by expiratory CT scan. J Comput Assist Tomogr 25:394399, 2001. Cody DD: AAPM/RSNA physics tutorial for residents. Topics in CT: Image processing in CT. Radiographics 22:1255-1268, 2002. Ferretti GR, Thony F, Bosson J, et al: Benign abnormalities and carcinoid tumors of the central airways: Diagnostic impact of CT bronchography. AJR Am J Roentgenol 174:1307-1313, 2000. Kwong JS, Muller NL, Miller R: Diseases of the trachea and mainstem bronchi: Correlation of CT with pathologic findings. Radiographics 12:645-657, 1992. McCarthy MJ, Rosado de Christenson ML: Tumors of the trachea. J Thorac Imaging 10:180-198, 1995. Meyer CA, White CS: Cartilaginous disorders of the chest. Radiographics 18:1109-1123, 1998. Remy-Jardin M, Remy J, Artaud D, et al: Volume rendering of the tracheobronchial tree: Clinical evaluation of bronchographic images. Radiology 208:761-770, 1998. Rosado de Christenson ML, Abbott GF, Kirejczyk WM, et al: Thoracic carcinoids: Radiologic-pathologic correlation. Radiographics 19:707736, 1999.

COMMENTS AND CONTROVERSIES Probably one of the greatest impacts of modern technology on the field of thoracic surgery has been in the area of thoracic imaging. This is particularly well illustrated in this chapter. The improved imaging obtained with rapid CT scanners, and the 3D image reconstructions now possible, have enhanced the surgeon’s ability to define, diagnose, and plan the treatment of conditions affecting the upper airway. Rapid CT scans also allow discrete imaging during

Ch016-F06861.indd 210

1/21/2008 10:49:04 AM

chapter

17

ANESTHESIA FOR AIRWAY SURGERY Charles Hantler Troy S. Wildes Michael Andritsos

Key Points ■ Coexisting pulmonary and cardiac diseases increase susceptibility

■

■

■

■

to the detrimental effects of sympathetic stimulation, hypoxemia, and hypercarbia that may accompany airway procedures. Pulmonary function needs to be optimized preoperatively. Perioperative management, including the preoperative medical regimen, can be tailored to reduce the risk of adverse myocardial events. Flow-volume loops are useful for assessing the severity of obstructive pulmonary disease and for the categorization of intrathoracic and extrathoracic airway obstructions. Inhalational induction of anesthesia may be indicated in patients with large-airway obstruction. Muscle relaxants are avoided until the site of airway compromise has been crossed by an endotracheal tube or rigid bronchoscope. Modern anesthetics can provide deep planes of anesthesia while preserving the possibility of rapid emergence with little residual respiratory depression. Total intravenous maintenance techniques are often required in airway surgeries. Short-acting neuromuscular blockers, β-adrenergic blockers, and vasodilators are useful adjuncts in airway surgery but provide no protection against patient awareness. Airway surgeries often require the use of alternative ventilatory strategies including jet ventilation modes, use of the ventilating rigid bronchoscope, cross-table ventilation, and selective bronchial intubation. Both anesthesiologist and surgeon must be knowledgeable regarding the limitations of these techniques, including the possibility of hypoxemia, hypercarbia, or barotrauma. Respiratory insufficiency after airway surgery may result from drug effects (e.g., residual neuromuscular blockade), large-airway pathology (e.g., vocal cord dysfunction, tracheomalacia), or intrinsic lung injury (e.g., atelectasis, lobar collapse, aspiration pneumonitis). In patients with large-airway obstruction, inhaled racemic epinephrine or ventilation with helium-oxygen mixtures may provide relief.

One of the most challenging tasks during surgery of the airway is ensuring adequate ventilation of the respiratory tree. Because the airway is shared between surgeon and anesthesiologist, successful oxygenation and ventilation of the patient can only be accomplished through collaboration during the stages of airway surgery. This includes periods in which surgical airway manipulation compromises adequate ventilation and periods in which ventilation interferes with the surgical environment. With continuous communication between the surgeon and anesthesiologist and careful prepa-

ration for these challenging cases, optimal outcomes can be achieved. The anesthetic techniques for these surgeries are determined by the surgical procedure itself and the degree of urgency for intervention. Considerations in the anesthetic technique include, but are not limited to, the choice of ventilation, anesthetic agents, preoperative evaluation of the patient, and anticipated postoperative complications. Clinicians have responded to the challenge of ventilating these patients with a host of innovative techniques. Additionally, advances in monitoring and anesthetic agents have allowed patients with increasing comorbidities to be candidates for higher risk procedures. Still, despite these advances, the complexity of these operations continues to require special expertise in anesthetic and patient management. The preoperative, intraoperative, and postoperative aspects of anesthetic management for airway surgeries are reviewed in this chapter.

HISTORICAL NOTE The complexity of manipulation of the airway was addressed as early as 1905 by Chevalier Jackson, a practitioner of endoscopy from the beginning of the 20th century.1 The hazards of general anesthesia and importance of patient positioning for endoscopy were recognized early on. Jackson recommended rapid insertion of the laryngoscope. He performed endoscopy primarily for the purposes of diagnosis, dilation of stenoses, and removal of foreign bodies (Jackson, 1907).2-5 These procedures were necessarily brief (McRae, 2001).6 Endoscopists advocated the use of topical agents but used additional modalities for facilitating manipulation of the airway.7-9 Even with topical anesthesia, extensive premedication was used (Jackson, 1912).10-13 Intramuscular opioids (most often morphine) and anticholinergic agents (scopolamine or atropine) were administered before topical anesthesia with adequate time allowed for onset (Jackson, 1912).13,14 Nembutal was sometimes used in patients with a sensitivity to local anesthetic agents because barbiturates were known to reduce the manifestations of local anesthetic toxicity (Jackson, 1912; McRae, 2001).6,13,15 Of the available local anesthetics, cocaine, tetracaine (Pontocaine), and larocaine saw frequent use. Over the years, bronchoscopic procedures increased in duration and complexity. Unfortunately, asphyxia and death were frequent.16 To overcome these adverse events, several strategies were utilized. These included induction of general anesthesia with sodium pentothal, brief neuromuscular block211

Ch017-F06861.indd 211

1/21/2008 10:50:06 AM

212

Section 2 Upper Airway

ade with succinylcholine, and intermittent ventilation by mask.15,17,18 This was followed by the application of nebulized cocaine to the airway for topical anesthesia (MacIntosh, 1947).19 Once airway anesthesia was established, bronchoscopy could be performed on the spontaneously breathing patient (McRae, 2001).6,20 Muendnich proposed a method of positive-pressure ventilation during bronchoscopy in 1953,21 and a ventilating bronchoscope was soon in use.22 The ventilating bronchoscope allowed for prolonged examinations in the apneic patient, followed by periods of positive-pressure ventilation with a glass obturator covering the end of the bronchoscope. With this method the anesthesia circuit was attached to the side arm of the bronchoscope, enabling the administration of inhaled volatile anesthetics. Shortly after its introduction, the use of halothane for bronchoscopic procedures in children was described in 1959 (McRae, 2001).6,23 The increasing availability of arterial blood gas analysis added controversy to the debate over topical versus general anesthesia and over spontaneous versus controlled ventilation. Patients who had been sedated with premedication and received topical anesthesia were not infrequently hypoxic and hypercapnic before bronchoscopy; their ventilation would improve only after surgical stimulation. Spontaneously breathing patients under general inhalational anesthesia were well oxygenated but exhibited hypercapnia during bronchoscopy.24 The ventilating bronchoscope allowed controlled ventilation under general anesthesia, which led to a combination of superior oxygenation and decreased hypercarbia.25 Another method of ventilation was introduced by Sanders26 in which a jet ventilator was used with a rigid bronchoscope. This allowed controlled ventilation in an open system. Jet boluses would entrain ambient air and augment the tidal volume delivered. After Sanders’ innovation, other methods of ventilation using high gas flows were introduced. These techniques included injectors placed on the side arm of the bronchoscope27,28 and ventilation catheters placed in the trachea.29 These strategies allowed for improved examination of the airway and for increasingly complex airway procedures. Fiberoptic bronchoscopy was finally introduced in 1968 and allowed access to more peripheral airway lesions. In the early 1970s, lasers were introduced into airway surgery, which further expanded therapeutic options (McRae, 2001).6,30

ANESTHETIC CONSIDERATIONS Airway surgery presents unique challenges for ensuring adequate ventilation and oxygenation during each stage of the procedure. Maintenance of anesthesia with traditionally used volatile anesthetic gases may similarly be difficult. Finally, patients presenting for airway surgery often have comorbidities that may influence anesthetic and surgical techniques and may increase the likelihood of perioperative complications. Elective surgery provides the opportunity for comprehensive patient evaluation and often allows for optimization of the patient before surgery. Early evaluation of the patient and procedure enables the surgical and anesthesiology team to anticipate procedural challenges and to collaboratively establish a strategy for airway management during each portion of

Ch017-F06861.indd 212

the surgical procedure. Emergent surgery forfeits some of these advantages, but preoperative evaluation of the patient remains critical. Preoperative patient evaluation includes a medical history, physical examination, and the review of any pertinent diagnostic tests. Specifically, information regarding systemic illnesses, respiratory function, functional capacity, prior anesthetics, and prior airway management is sought. Review of radiographic studies, in conjunction with the physical examination, may help the operative team to predict difficulties in controlling the airway during induction or other portions of the surgical procedure. The preoperative evaluation allows the anesthesiologist to predict the likelihood of perioperative complications and to select the most appropriate intraoperative technique and postoperative disposition. Discussion with the patient clarifies expectations regarding the day of surgery and may allay undue anxiety. Rapport is established with the patient and potential adverse outcomes are discussed. Detailed instructions regarding eating, drinking, and ongoing pharmacologic therapies are given. Patients with decompensated comorbid conditions may require the adjustment of ongoing therapy or the introduction of new therapy before surgery. Postponement of surgery may be necessary to ensure that the patient is in optimal condition. Patient evaluation may rarely reveal perioperative risks that are unacceptable in light of potential gains. These complicated decisions are made in conjunction with the patient, surgeon, anesthesiologist, and other members of the medical team. Potential risks and benefits associated with delay or cancellation of the procedure must be carefully considered.

Important Medical Conditions Comorbid conditions that may introduce the possibility of perioperative complications or dictate alterations in the anesthetic plan are identified before surgery. Many patients are smokers with a high incidence of pulmonary or ischemic cardiac disease, and further testing may be indicated before surgery. Consultation by cardiologists, pulmonologists, or other medical specialists may help to assess operative risk and the need for preoperative intervention. The American Heart Association/American College of Cardiology (AHA/ACC) guidelines (Fleisher et al, 2007)31,32 provide a useful framework when assessing the need for further cardiac diagnostic testing before surgery. These guidelines consider preexisting cardiac disease, functional capacity, categorized surgical risk for cardiac complications, and specific signs and symptoms. Most airway surgery is categorized as low cardiac risk, whereas major tracheal surgery is considered intermediate cardiac risk. Therefore, according to these guidelines, most patients with a functional capacity of 4 metabolic equivalents (METS) or more do not generally require additional preoperative cardiac testing in the absence of major clinical predictors. Major clinical predictors include unstable angina, recent myocardial infarction, decompensated heart failure, significant arrhythmias, or severe valvular disease. Importantly, decisions regarding preoperative cardiac testing or interventions need to consider potential hazards to

1/21/2008 10:50:07 AM

Chapter 17 Anesthesia for Airway Surgery

the patient and conversely whether results are likely to provide opportunities to minimize perioperative complications through tailoring care. Many patients have undergone preoperative assessment of pulmonary function to assess restrictive pulmonary disease, obstructive pulmonary disease, and large airway compromise. Patients with severe chronic pulmonary disease may benefit from aggressive preoperative pulmonary bronchodilator and inhaled or oral corticosteroid therapy. The severity of obstructive disease and CO2 retention may be a predictor of difficulty in resumption of adequate spontaneous ventilation, depending on the surgical procedure (Qaseem et al, 2006).33-35 Evidence of pulmonary hypertension and/or right ventricular dysfunction also must be sought on physical examination and diagnostic tests. Pulmonary hypertension is often associated with right ventricular dysfunction that may be exacerbated by hypercapnia, hypoxia, or increasing intrathoracic pressure related to positive-pressure ventilation. Therapy with pulmonary vasodilators, such as sildenafil or prostaglandins, needs to be considered in the perioperative period.36 It is estimated that as many as 2% to over 20% of the population has laboratory or overt obstructive sleep apnea. These numbers are expected to increase as the population ages and becomes more obese. The American Society of Anesthesiologists has published practice guidelines regarding the perioperative management of patients with obstructive sleep apnea because these patients are believed to be at increased risk for morbidity and mortality in the perioperative period (Gross et al, 2006).37,38 Among the risk factors for obstructive sleep apnea are increased body mass index, history of loud snoring, observation of apnea during sleep, and drowsiness. Recommendations about management include the preoperative use of airway devices, such as continuous positive airway pressure (CPAP), weight loss, and medications. There are recommendations about the anesthetic techniques employed, timing of extubation, and length and intensity of postoperative surveillance. In particular, there were recommendations regarding the appropriateness of outpatient surgery in these patients. Preoperative evaluation allows perioperative planning for patients on antithrombotic therapy, such as warfarin or clopidogrel.39,40 Patients with a high risk of thrombotic events receiving warfarin therapy (e.g., mechanical mitral valve) may require perioperative bridging with low-molecular-weight heparin while warfarin is discontinued. The platelet adenosine diphosphate receptor inhibitor clopidogrel is generally discontinued 5 to 7 days before surgical procedures that carry a risk of hemorrhage. Aspirin is often continued perioperatively in patients at high risk of thrombosis (e.g., drug-eluting coronary stents). Decisions regarding the discontinuation of antithrombotic therapy must carefully weigh hemorrhagic risks against risks associated with perioperative thrombosis. The patient’s cardiologist or primary care physician needs to be involved in these decisions.

Airway Evaluation One of the most feared clinical circumstances during general anesthesia is the inability to provide adequate oxygenation

Ch017-F06861.indd 213

213

after the induction of general anesthesia. Practice guidelines have been established in the United States and throughout the world on evaluation of the difficult airway along with management algorithms (Henderson et al, 2004).41,42 The incidence of inability to provide mask ventilation is low, and that of inability to intubate is still lower. The probability of both situations occurring in the same patient is still lower but represents a life-threatening emergency. The situation is further complicated when patients are at risk of aspiration. Estimates of unanticipated difficult airway with subsequent serious morbidity or mortality range from 1 : 10,000 to 1 : 100,000. Although there is no universal definition of difficult intubation, the criterion of multiple attempts at direct laryngoscopy by two experienced anesthesiologists, with either failure to intubate or inability to obtain an adequate view of the vocal cords or arytenoids, is commonly used.43 Individual tests used to predict difficult intubation are limited by low sensitivity, low specificity, or both. Indexes that combine multiple measures have demonstrated little improvement (Lee et al, 2006).44-47 Some signs that may predict difficult intubation include limited mouth opening (<5 cm), morbid obesity, limited neck extension, high Mallampati score (Mallampati 3 or 4), inability to protrude the mandible anterior to the maxilla, thyromental distance less than 6 cm, large tongue, high arched palate, and abnormal dentition. Specific conditions associated with difficult intubation include major trauma or infection of the upper airway such as submandibular abscess and epiglottitis (ASA, 2003; Henderson et al, 2004).42,48-51 Above all, records regarding previous airway management need to be obtained because these usually provide the most useful information. Additionally, information regarding prior airway procedures, including the presence and location of airway stents, often affects the airway management plan. When a difficult intubation is anticipated, additional equipment and ancillary staff must be immediately available. If a difficult airway is anticipated, an awake fiberoptic intubation is often performed.51,52 This technique is usually successful with minimal patient discomfort and/or harm and minimizes the risk of the loss of the patient’s ability to exchange respiratory gases.

Flow-Volume Loops Flow-volume loops are plots of maximal inspiration and exhalation that plot inspiratory and expiratory flow rates as a function of lung volume (Fig. 17-1A). Early forced exhalation from total lung capacity normally demonstrates very high flow but is also dependent on expiratory effort. As lung volume decreases during continued exhalation, flow decreases and becomes effort independent. After maximal exhalation, the normal flow-volume plot of inspiration (from residual volume) rapidly reaches a plateau. With fixed airway obstruction, as in tracheal stenosis, flows during exhalation and inhalation are both reduced (see Fig. 17-1B). As severity of obstruction increases, the peak expiratory flow falls while the FEV1/peak expiratory flow rate ratio increases. A FEV1/peak expiratory flow rate of greater than 10 mL/L/min is suggestive of significant airway obstruction.

1/21/2008 10:50:07 AM

Section 2 Upper Airway

Inspiration

A

Volume

RV

TLC

RV

TLC

Flow

Flow

Flow

Exhalation

214

RV

TLC

B

Volume

C

Volume

FIGURE 17-1 Characteristic flow-volume loops. A, Normal flow-volume loop. B, Fixed intrathoracic airway obstruction showing compromise of expiratory and inspiratory flow. C, Variable intrathoracic obstruction showing compromise of expiration with relative preservation of inspiration. A variable extrathoracic obstruction would show the reverse pattern. TLC, total lung capacity; RV, residual volume.

With variable obstructions, flow rates during inspiration and exhalation are affected differently. With a variable intrathoracic obstruction (see Fig. 17-1C), spontaneous exhalation is more markedly affected because of the decreased magnitude of negative intrapleural pressure during the expiratory phase. Variable extrathoracic obstructions exhibit more flow limitation during inspiration. This is because inspiration is driven by an intra-alveolar and airway pressure, which is below atmospheric pressure. Spontaneous expiration may limit the obstruction caused by a variable extrathoracic obstruction because it has the advantage of being driven by an intra-alveolar pressure that is positive relative to atmospheric pressure.

Anesthetic Agents Anesthetic agents are used to produce amnesia, hypnosis, analgesia, immobility, and the blunting of sympathetic responses. Agents are usually used in combination to achieve these goals yet permit the rapid return of airway reflexes, muscle strength, and an alert, conscious state on the conclusion of the surgical procedure.

Volatile Anesthetics Volatile anesthetics are administered by inhalation and are the most common mode of anesthetic maintenance. The ideal volatile anesthetic allows a rapid induction of anesthesia, easy titration of the agent, and swift recovery from general anesthesia. Modern volatile anesthetics have shown progress toward these goals by exhibiting low blood solubility, which permits rapid equalization of anesthetic partial pressure between tissues and rapid elimination via ventilation. Conversely, more traditional anesthetics with high blood solubility have been used advantageously in airway surgery because of the possibility of maintaining high concentrations during periods of interrupted ventilation. Inhaled volatile anesthetics have existed since Morton’s demonstration of ether anesthesia in 1846. Over the past 50 years, newer, nonflammable and less soluble agents have been introduced. All of the currently used volatile anesthetics are halogenated hydrocarbons. They produce unconsciousness

Ch017-F06861.indd 214

but are less effective at reducing sympathetic stimulation than opioids. The dose required to prevent movement with surgical stimulus is greater than that required to achieve unconsciousness. When volatile anesthetics are used, the expiratory concentration is monitored as a reliable marker of anesthetic depth. All volatile anesthetics cause a dose-dependent depression of cardiac contractility and a decrease in systemic blood pressure through a drop in systemic vascular resistance. Tidal volume is decreased during spontaneous ventilation, but minute ventilation is minimally altered because of a compensatory increase in respiratory rate. The volatile anesthetics produce bronchodilation and have been used in the treatment of status asthmaticus. These agents also depress sympathetic stimulation. Desflurane is a fluorinated methyl ethyl ether. It is pungent and is poorly tolerated by awake patients. Rapid increases in concentration may lead to sympathetic stimulation. Because of its fluorination, it is the least soluble in tissue and blood of all the currently used inhaled volatile agents. The low solubility provides the possibility for more rapid emergence from anesthesia.53-55 Sevoflurane is a fluorinated methyl isopropyl ether with a lower solubility and lower potency than isoflurane. It has minimal odor and pungency and is very useful for inhalation induction.56,57 Isoflurane is a halogenated methyl ether that has been used since the 1970s. It has a chemical structure similar to desflurane, similar hemodynamic effects, but a longer duration of action.58 There is decreasing use of halothane, which has the unique and occasionally desired property of prominent cardiac depression. Like sevoflurane, it is not an airway stimulant and has been used for inhalational inductions. Because of rare immune-mediated liver toxicity59 and the introduction of sevoflurane, halothane is rarely used in practice in the United States. Despite the impressive safety profile of the volatile anesthetics used today, serious adverse reactions are possible. Halothane may cause significant immune-mediated hepatitis. Desflurane and isoflurane may decompose to carbon monox-

1/21/2008 10:50:07 AM

Chapter 17 Anesthesia for Airway Surgery

ide when exposed to dry CO2 absorbents,60 whereas sevoflurane is degraded to vinyl halide (compound A),61 which is a dose-dependent nephrotoxin in rats; sevoflurane also has been associated with fires due to heat build-up in the CO2 absorber.62-64 With the introduction of new CO2 absorbents there is less drying and less heat and less carbon monoxide formation. The degradation products from sevoflurane, isoflurane, and desflurane are rarely a clinical problem in current practice.65,66 Finally, the use of inhaled anesthetics is difficult in some airway surgeries, where oxygenation and ventilation may not be administered by a closed system. The possibility of contamination of the operating room with significant concentrations of these agents is also introduced. Nitrous oxide is an insoluble inhaled agent with potent analgesic properties. It may supplement volatile anesthesia but does not produce general anesthesia. Its use is limited by the high inspired concentrations needed, which reduce the inspired oxygen available.

Intravenous Agents Intravenous (IV) induction agents include the barbiturates, ketamine, etomidate, and propofol. Propofol has become the most frequently used IV agent for induction of anesthesia and is often used as a continuous infusion as part of total IV anesthesia (Yuill and Simpson, 2002),67 in which combinations of IV agents are used in the absence of inhaled anesthetics. Total IV anesthesia techniques are frequently utilized when airway surgery makes administration of inhaled agents difficult. Profound hypnosis occurs within 15 to 45 seconds and lasts approximately 10 minutes (Kazama et al, 2001).68 Propofol is insoluble in water and is prepared in an egg-lecithin emulsion as a 1% solution.69 An aqueous formulation is in development, and it is a formulation of the prodrug, which releases propofol when contact is made with the endothelium. Propofol is rapidly metabolized in the liver to inactive metabolites. This makes it an attractive agent when postoperative sedation may be detrimental, as in patients with minimal respiratory reserve. Infusions of propofol lead to only slightly delayed emergence when compared with volatile anesthesia.53,70 Propofol is often preferred in patients with bronchospastic disease because of its bronchodilating effects. Propofol also may decrease pruritus associated with opioids, especially neuraxial opioids, and has some antiemetic properties. Side effects include pain on injection and dose-dependent vasodilation, myocardial depression, and depression of ventilation. The thiobarbiturates thiopental and thiamylal are used less frequently owing to their prolonged duration of effect, which may cause residual sedation. The oxybarbiturate methohexital is a shorter-acting alternative but lacks the desirable antiemetic and bronchodilatory effects of propofol. The barbiturates cause dose-dependent decreases in ventilation and blood pressure (vascular tone). The induction agents ketamine and etomidate are often used when sympathetic and cardiac depression must be avoided, as in shock states. Ketamine directly stimulates the sympathetic system, producing increases in heart rate and blood pressure, but may be detrimental in situations in which endogenous catecholamine stores are depleted. Ketamine is

Ch017-F06861.indd 215

215

useful in airway surgery when respiratory depression is undesirable and has analgesic and bronchodilating properties. Adverse effects include hallucinations and increases in salivation, although the latter may be attenuated by prior antisialagogue treatment. Etomidate causes minimal depression of ventilation and cardiovascular function but causes adrenocortical suppression and is emetogenic. Benzodiazepines are often administered preoperatively for their anxiolytic, sedative, and amnestic properties. Midazolam, the most commonly used agent, has a rapid onset, short duration of action, and high potency. The benzodiazepine antagonist flumazenil is a potent reversal agent, which is rarely used in clinical practice.

Opioids Opioids are used for analgesia and the attenuation of the sympathetic response generated by surgical stimulation, airway instrumentation, and mechanical ventilation. Morphine is a naturally occurring compound that mimics the effects of endogenous opioids at µ1 and µ2 receptors. The synthetic opioids have been developed over the past 30 years, with fentanyl, remifentanil, alfentanil, and sufentanil commonly used in clinical practice. These are potent agents and lack the histamine release associated with morphine or meperidine. However, high doses of these potent opioids may be accompanied by muscle rigidity, which may compromise the ability to ventilate. Remifentanil is an ultra short-acting µ-opioid agonist that is eliminated by blood and tissue esterases with a predictable context-sensitive half-time of less than 10 minutes despite prolonged infusions, allowing for predictable and rapid emergence (Egan et al, 1993).71 Bolus doses of 0.5 to 1 µg/kg effectively attenuate the hemodynamic response to airway instrumentation, and infusions of 0.05 to 1 µg/kg/min are commonly used for maintenance.72 It can effectively reduce respiratory movements without the need for deep neuromuscular blockade when jet ventilation or rigid bronchoscopic ventilation are employed. Although remifentanil provides potent opioid agonism, its short duration of action mandates the use of longer-acting analgesics or regional anesthesia when postoperative analgesia is desired. Opioids are not complete anesthetics. Many reports of intraoperative awareness have been published in which opioids, with or without nitrous oxide, were relied on for anesthetic maintenance. Anesthesiologists are well aware of the problems of acute pain tolerance, the potential for severe bradycardia, and chest wall rigidity with the use of these new potent opioids.

Neuromuscular Blockers Neuromuscular blocking drugs provide skeletal muscle relaxation after the induction of anesthesia. They facilitate tracheal intubation and airway manipulation, improve tolerance of mechanical ventilation, and avoid injuries that may accompany patient movement during instrumentation. Agents are chosen based on pharmacokinetics, mode of elimination, and side-effect profile. The shorter-acting agents succinylcholine and mivacurium are often selected for procedures of brief duration to prevent

1/21/2008 10:50:07 AM

216

Section 2 Upper Airway

delays in emergence. Succinylcholine (0.5-1.5 mg/kg) is the only available depolarizing neuromuscular blocker. Its short duration of action of approximately 10 minutes is produced by diffusion away from the neuromuscular junction. By depolarizing the nicotinic receptor, succinylcholine leads to a temporary increase in plasma potassium. This may be dangerously accentuated in the presence of lower motor neuron degeneration or other pathologic states (e.g., burns, immobilization). Mivacurium is the shortest-acting nondepolarizing agent and, like succinylcholine, is metabolized by plasma esterases. Vecuronium, rocuronium, atracurium, and cisatracurium are intermediate-acting neuromuscular blockers. Rocuronium is unique in that its dose-dependent onset can achieve intubating conditions in a similar rapidity as succinylcholine with a dose of 1 mg/kg73 at the cost of a prolonged duration. While most of the intermediate-duration neuromuscular blockers are metabolized by the kidney or liver, atracurium and cisatracurium undergo nonenzymatic Hoffman degradation. During general anesthesia, the degree of neuromuscular blockade is monitored with a nerve stimulator. Before emergence, the blockade of nondepolarizing agents is typically antagonized with an anticholinesterase drug to allow adequate return of muscle function and spontaneous ventilation. A novel agent, sugammadex, is currently undergoing clinical investigation; it forms a stable complex with rocuronium and vecuronium, rapidly reversing even dense neuromuscular blockade (Miller RD, 2007).74 There is a recent case report of the use of this experimental drug for emergency rescue in a patient who demonstrated residual muscle weakness after extubation.75 Neuromuscular blockers are useful adjuncts to anesthesia, but consideration for the possibility of an aware, paralyzed patient must be maintained. Despite the employment of monitors designed to assess anesthetic depth, there is no guarantee of an unaware patient.

Other Agents Tachycardia and hypertension are commonly observed during surgical procedures of the airway. Opioids attenuate these responses, but adjunctive therapies may be required to maintain optimal hemodynamic parameters, especially in patients with known or suspected coronary artery disease. The βadrenergic receptor antagonists are relatively contraindicated in patients with known reactive airway disease. Selective β1 antagonists are preferable when β-blocker therapy is initiated in these patients. Esmolol is a selective β1 receptor antagonist that is rapidly metabolized by plasma esterases, with a resultant half-life of less than 10 minutes.76 Esmolol may be administered by bolus (0.2-1 mg/kg) or infusion (100-300 µg/ kg/min). Longer-acting β blockers such as atenolol and metoprolol are likewise preferred because of β1 specificity. Hypertension with elevated systemic vascular resistance secondary to transient surgical stimuli is best treated with short-acting vasodilators such as the calcium antagonist nicardipine. Infusion doses of 5 to 15 mg/hr or boluses of 0.25 to 1 mg effectively control hypertension while allowing for relatively rapid offset. Dexmedetomidine is an α2 agonist first introduced for sedation in patients in intensive care units. It produces an

Ch017-F06861.indd 216

arousable state of sedation by binding to α2 receptors in the brain and spinal cord, producing sympatholysis. It also potentiates opioid action in the spinal cord. It has analgesic-sparing effects and has minimal depression of respiratory drive, making it an ideal adjuvant for awake intubations and fiberoptic bronchoscopies in spontaneously breathing patients.77,78 Dexmedetomidine is initiated by a bolus dose of 1 µg/kg over 10 to 20 minutes and then administered as an infusion at 0.2 to 0.7 µg/kg/hr. Bradycardia and hypotension are side effects, particularly when the drug is rapidly infused. The duration of action is short and depends on the duration of infusion.79 It is limited for use up to 24 hours.

MODES OF VENTILATION Standard positive-pressure ventilation is not always possible during surgery involving the airway. As airway surgery has expanded over the years, alternative modes of ventilation have been introduced to contend with the challenges that have arisen. The first such technique to be introduced to airway surgery was low-frequency jet ventilation. This form of ventilation is commonly employed when rigid bronchoscopy, laser surgery, or tracheal resection is performed. With low-frequency jet ventilation, a Sanders-type adapter is used to deliver high pressure (50-60 psi) through a small orifice positioned in the patient’s airway (Macintyre et al, 1987; Scamman and Choi, 1986).80-82 Hand triggering of the jet ventilator controls the duration and pressure of each delivered breath. Respiratory rates of 10 to 20 breaths per minute are usually used. Additional air is entrained into the airway at the injector site, producing the total inspiratory volume. Although the jet injector introduces pure oxygen, the entrained air limits the fraction of oxygen in the tidal volume. Still, adequate oxygenation and ventilation are usually achieved with low-frequency jet ventilation. Jet ventilation injectors have been designed that automatically set inspiratory time, respiratory rate, and pressure (Fig. 17-2). All forms of jet ventilation can produce barotrauma with resultant pneumothorax, subcutaneous emphysema, and mediastinal air.83,84 As knowledge regarding ventilator-induced lung injuries has evolved, newer forms of mechanical ventilation have been developed. Conservative ventilation (i.e., smaller tidal volumes) has been shown to improve outcome in patients with severe lung injury (Sessler, 1998).85,86 The extreme of small tidal volume ventilation is high-frequency ventilation (Sjostrand, 1989).87,88 High-frequency ventilation requires special equipment and has been primarily used in the intensive care unit for patients with severe lung disease. Highfrequency ventilation encompasses techniques in which the respiratory rates range from 60 to 3000 breaths per minute with tidal volumes that are typically less than the anatomic dead space. High-frequency ventilation may be administered by jet ventilator or by oscillation with extremely high respiratory rates (Froese and Byron, 1987).89-91 The concept of oscillatory flow was described in 1959 by Emerson, who suggested that a column of vibrating air would lead to better gas mixing in the lung in patients with lung injury.92,93 Along with low-frequency jet ventilation, these high-frequency ventila-

1/21/2008 10:50:07 AM

Chapter 17 Anesthesia for Airway Surgery

217

TABLE 17-1 Characteristics of Modes of Ventilation During Airway Surgery Can Ventilate Open Airway

Immobility of Operative Field

Specialized Equipment Required

Airway Pressure Monitoring

Potential for Barotrauma

Gas Entrainment During Ventilation

Airway Gas Composition and Monitoring

Intermittent positive-pressure ventilation

No

No

No, routine anesthetic machine

Pressure depends on ventilator settings, reliable

Minor

No

Stable and accurate

Low-frequency jet ventilation

Yes

No

Simple gas injector only

Intermittently high, difficult

Yes, high

Yes

Variable and difficult

High-frequency jet ventilation

Yes

Yes

Yes, specialized ventilator

Can be high*; difficult, especially around jet nozzle

Yes

Yes, degree of entrainment is application dependent

Variable and difficult

High-frequency positive-pressure ventilation

Yes

Yes

Yes, specialized ventilator

Low peak, mean, transpulmonary pressure; difficult

Yes

Minor

Stable and accurate

High-frequency oscillation

Yes

No

Yes, specialized

High mean pressure; difficult

Yes

No

Stable and accurate

*Gas trapping and hyperinflation common. Adapted from McRae K: Anesthesia for airway surgery. Anesthesiol Clin North Am 19:498, 2001.

techniques. Pulse oximetry, arterial blood gas analysis, or intermittent closed-circuit ventilation can be helpful to assess ventilation. We have used high-frequency jet ventilation for some of our tracheal resections with excellent success.

Respiratory rate

RIGID BRONCHOSCOPY Historical Note On-off Pressure Inspiratory time

FIGURE 17-2 An example of an automated jet ventilator used at our institution. The inspiratory time, inspiratory pressure, and ventilation rate are controlled by knobs.

tion techniques have seen use in airway surgery (Table 17-1). High-frequency ventilation leads to a stable surgical field and may offer advantages in limiting barotrauma. Despite these potential benefits, expensive equipment is required for the administration of high-frequency ventilation, and barotrauma is possible if exhalation is inhibited or the administered pressure is excessive. Furthermore, it is often difficult to assess adequacy of oxygenation and ventilation with high-frequency

Ch017-F06861.indd 217

Rigid bronchoscopy was introduced by Gustav Killian in 1897 as the only tool for direct examination of the airways.4 Rigid bronchoscopy still offers advantages over fiberoptic bronchoscopy for removal of foreign bodies, placement of airway stents, tracheal dilation, removal of airway tumors, and control of airway bleeding (Ayers and Beamis, 2001).94-96 Initial experiences with rigid bronchoscopy were in the sedated, spontaneously breathing patient. Even after the advent of general anesthesia for rigid bronchoscopy, spontaneous ventilation or apneic oxygenation remained the initial ventilatory techniques of choice (Frumin et al, 1959).97,98 Severe hypercarbia and hypoxia were common. The ventilating rigid bronchoscope was introduced in the 1950s and underwent further modifications over the ensuing 20 years. The attachment of a glass window to the operator end of the bronchoscope, and of the anesthesia circuit to a bronchoscope side port, allowed positive-pressure ventilation (Fig. 17-3). This technique requires an adequate seal between the bronchoscope and airway. Additionally, the glass window must be in place during ventilation, which precludes the use of instrumentation. To address these limitations, Douglas Sanders introduced an adapter in 1967, which allowed jet

1/21/2008 10:50:07 AM

218

Section 2 Upper Airway

Pressure reducing valve

Pressure on-off valve Jet adapter

Ventilating sidearm

Delivered pressure

Covered eyepiece

Anesthesia circuit

FIGURE 17-3 A rigid bronchoscope connected to a standard anesthesia circuit via the bronchoscope side arm. Positive-pressure ventilation may be delivered when the eyepiece is in place. Leaks may still occur between the bronchoscope and airway walls.

ventilation through the rigid bronchoscope using a highpressure source (50 psi). Intermittent high-pressure flow entrains room air that, when combined with passive exhalation, produces tidal ventilation (Fig. 17-4). This mode of jet ventilation is limited in the fraction of inspired oxygen and downstream ventilating pressure that can be provided. Modifications, particularly by Carden, allowed the use of so-called non-Venturi ventilation via a side port, providing greater downstream ventilating pressure and the ability to deliver enriched oxygen concentration. By using a larger side port for so-called jet ventilation, there was much less entrained room air, allowing the ability to add nitrous oxide to the inspired gases (Carden et al, 1970).28,99,100

Anesthetic Considerations Preoperative antisialagogues may be used to reduce airway secretions. Reliable IV access must be obtained, especially when IV anesthesia is used for maintenance. Additionally, standard monitors may be supplemented with a monitor of anesthetic depth (i.e., a processed electroencephalographic monitor) during total IV anesthesia. Rigid instrumentation of the upper airway produces potent sympathetic stimulation, leading to tachycardia and hypertension. It is critical to avoid this tachycardia in patients with coexisting coronary artery disease or stenotic valvular lesions. Useful strategies include potent opioid agonists or β-receptor blockade. Short-acting agents such as remifentanil or esmolol are ideal for these brief, but potent, periods of surgical stimulation. Local anesthesia of the airway is helpful in reducing the adrenergic response to bronchoscopy. If airway anesthesia has not already been administered for awake examination, 4% lidocaine can be delivered to the anesthetized patient using the bronchoscope, an atomizer, or a laryngotracheal anesthesia kit. Because consistent control of heart rate and blood pressure may be difficult, the use of invasive blood pressure monitoring for titration of opioids and vasoactive

Ch017-F06861.indd 218

A

Jet adapter 1

Jet adapter 2

B FIGURE 17-4 A, A currently available hand-operated jet ventilator (with pressure gauge) that can be connected to a wall oxygen outlet. B, Two bronchoscope adapters used for jet ventilation. These may be connected to the proximal end or side arm of the bronchoscope.

drugs is useful in patients who are at particular risk for complications related to hemodynamic disturbances. Patients presenting for rigid bronchoscopy may have intrathoracic or extrathoracic compromise of the airway lumen due to mass or stenosis. Depending on the nature of the obstruction, inhalational induction may be a safer approach than the IV route because loss of the ability to ventilate will likely lead to emergence. Sevoflurane is usually selected for inhalational induction because it is the most tolerable agent for the awake patient. Alternatively, IV induction may be performed in patients with airway obstruction if it is believed that rescue ventilation will be possible with rapid placement of the rigid bronchoscope. This strategy depends on the immediate availability of rigid bronchoscopic equipment and the presence of a physician skilled in rigid bronchoscopy. Further anesthetic considerations for patients with focal airway obstruction, including the possibility of postinduction

1/21/2008 10:50:09 AM

Chapter 17 Anesthesia for Airway Surgery

ventilatory deterioration, are discussed elsewhere in this chapter. IV techniques are often used for anesthetic maintenance because of frequent interruptions in ventilation and the potential for contamination of the operating suite with volatile anesthetics. Either way, a deep anesthetic state or adequate hypnosis paired with neuromuscular relaxation is required because of the potential for airway trauma with patient movement. These techniques also reduce spontaneous respiratory efforts that may compromise the ability to provide ventilation through jet or bronchoscopic techniques. Neuromuscular blockade is used in most cases; short-acting agents are predominantly chosen because procedures are often of short duration. During rigid bronchoscopy, it is possible to maintain ventilation through a small endotracheal tube positioned alongside a small rigid bronchoscope. However, thanks to refinements to the original rigid bronchoscopes, ventilation is now typically provided directly through the bronchoscope. This can be accomplished with jet ventilation techniques or with the anesthesia circuit attached to the rigid bronchoscope. Ventilation is difficult to quantify when jet ventilation techniques are used. Auscultation (e.g., with a precordial stethoscope) and the observation of chest wall excursion are used to provide an estimate of adequate ventilation, whereas pulse oximetry is used to assess oxygenation. These methods may be supplemented by arterial blood gas analysis when indicated. If prolonged ventilation via the bronchoscope proves unsatisfactory, the bronchoscope may be intermittently removed for mask ventilation with 100% oxygen. Ventilatory support is usually needed at the conclusion of the procedure while any neuromuscular blockade is reversed and adequate spontaneous ventilations are returning. An endotracheal tube may be placed when the rigid scope is removed, if not contraindicated. We often prefer mask ventilation or placement of a laryngeal mask airway during this period.

Patient Positioning Many patients presenting for bronchoscopic procedures exhibit some impairment of spontaneous ventilation. When dyspnea or stridor is present, it may be exacerbated or improved with varying the patient’s position. A careful history and the review of pulmonary function tests with flow-volume loops may be helpful in clarifying these effects. Careful positioning of the patient, often in a semi-sitting position, can improve the quality of ventilation during the pre-induction and postemergence periods. The optimal head and neck position used to facilitate insertion of the rigid bronchoscope varies from patient to patient.6 Anterior flexion of the lower cervical spine and cervicooccipital extension is achieved by placement of a pillow under the patient’s head. Reports from anatomic studies question the utility of the “sniffing position”; in our experience, glottic visualization is usually successful with simple head extension. Rigid bronchoscopy carries a risk of physical patient injury that may be prevented. Because neck positioning is often

Ch017-F06861.indd 219

219

used to facilitate rigid bronchoscopy, neck instability must be identified and evaluated. Manipulation of an unstable neck can cause bony impingement on the central nervous system or its vascular supply, leading to paralysis or death. Patients with rheumatoid arthritis, Down syndrome, or achondroplasia are at increased risk for cervical spine instability, and symptoms or signs of instability must be actively sought. The dentition may also be injured with rigid bronchoscopy. Teeth guards are often used, and the dentition needs to be carefully inspected both preoperatively and postoperatively. Eye padding and/or shields are necessary to prevent pressure injuries or abrasions.

Complications of Jet Ventilation During Rigid Bronchoscopy Barotrauma may occur with jet ventilation, manifested by pneumothorax, pneumomediastinum, major airway disruption, or subcutaneous emphysema. These injuries may occur with the use of excessive ventilating pressure, with progressive lung hyperinflation, or when the ventilating lumen is malpositioned in the airway. Exhalation is passive and must be carefully monitored to avoid stacking of successive lung inflations during low-frequency jet ventilation. Limitations in ventilation and in the achievable oxygen concentration can lead to hypoxemia during rigid bronchoscopy, especially in the patient with a previously abnormal alveolar-to-arterial oxygen gradient. Management options include increasing the fraction of administered oxygen by enriching the jet entrainment environment or conversion to positive-pressure ventilation via the ventilating bronchoscope. Ventilatory difficulty with the ventilating rigid bronchoscope may occur if the seal against the airway is inadequate. This seal may be improved by compressing the neck in the region of the cricoid cartilage or by applying packing to the upper airway. If ventilation is still inadequate, an alternative technique is used. Hypercarbia often occurs during rigid bronchoscopy. It is usually well tolerated with possible exceptions, including preexisting pulmonary hypertension, reduced cardiovascular reserve, elevated intracranial pressure, hyperkalemia, or a predisposition to cardiac dysrhythmias. In these situations, little leeway is allowed for inadequate ventilation. Intermittent interruption of the procedure for ventilation by mask, use of the bronchoscope as a ventilating bronchoscope with the open end covered, or a temporary endotracheal tube can be particularly useful.

FIBEROPTIC BRONCHOSCOPY The fiberoptic bronchoscope was introduced by Shigeto Ikeda during the 1970s, thus allowing examination of the airways without rigid bronchoscopy. Fiberoptic bronchoscopy is currently used for a variety of diagnostic procedures and interventions. Diagnostic indications include the evaluation of pulmonary nodules, tumors, infection, chronic cough, wheezing, stridor, tracheobronchial strictures, stenosis, fistulas, traumatic injury, and foreign bodies. Interventional procedures include biopsy, lavage, débridement, resection,

1/21/2008 10:50:15 AM

220

Section 2 Upper Airway

dilation, laser therapy, cryotherapy, brachytherapy, and the placement of airway stents.

Anesthetic Considerations If awake fiberoptic bronchoscopy is desired (e.g., evaluation of vocal cords during spontaneous ventilation), topical anesthesia of the airway supplemented with IV sedation is the preferred technique.101 Antisialagogues, either atropine or glycopyrrolate, may be administered to improve mucosal absorption of topical anesthetics. These are given at the earliest possible juncture to ensure dry mucous membranes when topical agents are applied. Because glycopyrrolate does not cross the blood-brain barrier and cause confusion, it is the preferred agent, especially in elderly patients. Multiple methods exist for achieving topical airway anesthesia and are described in the section on anesthesia for tracheal resection. For fiberoptic bronchoscopy, our choice is nebulization of 4% lidocaine via mouthpiece (Fig. 17-5), which may be supplemented by 4% lidocaine applied to the pharynx by atomizer. Endoscopists usually utilize IV or intramuscular benzodiazepines and opioids for sedation. Short-acting benzodiazepines (midazolam, 0.025-0.1 mg/kg IV) and opioids (fentanyl, 0.25-2.0 µg/kg IV) are most appropriate. Caution must be exercised in patients with limited respiratory and cardiovascular reserve, and slow titration is the safest strategy. Anesthesiologists will often administer small boluses of propofol as a brief-acting titratable sedative. Before crossing the glottis with the bronchoscope, 4% lidocaine is applied directly to the glottic region via the bronchoscope lumen and a short interval is allowed for onset of subglottic anesthesia. General anesthesia is often an acceptable technique for fiberoptic bronchoscopy and is usually induced via IV. Depending on what areas are to be examined, the patient may be intubated or a laryngeal mask airway may be used. When a laryngeal mask airway is used, the protective struts may need to be removed to allow easy passage of the bron-

choscope through the distal lumen. The fiberscope is introduced into the endotracheal tube or laryngeal mask airway using a swivel adapter, allowing the ventilating circuit to remain intact. When a laryngeal mask airway is used, the fiberoptic scope is used to administer topical anesthesia to the glottic region before examination of the trachea. General anesthesia may be maintained with IV or inhaled anesthetics during fiberoptic bronchoscopy. Ventilation is controlled when bronchoscopy is performed through an endotracheal tube because the high airway resistance produced by the fiberscope makes adequate spontaneous ventilation difficult. Even with controlled ventilation, intermittent removal of the bronchoscope for periods of improved ventilation and oxygenation may be necessary. Endotracheal tube size is chosen so that the airway obstruction is minimized and, most importantly, to avoid harmful levels of positive endexpiratory pressure (PEEP). Lindholm reported on how the combinations of various sizes of fiberscopes and endotracheal tubes affect the potential magnitude of PEEP (Fig. 17-6).102 The use of an 8-mm or larger endotracheal tube will usually minimize the possibility of dangerous levels of PEEP and usually allows acceptable ventilation with a fiberscope in position. Several authors have suggested attaining a 1.5- to 2.0mm difference between fiberscope and endotracheal tube diameter to avoid inadequate ventilation and barotrauma.103 In addition to difficulty with ventilation and the potential for barotrauma, complications associated with fiberoptic bronchoscopy include undesirable sympathetic stimulation, cardiac dysrhythmias, pneumothorax, and local anesthetic toxicity.

TRACHEOSTOMY Tracheostomy is the oldest and most commonly performed operation on the airway.104 The indications for tracheostomy include relief of upper airway obstruction, improved management of tracheal secretions, and ventilatory support with positive-pressure ventilation (Bourjeily et al, 2002).105,106 Tra-

Mouthpiece

9-mm ET Nebulizer Lidocaine 4% 8-mm ET

Oxygen cannula

FIGURE 17-5 An apparatus used for the administration of nebulized local anesthetic before the induction of anesthesia. Topical 4% lidocaine is commonly administered in this manner.

Ch017-F06861.indd 220

FIGURE 17-6 Two 5.7-mm (external diameter) fiberoptic bronchoscopes within 8-mm and 9-mm endotracheal tubes demonstrate the relative compromise of the ventilating lumina.

1/21/2008 10:50:15 AM

Chapter 17 Anesthesia for Airway Surgery

cheostomy is often performed in the anesthetized patient with a controlled airway. Conversely, imminent airway compromise may necessitate tracheostomy in the awake patient. Elective tracheostomy usually replaces prolonged endotracheal ventilation after 7 to 10 days.104,107,108 A tracheostomy reduces patient discomfort, reduces the risk of endotracheal tube plugging, reduces the likelihood of laryngeal damage from prolonged endotracheal intubation, and provides flexibility and safety during weaning from assisted ventilation. Tracheostomy is contraindicated in patients requiring high levels of ventilatory support, including high PEEP and fraction of inspired oxygen, in whom brief periods of apnea during the procedure will be poorly tolerated. Elective tracheostomy may also be performed in previously nonintubated patients undergoing surgical procedures that may introduce the risk of subsequent airway or ventilatory compromise. The patient is monitored in a standard fashion. Emergency airway equipment is immediately available. The neck is extended with the aid of a folded towel or an inflated roll placed between the shoulder blades. Typically, a horizontal incision is made to expose the second tracheal cartilage. Elective tracheostomy is usually performed with an endotracheal tube in place, in a sedated or fully anesthetized patient. Tracheostomy may be performed with an open surgical incision or by a percutaneous technique.109 When an open tracheostomy is performed, the endotracheal tube cuff may be deflated before surgical entry of the trachea. This may prevent damage to the cuff and allow for subsequent adequate ventilation should cannulation of the trachea via the tracheostomy be difficult. Under direct vision, the endotracheal tube is withdrawn so that the tip is just above the cannulation site. The tracheostomy tube is placed, and the anesthesia circuit is connected to the inflated tracheostomy tube. Bilateral breath sounds and the evidence of expired CO2 are immediately verified. Percutaneous tracheostomy is performed with the use of a fiberoptic bronchoscope. The endotracheal tube is withdrawn with fiberoptic guidance, to allow cannulation of the trachea with the needle and subsequent guidewire just below the endotracheal tube. The fiberscope is used to ensure that needle puncture has occurred at the desired tracheal cannulation site. Progressive dilation and placement of the tracheostomy tube is performed under direct fiberscope visualization. Bilateral breath sounds and expiratory CO2 are verified. The fiberscope is often passed via the tracheostomy tube to exclude impingement of tracheal structures on the distal orifice. Emergency tracheostomy may be performed when the upper airway is compromised with impending respiratory failure. When there is laryngeal tumor, supraglottic infection (e.g., Ludwig’s angina, epiglottitis), upper airway bleeding, or other circumstances that make awake fiberoptic endotracheal intubation treacherous, tracheostomy is performed with the patient awake and spontaneously breathing. When fiberoptic intubation is deemed safe, it may be performed before tracheostomy. Tracheostomy may then be obviated should the cause of airway compromise be rapidly reversible. During awake tracheostomy, the patient is positioned in a head-up position and 100% oxygen is administered via mask.

Ch017-F06861.indd 221

221

Local anesthesia is provided by the surgeon. Some patients will not tolerate sedatives or opioids, making communication and reassurance of the patient critical to maintaining a patent airway and suitable surgical conditions. The patient whose condition is not critical will often tolerate judicious doses of sedatives or opioids. Significant sedation of the patient is avoided until the tracheostomy tube position has been verified by expired CO2 and bilateral breath sounds. Electrocautery is often used to facilitate hemostasis during tracheostomy, and the potential for an airway fire needs to be considered. There are cases of airway fire associated with patients breathing enriched oxygen by mask as well as intubated patients receiving high concentrations of oxygen (Chee and Benumof, 1998).110 High concentrations of oxygen are avoided at the site of electrocautery, and fuels, including ointments, drapes, sponges and some antiseptic preparations, are avoided.

TRACHEAL RESECTION Providing adequate ventilation and oxygenation during surgical resection of the trachea is particularly challenging. Tracheal resection is most often performed for postintubation tracheal stenosis or tumor resection. Risk factors for postintubation tracheal stenosis include duration of intubation, overinflation of the endotracheal tube cuff, movement of the endotracheal tube, hypotension, infection, and comorbid conditions (e.g., diabetes). Other indications for tracheal resection include congenital lesions, inflammatory and infectious pathology, and trauma (Table 17-2).

Historical Note Surgical resection and reconstruction of the trachea had been delayed in early years due to concerns about healing of the airway, the amount of trachea that could be removed safely, and techniques for ventilation during these complex airway procedures. The first description of tracheal surgery—

TABLE 17-2 Causes of Tracheal Pathology Congenital Stenosis Weblike diaphragm, pulmonary sling abnormality Atresia Malacia Post-Traumatic Cervical tracheal trauma accompanying neck trauma Mediastinal tracheal trauma accompanying blunt chest injuries Tumors Malignant: adenocarcinoma, squamous cell carcinoma, sarcoma, others Benign: papilloma, chondroma, chondroblastoma, hemangioma, others Post Intubation After endotracheal intubation After tracheostomy Infectious/Inflammatory Tuberculosis, histoplasmosis, others Sarcoidosis, Wegener’s granulomatosis, others

1/21/2008 10:50:18 AM

222

Section 2 Upper Airway

tracheostomy—appeared in the 2nd century, whereas repair of the trachea was first described in the 16th century. Laboratory work in the 1880s showed the feasibility of end-to-end tracheal anastomosis in dogs. Limited cervical tracheal resection in humans was performed in the late 19th and early 20th centuries using tissue grafts. However, tracheal resection was considered largely impractical until the mid 1950s because it was postulated that tracheal cartilage would not heal and that removal of more than a limited amount of the trachea would preclude reanastomosis. After successes with end-to-end bronchial anastomoses during lung resections, concerns regarding tracheal healing diminished. Belsey’s 1950 manuscript (Belsey, 1950)111 was the first report of an intrathoracic tracheal resection and reconstruction. This repair used wire-reinforced fascia to support the anastomosis. By the late 1950s, several successful tracheal resections and reconstructions had been reported. The first report of carinal resection (without the use of supportive tissue) was by Barclay in 1957 (Barclay et al, 1957),112 when he removed an adenocarcinoma and reconstructed the carina. Using cross-table ventilation of the left mainstem bronchus, he anastomosed the trachea to the right main bronchus. Then, while ventilating the right lung using the original endotracheal tube positioned in the right mainstem bronchus, he anastomosed the left mainstem bronchus to the bronchus intermedius. With the development of tracheal mobilization techniques and further experimental studies, longer segments of trachea were safely removed and the former “2 centimeter” rule was abandoned. As experience grew and ventilation strategies developed further, large series of complex tracheal resections were reported (Grillo, 1973; Grillo and Mathison, 1990; Grillo et al, 1963; Mitchell et al, 1999; Pearson et al, 1974).113-125 Geffin’s report (1969)126 regarding the anesthetic management of the first 31 patients operated on by Grillo included descriptions of innovative ventilation strategies. His report detailed the use of two anesthetic machines, jet ventilation, and high-frequency jet ventilation, thus demonstrating the expanding field of tracheal resection. The three major concerns for performing tracheal resections have been alleviated, and very complex surgeries from several centers have demonstrated good success.

there may be evidence of inspiratory or expiratory stridor with prolongation of the inspiratory or expiratory phase. Radiologic evaluation and bronchoscopy remain the most important diagnostic modalities for assessment of tracheal pathology. Functional impairment is quantified through examination of flow-volume loops. Comorbid medical conditions are evaluated by a focused history and physical examination. Because the perioperative period for tracheal resection is associated with significant cardiovascular stress, it is important to quantify the severity of any myocardial ischemia, valvular disease, or ventricular dysfunction.

Flow-Volume Loops As discussed earlier, flow-volume loops allow the assessment of the inspiratory and expiratory compromise associated with tracheal pathology. The flow-volume loop may demonstrate a fixed or variable obstruction; delineation of this is important for operative airway management during tracheal resection. Tumor and tracheomalacia may be associated with variable intrathoracic obstruction. Severe, variable obstruction is best managed by maintaining spontaneous ventilation. Even when a lesion appears to be a fixed intrathoracic obstruction when assessed with awake flow-volume loops, the flow limitation may increase in severity when positive pressure is substituted for spontaneous ventilation. The negative intrapleural pressure associated with spontaneous inspiration may provide a stenting effect, which is lost with the cessation of spontaneous respirations. Additionally, CPAP may be applied with spontaneous respiration, which may reduce the flow limitation produced by a variable extrathoracic obstruction.

Radiologic Examination Standard radiographs of the neck and chest may delineate the extent of tracheal disease. CT of the chest and neck provides a more detailed assessment of lesion severity and is important in identifying the extent of any extratracheal or extrabronchial tumor involvement.127 MRI may provide additional information.

Bronchoscopy HISTORICAL READINGS Barclay RS, McSwan N, Welsh TH: Tracheal reconstruction without the use of grafts. Thorax 12:177, 1957. Belsey R: Resection and reconstruction of the intrathoracic trachea. Br J Surg 38:200, 1950. Geffin B, Bland J, Grillo HC: Anesthetic management of tracheal resection and reconstruction. Anesth Analg 48:884, 1969. Grillo HC: Development of tracheal surgery: a historical review: I. Techniques of tracheal surgery. Ann Thorac Surg 75:610-619, 2003. Grillo HC, Bendixen HH, Gephart T : Resection of the carina and lower trachea. Ann Surg 158:889, 1963. Gluk T: Die prophylactische Resecktion der Tradchea. Arch Klin Chir 26:427-436, 1881.

Preoperative Preparation Symptoms of significant airway pathology include dyspnea, wheezing, stridor, and tachypnea. On physical examination

Ch017-F06861.indd 222

Fiberoptic and rigid bronchoscopy allow direct examination of tracheal pathology. Bronchoscopy is required before tracheal resection and reconstruction. Rigid bronchoscopy may allow dilation of the stenotic airway and debulking of intratracheal tumor. This may ease positioning of an endotracheal tube across the site of airway pathology.

Patient Preparation Reliable IV access is necessary. Emergency airway equipment must be on hand, including a selection of normal, small, and armored endotracheal tubes. Rigid bronchoscopes and a physician skilled in the use of rigid bronchoscopy must be immediately available. Standard ASA monitors are used, but reliable pulse oximetry is particularly important. An intraarterial catheter is useful for continuous blood pressure monitoring and for additional intermittent monitoring of oxy-

1/21/2008 10:50:18 AM

Chapter 17 Anesthesia for Airway Surgery

genation and CO2 retention. Because the innominate artery lies anterior to the trachea, left upper extremity or femoral cannulation is preferred to avoid the confounding effect of surgical innominate artery compression or ligation. Central venous access is rarely needed. With total IV anesthesia, a monitor of anesthetic depth is usually used.

Induction of Anesthesia If awake examination or awake intubation is indicated, good topical anesthesia of the airway accompanied by light sedation is the preferred technique. Structures that must be anesthetized include the tongue, posterior pharynx, epiglottis, glottis, and infraglottic airway. The major nerve supply to these regions is provided by divisions of the trigeminal nerve, the glossopharyngeal nerve, the superior laryngeal nerve, and the recurrent laryngeal nerve. There are several methods of providing anesthesia to these areas; nebulized 4% lidocaine usually provides anesthesia for most of these structures. Cetacaine is commonly used, but caution must be exercised because of the risk of significant methemoglobinemia when administered with the currently available spray delivery system. More intense blockade of the tongue, pharynx, and superior epiglottis may be provided by an intraoral glossopharyngeal nerve block. The larynx is innervated by both the superior and recurrent laryngeal nerve. The recurrent laryngeal nerve supplies sensation below the true vocal cords, including the upper trachea. Effective topical anesthesia is applied to the lower airway with 4% lidocaine via transtracheal block, spray injection via a fiberoptic bronchoscope, or the awake inhalation of the nebulized local anesthetic. Drugs used for IV sedation include benzodiazepines, narcotics, propofol, or dexmedetomidine. Loss of consciousness is avoided. Limitation of respiratory depression and the ability to rapidly terminate sedation are prime goals of such sedation. With awake intubation, the induction of anesthesia is avoided until an airway has been passed beyond the site of pathology or the likelihood of postinduction obstruction has been deemed very unlikely based on direct examination. Rigid dilation, balloon dilation, or debulking may be necessary before placement of an endotracheal tube of adequate size. When airway obstruction is less severe, anesthesia may be induced with inhalational induction in a spontaneously breathing patient. This strategy has been suggested to be satisfactory in most patients requiring tracheal resection (Geffin et al, 1969).126,128,129 After stringent pre-oxygenation, which may require more than 5 minutes, inhalational induction is initiated. Sevoflurane has become the agent of choice for such inductions. When the depth of anesthesia is adequate, bronchoscopic evaluation and treatment may proceed. If ventilation becomes compromised during inhalational induction, the patient is awakened and the strategy is then abandoned in favor of awake airway management. When there is minimal airway compromise, IV induction of anesthesia is appropriate after pre-oxygenation. When positive-pressure ventilation is judged to be adequate, with the airway controlled distal to the lesion, muscle relaxants

Ch017-F06861.indd 223

223

may be administered. In all cases other than severe tracheal pathology, our group has performed IV induction, and muscle relaxants may be added to facilitate rigid bronchoscopy once the ability to perform positive-pressure ventilation has been determined. With laryngeal or subglottic involvement this is not always possible, and smaller tubes (uncuffed) may be required to pass the obstruction. In exceedingly rare circumstances, the use of cardiopulmonary bypass or extracorporeal membrane oxygenation can be used as a lifesaving maneuver to oxygenate the anesthetized patient during an airway catastrophe.130,131 This is extremely rare and must be anticipated preoperatively in the patients with the most severe airway pathology, including planning for a potential cannulation strategy. This has never been necessary at our institution. Awake femoral-femoral cardiopulmonary bypass has been described in these severe cases.

Maintenance of Anesthesia When ventilation is being provided with an endotracheal tube and anesthesia circuit, anesthetic maintenance with inhaled volatile anesthetics is possible. Maintenance with volatile anesthetics is often preferable because it is possible to monitor the concentration being administered. This provides an estimate of anesthetic depth. When maintenance with inhalational agents is impossible, an IV maintenance technique must be used with the employment of an alternative measure of anesthetic depth.

Surgical Approach The location and the extent of tracheal pathology determine the surgical approach.132 Potential incisions include isolated cervical for upper tracheal lesions, partial sternotomy with a cervical incision for complex tracheal lesions, and right thoracotomy for low tracheal and carinal resections (Fig. 17-7).

1

2

A

3

B

FIGURE 17-7 A, Resection of the cervical trachea may be approached from the neck (1) or via sternotomy with subcostal thoracotomy (2 and 3). B, Lower tracheal and carinal surgery is best approached through a right thoracotomy. (FROM GRILLO HC: SURGICAL APPROACHES TO THE TRACHEA. SURG GYNECOL OBSTET 129:347-352, 1969.)

1/21/2008 10:50:18 AM

224

Section 2 Upper Airway

During resection, the trachea is divided above and below the level of the stenosis. It is possible to ventilate with the original endotracheal tube after tracheal incision if the lumen is positioned distal to the tracheal lesion. However, the endotracheal tube must be withdrawn above the resection site to allow reconstruction. The endotracheal tube is withdrawn to above the resection site under the direct vision of the surgeon. Two differing techniques may be used for ventilation during the reconstruction after withdrawal of the original endotracheal tube. A sterile armored (flexible) endotracheal tube may be introduced directly into the distal trachea by the surgeon and connected to a sterile ventilating circuit, a strategy known as cross-table ventilation. When all but the anterior portion of the trachea has been reapproximated, the sterile endotracheal tube is removed and the original endotracheal tube is advanced across the anastomosis, allowing completion of the tracheal reconstruction (Fig. 17-8). When

A

B

lower tracheal lesions are present it is sometimes impossible to insert an endotracheal tube into the distal trachea, and an individual bronchus is typically intubated (usually the left) (Fig. 17-9). The alternative strategy is the use of jet or highfrequency ventilation via a small catheter that is positioned across the anastomosis site by the surgeon.133-136 These catheter techniques do not ensure adequate oxygenation or CO2 elimination. Isolated hypercarbia is usually well tolerated, and a degree of hypercarbia is usually accepted with these techniques. High-frequency ventilation may be used; typically, highfrequency jet ventilation is the technique used in the operating room. Because room air will be entrained through the open trachea in the surgical field during jet ventilation, hypoxemia may ensue. Insufflation of extra oxygen via the endotracheal tube can increase the fractional concentration of oxygen of air entrained into the distal trachea. With all forms of jet ventilation, special vigilance must be paid to the

C

D

FIGURE 17-8 A, Endotracheal tube placement above a high tracheal lesion. B, With tracheal incision, a sterile endotracheal tube is introduced into the distal trachea for cross-table ventilation. C, The posterior tracheal reconstruction is completed using cross-table ventilation. D, The sterile endotracheal tube is removed, and the original endotracheal tube is advanced past the anastomosis site so that the anterior tracheal anastomosis may be completed.

A

B

C

D

FIGURE 17-9 Technique for ventilation for a low tracheal resection. A, Endotracheal tube in place above the lesion. B, With tracheal incision, a sterile endotracheal tube is introduced into the left mainstem bronchus for cross-table ventilation. C, The posterior anastomosis is completed using cross-table ventilation. D, The anterior tracheal anastomosis can be completed once the sterile endotracheal tube has been removed and the original endotracheal tube has been advanced into the left mainstem bronchus.

Ch017-F06861.indd 224

1/21/2008 10:50:19 AM

Chapter 17 Anesthesia for Airway Surgery

patient’s airway compliance, position of the catheters used for jet ventilation, and adequacy of oxygenation and elimination of CO2. High-frequency oscillation has been described for tracheal resection, but advantages over these other techniques remain unclear. On conclusion of the procedure, rapid extubation is usually preferable to avoid trauma to the anastomotic site. When controlled ventilation must be continued, positioning the endotracheal tube cuff distal to the anastomotic site and the minimization of any positive airway pressure are desirable. Spontaneous ventilation is optimal when extubation is postponed, assuming that minute ventilation is adequate. Emergence from anesthesia after tracheal resection also presents unique challenges. Protection of the tracheal anastomosis usually requires that neck flexion be maintained during and after extubation. This may be necessary despite the use of laryngeal or hilar release maneuvers during the resection. While excess movement or coughing during emergence is avoided, ensuring that the patient can maintain adequate spontaneous ventilation is critical. If ventilation is significantly compromised after extubation, performing reintubation becomes extremely challenging and may compromise the reconstruction. Therefore, equipment for management of such a difficult airway, including the ability to perform fiberoptic intubation, must be available on extubation. Achieving the aforementioned goals during emergence from tracheal resection is difficult, but several strategies may be helpful. Short-acting IV or inhalational agents are preferred for anesthetic maintenance. Recent series have suggested that emergence using remifentanil, dexmedetomidine, and propofol allows a smooth transition and a cooperative patient.137-139 Experience is increasing with the use of dexmedetomidine for sedation and anesthesia, and our group has found dexmedetomidine helpful during emergence. Alternatively, some authors suggest extubation with the patient still deeply anesthetized to prevent coughing and excessive movement. If deep extubation is used, the patient remains in the operating room with emergency airway equipment on hand until awake. Although adequate analgesia is necessary, excess amounts of opioids must be avoided during these procedures. When sternotomy or thoracotomy incisions are used, epidural analgesia provides postoperative pain control, allowing decreased use of respiratory depressants. The use of other analgesics that do not directly cause respiratory depression (e.g., ketamine, acetaminophen, ketorolac) may be helpful when not contraindicated.140,141 If reintubation is required, head extension must be minimized. The ideal method is fiberoptic intubation via the nose or mouth. During reintubation, the tracheal anastomotic site can be examined and gross vocal cord dysfunction can be identified.

Carinal Resection When airway pathology involves the bronchi or distal trachea, management of ventilation is more complex. Ventilation may frequently be accomplished with a long endotracheal tube that can be advanced into the left mainstem bronchus provid-

Ch017-F06861.indd 225

225

FIGURE 17-10 A “long” 7-mm endotracheal tube may be used for selective endobronchial intubation. Here, a 7-mm endotracheal tube has been connected to a second 7-mm endotracheal tube segment using an adapter.

ing single-lung ventilation during thoracotomy and ventilation during dissection of the right bronchial margin (Fig. 17-10). When the right bronchus is anastomosed, cross-table ventilation with selective left-sided intubation occurs. Cross-table ventilation, jet ventilation, high-frequency ventilation, and combinations thereof may be used when carinal resections are performed. Typically the left bronchus is intubated directly, allowing cross-table one-lung ventilation while the right bronchial anastomosis is completed. The right bronchus is then intubated by advancing the long endotracheal tube, allowing the left bronchial anastomosis to be completed. Hypoxemia might ensue; therefore, methods of providing jet ventilation to the right, left, or both lungs need to be available. Right and left lung jet ventilation using two ventilating catheters has been described (Fig. 17-11).142 Geffin113 described the snaring of the right pulmonary artery to enhance oxygenation when left lung ventilation is utilized. Postoperative pain management is of paramount importance, particularly when a thoracotomy has been performed. Humidified oxygen is supplied, and chest physical therapy and early ambulation are important to recovery.

ANESTHESIA FOR LASER SURGERY Surgical lasers allow the application of large amounts of energy to a precise area through the emission of photons from a laser medium. The CO2 laser was introduced by Laforet in 1976143 for ablation of an endobronchial neoplasm. Since that time, several other laser mediums have been introduced into clinical practice. Both CO2 and neodymium : yttriumaluminum-garnet (Nd : YAG) are used as laser mediums in airway surgery.144 The varying tissue absorption of the wavelengths emitted from each medium defines the tissue effects of each laser. The long-wavelengths of CO2 laser beams are highly absorbed by water in surface cells, creating a shallow vaporizing effect. CO2 laser beams are most easily transmit-

1/21/2008 10:50:20 AM

226

Section 2 Upper Airway

FIGURE 17-11 The use of two catheters and an endobronchial blocker for highfrequency jet ventilation during carinal resection. (FROM PERERA ER, VIDIC DM,

RIGHT SIDE

ZIVOT J: CARINAL RESECTION WITH TWO HIGH-FREQUENCY JET VENTILATION DELIVERY SYSTEMS. CAN J ANESTH 40:5963, 1993.)

Bronchial blocker 14-gauge catheter

12-gauge catheter

ted through the air, making them most suitable for surgery of the upper airways. Nd : YAG lasers have a much shorter wavelength, leading to less surface tissue absorption and a deeper, less intense, tissue effect. The energy associated with Nd : YAG lasers is transmitted via a fiberoptic bundle to the target site and is therefore suitable for bronchoscopic application to more-distal airways.

Complications of Laser Surgery Lethal complications have been described with the use of lasers in airway surgery, and a familiarity with the prevention and treatment of laser surgery injuries is critical to management of these surgeries. Complications associated with laser surgery include venous gas embolism, perforation of airway structures, unintentional application of the laser beam, excessive levels of energy transfer, and environmental risks, including those associated with the laser plume. U.S. Food and Drug Administration reports of laser injuries include two cases of endobronchial Nd : YAG laser use in which air emboli were thought to be introduced via the pulmonary veins, either by jet ventilation or by the effect of the laser’s cooling gas. Perforation of the airway during laser surgery may cause pneumothorax, pneumomediastinum, or pneumopericardium (Conacher et al, 1987; Vanderschueren and Westermann, 1990).145-150 Laser injuries may affect the patient or operating room personnel. CO2 lasers can cause corneal damage, whereas

Ch017-F06861.indd 226

Nd : YAG lasers are associated with retinal injuries (Snow et al, 1974).151 The patient’s eyes are protected with tape and covered with saline-soaked eye pads or a metal shield. Operating room personnel must wear protective eyewear that has been specifically designed to absorb the wavelength of the laser being utilized; clear glass suffices for CO2 lasers whereas green glasses are often used if Nd : YAG lasers are used (McKenzie, 1984).152-154 The use of non-CO2 lasers also requires shielding of operating room windows. Complications related to excessive levels of energy transfer include burns and fires. An airway fire is perhaps the most feared complication in laser surgery. Airway fires can be fatal and may be associated with long-term airway pathology (i.e., stenosis). Airway fires require both a combustible medium and the presence of a gas that supports combustion.155,156 Both oxygen and nitrous oxide support combustion, whereas nitrogen and helium do not. The inspired oxygen concentration is limited to less than 40%, or the lowest tolerable oxygen concentration, by supplementation with air. Pulse oximetry is helpful in minimizing the concentration of oxygen. Using helium as the supplemental gas may provide small advantages in delaying combustion while also improving gas flow through small-lumen endotracheal tubes. Although some designs of endotracheal tubes are more resistant to combustion, all are potentially flammable. The wrapping of standard endotracheal tubes with metallic tape can decrease the susceptibility to ignition.157-159 Multiple

1/21/2008 10:50:21 AM

Chapter 17 Anesthesia for Airway Surgery

tapes are available and provide varying degrees of protection. The Laser-Flex Tracheal Tube (Mallinckrodt Inc., St. Louis, MO) is a stainless steel tube that is resistant to combustion with CO2 lasers (Fig. 17-12). It is not as protective against ignition with Nd : YAG lasers. Even with wrapping techniques or the use of specially designed tubes, the endotracheal tube cuff is still susceptible. Rupture of the cuff can lead to leakage of oxygen into the surgical field with concomitant ignition risk and can impair the ability to provide ventilation. Wetted packing is used to cover the cuff and lower the risk of rupture. The cuff is usually filled with saline instead of air to potentially extinguish a small ignition source.160 Methylene blue is sometimes added to improve recognition if cuff rupture occurs. In the event of an airway fire, the response of the operative team must be rapid. Ventilation must be stopped, oxygen discontinued, combustible materials removed (i.e., the endotracheal tube), and the fire extinguished with water. A container of water ready for this purpose must always be available during laser surgery. When the fire has been extinguished, mask ventilation can be resumed. Inspection of the airway with laryngoscopy and rigid bronchoscopy is recommended to determine the extent of the injury and to remove any debris. In the case of severe airway injury, prolonged intubation and ventilation may be required. Intermittent ventilation techniques, including jet ventilation, may be used with laser surgery to reduce the risk of airway fire. Periods of ventilation by endotracheal tube or jet ventilation catheter can be followed by periods of apnea, when the laser surgery can commence. Additionally, when an endotracheal tube is used, it can be intermittently removed during laser use and then replaced for continued ventilation. Laser vaporization produces a plume, which consists of smoke and microparticles. Although the risks associated with the plume are not well understood, possible adverse effects include inflammation or the spread of infection.161 These

227

potential risks apply to the patient and operating room personnel. Smoke evacuators are used at the surgical site to reduce any adverse effects associated with the plume, and specially designed surgical masks are needed to absorb the microparticles. The mode of anesthetic maintenance during laser surgery is often dictated by the type of bronchoscopy utilized (i.e., rigid or fiberoptic). The currently used inhaled anesthetics are nonflammable and may be administered in procedures using fiberoptic bronchoscopy or positive-pressure ventilation via the rigid fiberscope. Still, total IV maintenance techniques are popular for laser airway surgeries because of the possibility of intermittent ventilation techniques. Furthermore, although inflammable, volatile anesthetics may undergo toxic degradation in the event of an airway fire. Other considerations for patients undergoing rigid or fiberoptic bronchoscopic procedures have been described previously.

AIRWAY TRAUMA Injuries of the trachea and main bronchi may occur with blunt or penetrating trauma.162 Tracheal injury is be suspected when subcutaneous air, hemoptysis, dysphonia, laryngeal tenderness, or respiratory distress is present. Penetrating trauma is associated with injury to the cervical trachea. Conversely, the intrathoracic trachea is more likely to be injured with blunt trauma (Shrager, 2003),163 including deceleration injury or by rapid increases in intrathoracic pressure (e.g., compression injury) (Fig. 17-13). Tracheal injuries are also associated with injuries to the esophagus, jugular veins, carotid arteries, vertebral arteries, and spine. Suspicion for the presence of these related injuries must be maintained.

Hyperextension/direct blow

Sudden increase in intrathoracic pressure (membranous wall)

Deceleration

Sites of blunt injury to the airway

FIGURE 17-12 The Laser Flex Tube (Mallinckrodt, St. Louis, MO). The cuffs are usually inflated with saline. Methylene blue may be added to facilitate the recognition of cuff rupture.

Ch017-F06861.indd 227

FIGURE 17-13 The typical location of tracheal injuries by mode of injury. Deceleration injuries frequently damage the trachea at its points of fixation: the junction with the larynx and at the carina. Sudden compression of the chest may cause elevated airway pressures with concomitant intrathoracic tracheal rupture. (FROM SHRAGER JB: TRACHEAL TRAUMA. CHEST SURG CLIN NORTH AM 13:291-304, 2003.)

1/21/2008 10:50:21 AM

228

Section 2 Upper Airway

Cervical spine instability must be assumed in these patients unless it has been excluded, and measures to reduce neck manipulation are exercised. Injuries to the airway may also follow airway instrumentation, including the use of stylets, endotracheal tube exchangers, double-lumen endotracheal tubes, rigid bronchoscopy, mediastinoscopy, or tracheostomy. The membranous portion of the trachea is usually affected. Conservative or interventional management is dictated by the defect size and the presence of sequelae. Operative management may be urgent, limiting the time allowable for comprehensive patient evaluation. Control of the airway may already be established, and an endotracheal tube may have been positioned beyond the site of injury. If the airway is not already controlled, fiberoptic intubation in the awake or anesthetized patient is usually the ideal strategy. This avoids further injury by positive airway pressure or by positioning of an endotracheal tube without visual guidance. A cervical incision or thoracotomy approach may be utilized. At the time of tracheal incision, an armored endotracheal tube can be placed directly into the distal trachea by the surgeon. Ventilation strategies similar to those used for tracheal resection may be needed and have been discussed previously. The use of alternative modes of ventilation in severe airway trauma has been described.164 Penetrating injury of the neck may be associated with variable damage to the cervical trachea. The size and type of gunshot and knife injury will vary with the type of bullet and knife. Direct compression or hyperextension after blunt trauma may contribute to cervical tracheal injury.

POSTOPERATIVE MANAGEMENT Postoperative complications after surgical airway procedures include ventilatory insufficiency, hypoxemia, bleeding, and aspiration. Respiratory distress is not uncommon after airway surgery. Patients often have preexisting impediments to ventilation, and, when these are not the target of the surgical procedure, the end result will often be greater compromise than existed preoperatively. Even when airway surgeries directly address preexisting airway compromise, the presence of edema, blood, or secretions may produce conditions that hamper ventilation and gas exchange in the immediate postoperative period. Symptomatic airway swelling in the extubated patient is frequently treated with a nebulized vasoconstrictor, such as racemic epinephrine165 or L-epinephrine, and IV corticosteroids. Another potential treatment for airway obstruction is ventilation with oxygen and helium. The addition of high fractions of helium to oxygen reduces the density of inhaled gas, which is advantageous with turbulent flow, and also increases the likelihood of laminar flow by reducing the Reynolds number. Heliox, a fixed 70 : 30 mixture of helium and oxygen, has been shown to improve respiratory distress and gas exchange and decreases the work of breathing in children.166 Delivery systems are available that can vary the fraction of helium and oxygen administered, but the advantages associated with helium-oxygen mixtures are greatly diminished when higher fractions of inspired oxygen are necessary.

Ch017-F06861.indd 228

Therefore, helium-oxygen mixtures are of limited use in patients with significant impairment of oxygenation unrelated to airway obstruction. Refractory hypoxemia or airway obstruction may necessitate reintubation or tracheostomy. Establishing control of the airway in these patients is often challenging because of airway edema, bleeding, neck position restrictions (i.e., tracheal resection), and a limited oxygenation reserve. Ideally, reintubation occurs in the operating room, where the tools for difficult airway management, including the immediate possibility of a surgical airway, are present. Unfortunately, the impending loss of the airway or the danger of transporting such patients often prevents such ideal circumstances. Regardless, personnel skilled in difficult airway management and emergency airway equipment, including fiberoptic bronchoscopy, need to be present. Preparations for possible tracheostomy or tracheotomy are also made. When the airway is controlled, therapies targeted toward the etiology of the respiratory insufficiency are continued. Continued bleeding after airway surgery may require reoperation. Postoperative fiberoptic bronchoscopy may be required to evaluate the source and severity of bleeding. Major bleeding is best approached in the operating room with a secure airway. Hypoxemia with or without hemodynamic instability may be a sign of pneumothorax, which may occur after most surgeries on the airway. This occurs more commonly after biopsies or tumor resection and may also be secondary to barotrauma (e.g., jet ventilation, hyperinflation with fiberoptic bronchoscopy). Negative-pressure pulmonary edema is a clinical syndrome that follows periods of upper airway obstruction (Halow and Ford, 1993).167-169 Reports of negative-pressure pulmonary edema are numerous in the postoperative setting and may cause significant respiratory distress. Management involves increasing inspired oxygen as necessary, diuresis, and the use of positive airway pressure (i.e., PEEP in the mechanically ventilated patient and CPAP in spontaneously breathing patients). Reintubation is required in some patients. Because airway procedures often include periods where the airway is not controlled, patients are at risk for the aspiration of gastrointestinal contents with concomitant respiratory distress. Patients undergoing airway procedures also have a high incidence of postoperative laryngeal dysfunction. Therapies aimed at reducing the acidity of gastric secretions are often utilized. In the event of aspiration, particulate matter is removed using bronchoscopy. If respiratory compromise is present, postoperative positive-pressure ventilation with PEEP continues.

SUMMARY The perioperative care of the patient undergoing airway surgery provides unique challenges. Ensuring ventilation and oxygenation, mainstays of intraoperative management, often interferes with surgery. As a result, complicated techniques are often required, necessitating meticulous coordination between the surgeon and anesthesiologist. Additionally, patients presenting for these surgeries are frequently debili-

1/21/2008 10:50:22 AM

Chapter 17 Anesthesia for Airway Surgery

tated or critically ill. Coexisting diseases associated with perioperative complications are prevalent. For elective procedures, early evaluation of patients provides the ability for comprehensive evaluation, optimization of patient condition, and surgical planning. Pulmonary function testing with flow-volume loops is helpful for patients with diffuse or focal obstructive disease. The treatment of chronic obstructive airway disease needs to be optimized before surgery when possible. Assessment of the severity of cardiovascular disease often influences the anesthetic technique, with β-blockers frequently utilized in patients at risk for myocardial ischemia. Anatomic abnormalities in patients presenting for airway surgery may necessitate induction strategies including awake intubation, inhalational induction, or even proceeding immediately to ventilation through a rigid bronchoscope after IV induction. Ventilation during airway procedures may require techniques such as low-frequency jet ventilation, high-frequency jet ventilation, positive-pressure ventilation through the rigid bronchoscope, or selective bronchial intubation. Knowledge of the benefits and limitations of each airway management technique, collaboration between practitioners, the availability of emergency equipment, and the presence of organized backup plans are important in averting airway catastrophes during these complex cases. Anesthetic techniques used for airway surgery have been markedly affected by the development of short-acting inhalational and IV agents over the past 20 years. These drugs have allowed the combination of profound anesthesia, rapid emergence, and minimal postoperative residua. Total IV anesthesia with these characteristics has also been made possible and is necessary in some airway procedures. Several processed electroencephalographic monitors have been developed and are being used with these total IV anesthesia techniques. Although intermediate-acting neuromuscular muscular relaxants have favorable side-effect profiles, their duration of action can still be too long for airway procedures. A unique antagonist is currently being investigated and may alter techniques of neuromuscular relaxation in the future.

COMMENTS AND CONTROVERSIES Airway surgery, whether performed open or endoscopically or under general anesthesia or moderate sedation, requires close collaboration between the anesthesiologist and thoracic surgeon. Dr. Hantler has a wealth of experience in this field. He provides an extensive review of all aspects important to safe anesthesia for airway surgery. Preoperative consideration and pharmacologic strategies are reviewed. Anesthesia strategies for specific airway procedures are also covered in detail. A number of points must be emphasized. In our own program, percutaneous tracheostomy has almost completely replaced open procedures. From an anesthetic, patient transport, and surgical perspective, these percutaneous procedures are far safer than open tracheostomy in critically ill patients. Dr. Hantler reviews the ventilatory strategies for tracheal and carinal resection. A variety of techniques—periodic apnea, crossfield ventilation, and low-frequency and high-frequency jet ventilation—are effective. I prefer cross-field ventilation with periodic apnea. For these complicated airway procedures, the surgeon and

Ch017-F06861.indd 229

229

anesthesiologist need to utilize a strategy familiar and comfortable to both. Communication is key. As endoscopic airway intervention such as laser and cautery procedures as well as stent utilization become more widespread, newer anesthetic strategies will no doubt emerge. However, close anesthesia and surgical collaboration will always be required for safe management of these complicated airway problems. G. A. P.

KEY REFERENCES American Society of Anesthesiologists: Practice guidelines for management of the difficult airway: An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269-1277, 2003. Ayers ML, Beamis JF Jr: Rigid bronchoscopy in the twenty-first century. Clin Chest Med 22:355-364, 2001. Barclay R, McSwan N, Welsh TH: Tracheal reconstruction without the use of grafts. Thorax 12:177, 1957. Belsey R: Resection and reconstruction of the intrathoracic trachea. Br J Surg 38:200, 1950. Bourjeily G, Habr F, Supinski G: Review of tracheostomy usage: Types and indications: I. Clin Pulm Med 9:267-272, 2002. Carden E, Trapp WG, Oulton J: A new and simple method for ventilating patients undergoing bronchoscopy. Anesthesiology 33:454-458, 1970. Chee WK, Benumof JL: Airway fire during tracheostomy: Extubation may be contraindicated. Anesthesiology 89:1576-1578, 1998. Conacher ID, Paes ML, Morritt GN: Carbon dioxide laser bronchoscopy: A review of problems and complications. Anaesthesia 42:511518, 1987. Egan TD, et al: The Pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 79:881-892, 1993. Fleisher LA, et al: ACC/AHA 2006 guideline update on perioperative cardiovascular evaluation for noncardiac surgery: Focused update on perioperative beta-blocker therapy—a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg 104:15-26, 2007. Froese AB, Bryan AC: High frequency ventilation. Am Rev Respir Dis 135:1363-1374, 1987. Frumin M, Epstein RM, Cohen G: Apneic oxygenation in man. Anesthesiology 20:789, 1959. Geffin B, Bland J, Grillo HC: Anesthetic management of tracheal resection and reconstruction. Anesth Analg 48:884-894, 1969. Grillo HC: Reconstruction of the trachea: Experience in 100 consecutive cases. Thorax 28:667-679, 1973. Grillo HC, Bendixen HH, Gephart T : Resection of the carina and lower trachea. Ann Surg 158:889, 1963. Grillo HC, Mathisen DJ: Primary tracheal tumors: treatment and results. Ann Thorac Surg 49:69-77, 1990. Gross JB, Bachenberg KL, Benumof JL, et al: Practice guidelines for the perioperative management of patients with obstructive sleep apnea: A report by the American Society of Anesthesiologists Task Force on Perioperative Management of Patients With Obstructive Sleep Apnea. Anesthesiology 104:1081-1093, 2006. Halow KD, Ford EG: Pulmonary edema following post-operative laryngospasm: a case report and review of the literature. Am Surgeon 59:443-447, 1993. Henderson JJ, et al: Difficult Airway Society guidelines for management of the unanticipated difficult intubation. Anaesthesia 59:675-694, 2004.

1/21/2008 10:50:22 AM

230

Section 2 Upper Airway

Jackson C: Anesthesia for peroral endoscopy. Laryngoscope 22:12081213, 1912. Jackson C: Instrumental aids to bronchoscopy and esophagoscopy. Laryngoscope 17:492-494, 1907. Kazama T , et al: Relation between initial blood distribution volume and propofol induction dose requirement. Anesthesiology 94:205-210, 2001. Lee AP, et al: A systematic review (meta-analysis) of the accuracy of the Mallampati tests to predict the difficult airway. Anesth Analg 102:1867-1878, 2006. MacIntosh R: Technique of laryngeal anaesthesia. Lancet 2:54, 1947. Macintyre NR, Ramage JE, Follett JV: Jet ventilation in support of fiberoptic bronchoscopy. Crit Care Med 15:303-307, 1987. McKenzie AL: Safety with surgical lasers. J Med Eng Technol 8:207-214, 1984. McRae K: Anesthesia for airway surgery. In Pearson GP, Deslauriers J, Ginsberg, et al (eds): Textbook of Thoracic Surgery, 2nd ed. Edinburgh, Churchill Livingstone, 2001, p 223. Miller RD: Sugammadex: An opportunity to change the practice of anesthesiology? [Editorial]. Anesth Analg 104:477-478, 2007. Mitchell JD, et al: Clinical Experience with carinal resection. J Thorac Cardiovasc Surg 117:39-53, 1999. Pearson FG, et al: Adenoid cystic carcinoma of the trachea: Experience with 16 patients managed by tracheal resection. Ann Thorac Surg 18:16-29, 1974.

Ch017-F06861.indd 230

Pinsonneault C, Fortier J, Donati F: Tracheal resection and reconstruction. Can J Anaesth 46(5 Pt 1):439-455, 1999. Qaseem A, et al: Risk assessment for and strategies to reduce perioperative pulmonary complications for patients undergoing noncardiothoracic surgery: A guideline from the American College of Physicians. Ann Intern Med 144:575-580, 2006. Scamman FL, Choi WW: Low frequency jet ventilation for tracheal resection. Laryngoscope 96:678-679, 1986. Sessler CN: Mechanical ventilation of patients with acute lung injury. Crit Care Clin 14:707-729, 1998. Shrager JB: Tracheal trauma. Chest Surg Clin North Am 13:291-304, 2003. Sjostrand UH: In what respect does high frequency positive pressure ventilation differ from conventional ventilation? Acta Anaesth Scand Suppl 90:5-12, 1989. Snow JC, et al: Anesthesia for carbon dioxide laser microsurgery on the larynx and trachea. Anesth Analg 53:507-512, 1974. Vanderschueren RG, Westermann CJ: Complications of endobronchial neodymium-YAG (Nd : YAG) laser application. Lung 168(Suppl):10891094, 1998. Yuill G, Simpson M: An introduction to total intravenous anaesthesia. Br J Anasth CEPD Rev 2:24-26, 2002.

1/21/2008 10:50:22 AM

chapter

18

INTERVENTIONAL BRONCHOSCOPY FOR THE MANAGEMENT OF AIRWAY OBSTRUCTION Michael S. Kent Joseph J. Wizorek James D. Luketich

Key Points ■ No intervention is suitable for all cases of endobronchial obstruc-

■

■

■

■

■

tion. It is imperative to have a working familiarity with a wide range of endobronchial techniques. An expertise in all of the available therapeutic options for lung cancer is essential, as is a clear understanding of the relevant mediastinal anatomy. PDT has a shallower learning curve than laser therapy, can be used with higher fractions of inspired oxygen, and has similar success rates. The systemic photosensitization caused by porfimer sodium injection for PDT therapy may hamper remaining quality of life for the patient and therefore preclude its use. Brachytherapy is likely to be of greatest benefit in patients with proximal airway obstruction; use it in conjunction with externalbeam radiation therapy for central endobronchial obstruction. Endobronchial stents are ideal for obstruction due to extrinsic compression.

A wide variety of disease processes, both benign and malignant, can lead to airway obstruction. The management of benign airway obstruction, such as tracheal stenosis due to prolonged intubation, deserves special consideration and is covered in detail in other chapters of this text (see Chapters 20, 28, and 30). This chapter specifically focuses on the management of airway obstruction caused by endobronchial lung cancer or other malignancies. Most patients with non–small cell lung cancer (NSCLC) present with advanced-stage disease and consequently are not candidates for surgical resection. However, up to 20% of these patients have an endobronchial tumor that is often symptomatic. Indeed, dyspnea or hemoptysis may be the initial presentation of an unsuspected lung cancer, and these symptoms can be quite distressing to the patient. Most of these patients are candidates for chemotherapy and/or radiation therapy. However, in some patients, obstruction of a proximal airway must be addressed first because of the severity of symptoms or because of concerns that a postobstructive pneumonia might develop during chemotherapy. In other cases, hemoptysis may require urgent intervention. Regardless of the indication, endobronchial palliation of lung cancer is unlikely to prolong survival for most patients. However, the surgeon who is well trained in these techniques will be able to significantly improve the quality of life that does remain for the patient.

Several technologies are currently available to treat endobronchial disease. Some, such as rigid bronchoscopy, have been practiced for more than a century. Others, such as expandable metal stents (EMSs) and photodynamic therapy (PDT), are relatively new. Given the number of options available, it is important that the treating physician consider these as complementary rather than competing technologies. Often, several modalities are offered to a single patient, such as laser ablation of endobronchial disease followed by stent placement. Also, treatment must be individualized for each patient. For example, PDT may not be appropriate treatment for a patient with a limited life expectancy who wishes to spend a significant amount of time outdoors. For all these reasons, it is important to have a working familiarity with a wide range of techniques, including rigid and flexible bronchoscopy, laser and photodynamic therapy, and the use of endobronchial stents and endobronchial brachytherapy. Perhaps even more important, it is essential that the interventionalist, surgeon or otherwise, be an expert in all of the therapeutic options for lung cancer, including chemotherapy, radiation therapy, and surgery. It is not uncommon for a patient to be sent to a thoracic surgeon for palliation of endobronchial obstruction when instead curative resection may be possible. It cannot be stressed enough that the interventionalist needs to have a working knowledge of all of the options available so these patients can be appropriately evaluated and treated. In this chapter, the required equipment, advantages, and disadvantages of techniques for the endobronchial palliation of lung cancer are reviewed. In addition, data from randomized clinical trials, where available, are presented to help guide clinical decision-making in this area.

FLEXIBLE VERSUS RIGID BRONCHOSCOPY Endobronchial intervention cannot be undertaken without the bronchoscope. Although most thoracic surgeons and pulmonologists are comfortable using a flexible bronchoscope, this is not always the case for the rigid scope. However, the rigid scope is not only the safest way to establish an airway in patients with critical obstruction, but it can also be used to rapidly core out obstructing tumor. The rigid scope has other advantages as well: the barrel can be used to tamponade bleeding that may develop after airway débridement, and the scope is also large enough to accommodate a large-bore suction catheter to deal with significant hemorrhage. Specific details on the use of the rigid scope can be found in Chapter 7 of this text. However, we would emphasize that the rigid 231

Ch018-F06861.indd 231

1/21/2008 10:51:20 AM

232

Section 2 Upper Airway

scope is the most versatile instrument for the evaluation and treatment of airway obstruction. Although many of the techniques described here can be used with a flexible scope, the ability to quickly and safely convert to rigid bronchoscopy is what distinguishes the diagnostic from the therapeutic bronchoscopist.

LASER THERAPY Laser therapy is one of the oldest techniques available for the treatment of endobronchial disease. The first use of the laser to treat airway disease was reported by Strong and Jako1 in 1972. In their study, 15 patients with endobronchial obstruction were treated with a carbon dioxide laser. Since that landmark paper, the laser has become a standard tool for the treatment of endobronchial disease, against which other modalities are compared. Although individual techniques vary from center to center, the principles of laser physics, laser safety, and techniques to avoid serious complications are well described and must be understood by all thoracic surgeons treating endobronchial disease.

Laser Physics Two properties distinguish laser from ordinary light. The first is that laser light is monochromatic and is therefore emitted at a specific wavelength. The wavelength of the emitted light is what distinguishes the several types of lasers that are currently used in medical practice today. For instance, the carbon dioxide laser, which is now rarely used to treat endobronchial disease, emits light at a wavelength of 10,600 nm. The long wavelength of this light mandated a cumbersome system of articulated mirrors to deliver the light to the distal airway, requiring rigid bronchoscopy. In contrast, the wavelength of light emitted by the neodymium : yttriumaluminum-garnet (Nd : YAG) laser is only 1060 nm, and it can be transmitted through a quartz fiber within a flexible bronchoscope. The second distinguishing property of laser light is that it is spatially coherent, meaning that it travels in a narrow parallel beam from a light source, unlike ordinary light that radiates in all directions from its source. The high energy of this coherent beam is the major reason that lasers can cause such tissue destruction. The degree of tissue injury is dependent on several factors that are under the control of the bronchoscopist. The first is the distance between the laser probe and the target tissue. As the distance decreases, the intensity of energy delivered to the tissue increases. This leads to a rapid rise in the surface temperature and vaporization of the tissue. If the distance is somewhat greater, the primary effect of the laser is one of photocoagulation. This effect is seen specifically with the Nd : YAG laser and is attributable to the deep tissue penetration (5-10 mm) with this laser. Photocoagulation is caused by the scattering of light as it penetrates the target tissue. Coagulation of proteins and small blood vessels occurs, inducing hemostasis.2 It is this property that makes the Nd : YAG laser ideal for resecting endobronchial tumors, which can often be quite vascular.3 However, because of the deep tissue penetration possible with the laser, damage can be far more significant than what

Ch018-F06861.indd 232

is visible to the bronchoscopist. Also, the injury induced by laser therapy is not static; it will progress over the next several days.4 One technique to minimize the degree of damage to deeper structures is to avoid the continuous mode of energy delivery. Instead, the laser is employed in short bursts (0.5 seconds or less) at an energy level of 0.5 W or lower. It is also important to realize that the absorption of laser energy changes during the course of a treatment. Lighter tissue tends to reflect laser energy, whereas darker tissue absorbs it. As tissue is coagulated and carbonized by the laser, it turns darker and the absorption of laser light increases dramatically. At that point, further therapy is performed with caution to avoid potential complications.

Technique The Nd : YAG laser may be used with either rigid or flexible bronchoscopy, and the choice is largely one of individual preference. The quartz fiber that delivers the laser light is small and pliable enough to fit through the working channel of the flexible bronchoscope. The flexible scope is also more familiar to physicians and allows better visualization of the distal airways, particularly the right upper lobe. However, the rigid bronchoscope offers several advantages for those comfortable with its use. The scope is significantly larger and can accommodate a large-bore suction device or forceps to remove blood and debris during laser therapy. Significant bleeding into the airway is therefore much easier to control during rigid bronchoscopy. Because there is only one working channel with the flexible scope, the laser probe must be removed to suction away blood and then replaced to identify and coagulate the bleeding source. Two other issues limit the utility of the flexible scope. The first is the relatively small working port. Although smallvolume disease may be removed piecemeal with the biopsy forceps and the flexible scope, this is a time-consuming and often impractical process. The rigid scope, in contrast, allows endobronchial tumor to be cored out with relative ease. The other concern relates to the potential for airway fire during laser therapy. Although airway fire is extremely rare, every effort is made to prevent this complication because the consequences for the patient are often fatal. The cause of airway fire is the ignition by the laser of flammable material, such as the endotracheal tube or the flexible scope itself, in the setting of high oxygen tension. The use of the rigid metal scope, which allows for ventilation without the plastic endotracheal tube, minimizes but does not entirely prevent this possibility. The suction catheter used during rigid bronchoscopy can also catch fire, and it must be maintained proximal to the laser probe to prevent this occurrence. Importantly, the inspired oxygen fraction needs to be lowered to 30%, if at all possible, before the laser is used. Second to airway fire, the most feared complication of laser therapy is injury to a major vascular structure such as the pulmonary artery, a complication that is often fatal. A clear understanding of the relevant anatomy and a healthy respect for this complication is essential. The proximal third of the trachea is in close proximity to the thyroid anteriorly and the esophagus posteriorly (Fig. 18-1). No major vascular

1/21/2008 10:51:20 AM

Chapter 18 Interventional Bronchoscopy for the Management of Airway Obstruction

233

8

10

3 9

15

6

5

4

8

10 15

2 20

18

3

7

19

11

4

5

9

17

6 B3

1

1

16

B1

2 7

B2

B2

B1

12

A

B3

B

11

12

13

13

C

D 8 4

15 B3

5

10

5

9

B1

6

1

3

16

2 7 B2

11

B3

12

13

4

B1 B2

B4

13

B5

B3

B2

10

9 23 B1

6

3

E FIGURE 18-1 Endoscopic anatomy of the trachea and the bronchi. A, Superior to the aortic arch. B, Carina. C, Left main stem bronchus. D, Right main stem bronchus. E, Distal left main stem bronchus. 1, trachea; 2, right main stem bronchus; 3, left main stem bronchus; 4, aorta; 5, right pulmonary artery; 6, left pulmonary artery; 7, right upper lobe bronchus; 8, truncus intermedius; 9, left upper lobe bronchus; 10, left lower lobe bronchus; 11, vagus nerve; 12, recurrent nerve; 13, esophagus; 15, superior vena cava; 16, azygos vein; 17, right innominate vein; 18, left innominate vein; 19, innominate artery; 20, left carotid artery; 23, left upper pulmonary vein. (COURTESY OF J. F. DUMON.)

Ch018-F06861.indd 233

1/21/2008 10:51:20 AM

234

Section 2 Upper Airway

structures are susceptible to injury at this level. The anterior surface of the middle third of the trachea is in close contact with the left innominate vein and the innominate artery. At the level of the carina, the airway is adjacent to the aortic arch. The left main stem bronchus is in close proximity to the left pulmonary artery anteriorly and the descending aorta inferiorly. The right main stem bronchus is crossed anteriorly by the azygos vein and more distally by the pulmonary artery. On the left, the distal main stem bronchus is crossed anteriorly by the superior pulmonary vein and laterally by the pulmonary artery. In both lower lobes, the branches of the pulmonary artery are lateral to the bronchus, and branches of the pulmonary vein are medial to the bronchus. Although portions of the proximal airway are surrounded by vascular structures, it is in the distal airway that significant injury is more likely to occur. Distally, the bronchus has incomplete cartilaginous rings and therefore is more susceptible to laser injury. Also, the pulmonary artery and vein are more closely associated with the bronchus distally. The patency of the airway distal to an obstruction is critical to determining the success of therapy. Often, a lumen that initially appears to be completely occluded is in fact partially open, as is suggested by expanded lung parenchyma distal to the airway on a computed tomographic scan. With patience and careful probing with the scope, one may be able to identify a small crevice or space within the lumen and around the lesion. The ability to suction mucus through the scope also indicates that there is a patent airway, even if it cannot be immediately located. However, if indeed the airway is completely occluded, use of the laser is extremely dangerous. There is significant risk that energy will be delivered to the wall of the airway instead of to the tumor, leading to the possibility of airway perforation or bleeding from injury to adjacent vascular structures. Because of these issues, appropriate selection of patients for laser therapy is very important. Those with disease in either the trachea or a main stem bronchus who have a patent distal airway and functioning parenchyma are most likely to receive benefit from treatment. For the reasons discussed earlier, patients with disease in the distal airway are more difficult to treat (particularly with the rigid scope), more prone to complications related to bleeding, and less likely to be palliated. The rigid bronchoscope and the laser are typically used in concert to remove endobronchial disease. A useful technique is to use the laser to coagulate the base of the tumor, then core out the tumor using the beveled end of the scope. Large biopsy forceps may also be used to remove the tumor in a piecemeal fashion. If jet ventilation is used, it is temporarily discontinued while large pieces of tumor are being removed. Minor bleeding after core-out of tumor can be controlled by a variety of techniques. If appropriate, the laser can be used to coagulate discrete bleeding points. More diffuse oozing can be managed with topical thrombin, oxidized cellulose, or dilute epinephrine. The shaft of the rigid scope can also be used to tamponade bleeding. If the bleeding is more significant, an inflatable Fogarty balloon can be used, and, if necessary, the balloon can be kept in place for up to 48 hours. Another maneuver in cases of massive bleeding is to place a

Ch018-F06861.indd 234

double-lumen endotracheal tube and keep both cuffs inflated. Regardless of how bleeding is controlled, it is important to evacuate blood clots and debris before significant hypoxemia develops. The bronchoscopist must also remember to thoroughly evacuate clot from the contralateral lung. The flexible scope placed through the shaft of the rigid scope is very useful for this purpose.

Results of Laser Therapy Laser therapy leads to excellent palliation of symptoms of airway obstruction, provided that patients are properly selected. In a series of more than 1900 patients treated with the Nd : YAG laser, 93% showed improvement in symptoms and quality of life.5 Even among patients for whom radiation therapy and chemotherapy had failed, laser resection improved symptoms in 64%.6 Furthermore, the safety profile of laser resection is excellent in experienced centers. The incidence of serious complications, such as airway perforation, massive bleeding, or fire, is less than 4%.5 The major drawback to laser treatment is that treatment effects have limited durability, and recurrence of symptoms is frequently seen within 30 days.7

ELECTROCAUTERY AND ARGON PLASMA COAGULATION The use of alternating electrical current to cut and coagulate tissue has been a standard tool of surgeons for decades. It has also found widespread application in gastroenterology, for example, to allow removal of polyps with the colonoscope. Several electrocautery probes are currently available and may be used through either the flexible or the rigid bronchoscope. The effect of the current on the target tissue is determined by the voltage; a current of high amperage and low voltage coagulates tissue, and a current of low amperage and high voltage cuts it. In cautery mode, the probe can be used to quickly ablate bleeding tumors. The cutting mode is useful when a snare is available. The snare can be used to amputate a polypoid lesion at its base, and any subsequent bleeding can be controlled by coagulating the cut surface. Like the electrocautery familiar to surgeons, the probe used for endobronchial disease can char and become adherent to the target tissue. The use of argon plasma coagulation overcomes this limitation. The technique uses ionized argon gas, which conducts electrical energy evenly to the tissue. The probe itself does not need to be in direct contact with the tissue. The argon beam also clears the operative field of blood and mucus that would limit the efficacy of a standard probe. The penetration of the argon beam is not very deep compared with the laser, so it is ideal for superficial, bleeding tumors. The results of electrocautery for palliation are similar to those of laser therapy. Reported success rates in relieving dyspnea are in the range of 70% to 80%.8-10 Complications of the treatment, such as airway fire and hemorrhage, are also similar to laser therapy. The advantages of electrocautery over laser therapy are two: (1) the electrocautery is substantially less expensive than the laser, and (2) the handling characteristics of the electrocautery are quite familiar to the

1/21/2008 10:51:25 AM

Chapter 18 Interventional Bronchoscopy for the Management of Airway Obstruction

surgeon. As stated previously, the laser, although deceptively simple to operate, can cause significant tissue destruction if the bronchoscopist is not familiar with the safe principles of its use.

ENDOBRONCHIAL MICRODÉBRIDER Another mechanical method to treat endobronchial obstruction utilizes a device that was initially designed for otolaryngology.11,12 The microdébrider (Fig. 18-2) employs a small, spinning blade contained within a rigid suction cannula. Because the suction cannula is rigid, the device can be employed only with a rigid bronchoscope. With the microdébrider, tumor can be mechanically débrided while simultaneous suction and irrigation keep the operative field dry and unobstructed. The tracheal blades are 4 mm in diameter, and the suction cannula is produced in a 37-cm length that is sufficient to reach distal endobronchial lesions. The rotational speed of the blade can be controlled with a foot pedal and is in the range of 1000 to 3000 rpm. We and others have found that the microdébrider allows obstructed airways to be reopened quickly and safely, and bleeding is usually minimal.13 If needed, electrocautery, argon plasma coagulation, or the Nd : YAG laser may be used to control bleeding after débridement.

PHOTODYNAMIC THERAPY Mechanism of Action Phototherapy, the treatment of disease with light, has been practiced by physicians in both the ancient and the modern world. For example, more than 100 years ago, Kime described the use of sunlight refracted through a blue glass to treat patients with tuberculosis.14 Photodynamic therapy (PDT) involves both light and the administration of a photosensitizing agent. Local tissue destruction results when this agent is activated by light of a specific wavelength. The specificity of this technique relies on two factors: (1) the higher accumulation of the photosensitizer in tumor cells and their interstitium, compared with normal surrounding tissue, and (2) the selective application of light to the tumor. The major toxicity of PDT results from the accumulation of the photosensitizer in normal tissues. As a consequence, patients may develop severe sunburn when exposed to sunlight for even brief periods and for up to 6 weeks after treatment. The most commonly used sensitizer, Photofrin II (Axcan Scandipharm, Birmingham, AL), is a derivative of hematoporphyrin. This drug received approval by the U.S. Food and Drug Administration for the palliation of endobronchial cancer in 1998. Experimentally, the compound has been

FIGURE 18-2 The distal end of a microdébrider used through a rigid bronchoscope. The rotating blade removes tumor while irrigation and suction keep the operative field clean.

Ch018-F06861.indd 235

235

shown to accumulate preferentially in neoplastic tissue. The mechanism of this is not clear, although increased cellular proliferation, altered lymphatic drainage, and derangements in cell permeability have all been implicated. The sensitizer acts as a catalyst for the production of highly toxic oxygen species, such as singlet oxygen and peroxide anions, that lead to the initiation of apoptosis. PDT seems to directly initiate an apoptotic response without the use of signal transduction pathways, which may be absent in drug-resistant populations of tumor cells.15 Efficacy of PDT is, however, dependent on high oxygen tension within the target tissue.16,17 An important secondary effect of PDT is caused by accumulation of the sensitizer within the endothelium of the tumor tissue. Generation of reactive oxygen species within this compartment leads to alteration in neutrophil and platelet aggregation, intravascular thrombosis, and ultimately tumor ischemia.

Treatment Planning The ideal candidate for PDT has minimal extrinsic compression and a primarily endoluminal tumor. Given the edema that invariably occurs after PDT, patients with nearobstructing tracheal tumors are not suitable candidates. Porphyria is also considered a contraindication to PDT. Endobronchial PDT can often be performed as an outpatient procedure. The photosensitizer is administered 24 to 48 hours before treatment. This length of time is recommended to allow for selective concentration of the agent within the tumor. Treatment may be performed sooner than 24 hours after photosensitizer administration, but the possibility of local toxicity is theoretically somewhat higher. Our preference is to perform bronchoscopy with the patient under conscious sedation, although general anesthesia is certainly acceptable, especially if prolonged treatment times are anticipated. Because Photofrin is activated by coherent light at 630 nm, a laser tunable to this wavelength is required. The laser light is delivered to the tumor using a diffusion fiber, which can easily fit through the working channel of the flexible bronchoscope. The rigid bronchoscope is not strictly required for the administration of PDT, although it may be useful to core out large, central tumors before PDT treatment. The cylindrical diffusion fibers are available in lengths of 1, 2.5, and 5 cm (Fig. 18-3). Ideally, a length is chosen

FIGURE 18-3 A selection of diffusion fibers used for photodynamic therapy. The fibers are passed through the working channel of a flexible bronchoscope.

1/21/2008 10:51:25 AM

236

Section 2 Upper Airway

that will allow the entire tumor to be treated, but from a practical standpoint we usually use a 1- or 2.5-cm probe. Several cycles of illumination are required when the tumor length exceeds the length of the probe. The probe can be impaled into the tumor if the distal extent of the tumor cannot be visualized. This allows for maximum penetration of light to the tumor while minimizing toxicity to adjacent structures. The energy typically delivered depends on the location of the tumor: for tracheal disease 300 J/cm2 may be given; for main stem lesions, 200 to 300 J/ cm2 is common; and for lobar disease, 100 to 200 J/cm2 is used. The schedule of PDT treatment depends on the degree of endobronchial involvement and the performance status of the patient. For otherwise healthy patients with minimal dyspnea or hemoptysis, outpatient PDT is followed 2 days later by an additional bronchoscopy. This is necessary because occlusive, necrotic tissue often sloughs into the airway after PDT. This can usually be removed with the flexible bronchoscope, using the 3-mm working channel of the larger, laser bronchoscope to forcefully irrigate and suction larger pieces of tumor. For patients with central or more symptomatic lesions, we usually prefer inpatient treatment. This allows for careful observation in the post-treatment period. On occasion, patients develop signs of respiratory failure after treatment, due to either local tissue edema or sloughing of necrotic debris into adjacent airways, making outpatient treatment unwise. This period of worsening respiratory status is usually transient but needs to be considered in treatment planning.

Results and Complications Multiple single-institution series from the United States, Japan, and Canada have demonstrated that PDT can effectively re-establish luminal patency of the airway.18 In a representative series of 100 patients with advanced NSCLC reported by Moghissi and colleagues, all patients had subjective improvement in dyspnea after treatment. Improvement in performance status was noted in 44% of patients (Moghissi et al, 1999).19 There was also an increase in pulmonary function as measured by pulmonary function tests, although the improvements in 1-second forced expiratory volume (FEV1) and forced vital capacity (FVC) were not statistically significant. Similar results were observed in a series of 44 patients from the University of Pittsburgh group.20 At a mean follow-up of 2 months, obstruction was effectively palliated in 59% of patients. Only 30% of patients required a second course of treatment for refractory or recurrent symptoms. Major complications among patients treated with PDT have been low. In a review of the PDT literature for the treatment of inoperable lung cancer, there were no procedure-related mortalities among 636 patients.21 The most common toxicity was sunburn, which occurred in 8% of cases and was mild in most instances. Although the reporting of complications is not uniform among these case series, the incidence of mild hemoptysis after PDT treatment was 18% in a trial comparing PDT to endobronchial laser therapy.22 Fatal hemoptysis is rare after PDT therapy. The largest single-

Ch018-F06861.indd 236

institution series, comprising 175 patients, reported a 2% incidence of this complication (McCaughan and Williams, 1997).23 However, it can be difficult to determine whether massive hemoptysis after PDT is a direct complication of treatment or a result of progression of disease. Given that the depth of tissue damage after PDT is only 5 mm, disease progression is the more likely explanation.

PDT Compared to Endobronchial Laser Therapy Perhaps the greatest advantage of PDT is its ease of use and the relatively shallow learning curve associated with the technique. Physicians who are familiar with bronchoscopy find that they are comfortable performing PDT after only three or four sessions. In addition, the nonthermal mechanism of action allows PDT to be performed in patients who require high inspired oxygen, without the risk of airway fire. Also, pinpoint precision is not necessary during PDT, so it may be performed in a spontaneously breathing patient under conscious sedation. Three disadvantages of PDT limit its applicability to all patients with endobronchial disease. The first is that of cost. Although both techniques require the use of a laser, which can cost more than $100,000, PDT also requires the use of a photosensitizer. The cost of a single dose of Photofrin II is typically $2000 to $4000. In addition, one must consider that a significant proportion of patients undergoing PDT require additional bronchoscopy for removal of necrotic debris. A second limitation of PDT is the development of airway edema, which is often seen in the first 24 to 48 hours after treatment. Patients with critical airway obstruction are therefore probably better treated with Nd : YAG laser ablation or core-out with the rigid scope, which allows immediate restoration of airway patency. Finally, systemic photosensitivity may hamper remaining quality of life. The median survival time of patients with advanced lung cancer undergoing endobronchial palliation is on the order of 3 to 6 months, and avoidance of direct sunlight is recommended for at least 4 weeks after PDT treatment. This limitation may significantly affect the patient’s quality of life, and the issue must be carefully discussed before a treatment plan is selected. The single randomized study in the literature comparing PDT with laser therapy was reported in 1999.24 Thirty-one patients with inoperable lung cancer were randomized to either PDT or Nd : YAG laser ablation. Patients with tracheal obstruction were excluded from the study, given the concern for post-PDT airway edema after PDT. The local control rate was similar in both groups 1 month after treatment (PDT 39% versus laser 23%; P = not significant). Symptomatic improvement was also similar. The only differences noted were in time to treatment failure and overall survival. The median time elapsed before treatment failure was 50 days in the PDT group and 38 days in the laser group. The authors also noted that the median survival time was significantly longer in the PDT group. Given that the local control rate was similar, this difference was most likely due to differences in disease progression elsewhere.

1/21/2008 10:51:25 AM

Chapter 18 Interventional Bronchoscopy for the Management of Airway Obstruction

CRYOSURGERY Cryosurgery involves the use of extreme cold to effect tissue destruction. The technique was initially adapted for endobronchial disease in the United States more than 40 years ago. In North America, interest in cryosurgery was largely eclipsed by the introduction of laser technology. However, several centers in Europe have continued using cryosurgery for the ablation of endobronchial disease, with results that are similar to those seen with Nd : YAG laser treatment.

Equipment and Technique In addition to flexible and rigid bronchoscopes, cryosurgery requires the use of specially designed probes along with a cryomachine, which delivers an extremely cold compound (a cryogen) at a specific temperature. Several cryogens are available for use, including liquid nitrogen, carbon dioxide, and argon. Most cryogens are delivered in liquid form and generate extreme cold during sublimation. The cryogen most commonly used for endobronchial disease is nitrous oxide. The advantage of nitrous oxide is that it can be stored at room temperature in high-pressure cylinders. The cryogen is delivered through a small probe that can easily fit through the working channel of a bronchoscope and does not require any thermal insulation. When the nitrous oxide reaches the tip of the probe, it expands through a small nozzle and transitions from a liquid to vapor phase. This can generate temperatures as low as −89ºC for a distance of 10 to 20 mm from the probe tip. A variety of cryoprobes have been specifically designed for use within the airway. Flexible probes have a smaller diameter and are designed to be used through the working channel of a flexible bronchoscope. The larger probes require the use of a rigid bronchoscope, although they have several advantages. First, they are able to treat much larger areas of disease more quickly. In addition, they are available in both straight and right-angle configurations; the latter is designed for treating disease within the upper lobe or superior segment of the lower lobe. Finally, the larger probes are able to cool to a lower temperature and therefore have more destructive capability. Usually, cryosurgery is performed by rigid bronchoscopy with the patient under general anesthesia. This allows for longer treatment times as well as for the use of a larger, 3-mm suction catheter, which is placed alongside the cryoprobe and keeps the operative field free of necrotic debris. The tip of the bronchoscope is placed 5 mm proximal to the target lesion, and the probe is then impaled into the tumor. Cooling of the probe takes approximately 3 minutes, after which the tissue must be allowed to thaw so that the probe can be removed from the tumor. This process is repeated for larger tumors. Bleeding from the tumor can be controlled with dilute epinephrine after cryosurgery is completed. The average time required for a cryotherapy session is 20 to 30 minutes.

Results of Cryosurgery No randomized studies have compared cryosurgery with other forms of endobronchial therapy. The largest singleinstitution experience was published from the United

Ch018-F06861.indd 237

237

Kingdom and described 329 patients treated with cryosurgery over a 10-year period.25 For patients who were able to receive two treatments, improvement in dyspnea, cough, and hemoptysis were noted in 50%, 51%, and 36% of patients respectively. However, the palliation of symptoms was not particularly durable; by 1 month follow-up, 63% of patients reported that their dyspnea had returned. In part this may reflect progression of systemic disease rather than local, endobronchial failure. For example, dyspnea may result from a malignant pleural effusion or lymphangitic spread of tumor, developments that would not be addressed by cryosurgery. Importantly, the technique was shown to be safe. No cases of bronchial perforation were observed, and only 4% of patients developed new-onset hemoptysis after treatment. The median survival time after treatment was 8 months, reinforcing the notion that even patients with advanced disease warrant aggressive therapy for palliation.

ENDOBRONCHIAL BRACHYTHERAPY Endobronchial brachytherapy involves the delivery of localized radiation to the airway, utilizing afterloading catheters placed via bronchoscopy. After placement, the patient is brought to the radiation oncology suite, and a radioactive source (usually iridium-192) is loaded into the catheter. In contrast to external-beam radiation therapy (EBRT), the dose of radiation delivered with brachytherapy can be more precisely tailored to the extent of endobronchial disease, thereby minimizing toxicity to adjacent structures.

Technical Considerations Historically, brachytherapy was conducted using sources with a low rate of radiation delivery. As a consequence, treatment sessions with so-called low-dose-rate (LDR) brachytherapy required several hours and usually were performed on an inpatient basis. Over the past 15 years, the development of high-dose-rate (HDR) brachytherapy, using more active iridium-192, has shortened treatment times to less than 30 minutes, allowing for outpatient therapy. Treatment planning begins in the bronchoscopy suite, at which time the proximal and distal extent of the tumor are identified. Not infrequently, the placement of brachytherapy catheters is preceded by other endobronchial techniques such as the Nd : YAG laser or core-out of tumor using rigid bronchoscopy. This sequence has the benefit of not only relieving acute airway obstruction but also allowing the distal lumen to be identified, so that the brachytherapy catheters can be placed across the entire length of the tumor. Next, a 5- or 6-Fr catheter is placed across the tumor over a guidewire, with the aid of bronchoscopy and fluoroscopy. On occasion, it may be necessary to place more than one catheter. The catheter is secured to the nose, and the patient is transferred to the radiation oncology suite for treatment planning. This is done by loading the catheter with “dummy” (nonradioactive) seeds that are radio-opaque. Chest radiographs are taken, and planning is done with the aid of specialized software. With current HDR technology, a single radioactive source is then remotely loaded into the catheter, and, using a cable system, the source is programmed to dwell

1/21/2008 10:51:25 AM

238

Section 2 Upper Airway

or rest at specific locations within the catheter for specified periods of time. By altering these dwell times, the operator can precisely control the radiation exposure along the length of the tumor. A treatment plan for brachytherapy includes the overall dose delivered, the dose per fraction, and the radiation exposure at a specific distance from the tumor. For example, a treatment plan may prescribe a total dose of 15 Gy over a distance of 1 cm from the tumor, given over three fractions. The radiation exposure from brachytherapy catheters decays in a linear fashion as distance increases, so the exposure 2 cm from the radiation source is one-half the dose prescribed at 1 cm. Alterations in these treatment schedules affect both the efficacy and the toxicity of the therapy. For example, as the dose per fraction increases, the cytotoxic effect on tumor cells will increase. However, the toxicity to normal tissues will also increase to a significantly greater degree. As a consequence, schedules with higher doses per fraction may be more convenient to administer but are likely to be associated with a higher rate of complications.

Complications of Brachytherapy Brachytherapy is usually well tolerated, and immediate complications are more often related to the bronchoscopy and other concomitant procedures, such as laser therapy. However, two late complications are specifically associated with brachytherapy: radiation bronchitis (and subsequent airway stenosis) and massive hemoptysis. The overall incidence of radiation bronchitis is in the range of 15% in most series.26 The incidence of more severe radiation bronchitis leading to severe symptoms or requiring bronchoscopic intervention is approximately 5% to 10%. Massive hemoptysis is a particularly dreaded complication after brachytherapy because it is often fatal. The overall incidence of this complication is in the range of 10%, although the development is often multifactorial.23 For example, hemoptysis may often be caused by local tumor progression, or it can be related to other interventions, such as laser treatment. Large, retrospective studies have identified a fraction dose greater than 10 Gy and prior laser therapy to be strong predictors of massive hemoptysis. Laser therapy is more likely to be associated with extensive endobronchial disease and therefore may simply be a marker for increased risk rather than a direct cause.27-29

Efficacy of Brachytherapy Retrospective series of brachytherapy have demonstrated that symptoms of airway obstruction are palliated in approximately two thirds of patients. For example, in a series of 406 patients treated with brachytherapy, dyspnea and cough were improved in 60% of patients.30 Similar outcomes were reported by the M. D. Anderson group. In their retrospective review of 74 patients over a 10-year period, 66% reported symptomatic improvement, with a mean duration of response of 4 months. In that study, the overall response rate (as determined by repeat bronchoscopy) was 78%: 66% of patients showed a partial response, and 12% had a complete endobronchial response.31 The specific indication for brachytherapy over other technologies such as PDT has not been clearly defined. Often, brachytherapy is combined with EBRT, and the specific benefit of brachytherapy can be difficult to measure in retrospective studies if a variety of treatments were used. Randomized studies to define this benefit are few. A large prospective trial planned by the Medical Research Council in the United Kingdom to study brachytherapy was halted due to poor patient accrual.32 To date, three randomized studies on brachytherapy have been reported (Table 18-1). In the first,33 98 patients were randomized to receive either EBRT (60 Gy) or EBRT plus brachytherapy (4.8 Gy over two sessions). Survival and the development of massive hemoptysis were equal in the two groups, although local control was superior in the combined treatment group. In the second trial, 95 patients were randomized to EBRT alone (30 Gy) versus EBRT plus brachytherapy (7.5 Gy over two sessions).34 For patients with tumors obstructing the main stem bronchus, benefits of brachytherapy were seen in the improvement of dyspnea scores, lung re-expansion, and pulmonary function tests. No benefit was seen in patients with obstruction of the lobar bronchus. The final study investigated the benefit of brachytherapy alone versus EBRT (Stout et al, 2000).35 Among 108 patients randomized, EBRT was found to be associated with a higher increase in esophagitis but also more durable palliation of dyspnea compared with brachytherapy. There was also a small but statistically significant improvement in overall survival in the EBRT group. It is unlikely that these trials will be repeated, given the widespread use of chemotherapy in addition to radiation

TABLE 18-1 Randomized Trials of Endobronchial Brachytherapy Author (Year)

N

Study Design

Median Survival (Wk)

Comments

Huber33 (1997)

98

EBRT vs EBRT + endobronchial brachytherapy

28 vs 27 (P = NS)

Improved local control in combined group

Langendijk34 (2001)

95

EBRT vs EBRT + endobronchial brachytherapy

36 vs 30 (P = NS)

Improved palliation of dyspnea in combined group with central tumors; trial closed early due to poor accrual

Stout35 (2000)

99

EBRT vs brachytherapy

41 vs 36 (P = .04)

Longer duration of palliation with EBRT; increased esophagitis

EBRT, external-beam radiation therapy; NS, not significant.

Ch018-F06861.indd 238

1/21/2008 10:51:25 AM

Chapter 18 Interventional Bronchoscopy for the Management of Airway Obstruction

FIGURE 18-4 A silicone Dumon Y stent. The studs on the outer surface are designed to adhere to airway mucosa and prevent migration. (FROM CTSNET, INC., VENUTA F, RENDINA EA, DE GIACOMO T:

239

FIGURE 18-5 Bronchial stents. A, Y stent with inverted right bronchial arm. B, Bronchial stent and chest tube, used as a pusher, both fitted over a bronchoscope.

AIRWAY STENTING. CTSNET, INC. AVAILABLE AT: HTTP://WWW.CTSNET. ORG/SECTIONS/CLINICALRESOURCES/THORACIC/EXPERT_TECH-1.HTML [ACCESSED APRIL 20, 2007].)

therapy for the treatment of advanced lung cancer. However, based on these studies, it is reasonable to conclude that (1) for palliation of advanced lung cancer, brachytherapy is likely to be of greatest benefit in patients with obstruction of the proximal airway, and (2) for patients with central endobronchial obstruction, use of brachytherapy ought to be in conjunction with EBRT.

AIRWAY STENTS The ideal candidate for an airway stent is a patient with airway obstruction primarily due to extrinsic compression. Such compression may occur as a result of exophytic tumor that has grown outside the bronchial wall or bulky metastases within peribronchial or mediastinal lymph nodes. Often, patients have elements of both intrinsic and extrinsic compression. In these situations, stent placement may be combined with tumor core-out using the rigid scope, Nd : YAG laser, or other modalities described earlier. Endobronchial stents have been available for more than 50 years.36 However, the technology has progressed at such a rapid pace that some of the stents used today have been available for only 1 or 2 years. As a consequence, the treating physician has at his or her disposal a wide array of stent designs and deployment systems, but experience with some of the newer systems may be quite limited. Despite the wide range of individual designs, most stents in use today fall into one of two categories: silicone-based stents and EMSs. An expandable plastic stent (PolyFlex) also recently became available that combines characteristics of the traditional silicone and metal stents. Current silicone-based stents are based on the original airway stent that was made from Silastic rubber and designed

Ch018-F06861.indd 239

by Dumon in the 1960s. Given the lengthy and international experience with this design, the Dumon stent (Bryan Corporation, Woburn, MA) is considered by many to be the gold standard against which other systems ought to be compared. The Dumon stent (Fig. 18-4) is a straight cylindrical stent that comes in a selection of sizes for deployment in either the trachea or the main stem bronchus and has studs on the outer wall to prevent stent dislodgement. Several modifications of this design are currently available. For example, the Hood stent (Hood Laboratories, Pembroke, MA) is a smooth Silastic stent that has a distal or proximal flange, rather than studs, for prevention of stent migration. Also, stents are available in a Y configuration for deployment in both the distal trachea and main stem bronchi. A further evolution in design philosophy is the silicone Dynamic Stent (AG Kernan, Germany), the anterior wall of which is reinforced with metal hoops. The posterior wall is not reinforced and is meant to mimic the dynamics of the membranous trachea.37 A clear advantage of the Silastic stents is that they may be repositioned or removed easily. This is in contrast to the EMS, which, once expanded, become incorporated into the airway wall and are essentially permanent. However, one disadvantage of the Silastic stents is that rigid bronchoscopy is required for deployment. Our standard technique is to load both the stent and a large-bore chest tube over a rigid bronchoscope. The chest tube serves as a pusher to deploy the stent in the appropriate location. For Y-shaped stents, the shorter limb for the right main stem bronchus is invaginated into the stent lumen. The rigid scope is then passed through the tracheal limb and out the left main stem bronchial limb. The stent is then deployed with the chest tube, and a biopsy forceps is passed through the stent to push out the right bronchial limb (Fig. 18-5). Another technique involves the use of a Fogarty balloon catheter to guide appropriate deploy-

1/21/2008 10:51:26 AM

240

Section 2 Upper Airway

A

B

C

D

E

F

FIGURE 18-6 A covered Ultraflex stent. The ends of the stent are uncovered to allow the metal lattice to incorporate into the airway.

ment of the bronchial limbs, although this is often a cumbersome exercise. A potential complication of Silastic stents is the propensity for mucus to become inspissated between the wall of the stent and the airway. This is especially problematic in the case of T stents that open at the level of a tracheostomy site. The loss of the natural humidification of the inspired air leads to significant mucus impaction on the plastic stent. As a consequence, it is common for patients with Silastic T stents to require multiple bronchscopies for cleaning or replacement. Patients with completely endotracheal/endobronchial stents have far fewer problems; in these cases, humidified air and mucolytic nebulizers are usually sufficient to prevent mucus impaction. EMSs are less prone to the entrapment of inspissated secretions because the ratio of their inner to outer diameter is very low. Another advantage of metal stents is that they can be deployed with a flexible bronchoscope. As a consequence, conscious sedation alone may be used, although in practice we prefer general anesthesia, both for patient comfort and to allow precise stent placement. The major disadvantage of metal stents is that they become embedded by scar tissue within a few weeks and at that time are essentially permanent. Several designs of metal stents are currently available. Two popular designs are the Wallstent and the Ultraflex stent. Both expand automatically when released from their deployment system. Both are available in covered and uncovered versions. In the covered version, the stent is lined with polyurethane except at the proximal and distal ends (Fig. 18-6). The lining is meant to retard ingrowth of the stent by tumor. The ends of the stent are uncovered to allow the metal lattice to incorporate into the airway, minimizing the possibility of migration. The covered portion of the stent may also be used to occlude tracheobronchial and tracheoesophageal fistulas. Metal stents are deployed in the following manner (Fig. 18-7). Under fluoroscopy, metal markers are placed on the patient’s chest wall to delineate the proximal and distal ends of the stricture. A guidewire is then passed through the working channel of the bronchoscope. The length of the stricture is measured, and a stent is selected that will allow at least 1 cm to extend onto normal airway at either end. The scope is then withdrawn, and the stent and delivery catheter are passed over the guidewire. Radio-opaque markers at both ends of the stent allow for precise positioning before deployment. The deployment catheter is removed by pulling a suture, and the stent then automatically expands to the diam-

Ch018-F06861.indd 240

FIGURE 18-7 Deployment of an Ultraflex stent. A, A flexible bronchoscope is used to identify the location of the obstruction. B, A stent is selected so that there is at least 1 cm of uncovered stent on either side of the stricture. C, A flexible guidewire is passed across the stricture. D, The stent and delivery catheter are passed over the guidewire. E, A suture is pulled that allows the stent to expand. F, The stent has been deployed across the stricture.

eter of the airway. A stent placed too far distally may be repositioned by grasping the proximal end with a biopsy forceps and pulling gently. It is usually more difficult to reposition a stent that has been placed too far proximally. On occasion, it may be necessary to dilate the stent with a balloon to allow better apposition to the airway, although this is rarely required. It is also possible to overlap stents if necessary, such as in the trachea and proximal bronchus. A final design that incorporates some of the advantages of both the Silastic stent and the EMS is the PolyFlex stent (Boston Scientific, Natick, MA). The PolyFlex stent is a covered stent made of self-expanding Silastic. An advantage of this design is that the ratio of inner to outer diameter is much lower than in traditional silicone stents. Also, migration of the PolyFlex stent is prevented by the radial force of the stent itself, so that it is not necessary to use studs such as those on the outside of a Dumon stent, which, on occasion, can adhere to the airway, making stent removal more difficult. However, the smooth, inert surface of the PolyFlex stent may lead to a higher rate of stent migration. No large series investigating the PolyFlex stent have been reported, so it is difficult to determine whether the advantages of this design are more than just theoretical.

CONCLUSION No single intervention is suitable for all patients with endobronchial obstruction. The treating physician needs to be comfortable with several techniques and also needs to understand the appropriate roles of surgery, chemotherapy, and radiation therapy in these patients. In general, patients with obstruction of a proximal airway, such as the trachea or a main stem bronchus, are more likely to benefit from intervention than those with obstruction of a distal airway. For patients with primarily endoluminal tumor, both PDT and laser ablation are acceptable options, depending on tumor location and patient preference. Other options, such as cryosurgery or brachytherapy, may also be appropriate, although few centers have significant experience with these modalities.

1/21/2008 10:51:26 AM

Chapter 18 Interventional Bronchoscopy for the Management of Airway Obstruction

Placement of a stent is usually reserved for patients with extrinsic airway compression. KEY REFERENCES McCaughan J, Williams T: Photodynamic therapy for endobronchial malignant disease: A prospective fourteen year study. J Thorac Cardiovasc Surg 114:940, 1997.

Ch018-F06861.indd 241

241

Moghissi K, Dixon K, Stringer M, et al: The place of bronchoscopic photodyamic therapy in advanced unresectable lung cancer: Experience of 100 cases. Eur J Cardiothorac Surg 5:1-6, 1999. Stout R, Barber P, Burt P, et al: Clinical and quality of life outcomes in the first United Kingdom randomized trial of endobronchial brachytherapy (intraluminal radiotherapy) vs. external beam radiotherapy in the palliative treatment of inoperable non-small cell lung cancer. Radiotherapy Oncol 56:323-327, 2000.

1/21/2008 10:51:27 AM

Benign Conditions chapter

19

CONGENITAL ANOMALIES: VASCULAR RINGS Carl Lewis Backer Constantine Mavroudis Robert D. Stewart Lauren Holinger

Key Points ■ The diagnosis of a vascular ring requires a high index of suspicion

from the treating clinicians. ■ These children typically present with noisy breathing and varying

■

■

■

■

■

degrees of respiratory distress. Older children may present with dysphagia. We believe that a computed tomographic (CT) scan with contrast is the single best diagnostic study to confirm the diagnosis and to define the anatomy. Patients who have a double aortic arch or a right aortic arch with left ligamentum are typically approached through a left thoracotomy incision. The vascular ring is divided between vascular clamps. We treat innominate artery compression syndrome through a right anterolateral thoracotomy with suspension of the innominate artery to the posterior sternum. Pulmonary artery sling is repaired through a median sternotomy approach with the use of cardiopulmonary bypass. Patients with pulmonary artery sling are evaluated for the frequently associated tracheal stenosis (>50%), which is a significant part of the pathophysiology. Optimal outcomes for these patients depend on a close collaboration among the cardiovascular/thoracic surgery, otolaryngology, anesthesia, and intensive care unit teams.

Congenital malformations of the aortic arch system cause symptomatic tracheal and esophageal compression. These congenital anomalies are commonly referred to as vascular rings. Depending on the degree of compression, they can cause a continuum of symptoms ranging from dramatic airway distress in the newborn to subtle swallowing disorders in the adolescent. The age at presentation and the severity of the symptoms depend mostly on the tightness of the ring. This, in turn, is related chiefly to the anatomy of the ring. The nomenclature for vascular rings has been standardized by the International Nomenclature and Database Committee for Pediatric Cardiac Surgery.1 The four primary vascular ring classifications are double aortic arch, right aortic arch with left ligamentum, innominate artery compression, and pulmonary artery sling (Table 19-1). Each of the different vascular rings has anatomic variations, some of which are much more common than others. Double aortic arch and right aortic arch with left ligamentum form anatomically complete rings. Innominate artery compression syndrome and pulmonary

artery sling are not true complete anatomic rings, but they have a clinical presentation, diagnostic evaluation, and operative strategy similar to those of complete vascular rings; hence, both categories are considered as a single group. Almost all vascular rings require surgical intervention. The surgical approach varies depending on the precise anatomy of the ring. We have come to rely on multislice CT scanning with contrast as the single best diagnostic tool to identify the anatomy (Backer et al, 2005).2 In most patients, vascular ring repair leads to almost complete resolution of symptoms after a period of time.3 This chapter reviews the significant historical events in vascular ring surgery, the embryology and pathology of vascular rings, the clinical presentation and diagnostic evaluation, the surgical management, and the postoperative care and outcomes.

HISTORICAL NOTE Dr. Robert E. Gross is considered the father of vascular ring surgery. Gross was chief of surgery at Boston (Massachusetts) Children’s Hospital from 1947 to 1967. Gross not only reported the first successful repair of a vascular ring but conceptualized this repair 14 years before the actual clinical procedure (Gross, 1945).4 Before his surgical residency, Gross completed a pathology residency. In 1931, he performed an autopsy on a 5-month-old infant. The child had, he wrote, [W]heezing respirations since birth and had recently developed difficulty in swallowing. At this [autopsy] examination a ring of blood vessels was found encircling the intrathoracic portion of the esophagus and trachea in such a way that the esophagus was indented from behind, whereas the trachea was compressed on its anterior surface. The pathological findings at once suggested that a division of some part of the so-called “vascular ring” during life would probably have relieved the pressure on the constricted esophagus and trachea (Gross, 1945).4 This recollection, published in a surgical report in the New England Journal of Medicine in 1945, illustrates Gross’ thought process years before he performed the first successful vascular ring operation, the division of a double aortic arch in a 1-year-old child. In that same report, Gross postulated division of the ligamentum as treatment for patients with a right aortic arch if the ring is completed by a ligamentum arteriosum or patent ductus arteriosus.

242

Ch019-F06861.indd 242

1/21/2008 10:52:22 AM

Chapter 19 Congenital Anomalies: Vascular Rings

Three years later, Gross was the first to suspend the innominate artery to the posterior sternum to treat innominate artery compression syndrome.5 This syndrome occurs when the innominate artery, as it traverses through the mediastinum to the right subclavian artery, crosses over the trachea and compresses the trachea anteriorly, causing respiratory distress particularly with feeding. In 1953, Willis J. Potts performed the first successful repair of a pulmonary artery sling (Potts et al, 1954).6 This operation was performed at Children’s Memorial Hospital, Chicago, Illinois, on a 5month-old child with wheezing, dyspnea, and intermittent episodes of cyanosis. Potts operated on the child without a definite diagnosis and discovered that the left pulmonary TABLE 19-1 Classification of Vascular Rings and the CMH Experience: 1946-2006 Type of Vascular Ring

N

Anatomically Complete Double aortic arch Right aortic arch with left ligamentum

120 103

Anatomically Incomplete Innominate artery compression Pulmonary artery sling Total CMH, Children’s Memorial Hospital, Chicago, Illinois.

85 36 344

243

artery originated from the right pulmonary artery, compressing the trachea like a sling as it coursed to the left lung. That operation by Potts started a long tradition of caring for children with vascular rings at Children’s Memorial Hospital and led to the clinical series of almost 400 patients upon which this chapter is based.

EMBRYOLOGY AND PATHOLOGY Dr. Jesse Edwards, when he was at the Mayo Clinic, postulated that the double aortic arch system is an intermediate stage between the embryonic aortic arches and the fully developed aorta.7 The hypothetical intermediate double aortic arch system has two arches, one on the right side and one on the left side of the trachea. There is also a ductus arteriosus on each side. Figure 19-1 shows the embryonic aortic arches. All human embryos start with six pairs of aortic arches.8 These are connected by the primitive ventral and dorsal aorta. The development of the normal left aortic arch and all types of vascular rings results from deletions and preservations of specific segments of the rudimentary aortic arch complex.9 In almost all cases, the first, second, and fifth aortic arches regress. The third aortic arch on each side becomes the carotid artery. On the right side, the dorsal contribution to the sixth arch usually disappears. On the left side, it persists as the ductus arteriosus. A branch from the ventral bud of the sixth aortic arch on each side meets the lung bud to form the pulmonary artery. The subclavian arter-

FIGURE 19-1 Embryonic aortic arch development. Six pairs of aortic arches originally develop between the dorsal and ventral aorta. The first, second, and fifth arches regress. Preservation or deletion of various segments of the rudimentary arches results in either a double aortic arch, a right aortic arch, or the so-called normal left aortic arch. Ao, aorta; CCA, common carotid artery; L, left; M, main; PA, pulmonary artery; R, right; SA, subclavian artery. (FROM BACKER CL, MAVROUDIS C: VASCULAR RINGS AND PULMONARY ARTERY SLING. IN MAVROUDIS C, BACKER CL [EDS]: PEDIATRIC CARDIAC SURGERY, 3RD ED. PHILADELPHIA, MOSBY ELSEVIER, 2003, PP 234-250.)

Ch019-F06861.indd 243

1/21/2008 10:52:23 AM

244

Section 2 Upper Airway

ies develop from the seventh intersegmental arteries arising from the dorsal aorta. The fourth aortic arch becomes the ascending aorta and transverse aortic arch. Normally, the right fourth arch involutes, and the patient is left with the usual arrangement of a left-sided aortic arch. If both arteries persist, a double aortic arch (vascular ring) is formed. If the right fourth arch persists and the left fourth arch involutes, then the other most common complete vascular ring, a right aortic arch with left ligamentum, is formed. The sidedness of the aortic arch in the infant is determined by the relationship of the apex of the aortic arch to the trachea.

Double Aortic Arch If both the right and left fourth arches persist, a double aortic arch system is formed (Fig. 19-2). The right-sided arch is more commonly dominant. In our series, the right aortic arch was dominant in 75% of the patients, the left aortic arch was dominant in 18%, and in 7% the arches were equal in size (Backer et al, 2005).2 The carotid and subclavian arteries arise separately from their respective arches. The arches pass around the trachea and esophagus on either side and then join to form the descending aorta, producing an anatomically complete vascular ring.

anatomic configurations of right aortic arch (Figs. 19-3 and 19-4). These are commonly referred to as retroesophageal left subclavian artery (66%) and mirror-image branching (34%).2,10 The anatomic vascular ring is completed by the ligamentum arteriosum, which connects the descending thoracic aorta to the pulmonary artery. Hence, the ring configuration in both includes the right aortic arch, the pulmonary artery, and the ligamentum. In patients with a retroesophageal left subclavian artery, the ligamentum arteriosum almost always arises from the descending thoracic aorta, completing a vascular ring. If there is mirror-image branching, the ligamentum arteriosum can arise from either the descending thoracic aorta or the anterior left innominate artery. If the ligamentum arises from the left innominate a vascular ring is not formed (Fig. 19-5). The congenital cardiac anomalies tetralogy of Fallot and truncus arteriosus each have a 30% incidence of right aortic arch formation. Frequently, patients have mirror-image branching with an anterior ligamentum and do not have a complete vascular ring.

Pulmonary Artery Sling

If the right fourth arch persists with involution of the left fourth arch, a right aortic arch occurs. There are two primary

Formation of a pulmonary artery sling requires two embryologic abnormalities to occur.11 First, the left lung must capture its arterial supply from the right sixth arch instead of the left sixth arch. Second, these connections must occur caudad rather than cephalad to the developing tracheobronchial tree.

FIGURE 19-2 Double aortic arch. This illustration shows a dominant right arch with a smaller but patent left arch. Note the separate origins of the right and left carotid and subclavian arteries. LCA, left carotid artery; LSA, left subclavian artery; MPA, main pulmonary artery; RCA, right carotid artery; RSA, right subclavian artery.

FIGURE 19-3 Right aortic arch, left ligamentum, retroesophageal left subclavian artery. The vascular ring is formed by several components: the right aortic arch, the main pulmonary artery (MPA), and the ligamentum arteriosum. LCA, left carotid artery; LSA, left subclavian artery; RCA, right carotid artery; RSA, right subclavian artery.

Right Aortic Arch With Left Ligamentum

Ch019-F06861.indd 244

1/21/2008 10:52:28 AM

Chapter 19 Congenital Anomalies: Vascular Rings

FIGURE 19-4 Right aortic arch, left ligamentum, mirror-image branching. Note left innominate artery. The vascular ring is formed by the same components as in Figure 19-3, but the left subclavian artery has an anterior origin from the left innominate artery. LCA, left carotid artery; LSA, left subclavian artery; MPA, main pulmonary artery; RCA, right carotid artery; RSA, right subclavian artery.

FIGURE 19-5 Right arch, mirror-image branching with ligamentum from innominate artery. There is a space between the ligamentum and the descending aorta, and a vascular ring is not formed. LCA, left carotid artery; LSA, left subclavian artery; MPA, main pulmonary artery; RCA, right carotid artery; RSA, right subclavian artery.

The anatomic origin of the left pulmonary artery is then from the posterior aspect of the right pulmonary artery instead of from the main pulmonary artery. The left pulmonary artery courses posteriorly around the right main bronchus and then between the trachea and esophagus. This forms a sling that compresses primarily the right main stem bronchus and the posterior distal trachea (Fig. 19-6). For unknown reasons, there is a strong embryologic association between a pulmonary artery sling and complete cartilage tracheal rings that cause tracheal stenosis. This has been referred to as the ringsling complex.12

Left Aortic Arch, Aberrant Right Subclavian Artery

Innominate Artery Compression The innominate artery compression syndrome occurs when the innominate artery compresses the anterior trachea as it courses from left to right within the superior mediastinum.5 Although there is a suspicion that these patients have a more distal than usual takeoff of the innominate artery from the aorta, this has not been proven. It remains unexplained why some patients develop severe tracheal compression and tracheomalacia from innominate artery compression and others do not.13 Some patients may be more prone to tracheomalacia than others.

Ch019-F06861.indd 245

245

Note that the diagnosis of left aortic arch with aberrant right subclavian artery was not included in the table of vascular rings because this vascular anomaly is not a complete anatomic vascular ring, and in addition it almost never causes symptoms in children. The patients have a normal left-sided aortic arch but do not have a right innominate artery. The right subclavian artery has an independent origin from the descending thoracic aorta. This artery then courses through the mediastinum posterior to the esophagus on its way to the right arm (Fig. 19-7). Gross first reported ligation and division of the right subclavian artery in a 4-month-old child with dysphagia.14 Over the years, however, we and others have learned that this posterior indentation of the esophagus almost never truly cause symptoms. In fact, this is the most common vascular anomaly of the aortic arch system and occurs in 0.5% of all humans.15 Because this anomaly is so common, it has been (wrongly) considered the cause of vague swallowing symptoms in patients who have not been fully evaluated. This has led to the label, dysphagia lusoria, which refers to a so-called trick of nature. In actuality, the aberrant right subclavian artery is almost always not the true cause of

1/21/2008 10:52:36 AM

246

Section 2 Upper Airway

FIGURE 19-6 Pulmonary artery sling. The aorta has been cut away to reveal the right pulmonary artery (RPA) and the anomalous origin of the left pulmonary artery from the RPA. The left pulmonary artery courses posterior to the trachea, anterior to the esophagus, and anterior to the descending thoracic aorta on its way to the left lung. LCA, left carotid artery; LSA, left subclavian artery; MPA, main pulmonary artery; RCA, right carotid artery; RSA, right subclavian artery.

FIGURE 19-7 Aberrant right subclavian artery. The right subclavian artery (RSA) originates from the descending thoracic aorta distal to the takeoff of the left subclavian artery (LSA). It courses posterior to the esophagus as it travels to the right arm. LCA, left carotid artery; MPA, main pulmonary artery; RCA, right carotid artery.

a child’s dysphagia. (The exception to this is the adult with an aneurysmal dilation of the origin of the right subclavian artery, Kommerell’s diverticulum.16,17) At Children’s Memorial Hospital, we have not operated on a patient with this diagnosis since 1973.

was moved posteriorly during an arterial switch operation. The third group had airway compression caused by a pincer effect between a posteriorly malposed and enlarged ascending aorta and the descending aorta (Fig. 19-8A,B). These patients are treated by suspending the ascending aorta to the posterior sternum.21

Rare Vascular Rings Because of the infinite variety of potential deletions and preservations of the primitive embryonic aortic arch system, there are a number of very rare vascular ring anomalies that have been reported. A few of these occur more frequently than others and need to be considered in the diagnostic evaluation. One group is those with a left aortic arch, a right descending thoracic aorta, and right ligamentum arteriosum.18 Another rare vascular ring is a right aortic arch, right ligamentum, and absent left pulmonary artery.19 One of the largest reports of rare vascular rings was by Robotin and colleagues at Marie Lannelongue Hospital, Paris.20 They noted three unusual groups of patients with tracheoesophageal compression. One group comprised those with a circumflex aorta, consisting of a right aortic arch, a left-sided descending thoracic aorta, and a left ligamentum arteriosum. A second group of patients had airway compression after the ascending aorta

Ch019-F06861.indd 246

CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION Patients with vascular rings present with symptoms related to the esophagus, the trachea, or both (Table 19-2). In general, those patients who present earlier in life have respiratory symptoms caused by tracheal compression. The symptoms of dysphagia tend to present later in life, when the child begins to eat solid food. However, some patients can go for a very long time with tight compression of the esophagus before they demonstrate symptoms of dysphagia. The most common symptoms related to the tracheal compression are stridor (noisy breathing), a distinctive barky cough, wheezing, recurrent respiratory tract infections, respiratory distress, and apnea. Neonates and infants may hold their head in an opisthotonic position, in which the head is hyperextended to splint the trachea and lessen the anatomic effect of the

1/21/2008 10:52:44 AM

Chapter 19 Congenital Anomalies: Vascular Rings

247

AAo MPA

AAo

MPA DAo

DAo

A

B

FIGURE 19-8 A, CT scan of a child with a malposed ascending aorta. The left main bronchus was completely occluded by the pincer effect between the ascending and descending aorta. AAo, ascending aorta; DAo, descending aorta; MPA, main pulmonary artery. B, The child was treated by pexing the ascending aorta to the sternum after median sternotomy and closure of the ventricular septal defect.

TABLE 19-2 Symptoms of Patients With Anatomically Complete Vascular Rings (Double Aortic Arch, Right Aortic Arch With Left Ligamentum) Symptom

Patients (%)

Stridor

57

Recurrent upper respiratory tract infection

27

Cough

21

Dysphagia

15

Respiratory distress

10

Ventilator preoperatively

9

tracheal compression. The group of patients with innominate artery compression syndrome frequently have apneic episodes that are related to swallowing. The bolus of food pressing on the soft posterior trachea within the restrictive confines of the anterior vascular compression lead to a reflex apneic or cyanotic episode. Many patients who are later found to have a vascular ring are initially treated for asthma with bronchodilators and topical or systemic steroids. Another common finding in retrospect in these patients is frequent episodes of croup in infancy. One of the difficulties with the diagnosis of vascular rings is that they are relatively rare compared with other causes of respiratory and swallowing symptoms, such as asthma, croup, and reflux. Hence, the diagnosis requires a high index of suspicion on the part of the clinician when evaluating infants and children with respiratory or swallowing symptoms. Another important consideration in the evaluation of vascular rings is to proceed toward the diagnosis in a stepwise fashion, without ordering excessive examinations that simply continue to confirm the diagnosis. The two primary objectives are to establish the diagnosis of a vascular ring and to determine the anatomy precisely enough for the surgeon to proceed with an appropriate operative intervention.

Ch019-F06861.indd 247

The primary diagnostic modalities that we have emphasized are the chest radiograph, the barium esophagogram, CT with contrast, and bronchoscopy (Backer et al, 2005).2 Some centers recommend magnetic resonance imaging (MRI) instead of CT. For reasons discussed later, CT is our current diagnostic procedure of choice. Cardiac catheterization is no longer employed as a diagnostic tool for patients with a vascular ring. Echocardiography is used as a screening device because of the relatively high association of cardiac anomalies in patients with vascular rings. However, echocardiography has not been used to reliably establish the diagnosis of a vascular ring, except for pulmonary artery sling. The chest radiograph is an important first diagnostic step.22 It helps to rule out other causes of wheezing or noisy respiration, such as an aspirated foreign object or pneumonia. The critical site to be evaluated with the chest radiograph is the location of the aortic arch. As mentioned in the section on embryology, the apex of the aortic arch and its relationship to the trachea determine whether the patient has a left or a right aortic arch. Careful analysis for this knob adjacent to the trachea can be a very important clue leading toward the diagnosis of a vascular ring. The indentation of the lateral wall of the trachea caused by a right aortic arch can be quite dramatic and quickly leads to the correct diagnosis. Although, historically, a barium swallow was the next study typically obtained, in the current era our preference is to proceed directly to a CT scan with contrast if there is a high index of suspicion for a vascular ring. The barium esophagogram shows indentation in the esophagus caused by the components of the vascular ring. However, this does not yield the exact anatomy of the vascular ring. Therefore, the barium esophagogram is currently most useful as a screening device if there is a relatively low index of suspicion for a vascular ring. A completely normal barium esophagogram rules out double aortic arch and right aortic arch with left ligamentum. However, the patient may still have innominate artery compression syndrome or a pulmonary artery sling. Pulmonary artery sling is the only lesion that causes anterior compression

1/21/2008 10:52:52 AM

248

Section 2 Upper Airway

the scan demonstrates the anatomic origin of the left pulmonary artery from the right pulmonary artery and its course between the trachea and the esophagus. The CT scan also evaluates the trachea for the frequently associated tracheal stenosis. For many years we have recommended routine bronchoscopic evaluation of all patients with a vascular ring. A recent review of our patients confirmed this clinical judgment because there was a frequent association of vascular ring with tracheomalacia and bronchomalacia, and an infrequent but important association with tracheal stenosis secondary to complete cartilaginous tracheal rings, in addition to the occasional finding of aspirated foreign bodies, tracheal right upper lobe, and other conditions (Backer et al, 2005).2 The Toronto

of the esophagus on a barium esophagogram, but this can sometimes be subtle and difficult to recognize. Although there are differences of opinion as to whether a CT scan with contrast or an MRI is the best imaging study for anatomic detail, our service has elected to use the CT scan, for several reasons. The CT scan using the new multislice, multidetector technology can be obtained in a very short period of time, often less than 20 seconds. This is a great advantage, particularly for a patient with a compromised airway. The MRI study in contrast can take 30 to 60 minutes. Keeping an infant or small child quiet for this lengthy period is sometimes difficult and often requires general anesthesia instead of conscious sedation. Furthermore, one often obtains an MRI of marginal quality. The excellent anatomic detail provided by the CT scan and the potential for three-dimensional reconstruction makes this our current recommended diagnostic procedure of choice (Backer et al, 2005).2 This is also the recommendation of the Marie Lannelongue group (Lambert et al, 2005).23 The most specific diagnostic sign seen on the CT scan is the four-artery sign (Fig. 19-9).22 This sign is seen on coronal sections obtained superior to the aortic arch. The four arteries are the two dorsal subclavian arteries and the two ventral carotid arteries, which are evenly spaced around the trachea. This occurs both in patients with a double aortic arch and in those with a right aortic arch and left ligamentum. In patients with innominate artery compression syndrome, the CT scan demonstrates anterior compression of the trachea (Fig. 19-10A-C). The degree of tracheal compression can be accurately assessed with the CT scan. In patients with a pulmonary artery sling,

E

FIGURE 19-9 Four-artery sign. CT scan of a 3-year-old child with a right aortic arch with left ligamentum. Note the four brachiocephalic vessels grouped symmetrically around the trachea (arrows). Also note the dilated proximal esophagus (E).

Trachea

Esophagus

Esophagus

B

A

Trachea

Esophagus

C

Ch019-F06861.indd 248

FIGURE 19-10 Innominate artery compression syndrome. A-C, Serial CT scanning cuts in a 5-month-old infant with severe stridor. The tracheal lumen completely disappears in B. On bronchoscopy, the lumen was found to be almost completely occluded. The child responded very well to innominate arteriopexy.

1/21/2008 10:52:52 AM

Chapter 19 Congenital Anomalies: Vascular Rings

group has also emphasized the importance of preoperative bronchoscopy.24 The other interesting diagnostic point arising from our recent review was that 12% of patients with vascular ring in our series had an associated congenital intracardiac anomaly (Backer et al, 2005).2 In the Toronto series, this figure was 17%.24 For that reason, we recommend an echocardiogram preoperatively for all patients with a diagnosis of vascular ring. In the past, there was hope that echocardiography could be useful for diagnosis of the anatomy of a vascular ring. However, this has not turned out to be the case, for several reasons. One is that echo windows are not always able to completely visualize the arch system, especially in patients who have hyperinflated lungs due to tracheal compression. A second reason is that vascular ring segments without a lumen cannot be displayed. One exception to this generality is patients who are admitted with tracheal stenosis due to complete tracheal rings and suspected pulmonary artery sling. The echocardiogram is very useful for demonstrating a pulmonary artery sling because color flow Doppler can be used to show the blood flowing away from the right pulmonary artery and then coursing around the trachea to reach the left lung.25 Many of these patients are in a precarious state in the intensive care unit, and a bedside echocardiogram is preferable to moving the patient to the CT scanner. In summary, the diagnostic tool of choice for infants and children with suspected vascular ring at our institution is a CT scan with contrast. All patients with vascular rings need to have preoperative echocardiography to rule out an associated intracardiac lesion and should have preoperative or intraoperative bronchoscopy to evaluate the tracheobronchial tree.

SURGICAL MANAGEMENT Almost all patients diagnosed as having a vascular ring associated with clinical symptoms require an operation. Early surgical intervention helps to prevent complications that arise from attempted medical management of a vascular ring. Patients with vascular rings can develop severe upper respiratory tract infections or pneumonia requiring intubation and prolonged hospitalization. The use of prolonged intubation, tracheostomy, and nasogastric feeding tubes can lead to erosion of the esophagus into the tracheobronchial tree or the aorta.26 Late complications of an unrepaired vascular ring can include both aortic dissection and aneurysm formation.17,27 There are several principles of vascular ring surgery. One principle is that the vascular structures that are divided need to be divided between vascular clamps and fine Prolene suture. Simple ligation and division techniques are not acceptable because they can be associated with crushing of the vessel, leading to delayed hemorrhage. This principle was dramatically noted by Gross in his report regarding 1610 patent ductus arteriosus divisions: Eleven children were operated upon satisfactorily for ductus closure by ligation. The twelfth was a fourteenyear-old girl also treated by ligation. She was well at the time of hospital discharge. Two weeks after that, there was a party for her at her home. While dancing

Ch019-F06861.indd 249

249

with friends, she suddenly collapsed on the floor and was instantly dead! The family permitted an autopsy examination, which showed that the ductus ligature had cut through, permitting massive hemorrhage. I never again ligated a ductus. All subsequent patients were handled by careful local dissection placing double clamps on the ductus, then cutting the ductus in half and meticulously closing each end by suturing. This became the standard technique, giving completely satisfactory results. It was used with total satisfaction up through the last ductus operation I performed, which was number 1610 in March 1972.28 The last operative death from a vascular ring at our institution occurred in 1959, when a simple ligature slipped from the divided proximal end of a divided subclavian artery.29 Division and oversewing between vascular clamps is the standard we recommend. Another principle is to leave the pleura open after the vascular ring division. In our series, those patients who underwent reoperation for their vascular ring (almost all from other centers) had the pleura closed at the time of the original operation. This can lead to adhesions in the area of the divided vascular ring, resulting in recurrent symptoms.

Double Aortic Arch In patients with a dominant right aortic arch (75% of the cases), the vascular ring can be approached through a left thoracotomy. In patients with a dominant left aortic arch and a left-sided descending aorta, it is usually safer to approach the patient through a right thoracotomy.30 In patients with balanced arches and a left-sided descending aorta, the operative exposure is best achieved through a left thoracotomy. If the descending thoracic aorta is on the right, consideration may be given to a right thoracotomy. In all of the cases, however, the precise anatomic detail relayed by a CT scan with contrast can be used to make the decision before entering the operating room. In our series, we have used left thoracotomy (n = 113), right thoracotomy (n = 3), and median sternotomy (n = 4 patients, all with associated cardiac anomalies). The left thoracotomy can be performed with a musclesparing technique, sparing both the serratus anterior and the latissimus dorsi muscle. The chest is entered through the fourth intercostal space. The lung is retracted anteriorly. The posterior mediastinum is examined, and in almost all cases the supreme intercostal vein is doubly ligated and divided. The mediastinal pleura is opened superiorly and inferiorly. This incision is made parallel to the vagus nerve and is kept in a middle position between the anterior vagus nerve and the posterior thoracic duct. Deviation anteriorly can injure the vagus nerve and the associated descending recurrent laryngeal nerve; deviation posteriorly can injure the ascending recurrent laryngeal nerve or the thoracic duct. The arch anatomy must be carefully defined before any surgical intervention. In almost all cases, the left subclavian artery is identified and encircled with a vessel loop. The descending thoracic aorta may not be visible if there is a right-sided descending aorta, and instead the esophagus will be noted.

1/21/2008 10:52:53 AM

250

Section 2 Upper Airway

Tracing the esophagus superiorly leads to the components of the aortic arch system comprising the vascular ring. Most frequently, the left or anterior aortic arch is the smaller of the two arches. The left arch is most commonly the one that is divided. The left arch may be atretic where it inserts into the descending thoracic aorta. The vascular ring caused by the double aortic arch is released by dividing the smaller of the two arches, almost always at the posterior insertion site into the descending thoracic aorta (Fig. 19-11A,B). Before the arch is divided, temporarily occlude it and carefully examine the right and left upper extremity and carotid pulses with pulse oximetry, blood pressure cuff, or palpation to assess for any obstruction of flow to these structures. Again, preoperative mapping based on the CT scan helps to ensure arch division at a site that does not interrupt flow to the carotid or subclavian arteries. The arches are occluded between vascular clamps. We usually use the Potts ductus clamps. The arch is then divided, and the stumps are oversewn with fine Prolene suture (6-0, 7-0 Prolene). In most patients, in addition to the left aortic arch, the left ligamentum must also be divided. This is to prevent converting a double aortic arch to a right aortic arch with left ligamentum. However, if the left aortic arch is dominant, often the ligamentum remains anterior and is not a component of the vascular ring. In some cases in which the left arch is

divided distally and a ligamentum inserts onto the anterior left arch, the ligamentum travels anteriorly and again does not participate in any vascular compression. After arch division and ligamentum division, adhesive bands on the trachea and esophagus are divided. The recurrent laryngeal nerve encircles the ligamentum arteriosum in almost all cases. This is very carefully identified and preserved throughout the procedure. After the procedure, the mediastinal pleura is left open, which is an important technical point. Many patients who have required reoperation at our institution had had their pleura closed at the time of the original operation. This led to scar tissue and, consequently, recurrent tracheoesophageal compression. In most patients, the chest can be closed without the use of a chest tube. The pleural space can be evacuated of air with a small suction catheter passed through the corner of the incision. This can be pulled out as the incision is being closed during a Valsalva maneuver by the anesthesiologist. Almost all patients with a double aortic arch can be extubated in the operating room. We currently transfer all vascular ring patients to the intensive care unit for observation the first night after the surgery. Usually, they are transferred to the regular ward on the second postoperative day. The mean hospital stay for a patient with an isolated double aortic arch is now 2 days. It is important to counsel the parents that the

FIGURE 19-11 A, Double aortic arch, right arch dominant. B, Sutured stumps of divided distal left aortic arch. LCA, left carotid artery; LSA, left subclavian artery; RCA, right carotid artery. (FROM POTTS WJ, GIBSON S, ROTHWELL R: DOUBLE AORTIC ARCH: REPORT OF TWO CASES. ARCH SURG 57:227-233, 1948.)

Ch019-F06861.indd 250

1/21/2008 10:52:53 AM

Chapter 19 Congenital Anomalies: Vascular Rings

patient’s noisy respirations may not completely diminish until approximately 1 year has passed since the operation. Patients typically have a significant improvement immediately after the operation and then a slow improvement in their symptoms of tracheal compression as the trachea regains its cartilaginous form over the next several months. These patients can be difficult to manage in the initial time period after extubation. They may have tachypnea and retractions, which can be treated with humidified oxygen and, in some cases, heliox.31 Another helpful postoperative technique is to keep the patient mildly sedated with intravenous (IV) fentanyl, morphine, Ativan (lorazepam), or Versed (midazolam). This calms the patient and prevents a vicious cycle of pain, increased respiratory rate, worsened tracheomalacia, increased work of breathing, and more tachypnea. Often there is a sense from the intensive care unit team, anesthesiologists, or both that the patient requires reintubation. This impulse needs to be resisted as much as possible because the great majority of these patients improve significantly in the first several hours after the procedure. Often, by the next morning, their breathing is completely comfortable and they have no respiratory issues whatsoever. Other modalities that we have used in the postoperative period are inhaled corticosteroids, nebulized albuterol, and IV and inhaled steroids. In our experience, patients who can remain extubated for the first several hours after the surgery almost always maintain that status and go on to steady improvement in their airway. It is only the rare patient who requires prolonged intubation, and it is even rarer for a patient to require tracheostomy.

Right Aortic Arch With Left Ligamentum In many respects, surgical management for patients with right aortic arch with left ligamentum is similar to that for those with double aortic arch patients. For these patients, we use a left thoracotomy with a muscle-sparing incision (n = 90). The exceptions are those patients with associated cardiac anomalies being repaired via median sternotomy (n = 13) and those with situs inversus who have a left aortic arch with a right ligamentum, for whom we use a right thoracotomy (n = 4). The pleura is opened, and the ligamentum arteriosum is identified. The descending thoracic aorta can be on the right or left side. The origin of the left subclavian artery from the descending aorta is usually immediately adjacent to the origin of the ligamentum arteriosum. The ligamentum is double-clamped with vascular clamps, transected, and the stumps oversewn with running Prolene. Alternatively, if enough length can be achieved, the ligamentum can be doubly ligated with silk ligatures reinforced with Prolene sutures. Because the ligamentum does not have a lumen, it can be divided with much less fear of hemorrhage than a patent arch in a case of double aortic arch. Again, adhesive bands around the esophagus are divided. The pleura is left open. The chest is closed without a chest tube, using a small suction catheter to evacuate air. These patients are also monitored for 24 hours in the intensive care unit and are usually discharged in 2 days. An interesting subgroup of patients with right aortic arch with left ligamentum are those who have an aneurysmal dila-

Ch019-F06861.indd 251

251

tion of the base of the left subclavian artery. This aneurysmal dilation is a remnant of the left fourth aortic arch and was first identified by a German radiologist named Kommerell. This diverticulum may actually enlarge to the point at which it independently compresses the esophagus or the trachea, or both.17 Our initial experience with this condition was with referred patients who had had a ligamentum division with a Kommerell’s diverticulum left in place (Fig. 19-12A-C). These patients developed recurrence of their symptoms. These symptoms were successfully treated by a reoperation in which the Kommerell’s diverticulum was excised and the left subclavian artery was transferred to the left carotid artery (see Fig. 19-12B,C) (Backer et al, 2002).32 We have now performed this operation (Kommerell’s diverticulum resection, left subclavian transfer) as a reoperation in 10 patients and as a primary operation in 8 patients. Although some surgeons have repaired this condition by simply resecting the diverticulum and ligating and dividing the left subclavian artery, we strongly believe that the left subclavian artery needs to be reimplanted. We are aware of one case in which a patient had simple ligation/division and subsequently developed symptomatic subclavian steal syndrome. Another rare group of patients are those that have the socalled circumflex aorta.20 These patients have a right aortic arch, a left ligamentum, and a left-sided descending thoracic aorta. The aorta crosses posteriorly behind the trachea, and sometimes the tracheal compression is not significantly relieved by division of the ligamentum. In a small group of patients, a so-called aortic uncrossing procedure may be required. We have performed that operation in one patient at Children’s Memorial Hospital. Robotin reported that 3 of 468 vascular ring patients had this procedure.20 This operation is performed through a median sternotomy with the use of hypothermic cardiopulmonary bypass and circulatory arrest. The aorta is divided and reanastomosed anterior to the trachea to re-create a normal left aortic arch. These patients tend to have significant tracheomalacia and take a considerable amount of time to recover.

Innominate Artery Compression Syndrome Gross was the first to report suspension of the innominate artery to the posterior aspect of the sternum.5 He performed this operation through a left anterolateral thoracotomy, a technique that is still used at Boston Children’s Hospital.33 At Children’s Memorial Hospital, we have preferred a small right inframammary anterolateral thoracotomy. The number of patients undergoing an innominate arteriopexy per year at Children’s Memorial Hospital is illustrated in Figure 19-13. We have now operated on 85 children with this diagnosis. A significant increase in the number of cases performed occurred when we converted to general anesthesia for rigid bronchoscopy and an increased number of cases were diagnosed (late 1970s, early 1980s). However, with more careful patient selection, we currently operate on only 1 or 2 patients per year. The patients who are operated on now all have had significant symptoms such as apnea or cyanotic spells with feeding. These patients are evaluated carefully to make sure that they do not have other causes for their apparent

1/21/2008 10:53:06 AM

252

Section 2 Upper Airway

LCA RSA

LCA RSA

RCA

RCA LSA

LSA

Kommerell’s diverticulum

A

B

RSA

RCA LSA

LCA

C FIGURE 19-12 A, Kommerell’s diverticulum. The origin of the left subclavian artery (LSA) in some patients with a right aortic arch is an aneurysmal embryologic remnant of the left fourth arch. This is called Kommerell’s diverticulum. B, Resection of Kommerell’s diverticulum through a left thoracotomy. A vascular clamp partially occludes the descending thoracic aorta at the origin of Kommerell’s diverticulum. The clamp on the LSA is not illustrated. Kommerell’s diverticulum has been completely resected. C, The completed repair. The orifice at which Kommerell’s diverticulum was resected is usually closed primarily. The orifice can also be patched with polytetrafluoroethylene if necessary (inset). The LSA has been implanted into the side of the left common carotid artery with fine running polypropylene sutures. LCA, left carotid artery; RCA, right carotid artery; RSA, right subclavian artery. (FROM BACKER CL, HILLMAN N, MAVROUDIS C, HOLINGER LD: RESECTION OF KOMMERELL’S DIVERTICULUM AND LEFT SUBCLAVIAN ARTERY TRANSFER FOR RECURRENT SYMPTOMS AFTER VASCULAR RING DIVISION. EUR J CARDIOTHORAC SURG 22:64-69, 2002. COPYRIGHT ELSEVIER 2002.)

Ch019-F06861.indd 252

1/21/2008 10:53:06 AM

Chapter 19 Congenital Anomalies: Vascular Rings

253

Innominate Arteriopexy at Children’s Memorial Hospital, 1977-2006

Number of Patients

18 15 12 9 6 3 2004

2001

1998

1995

1992

1989

1986

1983

1980

1977

0

FIGURE 19-13 Innominate arteriopexy: Changing incidence of operative procedures at Children’s Memorial Hospital from 1977 to 2006.

FIGURE 19-15 Pulmonary artery sling. The left pulmonary artery (LPA) originates from the right pulmonary artery (RPA) and courses between the esophagus and trachea to reach the left lung. Lateral view (inset) shows anterior compression of the esophagus. MPA, main pulmonary artery.

FIGURE 19-14 Innominate arteriopexy: Through a right anterolateral thoracotomy, the right lobe of the thymus is excised. The innominate artery is pexed to the posterior sternum with three pledgeted mattress sutures. Ao, aorta; Inn. A., innominate artery; L. Inn. V., left innominate vein; PA, pulmonary artery; RA, right atrium; SVC, superior vena cava.

life-threatening events, such as gastroesophageal reflux or laryngeal abnormalities.34 For innominate arteriopexy, we use three separate pledgeted sutures. One is placed on the aortic arch itself, one is placed at the junction of the aortic arch with the innominate artery, and one is placed on the innominate artery. The sutures are then brought up to the posterior aspect of the sternum, passed through another pledget, and carefully tied (Fig. 19-14). The innominate artery cannot be overly elevated, or the pexy will cause obstruction of flow to the right innominate artery. This can be assessed by a blood pressure cuff and pulse oximetry monitoring on the right arm. We recently had to reoperate on a patient who, over a period of time, lost the pulse in the right carotid and brachial arteries due to complete occlusion of the innominate artery after the arteriopexy. Through a median sternotomy incision we were able to release the vessel, restoring the pulse, without

Ch019-F06861.indd 253

performing a vascular reoperation. An alternative technique for patients with innominate artery compression syndrome has been described by Bailey and Hawkins, who use a median sternotomy incision with division and transfer of the innominate artery to a site that is more right and anterior to the original origin.35 We have not used this technique because it sacrifices the active suspending mechanism obtained by pulling the innominate artery anteriorly while leaving the adhesions between the trachea and the innominate artery intact.36

Pulmonary Artery Sling Pulmonary artery sling occurs when the left pulmonary artery originates from the right pulmonary artery instead of from the main pulmonary artery (Fig. 19-15). Successful repair of this vascular anomaly was first performed by Willis J. Potts at Children’s Memorial Hospital in 1953.6 Potts divided the left pulmonary artery near its origin from the right pulmonary artery, removed it from the space between the trachea and esophagus, and reanastomosed it anterior to the trachea. This operation was performed through a right thoracotomy in a patient with an unknown diagnosis who had severe respiratory distress. Potts coined the term pulmonary artery sling to describe the findings. The child that Potts operated on survived the operation and had relief of tracheobronchial compression. However, on long-term follow-up, the left pulmonary artery was occluded.37 Occlusion or stenosis of the left pulmonary artery was, in fact, a significant problem in the early series of patients undergoing surgery for pulmonary artery sling.11

1/21/2008 10:53:14 AM

254

Section 2 Upper Airway

The approach for the next patient operated on at our hospital for pulmonary artery sling was through a median sternotomy incision. Then followed a series of six patients operated on through a left thoracotomy. The approach in these early cases was to transect the left pulmonary artery at its origin from the right pulmonary artery and then reimplant it into the main pulmonary artery at a site approximating the normal left pulmonary artery origin. However, our experience, and that of others, was that this technique was associated with a high incidence of left pulmonary artery stenosis. Since 1985, we have approached all of these patients through a median sternotomy and used cardiopulmonary bypass to facilitate the anastomosis (Backer et al, 1999).38 Cardiopulmonary bypass with a single atrial cannula allows decompression of the cardiac structures, and aortic cross-clamping is not required. The right pulmonary artery is mobilized, and the origin of the left pulmonary artery from the right pulmonary artery is divided between vascular clamps. The left pulmonary artery stump is oversewn. The left pulmonary artery must be dissected in the space between the trachea and the esophagus and then identified in the left posterior pericardium. The left pulmonary artery is then brought up into the pericardium anterior and to the left of the trachea. The left pulmonary artery is implanted into the main pulmonary artery at a site that approximates normal anatomy (Fig. 19-16). This is almost always at the site of the ligamentum arteriosum, which is ligated and divided, or adjacent to the ligamentum. We have performed this anastomosis with interrupted sutures using absorbable PDS suture to help prevent late vascular stenosis from either a circumferential suture line or the suture material itself. A total of 36 patients with pulmonary artery sling have now been operated on at Children’s Memorial Hospital, including 28 with cardiopulmonary bypass. All patients repaired with cardiopulmonary bypass have a patent left pulmonary

artery. We have assessed the flow to the left lung with a nuclear perfusion scan, and the mean flow to the left lung is 35%. The only deaths after operation for pulmonary artery sling have occurred in those patients with associated long-segment tracheal stenosis; the overall mortality rate is 8% (3 of 36 patients). Note that tracheal stenosis was present in 21 (58%) of the 36 patients. In all patients with a diagnosis of pulmonary artery sling, the trachea is evaluated for complete tracheal rings by CT scan or bronchoscopy, or both. We have treated a total of 66 patients with tracheal stenosis with several different approaches, including pericardial patch tracheoplasty (n = 28), tracheal resection (n = 13), slide tracheoplasty (n = 5), and the tracheal autograft technique (n = 20). Tracheal resection is our current procedure of choice if the length of the tracheal stenosis is less than one third of the total tracheal length.39 For patients with a longer stenosis (long-segment congenital tracheal stenosis, defined as >50% of the tracheal stenosis) we prefer the slide tracheoplasty technique or tracheal autograft.40 The issue of tracheal stenosis is addressed by Dr. Grillo in Chapter 21. An alternative technique to division and reimplantation of the left pulmonary artery is the translocation technique.41 This involves translocating the left pulmonary artery anterior to the trachea by dividing the trachea and not performing a vascular anastomosis. As noted earlier, many of these patients have an associated tracheal stenosis and require a tracheal procedure, frequently a tracheal resection. When the tracheal resection is performed, the left pulmonary artery can be translocated anterior to the trachea in an effort to repair the pulmonary sling anomaly. One problem with this technique is that, because of the severe rightward takeoff of the left pulmonary artery from the right pulmonary artery, even when the pulmonary artery is translocated anteriorly it still may be kinked and compressed because of its anomalous origin. Van Son and colleagues compared the reimplantation technique and the translocation technique and found that the translocation technique was associated with a significantly higher incidence of left pulmonary artery stenosis.42 The postoperative course of a patient with a pulmonary artery sling is essentially completely determined by the degree of tracheal involvement. The neonate with severe tracheal stenosis who requires an associated tracheal operation may require intubation and ventilation for longer than 1 week. Patients who have only associated tracheomalacia can often be extubated within 24 to 48 hours after the procedure. In our experience, the newborn patients appear to take considerably longer to be extubated than the older patients. The oldest patient in our series to undergo pulmonary artery sling repair was 10 years of age. This patient had a marked improvement in her pulmonary function testing after pulmonary artery sling repair.

FIGURE 19-16 Illustration of a repaired pulmonary artery sling. The left pulmonary artery (LPA) has been implanted into the main pulmonary artery (MPA) anterior to the trachea. The origin of the LPA from the right pulmonary artery (RPA) has been oversewn with interrupted Prolene suture.

SUMMARY

Ch019-F06861.indd 254

The outcome of infants with vascular rings after surgical repair is very good. The diagnosis of a vascular ring requires a high index of suspicion on the part of the treating clinicians.

1/21/2008 10:53:21 AM

Chapter 19 Congenital Anomalies: Vascular Rings

These children typically present with noisy breathing and varying degrees of respiratory distress. We believe that a CT scan with contrast is the single best diagnostic study to confirm the diagnosis and to define the anatomy. Patients with a double aortic arch or a right aortic arch with left ligamentum are typically approached through a left thoracotomy incision, with division of the vascular ring between vascular clamps. We treat innominate artery compression syndrome through a right anterolateral thoracotomy, with suspension of the innominate artery to the posterior sternum. Pulmonary artery sling is repaired through a median sternotomy approach with the use of cardiopulmonary bypass. With this technique, left pulmonary artery patency has been extremely high. All patients with pulmonary artery sling need to be evaluated for the frequently associated tracheal stenosis (>50%) which is a significant part of the pathophysiology. Optimal outcomes for these patients depend on a close collaboration among the cardiovascular-thoracic surgery, otolaryngology, anesthesia, and intensive care unit teams.

Ch019-F06861.indd 255

255

KEY REFERENCES Backer CL, Hillman N, Mavroudis C, Holinger LD: Resection of Kommerell’s diverticulum and left subclavian artery transfer for recurrent symptoms after vascular ring division. Eur J Cardiothorac Surg 22:6469, 2002. Backer CL, Mavroudis C, Dunham ME, Holinger LD: Pulmonary artery sling: Results with median sternotomy, cardiopulmonary bypass, and reimplantation. Ann Thorac Surg 67:1738-1745, 1999. Backer CL, Mavroudis C, Rigsby CK, Holinger LD: Trends in vascular ring surgery. J Thorac Cardiovasc Surg 129:1339-1347, 2005. Gross RE: Surgical relief for tracheal obstruction from a vascular ring. N Engl J Med 233:586-590, 1945. Lambert V, Sigal-Cinqualbre A, Belli E, et al: Preoperative and postoperative evaluation of airways compression in pediatric patients with 3-dimensional multislice computed tomographic scanning: Effect on surgical management. J Thorac Cardiovasc Surg 129:1111-1118, 2005. Potts WJ, Holinger PH, Rosenblum AH: Anomalous left pulmonary artery causing obstruction to right main bronchus: Report of a case. JAMA 155:1409-1411, 1954.

1/21/2008 10:53:24 AM

chapter

POSTINTUBATION INJURY

20

Michael A. Maddaus F. Griffith Pearson

Key Points ■ Posintubation injury, either from cuff or directly from the tube, is

the most common cause of benign stenosis of the upper airway. ■ Blood supply to the trachea is segmental. ■ Dyspnea on exertion with stridor is the usual symptom of airway

stenosis. Patients are frequently misdiagnosed as having asthma. ■ Dilation, laser, and segmental resection and primary anastomosis

of stenotic lesions of the airway are the primary methods of management of benign stenosis. ■ Arterial wall repair is contraindicated in tracheal innominate artery fistula. ■ Single-stage repair of tracheoesophageal fistulas with tracheal resection and repair of esophageal defect and muscle interposition is the primary method of treatment.

Postintubation injury is the most common cause of benign, stenotic lesions of the upper airway. Such injury may be produced by either translaryngeal intubation or tracheostomy. After tracheostomy, stenotic lesions may be the result of injury at the level of the tracheostoma or the inflatable cuff. Full-thickness erosion of the tracheal wall occasionally results in tracheoinnominate artery fistula or tracheoesophageal fistula. Translaryngeal intubation may result in damage to the glottis, the subglottic segment, or the trachea itself. It usually follows periods of prolonged intubation with a translaryngeal cuffed tube, in an intensive care setting, for the support of ventilation. The laryngeal injury most commonly occurs in the posterior interarytenoid area and restricts abduction of the vocal cords. Significant subglottic lesions usually result in circumferential stenosis.

HISTORICAL NOTE Postintubation injury is a rare complication of tracheostomy with an uncuffed tube. It only became a significant problem with the advent of mechanical ventilatory support using cuffed endotracheal tubes. Trendelenburg reported on the use of a cuffed tracheostomy tube in 1871,1 but the use of cuffed tubes did not become widespread until the introduction of mechanical ventilators and cuffed tracheostomy tubes during the 1952 epidemic of poliomyelitis in Europe.2 During the early 1960s, postintubation tracheal stenosis was increasingly recognized as a frequent, life-threatening complication of assisted ventilation with cuffed tubes. A prospective study initiated in 1967 identified a 17.5% incidence of functionally

significant tracheal stenosis in 153 surviving patients who had undergone mechanical ventilation with cuffed tracheostomy tubes.3,4 In that study, most of the postintubation strictures occurred either at the stoma or under the inflatable cuff; the most severe lesions were seen at the cuff level. Subsequent investigation focused on the mechanisms of injury. It soon became apparent that the greatest damage occurred because of pressure ischemia under the smallvolume, noncompliant inflatable cuffs that were used during those early years. In 1969, Cooper and Grillo showed that mucosal ulceration with exposure of underlying cartilage occurred within as few as 48 hours of cuff inflation.5,6 Inflation pressures of up to 100 mm Hg were necessary to obtain an airtight seal with these low-volume cuffs.7 Such high pressures deformed the wall of the trachea until the tracheal contour matched that of the balloon. Having identified the pathophysiology of these injuries, Grillo and associates8 then developed a large-volume, lowpressure cuff—a prototype for the cuff design in current use on tracheostomy and endotracheal tubes. This large-volume floppy cuff has a resting diameter of about 3 cm. Inflation with 2 to 6 mL of air usually fills the trachea, allows the cuff to conform to the normal tracheal shape, and provides an airtight seal. Most importantly, cuff inflation pressures are in the same range as the peak airway pressures generated during mechanical ventilation. These early experiences took place during a time when translaryngeal intubation was maintained for relatively brief periods preceding tracheostomy. During the 1970s, however, translaryngeal intubation was rarely maintained beyond 48 to 72 hours. But since then, the ongoing trend has been to maintain patients with longer and longer periods of nasotracheal or orotracheal intubation. Although the incidence of post-tracheostomy stenosis is now markedly reduced, longer periods of translaryngeal intubation (often for 2 or 3 weeks) have increased the incidence of postintubation stenosis at the level of the glottis and subglottic segment. HISTORICAL READINGS Andrews MJ, Pearson FG: The incidence and pathogenesis of tracheal injury following cuffed tube tracheostomy with assisted ventilation: An analysis of a two year prospective study. Ann Surg 173:249, 1971. Cooper JD, Grillo HC: Experimental production and prevention of injury due to cuffed tracheal tubes. Surg Gynecol Obstet 129:1235, 1969. Grillo HC, Cooper JD, Geffin B, et al: A low pressure cuff for tracheostomy tubes to minimize tracheal injury: A comparative clinical trial. J Thorac Cardiovasc Surg 62:898, 1971.

256

Ch020-F06861.indd 256

1/21/2008 10:55:09 AM

Chapter 20 Postintubation Injury

Lassen HCA: Management of life-threatening poliomyelitis. London, E & S Livingstone, 1956. Trendelenburg F: Beitrage zu den Operationen an den Luftwegen. Arch Klin Chir 12:112, 1871. Webb WR, Ozdemir IA, Ikins PM, et al: Surgical management of tracheal stenosis. Ann Surg 179:819, 1973. Wolman IJ: Congenital stenosis of the trachea. Am J Dis Child 61:1263, 1941. Yamaguchi M, Yoshihiro O, Hosokawa Y, et al: Concomitant repair of congenital tracheal stenosis and complex cardiac anomaly in small children. J Thorac Cardiovasc Surg 100:181, 1990.

BASIC SCIENCE Anatomy The trachea extends from the inferior cricoid margin to the carina, averages between 10 and 13 cm in length, and contains between 18 and 22 cartilaginous rings (∼2 rings per centimeter of length). The average internal diameter of the trachea is 2.3 cm. Tracheal blood supply arises from the inferior thyroid arteries above and from the bronchial circulation below. Anastomotic branches of these vessels enter the trachea at its posterolateral margin and are segmental in their distribution. In view of this segmental distribution, the tracheal circulation may be impaired if circumferential mobilization is extended beyond 1 to 2 cm (Fig. 20-1). The anatomy of the recurrent laryngeal nerves at the level of the larynx and upper airway is illustrated in Figure 20-2. A knowledge of this anatomy is essential during any circumferential resection of the trachea or adjacent cricoid cartilage. These nerves ascend in the tracheoesophageal groove; they pass deep to the inferior border of the cricothyroid muscle, posterior to the cricothyroid articulations. Only above this

257

level do the nerves enter the laryngeal musculature. Thus, it is possible to preserve the recurrent nerves when operating in the region of the posterior cricoid cartilage as long as the posterior perichondrium or a thin shell of posterior cricoid plate is maintained intact. The anatomy of the larynx and upper airway is provided in detail in Chapter 15. But to provide a clear understanding of postintubation injury at the level of the larynx and subglottis, some details of anatomy warrant emphasis. The larynx has three key cartilaginous components that provide skeletal support for the airway and vocal function: thyroid cartilage, cricoid cartilage, and paired arytenoid cartilages. The thyroid cartilage is the outer protective cover for the entire larynx; it articulates inferiorly with cricoid cartilage at the cricothyroid joints (Fig. 20-3). The cricoid cartilage is the first full ring of the upper airway; it has an anterior arch that is similar in height to a normal tracheal ring. This arch expands into a broadly based posterior plate or rostrum. Both the inner and the outer aspects of the cricoid cartilage are covered with a stout perichondrial layer, which may be an important feature during segmental resection and primary reconstruction at the subglottic level. The paired arytenoid cartilages rest on the superior surface of the posterior cricoid plate; they articulate with the cricoid cartilage at the cricoarytenoid joints. The vocal ligaments or cords arise behind, from the vocal processes of the arytenoid cartilages, and attach anteriorly to the thyroid cartilage (see Fig. 20-3). The action of vocal muscles on the arytenoid cartilages produces changes in both position and tension of the vocal cords. These changes are responsible for important aspects of the normal range of vocal function and require full mobility of the cricoarytenoid articulations. The subglottic Superior laryngeal nerve

Inferior thyroid artery

Internal branch

Lateral tracheal artery

External branch

Inferior constrictor muscle Esophageal artery

Ansa galeni

Bronchial artery

FIGURE 20-1 The important features of tracheal circulation. The most robust contributions to this circulation arise from the inferior thyroid arteries above and the bronchial arteries below. These vessels anastomose in an arcade lying along the posterolateral margins of the trachea. They feed the submucosal plexus by intercartilaginous branches, which are segmental in distribution.

Ch020-F06861.indd 257

Recurrent laryngeal nerve FIGURE 20-2 The course and anatomic relationships of the recurrent laryngeal nerves at the upper trachea and cricoid levels.

1/21/2008 10:55:09 AM

258

Section 2 Upper Airway

larynx begins immediately below the vocal folds; it extends to the inferior margin of the cricoid cartilage and the interface with the first tracheal ring. The subglottic space is the narrowest part of the upper airway aside from the larynx. The subglottis has an internal diameter between 1.5 and 2 cm. It is surrounded throughout by the cricoid cartilage, which provides rigid structural support for both the subglottic and the laryngeal apertures.

Pathophysiology The mechanisms by which translaryngeal intubation or tracheostomy produce airway injury are diverse: the injury may

Arytenoid cartilage Posterior cricoid plate Cricothyroid joint

Thyroid cartilage

Vocal cords

Anterior arch of cricoid

Recurrent nerve FIGURE 20-3 Anatomic relationships of the thyroid, cricoid, and arytenoid cartilages.

be secondary to the inflated cuff, to the rigid walls of the endotracheal tube, or to the site where a tracheostomy or cricothyroidotomy was created.

Cuff Level Injury Various degrees of injury under the inflatable cuff are the most frequent complication after either endotracheal intubation or tracheostomy. These injuries occur despite the widespread use of high-volume, low-pressure floppy cuffs. Normal capillary perfusion pressure is no more than 20 to 30 mm Hg; hyperinflation of the cuff may lead to circumferential mucosal ischemia and ulceration. Schmidt and associates9 demonstrated that mucosal injury occurred within as little as 4 hours after overinflation of a floppy cuff. When mucosal ulceration occurs, the underlying tracheal cartilage is exposed and may become devitalized and disappear. After extubation, healing usually occurs with the formation of a firm fibrous scar, which results in varying degrees of stenosis (Fig. 20-4). Circumferential injury and cicatrix produce the most extreme degrees of obstruction. On occasion, relatively little collagen is laid down in an area of destruction, which results in a malacic segment. Full-thickness erosion of the anterior wall of the mediastinal trachea may result in a tracheoinnominate artery fistula. Destruction of the posterior membranous trachea may lead to a tracheoesophageal communication. To minimize cuff-related injury, cuff pressure should be maintained below 20 mm Hg whenever possible. Alternatively, the cuff may be inflated to a level that provides an airtight system. Repeated checks are needed to ensure that minimal inflation is maintained. In some cases, if the peak airway pressures are unduly high, maintaining a small leak

STRICTURES—CUFF LEVEL

Normal

Stricture

A

B

FIGURE 20-4 A, Diagram of a typical concentric, fibrous stricture caused by injury under the inflatable cuff. These lesions are usually short (no more than 2 to 3 cm). B, A CT reconstruction shows a relatively tight cuff stricture.

Ch020-F06861.indd 258

1/21/2008 10:55:10 AM

Chapter 20 Postintubation Injury

around the cuff may be desirable to avoid hyperinflation injury.

Stomal Injury Stomal stenosis was clearly identified as a complication of cuffed tracheostomy tubes in a prospective study by Pearson.3,4 In that early study, functionally significant stomal stenosis occurred in 12% of surviving patients who had undergone mechanical ventilation with cuffed tracheostomy tubes. The incidence of stomal stenosis increased significantly with the use of larger-diameter tracheostomy tubes. The smallest possible tube that is satisfactory for ventilation and tracheal toilet is recommended for either translaryngeal intubation or tracheostomy. Factors promoting stenosis include (1) pressure and leverage on the stomal margins because of fixation of the ventilator attachments and (2) pooling of infected secretions above the inflated tracheostomy cuff. After extubation, the stomal margins fall together, with some degree of anterolateral scarring and loss of luminal diameter in every patient (Fig. 20-5A). In functionally significant lesions, the defect is usually triangular, with preservation of the posterior membranous airway (see Fig. 20-5B-D). On occasion, airway obstruction may be due to soft inflammatory granulations that develop at the margins of the stoma or adjacent to areas of ulceration under the inflatable cuff. These granulations may result in airway obstruction after decannulation but are usually easily managed by endoscopic removal. To prevent stomal stenosis, the tracheostomy tube should be introduced at the level of the second or third rings; the least amount of cartilage should be removed that still permits introduction of the tube. The smallest possible tracheostomy tube that still provides a satisfactory airway is recommended. Ventilator connections that result in leverage and pressure at the stoma margins, with tubing supports and swivel connectors, will reduce lateral pressure at the stoma.

Glottic and Subglottic Injury After translaryngeal intubation, the most common site of injury is the larynx or subglottis. This area is the narrowest part of the upper airway, and the subglottic segment is circumferentially encased with unyielding cricoid cartilage. At the level of the glottis and vocal cords, endolaryngeal tubes most commonly damage the posterior structures with ulceration of the interarytenoid mucosa. This damage may be followed by the development of a fibrous, posterior glottic stenosis. The most severe of these posterior injuries may involve one or both cricoarytenoid joints. The usual result is limited abduction of one or both vocal cords. Subglottic stenosis is more commonly due to circumferential injury, resulting in a concentric stricture, rather than to an isolated posterior injury. Occasionally, anterior commissure stenosis is produced at the glottic level. It is very likely that some degree of mucosal injury occurs in most patients undergoing translaryngeal intubation for more than a few days. But after recovery, most have reasonably normal function. One prospective study, by Whited,10 demonstrated a relationship between the incidence of posterior commissure stenosis and the length of time the patient

Ch020-F06861.indd 259

259

was intubated: stenosis occurred in 12% of patients intubated for longer than 11 days. Colice and associates11 and Kastanos and colleagues12 reported a high incidence of acute injury (mucosal ulceration) but did not find a clear correlation between the length of intubation and the degree of significant, permanent injury. Subglottic injury may occur when the tracheostomy is incorrectly placed through the first tracheal or anterior cricoid ring. It may also occur after cricothyroidotomy. In each of these circumstances, the anterior cricoid arch may be lost with variable degrees of injury of the posterior cricoid plate.

POSTINTUBATION STENOSIS Clinical Presentation Symptoms usually appear within 1 to 6 weeks after extubation. This delay in onset is due to the ongoing development and maturation of scar tissue at the site of airway damage. Both Andrews and Pearson, in 1971,13 and Couraud and Hafez, in 1987 (Couraud and Hafez, 1987),14 noted that 80% of patients develop symptoms within 3 months of extubation. Less commonly, symptoms may be evident immediately after extubation. Very rarely, symptoms may be delayed for up to several years. Dyspnea on exertion is the primary symptom in all patients with clinically significant obstruction. Depending on the degree of stenosis, dyspnea ranges from a mild limitation of breathing during heavy exertion to marked shortness of breath even during minimal activity such as speaking. In most patients, narrowing of the lumen to less than 50% of its normal cross-sectional area results in dyspnea only with significant exertion. Narrowing of the lumen to less than 25% of its normal cross-sectional area will usually produce dyspnea and stridor at rest; such patients may be at risk of asphyxia from an inability to clear secretions. Stridor is classically accentuated during inspiration. However, if the obstructive lesion is in the mediastinal trachea (where intrathoracic pressure increases with exhalation against an obstruction), or if there is associated tracheomalacia, the stridor may be predominantly expiratory. Frequent, but often overlooked, symptoms of severe airway narrowing are a characteristic brassy cough and difficulty raising secretions. Not infrequently these symptoms lead to a misdiagnosis of asthma or bronchitis. Because of the respiratory disorder that initiated the need for assisted ventilation, symptoms can understandably be attributed to manifestations of the original respiratory illness. The correct diagnosis is frequently delayed. Symptom severity usually correlates with the degree of stenosis. If the lumen is greater than 5 mm (in adults), symptoms may be subtle and diagnosis difficult. Such patients may accept a modest loss of exercise tolerance without seeking help. In patients whose pulmonary function is already impaired (e.g., those with chronic obstructive pulmonary disease), a lesser reduction in airway diameter may result in more severe symptoms. Stridor is present only when the diameter of the airway is reduced to 4 or 5 mm; it may be

1/21/2008 10:55:11 AM

260

Section 2 Upper Airway

C

D

FIGURE 20-5 A, A contrast tracheogram shows the typical anterolateral defect at the stomal level after tracheostomy. This relatively mild lesion was asymptomatic. B, This diagram illustrates the mechanism of stomal stenosis. A variable segment of cartilage is lost anteriorly (top); with healing, the remaining margins fall together and form scar tissue in the anterolateral parts of the trachea. The membranous trachea is relatively preserved, and a triangular stenosis results. C and D, A CT reconstruction, front and side view, illustrating a severe stomal stenosis due to inward collapse of the lateral tracheal walls due to anterior defect.

Ch020-F06861.indd 260

1/21/2008 10:55:11 AM

Chapter 20 Postintubation Injury

noticeable only with exertion or during forcible inspiration and exhalation. Changes in vocal function occur with lesions involving the glottis. Patients with postintubation laryngeal injury and stenosis have variable degrees of hoarseness and loss of vocal power. Rarely, recurrent nerve injury occurs as a complication of tracheostomy and may be the cause of hoarseness.

Radiology Radiologic evaluation begins with plain posteroanterior and lateral chest radiographs. These radiographs provide information about the status of the lungs; on occasion, a narrowing in the airway may be obvious. Laryngeal stenosis and subglottic stenosis are rarely defined on plain chest radiograph. Stomal stenosis in the cervical airway is sometimes evident on plain film—at a level above the manubrium. The mediastinal airway is rarely defined accurately on plain chest films. Tomograms (anteroposterior and lateral) of the larynx, trachea, and main bronchi are useful, providing reasonably precise information about the location, length, and extent of the stenosis. Familiarity and expertise with tomography has declined owing to the increasing use of computed tomography (CT). CT provides accurate information about the location, length, and extent of narrowing. CT also demonstrates changes in the tracheal wall and adjacent soft tissues (information not provided by tomography or plain chest films). However, CT has lacked the ability to provide sagittal images comparable in accuracy to those of tomography. The recent development of helical (or spiral) CT using thin cuts (13 mm) with multiplanar reconstruction provides outstanding cross-sectional and sagittal images. Helical CT with thin cuts and multiplanar reconstruction may be particularly useful in evaluating lesions involving both the larynx and the subglottis. Dynamic magnetic resonance imaging can provide functional information about areas of potential malacia. A more detailed evaluation of radiology is provided in Chapter 16.

Bronchoscopy Bronchoscopy is a mainstay of evaluation. Much can be learned from flexible endoscopy under topical anesthesia. With the patient breathing spontaneously and able to vocalize, an assessment can be made of vocal cord function and the more distal airway dynamics during inspiration, expiration, forced expiration, and coughing. Segments of tracheomalacia may only be evident at such an examination. However, the examiner has no control over a critically obstructed airway when using a flexible bronchoscope. Unlike a rigid scope, a flexible scope cannot be used to maintain the airway, nor is the suction satisfactory in the presence of abundant or tenacious secretions lying distal to a point of obstruction. At some point in the evaluation of all patients with functionally significant stenosis, rigid bronchoscopy (conducted in an operating room, preferably with the patient under general anesthesia) is desirable. With the patient awake, vocal cord function and areas of malacia may be assessed with the rigid bronchoscope as well. It is possible to identify the exact anatomic location and diameter of the stenosis (including its position relative to the larynx above and the carina below)

Ch020-F06861.indd 261

261

and to assess the rigidity of the stenosed segment. During either rigid or flexible bronchoscopy, it is important to evaluate the status of the mucosa adjacent to the proximal and distal margins of the damaged segment. Most importantly, a tight and disabling stricture may be dilated at the time of rigid bronchoscopy: dilation may be initiated by passing gumtipped bougies through the scope, then passing progressively larger-diameter bronchoscopes fully through the stenosis until a safe and adequate airway has been obtained. Dilation allows safe and satisfactory relief of obstruction in almost all patients, for days or weeks. It also permits a more leisurely approach to planning subsequent care.

Treatment Emergency Care On occasion, patients with severe stenosis and disabling, life-threatening obstruction require emergency intervention. Treatment is initiated with humidified oxygen or a mixture of helium and oxygen (heliox). It also includes measures to reduce the inflammatory or edematous component of the obstruction (e.g., nebulized racemic epinephrine inhalation, intravenous steroid [a 500-mg bolus of Solu-Medrol], or corticosteroid-containing [Beclovent] inhalation). These measures can be undertaken while preparing for emergency bronchoscopy in the operating room. Rigid bronchoscopy, with general anesthesia, is preferable. The techniques of anesthesia are detailed in Chapter 17. In patients with postintubation strictures, it is almost always possible to obtain airway control using a rigid bronchoscope. Indeed, Couraud and Hafez14 have found it unnecessary to do emergency tracheostomies in these patients. If possible, every effort should be made to avoid tracheostomy: it will only complicate the pathology and may make subsequent surgery more difficult. In that rare instance when tracheostomy is deemed unavoidable, the tube should be introduced through an area of damaged trachea, so that the extent of any subsequent resection is not increased. Emergency resection has no role in the care of these patients.

Elective Care The options in elective care for patients with subglottic or tracheal stenosis include interval dilation, laser resection, internal stents, staged plastic reconstructions, circumferential resection and primary anastomosis, and permanent tracheostomy. Dilation. Dilation is useful to establish a safe airway at the onset of treatment. Additional interval dilation may be useful in maintaining the airway while acute inflammatory features of the original injury resolve and mature. Except for very short strictures (<0.5 cm long), dilation alone is rarely successful in restoring an adequate airway. In the occasional patient who is reluctant to undergo resection, repeated elective dilations may maintain a safe level of airway patency. The need for repeated, and often increasingly frequent, dilations usually convinces the patient of the need for surgical resection. Laser Resection. Laser resection has been popularized in recent years for managing many airway lesions. For benign

1/21/2008 10:55:12 AM

262

Section 2 Upper Airway

strictures, however, its benefit is almost always temporary. Only very short strictures are amenable to definitive management by laser resection. Such strictures are usually weblike lesions in which a four-quadrant laser incision may be successful (Fig. 20-6). In the subglottic region, laser resection is generally contraindicated because of the potential for damaging the underlying cricoid cartilage. Internal Stents. A stent is useful in the following circumstances: (1) as a temporary measure to avoid the need for repeated dilations while waiting for inflammation to subside or while waiting for the patient’s general condition to improve before definitive surgical resection and (2) as an alternative to permanent tracheostomy in patients who are not candidates for resection and primary anastomosis. Of the variety of stents available, a silicone T tube (Montgomery T tube) is most commonly used in the trachea. A Silastic T tube has the distinct advantage over open tracheostomy of maintaining both adequate humidification of the airway and normal speech. In cases of subglottic stenosis, the proximal arm of the T tube must be positioned with the open end lying just above the level of the vocal cords. In this position, the tube is remarkably well tolerated. Although the vocal cords are unable to function, patients are able to produce a “hypopharyngeal voice,” which is sufficient for reasonable communication. Although aspiration is common initially, it usually resolves completely within a few days or weeks. Aspiration may be a more difficult problem for some elderly patients or for patients with other pathologic defects or complications.

FIGURE 20-6 Photograph of a resected, short, postintubation stricture at the cuff level. This stricture was less than 5 mm long.

Ch020-F06861.indd 262

Three other stent options exist. The Gianturco Z stent (Cook Inc., Bloomington, IN) is a stainless steel monofilament self-expanding stent. Its use is not recommended for tracheal or subglottic stenoses because of the potential for tracheal erosion from the high radial force exerted by the stent. The Wallstent (Schneider Inc., Minneapolis, MN), a self-expanding wire mesh stent, exerts less radial force than the Gianturco stent, is available in larger sizes to fit the trachea, and is available with a silicone covering that will prevent ingrowth of tissue. In patients with tracheal stenoses or malacia, the Wallstent is an alternative to the Montgomery T tube. Its advantages are its stability within the airway, no external components, and the ability of the airway to epithelialize over the non–silicone-covered stents. Disadvantages include the inability to use these stents for lesions near the vocal cords and the potential challenge of removal by rigid bronchoscopy. Although experience is very limited, stents made of nitinol (a titanium alloy that has a temperaturedependent “shape memory effect”)15 may be of value in select patients with tracheal and subglottic stenoses and tracheomalacia.16,17 Staged Plastic Reconstruction. Staged plastic reconstruction, popularized by otolaryngologists, is most widely used to manage subglottic strictures. Most procedures involve vertical division of the anterior and posterior walls of the subglottic space (cricoid cartilage) and placement of some type of autogenous tissue graft between the divided ends of the cartilage. These steps are designed to achieve permanent enlargement of the subglottic airway. Grafts have been obtained from many sources, including free segments of bone or cartilage, as well as composite pedicled grafts. As recently as 1991, McCaffrey18 reported on the use of costal cartilage grafts placed in anterior vertical incisions in the thyroid and cricoid cartilages. Of 21 patients with isolated subglottic stenosis, 16 (76%) had a satisfactory postoperative airway. Five patients (24%) could not be extubated. Segmental Resection and Primary Anastomosis. Most functionally significant postintubation strictures are best managed by segmental resection and reconstruction with primary anastomosis. Most postintubation injuries involve relatively short segments (1-4 cm). They can be reliably managed by circumferential resection and end-to-end anastomosis, without resorting to special techniques of airway mobilization at the upper and lower ends of the trachea. On occasion, longer segments are damaged; it is usually possible to resect about half the length of the adult trachea if supraglottic and infracarinal mobilization techniques are also used. Details of operative technique (including indications, perioperative management, complications, and results) are provided in Chapter 28. Several principles for successful reconstruction by primary anastomosis warrant emphasis: 1. Accurate, preoperative identification of the precise level and length of the lesion to be excised is critical. Doing so is particularly important in the case of benign strictures. This information determines the operative exposure and anticipates the mobilizing procedures. Preoperative tomo-

1/21/2008 10:55:12 AM

Chapter 20 Postintubation Injury

grams and CT scans, combined with the findings at bronchoscopy, are most useful. 2. The tracheal margins at the level of the anastomosis should be as healthy as possible. When appropriate, acute mucosal inflammation should be allowed to subside before resection, and the excision should include all significantly diseased tissue. Both preoperative and postoperative tracheostomy should be avoided if possible because an open tracheostomy inevitably results in some degree of chronic inflammatory change. 3. It is essential to preserve the tracheal circulation and to avoid undue tension at the anastomosis. These surgical platitudes are, nevertheless, critical for obtaining a healthy, healing suture line. With the mobilization required for resection, it is important to preserve the segmental blood supply, which enters the trachea through a series of small, posterolateral branches. Once the lesion has been resected, the remaining tracheal ends should not be mobilized circumferentially for more than about 1 cm. Grillo (1979)19 clearly defined these contraindications to resection: 1. Continued need for, or high likelihood of, future ventilatory support 2. Medical inability to withstand operation (rarely a contraindication if the resection is manageable through a cervical incision) 3. Tracheal lesions requiring resection of lengths that cannot be technically reconstructed by primary anastomosis 4. Anticipation of a future tracheostomy and presence of certain neurologic diseases associated with repeated aspiration. Relative contraindications include the use of high-dose corticosteroids at the time of surgery and a history of prior radical local irradiation in the field of the resection.

RESULTS OF RESECTION AND PRIMARY ANASTOMOSIS In general, the results of resection and reconstruction by primary anastomosis for benign tracheal stenoses are excellent. We reported on 34 patients with benign postintubation strictures.20 In that series, there was one operative death, and results were unsatisfactory, but not fatal, for 3 other patients; results were good to excellent for the remaining 30 patients. In that early period, 7 patients developed restenosis requiring reoperation and resection, 5 of whom ultimately obtained a good result. Grillo19 reported on resection and primary anastomosis in 208 patients with postintubation strictures: 185 of those lesions were produced by cuffed tracheostomy tubes. Between 2 and 7 cm of trachea was resected. Overall results were good in 168 patients and satisfactory in 21; treatment failed in only 9 patients (4%). Both of these early reports19,20 concerned patients with postintubation strictures involving the trachea; only an occasional lesion extended above the lower border of the cricoid cartilage. Similarly, the results of resection and primary anastomosis in patients with subglottic stenosis are excellent. Using the technique of partial cricoid resection, preservation of recur-

Ch020-F06861.indd 263

263

rent nerves, and primary thyrotracheal anastomosis,21 we reported on 38 patients with isolated, benign subglottic stenosis.22 Our series had no operative mortality; all 38 patients were decannulated. Restenosis occurred in 2 patients, which was successfully managed by re-resection in 1 patient and by dilation and laser ablation of anastomotic granulation tissue in the other. Ultimately, therefore, all 38 patients had satisfactory results. In that same article,22 we reported on 16 patients with combined laryngeal and subglottic lesions managed by synchronous subglottic resection combined with laryngeal reconstruction. The care of these 16 patients was in collaboration with our otolaryngology department. Of the 16 patients, 15 were decannulated and maintained a satisfactory glottic and subglottic airway. The technique of partial cricotracheal resection with primary anastomosis has also been applied successfully to children with subglottic stenosis. Grillo23 reported on 80 patients with subglottic stenosis managed by segmental resection and primary thyrotracheal anastomosis. He used his own modified technique for subglottic resection and reconstruction. Of these 80 patients, 50 had postintubation injuries. There was one operative death. All 49 survivors improved; most had good to excellent results. None required long-term tracheostomy. Couraud and coworkers24 reported on a large number of postintubation injuries involving either subglottis alone or subglottis with concomitant laryngeal injury. Results were good to excellent in 95% of the patients; all were extubated. Patients with recurrent stenosis after resection and primary anastomosis are a particular challenge. Donahue and colleagues25 at Massachusetts General Hospital reported on 75 patients who underwent reoperations for restenosis of the trachea; 16 of these patients came from a group of 32 with unsuccessful primary repair (of 450 patients who underwent primary resections and reconstructions at that institution). The cause of the restenosis was often difficult to determine. In about 50% of the patients, the cause was believed to be secondary to excessive anastomotic tension and tracheal devascularization. Granulations were also thought to play a role, particularly in anastomoses performed with permanent (as opposed to absorbable) sutures. Clinically, postoperative restenosis became symptomatic within 1 to 2 weeks after the original operation. Donahue and colleagues25 emphasize the following points in caring for this complex group of patients: 1. Initial management should be conservative. Reoperation should be delayed until inflammation and fibrosis subside, typically 4 to 6 months. During this time, 50% of Donahue and colleagues’ patients were cared for by either observation or repetitive dilation. The remaining patients had airway obstruction that was unmanageable by dilation and were managed by either a T tube (preferred) or tracheostomy placed through the most damaged or stenotic portion of the airway. 2. Most reoperations can be accomplished through an anterior cervical collar incision (73/75). In 18 patients, a partial upper sternotomy was added for additional exposure.

1/21/2008 10:55:13 AM

264

Section 2 Upper Airway

3. Avoiding anastomotic tension is critical. A laryngeal release was used in 19 patients (15 suprahyoid, 4 thyrohyoid). A suprahyoid release is preferred because it results in less laryngeal dysfunction and aspiration). The major complication rate in Donahue and colleagues’ series was 39%. Anastomotic granulations (most secondary to permanent suture use) occurred in 15 patients and significant dysphagia occurred in 4. Both of these complications could be minimized by using absorbable sutures and avoiding thyrohyoid laryngeal release. There were two postoperative deaths (2.6%). Yet, the overall outcome of reoperative tracheal resection in this series was good (normal activity and good voice) in 59 patients (78.6%) and satisfactory (dyspnea on exertion and an adequate voice) in 10 (13.3%). Reoperation failed (necessitating permanent tracheostomy or T tube) in 4 (5.3%) patients. Donahue and colleagues25 emphasized that the selection of patients for reoperation is governed primarily by the surgeon’s judgment of the degree of anastomotic tension that re-resection would create. Patients considered to be at risk for excessive anastomotic tension are best treated with a permanent T tube or other endotracheal stent.

TRACHEOINNOMINATE ARTERY FISTULA Historical Note The first report of massive hemorrhage caused by a tracheoinnominate artery fistula (TIF) after tracheostomy was by Korte in 1897.26 The patient, a 5-year-old girl with diphtheria, died of exsanguinating hemorrhage. In 1924, Schlaepfer27 reviewed the literature regarding 115 patients with TIF; the incidence of TIF was 0.5% to 4.5% after tracheostomy. Couraud and associates28 reported detailed pathologic observations in 6 patients: 4 had fistulas due to circumferential tracheal erosion by the cuff, extending through the anterior wall into the innominate artery. The anterior wall of the trachea was adherent to the artery, and hemorrhage occurred

Overinflated balloon causing erosion 1

directly into the airway through a fistula measuring between 0.5 and 3.0 mm in diameter. In the other 2 patients, erosion occurred at the inferior border of the tracheal stoma because of pressure necrosis of the arterial wall against the undersurface of the tracheostomy tube. Of the 6 patients, 2 had a premonitory hemorrhage of bright red blood at 8 and 124 days, respectively, after tracheostomy. HISTORICAL REFERENCES Cooper JD: Tracheo-innominate artery fistula—successful management of three consecutive cases. Ann Thorac Surg 24:439-447, 1977. Couraud L, Favarel-Garrigues JC, Chevais G, et al: Cataclysmic creation of the tracheal hemorrhage following tracheostomy: Anatomical etiological and therapeutical consideration. Ann Chir Thor Cardiol 5:772, 1966. Korte W: Uber einige Seltenere nach Krankheiten nach der Tracheotomie wegen Diphtheritis. Arch Klin Chir 24:238, 1897. Schlaepfer K: Fatal hemorrhage following tracheotomy for laryngeal diphtheria. JAMA 82:1581, 1924.

Incidence and Pathophysiology Tracheoinnominate artery fistula is a rare, but frequently lethal, complication of intubation or tracheostomy. Nelems and colleagues reviewed the literature in 1988.29 Of 175 reported patients, only 24 survived (86% mortality rate). The mechanisms of postintubation TIF are shown in Figure 20-7. The most common cause is due to too low of a placement of the tracheal stoma; such placement allows the cannula to abut and erode the innominate artery. This mechanism of fistula formation is preventable by placing the stoma at the level of the second or third tracheal ring. The innominate artery normally lies at the level of the fifth or sixth tracheal ring behind the manubrium. In children and young adults, however, it may lie in the neck above the sternal notch. In such patients, mobilization of the arterial wall adjacent to the stoma must be avoided and the stoma must be placed to avoid possible contact and erosion.

Inferior surface of tracheal cannula causing erosion 2

Abnormally high innominate artery

3 Low placement of tracheostomy

FIGURE 20-7 A tracheoinnominate artery fistula may occur from erosion of the anterior wall under the inflatable cuff or at the level of the stoma because of pressure from the tracheostomy tube itself. In the latter case, the innominate artery courses above the manubrium in the neck or the tracheal stoma is created at too low a level.

Ch020-F06861.indd 264

1/21/2008 10:55:13 AM

Chapter 20 Postintubation Injury

Other causes of TIF include tracheal wall necrosis that is due to cuff hyperinflation, which results in erosion of the anterior tracheal wall into the innominate artery. A normally placed tracheostomy may occasionally erode the adjacent distal tracheal cartilage and ultimately abut the innominate artery, with subsequent fistula formation. TIF can complicate tracheal resection, extended laryngectomy, and prosthetic tracheal reconstruction. Arterial fistula after tracheal resection was reported by Grillo19 in 0.5% and by Deslauriers30 in 3.0% of tracheal reconstructions with endto-end anastomoses. These fistulas result from erosion of the arterial wall by the contiguous tracheal anastomosis and suture material. Grillo19 recommends protecting any tracheal anastomosis that lies near the innominate artery and uses local tissue such as surrounding fat, thymus, or strap muscle. Nelems29 described fistula formation after extended laryngectomy in 2 patients who required extensive tracheal resection for distal tracheal spread of a laryngeal tumor. After dehiscence of the cutaneous tracheostomy stoma because of undue tension, the innominate artery was exposed and eroded by the laryngectomy tube.

Clinical Features Tracheoinnominate artery fistula presents as massive bleeding. Jones31 noted that 72% of patients bled within 21 days after tracheostomy. Premonitory hemorrhage, which is often significant but not life-threatening, may precede massive bleeding. Premonitory bleeding can manifest as bleeding around the tracheostomy tube (often falsely attributed to the tracheostomy wound), bleeding through the tracheostomy tube (often falsely attributed to tracheal suctioning or tracheitis), or bleeding through the mouth or nose (often ignored). It is critical to recognize that bleeding from any of the above sites may represent a TIF.

Management In all patients with a tracheostomy and with possible premonitory bleeding, flexible bronchoscopy is advised to define the cause. If the findings suggest arterial injury, the neck incision is reopened, and the wound is explored in the operating room. Before exploration, an endotracheal tube is placed with the tip above the tracheostomy. With the airway thus controlled, the tracheostomy tube is partially withdrawn and the neck incision is reopened to fully assess the tracheostomy site. If no fistula is found, the wound is closed and the tracheostomy is replaced. If a fistula is found, it is managed by resecting the damaged arterial segment, with subsequent closure of the divided ends. Repair of the defect in the arterial wall is contraindicated; the repair site subsequently breaks down, resulting in recurrent bleeding. In patients with massive bleeding, which is the usual scenario, care involves three simultaneous priorities: (1) control of the airway, (2) control of bleeding, and (3) resuscitation. Initially, the tracheostomy balloon is hyperinflated in an effort to compress the artery anteriorly (Fig. 20-8). If hyperinflation is successful, an assistant is assigned to hold the tracheostomy tube securely in position. Simultaneously, an endotracheal tube is passed, with the tip placed just above

Ch020-F06861.indd 265

265

the tracheostomy site to ensure control of the airway. If hyperinflation is unsuccessful, the tracheostomy wound is widely opened and the innominate artery is compressed anteriorly against the manubrium with a finger (see Fig. 20-8). A rigid bronchoscope can also be used to compress the hyperinflated tracheostomy balloon against the innominate artery and the sternum for control of bleeding (see Fig. 20-8) (Cooper, 1987).32 Blood can then be cleared from the distal tracheobronchial tree, and the patient can be ventilated. Jet ventilation may be preferable in this situation, if available. With the airway secure and the bleeding controlled, the patient’s blood is crossmatched and the patient is sedated if necessary and, if not already there, transported to the operating room. With the patient under general anesthesia, the entire neck and chest are prepared and draped. The incision for fistula repair extends the tracheostomy incision combined with a partial upper sternotomy with extension into the right third or fourth intercostal space.29,33 Full sternotomy adds a higher risk of infection from the contaminated tracheostomy site. After the thymus is cleared and the innominate vein is retracted, proximal and distal control of the innominate artery is obtained. The artery is dissected free from the trachea, and the fistula is resected. It may be necessary to resect the innominate artery at its point of origin from the aorta. The suture line may be flush with the aortic wall. Arterial wall repair is contraindicated. Jones and associates31 reported only an 18% survival rate after repair. Deslauriers and colleagues30 also noted that repair almost inevitably fails, even when bolstered with autogenous tissue. The controversy about vascular reconstruction is still unresolved, although anecdotal reports strongly suggest that bypass to the right carotid system is unnecessary. Most authors, therefore, advise resection of the innominate artery without vascular bypass. If the operative field is grossly infected, the tracheal defect may be packed open to await secondary closure with granulation tissue. If the operative field is clean, the defect may be closed primarily and covered with soft tissue. The airway is managed by translaryngeal intubation, with the balloon cuff positioned below the tracheal wall defect.

TRACHEOESOPHAGEAL FISTULA Tracheoesophageal fistula (TEF) results from destruction of the posterior membranous trachea, which most commonly occurs after prolonged mechanical ventilation, particularly in simultaneous association with nasogastric intubation.

Historical Note Before 1960, the most common cause of benign TEF was granulomatous mediastinal infection or trauma. In the early 1960s, Flege34 reported on TEF due to injury by cuffed endotracheal tubes. By 1973, Thomas35 had amassed 46 cases of benign postintubation TEF, documenting that cuffed tube intubation was the leading cause. A variety of methods have been used to manage these fistulas. Early attempts at direct repair were made by Braithwaite,36 Flege,34 and Thomas,35 all

1/21/2008 10:55:13 AM

266

Section 2 Upper Airway

1 Cuff hyperinflation

2 Digital control

Orotracheal tube ready in place if needed

Orotracheal tube replacing tracheostomy tube

3 Bronchoscopic compression

Forward pressure applied with bronchoscope

FIGURE 20-8 Steps in the emergency management of tracheoinnominate artery fistula.

with some success. In 1976, Grillo and associates37 noted that these fistulas were frequently associated with a damaged and stenosed tracheal segment at the same level as the fistula. They described a single-stage technique for simultaneous closure of the esophageal defect, circumferential tracheal resection, and primary tracheal anastomosis, performed through an anterior cervical approach. HISTORICAL READINGS Braithwaite FC: Closure of a tracheo-esophageal fistula. Br J Plast Surg 14:138, 1961. Flege JB Jr: Tracheoesophageal fistula caused by cuffed tracheostomy tube. Ann Surg 166:153, 1967. Grillo HC, Moncure AC, McEnany MT: Repair of inflammatory tracheoesophageal fistula. Ann Thorac Surg 22:112, 1976.

Ch020-F06861.indd 266

Clinical Presentation Tracheoesophageal fistulas occur predominantly in patients who require prolonged mechanical ventilation combined with nasogastric intubation. Cuff inflation compresses the membranous trachea and anterior esophageal wall against the nasogastric tube, leading to full-thickness necrosis and fistula formation. Many patients have a concurrent circumferential injury to the tracheal wall at cuff level. A TEF may be heralded by a marked increase in tracheal secretions with the characteristics of saliva. Patients on oral nutrition may cough when swallowing liquids; particulate food may appear in the tracheal aspirate. Patients with reflux may have repeated aspiration of gastric juice through the fistula and into the tracheobronchial tree. Gross gastric distention due to “ventilation” of the esophagus and stomach

1/21/2008 10:55:13 AM

Chapter 20 Postintubation Injury

through the fistula occurs if the cuff is positioned above the fistula. Confirmation of the suspected diagnosis is generally simple. Tracheoesophageal fistulas are usually sizeable. They are easy to visualize by removing the tracheostomy tube and identifying the TEF directly through the stoma. Alternatively, the tracheostomy tube can be pulled back and a flexible bronchoscope can be inserted through the tracheostomy to visualize the defect. Esophagoscopy, with the tracheostomy cuff inflated, allows visualization of the fistula, which is typically located on the anterior wall of the esophagus 1 to 2 cm below the tracheostomy stoma. Contrast studies are usually unnecessary. The large size of the fistula allows direct visualization in nearly all patients. Grillo eloquently described his extensive experience with nonmalignant TEF in his report with Mathisen and coworkers (Mathisen et al, 1991).38 The initial dilemma is whether to repair the fistula while the patient still requires assisted ventilation. The few reported attempts to achieve closure in this circumstance have been failures. With a documented tracheoesophageal fistula in a patient who still requires ventilation, Grillo recommends the following steps: 1. Remove the nasogastric tube. 2. Ensure that the tracheostomy has a low-pressure cuff that is not overinflated, and attempt to place the cuff below

267

the fistula. If absolutely necessary, keep the cuff at the level of the fistula. 3. Establish a gastrostomy (to prevent gastroesophageal reflux) and a feeding jejunostomy. 4. Manage salivary secretions by frequent suctioning. In the rare patient who appears disabled because of aspiration of salivary secretions, a tube pharyngostomy or cervical esophagostomy may be necessary. 5. The patient is weaned as tolerated from ventilator support. Esophageal diversion is only used if disabling and life-threatening aspiration continues, despite the above measures, or if supracarinal fistula cannot be controlled with the cuffed tube. Once the patient is off the ventilator, a single-stage repair is performed. Because many fistulas involve simultaneous circumferential tracheal injuries, repair often requires a segmental tracheal resection and reanastomosis, along with repair of the esophageal defect. Figure 20-9 illustrates placement of a collar incision over the tracheostomy stoma. Because many of these fistulas are at a level below the manubrium, partial upper sternotomy may be necessary. With small fistulas and lesser degrees of tracheal damage, repair consists of identifying and dividing the fistula, closing

Sternohyoid muscle

Cricoid

Stoma Level of tracheoesophageal fistula Skin incision Scar tissue Esophagus FIGURE 20-9 The position of a cervical incision, centered over the tracheostomy stoma with a vertical extension for partial upper sternotomy, in the management of postintubation tracheoesophageal fistula.

Ch020-F06861.indd 267

1/21/2008 10:55:15 AM

268

Section 2 Upper Airway

Recurrent laryngeal nerve

Esophagus Small tracheoesophageal fistula

A

C

B FIGURE 20-10 Illustration showing repair of a small tracheoesophageal fistula without significant tracheal injury. A and B, The fistula is closed on both tracheal and esophageal sides. C, A pedicle flap of strap muscle is interposed between the esophagus and the trachea at the level of the suture lines.

Esophagus

i ii

A

B

FIGURE 20-11 Steps in closure in a tracheoesophageal fistula in which extensive tracheal damage requires a concomitant tracheal resection. A, The fistula is divided, and the trachea is transected below the level of the tracheal injury. B, The tracheal side of the fistula is closed with a single layer of interrupted absorbable sutures, and the esophageal side of the defect is closed in two layers.

Ch020-F06861.indd 268

1/21/2008 10:55:15 AM

Chapter 20 Postintubation Injury

269

FIGURE 20-11, cont’d C, The damaged tracheal segment is removed, usually including the tracheostomy stoma, and a pedicled flap of sternohyoid muscle is sutured in place over the esophageal closure. D, The tracheal anastomosis is then completed. Esophagus Sternohyoid muscle Cricoid

C

D

the tracheal defect with interrupted 4-0 Vicryl sutures, and closing the esophageal defect in two layers. A pedicle of strap muscle is interposed between the esophageal and the tracheal suture line to prevent recurrence (Fig. 20-10). In patients with extensive or circumferential tracheal damage, the fistula is identified and divided, the damaged trachea is resected, and a primary tracheal anastomosis is performed. The esophageal defect is closed in two layers (Fig. 20-11), and strap muscle is interposed between the two suture lines. If a tracheostomy is required for postoperative airway management, it is placed, if possible, at least two tracheal rings below the tracheal anastomosis. Grillo (1991) with Mathisen and associates reported on 38 patients with nonmalignant TEF in whom 41 operations were performed.38 In 9 patients with smaller fistulas and a normal trachea, simple division and closure of the fistula was performed. Twenty-nine patients underwent tracheal resection and esophageal repair. There were three recurrent fistulas: two were managed by re-resection, and one healed spontaneously with simple drainage. Of the 34 surviving patients, 33 were capable of normal oral intake. Five patients required esophageal dilation because of narrowing at the level of the esophageal fistula repair. Thus, in most patients, a single-stage repair can be performed with a low rate of recurrence and with good prospects of restoring normal oral alimentation.

KEY REFERENCES Cooper JD: Complications of tracheostomy: Pathogenesis, treatment, and prevention. In Grillo HC, Eschapasse H (eds): International Trends in General Thoracic Surgery. Philadelphia, WB Saunders, 1987, vol 2. ■ This comprehensive review of postintubation injury caused by tracheostomy provides a clear exposition of pathogenesis and recognition. It also includes important statements about injury prevention in the current era. Couraud L, Hafez A: Acquired and non-neoplastic subglottic stenoses. In Grillo HC, Eschapasse H (eds): International Trends in General Thoracic Surgery. Philadelphia, WB Saunders, 1987, vol 2. ■ This is a comprehensive report of a large, carefully documented experience with laryngotracheal injury. It catalogs Couraud’s experience beginning in the early 1960s, which parallels the evolution in management of subglottic stenosis from simple dilation, through staged plastic reconstruction, and ultimately to techniques for circumferential resection and primary anastomosis. Mathisen DJ, Grillo HC, Wain JC, et al: Management of acquired nonmalignant tracheoesophageal fistula. Ann Thorac Surg 52:759, 1991. ■ This is a detailed review of the largest reported experience with postintubation tracheosophageal fistula in the world. It details pathogenesis, diagnosis, and patient care, with an emphasis on the importance of identifying and documenting significant associated tracheal injury.

tahir99-VRG vip.persianss.ir

Ch020-F06861.indd 269

1/21/2008 10:55:17 AM

chapter

IDIOPATHIC LARYNGOTRACHEAL STENOSIS

21

Hermes C. Grillo

Key Points ■ Idiopathic laryngotracheal stenosis is most often successfully

managed by one-stage resection and laryngotracheal reconstruction. Subsequent progression of the lesion is rare, and initial good results tend to remain stable. ■ Lower laryngeal and upper tracheal circumferential fibrous stenosis of idiopathic origin is occasionally seen, principally in women. Patients are characterized chiefly by the fact that they have no known cause of these stenoses, but the lesions do share typical features of location, configuration, clinical evolution, pathology, and response to surgical treatment.

HISTORICAL NOTE Brandenburg,1 in 1972, described three cases of idiopathic subglottic stenosis seen over 10 years, two of which were complicated by retro-orbital pseudotumor. Several other case reports followed.2-4 Grillo5 in 1982, and then Grillo6 and also Maddaus7 and their colleagues in 1992, noted a number of these patients in a series of single-stage laryngotracheal resection and reconstruction procedures. In 1993, Grillo and associates (Grillo et al, 1993)8 reported on 49 patients with this entity, described the natural history and pathology, and detailed satisfactory results of surgical treatment. Seventythree surgically treated patients have been reported since then by these authors (Ashiku et al, 2004),9,10 with generally long-term success. This contrasts with other reports of treatment, largely by laser and dilation, which are often required repeatedly because of recurrence and progression.11-15 Procedures for primary reconstruction of the airway after resection of lesions involving the subglottic larynx and upper trachea, with preservation of recurrent laryngeal nerves, evolved from work by Conley in 1953, by Ogura and colleagues in 1964 and 1971, and, notably, by Gerwat and Bryce in 1974 and Pearson and colleagues in 1975 (Pearson et al, 1975).16-20 Couraud and colleagues applied the procedure successfully in 1979, and Grillo described a modified operation in 1982 and 1992.21-24 The surgical technique for resection and reconstruction was recently definitively summarized (Grillo, 2004).25

only just below the cricoid, and extends into the upper trachea. The tissue is dense and fibrous, although mucosal bleeding occurs easily on instrumentation. In a few patients, more florid granulation tissue or even ulceration may be present, but this is unusual. The proximal end of the stricture begins subtly somewhere below the vocal cords, but its inferior border in the trachea is usually quite sharp. The point of maximal stenosis usually lies at the cricoid or first tracheal ring. The usual length of stenosis measures between 2 and 3 cm, with a range of 0.5 to 5 cm. Trachea distal to the lesion is normal. The effective lumen may be as narrow as 2 mm, but more frequently it ranges from 5 to 7 mm. At 5 to 6 mm, a patient may be dyspneic even at rest. Dense white fibrous tissue replaces the lamina propria of the trachea. Calcification and ossification are not encountered. Fibrosis is of keloidal type, with the bundles of eosinophilic collagen separated by sparse fibroblasts (Fig. 21-1) (Grillo et al, 1993).8 Some patients have areas of spindle cell proliferation with regimentation of nuclei, but such cellular regions represent a minority of the affected area. Mucous glands may be entrapped by fibrosis and become dilated. Lymphocytes are modest in number and sometimes almost lacking. A few histiocytes associated with lymphocytes are embedded in the cellular fibrosis. Surface epithelium usually shows squamous metaplasia (see Fig. 21-1). Sometimes granulation tissue is noted. Cartilaginous rings remain intact or in some cases show slight loss of basophilic chondroitin sulfate from chondrocytes along the inner perichondrium. Little, if any, destruction of cartilage is seen, and no pus, eosinophils, plasma cells, polychondritis, granulomas, vasculitis, granulomatosis of Wegener type, amyloid, organisms, or foreign particles are seen. Cultures for bacteria, mycobacteria, and fungi have been repeatedly negative. Antineutrophil cytoplasmic antibody (ANCA) tests are negative. Koufman26 postulated silent gastroesophageal reflux as a cause, but this was not borne out in the two large series (Ashiku et al, 2004).10,15 Fifteen of our 73 patients had symptoms of gastroesophageal reflux disease. None suffered recurrent laryngotracheal stenosis postoperatively, despite absence of antireflux therapy.

DIAGNOSIS Clinical Features

BASIC SCIENCE Idiopathic stenosis is a circumferential fibrotic stenosis that begins at a variable distance from the vocal cords, usually in the subglottic larynx but occasionally in the upper trachea

Seventy-one of 73 patients seen at Massachusetts General Hospital (Ashiku et al, 2004)10 were women. Ages ranged from 13 to 74 years (average, 46 years). Symptoms were initially dyspnea on effort, progressing to dyspnea at rest,

270 tahir99-VRG vip.persianss.ir

Ch021-F06861.indd 270

1/21/2008 10:56:20 AM

Chapter 21 Idiopathic Laryngotracheal Stenosis

271

Investigative Techniques

FIGURE 21-1 Histopathology of idiopathic tracheal stenosis. Dense fibrosis of keloidal type replaces the lamina propria of the mucosa. The epithelium (right) shows squamous metaplasia. The inner perichondrium (left) is normal (×30). (FROM GRILLO HC, MARK EJ, MATHISEN DJ, WAIN JC: IDIOPATHIC LARYNGOTRACHEAL STENOSIS AND ITS MANAGEMENT. ANN THORAC SURG 56:80, 1993.)

noisy breathing, and wheezing or stridor. None of these patients had been intubated for ventilation. Fifty-four had had brief anesthesia with or without intubation, not likely related to their pathology. None had had bacterial tracheitis, tuberculosis, histoplasmosis, diphtheria, scleroma, or other specific tracheal infections. None had suffered external trauma to the trachea, inhalation burns, or irradiation. The age at onset, the often relatively brief duration of symptoms, and the pathologic findings ruled out congenital lesions. Sarcoid, relapsing polychondritis, Wegener’s granulomatosis, and amyloid disease were not present. Most patients had had symptoms for 1 to 3 years before their clinical recognition, but in others symptoms could be traced back for as long as 32 years. Many had mistakenly been treated for asthma. Prior therapy had included dilation in 28 patients, laser ablation in 31, tracheostomy in 6, stent or Ttube placement in 6, laryngeal operative procedures in 2, and tracheal resection in 1. Stenosis had recurred with its original or even greater tightness over varying periods, weeks to years. Lesions never regressed spontaneously over long periods of follow-up. Systemic symptoms or illnesses that might relate to airway stenosis did not occur subsequently.

Differential Diagnosis Idiopathic stenosis is a diagnosis made initially by the typical clinical characteristics just described and by exclusion of other causes, including collagen vascular disease, relapsing polychondritis, scleroderma, polyarteritis, and sarcoid. Wegener’s granulomatosis may be clinically confused with idiopathic stenosis, but preoperative ANCA tests and later pathologic findings confirm the diagnosis (Grillo et al, 1993).8 The pathology of a resected specimen is typical and rules out diagnoses of polychondritis, Wegener’s granulomatosis, and other entities.

Simple radiologic techniques demonstrate the location and extent of the lesion very well (Fig. 21-2) (Grillo, 2004).25,27 These may be supplemented with tomograms. Crisp linear images such as these are generally of more use than computed tomographic (CT) scans, but linear CT reconstruction will do if the former are not available. Linear images show where the lesion begins and ends, its severity, and the amount of subglottic space remaining for reconstruction. Flow-volume loops demonstrate extrathoracic fixed obstruction, as might be expected (Fig. 21-3), but are not especially helpful therapeutically. Direct endoscopy usually demonstrates normal vocal cord function and subglottic stenosis (Fig. 21-4). The proximity and severity of the process in relation to the undersurface of the vocal cords are of greatest importance in determining the ease with which surgical correction may be done with likelihood of success. Conduct ANCA tests for every patient preoperatively, and serially if need be.

MANAGEMENT Principles Because of the unknown nature of the disease process and uncertainty about its future progression, patients were initially approached conservatively. Therapy consisted of dilation at intervals as required for relief of severe symptoms. The period of relief obtained varied greatly. Surgical resection and reconstruction were increasingly performed as favorable results were obtained, and this is now the treatment of choice for most patients. Correction is done in a single stage (Ashiku et al, 2004).9,10 I believe it is best to wean the patient from high-dose corticosteroids before the operation. If excessive inflammation is present, especially if it is close to the vocal cords, it seems best to temporize, using dilation as needed. Laser treatment adds little. If subglottic narrowing extends into the conus elasticus but is not too severe, a degree of residual narrowing may be deemed acceptable for anastomosis.

Operative Technique Dilation Dilation is performed under general anesthesia administered by inhalation technique without respiratory paralysis. The subglottic larynx is visualized with a rigid ventilating bronchoscope, through which small Jackson bougies are introduced to initiate dilation. When a lumen of adequate size is achieved, Jackson rigid pediatric bronchoscopes are passed serially, using selected sizes from the range of 3.5, 4, 5, and 6 mm (Grillo, 2004).25 If dilation is to be therapeutic, adultsized rigid bronchoscopes may also be used to obtain a more satisfactory aperture, but bronchoscopes cannot be so large that they cause severe damage. I prefer not to use a laser in these maneuvers, for fear of creating more subglottic damage that might compromise future surgical repair. Tracheostomy is never performed because it would complicate surgical repair. However, if a tracheostomy is already in place, anesthesia is delivered through the tracheostomy tube, and dilation becomes a simpler process.

tahir99-VRG vip.persianss.ir

Ch021-F06861.indd 271

1/21/2008 10:56:21 AM

272

Section 2 Upper Airway

FIGURE 21-2 Radiographs of the larynx and upper trachea in idiopathic laryngotracheal stenosis. A, Tomogram showing false and true vocal cords and a narrowed but still adequate subglottic space, with maximal narrowing in the lower subglottic larynx and uppermost trachea. The distal trachea is normal in diameter. B, Postoperative radiograph made with a copper filter for clarity. An almost normal subglottic configuration has been obtained. C, Subglottic narrowing is more severe in this patient and commences immediately below the vocal cords. D, Postoperative view. (FROM GRILLO HC, MARK EJ, MATHISEN DJ, WAIN JC: IDIOPATHIC LARYNGOTRACHEAL STENOSIS AND ITS MANAGEMENT. ANN THORAC SURG 56:80, 1993.)

tahir99-VRG vip.persianss.ir

Ch021-F06861.indd 272

1/21/2008 10:56:21 AM

L/sec

Chapter 21 Idiopathic Laryngotracheal Stenosis

8

8

6

6

4

4

2

2

0

0 2

4

6

8

⫺2

4

6

8

⫺2

⫺4

A

L 2

⫺4

B

FIGURE 21-3 Preoperative (A) and postoperative (B) flow-volume loops in idiopathic stenosis. Measurements were made at an interval of 3 years. Forced expiratory volume in 1 second rose from 2.7 to 3 L, and peak expiratory flow rate from 4 to 7.7 L/sec. Surgery corrected the marked reduction in inspiratory flow. (FROM GRILLO HC, MARK EJ, MATHISEN DJ, WAIN JC: IDIOPATHIC LARYNGOTRACHEAL STENOSIS AND ITS MANAGEMENT. ANN THORAC SURG 56:80, 1993.)

FIGURE 21-4 Bronchoscopic view of typical subglottic stenosis. Lesions are most often concentric. Mucosal vascularity, but no granulation tissue, is present. (FROM GRILLO HC, MARK EJ, MATHISEN DJ, WAIN JC: IDIOPATHIC LARYNGOTRACHEAL STENOSIS AND ITS MANAGEMENT. ANN THORAC SURG 56:80, 1993.)

Surgical Correction If idiopathic stenosis involves only the upper trachea or extends upward only to the lower margin of cricoid cartilage, standard segmental circumferential tracheal resection is performed with end-to-end anastomosis (Grillo, 2004).25 This usually requires anastomosis of the trachea to the inferior margin of the cricoid cartilage. However, if stenosis involves the subglottic larynx, as is most often the case, resection must be modified to preserve the posterior skeleton of the larynx to protect the entry point of the recurrent laryngeal nerves (Grillo 2004; Pearson et al, 1975).5,6,20,25 The anteroinferior portion of the larynx below the glottic commissure is resected, removing the anterior portion of the circumferential stenosis.

273

An arcuate line of incision transects the lateral laminae of the cricoid cartilage and sweeps up in a curve that goes beneath the inferior margin of the thyroid cartilage (Fig. 21-5A). The posterior portion of circumferential stenosis that remains is resected from the anterior surface of the cricoid plate, baring cartilage. The proximal line of mucosal resection lies below the arytenoid cartilages (see Fig. 21-5B). The distal normal trachea is beveled for use in reconstruction. The first normal cartilage below the stricture is salvaged and is cut backward in a sloping line toward its posterior ends on either side, to create a “prow” from this single cartilage (see Fig. 21-5B). This will slide into the similarly shaped defect formed in the inferior part of the anterior laryngeal wall. Posteriorly, a broad-based flap of membranous wall is fashioned, which will serve to resurface the bared posterior cricoid plate (see Fig. 21-5B). Traction sutures (2-0 Vicryl) are placed at lateral midpoints of the trachea on either side, below the line of anastomosis, and also proximally in the lateral laryngeal wall, at the junction of the thyroid cartilage and remaining cricoid laminae (see Fig. 21-5C). Four nonabsorbable sutures (4-0 Tevdek) are placed in a line across the back of the base of the posterior tracheal wall flap to the inferior margin of the posterior cricoid plate, to fix the flap against the cartilage (see Fig. 21-5C). These are clipped to the drapes on either side. Anastomosis is commenced with 4-0 Vicryl sutures, which are placed from the posterior mucosa of the larynx to the tracheal membranous wall flap with knots inverted from the lumen (see Fig. 21-5D). The sutures are placed but not tied. Anastomotic sutures posterior to the midline traction sutures on either side are placed through the mucosa and cartilage of the larynx and of the trachea, plus one or two sutures anterior to the location of the traction sutures on either side. The traction sutures are then approximated using a surgeon’s knot, while the neck is in moderate flexion, to relieve tension on the anastomosis. Sutures are next tied in the following order: 1. Posterior Tevdek approximating sutures 2. Posterior mucosal flap sutures 3. Anastomotic sutures posterior to the lateral traction sutures The remaining anterior anastomotic sutures are next placed, and the anastomosis completed (see Fig. 21-5E). The anterior flap of cartilage from the trachea that is used to fill in the defect in the larynx is fashioned from a single ring in order to avoid floppiness. Half of our 73 patients underwent extensive enough circumferential resection of laryngeal stenosis to require a posterior flap.

Perioperative Care In all laryngotracheal anastomoses in which a normal subglottic airway is not available even at the point of anastomosis, the patient must be observed closely postoperatively for signs of airway obstruction. If progressive glottic or subglottic edema occurs postoperatively, promptly intubate the patient with a small-bore uncuffed endotracheal tube. After several days, make a trial removal of tube. If the airway is still inad-

tahir99-VRG vip.persianss.ir

Ch021-F06861.indd 273

1/21/2008 10:56:22 AM

274

Section 2 Upper Airway

True vocal cord Cricoid

Thyroid Cricoid

A

B

D

E

C FIGURE 21-5 Technique of laryngotracheal resection and reconstruction. A, External lines of division of the larynx and trachea are indicated by dashed lines. The anterior cricoid arch is removed with the anterior stenosis. The first normal cartilage is beveled. B, If the subglottic intralaryngeal stenosis is circumferential, scar tissue is removed from the front of the posterior cricoid lamina, baring the cartilage, as shown. The residual posterior cricoid lamina protects the recurrent laryngeal nerves. Distally, the trachea is beveled over the length of one cartilage, as shown, to fit the anterolateral subglottic defect that was created. A broad-based flap of membranous wall is fashioned to resurface the bared cricoid plate. C, The base of the posterior flap is fixed to the lower margin of the cricoid plate with four extraluminal sutures (4-0 Tevdek). Midlateral traction sutures (2-0 Vicryl) are shown in the larynx proximally and in the trachea distally. D, Posterior mucosal anastomotic sutures (4-0 Vicryl) are placed with knots to lie behind the mucosa. Traction sutures are omitted in this diagram for simplicity. E, After placement of all the posterior and posterolateral anastomotic sutures as far anteriorly as the lateral stay sutures, the patient’s neck is flexed, and the stay sutures, external fixing Tevdek sutures, and posterior mucosal sutures are tied in that order. The anterior and anterolateral anastomotic sutures are then placed and finally tied serially. (A AND B FROM GRILLO HC: PRIMARY RECONSTRUCTION OF AIRWAY AFTER RESECTION OF SUBGLOTTIC LARYNGEAL AND UPPER TRACHEAL STENOSIS. ANN THORAC SURG 33:3, 1983. C-E FROM GRILLO HC, MATHISEN DJ, WAIN JC: LARYNGOTRACHEAL RESECTION AND RECONSTRUCTION FOR SUBGLOTTIC STENOSIS. ANN THORAC SURG 53:54, 1992.)

tahir99-VRG vip.persianss.ir

Ch021-F06861.indd 274

1/21/2008 10:56:22 AM

Chapter 21 Idiopathic Laryngotracheal Stenosis

equate, insert a small tracheostomy tube very carefully through the now-sealed planes at a premarked point on the trachea inferior to the anastomotic line. The anastomosis itself is protected at the original operation with thyroid isthmus or strap muscle, and, if the brachiocephalic artery is close to the area of potential tracheostomy, a strap muscle is sutured down to the trachea over the innominate artery to protect it.16 Using this technique, we have avoided arterial injury in these resections.

RESULTS Short-Term Results Resections ranged from 1 to 5 cm, averaging 2.6 cm.10 Sixtyseven of 73 patients were extubated in the operating room, 5 required protective temporary tracheostomy at the end of the operation, and 2 needed tracheostomy 5 and 10 days after operation. The tracheostomies were necessary to allow resolution of glottic or laryngeal edema, for a median of 16 days. We have used fewer tracheostomies as the series progressed, with only 1 in the last 30 patients. Intensive care unit stays averaged 1.3 days, and hospitalization averaged 8.5 days. There were no deaths. Six patients required bronchoscopic removal of granulation tissue early on.

Long-Term Results The median follow-up period was 8 years. Excellent results with respect to airway and voice were seen in 19 (26%) of 72 patients. Inability to project the voice and altered singing voice were seen in 47 patients, who were thus classified as having good results (64%). These deficits are caused by alteration of cricothyroid muscle intrinsic to anterior subglottic resection, so that vocal cord tension can no longer be increased during phonation. Patients are forewarned of this possibility and are willing to exchange this consequence for return of more normal respiration. Only fair results were found in five patients (7%), with residual shortness of breath on exertion and need for occasional dilation. A poor result was seen in 1 patient, who required yearly dilation. In contrast to the largely successful surgical management just described, Dedo and Catten15 treated 50 patients with multiple endoscopic laser submucosal resections. Twentyone obtained long-term relief, 13 had persistent tracheostomy, and 16 required more than 10 revisions. Treatment was regarded principally as palliative, with need for indefinite repetition. Resection failed in 7 patients. Distal tracheal and carinal idiopathic stenosis is also seen, although rarely (Grillo, 2004).25 Such stenoses may have a more inflammatory appearance and also may be more progressive over time. This type of distal stenosis has not been observed in association with idiopathic laryngotracheal stenosis as described, and different etiology is suggested.

COMMENTS AND CONTROVERSIES It was with a heavy sense of sorrow and loss that I reviewed this chapter by Dr. Hermes Grillo several weeks after his tragic and untimely death. This was tempered by warm memories and great appreciation for his inspiration, his mentorship, and his support,

275

which were responsible for my choosing a career in general thoracic surgery. This chapter reflects his stature as a great teacher and innovator, a master surgeon with meticulous attention to precision and detail, and a devoted physician with uncompromising standards and unimpeachable intellectual honesty. Seldom has one individual surgeon so completely defined and encompassed the surgical treatment of the entire gamut of conditions affecting one anatomic structure as Dr. Grillo did with the trachea. This is best reflected in his magnum opus, the authoritative text, Surgery of the Trachea and Bronchi, which he published in 2004 after years of painstaking, passionate gestation. As he said to me, with a twinkle in his eye, when autographing my copy of his textbook, “You know, there are over 70 pages here for each centimeter of the trachea.” The management of airway reconstruction for conditions affecting the subglottic and proximal tracheal region are among the most challenging in tracheal surgery. It was my good fortune to work with Dr. Grillo during my residency years and subsequently with Dr. Pearson during the next phase of my career. Both these giants made important contributions to surgery of the airway in general and to the management of subglottic problems in particular. Dr. Grillo was influenced by his work with Dr. William Montgomery, Chief of Otolaryngology at the Massachusetts Eye and Ear Infirmary, and Dr. Pearson by his work with Dr. Douglas Bryce, Chief of Otolaryngology at the Toronto General Hospital. In 1975, Pearson and colleagues published a new technique for primary tracheal anastomosis after resection of the cricoid cartilage with preservation of recurrent laryngeal nerves. This operation involved removing the anterior one third to one half of the cricoid ring, dissecting the posterior mucosa of the airway from the anterior surface of the posterior cricoid plate, and removing a portion of the posterior cricoid plate to allow the transected trachea to be advanced to a position just below the vocal cords with primary direct end-toend anastomosis. As noted in his textbook, Dr. Grillo described a modified operation in 1982, which is summarized in this chapter. Dr. Grillo’s modification leaves the posterior cricoid plate intact, excises the damaged airway mucosa in front of the cricoid plate, and uses a broad, short mucosal flap of membranous trachea to resurface the anterior portion of the intact posterior cricoid plate. Both the Pearson and the Grillo techniques essentially accomplish resection of the subglottic stenosis with an anastomosis very near the vocal cords. I would like to comment on several technical features and modifications that I employ. Dr. Grillo noted the value of tomograms, CT scans, and bronchoscopy in evaluating the lesions, especially the proximity and severity of the process in relation to the vocal cords and the conus elasticus immediately below them. Today, a high-resolution CT scan, with a three-dimensional reconstruction that can be viewed from all angles, is extremely helpful in delineating the extent and anatomic location of the stenosis. At bronchoscopy, one tends to focus on the narrowest part of the stenosis in terms of the relationship of the stricture to the vocal cords. However, the submucosal scarring often extends for 5 to 10 mm above the narrowest point, requiring the proximal resection line to be closer to the vocal cords than anticipated. Dr. Grillo’s caveat must be observed: “If subglottic narrowing extends into the conus elasticus but is not too severe, a degree of residual narrowing may be deemed acceptable for anastomosis.”

tahir99-VRG vip.persianss.ir

Ch021-F06861.indd 275

1/21/2008 10:56:23 AM

276

Section 2 Upper Airway

When performing diagnostic bronchoscopy for assessment of subglottic stricture, the use of a laryngeal mask for anesthesia is a very useful technique. The flexible bronchoscope can be easily introduced through the mask for careful observation of the glottic and subglottic region. In this chapter, Dr. Grillo recommended dilation, if necessary, to provide a safe airway, and noted that “Tracheostomy is never performed because it would complicate surgical repair.” I believe this to be generally true, especially if the patient is being managed at a center with experience in this condition. However, if the patient presents elsewhere with stridor and a critical airway, a tracheostomy, preferably performed through the first or second tracheal ring, may be the safest temporizing procedure until the patient can be transferred to a center experienced with subglottic resection. For most cases of idiopathic subglottic stricture, anastomotic tension is not a major problem, and the sacrifice of an extra ring or two of trachea may be a better compromise than damage to the subglottic region through attempted intubation or dilation. I completely agree that laser treatment of subglottic strictures should not be undertaken because it often leads to worsening damage to the airway. The conduct of the operation is greatly simplified by the use of a high-frequency jet ventilator through a small catheter. The operation, from incision to the point where the airway is ready to be divided, is usually carried out with the use of a very small endotracheal tube passed through the subglottic stricture. Alternatively, a laryngeal mask might be used. After subperichondrial resection of the anterior 30% to 50% of the cricoid ring has been accomplished, the scarred airway is divided in the bed of the excised cricoid ring. Once the anterior portion of the airway has been transected, the high-frequency jet catheter can be passed from above and into the distal trachea for ventilation. After the airway has been completely transected, during work on the subglottic region, the high-frequency jet catheter can be passed across the field and inserted into the cut end of the trachea for continued ventilation, without interfering with the subglottic portion of the excision. If the posterior line of mucosal resection extends high into the larynx, through the region of the conus elasticus, the posterior anastomotic sutures may be very difficult to tie once the larynx and trachea are held together with the traction sutures. In this situation, a laryngo fissure (i.e., incision of the larynx from the thyroid notch down to the bottom of the thyroid cartilage in the midline) allows the front of the larynx to be spread open like a book, providing excellent exposure of the posterior larynx as the posterior sutures are placed and tied. Accomplish the laryngo fissure with a scalpel, and carefully take the line of incision through the anterior commissure so as not to

damage the vocal cords. Alternatively, a partial laryngo fissure, beginning inferiorly at the bottom edge of the thyroid cartilage and extending up to a point just below the anterior commissure, may provide adequate posterior exposure without dividing the upper 25% of the laryngeal cartilage. When performing the posterior portion of the anastomosis at a high level, I have adopted the technique reported by Pearson; namely, the use of No. 34 stainless steel wire for the posterior sutures. Once placed, these can be tied carefully with an instrument tie if necessary. They are tied with a square knot, and the wires are cut adjacent to the knot. This produces a posterior suture line that is virtually invisible and does not lead to any granulation tissue. With this technique, the use of a laryngo fissure is seldom required. Dr. Grillo notes the use of a protective temporary tracheostomy at the end of the operation, which was used in the early part of his series but eliminated in all but 1 of the last 30 patients reported in this chapter. It has been my preference, most recently, to place a No. 4 mini tracheostomy tube through the lower skin flap and into the trachea, below the completed anastomotic suture line, before wound closure. Once this has been placed, the anastomosis and vocal cord function can be evaluated by substituting a laryngeal mask for the endotracheal tube and passing a bronchoscope through the laryngeal mask while closure of the wound is being performed. J. D. C.

KEY REFERENCES Ashiku SK, Kuzuzu A, Grillo HC, et al: Idiopathic laryngotracheal stenosis: Effective definitive treatment with laryngotracheal resection. J Thorac Cardiovasc Surg 127:99, 2004. ■ Updated report of clinical experience in the surgical management of 73 patients, the largest series recorded. Good long-term results and lack of progressive disease were observed. Grillo HC: Surgery of the Trachea and Bronchi. Hamilton, Ontario, BC Decker, 2004. ■ The entity and its treatment are fully described. Surgical techniques of resection and reconstruction are detailed and illustrated. Grillo HC, Mark EJ, Mathisen DJ, Wain JC: Idiopathic laryngotracheal stenosis and its management. Ann Thorac Surg 56:80, 1993. ■ Clinical aspects are defined and reported, and the pathology is detailed in this first series of 49 patients, 35 treated surgically. Pearson FG, Cooper JD, Nelems JM, Van Nostrang AWP: Primary tracheal anastomosis after resection of cricoid cartilage with preservation of recurrent laryngeal nerves. J Thorac Cardiovasc Surg 70:806815, 1975.

tahir99-VRG vip.persianss.ir

Ch021-F06861.indd 276

1/21/2008 10:56:23 AM

chapter

22

TRACHEOMALACIA Simon K. Ashiku Michael A. Maddaus F. Griffith Pearson

Key Points ■ Tracheomalacia can be divided into segmental and diffuse malacia.

■

■

■

■

■

Segmental malacia is usually a result of intubation cuff–related trauma. Pure segmental malacia is uncommon; rather, it is usually associated with adjacent areas of tracheal stenosis, creating complex so-called mixed lesions. It is best treated with definitive tracheal resection and primary anastomosis. Stenting with Montgomery T tubes provides a temporary or permanent alternative. Primary congenital tracheobronchomalacia (TBM) in newborns is most often seen in premature infants and results from immature cartilaginous and membranous components. Most children outgrow this condition by 1 to 2 years of age and can be managed with conservative measures. Diffuse forms of malacia in adults, such as acquired TBM and congenital Mounier-Kuhn syndrome, involve extensive regions of the airway and are best treated with restorative tracheobronchoplasty procedures. Overall results from the surgical treatment of malacic airways in properly selected patients is excellent. Adult patients with diffuse acquired TBM can be divided into two groups: nonsmokers with good lung capacity and long-time smokers with chronic obstructive pulmonary disease (COPD) and poor lung capacity. Patients with good lung capacity have almost uniform benefit from surgical repair. Patients with COPD require careful preoperative evaluation to screen out those whose functional status is limited by the small peripheral airway disease of COPD and will not sufficiently benefit from surgical correction of their TBM. A temporary trial of stenting with a silicone Y stent can be helpful in determining which patients are likely to benefit from definitive surgical correction. Stents are a poor long-term solution given their very high complication rate. They are difficult to manage and require constant maintenance. However, in selected cases, there may well be a place for internal stenting with silicone rubber tubes—T tubes, T-Y tubes, or Y tubes—as an alternative to external surgical stenting. As chronic dynamic airway computed tomographic (CT) imaging and functional bronchoscopic evaluations become more available, acquired TBM is being identified with increasing frequency. Further investigations need to focus on the prevalence of acquired TBM in the COPD population and define what role TBM plays in the debilitating dyspnea and recurrent pulmonary infections that COPD inflicts.

The normal trachea is relatively pliant and elastic, allowing its length and diameter to change under varying conditions. As the trachea enters the thoracic cavity, it is exposed to intrathoracic pressure variations that are opposite to those of the cervical trachea. The negative intrathoracic pressure created with inspiration creates a vacuum around the airway, leading to expansion of the intrathoracic trachea, while simultaneously creating a vacuum within the lumen of the cervical trachea, leading to its constriction. Forced expiration increases intrathoracic pressure, which causes compression of the intrathoracic trachea, while leading to an increase in intratracheal pressure, which causes cervical tracheal expansion (Fig. 22-1). Consequently, structural tracheal defects affect the physiology of the cervical and thoracic portions of the trachea differently. The normal trachea resists collapse by means of its semirigid, C-shaped anterior cartilaginous rings, which are bridged by the flat and muscular posterior membranous wall. At rest, the normal trachea is horseshoe or D shaped; with significant intrathoracic pressure increases (e.g., forceful expiration, coughing), the intrathoracic trachea is compressed, with lateral narrowing of the cartilaginous rings and mild to moderate anterior herniation of the membranous wall. In healthy individuals, this physiologic narrowing of airway diameter is functionally insignificant. It may, in fact, accelerate luminal air speed to assist with secretion clearance. Malacia is defined as a softening or loss of consistency of a tissue or organ. Tracheomalacia is a pathologic increase in tracheal compliance that leads to a propensity to excessive airway collapse with physiologic intrathoracic pressure swings. The structural failure results from malacia of the cartilaginous rings, the posterior membranous wall, or both. In all cases, the end result is a dynamic airway obstruction causing dyspnea on exertion and difficulty raising secretions, with impaired pulmonary hygiene and recurrent pulmonary infections.

ETIOLOGY Congenital Congenital anomalies include the following: 1. Occasional segmental cartilaginous defects 2. Congenital vascular malformations 3. Congenital tracheal collapse without airway compression (primary tracheobronchomalacia [TBM]) 4. Tracheobronchomegaly syndrome (also known as tracheal diverticulosis and the Mounier-Kuhn syndrome) 277 tahir99-VRG vip.persianss.ir

Ch022-F06861.indd 277

1/21/2008 10:57:24 AM

278

Section 2 Upper Airway

Segmental Cartilaginous Defects Isolated segmental cartilaginous defects from congenital agenesis or malformation of cartilaginous rings is rare and occurs more commonly in the bronchial airways.

Congenital Vascular Malformations Congenital segmental tracheomalacia most commonly is secondary to a vascular malformation. The anomalous artery causes a long-standing external compressive force on the developing cartilage, leading to incomplete or maldeveloped rings. The segment remains malacic even after correction of the vascular impingement. This condition is discussed separately in Chapter 19. Expiration

Inspiration

Congenital Tracheal Collapse Without Airway Compression

FIGURE 22-1 The influence of expiration and inspiration on variable intrathoracic and extrathoracic trachea collapse. See text for details.

Congenital tracheomalacia without extrinsic airway compression is one of the most common congenital anomalies of the trachea.1 It is more frequently seen in premature infants, although it can be seen in healthy infants as an isolated

A

B

C

Ch022-F06861.indd 278

FIGURE 22-2 Enlarged trachea and bronchi with redundant semicircular folds in a patient with Mounier-Kuhn syndrome. A, Standard chest radiograph. B, Reconstructed two-dimensional CT. C, Reconstructed three-dimensional CT.

1/21/2008 10:57:24 AM

Chapter 22 Tracheomalacia

A

279

B

FIGURE 22-3 A and B, Bronchoscopic appearance of saccular pouches in Mounier-Kuhn syndrome.

finding. It is thought to result from inadequate maturation and development of tracheobronchial cartilage (Jacobs et al, 1994).2 It usually resolves within the first 1 to 2 years of age, as the airway enlarges and matures, but on occasion requires invasive intervention.

A

C

Ch022-F06861.indd 279

Tracheobronchomegaly Syndrome The Mounier-Kuhn syndrome, first described in 1932, consists of diffuse dilation of the tracheobronchial tree, occasionally from the larynx to the subsegmental bronchi.3,4 In 1973,

B

FIGURE 22-4 Dynamic CT images of tracheal dilation on inspiration (A) and collapse on exhalation (B). C, Bronchoscopic view of tenacious secretions obstructing distal airways.

1/21/2008 10:57:25 AM

280

Section 2 Upper Airway

B

A

C FIGURE 22-5 Overinflation of endotracheal tube cuff seen on chest radiograph (A) and on reconstructed lateral two-dimensional CT (B). C, Schematic representation of overinflation of endotracheal tube cuff leading to segmental areas of tracheomalacia.

Ch022-F06861.indd 280

1/21/2008 10:57:28 AM

Chapter 22 Tracheomalacia

281

FIGURE 22-6 Experimental production of cuff stenosis in dogs. A, High-pressure early model endotracheal tube set at sufficient pressure to seal at standard ventilator pressure for 7 days. B, The mucosa is destroyed, the cartilage is bare, and the trachea is distended. C, Another specimen, exposed for 13 days, exhibits granulation tissue and malacia. (FROM GRILLO HC: POSTINTUBATION STENOSIS. IN GRILLO HC: SURGERY OF THE TRACHEA AND BRONCHI. HAMILTON, ONTARIO, BC DECKER, 2004, P 317.)

A

B

C

choscopy or dynamic airway imaging, there is striking airway dilation with inspiration and collapse with forced expiration and cough, accompanied by pooling of secretions in the trachea and main bronchi (Fig. 22-4).4

Acquired Acquired tracheomalacia results from airway trauma, longstanding extrinsic compression, or inflammatory states.

Post-traumatic

FIGURE 22-7 Substernal goiter with chronic tracheal compression that led to malacia in this patient.

Bateson and Woo-Ming5 reviewed 55 reported cases and noted that the syndrome occurs primarily in males, who typically present in the third and fourth decade with bouts of cough, purulent sputum, and occasionally pneumonia. Chest radiography is often diagnostic and reveals a striking enlargement of the trachea and bronchi (Fig. 22-2). Bronchoscopy reveals redundant semicircular folds of mucous membrane with formation of saccular pouches which may be entered directly with the bronchoscope (Fig. 22-3). The cause of the Mounier-Kuhn syndrome is unknown; a decrease in the number of airway elastic fibers has been found, and associations have been noted with the EhlersDanlos syndrome and other connective tissue disorders.6,7 Because the trachea and bronchi are abnormally compliant due to atrophic changes in the cartilage, they are prone to collapse easily with coughing or forced expiration.8,9 On bron-

Ch022-F06861.indd 281

Segmental areas of tracheomalacia may occur after any injury that results in loss or damage to cartilaginous elements or overdistention of the membranous wall. The most common cause is intubation-related injury due to poor healing of a tracheostomy stoma, torsion on the tracheostomy cannula, or pressure from overinflation of an endotracheal or tracheostomy cuff (Fig. 22-5). Constant pressure leads to impaired capillary blood flow, mechanical erosion, or simple overdistention with mechanical disruption (Fig. 22-6). Postintubation tracheomalacia is observed in the early phase of the injury in association with acute inflammation. Although most of these injuries result in the development of tracheal stenosis from exuberant growth of granulation tissue, with the eventual development of intense scarring and cicatrization, it is common to see a mixed lesion containing both stenosis and malacia. Pure postintubation malacia is less common, but in some cases (most notably with administration of high-dose steroids) scar formation is minimal, leading to a weak and unsupported segment of tracheal wall that easily collapses with vigorous expiration or cough. It has also been our impression that progressive malacic deterioration may occur after repetitive thermal damage to cartilage with laser management of stenotic airway lesions.

1/21/2008 10:57:29 AM

282

Section 2 Upper Airway

FIGURE 22-8 Postpneumonectomy syndrome. The right main bronchus is displaced leftward and compressed by the underlying thoracic spine.

A

B

C

D

FIGURE 22-9 Configuration of trachea in normal subject during inspiration (A) and expiration (B) shows minimal physiologic membranous wall protrusion. Trachea in acquired tracheobronchomalacia during inhalation (C) and exhalation (D) shows pathologic herniation of the membranous wall during periods of increased intrathoracic pressure.

Chronic External Compression of the Trachea Any cervical or mediastinal lesion that abuts and impinges on the trachea can lead to tracheomalacia by compromising the blood and nutrient flow to supporting cartilage. This is most commonly seen in the upper mediastinal trachea and is caused by a benign mediastinal goiter (Fig. 22-7). Mediastinal lesions contiguous with the trachea (e.g., teratoma, thymoma, bronchogenic cyst), if long-standing, may occasionally lead to an area of segmental tracheomalacia. Segmental malacia of a main bronchus may also occur after pneumonectomy, when the airway is significantly displaced and subsequently compressed by the underlying thoracic spine. This has been termed postpneumonectomy syndrome (Fig. 22-8).

Inflammatory The most common inflammatory airway malacic conditions are acquired TBM associated with emphysema and relapsing polychondritis. Acquired Tracheobronchomalacia. A significant portion of patients with advanced emphysema and chronic bronchitis have some degree of malacia involving part or all of the trachea and main bronchi. The etiology of this form of malacia may be related to chronic inflammation provoked by the chronic irritation of cigarette smoke. It has been suggested that the same factors that lead to emphysema and chronic obstructive pulmonary disease (COPD), which is essentially a form of lung parenchyma and small airways malacia, also lead to central airway malacia.10,11 Acquired TBM is also found in patients with no significant smoking history who have chronic bronchitis. It is not known whether chronic inflammation from recurrent bouts of bronchitis results in central airway malacia or preexisting central airway malacia leads to recurrent bronchitis. The typical structural changes associated with acquired TBM are malacia of the posterior membranous wall and car-

Ch022-F06861.indd 282

tilage extending to diffusely involve the entire central airway (trachea and bronchi). The normally firm, elastic cartilaginous struts soften and lose their C shape while the posterior membranous wall widens. The end result is an airway shaped like a crescent or fish mouth, with lateral widening and loss of anterior-to-posterior dimension (Fig. 22-9). Histologic analysis at autopsy has demonstrated atrophy of the longitudinal fibers of the membranous wall12,13 and fragmentation of the airway cartilage.14 However, compared with controls, the total collagen, elastin, and mucopolysaccharide content of the tracheal and bronchial cartilage was not dimininished.11 Relapsing Polychondritis. Relapsing polychondritis is a systemic disease involving cartilage in multiple areas of the body, including the pinna of the ear, nose, larynx, and the cartilaginous rings of the tracheobronchial tree. It usually occurs in the third or fourth decade and with equal incidence in males and females. It is an autoimmune connective tissue disease that is thought to be secondary to production of autoantibodies to cartilage.15,16 Pathologically, a tracheal chondritis is initially seen with infiltration of lymphocytes and plasma cells; with time, the destroyed cartilage is replaced by fibrous tissue. There may be variable and segmental involvement of the airway, but it is generally a diffuse disease involving the entire airway. Although involvement of the airways occurs in up to 56% of patients with relapsing polychondritis, respiratory symptoms are seen in only 14% of the patients at presentation.17 In addition, patients with respiratory involvement are less responsive to treatment with steroids.18 Consequently, central airway pathology often progresses unchecked, leading to extensive and severe damage. In fact, respiratory involvement is the leading cause of death in this disease.19 Involvement of segments may lead to either a fixed obstruction due to marked narrowing of the airway or a dynamic obstruction with a pathophysiology typical of diffuse TBM.20

1/21/2008 10:57:30 AM

Chapter 22 Tracheomalacia

Patients exhibit stridor and wheezing on inspiration with cervical lesions and on expiration with intrathoracic lesions. Although patients may find it harder to clear secretions, this does not usually lead to more frequent episodes of pulmonary infection. However, pulmonary infections that lead to increased volume and tenacity of secretions can precipitate a respiratory crisis when mucus coats the area of segmental malacia, converting it into a more fixed, life-threatening airway obstruction with narrowing of the lumen, further compromising the already tenuous airway. Diffuse forms of malacia, seen in premature infants and in acquired TBM and relapsing polychondritis, lead to both dyspnea on exertion and difficulty clearing secretions. Because the intrathoracic airway constitutes most of the airway, expiratory wheezing dominates. However, on occasion, the cervical airway involvement is sufficiently severe to lead to inspiratory stridor as well. Only the most severe cases exhibit symptoms at rest. Activities that lead to forced exhalation or to prolonged Valsalva maneuvers, such as strenuous lifting, lead to greater intrathoracic pressure and provoke symptoms. Patients with associated emphysema are affected even with

In the latter type, the cartilage rings shrink in size, but maintain their shape to resemble a pediatric airway (Fig. 22-10A). However, the cartilage becomes thick and noncompliant. The posterior membranous wall, having no cartilage, is not involved in the inflammatory process and remains essentially unaffected (see Fig. 22-10B). The end result is a small, stiff airway with a disproportionately large and redundant posterior membranous wall, leading to dynamic expiratory collapse (see Fig. 22-10C).

SYMPTOMS AND SIGNS Dyspnea on exertion and difficulty clearing secretions which results in recurrent pulmonary infections are the most common clinical manifestations. The extent of airway involvement (segmental or diffuse) and the location of the malacia (cervical or intrathoracic) determine the presenting symptomatology. Relatively short segmental lesions, seen in congenital and post-traumatic conditions, usually result in symptoms of exertional dyspnea due to dynamic airway obstruction.

A

C

Ch022-F06861.indd 283

283

B

FIGURE 22-10 A, Diffuse narrowing of tracheobronchial lumen from chronic inflammation of cartilage caused by relapsing polychondritis. B, Axial CT image demonstrates thickened and contracted cartilaginous rings. Note that the posterior membranous wall is not involved in the inflammatory process. C, Unaffected and relatively redundant posterior membranous wall leads to dynamic expiratory collapse.

1/21/2008 10:57:30 AM

284

Section 2 Upper Airway

slight activity because the lack of elastic recoil within the lung parenchyma leads to air trapping and the need for more forceful, active expiration. The increase in intrathoracic pressure, combined with air trapping, compresses the malacic airway between bilaterally hyperinflated emphysematous lungs (Fig. 22-11). The problem is further compounded by the inherently poor lung capacity that defines emphysematous patients. The abrupt reduction in airflow associated with diffuse airway malacia makes clearing secretions difficult. The airways collapse down onto viscous secretions, squeezing and trapping them between the posterior membranous wall and the flattened cartilaginous struts. Consequently, patients experience difficulty maintaining adequate pulmonary hygiene and develop recurrent bouts of bronchitis and pneumonia. They are particularly susceptible during the cold and flu season, when the increased volume and tenacity of secretions from the common cold can compound the clearance problem and lead to severe and even lethal lower respiratory infections. Airway malacia, particularly the diffuse forms, can be the cause of an intractable cough. Airway collapse forces the posterior membranous wall to herniate forward and contact the anterior cartilaginous rings. This mucosa-to-mucosa contact is not physiologic and can incite a contact-induced cough. The resulting distinctive sound has been likened to a barking seal. A single cough leads to a series of coughs, which can provoke a bout of coughing so severe that effective breathing is compromised and the patient collapses. Such spells have in the past been termed laryngeal epilepsy.21 Patients with severe diffuse malacia, especially those with associated obesity, develop positional orthopnea because gravity compounds airway collapse. Patients are often forced to sleep upright in reclining chairs. They respond well to continuous positive airway pressure (CPAP) therapy and are often diagnosed with obstructive sleep apnea. Children with primary congenital TBM not associated with malformations such as vascular rings or tracheoesophageal fistula have a similar physiology to that seen in the adult

A

diffuse forms. They often present early in infancy with increasingly noisy breathing and occasionally a so-called seal bark. Episodes of agitation or respiratory infections can lead to respiratory distress manifested by expiratory wheezing, intercostal retractions, and tachypnea. The end result may be spells of cyanosis and apnea, a common end point for many pediatric diseases, making a high index of suspicion imperative to allow for timely diagnosis.21

DIAGNOSIS On pulmonary function tests, patients with tracheomalacia may manifest a classic break in the expiratory phase of the spirogram.22-24 The break in the expiratory curve to a flat plateau is assumed to represent the moment of large airway collapse (Fig. 22-12). At this point in the respiratory cycle, it has been said that a sharp “knock” may be heard with the stethoscope placed over the upper sternum. Diminished forced expiratory volume in 1 second (FEV1) and low flow are seen on the expiratory loop, whereas the inspiratory loop is well preserved. However, the spirometry results are similar to those seen in patients with chronic obstructive lung disease and can be somewhat nonspecific. Furthermore, the physical examination is often unrevealing. A firm diagnosis of tracheomalacia requires visual confirmation of airway collapse, either on radiographic imaging studies or on bronchoscopy. Plain chest radiography may reveal the diagnosis of Mounier-Kuhn syndrome, by the overall increase in the caliber of the trachea and bronchi, which is immediately apparent, and the more subtle presence of a unique corrugated appearance of the airways, which is caused by the excess tissue between the cartilaginous rings (at times forming diverticula) (see Fig. 22-2A). It may also demonstrate the outline of an area of post-traumatic or congenital segmental malacia. However, airway malacia is a dynamic condition and requires a dynamic study to capture the intermittently collapsing airway. In the past, fluoroscopy was widely employed, but, with the advent of super-fast 64-detector CT helical

B

FIGURE 22-11 A, Severe emphysema with air trapping compresses the malacic airway between bilaterally hyperinflated emphysematous lungs in expiration. B, Widely patent airway on inhalation.

Ch022-F06861.indd 284

1/21/2008 10:57:31 AM

Chapter 22 Tracheomalacia

are created to demonstrate in digital motion the collapse associated with the human cough (Fig. 22-14). Finally, threedimensional reconstructions demonstrate the longitudinal extent of the airway involvement. Studies correlating airway CT findings with confirmatory functional bronchoscopy have demonstrated a high degree of sensitivity (Boiselle et al, 2003).25,26 Currently, there is no substitute for witnessed airway collapse in real time, and, therefore, dynamic bronchoscopy remains the gold standard for diagnosing airway malacia. It is performed with a flexible bronchoscope with the patient under light sedation. The airways are observed first during passive breathing, then during forced exhalation, and finally during a voluntarily induced cough. These dynamic maneuvers are reproduced as each area of airway is inspected, starting at the glottic opening and finishing at the lobar bronchial orifices. As with the cine studies, abnormal collapse of the proximal airway is typically identified during expiration, especially with forced expiration and cough. These changes may be diffuse, involving the entire trachea and the main bronchi distally to the origins of the lobar bronchi, or segmental in distribution. The type of malacia and extent of airway involvement can be documented with accuracy and with certainty. In segmental tracheomalacia, the pattern and extent of complex lesions of mixed stenosis and malacia can be assessed with a clarity that allows for confident surgical planning. In cases of acquired TBM, the membranous trachea is usually widened and redundant and may lack the normal longitudinal folds. During expiration, pronounced anterior displacement of the redundant membranous trachea occurs, resulting in a semilunar configuration of the airway lumen. In most symptomatic cases, the airway completely collapses on forced exhalation, as the redundant membranous trachea becomes apposed to the inner surface of the cartilaginous rings (Fig. 22-15). These changes are diffuse and may extend into the smaller lobar airways. The severity and the distal extent of airway involvement can be properly assessed by dynamic

scanners, the dynamic airway CT has practically replaced all other radiologic imaging studies. With this modality, the patient is first imaged in full inspiration and then put through a series of forced expirations during imaging (Fig. 22-13). Finally, the patient is asked to repeatedly cough during imaging. Up to 3 cm of the trachea can be imaged in a fraction of a second. A series of reconstructed images is created demonstrating the collapsing airway induced by swings in intrathoracic pressure. Short CT cinetracheobronchograms

3

2 FEV1 1

Flow liters/sec

FVC 0 1

2

3

4

⫺1 ⫺2 ⫺3 ⫺4 ⫺5

FIGURE 22-12 Flow-volume loop in acquired tracheobronchomalacia shows abrupt reduction in expiratory flow and a prolonged expiratory plateau. The inspiratory phase is normal. (FROM KANAREK DJ: PHYSIOLOGY OF THE TRACHEA. IN GRILLO HC: SURGERY OF THE TRACHEA AND BRONCHI. HAMILTON, ONTARIO, BC DECKER, 2004, P 71.)

A

285

B FIGURE 22-13 Dynamic airway CTs obtained during inspiration (A) and forced expiration (B) in a patient with tracheomalacia.

Ch022-F06861.indd 285

1/21/2008 10:57:31 AM

286

Section 2 Upper Airway

A

B

C

D

E bronchoscopy, allowing for the level of functional detail required to make sound management decisions. For example, diffuse lobar bronchomalacia, which is demonstrated by collapse of the lobar bronchial orifices only on functional bronchoscopy, may be the rate-limiting lesion and preclude any potential benefit from surgical correction of the central airways (Fig. 22-16).

Ch022-F06861.indd 286

FIGURE 22-14 A-E, Sequential images of the human cough captured on a 64-detector CT helical scanner with airway protocol. They can be viewed as a cinetracheobronchogram in digital motion.

MANAGEMENT Postintubation/Post-traumatic Malacia Pure postintubation tracheomalacia is relatively uncommon. Some degree of malacia is often observed during the early phase of postintubation injury, in association with acute inflammation. In most patients, this softening disappears

1/21/2008 10:57:32 AM

Chapter 22 Tracheomalacia

287

FIGURE 22-15 Functional bronchoscopy showing a widely patent airway on inhalation (A) and herniation of the membranous wall on expiration (B).

A

B mosis.30 These alternative techniques are more complex and require the implantation of foreign material, making them prone to failure. On occasion, the airway involvement is more extensive than can be safely resected, or comorbidities make operative risk prohibitive. In these circumstances, internal stenting with a Montgomery silicone rubber T tube restores a safe and satisfactory airway.

Chronic Compression

FIGURE 22-16 Lobar bronchial collapse observed during exhalation on bronchoscopy.

when inflammation subsides and the scar matures. The use of high-dose steroids for another condition can interfere with the formation of normal scar and thus predispose to the development of malacia. More commonly, the airway damage results in a mixed injury of malacia and scar stenosis. The pathology is typically segmental, and the length is rarely greater than 3 cm, similar to the much more common pure postintubation fibrous stricture (Carden et al, 2005; Grillo et al, 2004).27-29 Bronchoscopic dilation, of even mixed malacia and stenosis, is futile because the compliant malacic component dilates to accept the balloon or rigid scope, leaving the stenotic component unaffected. Whenever possible, manage functionally disabling postintubation malacia by segmental resection and primary anastomosis. The procedure effectively eliminates the diseased segment in a single-staged operation with durable results. Reports in the otolaryngology literature of alternative techniques (e.g., ceramic ring reinforcement of the malacic segment by Amadee) have shown variable success but appear unwarranted due to the demonstrated safety and success of resection with primary anasto-

Ch022-F06861.indd 287

The extent of underlying malacia secondary to chronic tracheal compression cannot be assessed until after surgical removal of the extrinsic compression. With the offending mass eliminated, the airway can be evaluated intraoperatively, both in the surgical field and bronchoscopically. The area is visually inspected and manually palpated. The compressive effects of forced expiration can be simulated under the passive conditions of general anesthesia by applying suction to the airway through the bronchoscope while the ventilatory tubing is partially closed. If a malacic segment is discovered, a judgment regarding management must be made. If the segment is completely devoid of structural cartilage and severely malacic, then simultaneous segmental tracheal resection and primary reanastomosis is indicated. If sufficient cartilage is present and arranged in a configuration that appears to provide structural support, then mild to moderate malacia can be left in place without an attempt at surgical correction. In most of these cases, the compressed segment of trachea is abnormally soft but does present an airway problem after extubation. Some patients require a period of postoperative airway support with short-term intubation. However, if breathing and coughing are critically impaired after a short period of intubation, an indwelling T tube or silicone tracheal stent offers an immediate solution and can almost always be removed within a few weeks or months. A T tube is usually superior to stenting because the external T limb prevents migration. Although a conventional open tracheotomy is effective, a T tube is superior because it stents above and below the stoma to custom lengths, is less traumatic, and allows for cough, speech, and normal humidification of the airways. Other options include application of a Marlex mesh

1/21/2008 10:57:33 AM

288

Section 2 Upper Airway

wrap or artificial rings of Gore-Tex and stainless steel wire to provide external support.31,32 As described earlier, these techniques are complex and prone to failure and are reserved for extensive reconstructions in the young and otherwise healthy patient who is resistant to lifelong T tube management.

Relapsing Polychondritis As the name implies, relapsing polychondritis is an incurable systemic and recurring disease. Therefore, avoid attempts at surgical correction because the process is ongoing and not amenable to a one-time surgical correction. Treatment is currently palliative. Diffuse or segmental malacic segments are managed with some type of internal stent (T tube, T-Y tube, or Y tube). Results are often poor because stents are by necessity of smaller diameter and longer length than are effective for the clearance of secretions (Fig. 22-17). They are prone to obstruction by inspissated secretions, and patients often die from sudden respiratory collapse. It is obviously best if relapsing polychondritis is discovered early and

A

FIGURE 22-17 A, Diffusely narrowed airways in relapsing polychondritis. B, Small-diameter Y tube used by necessity. C, Axial CT image demonstrating the tight fit even with a small-diameter Y tube.

Ch022-F06861.indd 288

systemic treatment initiated expeditiously to prevent further airway damage.

Primary Congenital Tracheobronchomalacia In most cases of primary congenital TBM, the malacia is not sufficiently severe to warrant treatment. As the child grows and matures, so do structural elements of the airway, resulting in larger, stiffer, and stronger cartilage. Symptoms usually resolve by age 1 to 2 years.1,2,33,34 When needed, conservative management with CPAP, chest physiotherapy, humidified oxygen, and aggressive treatment of respiratory infections is indicated until the child outgrows the condition.35,36 In severe, life-threatening cases in which conservative measures have failed, internal stenting with specially designed tracheostomies or T tubes is necessary. Surgical repair by external splinting with autologous or prosthetic material has been reported, and limited studies have not shown an adverse effect on airway growth. However, the invasive nature and inherent risks and uncertainties associated with surgical reconstructions of the pediatric airway should dissuade

B

C

1/21/2008 10:57:36 AM

Chapter 22 Tracheomalacia

attempts at early surgical correction. Most children ultimately outgrow the condition despite the need for early intervention; therefore, delay attempts at definitive surgical correction until the passage of time identifies those truly in need of surgical reconstruction.

Acquired Tracheobronchomalacia The natural history of adult patients with acquired TBM (either primary or associated with emphysema) or congenital Mounier-Kuhn syndrome is disease progression.11,37,38 Jokinen and colleagues11 monitored 17 patients with diffuse airway malacia and performed repeat bronchoscopy at 5 years. The severity and extent of airway malacia progressed in 13 of the 17 patients. Those with isolated tracheomalacia were shown to have progression of the disease to involve the main bronchi, and those with isolated main stem bronchomalacia progressed to involve the trachea as well. The severity of malacia in any location also progressed.11 As the airway disease progresses, many patients suffer worsening dyspnea on exertion and more frequent and severe respiratory infections. Some are simply inconvenienced by the recurrent infections and lifestyle restrictions, but for others the symptoms are debilitating and the infections life-threatening. Many patients spend long periods in acute care and pulmonary rehabilitation hospitals recovering from infectious complications. Patients with mild to moderate disease and those with comorbidities that preclude invasive interventions benefit from conservative management. Treatment is palliative and is directed at the infectious complications. This involves suppression of bacterial overgrowth with long-term rotating antibiotics and improved secretion clearance with CPAP, positive end-expiratory pressure (PEEP), flutter valves, vibration vests, and chest physiotherapy. Dyspnea on exertion can be partially ameliorated with supplemental oxygen therapy. Internal airway stenting is reserved for patients who fail conservative management but are not candidates for definitive surgical correction. It is a conceptually appealing treatment because the stents are relatively easily delivered through natural airway passages, and the internal support is immediate and effective. Patients usually experience a dramatic and immediate improvement in breathing, with improved comfort and less effort. Their ability to clear secretions and maintain effective pulmonary hygiene is usually improved but remains suboptimal. Although endobronchial stenting is effective in the short term, in the long term it is fraught with complications. We have had a complication rate greater than 80% with endobronchial stenting in patients with acquired TBM. Complications can be relatively minor, such as chest discomfort, intractable cough, dyspnea from thick secretions coating the internal lumen, and recurrent stent-associated tracheobronchial infections or pneumonia. Serious complications, such as stent migration, inspissated mucus, and exuberant granulation tissue, can lead to life-threatening airway obstruction. All such complications, minor or major, necessitate stent extraction and pulmonary rehabilitation. Occasionally, treatment with chronic indwelling stenting is necessary. To prevent stent migration in the oversized airways, silicone Y stents are preferred (Fig. 22-18). Management

Ch022-F06861.indd 289

289

with chronic stenting is a major commitment for both patient and physician because these devices require constant maintenance. Surveillance bronchoscopies are required to assess for impeding complications. If impending obstruction from inspissated sputum is detected, stents are replaced. If impending obstruction from granulation tissue is detected, stents are removed, granulation tissue is ablated, and the airway is allowed to heal before stents are again placed. This often requires a period of hospitalization with aggressive chest physiotherapy, intravenous antibiotics, and monitored recovery before discharge or stent replacement. Avoid metallic stents because extraction to treat complications is arduous and dangerous. In 1954, Herzog and Nissen39 were the first to describe the condition of expiratory stenosis of the trachea and main stem bronchi. They delineated the pathophysiology and pioneered the surgical treatment. The surgical principles they outlined were to restore airway shape and stabilize the posterior membranous wall. They performed early tracheoplasties by suturing thin bone grafts to the membranous trachea in an effort to stabilize it. Rectus abdominus fascia and polytetrafluoroethylene (PTFE) were employed later.39 In 1958, Herzog13 reported on 17 patients treated with tracheoplasty and described significant improvement in their ability to clear secretions and maintain pulmonary hygiene. Subjective improvement in breathing, with fewer episodes of dyspneic crises, was also noted. In 1965, Rainer and associates (Rainer et al, 1963; Rainer et al, 1965)40,41 described his technique in which a slab of specially prepared Marlex was secured to the membranous wall of the trachea with so-called reefing of the redundant membranous component. In patients with significant cartilaginous malacia, polypropylene rings were added anterolaterally. Among their 12 patients, 4 late deaths occurred (3-11 months after surgery): 3 due to unrelated disease and 1 due to erosion of the prosthesis into the airway with ultimately fatal distal pneumonia. Of the eight longer-term survivors, four were significantly improved clinically, and in each case there was quantitative documentation with improvement in pulmonary function tests. In a later publication (1968) reviewing 19 patients,42 the additional fatal complications of esophageal and aortic erosion by the prosthesis were reported. Grillo43 also experimented early with fascia lata, pericardium, and PTFE. He found that biologic materials attenuated with time and that PTFE failed to become incorporated with scar, instead forming seromas leading to partial obstruction. Reoperations to remove the PTFE and repair the airway were necessary. Grillo settled on the use of polypropylene mesh (Marlex), which by virtue of its mesh design allows for vigorous tissue ingrowth; this incorporates the mesh in scar, reducing the risk of foreign body infection and extrusion and eliminating seroma formation. The soft pliability of the mesh reduces the risk of erosion into surrounding mediastinal structures. The mesh is inexpensive and readily available. More recently, Grillo43 reported results in 14 patients over the past decade. All patients felt subjectively improved early, with decreased dyspnea, cough, and secretion retention. Mean FEV1 improved from 51% to 73%, and peak expiratory flow from 49% to 70%. Of the 10 patients available for long-term

1/21/2008 10:57:37 AM

290

Section 2 Upper Airway

A

C

E

Ch022-F06861.indd 290

B

D

FIGURE 22-18 A, Silicone Y tube with traction studs. B, Chest radiograph showing stent position. C-E, CT images showing large Y tube in oversized airways.

1/21/2008 10:57:37 AM

Chapter 22 Tracheomalacia

follow-up, 6 were judged to have an excellent result, 2 good, and 2 poor due to collapse of unsplinted bronchial airways. Over the past 4 years, we have managed more than 70 cases of acquired diffuse TBM and performed more than 40 tracheobronchoplasties with Marlex mesh as described by Grillo. We recently reported on the results of our first 19 patients undergoing surgical correction.45 On dynamic airway CT, tracheal cross-sectional area and anterior-posterior dimension during maneuvers of forced exhalation increased 24% and 20%, respectively. On functional bronchoscopy, all patients had improvement in their tracheomalacia, with only one patient having residual bronchomalacia. There were no overt failures and no deaths. More than 90% of the patients had good to excellent results, and all reporting subjective improvement in their breathing. Sixty-two percent of patients with moderate to severe dyspnea reported complete resolution, 18% described moderate residual dyspnea, and 18% had mild residual dyspnea. Eighty percent of patients with moderate to severe intractable cough preoperatively reported complete resolution, and the remaining 20% reported a residual mild cough. All patients described resolution of their orthopnea and no longer required nocturnal CPAP. Eightyfive percent of patients who had difficulty clearing secretions preoperatively reported complete resolution after surgery, and 78% had no further episodes of recurrent bronchitis. Only 1 patient developed pneumonia in the mean follow-up period of 12.4 months.

SURGICAL TECHNIQUE Maintaining lung isolation without interfering with airway surgery remains difficult. The abundant, thick secretions associated with TBM easily clog the left bronchial lumen of a double-lumen endotracheal tube, and the large diameter and stiffness distort the airway, interfering with the airway restoration. Single-lumen tubes have a large Murphy’s eye and long balloon cuff, making bronchial placement troublesome. An ideal endotracheal tube would have a large, 8.0-mm single lumen, a guidable tip, and a short balloon cuff with no Murphy’s eye. Because such a device is not commercially available, the best approximation is a large double-lumen tube that has been customized by cutting off the tracheal lumen. The larger size allows for improved suctioning to clear the abundant secretions while reducing the overall distortion of the airway from within the lumen. Patients are approached through a right posterolateral thoracotomy entering the chest through the fourth intercostal space. The azygos vein is divided, and the pleura is incised along the tracheoesophageal groove, from the thoracic inlet to below the subcarinal space. The esophagus is dissected off the trachea, exposing the entire membranous airway posteriorly, from cartilaginous-membranous junction to cartilaginous-membranous junction, extending from the thoracic inlet to the carina. Carinal retraction exposes the membranous wall of the left main bronchus down to the lobar bronchial origins. The right main bronchus and bronchus intermedius are then exposed down to the right lower lobe takeoff. Using the technique described by Grillo,43 a 1.5 cm wide strip of polypropylene mesh is sutured with 4-0 Prolene to

Ch022-F06861.indd 291

291

FIGURE 22-19 Lateral anchoring sutures are placed in the cartilaginous-membranous junction, whereas the embrocating membranous sutures are placed submucosally and in a manner to gather up the excess posterior wall. Tying the anchoring stitches reshapes the airway.

the back wall of the trachea, in horizontal rows of four sutures across the trachea, placed at 1 cm intervals along the length of the trachea. The lateral sutures are placed in a modified mattress technique: first through the mesh, and then anchored in the cartilage at the cartilaginous-membranous junction, and back out through the mesh. The two middle sutures are placed in a similar fashion; however, the stitch is placed in a submucosal manner to capture and bunch up a portion of the excess posterior membrane without entering the airway lumen (Fig. 22-19). One row at a time is placed, starting as high in the thoracic inlet as can be properly placed. The lateral anchoring sutures are tied first, followed by the two middle imbricating sutures. A 2-cm extension of mesh is placed up into the thoracic inlet, beyond where suturing is impractical, in an effort to extend the buttressing effect of the mesh beyond the affected intrathoracic trachea. After the tracheoplasty is completed, a strip of polypropylene mesh is cut 1.0 cm wide and sutured three to a row to the back wall of the left main bronchus, starting at the lobar bifurcation and extending to the carina, where it is secured to the tracheal mesh. Importantly, the endotracheal cuff must be deflated during placement of the left bronchial mesh, to avoid distorting the repair. Occasional periods of apnea are helpful to place the most difficult distal left bronchial sutures. A final piece of mesh is tailored to match the outline of a normal-sized right bronchial airway, with 1.5 cm of width for the right main bronchus and 1cm for the bronchus intermedius. Sutures are placed three or four to a row, starting distally at the middle and lower lobe bronchial takeoffs and extending to the carina, where it is secured to the bottom of the tracheal mesh (Fig. 22-20). Our practice is to extubate patients at the completion of the operation. Airway edema, increased secretions from irritated mucosa and submucosal glands, and post-thoracotomy pain contribute to an initially ineffective cough. Routine chest physiotherapy and intermittent therapeutic bronchoscopy are essential until patients can raise their own secretions.

INDICATIONS FOR SURGERY Surgical correction is the only definitive treatment, and consider all adult patients with diffuse forms of TBM for candidacy. There are no established criteria for determining when

1/21/2008 10:57:38 AM

292

Section 2 Upper Airway

SUMMARY

FIGURE 22-20 Polypropylene mesh is secured from high in the thoracic inlet to the distal lobar bronchi bilaterally.

TBM is sufficiently severe to warrant consideration for surgical treatment. However, it is our practice to offer tracheobronchoplasty if the airways demonstrate complete collapse on forced expiration in the absence of severe emphysema and in association with one of the following: 1. Severe dyspnea on exertion 2. Recurrent pulmonary infections 3. Severe intractable cough Patients can expect excellent results in such indications. For patients with severe emphysema and dyspnea on exertion as their dominant symptom, results are mixed. The ability to improve symptoms of dyspnea by restoring the integrity of the central airways is limited by the patient’s lung capacity. The extent to which the central airway collapse contributes to dyspnea must be determined. A trial of endobronchial stenting is currently the best method of taking the effect of central airway collapse temporarily out of the clinical equation. The improvement in dyspnea must be substantial to justify the risks and costs associated with surgery. In contrast to patients with dyspnea, it is reasonable to expect improvement in those with intractable cough and recurrent airway infections despite severe emphysema, and in selected patients this is a sufficient indication. The clinical implications of complete collapse on cough only, and not with forced expiratory maneuvers, are incompletely understood and deserve further investigation before this condition can be factored into indications for surgery. Patients with congenital MounierKuhn syndrome usually respond well to surgery, but only if there is a large redundant malacic posterior membranous wall that is responsible for the symptoms. A giant trachea with no malacia may lead to respiratory problems but is not correctable with the operative technique described here.

Ch022-F06861.indd 292

For practical purposes, tracheomalacia can be divided into segmental and diffuse malacia. In general, segmental malacia is best treated with definitive tracheal resection and primary anastomosis. Stenting with Montgomery T tubes offers a temporary or permanent alternative. Diffuse forms of malacia in adults, such as acquired TBM and congenital Mounier-Kuhn syndrome, involve extensive regions of the airway and are best treated with restorative tracheobronchoplasty procedures. Overall results from the surgical treatment of malacic airways in properly selected patients are excellent. The noted exception is primary congenital TBM in newborns. Most children outgrow this condition by age 1 to 2 years and can be managed with conservative measures. As chronic obstructive airway disease claims more victims and dynamic airway CT imaging and functional bronchoscopic evaluations become more available, acquired TBM is being identified with increasing frequency. Further investigations need to focus on the prevalence of acquired TBM in the COPD population and define what role TBM plays in the debilitating dyspnea and recurrent pulmonary infections that COPD inflicts. In summary, there is a scarcity of experience with the surgical treatment of this type of diffuse malacic change. There are undoubtedly patients who could benefit from the available techniques, but the indications for selection have yet to be clearly defined. Different or more sophisticated tests of airway dynamics may be necessary to better delineate the indications in the future. There may well be a place for internal stenting with silicone rubber tubes—T tubes, T-Y tubes, or Y tubes—as an alternative to external surgical stenting in selected cases.

COMMENTS AND CONTROVERSIES This chapter presents a well-organized, thoughtful approach to a difficult problem. Primarily, it is the acquired form of tracheomalacia in patients with COPD that poses the real dilemma. As the authors note, with the use of newer imaging techniques and fiberoptic bronchoscopy in spontaneously breathing patients, tracheomalacia is diagnosed quite frequently in patients with COPD. On fiberoptic bronchoscopy in such patients, it is common to observe prolapse of the membranous wall of the trachea and main bronchi, even to the point of complete occlusion of the airway. However, this finding is rarely the cause of the patient’s functional impairment. In fact, such membranous prolapse probably should not be classified as tracheomalacia, because, in most cases, the prolapse of the membranous wall is not associated with flattening of the cartilaginous arch. In the rare instance in which tracheomalacia may be causing a functional problem, bronchoscopic observation demonstrates flattening of the cartilaginous rings simultaneously with forward movement of the membranous wall. In this situation, the malacia may indeed be causing obstruction and retention of secretions, whereas in the case of pure membranous prolapse, the prolapse is merely reflecting the increased intrathoracic pressure generated during the forced expiratory maneuver required by patients with severe COPD. As the authors point out, if tracheomalacia is suspected as a contributing factor to the patient’s symptoms, temporary stenting

1/21/2008 10:57:39 AM

Chapter 22 Tracheomalacia

with a silicone prosthesis, either a T tube or a Y tube, may well demonstrate that stabilization of the large airways does not improve either expiratory flow or the patient’s symptoms. The authors’ caution against placement of metal stents for airway stabilization needs to be highlighted. With rare exceptions, there is no place for expandable wire stents in patients with benign airway occlusion because the granulation tissue caused by such stents and the consequent difficulty in removing them both create a potential hazard for the patient. One exception may be in patients with relapsing polychondritis who tend to get collapse of lobar orifices, the intermediate bronchus, and the entire lobar bronchi. In this situation, palliative stenting, while maintaining airway flow to the upper lobes, may require noncovered expandable metallic stents. It must be noted that, with relapsing polychondritis, laryngeal and subglottic strictures are common, even to the point of complete obliteration of the upper airway, as inflammatory changes in the cartilage of the larynx and cricoid produce progressive stenosis. Further down in the airway, the softening of the cartilage is more likely to produce malacia. If stenting a considerable length of trachea together with the main bronchi is desired, the use of a silicone bifurcation stent for the lower trachea and main bronchi, and a separate T tube placed above it with the lower limb intussuscepting into the upper limb of the bifurcation stent, produces a satisfactory result and is easier to accomplish than the use of the one-piece T-Y stent, which has a fixed distance between the carina and the horizontal limb of the T portion of the tube. The technique for the use of Marlex mesh to splint the membranous wall of the trachea and bronchi described in this chapter is

Ch022-F06861.indd 293

293

designed not only to reduce membranous prolapse (which is rarely the problem) but also to fix the distance between the ends of the cartilaginous rings, to avoid flattening of the rings during expiration. Of historical interest, when membranous prolapse was thought to be a source of obstructive symptoms in patients with COPD, Perelman, from Moscow, treated this condition with a bronchoscopic injection of hypertonic dextrose solution through the membranous wall of the trachea, in order to induce sclerosis in the tissues behind the membranous wall to restrict its forward prolapse on expiration (personal communication). J. D. C.

KEY REFERENCES Boiselle PM, Feller-Kopman D, Ashiku SK, et al: Tracheobronchomalacia: Evolving role of dynamic multislice helical CT. Radiol Clin North Am 41:626-636, 2003. Carden KA, Boiselle PM, Waltz DA: Tracheomalacia and tracheobronchomalacia in children and adults: An in-depth review. Chest 127:9841005, 2005. Grillo HC: Postintubation stenosis. In Grillo HC: Surgery of the Trachea and Bronchi. Hamilton, Ontario, BC Decker, 2004, pp 301339. Jacobs IN, Wetmore RF, Tom LW, et al: Tracheobronchomalacia in children. Arch Otolaryngol Head Neck Surg 120:154-158, 1994. Rainer WG, Feilder EM, Kelble L: Surgical technic of major airway support for pulmonary emphysema. Am J Surg 110:788, 1965. Rainer WG, Hutchinson D, Newby JP, et al: Major airway collapsibility in the pathogenesis of obstructive emphysema. J Thorac Cardiovasc Surg 46:559, 1963.

1/21/2008 10:57:39 AM

chapter

23

INFLAMMATORY CONDITIONS OF THE AIRWAY Farzaneh Banki Douglas E. Wood

Key Points ■ Medical treatment is the first line of therapy for inflammatory condi-

tions of the airway. ■ Surgical intervention is indicated for treatment of airway obstruc-

tion and in the presence of refractory response to medical therapy. ■ Discrete lesions with a known or predictable natural history are best treated by resection and bronchoplastic reconstruction. ■ Many patients are disabled by long-segment stenosis or an ongoing systemic disease and require aggressive and repeated interventional bronchoscopy to palliate the symptoms and signs of central airway obstruction.

INFLAMMATORY CONDITIONS The lungs and tracheobronchial tree are susceptible to a variety of inflammatory conditions that affect pulmonary function and cause central airway obstruction. The airway involvement may be the initial or heralding event in the presentation or may be only one manifestation of a more generalized systemic illness. These entities are rare but create very difficult management problems and are occasionally associated with life-threatening events. The recognition of these conditions is therefore crucial for the practice of thoracic surgery. The cause of most of these conditions is unknown. The underlying pathology associated with these conditions consists of a combination of degenerative granulomatous disease, vasculitis, amyloid deposition, and fibrosis of the lung parenchyma and surrounding airways. Operative management is usually reserved for patients presenting with complications or for patients demonstrating a poor response to nonoperative management. Often, these patients are poor candidates for definitive surgical correction of their airway stenosis because of the systemic nature of their disease, extent of airway involved, or an ongoing inflammatory process in the airway. The most common inflammatory conditions involving the tracheobronchial tree are Wegener’s granulomatosis, relapsing polychondritis, granulomatous changes in the airway due to tuberculosis, or histoplasmosis, sarcoidosis, and amyloidosis.

Wegener’s Granulomatosis Wegener’s granulomatosis is a multisystemic inflammatory disease characterized by disseminated necrotizing granulomatous inflammation and necrotizing vasculitis involving multi-

ple organs, including the eyes, lungs, kidneys, skin, and nervous system.1 In the lung this disease is manifested by necrotizing granulomatous vasculitis of the upper and lower respiratory tract.2 In 1966, Carrington and Liebow (Flye et al, 1979)3,4 introduced the concept of a localized pulmonary form of Wegener’s granulomatosis that differs from the systemic variety by the relatively indolent evolution of the lung lesion and absence of severe renal involvement.5 This type of presentation may, however, just represent an early form of generalized Wegener’s granulomatosis that has not yet disseminated.6 The cause of Wagener’s granulomatosis is unknown. The coexistence of granulomatous inflammation and vasculitis and the deposition of immune complex suggest that delayed hypersensitivity and antigen-antibody reactions or immunologic reactions mediated by immune complexes are occurring.4 The patient’s initial symptoms depend on the primary organ involved, and any organ system may be the initial focus for the patient’s complaints (Flye et al, 1979).4 Nonspecific constitutional symptoms such as arthralgia, fatigue, malaise, anorexia, and weight loss are the most frequent. Respiratory involvement is an absolute requirement for the diagnosis of Wegener’s granulomatosis.7,8 This may be confined to the upper or lower respiratory tracts, but often involves both. It is unusual for a patient to have pulmonary disease without evidence of upper airway disease.9 The presence of fever usually indicates a secondary bacterial infection of the paranasal sinuses. The involvement of the upper airway includes rhinorrhea, sinusitis, nasopharyngeal ulcerations, and serous otitis media10; and the lower airway symptoms are usually cough and hemoptysis. Occasionally, the hemoptysis will be of an exsanguinating degree.11 The radiologic findings include multiple nodules, ranging in size from several millimeters to 9 cm but more often between 2 and 4 cm. Central necrosis with ulceration into bronchioles may cause cavitation of some nodules.12 Several cases with diffuse miliary-type opacities have been variously reported as generalized infiltrative and nodular densities or diffuse woolly opacities.13 Wegener’s granulomatosis needs to be included in the differential diagnosis of any pulmonary nodule.14 Suspicion must increase when cavitation and multiple nodules of variable size are present. When upper airway disease such as paranasal sinusitis and mastoiditis are associated, Wegener’s granulomatosis needs to be the primary consideration.15 Open-lung biopsy remains the most certain method of diagnosis in this disease. The classic histologic features of

294

Ch023-F06861.indd 294

1/21/2008 10:58:44 AM

Chapter 23 Inflammatory Conditions of the Airway

Wegener’s granulomatosis in lung tissue include necrotizing granulomatous inflammation, necrotizing vasculitis, bronchocentric inflammation, eosinophilic infiltrate, alveolar hemorrhage, and interstitial fibrosis.16 Cyclophosphamide is the first line of therapy and results in dramatic long-term remissions that persist even after the tapering and cessation of therapy.17 It is administered orally in a single dose of 1 to 2 mg/kg/day. In cases of rapidly progressive disease, treatment may be initiated intravenously in doses of 2 to 3 mg/kg/day for a few days, followed by conversion to oral therapy at doses of 1 to 2 mg/kg/day. Short courses of corticosteroids may be beneficial under special circumstances, such as with eye involvement and severe skin disease,4 and methotrexate is an alternative treatment to cyclophosphamide. Airway complications occur in 20% to 60% of patients with Wegener’s granulomatosis, ranging from severe subglottic laryngotracheal stenosis to ulcerating tracheobronchitis that may progress to distal tracheobronchial stenosis.18,19 Persistent endobronchial obstruction may become more common in patients with Wegener’s granulomatosis who now have an increase in their life expectancy due to therapy with cyclophosphamide. In patients without obvious signs of systemic illness or other abnormalities, this may have a similar appearance to idiopathic laryngotracheal stenosis and result in consideration of surgery at an inappropriate time when there has been no medical control of the underlying disease. Primary management consists of systemic therapy with cyclophosphamide and corticosteroids, but a majority of patients require endoscopic or surgical palliation of symptoms of severe airway obstruction. The most common airway manifestation is laryngotracheal stenosis, which occurred in 25 of 158 (16%) patients in the series published by Lebovics and colleagues.18 Only 5 of these patients were able to have their disease managed with systemic therapy, and the others were initially treated with tracheal dilation, with or without intralesional corticosteroid injection. Five patients ultimately required surgical correction with a laryngotracheoplasty with postoperative T-tube stenting, and 13 patients (52%) required a tracheostomy.18 Herridge and associates performed a laryngotracheal resection with thyrotracheal anastomosis in 3 patients with good outcomes in 2 of them,20 and Grillo resected 6 patients with Wegener’s granulomatosis and laryngotracheal stenosis but restenosis occurred in 4 (Grillo, 2004).21 Because Wegener’s granulomatosis is a systemic illness with a sporadic natural history and potential, continued inflammation of the airway, conservative nonoperative management is recommended as initial therapy. This usually consists of periodic tracheal dilation with bougies, rigid bronchoscopes, or bronchial dilating balloons, with or without intralesional corticosteroids and may result in palliation of airway symptoms for weeks to months. However, endoscopic management is rarely corrective and requires repeated interventions with some long-term risk of exacerbating endoluminal scar formation. In refractory stenoses in patients with localized disease, systemic remission, and absence of active airway inflammation, surgical resection may be considered. This is usually a laryngotracheal resection with a thyrotracheal anastomosis.

Ch023-F06861.indd 295

295

Relapsing Polychondritis Relapsing polychondritis is a rare inflammatory disease of unknown etiology characterized by recurrent inflammation and destruction of cartilaginous structures and connective tissue.22 It is believed to be an autoimmune disease and has been reported to be associated with rheumatoid arthritis, Wegener’s granulomatosis, and systemic lupus erythematosus.23 Relapsing polychondritis can occur in nearly all age groups but is most common in patients in their fourth and fifth decades and affects men and women equally. Typical findings are collapse and inflammation of cartilaginous structures, with a saddle-nose deformity and thickening and inflammation of auricular cartilage. Other associated findings may be polyarthritis, nasochondritis, and ocular or vestibular inflammation. The clinical course is highly variable and may progress rapidly or episodically. Treatment consists of systemic corticosteroids and cytotoxic agents. Approximately half of patients with relapsing polychondritis will have airway symptoms.24 Respiratory tract involvement is the greatest threat to life, and airway involvement usually involves tracheal cartilage from the cricoid cartilage to the segmental level. The initial symptoms of upper airway obstruction are usually due to inflammation and edema, which may respond partially to corticosteroids and immunosuppressive agents; however, progressive loss of cartilage results in airway collapse and fibrosis. Patients may present with shortness of breath and rapidly progressive stridor as a result of airway stenosis. CT of the chest may show circumferential worm-eaten–like thickening of the trachea and edema of the tracheal mucosa. Bronchoscopy will usually show a diffusely narrowed trachea from the cricoid to the main stem bronchi or even extending to segmental orifices. There is loss of normal cartilaginous structure of the trachea, and with long-segment collapse it has a similar endoscopic appearance to the normal esophagus with longitudinal folds of mucosa. Deep biopsy of the trachea shows cartilaginous degeneration and infiltration with inflammatory cells. Patients with tracheobronchial malacia and stenosis are not candidates for surgical correction because of the longitudinal extent of airway involvement. Nearly all patients who present with airway symptoms will ultimately require a tracheostomy, and approximately 25% of patients who develop later airway symptoms will require a tracheal appliance.24 Patients with prominent involvement of the subglottic larynx and proximal trachea are best managed with a tracheostomy or tracheal T tube, but even a tracheostomy may not be adequate airway palliation when patients have more extensive distal airway disease. Dilation is not effective because a prominent component of the process is malacia rather than stenosis, so endoluminal stenting is the only feasible management for extensive airway involvement. Our experience is that these patients require long-segment stenting, often extending from the cricoid cartilage to the level of the main stem bifurcations, and still may be compromised by distal segmental stenosis. Involvement of the cricoid may make it very difficult to seat an endoluminal stent proximally that remains stable into the subglottic larynx, so often a tracheal T tube is necessary to accomplish this proximal

1/21/2008 10:58:44 AM

296

Section 2 Upper Airway

stenting. Customized T-Y stents can be fashioned to accomplish a long-segment airway appliance, or a T tube or tracheostomy can be combined with distal airway stenting. Because this is a benign disease with a prolonged natural history, limited dominantly by central airway management, we strongly recommend solid stents that can be removed or revised easily. Metallic stents are used only when lifethreatening airway stenosis cannot be adequately palliated by solid stents because metallic stents carry the longer-term complications of granulations and stent stenosis or airway perforation (Tsunezuka et al, 2000).25-27

Tuberculous Tracheobronchial Disease Tuberculous tracheitis is an inflammatory condition of the airway resulting in diffuse narrowing of the trachea by a tuberculous pseudomembranous lesion. The presenting symptom in these patients is usually cough and stridor due to tracheal narrowing. Unlike the other inflammatory conditions there is a potential for complete resolution of the condition with appropriate antituberculous chemotherapy. Endobronchial tuberculosis may rarely occur without involvement of lung parenchyma. Chest radiography in these patients may or may not show lung involvement; therefore, the bronchoscopy and biopsy remain the diagnostic methods of choice. Histologic examination will confirm granulomatous involvement of the tracheobronchial tree, and bronchial washing will show Mycobacterium tuberculosis.28 Airway healing is usually reliable with antituberculous therapy, but circumferential submucosal fibrosis may result in cicatricial stenosis and symptoms of airway obstruction. The lesions are more likely to be seen in the distal trachea and the main stem bronchi. If there is long-segment airway stenosis, surgical reconstruction is not possible and management consists of periodic dilation with or without stenting. However, short-segment stenosis is best managed definitively with resection and primary reconstruction, but only after successful eradication of active infection.29 In more severe cases with involvement of lung parenchyma, sleeve lobectomy or pneumonectomy may be indicated (Hoheisel et al, 1994).30

Tracheobronchial Amyloidosis Tracheobronchial amyloidosis is an idiopathic disorder characterized by deposition of fibrillar proteins in the tracheobronchial tree causing airway narrowing and mucosal thickening by amyloid infiltration. Amyloidosis is a rare disease; and although many patients will have some aspect of pulmonary involvement, central airway obstruction is less common, occurring in only 7% of patients with pulmonary manifestations of amyloidosis in a series from the Mayo Clinic.31 Systemic amyloidosis has a poor prognosis and includes diffuse pulmonary involvement. More localized forms of amyloid can result in deposits of protein in the lamina propria of the bronchial mucosa, resulting in a localized endoluminal mass, or amyloidoma, or diffuse involvement and narrowing of the tracheobronchial tree.32,33 Patients with central airway involvement usually present with stridor and signs of airway stenosis. The ability of CT

Ch023-F06861.indd 296

to map airway involvement and identify the extraluminal manifestation of tracheobronchial amyloidosis makes it the diagnostic tool of choice in establishing the extent of this disease (O’Regan et al, 2000).34 Amyloid deposition may also be apparent in peritracheal tissue and lymph nodes, including the esophagus, and may be calcified (Grillo, 2004).21 A localized amyloidoma has a benign course except for the consequences of progressive obstruction, which can result in obstructive pneumonia when it involves the main stem bronchi or life-threatening obstruction when it involves the trachea or carina. Localized disease may have a similar appearance to that of other endobronchial tumors, such as a carcinoid tumor, mucoepidermoid tumor, or hamartoma, but will be readily discernible on histologic examination. Initial management consists of a biopsy or endobronchial excision, usually best accomplished by simple so-called core out of the endoluminal portion of the tumor with a rigid bronchoscope. If there is limited airway involvement, tracheal or bronchial resection and reconstruction may be beneficial for prolonged control33,35; but because of the rarity of these lesions, the natural history and risk of recurrence is not well characterized (Grillo, 2004).21 In cases of widespread tracheobronchial amyloidosis, amyloid deposits cause long-segment obstruction of large airways, resulting in recurrent infections and atelectasis. These patients are not candidates for surgical resection and need to be managed by a variety of interventional bronchoscopy techniques. The simplest management is endobronchial débridement, or core-out, in areas of more severe obstruction, which can result in prolonged periods of palliation.21,36,37 Laser vaporization of prominent areas of amyloid deposition or stenting of longer and more diffuse areas of obstruction are other options for endobronchial palliation.

Sarcoidosis Sarcoidosis is a systemic disease, of unknown etiology, characterized by noncaseating granulomas frequently involving mediastinal lymph nodes and pulmonary parenchyma. Sarcoidosis has a widely variable natural history, ranging from asymptomatic mediastinal adenopathy to mild pulmonary symptoms to life-threatening involvement of the lung parenchyma and/or other organ symptoms. Respiratory symptoms are nearly always due to restrictive lung disease, but occasionally these patients may suffer from airway obstruction due to either extrinsic compression by mediastinal adenopathy or fibrotic narrowing at any level of the central airway.38 In sarcoidosis, airway involvement, when it occurs, is diffuse, so these patients are not candidates for surgical resection. Extrinsic compression can occur due to extensive mediastinal or hilar adenopathy. If symptoms are present, endobronchial stenting can provide palliation. Lung transplantation is occasionally indicated when sarcoidosis results in severe end-stage lung disease. Rarely, fibrotic stenoses may result in central airway obstruction independent of lymphadenopathy. Because these lesions are diffuse and progressive, management consists of endobronchial palliation with interventional bronchoscopy rather than surgical reconstruction. Periodic dilation alone is

1/21/2008 10:58:45 AM

Chapter 23 Inflammatory Conditions of the Airway

the best treatment for stenoses of the trachea and main stem bronchi, but stenting is also a reasonable option if dilation only results in short-term benefit or for recalcitrant stenoses.36,38 Sarcoidosis is a benign disease with a prolonged natural history, even in patients with airway complications. Therefore, if stenting is contemplated, it is far preferable to place solid stents rather than expandable wire stents. Solid stents allow easy repositioning or removal, if necessary, and avoid the complications of obstructive granulations developing within the stent.27 In our experience, the fibrotic stenoses in patients with sarcoidosis often affect more distal airways, with patients having multiple lobar or segmental stenoses. These are much more difficult to manage because of their small size and because they involve multiple segments of the lung. Dilation of these airways can still be accomplished using a small bronchial dilating balloon or angioplasty balloon or small-sized esophageal bougies through a rigid bronchoscope. However, these smaller airways cannot be effectively stented and may require frequent repeat dilations to maintain airway patency.

Histoplasmosis With the suppression of tuberculosis by a combination of chemotherapy and public health measure, histoplasmosis has become the most common etiology of mediastinal granulomatous disease in the United States. Histoplasmosis can affect the central airways by developing bulky mediastinal lymph nodes that produce extrinsic compression, calcified lymph nodes that erode into the airway (broncholiths), or generalized fibrosing mediastinitis with compression of involved airways and major vessels. Histoplasmosis is endemic in much of the central United States, and acute infection is managed by antifungal agents, typically amphotericin, itraconazole, or ketoconazole. Patients may present with localized disease characterized by a mediastinal granuloma or histoplasmoma. The main stem bronchi and bronchus intermedius are most commonly involved, either by extrinsic compression or erosion of the lymph node into the airway.39 Although focal obstruction may be temporized by a bronchial stent, these patients are best treated by thoracotomy for resection of the histoplasmoma. Because of the dense fibrotic reaction and adherence of the granuloma to the airway, these are enormously difficult procedures; and it is reasonable to leave behind the capsule of the mass to avoid serious airway or vascular injury (Garrett and Roper, 1986).40 Some patients will present with hemoptysis associated with stridor or dyspnea, and CT will show the characteristic calcified mediastinal lymph nodes surrounding the main stem bronchi. In these patients the hemoptysis typically signifies erosion of the histoplasmoma into the bronchus with bleeding from associated inflammatory granulation tissue or from enlarged bronchial arteries. Bronchoscopy will reveal partial airway obstruction with a hard calcified mass, although this may be obscured by hyperplastic granulations. It is tempting to consider endobronchial extraction of these broncholiths, but this is done only with careful consideration of the underlying anatomy because the visible endoluminal mass is only

Ch023-F06861.indd 297

297

the tip of the iceberg and the remainder of the granuloma may be densely adherent to the pulmonary artery. We have performed several such extractions, but only in cases in which the lymph node mass appears to be clearly free of the adjacent vessels. In the remainder of cases it is safer to approach these patients with an open resection. Ideally, the disease in these patients is managed with a resection of the granuloma including a bronchoplastic airway reconstruction, but extensive involvement of the distal airway may mandate concomitant pulmonary resection.41 Fibrosing mediastinitis is a rare benign condition caused by proliferation of acellular collagen and fibrous tissue within the mediastinum. Although many cases are idiopathic, many cases in the United States are caused by an abnormal immunologic response to infection with Histoplasma capsulatum. Patients present with signs and symptoms of obstruction or compression of the superior vena cava, pulmonary veins or arteries, central airways, or esophagus. Two patterns of the disease are recognized and are classified as focal or diffuse. The focal type manifests as a calcified mass in the paratracheal or the subcarinal regions or in the pulmonary hilum. The diffuse type manifests as a diffusely infiltrating, often noncalcified mass that affects multiple mediastinal structures. CT and MRI are the diagnostic procedures of choice.42 Fibrosing mediastinitis may be suggested by obliteration of fat planes and calcification with or without the presence of a discrete mass evident on CT. The acute phase of this condition is treated with antifungal therapy (e.g., amphotericin B), but this does not appear to be effective in the fibrotic phase in the absence of ongoing histoplasmosis. Surgical intervention may be necessary to exclude malignancy in the asymptomatic noncalcified pulmonary or mediastinal mass or to relieve symptoms from compression or invasion by mediastinal adenopathy (Garrett and Roper, 1986).40 As mentioned earlier, these are extremely challenging operations technically due to the widespread and dense fibrosis; the goal is debulking of mediastinal scar around the airway—essentially a decortication of the central tracheobronchial tree.

SUMMARY Inflammatory conditions of tracheobronchial tree are rare, and medical treatment is the first line of therapy. Surgical intervention is mostly indicated for the treatment of airway obstruction and in the presence of refractory response to medical therapy. Discrete lesions with a known or predictable natural history are usually best treated by resection and bronchoplastic reconstruction. However, many of these patients are disabled by long-segment stenosis or an ongoing systemic disease and require aggressive and repeated interventional bronchoscopy to palliate the symptoms and signs of central airway obstruction. KEY REFERENCES Flye MW, Mundinger GH Jr, Fauci AS: Diagnostic and therapeutic aspects of the surgical approach to Wegener’s granulomatosis. J Thorac Cardiovasc Surg 77:331–337, 1979. Garrett HE Jr, Roper CL: Surgical intervention in histoplasmosis. Ann Thorac Surg 42:711-722, 1986.

1/21/2008 10:58:45 AM

298

Section 2 Upper Airway

Grillo HC: Infectious, inflammatory, infiltrative, idiopathic, and miscellaneous tracheal lesions. In Grillo HC: Surgery of the Trachea and Bronchi. Hamilton, Ontario, BC Decker, 2004, pp 363-396. Hoheisel G, Chan BK, Chan CH, et al: Endobronchial tuberculosis: Diagnostic features and therapeutic outcome. Respir Med 88:593597, 1994.

Ch023-F06861.indd 298

O’Regan A, Fenlon HM, Beamis JF Jr, et al: Tracheobronchial amyloidosis: The Boston University experience from 1984 to 1999. Medicine (Baltimore) 79:69-79, 2000. Tsunezuka Y, Sato H, Shimizu H: Tracheobronchial involvement in relapsing polychondritis. Respiration 67:320-322, 2000.

1/21/2008 10:58:45 AM

chapter

24

TRACHEOESOPHAGEAL FISTULA Paul Mazur Ross M. Bremner

Key Points ■ Acquired tracheoesophageal fistula (TEF) is uncommon and

■ ■ ■

■

■

■

requires a high index of suspicion for accurate and early diagnosis. Prevention of airway soilage and maintenance of nutrition are critical in management. Patients need to be weaned from mechanical ventilation before surgical intervention, if possible. Repair of the fistula entails positioning healthy tissue between the esophageal and tracheal repairs. Primary repair without tracheal resection may be possible for small fistulas. An anterior approach is most useful for high fistulas with circumferential tracheal injury. Resection of the involved trachea, repair of the esophagus, and reconstruction of the trachea is a safe and effective method for dealing with benign acquired TEF. Lower fistulas, or fistulas involving the esophagus and a major bronchus, are approached through the right chest, and tracheal resection may not be required. A creative, individualized approach is frequently necessary for optimal outcomes

A tracheoesophageal fistula (TEF) is an unusual entity and may be either congenital or acquired in origin. As a congenital lesion, it occurs in approximately 1 of every 3000 to 4000 live births and is discussed elsewhere in this text. Acquired TEF are classified as either benign or malignant. Roughly 50% to 70% of acquired TEF arise from tumors; these are primarily esophageal or pulmonary in origin, but mediastinal tumors such as lymphoma may also result in this lesion. Benign acquired TEF may arise from a variety of causes, including trauma and infection, but as a general rule have a much better prognosis than those arising from malignancy. Most TEF seen today are a result of prolonged tracheal intubation and occur in the middle to upper trachea. In either malignant or benign TEF, the initial management is prevention of pulmonary soilage and maintenance of nutrition. The former may require esophageal diversion if the fistula is low. Nutrition is supported with the aid of a jejunostomy tube. Surgical repair is best undertaken after the patient has been weaned from mechanical ventilation because postoperative extubation and avoidance of positive-pressure ventilation provide the best chance of healing for the tracheal repair. Surgical intervention for benign TEF involves resection of the fistulous tract, and possibly a section of trachea, and repair of the esophagus. Interposition of healthy tissue, such as a muscle flap or omentum, between the esophagus and the

trachea reduces the incidence of recurrence. Various interventions aimed at palliation, such as luminal stenting, are employed for cases of malignancy, although occasionally surgical resection is indicated.

HISTORICAL NOTE The first published reports of acquired TEF were based on autopsy findings.1 A later review found most to be caused by malignancy, with trauma and infection recognized as other causes,2 but by the 1970s it was clear that postintubation fistulization was emerging as the most important cause. The management of these fistulas was notoriously difficult until Grillo and colleagues, in a manuscript published in 1976, detailed their experience with management of socalled inflammatory TEF (Grillo et al, 1976).3 They espoused the utility of the anterior approach for resection and reconstruction. This method provided a safe and effective means to deal with the problem, the principles of which have remained essentially the same over the past 3 decades. The techniques, which were updated by Mathisen in 1991, have become the basis for surgical intervention for most benign acquired TEF (Mathisen et al, 1991).4 Descriptions of malignant TEF have remained relatively constant over the past several decades. Prognostic significance has essentially remained unchanged because this usually represents end-stage disease. Relatively new techniques in palliation, involving stenting of the aerodigestive tract, have shown promise for this dismal complication and have enabled patients to orally ingest at least liquids and soft food without the need for an operation. There are few indications today for bypassing a tumor by the substernal route in the face of a malignant TEF.

ETIOLOGY Postintubation Tracheoesophageal Fistula Before 1967, there were no reports of endotracheal cuff– related TEF. Flege was first to describe these lesions in mechanically ventilated patients with high-pressure cuffed endotracheal tubes.5 Cooper and Grillo eloquently described the mechanism of injury.6 They noted a consistent pattern of injury involving mucosal ulceration over cartilaginous rings during a course of 3 to 5 days. A continuum of injury dependent on the duration of exposure was elucidated. Fullthickness necrosis leading to fistula formation represented the end point of injury (Fig. 24-1). This was exacerbated by the presence of a rigid nasogastric tube. Today, the almost universal use of high-volume, lowpressure cuffs on endotracheal and tracheostomy tubes has 299

Ch024-F06861.indd 299

1/21/2008 10:59:38 AM

300

Section 2 Upper Airway

Nasogastric tube

Cricoid Esophagus Stoma Fistula Stenosis

A

B

FIGURE 24-1 A and B, The pathophysiologic etiology of endotracheal cuff–induced tracheoesophageal fistula. A high-pressure or overdistended cuff results in pressure necrosis between the cuff and the rigid nasogastric tube, producing a fistulous tract. Note the circumferential injury to the trachea at the level of the fistula, which often necessitates a tracheal resection at the time of definitive surgical repair. (FROM GRILLO HC: SURGERY OF THE TRACHEA AND BRONCHI. HAMILTON, ONTARIO, BC DECKER, 2004.)

decreased the incidence of intubation-related TEF to 0.5%. However, long-term intubation remains the most common cause of benign acquired TEF. Contributing factors include cuff overinflation, excessive tube motion, infection, hypotension, and diabetes.

Inflammatory Causes Infectious organisms may lead to the development of TEF, either by direct inflammation of the esophageal or tracheal mucosa or by mediastinal lymph node involvement leading to erosion of the neighboring organs. Often, specific organisms cannot be isolated from the fistulous tract because the active infection may have subsided by the time of patient presentation. Alternatively, these cases may involve organisms that are difficult to detect by serology or culture. Patients are often made more susceptible to infection due to malignancy or an immunocompromised state. Tuberculosis, a major cause of infectious TEF in the past, may involve esophageal mucosa or produce a tracheal or laryngeal ulcer, which may progress to a fistula. More frequently, caseous necrosis of peribronchial lymph nodes results in erosion into the aerodigestive tract. Additionally, the esophagus can become secondarily involved from a vertebral abscess or long-standing empyema. Lesions caused by tuberculosis may be misdiagnosed as malignancy because of their clinical and radiographic appearance. Accurate diagnosis has frequently only been made after resection. Infection by syphilis can produce a TEF either directly, via ulceration, submucosal gumma, or diffuse inflammation of the esophagus, or secondarily by mediastinal gumma. Direct surgical repair of an actinomycotic fistula was performed by Poncet in 1896.7 Actinomycosis leading to TEF was also described by Vinson and Sutherland, who noted sulfur granules in the sputum.8 Successful treatment was via

Ch024-F06861.indd 300

resection. Additional case reports document the potential lethality of this disease.9 Prolonged penicillin is an important adjunctive therapeutic measure. Histoplasmosis, recently a more important cause of TEF in endemic areas, may produce caseous mediastinal lymphadenopathy that can erode into surrounding structures. An exuberant fibrotic reaction to the capsule of the fungus in lymph nodes can result in mediastinal fibrosis and occasionally in TEF. Resection of the bulky mediastinal adenopathy has been advocated to avoid complications of nodal erosion. Repair of the TEF follows the same principles as described later in this chapter. Other infectious agents, such as Aspergillus, Candida, and cytomegalovirus, as well as noninfectious inflammatory conditions such as Wegener’s granulomatosis, have also resulted in TEF.10-13 Human immunodeficiency virus (HIV) infection and other immunocompromised states predispose some patients to severe esophageal infections with these unusual organisms. Treatment is aimed at control of both the infectious agent and the fistula.

Post-traumatic Tracheoesophageal Fistula Blunt Trauma Vinson first reported tracheoesophageal fistula after blunt trauma in 1936.14 The patient died 2 weeks after a motor vehicle accident. The tracheal and esophageal rupture communicated with the mediastinum, leading to gangrenous mediastinitis. Today, motor vehicle accidents continue to remain a leading cause of blunt force TEF. The typical patient is a young male who has sustained blunt force injury from impact with a steering wheel or airbag.15 Multiple concomitant injuries such as rib fractures or flail chest, hemopneumothorax, and pulmonary contusions may be present but are not invariable. Mediastinitis is a rare occurrence, and delays in diagnosis are frequent because the presentation may be subtle. Hypothetical mechanisms of injury involve either compression or rupture. Direct compression between the sternum and vertebral column may tear the membranous trachea and contuse the esophagus. Progression of inflammation to necrosis leads to fistula formation. Preexisting fixation of the anterior esophagus to the membranous trachea or the presence of an esophageal diverticulum may predispose individuals to fistulization. Symptoms may therefore develop over a period of days to weeks, as opposed to simultaneous rupture of the trachea and esophagus with immediate fistula formation. Lesions are often located at or immediately above the carina and are therefore most accessible for surgical repair via a right posterolateral thoracotomy. Diagnosis can be made with computed tomography (CT). Repair of both airway and esophagus, with interposition of healthy tissue such as an intercostal muscle flap, pericardial fat pad, or omentum, is usually successful, as described later.16

Penetrating Trauma Penetrating injuries that lead to TEF have been described after gunshot wounds, stab wounds, and impalements to

1/21/2008 10:59:38 AM

Chapter 24 Tracheoesophageal Fistula

301

the neck or chest.17 The cervical trachea is most commonly involved because thoracic injuries are often accompanied by nonsurvivable heart or great vessel trauma.

Postsurgical TEF after surgery is most commonly seen after esophagectomy as a complication of the esophagointestinal anastomosis. Treatment depends on the size of the TEF and the severity of associated sepsis. Options include conservative management with continued drainage for small fistulas, stenting of the fistula, or takedown of the anastomosis, repair of the airway defect, and delayed reconstruction of gastrointestinal continuity.

Burns and Caustic Injury Inhalation or chemical burns and caustic injury to the esophagus have been described as causes of TEF.18 TEF may occur as a direct result of esophageal necrosis from caustic ingestion or from later dilation of the stricture that has resulted.19,20 The degree of injury to the esophagus that has resulted in the TEF is usually so severe that esophagectomy is frequently required, with consideration given to reconstruction of the alimentary tract via the substernal route.

Barrett’s Esophagus The term Barrett’s ulcer refers to mucosal breakdown in a columnar-lined segment of esophagus. Continued and unchecked reflux of noxious gastric juice may result in deep penetration of the ulcer, to the point that it perforates into an adjacent organ.21 A few such cases have been described where the perforation resulted in a large esophagorespiratory fistula (Fig. 24-2). This is a unique situation because the airway is soiled not only by alimentation from above but also by reflux from below. Esophageal isolation by proximal diversion, gastric drainage by gastrostomy tube suction, or gastroesophageal junction stapling and nutritional support via a jejunostomy tube may allow for pulmonary rehabilitation and control of pulmonary sepsis. Definitive therapy usually requires esophagectomy because a Barrett’s ulcer represents end-stage esophageal disease. Repair of the tracheal or bronchial defect can be complex because of the size of the defect and degree of associated inflammation.21 Repair or resection again needs to be buttressed with healthy tissue, and consideration must be given to reconstructing the gastrointestinal tract via the substernal route.

Foreign Bodies Fish bones or other foreign bodies may result in a TEF at any level of the airway. In children, a peculiar entity of TEF after swallowing of disc batteries has been reported on multiple occasions.22 Urgent removal of an impacted disc battery by endoscopy is attempted to avoid this complication.

Malignant Tracheoesophageal Fistula The appearance of a malignant esophagorespiratory fistula often heralds the end of life due to complications of pulmonary sepsis. Onset may occur after the initiation of treatment

Ch024-F06861.indd 301

FIGURE 24-2 Computed tomographic scan of a large tracheobronchial fistula. Note the air-filled esophagus and the obvious communication between the two organs. A, Left main stem bronchus; B, esophagus. (FROM NIGRO JJ, BREMNER RM, FULLER CB, ET AL: PERFORATING BARRETT’S ULCER RESULTING IN A LIFE-THREATENING ESOPHAGOBRONCHIAL FISTULA. ANN THORAC SURG 73:302-304, 2002.)

such as chemotherapy or radiation therapy. The median survival time after diagnosis is in the range of only a few weeks. Therapy therefore is directed toward palliation, so that the patient can return home as soon as possible.23 Palliative therapy aimed at relieving symptoms of dysphagia, supporting nutrition, and maintaining a clear airway can prolong and improve the quality of the patient’s life. The primary malignancies associated with TEF include esophageal (at least two thirds of all cases), pulmonary, tracheal, laryngeal, and thyroid. Metastatic mediastinal lymphadenopathy may also lead to the development of a TEF. Tracheoesophageal fistulas have also been reported in other malignancies such as lymphoma. TEF resulting from active disease or from tumor lysis after chemotherapy or irradiation has been well described.24,25 The largest published series describing malignant TEF was from the Memorial Sloan-Kettering Cancer Center. Burt and colleagues reported on 207 patients collected over a 62-year period.23 The majority of the patients were male with upper thoracic squamous cell esophageal tumors. Most patients received radiation therapy as part of the treatment regimen for their primary tumors. Symptoms developed in 90% of patients; symptoms were predominantly cough, aspiration, fever, or some combination of these. Diagnosis was ascertained mainly by contrast radiography (Fig. 24-3). Survival without treatment was 1 to 6 weeks. Palliation involved a variety of interventions, from chemotherapy or radiation therapy alone to esophageal exclusion or bypass. Survival could be extended up to 12 months, but most patients died within 3 months. An important conclusion was that a greater proportion of patients survived beyond 35 days with earlier intervention (i.e., within 1 week after diagnosis). The mode of death was predominantly pulmonary sepsis. However, most of these patients were treated in the era before selfexpanding covered stents, which have recently helped significantly in the management of this difficult complication (see later discussion).

1/21/2008 10:59:38 AM

302

Section 2 Upper Airway

FIGURE 24-4 A, Flexible esophagoscopy in a patient with a tracheoesophageal fistula resulting from a penetrating Barrett’s ulcer. The arrow shows the fistula. B, In the same patient, the esophageal lumen is distended by the inspiratory flow of the ventilator. (FROM NIGRO JJ, BREMNER RM, FULLER CB, ET AL: PERFORATING BARRETT’S ULCER RESULTING IN A LIFE-THREATENING ESOPHAGOBRONCHIAL FISTULA. ANN THORAC SURG 73:302-304, 2002.)

FIGURE 24-3 Barium esophagogram of a malignant tracheoesophageal fistula. Note the barium contrast in the left bronchial tree. This is often the best study in patients with suspected malignancy because the patients are usually extubated and the study provides information about the extent of the tumor for possible stent procedure planning.

PRESENTATION AND DIAGNOSTIC STUDIES A high index of suspicion is required to accurately detect a TEF. Patients are often critically ill and on continued mechanical ventilation. Presentation may be subtle, but rarely are patients asymptomatic. Increased secretions, aspiration of gastrointestinal contents (bilious contents in the tracheal aspirate), or recurrent or recalcitrant pneumonia prompt investigation. Other clues include sudden abdominal distention while on positive-pressure ventilation and inexplicably low exhaled tidal volumes. Another clinical sign noted in intubated patients is the so-called breathing bag sign, in which phasic inflation and deflation of a plastic nasogastric collection bag occurs with the respiratory cycle. Extubated patients may complain of choking while swallowing (Ono’s sign). This is often positional, exacerbated by upright or left lateral decubitus positioning. Because most fistulas arise from the anterior esophageal wall, patients often select the dorsal recumbent position to minimize coughing. Plain radiographs are usually inadequate to diagnose TEF, although nonspecific signs may be apparent. CT scans may also provide documentation of a TEF. In this era of highresolution, multislice CT scanning, the diagnosis can often be made or suggested by CT, and it is being used more frequently as the first diagnostic test (see Fig. 24-2). However, contrast radiography and fiberoptic endoscopy remain the mainstays

Ch024-F06861.indd 302

of diagnosis. Care is exercised to use thin barium only and to avoid the use of oral Gastrografin when esophagograms are performed because the latter can result in a severe pneumonitis if aspirated into the pulmonary tree. Upright barium esophagograms are most useful in the extubated patient with suspected malignant TEF (see Fig. 24-3). In intubated patients, endoscopy is more useful. The TEF is usually more apparent on bronchoscopy than on esophagoscopy, although either may be diagnostic and both are probably performed (Fig. 24-4). Biopsies of the fistulous margins may be indicated if the etiology of the TEF is unclear. Care is taken to evaluate the entire trachea in the intubated patient by withdrawing the endotracheal tube up to the cords to facilitate good exposure to the upper trachea.

MEDICAL MANAGEMENT Because most benign acquired TEF result from cuff injuries, prevention is possible by keeping the pressure in the cuff in the desired range and avoiding overinflation. Continued education of new intensive care unit staff and of respiratory therapists will help to continue to decrease the occurrence of this complex lesion. Acquired TEF rarely close spontaneously, although this has occasionally been described.26 Tissue sealants and glues have also been used, but they are likely to be successful only in very small fistulas, and their use is not to be routinely recommended. Surgical intervention is almost always required in benign TEF, whereas a more conservative approach, such as stenting, is indicated for malignant TEF. Of utmost importance to a successful eventual outcome is the initial medical management of these ill patients. Once the diagnosis of TEF has been made, prompt intervention is indicated. The first goal is to prevent further soilage of the airway. In intubated patients, this can be achieved by placing an endotracheal tube proximal to the carina but below the fistula. The head of the patient’s bed is elevated, and aggressive pulmonary toilet is instituted. The nasogastric tube, if present, is removed to relieve the mechanical pres-

1/21/2008 10:59:39 AM

Chapter 24 Tracheoesophageal Fistula

sure on the damaged airway. Drainage of gastric secretions can be continued through a gastrostomy tube. Nutritional support is necessary to allow for adequate healing and in preparation for eventual operation. This is best achieved by feeding through a jejunostomy tube. Infectious complications are aggressively treated, and the patient is weaned from mechanical ventilation. This approach permits a successful single-stage surgical intervention in the case of benign acquired TEF and allows for maximal palliation in the case of malignant TEF. A variety of treatment options for malignant TEF have been described, such as simple closure, tracheal resection, interposition of intestinal grafts and muscle flaps, and stenting, all with variable success. The goal is to again protect the lungs from soilage, to maintain nutrition, and to complete definitive therapy. Stent technology has recently improved to the point that either esophageal or tracheobronchial covered stents can be used fairly easily in the setting of most TEF. In fact, because many of these stents can be removed, they can be used temporarily in benign TEF to exclude the bronchial tree from further soilage and to facilitate extubation. Care is exercised when placing the esophageal stent in a malignant fistula because a bulky tumor may result in compression of the airway and life-threatening respiratory embarrassment. A maneuver of inflating a balloon in the esophagus and observing the tracheal lumen with a bronchoscope may give some indication of the risk of airway compression. An airway stent can always be placed first, before placing the esophageal stent, to offer some airway protection in this circumstance. In the unusual setting of a TEF occurring after tumor lysis in lymphoma, temporary exclusion of the airway from the digestive tract is important. The ability to place covered stents into both the airway and the esophagus has enabled separation of esophageal and tracheal lumens so that therapy for the lymphoma can be continued. If the therapy is successful and the patient’s prognosis is good, repair can be undertaken at a later stage. These fistulas may be large and are often in an irradiated field, so they represent an unusual challenge for definitive repair. Adherence to the principles described in the next section offers the best chance of success.

SURGICAL MANAGEMENT Anesthesia The management of anesthesia during surgical repair is complex. Spontaneous ventilation to assist with airway management has previously been advocated but is not always necessary. The use of short-acting muscle relaxants helps to ensure extubation at the end of the procedure. Lesion location has obvious implications because cross-field ventilation or various forms of bronchial blockers or double-lumen tubes may be required. In children, main stem intubation directed by bronchoscopy or placement of an occluding Fogarty balloon has allowed deflation of the lung for repair of lower TEF. In upper fistulas, orotracheal intubation with a small tube passed below the level of the fistula is often necessary in the beginning of the procedure. This may require removal of an exist-

Ch024-F06861.indd 303

303

ing tracheostomy tube. The balloon of the endotracheal tube can be placed across the fistulous connection to temporarily occlude the fistulous tract. During the procedure, if a tracheal resection is indicated, the tube can be drawn back to just below the cords and cross-field ventilation applied to the distal trachea after transection. A heavy silk suture tied to the endotracheal tube before retraction facilitates replacement of the tube during tracheal reconstruction. Paramount to a successful outcome are good communication and planning of the procedure by both anesthesiologist and surgeon. Control of the airway throughout the procedure and avoidance of further pulmonary soilage ensure a safe operation.

Diversion Occasionally, a patient cannot be stabilized with medical means alone and continues to soil the airway despite the measures discussed. In this situation, esophageal diversion may be necessary. This is most common for lower TEF or esophagobronchial fistulas.21 A cervical esophagostomy, stapling of the gastroesophageal junction, and gastrostomy and jejunostomy help exclude the gastrointestinal tract from the airway to aid with management of pulmonary sepsis and enable intestinal feeding (Couraud et al, 1996).26 The gastroesophageal junction is stapled with two layers of staples but not divided. In 1 to 3 months, the esophageal lumen will spontaneously re-establish continuity without further surgical manipulation, but in this period of time the patient can be stabilized and adequate nutrition instituted, so that definitive repair of the fistula and intestinal reconstruction can be performed. Definitive repair may require replacement of the esophagus with either stomach or colon via the substernal route.

Surgical Repair A variety of surgical approaches for the repair of acquired TEF have been advocated, including direct suture closure of both esophageal and tracheal defects, esophageal diversion, closure of defects with muscle flaps, intestinal interposition, and tracheal repair with defunctioned esophagus. The position of the fistula (high or low), the size of the fistula, and associated abnormalities of the surrounding trachea all play a role in surgical decision making. The approach to the fistula in the neck may be from the side, either in front of or behind the sternocleidomastoid muscle, or from the front, using a U-shaped cervical incision. The approach to low intrathoracic lesions (those near the carina or in either main stem bronchus) is through a right-sided posterolateral thoracotomy. Even fistulas between the left main stem bronchus and the esophagus can be approached this way.21 Lesions in the thoracic inlet can be approached from a cervical incision, splitting the manubrium in the midline if necessary. Mathisen and colleagues showed that small defects, in the absence of associated tracheal stricture, can be closed primarily with resection of the tract and interposition of healthy tissue (Fig. 24-5) (Mathisen et al, 1991).4 In this situation, exposure to the fistulous tract may be more easily done from the side. Care must be exercised to preserve the recurrent

1/21/2008 10:59:40 AM

304

Section 2 Upper Airway

FIGURE 24-5 Direct repair of a small tracheoesophageal fistula. A, The approach is from the side, and the recurrent laryngeal nerve is elevated with the trachea anteriorly. B, The tract is excised, and both trachea and esophagus are repaired. C, A transposition of a strap muscle separates the two repairs. (FROM MATHISEN DJ, GRILLO HC, WAIN JC, HILGENBERG AD: MANAGEMENT OF ACQUIRED NONMALIGNANT TRACHEOESOPHAGEAL FISTULA. ANN THORAC SURG 52:759-765, 1991.)

Recurrent laryngeal nerve

Small tracheoesophageal fistula

Esophagus

A

C

B

laryngeal nerve, by identifying it at a site remote from the inflammatory site and elevating it with the trachea while dissecting out the fistula from the esophageal side. The tract is transected and the trachea oversewn with absorbable suture. The mucosa of the esophageal defect generally is clearly delineated and then closed with interrupted suture; then, a second layer of esophageal muscle is closed over this repair, usually with fine silk suture. The suture lines, in the absence of a tracheal resection, abut one another, and in this case it is necessary to interpose some healthy tissue, such as a transposed strap muscle, between the two suture lines (see Fig. 24-5). A high fistula from a cuff injury is usually associated with a tracheal stricture that involves the entire circumference of the tracheal wall (see Fig. 24-1). The gold standard for repair of these defects is the procedure first described by Grillo, Moncure, and McEnany and later supported by Mathisen and colleagues (Grillo et al, 1976; Mathisen et al, 1991),3,4 wherein closure of the defect in the esophagus is followed by tracheal resection. This approach has had the best long-term results also in other centers (Macchiarini et al, 2000).27 Historically, cuff-related injuries repaired without a tracheal resection were complicated by long-term tracheal strictures, which often required a separate resection procedure. The approach is made from the front, using an anterior U-shaped incision or a collar incision with extension inferiorly to the manubrium as needed (Fig. 24-6). Advantages to this approach include the more direct dissection of the trachea, which is less likely to devascularize either structure, and a decreased potential of injury to the recurrent nerves. After induction of anesthesia, bronchoscopy and esophagoscopy are carried out to delineate the anatomy. Oral intubation follows, and the balloon is positioned to obturate the fistula. A nasogastric tube placed on suction keeps the stomach

Ch024-F06861.indd 304

deflated and helps identify the esophagus in the inflammatory field. A low collar incision, which may or may not include the tracheostomy stoma, provides initial exposure, with vertical extension over the upper sternum added as needed. Flaps that include the platysma muscle are elevated to provide excellent exposure to the entire cervical trachea. The trachea is then mobilized as fully as possible anteriorly, but with preservation of the lateral blood supply. The esophagus is exposed via lateral dissection at the level of the fistula. Devascularization of the distal trachea is avoided by limiting lateral margins to no more than 1 or 2 cm below the anticipated division point. The recurrent nerves do not need to be identified if dissection is kept close to the trachea and esophagus. In fact, it can be very difficult to identify the nerves because the tissues are often involved in a significant inflammatory reaction. Intraoperative bronchoscopy may aid in localizing the fistula to further direct dissection. At this point, the trachea is divided at the level of the fistula, and cross-field ventilation is instituted. The proximal damaged trachea is retracted upward, exposing the esophageal defect to allow an elliptical excision. Adequate mobilization needs to be ensured to allow a tension-free closure of the defect. The tracheal resection is then completed. This may or may not include the tracheal stoma because the location of the fistula is ordinarily lower, owing to the position of the cuff. Closure of the esophagus is performed using two longitudinal layers of 4-0 silk and inverting the mucosal layer, taking care not to narrow the esophageal lumen. Tracheal anastomosis is performed with 4-0 Vicryl or PDS sutures with the knots outside the lumen. Tracheal release measures are infrequent but need to be performed if there is excessive tension on the suture line. In the case of a tracheal resection, opposing suture lines are usually avoided

1/21/2008 10:59:40 AM

Chapter 24 Tracheoesophageal Fistula

Esophagus Esophagus

Level of tracheoesophageal fistula

305

FIGURE 24-6 A-D, Anterior approach to a high tracheoesophageal fistula with associated circumferential tracheal damage. A U-shaped incision in the front of the neck enables direct visualization of the anterior trachea, including the tracheostomy site if present. Dissection is kept very close to the tracheal wall to avoid injury to the recurrent laryngeal nerves. A, Transection of the trachea enables visualization of the fistula and the esophagus. B, Cross-field ventilation is necessary. C and D, A two-layer esophageal repair is undertaken, followed by a segmental tracheal resection and reconstruction. (FROM GRILLO HC, MONCURE AC, MCENANY MT: REPAIR OF INFLAMMATORY TRACHEOESOPHAGEAL FISTULA. ANN THORAC SURG 22:112-119, 1976.)

A

B

Esophagus Sternohyoid M.

C

D

because the esophagus does not change length, and the tracheal anastomosis is usually superior to the esophageal repair. A muscle flap or interposition of healthy tissue may not be necessary in this situation. Addition of a pedicled muscle flap of either sternothyroid or sternohyoid may be performed before completion of the tracheal anastomosis if concern exists in patients with massive inflammation or poorly aligned suture lines. However, a bulky interposition must be avoided because it could compromise the tracheal lumen. In the case of extensive tracheal damage that does not permit primary closure (Mathisen et al, 1991),4 placement of a tracheal T tube after esophageal repair may be necessary.

Ch024-F06861.indd 305

KEY REFERENCES Couraud L, Ballester MJ, Delaisement C: Acquired tracheoesophageal fistula and its management. Semin Thorac Cardiovasc Surg 8:392, 1996. Grillo HC, Moncure AC, McEnany MT: Repair of inflammatory tracheoesophageal fistula. Ann Thorac Surg 22:112-119, 1976. Macchiarini P, Verhoye J, Chapelier A, et al: Evaluation and outcome of different surgical techniques for post-intubation tracheoesophageal fistulas. J Thorac Cardiovasc Surg 119:268-276, 2000. Mathisen DJ, Grillo HC, Wain JC, Hilgenberg AD: Management of acquired nonmalignant tracheoesophageal fistula. Ann Thorac Surg 52:759-765, 1991.

1/21/2008 10:59:41 AM

chapter

25

MANAGEMENT OF VOCAL FOLD PARALYSIS Priya D. Krishna Clark A. Rosen

Key Points ■ Vocal fold paralysis is a risk associated with many thoracic surgical

procedures. ■ Paralysis significantly adds to postoperative morbidity by contribut-

■ ■ ■

■

ing to dyspnea on exertion due to loss of self-controlled positive end-expiratory pressure (auto-PEEP), poor cough and clearance of mucus, and aspiration. Unilateral vocal fold paralysis results in a breathy, weak voice. Bilateral paralysis causes airway compromise. Diagnosis is suspected based on clinical symptoms but requires direct visualization via flexible or rigid endoscopy for confirmation. Early treatment is recommended to decrease the risk of pulmonary complications and enhance quality of life and vocal function.

Vocal fold paralysis (VFP) is a known consequence of intrathoracic pathologic processes and is a complication of thoracic surgery. All too commonly, the issues related to VFP in thoracic disease and in patients undergoing thoracic surgery are neglected. This results in significant morbidity, mortality, and quality-of-life (QOL) issues for this patient population. VFP is accompanied by several sequelae that can greatly affect QOL and potentially can be fatal. The incidence of postoperative VFP in thoracic cancer surgery ranges between 4% and 31% in the literature and is 4% for subtotal esophagectomy (Schneider et al, 2003).1 Optimal evaluation and treatment of VFP can improve QOL and minimize an important source of morbidity and mortality after thoracic surgery.

RELEVANT ANATOMY AND PHYSIOLOGY One key to prevention of VFP is intimate knowledge of the anatomy of the motor nerve to the vocal fold, the recurrent laryngeal nerve (RLN). The nerve begins as the vagus nerve (cranial nerve X) at the level of the medulla oblongata. The jugular foramen contains the jugular ganglion, housing cell bodies of parasympathetic and sensory nerves of the vagus. The nodose ganglion is located just inferior to the jugular foramen and contains fibers that then join the pharyngeal plexus and contribute to the superior laryngeal nerve (SLN). The vagus then courses posteromedial to the jugular vein in the carotid sheath.2,3 The course of the right vagus follows the common carotid artery inferiorly, and the RLN separates just anterior to the subclavian artery. It then loops around the subclavian artery at its takeoff and resumes a superior direction, along the

superior lobe pleura, to rest in the tracheoesophageal groove. The right RLN is approximately 5 to 6 cm in length. The left RLN courses around the aortic arch just after its takeoff from the main trunk of the vagus. A plexus of the right and left RLNs supplies the esophagus below the roots of both lungs. The plexus has a muscular and a submucosal component. It contains preganglionic parasympathetic fibers from the vagus and ganglia. The left RLN is twice as long as the right RLN (12 cm) and therefore is more vulnerable because of a longer exposed length. The left RLN courses superiorly in an oblique fashion posterolateral to the trachea toward the larynx.3 With respect to the larynx itself, the upper ends of the RLNs enter the larynx just behind the cricothyroid joint after running in a cephalad direction in the tracheoesophageal groove from the thorax. The SLN separates from the main trunk of the vagus nerve at the level of the nodose ganglion of the vagus nerve. It then proceeds medial to the internal and external carotid arteries and divides into an internal and external branch. Although it does not pass through the thorax at any time, it is important to be aware of its function in order to differentiate injury to this nerve from injury to the RLN. The external laryngeal nerve is found inferiorly and anteriorly on the lateral aspect of the inferior constrictor muscle and supplies both that muscle and the cricothyroid muscle. The internal laryngeal nerve passes between the thyrohyoid muscle and thyrohyoid membrane and perforates that membrane, as part of the superior neurovascular pedicle of the thyroid, with the superior laryngeal artery. It supplies sensation to the lower pharyngeal mucosa and laryngeal mucosa of the supraglottis and the vocal folds. The RLN supplies sensation from the level of the vocal folds through the subglottis. Both the SLN and the RLNs receive fibers from the superior cervical ganglion and thereby receive sympathetic and parasympathetic innervation. The larynx has three primary functions: respiration, prevention of aspiration, and phonation. It also plays a critical role in swallowing. Injury to either the RLN, the SLN, or the upper vagus nerve may disrupt any one or all three of these functions. The intrinsic muscles of the larynx are primarily innervated by the recurrent nerve and serve to adduct and abduct the vocal folds. The folds also adduct as part of the glottic closure reflex, in response to irritation by potentially caustic substances, to prevent entry into the trachea and bronchi. This sphincteric action occurs at the level of the laryngeal aditus, the false vocal folds (or vestibular folds), and the true vocal folds.3 Finally, the vocal folds adduct and vibrate for normal phonation.

306

Ch025-F06861.indd 306

1/21/2008 11:00:39 AM

Chapter 25 Management of Vocal Fold Paralysis

Unilateral Vocal Fold Paralysis Injury to the RLN or upper vagus nerve anywhere along its course may affect all three of the functions of the larynx. Unilateral paralysis of the vocal fold results in an immobile vocal fold (Figs. 25-1 and 25-2). An immobile vocal fold results in incomplete vocal fold closure during phonation and swallowing. The severity of symptoms depends on the static position of the paralyzed vocal fold. Respiration is typically less affected because the glottis stays open, particularly when the vocal fold remains held laterally. Both prevention of aspiration and phonation are markedly affected because of sensory and motor deficits.4 Over time, reinnervation and synkinesis may occur, bringing the vocal fold closer to midline, maintaining muscle tone, and improving these functions, although the fold may likely remain immobile overall.

Bilateral Vocal Fold Paralysis Bilateral paralysis of the recurrent nerves can cause immediate dyspnea because the vocal folds are not able to abduct in response to respiration. The voice is less affected because the

307

vocal folds are held near midline, and aspiration may or may not occur depending on the position the vocal folds assume. Conversely, even with bilateral paralysis, the vocal folds may be held laterally, resulting in a poorer voice but less respiratory distress. In the acute situation, aspiration does occur but the patient usually compensates over time. Partial injury to the RLN (paresis of the RLN) affects the abductor muscles (posterior cricoarytenoid) more strongly than the adductor muscles.3

Superior Laryngeal Nerve Palsy Injury to the SLN affects mainly phonation because this nerve does not supply most of the intrinsic laryngeal muscles. Loss of cricothyroid muscular function (due to SLN injury) prevents changes in pitch and causes a generalized hoarseness, although the vocal folds can still adduct. SLN injury can be associated with aspiration because the internal branch supplies sensation to the supraglottic larynx, and also may cause dysphagia because of its innervation of the inferior constrictor muscle and cricopharyngeus.5

INCIDENCE AND ETIOLOGY

FIGURE 25-1 Unilateral vocal fold paralysis. The left vocal fold (seen on the right in the photograph) remains stationary when the right vocal fold abducts.

FIGURE 25-2 Unilateral vocal fold paralysis, showing vocal folds in adduction.

Ch025-F06861.indd 307

The etiology of VFP has changed over the past 50 years. In the past, VFP was usually associated with thyroid surgery. More recent studies point to extralaryngeal malignancy (i.e., lung cancer) as the primary cause.6 VFP occurring after thoracic procedures (including both pulmonary and esophageal surgery) has an incidence ranging from 4% to 45% (Schneider et al, 2003; Bhattaacharyya et al, 2003).1,7 Seventy percent of cases of bilateral VFP are related to thyroid surgery. The other 30% are mainly associated with mediastinal or esophageal surgery, anterior cervical approaches to the spine, malignancy, intubation, and central nervous system disease.6 Open heart surgery carries with it an incidence of unilateral VFP of 1% to 2%.8 Tracheal resection and mediastinal surgery especially put both RLNs at risk.2 The most common mechanisms of injury to the RLN are stretching of the nerve and sectioning of the nerve, either intentionally or unintentionally. Specific purported mechanisms of nerve injury include traction of the RLN during surgery of the cervical or upper third of the thoracic esophagus, endotracheal intubation with high cuff pressure causing compression injury to the RLN at the tracheoesophageal groove, and thrombosis or puncture site trauma during central venous catheterization. Additional mechanisms include thermal injury to the nerve, median sternotomy with sternal retraction that pulls on the subclavian arteries, mediastinal lymph node dissection as part of lung cancer surgery, irradiation of the mediastinum, and hypothermic injury secondary to collection of ice or slush in the pleural cavity around the left RLN.2,8 When VFP is caused by malignant infiltration of the RLN, the onset of paralysis is more gradual; there frequently is compensation by the mobile vocal fold, and symptoms may not be obvious.2 Mediastinal disease processes that can cause RLN injury include esophageal and lung cancer, metastatic lesions, aortic aneurysm, sarcoidosis, tuberculosis, silicosis, and lymphoma.2

1/21/2008 11:00:39 AM

308

Section 2 Upper Airway

CLINICAL PRESENTATION Typical symptoms of unilateral VFP are a weak, hoarse, and breathy voice accompanied by a weak cough. In the immediate postoperative period, there may be a short interval before unilateral VFP becomes clinically apparent. This may result from some significant vocal fold edema that masks the VFP; as the edema resolves, the symptoms appear. Many patients have dyspnea related to speech as well as exertional dyspnea, and more than 70% have aspiration (Abraham et al, 2002).9 Up to 60% have dysphagia, from mild to severe in degree.10 Aspiration leads to pulmonary complications that can greatly prolong assisted ventilation, as well as intensive care unit and overall hospital stays.5,11 Up to 70% of postesophagectomy mortality is attributable to pulmonary complications (Gockel et al, 2005).11 Patients with bilateral paralysis may have a normal or slightly hoarse voice because the vocal folds remain in an adducted position. However, the dyspnea is significant, and often biphasic stridor is present. These patients can also be at risk for aspiration due to decreased laryngeal sensation and the presence of a static gap between the vocal folds, even if the gap is small. Table 25-1 reviews the differences between unilateral and bilateral VFP.

CLINICAL EVALUATION AND DIAGNOSIS Key patient symptom review addresses hoarseness, history of aspiration pneumonia, dyspnea, and dysphagia. Specific complaints may include speaking in high pitch (falsetto), inability to project over background noise, and breathlessness on exertion. In addition, there may be a weak cough and inability to clear pulmonary secretions. The person may complain of fatigue of the voice and pain in the muscles of the neck secondary to straining the voice.12 Examination can involve both perceptual and objective voice and airway assessment. Voice samples are taken to measure vocal capability. Maximum phonation time (MPT) is particularly important in that it gives a measure of glottic closure and efficiency. The patient is asked to take a maximal

TABLE 25-1 Distinguishing Clinical Features of Unilateral and Bilateral Vocal Fold Paralysis

breath and then phonate continuously on a single pitch. A normal MPT is at least 10 seconds, and those with unilateral paralysis usually have an MPT score between 2 and 5 seconds.12 Laryngeal examination can be done with rigid endoscopes or by flexible endoscopy. The vocal fold is examined for its mobility, position in relationship to the midline of the glottis, and tone. If there is any concern of dysphagia or aspiration, a flexible endoscopic evaluation of swallowing (FEES) or a modified barium swallow can be performed to assess the patient’s risk of aspiration.12 If paralysis not related to surgery is present and its cause remains unknown, a computed tomographic (CT) scan or magnetic resonance imaging (MRI) is needed to image the course of the vagus/RLN from skull base to upper thorax, to evaluate the possibility of malignancy invading the vagus or RLN. Laryngeal electromyography (LEMG) is an important evaluation test for VFP. LEMG can confirm paralysis versus vocal fold dislocation and provide prognostic information regarding spontaneous recovery of the VFP. Because it takes several weeks for initial denervation to occur, an LEMG for prognostic purposes cannot be performed before 4 weeks after injury.13 If it is believed that the nerve will not recover, based on the clinical scenario or LEMG findings, then a permanent treatment for the paralysis is recommended. Radiologic imaging has a minimal role in the diagnosis of traumatic RLN injury. CT and MRI studies of the entire course of the RLN aid in diagnosis only when the cause of the paralysis is unknown (i.e., not related to surgery or intubation). Although dysphagia is more associated with a combined RLN and SLN injury, unilateral RLN injury can cause incompetence of the laryngeal sphincter.4 As mentioned previously, a FEES or modified barium swallow is performed in these situations to assess aspiration or penetration of the laryngeal inlet. The patient’s diet is then changed based on results of these examinations, usually with the assistance of a speech language pathologist. Patients with unilateral VFP usually have the most difficulty with liquids because the oral transit time and oropharyngeal bolus time are rapid and the glottis cannot protect the airway quickly enough to prevent aspiration.4 However, not all patients with VFP experience aspiration. Pulmonary function tests have a supplementary role. Patients with unilateral VFP may have either variable extrathoracic airway obstruction or both extrathoracic and intrathoracic obstruction if there is underlying pulmonary pathology.14

Feature

Unilateral

Bilateral

Voice perceptual characteristics

Hoarse, breathy, weak

Weak or normal

Time of diagnosis

Days or weeks after extubation/surgery

Hours after extubation/surgery

TREATMENT OF VOCAL FOLD PARALYSIS

Onset of symptoms

Days

Hours to days

Unilateral Vocal Fold Paralysis

Cough

Weak

Weak or normal

Aspiration/choking

Present

Present or absent

Major source of morbidity

Aspiration

Airway restriction

Modified from Hamdan AL, Moukarbel RV, Farhat F, Obeid M: Vocal cord paralysis after open-heart surgery. Eur J Cardiothorac Surg 21:671-674, 2002.

Ch025-F06861.indd 308

The treatment of VFP is primarily surgical. Medialization of the paralyzed vocal fold toward the midline is the desired outcome of these procedures. For unilateral paralysis, voice therapy is useful only in a selected group of patients whose paralysis is mild, and it may be used postoperatively to address any maladaptive muscular patterns in the larynx that develop as a result of the paralysis. Surgical medialization can be achieved via two approaches: injection augmentation and

1/21/2008 11:00:40 AM

Chapter 25 Management of Vocal Fold Paralysis

laryngeal framework surgery, also known as type I thyroplasty, with or without arytenoid adduction (AA).10 Injection augmentation serves to push the paralyzed vocal fold toward the midline. Several substances may be used for this purpose in either a temporary or a permanent fashion. The temporary substances include Gelfoam, Cymetra, Radiesse Voice Gel, collagen, and fascia from various sources. Permanent substances currently available are autologous fat and Radiesse (spherules of calcium hydroxyapatite).14 The temporary substances last 6 to 12 weeks on average. A temporary injection is used when it is unclear whether the RLN is irreversibly damaged. By the time the injectable material is absorbed, the vocal fold may have regained function. Vocal fold injection can be performed under local or general anesthesia. Especially in a thoracic surgical patient, who may have a tenuous medical situation, performing the procedure under local anesthesia with mild sedation submits the patient to much less anesthetic risk.15 This procedure can also be done in the office with a flexible laryngoscope and topical anesthesia in a suitable patient. After vocal fold injection, the patient is prescribed voice rest for 1 to 2 days, so that the injectable material will not extrude from the puncture site or sites. All attempts are made to prevent coughing immediately postoperatively. In addition, do not intubate the patient in the early postoperative period. Complications specific to the procedure include possible airway obstruction, overinjection or underinjection of the vocal fold, failure of improvement, or worsening of voice quality.15 Medialization laryngoplasty, or type I thyroplasty, involves placing an implant in the space next to the vocal fold, working through a surgically made window in the thyroid cartilage.

309

It is a permanent procedure. The implants can be made of Silastic (prefabricated or custom carved) or of Gore-Tex strips (Figs. 25-3 and 25-4). This procedure is done under local anesthesia with sedation so the patient may participate by voicing while different-sized implants are used to obtain the best possible voice quality (Figs. 25-5 and 25-6).16 AA is a procedure used to change the position of the vocal process of the arytenoid and thereby help medialize the vocal fold. This procedure is used selectively in patients with a markedly rotated arytenoid cartilage and shortening of the vocal fold due to paralysis. AA is typically performed in conjunction with a type I thyroplasty. These patients are typically more dysphonic and have a higher risk of aspiration due to a large gap in the posterior portion of the glottis.16 AA involves placement of a nonabsorbable suture through the muscular process of the arytenoid cartilage, with the ends of the suture brought anteriorly and tied around an inferior strut of thyroid cartilage. This simulates the vectors of the vocalis

FIGURE 25-4 A sheet of Gore-Tex 0.4 mm thick is cut into a strip for use in thyroplasty/medialization laryngoplasty. (COURTESY OF DR. PRIYA KRISHNA.)

FIGURE 25-3 A block of Silastic, with carved implant to be used in thyroplasty/medialization laryngoplasty resting on top of the block. (COURTESY OF DR. PRIYA KRISHNA.)

Ch025-F06861.indd 309

FIGURE 25-5 Flexible laryngoscopic view of unilateral vocal fold paralysis intraoperatively during left thyroplasty I, before implant insertion.

1/21/2008 11:00:40 AM

310

Section 2 Upper Airway

TABLE 25-2 Thoracic Surgeries Placing the Recurrent Laryngeal Nerve at Risk Low-Risk Procedures

High-Risk Procedures

Wedge/selected segmental resection

Left-sided lobectomy

Right-sided lobectomy/bilobectomy

Left-sided pneumonectomy

Right-sided pneumonectomy

Tracheal resection

Video-assisted thoracoscopy

Esophageal resection with cervical approach

Pleurectomy

Lymph node dissection in the aortopulmonary window Mediastinoscopy for staging

FIGURE 25-6 Flexible laryngoscopic view. Same patient as in Figure 25-5, after implant insertion. Note bulge in left vocal fold.

and lateral cricoarytenoid muscles, which both serve to adduct and medialize the vocal fold.16 Additional procedures, variations on this theme, include cricothyroid subluxation and adduction arytenoidopexy; they are beyond the scope of this chapter. The patient typically spends one night in the hospital for airway observation. As in most procedures for the vocal fold, there is a risk of airway obstruction. Other complications include implant extrusion (rare), wound breakdown or infection, allergic reaction to the implant, and dysphagia. Laryngeal reinnervation has been done for many years but without predictable results. The term encompasses direct neurorrhaphy, nerve-muscle pedicle technique, muscle-nerve muscle techniques, and direct implantation of a nerve ending into a muscle. Donor nerves include the ansa cervicalis and the hypoglossal nerve. It takes several months for reinnervation to occur, and this procedure has never been shown to consistently result in recovery of vocal fold motion.17 Finally, tracheotomy is reserved for patients with severe aspiration to assist in pulmonary hygiene, although the tracheotomy itself does not prevent aspiration. The timing of a permanent procedure for medialization is somewhat controversial. Several studies have reported that early intervention for vocal fold medialization in thoracic surgery patients with VFP reduces complications significantly (Bhattaacharyya et al, 2003; Gockel et al, 2005; Mom et al, 2001; Schneider, Bigenzahn et al, 2003; Schneider, Schickinger et al, 2003).1,5,7,11,18,19 There are fewer pulmonary complications (e.g., aspiration pneumonia) and therefore less need for therapeutic bronchoscopies. Medialization can help improve exercise tolerance and decrease the length of intensive care unit and overall hospital stays. It also improves QOL.1,20 A few studies have explored immediate or concomitant medialization with respect to the thoracic procedure.19 The main disadvantage is that, because patients are typically intubated at the time of the procedure, they are not awake to help determine voice quality and therefore the degree of medialization. Patients may be extubated immediately or after a few days and will have some degree of laryn-

Ch025-F06861.indd 310

Thyroid surgery for substernal thyroid disease From Schneider B, Schickinger-Fischer B, Zumtobel M, et al: Concept for diagnosis and therapy of unilateral recurrent laryngeal nerve paralysis following thoracic surgery. Thorac Cardiovasc Surg 51:327-331, 2003.

geal edema, which masks symptoms of unilateral VFP initially. This edema resolves after 2 to 4 days, and then the patient’s true voice quality is uncovered (Abraham et al, 2002).9 Table 25-2 discusses thoracic procedures that are associated with low versus high risk for injury to the RLN.

Bilateral Vocal Fold Paralysis The primary thoracic procedures that could lead to bilateral VFP are mediastinoscopy, mediastinal lymph node biopsies in the paratracheal region and aortopulmonary window, and lung transplantation, especially bilateral transplantation. As discussed earlier, bilateral VFP has more immediate potential to become life-threatening due to airway obstruction. The goal in treatment of bilateral VFP is enlargement or bypass of the airway. A medical option is injection of botulinum toxin into the adductory laryngeal muscles (thyroarytenoid and cricothyroid muscles). This is performed via percutaneous or per-os techniques with or without LEMG guidance to localize the injection to the adductor muscles. Tracheotomy is typically the first step employed in treatment of bilateral VFP to ensure a secure airway. Because of the major QOL issues associated with a tracheotomy, most patients are eager to consider other surgical options (i.e., glottic enlargement surgery) to allow decannulation. These choices include arytenoidectomy (medial or total), cordotomy, and cordectomy. These procedures are performed using a microlaryngoscopy approach with the carbon dioxide laser. They involve partial or total removal of the arytenoid cartilage and/or a portion of the vocal fold (Figs. 25-7 and 25-8). These procedures all serve to enlarge the glottic airway, with an attempt to preserve phonation. However, there is a tradeoff: the more the airway is enlarged, the worse the voice becomes. Postoperatively, patients may experience transient aspiration and a breathy voice but improved airway symptoms.21

1/21/2008 11:00:43 AM

Chapter 25 Management of Vocal Fold Paralysis

311

SUMMARY VFP is a potentially devastating complication of thoracic surgical procedures. Intimate knowledge of the anatomy of the motor supply to the vocal folds and the physiology of the larynx is crucial to prevent this complication. Preoperative education of the patient regarding risks of VFP is warranted. Early otolaryngology involvement can minimize morbidity and mortality and result in long-term adequate voice and airway function. Bilateral VFP may manifest as a life-threatening airway compromise requiring urgent reintubation or tracheostomy. Identify and treat clinically suspected VFP (especially unilateral VFP) before a thoracic procedure. Do a postoperative unilateral VFP evaluation soon after extubation, and consider early treatment (with temporary vocal fold injection) in most cases.

COMMENTS AND CONTROVERSIES FIGURE 25-7 Bilateral vocal fold paralysis. Intraoperative view of posterior right vocal fold. A metal laser-safe endotracheal tube is seen to the left.

The authors have presented a succinct overview of the issues of vocal fold paralysis in the thoracic surgical patient. One of the major hurdles to the application of therapeutic techniques for vocal fold paralysis is the recognition by the thoracic surgeon of a complication secondary to the original intervention (e.g., silent aspiration or impaired cough and clearance of secretions after esophagectomy or pneumonectomy). Once this is acknowledged, the implementation of treatment for vocal fold paralysis must be considered. Some of these clinical sequelae may occur with only subtle voice hoarseness, making it essential that the surgeon consider early evaluation by the otolaryngology and swallowing team, evaluation with a modified barium esophagogram or functional endoscopic evaluation of swallowing (FEES), and, if indicated, intervention to medialize the vocal fold and minimize the risks of these potentially deadly complications. J. D. L.

KEY REFERENCES

FIGURE 25-8 Bilateral vocal fold paralysis. Same patient as in Figure 25-7, after carbon dioxide laser cordotomy/medial arytenoidectomy. Note enlarged airway.

Laryngeal pacing is an experimental technique that serves to stimulate the posterior cricoarytenoid muscle to cause abduction of the vocal fold timed with respiration. The combination of pacing and botulinum toxin blockade of the laryngeal adductor muscles (thyroarytenoid/lateral cricoarytenoid) has been used in the research setting with positive results.22 Pacing is not currently clinically validated. A suture may be used to lateralize the arytenoid cartilage, but this can cause the voice to become breathy.21

Ch025-F06861.indd 311

Abraham MT, Bains MS, Korst RJ, et al: Type I thyroplasty for acute unilateral vocal fold paralysis following intrathoracic surgery. Ann Otol Rhinol Laryngol 111:667, 2002. Bhattaacharyya N, Batirel H, Swanson SJ: Improved outcomes with early vocal fold medialization for vocal fold paralysis after thoracic surgery. Auris Nasus Larynx 30:71, 2003. Gockel I, Kneist W, Kelmann A, Junginger T: Recurrent laryngeal nerve paralysis following esophagectomy for carcinoma. Eur J Cancer Surg 31:277, 2005. Mom T, Filaire M, Advenier D, et al: Concomitant type I thyroplasty and thoracic operations for lung cancer: Preventing respiratory complications associated with vagus or recurrent laryngeal nerve injury. J Thorac Cardiovasc Surg 121:642, 2001. Schneider B, Bigenzahn W, End A, et al: External vocal fold medialization in patients with recurrent nerve paralysis following cardio-thoracic surgery. Eur J Cardiothorac Surg 23:477, 2003. Schneider B, Schickinger-Fisher B, Zumtobel M, et al: Concept for diagnosis and therapy of unilateral recurrent laryngeal nerve paralysis following thoracic surgery. Thorac Cardiovasc Surg 51:327, 2003.

1/21/2008 11:00:43 AM

Neoplasms chapter

26

PRIMARY TUMORS OF THE TRACHEA Henning A. Gaissert Douglas J. Mathisen

Key Points ■ The most common cause of malignant tracheal obstruction—met-

astatic disease—must be considered carefully before the diagnosis of a primary tumor is made. ■ Expect a delay in diagnosis whenever a primary tracheal tumor is evaluated and do not assume that this delay indicates unresectable disease. ■ Evaluation by rigid bronchoscopy is possible in every patient with a tumor of the trachea or carina and provides the most useful information. ■ Balance the benefit of complete resection with negative airway margins against the risk of excessive tension at the anastomosis. If in doubt, decide in favor of a secure anastomosis.

In comparison to the common malignancies of larynx and lung, primary tumors of the trachea are rare. Malignant tracheal obstruction is caused far more often by metastatic than primary tumors. Surprising is therefore not the frequent delay in diagnosis and therapy but the high proportion of resectable primary tumors encountered in centers for airway surgery. Resection may be offered, at low operative risk in experienced hands, to a majority of patients with tracheal tumors, but the dismal survival and low resection rates observed in epidemiologic studies suggest that, other than at centers for tracheal surgery, resection is considered in very few patients. The establishment of regional referral centers has been proposed for this purpose. However, with increasing awareness of surgical techniques and nonsurgical treatment, the experience with this rare tumor is likely to scatter. In this chapter we summarize the current knowledge of the incidence, evaluation, and management of these tumors.

EPIDEMIOLOGY Reliable sources for epidemiologic data on tracheal tumors are few, and studies reporting their incidence usually do not include pathologic and radiologic review. Tracheal tumors account for less than 0.2% of all respiratory tract malignancies in the United States.1 The annual incidence was 1 in 1 million inhabitants in a study from Finland.2 During 18 years of observation, 95 primary tracheal carcinomas were encountered, with a male-to-female ratio of 7 : 3. A review of the Danish Cancer Registry established 130 primary malignant tracheal neoplasms during a 17-year period, equivalent to 0.02% of all malignancies.3 The Finnish epidemiologic study found pulmonary carcinoma 430 times and laryngeal carcinoma 30 times more common than tracheal cancer.2 A similar disparity was observed by Gelder and Hetzel, who reported

44 deaths in England and Wales in 1990 due to tracheal tumors compared with 803 from carcinoma of the larynx and 34,331 from carcinoma of the lung.4 This seemingly disproportionate incidence of tracheal carcinoma in adjacent anatomic regions exposed to the same carcinogens has been explained by relating the risk of carcinoma to local concentrations of tobacco smoke. In patients with squamous and adenoid cystic carcinomas, the average age diverges by about a decade. In a singleinstitution study of 270 patients, mean age was 61 years in those with squamous cell carcinoma and 49 years in those with adenoid cystic carcinomas.5 Tumors other than carcinoma have a diffuse age distribution and predominate in young adults. Tracheal tumors are rare in children.6,7 In epidemiologic series, in which bronchogenic carcinomas are the most common tumors, a majority of patients are male and smokers. In the report of Licht and associates, 59% were male and 73% smoked.3 At Massachusetts General Hospital (MGH), 46% of adenoid cystic carcinomas and 68% of squamous carcinomas occurred in male patients. At presentation, more than 25% of patients with bronchogenic carcinomas of the trachea had prior carcinomas of the lung. Smoking is not thought to predispose to any of the other tracheal neoplasms for whom risk factors are not known.

CLINICAL PRESENTATION The typical patient with a primary tracheal tumor presents with imperceptibly progressive respiratory symptoms. The average interval from onset of symptoms to diagnosis measures more than a year and is shorter in bronchogenic carcinoma compared with adenoid cystic carcinoma or benign neoplasms. Malignant tumors later found to be unresectable have a longer duration of symptoms.5 A tracheal tumor needs to be suspected in adult-onset asthma or audible breathing of recent duration. Hemoptysis occurs most commonly in lung cancer but is also observed in adenoid cystic and other benign and malignant tumors. The common misattribution of symptoms to underlying lung disease has two main consequences. Medical therapy, including corticosteroids, has often been instituted to treat presumed parenchymal disease. And tumors are often locally advanced, occupy long segments of trachea, or grow through the tracheal wall until dyspnea or near-asphyxiation eventually prompts evaluation. Hoarseness may be the first indicator of neoplastic disease, but not all patients with recurrent laryngeal nerve invasion have obvious vocal cord dysfunction and the gradual loss of one nerve may be surprisingly well tolerated. Indeed, only 4 of 25 patients with laryngotracheal tumors presented with hoarseness and none required resection of the recurrent

312

Ch026-F06861.indd 312

1/21/2008 11:01:52 AM

Chapter 26 Primary Tumors of the Trachea

313

computerized techniques. Chest radiographs may demonstrate mediastinal widening or give the first indication of metastatic disease. Plain tomography, where still available, provides a satisfactory estimate of the length of gross tumor and narrowing of the tracheal lumen.9 CT of the chest typically demonstrates a tracheal mass, but the surrounding mediastinal structures limit the interpretation of precise borders (Fig. 26-1). Neither plain tomography nor CT reliably predicts submucosal tumor or esophageal invasion. However, CT may identify invasion of the great vessels.10 Virtual bronchoscopy, produced by software algorithms from very thin CT images, provides elegant views of the airway that at present do not provide the detail offered by real bronchoscopy (Fig. 26-2). The advantages of CT over conventional tomography

laryngeal nerve; conversely, the nerve was resected in 7 other patients without hoarseness.8 There is no reliable distinction in symptoms between tumors invading the subglottic larynx and those occupying the trachea. Vocal cord dysfunction may be associated with tracheal tumors of any location. Dysphagia is uncommon at the time of presentation and may indicate a locally advanced or unresectable lesion; however, dysphagia does not prohibit resection.

DIAGNOSTIC EVALUATION Radiographic studies usually precede bronchoscopy, except in the asphyxiating patient. The radiographic evaluation of tracheal tumors may be pursued with traditional or advanced

A

B

C

D

FIGURE 26-1 Computed tomography of tracheal tumors. A, Squamous cell carcinoma of the cervical trachea. The border to the esophagus is indistinct and invasion, later found to be absent, cannot be excluded. B-D, Long adenoid cystic carcinoma of the trachea. B, Luminal and extrinsic mass bordering the esophagus. C, Coronal view of the tumor with calcification. D, The virtual bronchoscopic view of the tumor is not precise enough to substitute for real bronchoscopy. This tumor was resected, including 7 cm of trachea and esophageal muscle.

Ch026-F06861.indd 313

1/21/2008 11:01:52 AM

314

Section 2 Upper Airway

how debilitated, seemingly unresectable, or highly obstructed. When performed with care, endoscopy is well tolerated, provides a diagnosis, and may be used for dilation of a stricture or to remove tumor for relief of symptoms. The procedure requires close cooperation with an anesthesiologist trained in the management of airway obstruction and is preferably conducted under general anesthesia with rigid endoscopes. Biopsy specimens are obtained if a carcinoma is suspected or the tumor is extensive. Additional mucosal biopsies beyond gross tumor are occasionally important to determine the length of the lesion. Laryngoscopy precedes bronchoscopy if the tumor involves the subglottic airway or vocal cord dysfunction is known.

HISTOLOGY

A

B FIGURE 26-2 Bronchoscopic views of polypoid adenoid cystic carcinoma (A) and infiltrating squamous cell carcinoma (B). Either growth pattern may be observed in both tumor types.

There is a disparity between the distribution of tumor types in epidemiologic and clinical studies (Table 26-1). In clinical studies adenoid cystic carcinomas and bronchogenic carcinomas are by far the most common primary tumors, whereas epidemiologic data show a much lower incidence of adenoid cystic tumors and a higher incidence of nonsquamous bronchogenic carcinomas. This disparity may occur as a result of selection bias in surgical series. However, the bias does not explain the virtual absence of nonsquamous lung cancers among patients who have undergone resection of their tumors. Because epidemiologic studies include as a rule neither radiologic nor pathologic review of patients, clinical information based on diagnosis at experienced centers would appear more reliable. In particular, some epidemiologic studies seem to include tumors metastatic to the trachea, explaining high numbers of small cell carcinoma for example, and underestimate adenoid cystic carcinoma.4,12 Bias in clinical studies may be introduced by inclusion of resected cases alone. Of 357 patients with primary tumors of the trachea at MGH who either had resection or had tumors that were unresectable, squamous cell and adenoid cystic carcinoma comprised 75% of the total.5 Mucoepidermoid carcinomas,13 carcinoid tumors, and a group of sarcomas and mesenchymal tumors14 made up the remaining proportion of tumors.15 Table 26-2 shows the histologic types at MGH.

TREATMENT are not always measurable and may not be clinically important. Endoluminal ultrasonography of the trachea may distinguish reliably between compression and infiltration of the trachea by an extrinsic tumor,11 but submucosal infiltration, by far the most common cause of positive tracheal resection margins, cannot be detected. Optical coherence tomography may generate sufficiently precise images of the tracheal wall in the future. Before lamenting the shortcomings of locoregional staging over the past 40 years, consider that only 17 of 208 patients (8.2%) with tracheal carcinoma underwent operative exploration without resection at MGH.5 A search for metastatic disease is conducted in malignant tumors and typically includes radiographic evaluation of the lung, brain, bone, adrenal glands, and liver. Every patient suspected to have a tracheal tumor needs to undergo endoscopic examination of the airway, no matter

Ch026-F06861.indd 314

Three treatment modalities may be considered for tracheal tumors: endoscopic resection by various techniques, radiotherapy, and tracheal resection. Of these, tracheal resection alone provides pathologic confirmation of complete tumor removal and offers the best chance for long-term survival. Complete resection of tracheal tumors is the preferred treatment because airway obstruction is relieved, cure is achieved in benign and low-grade malignant tumors, and resection is associated with long-term survival in tracheal carcinomas. In patients referred for surgical evaluation, resection rates of 66% for squamous cell carcinoma and 74% for adenoid cystic carcinoma have been observed.5 Resectability of the tumor must therefore be determined before any other therapy, local or systemic, is instituted. Bronchoscopy may be performed to relieve airway obstruction. Endoscopic resection using the rigid bronchoscope is

1/21/2008 11:01:54 AM

Chapter 26 Primary Tumors of the Trachea

315

TABLE 26-1 Histology of Primary Tracheal Tumors* Clinical Studies (Year) Epidemiologic Studies (Year) Manninen et al (1991) No. patients Adenoid cystic carcinoma

95 6.3

Squamous cell carcinoma

72

Adenocarcinoma

13

Large cell carcinoma Small cell carcinoma

7.4

Anaplastic carcinoma

2.1

Gelder and Hetzel (1993) 321 11

Radiotherapy

Licht et al (2001) 109 7.3

54

63

4

10

Chao et al (1998) 42 7.1 68

Pearson et al (1984)

1.8

5

7.3

4.8

5.5

4.8

0

No diagnosis

0

6.5 14

3.7 0

Perelman et al (1996)

Grillo and Mathisen (1990)

208

120

198

64

31

55

40

20

45

17

35

0.9

Other

Regnard et al (1996)

44

4.8

5.9

Mucoepidermoid carcinoma

Surgery

1.9

0.8

0.5

0

0

0

0

2.5

0

0

0

0

2.4

0.8

2

0

16

19

23

21

12

0

0

0

0

*Numbers after tumor type indicate percentage of patients. Reprinted with permission from Gaissert HA: Tracheal tumors. Chest Surg Clin North Am 13:1-10, 2003.

suitable as an immediate intervention even if evaluation is incomplete.16 A lumen is cored out with the tip of the bronchoscope for this purpose, a technique that requires cautious precision to avoid tracheal injury. Laser or other locally destructive modalities may be employed but are not obligatory. The endoscopic procedure removes the urgency from a planned resection. Management with airway stents or primary radiotherapy, even when used to temporarily improve symptoms, is not acceptable unless resection is ruled out. Airway stents use up normal airway, either by requiring a tracheal stoma (T-tube, tracheostomy) or by eroding tracheal mucosa when anchoring an endoluminal type (Dumon, Wallstent, Microvasive Ultraflex).17 Radiotherapy as a preoperative adjuvant modality has deleterious effects on anastomotic healing. Tracheal resection conducted after radiation carries a greater risk and demands particular measures to augment blood supply to the anastomosis and separation from surrounding structures.18

Resectable Disease Once absence of distant metastasis and advanced regional disease has been established, the most important determinants of resectability are tumor length and extent of radial invasion into the mediastinum. The safe limits of tracheal resection are individual and vary with age, mobility of the neck, and body weight. A tumor measuring 4 cm in length, for example, may not be resectable in an older patient with a short neck and cervical kyphosis, whereas a thin, young patient with a long neck can undergo resection of 6 cm of trachea. Benign tumors are usually limited in length and therefore resectable. Conversely, length of airway involve-

Ch026-F06861.indd 315

ment prevents resection most commonly in patients with squamous and adenoid cystic carcinoma. Clinical judgment determines the limits of maximum airway length at which safe reconstruction is still feasible. If resectability is in doubt and the patient is a good surgical candidate, operative exploration is considered; an operation at the limits of resectability is best undertaken by an experienced surgeon. Because the trachea is surrounded by vital mediastinal structures, the radial soft tissue margin of any resection is inevitably close. Each resection is an individual compromise between radical intent and necessary conservatism to protect anastomotic integrity. There are virtually no radial margins in carcinomas with transmural growth because of the proximity of esophagus and great vessels. Tumor approaches to within 1 mm of the radial border in the majority of resectable tracheal carcinoma.5 This so-called positive margin, however, does not seem to have the same prognostic impact as microscopic tumor at the cut edge of the airway. The capacity to obtain tumor-free margins in the longitudinal axis is limited as each increment of resected trachea increases the tension on the anastomosis. Tumor-bearing tracheal margins must often be accepted in adenoid cystic carcinomas, as was the case in 58% of resections at MGH, particularly when the cut surface of the trachea is grossly normal. Local control in this situation is supported with postoperative radiation. Longterm survival, however, may be compromised. These limitations explain the regular use of postoperative radiation as a second local therapy, except for the most superficial tumors. The results of surgical therapy as reported by major centers reflect improvement of surgical judgment and technique, in particular in locally advanced adenoid cystic carcinoma.

1/21/2008 11:01:55 AM

316

Section 2 Upper Airway

TABLE 26-2 Tumor Histology in 357 Patients at Massachusetts General Hospital Malignant Tumors Adenoid cystic carcinoma Squamous cell carcinoma Nonsquamous bronchogenic carcinoma Small cell carcinoma Adenocarcinoma Large cell carcinoma Adenosquamous carcinoma Mucoepidermoid carcinoma Sarcoma Spindle cell sarcoma Chondrosarcoma Leiomyosarcoma Carcinosarcoma (pseudosarcoma) Invasive fibrous tumor Malignant fibrous histiocytoma Carcinoid tumors Typical Atypical Lymphoma Melanoma

135 135 15 5 4 4 2 14 13 6 3 1 1 1 1 11 10 1 2 1

Benign Tumors Capillary hemangioma Chondroblastoma Chondroma Fibrous histiocytoma Glomus tumor Granular cell tumor Hamartoma Hemangiomatous malformation of mediastinum Inflammatory pseudotumor (plasma cell granuloma) Leiomyoma Neurogenic tumor Schwannoma Plexiform neurofibroma Peripheral nerve sheath tumor Atypical schwannoma Paraganglioma Pleomorphic adenoma Pyogenic granuloma Squamous papillomas Multiple Solitary Vascular tumor of borderline malignancy Total

1 1 2 1 1 2 2 1 1 3 4 1 1 1 1 1 3 1 9 5 4 1 360

Note: Three patients had two synchronous tracheal tumors each. Data from references 5 and 15.

Patients with this tumor present often young and otherwise healthy, and tumor length is the main impediment to resection. Early in the experience at MGH, extended resection was attempted when the safe limits of resection were unknown. The operative mortality for tracheal carcinomas declined over 4 decades from 21% to 3%.5 This decline of risk appears to originate from several factors, predominantly preoperative selection and intraoperative judgment to accept a microscopically positive margin rather than attempting a complete resection. The increasing experience with tracheal resection has led to improved prediction of resectability; in carinal reconstruction, for example, it has been learned that

Ch026-F06861.indd 316

a gap of more than 4 cm between trachea and left main stem bronchus cannot be bridged without excessive tension. At Toronto General Hospital, Marlex mesh reconstruction used in the early experience for extended resection of adenoid cystic carcinoma was abandoned because of the associated complications.19 Tracheal resection in the presence of metastatic disease has been suggested in selected patients with adenoid cystic carcinoma because of the slow growth of these tumors even in the presence of pulmonary metastasis.20 This approach, however, is of unproven value and is perhaps best avoided in bronchogenic carcinoma. The surgical techniques of laryngotracheal, tracheal, and carinal resection have been described elsewhere.5,21-23 Here we discuss surgical considerations as they relate to airway tumors. Many patients arrive on systemic corticosteroid therapy that must be discontinued well before operation. The anesthetic management, including inhalation induction, selective use of jet ventilation, and early extubation, is described elsewhere.24 Mediastinoscopy may be used to stage bronchogenic carcinoma and to mobilize the trachea. A metastatic lymph node on the trachea, although lowering long-term survival, may not preclude resection. The location of the tumor influences the surgical approach. Tumors extending into the subglottic region and those in the upper and middle trachea are exposed through a cervical collar incision. Lower tracheal tumors involving the carina are accessible either via full sternotomy20 or through a right thoracotomy.22 Tumors at either margin of the trachea require particular consideration. Tumors of the trachea that are found on endoscopy to extend to the vocal cords are a contraindication to larynx-conserving resection. A recurrent laryngeal nerve may be sacrificed when tumor encases the nerve and the contralateral nerve is intact. Anterior tumors are removed by cricoid excision, dividing the lateral arches far back at the posterior cricoid plate. Involvement of the lateral subglottic wall and ipsilateral recurrent nerve may require removal of half of the cricoid with part of the posterior cricoid plate and the thyroid lamina. Tumor at the posterior cricoid plate alone may be removed by sloping excision of the mucosa with or without tangential excision of the posterior cricoid plate. Pearson and associates in 7 patients and we8 in 25 patients have reported successful resection of laryngotracheal tumors. None of our patients has so far required laryngectomy for recurrent disease. Tumors involving the carina pose the greatest challenge during the operative management of ventilation and airway reconstruction. When primary tracheal tumors are carefully separated from lung cancers that secondarily involve the carina, 31% of primary squamous and adenoid cystic carcinomas were found to be at the carina.5 Of uncommon other tracheal tumors, 24% were found to involve the carina.15 Carinal tumors are associated with a higher perioperative morbidity and mortality than either pure tracheal or laryngotracheal tumors for two related reasons. First, the carina is often involved by long tumors with submucosal extension that require experience and judgment in determining resectability because there is little tolerance for anastomotic tension at the time of reconstruction. Second, the risk of early respiratory failure due to pneumonia or adult respiratory distress

1/21/2008 11:01:55 AM

Chapter 26 Primary Tumors of the Trachea

100 80 Percentage

syndrome, probably facilitated by operative interruption of lymphatics, is increased. The hospital mortality in a group of 191 patients with tracheal carcinomas that were resected at MGH illustrates the point. There was no operative death in the small group of patients undergoing laryngotracheal resection, whereas mortality was 3.9% after tracheal resection and 16% after carinal resection. In Maziak and associates’ report on 44 adenoid cystic carcinomas, two of three deaths occurred after carinal resection.19 The role of adjuvant postoperative therapy is not clearly defined. After recovery from operation and bronchoscopic assessment of the anastomosis, usually after 2 months, we and others recommend adjuvant mediastinal radiotherapy in an amount of 5400 cGy for most patients except those with the earliest carcinomas. The purpose of radiotherapy is to improve local control and was conceived when late local recurrences were noted in patients with adenoid cystic carcinoma. Because the overall number of these tumors is small and any patient with more than an early tracheal carcinoma or other high-grade malignancy25 received the recommendation to undergo radiation, no meaningful comparative data exist to determine effectiveness of adjuvant therapy.

LONG-TERM RESULTS Surgical resection for benign or low-grade tracheal tumors is usually followed by recurrence-free long-term survival. There were no recurrences after surgical treatment of these lesions at MGH. Examples to the contrary raise doubt about either the completeness of the operation or the original diagnosis. Reports of typical tracheal carcinoids33 and invasive fibrous tumors14 from our institution did not record recurrence. Among 18 mucoepidermoid tumors of the lung, most in

Ch026-F06861.indd 317

60 40 20 0

77% (23)

71% (13)

73% (33)

57% (14)

47% (29)

36% (7)

NS P < .02 1

2

3

4

5

6

7

8

9

10

Years

( ) = No. of patients at risk Other tumors (n = 41) Adenoid cystic carcinomas (n = 63) Tracheal cancers (n = 94)

NS P < .02

FIGURE 26-3 Actuarial survival curves according to histologic type from a French multi-institutional study. NS, Not significant. (MODIFIED FROM REGNARD JF, FOURQUIER P, LEVASSEUR P: RESULTS AND PROGNOSTIC FACTORS IN RESECTIONS OF PRIMARY TRACHEAL TUMORS: A MULTICENTER RETROSPECTIVE STUDY. THE FRENCH SOCIETY OF CARDIOVASCULAR SURGERY. J THORAC CARDIOVASC SURG 111:808-813, 1996.)

Unresectable Disease Percentage

100

( ) = No. of patients at risk N– (n = 68) N+ (n = 26)

80 60

47% (7) NS

40 46% (22) 20 0

1

2

3

4

5

6

7

8

9

10

Years FIGURE 26-4 Survival according to lymph node involvement in tracheal carcinoma. NS, Not significant. (MODIFIED FROM REGNARD JF, FOURQUIER P, LEVASSEUR P: RESULTS AND PROGNOSTIC FACTORS IN RESECTIONS OF PRIMARY TRACHEAL TUMORS: A MULTICENTER RETROSPECTIVE STUDY. THE FRENCH SOCIETY OF CARDIOVASCULAR SURGERY. J THORAC CARDIOVASC SURG 111:808-813, 1996.)

100 82% (21)

80 Percentage

In the MGH experience, in a series of patients referred to thoracic surgeons for further management, tumor length as determined by bronchoscopy was the most common reason tracheal resection was declined, whereas distant metastatic disease at presentation occurred in only 4.8%.5 The goal of treatment in unresectable malignant tumors is to restore a patent airway and to slow progression of disease. Effective local therapy other than resection may provide meaningful palliation, either by regional radiation or bronchoscopic destruction. Mediastinal radiation with doses ranging from 5400 to 6000 cGy is administered as curative therapy to patients with good performance status. There is no defined role for chemotherapy in tracheal tumors, but bronchogenic carcinoma is often treated with combined radiochemotherapy. Local destruction of tumor alone may be accomplished by a number of methods other than bronchoscopic coring out: neodymium : yttrium-aluminum-garnet laser,26 cryosurgery,27 brachytherapy,28 photodynamic therapy,29 or argon beam coagulation.30 Malignant strictures may be stented using Ttubes.31,32 Because self-expanding stents once placed are almost impossible to remove, life expectancy is limited to a few months at the time of insertion so that secondary complications of stenting do not have an impact on quality of life.

317

63% (12) 60

P < .20

40

( ) = No. of patients at risk Complete resection (n = 36) Incomplete resection (n = 26)

20 0

1

2

3

4

5

6

7

8

9

10

Years FIGURE 26-5 Actuarial survival according to completeness of resection of adenoid cystic carcinomas. (MODIFIED FROM REGNARD JF, FOURQUIER P, LEVASSEUR P: RESULTS AND PROGNOSTIC FACTORS IN RESECTIONS OF PRIMARY TRACHEAL TUMORS: A MULTICENTER RETROSPECTIVE STUDY. THE FRENCH SOCIETY OF CARDIOVASCULAR SURGERY. J THORAC CARDIOVASC SURG 111:808-813, 1996.)

1/21/2008 11:01:55 AM

318

Section 2 Upper Airway

FIGURE 26-6 Overall survival of tracheal carcinoma by resection status and tumor type. ACC, adenoid cystic carcinoma; SCC, squamous cell carcinoma. (MODIFIED

ACC Resected ACC Unresectable SCC Resected SCC Unresectable

100

FROM GAISSERT HA, GRILLO HC, SHADMEHR MB, ET AL: LONG-TERM SURVIVAL AFTER RESECTION OF PRIMARY ADENOID CYSTIC AND SQUAMOUS CELL CARCINOMA OF THE TRACHEA AND CARINA. ANN THORAC SURG 78:1889-1897, 2004.)

Percentage

80 60 40 20

0

5

10

Years ACC Resected ACC Unresectable SCC Resected SCC Unresectable

96 33 88 43

52 11 34 4

FIGURE 26-7 Actuarial survival of tracheal carcinoma by type of resection. TR, tracheal resection; LTR, laryngotracheal resection; CR, carinal resection. (MODIFIED

Tracheal resection (TR) Laryngotracheal resection (LTR) Carinal resection (CR)

100 Percentage

FROM GAISSERT HA, GRILLO HC, SHADMEHR MB, ET AL: LONG-TERM SURVIVAL AFTER RESECTION OF PRIMARY ADENOID CYSTIC AND SQUAMOUS CELL CARCINOMA OF THE TRACHEA AND CARINA. ANN THORAC SURG 78:1889-1897, 2004.)

32 3 16 2

80 60 40 20

0

5

10

Years Patients at risk LTR 16 TR 107 CR 61

trachea and large bronchi, none of 15 low-grade tumors but all 3 high-grade carcinomas proved fatal.13 Reports of purely endoscopic resection of benign tumors reliably fail to provide long-term follow-up.26,30 Considerations of prognostic factors regarding long-term survival continue to be limited by the small number of observations. The disease-free survival after resection of malignant tumors is limited by distant metastasis and regional disease, whereas local recurrence is uncommon. The survival of malignant tumors reported by Perelman and colleagues was 35.9% at 5 years in 66 adenoid cystic carcinomas and 27.1% at 10 years in 21 squamous carcinomas.34 In their report of a large group of patients with adenoid cystic carcinomas, Maziak and colleagues of the University of Toronto noted an actuarial survival of 79% at 5 and 51% at 10 years in 32 patients treated with primary resection and adjuvant radiotherapy.19 Their study found no significant difference between patients

Ch026-F06861.indd 318

9 48 29

4 24 20

undergoing complete compared with incomplete resection. A collective French study found 5- and 10-year survival rates of 73% and 57% in adenoid cystic and 47% and 36% in squamous cell carcinoma, respectively, with longer survival after complete as opposed to incomplete resection (Figs. 26-3 to 26-5).35 At MGH, complete resection with negative airway margins resulted in higher survival than after incomplete resection with positive tracheal margins or unresectable tumors (Figs. 26-6 to 26-9). The difference assumed statistical significance in adenoid cystic carcinoma, but was not significant in squamous cell carcinoma because of fewer patients with tumor-bearing airway margins.5 The survival curves after incomplete resection for adenoid cystic carcinoma separate from unresectable tumors after 10 years; there were no survivors beyond 13 years in the unresectable group, whereas survival after incomplete resection at 15 years was 14.5%. A multivariate analysis found that long-term survival in tracheal

1/21/2008 11:01:56 AM

Chapter 26 Primary Tumors of the Trachea

FIGURE 26-8 Actuarial survival of adenoid cystic carcinoma (ACC) after resection by airway margin. Note 15-year observation interval. (MODIFIED FROM

100 ACC, Airway negative ACC, Airway positive ACC, Unresectable

Percentage

80

319

GAISSERT HA, GRILLO HC, SHADMEHR MB, ET AL: LONG-TERM SURVIVAL AFTER RESECTION OF PRIMARY ADENOID CYSTIC AND SQUAMOUS CELL CARCINOMA OF THE TRACHEA AND CARINA. ANN THORAC SURG 78:1889-1897, 2004.)

60 40 20

0

5

10

15

13 12 3

6 7 0

Years Patients at risk ACC, Airway negative ACC, Airway positive ACC, Unresectable

32 50 33

22 22 11

100

SCC, Airway negative SCC, Airway positive SCC, Unresectable

Percentage

80

60

FIGURE 26-9 Actuarial survival of squamous cell carcinoma (SCC) after resection by airway margin. Note 10-year observation interval. (MODIFIED FROM GAISSERT HA, GRILLO HC, SHADMEHR MB, ET AL: LONG-TERM SURVIVAL AFTER RESECTION OF PRIMARY ADENOID CYSTIC AND SQUAMOUS CELL CARCINOMA OF THE TRACHEA AND CARINA. ANN THORAC SURG 78:1889-1897, 2004.)

40 20

0

0

5

10

Years Patients at risk SCC, Airway negative 72 SCC, Airway positive 15 SCC, Unresectable 43

31 4 4

carcinoma was statistically significantly associated with complete resection, negative airway margins, and adenoid cystic histology, but not with tumor length, lymph node status (Fig. 26-10), or type of resection. Long-term survival with radiotherapy alone is unusual. Primary radiation in tracheal squamous cell carcinoma with 4000 to 6000 cGy resulted in a median survival of 5 months.36 Among 44 patients with squamous cell carcinoma undergoing radiotherapy in Finland between 1967 and 1985, the median survival time after the diagnosis was 8 months.37 Chao and associates treated 42 patients with primary tracheal tumors between 1962 and 1995.38 Eleven patients received at least 5000 cGy, whereas the rest were treated with lower doses. The median survival time was 5.7 months, and 13% lived for longer than 2 years. Six patients with adenoid cystic carcinoma treated with radiotherapy alone had a mean survival of 6.2 years.19 Mean duration of survival with palliative therapy in unresectable squamous cell carcinoma of the trachea evalu-

Ch026-F06861.indd 319

17 0 2

ated at MGH was 8.8 months and in unresectable adenoid cystic carcinoma, 41 months.5

COMMENTS AND CONTROVERSIES Bronchoscopic evaluation of a patient who presents with severe airway obstruction from either a benign stenosis or a malignant tumor requires the utmost skill, attention, and experience on the part of both the surgeon and the anesthesiologist. Whenever possible, preliminary high-resolution CT scan with three-dimensional reconstruction to evaluate the exact position, length, and degree of obstruction of the lesion provides a road map for the endoscopic restoration of a safe airway required in this situation. In general, the anesthetic management I prefer is the use of topical anesthesia and mild sedation, maintaining spontaneous or assisted ventilation as the flexible bronchoscope, passed through the nose, is used to visualize the lesion and to determine its exact location and the size of the compromised lumen. When the airway is critically narrowed,

1/21/2008 11:01:56 AM

320

Section 2 Upper Airway

100

ACC Node negative ACC Node positive SCC Node negative SCC Node positive

Percentage

80 60

FIGURE 26-10 Actuarial survival of primary tracheal carcinoma by lymph node status. ACC, adenoid cystic carcinoma; SCC, squamous cell carcinoma. (MODIFIED FROM GAISSERT HA, GRILLO HC, SHADMEHR MB, ET AL: LONG-TERM SURVIVAL AFTER RESECTION OF PRIMARY ADENOID CYSTIC AND SQUAMOUS CELL CARCINOMA OF THE TRACHEA AND CARINA. ANN THORAC SURG 78:1889-1897, 2004.)

40 20

0

5

10

Years Patients at risk ACC Node negative ACC Node positive SCC Node negative SCC Node positive

84 12 64 24

44 8 31 3

the flexible bronchoscope is not passed through the lesion to avoid any bleeding or swelling that might further compromise the airway. Once the obstructing lesion has been visualized from above, I prefer insertion of the rigid bronchoscope as described by the authors of this chapter. This is often done with the patient still breathing spontaneously but well sedated, before a paralytic agent is administered. Once the bronchoscope has been passed through the obstructing lesion, then the patient can be paralyzed for the remainder of the procedure, which usually involves the passage of successively larger rigid bronchoscopes to core out and/or dilate the obstructing tumor. For resection of malignant tumors of the lower trachea, I prefer the median sternotomy approach, unless preoperative evaluation suggests a posterior component to the tumor, in which case the right thoracotomy approach is utilized. This preference is true for tumors involving the carina as well as for tumors involving the lower trachea.

Ch026-F06861.indd 320

29 3 14 2

If the right thoracotomy approach is to be used for resection of a malignant tumor of the lower trachea or carina, preliminary cervical mediastinoscopy is employed to assess the radial extent of the tumor and the presence of any locally metastatic disease. At the same time, it is useful to use the suction dissector to mobilize the left recurrent laryngeal nerve away from the distal lower trachea. This facilitates encirclement of the distal trachea through the subsequent right thoracotomy approach, without injury to the left recurrent nerve. It is now generally accepted that incomplete resection of an adenoid cystic carcinoma, with microscopic positive margins and subsequent radiotherapy, yields much improved long-term survival compared with nonresection and radiotherapy alone. I would strongly endorse the author’s injunction to “balance the benefit of complete resection with negative airway margins against the risk of excessive tension at the anastomosis. If in doubt, decide in favor of a secure anastomosis.” J. D. C.

1/21/2008 11:01:56 AM

chapter

27

UPPER AIRWAY TUMORS: SECONDARY TUMORS Dennis A. Wigle Shaf Keshavjee

Key Points ■ The upper airway can be secondarily involved with tumor. ■ A curative airway resection is possible in selected cases.

either at the time of surgery or close to it. This maintains tissue planes and prevents difficulty in defining differences between scar and tumor. First-level nodal involvement (N1) significantly reduces 5-year survival, which drops further with N2 disease.1

Diagnosis Secondary tumors invading the upper airway typically arise directly from adjacent structures. This includes invasion from the lung, thyroid, larynx, and esophagus. These tumors rarely present in a manner amenable to surgical resection. Despite this, the situation occasionally arises in which resection of the trachea or carina is a consideration. In the case of non–small cell lung cancer (NSCLC), growing experience with stage T4 tumors in selected instances has suggested a role for aggressive surgical therapy.

NON–SMALL CELL LUNG CANCER INVADING THE UPPER AIRWAY Although techniques of carinal resection and reconstruction have been applied for bronchogenic carcinoma, the description of advanced techniques for NSCLC invading the trachea is much less common. The original classification of NSCLC invading the carina as stage IV disease was largely dictated by the rarity of technical expertise for such resections. When NSCLC invades the trachea directly from lung parenchyma, the disease is usually so extensive that segmental resection of the trachea is not a reasonable option. Only in circumstances in which a bronchogenic carcinoma is centered in the proximal main bronchus or involves the carina in a limited manner is resection a consideration. The disease must be localized such that resection of the involved carina will not result in a reconstructive anastomosis under tension. The generally safe limit of such resection in a right carinal pneumonectomy is approximately 4 cm from the distal end of the trachea to the left main bronchus. With carinal resection alone, preserving the right lung, resection may be somewhat more extensive because of the greater possibility for mobilization of the right lung unhindered by the aortic arch. On the left side, the bronchus is considerably longer, and carcinoma of the left upper lobe, which is less common than that of the right upper lobe, is less likely to extend to the carina. In all series, the number of right carinal pneumonectomies for bronchogenic carcinoma is far greater than that for left-sided resections. An extensive search for extrathoracic metastases is carried out as for any lung cancer. Considerations regarding lymph node involvement are also similar. All patients have their disease aggressively staged with mediastinoscopy performed

Involvement of the carina by NSCLC must be assessed with CT of the lower neck and chest. Tracheal reconstructions of the CT images can be useful to demonstrate the endoluminal and extrinsic extent of the lesion. Bronchoscopy is a strict requirement to confirm the endoluminal characteristics of the tumor. Even when flexible bronchoscopy has been performed as a preliminary assessment, rigid bronchoscopy under general anesthesia is typically required for precise definition of the lengths of airway involved. Extension of tumor down the opposite main bronchus for any distance, particularly down the left side when the tumor is predominantly on the right, may severely compromise or make impossible the approximation of the airway without tension. All patients who are being considered for carinal resection must be evaluated by pulmonary function studies, and in many cases quantitative ventilation-perfusion scans, to determine what postoperative pulmonary function will be.

Management One of the most important management considerations is whether the patient has disease with local extent to a degree such that resection will run the high risk of technical failure as a consequence of tension at the anastomosis. Lymph node involvement must be carefully assessed, and distant metastases ruled out. The patient’s functional limitations for resection must also be clearly defined. The technical aspects of these resections are reviewed in Chapter 30.

Results Early large series suggested mortality rates for carinal resection as high as 25% to 30%.2,3 Dartevelle and associates4 demonstrated a lower mortality rate of 11%. A more recent review of 119 patients undergoing carinal resection from 1981 to 2004 from the same group places the operative 30day mortality at 7.6%.5 In this series, carinal pneumonectomy was performed in 103 cases (96 right and 7 left pneumonectomies). The remaining patients included 3 cases of carinal resection plus right upper lobectomy, carinal resection after left pneumonectomy in 2, and carinal resection without pulmonary resection in 11. Overall 5- and 10-year survivals were 44% and 25%, respectively, for patients with bronchogenic 321

Ch027-F06861.indd 321

1/21/2008 11:02:55 AM

322

Section 2 Upper Airway

carcinoma (n = 100). With respect to nodal status, survival was significantly better in patients with N0 or N1 disease (n = 73) than in those with N2 or N3 disease (n = 27; 53% versus 15% survival at 5 years, respectively). The best outcome was observed in patients with neuroendocrine carcinoma (100% survival at 10 years) and adenoid cystic carcinoma (69% survival at 10 years). The authors suggested that the presence of positive N2 disease is considered a potential contraindication to carinal resection in patients with bronchogenic carcinoma because of the poor long-term survival. A similar series from Regnard and colleagues6 described 65 patients operated on between 1983 and 2002 with an operative mortality rate of 7.7%. Fifty-four of these patients had squamous cell carcinomas, whereas 11 had adenocarcinoma. Fifty-eight right sleeve pneumonectomies and 2 left sleeve pneumonectomies were performed, with resection judged to be complete in 61 patients. The overall 5-year and 10-year survival rates were 26.5% and 10.6%, respectively. Patients with N0 or N1 disease had a 5-year survival of 38% compared with 5.3% for those with N2 disease (P < .01). Multivariate analysis demonstrated that only nodal status (N0, N1 versus N2) had a significant impact on long-term survival. A review of the Massachusetts General Hospital experience with 60 carinal resections for bronchogenic carcinoma demonstrated an overall operative mortality of 15%. This was improved from the first half of the series (20%) to the second half (10%) and varied according to the type of resection performed. The series included 18 isolated carinal resections for tumor confined to the carina or proximal main stem bronchus, 35 carinal pneumonectomies, 5 carinal plus lobar resections, and 2 carinal resections for stump recurrence after prior pneumonectomy. Adult respiratory distress syndrome was responsible for 5 early deaths, with all late deaths related to anastomotic complications. In 34 patients, all lymph nodes were negative for metastatic disease. Fifteen patients had positive N1 nodes, and 11 patients had positive N2 or N3 nodes. The overall 5-year survival including operative mortality was 42%, with 19 absolute 5-year survivors. Survival was highest after isolated carinal resection (51%). Lymph node involvement had a strong influence on survival because patients without nodal involvement had a 5-year survival of 51%, compared with 32% for patients with N1 disease and 12% for those with N2 or N3 disease. Overall, these studies suggest that surgical intervention for carcinoma involving the carina is feasible, with acceptable mortality and good long-term survival in selected patients. However, given the outcomes with N2 or N3 disease, careful attention is given to accurate staging of the mediastinum before surgery, and caution is exercised in proceeding with resection in these patients.

sion, however, is directly responsible for many late deaths due to thyroid cancer and is a source of profound morbidity due to airway hemorrhage and obstruction.10 Thyroid cancer that invades the airway early usually does so by direct involvement of the airway closest to the tumor. This occurs in approximately 1% to 6.5% of patients.11 Tsumori and coworkers12 reported that 50% of papillary and follicular carcinomas that invaded the airway showed poor differentiation, as compared with 11.4% of noninvasive thyroid cancers of the same histology. Invasion also tends to be seen in older patients, in whom papillary and follicular thyroid cancers are more aggressive. The prognosis of thyroid cancers invading the airway appears to correlate with the site and depth of invasion.13 Because of the location of the thyroid gland, the subglottic larynx may also be invaded. The corresponding recurrent laryngeal nerve is often involved with tumor. Adjacent esophagus or cricopharyngeus may also be involved. Recurrent tumors are too often permitted to grow to large sizes even though they frequently respond little to radioactive iodine or external radiotherapy. Poorly differentiated tumors in their initial presentation may involve the larynx to such a degree that salvage is not possible. Recent literature has suggested that conservative shave procedures might be adequate resections for airway invasion.14 However, the standardization and safety of techniques of airway resection and reconstruction have made en-bloc resection a reasonable approach for the management of such carcinomas. Tracheal resection and reconstruction for thyroid carcinomas with airway invasion can provide long-term palliation and even cure in some patients.

Diagnosis The patient with differentiated thyroid carcinoma involving the airway may present with classic signs of airway involvement. These can include hemoptysis, dyspnea on exertion, or wheezing. More often, airway involvement is not symptomatic because the tumor has not yet penetrated the mucous membrane or projected any distance into the lumen. A firm mass that is not freely movable over the airway may be palpable. All too often, tracheal and laryngeal involvement is detected only at thyroidectomy. In addition to the usual diagnostic approach to thyroid cancer, which includes thyroid function studies, thyroid scan, and needle biopsy, flexible bronchoscopy is advisable in every patient. CT includes the chest to search for pulmonary metastases. The neck is imaged by means of thin-section CT scans, which are most likely to identify involvement of the tracheal wall or intrusion into the lumen. Direct laryngoscopy is necessary to assess function of the vocal cords. A barium swallow may define the bulk of the tumor and detect involvement of the adjacent esophagus.

THYROID CANCER Occasionally, thyroid carcinoma can involve the trachea or adjacent larynx to an extent that it is possible to resect the involved area with primary reconstruction of the airway. Such resections have been described dating back to the 1950s.7,8 Well-differentiated thyroid carcinoma typically runs an indolent course, with frequent long-term survival.9 Airway inva-

Ch027-F06861.indd 322

Management The purposes of resection of thyroid cancer invading the airway follow15: 1. To attempt to achieve cure by accomplishing complete resection of the tumor

1/21/2008 11:02:55 AM

Chapter 27 Upper Airway Tumors: Secondary Tumors

2. To provide prolonged palliation by relief or prevention of airway obstruction in patients with slowly progressive neoplasms 3. To prevent death by asphyxiation or hemorrhage Resection and reconstruction of involved airway as part of the complete local excision of thyroid cancer, particularly as an initial procedure, accomplishes the primary goals of conventional thyroid cancer surgery. The alternative is to refer a patient for resection of the airway immediately after discovery of such involvement in the operating theater. The airway resection and reconstruction is then carried out as a second procedure as soon as possible. Follow-up results suggest that patients in whom either of these alternatives has been followed have the best long-term results and cure rates.15 Late removal of recurrent tumor obstructing the airway occurring sometimes years after the initial tumor has been shaved off the trachea is effective palliation but is not often curative because remote metastases may have often occurred by this time. The finding of pulmonary metastases from slowly progressive differentiated carcinoma of the thyroid is not an absolute contraindication to resection for airway invasion. Almost uniformly, localized involvement of the airway by carcinoma of the thyroid involves only one recurrent laryngeal nerve. Thus, a functional larynx can be preserved by conserving the nerve on the opposite side. Radical techniques of cervical or cervicomediastinal exenteration are applied very selectively. Such approaches can be justifiable when the tumor is localized but involves extensive amounts of the larynx, pharynx, or esophagus. This occurs more commonly with aggressive, poorly differentiated carcinoma. A second situation justifying a radical approach is massive recurrence of differentiated carcinoma, often years after initial resection and after unsuccessful treatment with radioactive iodine and external-beam radiation therapy. Such patients may be miserable, with poorly functioning tracheostomies accompanied by local bleeding, loss of voice, and inability to swallow food or even saliva. Cervical pain further aggravates their condition. Radical excision may offer palliation even if pulmonary metastases are present.15

Results In general, well-differentiated thyroid cancer usually progresses slowly and rarely invades other tissues. However, cases with invasion of local structures, such as the larynx, trachea, or esophagus, present unique management difficulties. In situations in patients with limited involvement of the larynx or trachea, there is controversy over whether a socalled shave excision that may leave microscopic disease at the site or a complete resection that includes removal of a portion of these structures is the better approach. In the case of more extensive involvement of upper aerodigestive tract structures by thyroid carcinomas, the most appropriate method of resection and reconstruction is also at issue.16 Bayles and coworkers17 described 28 patients with invasive thyroid cancer involving the aerodigestive tract over a 20-year period. This was from 536 cases for an incidence of 5.6%. Histologic findings at the time of invasion for the 28 patients included 15 well-differentiated thyroid carcinomas and 13

Ch027-F06861.indd 323

323

poorly differentiated carcinomas. Eight of the 28 patients underwent surgical resection of some portion of the aerodigestive tract with curative intent. Ten patients underwent incomplete resection with tumor left adjacent to aerodigestive tract structures. All patients undergoing incomplete resection developed local recurrence. Six required salvage resection, as opposed to no recurrences in patients with welldifferentiated carcinomas after complete resection. Survival at 5 years for patients with well-differentiated carcinomas undergoing complete resection in one operation versus initial incomplete resection was 100% versus 50%, respectively. A series from Japan describes the results in 40 patients who underwent resection of the trachea in conjunction with thyroid resection.18 Anastomotic failure occurred in 4 patients. Two of these went on to develop massive bleeding from the carotid artery due to neck infection. The authors concluded that combined resection is a good treatment choice for survival and good quality of life when performed for local control in patients with differentiated thyroid cancer. A review of the Hannover University Medical School experience19 studied 33 patients who underwent 34 tracheal or laryngotracheal procedures for invasive differentiated thyroid carcinoma from 1990 to 1998. Procedures resulting in primary end-to-end anastomosis of the upper airway appeared to be associated with lower perioperative morbidity and improved recurrence-free survival when compared with window resections with muscle flap reconstruction. In cases of superficial tracheal tumor invasion, these authors believed that a shave procedure or laminar ablation was sufficient for local tumor control. Shave procedures were used in cases in which either the tumor was infiltrating the trachea superficially as verified by frozen section or when the patient was judged unfit to undergo a tracheal resection with primary anastomoses. The authors concluded that radical eradication of differentiated thyroid carcinoma infiltrating the upper airways followed by radioiodine application is considered the treatment of choice. McCarty and associates20 reviewed 597 patients undergoing thyroidectomy for thyroid cancer, 40 of whom were found to have laryngotracheal invasion. Acknowledging that locally advanced thyroid cancer invading the tracheal cartilage represents a difficult treatment dilemma during thyroidectomy, they sought to examine their results of laryngotracheal resection or tracheal cartilage shave with adjuvant radiotherapy in patients with locally advanced thyroid cancer invading the upper airway. In their series, 35 patients with invasion underwent cartilage shave procedures with adjuvant radiotherapy and 5 patients with full-thickness invasion underwent radical resection, including tracheal sleeve resection (3) or total laryngectomy (2). Decisions regarding extent of resection were made based on depth of tracheal invasion and operative fitness. Histologic subtypes included papillary (32), follicular (2), Hürthle cell (1), medullary (3), and anaplastic (2) carcinoma. Of the cartilage shave group, 25 were alive with no evidence of disease at a mean follow-up of 81 months. Six developed isolated local/regional recurrence and were managed with total laryngectomy (1), tracheal resection (1), cervical lymphadenectomy (1), or repeat radiotherapy (3). All six patients remained free of disease at a mean follow-up

1/21/2008 11:02:55 AM

324

Section 2 Upper Airway

of 5 years. Of those who underwent initial laryngotracheal resection, 4 remained free of disease at a mean follow-up of 5 years. The rates of 10-year disease-free survival and overall survival for all patients were 47.9% and 83.9%, respectively. It is likely that the patients in this series who underwent primary en-bloc airway resection at the time of thyroidectomy had more extensive disease. Indeed, the authors concluded that adequate management of thyroid cancer with laryngotracheal invasion can be achieved with a more conservative surgical approach and adjuvant radiotherapy, reserving more radical resections for extensive primary lesions or locally recurrent disease. In contrast, Nishida and colleagues21 reported on 117 patients with differentiated thyroid carcinoma invading surrounding structures retrospectively studied for local failures. The patients were divided into five groups on the basis of macroscopic findings. Group 1 consisted of 40 patients who underwent tracheal resection for deep tracheal invasion, group 2 consisted of 14 patients with deep tracheal invasion and no airway resection, group 3 consisted of 13 patients with superficial tracheal invasion and no airway resection, group 4 comprised 48 patients with extrathyroidal invasion other than laryngotracheal structures, and group 5 consisted of two patients who underwent tracheal resection for superficial invasion. Management of the airway with resection for patients with deep tracheal invasion appeared to decrease local recurrence and improve postoperative prognosis compared with nonresection of the tumor. These results were better than those achieved by shaving the tumor off the trachea for patients with superficial invasion, and resection did not increase postoperative local failures or mortality (group 3 versus groups 4, 5, and 1). The authors recommend that although differentiated thyroid carcinomas with superficially limited tracheal invasion can be treated successfully by nonresectional techniques, those with deep invasion are treated by resection of the invaded trachea. A review of the Massachusetts General Hospital experience with 52 patients with thyroid cancer invading the airway seen between 1964 and 1991 described 34 patients undergoing surgical therapy. Twenty-seven of these had reconstruction of the airway and 7 had cervical exenteration with end tracheostomies. Resection was not performed in 18 because of either distant disease, extensive local disease, or the desire to preserve laryngeal function in cases in which only an operation including laryngectomy would have been adequate.16 Among the patients who had the reconstructive procedure, 16 had papillary carcinoma, 5 had follicular carcinoma, 4 had carcinoma of mixed histology, and 2 had poorly differentiated carcinoma. Five of the patients were referred immediately after the operating thyroid surgeon identified tracheal invasion, but 13 others were referred at the time of recurrence, the original tumor having been shaved off the trachea. The interval between initial surgical treatment and airway resection ranged from l to 47 years. Ten patients underwent tracheal sleeve resection, 6 had partial oblique resection of the cricoid cartilage with a laryngotracheal anastomosis, and 10 underwent complex resection with individually designed lines of resection through the larynx to accomplish maximal tumor removal with preserva-

Ch027-F06861.indd 324

tion of laryngeal function. In 3 patients, a protective tracheostomy was performed because of concerns regarding airway patency at the conclusion of surgery. Of the 27 patients with airway reconstruction, 15 showed lymph node metastases and, in 13, positive resection margins were accepted in order to salvage the larynx. Eight patients received radioactive iodine therapy, and 7 received external radiation. Two early deaths occurred in this group of 27 patients. The first was the result of failure of anastomotic healing in a patient who had undergone 7800 cGy of irradiation 6 years before reconstruction after incomplete resection of cancer. A second patient died of respiratory arrest due to airway obstruction. One patient suffered right vocal cord paralysis not present preoperatively and not the result of elective resection of a recurrent laryngeal nerve. In the reconstruction group, 11 of the 25 survivors of surgery died of cancer from 3 months to 10 years after reconstruction. Two patients with undifferentiated thyroid cancer died of distant metastases within 6 months of resection. Cancer of the airway recurred in only 2 patients in the group, which indicates effective accomplishment of one of the primary goals of surgery—obviation of death by airway obstruction. The average duration of survival among these 11 patients was 3 years and 7 months. The usual cause of death was metastatic disease in the mediastinum, lungs, or brain. One patient died of leukemia, which was possibly related to earlier therapy with iodine-131. Of the 13 surviving patients, 12 were without evidence of cancer at the time of follow-up (1 month-141/2 years after airway surgery); the other patient had pulmonary metastases. The average survival of the 13 patients was 5 years and 9 months at the time of follow-up. In 2 patients, local nodal recurrences had been excised at varying intervals after the initial airway resection. Of the 13 surviving patients, 9 had undergone airway resection as part of the initial surgical treatment or had been referred immediately after a surgeon found evidence of tracheal invasion at thyroidectomy. It is also worth noting in this series that 7 patients had evidence of pulmonary metastasis at the time of airway resection performed to achieve palliation. The metastases were known to be slowly enlarging. Although 2 of these patients died within l year of the airway procedure (with undifferentiated carcinoma), the average survival for the whole group was 4.2 years and the patient surviving the longest was still alive 10 years after surgery.

Discussion Although differentiated thyroid carcinoma that invades the airway often appears to be aggressive, many tumors run an indolent course with excellent potential for long-term survival. Although controversial, complete resection of local disease, including involved airway, appears to be the best therapy. This provides potential for cure when it is done as part of the initial therapy and prolonged palliation when it is done for late recurrent disease. External irradiation, radioactive iodine, and chemotherapy have often proved not to be effective agents for management of residual disease. Various techniques of coring out the airway, either mechanically or by laser, in addition to stenting, provide temporary

1/21/2008 11:02:56 AM

Chapter 27 Upper Airway Tumors: Secondary Tumors

palliation but otherwise are applied only when resection is not possible. Even when cure is not achieved, prolonged palliation is often obtained by resection, and devastating airway complications can be avoided. For these reasons, bronchoscopy and careful CT examination are part of the preoperative investigation of all patients with thyroid carcinoma. Either the preoperative discovery of invasion or its finding at thyroidectomy dictates prompt referral to a center where appropriate airway resection and reconstruction can be performed. Every effort must be made to save the larynx. In a highly selected group of patients, radical resection, including laryngectomy in patients with no hope of laryngeal salvage, is indicated. The presence of slowly growing pulmonary metastases is not a contraindication for resection because this is compatible with prolonged survival.

OTHER TUMORS INVADING THE UPPER AIRWAY Cervicomediastinal exenteration has been performed for other secondary tumors invading the trachea, including postcricoidal squamous carcinoma of the esophagus that involves the larynx and upper trachea, where laryngeal salvage is impossible. Adenoid cystic carcinoma may also invade the larynx in an unsalvageable manner, as well as the upper portion of the trachea and less often the wall of the esophagus. Generally, resection of the trachea for direct involvement by esophageal carcinoma other than the postcricoidal type is not advised. The extent of involvement is usually so great that curative resection is unlikely. Tracheoesophageal fistula due to esophageal carcinoma is an extreme example. In the rare patient after preoperative neoadjuvant therapy if the

Ch027-F06861.indd 325

325

only point of apparent nonresectability is a short segment of trachea, it can be worthwhile to resect this segment and perform a direct tracheotracheal anastomosis. One must be particularly cautious in such cases because the blood supply of the trachea may well be compromised by the extensive dissection performed for removal of the esophagus. Through a large part of the body of the trachea, segmental arteries provide an anterior branch to the trachea and a posterior one to the esophagus. If combined resection is performed, flap coverage with omentum or other tissue is advisable. This is ideally brought up with the stomach tube used to reconstruct the esophagus.

SUMMARY It is not unusual to encounter a secondary tumor that is invading the trachea or carina from an adjacent organ of origin—most commonly the larynx, thyroid, lung, or esophagus. In general, if en-bloc complete resection of the tumor with the involved airway will lead to complete pathologic resection, this is the best-case scenario. The primary goals of airway resection in this setting are curative treatment, prevention of airway obstruction, and prevention of other complications related to airway involvement with tumor. If the airway resection is complex or has potential for significant morbidity, such as an irradiated airway with an anastomosis under some tension, then careful evaluation and surgical judgment are required. Cases of incomplete resection are generally treated with postoperative radiation therapy. Even if resection of the trachea cannot be carried out at the initial cancer operation, prompt referral to a tracheal surgery center for evaluation will ensure that the patient does not lose the opportunity for a potentially curative airway resection.

1/21/2008 11:02:56 AM

Surgical Techniques chapter

28

PRINCIPLES OF AIRWAY SURGERY: MANAGEMENT OF ACUTE CRITICAL AIRWAY OBSTRUCTION Alberto de Hoyos G. Alexander Patterson

Key Points ■ Acute central airway obstruction (CAO) is a life-threatening

emergency. ■ Expeditious diagnosis and management are necessary to avoid

suffocation and death. ■ Always consider resection and reconstruction as the optimal

therapy. ■ Rigid bronchoscopy is the preferred method to stabilize the

airway. ■ The most common benign cause of CAO is postintubation tracheal

injury. ■ Malignant CAO may be caused by intraluminal lesions, extrinsic

compression, or mixed lesions. ■ Close communication with the anesthesiologist is essential during

airway interventions. ■ A multidisciplinary and multimodality approach ensures the best

possible results. ■ Stenoses need to be dilated; endobronchial tumors need to be

removed and extrinsic compressions stented. ■ Most intraluminal tumors can be safely cored out with the rigid

bronchoscope. ■ Microdébridement is an effective procedure to recanalize obstruc-

tive airway tumors to the level of the main stem bronchi. ■ Adjunct modalities include Nd:YAG laser, electrocautery, and argon

plasma coagulation.

Acute airway obstruction is a life-threatening emergency that requires expeditious and effective diagnosis and treatment to avoid suffocation and death (Grillo, 2004; Sundaresan, 2004; Wood, 2002).1-4 The location, severity, and etiology of the obstruction dictate the methodology of management (Box 28-1). For obstruction proximal to the carina, control is established by securing an airway below that level to provide adequate ventilation and oxygenation. A discussion of upper airway obstruction (oronasal to glottic area) is beyond the scope of this chapter and is covered elsewhere.5 Thoracic surgeons, however, should be familiar with the “cannot intubate—cannot ventilate” scenario and provide the necessary assistance to establish and secure an airway. Central airway obstruction (CAO), as defined in this chapter, includes the area from the subglottic space to the level of the five lobar orifices. Acute obstruction above this level can be successfully treated with an expeditious tracheostomy if necessary and is covered in Chapter 29. Management of patients with CAO requires a thorough knowledge of the physiology, etiology, and diagnostic and treatment options, as well as a multidis-

ciplinary team approach that includes chest radiologists, thoracic anesthesiologists, medical and radiation oncologists, interventional pulmonologists, otolaryngologists, and thoracic surgeons (Chan et al, 2003; Ernst et al, 2004).6-8 A team approach provides patients with a variety of open or bronchoscopic alternatives and prevents physicians and surgeons from burning their bridges if one technique is initially chosen over another, more favorable, one. Although surgical resection and airway reconstruction provide the best opportunity for definitive management of CAO, it can only be achieved in a minority of patients (Grillo and Mathisen, 1990).9,10 For the majority of patients, bronchoscopic management is the first step in providing an accurate diagnosis and achieving effective recanalization of the obstructed airway. Box 28-2 depicts the goals in the emergency management of patients with CAO. In general, endobronchial intervention for CAO is indicated in two situations: (1) acute life-threatening obstruction of the central airways and (2) obstruction causing symptoms (dyspnea, postobstructive pneumonia, and hemoptysis), atelectasis, or reduction of the airway lumen of more than 50%. A variety of interventional bronchoscopic techniques can be utilized to provide recanalization or palliation of CAO as described in Box 28-3 and Chapter 18. Although the role of these interventions in the oncologic patient is predominantly palliative, in carefully selected patients these bronchoscopic techniques can improve the quality of life, lower the level of care, allow withdrawal of mechanical ventilation, and, on occasion, prolong survival (Baram, 2003; Brodsky, 2003; Cavaliere et al, 1996; Cosano et al, 2005; Lee et al, 2002; Morris et al, 2002; Stephens and Wood, 2000; Unger, 2003; Wood, 2001).11-24 Selected patients can undergo definitive surgical resection and airway reconstruction after emergent recanalization and subsequent evaluation of an obstructed airway.

CLINICAL PRESENTATION Box 28-4 is a list of the common symptoms and signs of CAO.

ETIOLOGY Central airway obstruction may be caused by a variety of malignant and nonmalignant processes (Table 28-1). The most common cause of malignant CAO is direct extension from adjacent tumor, most commonly bronchogenic carcinoma, followed by esophageal and thyroid carcinoma. Primary tumors of the trachea are relatively uncommon, with an estimated incidence in the United States of 600 to 700 cases per year (or one case for every 180 lung cancers; 3 new cases

326

Ch028-F06861.indd 326

1/21/2008 11:04:00 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

Box 28-1 Location of Airway Obstruction ■ Mouth

■ Glottic

■ Oropharynx

■ Subglottic

■ Pharynx

■ Tracheal

■ Hypopharynx

■ Carinal

■ Central airway obstruction

■ Main bronchi

■ Supraglottic

■ Lobar bronchi

Box 28-2 Goals in the Management of Patients with Central Airway Obstruction ■ Relief of airway obstruction ■ Recruitment of functional lung ■ Improvement in quality of life ■ Decrease in level of care (e.g., wean from mechanical ventilation) ■ Allow time for more definitive therapy (e.g., resection, radiotherapy,

chemotherapy) ■ Bridge to definitive operative management

Box 28-3 Bronchoscopic Procedures to Treat Central Airway Obstruction ■ Argon plasma coagulation ■ Balloon dilation (bronchoplasty) ■ Cryotherapy ■ Electrocautery ■ Endobronchial brachytherapy (high dose rate [HDR]) ■ Laser (Nd:YAG) ■ Microdébrider ■ Photodynamic therapy ■ Rigid bronchoscopy (core out, dilation) ■ Stents

Box 28-4 Symptoms and Signs of Central Airway Obstruction ■ Dyspnea

■ Wheezing

■ Cough

■ Hemoptysis

■ Stridor

■ Difficulty clearing secretions

■ Obstructive pneumonia

■ Hoarseness

■ Suffocation

■ Inability to lie recumbent

per million per year).25 The majority of primary tracheal tumors (70%-80%) in adults are malignant, either squamous cell carcinoma or adenoid cystic carcinoma.26-27 Carcinoid tumors account for the majority of primary airway tumors distal to the carina.28 Metastases from remote sites occur to the bronchi but rarely to the trachea.29 Primary sites, in descending order of frequency, include breast, kidney, and colon.30-32 Other sites include bladder, thyroid, ovary, nasopharynx, and skin (melanoma). Predominantly extrinsic compression occurs with neoplastic conditions involving

Ch028-F06861.indd 327

327

TABLE 28-1 Causes of Central Airway Obstruction Malignant Primary airway tumor Squamous cell carcinoma Adenoid cystic carcinoma Mucoepidermoid carcinoma Carcinoid Miscellaneous Metastatic disease Breast carcinoma Renal cell carcinoma Colon cancer Sarcoma Melanoma Thyroid Bronchogenic carcinoma Bladder Ovary Nasopharynx Adjacent tumor Lung cancer Esophageal cancer Thyroid cancer Head and neck cancer Mediastinal tumor Thymus Germ cell Lymphoma Nonmalignant Lymphadenopathy Sarcoidosis Infectious (e.g., tuberculosis, histoplasmosis) Vascular Sling Aneurysm Dissection with aneurysmal dilation Cartilage Relapsing polychondritis Granulation tissue, scar Stents Foreign bodies Surgical anastomosis Wegener’s granulomatosis Postintubation stricture Endotracheal intubation Tracheostomy tube Pseudotumor Hamartoma Amyloid Hyperdynamic Tracheomalacia Dynamic airway collapse Webs Idiopathic Tuberculosis Sarcoidosis Benign tumors Lipoma Leiomyoma Papillomatosis Fibroma Other Goiter Mucus plug Vocal cord paralysis Blood clot Epiglottitis

1/21/2008 11:04:00 AM

328

Section 2 Upper Airway

mediastinal structures such as thymic tumors, germ cell tumors, and lymphoma. The most common cause of nonmalignant CAO continues to be postintubation injury of the trachea.

GENERAL TREATMENT MEASURES Before any diagnostic or therapeutic interventions can be performed, the patient must be stabilized and a clear plan of action established. Imaging studies, discussed extensively in Chapter 16, should be carefully reviewed (Boiselle and Ernst, 2002).33-54 All the necessary equipment should be available before the patient enters the operating room. Close communication with the anesthesiologist is essential. Box 28-5 is a list of measures that can be valuable alone or in combination in the emergency stabilization of patients with critical airway obstruction (Sundaresan, 2004).3,55-59 Some of these measures are also recommended for the first 24 to 48 hours after the intervention.

DIAGNOSTIC ENDOSCOPY Bronchoscopic management is the first step in the evaluation of the patient with suspected CAO (Chao et al, 2005; Wood, 2002).1,60-62 Bronchoscopy allows confirmation of the diagnosis, stabilization of the obstructed airway, and evaluation for potential resectability. Esophagoscopy is added if the lesion is a tumor that may involve the esophagus, if there is a question of a fistula, or if there is another reason to suspect an esophageal pathologic process. If a laryngeal component is suspected, an endoscopy as a joint effort with a consulting otolaryngologist is arranged to inspect the supraglottic airway. Rigid bronchoscopy is preferred in any patient with CAO. A standard flexible bronchoscope (4.9 to 6 mm) may be introduced through the larger rigid instrument for inspection of the more distal airways or the upper lobes. An ultrathin bronchoscope (2.8 mm in diameter) with a 1.2-mm working channel can also be utilized to assess the obstruction and the distal airways when the residual lumen does not allow insertion of the regular-size flexible bronchoscope.63 The adjoining mucosa proximal and, if possible, distal to the obstructive lesion should be scrutinized carefully, and a biopsy should be performed on any area that is suspicious for extension of the pathologic process if indicated. During the bronchoscopic examination, specific features of the lesion should be noted (Box 28-6). Attention to these features will allow the bronchoscopist to assess properly the potential resectability of the lesion or choose the optimal endoscopic therapy.

ANESTHETIC MANAGEMENT Careful anesthetic management before and during bronchoscopy cannot be overemphasized (Alfille, 2004).64-75 Communication and coordination between the operating surgeon and the anesthesiologist is crucial. The fundamental principle of anesthesia for patients with critical CAO is the avoidance of any paralytic agent until the establishment of a secure airway to avoid the lethal combination of airway obstruction and apnea. The surgeon must be present when anesthesia is induced, with all the necessary bronchoscopic equipment at hand, particularly when difficult mask ventilation or intubation is anticipated. The goal is to establish a secure and effective airway distal to the lowest point of obstruction. If critical airway stenosis is present (<5 mm), spontaneous respiration should be maintained during the induction of anesthesia with an inhalation agent such as halothane or sevoflurane (Alfille, 2004).64,67,68,70 In patients without critical airway obstruction, satisfactory topical anesthesia of the upper airway should be achieved before the patient enters the operating room.4 This is achieved by having the patient carefully gargle a dilute solution of viscous lidocaine followed by nebulized 1% lidocaine solution (20 mL). Coughing should be prevented because it is likely to set off a chain of events that can reduce the airway to a critical size and even total obstruction. Topical anesthesia is then followed by inhalational or total intravenous anesthesia (Alfille, 2004).64,65,70 The advantage of inhalation anesthesia is that the patient maintains respiration, thus avoiding dangerous periods of apnea, and the patient will breathe spontaneously immediately after the procedure. Preoxygenation with 100% oxygen by a tight-fitting mask allows the gas in the patient’s functional residual capacity to achieve an increasing concentration, providing an oxygen reserve if difficulties arise during the establishment of an airway. Gentle positive airway pressure during induction may stent open nearly collapsed airways. Depending on the degree of airway obstruction, the patient’s minute ventilation, and

Box 28-6 Bronchoscopic Features of Airway Lesions ■ Location (intraluminal, extrinsic, mixed; supraglottic, glottic, sub-

glottic, tracheal, carinal, main bronchi, lobar, segmental) ■ Shape (circumferential or partial) ■ Length (long, short, number of tracheal rings involved, length in

centimeters) ■ Severity of obstruction (total, partial, percentage of airway lumen

obstructed, diameter of remaining airway lumen in millimeters)

Box 28-5 General Measures for the Management of Central Airway Obstruction

■ Distances from other anatomic structures (vocal cords, cricoid

■ Quiet environment

■ Type of stricture (simple, web-formed, complex, cicatricial, soft,

■ Elevation of the head of the bed

cartilage, main carina) mature, tumor)

■ Humidified oxygen delivered by high-humidity facemask

■ Components (firm, soft, early, mature, granulation tissue)

■ Diuretics (furosemide, 20 mg, intravenously q8h for 24 hr)

■ Associated abnormalities (malacia, post-stricture dilation, granula-

■ Corticosteroids (dexamethasone, 4-10 mg, q6h for 24-48 hr)

tion tissue, loss of cartilage support, presence of foreign material or purulent secretions) ■ Distal airways (open, obstructed, compressed)

■ Racemic epinephrine ■ Heliox (mixture of helium 60%-80% and 20%-40% oxygen)

Ch028-F06861.indd 328

1/21/2008 11:04:00 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

the induction agent used, an inhalation induction may require up to 20 minutes, and thus patience is required (Alfille, 2004).64,70 Once airway patency is established by placement of the ventilating rigid bronchoscope, a muscle relaxant may be used. The surgeon must be prepared to ensure establishment of an airway at any time during the induction phase. It must be kept in mind that the pathologic process causing CAO may not be adequately addressed by cricothyrotomy, tracheostomy, or transtracheal jet ventilation. In some patients with noncritical airway obstruction, a laryngeal mask airway can be seated into position using a combination of intravenous anesthesia (continuous propofol infusion) and inhalation anesthesia. The flexible bronchoscope is employed to assess the airway pathology, with the patient asleep but breathing spontaneously, receiving gentle assisted manual ventilation by the anesthesiologist. Additional lidocaine can be used to topically anesthetize the epiglottis, vocal cords, and upper airway as the bronchoscope is advanced into the airway. Care is necessary to avoid direct trauma to the lesion because this can result in swelling and bleeding, both of which may worsen an already tenuous situation. After proper assessment of the airway pathology, the appropriate-size rigid bronchoscope is then selected and exchanged for the laryngeal mask airway. Ventilation can be maintained via a closed system or with jet ventilation (Alfille, 2004).64,70 The team should also be alert for the redevelopment of CAO after the procedure, while still in the operating room, which is typically due to residual anesthetic effects, edema, mobilization of secretions, sloughed tissue, blood clots, or a migrated stent.65 Rigid bronchoscopy is usually required in these cases to stabilize and clear the airway of any endoluminal obstruction. This scenario is best avoided by leaving the rigid bronchoscope in situ at the completion of the procedure, until spontaneous ventilation and airway patency are ensured. Alternatively, some patients are electively intubated with an endotracheal tube or ventilated with a laryngeal mask airway and extubated once fully awake and an intact cough reflex is present. On rare occasions, transtracheal jet ventilation, percutaneous cardiopulmonary support, or extracorporeal membrane oxygenation may be required as preliminary steps in establishing an adequate airway or to facilitate complete resection of thoracic malignancies in patients with specific critical conditions.76-85 In most instances, however, a meticulous and systematic approach to the critical airway is successful in securing the airway employing the standard techniques as described earlier.

329

is also a therapeutic tool that allows passage of various instruments. With the rigid bronchoscope, an obstructing lesion can be safely cored out, a stenosis can be gently dilated, and therapeutic tools such as laser, electrocautery, and stent deployment devices can be introduced through the scope. In addition, the barrel of the bronchoscope can be utilized to tamponade a bleeding central lesion, and large suction devices and forceps can be used for mechanical débridement of obstructive lesions or removal of foreign material. Therapeutic approaches available in the armamentarium to relieve airway obstruction are shown in Box 28-3. The surgeon treating CAO needs to become familiar with the advantages and disadvantages of the different options to provide the safest and most efficient treatment to specific situations (Baram, 2003; Cavaliere et al, 1996; Ernst et al, 2004; Grillo, 2004; Stephens and Wood, 2000; Sundaresan, 2004; Wood, 2002).1-3,6,8,11,20-23 The use of multimodality and multidisciplinary approaches utilizing a combination of several interventions provide effective long-term success in some of these patients (Beamis, 2005; Bolliger, 2000; Bolliger and Mathur, 2002; Ernst et al, 2003; Freitag, 2004; Santos et al, 2004; Seijo and Sterman, 2001).86-103 A flexible and creative approach to the application of these techniques is necessary in some situations to provide the best opportunity for successful airway palliation.

RIGID BRONCHOSCOPY Endoscopic examination of the obstructed airway is best accomplished under general anesthesia with rigid instruments (Beamis, 2005; Brodsky, 2003; Chao et al, 2005; Ernst et al, 2004; Lamb and Beamis, 2004; Stephens and Wood, 2000; Wood, 2001; Wood, 2002).1,6,11,14-16,60-61,87,104 Box 28-7 depicts the necessary equipment to perform rigid bronchoscopy. In patients who have critical airway narrowing, even the minor

Box 28-7 Equipment Utilized for Therapeutic Rigid Bronchoscopy ■ Set of pediatric and adult rigid bronchoscopes ■ Ventilating rigid bronchoscopes and tracheoscopes ■ Set of Hopkins rod telescopes with 0-, 30-, and 90-degree

lenses ■ Light source ■ Video monitor ■ Rigid and flexible suction cannulas ■ Grasping and biopsy forceps

SECURING THE AIRWAY In patients with critical CAO, we recommend rigid bronchoscopy as the procedure of choice. Endotracheal intubation may be impossible and even dangerous, possibly leading to complete airway obstruction, and thus should be avoided. The ventilating rigid bronchoscope provides the safest and most effective means of airway control and stabilization in acute benign and malignant tracheobronchial obstructions. The rigid bronchoscope not only provides a secure airway, allowing excellent control of oxygenation and ventilation, but

Ch028-F06861.indd 329

■ Flexible bronchoscope ■ Syringes, saline, lubricant gel, epinephrine ■ Tapered esophageal dilators ■ Tracheal and bronchial stents ■ Various stent deployment devices ■ Endobronchial blocker for tamponade and control of hemoptysis ■ Various interventional applications: Nd:YAG laser, electrocautery,

argon plasma coagulation, photodynamic therapy, cryotherapy, microdébrider, stents ■ Jet ventilation system (optional)

1/21/2008 11:04:00 AM

330

Section 2 Upper Airway

FIGURE 28-1 Array of ventilating rigid bronchoscopes, biopsy forceps, and suction cannula.

FIGURE 28-2 Comparative tips of Hollinger (top) and Storz (middle and bottom) rigid bronchoscopes. The rounded-tip bronchoscopes (top and bottom) are more easily introduced into a tightly stenotic lesion with a rotatory motion than the shovel-like bronchoscope tip (middle).

trauma of flexible bronchoscopy may produce mucosal edema or bloody secretions that can precipitate airway obstruction and respiratory failure. This situation is less critical for airway obstruction distal to the carina. In most cases of CAO the Hollinger ventilating bronchoscope is satisfactory (Fig. 28-1). A variety of rigid bronchoscopes should be available, including pediatric (3.5, 4.0, 5.0, and 6.0 mm) and adult (7.0, 8.0, 9.0, 11.0, 14.0 mm) sizes. Nominal diameter is determined by the internal diameter of the tube, typically 2 to 3 mm less than its external diameter. The tips of the Hollinger bronchoscopes are oblique with rounded edges and are easier to introduce through tight stenoses or past a tumor than are the shovel-like tips of the Storz or Dumon-Harrell instruments (Fig. 28-2). Newer Storz bronchoscopes also feature this rounded tip. There are several methods to introduce the rigid bronchoscope, as described in Table 28-2 and Chapter 16. Once the scope is introduced into the trachea, a Hopkins telescope is introduced and a detailed examination is performed to observe the tracheal configuration in anteroposterior and lateral directions, abnormalities in the cartilaginous architecture, mucosal intraluminal lesions, and submucosal or extrinsic deformities. Figure 28-3 shows the different types of CAO. If possible, the flexible bronchoscope is passed through the telescope adapter via the rigid bronchoscope to complete a survey of the distal airways if necessary. If significant obstruction is present, however, no attempts should be made to pass the obstruction before establishing a secure airway. Measurements are obtained to determine the length of the lesion and its distance from normal landmarks. The simplest measurement technique is to measure the relational distances between the vocal cords, cricoid, top of the lesion, bottom of the lesion, carina, and major bronchial bifurcations (Fig. 28-4). A schematic drawing describing the tumor or stricture is created and incorporated in the patient’s medical record for future surgical planning.

TABLE 28-2 Methods to Intubate the Airway With the Rigid Bronchoscope

Ch028-F06861.indd 330

Classic Technique Looking through the eye piece of the instrument Using a Hopkins telescope through the instrument with a video camera and monitor Intubation with a laryngoscope Exchange of endotracheal tube for rigid bronchoscope

FIGURE 28-3 Types of central airway obstruction. Schematic illustration of the three most important types of CAO shown at the tracheal level with an identical degree of obstruction. Left, endoluminal obstruction; middle, extraluminal compression; and right, mixed obstruction. Superimposed on the schema is the value of the various endoscopic modalities in treating these obstructions: +++ = excellent; ++ = good; Ø = of no value. (FROM BOLLIGER CT: MULTIMODALITY TREATMENT OF ADVANCED PULMONARY MALIGNANCIES. IN BOLLINGER CT, MATHUR PN [EDS]: INTERVENTIONAL BRONCHOSCOPY. BASEL, KARGER, 2000, P 189.)

THERAPEUTIC APPROACHES Definitive surgical correction is the treatment of choice for CAO (Grillo and Mathisen, 1990; Wood, 2002).1,9-10,25-26 Carinal or bronchial resection and reconstruction permit

1/21/2008 11:04:00 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

331

airway has been achieved, more conventional treatments, such as radiation and chemotherapy, can be employed. On occasion, patients presenting with malignant CAO can undergo resection after an initial bronchoscopic procedure to recanalize and prepare an obstructed airway (Venuta et al, 2002).105-107 For malignant endobronchial or intrinsic obstruction, the most widely used technique is mechanical tumor debulking with forceps or core out of tumor with the tip and the barrel of the rigid bronchoscope. Electrocautery and neodymium: yttrium-aluminum-garnet (Nd:YAG) laser can be utilized as adjuncts to achieve hemostasis once the airway is recanalized. For airway lesions with a mixed extrinsic and intrinsic component, best long-term results are obtained by first removing the endoluminal tumor by mechanical debulking with the rigid bronchoscope, followed by laser coagulation or electrocautery of bleeding vessels and placement of a stent in the same setting. Additional radiation therapy, either externalbeam radiation therapy or brachytherapy, may prolong the time to recurrence of local tumor growth. Extrinsic stenosis or mixed lesions with a significant extrinsic component benefit the most from insertion of a stent. This is covered in detail in Chapter 18.

EMERGENT MANAGEMENT Benign Central Airway Obstruction Cicatricial Stenosis

FIGURE 28-4 Method for localization and measurement of the length of a lesion. A Hopkins telescope is just within the tip of the bronchoscope. A, With the tip of the bronchoscope at the carinal spur, distance is measured and recorded between the incisor teeth (or upper gingival ridge) and a proximal fixed point on the bronchoscope. Similar measurements are made with the bronchoscopic tip successively at the lower edge of the lesion (B), the upper edge of the lesion (C), the lower edge of the cricoid (D), and/or at the vocal cords. E, Recording of measurements and approximate lengths by subtraction. (FROM GRILLO HC: DIAGNOSTIC ENDOSCOPY. IN GRILLO HC [ED]: SURGERY OF THE TRACHEA AND BRONCHI. HAMILTON, ONTARIO, BC DECKER, 2004, P 169.)

complete excision of many otherwise unresectable lung cancers and may allow preservation of lung function in patients who otherwise would require a pneumonectomy. Most patients with CAO, however, present with severe obstruction or are not candidates for curative operative management, and immediate relief of the obstruction becomes the therapeutic goal (Grillo, 2004; Sundareson, 2004; Wood, 2002).1-4 Of critical importance is to establish the location, etiology, severity, and nature of the obstruction (Fig. 28-5). Cicatricial stenoses need to be dilated; malignant obstructions need to be recanalized, and extrinsic compressions need to be stented. Mixed lesions require a combination of techniques for optimal results (see Fig. 28-3). Once a stable

Ch028-F06861.indd 331

It is important to differentiate between simple weblike stenoses and complex stenoses (Fig. 28-6). Simple stenoses are ideal for endoscopic treatment because the tracheal wall is normal. Complex stenoses, which involve destruction of the cartilaginous support, may be idiopathic or occur after prolonged intubation or tracheostomy and require operative repair as definitive management. Stent placement should be reserved for patients who cannot undergo surgery or as a means for achieving immediate symptom relief until surgery can be performed. Temporary stent placement and removal after a mean interval of 18 to 32 months without subsequent surgery is only possible in 22% to 35% of all patients who have stents placed for benign tracheal stenoses and should not be considered a permanent solution. Postintubation stenosis is the most common non-neoplastic cause of severe CAO. Other causes of cicatricial stenosis include idiopathic, post-traumatic, postoperative, postirradiation, and postinfectious causes and sarcoidosis, amyloid, and Wegener’s granulomatosis. The goal of emergency treatment for cicatricial stenosis is to provide a secure and stable airway and not the definitive correction of the stenosis.2 The location of the stenosis determines the best initial approach to control the airway. If the patient has a severe cuff-induced airway obstruction, the patient is intubated with a rigid bronchoscope, suctioned, and ventilated. Gentle dilation can then be performed as described subsequently. If the obstruction is in the subglottic area, or at the stomal site, and the patient presents with severe CAO, an emergency tracheotomy through the old stomal site can be performed for control of the airway. Attempts to place an orotracheal tube may be

1/21/2008 11:04:03 AM

332

Section 2 Upper Airway

Central Airway Obstruction Life Threatening

No

Yes

Rigid bronchoscopy Flexible bronchoscopy

Rigid bronchoscopy

Benign

Malignant

Type of lesion: Web-like Granulomas Complex

Type of lesion: Endobronchial mass Extrinsic compression Mixed lesion

See: Benign Tracheal Stenosis

See: Non–life-threatening Malignant airway obstruction

Benign

Type of lesion: Web-like Granulomas Complex

Malignant

Type of lesion: Endobronchial mass Extrinsic compression Mixed lesion

Dilation with rigid bronchoscopy Nd:YAG laser

See: Life-threatening Malignant airway obstruction

See: Benign tracheal stenosis FIGURE 28-5 Algorithm for diagnosis of CAO.

futile, and the situation may worsen rapidly. A small rigid bronchoscope can also be utilized for rapid control of the airway while a tracheostomy is being performed through the stomal site. Any tight stricture should be dilated before resection. As a rule, any tracheal stenosis of less than 6 mm in diameter should be dilated immediately after induction of anesthesia to avoid retention of secretions, difficult ventilation, and progressive hypercapnia.2 A second goal of dilation is to allow safe deferral of the operation to complete the workup, to treat comorbidities, to optimize operating conditions, to clear obstructive pneumonia and airway inflammation, and to wean the patient from high doses of corticosteroids in preparation for definitive operative repair. Some patients may be maintained with periodic dilations; and if dilations are not required too frequently, this may be a preferred treatment option for patients with non-reconstructable lesions such as severe idiopathic stenosis extending to the vocal cords or severe late irradiation stenosis of the subglottic larynx and upper trachea (Grillo, 2004).2,108-109

Technique of Dilation A complete set of pediatric- and adult-sized rigid bronchoscopes should be available (Fig. 28-7). We prefer the

Ch028-F06861.indd 332

Hollinger or Storz ventilating bronchoscope with a somewhat rounded tip. In addition, Hollinger-Piling esophageal bougies, suction cannulas, biopsy forceps, and a 0-degree Hopkins telescope should be also available (Figs. 28-8 and 28-9). Once the bronchoscope is introduced into the airway and secretions are cleared, the area of stenosis is carefully assessed. Stenosis due to postintubation cuff injury consists primarily of a circumferential cicatrix and responds well to dilation. In contrast, stomal stenosis is the result of contraction of an anterior defect, which pulls the tracheal walls together, resulting in a triangular deformity. The dilating bronchoscope is easily passed through this stenosis, but the walls of the trachea snap back together again as soon as the bronchoscope is withdrawn (Fig. 28-10). The first step in dilating a tight cicatricial stenosis is the gentle introduction of successively larger bougies, taking care not to advance the full length of the dilator to avoid injury to the distal membranous airway. Next, the rigid bronchoscope is advanced over a large bougie with a firm but gentle corkscrewing motion, after engaging the tip of the bronchoscope in the stenotic orifice. Occasionally, tight strictures have a shallow neck, making it difficult to engage the tip of the rigid bronchoscope at that level (Sundaresan, 2004).3 Excessive force should not be used when trying to advance the rigid bronchoscope through stenotic areas. If excessive

1/21/2008 11:04:03 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

333

Benign Tracheal Stenosis

Web-like lesion

Complex Stenosis: Cartilage/Cricoid involvement Bottleneck; Hourglass Malacia 50% tracheal length

Granulomas

Dilation with rigid bronchoscopy Nd:YAG; Electrocautery (Repeat twice in case of recurrence)

Cure

Follow-up

Third recurrence

Inoperable

Operable

Rigid bronchoscopy

Silicone stent

Resection and reconstruction

Dilate and prepare airway for resection and reconstruction

Operable

Inoperable

Follow-up

Resection and reconstruction

Silicone stent T-tube

Stent removal

Recurrence

Cure

Recurrence

Follow-up

Dilation Silicone stent

Dilation Reresection Silicone stent

Cure

Follow-up

FIGURE 28-6 Algorithm for treatment of benign tracheal stenosis.

FIGURE 28-7 Set of rigid bronchoscopes. From top to bottom, tracheoscope (14 mm), ventilating bronchoscopes (9, 8, and 7 mm), and Hopkins telescopes. The ventilating bronchoscopes can be introduced through the larger tracheoscope to avoid repeat intubation of the airway.

Ch028-F06861.indd 333

FIGURE 28-8 Array of semirigid plastic esophageal bougies useful in dilating tracheal stenoses.

1/21/2008 11:04:03 AM

334

Section 2 Upper Airway

FIGURE 28-9 Array of biopsy forceps useful for débridement of airway tumors.

FIGURE 28-10 Surgical specimen of stomal stenosis showing the typical triangular lumen with apex anterior. A granuloma is also present at the stoma. The membranous wall is smooth. (FROM GRILLO HC: POSTINTUBATION STENOSIS. IN GRILLO HC [ED]: SURGERY OF THE TRACHEA AND BRONCHI. HAMILTON, ONTARIO, BC DECKER, 2004, P 310.)

force is used before adequate dilation, the bronchoscope’s tip could create a linear split of the softer membranous wall just above the stricture. If the stenosis is severe, after the esophageal dilators have been utilized, pediatric Hollinger bronchoscopes are passed through the vocal cords with a Hollinger or Miller laryngo-

Ch028-F06861.indd 334

scope, taking care to prevent injury to the vocal cords. Alternatively, suspension laryngoscopy can be performed to expose the vocal cords and free both hands of the operating surgeon.110 We prefer to place a tracheoscope (14 mm) just beyond the vocal cords and perform all the required instrumentation through this large scope (see Fig. 28-2). This avoids unnecessary trauma to the larynx due to repeated manipulations and expedites the procedure. A small-size adult or a pediatric rigid bronchoscope is introduced through the stenosis with a firm but gentle rotatory movement. Serial dilations are then performed until an adult-size bronchoscope of 7 or 8 mm can be advanced through the stenosis. The ability to pass an 8mm rigid bronchoscope beyond the stricture ensures an adequate caliber airway. At the completion of the procedure, ventilation is resumed, the airway is cleared of secretions, and, once breathing is maintained spontaneously, the bronchoscope is withdrawn. Rarely, the patient may need to be intubated for adequate ventilation and suctioning until fully awake. Dilation performed in this stepwise fashion is safe and effective. The airway that is attained may remain satisfactory in caliber for weeks to months, although the duration of palliation is highly unpredictable. Subsequent management depends on the specific plan for the underlying etiology. If patients are expected to require frequent dilations, require a long wait before definitive operative repair, or are unsuitable for repair, a T-tube or a Dumon self-retaining silicone stent should be considered (Wahidi and Ernst, 2003).111-115 Rigid silicone stents seem to be the most durable prostheses for long-term control of unresectable tracheobronchial stenoses (Liu et al, 2002).116-119 In some patients, intraluminal stenting may be the only alternative to preserve airway patency, improve quality of life, and prevent death from suffocation. Self-expandable metal stents should not be employed in these situations because they can create additional problems and lead to a longer segment of damaged trachea.120-122 Newer polypropylene (Polyflex) stents and bioabsorbable knitted poly-L-lactic acid stents may offer viable alternatives for the management of benign airway stenosis,123,124 but experience with their use for temporary stenting is limited. A laser (CO2 or Nd:YAG) can be used to treat stenoses in the airway. The CO2 laser (tissue penetration up to 0.5 mm) is preferred for most lesions involving the larynx and subglottic area (Colt, 2004; Lee and Mehta, 2004).125-127 For most other uses the Nd:YAG laser is preferred. The most important principle in treating benign airway stenosis is mucosal preservation to allow eventual healing and avoid fibrous tissue deposition and cicatrization of the airway. Best results are achieved when the lesion is less than 1 cm in length; the stenosis is limited, comprising mainly the subepithelial soft tissue, with minimal cartilage involvement; and there is good vocal cord function and absence of active inflammation or conditions that impair wound healing (e.g., chronic corticosteroid use, diabetes, hypothyroidism, liver disease). Features associated with poor outcome after laser therapy include circumferential scarring with cicatricial contracture, scarring longer than 1 cm in vertical dimension, tracheomalacia, carinal involvement, and combined laryngeal and tracheal stenoses (Colt, 2004).126

1/21/2008 11:04:05 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

The Nd:YAG laser has been utilized for the treatment of tracheal stenosis by applying radial incisions in four quadrants before mechanical dilation with the rigid bronchoscope (Baram, 2003; Beamis, 2005; Cavaliere et al, 1996; Colt, 2004; Cosano et al, 2005; Lee and Mehta, 2004; Unger, 2003).17,19,20,21,87,125-129 Nd:YAG laser treatment (tissue penetration, 5 to 8 mm) of web-like strictures involves making radial incisions at the 12, 3, 6, and 9 o’clock positions. So-called Mickey mouse ears can be made at the 2 and 10 o’clock positions. It is important to place the noncontact laser fiber very close to the target tissue to cut through the tissues with minimal thermal injury to adjacent tissues. The stricture can then be dilated using increasing-size bougies or rigid bronchoscopes. Laser resection should avoid exposure of the perichondrium because chondritis might develop and increase the risk of recurrent stenosis. By leaving islands of tracheal epithelium between the radial incisions, the epithelial layer regenerates quickly. In general, we advocate open surgical approaches or use of the Montgomery T-tube if bronchoscopic resection is unsuccessful after 3 interventions or the stenosis is associated with structural damage of the airway. In most cases, effective mechanical

335

dilation can be achieved, making the use of laser unnecessary. Optimal results are achieved with elective resection and reconstruction. Tracheostomy should not be used to manage acute CAO secondary to cicatricial stenosis, except in selected situations. If tracheostomy is necessary, it should be located at the stenotic segment to avoid further injury to the trachea and preserve as much normal tracheal length as possible.

NEOPLASTIC CENTRAL AIRWAY OBSTRUCTION Urgent Treatment of Malignant Central Airway Obstruction Obstruction by a tumor must be removed rather than dilated (Figs. 28-11 and 28-12). Therapeutic goals include the following: 1. Recanalization of the obstruction to allow comfortable spontaneous breathing 2. Preparation of the airway for definitive operative intervention 3. Resolution of obstructive pneumonia

Non–Life-Threatening Malignant Airway Obstruction Resectable

No

Yes

Type of lesion

Small lesion: resection and reconstruction

Endoluminal obstruction

Extrinsic compression

Mixed Lesion

Core-out with rigid bronchoscope Microdébridement Electrocautery Nd:YAG laser

Stent External-beam radiation

Residual disease

Microdébridement Electrocautery; Nd:YAG laser Cryotherapy; brachytherapy External-beam radiation therapy

Large lesion

Rigid bronchoscopy

Endobronchial component

Recanalize and prepare airway for resection and reconstruction

Core out with bronchoscope Microdébridement Electrocautery; Nd:YAG laser Photodynamic therapy Cryotherapy; brachytherapy External-beam radiation therapy Extrinsic compression

Stent External-beam radiation therapy FIGURE 28-11 Algorithm for treatment of non–life-threatening malignant airway obstruction.

Ch028-F06861.indd 335

1/21/2008 11:04:06 AM

336

Section 2 Upper Airway

Life-Threatening Malignant Airway Obstruction Rigid Bronchoscopy

Type of lesion

Endobronchial obstruction

Core out with rigid bronchoscopy Microdébridement Electrocautery Nd:YAG laser

Extrinsic compression

Silicone stent Self-expandable metal stent External-beam radiation therapy

Resection and reconstruction

Endobronchial component

Extrinsic compression

Core out with rigid bronchoscopy Silicone stent Microdébridement Self-expandable metal stent Electrocautery External-beam radiation therapy Nd:YAG laser

Resectable

Yes

Mixed lesion

No

Residual disease: Microdébridement Electrocautery; Nd:YAG laser Photodynamic therapy; brachytherapy External-beam radiation therapy FIGURE 28-12 Algorithm for treatment of life-threatening malignant airway obstruction.

4. Weaning from mechanical ventilation 5. Allowance for palliative radiation or other interventional bronchoscopic procedures (see Box 28-2) Purely intraluminal obstruction by polypoid tumor is easily dealt with by simple bronchoscopic techniques (Fig. 28-13). If the obstruction has a component of extrinsic compression by a tumor, a stent or a T-tube can provide temporary relief. A mixed lesion requires a combination of techniques, usually in the same setting. Caution must be exercised when dealing with a chronically obstructed bronchus (>3-4 weeks) or when simultaneous occlusion of the respective pulmonary artery is present. In these cases, failure to improve may be due to nonrectruitable lung or worsening gas exchange secondary to wasted ventilation secondary to an obstructed pulmonary artery. Detailed bronchoscopic examination of the airway must be performed to ensure patency of the airway distal to the site of obstruction to achieve recruitment of functional lung.

Technique of Airway Recanalization The most effective tool to relieve neoplastic obstruction of the airway to the level of the main stem bronchi is the rigid

Ch028-F06861.indd 336

bronchoscope.1 The rigid bronchoscope offers many advantages, including excellent visualization, efficient ventilation and suctioning, and the ability to biopsy and core out tumors, dilate tight strictures, and tamponade bleeding (Mathisen and Grillo, 1989).130 In addition, it allows the use of many other interventional bronchoscopic instruments. Once a secure airway has been established, the tumor is inspected with a Hopkins magnifying telescope or with a flexible bronchoscope passed through the rigid bronchoscope. Excessively vascular lesions should not be sampled but can be cored out safely with the rigid bronchoscope. On occasion, the Nd:YAG laser can be utilized to decrease the risk of severe bleeding before attempting to remove the tumor. In most instances, however, this is not necessary (Mathisen and Grillo, 1989).130 An airway can always be established promptly in any patient with neoplastic obstruction of the trachea or carina if some technical aspects are followed. If any portion of the tracheal circumference is free of tumor, a rigid bronchoscope can gently pass beyond the obstruction and a coring technique utilized to remove obstructing tumor down to the level of the main stem bronchi. The tumor and the tracheal wall will yield to the gentle passage of the bronchoscope. For

1/21/2008 11:04:06 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

A

337

B

FIGURE 28-13 Palliation of obstructing primary tracheal tumor by endobronchial core out. A, Emergent bronchoscopy revealed a polypoid tumor filling the upper trachea, based posteriorly on the membranous wall. B, The rigid bronchoscope was engaged into the tumor at the base of its pedicle, shearing off the polypoid portion of the tumor. This removed approximately 90% of the endobronchial tumor, which was extracted. This produced a stable airway and immediate relief of the patient’s life-threatening symptoms. (FROM WORD DE: BRONCHOSCOPIC PREPARATION FOR AIRWAY RESECTION. CHEST SURG CLIN NORTH AM 11:735-748, 2001, P 742.)

bilateral lesions involving both main stem bronchi, it is advisable to begin with the less obstructed side to establish an airway as soon as possible. In the situation where a tumor is completely circumferential, a bronchoscope can be carefully insinuated through a residual crescent lumen with a corkscrew motion. The axis of the airway must be kept in mind to avoid injury or perforation. Special care must be taken at the carinal spur, where the potential exists for injury to the pulmonary artery or other major mediastinal structures (Grillo, 2004).2 Fractured and detached fragments of tumor are removed with suction or forceps. All tissue extracted in this manner is sent for pathologic examination. Coring is continued until a satisfactory airway is obtained. The bronchoscope is periodically occluded to allow mechanical ventilation through the sidearm. If a large piece of tumor is detached from the airway wall, it can be held against the tip of the bronchoscope with the suction cannula or the forceps and the bronchoscope withdrawn along with the suction cannula and tumor. The bronchoscope is then reinserted. We prefer to use a large tracheoscope and introduce the tracheobronchoscopes and other working instruments through this larger scope to avoid repeat insertions and trauma to the larynx (see Fig. 28-2). Bleeding from a tumor is generally not a problem and is more common with primary airway tumors than with lung cancer invading the airway. Bleeding is controlled by expeditiously completing the removal of the tumor, by applying pressure with the barrel of the scope for 3 to 5 minutes, or by irrigation with dilute epinephrine solution or epinephrine-soaked pledgets (0.1 mg/mL) on long applicators. Coagulation of the base of the tumor can be performed with the Nd:YAG laser, electrocautery, or argon plasma coagulation (Ernst et al, 2004).6

Ch028-F06861.indd 337

Some patients presenting with obstructing airway tumors may in fact be surgical candidates (Venuta et al, 2002).105-107 Temporary relief of the obstruction is indicated in the acute situation, but attempts to treat the disease with endoluminal techniques alone must be resisted until the patient undergoes a formal assessment for potential curative surgical resection.

Microdébrider A powered endoscopic microdébrider can be utilized to debulk obstructive laryngeal and tracheal papillomas and carcinomas (Lunn et al, 2005).131-133 The technique employs a spinning blade contained within a rigid suction cannula to cut while providing suction to remove blood and tissue (Xomed, Hollingerville, FL). The instruments currently available are 37 cm in length and 4 mm in diameter. They are manufactured with either smooth or serrated blades, and the tips can be straight or angled (Fig. 28-14). The microdébrider is set at 1000 to 3000 rpm with an oscillating pattern. Debulking of tracheal, carinal, or main stem bronchial lesions is performed with the aid of rigid Hopkins telescopes or a flexible bronchoscope introduced through the rigid tracheoscope. For laryngotracheal lesions, a modified Dedo laryngoscope can be used to expose the lesion. The microdébrider provides good hemostasis and the ability to perform a precise and safe recanalization of obstructed airways to the level of the main stem bronchi (Fig. 28-15) (Lunn et al, 2005).133 Electrocautery, argon plasma coagulation, or the Nd:YAG laser can be utilized to cauterize the base of the lesion to control any residual bleeding. Advantages of this technique include the ability to rapidly remove critical obstructing tissue while simultaneously removing blood and debris and the ability to

1/21/2008 11:04:07 AM

338

Section 2 Upper Airway

A

B

FIGURE 28-14 A, Powered microdébrider. For airway tumor removal 1000 to 5000 rpm is utilized. B, Microdébridement cannulas (angled and straight) and hand-held device for débridement of trachea and main stem bronchi.

A

B

FIGURE 28-15 A, CT of the chest demonstrates a large esophageal tumor invading and obstructing the lumen of the left main stem bronchus (arrow). B, The left main stem bronchus was completely recanalized with the microdébrider, and a covered metal self-expandable stent was placed through the rigid tracheoscope.

perform the procedure with little risk of airway perforation. In addition, there is no risk of airway ignition, and the procedure can be performed safely in patients requiring a high FIO2. The microdébrider provides an alternative to the use of laser or the barrel of the rigid bronchoscope for recanalization of critical CAO to the level of the main stem bronchi.

Ch028-F06861.indd 338

Adjuncts to Relieve Central Airway Obstruction Additional endoscopic techniques utilized for the management of CAO include the Nd:YAG laser, electrocautery, argon plasma coagulation, cryoablation, photodynamic therapy, and brachytherapy. Of these, the Nd:YAG laser, electrocautery, and argon plasma coagulation provide imme-

1/21/2008 11:04:07 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

diate coagulating effects and may be useful when utilized in conjunction with rigid bronchoscopy for relief of acute CAO.

Nd:YAG Laser The Nd:YAG laser causes coagulation at low power (2030 W) and vaporization or combustion at high power (>40 W). The laser energy can penetrate nearly 5 to 8 mm in depth and can coagulate blood vessels of up to 2 mm in diameter. Today there is a consensus to apply Nd:YAG laser at lower energies of 20 to 30 W for coagulation of tissue and vessels and up to 40 W for thermal destruction by carbonization and vaporization. We do not recommend using higher energy under any situations. Because the 1064-nm wavelength of the Nd:YAG laser is in the invisible spectrum, another laser is added to the system to provide an aiming beam. This is usually a helium-neon (He-Ne) laser, which produces a visible red light.

Technique of Laser Photoresection Laser photoresection can be performed with a rigid or flexible bronchoscope (Diaz-Jimenez and Rodriguez, 2004).129,134-168 Rigid bronchoscopy allows prompt mechanical débridement of the obstructing tumor, reducing procedure time, laser exposure, and the risk of perforation. The flexible bronchoscope is reserved for treatment of small distant lesions producing noncritical airway obstruction or through the rigid bronchoscope. Location of the tumor is the most important factor influencing outcome of laser therapy. The best results are achieved in the trachea and main stem bronchi because these are the most accessible locations to rigid bronchoscopy. Laser resection in third-order bronchi poses special hazards owing to poor accessibility and thinness of the bronchial walls with increased risk of perforation. Some special situations require meticulous care with the laser, including lesions in the posterior wall of the trachea, previous radiation therapy, bilateral main stem bronchial obstruction, and postpneumonectomy patients. Absolute contraindications include the absence of inraluminal lesion (pure extraluminal compression) and complete bronchial or tracheal obstruction. The classic approach to laser photoresection of an obstructing endobronchial lesion is to first paint the entire surface of the lesion with a series of short low-energy laser pulses; 0.5second pulses at 20 to 30 W are best at minimizing complications while successfully obtaining hemostasis. This allows the laser energy to penetrate deep into the tumor, rather than be absorbed at the tissue surface. As the tumor develops an increasing whitish coloration, the energy will increasingly penetrate the tissue, causing vasoconstriction and coagulation of deep vessels. On the other hand, if the surface of the tumor is carbonized during laser firing, surface absorption will be high and penetration poor, risking severe hemorrhage during core out of the tumor. The goal is to use at least 1500 J/cm2 of laser energy without causing bleeding or carbonization. Next, the tip of the rigid bronchoscope can be used to shear off large pieces of the lesion, which are then removed with the forceps. Some endoscopists prefer to use

Ch028-F06861.indd 339

339

laser to vaporize the entire lesion; this technique, however, leads to a higher rate of complications, including airway fire, perforation, or fistula formation and is not recommended. For treatment of an endotracheal lesion, the rigid bronchoscope is advanced as close as possible to the proximal border of the tumor without disturbing it. The laser is set to a power that achieves more coagulation than vaporization. Common laser settings are an energy level of 20 to 30 W with pulse duration of 0.5 to 1.0 second. The tissue effects are than controlled by changing the distance between the laser fiber and the target tissue. The tip of the rigid Hopkins telescope should be kept inside the rigid bronchoscope at all times. This will allow a good view and, at the same time, will protect the lens from becoming coated with tumor debris or blood. A suction catheter or cannula is utilized to evaluate the consistency and friability of the tumor and to suction the tumor surface. Initially, brief laser pulses are used to coagulate the tumor by sweeping the surface with the laser beam. A characteristic change in color can be appreciated as the laser coagulates the tissue. This is used as a guide to avoid carbonization, which enhances laser absorption in the surface and limits deeper penetration. The laser beam should always be fired parallel to the wall to avoid inadvertent perforation of the airway. Once photocoagulation has been achieved, the rigid bronchoscope is utilized to core out the endoluminal tumor using a rotating movement. Pressure should be applied in a direction that is parallel to the airway rather than against the wall. Digging into the airway wall to resect tumor is dangerous and can result in perforation. Once the airway lumen approaches a nearly normal caliber or the tumor has been debulked as much as possible, the base of the lesion is thoroughly coagulated using low-power pulses (20-30 W). The bronchoscopist should always keep in mind that laser treatment of malignant conditions is palliative and that variable amounts of tumor will be left in the airway. The goal should be to achieve an airway diameter large enough to allow functional recovery of the lung located distal to the obstruction, provide drainage of the airway, and achieve symptomatic relief without damaging the bronchial wall or mediastinal structures in the process. When laser treatment is delivered to coagulate a bleeding tumor, the initial firings are aimed at the base of the tumor. As the tumor shrinks and becomes devascularized, the laser can be directed at the center of the tumor itself, surrounding the bleeding point but not shooting directly at it. Bleeding will stop because of retraction of the tissues and coagulation of deep vessels. The operator should avoid firing the laser directly onto the bleeding vessel or surface where the Nd:YAG wavelength will be immediately and superficially absorbed. Laser bronchoscopy used properly in carefully selected patients should result in near-zero morbidity and mortality. General laser safety principles should be followed. The Dumon’s “Ten Commandments” and Metha’s “Rule of Fours” are the most well known.142,168 The most common complications of laser therapy include airway fire and explosions, pneumothorax, bronchopleural fistula, bronchoesophageal fistula, hypoxemia, and bleeding. Other complications include myocardial ischemia, arrhythmias, and air embolism.136,140-144

1/21/2008 11:04:10 AM

340

Section 2 Upper Airway

Endobronchial ignition can be prevented by setting the laser to single-pulse mode, keeping the fiber clean, avoiding the use of combustible anesthetic agents, keeping the FIO2 at 0.4 or less, and avoiding the use of flammable materials, including polyvinylchloride endotracheal tubes.

Electrocautery Electrocautery application through the rigid or flexible bronchoscope employs high-frequency alternating electrical current to cut, coagulate, or vaporize endobronchial lesions (Machado et al, 2004; Sheski and Mathur, 2004).169-191 This method has been considered to be the economic version of a laser because it has laser-like tissue effects at a small fraction of the cost (the poor man’s laser) (Fig. 28-16). The degree of tissue destruction depends on the power settings, duration of contact, the surface area of contact, and the density and moisture of the tissue. Histologic effects of electrocautery application include early coagulative necrosis with acute inflammation followed by delayed fibrosis. Tissue penetration is limited to a depth of 5 to 8 mm. Technique. Endobronchial electrocautery is performed by lightly kissing the probe tip against the target tissue and with the electrical current set to “coagulate” (high amperage/low voltage), “cut” (low amperage/high voltage), or “blend” (settings midway between cut and coagulate) (Machado et al, 2004; Sheski and Mathur, 2004).170-185 The use of an insulated flexible bronchoscope (ceramic) minimizes the risk of electric

A

shock or burn to both the patient and the operator. Two main techniques for tumor ablation have been described: tumor debulking by cutting the stalk of a polypoid lesion with a cutting loop and electrodestruction of tumor by the contact method (Machado et al, 2004; Sheski and Mathur, 2004).170-190 All probes are available for use with both rigid and flexible bronchoscopes. The most commonly used electrosurgical accessories include blunt and spherical probes for coagulation and hemostasis; loop snare for removal of pedunculated and polypoid lesions; knife for broad-based surface coagulation and tissue resection; and biopsy forceps for sampling and debulking vascularized tumors (see Fig. 28-16B). Typical power settings include 20 to 40 W and variable application times from 1 to 5 seconds. The effect of electrocautery on the treated area becomes immediately apparent with blanching and contraction of the mucosa. In smaller airways, application times must be limited to 3 seconds or less, given the risk of cartilaginous injury and possible stricture. It is critical to keep the area of treatment as dry as possible and free of debris to prevent dispersion of the electrical current, reducing the tissue effect. The rapidity with which the electrocautery technique opens obstructed airways is similar to that achieved with laser therapy.170,172,179,182 Electrosurgery has been utilized successfully in the palliation of malignant airway obstruction as well as in the management of benign airway obstruction (Machado et al, 2004).170,172,178,181,183,184,186-191

B

FIGURE 28-16 A, Electrocautery equipment (ERBE, Atlanta, GA) with additional argon plasma coagulation. The electrosurgical generator and argon gas flow are controlled by the foot switches. B, Electrocautery probes useful for treating central airway tumors. From left to right: snare, blunt probe, biopsy forceps, and knife.

Ch028-F06861.indd 340

1/21/2008 11:04:10 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

341

Although rigid bronchoscopy is necessary for patients with CAO, endobronchial electrosurgery can be performed in the outpatient bronchoscopy suite under conscious sedation and topical anesthesia in patients with noncritical airway obstruction. Advantages of electrocautery include the less expensive equipment (compared with laser) and the ease of use. Complications include endobronchial fire, airway perforation, hemorrhage, and inadvertent electrical shock to the operator or patient.

Argon Plasma Coagulation Argon plasma coagulation is a noncontact form of electrocoagulation.185 It utilizes electrically conductive argon gas (the so-called plasma) as a medium to deliver high-frequency current via a monopolar probe to achieve noncontact electrocoagulation of tissue. It is ideal for coagulation of superficial hemorrhagic lesions and tumors of the upper lobe or superior segment of the lower lobe as well as stent-related obstructive granuloma (Freitag and Reichle, 2004).185,192 Argon plasma coagulation devitalizes tissue gradually by producing temperatures that coagulate and desiccate tissue. The thermal effect on the tissue depends on the power and the time. Higher power results in better hemostatic effect. Because tissue penetration is limited to the upper 2 to 3 mm, tumor debulking with the rigid bronchoscope and forceps is recommended for treatment of endobronchial tumors.200 Although argon plasma coagulation has been shown to be effective in the treatment of hemoptysis and obstructive lesions of the central airways, it causes only superficial tissue destruction when compared with the standard electrosurgical probe (Freitag and Reichle, 2004).185,192-203 Therefore, it is not considered the ideal for bulky lesions as a sole modality. It is, however, very effective when used in conjunction with tumor debulking with the rigid bronchoscope. The high-frequency current follows the lowest electrical impedance, and because blood is a better conductor than dry tissue, the argon plasma beam has a preferential effect on bleeding tissue. At present, it can be considered to be the method of choice for the management of hemoptysis provided the bleeding lesion is within reach of a bronchoscope. After desiccation and vessel shutdown, the argon plasma coagulation effect becomes selflimiting. This makes the device advantageous for the management of hemoptysis. It offers good coagulation combined with protection against airway wall perforation. Technique. The procedure can be performed either with a rigid or a flexible bronchoscope. The tip of the probe should be advanced at least 1 cm from the end of the bronchoscope and positioned within 3 to 8 mm from the target tissue. Power setting is adjusted between 30 and 60 W on a continuous or pulsed mode. The argon plasma exits the tip of the probe and, after ignition, delivers the electrical energy to the surface of the tissue, where it is transferred into heat (Fig. 28-17). A field voltage of 500 V/mm between the probe and the tissue is generated, resulting in a blue-glowing plasma beam up to 10 mm in length. The plasma beam is sprayed over the tumor surface to dehydrate the tissue and coagulate superficial blood vessels. The devitalized tumor is then removed with a forceps. The next layer is coagulated and

Ch028-F06861.indd 341

FIGURE 28-17 Probes for argon plasma coagulation. From top to bottom: hand-held control and probes for rigid bronchoscopy, pleuroscopy, and flexible bronchoscopy.

removed and so on until sufficient tumor debulking has been accomplished. Although this is more time consuming than Nd:YAG laser therapy, excellent results can be achieved with this step-by-step technique. The advantages of argon plasma coagulation include low cost, noncontact mode of therapy, easy portability of equipment, and ease of use. Because the equipment is less expensive and very versatile, it might replace the Nd:YAG laser in many institutions. Disadvantages include the risk of airway ignition and damage to the flexible bronchoscope. The procedure can be performed in an outpatient setting or at the bedside in the intensive care unit.191

Postoperative Management Significant improvement in symptoms is achieved when patency of an obstructed airway is restored to greater than 70%, and every effort should be made to achieve an airway as normal as possible. Subglottic edema is the most common complication after rigid bronchoscopy and is more common in pediatric patients and adults with proximal airway stenoses. It may be managed conservatively by elevating the head of the bed, humidification, oxygen, and aerosolized racemic epinephrine (0.2-0.5 mL of a 2% solution for 1 to 2 hours). Systemic methylprednisolone (20-80 mg, intravenously q6h) or dexamethasone (4-10 mg, intravenously q6h) for 24 to 48 hours may also be useful (Grillo, 2004; Sundaresan, 2004).2,3 On rare occasions, patients may require endotracheal intubation and ventilatory assistance for a short period of time after the procedure. Once the patency of the airway is ensured, reevaluation is performed to select the best additional therapeutic modality.

COMMENTS AND CONTROVERSIES No procedure in thoracic surgery is more stressful, requires more rapid decision making, experience, and flexibility of approach, and no more close cooperation with a skilled anesthesiologist than does the management of acute critical airway obstruction. In the preced-

1/21/2008 11:04:12 AM

342

Section 2 Upper Airway

ing chapter, the authors deal with this subject in a very clear, precise, and well-organized fashion. Whenever time permits, obtaining a high-resolution CT scan of the airway, with or without threedimensional reconstruction, provides the best assessment as to the exact location, length, degree of obstruction, and relationship of the lesion to known landmarks, such as the vocal cords and the carina. Furthermore, the angulation and pathway of the remaining air column may be helpful in directing the passage of the rigid bronchoscope through the obstructed remaining channel. As well noted by the authors, the initial inspection of the lesion, in the operating room, should be done with the patient awake or mildly sedated, using topical anesthesia. The patient should not be paralyzed until a safe airway has been established. Preliminary inspection of the lesion with a flexible bronchoscope, passed through the nose, is ideal, but the flexible bronchoscope should not be passed through the lesion. I have increasingly found that the use of a laryngeal mask airway to provide assisted ventilation to the spontaneously breathing patient is useful in terms of achieving a high oxygen concentration and providing an easy passageway for the flexible bronchoscope through the cords and down to the proximal end of the obstructing lesion, for the initial endoscopic assessment. For those of us first introduced to rigid bronchoscopy as a procedure done under topical anesthesia and sedation before the advent of a flexible bronchoscope, the use of the rigid bronchoscope to initially traverse and dilate the obstructed segment with the patient breathing spontaneously seems not at all daunting. The use of the rigid bronchoscope to initially traverse and dilate the narrowed segment of the airway cannot be overemphasized. Preliminary use of a dilating balloon in advance is occasionally useful but for a truly critical airway is more risky. However, the presence of a fibrotic stricture in the subglottic region, at the area of the cricoid, represents a special situation. Unlike fibrotic strictures in the trachea or main stem bronchi, the airway at the level of the cricoid is completely surrounded by a rigid, cartilaginous, often calcified ring and dilation of the airway itself is not possible. Passage of a rigid bronchoscope through a stricture at this level may cause immediate edema such that when the bronchoscope is withdrawn the airway may shut down immediately and not permit re-passage of even the same rigid bronchoscope. The only two so-called bare hands emergency tracheostomies that I have had to perform in my career both occurred in this situation when there was total occlusion of the subglottic airway after removal of the rigid bronchoscope initially used to dilate a very tight occlusion in this region. Therefore, the surgeon should be prepared to immediately perform a tracheostomy when using the rigid bronchoscope to dilate a tight subglottic stricture. Ideally, this is done with the bronchoscope still in place to provide ventilation as the tracheostomy is being performed. Just as the authors caution not to paralyze the patient until an airway is established with a rigid bronchoscope, it should also be remembered that the rigid bronchoscope should not be disassembled until the patient is safely exiting the operating room after endoscopic treatment for critical airway obstruction. When debulking a tumor after establishment of a safe airway, I much prefer the use of direct-contact cautery to the use of the laser. If the tumor is vascular, which is especially common in metastatic renal carcinoma to the large airways, injection of an epinephrine solution into the base of the tumor by use of a Wang needle may significantly reduce the bleeding associated with subsequent

Ch028-F06861.indd 342

débridement of the tumor whether by biopsy forceps, contact cautery, or laser. The tip of a cautery-snare device advanced 1 or 2 mm through its polyethylene sheath provides an excellent contact cautery device that is readily available and can be passed through the working channel of a bronchoscope containing a 2.8-mm channel. The use of the contact cautery is less expensive, more readily available, and actually more precise than the use of the laser, which sometimes misses the target and ends up causing mucosal injury to the noninvolved portion of the airway. The argon beam coagulator is the least accurate of the cautery techniques because the electrical spray can go in any direction, including back to the tip of the bronchoscope, if the tip of the coagulator is allowed to come too close to the tip of the bronchoscope. It is, however, useful, as the authors note, for diffuse superficial bleeding from a raw surface in the airway. When using the rigid bronchoscope with a jet (Venturi) ventilation system, it should be remembered that most of the tidal volume produced represents entrained room air so that even though the jet is powered with 100% oxygen, the actual inspired oxygen concentration is in the range of 30% to 35%. If the oxygen saturation is falling, attachment of the anesthesia ventilator to the sidearm of the bronchoscope, with a high flow 100% oxygen supplied to the channel of the bronchoscope, significantly increases the inspired oxygen concentration because the entrained gas now includes a good deal of pure oxygen. If the jet ventilator is providing insufficient ventilation, the anesthesia machine can be attached to the sidearm of the bronchoscope, the jet temporarily discontinued, and the end of the bronchoscope occluded with the surgeon’s thumb to allow direct mechanical ventilation through the rigid bronchoscope. If air leakage around the bronchoscope and out through the mouth occurs preventing adequate mechanical ventilation, then either the back of the pharynx can be packed with moist gauze or the surgeon’s cupped hand can be used to gently depress the larynx against the cervical spine, closing the passageway between the bronchoscope and the upper airway and permitting forceful mechanical ventilation of the lungs. Finally, it should be noted that the principles and techniques outlined in this chapter are for management of acute airway obstruction at the level of the subglottic, tracheal, and main stem bronchial levels and that obstruction of a lobar bronchus is not the cause of critical respiratory distress, and, with rare exceptions, endoscopic palliation of obstruction of a lobar bronchus is seldom indicated. J. D. C.

KEY REFERENCES Alfille P: Anesthesia for tracheal surgery. In Grillo HC (ed): Surgery of the Trachea and Bronchi. Hamilton, Ontario, BC Decker, 2004, pp 453-470. Baram D: Palliation of endobronchial disease: Flexible and rigid bronchoscopic options. Respir Care Clin North Am 9:237-258, 2003. Beamis JF: Interventional pulmonary techniques for treating malignant large airway obstruction: An update. Curr Opin Pulm Med 11:292295, 2005. Boiselle PM, Ernst A: Recent advances in central airway imaging. Chest 121:1651-1660, 2002. Bolliger CT: Multimodality treatment of advanced pulmonary malignancies. In Bolliger CT, Mathur PN (eds): Interventional Bronchoscopy. Progress in Respiratory Research. Basel, Karger, 2000, pp 187196.

1/21/2008 11:04:13 AM

Chapter 28 Principles of Airway Surgery: Management of Acute Critical Airway Obstruction

Bolliger CT, Mathur PN: ERS/ATS statement on interventional pulmonology. Eur Respir J 19:356-373, 2002. Brodsky JB: Bronchoscopic procedures for central airway obstruction. J Cardiothorac Anesth 17:638-646, 2003. Cavaliere S, Venuta F, Foccoli P, et al: Endoscopic treatment of malignant airway obstructions in 2,008 patients. Chest 110:1536-1542, 1996. Chan AL, Yoneda KY, Allen RP, Albertson TE: Advances in the management of endobronchial lung malignancies. Curr Opin Pulm Med 9:301-308, 2003. Chao YK, Liu YH, Hsieh WJ, et al: Controlling difficult airway by rigid bronchoscope—an old but effective method. Interac Cardiovasc Thorac Surg 4:175-179, 2005. Colt H: Laser bronchoscopy for benign disease. In Beamis JF, Mathur PN, Mehta AC (eds): Interventional Pulmonary Medicine. New York, Marcel Dekker, 2004, pp 127-156. Cosano A, Munoz L, Cosano FJ, et al: Endoscopic treatment of central airway stenosis: Five years’ experience. Arch Bronchoneumol 41:322327, 2005. Diaz-Jimenez JP, Rodriguez AN: Laser bronchoscopy for malignant disease. In Beamis JF, Mathur PN, Mehta AC (eds): Interventional Pulmonary Medicine. Hamilton, Ontario, BC Decker, 2004, pp 89-126. Ernst A, Feller-Kopman D, Becker HD, Mehta AC: Central airway obstruction. Am J Respir Crit Care Med 160:1278-1297, 2004. Ernst A, Silvestri GA, Johnstone D: Interventional pulmonary procedures: Guidelines from the American College of Chest Physicians. Chest 123:1693-1717, 2003. Freitag L: Interventional endoscopic treatment. Lung Cancer 45(Suppl 2):S235-S238, 2004. Freitag L, Reichle G: Argon plasma coagulation. In Beamis JF, Mathur PN, Mehta AC (eds): Interventional Pulmonary Medicine. Hamilton, Ontario, BC Decker, 2004, pp 203-214. Grillo HC: Postintubation stenosis. In Grillo HC (eds): Surgery of the trachea and bronchi. Hamilton, Ontario, BC Decker, 2004, pp 301-339. Grillo HC: Urgent treatment of tracheal obstruction. In Grillo HC (ed): Surgery of the Trachea and Bronchi. Hamilton, Ontario, BC Decker, 2004, pp 471-478. Grillo HC, Mathisen DJ: Primary tracheal tumors: Treatment and results. Ann Thorac Surg 49:69-77, 1990. Lamb CR, Beamis JF: Rigid bronchoscopy. In Beamis JF, Mathur PN, Mehta AC (eds): Interventional Pulmonary Medicine. New York, Marcel Dekker, 2004, pp 13-31.

Ch028-F06861.indd 343

343

Lee P, Kupeli E, Mehta AC: Therapeutic bronchoscopy in lung cancer. Laser therapy, electrocautery, brachytherapy, stents, and photodynamic therapy. Clin Chest Med 23:241-256, 2002. Lee P, Mehta AC: Therapeutic flexible bronchoscopy: Overview. In Beamis JF, Mathur PN, Mehta AC (eds): Interventional Pulmonary Medicine. New York, Marcel Dekker, 2004, pp 49-87. Liu HC, Lee KS, Huang CJ, et al: Silicone T-tube for complex laryngotracheal problems. Eur J Cardiothor Surg 21:326-330, 2002. Lunn W, Garland R, Ashiku S, et al: Microdebrider bronchoscopy: A new tool for the interventional bronchoscopist. Ann Thorac Surg 80:1485-1488, 2005. Machado RF, Saad CP, Mehta AC, Coulter TD: Endobronchial electrosurgery. In Beamis JF, Mathur PN, Mehta AC (eds): Interventional Pulmonary Medicine. Hamilton, Ontario, BC Decker, 2004, pp 67-179. Mathisen DJ, Grillo HC: Endoscopic relief of malignant airway obstruction. Ann Thorac Surg 48:469-475, 1989. Morris CD, Budde JM, Godette KD, et al: Palliative management of malignant airway obstruction. Ann Thorac Surg 74:1928-1933, 2002. Santos, RS, Raftopoulos Y, Keenan RJ, et al: Bronchoscopic palliation of lung cancer: Single or multimodality therapy? Surg Endosc 18:931936, 2004. Seijo LM, Sterman DH: Interventional pulmonology. N Engl J Med 344:740-749, 2001. Sheski FD, Mathur PN: Endobronchial electrosurgery: Argon plasma coagulation and electrocautery. Semin Respir Crit Care Med 25:367374, 2004. Stephens KE, Wood DE: Bronchoscopic management of central airway obstruction. J Thorac Cardiovasc Surg 119:289-296, 2000. Sundaresan S: Acute airway obstruction. In Yaung SC, Cameron DE (eds): Thoracic and Cardiovascular Surgery. St. Louis, Mosby, 2004, pp 74-75. Unger M: Endobronchial therapy of neoplasms. Chest Surg Clin North Am 13:129-147, 2003. Venuta F, Rendina EA, De Giacomo T, et al: Nd : YAG laser resection of lung cancer invading the airway as a bridge to surgery and palliative treatment. Ann Thorac Surg 74:995-998, 2002. Wahidi M, Ernst A: The Montgomery T-tube tracheal stent. Clin Chest Med 24:437-443, 2003. Wood DE: Bronchoscopic preparation for airway resection. Chest Surg Clin North Am 11:735-746, 2001. Wood DE: Management of malignant tracheobronchial obstruction. Surg Clin North Am 82:621-642, 2002.

1/21/2008 11:04:13 AM

chapter

TRACHEOSTOMY

29

Henning A. Gaissert

Key Points ■ Both the open and percutaneous surgical techniques permit safe

performance of tracheostomy. A low complication rate depends on close attention to surgical detail and adherence to existing protocols for tracheostomy care to limit the tracheal injury caused by tracheostomy tubes. ■ The available evidence suggests that early tracheostomy (within 7 days after intubation) for mechanical ventilation lowers the risk of laryngeal injury and is associated with a shorter duration of mechanical ventilation and a reduced length of stay in an intensive care unit.

DEFINITIONS The uses of the terms tracheostomy and tracheotomy vary according to custom and semantic reasoning. Without claiming authority on proper usage, the term tracheostomy in this chapter indicates an opening in the trachea, either permanent as an end-tracheostomy or temporary and held open by a tube, with the consequence of diverting airflow from the larynx. Tracheotomy, in contrast, refers to an incision in the trachea during the course of an operation. Permanent cervical or mediastinal tracheostomy with a circumferential tracheocutaneous anastomosis constructed after laryngectomy or laryngotracheal diversion is not the topic of this chapter. Cricothyroidotomy is a procedure resulting in a laryngostomy to establish temporary, emergent access to the subglottic airway. Mini-tracheostomy is a generally accepted misnomer for the same procedure when used for short-term placement of a small endotracheal tube to suction airway secretions.

HISTORICAL NOTE Until the early 20th century, tracheostomy was regarded as a procedure to provide preterminal relief of high-grade airway obstruction. As late as 1934, a prominent European surgical textbook stressed that “tracheotomy must be counted among the urgent operations since it is usually executed expediently and without extensive preparation, occasionally even by a general practitioner.”1(p442-443) Present-day tracheostomy, in contrast, is usually an elective operation to secure a controlled airway during the course of mechanical ventilation. Frost identified five stages in our historical perception of tracheostomy.2 The first was the stage of allusions, without descriptions of actual cases, beginning with depictions on Egyptian tablets dating back to 3600 BC, with references in the Papyrus Ebers (1500 BC) and the Rig Veda, a primary

Hindu scripture (100-1500 BC), and extending to AD 1500 with occasional citations in Islamic and European medieval literature. During the second stage from 1500 to the early 19th century, isolated reports of operations with survival occurred but failed to remove the odium from an often unsuccessful procedure. Antonio Musa Brassarolo is commonly credited as having performed the first successful recorded tracheostomy in 1546. The third stage of systematic investigation was launched amid some enthusiasm with Trousseau’s report in 1833 on 200 tracheostomies performed in children dying of advanced diphtheria (he saved one fourth of those operated) and concluded with Jackson’s analysis of technique and complications in 1909 (Jackson, 1909),3 which has served as example to a generation of surgeons. In the fourth stage, the recurring epidemics of poliomyelitis in the mid-20th century provided the impetus to consider mechanical ventilation with various other forms of intubation, prompting Wilson, in 1932, to suggest prophylactic tracheostomy. The modern times, according to Frost’s concept, ushered in a fifth stage with a complete consideration of mechanical ventilation, endotracheal intubation, and their interrelation.

INDICATIONS The indications for tracheostomy are influenced by geographic location, practice setting, and patient age. One recent multi-institutional study with data from Europe and North and South America identified acute renal failure as the most common indication for initiation of mechanical ventilation in adult patients.4 Tracheostomy provided the airway in a total of 24% of patients during mechanical ventilation, with minor variations between countries. While in adults prolonged mechanical ventilation is common after major surgery or trauma, chronic neuromuscular disorders, and acute trauma,5 infants and children undergo tracheostomy for tracheomalacia, acquired subglottic or tracheal stenosis, vocal cord paralysis, or central nervous disorders.6,7 Noninvasive methods of ventilation obviate the need for tracheostomy, but these newer methods at present have only a modest impact on long-term mechanical ventilation. Tracheostomy as emergency access in the nonintubated patient has declined during the past half century owing to the availability of alternative intubation techniques. The disadvantages of emergent tracheostomy consist of the potential for additional injury caused by haste and a greater risk of bleeding into the unprotected airway due to venous congestion and patient strain. Its application is therefore limited to a few conditions, the foremost being acute facial or cervical trauma. This change in attitude has resulted in a more discriminate approach to the

344

Ch029-F06861.indd 344

1/21/2008 11:05:21 AM

Chapter 29 Tracheostomy

unstable airway. The ideal circumstance to deal with an unstable airway provides for a team of surgeon and thoracic anesthesiologists with an operating room where tracheostomy is only one among several options to establish a safe airway. There are numerous resources for patients regarding airway management and the care of the mechanically ventilated patient. The reader may refer patients to web-based links containing tracheostomy care descriptions8,9 (although these sites are expected to change over time). Specific indications are discussed in the following sections.

Prolonged Mechanical Ventilation The principal reason to consider tracheostomy in ventilated patients is the damage induced by long-term use of translaryngeal tubes. There is agreement that long-standing translaryngeal intubation causes at least scarring of the glottic commissures and the subglottic space. When tracheostomy

345

is avoided, as in burn injury, or delayed, as in children, however, the incidence of lasting, important injury is low.10 The earliest injury occurs in the posterior glottic commissure as early as 5 days after intubation and increases in severity over time.11 This injury is prevented by removal of the endotracheal tube from the larynx. Other important reasons favoring tracheostomy are greater patient comfort, a more secure airway, lower airway resistance (see later), and a lower threshold to wean and disconnect the patient from the ventilator. In addition to limiting laryngeal injury, early tracheostomy seems to confer other advantages. A recent meta-analysis of 5 randomized controlled studies found that tracheostomy within 7 days after intubation reduced the duration of mechanical ventilation and intensive care unit stay (Griffiths et al, 2005).12 Tables 29-1 and 29-2 depict the relationship of early and late tracheostomy to these two variables in this study. These advantages would seem to apply only to those patients in whom respiratory failure is expected

TABLE 29-1 Effects of Early and Late Tracheostomy on Duration of Ventilation in Days Early Tracheostomy Author (Year)

No.

Mean (SD)

Late Tracheostomy No.

Mean (SD)

Weighted Mean Difference (Random) 95% CI

Weight (%)

Weighted Mean Difference (Random) 95% CI

Bouderka et al (2004)

31

14.50 (7.30)

31

17.50 (10.60)

28.34

−3.00 (−7.53 to −1.53)

Rodriguez et al (1990)

51

12.00 (7.14)

55

32.00 (22.25)

25.57

−20.00 (−26.20 to −13.80)

Rumbak et al (2004)

60

7.60 (4.00)

60

17.40 (5.30)

31.76

−9.80 (−11.48 to −8.12)

Saffle et al (2002)

21

35.00 (20.62)

23

31.40 (24.94)

14.32

4.10 (−9.38 to 17.58)

Total (95% CI) χ2 = 22.96, df = 3

163

169

100.00 -50

0

Favors early

-8.49 (-15.32 to -1.66)

50 Favors late

Random effects meta-analysis of weighted mean difference suggests a shorter duration after early tracheostomy. Reprinted with permission Griffiths J, Barber VS, Morgan L, Young JD: Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. BMJ 330:1243, 2005.

TABLE 29-2 Effects of Early and Late Tracheostomy on Length of Stay in the Critical Care Unit in Days Early Tracheostomy Author (Year)

No.

Mean (SD)

Late Tracheostomy No.

Mean (SD)

Weighted Mean Difference (Random) 95% CI

Weight (%)

Weighted Mean Difference (Random) 95% CI

Rodriguez et al (1990)

51

16.00 (7.14)

55

37.00 (29.66)

40.93

−21.00 (−29.08 to −12.92)

Rumbak et al (2004)

60

4.80 (1.40)

60

16.20 (3.80)

59.07

−11.40 (−12.42 to −10.38)

100.00

-15.33 (-24.58 to -6.08)

Total (95% CI) χ2 = 5.34, df = 1

111

115 -50 Favors early

0

50 Favors late

Random effects meta-analysis of weighted mean difference suggests a reduced length of stay after early tracheostomy. Reprinted with permission Griffiths J, Barber VS, Morgan L, Young JD: Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. BMJ 330:1243, 2005.

Ch029-F06861.indd 345

1/21/2008 11:05:21 AM

346

Section 2 Upper Airway

to respond to a short course of mechanical ventilation. A prospective multi-institutional study of more than 300 intensive care units in 12 countries, however, found that only 50% of patients have a tracheostomy between 3 and 4 weeks after onset of mechanical ventilation.13 Although these observations could be interpreted as emphasizing the importance of patient selection, the risk of laryngeal stricture due to longterm endolaryngeal intubation favors early tracheostomy.

Management of Secretions Abundant respiratory secretions, weakness of cough, or a combination of these factors during recovery from an operation or illness may require tracheal access without obligatory mechanical ventilation. If a period of mechanical ventilation appears likely, a regular tracheostomy is selected. Otherwise, a mini-tracheostomy may be considered for suctioning alone because it interferes less with speech and swallowing. A prospective trial found a markedly lower rate of sputum retention in high-risk patients undergoing prophylactic minitracheostomy compared with standard respiratory care.14 The key to avoiding mechanical ventilation for sputum retention, and the point of this study, is early or prophylactic insertion of a mini-tracheostomy. Wain and associates15 reported on its use in 56 patients and encountered airway hemorrhage at the time of insertion in 3%.

Neuromuscular Disorders Ventilator dependence in this class of disorders occurs as a result of profound weakness of respiratory muscles. Tracheostomy is considered during the management of acute symptoms (Guillain-Barré syndrome), for chronic long-term support (Duchenne muscular dystrophy), and for palliation during progressive decline (amyotrophic lateral sclerosis). The common perception that these patients universally have a poor quality of life once dependent on a ventilator in the hospital or at home may be erroneous. One study found a majority of patients satisfied with their life, although the poor prognosis of amyotrophic lateral sclerosis caused a more ambiguous attitude toward mechanical ventilation.16

byproducts of fire additionally causes a severe and prolonged mucosal inflammation with exaggerated cicatricial response to any additional injury.18 Tracheostomy in 99 patients with inhalation injury reported by a single burn center led to major airway complications in 28 and to tracheal stenosis in 6 of 25 survivors.19 In contrast to other indications, translaryngeal intubation in burn patients is better tolerated than tracheostomy, and extended efforts are therefore made to avoid tracheostomy. Kadilak and associates reviewed 98 children with inhalation injury who required mechanical ventilation from 7 to 92 days using oral or nasal translaryngeal intubation and observed a single subglottic stricture, a soft voice in 2 patients, and a tracheostomy rate of 2%.10 A recent comparison found lower cost and shorter procedure times after percutaneous tracheostomy than in historical open procedures among burn patients,20 an observation so far not confirmed by others.

Chronic Aspiration The inflated cuff of a tracheal tube may prevent tracheal aspiration of gastric contents; however, cuff inflation predisposes to orotracheal aspiration during swallowing (see later). Furthermore, the cuff is imperfect as the sole barrier against repeated or chronic aspiration. Additional measures, including nasogastric decompression or gastrostomy drainage, may be used for short-term control. Tracheostomy for long-term control of aspiration is unlikely to succeed.

Preexisting Tracheal Disease Although airway obstruction due to tracheal stricture is rare, the need for tracheostomy sometimes arises in patients with this condition. The placement of the stoma must be selected to preserve as much normal trachea as possible and not to extend the preexisting injury. If an emergent airway is required, a safe approach consists of performing a rigid bronchoscopy to dilate the stricture before placing the stoma at the level of the stricture. The relative merits of a tracheal stent like the silicone tracheal T tube are discussed in Chapter 32.

Trauma

OPEN OR PERCUTANEOUS TRACHEOSTOMY?

Immediate tracheostomy has an important role in the acute management of threatened airway obstruction due to cervicofacial trauma, particularly in complex fractures of the midface, mandibular fractures, laryngeal trauma, and highvelocity gunshot wounds.17 The critical nature of the airway and the indication for tracheostomy may be apparent on initial evaluation; however, impending airway obstruction is sometimes not recognized until sedation or general anesthesia instituted for other procedures leads to sudden airway obstruction. This risk is particularly acute with rapid induction of muscle relaxation and can be greatly reduced by slow induction of anesthesia using inhalational agents. Burn patients are an exception to the rule of early tracheostomy. When the burn involves the skin of the neck, placement of the tracheal stoma within eschar or next to burn wounds creates an entry for bacteria and predicts pulmonary sepsis. The associated inhalation injury mediated by the

Standard tracheostomy is being replaced in many medical centers, and its use may have been surpassed already by percutaneous dilational tracheostomy. This shift toward a procedure perceived to be minimally invasive is expected to continue, driven by cost considerations—even if the calculation of cost is skewed by comparison to standard tracheostomy performed in operating rooms—and by the interest of nonsurgeon physicians to perform a routine procedure in the critical care unit. Either procedure may be safely employed at the bedside in the intensive care unit. Small, randomized clinical trials from single institutions comparing the two procedures are listed in Table 29-3.21-30 Most of these trials reported advantages for percutaneous tracheostomy: lower cost and a more secure airway with the open method25; a shorter procedure time24,25,29 at lower cost27 or lower rate of postoperative bleeding30; and a lower rate of early postoperative complications but a higher rate of late sequelae with

Ch029-F06861.indd 346

1/21/2008 11:05:22 AM

Chapter 29 Tracheostomy

347

TABLE 29-3 Prospective Randomized Trials Comparing Open to Percutaneous Tracheostomy Complications No. Patients

Population

PDT Type

PDT Site

ST Site

Conversion PDT? ST?

PDT

ST

Procedural Death

53

Mixed adult

Ciaglia-Cook

Bed

OR

0

5 events

10 events

0

(1996)

53

Mixed adult

Not stated

Bed

OR

0

12%

41%

0

Heikkinen et al23 (2000)

56

Mixed adult

Portex

Bed

Bed

1

0

3.8%

0

(2001)

100

Mixed adult

Portex Per-Fit

Bed

OR

4

Not stated

Not stated

1

(2001)

Author (Year) Crofts et al21 (1995) 22

Friedman et al

24

Freeman et al

25

Massick et al

100

Mixed adult

Ciaglia-Cook

Bed

2

16%

21%

0

Sustic et al26 (2002)

16

Spinal cord injury

Portex UK*

Bed

OR

0

12.5%

37.5%

0

Melloni et al27 (2002)

50

Mixed adult

Ciaglia-Cook

Bed

OR/Bed

0

4%

36%

0

Kaylie et al28† (2003)

24

Mixed adult

Ciaglia-Cook

Bed

Bed

83

Mixed adult

Ciaglia

139

Mixed adult

Fantoni

29

Wu et al

(2003) 30

Antonelli et al

(2005)

Bed

OR

0

0

Same

Same

0

19%

37%

0

Selection criteria for study entry may have excluded severely ill patients in most trials. *Ultrasound-guided guidewire dilating forceps. † Procedure utilization study. OR, operating room; PDT, percutaneous dilational tracheostomy; ST, standard tracheostomy.

percutaneous tracheostomy.27 Kaylie and associates found no significant difference in procedure length, resident time, or staff time between both procedures.28 A meta-analysis of tracheostomy trials since 1960 found a greater incidence of intraoperative complications in percutaneous procedures, whereas the postoperative morbidity was greater after open tracheostomy.31 When percutaneous tracheostomy was introduced, certain patients were excluded because of anticoagulation, difficult anatomy, or emergent need for airway access; some authors32 have found that further experience has resulted in the expansion of indications. However, specific disadvantages and risks related to surgical technique have been identified in percutaneous tracheostomy: death from hemorrhage due to puncture of a major vessel or thyroid isthmus arteries has been reported at centers experienced in the use of percutaneous tracheostomy.33-35 Concerns over membranous wall tears and tracheoesophageal fistula created by blind insertion of needle and dilator resulted in recommendations to perform routine bronchoscopy for guidance36,37 or modify the technique to reduce the risk of vascular puncture.38 These disadvantages will probably not slow the expansion of the percutaneous technique.

SELECTING A TRACHEOSTOMY TUBE A working knowledge of commercially available tracheostomy tubes is useful to select and adjust the tube to the individual airway anatomy and purpose of use. Hess has summarized the current knowledge of tracheostomy appliances (Hess, 2005).39 Metal tubes are rigid, are more expensive, do not connect to a ventilator, and are not fitted with a cuff. They are still employed because they can be sterilized repeatedly and are durable. Plastic tubes are either made of polyvinyl chloride, which conforms to the airway at body

Ch029-F06861.indd 347

temperature, or of silicone, which is softer but does not change shape with temperature. Tube dimensions are described as outer (OD) and inner (ID) diameter, length, and curvature. Inner diameter matters because it, together with tube length, determines airway resistance. The outer diameter determines the ease of insertion through the stoma and the residual tracheal lumen when the cuff is deflated. Thus, an intubated patient will be given a tube with a larger outer diameter because the inner diameter is larger and airway resistance is lower. After extubation, a smaller tube size is desirable to increase the leak around the deflated cuff. Tracheostomy tubes are available as a single cannula or double cannula. An inner cannula is changed easily but narrows inner diameter and adds to airway resistance. When connected to a ventilator with humidification of inspired air, respiratory secretions are not likely to obstruct the lumen and the inner cannula may be removed unless this cannula provides the 15-mm ventilator adaptor (as in the Shiley Dual-Cannula Tube; Tyco, Pleasanton, CA). The tube shape is either curved or angled. The curved design has the advantage of easier insertion into the trachea and a straighter lumen for inner cannulas. Angled tubes often provide a better fit for the relationship of horizontal stomal tract and vertical trachea. Tracheostomy tubes are made in standard and extra length. The extra-long segment of the angled tube is either proximal, to fit the long stomal tract of obese patients, or distal, to place the tip of the tube below tracheal abnormalities. The most commonly used tracheal cuff has a low-pressure, high-volume design to lower the pressure applied to the tracheal mucosa. The volume of balloons made of latex is highly adaptive to inflation volume and over a wide range of cuff volumes does not translate into increased pressure; however, the material is avoided because latex allergy is common. The

1/21/2008 11:05:22 AM

348

Section 2 Upper Airway

sure points in the trachea; rather, it needs to slide loosely within the lumen. Stopcock

Pressure gauge 100 200 mm Hg 300

30 0

Inflating syringe

FIGURE 29-1 Setup for measurement of cuff pressure in endotracheal and tracheostomy tubes. (FROM HESS DR: TRACHEOSTOMY TUBES AND RELATED APPLIANCES. RESPIR CARE 50:497-510, 2005.)

widely used polyvinyl chloride (PVC) cuff loses compliance when overinflated, exposing mucosa to pressure. Alternatively, a silicone cuff filled with polyurethane foam is available. This cuff may be opened to air so that the expanded foam alone prevents a ventilator leak. If a leak persists, the cuff may be connected to the ventilator circuit. Independent of design, cuff pressures are checked two to three times daily to avoid mucosal necrosis. Tracheal cuff pressures must not exceed the capillary perfusion pressure of the mucosa, which is 23 to 25 mm Hg. Figure 29-1 shows a setup used to measure cuff pressure.

SURGICAL TECHNIQUE Complications after tracheostomy are uncommon as long as the factors leading to injury remain understood. Studies of postintubation stenosis after tracheostomy in patients and in animal models have demonstrated that injuries occur in two distinct locations: at the stoma and at the cuff (see Chapter 32) (Cooper and Grillo, 1969).40,41 Even the most complex stricture due to tracheal tube insertion evolves from one or a combination of these two mechanisms. Although other factors, such as comorbidity resulting from low cardiac output and inhalation injury, may influence the severity of postintubation tracheal stenosis, the reproducibility of these strictures affects the surgical technique, the design of the tracheal tube employed, and the care provided during the entire length of tracheostomy use. Several technical points have been found essential in lowering the risk of injury. Independent of surgical approach, the tracheal stoma needs to be located well below the cricoid ring, through the second and third tracheal ring, to eliminate or at least reduce tube pressure on the cricoid ring and the subglottic space. No part of the anterior tracheal wall is excised so that the anterior cartilaginous projection is preserved and to avoid narrowing of the tracheal lumen after tube removal. The selected tube needs to avoid causing pres-

Ch029-F06861.indd 348

Standard Open Tracheostomy In the operating room or the intensive care unit the patient is positioned with extension of the neck and elevation of the shoulders. The equipment includes a selection of tracheostomy tubes, a Morch swivel adapter (Portex, Smiths Medical, Keene, NH), a tracheal spreader, a tracheal suction catheter, and retractors. The operative team consists of the surgeon, an assistant or scrub nurse, the anesthesiologist, or, in the intensive care unit, a respiratory therapist, and a circulating nurse. After skin preparation, the trachea is approached by transverse skin incision between palpable cricoid and manubrium. Bleeding from anterior jugular veins is rarely observed, and division of the veins is usually unnecessary. The thyroid isthmus is divided if necessary. Despite countless modifications, certain steps need to be followed consistently to reduce the risk of postintubation complications. The tracheal stoma is created at the level of the second and third tracheal rings, leaving the first tracheal ring intact to protect the cricoid from pressure necrosis by the tube. A low tracheostomy, below the third ring, is undesirable because it exposes the superior mediastinal contents, specifically the innominate artery, to pressure. The surgical creation of a window in the anterior tracheal wall leads to tissue loss at the stoma and predisposes to stricture; the tracheotomy is therefore oriented in a vertical manner and no portion of the wall is excised. The tracheotomy is spread, and a tracheostomy tube of appropriate size is gently introduced. The Morch swivel is passed to the anesthesiologist or the respiratory therapist, and a ventilatory circuit is established. Current tubes contain a low-pressure, high-compliance cuff selected to fit the tracheal lumen comfortably. If the selected tube is too small, overinflation to achieve a seal must necessarily convert the tracheal cuff into a high-pressure, low-compliance device and lead to necrosis of the tracheal mucosa, expose cartilaginous rings, and thus lead to tracheomalacia and subsequent tracheal stenosis. Conversely, a tracheal tube that tightly fits the tracheal lumen is too large and risks injury to any points of contact. The new tracheostomy tube is best secured with two sutures to the two corners of the skin wound, allowing ample drainage of secretions along the tube. Variations in anatomy require the surgeon to adapt the procedure. Tracheal tubes in morbidly obese patients dislodge readily early after tracheostomy because the cervical skin is loose and pulls away from the anterior trachea; fiberoptic bronchoscopy at the time of tracheostomy will confirm whether the tube will dislodge with manipulation of the tracheal tube. A high innominate artery crossing the suprasternal region generally is protected with vascularized tissue from direct pressure by the tube, for example, by draping a strap muscle flap between tube and artery. After median sternotomy, tracheostomy is usually deferred for a period of 10 days to 3 weeks to reduce the risk of sternal wound infection. With this precaution, the rate of sternal wound infection is

1/21/2008 11:05:22 AM

Chapter 29 Tracheostomy

349

small, although it is increased compared with patients without tracheostomy (3.4% versus 0.8%42).

Percutaneous Dilational Tracheostomy The technique for insertion of a Ciaglia Blue Rhino (Cook Co., Bloomington, IN) or a Portex Ultraperc (Smiths Medical, Keene, NH) tracheostomy tube is described; both are offered as a kit. The operative team consists of a surgeon, an assistant, one additional physician who manages the airway and can perform bronchoscopy, and a circulating nurse. The procedure is performed in intubated patients under general anesthesia and may be supplemented by infiltration of the anterior tracheal wall with local anesthesia and luminal local anesthesia. In contrast to open tracheostomy there are additional contraindications to its use: pediatric patients, extubated patients, and the presence of a neck mass. The use of bronchoscopy for guidance of needles and guidewires is strongly recommended. After preoxygenation, the tip of the endotracheal tube is positioned in the subglottic space so that the cuff straddles the glottic larynx and the anterior trachea below the cricoid is visible through the endoscope. A short transverse skin incision is made below the cricoid cartilage. With endoscopic guidance and palpation, an introducer needle is inserted in the midline between the first and second, or the second and third, tracheal rings. Note that a tracheostomy is never inserted between the cricoid cartilage and the first tracheal ring, as suggested in Figure 29-2. For the Ciaglia method, a J-tipped guidewire is advanced through the introducer sheath and a 14-Fr introducer dilator is inserted over the guidewire into the tracheal lumen to begin dilation under endoscopic control. Observation by bronchoscopy as shown in Figure 29-3 reduces the risk of injury to the posterior tracheal wall even if the initial needle insertion is eccentric as demonstrated in Figure 29-4. Tracheal dilation is undertaken with a single, progressively tapered Blue Rhino dilator, followed by insertion of a regular tracheostomy tube over an introductory dilator. The Portex Per-Fit kit (Portex Per-fit Kit, Smiths Medical, Keene, NH) provides multiple graded dilators to enlarge the stomal tract. In other types of percutaneous tubes, the tract is dilated with a dilating forceps according to Griggs or multiple graded dilators. The tube may also be introduced via a peroral, translaryngeal route, dilating the tract from the tracheal lumen according to the technique of Fantoni.43

FIGURE 29-2 This illustration proposes locations for a tracheal stoma. Note the arrows suggesting the space between cricoid and first tracheal ring for placement of a percutaneous tracheostomy. Under no circumstance should a tracheal stoma rest on the cricoid cartilage to prevent necrosis and subglottic stenosis. (FROM SILVESTRI GA, COLICE GL: DECIDING TIMING AND TECHNIQUE FOR TRACHEOSTOMY. CONTEMP INTERN MED 5:20-31, 1993.)

Cricothyroidotomy This procedure is relevant to obtain emergent airway access only. Cricothyroidotomy cannot be regarded as an elective alternative to tracheostomy. The procedure may properly be described as a laryngostomy, and an airway tube resting in the larynx longer than absolutely necessary risks damage to both thyroid and cricoid cartilage. The airway is established with a horizontal incision above the cricoid ring, where the skin of the neck is immediately adjacent to the cricothyroid membrane. A small clamp may be spread to expose the cricothyroid membrane. The anterior jugular veins are located on either side of the incision and may be injured; bleeding from this source, however, is uncommon. The surgeon’s

Ch029-F06861.indd 349

FIGURE 29-3 Bronchoscopic image of introducing catheter inserted in midline. The potential of injury to the lateral or posterior tracheal wall is reduced by bronchoscopic observation.

1/21/2008 11:05:22 AM

350

Section 2 Upper Airway

1.2

WOBadd (J/L)

1.0 0.8 0.6 0.4 0.2

A

0 CPAP

IPS 5

IPS 10

IPS 15

ATC

CPAP

IPS 5

IPS 10

IPS 15

ATC

1.2

WOBadd (J/L)

1.0 0.8 0.6 0.4 0.2

B FIGURE 29-4 Eccentrically placed catheter sheath with wire guide. The potential of injury to the lateral or posterior tracheal wall is reduced by bronchoscopic observation.

finger is inserted into the opening, followed by a regular endotracheal tube or the handle of a knife if nothing else is available. The tube is inserted for no more than 5 cm, to prevent intubation into the main stem bronchus. Because a stricture in this location is far more difficult to treat than a similar injury in the trachea, the stoma is closed with sutures after creation of a tracheostomy.

Mini-Tracheostomy The use of a pediatric size 4 endotracheal tube inserted through the cricothyroid membrane for temporary treatment of sputum retention was first reported by Matthews and Hopkinson.44 The purpose of mini-tracheostomy is to prevent conventional endotracheal intubation in spontaneously breathing patients. A complete insertion kit is offered by Portex (Smiths Medical, Keene, NH). The procedure may be performed at the bedside and without further endoscopic guidance. Bronchoscopy, however, is strongly recommended to direct proper midline insertion and confirm endotracheal placement. Once the tube is inserted, the airway may be suctioned with a 10-Fr catheter. The maximal safe duration of use is not established. If the need for suctioning persists for more than 6 to 8 weeks, a regular tracheostomy may be considered.

EFFECTS OF TRACHEOSTOMY Work of Breathing The upper respiratory tract constitutes a major barrier to airflow, forming 80% of total resistance during nasal breathing and 50% during mouth breathing. A tracheostomy usually adds a net gain to overall airflow resistance because of the

Ch029-F06861.indd 350

0

FIGURE 29-5 Additional work of breathing (WOBadd) during continuous positive airway pressure (CPAP), inspiratory pressure support (IPS), and automatic tube compensation (ATC) in patients with tracheostomy at either normal (A, low ventilation group) or markedly increased (B, high ventilation group) minute ventilation. Mean values ± SD. (MODIFIED FROM HABERTHÜR C, FABRY B, STOCKER R, ET AL: ADDITIONAL INSPIRATORY WORK OF BREATHING IMPOSED BY TRACHEOSTOMY TUBES AND NON-IDEAL VENTILATOR PROPERTIES IN CRITICALLY ILL PATIENTS. INTENSIVE CARE MED 25:514-519, 1999.)

small diameter of the tube. The magnitude of this effect depends on minute ventilation and ventilator properties. Figure 29-5 shows that increasing minute ventilation in tracheotomized patients leads to increased work of breathing, an effect that is exacerbated during ventilatory weaning modes. As demonstrated in individual patients studied before and after decannulation,45 tracheostomy tubes are associated with greater airway resistance than the normal anatomy. In patients who repeatedly fail extubation, however, tracheostomy decreases work of breathing compared with both endotracheal tube and the anatomic airway.46 As demonstrated in Figure 29-6, the result of exchanging an endotracheal tube for a tracheostomy is decreased work of breathing and a lower intrinsic positive end-expiratory pressure.

Swallowing The patient with a tracheostomy is prone to aspiration and dysphagia. These conditions are mediated by the state of the tracheal tube. The notion that an inflated tracheal cuff prevents aspiration is probably often incorrect. Cuff inflation increases the esophageal pressure cephalad to the cuff. Both cuff inflation and fixation of the trachea to the skin by the tube tract reduce laryngeal elevation, thus preventing the epiglottic fold from covering the supraglottic larynx. Silent aspiration is further facilitated by the open lumen of the tube.47 Positive tracheal pressure appears to protect from glottic penetration of liquids and enables coughing to clear

1/21/2008 11:05:23 AM

Chapter 29 Tracheostomy

351

7

2

PEEPi (cm H2O)

WOB (J/L)

6

1

5 4 3 2 1

0

0 Before T

After T

A

Before T

After T

B

FIGURE 29-6 A, Work of breathing (WOB) in joules per liter and B, intrinsic positive end-expiratory pressure (PEEPi) with endotracheal tube (before T) and after tracheostomy (after T) in 8 patients. (FROM DIEHL JL, EL ATROUS S, TOUCHARD D, ET AL: CHANGES IN THE WORK OF BREATHING INDUCED BY TRACHEOTOMY IN VENTILATOR-DEPENDENT PATIENTS. AM J RESPIR CRIT CARE MED 159:383-388, 1999.)

secretions. Aspiration of thin liquids in tracheotomized patients, for example, is reduced when the tube orifice is closed with a one-way Passy-Muir speaking valve.48 The closed tracheal tube, however, does not change upper esophageal sphincter or pharyngeal pressure.49 The overall condition of the patient, including nutritional status, strength, age, and presence of comorbidity, is also an important determinant for the recovery of swallowing function.

DECANNULATION When recovery from respiratory failure has resulted in complete weaning from ventilatory support, the tracheal tube is first downsized and then removed. Downsizing and closure of the tube orifice while the cuff remains deflated lower the tube-related resistance, decrease tracheal injury, and minimize aspiration while allowing the patient to demonstrate his or her independence from mechanical ventilation. The tube is often reduced to size 4, corresponding to an inner diameter of 5 mm. When the patient has tolerated this size, the tube is removed. The likelihood of postintubation tracheal stenosis is low, and routine bronchoscopy in the absence of airway obstruction is probably not warranted. The patient is instructed to report any symptoms of airway obstruction. Patients with persistent cough, stridor, and increasing dyspnea undergo prompt bronchoscopic examination of the airway.

COMPLICATIONS While tracheostomy is considered a common intervention, some associated complications related to the airway are potentially life threatening. The challenge therefore is to devote attention to detail, both during and after operation, despite its reputation as an easy, routine procedure. The surgeon needs to be familiar with the pathophysiology of tracheal injury so that surgical techniques are applied that prevent these complications. Despite the institution of modifications in the design of cuffed tracheostomy tubes, these tubes can be used contrary to their purpose. A protocol regarding the appropriate care of tracheostomy is therefore

Ch029-F06861.indd 351

followed at every institution with patients who have tracheostomy tubes.39 There are numerous resources, in book form and online, that offer advice regarding care. According to the time of their occurrence, complications are divided into operative, early, and late.

Operative Hypoxia occurs commonly as a result of tracheal secretions and responds to suctioning. Elective tracheostomy may have to be deferred if hypoxia due to respiratory failure is pronounced. Hemorrhage is usually minor and may originate from injury to anterior jugular veins, the divided thyroid isthmus, and small tracheal arteries. Bleeding may be substantial in conscious patients when neck veins are engorged or in superior vena cava syndrome. Bleeding vessels are individually ligated to prevent postoperative hemorrhage. The use of electrocautery or other thermal coagulation devices must cease once a tracheotomy is created to avoid the risk of airway fire. Pneumothorax during tracheostomy is a rare complication; its etiology is unclear unless extensive dissection is performed in the mediastinum. Once identified, a chest tube is placed to reexpand the lung.

Early Postoperative Minor hemorrhage early after operation is not uncommon in patients receiving antiplatelet agents or anticoagulation. If the source is the tracheal cut edge, bleeding will usually respond to packing of the wound. If bleeding is brisk, the patient is returned to the operating room for control of the individual vessel. Nontrivial hemorrhage from the tracheal lumen requires investigation by bronchoscopy; often the site of bleeding was created by suction trauma. Accidental decannulation within the first week after insertion is an airway emergency. Control of the airway is established by peroral intubation, and prolonged efforts to reinsert through the fresh stoma must be avoided. The initial episode, unless provoked by unusual circumstance, may indicate that the tracheal tube is inadequate and needs to be replaced with a

1/21/2008 11:05:24 AM

352

Section 2 Upper Airway

better-fitting one. Wound infection is rare if the skin closure around the tube is loose. Conversely, an air-tight closure causes infection of the contaminated closed space. The subcutaneous tract is allowed to close and contract spontaneously, which often takes less than a week. Profuse secretions and lack of adequate suctioning and cleaning of the tube, or infrequent change of the inner cannula, may lead to gradual or sudden occlusion of the airway.

Late Postoperative Tracheal stenosis has become uncommon. The use of compliant tracheal cuffs has lowered the incidence of pressureinduced destruction of cartilage. However, even a compliant, low-pressure cuff can be converted into a noncompliant, high-pressure tool of injury by imprudent overinflation. Patients with stenotic lesions also now seem to present more often with comorbid conditions and laryngotracheal involvement due to cricoid injury. It is unclear whether the method of insertion is associated with a risk of stricture. In a retrospective study of patients undergoing tracheal resection for postintubation tracheal stenosis, Raghuraman and associates found longer strictures extending more often into the subglottic airway among patients who had percutaneous placement.50 This finding has not been confirmed by others. Tracheoinnominate artery fistula is a rare and life-threatening complication with two determinants: the anatomic position of the artery and the tentative position between the tracheal stoma and the artery. A low stoma favors pressure on the artery and therefore needs to be avoided. Acute bleeding is typically massive and requires temporary control by compression and immediate sternotomy with division of the innominate artery. Tracheoesophageal fistula most often is a result of the pinching action of a stiff nasogastric tube and the tracheal tube cuff with necrosis of the interposed membranous portion and esophageal wall. The presentation is usually sudden as an air leak escaping from the mouth and distending the stomach. Aspiration of esophageal contents may lead to pneumonia. The complication is prevented when the nasogastric tube is replaced at or soon after tracheostomy with a gastrostomy. A persistent tracheal stoma results from epithelial coverage of the stomal tract after prolonged intubation. Healing of the tract is thus impossible. The stoma is closed by separation of the tract from the skin and interposition of strap muscle between the closures of the tract and the skin.

COMMENTS AND CONTROVERSIES The preceding chapter presents a thoughtful, comprehensive, and well-documented review of the indications, technique, and complications of tracheostomy. The introduction of percutaneous, dilational tracheostomy in recent years has created a new set of technical considerations and cautions, as well as a thorough understanding of the potential early and late complications of tracheostomy that may not be familiar to the nonsurgeons now employing the percutaneous route. In this regard, it would be advisable for all such physicians to participate in several open tracheostomies to acquire a better understanding of the anatomic relationships involved in optimal placement of a tracheostomy tube. The relationship

Ch029-F06861.indd 352

between the tracheostomy stoma, the cricoid cartilage, the innominate artery, and the thyroid isthmus remains important regardless of whether the open or percutaneous route is selected. The introduction of mini-tracheostomy through the cricothyroid membrane as reported by Matthews and Hopkinson in 1984 for the treatment of sputum retention was viewed with considerable concern by many, lest the procedure result in injury to the subglottic region. However, experience has demonstrated that this procedure is of considerable value with very little risk when properly performed. For patients with increased sputum and a weak cough, the mini-tracheostomy has proven extremely valuable for improving pulmonary toilet. Its safe application, using only local anesthesia, is most easily and safely performed when using a kit that includes a needle to access the airway, a flexible guidewire to direct proper placement, a dilator, and a No. 4 tube of sufficient length to avoid easy dislodgement once it has been positioned. Although concomitant bronchoscopic guidance is ideal, it is not an absolute requirement for the safe placement of the mini-tracheostomy tube. When performing open tracheostomy, the author prefers that no portion of the anterior tracheal wall be removed. While agreeing with the principle of avoiding injury to the tracheal wall to reduce a subsequent incidence of stomal stenosis, I prefer removal of a very small portion of the second tracheal cartilage to create a small stoma that is then dilated as the tracheostomy tube is inserted. Regardless of the technique, the cause of subsequent postintubation stenosis at the stomal level is likely related to the increased damage to an enlargement of the stomal area by pulling and tugging on the tracheostomy tube by the attached ventilator tubing. A flexible connector between the tracheostomy tube and the ventilatory apparatus and fixation of the ventilator tubing to the patient’s gown, to avoid distraction of the tracheostomy tube, are important factors in reducing postintubation stomal stenosis. The author notes that the production of a tracheoesophageal fistula may relate to an overinflated tracheostomy cuff and an adjacent rigid nasogastric tube. However, note that even in the absence of a nasogastric tube, a tracheoesophageal fistula may result from the use of a high-pressure cuff or overinflation of a low-pressure cuff. J. D. C.

KEY REFERENCES Cooper JD, Grillo HC: The evolution of tracheal injury due to ventilatory assistance through cuffed tubes: A pathologic study. Ann Surg 169:334-348, 1969. ■ The pictures in this classic paper of postintubation tracheal injury should be committed to the memory of every surgeon performing tracheostomy. Griffiths J, Barber VS, Morgan L, Young JD: Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. BMJ 330:1243, 2005. ■ This meta-analysis of randomized and controlled studies comparing airway management in mechanical ventilation finds shorter duration of mechanical ventilation and reduced length of intensive care stay with early tracheostomy compared with late tracheostomy or prolonged endotracheal intubation. Hess DR: Tracheostomy tubes and related appliances. Respir Care 50:497-510, 2005. ■ An excellent introduction to tracheostomy tubes, their design and properties. Jackson C: Tracheostomy. Laryngoscope 19:285-290, 1909. ■ The classic monograph that has influenced several generations of surgeons.

1/21/2008 11:05:24 AM

chapter

SUBGLOTTIC RESECTION: ADULTS

30

Michael A. Maddaus F. Griffith Pearson

Key Points ■ The posterior aspect of the cricoid cartilage supports the arytenoid

cartilages and vocal cords. ■ The subglottic space is the narrowest part of the airway below the

larynx. ■ Postintubation injury is the most common cause of subglottic

stenosis. ■ During resection, identification of the recurrent laryngeal nerves is

not necessary if dissection of the trachea is maintained immediately against the outer surface of the airway.

The subglottic airway extends from the inferior margin of the vocal cords above to the lower border of the cricoid cartilage below. Resection of the subglottic airway is complicated by the following factors: 1. It is in close proximity to the vocal cords. 2. Complete transection of the subglottic airway at any level above the cricothyroid joints will divide the recurrent laryngeal nerves. 3. The posterior rim of the upper border of the cricoid cartilage supports the arytenoid cartilages, which play a critical role in vocal function. The technique of subglottic resection, which is described in detail later, allows transverse division of the airway up to the level of the inferior border of the vocal cords without transection of intact recurrent laryngeal nerves. At the level of the inferior border of the posterior cricoid plate, the recurrent nerves pass behind the cricoid cartilage. On each side, the nerve passes behind the cricothyroid articulation and continues a vertical ascent to the superior border of the cricoid cartilage, at which point it passes forward to supply the glottic muscles. As long as the tissues lying behind the cricoid cartilage are undisturbed, both recurrent laryngeal nerves can be predictably preserved.

HISTORICAL NOTE Ogura and Powers (1964) were the first to describe a segmental resection of the cricoid cartilage with primary thyrotracheal anastomosis. They reported on seven patients with subglottic obstruction secondary to blunt trauma. In all of these patients, however, the recurrent laryngeal nerves were avulsed and paralyzed on both sides as a result of the original trauma. In 1974, Gerwat and Bryce described a technique of

partial cricoid resection using an oblique line of transection of the subglottic airway (Fig. 30-1), which removed the anterior cricoid arch but preserved the posterior cricoid cartilage and recurrent nerves above the level of the cricothyroid joints. With this technique, however, the level of resection of the posterior subglottic airway was limited. In 1975, Pearson and colleagues described a technique of transverse resection of the subglottic airway at any level below the vocal cords, with preservation of intact recurrent laryngeal nerves. This was accomplished by maintaining a posterior shell of cricoid cartilage. A primary thyrotracheal anastomosis was performed within 1 cm or less of the inferior margin of the vocal cords. This is the technique that is described in detail in this chapter. HISTORICAL READINGS Gerwat J, Bryce DP: The management of subglottic laryngeal stenosis by resection and direct anastomosis. Laryngoscope 84:940, 1974. Ogura JH, Powers WE: Functional restitution of traumatic stenosis of the larynx and pharynx. Laryngoscope 74:1081, 1964. Pearson FG, Cooper JD, Nelems JM, et al: Primary tracheal anastomosis after resection of the cricoid cartilage with preservation of recurrent laryngeal nerves. J Thorac Cardiovasc Surg 70:806, 1975.

ANATOMY A clear knowledge of the anatomy of the region is essential to an understanding of this operative technique. The anatomy of the larynx and upper airway is described in detail in Chapter 15. Some features warrant emphasis (Fig. 30-2). The cricoid cartilage is the first full ring of the upper airway, has an anterior arch similar in height to a normal tracheal ring, and expands into a broad posterior plate or rostrum. Both the inner and outer aspects of the cricoid cartilage are covered with a stout perichondrial layer, which may be freed from the underlying cartilage during certain stages of the operation. Paired arytenoid cartilages rest on the superior border of the posterior cricoid plate and articulate at the cricoarytenoid joints. The vocal cords are attached posteriorly to the vocal processes of the arytenoid cartilages and anteriorly to the thyroid cartilage. The subglottic larynx begins immediately below the vocal folds and extends to the inferior margin of the cricoid cartilage. The subglottic space is the narrowest part of the upper airway aside from the larynx. The subglottis has an internal diameter that is between 1.5 and 2 cm in adults and is completely surrounded by the cricoid cartilage. 353

Ch030-F06861.indd 353

1/21/2008 11:06:32 AM

354

Section 2 Upper Airway

Arytenoid cartilage

Thyroid cartilage

Posteror cricoid plate Cricothyroid joint

Anterior arch of cricoid

Recurrent nerve FIGURE 30-1 Lateral view of larynx and upper airway. Line of resection begins at the inferior border of the thyroid cartilage anteriorly and passes below the cricothyroid joint behind. This line allows preservation of the recurrent laryngeal nerves and was the technique of partial cricoid resection described by Gerwat and Bryce (1974).

ANESTHETIC TECHNIQUE When necessary, the stenosis is dilated before operation. With the patient asleep, gum-tipped esophageal bougies are directed through a conventional intubating laryngoscope. This is the least traumatic technique for dilation of the sub-

A

FIGURE 30-2 Lateral view showing the pertinent anatomy of the larynx and the subglottic and upper tracheal airways.

glottic region. After passage of a 34 Fr gum-tipped bougie, the anesthetist should be able to easily pass a no. 6 or 6.5 endotracheal tube. If the intubation is difficult because of a tight stenosis, an uncuffed tube may be preferable because an air seal will be secured at the level of the stricture. A rigid

B

FIGURE 30-3 A, The airway has been divided just beyond the stenotic lesion, and the distal trachea has been intubated with the armored endotracheal tube. Stay sutures have been placed in the divided tracheal ends. The anterior and lateral components of the cricoid cartilage have been removed, and it is now possible to develop the subperichondrial plane in front of the posterior cricoid plate. This is usually done with a small orthopedic elevator. This avascular plane can be developed posteriorly and laterally to a level just below the arytenoid cartilages and vocal folds. B, The soft tissue airway is now divided above the lesion, through an area of healthy mucosa in the subglottic region. This line of division may lie within a few millimeters of the inferior margins of the vocal cords. A posterior shell of the remaining cricoid cartilage is exposed and protects the posteriorly situated recurrent nerves.

Ch030-F06861.indd 354

1/21/2008 11:06:32 AM

Chapter 30 Subglottic Resection: Adults

355

FIGURE 30-4 A, Postintubation injury. There is a polypoid granulation projecting from the posterior third of the left vocal cord (small arrow). In the subglottic area, a concentric stenosis is just visible (large arrow). B, In the same patient, a computed tomography scan (1.5-mm-interval cut) at the subglottic level shows a severe stenosis with marked circumferential submucosal thickening (scar). C, Photograph obtained 1 year after subglottic resection and reconstruction by primary thyrotracheal anastomosis. The subglottic airway is healthy throughout, with a complete mucosal covering and normal airway diameters. The thin line of scar that identifies the anastomosis is almost invisible (arrow). D, Contrast tracheogram obtained 1 year after operation in the same patient. The anastomosis is widely patent and lies within 1 cm of the inferior aspect of the vocal cords.

Ch030-F06861.indd 355

1/21/2008 11:06:34 AM

356

Section 2 Upper Airway

FIGURE 30-5 Diagram illustrating the location of a generous collar incision (upper left inset) and the subsequent exposure of the upper airway after retraction of upper and lower skin flaps developed in the subplatysmal plane. The airway is exposed from the level of the thyroid notch above to the suprasternal notch below. The strap muscles have been reflected from the midline, and the anterior aspects of the thyroid, cricoid, and upper tracheal cartilages have been exposed.

bronchoscope can be used as the dilating instrument, but this procedure is more traumatic than that using the tapered bougies. Once the distal airway is divided, an armored endotracheal tube is introduced through the distal trachea, and the proximal end of the tube is passed at the side of the cheek and under the drapes to the anesthetist (Fig. 30-3).

INDICATIONS Postintubation injury remains the most common cause of subglottic stenosis that is amenable to resection and primary reconstruction (Fig. 30-4). The injury can occur after translaryngeal intubation, with or without a subsequent tracheotomy. A high tracheotomy or cricothyroidotomy may result in injury within the cricoid ring, even in the absence of prior translaryngeal intubation. Other causes of benign stenosis are blunt trauma with cricotracheal disruption, idiopathic subglottic stenosis, inhalation injury owing to thermal or chemical burns, and rare miscellaneous conditions such as primary amyloidosis. On occasion, neoplasms of the upper airway may be amenable to subglottic resection with sparing of the larynx and voice. To date, we have used this approach in 13 patients: 4 with adenoid cystic carcinoma, 2 with squamous cell carcinoma, 2 with mucoepidermoid carcinoma, 2 with neurofibroma, 2 with thyroid carcinoma, and 1 with chondrosarcoma. It must be emphasized, however, that most primary malignancies involving the subglottic airway are best managed by a resection that includes a laryngectomy. Monnier and Savary (Monnier and Savary, 1993)1 were the first to demonstrate the successful application of this

Ch030-F06861.indd 356

A

B

FIGURE 30-6 Lateral (A) and anteroposterior (B) projections showing the resection margins for a benign postintubation stenosis that involves the subglottic airway, within the cricoid ring, as well as the proximal cervical trachea.

operation in infants and children with obstruction caused by postintubation stenosis or congenital subglottic stenosis. They have shown that such resections do not interfere with the normal growth and development of the larynx and subglottis in long-term follow-up. In this text, Monnier has described his modified technique and results in detail in Chapter 31.

1/21/2008 11:06:35 AM

Chapter 30 Subglottic Resection: Adults

357

MANAGEMENT Operative Technique Subglottic Resection

FIGURE 30-7 Diagram illustrating the technique of subperichondrial exposure of the anterior and lateral aspects of the cricoid cartilage. The perichondrium has been incised along the inferior border of the arch and is being freed from the underlying cartilage by means of a small orthopedic elevator. The damaged and stenotic lesion extends for several centimeters below the cricoid and has been mobilized circumferentially. The distal airway will be divided at the level of the dotted line, and an armored orotracheal tube has been secured along the left side of the neck for intubation of the distal airway after transection.

The neck is fully extended, with some type of bolster placed behind the scapulae. Exposure is obtained with a generous collar incision, which is located at a level that will best expose the pathology in the upper airway. Subplatysmal skin flaps are developed to provide exposure from the thyroid notch above to the suprasternal notch below. The strap muscles are reflected from the midline to expose the anterior aspect of the thyroid and cricoid cartilages and the adjacent cervical trachea (Fig. 30-5). In these cases, the pathology lies within the cricoid ring and commonly extends to the adjacent cervical trachea. The lines of resection for this isolated subglottic lesion are illustrated in Figure 30-6. The upper trachea in the region of the diseased segment is freed circumferentially to the level of the inferior border of the cricoid ring. Dissection is maintained immediately against the outer surface of the airway, which protects the recurrent laryngeal nerves posterolaterally. In patients with benign lesions, no attempt is made to identify the recurrent nerves, which are frequently obscured by peritracheal scar. When operating for neoplasm, however, it may be necessary to identify one or the other recurrent laryngeal nerve to determine the extent of neoplastic involvement. If the nerve is infiltrated by tumor, it may have to be sacrificed and resected. Once the inferior border of the cricoid cartilage has been identified, the exposed perichondrium is incised with a scalpel or by cautery. In most patients, it is possible to free the perichondrium from the underlying cartilage by use of a

FIGURE 30-8 A, Operative photograph illustrating the anterior cricoid cartilage after it has been freed completely of its perichondrial cover. B, The tip of a hemostat has been passed behind the anterior cricoid arch, demonstrating the circumferential mobilization.

Ch030-F06861.indd 357

1/21/2008 11:06:39 AM

358

Section 2 Upper Airway

FIGURE 30-9 Diagram illustrating removal of the exposed anterior and lateral aspects of the cricoid arch using a small rongeur.

small orthopedic elevator (Fig. 30-7). The entire circumference of the inferior border of the cricoid cartilage is exposed under the perichondrium, and the entire anterolateral ring of the cricoid cartilage is then freed from its perichondrial cover (Fig. 30-8). The exposed anterior and lateral aspects of the

A

B

FIGURE 30-10 A, Diagram illustrating the technique of plication of the membranous trachea to match the luminal diameters of the tracheal and subglottic airways at the level of anastomosis. This also restores a complete cartilaginous ring in the subglottic larynx. B, Diagram illustrating an end-to-end thyrotracheal anastomosis. This anastomosis is begun posteriorly using interrupted sutures of finegauge (35 Fr) stainless steel wire, with the knots tied inside. The lateral and anterior margins of the anastomosis are then closed by interrupted sutures of 3-0 or 4-0 Vicryl with the knots tied on the outside.

Ch030-F06861.indd 358

cricoid arch are then removed, usually in piecemeal fashion, with small rongeurs (Fig. 30-9). The trachea is then transected at the distal end of the lesion, and the distal airway is intubated with an armored endotracheal tube (see Fig. 30-3A). Stay sutures are placed in the divided tracheal ends, above and below. It is now possible to develop the subperichondrial plane in front of the posterior cricoid plate. Once again, with the use of an orthopedic elevator, this avascular plane can be freed almost to the inferior margins of the cricoarytenoid joints. The airway is then divided above the stenosis, through healthy mucosa in the subglottic region (see Fig. 30-3B). This line of division may lie within a few millimeters of the inferior margins of the vocal folds. The posterior shell of the remaining cricoid cartilage is exposed and protects the posteriorly situated recurrent laryngeal nerves. If the external, posterior aspect of the cricoid plate is freed subperichondrially, the posterior cartilage may also be removed up to the level of the proposed anastomosis. This may be necessary in patients with a damaged or chronically infected posterior cricoid cartilage. The remaining subglottic airway now consists of a stout tube of perichondrium with underlying mucosa and submucosa. There will inevitably be a discrepancy in luminal diameter between the subglottic airway (smaller) and the cut end of the distal trachea. It is

A

B

FIGURE 30-11 Lateral (A) and anteroposterior (B) diagrams illustrating the lines of incision and transection for subglottic resection and synchronous laryngeal reconstruction. In this operation, a laryngofissure is made by using a vertical incision in the midline of the thyroid cartilage anteriorly.

1/21/2008 11:06:41 AM

Chapter 30 Subglottic Resection: Adults

usually desirable to plicate the membranous component of the distal trachea to accommodate these differences in diameter (Fig. 30-10A). An end-to-end thyrotracheal anastomosis is performed using interrupted sutures (see Fig. 30-10B). Our preference is to use 35-gauge stainless steel wire on the posterior wall with knots tied on the inside. The lateral and anterior part of the anastomosis is completed with interrupted sutures of 3-0 or 4-0 Vicryl, with knots tied on the outside.

Subglottic Resection and Synchronous Laryngeal Reconstruction Synchronous laryngotracheal injury is commonly seen after prolonged translaryngeal intubation.2 The most common glottic injury is a posterior interarytenoid stenosis, which restricts abduction of the vocal cords. These combined injuries are best managed collaboratively with the otolaryngologist. A review of our group’s experience with postintubation glottic injury was reported by Pearson and Gullane (1996).3 The lines of incision and transection for a synchronous combined procedure are illustrated in Figure 30-11. The technique of mobilization of the cervical trachea and cricoid is similar to that used for resection of isolated subglottic stenosis (Fig 30-12). In these cases, however, the thyroid cartilage is divided in the midline anteriorly (Fig. 30-13A). When the margins of the laryngofissure are retracted laterally, the vocal cords and upper subglottic region are exposed. (In Figure 30-13B, the subglottic pathology is resected, but the interarytenoid scar remains—see dotted line.)

359

When the interarytenoid scar is excised, a posterior mucosal defect is created, which extends to the upper margins of interarytenoid mucosa (Fig. 30-14A). This defect will be resurfaced with the use of a pedicled flap of membranous trachea fashioned from the distal tracheal margins (see Fig. 30-14B). To create this vascularized pedicle of membranous trachea, it is necessary to resect one or two of the anterolateral cartilaginous rings. The mucosal flap is then secured with interrupted sutures of fine-gauge stainless steel wire, as illustrated in Figure 30-14. Figures 30-15 to 30-19 are operative photographs illustrating laryngofissure, excision of interarytenoid scar, and preparation of a pedicled flap of posteromembranous distal trachea, which will be used to resurface the posterior glottic defect. The remainder of the thyrotracheal anastomosis is completed with interrupted 3-0 or 4-0 Vicryl sutures. The laryngofissure is closed anteriorly with interrupted 3-0 or 4-0 Vicryl sutures (Fig. 30-20). When the subglottic anastomosis lies within a few millimeters of the vocal cords, there is an unpredictable risk of postoperative glottic edema. This problem is managed by placement of a small distal tracheostomy tube or placement of a silicone Montgomery T tube, with the upper limb of the T tube lying 0.5 to 1 cm above the vocal cords, as illustrated in Figure 30-20. Depending on the status of the airway at the margins of this high anastomosis, the T tube may be left in position for intervals varying from a few weeks to 3 months or longer. The incision is closed as described previously. A stout suture of 5-0 Tevdek secures the skin of the chin to the skin

FIGURE 30-12 A, Diagram illustrating mobilization and resection of the subglottic defect. The cricoid arch has been freed subperichondrially and resected, and the trachea has been divided below the lesion and intubated for ventilation. The avascular, subperichondrial plane in front of the posterior cricoid plate is being developed with a small orthopedic elevator. B, The stenotic lesion in the subglottic airway has been freed posteriorly to a level above the pathologic lesion.

A

Ch030-F06861.indd 359

B

1/21/2008 11:06:44 AM

360

Section 2 Upper Airway

A

B

FIGURE 30-13 A, Diagram illustrating the diseased and stenotic airway, which has been opened anteriorly in the midline to the level of the thyroid cartilage. The subglottic airway will be transected above the pathologic lesion (transverse dotted line) with the larynx exposed by a laryngofissure. B, The laryngofissure has been completed and the diseased subglottic segment resected. The margins of the thyroid cartilage are separated with small retracting hooks, which are positioned at the anterior ends of the vocal cords in the diagram. After resection of the subglottic stenosis, a broad plate of inferior cricoid cartilage is exposed. There is still a dense interarytenoid scar, which will be excised within the margins of the upper dotted line. A posterior pedicled flap of membranous trachea will be fashioned from the distal cut margin of the airway (lower dotted line) and will be used to resurface the interarytenoid defect.

A

B

FIGURE 30-14 A, The posterior mucosal flap has been developed at the distal resection margin, and the first of a series of interrupted sutures is placed to secure the flap in the interarytenoid defect. B, The completed closure of the posterior defect is illustrated. We prefer fine-gauge stainless steel wire for this part of the anastomosis, with the knots tied on the inside.

Ch030-F06861.indd 360

1/21/2008 11:06:45 AM

Chapter 30 Subglottic Resection: Adults

FIGURE 30-15 Operative photograph showing the larynx and subglottic areas after resection of the anterior cricoid arch and laryngofissure. Fine hook retractors are being used to spread the anterior margins of the thyroid cartilage. In the photograph, the vocal cords lie about 5 mm superior to the position of the hook retractors. The ulcerated, thickened, and stenosed subglottic segment begins immediately below these small retractors and extends posteriorly into the interarytenoid mucosa.

FIGURE 30-16 Photograph of the same patient as in Figure 30-15, after resection of the stenosed subglottic segment and interarytenoid scar. A broad plate of posterior cricoid cartilage is exposed below. The fine hook retractors lie just below the inferior margin of the vocal folds.

FIGURE 30-17 The distal airway has been stabilized with two posterolateral stay sutures. At the bottom of the photograph, the stoma of a prior tracheostomy is seen. The uppermost cartilaginous rings of the distal airway will be resected to develop a vascularized posterior mucosal flap.

FIGURE 30-18 The anterolateral margins of the distal airway have been trimmed back, with preservation of a pedicle of posterior membranous trachea. The pedicled flap has been stabilized with two fine stay sutures. The old tracheostomy now lies within a few millimeters of the tracheal margin. Just above the mucosal flap, a bare area of cricoid is seen, and above this the mucosal surface of the airway lies immediately below the vocal cords.

Ch030-F06861.indd 361

361

1/21/2008 11:06:48 AM

362

Section 2 Upper Airway

A

B

FIGURE 30-20 Lateral (A) and anteroposterior (B) diagrams illustrating the completed thyrotracheal anastomosis and closure of the laryngofissure. A silicone T tube has been placed with the proximal limb lying 0.5 cm above the vocal cords.

FIGURE 30-19 The distal airway has been elevated in preparation for the anastomosis. The posterior flap is now lying just below the mucosal defect between the arytenoid cartilages. This pedicle will be secured in place with interrupted sutures of fine gauge (35 gauge) stainless steel wire with the knots tied inside.

of the chest to maintain neck flexion during the first postoperative week.

Postoperative Management If a Montgomery T tube is placed, the cervical arm needs to be closed or corked, so that breathing occurs through the nose and mouth and the normal mechanisms for humidification of the airway are preserved. If the cervical arm of the T tube is not closed and the patient is allowed to breathe through the cervical stoma, there is a serious risk of lifethreatening airway obstruction. The tracheal arm of the T tube can become plugged with desiccated secretions owing to failure of adequate humidification. The Montgomery T tube has no inner cannula, and such obstruction may be relieved only by the immediate removal of the T tube. If a small distal tracheostomy is placed, this, too, may be corked if the patient can breathe adequately around it. If not, it is important to provide adequate humidification with a tracheostomy mask during the early postoperative period. The chin suture is removed at the end of 1 week. It is recommended that the anastomosis be examined by flexible bronchoscopy at that time. If the margins are well vascularized and healing cleanly, it is almost certain that a satisfactory

Ch030-F06861.indd 362

result will be obtained, and it is safe to discharge the patient.

COMPLICATIONS AND RESULTS The complications and results of subglottic and laryngotracheal resection in adults have been reported in publications by Pearson and colleagues (Pearson et al, 1975),4-6 Maddaus and coworkers,2 Couraud and others,7,8 Grillo (Grillo, 1982),9,10 Donahue and colleagues,11 Zannini,12 and Macchiarini and colleagues13 (2001). KEY REFERENCES Grillo HC: Primary reconstruction of the airway after resection of subglottic and upper tracheal stenosis. Ann Thorac Surg 33:3, 1982. Monnier P, Savary M: Partial cricoid resection with primary tracheal anastomosis for subglottic stenosis in infants and children. Laryngoscope 103:1273, 1993. ■ These authors were the first in the world to report a successful experience with subglottic resection in infants and children. The indications for operation and the details of technique in this age group are clearly outlined. Pearson FG, Cooper JD, Nelems JM, et al: Primary tracheal anastomosis after resection of the cricoid cartilage with preservation of recurrent laryngeal nerves. J Thorac Cardiovasc Surg 70:806, 1975. ■ The operative technique of partial cricoid resection, preservation of recurrent laryngeal nerves, and primary thyrotracheal anastomosis is described in detail in this original report. The description includes anatomic diagrams, intraoperative photographs, and photographs of cadaver dissections illustrating pertinent details of anatomy in this region.

1/21/2008 11:06:49 AM

chapter

31

SUBGLOTTIC RESECTION: INFANTS AND CHILDREN Philippe Monnier Florian Lang Marcel Savary

Key Points

because inappropriate initial management of subglottic stenosis may lead to permanent, intractable sequelae.

■ Perform a thorough preoperative endoscopy with assessment of

■ ■ ■

■

■

■

■ ■ ■

vocal fold mobility and potential extralaryngeal sites of obstruction (e.g., nasopharynx, oropharynx, tracheostoma). Evaluate for gastroesophageal reflux. Do not plan any surgery before a mature, cicatricial stenosis has been obtained. Use a single-stage partial cricotracheal resection (PCTR) for grade III and IV subglottic stenoses without glottic involvement in an otherwise healthy child. A double-stage PCTR in children with associated congenital anomalies or impaired cardiopulmonary or neurologic functions is preferred. Do not identify the recurrent laryngeal nerves but stay in close contact with the cartilaginous rings when dissecting the lateral tracheal wall. Stay anterior to the cricothyroid joint and place the stitches in a subperichondrial plane on the outer surface of the cricoid plate to avoid injury to the recurrent laryngeal nerves. Perform a laryngeal release procedure when resection of five or more tracheal rings is necessary. Follow the airway carefully for any sign of stridor after extubation for single-stage PCTR. Perform a control endoscopy at the third postoperative week to assess patency of the anastomotic site after double-stage PCTR without stenting.

The principle of subglottic resection in infants and children is basically identical to that described for adults. However, a child’s airway is smaller, thus the postoperative management is more challenging. Furthermore, pediatric subglottic stenosis is often associated with glottic scarring (e.g., posterior glottic stenosis, cicatricial fusion of the vocal cords) and sometimes laryngeal and mediastinal malformations significantly add to the therapeutic challenge. However, the worst situations seen in this group of pathologic processes always result from the following: 1. Previously failed laryngotracheal reconstructions (LTRs) that can distort the laryngeal framework 2. Inappropriate overuse of the laser 3. Misplacement of the tracheostoma that unnecessarily damages the normal trachea The best chance for the patient lies in a successful first surgery. This implies that the surgeon be fully trained in pediatric upper airway endoscopy and laryngotracheal surgery

HISTORICAL NOTE In 1953, Conley1 reported the first successful cricotracheal resection in a patient operated on for a chondroma of the cricoid cartilage. Almost 10 years later, Shaw and associates2 and then Ogura and Powers3 revisited this technique for the correction of traumatic stenosis of the larynx and trachea. However, cricotracheal resection only gained wider acceptance in the mid 1970s, which was due in part to the reports of data from large samples published by Gerwat and Bryce4 and Pearson and colleagues.5 These authors were the first to perform a partial cricotracheal resection (PCTR) with preservation of both recurrent laryngeal nerves. Since then, PCTR has become the treatment of choice for the resolution of subglottic stenosis in adults (Maddaus et al, 1992).6-10 Ranne and coworkers11 are credited with the first report of a series of seven PCTRs performed in children with recurrent subglottic stenosis. Decannulation was accomplished 3 to 12 weeks after surgery in all cases. However, this short-lived experience never stimulated the medical community and, for several reasons, including the lack of training in tracheal surgery, otolaryngologists and pediatric surgeons have been reluctant to use PCTR in infants and children. The main allegations have included the risk of injury to the recurrent laryngeal nerves, the possible dehiscence of the anastomosis, and the interference with the normal growth of the larynx. Although Savary’s pioneering work with PCTR in pediatric cases dates back to 1978, this surgical procedure only emerged as a superior alternative to LTR for the cure of severe subglottic stenosis in infants and children in 1993, after the first report of our experience in 15 cases,12 with an update in 2003 on 60 cases.13 In 1997, the Department of Pediatric Otolaryngology in Cincinnati, Ohio,14 supported use of this technique for selective indications and reported results from 16 additional pediatric cases, with an update in 2001 by Rutter and coworkers.15 Overall, decannulation for severe subglottic stenosis has been achieved after PCTR in 157 (91%) of the 172 pediatric cases published in the literature (Jaquet et al, 2005; Rutter et al, 2001).15-19 HISTORICAL READINGS Conley JJ: Reconstruction of the subglottic air passage. Ann Otol Rhinol Laryngol 62:477-495, 1953. Gerwat J, Bryce DP: The management of subglottic laryngeal stenosis by resection and direct anastomosis. Laryngoscope 84:940-957, 1974. 363

Ch031-F06861.indd 363

1/21/2008 11:08:03 AM

364

Section 2 Upper Airway

Monnier P, Savary M, Chapuis G: Partial cricoid resection with primary tracheal anastomosis for subglottic stenosis in infants and children. Laryngoscope 103:1273-1283, 1993. Pearson FG, Cooper JD, Nelems JM, Van Norstrand AWP: Primary tracheal anastomosis after resection of the cricoid cartilage with preservation of recurrent laryngeal nerves. J Thorac Cardiovasc Surg 70:806-816, 1975. Ranne RD, Lindley S, Holder TM, et al: Relief of subglottic stenosis by anterior cricoid resection: An operation for the difficult case. J Pediatr Surg 26:255-259, 1991.

ETIOLOGY AND PATHOPHYSIOLOGY In the pediatric age group, the most common reason for subglottic stenosis is prolonged intubation.20 In newborns, however, congenital subglottic stenosis represents the third most common laryngeal anomaly after laryngomalacia and bilateral vocal fold paralysis. According to Holinger,21 congenital subglottic stenosis is classified into cartilaginous and soft tissue stenoses. It is present when the lumen of the cricoid region measures less than 4 mm in diameter in a fullterm infant or 3 mm in a premature infant. The cartilaginous type results from a failure of complete recanalization of the laryngeal lumen after the eighth week of gestation. The cricoid may be normal in shape but too small for the infant’s size, or it may show different abnormalities such as a general thickening of the cricoid ring, a large anterior or posterior lamina, or an elliptical shape. Sometimes, a trapped first tracheal ring is responsible for the small size of the subglottis. In approximately 50% of cases, a congenital subglottic stenosis is associated with mediastinal malformations, including cardiovascular, tracheobronchial, or esophageal anomalies.22 For the otorhinolaryngologist, thoracic surgeon, and anesthetist, this implies that any mediastinal malformation warrants bronchoesophagoscopy before treatment to rule out a minor asymptomatic congenital subglottic stenosis. This will avoid the disastrous consequence of a failed extubation leading to subglottic stenosis after an elective cardiac or esophageal surgery in a newborn child who has been intubated with a normal-sized endotracheal (ET) tube for his or her age but that is obviously too large for the size of its subglottic airway. The trauma induced to the subglottic airway will result in the typical combined (congenital and acquired) subglottic stenosis. Since McDonald and Stocks23 introduced long-term intubation for the management of neonates requiring prolonged ventilatory support in 1965, subglottic stenosis has become a well-recognized entity in pediatric intensive care units (ICUs). Improving the stiffness and biocompatibility of ET tubes as well as the nursing conditions in the ICU has led to a gradual decrease in the incidence of subglottic stenosis resulting from elective intubation in full-term or premature infants. Injuries leading to subglottic stenosis in infants and children are more likely to occur after traumatic intubations for resuscitation, after intubation for severe cranial injuries, when laryngoscopy is difficult because of anatomic problems, or when a mild congenital subglottic stenosis has been overlooked. Any systemic condition that diminishes capillary perfusion (e.g., shock, anemia) or that increases the susceptibility to infection (e.g., diabetes, immunosuppression) will aggravate the subglottic damage caused by the indwelling ET tube.24,25

Ch031-F06861.indd 364

In the acute stage, hyperemia and edema of the vocal folds, ulcerated troughs at the medial surface of the arytenoids with flanges of granulation tissue, and swelling or ulceration of the subglottic mucosa may all explain the reasons for failed extubation (Benjamin, 1993).26 Before planning a tracheotomy, a conservative treatment always is attempted to avoid the development of cicatricial stenosis of the larynx and subglottis. In suspension microlaryngoscopy, endolaryngeal granulation tissue is gently removed with a biopsy forceps, and the child is reintubated with a tube that is one size smaller (e.g., soft Portex ET tube). An endolaryngeal plug of corticosteroid-gentamicin ointment is then applied around the tube to the endolarynx and subglottis, and systemic antibiotics and corticosteroids are given for 5 to 7 days. A tentative extubation is made 2 to 4 days later. If a tracheotomy is deemed unavoidable at this stage, then it is placed as close as possible to the subglottis to avoid any further damage to the normal trachea. Whenever possible, the larynx does not remain unstented because acute lesions of intubation will evolve into contracting scars, leading to subglottic stenosis or posterior glottic stenosis.

DIAGNOSIS Infants and children with mild to moderate (<60% reduction in luminal size) subglottic stenosis may become symptomatic only during exercise or upper respiratory tract infection. They present with inspiratory stridor, dyspnea, and marked suprasternal and intercostal retractions. Recurrent or prolonged episodes of croup indicate possible subglottic stenosis and warrant an endoscopic evaluation (Box 31-1). In cicatricial stenosis, the endoscopic evaluation of the larynx and trachea provides all of the information required for the preoperative workup. Vocal fold mobility is assessed by transna-

Box 31-1 Preoperative Assessment Endoscopy ■ Transnasal fibroscopy in spontaneous respiration to assess vocal fold mobility and potential extralaryngeal sites of obstruction (nasooropharynx, tracheostoma) ■ Rigid direct laryngotracheoscopy to assess location, extension, and size of subglottic stenosis and tracheostoma ■ Suspended microlaryngoscopy in case of vocal fold immobility to differentiate a neurogenic paralysis from a cicatricial fixation of the vocal folds ■ Esophagoscopy and 24-hour pH monitoring to detect gastroesophageal reflux ■ Bronchoesophagoscopy in all congenital subglottic stenoses to rule out associated mediastinal anomalies Patient’s General Condition ■ Obtain full medical history on the potential cause of the subglottic stenosis, including the cause for long-term intubation. ■ Assess cardiopulmonary condition especially in children with a history of prematurity. ■ Obtain full evaluation of multiple congenital anomalies, including a neurologic examination and a test of swallowing function.

1/21/2008 11:08:03 AM

Chapter 31 Subglottic Resection: Infants and Children

sal fiberoscopy with mask ventilation in deep sevoflurane anesthesia and spontaneous ventilation. This examination also provides information on the patency of the nose, the choanae, the nasopharynx, and the oropharynx (Fig. 31-1). Differentiating vocal fold immobility due to a neurogenic cause from an interarytenoid fibrous adhesion is done by

A

365

carefully inspecting the posterior commissure of the larynx using a 30-degree, angled telescope and by direct palpation of the arytenoid cartilages during suspension microlaryngoscopy. The systematic use of Lindholm’s self-retaining vocal cord retractor (Storz No. 8654 B) helps differentiate bilateral vocal fold paralysis from posterior glottic stenosis (Fig. 31-2).

B

FIGURE 31-1 Transnasal laryngotracheal fiberoscopy with mask ventilation. A, External view: in small children, this technique allows a thorough evaluation of extralaryngeal obstructions, vocal fold mobility, and tracheal dynamics in spontaneous respiration. B, Internal view: grade III subglottic stenosis with intact vocal folds.

A

B

FIGURE 31-2 Use of the self-retaining vocal folds retractor to assess arytenoid mobility. A, Vocal folds retractor. B, Spreading of posterior commissure with the self-retaining vocal folds retractor displays the scar tissue of a posterior glottic stenosis.

Ch031-F06861.indd 365

1/21/2008 11:08:03 AM

366

Section 2 Upper Airway

A

B

FIGURE 31-3 Endoscopic assessment of subglottic stenosis. A, Direct laryngotracheoscopy with a 0-degree bare telescope. The larynx is exposed with an intubation laryngoscope. The 0-degree bare telescope is used to assess the location, extension, and size of the stenosis. Examination to the carina is possible without mucosal trauma and risk of worsening a dyspneic, nontracheotomized child. B, Endoscopy report for subglottic stenosis. Precise measurements with reference to the vocal folds, tracheostoma, and carina need to be given in all cases, including the number of residual normal tracheal rings. A precise surgical strategy is made at that time, taking all parameters into account: vocal fold mobility, extension and degree of stenosis, location of tracheostoma, length of residual normal trachea, and segments of tracheomalacia.

A fixed arytenoid raises the suspicion of fibrous ankylosis of the joint, but in the most difficult cases this diagnosis is only safely made during open surgery. Location, extent, and degree of stenosis are assessed using a bare magnifying telescope and the intubation laryngoscope while the patient is under general anesthesia and fully relaxed. The exact location of the stenosis, with respect to the vocal folds, the tracheostoma, and the carina, is measured in millimeters and with respect to the number of residual normal tracheal rings above and below the tracheostoma (Fig. 31-3). The degree of the stenosis is measured by passing telescopes, endotracheal tubes, or bougies of different sizes through the stricture. In the pediatric community, the Myer-Cotton27 airway grading system is routinely used. This system classifies subglottic stenosis in four grades and helps predict the rate of success after LTRs because the less severe grades (I and II) have a far better outcome than do the most severe grades (III and IV), which correspond to a subtotal or total obstruction (Table 31-1). For PCTR, this grading system is not useful as a predictor of success or failure because the stenotic segment is fully resected. The endoscopy report also mentions the presence of any localized tracheomalacia as well as a possible infection of the airway. A bacteriologic smear is routinely taken.

Ch031-F06861.indd 366

TABLE 31-1 Myer-Cotton Airway Grading System Grade

Obstruction

I

0%-50%

II

51%-70%

III

71%-99%

IV

No lumen

Data from Myer CM, O’Connor DM, Cotton RT: Proposed grading system for subglottic stenosis based on endotracheal tube sizes. Ann Otol Rhinol Laryngol 103:319-323, 1994.

Finally, in the presence of congenital subglottic stenosis, a bronchoesophagoscopy is performed to rule out a mediastinal malformation (e.g., tracheoesophageal fistula, tracheobronchial anomalies, extrinsic vascular compression of the airway).22 If precise description and measurements of the stenosis are obtained from the endoscopy, then radiographs add little to the preoperative workup. However, lateral soft tissue and anteroposterior high kilovoltage radiographs, or CT scans with three-dimensional reconstructions, are useful in docu-

1/21/2008 11:08:08 AM

Chapter 31 Subglottic Resection: Infants and Children

menting the length of the segment to be resected in cases of complete stenosis of the airway. When a malformation of the mediastinum is suspected, CT and MRI are the examinations of choice.28 Finally, if a single-stage operation is planned, then pulmonary function tests and neurologic evaluation are considered, especially in children with malformations or previous longterm intubation for neonatal dyspnea of different causes. Gastroesophageal reflux disease is systematically ruled out or actively treated if present.

MANAGEMENT Indications PCTR is the procedure of choice for the treatment of severe subglottic stenosis (>70% luminal obstruction) of congenital or acquired etiology, but it is generally advisable to wait until the child reaches 10 kg of body weight before surgery is undertaken. The latter is performed as a single-stage operation (with concomitant resection of the tracheostoma during the surgery) when the stenosis is purely subglottic and the child is otherwise healthy. In children with multiple congenital anomalies or with impaired neurologic or cardiopulmonary function, a double-stage PCTR (with postoperative maintenance of the tracheostoma) is preferable. If the subglottic stenosis is combined with glottic involvement such as posterior glottic stenosis, cicatricial fusions of the vocal cords, anterior laryngeal web extending into the subglottis, or distortion of the laryngeal framework resulting from failed LTRs, then PCTR is supplemented with a posterior cricoid split and costal cartilage graft that need stenting and maintenance of the tracheostoma until a complete healing of the subglottic area is obtained. This procedure is called extended PCTR (Box 31-2).

Anesthetic Technique Jet Ventilation for Nontracheotomized Children In nontracheotomized children, the induction of anesthesia is done by mask ventilation with sevoflurane, followed by fentanyl and vecuronium. The stenosis is dilated with tapered bougies, and the child is intubated with the largest nasotracheal tube that will pass the stenosis. Because the stenosis will be resected, the trauma induced to the subglottis by dilation has no adverse consequence on the final outcome. Anesthesia is maintained with propofol, fentanyl, and

Box 31-2 Patient Selection ■ Single-stage PCTR for grade III or IV subglottic stenosis in an oth-

erwise healthy child ■ Double-stage PCTR for grade III or IV subglottic stenosis in children

with compromised neurologic or cardiopulmonary functions and/or multiple congenital anomalies ■ Double-stage extended PCTR with stenting for grade III and IV subglottic stenosis associated with cicatricial or congenital glottic involvement

Ch031-F06861.indd 367

367

vecuronium as needed. Once the cricothyroid membrane is incised, the ET tube is withdrawn, and its tip is securely fixed with a Mersilene thread. A 10-Fr and 400-mm long catheter (external diameter: 3.3 mm) is passed through the tube and placed distally into the tracheal stump by the surgeon. Once the jet catheter is correctly placed, the ET tube is further withdrawn out of the operation field. Resection of the stenosis is then performed under excellent visual control because the jet catheter can easily be displaced out of the operation field. The stenotic segment is resected, and after the posterior anastomosis is completed, all sutures for the lateral and anterior anastomosis are placed. Just before the sutures are tied, the distal trachea is rinsed with saline to moisten the mucosa and clean blood and secretions from it, and the ET tube is pushed down into the trachea over the jet catheter, using the leading Mersilene thread. The jet catheter is withdrawn, and normal ventilation is ensured through the ET tube repositioned beyond the anastomosis. All sutures are then tied with the knots on the outside.29

Conventional Ventilation System in Tracheotomized Children This setup is used in tracheotomized children whose tracheostomas will be resected during the same procedure. Two sets of ventilation tubes are prepared before draping the patient: one on the thorax for ventilation through the tracheostoma and another at the head of the patient for ventilation through a nasotracheal tube. The whole dissection and resection of the stenosis is done while the patient is ventilated through the tracheostoma. The nasotracheal tube is passed through the larynx, and its tip is securely fixed with a Mersilene thread. The tube is then withdrawn into the pharynx to provide a free operative field to the surgeon. The sutures of the posterior anastomosis and two lateral cricotracheal stitches are placed and tied while the child is still ventilated through the tracheal stump. Then, using the leading Mersilene thread, the nasotracheal tube is pushed beyond the posterior anastomosis into the distal trachea, and the remainder of the lateral and anterior sutures are placed with the knots tied on the outside.29

Operative Technique Purely Subglottic Stenosis The procedure is performed with the neck fully extended (Fig. 31-4). A collar incision is usually made at the level of the second tracheal ring. In tracheotomized children, a horizontal crescent-shaped excision of the skin is made around the stoma. The subplatysmal skin flaps are elevated, and the strap muscles are separated from the midline to provide exposure from the hyoid bone to the suprasternal notch. The isthmus of the thyroid gland is transected in the midline. The trachea is dissected anteriorly and laterally without identification of the recurrent laryngeal nerves by staying in close contact with the underlying cartilaginous rings. The vascular supply coming laterally from the tracheoesophageal grooves is always carefully preserved, especially in extensive mobilization of the distal trachea.

1/21/2008 11:08:10 AM

368

Section 2 Upper Airway

A

B

C

D

FIGURE 31-4 A, Resection lines for subglottic stenosis (lateral view). After careful preparation and mobilization of the trachea and larynx, the superior resection line is made at the inferior margin of the thyroid cartilage. The inferior resection line is carried out one ring below the first normal tracheal ring to harvest an anterior-pedicled wedge of cartilage that will be used to enlarge the subglottic lumen (see B and C). The lateral resection line is made just anterior to the cricothyroid joint on both sides. The recurrent laryngeal nerve is shown here for anatomic purposes only; it is deliberately not identified during the surgery. B, Oblique view of the subglottis after resection of the stenotic segment. After resection of the anterior arch of the cricoid, the fibrous tissue constituting the posterior aspect of the stenosis is fully resected. The uppermost posterior section of the mucosa passes immediately below the cricoarytenoid joints. The denuded cricoid plate is then flattened down with a diamond bur. This will allow a better adaptation of the tracheal stump to the subglottis. The cartilaginous wedge of anterior trachea will be used to enlarge the subglottic lumen. C, Partial inferior midline thyrotomy (frontal view). An inferior midline thyrotomy is carried out up to the anterior commissure of the vocal folds, without transecting it. This corresponds to half the distance from the thyroid notch to the inferior margin of the thyroid cartilage. The thyroid alae are easily spread apart in children to increase the subglottic lumen. The wedge of cartilage pedicled to the first normal tracheal ring (see B) is used to fill in the subglottic defect resulting from the inferior midline thyrotomy. Vicryl sutures (6-0 or 5-0) are used for the posterior anastomosis with the knots tied inside the lumen. D, Perioperative view of the anastomotic site during PCTR. The cartilaginous wedge pedicled to the tracheal stump is inserted into the triangular defect resulting from the inferior midline thyrotomy that has been spread apart. The 3- or 4-mm increase in circumference has a significant positive impact on the cross-sectional area of the subglottis, without compromising voice quality.

Ch031-F06861.indd 368

1/21/2008 11:08:10 AM

Chapter 31 Subglottic Resection: Infants and Children

E

369

F

FIGURE 31-4, cont’d E, Thyrotracheal anastomosis (lateral view). The first posterolateral stitch is passed between the first tracheal ring and the cricoid plate. The stitch should emerge in a subperichondrial plane from the outer surface of the cricoid plate to avoid any lesion to the recurrent laryngeal nerves. A second stitch, placed between the third tracheal ring and the inferior border of the cricoid plate, is used to release the tension at the site of the anastomosis. F, Completion of thyrotracheal anastomosis (oblique view). Except for the most posterolateral suture, which is placed between the trachea and the cricoid plate, all lateral and anterior stitches are passed between the tracheal ring and the thyroid cartilage. The adaptation of the large tracheal ring to the narrower subglottic space is facilitated by the enlargement of the subglottic lumen with a partial inferior midline thyrotomy. The triangular defect is then filled in with the cartilaginous wedge pedicled to the tracheal ring used for the anastomosis.

At the level of the cricoid arch, the cricothyroid muscles are sharply dissected from the underlying cartilage until the cricothyroid joint is identified bilaterally. After having placed stay sutures to the distal normal tracheal wall, the inferior resection line is made first at the lower end of the stenosis or at the level of the tracheostoma, if the latter is to be resected during the same surgical procedure. This allows a view of the stenosis from below and affords a good distal airway for ventilation. The membranous trachea is then dissected and separated from the anterior wall of the esophagus over a distance that corresponds to the height of the cricoid plate. Unnecessary extensive separation of the trachea from the esophagus is avoided. The advancement of the distal tracheal stump upward is achieved by freeing the cartilaginous rings from the mediastinal structures anteriorly and laterally only. Due to its elasticity, the esophagus will shorten spontaneously without anterior bulging. The superior incision is started at the inferior margin of the thyroid cartilage in front and is passed laterally just anterior to the cricothyroid joints. This results in the complete resection of the anterior cricoid arch, while avoiding injury to the recurrent laryngeal nerves that run posteriorly to the joint (see Fig. 31-4A). In the subglottis, the uppermost incision of the posterior mucosa is made just below the cricoarytenoid joints, and the submucosal fibrosis constituting the posterior aspect of the subglottic stenosis is fully resected, thus exposing the cricoid plate completely (see Fig. 31-4B). Because the luminal diameter of the distal airway is always much larger than that of the proximal subglottic resection line, the first normal tracheal ring used for the anastomosis must be adapted to the size of the subglottic lumen. In chil-

Ch031-F06861.indd 369

dren, the difference in diameter between the subglottic space and the tracheal stump is even more pronounced than it is in adults. Any attempt at reducing the caliber of the trachea is avoided. Instead, one enlarges the subglottic lumen as much as possible without compromising voice quality. This is best achieved by widening the cricoid plate posteriorly and laterally with a diamond bur and by performing an inferior midline thyrotomy up to the level of the anterior commissure of the larynx, without transecting it (see Fig. 31-4B and C). Because the thyroid cartilage is usually soft and pliable in infants and children, the inferior margins of both thyroid alae are easily spread apart. In this way, the subglottic lumen is enlarged considerably, while the anterior commissure is kept intact, thus preserving a good voice. The triangular defect is filled in with a mucosa-lined cartilaginous wedge that is obtained from the first normal tracheal ring below the resected stricture (see Fig. 31-4D). This requires an additional resection of the lateral portion of the first normal tracheal ring used for the anastomosis. The denuded cricoid plate is covered with the membranous trachea after its upward mobilization. Interrupted Vicryl sutures (6-0 or 5-0 in children) are used for the posterior anastomosis, with the knots tied inside the lumen. The disadvantage of having a few sutures tied inside the lumen posteriorly is largely compensated for by the optimal approximation of the mucosa that is difficult to obtain with the knots tied outside the lumen (see Fig. 31-4C). Fibrin glue is used to secure the membranous trachea to the cricoid plate. Depending on the child’s age, 4-0 or 3-0 Vicryl sutures are used for the anterior and lateral anastomosis. The first stitch is passed through the posterolateral aspect of the first normal tracheal ring and through the cricoid plate

1/21/2008 11:08:13 AM

370

Section 2 Upper Airway

the tracheostoma had been placed at the third or fourth tracheal ring. The absence of a postoperative tracheostoma is very favorable for the healing of the anastomosis, but longer tracheal resections carry greater risk of anastomotic dehiscence. If the location of the tracheostoma requires the resection of six or more tracheal rings, then it is preferable to use a steady and normal ring (situated between the subglottic stenosis and the upper pole of the tracheostoma) for the anastomosis and to close the tracheostoma separately or to keep it in the postoperative period. In some cases, owing to proxi-

laterally. It emerges in a subperichondrial plane from the outer surface of the cricoid plate to avoid any lesion to the recurrent laryngeal nerves. This stitch is extremely important and is placed as meticulously as possible to bring the mucosa of the subglottis in close contact with the mucosa of the trachea (see Fig. 31-4E). The thyrotracheal anastomosis is completed by placing the Vicryl sutures between the tracheal ring and the thyroid cartilage anteriorly, with the knots tied on the outside. A tension-releasing suture is also placed between the third or fourth tracheal ring laterally and the inferior border of the cricoid plate (see Fig. 31-4E and F). Various techniques of tracheal and supralaryngeal release may be used to diminish the tension on the suture line. This depends on the length of the tracheal segment to be resected and on the individual anatomy. Usually, the advancement of the distal tracheal stump upward is much easier in children than it is in adults. If necessary, a laryngeal release will suffice; hilar and pericardial mobilizations, sometimes used in adults, remain as exceptions in children. At the end of the procedure, the neck is maintained in a flexed position. Sutures placed from the chin to the chest are never used to limit the extension of the neck during the postoperative period, although this measure has been recommended by different authors (Fig. 31-5; Box 31-3).

Box 31-3 Operative Technique ■ Do not identify the recurrent laryngeal nerves but carry out the

■ ■ ■

■

Single-Stage Versus Double-Stage PCTR If the child is fit for a single-stage surgery, then two options usually exist, depending on the location of the tracheostoma. A single-stage PCTR with resection of the tracheostoma is chosen if no more than five tracheal rings must be resected with the subglottic stenosis. This was the case in 51 of 81 (63%) PCTRs performed at our institution and implied that

A

■

■

dissection of the lateral tracheal wall in close contact with the tracheal rings. Preserve the vascular supply to the trachea from the tracheoesophageal grooves. Stay anterior to the cricothyroid joints when resecting the cricoid arch to avoid injury to the recurrent laryngeal nerves. Remove all cicatricial tissue from the cricoid plate and flatten it down with a diamond bur to optimize proper adaptation of the tracheal ring used for the anastomosis. Keep an anterior cartilaginous wedge pedicled to the tracheal ring used for the anastomosis. Perform an inferior midline thyrotomy to enlarge the subglottic lumen and suture the anterior pedicled wedge of the trachea into the luminal defect. Perform a hyoid release when necessary to avoid tension at the suture line.

B

FIGURE 31-5 Single-stage partial cricotracheal resection for subglottic stenosis. A, Preoperative view: grade III subglottic stenosis without glottic involvement. B, Postoperative view 8 months after surgery: The subglottic lumen is widely patent, and the trachea is normal. The tracheostoma has been resected with the stenosis during the surgery (single-stage operation).

Ch031-F06861.indd 370

1/21/2008 11:08:15 AM

Chapter 31 Subglottic Resection: Infants and Children

mal damage of the trachea, insufficient steadiness of the upper tracheal rings prevents their use for the anastomosis. A longer tracheal resection must then be envisaged with a laryngeal release procedure. This was the case in only 11/81 (14%) infants and children in our sample. It is noteworthy that 2/11 (18%) children in this group sustained an anastomotic dehiscence, compared with 2/40 (5%) children who had a shorter tracheal resection among the 51 patients who underwent a single-stage PCTR at our institution.

Extended PCTR for Subglottic Stenosis Combined With Glottic Pathologic Processes Initially used for purely subglottic stenosis, partial cricotracheal resection with primary thyrotracheal anastomosis has proved to be very efficient also for the cure of combined

A

D

Ch031-F06861.indd 371

B

E

371

subglottic and glottic pathologies (posterior glottic stenosis; cicatricial fusion of the vocal cords; anterior glottic web extending into the subglottis; combined supraglottic, glottic, and subglottic scarring; and distortion of the larynx after failed LTR) (Fig. 31-6). The surgical procedure, extended PCTR, is then modified as follows. A complete laryngofissure is created, and the posterior cricoid plate is divided in the midline up to the transverse interarytenoid muscle. If the latter is embedded in scar tissue, then it is transected without injuring the underlying pharyngeal mucosa (see Fig 31-6A). The two parts of the posterior cricoid are then sufficiently distracted to allow the correct positioning of the costal cartilage harvested from the seventh or eighth rib (see Fig. 31-6B). The graft must be flush with the cricoid plate, with the perichondrium facing the lumen. Lateral flanges of perichondrium on the luminal side and small cartilaginous exten-

C FIGURE 31-6 Extended partial cricotracheal resection. A, PCTR is performed according to the conventional technique. A temporary midline thyrotomy gives access to the cricoid plate. B, A posterior midline incision of the cricoid plate is made and a costal cartilage graft is interposed between the two parts of the posterior cricoid (blue arrow). C, A pedicled flap of membranous trachea is obtained by removing one or two more rings of the tracheal stump distally. This also allows the delineation of the anterior cartilaginous wedge that will be used to fill in the triangular defect resulting from the inferior midline thyrotomy. D, The trachea is advanced upward (blue arrow), and its membranous portion is sutured to the mucosa of the posterior commissure of the larynx. E, The lateral and anterior anastomosis is completed as in conventional PCTR with a pedicled wedge of tracheal cartilage filling in the triangular defect of the inferior midline thyrotomy. Precise repositioning of the anterior commissure is essential to preserve a good voice when suturing both alae of the thyroid cartilage together.

1/21/2008 11:08:17 AM

372

Section 2 Upper Airway

sions of the graft under the cricoid plate help stabilize the graft that is fixed in place with 4-0 Vicryl sutures. By resecting one or two additional rings of the tracheal stump distally, a pedicled flap of membranous trachea is created (see Fig. 31-6C). The trachea is then advanced upward, and its membranous portion is sutured with 5-0 or 6-0 Vicryl sutures to the mucosa of the posterior commissure of the larynx (see Fig. 31-6D). The lateral and anterior anastomosis is completed as in conventional PCTR using 4-0 or 3-0 Vicryl sutures. A fully mucosalized anastomosis is thus obtained (see Fig. 31-6E). The closure of the laryngofissure over a nasotracheal tube or a stent is performed meticulously by placing a 3-0 Vicryl suture exactly at the level of the vocal cords to restore a sharp anterior commissure. We currently use a newly designed laryngotracheal stent (Easy LT-Mold) that conforms to the inner laryngeal contours to restore the closest to normal laryngotracheal airway. This prosthesis exists in 10 different sizes (6-15 mm in diameter) for use in children and adults30 (Fig. 31-7). The cartilaginous wedge pedicled to the tracheal ring that is used for the anastomosis is inserted between the alae of the thyroid cartilage inferiorly to enlarge the subglottic lumen without compromising voice quality (see Fig. 31-4D). Next, the isthmus of the thyroid gland is resutured in the midline, over the anastomosis, to optimize the vascular supply (Fig. 31-8).

are given to all patients for a minimum of 10 days or until a mucosalized anastomosis is obtained. Corticosteroids are started only on the day before extubation and continued for the following days, if necessary. Depending on the child’s age, a first control endoscopy is performed at 5, 7, or 10 days postoperatively. If there is only mild to moderate edema of the vocal folds and subglottis, then the child is tentatively extubated. Heliox (a mixture of helium and oxygen) is sometimes used to diminish the inspiratory stridor resulting from the postoperative laryngeal edema. In the case of significant edema, the child is reintubated with a one-size-smaller tube, and a plug of corticosteroid-gentamicin ointment is applied to the endolarynx. The next tentative extubation is planned for 2 days later. Additional endoscopic controls are routinely performed at 3 weeks and 3 months. The final result may then be optimized at 3 months by gentle bougienage with Savary-Gilliard dilators.

Box 31-4 Postoperative Care ■ Give broad-spectrum antibiotics and antireflux medication until a

mucosalized anastomosis is obtained. ■ Keep the child sedated or paralyzed in the ICU for single-stage

PCTR with nasotracheal intubation. ■ Attempt extubation at day 5 or 7 after single-stage PCTR. ■ Perform control endoscopies before extubation and any reintuba-

POSTOPERATIVE CARE

tion but routinely at 3 weeks and 3 months postoperatively.

After surgery, nontracheotomized children stay under close supervision in the ICU until extubation is achieved (Box 31-4). Broad-spectrum antibiotics and antireflux medications

■ Do not dilate the anastomotic site before the sixth postoperative

week.

FIGURE 31-7 Laryngotracheal mold (Easy LTMold) for splinting the airway after extended PCTR. A, Made of soft silicone, the Easy LT-Mold is designed to fit the inner laryngeal contours in the abducted position of the vocal cords, namely, for the treatment of posterior glottic stenosis. During the surgery, the prosthesis is cut at the appropriate length. A silicon cap is then glued to the inferior edge of the prosthesis to avoid any trauma to the suprastomal region. B, The LT-Mold is securely fixed with transtracheal sutures, and the child is ventilated through the cannula (double-stage PCTR).

A

Ch031-F06861.indd 372

B

1/21/2008 11:08:23 AM

Chapter 31 Subglottic Resection: Infants and Children

A

C

If a double-stage PCTR is performed without stenting, then no clinical information on subglottic airway patency is available because the child breathes through the tracheostoma. A control endoscopy at the third postoperative week is then mandatory to assess the quality of healing at the site of the anastomosis. To salvage a suboptimal result (i.e., beginning of restenosis), a laryngeal stent (LT-Mold) is placed endoscopically. In extended PCTRs and double-stage PCTRs with stenting, the tracheostoma is left in place until complete healing of the subglottic anastomosis is obtained. Stenting is usually necessary for about 3 weeks. However, depending on the complexity of the reconstruction after extended PCTR, stenting is sometimes maintained for up to 6 months or

Ch031-F06861.indd 373

373

B

FIGURE 31-8 Glotto-subglottic stenosis with bilateral cricoarytenoid joint fixation. A, Preoperative view: grade III subglottic stenosis associated with bilateral cricoarytenoid joint fixation. B, Supraglottic aspect of the LT-Mold 3 months after surgery. Note the absence of granulation tissue. C, Endoscopic view immediately after stent removal: widely patent glotto-subglottic airway. A suprastomal collapse is visible distally at the site of the tracheostoma.

longer, especially after reconstruction of distorted larynges resulting from previous failed LTRs.

COMPLICATIONS Injury to the recurrent laryngeal nerves generally is not a problem if the principles of the operation are carefully respected.31 In the series of 81 pediatric PCTRs performed at our institution,18 we never encountered this complication. In the literature it is reported to be less than 5% (Grillo, 2004).32 The concern of interference with normal laryngotracheal growth is now elucidated (Jaquet et al, 2005)18; all 20 patients who have been observed for more than 10 years have shown

1/21/2008 11:08:24 AM

374

Section 2 Upper Airway

normal development of their laryngotracheal airway, including 13 patients who have now reached adulthood. Partial dehiscence of the anastomosis only represents a potential complication if an extensive tracheal resection is needed. It is commonly reported that only one third of the length of a child’s trachea should be resected. Nevertheless, it has been our experience and that of Longaker and colleagues,33 that almost half of the trachea can be resected without adverse consequences. A laryngeal release procedure helps solve the problem in most instances. In infants and children we have never had to use a hilar or pericardial mobilization procedure. Minor anastomotic granulations are quite frequent (∼18% in our own series of 81 pediatric PCTRs) but rarely need endoscopic intervention unless they compromise airway patency. Overly aggressive excision with lasers is avoided because this can worsen the initial condition. Gentle removal with a biopsy forceps is the preferred method. Unfortunately, the most difficult situations in airway reconstructions always result either from failed previous LTRs or from misplacement of the stoma at the time of the tracheotomy. Better education of the medical community helps surgeons minimize undue tracheal damage by placing the tracheotomy through the stenosis in tracheal strictures and as close as possible to the subglottis (through the first tracheal ring) in laryngosubglottic stenosis.32 Another major problem is related to multiple congenital anomalies in some infants and children. A thorough preoperative evaluation including neurologic and cardiopulmonary examinations, as well as the search for gastroesophageal reflux, is performed before any surgery. A staged procedure is certainly preferable in these cases and with formerly premature children suffering from respiratory insufficiency owing to bronchopulmonary dysplasia, if one wishes to avoid severe postoperative complications.

INTERNATIONAL EXPERIENCE Starting in the early 1990s,11,12 successful PCTRs for the treatment of severe subglottic stenosis in infants and children have steadily been reported, with an overall decannulation rate of 91% (157/172 patients) for grade III and IV stenoses (Table 31-2). Analyzing these reports from a variety of countries (Jaquet et al, 2005; Rutter et al, 2001)11,15-19 in a more accurate way TABLE 31-2 International Experience With Pediatric Partial Cricotracheal Resection Author (Year)

No. Patients

Decannulation Rate

Ranne et al11 (1991)

7

7/7

Vollrath et al17 (1999)

8

8/8

16

(2000)

10

10/10

15

(2001)

Triglia et al

Rutter et al

44

38/44

Alvarez-Neri et al19 (2005)

22

20/22

Jaquet et al18 (2005)

81

74/81

Total (as of 2005)

172

Ch031-F06861.indd 374

157/172 (~91%)

reveals a high success rate of 98% (94/96 patients) for primary pediatric PCTRs (i.e., no previous airway surgery). This result drops to only 93% (42/45 patients) for salvage PCTRs, namely PCTRs performed after prior failed airway reconstructions. Altogether, decannulation rates are largely superior to laryngotracheal reconstructions with costal cartilage grafts, which are still used by many pediatric surgeons and otolaryngologists for the treatment of severe subglottic stenosis in infants and children (Cotton et al, 1995).34-37 For complex laryngotracheal stenoses, in which the subglottic stenosis is combined with severe glottic or supraglottic involvement (i.e., posterior glottic stenosis, acquired cicatricial fusion of the vocal cords, distorted larynx after failed LTR), the reported success rate of two centers that have addressed this problem with extended PCTRs is only 63% (Rutter et al, 2001)15 and 74% (Jaquet et al, 2005),18 respectively. This reflects the challenge of treating some of these extremely complex cases that have undergone several prior open surgeries. It is hoped, however, that by using the technique of extended PCTR and stenting with the LT-Mold,30 better results will be obtained as more experience is gained in the future. To address the problem of acquired total (grade IV) subglottic stenosis in children, Gustafson and coworkers (Gustafson et al, 2001)38 reported their experience in 56 patients. Using LTR with costal cartilage grafts, they achieved a decannulation rate of only 67% (14/21 patients) in the 1980s. This result increased to 81% (13/16 patients) in the 1990s with more expertise and refinements of LTR techniques. Although still in the learning phases in the 1990s, the same medical group immediately achieved a 92% (11/12 patients) decannulation rate with PCTRs. This single institution’s experience (pioneer since the 1970s in pediatric LTRs) clearly demonstrates the superiority of PCTR over LTR for the treatment of severe (grade III and IV) subglottic stenosis. Their results are very similar to our own experience with 19 grade IV subglottic stenoses treated by PCTR and followed up for more than 2 years, in which we achieved a decannulation rate of 95% (18/19 patients). It is noteworthy that more than a single procedure was necessary in 68% of the cases to reach the aforementioned results with LTRs, whereas only 18% of the cases needed a second open procedure to achieve decannulation with PCTR (Gustafson et al, 2001).38 In our own series, a second surgery was necessary in only 1 (5%) of 19 patients. Although pediatric surgeons and otolaryngologists have long been reluctant to use the technique of PCTR for the treatment of subglottic stenosis in infants and children, it is now clearly established that this technique has become the gold standard for the treatment of grade III and IV subglottic stenosis in the pediatric age group, as stated by a consensus paper from three European centers (Bailey et al, 2003).39

FUTURE PERSPECTIVES The unresolved issues are currently related to subglottic stenoses combined with vocal fold immobility and/or extensive tracheal damage.

1/21/2008 11:08:27 AM

Chapter 31 Subglottic Resection: Infants and Children

Posterior glottic stenosis without cricoarytenoid joint fixation can be treated with PCTR and resection of the interarytenoid fibrous tissue, or possibly with a posterior cricoid split and costal cartilage graft (extended PCTR). A pedicled flap of membranous trachea is then used to cover the denuded cricoid plate or the cartilage graft (see Fig. 31-6). In case of bilateral cricoarytenoid ankylosis combined with subglottic stenosis, the end result currently represents a trade-off between airway patency and quality of voice. Remobilizing the arytenoid cartilages by opening and deliberately freeing the cricoarytenoid joints is attempted because this cannot further compromise the situation of initially fixed arytenoids. The medial aspect of the cricoarytenoid joints is then covered by a pedicled flap of the membranous trachea that is sutured to the interarytenoid mucosa. This reconstruction needs stenting with a soft LT-Mold.30 In case of failure, a vocal fold lateralization procedure or a laser arytenoidectomy can be envisaged in a second stage. The risk of bronchial aspiration in these frozen larynges, however, is not to be underestimated. A discussion of the problem of extensive tracheal damage that requires the resection of more than one half of the trachea is beyond the scope of this chapter. Tracheal replacement, although still largely experimental,40 has been reported to be successful in one adult patient undergoing a complex reconstruction procedure.41 However, no information exists on the growth potential of this type of reconstruction, and long-term follow-up and reliability of the procedure are still pending. This type of reconstruction cannot yet be proposed in children.

SUMMARY In pediatric severe subglottic stenosis, PCTR with primary thyrotracheal anastomosis represents a real breakthrough in the surgical armamentarium to resolve this difficult problem. A decannulation rate of more than 90% can be expected in primary and salvage PCTRs. Similar and generally good results may be expected if the surgery is performed meticulously with magnifying glasses. The use of a steady normal tracheal ring for the anastomosis and the placement of stitches in a submucosal plane to obtain a fully mucosalized anastomosis in the subglottic area are of the utmost importance. Problems still exist when the subglottic stenosis is associated with extensive tracheal damage or with bilateral crico-

Ch031-F06861.indd 375

375

arytenoid ankylosis. For the latter, PCTR can be combined with a posterior costal cartilage graft (extended PCTR) covered by a flap of membranous trachea or with a vocal fold lateralization procedure in a second stage. Currently, the decannulation rate for these cases is still around 70%, but with more expertise and better laryngotracheal stents further improvements can be anticipated in the future. Last, pediatric surgeons and otolaryngologists need to carefully learn the technique of PCTR for use in infants and children to achieve better results than with LTRs.

COMMENTS AND CONTROVERSIES The foregoing chapter represents an outstanding, well-illustrated, lucid presentation of the problems associated with subglottic airway stricture and the techniques and strategies utilized to provide a single-stage repair. The challenging problems that these strictures present, and the techniques used to treat them, are all directly applicable to the adult population. This chapter should be the standard reference source for thoracic surgeons and their otolaryngologic colleagues who specialize in surgery of the upper airway. J. D. C.

KEY REFERENCES Bailey M, Hoeve H, Monnier P: Pediatric laryngotracheal stenosis: A consensus paper from three European centers. Eur Arch Otorhinolaryngol 260:118-123, 2003. Benjamin B: Prolonged intubation injuries of the larynx: Endoscopic diagnosis, classification and treatment. Ann Otol Rhinol Laryngol 160(Suppl):1-15, 1993. Cotton RT, Myer CM, O’Connor DM, Smith ME: Pediatric laryngotracheal reconstruction with cartilage grafts and endotracheal tube stenting: The single-stage approach. Laryngoscope 105:818-821, 1995. Grillo HC: Postintubation stenosis. In Surgery of the Trachea and Bronchi. Hamilton, Ontario, BC Decker, 2004, pp 301-339. Gustafson LM, Hartley BEJ, Cotton RT: Acquired total (grade IV) subglottic stenosis in children. Ann Otol Rhinol Laryngol 110:16-19, 2001. Jaquet Y, Lang F, Pilloud R, et al: Partial cricotracheal resection for pediatric subglottic stenosis: Long-term outcome in 57 patients. J Thorac Cardiovasc Surg 130:726-732, 2005. Maddaus MA, Toth JL, Gullane PJ, Pearson FG (1992): Subglottic tracheal resection and synchronous laryngeal reconstruction. J Thorac Cardiovasc Surg 104:1443-1450, 2005. Rutter MJ, Hartley BEJ, Cotton RT: Cricotracheal resection in children. Arch Otolaryngol Head Neck Surg 127:289-292, 2001.

1/21/2008 11:08:27 AM

chapter

TRACHEAL RESECTION

32

Robert E. Merritt Douglas J. Mathisen

Key Points ■ Diseases of the trachea that require surgical resection and

■ ■ ■ ■ ■ ■ ■

reconstruction include idiopathic tracheal stenosis, postintubation injuries, and primary tumors of the trachea. Simple radiologic techniques without use of contrast medium will delineate most pathologic conditions of the trachea. Bronchoscopy is invaluable in determining the extent of airway disease preoperatively. Tracheal strictures need to be serially dilated with pediatric rigid bronchoscopes before endotracheal intubation. Dissection of the trachea remains close to its lateral border to avoid injury to the recurrent laryngeal nerves. The tracheal anastomosis is done with interrupted absorbable suture material (4-0 Vicryl). Anastomotic tension is minimized by neck flexion and traction sutures (2-0 Vicryl). A strap muscle flap is interposed between the tracheal anastomosis and the innominate artery.

HISTORICAL NOTE The early development of tracheal surgery focused on the utilization of prosthetic material because it was believed that there was a finite amount of trachea that could be resected. Dacron, glass, stainless steel mesh, and polytetrafluoroethylene were all investigated as tracheal prosthetic replacements.1-8 Although there was some success achieved in the laboratory, the clinical application of prosthetics resulted in separations, occlusions from granulations, erosions, and infection. Concurrent with investigation of prosthetic replacement for the trachea was the evolution of resection and primary resection of the trachea. The earliest reports of tracheal resection and reconstruction described limited tracheal resections of 2 cm or less. Grillo and colleagues investigated the limits of tracheal resection in human cadavers that would allow primary reconstruction without tension and compromise of blood supply.9,10 With standard tension of 1000 to 1200 g, it was possible to resect a median length of 4.5 cm (seven rings). The other important issue to be resolved concerning resection of the trachea had to do with the lateral blood supply. Miura and Grillo determined that the blood supply of the upper trachea predominately comes from the inferior thyroid artery.9 The lower trachea and carina were supplied by bronchial arteries. These studies concluded that mobilization of the trachea is best accomplished by anterior and posterior dissection to preserve the lateral vascular pedicles.

These early investigations of the extent of tracheal resection, methods of mobilization, limits of tension, and preservation of blood supply allowed primary resection and reconstruction to become a viable option for treatment of most diseases of the trachea. It is now possible to primarily resect and reconstruct up to 50% of the adult trachea. Patient body habitus, prior surgery, disease process, and age greatly influence the extent of tracheal resection and reconstruction.

INDICATIONS Diseases of the trachea that require surgical resection and reconstruction encompass idiopathic tracheal stenosis, postintubation injuries, and primary tracheal tumors. Idiopathic tracheal stenosis describes an entity that involves the exclusion of all known and defined causes of non-neoplastic inflammatory stenosis, which occurs predominately in women. Tracheal resection and reconstruction for this rare entity was described by Grillo and colleagues in a retrospective review of 49 patients.11 They used a procedure also reported by Pearson and colleagues in 1975 (Pearson et al, 1975).12 Tracheal stenosis is the most common postintubation injury to the trachea. These injuries occur at the level of the tracheal stoma or at the level of tracheal cuff. Both of these injuries result from proliferative and cicatricial response to tracheal injury. Patients with tracheal stenosis have signs and symptoms of upper airway obstruction: dyspnea on exertion, wheezing, stridor, and obstructive pneumonia. The presentation of tracheal stenosis is often confused with adult-onset asthma; therefore, corticosteroid therapy is often initiated before the correct diagnosis is ascertained. Primary tracheal tumors are rare. It is estimated that tracheal tumors occur at a rate of approximately 2.7 new cases per 1 million population per year.13 The rarity of these tumors often leads to a delay in diagnosis and inappropriate treatment. Squamous cell carcinoma and adenoid cystic carcinoma account for two thirds of primary tracheal tumors. Our institution reported a large series of 198 patients in which 74% of patients underwent resection and reconstruction of primary tracheal tumors.13

PREOPERATIVE ASSESSMENT Before tracheal resection and reconstruction are undertaken, the definitive diagnosis of the underlying pathology of the airway must be established. A preoperative assessment includes a history and physical examination, radiologic imaging, and bronchoscopy. Relatively simple radiologic techniques without use of contrast medium will delineate most

376

Ch032-F06861.indd 376

1/21/2008 11:09:59 AM

Chapter 32 Tracheal Resection

pathologic conditions of the trachea.14 Radiographs can show the location of a lesion, its linear extent, any extratracheal involvement, and the amount of normal trachea (Fig. 32-1). A lateral neck view, using soft tissue technique with the patient swallowing and hyperextension of the neck, will bring the trachea above the clavicles, defining the anatomy of the upper trachea. CT offers little advantage over standard radiologic techniques for benign disease; however, in malignant

377

disease, CT effectively defines the extramural extent of the tumor and lymphadenopathy. Bronchoscopy is invaluable in determining the extent of airway disease preoperatively. The initial evaluation is performed with a rigid bronchoscope carefully inserted through the vocal cords just proximal to a point of stenosis. The rigid bronchoscope can be utilized to measure the length of a stenotic segment of trachea as well as to assess the mucosa for

B

A

C

D

FIGURE 32-1 A, Fluoroscopic spot film on inspiration shows diffuse narrowing of the tracheal lumen (arrowheads). B, Fluoroscopic spot film on expiration shows partial reconstitution of the lumen (arrows). C, Oblique view of the trachea shows stenosis in the middle third of the trachea with smooth, tapered margins. D, Oblique tomographic study of the trachea delineates tracheal stenosis in the middle third with slightly irregular margins due to granulation tissue.

Ch032-F06861.indd 377

1/21/2008 11:09:59 AM

378

Section 2 Upper Airway

inflammatory changes and granulation tissue.15 Measurements from a fixed point, usually the incisors, are made of the carina, bottom of the pathology, top of the pathology, and the vocal cords. These measurements estimate the length of the lesion and how much trachea is available for reconstruction. A rigid bronchoscope can usually be passed beyond most tracheal tumors, facilitating biopsy and core out of the tumor. Patients with tracheal tumors and postintubation stenosis may present with airway obstruction. Crucial to the management of all diseases of the trachea is the ability to control the airway. Control of the airway is best accomplished in the operating room with an assortment of rigid bronchoscopes.15 Attempting to pass a large rigid bronchoscope beyond a tight inflammatory stricture is usually difficult and can result in tracheal rupture or total airway obstruction from bleeding and edema. Jackson dilators passed through the rigid bronchoscope under direct vision and graduated rigid bronchoscopes (pediatric No. 3, 4, 5, 6) can be used effectively to serially dilate postintubation strictures. Racemic epinephrine and corticosteroids are often administered for 24 to 48 hours to minimize postdilation edema. Dilation of malignant or inflammatory strictures is only a temporizing measure. In the case of inflammatory stricture, restenosis usually develops within days to weeks. Dilation of tracheal strictures emergently reestablishes the airway and allows a more thorough evaluation of the patient. Tracheal resection can then be performed electively. By improving the airway, patients on high doses of corticosteroids for presumed asthma can have the corticosteroids tapered and discontinued. This allows tracheal resection to proceed without concern for impaired healing (Mathisen, 1998).16

ANESTHESIA Anesthesia for tracheal reconstruction is best administered by halothane or enflurane inhalation.17 A slow and gradual induction is usually necessary if there is a high degree of airway obstruction. This approach is preferable and safer than the paralysis of respiration with consequent urgent need to establish an airway. The surgeon needs to have available an array of rigid bronchoscopes during induction of anesthesia to control the airway. The residual airway through which a patient is breathing may measure as little as 2 to 3 mm in diameter. In most cases, dilation or core out via rigid bronchoscopy can establish enough of an airway to allow the anesthesiologist to insinuate a small endotracheal tube past a highly obstructing tumor or inflammatory stricture. Total intravenous (IV) anesthesia is also well suited for tracheal resection. This process decouples ventilation and the delivery of anesthesia and prevents the contamination of the operating room with inhalation agents. Total IV anesthesia is advantageous because it blunts airway reflexes well, and its effects wear off quickly at the completion of the operation. Remifentanil and propofol are delivered by infusion and are excellent agents commonly employed with total IV anesthesia.18 During resection of the trachea, the airway is divided and the distal end of the trachea can be directly intubated with

Ch032-F06861.indd 378

a flexible endotracheal tube (Tovell tube) by the surgeon on the surgical field. This technique allows ventilation during reconstruction of the trachea. Before completion of the tracheal anastomosis, a small endotracheal tube is retrieved from the proximal trachea and passed distal to the suture line. Ideally, it is possible for the patient to be extubated and breathe spontaneously at the conclusion of the operative procedure. It is not desirable to have even a low-pressure cuff in close contact with the anastomosis for any period of time. If the patient does require intubation after surgery, a small uncuffed endotracheal tube is preferred. The tube is removed within 48 to 72 hours. If the airway is still a concern, a small tracheostomy is placed two rings below the anastomosis. The innominate artery and the tracheal anastomosis are protected by a strap muscle flap that is carefully sutured to the trachea.

SURGICAL TECHNIQUE The cervical or upper cervicomediastinal approach is employed for limited tumors of the upper trachea and for most benign strictures of the trachea at any level.19 The patient is usually anesthetized by inhalation agents, and a rigid bronchoscope is passed. A stricture less than 6 mm in diameter is dilated under direct vision with rigid pediatric bronchoscopes. If the stricture is more than 6 mm, an endotracheal tube may be placed proximal to the lesion. If the stricture is located in the subglottic area, the lesion usually requires dilation to allow passage of a small endotracheal tube. In the cases involving tracheal tumors, an endotracheal tube can be usually passed by most lesions. In rare instances, a circumferential tumor may need to be cored out to allow passage of an endotracheal tube. The trachea is explored through a collar incision, which may encompass an existing tracheal stoma (Fig. 32-2A). Skin flaps are raised with platysma to the cricoid cartilage superiorly and the sternal notch inferiorly. The medial margins of the strap muscles are elevated, and the anterior surface of the trachea is exposed from the cricoid cartilage to the carina. The thyroid isthmus is divided, dissected from the trachea, and retracted laterally with sutures. It is essential to keep the dissection close to the trachea to avoid injury to the back wall of the innominate artery. If the innominate artery is adherent to the trachea and requires dissection, a strap muscle flap is interposed between the artery and tracheal anastomosis. For lesions that are too far below the sternum to be accessible through a collar incision, the exposure can be increased by making a T-shaped incision in which the vertical arm extends downward to a point 1 cm below the sternal angle (see Fig. 32-2A). The sternum is divided to that point and separated with a pediatric chest spreader (see Fig. 32-2B). No additional useful exposure is obtained by full median sternotomy because the carina lies at the level of the angle of Louis and the great vessels obstruct access from an anterior approach. The upper sternal division provides access to the lower trachea. The innominate vein, which lies anterior and caudad to the dissection, is not divided. The tissues containing the innominate artery are dissected away from the trachea without exposing the wall of the artery. The anterior carina

1/21/2008 11:10:01 AM

Chapter 32 Tracheal Resection

A

B

C FIGURE 32-2 Tracheal resection and reconstruction for postintubation stenosis. A, A collar incision provides access for many upper tracheal lesions. For a wider access to the upper thoracic inlet and the mediastinum, a partial sternotomy is performed. Usually the incision is not carried more than 1 to 2 cm below the angle of Louis. This provides exposure even for the supracarinal benign stenosis. B, Partial sternotomy with retraction of innominate vein and artery without their exposure. The pretracheal plane is dissected only. Circumferential dissection is performed only just below the lesion. C, After placement of lateral traction sutures above and below the points of the tracheal transection and after circumferential dissection around the distal trachea just below the lesion, the specimen is divided from the trachea. Upward traction on the specimen permits safe dissection of the esophagus and lateral tissues away from the specimen without injury to esophagus or recurrent laryngeal nerves. Eventually the specimen is transected above the level of stenosis.

and the right and left tracheobronchial angles can be exposed as necessary (Mathisen, 1998).16 In cases of inflammatory stenosis, the dissection is made meticulously along the lateral borders of the involved trachea and posteriorly approximately 1 cm below the lesion (see Fig. 32-2C). If there is difficulty in identifying the level of the lesion, intraoperative bronchoscopy may be needed to localize the lesion. The position of the bronchoscope light is identified at the upper and then the lower end of the lesion

Ch032-F06861.indd 379

379

while an assistant pushes a 25-gauge needle through the tracheal wall at the site of the stenosis for precise localization. These levels are marked with fine sutures. Dissection close to the tracheal wall avoids injury to the recurrent laryngeal nerves, which lie in the tracheoesophageal groove on either side. The recurrent laryngeal nerves are vulnerable to injury and are best not exposed by keeping the dissection close to the tracheal wall. This is particularly important if the stenosis lies just below the cricoid cartilage because the recurrent laryngeal nerves enter the larynx just medial to the inferior cornua of the thyroid cartilages. As the trachea is dissected circumferentially, great care must be taken to avoid perforation of the esophagus or the membranous wall of the trachea posteriorly. After the circumferential dissection of the trachea is completed, a tape is passed beneath the trachea for traction on the airway. Before the division of the trachea, sterile anesthesia equipment is assembled on the field and sterile corrugated tubing is passed off the table to the anesthetist. Lateral traction sutures of 2-0 Vicryl are placed on either side of the trachea in the midlateral position approximately 1 cm below the anticipated level of transection. These sutures pass vertically through the full thickness of the tracheal wall and around one or more rings (see Fig. 32-2C). The trachea is opened anteriorly just distal to the lesion, staying close to the lesion if it is a benign stricture. Healthy cartilage needs to be present at the cut edge of the trachea. Transection of the trachea is generally between rings, but it is acceptable to make the incision in the cartilage. When the airway is open, continuous suctioning prevents seepage of blood into the distal airway. After transection, an assistant holds tension on the two lateral traction sutures and holds the flexible armored Tovell tube in the distal trachea. This maneuver draws the distal trachea and the ventilating tube away from the dissection. Circumferential dissection of the remaining proximal and distal trachea is limited to no more than 1 cm to protect the segmental blood supply, which enters laterally. Devascularization of the healthy trachea that will be anastomosed invites possible necrosis and possible anastomotic dehiscence. To test the ease with which the tracheal ends can be brought together, the anesthetist flexes the patient’s neck and the surgeons draw on the crossed proximal and distal traction sutures, bringing the tracheal ends together. An experienced surgeon is able to judge whether the tension is excessive. The length of trachea that may be safely removed obviously needs to be determined before division of the trachea. The feasibility of resection is based on radiologic and endoscopic examinations made before the operation. The length of trachea that can be safely removed is influenced by the patient’s age, body habitus, the anatomy of the trachea, and previous treatments. Once it has been demonstrated that the tracheal ends will come together without excessive tension, the neck is hyperextended again. The first anastomotic suture (4-0 coated Vicryl) is placed in the posterior midline with the knots to lie on the outside. The sutures are carefully clipped to the drapes (Fig. 32-3A). The next suture is placed lateral to this and clipped to the drapes just caudad to the previous one. The sutures are placed serially until a point is reached just posterior to the midline to the midlateral tracheal traction

1/21/2008 11:10:01 AM

380

Section 2 Upper Airway

C A

B FIGURE 32-3 A, Tracheal anastomosis. Sutures are placed individually beginning in the midline posteriorly and ranging anteriorly on either side. B, After the sutures are placed on either side up to the level of the midlateral traction sutures, the anterior sutures are then placed. Frequently, the endotracheal tube is not advanced from above until after all sutures have been placed. C, The neck is placed in the flexed position, and the lateral traction sutures are tied on either side (not shown) to remove tension from the anastomotic sutures. After this, anastomotic sutures are tied from anterior to posterior on either side. The completed anastomosis is air tight.

suture (see Fig. 32-3B). The same placement of sutures is now carried out on the opposite side, from the posterior midline to the midlateral suture. Serial sutures are similarly placed anteriorly, proceeding from the lateral traction sutures to the midline. The sutures are placed through the cartilage approximately 4 mm from the cut edge of the trachea and 4 mm apart. When all of the sutures are placed, the oral endotracheal tube is advanced from above until the tip is visible in the wound. The distal trachea is suctioned, and the endotracheal tube is advanced farther, resuming ventilation through the original oral endotracheal tube. Care must be taken not to entangle the endotracheal tube in the anastomotic sutures. The patient’s head is firmly supported on blankets in full flexion. The crossed lateral traction sutures are pulled together on either side and tied with surgeon’s knots apposing the tracheal ends. The anterior anastomotic sutures are tied first without tension, and the ends are cut after each suture is tied. The assistant now rotates the trachea by carefully drawing medially on the traction sutures on the surgeon’s side of the table. The surgeon ties the suture just behind the lateral traction suture and ties sutures in the direction of the posterior midline. This same technique is repeated on the opposite side (see Fig. 32-3C). The cut traction sutures are left in place to guard against tension on the anastomotic sutures. The integrity of the anastomosis is checked by submersing the wound in saline solution, deflating the tube cuff, and insufflating to between 20 and 30 cm H2O of pressure. The sternohyoid

Ch032-F06861.indd 380

muscle or the thyroid isthmus is used to cover the suture line. If there is any concern of scar tissue involving the innominate artery, a pedicled strap muscle can be interposed between the innominate artery and the trachea. Flat suction drains are placed in the pretracheal and substernal spaces, and the strap muscles are approximated in the midline. After the incision is closed, a heavy suture is placed through the submental skin crease beneath the chin and through the presternal skin. This suture is tied with the patient’s neck in moderate flexion to prevent sudden hyperextension of the neck in the first week after the operation. If it is determined after neck flexion that excessive anastomotic tension exists, maneuvers are performed to reduce tension. The most helpful maneuver for the upper and middle trachea is the Montgomery suprahyoid release. This can be done by exposing the hyoid through a small horizontal incision just over the hyoid. The muscles inserting on the superior aspect of the hyoid between the lesser cornu are divided. The hyoid bone is divided just lateral to the lesser cornu on both sides. This release maneuver usually gives between 1 and 2 cm of additional mobility of the trachea.20 After tracheal resection, patients are usually extubated as they awaken from anesthesia. If the airway is not satisfactory at this point, it is not likely to improve later unless the problem is caused by laryngeal edema. A small endotracheal tube with the cuff deflated can be left in place for 48 hours while the laryngeal edema resolves. The patient is given 24 to 48 hours of corticosteroids (dexamethasone [Decadron], 4 mg IV q6h); fluids are restricted, and the head is elevated to reduce edema. We prefer to return the patient to the operating room at the end of the 48 hours and perform extubation using anesthesia. If there is still a problem, a small tracheostomy tube is placed two rings below the anastomosis. A pedicled strap muscle flap is employed to cover the anastomosis if not already done.

COMPLICATIONS Complications after tracheal surgery are similar regardless of the problem for which resection and reconstruction is performed. The most in-depth analysis of complications after tracheal surgery was reported by Grillo and colleagues in patients with postintubation stenosis (Grillo et al, 1995).21 The complications reported in this series of 503 patients are summarized in Table 32-1. Granulation tissue formed at the site of tracheal anastomosis in 49 patients in the series. After 1978, when the suture material was switched from nonabsorbable Tevdek to absorbable Vicryl only five such cases have occurred. Thirty-eight of these patients were treated with bronchoscopic removal of granulation tissue, whereas 5 other patients required reoperation with a second tracheal resection. Four patients required tracheostomy, whereas 2 patients were treated with T tubes. A total of 29 patients had anastomotic dehiscence or restenosis. Seven patients with this complication died, and 2 patients also had an erosion into the innominate artery, resulting in death. Eight patients with anastomotic dehiscence were treated with repeat tracheal resection with either good or satisfactory results. Four other patients were treated with

1/21/2008 11:10:02 AM

Chapter 32 Tracheal Resection

TABLE 32-1 Complications of Operations for Postintubation Tracheal Stenosis Major

Minor

Total

Granulations Before 1978 After 1978

11 10 1

38 34 4

49 44 5

Dehiscence

28

1

29

Laryngeal dysfunction

11

14

25

Malacia

10

0

10

Hemorrhage

5

0

5

Edema (anastomosis)

3

1

4

Infection Wound Pulmonary

7 5

8 14

15 19

Myocardial infarction

1

0

1

Tracheoesophageal fistula

1

0

1

Pneumothorax

0

3

3

Line infection

0

1

1

Atrial fibrillation

0

1

1

Deep venous thrombosis Totals

0

1

1

82

82

164

permanent tracheostomy, and another 5 patients were treated with T tubes, three of which were temporary. Three patients developed a dehiscence of a small portion of the anastomosis. Two patients required reoperation and primary closure, and 1 patient was treated with cervical wound drainage and antibiotics. An additional 2 patients required repeated dilations. A total of 25 patients had varying degrees of laryngeal dysfunction (aspiration or vocal cord dysfunction) after tracheal resection and reconstruction. Fourteen of these patients had temporary laryngeal dysfunction that required no specific intervention. Eleven cases presented with more severe laryngeal dysfunction requiring either tracheostomy or T tube. Two patients in this series required gastrostomy tube feedings for persistent aspiration as a result of glottic dysfunction. Other complications included tracheal malacia and hemorrhage. Ten patients were found to have residual tracheal malacia requiring either a second tracheal resection or tracheostomy. Five patients developed bleeding from the innominate artery that resulted in three mortalities. Infectious complications occurred in 34 patients, which included 15 wound infections and 19 cases of pneumonia or bronchitis. There were 12 perioperative deaths, 7 of which were related to the complication of anastomotic dehiscence.

COMMENTS AND CONTROVERSIES This excellent and concise review of tracheal resection heavily reflects the major contributions made by Dr. Hermes Grillo, the authors’ former colleague and my mentor. Since my residency days at Massachusetts General Hospital working with Dr. Grillo, I have

Ch032-F06861.indd 381

381

also been fortunate to benefit from the contributions of Dr. F. G. Pearson and several outstanding ENT surgeons. Based on this experience, the following are some of the modifications I now employ: The use of the high-resolution CT scanner with three-dimensional reconstruction of the airway, using some modern software packages, creates a three-dimensional model of the airway from the larynx to the main bronchi, which can be rotated in all directions on the monitor. This type of imaging gives the best possible road map of the passageway one may encounter when trying to establish an airway for the first time in a patient who presents with critical stenosis. I strongly endorse the authors’ recommendation to visualize the location and the upper end of the narrowed segment using a flexible bronchoscope with the patient topically anesthesized and spontaneously breathing. If the patient’s situation prevents such preliminary visualization because of agitation, hypoxia, and so on, then the use of a laryngeal mask in a spontaneously breathing, sedated patient helps facilitate the flexible bronchoscopy. The laryngeal mask increases the inspired oxygen concentration and provides ventilatory assistance to the spontaneous breaths of the patient. Through the mask, the flexible bronchoscope can be used to assess the vocal cords and the airway down to the point of obstruction. This is then followed by removal of the mask and passage of the pediatric rigid bronchoscopes as advocated by the authors. When dividing the airway at the site selected, completely encircling the trachea, without injury to either the adjacent esophagus or to the membranous wall of the trachea, can sometimes be difficult. I therefore prefer division of the cartilaginous arch all the way back to the membranous trachea on both sides without first having dissected the membranous wall off the trachea. At this point, the endotracheal tube is withdrawn to a point proximal to the airway division and a high-frequency jet catheter, passed through the endotracheal tube, is passed distal to the opened trachea for continued ventilation. This gives excellent visualization of the membranous wall of the trachea, which can then be sharply and carefully incised and separated under direct vision from the esophagus both proximally and distally. If a major resection of the trachea is contemplated, such as for an adenoid cystic carcinoma or a long segment of tracheal stenosis, I often perform a suprahyoid (Montgomery) release, as described by the authors, before transecting the trachea. This release is relatively innocuous and is more easily accomplished before the trachea has been opened, when it is anticipated that a resection of four or more rings may be required. In the case of adenoid cystic tumors, providing the release initially allows one to progressively remove more of the trachea while determining the resulting tension required to bring the ends together before deciding whether to take yet another piece of trachea. As noted in Chapter 26, it is better to leave positive margins and employ postoperative radiation than to risk a failed resection and tracheal dehiscence caused by too much tension on the anastomosis. By performing the suprahyoid release initially, one can better judge the amount of trachea that can be safely resected without undo tension. When performing the tracheal anastomosis, I prefer to place and tie the posterior anastomotic sutures first under direct vision, rather than at the end after the cartilaginous sutures have been tied. The posterior sutures, of 4-0 Vicryl, are tied with the knots on the inside, after which the lateral and anterior sutures are placed and tied. The jet catheter,

1/21/2008 11:10:02 AM

382

Section 2 Upper Airway

placed through the endotracheal tube from above, is used for ventilation during placement and tying of the membranous sutures and the first three or four lateral sutures on either side. The remaining sutures are then placed and left untied with the continued use of the jet catheter. The endotracheal tube is then advanced from above into the distal trachea for continued ventilation while securing the previously placed sutures in the anterior portion of the anastomosis. The suture guide, used for cardiac valve replacement operations, is very useful for keeping the tracheal anastomotic sutures as they are being placed, prior to subsequent tying of the sutures. After resection of a tracheal stricture or tumor involving the midportion of the trachea, it is uncommon to require placement of a tracheostomy at the end of the procedure. However, for an anastomosis done in the subglottic region, I increasingly employ a size 4 mini-tracheostomy tube inserted through a small skin incision in the lower skin flap and use the needle-guidewire-dilator kit supplied with the mini-tracheostomy. The mini-tracheostomy is placed before closing the wound and produces only a very small opening in the anterior tracheal wall, which is generally air tight and does not lead to contamination of the wound in the postoperative period. After skin closure, as the patient is emerging from anesthesia, the endotracheal tube is removed and replaced with a laryngeal mask.

Ch032-F06861.indd 382

This permits flexible bronchoscopy through the laryngeal mask to assess vocal cord function and to evaluate the anastomosis, as the patient is awakening. For a detailed description of laryngotracheal resection for subglottic lesions, the reader is referred to Chapters 30 and 31. J. D. C.

KEY REFERENCES Gaissert HA, Grillo HC, Shadnehr BM, et al: Laryngotracheoplastic resection for primary tumors of the proximal airway. J Thorac Surg 129:1006-1009, 2005. Grillo HC: Surgery of the Trachea and Bronchi. Hamilton, Ontario, BC Decker, 2004. Grillo HC, Donahue DM, Mathisen DJ, et al: Postintubation tracheal stenosis: Treatment and results. J Thorac Cardiovasc Surg 109:486493, 1995. Mathisen DJ: Surgery of the trachea. Curr Prob Surg 35:458-542, 1998. Pearson FG, Cooper JD, Nelems JM, Van Nostrand AWP: Primary tracheal anastomosis after resection of cricoid cartilage with preservation of recurrent laryngeal nerves. J Thorac Cardiovasc Surg 70:806815, 1975.

1/21/2008 11:10:02 AM

chapter

CARINAL RESECTION

33

Marc de Perrot Elie Fadel Philippe Dartevelle

Key Points ■ Careful patient selection and detailed evaluation of the lesion are

key to good surgical results in carinal resection. ■ The safe limit of resection between the lower trachea and the

contralateral main bronchus is about 4 cm. This is particularly important if a right carinal pneumonectomy is performed and the left main stem bronchus is to be reanastomosed end-to-end to the distal trachea. ■ Close cooperation between the anesthetist and the surgeon is important because of the need for adequate surgical exposure and simultaneous control of the airway.

Refinement in techniques of tracheal surgery and bronchial sleeve lobectomy has made carinal resection and reconstruction possible. However, the potential for complications remains high, and only a few centers have accumulated sufficient expertise to safely perform the operation. Surgery is still infrequently proposed because of the complexity of the operation and the paucity of data demonstrating benefit in the long term. However, results from recent series demonstrate that carinal resection is safe in experienced centers, with an operative mortality rate of less than 10%, and can be associated with good to excellent long-term survival in selected patients. The current results are considerably better than those from earlier reported series and most likely reflect the improvements in surgical and anesthetic techniques. Careful patient selection and detailed evaluation are also important requirements for good surgical results.

HISTORICAL NOTE In 1946, Belsey1 described a successful case of lateral wedge resection of the distal trachea and carina combined with the use of prosthetic material for reconstruction. In 1950, Abbott2 presented four patients undergoing right pneumonectomy associated with lateral resection of the tracheal wall and transverse closure above the right main bronchus. All four patients survived the operation but had problems with kinking and obstruction of the trachea that were related to excessive mediastinal shift, according to the author. In the same year, Mathey3 reported resection of a benign tumor of the carina without resection of pulmonary parenchyma. Reconstruction was accomplished by approximating the medial walls of the right and left main bronchi to one another to create a new carina with the trachea.

Barclay and colleagues4 reported the first carinal resection with complex reconstruction for a relapsing adenoid cystic carcinoma and a bronchogenic carcinoma in 1957. Through a right thoracotomy, the left main bronchus was transected with maintenance of anesthesia by left lung intubation; the trachea was divided distally and the right main bronchus proximally. The distal trachea was anastomosed end-to-end to the right main bronchus, and the left bronchus end-to-side to the bronchus intermedius, with interrupted silk sutures. A pneumoperitoneum was performed on the sixth postoperative day “to ease any strain on the suture lines.” Chamberlain and colleagues,5 Gibbon,6 and Hardin and Fitzpatrick7 described in 1959 successful resections of primary bronchogenic carcinomas involving the carina, and Grillo and associates8 presented in 1963 the first comprehensive approach to carinal resection and reconstruction. In 1966, Thompson and colleagues9 reported a left carinal pneumonectomy with anastomosis between the right main bronchus and the distal trachea using catgut sutures. Mathey and coworkers10 also presented their experience in 1966; they suggested that circumferential carinal resection be preferred to noncircumferential excision. Other significant reports of carinal resection and reconstruction included those by Eschapasse and associates,11 Perelman and associates,12 Jensik and coworkers,13 and Dartevelle and colleagues.14

PREOPERATIVE EVALUATION Careful patient selection and detailed evaluation of the lesion are key components to good surgical results in carinal resection. All patients are evaluated to ascertain that they can tolerate the operation and withstand the necessary removal of pulmonary parenchyma. The preoperative workup consists of chest radiography, chest computed tomography (CT), pulmonary function tests, arterial blood gas analysis, ventilation-perfusion scanning, electrocardiography, and echocardiography. Stress thallium studies, maximum oxygen uptake, and exercise testing are used when indicated. The operation is an elective procedure, and efforts are made to prepare the patients for surgery with chest physiotherapy, deep breathing, and cessation of smoking. Airway obstruction, bronchospasm, and intercurrent pulmonary infection are reversed. Steroids are discontinued before surgery. Flexible and/or rigid bronchoscopy is crucial to evaluate the overall length of the tumor, the adequacy of the remaining airway, and the feasibility of a tension-free anastomosis. In addition to routine investigation to rule out extrathoracic metastasis for patients with bronchogenic carcinoma, we also routinely perform a mediastinoscopy at the time of surgery 383

Ch033-F06861.indd 383

1/21/2008 11:11:12 AM

384

Section 2 Upper Airway

in patients presenting with bronchogenic carcinoma to exclude N2 or N3 disease. Pulmonary angiography is performed for carinal tumors arising from the anterior segment of the right upper lobe because invasion of the right upper lobe (mediastinal) artery usually indirectly reveals invasion of the posterior aspect of the superior vena cava (SVC) (Fig. 33-1). Superior cavography is performed if the SVC is potentially involved (Fig. 33-2). Transesophageal echography is occasionally performed to evaluate tumor extension to the posterior mediastinum, especially the esophagus or the left atrium.

INDICATIONS AND CONTRAINDICATIONS The safe limit of resection between the lower trachea and the contralateral main bronchus is usually considered to be 4 cm. This is particularly important if a right carinal pneumonectomy is performed and the left main stem bronchus is to be reanastomosed end-to-end to the distal trachea. Upward mobilization of the left main stem bronchus is limited because of the aortic arch and can easily result in excessive anastomotic tension. However, if carinal resection alone is planned, the resection may be more extensive because of the possibility of greater mobilization of the right lung unhindered by the aortic arch and the possibility of hilar release on the right and on the left sides if a median sternotomy is used. In patients with bronchogenic carcinoma, carinal resection is considered for tumors invading the first centimeter of the ipsilateral main bronchus, the lateral aspect of the lower trachea, the carina, or the contralateral main bronchus. This applies usually for right-sided tumors because left-sided tumors rarely extend up to the carina without massively invading structures situated in the subaortic space. The longterm results of carinal resection for patients with bronchogenic carcinoma and N2 or N3 disease is poor, so the finding of positive mediastinal nodes at the time of mediastinoscopy is usually considered a contraindication to surgery. Induction therapy may be offered for these patients, but we have found that it increases the technical difficulty of the operation and is associated with greater operative mortality, particularly if carinal pneumonectomy is required.

ANESTHESIA

FIGURE 33-1 Pulmonary angiogram demonstrating occlusion of the right upper lobe (mediastinal) artery (arrow), which indirectly suggests invasion of the posterior aspect of the superior vena cava.

FIGURE 33-2 CT showing a tumor arising from the anterior segment of the right upper lobe and invading the superior vena cava (same patient as in Figure 33-1).

Ch033-F06861.indd 384

Close cooperation between the anesthetist and the surgeon is important because of the need for adequate surgical exposure and simultaneous control of the airway. Ventilation during carinal resection has always been a major concern. Abbott2 recommended use of a long tube pushed through the divided end of the trachea into the left main bronchus, and Bjork and colleagues15 emphasized the role of the doublelumen tube. However, double-lumen tubes are rigid and cumbersome, rendering their introduction distal to the carina difficult. A major advance was made by Grillo and associates8 in 1963; they suggested ventilation of the distal airway by a sterile tube passed by the anesthetist across the operating field. El-Baz and coworkers16 advocated a high-frequency jet ventilation, delivering a small tidal volume at a rate of 100 to 150 respirations per minute. McClish and colleagues17 proposed continuous oxygen delivery through a high-flow catheter, but this approach can lead to carbon dioxide retention. Roviaro and colleagues18 described the use of a long, thin endotracheal tube of 45 cm with a small, self-inflating cuff that does not leak if accidentally pierced. Our technique is similar to that of Grillo and colleagues.8 The patient is initially intubated with an extra-long, armored oral endotracheal tube that can be advanced into the opposite bronchus if one-lung ventilation is desired. Once the carina has been resected, the opposite main bronchus is intubated with a cross-field sterile endotracheal tube connected to a sterile tubing system. The tube can be safely removed intermittently to place the sutures precisely. Any blood spillage

1/21/2008 11:11:12 AM

Chapter 33 Carinal Resection

into the contralateral lung is carefully suctioned to preserve the lung. Once the trachea and the bronchus are ready to be approximated, the cross-field tube is withdrawn, and ventilation is resumed with the original oral tube after the anastomosis is completed. If a secondary end-to-side anastomosis is required between the other bronchus and the lateral trachea, the oral tube is advanced across the first anastomosis, and ventilation can proceed uninterrupted until the secondary anastomosis is completed. Carinal resection must always be planned without cardiopulmonary bypass. In our experience with more than 100 carinal resections for carcinoma, only three patients have required the emergency use of cardiopulmonary bypass during the operation (de Perrot et al, 2006).19 Two of these patients developed intraoperative pulmonary edema of the left lung, and cardiopulmonary bypass was started to avoid any significant tension on the suture lines during the anastomotic procedure. The third patient had major bleeding from the right main pulmonary artery that required the institution of cardiopulmonary bypass to be fixed. None of the remaining 116 patients required cardiopulmonary bypass to undergo carinal resection.

SURGICAL TECHNIQUE Approaches The incision varies according to the type of carinal resection. Carinal resection without sacrifice of pulmonary parenchyma is approached through a median sternotomy. The pericardium is opened anteriorly, and the tracheobronchial bifurcation is exposed between the SVC and the ascending aorta. The exposure is facilitated by completely mobilizing the ascending aorta and both main pulmonary arteries. The ligamentum arteriosum is systematically sectioned. As previously reported by Pearson and associates (Pearson et al, 1984),20 we find that this approach offers several advantages over a right posterolateral thoracotomy. It allows any type of pulmonary resection, including a left pneumonectomy; it can provide access to a cervical collar incision for a laryngeal or suprahyoid release procedure; and it affords access to both a right and a left pulmonary hilar release if found to be necessary intraoperatively. Carinal resection with sacrifice of pulmonary parenchyma is best approached through an ipsilateral thoracotomy in the fifth intercostal space. On the right side, the lower trachea and the origin of both main bronchi are easily exposed. On the left side, however, exposure of the lower trachea and right main bronchus is hindered by the aortic arch. After division of the ligamentum arteriosum, the carina may be exposed by mobilizing the aortic arch, with or without sacrifice of the first two intercostal vessels. Bilateral thoracotomies, clamshell incision, and median sternotomy have also been reported for left carinal pneumonectomy with various successes. The clamshell incision provides an excellent exposure but requires opening of the contralateral pleura, necessitates more postoperative analgesia, and has the potential risk of pseudoarthrosis of the sternum. It is justified only for patients who are young and fit. The median sternotomy is our preferred approach for left carinal pneumonectomy. It

Ch033-F06861.indd 385

385

provides superb exposure to the tracheobronchial bifurcation, causes less incisional discomfort, and results in less ventilatory restriction than a thoracotomy. The main disadvantages are that it can be difficult to free pleuroparietal adhesions, and mobilization of the left hilum requires cardiac retraction that can cause some hemodynamic instability.

Anastomotic Technique The tracheobronchial anastomosis is usually performed in an end-to-end fashion first. Our technique consists of applying a running 4-0 polydioxanone (PDS) suture on the deepest aspect of the airway with respect to the surgeon. For instance, in right carinal pneumonectomy, this represents the left aspect of the cartilage wall of the trachea and left main bronchus. The running suture is then tied at each end with two independent PDS sutures whose knots are made outside the lumen. Thereafter, several interrupted stitches of 4-0 PDS or 3-0 Vicryl are placed in the remaining part of the anastomosis. They are tied after all of them have been placed, to correct for size discrepancies. The stitches applied on the membranous portion are tied at the end to avoid any traction and potential tears. If an end-to-side anastomosis is required, the lateral side of the trachea is opened in an ovoid fashion, with the size corresponding to the size of the bronchus to be implanted. The opening is performed at least 1 cm away from the first anastomosis and is placed on the cartilaginous part of the trachea or bronchus, to avoid any devascularization of the initial anastomosis and to provide additional rigidity to the end-to-side anastomosis. Again, a running suture of 4/0 PDS is used for the posterior part, and interrupted stitches of 4-0 PDS or 3-0 Vicryl are used for the anterior part of the anastomosis. The development of anastomotic complications is likely due to technical factors at the time of airway resection and reconstruction. Careful dissection and precise placement of anastomotic sutures limits tissue trauma and avoids devascularization of the anastomotic site. In addition, airway resection is limited to a maximum of 4 cm at the carinal level, particularly if a right carinal pneumonectomy is performed and the left main stem bronchus is to be reanastomosed endto-end to the distal trachea. Upward mobilization of the left main stem bronchus is limited because of the aortic arch and can result in excessive anastomotic tension.

Release Maneuvers Dissection of the pretracheal plane is always performed (usually at the time of the mediastinoscopy) to reduce the tension at the anastomotic site. Hilar release is performed with a U-shaped incision of the pericardium, starting on the anterior pericardium behind the phrenic nerve at the level of the upper pulmonary vein, coming down below the inferior pulmonary vein, and rising up behind the pulmonary veins along the posterior pericardium up to the pulmonary artery. This allows the hilar structures to advance by about 2 cm upward, reducing the anastomotic tension. Additional length may be gained by completely incising the pericardium around the hilar vessels. We do not find that laryngeal or supralaryngeal release is useful to reduce the anastomotic tension at the

1/21/2008 11:11:13 AM

386

Section 2 Upper Airway

FIGURE 33-3 Carinal resection with creation of a neocarina by anastomosing the right and left main bronchi together.

B A

FIGURE 33-4 A, Lines of carinal resection. Techniques of reconstruction can involve end-to-end anastomosis between the trachea and left main bronchus with end-to-side anastomosis of the right main bronchus into the distal trachea (B).

B

A C

level of the carina, and we do not routinely use a chin stitch in these patients.

TYPES OF CARINAL RESECTION Carinal Resection Without Pulmonary Resection Carinal resection without pulmonary resection is limited to tumors located at the carina or at the origin of the right or left main bronchus. Depending on the extent of invasion, different modes of reconstruction exist. For very small tumors implanted on the carina only, the medial walls of the main bronchi can be approximated together to fashion a new carina that is then anastomosed to the trachea (Fig. 33-3). The main

Ch033-F06861.indd 386

problem with this reconstruction is that the neocarina has very limited mobility because of the aortic arch, and therefore the trachea needs to be pulled down to the newly created carina. If the tumor is more extensive and requires that a larger portion of the trachea be resected, end-to-end plus end-toside anastomoses is the method of choice. Various methods of reconstruction have been described, according to the length of resection of the trachea and the right and left main bronchi (Figs. 33-4 and 33-5). The technique described by Barclay and colleagues4 involves end-to-end anastomosis between the trachea and right main bronchus, with end-toside anastomosis of the left main bronchus across the medi-

1/21/2008 11:11:13 AM

Chapter 33 Carinal Resection

B

387

FIGURE 33-5 A, Lines of carinal resection. If the right or left main bronchus is too short to reach the distal trachea without tension, the end-to-side anastomosis can be performed between the left main bronchus and the bronchus intermedius (B) or between the right main bronchus and the left main bronchus (C).

A C

astinum into the bronchus intermedius (see Fig. 33-5). This reconstruction is possible only if the right main bronchus remains sufficiently long, but it presents difficult access for the end-to-side anastomosis, often requiring hypoventilation of the right lung. Grillo and colleagues8 described anastomosis of the left main bronchus into the lateral wall of the trachea after an end-to-end anastomosis between the trachea and the right main bronchus. This technique is rarely indicated and is technically very demanding. Eschapasse and associates11 described the inverted technique of Barclay. The reconstruction is made by an end-to-end anastomosis between the left main bronchus and the lower trachea; then, depending on the length of the remaining right main bronchus, an end-to-side anastomosis is made between the right and left main bronchi (see Fig. 33-5), or between the right main bronchus and the lower trachea 1 cm above the first anastomosis (see Fig. 33-4). In our experience, the right main bronchus can usually be anastomosed to the lateral wall of the trachea after adequate release maneuvers, regardless of the residual length of the right main bronchus.

Right Carinal Pneumonectomy Right carinal pneumonectomy is the most frequent type of carinal resection for bronchogenic carcinoma (Fig. 33-6). No irrevocable step is taken until resection is certain. After division of the azygos vein, the tracheobronchial bifurcation is gently mobilized and dissected. Dissection is limited to the anterior surface of the lower trachea, preserving the lateral blood supply as much as possible. Umbilical tapes are passed around the distal trachea and contralateral main bronchus (Fig. 33-7). The hilum and esophagus are then dissected, and the esophagus is retracted posteriorly. If there is no SVC involvement, the pulmonary artery and veins are stapled at

Ch033-F06861.indd 387

FIGURE 33-6 Right carinal pneumonectomy is the most frequent type of carinal resection for bronchogenic carcinoma.

their extrapericardial origin, so that the lung is attached by the main bronchus only. Subsequently, the cross-field intubation system is installed. The trachea and contralateral main bronchus are divided by sharp, straight transection lines. The trachea is always sectioned first, to provide better exposure to section the left main bronchus. To accomplish a tension-free anastomosis, it is crucial to limit the length of resection between the distal trachea and left main bronchus to less than 4 cm. Frozen sections are obtained on the tracheal and bronchial margins.

1/21/2008 11:11:17 AM

388

Section 2 Upper Airway

The decision to resect further trachea or bronchus or to leave residual tumor at the bronchial margin in case of positive margins is balanced by the necessity to perform a tension-free anastomosis. Enlarged subcarinal nodes can be resected, but otherwise the soft tissue around the carina needs to be preserved as much as possible to ensure adequate vascularization of the anastomosis and good lymphatic drainage from the contralateral lung. After the anastomosis is completed, the endotracheal tube is pulled back a sufficient distance from the suture line to avoid any damage from the tip of the tube, and the anastomosis is checked for air-tightness. The anastomosis is then covered by the surrounding tissue. If segmental resection of the SVC is planned, the vascular procedure is usually performed before division of the airway. The SVC is clamped proximally at the confluence of the

Trachea

Tumor

Carina

Left main bronchus

brachiocephalic veins and distally at the cavoatrial junction, then divided on each side of the tumor. Section of the SVC facilitates exposure and stapling of the right pulmonary artery in the interaorto-caval groove. The SVC is reconstructed with a ringless, straight, size 18 or 20 polytetrafluoroethylene (PTFE) graft. The PTFE graft is protected with gauze soaked in Betadine during reconstruction of the airway to prevent graft contamination.

Carinal Resection With Lobar Resection Occasionally, the bronchogenic tumor can extend from the right upper lobe to the carina and lower trachea. The fissure is completed first, and the vessels for the right upper lobe are ligated and sectioned before the lower trachea and carina are divided as for a right carinal pneumonectomy. The bronchus intermedius is then transsected below the takeoff of the right upper lobe bronchus. The middle and right lower lobes can be preserved if the resection margins are negative for tumor on frozen sections. After the anastomosis between the trachea and the left main bronchus is completed, the bronchus intermedius is then anastomosed 1 cm below the initial anastomosis to the left main bronchus (Fig. 33-8). Mobilization of the pulmonary ligament and a right hilar release are always required to limit the tension on the anastomosis. Occasionally, the bronchus intermedius can be anastomosed to the lateral wall of the trachea if the tension on this anastomosis is not excessive.

Left Carinal Pneumonectomy

FIGURE 33-7 Operative picture showing umbilical tapes around the distal trachea and left main bronchus.

FIGURE 33-8 Carinal resection with resection of the right upper lobe. The bronchus intermedius is transected below the takeoff of the right upper lobe bronchus (A) and anastomosed end-to-side to the distal trachea (B) or to the left main bronchus (C) after completion of the end-to-end anastomosis between the trachea and the left main bronchus.

The aortic arch greatly hinders performance of the anastomosis in left carinal pneumonectomy and renders the procedure technically challenging through a left thoracotomy. A one-step procedure with mobilization of the aortic arch,

B

A C

Ch033-F06861.indd 388

1/21/2008 11:11:20 AM

Chapter 33 Carinal Resection

however, is preferred to a two-stage approach in which a left proximal pneumonectomy with positive bronchial margin is followed 2 to 3 weeks later by resection of the carina through a right thoracotomy or a sternotomy. Based on our experience, we have favored a median sternotomy over a left thoracotomy in the past few years if a left carinal pneumonectomy is anticipated. Exposure of the carina and main bronchi through a median sternotomy requires a transpericardial approach. The anterior pericardium is divided vertically to permit circumferential mobilization of the ascending aorta and aortic arch. The ascending aorta is then encircled and retracted laterally to the patient’s left. The key to an adequate exposure of the left main bronchus through a median sternotomy is to perform a large mobilization of the ascending aorta and aortic arch and to divide the ductus arteriosus (Fig. 33-9). Then, excellent exposure of the mediastinal trachea and carina can be displayed by encircling and retracting the SVC to the right and the right main pulmonary artery inferiorly. The posterior pericardium can then be divided vertically to improve accessibility to both the right and left main bronchi (Fig. 33-10). The left mediastinal pleura is opened anteriorly, below the sternal edge, to access the left pleural space and perform the left pneumonectomy. The hilum is dissected to expose the left pulmonary artery and both pulmonary veins. The pericardium can be opened anteriorly and posteriorly around the hilum to improve exposure and facilitate stapling of both pulmonary veins and the pulmonary artery. The pericardial opening is limited around the hilum and closed at the end of the procedure to avoid luxation of the heart into the left chest. The left lung can then be removed after transection of the distal trachea and right main bronchus. An end-to-end

389

anastomosis between the trachea and right main bronchus is performed. The left pleura is then closed to contain fluid accumulation into the pleural space. The anastomosis can be covered with surrounding tissue and the anterior pericardium closed. The left pleural space and the pericardium are drained separately.

POSTOPERATIVE CARE The anastomosis is always controlled by bronchoscopy at the end of the procedure, and secretions are cleaned up from the airways. All patients are extubated in the operating room or shortly after arrival in the recovery room. Pain relief is achieved with epidural analgesia or patient-controlled analgesia. Inadequate epithelial ciliary motility of the residual lung usually occurs after resection of the carina, but this can be controlled by adequate chest physiotherapy and occasionally repeated aspiration via flexible bronchoscopy in the first few days postoperatively. A temporary tracheostomy can be performed to reduce the physiologic respiratory dead space and facilitate direct aspiration whenever the predicted residual ventilatory functional reserve is borderline or the patient’s collaboration is reduced. The tracheostomy is performed early in the postoperative period to prevent possible complications. The most catastrophic complication is the development of noncardiogenic pulmonary edema. This complication usually occurs within the first 72 hours after surgery. Its cause is unknown, but ventilator-induced trauma and excessive fluid administration during the surgical procedure are often quoted as the main risk factors. Other risk factors for the development of postoperative pulmonary edema may include preoperative alcohol abuse, silent postoperative aspiration, and/or interference with lymphatic drainage. Once it develops, few patients are able to recover. Fluid restriction, diuretics, frequent bronchoscopy, and noninvasive ventilation are occasionally helpful to avoid reintubation and overcome the problem.

Right main bronchus

Trachea Aorta

SVC

FIGURE 33-9 The transsternal transpericardial approach to the carina offers an excellent view to the tracheal bifurcation if the ascending aorta is largely mobilized up to the aortic arch and the ductus arteriosus is sectioned.

Ch033-F06861.indd 389

FIGURE 33-10 Operative view of the transsternal transpericardial approach. The aorta is retracted to the left and the superior vena cava (SVC) to the right. Umbilical tapes encircle the distal trachea and right main bronchus.

1/21/2008 11:11:24 AM

390

Section 2 Upper Airway

The development of a bronchopleural fistula is another potentially fatal complication. Prevention includes early and close bronchoscopic monitoring of any ischemia or necrosis of the tracheobronchial anastomosis. If dehiscence occurs, the airway is secured by placing a single-lumen tube in the main bronchus of the remaining lung, beyond the anastomotic dehiscence, to ventilate and protect the lung from aspiration. Depending on the size of the dehiscence, the pneumonectomy space is drained either by closed chest tube drainage or by open thoracostomy, our preferred method. We have found that the best method to prevent and mitigate the development of a tracheobronchial fistula in high-risk patients requiring a carinal pneumonectomy (e.g., if an empyema has occurred preoperatively due to postobstructive pneumonia) is to fill the pleural cavity with the latissimus dorsi and serratus anterior muscles harvested before the pleural space is entered and to perform at the end of the procedure a limited tailored thoracoplasty. This method can avoid empyema of the postpneumonectomy space and limit the impact of partial tracheobronchial dehiscence.

RESULTS The results of carinal resection for bronchogenic carcinoma have improved over time. Recent series have shown that carinal resection is relatively safe in experienced centers and can be associated with good long-term survival in selected patients. The operative mortality rate ranges between 7% and 10% in recent series, and the 5-year survival rate varies between 33% and 44% (Table 33-1). In our experience, a total of 119 patients underwent carinal resection for carcinoma between 1981 and 2004.19 There were 99 men and 20 women, with a median age of 55 years (range, 36-73 years). Indications for surgery were non–small cell lung carcinoma (NSCLC) in 100 patients, adenoid cystic carcinoma in 8, neuroendocrine carcinoma (carcinoid tumor) in 5, mucoepidermoid carcinoma in 4, and metastatic renal cell carcinoma in 2. The operative mortality rate after carinal resection for carcinoma was 7.6% overall and 8.3% after right carinal pneumonectomy. Eight out of 9 deaths occurred after right carinal pneumonectomy and were caused by pulmonary edema and/or anastomotic dehiscence. Right carinal pneumonectomy was performed in 96 patients. Seven patients underwent a left carinal pneumonectomy through a left thoracotomy (n = 3) or through a median sternotomy (n = 4). Two patients underwent carinal pneumonectomy through a median sternotomy 3 and 4 weeks after

Author (Year)

Operative Mortality (%)

5-Yr Survival (%)

Mitchell et al21 (2001)

60

Rovario et al23 (2006)

53

7.5

33

100

7.6

44

19

de Perrot et al

Ch033-F06861.indd 390

(2006)

10

Right atrial anastomosis

Azygos vein

TABLE 33-1 Recent Series of Carinal Resections for Bronchogenic Carcinoma

No. Patients

a left pneumonectomy performed in another center. Both of these patients were referred to us because of a positive microscopic bronchial margin of the left main bronchus at the time of pneumonectomy. Three patients had carinal resection associated with a right upper lobectomy; the bronchus intermedius was reimplanted into the side of the trachea (n = 2) or into the side of the left main bronchus (n = 1). A total of 11 patients had carinal resection without lung resection. The carina was usually reconstructed with an endto-end anastomosis of the left main bronchus into the trachea and an end-to-side anastomosis of the right main bronchus into the trachea (n = 8). In one patient, the left main bronchus was too short to reach the trachea without tension, so the right main bronchus was anastomosed end-to-end to the trachea and the left main bronchus end-to-side to the bronchus intermedius. In two patients, the carina and the right main bronchus were partially resected, and the left main bronchus was anastomosed end-to-side to the defect. SVC resection was combined with a right carinal pneumonectomy in 25 patients with bronchogenic carcinoma. The SVC was completely resected en bloc with the tumor in 13 patients and was reconstructed with PTFE graft sized 16 (n = 1), 18 (n = 9), or 20 (n = 3). The SVC cross-clamp time ranged between 15 and 45 minutes (median, 23 minutes). The remaining 12 patients had only partial resection of the SVC and did not require graft interposition. One patient had complete agenesis of the inferior vena cava and had developed large collaterals draining into the azygos vein. The azygos vein was anastomosed to the right atrium after being sectioned from the SVC to maintain adequate venous return from the lower part of the body (Fig. 33-11). Part of the left atrium was resected in 10 patients, the muscular wall of the esophagus in 4 patients, the chest wall (2 ribs) in 1 patient, and the diaphragm in 1 patient. Complete resection (R0) was achieved in 112 patients. Microscopic positive resection margin (R1) was observed in

42

FIGURE 33-11 One patient requiring a right carinal pneumonectomy presented with complete agenesis of the inferior vena cava (IVC). The azygos vein was anastomosed to the right atrium after being sectioned from the superior vena cava (SVC) to maintain adequate venous return from the lower part of the body.

1/21/2008 11:11:26 AM

Chapter 33 Carinal Resection

4 patients with adenoid cystic carcinoma and in 3 with squamous cell carcinoma. Positive resection margins were usually seen at the bronchial or tracheal resection margins when the maximal length of airway had already been removed (n = 6). In one case, malignant cells were seen at the resection margin of the left atrium. NSCLCs were classified as squamous cell carcinoma (n = 76), adenocarcinoma (n = 16), large cell carcinoma (n = 7), and sarcomatoid carcinoma (n = 1). The nodal status of the NSCLC was classified as pN0 in 14 patients, pN1 in 59 patients, and pN2 or pN3 in 27 patients. Tumor size ranged from 1 to 10 cm (median, 4.5 cm). The long-term survival rate in patients with bronchogenic carcinoma reached 53% at 5 years and 31% at 10 years if the mediastinal nodes were negative. Patients with bronchogenic carcinoma and positive mediastinal nodes, either N2 or N3, had poor survival, only 15% at 5 years.19 Mitchell and colleagues21 reported very similar findings, with a 5-year survival rate of 51% for patients with N0 disease and 12% for those with N2 or N3 disease (Mitchell et al, 1999). Hence, the presence of metastatic mediastinal nodes in patients requiring carinal resection is considered a potential contraindication. This finding underscores the importance of performing routine preoperative mediastinoscopy in these patients. We recommend performing the mediastinoscopy at the time of the planned carinal resection, to avoid the development of scar tissue along the trachea and to take advantage of the tracheal mobilization to reduce tension at the anastomotic site. Further studies should determine the role of induction therapy in patients presenting with bronchogenic carcinoma and N2 disease. Induction therapy seems to improve survival if the mediastinal nodes can be sterilized before the lung resection. However, induction therapy could potentially be associated with increased operative morbidity and mortality in patients requiring right carinal pneumonectomy. The operative mortality increased from 6.7% to 13% after induction therapy in patients undergoing right carinal pneumonectomy in our series. Other authors have made similar observations and have reported an operative mortality rate as high as 24% after right pneumonectomy following induction therapy.22 The actuarial 10-year survival rate was 100% in patients who underwent carinal resection for carcinoid tumors and 69% in patients who underwent carinal resection for adenoid cystic carcinomas in our series. Among the four patients with mucoepidermoid carcinoma, two were alive 16 and 22 months after the surgery, whereas two died at 27 and 70 months after the surgery. Both patients with metastatic renal cell carcinoma died, at 22 and 23 months after the surgery.

SUMMARY In conclusion, carinal resection is a safe procedure in experienced centers and can be associated with good to excellent long-term survival. Patients presenting with bronchogenic carcinoma and negative mediastinal nodes are considered for carinal resection without any induction therapy. However, mediastinoscopy at the time of the planned surgery is important because the presence of positive N2 disease needs to be considered as a potential contraindication to carinal resection due to the poor long-term survival.

Ch033-F06861.indd 391

391

COMMENTS AND CONTROVERSIES This chapter, written by one of the most experienced groups in the world, presents a lucid, logical, well-illustrated, and comprehensive presentation and discussion of this complicated surgery. The excellent results obtained by the authors reflects the experience, judgment, and technical expertise so essential for optimal results. The thorough preoperative evaluation and the use of preoperative mediastinoscopy to exclude patients with N2 disease should be adopted by those who wish to develop special expertise in this area. I have several minor comments to make. When a tumor arising in the right upper lobe ascends the lateral wall of the main bronchus and extends to the first ring or two of the right lateral tracheal wall without involving the carina itself, I prefer to divide the trachea obliquely, beginning two or three rings above the right tracheobronchial angle, and to incise the trachea obliquely down to the medial aspect of the right main bronchus, ending about one ring below the carina, which gives a very satisfactory resection margin. Several interrupted sutures are then used to close about half of the tracheal defect, beginning at the top of the lateral tracheal wall defect. The remaining defect, namely the medial aspect of the defect, is used to implant the intermediate bronchus after a hilar release has been performed. At times, the lateral tracheal defect may be extended upward by taking an inverted V-shaped wedge out of the lateral aspect of the next two most proximal tracheal rings, to facilitate closure of the lateral tracheal defect without undue tension. The resulting narrowing of the distal trachea is mild and does not cause any significant airway obstruction. This lateral tracheal excision and reimplantation of the intermediate bronchus is technically much simpler than doing a complete carinal resection. If a right upper lobe sleeve resection is not feasible because of the distal extent of the tumor, then the same technique can be used for a right pneumonectomy with complete closure of the lateral tracheal defect down to the carina. In this case, removing a small wedge of the carina reduces the tension on the most medial, inferior sutures used to close the tracheal defect. When performing a carinal resection along with a right upper lobe resection, the intermediate bronchus, after hilar mobilization, can be brought up and attached side-to-side with the left main bronchus, just as one would do for a carinal resection when both the right main bronchus and left main bronchus are saved and attached to each other side-to-side. The new carina is then anastomosed end-to-end to the distal trachea. I prefer this technique to the one recommended by the authors—namely, end-to-end anastomosis of the trachea and the left main bronchus with reimplantation of the intermediate bronchus into the side of the left main bronchus, a procedure that is most appropriate if the intermediate bronchus cannot be brought up high enough to connect side-to-side with the left main bronchus, followed by anastomosis of the two to the distal trachea. J. D. C.

KEY REFERENCES de Perrot M, Fadel E, Mercier O, et al: Long-term results after carinal resection for carcinoma: Does the benefit warrant the risk? J Thorac Cardiovasc Surg 131:81-89, 2006.

1/21/2008 11:11:28 AM

392

Section 2 Upper Airway

■ This is a report on one of the largest series of carinal pneumonectomy for broncho-

genic carcinoma. This series demonstrated that carinal pneumonectomy can be safely performed in experienced centers and can be associated with good long-term outcome. Mitchell JD, Mathisen DJ, Wright CD, et al: Clinical experience with carinal resection. J Thorac Cardiovasc Surg 117:39-52, 1999. ■ This report describes the largest experience on carinal resection from the Massachusetts General Hospital, including benign and malignant indications. Detailed

Ch033-F06861.indd 392

information on the various techniques of carinal resection and reconstruction is provided. Pearson FG, Todd TRJ, Cooper JD: Experience with primary neoplasms of the trachea and carina. J Thorac Cardiovasc Surg 88:511518, 1984. ■ This report presents a fine description on the management of tracheal and carinal tumors from the Toronto General Hospital. The advantage of the median sternotomy for tracheal and carinal resection and reconstruction is emphasized.

1/21/2008 11:11:28 AM

chapter

34

COMPLICATIONS OF AIRWAY SURGERY Cameron D. Wright

Key Points ■ Complications after tracheal resection are uncommon. ■ It is important to diagnose anastomotic complications early, to

■ ■

■ ■ ■

avoid loss of the airway or development of a fistula to the esophagus or innominate artery. Any airway symptoms early after resection need to be investigated with bronchoscopy. Risk factors for anastomotic complications are reoperation, diabetes, lengthy resections, age younger than 17 years, laryngotracheal resections, and need for a tracheostomy before operation. Most anastomotic complications can be satisfactorily treated by reoperation, placement of a T tube, or tracheostomy. Anastomotic complications markedly increase the risk of death after tracheal resection. Laryngeal complications (edema, injury to the RLN, and swallowing dysfunction) are uncommon, rarely lead to major reintervention, and typically improve over a period of several months.

Complications after airway surgery are relatively uncommon but can be life-threatening if related to the anastomosis because an adequate airway is essential. General medical complications are uncommon after airway surgery and are not addressed here. Complications are, of course, best avoided; hence, the proper planning and execution of an airway resection and reconstruction represent major steps toward avoiding trouble. Airway resection is almost never an emergency, so the surgeon can carefully evaluate the patient, consult as needed, prepare the patient for operation, and have an optimal operating team. The one exception is a tracheoinnominate fistula (TIF) in which the airway is so damaged that it requires resection. A tracheoesophageal fistula (TEF) can almost always be temporized with a well-placed occlusive tracheostomy tube beyond the fistula. Airway obstruction can almost always be managed with bronchoscopy and dilation (for stenosis) or core-out (for tumor), converting an emergency to an elective eventual resection. Patients with tumors are easier to judge in terms of their candidacy for resection, with the length of potential resection obtained from a combination of bronchoscopic and computed tomographic (CT) measurements. The remaining trachea usually has both a normal structural integrity and mucosa, which facilitates normal healing. Patients with stenosis are more difficult to judge because the length of resection required is more difficult to ascertain and there is invariably a gradation of injury to the mucosa and the underlying carti-

laginous structure of the trachea. Invariably, more trachea is resected than was originally thought to be necessary. Malacic segments (especially around tracheostomy stomas) are identified to the best extent possible preoperatively because they are often unreliable as an airway if anastomosed rather than resected. Patients receiving therapeutic doses of steroids are weaned off of them before resection. Steroids impair wound healing and defense against infection, so their use before a resection makes little sense. Their use to reduce so-called edema makes little sense as well; if a patient has a marginal airway, the best temporizing treatment is usually a bronchoscopic intervention. Radiation is another factor my colleagues and I prefer to avoid before operation because it impairs wound healing. One of the cardinal rules of surgery is broken after every tracheal resection (avoidance of tension on an anastomosis) and to some extent impairs healing. Therefore, it makes little sense to further impair adequate healing with preoperative irradiation. We do not use induction therapy for marginally resectable tumors. If we think the tumor might be resectable, we resect it; if there are microscopically positive margins, we treat postoperatively.

HISTORICAL NOTE Airway reconstruction is a new field, and the number of patients has been relatively few. There is a paucity of published material regarding complications. Grillo in the United States (in 1986) and Courand in France (in 1982) were the first to publish their early experiences with complications after tracheal resection. Grillo and colleagues (1964, 1968) were the first to fully investigate the effect of tension on tracheal resection and reconstruction. They demonstrated a progressive rise in tension with increasing length of tracheal resection and suggested a safe limit of 4.5 cm (corresponding to about 1000 g of tension) to avoid anastomotic failure. HISTORICAL READINGS Courand L: Prevalence and treatment of complications and sequela of tracheal resection and anastomosis. Int Surg 67:235, 1982. Grillo HC, Zannini P, Michelassi F: Complications of tracheal reconstruction: Incidence, treatment and prevention. J Thorac Cardiovasc Surg 91:322, 1986. Grillo HC, Dignan EF, Miura T: Extensive resection and reconstruction of the mediastinal trachea without prosthesis or graft: An anatomical study in man. J Thorac Cardiovasc Surg 48:741, 1964. Mulliken JB, Grillo HC: The limits of tracheal resection with primary anastomosis. J Thorac Cardiovasc Surg 55:418, 1968. 393

Ch034-F06861.indd 393

1/21/2008 11:12:28 AM

394

Section 2 Upper Airway

TABLE 34-1 Complications and Results After Tracheal Resection

Variable

Overall (n = 901)

PITS (n = 589)

Complications, n (%)

164 (18.2)

109 (18.5)

6 (28.6)

8 (6.6)

41 (19.7)

.11

65 (11)

3 (14.3)

2 (2.4)

11 (5.3)

.009

1 (4.8)

0

2 (1)

.02

Anastomotic complication, n (%)

81 (9)

Death, n (%)

11 (1.2)

8 (1.4)

Result, n (%) Good Tube

853 (95) 37 (4.2)

553 (95.2) 28 (4.8)

TEF (n = 21)

ILTS (n = 83)

Tumor (n = 208)

P Value

.04 18 (90) 2 (10)

82 (98.8) 1 (1.2

200 (97.1) 6 (2.9)

ILTS, idiopathic laryngotracheal stenosis; PITS, postintubation tracheal stenosis; TEF, tracheoesophageal fistula.

TABLE 34-2 Nonanastomotic Airway Complications After Tracheal and Laryngotracheal Resection

Complication Glottic edema, n (%) Aspiration, n (%)

Tracheal Resection (n = 663) 4 (0.6)

RISK FACTORS FOR ANASTOMOTIC COMPLICATIONS Laryngotracheal Resection (n = 248) 13 (5)

15 (2)

9 (4)

Vocal cord paralysis, n (%)

9 (1)

5 (2)

Tracheostomy, n (%)

4 (0.6)

6 (2)

INCIDENCE OF COMPLICATIONS The incidence of complications varies according to the diagnosis treated and whether the anastomosis involves the larynx. Table 34-1 demonstrates the distribution of anastomotic and other complications in a large series of 901 airway resections (Wright et al, 2004).1 Patients with idiopathic laryngotracheal stenosis (ILTS) have the least complications, and those with a TEF have the most. ILTS patients have short resections and are typically healthy young women. TEF patients require lengthy resections and have multiple other preoperative risk factors for complications. Patients with tumors have the next highest rate of complications, reflecting their older age and the much more common use of a thoracic approach to resection. Anastomotic complications are most common in patients with TEF and postintubation tracheal stenosis (PITS). Patients with TEF have the highest death rate. Table 34-2 demonstrates the distribution of airway-related nonanastomotic complications, such as glottic edema, aspiration, vocal cord edema, and need for temporary tracheostomy. These complications were all more common with laryngotracheal resection than with simple tracheal resection. If the resection involves the larynx, glottic edema and laryngeal dysfunction resulting in aspiration more commonly occur. If the laryngeal complications are severe, then temporary tracheostomy is required. Injury to the recurrent laryngeal nerve (RLN) resulting in vocal cord paralysis is surprisingly uncommon.

Ch034-F06861.indd 394

Anastomotic complications after tracheal resection and reconstruction are uncommon but lead to severe morbidity. Anastomotic complications include granulations at the anastomotic line (presumably some degree of separation allows ingrowth of granulation tissue between the two cut edges of the divided trachea or, less commonly, suture material incites granulations), stenosis (slow distraction of the tracheal anastomosis allows scar to develop at the suture line), and separation (disruption of the suture line causing a catastrophic failure of the anastomosis). We recently thoroughly analyzed our anastomotic complications among a group of 901 patients who underwent a tracheal resection. The following factors were not associated with anastomotic complications: obesity (body mass index [BMI] >30), approach (cervical, cervicomediastinal, or thoracic), or steroid use. Only 63 patients (7%) were taking steroids at the time of surgery because it has been our practice to wean patients from steroids before operation. Those patients still on steroids were taking relatively low doses for short periods and are not representative of the usual patient who is taking substantial doses of steroids. We did not have enough patients who had preoperative radiation therapy to make any meaningful statistically valid conclusions. We regard these patients as high risk and carefully select patients for tracheal resection based on more conservative guidelines. We then typically wrap the suture line in either omentum or muscle to facilitate healing. The following factors were associated with anastomotic complications: age younger than 17 years, diabetes, very obese patients (BMI > 35), PITS as a diagnosis, preoperative tracheostomy, reoperation, length of resection, need for a release procedure, laryngotracheal resection, and need for a postoperative tracheostomy. A multivariable analysis was performed, and six variables were found to be predictive of an anastomotic complication (Table 34-3). The need for a suprahyoid release is a potentially confusing factor and must not be misinterpreted as a procedure that regularly causes an anastomotic complication. The surgeon performs a release when, in his or her judgment, reapproximation of the divided ends of the trachea would produce anastomotic tension so great that anastomotic failure would be likely. In the hands of an experienced surgeon, the per-

1/21/2008 11:12:28 AM

Chapter 34 Complications of Airway Surgery

TABLE 34-3 Multivariable Predictors of Anastomotic Complications

395

45

Odds Ratio

P Value

40

Length >4 cm

2.01

.007

35

Preoperative tracheostomy

1.79

.04

Age <17 yr

2.26

.03

Diabetes

3.32

.002

Reoperation

3.03

.0002

Laryngotracheal resection

1.80

.03

Anastomotic failure rate

Variable

30 25 20 15 10

ceived need for a release is a most reliable marker of otherwise excessive tension. An alternative way to view release as a variable would be that the expected anastomotic complication rate was 100% if a release is deemed necessary, but in our series the rate was only 25% (22/81) after release was performed, a substantial risk reduction. Reoperation as a risk factor is clinically intuitive because previous tracheal resection would translate to an increased anastomotic tension at the subsequent resection, although experience has shown that successive resections at intervals are not simply additive by length. However, militating against success is the dense surrounding peritracheal fibrosis from previous operation, which limits tracheal mobility and may increase tension. Despite the elevated risk, reoperation is usually successful (75% [77/101] in our series) if patients are selected carefully. Diabetes is a surprisingly important risk factor for anastomotic complication, with an odds ratio (OR) of 3.3. This may be a consequence of impairment of an already compromised collateral watershed circulation at the end of the divided trachea. Tension might be expected to put this area at further risk. Diabetes is known to impair the microcirculation, with resultant deleterious effects on wound healing. This risk factor cannot be modified, but it needs to be taken into account in stratifying risk. The fact that longer resections are at increased risk is no surprise. The influence of length of resection on anastomotic failure is illustrated in Figure 34-1. There can be no absolute guidelines to limits of resection in an individual patient, but prudence dictates that resections longer than 4 cm need to be considered for a release procedure. Pediatric patients have long been thought to tolerate tension less well than adults. Recent analysis of our pediatric experience in tracheal surgery confirmed the original supposition that only about 30% of the juvenile trachea can be resected before increased anastomotic failure rates are encountered (Wright et al, 2002).2 The current study confirms these findings when pediatric patients are compared to adults, with an OR of 2.3. We have long thought, based on clinical observation, that patients with postintubation lesions (PITS and TEF) represented a more difficult situation than patients with ILTS or tumors. This intuition was corroborated in the univariable analysis but not in the final multivariable analysis. Need for a tracheostomy before operation was an independent risk factor with an OR of 1.8, but in essence it was a marker for

Ch034-F06861.indd 395

5 0 ⬍2.5 cm

2.5 cm 3–3.5 cm 3.6–4 cm Length of resection

4–6.5 cm

FIGURE 34-1 Anastomotic failure rate and its relation to length of resection. Patients undergoing a first resection (n = 800) are represented by red bars and those undergoing reoperation (n = 101) by blue bars.

a particularly difficult postintubation stenosis because patients with tumor and ILTS rarely had a prior tracheostomy. Patients with stenosis tend to have gradations of injury to the trachea that make difficult the choices in lengthy resections as to what degree of residual airway injury to accept in order to limit anastomotic tension. Most lengthy resections have some degree of mucosal or cartilaginous abnormalities remaining, which can pose a problem with anastomotic healing. Stenosis patients often have peritracheal inflammation beyond the maximal stenosis that is resected, which may limit mobility for reapproximation. A laryngotracheal resection with anastomosis to the larynx was also associated with a higher anastomotic failure rate, with an OR of 1.8. A laryngeal anastomosis is always more delicate to perform and seems less robust when compared with tracheotracheal anastomoses. If laryngotracheal resection is required in patients with stenosis, this becomes another surrogate marker of severe disease with injury at two levels of the airway.

MANAGEMENT OF AIRWAY COMPLICATIONS Anastomotic Granulation Tissue Granulation tissue at the anastomosis was common when braided nonabsorbable sutures were used but is much less common now with the use of absorbable sutures (commonly 4-0 polyglactin). Exposed mesenchymal tissue also probably plays a role in the formation of granulation tissue. Patients present days to weeks after resection with airway obstruction and stridor. The diagnosis is made by bronchoscopy. The treatment is by scrapping off the loose granulations with the tip of the rigid bronchoscope. Recalcitrant granulations can also be injected at the base with long-acting steroids after débridement. Rarely, they cannot be controlled by

1/21/2008 11:12:28 AM

396

Section 2 Upper Airway

endoscopic means, and a tracheostomy tube or T tube must be inserted to maintain an airway. Reoperation is only very rarely required. An example of obstructing anastomotic granulations is seen in Figure 34-2.

Anastomotic Stenosis Stenosis at the site of the anastomosis is usually caused by excessive tension and slowly develops over weeks to months after resection. It may also be caused by excessive dissection of the divided ends of the trachea so as to make the ends relatively ischemic. Less commonly, it results from inadequate resection of the diseased trachea at the original operation for whatever reason. Patients present with obstructive symptoms again and are promptly investigated. The diagnosis is made by bronchoscopy. Simple dilation with graduated rigid bronchoscopes is usually the first step and may provide long-lasting improvement. If not, all the usual options (T tube, tracheostomy, or reoperation) must be considered. A T tube is always preferred over tracheostomy because speech is preserved, airway humidification is performed by the nose, and patients can maintain a near-normal appearance and lifestyle. Re-resection can be done only if there is enough residual trachea present to allow an anastomosis with an acceptable level of tension—not a common occurrence. Re-resection is deferred for 6 to 12 months to allow peritracheal inflammation to resolve.

Anastomotic Separation Anastomotic separation is the most serious and potentially catastrophic complication after tracheal resection. It typically

A

occurs early, in the first days to weeks after resection. It can manifest with subtle signs of airway obstruction (voice change, increased coughing, increased phlegm, stridor) and wound problems (swelling, pain, redness, subcutaneous air). It also may manifest with sudden loss of the airway, which will lead to a quick death if the airway is not immediately secured. Our unit used to check the integrity of the tracheal anastomosis with plain tracheal radiographs, but these proved insufficient to identify early partial anastomotic separation. We now perform a bronchoscopy before the patient is discharged to assess the integrity of the anastomosis. Any unusual airway symptoms after tracheal resection prompt a bronchoscopy to evaluate the anastomosis. Most separations begin anteriorly, where the most tension is placed on the anastomosis. If the patient has a stable airway, a CT scan of the neck and chest can be helpful to search for subtle air collections and unusual fluid collections adjacent to the anastomosis. Rarely, patients develop a small, limited air pocket adjacent to the repair, and the bronchoscopy does not show any problem or defect in the anastomosis. These patients can be safely observed after the air has been drained by insertion of a suction drain. The presumed mechanism is a tiny leak that develops after coughing and then quickly seals. More commonly, the anastomotic defect is larger, which leads to lots of air in the wound and an eventual infection around the anastomosis. Usually, the airway and the larynx develop significant edema, which complicates management. The principles of treatment are to maintain an open airway, to close or control the defect in the anastomosis, and to drain the infection. In unusual cases where there is no infection and a limited anterior dehiscence, a muscle flap can be

B

FIGURE 34-2 A, Bronchoscopic photograph of a patient 10 days after laryngotracheal resection for idiopathic laryngotracheal stenosis complicated by severe anastomotic granulation tissue. The patient had stridor and a very weak voice. B, Same patient immediately after rigid bronchoscopic débridement of the granulations. Note the exposed suture material, which probably was the cause of the granulations. One month later, repeat bronchoscopy revealed a normal healed anastomosis with no residual granulations.

Ch034-F06861.indd 396

1/21/2008 11:12:29 AM

Chapter 34 Complications of Airway Surgery

sutured over the defect or a T tube can be inserted through the defect. Some of these patients heal satisfactorily, and the T tube may be removed after months to years of stenting. More commonly, there is a significant surrounding infection with airway and laryngeal edema, resulting in an obstructed airway proximal to the anastomosis. In that case, the airway is controlled with a tracheostomy tube, and the infection is drained. Once the airway edema resolves, a T tube can usually be placed. Reoperation can occasionally be performed if enough residual trachea remains. Again, one defers a reoperation for quite some time, to allow all edema, healing, and inflammation to resolve. Only rarely can one contemplate re-suturing of an anastomotic dehiscence in the acute setting. Sudden violent coughing or hyperextension in the face of a limited resection without much tension causing a disruption would be the one situation in which re-suturing of the anastomosis might be successful.

Tracheoinnominate Fistula TIF is a rare, catastrophic complication after tracheal resection; it is almost always caused by an anastomotic separation adjacent to the artery, which leads to a localized infection that burrows into the innominate artery. Hemoptysis is the classic presenting sign of TIF, and there is often minor hemoptysis before a major bleed. There are often also signs of a partial airway separation, such as stridor from edema and wound problems. Hemoptysis prompts a bronchoscopy and a CT scan (if the patient is stable). If a TIF is present, reexploration is immediately performed. The innominate artery is divided where the artery is healthy and oversewn with monofilament suture material. The ends of the divided artery are separated from the trachea with viable tissue such as the omentum or a muscle flap. Division of the innominate rarely leads to any ischemic sequelae of the brain, as long as the bifurcation of the carotid and subclavian arteries is preserved. The anastomotic defect in the trachea must be dealt with, either with a muscle flap over the defect or with control of the airway by means of a tracheostomy tube, or both. Among our 901 patients who underwent tracheal resection, only 3 had a TIF, but 2 of these patients died from the TIF. If the tracheal anastomotic suture line at the primary operation lies adjacent to the innominate artery, it seems wise to separate these two structures with a pedicled tissue flap, usually a strap muscle. Another important prophylactic maneuver is to not bare the innominate artery, but rather to leave the thick investing connective tissue around the artery undisturbed.

Tracheoesophageal Fistula TEF is another rare but catastrophic complication of tracheal resection that is usually caused by a posterior dehiscence of the anastomosis. More rarely, there is inadvertent injury to the esophagus at operation which leads to a localized infection that burrows into the posterior aspect of the tracheal anastomosis. Patients can present with airway obstructive symptoms, wound problems, coughing after swallowing, and aspiration pneumonia. The diagnosis is by barium swallow or bronchoscopy. Satisfactory control of this complication is

Ch034-F06861.indd 397

397

difficult. If there is sufficient trachea remaining and there is not much infection, re-resection, closure of the TEF, and separation of the two suture lines with a pedicled strap muscle flap is preferred. Rarely, a small fistula with a largely intact anastomosis can be salvaged with closure of the esophagus and rotation of a muscle flap. More commonly, the airway and fistula are controlled with a tracheostomy tube, and the patient is switched to enteral feeding. Reoperation is deferred until the patient is better able to endure the surgery. TEF is a very rare complication of tracheal resection, and it occurred in only 3 patients among our 901 patients undergoing resection; in all three cases, salvage was successful.

LARYNGEAL COMPLICATIONS AFTER TRACHEAL RESECTION Laryngeal Edema Edema of the airway can complicate any repair involving the larynx, even in the absence of other complications. In general, the closer one comes to the vocal cords with the anastomosis, the greater the chance there is of problematic edema. Essentially any resection of the larynx causes some edema, especially of the vocal cords. This typically causes a change in voice quality, with development of a husky, whispered voice. Uncommonly, the cords and subglottic airway can swell to such an extent that stridor ensues and the airway becomes inadequate. The diagnosis is confirmed by bronchoscopy, and it is important to ascertain the status of the anastomosis because a partial separation can also manifest with edema. In the absence of a problem with the anastomosis, edema is treated in a graded fashion. Mild cases are treated with nebulized epinephrine, short courses of steroids, head elevation, voice rest, and diuretics. More severe cases can be temporized with a short course of intubation with a small uncuffed endotracheal tube, along with the preceding measures, to see what will happen. Persistent or severe edema requires tracheostomy and tincture of time. When very high laryngotracheal reconstructions are done (especially if a laryngofissure is done to accomplish the repair), it is usually best to perform a tracheostomy at the conclusion of the operation, rather than wait for the almost inevitable swelling to occur.

Recurrent Laryngeal Nerve Paralysis Surprisingly, paralysis of the RLN is quite uncommon after tracheal resection, despite the fact that the nerve is closely applied to the trachea and is often difficult to find in the scar around peritracheal inflammation from a stoma or PITS. In our series of 901 patients, RLN paralysis happened in only 14 patients (1.6%). We never look for the nerve but avoid it by keeping the dissection on the wall of the trachea. This strategy clearly works and is recommended. If a patient is hoarse immediately after operation, an RLN injury is suspected; this can be confirmed by bedside laryngoscopy with a flexible scope. Rarely is the true status of the nerve known, so conservatism is in order. Many nerve injuries are temporary and resolve in several months. We usually wait at least 6 months before performing medialization laryngoplasty, to ensure that we are dealing with a permanent injury. Patients

1/21/2008 11:12:30 AM

398

Section 2 Upper Airway

are evaluated by a speech pathologist, and their swallowing is assessed by a modified barium swallow. Usually, a chin tuck maneuver improves airway protection from aspiration. Young patients usually do better at swallowing with this injury than do older patients. Rarely, bilateral RLN injuries are present, and most patients with bilateral injuries require temporary tracheostomy.

Swallowing Dysfunction A small number of patients develop swallowing dysfunction after tracheal resection that leads to aspiration and possibly pneumonia. The use of a laryngeal release is often followed by poor swallowing because of improper glottic closure due to the functional separation of the larynx from the hyoid. This is invariably worse in older patients, but it typically improves with time. Many patients require a temporary gastrostomy for feeding until the laryngeal function improves. A speech pathologist is again important in assessment and rehabilitation of the patient. The suprahyoid release, described by Montgomery,3 has a much lower incidence of swallowing problems after the first few postoperative days. Swallowing problems also can occur after tracheal resection without a release, usually when there is a lengthy resection that effectively lowers and immobilizes the larynx during swallowing. Again, this is more common in older patients and typically improves over time. Twenty-four of our 901 patients developed swallowing difficulties and aspiration after tracheal resection.

Ch034-F06861.indd 398

OUTCOME AFTER TREATMENT OF ANASTOMOTIC COMPLICATIONS Of our 81 patients with an anastomotic complication, 41 (51%) had a satisfactory airway without need for an artificial airway after intervention. Treatment for surviving patients was as follows: multiple dilations in 2 patients, temporary tracheostomy in 7, temporary T tube placement in 16, permanent tracheostomy in 14, permanent T tube in 20, and reoperation in 16. All patients who underwent reoperation had a satisfactory result. Six patients died as a result of anastomotic separation; three patients died of anoxia due to airway obstruction, two died after repair of a TIF, and one died of mediastinitis. The mortality rate of patients who had anastomotic complications was 7.4% (6/81), whereas it was 0.01% (5/820) among those without anastomotic complications (OR, 13.0; P = .0001). The cause of death in the patients without anastomotic complications was aspiration pneumonia in 3, myocardial infarction in 1, and pulmonary embolism in 1. The median lengths of stay were 8 days without and 14 days with an anastomotic complication (P < .0001). KEY REFERENCES Wright CD, Grillo HC, Wain JC, et al: Anastomotic complications after tracheal resection: Prognostic factors and management. J Thorac Cardiovasc Surg 128:731, 2004. Wright CD, Graham BB, Grillo HC, et al: Pediatric tracheal surgery. Ann Thorac Surg 74:308, 2002.

1/21/2008 11:12:31 AM

Introduction chapter

ANATOMY OF THE LUNG

35

Thomas W. Rice

Key Points ■ A detailed understanding of the anatomy of the lung is essential to

perform pulmonary resections and reconstructions. ■ The anatomic and surgical subunit of the lung is the bronchopul-

monary segment. ■ A thorough comprehension of the intrapericardial anatomy is

essential for central resections and lung transplantation. ■ The relationship of bronchovascular structures at the pulmonary

hilum and in the interlobar fissures must be appreciated to permit lobectomy or segmentectomy.

HISTORICAL NOTE Graham and Singer1 reported the first successful pneumonectomy for treatment of bronchogenic carcinoma in 1933. The left pneumonectomy was performed by mass ligation of the pulmonary hilum. Although it was not the first pulmonary resection, this landmark procedure marked the beginning of modern thoracic surgery. Mass ligation became a curiosity, however, and careful identification and precise control of the individual structures of the pulmonary hilum, lobes, and segments was soon considered standard procedure. Recognition and preservation of the pulmonary arterial supply, the pulmonary venous drainage, and the bronchial anatomy permit conservation of the parenchyma. This is the cornerstone of pulmonary surgery. HISTORICAL READINGS Graham EA, Singer JJ: Successful removal of an entire lung for carcinoma of the bronchus. JAMA 101:1371, 1933.

BRONCHOPULMONARY SEGMENT The anatomic and surgical unit of the lung is the bronchopulmonary segment. A review of pulmonary embryology is helpful for understanding this pulmonary element and the congenital abnormalities of the lung bud (i.e., congenital lobar emphysema, cystic adenomatoid malformation, pulmonary sequestration, and bronchogenic cyst). The lung develops from a foregut bud with continual branching of the principal structures. The lung bud is first seen in the embryo at 3 weeks. In the fourth week, the branching begins with the growth of the right and left main bronchi. Further development is asymmetric, principally because of the absorption of the left eparterial bud. Rapid growth of the airway by terminal branching ensues. By the 17th week, 70% of the airway

has been formed. The alveoli appear between 20 and 24 weeks in utero. The pulmonary vascular plexus and venous drainage originate from the splanchnic plexus, which is carried with the developing lung buds. The pulmonary arteries arise from the sixth aortic arch as bilateral buds. These grow into the lung and connect with the developing pulmonary plexus. On the right, absorption of the dorsal sixth aortic arch bud allows the potential separation of the pulmonary from the systemic vasculature. On the left, persistence and growth of the dorsal bud and its connection to the ventral bud form the fetal and neonatal communication between the pulmonary and systemic vascular circuits—the ductus arteriosus. The repetitive branching of the airway and vasculature allows the evolution of independent lung units. Bronchopulmonary segments are subdivisions of the lung that function as individual units because they possess their own bronchus, pulmonary arterial supply, and venous drainage. Each segment may be individually removed without disturbing the function of adjacent segments if the bronchovascular anatomy is appreciated and precisely controlled. The bronchial anatomy of the segment is most constant. The pulmonary artery accompanies the bronchus but has a more variable pattern. The pulmonary veins do not accompany the artery and bronchus in the center of the bronchopulmonary segment but run in the intersegmental planes. Pulmonary veins drain adjacent segments and mark the boundaries of this anatomic unit (Fig. 35-1). In 1949, Ramsey2 emphasized the importance of the venous drainage pattern of the bronchopulmonary segments. Appreciation of the venous drainage is crucial for identification of the segment and successful completion of a segmental or lobar resection. The right lung, which is the larger of the two lungs, has three lobes: upper, middle, and lower. The right major fissure runs obliquely along the lateral surface of the lung from a superior and posterior position to an inferior and anterior position. The major fissure separates the lower lobe from the upper and middle lobes. The minor fissure, which is less well developed, runs horizontally to separate the upper lobe from the middle lobe. The right lung is composed of 10 segments (Fig. 35-2). The upper lobe has three segments: apical, posterior, and anterior. The middle lobe has two segments: lateral and medial. The lower lobe has five segments: superior, medial basal, anterior basal, lateral basal, and posterior basal. The left lung has two lobes: upper and lower. The lingula, which is the anatomic equivalent of the middle lobe, is part of the left upper lobe. The left major fissure runs obliquely along the lateral surface of the lung from a superior and 401

Ch035-F06861.indd 401

1/21/2008 11:13:51 AM

402

Section 3 Lung

posterior position to an inferior and anterior position. The major fissure separates the upper lobe from the lower lobe. The left lung is composed of eight segments (see Fig. 35-2). The upper lobe has four segments: apical posterior, anterior, superior (lingular), and inferior (lingular). The lower lobe has

four segments: superior, anteromedial basal, lateral basal, and posterior basal. Fewer segments exist in the left lung because of sharing of the segmental bronchi by subsegmental bronchopulmonary units, which in the right lung are segments. The apical and posterior segments of the right upper lobe correspond to one segment in the left upper lobe, where these two subsegments share a common segmental bronchus (apical posterior). Similarly, the anterior basal and medial basal subsegments of the left lower lobe share the common anteromedial basal segmental bronchus. This variation is of greatest interest at bronchoscopy. At surgery, these subsegments can be dissected; this may be useful in surgery of the left upper lobe but is generally not advantageous in the left lower lobe. Anomalies of lobation are usually the result of too few or too many fissures. Absence or incomplete development of the major or minor fissures causes fusion of adjacent lobes. Accessory fissures correspond to the planes of division between bronchopulmonary segments and account for many of the previously reported accessory lobes. The cardiac lobe is the medial basal segment of the lower lobe, which is demarcated by an intersegmental fissure. Similarly, the superior segment in the lower lobe and the lingula in the upper lobe can be separated by an accessory fissure. Accessory lobes are seen in two cases. If no bronchial communication exists, these accessory lobes are really extralobar sequestrations. Rarely, an accessory lobe has a bronchial connection; this is seen in the tracheal lobe. This lobe is the apical segment of the right upper lobe with a tracheal origin of the segmental

Pulmonary vein Bronchus

Pulmonary artery

Intersegmental plane FIGURE 35-1 The bronchopulmonary segment.

FIGURE 35-2 The lobes and segments of the lung. Right upper lobe segments: 1, apical; 2, anterior; 3, posterior. Right middle lobe segments: 4, lateral; 5, medial. Right lower lobe segments: 6, superior; 7, medial basal; 8, anterior basal; 9, lateral basal; 10, posterior basal. Left upper lobe segments: 1 and 3, apical posterior; 2, anterior; 4, superior (lingular); 5, inferior (lingular). Left lower lobe segments: 6, superior; 7 and 8, anteromedial basal; 9, lateral basal; 10, posterior basal.

1

1+3

3 2

1+3

2

2

1 3

4

2

4

5

5

4 4

7+8 5

6

5

6 10

10

9

6

9

7

8

9 10

6 6 9

6

8

10

10

7 8

Ch035-F06861.indd 402

10

9

7+8

9

1/21/2008 11:13:51 AM

Chapter 35 Anatomy of the Lung

bronchus. Agenesis or aplasia of the lung results from maldevelopment of the lung bud.

INTRAPERICARDIAL ANATOMY The control of the pulmonary vessels within the pericardium was first advocated by Allison3 in 1946 and further refined by Healey and Gibbon4 in 1950. The ability to control the pulmonary vasculature within the pericardium is crucial for lung transplantation, for the resection of central tumors and tumors with hilar invasion, and for the management of distal vascular problems in which proximal control is required. The serous pericardium reflects onto the pulmonary vessels, as they originate within or enter the fibrous pericardial sac, and must be divided to mobilize these vessels. The lack of complete pericardial investage sometimes obscures the vessel and may make identification and mobilization difficult. The pulmonary trunk arises from the infundibulum of the right ventricle and, at its origin, overlies the aorta. It then passes to the left and rises superiorly and posteriorly for 4 to 6 cm. It is contained in the serous pericardium with the aorta. In this position, it lies between the right and left atria. Below the aortic arch, it bifurcates into the right and left main pulmonary arteries. The right main pulmonary artery (Fig. 35-3) arises from the main pulmonary artery to pass transversely, posterior to the aorta and superior vena cava. More than three fourths of its length is within the pericardial sac. Behind the aorta and superior vena cava, this artery constitutes the superior border of the transverse sinus. It is covered by serous pericardium for more than three fourths of its circumference. Its posterior surface is directly applied to the fibrous pericardium and is not covered by serous pericardium. The pulmonary artery may be safely controlled in this location by retracting the aorta medially and the superior vena cava laterally. After the right pulmonary artery is mobilized, it may be retracted, and

Superior vena cava

Aorta

403

division of the posterior fibrous pericardium provides transpericardial access to the trachea and main bronchi. As the right pulmonary artery passes from behind the vena cava, it exits the pericardial sac. In this position, it forms the superior border of the postcaval recess of Allison. The medial border is the superior vena cava; the inferior border is the superior pulmonary vein; and the lateral border is the pericardial sac. In about 5% of patients, there is no postcaval recess. The right pulmonary artery exits the pericardial sac when it is still in the retrocaval position. The right superior pulmonary vein enters the pericardium and is covered by serous pericardium for more than two thirds of its circumference. It immediately drains into the left atrium. The right inferior pulmonary vein is covered by serous pericardium over only one third of its circumference, and total lack of this covering in half of patients with lung disease makes it appear that the right inferior pulmonary vein has no intrapericardial component. Mobilization of the inferior pulmonary vein’s short, stubby pericardial attachments and division of the frenulum of pericardium that runs to the inferior vena cava provide additional mobility of the hilum. This maneuver is sometimes required during intrathoracic tracheobronchial resections for relief of tension at the airway anastomosis. The vein drains into the left atrium. On the right, a common pulmonary vein is found in about 3% of patients. The junction between the right and left atria lies just anterior to the termination of the right pulmonary veins. Additional pulmonary venous length may be obtained by dissection within the (developing) intra-atrial groove. The left pulmonary artery (Fig. 35-4) arises from the main pulmonary artery and passes inferiorly and posteriorly before exiting the pericardium from under the aortic arch. As it leaves the pericardial sac, half of its circumference is covered by serous pericardium; this must be divided to control the pulmonary artery at this point. The left pulmonary recess is bordered by the left main pulmonary artery superiorly, the

Main pulmonary artery

Ascending aorta Left main pulmonary artery

Right main pulmonary artery Recess of Allison Right superior pulmonary vein

Fold of Marshall Left superior pulmonary vein

Right inferior pulmonary vein

Left inferior pulmonary vein

Inferior vena cava

FIGURE 35-3 The right intrapericardial anatomy.

Ch035-F06861.indd 403

FIGURE 35-4 The left intrapericardial anatomy.

1/21/2008 11:13:52 AM

404

Section 3 Lung

left superior pulmonary vein inferiorly, and the fibrous pericardium laterally. The medial border is the fold of Marshall, which contains the remnant of the left superior vena cava. This is patent in fewer than 1% of patients and may be divided to provide improved intrapericardial access to the left main pulmonary artery and left superior pulmonary vein. The left superior pulmonary vein enters the pericardium to be covered by serous pericardium on two thirds of its circumference. Immediately below and inferior to this is the left inferior pulmonary vein. This vein is the most distinct and free of all the pulmonary vessels, with 90% of its circumference covered by serous pericardium. In contrast to the pulmonary veins on the right, about 25% of patients have a common left pulmonary vein within the pericardium. Anomalies of the pulmonary arteries and pulmonary veins may be classified as abnormalities of number or of site of origin or termination. Aberrations of the main pulmonary artery are typically accompanied by anomalies of the heart and great vessels. Main pulmonary artery anomalies are uncommon and consist of agenesis, hypoplasia, or abnormal origin; they cause vascular rings that result in airway and esophageal compression. Accessory pulmonary arteries may arise from the aorta or its branches. This is usually seen in pulmonary sequestrations or pulmonary atresia with ventricular septal defect, but it may occur without associated disease. Anomalies of pulmonary veins are more common. An abnormal number of veins is seen most frequently as a common left pulmonary vein or as separate veins that drain the upper, middle, and lower lobes on the right. Anomalous pulmonary venous drainage can be partial or complete. The veins typically drain into the superior vena cava, right atrium, coronary sinus, inferior vena cava, persistent left vena cava, or systemic veins.

HILUM The principal structures passing to and from the lung at the mediastinal border are the bronchus, the pulmonary artery, and the superior and inferior pulmonary veins, which constitute the pulmonary hilum. The lung is fixed centrally by the hilum and the inferior pulmonary ligament. The inferior pulmonary ligament is the reflection of the inferior mediastinal parietal pleura onto the lung, where it envelops the inferior pulmonary vein. On both sides, the hilum is subtended by a vascular arch: on the right by the azygos vein and on the left by the aortic arch. The hilum is bordered by nerves and systemic vessels: the phrenic nerve and its vascular bundle anteriorly and the vagus nerve and bronchial vessels posteriorly. The right main bronchus is the most superior and posterior of the right hilar structures and passes into the hilum after exiting the mediastinum below the azygos vein (Fig. 35-5). The right pulmonary artery exits the pericardium behind the superior vena cava and enters the hilum. In the right hilum, the right pulmonary artery lies inferiorly and anteriorly to the bronchus, partially obscuring the bronchus. The truncus anterior, the first branch of the right pulmonary artery, originates from the pulmonary artery before it enters the lung. The superior pulmonary vein passes from the pulmonary paren-

Ch035-F06861.indd 404

Phrenic nerve Right main bronchus Truncus anterior Right main pulmonary vein Right superior pulmonary vein Right inferior pulmonary vein

FIGURE 35-5 The right hilar anatomy, anterior view.

Azygos vein

Right main bronchus Right upper lobe bronchus

Esophagus

Right inferior pulmonary vein Vagus nerve

Bronchus intermedius Superior segmental vein

FIGURE 35-6 The right hilar anatomy, posterior view.

chyma to lie anterior to the pulmonary artery and slightly below the truncus anterior branch of the right pulmonary artery. Here, it overlaps and obscures the intraparenchymal continuation of the pulmonary artery, the pars intralobares. The superior pulmonary vein receives four component branches. Three branches drain the upper lobe. The most superior is the apical anterior vein; just below this is the inferior vein, which drains the inferior surface of the anterior segment. Entering the vein deep from the pulmonary parenchyma and from its posterior aspect is the posterior vein, which principally drains the posterior segment of the right upper lobe. The most inferior venous tributary is the middle lobe vein. The inferior pulmonary vein lies posterior and inferior to the superior pulmonary vein. It comprises two tributaries: the superior and common basal branches. Lying anterior to the hilum on the superior vena cava and pericardium is the right phrenic nerve. The posterior right hilum (Fig. 35-6) is bordered superiorly by the azygos vein. The short membranous portion of the

1/21/2008 11:13:53 AM

Chapter 35 Anatomy of the Lung

Esophagus Azygos vein

405

Phrenic nerve

Azygos vein

Truncus anterior

Thoracic duct

Left main pulmonary artery Left superior pulmonary vein Left inferior pulmonary vein

Thoracic duct Esophagus Aorta

FIGURE 35-8 The left hilar anatomy, anterior view. Cysterna chyli

Vagus nerve

FIGURE 35-7 The course and relationships of the thoracic duct.

right main bronchus passes from under the arch of the azygos vein to terminate as the right upper lobe bronchus and the bronchus intermedius. Lying inferior and posterior to the bronchus intermedius is the inferior pulmonary vein. The superior branch of the inferior pulmonary vein, which drains the superior segment of the right lower lobe, is best identified posteriorly. The esophagus and the right vagus nerve lie immediately posterior to the right hilum. Lying behind these structures is the azygos vein, which arches over the right main bronchus just above the origin of the right upper lobe. The most constant position of the thoracic duct in the thoracic cavity is inferior to the right hilum (Fig. 35-7). Here, in its supradiaphragmatic location, it can be found between the azygos vein and aorta, bordered anteriorly by the esophagus and posteriorly by the vertebral column. The left main bronchus is 4 to 6 cm long and passes under the aortic arch to lie posteriorly in the hilum. Unlike the right side, where the bronchus remains the most posterior structure, the left main bronchus, on entering the lung on the left, is sandwiched between the superior pulmonary vein anteriorly, the pulmonary artery superiorly and posteriorly, and the inferior pulmonary vein inferiorly. The left pulmonary artery (Fig. 35-8) is the most anterior superior structure in the left pulmonary hilum. The ligamentum arteriosum is found as the pulmonary artery exits the pericardium. This is the remnant of the ductus arteriosus, which connects the aortic arch to the left pulmonary artery in utero. The left recurrent laryngeal nerve loops around the aorta at the lateral margin of the ligamentum arteriosum (Fig. 35-9). The pulmonary artery leaves the pericardium and passes over the left main bronchus. The first branch of the artery, the truncus anterior, which supplies the anterior

Ch035-F06861.indd 405

Left recurrent laryngeal nerve

Ligamentum arteriosum

Pulmonary artery Aorta FIGURE 35-9 The course and relationship of the left vagus and left recurrent laryngeal nerves.

segment of the left upper lobe, originates before the pulmonary artery passes around the left upper lobe bronchus to enter the left lung posteriorly. The superior pulmonary vein lies anterior and inferior to the pulmonary artery and is composed of three draining veins: apical posterior, anterior, and lingular. The inferior pulmonary vein lies inferior and posterior to the superior pulmonary vein and is found at the apex of the pulmonary ligament. The posterior left hilum (Fig. 35-10) consists of the pulmonary artery superiorly, the left main bronchus, and the inferior pulmonary vein inferiorly. The esophagus and the left vagus nerve lie immediately posterior to the left pulmonary

1/21/2008 11:13:54 AM

406

Section 3 Lung

Descending thoracic aorta Left pulmonary artery Left main bronchus Left inferior pulmonary vein Vagus nerve

FIGURE 35-10 The left hilar anatomy, posterior view.

hilum. The descending thoracic aorta lies behind these structures.

RIGHT UPPER LOBE The right upper lobe bronchus (previously called the eparterial bronchus) arises from the lateral wall of the right main bronchus immediately after the origin of the right main bronchus from the trachea. The bronchus passes at right angles to the right main bronchus and bronchus intermedius to enter the right upper lobe. The anomalies of the right upper lobe bronchus have been outlined by le Roux.5 The origin of the right upper lobe bronchus is anomalous in 3% of patients. The most common bronchial anomaly of the right upper lobe is the origin of the apical segmental bronchus from the trachea (tracheal bronchus) or from the right main bronchus, which is reported in 1.4% of patients. Absence of a true right upper lobe bronchus, with immediate division into the segmental bronchi, is seen in 1.1% of patients. The entire right upper lobe bronchus originates from the trachea in 0.5% of patients. The pulmonary arterial supply of the right upper lobe arises from two main branches: the truncus anterior branch, which originates in the hilum, and the ascending branches, which originate within the pulmonary parenchyma. The variations of the pulmonary artery anatomy of the right upper lobe were well outlined by Milloy and colleagues (Milloy et al, 1963).6 The truncus anterior is the first and largest branch of the right pulmonary artery. It usually bifurcates after traveling for about 1 cm. In 3.6% of patients, the anterior trunk is split, and two small branches arise separately from the main pulmonary artery. Rarely, the anterior trunk has three branches. The truncus anterior is found in all patients. In 10% of patients, the truncus anterior is the only arterial supply of the right upper lobe. The ascending branches of the right upper lobe originate from the pulmonary artery after it enters the pulmonary parenchyma. These branches ascend to enter the inferior surface of the right upper lobe. In 90% of patients, there is an ascending arterial contribution. In 60% of patients, there is

Ch035-F06861.indd 406

one branch; in 29%, two branches; and in 1%, three ascending branches. The ascending artery may be a posterior ascending branch that supplies the posterior segment of the right upper lobe. This is the most common ascending artery and is seen in 88% of patients with ascending arteries. This artery arises from the lateral and posterior aspect of the pulmonary artery, opposite the middle lobe branch, and it lies anterior to the junction of the inferior margin of the upper lobe bronchus and the bronchus intermedius. In 12% of patients, this artery originates from a common trunk with the superior segmental artery. The anterior ascending artery is seen in 25% of patients and supplies a portion of the anterior segment of the right upper lobe. It arises from the lateral aspect of the pulmonary artery opposite the middle lobe branch. Ninety-nine percent of these arterial branches are single, and only 1% arise from a common trunk with the middle lobe artery. The superior pulmonary vein drains both the upper and middle lobes. It is crucial during a right upper lobectomy to identify and preserve the middle lobe vein. The venous drainage of the upper lobe is variable but usually consists of three venous tributaries: the apical anterior, the inferior, and the posterior veins. The azygous lobe is the major anomaly of segmentation in the right upper lobe, and it is seen in fewer than 1% of patients. It is not a supernumerary lobe but instead is a segregated portion of the right upper lobe. As such, it does not have an individual or anomalous bronchovascular supply. The azygous lobe is associated with the azygos vein, which has a long, dangling mesentery; this accessory lobe is formed medial to the pleural septation of the azygos vein.

RIGHT MIDDLE LOBE The bronchus intermedius continues as the right bronchus after the origin of the right upper lobe. It is 2 to 4 cm long and terminates at the origin of the middle and lower lobe bronchi. The middle lobe bronchus is on average 1.8 cm long. Generally, the bronchus bifurcates to form the two segmental bronchi; rarely (in 3% of patients), a bifurcate bronchus is seen.7 An analysis of 225 specimens by Wragg and associates8 demonstrated that the pulmonary arterial supply of the middle lobe is from one artery in 46.5% of patients. It usually arises as the first branch of the pars intralobares after the origin of the truncus anterior. It originates from the anterior and medial surface of the pulmonary artery at the level of the ascending branch of the upper lobe. More commonly (in 51.5% of patients), the middle lobe is supplied by two arteries. The second artery arises, in 48.5% of patients, from the pulmonary artery at the level of and opposite to the branch to the superior segment of the right lower lobe. This second branch arises from the ascending branch of the right upper lobe in 0.5% of patients and from a common trunk with a basal segmental artery in 2.5% of patients. Rarely (in 2% of patients), three branches supply the middle lobe. The middle lobe vein joins the upper lobe vein to form the superior pulmonary vein. Lindskrog and associates9 demonstrated that, in most patients (64%), the two segmental veins join to form the middle lobe vein. In 36% of patients, the

1/21/2008 11:13:55 AM

Chapter 35 Anatomy of the Lung

two segmental veins terminate separately at the superior pulmonary vein.

RIGHT LOWER LOBE The segmental bronchi of the right lower lobe arise with the middle lobe bronchus at the termination of the bronchus intermedius. The superior segmental bronchus originates from the posterior and lateral aspect of the bronchus intermedius, usually opposite or slightly above the middle lobe bronchus. In 6% of patients, the superior segmental bronchus arises as two separate orifices that are 6 to 10 mm apart.10 Below these are the four basal segmental bronchi of the right lower lobe. Usually, the medial basal segmental bronchus is the most proximal basal branch. The anterior basal bronchus is next, and then a common stem for the lateral basal and posterior basal bronchi is usually seen. The middle lobe bronchus must be protected during right lower lobectomy. The abrupt termination of the bronchus intermedius into the middle lobe bronchus and superior and basal segmental bronchi makes compromise of the middle lobe bronchus a distinct possibility if the lower lobe segmental bronchi are taken en masse. Identification of all three bronchi and separate control of the superior segmental and basal segmental bronchi minimize this complication. Wragg and associates (Wragg et al, 1968)8 provided the largest modern description of the arterial supply of the right lower lobe. In 78% of patients, the superior segment of the right lower lobe is supplied by a single arterial branch. Two branches to the superior segment are seen in 21% of patients. Rarely (<1% of patients), three branches to this segment are found. Branches to the segment may be displaced in their origin or arise as common trunks, either from the ascending branch of the upper lobe or from the basal segmental arteries of the lower lobe. Between 12% and 14% of arterial branches to the superior segment arise from a common branch with the ascending branch of the upper lobe. In 6% of patients, the superior segmental artery arises from a basal segmental artery. The basal segmental arterial supply is variable, but in general this artery, which lies posterolateral to the bronchus, sends branches to the anterior basal and medial basal segments. The pulmonary artery then terminates by division into the lateral basal and posterior basal segmental arteries. The inferior pulmonary vein usually consists of two segmental tributaries: the superior and the common basal veins. In general, the common basal vein is composed of two major veins: the superior basal vein (which drains the medial basal, anterior basal, and lateral basal segments) and the inferior basal vein (which usually drains the lateral basal and posterior basal segments). One third of patients have three or four branches of the common basal vein. Rarely, venous drainage is received from the posterior segment of the right upper lobe or from the middle lobe.

407

lobe bronchus, bifurcates almost immediately, forming the lingular orifice and the common bronchus to the anterior and apical posterior segments. The left upper lobe has the most variable pulmonary arterial supply of all lobes. In an analysis of 300 specimens, Milloy and colleagues (Milloy et al, 1968)11 provided the most complete description of the left upper lobe arterial supply. The number of branches varies from one to eight. In 46% of patients, three branches supply the left upper lobe, and in 36%, four branches are found. The arterial branches arise as two groups: the truncus anterior and the posterior arterial branches, which originate in the fissure along the inner curve of the pulmonary artery. The truncus anterior is large, short, and partially hidden by the superior pulmonary vein. It is the origin of a hidden deep branch to the anterior or lingular segments in one fourth of patients and is frequently invaded by large left upper lobe tumors. All of these factors make mobilization of the truncus anterior hazardous and lead surgeons to refer to the truncus anterior as the “artery of sorrow.” In fewer than 1% of patients, the truncus anterior is the only arterial supply of the left upper lobe. In about 70% of patients, two branches of the anterior trunk are present; the remainder, in near-equal proportions, have one or three branches. In most patients, the apical posterior and anterior segments are supplied by this branch (62.3%). In 8% of patients, the anterior and lingular segments are supplied by this branch. In 15.6% of patients, three branches of this artery supply all segments of the left upper lobe. In 13.9% of patients, only one branch is seen, supplying variably the apical posterior or anterior segments. The remaining blood supply of the left upper lobe comes from the posterior segmental arteries. These arteries arise along the inner curve of the pulmonary artery, in the fissure as it wraps around the left upper lobe bronchus. These vessels pass into the posterior aspect of the left upper lobe. There may be zero to five posterior artery branches. In 65% of patients, no common trunks are seen. In 35% of patients, however, common trunks of these posterior branches are found. In 5% of patients, there is only one posterior branch to the left upper lobe; in 46%, two; in 36%, three; in 12%, four; and in 1%, five posterior branches. The segmental arterial supply to the left upper lobe is variable, with anterior and lingular segments receiving one to three branches. The apical posterior segment may receive as many as four separate branches. The venous drainage of the left upper lobe is similarly divergent. The superior pulmonary vein may receive two major branches, three major branches, or a number of radiating veins. Generally, it is the terminus of the anterior, apical posterior, and lingular veins; however, these veins may have multiple branches. Because the vein lies anterior to the pulmonary artery, all except its deep branches may be appreciated in the anterior dissection of the hilum.

LEFT UPPER LOBE The left main bronchus, which is 4 to 6 cm long, passes at an oblique angle under the aortic arch and bifurcates to form the upper and lower lobe bronchi. The left upper lobe bronchus, which originates much lower than does the right upper

Ch035-F06861.indd 407

LEFT LOWER LOBE The lower lobe bronchus arises with the upper lobe bronchus at the termination of the left main bronchus. The first segmental branch, the superior segmental bronchus, originates

1/21/2008 11:13:55 AM

408

Section 3 Lung

posteriorly and laterally. In fewer than 1% of patients, it has a bifurcate origin. About 1 to 2 cm beyond this, the common basal trunk is found. In 80% of patients, it immediately bifurcates; in the remainder, it branches into the three segmental bronchi.12 The arterial supply of the left lower lobe is derived solely from arteries arising in the fissure. The superior segment of the lower lobe is supplied by a single artery in 72% of patients (Wragg et al, 1968).8 In 26% of patients, two superior segmental arteries are found. In 2% of patients, three arteries supply the superior segment. These arteries usually arise directly from the pulmonary artery; however, in fewer than 3% of patients, one of them originates from a common trunk with a posterior artery of the left upper lobe. In as many as 12% of patients, a common trunk with a basal segmental artery is found. The frequency of a shared trunk with a basal segmental artery is similar for the superior segments of both the right and left lower lobes. A common trunk with an upper lobe artery is seen more commonly on the right. The basal segmental artery is the termination of the left pulmonary artery after the origin of the superior segmental

Confluence of the fissures

and lingular branches. In about half of patients, the artery bifurcates to supply the anteromedial segment and the combination of the posterior and lateral segments. In the remaining patients, the branching varies and ranges from two to four segmental branches. The venous drainage of the left lower lobe is similar to that of the right lower lobe. The inferior pulmonary vein receives two major branches: the superior segmental and the common basal veins.

FISSURES The relationship of the bronchovascular structures of the lobes and segments is best appreciated by describing their relationship during control of the fissures.

Right Major Fissure The pulmonary artery may be palpated at the confluence of the major and minor fissures (Fig. 35-11). Dissection of the pulmonary parenchyma permits the pulmonary artery to be identified in its interlobar position. The posterior branch of

Middle lobar pulmonary artery

Posterior ascending segmental artery

Basal segmental pulmonary artery

Superior segmental pulmonary artery

Lymph node #11

A

Right upper lobe bronchus

B

Bronchus intermedius Lymph node #11 Right main bronchus

C FIGURE 35-11 The posterior superior dissection of the right major fissure. A, Dissection at the confluence of the fissures allows identification of the pars intralobares of the pulmonary artery and its major branches. The dissection is carried out between the posterior ascending segmental artery and the superior segmental artery. B, The posterior hilar dissection is carried out between the inferior margin of the right upper lobe bronchus and the bronchus intermedius. C, The posterior superior portion of the right major fissure is completed by connecting the dissections of the pulmonary artery (A) and the bronchus (B).

Ch035-F06861.indd 408

1/21/2008 11:13:55 AM

Chapter 35 Anatomy of the Lung

the superior pulmonary vein commonly runs in this interlobar plane and may overlie and obscure the pulmonary artery. In addition, an interlobar lymph node (R11), commonly referred to as the sump node, is found overlying the pulmonary artery. After the pars intralobares has been identified, the branches of the pulmonary artery in this area may be mobilized. They are identified as follows: anteriorly, the superior branch of the middle lobe; posteriorly and superiorly, the posterior ascending branch of the right upper lobe; posteriorly and inferiorly, the superior segmental arterial branch of the right lower lobe; and inferiorly, the bifurcating termination of the pulmonary artery supplying the basal segments. Dissection in the notch between the posterior ascending and superior segmental arterial branches allows the identification of a posterior interlobar lymph node (R11; see Fig. 35-11A). Next, the hilum is approached posteriorly, and the angle between the inferior margin of the right upper lobe bronchus and the bronchus intermedius is dissected (see Fig. 35-11B). In this notch between the bronchi, the posterior aspect of the posterior interlobar lymph node is seen. The posterior superior portion of the major fissure may be controlled if the posterior interlobar lymph node is mobilized and the poste-

409

rior dissection around the bronchi is then connected to the posterior and lateral pulmonary arterial dissection in the fissure (see Fig. 35-11C). Return to the confluence of the fissures allows control of the anterior inferior portion of the right major fissure (Fig. 35-12A). Dissection in the notch between the inferior pulmonary artery branch of the middle lobe and the adjacent basal segmental artery reveals the bronchi deep to these arteries. An anterior interlobar lymph node (R11) is found lying in the notch between the middle lobe and the basal segmental bronchi. Next, the hilum is approached anteriorly, and the space between the superior and inferior pulmonary veins is cleared (see Fig. 35-12B). Dissection in this notch allows the identification of the middle lobe and basal segmental bronchi and the anterior surface of the previously identified anterior interlobar lymph node. The anterior inferior portion of the major fissure may be controlled if the anterior interlobar lymph node is mobilized and the anterior dissection around the pulmonary veins is connected to the anterior and lateral pulmonary arterial dissection in the fissure (see Fig. 35-12C).

Middle lobar pulmonary artery

Basal segmental pulmonary artery

Middle lobe vein Upper lobe vein Superior segmental pulmonary artery

Posterior ascending segmental artery

A

B

Right superior pulmonary vein Right inferior pulmonary vein

C FIGURE 35-12 The anterior inferior dissection of the right major fissure. A, Dissection at the confluence of the fissures allows identification of the pars intralobares and its branches in the fissure. The dissection is carried out between the inferior middle lobe artery and the basal segmental artery. B, The anterior hilar dissection is carried out between the superior and inferior pulmonary veins. C, The anterior inferior portion of the right major fissure is completed by connecting the dissections of the pulmonary artery (A) and the pulmonary veins (B).

Ch035-F06861.indd 409

1/21/2008 11:13:56 AM

410

Section 3 Lung

Right Minor Fissure (Horizontal Fissure)

Left Major Fissure

The horizontal fissure is usually incomplete (poorly developed). Usually, it is the last structure controlled in a middle or upper lobectomy; however, management of this fissure may be necessary as an early step in these surgical procedures. Again, the control of this fissure commences with a dissection at the confluence of the fissures. The pars intralobares of the pulmonary artery is identified in the fissure. The superior arterial branch of the middle lobe is identified anteriorly. In about one fourth of patients, the anterior ascending branch of the right upper lobe is found at this level, lying opposite the highest middle lobe branch (Fig. 35-13A). Next, the hilum is approached anteriorly, and the space between the middle lobe vein and the inferior segment vein of the upper lobe is dissected (see Fig. 35-13B). Care must be taken during dissection not to damage the posterior vein branch, which joins the upper lobe vein from deep within the pulmonary parenchyma. The minor fissure may be controlled if the anterior dissection around the superior pulmonary vein is connected to the lateral pulmonary arterial dissection in the fissure (see Fig. 35-13C).

The pulmonary artery may be palpated in the midportion of the major fissure (Fig. 35-14). Dissection of the pulmonary parenchyma permits the pulmonary artery to be identified in its interlobar position. An interlobar lymph node (L11), the left sump node, is found overlying the pulmonary artery. The branches of the pulmonary artery may now be mobilized: anteriorly, the posterior branches of the upper lobe supplying the apical posterior and lingular segments; posteriorly, the superior segmental artery; and inferiorly, the basal segmental arteries (see Fig. 35-14A). Next, the hilum is approached posteriorly, and the main pulmonary artery is mobilized as it enters the pulmonary parenchyma (see Fig. 35-14B). Dissection allows the posterior surface of the superior segmental artery to be defined. The posterior superior portion of the major fissure may be controlled if the posterior dissection of the pulmonary artery at the hilum is connected in the plane of the pulmonary artery to the lateral pulmonary arterial dissection in the fissure (see Fig. 35-14C). Care is taken to dissect in the plane above the pulmonary arterial adventitia and between the

Middle lobar pulmonary artery

Completed major fissure

Posterior ascending segmental artery Middle lobe vein

Basal segmental pulmonary artery

Upper lobe vein

Completed major fissure

Superior segmental pulmonary artery Right inferior pulmonary vein

A

Right superior pulmonary vein

B

C FIGURE 35-13 The dissection of the minor (horizontal) fissure. A, Dissection at the confluence of the fissures allows identification of the pars intralobares and the branches to the middle lobe. B, The anterior hilar dissection is carried out between the middle lobe vein and the inferior segmental vein of the upper lobe. C, The minor fissure is completed by connecting the dissections of the pulmonary artery (A) and the pulmonary veins (B).

Ch035-F06861.indd 410

1/21/2008 11:13:56 AM

Chapter 35 Anatomy of the Lung

posterior branches to the upper lobe and the superior segmental branch to the lower lobe. Return to the fissure allows control of the anterior inferior portion of the left major fissure. Dissection in the notch between the lingular segmental artery branch and the adjacent basal segmental artery reveals the bronchi deep to these arteries. An anterior interlobar lymph node (L11) is found lying in the notch between the lingular and basal segmental bronchi (Fig. 35-15A). Next, the hilum is approached anteriorly, and the space between the superior and inferior pulmonary veins is cleared (see Fig. 35-15B). Dissection in this notch allows identification of the lingular and basal segmental bronchi and the anterior surface of the previously identified anterior interlobar lymph node. The anterior inferior portion of the major fissure may be controlled if the anterior interlobar lymph node is mobilized and the anterior dissection around the pulmonary veins is connected to the anterior and lateral pulmonary arterial dissection in the fissure (see Fig. 35-15C).

PULMONARY LYMPHATICS Narake and colleagues13 were the first to propose a mapping system for the regional lymph nodes of the lung. This refined map is now a mainstay in the staging of primary bronchogenic

411

carcinomas (Fig. 35-16).14 The regional lymph nodes of the lung are arranged into 14 lymph node stations. Lymph nodes 1 through 9 are mediastinal lymph nodes. Metastases to mediastinal lymph nodes represent N2 or N3 disease in the TNM (tumor, nodes, and metastases) classification system, depending on whether the metastases are ipsilateral (N2) or contralateral (N3). Hilar lymph nodes are designated as station 10. Lymph nodes 11 through 14 are intrapulmonary lymph nodes. Metastases to lymph nodes 10 through 14 are termed stage N1 disease. If no lymph node metastases are found, the regional lymph node status is stage N0. Supraclavicular lymph nodes are not included in this map, but metastases to regional lymph nodes on either side of the neck are classified as N3 disease. The highest mediastinal node is a pretracheal node, sometimes called the Delphian lymph node. It is frequently involved with thyroid carcinoma but is infrequently a site of metastasis in primary lung cancer. It is encountered at the beginning of mediastinoscopy during the identification of the pretracheal plane. Lymph nodes 2, 4, and 7 are found around the trachea and are easily assessed at mediastinoscopy. These are the right and left paratracheal (2R and 2L), the right and left tracheobronchial angle (4R and 4L), and the subcarinal (7) lymph nodes. These nodes may also be identified at thoracotomy, but sampling of 2L and 4L may be difficult because they are obscured by the aortic arch.

Lingular segmental pulmonary artery Apical posterior-segmental pulmonary artery Mid portion of fissure

Superior segmental pulmonary artery

Basal segmental pulmonary artery

A

B Left inferior pulmonary vein

Left main pulmonary vein Left main bronchus

C FIGURE 35-14 The posterior superior dissection of the left major fissure. A, Dissection in the midportion of the left major fissure allows the pulmonary artery in its interlobar position and the branches of the pulmonary artery to be identified. B, The posterior hilar dissection of the pulmonary artery allows identification of the branches to the upper and lower lobes. C, The posterior superior portion of the left major fissure is developed by connecting the pulmonary arterial dissection in the fissure (A) to the posterior hilar arterial dissection (B).

Ch035-F06861.indd 411

1/21/2008 11:13:57 AM

412

Section 3 Lung

Lingular segmental pulmonary artery Apical posterior-segmental pulmonary artery

Left Left superior superior pulmonary veinvein pulmonary

Left Left inferior inferior pulmonary veinvein pulmonary

Left Left mainmain pulmonary artery pulmonary artery

Superior segmental pulmonary artery

A

B B

Basal segmental pulmonary artery

C FIGURE 35-15 The anterior inferior dissection of the left major fissure. A, Dissection at the midportion of the major fissure allows identification of the pulmonary artery and its branches. The dissection is carried out between the lingular pulmonary artery and the basal segmental pulmonary artery. B, The anterior hilar dissection is carried out between the superior and inferior pulmonary veins. C, The anterior inferior portion of the left major fissure may be developed by connecting the dissection around the pulmonary arteries (A) with the dissection around the veins (B).

FIGURE 35-16 Regional lymph nodes: 1, highest mediastinal; 2R and 2L, right and left paratracheal; 3a, prevascular; 3p, retrotracheal; 4R and 4L, right and left tracheobronchial; 5, aortopulmonary; 6, para-aortic; 7, subcarinal; 8, paraesophageal; 9, pulmonary ligament; 10R and 10L, right and left hilar; 11R and 11L, right and left interlobar; 12R and 12L, right and left lobar; 13R and 13L, right and left segmental; 14R and 14L, right and left subsegmental. Ao, aorta; PA, pulmonary artery.

3p Brachiocephalic (innominate) artery

1

3a

2L 2R

Right lateral view

5

Azygos vein

4R

Ligamentum arteriosum

4L

10R 12R 13R

11R

7 10L

8 9

14R

Pleural reflection Anterior view

Ch035-F06861.indd 412

11L

Left main pulmonary artery

12L 13L

14L Inferior pulmonary ligament Left lateral view

1/21/2008 11:13:57 AM

Chapter 35 Anatomy of the Lung

Not obtainable by standard cervical mediastinoscopy are lymph nodes in the prevascular (3a), retrotracheal (3p), subaortic (5), and para-aortic (6) spaces. These may be obtained by anterior mediastinotomy (the Chamberlain procedure), thoracoscopy, or thoracotomy. Extended cervical mediastinoscopy15 has been used to access lymph node stations 5 and 6. The paraesophageal (8) and inferior pulmonary ligament (9) lymph nodes can be sampled by thoracoscopy or dissected at thoracotomy. Hilar lymph nodes (10) may be obtained by mediastinotomy, thoracoscopy, or thoracotomy. Interlobar lymph nodes (11) are found in the fissures, surrounding the pulmonary arteries or bronchi. Lobar (12), segmental (13), and subsegmental (14) lymph nodes can be reliably sampled only at thoracotomy. The classic drainage pathway of the pulmonary lymphatics is from subpleural lymphatic vessels along lymphatic channels that are associated with the pulmonary veins to reach larger channels that run with the arteries and bronchi. These deeper lymphatic channels drain into segmental, lobar, interlobar, hilar, and mediastinal nodes. Riquet and coworkers16 demonstrated segmental drainage of subpleural lymphatic channels in 90.5% of patients. In 9.5% of patients, the drainage was intersegmental. In 77.8% of right-sided studies, intrapulmonary drainage was demonstrated; however, 22.2% of patients had direct drainage to mediastinal lymph nodes, bypassing the classic drainage pattern. This was slightly more common on the left. Twenty-five percent of studies show direct mediastinal drainage that circumvents the classic intrapulmonary pathway. The drainage of the parenchymal lymphatic channels to mediastinal lymph nodes is generally ipsilateral and directed toward the trachea. Anomalies of drainage are more likely to be found on the left. The left lower lobe lymphatic vessels drain through the subcarinal lymphatic channels to the rightsided mediastinal nodes in up to one third of patients. However, drainage appears to be predominantly left sided. Baker and associates17 demonstrated, in live human subjects, drainage of left lower lobe lymphatic channels to left scalene nodes in eight of nine patients, but to right-sided scalene nodes in only three of nine. The left upper lobe has dual drainage, with lymph flowing from lobar, interlobar, and hilar nodes to subcarinal, left tracheobronchial, and paratracheal lymph nodes. The alternative pathway is to the subaortic, periaortic, and anterior mediastinal nodes. Among patients with left upper lobe tumors and N2 disease, one third have metastases that are confined to the classic pathway, one third have metastases that are confined to the alternative pathway by the subaortic window, and one third have metastases to both chains. In patients with bronchogenic carcinoma and positive mediastinoscopy, Funatsu and colleagues18 found the greatest incidence of contralateral mediastinal metastases to be from left lung and lower lobe tumors. Spread to contralateral mediastinal nodes (N3 disease) was found in 50% of left lower lobe tumors and in 35% of left upper lobe tumors. For right lung tumors with positive mediastinoscopy, 42% of right lower lobe tumors, 18% of right upper lobe tumors, and none

Ch035-F06861.indd 413

413

of the middle lobe tumors had metastases to contralateral mediastinal nodes, despite the fact that middle lobe tumors often drain to subcarinal lymph nodes as their first mediastinal nodal station.

BRONCHIAL CIRCULATION Most bronchial arteries arise from the anterolateral aspect of the aorta or its branches within 2 to 3 cm of the origin of the left subclavian artery (Fig. 35-17). About 20% of origins are either higher or lower. Usually, the arteries to the right and left lungs arise separately; however, common trunks may be found in 25% of patients. Origin from the intercostal arteries is uncommon on the left but common on the right. Liebow19 and Cauldwell and associates,20 in two large autopsy series, found an intercostal origin for a right bronchial artery in 43% to 89% of specimens. There are two arteries to each lung in 20% to 30% of patients. The most common distribution is three bronchial arteries, with dual supply to the left being more common. There are two left arteries and one right artery in 20% to 40% of patients, and

Right intercostal artery

Right bronchial artery

Right intercostal artery

Left bronchial arteries

FIGURE 35-17 The bronchial arterial anatomy is variable. The most frequent bronchial arterial supply (top) is one right bronchial artery arising from an intercostal artery and two left bronchial arteries with separate aortic origins. The smaller images (bottom) demonstrate the next three most common bronchial arterial arrangements.

1/21/2008 11:13:59 AM

414

Section 3 Lung

two right arteries and one left artery in 10% to 16% of patients. In 10% to 21% of patients, there is only one artery to each lung. Before reaching the airway, the bronchial arteries give off esophageal branches. These, along with direct branches from the aorta, account for a significant portion of the midthoracic esophageal blood supply. The arteries then pass posteriorly to the airway to lie on the membranous portion of the main stem bronchi. They divide to supply lobar and segmental branches. There is a rich anastomosis with the pulmonary arteries. These anastomoses are important for the initial blood supply of the airway after bronchoplastic resections and pulmonary transplantation. Most of the venous drainage from the bronchial arteries passes into the pulmonary venous system. Marchand and coworkers21 pointed out, however, that a second group of veins forms a venous network around the first two or three divisions of the bronchi and drain a small portion of bronchial arterial blood into the azygos system on the right or the hemiazygos on the left.

COMMENTS AND CONTROVERSIES The importance of a detailed knowledge of the physical anatomy of the thorax cannot be underestimated in the training and practice of a general thoracic surgeon. For surgeons in training, this chapter should be read and reread. Intimate knowledge of the anatomy of the fissures, the recesses of the pericardium, and the relationships of the lobes and vascular structures of the mediastinum allows the thoracic surgeon complete command in the operating room, despite the intricacies of the surgery. Detailed knowledge of lymphatic drainage, including the anatomy of the thoracic duct, is important for staging of lung cancer and to avoid thoracic duct catastrophes. It has been our practice to review and reinforce this knowledge by spending time in the postmortem room, dissecting the area of concern on cadavers, before embarking on an unusual or new surgical procedure. Dr. Rice’s chapter provides a basis for knowledge of the surgical anatomy and of the practical applications in performing pulmonary resections and reconstructions. R. J. G.

KEY REFERENCES

PULMONARY NERVES The vagus nerve and the sympathetic ganglia send branches to the lungs. In the hilum, they form a poorly developed anterior plexus around the main pulmonary arteries and a well-developed posterior plexus around the bronchi. The nerves then pass into the pulmonary parenchyma, where they divide into the periarterial plexus or the peribronchial plexus. The periarterial plexus contains only nonmyelinated fibers; both myelinated and nonmyelinated fibers are found around the bronchus. Bronchoplastic procedures, lung transplantation, and sometimes hilar dissections result in denervation of the lung. The loss of neural control of the bronchial glands and the smooth muscle of the bronchi and arteries is of minimal clinical importance. Loss of the cough reflex as a result of this denervation can be critical.

Ch035-F06861.indd 414

Milloy FJ, Wragg LE, Anson BJ: The pulmonary arterial supply to the right upper lobe of the lung based upon a study of 300 laboratory and surgical specimens. Surg Gynecol Obstet 116:34, 1963. ■ A large, modern study using current terminology describes the variations in the pulmonary arterial supply of the right upper lobe. This is the first in a series of three articles that describe the lobar pulmonary artery supply. Milloy FJ, Wragg LE, Anson BJ: The pulmonary artery supply to the upper lobe of the left lung. Surg Gynecol Obstet 126:811, 1968. ■ The second in the series, this article outlines the variations in the pulmonary arterial supply of the left upper lobe. Wragg LE, Milloy FJ, Anson BJ: Surgical aspects of the pulmonary artery supply to the middle lobe and lower lobes of the lungs. Surg Gynecol Obstet 127:531, 1968. ■ The last of this series, this large, modern study describes the variations in the pulmonary arterial supply of the middle and lower lobes.

1/21/2008 11:13:59 AM

chapter

IMAGING THE LUNGS

36

Theresa McLoud

Key Points ■ Chest radiography is still the key imaging technique for evaluation

of the chest. However, multidetector computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose–positron emission tomography (FDG-PET) have become increasingly important. ■ CT has become the imaging method of choice for evaluation of pulmonary embolism. ■ High-resolution CT provides significant diagnostic information in diffuse infiltrative lung disease. FDG-PET has added a new dimension for both diagnosis of malignant nodules and local and distant staging of lung cancer.

EXAMINATIONS, TECHNIQUES, AND INDICATIONS Chest Radiography Plain chest radiography is the most commonly performed imaging procedure in most radiology practices, typically constituting between 30% and 50% of studies. The standard routine chest radiograph consists of an erect radiograph made in the posterior-anterior (PA) projection and a left lateral radiograph, both obtained at full inspiration. The target-film distance is 6 feet. Chest radiographs are exposed using a high kilovoltage peak (kVp) technique in the range of 100 to 140 kVp (Fig. 36-1). The main advantage of this technique is that the bony structures appear less dense, permitting better visualization of the underlying parenchyma as well as the mediastinum (McLoud, 1998).1 Shallow oblique radiographs (15 degrees) may be useful for determining the presence of a suspected nodule. Forty-five degree oblique radiographs are recommended for the detection of asbestosrelated pleural plaques. Apical lordotic views (Fig. 36-2) project the clavicles above the chest, improving visualization of the apices and also the right middle lobe (McLoud, 1998).1,2 Expiration chest radiographs can be used to detect air trapping or to confirm small pneumothoraces. Lateral decubitus radiographs are commonly employed to determine the presence or mobility of pleural effusions. These views can also be obtained to detect small pneumothoraces, particularly in patients who are confined to bed and unable to sit or stand erect. Bedside portable examinations may account for as many as 50% of chest radiographs obtained on inpatients. The diagnostic quality of such images is usually limited because of the increased exposure time needed, which results in

respiratory motion. Magnification of the heart and anterior mediastinal structures frequently occurs. For many very ill patients, including patients in the intensive care units, radiography must be performed at the bedside, resulting in radiographs with limited diagnostic information. During the past decade, rapid advances in electronics and computer technology have created new possibilities for x-ray imaging, including specific receptor systems independent of film, which permit imaging information to be recorded in digital form and displayed on a picture archiving and communication (PACS) workstation. These systems include photostimulable phosphors, computed radiography systems, and selenium-based digital chest systems.3-5 A new generation of direct readout x-ray detectors based on thin film transistor arrays has emerged, offering unsurpassed image quality from a compact digital detector. Storage phosphor computed radiography systems employ a reusable imaging plate in place of the traditional screen film detector.3 These were first introduced in the middle to late 1980s and have been widely used for bedside radiography. The linear response of photostimulable phosphors over an extremely wide range of radiation exposure makes their application particularly good for portable radiography. A new generation of digital x-ray systems based on flat panel detectors is now emerging which provides good image quality and very rapid direct access to digital images. Most of these systems use a large area of thin film transistor arrays. They offer compact packaging and direct connection to digital imaging networks. Imaging quality from digital acquisition systems has been shown to be equivalent and in many cases better than that of standard film radiography.

Fluoroscopy Fluoroscopy has become rather obsolete with the widespread application and utilization of CT. Fluoroscopy is mainly restricted to the evaluation of diaphragmatic motion. The patient is placed in an oblique position so that the hemidiaphragms can be visualized simultaneously. If diaphragmatic paralysis is present, the affected hemidiaphragm will move up during a rapid inspiratory maneuver, such as a sniff (McLoud, 1998).1

Computed Tomography CT is used as a diagnostic study, usually after abnormal findings on standard chest radiography. Indications for CT include the following (McLoud, 1998; Naidich et al, 1998)1,6: 1. Staging of lung cancer 2. A solitary pulmonary nodule, mass, or opacity 415

Ch036-F06861.indd 415

1/21/2008 11:15:01 AM

416

Section 3 Lung

A

B

FIGURE 36-1 Standard posterior-anterior (A) and lateral (B) chest radiographs obtained at 140 kVp with a 12-to-1 grid and automated phototimed exposure. Note the visibility of retrocardiac vessels and mediastinal structures. Note companion shadow of left clavicle (arrow). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

In regard to the lung parenchyma, CT may be used for the detection of occult disease. Indications include the following (McLoud, 1998; Naidich et al, 1998)1,6: 1. Detection of metastatic disease from extrathoracic neoplasms 2. Hemoptysis and/or suspected bronchiectasis 3. Evaluation of patients with endocrine abnormalities that are associated with suspected lung tumor 4. Search for an unknown source of infection, especially in immunocompromised patients 5. Evaluation of the pulmonary parenchyma in patients with normal chest radiographs and suspected diffuse infiltrative lung disease or emphysema 6. Quantification and determination of the extent of emphysema before lung reduction surgery FIGURE 36-2 Apical lordotic view. The clavicles are projected above the apices of the lungs. There is an excellent demonstration of right middle-lobe collapse. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

3. Diffuse infiltrative lung disease 4. Widened mediastinum, mediastinal mass, or other abnormality of the mediastinum 5. Abnormal hilum 6. Pleural abnormalities or the need to differentiate pleural from parenchymal abnormalities 7. Chest wall lesions 8. Trauma 9. Diagnosis of pulmonary embolism

Ch036-F06861.indd 416

CT scans are performed in deep inspiration and at total lung capacity. For routine helical CT of the chest, 2.5- to 5-mm sections are recommended. Thinner (1-2.5 mm) sections can be used to study fine details of the pulmonary parenchyma (high-resolution CT) (McLoud, 1998; Webb et al, 2000).1,7 A short scan time of 0.8 to 1 second is necessary to reduce the effect of motion. On routine studies the field of view is adjusted to the size of the thorax, but small fields of view may be selected for smaller anatomic parts that require study. In regard to window settings, the routine is to obtain or view at least three window settings: the lung parenchyma, the mediastinum, and the bony structures. High-resolution CT requires an algorithm with high spatial resolution that on most scanners corresponds to the bone algorithm (McLoud, 1998; Webb et al, 2000).1,7 With proper knowledge of medi-

1/21/2008 11:15:01 AM

Chapter 36 Imaging the Lungs

astinal and hilar anatomy, contrast material may not be required for routine CT of the thorax, especially with thinner slice thicknesses of 2.5 mm or less. However, contrast material is helpful in most circumstances, and it is necessary for the evaluation of known or suspected vascular abnormalities such as pulmonary embolism. A power contrast injector is always used. Injection of approximately 100 to 150 mL of a contrast agent with a 30% to 40% concentration of iodine, at an injection rate of 3 mL/sec, is recommended; for pulmonary embolism studies, a more rapid rate of delivery, 4 mL/ sec, is required. Although transit times vary among patients, I recommend a routine delay of at least 25 seconds between the onset of injection and the first image (McLoud, 1998; Wittram et al, 2004).1,8,9 Recent improvements in scanner technology have led to the introduction of spiral or helical volumetric CT (Fig. 36-3). Such a scanner acquires data continuously as the patient is transported through the scanner during a single breath-hold. Multidetector helical CT (MDCT) has revolutionized thoracic imaging by providing isometric volumetric scanning. Initial multidetector imaging involved four slice detectors, and these systems are still popular today. However, newer technology, involving 16 or even 64 slice detectors, allows the patient’s entire thorax to be scanned in less than 10 seconds. MDCT slice acquisition provides thinner slice thickness of an entire regional data set with the elimination of interscan gaps and minimal respiratory motion. Capabilities include multiplanar imaging with few or no artifacts of coronal, sagittal, and three-dimensional images. The greatest impacts of MDCT in the thorax have been in reconstruction of the vasculature and airways and in comprehensive imaging of trauma patients (Fig. 36-4).10,11 Pulmonary embolism studies are obtained in shorter imaging sessions, improving on patient artifact and providing better resolution of smaller subsegmental vessels.

417

pulmonary nodules and masses. PET can be routinely used for evaluation of a single pulmonary nodule that is 1 cm or larger in diameter, and for the staging and restaging of neoplasms such as lung cancer and extrathoracic malignancies (Fig. 36-5).12,13 A false-negative result in a pulmonary nodule may occur if the nodule is smaller than 1 cm. Also, tumors of relatively low metabolic activity, such as carcinoid tumor or bronchioalveolar carcinoma, may appear falsely negative.14 Because FDG-PET images the rate of glycolysis of tissues within the body, false-positive results can be seen with infection and inflammation. This may occur with focal infections such as organizing pneumonia. Because of its relatively low spatial resolution, FDG-PET imaging must be interpreted with cross-sectional imaging, as in CT. Interpretation of PET improves when CT images are also available. The added application of fusion imaging of PET and CT, either by computer registration or by dual PET/CT scanning, which is now becoming widely available, has led to even better radiologic sensitivity and specificity for detection of lymph node metastases and recurrent tumor. With dual PET/CT imaging, the CT scan is used for attenuation correction, thereby providing the high spatial resolution needed to better localize areas of increased FDG uptake on PET (Schoeder et al, 2005).15

Magnetic Resonance Imaging MRI has not had extensive application in the thorax, mainly because of problems caused by motion artifacts secondary to cardiac and respiratory motion (McLoud, 1998; Naidich

Positron Emission Tomography FDG-PET imaging, which detects the increased metabolism of neoplastic cells, is useful in the detection of malignancy in

Start of spiral scan

Direction of continuous patient transport

Path of continuously rotating x-ray tube and detector

0

z, mm

0

t, s

FIGURE 36-3 Helical CT scanning. (FROM KALENDER WA, SEISSLER W, KLOTZ E, VOCK P: SPIRAL VOLUMETRIC CT WITH SINGLE-BREATH-HOLD TECHNIQUE, CONTINUOUS TRANSPORT, AND SCANNER ROTATION. RADIOLOGY 176:181, 1990.)

Ch036-F06861.indd 417

FIGURE 36-4 Three-dimensional shaded surface display of the trachea. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

1/21/2008 11:15:02 AM

418

Section 3 Lung

A

C

et al, 1998).1,6 In addition, the normal lung does not produce a magnetic resonance signal because of magnetic susceptibility effects. Applications therefore are usually limited to the mediastinum and chest wall. MRI does provide direct imaging in the coronal and sagittal planes as well as the axial plane. It is particularly useful in the evaluation of superior sulcus tumors. In regard to techniques, they vary depending on the clinical indication. In general, a body coil is used, and images are obtained in the axial plane using two different spin-echo sequences. With high-field-strength magnets, electrocardiographic (ECG) gating is employed. T1-weighted images give information concerning the diagnosis of masses. The T2weighted images may render fluid collections distinguishable from solid masses and may help separate tumor from fibrosis (Fig. 36-6) (McLoud, 1998).1 Gadolinium contrast administration is also helpful to distinguish benign from malignant conditions. MRI of the chest is often used as a problem-solving procedure, and it needs to be correlated carefully with CT scanning.

Ch036-F06861.indd 418

B

FIGURE 36-5 Dual FDG-PET/CT scan of lung cancer. A, Fusion image from dual PET/CT scan shows increased FDG uptake in left upper lobe nodule. B, Subcentimeter hilar lymph node on CT scan is present. Although its size is less than 1 cm, this lymph node is not normally identified on CT at all. C, Fusion image from dual PET/CT scan demonstrates increased FDG uptake in this node. At surgical resection, this lymph node contained metastatic adenocarcinoma.

SIGNS OF DISEASE AND PATTERN RECOGNITION Radiographic signs of lung disease must be recognized when interpreting standard chest radiographs and CT scans of the lungs. Abnormalities on CT often parallel the changes observed on standard radiographs. However, CT often provides more detailed information because it eliminates the superimposition of abnormalities and provides more detailed and accurate anatomic localization even to the level of the secondary pulmonary lobule (McLoud, 1998).1

Alveolar Consolidation Alveolar consolidation is a term used to describe homogenous amorphous opacification in the lungs, often with air bronchograms. Alveolar disease typically has ill-defined margins with air space filling (Fig. 36-7) (McLoud, 1998).1,2,16 The appearance may be caused by the accumulation of edema, hemorrhage, or neoplastic elements within the alveolar spaces, and the interstitium may be involved as well. Parenchymal con-

1/21/2008 11:15:03 AM

Chapter 36 Imaging the Lungs

419

A

B FIGURE 36-6 MRI of bronchogenic cyst. A, T1-weighted image shows low signal intensity of the right paratracheal mass (arrow). The low signal intensity is caused by the water content of the cyst. B, On the T2-weighted image, the cyst (arrow) has greater signal intensity than fat or muscle because of the T2 value of water. (FROM MCLOUD

FIGURE 36-7 Alveolar disease caused by pulmonary edema. There are diffuse, poorly marginated central opacities with air bronchograms (arrowheads). Note the so-called butterfly or bat’s wing appearance. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

Infiltrative (Interstitial) Lung Disease

solidation is usually characterized radiographically by coalescent opacities that usually do not respect segmental boundaries. The edge characteristics are ill defined and show poor margination. An example is the so-called butterfly or bat’s wing appearance of acute pulmonary edema in left-sided congestive heart failure. Consolidation of the lung parenchyma often produces an air bronchogram. The normally invisible air within the bronchial tree becomes apparent because of the surrounding consolidation. On standard radiographs, this sign is seen for the most part when the bronchus is not occluded (e.g., by a lung carcinoma), although on CT air bronchograms can definitely be observed even distal to a bronchial obstruction (McLoud, 1998).1 Occasionally, rather minute radiolucencies may be seen within parenchymal consolidation. These may represent incompletely filled bronchioles and alveoli. This occurrence is sometimes called the air alveologram or is referred to as pseudocavitation or bubbly lucencies. One of the important features of air space consolidation is the absence of volume loss or atelectasis. There are many causes of parenchymal consolidation. This process may be either localized or diffuse. Malignancies that can cause this appearance include bronchoalveolar carcinoma and intraparenchymal lymphoma (McLoud, 1998).1

Ch036-F06861.indd 419

The infiltrative lung diseases are a group of diffuse diseases that primarily involve the interstitium, although they may eventually involve the alveoli. Examples include sarcoidosis, lymphangitic carcinomatosis, and the chronic interstitial pneumonias, such as usual interstitial pneumonitis. There are two major patterns of small opacities that can be identified in interstitial lung disease, linear and nodular.17 The nodular pattern consists of small, rounded opacities that are less than 1 cm in diameter. Nodules 1 to 2 mm in diameter are sometimes referred to as a miliary or micronodular patterns, as seen in the miliary tuberculosis. Diseases that produce a diffuse nodular pattern include the pneumoconioses, such as silicosis and coal workers’ pneumonoconiosis; the granulomatous diseases, such as sarcoidosis; and hematogenous dissemination of granulomatous infection, such as miliary tuberculosis (Fig. 36-8). The linear pattern may be fine, medium, or coarse. A typical example is interstitial edema (Fig. 36-9). Linear opacities are seen in severe fibrosis that may result in end-stage lung disease (Fig. 36-10). Typically, the lung consists of cystic spaces, which result from breakdown of alveolar walls and the dilation of terminal and respiratory bronchioles. These cystic spaces are thick walled and lined by fibrosis. The pattern is referred to as honeycombing and includes such diseases as usual interstitial pneumonitis (idiopathic pulmonary fibrosis), asbestosis, and, occasionally, end-stage sarcoidosis.

1/21/2008 11:15:04 AM

420

Section 3 Lung

FIGURE 36-8 Nodular pattern of silicosis. There are multiple small, rounded opacities or nodules ranging in size from 2 to 4 mm. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

A distinctive type of opacification may be identified in infiltrative lung diseases on CT. Referred to as ground-glass opacification, it is an amorphous increase in attenuation in the lung parenchyma through which the normal pulmonary vessels can be visualized (Müller, 1991; Naidich et al, 1998).6,18 The latter characteristic distinguishes ground-glass opacification from alveolar consolidation, which produces higher attenuation and usually obliterates the vessels within the lung parenchyma. Among the infiltrative lung diseases, some may produce a diffuse alveolar pattern, such as chronic eosinophilic pneumonia and pulmonary alveolar proteinosis. High-resolution CT delineates similar patterns but in addition provides better localization of disease and can often resolve anatomic abnormalities to the level of the secondary pulmonary lobule (McLoud, 1998; Naidich et al, 1998).1,6 Some of the characteristics of linear opacities observed on high-resolution CT include thickening of the bronchovascular bundles, interlobular septal thickening (septal lines), intralobular interstitial thickening, and honeycombing. Certain disease processes, such as lymphangitic spread of carcinoma and sarcoidosis, typically demonstrate thickening of the axial (central) interstitium. Diseases characterized by a diffuse nodular pattern often fall into one of three categories on high-resolution CT, based on the distribution of the nodules: lymphatic distribution (sarcoidosis), centrilobular distribution (hypersensitivity pneumonitis), and random distribution (miliary tuberculosis). Typically, cysts can be more easily identified and characterized on high-resolution CT (McLoud, 1998; Naidich et al, 1998).1,6 Honeycomb cysts are seen in end-stage fibrosis (Fig. 36-11). These are usually thick-walled and less than 1 cm in diameter, and they occur in the peripheral portions of the lungs. Thin-walled cysts can be identified in such diseases as Langerhans cell histiocytosis and lymphangioleiomyomatosis. High-resolution CT also provides a better depiction of the distribution of disease: an axial distribution characterized by thickening of the bronchovascular bundles (sarcoidosis, lymphangitic spread of tumor) or a peripheral distribution (organizing pneumonia, chronic eosinophilic pneumonia). Pure ground-glass opacification may be seen in such entities as pulmonary hemorrhage, Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia, desquamative interstitial pneumonitis, and pulmonary alveolar proteinosis (McLoud, 1998; Müller, 1991; Naidich, 1998).1,6,18

Atelectasis

FIGURE 36-9 Interstitial edema. There is thickening of the axial interstitium caused by edema fluid, manifested by thickened bronchial walls (larger arrowheads). The interlobular septa are also thickened (Kerley B lines) by edema fluid. These short subpleural lines are best seen at the lung bases (smaller arrowheads). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

Ch036-F06861.indd 420

Atelectasis may be defined as a decrease in volume of a lung or a portion of the lung. There are a number of types of atelectasis that are related to the mechanism by which the loss of volume occurs. The most common type is that caused by central bronchial obstruction, which usually leads to lobar or, less frequently, segmental collapse (McLoud, 1998).1,2 The second major type is passive atelectasis, which is collapse caused by extrinsic pressure on the lung, either from air, fluid, or both in the pleural space or at the edge of a local spaceoccupying lesion such as a mass in the lung. Atelectasis or loss of volume may also occur in areas of pulmonary fibrosis. Occasionally, atelectasis can be patchy and caused by widespread collapse of alveoli. This typically occurs in the post-

1/21/2008 11:15:05 AM

Chapter 36 Imaging the Lungs

operative situation or in the adult respiratory distress syndrome.

the affected lobe and displacement of the interlobar fissures (McLoud, 1998)1,2,19 (Fig. 36-12). There are multiple secondary signs, which include the following (McLoud, 1998)1,2,19:

Lobar Collapse

1. Hemidiaphragm elevation 2. Mediastinal displacement (heart, trachea, other mediastinal structures) 3. Hilar displacement

Collapse of a lobe may be complete or incomplete. The most common cause is obstruction of a central bronchus. The major or primary signs are opacification due to airlessness of

FIGURE 36-10 End-stage lung with honeycombing. Rheumatoid lung with diffuse fibrosis. Posterior-anterior chest radiograph shows multiple cystic spaces (arrowhead) that are thick walled and less than 1 cm in size. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE

421

FIGURE 36-11 Usual interstitial pneumonia. High-resolution CT scan demonstrating subpleural honeycomb spaces more marked on the right side (arrowheads). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

REQUISITES. ST. LOUIS, MOSBY, 1998.)

A

B

FIGURE 36-12 A and B, Right upper lobe atelectasis. A, Posterior-anterior view demonstrates opacification of the right upper lobe and elevation of the minor fissure (arrowheads). B, There is a large mass (arrowheads) in the right hilum (lung carcinoma), which is elevated slightly above the left hilum. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

Ch036-F06861.indd 421

1/21/2008 11:15:06 AM

422

Section 3 Lung

4. Crowded vessels in the affected lobe if it is still partially aerated 5. Compensatory overinflation of the remaining lung If the obstruction of the lobar bronchus is caused by a large tumor mass, it may cause a bulge in the contour of the collapsed lobe; alternatively, if the entire lobe is replaced by tumor, the lobe may appear lobular with undulation of the fissure. These signs, of course, apply to CT features of lobar collapse (Fig. 36-13) (McLoud, 1998; Naidich et al, 1998).1,6 On CT, air bronchograms may be present even if there is a central endobronchial tumor causing the lobar collapse. On CT, the bronchus appears narrow or occluded.

Segmental and Subsegmental Atelectasis It is unusual for a segment to undergo atelectasis; there are channels that produce collateral air drift, even when a seg-

mental or subsegmental bronchus within a lobe is occluded. These forces tend to keep the segment aerated, and obstructive overinflation and air trapping occur, rather than atelectasis (McLoud, 1998).1,2 Subsegmental, discoid, and plate atelectasis are terms used synonymously for linear opacities that range in thickness from 1 to 3 mm and in length from 4 to 10 cm. These are usually located in the lower lung zones and occur in a horizontal plane paralleling the diaphragm (Fig. 36-14). These linear opacities are almost invariably associated with other disease processes, producing diminished diaphragmatic excursion. They are commonly identified after thoracic or abdominal surgery or in patients who are bedridden and kept in the supine position.

Total Collapse of the Lung When an entire lung collapses, the hemithorax on that side becomes completely opaque. There is a shift of the mediastinum to the affected side. The opposite lung overinflates and moves across the midline, particularly anteriorly behind the sternum, creating a large retrosternal space on the lateral view (Fig. 36-15) (McLoud, 1998).1,2 This appearance differs

A

B FIGURE 36-13 A and B, CT of right upper lobe atelectasis. The major fissure is displaced forward (small black arrowheads), and the minor fissure is displaced around a central mass (medium black arrowheads). The remaining right middle lobe (large white arrowheads) and right lower lobe (posteriorly) are hyperinflated, and their vessels are spread apart. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE

FIGURE 36-14 Plate-like atelectasis. There is a broad band of decreased opacity at the left base paralleling the hemidiaphragm (arrowhead). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE

REQUISITES. ST. LOUIS, MOSBY, 1998.)

REQUISITES. ST. LOUIS, MOSBY, 1998.)

Ch036-F06861.indd 422

1/21/2008 11:15:07 AM

Chapter 36 Imaging the Lungs

A

423

B

FIGURE 36-15 Right pneumonectomy. Appearance is equivalent to complete right lung collapse. A, On the posterior-anterior view, there is a completely opaque right hemithorax with shift of the mediastinum toward that side. B, On the lateral view, there is large retrosternal clear space and loss of visualization of the right hemidiaphragm (recurrent lung cancer in the left lung). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

from that of a massive pleural effusion, which causes similar opacification of a hemithorax. In the latter condition, there is no increased retrosternal clear space, and the mediastinum shifts to the opposite side. In addition, on the lateral view, a hazy opacification or uniform so-called filter effect is observed.

Postobstructive Pneumonitis and Drowned Lung When a bronchus is obstructed, atelectasis is always accompanied by some fluid exudation or sequestration of blood in the obstructed lobe. Sometimes the amount of fluid is voluminous, resulting in a radiographic appearance in which little volume loss is noted within the lobe despite the endobronchial obstruction (McLoud, 1998).1,2 This appearance is sometimes referred to as drowned lung. Infection may also occur distal to an obstructed bronchus, and the development of inflammatory exudate may also result in little loss of volume of the affected lobe.

FIGURE 36-16 Benign nodule. Hamartoma. CT shows a 2.5-cm nodule with smooth borders in the right lower lobe. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

Nodules and Masses The definition of nodules and masses is somewhat arbitrary, but usually both are considered to be lesions that are roughly spherical; a nodule is usually less than 3 cm in diameter, and a mass is greater than 3 cm (McLoud, 1998).1,2 Nodules that are larger than 3 cm in diameter are highly likely to represent primary or secondary malignant disease in the lung. The smoothness of contour and edge characteristics of a nodular

Ch036-F06861.indd 423

mass may be important. In general, a smooth contour suggests benign disease and nodularity or lobulation indicates malignancy, although these findings are relatively nonspecific and cannot be relied on to distinguish malignant from benign disease (Figs. 36-16 and 36-17). The solitary pulmonary nodule still remains a diagnostic dilemma, with 50% of resected nodules at surgery being benign.20 Both CT and PET

1/21/2008 11:15:08 AM

424

Section 3 Lung

B

FIGURE 36-17 Lung carcinoma. A, There is a small, irregular nodule (arrowhead) in the left upper lobe on the posterior-anterior view. B, CT demonstrates that the nodule has spiculated and irregular margins. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE

A

REQUISITES. ST. LOUIS, MOSBY, 1998.)

FIGURE 36-18 CT scan of calcified nodule (hamartoma). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

can be used for determination of the malignant characteristics of a solitary nodule. CT is the imaging method of choice to determine growth and to evaluate the density of the lesion, its shape, and its margins.6,21,22 Enhancement with contrast material is a sensitive but nonspecific indicator of lung cancer (Swenson et al, 1995).23 There is general agreement that absence of growth of a solitary pulmonary nodule over a 2year period is an indication of benignity, although a malignant

Ch036-F06861.indd 424

nodule may occasionally have extremely slow growth.24 The tumor size on CT is traditionally measured in plane using electronic calipers. Recent advances with helical CT have permitted accurate determination of nodule volume. This is possible with computer-aided evaluation of data sets and dedicated software programs, which have been shown to allow volume calculation with 97% accuracy (Yankelevitz, et al, 2000).25 This allows more accurate determination of doubling time. Most benign lesions have doubling times of less than 30 days or greater than 450 days. CT densitometry can be used to determine two fairly specific characteristics of benign lesions, calcification and fat.26 Certain types of calcification are indicative of benign lesions: central, laminated, diffuse, and popcorn calcification (Fig. 36-18). Eccentric calcification is often an indicator of malignancy.21,26 These criteria are only useful when the nodule is less than 3 cm in diameter. Fat may be identified in hamartomas and localized lipid pneumonias. Calcification is seen in granulomas and hamartomas. Air bronchograms or bubbly lucencies are highly suggestive of malignancy such as bronchoalveolar carcinoma. Nodules on CT may be purely groundglass opacity that is nonsolid, part solid with a mixture of ground glass, or completely solid. The malignancy rate for part solid lesions is 63%, whereas it is less than 10% for solid lesions and less than 20% for nonsolid lesions.27 Swensen and colleagues (Swenson et al, 1995)23 showed that use of contrast with measurement of peak enhancement through the center of the nodule may be helpful in determining the presence of malignancy. The sensitivity for lung cancer with a 15 Hounsfield unit (HU) threshold for degree of enhancement

1/21/2008 11:15:09 AM

Chapter 36 Imaging the Lungs

A

425

B

FIGURE 36-19 Bronchogenic cyst. A, Posterior-anterior view shows an ovoid opacity that represents a fluid-filled cyst in the right lung. B, After needle biopsy, an air-fluid level is present, and a small, thin wall is seen superiorly (arrowheads). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

is 98%. However, specificity is considerably lower due to the increased circulation and subsequent enhancement of active inflammatory lesions. PET imaging that employs a positron-emitting glucose analogue (18F-FDG) has also been extensively employed for the analysis of solitary pulmonary nodules. It is useful as a diagnostic test only for nodules greater than 1 cm in diameter (see Fig. 36-5). The sensitivity for malignancy is fairly high, ranging from 83% to 100%. The specificity has been reported as being significantly lower, 63% to 85%.28 The low specificity is a result of the increased metabolism that is manifested in active inflammatory lesions, which often cannot be distinguished from malignant nodules. Also, false-negative results may occur with low metabolic activity tumors such as bronchoalveolar carcinoma and carcinoid tumors.

Calcification and Ossification Intrathoracic calcification is an important feature of pulmonary disease. It is usually dystrophic—that is, it occurs in areas of necrosis. Less commonly it is metastatic—that is, related to hypercalcemia. Calcification may occur in focal lesions such as pulmonary nodules, as discussed earlier. Diffuse pulmonary calcification can occur in a number of entities. These include pulmonary alveolar microlithiasis, silicosis, end-stage mitral stenosis with hemosiderosis, and certain healed disseminated granulomatous or viral infections such as histoplasmosis, tuberculosis, and varicella pneumonitis (McLoud, 1998).1,2

Cavities and Cysts Abnormal air-filled spaces in the lung may develop in a variety of lung diseases, which include infection, vascular embolic disorders, bronchiectasis, emphysema, pulmonary fibrosis,

Ch036-F06861.indd 425

adult respiratory distress syndrome, lymphangioleiomyomatosis, and Langerhans cell histiocytosis.

General Features A pulmonary cyst is usually defined as a thin-walled (<3 mm), well-marginated, and circumscribed lesion containing air and/ or fluid that is 1 cm or larger in diameter (Fig. 36-19). A cavity, on the other hand, is a lucency within a zone of pulmonary consolidation, a mass, or a nodule (Fig. 36-20).29 It may or may not contain an air-fluid level, and it is surrounded by a wall of varied thickness but usually greater than 3 mm in diameter. Pathologically, a cavity results from expulsion of a necrotic part of the lesion into the bronchial tree. This may result in an air-fluid level that forms a straight line parallel to the bottom of the image (McLoud, 1998).1,2 An air-fluid level implies communication with the bronchial tree and usually also indicates liquefaction necrosis as might be seen in a lung abscess. Fluid-filled cysts cannot be distinguished on standard radiographs from solid mass lesions. However, on CT they may have low attenuation, approximating that of water (0 HU).29 However, cysts may contain fluid that is hemorrhagic or high in protein content, in which case they may appear to be of soft tissue density on CT. On MRI, cysts containing hemorrhagic or proteinaceous fluid usually appear bright on T1-weighted sequences and relatively heterogeneous on T2-weighted images, unlike so-called spring water cysts, which have very low signal intensity on T1-weighted images and very bright signal intensity on T2-weighted images. Also, cysts do not enhance after the administration of gadolinium contrast material (McLoud, 1998; Naidich et al, 1998).1,6 The thickness and irregularity of the wall of the cavity of an abnormal space, as well as the location and number of such

1/21/2008 11:15:10 AM

426

Section 3 Lung

FIGURE 36-21 Septic infarcts. CT scan shows multiple nodules, many peripheral and some cavitary, in the lower lung zones. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

FIGURE 36-20 Cavity secondary to tuberculosis. There is a thickwalled, multiloculated cavity in the right upper lobe (arrowhead). (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

spaces, is important in differential diagnosis. For example, septic pulmonary infarcts associated with intravenous drug abuse are usually multiple and thick walled and occur in the lower lung zones peripherally. CT may be particularly helpful in characterizing abnormal spaces in the lung, especially in regard to their number and internal architecture (Fig. 36-21).

Congenital Cysts Most congenital spaces in the lungs are cysts. Most arise from the primitive foregut. Examples that occur in the lung include bronchogenic cysts, cystic adenomatoid malformation, and pulmonary sequestration.30

Acquired Cysts and Cavities Infection. Cavities may develop in pyogenic and nonpyogenic infections, and thin-walled cysts called pneumatoceles are a complication of some infections. Pneumatoceles are particularly seen in children after staphylococcal pneumonia, but they also can be seen with P. carinii pneumonia (McLoud, 1998).1 They are usually thin walled and do not contain airfluid levels. They resolve in most patients. Pyogenic abscesses develop as a result of liquefaction necrosis caused by bacteria. Lung abscesses are most frequently associated with aspiration and anaerobic pneumonia produced by mouth organisms. However, pyogenic abscesses can be seen in staphylococcal, Klebsiella, and streptococcal pneumonia. If the abscess does not communicate with the bronchial tree, it will appear as a water or soft tissue density mass surrounded by pneumonia, but occasionally a solitary isolated mass is visualized. When bronchial communication occurs, an air-fluid level develops as purulent material is

Ch036-F06861.indd 426

drained through the bronchial tree. Because lung abscesses are roughly spherical, the air-fluid level will be of equal dimensions or length on views obtained 90 degrees to each other (i.e., PA and lateral chest radiographs) (McLoud, 1998; Naidich et al, 1998; Vourtsi et al, 2001).1,6,30,31 The most classic example of nonpyogenic cavitary lesions are the cavities associated with tuberculosis. These usually have thick but rather smooth walls. They are typically located in the apical and posterior segments of the upper lobes or superior segments of the lower lobes. Similar cavities may occur in other granulomatous infections, particularly fungal infections. In immunocompromised patients, invasive fungi, particularly Aspergillus, may be associated with ischemic necrosis and the development of cavities with air crescents (McLoud, 1998; Vourtsi et al, 2001).1,29,31 Vasculitis and Granulomatoses. Cavities may be identified in a group of diseases often referred to as vasculitis and granulomatoses. These include Wegener’s granulomatosis, lymphomatoid granulomatosis, and other types of vasculitis. Necrobiotic nodules may be seen in rheumatoid lung disease. It is unusual for these cavities to contain air-fluid levels (McLoud, 1998; Vourtsi et al, 2001).1,29,31 Neoplasms. A neoplasm in the lung may cavitate when it outgrows its blood supply. Cavitation is most frequently identified with squamous cell carcinoma, either primary in the lung or metastatic. Such cavities are usually thick walled (Fig. 36-22) (McLoud, 1998; Vourtsi et al, 2001).1,29,31 Post-traumatic Pneumatoceles. Post-traumatic pneumatoceles occur secondary to penetrating or nonpenetrating trauma and result from laceration of the lung parenchyma. They are usually unilateral and peripheral in location at the site of injury. They may be filled with blood initially. However, communication with the bronchus may occur, creating an air-fluid level. These pneumatoceles usually resolve in a few weeks (McLoud, 1998; Vourtsi et al, 2001).1,29,31 Pulmonary Infarcts. Pulmonary infarcts rarely undergo cavitation unless they are associated with infection, which

1/21/2008 11:15:11 AM

Chapter 36 Imaging the Lungs

427

FIGURE 36-23 Bullae. There are multiple bullae with thin walls (arrowheads) in both lungs. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

FIGURE 36-22 Lung carcinoma. Cavitary squamous carcinoma in the right upper lobe. (FROM MCLOUD TC: THORACIC RADIOLOGY: THE REQUISITES. ST. LOUIS, MOSBY, 1998.)

results from septic emboli. The classic features consist of ill-defined cavities at the bases of the lungs, abutting the pleura (McLoud, 1998; Vourtsi et al, 2001).1,29,31 Blebs and Bullae. Bullae are air-containing spaces within the lung parenchyma that measure more than 1 cm in diameter when distended and have a wall thickness of less than 1 mm (Fig. 36-23). They result from obstruction to air flow and are usually associated with emphysema. A bleb is a gascontaining space within the visceral pleura of the lung. Radiologically, it appears as a sharply demarcated, thin-walled lucency contiguous with the pleura, usually at the lung apex (McLoud, 1998; Vourtsi et al, 2001).1,29,31 Bronchiectasis. Cystic or saccular bronchiectasis can produce an appearance of multiple cystic spaces in the lung. On standard radiographs, these cysts are usually associated with other signs of bronchiectasis such as bronchial wall thickening seen en face or end on. If the bronchiectasis is diffuse, the lungs will be overinflated. In addition, these cystic structures are usually more marked in the medial third of the lung, along the bronchovascular bundles. At CT, the connection with the bronchial tree and the association with other dilated and distorted bronchi is helpful in diagnosis. Coronal and sagittal reformatted images also determine the presence of these cystic structures as a component of a dilated bronchial tree (Naidich et al, 1998).6 Diffuse Infiltrative Lung Disease. A number of interstitial lung diseases are associated with cyst formation in the lung. These may be thin-walled cysts that occur secondary to bronchiolar obstruction, as in lymphangioleiomyomatosis or

Ch036-F06861.indd 427

histiocytosis. Honeycombing refers to thick-walled cystic structures that are produced secondary to dissolution of alveolar walls and fibrosis with architectural distortion. This represents the final common pathway of diffuse fibrotic diseases. Radiographically, honeycombing appears as closely approximated ring shadows, usually less than 1 cm in diameter, with walls that are 2 to 3 mm thick. It is associated with a coarse reticular pattern in the lungs. On high-resolution CT, these spaces typically line up, one on top of the other, in the subpleural or peripheral zones of the lung and are associated with traction bronchiectasis and architectural distortion of the lung (see Fig. 36-11) (McLoud, 1998; Naidich et al, 1998).1,6

Other Helpful Signs of Disease Localization of Disease The anatomic localization of disease is usually determined on standard PA and lateral chest radiographs. A classic radiographic sign that helps in the localization of disease processes that have caused an increase in opacification is the silhouette sign (McLoud, 1998).1,2 Normally, the mediastinal and diaphragmatic contours are visible because of their inherent contrast with the adjacent air-containing lung. When a lesion or opacity is situated in a portion of the lung adjacent to a mediastinal or diaphragmatic border, that border can no longer be seen. This sign is apparent only when structures have been adequately penetrated. An example of the use of the silhouette sign is in the differentiation of middle lobe and lingular disease from lower lobe disease (McLoud, 1998).1,2 If the disease process involves the former lobes, the heart border will be obliterated. It may be difficult on standard PA chest radiographs to identify minor degrees of consolidation or atelectasis in the basal segments of the lower lobes. Lack of visibility of the posterior portion of the hemidiaphragm in the lateral projection is often an important clue to identify such disease.

1/21/2008 11:15:11 AM

428

Section 3 Lung

Distribution of Disease Within the Lung Distribution of disease in the lungs may be a clue to diagnosis. Gravity is often an important factor. For example, aspiration pneumonia typically occurs in the posterior segments of the upper lobes and superior segments of the lower lobes when the patient is supine, and similarly, when the patient is erect, the involvement will be in the basal segments of the lower lobes (McLoud, 1998).1 Because there is much more blood flow to the bases of the lungs than the apices in the erect position, certain processes related to the pulmonary circulation occur at the bases. For example, pulmonary infarction is much more common in the lower lobes. Also, metastatic disease tends to occur at the bases (McLoud, 1998).1,2 Reactivation tuberculosis has an anatomic bias for the apices of the lung, particularly the apical and posterior segments of the upper lobes and superior segments of the lower lobes. A number of diffuse lung diseases have an anatomic bias. For example, idiopathic pulmonary fibrosis and fibrosis associated with collagen vascular disease, as well as asbestosis, tend to occur predominantly in the lower lung zones, whereas upper lobe predilection can be seen in diseases such as silicosis, sarcoidosis, and Langerhans cell histiocytosis. Central involvement occurs in such diseases as pulmonary alveolar proteinosis and sarcoidosis. Peripheral opacification is a more common feature of the eosinophilic syndromes and cryptogenic organizing pneumonia (BOOP).

COMMENTS AND CONTROVERSIES Thoracic surgeons are completely dependent on quality imaging in their daily practice. Recent technological advances in thoracic imaging have been stunning. Digitized imaging, the widespread availability of sophisticated multidetector CT imaging, PET scans,

Ch036-F06861.indd 428

and MRI have transformed the evaluation of benign and malignant thoracic disease. The author describes currently available technologies and their optimal application. The radiographic findings of common lung pathologies are reviewed in detail. This is a particularly informative section because it will help the reader in the formulation of differential diagnoses based on typical imaging patterns. Also helpful is the section describing the geographic distribution of various lung pathologies. G. A. P.

KEY REFERENCES McLoud TC: Thoracic Radiology. The Requisites. St. Louis, Mosby, 1998, pp 1-65. Müller NL: Computed tomography in chronic interstitial lung disease. Radiol Clin North Am 29:1085-1093, 1991. Naidich DP, Webb WR, Zerhouni EA, et al: Computed Tomography and Magnetic Resonance of the Thorax, 3rd ed. New York, Lippincott Williams & Wilkins, 1998, pp 1-300. Schoeder H, Yeung HW, Larson JM: CT and PET/CT: Essential features of interpretation. J Nucl Med 46:1249-1251, 2005. Swensen SJ, Brown LR, Colby AL: Pulmonary nodules: CT evaluation of enhancement with iodinated contrast material. Radiology 194:393398, 1995. Vourtsi A, Gouliamos A, Maulopoulos L, et al: CT appearance of solitary and multiple cystic and cavitary lung lesions. Eur Radiol 11:612622, 2001. Webb WR, Müller NL, Naidich DP: High Resolution CT of the Lung, 3rd ed. New York, Lippincott Williams & Wilkins, 2000, pp 1-688. Wittram C, Maher MM, Yoo AJ, et al: CT angiography of pulmonary embolism: Diagnostic criteria and causes of misdiagnosis. Radiographics 24:1219-1238, 2004. Yankelevitz DF, Reeves AP, Kostis WJ, et al: Small pulmonary nodules: Volumetrically determined growth rates based on CT findings. Radiology 217:251-256, 2000.

1/21/2008 11:15:12 AM

chapter

NUCLEAR IMAGING OF THE LUNG

37

Sigrid G. Stroobants

Key Points ■ A negative FDG-PET excludes malignancy in indeterminate lung

nodules larger than 1 cm and without “ground-glass” opacity.

response and the use of PET in planning of radiotherapy. Although small cell lung cancer (SCLC) also exhibits a very high FDG uptake, experience with FDG-PET is limited in this type of lung cancer.

■ In patients with no evidence of metastatic lymph nodes on FDG-

■

■ ■ ■

PET, mediastinoscopy can be omitted. Tissue confirmation is always required for PET-positive nodes. FDG-PET substantially improves noninvasive staging. It is expected that fusion PET/CT as a single test will be the reference in the near future. FDG-PET is a promising tool for evaluation of treatment efficacy, but standardized response criteria are lacking. Quantification of regional pulmonary perfusion and ventilation before surgery is predictive for postoperative lung function. Lung segments with preserved ventilation but reduced perfusion . . (V/Q mismatch) are suggestive of pulmonary embolism.

HISTORICAL NOTE

. . Initially, ventilation-perfusion scintigraphy (V/Q scanning) was the principal nuclear medicine test performed in diseases of the lung. The finding of lung segments with preserved ventilation but reduced perfusion is suggestive of pulmonary embolism. In lung cancer, quantification of regional pulmonary perfusion and ventilation before surgery is predictive for postoperative lung function. Over the past years, metabolic imaging with positron emission tomography (PET) has become a very promising technique in the management of patients with cancer. Because PET relies on the detection of metabolic alterations observed in cancer cells, this examination yields data independently of associated structural characteristics and therefore not only allows the detection of cancer but also gives insight in the biologic behavior of the tumor. Furthermore, the ability to perform whole-body imaging within one examination without increasing the radiation burden makes it an ideal technique to “screen” patients for cancer deposits. A major drawback is the limited spatial resolution and lack of anatomic detail, making it sometimes difficult to localize foci of tracer uptake properly. The development of hybrid PET/CT machines, integrating both systems into one gantry, has mostly overcome this problem. Lung cancer is probably the malignant tumor most extensively studied with FDG-PET. Most experience is gained in the characterization of indeterminate lung nodules and in the mediastinal and distant staging of non– small cell lung cancer (NSCLC). More recently, also promising results were obtained in the evaluation of treatment

PET IMAGING IN LUNG CANCER Basic Principles and Technical Aspects Positron emission tomography is an imaging technique that allows for accurate noninvasive measurements of many regional tissue functions. Positron-emitting isotopes such as fluorine-18 (18F), carbon-11 (11C), and oxygen-15 (15O) are radioactive variants of elements naturally occurring in organic molecules. Therefore, they can be incorporated without changing the chemical and biologic characteristics of the labeled molecule too much. Positron-emitting isotopes have an excess of protons and are, therefore, unstable. They decay by emission of a positron, which is the subatomic, positively charged, antiparticle of the negatively charged electron. The positron released in this process has kinetic energy, travels a short distance, and then annihilates with an electron. This annihilation creates two 511-keV photons, emitted in opposite directions. The detection of numerous annihilations by the detector rings of the PET camera generates high-resolution pictures (resolution, 5-10 mm), indicating the sites of tracer accumulation in the body. At present, PET is the most selective and sensitive (picomolar to nanomolar range) method for measuring molecular pathways and interactions in vivo. The most frequently used tracer in PET oncology is 18Ffluorodeoxyglucose (FDG). The use of FDG for in-vivo cancer imaging is based on the higher rate of glucose metabolism of cancer cells compared with nonmalignant tissue, a feature that was first described by Warburg and associates several decades ago.1 After malignant transformation, cells demonstrate an increased expression of glucose transport proteins and an upregulation of the hexokinase activity. FDG, a glucose analogue in which the oxygen molecule in position 2 is replaced by a positron-emitting 18F, undergoes the same uptake as glucose, but its first metabolite, FDG-6-phosphate, cannot be further metabolized in the glycolytic pathways. Because most tumors have low phosphatase activity, FDG-6phosphatase will be accumulated within the cells, resulting in a so-called metabolic trapping.2 The preferential accumulation of FDG in neoplastic cells permits differentiation between benign and malignant tissue. FDG uptake is, however, not specific for cancer cells; and increased FDG uptake is also observed in neutrophils, eosinophils, and macrophages. Therefore, increased FDG uptake can be seen in 429

Ch037-F06861.indd 429

1/21/2008 11:16:12 AM

430

Section 3 Lung

some inflammatory conditions and is the most common cause of a false-positive FDG signal (Shreve et al, 1999).3 In vitro studies demonstrated that the amount of FDG uptake in tumor tissue is mainly related to the number of viable cancer cells4 and their proliferation capacity.5 Therefore, FDG can be used to evaluate treatment efficacy because tumor cell kill results in a proportional reduction of the FDG signal.6 Furthermore, the correlation between FDG uptake and proliferation capacity makes in-vivo evaluation of tumor aggressiveness possible. Whereas FDG has made PET useful in clinical oncology, several other radiopharmaceuticals can be used to study processes such as blood flow (H215O), protein metabolism (11C-methionine, 11C-choline) and carbohydrate metabolism (11C-acetate), hypoxia (18F-MISO), and DNA synthesis (18F-fluorothymidine). Certainly with the development of more biologic or molecular-targeted treatments, assessment of metabolic processes noninvasively becomes increasingly important to evaluate the efficacy of these drugs. The most commonly used imaging protocol in clinical FDG oncology studies is whole-body imaging. FDG is injected outside the PET camera. After an uptake period of at least 1 hour, which is necessary to obtain a good tumor-to-normaltissue contrast, the patient is positioned into the camera. Because the field of view of the PET camera is limited to 15 to 30 cm, different bed positions need to be scanned to obtain a whole-body survey. At the end, the data of the different bed positions are reconstructed to a whole-body image by a computer algorithm, taking into account the physical decay of the FDG tracer during the examination. The advantage of this technique is that it allows a fast acquisition (usually <30 min) of the total body (trunk). The disadvantage is that, because no attenuation correction is performed, this technique only generates images for visual interpretation. Indeed, an important number of photons are absorbed in the patient’s body. This absorption depends on the position in the body (e.g., superficial lesions are less attenuated than those situated in deep layers of the body) and the type of surrounding tissue (e.g., lung tissue is less attenuating than muscle tissue). Because the intensity of the lesion depends on its position, the intensity seen on the images does not reflect the actual FDG uptake. If images are corrected for this photon attenuation by a so-called transmission scan using an external 511-keV source (e.g., germanium-68), which makes an estimate of the attenuating characteristics of the patient, quantification of the FDG metabolism becomes possible but will prolong the acquisition time substantially (10-30 minutes). In most clinical studies, FDG uptake is quantified using the standardized uptake value (SUV) (Hoekstra et al, 2000).7 The SUV of a lesion is a semi-quantitative index of the glucose utilization that is obtained by normalizing the accumulation of FDG in the tumor to the injected dose and patient’s body weight or surface area. Absolute quantification, when the FDG uptake is expressed in milligrams per gram of tissue, is also possible using certain kinetic models that describe the behavior of FDG in a tumor cell. This quantification, however, requires a dynamic acquisition over the target lesion from the time of injection until a steady-state situation is reached (usually 1 hour or more),

Ch037-F06861.indd 430

and arterial blood sampling is often necessary to measure the FDG input function. Because this procedure is time consuming, is rather invasive, and allows imaging in only one camera position (15 cm of the patient), its use is limited to more fundamental research studies. Interpretation of PET scans is hampered by the lack of anatomic detail, which makes it sometimes difficult to correctly localize hot spots or differentiate tumor tissue from benign structures with physiologic high FDG uptake, as seen in muscle, brown fat, gut, or inflammation. Therefore, FDGPET always has to be interpreted in conjunction with anatomic images like CT or MRI. Attempts to align or register CT and PET datasets acquired on separate machines with fusion software are generally only successful in the brain, whereas in the remainder of the body differences in scanner bed profiles, patient positioning, and internal organ movement present a challenge to the software approaches. Recently, these challenges have been addressed and largely resolved by the introduction of the combined PET/CT scanner, a more hardware-oriented approach to image fusion. Since the installation of the first clinical PET/CT in 2001, the technology has gained widespread use, and all new PET scanners installed today are integrated PET/CTs. Current designs comprise a CT scanner in tandem with a PET scanner with a common patient bed for both systems. Although the scanner appears externally as a single device, internally there is little or no mechanical integration. CT images are acquired first and are used to generate attenuation correction factors to be applied to the PET data to correct for photon attenuation. Second, PET data for the same axial extent of the patient are then acquired with a simple horizontal translation of the bed. On completion of the scan, CT and PET images are co-registered with fusion software and can be viewed either separately with linked cursors or superimposed with a selectable blending of the two modalities. Although CTbased attenuation correction of PET images reduces the scan time substantially (~50%), specific artifacts due to patient motion or dense objects can propagate into the PET images (Mawlawi et al, 2006).8 A specific motion artifact is caused by breathing (Fig. 37-1): owing to the difference in scan time to acquire a PET image (which takes several minutes and represents an average over many breathing cycles) and CT image (which takes only a few seconds and represents a snapshot at a certain respiration level), CT data obtained during maximum inspiration cannot be optimally co-registered with PET emission data and will not yield an adequate attenuation map for correction of PET images. This can result in the appearance of the typical curvilinear cold artifacts paralleling the dome of the diaphragm at the lung bases and the incorrect anatomic localization or obscuring of hot spots. When CT is used for attenuation correction, it is necessary to extrapolate from the attenuation characteristics obtained using relatively low-energy x-rays to those determined for 511-keV annihilation photons of PET. This process can introduce artifacts in relationship to dense objects such as metallic implants and barium and obscure or mimic tumor deposits (Fig. 37-2). Therefore, non–attenuation-corrected PET images also need to be reviewed to recognize these artifacts.

1/21/2008 11:16:13 AM

Chapter 37 Nuclear Imaging of the Lung

A

B

431

C

FIGURE 37-1 Patient with a cancer of the distal esophagus. A, CT scan also shows an enlarged lymph node adjacent to the primary tumor (arrow). B, Attenuation-corrected PET images (AC-PET) show the typical curvilinear cold artifact paralleling the dome of the diaphragm. C, Evaluation of the non–AC-PET images also shows the hypermetabolic adjacent lymph node (arrow), obscured by the breathing artifact on the AC images.

A

B

C

FIGURE 37-2 A, Attenuation-corrected (AC) PET images of a patient with esophageal cancer (primary cancer not seen on selected images). The increased uptake seen in the colon is an AC artifact due to barium residue. B, Also the CT images are degraded. C, Only after evaluation of the non–AC-PET images does a focal hot spot corresponding to a metastasis in the right liver lobe become apparent.

Ch037-F06861.indd 431

1/21/2008 11:16:13 AM

432

Section 3 Lung

Diagnosis of Solitary Pulmonary Nodules Peripheral solitary pulmonary nodules (SPNs) represent a diagnostic challenge, especially if they are noncalcified. With the increased interest in the use of low-dose spiral CT for early lung cancer detection, the number of coincidental SPNs will only increase. Absence of growth over a 2-year period is highly suggestive of a benign lesion,9 but many patients do not have comparative chest radiographs. Bronchoscopic samples from patients with a peripheral nodule of less than 3 cm often fail to yield a pathologic diagnosis.10 A transthoracic needle aspiration biopsy has a higher diagnostic yield but it can be complicated by a pneumothorax, requiring drainage in 5% to 10% of the procedures.11 Moreover, this technique is still hampered by the possibility of a falsenegative test result. A surgical procedure may be needed to avoid unacceptable expectation in early-stage lung cancer. In the past years, FDG-PET has been studied extensively in the evaluation of indeterminate pulmonary nodules and masses. Multiple studies have proven the accuracy of FDG-PET in the differentiation of malignant from benign lesions.12-25 Most of these data are on nodules larger than 1 cm, and overall sensitivity, specificity, and positive and negative predictive values of 96%, 78%, 91%, and 92%, respectively, have been estimated in a meta-analysis (Gould et al, 2001).26 Because a critical mass of metabolic active cells is required for detection on PET, false-negative findings can occur in small-volume disease. Herder and associates27 retrospectively evaluated the performance of PET in 36 nodules less than or equal to 1 cm, but only 8 were smaller than 1 cm. All but one lesion (one carcinoid of 10 mm) were detected. Nomori and colleagues (Nomori et al, 2004)28 evaluated the performance of PET in 136 uncalcified nodules less than 3 cm. All of the 20 lesions less than 1 cm were negative on PET, 8 of which were malignant. In a screening trial with low-dose spiral CT, Pastorino and associates29 examined the selective use of FDG-PET for nodules greater than or equal to 7 mm. FDG-PET was positive in 18 of the 20 cancers. One 8-mm adenocarcinoma and one 11-mm predominantly bronchioloalveolar tumor were missed. False-negative findings can also occur in tumors with low metabolic activity. In carcinoids, proliferation rate as measured by Ki-67 indexes is usually low and correlates with the degree of cell differentiation. The relation between FDG uptake and proliferation probably explains the limited FDG avidity especially in typical carcinoids.30,31 A lower proliferation potential is also observed in bronchioloalveolar cell carcinoma.32 Moreover, these tumors show a significantly lower expression of the glucose transporter Glut-1, the key regulator for glucose and FDG uptake in cancer cells, compared with the other NSCLC subtypes.33 FDG uptake and, thus, FDG sensitivity also seem to be related to the histologic subtype and radiologic characteristics. Heyneman and Patz34 found a higher sensitivity in multifocal disease compared with a single nodule (86% versus 38%). Yap and coworkers35 reported a lower sensitivity when the tumor showed a noninvasive growth pattern (sensitivity of 33%) or contained high levels of mucin (sensitivity of 50%). Nomori and colleagues28 evaluated the performance of PET in 15 patients with ground-glass opacities, a typical CT

Ch037-F06861.indd 432

pattern for noninvasive bronchioloalveolar cell carcinoma. PET was only positive in 1 of 10 malignant lesions and was false positive in 4 of 5 benign lesions (focal pneumonia), resulting in a sensitivity of 10% and a specificity of 20%. FDG uptake is not specific for malignancy, and falsepositive findings due to trapping of FDG in activated granulocytes and/or macrophages can occur in inflammatory conditions such as bacterial pneumonia,36,37 pyogenic abscess or aspergillosis,38 tuberculosis,39 histoplasmosis, and granulomatous diseases such as active sarcoidosis,40 cryptococcosis,41 Wegener’s disease, and coal miner’s lung. For a pictorial overview see the work of Shim and associates (Shim et al, 2006).42 In the meta-analysis of Gould and colleagues (2001),26 the specificity was found to be extremely variable, ranging from 50% to 100% (median, 78%), depending on the prevalence of certain inflammatory or infectious diseases. Several efforts have been made to improve the specificity of PET. Because the uptake of FDG in benign lesions tends to be lower compared with that in malignant tissue, quantification of the FDG uptake was used to improve the diagnostic accuracy. In the literature, an SUV above 2.5 is often used to discriminate benign from malignant nodules but without significant increase in accuracy.26 In fact, the use of a threshold value can decrease the sensitivity in small lesions substantially compared with the simple visual analysis because of considerable underestimation of the true activity due to partial volume effects, through which the SUV measurement drops under the threshold, although the lesion is clearly visible. In the study of Lowe and associates,19 the sensitivity for detecting malignant nodules less than 1.5 cm decreased from 100% using visual analysis to 80% using the threshold SUV value of 2.5. Not only the amount of FDG uptake but also the tracer kinetics are thought to be different in benign and malignant tissue, with continuous uptake in malignant lesions and a rapid uptake followed by a fast and then gradual wash-out in benign masses. Using dual-time point imaging at 1 and 2 hours after tracer injection, an increase of at least 10% in SUV between the first and the second scan proved to be more accurate than an SUV threshold of 2.5 at the first scan.43 Finally, tracers other than FDG can be used to reduce the false-positive rate. The results with 11C-methionine, a marker of the protein metabolism44-45 and 11C-choline, a component of phospholipids in the cell membrane,46 were disappointing. The most exciting new tracer is the thymidine analogue 18Ffluorothymidine (FLT), a marker of cell proliferation.47 Although FLT itself is not incorporated in DNA, accumulation is dependent on cytosolic thymidine kinase-1 (TK-1) activity, the key enzyme of the pyrimidine salvage pathway of DNA synthesis that phosphorylates FLT to FLT-5 phosphate. Because TK-1 is only functional in the S-phase of the cell cycle, a high correlation between FLT uptake and proliferation rate as measured by Ki-67 immunohistochemistry and DNA flow cytometry is observed.48-50 In the differentiation of SPNs, FLT proved to be more specific than FDG (100% in the studies from Vesselle48 and Buck49), although falsepositive uptake was seen in 1 patient with interstitial pneumonia in another study.50 Because the absolute uptake of FLT

1/21/2008 11:16:14 AM

Chapter 37 Nuclear Imaging of the Lung

is usually lower compared with FDG, especially in slowproliferating tumors, the sensitivity of FLT-PET is reduced. In the study of Yap and colleagues,50 the sensitivity on a lesion-by-lesion analysis (including both the primary tumor and the nodal metastasis) was only 58%, compared with 79% for FDG-PET. Therefore, FLT-PET will never replace but rather be complementary to FDG-PET in the diagnostic workup of SPNs. In summary, PET has been found to be a useful diagnostic tool in evaluating SPNs that have an indeterminate morphology on CT and are included as part of the workup of an SPN if clinical decision making will be changed by its findings.51 In this respect, PET is not only useful in visualizing the SPN but can also change patient management by detecting unsuspected nodal and metastatic disease (see later). For lesions greater than 1 cm, the negative predictive value of PET is high, and malignancy can correctly be excluded in the vast majority of cases (Fig. 37-3). In these patients, thoracotomy can be avoided and follow-up with radiography or CT scan at 3, 6, 12, and 24 months is advised.52 False-negative findings can occur in bronchioloalveolar cell carcinomas and carcinoids, and FDG results must be interpreted with scrutiny if clinical or radiologic characteristics (e.g., ground-glass opacities) suggest one of those histologic subtypes. The experience in lesions less than 1 cm is more limited, and a higher falsenegative rate is reported. Therefore, a negative PET does not exclude malignancy in these cases. Because of the specificity of 79%, the positive predictive value will be lower. In clinically suspicious cases, further

433

investigations for detection of infection, Wegener’s granulomatosis, or other granulomatous diseases are indicated (Fig. 37-4). In cases of doubt, SPNs with high FDG uptake require resection.

Staging of Lung Cancer Staging of lung cancer is done according to the tumor (T), node (N), metastasis (M) classification system.53 The T factor describes the primary tumor by size and invasiveness, going from T1 (<3 cm and entirely surrounded by lung tissue) to T4 (invading critical organs). The N factor describes the locoregional lymph node (LN) spread, either no metastatic nodes (N0), only intrapulmonary or hilar ones (N1), ipsilateral mediastinal ones (N2), or contralateral mediastinal or supraclavicular ones (N3). The M factor points at absence (M0) or presence (M1) of distant metastasis.

T Factor The assessment of the primary tumor extension is usually based on thoracic CT, occasionally complemented by MRI. PET itself does not add much to the assessment of local resectability, because its inferior spatial resolution does not give more detail of the exact tumor extent or infiltration of neighboring structures. In recent studies using PET/CT, it was therefore not surprising that the T classification was more accurately assessed on PET/CT compared with PET alone.54-58 In a minority of the patients, PET/CT proved also to be superior to CT alone, although this was only statistically

B

A

C

FIGURE 37-3 Incidental finding on CT (B) of an indeterminate lesion (arrow) in the right lower lobe adjacent to the esophagus. Endoscopic ultrasonography with fine-needle aspiration cytology was inconclusive. No increased FDG uptake was seen on PET (A and C), which is suggestive of a benign etiology. Histology after resection revealed a hamartoma.

Ch037-F06861.indd 433

1/21/2008 11:16:14 AM

434

Section 3 Lung

B

A

C

D

FIGURE 37-4 A solitary lung nodule detected on CT (B) during routine follow-up in a patient with a history of cardiac transplant for sarcoidosis was suspicious for primary lung cancer or post-transplant lymphoma. PET showed intense FDG uptake in the lung nodule supporting a malignant etiology (A) and detected an additional lesion in the right thigh (arrow). MRI findings were best suitable with schwannoma (C), and this was confirmed on histology after resection of the lesion. D, Because the diagnostic workup of the thigh lesion took more than 1 month, a repeat CT was performed to re-evaluate the lung lesion. Surprisingly, the lung nodule regressed almost completely, proving its benign nature. This case is a striking example of a false-positive PET scan.

significant in two studies.54,58 This improved accuracy is due to a better discrimination between the tumor and surrounding atelectasis or inflammation and to correct exclusion of tumor involvement in coexisting lung nodule(s) in the same lobe. Some studies also describe an additional value of PET in the detection of pleural metastasis, thereby changing the T factor from T1-T3 to T4. In a retrospective study on 25 NSCLC patients with suspected malignant pleural effusions, PET was reported to have a 95% sensitivity (21 of 22 patients).59 Because there were only 3 patients with benign pleural disease in this series, specificity could not be truly judged. In another study with a prevalence of malignant pleural involvement of about 50%, PET correctly detected the presence of malignant pleural involvement in 16 of 18 patients and excluded malignant pleural involvement in 16 of 17 patients (sensitivity 89%, specificity 94%, accuracy 91%).60 In a later study with pleural effusion in 92 patients, of whom 71% were deemed indeterminate on CT, PET had a sensitivity, specificity, and accuracy of 100%, 71%, and 80%, respectively.61 In this particular study, specificity and positive predictive value were lower, owing to the larger number of benign pleural effusions. One study specifically looked at the value of PET in dry pleural dissemination. Because this is often caused by multiple, very small pleural nodules beyond the resolution of a PET system, the sensitivity was only 25%.62

Ch037-F06861.indd 434

N Factor For years, CT has been the standard noninvasive staging method for the mediastinum. Enlarged lymph nodes (LNs) (i.e., >10 mm in the short axis) were considered to be metastatic. Size is, however, a relative criterion, because lymph nodes can be enlarged due to infectious or inflammatory causes and small-sized nodes can contain metastatic deposits. In a review, the pooled sensitivity of CT was 57% (95% CI, 49-66) and the specificity was 82% (95% CI, 77-86).63 Over the past years, several prospective studies yielded strong evidence that PET is significantly more accurate than thoracic CT for assessing the N factor in NSCLC, and this superiority has been confirmed in different meta-analyses (Fischer et al, 2001; Gould et al, 2003),64-67 with an overall pooled sensitivity and specificity of 85% and 90% for PET compared with 61% and 79% for CT in the most recent one by Gould and colleagues (Gould et al, 2003).67 The superiority of FDG-PET is explained by the more frequent correct identification of so-called small malignant nodes and large benign nodes (Fig. 37-5). Errors are related to minimal tumor load (false negatives), inflammation (false positives), or incorrect localization of a hot spot to an adjacent lymph node level. PET performance characteristics are conditional for nodal size: FDG-PET is more sensitive but less specific when CT showed enlarged lymph nodes (median sensitivity and specificity of 100% and 78%) than when CT showed no lymph

1/21/2008 11:16:15 AM

Chapter 37 Nuclear Imaging of the Lung

435

B

A

C

FIGURE 37-5 Incidental finding on CT of a small lung nodule in the left lower lobe (B) without nodal enlargement (T1 N0). PET revealed intense FDG uptake in the primary tumor and a suspected node in the left paratracheal space (level 4 L): PET stage T1 N2 (A). Mediastinoscopy confirmed nodal involvement by a squamous cell carcinoma in that region (C, arrow).

node enlargement (median sensitivity and specificity of 82% and 93%) (P = .002) (Gould et al, 2003).67 Reading of the PET scan in the presence of the CT images clearly improves the ability to localize metastatic mediastinal nodes and in some patients thus the N factor designation. Visual correlation with CT images improved the sensitivity of PET from 67% to 93% in one study68 and from 73% to 82% in another.69 PET/CT images are one step further, with the obvious advantage of decreasing the learning curve needed to optimize the visual correlation, but statistically significant increases in accuracy compared with visual site by site correlation are not yet reported. In all previously mentioned PET/CT studies, LN with focally increased FDG uptake above background activity are regarded as metastatic. In a study from Korea in 674 patients,70 the CT appearance of the LN was also taken into account with the aim to increase the specificity in this tuberculosis-endemic region: only LN with increased FDG uptake but without benign calcification or high attenuation (HU > 70) at unenhanced CT were regarded as malignant. This resulted in a high specificity (96%) and reasonably high accuracy (86%) but at the expense of a somewhat low sensitivity (61%). Can PET replace mediastinoscopy? The high negative predictive value of PET (93% in the meta-analysis of Dwamena and coworkers64) creates the possibility to leave out invasive staging if PET suggests the absence of LN disease. This is only valid when there is sufficient FDG uptake in the primary tumor and in absence of a central tumor or important hilar LN disease that may obscure coexisting N2 disease (Fig. 37-6).71 If these rules of interpretation are handled correctly, relevant LN disease will rarely be missed. In some patients, LNs with small tumor deposits, ranging from 1 to 7.5 mm,

Ch037-F06861.indd 435

may remain undetected owing to the spatial resolution of the PET camera.72 In these patients, minimal N2 disease may be discovered at surgical exploration but resection in these patients is rewarding.73,74 The positive predictive value of PET is less optimal, and therefore tissue confirmation of PETpositive nodes is always mandatory to avoid denial of radical surgery in node-free patients based on false-positive findings due to granulomatous or other inflammatory conditions, for example (Fig. 37-7).

M Factor The observation of metastases in patients with NSCLC implies that a patient can no longer be cured. Forty percent of the patients with NSCLC have distant metastases at presentation, most commonly in the adrenal glands, bones, liver, or brain.75 The current standard noninvasive staging tests (including ultrasound, CT, MRI, and bone scintigraphy) are far from perfect. A systemic relapse develops in up to 20% of surgically treated patients in the period from 3 to 24 months after complete surgical resection. The explanation of the high falsenegative rate of conventional imaging probably has to be found in the presence of micrometastatic spread at the time of diagnosis of biologically more aggressive tumors.76 PET offers a double additional value in the evaluation of distant metastases in potentially operable NSCLC patients. On the one hand there is the detection of unexpected metastatic spread, which occurs in 5% to 29% of patients with negative conventional imaging (Van Tinteren et al, 2002).77-89 This broad range is explained by several factors. First, there is variability in the extent or rigor of the pre-PET extrathoracic conventional imaging. Second, in some studies

1/21/2008 11:16:17 AM

436

Section 3 Lung

A

B

C

FIGURE 37-6 Patient with a central tumor at the left hilum (B) and enlarged nodes in level 4 L (C). Although no clear hot spots in the mediastinum are seen on PET (A), involvement of nodes adjacent to the tumor cannot be excluded due to the central localization of the primary tumor. Mediastinoscopy proved mediastinal involvement in level 4 L. Whole-body PET also revealed a secondary cancer in the rectum (A, arrow).

the “equivocal” lesions are regarded as “unexpected metastases” if PET confirms malignancy in these lesions,78,79 whereas this is not the case in most other studies. Finally, the chance of detecting metastases on PET varies with the population in the study, being found in 7% of the patients with pre-PET stage I, in 18% in stage II, and up to 24% in stage III.84 Focal unexpected FDG-PET uptake in sites unlikely to be metastatic for NSCLC may also reveal a second primary tumor in some patients (e.g., colorectal or breast cancer) and need to be further investigated (see Fig. 37-6).90 On the other hand, equivocal lesions on conventional imaging can be further assessed by PET. Because of the very high sensitivity of PET in the detection of adrenal metastases, a negative PET image of an equivocal adrenal lesion on CT usually points at a nonmetastatic etiology.91-93 This is important, because up to 10% of NSCLC patients have an adrenal mass at the time of staging and about one half to two thirds of these lesions actually are benign.94,95 Caution is required in lesions smaller than 1 cm. Specificity of PET for adrenal metastases is high (between 80% and 100%), but some falsepositive lesions are described.

Ch037-F06861.indd 436

The evaluation of bone metastases in NSCLC by PET has a sensitivity at least equal to technetium-99m (99mTc) bone scan (~90%) but a better specificity.96-100 Caution, however, is required with distal lesions (e.g., below the knee), which will fall outside the field-of-view of a standard “whole-body” PET acquisition or in osteoblastic lesions, which are more readily seen on 99mTc bone scan, as demonstrated in a study on breast cancer patients.101 Because most bone lesions in NSCLC are in the central skeleton, and nearly all are osteolytic, PET scan usually replaces bone scan, except in specific clinical indications. The standard method for the detection of liver metastases is ultrasonography or CT. There are no specific series on the use of PET in patients with liver metastases from NSCLC. Some general series on staging NSCLC suggest a superiority of PET by being more accurate than CT.78,81 In a meta-analysis comparing different imaging modalities in the detection of colorectal liver metastasis, helical CT, MRI at 1.5 T, and FDG-PET had similar sensitivities on a per-lesion analysis.102 In routine clinical practice, CT therefore remains the standard imaging technique for the liver. The use of PET is mainly

1/21/2008 11:16:19 AM

Chapter 37 Nuclear Imaging of the Lung

437

A

B

C

FIGURE 37-7 Patient with a T2 squamous cell carcinoma in the left lower lobe with bilateral enlarged mediastinal nodes on CT (C) that were also FDG avid on PET (A and B), resulting in a PET/CT stage T2 N0 M0. Mediastinoscopy and histopathology only revealed silicosis and downstaged the patient to T2 N0 and thus operable disease.

to provide additional information for the differentiation of hepatic lesions that are indeterminate on conventional imaging.103 FDG-PET is not sensitive enough to exclude brain metastases, owing to the high glucose uptake of normal surrounding brain tissue. MRI (or CT) remains the method of choice to stage the brain. Although some PET images can be considered definite proof of multifocal metastatic disease, caution is always indicated in solitary extrathoracic PET findings that determine the chances for radical therapy. In these patients, a confirmatory test is indicated (see Fig. 37-4). Accurate localization of FDG avid regions on fused PET/CT images reduces the risk of false-positive interpretations of physiologic phenomena such as uptake in bowel or metabolically active brown fat (Figs. 37-8 and 37-9). Accordingly, previous estimates of the impact of PET on the management of lung cancer are likely to be surpassed in current clinical practice. A further advantage of PET/CT is to select the most convenient, accessible site for biopsy confirmation of systemic metastases.

Impact on Overall Stage and Management Noninvasive lung cancer staging is substantially improved by the use of PET. The most exciting feature of PET is that it gives a reasonably cancer-specific imaging of the entire patient in one single noninvasive test with a better accuracy than conventional imaging, thus providing a potential impact on

Ch037-F06861.indd 437

stage designation and therapeutic decision. Most studies were performed as a complementary tool to conventional staging, and it is therefore not clear if PET could also replace a number of these tests. A retrospective Dutch cooperative study has illustrated that application of PET immediately after first presentation could not reduce the overall number of diagnostic tests in comparison with traditional workup.104 A limitation of this study was inherent to the protocol design whereby PET scans were not read in conjunction with CT, which is known to improve the accuracy of both tests. It is expected with the more widespread introduction of PET/CT systems that fusion PET/CT will become the standard staging examination. The additional use of PET in preoperative or preirradiation staging led to a stage shift in about half (range, 19%-62%) of patients staged with conventional CT, mostly upstaging (range, 12%-56%) and less frequently downstaging, and is related mainly to the detection of unexpected distant lesions by PET (range, 10%-36%). This also resulted in a change of treatment plan in 19% to 46% of cases, which can be a change in treatment intent (curative versus palliative), in treatment modality (surgery versus irradiation), or in treatment planning (e.g., field of irradiation).69,77,79,82,83,89,105-110 The impact of PET in staging lung cancer has also been prospectively evaluated by use of serial questionnaires.111 PET resulted in treatment changes in 50% of the patients, with cancelled surgery being the most frequent (35%). In 7% of the patients, PET resulted in a more aggressive treatment strategy.

1/21/2008 11:16:21 AM

438

Section 3 Lung

A

B

C

FIGURE 37-8 Patient with an undifferentiated large cell carcinoma of the left upper lobe with mediastinoscopy-proven N3 disease. Evaluation of mediastinum and spine on PET is hampered by the increased muscle uptake (A). PET/CT fusion images localize most spots at the muscle bone interface (A, B, arrowhead), except for two spots that are clearly localized in the vertebral body (A, B, arrow). C, Metastatic involvement of the spine at these levels was confirmed by MRI.

FIGURE 37-9 PET/CT after induction chemotherapy for a squamous cell carcinoma stage IIIA-N2. Persistent FDG uptake is seen in the primary tumor and adjacent hilar lymph node (B). PET also shows a focal hot spot suspected for N2 disease in level 2 L (A, C, arrow). PET/CT fusion images project the hot spot in brown fat tissue (C), downstaging this patient to stage T2 N1. Patient underwent thoracotomy with lymph node dissection. Pathology confirmed the absence of residual mediastinal involvement (pT2 N1).

A

B

Ch037-F06861.indd 438

C

1/21/2008 11:16:22 AM

Chapter 37 Nuclear Imaging of the Lung

The impact of PET on patient management has been addressed by two randomized studies with somewhat different conclusions. The Dutch “PLUS” study (Van Tinteren et al, 2002)87 included 188 patients (70% in stage I-II), and about 70% of the patients received mediastinoscopy. The patients were followed for 1 year after inclusion. The authors found a significant reduction in the number of futile thoracotomies, from 41% in the conventional imaging alone group to 21% in the conventional imaging plus PET group, irrespective of clinical stage. Furthermore, nonfutile thoracotomies were not decreased by PET (44% versus 41%), because PET improved identification of patients who would benefit from thoracotomy. An Australian study (Viney et al, 2004)112 randomized 184 patients (92% in stage I, 8% in stage II), and only 5% received mediastinoscopy. PET led to further investigation or change in management in 13% of the patients and revealed information that could have affected management in another 13%. However, no significant difference in the number of thoracotomies was found. There are a number of possible explanations for the differences between the two studies. First, the Australian study was highly biased by selection of patients with very early stage disease (92% had stage 1). Furthermore, review of the raw Australian data indicates that had the PET information been incorporated into decision-making (mediastinoscopy was not routinely performed after a positive PET) around 25% of patients could appropriately have had their management changed to avoid thoracotomy. In patients with NSCLC, PET is not only highly sensitive for detecting and staging malignancy but also serves as a predictor of long-term survival. The influence of PET stage on outcome was evaluated by comparing the outcome according to the pre- and post-PET stage in the same patients105,113 or by comparing cohorts with similar characteristics, staged with and without PET.114,115 Tumor stage as determined by PET proved to be a powerful prognosticator for survival.

Small Cell Lung Cancer Small cell lung cancer (SCLC) represents only 15% to 20% of all lung cancers and is often disseminated at the time of diagnosis,116 thereby obviating the need for PET in many patients. In contrast to NSCLC, a dual staging system is applied: patients with limited disease (LD), defined as disease limited to one hemothorax and still curable, and those with extensive disease (ED). The value of PET in staging SCLC has been evaluated by relatively small, mostly retrospective studies, all indicating a possible role for PET.117-122 Regarding the main goal of baseline SCLC staging—the distinction between LD and ED—one prospective study examined how often PET detects ED SCLC in patients considered to have LD based on conventional staging.123 PET correctly upstaged 2 of 24 patients to ED. PET also correctly depicted all tumor sites in the primary mass and nodal stations. PET impacted on the radiotherapy planning because of detection of unsuspected locoregional LN metastasis in 6 of 24 patients. In the largest study to date, a total of 91 SCLC patients underwent conventional staging, including cranial MRI or CT

Ch037-F06861.indd 439

439

and FDG-PET (Brink et al, 2005).124 In 14 patients, PET caused a stage migration, correctly upstaging 10 patients to ED and downstaging 3 patients to LD. PET was significantly superior to that of CT in the detection of extrathoracic metastases except for the brain.

Restaging After Induction Therapy One of the most challenging areas in noninvasive staging is the optimal reassessment of tumor response after induction therapy, which includes the pathologic response in the primary tumor as well as the downstaging of mediastinal lymph nodes. Noninvasive assessment of tumor response to induction treatment is usually performed on CT imaging. A reduction in tumor volume after induction therapy is considered as a predictor of pathologic tumor response. However, definitive pathologic assessment of the primary tumor and/or mediastinal LNs sometimes shows pathologic complete response or mediastinal downstaging, despite the absence of radiologic changes in the tumor volume after induction therapy. Because FDG preferentially accumulates in viable tumor cells and not in fibrotic or necrotic tissue, a change in FDG uptake on PET after induction therapy is supposed to be a better parameter for both response evaluation and restaging after induction chemotherapy. The clinical experience with PET for the detection of residual primary tumor and/or mediastinal lymph node involvement after induction therapy for operable NSCLC is rapidly increasing.125-134 Some of these studies demonstrated that a repeat PET after induction therapy accurately detects viable tissue in the primary tumor, with a sensitivity ranging from 67% to 97%.126-129 The presence of false-positive findings in the primary tumor, especially after chemoradiotherapy, however, hampers the usefulness of PET scan for prediction of complete pathologic response after induction therapy. The sensitivity of PET in staging nodes after induction treatment is lower than in the untreated patient, ranging between 50% and 67% (with an outlier of 20%), whereas the specificity was relatively maintained (ranging from 61%-100%). This rather low sensitivity may result from small residual tumor nests that are surrounded by fibrosis and are more difficult to detect. Very recently, the role of fusion PET/CT in stage IIIA-N2 NSCLC was studied in two prospective trials. De Leyn and colleagues (De Leyn et al, 2006)132 compared the role of integrated PET/CT and re-mediastinoscopy to assess pathologic staging after induction chemotherapy. The results of re-mediastinoscopy were disappointing, but sensitivity and specificity of integrated PET/CT were better than what was known with visually compared PET and CT images (77% and 92%, respectively). Furthermore, complete resection rate was significantly lower in patients with persistent nodal involvement (8/14 or 57%) compared with patients with nodal downstaging on PET (15/16 or 94%) (P = .018). The better accuracy of PET/CT is explained by the very sensitive reading of the PET part (even a slight increase in FDG uptake above mediastinal blood pool activity was regarded positive). However, because of the heterogeneous physiologic uptake in mediastinal structures, specificity could only be main-

1/21/2008 11:16:33 AM

440

Section 3 Lung

tained by fusion imaging (92% versus 69% for PET alone). Cerfolio and colleagues (Cerfolio et al, 2006)133 compared fusion PET/CT and repeated CT with definitive pathologic staging after induction chemoradiotherapy in 93 patients. LN with an SUV uptake higher than 2.5 was regarded positive. PET/CT was significantly better than repeat CT, with a sensitivity of 80% and a specificity of 75%. If the results of PET/CT are confirmed in larger (prospective) studies, PET/CT may be useful in guiding further treatment after induction therapy. In PET/CT-positive patients it can act as an indicator for repeat biopsy, whereas PET/CTnegative patients can proceed directly to definite local treatment. A few studies evaluated the use of PET to predict patient outcome after treatment. In a small pilot study on 15 stage IIIA N2 patients,125 PET response after induction (defined as reduction in SUV > 50%) proved to be a better predictor of patient outcome than standard CT response (P values of .0265 and .81, respectively). MacManus and associates135 compared response assessed on CT or on PET in 73 stage I to III NSCLC patients treated with radical radiotherapy (n = 10) or chemoradiotherapy (n = 63). PET was performed after a median of 70 days There was poor agreement between CT and PET responses (weighted kappa 0.35), which were identical in only 40% of the patients. Only PET response, defined as a visual reduction in FDG uptake, was correlated with survival in the multivariate analysis (P < .0001). In a multicenter prospective study in 47 patients undergoing induction chemotherapy,131 PET response after 1 cycle and 3 cycles was compared with CT response (World Health Organization criteria) and survival. Both the level of residual FDG uptake and the fractional change from baseline were associated with outcome. In a multivariate analysis, conventional response based on CT significantly improved by adding the level of residual FDG uptake after three cycles, especially in the patients with partial and complete response, whereas patients with stable disease on CT did poorly regardless of PET response. In a study by Weber and coworkers136 in 57 patients with advanced NSCLC treated with platinum-based chemotherapy, a close correlation between PET response after 1 cycle (defined as reduction in SUV > 20%) and best overall response on CT (RECIST) was reported (P = .0001). Furthermore, there was a significant difference in overall survival between PET responders and nonresponders (252 days versus 151 days, P = .005). The end point of metabolic response may be used in the future to reduce the morbidity and costs of ineffective therapy in nonresponders.

Use of PET in Radiotherapy Planning Although most of the FDG-PET studies of locoregional NSCLC staging were performed in a preoperative setting, the use of this technique could be of equivalent importance in patients scheduled for radiotherapy. The extent of the tumor will not only influence the treatment intention (i.e., curative or palliative) but also the volumes to be treated and therefore the toxicity to be expected. Classic radiotherapy planning uses computed tomography (CT) to describe the tumor

Ch037-F06861.indd 440

and to draw the target volume for irradiation. The main limitations are the poor demarcation of some tumors on CT, especially in the presence of atelectasis, and the inability of CT to distinguish between benign and malignant lymph nodes. At present, FDG-PET is useful in defining nodal extension for radiotherapy planning owing to the higher diagnostic accuracy of FDG-PET compared with CT for nodal staging. Van Uytsel and colleagues107 performed a simulation study on the potential impact of FDG-PET on the radiation treatment plan of 105 patients with NSCLC. For 73 of these patients, with positive lymph nodes on CT and/or on FDGPET, a theoretical study was performed in which for each patient the gross tumor volume (GTV) was defined based on CT and on PET/CT data. For each GTV, the completeness of tumor coverage was assessed, using the available surgical pathology data as the gold standard. Tumor coverage improved from 75% when the CT GTV was used to 89% with the PET GTV (P = .0005). In 45 patients (62%) the information obtained from FDG-PET would have led to a change of the treatment volumes. In selected patients, it also reduced the volume of normal tissues irradiated, and thus toxicity, opening possibilities for treatment intensification. The first clinical study in 44 patients with NSCLC supports the use of selective mediastinal irradiation guided by PET/CT scan because only 1 of 44 patients selectively irradiated on the FDG-PET positive areas in the mediastinum developed an isolated nodal recurrence (De Ruysscher et al, 2005).137 Moreover, this was a patient without detectable involved lymph nodes both on CT and on FDG-PET scan. In addition to the better detection of true-positive lymph node involvement, FDG-PET further alters the definition of the GTV by discriminating tumor tissue from atelectasis or necrosis.138,139 Some issues related to the use of PET for lung cancer radiotherapy are still unresolved. First, tumor volume delineation or contouring by PET is still unsatisfactory. The appropriate activity threshold to be used to automatically delineate the tumor contours varies with the size of the tumor and the tumor-tobackground ratio.140 Standardization is needed because the use of different delineation techniques for FDG-PET leads to different GTVs.141 Another problem is tumor motion. PET images are acquired over several minutes during free breathing. This results in an enlargement of the metabolic lesion in the axis of the respiratory movement. To increase the accuracy of tumor volume delineation, respiratory gating techniques are implemented.142 Future prospective comparative studies are indicated to examine whether these advantages of combined PET/CT radiation treatment planning will actually result in reduced toxicity, better local control, and increased survival.

VENTILATION AND PERFUSION SCINTIGRAPHY Ventilation and perfusion scintigraphy was developed in the 1970s and has become widely accepted in quantitating regional pulmonary function as well as estimating postoperative function after lung resection. Before the introduction of multidetector spiral CT it was the noninvasive imaging tech-

1/21/2008 11:16:33 AM

Chapter 37 Nuclear Imaging of the Lung

nique of choice in the diagnostic workup of patients suspected of having . pulmonary embolism. Perfusion (Q ) images are acquired after injection of 99mTcmacroagregated albumin (MAA). These radioactive particles, with a size ranging from 5 to 100 µm, are trapped in the pulmonary capillaries. The number of particles that impact in a particular volume of the lung is proportional to the pulmonary arterial flow to that region. To ensure that pulmonary flow is evenly distributed, the tracer is injected slowly (over 5-10 seconds) and with the patient supine and taking moderately deep breaths. Although these particles cause embolization, the effect is never physiologically significant because fewer than 1 in 1000 capillaries is obstructed (1 dose of 99m Tc-MAA contains 200,000 to 700,000 particles). Immediately after tracer injection, images are obtained with a gamma camera. This can consist of planar views from several directions (anterior, posterior, lateral, and oblique views). By rotating the detector system around the body, transverse images can be reconstructed (also called single photon emission computed tomography [SPECT]). . Ventilation (V) scintigraphy reflects the distribution of air flow in the lungs and involves the inhalation of radioactive gases or 99mTc-labeled aerosols.143 For many years xenon-133 (133Xe) was the gas of choice. It requires a special ventilation apparatus for administrating the gas and trapping the exhaled air. On injection of xenon gas into the delivery system, it starts to be taken into the lungs. Multiple images during wash-in, equilibrium, and wash-out phases of the test are acquired and clearance times are calculated. Because of the low photon energy of 133Xe, ventilation scintigraphy must be performed before perfusion scintigraphy to avoid misinterpretation. Moreover, its significant solubility and relatively long half-life (5.3 days) leads to high and often unnecessary radiation doses for the patient. Krypton-81m (81mKr) is now considered to be the reference gas for ventilation scintigraphy. It does not require expensive delivery systems, the static distribution of 81mKr reflects the pattern of lung ventilation, and its very short half-life (13 seconds) enables multiple views. The high photon . . energy (190 keV) allows simultaneous acquisition of V/Q, resulting in strictly comparable views and a short procedure time. Because 81mKr is not readily soluble, the absorbed radiation dose is low. Unfortunately, the rubidium-81 (81Rb) generator, from which 81mKr is eluted, has a very short half-life (4.7 hr) and is expensive, which limits the continuous availability of 81mKr. Radioaerosols (e.g., 99m Tc-diethylenetriaminepentaacetic acid [DTPA]) are very small radioactive particles inhaled through a nebulizer that produce a submicron aerosol that penetrates to the lung periphery. In case of excessive airway turbulence from rapid shallow breathing or partial airways obstruction there may be a substantial degree of central lung deposition that can lead to poor images of peripheral ventilation.144 Technegas is a relatively new aerosol that can be used for ventilation scintigraphy. In contrast to the 99mTc-DTPA, Technegas is considered to behave truly like a gas, because of the ultrafine dry dispersion of the 99mTc-labeled carbon particles.145,146 It provides speed and ease of administration, deep peripheral penetration with minimal bronchial deposition, and prolonged

Ch037-F06861.indd 441

441

pulmonary retention. The disadvantage is that a special delivery system is needed to produce the gas, which in turn makes it expensive.

Prediction of Residual Pulmonary Function After Lung Surgery The prediction of residual pulmonary function after the surgical resection of a lung is needed to prevent respiratory insufficiency, especially in patients with chronic pulmonary disease. Scintigraphy can noninvasively evaluate the contribution of each lung (region) to the overall pulmonary function. Anterior and posterior images are acquired simultaneously on a two-headed gamma camera. Two or three regions of interest are drawn on each lung, and counts in each zone are measured. Geometric means of anterior and posterior images are then used to calculate relative contributions of the different zones in relation to the total lung function. Postoperative lung function is then estimated to be the product of the preoperative function and the portion of lung function that will remain after .resection. . Based on the common assumption that pulmonary . . V and Q show a similar distribution pattern, both V and Q lung scintigraphy can be employed for the assessment of residual pulmonary function.. There is no. clear evidence as to whether it is better to use a V scan . or a Q scan alone or in combination. Due to its ease, the Q scan is often preferred. Furthermore, when radioactive aerosols are used . for V scanning, central deposits can hamper accurate quantification. The correlation between the actual and predicted postoperative forced expiratory volume at 1 second (FEV1) using quantitative lung scintigraphy has been variable, with correlations quoted between r = .54 and r = .9.147-155 Many of these investigators have found that the scintigraphically predicted postoperative FEV1 was lower than the actual postoperative FEV1 (up to 10% less than actual measured values 3 months after resection).147,151,152,155 This finding has potentially serious implications in deciding a patient’s fitness for lung cancer surgery, because underestimating a patient’s postoperative lung function may unnecessarily preclude the individual from curative surgery. The American College of Chest Physicians (ACCP) guidelines (Beckles et al, 2003),156 as well as those from equivalent European organizations such as the British. Thoracic Society (BTS),157 recommend using quantitative Q scintigraphy in patients with borderline lung function (FEV1 < 2.0 L) to predict the postoperative lung function in lung cancer patients who are considering undergoing pneumonectomy. Scintigraphic prediction of the residual pulmonary function after a lobectomy is not recommended because of difficulties in scintigraphically assessing the contribution of each single lobe to the overall respiratory function owing to spatial overlap of pulmonary areas on planar imaging, as well as to the minor clinical importance of functional prediction when surgery is restricted to a relatively small part of the lung. Spatial overlap can be avoided by using SPECT images, but this more sophisticated method was not superior to planar images owing to the limited anatomic resolution.158 Perhaps SPECT combined with CT can overcome this hurdle.

1/21/2008 11:16:33 AM

442

Section 3 Lung

Pulmonary Embolism

. . For nearly three decades, V/Q lung scanning has been the only noninvasive imaging modality for the diagnosis of acute pulmonary embolism (PE). Diagnosis is based on recognition of a parenchymal perfusion defect related to the embolized artery, . . associated .with . a normal regional ventilation, so called V/Q mismatch. V/Q scanning is able to show even small emboli, and this ability is enhanced by SPECT. The large . . prospective PIOPED I trial helped to define the role of V/Q scanning in the diagnostic workup of patients with suspected pulmonary embolism (Pioped Investigators, 1990).159 These data were critically analyzed, and modified interpretive strat160-163 egies were Most investigators believe that a . .suggested. normal V/Q scan rules out PE with enough certainty that no further consideration needs to be given to this diagnosis and another cause for the patient’s . . problems must be sought. In general, a high probability V/Q scan is specific enough that therapy can be given without further testing. In case of a contraindication for anticoagulant therapy, a confirmatory test is desirable to increase the certainty of PE diagnosis. Because emboli may take years to resolve, a high probability . . V/Q scan may reflect sometimes old embolic disease. Advancements in CT technology have enabled imaging of the entire chest with 1-mm slice collimation in one breathhold. This not only improves spatial resolution for small clot detection but also suppresses respiratory- and cardiac-related motion blurring. Furthermore, spiral CT seems to be attractive and advantageous because it is readily available, is noninvasive, provides direct visualization of the clot, or can define associated or alternative diagnosis, thus explaining the clinical symptoms. PIOPED II was designed to evaluate the efficacy of contrast-enhanced spiral CT for the diagnosis of acute PE (Stein et al, 2006).164 Unlike PIOPED I, this study uses a composite reference . . test for venous thromboembolic disease that is based on V/Q scan, venous compression ultrasonography of the lower extremities, digital subtraction angiography, and contrast venography. Owing to. the . excellent accuracy of CT to detect PE, the need of V/Q scanning has become marginal according to the recommendations of the PIOPED II investigators and is only performed when discordant findings between clinical assessment and CT result or in patients with contraindications for contrast medium–enhanced CTs (contrast allergy, impaired renal function).165 Because CT for PE . .results in high absorbed dose to the breast (10-40 mGy), V/Q scan is also preferred in young females with a normal chest radiograph (the absorbed dose to the breast is only 0.28 mGy).166

COMMENTS AND CONTROVERSIES In recent years the application of nuclear imaging of the lung has . . changed significantly. Formerly, ventilation/perfusion (V/Q ) imaging was critically important in the evaluation of pulmonary embolism. . . Current CT technology has allowed CT images to supplant V/Q . . imaging for the evaluation of pulmonary embolism. Quantitative V/Q imaging can be of help in the evaluation of patients with emphysema being considered for lung volume reduction surgery by demonstrat. . ing functionally what one might infer from CT. Quantitative V/Q imaging is also helpful in making the judgment regarding operability

Ch037-F06861.indd 442

in patients with localized lung cancer who have limited lung function, usually due to chronic obstructive pulmonary disease. However, currently the most frequent interaction between nuclear medicine physicians and thoracic surgeons is in the application of PET imaging for the staging of lung cancer. The author outlines the important physics of PET imaging and its limitations. The recent widespread use of PET/CT fusion imaging has improved accuracy. Evaluation of the solitary indeterminate pulmonary nodule is covered extensively. I believe PET does not add greatly to the evaluation of these lesions, especially in geographic areas where granulomatous disease is prevalent. PET positivity does not confer a malignant diagnosis. As the author points out, however, a negative PET for a lesion greater than 1 cm in diameter without ground-glass opacity on CT is highly suggestive of a benign diagnosis and an indication for continued follow-up imaging. PET does assist in the evaluation of mediastinal lymph nodes in patients with lung cancer. Certainly, false-positive and false-negative studies can occur. A positive study needs to be confirmed by needle aspiration, mediastinoscopy, or thoracoscopic biopsy. The author suggests that patients with no evidence of mediastinal nodal metastasis by PET do not need pre-resection mediastinoscopy. Whereas my experience suggests that this is true for T1-2 lesions, it is not correct for patients with locally advanced or central tumors. These patients always need to undergo mediastinal lymph node sampling before resection. PET is of definite value in the identification of occult hematogenous metastases. It appears that PET SUV is predictive of long-term outcome because early-stage lesions with a higher SUV seem to have a poorer long-term prognosis. Another potential area in which PET may prove useful is in the prediction of response to chemotherapy and radiation therapy. This is currently an area of intense study. G. A. P.

KEY REFERENCES Beckles MA, Spiro SG, Colice GL, Rudd RM: The physiologic evaluation of patients with lung cancer being considered for resectional surgery. Chest 123:105S-114S, 2003. Brink I, Schumacher T, Mix M, et al: Impact of 18F-FDG-PET on the primary staging of small cell lung cancer. Eur J Nucl Med Mol Imaging 31:1614-1620, 2005. Cerfolio RJ, Bryant AS, Ojha B: Restaging patients with N2 (stage IIIa) non–small cell lung cancer after neoadjuvant chemoradiotherapy: A prospective study. J Thorac Cardiovasc Surg 131:1229-1235, 2006. De Leyn P, Stroobants S, De Wever W, et al: Prospective comparative study of integrated positron emission tomography-computed tomography compared with remediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy proven stage IIIA-N2 non–small cell lung cancer: A Leuven Lung Cancer Group study. J Clin Oncol 24:3333-3339, 2006. De Ruysscher D, Wanders S, van Haren E, et al: Selective mediastinal node irradiation based on FDG-PET scan data in patients with non– small-cell lung cancer: A prospective clinical study. Int J Radiat Oncol Biol Phys 62:988-994, 2005. Fischer BM, Mortensen J, Hojgaard L: Positron emission tomography in the diagnosis and staging of lung cancer: A systematic, quantitative review. Lancet Oncol 2:659-666, 2001.

1/21/2008 11:16:33 AM

Chapter 37 Nuclear Imaging of the Lung

Gould MK, Maclean CC, Kuschner WG, et al: Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: A meta-analysis. JAMA 285:914-924, 2001. Gould MK, Kuschner WG, Rydzak CE, et al: Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small cell lung cancer: A metaanalysis. Ann Intern Med 139:879-892, 2003. Hoekstra CJ, Paglianiti I, Hoekstra OS, et al: Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography: An overview of different analytical methods. Eur J Nucl Med 27:731-743, 2000. Mawlawi O, Pan T, Macapinlac HA: PET/CT imaging techniques, considerations, and artifacts. Thorac Imaging 21:99-110, 2006. Nomori H, Watanabe K, Ohtsuka T, et al: Valuation of F-18 fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules less than 3 cm in diameter, with special reference to the CT images. Lung Cancer 45:19-27, 2004. PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: Results of the prospective investigation of pul-

Ch037-F06861.indd 443

443

monary embolism diagnosis (PIOPED). JAMA 263:2753-2759, 1990. Shim SS, Lee KS, Kim BT, et al: Focal parenchymal lung lesions showing a potential of false-positive and false-negative interpretations on integrated PET/CT. AJR Am J Roentgenol 186:639-648, 2006. Shreve PD, Anzai Y, Wahl RL: Pitfalls in oncologic diagnosis with FDG PET imaging: Physiologic and benign variants. RadioGraphics 19:6177, 1999. Stein PD, Fowler SE, Goodman LR, et al, PIOPED II Investigators: Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 354:2317-2327, 2006. Van Tinteren H, Hoekstra OS, Smit EF, et al: Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non–small cell lung cancer: The PLUS multicentre randomised trial. Lancet 359:1388-1393, 2002. Viney RC, Boyer M, King MT, et al: Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non–small-cell lung cancer. J Clin Oncol 22:2357-2362, 2004.

1/21/2008 11:16:34 AM

INVESTIGATION AND MANAGEMENT OF MASSIVE HEMOPTYSIS

chapter

38

Dennis A. Wigle Thomas K. Waddell

Key Points ■ Death is usually due to hypoxia, not exsanguination. ■ Common causes are inflammatory lung diseases, neoplasms, and

cardiac disease. ■ Endobronchial and/or angiographic control is usually possible. ■ Surgical treatment has high mortality and morbidity.

colleagues8 changed management forever with the first reports of bronchial artery embolization. Four patients with massive or repeated hemoptysis were treated, with technical success in all. Hiebert,9 in 1974, described the first successful use of a Fogarty balloon catheter through a rigid bronchoscope to tamponade bleeding in a patient with massive bronchial hemorrhage.

■ Surgery is delayed until bleeding is controlled, and surgery is

avoided if other measures suffice.

Hemoptysis is the coughing of blood that originates from the tracheobronchial tree or pulmonary parenchyma.1 Although there is no universally accepted volume that defines massive hemoptysis, the term is typically reserved for any volume of blood in the airway that represents an imminent threat to life. Various studies have quoted critical volumes ranging from 100 to more than 1000 mL over 24 hours. The anatomic dead space of the tracheobronchial tree is about 200 mL or less, so a more useful definition is any volume that is lifethreatening by virtue of airway obstruction or blood loss. Massive bleeding in the airway is potentially a lethal problem because of asphyxiation. Exsanguination itself is rarely the cause of death.2,3 The coughing up of blood prompts most people to seek medical attention. Although fewer than 5% of patients with hemoptysis expectorate large volumes, the incidence of acute fatality in this group ranges from 7% to 32%. Very rapid bleeding, such as from a fistula to a major vessel, is usually fatal. Assessment of the patient with a moderate amount of hemoptysis can represent a clinical dilemma because many patients cough up only small amounts of blood but aspirate massively. Expectorated blood is often swallowed and cannot be measured. Many patients with hemoptysis have compromised lung function, and even small quantities of blood in the bronchial tree can lead to significant respiratory distress.

HISTORICAL NOTE In 1938, Eloesser4 described sources of pulmonary hemorrhage and attempts at its control. He performed mass ligation of the hilum in seven patients, with only two recovering. He suggested that lobectomy might be less dangerous, although it was not until 1954 that Feldman and Gusmão5 described a successful right upper lobectomy for tuberculosis (TB). Pneumonectomy for control of massive hemoptysis was reported by Pitkin6 in a bronchiectatic patient in 1941 and by Ryan and Lineberry7 for TB in 1950. In 1973, Remy and

THE BRONCHIAL CIRCULATION Most cases of significant hemoptysis arise from the bronchial circulation. Hemoptysis arising purely from the pulmonary circulation is thought to account for only approximately 5% of cases.10 Bronchial arteries typically arise from the thoracic aorta or its branches, although as many as 30% can arise from other locations. They are usually less than 2 mm in diameter.11 The same vessels that supply the bronchial arteries may also supply the esophagus, the mediastinal nodes, and, importantly, the spinal cord, through a complex anastomotic network.12 The landmark study of the bronchial circulation, based on 150 human cadavers,13 demonstrated that the right bronchial arteries frequently arise from the lateral or dorsolateral aspect of the aorta, often in conjunction with an intercostal artery. The left bronchial arteries usually originate from the anterior surface of the thoracic aorta or from the concavity of the aortic arch. After reaching the main airway, they follow the course of the bronchi in a tortuous and variable pattern.14 Typically, they can be seen at the corners where the membranous and cartilaginous sections of bronchial circumference meet (at least until the airway becomes completely surrounded by cartilage). There are normally three levels of bronchopulmonary anastomoses.1 Firstly, so-called bronchopulmonary arteries arise from medium-sized bronchial arteries and anastomose with the alveolar microvasculature. Secondly, anastomoses also occur between small bronchial arteries and the veins of the pleural and pulmonary drainage systems. These are the vessels that contribute to anatomic shunt. Finally, as airways become smaller, more and more bronchial capillaries merge with pulmonary capillaries. There are also normally systemic arterial vessels within the pulmonary ligament that can enlarge and contribute to hemoptysis in a small number of cases. A much larger contribution is made by pathologic vessels, not normally seen, that course between the chest wall and the lung. These vessels are derived from neoangiogenesis triggered by inflammatory or ischemic conditions within the lung and are invariably associated with pleural adhesions, which are often dense and difficult to deal with if resection is required.

444

Ch038-F06861.indd 444

1/21/2008 11:31:37 AM

Chapter 38 Investigation and Management of Massive Hemoptysis

ETIOLOGY The most common causes of hemoptysis are listed in Table 38-1. It is important to remember to exclude nasopharyngeal or gastrointestinal bleeding as a source. Hemoptysis originates from the bronchial circulation in 95% of cases, and from the pulmonary circulation in 5%. Bleeding from the bronchial arteries has a greater propensity to cause massive hemoptysis, given the higher pressures involved.10

Inflammatory Disease Chronic inflammatory conditions are the most common cause of massive hemoptysis. The most common of these are bronchiectasis, cystic fibrosis, aspergillosis, and, more rarely in the developed world, TB. Less common causes include lung abscess and other necrotizing lung infections, with erosion into larger pulmonary vessels or from inflammatory bronchial vessels in the walls of the lesions.

Bronchiectasis Traction bronchiectasis, caused by parenchymal retraction due to alveolar fibrosis, is not usually associated with hemoptysis. Pathologically, inflammatory bronchiectasis is the destruction of the cartilaginous support of the bronchial wall. It is usually caused by repeated bouts of infection, with proliferation and enlargement of the bronchial arteries and

TABLE 38-1 Common Causes of Hemoptysis Infectious Chronic bronchitis Bronchiectasis Tuberculosis Nontuberculous mycobacteria Lung abscess Necrotizing pneumonia Mycetoma Cystic fibrosis Cardiovascular Severe left ventricular heart failure Mitral stenosis Pulmonary embolism or infarction Septic pulmonary embolism or right-sided endocarditis Aortic aneurysm or bronchovascular fistula Neoplastic Lung cancer Bronchial adenoma Metastatic disease (osteogenic sarcoma, choriocarcinoma) Vasculitis Wegener’s granulomatosis Systemic lupus erythematosus Miscellaneous Idiopathic pulmonary hemosiderosis Aspirated foreign body Pulmonary contusion or trauma Post-transthoracic needle biopsy or transbronchial lung biopsy Cocaine (“crack”) lung Factitious hemoptysis From Johnson JL: Manifestations of hemoptysis, Postgrad Med 112:101-113, 2002.

Ch038-F06861.indd 445

445

precapillary bronchopulmonary anastomoses. These communications are most widespread near the diseased third- or fourth-order bronchi and the bronchiectatic sacs.1,15

Cystic Fibrosis Massive hemoptysis is a serious complication in patients with cystic fibrosis, occurring more commonly in older patients with more advanced lung disease. Almost 1 in 100 patients have this complication each year, and infection with Staphylococcus aureus is a significant risk factor (Flume et al, 2005).16 It tends to occur in older patients, is not always associated with more advanced lung disease, but is a significant predictor of subsequent long-term mortality.17 Bleeding may arise either from bronchial arteries, which can be massively hypertrophied and dilated, or via neoangiogenesis directly from the chest wall.

Aspergillosis Aspergillus is ubiquitous in the environment and is routinely inhaled.18 Fungal infections can be severe and can cause necrotizing destruction of tissue, including significant vessels. This is a major concern for the rare infection mucormycosis, and it is occasionally seen with aspergillus, usually in immunocompromised patients. More commonly, aspergillus colonizes a previous area of pulmonary destruction. The intracavitary fungal ball is one of the most potent triggers for neoangiogenesis. The blood vessels that line the cavity are typically branches of the bronchial artery network. Because most cavities are in the posterior portions of the upper lobes, there is also potentially a contribution from branches of the axillary or subclavian arteries.

Tuberculosis Rasmussen analyzed 11 deaths from hemoptysis in 1868. Eight patients had rupture of a vessel in the wall of a tuberculous cavity. They turned out to be false aneurysms, most frequently in branches of a bronchial artery crossing the wall of the cavity. These have since been termed Rasmussen aneurysms.19 Tuberculous cavities have a rich bronchial blood supply, but pulmonary artery branches typically do not contribute to the blood supply of a tuberculous area because they undergo thrombosis in the early stages of the disease. Normal lung architecture is destroyed by TB, predisposing to the development of bronchiectasis with its attendant hypervascularized, dilated, tortuous bronchial circulation and anastomoses between the bronchial and pulmonary circulations. Bleeding may be seen in the early exudative phase of TB, as in any necrotizing infection, although this is rarely seen in the developed world and usually is not massive. Even the type of bleeding described by Rasmussen, with rupture of a pseudoaneurysm crossing the cavity wall, is now unusual. More commonly, healed and calcified lymph nodes impinge on and erode into the wall of the bronchus. As described earlier, cavities can become secondarily involved with aspergillus, which is probably the most common form of this rare disease in the modern era.

1/21/2008 11:31:37 AM

446

Section 3 Lung

Neoplasm Minor hemoptysis is common with lung cancer, particularly in patients with more proximal tumors. In most cases, the friable tumor has developed neoangiogenesis from the systemic circulation. Massive hemoptysis, however, is quite rare and is usually caused by direct invasion of the major vessels with subsequent necrosis of the invading tumor.2 A large retrospective analysis found that massive hemoptysis was the cause of death in only 3.3% of cancer patients.20 Not surprisingly, this development was significantly associated with cavitating squamous cell carcinoma, arising in either the right or the left main bronchus. External-beam radiotherapy did not appear to be responsible. High-dose-rate brachytherapy has been associated with an increased risk of massive hemoptysis, especially with large fraction size.21 Although it is effective anticancer therapy, targeted therapy directed at the vascular endothelial growth factor system also poses some risk of bleeding. This is especially the case for centrally located squamous cancers.22 On occasion, stents placed for palliation may also erode into major vessels, resulting in lifeending hemoptysis. Other neoplasms can also cause significant bleeding. Carcinoid tumor may be the most infamous, although in our experience they do not bleed significantly spontaneously. Bleeding after biopsy of carcinoid tumors is reputed to be dangerous and occasionally can be impressive. Other tumors with a propensity for endobronchial metastases, such as renal cell, prostate, and colorectal carcinoma, usually bleed only in a minor fashion. Direct extensions of esophageal carcinoma or mediastinal lymphoma into the airway are usually preterminal developments.

Trauma Deceleration injury and penetrating chest trauma commonly lead to airway injury. Pulmonary arterial branches may also be injured. Minor hemoptysis may occur from pulmonary contusion or may be a sign of more serious underlying airway trauma. Most cases of massive hemoptysis are caused by large vessel injury and are immediately fatal.1,3

Iatrogenic Causes Pulmonary Artery Catheterization Perforation of the pulmonary artery during or after pulmonary artery catheterization, with associated massive hemorrhage, is a well-recognized complication. Anticoagulation, hypothermia, and pulmonary hypertension are risk factors and are commonly present in the critically ill. Several mechanisms have been suggested.23 The balloon itself can directly tear the pulmonary artery (overdistention injury), or the tip can be propelled through the vessel wall by balloon inflation. The entire catheter can be advanced too far distally and perforate the vessel.

Bronchoscopy Minor bleeding is common from endoscopic trauma, or more often from brushing or biopsy. This can occur from either endobronchial or transbronchial needle aspiration of medias-

Ch038-F06861.indd 446

tinal nodes or masses. Massive hemorrhage is uncommon but can be seen in a couple of scenarios. With major central tumors and concurrent invasion of major vessels, bronchoscopy probably provokes the otherwise inevitable. We have also seen significant hemorrhage from endobronchial biopsy of carcinoid tumors and transbronchial lung biopsy, especially in patients with pulmonary hypertension. During awake flexible bronchoscopy, the patient’s ability to clear blood is diminished because of sedation, supine positioning, and airway anesthesia. The tracheobronchial tree can fill quickly with blood and overwhelm the suction capacity of a flexible bronchoscope. Desaturation and death may occur within a few minutes if the massive hemoptysis is not managed appropriately.2

Pulmonary Embolism Distal pulmonary embolus can cause infarction, hemorrhage, and alveolar edema, progressing to full necrosis. Bronchial arterial anastomoses into such a destroyed segment of lung parenchyma can cause significant bleeding, especially after systemic anticoagulation. Reversal of anticoagulation and placement of an inferior vena cava filter is usually sufficient to stop the bleeding.1,3

Arteriovenous Fistulas Pulmonary arteriovenous malformations are rare, direct, lowpressure, arterial-to-venous communications in the lung that may be single or multiple. Although these lesions are typically congenital, acquired lesions have been reported in rare instances after surgery, trauma, pulmonary infection, metastatic carcinoma, and hepatic cirrhosis.24 Arteriovenous fistulas constitute a rare cause of massive hemoptysis, accounting for approximately 2% of cases in a large series.3 Pulmonary arteriovenous fistulas have also been recognized as a manifestation of hereditary hemorrhagic telangiectasia in Osler-Weber-Rendu disease. Sixty percent of patients with pulmonary arteriovenous fistulas have associated telangiectasias of the skin or superficial mucous membranes. The precapillary pulmonary arteriovenous fistula communicates with the pulmonary arteries and veins, giving rise to a right-to-left shunt. The walls of these vascular structures are thin and may rupture.

Cardiovascular Disorders Hemoptysis is a well-known sequela of elevated pulmonary venous pressure caused by mitral stenosis or congenital heart disease. It does not usually occur from heart failure itself. It can also occur with pulmonary veno-occlusive disease. Small vessels rupture due to congestion and elevated back pressure, with bleeding that is rarely massive. Embolization to the lungs from tricuspid valve vegetations may produce pulmonary infarction and hemoptysis. Pulmonary hypertension in Eisenmenger’s syndrome, caused by a long-standing state of high flow or high pressure, or both, can lead to rupture of pulmonary artery atherosclerotic plaques. This is less commonly seen in primary pulmonary arterial hypertension, which develops more rapidly. Inadequate blood flow through the pulmonary artery, whether caused by tetralogy of Fallot,

1/21/2008 11:31:38 AM

Chapter 38 Investigation and Management of Massive Hemoptysis

pulmonic stenosis, or narrowing of the pulmonary outflow tract, triggers systemic collateralization via bronchial arteries, chest wall vessels, or both. Massive hemoptysis may occur after erosion of varicose bronchial vessels into the airway or rupture of bronchopulmonary anastomoses.2

Bronchovascular Fistulas Direct bronchovascular communication may be signaled by minor sentinel bleeding followed by fatal hemorrhage. It may be caused by trauma, neoplasm within the lung or mediastinum, or intrinsic disease of large vessels adjacent to the tracheobronchial tree.3 Aortobronchial fistula is a rare but highly lethal condition. Aortic aneurysm is the usual cause, but it can result from infection of the aorta.25,26 Tracheo-innominate artery fistula is a relatively rare complication. In patients with tracheostomies, this diagnosis is often considered, yet most cases of minor hemoptysis are caused by granulation tissue in the trachea or wound edge bleeding. Tracheostomy sites are examined by bronchoscopy in the operating room after careful removal of the tracheostomy device. If massive hemorrhage begins, immediate compression of the artery up toward the sternum and control of the airway, preferably by oral endotracheal intubation or rigid bronchoscopy, will stabilize the situation. Subsequently, the sternum can be divided, the arterial bleeding site oversewn, and healthy tissue placed between the artery and the airway. Strap muscles can be mobilized and interposed with good outcome.27

Diffuse Parenchymal Diseases Inflammatory or immunologic systemic diseases such as systemic lupus erythematosus, Goodpasture’s syndrome, idiopathic pulmonary hemosiderosis, polyarteritis nodosa, Wegener’s granulomatosis, or Takayasu’s arteritis may affect the lung and cause bleeding into it.1,28,29 Manifestations of alveolar hemorrhage include hemoptysis, alveolar infiltrates on chest radiographs, and prominent anemia due to the chronic nature of the disease.2 Massive bleeding is rare, and patients predominantly are affected by restrictive defects caused by secondary fibrosis induced by the bleeding or the underlying illness.

Miscellaneous Conditions Cryptogenic or idiopathic major hemoptysis is uncommon. Most causes of seemingly idiopathic hemoptysis are evident with simple investigations including bronchoscopy. Approximately 10% may remain undiagnosed after complete workup and bronchoscopy.2

DIAGNOSIS Clinical Features The initial diagnostic focus is to determine the site, or at least the side, of bleeding.1 To begin, one must exclude conditions that are easily confused with hemoptysis. Hematemesis from an upper gastrointestinal bleeding site can be misleading, as can epistaxis and bleeding from the gums or nasopharynx. Salient features about the bleeding, such as its amount, appearance, duration, and relationship to exertion, position,

Ch038-F06861.indd 447

447

or cough, are specifically elicited. The past medical history needs to focus on previous lung and heart diseases and tobacco exposure. Associated chest pain or sounds such as wheezing or bubbling may be present. These may be felt specifically on the side of bleeding. Similarly, some patients experience chest heaviness, presumably due to congestion of blood within the alveolar airspace. Even before bleeding has subsided, cultures for fungi and mycobacteria can be obtained.

Radiography A plain chest radiograph is the most readily available and often the most useful test. Compare it with prior films if at all possible. Localized pulmonary pathology, such as infiltrates, atelectasis, cavitation, cyst formation, or a mass, may be the best indicator of the source of bleeding. Only rarely does massive hemoptysis occur in the setting of a normal chest radiograph.30 More commonly, large amounts of aspirated blood are evident as pulmonary infiltrate. Pulmonary infiltrates are usually worst, and seen first, in the lobe or area from which the bleeding originates.31 Immediate computed tomographic (CT) scanning may more clearly delineate areas of infiltrate or may demonstrate cavities or masses missed on the plain chest film. After some of the blood has begun to be absorbed, delayed CT scans can also help identify areas of obstruction, stenosis, or signs of chronic bronchitis or bronchiectasis. CT abnormalities were identified in 50% of patients with hemoptysis, normal chest radiographs, and nondiagnostic bronchoscopy findings.32 CT angiography is currently the test of choice for pulmonary embolism. CT may also provide clues pointing toward pulmonary hypertension, based on the size of the main pulmonary artery, or demonstrate bronchial arterial dilation or aortopulmonary collaterals. Ongoing improvements in CT technology may also make CT angiography the diagnostic procedure of choice, rather than conventional angiography.33

Bronchoscopy Patients with massive hemoptysis require urgent bronchoscopy.1,2 Recognizing the functional definition of massive hemoptysis as bleeding that poses an imminent threat of asphyxiation, rigid bronchoscopy in an operating room environment is the preferred approach at the Toronto General Hospital. If the patient is awake, perform flexible bronchoscopy; use minimal sedation to ensure that the patient can evacuate as much blood via coughing as possible. Perform the procedure rapidly, and primarily aim to establish which lobe (or perhaps only which lung) seems to be the source of the blood. In major hemoptysis, there will undoubtedly be large amounts of blood on both sides. In experienced hands, the rigid bronchoscope has several advantages. Its large bore allows rapid suctioning of blood and easier removal of large clots. Fig. 38-1 demonstrates the much larger suction device that can be used with a rigid bronchoscope, compared with the small suction channel on the flexible bronchoscope. The rigid bronchoscope also allows for the passage of balloon catheters and rapid instillation of large volumes of ice-cold lavage solutions. With intermittent isolation of the bronchi, one may alternate suctioning blood

1/21/2008 11:31:38 AM

448

Section 3 Lung

TABLE 38-2 Medical Treatment of Hemoptysis Bed rest Trendelenburg position Affected side down Wide intravenous line Arterial blood gas monitoring Sedatives Cough suppressants (antitussives) Oxygen Broad-spectrum antibiotics Blood transfusion FIGURE 38-1 Comparison of rigid versus flexible bronchoscope suction ports. A, Large-bore suction for rigid bronchoscope. B, No. 8 rigid bronchoscope. C, Regular suction for rigid bronchoscope. D, Adult flexible bronchoscope. Suction port of adult flexible bronchoscope is marked with red arrow.

from one lung while ventilating the other. Once the bleeding has been controlled, a flexible bronchoscope may also be passed down its lumen to allow careful, detailed inspection with excellent optics.

Bronchial Arteriography Massive hemoptysis usually involves bleeding from the systemic circulation, either from the bronchial arteries or from pathologic collateral branches of the subclavian, axillary, intercostal, or phrenic arteries.2 By cannulating branches of the aorta, it is sometimes possible to obtain a precise anatomic diagnosis. For example, in TB, there is hyperplasia of the associated bronchial arteries, with numerous branches feeding the pulmonary lesions. These hyperplastic vessels are usually found either within or adjacent to the wall of the tuberculous cavity. In bronchiectasis, there is an enlargement of the proximal portion of the bronchial artery which winds around the ectatic bronchi. In contrast, enlargement of the main bronchial artery is minimal in neoangiogenesis associated with lung cancer, but large numbers of irregular branches that develop within and around the tumor are characteristic. Systematic bilateral arteriographic examination of the bronchial and nonbronchial collateral arteries has been used successfully to look for evidence of bleeding vessels. However, the contrast dye load is significant with such an approach. At our center, all patients undergo bronchoscopy for stabilization before bronchial arteriography. At a minimum, the side of bleeding must be determined. Angiography is usually performed under general anesthesia during truly significant bleeding; this allows ongoing airway suctioning via the endotracheal tube or lung isolation with bronchial blockers (see later discussion). Parenchymal hypervascularity, vascular hypertrophy, tortuosity, capillary stasis, bronchopulmonary shunting, aneurysm formation, and vessel thrombosis may all suggest a bleeding vessel. However, some of these findings can be widespread, particularly in patients with aspergillosis or cystic fibrosis. In patients with active and massive bleeding, contrast can actually be seen leaking from the vessel, and embolization may be performed with a high expectation of

Ch038-F06861.indd 448

Reversal of anticoagulation (embolism)

success. Pulmonary artery angiography has been described for a minority of patients with massive hemoptysis, usually after negative systemic angiographic examination.

PRACTICAL ASPECTS TO THE MANAGEMENT OF HEMOPTYSIS Initial management of massive hemoptysis needs to accomplish a number of objectives quickly and simultaneously. Figure 38-2 illustrates a general approach to massive hemoptysis to guide rapid decision making. Blood must be removed to prevent asphyxiation, and the site of bleeding must be determined to guide further surgical or radiologic control measures. If possible, the bleeding must be stopped. In the longer term, the root cause must be identified and the patient treated definitively.2,34 A patient with massive hemoptysis requires treatment in an operative or intensive care setting.

Medical Therapy The initial approach includes a focused history and physical examination, a chest radiograph, blood count, coagulation profile, and arterial blood gas determination (Table 38-2). Insert a large intravenous cannula, and make sure type- and cross-matched blood is available in the blood bank. Apply supplemental oxygen, particularly if the arterial partial oxygen saturation (PaO2) is less than 60 mm Hg. Position the patient in bed with the side of the bleeding dependent, to prevent aspiration and asphyxiation. However, if a patient feels safer sitting up to increase the effectiveness of their cough, we allow him or her to do so. Once the immediate danger has passed and bleeding is settling, sedatives (e.g., diazepam 5-10 mg every 6 hours) and antitussive agents (e.g., small doses of codeine) may be used to depress the excessive or violent coughing that can aggravate or stimulate hemoptysis. Do not administer bronchodilators because they can have vasodilator actions and may precipitate renewed bleeding.35 Treat systemic hypertension. Antibiotics are the mainstay of therapy in patients with bronchiectasis (including cystic fibrosis) and in those with a history of bronchitis or chronic obstructive pulmonary disease, evidence of leukocytosis, or other suggestion of a bacterial infection.31

1/21/2008 11:31:38 AM

Chapter 38 Investigation and Management of Massive Hemoptysis

449

FIGURE 38-2 Management algorithm of massive hemoptysis.

Hemoptysis

Massive or moderate hemoptysis

Volume of blood Respiratory status Comorbidities Lung pathology

Minor hemoptysis

Rigid bronch

Controlled

Admit Flexible bronch CT Chest

Uncontrolled

Secure airway

No

Operate

Yes

Angiographic embolization

Controlled

Admit Flexible bronch CT Chest

Uncontrolled

Operate

Antituberculosis therapy is effective in controlling the hemoptysis of active TB because such lesions are reversible. Care must be taken to ensure appropriate effective antibiotics, depending on the risk of drug-resistant TB in specific patients. Effective drugs reduce the morbidity and mortality of surgery, should it be required. Left undertreated, the outcome for patients with TB is poor. In 1982, Teklu and Felleke36 reported on a series of patients with massive hemoptysis in TB. They studied 74 patients at a sanatorium in Addis Ababa that had no surgical facilities. There were 17 deaths. All patients who died, except one who was operated on at another hospital, were managed conservatively, with a resultant mortality rate of 16/73 or 21.9%.

Methods of Control For massive hemoptysis, rigid bronchoscopy is preferable, and it is most easily performed under light general anesthesia. A large-bore suction catheter is very important to allow rapid suctioning of blood, clots, and irrigation fluid (see Fig. 38-1A). Topical anesthesia is used at the discretion of the

Ch038-F06861.indd 449

anesthetist to prevent laryngospasm. Collaborative management of the airway with the anesthesiologist is very important. Several methods of oxygenation and ventilation are possible. For significant hemoptysis, jet ventilation is preferred. After the bronchoscope has been passed through the vocal cords, visualization often becomes extremely poor; and suction and advancement of the scope, despite poor visualization, must proceed. Several techniques can be used to improve oxygenation. The jet itself is pure oxygen, but much of the air entering the lungs is entrained room air. Placing a mask of high-flow oxygen around the jet catheter at the entrance to the bronchoscope increases the fraction of inspired oxygen (FIO2) of the entrained gas. Functional residual capacity (FRC) can be increased by changing the pattern of ventilation—in particular, by stacking inspiration with small, frequent bursts of oxygen. This leads to alveolar recruitment, improved oxygenation, and, hopefully, tolerance of longer periods of intermittent apnea when the bronchoscopist can accomplish either clearance of the clots or identification of the side or cause of bleeding.

1/21/2008 11:31:39 AM

450

Section 3 Lung

TABLE 38-3 Endobronchial Measures for Control of Hemoptysis Ice-cold saline lavage and adrenaline Balloon tamponade Pulmonary separation Tamponade with vasoconstrictive substances

TABLE 38-4 Miscellaneous Control Measures Selective coagulative treatment Laser Topical thrombin Arterial embolization External tubular drainage Positive end-expiratory pressure Pneumoperitoneum Pneumothorax Intravenous angiotensin Radiotherapy

lavage continued in a similar fashion. For the right upper lobe, one can use the flexible scope to deliver most of the lavage solution, with wedging if possible. Guimarães (Guimarães, 2000)38 reported the use of ice-cold saline lavage in 303 patients with massive hemoptysis, with the bleeding stopping in 291 (96%). After the bleeding lobe or segment has been identified, send samples for pathologic and microbiologic evaluation. Ice-cold saline lavage allows time to evaluate the disease, localize the bleeding, and facilitate lung isolation, angiography, or surgery as required. It needs to be determined whether the bleeding has stopped or is continuing. If it is continuing, alternative control measures must be expeditiously instituted. If it has stopped, the decision between transfer of the patient to the intensive care unit, intubated and ventilated, or transfer to a recovery room for possible extubation depends on the level of parenchymal blood. If the amount of aspirated blood has been major, significant oxygenation support may be required. It is frequently necessary, and advisable, to repeat flexible bronchoscopy after a few days to evaluate whether the bleeding has stopped and to aspirate old clots in the tracheobronchial tree.

Intracavitary treatment Surgical therapy

Tables 38-3 and 38-4 list, respectively, endobronchial and other control measures for hemoptysis.

Ice-Cold Saline/Adrenaline Lavage Because most massive hemoptysis is from the systemic blood supply, vasoconstriction of muscular small arteries is possible with cold temperature alone.3 Lavage with large volumes of ice-cold saline solution allows clots to be removed, improves the oxygenation of the patient, and slows or stops most cases of bleeding. We use a modification of the technique reported by Conlan and colleagues37 in 1983. Rigid bronchoscopy is performed with a large-bore suction catheter available. One liter of saline solution (sterile for intravenous injection) is mixed with 1 mg of adrenaline, and the bag placed in a bowl of ice. All blood and clots are suctioned from the trachea and major bronchi. If possible, the side of the source of bleeding is determined, and adequate arterial saturation is obtained by ventilating the nonbleeding lung, or both lungs if necessary. After saturation is optimized, the bleeding side can be intubated and blood and clots suctioned out. Large aliquots (50100 mL) of the iced adrenaline-saline solution can be injected down the bronchoscope, left in for 10 to 15 seconds, and then rapidly removed by suction. The nonbleeding lung is reintubated, and ventilation is resumed. Rapid switching from ventilation to lavage and back can allow a large amount of irrigation fluid to be flushed into and out of the lung. As bleeding settles, one can ventilate both lungs, and perhaps even localize bleeding to a particular lobe. For detailed assessment, a flexible scope can be passed via the rigid bronchoscope. If bleeding is from anywhere other than the right upper lobe, the rigid bronchoscope can be partially wedged into the lobar orifice and semiselective

Ch038-F06861.indd 450

Balloon Tamponade If flexible endoscopy can be carried out during a pause in the bleeding, it may be possible to localize bleeding to the segmental bronchus level. If so, bleeding can be controlled by placement of Fogarty-type embolectomy catheters and subsequent balloon inflation in the bleeding segmental bronchus, using the flexible fiberoptic bronchoscope. This technique has been applied to patients who are not surgical candidates and also, preoperatively, to stabilize the patient before emergency surgical resection. In extreme cases, one might consider blockade of an entire bronchus with a bronchial blocker catheter; however, more secure techniques of lung isolation are probably better.

Pulmonary Isolation Take most patients with life-threatening hemoptysis to the operating room for assessment and stabilization as described in the earlier sections. If bleeding continues, isolate the bleeding lung, using either a double-lumen endotracheal tube or an ordinary endotracheal tube to selectively intubate the nonbleeding lung. A double-lumen tube can be difficult to position properly in the setting of massive airway clots and ongoing bleeding. Even anesthetists with significant experience in placement of these tubes can become disoriented, or the bleeding may overwhelm the suction capacity of the pediatric flexible bronchoscope used to guide placement. An alternative technique is to selectively intubate the left main stem bronchus with a rigid bronchoscope. Even with severe bleeding, it should be possible to determine left from right. Then, a large-bore ventilating tube exchanger can be passed via the rigid bronchoscope. This catheter is secured in place while the bronchoscope is removed. A double-lumen tube can then be blindly advanced over the exchanger. The small inner diameter is still problematic because it is not suitable for the

1/21/2008 11:31:39 AM

Chapter 38 Investigation and Management of Massive Hemoptysis

removal of large volumes of blood or clots from the airways. Postobstructive infection may result if the tube is not removed as quickly as possible after the bleeding has been controlled. Other complications include loss of lung separation owing to dislodgment of the tube and tracheobronchial rupture from a tube that is too large or from overinflation of the balloon. Selective intubation of the main bronchus of either lung with a long (uncut) endotracheal tube (8 mm in diameter) is another option to consider. It can be used easily for rightsided bleeding because it can be securely and reliably placed in the left main bronchus. It is more problematic for leftsided bleeding because proximal placement in the right main bronchus risks dislodgement, and distal placement occludes the right upper lobe orifice. This technique has the advantage that a larger, adult flexible bronchoscope can be passed into the good lung. On the other hand, it abandons any short-term attempt to save oxygenating ability in the bleeding lung, which may severely affect patients with extensive aspirated blood or those with advanced lung disease and compromised pulmonary function before the episode of hemoptysis.

Selective Coagulative Treatment Thrombin or fibrinogen-thrombin solutions can be injected via a flexible bronchoscope using dual-lumen catheters. Tsukamoto and colleagues39 reported a 60% success rate using topical thrombin alone and 100% success using a fibrinogenthrombin solution. Bense40 reported three cases of successful treatment with direct application of fibrin precursors. Despite these descriptions of success, we prefer to take all patients with massive hemoptysis to the operating room for rigid bronchoscopy to establish the airway and control bleeding. If an intrabronchial tumor is the site and cause of bleeding and bleeding has slowed to a minor level, the neodymium : yttrium-aluminum-garnet (Nd : YAG) laser is useful to cauterize the site of bleeding, débride the tumor, and open up partially obstructed airways.

Arterial Embolization Bronchial artery embolization has been a huge advance in treatment of patients with massive hemoptysis, both as a temporizing measure and as definitive treatment for some patients (Fig. 38-3). Embolization was initially considered as an alternative in patients who are unfit for surgery due to advanced lung disease or multiple bleeding sites. After a number of improvements, it is now the procedure of choice in all patients except those immediately exsanguinating. In 1977, Remy and colleagues41 pioneered the radiologic approach to hemoptysis, reporting on 104 patients with either massive or repeated hemoptysis treated by embolization of the bronchial arteries. Angiography was performed, with selective catheterization of the abnormal arteries. Fortynine patients were treated by embolization with absorbable material during active hemoptysis, with immediate cessation of bleeding in 41. Delayed relapse was seen in only 6 of these patients, who had relapses 2 to 7 months after the procedure.

Ch038-F06861.indd 451

451

Uflacker and colleagues42 reported on 35 patients treated with embolization of absorbable gelatin sponge. Immediate control of hemoptysis was achieved in 87%. Embolization alone caused long-term control of bleeding in 13 (76.5%) of 17 patients with massive bleeding. In 1987, Rabkin and colleagues43 reported a very large experience with 306 patients. Hemoptysis was massive in 120 patients. Most were treated during active bleeding. Effective hemostasis was obtained initially in 278 patients (90.8%), including 87.5% of those treated during active bleeding. Recurrent bleeding within l to 4 days requiring surgery was observed in only 39 of the patients who had initially successful hemostasis. When surgery could be avoided, long-term control of hemostasis was excellent; rebleeding occurred in only 36 of 158 patients. In 2000, Kato and colleagues44 described 101 patients receiving bronchial artery embolization with polyvinyl alcohol (PVA) particles and gelatin sponge for massive or continuing hemoptysis of benign cause. Bleeding stopped in 94 patients (94%). The immediate effect was unfavorable in cases in which feeder vessels were overlooked or embolization of the intercostal arteries was insufficient. There were higher incidences of early recurrence among those patients with massive hemorrhage or more marked vascularity and systemic artery– pulmonary artery shunt in angiography. Embolization may also be particularly useful in diffuse infectious and inflammatory lung disease; despite higher rebleeding rates, long-term control is still possible in these patients with repeated treatment. Ramakantan and colleagues45 reported on 140 patients with significant hemoptysis treated with gelatin sponge embolization on the side with the greater abnormality on the chest radiograph. Control of hemoptysis was achieved in 73%. More recently, Barben and colleagues17 reviewed a 15-year experience with bronchial artery embolization for treatment of hemoptysis in 23 young patients with cystic fibrosis at Royal Children’s Hospital in Victoria, Australia. Twenty children underwent embolization in a total of 38 procedures; the mean age at first treatment was 15 years. The majority (89%) of embolizations were performed using PVA. The immediate success rate (i.e., no recurrent bleeding within 24 hours) was 95%. Eleven patients (55%) required more than one procedure. Three patients died as a consequence of severe hemoptysis during induction of anesthesia with intermittent positive-pressure ventilation in preparation for embolization. The authors concluded that embolization had a high success rate for short-term control of bleeding, but that more than half of the patients required repeat embolization. Persistent bleeding after a technically good embolization suggests an origin from vessels other than those previously obstructed, and consequently the nonbronchial transpleural systemic arteries of the lung must be investigated as well. Jardin and Remy (Jardin and Remy, 1988)46 reported on seven patients in whom embolization of the internal mammary vessels was required after successful treatment of bronchial arteries. In two, the internal mammary artery was the only systemic nonbronchial vessel that was embolized percutaneously, whereas five patients required treatment of other vessels as well. Occasionally, persistent or recurrent bleeding

1/21/2008 11:31:39 AM

452

Section 3 Lung

A

B

C

D

FIGURE 38-3 Angiographic embolization of aspergilloma causing hemoptysis. A, Chest radiograph of left upper lobe aspergilloma. B, CT scan image of the aspergilloma. Angiographic embolization of bleeding from the cavity was performed. C, Left bronchial circulation before embolization. D, Bronchial circulation after embolization.

may also arise from the pulmonary artery, and examination of this arterial system is mandatory after other possibilities are excluded. Sancho and colleagues47 described 25 patients with 27 anomalous bronchial arteries in a series of 300 patients subjected to bronchial embolization. Eighteen of these 25 patients presented with recurrent hemoptysis (10 massive) and 7 with their first episode of massive hemoptysis. Of the 27 anomalous bronchial arteries demonstrated, 24 originated from the aortic arch, 1 from the left thyrocervical trunk, 1 from the right subclavian artery, and 1 from the lower descending thoracic aorta; 2 of the arteries demonstrated showed no pathologic findings. Hemoptysis resolved after the first embolization in 14 patients (56%). In 9 patients (36%), more than one procedure was necessary to arrest hemorrhage. In 2 patients, surgical intervention was required,

Ch038-F06861.indd 452

and 1 patient died from bleeding. The authors made the point from their experience that, in cases of hemorrhage for which the cause cannot easily be identified and in cases of recurrence despite accurate embolization of pathologic arteries, the presence of bronchial arteries of anomalous origin needs to be considered. In their series, embolization was more difficult in these cases, and there was an increased risk of complications associated with the procedure. In Rabkin’s large experience,43 26 of 28 patients without an initial response to systemic embolotherapy were found to have a pulmonary artery source of bleeding. Sbano and colleagues48 presented data suggesting that up to 11% of patients undergoing bronchial angiography for hemoptysis have peripheral pulmonary artery pseudoaneurysms. As a consequence, investigation of the pulmonary artery may be required more

1/21/2008 11:31:39 AM

Chapter 38 Investigation and Management of Massive Hemoptysis

frequently. An undiagnosed fungal ball in a pulmonary cavity is another potential cause of rebleeding after embolotherapy. In most patients, acute bleeding stops after bronchial artery embolization, but in most cases it recurs after some time if not treated definitively. Consider bronchial artery embolization a temporizing maneuver in patients with aspergilloma; surgical treatment or intracavitary antifungal therapy provide more long-term resolution. With respect to embolic agents, large Gianturco coils lodge too proximally, and although minicoils are more suitable, they are very expensive. To handle the numerous pathologic vessels stemming from one origin, particles or liquid material is more suitable for peripheral embolization. Gelfoam, because of its nonpermanence, is not a good embolic agent in hemoptysis. PVA particles (Ivalon), dura particles, Ethibloc, and tissue adhesives such as isobutyl-2-cyanoacrylate (IBC) and Nbutyl-2-cyanoacrylate (NBC) can be used safely and effectively to treat the bleeding site.49 At our center, PVA particles have been used in most of the recent cases. Renal dysfunction resulting from the contrast load is a concern, especially in patients who are hemodynamically unstable due to blood loss. Transverse myelitis is the most feared complication of bronchial artery embolization. Because of the anatomic variation of a shared origin of bronchial arteries with intercostal vessels, which also supply radiculomedullary branches to the anterior spinal circulation, injury to these vessels or inadvertent embolization leads to spinal cord ischemia. In the thoracic area, the supply to the anterior spinal artery is usually from a dominant anterior medullary branch. This so-called artery of Adamkiewicz is quite variable in its exact location and must be carefully avoided.12

Radiotherapy Radiotherapy remains an option to consider for inoperable patients with aspergilloma and hemoptysis. In 1980, Shneerson and colleagues50 reported on a single patient with massive hemoptysis and a fungus ball, who received two courses of irradiation because of recurrent bleeding. In 2002, Falkson and colleagues51 reviewed five patients who had lifethreatening hemoptysis secondary to a mycetoma that was treated with external beam radiotherapy. Radiotherapy of 3.5 Gy was given once a week, continuing for one fraction after the hemoptysis stopped. Three patients required 7 Gy, one required 10.5 Gy, and the fifth patient required 14 Gy before the hemoptysis had completely stopped. Irradiation was successful in achieving hemostasis, with no side effects being observed after treatment in all five patients. Radiation may slow the growth of the fungus, but more likely it destroys the vascular lining of the cavity.

Intracavitary Treatment Surgical resection of aspergilloma cavities remains a very high risk procedure because of extensive pleural and hilar fibrosis. Systemic antifungal therapy is of only limited value because the drugs penetrate poorly into the fungal ball within the cavity. Rumbak and colleagues52 injected sodium or potassium iodide in 11 patients with poor surgical risk. A transcricothyroid approach was used in six patients and a percutaneous

Ch038-F06861.indd 453

453

approach in five. Hemoptysis ceased within 72 hours, and all 11 patients survived for at least 1 year. In 1998, Giron and colleagues (Giron et al, 1998)53 reviewed 40 patients who underwent CT-guided percutaneous injection of amphotericin paste. Surgery was contraindicated because of respiratory compromise. Hemoptysis ceased in all 40 patients, 6 of whom were also treated with bronchial embolization. In 26 patients, the aspergilloma disappeared and serum tests for aspergillus became negative. Complete disappearance of both the aspergilloma and the cavity was obtained in three patients. The authors concluded that the technique appears to be a valuable contribution to nonsurgical treatment of inoperable patients with pulmonary aspergilloma. At our center, we prefer this approach in patients with aspergilloma after angiographic embolization has been initially employed to control hemoptysis. We will perform multiple repeat injections even in patients who are surgical candidates before resorting to surgical therapy. The usual dose is 50 mg amphotericin in sterile gelatin.

Surgical Therapy Historically, pulmonary resection has been the most effective method for control and prevention of recurrent bleeding. Several series have reported higher survival rates after surgery and concluded that surgery was optimal management. However, a growing literature emphasizes the role of conservative treatment in massive or life-threatening hemoptysis.3,19,30,31,54-57 Comparing the results with those of medical or surgical management is difficult for several reasons. The primary problem is selection bias—that is, patients who are more likely to die are less likely to be operated on. Emergency surgery for hemoptysis is far riskier than elective surgery. Contamination of the contralateral lung before, during, and after surgery is a main cause of postoperative respiratory failure leading to prolonged ventilation, nosocomial pneumonia, and death. Likewise, many patients who require emergency surgery have formidable pleural adhesions and aortopulmonary collaterals. Blood loss can be significant beyond that already lost to the airway. Finally, resection is often required in patients with significant compromise of preexisting lung function that has not been accurately determined or optimized. Erdogan and colleagues58 reviewed 59 patients with TBrelated hemoptysis in Turkey who underwent surgical therapy. A thoracotomy was performed urgently in 21 patients with massive (>600 mL/day) hemoptysis, and within the first 2 days in 24 patients with major (200-600 mL/day) hemoptysis. Chest radiography showed cavitary lesions in all of the patients with massive hemoptysis and in 22 of the 24 patients with major hemoptysis. Pneumonectomy was performed in 4 patients, lobectomy in 39, and segmentectomy or wedge resection in 16. The average hospitalization period was 13 days, with a perioperative mortality rate of 6.8%. The authors concluded that, although the frequency of conservative measures at their institution had been increasing in recent years, thoracotomy with double-lumen endotracheal intubation for resection of a bleeding tuberculous cavity can be curative and life-saving.

1/21/2008 11:31:40 AM

454

Section 3 Lung

A similar review by Uy59 described 75 consecutive patients who underwent thoracotomy for massive hemoptysis between 1993 and 1996. The most common causes were related to pulmonary TB and its sequelae. The overall operative mortality rate was 10.7%. The factors associated with increased morbidity were operation within 24 hours and increased operating time. Coexisting medical illness was the strongest association with mortality. The author suggested that, although surgery can be a life-saving measure, efforts need to be taken to temporize and convert an otherwise immediate operation to a semielective one. Similarly, at the Toronto General Hospital, we attempt to manage massive hemoptysis conservatively using rigid bronchoscopy, local control and stabilization with iced-saline lavage, and angiographic embolization as first-line therapy. Surgery is reserved as an absolute last resort for operative candidates not salvageable by embolotherapy.

Patient Selection and Choice of Surgical Technique To consider a patient for surgical treatment, one needs to know and localize the site of bleeding. Know the pulmonary function. The patient needs to be medically operable by traditional criteria and judgment. If bleeding is from a cancer, it should be resectable for cure. Unilateral lung ventilation is the optimal technique for anesthesia if it can be achieved. Standard approaches such as double-lumen endotracheal tubes are probably best if personnel are familiar with them. Complications, such as airway trauma and misplacement, are most commonly caused by suboptimal visualization associated with significant bleeding. As alternatives, a single-lumen tube may be inserted into the left main bronchus (for right-sided bleeding), or a bronchial blocker may be placed in the left main bronchus (for leftsided bleeding). Traditional incisions may be used, with excellent exposure suitable for the difficult dissection encountered in the pleural plane. The bleeding area needs to be removed with minimal loss of functional lung tissue. Guimarães (Guimarães, 2000)38 advised against resection if surgery is required during active bleeding and described a variety of alternatives. He described 18 patients who underwent cavernostomy with the bleeding cavity site marsupialized through the chest wall. Thirty-two patients had either plombage or thoracoplasty, and 11 had some form of devascularization, either pleural or by direct ligation of bronchial arteries. Overall, one third of the patients required pneumonectomy, and in those patients there was a 75% complication rate.

SUMMARY Endobronchial control measures and artery embolization have radically changed the management of massive hemoptysis. With the control of hemorrhage, nonsurgical patients can be identified and surgical candidates accurately assessed to allow

Ch038-F06861.indd 454

an elective operation, with lower morbidity and mortality, if conservative measures are unsuccessful.

COMMENTS AND CONTROVERSIES Nothing focuses the mind of a thoracic surgeon more than a patient with massive hemoptysis. Endoscopic or operative management in these cases presents a great challenge. Proper preparation is the key to success. I agree with the authors’ preference for rigid bronchoscopy in the initial management of truly massive hemoptysis. The endoscopist must be focused as much on keeping the good lung clear as on stopping the bleeding. Backup light sources and suction catheters must be available because clots frequently obscure vision or block suction catheters. As the authors mention, entrainment of high-concentration oxygen increases the FIO2 during jet ventilation. Postural adjustments can help maintain patency of the contralateral airway. Consider bronchial artery embolization a temporary maneuver in the majority of patients with inflammatory disease as a cause for massive hemoptysis. The risk of recurrent hemorrhage is significant. For apical cavitary disease, subclavian, axillary, or intercostal branches are the likely arterial source. Topical cavitary therapies usually are not effective. For focal causes, resection is the preferred option. In selected patients with poor pulmonary function, not amenable to resection, other strategies are available. Cavernostomy, if anatomically feasible, is a good option. We have occasionally used hilar and bronchial devascularization to arrest significant unilateral bleeding. This can be accomplished by small anterior and posterior thoracotomies or by video-assisted thoracic surgery (VATS). G. A. P.

KEY REFERENCES Flume PA, Yankaskas JR, Ebeling M, et al: Massive hemoptysis in cystic fibrosis. Chest 128:729, 2005. ■ Cystic fibrosis is one of the most important causes of massive hemoptysis in the developed world. This report reviews a large clinical experience, emphasizing the role of angiography and patterns of recurrence. Giron J, Poey C, Fajadet P, et al: CT-guided percutaneous treatment of inoperable pulmonary aspergillomas: A study of 40 cases. Eur J Radiol 28:235, 1998. ■ This report describes a large experience with intracavitary treatment of aspergilloma. We have found this to be an important advance, obviating surgery in many patients in this challenging group. Guimarães CA: Massive hemoptysis. In Pearson FG, Cooper JD, Deslauriers J, et al. (eds): Thoracic Surgery, 2nd ed. Philadelphia, Churchill Livingstone, 2000, p 717. ■ An excellent, detailed review of the subject, notable for the author’s large experience with surgical treatment, including nonresection options such as cavernostomy and pleuroparietal devascularization. Jardin M, Remy J: Control of hemoptysis: Systemic angiography and anastomoses of the internal mammary artery. Radiology 168:377, 1988. ■ A large review of angiography and embolotherapy from the pioneers of the technique.

1/21/2008 11:31:40 AM

chapter

39

INVESTIGATION AND MANAGEMENT OF THE INDETERMINATE PULMONARY NODULE Joseph B. Shrager Joel D. Cooper

Key Points

lesions and avoid delaying the excision of malignant lesions to a point at which cure is less likely.

■ There is no single test or combination of tests that can indicate,

with a high degree of reliability, whether a nodule is benign or malignant. ■ Clinical history, size of the nodule, CT appearance, FDG-avidity on PET, and accessibility to excisional (VATS) versus transthoracic or bronchoscopic biopsy are among the more important factors that come into play in deciding which approach to take with an individual nodule. ■ Perhaps more important than any of the above factors is the particular patient’s relative concern about the risk and discomfort of an “unnecessary” procedure versus his or her concern over leaving an unresected malignancy in place.

An individual surgeon’s approach to the solitary pulmonary nodule (SPN) is the role that perhaps best defines his or her character as the decision-maker who sits at the center of the workup and therapy for suspected lung cancer. The SPN is among the most common clinical scenarios that thoracic surgeons encounter, yet, because of the clinical intricacies involved and the imprecise data available on the subject, a wide range of management options remain acceptable. Although some would argue that almost every indeterminate SPN in a smoker needs to be removed relatively promptly, this attitude will most certainly result in a high rate of excision of benign nodules and is probably a disservice to patients. On the other hand, insufficiently aggressive management or inadequate follow-up of SPNs may lead to cancer progression before removal, reducing the chances of cure. The ideal goal is the removal of all malignant nodules at a curable stage, with as few resections of benign lesions as possible. The practical goal must be to find a reasonable middle ground. This chapter reviews the evidence supporting the various approaches to the diagnosis and management of SPNs and proposes what the we believe to be a reasonable set of algorithms based on the admittedly limited available data and our own individual approach. The increasing use of computed tomographic (CT) scanning for diagnostic purposes, as well as ongoing research evaluating CT screening to detect early lung cancer, has led to the presentation of increasing numbers of patients in the thoracic surgeon’s office with smaller and smaller nodules. This development makes the problem of distinguishing malignant from benign nodules even more difficult. The goal, however, remains the same: to provide the most efficient approach that will both minimize the excision of benign

DISCRIMINATING MALIGNANT FROM BENIGN NODULES If there were any single test or combination of tests that could reliably indicate whether a nodule is benign or malignant, then there would be no complexity on this issue. Unfortunately, no such tests exist. With each new technical development for the evaluation of SPNs (most recently highresolution CT and positron emission tomography [PET]), there has been initial optimism that a highly reliable technique has at last been found. However, in each case, carefully designed studies have shown that, although each technique does represent a substantial addition to the armamentarium, it is not the panacea that had been hoped for. Thoracic surgeons are thus left with a variety of diagnostic options that they must cobble together to decide on the likelihood that a lesion represents a malignancy (Table 39-1). From this impression, they can then recommend an appropriate invasive mode of diagnosis versus watchful waiting. The paragraphs that follow review the strengths and weaknesses of the available diagnostic modalities.

Clinical History Although it has become a cliché, the importance of clinical history in distinguishing malignant from benign nodules cannot be overstated. Obviously, an indeterminate lesion in a smoker is of far greater concern than one in a never-smoker or a light smoker. One representative study found that a smoker with a history of more than 40 pack-years has a likelihood ratio of 3.7 for a lesion’s being malignant, whereas a nonsmoker has a ratio of 0.15.1 A history of prior malignancy is at least as strong an indicator of malignancy as a history of smoking. Older age is also predictive of malignancy, but with a lower likelihood ratio. A history of recent pulmonary infection is often an equally important component of the clinical history. A patient who has a parenchymal abnormality that was first discovered on radiologic studies done during or shortly after a recent respiratory infection must be approached with the possibility firmly in mind that it may represent resolving pneumonitis. It is always appropriate to treat such a patient with a course of antibiotics and repeat the CT scan after approximately 1 month before considering a more aggressive workup. A lesion that is shrinking needs nothing further than follow-up CT scans. Although some such lesions may prove to be lung carcinoma, many will not, so the management approach must 455

Ch039-F06861.indd 455

1/21/2008 11:32:34 AM

456

Section 3 Lung

TABLE 39-1 Likelihood That an SPN Is Malignant According to Various Clinical and Imaging Parameters Characteristic

LR

Characteristic

LR

Age 60-69 yr

2.64

Lobulated

0.74

Nonsmoker

0.15

Spiculated

5.54

Smoker <30 pack-yr

0.74

Malignant growth rate

3.40

Smoker 30-39 pack-yr

2.00

Not calcified

2.20

Smoker >40 pack-yr

3.70

Benign calcification

0.01

Hemoptysis

5.08

Enhancement <15 HU on CT 0.04

Previous malignancy

4.95

Enhancement > HU on CT

2.32

Nodule 0-1 cm

0.52

SUV <2.5 on PET

0.06

Nodule 1.1-2.0 cm

0.74

SUV >2.5 on PET

Nodule 2.1-3.0 cm Nodule >3.0 cm

7.10

3.67

3

PET + (Gould et al)

4.30

5.23

PET − (Gould et al)3

0.04

CT, computed tomography; HU, Hounsfield units; LR, likelihood ratio; PET, positron emission tomography; SPN, solitary pulmonary nodule; SUV, standardized uptake value. Adapted from Fletcher JW: PET scanning and the solitary pulmonary nodule. Semin Thorac Cardiovasc Surg 14:268-274, 2002.

be tailored appropriately. Even if the pulmonary infection was more remote than a few weeks, but clearly interceded since a previous radiographic negative study, one needs to proceed with the thought of postinfectious scarring in mind. In this situation, it is often more reasonable to monitor a small lesion over time rather than proceed directly to an invasive diagnostic procedure.

Imaging Chest Radiography Many of the imaging characteristics on plain chest radiography historically noted to have value in the evaluation of the SPN have now become less relevant because essentially all SPNs are currently evaluated by CT. However, if a lesion is visible on chest radiography, its presence or absence on prior radiographs may immediately resolve the issue of benign versus malignant. A lesion that is unchanged from a radiograph obtained at least 2 years previously is either a benign lesion or a very slow-growing malignancy for which there is little urgency and which can probably be safely observed. Therefore, a search for prior chest films is critical in the initial evaluation of an SPN. It remains as true as ever that the single most important diagnostic tool for evaluating a pulmonary lesion may well be a previous chest radiograph or CT scan. In situations of recent pulmonary infection, review of chest films obtained during the acute infection and during its resolution often provides fairly firm evidence that a residual parenchymal abnormality is postinflammatory in nature.

Computed Tomography Certain characteristics seen on CT are pathognomonic for benignity. These include certain patterns of calcification (central, laminated, diffuse, and “popcorn”) and the presence

Ch039-F06861.indd 456

of fat within a nodule. Lesions with these characteristics therefore cannot truly be called indeterminate. Other CTbased characteristics, such as whether the edge of the lesion is spiculated (more likely malignant) or smooth/lobulated (more likely benign), are also of value and can be weighed into the overall management approach, but they have significantly lower reliability than the pathognomonic findings previously listed. If one of the benign pathognomonic findings is suspected to be present on an initial CT done with standard 7- to 10-mm cuts, a finer CT with 3-mm cuts through the lesion is ordered to investigate this possibility more thoroughly. Other CT techniques have been proposed in an attempt to provide greater reliability in separating benign from malignant lesions. Swensen and colleagues2 evaluated CT with timed contrast enhancement. Enhancement of greater than 15 Hounsfield units (HU) provided 98% sensitivity for malignancy of a nodule, but only 58% specificity. This approach has not gained wide acceptance. If a lesion is being monitored with serial CT scans, the use of volumetric rendering of the CT image is a promising technique but still without wide availability. With this approach, a detailed, three-dimensional image of the nodule is created, and its volume is computed so that even minor, asymmetric growth can be appreciated over time. Because this technique can detect growth at time intervals as short as 1 month—a time frame over which it would seem that a lesion is very unlikely to metastasize—volumetric CT may increase the comfort level of a watchful waiting approach to some lesions.

Positron Emission Tomography According to a meta-analysis of the diagnostic accuracy of PET for SPNs larger than 1 cm in diameter, this technique has a reasonably high sensitivity (94%) for malignancy but a lower specificity (83%) (Gould et al, 2001).3 The lack of higher sensitivity results in part from the fact that carcinoid tumors and bronchioloalveolar carcinomas (BACs) tend to be falsely negative on PET. However, these types of tumors often have characteristic CT appearances (carcinoids, lobulated; BACs, ground-glass opacity [GGO]), so that an experienced clinician either will not order PET on patients with these sorts of lesions or will at least interpret a negative PET with caution. More problematic is the low specificity of PET. A variety of infectious and inflammatory lesions are glucose-avid and therefore are often interpreted as being “positive” on PET. If one removes all PET-positive lesions, one will be removing a large number of benign lesions. More appropriate decisions can be made if one interprets the PET results in light of a carefully taken clinical history. For example, if a patient has a history of recent infection (suggesting that a positive lesion is an area of resolving pneumonia) or the patient is a thin, elderly, nonsmoking woman (in whom Mycobacterium aviumintracellulare infection is common), then it will be more appropriate to adopt an attitude of watchful waiting or needle biopsy rather than proceeding directly to a surgical procedure.

1/21/2008 11:32:34 AM

Chapter 39 Investigation and Management of the Indeterminate Pulmonary Nodule

Finally, PET is still more problematic in the evaluation of smaller (subcentimeter) SPNs. Although we are aware of no studies that report its sensitivity for subcentimeter lesions, one study suggested a PET sensitivity for malignancy of only 80% in lesions smaller than 1.5 cm.4 One might extrapolate that for lesions in the 7- to 10-mm range, PET is likely to have sensitivity in the range of 60% to 70%; its specificity, however, is likely to be quite high for small lesions. Coupled with the clear data suggesting that the higher the standardized uptake value (SUV) the more aggressive the malignancy,5 it can be expected that only the more aggressive of the smaller lesions will be PET-positive. Therefore, although its role in these small lesions certainly remains poorly defined, a positive PET study in a 7- to 10-mm lesion may be a useful additional piece of information pushing one toward an aggressive, excisional approach. On the other hand, the clinician should feel quite comfortable monitoring a subcentimeter lesion that is PET-negative with serial CT scans.

Size on Imaging as an Independent Determinant The size of an SPN is a very important factor that deserves separate discussion from other imaging characteristics. Greater attention was brought to this issue by the recent publication of the International Early Lung Cancer Action Project (IELCAP) survival results (International Early Lung Cancer Action Program Investigators et al, 2006)6 and the ongoing randomized study of CT screening sponsored by the National Cancer Institute called the National Lung Screening Trial (NLST). Clearly, the smaller an SPN, the less likely it is to be malignant. In fact, size has been known for some time to be the single most significant predictor of malignancy. Swenson and associates7 found, with a validated model, that a 1-cm nodule in a 55-year-old smoker has a 31% chance of being malignant. Clearly, it would not be appropriate to indiscriminately excise lesions smaller than this, even in smokers. The published IELCAP data6 yield further information on this issue. The authors employed a reasonably well-defined CT screening protocol and subsequent workup algorithm for detected nodules (although many parts of the protocol represented recommendations rather than requirements) (Fig.

39-1). They screened 31,567 asymptomatic individuals 40 years of age or older who were believed to be at risk for lung cancer and discovered 5646 nodules (defined as >8 mm nonsolid or >5 mm solid abnormality on initial screening or any new, noncalcified abnormality on subsequent screening). Of the 5646 nodules, only 484 (8.6%) were ultimately found to represent lung cancer. Clearly, therefore, the vast majority of asymptomatic small nodules are benign, even in a higher-risk population. Perhaps more importantly in this study, in which the IELCAP-suggested regimen (see Fig. 39-1) was apparently followed in most cases (on initial screening, either immediate biopsy, PET, or follow-up CT at 3 months for lesions >15 mm; or PET or follow-up CT at 3 months for lesions <15 mm, with biopsy only for growth or positive PET findings), 85% of the lesions proven to be cancer remained in stage I at the time of resection. This result suggests that careful follow-up of lesions smaller than 1.5 cm in diameter, reserving invasive evaluation for those that either grow on serial CT scans or are PET-positive, is a reasonably safe approach. However, there are problems with the IELCAP study that limit the broad applicability of its results. First, as mentioned earlier, the diagnostic protocol was largely recommended rather than stipulated, so a variety of approaches to diagnosis appear to have been employed by participating institutions. This created a number of problems in interpretation. For example, once it was decided by the protocol that biopsy would be carried out, not all patients underwent fine-needle aspiration. An unstated number apparently had excisional, surgical biopsy. Therefore, it is unclear whether it is correct to conclude that a negative result on fine-needle aspiration is sufficient to feel safe with further temporizing and continued radiologic follow-up. In fact, there is reason to believe (see later discussion of transthoracic needle biopsy) that fineneedle aspiration has a substantial incidence of false-negative findings. Second, most of the patients presented on the survival curves in the IELCAP study were still within 3 years of their resection, so the Kaplan-Meier estimates of survival remained just that—estimates from immature data. Finally, whether results garnered with nodules identified on a yearly screening protocol have any applicability to the patient who has a nodule identified on a CT obtained for vague symptoms 15 mm

5–14 mm Option 1

Option 2

CT in 3 months Growth No growth Biopsy
Operation



Yearly CT

457

Option 1

PET


Biopsy

 CT in 3 months

Immediate biopsy




Option 2

Option 3

CT in 3 months Growth No growth

Operation Yearly Biopsy CT

Yearly CT

PET


Biopsy



CT in 3 months

Yearly CT

FIGURE 39-1 Suggested protocol of the International Early Lung Cancer Action Project (IELCAP) for evaluation of nodules identified on initial screening. As a result of this protocol, 85% of lung cancers discovered were in stage I at the time of resection. CT, computed tomography; PET, positron emission tomography.

Ch039-F06861.indd 457

1/21/2008 11:32:34 AM

458

Section 3 Lung

(the more common situation in an unscreened population) is uncertain. Other investigations have attempted to shed light on the issue of whether it is safe to briefly observe most pulmonary nodules and how often to repeat imaging studies. The perspective of the radiology community was summarized in a recent position paper from the Fleischer Society.8 Quarterman and colleagues9 carried out a retrospective study looking at whether a 90-day delay had an impact on the prognosis in resected stage I and II non-small cell lung cancers (NSCLC). They found no impact of this 3-month delay. However, the study cannot be called conclusive for several reasons. First, the biases inherent in the retrospective study design are a factor. Further, the study was significantly underpowered with very wide confidence intervals, so that a survival difference even as large as 20% between the “delay” and “no delay” groups could have been missed. We can only conclude, then, that a 3-month delay in definitive diagnosis of most malignant pulmonary nodules is unlikely to play a role in ultimate prognosis. The data in support of this contention are not sufficiently definitive to make a stronger statement, leaving the precise course of action an open one that depends on the experience, philosophy, and riskaverseness of the surgeon or physician treating the patient.

Invasive Diagnostic Modalities Short of Surgery A variety of invasive diagnostic modalities are available to try to establish a tissue diagnosis. They are applicable to different types of lesions, provide different rates of accuracy, and may result in different degrees of morbidity.

Bronchoscopy Standard bronchoscopy with endobronchial biopsy and/or brushings, although associated with some patient discomfort, results in very little measurable morbidity. For centrally placed lesions, bronchoscopy has a substantial chance of establishing a diagnosis, and it provides the additional benefit of determining the involvement of major airways, which may have significance in planning surgical resection. For peripheral lesions less than 2 cm in size, however, standard bronchoscopy has an extremely low sensitivity (∼20%).10 This number is likely to improve with the wider adoption of more advanced methods of directed bronchoscopic needle aspiration biopsy (e.g., endobronchial ultrasound and use of ultrathin bronchoscopes and fluoroscopic or magnetic guidance). However, even with these advances, the limitations of any fine-needle biopsy technique will remain (see next section).

Transthoracic Fine-Needle Aspiration In contrast to bronchoscopy, transthoracic needle biopsy (TTNBx) is more applicable to lesions in the outer half of the lung parenchyma. By most conservative estimates, this technique correctly identifies approximately 80% of malignant nodules.11 In our own experience, the accuracy in diagnosing malignancy is closer to 90%. It must be noted, however, that this experience is not limited solely to small, indetermi-

Ch039-F06861.indd 458

nate nodules, and therefore results with subcentimeter lesions may be less definitive. This procedure is clearly dependent on the expertise of both the individual performing the aspiration and the cytologist interpreting the material. To achieve optimal results, the aspirate is examined by the cytologist in the radiology department, so that additional aspirates can be obtained by the radiologist if the specimen is inadequate or insufficient. A result that is “nondiagnostic” is of no utility to the surgeon if there is a reasonably high pretest probability that the lesion is malignant. In this situation, only if a specific benign diagnosis (e.g., cartilage or fat suggesting hamartoma, mycobacteria on stain/culture) is established can resection be reliably averted, and this is rarely achieved. More than one study has specifically looked at the ultimate outcome of nodules that were nondiagnostic for malignancy on needle aspiration.12,13 In one study, among the 21 needle diagnoses that were “benign specific,” all were true negative on extended follow-up. However, among the larger group of 74 TTNBx that were interpreted as “benign nonspecific” or “nondiagnostic,” 13 (18%) ultimately proved to be malignant. Another study found the rate of malignancy in lesions not proven malignant on TTNBx to be 29%.13 These studies nicely summarize the difficulties with using a “negative” TTNBx to guide management. A needle biopsy that does not establish malignancy provides only incomplete reassurance that observation of a suspicious lesion is safe. Although the morbidity of TTNBx is not often severe, pneumothorax does occur in 10% to 20% of patients, and this requires placement of a catheter or chest tube in 5% to 30%.12,14,15 A measure of the difficulty in knowing how best to apply all of this information to individual cases is the fact that even between the coauthors of this chapter there is some measure of disagreement over the appropriate role of TTNBx. The more junior author feels that TTNBx is helpful only in occasional clinical scenarios. These include patients in whom resection is contraindicated but who nevertheless require a tissue diagnosis (e.g., if small cell is suspected but has not been diagnosed at bronchoscopy), patients whose clinical history suggests that an infectious etiology is a substantial possibility, and patients who in the surgeon’s view (for any number of reasons) have a low pretest probability of malignancy but are uncomfortable with a watchful waiting approach without a “negative” biopsy. The senior author, on the other hand, is more liberal in his use of TTNBx. He believes that, if the lung lesion is considered highly suspicious for malignancy, a positive needle biopsy may be useful in facilitating discussion with the patient, planning for appropriate staging procedures, and streamlining the operative procedure by eliminating the need for excisional biopsy before proceeding with appropriate pulmonary resection.

Excisional (Surgical) Biopsy For highly suspicious lesions smaller than approximately 2.5 cm in size whose deepest margin is less than approximately 5 cm from the nearest visceral pleural surface on CT,

1/21/2008 11:32:34 AM

Chapter 39 Investigation and Management of the Indeterminate Pulmonary Nodule

video-assisted thoracoscopic (VATS) excisional biopsy is often an appropriate means of establishing a tissue diagnosis. Lesions larger or more deeply seated than this usually cannot be encompassed by a VATS wedge without risking stapling across the tumor and spilling it into the pleural space, but each lesion must be considered individually based on its precise location. Several localization techniques have been developed that may allow more reliable VATS excision of smaller, softer, or more deeply placed lesions; these include percutaneous hookwire placement, percutaneous barium injection with intraoperative fluoroscopy, percutaneous technetium injection with intraoperative gamma probing, intraoperative ultrasonography, intraoperative real-time CT, and the “endofinger.” These techniques are, for the most part, in early stages of development, and the concern noted earlier about stapling through more deeply seated malignant lesions may limit their utility. The primary advantage of VATS excision is that it provides a definitive diagnosis by a single procedure. None of the complexities of interpreting “negative” or “nondiagnostic” needle biopsies is applicable to VATS because the lesion is excised in its entirety, and a definitive pathologic diagnosis can be made immediately. The primary disadvantage of VATS is that it has greater cost and morbidity than bronchoscopy or TTNBx. However, if the patients undergoing VATS are carefully selected, so that a high proportion will be found to have lung cancer, then the additional cost or morbidity that VATS wedge adds to the anatomic resection those patients will be having under the same anesthesia is not dramatic. This approach saves the patient from having to come to the hospital for sometimes several separate procedures that may be nondiagnostic, allowing diagnosis and appropriate therapy in a single step. Studies attempting to address the issue of the cost-effectiveness of the various approaches have proved to be prohibitively difficult to design in such a manner that definitive results can be achieved. Most individuals who use VATS excision proceed as follows. A plan is made preoperatively with the patient for a VATS excision to be performed and the lesion evaluated immediately on frozen section by the pathologists. If the lesion represents a primary lung malignancy, lobectomy with lymphadenectomy will be immediately performed under the same anesthesia, whereas if the lesion is benign, the procedure will be terminated after the VATS wedge resection. In patients with highly suspicious lesions that meet one’s usual indications for a preoperative staging mediastinoscopy, this can be included in the algorithm, most conveniently just before the VATS wedge resection. Alternatively, the ipsilateral mediastinum can be staged thoracoscopically during the VATS wedge excision. It is critical to emphasize that, although some publications describing VATS wedge excision of lung nodules have reported rates of benign lesions as high as 50% to 75%,16,17 there is no reason that this should be the case. All of the clinical decision-making reviewed in this chapter that is typically used to decide whether a lesion is likely to be benign or malignant is brought to bear in deciding whether to excise a lesion by VATS or to monitor it on serial CT scans. VATS is

Ch039-F06861.indd 459

459

not used to excise lesions that are judged by usual criteria as likely to be benign, just as TTNBx need not be ordered for patients bearing these types of lesions. The patient harboring a lesion that is highly likely to be benign needs to be reassured of this fact and also of the fact that, even if the lesion is malignant, it is highly unlikely that it will spread and become less curable before it grows if followed carefully with serial CT scans, initially at 3-month intervals. If a lesion is not appropriately placed or too large for VATS excision, other approaches, such as bronchoscopy, TTNBx, or proceeding directly to thoracotomy, have greater applicability when a lesion is highly suspicious. In these situations, the clinical history and whether the lesion is PET-positive will have a still greater impact on the approach taken.

OTHER FACTORS AFFECTING AGGRESSIVENESS OF APPROACH The changing spectrum of lung cancer and new imaging technology may affect the aggressiveness of the diagnostic approach that one chooses to apply to a particular SPN. An example is the recent work on the clinical and pathologic features of BAC. This type of NSCLC, when it presents as an SPN (Fig. 39-2), clearly follows a less aggressive natural history than invasive NSCLC. Several papers from Japan and elsewhere have demonstrated that the presence of this cell type can be predicted with a high degree of accuracy by CT characteristics (Kodama et al, 2001).18-20 Further, on resection, these carcinomas very rarely have metastasized to lymph nodes,18 and they have a very high cure rate even after sublobar resection.21,22 A lesion that is entirely or almost entirely composed of GGO (see Fig. 39-2) most likely represents either a benign lesion that will resolve on follow-up CT or a BAC that is extremely unlikely to metastasize before growing or developing an invasive component (visible on CT as a higher-density region). Therefore, GGOs are the safest lesions for which to adopt a watchful waiting approach with serial evaluation by CT scan.

FIGURE 39-2 A typical ground-glass opacity that on resection was found to be a pure bronchioloalveolar carcinoma.

1/21/2008 11:32:34 AM

460

Section 3 Lung

7–10 mm Low operative risk High-anxiety patient PET




No change

Serial CT

Peripheral

Central

VATS Excision

Bronch
 TTNBx


Anatomic resection

CT in 3 months



Location




High operative risk Low-anxiety patient or pure GGO

CT q 6 months  2.5 years, then screening CT yearly

Anatomic Serial resection CT

FIGURE 39-3 Suggested algorithm for a suspicious, 7- to 10-mm noncalcified nodule in a smoker without a clinical history to suggest an infectious etiology (lesions <7 mm are monitored by serial CT scans). Bronch, bronchoscopy; GGO, ground-glass opacity; PET, positron emission tomography; TTNBx, transthoracic needle biopsy; VATS, video-assisted thoracic surgery. 10 –20 mm

PET  Or pure GGO


In nodule only

CT in 3 months

Location

No change Central Low operative risk High-anxiety patient Anatomic resection
 preliminary mediastinoscopy

Peripheral High operative risk Low-anxiety patient or pure GGO

Bronch
 TTNBx


Anatomic resection
 preliminary mediastinoscopy

VATS Excision
 preliminary mediastinoscopy

Serial CT

CT q 6 months  2.5 years, then screening CT yearly


Anatomic resection

FIGURE 39-4 Suggested algorithm for a suspicious 10- to 20-mm noncalcified nodule in a smoker without a clinical history to suggest an infectious etiology. Lesions approaching 2 cm that are pure ground-glass opacity (GGO) or lobulated in a manner that suggests carcinoid probably should be treated as in the “PET +” arm). CT, computed tomography; PET, positron emission tomography; TTNBx, transthoracic needle biopsy; VATS, video-assisted thoracic surgery.

PROPOSED ALGORITHMS Incorporating the issues discussed in the preceding paragraphs, one can easily create a variety of reasonable algorithms for the evaluation and management of an indeterminate SPN. However, the subtle differences among individual cases render it impossible to create algorithms that indicate the best approach for every nodule in every patient. Nevertheless, Figures 39-3 and 39-4 present algorithms that in our opinion are optimal for most nodules, based on the limited data available. If an infectious etiology is thought possible, a course of antibiotics and a repeat CT in approximately 1 month

Ch039-F06861.indd 460

is always an appropriate first step. Outside this circumstance, Figure 39-3 concerns nodules that are 7 to 10 mm in size, and Figure 39-4 concerns nodules in the range of 1 to 2 cm. Lesions that are smaller than 7 mm are most appropriately managed with watchful waiting with serial CT scans; suspicious lesions larger than 2 cm in a smoker are reaching such a high likelihood of malignancy that they also need to be considered separately from these recommendations. The major factors that are weighed into these algorithms, in addition to nodule size, are peripheral versus central location, whether the nodule is primarily composed of GGO, the PET scan result, and the individual patient’s surgical risk and

1/21/2008 11:32:35 AM

Chapter 39 Investigation and Management of the Indeterminate Pulmonary Nodule

anxiety level. How an individual patient weighs the uncertainty of whether a nodule has a small chance of representing a malignancy against the discomfort and morbidity of an operation or other invasive procedure is, in fact, paramount. Ultimately, most patients are sophisticated enough that, given the appropriate information, they will decide for themselves how they would like to proceed. The ultimate goal is not necessarily to remove early lung cancers immediately, but to do so before undue delay jeopardizes the chance for long-term survival, while at the same time alleviating unnecessary anxiety and reducing as much as possible the number of surgical procedures performed on lesions that are benign.

Ch039-F06861.indd 461

461

KEY REFERENCES Gould MK, Maclean CC, Kuschner WG, et al: Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: A meta-analysis. JAMA 285:914-924, 2001. International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, Libby DM, et al: Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 355:1763-1771, 2006. Kodama K, Higashiyama M, Yokouchi H, et al: Prognostic value of ground-glass opacity found in small lung adenocarcinoma on highresolution CT scanning. Lung Cancer 33:17-25, 2001.

1/21/2008 11:32:35 AM

Benign Lung Diseases chapter

40

CONGENITAL ABNORMALITIES OF THE LUNG Charles B. Huddleston

Key Points ■ Many of these lung lesions can be diagnosed in utero. ■ For some large cystic lung lesions it is possible to intervene pre-

natally, although the natural history includes the possibility of regression in some cases. ■ The clinical presentation of these congenital lesions varies considerably, from a neonate in extremis to an asymptomatic adult. ■ Resection of the affected portion of the lung nearly always will be necessary. ■ Long-term results are generally very good.

Congenital lung abnormalities include the broad category of bronchopulmonary foregut anomalies, simple cysts, hypoplasia, and agenesis of the lung. The clinical presentation of these infants varies from critically ill to asymptomatic. Many of these infants come to surgical therapy for their lesion, sometimes on an emergency basis. Prenatal ultrasonography is sophisticated to the point that the diagnosis of most of these lesions is possible during the second trimester of pregnancy. This obviously has had an impact on providing prompt therapy for these infants and also has provided a better understanding of the natural history of the diseases.

EMBRYOLOGIC DEVELOPMENT OF THE LUNG As with other congenital anomalies, the basis for these lung abnormalities is the pulmonary embryology.1 The lung parenchyma and vascular supply develop initially separate from one another. During the embryonic phase of pulmonary development, as early as the third week of gestation, the lung buds begin as outpouchings of the primitive foregut. Over the next 3 weeks, the lungs develop five distinct components ultimately to become the lobes. It is during this phase that the pulmonary arteries and veins become associated with the developing lung buds. The pulmonary arteries arise from the right and left sixth aortic arches and extend toward the developing lung bud, eventually becoming incorporated into this primitive tissue. The pulmonary veins begin as an outgrowth of the dorsal wall of the atrium, which divides into right and left pulmonary veins that then extend into the lung at the same time as the arterial development. The common pulmonary vein then becomes incorporated into the atrial wall as it develops. Arterial and venous channels develop within the primitive lung and unite with the pulmonary arteries from the sixth aortic arch and pulmonary veins formed

from the dorsal atrium to make the vascular connections. The pulmonary arteries follow the bronchi, but the veins do not. During the pseudoglandular period of development, the conducting airways as well as the cartilaginous components of the trachea develop; this occurs over weeks 6 through 16. There is also some differentiation of the airway endothelium into the pseudostratified columnar variety. Next, during the canalicular phase, the basic components to air exchange begin to develop, and by 28 weeks of gestation this pattern is firmly in place. At this same time, there is some development of type I and type II pneumocytes. Over the remaining period of gestation, the alveolar period, these distal air spaces become more complex and multiply in numbers, forming mature alveoli. After birth, there is a continued increase in the number of alveoli until approximately age 8 years. From that point further, the alveolar size increases up to age 21 years.2

FAILURE OF DEVELOPMENT OF THE LUNG BUD Failures of development of the lung bud presumably relate to errors occurring early in gestation. The disorders found include agenesis, aplasia, and hypoplasia of the lung. Congenital agenesis of the lung is the result of failure of the primitive lung bud to develop. This can be a bilateral process and is obviously universally fatal. The trachea ends in primitive lung tissue or just blindly. Unilateral pulmonary agenesis (Fig. 40-1) is often associated with other congenital anomalies, particularly when the right lung is absent. Interestingly, there seems to be some association of ipsilateral malformations in patients with unilateral pulmonary agenesis.3 The associated cardiac anomalies are usually minor (patent ductus arteriosus, patent foramen ovale). No known chromosomal aberrations have been identified with this process. Prognosis depends primarily on the associated congenital anomalies. The presence of esophageal atresia or tracheoesophageal fistula has a particularly poor prognosis.4 Many patients are asymptomatic because the total volume of lung tissue present can be almost normal due to compensatory growth of the contralateral lung. In this case, a chest radiograph performed for other reasons or because the heart sounds are displaced is diagnostic. Computed tomography (CT) of the chest provides confirmation of the diagnosis as well as information regarding other anomalies. The mediastinum is shifted to the affected side (see Fig. 40-1). The diagnosis may be made antenatally with ultrasound.5 A clinical picture similar to that of postpneumonectomy syndrome may be seen in some patients when the right lung is absent. As with treatment for the acquired form of this disease, insertion of a prosthesis

462

Ch040-F06861.indd 462

1/21/2008 11:34:05 AM

Chapter 40 Congenital Abnormalities of the Lung

A

463

B

FIGURE 40-1 A, Chest radiograph demonstrating atresia of the left lung. The cardiac silhouette is shifted further to the left because the right lung assumes most of the entire chest cavity. B, Representative cut from the CT scan of the same patient, showing the mediastinal contents in the left side of the thorax.

TABLE 40-1 Congenital Abnormalities of the Lung

Lesion

Location

Radiologic Findings

Lobar emphysema

LUL 40% RML 35% RUL 20%

Hyperlucent lobe Mediastinal shift

CCAM

Equal all lobes

Sequestration Extralobar Intralobar Bronchogenic cyst Mediastinal Parenchymal

Male : Female Ratio

Symptoms

Vasculature

2.5 : 1

Tachypnea, respiratory distress Wheezing

Normal

Type I—single cyst Type II—many small cysts Type III—solid mass

1:1

Respiratory distress

Normal

Basilar, left 80%

Wedge-shaped mass

2:1

Usually none

Posterior basal, left 60%

Cyst or solid

1:1

None or infection

Arterial—descending aorta Venous—hemiazygos Arterial—descending aorta Venous—Pulmonary vein

Pericarinal Lower lobes

Round mass May contain air

1:1 1:1

None or wheezing Infection, wheezing

Normal Normal

CCAM, congenital cystic adenomatoid malformation; LUL, left upper lobe; RML, right middle lobe; RUL, right upper lobe.

into the affected side may be of benefit.6 Pulmonary function tests may demonstrate evidence of airway obstruction secondary to stretching of the main stem bronchus across the mediastinal structures.7 Although many of these patients are asymptomatic, the overall survival of infants born with unilateral agenesis of the lung is somewhat poor, presumably because of the other associated anomalies but also due to airway issues related to the mediastinal shift and risk of infections. Aplasia of the lung is essentially the same as agenesis from a functional standpoint. In this case, a bronchial stump is

Ch040-F06861.indd 463

present. This may be a source for recurrent infections. In those cases, resection of this stump may be indicated. Hypoplasia of the lung can occur as a primary process or be related to other conditions that compromise the thoracic space available for lung growth (Table 40-1). It is defined as deficient or incomplete development of one or both lungs. Congenital diaphragmatic hernia predictably results in hypoplasia of one or both lungs by limitation of the thoracic volume available for pulmonary development in utero. Other conditions that produce this condition include agenesis of the diaphragm, pleural effusion, and restrictive chest wall (Jeune’s

1/21/2008 11:34:06 AM

464

Section 3 Lung

syndrome). Pulmonary hypertension frequently accompanies lung hypoplasia because of the diminished pulmonary vasculature. Clinical manifestations of pulmonary hypoplasia depend on the volume of lung present but can include severe respiratory distress and cyanosis. Cyanosis occurs as a result of pulmonary hypertension and right-to-left shunting across a patent foramen ovale or patent ductus arteriosus or both. Bilateral primary pulmonary hypoplasia may occur as a result of extrathoracic causes, including oligohydramnios, where the mechanism of development is thought to be compression of the fetal thorax by the uterus. This may occur in up to 20% of infants born after premature rupture of membranes at 15 to 28 weeks of gestation. It is suspected in an infant with respiratory insufficiency and small lungs on chest radiography. The lungs fail to develop to normal size but contain the usual distribution of bronchi. There are decreased numbers of alveolar ducts and alveoli for the number of bronchioles microscopically. The cause is unknown, and the mortality rate is high. Right pulmonary hypoplasia is commonly associated with scimitar syndrome (partial anomalous pulmonary venous return of the right lung to the inferior vena cava)8 (Fig. 40-2). In addition to right lung hypoplasia, there is commonly a systemic-to-pulmonary arterial connection from the descending thoracic aorta or abdominal aorta to a variable portion of the right lung. Partial anomalous pulmonary venous drainage of the right lung to the inferior vena cava is the essential

A

component of this syndrome. Other cardiac anomalies may also occur, including atrial and ventricular septal defects. Although bronchial abnormalities may also be present, these patients generally do not have a true sequestration because all parts of the lung communicate with the tracheobronchial tree. Scimitar syndrome has two clinical presentations, the infantile and the adult form. Affected infants are symptomatic from heart failure and pulmonary hypertension. The heart failure is related to a significant left-to-right shunt caused by the combination of a systemic arterial connection to the right lung pulmonary vasculature and the anomalously draining pulmonary vein. Pulmonary hypertension is usually present as a result of stenosis in the pulmonary vein where it connects to the inferior vena cava. The adult form of scimitar syndrome usually manifests with minimal symptoms because the right lung is hypoplastic to the degree that the left-to-right shunt is minimal. In an infant with hypoplasia of the right lung on chest radiography, suspect scimitar syndrome until proven otherwise.

LUNG BUD ANOMALIES Lung bud anomalies occur presumably because of aberrations of the parenchyma of the lung bud. Included among these anomalies are congenital lobar emphysema (CLE), congenital lung cysts, congenital cystic adenomatoid malformation (CCAM), sequestrations, and bronchogenic cysts. More than

B

FIGURE 40-2 A, Chest radiograph of a patient with scimitar syndrome. The right lung is small, and the heart is shifted into the right side of the chest due to the combination of a small right lung and compensatory growth of the left lung. B, Artist’s depiction of the anomalous right pulmonary vein draining into the inferior vena cava. This is the primary component of scimitar syndrome.

Ch040-F06861.indd 464

1/21/2008 11:34:06 AM

Chapter 40 Congenital Abnormalities of the Lung

one of these entities may occur in the same lesion, blurring the lines that are used to differentiate them (Langston, 2003; Panicek et al, 1987).9,10 The underlying mechanism for development of these lesions may be in utero bronchial obstruction. The differences may come from variations in the precise timing, location, and completeness of the obstruction. Although bronchial obstruction early during lung development seems to be the common developmental error, these lesions often have some sort of communication with adjacent normal lung or other bronchi. This accounts for the presence of air in most of these lesions as well as the risk for infection.

Congenital Lobar Emphysema CLE occurs when there is a ball-valve obstruction in the bronchial tree that produces overexpansion of the air spaces of a segment or lobe of the lung. In contrast to acquired chronic obstructive pulmonary disease seen in adults, the parenchyma itself is not destroyed, showing only air space enlargement. The cause of this ball-valve phenomenon may be inadequate development of the cartilage in the bronchi during the 18th week of gestation. Almost half of the patients with this diagnosis have a distinct abnormality in the bronchus leading to the affected lobe. This abnormality might be abnormal mucous folds, intrinsic webs,11 bronchial stenosis (Stiger et al, 1992),12 bronchial kinking, or bronchomalacia.13 It is also possible for CLE to develop from extrinsic compression of the bronchus by enlarged pulmonary arteries, as is seen in patients with a large left-to-right shunt or tetralogy of Fallot with absent pulmonary valve syndrome, both of which are associated with enlarged central pulmonary arteries.14 This accounts for a small percentage of cases of CLE. At least half of patients with CLE have no obvious abnormality in the bronchus.15 CLE may arise because of a so-called polyalveolar lobe.16 In this disease, there is a significant increase in alveolar number, outstripping the number of bronchi leading to them. Air may enter these alveoli via collaterals and have no way to get out, resulting in overdistention of the affected lobe and thus CLE. The upper lobes, particularly the left upper lobe, are affected more often than the lower lobes.12 These lesions occur in the left upper lobe approximately 40% of the time, in the right middle lobe in 35% of cases, and the right upper lobe in 20%. More than one lobe may be involved. CLE occurs in males two or three times more frequently than in females. The diagnosis is seldom made prenatally by ultrasound. This anomaly has a variable clinical presentation, ranging from severe life-threatening respiratory distress to mild or no symptoms at all. Most infants develop symptoms of tachypnea, cough, and/or wheezing within a few days after birth. Symptoms usually progress and may lead to severe respiratory distress if the hyperexpansion is sufficient to compress the trachea. Approximately half of patients with CLE present within the first month of life. A few present as adults. Physical examination typically demonstrates diminished breath sounds on the affected side, although that side of the chest may be significantly larger when viewed externally. The diagnosis is usually made on the basis of the chest radiograph,

Ch040-F06861.indd 465

465

which shows hyperlucency on the affected side with mediastinal shift to the opposite side, depression of the diaphragm, and compression atelectasis of the remaining normal lung (Fig. 40-3). One must be careful not to confuse this with a pneumothorax and unwittingly attempt treatment with placement of a chest tube. CT of the chest is often helpful to establish the diagnosis, detect a possible underlying cause, and rule out foreign body aspiration. Bronchoscopy may be helpful in defining extrinsic compression, but do not perform it if the infant is in severe respiratory distress. Other imaging studies, such as ventilation-perfusion lung scans or bronchography, are of little utility. Patients with isolated CLE who are symptomatic undergo thoracotomy with resection of the affected lobe. Careful anesthetic management is critical. Positive-pressure ventilation during the procedures can pose significant problems: worsening of the air trapping and further shift of the mediastinum with consequent hemodynamic instability. Anesthesiologists must take this potential complication into account when inducing and managing anesthesia in such patients during thoracotomy. The surgical mortality rate for CLE is approximately 15% and depends on the associated anomalies, which are usually cardiac. Those surviving surgery generally recover completely, and long-term follow-up has shown their exertional performance to be similar to that of normal control subjects. Pulmonary function tests likewise are almost normal, a reflection of the anticipated compensatory growth of the remaining lung. It is clear that, in some patients with minimal or no symptoms, CLE can be managed conservatively. Closely monitor these patients with serial chest radiographs and ventilationperfusion lung scans.17 Many infants presenting with CLE and minimal symptoms have progressive improvement in ventilation to the affected lobe and do not require surgical intervention.

FIGURE 40-3 Axial CT of the chest in an infant with congenital lobar emphysema involving the left lung. Note the displaced location of the mediastinum and the somewhat compressed normal right lung.

1/21/2008 11:34:07 AM

466

Section 3 Lung

Congenital Cystic Adenomatoid Malformation The underlying mechanism for the development of CCAM is segmental bronchial atresia, perhaps resulting from primary disruption during fetal lung bud development or from disruption of the fetal bronchial circulation. Lung growth beyond the atretic segment becomes dysplastic and may take on one of three distinct types, based on histology and macroscopic cyst appearance, described by Stocker and colleagues.18 Type I (55% of cases) consists of large cystic spaces within a single pulmonary lobe. Type II (40%) appears as numerous small cysts less than 20 mm in diameter. Type III (5%) has no cysts but is a solid mass of adenomatoid hyperplasia or bronchial structures (Fig. 40-4). Although this classification scheme would seem distinct, in reality there is overlap between these types.19 The distinguishing histologic features of CCAM include increased terminal respiratory structures appearing as cysts lined by cuboidal or pseudostratified columnar epithelium. Another classification scheme based on the prevailing histologic findings was developed by Cha and colleagues20; they classified the lesions as primarily pseudoglandular or canalicular in appearance. Both lungs are affected equally, and the lesion is most commonly seen in the lower lobes. The size of the lesion is the primary determinant of the prognosis, although other congenital anomalies, seen in approximately 15% of all cases, may also influence prognosis. In some cases, the mass is large enough to cause mediastinal shift, pulmonary hypoplasia, polyhydramnios, and hydrops in the fetus. This is more likely to occur with Stocker type I than with the other types. The diagnosis can often be made antenatally by ultrasonography as early as 11 to 12 weeks of gestation.21 Complicating the evaluation is the observation that the mass will regress in size in many cases, and in some Type I

Type II

cases there will be resolution of hydrops.22-24 This resolution may be more likely with Stocker type II or III lesions than with type I.25 Those cases not recognized before birth can be identified postnatally on chest radiography. Most infants present early in life with respiratory symptoms, caused by air trapping in the cyst, that are reminiscent of CLE because there are connections between the cyst and the tracheobronchial tree. This seems to be in contradiction with the underlying etiology, although these connections may be via collateral airways. In rare cases, a pneumothorax due to spontaneous rupture of the cyst is the presenting sign. Infants may present in extremis with a very large CCAM that prevents significant development of the contralateral lung (Fig. 40-5); such infants rarely survive. Older children complain of cough and recurrent pulmonary infections. Some children are asymptomatic and present with this lesion noted incidentally on chest radiography. The radiographic findings vary and include a single large cyst, multiple large or small cysts, or a solid-appearing mass according to the Stocker type. Often, a CT scan of the chest is performed to further characterize the lesion and the extent of involvement of the affected lobe (Fig. 40-6). Usually no additional imaging beyond this is necessary. There are controversies regarding this disease. Some lesions regress, as noted earlier, complicating the decision about intervening. Regression has been noted both antenatally by ultrasonography and in the first few months after birth.26 For asymptomatic patients, a period of observation with serial radiographs in the first year of life seems to be an appropriate conservative approach. Resection would then be advised at the onset of respiratory symptoms or if there is no evidence of regression. Because there is some malignant potential in these lesions, observation for a protracted period is not Type III

FIGURE 40-4 Stocker’s classification of congenital cystic adenomatoid malformation. Type I typically has one or more large cysts. Type II has numerous small cysts. Type III is essentially a solid mass of tissue. (FROM STOCKER JT, MADEWELL JE, DRAKE RM: CONGENITAL CYSTIC ADENOMATOID MALFORMATION OF THE LUNG: CLASSIFICATION AND MORPHOLOGIC SPECTRUM. HUM PATHOL 8:155-171, 1977. COPYRIGHT ELSEVIER 1977.)

Ch040-F06861.indd 466

1/21/2008 11:34:07 AM

Chapter 40 Congenital Abnormalities of the Lung

FIGURE 40-5 Radiograph of a male infant who presented within minutes after birth with severe respiratory distress. He had a large congenital cystic adenomatoid malformation of the left lung which prevented the development of the right lung. Resection was attempted, but there was insufficient remaining lung tissue to maintain life.

A

467

appropriate. The malignancies reported in association with CCAM include pleuropulmonary blastoma,27 rhabdomyosarcoma,28 squamous cell carcinoma,29 and bronchioloalveolar carcinoma.30-32 Bronchioloalveolar carcinoma is the most common neoplasm to arise in a CCAM, and it almost always occurs in Stocker type I lesions.33 Pleuropulmonary blastoma and rhabdomyosarcoma may occur in younger patients, and bronchioloalveolar carcinoma has been seen in older teenagers and young adults. Therefore, carry out resection relatively early in life if it is obvious that regression of the lesion is not occurring, even in asymptomatic patients. Furthermore, early resection, while the lung is still actively growing, is more likely to result in some compensatory lung growth to make up for that portion resected. A lobectomy is usually the procedure required for complete excision of these lesions. On rare occasions, a pneumonectomy may be necessary. Prenatal treatment of CCAM includes resection and drainage of the cysts. Drainage of cysts prenatally, using a pleuroamniotic shunt, may be performed if the mass is compromising contralateral lung development or causing hydrops. The mortality rate for this intervention is approximately 30% for the fetus.34 Given the possibility of spontaneous regression, one must enter into a high-risk prenatal procedure with some caution. Some predictors of poor natural history may suggest that fetal intervention is appropriate. These include recognition of fetal hydrops and polyhydramnios, measurement of a lung-to-thorax transverse area ratio of less than 0.25, and assessment of the volume of the lesion relative to head circumference (Adzick et al, 2003).35,36 The goal of fetal surgery is to decompress the chest so that there is relief of hydrops and room for the normal lung to grow. This can be accomplished by placing a catheter to act as a shunt from a large cyst into the amniotic fluid surrounding the fetus.

B

FIGURE 40-6 A, CT image of a patient with type I congenital cystic adenomatoid malformation located in the posterior aspect of the left lung. B, Coronal reconstruction of the lesion in the same patient. The cystic lesion is somewhat complex, involving a large portion of the lower lobe of the left lung and shifting the upper lobe around further anteriorly.

Ch040-F06861.indd 467

1/21/2008 11:34:08 AM

468

Section 3 Lung

Relatively solid or multicystic lesions do not respond as well as large single cysts. This shunt needs to remain patent for 5 to 10 weeks to be effective. Fetal thoracotomy with resection of primarily solid lesions can also be performed, although the infant mortality rate is quite high (50%).36

Sequestration Pulmonary sequestration is typically separated into two types, extralobar and intralobar (Fig. 40-7). The common element in these two distinct pulmonary lesions is the absence of communication with the tracheobronchial tree and pulmonary arterial vasculature. In addition, blood supply to the lesion is via a systemic arterial source, with the venous drainage into either the pulmonary or the systemic venous system (Fig. 40-8). The sequestration may be large enough to produce hemodynamic consequences as well as an audible continuous murmur. Some are quite small and found incidentally on routine chest radiographs (Fig. 40-9). Clinical presentation varies considerably, from respiratory difficulties in an infant to an asymptomatic mass in an adult. Chronic pulmonary infections typically occur in older children and teenagers and are often mistaken for recurrent pneumonia. Extralobar sequestration is a mass of abnormal lung tissue that is completely separate from the remaining lung and has its own pleural investment. It is usually located in the inferior portion of the thoracic cavity but can be anywhere from the neck to just below the diaphragm.37-41 It is postulated that this type of sequestration develops when independent collections of cells with respiratory potential arise from the primitive foregut caudal to the normal lung bud. The arterial supply almost always arises from the descending thoracic aorta or from the abdominal aorta. However, other sources of systemic arterial supply have been seen, such as the sub-

A

Intralobar sequestration

Extralobar sequestration

FIGURE 40-7 Artist’s depiction of the two types of sequestration, extralobar and intralobar. Typically, extralobar sequestration is a solid mass at the posteromedial base of the chest. Intralobar sequestration also typically involves the lower lobe. Both have systemic arterial supply. (FROM LUCK SR, REYNOLDS M, RAFFENSPERGER JG: CONGENITAL BRONCHOPULMONARY MALFORMATIONS. CURR PROBL SURG 23:251, 1986. COPYRIGHT ELSEVIER 1986.)

B

FIGURE 40-8 A, This frame from an angiogram on a patient with bilateral sequestrations clearly demonstrates the systemic arterial supply to each of these lesions. B, The venous phase of the angiogram shows that the right-sided lesion drains through the pulmonary venous system and the left-sided lesion drains into the systemic venous system via the hemiazygos vein.

Ch040-F06861.indd 468

1/21/2008 11:34:10 AM

Chapter 40 Congenital Abnormalities of the Lung

A

B

C

D

469

FIGURE 40-9 Clinical variability in sequestrations. A, Axial CT image from a patient who presented with recurrent episodes of pneumonia demonstrates a large, solid mass in the left chest and the origin of an anomalous vessel from the descending thoracic aorta directed toward it. B, Three-dimensional reconstruction of the chest of the same patient as in A demonstrates the lesion as well as the anomalous arterial supply throughout much of its course (dashed arrows). C, A representative axial CT image from a patient who was asymptomatic but was noted to have a subtle mass on plain chest radiography. Note the small, wedge-shaped mass located medially in the left posterior chest (arrow). D, Threedimensional reconstruction of the chest of the same patient as in C depicts the sequestration (solid arrow) and anomalous systemic arterial supply (dashed arrow).

clavian artery and intercostal arteries.42,43 The venous drainage is typically through the azygos or hemiazygos system but can be through the subclavian vein or portal vein.43,44 There may be connections with the esophagus. Histologically, there is maldevelopment of pulmonary tissue, with microcystic changes reminiscent of congenital adenomatoid malforma-

Ch040-F06861.indd 469

tion.38 The diagnosis may be made on prenatal ultrasonography.45 On occasion, the mass is large enough to produce fetal hydrops, polyhydramnios, and fetal demise (Adzick et al, 1998).46 As with CCAM, this is potentially treatable with a thoracoamniotic shunt if evidence of eminent fetal demise is present.47 Spontaneous regression prenatally has also been

1/21/2008 11:34:12 AM

470

Section 3 Lung

reported with this lesion.48 After birth, the diagnosis is often made when a solid mass is incidentally noted on plain chest radiography. These lesions generally do not contain air and therefore appear as a solid mass on plain chest radiography. CT of the chest is often the only additional diagnostic study that is necessary. It reliably demonstrates the anomalous systemic arterial supply to allow adequate planning for surgical therapy. Three-dimensional reconstruction using CT often provides excellent depiction of the mass and the precise relationship of the systemic arterial supply to the sequestration (see Fig. 40-9). Although angiography provides additive information regarding the arterial and venous anatomy, it is seldom necessary. Magnetic resonance angiography is another method of precisely defining the vasculature in a less invasive fashion. Extralobar sequestration is often associated with other congenital anomalies, including diaphragmatic hernia, pericardial defects, and anomalous pulmonary venous drainage. Undertake resection of lesions found postnatally soon after making the diagnosis. This usually involves resection of the lesion itself without any accompanying lung tissue. Take care in isolating the arterial inflow and venous outflow to avoid excessive blood loss. Lesions located within the abdomen obviously require a laparotomy for resection. Intralobar sequestration is considered a congenital lesion, although some have suggested that it is acquired. The diagnostic features are abnormal pulmonary tissue with no direct bronchial communication and a systemic arterial supply. These lesions are located in the lower lobes in virtually all cases, surrounded by normal lung, and without a separate pleural investment. The arterial source is usually the descending thoracic aorta, but it can be a variety of branches of the aorta.49-51 This vessel usually reaches the sequestration via the inferior pulmonary ligament. Venous drainage is usually via the pulmonary venous system, but it may occur through systemic veins. The presumed mechanism by which this

A

lesion might be acquired is chronic infection resulting in loss of communication with the normal tracheobronchial tree and inflammation resulting in the ingrowth of a systemic arterial vascular supply as well as loss of the normal histologic appearance of lung parenchyma. Most researchers, however, are convinced that this is a congenital lesion. It can be bilateral, and there are reported cases of communication across the midline with a bridging tunnel including a bronchus. This lesion often appears cystic on chest radiography. CT examination of the chest usually defines the abnormal systemic artery, as with the extralobar variety. The natural history of these lesions is that recurrent infection is common.52 Begin surgical therapy soon after the diagnosis is made. Resection usually requires removal of the entire lobe of lung in which the sequestration resides, including some of the normal lung.53 As with the extralobar sequestration, it is extremely important to isolate and divide the systemic artery early in the procedure.

Bronchogenic Cysts Bronchogenic cysts most likely arise before the formation of bronchi and represent defective growth of the lung bud. These lesions come in two basic forms—mediastinal and parenchymal—although may manifest in a variety of other locations, including the inferior pulmonary ligament, retroperitoneum,54 and neck.55 Approximately two thirds are found in the mediastinum. There they may be paratracheal, carinal, or hilar, with the carinal location being the most common. These lesions are typically solitary cysts lined with either squamous or ciliated columnar epithelium and may be filled with either fluid or mucus. They do not contain air unless they are instrumented or become infected. Cysts within the parenchyma, however, may have communication with the tracheobronchial tree (Fig. 40-10).

B

FIGURE 40-10 A, This chest radiograph reveals a large bronchogenic cyst. B, CT scan of the same lesion demonstrates the location to be in the posterior hilar region. The wall is somewhat thick. There is communication with the airway, as evidenced by the fact that the cyst is filled with air.

Ch040-F06861.indd 470

1/21/2008 11:34:14 AM

Chapter 40 Congenital Abnormalities of the Lung

Most patients present with respiratory symptoms that prompt a chest radiograph, which then leads to the diagnosis. Symptoms are caused by the size of the cyst, its position, or infection. Compression of the trachea or bronchus leads to wheezing, stridor, shortness of breath, or pneumonia. Obstruction of the bronchus may result in emphysematous changes in the lung distal to the involved bronchus, much as in CLE. Some infants have severe respiratory distress mandating urgent surgical therapy. In approximately one third of cases, however, the cyst is found incidentally on imaging studies done for other reasons in an asymptomatic child or adult. It is quite rare for this diagnosis to be made prenatally on ultrasound. Although chest radiography usually provides sufficient information to make the diagnosis, CT study of the chest helps to precisely localize the lesion and direct resection. Magnetic resonance imaging rarely supplies additional useful information. Flexible bronchoscopy may demonstrate the presence of bronchial compression or a fistulous tract draining mucus, but it is not a necessary component of the evaluation of these patients. Surgical therapy is indicated when the diagnosis is made because of the high likelihood of symptoms developing. For mediastinal locations, this is usually a simple resection. However, for those cysts located within the parenchyma, a more extensive resection may be required, even a lobectomy in some situations. Subcarinal lesions are best approached via a right thoracotomy. There may be situations in which a very large compressive cyst causing respiratory distress is best treated with percutaneous drainage before elective resection.56 Alternatively, severely inflamed cysts or cysts that are tightly adherent to the membranous tracheal or bronchial wall can be treated with removal of the bulk of the cyst as well as removal of the inner lining; this may prevent subsequent accumulation of fluid or mucus within the cyst. Some mediastinal bronchogenic cysts can be removed with videoassisted thoracoscopic techniques. In general, complete removal is the surgical goal. Small, asymptomatic bronchogenic cysts discovered incidentally in adults have been monitored with serial imaging studies; evidence of enlarging cysts or development of symptoms is followed by resection.57 There are rare cases of malignant degeneration in these cysts.

PULMONARY ARTERIOVENOUS MALFORMATIONS A pulmonary arteriovenous malformation is an abnormal connection between a pulmonary artery and vein that bypasses the alveolocapillary complex. The impact of this malformation is right-to-left shunting and, subsequently, a varying degree of cyanosis. The lesion is the product of abnormal development of the primitive pulmonary vasculature at the level of the terminal capillary loops. Although there may be only one large artery and one large draining vein, often there are multiple feeder and draining vessels. These lesions may be single, multiple, bilateral, or diffuse. A somewhat complex classification scheme was devised based on the number and relative location of these fistulas within the lung paren-

Ch040-F06861.indd 471

471

chyma.58 There is an association with Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia), a syndrome that is also associated with arteriovenous malformations elsewhere.59 Pulmonary arteriovenous malformations may develop in the presence of liver failure as a presumably acquired phenomenon. Clinical symptoms include dyspnea, easy fatigability, and hemoptysis. The patient may appear cyanotic on physical examination, and a bruit may be audible. Other complications seen in these patients as a result of the fistula include paradoxical embolus with cerebral injury and brain abscess.60 The diagnosis is usually made by pulmonary angiography. At the time of diagnosis, therapeutic embolization is possible and is the treatment of choice.61 Surgical therapy for these malformations has largely been supplanted by embolization therapy. Surgical resection would invariably require removal of otherwise normal lung in addition to that involved in the lesion, but in many cases resection provides long-standing relief of symptoms and clinical manifestations.60 The concern with embolization therapy is the possibility of recurrence due to recanalization, which may occur in 25% of the cases.62,63 The arteriovenous malformations may be too diffuse to effectively treat with either embolization or surgical resection. In rare cases, lung transplantation may be the only feasible treatment possible.

SUMMARY Congenital lesions of the lung are rare entities. A full understanding of the clinical presentation and radiographic findings is essential to the appropriate evaluation, timing, and type of intervention necessary. Presentation may be early in infancy or well into the adult years of life. It has become evident that not all lesions require resection, although most will. Some of these lesions are so large that significant distortion of the remaining normal portion of the ipsilateral lung may be present. It is important to establish the anatomy of the normal or unaffected lobe of the lung so that it is preserved. In addition, there is a risk of torsion of the remaining lung after resection of a large mass involving the other lobe. This may be prevented by suturing the remaining lobe of the lung in a properly oriented position. In general, children with these lesions can be cured with appropriate treatment and lead normal, healthy lives with virtually no residual pulmonary symptoms.

COMMENTARY The understanding of congenital abnormalities of the lung is dependent on knowledge of lung embryology. Dr. Huddleston covers this very well from the perspective of the practicing surgeon. The availability of quality imaging is key to the diagnosis and management of these lesions. New techniques of antenatal surgery are thoroughly reviewed. The anatomic considerations for standard operative procedures are important and are clearly described. Dr. Huddleston points out that surgical resection is preferable for most of these lesions because symptoms are present or will develop in most of the patients. G. A. P.

1/21/2008 11:34:15 AM

472

Section 3 Lung

KEY REFERENCES Adzick NS, Flake AW, Crombleholme TM: Management of congenital lung lesions. Semin Pediatr Surg 12:10-16, 2003. Adzick NS, Harrision MR, Cromblehome TM, et al: Fetal lung lesions: Management and outcome. Am J Obstet Gynecol 179:884-889, 1998.

Ch040-F06861.indd 472

Langston C: New concepts in the pathology of congenital lung malformations. Semin Pediatr Surg 12:17-37, 2003. Panicek DM, Heltzman ER, Randall PA, et al: The continuum of pulmonary developmental anomalies. Radiographics 7:747-772, 1987. Stiger KB, Woodring JH, Kanga JF: The clinical and imaging spectrum of findings in patients with congenital lobar emphysema. Pediatr Pulmonol 14:160-170, 1992.

1/21/2008 11:34:15 AM

chapter

41

BRONCHIECTASIS Clemens Aigner Walter Klepetko

Key Points ■ Although the overall incidence of bronchiectasis is decreasing in

developed countries, it remains high in less developed regions. ■ Accurate diagnosis and optimal management of underlying disease

are important. ■ Surgical resection yields the best results in localized disease. ■ In end-stage disease, lung transplantation is an appropriate

option.

Bronchiectasis is defined as a permanent and abnormal dilation of bronchi caused by destruction of the elastic and muscular components of the bronchial wall. The distribution pattern can be either localized or diffuse. Clinical manifestation is usually dominated by chronic or recurrent pulmonary infections with abundant sputum production. The overall incidence is decreasing in Europe and North America but remains high in less developed regions.

CLASSIFICATION The pathologic classification of bronchiectasis defines three main types1,2: Cylindrical: In this type, the bronchi are uniformly dilated until the junction of the smaller airways, which are usually obstructed due to massive secretion. This type is frequently associated with tuberculosis. Saccular: The peripheral bronchi are dilated and end in blind sacs without functional bronchial structures peripheral to the dilated area. Mixed or varicose: The affected bronchi have an irregular or beaded dilation pattern evocative of varicose veins. The distribution pattern may be either localized or diffuse. The lower lobes are more likely to be affected, and the left lung seems to be more vulnerable to bronchiectasis than the right lung (Ashour et al, 1999).3 An explanation might be the narrower diameter, longer mediastinal course, and limited peribronchial space of the left main bronchus when passing through the subaortic tunnel. These features might make the left bronchus more vulnerable to obstruction than the right.4,5 The underlying pathologic mechanism leading to a dilation of bronchi is destruction of the normal musculoelastic tissue and cartilage of the bronchial wall leading to fibrosis. This results in a loss of elasticity, loss of contraction of peribronchial tissue, and, ultimately, dilation of the involved bronchi.6-8

ETIOLOGY Bronchiectasis can be acquired or congenital. The distribution pattern in congenital bronchiectasis is more likely to be diffuse, whereas acquired bronchiectasis is more commonly localized.6-9 The localization depends on the site of the primary trigger. In general, the underlying causes of acquired bronchiectasis can be divided into infectious and noninfectious diseases. Congenital syndromes often accompanied by bronchiectasis include cystic fibrosis (CF), in which bronchiectasis predominantly involves the upper lobes. Usually patients with congenital syndromes leading to bronchiectasis develop symptoms during childhood, but in patients with CF there is a wide variation regarding the onset of symptoms. Some patients with mild forms develop symptoms as late as their 40s or 50s. Ciliary dysmotility syndromes are another frequent cause of bronchiectasis. Various defects are included in this classification.10-13 Because of the dyskinetic cilia, secretion clearance is impaired, leading to an increased risk of bacterial colonization and infection. Clinical manifestations in addition to bronchiectasis include recurrent respiratory infections, sinusitis, otitis media, and immotile sperm. This bronchiectasis combined with situs inversus has been named Kartagener’s syndrome.14,15 Congenital immunodeficiencies also predispose to the development of bronchiectasis. These include panhypogammaglobulinemia as well as selective immunoglobulin G (IgG) and IgA deficiencies.16,17 Infections are the most common cause of acquired bronchiectasis. Childhood infections such as measles and pertussis remain a potential cause for bronchiectasis in less developed regions, but in developed regions the incidence has been reduced by widespread vaccination. If bronchiectasis occurs in childhood, it is usually caused by an underlying disease. Adenoviruses and influenza virus are the most common viral pathogens, and Staphylococcus aureus, Klebsiella pneumoniae, and Haemophilus influenzae the most common bacterial pathogens. Aspergilloma is a fungal infection that occurs predominantly in immunocompromised patients; it potentially leads to primarily cylindrical, often centrally located, bronchiectasis.18,19 Tuberculosis is also predominantly a problem in less developed regions, although the incidence is increasing again in various countries. It can cause bronchiectasis, mainly in the lower lobes, by the necrotizing effect of mycobacteria on pulmonary airways and parenchyma.20,21 Furthermore, in immunocompromised patients with advanced stages of human immunodeficiency virus (HIV) infection, bronchiectasis may occur as a result of recurrent pulmonary infections.22 After lung transplantation, not only is immunosuppression itself a potential trigger for bronchiectasis, but 473

Ch041-F06861.indd 473

1/21/2008 11:35:30 AM

474

Section 3 Lung

FIGURE 41-1 Severe bronchiectasis on the right side, with mediastinal shifting and incipient alterations in the left lung.

also obliterative bronchiolitis can eventually result in formation of bronchiectasis.23 Noninfectious causes of bronchiectasis include extrinsic compression due to mediastinal lymphadenopathy. Patients with granulomatous mediastinitis may develop broncholiths, which can cause bronchial obstruction and distal bronchiectasis. Also, endobronchial stenosis caused by a neoplasm or an unrecognized foreign body may lead to bronchiectasis. Furthermore, inhalation of toxic gases or aspiration of gastric content can lead to a significant inflammatory reaction of the airways with the potential development of bronchiectasis.24 Rare causes of bronchiectasis include other immunologic diseases such as ulcerative colitis, rheumatoid arthritis, and Sjögren’s syndrome. It has been suggested that α1-antitrypsin deficiency leading to panacinar emphysema is also associated with bronchiectasis25; however, recent findings suggest that development of bronchiectasis is rather secondary to emphysema, regardless of the genetic defect.26,27

HEMODYNAMIC CONSIDERATIONS An important aspect with regard to impact on respiratory function and gas exchange is the perfusion of bronchiectasis. In 1949, bronchopulmonary shunt formation in bronchiectasis with dilation and hypertrophy of the bronchial circulation was initially described.28 Later, two types of bronchopulmonary shunt were described,29 one with forward flow and the other with reverse flow. It was demonstrated that specific hemodynamic changes correlate with specific types of bronchiectasis.30 Ultimately, bronchiectasis can be distinguished in perfused and nonperfused lungs by angiographic findings. Lungs with cylindrical bronchiectatic changes are usually perfused, whereas those with cystic bronchiectatic changes are nonperfused. Ashour and colleagues3 hypothesized that retrograde filling of the pulmonary artery via the systemic circulation is observed in nonperfused bronchiectasis; because of the capillary bed destruction, pulmonary capillary resis-

Ch041-F06861.indd 474

FIGURE 41-2 Bronchography showing bronchiectatic alteration mainly on the right side.

tance increases and the shunted blood is retrogradely transported to the hilum via the pulmonary artery. Therefore, when contrast media is injected, a false impression of an empty pulmonary artery is created. Perfusion might also reflect the stage of the disease. Whereas lungs with perfused bronchiectatic changes are more likely to be capable of gas exchange and thus able to participate in respiratory function, nonperfused bronchiectasis indicates end-stage disease.

CLINICAL PRESENTATION The leading clinical symptom is a recurrent or permanent cough with ample sputum production.31 Frequently the sputum is purulent, and in advanced stages of disease it is often accompanied by hemoptysis. Smaller bleedings may occur from the inflamed and vulnerable airway mucosa, whereas more severe bleeding, which can become lifethreatening, results from erosions of hypertrophic bronchial arteries or lesions in abnormal anastomoses between the pulmonary and bronchial arterial circulations. In some cases, especially if the disease is restricted to the upper lobes, symptoms may be mild, present only as unproductive cough, or even absent. Patients also may present with symptoms of the underlying disease leading to the formation of bronchiectasis.

DIAGNOSTIC EXAMINATIONS In addition to the clinical presentation, various morphologic and functional examinations help in establishing the diagnosis and planning optimal treatment. The primary examination in most cases is the chest radiograph.32 In mild forms of bronchiectasis, there may be no

1/21/2008 11:35:30 AM

Chapter 41 Bronchiectasis

FIGURE 41-3 Mild cylindrical bronchiectasis in the left lung.

FIGURE 41-4 Bullous disease is seen on the right side, and the left side shows a mixture of bronchiectasis and bullae.

distinctive pathologic features; however, especially in saccular bronchiectasis, cystic spaces with fluid levels may be present, as well as areas of bronchial wall thickening. In the dependent parenchyma, atelectasis or infiltration may be present. The current standard examination for establishment of the diagnosis is the computed tomography (CT) scan.33 Highresolution CT scanning is a very sensitive method for detection of bronchiectasis and assessment of the distribution of bronchiectatic alterations34-37 (Fig. 41-1). Bronchography with endobronchial instillation of iodinated contrast medium (Fig. 41-2) initially was the standard procedure for the diagnosis of bronchiectasis. It may be additionally performed in selected cases, but it has routinely been replaced by CT scanning (Figs. .41-3 . and 41-4). The ventilation-perfusion (V/Q) scan is an additional important test to assess distribution of the disease and evaluate whether bronchiectatic areas are perfused. Additionally, pulmonary angiography and thoracic aortography may be performed to precisely evaluate hemodynamics.38 To evaluate pulmonary reserve, standard lung function tests and arterial blood gas analyses are routinely performed. Echocardiography may additionally be performed to judge right ventricular function. Sputum culture is, of course, routinely performed to allow adequate antibiotic treatment. Germs often found include S. pneumoniae, H. influenzae, Pseudomonas aeruginosa, atypical mycobacteria, and Aspergillus.39

Bronchodilators improve obstruction and facilitate secretion clearance, especially in patients with reversible obstruction in pulmonary function tests. Chest physiotherapy must be an integral part of therapy, including percussion, vibration, and postural drainage. Mucolytics have proven benefit in patients with CF; in other forms of bronchiectasis a benefit is theoretically possible yet has never been adequately proven. The same applies for anti-inflammatory drugs.43 Controlled oxygen therapy and assisted ventilation are conservative palliative options in end-stage disease.

CONSERVATIVE THERAPY The primary therapeutic goal obviously has to be the treatment of a reversible underlying disease. Adequate antibiotic therapy, bronchodilators, and physiotherapy must accompany any form of treatment of bronchiectasis.40-42 Administer antibiotic courses for acute exacerbation according to recent resistance testing. Often, intravenous application for 2 to 3 weeks, followed by oral application, leads to prolonged remissions. Nebulized antibiotics offer an alternative option.

Ch041-F06861.indd 475

475

SURGERY Surgery is the only option offering a potential cure for bronchiectasis. Its role has changed with the development of more effective antibiotics and conservative treatment options; however, with careful patient selection, surgery offers substantial benefits (Agasthian et al, 1996; Fujimoto et al, 2001).44,45 The main role of surgery is in patients with localized disease. When evaluating a patient for surgical resection, the presence of an uncorrectable underlying disease must be excluded. For example, in ciliary dysmotility syndromes multifocal disease . is . always present (Tables 41-1 and 41-2). CT scan, V/Q scan, a recent antibiogram, pulmonary function testing, and arterial blood gas analysis are indispensable prerequisites before performing surgery. Eventually, a pulmonary angiography and, in addition, a systemic angiography may offer further information regarding the perfusion of bronchiectatic areas (Ashour et al, 1999).3 The localization is exactly determined by CT scan, and the . . perfusion can be judged by V/Q scanning. An adequate pulmonary reserve for the planned resection must be ensured. Complete resection is of utmost importance because otherwise infectious complications and recurrence are likely to occur (Balkanli et al, 2003; Kutlay et al, 2002; Haciibrahimoglu et al, 2004).46-48 Although as much healthy parenchyma as possible must be spared, radical resection of

1/21/2008 11:35:31 AM

476

Section 3 Lung

affected areas is paramount to achieve improvement of symptoms. In rare cases, even pneumonectomy can become necessary if the disease is purely unilateral and the other lung is mostly free from disease. Some authors have concluded that pneumonectomy may even be better than residual disease (Ötgün et al, 2004).49 In addition to the morphologic classification, a hemodynamics-based functional classification was suggested by Ashour and colleagues (Ashour et al, 1999).3 Resection is recommended by these authors only for nonperfused bron-

TABLE 41-1 Role of Surgery for Bronchiectasis Curative In strictly localized forms Palliative Removal of most diseased areas Decrease of mucus production Decrease of systemic shunt Ultimative Transplantation for end-stage disease

TABLE 41-2 Criteria for Surgical Intervention Localized disease Adequate pulmonary reserve Irreversible process Significant symptoms (e.g., cough, hemoptysis, recurrent pneumonia, shunt)

chiectasis, regardless of whether the disease is unilateral or bilateral. In their experience, perfused bronchiectatic areas have the tendency to recover their impaired function over time after resection of nonperfused areas. Recently, this same group reported on 66 patients with localized nonperfused bronchiectasis undergoing resection. With a mortality rate of 1.5% and a morbidity rate of 18%, 73% were considered cured after resection, and 26% had symptomatic improvement. Only one patient did not benefit from resection based on this classification (Al-Kattan et al, 2005).50 Another large series of 238 patients also experienced significantly better results with complete resection, which was achieved in 64.7% of the patients, with complete freedom of symptoms in 79.41% and improvement of symptoms in 12.18%. Mortality was zero, and morbidity was 8.82% in this series (Balkanli et al, 2003).46 A similar series with 166 patients came to the same conclusion (Kutlay et al, 2002).47 Two series dealing with pediatric patients especially stressed the importance of complete resection, with one report suggesting that, in unilateral disease, pneumonectomy may be preferred to leaving residual disease (Haciibrahimoglu et al, 2004; Ötgün et al, 2004).48,49 Others have reported satisfying results for palliative surgery in multifocal bronchiectasis, with removal of the most diseased areas (Mazieres et al, 2003; Schneiter et al, 2005).51,52 A complete overview of outcome and complication rates in various series is given in Table 41-3. An acute indication for surgery may be severe hemoptysis. In milder forms, resection is beneficial if the criteria mentioned earlier are fulfilled. In severe cases of hemoptysis originating from hypertrophic bronchial arteries or pathologic anastomoses, removal of the affected segment or lobe can be life-saving; however, adequate pulmonary reserve must be ensured. Embolization of the affected bronchial arteries can be performed, but there is a relatively high recurrence

TABLE 41-3 Results of Surgical Resection for Bronchiectasis Author (Year)

Patients (n)

Mortality (%)

Sealy58 (1966)

140

1.4

59

Ripe

(1971) 60

Sanderson

66

Improved (%)

58

95

Not stated

Not stated

41

60

0.4

33

31

85

84

0

11

77

96

62

24

8.3

13

46

Not stated

(1982)

63

Vejlsted

(1982)

Dogan64 (1989) 45

Agasthian

(1996)

3

242

3

Asymptomatic (%)

Wilson61 (1982) Annest

(1974)

Morbidity (%)

22

2.4

17

50

36

487

3.5

11

71

Not stated

134

2.2

24.6

59.2

29.1

Ashour (1999)

85

0

Not stated

74.1

22.4

Fujimoto44 (2001)

90

0

19.6

45.6

38

1.7

10.5

66.86

18.67

0

18

Kutlay47 (2002) 51

Mazieres

166

(2003)

16 (multifocal disease)

Balkanli46 (2003) 49

Ötgün

238

(2004) 48

Haciibrahimoglu

Ch041-F06861.indd 476

(2004)

0

31.25

50

8.8

79.41

12.18

54 (children only)

5.6

14.8

42.5

42.5

35 (children only)

2.8

17.6

64.7

23.5

1/21/2008 11:35:32 AM

Chapter 41 Bronchiectasis

rate.53 As an emergency measure, bronchoscopic balloon blockade of the bleeding segment may be used to stabilize the patient.54-56 In cases of severe generalized disease and absence of other contraindications, bilateral lung transplantation is a viable surgical option.57

SUMMARY Bronchiectasis is a disease with a declining incidence in developed countries; however, it plays a major role in less developed regions. An accurate diagnosis needs to be established. The underlying disease needs to be identified and managed adequately. Consider surgical resection if an uncorrectable multifocal underlying disease can be excluded; it yields the best results in localized disease. Complete resection is of utmost importance to achieve good results. Additionally, hemodynamic considerations need to be taken into account. Surgical resection provides better results in nonperfused bronchiectasis. In perfused bronchiectasis, regain of functional capacity may be observed. In cases of massive hemoptysis, surgical intervention or embolization in patients with insufficient pulmonary reserve are to be considered as emergency procedures. In end-stage disease, after utilization of all conservative treatment modalities and with no option for localized resection, lung transplantation is the appropriate surgical option. The ultimate goal remains prevention by optimal management of underlying diseases.

COMMENTS AND CONTROVERSIES As the authors point out, bronchiectasis is not the common problem it was before the era of immunization and proper public health protocols. However, in the developing world, it is still a major clinical problem. For localized disease worldwide, the predominant cause is infection. However, in the Western world, airway obstructive pathologies (e.g., broncholith, tumor) are the predominant causes. Diffuse bronchiectasis is most frequently seen in congenital defects such as CF or immunoglobulin deficiencies.

Ch041-F06861.indd 477

477

Localized bronchiectasis is usually the only indication for surgical resection. These patients require careful evaluation to be sure that residual lung function will be adequate postoperatively. Short of massive hemoptysis, there is no role for localized resection in patients with diffuse bronchiectasis. In such patients, hilar devascularization can be an effective way to arrest bleeding. For patients with massive hemoptysis, bronchial artery embolization needs to be viewed as a temporizing maneuver because recurrent hemoptysis is the usual scenario. G. A. P.

KEY REFERENCES Agasthian T, Deschamps C, Trastek VF, et al: Surgical management of bronchiectasis. Ann Thorac Surg 62:976-978; discussion 979-980, 1996. Al-Kattan KM, Hajjar WM, Essa MA, Ashour MH: Surgical Results for Bronchiectasis Based on Hemodynamic and Morphological Classifications. Abstract presented at the 85th Meeting of the American Association for Thoracic Surgery, San Francisco, April 1013, 2005. Ashour M, Al-Kattan K, Rafay MA, et al: Current surgical therapy for bronchiectasis. World J Surg 23:1096-1104, 1999. Balkanli K, Genc O, Dakak M, et al: Surgical management of bronchiectasis: Analysis and short-term results in 238 patients. Eur J Cardiothorac Surg 24:699-702, 2003. Fujimoto T, Hillejan L, Stamatis G: Current strategy for surgical management of bronchiectasis. Ann Thorac Surg 72:1711-1715, 2001. Haciibrahimoglu G, Fazlioglu M, Olcmen A, et al: Surgical management of childhood bronchiectasis due to infectious disease. J Thorac Cardiovasc Surg 127:1361-1365, 2004. Kutlay H, Cangir AK, Enon S, et al: Surgical treatment in bronchiectasis: Analysis of 166 patients. Eur J Cardiothorac Surg 21:634-637, 2002. Mazieres J, Murris M, Didier A, et al: Limited operation for severe multisegmental bilateral bronchiectasis. Ann Thorac Surg 75:382-387, 2003. Ötgün I, Karnak I, Tanyel FC, et al: Surgical treatment of bronchiectasis in children. J Pediatr Surg 39:1532-1536, 2004. Schneiter D, Meyer N, Lardinois D, et al: Surgery for non-localized bronchiectasis. Br J Surg 92:836-839, 2005.

1/21/2008 11:35:32 AM

chapter

42

BACTERIAL INFECTIONS OF THE LUNG Gail Darling Gregory P. Downey Margaret S. Herridge

Key Points ■ The treatment of pneumonia is based on whether it was acquired

■ ■

■

■

■ ■

■ ■

■

in the community or in a health care facility (including a nursing home), the presence of comorbid conditions, severity of illness, and whether treatment will be given on an inpatient or outpatient basis. The etiologic agent is rarely known at the time of presentation, and the clinical syndromes associated with the various pathogens cannot be reliably distinguished on clinical or radiographic grounds. Therefore, treatment is no longer initiated based on so-called typical or atypical organisms, as was done previously. In the presence of comorbidities and/or adverse prognostic factors, treat in the hospital. Cultures of sputum and blood are important, but do not delay treatment in order for these cultures to be obtained. The most important factor in successful treatment is early institution of antibiotic therapy. For community-acquired pneumonia, a macrolide or respiratory quinolone is usually the first choice. Amoxicillin-clavulanate is also a good choice. For hospital-acquired, especially ventilator-associated, pneumonia, broad-spectrum antibiotics are recommended. They are tailored once an organism is identified. Attention to prevention, including alcohol-based hand washing, is important in ventilator-associated pneumonia. Aspiration pneumonia is more common in postoperative patients than previously identified and must be differentiated from acid aspiration syndrome. Oral anaerobes are important pathogens in aspiration pneumonia and lung abscess. Indications for intervention in lung abscess include failure to resolve with antibiotics, abscess under tension, abscess increasing in size despite appropriate antibiotics, contralateral lung contamination, abscess larger than 4 to 6 cm in diameter, rising fluid level, persistent ventilator dependency, necrotizing infection with multiple abscesses, hemoptysis, rupture into the pleural space with pyopneumothorax, and inability to exclude a cavitating carcinoma. Percutaneous drainage has replaced surgery in most cases of lung abscess. Surgery is still required if cancer cannot be ruled out or if the abscess is complicated by significant hemoptysis.

Lower respiratory tract infections, including pneumonia and its complications, are of substantial importance to the thoracic surgeon. From an historical perspective, suppurative diseases of the lung, such as empyema, lung abscess, and bronchiectasis, provided a major impetus for the development of thoracic surgery as a specialty and, until as recently as 40 years ago, represented the major focus of practice. Currently, lower respiratory tract infections represent the principal cause of mortality globally and, in North America, the major cause of death due to infectious disease. Lower respiratory tract infections may lead to suppurative complications requiring surgical intervention or may complicate the postoperative course of thoracic surgical patients. Since the advent of antibiotics, the spectrum and clinical course of pneumonia have changed radically. The purpose of this chapter is to provide a practical review of this field with specific recommendations for diagnosis and treatment of lower respiratory tract infections.

PNEUMONIA Despite the advent of potent antibiotics and effective vaccines, pneumonia remains a common and potentially fatal illness. Although the exact incidence is difficult to ascertain, in North America, pneumonia represents the sixth most common cause of death and the most common cause of death from infectious disease.1-4 There are approximately 4 million cases of community-acquired pneumonia (CAP) annually, of which approximately 20% result in hospitalization.5 Although mortality in the outpatient setting is low (1%-5%), it approaches 25% among hospitalized patients and may be even higher among those requiring admission to an intensive care unit (ICU). Current recommendations for the treatment of pneumonia focus on the presence or absence of comorbid conditions, the severity of illness, and whether treatment is to be given on an outpatient or inpatient basis (Mandell, 2005; Mandell et al, 2000).5-8

Definition Pneumonia is defined as an infection of the lower respiratory tract that involves the secondary lobules of the lung: the respiratory bronchioles, alveolar ducts, and alveoli. Patients usually present with a constellation of symptoms and signs that include fever, cough with or without sputum production, dyspnea, and chest discomfort in association with abnormal findings on physical examination of the chest and parenchymal infiltrates on the chest radiograph. Pneumonia is to be

478

Ch042-F06861.indd 478

1/21/2008 11:36:35 AM

Chapter 42 Bacterial Infections of the Lung

distinguished from acute bronchitis, which, although it can have a similar clinical presentation, represents infection of the tracheobronchial tree without parenchymal involvement as determined radiographically.

Epidemiologic Classification of Pneumonia Because of dramatic changes in the epidemiology and treatment of pneumonia, traditional classification schemes and diagnostic approaches are obsolete.9-12 During the initial evaluation of patients with suspected pneumonia, the microbial pathogen is rarely known, making the initial choice of antibiotic therapy empiric. However, the use of a diagnostic algorithm and taxonomy based on epidemiologic evidence and the clinical characteristics of patients provides a rational process for the selection of antibiotics. According to this algorithm (Table 42-1), pneumonia is currently divided into CAP and hospital-acquired (nosocomial) pneumonia (HAP), rather than typical versus atypical pneumonias as in previous practice.13 Two additional important categories of pneumonia are aspiration pneumonia and pneumonia in the immunocompromised host. CAP occurs in patients who have not recently (within 14 days) been hospitalized in an acute or chronic care facility (including nursing homes), and it is usually caused by bacterial or viral pathogens. These pneumonias are further subdivided based on the mode of presentation and characteristics of the host. Pneumonia is increasingly common in older patients and in those with other comorbid conditions, including chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), diabetes mellitus, renal insufficiency, and chronic liver disease. This has important implications for the nature of the infecting organisms, the initial treatment recommendations, and, ultimately, the prognosis (Fine et al, 1997).14-16 HAP is defined as pneumonia that occurs 48 to 72 hours after admission to a hospital. This type of pneumonia commonly reflects some type of compromise in host defense mechanisms, and, although the cause is usually bacterial

(often due to gram-negative bacilli), fungal infections are also observed. Aspiration pneumonia can be further divided into chemical pneumonitis resulting from aspiration of gastric contents and bacterial aspiration pneumonia. Pneumonia in the immunocompromised host can be subdivided based on the nature of the immunocompromised state (e.g., associated with human immunodeficiency virus [HIV] infection, chemotherapy, organ transplantation).

Community-Acquired Pneumonia Pathogenesis

Type of Pneumonia

Subclassification

Community-acquired pneumonia

Age <60 year, no other illness Age >60 year or coexisting illness Severe or rapidly progressing pneumonia Pneumonia in nursing home residents

Bacterial pneumonia is most commonly the result of bronchogenic spread of infection after microaspiration of infected oropharyngeal secretions. An important consideration is that the oropharyngeal flora changes after 48 to 72 hours of hospitalization, and this is one factor that accounts for differences in bacteriology between CAP and HAP. Although aspiration of oropharyngeal secretions is common, occurring in 50% of normal subjects during sleep and in up to 70% of subjects with impaired consciousness,17 the host defenses of the lung (e.g., mucociliary clearance) are usually able to clear potential pathogenic organisms and prevent parenchymal infection. However, under the appropriate conditions, including impaired host defenses (smoking, malnutrition, impaired cough), large bacterial load, or a virulent pathogen, these infectious particles are able to reach the terminal airways and alveoli, where infection is initiated. The anatomic distribution of the resultant pneumonia is variable. Although the factors that predispose to a multifocal distribution of pneumonia are not completely understood, they include the characteristics of the infecting organism and the host (e.g., preexisting COPD); concomitant viral tracheobronchitis, which impairs mucociliary clearance; and aspiration of macroscopic particulate matter. Organisms such as Streptococcus pyogenes, virulent gram-negative bacteria, or anaerobic bacteria are often associated with multifocal pneumonia. Infectious agents can also reach the lower respiratory tract by direct inhalation. This route is common for the respiratory bacterial pathogens Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species, Mycobacterium tuberculosis, and certain fungi such as Histoplasma capsulatum. Less frequently, bacteria such as Staphylococcus aureus and gramnegative enteric bacilli can infect the lung hematogenously via the pulmonary and bronchial arteries, which may occur secondary to intravascular infections such as septic thrombophlebitis or right-sided endocarditis.

Nosocomial pneumonia

Ventilator-associated pneumonia Non–ventilator-associated pneumonia

Host Defense Mechanisms

Aspiration pneumonia

Infectious pneumonia Chemical pneumonitis

Pneumonia in the immunocompromised host

HIV/AIDS Chemotherapy for neoplastic diseases Organ or bone marrow transplant recipient Diabetes Other immunocompromised states (e.g., hypogammaglobulinemia, neutrophil deficiencies, cellular)

TABLE 42-1 Classification of Types of Pneumonia

Ch042-F06861.indd 479

479

The epithelial surface of the respiratory tract is a barrier between the host and the environment. That the lung is routinely exposed to potential pathogens and yet maintains its sterility is a testimony to the effectiveness of the defenses of the respiratory system. These defenses include the aerodynamic filtration provided by the upper airway, the cough reflex, mucociliary clearance, phagocytic cells of the innate immune system (neutrophils and macrophages), endogenous antimicrobial products of the epithelial cells (e.g., defensins,

1/21/2008 11:36:35 AM

480

Section 3 Lung

cathelicidins), specific humoral immunity (mucosal immunoglobulin A [IgA] and IgG), and cellular immunity (lymphocytes).18 These defenses can become compromised at many levels. The upper airway filtration system can be bypassed by intubation or tracheostomy, and these procedures represent important risk factors for nosocomial pneumonia (see later discussion). Diminished ability to cough and clear secretions may result from respiratory muscle weakness (severe COPD, prolonged steroid treatment, malnutrition), decreased level of consciousness, or severe incisional chest wall pain. Mechanical impedance to the clearance of secretions may be caused by an endobronchial tumor or foreign body, including stents and T tubes. Mucociliary clearance can be impaired by recent cigarette smoking (up to 1 month before operation), inhalational anesthetics, alcoholism, COPD, cystic fibrosis, or ciliary dysmotility syndromes. The immune system can also be compromised by malnutrition, alcoholism, renal or hepatic failure, hypoxia, chemotherapy or radiation therapy, and congenital or acquired immunoglobulin deficiencies. These factors must be recognized and corrected, if possible, for effective treatment of pneumonia.

Microbiology CAP can be caused by a wide variety of bacterial, viral, and fungal pathogens (Table 42-2). A definitive microbiologic diagnosis is made in only about 50% of cases, despite diagnostic efforts.19 Bacterial pathogens responsible for pneumonia have traditionally been divided into typical organisms, including Streptococcus pneumoniae, Haemophilus influenzae, S. aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and atypical organisms, including Legionella species, M. pneumoniae, and C. pneumoniae. Although this scheme is useful in the epidemiologic classification of pneumonias, it is important to note that the clinical syndromes associated with the various pathogens cannot be reliably distinguished on clinical or radiographic grounds.20

Pneumonia Caused by Streptococcus pneumoniae as a Paradigm for Bacterial Pneumonia S. pneumoniae (pneumococcus) remains the most common cause of CAP and is responsible for between 5% and 20% of cases. However, evidence suggests that many culturenegative cases of pneumonia are in fact caused by S. pneumoniae: sputum cultures are negative in about one half of cases with pneumococcal bacteremia21; invasive techniques to obtain uncontaminated lower respiratory tract secretions (transtracheal and transthoracic aspiration) have identified S. pneumoniae in a high percentage of cases22; and about two thirds of bacteremic pneumonias are attributable to S. pneumoniae.14 Risk factors for pneumococcal pneumonia include advanced age, alcoholism, cigarette smoking, dementia, malnutrition, infection with HIV, and the presence of chronic illness (e.g., CHF, chronic renal failure). Patients who have undergone splenectomy have an increased risk for pneumococcal bacteremia and overwhelming sepsis because the spleen is the primary site of clearance of the organism. The clinical features of this pneumonia are fever, cough, chest pain, and production of purulent sputum. Radiographically, infiltrates associated with S. pneumoniae can range from a classic lobar distribution to patchy bilateral infiltrates. Small parapneumonic effusions are commonly present, but empyema is uncommon (1%-2% of cases). Bacteremia occurs in 20% to 30% of cases, and extrapulmonary infections include sinusitis, otitis media, meningitis, and endocarditis. Until recently, penicillin has been the recommended treatment for S. pneumoniae. However, the increasing incidence of penicillin-resistant and, more recently, fluoroquinoloneresistant organisms has become a worldwide problem.23,24 In areas where penicillin resistance is high, alternative antibiotics, including second-generation cephalosporins such as cefuroxime and macrolides such as clarithromycin or azithromycin, need to be considered.

TABLE 42-2 Bacteriology of Community-Acquired Pneumonia (CAP) Outpatients Without Comorbidity and Age <60 Years

Outpatients With Comorbidity or Age >60 Years

Hospitalized Patients With CAP

Severely III Hospitalized Patients With CAP

Streptococcus pneumoniae

S. pneumoniae

S. pneumoniae

S. pneumoniae

Mycoplasma pneumoniae

Respiratory viruses

H. influenzae

Legionella species

Respiratory viruses

H. influenzae

Polymicrobial (including anaerobic bacteria)

Aerobic gram-negative bacilli

Chlamydia pneumoniae

Aerobic gram-negative bacilli

Aerobic gram-negative bacilli

M. pneumoniae

Haemophilus influenzae

S. aureus

Legionella species

Respiratory viruses

Legionella species

Moraxella catarrhalis

S. aureus

H. influenzae

C. pneumoniae

M. tuberculosis Endemic fungi

Staphylococcus aureus Mycobacterium tuberculosis

M. tuberculosis

Respiratory viruses

Endemic fungi

Endemic fungi

M. pneumoniae

Aerobic gram-negative bacilli

M. catarrhalis M. tuberculosis Endemic fungi

Ch042-F06861.indd 480

1/21/2008 11:36:35 AM

Chapter 42 Bacterial Infections of the Lung

Other Bacterial Pneumonias. Infections with other bacteria, including H. influenzae, S. aureus, Moraxella catarrhalis, and other gram-negative bacteria such as P. aeruginosa and K. pneumoniae account for between 3% and 10% of cases of CAP.22 Pneumonia caused by S. aureus is seen most commonly in the elderly and in patients recovering from influenza. This is usually a rapidly progressing pneumonia involving the formation of pneumatoceles and abscesses that are associated with a high mortality rate. Pneumonia caused by S. pyogenes (group A streptococcus) is usually a rapidly progressing infection associated with empyema formation. Anaerobic organisms of oropharyngeal origin (Bacteroides species, Fusobacterium) are the most common cause of socalled aspiration pneumonia and are associated with necrotizing pneumonia, abscess formation, and empyema. The role of anaerobic organisms in the syndrome of CAP is uncertain, in large part because routine culture techniques are not suitable for their culture. However, several studies have suggested that anaerobic organisms may account for up to 30% of pneumonias.22 Atypical organisms, including M. pneumoniae, Legionella species, and C. pneumoniae, are frequently seen in CAP in younger adults.25 M. pneumoniae is the second most common cause of pneumonia (after S. pneumoniae) in North America as well as other parts of the world.26 However, it is likely that the incidence may be higher than reported because undoubtedly many mild cases go unreported. M. pneumoniae is transmitted from person to person by infected respiratory droplets, and the incubation period varies from 1 to 3 weeks. The incidence of infection is highest in children of school age, military recruits, and college students. There are no clinical features—symptoms, physical findings, or radiographic appearances—that can reliably distinguish pneumonia caused by Mycoplasma species from CAP of bacterial origin. Moreover, the culture of M. pneumoniae is difficult, so a definitive diagnosis depends on serologic testing and is therefore retrospective. Pneumonia Caused by Mycoplasma Species. The clinical presentation of pneumonia caused by Mycoplasma species is usually gradual, involving headache, malaise, chills (but not rigors), low-grade fever, sore throat, rhinorrhea, ear pain, and cough, which is often intractable.27 Wheezing and dyspnea may occur, and infection due to M. pneumoniae has been associated with exacerbations of asthma.28 (The abnormalities found on physical examination of the chest are often minimal, although crackles and wheezes may be present.) Extrapulmonary involvement may include skin rash, arthritis, evidence of hemolysis, and involvement of the central nervous system (aseptic meningitis, peripheral neuropathy, cranial nerve palsies). Radiographic abnormalities that have been described commonly include pulmonary infiltrates in a peribronchial distribution, nodular infiltrates, areas of plate-like atelectasis, and hilar adenopathy. Pleural effusions occur in up to one quarter of cases. Laboratory abnormalities include anemia, which may be hemolytic and associated with a positive Coombs test due to cold agglutinins. The latter are not specific for M. pneumoniae and may be seen with other infections, such as Epstein-Barr virus infection. The white blood

Ch042-F06861.indd 481

481

cell count is usually normal. Definitive serologic diagnosis requires demonstration of a fourfold or greater rise in IgM or IgG (or a single titer >1 : 32), which is measured by a complement fixation test. Other tests are available, including enzyme-linked immunosorbent assay (ELISA), antigen detection (antigen-capture enzyme immunoassay), and polymerase chain reaction (PCR) detection of genomic DNA.29 Pneumonia Caused by Legionella Species. Pneumonia due to the Legionella species (Legionella pneumophila), first identified in 1976 during an outbreak of pneumonia at a convention of the American Legion in Philadelphia,30 is a relatively common cause of both CAP and HAP. Symptoms of pneumonia (chills, fever, cough, dyspnea, chest pain) are the predominant clinical manifestation of infection with Legionella species, but nonpulmonary manifestations such as gastrointestinal symptoms (diarrhea, nausea, vomiting, and abdominal pain), myalgias, arthralgias, lethargy, and neurologic abnormalities (headache, decreased level of consciousness) are common. Fever is usually present and can be higher than 40ºC, and bradycardia relative to the temperature elevation is common, especially in elderly patients. Crackles and signs of consolidation are commonly noted on physical examination of the chest. Nonpulmonary findings on physical examination include various rashes and neuropathies. A variety of laboratory abnormalities are observed in patients with pneumonia caused by Legionella species, including leukocytosis, hematuria, renal and hepatic dysfunction, thrombocytopenia, hyponatremia, and coagulopathy. Although there are no characteristic radiographic abnormalities, the most common pattern is a patchy unilobar infiltrate that progresses to consolidation. Other patterns can be present, including diffuse bilateral interstitial infiltrates. Pleural effusions are common. Clues to diagnosis of infection by Legionella species include the presence of gastrointestinal symptoms, the Gram stain of respiratory secretions showing many neutrophils but few organisms, hyponatremia, and failure to respond to β-lactam antibiotics. Pneumonia Caused by Chlamydia Species. Chlamydia species (C. pneumoniae, C. psittaci) are obligate intracellular parasites whose role in the pathogenesis of pneumonia became apparent during the 1990s. Estimates using serologic techniques have put incidence of infection with C. pneumoniae as high as 10% to 20% in patients with CAP who do not require hospitalization.26,31 There have also been associations of chlamydial infections with coronary artery disease32 and asthma.33 There are no distinguishing clinical features of pneumonia with C. pneumoniae, although gradual onset of symptoms, pharyngitis, hoarseness, and sinusitis have been commonly reported. As with other atypical pneumonias, the white blood cell count tends to be normal. The chest radiograph commonly demonstrates one or a few areas of patchy consolidation. Extrapulmonary manifestations of C. pneumoniae include meningoencephalitis, Guillain-Barré syndrome, arthritis, and myocarditis. The diagnosis of C. pneumoniae infection can be difficult to establish because most laboratories do not have the capability to culture the organism.

1/21/2008 11:36:35 AM

482

Section 3 Lung

Techniques that are useful include nasopharyngeal swabs (not sputum culture), serologic testing, antigen detection, and PCR.

Clinical Evaluation of Patients With Community-Acquired Pneumonia During the initial evaluation of a patient with suspected pneumonia, there are several immediate priorities (Fig. 42-1). The highest priority is given to cardiopulmonary stabilization, including treatment of acute respiratory failure if present. Early institution of antibiotic therapy is essential to effective treatment. Broad-spectrum antibiotics chosen according to the clinical situation need to be initiated promptly. Ideally, sputum and blood cultures are obtained before the institution of antibiotics, but do not delay antibiotic therapy if the patient is unable to provide a sputum sample. The next decisions are whether hospitalization is required and whether ICU monitoring is indicated.

Patients with CAP usually come to medical attention based on the development of symptoms that include fever or hypothermia, rigors, sweats, cough with or without sputum production, alteration of the color of respiratory tract secretion, chest discomfort, or dyspnea.34 Nonrespiratory symptoms such as headache, abdominal pain, anorexia, nausea, myalgias, arthralgias, or mental confusion may be present in 10% to 30% of patients. Nonspecific symptoms are common in elderly patients. Abnormalities on physical examination may include the presence of fever (80%), tachypnea (45%-70%), and tachycardia. Examination of the chest reveals the presence of crackles or wheeze in most patients or, less commonly (30%40% of patients), signs of consolidation. Because many of the symptoms and signs of pneumonia are nonspecific, it is essential that a chest radiograph be obtained for the proper diagnosis and management of pneumonia. The majority of patients have leukocytosis that ranges from 15 to 30 × 109/L, often with an increased percentage of

Blood culture, sputum Gram stain culture; consider saline-induced sputum or more invasive procedures such as bronchoscopy

Clinical diagnosis of pneumonia

Categorize host pneumonia presentation Tailor treatment to predominant organism when results become available

Outpatient CAP with no modifying factors

Macrolide or doxycycline

Outpatient CAP with COPD

No corticosteroids or antibiotics in the last 3 months

Second-generation macrolide or doxycycline

Corticosteroids or antibiotics in the last 3 months

Fluoroquinolone or amoxicillin/clavulanate or second generation cephalosporin
macrolide

Nursing home CAP

Hospital ward

Intensive care unit

Fluoroquinolone or amoxicillin-clavulanate or second-generation cephalosporin
macrolide

Fluoroquinolone or amoxicillinclavulanate or second- or thirdgeneration cephalosporin
macrolide

Third-generation cephalosporin
macrolide or piperacillin/tazobactam or fluoroquinolone

Risk of Pseudomonas aeruginosa Anti-pseudomonal fluoroquinolone (ciprofloxacin)  anti-pseudomonal β-lactam (ceftazidime, meropenem, or piperacillin/tazobactam) or macrolide  two anti-pseudomonal agents (aminoglycoside  ceftazidime, cefepime, meropenem, or piperacillin/tazobactam) FIGURE 42-1 Flow chart for antibiotic treatment of community-acquired pneumonia (CAP). COPD, chronic obstructive pulmonary disease.

Ch042-F06861.indd 482

1/21/2008 11:36:35 AM

Chapter 42 Bacterial Infections of the Lung

immature cells (left shift). The presence of leukopenia (white blood cell count <3 × 109/L) carries a poor prognosis. Radiographic Evaluation. The presence of a pulmonary infiltrate on a chest radiograph, when the clinical and microbiologic features are compatible, represents the gold standard for the diagnosis of pneumonia, although the radiographic picture may lag behind the clinical presentation. In concert with other clinical information, the radiographic picture can favor one or several causative agents.35 Possible radiographic

483

patterns include lobar or segmental consolidation (Fig. 42-2); patchy bronchopneumonia (Fig. 42-3); nodules (large, small, miliary) (Fig. 42-4); and interstitial process (Fig. 42-5). Lobar or segmental consolidation is commonly seen with pneumococcal or H. influenzae pneumonia but can also be associated with pneumonias caused by Legionella or Mycoplasma species. Pneumonia associated with large nodules raises the possibility of infection with S. aureus (Fig. 42-6) or gram-negative organisms such as P. aeruginosa, especially with hematoge-

FIGURE 42-2 Posteroanterior (A) and lateral (B) chest radiographs illustrating lobar consolidation in the lingula owing to Mycoplasma.

FIGURE 42-3 Posteroanterior (A) and lateral (B) chest radiograph illustrating bronchopneumonia in the posterior basal segment of the left lobe owing to Haemophilus influenzae.

Ch042-F06861.indd 483

1/21/2008 11:36:35 AM

484

Section 3 Lung

FIGURE 42-4 Nodular infiltrates with cavitation in the upper lobes on a posteroanterior chest radiograph of a patient with pneumonia caused by Enterobacter cloacae.

FIGURE 42-5 Interstitial infiltrates on the posteroanterior chest radiograph of a patient with cytomegalovirus pneumonia.

nous spread due to endocarditis or an infected vascular access catheter. Fungal pneumonias can be associated with nodules that commonly cavitate. A miliary pattern, with nodules the size of millet seeds (1-2 mm), is highly suggestive of mycobacterial (M. tuberculosis) or fungal infection (Fig. 42-7). An interstitial pattern (Fig. 42-8) is associated with infection by virus or Mycoplasma or Chlamydia species but can also be seen with bacterial pneumonias, including S. pyogenes. Pleural effusions may be associated with pneumonias caused by many infectious agents, but effusions that are large and appear early in the course of pneumonia are often associated with S. pyogenes pneumonia and anaerobic pneumonias.

Sputum Examination. The determination of the microbiologic cause of pneumonia is difficult and, despite best efforts, is successful in only about one half of cases.19 The utility of sputum examination in establishing the microbiologic source of pneumonia is controversial, and current guidelines deemphasize this procedure.36 However, examination of sputum, especially of sputum induced by inhalation of hypertonic saline and examined with the use of special stains, can be helpful in the identification of M. tuberculosis and Pneumocystis and Legionella species. A Gram stain of expectorated induced sputum is helpful if an adequate sample is obtained and if there is a predominant organism. Several

FIGURE 42-6 Posteroanterior chest radiograph illustrating cavitating large nodules in the right upper lobe in a patient with Staphylococcus aureus pneumonia.

FIGURE 42-7 Posteroanterior chest radiograph illustrating the typical military pattern of tuberculosis. Also note the prominent right paratracheal lymphadenopathy.

Ch042-F06861.indd 484

1/21/2008 11:36:36 AM

Chapter 42 Bacterial Infections of the Lung

485

example, the finding of Legionella antigen or a Chlamydia antigen in serum or urine may sometimes be rapidly available and therefore of use in determining or tailoring therapy. Obtain blood cultures from any patient who is sick enough to warrant hospitalization, even though only 10% to 20% of patients are bacteremic. Molecular Medicine and Diagnostic Testing. Rapid developments in the field of molecular medicine have had a strong impact on diagnostic testing, including that for pneumonia. Methods of detecting specific pathogens in respiratory secretions (e.g., sputum, BAL fluid) using sensitive immunofluorescent techniques are currently available. As an example, the direct fluorescent antigen (DFA) test for Legionella species is used commonly. The use of the PCR for the detection of mycobacterial, Chlamydia, and Legionella DNA is also becoming possible and has a rapid turnaround time. However, large studies are needed to validate these techniques before their use becomes widespread. FIGURE 42-8 Posteroanterior chest radiograph illustrating an interstitial pattern in a patient with Mycoplasma pneumonia. This pattern is one of several radiographic patterns seen with Mycoplasma (see Fig. 42-2).

factors may contribute to the unreliability of sputum examination, including delays in reaching the laboratory, operator variation in staining techniques, inability to produce a sputum specimen (one third of patients), and administration of antibiotics before the collection of the sputum specimen (up to one quarter of patients). However, when performed by experienced laboratory personnel, Gram stain of sputum has been shown to be valuable in the prediction of common types of bacterial pneumonia.37 Moreover, what is absent on the Gram stain (e.g., neutrophils, gram-negative bacilli) is often important in making decisions about initial antibiotic choices. Sputum cultures are helpful if there is a pure growth of a pathogen, of M. tuberculosis, of Legionella species, or of endemic fungi. Cultures are also useful if resistant organisms are identified. However, collection of a sputum specimen must never delay initiation of antibiotic therapy. Invasive Diagnostic Testing. Attempts to obtain uncontaminated lower respiratory secretions by means of invasive measures that include transtracheal aspiration, transbronchial protected specimen brush (PSB), and bronchoalveolar lavage (BAL) are not commonly performed in the setting of CAP.38 However, if an accurate diagnosis is essential in an extremely ill patient, consider bronchoscopy and PSB or BAL. Transtracheal aspiration is associated with significant morbidity and is not frequently used. If a pleural effusion is present, pleural fluid cultures are highly specific for the causative agent of the underlying pneumonia. Serologic and Other Blood Testing. Serologic studies are required to establish the cause of atypical pneumonias, including those caused by Mycoplasma, Legionella, and Chlamydia species. Because the results of these tests are often delayed as long as several weeks, clinical decisions regarding therapy must be made long before the test results are available. However, there are certain exceptions. For

Ch042-F06861.indd 485

Therapy for Community-Acquired Pneumonia At the time of initial evaluation of patients with suspected pneumonia, a specific microbiologic diagnosis can rarely be made because neither the clinical presentation nor the commonly used diagnostic tests (sputum Gram stain, chest radiograph) are sensitive or specific enough to identify the pathogenic microorganism; therefore, antibiotic therapy must be chosen empirically. Eventually, days or weeks later, a specific diagnosis may be made. This information is often more useful for epidemiologic purposes than for initial clinical decision making. Empiric therapy is based on the setting in which the infection was acquired and the clinical characteristics of the patient (see Table 42-1). Initial guidelines for the treatment of CAP focused on the presence or absence of comorbid conditions, the severity of illness, and whether treatment was to be given on an outpatient or inpatient basis.7,8,39-41 However, several developments have transpired since the publication of these guidelines. First, recent epidemiologic studies have provided a basis for more accurate risk prediction and decisions about hospital admission.15,42 Second, the prevalence of antibiotic resistance in common lower respiratory tract pathogens has increased the necessity of re-evaluating the choice of antimicrobial agents.43 Third, myriad antibiotics, including new macrolides and quinolones, are now available; they have improved activity and pharmacokinetic properties such as enhanced oral bioavailability. Finally, the availability of home intravenous (IV) antibiotic programs and home nursing care has greatly reduced the need for and duration of hospitalization.6 Choice of Antibiotic Therapy. The general approach to the treatment of CAP is to categorize patients according to whether they can be treated as outpatients, are nursing home residents, or require hospitalization. Hospitalize patients who have risk factors associated with a poor prognosis (Table 42-3). Note that bacterial pneumonia after recent influenza infection can be life-threatening, particularly in elderly patients.44,45 In the majority of patients with CAP, no pathogen has been identified. Therefore, in most instances, the physician initiates empiric antibiotic therapy on the basis of

1/21/2008 11:36:37 AM

486

Section 3 Lung

TABLE 42-3 Risk Factors Associated With Poor Outcome in Community-Acquired Pneumonia Coexisting Conditions Age >60 years COPD Bronchiectasis Chronic renal failure Congestive heart failure Chronic liver disease Alcoholism Malnutrition Previous splenectomy Recent hospitalization (<1 yr) Physiologic Abnormalities Respiratory rate >30 breaths/min Hypotension Systolic blood pressure <90 mm Hg Diastolic blood pressure <60 mm Hg Temperature >38.3ºC or <36.5ºC Tachycardia >120 bpm Laboratory Abnormalities Leukocytosis >30 × 109/L Leukopenia <4 × 109/L or absolute neutrophil count <1 × 109/L Urea >7 mmol/L (20 mg/dL) Hemoglobin <90 g/L Hypoxemia: PaO2 <60 mm Hg Hypercapnia: PaCO2 >50 mm Hg Metabolic acidosis Coagulopathy (increased partial thromboplastin time, decreased platelet count, or presence of fibrin split products) Multilobar or rapidly progressive infiltrates on radiography Presence of a pleural effusion Atypical Presenting Features Confusion Predominantly nonrespiratory complaints Absence of fever COPD, chronic obstructive pulmonary disease; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen.

epidemiologic data. If the causative pathogen is identified (either initially or at a later time), specifically direct the antibiotic spectrum against that organism. If no pathogen is discovered, broad-spectrum empiric antibiotics are continued.46 Table 42-4 outlines an approach to the initial antibiotic therapy for patients, based on the most recent guidelines (Mandell 2005; Mandell et al, 2000).5,6 It is to be emphasized that these are guidelines and not an inflexible set of rules. In making a final decision, consider individual patient factors, such as the presence of comorbid illness, the severity of illness, local microbiologic information (e.g., hospital resistance patterns), and response to initial therapy. For outpatients with no comorbid illness who are 60 years of age or younger, initial treatment with a macrolide (erythromycin, clarithromycin, or azithromycin) or doxycycline should suffice to cover common bacterial (S. pneumoniae) and atypical (M. pneumoniae, C. pneumoniae) pathogens. Erythromycin is often poorly tolerated, whereas the newer macrolides are substantially more expensive. Patients with

COPD who have received antibiotics or oral glucocorticoids in the past 3 months have an increased risk of infection with H. influenzae, M. catarrhalis, and enteric gram-negative rods, so treatment with a newer (respiratory) quinolone such as levofloxacin or sparfloxacin is recommended. Alternative treatment strategies for these patients include amoxicillinclavulanate or a second-generation cephalosporin (cefuroxime, cefpodoxime, or cefprozil), usually with the addition of a macrolide. For patients who are older than 60 years of age or who have comorbid illness, broader-spectrum antibiotics are recommended. For patients with suspected aspiration in an outpatient setting, amoxicillin-clavulanate, clindamycin, or a newer quinolone with activity against anaerobic oropharyngeal bacteria, such as clinafloxacin or moxifloxacin, is recommended. Evaluate residents of nursing homes who have pneumonia with the same prediction rules for hospitalization as patients with CAP. For patients who do not require hospitalization, a newer quinolone (levofloxacin or sparfloxacin) or amoxicillin-clavulanate with or without a macrolide is recommended. An alternative choice would be a second-generation cephalosporin with or without a macrolide. Patients with CAP who require hospitalization can be subdivided into those who can be managed on a general medical ward and those who require cardioventilatory support in an ICU. For the former, the focus of treatment is on several pathogens including S. pneumoniae (with the potential to be bacteremic), H. influenzae, enteric gram-negative bacilli, and severe infection by Legionella or Chlamydia species. Recommendations for the treatment of patients on a general medical ward include a respiratory quinolone (levofloxacin, sparfloxacin) or a second-generation (cefuroxime) or thirdgeneration (cefotaxime, ceftriaxone, ceftazidime, or cefepime) cephalosporin plus a macrolide. If aspiration is suspected, consider a respiratory quinolone with activity against anaerobes, such as clinafloxacin or moxifloxacin. For patients requiring ICU support, treatment is directed against the more resistant gram-negative bacilli, including P. aeruginosa, and the multiresistant gram-negative bacilli (which may be acquired nosocomially after admission to the ICU). For these patients, dual therapy with a respiratory quinolone plus either a β-lactamase (cefotaxime, ceftriaxone, ceftazidime, piperacillin-tazobactam, carbapenem, or aztreonam) or an aminoglycoside (gentamicin, tobramycin, or amikacin) is recommended. Alternatively, triple therapy with a βlactamase plus an aminoglycoside and a macrolide can be considered. Once the causative agent has been identified, the initial (empiric) therapy can be narrowed and directed at the specific pathogens. Special Considerations. Treatment with β-lactamase antibiotics such as penicillins and cephalosporins is effective for infections caused by sensitive pyogenic organisms such as S. pneumoniae, but these agents are not effective against organisms such as M. pneumoniae, C. pneumoniae, and Legionella species. First-generation macrolides such as erythromycin are effective against these three organisms as well as S. pneumoniae but not against H. influenzae, and they are often poorly tolerated because of gastrointestinal side effects. In outpatients in whom these organisms are a possibility (e.g., smokers), monotherapy with a second-generation macrolide,

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 486

1/21/2008 11:36:37 AM

Chapter 42 Bacterial Infections of the Lung

487

TABLE 42-4 Empiric Selection of Antimicrobial Agents for Adults With Community-Acquired Pneumonia Medications Patient Description

First Choice

Second Choice

Macrolide (erythromycin, clarithromycin, or azithromycin)

Doxycycline

Same as for outpatient without modifying factors Respiratory quinolone (levofloxacin, sparfloxacin) Amoxicillin/clavulanate or clindamycin

Same as for outpatient without modifying factors Amoxicillin/clavulanate ± macrolide or secondgeneration cephalosporin ± macrolide Respiratory quinolone with enhanced activity against anaerobes (clinafloxacin or moxifloxacin)

In hospital

Respiratory quinolone (levofloxacin, sparfloxacin) or amoxicillin/clavulanate ± macrolide Same as for other hospitalized patients

Second-generation cephalosporin plus macrolide Same as for other hospitalized patients

Hospitalized Patients On medical ward

Respiratory quinolone (levofloxacin, sparfloxacin)

Dual therapy with second- or third-generation cephalosporin plus macrolide

Dual therapy with respiratory quinolone (levofloxacin), plus β-lactamase (cefotaxime, ceftriaxone, ceftazidime, piperacillin-tazobactam, imipenem, meropenem, aztreonam) or dual therapy of respiratory quinolone + aminoglycoside (gentamicin, tobramycin, amikacin)

Triple therapy with β-lactamase plus aminoglycoside plus macrolide

Outpatients Without modifying factors With modifying factors With COPD but no recent antibiotics or steroids With COPD and recent antibiotics or oral steroids With suspected aspiration

Nursing Home Residents Residing in nursing home

In intensive care unit

COPD, chronic obstructive pulmonary disease.

such as clarithromycin or azithromycin, or a quinolone such as levofloxacin is possible. Interactions between macrolides and other drugs, including anticoagulants, theophylline, antiarrhythmics, and immunosuppressive agents (cyclosporin, tacrolimus), must be taken into consideration when prescribing these agents. Duration of Antibiotic Therapy. The optimal duration of parenteral therapy, the timing of conversion from IV to oral therapy, and the duration of oral therapy are important variables for which there are no firm answers.47 The presence of coexisting illness, the severity of the pneumonia, the nature of the infecting organism, the subsequent hospital course, the presence of bacteremia, and the presence of complications are all factors that need to be considered in making decisions about the route and duration of antibiotic therapy. In general, treat bacterial infections such as S. pneumoniae and H. influenzae for 7 to 10 days. Treat infection with M. pneumoniae or C. pneumoniae for 10 to 14 days. The duration of treatment of infection due to Legionella species is 14 days in immunocompetent patients and up to 21 days in immunocompromised patients. Shorter courses of therapy for pneumonia may be possible in certain cases. Newer macrolides such as azithromycin have a much longer serum half-life (11-14 hours) and tissue halflife than most other antibiotics, which allows shortening of treatment duration (equivalent to the area under the curve). A cautionary note must be added, however: at the doses currently approved, azithromycin does not achieve high serum levels and is not used in cases in which bacteremia is known

or suspected. The optimal duration of antibiotic therapy is uncertain, and additional studies are needed to address this important issue. Make the decision regarding timing of the switch from parenteral to oral therapy based on considerations concerning both the patient and the pharmacologic characteristics of the antibiotic. The patient must be able to take medication orally (i.e., must have an adequate level of consciousness or a feeding tube) and must have a functioning gastrointestinal tract. With respect to the antibiotic, the primary issue is whether oral administration is able to achieve adequate serum and tissue levels. For certain antibiotics, including chloramphenicol, trimethoprim-sulfamethoxazole, doxycycline, and fluoroquinolones such as ciprofloxacin, levofloxacin, and gatifloxacin, oral administration achieves levels comparable to those reached by means of the IV route.48 With other agents, in which bioavailability by means of the oral route is not as good, the switch from parenteral to oral therapy should occur after the patient has been stabilized and is improving on parenteral therapy (i.e., higher tissue levels are no longer required). Practically, 3 to 6 days of parenteral therapy is required for the clinical condition of the patient to stabilize and fever to subside.47,49 Assessment of the Initial Response to Therapy. Most patients with CAP respond to initial empiric therapy in 48 to 72 hours with resolution of fever and normalization of the white blood cell count. Abnormalities on physical examination (e.g., crackles) may persist for longer than 1 week in 40% of patients.

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 487

1/21/2008 11:36:38 AM

488

Section 3 Lung

Radiographic Clearance of Pneumonia. A difficult but not uncommon problem in pneumonia patients is slow recovery and delayed resolution of radiographically observable infiltrates. Factors that negatively affect pneumonia resolution include advanced age and the presence of serious comorbid illnesses such as diabetes mellitus, renal disease, or COPD. In addition, certain properties of the infecting agent (e.g., intrinsic virulence) may interact with host factors and advanced age to delay resolution of pneumonia. For example, 50% of patients with pneumococcal pneumonia have radiographic clearing at 5 weeks, and the majority clear within 2 to 3 months. Recent data demonstrate that radiographic resolution is most strongly influenced by the number of lobes involved and the age of the patient. Radiographic clearance decreases by 20% per decade after 20 years of age, and patients with multilobar infiltrates take longer to clear than those with unilobar disease. If the patient has no identifiable factors associated with prolonged resolution of pneumonia or the repeat chest radiograph at 1 month shows no appreciable change, further diagnostic testing is indicated. Failure to Respond Adequately to Initial Therapy. Several questions arise when a patient does not respond as expected to the initial therapy. Is the antibiotic therapy appropriate and adequate? Is the infection caused by an unusual organism? A careful re-evaluation of the history, including country of origin, travel, and unusual exposures, is important under these circumstances. Organisms to be considered in patients with persistent clinical and radiographic features include viral infections; M. tuberculosis; fungi such as Histoplasma species, Blastomyces species, and Coccidioides species; and parasites such as Pneumocystis jiroveci (Pneumocystis carinii [PCP]) and Paragonimus species. Is it an infective process or something unrelated, such as CHF, pulmonary embolus, pulmonary hemorrhage, eosinophilic pneumonia, or vasculitis? Has a nosocomial infection such as antibiotic-induced colitis developed, or is there a complication of the pneumonia? Complications of Pneumonia. Complications of pneumonia include empyema, lung abscess, bacteremia or septicemia, and extrapulmonary sites of infection, including otitis media, sinusitis, endocarditis, pericarditis, brain abscess, and meningitis. Consider these complications in patients who respond inadequately to antibiotics. The early identification and treatment of parapneumonic effusions is essential to prevent the need for operative drainage procedures.

ACUTE BRONCHITIS (TRACHEOBRONCHITIS) Acute inflammation involving the mucosa of the trachea and bronchi is extremely common and has diverse causes. Irritants such as constituents of the smoke of tobacco and cannabis, gases such as ammonia, trace elements such as vanadium and cadmium, air pollutants such as sulfur dioxide and nitrogen dioxide, and industrial byproducts, including cotton and bagasse, can induce acute inflammation of the trachea and bronchi. The most common cause of acute tracheobronchitis is infection due to viruses, Mycoplasma species, bacteria, or parasites. Viruses known to be associated with acute tracheobronchitis include respiratory syncytial viruses (RSVs); rhinoviruses; echoviruses; parainfluenza viruses types 1, 2, and

3; coxsackieviruses; influenza viruses; adenoviruses; herpesviruses; and coronaviruses. The syndromes caused by the viruses are virtually inseparable, although some reasonable estimations of the likelihood of a particular agent can be made on the basis of the season of the year and the age of the patient. With respect to bacterial bronchitis, the most common organisms are H. influenzae, S. pneumoniae, and M. catarrhalis. Other, less common causes include Bordetella pertussis, which is surprisingly common, even in adults; Legionella species; M. pneumoniae; and C. pneumoniae. Less common, but especially likely in patients who have resided or vacationed in tropical climates, are parasites such as those of the Strongyloides and Ascaris species as well as Syngamus laryngeus, which can be associated with acute tracheobronchitis. The clinical syndrome of acute tracheobronchitis is similar to that of pneumonia except that the chest radiograph is negative and there is production of mucoid or purulent sputum, frequently in association with a low-grade fever. Other symptoms may include small amounts of hemoptysis and substernal pain that is often of a burning quality and accentuated on inspiration. Dyspnea usually is not a significant component of acute tracheobronchitis except in the presence of underlying disease such as COPD (see later discussion), in patients with asthma, or in very young children. In particular, tracheobronchitis may precipitate an asthma attack, which must be treated specifically. Some patients are left with a nonspecific bronchial hyperreactivity syndrome characterized by a persistent nonproductive cough. A Gram stain of the sputum usually shows a predominance of mononuclear cells in viral tracheobronchitis (except in adenoviruses), whereas in infections by bacteria and Mycoplasma species, there is a striking predominance of neutrophilic polymorphonuclear leukocytes. The treatment of acute tracheobronchitis depends on the clinical setting in which it is observed, the appearance of the sputum (including the Gram stain), and findings on physical examination of the chest. In young, previously well patients, most episodes of acute bronchitis are caused by respiratory viruses. In smokers, H. influenzae is more common; in elderly patients with comorbidities, consider bacterial infection. Significant production of purulent sputum that has a neutrophilic predominance on Gram stain suggests a bacterial source, and antibiotic administration is appropriate. Reasonable antibiotics include amoxicillin with clavulanic acid, doxycycline, trimethoprim, sulfamethoxazole, a secondgeneration macrolide such as clarithromycin or azithromycin, or, if resistant organisms are suspected, a quinolone such as ciprofloxacin. The use of humidified air and the maintenance of oral hydration are useful; in the presence of wheezing, bronchodilator therapy is appropriate. In general, acute tracheobronchitis is not a life-threatening disease except in the presence of underlying disorders such as asthma or COPD or in young children, in whom it may precipitate respiratory failure. In cases in which acute tracheobronchitis is recurrent, consider the possibilities of a tracheoesophageal fistula in infants or gastroesophageal reflux with aspiration in adults and conduct appropriate diagnostic evaluations.

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 488

1/21/2008 11:36:38 AM

Chapter 42 Bacterial Infections of the Lung

EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE COPD refers to a group of disorders that most commonly coexist, including chronic bronchitis, emphysema, and smallairways disease.50-52 These disorders are characterized by limitation of airflow (obstruction) that is due in large part to smoking-related damage to the airways and lung parenchyma. As opposed to asthma, in which airway obstruction is mainly reversible, in COPD the obstruction is largely irreversible. Familiarity with these entities and their treatment is important for the thoracic surgeon because the presence of COPD can complicate the preoperative and postoperative course of many thoracic surgical patients. Acute exacerbations of COPD, also called acute exacerbations of chronic bronchitis, are common, especially during the winter months. The symptoms of an acute exacerbation include an increase in dyspnea, wheeze, cough, and sputum production, many of which may be present but to a lesser extent in their baseline state. There are many potential causes for an exacerbation of COPD, including viral or bacterial infection, cigarette smoke, environmental (air) pollution, allergies, drug toxicity, and coexisting medical illness such as CHF or pulmonary embolism. Indeed, several of these predisposing factors may coexist. The most appropriate therapy for such exacerbations, especially the benefits of antibiotic therapy, has been the subject of intense debate for more than 30 years.53 Among the problems are the heterogeneous nature of the patients, small sample sizes, and the lack of appropriate controls for many studies. Most current guidelines recommend a multifaceted approach to therapy that includes the use of bronchodilators, systemic glucocorticoids, antibiotics, measures to enhance sputum production, and attention to coexisting medical conditions. Inhaled bronchodilators are an important component of the initial therapy. Current guidelines recommend the use of inhaled ipratropium bromide (Atrovent), in part because it is an effective bronchodilator and also because of its relative lack of toxicity. Inhaled β2-agonists such as salbutamol, terbutaline, and metaproterenol are also effective bronchodilators but carry risks for toxicity, including tachycardia, cardiac arrhythmias, and hypokalemia. Systemic glucocorticoids are an important component of therapy for an acute exacerbation of COPD. Evidence has suggested that a 3-day course of IV methylprednisolone (Solu-Medrol, 125 mg IV four times daily), followed by completion of a 2-week course of tapering prednisone, is of maximal benefit (Niewoehner et al, 1999).54 However, the use of parenteral glucocorticoids is associated with increased complications, including gastrointestinal bleeding. Despite many studies, the role of bacterial infection and antimicrobial therapy in the treatment of acute exacerbations of COPD remains controversial.53,55 Up to one half of exacerbations are either viral or noninfectious in nature. However, current recommendations are to treat severe exacerbations with antibiotics. The major bacterial pathogens isolated during exacerbations of COPD are H. influenzae, M. catarrhalis, and S. pneumoniae. There is no single antibiotic that is

489

clearly superior in the treatment of the exacerbations. Reasonable choices include amoxicillin-clavulanate, doxycycline, trimethoprim-sulfamethoxazole, a second-generation cephalosporin such as cefuroxime axetil, ciprofloxacin, or azithromycin. Patients who have recently received antibiotic therapy or systemic corticosteroids have a higher incidence of resistant gram-negative bacilli; direct antibiotic therapy against these organisms. Perhaps the most important factor in treating these patients is attention to the details of the multiple medical problems that may contribute to or complicate the exacerbation.

HOSPITAL-ACQUIRED PNEUMONIA HAP is the second most common hospital-acquired infection after nosocomial urinary tract infection, and it has the highest fatality rate of all nosocomial infections.56 Crude mortality rates of up to 70% have been reported, and attributable mortality rates have been reported to be in the 33% to 50% range (Kollef, 1999).57 Mortality increases if mechanical ventilation is required. The pathogenesis is related to the microaspiration or silent aspiration of oropharyngeal flora. Normal individuals aspirate small amounts of oropharyngeal secretions during sleep. There are no untoward consequences because the flora in healthy individuals is composed of relatively benign commensal organisms (Kollef, 1999).57 However, with illness or trauma requiring hospitalization, oropharyngeal flora shifts to include gram-negative bacilli due to the relative loss of oropharyngeal cell surface fibronectin (Kollef, 1999).57 Although gram-negative organisms may predominate, in up to 50% of cases more than one pathogen is discovered, and in approximately half of cases no etiologic agent can be isolated (Kollef, 1999).57 Infections caused by grampositive cocci are more common in ICU patients and in those with diabetes mellitus or head trauma.58 Methicillin-resistant S. aureus (MRSA) has emerged as a prevalent pathogen, and the frequency of multiple-drug–resistant (MDR) organisms is increasing.59,60 Many factors can predispose patients to aspiration, but in many cases of nosocomial pneumonia, particularly in the postoperative patient, no gross aspiration episode is identified. Microaspiration is an important contributor to, and in the vulnerable host with impaired host defenses will lead to, the development of pneumonia. Surgery may be associated with impaired host cell-mediated immunity, and endotracheal intubation results in increased mucus production, impaired mucociliary clearance, and loss of the normal protective barrier of the glottis. In addition, the accumulation of subglottic secretions in the ventilated patient represents an important reservoir for gram-negative bacteria and source for ventilator-associated pneumonia (VAP).61 Painful incisions may result in decreased tidal volumes, atelectasis, decreased functional residual capacity, and impaired ability to cough and clear secretions.62,63 In general, risk factors for the development of HAP and VAP have been divided into modifiable and nonmodifiable conditions. Patient- and treatment-related factors (e.g., male gender, multiple-organ dysfunction, underlying pulmonary disease, intubation) are distinguished from those modifiable

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 489

1/21/2008 11:36:38 AM

490

Section 3 Lung

factors that need to be targeted to improve prophylaxis and management. Effective strategies include alcohol-based hand disinfection, strict infection control, monitoring and early removal of invasive devices, programs to reduce antimicrobial prescription, and active microbiologic surveillance with data on local MDR pathogens (Tablan et al, 2004).64 The issue of emerging MDR organisms has emphasized the need for rigorous local surveillance of endemic flora and sensitivity patterns and has also underscored the need for a more conservative approach toward empiric prescription of broad-spectrum antimicrobials. The approach to treatment of HAP is discussed later as part of the discussion on the recent American Thoracic Society Guidelines for Management of Adults with Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia (American Thoracic Society, 2005).65

Ventilator-Associated Pneumonia VAP refers to nosocomial bacterial pneumonia that has developed in patients receiving mechanical ventilation.66 VAP that occurs in the initial 48 to 72 hours after tracheal intubation usually results from aspiration complicating the intubation process and is caused by antibiotic-sensitive bacteria (S. aureus, H. influenzae, and S. pneumoniae). VAP occurring after this period (late-onset VAP) is commonly caused by antibiotic-resistant organisms, including oxacillin-resistant S. aureus, P. aeruginosa, Acinetobacter species, and Enterobacter species. The risk of VAP increases with the duration of intubation and may reach 68% in those ventilated for more than 30 days.67 The main risk factors for VAP are the need for reintubation and gastric aspiration.68 Other risk factors include old age, thoracic or upper abdominal surgery, malnutrition, obesity, chronic lung disease, and concurrent antibiotic use.69,70

Diagnosis and Treatment The role of fiberoptic bronchoscopy employing either the PSB or BAL to retrieve lower respiratory tract secretions in the initial evaluation of suspected VAP remains controversial.71,72 PSB is highly specific but has a high false-negative rate.73,74 BAL is highly sensitive but not specific.75,76 Its advocates argue that many noninfectious processes can produce a clinical picture indistinguishable from VAP, and knowledge of a specific cause of a VAP allows the physician to narrow the spectrum of antibiotic coverage, thus reducing the selection pressure for antimicrobial resistance and the cost of therapy. Others argue that, without knowledge of who should be tested, the frequency of testing, or the accuracy of the results, this procedure needs to be abandoned. To date, no studies have demonstrated that these interventions have altered patient outcome. BAL or PSB may be useful in a patient with diffuse infiltrates if pneumonia is suspected, if a patient fails to respond to clinically appropriate treatment, or if a patient develops signs of new infection while receiving therapy. The value of blind sampling techniques and quantitative culture of tracheal aspirates is uncertain because research in both areas suffers from poor study design and inconclusive results.56

Treatment of VAP consists of general supportive care and the administration of broad-spectrum antibiotics. Recent recommendations are outlined in the next section.

Current Guidelines for the Management of HospitalAcquired and Ventilator-Associated Pneumonia Several important recommendations and treatment principles are outlined in these new, evidence-based guidelines (American Thoracic Society, 2005).65 Highlights include the following: 1. Prescribe early, appropriate, broad-spectrum antibiotic therapy that includes agents from a different antibiotic class than what the patient received previously. 2. Consider de-escalation or discontinuation of antibiotics at 48 to 72 hours after initial prescription, based on the results of lower respiratory tract cultures and the patient’s clinical status. 3. A shorter duration of antibiotic therapy (7-8 days) is recommended for uncomplicated HAP and VAP in patients who initially received appropriate antimicrobial therapy and had a good clinical response. These guidelines highlight risk factors for MDR pathogens in HAP and VAP and use the presence or absence of these factors to help risk-stratify patients and guide initial empiric antimicrobial therapy. These risk factors include any antimicrobial therapy in the preceding 90 days, current hospitalization for 5 or more days, a high frequency of antibiotic resistance in the community or hospital unit, risk factors for health care–associated pneumonia (formerly called nursinghome pneumonia), and immunosuppressive disease or therapy. Initial treatment for HAP and VAP in a patient with no known risk factors for MDR pathogens includes ceftriaxone or levofloxacin/moxifloxacin/ciprofloxacin or ampicillin and sulbactam or ertapenem. The initial recommended therapy for those patients at risk for MDR organisms such as P. aeruginosa and K. pneumoniae (extended spectrum β-lactamase [ESBL]), Acinetobacter species, or MRSA is a combination antibiotic regimen. This regimen includes an antipseudomonal cephalosporin (cefepime, ceftriaxone) or antipseudomonal carbapenems (imipenem or meropenem) or β-lactam/βlactamase inhibitor (piperacillin-tazobactam), plus an antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) or aminoglycoside (amikacin, gentamicin, or tobramycin), plus linezolid or vancomycin if there is a high suspicion for MRSA. This initial antimicrobial spectrum is somewhat staggering, but the guidelines recommend discontinuation of these medications at 48 to 72 hours if lower respiratory cultures have been negative and the patient has had clinical improvement over this time interval.

PNEUMONIA IN THE IMMUNOCOMPROMISED HOST Approach to the Diagnosis of Pulmonary Infection in the Recipient of a Solid-Organ Transplant Susceptibility to different infections occurs at different time points in the clinical course of solid organ recipients after tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 490

1/21/2008 11:36:38 AM

Chapter 42 Bacterial Infections of the Lung

transplantation. The post-transplant course for all organ transplant recipients can be divided into three time periods: the first month after transplantation, the period 1 to 6 months after transplant, and the late period, more than 6 months after transplant. When considered in conjunction with various radiographic patterns, a valuable differential diagnosis can be associated with each time point (Table 42-5) (Fishman and Rubin, 1998).77,78 Two major causes of pneumonia in the first month after transplantation are the recurrence of an incompletely treated pneumonia that was present before transplantation and infection due to aspiration of nosocomial flora as a result of postoperative vomiting.77 Extensive lung injury and prolonged intubation in the lung transplant recipient lead to an early increased risk of postoperative bacterial pneumonia. Despite this being the period of highest daily dose of immunosuppression, opportunistic infections are not prominent in the first month. This underscores the importance of sustained exposure to immunosuppressive therapy as the major determinant of susceptibility to opportunistic pathogens.78 Cytomegalovirus (CMV) and other immunomodulating viruses are the predominant opportunistic infections that occur between 1 and 6 months after transplantation. CMV exerts its effects by directly causing pneumonia; it also can contribute to graft-versus-host disease (GVHD), leading to an increased need for immunosuppression and an escalation in the risk for opportunistic infection, and it can increase the likelihood of pulmonary infections, including Aspergillus species, PCP, and Nocardia asteroides. The risk of active disease is greatest in the seronegative recipient of a solid organ from a seropositive donor. Also, in the absence of spe-

TABLE 42-5 Differential Diagnosis of Fever and Pulmonary Infiltrates in Organ Transplant Recipients Rate of Progression of Illness Radiographic Pattern Consolidation

Acute (<24 hr) Pulmonary edema Pulmonary hemorrhage Bacterial pneumonia Thromboembolism

Subacute-Chronic (day-wk) Fungal Nocardial Tuberculous Viral PCP Drug-related

Peribronchovascular Pulmonary edema

Viral PCP Fungal Nocardial Tuberculous Tumor (posttransplantation lymphoproliferative disorder)

Nodular infiltrate

Fungal Nocardial Tuberculous PCP

Bacterial pneumonia Pulmonary edema

PCP, Pneumocystis jiroveci (Pneumocystis carinii) pneumonia.

491

cific prophylaxis, pulmonary infections caused by Aspergillus and Nocardia species and PCP are common. Beyond 6 months after transplantation, patients with good graft function will have more modest immunosuppression and are susceptible to community-acquired RSV and influenza as well as pneumococcal pneumonia. Patients with poorer graft function and those who require more aggressive immunosuppression are at high risk for infection with Cryptococcus neoformans, PCP, N. asteroides, and Aspergillus species. The principles for diagnosis in organ transplant recipients are very similar to those for neutropenic and bone marrow transplant patients. The cornerstone of diagnosis is BAL, with or without transbronchial biopsy. Several centers strongly advocate the routine inclusion of transbronchial biopsies in patients with diffuse pulmonary involvement because of the increased diagnostic yield in PCP and cryptococcal infection.79 Thoracoscopic biopsy has come into wider use in patients with peripheral or pleural-based processes because it provides a better specimen for culture and pathologic assessment and has less associated morbidity and mortality than open lung biopsy.78 Percutaneous needle biopsy is the procedure of choice for invasive diagnosis of focal pulmonary processes; reserve open lung biopsy for patients with rapid clinical deterioration and those who have central radiographic findings not amenable to thoracoscopic biopsy.78

ASPIRATION PNEUMONIA The term aspiration may refer to one of three aspiration syndromes: gastric acid aspiration, bacterial pneumonia secondary to aspiration of oropharyngeal secretions, or aspiration of a foreign body causing airway obstruction. This section discusses only the first two types.

Acid Aspiration Syndrome Acute lung injury secondary to gastric acid aspiration was first described by Mendelsohn in association with parturition.80 The incidence of aspiration associated with elective anesthesia is very low, 0.00002%81 to 0.0003%,82 but increases for emergency procedures to 0.001%. Aspiration occurred in 3.5% of patients intubated in the emergency room but sequelae were rare.83 In the pediatric population, the incidence of aspiration is 0.10% for elective general surgery.84 However, in a series of surgical patients, the prevalence of aspiration pneumonia as reported on discharge summary was 0.8% (Kozlow et al, 2003).85 This suggests that, although the incidence of aspiration on induction of anesthesia is rare, aspiration pneumonia in surgical patients is a more common occurrence at intubation or later in the perioperative period. Historically, gastric acid aspiration was associated with a 50% to 60% mortality rate. The severity of the injury is related to the pH and amount of gastric acid aspirated.86-90 Aspiration of volumes greater than 50 mL with a pH of less than 2.5 results in a significant and potentially life-threatening lung injury. The presence of particulate matter in addition to acid is especially damaging.91 Neutralization of acid or reduction in acid production by the use of sodium citrate, histamine 2 (H2) antagonists, or tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 491

1/21/2008 11:36:38 AM

492

Section 3 Lung

proton pump inhibitors has become a standard part of the anesthetic management in high-risk patients. This change may be responsible for the decreased morbidity and mortality (0%-5%) currently reported in association with aspiration on intubation.89,90

Diagnosis If aspiration is unwitnessed, the diagnosis may be difficult to prove. There are four situations in which aspiration is more likely to occur: loss of airway-protective reflexes, as in general anesthesia; structural and functional abnormalities of the esophagus and pharynx; gastroesophageal reflux; and postoperative acute gastric dilation. A patient with minimal symptoms and no sequelae may go undiagnosed; more commonly, patients present with respiratory distress and hypoxia. Possible chest radiographic abnormalities include localized air space disease, either in a single segment (most commonly the superior segment of the right lower lobe) or in multiple dependent areas of the lung, or diffuse bilateral infiltrates. Bronchoscopy may reveal particulate debris, gastric fluid, or bile. If there are no obvious findings, BAL may suggest the diagnosis if lipid-laden macrophages are detected.

Pathophysiology Aspiration of acid results in a biphasic pattern of injury. The initial phase is the result of direct tissue injury by acid. The second phase results from neutrophil activation and a systemic inflammatory response.92 A third phase resulting from secondary bacterial infection may cause further injury. Acid aspiration causes immediate damage to the ciliated respiratory epithelium and the cells of the alveolar lining, resulting in a significant loss of pulmonary defenses. A volume of 25 to 50 mL may be dispersed throughout the lungs in less than 1 minute.93,94 Acid alone destroys preformed surfactant and damages the alveolar lining cells, resulting in loss of surfactant production. Furthermore, the surfactant that remains is functionally abnormal.95 Destruction of the alveolar capillary barrier and basement membrane, mediated by reactive oxygen species and elastase, results in increased capillary permeability.96 The protein-rich alveolar fluid that results from the increased capillary permeability inactivates any remaining surfactant but also neutralizes any gastric acid. A cascade of neutrophil-mediated injury may then occur.97 Neutrophil migration mediated by intercellular adhesion molecule-1 (ICAM-1)98 is followed by thromboxane-dependent sequestration of neutrophils and subsequent activation. Important mediators include monocyte chemoattractant protein (MCP), nitric oxide, nuclear factor κB (NF-κB), phospholipase A2, tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), IL8, IL-10, and complement. The resulting local and systemic inflammatory response may cause diffuse lung injury, acute respiratory distress syndrome (ARDS), or multiorgan failure.99-107 The patient may die from refractory respiratory failure within days, or the chemical pneumonitis may resolve quickly without significant sequelae. However, progression to ARDS (Fig. 42-9) and multiorgan failure may occur. Acid aspiration leads to increased bacterial adherence to tracheal epithelium,

FIGURE 42-9 Chest radiograph showing adult respiratory distress syndrome caused by massive gastric acid aspiration. The patient is intubated and has a balloon flotation catheter in place.

which may facilitate the development of a secondary bacterial pneumonia that may further compromise the damaged lungs.108,109

Treatment Once acid aspiration has occurred, treatment is supportive. Prophylactic antibiotics or steroids are not indicated.110-115 Perform bronchoscopy, particularly in the setting of a witnessed aspiration, to suction out the airways and remove particulate debris. Small-volume aspiration can cause asthmalike symptoms that respond to aerosolized bronchodilators. Although adrenergic bronchodilators are most commonly used, anticholinergic bronchodilators may be useful because evidence suggests that bronchospasm is vagally mediated.116 Adequate oxygenation must be maintained, but if mechanical ventilation is required, care must be taken to avoid further lung injury by avoiding hyperoxia.117,118 Animal studies suggest that even so-called safe levels of oxygen may be harmful because acid aspiration may increase the sensitivity of the lungs to oxygen.119 Early prone positioning in patients requiring mechanical ventilation may be beneficial.120 Experimental studies suggest that perfluorocarbons administered systemically or intratracheally, with or without surfactant, or intratracheal recombinant surfactant protein alone reduces lung injury in acid aspiration syndrome.121-125 Other potential therapeutic options in the future may include

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 492

1/21/2008 11:36:38 AM

Chapter 42 Bacterial Infections of the Lung

cytokine blockade, nitric oxide synthase inhibitor, or pentoxifylline.126-130 Vigilance in detecting and aggressively treating any secondary bacterial pneumonias is essential. The ultimate choice of antimicrobial treatment, if infection supervenes, is determined by the clinical setting in which the aspiration occurred.

Bacterial Aspiration Pneumonia Even normal individuals aspirate small volumes during sleep17,131; in order for pneumonia to occur, there must be a breakdown in host defenses or the volume of bacterial inoculum of the aspiration must be large or particularly virulent. Most commonly, a depressed level of consciousness leads to loss of protective airway reflexes and allows a more significant volume of aspiration to occur. This may occur as a result of general anesthesia, sedatives or analgesics, drug overdose, trauma to the central nervous system, infection, or stroke. Structural or functional abnormalities of the larynx, pharynx, or esophagus predispose to aspiration. Recurrent laryngeal nerve paralysis or neuromuscular disease affecting the pharynx impairs the ability to protect the airway; esophageal disease such as achalasia, Zenker’s diverticulum, malignant obstruction, or reflux may overwhelm intact defenses with large quantities of aspirated material.132 Injury to the tracheobronchial tree and lung resulting from acid aspiration impairs host defenses and predisposes the patient to secondary bacterial pneumonia. Smoke or noxious gas inhalation injuries can cause a similar breakdown in host defenses. Aspiration pneumonia is a significant cause of morbidity and mortality in intubated patients and in patients recovering from stroke. Much effort has been directed toward preventing aspiration pneumonia in intubated patients. Placing mechanically ventilated patients in a semirecumbent position significantly reduces the risk of aspiration pneumonia compared with supine positioning,133 but subglottic drainage,134 nasojejunal enteral feeding,135 prokinetics,136 acid suppression, and antibiotic strategies have not proved to be efficacious. Monitoring of gastric residual volumes has not proved to be useful because aspiration events occur even with gastric residuals as low as 30 mL.137 There appears to be no difference between a surgically placed feeding gastrostomy versus a jejunostomy; or between nasojejunal/nasogastric versus surgical or percutaneous feeding tubes.138-140 However, oral decontamination and attention to dental hygiene appear to be beneficial, probably because of the decrease in bacterial load.141,142 There is some suggestion that treatment with angiotensinconverting enzyme (ACE) inhibitors may reduce the risk of aspiration by decreasing the catabolism of substance P, which in turn may improve cough and swallowing reflexes, because both of these reflexes are mediated through substance P in the vagal and glossopharyngeal nerves.143

Diagnosis and Treatment The diagnosis of aspiration pneumonia is based on clinical suspicion in the appropriate clinical setting, associated with the typical radiologic findings of air-space disease in dependent areas of the lung, most commonly the superior

493

segment of the right lower lobe and the posterior segment of the right upper lobe, particularly if more than one area is involved. In a setting in which aspiration due to swallowing dysfunction is suspected, video fluoroscopy is the gold standard to assess function and detect silent aspiration. Although documentation of aspiration does not prove the cause of pneumonia, increased severity of aspiration on videofluoroscopy has been found to be associated with increased risk of pneumonia.144,145 Pulse oximetry during swallowing assessment detects aspiration in dysphagic stroke patients with a reliability of 81.5%.146,147 The addition of methylene blue to tube feedings is not reliable in detecting aspiration, and testing of tracheal aspirates with glucose oxidase strips has had mixed success.148,149 The use of a lipid-laden macrophage index greater than 100 on BAL for diagnosis of aspiration has a sensitivity of 94%, a negative predictive value of 98%, a specificity of 89%, and a positive predictive value of 71%.150 The detection of pepsin in tracheal secretions or on BAL may also be useful in the diagnosis of aspiration.151 In the setting of bacterial aspiration pneumonia, as opposed to gastric acid aspiration, treatment with antibiotics is appropriate. In a nonhospitalized population, coverage against gram-positive organisms and oral anaerobes is required. The choice of antibiotics may include penicillin or clindamycin.152-154 Clindamycin monotherapy is effective, is less expensive, and may be associated with lower rates of posttreatment MRSA infection.155 Ticarcillin-clavulanate has also been found to be effective in treating penicillin-resistant anaerobes; ceftriaxone and metronidazole are not as effective. In hospitalized (including institutionalized) patients, antibiotics must also be effective against gram-negative organisms (see Table 42-4). Gram-negative enteric bacilli were the most common isolates (49%) in institutionalized elderly patients, followed by anaerobes (16%) and S. aureus (12%) (El-Solh et al, 2003; Kadowaki et al, 2005).156,157

LUNG ABSCESS Definition A lung abscess is a localized collection of pus contained in a cavity that is formed by the destruction of pulmonary parenchyma. This definition excludes infected bullae and cysts in which infection develops within a preexisting space. Nonetheless, the diagnosis and management of these conditions have some features in common with those for a true lung abscess. Although lung abscess is most often solitary, multiple abscesses may occur secondary to a primary bacteremia or in immunosuppressed patients. An abscess that is present for more than 6 weeks is considered chronic. Lung abscess may be further classified, based on etiology, as primary or secondary. Primary lung abscesses occur as a result of necrotizing pulmonary infections, including those in immunosuppressed hosts, or because of aspiration of either gastrointestinal contents or oropharyngeal secretions (Table 42-6). Secondary lung abscesses occur as a complication of bacteremia or bronchial obstruction, as an extension of adjacent suppurative infections, or from infection of previously destroyed or damaged lung parenchyma.

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 493

1/21/2008 11:36:39 AM

494

Section 3 Lung

TABLE 42-6 Etiologic Classification of Lung Abscesses Primary Aspiration Impaired level of consciousness (e.g., general anesthesia, drug or alcohol, stroke) Poor oral hygiene (gingivodental sepsis) Esophageal disease (achalasia, Zenker’s diverticulum, gastroesophageal reflux disease) Necrotizing pneumonia Virulent organisms (Staphylococcus aureus, Klebsiella pneumoniae, Friedländer’s bacillus) Fungi Tuberculosis Immunodeficiency Immunosuppression for organ transplantation Steroid therapy Cancer chemotherapy Diabetes Malnutrition Secondary Bronchial obstruction Cavitating lesions (neoplasm, infarct) Direct extension (amebiasis, subphrenic abscess) Hematogenous Congenital or Acquired Cysts Hydatid, tuberculosis, bronchogenic cyst, bullae

Historical Note The monograph on lung abscess written by Brock and colleagues in 1942 described the clinical features of lung abscess and proposed that its pathogenesis is aspiration of infected oropharyngeal secretions.158 This theory was based on the observation that most abscesses occur in the posterior segment of the right upper lobe and the superior segment of the right lower lobe; these are the axillary segments, so called because of their proximity to the lateral chest wall. The orifices of these segments are directly in line with the upper respiratory tract when the patient is recumbent. Brock’s hypothesis was supported by the finding that 75% of all lung abscesses occur in these segments and in the superior segment of the left lower lobe.159,160 Hippocrates is credited with the first description of the treatment of a lung abscess by percutaneous drainage, an approach that is enjoying a resurgence in popularity. The importance of pleural symphysis before the performance of any drainage procedure became appreciated in the late 19th century. It was recognized that, in the absence of pleural symphysis, percutaneous drainage of a lung abscess might result in a pyopneumothorax, which was commonly fatal. In 1947, Monaldi reported on a two-stage procedure in which pleural symphysis was induced by performing a short rib resection and inserting a piece of gauze to act as an irritant; after 4 to 7 days, drainage could be safely accomplished as a second stage.161 Current techniques for percutaneous drainage employ the principle of pleural symphysis by using computed tomography (CT) scanning or ultrasound to minimize the amount of lung parenchyma traversed and to localize sites where pleural symphysis has most likely occurred.

After the development of antibiotics, the sulfonamides in 1938 and penicillin in 1941, the incidence of lung abscess diminished with effective therapy for primary pneumonias. Cancer chemotherapy, immunosuppression for transplantation or autoimmune diseases, and infections such as HIV162 have resulted in an increase in lung abscess due to unusual or opportunistic organisms.

Pathophysiology Aspiration of infected oropharyngeal secretions is the most common cause of primary lung abscess. Gingivodental sepsis is associated with an increased risk of pneumonia and abscess because it increases the bacterial load of the aspirated oropharyngeal secretions. The risk of aspiration is increased by conditions of impaired consciousness or suppressed cough reflex, including general anesthesia, IV sedation, ingestion of alcohol or other drugs, seizure, or coma resulting from any cause. Neurologic diseases acting centrally, such as a stroke, or locally, such as amyotrophic lateral sclerosis, may impair swallowing and increase the risk of aspiration. Esophageal diseases, including gastroesophageal reflux, diverticula (especially Zenker’s diverticulum), achalasia or other motility disorders, strictures, and esophageal cancer causing either obstruction or fistulization into the trachea are also associated with an increased risk of aspiration. Secondary lung abscess is most often caused by an obstructing bronchial carcinoma or, rarely, an aspirated foreign body or extrinsic compression of the bronchus by lymphadenopathy. Secondary infections of cavitating necrotic lung cancers or other cavitating lesions due to pulmonary infarction, tuberculosis, or other granulomatous diseases are also considered lung abscesses. Infected cysts or bullae are not true abscesses but manifest in a similar fashion. Lung abscesses may also occur secondary to extension of adjacent infection in the liver or subphrenic space penetrating across the diaphragm. Bacteremia causing multiple small lung abscesses may mimic metastases and are associated with infected indwelling vascular access catheters, IV drug use, or endocarditis.

Microbiology Bacteria isolated from lung abscesses reflect the underlying pathophysiology. In 40% of cases, necrotizing pneumonia caused by a virulent organism such as S. pyogenes, K. pneumoniae, S. aureus, Streptococcus viridans, S. pneumoniae, αor β-hemolytic streptococcus, or H. influenzae was the cause of lung abscess.163 However, in an immunosuppressed host, pneumonia and lung abscess may be also caused by opportunistic organisms such as Salmonella species, Legionella species, PCP, atypical mycobacteria, and fungi.164 In HAP, the responsible organisms are most commonly gram-negative bacteria (60%-70%), including K. pneumoniae, H. influenzae, and others such as Proteus species, P. aeruginosa, Escherichia coli, Enterobacter cloacae, and Eikenella corrodens.165 In lung abscess due to aspiration, mixed flora are often present, and anaerobes play an important role. Aerobic grampositive cocci and facultative gram-negative bacilli have been most commonly cultured, including S. aureus, S. pyogenes, K. pneumoniae, E. coli, and Pseudomonas species.165-167 However,

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 494

1/21/2008 11:36:39 AM

Chapter 42 Bacterial Infections of the Lung

with improved anaerobic culture and invasive sampling techniques, a predominance of anaerobic bacteria such as species of the Bacteroides, Peptococcus, Peptostreptococcus, Fusobacterium, Veillonella, Prevotella, and Clostridium genera have been reported in abscess aspirates.168 An average of 2.1 to 3.25 isolates per patient have been cultured from samples obtained by percutaneous aspiration of lung abscesses (Hammond et al, 1995),166-172 and 58% to 66% of isolates contain anaerobes.

Clinical Presentation The typical presentation may include cough, fever, chills, malaise, fatigue, weight loss, pleuritic chest pain, dyspnea and, less commonly, hemoptysis, but the onset may be insidious, and chronicity, weight loss, and malaise may predominate. Putrid sputum, although uncommon early in the course of the illness, occurs in 40% to 75% of patients once cavitation takes place (Wiedmann and Rice, 1995).173 Production of large quantities of foul sputum, once communication with the bronchial tree has occurred, may lead to infection of the noninvolved lung and respiratory failure. Hemoptysis may occur and varies from blood-streaked sputum to life-threatening hemorrhage. Sudden onset of septic shock and respiratory failure may result from rupture of the abscess into the pleural space and subsequent pyopneumothorax. The mortality rate in the preantibiotic era was 56% to 60%, but it has now decreased to 5% to 10% except in the presence of immunosuppression, where it is 9% to 28% (Wiedmann and Rice, 1995).159,163,173-178 Physical findings may be minimal, but most commonly they are consistent with those of pneumonia. In a chronic abscess, clubbing and cachexia may be the predominant findings. Obtain a careful history, focusing not just on the symptoms of the infection and its complications but also on the possible predisposing factors, and looking for causes of impaired consciousness, neurologic and esophageal conditions, and causes of bronchial obstruction.

Diagnosis The diagnosis is suspected based on the clinical presentation. The plain chest radiograph may demonstrate a cavitating lesion with an air-fluid level usually on both the posterioranterior (PA) and lateral views. The wall of the abscess is relatively thin.179 However, in some patients, a slowly resolving infiltrate may be all that is seen on the plain radiographs. This is a problem particularly in mechanically ventilated patients in the ICU who are examined only by portable chest radiography.180 In such situations, a CT scan is invaluable for demonstrating a cavitating lesion, to clarify the diagnosis when a plain radiograph is not diagnostic, to help rule out endobronchial obstruction, to more accurately assess the thickness of the walls of the cavity, and to look for an associated mass or other pathology, including other small abscesses. A cavitating carcinoma is not infrequently mistaken for a lung abscess. The lack of fever and leukocytosis suggests a

495

noninfectious cause, but if the tumor is infected, the clinical presentations of the two conditions are indistinguishable. The failure of the abscess to resolve with appropriate management or the finding of a thick, irregular wall or a mass associated with the abscess suggests an underlying malignancy. A loculated or interlobar empyema may be mistaken for a lung abscess, but CT findings clearly differentiate the two in most cases. A loculated empyema has smooth borders. If in the fissure, it has a lenticular shape; if adjacent to the chest wall, it forms an obtuse angle with the chest wall. A split pleura sign may be present, and an air-fluid level is uncommon. Infected cysts or bullae manifest with the same clinical picture as a lung abscesses, and their management is similar. They are easily distinguished by CT scanning, which shows a smooth, thin-walled cavity with little surrounding inflammation. A parasitic cyst may be associated with peripheral eosinophilia. Less common differential diagnoses include other cavitating lesions such as tuberculosis, fungal infections, actinomycosis, bronchiectasis, and noninfectious inflammatory conditions such as Wegener’s granulomatosis. Additional investigations include a complete blood count with differential white cell count, sputum culture, blood cultures, and bronchoscopy. Bronchoscopy is essential to rule out endobronchial obstruction caused by a tumor or a foreign body. During bronchoscopy, cultures may be obtained by means of BAL, but if the patient has been taking systemic antibiotics for more than 24 hours, bronchoscopic cultures are commonly sterile. PSB appears to offer no additional benefit over BAL. Historically, bronchoscopy has been used to establish drainage of the abscess, but sudden drainage of a giant abscess can be hazardous, causing flooding of the tracheobronchial tree, disseminating infection and possibly causing asphyxia. Transtracheal aspiration has been reported to yield more accurate culture data but is not well tolerated by most patients. Alternatively, samples for culture can be obtained by means of fine-needle aspiration (FNA) using ultrasound or CT guidance. This technique is usually well tolerated by patients, obtains samples uncontaminated by upper respiratory tract flora, allows for more reliable anaerobic culture, and may be accompanied by therapeutic percutaneous drainage of the abscess.170,172,180 Yang and colleagues172 reported a 94% success rate in obtaining a culture of pathogens using FNA, compared with 11% using sputum culture and 3% using BAL. There was a low rate of pneumothorax (6%), and none of those patients required a chest tube. Grinan and coworkers170 reported similarly encouraging results, with 82% positive cultures and a 14% rate of pneumothorax. It is important to note that, in 43% of patients, antibiotics were changed as a result of an FNA. This procedure is particularly important in identifying unusual organisms.

Management The mainstay of treatment is systemic antibiotics. The choice of antibiotic depends on the clinical situation. Administer IV antibiotics until the patient is no longer toxic (1-2 weeks).

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 495

1/21/2008 11:36:39 AM

496

Section 3 Lung

The antibiotics may then be changed to an oral regimen of equal efficacy and continued for a prolonged course of 4 to 8 weeks.181 High-dose penicillin (up to 20 million units per day) is effective for most abscesses and historically has been the drug of choice. However, recent studies have demonstrated the superiority of clindamycin (600 mg IV every 6 hours), primarily because of penicillin-resistant Bacteroides species.182,183 Metronidazole alone is insufficient, presumably because of the presence of aerobic and microaerophilic streptococci, resulting in only 50% response rates,184 but in nosocomial infections a third-generation cephalosporin and metronidazole may be an appropriate choice. Clindamycin with or without a cephalosporin was found to be equivalent to ampicillin plus sulbactam.185 Supportive therapies include nutritional support and treatment of predisposing factors. Chest physiotherapy and possibly bronchoscopy to facilitate bronchial toilet are often recommended, but most abscesses communicate with the bronchial tree and drain spontaneously. Because of the risk of flooding the contralateral lung with infected secretions, bronchoscopy is best reserved for diagnostic purposes. Most lung abscesses (85%-90%) respond within 2 weeks to medical management and resolve radiographically over 2 to 5 months (Wiedmann and Rice, 1995).173 Lack of clinical response to medical therapy within 2 weeks suggests the need for invasive culture techniques (FNA) to ensure that antibi-

A

D

otic coverage is appropriate; bronchoscopy, if not already performed, to rule out endobronchial obstruction; re-evaluation of the diagnosis; and possibly external drainage or surgical resection. Indications for intervention include failure to resolve with antibiotics, abscess under tension, abscess increasing in size despite appropriate antibiotics, contralateral lung contamination, abscess larger than 4 to 6 cm in diameter, rising fluid level, persistent ventilator dependency, necrotizing infection with multiple abscesses, hemoptysis, rupture into the pleural space with pyopneumothorax, and inability to exclude a cavitating carcinoma. In the past, these were indications for surgery, but percutaneous drainage has become the treatment of choice for most of these clinical situations, with the exceptions of massive hemoptysis and inability to rule out cancer. Historically, external drainage was accomplished by means of tube thoracostomy or surgical cavernostomy, but these techniques have been replaced by percutaneous drainage using CT or ultrasound guidance. The exact timing of and indications for percutaneous drainage require the judgment of the treating physician or surgeon. Based on expanding experience and success, early drainage has been practiced with increasing frequency (Fig. 42-10). The effectiveness of percutaneous drainage is high, with cure rates of 73% to 100% (Lambiase et al, 1992; Wiedmann and Rice, 1995).173,186-190 The major

B

C

E

F

FIGURE 42-10 A-C, Lateral and posterior-anterior views and CT scan of a large acute lung abscess. D-F, Resolution with simple percutaneous drainage followed by the chest tube insertion using the percutaneous tract.

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 496

1/21/2008 11:36:39 AM

Chapter 42 Bacterial Infections of the Lung

concerns are the risk of empyema, hemorrhage, pneumothorax, or bronchopleural fistula; however, the rate of complications is lower with radiologically placed drainage tubes than with bedside or operative tube thoracostomy. Insertion of a percutaneous drain into an area of necrotizing pneumonia may have a slightly higher rate of parenchymal-pleural fistula compared with percutaneous drainage of a well-demarcated lung abscess.191 Overall morbidity is low (0%-21%), as is mortality (0%-9%), with most deaths occurring in critically ill patients (Lambiase et al, 1992).186 The technique for percutaneous drainage of a lung abscess utilizes either CT or ultrasound to localize the abscess and determine the optimal location for tube placement in order to take advantage of pleural symphysis or at least minimize the amount of lung traversed by the catheter.189,192 The patient is positioned so that the abscess is in a dependent position to minimize the chance of soilage of the contralateral lung. Using either a Seldinger or a trocar technique, the abscess is localized, punctured, and then drained by means of a 12-Fr (or larger) catheter, with manual aspiration of as much of the abscess contents as possible, followed by irrigation of the cavity with saline. The drainage catheter is attached to a standard chest drainage system. Radiologically guided percutaneous tube drainage has essentially replaced bedside tube thoracostomy or surgical cavernostomy, both of which are associated with a higher complication rate; in addition, tube thoracostomy may be less efficacious if the abscess is deep and harder to localize. Bedside tube thoracostomy remains the procedure of choice for an acutely ill patient with an abscess that has ruptured into the pleural space. Surgical resection is required in fewer than 10% of cases of lung abscess (Wiedmann and Rice, 1995).173 The most common indication for surgery is the suspicion of, or inability to rule out, a cavitating lung cancer. Lack of response to antibiotics as seen on radiology, absence of fever and leukocytosis, and a thick-walled cavity may be clues to an underlying malignancy. Massive hemoptysis is less common but is also an indication for emergency surgery. Hemoptysis occurs in 11% to 15% of cases of lung abscess; of these, 20% to 50% include massive hemoptysis.193,194 Medical management of massive hemoptysis in this setting is associated with a 70% mortality rate. In the presence of a destructive infection, rebleeding is highly probable and resection is recommended, once the patient is stabilized, assuming the patient can tolerate a pulmonary resection from the perspective of pulmonary reserve. Lobectomy is the preferred resection. Rupture into the pleural space with resulting pyopneumothorax has historically been an indication for emergency surgery. However, even this catastrophic complication may be managed either temporarily or even definitively with tube drainage of both the pleural space and the abscess. If the adequate drainage cannot be accomplished nor sepsis controlled with percutaneous drainage, surgery is required. Better drainage may be all that is required, but if resection is needed, a lobectomy is preferred. A Monaldi procedure or other rib resection procedures may be performed for drainage of a pyopneumothorax if the patient’s condition is unstable or cannot tolerate resection. For drainage of an uncompli-

497

cated lung abscess, the Monaldi procedure has been superseded by percutaneous radiologic techniques. The most important intraoperative consideration is protection of the contralateral lung, whatever the indication for surgery. The use of a double-lumen tube, a bronchial blocker, or contralateral main stem intubation minimizes contamination of the dependent lung during surgery. Particularly in the presence of massive hemoptysis, rapid control of the airway is essential. Once the chest is open, early clamping of the involved bronchus and minimal manipulation of the involved lobe also help to minimize spillage. These resections are usually challenging because of the increased vascularity and lymphadenopathy secondary to the infection, making access and control of the hilum difficult.

Results In the preantibiotic era, the rate of death in cases of lung abscess was 30% to 50%. In the modern era, the mortality rate is 5% to 20%, with 75% to 88% of patients cured by medical therapy alone. Surgical treatment has a 90% success rate, with a mortality rate of 1% to 13%.175,177,178 The success rate with percutaneous drainage varies from 73% to 100%, with no mortality reported. Because of the increase in the number of immunosuppressed patients, the incidence of lung abscess is rising and, with it, the mortality rate, reported to be 28% in this patient population. Factors contributing to higher mortality include multiple comorbidities, COPD, pneumonia, neoplasm, altered level of consciousness, immunosuppression, periodontal disease, and generalized debility. Larger abscesses are also associated with increased duration of hospitalization and somewhat higher mortality.195

SUMMARY Despite the advent of newer and more potent antibiotics, bacterial infections of the respiratory tract remain an important cause of morbidity and mortality. The ability of the medical profession to treat critical illnesses and immunosuppressive diseases with life-supporting therapies and potent new drugs has resulted in an increase in these infections, which are often caused by unusual or opportunistic organisms. This increasing complexity of illness is associated with increases in mortality. Treatment of CAP is based on epidemiologic principles because the infecting organism is rarely known at the time of presentation. These principles classify pneumonia into CAP and HAP. The earlier classification of pneumonia as typical or atypical is obsolete and not clinically useful because the clinical syndrome associated with the various pathogens cannot be reliably distinguished on clinical or radiographic grounds. Prompt institution of antibiotic therapy is key to the successful treatment of pneumonia and must never be delayed while waiting for a sputum sample to be obtained, much less cultured. Sputum cultures are often negative or nondiagnostic, but this does not indicate the absence of infection. CAP is commonly caused by gram-positive and atypical organisms, whereas HAP is commonly caused by gramnegative organisms and occasionally by fungi. VAP is a

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 497

1/21/2008 11:36:40 AM

498

Section 3 Lung

subcategory of HAP, and treatment must be aimed at gramnegative organisms, particularly Pseudomonas species. Another category, aspiration pneumonia, has caused some confusion because it comprises three syndromes: chemical gastric acid pneumonitis, bacterial-aspiration pneumonia, and foreign body aspiration. Although antibiotics have no role in chemical-aspiration pneumonitis, they are critical in bacterial-aspiration pneumonia and in the bacterial pneumonia that may complicate chemical-aspiration pneumonitis. Treatment of a COPD exacerbation is controversial, but current guidelines recommend combination therapy including antibiotics, inhaled bronchodilators, and systemic corticosteroids. Also, address comorbidities because they are often important coprecipitants. The incidence of lung abscess is again rising with the increasing numbers of immunosuppressed patients. The most common cause of lung abscess is aspiration of infected oropharyngeal secretions, followed by necrotizing primary pneumonias. Bacteremia may result in multiple abscesses. Most abscesses contain mixed flora of anaerobes with either grampositive cocci (if community-acquired) or gram-negative bacilli (if nosocomial). In immunosuppressed patients, unusual or opportunistic infections must be considered. In the assessment of the patient with a lung abscess, predisposing factors such as esophageal or neurologic problems must be ruled out. The differential diagnosis of cavitating lung lesions must be addressed, particularly if the abscess fails to respond to appropriate therapy. The primary treatment is prolonged IV antibiotics. Percutaneous techniques (FNA) for obtaining culture material have proved to be useful in establishing a microbiologic diagnosis and guiding appropriate antibiotic choice. External drainage using percutaneous radiologic techniques is now preferred over surgical drainage and is indicated for failure to resolve, tension, increasing size, contralateral lung contamination, abscess larger than 4 to 6 cm in diameter, and rising fluid level. The indications for surgical intervention have changed and primarily include inability to rule out cancer, massive hemoptysis, and rupture into the pleural space. The mortality rate among patients with lung abscesses has diminished dramatically since the preantibiotic era but is higher among immunosuppressed patients. Bacterial infections remain important in the practice of thoracic surgery as a major cause of morbidity and, occasionally, of mortality, but the role of surgery in the management of these problems is usually limited to the treatment of complications.

COMMENTS AND CONTROVERSIES Initially, one might question the presence of such an extensive chapter on pulmonary infection in a thoracic surgical textbook. However, the significance of infectious lung disease in any thoracic surgical practice cannot be underestimated. Indeed, pulmonary infection is becoming an increasing problem, despite the decadeslong availability of sophisticated broad-spectrum antibiotics. In fact, with the increasing problem of MDR organisms and immunocom-

promised hosts, pulmonary infections are likely be an even bigger obstacle in the future. In addition, as we are asked to provide surgical evaluation of patients with advanced COPD, preoperative and postoperative management of COPD exacerbations will also be important. The authors have concisely discussed recent noninvasive treatment options for patients with lung abscess. The use of percutaneous drainage procedures guided by ultrasound or CT have markedly facilitated the management of lung abscess, offering most patients a relatively noninvasive drainage strategy. G. A. P.

KEY REFERENCES American Thoracic Society: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcareassociated pneumonia. Am J Respir Crit Care Med 171:388-416, 2005. El-Solh AA, Pietrantoni C, Bhat A, et al: Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med 167:1650-1654, 2003. Fishman JA, Rubin RH: Infection in organ-transplant recipients. N Engl J Med 338:1741-1751, 1998. Fine MJ, Hough LJ, Medsger AR, et al: The hospital admission decision for patients with community-acquired pneumonia: Results from the pneumonia Patient Outcomes Research Team cohort study [see comments]. Arch Intern Med 157:36-44, 1997. Hammond JM, Potgieter PD, Hanslo D, et al: The etiology and antimicrobial susceptibility patterns of microorganisms in acute community-acquired lung abscess. Chest 108:937-941, 1995. Kadowaki M, Demura Y, Mizuno S, et al: Reappraisal of clindamycin IV monotherapy for treatment of mild to moderate aspiration pneumonia in elderly patients. Chest 127:1276-1282, 2005. Kollef MH: The prevention of ventilator-associated pneumonia. N Engl J Med 340:627-634, 1999. Kozlow JH, Berenholtz SM, Garrett E, et al: Epidemiology and impact of aspiration pneumonia in patients undergoing surgery in Maryland 1999-2000. Crit Care Med 31:1930-1937, 2003. Lambiase RE, Deyoe L, Cronan JJ, et al: Percutaneous drainage of 335 consecutive abscesses: Results of primary drainage with 1 year followup. Radiology 184:167-179, 1992. Mandell LA: Update on community-acquired pneumonia: New pathogens and new concepts in treatment. Postgrad Med 118:35-36, 41-46, 2005. Mandell LA, Marrie TJ, Grossman RF, et al: Summary of Canadian guidelines for the management of community-acquired pneumonia: An evidence-based update by the Canadian Infectious Disease Society and the Canadian Thoracic Society. Can Respir J 7:371-382, 2000. Niewoehner DE, Erbland ML, Deupree RH, et al: Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease: Department of Veterans Affairs Cooperative Study Group [see comments]. N Engl J Med 340:1941-1947, 1999. Tablan OC, Anderson IJ, Besser R, et al: Healthcare Infection Control Practices Advisory Committee, Centers for Disease Control and Prevention: Guidelines for preventing health-care-associated pneumonia, 2003: Recommendations of the CDC and the Health-Care Infection Control Practices Advisory Committee. MMWR 53(RR3):1-36, 2004. Wiedemann HP, Rice TW: Lung abscess and empyema. Semin Thorac Cardiovasc Surg 7:119-128, 1995.

tahir99-VRG vip.persianss.ir

Ch042-F06861.indd 498

1/21/2008 11:36:40 AM

chapter

43

TUBERCULOSIS AND ATYPICAL MYCOBACTERIAL DISEASES Reza John Mehran Jean Deslauriers

There is no more dangerous disease than pulmonary phthisis, and no other is so common . . . it destroys a very great part of the human race. Antoine Portal, Paris, 1832

Key Points ■ Tuberculosis is still a prevalent disease in developing countries. ■ Treatment is problematic due to a problem with multidrug-resistant

strains. ■ Surgery can effectively cure selected groups of patients. ■ Hemoptysis and pleural space complications are the main indica-

tions for hospital intervention.

Pulmonary mycobacterial diseases are pathologic processes in which the lung is infected with mycobacterial organisms. Tuberculosis is caused by Mycobacterium tuberculosis, but species of Mycobacteria other than tuberculosis can produce similar pathologic changes. The infection involves mainly the lungs, where cell-mediated immunity results in the formation of granulomas. In 2007, the World Health Organization reported that 8.8 million people worldwide became infected with tuberculosis in 2005, but new cases were up by only 70,000; 26 million people were cured of tuberculosis in that year. A new strain, called extensively drug-resistant tuberculosis or XDR, has broken out in South Africa and 34 other countries, including 17 cases from 2002 to 2005 in the United States. XDR is resistant to “both first and second line drugs” and killed 52 of the 53 patients initially identified. It is “still not under control” in South Africa, and countries to the north of there do not have the laboratory capacity to recognize it.1 The study of tuberculosis is a fascinating travel through the history of medicine and surgery that starts from the dawn of civilization. At the beginning of the 20th century, tuberculosis was the foremost single cause of death among adults, and at that time, a system of sanatoriums that emphasized bed rest and nutrition was created to help fight the disease. It was in those institutions that the closure of tuberculous cavities by means of surgical modalities, such as phrenic nerve crush, thoracoplasty, and plombage, was found to be of value in controlling the infection. In the United States as well as throughout Europe, these developments paralleled very closely those of thoracic surgery as a surgical specialty. This chapter reviews the pertinent aspects of the surgical treatment of mycobacterial diseases as they apply to the practice of thoracic surgery in the 21st century.

HISTORICAL NOTE In the Paleolithic period (the Stone Age), human species were essentially living in herds and did not have domesticated animals. Tuberculosis and other infectious diseases may have occurred sporadically, but they probably did not occur in epidemic forms. In the Neolithic period (10,000-7000 BC), humans apparently shifted from food gathering to food producing. Primitive settlements were developed, and animals were raised and maintained. Because a social network of more than 180 to 440 persons is required for a tuberculosis infection to become endemic in a community, the disease probably became endemic among animals long before it affected humans. Epidemic transmission began with increasing population density, and it slowly spread as members of large European communities traveled worldwide (Diamond, 1992). Because of its enormous ravages, tuberculosis became known as the Great White Plague throughout feudal Europe (Dubos and Dubos, 1952). In the late 18th century, 40% of deaths in London were thought to be due to tuberculosis. Among Native Americans, there is almost no evidence of tuberculosis before the European incursion. From the time of Hippocrates (Table 43-1), tuberculosis was known as phthisis, a term derived from the Greek language and meaning “decaying.” The swollen glands of the neck were known as scrofula and the King’s Evil. Ever since the reign of Clovis (5th century AD), the kings of France were believed to have received a healing power from God, and this power started the ceremony of the Touch to cure the swollen glands of the neck. Tuberculosis of the skin was termed lupus vulgaris and that of the spine Pott’s disease, a term derived from the name of Percivall Pott, an 18th century British surgeon. The vertebral fusion and deformity of the spine that characterize Pott’s disease have enabled historians to establish the existence of tuberculosis in mummies dating from 2000 to 4000 BC. In the early 17th century, tuberculosis was also known as consumption (from the Latin word consumere, meaning “to eat up, to devour”), asthenia, tabes (“to decline”), bronchitis, inflammation of the lungs, lactic fever, and gastric fever. Until the late 19th century, however, these terms were also used when referring to other diseases of the lungs, such as cancer, lung abscesses, and silicosis. During those times, tuberculosis struck hardest among young men and women, condemning many of them to an early death. A Florentine physician named Hieronymus Fracastorius described the theory of contagion in 1546. This discovery led not only to increased efforts to find the cause of the disease but also to the spread of dangerous habits throughout Europe. 499 tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 499

1/21/2008 11:37:31 AM

500

Section 3 Lung

TABLE 43-1 Milestones in the Evolution of the Description of Tuberculosis Event

Date

Pott’s disease in the Neolithic age

2,0004,000 BC

Clay tablets from the library of Assyrian King Assurbanipal

668-626 BC

Earliest description of tuberculosis

Hippocrates, Greece

460-375 BC

Phthisis described in the second book of De Morbis

Galen, Greece

129-200

Contagiousness of tuberculosis

King’s Evil

Middle Ages

The magic touch of the hands of the kings of France on scrofula

The Great White Plague

1600s

Spread of tuberculosis throughout Europe

Franciscus Delaboe Sylvius, Holland

1679

Tubercle; line of beads; pathologic description of tuberculosis adenopathy

James Carson, England

1819

Idea of pneumothorax in the treatment of tuberculosis; animal model

J. Hastings and R. Storks, England

1844

Cavernostomy

William Morton, Boston

1846

Discovery of anesthesia

Herman Brehner, Germany

1859

Notion of rest in sanatorium for the treatment of tuberculosis

Carlo Forlanini, Italy

1882

First artificial pneumothorax

Robert Koch, Germany

1882

Identification of tubercle bacilli

Édouard Bernard de Cerenville, Switzerland

1885

Description of thoracoplasty

Marin Théodore Tuffier, France

1926

Apicolysis

E. Delorme, France

1894

Pulmonary decortication

Wilhelm Conrad Roentgen, Germany

1895

Discovery of radiography

H. Schlange, Germany

1907

Extrapleural plombage

Hans Christian Jacobeus, Sweden

1925

Thoracoscopy for parietal pneumolysis

A. Bernou

1922

Oleothorax

H. Lilienthal, USA

1933

Pneumonectomy

S. Freedlander, USA

1935

Lobectomy

Selman Waksman, USA

1944

Streptomycin, isolated from soil saprophytes; Nobel prize in 1952

E. H. Robitzek and I. J. Selikoff, USA

1952

First clinical trial proving the efficacy of isoniazid, discovered by V. Clarin in 1945, France

Worldwide

1980s

Resurgence of resistant strains of tuberculosis and renewed interest in surgery as a treatment modality

Examples include the story of a physician who became “consumptive” because he was in the habit of “tasting” the sputum of his patients and the practice of treating tuberculosis with human milk. As early as 1699, Italy and later Spain developed restrictive quarantine laws, which were not without consequence to the misery of many, including Frederic Chopin, who was denied hospitality on the Island of Majorca. In those days, the sanitation rules of Majorca were very strict, and everything touched by phthisic patients had to be burned, a burden no hotel wanted to assume. In 1650, the Medical Faculty of Paris expressed some doubts about the contagiousness of phthisis, and this concept soon spread all over northern Europe, where some physicians believed that heredity had more to do with the spread of the disease than did contagion. In 1679, Franciscus Delaboe Sylvius, a Dutch iatrochemist (a physician who explained and treated disease based on

Comment

chemical principles), described in his work, Opera Medica, the characteristic lung nodules associated with tuberculosis. He called them tubercula, or small knots. The first credible theory that tuberculosis might be caused by infectious organisms (the germ theory) was put forth in 1722 by Benjamin Martel of London. He proposed that tuberculosis was caused by animalicula (small animals) that could be transmitted from a consumptive lung. In 1821, Rene Theophile Hyacinthe Laënnec, a French physician, was the first to group tuberculosis in all of its forms into a single disease, and this became known as the totalitarum theory of Laënnec. The following paragraph is from Comroe (1978), who commented on the work of Laënnec: By careful examination of tuberculous patients during life and complete study of the lungs (Fig. 43-1) of the unfortunate patients who came to the autopsy

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 500

1/21/2008 11:37:31 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

FIGURE 43-1 Laënnec’s illustration of different forms of tuberculous matter. a, immature or crude tubercles; b, yellow groups of incipient tubercles, still gray and semitransparent externally; c, small cartilaginous cysts emptied of tuberculous contents; d, tuberculous excavation entirely empty and lined by two membranes, the exterior semicartilaginous and the interior soft (a bronchial tube opens into this excavation); e, small, empty, tuberculous excavation, not lined by any membrane; f, surface of the lung; g, tubercle partly softened and evacuated; h, incipient tuberculous infiltration of the pulmonary tissue. (FROM COMROE JH JR: T.B. OR NOT T.B.? I. THE CAUSE OF TUBERCULOSIS. AM REV RESPIR DIS 117:138, 1978.).

room (which was the early fate of most of them), he determined that the characteristic lesion of “consumption” in all of the organs and tissues that it attacked was the tubercle; that tubercles may break down in lungs and form cavities but that the latter may be sealed over by a new membrane and in effect healed. The existence of cavities can be detected using a stethoscope during the life of a patient, by a new physical sign, pectoriloquism (transmission of the patient’s voice through a cavity in the lungs and the chest wall to a stethoscope on the chest). In 1839, Johann Lucas Schonlein, professor of medicine in Zurich, suggested using the term tuberculosis for all manifestations of phthisis because the tubercle was the fundamental anatomic basis of the disease. The first convincing evidence that tuberculosis was an infectious disease was provided in 1868 by Jean-Antoine Villemin, who performed experiments on rabbits and was able to reproduce the disease by injecting infectious sputum and caseum material into healthy animals. In 1882, Robert Koch made a presentation at the Berlin Physiologic Society that forever changed the thinking about tuberculosis as an infectious disease. He described the tuberculous bacillus, an organism known to this day as the Koch bacillus, and convincingly demonstrated it to be the cause of disease. He also established the principles of its bacteriology

501

by specifying that it was necessary to isolate the bacteria from the body, to grow them in pure culture, and to administrate the isolate to animals to reproduce the same morbid condition (Koch’s principles) (Koch, 1882). Soon after his discovery, Koch introduced a secret vaccine for the treatment of tuberculosis, but, unfortunately, the vaccine was made of virulent bacteria and patients became actively infected after the vaccination. Koch was severely criticized for not revealing the content of his vaccine (Dubos and Dubos, 1952). Albert Calmette was a French physician who was appointed in 1895 to the directorship of the newly founded Pasteur Institute in Lille, France. With the help of Camille Guérin, a veterinarian, they produced a vaccine of boiled, completely attenuated cultures of Mycobacterium bovis. Even though the efficacy of the bacille Calmette-Guérin (BCG) vaccine is still largely unknown, it is now used worldwide (Centers for Disease Control and Prevention, 1991). Simple rest resulted in the cure of some patients, but not all of those afflicted with tuberculosis were so lucky. Indeed, the mortality rate of patients admitted to New York State sanatoriums between the years 1908 and 1914 was 69% for those with advanced disease, 23% for those with moderately advanced disease, and 13% for those with minimal disease (Alling and Bosworth, 1960). The history of operation for pulmonary tuberculosis is nowhere better summarized than in John Alexander’s The Collapse Therapy of Pulmonary Tuberculosis published in 1937. The original idea of accelerating the healing of tuberculous cavities by facilitating their collapse dates back to the end of the 18th century. After having observed a favorable evolution of tuberculous lesions in patients with spontaneous pneumothoraces, Forlanini (Fig. 43-2), in 1894, thought that adequate treatment of active tuberculosis could be supplemented by the creation and maintenance of intrapleural pneumothoraces. This concept led to the reporting of good results a full 2 years before the actual discovery of radiography. The theory behind the treatment of tuberculosis by means of artificial pneumothoraces was to promote immobilization and collapse of the cavity by suppressing the effects of lung elasticity. By freeing pleural adhesions with a thoracoscope, Jacobeus (Fig. 43-3), in 1925, re-emphasized the importance of this technique and was able to widen its indications. The procedure was done with two incisions, one for the thoracoscope and one for a galvanocautery. It was a long operation, often done in several sittings. Because lung tissue was commonly contained within the adhesion, Eloesser and Brown, in 1924, suggested that these adhesions be divided extrapleurally to avoid tearing the lung (Fig. 43-4) (Fey et al, 1955). However, the technique was not without its problems, and accidental lung perforation could lead to bronchopleural fistulas and empyema. The collapse had to be maintained for a period of 4 years after a good result had been obtained, and this could be done only in a sanatorium. Phrenicectomy (Stuertz, 1912) was also advocated to reduce respiratory movements by way of diaphragmatic paralysis. The procedure became rapidly popular because it was considered a small operation with no major sequelae (Fey et al, 1955). Unfortunately, phrenicectomy immobilized

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 501

1/21/2008 11:37:31 AM

502

Section 3 Lung

FIGURE 43-2 Carlo Forlanini (1847-1918), Pavia, Italy. (FROM ALEXANDER J: THE COLLAPSE THERAPY OF PULMONARY TUBERCULOSIS. SPRINGFIELD, IL, CHARLES C THOMAS, 1937.)

A

B

FIGURE 43-3 Hans Christian Jacobeus, Stockholm, Sweden. (FROM ALEXANDER J: THE COLLAPSE THERAPY OF PULMONARY TUBERCULOSIS. SPRINGFIELD, IL, CHARLES C THOMAS, 1937.)

C

FIGURE 43-4 Technique for open division of adhesions. A, Large insertion of the adhesion, B, mobilization and division in the endofascial plane. C, Division of the adhesion around its base (arrows). (FROM FEY B, MOROCQUOT P, OBERLIN S, ET AL: TRAITÉ DE TECHNIQUE CHIRURGICALE. PARIS, MASSON ET CIE ÉDITEURS, LIBRAIRIES DE L’ACADÉMLE DE MÉDECINE, 1955.)

FIGURE 43-5 Technique of tearing the phrenic nerve by rolling it around a clamp. (FROM FEY B, MOROCQUOT P, OBERLIN S, ET AL: TRAITÉ DE TECHNIQUE CHIRURGICALE. PARIS, MASSON ET CIE ÉDITEURS, LIBRAIRIES DE L’ACADÉME DE MÉDECINE, 1955.)

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 502

1/21/2008 11:37:31 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

FIGURE 43-6 Édouard Bernard de Cerenville (1843-1915), Lausanne, Switzerland. (FROM ALEXANDER J: THE COLLAPSE THERAPY OF PULMONARY TUBERCULOSIS. SPRINGFIELD, IL, CHARLES C THOMAS, 1937.)

mostly the lower lobes, whereas the lesions were usually located in the upper lobes. Often the phrenic nerve had collaterals, and it was necessary to divide the subclavian nerve or tear the nerve for a certain distance (Fig. 43-5) to ensure that no collateralization or regeneration would occur. The phrenic nerve could also be destroyed by alcoholization, which was carried out by injecting 2 mL of alcohol until the nerve “turned white.” While this procedure was being performed, gauze was put around the nerve so that the brachial plexus would not be injured. Often, scalenotomy was done to increase the benefits of phrenicectomy by immobilizing the first two ribs. It was done at the same time as phrenicectomy and through the same incision. Other procedures used to increase the collapse of the lung included the creation of a pneumoperitoneum (Vajda, 1933) or intercostal neurotomy (open division or alcoholization). In 1993, Andreas Naef commented on the physicians who performed these operations: These procedures were conceived and performed by physicians, often themselves former tuberculosis patients who tried to break away from the frustrating passivity of “bed rest.” Some of these medical men were highly skillful and monopolized the field before surgeons could get into the act—a lesson to be remembered today. At about the same time, surgical collapse of underlying pulmonary cavities was being practiced by rib resection, an operation called thoracoplasty. In 1885, a physician from

503

FIGURE 43-7 Théodore Tuffier (1857-1929), Paris, France. (FROM ALEXANDER J: THE COLLAPSE THERAPY OF PULMONARY TUBERCULOSIS. SPRINGFIELD, IL, CHARLES C THOMAS, 1937.)

Lausanne, Switzerland, named Édouard Bernard de Cerenville (Fig. 43-6) described a technique in which short segments of two or more ribs were resected in order to collapse the chest wall over areas of apical cavitary tuberculosis. The concept used in this operation was to promote “scar” retraction of tuberculous cavities—that is, to promote retraction of the lung and subsequent scarring by secondary healing. The thoracoplasty described by Schede in 1890 was an operation that included not only multiple rib resections but also the removal of the periosteum, intercostal muscles and nerves, and parietal pleura. In 1926, Marin Théodore Tuffier (Fig. 43-7) was able to free the apex of the lung by using a procedure he called apicolysis. This could be done extrapleurally or extrafascially (outside the endothoracic fascia) in such a way as to create a space, which he filled with fatty tissues taken from the patient. This concept became the basis for future procedures such as the extrapleural plombage collapse therapy, in which the space was filled with slightly heated paraffin (oleothorax) or Lucite balls. Each of these techniques had its advantages and disadvantages (Table 43-2). Collapse therapy for tuberculosis was rendered obsolete by surgical resection of the lung. This change of procedure was received with much skepticism, and when Freedlander had the courage to present an unsuccessful case of lobectomy for tuberculosis at the 1935 meeting of the American Association for Thoracic Surgery, he was congratulated by Coryllos and Eloesser but criticized by Alexander (Naef, 1993), who favored thoracoplasty in all but a few exceptional situations.

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 503

1/21/2008 11:37:35 AM

504

Section 3 Lung

TABLE 43-2 Collapsotherapy Procedure

Advantages

Disadvantages

Thoracoplasty

Good patient tolerance if <6 ribs are resected

Definitive collapse Deformities of the thorax Often done in two or three stages

Extrapleural pneumothorax

Reversible No deformity Advantageous in extensive lesions

Maintenance of pneumothorax Infection of the space

Extramusculoperiosteal plombage

Same as for extrapleural pneumothorax

Infection Late complications

Pulmonary resection was very dangerous in sputum-positive patients because bronchial closure seldom healed, and the resulting postoperative tuberculous or mixed tuberculous and pyogenic empyemas usually resulted in death (Meyer, 1991). The outcome for patients with tuberculosis changed dramatically in November, 1944, when a 21-year-old woman with advanced pulmonary tuberculosis received the first injection of streptomycin, which was isolated by Selman Waksman from a soil yeast called Streptomyces griseus. Equally or even more dramatic were the results of the first use of isoniazid, reported in a clinical trial by Robitzek and Selikoff (1952). Soon, many of the sanatoriums around the world became deserted. One can reflect on how the sanatoriums actually helped patients, by providing a stress-free lifestyle lived in the open air and combined with good hygiene and nutrition, treatment modalities that are still acknowledged as being beneficial in the treatment of many diseases.

Meyer JA: Tuberculosis, the Adirondacks, and coming of age for thoracic surgery. Ann Thorac Surg 52:881, 1991. Naef AP: The 1900 tuberculosis epidemic—starting point of modern thoracic surgery. Ann Thorac Surg 55:1375, 1993. Pepper W: A System of Practical Medicine by American Authors, Vol. 3. Philadelphia, Lea Brothers, 1885. Robitzek EH, Selikoff IJ: Hydrazine derivatives of isonicotinic acid (Rimifon, Marsilid) in the treatment of active progressive caseouspneumonic tuberculosis: A preliminary report. Am Rev Tuberc 65:402, 1952. Schede M: Die behandlung der empyeme [German]. Verh Long lnnere Med Wiesbaden 9:41, 1890. Stuertz A: Experimenteller beitrag zur “zserchfellbwegung nach einselitiger phrecus durchtrennung” [German]. Dtsch Med Wochenschr 38:897, 1912. Tuffier T: Du décollement pariétal en chirurgie pulmonaire [French]. Arch Med Chir App Respir 1:32, 1926. Vajda L: Ob das pneumoperitoneum in der kollapsetherapie der beiderseitigen lungentuberkulose angewandt werden kenn? [German]. Ztschr Tuberk 67:371, 1933.

HISTORICAL READINGS

BASIC SCIENCE Alexander J: The Collapse Therapy of Pulmonary Tuberculosis. Springfield, IL, Charles C Thomas, 1937. Alling DW, Bosworth EB: The after-history of pulmonary tuberculosis. VI: The first fifteen years following diagnosis. Am Rev Respir Dis 81:839, 1960. Centers for Disease Control and Prevention: Case Curriculum on Tuberculosis. Atlanta, CDC, 1991. Comroe JH Jr: T.B. or not T.B.? 1. The cause of tuberculosis. Am Rev Respir Dis 117:137, 1978. de Cerenville EB: De l’intervention dans les maladies du poumon [French]. Rev Med Suisse Normande 5:441, 1885. Diamond JM: The arrow of disease. Discover 13:64, 1992. Dubos R, Dubos J: The White Plague. Boston, Little Brown, 1952. Fey B, Morocquot P, Oberlin S, et al: Traité de technique chirurgicale, Vol IV, 2nd ed [French]. Paris, Librairies de l’Academie de Medecine, 1955. Forlanini C: Primi tentative di pneumothorax artificiale della tisi pulmonare [Italian]. Gazzetta Medicale di Torino 45:381, 1894. Jacobeus HC: Die thorakoscopic und ihre praktische bedeutung [German]. Ergebges Med (Berlin) 7:112, 1925. Koch R: Die aetiologie der tuberkulose. Berlin Klin Wochenschr 19:221, 1882. Laënnec RTH: De l’auscultation médiate ou traité du diagnostic des maladies des poumons et du coeur [French]. Paris, Brosson et Chaudé, 1819; Forbes J: A treatise on the diseases of the chest [trans.] London, T and C Underwood, 1821.

Microbiology Most Mycobacterium species are soil and water saprophytes capable of degrading organic material into other biologic forms that are usable by many other organisms. These bacteria have characteristics that are close to some yeasts; hence, the term mycobacteria. Their most defining characteristic, however, is the property of acid-fastness—that is, the ability to withstand decolorization by an acid-alcohol mixture after being stained with such stains as Ziehl-Neelsen (Fig. 43-8) or auramine O.2 In addition to being acid-fast, Mycobacterium species are primarily intracellular parasites, have slow rates of growth, are obligate aerobes, and, in normal hosts, induce a granulomatous response. A classification of the most common Mycobacterium species is given in Table 43-3. The tuberculosis complex includes Mycobacterium tuberculosis (MTB), which is the agent of almost all tuberculosis in humans; Mycobacterium bovis, which occurs infrequently because milk is pasteurized; and Mycobacterium africanum, a cause of disease in Africa. The DNA structures of MTB and M. bovis are so similar that it has been suggested that MTB, which appears to be a more highly evolved species, is the result of a mutation of M. bovis. According to Manchester,3 this mutation may have

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 504

1/21/2008 11:37:36 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

505

FIGURE 43-8 Acid-fast tuberculous bacilli. The bacteria form a curved rod that measures approximately 0.3 to 0.6 µm.

TABLE 43-3 Species of Mycobacterium Tuberculosis Complex M. tuberculosis (MTB) M. bovis M. africanum Mycobacteria Other Than Tubercle Bacilli (MOTT): Slow-Growing Organisms M. avium-intracellulare complex M. kansasii M. scrofulaceum M. ulcerans M. xenopi M. szulgai M. simiae M. haemophilum M. genavense Mycobacteria Other Than Tubercle Bacilli (MOTT): Fast-Growing Organisms M. fortuitum M. chelonae (M. abscessus) From Wolinsky E: Nontuberculous mycobacteria and associated diseases. Am Rev Respir Dis 119:107, 1979.

occurred once humans started to live in larger groups and to domesticate cattle, sometime between 8000 and 4000 BC. MTB is an aerophilic organism, as opposed to the microaerophilic nature of M. bovis, which is why the preponderance of MTB infections occurs in the lungs.

Transmission and Pathogenesis The transmission of MTB and M. africanum usually occurs by way of an airborne or aerosol route, whereas the transmission of M. bovis to humans usually occurs by way of the gastrointestinal tract, with cattle being the intermediate host.

Bronchial air flow favors the deposition of inhaled bacilli in the basal segment of the lower lobes and the anterior segment of the upper lobes, areas known as the primary infection segments. In 1989, Dannenberg described the three stages of primary infection.4 In the first stage, scavenger nonactivated alveolar macrophages ingest the tubercle bacilli. During that stage, depending on their virulence and the macrophages’ microbicidal activity, bacilli multiplication is inhibited or the bacilli are destroyed. Infected macrophages release chemotactic factors that attract additional macrophages. The second stage, the symbiotic stage, occurs from day 7 to day 21. During that time, the bacteria grow in the macrophages, and monocytes migrate to the site of infection. The patient is often asymptomatic, and chest radiographs may be entirely normal or show only small areas of pneumonitis. The third stage, which occurs after 3 weeks, is characterized by the onset of cell-mediated immunity and delayed hypersensitivity. Alveolar macrophages demonstrate an increased ability to destroy the bacilli, and, as a result, there is no longer an increase in the number of organisms. There is an increase in macrophage death, which results in the formation of a granuloma, the characteristic pathologic finding in tuberculosis. Tuberculous granulomas are characterized by the accumulation of blood-derived macrophages; epithelioid cells, which are the degenerating macrophages; and multinucleated giant cells, which are fused macrophages with nuclei around the periphery (Langhans’ cells). T lymphocytes are also found around the periphery of the granuloma. Macrophage death causes central caseation. Caseum, the Latin word for cheese, is cellular debris of the consistency of soft cheese; in such an environment, low oxygen tension inhibits both macrophage function and bacillary growth. The caseum is surrounded by activated and nonactivated macrophages. A Ghon focus is a single small lesion in the lung, typically located at the apex of the upper lobes or in the

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 505

1/21/2008 11:37:37 AM

506

Section 3 Lung

upper part of the lower lobes. Although Anton Ghon was not the first to describe the primary pulmonary lesion, he was the first to provide a detailed description of active pulmonary tuberculosis based on autopsy findings.5 A Ghon complex, or Ranke complex, is a combination of a lung lesion and a calcified hilar node. A Ghon complex is often the only remaining evidence of the primary infection. During the fourth stage of infection, called reactivated tuberculosis, hydrolytic enzymes liquefy the caseum, transforming it into an excellent medium for the growth of Mycobacterium species. Once the bronchial structures are involved, the liquefied material is easily expectorated to the outside world, resulting in contamination of the outside environment. Bloodstream seeding also occurs during this stage. Typically, but not exclusively, reactivated tuberculosis starts in the apical or posterior segments of one or both of the upper lobes. These sites, referred to as Simon’s foci, are believed to be seeded during the early bacteremia of primary infection. It is likely that reactivation occurs because of the relatively higher partial oxygen tension in the upper portions of the lung, MTB being an obligate aerobe that reproduces most successfully in a high-oxygen environment. In human immunodeficiency virus (HIV) infection, the macrophages and T lymphocytes that normally control primary infection are disabled; this results in greater susceptibility to and virulence of tuberculosis in HIV-infected patients. Exposure to a patient with active tuberculosis results in infection in approximately one third of individuals who do not have HIV infection.6 Of these, 3% to 5% develop active tuberculosis within 1 year, and an additional 3% to 5% reactivate at a later date. There is convincing evidence that, in most adults, tuberculosis occurs as a result of the reactivation of organisms that were seeded during primary infection.7

Epidemiology Crowding in European cities and the occurrence of the Industrial Revolution in Europe provided the environmental conditions necessary for an endemic disease to become epidemic. Currently, about 1.7 billion people, or about one third of the world’s population, are or have been infected with MTB.8 Eight million new cases of tuberculosis were documented in the early 1990s, and 95% of them occurred in the developing countries of the western Pacific and Southeast Asia. During that time, more than 2 million people died of the disease, making tuberculosis a huge socioeconomic burden on both industrial and developing countries. In industrial countries, most cases occur in the elderly population, whereas in developing countries, 80% of cases occur in people younger than 60 years of age, resulting in a significant impact on productivity. Since 1984, more than 20,000 cases of tuberculosis have been reported annually in the United States. These cases are seen predominantly in geographic areas and demographic groups that include large numbers of people with acquired immunodeficiency syndrome (AIDS) as well as foreign-born persons who have emigrated from regions such as Asia, Africa, and Latin America, in which rates of occurrence are high. Other high-risk groups include patients in close contact with

others who are known to have tuberculosis; people with medical conditions such as silicosis, diabetes, immunosuppression, intestinal bypass, and malignancy; low-income individuals who have poor medical resources; alcohol and intravenous drug abusers; and persons institutionalized in correctional and nursing home facilities. In North America, multiple-drug-resistant tuberculosis (MDRTB) is a problem that has emerged in several major urban centers. In a study done in New York City, for instance, 33% of patients with positive cultures had isolates that were resistant to one or more antituberculous drugs.9 The strongest predictor of drug resistance was a previous history of antituberculous therapy. Other risk factors for MDRTB were HIV infection and intravenous drug abuse.

Screening for Tuberculosis Infection The objective of screening for tuberculosis in countries such as Canada and the United States, where administration of the bacille Calmette-Guérin (BCG) vaccine is not universal, is the identification of infected people who could benefit from preventive therapy. The Mantoux single subdermal injection of 0.1 mL purified protein derivative (PPD) containing 5 tuberculin units is the favored method. At 48 hours, an erythematous reaction 5 mm or larger is considered positive in individuals who have been in close contact with persons known to be infected, those with suspicious chest radiographs, and HIV patients. A 10-mm reaction is considered positive for people without those risk factors. A 15-mm reaction is classified as positive in all other persons. Positive tuberculin reactions in BCG-vaccinated persons usually indicate infection with MTB, but this is unpredictable. Mycobacteria other than tubercle bacilli (MOTT) react to other specific PPD skin tests, such as the PPD-B, which is used for the screening of Mycobacterium avium (Battey bacillus). Interferon-γ assays are being developed as a screening tool for patients with latent tuberculosis. These assays hold great potential because they may be more specific and more convenient than the ubiquitous skin test. The role of these tests is yet to be determined.10

Clinical Presentation The clinical presentation of a patient infected with MTB is determined by the site of primary infection, the stage of disease, and the magnitude of cell-type immunity response mounted by the host to resist the infection. Current experience indicates that in 80% to 90% of cases of tuberculosis occurring in patients without HIV, the disease involves the lungs. In most of these patients, involution and healing occur, and a dormant phase, which can last a lifetime, follows in 85% to 90% of those infected. During this dormant phase, the only evidence of infection with MTB may be a positive skin test to tuberculin or a Ghon complex seen on a chest radiograph. Reactivation occurs in 10% to 15% of infected persons, with half reactivating within the first 2 years after primary infection. In North America, reactivation classically occurs in middle-aged adults, and in 80% of cases, it involves the lungs. Reactivation at extrapulmonary sites, such as lymph nodes, pleura, or the musculoskeletal system, occurs in 20%

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 506

1/21/2008 11:37:37 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

of patients without AIDS but in 50% of patients who are HIV-positive.11 During the first weeks after contamination, pulmonary tuberculosis is often asymptomatic because the host’s immune reaction is minimal. Indeed, systemic symptoms of low-grade fever, malaise, and weight loss often arise so gradually that they are largely unnoticed. Cough due to the accumulation of secretions is most commonly seen when cavitation occurs, and, in general, the amount of sputum increases with progressive pulmonary excavation. Hemoptysis is often caused by complications such as bronchiectasis, erosion into vascular malformations associated with cavitation (Rasmussen’s aneurysms), or aspergillosis. Pleural or chest wall pain occurs with pleural involvement; dyspnea is common during acute febrile periods. Acute dyspnea may also result from a spontaneous pneumothorax or a rapidly developing pleural effusion. Extrapulmonary tuberculosis is secondary to hematogenous or lymphatic spread of pulmonary lesions, and virtually any organ can become infected. Swallowed secretions can result in infection of the gastrointestinal tract. In a retrospective review of 104 patients with thoracic tuberculosis published in 1997, Lardinois and colleagues12 showed that 69.2% of patients presented with an infection of the pulmonary parenchyma, 20.2% with pleural tuberculosis, 29% with tuberculosis of the chest wall, 7.7% with mediastinal tuberculosis, and 3.8% with bronchial stenosis. Other extrapulmonary sites of interest to the thoracic surgeon are the larynx13; the pericardium, where tuberculosis can cause constrictive pericarditis14; and the pleural space.15

TREATMENT

507

TABLE 43-4 Treatment of Tuberculosis: Indications for Surgery Complications Resulting From Previous Surgery Delayed complications of plombage Complications of insufficient surgery Failure of Medical Therapy Progressive disease, lung destruction, and left bronchus syndrome Lung gangrene Drug resistance Aspergillosis complicating treatment Surgery for Diagnosis Pulmonary lesions of unknown cause Mediastinal adenopathy of unknown cause Complications of Scarring Massive hemoptysis Cavernoma Lung cancer Tracheoesophageal or bronchoesophageal fistula Bronchiectasis Extrinsic airway obstruction by tuberculous lymph nodes Endobronchial tuberculosis and bronchostenosis Middle lobe syndrome Extrapulmonary Thoracic Disease Tuberculosis of the heart and great vessels Vascular malformations Constrictive pericarditis Cold abscesses and osteomyelitis of the chest wall Pott’s disease Pleural Tuberculosis Pleural effusion Bronchopleural fistula Infections With Mycobacteria Other Than Tubercle Bacilli (MOTT)

Medical Treatment The initial prescribed treatment for active tuberculosis is a 6- to 9-month regimen consisting of four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. With this regimen, almost 90% of patients have bacteriologically negative sputum at the end of the 6-month period. If resistant organisms are suspected, alternative drugs, such as streptomycin, can also be started until drug sensitivities are obtained. Patients with latent tuberculosis who are at high risk for progression to tuberculosis disease, such as patients with HIV infection and those who are at increased risk for recent infection (e.g., contacts of patients with tuberculosis), are treated with 9 months of isoniazid.16

Indications for Surgical Treatment With the advent of effective antituberculous medication, the role of surgery in the management of tuberculosis has greatly diminished; it is now reserved mainly for the treatment of complications of the disease. Indications for surgery differ slightly depending on geographic location. The most common surgical indication in the United States, for example, is MDRTB with destroyed lung and persistent cavitary disease. By contrast, the majority of operations in Canada and Europe are performed for complications of therapy or late sequelae of previously cured tuberculosis. The indications for surgery in tuberculosis can be grouped into seven main categories (Table 43-4):

1. 2. 3. 4. 5. 6. 7.

Complications resulting from previous surgery Failure of medical therapy Diagnosis Complications of scarring Extrapulmonary thoracic disease Pleural tuberculosis Infection by MOTT

Complications Resulting From Previous Surgery Delayed Complications of Plombage. Enthusiasm for the surgical treatment of tuberculosis by thoracoplasty began at the end of the 19th century and was greatest at the time of John Alexander’s publication in the early part of the 20th century. During those years, a large number of patients were treated with thoracoplasty and plombage. Many of them were still alive in the latter part of the century and some were suffering from late complications of these procedures. Although various materials, such as rubber bags and sheeting, paraffin packs, Polystan sponges, and fiberglass, were used for plombage, Lucite balls (Fig. 43-9) were universally preferred. These spheres were made of translucent methyl methacrylate with a diameter of about 2.5 cm. Despite an increasing number of delayed complications (Table 43-5) and the abandonment of the procedure at Duke University in

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 507

1/21/2008 11:37:38 AM

508

Section 3 Lung

FIGURE 43-9 Posteroanterior chest radiograph of a 74-year-old man who presented with an unrelated upper respiratory tract infection. He had previously been treated for tuberculosis by thoracoplasty on the right and plombage with Lucite balls on the left.

FIGURE 43-10 Posteroanterior chest radiograph of an asymptomatic 62-year-old man treated 30 years previously with paraffin plombage. Note the large collection, which is sometimes called a paraffinoma.

TABLE 43-5 Common Late Complications of Plombage

cava was also documented.20 Cephalad migration with impingement on the branches of the brachial plexus often caused new onset of chest wall pain. Oleothorax used a malleable material made of paraffin, bismuth, and mineral oil to induce pulmonary collapse. After insertion, the material became surrounded by a calcified membrane (Fig. 43-10), which could break after trauma or other abnormal contusion of the chest wall. The oil or the wax could then migrate toward the skin, causing a pleurocutaneous fistula,21 or toward the mediastinum, causing a bronchopleural fistula.22,23 Patients could also experience septic complications of the plombage space. With infection, because of an increased intracavitary tension, the foreign body used for the plombage could be pushed out of the space and into the subcutaneous tissues. A surgeon, unaware of the underlying condition, may incise and drain what is assumed to be a subcutaneous abscess and, instead of pus, be met by draining oil. Late empyema can develop years after artificial pneumothorax24 or longstanding oleothorax.23 Aspergillus species, anaerobes, Haemophilus influenzae, Staphylococcus aureus, Klebsiella species, Streptococcus pneumoniae, and even MTB have been isolated from sites of a plombage-cutaneous fistula.25 Treatment of an infected plombage space or of migration of plombage material consists of the removal of the foreign bodies, empyemectomy, and thoracoplasty with or without the use of muscle transposition to fill the residual space.26-28 Intraoperative fluoroscopy may be necessary to ascertain that all foreign material has been removed. Often, the Lucite balls were inserted within a bag or were attached to a string, which makes their removal easier.

Superinfection Migration of foreign material Erosion of adjacent organs Malignant changes Expanding hematomas

1948, plombage with Lucite balls remained in vogue for many more years because it could be performed in one stage, could be done on sick patients, and was associated with less physical deformity than was thoracoplasty. Initially performed extrapleurally, the procedure was regularly complicated by erosion into the lung. Because of this complication, the procedure was later performed extraperiosteally, where a thick layer of tissue between the foreign material used in the plombage and the lung itself could prevent erosion. Because of its final appearance, the procedure became known as the “birdcage operation.” Unfortunately, Lucite balls tended to migrate, either in the mediastinum, where they compressed mediastinal structures, or under the skin, which was more common because of the low resistance to migration offered by the devitalized ribs. Migration in the mediastinum could lead to erosion of the esophagus, sometimes including passage of the balls into the esophagus, causing small bowel obstruction.17,18 Erosion of the aorta or subclavian artery occurred with ball migration into the big vessels. Severe hemoptysis was reported after erosion of intercostal arteries,19 and obstruction of the vena

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 508

1/21/2008 11:37:38 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

Tension pleural effusion can occur 20 or more years after therapeutic pneumothorax. It usually manifests with a sudden increase in dyspnea, and chest radiographs may show increased opacity with mediastinal shift.29 Patients with chronic residual spaces after treatment for tuberculosis can also present with effusions, yielding fluid that has the appearance of lymph. Although cholesterol concentrations can be greater than 150 mg/dL, no chylomicrons are found—hence, the term pseudochylothorax is used to describe these effusions.15 Some patients, after having sustained thoracoplasty for the treatment of tuberculosis as well as other pathologic conditions of the chest, present with rapidly growing chest wall or intrathoracic tumors. These lesions are called chronic expanding hematoma and are made of non-neoplastic reactive tissue consisting of blood surrounded by dense fibrous tissue. Other terms used for this unusual entity include old ancient hematoma, Masson’s pseudoangiosarcoma, and papillary endothelial hyperplasia.30,31 The hematoma manifests as a new, expanding lesion on the chest wall or thoracic cavity years after the initial procedure, and it is often difficult to differentiate it from a relatively more common malignant vascular neoplasm such as an angiosarcoma. The cause of this pseudotumor is unclear, but reaction to a foreign body was suggested by Fukai and colleagues.32 Another unusual problem associated with the long-term presence of foreign bodies in the chest is the development of a malignancy. Whether the malignancy is caused by the chemical structure of the implanted material or by associated chronic inflammation resulting from the implantation is still debated. Primary extraskeletal chondrosarcoma,33 malignant fibrous histiocytoma,34,35 liposarcoma,36 and type B nonHodgkin’s lymphoma37,38 have been documented in plombage space years after the initial procedure. In view of the severity of some of these late complications, it is probably safe to recommend ablation of plombage material, even in asymptomatic patients. Complications of Insufficient Surgery. The most important surgical principle of pulmonary resection for tuberculosis is to remove all gross disease while leaving enough tissue for adequate pulmonary function. Another important principle is to undertake lung resection only in patients who have converted their sputum. Antituberculous medications do not always sterilize necrotic or scarred lesions, and MTB can remain active despite appropriate sensitivity and compliance with drug regimins.39 Whether microscopic active disease should be allowed to remain (especially in patients with resistant MTB) in order to preserve pulmonary function or whether the resection should be extended to encompass all disease is still a matter of controversy. It is not unusual to encounter patients with complications such as bronchopleural fistula that are clearly related to persistent or reactivated disease40 or with recurrences in the pleural space, where effusions containing mixed bacteria and mycobacteria have been reported in a number of series, particularly in patients with active disease at the time of surgery.41 Other sites of postoperative recurrence that may require surgical reintervention include the pericardium and lymph

509

nodes. Tuberculous pericarditis is estimated to occur in 1% to 2% of cases of pulmonary tuberculosis, and most patients present with symptoms of constrictive pericarditis.42,43 Despite adequate medical treatment, some patients require pericardial resection to relieve the symptoms of tamponade. Because complete pericardial resection usually is not possible, the procedure leaves foci of active disease, which can be associated with late complications such as chronic sinus tracts or mediastinal abscesses.14 Incomplete resection of tuberculous adenitis in the neck can also lead to the formation of sinus tracts to the skin. If biopsy of these nodes is necessary for diagnostic purposes, complete excision followed by adequate long-term medical therapy is recommended to avoid this problem.

Failure of Medical Therapy Progressive Disease, Lung Destruction, and Left Bronchus Syndrome. Unilateral total and complete lung destruction is a well-recognized complication of tuberculosis. Late presentation, errors in diagnosis, poor compliance, or insufficient treatment account for the largest number of patients presenting with this condition. Lung destruction is characterized by extensive disease that includes fibrosis, widespread cavitation, and bronchiectasis. In a review of 1600 cases of pulmonary tuberculosis, Ashour and colleagues44 found that post-tuberculous lung destruction occurred in 1% of patients. Characteristically, these individuals had had tuberculosis for many years and presented with huge cavitary complexes involving one of the hemithoraces (Fig. 43-11). In the series published by Bobrowitz and colleagues of 18 patients whose lungs had been destroyed secondary to tuberculosis, the most disabling symptom was shortness of breath due to functional exclusion.45 Hemoptysis was also an important complication and was the cause of death in three patients. Post-tuberculous lung destruction occurs more commonly on the left side (Fig. 43-12), a finding thought to result from the anatomy of the left main stem bronchus, which is longer and narrower than the right and therefore more prone to extrinsic compression as it courses beneath the aorta.44 This is known as the left bronchus syndrome. In these cases, pneumonectomy is usually indicated for hemoptysis, for chronic bacterial superimposed infection, or simply to provide symptomatic relief. In a series of 118 consecutive patients who underwent pneumonectomy for destroyed lung (tuberculosis: n = 43) between 1986 and 1996, Halezeroglu and colleagues40 reported that the combined morbidity and mortality rate of the operation was significantly higher in patients with preoperative empyema (P < .003), tuberculosis (P < .03), or right pneumonectomy (P < .03). The authors concluded that extrapleural dissection, buttressing of the bronchial stump, and postoperative irrigation of the cavity could help decrease the rate of postoperative complications. Lung Gangrene. Lung gangrene is a rare form of parenchymal destruction that has a rapid and virulent clinical course. Initially, the radiographic features show pulmonary consolidation; this is soon followed by extensive necrosis with cavi-

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 509

1/21/2008 11:37:39 AM

510

Section 3 Lung

FIGURE 43-11 Posteroanterior chest radiograph of a 46-year-old man with a destroyed right lung; there are disseminated cavities throughout the entire lung field.

tation. The necrotic tissue can manifest as a mass within the cavity and can simulate a mycetoma. Acute pulmonary gangrene is usually caused by bacteria such as Klebsiella pneumoniae, S. pneumoniae, and H. influenzae, but, in a review of 22 cases, Khan and colleagues46 were able to document that some cases could also be related to MTB. Vascular thrombosis and arteritis can be found in these patients, and this vascular complication is thought to be the likely cause of pulmonary gangrene. The indication for surgery must be individualized; patients who are not responding to medical therapy and those who are progressing to the formation of an abscess are likely to benefit from pulmonary resection. Because all cases harbor active infection, prophylactic measures are taken to prevent the formation of bronchopleural fistulas and empyema. For instance, the incision must be designed to allow preservation of the latissimus dorsi or the serratus anterior, either of which can be used as a vascularized pedicled tissue flap. Drug Resistance. Despite aggressive prophylactic education, tighter control of the care of tuberculosis patients, and the commitment of additional resources to tuberculosis control programs, compliance with medical therapy has always been difficult to enforce. The more recent problem of MDRTB, which is on the rise throughout the world, is particularly prevalent in countries that cannot afford increasing costs of treatment. In the United States, resistant organisms cause approximately 7% of cases of tuberculosis, but in some cities, resistant organisms may cause 12% to 56% of cases.47 In California, about 2% of patients have resistant

FIGURE 43-12 A, Posteroanterior chest radiograph of an elderly man with a destroyed left lung, bronchopleural fistula, and empyema. In a case such as this, it is difficult to differentiate between a truly destroyed lung and a tuberculous empyema with relatively expandable underlying lung. B, Thick pus (mixed bacterial and tuberculous) contained within the space.

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 510

1/21/2008 11:37:39 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

MTB, and this number has not changed despite an aggressive antituberculosis campaign. Patients with MDRTB are twice as likely to have cavitary lesions on chest radiographs, compared to those with non-MDRTB.48 MDRTB, which is defined as resistance to two or more drugs, including isoniazid and rifampin, is a major challenge because relapse rates as high as 44% have been reported with medical therapy alone.49 Although drug resistance is usually caused by inadequate prior medical therapy or by secondary resistance, some reports have identified a number of patients with de novo drug resistance. Sputum conversion in patients with sensitive organisms takes place within 3 months after the initiation of treatment. Failure to convert sputum after that length of time is highly suspicious for the presence of a resistant strain.50 Once drug resistance has been established, administration of medical therapy alone has been associated with mortality rates as high as 50%.51 The association of MDRTB with HIV is a major health problem. In 1992, Busillo and associates reported a mortality rate of 62% in 24 patients with HIV who were infected with MDRTB.52 Management of these cases is very difficult because of the large number of drugs required, each of which has its own toxicity. It is possible that surgery may have a role to play in this subset of patients also. When surgery is combined with postoperative chemotherapy, cure rates of up to 90% have been achieved. The presence of MDRTB is therefore an indication for surgery, provided that the disease is localized and the patient can tolerate surgery (Iseman et al, 1990).53-58 The presence of MDRTB is associated with significantly higher operative morbidity, compared with nonresistant disease.59 This increased morbidity is related to positivity of sputum at the time of surgery (up to 50% of patients), previous thoracotomy, previous chest irradiation, polymicrobial contamination, and poor nutritional status. In a series of 99 patients with MDRTB, Iseman and coworkers56 used three criteria to select patients who would benefit from surgery: (1) drug resistance and high probability of failure, (2) localized disease amenable to resection, and (3) enough drug reactivity to allow healing of infected bronchial stumps. In this group of patients, sputum negativity was obtained in 25 of 27 survivors. The optimal duration of preoperative and postoperative chemotherapy is still debated, but the presence of negative cultures at the time of surgery clearly decreases operative morbidity and mortality.60 For this reason, prior medical treatment of at least 3 to 6 months is recommended.61 At the time of surgery, the extent of resection is based on both the amount of lung involved and the preoperative functional status. Whenever possible, all cavitary lesions and areas of destroyed lung are removed. Whether residual infected tissue can act as a nidus for relapse is controversial. In 1997, van Leuven and colleagues showed that higher percentages of nonconversion and failure of surgical therapy occurred when lobectomies or segmentectomies were done, compared with pneumonectomies.61 Other factors thought to increase the likelihood of relapse after lung resection are the postoperative occurrence of bronchopleural fistulas and infected spaces.62

511

To prevent these complications, Pomerantz and colleagues55 recommended routine use of muscle and omental plombage to cover bronchial stumps and fill the pleural space. In their series, only 5 fistulas were reported in 180 pulmonary resections. If pneumonectomy is necessary, an extrapleural approach eliminates the possibility of contamination of the residual thoracic space. Surgery decreases the pool of viable bacteria, but seldom does it eradicate it completely. Therefore, drug therapy must be continued postoperatively. Some authors advocate treatment for as long as 3 years postoperatively,56 but this seems long and impractical. In 1997, van Leuven and colleagues61 proposed a tailored approach that takes into account the amount of residual disease, the sputum status at the time of operation, the microbiology of the resected specimen, and the initial indication for surgery when determining the length of postoperative drug therapy. In their series, the average length of postoperative drug therapy was about 8 months. In all cases, adequate long-term follow-up is necessary to document relapses that occur during treatment and reinfections that occur once the treatment has been completed. Aspergillosis. Aspergillosis is an infectious disease caused by various Aspergillus species, the most common being Aspergillus fumigatus. This fungus grows as a saprophyte in patients with structural lung damage and colonizes cavities secondary to tuberculosis, lung cysts, lung abscesses, bronchiectasis, neoplasms, and sarcoidosis. Other types of aspergillosis involving the lung include allergic bronchopulmonary aspergillosis, which is seen in atopic patients, and invasive aspergillosis, which occurs in immunodeficient patients.63 When aspergillosis infects a lung cavity, necrotic tissue loosens and forms a mass of hyphae tangled with inflammatory cells and red blood cells (Fig. 43-13). It appears on chest radiographs as a dense ball capped by a slim meniscus of air within the cavity (fungus ball, or mycetoma). The most common clinical presentation of aspergilloma is hemoptysis, which in some series occurs in up to 91% of patients.64 Massive hemoptysis, which results from vascular erosion by the fungus or occurs secondary to the production of endo-

FIGURE 43-13 Resected specimen showing a typical aspergilloma within a preexisting tuberculous cavity. The fungus ball is made of fungi, necrotic debris, inflammatory cells, and red blood cells.

tahir99-VRG vip.persianss.ir

Ch043-F06861.indd 511

1/21/2008 11:37:40 AM

512

Section 3 Lung

toxins with hemolytic properties,65 is associated with mortality rates varying from 25% to 100%.66,67 Medical therapy for aspergillomas that involves antifungal agents is usually ineffective, but cavernoscopic evacuation of aspergillomas followed by repeated intracavitary instillation of antifungal agents has been used successfully as an alternative method of palliation in patients for whom surgery would be a great risk.68 Bronchial artery embolization can also be used to gain time until further therapy can be initiated.69 Ultimately, surgical resection offers the best chance for cure. Operative mortality rates are in the range of 5% to 7%,70-72 and the complications of resection are low, especially if the patient does not have active tuberculosis at the time of operation.

Surgery for Diagnosis Pulmonary Lesion of Unknown Etiology. The various clinical presentations of pulmonary tuberculosis represent different manifestations of the host’s reaction to the infection. At one end of the spectrum, there is a simple granuloma, known as tuberculoma; at the other end, there is cavitation with or without pulmonary destruction. Lymph node involvement may result in bronchial invasion with secondary stenosis or distal bronchiectasis. On standard chest radiographs, tuberculomas manifest as pulmonary nodules. Overall, they represent about 15% of all solitary pulmonary nodules.73 They are usually located at the periphery of the lung, immediately beneath the pleura. On cut section, they appear as concentric rings of lamellar layers with some degree of caseation not always visible to the naked eye. No single microscopic feature differentiates tuberculomas from other granulomatous lesions of the lung, and the diagnosis must be confirmed by Ziehl-Neelsen staining, culture, or other fluorescent or immunoperoxidative techniques. Because most patients have no documented history of tuberculosis, the diagnosis of tuberculoma is often made after resection of a solitary nodule of unknown cause.74 On chest radiography, the differential diagnosis between a tuberculous granuloma and lung cancer is not always clear, and there is great variation among individuals in the interpretation of radiographic signs, even among chest specialists.75 Most radiologic signs are of low specificity for predicting malignancy, and, in addition, the site of the lesion has no real predictive value.76 In recent years, several authors have shown that contrast computed tomography (CT) scanning with incremental dynamic studies, using 20 Hounsfield units (HU) as a threshold, appears to be a good indicator of malignancy.77,78 The CT halo sign is a low attenuation zone around a pulmonary nodule, which is usually seen with aspergillomas but has also been reported with tuberculomas.79 The discovery on thin-section CT of a bronchus leading into the lesion, also called a positive CT bronchus sign, is more often seen with malignant lesions,80 whereas ring or central curvilinear enhancement due to central caseation has been reported in 75% of tuberculomas.81 In a study carried out in an area endemic for tuberculosis, Lai and associates74 found that transbronchial needle aspira-

Ch043-F06861.indd 512

tions and brushings were diagnostic in 55% of patients with tuberculomas and in 70% of patients with malignancies. Of the tuberculomas, 45% yielded positive cultures, and rates were even higher with larger lesions. When transthoracic needle biopsy is used, a specific diagnosis of benign disease is definitely helpful, but a report that suggests only nonspecific cellular elements prompts repeat biopsy or excisional biopsy.82 Pulmonary mucoceles are the result of chronic airway obstruction caused by broncholithiasis, strictures, or tuberculomas. Mucoceles often manifest as solitary masses that are indistinguishable from malignancies on radiographs.83 Although CT scanning may provide more information about the content of the cyst, surgical resection is often necessary to establish the diagnosis. Mediastinal Adenopathy of Unknown Etiology. Tuberculosis of the lymph nodes is one of the most common presentations of extrapulmonary tuberculosis. Although it is most commonly found in the cervical region, tuberculous lymphadenitis can also involve mediastinal lymph nodes (Fig. 43-14). Typically, patients have few or no systemic symptoms, but radiologic evidence of slowly enlarging mediastinal adenopathy may be found, and it can be difficult to differentiate this from other causes of mediastinal node enlargement. Because most patients do not have active pulmonary disease at the time of presentation, positive diagnosis is based on the isolation of mycobacteria in lymph nodes. Fine-needle aspiration is safe and has a sensitivity of about 80% and a very good specificity.84 On CT-guided transthoracic core biopsy, the diagnosis of tuberculosis can be established with bacteriologic confirmation based on the presence of any two of the following three findings: epithelioid cells, multinuclear giant cells, and caseous necrosis.85 Cervical mediastinoscopy and transtracheal and thoracoscopic biopsies are alternative methods that can be used to obtain tissue for diagnosis. Surgical removal of the nodes is indicated only for patients with complications resulting from the adenopathy. Patients with mediastinal tuberculous lymphadenitis are treated with a 6-month regimen, as described previously.86 Lymph nodes may enlarge during treatment, and this is not an indication of relapse.

Complications of Scarring Massive Hemoptysis. Most patients with hemoptysis and active tuberculosis (Fig. 43-15) bleed because of the development of systemic bronchial circulation around the infected sites. In addition, the incorporation of pulmonary vessels into the wall of tuberculous cavities causes small dilations of these vessels, which are referred to as Rasmussen’s aneurysms.87 These aneurysms have been found to be present in 4% of autopsies of patients with tuberculosis.88 Bleeding from tuberculous lesions is usually the result of bronchial ulcerations into bronchial arteries or into Rasmussen’s aneurysms. Occasionally, bleeding is secondary to necrosis of small branches of pulmonary veins; erosion of old, calcified nodes through a bronchus (broncholith); or acute tuberculous ulcerations of the bronchial mucosa. The treatment of massive hemoptysis is reviewed in Chapter 38. It involves, first, bron-

1/21/2008 11:37:41 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

513

FIGURE 43-14 Posteroanterior chest radiograph (A) and CT scan (B) of a 19-year-old woman with nonspecific upper respiratory tract symptoms. Note the enlarged lymph nodes, mostly visible in the subcarinal space (arrow). Thoracoscopic biopsy showed caseous granulomatosis, and a smear was positive for acid-fast bacilli.

FIGURE 43-15 Posteroanterior chest radiograph (A) and CT scan (B) of a 30-year-old woman who presented with massive hemoptysis owing to active cavitary tuberculosis in the right lower lobe.

Ch043-F06861.indd 513

1/21/2008 11:37:41 AM

514

Section 3 Lung

chial artery embolization, and then, if the patient can tolerate surgery, resection of the source of bleeding. Cavernoma. One of the main indications for surgery in the golden days of tuberculosis was a large pulmonary cavern, which was the result of limited pulmonary destruction and represented a walled-off portion of acutely infected parenchyma, often located at pulmonary apices. The wall of a cavern is made of granulation tissue encircled by a layer of fibrous tissue in which Rasmussen’s aneurysms can be found. Caverns are often the site of reactivation and can be associated with such complications as bleeding and formation of aspergillomas. Whenever possible, large caverns are resected, but such lesions commonly occur in debilitated patients with severe underlying lung disease, in whom major resection is not possible. In such patients, thoracoplasty combined with muscle plombage may be useful to collapse the cavern. Another option is cavernostomy or cavernoplasty, known as speleoplasty. This technique involves sterilization of the cavern by drug instillation, followed by opening of the cavern and closure of the visible bronchi that open into it. The cavity is then obliterated with stitches or muscle plombage (Perelman and Strelzov, 1997).89,90 Lung Cancer. The association of lung cancer and tuberculosis has been reported with sufficient frequency to suggest that there is more than a coincidental connection. The linkage could occur by way of two different pathways. First, tuberculosis can be reactivated by bronchogenic carcinoma,91 either locally, by means of erosion of encapsulated caseous foci, or systemically, by means of the debilitation associated with the malignancy. The second possible link is the development of malignancies in areas of healed tuberculosis, known as scar carcinoma. In 1991, Dacosta and Kinare92 reported on 29 cases of tuberculosis associated with 221 cases of mostly undifferentiated carcinomas, as well as adenocarcinomas of the lung. The typical presentation was that of a lung cancer developing at the site of a parenchymal scar that had been stable for many years. In another study of 124 patients with coexisting bronchogenic carcinoma and pulmonary tuberculosis, Snider and Placik91 found that tuberculosis preceded the discovery of carcinoma in 56% of patients, and in 44% of cases, the two conditions were synchronous and were documented within 6 months of each other. The association of carcinoma with scarring is thought to be due to the poor clearance of carcinogens in scar areas or to the hyperplasia and metaplasia associated with healing and the production of growth factor–like substances. Tuberculosis is not the only source of scarring, and virtually any pathologic condition that produces scars within the lung can be associated with malignancy. For instance, malignancies have been described at sites of traumatic scarring associated with explosive shrapnel injuries, bullet wounds, or knife injuries93 and in association with silicosis,94 fibrosing alveolitis end-stage lung disease,95 and scleroderma.96 The recovery of acid-fast bacilli in suspected cases of bronchogenic carcinoma must never delay diagnostic procedures aimed at confirming the cancer. Similarly, patients with a known history of tuberculosis need to be followed regularly, to detect not only recurrences of the disease but also the development of scar carcinomas.

Ch043-F06861.indd 514

Tracheoesophageal or Bronchoesophageal Fistula. Although the majority of acquired nonmalignant tracheoesophageal fistulas result from complications of mechanical ventilation,97 they can occasionally be associated with mediastinal granulomatosis. In these cases, the fistulas are produced by the continuous pressure on and scarring of infected mediastinal nodes located between the trachea and the esophagus. The anatomic locations of fistulas are variable; they have been reported at the levels of the trachea, right main stem bronchus, left main stem bronchus, and right lower lobe bronchus.98 Unless surgery is urgently required, a trial of medical therapy seems to be a reasonable first-line approach because some of these fistulas heal with medical therapy alone.99 Patients with significant associated esophageal or bronchial stenosis and patients in whom the diagnosis of malignancy cannot be excluded might require surgery.98 Correction requires closure of the esophageal defect, segmental resection of the trachea, and tissue interposition.100 Bronchiectasis. The true incidence of bronchiectasis associated with tuberculosis is unknown, but it can be the cause of recurrent and sometimes massive hemoptysis as well as chronic infection.101 Bronchiectasis is caused by fibrosis and destruction of the lung, which causes retraction and dilation of the bronchi,101 or it occurs secondary to bronchial obstruction and includes postobstruction bacterial colonization. The bronchial obstruction itself results from bronchial stenosis due to fibrosis or extrinsic compression by cavernomas or enlarged lymph nodes.102 Bronchiectasis associated with tuberculosis is most often found in the spontaneously well-drained apical and posterior segments of the upper lobes (dry bronchiectasis), and in these cases, the clinical presentation is most commonly in the form of hemoptysis. Unless the hemoptysis is massive, patients need to be considered for surgery only after a long trial of medical therapy. If the hemoptysis is recurring despite adequate medical management, surgical resection is considered, particularly if the bronchiectasis is localized and if resection is likely to result in complete removal of the disease (Fig. 43-16). Extrinsic Obstruction by Tuberculous Lymph Nodes. Enlarged tuberculous nodes can occasionally compromise the lumen of airways. Although mediastinal adenopathy can be found in about 50% of patients requiring admission for complications of pulmonary tuberculosis, in only 2% do they cause airway compression severe enough to require surgical intervention.103 In extreme cases, the nodes can actually unload caseum into the bronchial lumen, resulting in sudden respiratory deterioration and even death. Children are particularly prone to mediastinal lymph node compression, probably because of yet poorly developed cartilaginous support. Rarely, calcified lymph nodes (broncholiths) erode into airways and cause bleeding and obstruction. Extrinsic airway obstruction is usually responsive to medical therapy, primarily to corticosteroids. In the rare cases in which the obstruction becomes clinically significant, surgical decompression may be necessary. The operation is carried out through a right thoracotomy and consists of incision and aspiration or curettage of nodal contents. Excision of the

1/21/2008 11:37:42 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

FIGURE 43-16 A CT scan of a 51-year-old woman previously treated for tuberculosis and referred for massive hemoptysis. Note the bronchiectasis in the apical segment of the left lower lobe.

entire lymph node is usually not recommended, to avoid iatrogenic lacerations of the airways.103 Because some of these lymph nodes may contain a liquefied core, endobronchial débridement and drainage are sometimes possible.104 Endobronchial Tuberculosis and Bronchostenosis. Endobronchial tuberculosis is seen in 10% to 37% of patients with pulmonary tuberculosis105 and, if untreated, leads to bronchostenosis.106 The stenosis results from local infection and subsequent scarring. Because the lower and middle lobes are more commonly affected than the upper lobes, it is possible that gravity plays an important role in the pathogenesis of this complication. Clinically, patients present with cough, bronchorrhea, and shortness of breath on exertion, with typical collapse or consolidation seen on chest radiographs (Fig. 43-17). The diagnosis of post-tuberculous bronchostenosis is made by bronchoscopic examination and bronchial biopsy. Sputum analysis and smears are notoriously unreliable in the majority of these patients, even in the early stages of disease. If the condition is diagnosed early, the progression to fixed stenosis can be prevented by administration of inhaled steroids.107 Once cicatricial bronchostenosis is well established, medical management has little to offer unless the patient has evidence of active tuberculosis.108 Surgical treatment needs to be based on the general status of the patient and the location of the stenosis. Balloon dilation, metallic stenting, laser vaporization, and bronchoplastic resection have been accomplished with good results.105,109-112 To prevent relapses or restenosis, continuous antituberculous chemotherapy is given for 9 to 12 months postoperatively. Middle Lobe Syndrome. Isolated atelectasis of the middle lobe is known as middle lobe syndrome. Although originally described as occurring only in the middle lobe, the process can involve the lingula as well. The syndrome is caused by extrinsic nodal compression of the bronchus of lingula or

Ch043-F06861.indd 515

515

middle lobe, which results in postobstructive atelectasis and chronic pneumonitis. Although this process could conceivably occur anywhere in the lung, the middle lobe and lingula are particularly susceptible because of the long and narrow bronchus and the absence of collateral ventilation in patients with complete fissures.113 The predominant symptoms are recurrent infection and atelectasis of the middle lobe on chest radiograph, with or without hilar lymphadenopathies. Bronchoscopy often shows a tight stenosis of the middle lobe bronchus.114 In patients with middle lobe syndrome, it is important to rule out endobronchial obstruction by a malignant neoplasm, which could produce the same radiologic appearance. Once the diagnosis of benign disease has been established, patients are screened for tuberculosis, and symptomatic patients who are fit for surgery undergo pulmonary resection. In a series of 229 patients infected with mycobacterial organisms, Pomerantz and colleagues113 found 13 cases of middle lobe syndrome. The authors noted that all patients involved were slender females with various combinations of skeletal abnormalities. All were treated by resection of the involved lobe or segments, and only two patients experienced postoperative reactivation of tuberculosis requiring additional antibiotic therapy. All patients were symptomatically improved after surgery.

Extrapulmonary Thoracic Disease Tuberculosis of the Heart and Great Vessels. Tuberculosis extends to the heart and great vessels by way of direct spread from the lung or mediastinal lymph nodes or by means of bloodstream dissemination.115 In 1935, Horn and Saphir116 classified myocardial tuberculosis into three main categories: miliary, nodular, and infiltrating. The most common clinical presentations were those of bleeding due to the rupture of tuberculomas or tuberculous abscesses, obstruction of the inflow or outflow tracts of the heart by tuberculomas, and conduction disturbances.115,117 Commonly, however, patients with cardiac tuberculosis present with nonspecific symptoms of weight loss, asthenia, dyspnea, and cardiac dysrhythmias. They almost always have evidence of concomitant active tuberculosis; therefore, any patient presenting with active tuberculosis and cardiac arrhythmias is evaluated for cardiac tuberculosis. The treatment of cardiac tuberculosis involves antituberculous medication unless mechanical consequences ensue. In such cases, surgical therapy aims at resolving the mechanical complication rather than at full resection of the disease. Postoperatively, all patients begin or continue antituberculous medication to treat residual disease as well as to avoid recurrences. Vascular Malformations. Tuberculous involvement of the great vessels is caused primarily by invasion of the wall of the vessel by adjacent tuberculous processes or, occasionally, by direct implantation of circulating mycobacteria.118 The result is either compression and stenosis of the involved segment of the vessel, with vascular insufficiency, or aneurysmal dilation with the risk of rupture. Because of its hilar-mediastinal location, the pulmonary artery is particularly prone to com-

1/21/2008 11:37:42 AM

516

Section 3 Lung

FIGURE 43-17 Posteroanterior chest radiograph (A) and CT scan (B) of an 80-year-old woman with complete obstruction of the distal left main stem bronchus. Both the radiograph and the scan show complete atelectasis of the left lung. At operation, the lung (C) was found to be completely consolidated and had to be removed.

pression by surrounding lymph nodes. In 1996, Cohen and colleagues119 reported the case of a 35-year-old woman with symptoms similar to those of pulmonary embolism who was found to have near-complete obstruction of the right pulmonary artery due to tuberculous lymphadenitis. The diagnosis was made by the recovery of acid-fast bacilli in the resected specimen. In 1976, Efremidis and coworkers118 reported the case of a 60-year-old woman with a rapidly expanding saccular aneurysm of the aortic arch but with no clinical evidence of ongoing tuberculosis. The diagnosis was made by the recovery of acid-fast bacilli in the resected aneurysmal wall. In 1988, Masjedi and associates120 reported a rare case of a bronchoaortic fistula in a patient who presented with massive hemoptysis. Bronchoscopy showed a brown vegetative mass protruding into the left main stem bronchus 2 to 3 cm below the carina, and postmortem examination revealed the cause of the fistula to be mediastinal granulomatous disease compatible with MTB disease. A number of other extrapulmonary vascular malformations due to tuberculosis can also occur within the chest. They

Ch043-F06861.indd 516

manifest with abnormal communications between chest wall systemic vessels and pulmonary artery circulation as a result of chronic scarring of the interposing tuberculous lung. Cohen and colleagues120a described such communications between the internal thoracic artery and the pulmonary artery branches of the left upper lobe in a 25-year-old, asymptomatic man who presented with a continuous murmur over the left precordium. In 1996, Ando and associates121 reported the case of a 77-year-old woman with active tuberculosis and a continuous flow murmur over the left anterior chest wall. Cardiac catheterization and subclavian arteriography revealed abnormal communication between the subclavian and pulmonary arteries. Untreated pulmonary systemic shunts caused by tuberculosis can result in pulmonary hypertension, heart failure, and possibly rupture. Medical therapy must always supplement surgical resection. Constrictive Pericarditis. Tuberculous pericarditis occurs in 1% to 4% of patients with tuberculosis,122 and it is a common cause of pericardial effusion in patients with AIDS. The evolution of tuberculous pericarditis classically occurs in

1/21/2008 11:37:43 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

four stages. The fibrinous stage (stage I) is characterized by deposition of fibrin and a granulomatous reaction within the pericardium and pleural space. This is followed by an effusion (stage II) with a predominance of lymphocytes; over time, the effusion resolves and the pericardium thickens (stage III). In the third stage, there is dense deposition of scar tissue and calcifications within the pericardium. The organization of this fibrous tissue eventually leads to myocardial constriction (stage IV). Clinically, the symptoms are those of a chronic nonspecific illness associated with the signs and symptoms of restrictive pericardial disease. Dyspnea, chest pain, and pedal edema are common.122 Electrocardiography is usually nonspecific, whereas chest radiographs may show some evidence of cardiomegaly. Tuberculin skin testing is unreliable, especially in patients with AIDS.123,124 On the other hand, echocardiography is extremely valuable in assessing the size of the effusion and the status of the underlying myocardium, but it is less useful in evaluating the thickness of the pericardial sac, a finding that is essential for the diagnosis of constrictive pericarditis. A thoracic CT scan with contrast is a better examination, and it has eliminated the need for cardiac catheterization.125 A positive diagnosis of pericardial tuberculosis can be made only by the identification of mycobacterium in the pericardial fluid or by direct visualization of the stigmata of the infection on the pericardium itself. Measurement of adenosine deaminase and carcinoembryonic antigen (CEA) levels in the pericardial fluid can be useful in differentiating an effusion secondary to tuberculosis from one associated with malignancy or acute viral pericarditis. Adenosine deaminase is elevated in the pericardial fluid of a patient with tuberculosis, whereas the CEA is significantly higher in a patient with a malignancy.126 Surgical procedures are generally indicated for patients with cardiac tamponade, patients with progressive pericardial effusion who are receiving appropriate medical therapy, and patients with constrictive pericarditis.123 In patients with suspected effusive tuberculous pericarditis, it is recommended that a pericardial window be performed; this not only allows for rapid evacuation of the fluid but also provides a large specimen for analysis. The subxyphoid, left anterior thoracotomy, and left thoracoscopic approaches are all safe and effective. Patients with thick pericardium are prone to develop severe constrictive pericarditis, so early pericardiectomy has been advocated in that circumstance. Patients with constrictive pericarditis are considered for surgery if they have evidence of calcifications or show no clinical improvement after 4 to 6 weeks of antituberculous medication.127 The surgical approach can be a median sternotomy or a left anterolateral thoracotomy, and the pericardium is excised from phrenic nerve to phrenic nerve, with decortication of the diaphragm and the anterolateral surfaces of the heart. The procedure is generally well tolerated, and most patients do not require cardiopulmonary bypass.128,129 In a series reported by Heurich and colleagues,122 complete resolution of cardiac symptoms occurred in 94% of patients. Cold Abscesses and Osteomyelitis of the Chest Wall. MTB can spread to the chest wall directly from a contiguous infected lung or through lymphatic dissemina-

Ch043-F06861.indd 517

517

tion.130 The clinical presentation may mimic that of a pyogenic abscess, although most patients have active pulmonary tuberculosis or a history of prior tuberculosis at the time of presentation.131 Tuberculous abscesses occur more frequently in the parasternal area (Fig. 43-18) and over the shaft of the ribs. Because most of the abscesses are asymptomatic, with the contents under no tension, and the skin overlying the abscess is usually of normal appearance, the term cold abscess has been used to describe them. Often, the lesions are accompanied by destructive changes in the underlying bone or cartilage. In the absence of pleuropulmonary tuberculosis, the diagnosis is difficult to establish because needle aspirates are diagnostic in only 22% to 28% of patients.130,132 However, the combination of rib destruction and an extrapleural soft tissue mass in an Asian or African immigrant makes the diagnosis of tuberculosis very likely.133 CT characterizes these cold abscesses as low-density collections, often with enhancing rings and occasional calcifications.134 Chest wall abscesses are treated with a combination of medical and surgical therapies. If a lesion continues to develop or fails to show regression with medical treatment, surgical débridement, including resection of the necrotic ribs, cartilages, and visible adenopathies, is necessary. We usually leave the skin incision open, but some surgeons prefer to close it so as to avoid the formation of sinus tracts. Chemotherapy after surgery is continued for 6 to 9 months. Using this regimen, the only recurrences reported have been in patients who failed to comply with chemotherapy after surgery.130,132 Pott’s Disease. Tuberculosis of the spine, also known as Pott’s disease, occurs in approximately 1% of patients with tuberculosis.135 It is characteristically a chronic and slowly progressive disease when compared with pyogenic osteomyelitis, which has a more acute course. The presentation of spinal tuberculosis is nonspecific, and most patients have back pain with varying degrees of neurologic impairment. Neurologic complications are more common if the disease involves the thoracic spine. Clinicians encountering destructive spinal disease must have a high degree of suspicion for a diagnosis of tuberculosis. Indeed, none of the presently available diagnostic modalities is very specific or sensitive. In a study of 19 patients with Pott’s disease, Omari and coworkers136 found a positive tuberculin skin test in 18, but only 42% of patients had abnormal chest radiographs. In a similar study involving 20 patients, Rezai and associates137 found a positive tuberculin skin test in 19 patients, and 65% showed evidence of concomitant pulmonary tuberculosis. Currently, CT scanning and magnetic resonance imaging (MRI) are important diagnostic tools for assessing the side and degree of vertebral involvement. Some of the typical CT findings are vertebral body destruction, space narrowing, and psoas or paraspinous abscesses.136 CT-guided biopsy can also be used in most patients. It could reveal acid-fast bacilli or granulomatous disease in 50% to 75% of cases.136,137 Treatment of Pott’s disease without neurologic complications can be medical or surgical. However, operative débridement results in faster recovery and less spinal deformity.137 Pott’s disease with neurologic deficit is best treated by radical

1/21/2008 11:37:43 AM

518

Section 3 Lung

FIGURE 43-18 A, A CT scan of a 29-year-old man with active pulmonary tuberculosis and a fluctuant lesion of the anterior chest wall. B, Photograph showing large anterior chest wall abscesses (arrows) that, at surgery, were found to extend to the underlying sternum and ribs. The patient had a good response to débridement and medical therapy.

surgery. Early operative treatment minimizes neurologic deterioration and spinal deformity and allows for early ambulation.136,137 The indications for surgery are given in Table 43-6. Spinal tuberculosis is best approached through a thoracotomy. A thoracic surgeon is often called upon to perform the opening of the chest and exposure of the vertebral bodies. The side on which the thoracotomy is performed is determined by the side where there is maximal bony involvement or spinal cord compression. The disks above and below the affected vertebral bodies are resected along with the posterior longitudinal ligament in order to drain any epidural abscess. Intervertebral instrumentation and autologous iliac crest bone grafting are then performed. To avoid relapse, all patients receive antituberculous medication postoperatively for periods of 6 to 9 months.

Pleural Tuberculosis Pleural Effusion. Involvement of the pleura (Fig. 43-19) is a common extrapulmonary manifestation of pulmonary tuberculosis. Pleural tuberculosis is caused by the presence of MTB in the pleural space and is thought to be secondary to the rupture of a caseous pulmonary lesion. The amount of pleural effusion is determined by the interaction between the bacilli antigen and sensitized CD4+ T lymphocytes. The result of this interaction is a delayed hypersensitivity reaction, which produces an increase in capillary permeability. There

Ch043-F06861.indd 518

TABLE 43-6 Criteria for Surgical Management of Pott’s Disease Neurologic deficit Spinal instability or deformity Unresponsiveness to medical therapy Noncompliance with medication Nondiagnostic biopsy From Rezai AR, Lee M, Cooper PR, et al: Modern management of spinal tuberculosis. Neurosurgery 36:87, 1995.

is also an accumulation of helper T cells, potentiating the inflammatory reaction.138 Pleural effusions can appear at any time during the natural course of tuberculosis and can be associated with both primary and reactivation disease. Typically, patients present with symptoms of pleural involvement, including pleuritic chest pain, fever, dyspnea or, rarely, chest wall masses and pleurocutaneous sinus tracts. The effusion commonly appears in the absence of radiographic or clinical evidence of pulmonary tuberculosis. Although tuberculous pleural effusions can regress spontaneously, active pulmonary tuberculosis develops in 30% to 50% of such patients, indicating the importance of diagnosing and treating these effusions early.139 Up to one third of patients do not demonstrate positive tuberculin skin tests at the time of presentation, a phenom-

1/21/2008 11:37:44 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

519

FIGURE 43-19 Posteroanterior (A) and lateral (B) chest radiographs of a 30-year-old woman with a loculated right pleural tuberculous empyema. Note the pericardial calcifications (arrow), indicating concomitant pericardial involvement.

enon explained by the preferential sequestration of antigenspecific CD4+ T cells in the pleural space and by the presence of suppressor cells in the blood.138 Unless anergic, most patients eventually convert, usually 6 to 8 weeks later. The pleural fluid of tuberculous effusions is clear and citrus in color and is an exudate. Pleural fluid protein and lactate dehydrogenase are elevated, whereas the pH is less than 7.4 and the glucose concentration is approximately 60 mg/dL. The total cell count is usually fewer than 6000/µL, the cell population being predominantly T lymphocytes, with an absence of mesothelial cells.140 The ratio of pleural fluid to serum adenosine deaminase has been found to be greater than 1.5 in 85.7% of tuberculous effusions.141 The concentration of cholesterol increases in chronic tuberculous effusions, and in some cases the pleural fluid may even have a milky appearance (pseudochylothorax). Pleural fluid cultures are not sensitive; they may yield MTB in only 50% of cases.140 The diagnosis must therefore be confirmed by pleural biopsy, which can yield MTB or granulomas in 75% to 80% of patients. If bedside pleural biopsy fails to provide a diagnosis, diagnostic thoracoscopy is carried out.142 With open biopsy, granulomas can be found in up to 60% of cases, but this finding is not pathognomonic of tuberculosis because granulomas can also be present in other pathologic conditions, such as sarcoidosis, rheumatoid arthritis, and fungal infections. Pleural biopsies can be complemented by internal mammary lymph node biopsy. Using this technique, Villegas and colleagues143 were able to confirm a diagnosis in 62.5% of cases of tuberculous pleural effusion.

Ch043-F06861.indd 519

Surgical drainage of the pleural space is performed only in patients who have large effusions. The management of pleural tuberculosis is otherwise mainly medical. Treatment with two drugs for a period of 9 months is recommended, although successful treatment courses of 6 months, using isoniazid and rifampin, have also been reported.144 Drugs must be adjusted to the sensitivity of the organism, and treatment is prolonged in cases of drug resistance and in HIV patients. The concomitant administration of oral steroids may lead to a more rapid resolution of the symptoms,145 but this does not seem to decrease the incidence of pleural thickening and trapping. As a result of lung trapping, failure of pulmonary expansion after adequate medical therapy can occur in up to 50% of patients.146 If this situation develops, intervention is indicated in young patients and in patients with significant pulmonary restriction (Fig. 43-20). Another possible complication of tuberculous pleurisy that requires surgical management is bacterial contamination of the pleural space (empyema). In this condition, tube thoracostomy with negative suction is used first, but if lung expansion cannot be obtained, open decortication or empyemectomy may become necessary. Bronchopleural Fistula. A bronchopleural fistula is a rare complication of pulmonary tuberculosis. It results from the opening of a pulmonary cavitation into the pleural space or from the erosion of a pleural empyema into the lung. The clinical picture is variable; some patients have an air-fluid level that is found incidentally on a chest radiograph, whereas others present with a life-threatening tension pneumothorax. The most common clinical presentation, however, is in the

1/21/2008 11:37:44 AM

520

Section 3 Lung

FIGURE 43-20 Posteroanterior chest radiograph (A) and CT scan (B) of a 60-year-old man with post-tuberculous fibrothorax.

form of a slowly progressive, emaciating disease that can eventually lead to the death of the patient if left untreated. In a study reported by Donath and Khan in 1984, 7 of 13 patients with bronchopleural fistula had prior evidence of pleural disease in the form of a fibrothorax.147 All patients had a history of tuberculosis, and none had been compliant with medications. These findings underline the importance of early and adequate treatment of pleural tuberculosis as well as the importance of pleural scarring in the etiology of bronchopleural fistula. The initial management of tuberculous bronchopleural fistula consists of tube drainage and antibiotic therapy. Although tube thoracostomy has been used on a permanent basis,147 it is usually a temporary measure that allows rapid resolution of sepsis and optimal preparation of patients for more definitive therapy. In elderly patients with chronic sepsis and in patients with AIDS, open drainage by way of a thoracic window is an alternative. Once drainage of the pleural cavity has been established, sepsis is under control, and tuberculosis is adequately treated medically, low-risk patients can be offered permanent repair of the fistula. Preparation for this can take 3 to 6 months because patients with ongoing active tuberculosis at the time of surgery have higher risks for surgical complications in the form of pleural empyema and dehiscence of the repair. The objective of surgery is to close the fistula and obtain full lung re-expansion through decortication alone or by filling the pleural cavity with muscle or omentum flaps. Pulmonary resection is reserved for patients in whom the underlying lung has been seriously damaged and is beyond salvage. Because patients undergoing pulmonary resection, especially pneumo-

Ch043-F06861.indd 520

nectomy, are at high risk for bronchial dehiscence, the bronchial stump is always reinforced with viable vascularized autografts. Miller and associates148 suggested that, if the pleural space has been contaminated during pneumonectomy, balanced drainage needs to be used for 2 to 3 weeks, followed by the establishment of a continuous irrigation system with antibiotics for another 2 weeks. Tubes are removed once the cavity is sterile.

Infections With Mycobacteria Other Than Tubercle Bacilli In North America, MOTT infections are more common than MTB infections, and this is particularly true for patients affected by AIDS. The most common organs involved by atypical mycobacteria are the lungs, cervical lymph nodes, soft tissues, bones, and joints. These infections share with MTB a number of clinical and bacteriologic similarities, and they often are indistinguishable from one another. Most nontuberculous mycobacteria are resistant to usual antituberculous therapies. MOTT infections are also known as nontuberculous mycobacterial disease (NTM), yellow bacillus (Mycobacterium kansasii), Battey bacillus (M. avium), anonymous mycobacteria, Lady Windermere syndrome (M. avium), and MAC (M. avium and M. intracellulare complex). Many atypical mycobacteria are human saprophytes, but some can produce clinical infections. The MOTT most commonly associated with lung disease are M. avium-intracellulare, M. kansasii, and Mycobacterium abscessus. M. fortuitum has also been found to cause sternal osteomyelitis and contamination of

1/21/2008 11:37:45 AM

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases

porcine valves.149 M. kansasii is the most common atypical mycobacterium in the central United States, whereas MAC is the most common in the southern and southeastern parts of the country. In some laboratories, MAC is even more common than MTB and has become the most common mycobacterial species.150 Some atypical mycobacteria can be normal inhabitants of the airway, so clinically significant disease is diagnosed by evidence of lung lesions on radiographs and by repeated isolation of the organisms from bronchial secretions.151 MAC produces a fibrocavitary disease of the upper lobes, typically in white men who are alcoholic and in smokers with underlying chronic obstructive pulmonary disease. It can also affect patients with few or no risk factors, and it has shown a predilection for the lingula and middle lobe in nonsmoking women, a clinical condition known as Lady Windermere syndrome.152 At the present time, the most effective drug therapy is the combination of clarithromycin with rifabutin or rifampin and ethambutol until the patient is culture-negative for 1 year. For the first 2 to 4 months, streptomycin is added to the regimen if there is extensive disease, such as the presence of cavitary lesions. In a significant number of patients, sterile sputum is the desired outcome of this regimen, but the main drawback of medical management remains drug toxicity and treatment compliance. Surgical resection is indicated for localized disease. By combining surgery with medical therapy, sputum conversion can be achieved in 88% to 94% of patients, with relapse rates of less than 6%.150,153,154 Sputum conversion seems to be more permanent after surgery. In 1983, Moran and colleagues153 documented that 90% of their patients who were sputumnegative at the time of operation had positive cultures or smears from resected lung tissue. It is possible that the resection of these foci of persistent disease may lead to better long-term outcome when compared with medical therapy alone. The length of postoperative medical therapy is not standardized, although it is believed that drugs need to be given for at least 1 year. Patients infected with M. kansasii are typically in their 50s; risk factors for this disease include cigarette abuse, pneumoconiosis, HIV infection, and living in the midwestern United States. This infection is medically easier to treat than MAC, so surgery is seldom indicated. Infection by M. abscessus has a clinical presentation different from that of infection by other MOTT. It tends to affect white women, who present radiographically with a diffuse, patchy interstitial disease that is difficult to differentiate from scarring or fibrosis. M. abscessus pneumonia has a progressive and slow course that can cause death if left untreated. Because M. abscessus is resistant to antituberculous medication, medical therapy alone is usually not successful, and surgery is considered if the disease is localized and the patient can tolerate surgery.

Outcome of Surgical Treatment The surgical experience accumulated over the past 50 years indicates that the role of surgery in the treatment of tuber-

Ch043-F06861.indd 521

521

culosis is unquestionable (Table 43-7). With proper indications for surgery, sputum conversion rates of more than 90% can be obtained. Because the same results can be expected in patients harboring sensitive organisms who comply with treatment, surgery is always considered as an adjunct to proper medical therapy. In established cases of tuberculosis, no patients are operated on without proper antibiotic coverage of at least 3 months’ duration, and surgeries are always followed by complete courses of therapy, the lengths of which are dictated by the resistance of the organisms and the susceptibilities of the hosts. In patients with normal immune systems, postoperative medical treatment includes at least two drugs (isoniazid and rifampin) for 6 months. In immunocompromised patients, such as those with HIV infection, in whom MDRTB is prevalent, postoperative treatments are carried out for periods of 9 to 12 months, or longer in cases of true resistance (Iseman et al, 1990).56 The role of surgery is to remove the burden of mycobacteria in actively infected patients or to treat debilitating consequences caused by the ongoing scarring process that characterizes the healing of tuberculosis. It is indeed very difficult to sterilize cavernomas or destroyed lungs, probably because the disease is too far advanced or medications are unable to penetrate the lesions. After such permanent anatomic changes occur, medical treatment alone has a high failure rate, and the addition of surgery to remove nidus of active tuberculosis may improve the cure rate of the disease (Mouroux et al, 1996).155 Proper preoperative evaluation and optimization of the patient’s status are essential, and unless there is an emergency, such as massive hemoptysis, time must be taken to sterilize the sputum of all patients before surgery. The nutritional status of the patient is addressed because many of these patients present with advanced states of malnutrition due to months of chronic debilitating disease. The feasibility of resection is evaluated, and attention is given to cardiorespiratory status, as for any other patient undergoing major pulmonary resection. A CT scan needs to be available to all patients to determine the extent of the disease, predict operative difficulties, and assess the status of the contralateral lung. Bronchoscopy is always performed to document possible tuberculous endobronchial disease and to determine the extent of resection likely to be necessary. If a bronchial stump closure encompasses an area involved by tuberculous bronchitis, there will be a significantly higher risk of dehiscence and formation of a bronchopleural fistula (Pomerantz, 1993).156 During surgery, double-lumen endotracheal tubes are used, not only to deflate the lung but also to avoid contamination of the contralateral lung by pus and debris produced by the manipulation of the resected lung. In patients with chronic pulmonary tuberculosis, pleural adhesions are common, and a network of systemic-to-pulmonary neovascularization often involves these adhesions. The presence of adhesions makes the dissection of the lung tedious and prone to a significant amount of blood loss. Lymph nodes involved by granulomatosis are often adherent to surrounding vessels,

1/21/2008 11:37:45 AM

Ch043-F06861.indd 522

513

207 43 186

146 805

37 24

31

59

206

107

Dagher et al (1959) USA

Floyd et al (1959) USA

Neptune et al (1970) USA

Delarue et al (1975) Canada

Das and David (1975) India

Moran et al (1983) USA

Reed et al (1989) USA

Whyte et al (1989) UK

Treasure and Seaworth (1995) USA

Rizzi et al (1995) Italy

Wu et al (1996) China

N

Cole and Alley (1955) USA

Author (Year) Location

Cavity 35.5%, aspergilloma 25%, destroyed lung 8.7%, tuberculoma 13%, empyema 3.7%, tracheobronchial stenosis 3.7%

Possible cancer 24%, cavity 22%, bronchiectasis 16%, hemoptysis 16%, progression 8.5%, lung destruction 8%, BPF 3%

MDRTB 32%, BPF 20%, destroyed lung 12%, solitary nodule 12%, hemoptysis 8%, cavity 7%, trapped lung, empyema

Destroyed lung, hemoptysis, cavity, BPF/empyema

Hemoptysis 58%, drug resistance 21%, possible neoplasia 12.5%, bronchiectasis 8%

Localized disease (MOTT) with failure of medical therapy

Cavities, tuberculoma, lung destruction, positive sputum, drug resistance, bronchiectasis, bronchostenosis

Cavity 32%, positive sputum 30%, resistance 24.6%, empyema 1.3%

Cavity 56%, tuberculoma 13%, drug resistance 9.7%, empyema 4.8%, possible carcinoma 3.7%, removal of plombage 9%

Surgery for TB, not specified

Surgery for moderately advanced and advanced TB

Tuberculoma to destroyed lung

Indication for Surgery

TABLE 43-7 Review of Worldwide Experiences in Performing Surgery for Tuberculosis

16.8

29.1

20.3

16

46 (major 16.7%)

NA

12.8

49

8

18.8

27

34

Morbidity (%)

1.8

3

0

0

0

0

2.8

9

1.3

2.3

4.8

6.4

Mortality (%)

96% conversion

86.2% conversion

89% cure rate in MDRTB

NA

2 reactivations in the contralateral lung

—

2.6% reactivation

NA

0.5% reactivation due to early discontinuation of drugs

NA

NA

85% conversion

Outcome

6.5% BPF; muscle flaps used with cavernostomy in 6.50%

Tuberculoma and pleural TB were excluded from the study; association with scar cancer existed in 33% and with mycetoma in 45%; 1.4% had MOTT; 38.8% had positive sputum at surgery; higher morbidity occurred in patients with positive sputum

Pneumonectomy with muscle flaps in 23%; BPF in 3% of patients

In patients with suspected carcinoma, 16% had a history of TB and 12% had been exposed to TB; only 1 patient received preoperative chemotherapy; 10% had carcinoma; all complications occurred in patients with active TB

12.5% had MOTT; 12.5% had BPF/empyema

All were MAC; 67% were sputum-negative at the time of surgery

BPF in 3.1%; all patients had at least 6 mo of preoperative chemotherapy

BPF in 20%

Collapse therapy in 20%; 12.3% of patients were taking steroids

BPF in 10.5% of cases (28% of pneumonectomies); 11% had positive cultures

—

32.5% had no medical therapy before surgery; 20.6% had septic complications; only 4% of patients had antibiotherapy before surgery; all patients with BPF had positive TB cultures in the bronchial resection margin

Comments

522 Section 3 Lung

1/21/2008 11:37:46 AM

Ch043-F06861.indd 523

33 35

Shiraishi et al (1998) Japan

Takeda et al (2005) Japan

31.2

Group III, 27%: Pyothorax, bronchiectasis, aspergilloma, fistulized nodes

MDRTB 26/35, hemoptysis, destroyed lung, drug allergy

Localized MAC 100%

Cavitary disease in MAC 100%

Hemoptysis, bronchial stenosis, BPF, cavity lesions, destroyed lung

Failure of conversion 39%, high risk of relapse 22%, drug resistance 21%, relapse 18%

Destroyed lung 18.5%, cavitary disease

Destroyed lung 100%; active TB 43%

14.3

15+

32

12

23

NA

11.9

20

16.6

Group II, 30.5%: Cavity, destroyed lung, chronic loculated pleural effusion

Cavernous TB 39%, tuberculoma 32%, pleuritis/empyema 26%, mediastinal adenopathy 13%, focal TB 2.8%, caseous pneumonia 0.8%

4

Group I, 42%: Solitary nodule, pulmonary lesion/infiltrate, pleural effusion

2.9

0

7

3.3

1.6

0

5.9

2

12.5

5.5

4

91.4% free of disease

94% conversion, 6% relapse

Hand suture of the stump, mainly no flaps; no BPF; sputum positivity not a negative prognostic factor

55% sputum-positive at time of surgery; 15% had thoracoplasty for residual space; BPF in 3%

Poor nutritional status; 50% culture-negative at time of surgery; most common complication was prolonged air leak, which was treated by thoracoplasty; BPF in 3.6% was treated with omentopexy; drug therapy was continued for 3 to 12 mo postoperatively

Muscle flap; 3% BPF

≅90% cure rate 93% conversion rate at 3 mo, 3.6% relapse

All MDRTB

All MDRTB in HIV-negative patients; all patients were receiving antibiotherapy before surgery; good nutritional status; all patients had negative preoperative cultures; BPF in 7.4% due to extensive bronchial dissection

Increased rate of BPF and mortality if empyema, active TB, and right pneumonectomy were present

50% had positive sputum; no HIV; most complications were associated with pleural TB

Classic 6-mo treatment if the cultures of the specimen were positive; 4 mo empiric treatment with 2 drugs if the cultures were negative

9 to 12 mo medical treatment: 4-drug treatment for 3 to 6 mo followed by 2 drugs 3 to 6 mo later, depending on sputum status

Classic 6-mo postoperative medical treatment: 4 drugs for 2 mo, 2 drugs for 4 mo

75% conversion with surgery alone, 80% relapse-free

3.7% relapse

NA

6.6% reactivation, 82.7% conversion

Favorable in all

Favorable in all

Favorable in all

BPF, bronchopleural fistula; MAC, Mycobacterium avium complex disease; MDRTB, multiple-drug-resistant tuberculosis; MOTT, mycobacteria other than tubercle bacilli; NA, not available; TB, tuberculosis.

28

172

Pomerantz et al (2001) USA

Nelson et al (1988) USA

62

van Leuven et al (1997) South Africa

118

Halezeroglu et al (1997) Turkey 27

502

Perelman and Strelzov (1997) Russia

Kir et al (1997) Turkey

59

Mouroux et al (1996) France

Chapter 43 Tuberculosis and Atypical Mycobacterial Diseases 523

1/21/2008 11:37:46 AM

524

Section 3 Lung

making their skeletonization around the hilum more dangerous. In such cases, the dissection must be extended more proximally in order for the resection to encompass as much disease as possible. If pneumonectomy is required, care must be taken not to contaminate the pleural space. If the risks of contamination are high, pneumonectomy is performed in an extrapleural fashion. On occasion, thoracoplasty may be a useful adjunct to reduce the size of the pleural cavity occupied by a small lung or to treat a bronchopleural fistula.157 Proper chest drainage is essential after any kind of surgery for tuberculosis. Large tubes with side holes must be used to avoid the accumulation of clots in the pleural cavity, which can result in lung entrapment, empyema, or even disseminated intravascular coagulation.158 Bronchopleural fistula is a serious complication of surgery for tuberculosis, but in most recent series the incidence has been less than 10%. The type of closure (sutures versus stapler) does not appear to be a risk factor,53 but active tuberculosis and active ongoing superinfection by gram-negative bacteria are significant risk factors for this complication.60 Pulmonary resection therefore always is complemented by covering the bronchial stump with vascularized pedicled flaps, such as intercostal muscle, latissimus dorsi, serratus anterior, or omentum. Patients with bronchopleural fistulas are treated first with tube thoracostomy, and the surgeon’s urge to close the fistula must be restrained until sputum and pleural cultures have tested negative. The rate of relapse is high in patients with sputum positivity at the time of surgery, in patients who develop postoperative bronchopleural fistula or empyema, in patients with positive smear or culture of the resected specimen,62 in patients with MDRTB,159 and in patients with inadequate medical therapy.160 There is also a higher percentage of nonconversion with lobectomy and segmentectomy compared to pneumonectomy, suggesting that a more radical procedure may be more effective than a smaller resection.61

SUMMARY Successful treatment of tuberculosis depends on prompt diagnosis and proper medical therapy. The increase in the number of new tuberculosis cases and the number of patients with MDRTB is related at least in part to pitfalls in the primary care of patients. In a study of 35 patients, Mahmoudi and Iseman160 detected errors of management in 28. These errors led to prolonged hospital stays, to the development of sclerotic pulmonary lesions, and to increased costs. When patients fail medical therapy or are at high risk to do so, surgery remains a very effective tool in the management of this difficult problem.

COMMENTS AND CONTROVERSIES With the advent of effective chemotherapy and early diagnosis, the role of surgery in tuberculosis has decreased. However, because of the high incidence of the disease in developing countries such as India, a significant number of our patients do require surgical intervention. One of the main indications in our clinic for surgery is massive hemoptysis. This can occur at any stage of the disease. It may be the first symptom to occur during treatment of the active phase of disease, or it may occur as a result of healed scars. We still perform staged thoracoplasties for patients who are unsuitable for resection because of extensive endobronchial disease for MDRTB and for tubercular empyema with bronchopleural fistula. R. S. The role of the thoracic surgeon in managing pulmonary tuberculosis has decreased remarkably since the advent of effective antimicrobial agents. Table 43-1 describes the evolution of thoracic surgical treatments over the past 150 years. Indeed, the foundations and development of thoracic surgery lie in the management of infectious diseases such as tuberculosis and empyema. The recent resurgence of resistant forms of tuberculosis, especially in the immunocompromised host, makes this infection a common presentation to thoracic surgeons for diagnosis and for management of its complications. This is especially true in underdeveloped countries. Dr. Rajan Santosham has commented on the practice in India, where tuberculosis is prevalent. He mentions the common necessity of surgery or the treatment of hemoptysis. This is discussed in Chapter 38 in relation to tuberculosis. The reader is also referred to further discussions of tuberculosis in the immunocompromised host and in the patient with AIDS (Chapter 47). R. J. G.

KEY REFERENCES Rizzi A, Rocco G, Robustellini M, et al: Results of surgical management of tuberculosis: Experience in 206 patients undergoing operation. Ann Thorac Surg 59:896, 1995. ■ This article shows that aggressive surgical treatment of MDRTB is warranted to achieve eradication of the disease. Pomerantz M: Surgery for tuberculosis. Chest Surg Clin North Am 4:723, 1993. ■ This is an excellent review of indications for surgery of tuberculosis. Mouroux J, Maalouf J, Padovani B, et al: Surgical management of pleuropulmonary tuberculosis. J Thorac Cardiovasc Surg 111:662, 1996. ■ This article evaluates the role of surgery for diagnostic and therapeutic purposes in the management of pleuropulmonary tuberculosis.

Acknowledgment

Iseman MD, Madsen L, Gable M, Pomerantz M: Surgical intervention in the treatment of pulmonary disease caused by drug-resistant Mycobacterium tuberculosis. Am Rev Respir Dis 141:623, 1990. ■ This review shows that resectional surgery benefits selected patients with MDRTB.

The authors thank Dr. Andre Crepeau, senior thoracic surgeon, for his bibliography and Dr. Ian Hammond, chief of radiology at Ottawa General Hospital, for some of the radiographs used to illustrate this chapter.

Perelman MI, Strelzov VP: Surgery for pulmonary tuberculosis. World J Surg 21:457, 1997. ■ The authors report one of the largest recent experiences with surgery for tuberculosis.

Ch043-F06861.indd 524

1/21/2008 11:37:46 AM

chapter

44

MYCOTIC INFECTIONS OF THE LUNG Stephen D. Cassivi

Key Points ■ A multitude of different organisms can cause mycotic lung infec-

tions, and there are equally varied clinical presentations that range from the asymptomatic patient with a subclinical infection to the immunocompromised patient with a life-threatening invasive opportunistic fungal infection. ■ A heightened index of suspicion is essential when confronted with patients with pulmonary symptoms, especially those with atypical infections. Patients who are malnourished, debilitated, diabetic, or receiving intensive or long courses of antibiotic therapy are at increased risk of mycotic infections. Patients with blood dyscrasias or lymphatic malignancies such as Hodgkin’s disease also are at increased risk. ■ Symptoms related to the upper or lower respiratory tract consisting of fever, cough, sputum production, hemoptysis, or pleuritic pain usually provide the usual indication for a conventional chest radiograph. This tends to be helpful in delineating pulmonary mediastinal or pleural involvement. ■ Remember: A confirmed diagnosis of fungal infection can be made only after the demonstration of the presence of the organism in body exudates or tissues. Stronger proof is provided by growth in culture; however, the mere recognition of the organisms in smears, fresh mounts, or tissue sections has usually been sufficient for diagnosis.

The presence of fungi in the lung results most frequently from inhalation of fungal organisms. In the vast majority of patients, asymptomatic or mild pulmonary infection occurs and clears spontaneously without significant clinical debility. In cases of systemic fungal infection remote from the lung, the portal of entry again, with rare exception, is the airway. It is almost 100 years since the first descriptions of fungal infections with pulmonary manifestations. Some of the first advances and developments in the understanding of fungal infections of the lung occurred in the early 1950s during the emergence of resectional surgery for the therapy of tuberculosis. With the advent of pulmonary resection as a therapy for tuberculosis, it became apparent that some of the patients thought to be afflicted with tuberculosis on the basis of their chest radiographic findings were, in fact, suffering from invasive and pathogenic fungal infections.1 The first major nonsurgical therapy for pulmonary fungal infections came with the isolation of amphotericin B from a soil actinomycete.2 It has become apparent with more detailed clinical observation that serious pulmonary fungal infection represents a relatively small proportion of pulmonary fungal infections in

general. Serious infections represent the tip of a very large iceberg, whereas the vast majority of patients present with minimal evidence of clinical disease that rapidly subsides and has no sequela. An even larger number of patients develop primary fungal infections of a subclinical nature that is evidenced only by conversion of skin tests or serology. With the advent of immunosuppression for a growing number of medical conditions including organ transplantation, the widespread use of chemotherapy to treat neoplasms, and the discovery and description in the 1980s of acquired immunodeficiency syndrome (AIDS), there is an ever-increasing experience with fungal infections due to secondary or opportunistic pathogens in these immunocompromised patients. Although they form a small minority of patients, it is in this group of patients that we see the most serious manifestations of mycotic infections of the lung.

HISTORICAL NOTE The history of our understanding of pulmonary fungal infections dates back to the late 19th and early 20th centuries. Darling, in 1906, described the first two cases of histoplasmosis in young adult laborers from Martinique who died within 6 months of beginning work on the Panama Canal.3 The first clinical case of histoplasmosis recognized in the United States was reported in Minnesota in 1926.4 The first examples of pulmonary resection for pulmonary histoplasmosis were described in 1951 by Hodgson and coworkers at the Mayo Clinic.5 It was in 1950 that Klingman and Mescon, using the periodic acid–Schiff stain, properly diagnosed Histoplasma capsulatum in previously designated tuberculomas.6 Blastomycosis, in the cutaneous form, was first described in 1894 by Gilchrist.7 The systemic form was reported in 1902 by Walker and Montgomery.8 Coccidioidomycosis was first reported by Wernicke in 1892 in Buenos Aires, Argentina.9 As with histoplasmosis and blastomycosis, coccidioidomycosis was, in its first description, incorrectly identified as a protozoan infection. Schenck described the first case of Sporotrichum schenckii in 1898.10 This organism has since been renamed Sporothrix schenckii. Cryptococcosis in humans was first described in its pathologic and clinical features by Stoddard and Cutler in 1916 and was called torulosis.11 The first description of aspergillosis was by Sluyter in 1847.12 The first cases of pulmonary mucormycosis were reported in Germany by Furbringer in 1876.13 The first pulmonary mucormycosis cases in the United States were reported in 1948 by Baker and Severance.14 525

Ch044-F06861.indd 525

1/21/2008 11:38:41 AM

526

Section 3 Lung

DIAGNOSIS Not only are there a multitude of different organisms that can cause mycotic lung infections, but there are equally myriad clinical presentations that vary from the asymptomatic patient with a subclinical infection to the immunocompromised patient with a life-threatening invasive opportunistic fungal infection. A heightened index of suspicion is essential when confronted with patients with pulmonary symptoms, especially those with atypical infections. The fundamentals of diagnosis still apply: a careful and thorough history will usually prove to be illuminating in these challenging patients. Patients who are malnourished, debilitated, diabetic, or receiving intensive or long courses of antibiotic therapy are at increased risk of mycotic infections. Similarly, patients with blood dyscrasias or lymphatic malignancies such as Hodgkin’s disease also are at increased risk. Patients suffering from AIDS or other similar immunosuppressed states are also at higher risk. It is also known that patients with pulmonary manifestations of sarcoidosis or tuberculosis as well as those patients with primary bronchogenic carcinoma can be at increased risk of acquired pulmonary mycotic infections.15-20 As part of a complete history, it must be remembered that the geographic nature of the three major pulmonary mycotic infections, namely, histoplasmosis, coccidioidomycosis, and blastomycosis, were defined by Takaro in 1967.21 Knowledge of the endemic areas can usually assist in narrowing the scope of diagnosis. Histoplasmosis is most commonly encountered in the Missouri, Ohio, and Mississippi River valleys. Blastomycosis is most commonly seen in the southeastern United States as well as the Kenora region of northern Ontario in Canada. Coccidioidomycosis is found predominantly in the southwestern United States and typically in the area of the San Joaquin valley. Symptoms related to the upper or lower respiratory tract consisting of fever, cough, sputum production, hemoptysis, or pleuritic pain will usually provide the usual indication for a conventional chest radiograph. This is usually helpful in delineating pulmonary mediastinal or pleural involvement. An important hallmark to be remembered and emphasized is that a confirmed diagnosis of fungal infection can be made only after the demonstration of the presence of the organism in body exudates or tissues. Stronger proof is provided by growth in culture; however, the mere recognition of the organisms in smears, fresh mounts, or tissue sections has usually been sufficient for diagnosis. Once a pulmonary site of infection is suspected, a number of specific diagnostic methods can be applied. Single sputum for retrieval for culture is best accomplished by inducing sputum production with warm aerosol treatments. There is no value to a 24-hour sputum collection given the problems of overgrowth by bacteria and saprophytic yeasts. A minimum of six induced sputum specimens obtained on successive mornings has been recommended.22 Although bronchial washings or brushings may sometimes be useful, induced sputum specimens tend to be more reliable. Successful growth of fungi relies on prompt delivery of the specimen to the laboratory. Bronchoalveolar lavage (BAL)

Ch044-F06861.indd 526

of a bronchus that serves the involved area of the lung is increasingly used. More recently, BAL accompanied by polymerase chain reaction (PCR) assays has shown potential increased clinical value.20 Although previously, open-lung biopsy was the procedure of choice to definitively identify pulmonary processes, the improvement of less invasive transbronchial techniques and the addition of transthoracic needle biopsy have been useful diagnostic adjuncts with less inherent risk to the patient. Bonfils-Roberts and colleagues demonstrated the poor yield of open-lung biopsy in seriously ill patients with AIDS.23 They noted in only 1 of 66 cases was a successful therapeutic change initiated based on the findings of open-lung biopsy. They had a 33% mortality rate within 1 month due to severe respiratory failure. Only 3 of the 66 patients had fungal infections in this study. Conversely, Ahmad and coworkers found that surgical lung biopsy in human immunodeficiency virus (HIV)-infected patients brought a specific diagnosis in 84% of the cases, with 58% of the cases in their series being of an infectious etiology.24 Pneumocystis carinii (now P. jiroveci) was the most common diagnosis of all biopsies, occurring in 34%. The results of the surgical lung biopsy led to a change in management in 65% of their cases. Their in-hospital mortality rate was 27%. In this study, in 42% of the cases videoassisted thoracoscopy was performed. Other diagnostic procedures include sampling of lymph nodes by scalene node biopsy, transbronchial needle biopsy, esophagoscopy with ultrasound and fine needle aspirate, or mediastinoscopy. The specimens are used for a direct examination or culture. Between 10% and 15% of patients with blastomycosis have involvement of the genitourinary tract and that prostatic secretions may contain the offending organism.22 Similarly, in patients with AIDS and cryptococcal meningitis who experience relapse after initially successful primary therapy, recurrent infection can be diagnosed in the urine obtained after prostatic massage.25 Fractional urine samples may also be helpful in identifying Coccidioides immitis as the offending organism in the prostate.26 This emphasizes the importance of including a rectal examination with collection of prostatic secretions for culture. In a similar vein, cerebrospinal fluid analysis can be useful in cases of related meningitis due to Cryptococcus, Coccidioides, or Histoplasma species. Extrapulmonary mycotic infections may be diagnosed occasionally by blood, bone marrow, joint fluid, or skin biopsy specimens including ulcerative lesions or draining sinus tracts. In general, skin testing is not used for diagnosis for several reasons: 1. Cross reactions occur with histoplasmosis, coccidioidomycosis, and blastomycosis 2. A positive skin test, although it indicates prior infection, does not necessarily connote ongoing or current infection 3. Positivity for skin testing develops usually only after several weeks of infection and is therefore of little or no use early in the disease process 4. Skin testing increases the level of serologic titers and therefore interferes with their important role in the estab-

1/21/2008 11:38:41 AM

Chapter 44 Mycotic Infections of the Lung

lishment of a diagnosis or an interpretation of disease progress. For these reasons, skin testing has, for the most part, been abandoned as a primary diagnostic tool.

Culturing of Clinical Specimens Once clinical specimens have been obtained, they are promptly delivered to the laboratory where the growth of the culture becomes the responsibility of the clinical mycology laboratory. Basic knowledge, however, of the useful media for growth of clinical specimens suspected of having fungal infections enhances the possibility that the physician will reach a correct diagnosis. A variety of media are available for the primary inoculation and recovery of fungi from clinical specimens. No one specific medium or combination of media is adequate for all specimens. Media must be carefully selected based on specimen type and the suspected fungal agent. When the specimen is obtained from a potentially contaminated site, it is important to use media that contain inhibitory substances, such as chloramphenicol, gentamicin, or cycloheximide. Chloramphenicol or gentamicin will inhibit most bacterial contaminants, whereas cycloheximide inhibits most saprophytic molds. Cycloheximide may, however, inhibit opportunistic fungi such as some species of Aspergillus, Fusarium, and yeasts such as Cryptococcus neoformans, and some Candida species. Antibacterial agents may inhibit the growth of aerobic actinomycetes such as Nocardia species. The basic culture media used clinically are Sabouraud’s dextrose agar, Sabouraud’s heart infusion agar, and brain-heart agar.27 Before inoculating the culture, the mycology laboratory technician will apply techniques such as the selection of purulent parts of the specimen, homogenization, filtration, or centrifugation to concentrate the suspected organism and enhance the likelihood of producing a successful culture. In general, fungi grow slowly in culture, and cultures must be kept for a minimum of 4 to 8 weeks before the results are reported to be negative.

Serologic Diagnosis of Fungal Infections Although culture methods are by far the gold standard in establishing the diagnosis of invasive fungal infections, fungal cultures have the clear limitations of delayed growth, poor sensitivity, and the need for invasive collection procedures. The need for rapid diagnosis of fungal disease to allow for early treatment of these infections has led to the development of serologic testing. Three main types of serologic tests are currently used in the diagnosis of mycotic disease. Direct detection of specific circulating fungal antigens allows for the indication of the presence of a fungus and its active ongoing infection. Testing for antibody response is also a common serologic modality. These techniques are especially useful in a diagnosis of histoplasmosis and coccidioidomycosis, although sensitivity may be reduced by immunosuppression. The third modality uses molecular diagnostic methods such as PCR. Although these methods are available in certain specialized laboratories, there is currently a lack of well-characterized

Ch044-F06861.indd 527

527

assays and their accuracy has not yet been clearly established, and thus their role in patient care remains uncertain. Single specimen serologic testing is much less effective than serial examinations that allow for titers to be followed. Titers vary not only among laboratories but also within the same laboratory. For this reason when serial testing is desired, a portion of the specimen is kept frozen and used along with later specimens for simultaneous analysis. In general, serial examination with intervals of fewer than 3 weeks have not been shown to be of clinical use. The most useful serologic tests in specific fungal infections are outlined in the sections that describe each disease.

INDIVIDUAL FUNGAL INFECTIONS Pulmonary mycosis can present a challenge to the general thoracic surgeon. Although the role of surgery is commonly one of diagnosis, many interesting and difficult therapeutic situations can arise. Because fungal infection of the lung begins with various spectra of illness, the approach to treatment of pulmonary mycoses needs to be individualized. A discussion of individual fungal infection highlights the current knowledge of these conditions.

Histoplasmosis Histoplasmosis is a fungal infection caused by the dimorphic fungus Histoplasma capsulatum. It exists in mycelial form in the soil and in yeast form at body temperature. In the United States, this disease is endemic to the Midwest and Mississippi River Valley. The reasons for this particular geographic distribution are unknown but are believed to include the moderate climate, humidity, and soil characteristics of this area. Bird and bat feces accelerate sporulation and thereby enhance the growth of the organism in the soil.28 Although millions of people have been infected with this fungus, relatively few show signs of the disease. Occasionally, particularly in immunocompromised hosts, the infection becomes systemic and more virulent. Acute forms of the disease present as primary or disseminated pulmonary histoplasmosis, and chronic forms present as pulmonary granuloma (histoplasmoma), chronic cavitary histoplasmosis, mediastinal granuloma, fibrosing mediastinitis, or broncholithiasis.

Historical Note The first case of human infection by H. capsulatum was described by Samuel Darling in 1905 based on an autopsy specimen from a native of Martinique who had died of disseminated histoplasmosis within 6 months of his arrival to work on the construction of the Panama Canal.3 Because the organism was found in histiocytes with capsules, it was erroneously thought to be a protozoan and thereby received its name. Later studies showed this to be a fungus without a capsule.29,30 The first case in the United States was reported in 1926 by Riley and Watson4; and the first report of the disease in a living patient, an infant with disseminated histoplasmosis, was made in 1935 by Dodd and Tompkins.31 A dramatic shift in the understanding of the disease occurred in the 1940s when the histoplasmin skin test was developed. During World War II, many healthy young men and women

1/21/2008 11:38:41 AM

528

Section 3 Lung

were rejected for military service because of calcifications seen on their routine chest radiograph. This was thought to be evidence of healed miliary tuberculosis. However, extensive skin testing surveys for histoplasmosis proved that infection by H. capsulatum was the most common cause of pulmonary calcification in the United States.32 These reports changed the perception of histoplasmosis, once considered to be a fatal disseminated disease. It became clear that it was a common and usually self-limited infection in endemic areas. The arrival of amphotericin B in the 1950s provided highly effective therapy for patients requiring treatment. In the 1980s, new oral therapy for histoplasmosis first appeared in the form of azole compounds. The appearance of AIDS and the increased number of immunosuppressed and immunocompromised hosts due to the growth of chemotherapy and organ transplantation provided the background for further understanding of the disease and its potential therapies. The largest recorded outbreak of acute respiratory histoplasmosis occurred between September 1978 and August 1979 in Indianapolis, Indiana. During that period, it is estimated that over 100,000 people were infected, with more than 300 hundred requiring hospitalization. Forty-six patients developed progressive disseminated histoplasmosis, whereas 15 deaths were directly or indirectly attributed to histoplasmosis infection. Epidemiologic studies showed that the source of this outbreak was an abandoned amusement park that had been recently dismantled. Interestingly, H. capsulatum was unable to be recovered from any of the collected soil samples at the site.33

Epidemiology The overall incidence of histoplasmin sensitivity in the United States is approximately 22%.34 However, in endemic regions, it was been shown that by age 20, 80% to 90% of the population has a positive histoplasmin skin test. Forty million people in the United States are estimated to have been infected by H. capsulatum, with approximately 500,000 new infections occurring each year.35 The yeast phase of H. capsulatum that exists in the body tissue is not thought to be contagious. There have been no reports of human-to-human or animal-to-human spread except for unusual cases such as direct inoculation during surgery or autopsy. The infectious particles are microspores from the mycelial phase. Asymptomatic or subclinical infection is the rule after low-dose exposure to small numbers of airborne spores. In fact, approximately 95% of histoplasmosis cases are inapparent and self-limited. The extent of acute pulmonary involvement usually depends on the dose of the inoculum and the immunologic status of the host. In urban areas, people can be infected by exposure to dust emanating from major public works construction projects.

Pathophysiology H. capsulatum is the etiologic agent of histoplasmosis, the most common pulmonary mycosis of humans and animals. Histoplasmosis affects primarily the respiratory system. Inhaled spores or mycelial fragments can lodge in an alveolus

Ch044-F06861.indd 528

or interstitial space where, because of the warmer temperature, they germinate into the yeast form, causing a localized or patching pneumonitis. Fungemia and subsequent hematogenous dissemination from the lungs to other tissues likely occurs in all infected individuals during the first 2 weeks of infection before the development of specific immunity. In the majority of cases, it is nonprogressive and leads only to the development of calcified granulomas in the liver and/or spleen.28 Ten to 14 days after inoculation the cellular immune response develops, mediated initially by polymorphonuclear leukocytes and later by lymphocytes and mononuclear phagocytes. The organism reproduces within macrophages and subsequently spreads by lymphatics to mediastinal lymph nodes and then throughout the reticuloendothelial system.36 Immune T-cell lymphocytes and activated macrophages assume fungicidal properties.37 Progressive illness such as hematogenous dissemination involving extrapulmonary tissue may follow in the immunocompromised host.38 As cellular immunity develops, an intensive inflammatory reaction occurs that produces varying degrees of caseating necrosis at the site of involvement. The histoplasmin serum antibody to H. capsulatum appears 4 to 6 months after inoculation, and skin tests then become positive. Eventually the lesion heals by fibrous encapsulation and subsequent calcification. It is common for the lung to develop such a scar, which presents clinically as an indeterminate nodule. Lymphadenopathy in the lymph nodes draining the affected area can occur in either a calcified or an uncalcified form. If the process progresses with subsequent rupture of the lymph node and spread of the caseating material, an intense immunogenic response can occur, causing further mediastinal sclerosis in the area. Infection by H. capsulatum can therefore cause a spectrum of problems. An uncalcified, indeterminate mass in the lung or mediastinum may prompt invasive surgical diagnostic procedures to rule out carcinoma. Other problems may occur, including erosion or compression of surrounding mediastinal structures such as the esophagus, trachea, pulmonary vasculature, pericardium, and superior vena cava (Fig. 44-1).

Clinical Features Infection with H. capsulatum can have various clinical presentations depending on the intensity of exposure and a number of host factors, such as immune status, previous exposure, and the presence of other chronic pulmonary disease. Acute Pulmonary Histoplasmosis. After low-level exposure, less than 5% of exposed individuals develop symptomatic disease. In some cases, however, symptoms can be elicited following exposure with infection. Most commonly, these include a flu-like pulmonary illness with fever, chills, headache, arthralgia, myalgia, anorexia, nonproductive cough, and pleuritic chest pain. Radiographs of the chest may be normal or may show enlarged hilar or mediastinal lymph nodes with or without small areas of parenchymal patchy infiltrates. Symptoms, if present, usually improve within a few weeks of onset. It has been suggested that antifungal

1/21/2008 11:38:41 AM

Chapter 44 Mycotic Infections of the Lung

Initiating event

Mediastinal granuloma lymphadenopathy

Calcified lymphadenopathy

Sclerosing mediastinitis

Acute infection

Obstruction Mass Rule out malignancy

Obstruction Tracheobronchial Esophageal Vascular Erosion Broncholithiasis Fistulae Mass effect Rule out malignancy

Encasement Entrapment Vascular Tracheobronchial Esophageal Nerves Pericardium Mass effect Rule out malignancy

529

FIGURE 44-1 Spectrum of clinical disease caused by Histoplasma capsulatum. (COPYRIGHT © THE MAYO CLINIC.)

therapy may be helpful in patients who remain symptomatic without improvement after the first month of infection. Progressive dissemination of the disease may be manifested by fever that persists for more than 3 weeks. In the absence of prospective trials, it remains unclear whether antifungal therapy hastens recovery or prevents complications in these particular cases.28 Diffuse radiographic involvement may indicate a more intense exposure and potentially more severe course of disease. Antifungal treatment is recommended in patients who become hypoxemic. The Infectious Diseases Society of America (IDSA) has published consensus guidelines regarding the treatment of acute pulmonary histoplasmosis.28 The recommendations were for treatment of patients with no clinical improvement after 1 month of observation or with hypoxemia. Treatment initially is recommended with itraconazole, 200 mg, orally once daily for 6 to 12 weeks. It was recommended to monitor blood concentrations of itraconazole in cases of suspected treatment failure, concern regarding compliance or absorption, and use of medications that may reduce the solubility of itraconazole or accelerate its metabolism. It is recommended that serum concentrations of 1 µg/mL measured by bioassay would be considered therapeutic. Histoplasmoma. Localized pulmonary histoplasmosis or histoplasmoma occurs as pulmonary infiltrates from acute pulmonary histoplasmosis heal and consolidate into a solitary nodule. Histoplasmoma is usually found as an asymptomatic coin-shaped lesion on routine chest radiographs. In rare instances, progressive enlargement may occur at a rate of 1 to 2 mm per year to produce a 3- to 4-cm mass over 10 to 20 years.39 Histoplasmoma developing into an inflammatory myofibroblastic tumor of the lung or pseudotumor has also been reported.40 Most granulomas eventually become calcified. Central calcification and concentric laminations are pathognomonic of benign disease.41 When noncalcified, however, these lesions may be extremely difficult to differentiate from neoplasm. In this situation, appropriate diagnostic evaluation is undertaken, including chest CT. Serial CT scanning may be required to demonstrate the static, unchanged nature of the lesion and infer its benign nature. At times, surgical excision is required to exclude malignancy and can often be done by video-assisted thoracoscopic techniques. Antifungal

Ch044-F06861.indd 529

therapy is not required or beneficial in the treatment of a histoplasmoma. Mediastinal Granuloma. Fusion of caseous mediastinal lymph nodes can result in a single large mass that becomes encapsulated.42 This is usually asymptomatic and is often detected incidentally on imaging the chest for other reasons. Histoplasmosis has been implicated as the most common cause of mediastinal granuloma. Most commonly this develops in the right paratracheal and hilar area (Fig. 44-2).43 The mass is indeterminate when noncalcified, and a tissue diagnosis is usually required to exclude malignancy.44 Depending on the location and suspected diagnosis, various diagnostic methods such as mediastinoscopy, mediastinotomy, thoracoscopy, or thoracotomy may be used to obtain tissue.45-48 With progressive increase in the size of the mediastinal mass, obstructive syndromes may result in compression of the superior vena cava, tracheobronchial tree, or pulmonary artery.44,48 Rarely, mediastinal masses or nodes may cause external compression on the esophagus, leading to dysphagia.49 Caseating lymph nodes have also been reported to rupture into the esophagus (Fig. 44-3), airway, and mediastinum.50-52 These syndromes represent active inflammation of the mediastinal lymph nodes and usually improve slowly. Dines and colleagues described how approximately 40% of patients with mediastinal granuloma are asymptomatic, with the remainder manifesting symptoms such as cough, dyspnea, chest pain, fever, wheezing, dysphagia, and hemoptysis.48 The consensus statement from the IDSA recommends treatment with amphotericin B, 0.7 to 1.0 mg/kg/day, in patients with severe obstructive complications from mediastinal histoplasmosis. Once sufficient improvement has been seen and outpatient treatment is possible, the therapy can be changed to itraconazole, 200 mg, orally once or twice daily.28 In milder manifestations of symptomatic mediastinal granuloma, the IDSA recommends itraconazole, 200 mg, once or twice daily for 6 to 12 months when symptoms have been found to persist for more than 1 month. Occasionally when major airway obstruction is identified, prednisone, 40 to 80 mg, daily for 2 weeks also has been recommended. Surgical resection of symptomatic mediastinal granuloma is usually reserved for cases in which tissue diagnosis is required to exclude malignancy. Surgical resection also plays a role in patients who remain symptomatic or demonstrate

1/21/2008 11:38:41 AM

530

Section 3 Lung

FIGURE 44-2 A-C, Mediastinal granuloma in a 45year-old woman. Note enlarged, calcified lymph node in the lower right paratracheal area.

A

B

C obstruction of major mediastinal structures despite appropriate antifungal therapy. Fibrosing Mediastinitis. Fibrosing mediastinitis is a late complication of mediastinal granuloma caused by histoplasmosis arising from mediastinal lymph nodes with subsequent inflammation and invasion, narrowing, and, ultimately, occlusion of central blood vessels and airways. This is likely due to rupture and spreading of the caseous material into the mediastinum, where an intense inflammatory reaction develops. As the resultant inflammation heals, variable amounts of collagen are deposited, resulting in the dense fibrous encasement of mediastinal structures. This process, due to tissue response to the fungal antigen, is distinct from the compressive mass effect occurring in cases of mediastinal granuloma. Fibrosing mediastinitis can affect all mediastinal structures and is the most common cause of benign obstruction of the superior vena cava. Signs and symptoms are determined by

Ch044-F06861.indd 530

the extent of fibrosis and subsequent constriction and narrowing of mediastinal structures. Fibrosis may also invade the thoracic duct, recurrent laryngeal nerve, and, in rare cases, the atria.53 Signs and symptoms tend to progress over several years’ duration. Recurrent and often serious hemoptysis may result from parenchymal damage caused by airway obstruction and vascular compromise.54 Conventional chest radiographs are commonly normal in appearance but may show superior mediastinal widening, a paratracheal mass, and calcifications resulting from healed prior infection.48 CT of the chest may delineate the extent of the fibrosis and identify involved structures.55 Fused fluorodeoxyglucose (FDG)-labeled positron emission tomography (PET)/CT imaging can sometimes be used to identify “burnt out” fibrosis, which has negative FDG uptake. Ventilation-perfusion lung scans may show reduced blood flow in patients with pulmonary artery or vein obstruction (Fig. 44-4).

1/21/2008 11:38:42 AM

Chapter 44 Mycotic Infections of the Lung

531

FIGURE 44-3 A-C, Mediastinal granuloma eroding into the esophagus of a 63-year-old woman.

A

B

C

B

A

C

FIGURE 44-4 Mediastinal fibrosis in a 37-year-old man. A and B, Chest radiograph and CT scan show collapse of the left upper lobe secondary to occlusion of the left upper lobe bronchus. The left pulmonary artery is encased by fibrosis of the mediastinum. C, The perfusion scan demonstrates reduced blood flow to the left lung.

Ch044-F06861.indd 531

1/21/2008 11:38:42 AM

532

Section 3 Lung

tions. The inflammatory process leads to dystrophic calcification and is most frequently due to histoplasmosis but can also occur secondary to tuberculosis.62 When the lymph nodes and pulmonary granulomas calcify over time, they may induce pressure atrophy of the bronchial wall with subsequent erosion and migration of the lymph node into the bronchial lumen, forming broncholithiasis (Fig. 44-5). Broncholithiasis usually presents as cough, hemoptysis, and dyspnea due to obstruction. Occasionally, patients describe expectorating rock-like particles of tissue (see Fig. 44-5). Occasionally, life-threatening complications such as massive hemoptysis or bronchoesophageal fistula may occur.62,63 The diagnosis of broncholithiasis may sometimes be challenging and is most commonly based on symptoms, radiographic findings, and bronchoscopic observations. A conventional chest radiograph or CT scan may show hilar or mediastinal calcification whereas bronchoscopy may reveal an image of the stone within the bronchial lumen or embedded in the bronchial wall. Because neoplasm must always be excluded, biopsy with bronchial washing for cytologic examination is always performed during bronchoscopy. Organisms may be demonstrated by fungal stains within the calcified nodes, although cultures are usually negative. Antifungal therapy has no role in the treatment of isolated broncholithiasis. In general, three treatment modalities are available for management of patients with broncholithiasis: observation, endoscopic removal, and surgical resection. The indications for surgical treatment of broncholithiasis are related to the complications of this condition: intractable cough, persistent or massive hemoptysis, suppurative lung disease, bronchiectasis or bronchial stenosis, bronchoesophageal or aortotracheal fistula, and uncertainty regarding diagnosis. Potaris and colleagues from the Mayo Clinic recently reported on their extensive experience with this condition.62 Over a 15-year period, 118 patients were diagnosed with broncholithiasis, with 47 of those patients proceeding to surgical intervention. The median age of the patients was 58

Fungal stains of tissues obtained from fibrosing mediastinitis as well as mediastinal granulomas are positive in over half of the cases, although cultures are usually negative.44 This supports the hypothesis that fibrosing mediastinitis is an excessive scarring reaction due to past infection. Serologic tests are positive in two thirds of cases.56 Strongly positive histoplasmin skin tests, as evidence of prior histoplasmosis infection, can be demonstrated in most cases.44 Although there is a paucity of information on which to make antifungal treatment recommendations, the IDSA consensus statement described a general angst in withholding antifungal therapy when the course of this syndrome is progressive. The IDSA recommended treatment if clinical findings were consistent with a more acute inflammatory process than a chronic fibrotic process. It was thought that if complement fixation titers and the erythrocyte sedimentation rate were elevated, then treatment may be indicated. The IDSA recommended a 12-week trial of itraconazole, 200 mg, once or twice daily. Prolongation of the 12-week course of antifungal therapy is only recommended with obvious radiographic evidence of decreasing obstruction. In these cases, the IDSA recommended continuing itraconazole for 12 months. Corticosteroid therapy in fibrosing mediastinitis has not been shown to be useful.48,57 Note that patients with true fibrosing mediastinitis cannot be expected to respond to antifungal therapy. Surgical correction of strictures and obstructions due to fibrosing mediastinitis is exceedingly challenging. There are very few reports of successful series of surgical successes with this disease.58-60 There has been much more success using intravascular stents for patients with obstruction of the superior vena cava, pulmonary artery, or pulmonary vein.61 Broncholithiasis. Broncholithiasis is defined as the presence of calcified material within a bronchus or within a cavity communicating with a bronchus. The majority of broncholiths emanate from peribronchial lymph nodes with the pathogenesis thought to be related to the late response of the tissues to healing from prior granulomatous pulmonary infec-

A

B FIGURE 44-5 A and B, Gross pathology of broncholithiasis.

Ch044-F06861.indd 532

1/21/2008 11:38:44 AM

Chapter 44 Mycotic Infections of the Lung

years, with a range of 18 to 90 years of age. Thirty patients underwent lung resection, 16 had broncholithectomy with or without bronchoplasty, and 1 patient underwent segmental bronchial resection. There were no operative deaths. Postoperative complications occurred in 34% of patients, including seven major complications such as hemothorax, empyema, wound dehiscence, pulmonary artery thrombosis, and lingular necrosis. With a median follow-up of 74 months, there was an overall survival of 89.1%. None of the five deaths that occurred were directly related to the initial broncholithiasis or recurrent disease. Sixty-eight percent of the patients were asymptomatic at the time of follow-up. Of the approximately one third of patients who continued to have symptoms, approximately one third had lithoptysis, one third had recurrent coughing, and one third had hemoptysis. Recurrence of broncholithiasis was seen in 13%. The recurrences were found in the previous site in only one third of the recurrent cases. Pericarditis and Rheumatologic Symptoms. Pericarditis occurs in 5% to 10% of patients with acute histoplasmosis and is an immunologic and inflammatory reaction to histoplasmosis infection of adjacent mediastinal lymph nodes rather than infection of the pericardium itself.64 A history of acute pulmonary histoplasmosis can usually be identified. Pericardial fluid is most often sterile, which corroborates the inflammatory reaction hypothesis rather than an infection of the pericardium. The pericardial effusion usually resolves in response to anti-inflammatory medications without the use of antifungal therapy. Occasionally, patients with large pericardial effusions causing hemodynamic compromise may require drainage of the pericardial fluid by percutaneous, thoracoscopic, or open approach. Constrictive pericarditis is an occasional late sequela of this syndrome. There appears to be no evidence that antifungal, anti-inflammatory, or surgical therapy has any effect or prevents subsequent constrictive pericarditis.28 Rheumatologic symptoms can occur in less than 10% of patients with acute histoplasmosis. The symptoms include arthralgia, arthritis, and erythema nodosum.65 In fact, nearly half of patients with rheumatologic manifestations exhibit erythema nodosum and/or erythema multiforme. The arthritis is polyarticular and symmetrical in 50% of cases. Upper and lower extremities are affected with similar frequency. Symptoms usually resolve spontaneously or in response to treatment with nonsteroidal anti-inflammatory agents. Antifungal therapy is not recommended. The usual course of nonsteroidal anti-inflammatory treatment is 2 to 12 weeks and may require reinstitution of the dosage for a further 4 to 8 weeks if relapse occurs.28 Adult Respiratory Distress Syndrome. Severe acute infections may occur after heavy exposure to H. capsulatum. Severe dyspnea, fever, and cough usually develop within 2 weeks of exposure; they are associated with the observance of diffuse nodular infiltrates on chest radiograph. These patients may become markedly hypoxemic and show a clinical pattern similar to that of adult respiratory distress syndrome. These patients, however, respond relatively rapidly to antifungal therapy without or in combination with glucocorticosteroid therapy.66

Ch044-F06861.indd 533

533

Chronic Cavitary Histoplasmosis. Chronic cavitary histoplasmosis occurs in approximately 10% of patients presenting with symptomatic histoplasmosis. The majority of these patients have underlying lung disease such as chronic obstructive pulmonary disease.41 The symptoms and chest radiographic findings resemble those of pulmonary tuberculosis. Typical patterns seen on radiographic imaging are repeated episodes of patchy consolidation followed by cavitation, scarring, and partial resolution, which ultimately leads to progressive loss of functioning lung tissue. Patients present with symptoms related to the underlying lung disease as well as those of chronic infections such as fever, night sweats, and weight loss. The lesions may progress into cavitary enlargement and may spread to other areas of the lungs as well as form bronchopleural fistulas.67 Because concurrent neoplastic and other infectious diseases can coexist in chronic pulmonary histoplasmosis, steps are taken to exclude malignancy if the patient does not respond to treatment. Disseminated Histoplasmosis. Progressive disseminated histoplasmosis may result from exogenous infection, reinfection, or reactivation of dormant foci.68 Although this may occur in immunocompetent patients, most cases occur in patients with underlying immunosuppressive conditions with depressed T-cell function. Examples of this include patients with Hodgkin’s disease and other lymphoreticular malignancies, patients receiving immunosuppressive therapy as treatment after organ transplantation, and those undergoing treatment of other chronic diseases. Patients at the extremes of ages are also in the at-risk group for disseminated histoplasmosis. HIV-infected patients have the highest risk for developing disseminated histoplasmosis. Serologic testing for anti-HIV antibodies is therefore indicated in any patient with unexplained progressive disseminated histoplasmosis. Symptoms of progressive disseminated histoplasmosis are nonspecific and include low-grade fever, weight loss, and malaise. Physical findings include hepatomegaly, splenomegaly, or lymphadenopathy. Conventional chest radiography may be normal or diffusely abnormal. Severe cases may present with overwhelming infection manifested by shock, respiratory distress, hepatic and renal failure, obtundation, and disseminated intravascular coagulopathy.28 Central nervous system (CNS) involvement may occur in 5% to 20% of cases and is manifested by chronic meningitis or focal intracerebral lesions. The mortality without treatment is 80%, but with appropriate antifungal therapy it can be reduced to less than 25%. Antifungal treatment is therefore indicated in all patients with progressive disseminated histoplasmosis.68 Antifungal therapy includes treatment with amphotericin B followed by prolonged oral therapy with itraconazole. Surgical intervention in progressive disseminated histoplasmosis is extremely high risk and is of potential diagnostic value only.

Diagnosis The diagnosis of acute histoplasmosis can be made by means of a smear, culture, direct tissue biopsy, or serology. Fungal staining of tissue sections or Wright staining of peripheral blood smears may be helpful for rapid diagnosis (Fig. 44-6).

1/21/2008 11:38:44 AM

534

Section 3 Lung

Serologic tests have been used to make presumptive diagnoses in patients from endemic areas with typical symptoms. Because less than 5% of residents of endemic areas are seropositive by complement fixation, background seropositivity does not present a limiting factor for this testing.69 Antibodies measured by immunodiffusion or complement fixation first appear 4 to 8 weeks after exposure to histoplasmosis and remain persistent for several years. Patients who are immunocompromised, however, may not mount an antibody response. Although antibody levels will correlate with severity of infection and extent of disease, they cannot discriminate between self-limited versus progressive disease and therefore are not recommended to be used to guide treatment decisions. A serum complement fixation titer of 1 : 32 or more or a fourfold rise in titer during illness is considered diagnostic.70 Whereas antibody titers decline with spontaneous recovery in patients with self-limited disease as well as after treatment in those with progressive disease, the time course of this decline has not been fully investigated; therefore, treatment decisions are not based on antibody titers. No studies have analyzed the rate of seroreversion after therapy. Although several molecular biology centers offer PCR for diagnosis of histoplasmosis, the accuracy of this modality has not been fully evaluated. Currently, PCR does not provide a consistent and useful means of diagnosis of histoplasmosis. Detection of antigen in body fluids can provide a rapid diagnosis in patients with progressive disseminated histoplasmosis. Antigen can be found in the urine in over 90% of patients with disseminated disease and in 80% with diffuse pulmonary disease. Antigen can also be detected in BAL fluid. Antigen levels decline during treatment and increase with relapse. This offers a valuable way to monitor therapy. It is usually recommended that if treatment is halted before clearance of antigen, patients are followed closely for relapse or increasing antigen levels. Although the histoplasmin skin test has been a valuable epidemiologic tool, the strong likelihood of positive skin reac-

tions in endemic areas invalidates the test as a useful diagnostic procedure.71 Skin test positivity persists for years after recovery from histoplasmosis. Furthermore, skin tests may be falsely negative in up to 20% of patients with chronic pulmonary histoplasmosis and in more than 50% of patients with disseminated histoplasmosis. A definitive diagnosis of histoplasmosis is made by isolation of H. capsulatum in clinical specimens. It may, however, be difficult to demonstrate the organism, owing to the required long incubation time for culture or because of inadequate specimens. Cultures are positive in 85% of patients with disseminated histoplasmosis, with the highest yield coming from the bone marrow.72 In patients with diffuse interstitial or miliary infiltrates, the organism may be cultured from the sputum, alveolar lavage specimens, or lung biopsy tissue in up to 70% of cases.73,74 Patients with self-limited acute pulmonary histoplasmosis, mediastinal granulomas, pericarditis, or rheumatologic manifestations demonstrate positive culture rates of only 10%. Failure to document the organism, however, does not exclude H. capsulatum as the causative agent.

Aspergillosis Aspergillus is a ubiquitous fungal genus that comprises more than 350 recognized species, of which A. fumigatus, A. flavus, A. niger, and A. terreus are the most common pathogenic species. The conidia (spores) released from the conidiophores of Aspergillus species are small in diameter (2.5-3.0 µm) and are therefore easily inhaled. The lung is therefore the most common site of infection. Clinical manifestations of pulmonary Aspergillus infection include three specific types: 1. A localized form, aspergilloma, which is generally considered to be an opportunistic infection in individuals with underlying lung disease 2. An allergic bronchopulmonary aspergillosis, which represents a complex immunologic reaction of the host to a relatively innocuous exposure to noninvasive Aspergillus species 3. A disseminated form that develops in immunosuppressed patients Surgical intervention is called for in two specific circumstances: lung biopsy for diagnosis of invasive aspergillosis in an immunocompromised patient and resection for complications of aspergilloma.

Historical Note

FIGURE 44-6 Mediastinal lymph node biopsy specimen demonstrating organisms of Histoplasma capsulatum. (Silver methenamine; original magnification ×100.)

Ch044-F06861.indd 534

The Aspergillus genus was first identified in 1729 by Micheli, who chose the name because of the similarity in appearance of the spore-bearing heads and the brush (aspergillum) that Micheli, as a priest, used to sprinkle holy water.75 The first human infection was described by Bennett in 1842 in a patient with tuberculosis.76 In 1847, Sluyter described a patient who had died of a chest illness and was subsequently found to have a fungal mass in a lung cavity.12 The fungus was originally reported as Mucor but later recognized as Aspergillus. Virchow reported in 1856 the first four cases of this disease with pathologic evidence at autopsy.77 Subsequent

1/21/2008 11:38:44 AM

Chapter 44 Mycotic Infections of the Lung

reports verified the existence of this entity as a definitive clinical problem.

Epidemiology Aspergillus species are ubiquitous saprophytes that have a worldwide distribution in nature (Fig. 44-7). They exist in soil, decaying vegetation, rotting wood, fur, swimming pool water, flour, human hair, and hospital wards and are a common contaminant in bacteriology laboratories. Aspergillosis is common to all races. It is more common in adults than in children and in males than in females.78 A. fumigatus remains the most frequently isolated of this genus. The epidemiology, however, appears to be changing. A. fumigatus accounted for 82% of cases of invasive Aspergillus in 1985 compared with only 66% in 1999 in stem cell transplant patients.79 A. terreus is increasingly recognized as a pathogen, rising from less than 2% of isolates in 1996 to 15% of isolates in 2001 in a study by Baddley and colleagues.80 The number of spores of Aspergillus species in the air increases during the autumn and winter. The incidence of aspergillosis in humans has increased, and it is now the third most common systemic fungal infection requiring hospitalization in the United States.81 Although Aspergillus may lead to aspergilloma, allergic bronchopulmonary aspergillosis, and invasive pulmonary aspergillosis, colonization without infection can occur.

Classification Aspergillosis manifests itself in a range of severity from saprophytism to fulminant, fatal infection, depending on the quantity of the inoculum and the underlying immunologic condition of the patient. In 1952, Hinson and colleagues classified pulmonary aspergillosis into three types75: 1. Saprophytic aspergilloma 2. Allergic bronchopulmonary aspergillosis 3. Invasive pulmonary aspergillosis

535

Saprophytic disease is caused by the colonizing of preexisting pulmonary parenchymal cavities. This leads to the formation of a tangled mass of hyphae, blood elements, and debris in the cavity. This is referred to as a mycetoma, a fungus ball most commonly known as an aspergilloma. This is the most common manifestation of pulmonary aspergillosis. The second, noninvasive allergic, form results in respiratory symptoms related to immunologic reaction to the fungus in the tracheobronchial tree. This form of aspergillosis causes productive cough, fever, episodic wheezing, variable pulmonary infiltrates, eosinophilia, and elevated IgE antibodies to Aspergillus. This is usually a condition that does not require surgical intervention unless severe bronchiectasis results. The third type, invasive pulmonary aspergillosis, occurs almost exclusively in immunocompromised hosts. It arises in necrotizing bronchopneumonia and invades the lung parenchyma and pulmonary vessels. This leads to thrombosis and hemorrhagic infarction. Lysis of the infarcted lung results in development of a mycotic lung sequestrum that may appear radiographically as a cavitary mass.82 Although this classification system attempts to define three distinct disease processes, there may be considerable clinical overlap among these three syndromes. Patients with mycetoma may develop an allergic bronchopulmonary aspergillosis component to their disease.83 Similarly, rapidly invasive pneumonia may suddenly arrest and manifest as a mycetoma.84 Furthermore, a chronic mycetoma may suddenly break down and become a rapidly invasive pulmonary infection.85

Incidence and Predisposing Factors The incidence of aspergilloma in the general population is unknown. Various diseases that create cavitary lung lesions such as fibrocystic sarcoidosis, histoplasmosis, tuberculosis, bullous emphysema, or fibrotic lung disease can be predisposing factors for aspergilloma.86 The most common antecedent to the development of an aspergilloma is tuberculosis. Systemic diseases such as myeloproliferative disease, diabetes, chronic corticosteroid therapy, and other immunosuppressed conditions may increase the susceptibility to aspergilloma formation.

Pathogenesis

FIGURE 44-7 Aspergillus fumigatus organisms demonstrating a dichotomous branching pattern with prominent septation.

Ch044-F06861.indd 535

The natural history of an aspergilloma is highly variable. Initially, these sporulating conidiophores grow on the wall of a pulmonary parenchymal cavity. Although mycelia frequently grow into the walls of the cavity, the fungus does not generally invade surrounding lung parenchyma or disseminate via the bloodstream. The growing mycelia subsequently slough off the wall and form a fungus ball (Fig. 44-8). In its fully developed stage, the fungus both grows and dies in the cavity. Subsequently, the mycetoma is composed of both living and dead fungus. The growing fungus forms one or more browncolored balls as mycelia and debris are shed. The epithelial lining of the cavity is rarely maintained and enlarges as the result of the growth of mycelia and the inflammatory reaction caused by the mycotoxin. Fibrotic scarring develops after the formation of granulation tissue. The eventual course of the mycetoma is apparently determined by the predominance of

1/21/2008 11:38:45 AM

536

Section 3 Lung

living or dead organisms. If local conditions favor death, the mycetoma usually liquefies and is expectorated in sputum. Less commonly, the mycetoma remains as a calcification of the residual mass of dead fungi. In 1960, Belcher and Plummer classified aspergillomas into simple and complex types.87 Simple aspergillomas develop in

isolated, thin-walled cysts lined by ciliated epithelium with the surrounding lung remaining normal (Fig. 44-9). The formation of the cysts in these cases precedes the formation of the mycetoma. Complex aspergillomas develop in cavities formed by preexisting gross disease in the surrounding lung parenchyma, such as chronic tuberculosis, chronic lung abscess, advanced sarcoidosis, or bronchiectasis (see Fig. 44-9). A large proportion of patients with complex aspergillomas are also immunocompromised. Fungal septa in these cases may be observed to be invading lung parenchyma. In general, complex aspergillomas cause more severe symptoms and carry a poorer prognosis.

Clinical Features

FIGURE 44-8 Gross pathology specimen of a pulmonary aspergilloma.

Patients with aspergilloma may be asymptomatic, with the lesions remaining stable for many years. In some cases, the diagnosis is made on routine chest radiography. The most common symptom associated with aspergilloma is hemoptysis. The severity of this symptom may vary from infrequent, small episodes of blood-tinged sputum to massive hemorrhage with death caused by asphyxiation. Less common symptoms include chronic productive cough, clubbing, malaise, weight loss, anorexia, and reactive airway disease. Fever may be due to superimposed bacterial infection resulting from bronchial obstruction. The underlying pulmonary

FIGURE 44-9 Chest radiographs of a simple aspergilloma (A) and a complex aspergilloma (B). The simple aspergilloma shows a characteristic round, dense opacity occupying the cavity and surrounded partially by a crescent of air (Monod’s sign). Note the severely destroyed lung parenchyma associated with the complex aspergilloma.

A

B

Ch044-F06861.indd 536

1/21/2008 11:38:46 AM

Chapter 44 Mycotic Infections of the Lung

condition is a key prognostic factor in determining the overall outcome because most deaths are due to chronic respiratory failure or pneumonia.82

Diagnosis In many instances, an aspergilloma is found incidentally during routine chest radiography. A characteristic radiographic sign of aspergilloma is a round dense opacity occupying some or most of the cavity and surrounded partially by a crescent of air (Monod’s sign) usually in the upper lung fields.88 CT may help to define the mycetoma within the cavity and also evaluate the degree of inflammation in the surrounding lung parenchyma. CT will also better define the underlying pulmonary disease that may predispose to the formation of the aspergilloma. Direct examination of the sputum using polarizing light microscopy in patients with hemoptysis may reveal the birefringent calcium oxylate crystals that are commonly found in pulmonary aspergillosis. Sputum cultures frequently yield the fungus but are dependent on whether the mycetoma consists of predominantly viable or dead fungus as well as the patency of the airways leading to and from the aspergilloma. A single positive sputum culture, however, has little specificity given the ubiquitous nature of Aspergillus species. If the cavity does not communicate with the bronchial tree, a sputum culture may also be falsely negative. BAL may significantly increase the likelihood of isolating the fungus and is thought to be more meaningful than sputum culture. In cases of hemoptysis, bronchoscopy is also indicated to localize the site of bleeding. When the cavity is located in the peripheral lung parenchyma, percutaneous transthoracic needle aspiration may be of diagnostic benefit. Direct staining of the aspirate with methenamine silver can confirm the diagnosis.89 Serologic testing may be helpful in situations in which cultures are negative. A serum-precipitating antibody test is both sensitive and specific in the setting of radiologically suspicious lesions. Furthermore, antigenemia may be detectable using either the galactomannan antigen test or the βglucan assay. Note that in the case of the galactomannan antigen test, false-positive results may result with concurrent use of β-lactam antibiotics. Similarly, with the β-glucan test, false-positive results are known to occur in nearly 60% of bacteremic patients.90 Skin testing with the antigen to the Aspergillus species is positive in 22% of patients and is less helpful in the evaluation of patients with aspergilloma. In practical terms, in patients with massive hemoptysis, the diagnosis is often made retrospectively after surgical resection.

Treatment Because the natural history of aspergilloma may be highly variable, any treatment plan is individualized for each patient. There are no double-blind, placebo-controlled, randomized trials dealing with the treatment of aspergilloma. Literature concerning this condition is restricted to uncontrolled trials and case series. Because most aspergillomas are ultimately not life threatening, the first major decision in the manage-

Ch044-F06861.indd 537

537

ment of aspergilloma is whether therapy is required at all. An asymptomatic aspergilloma usually does not require treatment unless the patient presents with a mass of unknown cause and malignancy cannot be otherwise ruled out. Because hemoptysis is the cause of death in up to 26% of patients with aspergilloma, therapeutic decisions usually hinge on preventing life-threatening hemoptysis.91 Indicators of poor prognosis have been identified and include severity of underlying lung disease, increasing size or number of aspergillomas on chest imaging, immunosuppression, rising Aspergillus-specific IgG titers, underlying sarcoidosis, and HIV infection.85,92-95 Massive hemoptysis can occur in both simple and complex aspergillomas. In general, when a patient presents with mild non–lifethreatening hemoptysis, the initial treatment can be limited to conservative medical management, including oxygenation, humidification, cough suppressants, postural drainage, and oral or intravenous antibiotics. These patients are followed closely for evidence of rebleeding. Flexible bronchoscopy is used to rule out more serious causes of airway bleeding. In cases of more severe hemoptysis, bronchoscopies are performed early to confirm the focus of bleeding, which may also be evident radiologically. Topical intrabronchial instillation of cold saline with or without epinephrine may assist in arresting bleeding temporarily. Bronchial artery embolization is another option that has been used with success to stop, at least initially, most bleeding. Hemoptysis, however, recurs in more than 50% of cases, likely due to extensive collateral vessels.82 If bleeding is massive, tamponade of the bleeding focus with properly placed balloons may be required to control an acute episode. Double-lumen endotracheal intubation may be necessary to isolate the bleeding and protect the contralateral lung from aspiration of blood. Expeditious thoracotomy and resection of the aspergilloma are performed if the patient is deemed to be able to tolerate such a procedure. Systemic antifungal agents are not effective for aspergilloma.96 Direct endobronchial or intracavitary instillations of various antifungal agents have been reported. Yamada and colleagues reported the use of endobronchial intracavitary instillation of amphotericin B for aspergilloma and showed resolution or clinical improvement in 12 of 14 patients.97 This treatment modality is obviously more problematic in patients with compromised pulmonary function. This experience is encouraging and suggests a nonsurgical alternative for poor surgical candidates. Others have reported profound bronchospasm and advised considerable caution when attempting such local instillations of antifungal agents.81 The choice of surgical management of aspergilloma is based on the balance between the benefit from resection of disease and the risk involved with surgery. In the case of a simple aspergilloma, the risk for hemoptysis is present and the surgical risk is minimal. In this situation, surgical resection appears more favorable. In the case of complex aspergilloma, because of the inherent higher surgical risk, resection is recommended only in patients with a low overall surgical risk. In high-risk patients, intracavitary instillation of antifungal agents and bronchial embolization may be more favorable options. In a comparison study of medical and resectional therapy, Jewkes

1/21/2008 11:38:47 AM

538

Section 3 Lung

and colleagues found a similar 5-year survival rate in patients with minor or no hemoptysis who had undergone medical therapy (65%) versus surgical resection (75%).98 However, for patients with recurrent frank hemoptysis or a single major hemorrhage, the 5-year survival rate was only 41% in the medically treated group and 84% in the surgically resected group, demonstrating the superiority of surgical resection in patients at higher risk of bleeding. In general, indications for surgical resection include the following: 1. 2. 3. 4. 5.

Recurrent gross hemoptysis Life-threatening hemoptysis Chronic cough with systemic symptoms Progressive infiltrate surrounding the mycetoma The inability to rule out malignancy in an indeterminate mass

The goal of surgery is a limited resection that encompasses all diseased tissue. Complex aspergillomas present a particular challenge due to the dense fibrosis surrounding the cavity, the obliteration of the pleural space and fissures, the enlarged and tortuous bronchial arteries, and the diseased pulmonary parenchyma surrounding the lesion. The inflammatory fibrosis of the pulmonary parenchyma and pleura often lead to pleural space problems because the remaining lung is often unable to expand fully to fill the pleural space after resection. Efforts are always made to obliterate any post-resectional residual space. To avoid recurrent contamination and infection of the remaining unfilled pleural cavity, various techniques, including a pleural tent (soft thoracoplasty), decortication, muscle flap, omental transposition, or, in rare conditions, a hard thoracoplasty, are considered after the resection.99,100 Consideration is also given to reinforce the bronchial stump with viable, perfused, and healthy tissue to prevent subsequent bronchopleural fistula. In a recent 19-year series from South Korea, Kim and associates reported on 90 surgical procedures in 88 patients with pulmonary aspergilloma.101 Seventy-two of these cases included complex aspergillomas. The majority of cases were secondary to tuberculosis (65%). Of the 90 surgical procedures performed, 52 were lobectomies, 33 were segmentectomies or wedge resections, 3 were pneumonectomies, and 2 were cavernostomies. There was a 1.1% operative mortality and a 27% morbidity, including prolonged air leaks, persistent intrapleural spaces, postoperative bleeding, empyema, pneumonia, and wound infection. Risk factors identified for postoperative complications included increased age and complex aspergilloma. The 10-year actuarial survival rates for both simple and complex aspergillomas were 80.0% and 79.6%, respectively. These findings are in contradistinction to an earlier publication by Daly and colleagues that reported on a series of 53 patients surgically treated for aspergilloma with an operative mortality of 23%.99 In this series there was a clearly higher risk of mortality and poorer long-term survival in the complex aspergilloma group as a result of the underlying disease. Recurrence of aspergilloma after resection has been reported in 7% of patients.98 Careful follow-up is therefore recommended. When parenchymal invasion is found in the resected specimen, the use of antifungal medications postop-

Ch044-F06861.indd 538

eratively is indicated to prevent subsequent dissemination of the invasive aspergillosis.83

Invasive Pulmonary Aspergillosis Invasive aspergillosis occurs most commonly in immunocompromised patients. It can be a devastating infection that produces necrotizing bronchopneumonia with invasion of pulmonary parenchyma and blood vessels leading to thrombosis, hemorrhage, and, eventually, dissemination. Risk factors identified for the development of invasive pulmonary aspergillosis include prolonged neutropenia (particularly if longer than 3 weeks), chronic corticosteroid therapy, hematologic malignancy, cytotoxic drugs, AIDS, and organ transplantation. This is particularly evident in bone marrow transplant recipients in whom invasive pulmonary aspergillosis is seen in up to 13% of allograft and autograft recipients.79 When considering solid organ transplant patients, lung and heart-lung transplant recipients are by far the most at risk. Infection has been found to occur in 14% to 18% of these patients.102 The transplanted lung appears to be the solid organ at greatest risk because the respiratory tract is the primary portal of entry for aspergillosis. With the lung being denervated below the anastomosis, there is a loss of cough reflexes and initially poor mucociliary clearance. Other processes that may be implicated include inadequate blood flow, episodes of rejection, and cytomegalovirus infection. In contrast, only up to 7% of liver transplant patients develop invasive aspergillosis. Similarly, less than 1% of renal transplant cases develop invasive aspergillosis.103

Clinical Features and Diagnosis Individuals with invasive pulmonary aspergillosis commonly present with unexplained or unremitting fever that does not respond to antibacterial agents. This usually occurs during a period of neutropenia. Other signs and symptoms include pleuritic chest pain, dyspnea, cough, and hemoptysis. Because Aspergillus species have a tropism for the vascular wall, hemoptysis is seen in approximately 31% of patients with invasive pulmonary aspergillosis.104 The characteristic finding on chest radiographs of rounded infiltrates accompanied by fever in immunocompromised patients strongly suggests invasive pulmonary aspergillosis. CT of the chest is warranted because it can show two typical findings: (1) a nodular pattern with or without a surrounding “halo sign,” which usually appears during early periods when there is a lower absolute neutrophil count; and (2) a cavitary pattern with or without an air crescent sign (Monod’s sign), which is generally seen after engraftment.105 Unfortunately, sputum cultures and bronchoscopic lavage tend to be nondiagnostic. Furthermore, positive results for Aspergillus species present an equivocal dilemma because they may indicate only colonization.106 Percutaneous needle biopsy of nodular infiltrates is usually not done owing to the risk of bleeding in these commonly thrombocytopenic patients. As noted previously, serologic testing may be helpful with new or more sensitive antigen testing, although falsepositive results may occur.

1/21/2008 11:38:47 AM

Chapter 44 Mycotic Infections of the Lung

Diagnosis, therefore, of invasive pulmonary aspergillosis depends mainly on clinical suspicion and radiologic findings. Baron and colleagues described five criteria that are highly suggestive of invasive pulmonary aspergillosis107: 1. 2. 3. 4. 5.

Neutropenia Pneumonia Persistent fever despite broad-spectrum antibiotics Hemoptysis Air crescent sign on CT of the chest

Reliance on these criteria appears to be much more practical than resorting to the extremely high risk of lung biopsy.

Treatment Because a delay in treatment can be uniformly fatal and early definitive diagnosis is often difficult, it is entirely appropriate to institute empirical antifungal therapy with amphotericin B when invasive aspergillosis is suspected from clinical findings.108 Lipid-based preparations of amphotericin B may be preferred as initial therapy in patients with marginal renal function or in patients receiving other nephrotoxic drugs. Unfortunately, however, even early aggressive medical treatment of invasive pulmonary aspergillosis results in a high mortality rate. Ninety-three to 100% mortality rates have been reported in bone marrow transplant recipients, with mortality rates approaching 100% in liver transplant recipients.109,110 Although the mortality rate in renal transplant patients is somewhat less at approximately 38%, 60% of survivors lose the allograft kidney due to rejection. This occurs during the period when antirejection immunosuppression is being limited due to ongoing antifungal therapy.111 Reduction of the duration of neutropenic periods with the use of hematopoietic growth factors such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and erythropoietin have been used.112 The poor overall outcome of medical treatment for invasive pulmonary aspergillosis has led some to advocate for surgical removal of the pulmonary focus of infection as a treatment option. In 1988, Kibbler and colleagues reported a total of eight surgical cures of invasive pulmonary aspergillosis, with no surgical mortality in neutropenic leukemia patients.113 Since that time, various investigators have reported successful surgical cure of invasive pulmonary aspergillosis with very low mortality rates in patients who had hematologic malignancies that were treated with high-dose chemotherapy or bone marrow transplantation.107 From their 20-year experience in surgical resection of invasive pulmonary aspergillosis, Matt and associates reported on 41 such consecutive patients. There was an operative mortality of less than 10% with a perioperative major complication rate of 10%.114 Equally impressive was the overall survival rates at 6 and 12 months of 65% and 58%, respectively. The 5-year survival rate after surgical resection was 40%. These are substantial improvements on the aforementioned high mortality of medically treated invasive pulmonary aspergillosis. The authors conclude that given the low response rate to classic antifungal medications, prompt and expeditious surgical resection is offered to patients in whom there is a high

Ch044-F06861.indd 539

539

suspicion of invasive pulmonary aspergillosis with only one or very few resectable pulmonary lesions. Furthermore, they recommend combining pulmonary resection with continued antifungal therapy consisting of voriconazole. If there is evidence of extrapulmonary spread to other organs, the risk of surgical resection may outweigh any potential benefit. Ventilator dependency is also a relative contraindication for surgery. The condition of pleural aspergillosis is thankfully rare. It occurs as a result of advanced pulmonary infection with Aspergillus species and direct spread to the pleural cavity. These are extremely complex and challenging surgical problems that often are complicated by empyema, bronchopleural fistula, and chronic pleural space problems. Given these considerable potential complications, it has been advised that surgery be limited to those patients who are symptomatic.

Coccidioidomycosis Coccidioidomycosis is a fungal disease caused by Coccidioides immitis. This dimorphic fungus is found in the soil and dust and is endemic to the deserts of the southwestern United States. Infection can occur in several forms, which include persistent or chronic pneumonia, miliary disease, pulmonary infiltrates, and pulmonary nodules with or without cavitation. Although coccidioidomycosis requires no treatment, disseminated disease may be fatal. Amphotericin B is the standard medical therapy for patients with respiratory failure due to coccidioidomycosis or rapidly progressive coccidioidal infections. Chronic manifestations of coccidioidomycosis may be treated with oral agents such as fluconazole, itraconazole, or ketoconazole. Often, chronic suppressive therapy is needed to prevent relapses.115 Pulmonary resection is rarely indicated but may play a role in granulomatous disease to rule out malignancy or in cases of cavitation with hemoptysis. There are few data regarding the use of perioperative antifungal agents. They appear to be of little benefit in cases of completely resected asymptomatic pulmonary nodules with or without cavitation. It is unclear whether they are of benefit around the time and after the resection of a symptomatic coccidioidal cavity in the lung. Antifungal therapy has been recommended, however, for perioperative coverage in patients with a ruptured coccidioidal cavity resulting in pyopneumothorax.115,116

Historical Note Coccidioidomycosis has been recognized as a distinct disease in humans since 1892 when it was first described in a patient suffering from multiple cutaneous granulomatous lesions.117 In the early 1900s, coccidioidomycosis became known as a fatal infectious disease manifested by widely disseminated granulomatous lesions primarily of the meninges, bone, and skin. The disease has been considered as a pulmonary disease since Dickson and Gifford in 1938 connected a relatively benign pneumonitis with the constellation of erythema nodosum, fever, and arthralgias as the usual clinical syndrome manifested with C. immitis infection.118 In most instances, coccidioidomycosis has been believed to run a relatively benign course. Disseminated coccidioidomycosis, however,

1/21/2008 11:38:47 AM

540

Section 3 Lung

was almost universally fatal until the development of amphotericin B in the late 1950s.

Epidemiology Coccidioides immitis is endemic to the southwestern United States, including California, Arizona, Texas, and New Mexico. It is also found in parts of Mexico and Central and South America. The fungus lives in the soil and dust. The soil is an exceedingly fertile environment for growth during the rainy portions of the year. The arthroconidia, the infectious form of C. immitis, is formed and contaminates the air during the dry season. Any outdoor activities that involve significant disruption to the soil may lead to infection. These conditions are amplified in the cases of dust storms, which are not uncommon in these areas. Large numbers of people apparently contract the disease, with most running an entirely asymptomatic subclinical course. Skin test conversion is often the only manifestation of prior infection. It is estimated that 100,000 infections occur each year in the United States with 50% to 70% of cases being subclinical.115 Only 5% to 10% of infections result in residual pulmonary sequelae, usually manifesting as pulmonary nodules or peripheral thin-walled cavities. One-half to 1 percent of cases develop chronic pulmonary or extrapulmonary infection.115 Extrapulmonary dissemination is most frequently seen in the skin, bones, and meninges, although this may occur in any part of the body.119

attempts.122 The infection also stimulates T lymphocytes, which are central to the immune response against C. immitis. Classic granuloma formation occurs secondary to the influx of lymphocytes and macrophages. Intense neutrophil infiltration produces extensive surrounding suppuration and microabscess formation. As the disease progresses, cell-mediated immune response may become deficient due to antigen overload, suppressor cells, immune complexes, or fungal immunosuppressive substances.

Pathophysiology

Clinical Features

C. immitis is a saprophyte and grows as a mycelium in nature. As the mycelium grows, it comprises a series of separate hyphae. These ultimately develop into a series of arthroconidia. Mature arthroconidia are quite resistant to drying. They become easily detached and therefore easily airborne. The arthroconidia infect mammals when they are inhaled. Once inhaled into the lung, C. immitis develops a distinctly different morphology and matures into a parasite form. Within the lung, arthroconidia swell into a spherule, which is the organism that is histologically identified in infected tissue by its characteristic doubly refractile cell wall (Fig. 44-10). The large (10-80 µm) spherule undergoes internal cleavage into many endospores (2-5 µm). When the spherule matures, it ruptures and releases endospores into the surrounding lung tissue. Each resultant endospore then matures itself into a spherule and the process repeats again. Unlike the arthroconidia, the spherule is not infective. The spherule/endospore, the only form of the fungus that exists in humans, is not infective and therefore human-to-human transmission is not usually seen. Patients with coccidioidomycosis do not therefore have to be isolated, although care must be taken in disposing of materials contaminated with their secretions. In response to C. immitis infection, host defense mechanisms, including complement activation and chemotactic factors, are generated.120,121 Macrophages and neutrophils accumulate due to the chemotactic factors and attempt phagocytosis, although the arthroconidia, endospores, and especially spherules are resistant to these fungicidal

Primary Coccidioidomycosis. In the majority of people who inhale airborne arthroconidia, either no symptoms result or a very mild illness indistinguishable from a common upper respiratory tract infection is the result. In these patients, infection is indicated only by positive coccidioidal skin test. In the remaining 40% of people, symptoms develop 1 to 3 weeks after exposure, with over 90% of these people having symptoms limited to the pulmonary system. Typical symptoms include fever, sweating, anorexia, weakness, arthralgia, cough, sputum production, and pleuritic chest pain. When these symptoms are accompanied by erythema nodosum or erythema multiforme, the disease has traditionally been called valley fever in reference to the endemic area around the San Joaquin Valley. When symptoms are associated with arthralgias, this process has been referred to as “desert rheumatism.” Persistent Coccidioidomycosis. Persistent coccidioidomycotic pneumonia is defined when symptoms and positive chest imaging findings persist for more than 6 to 8 weeks. In these cases, symptoms may be persistent for several months and chest radiographic findings may not be expected to clear for 6 or more months. The protracted symptoms include cough, fever, hemoptysis, dyspnea, and weight loss.123 The abnormal findings on chest radiography usually comprise bilateral apical nodular lesions. Sometimes multiple cavities resembling tuberculosis or chronic histoplasmosis are found. Asymptomatic pulmonary residua may persist in 5% of people infected by coccidioidomycosis. These include nodules and thin-walled cavities. Coccidioidal nodules (coccidioidoma)

Ch044-F06861.indd 540

FIGURE 44-10 Coccidioides immitis spherules demonstrating a characteristic doubly refractile cell wall.

1/21/2008 11:38:47 AM

Chapter 44 Mycotic Infections of the Lung

are composed of gelatinous centers that often contain identifiable spherules.124 It has been reported that as many as 30% to 50% of solitary pulmonary nodules in affected persons in the southwestern United States are actually coccidioidomas.125 Interestingly, coccidioidomas usually do not calcify and therefore may be difficult to differentiate from carcinoma, often leading to the necessity of their surgical resection to rule out malignancy. The pulmonary coccidioidal cavity develops as a sequela to primary coccidioidal pneumonitis that consolidates. The consolidation is followed by central necrosis, which then leads to the cavity formation. Mild hemoptysis may occur in 70% of patients during the necrosis and cavity formation phases. Often, the cavity remains asymptomatic and is found only on routine chest imaging done for other reasons. It usually appears as a single thin-walled cavity in the upper lung field with little or no surrounding infiltrate. Spontaneous closure has been reported to occur in approximately 27% of patients within 4 years.126 Coccidioidal cavities may become complicated by secondary infection with pyogenic organisms or the formation of a lung abscess or mycetoma. These mycetomas are most commonly caused by Aspergillus species but may also be composed of mycelial elements of C. immitis. Coccidioidal cavities may also become complicated by rupture with bronchopleural fistula, empyema, and hemoptysis being possible.119 Disseminated Coccidioidomycosis. Disseminated extrapulmonary disease may occur in approximately 0.5% of infected people and may occur in the meninges, bones, joints, skin, or soft tissues. The bones of the skull, hands, feet, spine, and tibia are common sites of infection. Joint lesions are unifocal in 90% of cases, with the ankles and knees being the most commonly involved joints. Skin lesions appear as wartlike nodules. Basilar meningitis is common when the disseminated disease involves the meninges.127 If left untreated, 90% of patients with meningitis die within 12 months.128 The cerebrospinal fluid culture is usually negative. The diagnosis, however, may be made by demonstration of IgG antibody in the cerebrospinal fluid along with a mononuclear pleocytosis, low glucose level, and elevated protein level. Patients who are particularly at risk for disseminated coccidioidomycosis are immunocompromised patients, infants, pregnant women, and patients with decreased T-cell immunity, such as those who have had a thymectomy or are on corticosteroid therapy. Organ transplant recipients, patients with malignancies (especially hematologic malignancies), and HIV-infected patients are also at significantly increased risk. The mortality rate in the immunocompromised population is above 40%.112

Diagnosis The diagnosis of coccidioidomycosis can be made by several methods, including histology, culture, and serology. In tissue specimens, a mature spherule of C. immitis with endospore is pathognomonic of infection. The surrounding tissue also shows a granulomatous reaction. Clinical specimens that are often able to provide early diagnosis include pus, sputum,

Ch044-F06861.indd 541

541

and aspirates of infected areas. Occasionally, bronchoscopy or needle aspiration is necessary to obtain an adequate specimen. In the HIV-infected population, sputum or BAL fluid cultures are commonly negative, thus prompting the need in these patients for lung biopsy to obtain adequate tissue for diagnosis. C. immitis grows best on Sabouraud’s glucose agar. It forms colonies within 3 to 4 days that are extremely infectious and therefore are handled only by experienced personnel using appropriate equipment. Serologic testing using the mycelial-phase antigen, coccidioidin, is a reliable method of detecting coccidioidal antibodies.129 Serum IgM is detected in 75% of patients with primary infection during the initial 1 to 3 weeks. It then usually disappears after 4 to 6 weeks but reappears with the spread or progression of the disease. Serum IgG antibody is detected at 4 to 6 weeks after primary infection and attains its maximal level at 2 to 3 months. It then disappears in several months if the infection resolves. Titer levels are prognostic of the severity of the disease.90 Skin test responses to coccidioidal antigens become positive soon after the development of symptoms in virtually all people with primary infections. Cross reactions with other infections are rare. If patients present with erythema nodosum, their skin test involves a diluted agent so as to avoid severe reactions to the test. In patients with progressive infection, anergy is common and the skin test can be used to follow its course. The skin test does not interfere with serologic testing.

Treatment In most asymptomatic immunocompetent patients, no treatment is necessary other than periodic reassessment of emerging symptoms or persistent radiographic findings to ensure resolution or rule out progression. Certain prognostic factors, however, may lead to preemptive treatment of a seemingly uncomplicated primary respiratory infection. These include HIV infection, prior organ transplantation, concurrent corticosteroid use, third trimester of pregnancy, or immediate postpartum period. Note that during pregnancy, amphotericin B is the treatment of choice, if needed, because fluconazole and other azole antifungal agents are teratogenic.115 The disease severity of a primary respiratory infection may be assessed by attention to certain criteria that may be indicators of a more severe course. These include weight loss of greater than 10%, night sweats persisting for more than 3 weeks, large pulmonary infiltrates involving more than one half of one lung or large portions of both lungs, prominent or persistent hilar adenopathy, or failure to develop dermal hypersensitivity to coccidioidal antigens. In these situations, the commonly prescribed therapies include oral azole antifungal agents. The recommended treatment courses range from 3 to 6 months.115 In the case of diffuse pneumonia, amphotericin B is usually recommended.115,130 Improvement is usually only seen after several weeks of therapy, at which point amphotericin B may be replaced by an oral azole antifungal agent. This is usually continued for at least 1 year in immunocompetent patients

1/21/2008 11:38:47 AM

542

Section 3 Lung

and lifelong as secondary prophylaxis in immunodeficient patients.115 Chronic pulmonary coccidioidomycosis is also best treated medically with antifungal agents. Surgical experience has been fraught with high complication rates with this group of patients. The most common surgery performed for coccidioidomycosis is the resection of an indeterminate solitary pulmonary nodule to rule out malignancy. As noted previously, at least 60% of solitary nodules in endemic areas are due to coccidioidomycosis.125,131 Nevertheless in these two studies, the incidence of malignancy ranged from 26% to 35%. The resection of these usually noncalcified indeterminate nodules therefore appears to be prudent even within endemic areas. Since the advent of minimally invasive thoracoscopic techniques, this strategy is even more supported. If a solitary nodule can be determined to be due to C. immitis by noninvasive means such as fine-needle aspiration, specific antifungal therapy is not necessary. Further followup, however, would be prudent to guard against false-negative results from an underlying pulmonary malignancy. Coccidioidal nodules removed by surgical excisional biopsy do not require follow-up antifungal therapy in the absence of diffuse disease or significant ongoing immunosuppression. Most cavities due to C. immitis have a benign, natural history. Although these cavities often harbor viable fungus and cultures of sputum or other respiratory secretions commonly yield colonies of C. immitis, the consensus of authorities is to not initiate treatment in asymptomatic cases. There is a complete absence of controlled clinical trials in this area, and therefore the true potential benefits of antifungal therapy are unknown. Often, these cavities may spontaneously resolve, especially if the lesions are smaller than 2 cm. Indefinite radiologic follow-up is clearly appropriate for most patients. Surgical resection may be recommended to avoid future complications. Cavities that persist for more than 2 years demonstrate progressive enlargement, are immediately adjacent to the pleura, or have a nodular component suspicious for possible malignancy may warrant surgical resection. With regard to surgical resection of coccidioidal pulmonary cavities, Hyde and colleagues suggested caution owing to a high rate of morbidity associated with these operations.132 There remains a paucity of reported series of surgical resection for pulmonary coccidioidal disease. Although morbidity appears to have decreased in the past 40 years since Hyde’s report, the complexity of these cases and the historic reticence due to high complication rates need to be remembered.125,131-133 Pyopneumothorax resulting from rupture of a complicated coccidioidal cavity is rare but usually requires surgical management.116 Decortication with surgical closure of the ruptured cavity by either limited resection or formal anatomic resection such as lobectomy is usually the treatment of choice in healthy patients. This is combined with systemic antifungal therapy generally consisting of amphotericin B. Disseminated extrapulmonary infection is treated medically with oral azoles in the immunocompetent patients and parenteral amphotericin B in high-risk groups such as those who are immunocompromised.115

Ch044-F06861.indd 542

Blastomycosis Blastomycosis is caused by the fungus Blastomyces dermatitidis. It can occur in pulmonary, cutaneous, and disseminated forms. The pulmonary form is often occult and has no particular diagnostic features. Most patients are asymptomatic with the fungal infection being discovered after an incidental finding of infiltrate on a chest radiograph. Treatment is usually only necessary in patients who are immunocompromised, have progressive pulmonary disease, or have extrapulmonary manifestations of the infection. Surgery is usually reserved as a diagnostic tool to rule out malignancy.

Historical Note Gilchrist, in 1894, is credited with first describing the clinical aspects of blastomycosis while working at Johns Hopkins University.7 Although he originally erroneously attributed the case of cutaneous blastomycosis to a protozoan infection, he later correctly isolated the fungus from a patient with a long history of blastomycosis of the facial skin. Gilchrist and Stokes then inoculated the organism into several animals and subsequently recovered the organism, thus fulfilling Koch’s postulates.134 Blastomycosis came to be known and is often still referred to as Gilchrist’s disease. Hektoen, in 1907, while working at Cook County Hospital, reported several more patients with blastomycosis and, because of this, in certain circles, the disease was referred to, for a time, as “Chicago’s disease.”135 Schwary and Braum demonstrated that blastomycosis almost always enters the body via the lungs and that skin, bone, or CNS infections result from lymphohematogenous spread of the primary pulmonary infection.136 In so doing, they debunked the previously held belief that there were two forms of the disease: one pulmonary and one dermatologic.137

Epidemiology The epidemiologic understanding of blastomycosis has been challenging owing to the lack of sensitive and specific serologic testing as well as the difficulty in recovering the organism from its natural habitat. Subclinical infections or patients with resolving infection are therefore difficult to identify. Endemic areas therefore can only be defined by reported cases. Because most local health authorities do not require the reporting of this disease, true incidence is not known but may be as high as 0.5 to 4 new cases per 100,000 population per year in endemic areas.138-140 This is 10 times less common than histoplasmosis. Blastomycosis is endemic in North America in the area east of a line that begins at the Manitoba/Saskatchewan border and extends to the Texas Gulf Coast with the exception of Florida and New England. The highest incidence in the United States is found in Arkansas, Kentucky, Louisiana, North Carolina, Tennessee, and Wisconsin. Occurrences in western North America are extremely rare. Although once referred to as North American blastomycosis, the disease has been reported worldwide.137,141,142 Blastomycosis occurs most commonly in middle-aged men. In a large historic review, 60% of patients were between 30

1/21/2008 11:38:48 AM

Chapter 44 Mycotic Infections of the Lung

543

and 60 years of age, with only 3.4% of patients younger than 20 years of age.143 The usual ratio of infected males to females ranges from 6 : 1 to 15 : 1. This may be due to a preponderance of outdoor exposures by males but also may be due to a host susceptibility factor that protects females from such infection.144 Several laboratory experiments have shown animals with higher levels of estrogen to have a lower infection rate with B. dermatitidis. The fungus is thought to grow well in nitrogen-rich soil close to streams, rivers, and lakes. Its growth is facilitated by rapidly increasing soil temperature. Disturbances of contaminated soil, as with rainfall or excavation, facilitate aerosolization of the fungus. In highly endemic areas, cases are also linked to residences in close proximity to recreational water.142

Pathophysiology In nature, the organism grows as an aerial mycelium in which the microconidia, the infecting particles, are lined up. Once in the lung and eventually the alveoli, the organism converts to a parasitic form of yeast. The yeast then multiplies and a neutrophilic reaction results in an area of pneumonitis. Regional lymph nodes are commonly involved. Histologically, the area of infiltrates shows a mixed neutrophilic and mononuclear cell infiltration. The inflammatory response to blastomycosis includes both pyogenic and granulomatous components.145 Once all organisms are contained, the infiltrate begins to round off and fibrosis takes place. This healed area of pneumonitis may be found incidentally as a coin lesion on a chest radiograph. Calcification of these nodules in blastomycosis is less common than found in histoplasmosis or coccidioidomycosis. If delayed hypersensitivity does not develop, the fungus may disseminate through the body and involve the skin, bone, meninges, prostate, and adrenal glands and produce progressive disease. Progressive infection can occur more commonly in patients with T-cell immunity defects such as transplant recipients, AIDS patients, and those patients receiving highdose immunosuppression for malignant or nonmalignant diseases.146 Blastomycosis is much less common than histoplasmosis in immunocompromised hosts.

Clinical Features Three forms of blastomycosis exist: pulmonary, cutaneous, and disseminated. Most cases of pulmonary blastomycosis are sporadic, and only a few cases have actually been recognized. Evidence does suggest that asymptomatic infections can occur; but for reasons mentioned previously, their true incidence remains unknown. Infected hosts may have a brief flu-like illness manifested by fever, chills, headache, myalgias, and nonproductive cough that usually resolves rapidly.147 The disease in these patients is usually only detected during epidemic outbreaks. Most patients present with initial symptoms resembling bacterial pneumonia and are first treated for this. The physical examination is usually negative. However, if patients have segmental or lobar disease, signs of pulmonary consolidation may exist. Patients are usually not correctly diagnosed until

Ch044-F06861.indd 543

FIGURE 44-11 Transbronchial lung biopsy specimen demonstrating Blastomyces dermatitidis in pulmonary tissue. Note the thick walls and broad-based budding characteristic of this fungus.

more aggressive diagnostic strategies are employed after the failure of initial antibacterial therapy. Sputum examinations including sodium–potassium hydroxide (KOH)–digested smears and fungal cultures normally allow the diagnosis to be made. Occasionally, more invasive diagnostic methods such as bronchoscopy, needle aspiration, or thoracoscopic lung biopsy may be required for the correct diagnosis to be made (Fig. 44-11). Chest radiographs have variable findings ranging from multiple pulmonary nodules to focal, even lobar, alveolar infiltrates. Although rare, a scattering of new skin lesions during unsuccessful antibacterial therapy may provide a clue to the correct diagnosis. In approximately 25% of patients, extrapulmonary lesions such as in the skin or bone are present. Direct smears, cultures, or histologic examinations of these lesions may be helpful for diagnosis. Rarely, a patient with pulmonary blastomycosis may present with a fulminant infectious acute respiratory distress syndrome. Pleuritis and pleural effusions may be present. Aspiration of pleural fluid may reveal the organism. Gas exchange is usually impaired and ventilatory support may be necessary. Air space consolidation is usually present on chest radiographs when the disease reaches this severity. Mortality in such cases may reach as high as 50% with ultimate survival depending on rapid diagnosis and early institution of full-dose amphotericin B therapy. The cutaneous form is the second most common manifestation of blastomycosis. Although infection may be contracted by direct skin inoculation, this is extremely rare. Most cutaneous manifestations of the disease are thought to represent dissemination from lymphohematogenous spread of an initial pulmonary focus. Most lesions occur in patients with untreated or inadequately treated pulmonary infections. Skin lesions may occur without any pulmonary signs or symptoms, given the occult nature of most pulmonary infections. The disseminated form presents as one or more subcutaneous nodules that eventually break through the skin’s surface. The lesion may take weeks or months to evolve and after time may spread to other areas of the body. If left untreated, the ulcers spread by slow advancement, often taking years to

1/21/2008 11:38:48 AM

544

Section 3 Lung

evolve. The organism may be identified by aspiration of the pustule.148-150 Disseminated blastomycosis can manifest as infection of the bones, commonly including the vertebrae, ribs, and skull.148 The long bones may be involved in one third of cases.151 Bone infection presents as a chronically draining sinus or as an abscess. Débridement may be required for cure, although most bone lesions resolve with appropriate antifungal therapy alone. Disseminated infection may also affect the genitourinary system, including prostatitis and epididymoorchitis. A CNS infection occurs in 5% to 10% of disseminated blastomycosis and presents as either an abscess or meningitis. The organism is difficult to recover in the cerebrospinal fluid; therefore, diagnosis of blastomycotic meningitis is challenging. Aspiration of ventricular fluid may be necessary to obtain a positive culture.152 Hematogenous spread to the oropharynx and larynx has also been described.153

A

Diagnosis The definitive diagnosis of blastomycosis depends on demonstration of the presence of B. dermatitidis in body fluids or tissue specimens by staining or culture. Because the inflammatory response to a blastomycotic infection is predominantly a polymorphonuclear leukocyte reaction, large amounts of sputum or pus are usually produced in the infected area. Also because the organism is relatively large in its tissue phase (5-20 µm) and shows a characteristic wide-based budding with double refractile walls, direct microscopic diagnosis of blastomycosis is much more common than with other forms of fungal infections. Repeated microscopic examination of early morning sputum samples commonly reveals the organism. Fiberoptic bronchoscopy with brushings and washings as well as transbronchial biopsy may be used to obtain adequate specimens. When bronchoscopy is performed, the concentration of lidocaine used for local anesthesia of the airway must not exceed 1 g/dL so as to reduce its antifungal effect.154 Even when initial smears do not reveal the organism, cultures are commonly positive. Growth may be detected as early as 5 to 7 days or as late as 30 days depending on the size of the inoculum. Specimens, therefore, are not considered negative until 4 weeks of incubation have passed without growth. When the number of B. dermatitidis organisms is small, the use of specific immunofluorescent reagents is recommended for accurate and specific identification.155 If more rapid identification is needed, 24-hour exoantigen tests or even more rapid 2-hour DNA probes are commercially available.90,156 Radiographic findings in pulmonary blastomycosis are extremely variable. The most common finding in a review of Mayo Clinic cases was a mass (Fig. 44-12), whereas in other series an infiltrate was reported to be the most common finding.157,158 In the cases of acute pulmonary disease, the chest radiograph usually shows a pattern of consolidation resembling bacterial pneumonia that is either unilateral or bilateral and may demonstrate regional lymph node enlargement. On occasion, there is a diffuse miliary pattern. The infiltration is typically patchy, with poorly defined borders. The density may become mass-like or may cavitate.

Ch044-F06861.indd 544

B FIGURE 44-12 A and B, Chest radiograph and CT scan of a left hilar mass (arrows). Transbronchial biopsy demonstrated Blastomyces dermatitidis.

After resolution of the acute process, the pattern changes to a granuloma formation, fibrosis, and volume loss.159 In chronic blastomycosis, a chest radiograph can reveal nodular densities with extensive fibrosis and contraction. The organism has a predilection for the upper lobes but can affect any lobe. Although pleural effusions may be seen in the chronic form of blastomycosis, this is not a common finding. The infiltrate of chronic blastomycosis often extends to the hilum and may mimic bronchogenic carcinoma. In the Mayo Clinic review of 35 patients with blastomycosis, 55% of the patients underwent thoracotomy to rule out carcinoma.158 Radiologic studies by themselves most often cannot exclude carcinoma. This leads to the most common indication for surgical intervention in blastomycosis, the exclusion of underlying malignancy.

Treatment Before the availability of effective antifungal therapy, more than 90% of cases of blastomycosis were fatal.137 With the advent of amphotericin B and other antifungal agents, most patients with blastomycosis can be treated successfully. Not all patients require antifungal medications. Immunocompetent patients with limited pulmonary disease may be treated with observation alone. After adequate follow-up, if improvement occurs without further progression, no further therapy

1/21/2008 11:38:48 AM

Chapter 44 Mycotic Infections of the Lung

is required.160 In the case of disseminated or severe local disease, antifungal therapy is mandatory. There are no data to suggest that aggressive treatment of the limited disease in immunocompetent patients decreases the subsequent development of disseminated disease. The role of surgery in blastomycosis is most often limited to confirming the disease or ruling out malignancy. The indications, therefore, for resectional pulmonary surgery are few, owing to the effectiveness of medical antifungal therapy.

Pulmonary Cryptococcosis Cryptococcosis is caused by the encapsulated yeast-like budding saprophyte Cryptococcus neoformans. It is found in the soil and in avian excrement, especially that of the pigeon. It has also been previously known as torulosis and European blastomycosis. Its typical portal of entry appears to be the respiratory tract, although CNS involvement has also been encountered. CNS involvement is usually much more serious and life-threatening than its pulmonary counterpart. Interestingly, the diagnosis of pulmonary cryptococcosis is usually made retrospectively or when the organism has been recovered from another body site.

Historical Note The first clinical case of isolated pulmonary cryptococcosis was reported in 1924 by Sheppe.161 By 1929, it was noted that the organism had a clear predilection to involve the brain and meninges.162 The association of cryptococcosis with AIDS was first reported in 1983 by Snider and coworkers.163

Epidemiology C. neoformans exists as yeast both in nature and in living tissue. It is notable for its distinguishing capsule and ranges in size from 5 to 20 µm. In some instances, nonencapsulated strains have been encountered in a clinical setting.164 C. neoformans has a worldwide distribution. It grows in the soil and surrounding areas that are heavily contaminated with bird droppings, particular those of the pigeon. The incidence of cryptococcosis has steadily increased, owing in great part to the existence of AIDS and other immunodeficiency syndromes.165

Pathophysiology C. neoformans infects the respiratory tract through inhalation. Despite the organism’s large, thick, and adhesive capsule, which makes it difficult to be aerosolized or reach the alveolar space, organisms found in desiccated pigeon droppings are generally not encapsulated, easily aerosolized, and commonly smaller than 2 µm, allowing for easy dissemination in the distal airways.166 Likely because of the size of the encapsulated organism, there are no reports of animal-to-human transmission of this disease and only rare instances of possible human-to-human transmission. To date, there have been no reports of infection by means of exposure in the laboratory. Clearly, the course of the clinical disease of cryptococcal infection is determined in large part by the immune function

Ch044-F06861.indd 545

545

of the individual host. There is a wide spectrum of disease ranging from asymptomatic nodular disease to severe acute respiratory distress syndrome. Similarly, the histopathologic findings vary from complete absence of inflammatory cells to the presence of exuberant granulomata. Cell-mediated immunity is the major defense against this organism.167,168 Disseminated disease is therefore most commonly seen in patients with AIDS, those with lymphoreticular system malignancies, patients on chronic corticosteroid therapy, immunosuppressed solid organ transplant recipients, and patients with sarcoidosis. In the case of infection with C. neoformans, destruction of surrounding tissues is the result of mechanical pressure, secondary to the increased number of yeast cells, rather than any toxin produced by the organism. It has also been demonstrated that the cryptococcal antigen can reduce the production of anticryptococcal antibodies.169 Similarly, the cryptococcal antigen can also induce suppressor lymphocytes.170 In this way, the organism can, in fact, suppress the host immune system, allowing for enhanced organism proliferation even within an otherwise immunocompetent host. These facts are also used to explain occasional occurrences of cryptococcal meningitis in otherwise immunocompetent hosts.

Clinical Features The clinical features of pulmonary cryptococcosis are both nonspecific and varied. Symptoms in immunocompetent patients can range from complete absence of symptoms to classic symptoms of pneumonitis, including cough, fever, sputum production, chest pain, dyspnea, hemoptysis, night sweats, and weight loss.171,172 Although the lung is the principal route of entry for infection, the organism has a clear predilection for infecting the CNS and, in less common cases, other organs of the body. Patients are commonly found to have extrapulmonary disease at the time of presentation. Physical examination findings are equally nonspecific. Extrapulmonary involvement of the CNS, skin, or prostate raises a suspicion of pulmonary cryptococcal infection.

Diagnosis Just as the clinical features are varied, so, too, are the radiographic findings in cryptococcal infection. Asymptomatic immunocompetent patients may be found to have solitary or multiple pulmonary nodules on imaging of the chest.173,174 Occasionally, an asymptomatic immunocompetent patient may present with a large pulmonary mass that on excision is shown to contain a gelatinous collection. In the immunocompromised patient such as those with HIV infection, the most common finding is a diffuse interstitial infiltrate.175 The most common radiologic finding, when one is present, is a single or multiple groups of nodular lesions. These lesions may sometimes cavitate or, in the case of a large cavitary nodule, mimic a pulmonary abscess. Concomitant hilar adenopathy may also be found. Pleural effusions rarely occur. C. neoformans organisms isolated in the sputum may represent simple colonization of the airway or true cryptococcal infection. It is known that carrier states or colonization do

1/21/2008 11:38:49 AM

546

Section 3 Lung

exist in humans.176 It is suggested, therefore, that when the presence of true infection is questionable, specimens from deeper in the lung such as BAL, fine-needle aspiration, or thoracentesis specimens are occasionally required. In the case of pulmonary nodules or masses, CT is useful to localize the lesion and, when necessary for diagnosis, a CT-guided transthoracic fine-needle aspiration can sometimes be helpful. Occasionally, thoracoscopic or open-lung biopsy is required. If the patient has a skin ulcer, a swab of the lesion stained with India ink will permit identification of the yeast under the microscope. When considering the histologic examination of potentially involved tissue, routine hematoxylin and eosin will be useful to evaluate the inflammatory response but will not allow for staining of the yeast. Periodic acid–Schiff stain can be used to stain the organism. C. neoformans is suspected on the basis of the presence of a capsule and narrow budding (Fig. 44-13). Whereas mucicarmine stain will color the cryptococcal capsule yellow to red, Gomori methenamine silver stains the organism black but not the capsule. Fontana-Masson stain may be helpful in patients with AIDS when suspected capsule-deficient cryptococcal infection is being investigated.177 Cryptococcal skin tests are not standardized and are therefore not usually recommended. The cryptococcal antigen detection has a high sensitivity and specificity (90% and 95%, respectively).178 Causes for false-positive results in this highly specific test include rheumatoid factor, anti-idiotype antibodies, infection with cross-reactive organisms (Trichosporon asahii, Capnocytophaga canimorsus), and certain rare laboratory mishandling processes. The serum cryptococcal antigen is usually not detected in patients with pulmonary Cryptococcus unless there is extrapulmonary dissemination. Therefore, a negative result for serum cryptococcal antigen does not necessarily rule out pulmonary cryptococcosis. A negative serum antigen test, however, does suggest that the likelihood of CNS involvement is very low. Definitive diagnosis of cryptococcal infection can be made by culturing the specimen. This is done using routine fungal medium that does not contain cycloheximide. Growth is enhanced at temperatures below 37ºC and is usually identifiable by 72 to 96 hours.

Treatment Before the advent of effective antifungal agents in the 1950s, disseminated cryptococcal disease was uniformly fatal. In the modern era of antifungal therapies, the treatment for pulmonary cryptococcosis is largely determined by the immune status of the patient, which in turn determines the likelihood of dissemination. It is clear that all immunocompromised patients with cryptococcosis require treatment because they are at high risk for developing disseminated infection. Similarly, patients with symptoms are also treated with an antifungal regimen. Controversy exists in the case of asymptomatic immunocompetent patients with positive airway cultures. It has been suggested that these patients may be observed without specific antifungal therapy.171 Whether specific therapy is instituted or not, it is a clear requirement that all patients with isolated pulmonary cryptococcal disease undergo lumbar puncture to rule out concomitant CNS infection. In immunocompetent patients who present with mild to moderate symptoms, initial treatment with fluconazole is recommended. When use of fluconazole is not possible, an acceptable alternative is itraconazole to avoid the toxicity known when employing amphotericin B. Immunocompromised patients with isolated pulmonary cryptococcosis are treated aggressively with antifungal therapy to avoid dissemination of the disease. Surgery is rarely needed and is generally performed to provide a diagnosis or rule out a neoplasm. Surgical resection of refractory pulmonary disease is rarely necessary.

Mucormycosis Pulmonary mucormycosis is a fortunately rare but often fatal disease due to infection by fungi of the subclass Zygomycetes. Mucormycosis has also been known as zygomycosis or phycomycosis. Although these organisms are ubiquitous in nature, they rarely result in pathogenic disease in immunocompetent humans. Conversely, immunocompromised patients are at increased risk of the disease, which has grown in prevalence among immunosuppressed patients and particularly in patients after bone marrow transplantation.

Historical Note The diagnosis of mucormycosis was first described by Harris in 1955.179 The first report of a surgical cure of pulmonary mucormycosis was by Dillon and colleagues in 1958.180

Epidemiology and Pathophysiology

FIGURE 44-13 Cryptococcus neoformans demonstrating the characteristic capsule and narrow budding pattern.

Ch044-F06861.indd 546

Mucor species are ubiquitous and are found in the soil and in decaying fruit. They are sometimes also found in laboratory contaminants. There is no specific geographic distribution for this organism. Infection occurs after inhalation of the spores. Because Mucor species grow favorably in acidic, high-glucose media, diabetic ketoacidosis patients are particularly susceptible. The clinical manifestations of Mucor infection are determined in large part by the site of entry, the port of entry, and the immune status of the host. The most characteristic feature of mucormycosis is hyphal invasion of blood vessels.

1/21/2008 11:38:49 AM

Chapter 44 Mycotic Infections of the Lung

Once the organism invades the blood vessels, vascular thrombosis with tissue ischemia and infarction of adjacent areas of tissue generally occurs. Necrotic debris and infected tissue then form black-colored pustules. The infarcted tissue promotes rapid extension of the infection. In pulmonary infection with mucormycosis, it has been shown that the fungi frequently penetrate the bronchial walls and invade the nearby vasculature. The organisms have been shown to dissect within the layers of the pulmonary vessels, specifically the pulmonary arteries, predisposing the patient to pulmonary artery rupture and resultant hemoptysis.181

Clinical Features Six distinct syndromes have been identified to describe the various manifestations of mucormycosis: 1. 2. 3. 4. 5. 6.

Rhinocerebral Pulmonary Cutaneous Gastrointestinal Disseminated CNS Other tissues (including bone, kidneys, heart, and mediastinum)

In otherwise healthy individuals, Mucor spore inhalation results in colonization rather than infection due to elimination of the organism by competent pulmonary macrophages. In the immunocompromised patient, inhalation often leads to severe pulmonary infection. This may or may not be accompanied by rhinocerebral mucormycosis. Pulmonary mucormycosis in neutropenic patients resembles pulmonary aspergillosis. These features involve persistent fever and pul-

A

547

monary infiltrates, which are refractory to antibacterial therapy. The initial bronchopneumonia seen in pulmonary infection progresses to vascular invasion with thrombosis and subsequent infarction followed by late dissemination to extrapulmonary tissues. The organism is known to directly invade nearby structures such as the chest wall, diaphragm, pericardium, myocardium, and, rarely, trachea.182

Diagnosis Chest radiographic features are variable. These range from bronchopneumonia to segmental or lobar consolidation to infarction and cavity formation (Fig. 44-14). Diagnosis is clearly assisted by a heightened level of diagnostic suspicion in the appropriate clinical situation, namely, that of the immunocompromised patient. Hemoptysis, because of the implications of pulmonary arterial invasion, is clearly an ominous sign. Concomitant airway colonization with other opportunistic fungi such as Aspergillus or Candida species sometimes may confuse the picture. Culture results are commonly negative but have a low false-positive rate. Positive cultures, therefore, strongly suggest invasive disease. The diagnosis of pulmonary mucormycosis is usually made on histopathologic examination of specimens. Classically, a clinical specimen such as KOH-digested sputum that shows characteristic broad aseptate hyphae with stubby, rightangled, finger-like, 45-degree branches is highly suggestive of mucormycosis. If the initial sputum examination is negative, BAL bronchial brushings or transbronchial biopsies may be necessary to obtain an adequate specimen. Occasionally, thoracoscopic or open-lung biopsy is necessary to obtain

B

FIGURE 44-14 Chest radiograph (A) and CT scan (B) of a 70-year-old diabetic woman who presented with hemoptysis secondary to pulmonary mucormycosis that was subsequently surgically resected.

Ch044-F06861.indd 547

1/21/2008 11:38:50 AM

548

Section 3 Lung

adequate tissue for diagnosis. There are no currently available serum immunologic assays for the detection of mucormycosis.

Treatment The overall mortality rate of patients with pulmonary mucormycosis is 56%.183 Initial treatment consists of correcting underlying factors such as ketoacidosis in a diabetic patient. Reversal of iatrogenic immunosuppression also plays a key role in attempts to resolve this infection. Often, granulocytopenia must be treated using various hematopoietic growth factors such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factors.183-185 Amphotericin B remains the only effective antifungal agent. Therapy using amphotericin B begins at the time of presumed diagnosis with a dose of 1.0 to 1.5 mg/kg/day.186 Optimal duration of treatment is unknown and is individualized to the patient’s clinical response. When poor or no response is seen, pulmonary resection of localized disease is performed.187 When resecting lung tissue for mucormycosis, all devitalized tissue and necrotic debris is removed. Even when the localized disease has been apparently completely excised, continued antifungal therapy with amphotericin B is usually recommended. When lesions are localized or restricted to one area of the lung, anatomic lobar segmental resection of these lesions may be as effective in controlling progression of pulmonary mucormycosis as amphotericin B antifungal therapy.188

Actinomycosis and Nocardiosis Although previously thought to be fungi, actinomycetes, which include the families Actinomycetaceae and Nocardiaceae, are now known to be true bacteria. This is evidenced by their cell wall composition, which is made up of muramic and diaminopimelic acids and lysine whereas fungal cell walls are composed of chitin or glucans. These organisms also have a separate mode of reproduction by bacterial fission rather than spores or buds. Furthermore, these organisms have prokaryotic traits in that they lack a nuclear membrane and mitochondria, which are both present in fungi. Lastly, these organisms are now known to be sensitive to antibacterial antibiotics and resistant to antifungal agents. Nevertheless, these organisms are often still included in discussions of pulmonary mycotic infections. The diagnosis of actinomycosis can be challenging. Progressive, peripheral pulmonary fibrosis is common in the lung with predominance in the lower lobes. Pleuritic dull and aching pain often accompanies this fibrosis and is caused by infection that permeates the pleura and creates periostitis around the nearby ribs. This periostitis helps to indicate the diagnosis. It is common for surgeons to be called on to treat patients with this pleuritic chest wall pain in a workup for presumed empyema or pulmonary/chest wall neoplasm. The findings at thoracotomy usually are that of a highly vascular fibrosis when biopsies fail to reveal an organism or the definitive diagnosis. This is often the case because actinomycosis is not usually suspected and therefore appropriate bacteriologic

Ch044-F06861.indd 548

examination is not made. The classic sulfur granules are rarely seen in pulmonary actinomycotic infection. Because of the extremely intense fibrosis encountered in the lung, resection of the affected area is usually futile. Actinomycosis is considered as a possible diagnosis in patients with poor oral hygiene who have suspected aspiration pneumonia. Medical therapy consists of long-term administration of penicillin. Surgery is rarely necessary.189 Nocardiosis is suspected in any immunocompromised patient who has an antibiotic-refractory pneumonia. Concomitant cerebral and pulmonary abscesses are also suggestive of this diagnosis. Occasionally, sputum analysis may provide the diagnosis, although usually deeper specimens such as bronchial washings or biopsy tissue are needed.190 Sulfamethoxazole-trimethoprim is the treatment of choice.

Candidiasis Although Candida species are among the most prevalent fungi, pulmonary candidiasis is rarely encountered by the thoracic surgeon. The rare clinical situation in which a thoracic surgeon will encounter this disease is in candidal pneumonia, esophagitis, endocarditis, or meningitis.

Diagnosis Diagnosis of invasive candidiasis may be challenging given that Candida species are present in 50% to 60% of respiratory secretions taken from uninfected patients. It is impossible to distinguish by culture techniques alone between colonization versus tissue invasion.191,192 When positive blood cultures are encountered, a vigorous search for the source must be undertaken, with indwelling vascular catheters being the most likely source. Diagnosis may be assisted by the β-glucan test, which has a sensitivity of 78% in candidiasis.90 Candidal pneumonia has two forms. The first occurs after aspiration of Candida-laden oropharyngeal material. This is a rare occurrence. More commonly, hematogenously disseminated candidiasis produces pulmonary lesions, usually in concert with extrapulmonary involvement. Because injudicious use of antifungal therapies in patients with noninvasive tracheobronchial colonization or oropharyngeal contamination of respiratory secretions is likely to result in selection of resistant organisms, histopathologic confirmation of candidal pneumonia is necessary for definitive diagnosis.193 The main treatment for candidial pneumonia, both primary as well as secondary, has been amphotericin B. Prompt diagnosis and institution of therapy has led to improved outcomes.

Sporotrichosis Sporotrichosis is caused by infection with the organism Sporothrix schenckii. This is a biphasic fungus with a worldwide distribution in the soil. This organism regularly is found in plants and thorn bushes, and the cutaneous form of this disease is therefore often seen in gardeners and florists. Pulmonary infection is rare. It may mimic the findings that are usually associated with tuberculosis. This includes hilar adenopathy, persistent pulmonary infiltrate, and cavitary disease.194,195

1/21/2008 11:38:50 AM

Chapter 44 Mycotic Infections of the Lung

Successful resection of cavitary sporotrichosis was reported in two patients in 1962 by Ridgeway and colleagues.196 In general, this is a very rare disease and surgical resection is rarely necessary.

Diagnosis Diagnostic suspicion is awakened in patients who present with chronic respiratory illness who have a strong history of gardening activity. With an insidious onset, sporotrichosis presents as a low-grade fever and slow but gradual weight loss. Chronic pneumonitis with fibrosis and cavitation are seen on chest radiographs and closely resemble the findings of histoplasmosis or tuberculosis. Pulmonary sporotrichosis is most common in middle-aged men with underlying risk factors such as alcoholism and chronic obstructive pulmonary disease.197-199 Often the outcome is poor due to delay in diagnosis and severity of underlying pulmonary disease. Disease severity generally governs the treatment options, which include amphotericin B and itraconazole. The most effective therapy appears to be a combination of amphotericin B and subsequent surgical resection.195,199 Commonly, however, surgical resection is not possible owing to the severe underlying pulmonary disease that often accompanies sporotrichosis.

Ch044-F06861.indd 549

549

SUMMARY It is often difficult to grasp the expanse in the spectrum of presentations of pulmonary mycoses. It is, however, important for the general thoracic surgeon to remain aware of these infections and the diseases with which they are associated. Surgical intervention, although not commonly performed, can be challenging and associated with significant risk in this patient population.

COMMENTS AND CONTROVERSIES Dr. Cassivi has provided an excellent review of pulmonary fungal infection. These infections rarely produce acute management problems for thoracic surgeons. The use of various laboratory assays is outlined clearly and important because appropriate handling of diagnostic specimens can mean the difference between a secure diagnosis and the need for open biopsy procedures. The pulmonary pathology of histoplasmosis, coccidioidomycosis, and blastomycosis can all be confused with bronchogenic carcinoma. The chapter provides a thorough review of the common fungal infections: histoplasmosis, aspergillosis, coccidioidomycosis, and blastomycosis. In addition, a concise review of cryptococcosis, mucormycosis, actinomycosis, nocardiosis, candidiasis, and sporotrichosis rounds out this chapter with essential infection for the thoracic surgeon. G. A. P.

1/21/2008 11:38:50 AM

chapter

45

PARASITIC DISEASES OF THE LUNG AND PLEURA Andrés Varela Raul Burgos Evaristo Castedo Key Points

■ Hydatid disease is characterized by the development of cysts as

a consequence of the parasitization of humans by the larva of Echinococcus. ■ Protozoal infections include amebiasis, which is a parasitic infection produced by Entamoeba histolytica. ■ Helminthic infections, such as Dirofila riaimmitis (also known as heartworm in dogs), produce pulmonary dirofilariasis in people.

The term parasite is derived from a Greek word meaning “he who eats at the table of another.” Although in a broader sense all infectious microorganisms could be considered parasites, the term parasitic infections refers to those infections caused by protozoa and helminths. Their main feature is their transmission to humans via biologic vectors or intermediate hosts (insects, mollusks, or mammals). Once lodged in the definitive host, they present complex life cycles and produce longterm chronic infections. Parasitic diseases of the chest can manifest as hypersensitivity reactions, as eosinophilic lung disease, or as direct invasion of the lungs or pleura. The clinical profile to watch for is peripheral blood eosinophilia in immunocompetent individuals who have traveled to endemic regions. The other group at great risk comprises those who are immunocompromised, such as organ transplant recipients and patients with acquired immunodeficiency syndrome (AIDS), in whom the prevalence is notably higher. The presence of eggs or larvae in stool, sputum, bronchoalveolar lavage fluid, pleural fluid, or lung tissue generally indicates pleuropulmonary involvement, although this is an exceptional finding. Therefore, the diagnosis is usually based on serologic evidence provided by enzyme-linked immunosorbent assay (ELISA) or monoclonal antibodies. This chapter, which is directed particularly to thoracic surgeons, reviews all the parasitic diseases that affect humans, particularly those found in pleura or lungs. They have been grouped into tables for easy referral (Tables 45-1 through 45-4). Hydatid disease, which is endemic not only in the Mediterranean basin but also in regions as widely dispersed as Australia and South America, is dealt with in particular depth. It occasionally requires surgical intervention, whereas other parasitic infections can almost always be treated successfully without surgery.

HYDATID DISEASE Hydatidosis is characterized by the development of cysts as a consequence of the parasitization of humans by the larva of Taenia echinococcus (Echinococcus granulosus). In the adult stage, it is a platyhelminthic worm belonging to the class Cestoda and the family Taeniidae. Of the four known species of Echinococcus (E. granulosus, E. multilocularis, E. oligarthrus, and E. vogeli), only E. multilocularis and E. granulosus are human pathogens. The latter is the causative organism in most cases of human infection. In North America, almost all cases of this disease are seen in immigrants with the classic syndromes outlined in this section. It is colloquially referred to as the pastoral variety of hydatid disease. The sylvatic form is most commonly seen in indigenous North Americans, mostly in northern Canada and Alaska. In this type, a different strain of tapeworm is implicated, and the dog, deer, and moose are the usual intermediate hosts. In the sylvatic form, lung cysts occur more commonly than liver cysts.

Epidemiology Hydatid disease, known in the times of Galen, was described by Thebesius in the 17th century. It is thought to have originated in Iceland and to have been brought to continental Europe by dogs accompanying whaleboats in the 18th century. Infestation is confined to geographic areas in which there is continuous contact between humans and certain domestic carnivores such as dogs and cats and some ungulates such as sheep. Echinococcosis is endemic to the Mediterranean region, South America, Australia, New Zealand, the Middle East, Alaska, and Canada, where it is widespread among Native American tribes.1 In Spain, the epidemiologic data on hydatid disease have improved considerably, and, at the present time, the number of cases reported is minimal. This is illustrated by the fact that surgical treatment for this disease in 1966 was performed in 4.62 patients per 100,000 population per year, whereas by 1988 the incidence had dropped to 1.77 patients per 100,000 population per year, and in 1997 it was recorded at 0.78 patients per 100,000 population per year. The number of hospital admissions for hydatid disease likewise has decreased, from 6690 in 1966, to 2343 in 1988, 972 in 1997, and down to 50 in 2005. These data were obtained from Boletín Epidemiológico, which based its reports on the Survey of the Obligatory Declaration of Infectious Diseases and the Survey on Hospital Morbidity carried out by the Spanish National Statistical Institute.2 Text continued on p 557

550

Ch045-F06861.indd 550

1/21/2008 11:40:36 AM

Ch045-F06861.indd 551

Nematodes Intestinal Ascaris lumbricoides (roundworm)

Taenia solium (cysticercosis)

Tropical and subtropical zones, rural southeastern U.S.

Worldwide

Choi et al27 (1991)

Neafie and Connor28 (1976)

Sheep-raising and hunting areas

Salih et al12 (1998) Moore et al24 (1994) Goel et al25 (1994) Agrawal er al26 (1993)

Africa, Middle East

Schaberg et al21 (1991) Sadigursky and Andrade22 (1982) Magnussen et al23 (1995)

Schistosoma haematobium

Cestodes Echinococcus granulosus (hydatid disease)

Far East

Schaberg et al21 (1991) Sadigursky and Andrade22 (1982)

Schistosoma japonicum

Far East

Geographic Distribution

South America, Caribbean, Middle East, Africa

Singh et al19 (1986) Johnson and Johnson20 (1983)

Author (Year)

Schaberg et al21 (1991) Sadigursky and Andrade22 (1982)

Blood Flukes Schistosoma mansoni

Trematodes (Flukes) Lung Flukes Paragonimus westermani (lung-dwelling trematodes)

Parasite

Soil, fecal–oral

Swine, dogs, cats, sheep, humans

Sheep, cattle, humans, goats, camels, horses

Snails

Snails

Snails

Snails, crabs, crayfish

Intermediary (Transmission)

Humans

Humans

Dogs

Humans

Humans

Humans

Humans, other mammals

Definitive

Life-Cycle Hosts

Lung phase of larval migration: Eosinophilic pneumonitis (fever, irritating cough, burning substernal discomfort, dyspnea, blood-tinged sputum, eosinophilia, infiltrates in chest radiograph) Intestinal phase: Rarely gastrointestinal or biliary obstruction

Neurologic symptoms: Seizures, focal deficits, hydrocephalus, meningitis Skeletal muscle cysticerci: Thoracic pain if respiratory muscles involved, intraocular cyst, calcified subcutaneous nodules Lung lesions: uncommon and asymptomatic

Liver cyst: Abdominal pain, palpable mass, jaundice Pulmonary cyst: Cough, chest pain, hemoptysis, pneumothorax, empyema

Acute: Loeffler-like pneumonitis Chronic: Bladder and ureteral fibrosis; cor pulmonale

Acute: Loeffler-like pneumonitis Chronic: Periportal or Symmer’s fibrosis, portal hypertension; cor pulmonale, pulmonary hypertension; glomerulonephritis

Acute: Loeffler-like pneumonitis Chronic: Periportal or Symmer’s fibrosis, portal hypertension; cor pulmonale, pulmonary hypertension; glomerulonephritis

Acute (uncommon): Fever, cough, hepatosplenomegaly, pleural effusion, pneumothorax, eosinophilia Chronic: Cough, hemoptysis; chest radiograph: infiltrates, empyema, pleural effusion, calcification, pleural thickening, nodular, cystic, cavitary patterns

Clinical Manifestations*

TABLE 45-1 Epidemiology and Clinical Features of Helminthic Infections That May Involve Lung and Pleura

Continued

Only in heavy infections in patients with pulmonary hypersensitivity

Uncommon

25% of adults infected by E. granulosus

Acute: Common in visitors to an endemic area. Chronic: Uncommon

Acute: Common in visitors to an endemic area Chronic: 15% of patients with periportal fibrosis

Acute: Common in visitors to an endemic area Chronic: 15% of patients with periportal fibrosis

Common

Incidence of Pulmonary or Pleural Involvement

Chapter 45 Parasitic Diseases of the Lung and Pleura 551

1/21/2008 11:40:36 AM

Ch045-F06861.indd 552

Wuchereria: Coastal in tropics and subtropics Brugia: Asia, Indian subcontinent

Worldwide

Singh et al37 (1992) Quah et al38 (1997) Chitkara and Sarinas35 (1997) Marshall et al39 (1998) Ong and Doyle40 (1998) Ro et al41 (1989) Cordero et al42 (1990) Chitkara and Sarinas35 (1997)

Worldwide

Goldwater et al36 (1935)

*Pleuropulmonary involvement is indicated by boldface type. IgE, immunoglobulin E.

Dirofilaria immitis (dirofilariasis)

Filariasis Wuchereria bancrofti, Brugia malayi (tropical pulmonary eosinophilia)

Trichinella spiralis (trichinosis)

Moist tropics and subtropics, southern U.S.

Tropical and temperate zones

Stone and Schaffner31 (1990) Gompels et al32 (1991) Thompson and Berger33 (1991)

Strongyloides stercoralis (strongyloidiasis)

Necator: U.S., equatorial Africa Ancylostoma: southern Europe, northern Africa, northern Asia

Geographic Distribution

Beshear and Hendley34 (1973) Chitkara and Sarinas35 (1997)

Schad and Warren29 (1990) Hotez and Pritchard30 (1995)

Necator americanus, Ancylostoma duodenale (hookworm)

Tissue Toxocara canis and Toxocara cati (visceral larva migrans)

Author (Year)

Parasite

Mosquito

Mosquito

Swine–humans

Soil, fecal–oral

Soil–skin

Soil–skin

Intermediary (Transmission)

Dogs, cats, humans (zoonotic)

Humans

Swine, humans (zoonotic)

Dogs, cats, humans (zoonotic)

Humans

Humans

Definitive

Life-Cycle Hosts

Solitary pulmonary nodule; cough, chest pain, hemoptysis (less common)

Nocturnal cough and wheezing, low-grade fever, weight loss, adenopathy, eosinophilia, elevated IgE, leukocytosis; pulmonary fibrosis (nontreated), pleural effusion (rare)

Enteric invasion: Abdominal symptoms Larval migration: Fever, hypereosinophilia, periorbital edema, hemorrhages, myocarditis, pneumonitis, encephalitis Larval encystment: Myositis (if diaphragm involved: dyspnea)

Fever, malaise, anorexia, weight loss, cough, wheezing, rash, hepatosplenomegaly, transient pulmonary infiltrates–pneumonitis, myocarditis, encephalitis

Uncomplicated: Urticaria, abdominal symptoms, eosinophilia Complicated or disseminated in immunocompromised host: Pneumonia, meningitis, sepsis

Lung phase of larval migration: Mild transient pneumonitis Intestinal phase: Abdominal pain, diarrhea; eosinophilia, iron-deficiency anemia, hypoproteinemia, dermatitis

Clinical Manifestations*

TABLE 45-1 Epidemiology and Clinical Features of Helminthic Infections That May Involve Lung and Pleura—cont’d

30%-40% of infected patients

Common

Only in heavy and severe infections

Only in severe disease

Only in disseminated form in immunocompromised host

Only in heavy infections (less common than with Ascaris)

Incidence of Pulmonary or Pleural Involvement

552 Section 3 Lung

1/21/2008 11:40:36 AM

Ch045-F06861.indd 553

Worldwide

Subtropics and tropics

Widespread in tropics and subtropics

Wreghitt et al45 (1989) Oksenhendler et al46 (1990) Garcia et al47 (1991) Evans and Schwartzman48 (1991) Gallant and Ko49 (1996) Charoenpan et al50 (1990) Cosgriff51 (1990) Tatke and Malik52 (1990) Hashimoto et al53 (1993) Botella et al54 (1998) Matzner et al55 (1979) Jokipii et al56 (1992)

Toxoplasma gondii (toxoplasmosis)

Plasmodium spp. (malaria)

Leishmania donovani (visceral leishmaniasis, kala-azar) Sand flies (phlebotomus), percutaneous, congenital

Mosquito

Humans, other mammals (orally, transplacentally, in organ transplantation)

Fecal–oral

Intermediary (Transmission)

Humans, dogs, wild carnivores

Humans

Cats

Humans

Definitive

Hepatosplenomegaly, fever, diarrhea, cough, lymphadenopathy, cachexia, pancytopenia, hypoalbuminemia, hypergammaglobulinemia, cutaneous lesion, pneumonitis

Nonsevere: Nonspecific Severe: coma, anemia, renal failure, acute noncardiogenic pulmonary edema, ARDS, lactic acidosis, hypoglycemia, DIC

Immunocompetent patient: Lymphadenopathy Immunocompromised patient: Encephalitis, chorioretinitis, interstitial pneumonitis (dyspnea, fever, cough, hemoptysis, acidosis, respiratory failure, hypotension, DIC) Congenital: Mental sequelae, chorioretinitis, pneumonitis

Intestinal: Colitis, toxic megacolon, ameboma; liver abscess; right pleural effusion, empyema, hepatobronchial fistula, pulmonary consolidation (right lower or middle lobe), lung abscess; genital ulcers

Clinical Manifestations*

*Pleuropulmonary involvement is indicated by boldface type. AIDS, acquired immunodeficiency syndrome; ARDS, adult respiratory distress syndrome; DIC, disseminated intravascular coagulation.

Worldwide, especially tropics

Ibarra-Perez et al43 (1977) Furst et al44 (1991)

Entamoeba histolytica (amebiasis)

Geographic Distribution

Author (Year)

Parasite

Life-Cycle Hosts

TABLE 45-2 Epidemiology and Clinical Features of Protozoal Infections That May Involve Lung and Pleura

Uncommon (nontreated patients, AIDS patients)

3.5%-7% of patients with Plasmodium falciparum malaria

Common in immunocompromised patients (AIDS, malignancy, immunosuppressive therapy)

0-1%, but 20%-30% of patients with liver abscess

Incidence of Pulmonary or Pleural Involvement

Chapter 45 Parasitic Diseases of the Lung and Pleura 553

1/21/2008 11:40:36 AM

Ch045-F06861.indd 554

Microscopic examination of cyst content*

Cestodes Echinococcus granulosus (hydatid disease)

Nematodes Intestinal Ascaris lumbricoides (roundworm) Detection of eggs in fecal samples*

Identification of the cysticercus within an involved tissue (muscle, CNS)*

Identification of eggs in urine or bladder biopsy*

Schistosoma haematobium

Taenia solium (cysticercosis)

Identification of eggs in feces or liver biopsy*

Identification of eggs in feces, liver or rectal biopsies*

Identification of eggs in stool or sputum*

Main Features

Schistosoma japonicum

Blood Flukes Schistosoma mansoni

Trematodes Lung Flukes Paragonimus westermani (lungdwelling trematodes)

Parasite

—

WB

WB

EIA, WB

EIA, WB

EIA, WB

WB

Serologic Test

Diagnosis

Chest radiograph, ultrasound, ERCP

CT, MRI, chest radiograph

Chest radiograph, CT, MRI, ultrasound

Ultrasound

Ultrasound, CT

Ultrasound

Chest radiograph, CT, MRI

Other

Other causes of eosinophilic pneumonitis, Loeffler’s syndrome

—

Pulmonary carcinoma

Loeffler’s syndrome; other causes of cor pulmonale; TB

Loeffler’s syndrome; other causes of cor pulmonale; TB

Loeffler’s syndrome; other causes of cor pulmonale; TB

TB

Differential Diagnosis

TABLE 45-3 Diagnosis and Treatment of Helminthic Infections That May Involve Lung and Pleura

MBZ 100 mg bid for 3 days or PPZ 75 mg/kg (max 3.5 g) for 2 days

Asymptomatic: no treatment Neurocysticercosis: PZQ 50 mg/kg/day in 3 doses for 15 days or ABZ 15 mg/kg/day in 3 doses for 8-30 days plus glucocorticoids

Surgical excision plus ABZ 400 mg bid for 20 days, repeated as necessary

PZQ 40 mg/kg in 2 doses for 1 day

PZQ 60 mg/kg in 3 doses for 1 day

PZQ 40 mg/kg in 2 doses for 1 day

PZQ 75 mg/kg/day in 3 doses for 2 days

Choice

ABZ, PP

Surgery (ocular, ventricular, or spinal involvement)

ABZ 400 mg bid for 28 days, repeated 1 to 8 times

MTF

—

OXM

BTH

Alternative

Treatment

554 Section 3 Lung

1/21/2008 11:40:36 AM

Ch045-F06861.indd 555

—

—

BF*

EIA*

EIA

—

Chest radiograph

Chest radiograph (reticulonodular pattern); pulmonary function test (restrictive pattern)

Surgical muscle biopsy,* chest radiograph (infiltrates, calcified cysts within respiratory muscles)

Chest radiograph

Chest radiograph

Chest radiograph

Pulmonary carcinoma

Asthma, Loeffler’s syndrome, allergic bronchopulmonary aspergillosis, Churg-Strauss vasculitis, Wegener’s vasculitis, chronic eosinophilic pneumonia

Other eosinophilic pneumonitis

Other eosinophilic pneumonitis

Other causes of pneumonia in immunocompromised host

Other causes of eosinophilic pneumonitis, Loeffler’s syndrome

Excisional lung biopsy

DEC 6 mg/kg/day in 3 doses for 21 days

Glucocorticoids (in severe myositis or myocarditis); MBZ or TBZ (enteric stages)

Glucocorticoids (in severe myocardial, CNS, or pulmonary involvement)

TBZ 25 mg/kg bid for 2 days; for disseminated disease continue for 7 days or longer

MBZ 100 mg bid for 3 days

—

—

—

—

IVR, ABZ

PP, ABZ

*Definitive diagnostic test. ABZ, albendazole; BF, bentonite flocculation; BTH, bithionol; CNS, central nervous system; CPK, creatine phosphokinase; CT, computed tomography; DEC, diethylcarbamazine; EIA, enzyme immunoassay; ERCP, endoscopic retrograde cholangiopancreatogram; IgE, immunoglobulin E; IVR, ivermectin; LDH, lactate dehydrogenase; MBZ, mebendazole; MRI, magnetic resonance imaging; MTF, metrifonate; OXM, oxamniquine; PP, pyrantel pamoate; PPZ, piperazine; PZQ, praziquantel; TB, tuberculosis; TBZ, thiabendazole; WB, Western blot.

Excisional lung biopsy*

Nocturnal wheezing, high levels of antifilarial antibodies, rapid response to treatment

Filariasis Wuchereria bancrofti, Brugia malayi (tropical pulmonary eosinophilia)

Dirofilaria immitis (dirofilariasis)

Eosinophilia, elevated IgE, CPK, LDH

Trichinella spiralis (trichinosis)

Eosinophilia, leukocytosis, hypergammaglobulinemia

Detection of larvae in stool, duodenal aspirate, or sputum*

Strongyloides stercoralis (strongyloidiasis)

Tissue Toxocara canis and Toxocara cati (visceral larva migrans)

Identification of eggs in fresh stool or larvae in old stool*

Necator americanus, Ancylostoma duodenale (hookworm)

Chapter 45 Parasitic Diseases of the Lung and Pleura 555

1/21/2008 11:40:36 AM

Ch045-F06861.indd 556

Demonstration of trophozoites or cysts in stool, liver aspirate, or pleural exudate*

Isolation of the parasite after subinoculation of body fluids into mice or in tissue biopsy* Demonstration of asexual form in peripheral blood smears stained with Giemsa*

Demonstration of amastigotes in aspirates or biopsy (bone marrow, spleen, liver, lymph node)*

Entamoeba histolytica (amebiasis)

Toxoplasma gondii (toxoplasmosis)

Plasmodium spp. (malaria)

Leishmania donovani (visceral leishmaniasis, kala-azar)

EIA

Little use

Sabin-Feldman EIA, IIF

ID, IHA

Serologic Test

Chest radiograph

PCR, chest radiograph

Cerebral CT, MRI; chest radiograph

Intestinal biopsy; liver CT; ultrasound, MRI; chest radiograph

Other

Malaria, brucellosis, TB, typhoid, leukemia, lymphoma

Other causes of ARDS

PCP

Other causes of basal pleuropulmonary disease

Differential Diagnosis

Stibogluconate sodium 20 mg/kg/day IV or IM for 28 days

Severe malaria, chloroquine-resistant: Quinidine gluconate 10 mg of base/kg IV over 1 hr followed by 0.02 mg/kg/min for maximum of 3 days. Severe malaria, chloroquine-sensitive: Chloroquine 10 mg of base/kg IV over 8 hr followed by 15 mg of base/kg over 24 hr

Pyrimethamine 75 mg/day plus sulfadiazine 4-6 g/day plus calcium folinate 10-15 mg/day for 4-6 wk

Asymptomatic: Diloxanide furoate 500 mg tid for 10 days. Colitis, liver abscess: Metronidazole 750 mg tid for 5-10 days plus iodoquinol 650 mg tid for 20 days

Choice

Treatment

Meglumine antimonate, amphotericin B, pentamidine

Exchange transfusion (high parasitemia and altered mental status); treatment of complications

Clindamycin plus pyrimethamine plus calcium folinate; spiramycin

Aspiration of liver abscess, drainage of pleural effusion (if massive)

Alternative

*Definitive diagnostic test. ARDS, adult respiratory distress syndrome; CT, computed tomography; EIA, enzyme immunoassay; ID, immunodiffusion; IHA, indirect hemagglutination; IIF, indirect immunofluorescence; IV, intravenous; IM, intramuscular; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PCP, Pneumocystis jiroveci (Pneumocystis carinii) pneumonia; TB, tuberculosis.

Main Features

Parasite

Diagnosis

TABLE 45-4 Diagnosis and Treatment of Protozoal Infections That May Involve Lung and Pleura

556 Section 3 Lung

1/21/2008 11:40:37 AM

Chapter 45 Parasitic Diseases of the Lung and Pleura

Life Cycle In its adult stage, the parasite lives in the intestinal tract of carnivores. The head is composed of a double crown of hooklike structures, and the body is formed by three or four rings, the last of which bears the eggs (Fig. 45-1). After being eliminated with the feces, the eggs contaminate fields, irrigated land, and wells. Herbivores ingest the eggs, which develop into larvae, or hydatids, within the viscera of these animals. The cycle is completed with the ingestion of the infected viscera by carnivores. Humans contract the disease from water or food or by direct contact with dogs. Once the eggs reach the stomach, the hexacanth embryos are released. They pass through the intestinal wall and reach the tributary veins of the liver, where they undergo a vesicular transformation and develop into the hydatid. If they overcome the hepatic obstacle, they may become lodged in the lung, where they are also transformed into hydatids. If they advance beyond the lung, they may remain in any organ to which they are carried by the bloodstream. It has been shown that the embryos can reach the lung via the lymphatic vessels, bypassing the liver, and there is also evidence that the disease can be contracted through the bronchi (Jerray et al, 1992).3 Within the thorax, the lung is the organ most commonly colonized, especially the lower lobes, as was observed in our own series.4 If the hexacanth embryo manages to get past the pulmonary filter, it reaches the left side of the heart and, by way of the aorta, the remainder of the organism. According to Devé in 1934, the prevalence of the various locations in which hydatid cysts can develop in humans is as follows5: liver, 55.6%; lung, 26%; muscles and connective tissue, 6.8%; spleen, 2.1%; kidney, 2.1%; brain, 1.4%; heart, 1.2%; and other organs, such as thyroid glands, bones, breast, pancreas, ovaries, and eyes, 4.2%.

FIGURE 45-1 Microscopic preparation of the scolex of a hydatid cyst showing the ring of hooks.

Ch045-F06861.indd 557

557

Complications The natural course of a hydatid cyst is progressive growth over a long period, although at times it may appear to remain static. The growth is usually slow and depends to a large degree on the resistance of the structure of the organ in which it develops. Growth is more rapid in organs such as the lung and peritoneum and slower in others of greater consistency, such as the heart and liver. Throughout its development, the pulmonary hydatid cyst can compress bronchial structures and produce pulmonary atelectasis accompanied by pneumonia. Various circumstances, such as calcification, infection, or rupture, can affect its course. Spontaneous cure of a pulmonary cyst is rare and should not be considered from the therapeutic point of view. Calcification is caused by the deposition of calcium salts in necrotic foci in the adventitial layer. The necrosis may result from several circumstances, such as ischemia due to compression, inflammatory or toxic processes, or immune responses. The calcifications are initially microscopic but become macroscopic over the course of time, partially or totally affecting the adventitial layer and appearing in diagnostic imaging studies. This eventuality, which is common in slow-growing cysts located in the liver, spleen, or heart, is rare in pulmonary cysts, perhaps because of their more rapid growth. Calcification is not synonymous with the death of the parasite, although these two circumstances can be associated, in that adventitial calcification leads to malnutrition of the metacestode, which first becomes dehydrated and later establishes hyaline degeneration on the germinal membrane and daughter vesicles. Infection of the cyst usually produces its suppuration. Its expansion can result in the compression of blood vessels and bronchi, leading to wall necrosis. This makes it possible for pathogens to reach the perivascular lymphatic space, producing infection. Another possible cause is septic puncture, which is an extremely rare event owing to the fact that diagnostic puncture is contraindicated when pulmonary hydatidosis is suspected. Cyst suppuration leads to the death of the metacestode, although some daughter vesicles may survive. The clinical signs include chills, fever, tachycardia, local pain, and leukocytosis. Suppuration may facilitate the rupture of the cyst, which complicates the situation even more. When rupture occurs, the contents of the cyst may escape into an open space such as the pleural cavity or drain via the bronchi. Rupture of a pulmonary cyst is one of the most severe complications, and it can occur under many circumstances, such as accident, progressive growth of the cyst, infection, and surgery. Dissemination of the fluid produces general symptoms that vary widely from one patient to another; in one they may go undetected, whereas in another, they can result in death due to anaphylactic shock. If the cyst is infected at the time of rupture, the general symptoms are accompanied by those of infection. The intensity of the general symptoms depends on the characteristics of the tissue exposed to the hydatid cyst fluid because they determine the amount of fluid and the speed with which it is absorbed. In pulmonary hydatid cysts, the general reaction is severe when the fluid comes into contact

1/21/2008 11:40:37 AM

558

Section 3 Lung

with the pleural serosa or reaches the bloodstream. It is less intense if the fluid is eliminated via the airways. Another problem resulting from the rupture of a pulmonary cyst, especially over the long term, is the possible development of secondary hydatidosis. This occurs primarily in cases in which the rupture is not due to infection because, if infection is present, suppuration eliminates the fertile elements that could contaminate another organ. Secondary echinococcosis is caused by protoscolices, which undergo vesiculation to become hydatid, or daughter, vesicles, which can detach from the mother cyst and nest in a new location, growing as autonomous cysts. If a cyst opens toward the pleura, secondary pleural hydatidosis can develop. In contrast, if a ruptured cyst releases its fluid toward the airway, the patient eliminates it in the form of vomica, which can be accompanied by hydatid membranes. The elimination of the cyst in this way may lead to cure, to secondary infection of the residual cavity, or to seeding, which results in the development of multiple pulmonary cysts, all of the same size. If a cyst ruptures toward a blood vessel or the heart, the protoscolices may be carried by the blood simultaneously to a number of sites, forming what is referred to as metastatic hydatidosis. The rupture of a cyst sometimes occurs gradually, through a fissure, with release of only small amounts of hydatid fluid. In sensitized patients, this can produce urticaria or pruritus. However, some authors consider that the fissure of a cyst may immunize the patient, impeding secondary hydatidosis should the cyst suddenly rupture.

Laboratory Tests The laboratory tests that are used for the biologic diagnosis of hydatid disease are based primarily on the detection of immune or cellular responses to the presence of the parasite in the host (immunodiagnosis).

Peripheral Blood Eosinophilia Peripheral blood eosinophilia is neither a specific nor a constant factor because not all patients with hydatidosis present with eosinophilia and, on the other hand, eosinophilia can exist in patients with other parasites or allergic processes. Relative eosinophilia is considered evaluable when eosinophils represent more than 5% on a differential leukocyte count. Absolute eosinophilia is more constant and is evaluable when there are more than 200 to 300 eosinophils per cubic millimeter. We have observed a statistically significant correlation between peripheral blood eosinophilia and ruptured pulmonary hydatid cyst, a finding that we have confirmed intraoperatively. However, there is no such correlation when the hydatid cyst is intact.4

Weinberg Reaction The Weinberg reaction test is also referred to as complement deposition or complement fixation. It is based on the existence, in the plasma of hydatid cyst carriers, of circulating reagins. When a patient’s serum is mixed with fluid from a sheep hydatid cyst, which serves as an antigen, the antibody and patient serum complement bond with the hydatid

Ch045-F06861.indd 558

antigen. If rabbit red blood cells and guinea pig serum sensitized against the rabbit red cells are added to this mixture, hemolysis does not occur because the complement necessary for this process is fixed to the antigen and to the antihydatid antibodies. The Weinberg reaction is positive in 70% to 80% of cases, and false-positive reactions are rare. A negative result does not rule out the diagnosis of hydatidosis. Although it is not employed much anymore, this test can be useful in the follow-up of patients under treatment because the test results become negative within 1 year of freedom from the disease.

Casoni Intradermal Test The Casoni intradermal test consists of intradermal injection of 0.1 to 0.3 mL of hydatid fluid from sheep cysts, filtered and undiluted, into the anterior aspect of the patient’s forearm. The fixation of circulating reagins produces a local papular rash measuring 1 to 2 cm in diameter. This reaction may appear 5 or 10 minutes after injection (the early reaction) and persist for more than 24 hours, and it may reappear after the early reaction disappears (the late reaction). Occasionally, in addition to this local reaction, focal phenomena (e.g., pain in upper quadrant, hemoptysis) or even generalized signs can occur, enhancing the diagnostic value of the test. The Casoni reaction is positive in 80% to 95% of cases, but its negativity does not rule out the presence of hydatid disease. On the other hand, false-positive reactions can occur in patients with other parasitic and nonparasitic diseases. This test may remain positive for a long time, even years after the cyst has been treated surgically.

Prausnitz-Kustner Reaction or Passive Anaphylaxis The Kustner-Kustner reaction consists of the detection of circulating reagins by their transmission to a person who is free of hydatidosis. Serum from the patient (the presumed carrier of hydatidosis) is injected into the forearm of a healthy individual. Hydatid antigen is then injected into the same site. The development of a papular rash, similar to that of the Casoni test, indicates a positive reaction.

Serologic Diagnosis Serologic diagnosis is usually more reliable than that based on the aforementioned tests. Moreover, it is useful in the follow-up of surgically or medically treated patients. In any case, on the one hand, negative serologic results do not invalidate the diagnosis of hydatidosis because some patients do not have detectable antibodies. On the other hand, the immune response depends on a wide range of factors: 1. Patient’s age because serologic tests are less effective in children younger than 15 years of age than in adults 2. Location of the hydatid cysts because the reactions are more intense in cases of hepatic and peritoneal cysts than with pulmonary and cerebral cysts 3. Vitality of the metacestode because when the parasite dies, the serologic results become negative

1/21/2008 11:40:37 AM

Chapter 45 Parasitic Diseases of the Lung and Pleura

4. Integrity of the cystic sac because when it tears or bursts as a consequence of the massive release of the antigen, there is a spectacular increase in the number of antibodies in a matter of days 5. Surgical excision of the cyst or pharmacologic treatment, which also modifies serologic reactions The tests most widely employed are described in the following paragraphs. Indirect or Passive Hemagglutination. This approach consists of the agglutination of sheep red blood cells coated with hydatid antigen when mixed with serum of patients with antibodies. The test is positive in 70% of patients with pulmonary hydatidosis and in 95% of patients with liver hydatidosis. Latex Agglutination. Similar to the preceding test, this test consists of the flocculation of latex particles coated with hydatid antigen in the presence of specific antibodies in the patient’s serum. Although other, similar tests using ebonite and a colloidal dye as particles have also been carried out, latex agglutination is the one most widely applied. The results are positive in 70% of patients with pulmonary hydatidosis and in 90% of those with liver hydatidosis. Immunoelectrophoresis. This test determines the serum concentration of each immunoglobulin; patients with hydatid disease have been shown to have immunoglobulin G (IgG), IgM, IgA, and IgE antibodies against T. echinococcus antigens. Within 6 months after surgical extirpation of pulmonary hydatid cysts, plasma IgM levels return to normal, whereas IgG remains abnormally high for a longer period. These patients often exhibit hypergammaglobulinemia, and if the cyst is infected, the levels of α1 and α2 globulins are elevated. Double–Diffusion Immunoelectrophoresis. Special importance is given to arc 5, which is considered specific for antibodies to antigen 5, one of the 10 or more antigens found in E. granulosus. It is present in the fluid and structures of the cyst. The presence of antibodies to this antigen in a patient’s serum is of great diagnostic value in hydatid disease, although antibodies are also detected in some cases of human cysticercosis and of hydatidosis caused by E. multilocularis or E. vogeli. The double-diffusion technique, which detects antibodies to antigen 5, is as specific as, and more sensitive than, immunoelectrophoresis. Total Immunoglobulin E or Specific Immunoglobulin E. These immunoglobulins, which are usually abnormally high in patients with hydatid disease, are detected by radioimmunoassay. Specific IgE concentrations decrease after pharmacologic or surgical treatment but generally do not return to normal levels. Indirect Immunofluorescence. This method is based on fixation of the antibodies in patient serum to protoscolices obtained from hydatid cysts using a fluorescein-labeled human antiglobulin. It is a highly sensitive test but can produce falsepositive results in some cases of cysticercosis. Enzyme–Linked Immunosorbent Assay or Western Blot. This approach consists of detection of an antigenantibody complex using an enzyme-bound rabbit antihuman IgG which, acting on a specific substrate, produces a color

Ch045-F06861.indd 559

559

change that can be measured and is proportional to the amount of antibody present. The complex antigen comes from the cystic fluid of a sheep, pig, or rabbit, smeared on a polystyrene surface; the antibody is provided by the patient’s serum. This serologic test has a sensitivity of 80% to 100% and a specificity of 88% to 90% in the case of hepatic hydatid cysts, but it is less sensitive in detecting hydatid cysts in the lung (50%-56%) and other organs (25%-26%). New techniques involving the use of recombinant antigens to Echinococcus species may prove more specific. Imaging studies such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are more sensitive than serodiagnostic techniques. If these tests suggest hydatidosis, the diagnosis can be confirmed by means of serodiagnosis.

Diagnosis We assessed some of the diagnostic tests for hydatid disease, such as the eosinophil count, the Casoni test, the Weinberg test, and the erythrocyte sedimentation rate, to determine whether any of them showed a statistically significant correlation with the presence of the disease. No correlation was found when the cyst remained intact during the preoperative evaluation or the surgical procedure. However, when rupture of the cyst occurred, an eosinophil level greater than 3%, episodes of vomiting, expectoration of so-called spring water and small particles of hydatid cyst membrane with the appearance of grape skin, and the existence of three or more clinical symptoms showed statistically significant correlations according to Student’s t test (P < .05). In clinical practice, plain radiographs of the chest have been shown to be most reliable in the diagnosis of pulmonary hydatid disease.6 Numerous images have been described: those typical of the intact cyst (Fig. 45-2); round or oval shapes, solitary or multiple (Fig. 45-3); homogeneous density and perfectly defined margins as though drawn with a marking pen; ruptured or complicated cysts with membranes floating in fluid resembling a water-lily sign (Fig. 45-4); an incarcerated membrane folded back in the form of a barricade which appears as a fluid-filled abscess (Fig. 45-5), with or without air-fluid levels; images of pneumonitis of the lung; and areas of lung atelectasis. In these cases, the differential diagnosis with certain lesions such as bronchial tumors, sarcomas, and tuberculomas is a difficult challenge. In our series,4 plain radiographs of the chest and clinical assessment of the symptoms made it possible to establish the correct diagnosis preoperatively in 228 cases (95%). In six cases (2.5%), imaging studies such as ultrasonography, CT (Fig. 45-6), and MRI (Fig. 45-7) were required, and in the remaining six cases (2.5%), the diagnosis was established intraoperatively or in the subsequent histopathologic study. The preoperative diagnosis of hydatid disease of the lung was incorrect in six cases; the correct diagnoses were lung abscess (n = 3), tumor (n = 2), and bronchogenic cyst (n = 1). Bronchoscopy was used in the diagnosis of pulmonary hydatidosis with considerable success before ultrasound and other imaging techniques such as CT and MRI became available; its use has been limited by the risk of rupture of the

1/21/2008 11:40:37 AM

560

Section 3 Lung

FIGURE 45-2 Plain chest radiograph showing a hydatid cyst located in the lower left lobe of the lung.

FIGURE 45-3 Plain chest radiograph showing multiple hydatid cysts located in the lower lobes of the lung.

FIGURE 45-4 Water-lily sign. Radiographic image of a complicated hydatid cyst.

FIGURE 45-5 Radiographic image of an incarcerated hydatid membrane.

cyst and the subsequent development of severe complications. It still may be useful in cases of ruptured hydatid cyst of the lung because it enables visualization of the hydatid membrane, which resembles the shininess of cooked egg white, and small fragments of the cystic membrane can be removed during bronchoscopic examination using the technique of Coll and Collomé.7 Bronchography, the approach

employed years ago, has followed in the steps of bronchoscopy, being replaced entirely by imaging techniques such as CT and MRI (Elburjo and Gani, 1995).8,9

Ch045-F06861.indd 560

Surgical Treatment The incision most commonly used in cases of solitary pulmonary cysts is a lateral thoracotomy. In earlier cases, when

1/21/2008 11:40:38 AM

Chapter 45 Parasitic Diseases of the Lung and Pleura

FIGURE 45-6 Chest CT scan showing a hydatid cyst located in the lower left lobe of the lung containing fragments of the hydatid membrane.

bilateral cysts were present, the operation was done in two stages, with the first thoracotomy being performed on the side on which the risk of rupture appeared to be greater or on which the cyst was more complicated.10 These cases are now treated in a single procedure, using a median sternotomy for cysts located in the anterior position and a transsternal bilateral thoracotomy for cysts in the anterior or posterior position or associated with hydatid disease of the heart. In some cases, we have performed an anterior bilateral thoracotomy in a single procedure. The objective of surgical treatment of pulmonary hydatidosis is to eradicate the parasite, to prevent the intraoperative rupture of the cyst with its subsequent dissemination, and to remove the residual cavity. Most authors agree that the attempt should be made to remove as little lung tissue as possible and that resection of pulmonary parenchyma is indicated only if the adjacent tissue is seriously damaged or infected or if the atelectatic areas are presumed to be irrecoverable. Initially, surgical treatment of pulmonary hydatidosis involved marsupialization of the cyst after it was attached to the pleura, which was done in two stages: first, pleurodesis was produced, followed by marsupialization in a second procedure. These techniques have since been abandoned. Simple cystectomy with capitonnage (suture approximation of the pericystic tissue, the method of Posadas) (Fig. 45-8) or with cystopericystectomy has also been carried out. If the cyst is small and there is no risk of rupture, its complete removal can be attempted by incising the pleura and delivering the complete cyst, aided by an increase in airway pressure provided by the anesthetist (the Ugón technique). In 276 cases (92%) treated surgically, after thoracotomy, we performed needle aspiration of the cyst using a trocarsuction device (Fig. 45-9) designed by Figuera.11 The device is composed of a trocar containing a needle connected to a negative-pressure aspiration system and surrounded by a suction cup that fits over the convex part of the cyst wall. When the device is applied to the cyst, the negative pressure makes the suction cup adhere hermetically to the cyst wall,

Ch045-F06861.indd 561

561

FIGURE 45-7 Chest MRI showing a hydatid cyst located in the upper left lobe of the lung, containing fragments of the hydatid membrane.

FIGURE 45-8 Cystectomy (method of Posadas).

thus impeding extravasation of the contents as the cyst is sucked out and eliminating the possibility of intraoperative contamination (Fig. 45-10). This surgical technique has been shown to be effective in preventing rupture and dissemination of the cyst, and it facilitates excision of the residual cavity. With this approach, we have observed no recurrences of pulmonary hydatidosis in those cases in which the cysts remained intact at the time of the operation. In patients with hydatid cysts at nonpulmonary sites, we treat the other cyst in a second surgical procedure. The decision as to which cyst to remove first is based on the susceptibility of each to rupture, on their size, on the risk of dissemination, and on the vital importance of the organ in which each is located.12 Cysts in the lower right lung lobe may be connected to hepatic cysts that have passed through the diaphragm and resemble an hourglass.13-15 Controversy exists as to the best surgical approach to these lesions. We choose thoracotomy or laparotomy, depending on the size of the cyst and the existence of signs of complications. If the cyst appears to affect the lung predominantly, thoracotomy is performed; if the liver is at risk, laparotomy is attempted, although, on

1/21/2008 11:40:39 AM

562

Section 3 Lung

FIGURE 45-9 A, Illustration of the trocar-suction device designed by Figuera. This device consists of a chamber (C) that acts like a suction cup (SC) as it generates negative pressure by means of a source of external aspiration (EA), which is transmitted to the chamber via an auxiliary tube (AT). The distal portion of the chamber is open to allow the suction cup to be applied to the convex surface of the hydatid cyst. A trocar (T) with a guidewire (GW) runs through it. The chamber also has a lateral exit (LE) connected by the auxiliary rubber tube. A switch (S) makes it possible to interrupt the emptying of the chamber at any time. The guidewire is cut irregularly, and its thicker distal end fits exactly into the trocar lumen. Its length is calculated so that when it is totally withdrawn, it remains in segment A-B, allowing external aspiration via the trocar and the lateral exit. The proximal end of the chamber has a rubber ring (RR) that is situated between two metallic rings, all of which have a hole in the center. They allow the trocar to glide smoothly through them but prevent air from entering the chamber. B, Photograph of the device showing the trocar (T) disconnected from the chamber (C), which remains connected to the source of external aspiration (EA) by means of an auxiliary tube (AT). C, Photograph of the trocar-suction device assembled for use.

occasion, the approach must be extended to include thoracotomy because of the need to perform a right lower lobectomy. If thoracotomy alone has been used, it is sometimes necessary to extend the incision to include a laparotomy so as to allow for placement of a T tube when a hepatic cyst involves the bile ducts. An atypical resection is usually performed when rupture or peripheral infection is detected. However, pulmonary lobectomy is commonly required if the cyst is associated with abscesses or severe pulmonary changes or with atelectasis that remains unresolved by standard surgical procedures, or if there is evidence that a given lobe contains infected hydatid membranes or several cysts. All authors agree on the need to

Ch045-F06861.indd 562

preserve as much of the lung tissue as possible and to perform resection only if the lung is found to be destroyed (Burgos et al, 1991; Salih et al, 1998).16,17 Whenever possible, we opt for complete resection of the pericystic tissue and total eversion of the cavity, performing capitonnage in only 13.7% of patients because that approach has been found to result in the persistence of residual cavities. The surgical area is always protected with hypertonic saline solution or formaldehyde-soaked sponges so as to avoid anaphylaxis and seedings if spillage should occur. Since the first pilot studies with mebendazole in 1974, we have employed this drug as perioperative therapy according to the protocol proposed by Bekhti and his team18 in 1977:

1/21/2008 11:40:39 AM

Chapter 45 Parasitic Diseases of the Lung and Pleura

FIGURE 45-10 Surgical technique using the trocar-suction device shown in Figure 45-9.

400 to 600 mg is given every 8 hours, as follows. Administration commences 7 to 10 days before surgery. If the cyst is intact and there appears to be no risk of its rupture during the surgical procedure, the treatment is administered for 1 month. If the cyst has ruptured or the possibility of its intraoperative dissemination is suspected, treatment is continued for 3 to 6 months. If dissemination is confirmed and total or partial resection of the lesions is not feasible, it is necessary to excise as many of the cysts as possible, attempting to conserve a maximum of lung parenchyma, and to administer mebendazole until there is no radiologic evidence of the lesions. Albendazole has been substituted for mebendazole, using the same regimen.

INFECTIONS THAT SOMETIMES REQUIRE SURGERY Protozoal Infections Amebiasis Amebiasis is a parasitic infection produced by Entamoeba histolytica. Amebic dysentery is of worldwide distribution. It is estimated that about 500 million people are infected, and that 10% of this population will eventually develop the disease. Whereas amebic dysentery shows no age or sex predominance, pleuropulmonary involvement develops most commonly between the ages of 20 and 40 years and is 10 to 15 times more common in men than in women.

Ch045-F06861.indd 563

563

Pleuropulmonary complications in amebic dysentery have been estimated to occur in 0.1% of patients, but if a liver abscess is present, the incidence may be as high as 20% to 30%. Amebiasis is acquired by ingesting the cysts in fecally contaminated food or water. In the small bowel, each cyst produces four trophozoites that invade the intestinal epithelium and enter the venous circulation. Although any organ may be affected, the liver is the most common site of secondary amebic abscesses. Pulmonary amebiasis can occur in two ways. The most common way is by direct spread of an amebic liver abscess through the liver capsule, peritoneum, diaphragm, and pleura. In fact, pleuropulmonary contamination is the most common complication of amebic hepatic abscesses. Less commonly, pulmonary involvement can occur by means of hematogenous spread. The right lower lobe of the lung is most commonly involved because of its contiguity with a liver abscess. The majority of amebic hepatic abscesses develop over the superior and posterior surfaces of the right lobe, and as the abscess enlarges, it includes the diaphragm in its wall. If the abscess develops slowly, it may produce a pleural reaction that generates adhesions at the base of the right lung, right pleural effusion, pulmonary consolidation, and sometimes a hepatobronchial fistula. If, on the other hand, the abscess enlarges rapidly, it may rupture in the pleural cavity, with consequent empyema and lung abscess. Less commonly, amebic hepatic abscesses extend into the pericardium and cause amebic pericarditis. The most common presenting symptom of pleuropulmonary amebiasis is right-sided chest pain with radiation to the shoulder. A dry cough characterizes the early stages of pleuropulmonary disease, but later the cough may become productive of so-called chocolate sauce material, indicating hepatobronchial communication. Expectoration of bile (biloptysis) may occur as a result of a bronchohepatic or bronchobiliary fistula. Fever is more pronounced with pleural involvement, and there often is general malaise, weakness, anorexia, and weight loss. Diagnostic tests and treatment of this parasitic disease are summarized in Table 45-4. Adequate drug therapy is essential for the management of hepatic and pleuropulmonary amebiasis, but there are some situations in which invasive procedures are required. Massive pleural or pericardial effusions and empyemas must be drained. Postural drainage is useful in cases of hepatobronchial fistula. The prognosis of pulmonary amebiasis is poorer than that of uncomplicated liver abscess and becomes even worse if the pleura is involved. Empyema kills one in five patients, and the overall mortality rate associated with thoracic amebiasis ranges from 11% to 14%.

Helminthic Infections Dirofilariasis Dirofilaria immitis, the dog heartworm, produces pulmonary dirofilariasis in humans. The typical clinical manifestation of this disease is a solitary pulmonary nodule. Radiographs of the chest show a solitary, well-circumscribed spherical or wedge-shaped nodule, 2 to 3 cm in diameter. It is usually

1/21/2008 11:40:40 AM

564

Section 3 Lung

located at the periphery of the lung, attached to the pleura. Most patients are asymptomatic, and only 30% have cough, chest pain, and hemoptysis. Eosinophilia is uncommon. Excisional lung biopsy with identification of the worm is required for diagnosis and is, at the same time, the treatment of choice. Most of the time, the diagnosis is made after pulmonary resection has been carried out because of suspected pulmonary carcinoma.

INFECTIONS THAT DO NOT REQUIRE SURGICAL INTERVENTION Protozoal Infections Toxoplasmosis Toxoplasmosis is caused by Toxoplasma gondii, an obligate intracellular coccidian protozoan. This parasitic disease is of worldwide distribution and is a common human infestation. Most infected immunocompetent individuals are asymptomatic. Disseminated disease is common in immunocompromised patients (those with AIDS or malignancy and those receiving immunosuppressive therapy). This disseminated form commonly involves the lung, producing interstitial pneumonitis with dyspnea, fever, cough, hemoptysis, acidosis, and even respiratory failure, hypotension, and disseminated intravascular coagulation. Pulmonary involvement is rare in the transplacentally transmitted congenital form of this disease, but it may occur in the form of pneumonitis.

Malaria Malaria caused by Plasmodium falciparum can be associated in 3.5% to 7% of cases with acute noncardiogenic pulmonary edema and adult respiratory distress syndrome. The prognosis for patients with pulmonary involvement is very poor, and more than 80% die within 1 day after developing pulmonary edema, despite intensive therapy. Less commonly, patients develop milder forms of pulmonary involvement, including interstitial edema, pleural effusion, and lobar consolidation.

Visceral Leishmaniasis (Kala-azar) Leishmania donovani, the cause of visceral leishmaniasis, can be found as an amastigote in pulmonary macrophages. Pulmonary disease that causes symptoms is rare, but a few cases of pneumonitis have been reported, especially in untreated patients and in patients with AIDS.

Helminthic Infections Trematodes (Flukes) Paragonimiasis. Paragonimiasis is an infection caused by a lung fluke, most commonly Paragonimus westermani, the Asian lung fluke. Acute disease is rare and is characterized clinically by fever, cough, hepatosplenomegaly, pleural effusion, pneumothorax, and eosinophilia. The chronic form is more common; patients classically present a diagnostic triad of cough, hemoptysis, and eggs of Paragonimus species in sputa or feces. Radiographs may show transient, diffuse pulmonary infiltrates, pleural effusion, empyema, calcified lesions, pleural thickening, and nodular, cystic, or cavitary

Ch045-F06861.indd 564

patterns. Pulmonary involvement tends to mimic postprimary tuberculosis. Schistosomiasis. Schistosomiasis is caused by blood flukes of the genus Schistosoma, three of which (S. mansoni, S. japonicum, and S. haematobium) are traditionally regarded as the most important in human infestation. The acute form of the disease is associated with an eosinophilic, Loefflerlike pneumonitis. Chronic schistosomiasis leads to the development of periportal or Symmer’s fibrosis with portal hypertension. Schistosomal cor pulmonale with pulmonary hypertension occurs in 15% of patients with periportal fibrosis and is most commonly reported in S. mansoni infections from Egypt and Brazil. Patients present with hemoptysis and right ventricular hypertrophy, and the prognosis is poor.

Cestodes Cysticercosis. Cysticercosis is a parasitic infection caused by the larval stage of Taenia solium, a human tapeworm. Humans acquire the disease by ingesting infected undercooked pork. Cysticerci can lodge anywhere in the body, but the usual sites are subcutaneous or intramuscular. Thoracic involvement results from deposition of cysticerci in the respiratory muscles, where their presence may occasion pain. Lung and pleural lesions are uncommon and are usually asymptomatic.

Nematodes That Attack the Intestines Ascariasis (Roundworm). Ascariasis is one of the most common helminthic infections of humans. In most cases, it is caused by Ascaris lumbricoides. Most patients infected by this nematode have no pulmonary symptoms. Only allergic patients with heavy infection are at risk of developing an eosinophilic pneumonitis, an asthma-like reaction, during the lung phase of larval migration. The symptoms usually resolve spontaneously in 2 to 3 weeks, when the larvae migrate out of the lungs. Ancylostomiasis (Hookworm). Ancylostomiasis is caused by the nematodes Ancylostoma duodenale and Necator americanus. During the lung phase of larval migration, patients may develop mild, transient eosinophilic pneumonitis. Pulmonary disease appears less commonly than with infection by species of Ascaris or Strongyloides, but severe infestation may give rise to transient cough, hemoptysis, and pulmonary consolidation. Strongyloidiasis. Strongyloides stercoralis, the threadworm, produces strongyloidiasis in humans. Pulmonary disease is caused by the migration of larvae through alveolar capillaries into air spaces. In most cases, pulmonary symptoms are mild or absent. It is only in disseminated strongyloidiasis in an immunocompromised host that the infection can lead to life-threatening pneumonia, with dyspnea, hemoptysis, and bronchospasm. Fatal adult respiratory distress syndrome is uncommon but can occur despite treatment.

Nematodes That Attack Tissue Visceral Larva Migrans. Visceral larva migrans results from infestation by larvae of dog and cat roundworms, Toxocara canis and Toxocara cati. The disease occurs pre-

1/21/2008 11:40:41 AM

Chapter 45 Parasitic Diseases of the Lung and Pleura

dominantly in children who swallow soil containing eggs passed in the feces of dogs and cats. The larvae travel throughout the body and can lodge in any organ, particularly the liver, brain, eyes, lungs, cardiac muscle, and lymph nodes. Most children are asymptomatic, and only those with severe disease and a significant number of larvae may develop transient pulmonary infiltrates and Loeffler’s syndrome. Severe lung disease is rare. Trichinosis. Trichinosis is caused by the ingestion of larvae of the roundworm Trichinella spiralis. Pulmonary manifestations in humans are rare. It is only in heavy and severe infections that patients may develop pneumonitis during the larval migration phase. The phase of larval encystment is characterized by myositis. Any muscle of the body may be parasitized, including the diaphragm and intercostal muscles. If these respiratory muscles are affected, patients may complain of dyspnea and tachypnea. Calcified walls of larval cysts within the respiratory muscles may be visible on radiographs of the chest.

Nematodes of the Filarioidea Superfamily Tropical Pulmonary Eosinophilia. Tropical pulmonary eosinophilia is a distinct syndrome that develops in some individuals who are infected by lymphatic filarial species. The organisms most strongly implicated as the causative agents of this parasitic disease are the mosquito-transmitted Wuchereria bancrofti and Brugia malayi. Patients present with an asthmalike syndrome, malaise, episodes of nocturnal cough and wheezing, low-grade fever, weight loss, and adenopathy. Leukocytosis is usually severe, and extreme eosinophilia and high IgE levels persist for weeks. In addition to a geographic history of filarial exposure, a characteristic triad of this disease is nocturnal wheezing, high titers of filarial antibodies, and a rapid response to diethylcarbamazine. Radiographs of the chest usually show a diffuse reticulonodular pattern. Pleural effusions are rare; pulmonary fibrosis may develop in untreated patients.

Ch045-F06861.indd 565

565

COMMENTS AND CONTROVERSIES This chapter provides a thorough review of parasitic diseases affecting lung and pleura. Greatest emphasis is placed on hydatid disease. Dr. Varela and his colleagues have an impressive experience in the management of pulmonary-pleural hydatid disease. This condition is uncommonly encountered by thoracic surgeons in North America. However, our colleagues in the Mediterranean and in South America in particular have added significant new information in the management of this persistent problem. Natural history, diagnosis, and management are covered extensively. Of particular importance are the technical details of surgical management to ensure complete resection without spillage, by pericystectomy, enucleation, or wedge resection for small lesions. In this era of global travel, all thoracic surgeons need to have an understanding of these pleural pulmonary parasitic diseases. G. A. P.

KEY REFERENCES Burgos R, Varela A, Castedo E, et al: Pulmonary hydatidosis: Surgical treatment and follow-up of 240 cases. European J Cardiothorac Surg 16:628, 1999. Elburjo M, Gani EA: Surgical management of pulmonary hydatid cysts in children. Thorax 50:396, 1995. Furst SR, Weinger MB, Simons SM: Pleuropulmonary amebiasis. Chest 100:293, 1991. Jerray M, Benzarti M, Garrouche A, et al: Hydatid disease of the lungs: Study of 386 cases. Am Rev Respir Dis 146:185, 1992. Ong RK, Doyle RL: Tropical pulmonary eosinophilia. Chest 113:1673, 1998. Salih OK, Topcuoglu MS, Celik SK, et al: Surgical treatment of hydatid cysts of the lung: Analysis of 405 patients with pulmonary hydatidosis. J Thorac Cardiovasc Surg 102:427, 1998. Schad GA, Warren KS (eds): Hookworm Disease: Current Status and New Directions. London, Taylor & Francis, 1990.

1/21/2008 11:40:41 AM

chapter

46

INTERSTITIAL LUNG DISEASE Steve Yang Ganesh Raghu

Key Points ■ Interstitial lung disease (ILD) encompasses a wide range of pulmo-

■

■ ■

■

nary disorders that affect the lung parenchyma and distal air spaces and result in disrupted gas exchange across the alveolar septa. An assessment of a patient with ILD includes a thorough medical history, a detailed physical examination, and diagnostic testing (laboratory tests, chest radiograph, high-resolution computed tomography [HRCT] scan, and pulmonary function tests). The surgical lung biopsy is the best procedure to obtain an accurate diagnosis in patients with indeterminate ILD. Surgical lung biopsy must be obtained from several sites in the lung, guided by HRCT selection of appropriate areas to biopsy, to ensure that the specimens obtained reflect the true underlying histology. Dynamic interactions between pulmonologists, chest radiologists, and pulmonary pathologists increase diagnostic yield.

BACKGROUND Interstitial lung disease (ILD) encompasses a wide range of acute and chronic pulmonary disorders that affect the lung parenchyma, including the distal air spaces, with varying degrees of inflammation, fibrosis, and architectural distortion that result in disrupted gas exchange across the alveolar septa in an apparently immunocompetent person. This heterogeneous disease of more than 150 distinct clinical entities is associated with a number of diverse contributing causes, including granulomatous inflammation (e.g., sarcoidosis), systemic diseases (e.g., rheumatoid arthritis), environmental exposures (domestic and occupational), iatrogenic causes (e.g., drugs), and inherited and idiopathic interstitial pneumonias. The term ILD is, in fact, a misnomer because the interstitium is confined to the microscopic anatomic space that is bounded by the basement membranes of epithelial and endothelial cells. However, ILD involves cellular and acellular components beyond the microscopic interstitial space and extends into the alveolar space, with some diseases affecting the distal small airways, the blood vessels and even the pleura. Because of the extent of differential diagnostic possibilities that are involved, it is often useful to categorize ILD in the immunocompetent patient into seven main groups1 (Fig. 46-1):

1. Idiopathic interstitial pneumonias (e.g., idiopathic pulmonary fibrosis [IPF]) 2. Granulomatous ILD (e.g., sarcoidosis) 3. Connective tissue disease (CTD)–induced ILD (e.g., rheumatoid arthritis) 4. Occupational/environmental-induced ILD 5. Inherited ILD (e.g., tuberous sclerosis) 6. Iatrogenic/drug-induced ILD 7. Unique entities (e.g., alveolar proteinosis, lymphangioleiomyomatosis [LAM]) Although the presence of ILD poses a significant diagnostic and therapeutic challenge, clinicians identify ILD with characteristic features. In the absence of infection and neoplasms, these include the following: 1. Exertional dyspnea or cough 2. Bilateral diffuse interstitial infiltrates on chest radiographs 3. Physiologic and gas exchange abnormalities, including a decreased diffusion capacity for carbon monoxide (DLCO) and an abnormal alveolar-arterial difference in partial pressure of oxygen [PAO2 − PaO2], termed the alveolararterial gradient, at rest or with exertion 4. Histopathologic abnormalities of the pulmonary parenchyma that are characterized by varying degrees of inflammation, fibrosis, and remodelling

INCIDENCE AND PREVALENCE RATES The incidence and prevalence rates of ILD have not been precisely estimated. This may in part be due to the difficulties in ascertaining a specific diagnosis of a specific disease. Because ILD remains a diagnosis of exclusion, extensive investigations are required to differentiate ILD from other disease.2 In addition, available data from registries or hospitals suffer from selection biases, making them unrepresentative of the general population.3 A study undertaken in Bernalillo County, New Mexico, USA, used data from a dedicated ILD registry and employed broad case-identification procedures and systematic chart review. The estimated incidence of ILD was 30 per 100,000 per year, with approximately one third in the IPF category; and was higher for men than for women.4 The estimated prevalence of ILD was almost three times as high as the incidence, suggesting a mean survival time of approximately 3 years. Published reports suggest that there are international differences in the prevalence of IPF. It was estimated to be 4.1 per 100,000 in the Japanese Hokkaido registry5 and 7 to 12

566

Ch046-F06861.indd 566

1/21/2008 11:41:32 AM

Chapter 46 Interstitial Lung Disease

Iatrogenic/ drug-induced

Granulomatous diseases Sarcoidosis Hypersensitivity pneumonitis

Occupational/ environmental

Diffuse Parenchymal Interstitial Lung Disease

Inherited Hermansky-Pudlak syndrome Tuberous sclerosis Neurofibromatosis Metabolic storage disorders

Idiopathic interstitial pneumonia

567

Connective tissue disease

Unique entities Pulmonary alveolar proteinosis Langerhans cell granulomatosis Lymphangioleiomyomatosis Eosinophilic lung diseases

FIGURE 46-1 Interstitial lung disease in the immunocompetant host can be categorized into seven main groups.

per 100,000 in the Finnish registry,6 compared to the 30 per 100,000 in Bernalillo County. Comparing data from the Bernalillo County with earlier U.S. estimates suggests that the prevalence of IPF is increasing, from 3 to 5 per 100,000 in 19847 to 30 per 100,000 in 1994. Although this might reflect a true increase in IPF prevalence over 10 years, it is more likely that earlier studies underestimated IPF prevalence because they were based on selected populations and lack of general awareness of ILD.

DIAGNOSIS Medical History Without a thorough medical history, all ILDs are of unknown cause. For an accurate diagnosis, the key is a complete clinical evaluation. This includes a thorough history elicitation, with elaboration of the chief complaint; a comprehensive review of multiple systems; identification of all medications or drugs, including over-the-counter and naturopathic medications; and an exhaustive review of past medical, social, family, and occupational histories with an exploration of all potential environmental exposures. A careful physical examination is absolutely essential. The clues that surface during this evaluation help clinicians to narrow the broad differential diagnosis to a few possibilities.

History of Onset of Illness The presenting respiratory system complaints of a patient with ILD must be characterized fully, with a focus on the onset and duration of symptoms, rate of progression, and any associated extrathoracic or musculoskeletal symptoms and constitutional symptoms such as fever, night sweats, and weight loss. Acute symptoms (days to a few weeks) of cough, dyspnea, and fever necessitate evaluation for infection (viral, bacterial), particularly atypical organisms. In the absence of infection, possible causes of acute ILD include cryptogenic organizing pneumonia (COP), acute interstitial pneumonia, acute eosinophilic pneumonia, drug-induced pulmonary injury, and hypersensitivity pneumonitis (HP). In contrast,

Ch046-F06861.indd 567

patients with IPF, pulmonary Langerhans cell granulomatosis (LCG), or CTD-associated ILD present with insidious onset of symptoms. However, systemic lupus erythematosus (SLE) and, rarely, polymyositis may manifest with acute symptoms. Acute symptoms that rapidly progress to respiratory failure raise the possibility of acute interstitial or acute eosinophilic pneumonia. Subacute (weeks to months) presentations include COP, acute HP, chronic eosinophilic pneumonia, drug-induced ILD, and CTD-induced ILD. Chronic symptoms (months to years) usually indicate IPF, nonspecific interstitial pneumonia (NSIP) of the fibrotic variety, chronic HP, chronic occupation-related lung disease (e.g., asbestosis), or CTD-induced ILD.

Respiratory Symptoms Other Than Dyspnea Cough, hemoptysis, chest pain, and wheezing are other specific respiratory symptoms that may coexist with exertional dyspnea in patients with ILD. Although cough is nonspecific, it does raise the possibility of superimposed or coexisting airway disease that is associated with respiratory bronchiolitis–interstitial lung disease (RB-ILD), sarcoidosis, HP, and acid gastroesophageal reflux. A chronic irritable cough has been associated with lymphangitic carcinomatosis; mucoid or “salty” sputum is suggestive of bronchoalveolar cell carcinoma. In long-standing and advanced pulmonary fibrosis that is associated with traction bronchiectasis, cough may become productive and unresponsive to conventional treatment and remedies. Hemoptysis is suggestive of a diffuse alveolar hemorrhage syndrome; pulmonary capillaritis; vasculitides such as Wegener’s granulomatosis or Goodpasture’s syndrome; or catemenial hemoptysis. The absence of hemoptysis does not exclude diffuse alveolar hemorrhage (especially chronic) or other underlying conditions that are associated with microscopic hemorrhage (e.g., SLE). In patients with known IPF, new-onset hemoptysis raises the concern for superimposed malignancy, pulmonary embolus, or infection. Pleuritic chest pain raises the possibility of a pneumothorax. This is usually seen in patients who have LAM, tuberous

1/21/2008 11:41:33 AM

568

Section 3 Lung

sclerosis, pulmonary LCG, neurofibromatosis, or catemenial syndrome. Alternatively pleuritis can be seen in the CTDs, such as SLE. Wheezing suggests ILD that is associated with airway disease, such as allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, chronic eosinophilic pneumonia, and parasitic manifestation. Rarely, endobronchial lesions may result in wheezing (e.g., sarcoidosis, Wegener’s granulomatosis, amyloidosis, inflammatory bowel disease, endobronchial metastases).

Extrapulmonary Symptoms Several extrapulmonary (gastrointestinal tract, rheumatologic, cutaneous, musculoskeletal, neurologic, renal) symptoms can provide useful clues to the diagnosis. A history of dyspepsia or gastroesophageal reflux disease may suggest scleroderma-related ILD. Overt aspiration or dysphagia suggests aspiration pneumonia, scleroderma, or mixed connective tissue disease. Lower gastrointestinal symptoms may suggest inflammatory bowel disease. Frank arthritis may suggest a CTD or sarcoidosis, and combined muscle and skin symptoms suggest polydermatomyositis. Skin lesions such as lupus pernio suggest sarcoidosis. Other skin lesions can occur in neurofibromatosis, tuberous sclerosis, or SLE. Albinism can occur in patients with the Hermansky-Pudlak syndrome. Neurologic symptoms (cranial nerve involvement, Bell’s palsy) suggest the possibility of vasculitis or sarcoidosis. A history of epilepsy or mental retardation may be seen in tuberous sclerosis. Polyuria and polydyspsia of diabetes insipidus suggest sarcoidosis or pulmonary LCG. Hematuria raises the possibility of pulmonary-renal syndromes.

Demographics and Family Medical History The patient’s age, cigarette-smoking status, and gender can provide important clues in the specific diagnosis of ILD. IPF is always an adult disorder and typically occurs in patients who are older than 60 years of age. Patients with NSIP usually are relatively younger than those with IPF. Although pulmonary sarcoidosis can manifest in the elderly patient, it is more common in the young and middle-aged. Pulmonary LCG typically occurs in young, cigarette-smoking men. RB-ILD is seen exclusively in cigarette smokers, and desquamative interstitial pneumonia is frequently seen in active smokers. LAM is a rare disorder that occurs exclusively in women, most often in those of childbearing age. Although ILD associated with tuberous sclerosis seems to be virtually identical to LAM, in this rare genetic disorder the lung disease also can occur in men. ILD also occurs in a subgroup of patients who are known to have certain inherited diseases, including neurofibromatosis, tuberous sclerosis, Hermansky-Pudlak syndrome, and metabolic storage disorders.1 A history of documented ILD among first-degree biologic relatives (siblings, parents, children) raises the strong possibility of a hereditary ILD (e.g., familial pulmonary fibrosis).8

Ch046-F06861.indd 568

Environmental/Occupation/Medication History: Identifying Exposures An exhaustive environmental and occupational exposure history is essential because it may lead to identification of a specific cause of ILD. At-risk workers include miners (pneumoconiosis); sandblasters and granite workers (silicosis); welders, shipyard workers, pipe fitters, electricians, and automobile mechanics (asbestosis); farm workers (HP); poultry workers, bird fanciers, and bird breeders (HP); and workers in aerospace, nuclear, computer, and electronic industries (berylliosis). A history of existing, persistent environmental “fibrogenic” factors at home, in the workplace, in automobiles, in frequently visited facilities or homes, or associated with hobbies (e.g., exposure to birds, molds, woodworking) or the use of saunas and hot tubs often is ignored but is equally important and may provide the useful clue for specific diagnosis and management of HP. Several drugs are well-known causes of ILD.9 These include chemotherapeutic and cytotoxic agents, nonsteroidal antiinflammatory agents (NSAIDs), antibiotics, narcotic analgesics, amiodarone, hydralazine, tricyclic antidepressants, methotrexate, and penicillamine. Use of over-the-counter medications and “alternative medicines” must not be overlooked.

Physical Examination Pulmonary Signs Auscultated crackles, typically described as “dry,” “Velcrolike,” end-inspiratory, and predominantly basilar, are detected in more than 80% of patients who have IPF.10 Crackles due to ILD may be detected on physical examination despite a normal chest radiograph and are less commonly detected in granulomatous ILDs (e.g., sarcoidosis). Midinspiratory highpitched squeaks are reported in the primary bronchiolitides and other diseases with airway-centered pathology (e.g., HP). Signs of secondary pulmonary hypertension (increased intensity of the pulmonary component of the second heart sound, the holosystolic murmur of tricuspid regurgitation, a right-sided third heart sound, elevated jugular venous pressure, lower limb edema) may be encountered in the later stages of all chronic ILDs as a result of progressive interstitial fibrosis and alveolar hypoxemia, but they have been identified more specifically as part of the pathogenesis in CTD-associated ILD and pulmonary veno-occlusive disease. In patients with advanced IPF (extensive bilateral honeycomb cysts with traction bronchiectasis) demonstrating hypoxia at rest, secondary pulmonary hypertension may be present. Such patients usually have a forced vital capacity (FVC) of 50% or less of the predicted value, and/or a DLCO of 30% or less of predicted.

Extrapulmonary Signs Additional insight is often gained from the presence or absence of significant extrathoracic findings. Clubbing may be seen in patients who have IPF,10 but also is seen in patients with asbestosis, chronic HP, or desquamative interstitial pneumonia. It is rare in RB-ILD and uncom-

1/21/2008 11:41:33 AM

Chapter 46 Interstitial Lung Disease

mon in CTD-associated ILD, sarcoidosis, COP, lymphocytic interstitial pneumonitis, acute ILD, and other ILDs. Skin abnormalities, peripheral lymphadenopathy, and hepatosplenomegaly are associated commonly with sarcoidosis. Characteristic skin rashes and lesions also occur in CTDs (SLE, dermatomyositis, scleroderma, rheumatoid arthritis), amyloidosis, pulmonary LCG, tuberous sclerosis, and neurofibromatosis. Subcutaneous nodules (especially around the elbow and metacarpophalangeal joints) are suggestive of rheumatoid arthritis. Muscle tenderness and proximal weakness raise the possibility of coexisting polymyositis. Signs of arthritis may be associated with sarcoidosis or CTD. Fever, erythema nodosum, and arthritis raise the likelihood of Lofgren’s syndrome. Often, patients with IPF also have arthralgias but do not have active synovitis; however, if they do, the ILD and arthritis are usually secondary to an occult CTD. Sclerodactyly, Raynaud’s phenomenon, and telangiectatic lesions are characteristic features of scleroderma and CREST syndrome. Iridocyclitis, uveitis, or conjunctivitis may be associated with sarcoidosis, Behçet’s disease, inflammatory bowel disease, and autoimmune syndromes. Oculocutaneous albinism raises the possibility that ILD is associated with Hermansky-Pudlak syndrome. Abnormalities of the central nervous system suggest the diagnosis of sarcoidosis (cranial nerve abnormalities, diabetes insipidus, anterior pituitary dysfunction), pulmonary LCG (diabetes insipidus), or tuberous sclerosis (epilepsy, mental retardation).

569

Diagnostic Tests Laboratory Testing Laboratory blood testing alone rarely permits one to either rule in or rule out a specific diagnosis, but the results may be strongly supportive in the appropriate clinical setting (Table 46-1). Routine laboratory tests include a complete blood count with leukocyte differential, platelet count, erythrocyte sedimentation rate, and chemistry profile (serum electrolytes, serum urea nitrogen, creatinine, liver tests, and calcium). Antinuclear antibody (ANA) and rheumatoid factor are measured in the setting of a history or physical findings that are suggestive of CTD. Low titers of ANA (<1 : 160) and rheumatoid factor occur in 10% to 20% of patients who have IPF. Such patients may manifest other typical clinical features of CTD later in the course of the disease. A slightly elevated erythrocyte sedimentation rate, C-reactive protein, and hypergammaglobulinemia are common and nonspecific findings. An elevated level of angiotensin-converting enzyme may be seen with sarcoidosis, but this finding is insensitive and nonspecific because the value is also abnormal in other diseases (e.g., silicosis, HP, lymphocytic interstitial pneumonitis, acute respiratory distress syndrome [ARDS]). Serum precipitins that are focused on known exposures may be considered if the environmental history suggests HP; however, false-negative results may be encountered, and,

TABLE 46-1 Clues From Blood and Urine Tests for Patients Who Have Interstitial Lung Disease Laboratory Test

Indications

Interpretation

Complete blood count, liver function test, creatinine, BUN

All patients with suspected ILD

Eosinophilia (CEP, drugs), normocytic anemia (CTD), iron-deficiency anemia (DAH), leucopenia/thrombocytopenia (CTD, sarcoidosis, lymphoma), liver disease (sarcoidosis, amyloidosis), renal disease (CTD, amyloidosis, WG, GS)

Aldolase, creatine kinase, Jo-1 antibody

Muscle pain, weakness

Elevated values are supportive of polymyositis

Immunoglobulins

Clinically suspected or histopathologic diagnosis of LIP

Low levels of immunoglobulins may indicate an underlying diagnosis of CVID

Urinary sediment

Suspected vasculitis (CTD, WG, MPA, GS)

RBC casts or dysmorphic RBCs suggest systemic vasculitis

ANA, RF

Suspected IIP, IPF, CTD, or ILD for which CTD cannot be ruled out

Low titers of ANA (<1 : 160) and RF occur in 10-20% of patients who have IPF

C-ANCA, P-ANCA

Suspected WG or MPA (lung nodules, sinusitis, DAH)

Positive C-ANCA or antiproteinase 3 is most suggestive of WG; P-ANCA may be seen in WG but suggests MPA

Anti-GBM antibody

Suspected GS (i.e., DAH)

Positive result in a patient with DAH is diagnostic for GS

Specific serum precipitins

Exposure history appropriate for HP

Interpret within clinical context. A negative result does not rule out HP; a positive result is not diagnostic of HP

ANA, antinuclear antibody; BUN, blood urea nitrogen; C-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; CEP, chronic eosinophilic pneumonia; CTD, connective tissue disease; CVID, common variable immunodeficiency; DAH, diffuse alveolar hemorrhage; GBM, glomerular basement membrane; GS, Goodpasture’s syndrome; HP, hypersensitivity pneumonitis; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; LIP, lymphocytic interstitial pneumonitis; MPA, microscopic polyangiitis; P-ANCA, perinuclear antineutrophil cytoplasmic antibody; RBC, red blood cell; RF, rheumatoid factor; WG, Wegener’s granulomatosis. Adapted from Raghu G, Brown KK: Interstitial lung disease: Clinical evaluation and keys to an accurate diagnosis. Clin Chest Med 25:409-419, 2004.

Ch046-F06861.indd 569

1/21/2008 11:41:33 AM

570

Section 3 Lung

similarly, the presence of precipitating antibody may represent sensitization to an environmental antigen and not disease. Random “HP panels” are almost never helpful in the absence of a specific exposure and seldom provide useful information. A careful history elucidation is key to diagnosing HP. If pulmonary vasculitis (pulmonary nodules, hemoptysis, arthritis, rash, sinusitis) or diffuse alveolar hemorrhage (hemoptysis) is suspected, antineutrophil cytoplasmic antibody (C-ANCA and P-ANCA), antiglomerular basement membrane antibody, ANA, and urine sediment must be checked. Proximal muscle weakness or tenderness prompts measurement of aldolase, creatine kinase, anti–Jo-1 antibody, and possibly an electromyogram and muscle biopsy to rule out polymyositis. A clinically suspected or histopathologic diagnosis of lymphocytic interstitial pneumonitis prompts serologic studies (to rule out a CTD, particularly Sjögren’s syndrome), measurement of immunoglobulin levels (to evaluate for associated common variable immunodeficiency), and a human immunodeficiency virus (HIV) test. Peripheral blood lymphocyte proliferation that is stimulated by the antigen that may be causing the ILD has a high sensitivity (e.g., berylliosis–beryllium lymphocyte proliferation test).

Chest Radiograph: Useful Diagnostic Patterns A diffusely abnormal chest radiograph is often the initial finding that alerts the physician to the possibility of ILD. The clinician needs to make every effort to obtain previous chest radiographs for review. This may allow one to ascertain the onset, chronicity, rate of progression, or stability of the patient’s disease. Although HRCT of the chest is more sensitive in detecting ILD, classification of abnormalities on routine chest radiograph that is based on distribution, location, and overall appearance is useful to narrow the differential diagnosis (Table 46-2). A pattern of upper lobe/zone predominance in ILD suggests sarcoidosis, berylliosis, pulmonary LCG (especially with preserved lung volumes), HP, silicosis, and ankylosing spondylitis. Conversely, lower lobe predominance with decreased lung volumes is seen characteristically in IPF, chronic HP, fibrotic NSIP, polymyositis, systemic sclerosis, and asbestosis. Normal and increased lung volumes on the chest radiograph in the context of ILD suggest the coexistence of an obstructive airflow defect and a few specific disease entities such as LAM, pulmonary LCG, HP, tuberous sclerosis, and sarcoidosis. Associated pneumothorax raises the possibility of LAM or pulmonary LCG.

TABLE 46-2 Useful Chest Radiographic Patterns Pattern

Suggested Diagnosis

Low lung volumes

IPF, CTD-related ILD, chronic HP, asbestosis, NSIP, chronic drug-induced ILD, subgroup of chronic COP, CEP, DIP

Increased or preserved lung volumes

RB-ILD, IPF with coexisting emphysema, sarcoidosis, acute HP, LAM, TS, pulmonary LCG, neurofibromatosis, bronchiolitis, cigarette smoking

Upper zone predominance

Sarcoidosis, silicosis, coal workers’ pneumoconiosis, HP, pulmonary LCG, berylliosis, AS, CEP, Caplan’s syndrome, nodular rheumatoid arthritis

Lower zone predominance

IPF, CTD-related ILD, asbestosis, DIP

Peripheral predominance

COP, CEP

Micronodular

Infection, sarcoidosis, HP

Septal thickening

Malignancy, chronic congestive heart failure, infection, pulmonary veno-occlusive disease

Honeycombing

IPF, asbestosis, CTD-related ILD, sarcoidosis, chronic HP

Migratory infiltrates

COP, HP, ABPA, Loffler’s syndrome

Pleural disease

CTD-related ILD, asbestosis, malignancy, radiation-induced ILD, sarcoidosis

Pneumothorax

LAM, pulmonary LCG, TS, neurofibromatosis, catamenial syndrome

Mediastinal/hilar lymphadenopathy

Sarcoidosis, malignancy, silicosis, infection, chronic beryllium disease, CTD

Normal (encountered rarely)

HP, NSIP (cellular), CTD-related ILD, bronchiolitis, RB-ILD, sarcoidosis

Along bronchovascular sheath

Sarcoidosis

Along Kerley B lines

Lymphangitic carcinomatosis

ABPA, allergic bronchopulmonary aspergillosis; AS, ankylosing spondylitis; CEP, chronic eosinophilic pneumonia; COP, cryptogenic organizing pneumonia; CTD, connective tissue disease; DIP, desquamative interstitial pneumonia; HP, hypersensitivity pneumonitis; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; LAM, lymphangioleiomyomatosis; LCG, Langerhans cell granulomatosis; NSIP, nonspecific interstitial pneumonia; RB-ILD, respiratory bronchiolitis–interstitial lung disease; TS, tuberous sclerosis. Adapted from Schwarz M, King TE, Raghu G: Approach to the evaluation and diagnosis of interstitial lung disease. In Schwarz MI, King TE (eds): Interstitial Lung Disease, 4th ed. Hamilton, Ontario, BC Decker, 2003; and Lynch D: Imaging of diffuse parenchymal lung disease. In Schwarz MI, King TE (eds): Interstitial Lung Disease, 4th ed. Hamilton, Ontario, BC Decker, 2003.

Ch046-F06861.indd 570

1/21/2008 11:41:33 AM

Chapter 46 Interstitial Lung Disease

The presence of pleural plaques or localized pleural thickening with parenchymal opacities that affect the lower lobe suggests asbestosis. Unilateral or bilateral pleural thickening can result from asbestos pleurisy, rheumatoid arthritis, scleroderma, or malignancy. The coexistance of exudative pleural effusion raises the possibility of rheumatoid arthritis, SLE, a drug reaction, asbestosis-related lung diseases, amyloidosis, LAM (chylothorax), or lymphangitic carcinomatosis. Associated mediastinal adenopathy raises the possibility of sarcoidosis, CTD, or malignancy.

High-Resolution Computed Tomography HRCT has evolved into a standard procedure during the evaluation of almost all patients who have ILD. It is a more sensitive test than plain chest radiography in identifying ILD (sensitivity >90%), and the image pattern of parenchymal abnormalities on HRCT often suggests a particular set of diagnostic possibilities (Table 46-3). HRCT also identifies “mixed” patterns of disease (e.g., ILD plus emphysema) or additional pleural, hilar, or mediastinal abnormalities. It has a better correlation with physiologic impairment and is especially useful in guiding the site of bronchoalveolar lavage (BAL) or lung biopsy. A completely normal HRCT image of the pulmonary parenchyma rules out IPF but does not rule out microscopic inflammation and granulomatous changes associated with ILD.

Pulmonary Function Testing Initial pulmonary function tests should include a spirometry (with and without bronchodilator challenge), plethysmographic lung volumes, and DLCO (corrected to hemoglobin). Pulmonary function tests cannot diagnose a specific ILD and cannot distinguish between active lung inflammation and fibrosis, but they are critically important in the objective assessment of respiratory symptoms as well as in paring the differential diagnosis, grading the severity of disease, and monitoring response to therapy or progression.

571

Pulmonary function test abnormalities generally reflect the effects of elevated elastic recoil (restrictive lung defect) and alveolar-capillary dysfunction (decreased DLCO when corrected to hemoglobin), although increased lung volume (e.g., LAM) and increased diffusion capacity (e.g., diffuse alveolar hemorrhage) can be seen. A typical pattern in ILD is a restrictive lung defect with symmetrically decreased lung volumes (total lung capacity [TLC], functional residual capacity [FRC], and residual volume [RV] all <80% of predicted); a decreased forced expiratory volume in 1 second (FEV1) and FVC decreased in parallel, with a normal or elevated FEV1/FVC ratio; and a decreased DLCO corrected for hemoglobin. Coexisting obstructive airflow defect, when present, can help significantly with diagnosis. A mixed pattern of restriction and obstruction (decreased FEV1/FVC ratio, elevated RV, lack of supranormal airflows on a flow-volume loop, or a significant response to bronchodilator therapy) in a patient without coexisting emphysema may suggest sarcoid, HP, RBILD, pulmonary LCG, LAM, and ILD associated with asthma (chronic eosinophilic pneumonia, Churg-Strauss syndrome). An obstructive defect without significant restriction may reflect bronchiolitis obliterans (without associated organizing pneumonia) and constrictive bronchiolitis. A DLCO that is decreased out of proportion to other tests may indicate concomitant pulmonary vascular disease, as in scleroderma, CREST syndrome, pulmonary veno-occlusive disease, and chronic pulmonary emboli; it also can be seen occasionally in pulmonary alveolar proteinosis, pulmonary LCG, and LAM. Because TLC and FVC are effort- and muscle strength– dependent maneuvers, occasionally a restrictive pattern (TLC < 80%) may be due in part or wholly to respiratory muscle weakness (e.g., polymyositis); this is revealed by decreased maximal inspiratory pressure, maximal expiratory pressure, and maximum minute ventilation. Presence of air-trapping (↓ RV) in the absence of significant airflow obstruction (↓ FEV1/ FVC ratio) raises the possibility of underlying respiratory muscle weakness.

TABLE 46-3 Useful High-Resolution Computed Tomography Patterns in Interstitial Lung Disease Findings

Common Clinical Disorders/Syndromes

Reticular lines, honeycombing, traction bronchiectasis

CTD-related ILD, IPF, asbestosis, sarcoidosis, CEP

Air space opacity, “ground-glass”

COP, CEP, AIP, PAP, consolidation, lymphoma, sarcoidosis

Nodular pattern

Granulomatous diseases, pneumoconiosis, malignancy, rheumatoid arthritis

Septal thickening

Infection, edema, malignancy, drug reaction, pulmonary veno-occlusive disease

Cystic changes

LAM, LIP, pulmonary LCG (emphysema must be distinguished)

Mosaic patterns

Air-trapping (constrictive bronchiolitis)

AIP, acute interstitial pneumonia; CEP, chronic eosinophilic pneumonia; COP, cryptogenic organizing pneumonia; CTD, connective tissue disease; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; LAM, lymphangioleiomyomatosis; LCG, Langerhans cell granulomatosis; LIP, lymphocytic interstitial pneumonitis; PAP, pulmonary alveolar proteinosis. Adapted from Schwarz M, King TE, Raghu G: Approach to the evaluation and diagnosis of interstitial lung disease. In Schwarz MI, King TE (eds): Interstitial Lung Disease, 4th ed. Hamilton, Ontario, BC Decker, 2003; and Lynch D: Imaging of diffuse parenchymal lung disease. In Schwarz MI, King TE (eds): Interstitial Lung Disease, 4th ed. Hamilton, Ontario, BC Decker, 2003.

Ch046-F06861.indd 571

1/21/2008 11:41:33 AM

572

Section 3 Lung

Exercise Testing Occasionally, pulmonary function tests and the results of resting arterial blood gas analysis are entirely normal in patients who have ILD in early stages, and the only physiologic abnormality that is discovered is an abnormal arterial blood gas sample obtained during exercise (decreased PaO2, widening alveolar-arterial gradient). Hence, gas exchange evaluation at rest and with ambulation using pulse oximetry (i.e., a formal 6-minute or modified walk test) initially need to be performed because the results can guide prompt diagnostic and therapeutic interventions besides directing oxygen therapy based on physiologic needs. A decrease of 4 or 5 absolute percentage points (e.g., from 94% to 89%) or greater with exertion is considered to be clinically significant and has been associated with a poor prognosis in IPF. Formal cardiopulmonary exercise testing that allows measurement of peak oxygen consumption, exercise gas exchange, and dead space ventilation may be helpful, especially in patients with early ILD who have minimal or no symptoms and do not demonstrate significant oxygen desaturation while walking in the clinic.

Bronchoscopy and Bronchoalveolar Lavage Because subacute infection can masquerade as or coexist with noninfectious ILD, the examination of BAL fluid includes screening for mycobacterial and fungal infections, as well as the analysis of BAL cellular components. The gross appearance of the BAL fluid can be highly suggestive or virtually diagnostic of specific ILDs in the appropriate clinical setting. Bloody BAL fluid that does not clear or become more pronounced as sequential aliquots are aspirated indicates alveolar hemorrhage.11 If a freshly obtained BAL has a cloudy appearance that is milky or light brown with flocculent debris that settles to the bottom without centrifugation, pulmonary alveolar proteinosis is the likely diagnosis.12 Mast cells are present in low numbers in the normal lung but are increased in certain ILDs, such as HP, IPF, and sarcoidosis.13,14 Plasma cells are usually absent in the BAL fluid, and their presence usually indicates HP or chronic eosinophilic pneumonia and correlates with a more intense inflammation.15 Macrophages, which are normally seen in a BAL specimen, can have a foamy appearance in HP or display red blood cell fragments and hemosiderin in alveolar hemorrhage. Increases in the relative percentages on a differential cell count for a given white blood cell type (lymphocytes, neutrophils, or eosinophils), previously termed alveolitis, are nonspecific cellular characteristics of ILD. If more than one white blood cell type is increased, a mixed cellularity is said to be present.16 These increases in percentages indicate an underlying pulmonary disorder that disturbs the alveolar cell populations and is suggestive of certain ILDs when used in conjunction with a clinical history, physical examination, and radiographic findings. Lymphocytosis that is greater than 25% is likely to be caused by an ILD that is associated with granuloma formation, particularly sarcoidosis or HP. Flow cytometry using antibodies directed against cell surface markers has been

Ch046-F06861.indd 572

applied to BAL specimens from patients with ILD and can detect alterations in lymphocyte subset populations. Clinically active pulmonary sarcoidosis characteristically has elevated BAL lymphocytes17 and an elevated CD4/CD8 T-lymphocyte ratio (≥3.5).18,19 Depressed CD4/CD8 ratios have been observed in patients who have other forms of ILD, such as HP, drug-induced lung disease, chronic eosinophilic pneumonia, or cryptogenic organizing pneumonia (COP).20 Many forms of ILD lead to an increased number of eosinophils, but the differential rarely exceeds 10%. An eosinophil differential count that is greater or equal to 25% in a patient who has an acute presentation is highly likely to be caused by acute eosinophilic pneumonia or other forms of eosinophilic lung disease associated with high BAL eosinophil numbers.21,22 However, a specific diagnosis cannot be ascertained from the BAL differential cell populations alone.

Lung Biopsy In a symptomatic and/or functionally impaired patient with unexplained physiologic and radiologic features that do not have a characteristic recognizable pattern of ILD (e.g., usual interstitial pneumonia [UIP] or sarcoidosis), surgical lung biopsy or transbronchial lung biopsy (TBLB) are considered as the final diagnostic step. If the clinical features (in the following list) are suggestive of specific diagnoses other than IPF, the diagnosis of IPF requires histologic exclusion of other specific entities by surgical lung biopsy/TBLB: 1. 2. 3. 4. 5. 6.

7. 8. 9. 10. 11. 12.

Relatively younger patient (<65 years of age) History of fever, weight loss, sweats, hemoptysis Family history of apparent ILD Symptoms and signs related to peripheral vasculitis History of pneumothorax (especially recurrent) Atypical radiographic features of IPF: in the conventional chest radiograph with adequate inspiration (posteroanterior and lateral views), upper lobe disease; nodular/ patchy, subsegmental lesions superimposed on “interstitial patterns”; associated hilar/mediastinal adenopathy; pleural effusions/scar; Kerley B lines Normal chest radiograph Unexplained extrapulmonary manifestations Unexplained pulmonary hypertension Unexplained, associated cardiomegaly at the time of presentation Rapidly progressive disease (functional, objective) Rapid deterioration or new symptoms with new radiologic abnormalities in focal areas in a patient with longstanding stable ILD.

TBLB is diagnostically useful only if any of the following findings are present in the retrieved specimen: granuloma (sarcoidosis/HP), infection, and malignancy. Experienced pathologists can differentiate the tight, well-formed noncaseating granulomas of sarcoidosis from the relatively loosely formed granulomas of HP in the lung specimen.23 Pulmonary LCG can be diagnosed using markers of Langerhans cells by immunohistochemical methods.24 Because the diagnostic yield of TBLB appears to be dependent on the presence of alveolar tissue, it is essential to ascertain the adequacy of the

1/21/2008 11:41:33 AM

Chapter 46 Interstitial Lung Disease

specimen before pronouncing a TBLB specimen as nondiagnostic or inadequate.25 Often, specimens obtained from a TBLB are unselected, small, with lung tissue usually crushed, and from regions adjacent to the bronchial tree where nonspecific fibrosis and chronic inflammation are present but may not be representative of the actual pathologic process.26 Surgical lung specimens are obtained by surgical techniques in the operating room under general anesthesia via videoassisted thoracoscopic surgery (VATS) or open lung biopsy by thoracotomy. Surgical lung biopsy is indicated when the patient’s medical history, physical examination, laboratory investigations, radiologic studies (chest radiography and HRCT), and invasive procedures (bronchoscopy with BAL and TBLB) fail to ascertain the diagnosis. Open lung biopsy was previously considered to be the best procedure to obtain an accurate diagnosis in more than 90% of patients.27 Access to the lung via thoracotomy is usually obtained through a small incision (<1 inch). The advantages of this access are a more aesthetic appearance, less postoperative pain, and lower morbidity than with the posterolateral thoracotomy approach.28 The evolution of video technology allows VATS to be used more widely in the diagnosis or treatment of various intrathoracic pathologies.29,30 VATS allows excellent visualization of the whole lung and pleural surfaces and requires less operative time compared with a limited thoracotomy. Open lung biopsy, on the other hand, provides relatively limited visualization through the thoracotomy, thus limiting the choice of biopsy sites to the areas most easily accessed. The use of analgesia and the postoperative hospital stay for patients undergoing VATS were also reduced in one study.31 The use of small incisions and the avoidance of rib retraction (as needed with a thoracotomy/open lung biopsy) have demonstrated a trend toward a lower requirement for postoperative analgesics; these patients also were mobilized faster and had a shorter hospital stay.32,33 In one study of patients with ILD, the diagnostic accuracy with lung specimens obtained by VATS equalled that of open lung biopsy via thoracotomy.34 In other studies, patients undergoing VATS demonstrated a significant reduction in preoperative morbidity and length of hospital stay, and the lung specimens obtained provided equivalent specimen volume and diagnostic accuracy.31-33 Morbidity has generally been found to occur in 20% to 50% of patients undergoing open lung biopsy, with mortality rates varying from 0% to 21%, whereas morbidity with VATS biopsy has ranged from 0% to 25% and mortality rates vary from 0% to 10%.32,33,35-37 Conversion of VATS to thoracotomy may be needed in some cases due to the presence of extensive pleural adhesions or a noncompliant lung.38 The coordinated efforts and interaction of the pulmonologist, surgeon, and pathologist are essential for deciding the site of lung biopsy for optimal diagnostic yield guided by HRCT findings. Regions of honeycombing cysts seen in HRCT reveal mere end-stage pulmonary fibrosis of no diagnostic value.27 Biopsy samples must be obtained from several sites; apparently normal lung parenchyma adjacent to and remote from obviously abnormal sites, as well as visibly abnormal areas, must be sampled. A preoperative chest

Ch046-F06861.indd 573

573

HRCT guides selection of appropriate areas to biopsy. If the process appears to be relatively uniform and diffuse, two or three specimens from different sites/lobes (right or left lung based on CT images) are sufficient. The tip of the lingular segment or middle lobe are generally avoided in diffuse ILD because inflammatory changes and scarring unrelated to the diffuse disease, as well as passive congestion, are likely to be affected in these sites.39-41 Figure 46-2 is a suggested algorithm for diagnostic evaluation of ILD. Variations in histology results obtained from different lobes of the lung are common in idiopathic interstitial pneumonias, complicating the histologic classification of the disease. Heterogeneity of histologic patterns among lobes documents the fact that significant sampling errors may result from protocols that obtain only one biopsy specimen in these cases. Therefore, the value of obtaining a biopsy specimen from multiple lobes during a diagnostic evaluation for idiopathic interstitial pneumonia is critical. A histologic pattern of UIP in any lobe, even if a pattern of NSIP is seen in other lobes, is associated with a poor prognosis. This is based largely on findings that UIP-concordant and UIP-discordant patients had similar relative risks of mortality, and the mortality of each of these groups was poor compared with that for patients with NSIP.41,42 To maximize the diagnostic yield, proper handling and processing of the lung specimen must be carried out.43 Fresh lung specimens are divided immediately for different studies; representative pieces adhere to the following guidelines: 1. Be submitted in the untreated state under sterile conditions for bacteriologic and virologic studies 2. Be fixed in 10% formalin (inflation-fix with fine needle is preferred by some pathologists) 3. Be fixed in methacarnoys solution for potential immunofluorescence studies 4. Be fixed in gluteraldehyde for subsequent electron microscopy studies 5. Be cryopreserved for subsequent or potential immunologic and molecular studies However, hematoxylin/eosin stain is generally sufficient for routine diagnostic purposes.

SPECIFIC INTERSTITIAL LUNG DISEASES Idiopathic Interstitial Pneumonias The idiopathic interstitial pneumonias are a subgroup of the wide spectrum of bilateral fibrotic lung disease44 of unknown origin. A recent international consensus of expert clinicians, radiologists, and pathologists classified idiopathic interstitial pneumonia into seven different histologic patterns (American Thoracic Society, 2002)45: UIP, NSIP, diffuse alveolar damage, organizing pneumonia, desquamative interstitial pneumonia, RB-ILD, and lymphocytic interstitial pneumonitis, each characterized with a clinico-radiological-pathological entity, the most well-defined being UIP and cryptogenic fibrosing alveolitis/IPF.

Usual Interstitial Pneumonia UIP is the most common histologic pattern in cases of idiopathic interstitial pneumonia, and in the appropriate clinical

1/21/2008 11:41:33 AM

574

Section 3 Lung

INTERSTITIAL LUNG DISEASE

Hx and PE, routine laboratory studies, pulmonary function tests, CXRs, HRCT

Pertinent exposure? (e.g., occupational, environmental, drug)

Yes

Remove from exposure

Mild disease

Complete clinical recovery

Moderate to severe disease

No

No

When appropriate: • Biopsy from skin, muscle, kidney, fat, sinus • Connective tissue disease-specific serology

No

BAL/TBLB

Specific systemic disease Yes

No further Dx workup needed

Yes

Specific diagnosis from BAL/TBLB

No further Dx workup

No Typical clinical and HRCT features of IPF?

Yes

IPF clinical Dx

No Surgical lung biopsy from multiple areas based on areas of disease on HRCT findings

IIP, other than IPF

No

Histologic pattern of usual interstitial pneumonia?

Yes

IPF

FIGURE 46-2 Suggested algorithm for diagnostic evaluation for interstitial lung disease. (ADAPTED FROM RAGHU G: INTERSTITIAL LUNG DISEASE: A DIAGNOSTIC APPROACH. ARE CT SCAN AND LUNG BIOPSY INDICATED IN EVERY PATIENT? AM J RESPIR CRIT CARE MED 151:909-914, 1995.)

setting it correlates clinically with the distinct clinical entity IPF or cryptogenic fibrosing alveolitis.46 IPF is typically characterized by chronic progression to death with an average survival time of 2 to 3 years.46-49 The histologic pattern of UIP is also seen in some patients with CTD or asbestosis. IPF usually manifests insidiously, with gradual onset of nonproductive cough and dyspnea, the latter being the most prominent and disabling symptom. Dyspnea is usually progressive and is present for longer than 6 months before presentation. Auscultation of the chest reveals dry, end-inspiratory crackles in more than 80% of patients, typically at the lung bases. Clubbing is noted in 25% to 50% of patients.50,51 Cyanosis, cor pulmonale, an accentuated pulmonic second heart sound, and peripheral edema are signs of pulmonary hypertension that may be seen in the late phases of disease.50,52,53 UIP (fibrotic foci and temporal heterogeneity of disease) is the histopathologic pattern that identifies patients with IPF. Surgical lung biopsy via VATS or open thoracotomy

Ch046-F06861.indd 574

provides the best tissue samples to distinguish IPF from other forms of idiopathic interstitial pneumonia and is recommended for any patient with clinical or radiologic features that are not typical for IPF. Biopsies must be obtained from several different sites to adequately diagnose UIP. UIP is more marked in the lower lobes of the lungs and at the periphery (Figs. 46-3 and 46-4). Although certain therapies can preserve lung function after 1 year, to date no tests have been demonstrated to improve survival. Moreover, there are no treatments that have been compared with placebo. Several clinical trials are underway to assess the efficacy of newer therapies.

Organizing Pneumonia The pathology of organizing pneumonia is characterized by the histologic presence of buds of granulation tissue (consisting of fibroblasts and myofibroblasts embedded in a loose connective matrix) in the lumen of air spaces (alveoli and

1/21/2008 11:41:34 AM

Chapter 46 Interstitial Lung Disease

575

arthritis, dermatomyositis), ulcerative colitis, lung transplantation, or bone marrow transplant. The radiologic features consist of patchy alveolar opacities that are usually bilateral, migratory, and predominant in the lower lobes.57,58 On chest HRCT, the densities can range from a few centimeters to an entire lobe. These are peripheral and bronchocentric, and they sometimes take the shape of large nodules or masses that have air bronchograms.59 Corticosteroids are the current treatment of choice, with clinical improvement manifesting within 48 hours. Radiologic resolution occurs within a few weeks without significant sequelae. Although the response to corticosteroids is excellent, relapse occurs in 13% to 58% of patients.60,61 Spontaneous remissions have been reported.

Granulomatous Lung Disease Sarcoidosis FIGURE 46-3 Chest radiograph of a patient with idiopathic pulmonary fibrosis, demonstrating peripheral, diaphragmatic, and subpleural interstitial markings.

FIGURE 46-4 Chest HRCT scan in a patient with idiopathic pulmonary fibrosis, showing subpleural honeycombing and traction bronchiectasis.

alveolar ducts). Buds may be found in the distal bronchioles, and the condition is thus termed bronchiolitis obliterans organizing pneumonia. If no definite cause or characteristic clinical context is present (e.g., CTD), the disease is termed COP. Organizing pneumonia may result from infection by bacteria, viruses, parasites, or fungi. Other triggers include drugs and radiation.54-56 Organizing pneumonia also can occur in the context of certain disorders such as CTDs (rheumatoid

Ch046-F06861.indd 575

Sarcoidosis is a multisystemic granulomatous disease that occurs throughout the world and affects people of all races and ages. This disease is characterized by the presence of noncaseating granulomas in affected organs; these are found in the lungs and lymph nodes of most patients. Patients with sarcoidosis may be asymptomatic, with an incidental abnormal chest radiograph.62-64 Alternatively, they may present with severe and rapidly deteriorating respiratory symptoms such as dyspnea, dry cough, and chest pain. The diagnosis of sarcoidosis is based on the finding of noncaseating granulomas in a patient with a collaborating history and in whom no other cause of granulomatous disease, such as tuberculosis, fungal infection, Wegener’s granulomatosis, berylliosis, cancer, or lymphoma, can be identified.65 The initial clinical evaluation needs to focus on the extent and severity of individual organ system involvement.65-67 The chest radiograph can be divided into four stages: stage 1, adenopathy alone; stage 2, adenopathy with pulmonary infiltrates; stage 3, infiltrates alone; and stage 4, fibrosis. Most patients present with stage 1 to 3 at the time of initial diagnosis (Fig. 46-5).68 Sites that usually undergo biopsy include the skin, lymph nodes, and lung. To obtain lung specimens, clinicians use an array of diagnostic methods, such as needle aspirations, BAL, TBLB, surgical lung biopsy, and mediastinoscopy. Needle aspirations can be used when there is extrathoracic adenopathy, or when using a bronchoscope to sample lymph nodes within the mediastinum and hilum. A significant drawback of this method is the limited sample obtained, which may miss a granulomatous reaction secondary to lymphoma. Biopsy of lung tissue or endobronchial lesions can reveal noncaseating granulomas, a finding that is diagnostic of sarcoidosis in the absence of other causes of granulomatous lung disease. TBLB has been the main diagnostic method for sarcoidosis for the past 25 years.69,70 The yield is usually higher in patients with parenchymal lung disease on chest radiography (stage 2 and 3).70 If bronchoscopy has failed to make the diagnosis, the next option is usually either surgical lung biopsy or mediastinoscopy. Mediastinoscopy is preferred if there is significant paratracheal lymphadenopathy. In addition, the large samples

1/21/2008 11:41:34 AM

576

Section 3 Lung

A

B

C

D

FIGURE 46-5 A, Chest radiograph of sarcoidosis stage 1, showing hilar lymphadenopathy. B, Chest radiograph of sarcoidosis stage 2, showing pulmonary infiltrates and hilar lymphadenopathy. C, Chest radiograph of sarcoidosis stage 3 showing pulmonary infiltrates. D, Chest radiograph of sarcoidosis stage 4, showing progressive fibrosis.

obtained can help distinguish between sarcoidosis and lymphoma. VATS is an alternative approach in a patient with minimal adenopathy. To increase the yield, multiple biopsies are recommended, avoiding areas of end-stage lung disease and bronchiectatic areas. Therapeutic bronchoscopy is indicated if there is significant tracheobronchial obstruction (endobronchial granulo-

Ch046-F06861.indd 576

mas, extrinsic compression by enlarged lymph nodes), usually in patients with stage 3 to 4 disease, but sometimes in stage 2 disease.71 Laser ablation, electrocautery, and cryotherapy have limited utility because of the diffuse submucosal nature of endobronchial occlusions or because compression is from an extrinsic source. Therefore, dilation with balloons and stents is the procedure of choice.

1/21/2008 11:41:34 AM

Chapter 46 Interstitial Lung Disease

577

TABLE 46-4 Diffuse Lung Diseases and Selected Occupational Causes Clinical Entity

Pathologic Description

Occupational Causes

Idiopathic pulmonary fibrosis (IPF)

Usual interstitial pneumonia

Asbestosis, uranium mining, plutonium, mixed dusts

Nonspecific interstitial pneumonia (NSIP)

Nonspecific interstitial pneumonia

Organic antigens

Desquamative interstitial pneumonia (DIP)

Desquamative interstitial pneumonia

Textile work, aluminum welding, inorganic particles

Bronchiolitis obliterans and organizing pneumonia (BOOP)

Bronchiolitis obliterans and organizing pneumonia

Spray painting of textiles—acramin-FWN; NOx

Pulmonary alveolar proteinosis

Alveolar proteinosis

High-level silica exposure, aluminum dust

Giant cell interstitial pneumonia (GIP)

Giant cell interstitial pneumonia

Cobalt (in hard metal)

ARDS/AIP

Diffuse alveolar damage

Irritant inhalational injury—NOx, SOx, cadmium, beryllium, chlorine, acid mists

Bronchiolitis obliterans (BO)

Constrictive bronchiolitis

NOx, chlorine gas

Bronchiolitis

Cellular bronchiolitis

Organic antigens

Sarcoidosis

Granulomatous inflammation

Beryllium, organic antigens, zirconium, aluminum, titanium

Lipoid pneumonia

Lipoid pneumonia

Oil-based fluid exposure

ARDS/AIP, acute respiratory distress syndrome/acute interstitial pneumonitis; NOx, oxides of nitrogen; SOx, oxides of sulfur. Adapted from Glazer CS, Newman LS: Occupational interstitial lung disease. Clin Chest Med 25:467-478, 2004.

Hypersensitivity Pneumonitis

Occupational Interstitial Lung Diseases

HP, also called extrinsic allergic alveolitis, is a heterogeneous group of diseases that result from inhalation of various organic substances which, in a susceptible host, induce a diffuse immunopathologic reaction of the small airways and lung parenchyma.72 It can manifest as an acute, subacute, or chronic illness, any of which can mimic other diseases. A wide spectrum of causative antigens, such as mammalian and avian proteins, fungi, bacteria, small-molecular-weight chemical compounds, and airborne organic particles, can induce HP. HP presentation can be divided into acute, subacute, and chronic forms:

ILDs caused by exposure to agents in the workplace are an important and preventable group of diseases (Table 46-4). The list of inciting agents continues to expand; some are well described, but others are poorly characterized. Recognition of occupational ILD is important because of the implications of primary and secondary prevention in exposed workers. Consider occupational exposures in any new patient who has ILD without an obvious cause. Important clues include clustering of ILD in coworkers, exposure to agents known to cause ILD, young age, work-related exacerbation of symptoms, and slower than expected progression of disease.

1. Acute HP occurs usually 4 to 8 weeks after antigen exposure. Signs and symptoms include sudden onset of fever, chills, dyspnea, and cough (which may be dry or mildly productive), with symptoms gradually improving over the next few days unless there is re-exposure to the causative agent. 2. Subacute HP usually occurs weeks to months after continued exposure. Patients develop symptoms similar to those of acute HP but less severe. Additional symptoms include fatigue, anorexia, and weight loss. 3. Chronic HP can occur either in the context of a continuous, long-term but low-level antigen exposure or in the setting of recurrent undiagnosed acute or subacute episodes.73 Chronic HP may progress to pulmonary fibrosis or emphysema, depending on the inciting agent. Interstitial fibrosis is a common consequence of chronic pigeon breeder’s disease,73-76 whereas airway obstruction and emphysema are seen more commonly in patients with farmer’s lungs.77-80

Ch046-F06861.indd 577

Specific Agents The best-described occupational agents that cause ILD are inorganic fibrous dusts, nonfibrous dusts, and metals. Fibrous Dusts. Asbestos exposure leads to asbestosis, which is defined as interstitial fibrosis caused by asbestos fibers.81,82 In addition, asbestos exposure can lead to benign pleural effusions, pleural and diaphragmatic plaques, diffuse pleural thickening, and increased risk of malignancies (most prominently lung cancer and mesothelioma) in exposed individuals. Chest radiography typically shows bilateral, predominant, irregular, or reticular opacities at the lung bases, with honeycombing occurring in advanced disease. The presence of bilateral pleural plaques and slow radiographic progression of interstitial opacities increases the confidence of a correct diagnosis (Fig. 46-6). Asbestosis progresses in 20% to 40% of patients. Risk factors for progression include cumulative exposure, severity of disease at diagnosis, and fiber type.83,84 No treatment has been demonstrated to be effective.

1/21/2008 11:41:35 AM

578

Section 3 Lung

FIGURE 46-6 Chest radiograph of a patient with asbestosis, showing pleural calcifications (arrows).

FIGURE 46-7 Chest radiograph of a patient with progressive massive fibrosis from silicosis.

Nonfibrous Dusts. Silicosis is the best-characterized occupational ILD caused by exposure to nonfibrous inorganic dusts. The disease occurs after inhalational exposure to crystalline silica or silicate-containing dusts. ILD caused by silica manifests in three ways:

initially limited to workers involved in the manufacture and production of beryllium in the nuclear weapons industry and those living in the neighborhoods surrounding berylliummanufacturing facilities.89 But, concurrent with the decreased use of beryllium in nuclear weapons, there has been an increase in its use in other industries; these produce respirable beryllium particulates that can cause sensitization and, subsequently, chronic beryllium disease. The greatest cause of morbidity in chronic beryllium disease is lung involvement that is associated with a progressive decline in lung volumes and diffusing capacity, eventually resulting in respiratory failure and cor pulmonale. Studies have demonstrated that stopping beryllium exposure itself is associated with an improvement in pulmonary functions in most patients. There is no known treatment for beryllium sensitivity.

1. Chronic simple silicosis, which occurs after a latency period of 10 to 40 years85 2. Accelerated silicosis, which occurs in the setting of higher exposures and has a latency period of 5 to 10 years, with a more severe disease 3. Acute silicoproteinosis, which occurs in the setting of high levels of exposure over a period of months to 2 years and is similar clinically and pathologically to pulmonary alveolar proteinosis86,87 In addition to ILD, silica exposure increases the risk of developing pulmonary tuberculosis and nontuberculous mycobacterial infections, chronic bronchitis, and chronic obstructive pulmonary disease. Patients with chronic simple silicosis are frequently asymptomatic and only develop symptoms of cough and dyspnea insidiously on exertion, when complicated by progressive massive fibrosis (which is the situation in which individual silicotic nodules coalesce and form large masses of dense fibrosis (Fig. 46-7). Typical radiographic findings in silicosis are upper lobe predominant nodular opacities with hilar adenopathy of the characteristic “eggshell” or peripheral calcification pattern. Nodules are typically smaller than 5 mm in diameter and well circumscribed, unless they coalesce to form masses larger than 1 cm in diameter, termed progressive massive fibrosis. Metals. Beryllium is a lightweight metal with high tensile strength and high heat absorptive properties that has many uses as an alloy together with copper, nickel, aluminium, and magnesium in numerous applications, including electronics, aerospace, automotive manufacture, communications, nuclear weapons, and household appliances. Beryllium exposure was

Ch046-F06861.indd 578

Inherited Interstitial Lung Disease ILD and specifically pulmonary fibrosis have been associated with several known genetic diseases that are inherited in a mendelian fashion. For all these diseases, the lung is secondarily involved as part of the systemic derangements. The extent of pulmonary involvement may range from incidental to being a consistent clinical feature of the disease.

Tuberous Sclerosis Tuberous sclerosis is a dominantly inherited disease of variable penetrance characterized by the presence of hamartomas in multiple organ systems. The well-known clinical features include epilepsy, mental retardation, and skin lesions, such as facial angiofibromas, shagreen patches, and ash-leaf hypopigmented macules. Other clinical features include renal angiomyolipomata, renal cysts, central nervous system tubers, nodules, giant cell astrocytomas, cardiac rhabdomyomas, retinal astrocytomas, and pulmonary LAM (see later discussion).

1/21/2008 11:41:35 AM

Chapter 46 Interstitial Lung Disease

ILD, typically LAM, occurs in only 1% of patients with tuberous sclerosis, usually in individuals with little or no mental retardation. When it occurs, it typically affects female patients older than 30 years of age. The usual presenting symptoms include exertional dyspnea, recurrent pneumothoraces, and hemoptysis. Most cases of familial tuberous sclerosis have been linked to two different loci: TSC1 at chromosome 9q34 and TSC2 at chromosome 16p13.

Neurofibromatosis Neurofibromatosis is an autosomal-dominant disorder that manifests in two forms. Type 1 neurofibromatosis, also called von Recklinghausen’s disease or classic neurofibromatosis, is characterized by the presence of café-au-lait spots, neurofibromas, optic gliomas, Lisch nodules, and distinctive bony lesions. Type 2 is rarer and is associated with bilateral acoustic neuromas. Coexisting ILD in patients with type 1 neurofibromatosis ranges from less than 7% to 20%.90,91 Characteristic radiographic findings include bilateral lower lobe fibrosis, bullae, and cystic changes. Pathologically, there is interstitial fibrosis and alveolitis with alveolar septa thickening and a cellular infiltrate.92 Neurofibromas can also manifest in the intrathoracic region as “dumb-bell” neurofibromas, intercostal neurofibromas, and intrathoracic meningocoeles.

Metabolic Storage Diseases Several rare diseases seen in the pediatric population are associated with diffuse ILD. All are inherited in an autosomal recessive manner. Gaucher’s disease is a lysosomal glycolipid storage disorder characterized by the accumulation of glucosylceramide (glucocerebroside), a normal intermediate in the catabolism of gangliosides. This disease is common in the Ashkenazi Jewish population. Other clinical features include hepatosplenomegaly, hematologic abnormalities, skin pigmentation, and pulmonary involvement. Three types of lung involvement have been noted93: 1. Interstitial infiltration by Gaucher cells with fibrosis 2. Alveolar consolidation and filling of alveolar spaces by Gaucher cells 3. Capillary plugging by Gaucher cells and subsequent pulmonary hypertension Niemann-Pick disease is a rare lipid storage disease characterized by the accumulation of sphingomyelin in cells due to a lack of the enzyme sphingomyelinase. Type A is a fatal disorder of infancy characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course. Patients with type B Niemann-Pick disease survive into adulthood with prominent involvement of the lung, liver, and spleen but no neurologic involvement. The characteristic pathology is the “foam cell,” which is a histiocyte with multiple, uniformly sized lipid droplets within the cytoplasm. Pulmonary involvement consists of infiltration of these “foam cells” throughout the pulmonary lymphatics, pulmonary arteries, and pulmonary alveoli.94

Ch046-F06861.indd 579

579

Iatrogenic/Drug-Induced Interstitial Lung Disease An ever-increasing number of drugs can cause injury to the lung parenchyma, upper and lower airways, pleura, mediastinum, lymph nodes, neuromuscular system, and pulmonary circulation. Some drugs produce ILD as a manifestation of a drug-induced systemic autoimmune or hypersensitivity condition. Novel therapies such as γ-interferons, monoclonal antibodies, and colony-stimulating factors can also produce ILD. Drug-induced infiltrative lung disease includes interstitial disease, alveolar changes, and vasculitides. Virtually all histopathologic subtypes of interstitial lung disease can be observed in drug-induced ILD. Occurrence of drug-induced ILD is difficult to predict, and detection remains a problem because there are virtually no reliable, clinical, imaging, BAL, or histopathologic features that are specific or diagnostic for drug-induced ILD. Therefore, the diagnosis of drug-induced ILD requires a definite temporal relationship between exposure to the inciting agent and the onset of lung disease. Drug-induced ILD must be differentiated from left ventricular failure, coincidental ILD, or an opportunistic infection, which is always a differential diagnosis in patients who are receiving immunosuppressive agents. The time to onset of ILD is variable. Avoidance of the offending drug is the treatment of choice. Depending on the severity of disease, treatment with corticosteroid may be needed because the disease may not improve after removal of the drug.

Connective Tissue Disease–Induced Interstitial Lung Disease ILD commonly complicates the management of CTD. Furthermore, pulmonary symptoms such as cough, dyspnea, or ILD may be the first manifestation of an underlying rheumatologic disease.

Systemic Lupus Erythematosus The most common pulmonary manifestations of SLE are pleurisy, pneumonitis, shrinking lung syndrome, bacterial pneumonia, capillaritis with alveolar hemorrhage, pulmonary emboli associated with lupus anticoagulants, and pulmonary arterial hypertension. SLE pneumonitis may be the first manifestation of SLE, with patients presenting abruptly with cough, dyspnea, fever, and diffuse alveolar infiltrates which can progress to fullblown ARDS. Other manifestations of SLE, such as lupus pleuritis, arthralgias, nephritis, and cerebritis, may be present. Treatment usually involves high-dose corticosteroids, but this therapy must be delayed until the possibility of an infectious disease has been excluded. Suspect alveolar hemorrhage if the patient presents with hemoptysis, a decrease in hematocrit, and diffuse alveolar infiltrates. This alveolar hemorrhage is usually secondary to pulmonary capillaritis and is diagnosed by progressively bloody aliquots on BAL.

1/21/2008 11:41:36 AM

580

Section 3 Lung

cially the lungs, either primarily or through complications of muscle weakness, and result in ILD, aspiration pneumonia, and ventilatory insufficiency. Polymyositis/dermatomyositis can also have an acute pulmonary presentation that causes ARDS. The overall mortality rate of polymyositis/dermatomyositis with associated lung disease was described as 50% at 5 years,99 suggesting that all patients with this condition need to be screened for pulmonary abnormalities at diagnosis, using pulmonary function tests and chest HRCT. UIP and NSIP are the usual pathologic entities seen in these patients.

Sjögren’s Syndrome

FIGURE 46-8 Chest CT of a patient with lymphangioleiomyomatosis, showing multiple lung cysts and pneumothorax.

Rheumatoid Arthritis Rheumatoid arthritis is characterized by a symmetrical inflammatory arthritis with a high prevalence for extraarticular manifestations. Common pulmonary abnormalities associated with rheumatoid arthritis are bronchiolitis, bronchiectasis, ILD (NSIP, UIP, COP, diffuse alveolar damage), exudative pleural effusions, rheumatoid nodules, vasculitis, pulmonary hypertension, and ILD secondary to therapy (methotrexate ILD and gold pneumonitis). Because arthritic symptoms can occur up to 2 years after the onset of lung disease, screen patients with UIP on pathology findings or a suggestive chest CT for rheumatoid arthritis. COP can be rapidly progressive in rheumatoid arthritis and can simulate ARDS. Although this disease responds to steroids, the long-term prognosis is poor because it tends to recur when the steroids are withdrawn.

Systemic Sclerosis Scleroderma is a systemic fibrotic disease of unknown etiology that has two clinical presentations: limited scleroderma (CREST variant) and diffuse scleroderma. ANA is positive in both subsets of disease; anticentromere or antibodies to TO/ TH (anti-TO/TH ribonucleoprotein or anti 8-2/7-2 RNA) are predominant in the limited disease95; and anti-SCL70 antibodies are present in the diffuse disease and are associated with a high prevalence of ILD. Pulmonary fibrosis of the NSIP type occurs in most patients with scleroderma, with an average prevalence of 70%,96-98 although UIP can occur. It progresses to severe restrictive lung disease in about 15% of patients with diffuse disease.

Polymyositis/Dermatomyositis Polymyositis and dermatomyositis are systemic inflammatory disorders that affect skeletal muscles and other organs, espe-

Ch046-F06861.indd 580

Sjögren’s syndrome is an autoimmune exocrinopathy and autoimmune epithelitis that is characterized by lymphoproliferation and lymphocytic infiltration of glandular and nonglandular tissue. Patients with Sjögren’s syndrome typically present with dry mouth (xerostomia), dry eyes (keratoconjunctivitis), and arthritis. Pulmonary symptoms of Sjögren’s syndrome include cough and dyspnea, usually due to xerotrachea (dry trachea), small airway inflammation (causing obstructive airway disease), and bronchiectasis (secondary to lymphocytic bronchiolitis). ILD is common in these patients, with histology specimens typically showing NSIP.

Unique Entities Lymphangioleiomyomatosis LAM is a rare disease that occurs almost exclusively in women of childbearing age. There are three groups of patients who can develop LAM-like lung disease: LAM patients who do not have any clinical evidence of tuberous sclerosis; LAM patients who have renal angiomyolipomas; and patients with LAM who have tuberous sclerosis as their primary disease. The pulmonary manifestations of LAM are spontaneous pneumothorax, chylous pleural effusion, progressive exertional dyspnea, cough, and hemoptysis.100 LAM is one of the pulmonary diseases that worsens during the onset of menses,101 during pregnancy,101-105 and with oral contraceptive use.100,101 Most patients experience progressive dyspnea on exertion in the fourth or fifth decade of life, with the average interval between onset of symptoms and diagnosis approximating 3 to 4 years.100 No infectious cause has been identified to date. Radiologically, there is hyperinflation with an interstitial pattern that may be reticular, reticulonodular, or associated with cysts (wall thickness <4 mm), bullae, and pneumothoraces (Fig. 46-8).100 The disease usually has been managed with progesterone therapy. Another management challenge is the treatment of pneumothoraces in patients with LAM. Management of pneumothorax has been complicated by concern related to lung transplantation. Current recommendations include ipsilateral pleurodesis at the time of initial pneumothorax in patients with LAM. Bilateral pleurodesis needs to be considered if pneumothorax develops in the contralateral lung.

1/21/2008 11:41:36 AM

Chapter 46 Interstitial Lung Disease

581

Eosinophilic Lung Diseases The eosinophilic lung diseases are a heterogeneous group of clinical entities in which an increased number of eosinophils are found in the airways or lung parenchyma or both. These disorders may or may not be accompanied by peripheral eosinophilia. Eosinophilic lung diseases can be classified into two broad clinical categories: airway disorders (asthma, allergic bronchopulmonary aspergillosis, eosinophilic bronchitis, and bronchocentric granulomatosis) and parenchymal (interstitial) disorders. Eosinophilic parenchymal/interstitial disorders can also be idiopathic (acute and chronic eosinophilic pneumonia) or associated with known diseases (parasitic infestations, drug reactions, hypereosinophilic syndrome, vasculitis, eosinophilic granuloma). Acute eosinophilic pneumonia presents similarly to an acute infectious process or ARDS. Patients usually present with an acute febrile illness accompanied by myalgias, pleuritic chest pain, and hypoxemic respiratory failure, often requiring mechanical ventilation. The pneumonia usually responds rapidly to high doses of corticosteroids, typically within 24 to 48 hours. The dose is tapered and then continued for 2 to 4 weeks. Most patients survive and recover normal lung function. Chronic eosinophilic pneumonia is a serious disease that affects middle-aged atopic women, although it has been reported in both genders and all ages. The onset of disease is insidious, with progressive respiratory and constitutional symptoms.106 The most common symptoms are cough, dyspnea, fever, night sweats, malaise, and weight loss. The disease responds quickly and dramatically to corticosteroid therapy, with patients becoming asymptomatic in hours or a few days. The prognosis is excellent, although prolonged treatment (3-6 months) is usually necessary. Loffler’s pneumonia, first described in 1932,107 is characterized by migratory pulmonary infiltrates accompanied by peripheral eosinophilia. Patients may present with malaise, fever, and cough, although respiratory symptoms are usually minimal. Chest radiographs are almost diagnostic, with transitory and migratory ill-defined peripheral, nonsegmental, and relatively homogeneous densities. The disease resolves within 4 weeks; affected patients have an excellent prognosis and complete resolution with or without treatment.

Pulmonary Alveolar Proteinosis Pulmonary alveolar proteinosis is a rare pulmonary ILD characterized by the accumulation of surfactant lipoprotein in pulmonary alveoli and the associated disturbance in pulmonary gas exchange.108 Patients typically present at the median age of 39 years with slowly progressive dyspnea and associated symptoms of fatigue, weight loss, and low-grade fever. Less common symptoms include cough, chest pain, and hemoptysis. There is a strong association between pulmonary alveolar proteinosis and tobacco smoking, with approximately three fourths of patients being smokers at the onset of disease. Physical examination is typically normal, although some patients may have signs of crackles, clubbing, and cyanosis.

Ch046-F06861.indd 581

FIGURE 46-9 Chest computed tomogram of a patient with pulmonary alveolar proteinosis, showing crazy-paving pattern.

CT of the chest typically demonstrates bilateral alveolar consolidation, which often appears in a “crazy-paving” pattern that consists of scattered diffuse ground-glass attenuation with superimposed interlobular septal thickening and intralobular lines (Fig. 46-9).109 Therapeutic lung lavage via a double-lumen tube is the standard of treatment in symptomatic patients. This procedure requires general anesthesia and single-lung ventilation via a double-lumen endotreacheal tube. It is fairly well tolerated, with significant clinical, physiologic, and radiologic improvements seen in up to 84% of cases after the first lavage.110 Additional data suggest that exogenous therapy with granulocyte-macrophage colony-stimulating factor (GMCSF) may improve the lung disease in some patients with pulmonary alveolar proteinosis.

Pulmonary Langerhans Cell Histiocytosis Pulmonary Langerhans cell histiocytosis is an uncommon but important cause of ILD that occurs predominantly in cigarette smokers111 and is characterized by uncontrolled proliferation and infiltration of various organs by Langerhans cells.112,113 Patients commonly present with cough and exertional dyspnea,111,114,115 although 25% of patients are asymptomatic at the time of presentation. Spontaneous pneumothorax is the presenting symptom in 10% to 15% of patients.111 Physical examination is usually normal. Smoking cessation is the first therapeutic intervention that must be pursued in all smokers; it leads to stabilization of symptoms as well as radiographic and physiologic improvement. For patients with persistent pulmonary or constitutional symptoms and those who demonstrate a decline in pulmonary function, corticosteroid therapy is often used.

1/21/2008 11:41:36 AM

582

Section 3 Lung

Pneumothorax is a well-recognized complication of pulmonary Langerhans cell histiocytosis and recurs in more than 50% of patients if managed conservatively or with chest tube therapy alone.116 Patients with progressive disease associated with severe respiratory impairment and limited life expectancy are evaluated for lung transplantation.

various biopsy techniques, including BAL, TBLB, and surgical lung biopsy. Also emphasized is the importance of proper tissue handling from biopsy to the pathology or microbiology setting, so as to maximize the likelihood of a high-yield diagnostic biopsy. T. L.

KEY REFERENCES

COMMENTS AND CONTROVERSIES As the authors correctly note, interstitial lung disease is a misnomer. Nonetheless, the broad spectrum of conditions falling under this description are of importance to thoracic surgeons. ILD is not by any means a single condition. The causes are multiple, the presentations myriad, the physical findings variable, and the imaging appearances different. The careful clinical thoracic surgeon must be able to narrow the differential diagnosis by a thorough history and physical examination as well as a thoughtful review of chest films and CT images. The differentiating imaging findings are well described and are in agreement with the opinions of Dr. McLoud expressed in Chapter 36. The subtleties of pulmonary function interpretation are covered nicely and stress to the reader that not all restrictive physiology is caused by ILD. Of particular interest to the surgeon is the excellent outline of indications for biopsy and the limitations and advantages of the

Ch046-F06861.indd 582

American Thoracic Society/European Respiratory Society: International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 165:277-304, 2002. Clinics in Chest Medicine. [Special issue, September.] 25:409-613, 2004. Clinics in Chest Medicine. [Special issue, December.] 25:621-782, 2004. Drent M, Jacobs JA: Bronchoalveolar lavage. In Baughman RP, Du Bois RM, Lynch JP III, Wells AU (eds): Diffuse Lung Disease: A Practical Approach. New York, Oxford University Press, 2004, pp 56-64. Ferson PF, Landreneau RJ, Dowling RD, et al: Comparison of open versus thoracoscopic lung biopsy for diffuse infiltrative pulmonary disease. J Thorac Cardiovasc Surg 106:194-199, 1993. Raghu G, Brown KK: Interstitial lung disease: Clinical evaluation and keys to an accurate diagnosis. Clin Chest Med 25:409-419, 2004. Zegdi R, Azorin J, Tremblay B, et al: Video-thoracoscopic lung biopsy in diffuse infiltrative lung disease: A 5-year surgical experience. Ann Thorac Surg 66:1173-1179, 1998.

1/21/2008 11:41:37 AM

chapter

47

PULMONARY INFECTIONS IN THE IMMUNOCOMPROMISED HOST Yves Bergeron Michel G. Bergeron

Key Points ■ Lower respiratory tract infections, especially pneumonia, are the

first cause of mortality worldwide.

tical microbial challenge. Environmental issues such as pollution, smoking, and exposure to allergens further complicate the picture because these factors may also increase the susceptibility of the host to infectious agents.

■ Pneumonia in an immunocompromised host is difficult to

diagnose. ■ A high degree of suspicion is key to outcome. ■ Microbiologic diagnosis is slow, but new rapid DNA-based tests

are coming. ■ Pathogenesis and clinical radiographic manifestations are different

in normal and immunocompromised hosts. ■ Recent therapeutic guidelines are useful.

CLINICAL DEFINITION OF IMMUNOCOMPROMISED HOST Lower respiratory tract infections, especially pneumonia, are the first cause of mortality worldwide, killing approximately 4 million people every year. Tuberculosis kills an additional 1.8 million patients. In immunocompromised hosts, pneumonia is also the most frequent infectious disease. The definition of an immunocompromised host varies. Some authors have a very strict definition and limit it to immunosuppression induced by cytotoxic chemotherapy in patients with cancer or autoimmune diseases or who have been transplanted with solid organ or stem cell transplantation, patients with AIDS, or congenital immune defects (Stover and Rivera, 2002).1,2 Many clinicians and surgeons have a much wider definition of the immunocompromised patients and will include patients who have suffered different types of stress, including surgery, or patients who have underlying diseases such as cirrhosis, diabetes mellitus, and renal insufficiency, especially if they are on dialysis. In developing countries, for example, malnourished children or adults are highly susceptible to pneumonia and other infectious diseases and are also considered immunocompromised. For people who have these chronic underlying diseases, the threat of the pneumonia increases as their pathologic process progresses, but for those who have drug-induced immunosuppression with corticosteroids, immunomodulator agents, or anticancer chemotherapy their chance of getting infected increases with concomitant increase in the dosage of these agents. Moreover, whereas these general principles seem logical, individual susceptibility, most likely genetically defined, probably plays a major role in patients’ outcomes. In fact, no two individuals whether normal or immunocompromised respond similarly to an iden-

CLINICAL DIAGNOSIS The classic symptoms and signs of pneumonia including fever, chills, cough, pleuritic chest pain, sputum production, tachypnea, crackles, wheezes, pleural friction rub, or signs of consolidation that are often present in the normal hosts may be absent or very silent in severely immunodeficient patients. Even the appearance of radiographic features of consolidation may be absent or delayed by a few days in these populations. In fact, the clinical indicators and radiologic observations are proportional to the degree of inflammatory responses that occurs in the lung. After bacterial challenge, for example, alveoli get filled rapidly with white blood cells (mainly polymorphonuclear), which then release cytokines that irritate the lung and chemokines whose rate is to further increase the number of phagocytic cells to the site of infection (Bergeron and Bergeron, 1999, 2006)3-8 (Fig. 47-1). This accelerated mobilization of cells disturbs vascularization (vasoconstriction and/or vasodilation), which induces edema, local migration of red cells, and deposit of fibrin in the alveoli. In extreme cases one can observe at autopsy that the normal lung architecture, which is normally composed of millions of well-aerated alveoli, is replaced by very compact lung parenchyma called hepatization of the lung. Hypoxemia secondary to this exaggerated inflammatory process is the cause of death. In fact, what kills the normal host suffering from pneumonia is not the microbes themselves but this uncontrollable response to specific components of microbial cells (Bergeron and Bergeron, 1999).4 For example, teichoic acid observed in the cell wall of Streptococcus pneumoniae is an extremely potent stimulator of host defenses. In contrast to the normal individual, the immunodeficient host will react quite differently, and the local inflammation within the lung will vary enormously depending on the degree of immunosuppression and on the underlying disease. In some cases the clinical signs of pneumonia are absent and the lung may appear normal on radiography. These pneumonias are thus very difficult to diagnose, and a high degree of suspicion is needed to ensure the rapid and proper treatment of this disease. Even though bacteria or other pathogens (viruses, fungi, parasites) in this case may not be able to provoke a dramatic immune response as observed in normal subjects, the absence or decrease of defense will favor the rapid 583

Ch047-F06861.indd 583

1/21/2008 11:42:29 AM

584

Section 3 Lung

A

B

FIGURE 47-1 Histopathology of lung tissue in a murine model of pneumococcal pneumonia. A, Normal lung architecture in CD1 mice. B, Mice infected with 107 colony-forming units of Streptococcus pneumoniae serotype 3 were sacrificed 72 hours later. A, alveoli; I, interstitium; M, macrophage; N, neutrophil; P, pneumococcus cell; PP, pneumococcus cell in phagocyte; RBC, red blood cell (×1000).

multiplication of the pathogens, which may disseminate systemically and induce septicemia and invasion of other crucial organs. For example, bacteria double their population every 20 minutes. If the different lines of defense are not functioning, within 24 to 48 hours there are already billions of bacteria per gram of lung tissue; and it is through their own microbial mechanisms of invasion that pathogens will kill patients. One of the major issues we are now facing is that these patients have concomitant morbidities that further facilitate the task of microorganisms. Moreover, depending on the underlying pathology, the degree of immunosuppression, age, or past exposure to different types of infection or vaccination status, their responses to respiratory tract infections may be quite variable. Finally, our biggest challenge as clinicians is that today, as in the time of Pasteur, it still takes at least 2 days to identify microbes causing pneumonia or any other type of infectious diseases. Sometimes, as in the case of tuberculosis or some viral or fungal infection, it may take several weeks to detect the infectious agent. Empirical treatment is thus the norm, and most patients are treated with broad-spectrum antibiotics, which has induced the rapid development of antimicrobial resistance.9,10 We hope that rapid DNA-based diagnostic tests now in development will one day quickly orient management.

MICROBIAL ETIOLOGIES: PATHOGENS VERSUS TYPE OF IMMUNOSUPPRESSION It is extremely difficult to make a direct correlation between the type and degree of immunosuppression and the microbes that infect these hosts, but we can state that depending on the degree of impairment of their cellular and/or humoral

Ch047-F06861.indd 584

TABLE 47-1 Most Common Microbes Responsible for Pneumonia Nonopportunistic

Opportunistic

Bacteria

Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Pseudomonas aeruginosa Klebsiella pneumoniae Legionella species Mycobacterium tuberculosis

Nocardia species Atypical mycobacteria

Viruses

Influenza Parainfluenza Adenovirus Human metapneumovirus

Cytomegalovirus Herpes simplex Varicella-zoster

Fungi

Cryptococcus neoformans Histoplasma capsulatum Coccidioides immitis

Pneumocystis species Aspergillus species Candida species Mucor species

Parasites Toxoplasma gondii

Strongyloides stercoralis

Data from references 1, 31, 62, 65, 121, and 122.

immune function that these patients may be at a relatively greater risk for infections caused by opportunistic pathogens and/or nonopportunistic microbes (Table 47-1). Immunocompromised hosts can be classified according to the cause of their immune deficiency, whether it is cellular or humoral. Depending on their basic pathology (e.g., organ transplantation, human immunodeficiency virus/acquired immunodeficiency syndrome [HIV/AIDS]) or on the immunosuppressive drugs they are receiving, these patients may have abnormal numbers of, or functionally deficient, antigen-processing cells

1/21/2008 11:42:29 AM

Chapter 47 Pulmonary Infections in the Immunocompromised Host

or effector cells such as macrophages, neutrophils, T lymphocytes, and/or B lymphocytes. These immunodeficiencies may be associated with specific types of infectious diseases and may favor the growth of selected pathogens. For example, patients who have B-cell deficiency such as those associated with asplenia and multiple myeloma will develop pneumonia caused by encapsulated bacteria such as S. pneumoniae and Haemophilus influenzae. As shown in Table 47-2, although there are some correlations between the types of pathogens and subgroups of immunosuppressed patients, there is also great overlap, suggesting that host response is complex and that the different host response pathways and signalization process are complementary and synergistic. Clinically, it is also extremely difficult to make a correlation between the type of infiltrates on the radiograph versus the pathogens causing this infection in either normal or immunocompromised hosts. For example, mycobacteria may induce localized infiltrates, hilar or mediastinal adenopathy,

585

cavitation, pleural effusion, and/or lung nodules but several other pathogens can induce similar changes. It is thus crucial for both physicians and surgeons to be able to identify the distinctive lesions that each of the pathogens provokes (Table 47-3) and to realize that the ultimate diagnosis will be provided by a combination of procedures, including bronchoscopy, aspiration of respiratory tract secretions and/or biopsy, and sputum analysis through Gram stain, direct immunology tests, microbial culture, or nucleic acid detection methods that will progressively compete with and/or replace culture.

CLINICAL ALGORITHMS TO GUIDE PREVENTION, DIAGNOSIS, MANAGEMENT, AND TREATMENT To properly evaluate the patient with suspected lung infection, the clinician first needs to recognize whether the patient is immunocompetent or immunocompromised. The

TABLE 47-2 Patterns of Immune Deficiencies and Associated Pathogens Underlying Disease

Type of Immunosuppression

Pathogens

Inherited antibody deficiency, chronic lymphocytic leukemia, asplenia, multiple myeloma

B cells

Encapsulated bacteria (S. pneumoniae, H. influenzae)

Anticancer chemotherapy/corticosteroids

Phagocytes, T and B cells

Gram-positive and gram-negative bacteria Fungi (Aspergillus species), Pneumocystis jiroveci

Solid organ transplantation

Polymorphonuclear leukocytes (early phase) T cells (late phases)

Gram-positive and gram-negative bacteria Herpesviruses Herpesviruses (cytomegalovirus) Fungi (Aspergillus species), P. jiroveci

Stem cell transplantation

Polymorphonuclear leukocytes (early phase)

Gram-positive and gram-negative bacteria Herpesviruses Fungi (Aspergillus species) Herpesviruses (cytomegalovirus) Fungi (Aspergillus species), P. jiroveci

T cells (late phase) T cells (CD4 > 50/µL), phagocytes

HIV infection

T cells (CD4 < 50/µL), B cells, polymorphonuclear leukocytes

Gram-positive and gram-negative bacteria, Mycobacterium tuberculosis, P. jiroveci Pseudomonas aeruginosa, Aspergillus species, atypical mycobacteria

Data from references 1, 31, 62, 65, 121, and 122.

TABLE 47-3 Radiographic Features of Pulmonary Infections in the Immunocompromised Host Feature

Pathogens

Localized infiltrates (segmental or lobar)

Bacteria, Mycobacterium species (especially M. tuberculosis), fungi

Diffuse infiltrates

Pneumocystis jiroveci, viral pneumonia, adult respiratory distress syndrome (sepsis with bacteria or fungus)

Hilar or mediastinal adenopathy

Tuberculosis and atypical mycobacteria, pathogenic fungi, Cryptococcus species (occasionally)

Cavitation

Bacteria (gram-negative bacilli, anaerobes, and Nocardia, Actinomyces, and Legionella species), tuberculosis and atypical mycobacteria, septic emboli (bacterial and fungal)

Pleural effusion

Bacteria, tuberculosis, fungi (occasionally)

Nodules

Nocardia and Actinomyces species, atypical mycobacteria, opportunistic fungi (especially Aspergillus species)

Data from references 1, 31, 62, 65, 121, and 122.

Ch047-F06861.indd 585

1/21/2008 11:42:31 AM

586

Section 3 Lung

familial history, the epidemiologic context and environmental issues, the patient’s medications, and the use of hard drugs, alcohol, or cigarettes are important issues that will orient the physician and lead to a precise diagnosis of pneumonia. It is also important to distinguish between community-acquired and nosocomial infection because it will also determine therapy. Several algorithms developed by national and international societies are useful guides in the management of the patient with a pulmonary infection. The Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the management of community-acquired pneumonia in adults published in 2007 (Mandell et al, 2007)11 is the most recent and, to our knowledge, the best guide to manage pneu-

monia. Because it covers most pathogens inducing lung infections in both the immunocompetent and immunocompromised host it is an excellent guide for any clinician. Table 47-4 summarizes vaccine prevention in different populations whereas Table 47-5 is an outstanding summary of antimicrobial treatment based on the etiology of the pneumonia that should provide good guidance and facilitate the task of clinicians. For example, pneumonia can be subdivided in communityacquired pneumonia in the elderly, early- and late-onset pneumonia, as well as nosocomial health care–related pneumonia (Mandell et al, 2007; Marrie et al, 2005).11-25 In the absence of a precise identification of the microbes involved (50% of the cultures are negative), occasional clinical clues may guide the experienced clinician, who may occasionally be able to

TABLE 47-4 Recommendations for Vaccine Prevention of Community-Acquired Pneumonia Pneumococcal Polysaccharide Vaccine

Inactivated Influenza Vaccine

Live Attenuated Influenza Vaccine

Route of Administration

Intramuscular injection

Intramuscular injection

Intranasal spray

Type of Vaccine

Bacterial component (polysaccharide capsule)

Killed virus

Live virus

Recommended Groups

All persons >65 years of age

All persons >50 years of age

Healthy persons 5-49 years of age,* including health care providers and household contacts of high-risk persons

High-risk persons 2 to 64 years of age Current smokers†

High-risk persons 6 months-49 years of age Household contacts of high-risk persons Health care providers Children 6-23 months of age

Chronic cardiovascular, pulmonary, renal, or liver disease Diabetes mellitus

Chronic cardiovascular or pulmonary disease (including asthma) Chronic metabolic disease (including diabetes mellitus) Renal dysfunction Hemoglobinopathies Immunocompromising conditions/ medications Compromised respiratory function or increased aspiration risk Pregnancy Residence in a long-term care facility Aspirin therapy in persons <18 years of age

Avoid in high-risk persons

Annual revaccination

Annual revaccination

Specific High-Risk Indications for Vaccination

Cerebrospinal fluid leaks Alcoholism Asplenia Immunocompromising conditions/ medications Native Americans and Alaskan natives Long-term care facility residents

Revaccination Schedule One-time revaccination after 5 years for 1. Adults >65 years of age, if the first dose is received before age 65 years 2. Persons with asplenia 3. Immunocompromised persons

*Avoid use in persons with asthma, reactive airways disease, or other chronic disorders of the pulmonary or cardiovascular systems; persons with other underlying medical conditions, including diabetes, renal dysfunction, and hemoglobinopathies; persons with immunodeficiencies or who receive immunosuppressive therapy; children or adolescents receiving salicylates; persons with a history of Guillain-Barré syndrome; and pregnant women. † Vaccinating current smokers is recommended by the Pneumonia Guidelines Committee but is not currently an indication for vaccine according to the Advisory Committee on Immunization Practices statement. Adapted from Harper SA, Fukuda K, Uyeki TM, et al: Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 54:1-40, 2005.

Ch047-F06861.indd 586

1/21/2008 11:42:31 AM

Chapter 47 Pulmonary Infections in the Immunocompromised Host

587

TABLE 47-5 Recommended Antimicrobial Therapy for Specific Pathogens Organism

Preferred Antimicrobial(s)

Alternative Antimicrobial(s)

Streptococcus pneumoniae Penicillin nonresistant; MIC < 2 µg/mL

Penicillin G, amoxicillin

Macrolide, cephalosporins (oral [cefpodoxime, cefprozil, cefuroxime, cefdinir, cefditoren] or parenteral [cefuroxime, ceftriaxone, cefotaxime]), clindamycin, doxycycline, respiratory fluoroquinolone* Vancomycin, linezolid, high-dose amoxicillin (3 g/day with penicillin MIC ≤4 µg/mL)

Penicillin resistant; MIC ≥2 µg/mL Haemophilus influenzae Non–β-lactamase producing β-Lactamase producing Mycoplasma pneumoniae/ Chlamydophila pneumoniae Legionella species Chlamydophila psittaci Coxiella burnetii Francisella tularensis Yersinia pestis Bacillus anthracis (inhalation) Enterobacteriaceae Pseudomonas aeruginosa Burkholderia pseudomallei Acinetobacter species Staphylococcus aureus Methicillin susceptible Methicillin resistant Bordetella pertussis Anaerobe (aspiration) Influenza virus Mycobacterium tuberculosis Coccidioides species Histoplasmosis Blastomycosis

Agents chosen on the basis of susceptibility, including cefotaxime, ceftriaxone, fluoroquinolone Amoxicillin Second- or third-generation cephalosporin, amoxicillin-clavulanate Macrolide, a tetracycline

Fluoroquinolone, doxycycline, azithromycin, clarithromycin† Fluoroquinolone, doxycycline, azithromycin, clarithromycin† Fluoroquinolone

Fluoroquinolone, azithromycin A tetracycline A tetracycline Doxycycline Streptomycin, gentamicin Ciprofloxacin, levofloxacin, doxycycline (usually with second agent) Third-generation cephalosporin, carbapenem‡ (drug of choice if extended-spectrum β-lactamase producer) Antipseudomonal β-lactam|| plus (ciprofloxacin or levofloxacin¶ or aminoglycoside) Carbapenem, ceftazidime Carbapenem

Doxycycline Macrolide Macrolide Gentamicin, streptomycin Doxycycline, fluoroquinolone Other fluoroquinolones; β-lactam, if susceptible; rifampin; clindamycin; chloramphenicol β-Lactam/β-lactamase inhibitor,§ fluoroquinolone

Antistaphylococcal penicillin** Vancomycin or linezolid Macrolide β-Lactam/β-lactamase inhibitor,§ clindamycin Oseltamivir or zanamivir Isoniazid plus rifampin plus ethambutol plus pyrazinamide For uncomplicated infection in a normal host, no therapy generally recommended; for therapy, itraconazole, fluconazole Itraconazole Itraconazole

Cefazolin, clindamycin TMP-SMX TMP-SMX Carbapenem

Aminoglycoside plus (ciprofloxacin or levofloxacin¶) Fluoroquinolone, TMP-SMX Cephalosporin-aminoglycoside, ampicillin-sulbactam, colistin

Refer to reference 124 for specific recommendations Amphotericin B Amphotericin B Amphotericin B

Note: Choices should be modified on the basis of susceptibility test results and advice from local specialists. Refer to local references for appropriate doses. *Levofloxacin, moxifloxacin, gemifloxacin (not a first-line choice for penicillin-susceptible strains); ciprofloxacin is appropriate for Legionella and most gram-negative bacilli (including H. influenzae). † Azithromycin is more active in vitro than clarithromycin for H. influenzae. ‡ Imipenem-cilastatin, meropenem, ertapenem. § Piperacillin-tazobactam for gram-negative bacilli, ticarcillin-clavulanate, ampicillin-sulbactam, or amoxicillin-clavulanate. || Ticarcillin, piperacillin, ceftazidime, cefepime, aztreonam, imipenem, meropenem. ¶ 750 mg daily. **Nafcillin, oxacillin, flucloxacillin. ATS, American Thoracic Society; CDC, Centers for Disease Control and Prevention; IDSA, Infectious Diseases Society of America; MIC, minimal inhibitory concentration; TMP-SMX, trimethoprim-sulfamethoxazole. From Mandell LA, Wunderink RG, Anzueto A, et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27-S72, 2007.

guess with a certain level of confidence the microbes involved. For example, patients with B-cell dysfunction are more likely to be infected by S. pneumoniae and H. influenzae whereas tuberculosis is associated with patients having T-cell dysfunction and infection with Pseudomonas aeruginosa is a late complication of HIV infection. Invasion of the lung of neutropenic patients by Aspergillus will cause cavitation and will

appear on a radiograph as patchy infiltrates along pulmonary vessels, whereas apical and cavitating infiltrates in patients with chronic obstructive pulmonary disease (COPD) on corticosteroids will suggest tuberculosis or chronic necrotizing aspergillosis. Interstitial infiltrates are associated with atypical bacteria (e.g., legionellosis, Mycoplasma infection) or respiratory virus, but in solid-organ transplant patients receiving

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 587

1/21/2008 11:42:31 AM

588

Section 3 Lung

intensive immunosuppression they indicate cytomegalovirus pneumonitis.

PATHOGEN VERSUS DIAGNOSTIC PROCEDURES A high level of suspicion is the best guide to orient the investigation of pneumonia in the immunocompromised host. Because expectoration and sputum are often absent and parenchymal lesions are not always present on a radiograph, physicians and/or surgeons must rely on their experience and clinical intuition. Fiberoptic bronchoscopy designed and developed by Shigeto Ikeda in Tokyo in 1967 has revolutionized the diagnostis of pneumonia especially in these populations. Because it can also be performed in patients on mechanical ventilation1 and has few complications, this procedure is safe and practical. The diagnostic steps needed for investigating patients with suspected respiratory disease include imaging studies and laboratory in vitro tests (cultures, pulmonary function tests, and gas exchange).26,27 Routine chest radiography is an essential part of the diagnostic evaluation of pneumonia. Computed tomography (CT) offers several advantages over routine chest radiography because the use of cross-sectional images facilitates the distinction between densities that would be superimposed on plain radiographs and subtle differences between adjacent structures,28-31 but its routine use is not recommended. Magnetic resonance imaging (MRI) is not as precise as CT, and its usefulness is limited. Pulmonary angiography and scintigraphy are used for evaluation of pulmonary embolism, and positron emission tomographic (PET) scanning is useful to identify malignant lesions of the lung. Bronchoscopy allows the visualization of all airways down to the level of segmental bronchi and to sample by washing, brushing, or biopsy any lesion for analysis of cellular material or tissue.32 When necessary, percutaneous needle aspiration guided by CT can be done to aspirate material for analysis. On rare occasion, thoracocentesis can be done to sample large pleural effusion. To avoid open-lung biopsy, video-assisted thoracoscopic surgery (VATS) is now becoming a useful tool to perform biopsy under direct vision.

FROM PASTEUR MICROBIOLOGY TO RAPID NUCLEIC ACID DIAGNOSTIC TESTS Although over the past 40 years bronchoscopy, brushing, alveolar lavage, and imaging technologies have evolved to ensure the quality of the clinical samples (sputum, bronchial secretions) and to improve the diagnosis of pneumonia, microbial diagnostics has not evolved. In fact, today we are still using the same microbiologic methods initially developed by Louis Pasteur more than 140 years ago. Beside a few rapid techniques such as Gram’s stain that orient as to whether there is a gram-positive or a gram-negative microorganism (but do not specifically identify the pathogens) and a few immunologic tests to identify rapidly Legionella pneumophila and Pneumocystis jiroveci, the identification of most microorganisms takes a minimum of 48 hours and for certain microbes such as Mycobacterium tuberculosis it takes several weeks.

Contrary to other medical diagnostic disciplines (e.g., biochemistry, hematology, and radiology), which can provide within 1 hour accurate in-vitro diagnostic results, microbiology, which has evolved technically to robotize its systems, does not in general provide immediate answers that could be useful to the clinician. This 48-hour delay between clinical sampling and results is a critical time period during which microbial pathogens may cause irreversible damage that could be fatal. Diagnostic uncertainty also increases the risk of disease transmission to other patients and health care workers. In addition, the availability of broad-spectrum antimicrobial agents in the absence of rapid diagnosis has favored the installment of empirical treatment practices that significantly impacted on the content and constant evolution of antimicrobial resistance genes of causal pathogens, leading to increasing health care costs but, most importantly, to dramatic treatment outcomes and failures for diseases once considered benign. For life-threatening infections such as pneumonia in the immunocompromised host, time to treatment is critical for appropriate patient management. The maturation of recombinant technology and bioinformatics has provoked the burgeoning of theranostics, a new concept in which rapid diagnostics serves to guide and accelerate therapy (Bissonette and Bergeron, 2006).33 This is especially important for infectious diseases. For the past 15 years or so, the advent of faster and more sensitive molecular medicine assays occurred mainly in the form of “home-brew” nucleic acid–based amplification methods that are complementing or gradually replacing somewhat lengthy and cumbersome conventional microbiologic and serologic gold standard methods. Molecular microbiology tests provide key additional weaponry to alleviate the burden of infectious diseases and rapidly detect pathogens or groups of pathogens associated to an infection. For classic polymerase chain reaction (PCR)–based molecular amplification methods, however, the advantages offered by their exquisite sensitivity constitute a (paradoxical) source of false-positive results. The performance paradox of nucleic acid–based tests was partially resolved when real-time PCR technology (enabling the detection of amplification products without opening the reaction vessels to conduct gel electrophoresis) reached the life science laboratories. The true clinical potential of this technology for molecular diagnostics was first demonstrated by Dr. Michel G. Bergeron from Université Laval in Quebec City. The first two rapid DNA-based tests developed in his laboratory, IDIStrep B and IDI-MRSA, diagnostic tests of Infectio Diagnostic Inc. (now B-D Diagnostics–GeneOhm), were approved by the U.S. Food and Drug Administration (FDA) in 2002 and 2004, respectively.34,35 This is a real clinical revolution because these theranostic assays allow the detection of microbes within 1 hour, thereby permitting the clinician to manage and/or treat patients rapidly without having to treat empirically while waiting for a minimum of 2 days for culture results. There are not yet rapid FDA-approved real-time PCR tests for respiratory tract infections. There are multiple situations in which a disease could be caused by more than one microbe, such as bloodstream, respiratory tract, or many other infections. Real-time PCR is a great technology but has limitations for the development

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 588

1/21/2008 11:42:31 AM

Chapter 47 Pulmonary Infections in the Immunocompromised Host

of multiparametric assays required for the detection of multiple microbial genes, either from virus, bacteria, fungi, or parasites. Ideally, a unique test should be performed for identification of a panel of potential microorganisms. To address this need, the microarray technology was elevated as the next tool of choice for molecular diagnostics and, in December 2004, Roche Molecular Diagnostic’s AmpliChip CYP450 became the first microarray-based genotyping test approved by the FDA (Bissonnette and Bergeron, 2006).33 For commercially available nucleic acid tests, the number of experimental steps may vary from 5 to more than 60, thereby imposing major challenges to assay developers who must design extremely compact analytical systems offering an equivalent performance. To conceptually mimic real-time PCR and bring diagnostic technologies closer to the bedside, several multidisciplinary teams of academic and industrial researchers have undertaken the development of microfluidic laboratories-on-a-chip. These miniaturized platforms, derived from approaches of the semiconductor industry, may contain chambers for cell separation, cell lysis, molecular amplification, chemical or enzymatic modification, macromolecular separation, or oligodeoxyribonucleotide microarray hybridization (Bissonnette and Bergeron, 2006).33 These chambers are interconnected by microchannels through which biologic fluids and reagents are transported. The lab-on-a-chip concept evolves mainly through the convergence of advances in the fields of microfabrication, microfluidics, surface chemistry, microarrays, biosensor chemistry, and nanotechnology. It is aimed at designing integrated, easy-to-use, and economical biologic detection devices. The next generation of DNAbased tests will include “compact disks” (CDs) for identification of microbes within minutes at the point of care. It will be achieved shortly and will revolutionize the clinical practice in infectious diseases, enabling multiparametric genetic evaluation of several medical conditions in an integrated view of personalized medicine (Peytavi et al, 2005).36

BACTERIAL PNEUMONIA Immunocompromised people who have B-cell or granulocyte defects (hence, low antibody production and reduced phagocytic efficacy) are particularly vulnerable to common bacterial pathogens encountered in immunocompetent hosts. They are quite susceptible to gram-negative organisms such as H. influenzae, P. aeruginosa, Escherichia coli, and Klebsiella species. However, clinicians have observed a noticeable increase in the recovery of gram-positive organisms in neutropenic patients over the past decade, particularly pneumonia induced by S. pneumoniae. In the setting of granulocytopenia, the usual clinical signs and symptoms of bacterial pneumonia may be atypical or absent. Sputum production is seen in fewer than 60% of cases, and fever is observed in almost 100% of cases; however, the chest radiograph is abnormal in 95% of cases and commonly shows localized infiltrates (Stover and Rivera, 2002).1 The incidence of bacteremia is high, and because bacterial pneumonias in immunocompromised patients may progress rapidly, empirical broad-spectrum antibiotic coverage should be initiated as soon as the diagnosis is suspected.

589

Immunocompromised patients are also susceptible to atypical bacterial pneumonias induced by Legionella and Mycoplasma species. Although community-acquired outbreaks of Legionnaires’ disease have been reported in these patients, infection is more commonly acquired from a nosocomial source.1,37 The diagnosis of infections by Legionella species is difficult to make in immunocompromised patients. It can be made after culture of the organism (from the respiratory tract, blood, tissue, or pleural fluid), but direct fluorescence antibody staining tests are quicker and clinically more applicable. Macrolides are the drugs of choice because they can kill Legionella intracellularly by entering alveolar macrophages. Severe pulmonary disease by Mycoplasma pneumoniae is also seen in patients with antibody deficiencies and in those with chemotherapy for cancer. Clinical manifestations include headache, fever, myalgias, loss of appetite, sore throat, and a dry cough. Radiographic findings often show patchy or reticular interstitial infiltrates in the lower lobe. However, the culture of Mycoplasma species is not made in all laboratories and patients are often treated empirically.

Sequential Pathogenesis of Pneumococcal Pneumonia in Immunocompetent and Immunosuppressed Hosts Streptococcus pneumoniae remains the most threatening bacteria responsible for acute lower respiratory tract infections throughout the world. Death still occurs despite complete bacterial eradication with potent antibiotics. In fact, the persistence of this deadly infection in both immunosuppressed and immunocompetent hosts, the profound problem posed by childhood pneumonia in developing countries, and the widespread emergence of multi-resistant strains throughout the world emphasize the importance of acquiring a better understanding of the mechanisms by which this formidable pathogen causes disease. Why does pneumococcus kill? There is evidence that many bacterial virulence factors and host immune response together contribute significantly to the outcome of pneumonia: whereas immunosuppressed patients die as a consequence of poor host response, immunocompetent hosts face overwhelming inflammatory reactions that contribute to tissue injury, shock, and death (Bergeron and Bergeron, 1999).4 The colonization of airways, development of pneumonia and bacteremia, cellular and humoral responses, and release of inflammatory mediators are all elements that need to be documented from the initial infection to death to properly elaborate preventive and therapeutic strategies with more effective vaccines, clinical markers of evolution of the pathology, antibiotics, and immunomodulator drugs that will control the bacteria and its toxins and optimize host response. To characterize the chronology of events associated with fatal pneumococcal pneumonia, Bergeron and colleagues (Bergeron and Bergeron, 2006; Bergeron and Bergeron, 1999)3-6,8,38-49 developed a murine model to follow the steps in pathogenesis from the initial infection to death in immunocompetent and immunosuppressed mice. In these sequential studies, correlations were made between cytokine levels within lung tissue, bronchoalveolar lavage (BAL) fluid, and

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 589

1/21/2008 11:42:32 AM

590

Section 3 Lung

serum simultaneously, time course of the disease, and outcome of pneumonia and sepsis in mice infected with various sizes of inocula of penicillin-susceptible or -resistant strains, treated with either antibiotics alone or combined with immunomodulator drugs. The chronology of inflammatory cell infiltration in lungs, the kinetics of cytokines/chemokines and nitric oxide release, as well as histopathology during pneumococcal pneumonia were reported. Overall, these studies revealed very different patterns of cytokine/ chemokine expression in tissues and fluids over time as infection progresses toward resolution or fatal outcome. In fatal pneumonia, five steps were described: 1. The bacterial load in lungs decreased over the first 4 hours of infection, when phagocytic alveolar macrophages constituted more than 90% of the inflammatory cells recovered in BAL fluid, and early cytokine release included tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 in BAL fluid and lung tissue, and IL-6 in blood. 2. Rapid bacterial growth followed from 4 to 24 hours, associated with peak secretion of CXC chemokines (KC and MIP-2, which are chemoattractant for polymorphonuclear leukocytes [PMNs]) and rapid PMN emigration into the lungs and BAL fluid, which reached a plateau thereafter. 3. The first histopathologic signs of lung injury appeared from 24 to 48 hours, characterized by tissue edema and enhanced secretion of surfactant by type II pneumocytes and bacterial proliferation in tissues. 4. The 48- to 72-hour period was characterized by peak secretion of C-C chemokines (MIP-1α and MCP-1, which are chemoattractant for monocytes), strong monocyte emigration into the lungs that coincided closely with the kinetics of nitric oxide release, as well as bacteremia and peak blood levels of TNF. 5. The 72- to 96-hour period was characterized by enhanced tissue injury (disorganization of lung architecture, lipid peroxidation, proliferation of type II pneumocytes), lymphocyte emigration into the lungs and BAL fluid, leukopenia, respiratory distress, body weight loss, shock, and death. There was a direct correlation between bacteremia and death. The pathogenesis of pneumococcal pneumonia was also investigated in mice rendered leukopenic by the immunosuppressor antineoplastic drug cyclophosphamide.39 The high mortality rate in leukopenic patients occurs at an early stage of the infection and has been associated with signs and symptoms that resemble those in acute respiratory distress syndrome.50 In the mouse model, cyclophosphamide-induced leukopenia did not prevent IL-1, IL-6, MIP-1α, MIP-2, and MCP-1 production in infected lungs. In fact, proinflammatory cytokine and chemokine levels in severely leukocytedeprived lungs were consistently equivalent to those found in lungs of immunocompetent mice that are filled with leukocytes. It is likely that alveolar epithelium and endothelium as well as pulmonary interstitial cells and some undepleted resident alveolar macrophages were capable of producing appreciable amounts of cytokines and chemokines on stimulation by pneumococcal toxins. By contrast, leukocyte depletion significantly reduced nitric oxide release in BAL fluid

during the late stage of pneumonia, suggesting that monocytes/macrophages recruited into the lungs could be a major source of nitric oxide production in pneumonia. Surprisingly, leukopenia did not facilitate bacterial dissemination into the bloodstream despite enhanced bacterial proliferation into lung tissues. Apparently, lungs could be a more susceptible target than blood for pneumococci in cyclophosphamide-treated patients. At early stage of pneumonia, the vascular permeability observed in the lungs of immunocompetent mice was higher than that observed in leukopenic animals, suggesting it was related to neutrophil activity (which differed greatly between immunocompetent and leukopenic mice) rather than to bacterial virulence factors because bacterial counts did not differ between groups early after infection. This observation corroborates the limited pulmonary PMN infiltration and edema observed on radiographs on leukopenic patients at an early stage of pneumonia. By contrast, high vascular permeability and edema were observed at later stages of pneumonia in leukopenic mice, at times when PMN counts were still very low in lungs, suggesting that neutrophils are ultimately not required for lung injury and that bacterial virulence factors prevail for lung injury when bacteria proliferate in immunosuppressed hosts. Scanning and transmission electron microscopy revealed extensive disruption of alveolar epithelium and a defect in surfactant production, which were associated with alveolar collapse, hemorrhage, and fibrin deposits in alveoli. These results contrasted to those observed in immunocompetent animals and suggested that leukopenic hosts suffering from pneumococcal pneumonia are at a higher risk of developing diffuse alveolar damage. One of the benefits of such experimental pathogenesis studies is that they will help identify clinical markers of pneumonia that could be converted in specific host response rapid diagnostic tests that will in the future orient therapy with immunomodulator drugs to be used in combination with antibiotics.

Antibiotic Therapy and Immunotherapy, Including Corticosteroids Guidelines for the management of community-acquired pneumonia in immunocompetent adults can easily be accessed from the literature. Among the groups that have established treatment guidelines for community-acquired pneumonia are the American Thoracic Society (ATS), the Infectious Diseases Society of America (IDSA), and the Centers for Disease Control and Prevention (CDC) (Mandell et al, 2007).11,12,16,23 The most recent guidelines are shown in Table 47-5. By contrast, guidelines for the treatment of immunocompromised patients with pneumonia are rather scarce. Moreover, because the resistance to multiple antibiotics increases worldwide, it becomes progressively more difficult to treat pneumonia in immunocompromised and hospitalized patients. Anti-infectious agents that have new modes of action are needed urgently. In the past few years, genes that are required for either virulence or pathogenesis have been targeted.51-53 The most promising alternative treatments for pneumonia that are under development are interfering with bacterial adhesion; inhibiting, neutralizing, and clearing endotoxin; and administering cytokines as immunoadjuvants. In fact, a

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 590

1/21/2008 11:42:32 AM

Chapter 47 Pulmonary Infections in the Immunocompromised Host

diverse array of recombinant, synthetic, and natural immunomodulatory preparations for prophylaxis and treatment of various infections are available. Some of these substances, such as hematopoietic growth factors, interferons, interleukins, monoclonal antibodies, soluble receptors, and bacterialderived preparations are already licensed for use in patients (Wunderink, 2006).54-59 Other compounds are being investigated extensively in clinical and preclinical studies, including sodium nitroprusside, a nitric oxide donor that was recently shown to promote pneumococcal killing, thus reducing inflammation and improving blood oxygenation and survival rate in experimental pneumonia.48 Most therapeutic strategies aimed at modulating cytokine activity thus far have focused on selective downregulation of the inflammatory response in patients with sepsis. Tested compounds included bradykinin/kallikrein antagonists, antiTNFα antibodies, soluble TNF receptors, IL-1 receptor antagonists, platelet-activating factor antagonists, and other inhibitors.60,61 In general, despite numerous clinical trials in a large number of patients, these investigative approaches have not met with success. TNFα is a key mediator in the host defense response to a variety of infectious pathogens; therefore, one might assume that this cytokine should be a potential agent for immunotherapy. In fact, neutralization of TNFα has emerged in recent years as an advance in the treatment of rheumatoid arthritis, Crohn’s disease, and several systemic noninfectious inflammatory diseases (Ewig, 2006).62 However, TNFα antagonists and antibodies have been associated with an increased risk of tuberculosis, histoplasmosis, listeriosis, aspergillosis, coccidioidomycosis, and candidiasis (Gennery and Cant, 2005).63-65 As for the systemic administration of TNFα, it was associated with significant toxicity and poor penetration into the lung.66 To avoid systemic complications, researchers have investigated the intrapulmonary delivery of TNF70-80, a peptide that possesses many of the leukocyteactivating properties of TNFα without the associated toxicity, and they found it to improve survival of mice from Klebsiella pneumoniae pneumonia.51 The hypothesis that restoration or amplification of the immune system of the host would be an appropriate strategy in selected patients with serious infections has also been tested. Granulocyte, granulocyte-macrophage, and macrophage colony-stimulating factors (G-CSF, GM-CSF, MCSF), TNFα, interferon gamma (IFNγ), and IL-12 have received increasing attention as potential adjuvant drugs for the treatment of pneumonia in preclinical and clinical studies.50-52,67,68 Exogenous administration of recombinant GCSF has found extensive use in the treatment of febrile neutropenia.54 G-CSF was also studied in large clinical trials in non-neutropenic patients with either community-acquired pneumonia or hospital-acquired pneumonia, complicated or not with sepsis.50,69-72 The addition of G-CSF to the antibiotic and supportive care treatment appeared to be safe but not efficacious in reducing mortality rates in these patients. How can we explain that several immunomodulating agents failed to improve outcome in clinical trials while so many agents have been found effective in preclinical sepsis and pneumonia models?44,67,70,73 Nelson and associates54,55 suggested that, unlike the clinical situation, most of the preclinical models

591

are devoid of a localized infectious source from which the infection disseminates. For example, in animal models, intravenous administration of bacteria is achieved, which is likely to induce a quite different pattern of inflammation than clinical sepsis. Sequential pathogenesis studies in immunocompetent and immunocompromised patients are therefore needed to find out relevant markers of the evolution of pneumonia and to select the appropriate immunonoadjuvant to administer, in combination with an antimicrobial drug. The Th1-related cytokines were recently proposed as potential candidates for the treatment of difficult pathogens. IFNγ and IL-12 were shown to be effective against Mycobacterium tuberculosis and Cryptococcus neoformans.74,75 The effect of IL-12 further extends to humoral immunity, especially mucosal immunity. This is interesting for the development of vaccines that might produce secretory IgA or IgG antibodies on the surface of the nasopharynx and airways.76 Intranasal vaccination in the presence of IL-12 was shown to enhance systemic and mucosal immune responses to pneumococci and efficiently protected against both invasive infection and bacterial carriage.77 Other cytokines are being investigated in animals to verify their potential usefulness in human respiratory tract infections.41,42,57 The relationship between the cytokine profile and the clinical outcome in pneumonia remains unclear, owing to the complexity of the cytokine and the chemokine networks (Bergeron and Bergeron 1999; 2006).3-6,38,39,43 The activation and inhibition of the cytokine network vary as the infection progresses toward severity or resolution.78,79 As for systemic corticosteroids, they are widely used across many medical disciplines and they may induce deleterious effects when acting as immunosuppressor drugs, being a risk factor for lung infections induced by gram-positive and gramnegative bacteria, tuberculosis, and fungal infections (particularly Aspergillus species).80,81 By contrast, they can also exert potential benefits when used in immunocompetent hosts suffering from severe pneumonia. In fact, one of the most determinant factors influencing the evolution of pneumonia is the specific inflammatory response of the host. The concentrations of proinflammatory and anti-inflammatory interleukins in the blood and lungs correlate with different severity scores in severe pneumonia, and treatment with low doses of hydrocortisone was recently shown to reduce morbidity and mortality by downregulating the associated inflammatory response.82 Future studies should elucidate which patients can potentially benefit from corticosteroids and what treatment regimen is optimal to create an appropriate balance between the beneficial and harmful effects of the inflammatory response. The risk of developing infectious complications after therapy with prednisone seems to be dose dependent: patients taking systemic corticosteroids are at a relevant risk for infections with opportunistic pathogens when dosages exceed a certain level.83 The diagnosis of opportunistic lung infections is frequently delayed in patients taking corticosteroids because an aggressive workup for such infections is not always undertaken. It is also important to recognize that systemic corticosteroids frequently prevent fever as a main symptom of infectious complications.

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 591

1/21/2008 11:42:32 AM

592

Section 3 Lung

MYCOBACTERIAL PNEUMONIA The prevalence of tuberculosis is reported to be higher in immunocompromised patients, particularly those with lung cancer, lymphoproliferative disorders, and HIV infection (Stover and Rivera, 2002).1,84 In those patients, tuberculosis develops rapidly after reactivation of a latent pulmonary infection. The symptoms and signs are nonspecific and are often attributed to the concomitant pathology, which delays the diagnosis. Chest radiographs show the typical upper lobe cavitation, but nodules that mimic cancer also occur. Opportunistic infections such as histoplasmosis, nocardiosis, and cryptococcosis are also diagnostic possibilities in patients with tuberculosis and nodular infiltrates. Pulmonary tuberculosis can be confirmed in most cases by sputum examination, but bronchoscopy may be necessary in some patients. This technique has been reported to have a diagnostic yield of more than 90% for the diagnosis of tuberculosis in immunocompromised hosts (Stover and Rivera, 2002).1 Tuberculosis in HIV-infected persons also results primarily from reactivation of a latent infection (Stover and Rivera, 2002).1 The highest incidence occurs in those with positive tuberculin skin tests or known tuberculosis exposure such as immigrants from countries with endemic tuberculosis. Since M. tuberculosis is a more virulent organism than opportunistic pathogens, it tends to occur earlier in the course of HIV disease, often coinciding with the diagnosis of AIDS. If Thelper lymphocytes are still high, the disease may present clinically in a manner similar to that of tuberculosis in the immunocompetent patient, with classic findings of upper lobe infiltrates (with or without cavitation). When tuberculosis develops later in the course of HIV, it tends to present atypically, with nonspecific signs and symptoms, which may cause a delay in diagnosis and initiation of appropriate therapy. Fever is the most common symptom because it occurs in approximately 90% of cases. Night sweats, cough, sputum production, and dyspnea are common. In severely HIVinfected immunosuppressed patients, radiographs reveal diffuse infiltrates; intrathoracic adenopathy, with or without infiltrates; and pleural effusions. Generally, therapy for tuberculosis is similar and equally effective in the HIV-infected host and in the normal population. In cases of multiple-drug resistance, drug regimens are individualized and are based on patterns of drug sensitivity within particular areas.

VIRAL PNEUMONIA Viruses are an important cause of pneumonia in patients whose immune systems have been weakened, especially those with deficiencies of cellular immunity. Three herpesviruses— cytomegalovirus (CMV), herpes simplex (HSV), and varicella-zoster—commonly cause respiratory tract infections in immunocompromised patients, and severe morbidity and death can occur during primary infection or reactivation of herpesviruses.85,86 Respiratory syncytial virus (RSV), rhinovirus, adenovirus, influenza A virus, and measles virus are also significant causes of respiratory disease in this population.87-90 An overview of the detection methods and antiviral treatments for common viral respiratory pathogens in the immunocompromised host has been published.65

Cytomegalovirus pneumonia is a significant cause of morbidity and death in bone marrow transplant recipients. CMV may be reactivated in the host, or it may be transmitted in donor marrow or by transfusion of blood products (Stover and Rivera, 2002).1 It manifests itself by interstitial pneumonitis that begins 8 to 12 weeks after bone marrow transplantation. The clinical signs, symptoms, and radiographic findings of CMV pneumonia are nonspecific and indistinguishable from those of other common pneumonias seen in this patient population. Because of the ubiquity of the organism, CMV pneumonia is often difficult to document. Diagnosis is based on clinical and radiographic evidence of interstitial pneumonia, when CMV antigens are detected in alveolar macrophages or epithelial cells obtained by BAL, or when CMV is isolated by culture from BAL fluid or lung tissue. Unlike the situation in bone marrow transplantation, the degree to which solid organ recipients experience CMV-associated illness is related to whether the infection is primary or is a reactivation of a previous infection. The incidence of symptomatic disease is higher in those with primary CMV infection.91 Ganciclovir is the drug of choice for treatment of CMV disease in the solid organ transplant recipient, and most episodes of CMV pneumonia respond to a 2- to 3-week course of therapy (Stover and Rivera, 2002).1,65 Foscarnet is a good alternative for ganciclovir-resistant infection. Herpes simplex virus is a common cause of mucocutaneous disease in immunocompromised patients, but lung involvement is uncommon.1 Nevertheless, tracheobronchitis and bronchopneumonia have been noted. Cough, dyspnea, and fever are common symptoms. Chest radiographs that show focal lesions are an indication of oropharyngeal aspiration of organisms into the lung, whereas diffuse infiltrates correlate with hematogenous spread to the lung. The diagnosis of pulmonary infection by HSV is based on isolation of the organism from respiratory specimens in the absence of contamination by oral or upper airway lesions. Acyclovir is the recommended antiviral drug for therapy of HSV. Varicella-zoster virus is a highly contagious herpesvirus infection, and both primary and reactivated varicella can be a devastating illness in immunocompromised hosts. The histologic and cytologic features of varicella pneumonia are identical to those of herpes simplex virus, but the diagnosis of varicella pneumonia is generally easier because the symptoms occur 3 to 7 days after the onset of cutaneous lesions. Therapy with acyclovir is recommended in both immunocompetent and immunocompromised patients because of the high mortality rate involved. Respiratory syncytial virus (RSV) is an unusual but very important member of the paramyxovirus group. In cell cultures it readily induces large syncytia with cytoplasmic inclusions, hence its name. It is the most frequent reason for hospitalization of infants in developed countries. Premature birth without or, especially, with chronic lung disease of prematurity, congenital heart disease, and T-cell immunodeficiency are conditions that predispose to more severe forms of RSV infection. RSV pneumonia can occur in immunocompromised children as well as adolescents and adults, particularly transplant recipients.87,88,90 Epidemics occur in late fall and spring. The clinical presentation of RSV in HIV-infected

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 592

1/21/2008 11:42:32 AM

Chapter 47 Pulmonary Infections in the Immunocompromised Host

persons is similar to its presentation in individuals without HIV infection. Cough is invariably present, and chest radiographs usually show bilateral infiltrates. RSV can be isolated from respiratory secretions, throat swabs, or nasooropharyngeal washes. Ribavirin, which is the treatment of choice, has given varying results. Human rhinoviruses are the most common cause of upper respiratory tract infections in both adults and children. Rhinoviruses belong to the Picornavirus family, for which more than 100 serotypes have been shown to be responsible for about 50% of common colds. Increasing evidence indicates that rhinovirus infections are associated with lower respiratory tract involvement and severe disease in iatrogenically immunocompromised hosts, particularly transplant recipients. A retrospective analysis of 431 virus-positive BAL or bronchial biopsy cultures over a 10-year period at an academic medical center identified 7% that were rhinovirus positive, representing the third most common virus detected after cytomegalovirus (64%) and herpes simplex virus (21%).92

FUNGAL PNEUMONIA Fungi are ubiquitous in nature, and the respiratory tract is exposed to aerosolized spores of fungi that are pathogenic even in the normal host, such as Cryptococcus, Histoplasma, Coccidioides, and Blastomyces species, and opportunistic, such as Candida and Aspergillus species, among others.93,94 Opportunistic fungi have emerged during the past decade as important causes of morbidity in immunocompromised patients.95,96 In fact, fungal infections of the lung are among the most feared infections occurring in these patients because they have historically been associated with extremely high mortality. Aspergillus species are the most common infectious cause of pneumonic mortality in bone marrow/stem cell transplant recipients, and Candida species constitute the third to fourth most common causes of nosocomial bloodstream infections. An increasing number of different members of the class of Zygomycetes are reported as causing lethal infections, despite aggressive medical and surgical interventions. Patients who have primarily T cell defects are more often infected by Cryptococcus species and the endemic fungi, such as species of Histoplasma, Coccidioides, and Blastomyces, which have been reported to expand rapidly in response to environmental exposures and increased numbers of vulnerable hosts in endemic regions of the world. An increasing number of patients that must remain in intensive care units for long periods of time also experience invasive fungal infections. As we enter the third millennium, it is expected that emergent fungal infections will continue to develop in the expanding population of immunocompromised hosts.95 Pneumocystis jiroveci has been recognized for more than 60 years as a cause of severe pneumonia in immunocompromised hosts, especially those with B and T cell deficiencies, but it attracted particular attention in the scientific community since the emergence of the HIV infection (Stover and Rivera, 2002).1,97 The organism is found in all mammalian species on every continent, but research has been hampered

593

by the inability to grow it in vitro. Asymptomatic infection is thought to occur early in life in normal hosts, but active pneumonia occurs when an infected individual becomes immunosuppressed months or years after the primary infection. Nonproductive cough, dyspnea, and fever are the typical symptoms usually observed. It can be subclinical or chronic in HIV-infected patients or rapidly progressive in patients with cancer or transplants.1,98 In fact, progressive involvement of the lungs culminates in death if it is untreated. Routine laboratory and radiographic studies do not provide specific information about the diagnosis of P. jiroveci. The typical radiographic appearance is that of diffuse bilateral, symmetrical, interstitial infiltrates, which progress to alveolar infiltrates as the disease worsens. The diagnosis can be established by demonstrating the organism in respiratory secretions or body tissues, and bronchoscopic diagnosis is more sensitive than induced sputum to achieve this goal, especially in non– HIV-infected patients who have a lower burden of organisms than HIV-infected ones. Conventional drugs that have been extensively used for the therapy of P. jiroveci are trimethoprim-sulfamethoxazole and parenterally administered pentamidine. Aspergillus species are ubiquitous fungi commonly found in soil, water, and spoiled vegetables. Aspergillus fumigatus and A. flavus are the most common species that cause disease in humans, and patients at highest risk for invasive pulmonary aspergillosis are those with prolonged neutropenia, those receiving chronic corticosteroids or chemotherapy, and those with a prior episode of pneumonia caused by Aspergillus.1 Infections with Aspergillus are difficult to diagnose and to treat effectively. Infection commonly presents as an invasive necrotizing pneumonitis in an immunocompromised patient because of its propensity to erode blood vessels. The clinical features include fever, dyspnea, nonproductive cough, and acute pleuritic chest pain. Often, the only evidence of the presence of an Aspergillus species is prolonged fever with pulmonary infiltrates that do not respond to antibiotics. The earliest radiographic manifestation of invasive aspergillosis may be the presence of a single nodule or multiple nodules that progress to show cavitation and then areas of homogeneous consolidation. Because noninvasive tests lack specificity and sensitivity, invasive techniques are the most effective way to establish a diagnosis of pulmonary aspergillosis, and empirical therapy with antifungal drugs is recommended. Fortunately, the most significant advance in the last 2 to 3 years concerning fungal pneumonia has been the management of aspergillosis.99,100 This includes the detection of Aspergillus galactomannan by enzyme immunoabsorbent assay in recipients of allogeneic hematopoietic stem cell transplantation.101 The sequential pathogenesis of pulmonary aspergillosis was studied and the role of inflammatory cytokines in host response to A. fumigatus was characterized in immunocompetent and immunosuppressed mice.102 Two distinct phases were observed in immunocompetent mice. First, an intense clearance of A. fumigatus occurred, possibly through alveolar macrophages and recruited neutrophils, accompanied by rapid release of TNF-α, IL-6, and IL-1β, and, second, cellular and fungal debris was cleaned by recruited monocytes, cytokine production rapidly decreased, and pneumonia

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 593

1/21/2008 11:42:32 AM

594

Section 3 Lung

self-healed. In contrast, cortisone-treated animals had, first, an altered clearance of conidia and delayed cytokine production and inflammatory cell recruitment; second, an invasive process in lungs, recruitment of neutrophils, and release of IL-6 and IL-1β; and, third, widespread tissue necrosis, sustained release of IL-6 and IL-1β, further increases in neutrophil trafficking but no monocyte recruitment, respiratory failure, and 100% mortality within 5 days. Mucormycoses, which are induced mainly by the genera Mucor, Absidia, and Rhizopus, are uncommon infections in immunocompromised patients. However, since they share several common clinical and histologic features with Aspergillus species (especially their predilection for infecting the lung and vasculature), they should be considered as potential invasive pathogens, especially if they are found in sputum.1 Invasive candidiasis sometimes occur also in immunocompromised hosts because these organisms are part of the human gastrointestinal tract flora. However, pneumonia is rare (even in severely neutropenic patients) despite the high incidence of oral and pharyngeal Candida species, probably because the alveolar macrophage rather than the neutrophil is the lung’s major defense against Candida species. Cryptococcus neoformans is ubiquitous worldwide and is commonly recoverable from the environment, being likely acquired as an airborne pollutant. The disease is commonly associated with patients who have defects in cell-mediated immunity. Disseminated cryptococcosis is the most common presentation in immunocompromised patients, with up to 50% of those patients developing pulmonary involvement. Clinical manifestations of pulmonary cryptococcosis are usually minimal but do include fever, cough, dyspnea, and pleuritic pain. Radiographically, cryptococcal pneumonia usually presents as a single well-defined mass that resembles primary lung cancer. In HIV-infected patients, hilar or mediastinal adenopathy and pleural effusions are common features. The latex agglutination test for cryptococcal polysaccharide antigen is one of the most useful of all fungal serologic tests. Amphotericin B and fluconazole have been widely used in the therapy for cryptococcal infections (Stover and Rivera, 2002).1 Histoplasma capsulatum is an endemic fungus that may induce pulmonary and disseminated infections in patients whose cell-mediated immunity is impaired, such as HIVinfected patients. Histoplasmosis is characterized by progressive illness with evidence of extrapulmonary spread of infection. The clinical manifestations include fever, weight loss, hepatosplenomegaly, and cough (Stover and Rivera, 2002).1 When Histoplasma disseminates, bone marrow cultures have the highest yield and fungi can be visualized on blood smears after Wright or Giemsa staining. Radioimmunoassay of the H. capsulatum antigen also offers a rapid method of diagnosing disseminated histoplasmosis. Coccidioides immitis can also cause pulmonary infections in immunocompromised people that inhale the fungus in endemic areas (Stover and Rivera, 2002).1 Because this organism does not usually colonize tissues, its isolation signifies active infection. Disseminated coccidioidomycosis is the most common manifestation of the disease; it may occur as a complication of the primary illness or as a result of reactiva-

tion of latent disease. The symptoms are often nonspecific, but pulmonary symptoms (cough, dyspnea, chest radiographic abnormalities) occur in up to 40% of patients. In HIV disease, relapses are common and maintenance therapy is recommended.

PULMONARY INFECTIONS AFTER BONE MARROW STEM CELL OR SOLID ORGAN TRANSPLANTATION Neutropenia is a frequent event during antineoplastic cytotoxic treatment. Particularly, stem cell transplantation requires aggressive immune suppression that predisposes to infections with gram-positive and gram-negative bacteria (including P. aeruginosa) and fungi (particularly Aspergillus species).103,104 The risk for pneumonia increases significantly with neutrophil counts below 1000/µL, and the risk for fungal infections increases with the duration (>10 days) of neutropenia. Cytomegalovirus pneumonitis is also a major problem associated with high mortality rate in cancer and transplant patients.105 Patients with focal infiltrates on chest radiograph are usually investigated only by noninvasive procedures, whereas bronchoscopy is mandatory for patients with diffuse infiltrates.62 When pulmonary infiltrates are present, patients must be hospitalized and treated rapidly with antibiotics (mainly a combination of β-lactam and either aminoglycoside or fluoroquinolone) and antifungal drugs.106 Frequently used antibiotics for respiratory infections and their activities against common respiratory pathogens are listed in detail elsewhere11,107 and in Table 47-5. Pulmonary infections have also become a major complication in patients receiving organ transplant because they also receive immunosuppressive drugs to prevent organ rejection.108 Those patients are vulnerable to different pathogens at three different periods after transplantation: in the first acute postoperative period (0-2 months), nosocomial infections extend the typical bacterial pathogen pattern and include herpesviruses, fungi, and parasites; the most intensive immunosuppression occurs in the second period (2-6 months) and is characterized by opportunistic infections with pathogens such as cytomegalovirus, P. jiroveci, as well as yeasts and molds (Candida and Aspergillus species); the risk for opportunistic infections in the third period (>6 months) depends on the amount of immunosuppression needed, and it is characterized by community-acquired or persistent infections.108-114 Characteristic radiographic presentations and diagnostic tests for the evaluation of specific pathogens associated with respiratory tract infections in organ transplant recipients have been reviewed.108

PULMONARY INFECTIONS IN HIV-INFECTED PATIENTS Speich115 describes one of the first cases of AIDS as follows: A young male homosexual was hospitalized at the Zurich University Hospital in March 1981. He suffered from oral candidiasis and bilateral pneumonia. Despite broad-spectrum antibiotic therapy, his

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 594

1/21/2008 11:42:32 AM

Chapter 47 Pulmonary Infections in the Immunocompromised Host

condition deteriorated. Ten days later Pneumocystis was found in a transbronchial lung biopsy specimen. Shortly after the initiation of cotrimoxazole treatment the patient developed an ARDS-like picture and had to be mechanically ventilated because of respiratory failure. He died 9 days later. Although the physicians wisely suspected some kind of cellular immunodeficiency, the reason for this strange infection in an otherwise healthy young man remained unclear. In fact, HIV infection leads to severe depletion of CD4positive T cells known as helper T cells. The cellular immune response clearly is impaired to the greatest extent.116 This leads to diseases such as Pneumocystis pneumonia, cytomegalovirus disease, other herpesvirus infections, endemic fungi, and mycobacterioses. The humoral immune response is also compromised, resulting in an increased incidence of bacterial infections, particularly those with the encapsulated bacteria S. pneumoniae and H. influenzae. Multiple simultaneous infectious and noninfectious complications frequently occur in HIV-infected patients; the presentation of disease is often altered by the underlying immune dysfunction and various prophylactic treatments; clinical signs and symptoms and laboratory as well as radiologic changes are often nonspecific; the response to therapy is often delayed; and toxic side effects are common and often severe. Nevertheless, pathogen patterns that have to be taken into account in HIV-infected patients have today been clearly elaborated, and diagnostic algorithms have been suggested.62,117 Straightforward workup relies primarily on sputum examination and, if nondiagnostic, BAL. Differential diagnosis of HIV-related pulmonary complications according to different radiographic patterns have also been reported.115 Actually, these patients are at risk for specific pathogens according to their current CD4 cell numbers. Whereas bacterial pneumonia and tuberculosis may occur already at relatively high CD4 cell numbers, P. jiroveci pneumonia usually is observed at less than 200/µL CD4 cell numbers. Aspergillus species, recurrent P. aeruginosa pneumonia, and, rarely, cytomegalovirus as well as Mycobacterium avium-intracellulare are pathogens typically occurring in patients with less than 50/µL CD4 cell numbers. Infections with Aspergillus species and P. aeruginosa are late complications requiring additional neutrophilic depletion. Other pathogens are exceedingly rare (e.g., Cryptococcus neoformans and other fungi and parasitic infections). The incidence and the spectrum of pulmonary infections have considerably changed since the introduction of highly active antiretroviral therapy (HAART); nevertheless, bacterial pneumonia and P. jiroveci infection continue to represent the most frequent pulmonary infections.118-120 Bacterial infections predominate by far, but Pneumocystis remains the main opportunistic infectious agent. Today, most HIV-infected patients in developed countries are under regular medical supervision. By contrast, most patients in underdeveloped countries receive no medication and tuberculosis is seen at much higher frequency. Therefore, perhaps the main current challenge in general or specialist practice is not to overlook patients with first HIV-associated complications who are unaware of their HIV infection.62

595

SUMMARY Pneumonia in the immunocompromised host is complex. Its clinical manifestations are often silent and reflect a major difference between the pathogenesis of pneumonia in normal and immunocompromised hosts. There are variable levels of immune deficiency, and a high degree of suspicion is the key to a proper diagnostic and management of these patients. Microbial diagnostics has not evolved greatly since Louis Pasteur because culture and other methods still take 48 hours to identify pathogens responsible for those infections. Empirical therapy is still the norm but recent management guidelines offer good guidance for prevention and treatment of this disease, which is the first cause of mortality within all infectious diseases. There is hope at the horizon because within 5 years, rapid nucleic acid–based tests to identify in less than 1 hour microbes and host response markers associated with pneumonia will be available. Although antimicrobial resistance is increasing, better-targeted therapy guided by these rapid tests will reduce resistance, costs, and mortality. By 2020, physicians not only will have the appropriate diagnostic tools to monitor microbes and host response but also, in addition to antimicrobial agents, will have antitoxins (antiteichoic acid and anti-endotoxin monoclonal antibodies) and the proper biological response modifiers to control pneumonia at any stage of disease. Mortality will then decline.

COMMENTS AND CONTROVERSIES This is an excellent review of pulmonary infections in the immunocompromised host. There have been exciting developments in molecular and microbiologic diagnostic techniques. Therapeutic options not available only a few years ago have transformed the management of bacterial, mycobacterial, viral, and fungal infection in patients with compromised immunity. The prevalence of HIV infection; the worldwide development of transplant medicine; the widespread application of chemotherapy as induction, adjuvant, and definitive therapy; and the millions of patients coping with other chronic diseases make it impossible for the practicing thoracic surgeon to avoid involvement in the management of pulmonary infection in the immunocompromised patient. This chapter provides a clear analysis of the problem. Definitions are established. Diagnostic strategies are outlined for the major infections encountered. Management protocols are described that should be clear to every thoracic surgeon. G. A. P.

KEY REFERENCES Bergeron Y, Bergeron MG: Cytokine and chemokine network in the infected lung. In Torres A, Ewig S, Mandell L, Woodhead M (eds): Respiratory Infections. London, Edward Arnold, 2006, pp 57-74. Bergeron Y, Bergeron MG: Why does pneumococcus kill? Can J Infect Dis 10:49C-60C, 1999. Bissonnette L, Bergeron MG: Next revolution in the molecular theranostics of infectious diseases: Microfabricated systems for personalized medicine. Expert Rev Mol Diagn 6:433-450, 2006. Ewig S: Pneumonia in the immunosuppressed host—a general clinical approach. In Torres A, Ewig S, Mandell L, Woodhead M (eds): Respiratory Infections. London, Edward Arnold, 2006, pp 697-706.

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 595

1/21/2008 11:42:33 AM

596

Section 3 Lung

Gennery AR, Cant AJ: Respiratory infection in the immunocompromised host: Recognition and treatment. In Kimpen JLL, Ramilo O (eds): The Microbe-Host Interface in Respiratory Tract Infections. Norwich, UK, Horizon Bioscience, 2005, pp 47-94. Mandell LA, Wunderink RG, Anzueto A, et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27-S72, 2007. Marrie TJ, Campbell GD, Walker DH, Low DE: Pneumonia. In Kasper DL, et al (eds): Harrison’s Principles of Internal Medicine, 16th ed. New York, McGraw-Hill, 2005, pp 1528-1540.

Peytavi R, Raymond FR, Gagne D, et al: Microfluidic device for rapid (<15 min) automated microarray hybridization. Clin Chem 51:18361844, 2005. Stover DE, Rivera MP: Pulmonary infections and the immunocompromised host. In Pearson FG, Cooper JD, Deslauriers J, et al (eds): Thoracic Surgery, 2nd ed. Edinburgh, Elsevier Churchill Livingstone, 2002, pp 632-651. Wunderink RG: Non-antibiotic therapy. In Torres A, Ewig S, Mandell L, Woodhead M (eds): Respiratory Infections. London, Edward Arnold, 2006, pp 157-166.

tahir99-VRG vip.persianss.ir

Ch047-F06861.indd 596

1/21/2008 11:42:33 AM

Diffuse Lung Disease chapter

48

ROLE OF LUNG BIOPSY IN INTERSTITIAL LUNG DISEASE Vitaliy Poylin Malcolm M. DeCamp, Jr.

Key Points ■ Thoracic surgeons evaluate two distinct patient populations with

■

■

■ ■

interstitial lung disease: those with acute respiratory illness, often with impaired immunity, and those with progressive dyspnea and an insidious decline in lung function. The goal of a surgical lung biopsy is to define pathology leading to revised therapy that in turn leads to improved outcome. The goal is not to merely make a diagnosis. Surgical lung biopsy has greater utility in classifying the disorder and leading to effective therapy if it is performed early in the acute or chronic illness. Thoracoscopic and open lung biopsy techniques provide equivalent diagnostic information. Thoracoscopy facilitates sampling of divergent areas of the same lung and results in less trauma and faster recovery compared with a limited thoracotomy.

Interstitial lung disease (ILD) is a heterogeneous group of lung conditions of both known and unknown etiology. There are more than 200 different diseases in the group, which broadly can be divided into infectious, occupational, iatrogenic, granulomatous, malignant, autoimmune/connective tissue disorder–related, and idiopathic categories (Table 48-1) (Kim et al, 2006).1 Despite disparate etiologies, they often have similar clinical features, including dyspnea and hypoxemia, restrictive spirometry, depressed diffusion capacity, and a diffusely abnormal interstitium on lung imaging. Patients with ILD present a therapeutic conundrum for clinicians because these varied disorders with similar clinical presentations often require radically different therapies (e.g., antimicrobial therapy versus augmented immunosuppression).

CLINICAL PRESENTATION When patients with ILD are encountered by a surgeon, they are usually symptomatic with progressive dyspnea, nonproductive cough, occasional weight loss, and fever. Known environmental exposure, a prior malignancy, or a detailed drug history may suggest a cause in a fraction of these cases. Insidious onset is the most common presentation, although fulminant onset is more common in patients who are immunocompromised. Physical examination often reveals nonspecific findings consistent with hypoxemia (clubbing, tachypnea, and tachycardia), wheezing, and/or fine or coarse crackles. Extrapulmonary manifestations of collagen-vascular disease, as are seen in scleroderma or systemic lupus erythematosus

(SLE), may help narrow the differential diagnosis. Pulmonary hypertension with a fixed split second heart sound, peripheral edema, and/or ascites speaks to the chronicity of the underlying process. Spirometry usually shows a nonspecific restrictive pattern with symmetrical reduction in both forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) as ILD progresses. Worsening diffusing capacity of the lung for carbon monoxide (DLCO) is perhaps the most sensitive measure to detect disease progression. From a surgical standpoint, the issue with such a nonspecific presentation is that too few patients get referred for biopsy early in the disease, when a specific diagnosis can potentially make a difference. By the time a surgeon encounters these patients, many have progressed significantly toward end-stage fibrotic disease, with mature collagen replacing and expanding the air-blood barrier. At such a time, the utility of an invasive, diagnostic surgical intervention and even the subsequent institution of potentially toxic pharmacologic therapy is questionable.

IMAGING Routine chest radiographs contribute little to the timely diagnosis of ILD. Radiographic changes are not obvious early in the process. As disease progresses, diffuse linear and reticular infiltrates are seen and are commonly more pronounced in the lower lobes. High-resolution computed tomography (HRCT) provides a detailed image of lung parenchyma and differentiates areas of active disease with ground-glass opacification (Fig. 48-1) from areas of the common end-stage socalled honeycomb changes of fibrosis and scarring (Fig. 48-2). These distinctions become critical when choosing a biopsy site if one is needed.

AMBULATORY DIAGNOSTIC MODALITIES Routine sputum cultures are usually obtained but are likely to be relevant only in patients with predisposing comorbidities or historical factors such as active immunosuppression, unique occupational or environmental exposures, or exotic travel. The low diagnostic yield from sputum cultures can be marginally improved by fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) for microbiology and cytology studies. These two modalities are useful in identifying certain infectious sources, such as Pneumocystis jiroveci (Pneumocystis carinii) pneumonia (PCP) and fungal infections. Transbronchial biopsy has been reported to have a success rate of 25% to 59% in establishing a specific histologic diagnosis.2 The low complication rate of about 3% makes this a useful addition to bronchoscopy and BAL. This technique is 597 tahir99-VRG vip.persianss.ir

Ch048-F06861.indd 597

1/21/2008 11:43:25 AM

598

Section 3 Lung

TABLE 48-1 Classification of Interstitial Lung Disease Infectious

Idiopathic

Occupational

Iatrogenic

Granulomatous

Malignant

Autoimmune/CTD

Bacterial

UIP

Asbestos

Radiation

Sarcoidosis

Lymphoma

Scleroderma

Fungal

DIP

Silica

Bleomycin

Histiocytosis

Lymphangitic carcinomatosis

Viral

NSIP

Coal

Amiodarone

Hypersensitivity

Mycobacterial

COP

Organic

Methotrexate

Protozoan

RB-ILD

Heavy metal

Polymyositis Dermatomyositis Rheumatoid arthritis SLE

COP, cryptogenic organizing pneumonia; CTD, connective tissue disorder; DIP, desquamative interstitial pneumonitis; NSIP, nonspecific interstitial pneumonitis; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease; SLE, systemic lupus erythematosus; UIP, usual interstitial pneumonitis. Adapted from Kim DS, Collard HR, King TE Jr: Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 3:285-292, 2006.

FIGURE 48-1 Axial image with lung windowing from an HRCT. Slice taken at the level of the inferior pulmonary veins. Note the diffuse areas of ground-glass opacification suggestive of active inflammation affecting both lungs.

FIGURE 48-2 Axial image with lung windowing from an HRCT of a patient with advanced interstitial lung disease. Slice taken below the level of the inferior pulmonary veins depicts extensive peripheral fibrosis with honeycomb changes affecting the left lower lobe more than the right.

very successful in accurately diagnosing such conditions as sarcoidosis and lymphangitic carcinomatosis. Yet, small sample size and the limited number of accessible sites limits its use in most cases of ILD. Despite its ambulatory application and less invasive profile, flexible fiberoptic bronchoscopy with BAL and transbronchial biopsy remains inferior to surgical lung biopsy if the end point is a discrete histologic diagnosis.3

and included patients with diverse presentations, including those who were severely ill and already confined to an intensive care unit alongside other patients who remained ambulatory and otherwise functional.4 A more timely and relevant debate asks whether the diagnosis can be established by noninvasive means alone. The ubiquitous availability of HRCT has made this a feasible concept. Two recent prospective studies have validated a noninvasive diagnostic strategy for selected patients, but both emphasized the importance of surgical biopsy for establishing diagnosis in clinically unclear cases. Hunninghake and colleagues5 reported that, when evaluating clinical and radiologic data, an experienced pulmonologist and radiologist were accurate in diagnosing usual interstitial pneumonitis (UIP) in 90% and 77% of cases, respectively. However, when asked for a definitive diagnosis, the accuracy dropped to 75% to 77%. Raghu and colleagues6-8 similarly found that the accuracy of radiologic, clinical, and transbronchial diagnosis was

SURGICAL LUNG BIOPSY The debate regarding the role of surgical lung biopsy for the patient with ILD centers on three questions: 1. Is a biopsy necessary to establish a diagnosis? 2. Will establishing a histologic diagnosis change therapy? 3. Will biopsy-driven therapy change outcome? Historical reports failed to delineate changes in therapy and overall outcome. These studies were largely retrospective

tahir99-VRG vip.persianss.ir

Ch048-F06861.indd 598

1/21/2008 11:43:26 AM

Chapter 48 Role of Lung Biopsy in Interstitial Lung Disease

90% to 97% specific for interstitial pulmonary fibrosis (IPF), but sensitivity remained low at 50% to 78%. For non-IPF ILD, sensitivity and specificity were both low at 62% to 70%. Both studies concluded that, although surgical biopsy may not be necessary for some cases of IPF (especially UIP), it remains essential in more than one third of patients. It is also important to point out that these studies surveyed only experienced pulmonologists and radiologists from centers of recognized authority in ILD. Overall, it is clear that lung biopsy increases the chance of definitive tissue diagnosis in almost all patient populations. The next question is whether establishing the diagnosis will make a difference in patient management or outcome. Historical reports noted that surgical lung biopsy achieves a discrete diagnosis in 37% to 93% of cases.2-4 Although it is difficult to derive useful information from these retrospective analyses, if we try to tease out the effects on the specific patient groups, a few distinct patterns emerge. For immunocompetent patients, two recent reports found that a discrete diagnosis caused a change in therapy in 57% to 63% of cases (Kramer et al, 1998).9,10 In the few studies that reported overall benefit and survival, change in therapy for immunocompetent patients resulted in moderate likelihood of patient benefit (18%-26%).9,10 At the same time, the overall operative morbidity and mortality relative to the actual procedure for these patients remained sufficiently low to make lung biopsy a rational and safe addition to management. Overall, in immunocompetent patients without respiratory distress whose HRCT shows minimal end-stage fibrotic change, biopsy is likely to change or guide therapy, and there is some evidence of improvement in survival (Tables 48-2 and 48-3). This pattern does not hold true for elderly or immunocompromised patients or those with end-stage disease. Patients with end-stage fibrosis on top of poor overall status have a higher rate of complications from anesthesia and the procedure itself, resulting in higher mortality and important morbidity, such as extra days of mechanical ventilation and prolonged air leak.11,12 For ventilated immunocompetent patients, the rates of diagnosis and changes in therapy seem to be compatible with studies of ambulatory patients (approximately 46%). This ventilated group did experience significantly higher mortality (approaching 60%), calling into question the therapeutic index for lung biopsies once a patient is intubated.

599

Timing of biopsy has also been debated. Delaying the biopsy may be related to some degree of therapeutic nihilism, given the absence of effective remedies for UIP (see Table 48-2)1,11 or the pattern of diffuse alveolar damage seen frequently on specimens from critically ill patients. Performing biopsy late in the course of the disease decreases the chance of diagnosis due to coalescence of heavy indiscriminant fibrosis (honeycombing). These patients also are more likely to be in respiratory distress, which, as described earlier, reduces the likelihood that a tissue diagnosis will change the overall outcome and is certainly accompanied by much higher morbidity and mortality. In patients with fulminant forms of the disease, choosing the appropriate time may not be possible. This group of patients needs urgent or emergent lung biopsy if there is any clinical likelihood of a reversible process.

IMMUNOCOMPROMISED PATIENTS Immunocompromised hosts comprise a large patient cohort affected by diffuse lung disease. Unlike patients with fibrotic lung disease, these hosts have a much higher risk of developing infectious complications. They are usually acutely ill with fever, cough, dyspnea, and progressive hypoxemia. They have

TABLE 48-2 Characteristics of Idiopathic Forms of Interstitial Lung Disease Characteristic

UIP

NSIP

COP

RB-ILD

Mean age at presentation (yr)

57

49

42

36

Onset

Insidious

Subacute

Subacute

Insidious

Smoking-related

Increased risk

No

No

Required

Steroid-responsive

No

Yes

Yes

Slightly

Complete recovery

No

Possible

Yes

Yes

Mortality (%)

90

30

5

0

COP, cryptogenic organizing pneumonia; NSIP, nonspecific interstitial pneumonitis; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease; UIP, usual interstitial pneumonitis. Adapted from Kim DS, Collard HR, King TE Jr: Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 3:285-292, 2006.

TABLE 48-3 Effect of Lung Biopsy (VATS and Open) on Change in Therapy and Outcome Author (Year)

No. Patients

Patient Status

% Change of Therapy

% Change in Outcome

Lee et al21 (2005)

196

Immunocompromised and immunocompetent

84

63

Kramer et al (1998)

103

Immunocompromised Immunocompetent

59 18

46* 18

White et al16 (2000)

63

Immunocompromised

57

26

Temes et al10 (1999)

75

Immunocompetent

77

39

9

*The mortality rate of this group was 39%. VATS, video-assisted thoracic surgery.

tahir99-VRG vip.persianss.ir

Ch048-F06861.indd 599

1/21/2008 11:43:26 AM

600

Section 3 Lung

often been exposed to other potential lung-damaging therapies, such as immunosuppressive drugs, chemotherapy, and irradiation. The prognosis for immunocompromised patients with pulmonary infiltrates is grim, especially if mechanical ventilation is required. In these circumstances, prompt diagnosis may be critical for survival. Because opportunistic infections can be a common cause of ILD, the workup for these patients begins with expeditious sputum culture, bronchoscopy, and BAL. Microbiologic examination of expectorated sputum and/or lavaged airway secretions has successfully identified a discrete diagnosis in 40% of immunocompromised patients.13,14 For the balance of the patients in whom the diagnosis remains unclear, a more invasive approach is controversial. Many reports suggest that patients in whom lung biopsy is pursued do not fare better than those treated empirically.12,15,16 Rano and colleagues17 examined patients with hematologic malignancies and solid organ transplantation who presented with fever, dyspnea, and pulmonary infiltrates. Their overall mortality rate after surgical lung biopsy was 39% (see Table 48-2). Although prolonged time to diagnosis (>5 days) was predictive of the need for mechanical ventilation and of higher mortality, patients who underwent lung biopsy experienced outcomes similar to those diagnosed by less invasive methods. Despite a higher rate of finding a specific diagnosis with biopsy than in immunocompetent patients, the extra information did not translate into salutary clinical outcomes.

VIDEO-ASSISTED THORACIC SURGERY VERSUS OPEN BIOPSY For decades, open biopsy via a limited thoracotomy has been a gold standard for the surgical diagnosis of ILD. However, this approach is associated with increased pain, some limitation in accessible biopsy sites, and, in some uncontrolled studies, increased mortality. The emergence of video-assisted thoracic surgery (VATS) has proved to be an attractive alternative to the open technique. In largely retrospective studies, VATS has been shown to decrease the length of hospital stay and postoperative analgesic requirements, with better preservation of shoulder strength and range of motion and faster return to baseline pulmonary function.18 There are also intriguing reports of a decrease in surgery-associated immunosuppression when patients undergoing VATS procedures were compared with those having open thoracotomy.19 Direct comparisons between open and minimally invasive approaches suggest equivalency in diagnostic efficacy. Miller and coworkers (Miller et al, 2000),20 in a prospective randomized study of 42 patients, found no clinical or statistical differences between the two techniques with regard to diagnostic yield, operating time, duration of chest tube drainage, postoperative length of stay, pain scores, complications, or spirometry measured both preoperatively and postoperatively. Ultimately, the choice between an open or VATS approach to lung biopsy is a clinical one based on patient anatomy, physiology, and the surgeon’s facility with minimally invasive techniques. For ambulatory patients referred for biopsy to define ILD, VATS has largely supplanted thoracotomy as the

procedure of choice, both for patients and for their referring physicians. These patients almost uniformly tolerate singlelung ventilation, which is a practical requirement for VATS lung biopsy. The need to convert VATS to a thoracotomy is rare and in most series is limited to 0% to 5.3%. This is usually related to the patient’s inability to tolerate single-lung ventilation, pleural adhesions, or iatrogenic lung injury (Lee et al, 2005; Miller et al, 2000).20-25 In contrast, the critically ill, severely dyspneic, oxygendependent or mechanically ventilated patient with a clear indication for surgical lung biopsy cannot tolerate single-lung ventilation. This necessitates the use of a thoracotomy (albeit limited) and brief intermittent periods of apnea to successfully biopsy the affected lung.

LOCATION OF THE BIOPSY AND NUMBER OF SITES Contemporary imaging modalities such as HRCT guide the surgeon and represent an invaluable resource in performing high-yield biopsy. HRCT allows the surgeon to avoid areas of high fibrosis (see Fig. 48-2), the common end stage for multiple lung disorders, and guide biopsy to areas of active disease, which often appear as ground-glass opacifications (see Fig. 48-1). The site for biopsy in generalized disease remains controversial. Traditionally, the lingula was considered a poor site for the biopsy because the location was believed to be akin to the basilar aspects of the lower lobes, where fibrosis is usually more advanced.26 More recent studies by Ayed, Miller, and Blewett and their colleagues have found that lingular (and right middle lobe) biopsies provide a diagnostic yield similar to that obtained from tissue sampled from the other areas of either lung.24,26,28 The optimal number of samples is also debated. In a study of 100 patients with ILD, Qureshi and Soorae25 demonstrated that a single biopsy from an active disease area is adequate for diagnosis. In their study, the site, size, number, or laterality of the biopsy specimen had no statistical influence on diagnostic yield, although there was a trend favoring two or more biopsies on the right lung. They and others have also confirmed that obtaining multiple biopsies does not increase postoperative morbidity. Given these data and the lack of evidence that multiple biopsies engender increased risk, we recommend two wedge biopsy samples from separate lobes when investigating idiopathic ILD in an ambulatory patient. The anatomic separation of such samples may assist the pathologist in classification of the underlying process and its severity. For the acutely ill, hospitalized, immunocompromised, or febrile patient, the underlying process is more likely to be diffuse. Multiple biopsies in this clinical scenario are not necessary as long as lesional tissue is obtained and confirmed by either gross examination or frozen section. Moreover, multiple biopsies in these more fragile patients are associated with important morbidity, including bleeding and prolonged air leaks. The more critical technical issue for these patients is to obtain sufficient tissue in a single wedge resection to allow for both histology and microbiologic analysis for bacteria, mycobacteria, fungi, viruses, and parasites.

tahir99-VRG vip.persianss.ir

Ch048-F06861.indd 600

1/21/2008 11:43:26 AM

Chapter 48 Role of Lung Biopsy in Interstitial Lung Disease

TECHNIQUE Surgical lung biopsy, whether performed via VATS or thoracotomy, is done with the patient under general anesthesia in the lateral decubitus position. Selective bronchial intubation and single-lung ventilation are mandatory for VATS. For leftsided biopsies, a bronchial blocker can be used, but it limits anesthetic maneuvers such as continuous positive airway pressure (CPAP) if intraoperative hypoxemia becomes problematic. Many ambulatory patients who present with hypoxemia requiring supplemental oxygen actually tolerate single-lung ventilation well. Similarly, the acutely ill patient with a focal lung process may tolerate selective ventilation for a brief procedure if the more diseased lung is the target for biopsy. If intraoperative hypoxia creates instability, brief periods of ventilation of the deflated lung or low levels of CPAP (5 cm H2O) may allow the procedure to be completed without progressing to thoracotomy. The ipsilateral arm is abducted and strapped to an ether screen or arm holder to open the axilla and provide port access to the upper thorax (Fig. 48-3). This also facilitates a minithoracotomy low in the axilla if the patient cannot tolerate single-lung ventilation or extensive pleural adhesions are encountered. It is helpful to extend the operating table or flex the patient’s hip to widen the lower intercostal spaces and deflect the hips down and away from the field. Three access ports are used (see Fig. 48-3). The camera port is usually placed in the seventh intercostal space in the

1 2

Possible port sites

3 4 5

Port site

6 7 8 9 10 11 12

FIGURE 48-3 Proper positioning for surgical lung biopsy. The operative-side arm is abducted and secured with appropriate padding to an ether screen or arm holder to provide access to the axilla for either a utility thoracotomy or more apical port sites. If a videoassisted thoracic surgery (VATS) approach is planned, suggested camera positioning and port site options are indicated. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

601

midaxillary line. A 5- or 10-mm telescope with a 30-degree lens allows the camera to visualize the entire thorax. The lung is inspected, and the proposed site for biopsy (based on HRCT) is identified. The other two ports are usually placed under thoracoscopic guidance in the sixth or seventh intercostal spaces, posteriorly below the scapular tip and anteriorly below or immediately lateral to the breast. Attractive targets for biopsy include the upper lobe apices, the superior segment of the lower lobes, the basilar edges of the lower lobes, and any of the lobes along the fissures. The broad surfaces of the lung must be approached with care if there is underlying fibrosis or induration because the lung may not be compressible, resulting in malformed staples and air leak. The lung adjacent to the biopsy target is gently grasped with a ringed forceps, and an endomechanical stapler with a thick tissue cartridge is introduced and fired via the opposing port site. The instruments are reversed and a second staple firing is made, completing the wedge resection with intersecting staple lines. Remove all specimens from the chest in an impenetrable bag to prevent dissemination of disease within the pleura or seeding/contamination of the chest wall. Staple lines and each port site are inspected for hemostasis. This may necessitate relocating the camera to any or all port sites used. All staple lines should intersect to ensure pneumostasis. A single, small chest tube is placed via the original camera port and positioned in the posterior gutter with its tip in the apex. The lung is reinflated in a controlled fashion under thoracoscopic visualization to ensure re-expansion of all lobes and segments. The remaining port sites are reapproximated in layers with absorbable suture, including a subcuticular skin closure. Surgical lung biopsy for the intubated patient who requires high levels of inspired oxygen (FIO2 ≥0.6) or positive endexpiratory pressure (PEEP ≥10) is best accomplished via a limited lateral or axillary thoracotomy. These patients are unlikely to tolerate single-lung ventilation, and manipulation of the airway to place a bronchial blocker or double-lumen endotracheal tube may precipitate a crisis. Again, the patient is positioned laterally with the arm abducted (see Fig. 48-3). A muscle-sparing approach lateral to the pectoralis major and anterior to the latissimus dorsi in front of the scapular tip exposes either lung along the fissure. The serratus anterior fibers can be split, with care taken not to divide the long thoracic nerve. Either the upper or the lower lobe can be biopsied through this exposure. We prefer to use the thick tissue cartridges and the endomechanical stapler even during open biopsies. Use of a more inferiorly placed chest tube incision to pass the stapler for one or several firings may facilitate the geometry of the biopsy. Very brief episodes of apnea during application of the stapler may help decrease pleural injury and subsequent air leak. A hemostatic survey, chest tube placement, and wound closure are standard as for any thoracotomy. Specimen handling depends on the immune status of the patient. Although a frozen section is rarely definitive, it often confirms the adequacy of the biopsy as representative of lesional tissue. Examination of fresh tissue by the pathologist may also guide further investigation, such as immunohistochemistry, fungal stains, flow cytometry, or electron micros-

tahir99-VRG vip.persianss.ir

Ch048-F06861.indd 601

1/21/2008 11:43:26 AM

602

Section 3 Lung

copy. Granulomas are readily identified by frozen section. Although these lesions can be infective or noninfective, such tissues must always be cultured for fungal and mycobacterial organisms. In the immunocompromised patient, in addition to histology, tissue is routinely assayed for bacterial, fungal, acid-fast, viral, and protozoan organisms (especially PCP). Procedure-related morbidity and mortality are uncommon for VATS lung biopsy. The risk of death after an elective biopsy for ILD is reported at 0% to 2%, whereas the need to convert to open thoracotomy ranges from 0% to 5.3%. Other complications include hemothorax (0%-5%), persistent leak requiring prolonged chest tube drainage (1%-8%), and bleeding requiring re-exploration (1%-2%). As described earlier, in immunocompromised patients or in clinical crises where intubation has occurred or is eminent, complication rates (especially respiratory failure, need for mechanical ventilation, and air leak) tend to be higher and are less likely to be caused by errors in technique. Operative mortality in this population may approach 40% to 60%, similar to that experienced by any critically ill patient in whom respiratory distress deteriorates into multisystem organ failure.9,11,12,16,20-25,28

COMMENTS AND CONTROVERSIES Current CT imaging techniques and relatively noninvasive bronchoscopic biopsy strategies have lessened the need for surgical biopsy in patients with ILD. Opportunistic infections and sarcoidosis can usually be diagnosed by BAL and transbronchial biopsy, respectively. The CT imaging pattern of UIP is typical in its early stages. In many cases, surgical biopsy can be avoided. As the authors correctly point out, the goal of surgical biopsy is not only to establish a diagnosis but, more importantly, to effect a change in management to the patient’s benefit. If this latter goal is unlikely to be achieved, the biopsy is of questionable utility, especially in a critically ill patient. VATS has proved to be an effective strategy for lung biopsy, but only in the elective situation of a stable patient. Adequate multifocal biopsies can be obtained by VATS, but use of a double-lumen tube and an arterial line and a more expensive operative setup are required. This commentator does not believe that VATS offers benefit over minimal anterolateral thoracotomy in terms of pain, postoperative morbidity, and operative time. This anterolateral approach is definitely superior in the critically ill patient. G. A. P.

KEY REFERENCES Kim DS, Collard HR, King TE Jr: Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 3:285292, 2006. ■ This paper led off a contemporary international symposium on ILD. The authors clearly define the distinct differences in clinical, radiologic, and histologic features; treatment; and prognosis for the noninfectious types of ILD. Kramer MR, Berkman N, Mintz B, et al: The role of open biopsy in the management and outcome of patients with diffuse lung disease. Ann Thorac Surg 65:198-202, 1998. ■ In one of the first papers to emphasize the clinical utility of the biopsy for more than a diagnosis, these authors remind us to exercise judgment when considering risks and benefits of surgical lung biopsy. They documented an alarming operative mortality in the immunocompromised group, especially if the decision to proceed to biopsy was made late. Lee YC, Wu CT, Hsu HH, et al: Surgical lung biopsy for diffuse pulmonary disease: Experience of 196 patients. J Thorac Cardiovasc Surg 129:984-990, 2005. ■ In this large recent series, the investigators report a high rate of change in both therapy and outcome based on the surgical biopsy. Unfortunately, it is difficult to tease apart the results between immunocompetent and immunosuppressed hosts. Miller JD, Urschel JD, Cox G, et al: A randomized, controlled trial comparing thoracoscopy and limited thoracotomy for lung biopsy in interstitial lung disease. Ann Thorac Surg 70:1647-1650, 2000. ■ One of two small, prospective, randomized trials comparing open to thoracoscopic lung biopsy for ILD. The patients selected were largely ambulatory; critically ill, severely hypoxic, and ventilated patients were excluded. Given these restrictions, there were no differences in any of the measured surgical, pathologic, or clinical outcomes of the two groups. It is doubtful that the study was adequately powered to detect meaningful differences based on choice of incision. That the procedures yielded comparable results underscores the need for surgeons contemplating lung biopsy to select an approach that best meets the patient’s needs. White DA, Wong PW, Downey R: The utility of open lung biopsy in patients with hematologic malignancies. Am J Respir Crit Care Med 161:723-729, 2000. ■ Thoracic surgeons are often asked to evaluate patients whose bone marrow is failing because of disease or therapy. The authors, from Memorial Sloan Kettering Cancer Center, report that, although therapy changed in more than half of patients biopsied, the outcome changed only one quarter of the time.

tahir99-VRG vip.persianss.ir

Ch048-F06861.indd 602

1/21/2008 11:43:27 AM

chapter

49

MEDICAL MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Barbara A. Lutey Stephen S. Lefrak

Key Points ■ Patients who have smoked for more than 10 years should be

evaluated by spirometry before undergoing thoracic surgical procedures. ■ For patients with moderate to severe airflow obstruction, a rehabilitation regimen of smoking cessation, graded exercise, supplemental oxygen if required, and tiotropium inhalation may improve perioperative mortality. ■ An intensive regimen of short-acting bronchodilators such as albuterol and ipratropium and controlled oxygen therapy, airway care, and monitoring of arterial blood gases in the postoperative period may avert the need for mechanical ventilation. ■ Noninvasive ventilation in the postoperative period for patients with hypercarbic respiratory failure may avert the need for endotracheal intubation and mechanical ventilation.

Many of the diseases treated by thoracic surgeons are associated with long-term use of cigarettes. From aortic aneurysms to esophageal cancer, cigarette smoke inhalation is a common factor. Therefore, it is not surprising that many of the patients seen by thoracic surgeons have chronic obstructive pulmonary disease (COPD). COPD is a preventable and treatable disease state characterized by expiratory airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases primarily caused by cigarette smoking.1 Approximately 16 million Americans have COPD. COPD is the fourth leading cause of death in the United States (Ryu and Scanlon, 2001).2 This disease is projected to be the third leading cause of death for both males and females by the year 2020.3

PATHOPHYSIOLOGY The clinical syndrome known as COPD comprises predominantly two disease entities: emphysema and chronic bronchitis. Emphysema is defined anatomically as dilation of the airspace distal to the terminal bronchioles associated with alveolar wall destruction and without obvious fibrosis.4 Previously, this diagnosis required pathologic examination of inflated lung. Today, the diagnosis may be suspected when examination by computed tomography (CT) shows abnormally decreased attenuation in significant volumes of lung. Chronic bronchitis is clinically defined as cough productive of sputum on most days of 3 months for 2 consecutive years,

in the absence of any other lung disease that could produce cough.5 Inhalation of tobacco smoke over prolonged periods is likely to produce both emphysema and bronchitis in varying proportions, for reasons that are unknown.4,5 Genetic factors are also involved, because not all smokers develop COPD.6 It is the small airway obstruction common to both diseases that link the anatomic abnormalities to the diminished maximum expiratory airflow by which COPD is defined. Expiratory airflow becomes limited either because of intrinsic airways disease or because of decreased elastic recoil (emphysema). In many cases, both abnormalities are present. The decreased expiratory airflow characteristic of COPD results in hyperinflation of the lungs, which, in turn, produces abnormalities in chest wall and respiratory muscle function that increase the work of breathing. Because every breath requires extra effort, COPD patients may be dyspneic eventually even at rest. An increased respiratory rate, when combined with preexisting decreased expiratory airflow, results in worsened hyperinflation. This phenomenon, known as dynamic hyperinflation, further increases the work of breathing.7-10 COPD patients who have underlying coronary or other heart disease may develop cardiac complications. At baseline, COPD patients often have maldistribution of ventilation, increased mucus production, and impaired clearance mechanisms. Thus, COPD patients may be unable to compensate in situations in which their respiratory rate is increased or their gas exchange is compromised. These preexisting abnormalities in pulmonary mechanics and gas exchange and possible comorbid cardiac conditions impair the patient’s ability to adapt to the predictable physiologic changes that follow thoracic or upper abdominal surgery. These include, but are not limited to, diaphragm dysfunction, change in breathing patterns, decreased lung volumes, increased intravascular lung water, impaired alveolar gas exchange, impaired cough and mucociliary clearance, and respiratory depression due to anesthetics and narcotics. The mortality risk is not inconsiderable for those patients with advanced disease who undergo major thoracic surgery, but if the pulmonary disease is recognized, measures can be taken to optimize pulmonary function and decrease the risk (Grichnik and Hill, 2003).11-16 Therefore, it is important to consider this diagnosis in all tobacco smokers who present for surgery.

EVALUATION If COPD is far advanced and clinically manifest, patients in need of therapy, and who present greater operative risk, can 603 tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 603

1/21/2008 11:44:22 AM

604

Section 3 Lung

usually be identified. However, the disease may be clinically subtle even when well established. Patients may have significant obstructive disease, including disordered alveolar gas exchange, without being symptomatic or manifesting clinical signs on physical examination. Consequently, unless specifically tested for, physiologically abnormal airway obstruction may go unnoticed until complications, including respiratory failure, develop postoperatively. Therefore, any patient presenting for diagnosis or treatment by a thoracic surgeon who has a history of cigarette smoking should be evaluated with pulmonary function tests.

History The hallmark of COPD is progressive dyspnea with exercise, but this history may be difficult to elicit. Because COPD is so common in the smoking population, patients frequently attribute the dyspnea it produces to aging or to comorbidity. In addition, patients may not report dyspnea because they have unconsciously curtailed their activities to avoid situations in which they become short of breath. In order to get a true picture of the degree of debility, it is helpful to ask specifically what activities of daily living (ADLs) they find most demanding, or what activities they have to forgo because of their pulmonary limitations. For example, many patients with severe COPD report that tying their shoes, carrying groceries, or taking showers is particularly difficult for them. Others are able to walk comfortably on level ground, but only if they are allowed to go at their own pace, without hurrying. By consistently asking about the same activities at each visit, the patient’s level of function can be followed over time. In addition to dyspnea, patients may also complain of cough that may be productive of sputum and of wheezing.

Physical Examination Most patients show few signs of COPD until the disease is advanced. Diminished breath sounds or wheezing may be noted on auscultation, and there may be a slightly prolonged expiratory phase. In advanced stages, patients have an increased respiratory drive and inspiration may begin before exhalation is completed. The expiratory phase may be notably prolonged. Long-standing hyperinflation produces the appearance of a so-called barrel chest, and there may be accessory muscle use with breathing. Inward movement of the lower costal margin during inspiration (Hoover’s sign) is another indication of marked hyperinflation. The effects of COPD may extend beyond the lung. Ankle edema may be a sign of right heart failure usually caused by alveolar hypoxia. Many patients have global muscle weakness directly attributable to COPD, or to corticosteroid myopathy or general malnutrition. In very advanced disease, significant weight loss may be seen.17-19 It is important to note that clubbing of the fingers is not a sign of COPD, and this finding should stimulate an investigation for other causes, notably lung cancer.

Pulmonary Function Testing Spirometry is the only method that reliably diagnoses airway obstruction (Global Initiative for Chronic Obstructive Lung

Disease, 2006).20-22 During this testing, patients are asked to execute a forced vital capacity maneuver that measures the exhaled volume and rate of flow during forcible exhalation from full inspiration. The patient’s efforts are compared to results predicted by equations for a subject of the same gender, age, height, and race. Obstruction is considered to be present if, at any lung volume, the maximum expiratory flow is diminished. The measurement of spirometry before and after inhaled bronchodilator use may aid in classifying whether a patient has reversible airway disease. However, the lack of an immediate response to inhaled bronchodilators does not preclude their use and effectiveness in these patients on a long-term basis. Spirometry may also lead to diagnosis of previously unsuspected upper airway lesions (Ryu and Scanlon, 2001).2 Spirometry is also used to classify the disease by the severity of impairment of airway obstruction. One such classification system was developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). It is based on the forced expiratory volume in 1 second (FEV1) after use of a bronchodilator. The stages are shown in Table 49-1.23 Predicted mortality correlates with the severity of the airflow obstruction as measured by the FEV1.22,24,25 This classification system has also been used in the development of treatment guidelines.26 A measurement of arterial blood gases (ABGs) should be obtained in patients with moderate to severe impairment, to assess both oxygenation and alveolar ventilation. Additional pulmonary function tests, such as lung volumes and the carbon monoxide diffusing capacity of the lung (DLCO), are not necessary for all patients and should be ordered only if needed to answer specific questions. Patients who complain of shortness of breath but who have an FEV1 greater than 60% of predicted are probably dyspneic for reasons other than COPD, such as heart disease, pulmonary vascular disease, or anemia, and these should be investigated.

TABLE 49-1 COPD Severity Based on Post-Bronchodilator FEV1 Stage I—Mild

FEV1/FVC <0.70 FEV1 ≥ 80% predicted

Stage II—Moderate

FEV1/FVC <0.70 50% ≤ FEV1 <80% predicted

Stage III—Severe

FEV1/FVC <0.70 30% ≤ FEV1 <50% predicted

Stage IV—Very Severe

FEV1/FVC <0.70 FEV1 <30% predicted, or FEV1 <50% predicted plus chronic respiratory failure

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. From Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2006. Chapter 1: Definition, pp 3-6. Complete document available at: http://www.goldcopd.org (accessed March 31, 2007).

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 604

1/21/2008 11:44:23 AM

Chapter 49 Medical Management of Chronic Obstructive Pulmonary Disease

Oxygen Assessment Patients with moderate to severe disease (GOLD stage II-IV) who are able to maintain adequate oxygenation at rest may become hypoxemic with exercise. Consideration should be given to oxygen requirements, not only during exercise, but also during sleep and air travel.27 The 6-minute walk test not only provides information about the level of supplemental oxygen needed with activity, if any, but also gives insight into the patient’s exercise tolerance.28 During this test, patients walk a premeasured course as quickly as possible for 6 minutes. Supplemental oxygen requirements during activity can be determined if patients walk while wearing a pulse oximeter and nasal cannula attached to a portable oxygen source. An accompanying respiratory therapist monitors the patient’s oxygen saturation by pulse oximetry (SpO2) and provides supplemental oxygen as needed to maintain the SpO2 at 89% or higher. An ABG analysis should be obtained to document whether hypoxemia is present and to determine the tension of arterial carbon dioxide (PaCO2). Supplemental oxygen is indicated in the following situations: (1) arterial oxygen tension (PaO2) 55 mm Hg or less, or SpO2 88% or less, at rest or (2) evidence of cor pulmonale or hematocrit greater than 55% with PaO2 of 56 to 59 mm Hg or SpO2 of 89% or less during exercise.29 Supplemental oxygen requirements may change. Oxygen reassessment is advised within 1 to 3 months after initiation of intense medical therapy and surgery, or if the patient experiences a decline in function. Patients who require oxygen either at rest or with exercise usually require supplemental oxygen during sleep. Patients with COPD may develop significant abnormalities of gas exchange during sleep.30-32 In addition, patients who have unexplained polycythemia or pulmonary hypertension may also require oxygen during sleep. Using overnight oximetry, it is possible to determine the exact amount of supplemental oxygen needed. Patients who report poor sleep or who appear to be sleep-deprived may have obstructive sleep apnea. In these patients, polysomnography during sleep is the appropriate evaluation. Patients should be educated about the importance of compliance with oxygen therapy and helped to understand that oxygen therapy is usually a lifetime commitment. Patients should be discouraged from attempting to ration their oxygen or to wean themselves from use.33

Imaging Chest radiographs are usually obtained to eliminate comorbidities such as lung cancer. Imaging can also provide an assessment of the degree of hyperinflation and the presence of bullae. Although chest CT scans may provide more detailed information about the extent and distribution of emphysematous changes in the lung, they are not required in all patients.34,35

a1-Antitrypsin Deficiency The α1-antitrypsin level should be measured in patients who have a family history of α1-antitrypsin deficiency or early-

605

onset COPD, who have presented with emphysema before the age of 50 years, or who have an unusual distribution (i.e., basilar) of emphysematous changes or associated liver disease. This test should also be ordered for patients who have chronic bronchitis but no history of tobacco use or who have unexplained bronchiectasis or cirrhosis. Patients who have abnormally low levels and a history consistent with α1-antitrypsin deficiency should be referred to a pulmonologist.36

Summary Thoracic surgeons should be cognizant of the following points. First, almost all patients (smokers) who are evaluated and treated by thoracic surgeons should be considered to be at risk of developing COPD. Second, the diagnosis of impairment as measured by spirometry is critical, so that almost all patients contemplating thoracic surgery should have this test performed. Finally, patients with moderate to severe disease would benefit from a consultation with a pulmonologist during their preoperative evaluation and treatment. Once they have been diagnosed and classified, preoperative treatment and preparation may be initiated appropriately to improve perioperative morbidity.

PREOPERATIVE TREATMENT AND PREPARATION A wide range of interventions can be used to optimize function during the preoperative period, and preparation can be tailored to each patient’s specific needs. All patients should be assisted with smoking cessation and provided with education about their disease. Routine health maintenance issues should not be overlooked. Patients with more severe disease may require pharmacologic therapy to optimize lung function, as well as supplemental oxygen and a supervised exercise program.

General Management for All GOLD Stages Smoking Cessation All patients should cease smoking, but tobacco cessation is particularly important for patients with COPD. It is the only intervention that has been shown to slow the rate of decline in pulmonary function.14,22,37 In addition to these long-term benefits, tobacco cessation is an important preoperative intervention that has been shown to decrease postanesthetic morbidity. Ideally, patients should be abstinent from tobacco for 4 to 8 weeks before surgery.13 The physician should make opportunities to discuss tobacco addiction and to offer assistance with cessation both at office visits and during hospitalization. Nicotine is extraordinarily addictive, and patients will need encouragement and support to quit. Relapse is common. Nicotine replacement agents such as gum, transdermal patches, inhalers, and nasal sprays have been shown to improve the success rate. Bupropion hydrochloride has also proved helpful.38 The U.S. Food and Drug Administration has recently approved a new drug, varenicline, which has been shown to be efficacious in smoking cessation.39,40

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 605

1/21/2008 11:44:23 AM

606

Section 3 Lung

Educational Materials All patients should be given access to educational materials about their disease, written to an appropriate educational level. A better understanding of pathophysiology, how therapeutic decisions are made, and the goals of therapy may improve compliance with physician recommendations. It is also important to reassure patients that their disease is not rapidly progressive; rather, it is a chronic condition that can be appropriately managed and for which exercise has an important therapeutic role. The local chapter of the American Lung Association or its website (http://www.lungusa.org) can provide valuable assistance with patient education.

Health Maintenance All patients should be kept up-to-date with their Pneumovax inoculation and the annual influenza vaccine. Comorbidities such as coronary artery disease, hypertension, or diabetes should be managed appropriately. All patients should strive to maintain a healthy weight.

Pharmacologic Therapy Pharmacologic agents do not change the course of COPD or slow the rate of decline in pulmonary function. However, appropriate therapy can relieve dyspnea, decrease symptoms, and improve exercise tolerance and quality of life.

Inhaled Bronchodilators Rationale for Therapy. Bronchodilators act to relax airway smooth muscle and thereby improve lung emptying during exhalation.1,41 Although improvements in FEV1 may be small, larger changes in lung volume may lead to favorable clinical effects on dynamic hyperventilation during exercise.1 The two classes of inhaled bronchodilators are β-agonists, which directly produce bronchodilation through acting on β2-adrenergic receptors, and anticholinergic agents, which relax smooth muscle by antagonizing acetylcholine at muscarinic receptors.41 β-Agonists can be found in a short-acting form, such as albuterol, which is given every 4 to 6 hours or as needed, and long-acting forms such as salmeterol and formoterol, which are given twice daily. Ipratropium is a short-acting anticholinergic that is administered four times each day or as needed. Tiotropium is a recently developed long-acting anticholinergic agent that is administered once each day. Because β-agonists and anticholinergic agents work by different mechanisms, their effects are additive, and patients may benefit from using medications from both classes.1 Guidelines. The GOLD provides general guidelines for pharmacologic therapy based on severity of disease. Patients with mild disease (stage I) may need no treatment, or only as-needed treatment with a short-acting bronchodilator. Patients in stages II through IV, whose disease is classified as moderate, severe, or very severe, respectively, may require scheduled doses of one or more long-acting bronchodilators in addition to short-acting agents. Additional therapy, in the form of theophylline or inhaled or systemic corticosteroids, may be added as needed. Inhaled corticosteroids are recom-

mended for patients who have an FEV1 less than 50% of predicted and repeated exacerbations, to decrease the occurrence of exacerbations. No recommendations as to specific agents are given in the guidelines.26 As always, clinicians need to tailor therapy to patients’ individual needs. Initial Therapy. For patients who have not obtained sufficient relief from as-needed use of short-acting bronchodilators— either albuterol, ipratropium, or combination therapy— a long-acting bronchodilator should be prescribed. Initial therapy should be begun with tiotropium. This is a longacting anticholinergic agent that has been shown to be very effective at improving the FEV1 over the long term, and some studies have shown improvement in other clinical measurements, such as dyspnea, number of exacerbations, and quality of life (Sutherland and Cherniack, 2004).37,41-44 It also decreases hyperinflation, especially the dynamic hyperinflation that occurs with exercise. One inhalation per day is administered. Patients who do not use tiotropium can use scheduled ipratropium. The usual starting dose is 2 inhalations given four times each day, but patients may increase the number of inhalations as long as they do not exceed 12 inhalations in 24 hours. The current recommendation is that patients who are using tiotropium should abstain from ipratropium. Patients who use either tiotropium or scheduled ipratropium should also be prescribed a quick-acting β-agonist such as albuterol. This so-called rescue medication provides quick-onset relief of wheezing or shortness of breath if these symptoms occur, and patients should also use this medication 15 minutes before beginning an activity that they anticipate will cause dyspnea. Dosing for albuterol is 2 to 4 inhalations every 4 to 6 hours as needed. Ipratropium is also available in combination with albuterol. The starting dose is 2 inhalations four times each day. Patients may use more inhalations as long as they do not exceed 12 inhalations in 24 hours. If patients are not improved on a regimen of anticholinergic medication (tiotropium or ipratropium) and albuterol, a longlasting β-agonist such as salmeterol can be added to the regimen. The dose of this medication is 1 inhalation twice each day. This medication may produce further symptomatic improvement, especially if the patient is awakening at night to use the inhaler (Sutherland and Cherniack, 2004).44 Regardless of what medications are used, patient education in proper use of the bronchodilator delivery device is critical. For those patients who have difficulty coordinating activation of the metered-dose inhaler (MDI) with inhalation of the dose, a spacer may be of benefit. Although many medications are delivered by MDI, other devices are becoming increasingly more common. Nebulizers deliver a larger dose, but most patients are adequately treated by MDIs, and the MDIs, unlike the nebulizers, are portable.

Theophylline A trial of this medication should be considered only if combined therapy using anticholinergic and β-agonist agents does not provide sufficient improvement in dyspnea. When initiating this medication, it is important to review all other medications the patient is currently taking, because there can be significant interactions between the metabolism of theophyl-

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 606

1/21/2008 11:44:23 AM

Chapter 49 Medical Management of Chronic Obstructive Pulmonary Disease

line and that of many other drugs. For example, inhalation of tobacco smoke may lower theophylline levels. Elevated blood levels of theophylline are of greater concern. Patients who develop nausea, vomiting, or tachyarrhythmias should be suspected of having theophylline toxicity. If these symptoms develop, the drug should be stopped immediately, because seizures and death have been reported in patients with serious toxicity. Even if patients do not develop toxicity, the physician should periodically review the risk-benefit ratio of this medication. Some patients feel that slight improvement in their dyspnea does not justify continuing a medication that can cause anxiety and tremor.

Anti-inflammatory Agents Inhaled Corticosteroids There is very little evidence supporting the routine use of inhaled steroids in COPD. However, for patients who have responded to oral corticosteroid therapy, inhaled corticosteroids may sustain the improvement at less risk of systemic effects. Beclomethasone is available in doses of 40 or 80 µg per inhalation. The medication is administered twice daily, and the number of inhalations is prescribed according to whether the plan is to dose at low, medium, or high levels. Fluticasone is available in MDI form. The strengths of the MDI are 44 µg, 110 µg, or 220 µg per inhalation. Regardless of strength or delivery device, the dose is 1 inhalation twice each day. Fluticasone is also available in combination with salmeterol. This product delivers 50 µg of salmeterol and 100, 250, or 500 µg of fluticasone, depending on strength, with each activation. The dosing regimen for all strengths is 1 inhalation twice each day. Combination therapy may be more effective than the individual agents taken separately. Some research has suggested that inhaled corticosteroids may decrease the risk of acute exacerbations in COPD.45,46 The GOLD has also recommended use of inhaled corticosteroids for patients who have FEV1 less than 50% and repeated exacerbations, in order to decrease the occurrence of exacerbations.26 The recent TORCH trial, which compared a combination of fluticasone propionate and salmeterol versus placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years, showed significantly fewer exacerbations and improved health status and lung function for the combination when compared with placebo. However, the reduction in mortality from any cause in the combination-therapy group, as compared with the placebo group, did not meet the predetermined level of statistical significance.47 Therefore, a decision about using inhaled corticosteroids, either alone or in combination with a long-acting bronchodilator, in COPD is not well supported by the current evidence.

Systemic Corticosteroids A trial of prednisone is reasonable in a patient who has severe wheezing or severe limitation to activity, even before surgery. The suggested dosing is 40 mg prednisone per day for 10 to 14 days. Because of the systemic toxic effects of prednisone, it is advisable to taper the dose and discontinue this medica-

607

tion as soon as it is safe to do so. Continuation of therapy should be rigorously dependent on demonstration of improvement in such objective measures as the FEV1 or other parameters of measured pulmonary function, not merely on patients’ subjective reports of improved well-being. If continued systemic corticosteroid therapy is deemed necessary, the dose should be tapered to the minimum dose that produces the beneficial effect. The possibility of discontinuing systemic therapy should be readdressed in the near future.

Oxygen Therapy Providing supplemental oxygen to patients with significant hypoxemia as a result of COPD has been shown to reduce mortality and improve physical and mental function.29 Oxygen delivery systems are intended to provide the patient with an adequate supply of oxygen, at suitable rates of flow, while still permitting the patient to be as active as possible. Patients may use a concentrator while at home or sleeping. Portable tanks of compressed oxygen or tanks of liquid oxygen are intended for use outside the home. Most patients are able to use continuous-flow dual-prong nasal cannulas. Those patients who require higher flow may benefit from a reservoir system such as the Oxymizer. When writing a prescription for supplemental oxygen, the physician should always specify not only the amount of oxygen (liters per minute) to be used during rest, exercise, and sleep but also the delivery system.

Pulmonary Rehabilitation Patients with GOLD stage III or stage IV disease are often severely limited by dyspnea. Because even minimal activity can cause shortness of breath, patients decrease their physical activity as the disease progresses. The consequence is deconditioning, both of the cardiovascular system and the peripheral muscles, sometimes to the point of being unable even to perform ADLs. Pulmonary rehabilitation programs provide a multidisciplinary approach to COPD, addressing such areas as strength and endurance training, nutrition, and psychosocial support. Graded exercise wearing oxygen as needed to maintain an SpO2 of 90% is a critical part of such programs. In addition to such endurance training, supervised strength training with weights may improve overall feelings of wellbeing. Pulmonary rehabilitation does not significantly change measured pulmonary function but has been shown to have positive effects on dyspnea, exercise ability, and health care utilization. This intervention should be offered to all patients with GOLD stage III or greater. The only exceptions are those patients who are not motivated to participate or who have disabling nonpulmonary comorbidities.48-50

POSTOPERATIVE CARE Because of abnormal respiratory muscle function, thoracic mechanics, and impaired alveolar gas exchange, patients with COPD are at increased risk of being unable to withstand the physiologic changes that ensue with thoracic surgery, anesthesia, and analgesia. Careful preoperative and postoperative monitoring and early and meticulous intervention are required to prevent

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 607

1/21/2008 11:44:23 AM

608

Section 3 Lung

respiratory failure, pulmonary infection, myocardial infarction, or pulmonary embolism in these patients.

General Management The patient’s preoperative medication regimen may be reinstituted as soon as recovery from anesthesia is achieved. In general, long-acting bronchodilators are replaced with shortacting drugs such as ipratropium bromide in the perioperative period and may be administered by nebulizer rather than by MDI, to facilitate utilization. This increases the dose 100-fold compared with an MDI but usually results in no untoward effects. Virtually all patients require supplemental oxygen as well, and this must be delivered in a controlled manner to avoid a precipitous increase in PaCO2 and the development of respiratory acidosis. Early ambulation and resumption of exercise training should be a priority in the postoperative period, with treadmill exercise initiated at the bedside no later than the second postoperative day. This should be part of a general regimen of deep breathing, coughing, and secretion mobilization, aggressive pain management, and prophylaxis against deep venous thrombosis.11,12

Physical Examination and Vital Signs Respiratory rate is a critical vital sign in these patients. An increased respiratory rate in the postoperative period may produce dynamic hyperinflation, further increasing the work of breathing and impairing diaphragmatic function. Respiratory rates greater than 25 breaths/min are a sign of distress, and rates greater than 35 breaths/min always require immediate attention. Patients with respiratory rates greater than 40 breaths/min almost always require positive-pressure ventilatory support. Respiratory rates of less than 15 breaths/min are also unusual and may indicate inadequate alveolar ventilation. In such patients, an ABG analysis should be obtained immediately. A pulse oximetry reading is not sufficient, because it does not provide the critical information about PaCO2 and pH. A portable chest radiograph should also be obtained. The presence of either increased wheezing or increasing dynamic hyperinflation calls for intensified measures, such as increased frequency of bronchodilator administration and perhaps systemic anti-inflammatory drugs, to improve respiratory status. Tachycardia is often present. The development of atrial dysrhythmias such as flutter and fibrillation are not uncommon in older patients after thoracotomy. If a dysrhythmia is present, or if the heart rate is faster than 130 beats/min, use of β-sympathomimetics (albuterol) should be halted and ipratropium should be used. Hemodynamic instability, if not corrected rapidly, almost always necessitates intubation and mechanical ventilation. Crepitations (rales) are unusual and may signify fluid overload or left-sided heart failure. Ankle or presacral edema caused by fluid retention, excess fluid administration, or right-sided heart failure is uncommon and should be treated with diuretics. Altered mentation, especially confusion and delirium, may result from multiple causes in the postoperative period. In

addition to investigating all other causes, a rapid evaluation for cerebral hypoxia or respiratory acidosis must be carried out in this population. Administration of narcotics, as well as other sedatives, must be very judiciously managed in these patients because of their tenuous respiratory status.

Oxygen Therapy The fraction of inspired oxygen (FIO2) delivered should be closely matched to what the patient requires and should not exceed this amount. The goal of oxygen therapy is to achieve an oxygen saturation of 90% and a PaO2 of 60 mm Hg without precipitating significant respiratory acidosis. Patients usually require only 2 to 4 L/min of oxygen, or a ventimask setting of less than 40% FIO2. A patient who requires more than this rate should be evaluated for other complications and the need for more intensive therapy and monitoring. ABG analysis must be used to determine at what reading the SpO2 correlates with this goal. It is not sufficient to assess arterial oxygenation by pulse oximetry alone, because an adequate SpO2 achieved by an increase in FIO2 may be accompanied by a rise in PaCO2 that produces an unacceptable fall in pH and subsequent respiratory acidosis. Postoperative COPD patients are at particularly high risk for hypercarbia and respiratory acidosis because the effects of surgery, anesthetics, and pain medications impose significant stress on their already-limited pulmonary reserves. Oxygen therapy may exacerbate this risk. Three mechanisms explain the hypercarbia that can result from supplemental oxygen therapy. First, oxygen therapy increases the alveolar oxygen tension in poorly ventilated alveoli. This increased oxygen tension reverses pulmonary vasoconstriction, thus allowing more blood flow into areas that remain poorly ventilated. This increase in blood flow brings more carbon dioxide to the lung, but, because alveolar ventilation is unchanged, the PaCO2 rises. Second, as hemoglobin saturation with oxygen rises, the hemoglobin becomes less capable of carrying carbon dioxide, which dissolves in plasma and results in a rise in PaCO2. Third, the last and probably least important mechanism is that an increase in arterial PaO2 decreases the ventilatory drive in these patients. This effect is exacerbated by the effects of narcotics and anesthetic residual in the perioperative period. The evidence to support the importance of hypoxic drive in these patients is very limited, and the current weight of opinion favors the first two mechanisms (Schumaker and Epstein, 2004).51

Airway Care The clearance of secretions is of paramount importance to maintain patent airways. Assistance with coughing and frequent turning and positioning is helpful in achieving this goal. Nasotracheal suctioning is rarely indicated and may actually worsen the airway by producing laryngeal edema. Many patients have a minitracheostomy performed at the time of surgery to aid in removal of secretions.

Pharmacologic Therapy The postoperative pharmacologic therapy for patients with COPD of GOLD stage II or greater severity requires inten-

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 608

1/21/2008 11:44:23 AM

Chapter 49 Medical Management of Chronic Obstructive Pulmonary Disease

sive use of inhaled bronchodilators. During the first 2 to 4 postoperative days, and in the patient with worsening respiratory status, intensive use of ipratropium bromide or ipratropium combined with albuterol should be provided via nebulizer and aerosol mask. The use of long-lasting inhaled bronchodilators should be avoided until the patient appears well on the way to recovery and ready to assume the prescribed ambulatory care regimen. If tachycardia or dysrhythmia is present, then either no βagonists should be used or a trial of levalbuterol may be combined with the ipratropium. Inhaled corticosteroids should not be used in the immediate postoperative period or in the acutely dyspneic patient. However, systemically administered prednisone by mouth, or intravenous methylprednisolone if the patient is unable to take oral medications, can be very useful. Corticosteroids have been shown in several randomized controlled trials to affect the outcomes during acute exacerbations of COPD, and there is reason to speculate that they may be helpful in a similar way in the postoperative patient with COPD who is wheezing, whose gas exchange is deteriorating, or who is more dyspneic. The usual dose is 40 to 60 mg of prednisone, or its equivalent, per day. As the patient improves and begins to ambulate, the systemic prednisone may gradually be tapered and replaced by inhaled corticosteroids or a combination of corticosteroids and a long-lasting β2-agonist.

DECOMPENSATION Despite optimal therapy, some patients with COPD have acute episodes of decompensation, during which they experience increased respiratory distress, decreased exercise tolerance, and increased sputum production. Symptoms may progress to overt respiratory failure. These episodes are collectively known as exacerbations. They are often attributed to infection or to air pollution, but in many cases the definitive cause is never identified (O’Donnell and Parker, 2006).52,53 Patients with severe disease are more susceptible to exacerbations than those with mild disease, and exacerbations may accelerate the rate of decline in lung function. A hospitalized postoperative patient with worsening respiratory status may be experiencing a COPD exacerbation, but several other possibilities must also be considered. The differential diagnosis includes nosocomial pneumonia, myocardial infarction, cardiac dysrhythmias, congestive heart failure, pulmonary embolism, and pneumothorax. All possibilities must be quickly explored, so that appropriate therapy in the appropriate setting may be provided and further deterioration prevented.

609

work is reflected in such abnormal findings as worsening abdominal paradox and increased accessory muscle use. Decreased mentation is an ominous sign, because it suggests that the patient’s efforts to oxygenate and ventilate are inadequate and hypoxemia and/or hypercarbia may be developing.

Laboratory Evaluation The chest radiograph and electrocardiogram are valuable noninvasive studies that may help to determine the cause of the patient’s distress. If pulmonary embolism is sufficiently high in the differential diagnosis, a pulmonary embolism protocol CT should be obtained. If signs of heart failure are seen on physical examination, then an echocardiogram may help provide an assessment of cardiac function. An ABG analysis must be obtained. Pulse oximetry is not an adequate evaluation of alveolar gas exchange in this setting, because it provides no information about pH or PaCO2.

Pharmacologic Therapy Patients who are having an exacerbation need more aggressive medical therapy. The dose and frequency of short-acting bronchodilators may need to be increased. Severely dyspneic patients may be more comfortable using a nebulizer rather than an MDI. Patients whose maintenance medication includes theophylline may continue on this medication if the theophylline level is appropriate, but initiation of intravenous theophylline is not usually recommended. A short course of systemic corticosteroids has been shown to result in earlier improvement and may also increase the time to a subsequent exacerbation. GOLD guidelines recommend a 10-14 day course of 30 to 40 mg prednisolone per day. Patients who are dyspneic, with increased volume and purulence of sputum, should also be given a course of antibiotics appropriate to the situation.54-56

Level of Care Hospitalized patients who have marked impairment of vital signs, such as elevated respiratory rate, hypoxemia that persists or worsens despite supplemental oxygen, or severe or worsening respiratory acidosis (pH < 7.30) are at risk for respiratory failure. They should be moved to an intensive care setting as early as possible. With intensive nursing care and monitoring, it may be possible to avert intubation and mechanical ventilation.

Positive-Pressure Ventilation Physical Examination The importance of the respiratory rate to the assessment of patients in these situations is often underappreciated. An increasing respiratory rate is not only a sign of worsening pulmonary status; an increased rate also contributes to worsening pulmonary function. This occurs because of the preexisting expiratory airflow limitation that is characteristic of COPD. An increased respiratory rate can result in dynamic hyperinflation and increased work of breathing. This increased

Positive-pressure ventilation accomplishes several physiologic goals. First, the device shares the work of breathing, thus lessening the efforts of the patient. Second, it decreases the respiratory rate and applies positive end-expiratory pressure (PEEP), reducing dynamic hyperinflation. Third, it decreases the work of breathing and increases minute ventilation, reducing the PaCO2 and normalizing the pH. Fourth, positivepressure ventilation improves oxygenation and thus improves hemodynamics by decreasing pulmonary artery pressure.

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 609

1/21/2008 11:44:23 AM

610

Section 3 Lung

Lastly, because the mean intrathoracic pressure is increased, the left ventricular afterload is decreased.57

Noninvasive Ventilation Noninvasive positive-pressure ventilation (NPPV) is the delivery of positive-pressure ventilation to spontaneously breathing patients through a mask instead of an endotracheal tube. It has been demonstrated to be most useful in patients with hypercarbic respiratory failure. When used in appropriately selected patients who are experiencing a COPD exacerbation, NPPV can avert the need for intubation and mechanical ventilation.58,59 Patients who have clinical evidence of respiratory distress, such as a respiratory rate greater than 25 breaths/min, a PaCO2 of 45 mm Hg or higher, and a pH less than 7.35, could be considered for this therapy as long as they have minimal secretions and are conscious and cooperative. Contraindications include respiratory arrest, upper airway obstruction, uncontrolled cardiac arrhythmia, decreased mentation (e.g., inability to cooperate, confusion, agitation), unsuitable anatomy, hemodynamic instability, inability to manage secretions, undrained pneumothorax, recent gastrointestinal surgery or bowel obstruction, and active gastrointestinal bleeding.57,60 The equipment consists of a ventilator and mask. The choice of nasal or full-face mask depends on individual patient circumstances. Nasal masks have the advantages of decreased risk of aspiration, easier clearance of secretions, less claustrophobia, and less dead space, and the patients are able to talk. The nasal mask also has the disadvantages of mouth leak, nasal irritation, and rhinorrhea, and therapy is less effective if there is any nasal obstruction. The full-face mask is more effective for dyspneic patients, but there is increased dead space; it is difficult to maintain an adequate seal; and there is a risk of asphyxiation with ventilator malfunction. In addition, when compared with the nasal mask, there is increased risk of facial pressure sores, claustrophobia, and aspiration. Patients who use the full facial mask are unable to speak, eat, or drink.

The physician not only must be familiar with the NPPV equipment used in his or her hospital but also be able to clearly communicate the various modes to be applied. All ventilator modes have theoretical advantages and limitations, but flow-triggered systems require less inspiratory effort from the patient than pressure-triggered systems. Continuous positive airway pressure (CPAP) maintains constant airway pressure throughout the respiratory cycle. Pressure support ventilation (PSV) provides a preestablished inspiratory pressure sometimes designated as the inspiratory positive airway pressure (IPAP). Biphasic positive airway pressure (BIPAP) provides both a set IPAP and PEEP at fixed intervals. The expiratory positive airway pressure is also called EPAP. When initiating NPPV, the initial settings should be the lowest inspiratory pressures needed to produce a decrease in respiratory rate, respiratory muscle unloading, and improved gas exchange. As patients become accustomed to the therapy, settings may be adjusted to provide increased support. See suggested settings in Table 49-2.57,61 Close monitoring of mental status, vital signs, and ABG values is essential to assess the response to therapy. In general, a patient is said to be improved if one parameter improves and the others are no worse. Patients who are able to tolerate the intervention, decrease their respiratory rate and work of breathing, and show an improvement in their pH can continue on NPPV and may be able to avoid invasive mechanical ventilation. Patients who are unable to tolerate the intervention, who show no decrease in respiratory rate or work of breathing, or who exhibit worsening acidosis, hypercarbia, or hypoxemia on ABG are failing NPPV and should be prepared for invasive mechanical ventilation. Decreased mentation and hemodynamic instability are also reasons to discontinue NPPV and initiate invasive mechanical ventilation.57,60,62

Invasive Mechanical Ventilation The goals of invasive mechanical ventilation are to decrease the patient’s work of breathing, to allow the patient to recover from fatigue, and to provide adequate alveolar gas exchange

TABLE 49-2 Noninvasive Ventilation Initial Settings Parameter

Initiation

Maintenance

EPAP

0-4 cm H2O

Slowly increase by 3-5 cm H2O; 8-10 cm H2O maximum

IPAP

10 cm H2O

Increase gradually to obtain VT >7 mL/kg and RR <25 breaths/min

FIO2

Sufficient to provide SpO2 ~90%

Same

Mask Application

Gently hold on face until patient is comfortable and in synchrony

Secure with straps

Clinical Assessment

HR, RR, BP, chest wall movement, mental status

Same

Monitoring

7.25 > pH <7.45 45 > PaO2 <70

7.30 > pH <7.45 55 > PaO2 <70

BP, blood pressure; EPAP, expiratory positive airway pressure; FIO2, fraction of inspired oxygen; HR, heart rate; IPAP, inspiratory positive airway pressure; PaO2, arterial partial pressure of oxygen; RR, respiratory rate; SpO2, oxygen saturation as measured by pulse oximetry; VT, tidal volume.

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 610

1/21/2008 11:44:23 AM

Chapter 49 Medical Management of Chronic Obstructive Pulmonary Disease

such that the PaO2 is 90% and the pH is between 7.25 and 7.45. The goal is not to fully normalize the ABG.57,63,64 The choice of modes depends on the individual patient situation. Control, assist control, or PSV with intermittent mandatory ventilation (IMV) backup rate are all acceptable. As with NPPV, the ventilator should be triggered by flow, not pressure. The initial settings depend on the individual patient’s situation. The FIO2 should be 1.0 at first, then decreased to 0.4 as soon as possible. If more than 0.4 is required, then the physician should search for other responsible pathophysiologic processes in addition to COPD. The initial PEEP should be 5 cm H2O, and it rarely needs to be increased unless diffuse lung injury or heart failure has supervened. The initial respiratory rate should be 8 to 12 breaths/min, with a tidal volume of no more than 5 to 7 mL/kg of ideal body weight.63,64 Because of the nature of obstructive lung disease, expiratory flow is decreased in patients with COPD. If the respiratory rate is set too high, the lung may not fully empty before the next breath is initiated. The result is dynamic hyperinflation, which may decrease venous return and result in hemodynamic compromise. Dynamic hyperinflation can be diagnosed by several findings. On physical examination of the chest, it may be clear by inspection or auscultation that expiration is not completed before the ventilator delivers the next breath. Patients may also have a pulsus paradoxus. Looking at the ventilator waveform on the monitor, it can be seen that the flow to the patient does not cease before the next breath is delivered. Similar findings may be observed on the endtidal CO2 waveform. To decrease dynamic hyperinflation, an excessive respiratory rate must be avoided. A high inspiratory flow allows maximum time for expiration and may be helpful in these circumstances.14,16,51,65,66

Discontinuance of Support As the patient improves, he or she may be weaned from mechanical ventilation or NPPV as in any other situation. To facilitate removal of mechanical support, pharmacologic treatment and rehabilitation must be maintained in an intensive manner. Some patients who have required mechanical ventilation after a postoperative exacerbation need a pro-

611

longed period of mechanical support. In such cases, temporary placement in a specialized unit dedicated to rehabilitation and ventilator weaning may be necessary for successful completion of their hospital stay.66

KEY REFERENCES Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2006. Full document available at: http://www.goldcopd.org (accessed March 31, 2007). ■ This publication provides a comprehensive treatment of all issues pertinent to COPD: diagnosis, staging, and management of both stable disease and acute exacerbations. Grichnik KP, Hill SE: The perioperative management of patients with severe emphysema. J Cardiothorac Vasc Anesth 17:364-387, 2003. ■ This paper reviews the anatomic and clinical findings in emphysema and the medical and surgical treatments currently available. Special issues with regard to patient preoperative evaluation and perioperative issues such as anesthesia, analgesia, and ventilator management are also discussed. O’Donnell DE, Parker CM: COPD exacerbations 3: Pathophysiology. Thorax 61:354-361, 2006. ■ This paper reviews the etiologies of COPD exacerbations and how stresses superimposed on the expiratory airflow, characteristic of the disease, can result in respiratory failure and associated cardiac dysfunction. Ryu JH, Scanlon PD: Obstructive lung disease: COPD, asthma, and many imitators. Mayo Clin Proc 76:1144-1153, 2001. ■ This paper presents a detailed review of the spirometric diagnosis of obstructive pulmonary diseases. Schumaker GL, Epstein SK: Managing acute respiratory failure during exacerbation of chronic obstructive pulmonary disease. Respir Care 49:766-782, 2004. ■ This paper presents the multiple etiologies of COPD exacerbations and provides guidelines for assessment, oxygen therapy, pharmacologic therapy, and ventilatory support. Sutherland ER, Cherniack RM: Management of chronic obstructive pulmonary disease. N Engl J Med 350:2689-2697, 2004. ■ This paper presents information on diagnosis, staging, and management of stable COPD with an emphasis on medical treatment. The authors also briefly review other important interventions, such as tobacco cessation, pulmonary rehabilitation, oxygen therapy, and surgical treatment of emphysema.

tahir99-VRG vip.persianss.ir

Ch049-F06861.indd 611

1/21/2008 11:44:23 AM

chapter

50

LUNG VOLUME REDUCTION SURGERY Nirmal K. Veeramachaneni Bryan F. Meyers

Key Points ■ Lung volume reduction surgery is a viable option in a select group

of patients with emphysema. ■ Preoperative pulmonary rehabilitation and careful patient selection

is essential for favorable outcomes. ■ In the appropriately selected patient, LVRS improves dyspnea,

improves exercise tolerance, and may provide a survival advantage.

Over 12 million Americans have chronic obstructive pulmonary disease (COPD). As many as 2 million of these have emphysema.1 Emphysema is a progressive disease that results in a continued decline in pulmonary function. When pulmonary function tests document a forced expiratory volume in 1 second (FEV1) of less than 30% of the value predicted by nomograms, the 3-year mortality risk has been estimated at 40% to 50%. Medical therapy is the mainstay of treatment (Sutherland and Cherniack, 2004).2 Although lung transplantation is a viable option, the scarcity of available donors and comorbidities of patients with advanced COPD limit this procedure to a select few. An additional surgical therapy— lung volume reduction surgery (LVRS)—has become a viable treatment modality in the past 2 decades. In this chapter we review the physiologic basis of LVRS and the data that support the use of this procedure in properly selected patients.

HISTORICAL NOTE AND RATIONALE The surgical treatment of emphysema has evolved throughout the 20th century. Based on faulty physiologic premises and no proven benefit, a number of procedures, including phrenic nerve crush and chondroplasty, have been attempted and subsequently abandoned. An excellent review on the history of emphysema surgery has been written by Deslauriers (1996).3 LVRS is the only form of surgical therapy for emphysema that has withstood vigorous investigation. In 1957, Dr. Otto C. Brantigan proposed a surgical treatment for patients disabled by diffuse pulmonary emphysema. He resected peripheral lung tissue, anticipating restoration of the elastic recoil of the lung and improved mechanics of the thorax and diaphragm. A unilateral thoracotomy was used with a radical hilar denervation procedure in the belief that this would decrease pulmonary secretions. Brantigan planned to return

a few months later to operate on the contralateral side. Overall improvement was reported in 75% of the patients. However, few quantitative corroborating data were provided and the in-hospital mortality rate was 19%. As a result, Brantigan’s procedure did not gain wide acceptance. Observations in lung transplant patients led Cooper to resurrect Brantigan’s ideas in 1993 (Cooper et al, 1995).4 It was observed that the transplantation of normal lungs into patients with emphysema led to restoration of a normal thoracic configuration. Additionally, if properly ventilated, even a diseased emphysematous lung could provide adequate gas exchange. This is demonstrated in the ability to utilize offbypass single-lung ventilation to perform lung transplantation in patients with COPD. Similar to Brantigan’s procedure, Cooper removed approximately 30% of the patient’s lung volume by performing peripheral resection of the most emphysematous portions. Distinct from Brantigan’s approach, Cooper used linear cutting/stapling devices, buttressed the suture line, and performed a simultaneous bilateral procedure through a median sternotomy. The procedure was considered palliative and was designed to reduce dyspnea, increase exercise tolerance and performance in activities of daily living, and improve quality of life. In most patients, these goals were achieved with concomitant physiologic improvement in airflow limitation, hyperinflation, and alveolar gas exchange. Enthusiasm for LVRS after this sentinal report led to its widespread application. However, analysis of data of patients enrolled in U.S. government–sponsored health care (Medicare) revealed a 23% mortality at 12 months with this procedure.5 Because of the high risks and costs associated with the application of the operation, Medicare funding for the procedure was stopped in 1996. The National Heart, Lung and Blood Institute of the National Institutes of Health began a clinical trial to evaluate the benefit of the procedure.6 The result of the effort, the National Emphysema Treatment Trial (NETT), began enrolling patients in 1999. This prospective randomized study of 1218 patients provides the best evidence for the efficacy and safety of LVRS.

CLINICAL FEATURES OF EMPHYSEMA Emphysema is defined as the dilation of the terminal lung units beyond the terminal bronchiole associated with alveolar wall destruction with limited, if any, fibrosis. A decrease in lung elastic recoil pressure occurs as a result of both the loss of surface area as alveoli coalesce into larger units and the deterioration of the intrinsic structure of the lung as remodeling takes place.

612

Ch050-F06861.indd 612

1/21/2008 11:45:18 AM

Chapter 50 Lung Volume Reduction Surgery

The increased distensibility of emphysematous lung results in a lung that, although easily inflated, tends to remain inflated. Areas of severely emphysematous lung are essentially nonfunctional but occupy volume that is commensurate with the severity of destruction. As a result, more normal adjacent lung becomes less capable of exerting its betterpreserved elastic recoil on its adjoining airways, and the result is an increase in airway resistance. Furthermore, this decreased recoil pressure results in expiratory airflow limitation because of decreases in both the driving pressure for expiratory flow and the transmural pressure, which maintains the patency of intraparenchymal airways. Emphysema is unevenly distributed throughout the lungs, resulting in regional variation in both structure and function. During inspiration and exhalation, the emphysematous lung has regions that are emptying and filling out of phase with one another. The heterogeneous distribution of emphysema throughout the lungs also adversely affects alveolar gas exchange. Portions of the lung that are more affected by the disease process ventilate more slowly than do the more normal regions. The relative distribution of blood flow to these poorly ventilating regions determines both the amount of dead space and the venous admixture that are present, thus affecting the overall ventilatory requirement and levels of PaO2 and PaCO2. Poor gas exchange is compounded by an increase in ventilatory drive, producing premature initiation of inspiration. In addition to producing hyperinflation, the premature onset of inspiration results in positive alveolar pressure at endexhalation. This so-called autogenous positive end-expiratory pressure (auto-PEEP) then serves as a threshold inspiratory load to the inspiratory muscles. Initiation of inspiratory flow becomes more difficult because more negative intrathoracic pressures must be generated to overcome this positive pressure. As thoracic hyperinflation advances, the diaphragm assumes its characteristic flattened position observed on chest radio-

613

graphs (Fig. 50-1). This has profound effects on inspiratory muscle function. The zone of apposition between the diaphragm and the abdominal wall is lost as the diaphragm flattens. As a result, any positive abdominal pressure generated during inspiration is not as effectively applied to the chest wall, hindering rib cage movement and impairing inspiration. The flattened diaphragm becomes a less effective lever for moving the rib cage upward and outward. With severe hyperinflation, the lower rib cage may be observed to move inward during inspiration. As hyperinflation progresses, the thoracic cage operates at a mechanical disadvantage. Normally, at functional residual capacity, the rib cage is at a lower volume than at its resting position. During normal inspiration, the thoracic cage tends to passively expand or recoil outward toward its resting position. As thoracic hyperinflation occurs, the rib cage assumes a higher volume, well above its resting volume. As a result, the inspiratory muscles, instead of gaining assistance from the rib cage during tidal inspiration, now must work to overcome the resistance of the rib cage.

PREOPERATIVE MEDICAL MANAGEMENT Lung volume reduction surgery is an invasive procedure with both risk of morbidity and mortality. It is directed at patients who remain sufficiently symptomatic despite optimal medical treatment. Foremost among medical interventions, the cessation of smoking is essential. Most programs require at least 6 months of abstinence from tobacco before considering patients for surgery. In addition, all patients are enrolled in a structured pulmonary rehabilitation program. The comprehensive program includes exercise training, optimization of medical management, patient education, psychosocial assessment, and treatment and optimization of nutrition. A graded exercise program is essential to pulmonary rehabilitation. Many patients with COPD remain breathless and

FIGURE 50-1 Characteristic anteroposterior and lateral chest radiographs of a woman with severe emphysema. Note the hyperinflated lungs, flattened diaphragm, and diminished pulmonary vascular markings at the apices suggesting disease that is predominant in the upper lobes.

Ch050-F06861.indd 613

1/21/2008 11:45:18 AM

614

Section 3 Lung

fear overexertion. As a result, these patients become increasingly sedentary, leading to progressive deconditioning. Patients then experience a diminished exercise tolerance, and a selfreplicating cycle continues. Therefore, a graded exercise program is initiated immediately for all patients. Exercise therefore acts as a cornerstone of the patient’s return to a more active lifestyle. Exercise training is designed to decrease exertional dyspnea and to increase endurance and maximal exercise capacity. Before surgery, patients in the Washington University Medical Center program are required to complete an exercise program that has a minimal goal of 30 minutes of daily continuous exercise (at least 5 days per week) on a treadmill or stationary bicycle. Heart rate limits are set at 80% of the maximal predicted heart rate. Patients are periodically reevaluated throughout the graded exercise program with 6-minute walk tests. A program used in the NETT trail is described by Ries and associates.7 The Joint Commission on Accreditation of Hospitals and Organizations uses a minimal performance of 3 minutes of unloaded pedaling on a stationary bicycle as a condition for acceptance for LVRS surgery. A significant number of patients achieve enough improvement in their overall well-being that they decline to undertake the risks of LVRS after undergoing pulmonary rehabilitation.7,8 Unfortunately, the efficacy of pulmonary rehabilitation is self-limited. Re-enrollment in a pulmonary rehabilitation program after a patient has completed a course of supervised pulmonary rehabilitation therapy is less efficacious. Oxygen therapy for the hypoxemic patient is the only medical therapeutic intervention that increases survival for COPD, as has been demonstrated in randomized controlled trials.9 In addition, exercise-induced hypoxemia is common in patients with severe COPD and oxygen supplementation may improve exercise performance. Oxygen therapy is indicated for any patient with a PaO2 less than 55 mm Hg or an SaO2 less than 88%. If a patient has evidence of cor pulmonale or a hematocrit of more than 55%, oxygen therapy is indicated even with higher baseline PaO2 levels. Patients are evaluated during exercise as well as at rest. Bronchodilator therapy is useful in symptomatic airflow limitation. Although a large proportion of patients with COPD may have partially reversible airways disease, aerosolized bronchodilators have not been demonstrated to slow the rate of deterioration of lung function. A stepwise approach to employing adrenergic receptor agonists, anticholinergics, and possibly methylxanthines is routinely recommended in COPD; however, the patients evaluated for surgery have markedly compromised pulmonary function, have often already progressed along the stepwise approach, and now require intensified maximal therapy.2 Virtually all patients have previously been prescribed metered-dose inhalers, yet many patients use them incorrectly. Thus, it is imperative to observe inhaler use and then instruct patients on how to correctly use the inhaler, possibly with the addition of a spacer. As many as half of the patients evaluated for LVRS at our medical center use long-term systemic corticosteroid therapy. Unfortunately, most patients with stable COPD do not show

Ch050-F06861.indd 614

a positive response in airflow limitation with oral corticosteroid therapy. There are no prospective data to support an improvement in the decline of respiratory function with the use of systemic corticosteroids. COPD patients with a large component of reactive airways disease may benefit most from corticosteroid therapy, but studies have not definitively supported this suggestion. Therefore, reduction or elimination of dependence on systemic corticosteroids is the goal of a comprehensive rehabilitation program. Similarly, the role of inhaled corticosteroid therapy is undefined. Inhaled corticosteroids may diminish the number of exacerbations requiring hospitalization. The benefit to patient mortality and decline in pulmonary function is unknown. For those patients who are dependent on oral corticosteroids preoperatively, tapering to the lowest possible dose during the rehabilitation phase is mandatory to avoid the associated increased postoperative risks, including poor wound healing and perioperative infection. For those patients who remain on long-term systemic corticosteroid therapy within weeks preceding surgery, supplementation with socalled stress dose hydrocortisone is required. Education, which is an important component of pulmonary rehabilitation, may include teaching patients about the basic physiology of COPD, medical management options, and the importance of compliance. This teaching may result in improved understanding and coping, decreased anxiety, and positive behavioral changes. As part of the initial comprehensive rehabilitation evaluation, counseling may be offered to address coping with anger, depression, and fear related to the chronic illness. In addition, counseling provides encouragement and support. Patients may also benefit from enrollment in a support group. Malnutrition, especially that marked by progressive weight loss and muscle wasting, commonly occurs in patients with marked COPD and is associated with increased mortality. Patients may benefit from nutritional counseling and the use of nutritional supplements when indicated. Although a structured pulmonary rehabilitation program may not significantly improve pulmonary function tests, many authors have documented an improvement in exercise tolerance, dyspnea, and quality of life with this nonoperative intervention. After successful completion of the preoperative program, the average increase in the distance walked in 6 minutes has been 20% (Ciccone et al, 2003).8,10 During the preoperative program, patients also experience decreases in dyspnea. The NETT investigators reported similar improvements in ability to exercise, in 6-minute walk test, sensation of dyspnea, and quality of life.7 In the NETT trial, 16% of patients were reassessed to be in the “high exercise” functioning group, although they were initially assessed to be of “low exercise” function. More importantly, 5% of patients were found to have deteriorated during the course of pulmonary rehabilitation. This is of considerable prognostic benefit and is discussed in the section on patient selection.

EVALUATION OF PATIENTS The goals of the preoperative assessment are to identify patients who remain disabled by emphysema in spite of

1/21/2008 11:45:19 AM

Chapter 50 Lung Volume Reduction Surgery

maximal medical therapy, to classify patients according to ability to benefit from surgery with an acceptable surgical risk, and to accurately and appropriately exclude those patients likely to have a poor outcome. The initial evaluation schema developed at Washington University has been refined by analysis of surgical results of the NETT trial and other studies. As can be expected from our understanding of the pathophysiology of emphysema, this schema suggests that the patients who will have the best outcome from volume reduction surgery are those patients with marked hyperinflation and heterogenous involvement of emphysema. Ideally, an isolated portion of the lung is affected most and is nonfunctioning. The remaining lung, although emphysematous, is not totally destroyed and is capable of maintaining adequate gas exchange. The more closely a patient approaches this ideal model, the better the anticipated outcome. The patient profile used at Washington University Medical Center for evaluation of patients with COPD is shown in Table 50-1.

615

Some of the most salient points in the evaluation include the following characteristics: 1. Airway obstruction produced predominantly by emphysema rather than by intrinsic airways disease 2. Emphysematous lungs with sufficient regional variation in the distribution of emphysema (heterogeneity) to provide target areas of virtually nonfunctioning lung accessible to surgical resection 3. Marked hyperinflation of the thorax In addition to the very important history and physical examination, the evaluation relies heavily on physiologic and imaging studies. The specific methods for assessing patients for surgery are listed in Table 50-1. Inspiratory chest radiographs are used to evaluate the degree of thoracic hyperinflation, as evidenced by downward displacement and flattening of the diaphragm, as well as distention of the thorax with enlarged retrocardiac and retrosternal air spaces. Expiratory films provide additional information and may demonstrate

TABLE 50-1 Summary of Washington University Guidelines for Bilateral Lung Volume Reduction Surgery Indications

Contraindications

General

Disability despite maximal rehabilitation Ability to meet rehabilitation goals Cessation of tobacco use >6 mo Weight 80%-120% ideal body weight Patient expectation of goals reasonable

Minimal disability after completing pulmonary rehabilitation Inability to participate in rehabilitation Continued use of tobacco Significant comorbidity Previous pleurodesis or thoracotomy Significant purulent secretions or predominant airways disease Inability to taper from high-dose corticosteroid therapy Underweight, overweight

Anatomic Radiographic Evaluation

Marked emphysema

Minimal radiographically evident emphysema Bronchiectasis Homogeneously distributed emphysema

Heterogeneously distributed emphysema ■ Large target zones of poorly perfused lung with marked parenchymal destruction ■ Large areas with better preserved lung Marked thoracic hyperinflation Physiologic Evaluation

Marked airflow obstruction ■ FEV1 <45% predicted ■ FEV1 >15% if age >70 yr ■ FEV1 or DLCO >20% predicted

Marked hyperinflation ■ RV >150% predicted ■ LC >100% predicted

Alveolar gas exchange ■ DLCO <80% predicted ■ PACO2 <60 mm Hg ■ PaO2 >45 mm Hg ■ Exercise O2 requirements <6 L/min Cardiovascular function ■ Normal ejection fraction ■ No significant coronary artery disease ■ No pulmonary hypertension Exercise ■ Post-rehabilitation 6-min walk distance >500 ft ■ Able to complete 3 minutes of unloaded pedaling on a cycle ergometer

Minimal thoracic hyperinflation Chest wall or thoracic cage abnormalities Minimal to moderate airflow obstruction ■ FEV1 >45% predicted ■ FEV1 <15% if age >70 yr ■ FEV1 or DLCO <20% predicted Minimal hyperinflation ■ RV <150% predicted ■ LC <100% predicted Disordered alveolar gas exchange ■ DLCO <10% or >80% ■ PaCO2 >60 mm Hg ■ PaO2 <45 ■ Exercise O2 requirements >6 L/min Cardiovascular dysfunction ■ Diminished ejection fraction ■ Significant coronary artery disease ■ Mean PAP >35 mm Hg or systolic PAP >45 mm Hg Exercise ■ Post-rehabilitation 6-min walk distance <500 ft ■ Unable to complete 3 minutes of unloaded pedaling on a cycle ergometer

PAP, pulmonary artery pressure.

Ch050-F06861.indd 615

1/21/2008 11:45:19 AM

616

Section 3 Lung

asymmetry of air trapping in one lung, as well as the degree of impairment in movement of the chest wall and diaphragm. The chest radiographs also provide an initial indication of the overall severity and relative distribution of emphysema. Other findings on these films, such as marked pulmonary

FIGURE 50-2 CT scans of the same patient as in Figure 50-1. Severe emphysema involved upper lobes (top) more than the middle (middle) or lower lobes (bottom).

A

B

scarring, pleural disease, infiltrates, adenopathy, effusions, and cardiovascular abnormalities, may be useful for determining ineligibility for surgery. The standard chest computed tomography (CT) examination without intravenous contrast provides critical information for the selection process (Fig. 50-2). Most important, it provides a detailed depiction of the severity and distribution of emphysema. This is most helpful in characterizing whether the patient’s limitations are secondary to emphysema or airway disease. It is also important in establishing the presence and location of target areas. High-resolution CT provides increased sensitivity for revealing occult bronchiectasis or underlying interstitial lung disease. In addition, CT may demonstrate evidence of underlying pathology, such as pleural disease, bronchiectasis, infection, cancer, or cardiovascular disease, which might preclude LVRS. Nuclear medicine ventilation-perfusion lung scans depicting regional blood flow patterns (Fig. 50-3) provide a valuable roadmap for surgery. The absolute severity of emphysema cannot be assessed because the distribution of the perfusion agent is relative, but the presence of diffuse or upper or lower lobe predominant disease can be assessed. There is considerable variation in the interpretation of CT scans to evaluate patients for LVRS. Because the entire lung is affected to some degree by emphysema, it may be difficult to assess if the disease is truly heterogenous in distribution. Hersh and colleagues assessed the ability of radiologists and pulmonologists to interpret the distribution and severity of emphysema on CT imaging. There was considerable interobserver variability.11 Quantitative measures based on CT scan densitometry may improve characterization of what constitutes heterogenous emphysema from homogenous involvement and upper lobe predominance from diffuse disease. In the NETT trial, a single radiologist evaluated a given patient’s CT scan. Illustrating the difficulty of radiographic interpretation using visual scoring methods, the authors reported that 63% of patients were classified as having “upper lobe predominance,” but 54% of the same group of patients were classified as having “heterogeneous” involvement (Fishman et al, 2003).12

C

FIGURE 50-3 Perfusion lung scans, posterior view, of three patients evaluated for lung volume reduction surgery. A, Virtually absent perfusion of both upper lung zones, providing “target areas” for surgical resection. B, Virtually absent perfusion of both lower lung zones, providing “target areas” for surgical resection. C, Patchy perfusion throughout both lungs, with no “target area” accessible (see text).

Ch050-F06861.indd 616

1/21/2008 11:45:19 AM

Chapter 50 Lung Volume Reduction Surgery

Assessment of cardiac function is a critical portion of the evaluation for lung volume reduction surgery. This includes an appraisal for underlying pulmonary hypertension, coronary artery disease, and other significant cardiac dysfunction. Rest and exercise dobutamine echocardiography, radionuclide ventriculograms, thallium imaging, and other similar studies may provide useful information for risk stratification. However, these noninvasive tests of cardiac function are often limited. Exercise testing is often not useful owing to the patient’s inability to exercise to heart rate limits. Echocardiography may not provide adequate information because of chest hyperinflation, resulting in poor visualization of the heart. Concern for inducing bronchoconstriction may limit the use of dipyridamole or adenosine. To obtain a definitive answer, many LVRS candidates eventually undergo right- and leftsided heart catheterization. Review of the surgical results of LVRS reveals several predictors of surgical mortality. Most notably, the NETT trial initially included patients who did not meet the concepts that form the basis of the surgery—lack of appropriate targets to resect or severe impairment of the remaining lung. Patients with FEV1 less than 20% of predicted and homogeneous distribution of emphysema on CT scan, or carbon monoxide diffusion capacity (DLCO) of less than 20% of predicted, had no change in ability to exercise, no improvement in FEV1, no change in 6-minute walk test, no improvement in quality of life, and a 16% 30-day mortality rate.13 The high mortality rate seen in these high-risk patients prompted a modification of the NETT protocol to exclude from randomization any patients meeting these criteria. However, these criteria may not present an absolute contraindication. Retrospective review of patients meeting the NETT “high risk” criteria for FEV1 and DLCO by Cooper and colleagues in their own series did not demonstrate excess mortality and showed improvement in respiratory function.14 This suggests that presence of suitable anatomic heterogeneity may be the most important determinant of outcome. In the follow-up publication on the morbidity and mortality experienced by patients undergoing LVRS, the NETT trial investigators reported a 5.5% 90-day mortality among the 511 non–high-risk patients who were randomized to surgery and underwent LVRS. Non–upper lobe–predominant emphysema was the only predictor of 90day mortality.15 In summary, (1) patients with emphysema may be effectively distinguished from those limited by intrinsic airway disease by history, physical examination, and, most useful, pulmonary CT; (2) the degree of regional parenchymal destruction is analyzed by CT of the chest, and the regional distribution of function is assessed by radionuclide ventilation-perfusion lung scanning; and (3) thoracic distention is evaluated by chest radiograph and plethysmographic determination of lung volumes. All patients will benefit to some degree from pulmonary rehabilitation, but only a selective few are candidates for LVRS because of significant comorbidities, homogeneous distribution of disease, or inadequate pulmonary reserve. There is an element of subjectivity to section criteria. The authors of this chapter continue to be conservative in patient selection. Eligibility criteria are summarized in Table 50-1.

Ch050-F06861.indd 617

617

At Washington University Medical Center, approximately 80% of patients referred for this procedure have been excluded from surgery, most commonly because of lack of target areas for surgical resection (30%), insufficient thoracic distention (16%), and the presence of significant comorbidity (16%) (Ciccone et al, 2003).10 Of note is that 8% of referrals were denied surgery because it was believed that their FEV1 was too well preserved. In the NETT experience, of 3777 patients considered for entry into the NETT trial, only 1218 were able to undergo randomization (Fishman et al, 2003).12

OPERATIVE APPROACH A number of variations to the surgical approach have been described. Both video-assisted thoracoscopic surgery (VATS) and median sternotomy have been widely utilized at different centers. In the randomized NETT trial, of the surgical procedures performed, 359 underwent median sternotomy and 152 patients underwent bilateral VATS procedures.5 If a center had expertise in both approaches, the patients in the surgical arm were randomized to either approach (29% of patients, n = 148). The authors reported no intraoperative death with either approach and equal 30-day mortality. There was no difference in complication rate, including the incidence of sustained air leak. The median hospital length of stay was 1 day longer for the median sternotomy group, and the costs associated with the operation were less in the VATS group, likely owing to the length of stay. The VATS group achieved independent living after LVRS sooner than the median sternotomy group. By 1 year, the functional outcomes were identical. We favor a median sternotomy approach because of our comfort and experience with it. Preoperatively, a thoracic epidural catheter is placed under fluoroscopic guidance to ensure optimal postoperative relief of pain with minimal need for systemic narcotics or respiratory depressants. A left-sided double-lumen tube is used to provide isolated ventilation to either lung. The operative approach we have employed was described by Cooper and colleagues.16 Before sternal division, a long, curved sponge forceps holding a rolled gauze pad is inserted upward behind the sternum from the subxiphoid position and is used to sweep the mediastinal pleura on either side away from the midline. This avoids entry to either pleural space at the time of sternal division. The intact pleura can be deliberately incised after sternotomy, which keeps the opposite lung from protruding into the operative field when reduction of the first lung is taking place. The initial lung is deflated, and adhesions, if present, are carefully dissected free to avoid laceration of the surface of the lung. Most patients with emphysema have few or minimal adhesions, although occasionally, widespread dense adhesions are encountered, usually as a result of a previous pneumonia. Once the lung has become atelectatic, direct visualization of most areas is quite satisfactory. After 5 to 10 minutes of deflation, the less-diseased portions of the lung become atelectatic by the process of absorption atelectasis. However, the more destroyed portions of the lung, those generally targeted

1/21/2008 11:45:20 AM

618

Section 3 Lung

for resection, may remain distended, owing to the loss of elasticity and the absence of blood flow. Simple cautery puncture of the surface of the region to be excised usually leads to immediate deflation because of the enormous collateral ventilation from one portion of the lung to another in patients with severe emphysema. Most candidates for bilateral lung volume reduction have a pattern of upper lobe–predominant disease. About 80% of the right upper lobe is excised by multiple applications of a linear stapler device buttressed with strips of reinforcing material such as bovine pericardium attached to the surfaces of the stapler before its application. The right inferior pulmonary ligament is usually divided to improve the ability of the remaining lung to fill the apical pleural space. On the left side, the lingula is generally spared, as it is usually less diseased than the superior subdivision. Thus, about 60% of the left upper lobe is excised with multiple applications of the linear stapler. The pulmonary ligament on the left side is divided when possible, but in older patients the temporary displacement of the heart needed to visualize this area may be poorly tolerated, in which case the ligament is left intact. If there is concern that the remaining lung will not easily reoccupy most of the upper portion of the pleural space, then the apical pleura can be released from the chest wall to form a so-called pleural tent, which loosely drapes over the upper surface of the remaining lung. The space above the tent fills with fluid, resulting in a temporary “soft thoracoplasty.” It is important to remember that the purpose of LVRS is not to excise all grossly diseased lung but to achieve sufficient volume reduction to improve respiratory mechanics and the function of the remaining lung. An overly aggressive approach may increase postoperative morbidity and mortality, whereas insufficient reduction will diminish the magnitude and duration of benefit achieved. VATS resection employs a similar strategy of lung resection.5 As described by Schrager,17 the patient is positioned in the lateral decubitus position after general endotracheal anesthesia is induced using a double-lumen tube to facilitate lung isolation. The trocar and thoracoscope are placed in the posterior axillary line in the seventh intercostal space. Two additional ports are placed for the endoscopic stapler and for a grasping instrument. To facilitate resection, the incision for the grasper is placed one or two rib spaces superior and posterior to the thoracoscope port, and the incision for the stapler is placed at the same level as the grasper port but 8 cm anteriorly. Although some authors have suggested that a unilateral approach may be preferred due to the benefits achieved with unilateral LVRS, and with the implication that unilateral LVRS is intrinsically less morbid, larger studies have demonstrated this not to be the case. In a sequential treatment case series of 166 patients utilizing VATS technique, McKenna and coworkers demonstrated that although patients undergoing unilateral LVRS had good response to improvement in FEV1 (31% change from baseline) and oxygen independence (35%), bilateral surgery yielded a greater improvement in FEV1 (57% change from baseline) and greater oxygen independence (68%).18 However, operative morbidity and mor-

Ch050-F06861.indd 618

tality were the same in both groups. Given the improvement with unilateral surgery, unilateral operation may still be offered to some patients who are not candidates for a bilateral operation due to prior thoracic intervention or inappropriate anatomy for bilateral LVRS. The National Emphysema Treatment Trial did not address the issue of unilateral procedures and, therefore, the Medicare coverage decision in the United States does not address unilateral LVRS procedures. The method of lung parenchyma transection using buttressed staple line (bovine pericardium or other substance) has also been extensively studied. The most frequent complication of LVRS is air leak. In Cooper’s series of 250 patients, 45.2% of patients suffered parenchymal air leaks lasting greater than 1 week (Ciccone et al, 2003).10 All patients underwent bovine pericardial strip reinforcement of the staple line. In the NETT trial, 90% experienced an air leak in the first 30 days.19 The median duration was 7 days. Within the NETT trial, the occurrence was independent of the type of incision (median sternotomy versus VATS), and of the use or nonuse of a staple line buttressing material. Most patients received some form of staple line reinforcement. One smaller randomized study of patients undergoing VATS for bilateral LVRS demonstrated 39% incidence of air leak in the bovine pericardium group and 77% incidence in the control group.20 There was also a decrease in the duration of air leak with the use of staple line reinforcement. The authors of the study were unable to demonstrate a change in the length of hospital stay with the diminished duration of air leak complications.

POSTOPERATIVE CARE Virtually all patients are extubated in the operating room. If excessive secretions are present, as indicated by history or by routine preoperative bronchoscopy, then a minitracheostomy is performed in the operating room at the time of extubation, to facilitate clearance of secretions. Patients rarely require reintubation in the initial 48 hours. However, significant hypercarbia and acidosis may be present for several hours owing to the residual effects of the anesthesia or incomplete analgesia. Contrary to the management of other patients undergoing pulmonary resection, the chest tubes in these patients are attached to water-seal drainage without the use of suction. The loss of elastic recoil and the obstructive physiology of the remaining lung make it rather resistant to the usual loss of volume ordinarily associated with a postoperative pneumothorax. The fragile nature of the lungs renders them more susceptible to the adverse effects of increased transpulmonary pressure and overdistention caused by chest tube suction. This has a tendency to increase the magnitude and prolong the duration of air leaks in these patients. Postoperative management is directed at adequate pain relief, early ambulation, vigorous chest physiotherapy and management of secretions, use of inhaled bronchodilators, and minimal use of systemic corticosteroids.

MORBIDITY AND MORTALITY Over one half of patients undergoing LVRS experience some form of postoperative complication. This has been demon-

1/21/2008 11:45:20 AM

Chapter 50 Lung Volume Reduction Surgery

strated in both large randomized trials and in large case series (Ciccone et al, 2003).10,18,19 As discussed previously, air leaks occur in essentially all patients but are sustained (>7 days) in approximately one half of patients. Risk factors for prolonged air leaking include the degree of pleural adhesions, a lower DLCO reflecting the extent of underlying lung destruction, and the use of corticosteroids.19 Other significant morbidity including prolonged ventilator dependence, pneumonia, or need for reintubation occurred in one third of patients. Major cardiac morbidity including arrhythmia, myocardial infarction, or pulmonary embolism occurred in one fifth.15 Advanced age and advanced lung disease are the predictors for both major pulmonary and cardiovascular morbidities.15

RESULTS

FEV1 (mL) and 6-minute walk (feet)

In keeping with known natural history of emphysema, the improvements in objective measures of lung function (FEV1) and exercise tolerance (6-minute walk) are not sustained (Fig. 50-4). The greatest improvements in function occur in the first year and diminish back to the presurgical baseline at around 5 years (Ciccone et al, 2003).10 The improvement in FEV1 at 6 months averaged 51%; at 3 years, 23%; and at 5 years, 9%. However, subjective improvement as determined by SF-36 scoring persists for much longer. Patients undergoing medical management continue to experience deterioration in their functional measures well below baseline. The randomized NETT trial has demonstrated these findings in patients with a median follow-up of 4.3 years (Naunheim et al, 2006).21 Patients with non–upper lobe disease may not fare as well with LVRS. Results of cohort analysis of patients with isolated lower lobe disease have shown the benefits of LVRS to be less pronounced and less sustained. There is an accelerated

1400 1300 1200 1100 1000 900 800 6-min. walk (ft) FEV1

700 600

PO 5

y

PO 3

y

PO y 1

6

m on th s

PO

tio n lit a eh ab i

rr te Af

Ev al ua tio n

ba se lin e

500

FIGURE 50-4 In patients who had completed 5 years of follow-up there is a decrement in both FEV1 and exercise capacity. PO, postoperative. (ADAPTED FROM DATA FROM CICCONE AM, MEYERS BF, GUTHRIE TJ, ET AL: LONG-TERM OUTCOME OF BILATERAL LUNG VOLUME REDUCTION IN 250 CONSECUTIVE PATIENTS WITH EMPHYSEMA. J THORAC CARDIOVASC SURG 125:513-525, 2003.)

Ch050-F06861.indd 619

619

rate of decline in FEV1 and objective measure of exercise tolerance by the 6-minute walk (Ciccone et al, 2003).10 The exact reason for the reduced benefit with lower lobe LVRS is unclear. It has been suggested that these patients tend to have more extensive disease and require a more extensive lung resection than patients with predominantly upper lobe disease and that subsequent tethering of the diaphragm results in less restoration of the emphysematous thorax to normal chest configuration. A large percentage of these patients with predominantly lower lobe emphysema have α1-antitrypsin deficiency. In randomized trials there was a trend, not statistically significant, toward increased mortality in this small subset of patients.22 Given the limited data, no strong recommendation can be given to guide the application of LVRS in patients with α1-antitrypsin deficiency, especially in patients with predominantly lower lobe disease. LVRS was developed as a palliative procedure. In the highly selected patients presented in Cooper’s series, Kaplan-Meier analysis demonstrated 67.7% survival at 5 years.10 The broader inclusion criteria of the NETT trial resulted in an interim report demonstrating increased mortality in LVRS patients with FEV1 less than 20% and either a DLCO less than 20% or homogeneous distribution of disease or both.13 Excluding these admittedly high-risk patients, an overall survival advantage has been demonstrated in patients treated with LVRS as compared with best medical care. The survival benefit is greatest in patients with upper lobe predominant disease and low baseline exercise tolerance (below the sex-specific 40th percentile for exercise capacity). This subgroup of patients also has the best improvement in exercise tolerance and the most sustained benefit in self-assessed quality of life (Fig. 50-5) (Naunheim et al, 2006).21 In the entire cohort of patients, exercise capacity improved (>10 watts work from baseline) in 23%, 15%, and 9% after LVRS at 1, 2, and 3 years, respectively, compared with 5%, 3%, and 1% of medically managed patients. Patients with upper lobe emphysema and high exercise tolerance demonstrated no survival benefit from surgery. These patients did, however, have improvement in exercise tolerance and quality of life, although the effects were less pronounced than in patients with upper lobe emphysema with low exercise tolerance (Fig. 50-6). Overall there was wide variation in exercise capacity and quality-of-life perception in both surgical and medical groups, making it difficult to predict long-term benefit for a given patient (Naunheim et al, 2006).21 The physiologic changes responsible for the subjective and functional improvement experienced by patients remain unclear. Not all objective parameters improve to the same degree. For example, in any individual patient, a minor improvement in FEV1 may be associated with a marked reduction in residual volume or with a very significant increase in PaO2. However, the significant improvement observed in virtually all objective parameters for LVRS patients as a whole confirms that the subjective benefits perceived by patients are related to physiologic alterations produced by the procedure. This is in contrast to the “sham effect” produced by numerous procedures performed in the last century, for which no demonstrable objective improvement could be documented.

1/21/2008 11:45:20 AM

MOHSENIFAR Z, ET AL: LONG-TERM FOLLOW-UP OF PATIENTS RECEIVING LUNG-VOLUME-REDUCTION SURGERY VERSUS MEDICAL THERAPY FOR SEVERE EMPHYSEMA BY THE NATIONAL EMPHYSEMA TREATMENT TRIAL RESEARCH GROUP. ANN THORAC SURG 82:431-443, 2006.)

1.0 Overall: RR = .88 P = .19

0.8 Probability of death

FIGURE 50-5 A, There is a survival advantage to patients undergoing lung volume reduction surgery. B, The benefit is most pronounced in patients with upper lobe–predominant disease and low baseline exercise tolerance. C, The benefit is lost in patients with non–upper lobe– predominant disease or in patients with upper lobe–predominant disease and high exercise capacity. (ADAPTED FROM NAUNHEIM KS, WOOD DE,

0.6

Medical

0.4 LVRS 0.2

0 0

1

2

A

3

4

5

6

7

8

7

8

7

8

Years after randomization 1.0 Overall: RR = .57 P = .01

Probability of death

0.8

Medical

0.6 LVRS 0.4 0.2 0 0

1

2

B

3

4

5

6

Years after randomization 1.0 Overall: RR = .85 P = .02

Probability of death

0.8

Medical

0.6 LVRS 0.4 0.2 0 0

1

2

C FIGURE 50-6 Summary of long-term benefits of LVRS.21

4

5

6

Years after randomization Survival 5 Years Postop

Quality of Life 5 Years Postop

Exercise Tolerance 3 Years Postop

Upper lobe predominance

Low exercise tolerance

↑↑

↑↑

↑↑

Upper lobe predominance

High exercise tolerance

–

↑

↑

Non–upper lobe predominance

Low exercise tolerance

–

–

–

Non–upper lobe predominance

High exercise tolerance

–

–

–

↑

↑

↑

All patients

Ch050-F06861.indd 620

3

1/21/2008 11:45:20 AM

Chapter 50 Lung Volume Reduction Surgery

In summary, lung volume reduction surgery is a viable option in only a select group of patients with emphysema. Patients must be motivated. They must have successfully completed pulmonary rehabilitation and continue to have significant dyspnea, and they must have the appropriate anatomy to benefit from LVRS. Meticulous patient selection remains essential to minimizing morbidity and ensuring maximal benefit—improvement in physical function, mental well-being, and overall survival.

COMMENTS AND CONTROVERSIES In the early 1990s, LVRS was revived by Cooper and his colleagues as an operative strategy to palliate the symptoms and possibly prolong the life of highly selected patients with emphysema. There was immediate and widespread enthusiasm for its application. Not surprisingly, it was employed too widely, often in poorly selected patients and in less experienced centers. Less than satisfactory overall results in Medicare beneficiaries prompted the development of the National Emphysema Treatment Trial (NETT). The NETT trial confirmed what most experienced centers already knew—that well-selected patients operated on in experienced centers derived benefit. The authors have extensively reviewed the historical background of LVRS, the proper selection and management of patients, and the operative options for the current applica-

Ch050-F06861.indd 621

621

tion of LVRS. Results of the NETT trial and other large collected series are described in detail. G. A. P.

KEY REFERENCES Ciccone AM, Meyers BF, Guthrie TJ, et al: Long-term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg 125:513-525, 2003. Cooper JD, Trulock EP, Triantafillou AN, et al: Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 109:106-116, 1995; discussion 116-119. Deslauriers J: History of surgery for emphysema. Semin Thorac Cardiovasc Surg 8:43-51, 1996. Fishman A, Martinez F, Naunheim K, et al: A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 348:2059-2073, 2003. National Emphysema Treatment Trial Research Group: Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 345:1075-1083, 2001. Naunheim KS, Wood DE, Mohsenifar Z, et al: Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg 82:431-443, 2006. Sutherland ER, Cherniack RM: Management of chronic obstructive pulmonary disease. N Engl J Med 350:2689-2697, 2004.

1/21/2008 11:45:20 AM

chapter

51

EMERGING SURGICAL TECHNOLOGIES FOR EMPHYSEMA Federico Venuta Erino A. Rendina

Key Points ■ Airway bypass and bronchoscopic lung volume reduction (BLVR)

are moving toward clinical application. ■ Lung morphology (heterogeneity) and collateral ventilation are

important factors in selecting the most appropriate procedure. ■ The airway bypass allows bypassing the small obstructed

airways. ■ The creation of artificial communications between lung paren-

chyma and segmental bronchi facilitates lung deflation, taking advantage of collateral ventilation. ■ BLVR with one-way valves facilitates deflation of the most overinflated emphysematous parts of the lung. ■ One-way valves are designed to control and redirect airflow by preventing air from entering the target lung but allowing air and mucus to exit.

Emphysema is a debilitating lung disease that continues to be a major source of morbidity and mortality in developed countries. Estimates suggest that as many as 2 million people are affected in the United States; many of them develop severe dyspnea and subsequent deterioration in quality of life, with associated costs of US$2.5 billion annually and almost 17,000 deaths each year.1-4 Medical therapy is the mainstay of treatment and primarily consists of smoking cessation, pulmonary rehabilitation, administration of bronchodilators, and, when indicated, steroids and supplemental oxygen.

EMPHYSEMA: DEFINITION AND PATHOPHYSIOLOGY Emphysema is characterized by permanent and anatomically irreversible enlargement of air spaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis.5 This definition is probably the only concept about emphysema that has not been modified over the past 50 years. In fact, the clinical approach and the therapeutic policy have been progressively changed to reach the current state. From the functional point of view, a considerable degree of emphysema is suspected when the forced expiratory volume in 1 second (FEV1) is significantly decreased, the total lung capacity (TLC) and residual volume (RV) are increased, and single-breath carbon monoxide diffusion capacity (DLCO) is reduced. The regional severity of emphysema within each lung or between both lungs may significantly vary; heterogeneity

refers to the regional variation of severity of emphysema throughout the parenchyma. Patients who have areas of severe emphysema among areas of relatively mild or moderate disease are said to possess a high degree of heterogeneity. Heterogeneity may exist within the same lobe or between different lobes. When the emphysematous destruction is diffuse throughout the lungs, with all regions similarly affected, the heterogeneity is said to be low and the disease is considered homogeneous. Heterogeneity can be assessed with chest radiographs, computed tomography (CT), and lung scans.6 The major pathophysiologic consequences of emphysema can be attributed to a loss of elastic recoil that results in static and dynamic hyperinflation. The loss of elasticity causes a progressive enlargement of the lung and thoracic diameters; the rib cage expands to an abnormal position, and the diaphragm becomes flattened. This results in severely impaired respiratory mechanics with consequent dyspnea; the work of breathing is markedly increased, and the amount of air moved in and out of the chest with each breath is quite limited. The main symptom for patients with severe emphysema is shortness of breath during minimal physical activity. Despite all the available therapies, the course of the disease is progressively disabling, with a significant increase in overall morbidity and mortality; over the past 50 years, many investigators have attempted to determine which factors influence survival of patients with chronic obstructive pulmonary disease (COPD). For example, if the FEV1 is lower than 30% of the predicted value, fewer than 50% of patients will survive for 3 years7,8 notwithstanding optimal medical therapy. Therefore, medical treatment certainly shows some limitations in the most advanced phases of the disease.

SURGICAL THERAPY FOR EMPHYSEMA: HISTORICAL NOTES Various surgical procedures have been promoted in the past to relieve dyspnea and improve quality of life in patients with advanced emphysema, including costochondrectomy, thoracoplasty, phrenicectomy, pneumoperitoneum, pleural abrasion, denervation of the lung, glomectomy, and many others.9,10 Although early results were often encouraging, a sustained objective functional improvement was rarely achieved, and most of these procedures were progressively abandoned. Bullectomy is the only operation that has stood the test of time. Lung transplantation and lung volume reduction surgery (LVRS) are now established treatment modalities in selected patients. Despite controversies, LVRS has been shown to be beneficial for selected patients with end-stage emphysema when

622

Ch051-F06861.indd 622

1/21/2008 11:46:08 AM

Chapter 51 Emerging Surgical Technologies for Emphysema

medical therapy has failed.11,12 This operation was rescued and popularized by Cooper and associates13 in the early 1990s and progressively gained acceptance in the medical community. The basic principle of this procedure is that removal of the most diseased parts of the hyperinflated lungs helps to remodel and restore the chest wall and diaphragmatic mechanics during respiration. There is no doubt that LVRS allows a significant functional improvement in a selected group of patients; however, it still carries a substantial morbidity, even if mortality is low at the centers with the larger experience.14 Patients with the most advanced functional deterioration show a higher surgical mortality and less impressive functional results, suggesting that LVRS needs to be considered more carefully in these situations.15 In particular, patients with very low FEV1 and either homogeneous emphysema or a very low DLCO are at high risk of death, and the most recently published data have indicated that patients with non–upper lobe disease have a higher operative mortality.15 Bronchoscopic alternatives to the surgical approach have been recently proposed, and some of them could play an important role in the future. In particular, airway bypass and bronchoscopic lung volume reduction (BLVR) with one-way valves are moving toward clinical application.

AIRWAY BYPASS Airway bypass, a new experimental endoscopic procedure for the treatment of emphysema, is based on the concept of collateral ventilation, first described by Van Allen and colleagues16 in 1930. Collateral ventilation is defined as the ability of gas to move from one part of the lung to another through nonanatomic pathways. Van Allen’s group obstructed sublobar bronchi in canine lungs and noted no collapse distal to the obstruction. They used the term collateral respiration to explain how gases may enter one lobule from another in the lung without resorting to known anatomic pathways. Hogg and coworkers17 demonstrated that resistance to collateral airflow in postmortem emphysematous human lungs was low in comparison to normal lungs, concluding that collateral channels may be important ventilatory pathways in emphysema. Terry and coworkers18 studied collateral ventilation in normal and emphysematous subjects. In young normal persons, they found that resistance to collateral ventilation is high at functional residual capacity and concluded that there was a negligible role for collateral channels in the distribution of ventilation in these subjects. However, patients with emphysema had lower resistance through collateral channels than through the airways. At that time, it was postulated that these results might have startling therapeutic implications.19 Collateral ventilation is present in normal lungs but does not play an important role; in emphysematous lungs, the destruction of alveolar septa create a preferential route for collateral air flow. Gunnarsson and coworkers20 looked in detail at patients with COPD undergoing general anesthesia; they described significantly less atelectasis and shunt in these patients compared with the population with normal lungs. Three levels of collateral ventilation have been described in human lungs. Kohn first described intra-alveolar pores

Ch051-F06861.indd 623

623

more than a century ago, and in 1955, Lambert described accessory bronchiolar-alveolar connections.21 Interbronchial channels were described by Martin in dogs and were subsequently verified to be present in humans.22 Morrell and colleagues23 discovered that segmental collateral ventilation occurs to a much greater extent in the emphysematous lung than in the normal lung. Although it has not been described in the most recent reviews,22,24 the older medical literature provides some support for the concept of poorly characterized interlobar communications.25 Using careful dissection techniques and selective lobar intubation, Hogg and coworkers17 noted complete upper/lower lobe fissures in only three of eight normal lungs and one of eight emphysematous lungs, with substantial flow across the incomplete fissures. Rosenberg and Lyons26 examined 13 isolated lungs from patients with various diseases, including one patient with emphysema and pneumonia with significant crosslobar flow; their microscopic analysis of the regions adjacent to the fissures where interlobar collateral flow had been seen demonstrated lobar/alveolar pores, potentially variants of the pores of Kohn. Such interlobar flow and communications were not observed in pediatric lungs. It has been speculated that pathologic collaterals may represent inflammatory or sheer force damage between airways and the parenchyma and serve to even out inhomogeneous areas.22,24 Macklem19 suggested that creating extra-anatomic pathways through the chest wall, between the surface of the lung and the skin, might alleviate hyperinflation and improve respiratory mechanics; in fact, bypassing the small obstructed airways should allow trapped gas to exit from the hyperinflated emphysematous lung. The extensive collateral ventilation present in emphysematous lungs can be demonstrated at the time of LVRS. The portion of the lung to be removed remains distended after suspension of ventilation to that lung. Compression of the lung does not significantly deflate the lobe through collapse of the small airways. However, a 1-mm puncture on the surface of the lung leads to rapid collapse of the lobe because of the extensive collateral ventilation from other parts of the lobe to the lobule that has been punctured.27 The procedure proposed by Macklem was certainly a great idea; however, it could create some problems of acceptance and management in the clinical setting. The concept of bypassing the small obstructed airways was recently rescued and simplified by the group at Washington University in St. Louis (Lausberg et al, 2003).27 They proposed that the creation of artificial communications between lung parenchyma and segmental bronchi would facilitate lung deflation and improve expiratory air flow and, consequently, respiratory mechanics. On inspiration the regular airways could open, allowing air passage through normal channels; on expiration, the new passageways could provide escape pathways that bypass the obstructed small airways. This procedure is particularly indicated for patients with a homogeneous distribution of the disease, to maximize deflation and functional results. The airway bypass procedure was initially performed by bronchoscopically puncturing the wall of segmental bronchi with a radiofrequency catheter and inserting a specially designed stent to keep open the internal bronchopulmonary

1/21/2008 11:46:08 AM

624

Section 3 Lung

communications (Fig. 51-1). The first step to evaluate the potential for this procedure was performed in the laboratories of the Washington University School of Medicine in St. Louis.27 A specially designed ventilation chamber (Fig. 51-2) was prepared to evaluate the improvement obtained by creating airway bypass in emphysematous lungs resected for lung transplantation. Twelve lungs were closed in the chamber and

connected to a pneumotachygraph to measure the airflow. The baseline FEV1 was measured, and then flows were measured again after creation of stented passages. The FEV1 increased from an average of 245 mL at baseline to 447 mL after the creation of three stented passages in each lung, and to 666 mL after six stented passages were created. The experimental procedure was repeated in normal lungs that

FIGURE 51-1 Technique for insertion of bronchopulmonary stents. A, The flexible bronchoscope is inserted to the level of the segmental bronchus. B, A radiofrequency probe inserted through the working channel of the bronchoscope is used to create a hole through the bronchial wall into the adjacent lung parenchyma. C, A balloon-expandable stent is passed down the bronchoscope and expanded with the proximal end just inside the bronchial lumen. (FROM LAUSBERG HF,

B

CHINO K, PATTERSON GA, ET AL: BRONCHIAL FENESTRATION IMPROVES EXPIRATORY FLOW IN EMPHYSEMATOUS HUMAN LUNGS. ANN THORAC SURG 75:393-398, 2003. REPRINTED WITH PERMISSION. COPYRIGHT ELSEVIER 2003.)

A C FIGURE 51-2 Schematic diagram of excised lung in a ventilation chamber. The lung is inflated by reducing pressure in the chamber to −10 cm of water pressure. A forced expiratory maneuver is produced by suddenly connecting the chamber to the large drum, which has been pressurized to 20 cm of water. Airflow exiting the bronchus is measured with a pneumotachygraph.

Pneumotach

(FROM LAUSBERG HF, CHINO K, PATTERSON GA, ET AL: BRONCHIAL FENESTRATION IMPROVES EXPIRATORY FLOW IN EMPHYSEMATOUS HUMAN LUNGS. ANN THORAC SURG 75:393-398, 2003. REPRINTED WITH PERMISSION. COPYRIGHT ELSEVIER 2003.)

Vacuum source

Ch051-F06861.indd 624

Barrel pressurized to 20 cm H20

1/21/2008 11:46:08 AM

Chapter 51 Emerging Surgical Technologies for Emphysema

had been harvested but not used for lung transplantation: with three stented holes, the FEV1 did not differ from baseline, confirming that the modifications in emphysematous lungs and probably the presence of collateral ventilation were the basis of the observations in the first part of the experiment. The improved flow rates observed in this simple ex vivo model with emphysematous lungs were encouraging and warranted further exploration. The second step was designed to assess the safety of the procedure and the ability to avoid injury to the adjacent blood vessels. A specially designed Doppler probe (Bronchus Technologies, Mountain View, CA) was used to map the extrabronchial vessel distribution (Rendina et al, 2003).28 This probe can be introduced through the operating channel of the flexible bronchoscope and used to scan, from the inner surface of the bronchus, the bronchial and pulmonary vessels located outside it. A preliminary safety study was performed in patients undergoing lobectomy for lung cancer and lung transplantation for emphysema. In this group of patients, after the target site was selected, the Doppler probe was withdrawn and a radiofrequency catheter was advanced to create a passage through the bronchial wall into the lung parenchyma. Twenty-nine passages were performed in the lobectomy patients with only two episodes of mild bleeding, and 18 passages were created in patients with emphysema undergoing lung transplantation. No major complications were observed. Further laboratory observations and preliminary clinical work demonstrated that the new pathways progressively closed within 2 to 3 weeks after the procedure, and that stents derived from intracoronary devices could prolong patency for only a limited period of time. The radiofrequency probe has the disadvantage of injuring adjacent tissue because of the radial spread of heat and of penetrating too deeply, with potential hemorrhage and pneumothorax. For this reason the technique was subsequently simplified and tested experimentally (Choong et al, 2005).29 Once the appropriate site within the airway was identified, the Doppler probe was exchanged for a 22-gauge transbronchial needle, which was advanced through the bronchial wall to create a small passage into the lung parenchyma. Aspiration through the needle was performed as it was slowly withdrawn out of the bronchial wall. The transbronchial needle had transparent tubing connected to it that provided visualization of the aspirated contents. The target site was not used if blood was aspirated or if there was evidence of blood oozing out of the small hole. An angioplasty catheter with an expandable balloon diameter of 2.5 mm and a length of 30 mm was then inserted into the fenestration and dilated. A 3 mm × 3 mm balloon-expandable stainless steel stent covered with a sleeve of silicone rubber was placed into the dilated passage (Fig. 51-3). To avoid, or at least delay, obstruction by granulation tissue, mitomycin C (1 mg/mL) was delivered over the stent with a delivery catheter. This is an anti-inflammatory and antifibrotic agent that has been reported to be useful in the treatment of airway stenosis.30,31 This compound selectively inhibits DNA synthesis through mitomycin C–induced cross-linking, which occurs primarily at guanine and cytosine. At sufficient drug concentrations, RNA and protein synthesis are also suppressed. Four episodes of minor and brief bleed-

Ch051-F06861.indd 625

625

FIGURE 51-3 Equipment used in the procedure for airway bypass stent placement. From top to bottom: 4.8-mm flexible bronchoscope, Doppler probe, 22-gauge transbronchial cytology needle, 2.5-mm angioplasty balloon, stent mounted on delivery device, expanded 3 mm × 3 mm stent seen front on, and expanded balloon of the stent delivery device. (FROM CHOONG CK, HADDAD FJ, GEE EJ, COOPER JD: FEASIBILITY AND SAFETY OF AIRWAY BYPASS STENT PLACEMENT AND INFLUENCE OF TOPICAL MITOMYCIN C ON STENT PATENCY. J THORAC CARDIOVASC SURG 129:632-638, 2005. COPYRIGHT ELSEVIER 2005.)

ing occurred during stent placement; these were treated with diluted topical epinephrine solution and resolved without incident. Also, one pneumothorax and one episode of leukopenia developed. Control stents, without drug application, were all occluded at the first week of bronchoscopic followup. In contrast, mitomycin C–treated stents had a prolongation of patency, and the duration of stent patency was also associated with the number of once-weekly topical mitomycin applications, reaching 20 weeks for dogs treated for 9 weeks with topical applications of the drug (Figs. 51-4 and 51-5). A combined needle and balloon device was subsequently developed to overcome the disadvantages encountered with the separate needle and balloon devices used in this study. To further improve patency and avoid multiple drug instillations within the airway, a drug-eluting stent has been proposed and tested experimentally in an animal model. A total of 107 controlled-release Paclitaxel stents have been implanted in dogs and compared with 50 control stents with no impregnation; the follow-up studies at 12 weeks demonstrated that 65% of the Paclitaxel stents were patent but no control stent was patent.32 The experimental studies reported in the literature have clearly demonstrated that the creation of bronchial fenestra-

1/21/2008 11:46:09 AM

626

Section 3 Lung

cantly prolong patency; this will probably bring this procedure to the clinical arena after testing in multicenter trials.

BRONCHOSCOPIC LUNG VOLUME REDUCTION WITH ONE-WAY VALVES

FIGURE 51-4 Kaplan-Meier freedom from stent closure after airway bypass in dogs; data stratified by treatment group. Group A, one treatment only with mitomycin C; Group B, treatment for 4 weeks (once weekly); Group C, treatment for 7 weeks; Group D, treatment for 9 weeks; Control, no Mitomycin C. (FROM CHOONG CK, HADDAD FJ, GEE EJ, COOPER JD: FEASIBILITY AND SAFETY OF AIRWAY BYPASS STENT PLACEMENT AND INFLUENCE OF TOPICAL MITOMYCIN C ON STENT PATENCY. J THORAC CARDIOVASC SURG 129:632-638, 2005.)

A

C

B

D

FIGURE 51-5 Examples of patent and occluded stents after airway bypass visualized on bronchoscopy. A, Stent at the time of placement. B, Occluded control stent at the 1-week follow-up. C, Patent mitomycin C–treated stent at the 1-week follow-up. D, Patent mitomycin C stent at the 14-week follow-up. (FROM CHOONG CK, HADDAD FJ, GEE EJ, COOPER JD: FEASIBILITY AND SAFETY OF AIRWAY BYPASS STENT PLACEMENT AND INFLUENCE OF TOPICAL MITOMYCIN C ON STENT PATENCY. J THORAC CARDIOVASC SURG 129:632-638, 2005. COPYRIGHT ELSEVIER 2005.)

tion is feasible and safe in normal lungs as well as in severely emphysematous organs. The registered functional improvement probably can last only as long as the new passageways stay open. The use of anti-inflammatory, antifibrotic, or antiblastic agents topically instilled or stent-eluted may signifi-

Ch051-F06861.indd 626

The airway bypass is not the only endoscopic procedure proposed to improve symptoms and quality of life in patients with emphysema. Other procedures have been described both experimentally and in selected clinical settings with the use of occlusive stents, synthetic sealants, and unidirectional valves (Ingenito et al, 2001; Lausberg et al, 2003).27,33-37 These procedures were all designed to reduce hyperinflation and obtain atelectasis of the most destroyed, functionless parts of the emphysematous lungs (heterogeneous emphysema). They have been evaluated in an attempt to find safe alternatives to LVRS, especially for patients with the most advanced disease; this group of patients, as mentioned earlier, show a higher surgical mortality, suggesting that LVRS may not be suitable for all of them. It has been postulated that blocking an airway that supplies the most overinflated emphysematous parts of the lung could cause atelectasis of these regions and contribute to the alleviation of symptoms. This was experimentally demonstrated by Ingenito and colleagues in 2001 (Ingenito et al, 2001).37 Among the experimental papers, this is probably the most interesting, and it clearly demonstrates the functional effectiveness of bronchoscopic exclusion of lung segments. Ingenito studied three groups of sheep with papain-induced emphysema and compared the effectiveness of LVRS, BLVR performed by occlusion of lung segments with a synthetic sealant, and a sham procedure that was a simple bronchoscopy. The results of this experimental work showed that, with this model, BLVR can produce the same functional results as LVRS. Instead of sealants, other authors have used endobronchial devices working as one-way valves. These devices allow air to exit from the lung parenchyma but not to enter, and they should also allow a sufficient clearance of bronchial secretions. There are basically two devices under clinical evaluation: the Spiration Umbrella (Fig. 51-6) and the Emphasys oneway valve (Fig. 51-7). These devices are placed in the segmental or subsegmental bronchi to obtain lobar exclusion. The goal of the procedure is deflation of the target area in patients with heterogeneous emphysema, mimicking LVRS. The Umbrella Implantable Intrabronchial Valve (IBV; Spiration, Redmond, WA) is a one-way valve designed for placement in the bronchi via flexible bronchoscopy. The valve is made of a nitilol (nickel-titanium) framework with five anchors that seat distally, engaging the airway without perforation and providing stability. The proximal portion is made up of six support stents that expand radially. These struts are covered by a synthetic polymer, forming an umbrella shape that conforms to the airway wall. The flexible membrane and struts allow conformation to the airways to improve sealing with minimal pressure on the mucosa. The valve is designed to limit airflow distally, but the membrane and support stents allow mucociliary clearance. Air and mucus flow proximally

1/21/2008 11:46:10 AM

Chapter 51 Emerging Surgical Technologies for Emphysema

627

FIGURE 51-7 First-generation endobronchial valve (EBV) designed to both control and redirect air flow.

FIGURE 51-6 The Spiration Umbrella Implantable Intrabronchial Valve (IBV). (COURTESY OF DR. D. WOOD, SEATTLE, WA.)

past the valve to allow decompression of collateral ventilation and to reduce the hazards of mucus impaction and obstruction pneumonia. The valve design includes a proximal center rod that allows repositioning or removal if required (Fig. 51-8). This device is currently under evaluation in a North American multicenter trial. The first generation Emphasys endobronchial valve (EBV; Emphasys, Redwood City, CA) is an endobronchial prosthesis designed to both control and redirect air flow. It is a oneway, polymer, duckbill valve that is mounted inside a stainless steel cylinder which is attached to a nitilol self-expanding retainer (see Fig. 51-7). It prevents air from entering the target lung but allows air and mucus to exit. The EBV is provided in three sizes, each intended for a different range of target bronchial lumen diameters: 4.0/5.5 mm (inner/ outer diameter), 5.0/7.0 mm, and 6.5/8.5 mm; the valve is 10 mm long. These valves are usually placed in the operating room, with the patient intubated under intravenous anesthesia (Propofol infusion) and spontaneous assisted ventilation. After the patient is intubated, the flexible bronchoscope is advanced into the endotracheal tube, and the target bronchi are chosen. They correspond to the most hyperinflated parts of the lung affected by heterogeneous emphysema. The valves are usually placed in the segmental bronchi, but subsegmental orifices can also be stented to obtain complete lobar occlusion. A guidewire is inserted through the operating channel of the bronchoscope and left in place while the bronchoscope is withdrawn; a flexible delivery catheter is guided to the target bronchus by the guidewire. Local anesthesia is generously administered before the valves are inserted to prevent coughing. The fiberoptic bronchoscope is reinserted after advancement of the delivery catheter; the tip

Ch051-F06861.indd 627

FIGURE 51-8 CT scan showing umbrella valve (IBV) in place in the segmental bronchi of the right upper lobe, which is partially atelectatic. (COURTESY OF DR. D. WOOD, SEATTLE, WA.)

of the delivery catheter containing the valve is pushed with a gentle rotation into the selected bronchial orifice, and the valve is delivered. Fiberoptic bronchoscopy performed after removal of the delivery catheter confirms correct placement of the valve. Gentle suction through the bronchoscope ensures correct opening of the valve to allow deflation of the lung and clearance of secretions. No fluoroscopy is required. The valves can be removed easily, if placement is not satisfactory, with the use of a rat-tooth grasper through the working channel of the bronchoscope. The EBV can be clearly seen on chest radiographs (Fig. 51-9). The first-generation EBVs have been extensively employed in several prospective, nonrandomized, single-center, longitudinal pilot studies to evaluate safety and short-term efficacy, with promising results in a selected group of patients with heterogeneous end-stage emphysema. A new generation of EBV, the Zephyr endobronchial valve (Fig. 51-10), is currently under evaluation in a multicenter prospective trial. This new device incorporates a one-way

1/21/2008 11:46:12 AM

628

Section 3 Lung

FIGURE 51-11 Bronchial diameter measurement gauge made of flexible polymer is attached to the proximal end of the distal housing of the Zephyr endobronchial valve (see text for description). FIGURE 51-9 Chest roentgenogram showing the one-way endobronchial valve (EBV) placed in the segmental orifices of the right upper lobe. (FROM VENUTA F, DE GIACOMO T, RENDINA EA, ET AL: BRONCHOSCOPIC LUNG VOLUME REDUCTION WITH ONE WAY VALVES IN PATIENTS WITH EMPHYSEMA. ANN THORAC SURG 79:411-417, 2005. COPYRIGHT ELSEVIER 2005.)

FIGURE 51-10 Zephyr endobronchial valve.

valve supported by a stent-like self-expanding retainer that secures the EBV in place during all physiologic conditions, including coughing. The retainer is a self-expanding tubular mesh structure that is cut from nitilol superelastic alloy tubing and processed to its final expanded dimensions. It is covered with silicone to create a seal between the implant and the bronchial wall; the silicone membrane is formed integrally with the struts of the self-expanding retainer component. When the EBV is delivered into the target bronchus, the retainer expands to contact the walls of the lumen. Also, this valve has been designed to allow air to be vented from the isolated lung segment while preventing air from refilling the isolated lung area during inspiration: it vents during expiration and closes when flow is reversed during inhalation. The Zephyr EBV is provided in two sizes: the EBV 4.0, designed for bronchial lumens with diameters of 4.0 to 7.0 mm, and

Ch051-F06861.indd 628

the Zephyr EBV 5.5, designed for bronchial lumens with diameters of 5.5 to 8.5 mm. The previous version of the device, as mentioned earlier, was provided in three different sizes for the same overall treatable lumen diameter range of 4.0 to 8.5 mm. The performance of the valve is different according to the type of valve (first generation versus second generation of EBV) and the size of the device itself. The cracking pressure, and therefore the flow resistance, is higher for the firstgeneration EBV than for the Zephyr valve. Moreover, within the two different models of valves, flow resistance is lower for valves of the larger diameter. Therefore, air expiratory flow is much higher for large valves of the second generation. A flexible delivery catheter is used to place the secondgeneration EBV valve in the targeted bronchial lumen. The catheter is constructed of a flexible stainless steel and polymer composite shaft. It has an actuation handle on the proximal end and a retractable polymer housing to contain the compressed Zephyr EBV on the distal end. A bronchial diameter measurement gauge made of flexible polymer is attached to the proximal end of the distal housing (Fig. 51-11). This measurement gauge allows the user to visually (bronchoscopically) measure the diameter of the bronchial lumen before the device is deployed, to verify that the size gauge of the valve is appropriate for the target lumen. The measurement gauge consists of two sets of flexible gauges. On the delivery catheter for the Zephyr EBV 4.0, the larger gauge spans a 7-mm diameter and the smaller gauge spans a 4-mm diameter, indicating the maximum and minimum treatable bronchial diameters, respectively, for this size of device. On the delivery catheter for the Zephyr EBV 5.5, the two gauges are sized to span diameters of 8.5 mm and 5.5 mm. The EBV is compressed into the retractable distal housing by the operator, using a specifically designed EBV loader system. The loaded catheter is advanced to the target location, and the valve is deployed by actuating the deployment handle, which retracts the distal housing and releases the EBV. The delivery catheter is designed to be inserted through a 2.8-mm diameter working channel of a flexible bronchoscope. Therefore, this new generation of valves can be placed under local anes-

1/21/2008 11:46:13 AM

Chapter 51 Emerging Surgical Technologies for Emphysema

thesia because the deployment maneuver is much simpler (Fig. 51-12). After a series of animal experiments, more than 100 patients have been treated so far in pilot studies performed at several centers worldwide, with selection criteria similar to those for LVRS. All patients had heterogeneous emphysema with clear target areas. The first series of 10 patients treated with a first-generation EBV was reported by Snell and colleagues.38 They demonstrated that the EBV bronchoscopic

FIGURE 51-12 First-generation endobronchial valve (EBV) (right side) and Zephyr valve (left side) correctly placed in two adjacent segmental bronchi.

629

prosthesis could be safely and reliably placed into the human bronchi; however, symptomatic improvement was observed only in four patients, with no major changes in radiographic findings, lung function, or 6-minute walk distance at 1 month, although baseline transfer improved from 7.47 ± 2.0 to 8.26 ± 2.6 mL/min/mm Hg and upper lobe nuclear perfusion fell from 32% ± 10% to 27% ± 9%. Toma and colleagues39 subsequently reported on eight patients who underwent unilateral volume reduction with a second-generation EBV. Five patients had emphysema judged too severe for LVRS, and three refused the operation. After valve placement, there was a 34% increase in FEV1 and a 29% difference in DLCO; CT scans showed a substantial reduction in regional volume in four of the eight patients. The same group also reported that, in a subgroup of patients in whom invasive measurements were performed, improvement in exercise capacity was associated with a reduction of lung compliance and isotime esophageal pressure–time product (Hopkinsons et al, 2005).40 Two other series of patients treated with EBV have been reported (Venuta et al, 2005).41,42 Overall, all patients tolerated the treatment well. Between three and five valves were placed in the target lobe, and most patients received unilateral treatment. It has been demonstrated that the procedure can be safely performed with encouraging short-term results (Table 51-1). In our experience (Venuta et al, 2005),42 we observed 1 contralateral and 2 bilateral pneumothoraces in 17

TABLE 51-1 Functional Capacities of Patients Undergoing Bronchoscopic Lung Volume Reduction With One-Way Valves* Parameter

Preoperative

24-48 Hours

1 Month

FEV1 (L/sec)

0.75 (0.45-2.09)

0.95 (0.5-2.6)

1.1 (0.2.5)

FEV1 (%)

22 (15-52)

33 (17-68)

30 (18-63)

3 Months 1 (0.5-2.3) 29 (18-58)

P Value 0.01 0.01

RV (L)

5.3 (3.6-7.1)

4.5 (2.9-6.2)

4.8 (2.5-5.8)

4.5 (3.2-6.3)

0.01

RV (%)

233 (178-329)

196 (157-329)

207 (112-260)

207 (144-278)

0.01

ITGV (L)

6.5 (4-8.1)

5 (3-6.6)

5.6 (3.4-6.4)

5.5 (3.9-7.1)

0.005

ITGV (%)

176 (135-222)

146 (111-200)

159 (126-198)

153 (127-195)

0.005

TLC (L)

7.9 (5.1-10.1)

7 (4.4-8.8)

7.1 (4.8-8.5)

7 (5-8.7)

0.04

TLC (%)

123 (86-134)

106 (87-138)

109 (87-133)

110 (88-129)

0.04

FVC (L)

1.86 (1.2-3)

1.8 (1.5-3.4)

2.3 (1.5-3.4)

2.1 (1.2-3.1)

1

FVC (%)

47 (35-63)

51 (42-73)

57 (41-82)

57 (34-66)

1

DLCO (%)

33 (27-76)

26 (12-49)

45 (21-47)

50 (30-89)

0.01

0 (0-3)

0.007

Suppl. O2 (L/min)

1.4 (0-3)

PaO2 (mm Hg)

77 (55-100)

76 (62-89)

71 (58-102)

74 (56-136)

0.57

PaCO2 (mm Hg)

43 (27-46)

38 (30-46)

40 (34-50)

40 (35-48)

0.57

375 (200-500)

410 (245-520)

0.005

6MWT (m) MRC Scale

223 (120-460) 4 (3-5)

0 (0-3)

— 3.5 (1-5)

0 (0-3)

2 (1-4)

2 (1-4)

0.004

*The values are means; ranges are shown in parentheses. DLCO, carbon monoxide diffusion in the lung; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ITGV, intrathoracic gas volume; MRC, Medical Research Council; PaCO2, partial arterial pressure of carbon dioxide; PaO2, partial arterial pressure of oxygen; RV, residual volume; 6MWT, 6-minute walk test; TLC, total lung capacity. From Venuta F, De Giacomo T, Rendina EA, et al: Bronchoscopic lung volume reduction with one-way valves in patients with heterogeneous emphysema. Ann Thorac Surg 79:411-417, 2005.

Ch051-F06861.indd 629

1/21/2008 11:46:14 AM

630

Section 3 Lung

second functional improvement if pulmonary function tests start to deteriorate again, as it is done for LVRS.43 A contralateral BLVR was performed in two of our patients, but neither was required for functional reasons: both patients had pneumothorax on the contralateral side, and valves were placed with the aim of stopping the air leak. This result was easily obtained, along with further functional improvement. With more experience, simultaneous bilateral insertion of the valves could be attempted. One of the advantages of endobronchial lung volume reduction is that the procedure can be reversed and other treatments tried if necessary. The short-term results with BLVR are encouraging, but long-term follow-up is required, as well as multicenter trials, to evaluate the therapeutic potential of this procedure.

A

B FIGURE 51-13 Chest roentgenograms of a patient who underwent bilateral, staged bronchoscopic lung volume reduction before treatment (A) and after bilateral treatment (B). (FROM VENUTA F, DE GIACOMO T, RENDINA EA, ET AL: BRONCHOSCOPIC LUNG VOLUME REDUCTION WITH ONE WAY VALVES IN PATIENTS WITH EMPHYSEMA. ANN THORAC SURG 79:411-417, 2005. COPYRIGHT ELSEVIER 2005.)

treatments (2 staged bilateral procedures). One patient had pneumonia in the nontreated lobe; this complication was easily managed with the administration of broad-spectrum antibiotics. The functional improvement (see Table 51-1) was statistically significant. In particular, FEV1 markedly improved and the residual volume decreased. At 3 months, more than 50% of the patients still showed at least a 30% functional improvement; most of them required less supplemental oxygen, and 7 of 15 were able to stop it. We were not able to observe a complete atelectasis of the lobe where valves where implanted, although this has been described by other authors; however, in most of the patients, the shape of the chest was redesigned (Fig. 51-13). Exercise tolerance was also improved and remained stable after 3 months of followup. Contralateral BLVR could be attempted to obtain a

Ch051-F06861.indd 630

COMMENTS AND CONTROVERSIES In recent years, much has been learned about the pathophysiology of emphysema and the mechanism of benefit of LVRS. Despite positive results in terms of function and survival from the National Emphysema Treatment Trial (NETT) in selected patients, LVRS is not widely accepted by pulmonary medicine physicians. As a result, LVRS is not widely utilized. In this context, noninvasive options to achieve similar results would offer significant attraction. The authors have extensive preliminary experience in the experimental and clinical application of airway bypass and BLVR. Airway bypass is a very interesting concept, nicely described in this chapter. Although successful experiments have demonstrated proof of principle, long-term patency of airway bypass fenestrations has not been demonstrated, and, as a result, there are no data confirming long-term efficacy. BLVR by lobar obstruction or use of airway valves has demonstrated promising initial results. Clinical trials are currently ongoing and results are pending. A significant complication rate, including pneumonia and pneumothorax, demonstrates the need for adequate long-term results to judge the practicality of this strategy as a treatment for significant numbers of patients with substantial hyperinflation due to emphysema. G. A. P.

KEY REFERENCES Choong CK, Haddad FJ, Gee EJ, Cooper JD: Feasibility and safety of airway bypass stent placement and influence of topical mitomycin C on stent patency. J Thorac Cardiovasc Surg 129:632-638, 2005. Hopkinsons NS, Toma TP, Hansell DM, et al: Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and exercise in emphysema. Am J Crit Care Med 171:423-424, 2005. Ingenito EP, Reilly JJ, Mentzer SJ, et al: Bronchoscopic volume reduction: A safe and effective alternative to surgical therapy for emphysema. Am J Respir Crit Care Med 164:295-301, 2001. Lausberg HF, Chino K, Patterson GA, et al: Bronchial fenestration improves expiratory flow in emphysematous human lungs. Ann Thorac Surg 75:393-398, 2003. Rendina EA, De Giacomo T, Venuta F, et al: Feasibility and safety of the airway bypass procedure for patients with emphysema. J Thorac Cardiovasc Surg 125:1294-1299, 2003. Venuta F, De Giacomo T, Rendina EA, et al: Bronchoscopic lung volume reduction with one-way valves in patients with emphysema. Ann Thorac Surg 79:411-417, 2005.

1/21/2008 11:46:16 AM

chapter

52

SURGERY FOR BULLOUS DISEASE Paul H. Schipper Bryan F. Meyers

Key Points ■ Preoperative workup for giant bullectomy includes cardiac risk

■ ■

■

■

■

assessment, pulmonary function testing, chest CT scan, and sometimes quantitative ventilation-perfusion scanning. Pulmonary function testing values are difficult to interpret without a chest CT. The best candidates for surgical benefit have dyspnea, an isolated bulla larger than 30% of the hemithorax, and a collapsed but otherwise normal underlying lung. Giant bullectomy in the setting of diffuse emphysema in the remaining lung is not a contraindication to surgery but may be better considered in the context of lung volume reduction surgery. Operative techniques include stapled bullectomy, excision, ligation, plication, and endocavitary drainage. These are accomplished with thoracoscopy, thoracotomy, or median sternotomy. Most patients can expect symptomatic and functional improvement. The duration of this improvement is dependent on the progression of emphysema in the remaining lung parenchyma.

Surgery for emphysema has a long, colorful, and sometimes controversial history. Many creative and thoughtful operations have failed to show benefit after closer scrutiny. Lung transplantation, lung volume reduction surgery (LVRS), and surgery for giant bullae have emerged as techniques that, when applied appropriately, can help this otherwise severely debilitated and desperate group of patients. This chapter seeks to review the history, classification, terminology, and pathophysiology of giant bullous lung disease as well as the indications, procedures, and outcomes of its surgical treatment.

HISTORY The history of surgery for giant bullae is intimately associated with the history of surgery for emphysema in general. This story has been well told by others, and the interested reader is directed to the historical reviews of Cooper, Deslauriers, and Naef.1-3 In the Annals of Thoracic Surgery, in its first year of publication, Knudson and Gaensler summarized the philosophy, successes, and failures of emphysema surgery before 1965.4 As early as 1906, Freund observed in emphysema patients a fixed, hyperexpanded thorax and performed costochondrectomy in an attempt to restore mobility of the thoracic cage and permit further expansion of the lungs.5 Other attempted solutions included transverse sternotomy,

pneumoperitoneum,6,7 abdominal belts,8 phrenic nerve crush,9 thoracoplasty,10 lung denervation,11 pleural abrasion, parietal pleurectomy and talc poudrage,12 resection of the carotid body,13-16 and reinforcement of the membranous portions of the trachea (tracheoplasty) and main bronchi.17,18 All of these were tried with modest or no success. In the case of abdominal belts and pneumoperitoneum, symptoms and lung function improved, but the treatments were impractical and uncomfortable and, in the case of pneumoperitoneum, required repeated treatments due to absorption of the air. In 1939, Kaltreider and Fray reported one of the first surgical excisions of bullae for dyspnea.19 Rudolph Nissen described a method of plication of bullae in 1945.20 In 1938, Vincent Monaldi proposed a technique for intracavitary drainage of a tuberculous cavity.21 In 1949, Head and Avery presented a series of nine patients in whom they applied Monaldi’s technique of intracavitary suction drainage to a giant bulla, effectively shrinking the bulla, reducing thoracic volume, and improving patient symptoms.22 In 1959, Otto Brantigan presented his work describing resection of functionally useless lung in order to improve the mechanics of breathing. This was not an operation for giant bullae, but for diffuse but heterogeneous emphysema.23 Because his operative mortality rate was high (16%) and he made no effort to objectively evaluate patient improvement, this procedure did not gain acceptance. Over the last half of the 20th century, several authors presented their series of surgeries for giant bullae, often spanning many years or an entire career, and defined the indications and outcomes (FitzGerald et al, 1974; Gaensler et al, 1986; Shah et al, 1994).24-35 Surgeons in the middle of the 20th century recognized that patients undergoing giant bullectomy with underlying, relatively normal lung had better and more sustained outcomes than those whose giant bullae were a local exacerbation of diffuse disease (FitzGerald et al, 1974; Gaensler et al, 1986).30,35 There is, however, a continuum between giant bullae, heterogeneous emphysema, and homogenous emphysema, and there is similarity in the mechanisms of functional improvement after giant bullectomy and after LVRS. The surgical treatment of giant bullae became accepted relatively early, whereas LVRS has taken much longer to evolve. LVRS has recently been evaluated by the National Emphysema Treatment Trial (NETT).36,37 Surgery for giant bullae, however, was not a component of the NETT trial. The close scrutiny and rapid evolution of LVRS indications, techniques, and management skills have led to parallel advances in the care of giant bullae. Since the work of Head and Avery,22 multiple techniques to obliterate giant bullae have been developed, including 631

Ch052-F06861.indd 631

1/21/2008 11:47:15 AM

632

Section 3 Lung

TABLE 52-1 DeVries and Wolfe Classification of Giant Bullae*

TABLE 52-2 Witz and Roeslin Classification of Giant Bullae*

Group

Bullae

Underlying Lung

Group

Description

I

Single large

Normal

I

II

Multiple

Normal

Bullae with normal underlying parenchyma, paraseptal emphysema

III

Multiple

Diffuse emphysema

II

Bullae with diffuse emphysema; bullae are a local exacerbation of diffuse panacinar emphysema

IV

Multiple

Other lung diseases

III

Vanishing lung syndrome; entire lobe or lung replaced by bullae

*Based on the nature of the bullae and the underlying lung. From DeVries WC, Wolfe WG: The management of spontaneous pneumothorax and bullous emphysema. Surg Clin North Am 60:8, 1980.

segmental resection,38 lobectomy,39 plication,28 and local excision.29 More recently, thoracoscopy has been used in combination with hemoclips, laser technologies, Endoloops, sutured bullectomies, and stapled bullectomies to ablate or resect giant bullae.40-46 HISTORICAL READINGS Brantigan OC, Mueller E, Kress MB: A surgical approach to pulmonary emphysema. Am Rev Respir Dis 80:194-206, 1959. Cooper JD: The history of surgical procedures for emphysema. Ann Thorac Surg 63:312-319, 1997. Deslauriers J: History of surgery for emphysema. Semin Thorac Cardiovasc Surg 8:43-51, 1996. Kaltreider NL, Fray WW: Pathologic physiology of pulmonary cysts and emphysematous bullae. Am J Med Sci 197:62, 1939. Knudson RJ, Gaensler EA: Surgery for emphysema. Ann Thorac Surg 1:332-362, 1965. Monaldi V: Endocavitary aspiration: Its practical applications. Tubercle November:223-228, 1947. Naef AP: History of emphysema surgery. Ann Thorac Surg 64:15061508, 1997.

BASIC SCIENCE Definitions of Terms Blebs, Bullae, and Emphysema A bleb is a subpleural collection of air contained within the layers of the visceral pleura. It forms when an alveolus ruptures and air subsequently leaks out, dissects through the interstitial tissues to the surface of the lung, but is contained by the thin fibrous tissues of the visceral pleura.47 Blebs are usually small (<2 cm in diameter); they tend to develop in the apical segment of the upper lobe and the superior segment of the lower lobe, and they are the usual cause of a primary spontaneous pneumothorax. They can occasionally coalesce to form a giant bulla (Deslauriers and LeBlanc, 1994).48 Blebs may or may not be associated with emphysematous changes in the remaining lung. Emphysema is an abnormal and permanent enlargement of the air spaces distal to the terminal nonrespiratory bronchioles which arises from the destruction of the alveolar walls and has no obvious fibrosis.49-51 Knudson and Gaensler4 described emphysema as a departitioning of the distal lung architecture.

Ch052-F06861.indd 632

*Based on underlying lung. From Witz JP, Roeslin N: La chirurgie de l’emphyseme bulleux chez l’adulte. Revue Francais de Maladies Respiratoire 8:121, 1980; as in Mehran RJ, Deslauriers J: Indications for surgery and patient work-up for bullectomy. Chest Surg Clin North Am 5:717-734, 1995.

A bulla is defined as an air-filled space, 1 cm or greater in distended diameter, within the lung parenchyma that forms as a result of the destructive process of emphysema. Anatomically, bullae have a thin outer fibrous wall consisting of the visceral pleura and an inner wall of variable thickness—often relatively thin—consisting of the remnants of disintegrating emphysematous lung. The inside of a bulla may be either smooth or trabeculated and crossed by fibrous strands, which are considered the remnants of alveolar and interlobular septa (Deslauriers and LeBlanc, 1994).48 Multiple dilated, thin-walled vessels can pass through the walls of the bulla or be suspended within the bulla within these fibrous septa. Rarely, one or more bullae enlarge to such a degree that they occupy more than one third of the hemithorax. The term giant bulla is then applied. Patients with bullae have traditionally been divided into two groups: those in whom the rest of the lung is structurally normal (20% of patients) and those in whom the rest of the lung exhibits changes of emphysema (80% of patients). Although the latter group is said to have bullous emphysema, this term is imprecise and vague because almost all emphysema involves the formation of bullae to some extent. This process may, in fact, represent a continuum, with the isolated giant bulla with normal underlying lung on one end and increasing degrees of destruction of the underlying lung representing the rest of the continuum.

Classification of Bullae Several authors have proposed classification systems for giant bullae based on the presence of bullae and the condition of the remaining lung.52-54 Although these systems are conceptually useful, none of them has gained widespread usage (Tables 52-1, 52-2, and 52-3).

Classification of Emphysema The acinar classification of emphysema was originally proposed in 195955 and has been defined by several authors (FitzGerald et al, 1974).30,56,57 It divides emphysema into three anatomic variants based on the portion of the acinus that is predominantly involved. An acinus is a unit of bronchopulmonary tissue distal to a terminal bronchiole (Fig. 52-1A). There are three variants:

1/21/2008 11:47:15 AM

Chapter 52 Surgery for Bullous Disease

TABLE 52-3 Reid Classification of Giant Bullae*

633

Alveolous AS

RB1

TB

AD

RB2

RB3

A *Based on amount and location of lung involved, degree of hyperinflation, and composition of the inside of the bullae. From Reid L: The Pathology of Emphysema. London, Lloyd-Luke (Medical Books) Ltd., 1967, pp 211-240.

AS + AS Septum

RB3

TB

1. Proximal acinar 2. Panacinar 3. Distal acinar or periacinar (see Fig. 52-1B-D) A second classification, the lobular classification, is an older system and refers to the secondary lobule, the smallest unit of lung parenchyma surrounded by connective tissue septae. Secondary lobules are visible to the naked eye in dried lung slices. In the center of each secondary lobule is a terminal bronchiole (Fig. 52-2). Because the proximal portion of an acinus is a terminal bronchiole, the term centrilobular is synonymous with proximal acinar. This has created a group of synonyms that can be used interchangeably:

Inflamed RB1

B AD, AS, A RB3 RB1 TB

1. Centrilobular for proximal acinar 2. Panlobular for panacinar 3. Paraseptal for distal acinar or periacinar These classifications are useful in mild to moderate emphysema. As the disease progresses, classification into these subtypes becomes difficult.49,58 These classifications attempt to explain the gross anatomic variability of emphysema compared with the histology of emphysema and how bullae can develop in some locations with the remainder of the lung less affected. Proximal Acinar Emphysema. Proximal acinar emphysema, or centrilobular emphysema, involves the respiratory bronchioles (see Fig. 52-1B), which are enlarged and destroyed by inflammation, typically as a result of cigarette smoking. The acini affected are commonly in the upper lung fields. Fifty percent of smokers with emphysema exhibit this subtype. Because this form of emphysema is associated with inflammation of the bronchi, patients most often have signs and symptoms of chronic bronchitis.4 Panacinar Emphysema. Panacinar emphysema, or panlobular emphysema, involves uniform destruction of the entire acinus (see Fig. 52-1C). α1-Antitrypsin deficiency is associated with this subtype. This is a much more virulent disease than distal acinar emphysema, and it may progress irregularly and diffusely throughout the lungs. However, it is often exaggerated peripherally and apically, possibly due to the increased effect of gravity in the upper lung zones

Ch052-F06861.indd 633

RB2

Septum

RB2

C AS

AD RB3 RB1 TB

RB2

D FIGURE 52-1 Acinar classification of emphysema. A, Normal acinus. B, Proximal acinar/centrilobular emphysema. C, Panacinar/panlobular emphysema. D, Distal acinar/periacinar/paraseptal emphysema. AD, alveolar duct; AS, alveolar sac; RB, respiratory bronchiole; TB, terminal bronchiole. (FROM THURLBECK WM: MORPHOLOGY OF EMPHYSEMA AND EMPHYSEMA-LIKE CONDITIONS IN CHRONIC AIRFLOW OBSTRUCTIONS IN LUNG DISEASE. PHILADELPHIA, WB SAUNDERS, 1976.)

1/21/2008 11:47:15 AM

634

Section 3 Lung

FIGURE 52-2 Lobular classification of emphysema. The schematic drawing shows four adjacent secondary lobules demonstrating the lobular classification of emphysema. A, normal acinus; B, centrilobular emphysema; C, panlobular emphysema; D, paraseptal emphysema.

A

(FROM GAENSLER EA, CUGELL DW, KNUDSON RJ, FITZGERALD MX: SURGICAL MANAGEMENT OF EMPHYSEMA. CLIN CHEST MED 4:443, 1983.)

C

Terminal bronchiole

D Respiratory bronchiole

Septum

B (FitzGerald et al, 1974).30 Patients with panacinar emphysema typically desaturate with exercise and have a reduced carbon monoxide diffusing capacity (DLCO). This form is not necessarily associated with inflammation.4 Distal Acinar Emphysema. Distal acinar emphysema, also called periacinar emphysema or paraseptal emphysema, involves the peripheral portions of each acinus (the alveolar sacs and alveolar ducts) (see Fig. 52-1D). It is most striking adjacent to the pleura and along lobular septa (paraseptal). When these destroyed acini border the visceral pleura, small bullae can coalesce and develop into giant bullae. This form of emphysema is associated with the most spontaneous pneumothoraces and is believed to be responsible for the development of giant bullae when the remainder of the lung parenchyma appears normal.57

D

Pleura

coccal pneumonia but also occurs in those with gram-negative pneumonia,62 Pneumocystis jiroveci (Pneumocystis carinii) pneumonia,63,64 acute Mycobacterium tuberculosis pneumonia,65 and measles virus infection. A peribronchial abscess erodes into the airway, and the abscess is filled with air. Edematous bronchiolar mucosa and secretions create a check valve, and the space inflates. Although most pneumatoceles remain small, they can enlarge to fill the chest cavity and mimic a tension pneumothorax.59 Pneumatoceles can be single or multiple, can form within 1 week after the onset of the pneumonia, and generally disappear within 6 weeks but may persist for 1 year or longer.66 In rare instances a pneumatocele requires operative intervention, but most spontaneously resolve with time. This is in direct contrast to the natural history of giant bullae, which usually do not resolve without intervention.

Cysts, Cavities, and Pneumatoceles Histologically, the term cyst is reserved for a space lined by epithelium. Congenital bronchogenic cysts are lined with cuboidal respiratory epithelium. A lesion is considered a cyst if its wall is thinner than 2 to 3 mm and a cavity if the wall is thicker than 3 mm. Bronchopulmonary dysplasia, cystic adenomatoid malformations, and cystic bronchiectasis are all examples of cystic lesions that develop as the result of air trapping and hyperdistention of the distal airways.59 These cysts are sometimes called acquired cysts to distinguish them from congenital bronchogenic cysts.60 Cysts can reach large dimensions and behave like giant emphysematous bullae with respect to their impact on pulmonary function and their risks for other complications. The term pneumatocele is derived from the Greek words pneuma, “air,” and kele, “hernia,” denoting an “air hernia.”61 The term pneumatocele is most often used to describe a process that occurs in up to 60% of patients with staphylo-

Ch052-F06861.indd 634

PATHOPHYSIOLOGY Bullae were originally believed to develop, pressurize, and compress adjacent lung parenchyma secondary to the development of one-way valves,67-69 but this hypothesis has been proven incorrect (Morgan et al, 1989).70,71 In 1989, Morgan and colleagues (Morgan et al, 1989; Ting et al, 1963)70 measured intrabulla pressure and pleural space pressure under the condition of spontaneous ventilation and again under positive pressure ventilation. During spontaneous ventilation, the pressure changes in the two spaces were the same in both phase and degree. Bulla pressures were never positive in inspiration and never more positive than pleural pressure at end expiration. During positive pressure ventilation, the two pressures were also similar, the only notable difference being the development of positive end-expiratory pressure in the bulla. Morgan and colleagues hypothesized that bullae do not compress adjacent lung; rather, they experience the same

1/21/2008 11:47:16 AM

Chapter 52 Surgery for Bullous Disease

pressures as the rest of the lung parenchyma, but simply fill to capacity before the less compliant adjacent lung. Ting and colleagues (Ting et al, 1963)71 examined the volume-pressure relationship in bullae and adjacent lung in resected specimens. They found that the bullae had little or no elastic properties and behaved like a paper bag, increasing in volume without large increases in pressure until filled to capacity, then greatly increasing in pressure with little change in volume. Mehran and Deslauriers (Mehran and Deslauriers, 1995)72 coined the term preferential ventilation. According to this theory, bullae are initially formed by the local destruction of pulmonary tissue, as in emphysema. As the space gradually enlarges, its compliance increases in relation to the surrounding, less destroyed lung. Because of this increased compliance, air flows preferentially to the bulla, and it continues to expand. The surrounding lung, with its preserved elastic recoil, retracts from the bullae. Under this theory, the bulla has no compressive effect, but rather redirects airflow from normal lung to itself, creating restriction and hypoventilation of the normal lung. Because the giant bullae have disrupted the architecture of the lung, static elastic recoil pressure is diminished; the airways that this pressure normally holds open are not held open, and airway resistance is increased. Gelb and colleagues73 noted that this airway resistance is mostly increased at low lung volumes. Pulmonary function testing to measure airway resistance commonly takes place at the upper end of a tidal volume—panting in a body box plethysmograph or forced expiratory volume in 1 second (FEV1). Increased airway resistance at lower lung volumes may be significantly increased but is not demonstrated by these techniques. Understanding of the mechanism of benefit in bullectomy has evolved over the last two decades, and there may be several contributing factors. Elimination of the giant bullae relieves the surrounding lung of its ventilatory competitor, restores the architecture of the lung, increases static elastic recoil pressure, opens airways, and increases FEV1. In addition, some of the adverse effects of hyperinflation of the chest may be ameliorated. Travaline and colleagues (Travaline et al, 1995)74 postulated that the adverse effects of hyperinflation on diaphragm mechanics include foreshortening of diaphragm precontraction length, decreased area of apposition of the costal diaphragm with the chest wall, reduced radius of diaphragm curvature, impaired blood flow, decreased insertional action on the rib cage, and increased internal elastic inspiratory load (Travaline et al, 1995).74 Removal of functionally useless lung creates space in the chest to allow the diaphragm and chest wall to resume a physiologic position.

Ventilation and Perfusion of Giant Bullae Morgan and colleagues (Morgan et al, 1989)70 showed that, under tidal conditions, giant bullae contain gas identical to that in alveoli. When inspired oxygen is increased, partial pressure of oxygen (PO2) rises more slowly in the bulla than in the arterial blood, indicating that, although the bulla is ventilated, this ventilation is slow. Using xenon 133 ventilation, Klein and colleagues75 showed that gas turnover was present but slow in bullous regions. Using chest CT scanning

Ch052-F06861.indd 635

635

to calculate bulla volume in inspiration and expiration, Morgan and colleagues (Morgan et al, 1986) 76 showed, in 22 of 23 patients studied, that the bulla changed little in size and therefore contributed little to ventilation. They calculated the vital capacity of the bulla at 8% of the overall vital capacity. In one instance, a bulla did contribute 20% of the vital capacity, indicating an increase in dead space ventilation. Pulmonary angiography, chest radiograph, CT of the chest, operative findings, and autopsy pathology all show a paucity of blood vessels in the region of a giant bulla. In addition, Xe-133 perfusion scanning shows diminished perfusion in the area of the giant bullae.

Causes of Bullae Smoking and α1-antitrypsin deficiency are the two main causes of emphysema (Deslauriers and LeBlanc, 1994).48,77 In addition, acquired immunodeficiency syndrome (AIDS), with and without concurrent pulmonary infection,78 has been associated with bullous changes in the lungs. Crack cocaine smoking,79 intravenous (IV) drug abuse80 including abuse of methylphenidate,81 and marijuana smoking82 have been associated with the development of bullous emphysema. Although all of these factors occurred in the setting of cigarette smoking, they are linked to bulla formation in patients at younger ages and with less cigarette exposure than in smokers of cigarettes alone. The root cause appears to be an inflammatory or destructive insult to the alveolus, resulting in destruction of its walls. In the case of IV drug abuse, it is not known whether this insult is the drug itself, talc granulomas, or possibly septic emboli.80 Once this destructive process has started, it may be mechanically or chemically self-perpetuating. A genetic predisposition may play a role,83 and bullous emphysema and giant bullae have been associated with Ehlers-Danlos syndrome.84,85 However, several studies have failed to show a hereditary component.86-89 Giant bullae and bullous emphysema have been seen in conjunction with sarcoidosis and in the setting of autoimmune dysfunction.90-95 The majority of patients with pulmonary sarcoidosis clear their lung disease completely without treatment in 1 to 2 years. A few require corticosteroid treatment. The development of bullae in sarcoidosis is very rare and usually occurs during the fibrotic stage of the lung disease. This stage of sarcoid lung disease most closely resembles the so-called vanishing lung syndrome, with diffuse progressive destruction of the lung. In at least one reported instance, the bullous disease was more localized and a giant bullectomy was performed with short-term success.96 Several cystic lesions of the lung consist of giant air spaces that resemble and physiologically behave like giant bullae, including acquired cysts (pneumatoceles, traumatic lung cysts, pulmonary lymphangioleiomyomatosis,97 hydatid cysts, cystic fibrosis) and developmental cysts (cystic adenomatoid malformation, intralobar sequestration, congenital lymphangiectasis, congenital lung cysts, congenital lobar emphysema).65 Although these lesions appear similar to the bullae associated with emphysema, they are distinct problems and must be considered as such when planning therapy.

1/21/2008 11:47:16 AM

636

Section 3 Lung

NATURAL HISTORY OF EMPHYSEMA AND BULLAE Natural aging results in a decline in the FEV1 of 25 mL or less per year. During the 1960s, Jones, Burrows, and Fletcher98 reported on the clinical course of 100 patients with severe emphysema who were monitored for 3 years: 30% died of their emphysema, and 10% showed symptomatic improvement. The FEV1 declined on average 46 mL/year, or 5% per year of the initial value. The vital capacity declined 120 mL, or 4% of the initial value, per year. The venous PCO2 increased by 1 mm Hg per year. In 1969, as a follow-up to this original study, Burrows and Earle (Burrows and Earle, 1969)99 reported on 200 patients diagnosed with emphysema (FEV1 < 60% of predicted) who were monitored for 4 and 8 years. They observed a 73 to 84 mL/year decline in FEV1, an 86 mL/year decrease in forced vital capacity (FVC), a 0.5% per year increase in residual volume/total lung capacity (RV/ TLC), and a 7.5% per year decline in the percent of predicted normal diffusion capacity. In 1968, Boushy and colleagues100 reported on 49 patients with bullous emphysema whom they

had monitored with serial chest radiographs and pulmonary function tests; 27 of these patients had a single bulla occupying more than 30% of the hemithorax. The authors noted a consistent tendency for the bullae to enlarge and the airway obstruction to worsen. In some patients these changes were gradual, and in others they remained stable for several years and then worsened (Fig. 52-3). The only patients whose bullae decreased in size were 4 patients whose bullae became infected. Other authors have noted that giant bullae may be asymptomatic at initial presentation but rarely remain so.101 There are a few case reports of emphysematous bullae regressing or even disappearing (Fig. 52-4).102,103 The natural history of emphysema appears to be progressive worsening until death, and the natural history of bullae appears to be progressive but unpredictable enlargement.

INDICATIONS FOR OPERATION AND PREOPERATIVE EVALUATION In 1950, Baldwin and associates67 suggested that ventilatory insufficiency and the absence of generalized emphysema were

FIGURE 52-3 A-C, Chest radiographs showing enlargement of a left lower lobe solitary bulla over 3.5 years. Note flattening of the hemidiaphragm and mediastinal displacement on radiograph (C).

Ch052-F06861.indd 636

1/21/2008 11:47:16 AM

Chapter 52 Surgery for Bullous Disease

A

637

B

FIGURE 52-4 Serial chest CTs of a left hemithorax giant bulla that underwent spontaneous regression. A, Initial presentation. B, Several months later.

among the criteria predicting the need for, and the success of, excisional surgery. The most accepted criteria for giant bullectomy follow: 1. Isolated bullae occupying 30% or more of a hemithorax 2. Evidence of relatively nonventilated (compressed) and nonemphysematous underlying lung parenchyma 3. Dyspneic patient Less well accepted, but possible, indications for surgery include bullae greater than 30% of a hemithorax in asymptomatic patients, patients with underlying emphysema, and expanding bullae. Less common indications for surgical treatment include pneumothorax, hemoptysis, infection, cancer, and chest pain.

TABLE 52-4 Modified Hugh-Jones Criteria for Dyspnea Grade

Definition

0

No dyspnea on exertion

I

Dyspnea on running or climbing two flights of stairs

II

Dyspnea while walking or cycling against the wind

III

Unable to walk or cycle more than 1000 m

IV

Unable to walk more than 100 m

V

Dyspnea on walking in the house, dressing, and washing

From Hugh-Jones P, Lambert AV: A simple exercise test and its use for measuring exertion dyspnea. BMJ 12:65, 1952.

Asymptomatic Patient As discussed earlier, the natural history of bullous disease is progressive enlargement of the bulla and worsening of dyspnea and pulmonary function. Although some authors have cautioned against operating on asymptomatic giant bullae because of the high incidence of postoperative complications101,104,105 others have advocated that preventive surgery is justified if the bulla occupies more than 50% of a hemithorax, adjacent lung is collapsed, or the bulla has enlarged over a period of years.48,106,107

Symptomatic Patient Most authors agree that a symptomatic patient with a giant bulla and otherwise preserved underlying lung stands to benefit from surgical treatment of the bulla. The most common presenting symptom is dyspnea. The treatment of giant bullae in patients with varying degrees of emphysema in their underlying lung is more controversial.

Ch052-F06861.indd 637

Dyspnea can be measured using either the modified HughJones criteria (Table 52-4) or the Medical Research Council (MRC) Dyspnea Scale (Table 52-5).108,109 Any grade of dyspnea greater than 0 on either scale is abnormal and can be considered symptomatic. A patient whose degree of dyspnea is out of proportion to the size of a bulla raises the question of underlying emphysema. These scales can help quantitate a subjective complaint and assist in the evaluation of treatment outcomes. The preoperative evaluation of a patient for giant bullectomy includes a determination of the overall medical status of the patient, including age, presence of comorbid diseases, past surgical and medical history, and smoking history and status. Cardiac status is assessed both to determine fitness for a thoracic procedure and for the presence of right-sided heart failure or cor pulmonale. Pulmonary function testing and CT of the chest are usually sufficient to determine

1/21/2008 11:47:17 AM

638

Section 3 Lung

TABLE 52-5 Medical Research Council of Great Britain Dyspnea Scale Grade

Degree

Definition

0

None

Not breathless, except with strenuous exercise

1

Slight

Short of breath hurrying on the level or walking up a slight hill

2

Moderate

Walks slower than people of the same age on the level because of breathlessness, or has to stop for breath when walking at own pace on the level

3

Severe

Stops for breath after walking about 100 yards or after a few minutes on the level

4

Very severe

Too breathless to leave the house or breathless when dressing or undressing

From American Thoracic Society: Surveillance for respiratory hazards in the occupational setting. Am Rev Respir Dis 126:952-956, 1982.

operability and form an operative plan. Radioisotope scanning may be useful in certain situations, as discussed later, but pulmonary angiography is rarely needed.

Pulmonary Function Testing Pulmonary function testing results cannot be used in isolation as criteria for surgery. Rather, they must be interpreted in light of the results of other tests evaluating the nature of the lung parenchyma. In patients confirmed to have a localized giant bulla and underlying normal-appearing lung, FitzGerald and colleagues (FitzGerald et al, 1974)30 noted excellent correlation between the decline in FEV1, the size of the bulla, and the improvement in FEV1 after bullectomy. Alternatively, if a bulla occupies less than one third of the hemithorax and the FEV1 is reduced, the decreased pulmonary function and any accompanying symptoms are most likely related to underlying emphysema. Ohta and colleagues110 evaluated 25 bullectomies with preoperative and postoperative pulmonary function data and a mean follow-up of 4 years. In the group of 20 patients who remained symptomatically improved, compared with 5 patients whose symptoms improved for 1 year and subsequently declined, they found only two preoperative pulmonary function measures that predicted improvement: FEV1 and ∆N2. The term ∆N2 describes the slope of the third phase of a nitrogen washout curve. A low value for ∆N2 indicates uniform ventilation, and a high value indicates nonuniform ventilation. Postoperatively, in the symptomatically improved group, the authors found vital capacity, FEV1, and RV/TLC all to be improved; in the group with transient symptomatic improvement, none of these variables was improved. Despite its ability to predict a sustained symptomatic improvement after operation, in both groups the ∆N2 did not change with operation. In the multivariate analysis, only a high FEV1 and a uniform distribution of ventilation (low ∆N2) were preoperatively able to predict a sustained symptomatic postoperative improvement.110 It is unclear to what extent a reduced FEV1 results from the presence of a bulla and to what extent it results from emphysema in the underlying lung. If the dysfunction is caused by the bulla, it could be expected to improve with resection. If it is an indicator of global lung dysfunction, less improvement is likely. In 1973, Pride and colleagues111 postulated that tests of overall lung function reflect the condition

Ch052-F06861.indd 638

of the nonbullous lung. Using CT lung density to identify extent of emphysema, Gould and colleagues112 confirmed that pulmonary function testing is poorly correlated with the extent of the bullous portion of the lung but rather is strongly related to the extent of underlying emphysema in the rest of the lung. Lopez-Majano and associates,105 before the era of CT scanning, suggested that, in the case of low FEV1, regional lung function is evaluated by perfusion lung scanning, inspiratory and expiratory chest radiography, and pulmonary angiography. With these tests, the true cause of the low FEV1 could be better determined. Performing a giant bullectomy on a patient with substantial underlying emphysema has been associated with higher morbidity and mortality rates104,113 and shorter long-term benefit (FitzGerald et al, 1974).30 This situation may be more aptly considered a special case of LVRS (Snider, 1996).114 DeGiacomo and colleagues (DeGiacomo et al, 2002)115 compared their experience with resection of bullous areas with underlying emphysematous lung versus LVRS in nonbullous end-stage heterogeneous emphysema and found similar significant improvements in dyspnea, FEV1, and RV, with similar morbidity and mortality. Haerens and colleagues (Haerens et al, 1988)116 reported on 15 excisional giant bullectomies, 10 with generalized emphysema and 5 with normal underlying lung. Preoperatively, the FEV1 of those with underlying normal lung was higher (74.2% ± 24.9% versus 34.6% ± 12.4%). Both groups experienced relief of their dyspnea with operation, although those with underlying emphysema had a greater relative improvement in FEV1 (34.6%-58.4% versus 74.2%-93.4%). Although patients with underlying normal lung had higher FEV1 values overall, on a patient-to-patient basis, it was difficult to predict the nature of the underlying lung based on pulmonary function testing. Chest CT was a more useful modality (Haerens et al, 1988).116 Baldi and colleagues117 examined the outcomes of 25 patients undergoing giant bullectomy, half of whom had radiographic evidence of underlying emphysema. FEV1 was improved in all cases, and the degree of improvement was associated with the volume of the resected bullae. Consideration of preoperative FEV1, DLCO, TLC, and evidence of lung compression did not improve the ability to predict the improvement in FEV1. This is evidence that a giant bulla contributes to airflow obstruction that is reversible after giant bullectomy, independent of the presence of coexisting emphysema.117

1/21/2008 11:47:18 AM

Chapter 52 Surgery for Bullous Disease

There is no generally accepted absolute cutoff in pulmonary function values below which surgery is contraindicated. Nakahara and colleagues113 found that patients with giant bullae who showed disturbed ventilation by Xe-133 washout in the remaining lung (i.e., underlying emphysema) and had an FEV1 less than 35% of predicted had less improvement in symptoms and function after bullectomy. In contrast, several surgeons have found that, even with an extremely low FEV1 and maximum voluntary ventilation (MVV) but preserved underlying lung, appropriate resection of giant bullae (70%100% of the hemithorax) can result in significant improvement in symptoms and pulmonary function (FitzGerald et al, 1974).30,31 A reduction in the DLCO has been noted as an indicator of underlying emphysema,56,111 and patients with normal DLCO have been found to have better short-term and long-term outcomes after removal of bullae (FitzGerald et al, 1974; Gaensler et al, 1986).30,35,118 A normal DLCO can indicate normal underlying lung.119 However, reversible conditions leading to extreme airway obstruction can give falsely depressed results for DLCO testing; therefore, caution must be exercised before rejecting a surgical candidate on the basis of a low DLCO. Although pulmonary function testing can inform patient selection for surgery, the results must be interpreted in light of a good understanding of the nature of the underlying lung, usually best obtained by CT scanning. Severe underlying emphysema is not necessarily a contraindication for bullectomy but may be better considered in the context of LVRS, the bullous region representing a heterogeneous target zone for resection (see Chapter 50).

Imaging Imaging is used to define the size, location, number, and nature of the bullae. Radiography can also be used to predict outcomes after resection. Surgical resection is not recommended for bullae occupying less than 30% of the hemithorax (FitzGerald et al, 1974).25,30,32,33,120 The larger the isolated bulla resected, the greater the decrease in dyspnea.121 Bullae occupying more than 50% of the hemithorax are associated with better postoperative results (Morgan et al, 1986).76 Patients with the greatest increase in FEV1 and decrease in symptoms are those with bullae occupying more than 70% of their hemithorax (FitzGerald et al, 1974).30 Imaging is also important in assessing the extent of emphysema in the remaining lung. Although giant bullae with underlying severe emphysema can still be resected with expectation of functional improvement, the complexity and potential morbidity of the surgery are increased and long-term benefit is diminished (see later discussion).

Chest Radiography Giant bullae are often first detected on chest radiographs (Fig. 52-5A). The volumes of giant bullae as measured by chest CT scanning and by chest radiography correlate well.117 Old chest radiographs can define the progression of giant bullae; if there has been an acute worsening of dyspnea without a large change in the bullae, other reasons for the dyspnea need to be sought. With an isolated giant bulla and

Ch052-F06861.indd 639

639

underlying normal lung, the normal lung will change in volume to some degree in response to ventilation (i.e., inflate with inspiration, deflate with expiration). Diffuse emphysema shows less change between inspiration and expiration. Inspiratory and expiratory films can be performed looking for this change in volume (Gaensler et al, 1986).35 In 1937, Burke122 coined the term vanishing lung. Vanishing lung is the chest radiograph appearance of bullous emphysema progressing and replacing the normal lung. In particular, the lung vascular markings disappear (Fig. 52-6). Generalized emphysema may be sought on the chest radiograph by looking for this loss of lung markings. Preserved, underinflated lung appears as denser areas with crowding of the vasculature. CT scanning is a more accurate method of making these distinctions.

Chest Computed Tomography CT scanning of the chest is the most useful imaging procedure and needs to be obtained before surgery is performed on a bulla (Morgan et al, 1986).76,123,124 The size, location, and number of the bullae can be well visualized. On CT, bullae appear as avascular areas with curvilinear boundaries (see Figs. 52-4 and 52-5B). A pneumothorax can usually be differentiated from bullae. A pneumothorax has air on either side of the bulla wall, and that wall is parallel to the chest wall, the so-called double-wall sign (Fig. 52-7).125 The presence of lung masses and infiltrates can also be sought. Importantly, the consistency of the underlying lung can be assessed. Chest CT has replaced pulmonary angiography and bronchography in evaluating for underlying emphysema. Chest CT exceeds the ability of chest radiography to determine whether the remaining lung is diseased. In the 1984 study of Carr and Pride,126 CT scans showed more emphysema than was suspected on the basis of chest radiography in 67% of their cases. In 1986, Morgan and coworkers (Morgan et al, 1986)76 reviewed 43 patients with apparent bullous lung disease. CT scanning differentiated 20 patients with generalized emphysema whose area of suspected giant bullae was merely a local exaggeration of emphysema from 23 patients with well-defined bullae and relatively normal underlying lung. The values of FEV1 (40% and 33%), FVC (69% and 74%), and RV (70% and 60%) respectively in these two groups were statistically similar, emphasizing the need to evaluate pulmonary function in light of CT findings. Gould and colleagues127,128 showed that CT scan measurements of lung density correlate well with measurements of airflow limitation. CT density is measured in Hounsfield units (HU) or electromagnetic imaging (EMI) units (2 HU = 1 EMI unit). In Hounsfield units, water = 0, air = −1000, and normal lung tissue = −400 to −900 HU. Emphysematous tissue is in the range of −900 to −980 HU. Gould and associates112 studied patients whose apparent bullae were actually a local exaggeration of diffuse emphysema and found that the percentage of the lung occupied by bullae correlated poorly with measurements of respiratory function (FEV1, FVC, RV, and DLCO). The severity of the underlying emphysema, as expressed by the mean CT density in the nonbullous lung parenchyma, correlated strongly with the degree of impairment of DLCO and FEV1.112

1/21/2008 11:47:18 AM

640

Section 3 Lung

B

A

FIGURE 52-5 Left lower lobe giant bulla. A, Chest radiograph. B, Chest CT. C, Ventilation-perfusion scan.

Radioisotope Scanning

. . Isotope scanning or ventilation-perfusion (V/Q) scanning is an effective method of evaluating the vascular and parenchymal integrity of the lung (see Fig. 52-5C) (Mehran and Deslauriers, 1995).72,129 It can provide quantitative analysis of regional pulmonary function. Bullae are poorly ventilated and poorly perfused, so they appear as matched ventilation/ perfusion deficits.75 Xe-133 washout curves can be used to calculate the regional dynamic ventilation rate, a value indicative of the amount of homogeneity of ventilation in the lung (a higher value indicates more homogeneity). Nonhomogenous ventilation is an indicator of underlying emphysema, and patients with a value of less than 0.5 in their underlying lung have had less symptomatic and functional improvement after bullectomy.113 Although the usefulness of ventilationperfusion scanning in preoperative planning has been largely supplanted by that of CT scanning,60 we have used it to provide additional information for evaluating the integrity of

Ch052-F06861.indd 640

C

the underlying lung in the few instances in which CT scanning does not give a clear picture. This situation most often arises when the giant bullae are a local exaggeration of diffuse emphysema.

Pulmonary Angiography Before good-quality CT scanning was available, pulmonary angiography was considered the most useful test to evaluate the remaining lung for evidence of emphysema (Snider, 1996).114,130 A winter tree appearance of pulmonary arteries that appear pruned, with loss of the smallest caliber vessels (visible as a faint haze), indicates emphysema. In contrast, a capillary blush in underlying lung tissue indicates the absence of emphysema, and crowded vessels indicate collapsed parenchyma, which may expand if the bullae are removed. Pulmonary angiography is currently rarely necessary, and similar information is better obtained on a contrast CT scan of the chest (Snider, 1996).114,119

1/21/2008 11:47:18 AM

Chapter 52 Surgery for Bullous Disease

A

641

B

FIGURE 52-6 Bilateral vanishing lung. Note the paucity of lung markings in upper lung fields on chest radiograph (A) and multiple bullae extending deep into the lobes, approaching the hilum of the lung, on the chest CTs (B and C). (RADIOGRAPHS COURTESY OF DR. MARC GOSSELIN, ASSISTANT PROFESSOR, RADIOLOGY, OREGON HEALTH AND SCIENCE UNIVERSITY, PORTLAND, OR.)

C

Pneumothorax

Double-wall sign Large bulla

FIGURE 52-7 Double-wall sign. Drawing of axial chest CT with a large bulla and a pneumothorax. Note that, without visualization of the outer wall of the bulla, a large air space in the chest could be a pneumothorax or a bulla.

Lung Possible adhesion

Ch052-F06861.indd 641

1/21/2008 11:47:19 AM

642

Section 3 Lung

Communicating Versus Noncommunicating Bullae Much discussion in the early literature concerned the significance of a bulla that is in communication with the airway and possibly contributing to dead space ventilation versus one that is not.33,100,104,120,131 An open or communicating bulla has a free connection to the bronchial tree and contributes to vital capacity (its contribution represents dead space ventilation) and to RV, as measured by helium dilution. A closed or noncommunicating bulla does not have a free connection to the bronchial tree. Closed bullae do not contribute to the TLC, and their volume does not appear as part of residual volume on helium dilution. Most bullae communicate with the central airway and receive ventilation. However, because they ventilate slowly, true communicating bullae that contribute to dead space ventilation are very rare (Gaensler et al, 1986; Morgan et al, 1989).35,70 The degree to which bullae contribute to ventilation can be determined by the difference between two methods used to measure residual lung volume. Plethysmography using a body box measures total bullae volume as a component of the RV, regardless of whether it receives ventilation. Helium dilution measures only the volume that is able to receive ventilation from the airway. In the helium dilution method, a known quantity of helium is dissolved via the airways into the volume of the lungs, including the RV; RV is calculated from the concentration of helium exhaled in subsequent breaths. (See Chapter 3 for further details on measurement of lung volumes.) The difference between the RV as calculated by plethysmography and the RV as measured by helium dilution is an estimate of the nonventilated or noncommunicating portion attributable to the bullae. As this value approaches zero, or as the RV measured by plethysmography becomes similar to the RV measured by helium dilution, the bullae is said to be communicating. This determination is of academic interest only, however, because both communicating and noncommunicating giant bullae have been shown to respond well to surgical resection.33,116,119

Other Indications for Surgery Hemoptysis/Pulmonary Hemorrhage Massive hemorrhage has rarely been associated with rupture of vessels in a giant bulla.132 Boushy and colleagues100 noted, in the 12 patients in their series who underwent pulmonary angiograms, that none had pulmonary arterial branches traversing a bullous lesion. Gaensler and colleagues (Gaensler et al, 1986)35 noted that only one bullectomy in their career series was performed due to bleeding. Because of the rarity of hemoptysis caused by ruptured vessels in the vicinity of a bulla, hemoptysis in a patient with bullous emphysema mandates an investigation for other sources of bleeding, such as carcinoma, bronchiectasis, or aspergillus superinfection (Deslauriers and LeBlanc, 1994).48

Chest Pain Although rarely the indication for surgery, chest pain associated with giant bullae has been reported. It can be substernal

Ch052-F06861.indd 642

and squeezing, radiating to the arms, and exercise related. It is believed to be the result of air trapping in a bulla, with distention of the visceral or mediastinal parietal pleura. Once cardiac origins have been excluded, the pain has been relieved by bullectomy (Gaensler et al, 1986).35

Pneumothorax Bullous emphysema predisposes patients to pneumothorax. Giant bullae can be mistaken for a large pneumothorax on radiography. Subsequent tube thoracostomy is not warranted and may penetrate the bullae, causing a pneumothorax and bronchopleural fistulas. Spontaneous pneumothorax can be divided into primary and secondary types. Primary spontaneous pneumothorax occurs in lung that is otherwise apparently normal, most often because of rupture of an isolated apical bleb. Secondary spontaneous pneumothorax is the result of an underlying lung disease. The most common cause of secondary spontaneous pneumothorax is emphysema. Less common causes include tuberculosis, pneumoconiosis, pulmonary fibrosis, sarcoidosis, asthma, cystic fibrosis, and pneumonia.133 The incidence of pneumothorax in emphysema is low, 0.003% (57 of 22,000 cases),134 but the treatment can be complicated and difficult. The risk of a recurrent spontaneous pneumothorax is substantially higher in bullous emphysema (50%) than in bleb disease (15%) (Deslauriers and LeBlanc, 1994).48 The first and second most common presenting complaints of a secondary pneumothorax are dyspnea and chest pain. Emphysema patients who already have dyspnea may not recognize or report worsening dyspnea or chest pain. Chest radiographs can be difficult to interpret. A pneumothorax is usually recognized by a line representing the pleura convex toward the chest wall. A bulla forms a concave line (the interface of its base with the lung parenchyma) (Fig. 52-8; see also Fig. 52-5B). Multiple lines from multiple bullae and adhesions from previous pneumothoraces can confuse this appearance. CT scanning of the chest can sometimes distinguish a bulla from a pneumothorax by better defining the thin outer wall of a bulla or the shape of a pneumothorax. Treatment of Pneumothorax. Once identified, a pneumothorax in an emphysematous patient is immediately treated. These patients have diminished respiratory reserve, and even a small pneumothorax can be fatal.4 Treatment consists of re-expanding the lung, closing the fistula, and preventing recurrence. This can be accomplished by observation, needle aspiration, tube thoracostomy, thoracoscopy, or thoracotomy. The last three can be done with or without pleurodesis, and the last two utilize a variety of maneuvers to resect the bulla and seal the air leaks. Because these patients are often poor candidates for extensive surgery, tube thoracostomy is the first-line treatment in most cases.133-135 Indications for surgical intervention include persistent air leak, recurrent pneumothorax, bilateral pneumothorax, hemopneumothorax with massive hemorrhage, and giant bullae. Although it is common practice to tolerate a persistent air leak for a considerable time, Tanaka and colleagues133 reported that, in 76% of their surgical patients, the indication for surgery was air leak persisting for longer than 5 days. Patients with emphysema and a pneumothorax tend to have air leaks of longer duration and

1/21/2008 11:47:20 AM

Chapter 52 Surgery for Bullous Disease

Pneumothorax

Bulla

C

A

onvex

oncav

B

C

with more infectious complications.136 Because emphysema involves the destruction and/or enlargement of the terminal bronchioles and acini, the air leak resulting from rupture of an emphysematous bulla originates much more proximally in the bronchial tree and is therefore less likely to close spontaneously. If it involves a segmental or more proximal bronchi, it can be considered a bronchopleural fistula. Tanaka and colleagues135 reported a 48% recurrence rate with tube thoracostomy alone and a 19% recurrence rate with tube thoracostomy and chemical pleurodesis. In the same series, the recurrence rate with open thoracotomy and pleural abrasion was 12.5%. Given the small benefit of the open procedure over tube thoracostomy and chemical pleurodesis, a conservative approach would favor the latter. Waller and colleagues137 reported performing thoracoscopic bullectomy and pleurectomy in 22 patients for spontaneous pneumothorax in the setting of emphysema (mean preoperative FEV1, 48%). Preoperatively, 18 of these patients had a pneumothorax and a persistent air leak. The perioperative mortality rate was 9%. In 18% of the patients, the procedure failed and a thoracotomy was required.

CONTRAINDICATIONS TO SURGERY FOR BULLOUS LUNG DISEASE Early on, hypoxemia and cor pulmonale were considered contraindications to resection.67 However, other authors

Ch052-F06861.indd 643

FIGURE 52-8 A, A bulla forms a concave pleural line. B, A pneumothorax forms a convex pleural line. C, A pneumothorax with adhesions may also appear as a concave pleural line.

e

C

Adhesion pneumothorax

643

observed good results with giant bullae resected under these circumstances, including short-lived or sustained decreases in pulmonary artery pressures, amelioration of right-sided heart failure, and improvement of hypoxia.4,138-140 Preoperative hypercapnia has been associated with a perioperative mortality rate of up to 30%.31 The presence of chronic bronchitis with cough, sputum production, and recurrent infections is a relative contraindication31,35 but can be compensated for with good preoperative and postoperative pulmonary toilet, adequate pain control, bronchoscopy when necessary, and, in some instances, minitracheostomy for airway suctioning.

OTHER CONSIDERATIONS Smoking Cigarette smoking is a well-documented cause of both emphysema and bullae (Deslauriers and LeBlanc, 1994).48,77 Hughes and colleagues141 monitored a group of 11 patients for a mean of 8.8 years after bullectomy. Patients who continued to smoke had a significantly greater decline in lung function than patients who quit before or at the time of their surgery. Those continuing to smoke lost 34 mL/year of their FEV1, 37 mL/year of VC, and 0.18 mmol/kPa/min/year of their DLCO. Patients who quit smoking showed respective declines of 14 mL/year, 19 mL/year, and 0.08 mmol/kPa/ min/year. Ex-smokers showed a functional decline equivalent to that of normal aging in nonsmokers.141 Surgical treatment

1/21/2008 11:47:20 AM

644

Section 3 Lung

of bullae is not performed on patients who continue to smoke cigarettes. These patients are offered every assistance and encouragement to give up this habit. Although there is some controversy regarding the optimal timing of smoking cessation and surgery, there is clear evidence that nonsmokers experience fewer complications than smokers after thoracotomy.142

Lung Cancer Although cigarette smoking has been shown to cause both bullous emphysema and lung cancer, patients with bullous emphysema may be at an even higher risk of cancer.143-146 Stoloff and colleagues143 found 34 lung cancers in 17,708 patients with no bullous disease and 3 lung cancers in 49 patients with bullous disease. The prevalence of lung cancer in bullous disease was 61/1000, compared with 1.9/1000 in nonbullous disease, for a relative risk of lung cancer with bullous disease 32 times higher. They also noted that, in 23% of lung cancers with bullous disease, the cancer arose in or as part of the bulla. Although this study was not controlled for cigarette smoking, studies from a similar time period showed a relative risk only 10 times greater than that of the general population for lung cancer in heavy smokers.147-149 The mean age at presentation for lung cancer in patients with bullous disease, 46 ± 10 years, is considerably younger than that in the general population, 70 to 74 years.144 The reason for this increased risk is not well known. Carcinogens may be trapped or may accumulate in poorly ventilated bullae. The inner lining of a bulla, already damaged, may be more susceptible to malignant transformation.146 The characteristic radiographic features of carcinoma arising in or near a bulla were described by Tsutsui and colleagues150 and include the following: 1. An opacity in or adjacent to the bulla. If the opacity is inside, it is often at the base of the bulla, well-circumscribed, and nodular or lobulated in appearance—sometimes resembling a fungus ball. 2. A focal or diffuse thickening of the wall of the bulla with an irregular inner surface (from neoplasm growing along the inner wall). 3. Secondary signs including sudden enlargement or shrinkage of the bulla (possibly related to tumor obstructing the feeding airways), straightening of the thin curvilinear shadow of the bulla (caused by traction from the neoplasm), fluid retention within the bulla, and pneumothorax. Survival after lung cancer resection and giant bullectomy has not been well studied. Tanaka and colleagues133 reported on 13 patients with bullous emphysema and concomitant lung cancer in the bullae who underwent resection. Sixty-two percent were found to have stage I disease and had a 5-year survival rate of 67%. Choong and colleagues151 reviewed their experience with 21 patients undergoing LVRS and lung cancer resection. Eighteen patients underwent lobectomy, and three had wedge resections. Notably, all cancers were in lung parenchyma considered part of the target zones for LVRS. Sixteen were stage I, two were stage II, two were stage III, and one

Ch052-F06861.indd 644

was stage IV. The 1- and 5-year survival rates were 100% and 62.7%, respectively.151

Infected Bullae The incidence of infection in emphysematous bullae is not known. In some cases, fluid observed in a bulla is sterile and is the result of inflammation caused by infection in the surrounding parenchyma.133 In others, it may be an ominous sign of a neoplasm now obstructing the communicating airway. Radiographically, infected bullae may resemble single or multiple cavitating abscesses. An infected bulla may be distinguished from a lung abscess by the following102: 1. Knowledge of preexisting bullous disease in the involved lung 2. Other bullae in the same or contralateral lung 3. Very rapid appearance of the air-fluid levels and extensive apparent cavitation after only a few days of illness 4. Relatively slight involvement of surrounding lung 5. Initial absence of any pleural reaction True purulence in a bulla can be managed like a lung abscess. Antibiotics are the mainstay of treatment, including penicillin, clindamycin, or a third-generation cephalosporin. Other treatments include chest physiotherapy and good nutrition. Drainage is indicated under several circumstances, including no clinical response to treatment after 2 to 4 weeks of antibiotic therapy, evidence of purulence under tension, and increasing cavity size. Treatment can be accomplished percutaneously, thoracoscopically, or with an open procedure. Hemoptysis, suspected carcinoma, and rupture into the airway or pleural space are special situations in which drainage must be accomplished urgently. As the infection subsides, bullae have been seen to fibrose and spontaneously regress (see Fig. 52-4).100,102,152

SURGICAL TREATMENTS Surgery for giant bullae seeks to remove the volume occupied by the bulla while preserving as much underlying lung and lung function as possible. This can be accomplished by either of the following: 1. Resecting the wall of the bulla, as in bullectomy, with either a thoracotomy or median sternotomy or through a thoracoscope 2. Removing the air within the bulla, effectively collapsing it, as in endocavitary drainage

Bullectomy The goal of bullectomy is to resect as much bullous tissue as possible without resecting the underlying, more normal lung and without limiting the ability of that lung to fully expand. Several techniques have been described to accomplish these goals. Care is taken in opening the pleural space because injury to underlying preserved lung can be difficult to repair and can result in protracted air leaks. A complete adhesiolysis reveals the full extent of the bullous disease and allows the underlying lung to fully expand into the vacated pleural space. Anatomic resections, including lobectomy, segmentec-

1/21/2008 11:47:20 AM

Chapter 52 Surgery for Bullous Disease

tomy, and pneumonectomy, are largely avoided unless indicated for other reasons.4,31 Narrow-necked bullae can be excised with their pedicle ligated. Deflating the bulla and twisting the stalk can provide firmer tissue at the base to ligate. Deslauriers and Dartevelle and their colleagues153,154 have described a technique of incision and plication that is applicable to patients with large bullae and relatively normal underlying parenchyma. The largest bulla is opened longitudinally; its cavity is explored from within, and any septa are divided. Allis, Babcock, or Duvall clamps are used to grasp the bulla from the inside at the reflection of the bullous wall with normal lung. Gentle ventilation of the lung can help identify this interface. The wall of the bulla is folded over and used as a staple line buttress. A linear stapler is fired completely across the base of the bulla. At completion, all raw lung surfaces are sealed, and the buttressed staple line consists of four layers of parietal pleura and bulla wall (Fig. 52-9). Alternatively, a giant bulla that represents local exacerbation of diffuse emphysema can be excised using the stapling technique of LVRS (see Chapter 50). This technique does not widely open the bulla. Rather, target areas of lung . includ. ing the giant bulla, previously identified on CT or V/Q scanning, are located. The bulla is deflated by incising its lateral

FIGURE 52-9 Bullectomy by incision and stapled plication. A, Longitudinal opening of the bulla. B, Visceral pleura is folded over and the base of the bulla is stapled. C, Completed bullectomy. (FROM DESLAURIERS J, LEBLANC P, MCCLISH A: GENERAL THORACIC SURGERY, 3RD ED. PHILADELPHIA, LEA & FEBIGER, 1989.)

Ch052-F06861.indd 645

645

wall. The bulla is then held up, and sequential firings of a bovine pericardium– or expanded polytetrafluoroethylene (E-PTFE)–reinforced stapler-cutter are applied to resect as much of the bulla as possible while not removing the more normal underlying lung.155-158 Finger compression of the area of the lung where the stapler is to be applied can ease its application and prevent injury to the lung (Fig. 52-10). Bullae may also be removed by simple excision with suturing of any air leaks. The wall of the bulla is excised down to its junction with normal lung; any air leaks in the base of the bulla are sutured closed; a chest tube is placed in the pleural space; and the lung is re-expanded.159 Whichever technique is used, care in handling the lung to prevent inadvertent tears minimizes air leaks, and air leak is the most common complication of bullectomy. Its prevention is discussed later in this chapter.

Thoracoscopic Bullectomy Because thoracoscopy has the potential of avoiding a thoracotomy, with its concomitant pain and respiratory compromise, many surgeons have adopted thoracoscopy to the treatment of giant bullae. Wakabayashi40 reported the first series of thoracoscopically treated giant bullae in 1993. Wakabayashi either contracted the bullae with a carbon dioxide or neodymium : yttrium-aluminum-garnet (Nd : YAG) laser or resected the bulla wall and sutured the base closed. In his series of 17 patients, there were no mortalities, and all patients showed symptomatic improvement. The most common complication was prolonged air leak. Application of heat energy to giant bullae has been seen to cause contraction of the bullae, potentially ablating them. Electrocautery, defocused carbon dioxide laser,160 and Nd : YAG laser43 have been used to this end. Early reports showed significant improvements in symptoms as well as FEV1, FVC, and RV, without significant changes in DLCO.43 Air leak remained the most common complication. Perioperative mortality rates between 0% and 12.5% have been reported.40,43,160 For a giant bulla with underlying normal lung, the laser may be a useful means to cut and coagulate the wall of the bulla to be resected.40 However, applying the laser directly to a bulla to cause heat contraction bullectomy can no longer be advocated. Contraction bullectomy as part of LVRS has been found to provide significantly less improvement in FEV1 than stapled bullectomy, with a greater number of delayed pneumothoraces (Hazelrigg et al, 1996; McKenna et al, 1996).161,162 Bilateral and unilateral thoracoscopic stapled giant bullectomies have been performed.44,163 Thoracoscopy can be performed with either a small (4 cm) working incision and a separate camera port or with the so-called baseball diamond configuration of three ports (Figs. 52-11 and 52-12). Take care in initial port placement because injury to emphysematous lung that is not to be resected can be difficult to repair and results in extended air leaks. A thorough adhesiolysis exposes all surfaces of the lung to better visualize the giant bulla and allows the lung, when re-expanded, to completely fill the chest cavity. If a pleural tent is to be used, take care in the adhesiolysis not to damage the parietal pleura. Even

1/21/2008 11:47:20 AM

646

Section 3 Lung

Left upper lobe

A

B

C

D

FIGURE 52-10 Stapled bullectomy. A, Identify and puncture bulla. B, Elevate bulla with clamps, and manually compress the lung along the area of the intended staple line. C, Apply buttressed endoscopic linear stapler. D, Completed stapled bullectomy.

with good single-lung ventilation, and despite the best efforts of the anesthesiologist, a giant bulla can remain inflated, obscuring the view (Fig. 52-13A). The bullae often need to be surgically punctured to obtain visualization (see Fig. 52-13B). Once the bulla is identified, a stapled bullectomy is performed with sequential firings of a bovine pericardium– or PTFE-buttressed endoscopic stapler-cutter (see Fig. 52-13C,D).155-158 Examples of excised bullae are shown in Figure 52-14. Take care to trim excess edges of the staple lines and to keep the staple lines as even and sequential as possible, to avoid the creation of jagged edges. The underlying lung is reinflated under direct vision. If the underlying lung does not reinflate, bronchoscopy can be performed to suction clean the involved airways. Occasionally, even with clear proximal airways, a portion of the lung does not reexpand. This situation occurs when a bulla has led to chronic collapse of an adjacent section of lung. The airway pressure required to reopen a chronically collapsed lobe or segment is high, and the abnormally compliant diseased lung is preferentially inflated. The bronchoscope can be used to apply gentle jet ventilation to isolated segments of collapsed lung, to avoid barotrauma to the rest of the lung. One or two pleural drains are placed and kept on water seal.

Ch052-F06861.indd 646

Although previous ipsilateral thoracotomy can be a relative contraindication to subsequent thoracoscopic procedures, Yim and colleagues164 were able to complete 38 of 40 attempted thoracoscopic procedures in the face of a previous ipsilateral thoracotomy, with 12 of these thoracoscopies done to perform bullectomy. As an alternative to resection, other surgeons have thoracoscopically introduced fibrin glue and thrombin into the deflated bulla, effectively sealing the bulla wall to the remaining lung. The lung is then reinflated.45

Endocavitary Drainage Monaldi165 described a technique of endocavitary drainage in 1938. Its purpose was to relieve tension in a tuberculous cavity. To avoid the danger of a pneumothorax, Monaldi’s original procedure involved two stages. In the first stage, a section of rib overlying the affected lung was carefully removed so as not to disrupt the parietal pleura. An iodine pack was placed extrapleurally to induce symphysis between the visceral and parietal pleura. Three weeks later, the pack was removed, and a drainage catheter was placed directly into the involved lung, traversing the now fused pleura. In 1946, John Alexander first applied this method to emphysematous

1/21/2008 11:47:21 AM

Chapter 52 Surgery for Bullous Disease

FIGURE 52-11 Two variations on port placement for thoracoscopic bullectomy. A, Baseball diamond configuration. The camera is inserted at home plate, with pathology of interest at second base; first and third bases are instrument ports. B, Working port configuration. A 4-cm anterior working port and camera port are placed in the interspace between the 6th and 7th ribs along the anterior to midaxillary line.

Target 2nd base

Working port

1st base

3rd base

647

Home Camera port

A

B

A

B

C

D

FIGURE 52-13 Thoracoscopic stapled giant bullectomy of the bulla shown radiographically in Figure 52-5. A, Large distended bulla obscures visualization despite good single-lung ventilation. B, The bulla is deflated by puncturing its wall (black arrow). C, A narrow stalk to the left lower lobe is divided with a buttressed endoscopic staplercutter. D, Finished giant bullectomy. (COURTESY OF DR. MITHRAN FIGURE 52-12 Thoracoscopic bullectomy with so-called working port configuration.

Ch052-F06861.indd 647

SUKUMAR, SECTION OF GENERAL THORACIC SURGERY, OREGON HEALTH AND SCIENCES UNIVERSITY, PORTLAND, OR.)

1/21/2008 11:47:22 AM

648

Section 3 Lung

A

B

C FIGURE 52-14 Resected, deflated giant bullae. A, A broad-based giant bulla resected from a lung with underlying emphysema. B, The same bulla as in A, insufflated with air at 7 mm Hg pressure. C, A bulla with a narrow base, which was resected from the lung imaged in Figure 52-5 by the procedure shown in Figure 52-13. Note the vessels in the walls of the bulla. An endoscopic stapler-cutter, 60 mm in length, was used for resection of both of these bullae.

bullae. In 1949, Jerome Head and Edward Avery22 reported on nine patients with giant bullae treated with endocavitary drainage in the manner of Monaldi. In eight of these nine patients, they were able to largely eliminate the bullae, reexpand underlying relatively normal lung, and produce symptomatic improvement. Endocavitary drainage was further modified to a single-stage procedure by foregoing the iodine pleurodesis and instead approximating the parietal and visceral pleura with a purse-string suture and placing the drain within this purse-string.22 This technique was modified further by surgeons at the Brompton Hospital in London and was described well in their 1995 monograph.166 CT scanning is used to select the optimal placement of a small (7-cm) thoracotomy. The incision is placed over the bulla and situated so that the endocavitary

Ch052-F06861.indd 648

drain can exit the same incision. The anticipated re-expansion of underlying lung needs to be taken into account; if needed, the drain can exit the chest in a separate stab wound, especially to maximize patient comfort. Through the incision, a piece of rib is excised and the parietal pleura overlying the bulla is incised; the bulla is visualized and then incised on its lateral wall. Two concentric polypropylene purse-string sutures are placed around the hole in the bulla, taking many small bites of the wall at a generous distance from the lung edge. Any septa in the interior of the bulla are excised to create a single large cavity. Although some authors performing endocavitary drainage have not used talc,22,26,167 surgeons at the Brompton Hospital have insufflated talc into the bulla to produce a more rapid and permanent sclerosis of the cavity. A 32-Fr Foley catheter is inserted into the bulla to serve as the endocavitary drain. The balloon is inflated with 30 to 40 mL of air, and the purse-string sutures are tied to seal the balloon within the bulla. Suction is applied to the Foley catheter, the bulla collapses, and the remaining lung is allowed to expand. Any remaining bullae can be excised or similarly drained. Talc pleurodesis is performed to lessen the impact of air leakage around the drains. The visceral to parietal pleural symphysis permits any bullae discovered postoperatively to be treated with local anesthesia and a percutaneously placed drain. A pleural drain is also placed and kept on water seal. The authors described the postoperative air leak from the endocavitary drain as brisk; they keep the drain under water seal for 12 to 24 hours and then apply gentle suction. The pleural drain is removed after the air leak ceases (usually 48 hours), and the endocavitary drain is removed between 8 and 21 days after surgery (Fig. 52-15).26,166,167 Endocavitary drainage of giant bullae is attractive in that it requires a limited surgical approach, avoiding resection or compression in the suture line of underlying normal lung, yet providing symptomatic relief and functional improvement. Although endocavitary drainage has been reserved for patients who would not otherwise tolerate a thoracotomy,167 some authors advocate it as a first choice procedure for surgical treatment of all giant bullae.27 The same authors, however, caution against even this minimal approach in patients with an FEV1 of less than 500 mL because a 30% improvement in FEV1 would still leave the patient severely debilitated. In addition, the operative mortality rate in this small subgroup of their series was 66% (2 of 3 patients died).27,168

Bulloscopy Before the availability of chest CT, it was sometimes difficult to distinguish a giant bulla with relatively preserved underlying lung from diffuse bullous emphysema with a dominant bulla. Using an adaptation of endocavitary drainage, Kuwabara and colleagues169 inserted a flexible endoscope through a large-bore drainage tube placed into the bulla and performed bulloscopy. They noted that the wall and floor of a giant bulla was smooth with some air leakage, like a pinhole. A dominant bulla in emphysematous lung, on the other hand, had a rough inner wall and many air leaks in its floor, like a lattice. This procedure is now only of historical interest.

1/21/2008 11:47:24 AM

Chapter 52 Surgery for Bullous Disease

A

649

B

FIGURE 52-15 Endocavitary drainage (Brompton approach). A, A bulla herniated through the thoracotomy incision. B, The bulla has been incised and collapsed and talc is being insufflated. C, A large Foley catheter has been inserted into the bulla and is held in place by purse-string sutures. (FROM GOLDSTRAW P, PETROU M: THE SURGICAL

C

Median Sternotomy Giant bullectomy can be performed through a median sternotomy, and in bilateral disease this may be the preferred open approach (Haerens et al, 1988).25,116,119,170 Cooper and colleagues170 showed that respiratory function, as measured by vital capacity and peak flow, is reduced by 50% with both unilateral thoracotomy and sternotomy, but respiratory function is quicker to recover after sternotomy. Exposure is aided during this approach by early division of the inferior pulmonary ligament and double-lumen endotracheal tube placement with single-lung ventilation. A Rultract skyhook retractor (Rultract, Independence, OH), Delacroix-Chevalier asymmetric sternal retractor (Delacroix-Chevalier, Paris, France), or other sternal spreader designed to both lift the sternal plate on the operative side and spread the divided sternum can improve exposure. In addition, the table can be tilted away from the operating surgeon. Patients with bilateral giant bullae with preserved underlying lung are an extremely rare entity. Bilateral giant bullae raise the suspicion of more severe emphysema in the underlying lung.

Choice of Procedure Unless an operation for cancer is being performed, anatomic resections are generally avoided.4,31 Even with apparently

Ch052-F06861.indd 649

TREATMENT OF EMPHYSEMA. CHEST SURG CLIN NORTH AM 5:777-796, 1995. COPYRIGHT ELSEVIER 1995.)

largely destroyed lung, there is often functional tissue near the hilum.30 Rarely, an entire lobe is destroyed and an anatomic resection is appropriate. No clear advantage has been shown for thoracoscopy, median sternotomy, thoracotomy, or endocavitary drainage. The advantages and disadvantages of these procedures have been discussed, and the choice is based on the experience and preference of the operating surgeon and patient.

OPERATIVE OUTCOMES Operative Mortality In 1996, Snider (Snider, 1996)114 reported on a meta-analysis of 22 series of giant bullectomies published since 1950. The weighted operative mortality rate for the 262 patients for whom mortality was reported was 8%. In a contemporary series of 43 patients at Washington University in St. Louis, the operative mortality rate was 2.3% (Schipper et al, 2004).171 This is similar to the 2.1% mortality reported by FitzGerald in 1974 and comparable to the rates between 5% and 14% reported by various authors from 1970 to 2002 (DeGiacomo et al, 2002; FitzGerald et al, 1974; Haerens et al, 1988).24,29-32,39,104,115,116,130,172 In 1989, Connolly and Wilson34 reported no mortality in 19 patients undergoing thoracotomy and bullectomy. In 2005, Palla173 reported no

1/21/2008 11:47:26 AM

650

Section 3 Lung

perioperative mortality in 41 giant bullectomies. These series used variations on excision, resection, or ligation. Perioperative mortality rates for thoracoscopic stapled resection or thoracoscopic laser bullectomy have been reported by various authors to be between 0% and 12%.40,43,44,160,163 Mortality with the Monaldi or Brompton techniques has been reported by several authors to fall into the same range of 0% to 15%.26,27,167,168

Operative Morbidity The overall complication rate in our own series of giant bullectomies was 79%. Fifty-three percent of patients had an air leak lasting longer than 7 days, 12% experienced atrial fibrillation, 9% were ventilated beyond the period of the operation, and 7% developed notable subcutaneous emphysema (Schipper et al, 2004).171 Complications after bullectomy have not always been thoroughly or uniformly addressed in the literature. Overall complication rates have been reported by Wesley29 (14%), FitzGerald30 (24%) (1974), Potgieter31 (43%), and Ray172 (57%) and their colleagues. Prolonged air leak after giant bullectomy is almost universally the most common reported complication. The frequency of prolonged air leak is approximately 50% in most series (DeGiacomo et al, 2002; Schipper et al, 2004).115,171,172 Other commonly reported complications are subcutaneous emphysema, ranging from 7% to 53%; arrhythmia, 12% to 13%; and empyema, 6% to 14% (DeGiacomo et al, 2002; FitzGerald et al, 1974).29-31,115,167

Air Leak Several authors have developed methods of minimizing air leaks. In both open and thoracoscopic procedures, gentle handling of lung tissue is essential. Bovine pericardial strips, pleura, and E-PTFE strips can be used to buttress staple lines.155-158 Because giant bullae can fill a large volume, the underlying lung may not be able to completely re-expand after surgery into the vacated hemithorax. An apical pleural tent can help ameliorate this space issue. Pleural tents can be constructed thoracoscopically, or in an open fashion through a median sternotomy or thoracotomy. Often a decision must be made as to what portions of the lung will be resected versus what portion of the pleura will be used in the tent and during the adhesiolysis—whether to risk injury to the lung or injury to the pleura. Chest tubes are placed between the parietal and visceral pleura, and not between the pleural tent and the chest wall. Although many surgeons allow the tent to fall on top of the staple line after resection, Busetto and colleagues174 used a parietal pleural tent placed over the bulla to be excised and fired the stapler across both the tent and the bulla. Liu and colleagues reported persistent air leak in only 9.7% of 93 patients treated with loop ligation of giant bullae. The bullae were deflated and twisted to their base until normal lung parenchyma was reached; then, one or several No. 1 Endoloops were applied to the base.175,176 It is difficult to determine whether endocavitary drainage offers any advantage over thoracotomy and resection in terms of preventing air leaks. MacArthur and Fountain26 reported keeping the drainage catheter on underwater seal routinely

Ch052-F06861.indd 650

for 21 days. This was done in part to cause a fibrosis of the cavity and pleurodesis from the inevitable secondary infection. Shah and Goldstraw27 used the Brompton technique; they removed the pleural drains within 48 hours, but routinely left the endocavitary drainage catheter in place for 8 days. Cerfolio177 demonstrated the importance of water seal, as opposed to suction drainage of the pleural space, in encouraging air leaks to seal after pulmonary resections. He noted that water seal may not resolve a pneumothorax if a large leak is present. It is our practice to place all pleural drains on water seal after emphysema surgery. The chest radiograph is observed, and a small pneumothorax is tolerated. On rare occasions, the pneumothorax is large enough that we attempt to expand the lung, using as little suction as possible (7-10 mm Hg). The treatment of massive subcutaneous air may also require the placement of chest tubes on low suction.

Short- and Long-Term Outcomes Open Bullectomy Short-term outcomes for properly selected patients are good. In general, dyspnea is relieved and pulmonary function improved. Pearson and Ogilvie32 noted symptomatic improvement in 90% of patients operated, and Laros and colleagues33 observed improvement in 100% of patients with bullae larger than 50% of the hemithorax. Baldi and coworkers117 reported a dyspnea reduction of 1 integer point on the 5-point MRC Dyspnea Scale. Vejlsted and Halkier130 reported 100% symptomatic improvement early and 81% improvement at 5 years. Lopez-Majano and associates105 reported that 61% of patients were very improved or better, 17% fair, and 22% worse or not improved symptomatically. Ohta and associates110 reported 100% symptomatic improvement in 25 bullectomies; 20 of these patients had sustained improvement at 4 years, and 5 had a return of their symptoms. Gunstensen and McCormack104 reported symptomatic improvement in only 50% of 23 patients with surgically treated giant bullae. In our series, 86% of patients reported improved dyspnea at 6 months after surgery, 10% reported no change, and 4% reported worse dyspnea. At 3 years, 81% still reported improved dyspnea, 11% described no change, and 8% thought their dyspnea was worse (Schipper et al, 2004).171 Many surgeons have also observed objective improvement in pulmonary function after giant bullectomy. Baldi and coworkers117 reported a 50% to 60% increase in FEV1. FitzGerald’s group (FitzGerald et al, 1974)30 reported increases of between 50% and 200% of preoperative FEV1. DeGiacomo and associates (DeGiacomo et al, 2002)115 reported a more modest 26% to 36% improvement in FEV1. In our series (Schipper et al, 2004),171 FEV1 improved from a mean baseline (after pulmonary rehabilitation) of 34% of predicted to 55% of predicted at 6 months, then declined to 49% of predicted at 3 years, still significantly improved over the preoperative values. In general, long-term follow-up data are lacking. In series reporting long-term follow-up, one third to one half of patients appear to maintain their improvement out to 5

1/21/2008 11:47:27 AM

Chapter 52 Surgery for Bullous Disease

years.114 The longevity of improvement appears to be related to the condition of the underlying lung. Using FEV1 and symptoms as measures, FitzGerald and colleagues (FitzGerald et al, 1974)30 monitored patients for as long as 20 years and noted that those whose bullae were merely localized exaggerations of diffuse underlying emphysema showed initial and sustained improvement for 1 to 2 years but subsequently declined thereafter. In the group with bullae occupying greater than 70% of the hemithorax, the improved FEV1 was maintained for 5 years but then declined. An annual decline in FEV1 of 101 mL/year was observed. Those patients with bullae occupying less than 30% of the hemithorax showed no improvement or even demonstrated a worsening of postoperative FEV1. Laros and associates33 performed giant bullectomies on 27 patients and also noted immediate improvement in symptoms and vital capacity that lasted 2 years before declining. Pearson and Ogilvie32 reported on a series of 11 patients undergoing lobectomy or bullectomy for giant bullae. They observed a significant early (3-6 month) improvement in FEV1, FVC, and dyspnea. After 5 to 10 years of follow-up, only FVC remained significantly improved. FEV1 and dyspnea grade had declined to levels no different from the preoperative values. In general, patients showed a decline in FEV1 of 82 mL/year after bullectomy. Haerens and colleagues (Haerens et al, 1988)116 also noted, in their patients who were monitored for longer than 2 years, that FEV1 declined at a rate of 49 ± 51 mL/year. This decline occurred in the absence of recurrence of giant bullae on chest radiography and was therefore believed to be caused by progression of underlying emphysema. In patients with an isolated giant bulla and well-preserved underlying lung, sustained improvement to 20 years or more has been observed (FitzGerald et al, 1974).30,34 Patients meeting these criteria are exceptionally rare, however.

Thoracoscopic Bullectomy DeGiacomo and colleagues44 presented a series of 25 patients, 4 with giant bullae associated with almost normal parenchyma in the remainder of the lung. Twenty-one had giant apical bullae as well as some degree of emphysematous change in the remainder of the lung. Using the American Thoracic Society criteria for respiratory impairment, these 21 patients were divided into three groups according to FEV1. Five patients had an FEV1 greater than 50% of predicted; eight had a value between 35% and 49% of predicted, and 12 had less than 35% of the predicted value. In this way, an attempt was made to evaluate the degree of underlying emphysema. Twenty-three patients underwent a unilateral thoracoscopic stapled bullectomy (two bilateral procedures). At 3 months, all three groups had significantly improved FEV1, MVV, FRC, and DLCO percentages. Although those patients with the best underlying lung (FEV1 35%-49% or FEV1 > 50% of predicted) had the greatest improvement in their pulmonary function; patients with FEV1 less than 35% of predicted were significantly functionally and symptomatically improved. Palla and colleagues173 reported on 41 giant bullectomies performed between 1985 and 1999. Fourteen of these were done thoracoscopically, and 27 with a thora-

Ch052-F06861.indd 651

651

cotomy. Postoperatively, all patients improved symptomatically and showed an increased FEV1. Long-term outcome was again dependent on the underlying lung. At 5 years, those with underlying emphysema had symptomatically and functionally returned to values no different from their preoperative state, whereas those with preserved lung showed sustained improvement.

Endocavitary Drainage Using endocavitary drainage, surgeons at the Brompton Hospital, London, have reported two series, one in 1988 and one in 1994. They noted median increases in FEV1 of 22% and 28%, respectively. In 1994, they also observed that 90% of their patients had improved symptoms, as demonstrated by a mean change of MRC Dyspnea Scale score from 3.7 preoperative to 2.1 postoperatively.27,168 MacArthur and Fountain noted that 90% of patients treated in this manner had symptomatic relief.26 In the initial report of the Brompton technique, 88% of patients were still symptomatically improved at a median of 1.6 years.168 In a subsequent report, with a mean follow-up of 2.5 years, 6.7% of patients required redrainage of a bulla, which was accomplished percutaneously. Ninety-five percent of patients maintained their symptomatic improvement through the 2.5-year follow-up period.166

Reoccurrence of Bullae FitzGerald and colleagues (FitzGerald et al, 1974)30 radiographically monitored 62 patients after bullectomy for a mean of 9.3 years. Forty-eight (77%) of the 62 patients showed neither a significant change in the size of any residual bullae nor development of new bullae. In comparing patients with unilateral versus bilateral resections, there were 3 recurrent bullae (12%) in 26 unilateral resections and 11 recurrent bullae (30%) in 36 bilateral resections. The bullae recurring after unilateral resection appeared on average 10 years postoperatively and exhibited a diffuse bilateral pattern, rather than reoccurrence of another isolated bulla (FitzGerald et al, 1974).30 Nickoladze25 noted, in 18 patients with bilateral giant bullae, that none had reoccurred radiographically at 5 years. In 27 patients with resection of bullae occupying more than 50% of the hemithorax, Laros and colleagues33 noted no radiographic reoccurrences of giant bullae at 10 years. In patients with underlying emphysema, they did observe radiographic progression of the emphysema, including bullae (<30% of hemithorax). Palla and colleagues173 performed 41 giant bullectomies and with 5 years of CT scan follow-up saw no new bullae at the site of bullectomy and no enlargement of residual small bullae. Goldstraw and Petrou166 did observe a 6.7% ipsilateral reoccurrence rate after endocavitary drainage of bullae, but they were able to treat all of these with a percutaneously placed drain.

SUMMARY Surgery for bullous lung disease falls into two broad categories: operations to treat complications such as pneumothorax,

1/21/2008 11:47:27 AM

652

Section 3 Lung

infection, concurrent lung cancer, and, rarely, hemoptysis, and operations to help alleviate dyspnea and improve pulmonary function. The best candidates are patients with an isolated bulla occupying more than 30% of the hemithorax, collapsed and otherwise normal underlying lung, and dyspnea. Evaluation includes quantification of the patient’s dyspnea and degree of physical limitation, pulmonary function testing, and radiographic imaging, including a CT scan of the chest and possibly radioisotope scanning. The operative goal is to remove the bulla but preserve the underlying lung as functional and ventilated. Several operative techniques are used to accomplish these goals, including stapled bullectomy, excision, ligation, and endocavitary drainage. Several approaches can be used to perform these techniques including thoracoscopy, thoracotomy, and median sternotomy. In properly selected patients, most can be expected to have subjective improvement of their dyspnea as well as demonstrable improvement in pulmonary function testing. The long-term resilience of this improvement is dependent on the quality of the underlying lung and the progression of any disease in that lung.

COMMENTS AND CONTROVERSIES The surgical management of bullous emphysema has a long and interesting history. As the authors point out, only lung transplantation, LVRS, and bullectomy or bulla decompression have emerged as effective surgical options. Lung transplantation and LVRS are employed for patients with more diffuse disease. The true giant bulla with relative preservation of the rest of the lung is a rare lesion. This explains why there are no large series describing their management or prospective trials comparing different treatment options. However, it is clear that the indication for surgical excision (bullectomy) or decompression is large size with underlying compression of surrounding lung or other complications such as infection. Decompression is reserved for those patients judged to be highrisk candidates for resection. Bullectomy has been shown to be associated with low operative mortality and impressive improvement in pulmonary function and quality of life. The techniques (e.g., open, video-assisted thoracic surgery [VATS], buttressed staples) are effective and largely a matter of surgical preference. J. D.

Ch052-F06861.indd 652

KEY REFERENCES Burrows B, Earle R: Course and prognosis of chronic obstructive lung disease: A prospective study of 200 patients. N Engl J Med 280:397404, 1969. DeGiacomo T, et al: Bullectomy is comparable to lung volume reduction in patients with end-stage emphysema. Eur J Cardiothorac Surg 22:357-362, 2002. Deslauriers J, LeBlanc P: Management of bullous disease. Chest Surg Clin North Am 4:539-559, 1994. FitzGerald MX, Keelan PJ, Cugell DW, Gaensler EA: Long-term results of surgery for bullous emphysema. J Thorac Cardiovasc Surg 68:566587, 1974. Gaensler EA, Jederlinic PJ, FitzGerald MX: Patient work-up for bullectomy. J Thorac Imag 1:75-93, 1986. Haerens M, Deneffe G, Billiet L, Demedts D: Effect on pulmonary function of surgical treatment of bullous lung disease. Acta Clin Belg 43:356-373, 1988. Hazelrigg S, et al: Thoracoscopic laser bullectomy: A prospective study with three-month results. J Thorac Cardiovasc Surg 112:319-327, 1996. McKenna RJ Jr, Brenner M, Gelb AF, et al: A randomized prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg 111:317-322, 1996. Mehran RJ, Deslauriers J: Indications for surgery and patient work-up for bullectomy. Chest Surg Clin North Am 5:717-734, 1995. Morgan MDL, Denison DM, Strickland B: Value of computed tomography for selecting patients with bullous lung disease for surgery. Thorax 41:855-862, 1986. Morgan MDL, Edwards CW, Morris J, et al: Origin and behaviour of emphysematous bullae. Thorax 44:533-538, 1989. Schipper PH, Meyers BF, Battafarano RJ, et al: Outcomes after resection of giant emphysematous bullae. Ann Thorac Surg 78:976-982, 2004. Shah SS, Goldstraw P: Surgical treatment of bullous emphysema: Experience with the Brompton technique. Ann Thorac Surg 58:14521456, 1994. Snider GL: Reduction pneumoplasty for giant bullous emphysema: Implications for surgical treatment of nonbullous emphysema. Chest 109:540-548, 1996. Ting EY, Klopstock R, Lyons HA: Mechanical properties of pulmonary cysts and bullae. Am Rev Respir Dis 87:538-544, 1963. Travaline JM, Addonizio VP, Criner GJ: Effect of bullectomy on diaphragm strength. Am J Respir Crit Care Med 152:1697-1701, 1995.

1/21/2008 11:47:27 AM

SURGICAL MANAGEMENT OF CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

chapter

53

Michael Mulligan

Key Points ■ Chronic thromboembolic pulmonary hypertension is underdiag-

nosed and undertreated. ■ Candidates for pulmonary endarterectomy must have pulmonary

vascular obstructive disease with significant hemodynamic and cardiopulmonary impairment. ■ Pulmonary endarterectomy must be bilateral, conducted in the plane of the media, and performed under cardiopulmonary bypass with intermittent circulatory arrest. ■ Postoperative intensive care is focused on minimizing pulmonary vascular resistance and limiting pulmonary reperfusion edema.

Each year, more than 500,000 Americans are diagnosed with acute pulmonary embolic disease.1 Clot resolution after anticoagulation therapy is the typical outcome, with minimal residual irregularities or obstructions left within the pulmonary arteries (PAs). However, in 0.1% to 0.5% of these patients, there is incomplete resolution of the thromboembolism, and these patients ultimately manifest chronic thromboembolic pulmonary hypertension (CTEPH).2 That means that between 500 and 2500 new cases of CTEPH are generated annually in the United States. Because only 150 to 175 operations are done each year for CTEPH in the United States, this more chronic disease appears to be underdiagnosed and undertreated. Risk factors for the development of CTEPH have not been identified. About 90% of the patients have no detectable coagulation abnormalities; 10% have a lupus anticoagulant, and fewer than 1% have deficiencies of AT3, protein C, or protein S or deficiencies or other abnormalities of factor V Leiden.3

CLINICAL PRESENTATION Many patients present without a history of known acute pulmonary embolism. Rather, they have typically had lengthy evaluations for chronic and progressive dyspnea.4 Unless an index of suspicion exists, the diagnosis of CTEPH can be particularly difficult to make and is often quite delayed. If a history of acute pulmonary embolism is documented, the therapy for that event typically has been entirely appropriate. Other patients report that the diagnosis was not made until some months after the acute event, or perhaps that therapy was suboptimal. After recovery from the inciting or initial embolic event, there is usually clinical improvement associated with partial clot lysis. Many patients report that at this stage they felt

relatively well. This honeymoon period may last months to years. Patients then begin to manifest progressive exertional dyspnea. Because dyspnea on exertion is a symptom common to many diagnoses and CTEPH is less common, the diagnosis is not usually made at this stage. Late in the course of the disease, hypoxemia and symptoms of right-sided heart failure develop.5 Often the diagnosis is not secured until this stage. The explanation offered to explain symptomatic progression is often recurrent pulmonary emboli. Many patients progress despite having vena caval filters in place and appropriate anticoagulation therapy. Imaging studies in these patients can demonstrate progression of existing lesions but no new defects in arterial segments that were previously unaffected. In many of these patients, there appears to be a secondary fibroproliferative response within the PAs that produces progressively more distal obstructions. In other patients, disease may develop in segments that were never documented to contain any obstructing lesions or thrombus. Conceivably, these unobstructed segments might have been subjected to excessive flow that resulted in vascular injury. If this process were entirely responsible, however, one would not see the progressive arteriopathy that often develops in arterial segments that are distal to a point of anatomic obstruction. Most likely, progressive increases in pulmonary vascular resistance are the result of multiple inflammatory, hemodynamic, and fibroproliferative influences. As mentioned, the earliest symptom of CTEPH is exertional dyspnea. Although it is variable in presentation, it can be debilitating. In some patients, the simple act of having a conversation can result in marked hypoxemia. Young, otherwise fit patients may have minimal symptoms at rest but become profoundly short of breath with even minimal exercise. Obviously, patients with coronary disease may develop angina. However, the excessive right heart strain in these patients can also produce ischemic chest pain in the absence of coronary disease. A history of lightheadedness or syncopal episodes is relatively common. These symptoms are typically worsened by coughing or straining. This relates to the fact that the Valsalva maneuver and other maneuvers that transiently increase intrathoracic pressure dynamically worsen already elevated pulmonary vascular resistance. Exercise produces a relative increase in pulmonary vascular resistance and decrease in systemic vascular resistance, which also contributes to these symptoms. In CTEPH, pulmonary vascular resistance is fixed at a high level; as oxygen demands increase with exercise and peripheral systemic vascular relaxation occurs, the patient is unable to mount an increase in cardiac output to compensate for 653

Ch053-F06861.indd 653

1/21/2008 11:48:26 AM

654

Section 3 Lung

dilation, and systemic blood pressure drops. Likewise, without a compensatory increase in cardiac output, the mixed venous oxygen saturation progressively drops to very low levels. Furthermore, because 25% of this population have an atrial level shunt (typically a patent foramen ovale), dynamic increases in right-sided pressures exacerbate right-to-left shunting and can cause precipitous desaturation. The physical findings may be limited early in the course of the disease. Most patients demonstrate some degree of lower extremity swelling. Because the source of the original inciting pulmonary embolus was a deep venous thrombosis, some component of these findings may be secondary to a chronic postphlebitic syndrome. As right-sided pressures rise and tricuspid insufficiency worsens, venous hypertension exacerbates the swelling.6 Forty percent of patients present with ascites that may be pronounced. The subcutaneous vasculature is more prominent on the torso (although not nearly to the degree that is seen with a superior vena cava syndrome), and jugular venous distention is often obvious.7 There is a fixed split of the second heart sound, with a loud pulmonic component. A ventricular heave is often present, and a right ventricular third heart sound develops late, as right-sided heart failure worsens. A tricuspid regurgitant murmur is almost always present, but murmurs of pulmonary insufficiency are rare. Although many of these findings are also present in patients with primary pulmonary hypertension (PPH), one can also begin to distinguish CTEPH from smaller resistance vessel disease on physical examination. Continuous machine-like murmurs are heard over the lung fields in CTEPH patients, related to turbulent flow through recanalized, partially obstructed vessels.8 These murmurs are more readily detectable while the patient is holding his or her breath. In patients with PPH, such murmurs are not detectable.

DIAGNOSTIC EVALUATION The diagnostic evaluation has often begun long before the patient presents to a surgeon. Without attention, the evalua-

tion can quickly become redundant or misdirected. It is essential to organize existing information and order further studies with three specific goals in mind: 1. To determine whether the patient has pulmonary hypertension 2. To determine the cause of that pulmonary hypertension 3. To determine whether the patient’s disease is surgically accessible. Blood tests generally provide nonspecific information. Some degree of secondary polycythemia is common as a result of chronic hypoxemia. Nonspecific liver function test abnormalities presumably are caused by hepatic congestion, and increased blood urea nitrogen (BUN) and urate levels are commonly associated with a chronic low cardiac output state. The partial thromboplastin time (PTT) may also be slightly prolonged, although the reasons for this are unclear. Right ventricular hypertrophy and right ventricular strain are evident on the electrocardiogram. Right atrial enlargement may produce P wave enlargement. Conduction abnormalities are uncommon, and often the cardiogram is relatively normal. On chest radiography, enlargement and some degree of asymmetry of the central PAs are usually evident. Peripherally, areas of hypoperfusion and hyperperfusion are demonstrated by varying densities of vascular markings. Marked right-sided heart enlargement is evident in the cardiac silhouette, and the retrosternal space may be obliterated on the lateral view (Fig. 53-1). More important than documenting any specific numbers or threshold values, one must be able to recognize the pattern of abnormalities seen on pulmonary function testing. Typically, abnormalities in gas exchange are far greater than any spirometric defects.9 There is often a significant reduction in the diffusion capacity, with typically lesser restrictive or obstructive defects. Chronic small pulmonary infarctions may result in some mild, patchy peripheral pulmonary fibrosis that could produce a restrictive defect. The compensatory and often

FIGURE 53-1 Posterior-anterior (A) and lateral (B) chest radiographs demonstrating enlargement and asymmetry of the central pulmonary arteries. Areas of hypoperfusion and hyperperfusion are evident. The lateral view demonstrates enlargement of the right ventricle with crowding of the retrosternal space.

A

Ch053-F06861.indd 654

B

1/21/2008 11:48:26 AM

Chapter 53 Surgical Management of Chronic Thromboembolic Pulmonary Hypertension

excessive development of bronchial collateral flow frequently causes intermittent bronchial submucosal swelling. This is a dynamic phenomenon that, although mild, sometimes causes a mild obstructive pattern on spirometry. In fact, it is quite common for patients to report that they have been treated chronically for asthma. Not surprisingly, with significant perfusion defects there is an increase in dead space, and the minute ventilation may be quite increased. The presence of severe obstructive or restrictive disease may represent an alternative explanation for the patient’s dyspnea. In such cases, symptoms are unlikely to resolve with operation, and surgery may in fact be contraindicated. There are no threshold values on pulmonary function testing that represent an absolute contraindication to surgery. Physician judgment gained with experience is ultimately required. However, do not consider pulmonary thromboendarterectomy in patients with severe obstructive or restrictive lung disease because the outcomes are poor. Likewise, although the abnormalities in diffusion capacity are proportionately worse in most patients, severe diffusion abnormalities are a contraindication to operation. The San Diego group has recently indicated that this condition has a particularly negative influence on outcomes. Patients are usually hypoxemic on arterial blood gas analysis. Although this may not be true at rest, desaturation with exercise is exceedingly common and can be severe. This is due in part to the inability to adequately increase cardiac output because of elevated and fixed pulmonary vascular resistance. As mixed venous saturation falls in the face of inadequate pulmonary blood flow, progressive hypoxemia develops. With exercise, systemic vascular resistance drops, and there is a rapid rise in PA and right heart pressures. Resultant right-to-left shunting through a patent foramen ovale (in 25% of the population) can precipitate marked decreases in arterial oxygen saturation. To screen for the presence of pulmonary hypertension, echocardiography is a noninvasive and appropriately sensitive screening test. Right atrial and ventricular enlargement (Fig. 53-2) and leftward displacement of the interventricular septum are classic findings of right-sided pressure overload. The hypertensive right ventricle does not conform to the normally rounded left ventricle. Rather, as the ventricular septum is shifted from right to left, the left ventricle may assume a classic D shape (Fig. 53-3). As stated, a patent foramen ovale is detectable in 25% of these patients. An agitated saline contrast study enhances the sensitivity for detecting any meaningful shunt that requires closure at the time of operation.10 Tricuspid regurgitation is usually moderate to severe,11 whereas pulmonic valve insufficiency is exceedingly uncommon. Having demonstrated pulmonary hypertension with echocardiography, it is appropriate to pursue additional, more invasive testing to determine its cause and suitability for surgical intervention. . . Previously the ventilation-perfusion (V/Q) scan was thought to demonstrate a dramatic moth-eaten appearance identifying clinically significant thromboembolic disease. More recently, the threshold findings for identifying CTEPH have become less restrictive.12 Typically, segmental or larger mismatched defects are detected, but the number of mismatched segments necessary to make the diagnosis may be limited.

Ch053-F06861.indd 655

655

Right atrium

Right ventricle

FIGURE 53-2 The four-chamber view on echocardiography depicts marked right atrial and ventricular enlargement. The interatrial septum is also deflected from right to left.

Leftward shift of interventricular septum

FIGURE 53-3 The cross-sectional view on echocardiography demonstrates how the hypertensive right ventricle assumes a spherical shape and causes a leftward deflection of the interventricular septum. As a result, the normally spherical left ventricle now assumes a classic D shape.

With PPH, the defects may be patchy or subsegmental, or the scan may be entirely normal. Despite its ability to help classify the . . disease (and therefore justify more invasive testing), V/Q scanning tends to underestimate the degree of central obstruction. Recanalized vessels have a higher resistance to flow but may still allow isotopes to reach the periphery. As a result, scans may look deceptively normal, and many patients with relatively minor abnormalities . . may have disease appropriate for surgical correction. V/Q scanning also does not demonstrate the precise location or proximal . . extent of the lesions. It therefore is inappropriate to use V/Q scanning alone to select patients for operation. It is best to wait at least several months after the initial inciting pulmonary embolus before proceeding with invasive

1/21/2008 11:48:26 AM

656

Section 3 Lung

presurgical testing. This wait allows for maximum resolution of immature thrombus to ensure that what remains becomes organized and fibrotic. This development is absolutely critical because otherwise the thrombotic remains may be too friable to be completely removed. The risk associated with temporary cessation of anticoagulation in order to perform rightsided heart catheterization and pulmonary angiography is greatest during the first several months after an embolic event. It is most appropriate, therefore, to defer invasive procedures until patients are out of that high-risk interval. Occasionally, patients complain of severe dyspnea on exertion and have anatomic findings suggestive of CTEPH but have relatively normal PA pressures at rest. In those cases, definitive assessment of pulmonary pressures and pulmonary vascular resistance may require provocative exercise testing. In the setting of CTEPH, such patients typically demonstrate a steep rise in PA pressures with minimal exertion. Correlation of the symptoms with a significant dynamic increase in PA pressures is critically important in selecting these patients for surgery. We prefer to obtain venous access at the neck, so as to avoid disturbing any iliofemoral thrombus that may still be present. These patients often have significant right-sided heart dysfunction, and their intravascular volume is typically quite expanded. For these reasons, they may be vulnerable to decompensation with excessive volume injections. It is therefore preferable to use single power injections per side, with very limited volumes. Use selective injections only when absolutely necessary to provide details important to operative decision making. Early in an institution’s experience, in order to optimize the efficiency of the studies and limit the number of injections, it is preferable for the surgeon to be present in the angiography suite to assist in selection of quality views. Angiographic findings indicative of CTEPH include pouch defects, webs or bands, intimal irregularities, and abrupt tapering of pulmonary branch vessels with loss of peripheral arborization or delayed filling of segmental and subsegmental vessels (Fig. 53-4).13 All patients must have a preoperative inferior vena cava filter placed if anatomically possible (i.e., if the inferior vena cava is not completely obstructed). In general, we have filters placed at the time of pulmonary angiography. The filter is extremely important in the prevention of recurrent thromboembolism. Defining the proximal extent of disease is essential in determining surgical accessibility. If questions remain regarding the proximal extent after angiography, adjunctive studies may be required. Intravascular ultrasound has been used with limited experience but does appear to have reasonably good correlation with surgical findings. It is limited by the fact that it provides information only about the wall with which it is in contact. With dilated central arteries, the view generated is very limited and far from circumferential. Pulmonary angioscopy14 has been used, but the techniques have been difficult to reproduce, and the images generated can be difficult to interpret. We currently employ spiral computed tomographic scanning15 with a PA-specific protocol and threedimensional reconstructions in the coronal plane in order to examine for thickening of the arterial walls and residual thrombus in the main and proximal lobar PAs (Fig. 53-5).

Ch053-F06861.indd 656

FIGURE 53-4 The pulmonary arteriogram classically demonstrates rapid tapering of vessels, webs, and bands in the recanalized lumen and diminished arborization or a pruned appearance to the peripheral vessels.

Any patient who presents with angina, as well as men older than 40 years of age and women older than 50 years, typically undergo left-sided heart catheterization to rule out coexisting coronary artery disease. If significant coronary disease is identified, revascularization is planned concurrently with pulmonary endarterectomy.

SURGICAL SELECTION Candidates for operation must have pulmonary vascular obstructive disease with significant hemodynamic and cardiopulmonary impairment. A pulmonary vascular resistance of at least 300 dynes/sec/cm5 at rest or with exercise also needs to be present. The thrombi must be surgically accessible; with increasing experience, individual surgeons can become more adept at accessing more distal disease.16,17 The recent development of a classification scheme of the anatomic distribution has been helpful in identifying appropriate patients. Type 1 disease is associated with obvious central thrombus. Type 2 disease demonstrates no major vessel thrombus but, rather, intimal thickening and webs that begin at the main lobar and segmental level. Type 3 describes disease that is restricted to the segmental and subsegmental levels. Finally, type 4 disease affects only very small, peripheral resistance vessels (i.e., PPH) and is not amenable to surgical correction. Type 1 and type 2 are appropriate for endarterectomy, but only a surgeon experienced with these techniques should approach type 3 disease. Ideally, the proximal dissection plane starts in the main PA; however, the plane is also readily developed at the lobar level. If disease starts distal to the lobar origins, the plane must be

1/21/2008 11:48:27 AM

Chapter 53 Surgical Management of Chronic Thromboembolic Pulmonary Hypertension

A

657

B

FIGURE 53-5 A, The centralmost portion of the appropriate surgical plane can at times be difficult to define. B, CT scanning can be useful, particularly with reconstructed views that can be mapped to the angiographic images.

developed at several individual points with a freehand knife. This is particularly hazardous because perforation at this level is exceedingly difficult to repair and may be associated with fatal hemorrhage. Pulmonary resections for such injuries are not tolerated well in this population. Candidates for operation should have limited comorbidities. As mentioned, significant restrictive or obstructive lung disease is a risk factor for prolonged postoperative mechanical ventilation, limited improvement in dyspnea, and mortality. Peripheral vascular disease is a strong relative contraindication, and chronic renal insufficiency makes postoperative fluid management troublesome. Right ventricular function typically recovers well after successful operation, but significant left ventricular dysfunction without a correctable cause is also a relative contraindication. Finally, when considering patients older than 80 years of age, it is appropriate to be very selective. Although the extent of operation can be intimidating for some patients, in general they are very enthusiastic about surgical intervention after the natural history of their disease has been explained. Once mean PA pressures exceed 30 mm Hg, the 5-year survival rate is only 30%. With pressures exceeding 50 mm Hg, the 5-year survival is only 10%.16 Most of our patients have presented with mean PA pressures of almost 50 mm Hg, implying a 90% risk of death over the next 5 years.18 With our current perioperative survival rate of 95%, the risks and extensive nature of this surgical operation are justified and seen as quite acceptable by our patients.

SURGICAL TECHNIQUE With progressive CTEPH, the PA system becomes obstructed, but nutrient bronchial flow maintains tissue viability. Therefore, even long-standing disease can be corrected, and chronically underperfused lung can once again participate in normal gas exchange. However, the abundant bronchial collateral flow that has increased over time can also significantly obscure operative visualization (even on full cardiopulmonary bypass). Certain technical maneuvers are required to compensate for this.

Ch053-F06861.indd 657

The simple removal of residual central thrombus will not result in an effective reduction in pulmonary vascular resistance. Rather, the operation requires an actual endarterectomy with a dissection plane that is in the middle of the media.19-21 A dissection plane that is too superficial will not achieve the appropriate hemodynamic result, and one that is too deep runs the risk of vascular perforation. A plane that is too deep is recognized when the underlying vessel wall appears pink, raw, or slightly rough. This is the adventitia; redirect the dissection to a more superficial plane. The correct plane is carried peripherally quite readily, and the underlying vessel wall should appear smooth and glistening. In almost all cases, elevate any calcifications with the specimen. Occasionally, slight intramural calcifications may be present. Overzealous attempts to remove them expose the adventitia and risk perforation. The operation must be considered a bilateral procedure. Explore both sides at least, even if angiography suggests a predominance of disease on one side. Relief of obstruction on both sides allows for optimal redistribution of pulmonary blood flow, improved oxygenation, and optimal functional recovery. The operation is therefore conducted through a median sternotomy. The operation is performed using cardiopulmonary bypass, and excessive bronchial collateral flow is controlled with brief periods of deep hypothermic circulatory arrest. To expose the right PA, extensive mobilization of the superior vena cava (SVC) is required. Use of the cautery limits bleeding at the end of the operation, but great care must be taken to avoid injury to the phrenic nerve. Cannulation for cardiopulmonary bypass is at the ascending aorta, and venous drainage via the right atrium or bicaval access, depending on whether a patent foramen ovale has been detected on an agitated saline contrast echocardiogram. The left ventricle is vented via the right superior pulmonary vein. Phenytoin is used to prevent postoperative seizures, and barbiturates are used to ensure electroencephalographic silence after the patient is cooled to 18ºC. After the patient is cooled to 22ºC, an aortic cross-clamp is applied and cardioplegia is administered. The SVC is retracted anteriorly and laterally, and the aorta is retracted

1/21/2008 11:48:28 AM

658

Section 3 Lung

medially to expose the main right PA. An incision is made in the right PA from underneath the aorta out toward the lower lobar division. This dissection is contained within the pericardium. Central thrombus can be removed, and often the endarterectomy of the superior trunk to the right upper lobe can be performed before circulatory arrest. After the endarterectomy plane is raised in the main PA, it is carried out to the segmental and then on to the subsegmental vessels. After the patient’s temperature has reached 18ºC and all that is safe to perform without compromising distal dissection has been done, intermittent circulatory arrest is used for no more than 20 minutes at a time. Between arrest periods, cardiopulmonary bypass is recommenced for 10 minutes or until the mixed venous saturation returns to 90%. After completion of the right side, the vessel is closed with running 5-0 polypropylene suture and the retraction on the aorta and SVC is released. Additional cardioplegia may be administered at this time. The heart is retracted anteriorly and to the right to expose the left PA. Because the heart is elevated out of the pericardium at this point and because slush in the pericardial well melts and runs down into the left PA, we prefer to use a cold saline circulating jacket to enhance myocardial protection with topical cooling. The left PA is opened from the main PA, and the dissection is extended to the pericardial reflection. An endarterectomy is then performed on that side, and the left PA is closed. The specimen typically demonstrates some degree of acute or subacute thrombus, with the more mature fibrotic disease originating at the segmental level and beyond (Fig. 53-6). If a patent foramen ovale is present or if significant suspicion exists, the atrial septum is then inspected after rewarming has begun. Likewise, any revascularization or adjunctive procedures may be undertaken at this point if not already completed during the cooling phase. Specific tricuspid valve repair usually is not required. There is marked resolution of the tricuspid regurgitation, which occurs to a great degree in the operating room and continues postoperatively. This relates to the right ventricular remodeling that occurs acutely after surgery. Valvular regurgitation is typically absent by 4 to 5 days after surgery. It is critical to use gradual cooling and warming so as to accomplish more uniform tissue temperatures and optimize

Acute

Chronic/segmental

FIGURE 53-6 This operative specimen from a patient with type 1 disease depicts subacute thrombus centrally and fibrotic/obstructive disease that extends peripherally out beyond the segmental bifurcations.

Ch053-F06861.indd 658

metabolic protection. Maintaining an 8ºC to 10ºC gradient while rewarming may help limit reperfusion injury that would otherwise be exacerbated by a hyperthermic perfusate.

POSTOPERATIVE MANAGEMENT Make every attempt to minimize pulmonary vascular resistance. A target partial pressure of carbon dioxide (PCO2) on blood gas analysis of 30 to 35 mm Hg is desirable. The fraction of inspired oxygen (FIO2) is minimized so long as oxygen saturations of 92% are maintained. Inhaled nitric oxide may be helpful, not only for potentiating the reductions in pulmonary vascular resistance that will develop over time but also to help support patients who .develop reperfusion injury. . It appears to do so by optimizing V/Q matching and may have inherent anti-inflammatory properties related to effects on platelet and leukocyte adherence to vessel walls. Inverse ratio and pressure control ventilation have at times been helpful. Minimizing plateau inspiratory pressures enhances alveolar recruitment and must be strongly considered. Subcutaneous heparin and the use of sequential compression devices are begun immediately postoperatively, and Coumadin or fractionated heparin therapy is initiated 48 hours after surgery and maintained for life. Preoperatively, the patients tend to have increased intravascular and interstitial volumes. With the abrupt reduction in pulmonary vascular resistance produced by surgery, they typically require assisted diuresis 24 hours after surgery. Immediately after surgery, the recovering right heart may still require somewhat elevated filling pressures. However, with the rapid ventricular remodeling that occurs, diuresis usually can be sustained after the first 24 hours.

POSTOPERATIVE COMPLICATIONS Our 30-day mortality rate at present is 5%. Considerably higher mortality rates have been reported in the literature, and anecdotal institutional reports have revealed prohibitive perioperative mortality. Certainly, as institutional experience, and in particular a single surgeon’s experience, is gained, mortality rates decline. In a recent report from the University of California, San Diego, the most common cause of 30-day mortality was unrelieved pulmonary hypertension. Less commonly, mediastinal hemorrhage, intraoperative cardiac arrest, and severe reperfusion pulmonary edema were cited. Cerebral vascular accidents accounted for several deaths, and cannulation site dissections resulted in two deaths.22 Complications associated with cardiac surgery in general include arrhythmias, atelectasis, wound infections, and phrenic nerve injury (particularly on the right, related to the required SVC mobilization). Transient delirium or mental status changes are present in 10% of patients, but these resolve in virtually all cases. Pericardial infusions may develop late in the postoperative course. To prevent tamponade, a closed suction drain can be left in place, or the posterior pericardium can be fenestrated anterior and to the left of the esophagus. Reperfusion pulmonary edema develops in 10% to 25% of patients.23 It is often mild but may be hemorrhagic and fatal.

1/21/2008 11:48:28 AM

Chapter 53 Surgical Management of Chronic Thromboembolic Pulmonary Hypertension

TABLE 53-1 Results of Pulmonary Thromboendarterectomy for Chronic Thromboembolic Pulmonary Hypertension Parameter

Preoperative

659

PREOPERATIVE

Postoperative NYHA 1

Mean pulmonary arterial pressure (mm Hg) Cardiac output (L/min) Pulmonary vascular resistance (dynes/sec/cm5)

51

22

NYHA 3 2.8 720

5.4

NYHA 4

134

No preoperative factors reliably predict its development, and it typically manifests within 8 to 12 hours after operation. It develops only in previously obstructed segments and therefore may have a patchy appearance on radiography, compared with more diffuse patterns of reperfusion injury that may develop after lung transplantation. Therapy is generally supportive, although a brief pulse of systemic steroids may be helpful. PA steal can also develop and is associated with significant hypoxemia.24 The diseased segments that underwent endarterectomy have a resistance that is low relative to nondiseased segments that were not instrumented. The lower-resistance segments supply those areas of lung that are vulnerable to reperfusion injury. Ultimately, the preponderance of pulmonary blood flow may be directed to the most edematous lung. The result can be fairly profound hypoxemia. Much of this hypoxemia resolves over the first several days postoperatively, but prolonged mechanical ventilation may be required. The distribution of pulmonary blood flow normalizes completely over 6 to 8 weeks, and patients should no longer require any supplemental oxygen at that time.

RESULTS Significant improvements in cardiopulmonary hemodynamics are evident immediately after operation. Typically, the pulmonary vascular resistance continues to fall over the first few days or weeks after surgery. This is particularly true in patients with long-standing disease. In our initial series, the mean PA pressures fell from 51 mm Hg preoperatively to 22 mm Hg postoperatively (Table 53-1). Pulmonary vascular resistance fell dramatically, and the cardiac output almost tripled. Tricuspid regurgitation resolved in almost all patients, and New York Heart Association classification improved substantially (Fig. 53-7).25 Lower extremity edema resolved or significantly improved in more than 90% of patients. Because some of those patients had chronic postphlebitic syndrome from previous deep venous thromboses, complete resolution was not expected. Ascites likewise resolved in virtually all patients. Although many patients required supplemental oxygen at the time of discharge (most likely secondary to residual reperfusion edema or PA steal), the requirement for supplemental oxygen at follow-up (6-8 weeks) was exceedingly uncommon.

SUMMARY Timing of operation and patient selection present difficult issues in CTEPH. However, acceptable morbidity and mor-

Ch053-F06861.indd 659

NYHA 2

POSTOPERATIVE

NYHA 1 NYHA 2 NYHA 3 NYHA 4 FIGURE 53-7 Although almost all patients were classified as New York Heart Association (NYHA) class III or IV preoperatively, the overwhelming majority were class I or II at midterm follow-up.

tality have been achieved in a limited number of centers, largely due to the experience and skill of multidisciplinary teams that work together during patient evaluation, surgery, and postoperative care. Five-year survival in patients without operation is severely limited. With acceptable 30-day mortality rates, pulmonary endarterectomy can convey a marked survival benefit for appropriately selected patients.

COMMENTS AND CONTROVERSIES During the past decade, a number of centers have developed impressive experience in the application of pulmonary thromboendarterectomy. Dr. Mulligan directs one of the most successful programs. The challenges in diagnosis and patient selection are clearly outlined. Specific selection criteria must be met if satisfactory results are to be achieved. The technical demands of the operation are obvious. Dr. Mulligan points out a number of important technical points, such as the plane of dissection, the extent of dissection, and the timing of circulatory arrest. The postoperative management is critical and is reminiscent of the postoperative care of patients undergoing lung transplantation for pulmonary hypertension. Pulmonary vascular resistance must be minimized, and lung reperfusion injury must be managed aggressively. In an experienced center, excellent outcomes can be expected in carefully selected patients. G. A. P.

1/21/2008 11:48:28 AM

chapter

LUNG TRANSPLANTATION

54

Daniel Kreisel Alexander S. Krupnick G. Alexander Patterson

Key Points ■ Lung transplantation has become an established therapy for a

variety of end-stage lung disorders. ■ Improved donor and recipient selection, technical advances, supe-

rior immunosuppression strategies, and newer antibiotic regimens have improved early and midterm results dramatically. ■ The most formidable obstacle to long-term success of lung transplantation remains chronic rejection, which manifests as the bronchiolitis obliterans syndrome.

HISTORICAL NOTE Experimental lung transplantation began in the 1940s. Metras in France and Hardin and Kittle1 in the United States demonstrated the technical feasibility of canine lung transplantation. Of note, early experiments demonstrated the feasibility of lung implantation in autotransplanted lungs. The initial perception that pulmonary vascular resistance increased in the lung allograft was dispelled by reports that meticulous vascular anastomotic technique resulted in normal pulmonary artery pressures. Based on a background of extensive experience with lung and heart-lung transplants in experimental animals and eventually obtaining good early results, James Hardy and Watts Webb performed the first human lung transplantation at the University of Mississippi on June 15, 1963.2 The recipient was a 58-year-old man with a history of heavy smoking and emphysema, who was diagnosed with an endobronchial squamous cell carcinoma with near-complete occlusion of the left main stem bronchus and postobstructive pneumonia. The donor left lung was retrieved from a patient who had died of a massive intracranial hemorrhage. Of note, at the time of the lung transplantation it became evident that the recipient’s tumor had invaded the parietal pleura. The immunosuppressive regimen consisted of corticosteroids, azathioprine, and irradiation of the thymus gland. Although the patient died after 19 days from renal failure, this short-lived success demonstrated the technical feasibility of the operation and stimulated worldwide interest in lung transplantation. Histologic examination of the lung allograft revealed only minimal evidence of rejection. During the subsequent 15 years, approximately 40 clinical lung transplantations were performed in centers around the world. None of these procedures was successful. Only one recipient was actually discharged from the hospital, a 23-

year-old patient.3 This patient left the hospital 8 months after transplantation but died a short time later as a result of chronic rejection, sepsis, and bronchial stenosis. Most patients died within the first 2 weeks after transplantation, as a result of primary graft failure, sepsis, or rejection. The most frequent cause of death beyond the second postoperative week was bronchial anastomotic disruption. The initial lung transplantation in the Toronto experience was performed for a young ventilator-dependent patient with inhalation burns.4 The patient died during the third postoperative week after a bronchial anastomotic dehiscence. This problem of bronchial anastomotic dehiscence stimulated the interest of a number of surgical laboratories. Lima’s group,5 working with Cooper and colleagues in Toronto, demonstrated that high-dose corticosteroid therapy (2 mg/kg/day, which at that time was believed to be necessary for adequate immunosuppression) had an adverse effect on bronchial anastomotic healing. The same group also demonstrated that the ischemic donor bronchus could be revascularized within a few days by a pedicled flap of abdominal omentum.6 Not only could the omental pedicle provide new collateral circulation to the ischemic bronchus, but the omentum provided additional benefit by containing anastomotic dehiscence in the event of partial disruption. During this same interval, it became apparent that cyclosporine had impressive immunosuppressive properties and could eliminate the need for high-dose corticosteroid immunosuppression. Furthermore, the Toronto group also demonstrated that cyclosporine had no adverse effect on bronchial anastomotic healing.7 In 1981, the Stanford group reported initial clinical experience with combined heart-lung transplantation in patients with pulmonary vascular disease.8 A combined heart-lung transplant had been previously attempted without success by Cooley and then by Lillehei and Barnard. The Stanford experience demonstrated conclusively that, with the new immunosuppressive drug cyclosporine, the transplanted lung would provide acceptable long-term function for patients with pulmonary hypertension and right ventricular failure. However, by 1983, successful isolated lung transplantation had not been performed. Satisfactory patient selection remained the final obstacle to successful clinical lung transplantation. The Toronto group reasoned that end-stage respiratory failure from pulmonary fibrosis would provide ideal conditions for single-lung transplantation. The increased resistance to perfusion and ventilation in the native lung would preferentially direct both perfusion and ventilation to the transplanted lung. A clinical lung transplantation program at the University of Toronto was

660

Ch054-F06861.indd 660

1/21/2008 11:49:22 AM

Chapter 54 Lung Transplantation

initiated in 1983 with a policy of careful recipient selection and strict adherence to rigid donor criteria. Bronchial omentopexy was used in every procedure, and early perioperative corticosteroids were avoided. With these strategies, Joel Cooper and colleagues at Toronto performed the first successful lung transplantation on November 7, 1983, in a 58year-old man with idiopathic pulmonary fibrosis.8a Subsequent development of an experimental9 and clinical10 en bloc double-lung replacement technique enabled the application of bilateral lung replacement to patients for whom single-lung transplantation was not appropriate. Although this procedure did have the definite attraction of preserving the recipient’s heart, it was a technically complex procedure. In addition, it was associated with a high incidence of complications, notably donor airway ischemia11 and cardiac denervation.12 Innovations were achieved in the ensuing years that expanded the application of pulmonary transplantation. In the initial experience, patients with obstructive pulmonary disease had been considered suitable only for bilateral lung replacement. It was later shown that single-lung transplantation offers an attractive option for such patients.13 Combined heart-lung transplantation was formerly thought to be the only option for patients with pulmonary vascular disease; however, many have shown that single14 or bilateral lung transplantation15 provides satisfactory functional results in this patient group. Technical advances have steadily accrued, most notably the development of a simplified method for bilateral sequential lung replacement (Pasque et al, 1990).16 Anterior thoracotomies and transverse sternal division (the clamshell incision) provide superior exposure for safe division of pleural adhesions. Sequential excision and replacement of both lungs often avoids the need for cardiopulmonary bypass (CPB). A logical extension of the clamshell is bilateral anterior thoracotomies with omission of the transverse division of the sternal bone. This approach offers excellent access without the morbidity of sternal complications commonly seen with the clamshell technique.17 For single-lung transplantations, some groups have adopted muscle-sparing thoracotomies to minimize morbidity and improve healing and postoperative function.18 The shortened length of donor bronchus in single-lung allografts reduces the incidence of bronchial anastomotic complications. Direct bronchial artery revascularization for double-19,20 and single-lung transplants21 has been described and is used in a number of programs. Improved strategies of pulmonary preservation have enabled reliable long-distance procurement and satisfactory early allograft function in the majority of cases. Retrograde delivery of the perfusate improves the uniformity of the lung perfusion and has been credited with improved results by several investigators.22,23 Advances have also been made in the prevention and treatment of postoperative sepsis. Bacterial infection, which is particularly troublesome in patients with cystic fibrosis, has been lessened by the routine use of broad-spectrum prophylactic antibiotics and inhaled aminoglycosides. Herpes simplex infections have been lessened by routine prophylactic use of

Ch054-F06861.indd 661

661

acyclovir. Cytomegalovirus (CMV) infection, a potentially fatal complication in recipients of lung transplants, has been markedly reduced by appropriate matching of donor and recipient CMV serologic findings whenever possible and prophylactic use of ganciclovir. Nevertheless, chronic allograft dysfunction, manifested as bronchiolitis obliterans syndrome, remains the main limitation to long-term success of lung transplantation. Most investigators in the field of lung transplantation are in agreement that a better understanding of the mechanisms, both immunologic and nonimmunologic, that contribute to the development of obliterative bronchiolitis is the biggest challenge in this field during the upcoming years. It is apparent that better experimental models need to be developed in small and large animals to accomplish this goal. Similar to the transplantation of other solid organs, the ultimate goal in lung transplantation is the development of strategies to induce immunologic tolerance.

PATIENT SELECTION AND ORGAN ALLOCATION Recipient General Considerations As lung transplantation has become an acceptable method of treating end-stage lung disease, the disparity between clinical demand for transplantation and organ supply has widened. Based on the large number of potential lung recipients who have died while on the United Network for Organ Sharing (UNOS) lung transplant waiting list24 and a 1998 report25 that failed to document a survival advantage for a large number of lung transplant recipients despite improved quality of life, the established lung allograft allocation system within the United States was recently revised. Traditionally, lung allocation in the United States was based on waitlist time. Patients who had accrued the most time on the waitlist were transplanted first, regardless of medical urgency or any sudden deterioration in clinical condition. Such a system often led to so-called early listing of potential transplant recipients, so that individuals with near end-stage pulmonary failure could accrue waiting time and advance on the list before transplantation became a clinical necessity. Such gaming of the system resulted in many wasted hours spent by donor management coordinators in trying to place organs for recipients whose listing centers had no intention of immediate transplantation, as well as potential transplantation of recipients before the advent of true clinical necessity. Aside from potential system manipulation, an allocation system based mostly on waiting time favors patients who are well enough to survive while on the list. Such a system may lead to selection of patients who might have survived even without transplantation and death while waiting for those who might have benefited the most. An alternative system that bases organ allocation solely on clinical necessity or eminent risk of death without transplantation might result in the transplantation of a large number of critically ill patients who are unable to recover from the operation. In order to balance these two factors, a subcommittee of the UNOS Thoracic Organ Committee modified the listing

1/21/2008 11:49:23 AM

662

Section 3 Lung

algorithm by assigning each individual a lung allocation score (LAS), based on both the immediate need for transplantation and the probability of post-transplantation survival. In 2005, the UNOS wait list for adult lung transplantation was rearranged based on the LAS score for each individual patient. Details of the new allocation system can be found on the official Organ Procurement and Transplantation Network Web site, http://www.optn.org/PoliciesandBylaws/policies/ pdfs/policy_9.pdf (accessed December 11, 2006). However, the LAS score is calculated by an estimate of waitlist urgency, which is defined as the expected number of days that could be lived without a transplant (Table 54-1), and posttransplantation survival, which is defined as the expected number of days lived during the first year after transplantation (Table 54-2). After these measures are developed using the Cox proportional hazards models, the transplant benefit measure is calculated by subtracting the waitlist urgency from the post-transplantation survival to obtain the raw allocation score (calculated in days). This score is normalized to the LAS on a scale of 1 to 100. Those with the highest scores are patients with the highest risk of death while on the waitlist and the longest expected post-transplantation survival benefit, and they are listed first for transplantation. Factors used to predict risk of death and post-transplantation survival TABLE 54-1 Factors Used to Predict Risk of Death While on the Lung Transplant Waitlist 1. Forced vital capacity 2. Pulmonary artery systolic pressure 3. Oxygen required at rest 4. Age

are to be reviewed approximately every 6 months by the Thoracic Organ Transplantation Committee and updated as appropriate. Previous thoracic surgery or pleurodesis is not a specific contraindication to lung transplantation. With the development of lung volume reduction surgery,26 increasing numbers of patients are referred for transplantation after unilateral or bilateral reduction pneumoplasty. Adhesions and anatomic distortion from previous surgery complicate the conduct of a transplantation procedure, and allowance for this must be made during operative planning. Patients receiving high-dose corticosteroid therapy (e.g., prednisone 20 mg/day) are not eligible for lung transplantation. Such high doses of corticosteroids cause a well-documented negative effect on bronchial healing and an increased susceptibility to postoperative infection. Patients receiving low- or moderate-dose steroid therapy (e.g., prednisone 10 mg/day or less) are candidates, and such patients have undergone pulmonary transplantation without an increased incidence of bronchial anastomotic complications. Ventilator dependency is not a contraindication to transplantation and has now been incorporated into the LAS score as a risk factor for death while on the transplant waitlist. We insist that all patients listed for transplantation, except those with primary pulmonary hypertension (PPH) or Eisenmenger’s syndrome, participate in a progressive monitored exercise rehabilitation program while they await transplantation. Virtually all patients experience a marked improvement in strength and exercise tolerance without any measurable change in pulmonary function. We are convinced that this improved endurance enables patients to better withstand the rigors of a transplantation procedure and the subsequent rehabilitation.

5. Body mass index 6. Diabetes

Disease-Specific Considerations

7. Functional status

Group A patients are those with obstructive pulmonary disease, including chronic obstructive pulmonary disease (COPD), α1-antitrypsin deficiency, emphysema, lymphangioleiomyomatosis, bronchiectasis, and sarcoidosis with mean pulmonary artery pressures of less than 30 mm Hg. Obstructive pulmonary disease, notably emphysema and α1antitrypsin deficiency, is the most common indication for lung transplantation. The largest number of procedures reported to the International Society for Heart and Lung Transplantation (ISHLT) Registry were performed for obstructive lung disease (Trulock et al, 2005).27 Most patients have deteriorated to a point at which oxygen supplementation is required. In our experience, the mean supplemental oxygen requirement is slightly more than 4 L/min. The obstructive physiology in these patients produces a forced expiratory volume at 1 second (FEV1) well below 1 L, or approximately 15% of predicted normal values. Fortunately, this patient group has a relatively stable course during the inevitably long wait for a suitable donor, and such stability might affect their ranking within the LAS score. Although obstructive pulmonary disease is the most common indication for single-lung transplantation, the ideal operative procedure for these patients is not yet defined.28,29

8. Six-minute walk distance 9. Continuous mechanical ventilation 10. Diagnosis From Organ Procurement and Transplantation Network, available at: http://www.optn.org/PoliciesandBylaws/policies/pdfs/policy_9.pdf (accessed December 11, 2006).

TABLE 54-2 Factors That Predict Survival After Lung Transplantation 1. Forced vital capacity 2. Pulmonary capillary wedge pressure ≥20 mm Hg 3. Continuous mechanical ventilation 4. Age 5. Serum creatinine 6. Functional status 7. Diagnosis From Organ Procurement and Transplantation Network, available at: http://www.optn.org/PoliciesandBylaws/policies/pdfs/policy_9.pdf (accessed December 11, 2006).

Ch054-F06861.indd 662

1/21/2008 11:49:23 AM

Chapter 54 Lung Transplantation

The functional outcomes after single and bilateral lung transplantation for these patients are discussed later. In general, for young patients, particularly those with α1-antitrypsin deficiency, we prefer to use bilateral sequential single-lung transplantation. The bilateral option is also more attractive in larger recipients, for whom an oversized single-donor lung would be difficult to obtain. On the other hand, for smaller recipients, single-lung transplantation offers a more attractive option, particularly if an oversized donor lung can be used. Finally, in the older patient, single-lung transplantation offers an attractive option because it is a technically simpler procedure and is associated with a lower operative mortality rate. Group B patients have pulmonary vascular disease, including PPH, Eisenmenger’s syndrome, and other uncommon pulmonary vascular diseases. Fremes and associates,30 at the University of Toronto, reported the first successful singlelung transplantation in a patient with a patent ductus arteriosus and associated Eisenmenger’s syndrome. Since that report, a number of centers have demonstrated that right ventricular function improves immediately after transplantation and that the improvement is maintained in long-term follow-up.31,32 There are reliable predictors of early death in patients with PPH.33 Mean pulmonary artery pressures greater than 60 mm Hg, syncopal episodes, clinical evidence of right ventricular failure, significant elevation of central venous pressure, and depression of the cardiac index are predictors of death in patients with PPH. Among our first 22 patients undergoing single-lung transplantation for pulmonary vascular disease, the mean New York Heart Association functional class preoperatively was 3.4. In the late 1980s and early 1990s, lung transplantation was the only effective therapy for patients with end-stage pulmonary hypertension. Despite the comparatively short waiting time for donor lungs seen in that era compared with the present, there was a very high rate of death among patients with PPH waiting for lungs.34 Subsequent work has shown that continuous intravenous (IV) infusion of epoprostenol, a vasodilating prostaglandin, produces a symptomatic and hemodynamic benefit as well as improved survival for patients with pulmonary hypertension.35 Since that discovery, the absolute number of patients transplanted annually for PPH has decreased dramatically as fewer patients are referred for transplantation. More recent work has delineated a stepwise regimen of medical therapy, including oral and inhaled prostanoids followed by IV therapy followed by lung transplantation, that can improve survival from the time of PPH diagnosis and decrease mortality while on the transplant waitlist.36 Despite having equivalent degrees of pulmonary hypertension, patients with Eisenmenger’s physiology have a less predictable rate of deterioration, and the appropriate timing for transplantation in these patients is less certain. In these patients, we rely on the development of intractable and progressive symptoms of right ventricular failure as the predominant selection criterion. Group C includes patients with cystic fibrosis and other immunodeficiency disorders such as hypogammaglobinemia. Cystic fibrosis is the most frequently encountered condition

Ch054-F06861.indd 663

663

in this category.31 Cystic fibrosis is a common inherited disorder that results in diffuse bronchiectatic destruction of both lungs. Without transplantation, most patients die from progressive respiratory failure in the second or third decade of life. The most reliable predictors of life expectancy in patients with cystic fibrosis have been published.37,38 An FEV1 of less than 30% of predicted, an elevated partial carbon dioxide pressure (PaCO2), a requirement for supplemental oxygen, frequent admissions to the hospital for the control of acute pulmonary infections, and failure to maintain acceptable body weight are reliable predictors of early death. After reaching this stage of disease, patients with cystic fibrosis typically have a rapidly progressive downhill course, and in previously published series, approximately one third of cystic fibrosis patients accepted for transplantation died while waiting for a donor.39 In order to offset such high mortality on the waitlist, some of the factors listed previously have been incorporated into calculating the LAS score for these patients (see Tables 54-1 and 54-2). Group D includes candidates with restrictive lung disease such as idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis of other causes, sarcoidosis with mean pulmonary artery pressure greater than 30 mm Hg, and obliterative bronchiolitis (not retransplantation cases). Although, in the past, patients in this category represented one of the less common indications for single-lung transplantation, the 2005 ISHLT Registry report indicated that IPF was the second most common indication for single-lung transplantation and the third most common for bilateral lung transplantation.27 In our experience, candidates for transplantation have had classic restrictive physiologic findings, with a mean forced vital capacity (FVC) of 1.35 L and an FEV1 of 1.14 L.40 All were using supplemental oxygen and demonstrated marked impairment of exercise tolerance, with oxygen desaturation after minimal exertion. Moderate pulmonary hypertension is common in these patients. In contrast to the stability of patients with obstructive physiology, patients with pulmonary fibrosis who require a transplant have a rapid downhill course, which should affect the ability of these patients to advance on the waiting list.

Donor Rapid progress in transplantation has resulted in a shortage of suitable allografts for all organs. This is a particularly significant problem for lung transplantation because at most only 20% of otherwise suitable organ donors have lungs that meet the standard donor lung criteria. Most of the conditions that result in brain death (e.g., trauma, spontaneous intracerebral hemorrhage) are associated with significant pulmonary parenchymal pathologic findings as a result of lung contusion, infection, aspiration, or neurogenic pulmonary edema. Satisfactory gas exchange is imperative for donor lungs. This can be confirmed by a PaO2 greater than 300 mm Hg with the ventilator delivering a fraction of inspired oxygen (FIO2) of 1.0 and 5 cm H2O positive end-expiratory pressure (PEEP). A PaO2-to-FIO2 ratio of 300 or greater provides adequate evidence of satisfactory gas exchange. A donor chest radiograph taken shortly before harvest must reveal clear lung

1/21/2008 11:49:23 AM

664

Section 3 Lung

fields. Bronchoscopic assessment at the donor institution often reveals mucopurulent secretions from which a variety of organisms might be cultured. This finding is commonly observed and is not a contraindication to lung transplantation if the donor organ is otherwise suitable. However, bronchoscopic evidence of aspiration or frank pus in the airway is a definite contraindication to transplantation. Donor and recipient ABO blood compatibility is essential. Donor and recipient histocompatibility antigen (HLA) matching is not currently performed. There is controversy regarding the importance of HLA matching, and no data in the literature support its impact on subsequent graft function. Furthermore, any delay in donor harvest to conduct HLA matching places the donor lungs at risk for deterioration. Unfortunately, we do not have at our disposal satisfactory preservation strategies to permit postharvest tissue matching. We prefer to use CMV-negative donors for CMV-negative recipients whenever possible. A significant consideration is size matching between the donor and the recipient. Acceptable size matching depends on the nature of the recipient’s pulmonary disease and the type of transplantation planned. Size matching can be achieved by a comparison of vertical lung height, transverse chest diameter, and chest circumference. However, we have found these donor measurements to be unreliable when made by busy and inexperienced donor coordinators in remote donor hospitals. Much more reliable are predicted donor and recipient pulmonary volumes, which are calculated using standard nomograms based on age, gender, and height. In patients undergoing single-lung transplantation for obstructive pulmonary disease, we attempt to place allografts that are 15% to 20% larger than the predicted recipient lung volume. Implantation of such a large allograft is easily achieved in a patient with obstructive pulmonary disease because of the enormous size of the recipient’s pleural space. However, in patients with pulmonary fibrosis or pulmonary vascular disease, the pleural spaces are reduced or normal in size. It is therefore inadvisable to oversize these patients. In patients undergoing bilateral lung replacement, we prefer to match the donor’s lung volumes to the estimated volume that the recipient would possess in the absence of disease. Table 54-3 summarizes standard lung donor selection criteria that our group uses at Washington University in St. Louis.

Marginal Donor Certain circumstances allow relaxation of the normally strict donor selection criteria. A minor degree of pulmonary infiltrate can be accepted in donor lungs being used for a bilateral transplantation. We analyzed 133 consecutive donor lungs and identified 37 with marginal quality, as judged by arterial blood gas analysis and radiographic assessment. The marginal donors provided postoperative function equivalent to those judged excellent.41 On occasion, a donor is identified with marginal gas exchange and radiographic evidence of a unilateral pulmonary infiltrate. In a number of such situations, we have made an intraoperative donor assessment with ventilation and perfusion only to the seemingly normal donor lung, judged that lung to be acceptable, and conducted a successful unilateral transplantation.42

Ch054-F06861.indd 664

TABLE 54-3 Standard Lung Donor Selection Criteria 1. Age <55 yr 2. No history of pulmonary disease 3. Normal serial chest radiographs 4. Adequate gas exchange (PaO2 300 mm Hg on FIO2 1.0 and PEEP 5 cm H2O) 5. Normal bronchoscopic examination 6. Negative serologic screening for hepatitis B virus and HIV 7. Recipient matching for ABO blood group 8. Size matching FIO2, fraction of inspired oxygen; HIV, human immunodeficiency virus; PaO2, arterial partial pressure of oxygen; PEEP, positive endexpiratory pressure.

Living Lung Donor Transplantation Living donor lung transplantation was pioneered by the group at the University of Southern California in an attempt to expand the donor pool and offer lung transplantation to a larger number of patients. Two donors, usually family members, undergo right lower and left lower lobectomy, respectively. Close attention needs to be paid to the preparation of adequate vascular and bronchial cuffs for the subsequent implantation. The pulmonary artery and vein of the allograft are cannulated and flushed with pulmonoplegic solution both antegrade and retrograde. As with living-related kidney or liver transplantation, the cold ischemic times are relatively short compared with those of cadaveric lung transplants. The recipient operation is usually performed through a transverse thoracosternotomy incision with the use of CPB. Prolonged postoperative ventilatory support may help decrease atelectasis. Recipients of living donor lobes may be at an increased risk for development of pulmonary edema postoperatively because the entire cardiac output flows to only two lobes. Therefore, close attention needs to be paid to volume status and pulmonary arterial pressures in the postoperative period. Furthermore, because these patients typically have higher outputs from their chest tubes due to space considerations, it has been the practice of the group at the University of Southern California to keep the chest tubes in place for a prolonged period. Between 1993 and 2003, 123 patients underwent living lobar lung transplantation at the University of Southern California, which represents the largest single-center experience.43 This procedure was predominantly employed for patients with cystic fibrosis, and approximately one third of the recipients were children. The 1-, 3-, and 5-year survival rates were 70%, 54%, and 45%, respectively, comparable to outcomes for bilateral cadaveric lung transplantation. Infection was the major cause for recipient mortality, and the freedom from bronchiolitis obliterans syndrome in their adult population was 76% at 5 years, which is lower than for recipients of bilateral cadaveric grafts.

Non–Heart-Beating Donors Unlike other organs, the ventilated lung may be an ideal organ for transplantation after cessation of circulation because of the ability of pulmonary parenchymal cells to continue

1/21/2008 11:49:23 AM

Chapter 54 Lung Transplantation

aerobic cellular metabolism by relying on the oxygen within the alveoli. Preliminary animal work supported this notion and showed that lungs harvested from non–heart-beating dogs as long as 4 hours after death continued to have acceptable function.44 Several clinical series have now been published supporting these animal data. A recent series from Spain documented excellent early allograft function with no ischemia-reperfusion injury even after 11 hours of total ischemia, and outpatient follow-up for as long as 13 months after transplantation documented adequate lung function and normal quality of life.45 Based on such encouraging results, we have started to accept organs from non-heart-beating donors in our program, with preliminary results similar to those of our conventional cadaveric donors.

LUNG PRESERVATION Lung preservation has been the focus of intense laboratory interest for a number of years. Detailed reviews of this subject have been published.46,47 Clinical pulmonary preservation has progressed considerably since the Toronto group initially reported unilateral lung transplantation using donor lungs harvested in an atelectatic state and stored after topical hypothermic immersion.48 There are minor differences in the preservation strategies of most clinical lung transplant programs, but basic principles remain the same. After systemic donor heparinization and just before circulatory arrest, a pulmonary vasodilator is administered. We use prostaglandin El (PGE1), 500 µg as a direct bolus injection into the pulmonary artery. Pulmonary arterial flushing is then achieved after placement of the cross-clamp and cardiac arrest with ongoing ventilation by the anesthesiologist. We prefer FIO2 greater than room air (usually 100%). Whereas in the past we relied on an intracellular flush solution, most commonly a modified Euro-Collins solution (4 mEq/mg SO4 and 3% glucose) or University of Wisconsin solution,49 our program has recently switched to a high-dextrose extracellular preservation solution, Perfadex. This switch was prompted by our clinical observation that the use of highpotassium solutions resulted in a high degree of ischemiareperfusion injury and primary graft dysfunction. This conjecture was supported by animal experimental data indicating that high-potassium preservation solutions can cause pulmonary vasoconstriction and may have a direct toxic effect on vascular endothelial cells.50 Further animal data confirmed the superiority of a low-potassium and high-osmolality solution in improving pneumocyte integrity, reducing cell swelling, and ameliorating ischemia reperfusion injury.51 Human clinical trials further confirmed this experimental animal data.52 At Washington University, we use high-dextrose, lowpotassium Perfadex for both antegrade and retrograde flush while the lungs are being ventilated. After extraction, the lung allograft is immersed in iced crystalloid solution and maintained in a semi-inflated state during transport. This technique results in reliable allograft function after ischemic times of up to 6 hours. On occasion, we have extended the ischemic time, particularly for the second lung of a bilateral sequential transplantation procedure, and the ischemic time has occasionally reached 8 to 10 hours with satisfactory subsequent function. Work by Snell

Ch054-F06861.indd 665

665

and colleagues53 showed an effect on outcome with longer ischemic times, particularly times exceeding 5 hours. Novick and coworkers54 reported a complex relationship between donor age and ischemic time affecting outcome, with older donor lungs being more sensitive to prolonged ischemic time than younger lungs.

Inflation The state of lung inflation during pulmonary artery flush and storage probably has a significant impact on post-transplantation pulmonary function. Puskas and coworkers55 demonstrated that canine lungs flushed and stored in a hyperinflated state produced more reliable post-transplantation lung function after a 30-hour storage period, compared with lungs stored at low pulmonary volumes. However, when we adopted a policy of donor hyperinflation in our clinical program, we noted a disturbing incidence of allograft dysfunction. Recent evidence from our laboratory using a rabbit model suggests that hyperinflation produces increased pulmonary capillary permeability. We confirmed this finding in a recent series of canine allotransplants. For this reason, we recommend that lungs be flushed and stored in a state of moderate inflation that is consistent with normal end-tidal inspiration.56 Avoiding such hyperinflation is even more pertinent during distant harvests because any change in airplane cabin pressure is transmitted to the pulmonary allograft as well.

Temperature of Flush and Storage Clinical lung transplant programs use pulmonary artery flush solutions with temperatures of 1ºC to 4ºC. Lungs are extracted, immersed in flush solution, and packed in ice, with the result being storage and transport at approximately 1ºC. A number of investigators have shown that moderate degrees of hypothermia (10ºC) result in superior pulmonary function. This has been demonstrated in our own laboratory in an in vitro rabbit lung perfusion model,57 a standard model of canine left lung allotransplantation,58 and bilateral baboon lung transplantation.59 However, in a previous canine allograft study, Mayer and colleagues60 were unable to show a difference between storage at 4ºC versus 10ºC in canine left lung allografts. Although there are some studies suggesting improved lung function in small animal models after storage at even higher temperatures, hypothermic flush and storage remains the standard of care at virtually all lung transplant centers.61

Pharmacologic Manipulation In addition to the apparent benefit gained when prostaglandins are administered before pulmonary artery flush,60 recent evidence suggests that infused prostanoids are useful in the early post-transplantation period. Matsuzaki and associates62 demonstrated that PGE1 infusion decreased reperfusion injury after 2 hours of warm ischemia in a rabbit lung model. We continued this work, demonstrating that PGE1 improved canine lung allograft function after an 18-hour ischemic period.63 We use a PGE1 infusion routinely during the postoperative period in our clinical program. Pentoxifylline and nitroglycerin also ameliorate lung allograft reperfusion injury in experimental animals.64

1/21/2008 11:49:23 AM

666

Section 3 Lung

There is a mounting body of evidence suggesting that oxygen free radicals are important in the genesis of ischemiareperfusion injury in the lung. A number of antioxidant interventions, including enzymatic (superoxide dismutase, catalase, or glutathione peroxidase) and nonenzymatic (allopurinol, glutathione, dimethylthiourea, and lazaroid) agents, have been shown to reduce lung reperfusion injury, and some have been used with success in clinical lung transplant programs. However, the use of antioxidants in preservation solution is not currently within our clinical practice. It is well established that levels of endogenous nitric oxide, a potent vasodilator, drop after ischemia and reperfusion of lung grafts. Several studies have been conducted to test the effect of inhaled nitric oxide on graft function. Although the issue is still controversial, the majority of studies seem to indicate that inhaled nitric oxide offers no benefit in reducing graft dysfunction related to ischemia and reperfusion.65-67 Further pharmacologic avenues that have shown some promising results in experimental studies and small clinical series include surfactant therapy, platelet-activating factor antagonists, and complement inhibitors.68-72

Metabolism The lung is unique among solid organs that are harvested and preserved for transplantation. Oxygen in the inflated alveoli and intracellular glucose augmented by glucose in the flushing solution allow the cooled lung to maintain aerobic metabolism and preserve cellular adenosine triphosphate (ATP) levels during extended periods of preservation.73 In fact, the lung probably maintains a state of aerobic metabolism within the cadaver for a short period after death. Egan and colleagues74 demonstrated satisfactory gas exchange in lung allografts harvested from canine donors some hours after death. Van Raemdonck and associates75 showed acceptable lung function in grafts procured up to 2 hours after death as long as the lungs were ventilated or kept in a state of static inflation. Such ongoing aerobic metabolism is the foundation for the use of lung allografts from non–heart-beating donors.

Controlled Reperfusion A recent innovation adapted from the experience gained by cardiac surgeons in the reperfusion of ischemic myocardium is the notion of controlled reperfusion. Many authors have explored the impact of altering pressure,76,77 leukocyte content,78 or both79 during the initial 10 minutes of reperfusion of pulmonary grafts after prolonged ischemia. The evidence indicates beneficial effects gained by initial reperfusion with low-pressure, leukocyte-depleted, substrate-enhanced blood to reduce or eliminate reperfusion injury. To this end, the group at the University of California Los Angeles was recently able to demonstrate amelioration of ischemiareperfusion injury of lung allografts using a modified reperfusion technique. Lungs were initially reperfused at relatively low pressures with a mixture of leukocyte-depleted recipient blood and a reperfusion solution containing various nutrients.80

Ch054-F06861.indd 666

TECHNIQUE Donor Extraction Our donor extraction technique remains virtually identical to that reported by Sundaresan and colleagues.59 On arrival at the donor hospital, the lung extraction team assesses the chest radiographs and performs fiberoptic bronchoscopy to assess for evidence of aspiration or purulent secretion. The final assessment is made by gross inspection and palpation of the lungs once they are exposed by a median sternotomy in conjunction with the midline laparotomy for the extraction of abdominal organs. We also assess the compliance of the lungs; disconnection of the donor from the ventilatory circuit should result in rapid deflation of the lungs. The abdominal organs are prepared for extraction by their respective surgical teams. It is preferable for the liver team to insert a large-caliber cannula in the inferior vena cava (IVC) for liver flush effluent, rather than planning to vent the hepatic flush into the chest through the divided IVC, thereby obscuring the view of the thoracic organ extraction team. The superior vena cava (SVC) is encircled within the pericardium. The aorta is mobilized and encircled. The periadventitial tissue overlying the right pulmonary artery is dissected, thereby separating it from the posterior surfaces of both the SVC and the ascending aorta. This maneuver minimizes injury to the right pulmonary artery during excision of the heart. Of note, the right pulmonary artery is the most commonly injured structure during lung retrieval. If the donor is hemodynamically stable, we develop the plane overlying the trachea by incising the posterior pericardium between the SVC and the aorta just superior to the right pulmonary artery. Once all retrieval teams have completed their dissections, the donor is heparinized. In case of concomitant cardiac retrieval, a cardioplegia cannula is placed in the ascending aorta. A large-bore curved pulmonary flush cannula is then placed in the main pulmonary artery immediately proximal to its bifurcation. PGE1 (500 µg) is administered directly into the main pulmonary artery and allowed to circulate for up to 1 minute. This may produce a fall in systemic pressure. Ligation of the SVC and division of the IVC at the diaphragm results in decompression of the right side of the heart. The left atrial appendage is amputated to decompress the left side of the heart. The aorta is cross-clamped, and pulmonary flushing is initiated (Fig. 54-1). With the lungs continuously ventilated, pulmonary artery flushing is achieved with 60 mL/ kg of Perfadex solution delivered at a pressure of 30 cm H2O. Cold effluent is allowed to collect in both pleural spaces. Topical hypothermia is supplemented by crushed ice. It is our preference to extract the donor heart in situ. Satisfactory cardiac and bilateral lung grafts can always be safely extracted with appropriate cooperation between the heart and lung transplantation teams. We begin the extraction of the heart by dividing the IVC and dissecting superiorly until we visualize the right inferior pulmonary vein. Next, we excise the left atrial cuff. The heart is elevated and retracted to the right. The left atrium is opened midway between the coronary sinus and the left inferior pulmonary vein. The left

1/21/2008 11:49:23 AM

Chapter 54 Lung Transplantation

667

FIGURE 54-2 The donor heart is removed by dividing the ascending aorta and the main pulmonary artery at its bifurcation. Sufficient left atrial cuff needs to be left on the lung allografts. (FROM SUNDARESAN S, TRACHIOTIS GD: DONOR LUNG PROCUREMENT: ASSESSMENT AND OPERATIVE TECHNIQUE. ANN THORAC SURG 56:1409, 1993.)

FIGURE 54-1 Pulmonary flush solution is administered through the main pulmonary artery and vented through the amputated tip of the left atrial appendage. (FROM SUNDARESAN S, TRACHIOTIS GD: DONOR LUNG PROCUREMENT: ASSESSMENT AND OPERATIVE TECHNIQUE. ANN THORAC SURG 56:1409, 1993.)

atrial incision is then continued toward the right. The right side of the left atrial wall is then divided, taking care to preserve a rim of atrial muscle on the pulmonary vein side (Fig. 54-2). The right inferior pulmonary vein is the most commonly injured structure during preparation of the left atrial cuff. It is our practice to continuously visualize the orifices of the pulmonary veins from within the atrium, to minimize injury and to ensure an adequate atrial cuff. Again, it is always possible to prepare the left atrial cuff in a fashion that leaves enough left atrial tissue for both lung and heart teams. The SVC is then divided between the previously placed ligatures, taking care not to injure the underlying right main pulmonary artery. The aorta is divided distal to the cardioplegia cannula. The main pulmonary artery is then divided through the cannulation site, typically just proximal to the bifurcation. This completes the cardiac excision. Before extraction of the lungs, we flush them retrograde by administering 250 mL of Perfadex solution through each pulmonary vein orifice. Occasionally, fragments of clot can be seen emanating from the pulmonary artery during the retrograde flush. Removal of the lungs is then continued by mobilization and division of the trachea well above the carina. It is our preference to divide the trachea with a stapling instrument and keep the lungs moderately inflated. The esophagus is transected with a stapling instrument. The entire remaining tho-

Ch054-F06861.indd 667

racic contents are then extracted by lifting and dissecting them off the spine in a cranial-to-caudal direction. The thoracic aorta and esophagus are transected at the diaphragm. The lung allografts are then immersed in cold Perfadex solution and transported semi-inflated. If the individual lungs are destined for use by different transplant centers, they are separated into separate allografts at the donor hospital. The donor left main bronchus is divided at its origin with a cutting stapling device to leave the airway to both lungs sealed. Otherwise, the grafts are transported en bloc for separation immediately before implantation. On arrival at the recipient hospital, the graft is exposed and kept cold during the remainder of its preparation. The esophagus and aorta are removed, leaving all other soft tissues on the specimen side, to maximize bronchial arterial collateral flow to the donor lung. Viewing the double-lung block from its anterior aspect, the posterior pericardium is divided inferiorly to superiorly. The posterior left atrium is divided, leaving equal atrial cuffs on both sides. The remaining pericardium posterior to the left atrium is then divided. The pulmonary artery is divided at its bifurcation (Fig. 54-3). It is important to separate the pulmonary artery from its pericardial attachments on each side out to the first pulmonary arterial branch. This prevents postimplantation kinking of pulmonary artery distal to the pulmonary artery anastomosis. Subcarinal nodes are divided, and the left main bronchus is transected. The left main bronchus is then dissected from the nodal tissue and divided at a point two rings proximal to the upper lobe orifice. On the right side, excision of the carina usually provides an adequate length (two rings proximal to the upper lobe origin) for subsequent bronchial anastomosis. It is important during dissection of the bronchus to minimize any nodal dissection at the site of bronchus tran-

1/21/2008 11:49:23 AM

668

Section 3 Lung

FIGURE 54-3 The pericardium and left atrium are divided. The airway has been divided with a stapling device. (FROM SUNDARESAN S, TRACHIOTIS GD: DONOR LUNG PROCUREMENT: ASSESSMENT AND OPERATIVE TECHNIQUE. ANN THORAC SURG 56:1409, 1993.)

section, to maximize retrograde bronchial collateral blood flow to the donor bronchus after transplantation.

Recipient Anesthesia A successful lung transplant program requires active involvement of expert anesthesiologists who are familiar with complex cardiothoracic anesthesia techniques, bronchoscopy, and CPB. Full hemodynamic monitoring is required for every patient. We routinely use a Foley catheter, central venous line, pulmonary artery catheter, radial artery catheter, and femoral artery catheter. It is useful to supplement the radial artery catheter with a femoral artery line, especially if CPB is anticipated. We routinely use a transesophageal echocardiographic probe and believe it is critical for patients with severe pulmonary hypertension and coexisting right ventricular dysfunction. The airway is routinely intubated with a left-sided doublelumen endobronchial tube, which enables independent ventilation of either or both lungs. A single-lumen tube with an endobronchial Fogarty catheter enables independent ventilation. However, this technique lacks the reliability of a doublelumen tube. A single-lumen tube can present difficulties, particularly in a bilateral transplant recipient, in whom intraoperative maneuvering of the tube can be troublesome. In patients with cystic fibrosis, thick, purulent secretions are continuously expressed into the bronchial lumen during manipulation of the lungs for extraction. These patients require a large-caliber single-lumen tube and a flexible fiberoptic bronchoscope to aspirate the airway completely before placement of the double-lumen tube. For patients of small stature, a single-lumen tube must be used. If a bilateral procedure is planned in such patients, CPB is used routinely during extraction and implantation. This is the standard technique for bilateral transplantation in children.81

Ch054-F06861.indd 668

FIGURE 54-4 Exposure through bilateral anterior thoracotomies without division of the sternum. A combination of chest retractor and Balfour retractor provides excellent exposure. (FROM MEYERS BF: TECHNICAL ASPECTS OF ADULT LUNG TRANSPLANTATION. SEMIN THORAC CARDIOVASC SURG 10:213, 1998.)

Sequential Bilateral Lung Transplantation Exposure The vast majority of bilateral sequential single-lung transplantations, which is our procedure of choice for most indications, are conducted through bilateral anterolateral fourth interspace thoracotomies (Fig. 54-4). The internal mammary arteries are identified and divided. This incision provides adequate exposure for safe division of pleural adhesions. In patients with cystic fibrosis, adhesions can be particularly dense at the apex and posterior aspect of the chest. In addition, this incision provides satisfactory exposure for institution of CPB by ascending aortic and right atrial cannulation. The addition of a transverse sternal division, the so-called clamshell incision or thoracosternotomy, is generally reserved for patients who need concomitant cardiac surgery, patients with restrictive lung disease and small chest cavities, and patients with pulmonary hypertension and secondary cardiomegaly (Fig. 54-5).

Recipient Pneumonectomy It is general practice to transplant, first, the lung with the worse preoperative function as judged by ventilationperfusion scan. Pleural adhesiolysis and mobilization of the pulmonary hila are performed bilaterally before explantation of the first lung. This strategy helps minimize the period during which the newly implanted lung is exposed to the entire cardiac output. Pleural adhesions can be extensive in patients with fibrotic or septic lung disease, as well as patients with previous thoracic procedures, and are ordinarily absent in patients with emphysema and PPH. Extreme care is taken not to injure the phrenic and recurrent laryngeal nerves. The

1/21/2008 11:49:25 AM

Chapter 54 Lung Transplantation

669

FIGURE 54-5 Clamshell incision through the fourth interspace. (FROM SHIELDS TW: GENERAL THORACIC SURGERY, PHILADELPHIA, LEA AND FEBIGER 1994.)

inferior pulmonary ligament is divided. The pulmonary veins and main pulmonary artery are encircled outside the pericardium. During this dissection, the need for CPB is determined. The ventilation of the contralateral lung and occlusion of the ipsilateral pulmonary artery determine whether the contralateral native lung provides adequate gas exchange and hemodynamics to tolerate pneumonectomy and implantation without CPB. Assessment of right ventricular contractility with the transesophageal echocardiogram probe is especially useful at this point.82 Easily accessible upper lobe pulmonary artery branches are ligated and divided. This increases the length of pulmonary artery available for subsequent pulmonary artery anastomosis. It also decreases the caliber of the pulmonary artery to match the donor’s size to the recipient’s pulmonary artery, particularly when significant pulmonary hypertension is present. Furthermore, having a ligated recipient upper lobe branch helps with proper orientation of the donor and recipient pulmonary arteries. The pulmonary artery just distal to this branch is stapled proximally after ensuring that the pulmonary artery catheter is not included in the staple line. A distal pulmonary artery clamp is placed, the vessel is divided, and its distal aspect is ligated to minimize back-bleeding, which can be torrential if vigorous bronchial circulation is present. Pulmonary veins are divided between staples or between silk ligatures placed on each venous branch at the hilum. The latter option increases the size of the subsequent left atrial cuff. Pulmonary artery division is often made easier after division of the superior pulmonary vein.

Ch054-F06861.indd 669

Peribronchial nodal tissue is divided, and bronchial arterial vessels are secured with electrocautery or ligatures. The bronchus is transected just proximal to the upper lobe origin, and the lung is excised. The recipient bronchus is then trimmed back up into the mediastinum, taking care to avoid any devascularization of the recipient bronchus at the site of anastomosis. The pulmonary artery stump is grasped with a clamp and retracted medially to provide access for the bronchial anastomosis. Similarly, the vein stumps are grasped with clamps, and the pericardium around the vein stumps is opened widely and retracted medially in preparation for the implantation.

Implantation The donor lung, wrapped in cold moist gauze, is placed in the posterior portion of the thorax. In this position, manipulation of the lung can be avoided during the entire implantation. The lung is kept cold by topical application of crushed ice. The bronchial anastomosis is performed first. After approximating donor and recipient peribronchial tissue with running 4-0 absorbable monofilament suture, we close the membranous wall of the bronchus using a continuous 4-0 absorbable monofilament suture (Fig. 54-6). The anterior cartilaginous airway is then closed by interrupted figure-of-eight sutures (Fig. 54-7A). Small-caliber bronchi can be narrowed by the figure-of-eight technique. In this circumstance, an end-to-end closure is obtained by using simple interrupted sutures of monofilament absorbable material (see Fig. 54-7B). A number of experienced centers use a continuous suture technique for

1/21/2008 11:49:26 AM

670

Section 3 Lung

A

FIGURE 54-6 The recipient pulmonary artery and pulmonary veins have been retracted with clamps. The membranous portion of the bronchial anastomosis is performed with a running suture. (FROM MEYERS BF: TECHNICAL ASPECTS OF ADULT LUNG TRANSPLANTATION. SEMIN THORAC CARDIOVASC SURG 10:213, 1998. COPYRIGHT ELSEVIER 1998.)

the bronchial anastomosis and report excellent results. We have recently adopted this technique in some cases and have been pleased with the results. We then complete the approximation of the peribronchial tissue on the anterior surface of the bronchus. A vascular clamp is then placed as proximal as possible on the recipient pulmonary artery. The donor and recipient arteries are trimmed to size, and an end-to-end anastomosis is created using 5-0 polypropylene suture (Fig. 54-8). Care must be taken to excise an adequate length of donor and recipient pulmonary artery. Excessive length results in kinking of the pulmonary artery after allograft inflation. Lateral traction on the pulmonary vein stumps enables central placement of an angled atrial clamp. The pulmonary vein stumps are then amputated, and the bridge of tissue between the two is incised to create a suitable cuff for the left atrial anastomosis (Fig. 54-9). This venous anastomosis is performed with 4-0 polypropylene suture. After completion of this anastomosis, but before the final stitch is tightened and tied, the lung is gently inflated while the pulmonary artery clamp is temporarily removed, enabling the lung to be deaired through the open left atrial anastomosis. All suture lines are then secured and inspected, and the vascular clamps are removed. The contralateral implantation is performed in analogous fashion. Two pleural drains are left in each pleural space, and routine closure is achieved with absorbable suture material. At the termination of the procedure, the double-lumen endotracheal tube is replaced with a large-caliber single-lumen tube. Flexible bronchoscopy is then performed to inspect the bronchial anastomosis and evacuate any blood or secretions from the airway. CPB may be necessary at several junctures during bilateral sequential transplantation.82 First, patients with small airways

Ch054-F06861.indd 670

B FIGURE 54-7 A, Anterior bronchial wall anastomosis with interrupted figure-of-eight 4-0 PDS sutures. B, The anterior wall anastomoses of small-caliber bronchi are performed with simple interrupted sutures of monofilament absorbable material. (FROM MEYERS BF: TECHNICAL ASPECTS OF ADULT LUNG TRANSPLANTATION. SEMIN THORAC CARDIOVASC SURG 10:213, 1998. COPYRIGHT ELSEVIER 1998.)

not amenable to double-lumen tube placement require CPB to be instituted after mobilization of both lungs and maintained during bilateral extraction and implantation. Occasionally, a patient with airways suitable for a doublelumen endotracheal tube has inadequate contralateral native lung to allow satisfactory gas exchange or hemodynamics during removal or replacement of the first lung. In such cases, CPB is instituted at this point. The most common situation requiring bypass occurs after implantation of the first lung. An acutely dysfunctional transplanted lung may not support the recipient’s circulation and gas exchange. This problem presents itself as a progressive increase in pulmonary artery pressure. If increased pulmonary artery pressure is genuine and substantial, pulmonary edema will develop and cause hypoxemia. The cause of this typical clinical phenomenon is not well understood, although it is likely to be the result of poor preservation. Alternatively, it may be caused by recipient systemic bacteremia, as it is commonly observed after implantation of the first lung in patients with cystic fibrosis. It is prudent to institute CPB for completion of the procedure as soon as clinical problems arise, rather than waiting for an emergent situation in an unstable patient. Whereas, in the situations just described, CPB is dictated by the patient’s clinical condition, the routine use of CPB

1/21/2008 11:49:27 AM

Chapter 54 Lung Transplantation

FIGURE 54-8 A Satinsky clamp occludes the recipient pulmonary artery proximally, and an end-to-end pulmonary artery anastomosis is performed with a continuous 5-0 monofilament suture. (FROM MEYERS

FIGURE 54-9 An atrial clamp is in place centrally, and the pulmonary venous anastomosis is performed with a continuous 4-0 monofilament suture. (FROM MEYERS BF: TECHNICAL ASPECTS OF ADULT LUNG

BF: TECHNICAL ASPECTS OF ADULT LUNG TRANSPLANTATION. SEMIN THORAC CARDIOVASC SURG 10:213, 1998. COPYRIGHT ELSEVIER 1998.)

TRANSPLANTATION. SEMIN THORAC CARDIOVASC SURG 10:213, 1998. COPYRIGHT ELSEVIER 1998.)

for sequential double-lung transplantation is controversial. Opponents note that the systemic inflammatory response to CPB can potentiate lung injury,83 and some centers have documented a higher incidence and grade of clinical reperfusion injury and prolonged duration of mechanical ventilation and intensive care stay in patients transplanted with the use of CPB.84 Because of the requirement for systemic anticoagulation, bleeding may be a major complication of the recipient pneumonectomy, especially in light of severe pleural adhesions encountered in cystic fibrosis patients. Proponents of the routine use of CPB argue that diverting the entire cardiac output to the newly transplanted lung during implantation of the second allograft, as well as relying on an acutely ischemic organ to support oxygen exchange, can exacerbate lung injury and primary graft dysfunction. One retrospective study of 50 patients with COPD specifically addressed the clinical outcome of patients undergoing bilateral lung transplantation with or without routine, nonemergent use of CPB. These investigators were unable to detect any differences in duration of mechanical ventilation, postoperative PaO2/FIO2 ratio, duration of hospitalization, or mortality in the two groups, but there was a much higher postoperative blood product requirement in patients transplanted with the use of CPB.85 Although this study documented few deleterious effects resulting from the routine use of CPB, the inclusion of only a small number of patients, all

of whom had COPD with limited pleural adhesions, might have led to underestimation of the bleeding complications encountered in patients with cystic fibrosis. Because of this controversy, the use of CPB currently depends on the surgeon and center. It is our policy to selectively use CPB for patients with initially high pulmonary artery pressures or in cases of hemodynamic instability or difficulty in oxygenation after the implantation of the first lung. Because CPB allows emptying of the heart and exposure of the pulmonary hilum, especially on the left, not using CPB can occasionally lead to poor exposure and difficulty in performing the implantation. To overcome this difficulty, it has become our routine practice to lower the diaphragm by means of a traction figure-of-eight stitch that is placed through the membranous central tendon and brought out through a midclavicular stab wound below the diaphragm. To facilitate exposure of the left hilar structures, especially for the left atrial anastomosis, without the use of CPB, it has become our practice to use the Urchin heart positioning device (Medtronic, Minneapolis, MN) to improve exposure. Although this device was originally designed for off-pump cardiac surgery, to improve exposure to the coronary arteries, we have been able to use it to retract the heart when difficult exposure precludes safe performance of the left-sided anastomoses.86 Retraction of the heart with this device can be performed through either bilateral anterior thoracotomies or a clamshell

Ch054-F06861.indd 671

671

1/21/2008 11:49:28 AM

672

Section 3 Lung

incision. After removal of the left lung, the pericardium is opened vertically, with careful attention to avoid injury to the phrenic nerve. The Urchin device is placed on the apex of the heart, and suction is applied to position the heart out of the left chest and expose the left hilar structures (Fig. 54-10). After completion of the anastomoses in the standard fashion of bronchus, artery, and vein, the left lung is deaired and reperfused. After hemostasis is achieved at the suture lines and the cut edge of the pericardium, the suction is released and the heart is returned to its normal position within the pericardium. We have now made it our practice to routinely use this device to facilitate exposure, as an alternative to CPB, without adverse outcomes.

right-sided transplantations in which CPB is anticipated, cannulation of the ascending aorta is facilitated somewhat by the use of a fourth interspace incision. A median sternotomy can be used for right-sided transplantation, especially if associated cardiac repair dictates an anterior approach, permitting access to the left side of the heart. The patients are always positioned with the ipsilateral groin in the operative field for subsequent cannulation if necessary. Femoral partial bypass was formerly our technique of choice. However, intrathoracic cannulation avoids a groin incision and the necessary arterial and venous repairs after decannulation. The ascending aorta and right atrium are easily cannulated through the right chest. The cannulae are positioned in the anterior aspect of the incision and remain well out of the operative field throughout the procedure. Through a left posterolateral thoracotomy, the proximal left pulmonary artery and descending aorta are easily cannulated.

Single-Lung Transplantation Choice of Side In general, we prefer to transplant the side with the least pulmonary function, as judged by preoperative quantitative nuclear perfusion scans. It was previously argued that the right side was preferable for patients with obstructive pulmonary disease. However, in our experience and that of others,87 there is no difference in functional outcome among single-lung recipients, regardless of the transplanted side. If CPB is anticipated, as in patients with PPH or severe pulmonary fibrosis with associated pulmonary hypertension, the right side is the preferred transplant side. For patients with Eisenmenger’s syndrome, we prefer the right side to facilitate closure of the coexisting atrial or ventricular septal defects. A patent ductus arteriosus can be repaired in association with transplantation on either side.

Implantation The implantation technique for single-lung transplantation is similar to that outlined for sequential bilateral lung transplantation. One important difference involves the bronchial anastomosis. We reapproximate the anterior surface of the bronchi first, followed by arterial and venous anastomoses. All of these anastomoses are performed with the donor lung retracted posteriorly. At the completion of these anastomoses, we retract the lung anteriorly and complete the membranous portion of the bronchus using long ends of previously placed corner stitches.

Pediatric Lung Transplantation Exposure

Pediatric lung transplant recipients are defined as patients younger than 18 years of age. A total of 862 pediatric lung transplantations were performed worldwide between 1986 and 2003, including 63 procedures in 2003.88 This number

A generous posterolateral thoracotomy through the fifth interspace is the preferred approach, although a musclesparing incision has been advocated by some authors.18 For

A

B

FIGURE 54-10 A, Preoperative CT scan of the chest of a lung transplant recipient with mediastinal shift, in whom the Urchin apical heart suction device was used to expose the left chest cavity through a clamshell incision. B, Placement of Urchin apical heart suction device on the apex of the left ventricle improves the exposure for implantation of the left lung. (FROM LAU CL, ET AL: USE OF AN APICAL HEART SUCTION DEVICE FOR EXPOSURE IN LUNG TRANSPLANTATION. ANN THORAC SURG 81:1524-1525, 2006, FIGURE 1.)

Ch054-F06861.indd 672

1/21/2008 11:49:29 AM

Chapter 54 Lung Transplantation

has remained relatively stable over the last 5 years and represents a relatively small proportion of the total lung transplantation procedures performed. Moreover, other solid organs are transplanted far more frequently than lungs in the pediatric population. Therefore, it is not surprising that most studies involving pediatric lung transplantation are retrospective in nature and are limited to the experience at a single center. Between 1998 and 2002, only four pediatric hospitals in the United States reported four or more lung or heart-lung transplantations. Between 1996 and 2004, approximately 70% of all pediatric lung transplantations were performed for patients between 10 and 17 years of age. The most common indication for lung transplantation in infants (<1 year) is congenital heart disease, representing 47% of the procedures performed in this age group between 1991 and 2004. Other indications in this age group include PPH, pulmonary vascular disease, and pulmonary alveolar proteinosis. In the group between 1 and 10 years of age, 36.5% of lung transplants were performed for cystic fibrosis during 1991 to 2004; other indications include PPH, congenital heart disease, and retransplantations for obliterative bronchiolitis. Cystic fibrosis is the predominant indication for lung transplantation in teenagers aged 11 to 17 years, accounting for approximately two thirds of procedures performed in this age group. The lung allocation system has recently been revised, and currently lungs are allocated to potential recipients younger than 12 years of age based on waiting time on the transplant list. Alternatively, potential recipients aged 12 to 17 years of age are prioritized based on their LAS, which is derived from their predicted survival with or without a transplant.89 The vast majority of pediatric lung transplantations are bilateral. In the series from St. Louis Children’s Hospital, which represents the largest single-center experience in the world, more than 95% of all lung transplantations were bilateral. Lung transplantation in the pediatric population is usually performed through bilateral anterolateral transsternal thoracotomy incisions. Virtually all lung transplantations at St. Louis Children’s Hospital have been performed using CPB. This is related to the fact that, especially in small patients, single-lung ventilation is not feasible due to the inability to place double-lumen endotracheal tubes. In light of the shortage of cadaveric donors, living donor lung transplantation has emerged as a viable option, especially for pediatric patients.43 Virtually all pediatric lung transplant recipients receive triple-drug immunosuppression, consisting of prednisone, an antimetabolite, and a calcineurin inhibitor. As in the adult population, there has been a recent trend to replace cyclosporine with tacrolimus and azathioprine with mycophenolate mofetil.88 Induction therapy was used in almost 50% of pediatric lung transplant recipients between 2001 and 2004. Interleukin 2 (IL-2) receptor antagonists were used in more than 70% of these patients, and the remainder received polyclonal anti–T cell agents. There are some important postoperative considerations unique to lung transplantation in the pediatric population. Despite potentially deleterious factors such as chronic use of corticosteroids and denervation at the time of the transplan-

Ch054-F06861.indd 673

673

tation, immature transplanted lungs have the ability to grow.90,91 Animal studies have suggested that this lung growth is secondary to an increase in alveolar numbers.92 Although skin malignancies are rare in pediatric lung transplant recipients, 13% of recipients in the series from St. Louis Children’s Hospital developed a post-transplantation lymphoproliferative disorder (PTLD). One report from the same institution suggested a higher risk of developing this complication in a subgroup of patients with cystic fibrosis, who had experienced multiple early episodes of acute rejection.93 Another study from St. Louis Children’s Hospital demonstrated that a single episode of CMV viremia after discontinuation of ganciclovir is associated with a higher risk of death and retransplantation during the first year after transplantation.94 A recent retrospective review from the same institution showed that the incidence of airway complications after lung transplantation is similar to that in adults and is generally amenable to bronchoscopic interventional techniques.95 Very young recipients seem to experience fewer episodes of rejection.96 Nevertheless, as in adults, chronic rejection remains the Achilles heel of pediatric lung transplantation. The 1-, 3-, and 5-year survival rates at St. Louis Children’s Hospital were reported to be 77%, 63%, and 54%, respectively.97 Although there has been a recent trend toward improved early survival, there has been no significant change in long-term survival.88 To this end, bronchiolitis obliterans remains the main cause for late death after lung transplantation in children, and 50% of surviving pediatric patients develop bronchiolitis obliterans syndrome by 5 years after transplantation.88

Heart-Lung Transplantation The first successful heart-lung transplantation was performed by Reitz and colleagues8 at Stanford University in 1981. The recipient was a 45-year-old woman with PPH. Although this procedure was initially offered to patients with end-stage cardiopulmonary disease as well as those with septic lung disease, the success of lung transplantation and the donor shortage have led to an overall decline in heart-lung transplantation since a peak in the early 1990s. At that time, the annual number of heart-lung transplantations reported to the ISHLT Registry exceeded 200. In 2003, only 74 heart-lung transplantations were recorded, and the decline appears to continue. Between 1998 and 2004, only five centers had performed more than four heart-lung transplantations per year. PPH and pulmonary hypertension associated with congenital heart disease remain the main indications for heartlung transplantation. The recipient operation is performed via a median sternotomy, or through a clamshell approach if dense adhesions in the pleural cavities are anticipated. Great attention needs to be paid to avoiding injury to the phrenic nerves. The ascending aorta and both venae cavae are dissected and cannulated for CPB. Subsequently, the heart and both lungs are excised. After the heart-lung block is positioned in the chest, both lungs are introduced into the respective pleural cavities by guiding the lungs behind the phrenic nerves. The tracheal anastomosis is performed with a running 4-0 absorbable

1/21/2008 11:49:30 AM

674

Section 3 Lung

monofilament suture on the membranous wall and interrupted figure-of-eight stitches on the anterior wall. A right atrial anastomosis is performed with continuous 3-0 polypropylene, and the aorta is anastomosed with running 4-0 polypropylene. Early survival after heart-lung transplantation is markedly worse than after lung transplantation. The survival rate at 3 months is only 71%, and at 12 months it is 63%, with infectious complications and graft failure accounting for most of the deaths. The 5- and 10-year survival rates are 43% and 28%, respectively. Although heart-lung transplantation seems to be associated with a lower incidence of cardiac allograft vasculopathy in the heart graft, 43% of surviving heart-lung transplant recipients develop bronchiolitis obliterans by 5 years after transplantation.

Retransplantation Many forms of acute graft failure and most chronic lung allograft failures are not amenable to medical therapy. For these patients, lung retransplantation often remains the only therapeutic option. In 1991, Novick and colleagues established an international registry for pulmonary retransplantation. In 1998, they reported the results of 230 patients who had undergone lung retransplantation at 47 centers in North America, Europe, and Australia from 1985 to 1996.98 Sixtythree percent of these patients underwent lung retransplantation for obliterative bronchiolitis and 22% for acute graft failure. Indications for retransplantation in the remainder of the patients included intractable airway complications and acute severe rejection. The median time interval between the initial transplantation procedure and retransplantation in patients with obliterative bronchiolitis was 639 days. Most of the retransplant patients in this series underwent a singlelung retransplantation procedure, either ipsilaterally or contralaterally after a previous single-lung transplantation or a double-lung transplantation. The overall survival rate after retransplantation was 47% at 1 year, 40% at 2 years, and 33% at 3 years. Factors associated with improved survival included a longer time interval since the initial transplantation procedure, freedom from ventilator support before retransplantation, and retransplantation performed after 1991. Based on these data, many lung transplantation physicians believe that retransplantation should be limited to ambulatory patients. The three major causes of death in this series were opportunistic infections, acute graft failure, and obliterative bronchiolitis. The freedom from bronchiolitis obliterans syndrome was 81% at 1 year, 62% at 3 years, and 50% at 5 years after retransplantation, results comparable to those after primary lung transplantation. A time interval of greater than 2 years between primary transplantation and retransplantation was found to be associated with freedom from obliterative bronchiolitis. The thoracic transplantation group at Hannover, a center with one of the largest experiences in pulmonary retransplantation, reported that survival rates after lung retransplantation for obliterative bronchiolitis were equivalent to those after primary transplantation.99 However, patients who underwent retransplantation for acute graft failure or intractable airway complications had markedly worse outcomes. A single-center experience with pulmonary

Ch054-F06861.indd 674

retransplantation in 15 patients with bronchiolitis obliterans syndrome was published in 2003.100 All retransplantations involved a single lung. The median time between primary transplantation and retransplantation was 31 months, which was longer than in the series from the international registry for pulmonary retransplantation. There was a relatively high early mortality rate in this series, with an overall survival rate of 60% at 1 year, 53% at 2 years, and 45% at 5 years. The rate of freedom from bronchiolitis obliterans syndrome in this cohort was 90% at 1 year, 72% at 3 years, and 54% at 5 years. The primary cause of death was infection. Interestingly, the primary retained graft was thought to be the source of infection in patients who had undergone a contralateral single-lung transplantation after previous single-lung transplantation or a single-lung transplantation after previous double-lung transplantation. Therefore, the authors recommended that the primary graft be removed at the time of retransplantation. Huddleston and colleagues101 reported the pulmonary retransplantation experience in 14 pediatric patients at St. Louis Children’s Hospital. Unlike the adult retransplantation series, all patients in this pediatric series underwent a doublelung procedure in retransplantation, and four patients received transplants from living donors. The average age of these children at their initial transplantation was 9.9 years, and at the time of retransplantation it was 11.2 years. Fifty-seven percent of the patients underwent retransplantation because of the development of obliterative bronchiolitis, at a median interval of 639 days after their initial transplantation. The remainder of the patients underwent retransplantation because of graft failure secondary to reperfusion injury, at a median time interval of 63 days after initial transplantation. There was a 21% mortality rate within the first month after the retransplantation, and the 1-year survival rate was 58%, considerably lower than the rate after primary transplantation (80%) in children at the same institution during the same time period. Early deaths were mostly due to infectious complications. Pulmonary retransplantation is a technically challenging procedure. In fact, lung retransplantation has been reported to be a significant risk factor for early mortality after lung transplantation.102 This procedure is generally associated with a higher requirement for blood transfusions. Moreover, dense hilar adhesions can lead to phrenic nerve injuries. The severe shortage of donor organs raises the question whether lung retransplantation should be performed at all. Kotloff103 captured the ethical dilemma of pulmonary retransplantation by asking the question: “Can we justify a policy of retransplantation that affords a patient a second opportunity while depriving another of a first?” The new lung allocation system has attempted to address some of these issues. At this point, retransplantation offers the only hope to many lung transplant recipients who suffer from obliterative bronchiolitis. It is our opinion that the good survival rates and rates of freedom from bronchiolitis obliterans after retransplantation for obliterative bronchiolitis justify this procedure in selected cases. Furthermore, we believe that pulmonary retransplantation must be performed only by experienced surgeons at highvolume centers.

1/21/2008 11:49:30 AM

Chapter 54 Lung Transplantation

POSTOPERATIVE MANAGEMENT Ventilation In general, patients are ventilated with standard ventilatory techniques. The FIO2 is kept at a level to maintain a PaO2 greater than 70 mm Hg. A tidal volume of 12 to 15 mL/kg is usually sufficient, and a PEEP of 5 to 7.5 cm H2O is used, except in single-lung recipients with obstructive pulmonary disease. Extubation is performed in accordance with standard requirements of satisfactory gas exchange and mechanics. Most patients are extubated between 24 and 48 hours after transplantation. A standard intermittent mandatory ventilation or pressure support wean is used in all bilateral lung transplant recipients and in single-lung recipients transplanted for pulmonary fibrosis. Patients who have undergone single-lung transplantation for COPD and pulmonary vascular disease are managed differently.104 In the former condition, we avoid the use of PEEP and select tidal volumes lower than would ordinarily be used. These adjustments reduce hyperinflation of the excessively compliant native lung and minimize compression of the less compliant transplanted lung. This trapping of air in the native lung results in major problems, including high airway pressures, inadequate removal of carbon dioxide, and hypotension due to reduced venous return to the heart. Some patients have required a volume reduction of the native lung by lobectomy or even pneumonectomy to decompress the contralateral transplanted lung. In single-lung recipients with pulmonary vascular disease, we have elected to use a more prolonged period (48-72 hours) of mechanical ventilation. Patients are kept heavily sedated and often paralyzed for that period. We choose to maintain these patients in a position with the native lung dependent to maintain inflation and appropriate drainage of the transplanted lung. Standard tidal volumes are used, but an increased PEEP of 7.5 to 10 cm H2O is applied. Early graft dysfunction, rejection, or infection necessitates a prolonged period of postoperative mechanical ventilation for occasional patients. We do not hesitate to perform a tracheostomy because the tracheostomy improves patient comfort, facilitates mobilization, permits oral nutrition, and enhances the attitude of the ventilator-dependent patient.

Fluid Management During the first few postoperative days, fluid management is managed by a determination of pulmonary capillary wedge pressure and daily weight. Despite the vigilance of our anesthesiology colleagues, most patients leave the operating room with a significant positive fluid balance. Diuretics are used aggressively during the early postoperative period. Recipients of single-lung transplants for PPH may develop hemodynamic instability if their right heart filling pressure is excessively reduced. Of note, we try to avoid the use of vasoconstricting agents in the immediate postoperative period because we believe that it can lead to ischemic changes in the bronchial anastomosis and therefore may impair healing.

Ch054-F06861.indd 675

675

Immunosuppression Immunosuppression in clinical lung transplantation can be categorized into maintenance immunosuppression, induction therapy, and treatment for rejection. The introduction of cyclosporine A into clinical transplantation in the 1980s revolutionized solid organ transplantation. Essentially all clinical lung transplantation programs have relied on triple-agent therapy for maintenance immunosuppression, usually consisting of corticosteroids, a calcineurin inhibitor, and a cell cycle inhibitor. Corticosteroids remain key components of current immunosuppressive regimens. Some surgeons are reluctant to use high-dose steroids in the early postoperative period because of concerns about bronchial anastomotic healing. At our center, methylprednisolone 10 to 15 mg/kg IV is given intraoperatively just before graft perfusion. Most programs have adopted the use of moderate-dose corticosteroid therapy (methylprednisolone 0.5-1 mg/kg/day IV) for several days before initiating an oral dose of prednisone of 0.5 mg/kg/day. There have been attempts in kidney and liver transplant recipients to reduce the dose of steroids or to withdraw them completely. Although a recent study reported on the withdrawal of steroids in a relatively small number of lung transplant recipients, no large-scale studies have yet been conducted to examine the efficacy of steroid-free maintenance immunosuppression.105 Data from the ISHLT Registry in 2005 reported that 75% of all lung transplant recipients were receiving a calcineurin inhibitor and a purine synthesis inhibitor at 1 and 5 years after transplantation. Tacrolimus and mycophenolate mofetil was the predominant combination, representing a shift from the use of cyclosporine and azathioprine in previous years. Both cyclosporine and tacrolimus are calcineurin inhibitors, and both agents suppress the transcription of IL-2 and inhibit proliferation of T lymphocytes. In addition, tacrolimus may suppress the transcription of IL-10 and downregulate the expression of receptors for transforming growth factor-β (TGF-β). Although the available data are not conclusive to date, some studies suggest that tacrolimus used as a maintenance immunosuppressant may decrease the incidence of acute rejection and may have a beneficial effect on the development of bronchiolitis obliterans syndrome.106,107 The lung transplantation group at the University of Pittsburgh recently reported their experience with the administration of inhaled cyclosporine in addition to conventional maintenance immunosuppression of corticosteroids, azathioprine, and tacrolimus.108 Although there was no change in the incidence of acute rejection, the survival free of bronchiolitis obliterans syndrome and overall survival at 3 years after transplantation were significantly improved in the patient cohort receiving inhaled cyclosporine. Of note, patients who received inhaled cyclosporine did not experience a higher rate of nephrotoxicity or a higher rate of infections. Azathioprine has been used since the early days of solid organ transplantation. It inhibits de novo purine synthesis and suppresses proliferation of both T and B lymphocytes. Encouraging data with the use of mycophenolate mofetil instead of azathioprine in renal and heart transplantation have

1/21/2008 11:49:30 AM

676

Section 3 Lung

led to increased use of this drug in clinical lung transplantation as well. The ISHLT Registry in 2005 reported that almost 38% of lung transplant recipients were receiving azathioprine and 42% were receiving mycophenolate mofetil at 5 years after transplantation. The shift toward the use of mycophenolate mofetil was documented by its use in 50% of lung transplant recipients, compared with azathioprine in 34% of recipients, at 1 year after transplantation during the period 2001 to 2004. Mycophenolate mofetil is a prodrug that is converted to its active compound mycophenolic acid in vivo. It leads to the inhibition of the de novo purine synthesis pathway and suppresses the proliferation of T and B lymphocytes. Data on the superiority of mycophenolate mofetil over azathioprine in lung transplantation are controversial. Although several retrospective series have documented decreased incidences of acute rejection with the use of mycophenolate mofetil, two prospective studies failed to demonstrate significant differences in episodes of acute rejection.109-111 Sirolimus and its derivative, everolimus, have been recently introduced into clinical lung transplantation. These agents block growth factor–driven cell cycle progression and proliferation of lymphocytes as well as a variety of nonhematopoietic cells such as vascular smooth muscle cells. Therefore, they may hold promise for lowering the incidence of chronic allograft rejection. The ISHLT Registry in 2005 reported that approximately 10% of lung transplant recipients were receiving rapamycin at 5 years after transplantation. A matter of considerable controversy is the use of postoperative induction therapy. Potential advantages of induction immunosuppression include a reduction in the incidence of acute rejection and a delayed use of calcineurin inhibitors (and therefore a potentially lower incidence of renal failure). Disadvantages are the higher risk of infectious complications and post-transplantation malignancies. Another concern could be the recent demonstration that the homeostatic proliferation of lymphocytes that occurs after lymphodepletion could represent a barrier to achieving immune tolerance.112 According to the ISHLT Registry, approximately 40% of all patients undergoing lung transplantation between 2000 and 2003 received induction immunosuppression. Although there has been a marked decrease in the use of polyclonal antilymphocyte or antithymocyte preparations as well as monoclonal OKT3, there has been a progressive increase in the use of anti–IL-2 receptor antagonists. Whereas antithymocyte globulin, antilymphocyte globulin, and OKT3 deplete both quiescent and activated T lymphocytes, IL-2 receptor antagonists block activated T lymphocytes. In 2003, approximately 75% of lung transplant recipients who were given induction immunosuppression received anti–IL-2 receptor antagonists. IL-2 receptor antagonists are associated with a lower risk of infectious complications and a lower risk of developing PTLD.113,114 The use of both IL-2 receptor antagonists and polyclonal antilymphocyte/antithymocyte preparations is believed to be associated with a decrease in the number of episodes of acute rejection. A recent study suggested that induction therapy with antithymocyte globulin is more effective at preventing episodes of acute rejection when compared with the IL-2 receptor antagonist daclizumab.114 At any rate, there do not exist any conclusive data that induc-

Ch054-F06861.indd 676

tion therapy has an impact on either freedom from bronchiolitis obliterans syndrome or overall survival. Based on data from the renal transplant literature, the group at the University of Pittsburgh reported favorable results with pretreatment of lung transplant recipients with the lymphoid-depleting humanized anti-CD52 monoclonal antibody, Campath, and post-transplantation monotherapy with tacrolimus.115 Patients undergoing this regimen experienced fewer rejection episodes, and the episodes were less severe.

Infection and Rejection Surveillance Acute rejection after lung transplantation is expected. Most of the recipients in our program were treated for acute rejection on at least one occasion during the first 3 postoperative weeks. Early acute rejection episodes are characterized by dyspnea, low-grade fever, moderate leukocytosis, hypoxemia, and a diffuse perihilar interstitial infiltrate on the chest radiograph. This clinical picture most typically occurs on about the fifth to seventh day after transplantation. All of these clinical features are also consistent with infection. Clinical examination, radiographic assessment, and fiberoptic bronchoscopy are valuable tools in resolving the frequent dilemma of infection versus rejection in lung transplant recipients. During the early years of our experience, if early acute rejection was suspected, our usual strategy was to administer a trial bolus dose of 500 to 1000 mg of methylprednisolone and observe the clinical response. If rejection was truly the problem, a dramatic improvement in clinical findings, radiographic appearance, and PaO2 was observed within 8 to 12 hours. In that case, the patient received two additional daily IV bolus doses of methylprednisolone, and the event was recorded as an episode of acute rejection. If improvement did not occur, other causes were sought to explain the clinical findings. Our current approach to the same problem is to perform routine fiberoptic bronchoscopy whenever there is a clinical lung dysfunction in the absence of a recently identified but untreated infection. The advantage of routine flexible bronchoscopy is that it enables the performance of bronchoalveolar lavage (BAL) and transbronchial biopsy. Although BAL has not been useful in the diagnosis of rejection, it is invaluable in the identification of opportunistic infections commonly encountered in transplant recipients. Transbronchial biopsy is the procedure of choice for the diagnosis of pulmonary rejection. We have used this modality frequently in patients with unexplained pulmonary infiltrates not responsive to corticosteroid therapy. Transbronchial biopsy is a highly sensitive and specific diagnostic tool for the evaluation of acute rejection. Routine BAL and transbronchial biopsies are performed at 3 weeks; at 3, 6, 9, and 12 months; and on an annual basis thereafter.

COMPLICATIONS Technical Error As in any major operative intervention, a variety of technical complications may be encountered during the postoperative period. In former years, hemorrhage was a frequent compli-

1/21/2008 11:49:30 AM

Chapter 54 Lung Transplantation

cation. In the early experience of some programs undertaking heart-lung and en bloc double-lung transplantations, approximately 25% of patients required reoperation for postoperative hemorrhage. However, with currently used surgical techniques, such as the posterolateral thoracotomy for singlelung transplantation and the clamshell incision for bilateral lung replacement, surgical exposure is superb. In addition, aprotinin has dramatically reduced intraoperative and postoperative bleeding, especially in patients with extensive pleural adhesions requiring CPB. Anastomotic complications can also occur and result in postoperative graft dysfunction. The University of Pittsburgh group116 recently reported their experience with anastomotic complications after lung transplantation and made a number of important technical points. An unsatisfactory bronchial anastomosis is routinely identified in the operating room during the postimplantation bronchoscopy. Inadequate anastomotic caliber dictates an immediate surgical revision. Persistent pulmonary hypertension and unexplained hypoxemia can occur as a result of stenosis at the pulmonary artery anastomosis. This problem may be suggested by a nuclear perfusion scan, which demonstrates less than the anticipated flow to a single-lung graft or unequal distribution of flow in a bilateral-lung recipient. Occasionally, a stenotic anastomosis can be visualized by transesophageal echocardiography. However, contrast angiography needs to be performed in any patient in whom there is a concern. At the time of angiography, the pressure gradient across the pulmonary artery anastomosis must be determined. A gradient of 15 to 20 mm Hg is commonly encountered, especially in single-lung recipients in whom most of the cardiac output is directed to the transplanted lung, or in bilateral recipients with a high cardiac output. The need for anastomotic revision is dictated by the clinical situation. Compromise in flow across the atrial anastomosis can also occur as a result of unsatisfactory anastomotic technique. Compression of the anastomosis by a clot or by an omental or pericardial flap brought anterior or posterior to the atrial anastomosis for purposes of bronchial anastomotic coverage can also impair ipsilateral pulmonary venous drainage. Impaired venous outflow results in elevated venous pressure and ipsilateral pulmonary edema. Pulmonary artery pressures remain unexpectedly high, and flow through the graft is less than expected. Transesophageal echocardiography can image the atrial anastomosis clearly. Contrast studies may be helpful in demonstrating reduced flow through the anastomosis. Open exploration is occasionally necessary to confirm the diagnosis and conduct an appropriate repair.

trates on postoperative chest radiographs (Fig. 54-11). The development of immediate postoperative florid pulmonary edema, severe hypoxemia, persistent pulmonary hypertension, and reduced pulmonary compliance can present a formidable management problem. The ISHLT has recently issued a grading system for primary graft dysfunction, which is based on the PaO2/FIO2 ratio as well as findings on chest radiography (Table 54-4).119 Primary graft dysfunction may arise as a result of unsuspected donor lung pathologic conditions such as aspiration, infection, or contusion. However, it is generally believed that ischemia-reperfusion injury accounts for most of these cases. One of the main mechanisms underlying ischemia-reperfusion injury is membrane damage due to membrane oxygenation induced by reactive oxygen species. Further effects of cold storage that can contribute to primary dysfunction are intracellular calcium overload, release of iron from ferritin, reduced production of anticoagulant factors by endothelial cells, and activation of the complement system. Adhesion molecules that are important for leukocyte adherence and extravasation into tissues are upregulated on pulmonary endothelial cells, and a variety of proinflammatory cytokines and chemokines are released during cold ischemia. Lungresident macrophages and neutrophils and T lymphocytes that are recruited to the lung allograft from the recipient on reperfusion are known to be important mediators of ischemia-reperfusion injury. To this end, levels of IL-8, a potent chemoattractant for neutrophils, have been shown to increase during reperfusion of both renal and lung grafts and appear to correlate with the duration of the ischemic time.120,121 Interestingly, IL-8 levels early after reperfusion were found to negatively correlate with early lung function.121 Primary graft dysfunction usually can be managed with aggressive cardiopulmonary support in the intensive care unit. High levels of PEEP, inhaled nitric oxide, inotropic support, and vigorous diuresis are important strategies. In most patients, primary graft dysfunction resolves over several days of intensive care support, with patients obtaining satisfactory long-term allograft function.117 However, some patients with severe graft dysfunction require extracorporeal membrane oxygenation (ECMO) support or even retransplantation. In our entire experience with 983 lung transplant recipients, 47 have required ECMO for primary graft dysfunction during the immediate postoperative phase. Remarkably, ECMO was TABLE 54-4 Grading System for Primary Graft Dysfunction Grade

PaO2/FIO2

Infiltrates*

0

>300

Absent

Primary Graft Dysfunction

1

>300

Present

Most centers observe primary graft dysfunction in up to 25% of their lung transplant recipients.117 A recent review from our own institution identified primary graft dysfunction in 22.7% of adult and 22.4% of pediatric lung transplant recipients.118 Mortality from primary graft dysfunction can be as high as 30%, and in our own series it was 28.8%. The two main criteria for identification of primary graft dysfunction have been the PaO2/FIO2 ratio in the first 48 hours after transplantation and the presence of panlobar alveolar infil-

2

200-300

Present

3

<200

Present

Ch054-F06861.indd 677

677

FIO2, fraction of inspired oxygen; PaO2, arterial partial pressure of oxygen. *Radiographic infiltrates consistent with pulmonary edema. From Christie J, Carby M, Bag R, et al: Report of the ISHLT Working Group on primary lung graft dysfunction, part II: Definition. A Consensus Statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 24:1454-1459, 2005.

1/21/2008 11:49:30 AM

678

Section 3 Lung

A

B

FIGURE 54-11 Severe primary graft dysfunction. Chest radiographs of a patient before (A) and 12 hours after (B) bilateral lung transplantation for primary pulmonary hypertension.

used in 9.7% of the pediatric lung transplant recipients in our series but in only 2.8% of adult recipients. Only 38% of patients who received ECMO survived and were discharged from the hospital (Meyers et al, 2005).118 Among our 983 lung transplant recipients, retransplantation has been employed in 11 patients for primary graft dysfunction (Meyers et al, 2005).118 Force and colleagues122 recently advocated delayed chest closure as a strategy in patients who are anticipated to develop primary graft dysfunction. One important long-term complication of primary graft dysfunction is the development of chronic rejection. In our series, we found a statistically significant association between primary graft dysfunction and the development of bronchiolitis obliterans syndrome. The time interval from transplantation to the development of bronchiolitis obliterans syndrome was significantly shorter in patients with primary graft dysfunction than in recipients who did not develop this complicaton (Meyers et al, 2005).118

Infection Bacterial Bacterial pneumonia is the most commonly encountered infection after lung transplantation. Whereas all patients are given routine empiric antibacterial prophylaxis with cefepime and vancomycin for several days after transplantation, an aggressive approach is taken to identify a specific organism if a clinically apparent pneumonia is documented. Fiberoptic bronchoscopy with a protected brush is undertaken if routine sputum cultures do not provide an identifiable organism. Routine IV antibiotic therapy is used, and in most patients the pneumonia rapidly clears. Patients with cystic fibrosis present a management dilemma during the postoperative period because they are susceptible to recurrent post-trans-

Ch054-F06861.indd 678

plantation pulmonary infections from organisms harbored in the airway and the paranasal sinuses. A recent study reviewing the experience from the Toronto lung transplant program demonstrated that the 10-year survival rate of their cystic fibrosis patients who tested positive for Burkholderia cepacia before transplantation was only 15%, compared with 52% for those without B. cepacia infection.123 As a result of this observation, immunosuppressive regimens have been reduced and antimicrobial therapy has been enhanced in this patient population. A recent study outlining the potential transmission of bacterial infections from donor to recipient found the incidence of donor infection to be greater than 50%.124 These infections were secondary to donor colonization, donor bacteremia, or contamination of preservation fluid. It is therefore important to adjust the antimicrobial regimen according to donor cultures. A review from St. Louis Children’s Hospital revealed that 26% of pediatric lung transplant recipients experienced at least one episode of a bloodstream infection.125 Most of these infections occurred within the first 30 days after transplantation and may have been related to the presence of indwelling catheters in the majority of these patients. The most prevalent bacteria were Staphylococcus species and Pseudomonas aeruginosa. Lung abscess is occasionally encountered in lung transplant recipients. Patients with cystic fibrosis occasionally develop multifocal lung abscesses, presumably as a result of inhaled contamination from an upper airway or sinus infection. In single-lung recipients, the native lung is also susceptible to bacterial infection, which on occasion can cavitate, producing a lung abscess. This is treated like any other lung abscess. Appropriate broad-spectrum antibiotic therapy is administered, and bronchoscopy is performed to ensure that no airway obstruction is present. Occasionally, external drainage is required.

1/21/2008 11:49:30 AM

Chapter 54 Lung Transplantation

679

Viral CMV infection remains a significant problem in pulmonary transplant recipients. In fact, because the lung can harbor high latent CMV loads, the incidence of CMV infection is higher after lung transplantation than after transplantation of other solid organs. Importantly, in addition to its infectious effects, CMV may predispose to the development of chronic allograft rejection. Most programs have adopted the strategy of matching seronegative donors with seronegative recipients whenever possible. The highest incidence of severe CMV infection occurs with donor-negative/recipient-positive transplants. However, all donor-recipient combinations except for seronegative donor and seronegative recipient should receive antiviral prophylaxis. Prophylactic regimens differ between centers and include oral or IV ganciclovir with or without CMV IV immunoglobulin. Although there is a concern about development of resistance with prolonged administration of prophylactic agents, longer courses of prophylaxis may be more effective at preventing CMV infection. Recent studies have demonstrated the efficacy of valganciclovir as a prophylactic agent.126 Valganciclovir is an oral prodrug of ganciclovir and has a higher bioavailability. Prolonged use of valganciclovir after a short course of IV ganciclovir and IV immunoglobulin was also effective at preventing infection with CMV.127 Although CMV infection or disease is uncommon during prophylaxis, there is a high rate of CMV disease after cessation of prophylactic therapy, especially with the donor-negative/recipient-positive combination (Fig. 54-12). In such cases, the immunosuppressive regimen should be reassessed and treatment with valganciclovir or IV ganciclovir initiated, alone or in combination with CMV IV immunoglobulin. Community-acquired respiratory viral infections can also occur after lung transplantation. The most common pathogens are respiratory syncytial virus, parainfluenza virus, influenza virus, and adenovirus. These infections have been linked to later development of chronic allograft rejection.128,129 Interestingly, viral infections have been observed to occur simultaneously with episodes of acute rejection.130 Treatment includes supportive care and antiviral therapy. Antiviral therapy may play a role in reducing the incidence of obliterative bronchiolitis.129

Fungal Although it has not been our practice to use routine antifungal prophylaxis, documented fungal airway colonization or infection warrants treatment (Fig. 54-13). The most frequent cause of significant fungal infection after transplantation is Aspergillus. Aspergillus fumigatus often colonizes the airways of cystic fibrosis patients and appears to be a risk factor for the development of post-transplantation tracheobronchial aspergillosis.131 Moreover, immunosuppressed lung transplant recipients are at risk of developing invasive infections, which can be fatal. One series reported a mortality rate of 78% among lung transplant recipients who developed invasive Aspergillus infections.132 Once Aspergillus has become a resident organism, it is difficult to clear. Postoperative administration of aerosolized amphotericin B in patients who were

Ch054-F06861.indd 679

FIGURE 54-12 A, Transbronchial lung biopsy specimen showing cytomegalovirus (CMV) pneumonitis with demonstration of CMV inclusion bodies. (hematoxylin and eosin stain). B, Demonstration of CMV inclusion bodies. (FROM LAU CL, PATTERSON GA: CURRENT STATUS OF LUNG TRANSPLANTATION. EUR RESPIR J 22:57S-64S, 2003, FIGURE 4.)

colonized with Aspergillus has been reasonably successful at preventing invasive infections. Other regimens have included itraconazole or fluconazole in addition to aerosolized amphotericin B.133 The toxicity of systemic amphotericin B is too significant to justify its use as a prophylactic agent. However, in patients whose infections do not clear with ketoconazole or who have developed an invasive infection and are therefore at risk for fatal complications such as pulmonary hemorrhage, systemic amphotericin B is required. A particularly interesting group of patients are those who have had single-lung transplants for pulmonary fibrosis and who develop Aspergillus infection in the diseased native lung. These patients need to be treated aggressively with the expectation that the Aspergillus will probably not clear from the native lung. In this circumstance, contralateral native lung pneumonectomy may be warranted.

Pleural Space Complications Pleural space complications occur frequently after pulmonary transplantation. Pneumothorax is encountered in two circumstances. It can occur as a result of airway dehiscence with

1/21/2008 11:49:31 AM

680

Section 3 Lung

FIGURE 54-13 Chest CT demonstrating cavitary nodule in the left lower lobe in a lung transplant recipient. (REPUBLISHED WITH PERMISSION OF AMERICAN COLLEGE OF CHEST PHYSICIANS. FROM LEE, ET AL: PULMONARY NODULES IN LUNG TRANSPLANT. CHEST 125:165-172, 2004. WITH PERMISSION CONVEYED THROUGH COPYRIGHT CLEARANCE CENTER, INC.)

communication into the pleural space (Fig. 54-14). However, this is not a frequent occurrence, and, when present, it is usually readily managed by intercostal tube drainage with appropriate re-expansion of the underlying lung. A more common circumstance is the development of insignificant pneumothoraces in patients with obstructive pulmonary disease, either emphysema or cystic fibrosis, who have undergone bilateral replacement and received lungs much smaller than the pleural space into which they were implanted. Often a minimal degree of bilateral pneumothocaces occurs after chest tube replacement. In general, these pneumothoraces can be ignored; the pleural air eventually resorbs, and any remaining space fills with fluid. Pleural effusions are commonly encountered, particularly in the group just noted in whom the pulmonary volume is somewhat smaller than the pleural space. A sympathetic effusion may occur in association with an underlying pulmonary infection or rejection. As with other effusions, these usually clear with appropriate treatment of the underlying parenchymal condition. Empyema is infrequently encountered in lung transplant recipients. Spontaneous development of an empyema is rare. More commonly, an empyema develops after any prolonged air leak as a result of the open lung biopsy performed on a patient receiving high-dose corticosteroids. Persistent air leak, failure to achieve re-expansion of the lung, and subsequent pleurodesis result in a chronic pleural space that eventually becomes infected. A number of these patients have been treated by open drainage, by rib resection, or by formal creation of a Clagett window or Eloesser flap. Interestingly, an empyema rarely occurs as a result of bronchial dehiscence in communication with the pleural space. In most of these patients, satisfactory intercostal tube drainage with re-expansion of the underlying lung results in anastomotic healing and the absence of any significant pleural space infection.

Ch054-F06861.indd 680

FIGURE 54-14 In a patient receiving bilateral sequential lung allografts for obstructive pulmonary disease, a small right main bronchial dehiscence developed. The dehiscence can be seen on this CT, and there is a small pneumothorax. The anterior chest tube maintained satisfactory expansion of the lung until the membranous wall healed completely and the air leak ceased.

Airway Complications Airway complications were formerly a major cause of morbidity and mortality after lung transplantation. In fact, they were the main cause of death in the early era of lung transplantation. Under standard methods of implantation, the donor bronchus is rendered ischemic, without reconstitution of its systemic bronchial artery circulation. The donor bronchus thereby relies on a tenuous blood supply during the first few days after transplantation. It has been demonstrated that pulmonary collateral flow makes a substantial contribution to the viability of the distal main bronchus and lobar bronchi. Blood flows in retrograde fashion from the pulmonary capillary system into the bronchial capillary system through a submucosal plexus. A shortened donor bronchial length—two rings proximal to the upper lobe takeoff—reduces the length of donor bronchus at risk for ischemia. In addition, improved techniques of preservation have resulted in increased bronchial viability after transplantation. We pay great attention to preserve peribronchial nodal tissue on the donor bronchus during preparation of the lung. Although early enthusiasm for omentopexy or bronchial artery revascularization has been abandoned at most centers, we advocate covering the bronchial anastomosis with peribronchial tissue circumferentially. This may lead to indirect revascularization through neoangiogenesis. In addition, telescoping the bronchial anastomosis has not been shown to reduce the rate of airway complications, and we do not use the telescoping technique unless we encounter a significant luminal discrepancy between donor and recipient. Post-transplantation pulmonary parenchymal pathologic changes also result in decreased collateral flow, rendering the ischemic donor bronchus at increased risk for necrosis and subsequent dehiscence. Therefore, pulmonary allograft preservation and adequate postoperative pulmonary

1/21/2008 11:49:32 AM

Chapter 54 Lung Transplantation

blood flow are critical to minimize ischemic changes to the bronchial anastomosis in the early postoperative period. The role of perioperative steroids is important in this regard. Davreux and coworkers134 reported our work showing that epithelial regeneration and revascularization of rat heterotopic tracheal allografts are improved by postoperative corticosteroid administration. In addition, Inui and coworkers135 of the Hannover group demonstrated that postoperative corticosteroid therapy improves retrograde bronchial blood flow in porcine lung allografts. In our own experience, we did not observe a deleterious effect of perioperative corticosteroids on airway healing. Superior preservation, improved sepsis prophylaxis, and immunosuppression have reduced the incidence of airway complications. In a review of the experience at Washington University, there was an association between the rate of airway complications and the time period during which the transplantation was performed. The rate of airway complications during the initial period of the lung transplantation experience at Washington University, from 1988 through 1993, was almost 16%; this decreased to less than 10% during later time periods. Importantly, airway complications did not seem to have an adverse impact on overall survival.118 Airway complications are identified in a number of ways. Routine postoperative bronchoscopic surveillance generally provides early detection of anastomotic complications. On occasion, a CT scan performed for some other indication demonstrates an unexpected airway stenosis or dehiscence. We have learned that the CT scan is a useful diagnostic tool in the evaluation of documented or suspected donor airway complications. Late airway stenoses typically cause symptoms of dyspnea, wheezing, or a decreased FEV1, and bronchoscopic assessment confirms the diagnosis. Most airway complications are identified in the first weeks or months after transplantation. A normal bronchial anastomotic suture line demonstrates a narrow rim of epithelial sloughing, which ultimately heals. On occasion, patchy areas of superficial necrosis of the donor bronchial epithelium are observed. These are also of no concern and ultimately heal without incident. Minor degrees of bronchial dehiscence are also of little long-term consequence. Membranous wall defects usually heal without any airway compromise, whereas cartilaginous defects usually result in some degree of late stricture. Significant dehiscence (>50% of the circumference) may result in compromise of the airway. This problem should be managed expectantly by gentle mechanical débridement of the area to maintain satisfactory airway patency. Laser enthusiasts must be cautious; zealous attempts to maintain airway caliber have the potential to injure the normal distal donor airway that must be preserved for the subsequent placement of a stent. Occasionally, a significant dehiscence results in direct communication with the pleural space (see Fig. 54-14) or pericardium. However, if the lung remains completely expanded and the pleural space is evacuated, the leak ultimately seals, and the airway usually heals without stenosis. A dehiscence may communicate directly with the mediastinum, resulting in mediastinal emphysema (Fig. 54-15). If the lung remains completely expanded and the pleural space is filled, then adequate drainage of the mediastinum can be achieved by mediastinoscopy, placing a drain in

Ch054-F06861.indd 681

681

FIGURE 54-15 Chest CT scan demonstrates mediastinal emphysema secondary to airway dehiscence after lung transplantation.

close proximity to the anastomotic line. This also results in satisfactory healing of the anastomosis, often without stricture. Surgical revision of the anastomosis is possible only if an adequate length of donor airway is available for resuturing. This type of reconstruction has been successfully performed.136 However, it is rarely possible if the donor bronchus was cut to an appropriate short length at the time of the initial procedure. Massive dehiscence of the airway with uncontrolled leak or mediastinal contamination has been treated successfully by retransplantation in a number of programs. Chronic airway stenoses can present significant management problems. A right main bronchial anastomotic stricture is usually easily managed by repeated dilation and ultimate placement of an endobronchial stent (Fig. 54-16). The right main bronchus is easily dilated with a rigid bronchoscope, and there usually is room for the placement of a right main bronchial orifice stent without impingement of the right upper lobe bronchus. However, on the left side, strictures can be somewhat more difficult to manage. Dilation of the distal left main bronchus with a rigid bronchoscope is technically more difficult because of its angulation. In addition, the lobar bifurcation immediately distal to the usual site of anastomosis does not provide a suitable length of bronchus distal to the stricture for the placement of large-caliber dilating bronchoscopes. Alternatively, dilation with balloon catheters that can be advanced through flexible bronchoscopes may be used. Finally, a stent placed across a distal left main bronchial anas-

1/21/2008 11:49:32 AM

682

Section 3 Lung

A

B

FIGURE 54-16 A, Stenotic left main stem anastomosis after bilateral lung transplantation. B, Successful placement of stent in the same patient after dilation.

tomotic stricture may occlude the upper or lower lobe orifice as it bridges the stricture. We have used Silastic endobronchial stents preferentially. Straight bronchial stents have been used for main bronchial strictures. Y stents have been used for the occasional tracheal stricture seen after heart-lung transplantation or, more commonly, after en bloc double-lung transplantation with tracheal anastomosis. We previously described the technique of insertion.137 Silastic stents are tolerated exceptionally well. However, patients may require daily inhalation of N-acetyl cysteine to keep the stents patent. Stents have resulted in dramatic improvements in pulmonary function.138 Fortunately, most of these stents have been required only temporarily. After a period of several months, most patients are able to maintain satisfactory airway patency without having the stent in place. The real advantage of a Silastic stent is seen at the time of removal, for it is well tolerated without the development of granulation tissue or mucosal overgrowth seen with wire mesh stents. Finally, distal bronchial strictures on occasion can be unmanageable by dilation or stent insertion. In these patients, retransplantation is an option and has been used successfully.139 There are a few aspects with regard to airway complications that are unique in the pediatric population. Obviously, the airways are smaller and the cartilage is somewhat softer, rendering it more compliant. Overall, in our experience at Washington University, the incidence of airway complications after lung transplantation in children was similar to that in adults. At St. Louis Children’s Hospital, small size and young age did not seem to be associated with a higher rate of airway complications. There was a trend toward a higher rate of

Ch054-F06861.indd 682

airway complications among pediatric lung transplant recipients who had septic lung diseases, particularly those who carried A. fumigatus.

Malignancies Many experimental studies suggest that immunosurveillance plays an important role in the elimination of tumors, and it is well recognized that immunosuppression is associated with a higher risk of developing malignancies. Not surprisingly, longer patient survival after transplantation and the chronic use of immunosuppression have led to a higher incidence of post-transplantation malignancies. The cumulative incidence of malignancies in all recipients of solid organ transplants has been estimated to be approximately 20% at 10 years. In fact, some investigators believe that more transplant recipients will die from malignancies than from cardiovascular disease.140 Although transplant recipients are at risk for developing a wide spectrum of malignancies, nonmelanoma skin cancers and PTLDs are the most common malignancies in recipients of solid organ transplants, including lung transplants. Immunosuppressive agents may enhance the carcinogenic effects of ultraviolet radiation and viruses. In a recently published retrospective series analyzing the development of malignancies after lung transplantation, 15% of recipients were diagnosed with cancer, at a mean time interval of 4.2 years after transplantation.141 Most of these patients developed nonmelanoma skin cancers, followed by PTLDs and transitional cell carcinomas of the bladder. The term PTLD describes a wide spectrum of lymphoproliferative disorders that range from infectious mononucleosis to malignant lymphoma (Fig. 54-17). PTLD after solid organ transplantation originates from the recipient lymphoid system

1/21/2008 11:49:32 AM

Chapter 54 Lung Transplantation

683

suppression. Other therapies include anti–B cell monoclonal antibodies, chemotherapeutic agents, cytokines such as interferon-α or IL-6, and cellular immunotherapy using adoptive transfer of cytotoxic T lymphocytes, as well as surgical resection or radiation therapy.147

Acute Rejection

FIGURE 54-17 Chest CT demonstrating a single nodule in the left lower lobe in a lung transplant recipient. (REPUBLISHED WITH PERMISSION OF AMERICAN COLLEGE OF CHEST PHYSICIANS. FROM LEE, ET AL: PULMONARY NODULES IN LUNG TRANSPLANT. CHEST 125:165-172, 2004. WITH PERMISSION CONVEYED THROUGH COPYRIGHT CLEARANCE CENTER, INC.)

and is of B cell origin. It arises from uncontrolled proliferation of B lymphocytes that are infected with the Epstein-Barr virus, a member of the herpesvirus family. PTLD is more commonly observed after lung transplantation than after transplantation of other solid organs, and its incidence has been as high as 20% in some reports.142 In our own series, the incidence of PTLD was 5.9% in the adult population. Consistent with other reports, the incidence of PTLD was higher among pediatric recipients (11.6%) in our series.118 Because, unlike adults, most children are seronegative for Epstein-Barr virus, this higher incidence of PTLD in the pediatric population may be related to primary infection and seroconversion after transplantation. The Toronto Lung Transplant group reported a 6.8-fold increased risk of developing PTLD among Epstein-Barr virus–seronegative recipients and recommended prolonged antiviral prophylaxis for these patients.143 Moreover, HLA matching between donor and recipient has been suggested as a risk factor for the development of PTLD among Epstein-Barr–seronegative recipients of lungs from seropositive donors.144 This may be related to decreased alloreactivity against Epstein-Barr–infected donorderived B lymphocytes in this patient cohort. It is generally accepted that the risk of developing PTLD is related to the overall immunosuppressive burden. To this end, some studies have suggested that high doses of cyclosporine, the use of tacrolimus, and the use of monoclonal antibodies increase the risk for developing PTLD.145 An interesting observation from our institution was an apparent temporal relation between the time of onset of PTLD and the organ involvement.146 Whereas cases that were diagnosed more than 12 months after lung transplantation involved extrathoracic sites, PTLD discovered within the first year after transplantation had a predilection for the thorax, such as the allograft or mediastinal lymph nodes. Cases that were diagnosed within the first year carried a better prognosis. The first-line treatment for PTLD is reduction in immuno-

Ch054-F06861.indd 683

Insofar as immunologic matching is crude (ABO blood group only) and immunosuppression strategies are imperfect, it is not surprising that rejection is a troublesome problem after lung transplantation. Acute rejection is encountered during the early postoperative period in almost all patients.31 This rarely presents a significant clinical problem in the acute setting. However, it is generally accepted that episodes of acute rejection increase the risk of later development of chronic allograft rejection. Acute rejection has a typical clinical presentation of dyspnea, low-grade fever, perihilar interstitial infiltrate, hypoxia, and increased white blood cell count. Typically, the first episode occurs within the first 5 to 7 postoperative days. Several episodes during the first 2 months are not unusual. In the early years of lung transplantation, the diagnosis was confirmed by an abrupt favorable response to a bolus dose of methylprednisolone (500-1000 mg). At present, the clinical parameters noted earlier are the most commonly used indicators of rejection. Intensive laboratory investigation continues in a number of centers to find noninvasive techniques to diagnose rejection. Nuclear scanning may play a role in differentiating infection from rejection. Although infections are associated with high signals on positron emission tomography, this is not the case for rejection.148 Radionuclide imaging with technetium 99m–labeled annexin V has been described as an imaging modality to diagnose acute lung allograft rejection in rats.149 However, it does not play a role in clinical lung transplantation. Various immunologic tests have also been advocated. We have demonstrated increased cytotoxicity of BAL lymphocytes in patients with biopsy-proven rejection, and there is mounting evidence that cytokines are important mediators in the development of rejection. To this end, our group has demonstrated elevated levels of IL-15 as well as granzyme B in the BAL fluid of lung transplant recipients who were undergoing acute rejection.150 The technique of choice in the diagnosis of rejection is transbronchial biopsy performed under fluoroscopic control. The Papworth group151 deserves credit for demonstrating the safety and value of this technique in the lung transplantation population. The typical histologic appearance is that of perivascular lymphocytic infiltrate (Fig. 54-18). The internationally accepted classification for pulmonary rejection was reported by Yousem and associates152 (Table 54-5). The factors that predispose patients to an increased incidence of rejection are unclear. There is experimental evidence that poorly preserved allografts are more likely to suffer subsequent rejection. There is some evidence that expression of major histocompatibility complex class II antigens on bronchial epithelium and pulmonary capillary endothelium is increased after extended periods of preservation. In addition, we have demonstrated increased expression of

1/21/2008 11:49:34 AM

684

Section 3 Lung

TABLE 54-5 Working Formula for Classification and Grading of Pulmonary Rejection A. Acute rejection 0. Grade 0—no significant abnormality 1. Grade 1—minimal acute rejection* 2. Grade 2—mild acute rejection* 3. Grade 3—moderate acute rejection* 4. Grade 4—severe acute rejection* B. Active airway damage without scarring 1. Lymphocytic bronchitis 2. Lymphocytic bronchiolitis

A

C. Chronic airway rejection 1. Bronchiolitis obliterans, subtotal a. Active b. Inactive 2. Bronchiolitis obliterans, total a. Active b. Inactive D. Chronic vascular rejection E. Vasculitis *Grades 1 to 4 are subdivided according to bronchial inflammation, as follows: a, With evidence of bronchiolar inflammation; b, Without evidence of bronchiolar inflammation; c, With large airway inflammation; d, No bronchioles are present. From Yousem SA, Berry GJ, Cagle PT, et al: Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 15:1-15, 1996.

tacrolimus or cytolytic therapy with antithymocyte gammaglobulin (ATGAM) or OKT3.

B FIGURE 54-18 A, Photomicrograph of a transbronchial biopsy specimen showing perivascular cuffs of lymphocytes consistent with acute rejection (type A1b on Table 54-5). B, A more severe degree of rejection is evident in this photomicrograph of a transbronchial biopsy specimen. There are perivascular and interstitial lymphoid infiltrates, which is consistent with grade 3 rejection (type A3a on Table 54-5).

the intercellular adhesion molecule (ICAM) after extended preservation of human lung allografts.153 Infection may also predispose to subsequent rejection. A number of groups have reported serious rejection episodes following close on the heels of established bacterial or viral infection. Activation of pattern recognition receptors on both hematopoietic and nonhematopoietic cells of the lung allograft that are constantly exposed to the environment represents a link between innate and adaptive immune responses and may explain why ischemia or infection might be associated with higher rates of allograft rejection.153a Acute rejection can be effectively controlled in most patients regardless of its cause. The majority of patients respond promptly to the first course of methylprednisolone. Occasionally, a second course of steroid may be necessary to bring a serious rejection episode under control. Persistent rejection despite this intervention is distinctly unusual. In this circumstance, consider substituting cyclosporine with

Ch054-F06861.indd 684

Chronic Rejection—Bronchiolitis Obliterans Syndrome Chronic allograft rejection occurs more frequently in lung transplant recipients than in recipients of other solid organs and remains the Achilles heel of clinical lung transplantation. The 20th report by the ISHLT Registry noted survival rates of only 45% at 5 years and 23% at 10 years after lung transplantation. It is generally thought that injury to epithelial cells and subepithelial structures, with subsequent aberrant tissue repair, ultimately leads to excessive fibroproliferation. The histologic hallmark of chronic lung allograft rejection is partial or complete occlusion of the lumina of terminal and respiratory bronchioles by inflammatory and fibrous tissue (Fig. 54-19). This process is referred to as obliterative bronchiolitis, and it affects more than 50% of lung transplant recipients who survive for longer than 5 years after transplantation. The clinical correlate of obliterative bronchiolitis is bronchiolitis obliterans syndrome. Bronchiolitis obliterans syndrome is a heterogeneous condition that is marked by progressively worsening airflow obstruction with a decline in FEV1. A classification system for bronchiolitis obliterans syndrome was originally formulated in 1993, and mild bronchiolitis obliterans syndrome was defined as a decline in FEV1 of more than 20% from the post-transplantation baseline. This system was not found to be sensitive enough to identify early stages of bronchiolitis obliterans syndrome, and the classification was

1/21/2008 11:49:35 AM

Chapter 54 Lung Transplantation

FIGUR 54-19 Transbronchial biopsy specimen demonstrating cellular fibroproliferative tissue narrowing the lumen of a bronchiole, consistent with obliterative bronchiolitis. (FROM LAU CL, PATTERSON GA: CURRENT STATUS OF LUNG TRANSPLANTATION. EUR RESPIR J 22:57S-64S, 2003, FIGURE 5.)

TABLE 54-6 Bronchiolitis Obliterans Syndrome Classification System Classification

FEV1

FEF25%-75%

BOS 0

>90% of baseline

>75% of baseline

Potential BOS (BOS-0-p)

81-90% of baseline

<75% of baseline

BOS 1 (mild BOS)

66-80% of baseline

BOS 2 (moderate BOS)

51-65% of baseline

BOS 3 (severe BOS)

<50% of baseline

BOS, bronchiolitis obliterans syndrome; FEF25%-75%, midexpiratory forced expiratory flow; FEV1, forced expiratory volume in 1 second. From Estenne M, Maurer JR, Boehler A, et al: Bronchiolitis obliterans syndrome 2001: An update of the diagnostic criteria. J Heart Lung Transplant 21:297-310, 2002

revised in 2001.153b Midexpiratory rates of forced expiratory flow (FEF25%-75%), which were found to be more sensitive than FEV1 in the detection of early stages of bronchiolitis obliterans syndrome, were included in this revised system. Moreover, a new category, potential bronchiolitis obliterans syndrome, was added to the classification system in an attempt to identify these patients at earlier stages (Table 54-6). Three patterns of clinical presentation have been described154: 1. Sudden onset of symptoms with rapid deterioration in lung function 2. Rapid initial decline in pulmonary function with subsequent stabilization 3. Insidious onset with slow decline in lung function The median time between transplantation and onset of bronchiolitis obliterans syndrome can range from a few months to several years; in our own experience, it was 4.5 years.118 Risk factors for the development of obliterative bronchiolitis after lung transplantation can be categorized into alloimmune-dependent and alloimmune-independent factors. It

Ch054-F06861.indd 685

685

seems intuitive that early episodes of acute rejection increase the likelihood of subsequent chronic rejection. Most studies have found a correlation between early acute rejection and later development of obliterative bronchiolitis.154a The Pittsburgh group showed a clear relationship between the frequency and severity of biopsy-proven acute rejection and the subsequent development of chronic rejection. Recently, a retrospective study from our own institution extended these observations and reported that even minimal acute rejection (type A1) was associated with an increased risk for development of bronchiolitis obliterans syndrome.129 Several groups have also found that lymphocytic bronchitis is associated with a higher risk of developing bronchiolitis obliterans syndrome.155 Although there are some indications that patients with bronchiolitis obliterans syndrome have antibodies against human leukocyte antigens (HLA), there is no clear evidence that HLA mismatching is a risk factor for this syndrome. Importantly, however, some patients who develop bronchiolitis obliterans syndrome do not have any reported episodes of acute rejection, supporting the role of alloimmune-independent risk factors. Most alloimmune-independent risk factors are inflammatory stimuli that could alter the milieu in the lung allograft to increase antigenicity and thereby indirectly influence the alloimmune response. The impact of CMV infection on the development of bronchiolitis obliterans syndrome remains controversial. One complicating factor in the interpretation of several studies examining this issue is that not infrequently CMV pneumonia follows episodes of acute rejection, possibly as a consequence of increased immunosuppression. Whereas earlier studies suggested a role for CMV infection, a recent study failed to show an association between CMV serologic matching or CMV pneumonia that was treated with ganciclovir and the development of bronchiolitis obliterans syndrome.156,157 A recent retrospective study from our own institution described an association between communityacquired respiratory viral infections such as respiratory syncytial virus and parainfluenza virus and the later development of bronchiolitis obliterans syndrome, corroborating findings of previous studies.129,128 Studies from Duke University have focused on the role of gastroesophageal reflux disease in the development of bronchiolitis obliterans syndrome. Lung transplant recipients experience esophageal dysmotility, possibly as a result of vagal injury, and therefore have a relatively high incidence of gastroesophageal reflux. It has been postulated that chronic aspiration of gastric contents damages the epithelial layer of the lung allograft and ultimately contributes to chronic allograft dysfunction. This same group recently showed that a fundoplication performed early after lung transplantation may reduce the incidence of bronchiolitis obliterans syndrome.158 The Duke University lung transplantation group has also reported a lower incidence of bronchiolitis obliterans syndrome in a population of patients who received bilateral lung transplants rather than single-lung transplants.159 These observations have been confirmed in rodent models of single-lung transplantation. Other alloimmune-independent risk factors that have been proposed include the severity of ischemia-reperfusion injury, donor age, medication noncompliance, and cause of donor death.

1/21/2008 11:49:36 AM

686

Section 3 Lung

Early detection of bronchiolitis obliterans syndrome may allow for timely therapeutic intervention before irreversible airway fibrosis occurs. Several noninvasive and invasive modalities have been reported to diagnose bronchiolitis obliterans syndrome or obliterative bronchiolitis. Spirometry, which is the basis for the bronchiolitis obliterans syndrome classification system, probably is the most important and widely used modality. Earlier detection of airflow obstruction has been reported with home spirometry, which could be an attractive surveillance method for patients who do not have easy access to health care facilities.160 Bronchial hyperresponsiveness to methacholine in the early post-transplantation period has yielded conflicting results as a predictor for the development of bronchiolitis obliterans syndrome.161,162 Multiple investigations have focused on the analysis of BAL fluid. Markers that have been suggested to be associated with the development of bronchiolitis obliterans syndrome include increased neutrophil numbers and their activation. Moreover, increased levels of the potent neutrophil chemokine IL-8, which is produced by both hematopoietic cells such as macrophages and non-hematopoietic cells such as vascular endothelial cells and airway epithelial cells, have been reported in the BAL fluid of lung transplant recipients with bronchiolitis obliterans syndrome; not surprisingly, the level of IL-8 seems to correlate with the number of neutrophils. A potentially confounding factor is that neutrophilia in BAL fluid can also be observed in lung transplant recipients who have pulmonary infection but no evidence of obliterative bronchiolitis. Other markers that have been examined in BAL fluid include CD8+ T lymphocytes, a variety of cytokines, and, more recently, matrix metalloproteinases.163 Some studies have suggested that the exhaled nitric oxide fraction may be an early predictor for development of bronchiolitis obliterans syndrome. However, the interpretation of exhaled nitric oxide levels may be confounded by its reported elevation in pulmonary infection.164,165 Chest radiographs may be normal despite advanced chronic rejection. Air trapping is the most frequent abnormality on high-resolution computed tomography (CT) and has been discussed as an early diagnostic marker. To date, however, there is no evidence that any of these biochemical or radiologic markers has better predictive value than the classification of bronchiolitis obliterans syndrome based on pulmonary function tests. There is ongoing research analyzing gene expression profiles and protein biomarkers in BAL fluid of lung transplant recipients that could help predict the development of bronchiolitis obliterans syndrome.166 More invasive means to make a diagnosis of obliterative bronchiolitis are transbronchial biopsy, video-assisted thoracoscopic biopsy, and open lung biopsy. Our own institution has recently reported the usefulness of open lung biopsies in the diagnosis of obliterative bronchiolitis in a pediatric lung transplant population.167 Although acute rejection is commonly manageable, therapeutic options for established bronchiolitis obliterans are limited, and this condition is generally not reversible. Standard therapy consists of augmentation of immunosuppression and attempts to stabilize the disease process. Regimens such as high-dose corticosteroids, cytolytic therapy, substitution of

Ch054-F06861.indd 686

mycophenolate mofetil for azathioprine, and conversion of cyclosporine to tacrolimus have on occasion been successful at preserving pulmonary function at a stable, albeit diminished, level.168,169 Other medical strategies have included inhaled cyclosporine, inhaled high-dose corticosteroids, and photopheresis.170 Agents such as rapamycin that have antiproliferative effects may hold promise for the treatment of obliterative bronchiolitis.171 Unfortunately, most patients either develop progressive obliterative bronchiolitis or contract some lethal opportunistic infection as a result of the augmented immunosuppression. Retransplantation has been offered to a large number of patients with bronchiolitis obliterans syndrome.98,100 In a large proportion of such patients, the process reappears within a short period after retransplantation. In light of the paucity of available donor organs, this raises the question whether retransplantation should be offered at all to patients who suffer from obliterative bronchiolitis.103 Nonetheless, a small number of patients have survived and obtained excellent long-term results after retransplantation for this devastating condition.

RESULTS Operative Mortality When the most recent era of lung transplantation is compared with previous eras, the biggest improvement in survival has been achieved within the first 3 months after transplantation. This dramatic reduction in early mortality is clearly the result of improvements in selection, operative technique, and management in the immediate postoperative period. We recently reported a hospital mortality rate of 9.8% in our cumulative experience with 983 lung transplantations at Washington University and Children’s Hospital in St. Louis.118 The mortality rate was only 7% for adults and 17% for children. This group of pediatric patients represents a particular challenge, especially those with Eisenmenger’s syndrome, in whom technically difficult operative procedures can now be undertaken successfully. The mortality rate after lung transplantation is highest during the first year. The current data from the ISHLT Registry shows survival rates of 86% at 3 months and 76% at 12 months.27 The two main causes of death within the first 12 months after transplantation are non-CMV infections and graft failure. The underlying disease appears to play a role in the early mortality rate (Fig. 54-20). The current ISHLT data show that lung transplantation for PPH or pulmonary fibrosis is associated with higher mortality rate at 12 months than transplantation for cystic fibrosis or emphysema. In previous eras, bilateral lung transplantation was associated with a higher early postoperative mortality rate than was single-lung transplantation. This probably was a reflection of the greater technical difficulty and increased risk of septic complications in the cystic fibrosis patients who traditionally made up a large fraction of bilateral transplant recipients. The Toronto group172 reported a high incidence of postoperative death caused by sepsis. This was particularly frequent among those recipients harboring highly resistant B. cepacia organisms. Currently, the ISHLT Registry data show that both procedures carry similar 1-year mortality rates, which is a

1/21/2008 11:49:36 AM

Chapter 54 Lung Transplantation

687

100 Alpha-1 (N
1,127)

CF (N
1,934)

IPF (N
2,058)

PPH (N
533)

COPD (N
4,888)

Survival (%)

75

50

Survival comparisons COPD vs. IPF: P  .0001 Alpha-1 vs. CF: P
.0248 Alpha-1 vs. IPF: P  .0001 Alpha-1 vs. PPH: P
.0021 CF vs. COPD: P
.0006 CF vs. IPF: P  .0001 CF vs. PPH: P  .0001

25

HALF-LIFE Alpha-1: 5.1 years; CF: 5.8 years; COPD: 4.8 years; IPF: 3.7 years; PPH: 4.3 years

0 0

1

2

3

4

5 Years

6

7

8

9

10

FIGURE 54-20 Kaplan-Meier survival by diagnosis for adult lung transplantations performed between January 1994 and June 2003. Alpha-1, α1-antitrypsin deficiency emphysema; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; PPH, primary pulmonary hypertension. (FROM TRULOCK EP, EDWARDS LB, TAYLOR DO, ET AL: REGISTRY OF THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION: TWENTY-SECOND OFFICIAL ADULT LUNG AND HEART-LUNG TRANSPLANT REPORT—2005. J HEART LUNG TRANSPLANT 24:956967, 2005.)

reflection of improvements in technique and more widespread use of bilateral transplantation in patients with emphysema.

Late Mortality It is only during the past 15 years that large numbers of patients have undergone pulmonary transplantation. Data from the recent report of the ISHLT Registry show survival rates of 60% at 3 years, 49% at 5 years, and 24% at 10 years.27 The main cause of death after 12 months remains bronchiolitis obliterans. Non-CMV infectious complications also account for a large number of late deaths. Bilateral lung transplantation appears to offer a survival advantage for patients with COPD or α1-antitrypsin deficiency–related emphysema at late time points, when compared with singlelung transplantation. However, bilateral lung transplantation does not have an impact on survival in patients with PPH or idiopathic pulmonary fibrosis.

Functional Results With improvement in surgical technique and postoperative management, results after lung transplantation at most high volume centers have been excellent. The usual patient can return to normal levels of exercise tolerance without oxygen supplementation within 6 to 8 weeks after transplantation.

Obstructive Pulmonary Disease Obstructive pulmonary diseases, such as COPD and α1antitrypsin deficiency, were the most common indications for lung transplantation in the previous system of organ allocation and represent the largest disease-specific experience with human lung transplantation.27 We have recently reviewed and published long-term results of more than 300 patients with emphysema transplanted at Washington University in St. Louis from the years 1988 to 2000.173 The overall hospi-

Ch054-F06861.indd 687

TABLE 54-7 Functional Results After Lung Transplantation for Obstructive Pulmonary Disease (Mean ± Standard Deviation) Parameter

COPD

FVC (% of predicted) Evaluation 6 mo 1 yr 5 yr

51 85 84 72

± ± ± ±

1 2 2 3

54 81 89 80

± ± ± ±

2 2 3 3

FEV1 (% predicted) Evaluation 6 mo 1 yr 5 yr

16 84 79 62

± ± ± ±

1 2 2 3

17 83 88 73

± ± ± ±

1 3 3 3

738 1038 1579 1182

± ± ± ±

19 21 23 43

813 1127 1704 1340

± ± ± ±

35 38 39 54

49 38 38 36

± ± ± ±

1 1 1 1

44 38 37 36

± ± ± ±

1 1 1 1

6-minute walk (feet) Evaluation 6 mo 1 yr 5 yr PaCO2 (mm Hg) Evaluation 6 mo 1 yr 5 yr

AAD

AAD, a1-antitrypsin deficiency; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PaCO2, arterial carbon dioxide tension. From Cassivi SD, et al: Thirteen-year experience in lung transplantation for emphysema. Ann Thorac Surg 74:1663-1669; discussion 1669-1670, 2002.

tal mortality rate during this 13-year period was 6.2%; during the period 1995 to 2000, it decreased to 3.9%. All patients showed a significant improvement in post-transplantation functional outcomes measured by parameters such as FVC, FEV1, and a 6-minute walk test (Table 54-7).

1/21/2008 11:49:36 AM

688

Section 3 Lung

100

100

P
.001

P
.06 80 Survival (%)

Survival (%)

80 60 40 Bilateral (n
220) 20

Single (n
86) 0

1

2

60 40 1988–1994 (n
124) 20

3

4

5

1995–2000 (n
182) 0

Years

1

2

3

4

5

Years

78.3% 71.7% 66.7% 81.8% Bilateral 86.4% (n
170) (n
136) (n
108) (n
75) (n
65)

1988–1994

83.7% 81.3% 75.6% 62.6% 53.7% (n
104) (n
101) (n
94) (n
78) (n
67)

44.9% 70.7% 56.6% (n
55) (n
38) (n
26)

1995–2000

88.6% 81.2% 75.6% 72.9% (n
140) (n
101) (n
72) (n
47)

Single

87.0% (n
74)

79.6% (n
60)

FIGURE 54-21 Actuarial survival of lung transplantation for emphysema by type of procedure (single versus bilateral lung transplantation). (FROM CASSIVI SD, ET AL: THIRTEEN-YEAR EXPERIENCE IN LUNG TRANSPLANTATION FOR EMPHYSEMA. ANN THORAC SURG 74:1663-1669; DISCUSSION 1669-1670, 2002, FIGURE 3.)

Overall 5-year survival was 58.6% ± 3.5%, with emphysema patients receiving bilateral lung transplants having a significantly better 5-year survival then single-lung transplant recipients (Fig. 54-21). Actuarial survival also improved in the latter period of 1995 to 2000 compared with 1988 to 1994. Cox multivariate proportional hazards regression analysis determined that only single-lung transplantation and use of CPB correlated with poor long-term survival; other complicating factors, such as use of a marginal donor, primary graft dysfunction, total ischemic time, and episodes of acute rejection, were not associated with higher mortality (Fig. 54-22).

Pulmonary Vascular Disease End-stage pulmonary vascular disease may occur as a result of disorders of ventilation, parenchymal lung disease, congenital heart disease, chronic pulmonary embolism, or idiopathic pulmonary hypertension. PPH was the fifth most common diagnosis leading to lung transplantation in the adult population and the second most common diagnosis in children.27,88 From 1989 to 2001, our program performed 100 transplantations for either PPH or secondary pulmonary hypertension, with 55 adult and 45 pediatric recipients of 51 bilateral-lung, 39 single-lung, and 10 combined heartlung transplants. The overall hospital mortality rate in this complicated group of patients was 17%, with a rate of 10.4% among those transplanted for PPH and 23.1% among those transplanted for secondary pulmonary hypertension. Inhospital morbidity was also significantly higher, compared with patients transplanted for emphysema: almost 25% of patients required reoperation for bleeding, 24% required reintubation, 17% required tracheostomy for prolonged ventilator support, and 16% required ECMO support. Among the surviving patients, there was a significant and sustained

70.4% (n
30)

FIGURE 54-22 Actuarial survival of lung transplantation for emphysema by era (1988-1994, 1995-2000). (FROM CASSIVI SD, ET AL: THIRTEEN-YEAR EXPERIENCE IN LUNG TRANSPLANTATION FOR EMPHYSEMA. ANN THORAC SURG 74:1663-1669; DISCUSSION 1669-1670, 2002, FIGURE 4.)

improvement in right ventricular function as well as pulmonary artery pressure and resistance. Such improvement was seen in recipients of both single-lung and double-lung transplants (Fig. 54-23). Our program has been particularly interested in single-lung transplantation for patients with PPH and Eisenmenger’s syndrome.174 It is well documented that the cardiac function of these patients recovers promptly with the reduction in right heart afterload provided by a satisfactory lung allograft. However, the early postoperative course of these patients is complicated because of the impressive ventilation-perfusion mismatch that can occur because 90% to 95% of the right heart output is directed to the transplanted lung, and more than 50% of the ventilation is directed to the native lung. The unique nature of these patients is reflected in the fact that most of the patients requiring ECMO support after transplantation in our program have been pulmonary hypertension patients. We have evolved a rigorous protocol for the early postoperative management of these patients, and the results have been gratifying. Notwithstanding our results, other groups have had significant difficulty with the application of single-lung transplantation in these patients. Bilateral-lung replacement has been advocated by a number of other programs,15 although later reports from the same institutions have acknowledged equivalent long-term results with single-lung transplantation.34 The standard operation previously offered these patients, combined heart-lung transplantation, is still practiced in our institution and others but is often hampered by organ shortage.

Cystic Fibrosis and Immunodeficiency Disorders A number of centers have reported satisfactory results with the application of bilateral lung transplantations in these

tahir99-VRG vip.persianss.ir

Ch054-F06861.indd 688

1/21/2008 11:49:36 AM

Chapter 54 Lung Transplantation

80

1

n
25 (61%)

0.8

n
71 (84%)

Survival

PAM (mm Hg)

60

40

20

0.6

n
48 (79%)

0.4

0 1 Year 2 Years 3 Years Years After Transplantation

0 Evaluation (n
100)

24 Hours (n
98)

1 Year (n
69)

FIGURE 54-23 A, Preoperative and postoperative mean pulmonary artery pressures (PAMs) for single-lung transplant (SLT) and bilateral lung transplant (BLT). (FROM MENDELOFF EN, ET AL: LUNG TRANSPLANTATION FOR PULMONARY VASCULAR DISEASE. ANN THORAC SURG 73:209-217; DISCUSSION 217-219, 2002, FIGURE 1.)

patients. Ramirez and colleagues,172 from Toronto, reported excellent gas exchange, pulmonary function, and exercise capabilities among operative survivors. Our Washington University experience is similar, with overall survival comparable to that of patients with other indications for lung transplantation (Fig. 54-24).

Restrictive Pulmonary Disease Since the institution of the revised lung allocation system, fibrotic diseases such as idiopathic pulmonary fibrosis have been the reason for lung transplantation in more than one third of all patients transplanted at Washington University in St. Louis. The long-term functional result in this group of patients is excellent, and their long-term survival is similar to that of patients with other diagnoses (Fig. 54-25). Our institution has had a significant interest in single-lung transplantation for pulmonary fibrosis because the restrictive pulmonary

4 Years

FIGURE 54-24 Four-year survival of adults and children undergoing lung transplantation for cystic fibrosis. (FROM MENDELOFF EN, HUDDLESTON CB, MALLORY GB, ET AL: PEDIATRIC AND ADULT LUNG TRANSPLANTATION FOR CYSTIC FIBROSIS. J THORAC CARDIOVASC SURG 115:404-414, 1998, FIGURE 3A.)

function and moderately elevated vascular resistance can theoretically lead to selective ventilation and perfusion of the transplanted lung. Our recent review of our own experience showed that single-lung transplantation provides satisfactory pulmonary volumes for these patients, with adequate gas exchange and exercise tolerance. Although single-lung recipients with pulmonary fibrosis had a slightly lower FEV1 compared to bilateral transplant recipients (Fig. 54-26), no functional differences were evident, and no statistically significant difference in survival was detected at 5 years (Fig. 54-27).

COMMENTS AND CONTROVERSIES Lung transplantation has evolved into an effective therapeutic option for a large number of patients with end-stage pulmonary disease. The successful lung transplantation programs are those with a dedicated multidisciplinary approach to the investigation and man-

100

FIGURE 54-25 Graph showing survival of lung transplant recipients after 443 operations at Washington University in St. Louis from 1988 to November 1998. Survival was stratified according to the underlying diagnosis that led to transplantation. (FROM

80

Survival (%)

n
19 (53%)

0.2

SLT BLT

MEYERS BF, ET AL: LUNG TRANSPLANTATION A DECADE OF EXPERIENCE. ANN SURG 230:362, 1999.)

60

40

689

Emphysema Cystic fibrosis

20

Pulmonary fibrosis Pulmonary hypertension Other

0 1

2

3

4

5

Years

tahir99-VRG vip.persianss.ir

Ch054-F06861.indd 689

1/21/2008 11:49:37 AM

Section 3 Lung

FIGURE 54-26 Forced expiratory volume in 1 second (FEV1) in all patients undergoing lung transplantation for pulmonary fibrosis. The orange line describes bilateral transplant recipients, and the blue line describes singlelung transplant recipients. Error bars represent the standard error of the mean (SEM). The number of patients evaluated at each time interval is listed next to each curve. (FROM MEYERS BF, ET AL: SINGLE VERSUS BILATERAL LUNG TRANSPLANTATION FOR IDIOPATHIC PULMONARY FIBROSIS: A TEN-YEAR INSTITUTIONAL EXPERIENCE. J THORAC CARDIOVASC SURG 120:99-107, 2000, FIGURE 1.)

3.5 N
5

3 N
12

2.5 Liters

690

2

N
3

N
13 N
27

1.5 1

N
10

N
8

N
25

N
22

N
19 N
15

N
32

Bilateral 0.5

Single

0 Eval

100 80

N
26

60

N
10

N
26 N
20 N
7

40

N
16

N
16

N
5

N
5

N
7

Type of Transplant

3 Months

6 Months

1 Year

2 Years

3 Years

elucidating mechanisms that can initiate alloimmune responses in this allograft that is constantly exposed to the environment. A better understanding of the immune responses to the lung allograft is necessary before the induction of specific tolerance, the so-called holy grail of transplantation, can be achieved. G. A. P.

KEY REFERENCES

Bilateral

20

Single 0 0

1

2

3

4

5

Years FIGURE 54-27 Kaplan-Meier survival estimates for 45 patients undergoing transplantation for interstitial pulmonary fibrosis from 1988 to 1998. Error bars at each event represent 70% confidence intervals. Survival estimates for single-lung transplantation (n = 32) and bilateral lung transplantation (n = 13) were not statistically different when tested by the Mantel-Haenszel log-rank test (P = .42). (FROM MEYERS BF, ET AL: SINGLE VERSUS BILATERAL LUNG TRANSPLANTATION FOR IDIOPATHIC PULMONARY FIBROSIS: A TEN-YEAR INSTITUTIONAL EXPERIENCE. J THORAC CARDIOVASC SURG 120:99-107, 2000, FIGURE 3.)

agement of patients with pulmonary diseases. Significant advances have been achieved. Marginal lungs are used in selected patients with good results. Non–heart-beating donors have been successfully used and offer the promise of significantly increasing the donor supply. Successful multi-institution studies have been completed to investigate various questions of lung preservation and immunosuppression. Others are currently underway. In addition, new information is available regarding the molecular mechanisms of reperfusion injury and acute rejection. Indeed, a multicenter trial is ongoing to determine whether a noninvasive gene array analysis can predict graft rejection and differentiate it from infection. Among the number of major problems that await solution, chronic allograft rejection is the most formidable. The development of animal models appears to be critical to elucidate the pathogenesis of this condition, which remains the Achilles heel of lung transplantation. Investigations into activation of innate immune responses may hold great promise for

Meyers BF, de la Morena M, Sweet SC, et al: Primary graft dysfunction and other selected complications of lung transplantation: A singlecenter experience of 983 patients. J Thorac Cardiovasc Surg 129:1421, 2005. ■ This retrospective account reviews postoperative complications after 983 adult and pediatric lung transplantations that were performed at Washington University between 1988 to 2003. Freedom from bronchiolitis obliterans syndrome at 5 and 10 years was 45% and 18% for adults and 48% and 30% for children, respectively, clearly demonstrating that this represents the main limitation to long-term success of clinical lung transplantation. This compilation of results from one of the busiest lung transplant centers in the world provides a benchmark for clinical lung transplantation. Pasque MK, Cooper JD, Kaiser LR, et al: Improved technique for bilateral lung transplantation: Rationale and initial clinical experience. Ann Thorac Surg 49:785, 1990. ■ This paper by the Washington University group represents the initial description of the bilateral sequential single-lung transplantation technique. The previously employed en bloc double-lung procedure was a tedious operation requiring CPB and cardioplegic arrest. The simpler bilateral sequential single-lung technique has become the procedure of choice, employed worldwide for bilateral lung replacement. Toronto Lung Transplant Group: Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 314:1140, 1986. ■ This report describes the first successful lung transplantation, which was performed by Joel Cooper and colleagues at Toronto on November 7, 1983, in a 58-year-old man with idiopathic pulmonary fibrosis. Trulock EP, Edwards LB, Taylor DO, et al: Registry of the International Society for Heart and Lung Transplantation: Twenty-second official adult lung and heart-lung transplant report—2005. J Heart Lung Transplant 24:956, 2005. ■ This is the most recent report from the ISHLT Registry outlining indications, survival, immunosuppressive regimens, complications, and causes of death. Bronchiolitis obliterans remains the main source for long-term morbidity and mortality.

tahir99-VRG vip.persianss.ir

Ch054-F06861.indd 690

1/21/2008 11:49:37 AM

Benign Tumors chapter

55

BENIGN LUNG TUMORS Joseph B. Shrager Larry R. Kaiser

Key Points ■ A number of tumor types straddle the line between benign and

malignant, or, although generally benign, they may rarely behave in a malignant fashion. ■ Only specific patterns of calcification or presence of fat density on CT are reliable radiographic indicators of benignity; PET scan provides further diagnostic assistance. ■ Parenchymal lesions that remain indeterminate after radiography require careful short-term follow-up or tissue diagnosis generally obtained by needle biopsy or thoracoscopic excision. ■ Benign endobronchial lesions can be resected bronchoscopically, but such resections are often incomplete; therefore, the patients need to be followed closely, and parenchyma-sparing sleeve resections need to be considered for recurrence.

Most benign tumors of the lung are rare neoplasms. Although many of these lesions manifest as solitary pulmonary nodules, and occasionally as multiple nodules, slightly less than 15% of such nodules are benign (Oldham, 1980).1 The classification of benign tumors (Box 55-1) remains somewhat controversial because of disagreement regarding the origin and prognosis of some of the more common lesions. A modification of the classification proposed originally by Liebow (Liebow, 1952)2 seems to be the simplest and most elegant scheme and serves our purposes well. The Liebow classification organizes lesions according to their presumed origin, whether epithelial or mesodermal. A number of the lesions, however, must be classified as unknown in origin and some as inflammatory. Electron microscopy provides more accurate detail than does light microscopy with regard to ultrastructure. The availability of this technique led to a revision in the classification of several lesions that were previously thought to be benign. Intravascular bronchoalveolar tumor, also known as sclerosing hemangioendothelioma, and pulmonary blastoma were both considered to be benign but now are known to behave in a malignant fashion. Hemangiopericytoma is a tumor that straddles the line between benign and malignant. The names themselves imply the benign nature originally attributed to these tumors. The current understanding of the lesion formerly known as pseudolymphoma, which appears to represent a true lowgrade lymphoma, and of atypical adenomatous hyperplasia, which appears likely to represent a premalignant lesion, is slightly more complex and is discussed later.

This chapter discusses the presentation, diagnosis, pathology, and management of the benign neoplasms encountered in the lung and focuses in particular on the influence that thoracoscopic excision plays, now that it is firmly established in the armamentarium of the general thoracic surgeon.

HISTORICAL NOTE The history of the surgical treatment of pulmonary neoplasms encompasses less than 60 years. The greatest attention has been paid to malignant neoplasms, which account for the overwhelming majority of lesions. In a landmark report published in 1963, Steele,3 writing on behalf of the Veterans Administration Armed Forces Cooperative Study of Resected Asymptomatic Solitary Pulmonary Nodules, presented the data obtained from 887 resected lesions collected beginning in 1959. In this series, there was a 12.5% incidence of benign tumors. Most patients in this study (61%) were older than 50 years of age, and all were male. Certainly, the incidence of benign lesions among resected nodules varies depending on the histories of those in the study group—in particular, whether they are smokers—and the stringency of the selection criteria for operation. Steele3 concluded that the data confirmed the then generally accepted fact that most solitary pulmonary nodules must be resected if cancer is to be ruled out. Radiographic evidence of dense or concentric calcification was thought to be the only finding that eliminated the possibility of malignancy. Little has changed in the intervening years, despite the advent of computed tomography (CT) scanning and fiberoptic bronchoscopy and the refinement of needle biopsy (both percutaneous and transbronchial). The principle remains intact that unless a new nodule can be proven to be benign, it should be removed, and we remain unable in many cases to prove a nodule benign without resecting it. The development of videothoracoscopic techniques of pulmonary resection may have resulted in the resection of a few more benign lesions, but this seems a small cost to pay because it has allowed us to definitively rule in or rule out malignancy in many cases with a minimally morbid procedure. In a review of a 10-year experience of 1822 cases at the Mayo Clinic, Clagett and colleagues4 found only 86 (4.7%) benign pulmonary tumors, most of which (66) were hamartomas. Included in this series were 11 benign mesotheliomas. A subsequent 10-year period at the same institution yielded 130 patients who underwent surgical resection of benign lung tumors.5 The spectrum of benign lung tumors in this series 691 tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 691

1/21/2008 11:50:37 AM

692

Section 3 Lung

Box 55-1 Classification of Benign Lung Tumors

TABLE 55-1 Spectrum of Benign Lung Tumors and Their Relative Frequency of Occurrence

Origin Unknown Hamartoma

Tumor

No. (%)

Clear cell (sugar) tumor

Hamartoma

100 (76.9)

Teratoma

Benign mesothelioma

16 (12.3)

Xanthomatous and inflammatory pseudotumors

7 (5.4)

Epithelial Tumors Papilloma

Lipoma

2 (1.5)

Leiomyoma

2 (1.5)

Polyps

Hemangioma

1 (0.8)

Atypical adenomatous hyperplasia

Adenoma of mucous glands

1 (0.8)

Mixed tumor

1 (0.8)

Mesodermal Tumors Fibroma Lipoma

Adapted from Arrigoni MG, Woolner LB, Bernatz PE, et al: Benign tumors of the lung: A ten-year surgical experience. J Thorac Cardiovasc Surg 60:589, 1970.

Leiomyoma Chondroma Granular cell tumor Sclerosing hemangioma (alveolar pneumocytoma) Other Inflammatory myofibroblastic tumor (histiocytoma, plasma cell granuloma, inflammatory pseudotumor, fibroxanthoma) Xanthoma Amyloid Mucosa-associated lymphoid tumor—formerly pseudolymphoma (probably not a benign neoplasm)

FIGURE 55-1 Microscopic section of a hamartoma, demonstrating a mixture of cartilage, fat cells, and undifferentiated mesenchymal cells. There are clefts lined by a single layer of cuboidal epithelial cells.

and their relative frequency of occurrence are presented in Table 55-1. Hamartomas account for most of these benign lesions, a finding that is true in all series. In any series of resected lesions, there is and needs to be a certain incidence of resection of benign neoplasms. These lesions grow over time, often do not have characteristic calcification, and may not have been present on a previous radiograph, or such a radiograph may be unavailable. If there is any doubt, the safest course to follow has been, and remains, complete removal of the lesion. HISTORICAL READINGS Arrigoni MG, Woolner LB, Bernatz PE, et al: Benign tumors of the lung: A ten-year surgical experience. J Thorac Cardiovasc Surg 60:589, 1970. Clagett OT, Allen TH, Payne WS, Woolner LB: The surgical treatment of pulmonary neoplasms: A 10-year experience. J Thorac Cardiovasc Surg 48:391, 1964. Steele JD: The solitary pulmonary nodule: Report of a cooperative study of resected asymptomatic solitary pulmonary nodules in males. J Thorac Cardiovasc Surg 46:21, 1963.

SPECIFIC BENIGN TUMORS OF THE LUNG Hamartoma The most common benign tumor of the lung is the hamartoma, which is found in about 0.25% of patients at autopsy. It accounts for about 8% of pulmonary neoplasms.6 These lesions represent an abnormal proliferation and mixing of the normal components of the lung. On histologic section, they are composed mainly of cartilage and gland-like formations and may include a significant amount of fat (Fig. 55-1). Half of these tumors have chromosomal abnormalities involving 12q14-15.7 Most hamartomas are asymptomatic and come to clinical attention because they must be differentiated from carcinomas after identification on a routine chest radiograph. They occur most commonly in male patients (2 : 1 or 3 : 1 predominance) and are distributed across a spectrum of age ranges, but most are seen in patients between 30 and 60 years of age (Hansen et al, 1992).8 Hamartomas occur in all parts of the lung, but most commonly they are found in the periph-

tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 692

1/21/2008 11:50:37 AM

Chapter 55 Benign Lung Tumors

ery. They occasionally occur as endobronchial lesions with manifestations of obstruction, such as volume loss. Radiographically, most hamartomas are solitary pulmonary nodules, rarely multiple nodules, at presentation. They tend to be well-circumscribed lesions, usually ranging between 1 and 2 cm in diameter, although larger ones, in the 5- to 6-cm range, are occasionally seen. Calcification may be present but may not be obvious on the plain chest radiograph. The CT scan may be more useful for demonstrating calcification, and in up to 50% of cases it may also show fat.9 The presence of fat density or so-called popcorn calcification in a welldemarcated lesion is highly suggestive of a benign neoplasm. In a frail patient, this finding might conclude the diagnostic evaluation and prompt the clinician to monitor the patient with radiographic studies. Needle aspiration biopsy might provide a definitive diagnosis of hamartoma by obtaining cartilage or fat, but it might also be nondiagnostic. The use of a larger needle, designed to obtain a core biopsy specimen, increases the likelihood of success.10 In patients with acceptable operative risk, lesions that cannot be proved benign are resected. Slow growth is the norm for these tumors. In a series reported by Hansen and colleagues (Hansen et al, 1992),8 tumor growth was observed in 48% of patients during a mean observation period of 4.1 years, with an average increase in diameter of 3.2 ± 2.6 mm/year. Based on this finding, it is reasonable to watch these lesions if the clinician is fairly certain that a lesion is a hamartoma. Malignancy is rare, if it occurs at all, and only a few cases have been reported.11 Endobronchial hamartomas occur in 3% to 20% of cases.12,13 In the series reported by Hansen and colleagues (Hansen et al, 1992),8 only 1 patient in a series of 89 had an endobronchial hamartoma, but lesions in this location would be expected to be symptomatic. Figure 55-2A is the chest radiograph of a young woman presenting with dyspnea and cough who was found to have a hamartoma in the left main bronchus at bronchoscopy. Note the volume loss on the left with mediastinal shift and hyperinflation of the right lung. Figure 55-2B, a perfusion lung scan, demonstrates a paucity of perfusion to the left lung, probably secondary to hypoxic vasoconstriction. After bronchoscopic removal of the lesion, the chest radiograph returned to normal (see Fig. 55-2C).

Hemangiopericytoma Hemangiopericytoma is a difficult diagnosis in any site because the histologic pattern is often consistent with that of other sarcomas. Pulmonary hemangiopericytoma can occur at almost any age. These tumors are similar in appearance to lesions that are found in several other sites. The name was originally suggested because these are vascular tumors composed of capillary pericytes. They can be of any size, and in 1974, Meade and colleagues reported14 that they ranged from 2 to 15 cm in diameter. Approximately one half were asymptomatic at the time of presentation. The signs and symptoms included hemoptysis, dyspnea, and chest pain. Pathologically, the tumor is characterized by its vascularity and the peritheliomatous arrangement of the tumor cells. There are wellpreserved vascular channels, although in larger tumors there

693

may be significant central necrosis. These vascular channels are surrounded by sheets of rounded or spindle-shaped cells that have pale cytoplasm and large vesicular nuclei. Mitoses are infrequently seen. This tumor may behave in a benign or a malignant fashion, and complete excision is the treatment of choice. The prognosis seems to be best in female patients with small tumors. Meade and colleagues14 found 25 cases in the world literature, with 4 deaths in 16 female patients and 6 deaths in 9 male patients. Whether this tumor should even be considered in a discussion of benign lung lesions is questionable.

Sclerosing Hemangioma Sclerosing hemangioma was first described by Liebow and Hubbell.15 This is an uncommon benign lung tumor that occurs most frequently in middle-aged women, who are usually asymptomatic. The lesion manifests as a solitary, peripheral, well-circumscribed nodule that may be partially calcified (Fig. 55-3). Grossly, the lesion may appear hemorrhagic. In a study by Sugio and colleagues,16 this tumor was the second most common neoplasm seen among the benign lesions (n − 45) resected from a cohort of 919 patients over a 17-year period. Ten patients (22.2%) had sclerosing hemangiomas, compared with 22 who had hamartomas. The tumors ranged in diameter from 1.3 to 8 cm. Radiographically, these lesions appeared to be well-defined, homogeneous, round or oval masses in all patients. The histologic features of sclerosing hemangioma vary, and four major patterns may be found in the same tumor: solid, papillary, vascular (see Fig. 55-3A), and sclerotic (see Fig. 55-3B). As Yousem17 pointed out in his invited commentary after Sugio and colleagues’ article,16 there has been a significant evolution in understanding of this tumor. There may be malignant variants of this tumor that manifest as multiple nodules or with nodal metastasis, in contradistinction to the benign form, which manifests as a solitary nodule. The cell of origin, as suggested by immunohistochemical studies, is most likely a primitive respiratory epithelial cell, not a mesenchymal cell. The tumor perhaps would be more appropriately labeled an alveolar pneumocytoma, based on this recent information. Surgical resection would be expected to result in cure in the overwhelming majority of cases. The occasional presence of lymph node metastases18 suggests that lymphadenectomy should be considered.

Granular Cell Tumor Granular cell tumors, formerly called myoblastomas and now perhaps more appropriately called schwannomas, may occur as solitary pulmonary nodules, or they may occur in the trachea or main stem bronchi, occasionally as multiple lesions.19,20 Despite the name, skeletal muscle cells are not identified in most myoblastomas. In 1950, Pearce21 proposed that the cells represent granular degeneration of perineural fibroblasts. They occur with equal frequency in both sexes, and the median age of patients with these tumors is 38 years, younger than that typically of patients with endobronchial malignancies. Patients usually present with cough or other symptoms suggestive of bronchial obstruction; hemoptysis

tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 693

1/21/2008 11:50:38 AM

694

Section 3 Lung

FIGURE 55-2 A, Preoperative chest radiograph of a young woman with a hamartoma in the left main stem bronchus. Note the loss of volume evident on the left, as manifested by the mediastinal shift and hyperinflation of the right lung. B, Perfusion lung scan of the same patient, demonstrating significantly diminished blood flow to the left lung. C, After bronchoscopic removal of the hamartoma, the chest radiograph returned to a completely normal appearance.

occurs occasionally. Valenstein and Thurer22 reported only one recurrence of myoblastoma (6 years after bronchoscopic excision) among 46 cases of granular cell tumor. Treatment ranged from bronchoscopic removal to open, anatomic resection.

Pseudolymphoma Pseudolymphomas, bronchial-associated lymphoid tumors (BALTs), are fascinating lesions that for many years were thought to be entirely benign. Most manifest as asymptomatic pulmonary nodules noted on a routine chest radiograph. Grossly, they appear to be well-demarcated masses with smooth, soft, pale cut surfaces (Fig. 55-4A). A few

patients complain of chest pain or fever. In their original report of pseudolymphoma of the lung, Hutchinson and colleagues23 commented on the radiographic finding of air bronchograms within the lesion, which resulted from this presumed inflammatory mass surrounding a small bronchus without constricting it. This is not a consistent finding, however, and there are no distinct radiologic criteria to distinguish these lesions from any other neoplasm. There is a growing body of evidence based on immunohistochemical, molecular, and cytogenetic study that these lesions are actually low-grade, primary B-cell lymphomas of mucosa-associated lymphoid tissue. Microscopically, the lesion consists of small lymphoid cells interspersed among clusters of plasma cells (see Fig. 55-4B). Tumor cells infiltrate

tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 694

1/21/2008 11:50:38 AM

Chapter 55 Benign Lung Tumors

FIGURE 55-3 A, Histologic section of sclerosing hemangioma, demonstrating a vascular pattern marked by the finding of multiple dilated vascular spaces, often filled with blood cells and surrounded by tumor cells and/or fibrous tissue. B, Sclerosing hemangioma, showing a pattern more consistent with the fibrous type.

along the alveolar septa, resulting in the characteristic lymphoepithelial lesion. The tumor usually has a nodular appearance because of its tendency to localize around lymphoid follicles. Wotherspoon and colleagues24 described a case of a lung lesion with the definitive histologic features of a pseudolymphoma in which cytogenetic studies revealed an abnormal karyotype with a t(1;14) translocation characteristic of B-cell lymphomas. After excision of these lesions, we carry out a complete lymphoma staging workup to rule out the presence of systemic disease. If no other evidence of lymphoma exists, we recommend follow-up only, fully recognizing that a percentage of these patients may develop disseminated lymphoma over a period of years. Despite Saltzstein’s contention25 that these are reactive lesions, most are probably bona fide lymphomas, albeit of low grade, and the term pseudolymphoma has probably outlived its usefulness.

Fibroma Bronchopulmonary fibromas may occur in either the tracheobronchial tree or within the pulmonary parenchyma. Pure fibromas are infrequently diagnosed in the lung or in the soft tissues. There may be myxomatous elements intermixed in

695

FIGURE 55-4 A, Gross appearance of the cut surface of a bronchialassociated lymphoid tumor (BALT), demonstrating a clear demarcation from the surrounding lung tissue. B, Microscopic appearance of BALT, showing the small lymphoid cells interspersed among clusters of plasma cells. These cells tend to localize around lymphoid follicles, often replacing the mantle zone and invading the follicle’s center.

these lesions. An endobronchial fibroma would be expected to produce atelectasis or other signs and symptoms of obstruction.26 Lesions of this type in this location lend themselves to easy removal through the rigid bronchoscope, or they may be excised with the laser. Similar to other benign tumors, fibromas occurring in the pulmonary parenchyma usually are asymptomatic and appear as well-circumscribed nodules without specific characteristics to differentiate them from other lesions. Wedge excision is both diagnostic and curative and can usually be undertaken thoracoscopically. Histologically, these lesions show an abundance of collagen and bland spindle cells, which are also typical of fibromas seen elsewhere in the body.

Lipoma Most lipomas are bronchial in origin, arising from the submucosal fat that is present between cartilaginous rings. Parenchymal lipomas are rare. In the classic study of 130 benign lung tumors from the Mayo Clinic, only 2 were bronchopulmonary lipomas.5 The symptoms and signs associated with this lesion depend on its size and location. Because most are endobronchial in origin, manifestations of obstruction predominate with the larger lesions. Cough is especially

tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 695

1/21/2008 11:50:38 AM

696

Section 3 Lung

common. Endobronchial lipomas are usually pedunculated tumors with a narrow stalk that are covered by normal respiratory mucosa.27 If there is significant destruction of lung tissue distal to one of these lesions, lobectomy or segmentectomy may on rare occasions be required, despite the ability to remove the lipoma bronchoscopically.28 Lipomas of both the visceral and parietal pleura may also be seen but are much less common than the endobronchial variety.29

Leiomyoma Although rare, leiomyoma is the most common soft tissue tumor of the lung. It is composed essentially of smooth muscle fibers.30 Women account for two thirds of the affected patients, and the mean age of all reported patients is 35 years.31 Approximately one third of patients are younger than 20 years of age. As with other benign tumors, the location of the lesion dictates the symptoms. Most of these lesions are solitary, peripheral, pulmonary nodules and, therefore, asymptomatic. They are found incidentally on plain chest radiographs or CT scans of the chest. There are no specific characteristics that distinguish this lesion from other pulmonary nodules. A few patients present with symptoms secondary to endobronchial involvement. There is substantial controversy regarding the origin of these tumors of the lung. Hypotheses include origination from the bronchial wall smooth muscle or the wall of bronchial arteries. On histologic section, they resemble the smooth muscle tumors seen in several other sites. There is some support for the hypothesis that these tumors are metastatic myomas of uterine origin, despite their bland cytologic appearance (Mackay et al, 1991).32 These so-called benign metastasizing leiomyomas have a bland histologic pattern with minimal mitosis or necrosis and seem identical to myomas found in the uterus. Because these tumors would by this theory have disseminated via a hematogenous route, many would argue against the benign designation, no matter what the histologic appearance.

they often have a granular eosinophilic cytoplasm. Based on their intense periodic acid–Schiff positivity, the granules are most likely glycogen, and the eosinophilic appearance of the cytoplasm is imparted when granules are present in large numbers. The nuclei are characteristically bland and vary in size; mitoses are usually absent. The chromatin is finely granular, and intranuclear cytoplasmic invaginations are seen occasionally. Although not distinctly encapsulated, the lesions easily shell out of the surrounding lung tissue, are usually peripherally located, and are typically 2 cm or less in size. Immunohistochemical analysis allows for the definitive diagnosis of clear cell tumors of the lung and their distinction from renal cell carcinomas.

Inflammatory Myofibroblastic Tumor The term inflammatory myofibroblastic tumor is applied to a group of tumors that have been described by a variety of terms, including plasma cell granuloma, histiocytoma, fibroxanthoma, and inflammatory pseudotumor.36 These lesions are thought to be reactive in nature because many of the patients who develop them have a history of previous infection, inflammation, or neoplasm of the lung. The tumors are nonencapsulated and contain varying proportions of plasma cells and histiocytes, constituting an abundant inflammatory infiltrate with a large spindle cell component of primarily myofibroblasts (Fig. 55-5). In one of the largest series of these lesions, consisting of 20 patients,36 40% were asymptomatic and 60% had symptoms consisting of cough, fever, chest wall pain, or dyspnea. The average age was 30 years, but the lesion represents 57% of benign lung tumors in children. There were nine peripheral coin lesions, three more irregular lesions, and one endobronchial lesion. Two patients had more than one nodule. Three patients had extrapulmonary extension into the mediastinum, and one was believed to have a primary mediastinal tumor, but even these patients were cured by resection or had only local recurrence (one patient).

Clear Cell (Sugar) Tumor Clear cell tumors of the lung are rare neoplasms that were originally described by Liebow and Castleman.33 In a detailed review of this tumor in 1990, Gaffey and colleagues34 added 8 additional cases to the 21 cases previously reported. The patients were usually asymptomatic and presented with a peripheral solitary pulmonary nodule found incidentally on a plain chest radiograph. There was no gender predilection, and most patients were in their 40s or 50s. Until recently, these tumors were universally considered benign, but a report by Sale and Kulander35 described one patient who died of metastatic clear cell tumor of the lung. These tumors bear a striking microscopic resemblance to metastatic renal cell carcinoma, and Gaffey and colleagues34 attempted to clarify the pathologic distinctions between clear cell tumors of the lung and renal cell carcinomas by clinical, histologic, immunohistochemical, and ultrastructural features. They are characterized by sheets and cords of polygonal cells separated by a prominent fibrovascular stroma. The so-called clear cells may indeed have a clear cytoplasm, but

FIGURE 55-5 Inflammatory myofibroblastic tumor (hematoxylin and eosin stain, ×100). The tumor consists of a mix of fibroblasts and chronic inflammatory cells, including conspicuous numbers of plasma cells. (PHOTOMICROGRAPH COURTESY OF LESLIE A. LITZKY, MD, DEPARTMENT OF PATHOLOGY AND LABORATORY MEDICINE, UNIVERSITY OF PENNSYLVANIA MEDICAL CENTER, PHILADELPHIA, PA.)

tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 696

1/21/2008 11:50:40 AM

Chapter 55 Benign Lung Tumors

Germ Cell Tumors Benign teratomas in the lung are rare, but many have been reported.37 Some of the reported cases may be mediastinal lesions that involve contiguous lung. They occur generally in young patients, may occasionally manifest with trichoptysis (coughing out hair) but more commonly produce only nonspecific symptoms, and have radiographic characteristics similar to those of mediastinal teratomas.

Atypical Adenomatous Hyperplasia Atypical adenomatous hyperplasia (AAH)—also variably termed alveolar cell hyperplasia, atypical alveolar hyperplasia, or bronchioloalveolar cell adenoma—has aroused significant interest in the past few years. It usually appears as one or more small, asymptomatic ground-glass opacities in the periphery of the lung. Although many studies suggest that it is a premalignant lesion to adenocarcinoma, specifically to bronchoalveolar carcinoma (BAC), the evidence for this is circumstantial and based on the fact that the lesion is usually seen adjacent to adenocarcinoma and is sometimes identified within the same mass as an invasive adenocarcinoma. Histologically, it demonstrates a proliferation of minimally atypical cuboidal type II pneumocytes. Clinical differentiation between AAH and true BAC is essentially impossible, and clinical management of both of these types of lesions is in evolution. Certainly, if a focus of ground-glass opacity is resected and found to represent AAH, then nothing more than a wedge resection is required. Even for BAC, there is an emerging consensus that sublobar resection may be appropriate therapy.38

Rarer Tumors Other benign tumors that have been reported in the lung in a few patients include pulmonary meningioma, ganglionoma, and lymphangioma.

DIAGNOSIS Most benign tumors manifest as asymptomatic nodules found on a routine chest radiography or CT performed for other reasons. This is almost universally the case with lesions located in the peripheral lung parenchyma. The presence of multiple nodules most commonly represents metastatic malignancy, which was the case in 73% of 114 patients reported by Gross and colleagues.39 A small percentage of benign lesions are in an endobronchial location and may be manifested by lobar or whole lung collapse, hyperinflation secondary to a ball-valve mechanism, cough, pneumonia, or, occasionally, hemoptysis. Infrequently, a wheeze may be audible. In a series of 130 benign lung tumors, Arrigoni and colleagues5 identified 8 endobronchial lesions. Carcinoid tumors, which frequently manifest in this fashion, are in fact malignant lesions and are discussed elsewhere in this text. Except for lesions demonstrating one of a few pathognomonic patterns of calcification or the presence of fat, a definitive diagnosis may be made only by obtaining tissue. This is easily accomplished by bronchoscopy when there is an endobronchial lesion, but the much more common peripheral

697

tumors present a major diagnostic challenge, and the approach to these lesions continues to evolve as new technology is developed. Although no criteria are absolute, a number of factors point to a benign diagnosis.40 Lesions in nonsmokers younger than 30 years of age are extremely unlikely to be malignant. Moreover, if the lesion has not changed in size over 2 years or longer, it is also generally safe to consider it benign, unless it might represent a BAC (i.e., ground-glass opacity on CT). Therefore, the importance of review of prior radiographic studies cannot be overemphasized. Dense or central calcification is considered to be a reliable indicator that a lesion is benign, as is popcorn calcification, which suggests a hamartoma. The application of quantitative CT densitometry41 has taken these concepts a step further, but this technique identifies benignity in only 22% to 28% of those nodules that show no diagnostic calcification on a plain radiogram (Zerhouni et al, 1986).42,43 Positron emission tomography (PET) has been advanced as a means of separating benign from malignant pulmonary nodules by virtue of the differing intensity with which they process glucose, but there is clearly significant overlap between the two groups. Low-grade neuroendocrine malignancies and BAC, for example, tend to be negative on PET. Therefore, despite the available noninvasive methods of attempting to determine the nature of a solitary pulmonary nodule, a large number of such lesions remain indeterminate and, therefore, require tissue obtained by one means or another to establish a diagnosis. Only 10% to 20% of patients with malignant solitary pulmonary nodules have sputum that is positive for cancer.42 Furthermore, a preponderance of benign tissue fragments obtained from a nodule by one of the other available nonoperative but invasive diagnostic studies (i.e., bronchoscopy or transthoracic needle biopsy [TTNB]) does not guarantee that the lesion is, in fact, benign. A specific benign diagnosis is made only 10% of the time by bronchoscopy44 and between 12% and 67% of the time by TTNB.44,45 Because as many as 29% of patients without a diagnosis of malignancy on TTNB are found ultimately to have carcinoma,45 only a definitive benign diagnosis by cytology or microbiologic examination can, in our view, avert a further procedure. Specific benign findings include cartilage or fat suggestive of a hamartoma or fungal elements or acid-fast organisms diagnostic of an infectious process. Most negative results from TTNB are actually not diagnostic of any specific process and therefore provide no reassurance to the patient. Such a result simply mandates a further diagnostic procedure, whereas a diagnosis of malignancy merely confirms that complete excision needs to be carried out. Furthermore, there is a modest risk of morbidity from TTNB, with the rate of chest tube placement for significant pneumothorax at approximately 5%. For these reasons, many groups currently do not perform TTNB for indeterminate pulmonary nodules that are peripheral enough to be amenable to thoracoscopic excision. The exceptions would be the patient with multiple, unresectable nodules who simply needs a tissue diagnosis and in whom the diagnosis is highly likely to be malignant or the patient with an absolute contraindication to operation. The practice used by these groups is complete removal of the lesion by videoassisted thoracic surgical (VATS) wedge resection.

tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 697

1/21/2008 11:50:40 AM

698

Section 3 Lung

MANAGEMENT In general, simple excision of a benign lesion is curative. Often, excision may be done without the need for an anatomic resection, although the type of resection is obviously dependent on the location of the lesion. The guiding principle, however, when dealing with a benign lesion is conservation of lung tissue. This may include the use of segmental resections and bronchoplastic procedures. Bronchoscopic excision may suffice for endobronchial lesions—most commonly lipomas or hamartomas. In our opinion, this is best performed via rigid bronchoscopy. Even though there is a certain rate of recurrence after bronchoscopic excision of these tumors, this is generally preferable to the alternative, which is often a complex sleeve resection. Certainly, if sleeve resection with total conservation of lung tissue or no more than lobectomy is possible, consider it after a first recurrence following bronchoscopic excision. Use the laser judiciously during bronchoscopic excision, so that, if a recurrence does occur, scarring from previous thermal injury does not require extension of what would have been a limited resection to a more morbid operation. Advances in minimally invasive techniques render it somewhat less important to look for ways to avoid removing a lesion that may be benign. The advent of VATS has somewhat changed the approach to solitary pulmonary nodules.46 No longer must a patient be subjected to a thoracotomy to make a diagnosis or definitively treat a large proportion of benign lesions. Wedge excision through a thoracoscopic approach provides a definitive diagnosis and treatment for many benign pathologic conditions with less morbidity than a thoracotomy. Patients leave the hospital sooner and return to normal activities sooner than after thoracotomy.47,48 Surgical therapy of benign lesions located in the parenchyma is mandated largely by the fact that the diagnosis usually cannot be definitively established until the lesion is removed. Most lesions that are relatively peripheral and are within 3 to 4 cm (on CT) of the chest wall or a fissure can be palpated at the time of thoracoscopy and wedge-excised. Hamartomas may be wedged out or enucleated, as has been classically done during an open procedure because they shell out easily after an incision in the visceral pleura. Lesions with

a ground-glass appearance on CT are often softer in consistency and therefore more difficult to palpate at thoracoscopy unless they are close to the visceral pleural surface. Several techniques have been proposed to localize these softer lesions preoperatively so that they, too, can be excised thoracoscopically. Small ground-glass lesions are commonly monitored closely for growth, as are other indeterminate lesions that the surgeon has a high suspicion may be benign but are more centrally placed within the parenchyma and thus inaccessible to thoracoscopic wedge. KEY REFERENCES Hansen CP, Holtveg H, Francis D, et al: Pulmonary hamartoma. J Thorac Cardiovasc Surg 104:674, 1992. ■ The authors report a series of 89 cases of pulmonary hamartoma; 75 patients underwent surgery. This is an excellent review on the topic of hamartoma, which is by far the most common benign lung tumor encountered. The authors obtained a diagnostic result in 34 (85%) of 40 patients who underwent needle biopsy, a higher percentage than would be expected. Liebow AA: Tumors of the lower respiratory tract. In Atlas of Tumor Pathology, Section V. Fascicle 17. Washington DC, Armed Forces Institute of Pathology, 1952. ■ This article includes the classic description of the pathologic findings of benign and malignant tumors of the lung and bronchi. A classification scheme, essentially still in use today, is proposed in this monumental work. Mackay B, Lukeman JM, Ordóñez NG: Tumors of the lung. In Bennington JL (ed): Major Problems in Pathology, Vol 24. Philadelphia, WB Saunders, 1991. ■ This is an outstanding monograph on both benign and malignant tumors of the lung based on the authors’ experience at M.D. Anderson Cancer Center in Houston, Texas. An excellent discussion on the pathologic findings of the benign lung tumor is included in the chapter on uncommon lung tumors, which also has an excellent bibliography. Oldham HN: Benign tumors of the lung and bronchus. Surg Clin North Am 60:825, 1980. ■ This is an excellent overview of the topic that deals with the entire spectrum of benign lung tumors. Zerhouni EA, Stitik FP, Siegelman SS, et al: CT of the pulmonary nodule: A cooperative study. Radiology 160:319, 1986. ■ This is the definitive study detailing the CT findings of the solitary pulmonary nodule, which includes criteria for establishing or at least suspecting benignity.

tahir99-VRG vip.persianss.ir

Ch055-F06861.indd 698

1/21/2008 11:50:40 AM

Lung Cancer chapter

BRONCHIAL GLAND TUMORS

56

Shari L. Meyerson David H. Harpole, Jr.

Key Points ■ Bronchial gland tumors is a general term encompassing several

subgroups with different behaviors, treatment, and prognosis. ■ The treatment of choice for bronchial carcinoids is surgical resec-

tion. Prognosis is most significantly dependent on histology (typical versus atypical), with typical cases having an excellent long-term prognosis. ■ Adenoid cystic carcinoma is most commonly central or tracheal and often has extensive submucosal and perineural invasion as well as metastatic disease at presentation. Complete resection offers the best long-term survival; however, endobronchial debulking may provide symptomatic improvement for patients with unresectable tumors. ■ Mucoepidermoid carcinomas are found in the proximal segmental bronchi. Low-grade tumors can be resected for cure. High-grade tumors are more aggressive and need to be treated similar to standard non–small cell lung cancers.

The commonly used term bronchial adenomas refers to a group of tumors arising beneath the bronchial epithelium or in bronchial glands. Unfortunately, adenoma suggests a benign process, which is accurate only in a relative sense. These tumors represent a spectrum of biologic activity that is quite broad. However, their clinical course is generally more benign than that of bronchogenic carcinomas. The more descriptive term for these tumors is bronchial gland tumors. Four distinct entities make up the majority of bronchial gland tumors: bronchial carcinoids, adenoid cystic carcinomas (cylindromas), mucoepidermoid carcinomas, and mucous gland adenomas. The four types of bronchial gland tumors are similar in that they arise or occur in the trachea or bronchi and are typically less aggressive than bronchogenic carcinomas; however, the similarities end there. Together, these lesions account for 2% to 6% of all lung tumors (Harpole et al, 1992).1,2 Adenoid cystic carcinoma (ACC), typical and atypical carcinoids, mucoepidermoid carcinoma, and mucous gland adenoma can be distinguished from one another on the basis of histology, immunostaining, histochemistry, genetics, and clinical activity. Each of these tumors is discussed in detail in this chapter.

HISTORICAL NOTE The first clear description of a bronchial carcinoid was made by Laennec in 1831. In 1907, Oberndorfer subsequently introduced the term Karcinoide, meaning “resembles carci-

noma.” In 1930, Kramer grouped bronchial carcinoids with cylindromas as bronchial adenomas because of the marked difference in prognosis between these tumors and bronchogenic carcinoma. In the past 25 to 30 years, the underlying biochemical and genetic differences between these tumors have been discerned. HISTORICAL READINGS Engelbreth-Holm J: Benign bronchial adenomas. Acta Chir Scand 90:383, 1944. Heschl R: Über ein Zylindrom der Lunge. Wien Med Wochenschr 17:385, 1877. Kramer R: Adenoma of bronchus. Ann Otol Rhinol Laryngol 39:689, 1930. Laennec RTH: Traité de L’Auscultation Médiate et des Maladies des Poumons et du Couer, 3rd ed. Paris, Chaud, 1831. Muller H: Zur Entstehungsgeschichte der Bronchialerweiterungen, Vol 15. Inaug Diss Univ Halle. A. Busch, Ermsleben am Halle, Germany, 1882. Oberndorfer S: Karzinoide: Ergebnisse der allgemeinen Pathologie und pathologischen Anatomie des Menschen und der Tiere. 13:527, 1909.

BRONCHIAL CARCINOID TUMORS Pathology The embryonic origin of bronchial carcinoid tumors has been a subject of debate in the literature. The belief that these tumors arise from amine precursor uptake and decarboxylation (APUD) cells originating in the neural crest has been challenged by experimental evidence that suggests a bronchial epithelial stem cell origin.3 Regardless of the cell of origin, cytoplasmic neurosecretory granules can be identified in these tumors using either argyrophilic staining or electron microscopy.3-5 Carcinoid tumors have been shown to produce many different peptide hormones (Table 56-1). The most frequently seen product is serotonin (5-hydroxytryptamine), which, when released in the systemic circulation, can lead to carcinoid syndrome. Other clinically significant products include adrenocorticotropic hormone (ACTH) and growth hormone, which lead to Cushing’s syndrome and acromegaly, respectively. Eighty percent to 85% of carcinoids display typical histology, which consists of clusters of homogeneous, polyhedral cells in a fibrovascular stroma with no evidence of necrosis and less than two mitoses per 10 high-power fields (Fig. 56-1). In 1972, Arrigoni and colleagues6 identified a subset of bronchial carcinoids that exhibited more aggressive biology than expected. These have been termed atypical carcinoids 699 tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 699

1/21/2008 12:10:55 PM

700

Section 3 Lung

TABLE 56-1 Peptide Hormones Produced by Carcinoid Tumors Bombesin

Bradykinin

Calcitonin

Corticotropin

Epinephrine

Gastrin

Glucagon

Growth hormone

Histamine

Insulin

Leu-enkephalin

Melanocyte-stimulating hormone

Neuron-specific enolase

Norepinephrine

Serotonin

Somatostatin

Substance P

Vasoactive intestinal polypeptide

Vasopressin From Blobel GA, Gould VE, Moll R, et al: Coexpression of neuroendocrine markers and epithelial cytoskeletal proteins in bronchopulmonary neuroendocrine neoplasms. Lab Invest 52:39, 1985; and Warren WH, Memoli VA, Gould VE: Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms. I: Carcinoids. Ultrastruct Pathol 6:15, 1984.

and are histologically distinguishable by their increased cellularity, so-called moderate mitotic activity (2-10 mitoses per 10 high-power fields), nuclear hyperchromasia, heterogeneity of cell size and shape, disorganized architecture, and punctate necrosis (Figs. 56-2 and 56-3). This distinction is clinically significant because atypical histology is associated with a more aggressive clinical course, including metastatic disease in 70% of atypical cases, compared with 5.6% of typical carcinoids. Because of the ultrastructural and histochemical similarities between carcinoids and small cell lung carcinomas, carcinoids are often described as part of the spectrum of malignant pulmonary neuroendocrine tumors, ranging from low-grade typical carcinoid through intermediate-grade atypical carcinoid to high-grade large cell neuroendocrine carcinoma and small cell lung carcinoma. Rusch and colleagues7 reported that the higher-grade neuroendocrine tumors can be distinguished from the lower-grade typical and atypical carcinoids on the basis of immunohistochemical staining against the molecular genetic markers MKI67 (Ki67), TP53 (p53), and RB1 (Rb). These differences in immunohistochemical staining are supported and complemented by reports of chromosomal abnormalities that also can be used to differentiate these tumors. Walch and colleagues8 reported that both typical and atypical carcinoids frequently lack a portion of the 11q chromosome including the MEN 1 gene locus. This deletion is seen in bronchial carcinoids and not in gastrointestinal carcinoids, which commonly show deletions of 18p or 18q, suggesting that carcinoid tumors in different locations develop by different pathways.9 Significant chromosomal differences also exist between typical and atypical carcinoids. Atypical carcinoids show additional deletions of 10q and 13q, including the RB1 locus, which is known to relate to tumor suppressor genes and is associated with progression in several tumor types. Large cell neuroendocrine carcinoma and small cell lung carcinomas demonstrate different complex patterns of genomic losses and gains on multiple chromosomes.

FIGURE 56-1 Histopathologic examination of a typical carcinoid (hematoxylin and eosin stain [H&E], ×325).

Epidemiology Bronchial carcinoids account for 85% to 90% of bronchial gland tumors and 1% to 2% of all lung malignancies. They are seen in patients of all ages (mean, 47-53 years) with no overall gender predominance (Harpole et al, 1992).1,10 However, there is some evidence that, among patients younger than 50 years of age, carcinoid tumors are more common in women; in addition, atypical histology is more common in older patients (Quaedvlieg et al, 2001).11-13 Atypical histology may also be related to smoking history. Positive smoking history is identified in 64% to 80% of patients with atypical carcinoid but only 20% to 33% of patients with typical histology.14,15 Anatomically, 10% of carcinoid tumors are found in the main stem bronchi, 75% in the lobar bronchi, and 15% in the peripheral lung.16 Carcinoids are more common in the right lung, especially in the middle lobe.17 Atypical carcinoids more commonly are associated with nodal metastases at the time of presentation. Fink and colleagues18 found, in patients with typical histology, N1 disease in 10%, N2 disease in 3%, and no cases of N3 disease. This was distinctly better than for patients with atypical histology, among whom N1 disease was found in 29%, N2 in 14%, and N3 in 14%. Distant metastases are distinctly more frequently seen with atypical histology lesions and are most commonly found in liver, bone, brain, adrenal glands, and ovary.19

tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 700

1/21/2008 12:10:55 PM

Chapter 56 Bronchial Gland Tumors

701

FIGURE 56-2 A, Histopathologic examination of an atypical carcinoid (H&E, ×325). B, Higher magnification of an atypical carcinoid showing mitotic figures, nuclear pleomorphism, and granular chromatin (H&E, ×680).

TABLE 56-2 Symptoms of Bronchial Carcinoids Symptom

% of Population (N = 126)

No symptoms

39

Nonproductive cough

25

Productive cough

27

Hemoptysis

30

Dyspnea or wheezing

25

Chest pain

18

Sweating/flushing

12

Diarrhea

10

From Harpole DH, Feldman JM, Buchanan S, et al: Bronchial carcinoid tumors: A retrospective analysis of 126 patients. Ann Thorac Surg 54:50, 1992.

Clinical Presentation

FIGURE 56-3 Histopathologic examination of small cell carcinoma of the lung (H&E, ×325).

In many patients, a long history of recurrent pneumonia or asthma may precede the diagnosis. The most common presenting symptoms of bronchial carcinoids are shown in Table 56-2. Obstructive symptoms are usually caused by central tumors. Peripheral tumors are often asymptomatic unless they overproduce an active peptide hormone. Approximately 1% to 10% of all patients with bronchial carcinoids exhibit symptoms consistent with the carcinoid syndrome (flushing, palpitations, wheezing, and diarrhea) (Harpole et al, 1992).1,18

tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 701

1/21/2008 12:10:55 PM

702

Section 3 Lung

Carcinoid syndrome is typically seen in patients with very large tumors or liver metastases allowing peptide release into the systemic circulation. The etiology of carcinoid syndrome is a matter of debate, but the most commonly implicated peptides are serotonin (or one of the serotoninergic metabolites), histamine, tachykinins, prostaglandins, and bradykinin. Diagnosis of carcinoid syndrome is confirmed by measurement of elevated levels of serotonin or its metabolites in either blood or urine. Serum levels of either serotonin or its metabolite 5-HIAA (5-hydroxyindoleacetic acid) were elevated in 35 (34%) of 106 patients with pulmonary carcinoid in one series (Harpole et al, 1992).1 An interesting but infrequent phenomenon that occurs with pulmonary carcinoids is left-sided cardiac valvular disease. Classic carcinoid heart disease causes right-sided cardiac valvular thickening and fibrosis. It is thought that the lung deactivates some of the tumor products, leading to a much lower incidence of left-sided valve disease. Pulmonary carcinoids can deliver a higher concentration to the left-sided circulation, preferentially affecting the left heart valves. The exact pathogenesis of carcinoid heart disease is unclear; however, circulating levels of serotonin have been shown to be higher in carcinoid patients with valvular heart disease.20 The second most common paraneoplastic syndrome seen with carcinoid tumors is Cushing’s syndrome. This is caused by tumor production of ACTH and occurs in 2% of patients with pulmonary carcinoid tumors. Bronchial carcinoid is the most common cause of ectopic ATCH production (25%), followed by small cell lung carcinoma (11%) and disseminated neuroendocrine tumors of unknown primary (7%).21 Signs of Cushing’s syndrome include weakness, hypertension, glucose intolerance, and hypokalemia. Other endocrine disorders are occasionally associated with this tumor, including acromegaly (elevated growth hormone), excessive pigmentation (elevated melanocyte-stimulating hormone), inappropriate antidiuretic hormone secretion, and hypoglycemia.

Diagnosis Abnormal findings on chest radiograph are seen in 75% of patients with bronchial carcinoid tumors. In patients with central lesions, more than 90% of chest radiographs demonstrate a mass with or without atelectasis or postobstructive pneumonia.16,22 After the initial history, physical examination, and routine chest radiograph, computed tomography (CT) of the chest is the most commonly used study for evaluating the local extent and extrapulmonary metastases. However, nothing about the CT appearance of these tumors diagnostically distinguishes carcinoid tumors from bronchogenic carcinomas. Carcinoid tumors usually have discreet rather than spiculated borders. In addition, with good-quality contrast CT imaging, carcinoid tumors often demonstrate contrast enhancement not seen in bronchogenic cancers. Positron emission tomography (PET) generally demonstrates low-level uptake of fluorodeoxyglucose in carcinoid tumors. Patients with carcinoid tumors are more likely to have a negative PET scan than those with other types of lung tumors.14 Nuclear medicine techniques such as indium 111–labeled octreotide scanning can be useful both in initial diagnosis and staging, as well as for monitoring recurrent and metastatic disease.23 It

is important to remember that small cell lung cancer can also have somatostatin receptors, leading to a positive scan. Bronchoscopy can provide useful anatomic information as well as the opportunity for tissue diagnosis. The tumor generally appears highly vascular on visual evaluation, with a smooth surface and intact overlying epithelium. This intact epithelium often leads to false-negative results from analysis of bronchial washings or brushings. Biopsy can establish a diagnosis in 40% to 50% of patients; however, because of the vascularity of carcinoid tumors, biopsy can rarely result in considerable hemorrhage. Topical epinephrine applied through the bronchoscope before biopsy can reduce the risk of bleeding. Because of this risk, many surgeons believe that bronchoscopy with biopsy is best performed in the operating room, where rigid bronchoscopy can be used for control of hemorrhage, if necessary. In peripheral tumors, fine-needle aspiration may be diagnostic but can lead to a misdiagnosis of small cell carcinoma.

Treatment The treatment of choice for most carcinoids is complete surgical resection. The goal of resection is complete excision of the tumor while sparing as much lung tissue as possible. Although endoscopic resection or ablation is an attractive, minimally invasive approach, the extensive extrabronchial component of most carcinoid tumors does not allow complete endoscopic extirpation in most cases.24 Endobronchial therapy is useful in three specific situations. Patients with central endobronchial obstructing lesions who are not candidates for surgical resection due to other medical conditions may achieve some symptomatic relief with endobronchial resection with or without laser ablation. Patients who are significantly ill from postobstructive pneumonia may benefit from initial bronchoscopic debulking, both to allow resolution of the infectious process and to evaluate the condition of the lung distal to the obstruction for possible lung parenchyma–sparing resection. Finally, carcinoid tumors are occasionally pedunculated and can be amenable to endoscopic treatment alone.25 If this course of therapy is employed, careful endoscopic follow-up is required. Carcinoids located in the periphery of the lung are often amenable to limited resections, such as large wedge resections or segmentectomies, but care must be taken. It is often difficult to differentiate typical and atypical histology on frozen section, and in fact there is evidence that peripheral carcinoids are more likely to have atypical histology.26 Because of the increased frequency of lymph node involvement with atypical carcinoids, wedge resection is not sufficient. Unless the preoperative diagnosis of typical histology is certain, carcinoids in the periphery are treated by lobectomy with removal of first-order lymph nodes.27,28 More extensive resections may be required for central tumors because of either postobstructive parenchymal damage or involvement of the main stem bronchi. The increasing use of bronchial sleeve resections has decreased the frequency of pneumonectomy for resection of tumors involving the main stem bronchi. Bronchoplastic or bronchial sleeve resection can be considered if histologically negative margins can be obtained and the distal lung has not been irreversibly damaged.29,30 tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 702

1/21/2008 12:10:56 PM

Chapter 56 Bronchial Gland Tumors

Pneumonectomy is reserved for large central tumors, extensive lymph node involvement, or destroyed lung distal to the obstructing lesion. Complete lymph node dissection is undertaken at the time of resection for both staging and treatment of carcinoid tumors. Mediastinoscopy does not generally play a role in these patients. The lack of established effective chemotherapy regimens and the reasonable long-term survival after resection even in the presence of nodal metastases suggests that all patients with disease localized to the chest be offered surgical resection regardless of nodal status. In the face of limited success with chemotherapy, mediastinal lymph node dissection plays a role in local control for patients with atypical carcinoid. Adjuvant therapy (chemotherapy, irradiation, or both) after resection remains controversial. There is no definitive evidence for the efficacy of radiation therapy to improve local control. Several reports have demonstrated a low rate of local recurrence with postoperative radiation therapy; however, these results did not differ significantly from the natural history of these tumors after resection. Martini and colleagues31 described a group of 15 patients with N2 disease, 9 of whom received postoperative radiation therapy. No patient developed a local recurrence, regardless of treatment. Patients with atypical carcinoid with positive lymph nodes, which has a higher local failure rate, may benefit from postoperative irradiation. Radiotherapy has also been used in the treatment of locally advanced unresectable tumors and metastatic carcinoid, with symptomatic palliation. Among patients with unresectable or metastatic disease and symptoms of carcinoid syndrome, symptomatic control can be achieved in 60% with octreotide.32 A positive octreotide scan indicating the presence of somatostatin receptors in the tumor is predictive of response to octreotide therapy.33 Intra-arterial embolization of liver metastases has been used with some benefit. Investigations involving many different chemotherapeutic agents have proved metastatic carcinoid to be a relatively chemoinsensitive tumor. Single-agent therapies, including fluorouracil, doxorubicin, streptozocin, and docetaxel, have been tested and produced response rates between 0% and 25%.34,35 Combination therapies have not shown obvious benefit over single-agent regimens, producing low response rates and short-lived remissions. The indolent nature of especially metastatic typical carcinoid has led some authors to suggest that the toxicity of chemotherapy is not worth the limited benefit and is not routinely offered outside of clinical trials.36

703

TABLE 56-3 Survival Rates for Patients With Typical Carcinoid Tumors Survival (%) No. Patients

Institution (Year)

5-Year

10-Year

National Cancer Institute37 (1975)

151

96

—

Mayo Clinic38 (1976)

190

94

87

111

90

82

210

97

95

106

93

90

139

92

88

1595

93

82

105

87

—

Massachusetts General28 (1984) Emory/State of Iowa

39

(1987)

Duke University1 (1992) 22

Strasbourg/Marseille 41

Niigata Japan

(1999)

Denmark12 (2002)

(1998)

tion have excellent long-term survival. Martini and colleagues31 reported on a series of 12 patients with N1 or N2 disease and no evidence of distant metastases. Their 5- and 10-year survival rates were 92% and 76%, respectively. Similar outcomes were reported by Thomas and colleagues40 in 23 patients with lymph node metastases showing a 95% 5-year survival rate. On the other hand, atypical carcinoids have a much poorer prognosis, with a 5-year disease-free survival rate of 44% to 71%.12,41 Ultimate prognosis depends on the stage of the disease, with nodal involvement having an adverse effect. Beasley and colleagues19 reported a 5-year survival rate in patients with atypical carcinoid of 71% in stage I, 46% in stage II, and 37% in stage III disease.

ADENOID CYSTIC CARCINOMA (CYLINDROMA) ACC, also called adenocystic basal cell carcinoma, adenomyoepithelioma, cylindroma, and pseudoadenomatous basal cell carcinoma, is a slow-growing, malignant tumor that most commonly arises in the salivary glands. ACCs arising in the bronchi are less common than carcinoids, constituting only 10% of bronchial gland tumors. Although these are very slowgrowing tumors, they have a propensity for extensive submucosal and perineural invasion as well as distant metastases at presentation.42-44 ACCs are central tumors that typically exhibit both tracheal and bronchial involvement at presentation. These tumors demonstrate no gender predominance and have been observed in all age ranges, although diagnosis in the fifth decade is most common.

Results

Pathology

The strongest independent predictor of outcome in carcinoid tumors is atypical histology. Patients with typical bronchial carcinoids have an excellent long-term prognosis, with 5- and 10-year survival rates in the range of 90% to 97% and 82% to 95%, respectively (Table 56-3). Factors associated with a worse prognosis include the presence of symptoms at presentation, atypical histology (see Fig. 56-2), size greater than 2 cm in diameter, expression of serotonin, central location, and the presence of lymph node metastases (Harpole et al, 1992).1 Even patients with nodal disease at the time of resec-

ACCs have three distinct histologic patterns of growth, which occur with approximately equal frequency: cribriform, tubular, and solid (Figs. 56-4 and 56-5).45 Cribriform and tubular forms commonly display perineural and lymphatic invasion, whereas the less differentiated solid type has been associated with extensive extraluminal growth and distant metastases.46 Other reports have found no correlation between histologic subtype and clinical activity. Immunohistochemistry demonstrates a myoepithelial cell component with immunoreactivity for keratin, actin, and tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 703

1/21/2008 12:10:56 PM

704

Section 3 Lung

S-100.44 Tumor cells are also positive for CD117, a tyrosine kinase receptor seen in gastrointestinal stromal tumors and germ cell tumors.47

Clinical Presentation Up to 80% of patients present with symptoms.48 Because most ACCs are centrally located, the most common symptoms are the result of airway obstruction or irritation. Cough, hemoptysis, and wheezing can be related to airway irritation, whereas recurrent pneumonias, fevers, and stridor are common obstructive symptoms. Some patients present with dysphagia because extraluminal tumor compresses or directly invades the esophagus.

Diagnosis Standard chest radiographic examination of a patient with ACC can demonstrate a centrally located mass that is indistinguishable from bronchogenic carcinoma; however, the most frequent radiologic findings are subtle airway abnormalities or pulmonary changes caused by obstruction. CT and magnetic resonance imaging can be useful in delineating the extent of local invasion and locations of metastases.49,50 Bronchoscopy demonstrates two classic appearances: localized polypoid masses or sessile lesions with diffuse submucosal involvement.2 Bronchoscopic biopsy is usually diagnostic. FIGURE 56-4 Adenoid cystic carcinoma of the bronchus, featuring classic infiltrating cribriform cylindromatous architecture (H&E, ×130).

FIGURE 56-5 Adenoid cystic carcinoma of the bronchus, demonstrating the propensity to invade perineurium and nerve proper. Characteristic spread along neural routes makes this tumor extremely difficult to eradicate (H&E, ×250).

Treatment Complete surgical resection offers the best chance for longterm survival. However, only 60% of patients have disease that allows complete resection. Local invasion through the wall of the trachea is uniform, and extensive submucosal invasion well beyond the gross margins of the tumor is the rule rather than the exception. Unresectable lesions can have either extensive airway involvement precluding adequate reconstruction or invasion of unresectable surrounding structures such as the aorta. Because of the propensity of ACCs to extend along the submucosal plane and perineural lymphatics, frozen-section evaluation of the bronchial margins is important. The extent of resection required varies considerably with the size and location of the tumor. In the largest published series of 32 resected patients, Maziak and colleagues (Maziak et al, 1996)43 performed tracheal resections ranging from 3 to 8 cm in length, including 12 carinal resections, 9 of which also necessitated lung resection including sleeve lobectomy or pneumonectomy. Complete local lymph node dissection has also been advocated in these patients.51 Patients with unresectable disease may benefit from tumor debulking, either surgically or through endobronchial techniques. Useful endobronchial techniques include mechanical debulking and laser ablation. The role of photodynamic therapy has not been defined in these rare lesions. There have been reports of long-term survival after incomplete resection with gross tumor left behind at the radial margin.52 After incomplete resection, patients may benefit from postoperative radiotherapy, which appears to improve local control and long-term survival.48 Primary radiation therapy has been used for unresectable ACCs with mixed results. Almost all tumors respond initially

tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 704

1/21/2008 12:10:56 PM

Chapter 56 Bronchial Gland Tumors

705

TABLE 56-4 Adenoid Cystic Carcinoma Series Overall Survival (%) Institution (Years)

No. Patients

5-Year

10-Year

Toronto, Canada53 (1952-1972)

16

39

20

20

61

35

12

83

0

16

70

38

Mayo Clinic

51

(1927-1977)

Tokyo, Japan46 (1964-1988) 44

Armed Forces Institute of Pathology 43

Toronto, Canada

(1970-1992)

32 resected

79

51

Innsbruck, Austria54 (1966-1992)

(1963-1995)

16

79

57

Minami-ku, Japan48 (1972-1998)

11 resected

91

76

to radiation, but local recurrence is common. Maziak and colleagues (Maziak et al, 1996) 43 described six patients who received primary radiation therapy, reporting two local recurrences and reduced mean survival in these patients compared with those with resectable disease. Kanematsu and colleagues48 described a similar group of five patients, of whom three had local recurrence at 5 years. Chemotherapy has been relatively ineffective in the treatment of head and neck ACC, suggesting that current chemotherapeutic agents will prove to be similarly ineffective for bronchial ACC.

Results Because of the relative rarity of this tumor, the largest series in the literature includes only 38 patients. As a result, there have been no randomized trials studying the effects of neoadjuvant or adjuvant radiation therapy or chemotherapy. Long-term survival is most often limited by late local recurrence or hematogenous metastases (Table 56-4). The most common site of metastases is pulmonary, followed by liver, bone, and brain. Metastatic disease in one study was identified in 45% of patients at a mean of 100 months after initial therapy (Maziak et al, 1996).43 Pulmonary metastases often remained asymptomatic for long periods, and even after diagnosis of metastatic disease patients lived a mean of 37 additional months. Local recurrence similarly occurred late, at a mean of 88 months after initial treatment, and subsequent survival averaged 33 months. Regional lymph node involvement at the time of initial resection demonstrated a trend toward decreased survival (mean, 42 versus 111 months), but the difference was not statistically significant. It is important to remember that the patients described in the studies included in Table 56-4 underwent a variety of treatment protocols over a span of 65 years. Survival data represent a rough estimate of prognosis at best.

MUCOEPIDERMOID CARCINOMA Mucoepidermoid carcinoma is a rare tumor constituting 0.1% to 0.2% of all lung tumors and only 1% to 5% of bronchial gland tumors.55,56 As with the other bronchial gland tumors, this tumor is seen across a wide age range, most commonly in the fifth decade. There is no gender predominance.

FIGURE 56-6 Mucoepidermoid carcinoma of the bronchus, low grade, composed of squamous, glandular, and intermediate elements. Note invasion of bronchial cartilage (H&E, ×130).

Pathology Unlike ACCs, most mucoepidermoid carcinomas arise in the proximal segmental bronchi rather than in the trachea. Histologically, these tumors are composed of squamous, mucous, and intermediate cell types with varying proportions depending on the grade of the tumor. Tumors are classified as low or high grade depending on the number of mitoses present, level of necrosis, and nuclear pleomorphism (Figs. 56-6 and 56-7).56,57 Low-grade tumors tend to contain a higher proportion of mucous cells and high-grade tumors contain more squamous cells.56,58

tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 705

1/21/2008 12:10:57 PM

706

Section 3 Lung

TABLE 56-5 Mucoepidermoid Carcinoma Series Overall Survival (%) Institution (Years)

No. Patients

Memorial Sloan-Kettering60 (1948-1968)

12 high grade

Mayo Clinic

51

(1927-1977)

5-Year

10-Year

0

0

12

56

43

Armed Forces Institute of Pathology58 (1960-1986)

41 low grade 13 high grade

95 69

— —

Massachusetts General56 (1948-1988)

15 low grade 3 high grade

100 0

— —

grade mucoepidermoid carcinoma. Sixteen patients with no regional node involvement had a 5-year survival rate of 44%. In eight patients with N1 metastases 5-year survival was reduced to 25%, and no patient with N2 metastases survived for 5 years. As with carcinoid tumors, mucoepidermoid carcinomas can arise peripherally and extend centrally. In such cases, lung preservation through the use of lobectomies or sleeve resections are considered. Adjuvant radiation and chemotherapy have not been shown to be effective in patients with highgrade histology or incomplete resection.56

MUCOUS GLAND ADENOMA

FIGURE 56-7 Mucoepidermoid carcinoma of the bronchus, low grade, with predominance of intermediate cells (large size with clear cytoplasm and bland nuclei). These stand in contrast to cells with more eosinophilic and hyperchromatic nuclei (arrows) (H&E, ×250).

Diagnosis, Treatment, and Results As with the other bronchial gland tumors, mucoepidermoid carcinomas usually manifest with signs of bronchial irritation or obstruction (cough, hemoptysis, wheezing, and postobstructive pneumonia). Radiologic studies demonstrate either the tumor itself or signs of airway obstruction. On CT, mucoepidermoid carcinoma appears smoothly marginated, either oval or lobulated, and often conforms to the branching pattern of the airways.59 Complete surgical resection is the treatment of choice. Surgical resection with negative margins is curative for most low-grade tumors. High-grade tumors tend to be more aggressive, with larger tumor size and a higher incidence of lymphatic and distant metastases at presentation. These are investigated and treated in a fashion similar to that for non– small cell tumors, with hilar and mediastinal lymph node sampling or dissection. The prognosis is worse for high-grade tumors than for low-grade tumors (Table 56-5). Regional lymph node involvement at the time of resection also portends a worse prognosis. Vadasz and Egervary (Vadasz and Egervary, 2000)61 reported a series of 29 patients with high-

The least common of the bronchial gland tumors is the mucous gland adenoma. There have been multiple case reports of this rare tumor in the literature; however, the largest reported series consisted of only 10 patients (England and Hochholtzer, 1995).62 Mucous gland adenoma arises most commonly from the submucosal mucous glands of the bronchi, but it can also occur in the trachea. Histologically, mucous gland adenomas may appear glandular, tubulocystic, or papillocystic, and they often show a mixture of these features. The tumors are rich in mucins and are immunopositive for epithelial markers. The tumor commonly extends into the lumen of the airway. Patients present with symptoms of progressive airway obstruction. These tumors are completely excised with a negative margin because there have been reports of recurrences after local excision. If the tumor is diagnosed preoperatively, endoscopic resection can be considered. If this is successful, close follow-up with repeat bronchoscopy is advised. These are entirely benign tumors, with neither invasion of pulmonary parenchyma or lymph node metastases reported.63

COMMENTS AND CONTROVERSIES These uncommon, but not rare, tumors can present diagnostic and management dilemmas. Distinction from bronchogenic carcinoma is critical because conservative or lung-sparing resection, often by bronchoplastic procedures, is usually curative. The classification of carcinoid tumors is confusing. The author does not emphasize the currently accepted classification of neuroendocrine carcinomas: grade I (typical carcinoid), grade II (atypical carcinoid), and grade III (large-cell neuroendocrine carcinoma).1,2

tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 706

1/21/2008 12:10:58 PM

Chapter 56 Bronchial Gland Tumors

The differentiation of grade I and grade II neuroendocrine carcinoma is clearly described and is based on the number of mitoses and the presence of necrosis. The author correctly notes the propensity of ACCs to manifest with extensive perineural and lymphatic spread, making negative surgical margins difficult to achieve. Yet, long-term survival can be observed, even when surgical margins are microscopically positive. Postoperative radiation probably improves local control. Therefore, overly radical resections are not warranted for this pathology. 1. Travis WD, Rush W, Flieder DB, et al: Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 22:934-944, 1998. 2. World Health Organization: Histologic Typing of Lung and Pleural Tumors, 3rd ed. Geneva, The World Health Organization, 1999.

707

KEY REFERENCES England DM, Hochholtzer L: Truly benign “bronchial adenoma.” Report of 10 cases of mucous gland adenoma with immunohistochemical and ultrastructural findings. Am J Surg Pathol 19:887-899, 1995. Harpole DH Jr, Feldman JM, Buchanan S, et al: Bronchial carcinoid tumors: A retrospective analysis of 126 patients. Ann Thorac Surg 54:50, 1992. Maziak DE, Todd TRJ, Keshavjee SH, et al: Adenoid cystic carcinoma of the airway: Thirty-two-year experience. J Thorac Cardiovasc Surg 112:1522-1532, 1996. Quaedvlieg PF, Visser O, Lamers CB, et al: Epidemiology and survival in patients with carcinoid disease in the Netherlands. An epidemiological study with 2391 patients. Ann Oncol 12:1295-1300, 2001. Vadasz P, Egervary M: Mucoepidermoid bronchial tumors: A review of 34 operated cases. Eur J Cardiothorac Surg 17:566-569, 2000.

G. A. P.

tahir99-VRG vip.persianss.ir

Ch056-F06861.indd 707

1/21/2008 12:10:58 PM

chapter

BIOLOGY AND EPIDEMIOLOGY OF LUNG CANCER

57

Philip W. Smith David R. Jones

Key Points ■ Ninety percent of lung cancers are caused by smoking tobacco,

■

■

■

■

and lung cancer is the leading cause of cancer death among both men and women in the United States. Eighty percent of lung cancers are non–small cell lung cancers, with adenocarcinoma currently the most common histologic type. Advances in genomics and proteomics will allow improved classification and identification of prognostic markers in non–small cell lung cancer. Epigenetic changes, including promoter methylation and histone deacetylation, are a crucial early event in lung carcinogenesis and represent potential targets for screening and therapy. An improving understanding of the molecular events in lung cancer is guiding ongoing translational research with an emphasis on molecularly targeted therapies.

HISTORICAL NOTE Early in the 20th century, primary lung cancer was vanishingly rare. When Alton Oschner was a medical student in St. Louis in 1919, his entire class was summoned to observe the autopsy of a man who had died from lung cancer because the instructor believed that his students would never again have the chance to observe this obscure disease. In 1936, Dr. Ochsner saw his next case of lung cancer, and he treated nine such patients over 6 months. He soon became one of the first physicians to suggest that smoking was the cause of this nascent epidemic and published his series in 1939 with Dr. Michael DeBakey. F.H. Muller, a German physician, was one of the other early physicians to make the association between increases in smoking and lung cancer in his 1939 manuscript. The incidence of lung cancer began to accelerate in the 1930s. Throughout most of the rest of the century, the incidence and mortality continued to rise in men, and subsequently in women as well. Early in the epidemic, much attention was focused on automobile exhaust and air pollution as etiologic agents for lung cancer, until case-control studies by Doll, Hill, Wynder, and Graham in the 1950s provided stronger epidemiologic support for tobacco smoke as the primary cause of lung cancer. Other environmental causes have been identified, but none with the overwhelming impact of smoking. The epidemiologic evidence has become irrefutable over time, and investigations into the underlying biology have provided further support. Great strides have been made in tumor

biology, including in the field of lung cancer. The observation of Stehelin that the genes responsible for carcinogenesis are altered forms of genes that are normally present initiated many of the advances that have increased understanding of lung carcinogenesis at the molecular level. Shih and Murray were among the first to identify and sequence human oncogenes. Current work in lung cancer biology focuses on identifying molecularly targeted therapies, some of which are now in clinical trials. Despite all the efforts and advances, lung cancer remains a highly fatal disease with little improvement in overall survival despite modern surgical and medical care. This has provided a significant impetus to more fully investigate the tumor biology of lung cancer, in the hope that potential targets for molecularly based treatment strategies can be identified. Although advances in screening, diagnosis, and surgical and medical therapy are crucial, Dr. Ochsner’s hypothesis remains true. Eradication of tobacco smoking remains paramount, and if this were achieved, lung cancer could again become a rare disease. HISTORICAL READINGS Doll R, Hill AB: A study of the aetiology of carcinoma of the lung. BMJ 13:1271, 1952. Doll R, Hill AB: The mortality of doctors in relation to their smoking habits: A preliminary report. BMJ 1:1451-1455, 1954. Murray MJ, Shilo BZ, Shih C, et al: Three different human tumor cell lines contain different oncogenes. Cell 25:355-361, 1981. Ochsner A, DeBakey M: Primary pulmonary malignancy: Treatment by total pneumonectomy. Analysis of 79 collected cases and presentation of 7 personal cases. Surg Gynecol Obstet 68:435-451, 1939. Shih C, Padhy LC, Murray M, Weinberg RA: Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:261-264, 1981. Stehelin D, Varmus HE, Bishop JM, Vogt PK: DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170-173, 1976.

DESCRIPTIVE EPIDEMIOLOGY Lung cancer is a worldwide epidemic, and it is the second most common non–skin cancer, behind prostate cancer in men and breast cancer in women. Lung cancer mortality rates remain high, with an overall 5-year survival of only 15%. It is the leading cause of cancer death in the United States for both men and women, representing 28.7% of all cancer mortality. This exceeds the mortality rates from colorectal cancer, prostate cancer, and breast cancer combined. In the year 2005, there are estimated to be 172,570 new cases of lung cancer and 163,510 deaths.1

708 tahir99-VRG vip.persianss.ir

Ch057-F06861.indd 708

1/21/2008 12:11:49 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

Lung cancer represented fewer than 1% of all malignancies in the United States in 1920. Subsequently, increased exposure to smoking, as well as an increased lifespan, combined to promote a remarkable rise in lung cancer incidence and mortality. The current epidemic of lung cancer mortality in the United States began in approximately 1930, initially in men (Fig. 57-1). By the mid 1950s lung cancer was the most common cause of cancer death among men. The rise of lung cancer in women occurred almost 30 years later, mirroring their smoking patterns (Fig. 57-2). Over most of the rest of the century, the incidence and mortality of lung cancer continued to rise in both women and men. Lung cancer is the most commonly diagnosed cancer worldwide, with more than 1.2 million cases annually. Incidence varies widely across the world, with lung cancer being more common in developed than undeveloped countries. Although pollution and other exposures are also important, the spreading epidemic mirrors the increased rates of cigarette smoking.

Gender Distribution Because the lung cancer epidemic in women lagged behind that in men, the initial Surgeon General’s Report in 1964 could only support that smoking caused lung cancer in men. Smoking has since been well established as the primary cause of lung cancer in both sexes.2 As seen in Figure 57-2, lung cancer surpassed breast cancer as the leading cause of cancer

709

death in women in 1987 and accounted for about 27% of all female cancer deaths in 2005.1 Despite its declining incidence in men since the early 1980s, lung cancer remains more common in men than in women, with the incidence twice as high in men in most nations (Alberg and Samet, 2003).3 Lung cancer incidence rapidly accelerated in women beginning in the 1960s, and the death rate from lung cancer among U.S. women increased by 600% from 1930 to 1997.2 Decreased smoking rates have had significant impacts on lung cancer incidence, and although smoking prevalence in men has decreased by almost one half from its peak in the 1960s, smoking prevalence in women has decreased by only 25%. Accordingly, declines in lung cancer incidence have not manifested in women as they have in men. Recently, the lung cancer mortality rate in women has leveled off for the first time after decades of steady increase. It remains unclear whether this represents a true peak because birth cohorts of women with the highest smoking prevalence have yet to reach the ages of highest lung cancer risk.4 Some have predicted that lung cancer incidence in women will not show a true decline until 2020.5 If lung cancer incidence has indeed peaked in women, it will be at a significantly lower level than the peak seen in men. Based on recent trends in both lung cancer prevalence and smoking patterns, lung cancer is predicted to be equally common in both genders by 2030.6 It has been suggested that women may be more susceptible to the carcinogens of cigarette smoke than men, although this

FIGURE 57-1 Annual age-adjusted cancer death rates among males for selected cancer types, United States, 1930 to 2001. Rates are ageadjusted to the 2000 U.S. standard population. (FROM JEMAL A, MURRAY T, WARD E, ET AL: CANCER STATISTICS, 2005. CA: CANCER J CLIN 55:1, 2005, FIGURE 4, P 17.)

tahir99-VRG vip.persianss.ir

Ch057-F06861.indd 709

1/21/2008 12:11:49 PM

710

Section 3 Lung

FIGURE 57-2 Annual age-adjusted cancer death rates among females for selected cancer types, United States, 1930 to 2001. Rates are ageadjusted to the 2000 U.S. standard population. (FROM JEMAL A, MURRAY T, WARD E, ET AL: CANCER STATISTICS, 2005. CA: CANCER J CLIN 55:1, 2005, FIGURE 5, P 18.)

Age Distribution Lung cancer is primarily a disease of older populations, with fewer than 0.5% of lung cancer deaths occurring in those younger than 40 years of age.1 Both men and women have a 0.03% likelihood of developing lung cancer from birth to age 39. In comparison, from age 60 to age 79, the probability of

800 700 Rate per 100,000

is controversial. In a 1993 case-control study of more than 800 Canadian smokers, Risch and colleagues7 found that, among smokers with a 40 pack-year history, the odds ratio of developing lung cancer was 27.9 for women and 9.6 for men. A subsequent U.S. hospital-based case-control study had similar findings.8 These studies have been questioned in part based on the methodology of the control data and have recently been contradicted. The report of a large prospective cohort study by Bain and associates10 in 2004 found no evidence of increased susceptibility in women compared to men with similar smoking history. These data added to the findings of cohort studies from American Cancer Society Cancer Prevention Studies I and II, as well as multiple non-U.S. cohort studies, none of which demonstrated increased susceptibility in women.9-12 Therefore, current evidence suggests that there is minimal, if any, increased susceptibility to the lung carcinogenicity of tobacco smoke in women. Nevertheless, the biologic explorations stemming from this debate have revealed some biologic gender differences in lung cancer, including differences in estrogen and progesterone receptor effects, differential responses to growth factors, and a higher percentage of adenocarcinoma in women.9

White males White females Black males Black females

600 500 400 300 200 100 0 0

10

20

30

40 50 Age in Years

60

70

80

FIGURE 57-3 Age-specific rates of lung cancer in the United States by gender and race. (FROM PARKIN DM, WHELAN SL, FERLAY J, ET AL: CANCER INCIDENCE IN FIVE CONTINENTS, VOL 7. IARC SCIENTIFIC PUBLICATIONS NO. 143. LYON, INTERNATIONAL AGENCY FOR RESEARCH ON CANCER, 1997, PP 314-321, 842, 843.)

developing lung cancer is 5.75% in men and 3.91% in women.1 As shown in Figure 57-3, among men in North America, lung cancer rates rise throughout life, most steeply after 50 years of age, except at extreme old age. The downturn observed at earlier ages in women reflects the fact that the female cohorts of heavier smokers have not yet reached the age of highest cancer incidence; lung cancer incidence and mortality trends follow the trend of prevalence of cigarette smoking, with a latency of approximately 20 years.4

tahir99-VRG vip.persianss.ir

Ch057-F06861.indd 710

1/21/2008 12:11:49 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

Race Distribution Lung cancer is not evenly distributed across racial lines. African American populations having a higher incidence of lung cancer than Caucasian populations do. There is a particularly high incidence of lung cancer among African American men which is seen at almost every age (see Fig. 57-3). From 1997 to 2001, the age-standardized U.S. annual incidence of lung cancer per 100,000 was 117 among black men but only 80 among white men (a 46% difference). This disparity has been present for at least the last 40 years and is only partially explained by controlling for socioeconomic status.13,14 In women, there is far less racial disparity; with rates of 51 and 54 per 100,000 among white and black American women, respectively.1,15 Ethnic communities in America that have markedly lower incidences of lung cancer include Asian Americans/Pacific Islanders, American Indians/ Alaskan Natives, and Hispanics; the incidence of lung cancer in these groups ranges from 23 to 29 per 100,000 in women and from 45 to 61 per 100,000 in men.1 Although the clinical stage at presentation is not markedly different between black and white Americans, there are significant differences in survival.1,15 For all clinical stages of lung cancer, the 5-year survival rate between 1995 and 2001 was 12% to 15% lower in black men and women than in their white counterparts (depending on stage).15 Despite investigation, no clear reason for this racial disparity in incidence and survival has been identified. Although examination of historic smoking patterns has not yielded an answer, the type of cigarette smoked may play some role. It has been proposed that menthol cigarettes carry a greater risk for lung cancer than standard cigarettes. African Americans are approximately three times more likely to smoke mentholated cigarettes than white Americans.16 However, available data on the relative carcinogenicity of mentholated cigarettes are inconclusive and at best only partially explain the observed racial differences in lung cancer incidence.6,16,17

Geography and Socioeconomic Status There is wide variation in incidence by country and within geographic regions of countries, with age-standardized mortality rates varying over 25-fold in both men and women.18 Currently, lung cancer tends to be more common in developed countries (North America and Europe) than in developing countries (Africa and South America) and follows historical smoking trends of the last 40 years.6 As smoking prevalence continues to change across the world, international differences in lung cancer will also change. The number of lung cancers diagnosed each year in many of the countries of Asia, Africa, and South America is predicted to increase substantially. By the middle of the 21st century, lung cancer is likely be most common in China and Japan, whereas declines are expected to continue in much of Europe and North America. The increased incidence of lung cancer in less developed areas is also reflected in the lung cancer distribution stratified by socioeconomic status (SES). For cancer in general, there is consistent evidence of a significant association between lower SES and cancer incidence and mortality. Specifically,

711

lung cancer incidence and mortality are greater in lower socioeconomic groups, and there may also be an association between SES and lung cancer survivorship. Lower SES is associated with higher rates of smoking, worse environmental and occupational exposures to carcinogens, and unfavorable diets.19 In a 17-year prospective Copenhagen male cohort study, Hein and colleagues20 found that the relative risk (RR) of lung cancer was 3.7 for the group with the lowest SES compared to the group with the highest SES. Significantly, this RR only dropped to 2.9 after controlling for smoking habits. In Canada, the risk of lung cancer in both sexes was found to have a significant inverse association with income, education, and social class that was not explained by smoking.19 In less developed countries, the SES effect remains. In China, those in lower SES groups had a six-fold increased risk of lung cancer compared to those with higher SES, again including controls for smoking.6,21 Overall, there is a disproportionately increased incidence of lung cancer in both genders in less developed countries as well as in lower SES groups.

Histology Distribution As with liver and brain malignancies, the most common lung neoplasm is a metastatic lesion from another primary site. This chapter focuses on primary lung cancer. Primary lung cancer is generally classified into two major types, small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). NSCLC is further subdivided into three major histologic types: squamous carcinoma, adenocarcinoma, and large cell carcinoma. The categorization of SCLC versus NSCLC has proved useful because the two types have different basic therapeutic approaches. SCLC represents about 20% of primary lung cancers, is highly responsive to chemotherapy, and is usually disseminated at presentation. Therefore, nonoperative management is the primary therapy for SCLC, although most patients have relapse within 1 year. In contrast, NSCLC represents about 80% of lung cancers and responds poorly to chemotherapy; the basis for curative therapy for NSCLC consists of local treatment with irradiation or surgery. Adenocarcinoma is currently the most common histologic variety of NSCLC. Squamous cell lung cancer was previously more prevalent. As recently as 1973-1977, the age-adjusted incidence per 100,000 people was 13.4 for squamous cell lung cancer and 10.5 for adenocarcinoma. Adenocarcinoma surpassed squamous cell carcinoma in the mid 1980s, and the trend has continued. In the period from 1992 to 1998, the incidence per 100,000 was 18.9 for adenocarcinoma and 11.5 for squamous cell carcinoma (Alberg and Samet, 2003).3 While the overall incidence of lung cancer continues to decline, the population incidence of adenocarcinoma has remained steady overall and continues to rise in women (Wingo et al, 1999).22 Although it was once believed that adenocarcinoma was minimally related to smoking, it is now clear that smoking is the primary cause of all histologies of primary lung cancer, with the dose-response relationship being steepest for SCLC.23 The cause of the shift in histology is controversial. It was previously postulated that improved diagnostic techniques

tahir99-VRG vip.persianss.ir

Ch057-F06861.indd 711

1/21/2008 12:11:50 PM

712

Section 3 Lung

discover more adenocarcinomas in the distal airways, and that improvements in mucin staining allow better histologic sensitivity for adenocarcinoma. Changes in cigarettes and in smoking behavior have also been investigated. Newer cigarettes have higher concentrations of nitrosamines, which have been associated with adenocarcinoma in animal models, and the smoke also tends to be inhaled more deeply into the distal airways. A large retrospective analysis revealed that increases in adenocarcinoma corresponded temporally with changes in smoking behavior and cigarette design, and that the observed shift could not be directly associated with diagnostic advances.23

Stage at Presentation Although lung cancer is frequently fatal even with only localized disease at presentation, one of the reasons for the overall poor survival is that a large percentage of patients present with locoregionally advanced or distant metastatic disease. This is largely attributed to the asymptomatic nature of early-stage lung cancer. Only 16% of patients have localized disease at presentation, 37% have regional disease, and 39% have advanced disease (8% are unstaged).1,15 This distribution is very similar in both the Caucasian and the African American population. When these data are coupled with 5year survival rates of 49% for localized disease, 16% for regional disease, and 2% for distant metastatic disease, the reason for the overall 15% all-stage 5-year survival rate becomes clear.

RISK FACTORS/ANALYTIC EPIDEMIOLOGY The likelihood that an individual will develop lung cancer is based on a synergy of individual factors and environmental exposures. Lung cancer is unique in having a very clearly identified and accepted primary etiologic factor: tobacco smoke. In the United States, population attributable risk estimates show that active smoking is responsible for 90% of lung cancer cases, occupational exposures for 9% to 15%, radon for 10%, outdoor air pollution for 1% to 2%, and environmental tobacco smoke for 1% to 2%. The total is greater than 100% because of interactions among risk factors (Alberg and Samet, 2003).3

History As early as 1912, there were published suspicions of the relationship of smoking to lung cancer, although they received little notice at the time.26 In the early 1950s, epidemiologic case-control studies in both the United States and Britain (including the landmark publications of Peto and Doll) demonstrated that there was a strong association between cigarette smoking and lung cancer.27-29 Following the epidemiologic studies, biologic evidence was presented. In 1953 and 1957, bioassays showed a dose-response relationship between the amount of cigarette tar applied to mouse skin and induction of skin tumors.30,31 In 1973, inhalation studies with hamsters demonstrated a dose-response relationship between the amount of smoke inhaled and the induction of respiratory tract cancers.32 By 1964, the accumulated evidence was adequate for the U.S. Surgeon General to issue a report that smoking causes lung cancer.33 In 1986, an international working group also established the relationship between smoking and many primary cancer sites, including lung.34 The data are strong enough that even tobacco industry literature now describes the strong association.35 In countries, such as the United States, where cigarette smoking is common, it is now believed that approximately 90% of lung cancers are caused by smoking.24 There is an overwhelming amount of almost universally accepted epidemiologic and biologic evidence that smoking causes lung cancer.

Dose Effect Cohort and case-control studies have demonstrated the dose effect of smoking in lung cancer risk for both duration of smoking and number of cigarettes smoked per day.36 In the mid-1980s, Peto37 proposed that duration of smoking was much more important than amount of smoking, demonstrating an exponential effect of duration of smoking on lung cancer risk, compared with an essentially linear effect for the amount smoked per day. The far greater impact of duration of smoking has been further validated and remains widely accepted. One effect of this dependence on duration is that the lifetime risk of lung cancer varies substantially according to whether cigarette smoking starts at the age of 15 years or younger or is delayed until 20 or 25 years of age.34 It also underlines the importance of complete smoking cessation to decrease lung cancer risk, rather than simply cutting back.

Smoking The deleterious effects of smoking on many aspects of health are now well accepted. Smoking kills not only through lung cancer but also in many other ways, including non-neoplastic lung disease, cardiac disease, vascular disease, and cancers outside the lung. It is estimated that 20% of all people living in developed countries will eventually die from tobaccorelated disease.24 Smoking-related illnesses account for 440,000 deaths per year, which occur 12 years earlier than would be expected, resulting in an annual loss of 5 million life-years to smoking.25 Smokers have an approximately 20fold increased risk of lung cancer compared with those who have never smoked, and smoking is by far the leading cause of lung cancer.3

Ch057-F06861.indd 712

Cigars, Pipes, and the Changing Cigarette Cigarettes have changed significantly over time. The concept of the so-called less harmful cigarette has been, and continues to be, an alternative approach toward reducing smokingrelated illness and mortality. Wynder and Hoffmann38 began research on a less harmful cigarette soon after the recognition of the harm caused by cigarettes, but it has always been realized that there is no safe cigarette.39 In addition to public health efforts toward smoking cessation, manufacturers have decreased tar and nicotine yields significantly. Filter tips have become widespread. Side holes designed to allow inflow of air to dilute the inhaled smoke were introduced. Although all of these changes have produced improved parameters on

1/21/2008 12:11:50 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

machines that are used to analyze cigarettes, they are of questionable benefit in vivo because the expected reduction of cigarette-associated mortality in smokers has not occurred.39 Cigarette smoke is a very complex mixture, in which more than 4800 separate compounds have been identified, some in the volatile phase and many in the tar. Tar is the name given to the residue of cigarette smoke that is trapped on a filter (excluding water and nicotine). The International Agency for Research on Cancer (IARC) classifies 10 of these compounds as known human carcinogens, 9 as probable human carcinogens, and 227 as possible carcinogens.39-42 The major toxic agents are nicotine, carbon monoxide, hydrogen cyanide, nitrogen oxides, volatile aldehydes, alkenes, and aromatic hydrocarbons. Because tar as a whole is the major carcinogen, and nicotine the major toxic and addictive agent, these were chosen as the analytic parameters in attempting to produce the less harmful cigarette.39 Cigarette manufacturers have created low-yield cigarettes, which have decreased tar and nicotine as measured by a standardized smoking machine. From 1953 to 1996, the yield of tar in an average cigarette was reduced from 37 to 12 mg, and the nicotine yield was reduced from 2.7 to 0.85 mg. This is largely due to increased prevalence of filters; over approximately the same time frame, filtered cigarette sales increased from 0.5% of the U.S. market share to 97%.39 In the United States, the vast majority of filters are made of cellulose acetate and have been shown to significantly decrease the tar and nicotine yield as well as that of volatile nitrosamines and phenols. Approximately two thirds of modern cigarettes have perforated filters or side holes that cause air dilution of the smoke by 20% to 45%. Newer processing techniques result in reconstituted tobacco with reduced concentrations of tar, nicotine, volatile phenols, and polycyclic aromatic hydrocarbons, as well as significantly less tobacco mass per cigarette.39 Early studies of the effects of modified cigarettes were promising. Multiple case-control and cohort studies published between 1968 and 1981 reported that the long-term smoker of low-yield cigarettes had a 20% to 50% lower risk for lung cancer than the smoker of conventional higher-yield cigarettes. This conclusion was accepted by the Surgeon General in 1981.39,43-48 However, more recent studies have contradicted these results. Between 1983 and 2001, at least 10 epidemiologic studies reported that the lung cancer risk of smokers of low-yield cigarettes is comparable to, or only slightly lower than, that of smokers of nonfilter cigarettes, and biomarker studies have not correlated with actual decreased exposures to toxins in smokers of the so-called less harmful cigarettes.39,49-55 One reason for the failure of modern cigarettes to decrease their associated health hazards is the change in smoking habits of smokers. The main driving force for individuals in the amount that they smoke is the level of nicotine to which they are addicted. Because lower-tar cigarettes are also lower in nicotine, smokers compensate by adopting practices that increase the amount of nicotine, and therefore the amount of tar, they inhale. These include deeper puffs, smoking more

Ch057-F06861.indd 713

713

cigarettes per day, and covering ventilation holes.56-59 The increased incidence of peripheral adenocarcinoma relative to other histologic types is thought to be associated with increased puff volumes.23 The compensatory changes in smoking patterns reduce the theoretical benefit of loweryield cigarettes, and changes in cigarette design over the last 50 years have not benefited public health.39 Cigarette smoking confers greater risk than smoking other types of tobacco, such as cigars and pipes. This was reported by Peto and Doll60 in 1976, in their report of 20 years of data from the British doctors study. This finding remained true in the 40-year follow-up of that same study,61 in which the risk for current smokers of cigarettes was approximately double that of smokers of other types of tobacco. Another large cohort study similarly found that the RR for lung cancer was 2.1 for cigar smokers compared with nonsmokers and increased in a dose-response fashion. Although this risk is significant, it is below that conferred by cigarette smoking.62

Second-Hand or Passive Smoking The number of never-smokers who die from lung cancer is approximately equal to the annual number of deaths from ovarian cancer.15 Most of these individuals have had significant exposure to environmental tobacco smoke (ETS). Passive smoking, or second-hand smoking, is the involuntary inhalation of ETS by nonsmokers. ETS has the same components as inhaled mainstream smoke, although with variation in relative proportions. The first studies to indicate a possible increased risk of lung cancer from passive smoking came from Japan and Greece, countries with a larger proportion of female nonsmokers than in North America. In a large cohort study, Hirayama63 reported an RR of 1.8 for female nonsmokers married to husbands who smoked, relative to those whose husbands did not smoke. Analysis of the amount of smoking by the husbands suggested a dose-response relationship between the extent of ETS exposure and the likelihood of developing lung cancer.63 A Greek hospital-based study, also from 1981, had almost identical findings.64 These early studies were greeted with modest skepticism and led to a succession of further investigations. Some were largely negative,65-67 probably secondary to the relative rarity of lung cancer in nonsmokers. To obtain sufficient subjects in a case-control study, Garfinkel and associates68 identified cases from four hospitals over 11 years. They found a significant doubling of risk for nonsmoking women whose husbands smoked 40 or more cigarettes a day, or 20 cigarettes while at home, relative to women with nonsmoking husbands. Further study supported this relationship, and in 1986 the Surgeon General concluded that ETS can cause lung cancer in nonsmokers.69 In 1992, ETS was classified as a known human carcinogen (Alberg and Samet, 2003).3 Despite multiple challenges, consensus opinion and mounting evidence from more than 50 studies (both case-control and cohort) support the carcinogenicity of ETS.70,71 The risks associated with ETS have been quantified. A recent cohort study involving more than 300,000 nonsmokers

1/21/2008 12:11:50 PM

714

Section 3 Lung

found an increased risk in association with exposure to ETS for lung cancer (odds ratio, 1.76). The risk was higher among former smokers than among never-smokers, perhaps indicating a greater susceptibility due to already existing mutations.72 Nonsmokers have a 20% higher risk of developing lung cancer if married to a smoker, compared with a nonsmoker married to a nonsmoker. One quarter of the relatively rare cases of lung cancer in never-smokers are thought to be caused by passive smoking, resulting in approximately 3000 lung cancer deaths annually in the United States.3,73,74

Impact of Cessation Tobacco products are the single most avoidable cause of all cancers, and avoidance of tobacco is by far the most effective measure to prevent lung cancer. One powerful indicator of the benefit of reduced tobacco consumption is the decline in overall age-adjusted lung cancer mortality among men since the mid 1980s, which is consistent with the reductions in smoking prevalence in this population since the 1950s.75,76 Smokers can benefit from smoking cessation at any age, although greater benefit is seen with quitting at an earlier age.25 As shown in Table 57-1, the longer that prior smokers continue not to smoke, the lower their risk of developing lung cancer becomes. After 10 years of abstinence, the risk of lung cancer is 30% to 50% lower than that of continuing smokers.25 Light smokers (1-9 cigarettes/day) can approach, but not reach, the general population risk of lung cancer after 30 years of cessation. Even heavy smokers (>40 cigarettes/day) have just over twice the population risk of lung cancer after 40 years of cessation (compared with >130 times the population risk were they to have continued smoking for that time).3,25,77,78 In general, studies have shown comparable

TABLE 57-1 Relative Risk (RR) of Lung Cancer Among Ex-Smokers,* by Length of Time Since Smoking Cessation and Number of Cigarettes Formerly Smoked, Among a Cohort of U.S. Veterans Cigarettes Smoked per Day While Smoking

Years Since Smoking Cessation

1-9

10-20

<5

7.6

12.5

5-9

3.6

5.1

10-19

2.2

4.3

20-29

1.7

30-39

0.5

≥40

1.1

≥40

All Ex-Smokers

20.6

26.9

16.1

11.5

13.6

7.8

6.8

7.8

5.1

3.3

3.4

5.9

3.3

2.1

2.8

4.5

2.0

1.6

1.8

2.3

1.5

21-39

*Compared to referent category of never-smokers (RR = 1.0). Adapted from Hrubec Z, McLaughlin JK: Former cigarette smoking and mortality among US veterans: A 26-year follow-up, 1954-1980. In Burns DM, Garfinkel L, Samet J (eds): Smoking and Tobacco Control Monograph No. 8: Changes in Cigarette-Related Disease Risks and Their Implication for Prevention and Control. NIH Publication No. 97-4213. Bethesda, MD, National Institutes of Health, 1997; and Alberg AJ, Samet JM: Epidemiology of lung cancer. Chest 123(1 Suppl):21S-49S, 2003, Table 3, p 27S.

Ch057-F06861.indd 714

reductions in risk after cessation, regardless of gender, type of tobacco smoked, or histologic type of lung cancer (Alberg and Samet, 2003).3 It is well known that smoking cessation is difficult, and those who are successful require an average of two to three attempts.25 Adjuncts to assist in smoking cessation have proved beneficial. Clinical interventions targeted at individuals have shown greater success than community-based public health interventions,76 and nicotine replacement therapy (NRT) plays a central role. A Cochrane Review of randomized controlled trials showed that 6- to 12-month cessation rates are significantly improved with the use of NRT. All of the commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler, and sublingual tablet) are effective and increase the odds of long-term cessation by approximately 1.5- to 2-fold regardless of setting.79 Antidepressant medications are another important adjunct. Two clinical trials have demonstrated evidence of significant effect from bupropion at both short-term (7 weeks) and 1-year follow-up. The bupropion group had twice the 1-year quit rate (30%) compared to the placebo group (15.6%). Further benefit was seen with the addition of NRT to bupropion (35%).80,81 The only drug approved by the U.S. Food and Drug Administration for this purpose is bupropion (Zyban or Wellbutrin), although fluoxetine (Prozac) has also been shown to be effective.76 Physician counseling is also effective; even less than 5 minutes of physician counseling time produces a small but measurable effect, as evidenced by 1 more patient in 40 successfully stopping smoking.82

General Occupational Exposures Although most lung cancers are caused by cigarette smoking, occupational exposures are the next most significant contributor, causing 9% to 15% of new lung cancers.3 Risk factors often overlap, and cigarette smoking is known to potentiate the effects of occupational carcinogens. Occupational exposures to asbestos, radon, tar, soot, arsenic, chromium, and nickel have all been shown to cause lung cancer. The evidence is less strong for other occupational exposures. For instance, exposure to diesel exhaust has been consistently associated with lung cancer in some populations (truck drivers) but inconsistently or not at all associated in other populations (heavy equipment operators).83 The reason for this difference is unknown. The role of silica as a direct carcinogen is also unclear. In 1997, an American Thoracic Society consensus stated that, although available data supported the conclusion that silicosis (a result of silica exposure) results in increased risk for bronchogenic carcinoma, the evidence was not clear for those exposed to silica who had never smoked or for those who were exposed to silica but did not develop silicosis.84

Asbestos Asbestos is the term for a group of naturally occurring fibers composed of hydrated magnesium silicates that are well suited to a variety of construction and insulation purposes. Exposure to asbestos occurs in shipyards, other manufacturing sites, mining, and insulating industries, among others.

1/21/2008 12:11:50 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

An association between asbestos exposure and lung cancer has been supported since the 1950s, and evidence has continued to mount. Similar to the controversy regarding silica, there remains debate as to whether lung cancer can be attributed to asbestos exposure in the absence of asbestosis.85,86 A recent review of nine epidemiologic studies on the topic found that two studies concluded asbestosis was necessary and seven did not. Overall, there were inadequate data to firmly support either position.87 Despite this debate, it is well accepted that asbestos exposure leads to lung cancer, directly or via asbestosis. Although smoking and asbestos are both independent causes of lung cancer, the combination of the two creates a powerful synergistic risk for lung cancer. The risk of lung cancer in a nonsmoker with asbestos exposure is approximately 5 times the population risk, but the risk in a smoker with asbestos exposure is more than 50 times greater than that of a nonexposed nonsmoker.88

Radiation X-radiation and γ-radiation have been shown to increase lung cancer risk.89 Lung cancer risk due to X-radiation has primarily been studied in three groups: Japanese atomic bomb survivors, patients receiving radiation therapy, and those with occupational exposures. The atomic bomb survivors had a single, high-dose exposure and were shown to have a significantly increased risk of lung cancer, among other malignancies, a relationship that held true after controlling for tobacco use.90-92 Initial estimations of lung cancer risk based on lower-dose X- and γ-radiation were based on extrapolation from the exposure of the atomic bomb cohort. Further study has not fully supported this model. One study of more than 64,000 Canadian patients with tuberculosis undergoing repeated chest fluoroscopy found no increased incidence of lung cancer.93 By contrast, the higher radiation doses given in older regimens of breast cancer radiation therapy conferred a RR of 1.8 for developing lung cancer at 10 years compared to those without breast irradiation, and the RR continued to increase with time after treatment.94 The available data do not clearly define lung cancer risk at lower exposures to X- and γ-radiation; nor is it known what level of exposure could be considered safe. This contrasts with radon exposure, where it is believed that there is no minimum dose that does not contribute to lung cancer risk. Radon is an inert gas that is naturally produced as a decay product of uranium and radium. Two of the daughters of radon decay produce high-energy alpha particles that can result in DNA damage in respiratory epithelium. Radon is present in indoor air, in outdoor air, and in many underground mines. Exposure to radon in the home accounts for about half of all nonmedical exposures to ionizing radiation. Radon exposure has been associated with lung cancer in both smokers and nonsmokers, and a synergistic effect has been demonstrated between smoking and radon exposure.3,95,96 High-level radon exposure (50-100 times that seen in homes) may occur occupationally, particularly in miners, and has been linked to an almost 13-fold increase in lung cancer mortality among never-smoking uranium miners.97

Ch057-F06861.indd 715

715

The risk associated with radon in the home has been the cause of much public concern over the past 20 years, spawning multiple studies with varied results. A meta-analysis of 13 such studies was published in 2005 and encompassed more than 21,000 patients. The collective findings revealed a small, but strongly significant, linear dose-effect relationship between home radon exposure and lung cancer. The same study concluded that home radon exposure causes 9% of lung cancer deaths in Europe.96 This matched the estimate of another study, which further concluded that 30% of lung cancers in never-smokers are attributable to indoor radon exposure.98 Radon exposure in homes can be decreased by relatively low-cost measures in existing homes and in new construction.

Air Pollution Early investigations into the lung cancer epidemic focused on air pollution. The eventual conclusion was that at most a small percentage of lung cancer cases are due to air pollution (∼1%). The burden of air pollution, and its potential carcinogens, demonstrates significant geographic variation. Areas with extreme air pollution, such as parts of China that depend on burning large amounts of coal, have demonstrated a significant and attributable increase in lung cancer incidence.99 In contrast, data from the United States have shown somewhat conflicting results. Some studies found no association between moderate air pollution and lung cancer, and others found that cities with high air particulate concentration had 1.4 times higher lung cancer mortality, and that the RR for residents in areas of high compared to low air sulfite concentration was 1.4.100,101 One 2005 study monitored more than 14,000 people in France over a 25-year period. Exposure to higher amounts of air pollution at the beginning of the study was associated with increased all-cause mortality, and specifically lung cancer mortality, over the follow-up period after controlling for smoking and other variables.102 Other studies, including those examining residence in proximity to point sources of pollution, support the idea that outdoor air pollution probably does contribute to lung cancer mortality, and does so in a dose-dependent fashion. Indoor air may be polluted with radon, asbestos, cigarette smoke, and exhaust from fires and cooking stoves (Alberg and Samet, 2003).3 As has been discussed, passive smoking, radon, and asbestos are causally associated with lung cancer. In poorer areas of the world, more severe indoor air pollution is seen as a result of combustion for heating and cooking. Burning coal indoors was probably a contributor to the elevated lung cancer mortality seen in some areas of China, as described earlier.99

Diet and Dietary Supplements Determining the effects of diet as either protective against, or a risk factor for, lung cancer is inherently difficult due to the overwhelming attributable risk of tobacco smoking and the confounding fact that cigarette smoking is associated with less healthy diets (Alberg and Samet, 2003).3 Early evidence for a dietary role in lung cancer preceded the lung cancer epidemic and came from the work of Wolbach and Howe,

1/21/2008 12:11:50 PM

716

Section 3 Lung

who reported in 1925 an association of squamous metaplasia in the respiratory tree with vitamin A deficiency.101a More recent interest in diet and lung cancer expanded after Bjelke’s report of a cohort study in Norway in 1975 indicating that vitamin A intake was negatively associated with lung cancer at all levels of smoking.103 Subsequent study has shifted the focus from vitamin A to β-carotene, a powerful antioxidant that can be converted to vitamin A and to antioxidant micronutrients in general. Broad evaluations of healthy versus unhealthy diets have found a protective effect against lung cancer with overall healthy diets, particularly diets high in fruits and vegetables. Several case-control and prospective cohort studies have consistently found a protective effect against lung cancer incidence and mortality for diets high in fruits and vegetables and those with high Recommended Food Scores. Because people with worse diets also have higher smoking rates, these results have been interrogated for the confounding effects of smoking. Numerous times, the protective effect was found to persist after controlling for smoking habits, although it is greatest among never-smokers.6,103-107 A pooled analysis of seven cohort studies in 2004 supported this finding and found the protective association to be stronger for fruits than for vegetables.108 Three correlation studies demonstrated an association between lung cancer mortality and consumption of dietary fat.109-111 Two of these studies controlled for tobacco consumption, both finding an independent contribution from dietary fat.110,111 The report of Xie and colleagues111 separately evaluated the lung cancer risk for animal versus vegetable fats. They found a highly significant correlation between animal fat and lung cancer, but no association with vegetable fat. In contrast, three cohort studies from 1993 to 1999 found no relationship between dietary fats and lung cancer.112-114 Further, a 2002 meta-analysis of eight prospective cohort studies encompassing more than 400,000 patients found no association between intakes of total or specific types of fat and lung cancer risk among never, past, or current smokers.115 The same meta-analysis also found no association of cholesterol with lung cancer incidence. Although the negative health effects of high-fat and high-cholesterol diets are generally accepted, the data remain unclear for their direct effect on lung cancer.

Vitamin A and β-Carotene After reports that the administration of preformed vitamin A (retinol) failed to decrease lung cancer risk,116 several authors found evidence for protective effects of diets high in vitamin A and β-carotene.117-121 A particularly strong protective effect was seen with high consumption of carrots.114 In contrast, the 1990 report of Jain and colleagues did not demonstrate a protective effect for β-carotene, retinol, or total vitamin A consumption.122 Subsequent studies shifted the focus from dietary β-carotene and vitamin A consumption to chemopreventive studies with administration of carotene and vitamin A as dietary supplements. The α-tocopherol, β-carotene (ATBC) study evaluated the antioxidants βcarotene and vitamin E in a randomized controlled trial for

Ch057-F06861.indd 716

lung cancer prevention. A statistically significant and unexpected 18% increase in lung cancer incidence and mortality was observed with β-carotene administration.123 The ATBC result was substantiated by the similar findings of the βCarotene and Retinol Efficacy Trial (CARET), which included asbestos-exposed patients and was stopped early due to the finding of no benefit and potential harm from β-carotene.124 Diets that are rich in β-carotene and vitamin A are probably beneficial, but administration of either as a pharmacologic supplement yields no benefit and β-carotene confers harm, particularly in heavy smokers. Despite investigations into molecular responses to β-carotene, the mechanisms of the adverse effect are not understood.125

Vitamin E The antioxidant vitamin E was evaluated with β-carotene in the ATBC trial. The initial analysis of ATBC found no effect for vitamin E on the incidence of lung cancer.123 Subsequent analyses indicated a beneficial effect with the highest versus the lowest quintile of vitamin E use and a stronger protective effect among those with less smoking history.125 The randomized, phase III Selenium and Vitamin E Cancer Prevention Trial (SELECT) is designed primarily to evaluate prostate cancer but also includes lung cancer as a primary end point. This study is ongoing.

Selenium Selenium is a trace mineral that is incorporated into proteins, forming selenoproteins which act as antioxidant enzymes. Selenium is found primarily in plant sources in concentrations that depend on local soil concentrations; high levels are found in whole grains, Brazil nuts, and legumes grown in the selenium-rich soil of the western United States.126 Selenium also inhibits DNA methyltransferase (DNMT) activity, an important aspect of epigenetic modifications early in lung cancer progression, and plays a role in the metabolism of polyunsaturated fat (Belinsky, 2005).127 A study designed to evaluate selenium supplementation for prevention of nonmelanoma skin cancers failed to demonstrate that effect but secondarily demonstrated a trend toward decreased incidence and mortality from multiple sites of carcinoma, including lung cancer.128 A 2004 meta-analysis of 16 case-control and cohort studies of selenium and lung cancer found an overall RR of 0.74 for development of lung cancer in subjects with high selenium exposure. This effect was most significant in those populations with a low average selenium level.129 As with vitamin E, the results of the SELECT trial are awaited for further evidence of the protective effect of selenium supplementation.

Flavonoids Flavonoids (found in whole grains and soybeans) are a group of potent plant-derived antioxidants. A 1997 cohort study of almost 10,000 Finnish women demonstrated an inverse association between the intake of flavonoids and incidence of all sites of cancer, but most strongly for lung cancer (RR = 0.54).130 Although most data have suggested a protective effect,130,131 a 2004 case-control study of three isoflavonoids

1/21/2008 12:11:51 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

among Greek women found no protective effect and even an unexpected positive association between one isoflavonoid and lung cancer.132

Isothiocyanates Isothiocyanates are metabolites of glucosinolates, a class of phytochemicals that are found in high concentrations in cruciferous vegetables. Isothiocyanates are thought to exert a cancer-protective effect by inhibiting phase I enzymes that are responsible for the bioactivation of carcinogens and by activating phase II enzymes that are involved in detoxification pathways, including glutathione S-transferase (GST).133 GST also serves as the clearance pathway for isothiocyanate. High isothiocyanate urine levels and high intake levels of glucosinolates have been found to have a protective effect against lung cancer. This effect was strongest in individuals with GST genetic polymorphisms that slow clearance of isothiocyanate, thus leading to higher maintained isothiocyanate levels.133-135

Inherited Genetic Factors Inclusive of tobacco and other exposures, individuals with the same exposure profile may develop lung cancer at different ages, cancers of different histologies, or no cancer at all. Although 90% of lung cancer is attributed to smoking tobacco, the lifetime risk of a smoker for development of lung cancer is only 10% to 20%.136 This suggests individual variation in susceptibility to lung carcinogens, and it has proved difficult

717

to identify those smokers who are at greatest risk.137 An association of lung cancer with positive family history was first noted in 1963 by Tokahuta and Lilienfeld.138 Multiple case-control studies, reviewed in Table 57-2, most of which controlled for smoking, have demonstrated an increased odds ratio for development of lung cancer if there is a positive family history.3 Further, there is evidence for mendelian inheritance of a tendency toward lung cancer from a proband segregation analysis of Louisiana families demonstrating a pattern of codominant inheritance.151 Twin studies, however, have not supported these findings,152 and overall evidence is mixed. It is hypothesized that an individual’s ability to activate and detoxify components of tobacco smoke may play a role in lung cancer susceptibility. Many tobacco smoke carcinogens are activated by phase I cytochrome P450 (CYP) enzymes. In phase I reactions, unreactive, nonpolar compounds are converted by oxidative reactions to highly reactive intermediates. In phase II reactions, these intermediates are conjugated, leading to generally less reactive and easily excretable compounds. The reactive intermediates have a potential to react with DNA, which may be an inciting event in carcinogenesis (Alberg and Samet, 2003).3,153 Polycyclic aromatic hydrocarbons, and other carcinogenic compounds in tobacco smoke, undergo phase I P450 activation. Two of the enzymes in this system, CYP1A1 and CYP2D6, have been investigated with regard to lung cancer risk. Studies of two different polymorphisms of CYP1A1 have yielded mixed results across different nationalities and

TABLE 57-2 Case-Control Studies Comparing People With and Without a Family History of Lung Cancer Author (Year)

Odds Ratio*

Comment

Tokuhata138 (1963)

2.4 (1.1, 5.2)

Adjusted for cigarette smoking, age, gender, generation

2.6 (1.7, 4.2)

Adjusted for gender, age, generation

2.7 (1.7, 4.2)

Adjusted for smoking, age, gender, occupational exposure

Parent: 5.3 (2.2, 12.8)

Adjusted for cigarette smoking, age, gender, ethnicity

3.9 (2.0, 7.6)

Adjusted for smoking

Parent: 1.1 (0.6, 2.3) Sibling: 3.0 (0.7, 12.5)

Adjusted for smoking, age

Tsugane144 (1987)

1.0 (0.7, 3.9)

Smoking and occupational exposure data collected, but not adjusted for

145

Tokuhata Ooi

140

139

(1964)

(1986)

Samet141 (1986) Wu

142

Gao

(1988)

143

(1987)

Horwitz

2.3 (0.6, 9.7)

Adjusted for smoking

McDuffie146 (1991)

2.0 (1.2, 3.4)

Smoking and occupational exposure data collected, but not adjusted for

Osann147 (1991)

1.9 (0.7, 5.6)

Adjusted for cigarette smoking, education; matched on age and race

One first-degree relative: 1.7 (1.2, 2.4) Two first-degree relatives: 2.8 (1.2, 6.6)

Adjusted for cigarette smoking, passive smoking, and number of first-degree relatives

Wu149 (1996)

1.3 (0.9, 1.9)

In nonsmokers, adjusted for environmental tobacco smoke

Bromen150 (2000)

One sibling: 1.7 (1.1, 2.5) Two or more first-degree relatives: 3.0 (0.3, 28)

Adjusted for age, gender, and asbestos exposure

Shaw

148

(1988)

(1991)

*Odds ratio for referent category of persons with no family history of lung cancer = 1.0. Values in parentheses are 95% confidence limits. Adapted from Alberg AJ, Samet JM: Epidemiology of lung cancer. Chest 123(1 Suppl):21S-49S, 2003, Table 7, p 39S.

Ch057-F06861.indd 717

1/21/2008 12:11:51 PM

718

Section 3 Lung

studies, but pooled analyses of the current evidence suggests that both the MspI polymorphism154 and a polymorphism in exon 7155 are associated with increased risks of lung cancer. The CYP2D6 pathway determines the phenotype for the metabolism of debrisoquin. Individuals who are faster metabolizers were initially found to be at greater risk for lung cancer.156 More recent studies have generated inconsistent results, suggesting that CYP2D6 fast metabolism may be weakly associated with lung cancer risk.6,157-159 GSTs are a family of phase II enzymes that play a role in the detoxification of polycyclic aromatic hydrocarbons by conjugating them with glutathione. Among this gene family, studies of the GSTM1 gene have shown moderately increased lung cancer risk associated with the null variant.160,161 A recent case-control study suggested that the GSTP1 polymorphism confers increased risk of lung cancer among never-smokers, particularly when present in combination with GSTM1.137 As described earlier in reference to isothiocyanates, individuals with the µ-polymorphism conferring increased GST activity actually have a decreased risk of lung cancer.

BIOLOGY OF CARCINOGENESIS Most patients with lung cancer present at an advanced stage, and current systemic chemotherapeutic regimens offer little hope for clinically relevant survival.162 This has provided a significant impetus to more fully investigate the tumor biology of lung cancer, with the hope that understanding the relevant chromosomal abnormalities, signal transduction pathways, and genetic and epigenetic events will lead to identification of potential targets for molecularly based treatment strategies. The relationships between the molecular, genomic, and environmental factors that are involved in tumorigenesis, tumor growth, propagation, angiogenesis, cell cycle regulation, apoptosis, and metastatic movement are complex. To date, this complexity has limited the translation of what is known about lung cancer biology into meaningful treatments for patients. Two basic concepts in the biology of carcinogenesis are the multistep nature of carcinogenesis and the diffuse-field carcinogenic process. Models of multistep carcinogenesis were most extensively studied by Stehelin163 and Goldsworthy164 and their associates. Epithelial cancers in the lung appear to develop in a predictable series of events extending over years, which can conceptually be divided into three phases: initiation, promotion, and progression. This process has been inferred from human studies identifying clinical-histologic premalignant lesions (e.g., metaplasia, dysplasia). Cells exposed to a carcinogen undergo an initiation event in which the cells are altered in their heritable structure. Exposure to a second agent or promoter causes an expansion of the initiated cells. Additional changes may cause the cells to enter the progression stage, with expression of features of the malignant phenotype, including metastatic potential. The precise biologic changes involved in lung tumorigenesis are still under investigation, and some of them are reviewed here. The concept of field carcinogenesis is that multiple independent neoplastic lesions occurring within the lung can result from exposure to carcinogens, primarily from tobacco.

Ch057-F06861.indd 718

Patients developing cancers of the aerodigestive tract secondary to cigarette smoke are likely to have multiple premalignant lesions of independent origin within the carcinogen-exposed field.75,165 The formation of metastases is a complex phenomenon that occurs in several steps, as described by Nicolson in 1988.166 These include growth and invasion of the primary malignant cells, penetration of the cells into the blood and lymphatic circulation, implantation into distant tissue, and response to their new microenvironment leading to survival and proliferation. The most exciting work in lung cancer biology today is focused on identifying molecularly based therapeutics. In order for these to be successful, it is imperative that the science behind these therapies be as robust and complete as possible. Therefore, an understanding of the common genes and their mutations associated with lung cancer is important. Likewise, a working knowledge of proteins involved in angiogenesis, apoptosis, and metastasis is also important. Finally, epigenetic changes, particularly gene silencing through methylation and chromatin modifications, may have more relevant and immediate clinical importance than previously described genomic changes.

TP53 The TP53 (formerly p53) tumor suppressor gene is mutated in more than half of all human cancers, including lung cancer.167 Specifically, TP53 mutations are present in more than 90% of SCLCs and more than 50% of NSCLCs. The loss of TP53 function appears to be an early event in lung tumorigenesis, as evidenced by the presence of TP53 mutations and protein stabilization in preneoplastic lesions such as bronchial epithelial dysplasia.167,168 There is a low level of latent and post-transcriptionally modified TP53 in normal cells. TP53 is activated in response to cellular stresses such as DNA damage, oncogene activation, and loss of cell adhesion. There are two dominant pathways leading to TP53 stabilization167: 1. Responses to genotoxic stresses such as DNA damage (e.g. ionizing radiation) 2. Oncogene activation As shown in Figure 57-4, both pathways result in stressinduced TP53 stabilization, which results in changes in cell cycle regulation, DNA repair, apoptosis, and cell senescence. TP53 exerts its most significant downstream effects through CDKN1A (p21, CIP1/WAF1), modulation of cell cycle arrest, and permanent arrest or senescence. Additionally, TP53 initiates apoptosis through the transactivation of genes such as Bax, TNFRSF10B (formerly DR5, in the tumor necrosis factor [TNF] receptor superfamily), and APAF1. Initiation of apoptosis or senescence inhibits tumorigenesis through the elimination of potentially mutated cells from the viable population. Thus, a lack of appropriate cellular apoptosis secondary to TP53 mutations may result in the development of lung cancer. Approximately 75% of TP53 mutations are missense mutations. This is different from most mutations in other tumor

1/21/2008 12:11:51 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

suppressor genes, which are typically loss of function, nonsense, or frame-shift mutations. The frequency type and pattern of TP53 mutations in lung cancer have been extensively analyzed.167,169 The TP53 mutational spectrum is dominated by cytosine (C)-to-thymine (T) transitions, most of which occur at six mutational hot spots: codons 175, 245, 248, 249, 273, and 282. With the exception of codon 249, all of these mutational hot spots contain methylated CpG sequences (see later discussion).169 A recent report by Toyooka and colleagues (Toyooka et al, 2003)170 demonstrated that there are significant differences in the guanosine:cytosine (G:C) to tyrosine:adenine (T:A) transversion between smokers and nonsmokers. These TP53 mutations occur mainly in female smokers, who have a higher frequency of such changes compared with female nonsmokers. The authors found no relationship between adenocarci-

UV HIPK2

Ionizing radiation ATM, ATR, CHK2

Oncogene activation (myc, E1A, ras, E2F-1)

ATM, c-abl

p73 p14ARF

HDM2

p53

HDM2

Cell cycle checkpoints

DNA repair

Apoptosis

Senescence

p21WAF1 14-3-3 σ GADD45

GADD45 p48/DDB2

Bax, PIGs Killer/DR5, APAF-1

p21WAF1

XPB, XPD (NER) APE1, Polβ (BER) Rad51, BRCA1 (HR)

XPB, XPD, WRN, BLM

PML p33ING1

FGURE 57-4 The TP53 network. Major pathways of stress-induced TP53 (p53) stabilization, as well as the downstream effects of TP53 activation, are depicted. Genes involved in each of the signaling pathways controlled by TP53 are listed. Transcriptional targets are listed on top, functional interactions below. The TP53 homologue TP73 (p73) may perform certain TP53-associated functions redundantly or as a backup for TP53 loss. BER, base excision repair; HR, homologous recombination; NER, in nucleotide excision repair; UV, ultraviolet. (FROM ROBLES AI, LINKE SP, HARRIS CC: THE P53 NETWORK IN LUNG CARCINOGENESIS. ONCOGENE 21:6898, 2002, FIGURE 2, P 6899.)

719

nomas and squamous cell carcinomas independent of gender. An examination of the previously described codons identified as mutational TP53 hot spots revealed no specific codon that was strongly related to prior smoking exposure. There are two TP53 homologues, TP73 and TP63, that share many of the characteristics of TP53, including gene transactivation and apoptotic induction.171 However, few TP73 mutations and no TP63 mutations have been found in lung cancer cell lines. The clinical significance of TP53 mutations has been addressed in numerous reports.172,173 However, the results of these reports have been controversial with no clear-cut prognostic relevance. This is largely because of varying methods of TP53 detection. Results obtained by immunohistochemistry have not always correlated with molecular analyses examining TP53 exons 5 through 8, the location of most of the TP53 mutations. Mitsudomi and coworkers174 performed a meta-analysis of 43 published reports and concluded that TP53 mutations, as determined by immunohistochemistry and mutational analysis, were a significant marker of poor prognosis in patients with pulmonary adenocarcinoma (Toyooka et al, 2003).170,174 The prognostic value of TP53 is important, but the role of NSCLC TP53 mutations in predicting treatment responses may have more immediate clinical relevance.175 The TP53 tumor status in predicting radiotherapy responses in patients with locally advanced NSCLC is shown in Table 57-3. In the four clinical trials that used radiation therapy alone, there was a statistically significant decrease in tumor response rate for tumors with TP53 mutations, compared with wild-type TP53. The impact of aberrant TP53 on cisplatin-based chemotherapy for locally advanced or metastatic NSCLC has been more extensively studied (Table 57-4). Again, the majority of studies demonstrated a significantly decreased response rate to chemotherapy in TP53-mutated tumors. Finally, several studies have looked at the role of TP53 mutations in induction chemotherapy regimens in patients with locally advanced NSCLC (Table 57-5). The majority of induction regimens using either cisplatin- or carboplatinbased treatments resulted in no significant impact on response rates, as measured by standard radiographic treatment response criteria. Given the high frequency of TP53 mutations and the importance of this gene in lung cancer tumorigenesis, TP53 replacement strategies have been employed using gene

TABLE 57-3 Impact of Aberrant TP53 on Response to Radiotherapy in Patients With Locally Advanced NSCLC Author

TP53 Assay (MoAb or Exons Analyzed)

No. Patients (% With Aberrant TP53)

Predictive Role

Hayakawa176

IHC (DO-7)

36 (69%)

↓ RR

Langendijk

177

IHC (DO-7)

161 (61%)

↓ RR

Langendijk

178

IHC (DO-7)

65 (57%)

No impact

PCR (5-8)

34 (38.2%)

↓ RR

Matsuzoe179

IHC, immunohistochemistry; MoAb, monoclonal antibody; NSCLC, non–small cell lung cancer; PCR, polymerase chain reaction; ↓ RR, statistically significant decrease in response rate. Modified from Viktorsson K, De Petris L, Lewensohn R: The role of p53 in treatment responses of lung cancer. Biochem Biophys Res Commun 331:868-880, 2005, Table 1, p 873.

Ch057-F06861.indd 719

1/21/2008 12:11:51 PM

720

Section 3 Lung

TABLE 57-4 Impact of Aberrant TP53 on Response to Chemotherapy in Patients With Locally Advanced or Metastatic NSCLC Author Gajra180

TP53 Assay (MoAb or Exons Analyzed)

No. Patients (% With Aberrant TP53)

Chemotherapy

Predictive Role

IHC (240, 1801)

89 (56%)

C-based

↓ RR

IHC (p1801)

102 (45%)

C-based

↓ RR

Kawasaki182

IHC (DO-1)

111 (55%)

C-based

↓ RR

183

IHC (DO-1)

30 (60%)

C-based

↓ RR

Gregorc

181

Kawasaki Ludovini

IHC (p1801)

85 (44%)

C-based

↓ RR

185

IHC (DO-1)

45 (40%)

C-based

↓ RR

186

IHC (DO-1)

54 (63%)

C-based

↓ RR

PCR-SSCP (5-8)

25 (32%)

Paclitaxel

No impact

PCR-SSCP (5-8)

30 (33%)

Paclitaxel

↓ RR

184

Miyatake Nakanishi King

187

Rosell188

C, cisplatin; IHC, immunohistochemistry; MoAb, monoclonal antibody; NSCLC, non–small cell lung cancer; PCR-SSCP, polymerase chain reaction–single-strand conformational polymorphism; ↓ RR, statistically significant decrease in response rate. Modified from Viktorsson K, De Petris L, Lewensohn R: The role of p53 in treatment responses of lung cancer. Biochem Biophys Res Commun 331:868-880, 2005, Table 2, p 875.

TABLE 57-5 Impact of Aberrant TP53 on Response to Induction Treatment in Patients With Locally Advanced NSCLC Author Johnson189 Korobowicz Rusch

190

191

Junker192 Junker

192

Kandioler-Eckersberger

193

Kandioler-Eckersberger193

TP53 Assay (MoAb or Exons Analyzed)

No. Patients (% With Aberrant TP53)

Chemotherapy

Predictive Role

IHC (DO-7)

49 (51%)

C-based

No impact

IHC (BP-53-12)

35 (60%)

C-based

No impact

IHC (p1801)

52 (38.4%)

C-based

↓ RR

IHC (CM1)

36 (41.7%)

Carbo-based

No impact

PCR-SSCP (5-8)

33 (45.4%)

Carbo-based

No impact

IHC (p1801)

24 (—)

C-based

No impact

PCR-SSCP (2-11)

24 (33%)

C-based

↓ RR

C, cisplatin; Carbo, carboplatin; IHC, immunohistochemistry; MoAb, monoclonal antibody; NSCLC, non–small cell lung cancer; PCR-SSCP, polymerase chain reaction–single-strand conformational polymorphism; ↓ RR, statistically significant decrease in response rate. Modified from Viktorsson K, De Petris L, Lewensohn R: The role of p53 in treatment responses of lung cancer. Biochem Biophys Res Commun 331:868-880, 2005, Table 3, p 875.

therapy techniques. A phase I clinical trial of adenovirally delivered TP53 in locoregionally advanced NSCLC demonstrated little toxicity and a modest clinical effect.194 More recently, in a single-arm phase II study, adenovirally delivered TP53 in stage IIIA/B NSCLC was combined with irradiation (60 Gy).195 There was an enhanced tumor response rate, with 1/19 (5%) of patients having a complete pathologic response and 11/19 (58%) having a partial response. Despite the obvious promise evident in the results of these studies, there are still gaps in knowledge and technology to address. The technical limitations that currently prevent the widespread application of gene therapy to cancer are likely to be overcome by the development of more efficient vectors and combined modality approaches.175,196

CDKN2A-RB1 Pathway The retinoblastoma gene, RB1 (formerly Rb), is another tumor suppressor gene that has been shown to be inactive in lung cancer.197 The RB1 protein negatively regulates cell cycle progression in that it is hypophosphorylated at the G1 phase,

Ch057-F06861.indd 720

then sequentially phosphorylated by cyclin D-CDK4/6 and cyclin E-CDK2 during the G1/S transition. This modification induces dissociation of RB1 from the E2F/DP heterodimer, which in turn promotes cell proliferation and cell cycle progression (Osada and Takahashi, 2002).198 CDKN2A (cyclindependent kinase inhibitor 2A, formerly called p16, INK4A) maintains the RB1 protein in a hypophosphorylated state by inhibiting cyclin D-CDK4/6 and consequently prevents activation of the E2F/DP heterodimers (Osada and Takahashi, 2002).198 Thus, CDKN2A is another important tumor suppressor involved in cell cycle regulation through its interactions with RB1 and cyclin D. Mutations in the RB1 gene are observed in more than 90% of SCLCs but only 15% to 30% of NSCLCs. Approximately 70% of NSCLCs have mutations in the CDKN2A gene, whereas CDKN2A mutations are uncommon in SCLC. The inactivation of RB1 in NSCLC does not correlate with disease-free survival or overall survival.199 RB1 and CDKN2A mutations have been identified more commonly in heavier smokers and in squamous cell carcinomas (Osada and Takahashi, 2002).198,199

1/21/2008 12:11:52 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

Ras Family The Ras family consists of three proto-oncogene members, KRAS, HRAS, and NRAS (Osada and Takahashi, 2002).198 These proteins are guanosine triphosphate (GTP)-binding proteins and act as molecular switches: when bound to GTP, they are in their active configuration, which permits transduction of a growth signal to the nucleus. These proteins transmit growth factor signals through Raf signal transduction pathways, thus modulating alterations in cell cycle and transcription factors. No Ras mutations have been identified in any SCLC. Of the previously described Ras family members, KRAS is mutated in approximately 30% to 50% of pulmonary adenocarcinomas. The most common mutation is a single amino acid substitution, usually at codon 12 but also at codons 13 and 61. This mutated Ras affects GTPase activity, resulting in constitutive activation of the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. This, in turn, reduces transcription of several growth-prompting genes, including that for cyclin D1. In addition, oncogenic Ras mutations induce cell cycle arrest through induction of the two CDKN2A gene products, ARF (p19ARF) and CDKN2A (p16INK4A), and TP53. KRAS is frequently mutated with these other oncogenes, suggesting that the KRAS mutation is but one event in a multistep process. Examination of the effect of KRAS mutations on the response of advanced NSCLC to chemotherapy was reported by Rodenhuis and colleagues.200 In this study, patients with inoperable stage III or stage IV pulmonary adenocarcinoma were treated with a four-drug chemotherapeutic regimen. The authors concluded that patients with an advanced lung adenocarcinoma who harbor a KRAS mutation had similar results to chemotherapy as well as similar progression-free survival and overall survival as those patients without a KRAS mutation. Therefore, it appears that KRAS mutations do not confer any resistance or sensitivity to chemotherapy, at least in pulmonary adenocarcinomas. Protein farnesylation is required for the localization and function of signal transduction proteins that are involved in cytoskeleton organization. The primary protein that requires farnesylation before it can mediate its proliferative functions and oncogenetic capabilities is the Ras protein. Given the number of primary pulmonary adenocarcinomas that have KRAS mutations, it was thought that farnesyl-transferase inhibitors (FTI) might be effective therapeutic agents in the treatment of this histologic subtype of lung cancer. More recently, it was shown that the cytotoxic actions of FTIs are not a result of the inhibition of Ras proteins exclusively but also involve inhibition of RHOB, centromere-binding proteins, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT1) pathway.201 Therefore, it is likely that the antineoplastic activities of FTIs are dependent on inhibition of multistep farnesylation of various proteins and not inhibition of a single protein. Preclinical studies have suggested that the cytotoxic effects of FTIs occur regardless of the presence or absence of a Ras mutation.201 Most of the FTIs currently under investigation are cytostatic; that is, drug removal results in tumor regrowth

Ch057-F06861.indd 721

721

in in vivo models. Several of the compounds currently under investigation have been evaluated in both phase I and phase II clinical trials in patients with lung cancer. All agents are reasonably well tolerated, with gastrointestinal toxicity and fatigue being the most common reasons for dose limitation.202 However, single-agent FTI therapy has resulted in no significant clinical activity in phase II studies in either NSCLC or SCLC.203 Current FTI strategies are centered on combining these agents with cytotoxic platinum analogues and taxanes. Preliminary studies suggest that combined FTI and paclitaxel may be clinically active.204

Myc Family The Myc oncogene family encodes a group of nuclear phosphoproteins that regulate cell growth and tumorigenesis.173 MYC promotes cell cycle progression mainly through repression of CDKN2B (p15, INK4B) and downregulation of the CDK inhibitor CDKN1B (p27) (Osada and Takahashi, 2002).198 More recent microarray analyses205,206 have demonstrated that MYC induces expression of cyclin D2 and CDC2 and represses CDKN1A. Overexpression of MYC occurs in the majority of SCLCs and is very rare in NSCLCs. It is likely that one of the primary roles of MYC in lung cancer tumorigenesis occurs when there is a loss of a tumor suppressor gene, such as RB1 or CDKN2A, leading to loss of cell cycle arrest and uncontrolled tumor growth. The clinical relevance of the amplification and increased expression of the MYC gene in SCLC has not been well studied.

Epidermal Growth Factor Receptor Epidermal growth factor receptor (EGFR), also called ERBB1, is a transmembrane glycoprotein with an intracellular domain possessing intrinsic tyrosine kinase activity. EGFR is overexpressed in more than 80% of squamous cell carcinomas and more than 60% of adenocarcinoma and large cell carcinomas.207 In contrast, EGFR is not overexpressed in SCLCs. ERBB2 (HER2/neu), another member of the EGFR superfamily, is overexpressed in one third of NSCLCs, although typically not in squamous cell carcinomas. A major downstream signal transduction pathway of all EGFR is the Ras-Raf-MAPK pathway. Other pathways affected by EGFR signaling include PI3K/AKT1, protein kinase C (PKC), and the extracellular signal-regulated MAPK pathway (ERK1/2). The biologic consequences of EGFR overexpression are enhanced tumor cell proliferation, tumor cell invasion, angiogenesis, and metastasis.208 The association between EGFR overexpression and prognosis in NSCLC is controversial. A recent meta-analysis concluded that EGFR overexpression was a negative prognosticator for survival in patients with NSCLC, although the amplitude of the impact was small.208,209 Because EGFR is differentially expressed between malignant and noncancerous tissues, the EGFR pathway has been targeted for molecularly based therapies in lung cancer. There are several strategies to block EGFR-dependent signal transduction pathways, with two primary areas of focus. One

1/21/2008 12:11:52 PM

722

Section 3 Lung

involves monoclonal antibodies to the EGFR receptor, of which the best examples are trastuzumab (Herceptin) and cetuximab (Erbitux). The other approach employs receptor tyrosine kinase inhibitors (TKI) to block phosphorylation, inhibiting downstream signal transduction pathways even in the absence of a ligand binding to the receptor. Two such TKIs are gefitinib (Iressa) and erlotinib (Tarceva), both of which have demonstrated activity in patients with locoregionally advanced or metastatic NSCLC.208,210 Despite its almost universal presence in NSCLC, inhibition of EGFR using TKI therapy results in significant tumor regression in only 10% to 15% of patients (Janne et al, 2005).211 In patients with previously treated advanced-stage NSCLC, EGFR TKIs have shown promising clinical activity as monotherapy. Neither gefitinib nor erlotinib provided any additional benefit when combined with doublet chemotherapy, as measured by response rates and 1-year survival rates, compared with conventional cytotoxic chemotherapy.212 However, a subset analysis demonstrated a significant increase in response rates in patients with EGFR mutations treated with erlotinib and chemotherapy, compared to patients with wild-type EGFR tumors.211 Currently, erlotinib is approved for second- and third-line treatment of advanced-stage or metastatic NSCLC, and gefitinib is approved for third-line treatment.212,213 Recent investigations have uncovered somatic mutations in the EGFR that make these tumors more sensitive to the TKIs (Janne et al, 2005).210,211 In contrast to mutations for other receptor tyrosine kinases, EGFR mutations have been identified only in the tyrosine kinase domain of the gene. Therefore, patients with a specific EGFR mutation will have an improved response to TKI monotherapy. One mutation in the adenosine triphosphate (ATP)-binding region of the EGFR appears to confer sensitivity to TKIs, but it has recently been shown that a second mutation (T790M) in the catalytic cleft of the EGFR tyrosine kinase domain inhibits TKI access to the binding site.214 Thus, the oncogenic function of the mutated EGFR is retained, but the ability of the TKI to bind to the receptor is lost, resulting in resistance to TKI-based therapy. Testing for EGFR mutations is currently available only in selected centers. The mutation can be identified only by DNA sequencing, which requires a sufficiently large enough specimen (at least a core biopsy) to provide enough DNA for sequencing. Neither fine-needle aspiration nor bronchoscopic washings provide sufficient diagnostic material, so the ability to determine EGFR mutation before making therapeutic decisions is limited. EGFR mutations have been observed only in patients with adenocarcinoma. Among those patients with adenocarcinoma, EGFR mutations are more frequently observed in nonsmokers, smokers with a history of less than 15 pack-years, women, patients of Asian ethnicity, and tumors with a bronchioloalveolar component (Janne et al, 2005).211,215 Interestingly, mutations in KRAS, a mediator of EGFR signaling, are mutually exclusive of EGFR mutations and are associated with resistance to TKIs. Therefore, patients with known KRAS mutations are highly unlikely to respond to EGFR TKI therapy (Janne et al, 2005).211,215

Ch057-F06861.indd 722

Angiogenesis Angiogenesis is required for tumors to grow beyond 1 mm3 in size and for metastases to develop. These events are tightly regulated by various angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast factor, angiopoietins, interleukin-8 (IL-8), and thymidine phosphorylase.216 Of these, the most potent stimulus for tumor cell angiogenesis is VEGF. In addition to promoting endothelial cell growth, VEGF has been shown to be important in promoting metastatic movement by the tumor, thus linking the biologic processes of angiogenesis and metastasis. Determination of angiogenesis in NSCLC and other tumors is primarily by VEGF expression, but also by expression of factor VIII, CD31, and CD34.217 There are four isoforms of VEGF, and an analysis of NSCLCs demonstrated that only VEGF-189 messenger RNA levels correlated with increased intratumoral microvessel density and decreased disease-free and overall survival rates.218 The majority of studies demonstrated that intratumoral VEGF levels are an independent negative predictor of survival for patients with NSCLC.217,219 A recent meta-analysis of 23 studies, including more than 4000 patients, demonstrated that microvessel density, a surrogate of angiogenesis, was a significant negative prognostic indicator.220 More recently, Shimanuki and associates221 showed that serum levels of VEGF and matrix metalloproteinase 9 (MMP-9) correlate with increased intratumoral microdensity levels and overall survival. An important component in the process of angiogenesis is degradation of the extracellular membrane matrix. This process is regulated by a family of zinc-dependent MMPs that now numbers more than 30 members. These MMPs are necessary for new blood vessel penetration, and, as such, they regulate both tumorigenesis and angiogenesis.222 MMP-1, -2, -9, and -12 appear to be more commonly associated with NSCLCs.223 Gene array analysis suggests that MMP-12 has independent prognostic value in patients with NSCLC,224 although other studies have shown high levels of MMP-9 to be a negative prognosticator. Several studies have evaluated antiangiogenic treatment strategies for patients with NSCLC.219 Bevacizumab (Avastin) is a recombinant human monoclonal antibody to VEGF that has been evaluated alone and in combination with cytotoxic chemotherapy and has shown little efficacy. An unusual toxicity associated with bevacizumab is fatal hemoptysis, which has occurred mainly in patients with central squamous cell cancers.225 Future trials with bevacizumab, therefore, will include only non–squamous cell histologies. A recently published study comparing paclitaxel and carboplatin to the same doublet combined with bevacizumab suggested improved overall and disease-free survival with the addition of bevacizumab.226 Another study combining bevacizumab with the EGFR TKI erlotinib suggested that there may be clinical efficacy and certainly that the combination is well tolerated.223 There have been several phase I/II trials evaluating MMP inhibitors, but most have been halted or demonstrated significant dose-limiting toxicities secondary to joint toxicity.219

1/21/2008 12:11:52 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

The results of the other studies have not yet been fully reported.

Bcl-2 Family The Bcl-2 family of proteins regulates apoptosis primarily through modulation of cytochrome c at the mitochondrial membrane. Increased release into the cytoplasm by cytochrome c initiates the terminal phases of apoptosis.227 Cellular apoptotic homeostasis is regulated by family members that induce apoptosis and those that are antiapoptotic. Examples of proapoptotic Bcl-2 family members include BAX, BAD, BID, and the Bcl-xS form of BCL2L1. Examples of antiapoptotic proteins are BCL2, BCL2A1 (Bfl1/A1), and the Bcl-xL (alternative splicing) form of BCL2L1. Bcl-2 overexpression occurs in approximately 20% to 40% of NSCLCs and more than 80% of SCLCs. As shown in Table 57-6, the effect of Bcl-2 on overall prognosis in NSCLC is controversial, although most of the larger series suggest that it is a positive prognosticator.239 Whereas Bcl-2 expression can be relatively low in NSCLCs, especially adenocarcinomas, the other antiapoptotic gene, BCL2L1/Bcl-xL, is overexpressed in the majority of NSCLCs.240,241 In contrast, there appears to be no prognostic relevance for Bcl-xL in NSCLC.241 BAX is a proapoptotic Bcl-2 family member that is overexpressed in 60% to 80% of NSCLCs.227,241 Overexpression of BAX has been linked to adenocarcinoma and is associated with increased patient survival.242 As pointed out by Daniel and Symthe,227 it is likely that there is a dynamic functional interdependence between Bcl2 family members and other genes (i.e., TP53) involved in apoptosis. Therefore, examination of only one Bcl-2 family member and attempts to correlate expression levels to patient prognosis are at best simplistic.

723

Nuclear Factor-kB The transcription factor, nuclear factor-κB (NF-κB), is a common signal transduction convergence point for antiapoptotic pathways in NSCLC. NF-κB is composed of homodimers and heterodimers from the Rel homology family, with the RELA (p65) and c-Rel subunits being the most transcriptionally active. Immunohistochemical analysis of resected NSCLC specimens compared with adjacent noncancerous tissues suggests that NF-κB (specifically RELA) is overexpressed in most NSCLCs, regardless of histology.243 Additionally, NF-κB has been shown to be activated by tobacco smoke through mechanisms similar to TNF-mediated activation, and the tobacco-related carcinogen, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone, has been shown to induce neoplastic transformation of xenografted human bronchial epithelial cells.244,245,245a NF-κB is normally sequestered in cytoplasm by the inhibitory protein IκB, where it is transcriptionally inactive. Classic NF-κB activation occurs via the cytosolic kinase mediated by the IκB kinase (IKK) complex, which culminates in IκB phosphorylation, ubiquitination, and degradation by the 26S proteasome. Once liberated from IκB, NF-κB translocates into the nucleus, where it promotes transcription of several antiapoptotic and/or proangiogenic dependent genes.246 Examples of NF-κB–regulated genes include the genes encoding BCL2L1/Bcl-xL, BCL2A1, the caspase-8 inhibitor CFLAR (FLIP), cellular inhibitor of apoptosis protein 1 (cIAP-1), cIAP-2, MMP-2, MMP-9, IL-8, and VEGF.243 There is increasing evidence supporting the role of NF-κB in oncogenesis and tumor cell survival.246 There is an increasing amount of preclinical evidence indicating that almost every chemotherapeutic agent used to treat NSCLC upregulates NF-κB–dependent transcription and that this is a primary mechanism mediating chemoresistance.247 Inhibition

TABLE 57-6 Summary of Bcl-2 Expression Studies in NSCLC Author

No. Patients

NSCLC Category

% Bcl-2 Positive

Bcl-2 Effect on Prognosis

Method

Borner228

49

Stage I-III

31

Negative

IHC

167

Stage I-III

36.1

Positive

IHC

Cox

229

Higashiyama

230

182

All stages

19.8

Positive

IHC

Huang231

91

Stage I-II (70%)

53

Negative

WB

Ishida232

114

All Stages (adc)

43

Positive

IHC

227

All Stages

33.7

Positive (adc only)

IHC

99

All Stages

19.2

Positive

IHC

Pastorino

515

Stage I

17

No difference

IHC

236

122

Stage I-II

20.4

Positive

IHC

53

Stage I

30.1

Negative

IHC

60

pN2

20

Positive

IHC

Moldvay

233

Ohsaki234 235

Pezella

Poleri237 Tomita

238

adc, adenocarcinoma; IHC, immunohistochemistry; NSCLC, non–small cell lung cancer; WB, Western blot. From Daniel JC, Smythe WR: The role of Bcl-2 family members in non–small cell lung cancer. Semin Thorac Cardiovasc Surg 16:19-27, 2004, Table 2, p 21.

Ch057-F06861.indd 723

1/21/2008 12:11:52 PM

724

Section 3 Lung

of NF-κB–dependent transcription by small molecular inhibitors or adenoviral delivery of a dominant negative inhibitor of NF-κB also results in dramatic sensitization of NSCLC to chemotherapy.247,248 The proteosome inhibitor bortezomib (Velcade) is the primary pharmacologic inhibitor of NF-κB, as well as other proteins, that is currently available in clinical trials. Preclinical and small animal studies have been performed and showed dramatic chemosensitization of NSCLC when Velcade was combined with cytotoxic chemotherapeutic agents.248 Another strategy to silence NF-κB–dependent transcription is the use of histone deacetylase inhibitors. We recently demonstrated that histone deacetylase inhibition blocks acetylation of RELA in a PI3K/AKT1-dependent manner.249,250 This results in dramatic in vitro and in vivo apoptotic cell death in NSCLC model systems. Combined histone deacetylase inhibition and proteosome inhibition (Velcade) has also been evaluated in NSCLC and also results in dramatic increases in apoptotic cell death.251 Therefore, inhibition of NF-κB–dependent transcription appears to be a worthy target for molecularly targeted therapies, particularly when combined with cytotoxic chemotherapy or novel histone deacetylase inhibitors. A phase I clinical trial with an induction strategy of combined suberoylanilide hydroxamic acid (SAHA or vorinostat) and Velcade in patients with operable NSCLC is ongoing at the University of Virginia.

Genomics and Proteomics Genomics is the branch of biotechnology that applies the techniques of genetics and molecular biology to the genetic mapping and DNA sequencing of sets of genes or complete

genomes, including noncoding segments, using high-speed methods. Genomic analyses cannot detect post-translational modifications of proteins that are known to be dysregulated in cancer. Proteomics is the field concerned with analyzing the structure, function, and interactions of the proteome of a particular cell, tissue, or organism. RNA expression levels are only modestly associated with protein abundance. Unlike the study of a single gene or pathway, genomic and proteomic technologies enable a systematic overview that allows rapid, complete, and parallel analysis of the genes and proteins that are expressed in a given cell or tissue type. In the context of cancer, differential profiling can be used to determine whether the genomic or proteomic profile of a set of cancers differs from that from a set of normal tissues or from another tumor. In addition, gene and protein expression profiles have the potential to improve the clinical management of lung cancer by providing classification schemes and diagnostic, predictive, or prognostic markers (Granville and Dennis, 2005).252,253 These approaches are built on technologies that allow highthroughput analysis of gene and protein expression. These technologies were largely developed over the past decade, and they have been applied to lung cancer since the year 2000 (Fig. 57-5). Microarray technology has made it possible to quantitate the expression of many thousands of genes simultaneously in a given sample and was initially described for the analysis of complementary DNA by Schena and colleagues254 in 1995. In 2001, microarray technology was first applied to the global analysis of a large number of histologically diverse lung cancer specimens,255 and it has provided reproducible results across institutions.256 Two-dimensional gel electrophoresis and mass spectrometry, used in proteomics along with protein microarrays, are not as new, but it was not until 1995 that high-throughput analysis was possible due to the ability

FIGURE 57-5 A timeline of key advances in the development of microarray-based genomic and mass spectrometry–based proteomic technologies and the application of these technologies to the analysis of lung cancer specimens. (FROM GRANVILLE CA, DENNIS PA: AN OVERVIEW OF LUNG CANCER GENOMICS AND PROTEOMICS. AM J RESPIR CELL MOL BIOL 32:3, 2005, FIGURE 1, P 170.)

Ch057-F06861.indd 724

1/21/2008 12:11:52 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

to use mass spectrometry for the quantitative analysis of complex mixtures.257,258 The first proteomic study of lung cancer was published in 2002, and by 2005, approximately 40 articles describing the application and potential utility of microarray and proteomic technologies to the analysis of clinical lung cancer specimens had been published (Granville and Dennis, 2005).252 These studies can be broadly categorized in the following ways (Granville and Dennis, 2005)252: 1. Classifications that define categories or tumor subsets 2. Prognostic associations of gene expression profiles with outcomes 3. Identification of genes or proteins that could serve as molecular targets for diagnosis or therapy Studies using microarray analysis to define lung cancer tumor category or class have shown that gene expression profiles not only recapitulate the classic histologic types but can also identify subgroups within histologic classes. Studies using microarray analysis have identified multiple subgroups of lung adenocarcinoma.259-261 The differences in number of subgroups identified correlated with the sample size, with the largest study analyzing 139 adenocarcinoma specimens259 and the smallest analyzing 18.260 Another group identified two subclasses of squamous NSCLC and demonstrated an association of subclass with patient outcome.262 Further validation of methods and larger sample sizes are needed to determine whether these molecular profiles of adenocarcinoma and squamous cell carcinoma reflect clinically meaningful biologic differences.252 Genomic analyses have provided assistance regarding broader diagnostic distinctions between tumors with similar histology. The first microarray analysis addressing lung cancer helped to clarify the cell of origin of SCLC.263 This study provided support for a pulmonary epithelial origin for SCLC, rather than a neuroendocrine origin, as was believed based on morphologic and molecular markers. Another example is the importance of distinguishing between pleural mesothelioma and adenocarcinoma, which has obvious clinical implications and can be challenging based on histology alone.264 Gordon and colleagues265 showed that mesothelioma and adenocarcinoma can be distinguished with 99% specificity using a set of three gene pairs. Using genomic analysis to identify a small number of predictive genes is attractive in reference to clinical applicability. Subsequent studies have also used small groups of genes as well as proteins to discriminate the NSCLC classes and to distinguish primary from metastatic tumors.266,267 Survival of patients with NSCLC is known to vary with stage, but histopathology is inadequate to predict individual survival. Microarray analysis has the potential to provide improved prognostic and staging information. Beer and coworkers268 used gene expression profiling and found that, based on the top 50 genes, they could identify low-risk and high-risk stage I lung adenocarcinomas, which had significant correlation with patient survival. This demonstrated that a genomic analysis can predict prognosis independent of the clinical stage of disease at time of diagnosis, thus potentially guiding therapy. Other studies have also correlated gene or

Ch057-F06861.indd 725

725

protein expression with prognosis, finding subsets of genes or proteins that predicted survival differences in patients with lung adenocarcinoma.259,261,262,266-275 In addition to environmental exposures, lung cancer in never-smokers may be a result of the individual’s unique susceptibility, as evidenced by the selective expression of EGFR mutations in NSCLCs from never-smokers.276,277 Gene expression profiles from the tumors of smokers compared with those of never-smokers indicated significant differences in gene expression in the study by Miura’s group,271 but not when examined by Powell and associates.278 Powell’s study did find significant differences in the nontumor samples of smokers compared with nonsmokers and identified several genes whose expression levels either positively or negatively correlated with pack-years of smoking. Spira and coworkers279 compared so-called normal bronchial epithelial cells of current, former, and never-smokers and found several gene expression changes that were present in current smokers but not in never-smokers. These changes persisted in former smokers, which may be the reason for the increased risk of lung cancer in former smokers, and may also represent good targets for chemoprevention strategies (Granville and Dennis, 2005).252

Epigenetics Methylation Events Epigenetics refers to changes in gene expression that persist through cell division (i.e., that are heritable) but do not involve a change in DNA sequence. Epigenetic changes are a normal and powerful modulator of cellular phenotype, with much of the wide variety of histologic differentiation seen in embryogenesis controlled by epigenetic modulation.280 Transcriptional silencing of genes by DNA methylation and chromatin remodeling through histone acetylation and/or deacetylation are interrelated processes that alter gene expression and are critical in the initiation and progression of lung cancer. It is likely that tumors have both genetic and epigenetic changes that together lead to malignant change.127,281 In human cancer, there are three common alterations in DNA methylation: 1. Global hypomethylation 2. Dysregulation of methyltransferases that maintain methylation patterns 3. Regional hypermethylation in CpG islands, a particular focus of epigenetic research in lung cancer CpG sites are regions of DNA nucleotide sequence where cytosine lies adjacent to guanine. There are a relatively small number of CpG sites in the genome, primarily because of the action of DNMT, which has the end result of converting the cytosine to thymine. Regions of DNA that do have high concentrations of CpG sites are known as CpG islands, are found in promoter regions, and usually remain unmethylated in normal cells.282 Aberrant methylation at these sites has been linked to tumor suppressor gene silencing (Fig. 57-6).283 As described previously, the CDKN2A gene encodes a CDK inhibitor that regulates the phosphorylation status of

1/21/2008 12:11:53 PM

726

Section 3 Lung

FIGURE 57-6 Epigenetic regulation of gene expression by methylation. (FROM VERMA M, SRIVASTAVA S: EPIGENETICS IN CANCER: IMPLICATIONS FOR EARLY DETECTION AND PREVENTION. LANCET ONCOL 3:755, 2002, FIGURE 1, P 755.)

the RB1 protein and plays a key role in cell cycle regulation.281 In multiple solid tumors, CDKN2A was found to be inactivated but not mutated, which led to its being the first tumor suppressor gene discovered to be inactivated in lung cancer by promoter hypermethylation.284,285 CDKN2A methylation is associated with smoking and is present in 60% to 70% of lung squamous cell cancers and adenocarcinomas.125,127,286 The methylation changes associated with smoking have a dose-response effect in relation to pack-years smoked, persist in former smokers, but decrease with time after smoking cessation.287 Evaluation of the timing of gene deactivation is part of the effort to develop a progression model for lung cancer. DNA methylation has been shown to be an early event in lung carcinogensis (Belinsky, 2005).127 Belinsky and colleagues,286 using an animal model, were the first to show that CDKN2A methylation is present in a lung cancer precursor lesions. The same group later showed, in biopsy specimens taken from bronchial epithelium of smokers and never-smokers, that CDKN2A methylation was present in 18% of smokers with normal epithelium, 24% of those with metaplasia, and 50% of those with carcinoma in situ. No methylation was seen in the epithelium of non-smokers.288 More than 30 other genes are inactivated via promoter methylation in lung cancer, including the adenomatous polyposis coli gene (APC), RAB40B (RAR-β), CDH1 (Ecadherin); the genes encoding laminins (LAMs), insulin-like growth factor binding protein 3 (IGFBP3), methyl-guaninemethyltransferase (MGMT, a DNA repair gene), and deathassociated protein kinase (DAPK); and the tumor suppressor gene RASSF1A.125,281,289 The products of these genes have roles in receptor-mediated signaling, Ras signaling, DNA repair, and apoptosis.281 Specific methylation patterns have emerged for the different histologic types of NSCLC, with squamous cell carcinoma having a higher frequency of CDKN2A methylation290 and adenocarcinoma having a higher

Ch057-F06861.indd 726

frequency of APC and CDH13 methylation.291 Study of these genes has added further evidence that promoter methylation is an early component of lung carcinogenesis. Whereas tumor suppressor gene mutations may occur at any point along the gene, CpG islands are in a constant position, allowing detection by a focused assay. Using available technologies, CpG island hypermethylation can be relatively easily detected with high sensitivity.292,293 Because much of lung cancer mortality is related to late-stage presentation and no lung cancer screening technique has proved adequate, the application of DNA methylation as a screening tool is being investigated.294,295 Methylation has been detected in the serum of up to 70% of patients with known NSCLC and may prove useful in screening or for monitoring therapy.296 Palmisano and associates297 were able to detect aberrant methylation of CDKN2A and/or MGMT in DNA from sputum in 100% of patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis. Moreover, the prevalence of these markers in sputum from cancer-free, high-risk subjects approximated their lifetime risk for lung cancer.297 Hirsch and others are leading a study at the University of Colorado evaluating a high-risk cohort of heavy smokers prospectively with traditional sputum cytology coupled with sputum DNA methylation markers. Initial results, presented in 2003, were promising for future use of this technology as a screening tool.298 Promoter methylation represents a pharmacologically reversible event that alters gene expression in tumorigenesis, making it an attractive target for therapy. DNMTs are crucial to the heritability of methylation, with DNMT1 being the primary such enzyme in humans.299 The DNMT1 inhibitor, 5-aza-2′-deoxycytidine (5-AZA-CdR or decitabine) is a nucleoside analogue and an active drug for the treatment of acute leukemia.293,300 The incorporation of decitabine into DNA blocks DNA methylation and can result in the in vitro re-activation of specific genes, such as tumor suppressor genes.301 Momparler and colleagues302 saw a potent antineoplastic effect of decitabine against human lung carcinoma cell lines and subsequently performed an initial trial of decitabine in stage IV NSCLC patients. Although only nine patients were included, survival was greater than expected and increased with the number of cycles of decitabine administered. Work is also ongoing to develop therapeutic approaches that would allow control of methylation in a target-specific fashion. It was recently demonstrated that short interfering RNAs (siRNAs) could be targeted to DNMT, abolishing DNA methylation, or to several specific promoter sites, effecting transcriptional repression.303 These techniques may have potential as a new type of gene therapeutic agent. Global hypomethylation is less well studied than promoter hypermethylation, but it is known to occur in human tumors,304 and to induce genomic instability, and it can both suppress305 and induce306 tumors in animal models (see Fig. 57-6). DNA hypomethylation has been shown to activate members of the cancer/testis antigen family which is overexpressed in 44% to 85% of NSCLCs and may represent a critical early event in NSCLC carcinogenesis.307,308 Hypomethylation of TP53 in peripheral blood lymphocytes

1/21/2008 12:11:53 PM

Chapter 57 Biology and Epidemiology of Lung Cancer

727

has also been found to be associated with lung cancer.309 Although, overall, the cancer biology associated with hypomethylation is still largely unknown, it may prove to be a clinically useful marker.310

Acetylation Events Acetylation and methylation of lysine residues in the tails of core histones are specifically associated with transcriptional activation and gene repression, respectively. Transcriptionally active genes typically demonstrate increased histone acetylation, whereas low levels of acetylation typically correlate with chromatin condensation and transcriptional repression. These processes are controlled by the action of histone deacetylases (HDACs) and histone acetyltransferases (HATs).311,312 A balance between histone acetylation and deacetylation is essential for normal cell growth,313 and HDACs have been associated with the TP53 and RB1 tumor suppressor genes and the MYC oncogene.311 Further, gene silencing by HDAC complexes has been shown to be an important mechanism in the development of certain lymphomas and leukemias.314,315 Several distinct HDAC inhibitors have been developed which, by promoting histone acetylation, permit chromatin to assume a more relaxed state, thereby allowing gene transcription.312 HDAC inhibitors have been shown to induce tumor cells to undergo cell cycle arrest,316,317 to upregulate CDKN1A and TP53 expression,316,318 to inhibit angiogenesis,319 and to promote apoptosis.320,321 Encouraging preclinical results in a variety of hematologic and solid tumor types have led to clinical trials evaluating several HDAC inhibitors, including SAHA,322-325 pivaloyloxymethyl butyrate,326 phenylbutyrate,327 and depsipeptide.328 In an evaluation of the effect of butyrate in NSCLC cells, Denlinger and colleagues251 found that, although SAHA very effectively inhibited all HDAC activity, it failed to induce apoptosis even with suprapharmacologic doses. Other HDAC inhibitors, including trichostatin and SAHA, yielded similar results.249,329 This is attributed, in part, to activation of the antiapoptotic transcription factor, NF-κB, by HDAC inhibitors. As discussed previously, combined strategies to inhibit both NF-κB activation and histone deacetylase activity are promising and ongoing.251,329 Currently, therapies based on promoter methylation and histone acetylation are in clinical trials. The antimethylating agent decitabine has been initially examined in stage IV NSCLC, as described previously. For gene reactivation, the combination of the HDAC inhibitor trichostatin and decitabine, as depicted in Figure 57-7, has proved effective in cancer cell lines for both tumor suppressor gene reactivation and induction of cell death.330,331 Clinical studies are also ongoing to evaluate the combined effect of the HDAC inhibitor depsipeptide with decitabine in multiple solid tumors, including lung cancers.

SUMMARY The link between the epidemiology and tumor biology of lung cancer is increasingly being explored, particularly as it relates to amount and duration of smoking. The observation that EGFR mutations occur much more commonly in nonsmok-

Ch057-F06861.indd 727

FIGURE 57-7 Inhibition of gene transcription by inhibitors of methyltransferase and histone acetyltransferase. (FROM VERMA M, SRIVASTAVA S: EPIGENETICS IN CANCER: IMPLICATIONS FOR EARLY DETECTION AND PREVENTION. LANCET ONCOL 3:755, 2002, FIGURE 3, P 760.)

ers, in women, and in pulmonary adenocarcinomas are but one example of this phenomenon. Similar links are likely to be established in the coming years between diet, genomics, and epigenetic changes. Lung cancers comprise a very heterogeneous population of tumor cells that make targeted therapy extremely difficult, as evidenced by the first generation of molecularly targeted therapies. Nevertheless, advances in the understanding of tumor biology and the ability to perform high-throughput array analyses will result in significant improvements in patients with lung cancer. The various oncogenes, tumor suppressor genes, and genes involved in methylation and acetylation are but a few of the multitude of proteins, mutations, signal transduction pathways, and chromosomal changes being investigated in lung cancer. Soon, NSCLC will be more thoroughly interrogated for genomic and epigenetic changes that will guide subsequent treatment. The practicing thoracic surgeon must have an understanding of the epidemiology of the disease as well as the associated tumor biology underlying the next generation of novel molecularly targeted therapies.

COMMENTS AND CONTROVERSIES Drs. Smith and Jones have produced an outstanding review of the current status of biology and epidemiology of lung cancer. For the first time, in this edition, this chapter has been written by thoracic surgeons. It is particularly exciting to see the productive work of so many surgical laboratories referenced in this chapter. The sections on descriptive and analytic epidemiology are comprehensive and clearly stated. New data are emerging regarding the relationship of gender and race in lung cancer. Some of this information will be important in the determination of public policy and allocation of research funding. The extensive discussion of the biology of carcinogenesis is essential reading for the student of thoracic surgical oncology.

1/21/2008 12:11:53 PM

728

Section 3 Lung

Important oncogenes are discussed. Signaling pathways of angiogenesis, apoptosis, and antiapoptosis are also covered in detail. Emerging theories in genomics and proteomics, as well as epigenetic events such as DNA methylation and acetylation, are being extensively studied in lung cancer. New technology enables rapid-throughput molecular and genetic interrogation of human lung cancer and offers hope for real progress in the development of targeted therapeutics for this devastating disease. G. A. P.

Janne PA, Engelman JA, Johnson BE: Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 23:3227-3234, 2005. ■ This review provides a complete understanding of the current status of EGFR therapies for NSCLC, with an emphasis on the tyrosine kinase inhibitors.

KEY REFERENCES

Osada H, Takahashi T: Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer. Oncogene 21:7421-7434, 2002. ■ This paper provides an up-to-date review of the relevant tumor suppressor genes and oncogenes involved in lung cancer.

Alberg AJ, Samet JM: Epidemiology of lung cancer. Chest 123(1 Suppl):21S-49S, 2003. ■ This article provides a summary of the epidemiologic evidence on lung cancer, with an emphasis on issues relevant to prevention. Belinsky SA: Silencing of genes by promoter hypermethylation: Key event in rodent and human lung cancer. Carcinogenesis 26:14811487, 2005. ■ Discusses current findings of the importance of CpG island hypermethylation in epigenetic initiation events of lung cancer. Granville CA, Dennis PA: An overview of lung cancer genomics and proteomics. Am J Respir Cell Mol Biol 32:169-176, 2005. ■ Review of the history and methods of genomics and proteomics and the studies that have generated profiles of gene and protein expression in lung cancer and their potential clinical applications.

Ch057-F06861.indd 728

Jones DR: The molecular biology of lung cancer. Semin Thorac Cardiovasc Surg 16:2-50, 2004. ■ This collection of articles highlights the dynamic processes of growth receptors, angiogenesis, apoptosis, and metastases in NSCLC. An emphasis is placed on the potential translational research benefits associated with these important events in the tumor biology of NSCLC.

Toyooka S, Tsuda T, Gadzar AF: The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 21:229-239, 2003. ■ A complete analysis of the role of TP53 in lung cancer carcinogenesis with an emphasis on the smoking exposure and TP53 mutations in patients with lung cancer. Wingo PA, Ries LA, Giovino GA, et al: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Nat Cancer Inst 91:675-690, 1999. ■ The 1999 American Cancer Society analysis of new cancer cases and deaths in the United States with a focus on lung cancer and tobacco smoking.

1/21/2008 12:11:54 PM

chapter

PATHOLOGIC FEATURES OF CARCINOMA OF THE LUNG

58

Mark R. Wick Jon H. Ritter

Key Points ■ Small biopsy specimens are inherently limited for purposes of

histologic tumor typing. ■ Microscopic heterogeneity is common in carcinomas of the lung. ■ “Atypical adenomatous alveolar hyperplasia” exists in a con-

■

■ ■

■

tinuum with bronchioloalveolar carcinoma, with similar clinical associations. Neuroendocrine tumors of the lung are all potentially malignant; they can be divided into three grades, linked to traditional terms such as typical carcinoid, atypical carcinoid and small-cell or largecell neuroendocrine carcinoma. The overwhelming majority of spindle-cell malignancies of the lung are sarcomatoid carcinomas. Solitary metastatic carcinomas in the lung are often difficult for pathologists to separate from primary tumors, especially by frozen section examination; a practical approach is to treat them surgically as primary lesions. Pathologists should use “synoptic” forms in reports on lung carcinomas.

Seventy-five years ago, the first attempt at morphologic classification of lung cancer was undertaken by Marchesani. This scheme, outlining the now-classic categories of squamous cell carcinoma, adenocarcinoma, small cell undifferentiated carcinoma, and large cell undifferentiated carcinoma, is still widely recognized and has gone through several iterations over the ensuing decades. In recent times, a pragmatic, clinically attuned movement has been enjoined wherein a more simplified system has been embraced, dividing malignant epithelial tumors of the lung into small cell and non–small cell carcinomas. At the same time, research by pathologists has resulted in ever-greater refinement of morphologic categorization, and the interface between the practical needs of the operating suite and data generated in the clinical laboratory has become problematic. In light of this situation, a prognostically oriented nosologic scheme for lung cancer was devised by the Veterans Administration Lung Group (Yesner et al, 1991)1 in 1991, and it has since been modified by other organizations. Whether any given pathologist elects to use one or another of these systems is a decision that he or she needs to make after consultation with clinical colleagues. In any event, nonstandard designations for pulmonary carcinomas (i.e., those that are not sanctioned by the World Health Organization [Travis et al, 2004]2) (Table 58-1) need to be well-defined in

surgical pathology reports, with pertinent references being provided in cases that are particularly uncommon or conceptually contentious. A particular problem that must be recognized forthrightly by everyone involved in treating lung cancer is the common heterogeneity that it may demonstrate at a light microscopic level. The literature is now well supplied with reports of admixtures of virtually all of the lung carcinoma histotypes in the same tumor mass (Fraire et al, 1992).3,4 An analysis by Roggli and colleagues (Roggli et al, 1985)5 demonstrated such heterogeneity in fully 66% of a consecutive series of lung cancers, and others have reported similar findings. This biologic diversity may attain prognostic importance in the future, particularly in light of recent work that appears to affirm the impact of histologic features on tumor evolution.6 In any event, neoplastic heterogeneity is a practical diagnostic problem for surgeons and other oncologists because small biopsies often fail to represent so-called divergent tumor elements as a consequence of sampling bias. At a time when ever more limited methods of tissue procurement are being advanced, it is clear that substantial discrepancies will be observed between biopsy results and examination of resection specimens in the surgical pathology laboratory. That is not to imply that such techniques as fine-needle aspiration biopsy should not be used because they are extremely helpful in planning therapy in many cases. Nonetheless, the potential limitations of all sampling procedures must be weighed carefully against their benefits.

CLINOCOPATHOLOGIC FEATURES OF NONENDOCRINE PULMONARY CARCINOMAS Squamous Cell Carcinoma Morphogenesis Squamous cell carcinoma (SCC) is no longer the most common type of lung cancer; it has been eclipsed by adenocarcinoma (ACA) in recent years.4,7 However, SCC has retained its classic clinicopathologic attributes in those cases in which it is seen. These include a tendency for multifocal but clonal in situ disease in the bronchial mucosa, often preceding the appearance of a discrete mass by several years, and a propensity to arise in large central airways that are proximal to the subsegmental bronchi. Because of the common presence of an endobronchial tumor mass, obstructive pneumonia is a relatively frequent accompaniment of this neoplasm, albeit by no means pathognomonic of it. So-called pure SCC may certainly take origin in the peripheral pulmonary parenchyma as well, and rare examples are even found in the subpleura.4 729

Ch058-F06861.indd 729

1/21/2008 12:12:49 PM

730

Section 3 Lung

TABLE 58-1 2004 WHO/IASLC Histologic Classification of Malignant Invasive Epithelial Lung Tumors 8070/3 Squamous Cell Carcinoma Variants 8052/3 Papillary 8084/3 Clear cell 8073/3 Small cell 8083/3 Basaloid 8041/3 Small Cell Carcinoma Variant 8045/3 Combined small cell carcinoma 8140/3 Adenocarcinoma 8255/3 Adenocarcinoma, mixed 8550/3 Acinar adenocarcinoma 8260/3 Papillary adenocarcinoma 8250/3 Bronchioloalveolar carcinoma Subtypes 8252/3 Nonmucinous 8253/3 Mucinous 8254/3 Mixed nonmucinous-mucinous or indeterminate 8230/3 Solid adenocarcinoma with mucin production Variants 8333/3 Fetal adenocarcinoma 8480/3 Mucinous (“colloid”) adenocarcinoma 8470/3 Mucinous cystadenocarcinoma 8490/3 Signet-ring cell adenocarcinoma 8310/3 Clear cell adenocarcinoma

8012/3 Large Cell Carcinoma Variants 8013/3 Large cell neuroendocrine carcinoma Subtype 8013/3Combined large cell neuroendocrine carcinoma 8123/3 Basaloid carcinoma 8082/3 Lymphoepithelioma-like carcinoma 8310/3 Clear cell carcinoma 8014/3 Large cell carcinoma with rhabdoid phenotype 8560/3 Adenosquamous Carcinoma 8033/3 Sarcomatoid Carcinoma Variants 8022/3 Pleomorphic carcinoma 8032/3 Spindle cell carcinoma 8031/3 Giant cell carcinoma 8980/3 “Carcinosarcoma” 8972/3 Pulmonary blastoma 8240/3 Carcinoid Tumor Variants 8240/3 Typical carcinoid 8249/3 Atypical carcinoid 8430 Carcinomas of Salivary Gland Type 8430/4 Mucoepidermoid carcinoma 8200/3 Adenoid cystic carcinoma 8562/3 Epithelial-myoepithelial carcinoma

IASLC, International Association for the Study of Lung Cancer; WHO, World Health Organization. From Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (eds): World Health Organization Classification of Tumors: Tumors of the Lung, Pleura, Thymus, and Heart. Geneva, IARC Press, 2004.

Morphologic Findings Squamous cancer of the lung has an irregular, often friable, gray-white cut surface, commonly showing a large area of central necrosis, with or without cavitation8 (Fig. 58-1). The surrounding pulmonary parenchyma is frequently tethered to the mass, giving it a spiculated appearance that may be well shown on radiographic images. Microscopically, SCC is defined by its resemblance to stratified squamous epithelium of the upper airway but with disordered architectural and cytologic maturation. Anucleate keratin and squamous pearls are observed in only the better differentiated of these lesions, which account for a minority of pulmonary carcinomas (Fig. 58-2). Poorly differentiated SCC may be extremely difficult for the pathologist to distinguish from high-grade ACA or large cell undifferentiated carcinoma (LCUC), inasmuch as all of them commonly take the form of rather nondescript proliferations of primitive epithelioid cells, arranged in nests and sheets with no other distinguishing features. In the absence of special studies, one may have to use the default terminology of non–small cell carcinoma, not further specified in the frozen section laboratory and in reference to small biopsies of such lesions. Other recognized and distinct subtypes of poorly differentiated SCC include spindle cell and pleomorphic forms9 (see later discussion of sarcomatoid carcinoma); adenoid (pseudoglandular) variants10; a pseudovascular (angiosarcoma-like) subtype10,11; lymphoepithelioma-like carcinoma12; and a form that may be confused with small cell neuroendocrine tumors

Ch058-F06861.indd 730

FIGURE 58-1 Central cavitary necrosis in a squamous cell carcinoma of the lung.

(small cell squamous carcinoma)13 that is analogous to primary poorly differentiated squamous carcinoma of the anorectum, hypopharynx, thymus, and other anatomic sites. Other than confronting the pathologist with special problems in microscopic differential diagnosis, these tumor variants have no singular clinical significance.

1/21/2008 12:12:49 PM

Chapter 58 Pathologic Features of Carcinoma of the Lung

FIGURE 58-2 Keratinization, with formation of squamous pearls, is seen in a minority of pulmonary squamous cell carcinomas, as shown in this photomicrograph.

A

731

FIGURE 58-3 Peripheral adenocarcinomas of the lung are usually solid, lobulated masses that often closely approach the pleural surfaces.

B FIGURE 58-4 Adenocarcinoma of the lung demonstrating obvious glandular formations (A) and nucleoli and mitotic figures (B).

Adenocarcinoma Morphogenesis ACA has now successfully rivaled SCC as the most common form of monodifferentiated lung cancer. In North America and Europe, most ACAs are predominantly peripheral parenchymal masses; however, histologically identical lesions in India and Asia are as likely to be central as peripheral in location.

Morphologic Findings Grossly, ACA typically has an irregularly lobulated configuration, with a gray-white cut surface (Fig. 58-3). Anthracotic pigment is commonly entrapped in the tumor mass as well, but foci of necrosis and hemorrhage are seen only in large lesions (>5 cm). A relationship to tubular airways is only rarely obvious. Close inspection also may demonstrate the

Ch058-F06861.indd 731

presence of satellitotic nodules around the main tumor mass; however, this phenomenon may in fact be a reflection of the tendency for pulmonary ACA to be synchronously or metachronously multifocal, either in one lobe of the lung or in both lungs. The latter statement particularly applies to a special subtype of ACA, bronchioloalveolar carcinoma (BAC; see later discussion). One peculiar and uncommon macroscopic presentation of pulmonary ACA merits special mention. It is the pseudomesotheliomatous form, wherein the pleurotropic growth of extremely peripheral intrapulmonary tumors creates a kind of rind of tumor tissue surrounding the lung. This almost perfectly simulates the appearance of mesothelioma, both intraoperatively and on radiographic imaging studies (Attanoos and Gibbs, 2003).14-19 Microscopically, there are four major subtypes of pulmonary ACA: acinar (the most common type [Fig. 58-4]), papillary, bronchioloalveolar, and solid.20 However, additional

1/21/2008 12:12:50 PM

732

Section 3 Lung

variants exist, such as sarcomatoid, well-differentiated mucinous (colloid); signet-ring cell; clear cell; and enteric (intestinal-like).21-25 In some cases, because of the overlaps between these histologic groups and the appearances of metastatic ACAs in the lung, it is extremely difficult for the pathologist to separate primary from secondary lesions. This is particularly true of enteric and signet-ring cell tumors, which can closely imitate the attributes of gastric or colorectal carcinomas. Psammoma bodies also can be seen in primary papillary ACAs of the lung,26,27 and these structures raise the question of whether one is instead viewing a solitary metastasis from an occult tumor of the thyroid, ovary, or other location wherein psammomatous carcinomas are potentially found. Special studies, including electron microscopy and immunohistology, are not particularly helpful in resolving this differential diagnosis. Needless to say, in cases featuring multifocality of ACA in more than one lobe, this problem is even more striking. Ultimately, reliance is usually placed on such banal characteristics as peritumoral fibrosis and inflammation, which are generally more common in primary pulmonary lesions than in metastases. Pulmonary ACA may rarely involve the bronchial epithelium diffusely in a pagetoid fashion.28 Whether this represents intraepithelial spread of the tumor or multifocal synchronous growth is an open question, but pagetoid lesions are excruciating management problems because of the difficulty in obtaining tumor-free bronchial margins. Pseudomesotheliomatous (pleurotropic) ACAs are separable from true mesotheliomas by adjuvant pathologic techniques, particularly immunophenotyping (Attanoos and Gibbs, 2003; Wick, 1997),14,29 but whether this exercise has any more than academic significance is an open question. At present, available therapies for both of these tumor types are suboptimal to say the least, and the only real significance of their differential diagnosis may be a medicolegal one.

Bronchioloalveolar Carcinoma Morphogenesis BAC of the lung was initially described in the 1800s but was most fully characterized as a distinct entity by Liebow30 in 1960. Since that time, BAC has been the subject of intense interest and controversy. In particular, the pathologic criteria that apply to the diagnosis of this tumor entity, and how its histologic attributes relate to prognosis, represent perhaps the two most contentious issues (Clayton, 1986; Manning et al, 1984).31-41 There are no particular distinguishing demographic features that are associated with BAC in comparison with other ACAs of the lung. BAC tends to occur in elderly individuals, with an essentially equal distribution by gender.32,40 Contrary to reports made in the 1970s,38 before such phenomena as passive tobacco exposure were recognized, there is a definite relationship between cigarette smoking and the genesis of this tumor, as is true of virtually all pulmonary carcinomas. Nonetheless, BAC is over-represented (with regard to other histotypes of lung cancer) in patients who have never smoked and who have never lived with smokers. Radiologically and

Ch058-F06861.indd 732

FIGURE 58-5 Diffuse lobar consolidation of the pulmonary parenchyma is apparent in this pseudopneumonic bronchioloalveolar carcinoma of the lung.

clinically, three discrete subsets of patients with BAC are recognized40,42: 1. Individuals who have chest radiographic findings and clinical complaints that suggest the presence of pneumonia (fever, productive cough, and lobar or segmental consolidation)43 (Fig. 58-5) 2. Individuals with a solitary peripheral mass lesion 3. Individuals with multiple rounded densities throughout one or both lung fields On computed tomograms (CTs), these last lesions may assume a donut shape, in that they commonly demonstrate small central areas of cavitation. Hence, BAC may simulate an infectious disease, represent a nondescript coin lesion of the lung, or imitate the pattern of metastases to the lung from an occult visceral neoplasm.

Morphologic Findings Histologically, two distinct cytologic subtypes of BAC (mucinous and nonmucinous) are recognized (Travis et al, 2004),31,32,37 although the current World Health Organization schema concedes that they may not always be easily recognizable (Clayton, 1986; Manning et al, 1984).2 These are of importance because of their clinical associations. Mucinous tumors are those that tend to assume a pseudopneumonic or multifocal/multinodular clinical appearance, whereas nonmucinous (serous) BAC (Fig. 58-6) is more often a solitary lesion. Furthermore, stage for stage, nonmucinous variants may show a more favorable clinical evolution (Manning et al, 1984).37 The criteria for distinction of BAC from type ordinaire pulmonary ACA have been debated. We restrict the use of this diagnosis to neoplasms that demonstrate a mantling

1/21/2008 12:12:53 PM

Chapter 58 Pathologic Features of Carcinoma of the Lung

FIGURE 58-6 A lepidic growth pattern, conforming to the preexisting pulmonary architecture, is evident in this nonmucinous bronchioloalveolar carcinoma of the lung.

of preexisting air spaces (lepidic growth) by single layers or limited strata and micropapillae of only modestly atypical cuboidal or columnar epithelial cells, with or without intracellular or extracellular mucin production. Intranuclear inclusions of cytoplasm containing surfactant proteins are also common.44 Except for mucin production, such characteristics are shared by both of the forms of BAC. Moreover, there must be no sclerosis or inflammation within or around the lesion if it is to be considered a bona fide BAC. This demanding definition differs from that of other observers, who have accepted the existence of a sclerosing BAC subtype (Sorenson et al, 1993).45 Justification for more narrow requirements is gained from biologic data, which show a worse behavior of sclerosing BAC than that of nonfibrotic tumors.31 Indeed, Clayton, who has devoted much attention to BAC, has stated that “bronchioloalveolar carcinomas with sclerosis need to be classified with other peripheral adenocarcinomas.”32 (p389) In that regard, one must also remember that many conventional ACAs of the lung contain some areas that have the histologic pattern of BAC. Another traditional point of discussion pertaining to the microscopic features of BAC (particularly its mucinous form) is that this neoplasm is said to disseminate within the lung by aerogenous means. That is to say, it has been believed that tumor cells are detached from a mother lesion and spread to other foci in the pulmonary parenchyma by the process of inhalation and exhalation. However, some molecular analyses have cast doubt on that premise and instead suggest that the lesions are multiclonal.46 With respect to other lesions that may be confused pathologically with BAC, they include foci of florid type II pneumocytic hyperplasia surrounding areas of diffuse alveolar damage47 and interstitial fibrosing pneumonitides or organizing pulmonary infarcts (Ritter et al, 1995)48; the proliferation known as atypical adenomatous alveolar hyperplasia, or AAAH (see later discussion)49; and the unicentric neoplasm known as papillary alveolar adenoma.50 The latter entity is

Ch058-F06861.indd 733

733

extremely bland cytologically and shows a sharp interface with the surrounding pulmonary parenchyma, unlike BAC. Another point that was often raised in the older literature on BAC concerned the great difficulty with which metastases to the lung are distinguished from BAC. It is still true that there are no immunohistologic or ultrastructural markers that can be used with absolute certainty to distinguish BAC from all extrapulmonary ACAs, and this separation must ultimately rest on careful analysis of conventional clinicopathologic data. Prognostically, patients with multifocal BACs have a much worse outlook than those with unicentric tumors of this type, simply because the former lesions are inoperable. Furthermore, mucinous tumors tend to behave more aggressively—with a higher incidence of extrapulmonary metastasis—than nonmucinous BACs matched by size and stage.31,32 Overall, nonmucinous tumors measuring less than 3 cm in maximum dimension have a good prognosis, approximating 90% survival at 5 years (Volpino et al, 2003).51 Remember that the natural history of BAC is more protracted than that of more conventional pulmonary ACAs, and tumor-related fatalities continue to accrue even 10 years after diagnosis (Clayton, 1986).31,38 Nevertheless, in an often-cited study by Manning and colleagues,37 the 5-year survival rate for nonmucinous BAC was 72%, whereas only 26% of patients with mucinous tumors survived that long.

Atypical Adenomatous Alveolar Hyperplasia and Its Relationship to Bronchioloalveolar Carcinoma Kitamura and coworkers52 have addressed the conceptual mechanistic relationship between topographically small atypical glandular proliferations of the lung AAAH and BAC. Their model appears to demonstrate a stepwise progression from atypical adenomatous hyperplasia (AAH) to BAC, with further evolution to invasive growth. This concept was advanced before, especially by Miller and colleagues,53 who postulated that such a stepwise process existed in the lung in analogy to the adenoma-carcinoma sequence in the colon. AAH must be differentiated from reactive or regenerative pneumocytic lesions, at one end of the spectrum, and from small bona fide ACAs, at the other. With regard to separation of AAAH from various reactive lesions, Kitamura and coworkers52 emphasized the tendency of reactive lesions to include multiple cell types, including type II pneumocytes, ciliated cells, and mucinous cells, and they described the relatively more conspicuous interstitial inflammation and edema in localized interstitial pneumonitis. Additional criteria that are helpful in this context involve assessment of the lesional borders and patterns of fibrosis. There is a tendency for lesions of AAAH to be more sharply circumscribed and for the mild interstitial fibrosis and inflammation to stop at the same boundary as the atypical alveolar cells. Conversely, reactive lesions tend to be less well defined, and the interstitial scarring extends beyond the areas of alveolar cell atypia. The individual cells in AAAH, although they are less homogeneous than those in BAC, tend to be more uniformly atypical

1/21/2008 12:12:54 PM

734

Section 3 Lung

A

B

FIGURE 58-7 A, Atypical adenomatous alveolar hyperplasia (AAAH) is conceptually related to bronchioloalveolar carcinoma and probably represents its precursor. B, Note the striking similarity between this photomicrograph of AAAH and the features shown in Figure 58-6.

than those of reactive hyperplasias (Fig. 58-7). Remember that a variety of chemotherapeutic agents can induce striking degrees of cytologic atypia, and this phenomenon is a welldocumented pitfall in exfoliative cytology (Ritter et al, 1995).48,54 We have also seen several examples of pneumocytes with intranuclear cytoplasmic inclusions in clearcut cases of organizing phase diffuse alveolar damage; hence, their presence cannot be viewed as pathognomonic of neoplasia. It is our view that the distinction of AAAH from small BAC is conceptually arbitrary and probably fallacious. Standard criteria that have been cited as useful in this task include uniformly atypical nuclei, large lesional size, and complex growth with budding or tufting of tumor cells in the alveolar spaces in BAC but not AAAH.49,55 Kitamura and coworkers52 suggested that a nuclear area of less than 40 µm2 and a lesional diameter of less than 5 mm could effectively identify AAAH, as opposed to small BAC. Miller56 also proposed a cutoff of 5 mm to separate bronchioloalveolar cell adenoma from BAC. Nevertheless, morphometric and immunohistologic analyses have shown a synonymity rather than a disparity between AAAH and BAC (Nakanishi, 1990).57,58 Similarly, molecular studies, while showing some differences in statistical groups, have demonstrated many more shared features than differences.59 The most important consideration of this discussion concerns the clinical significance of AAAH. In practice, this lesion is not appreciated until microscopic sections arrive on the pathologist’s desk, and they are seen in four main contexts: in sections of a wedge biopsy specimen of a nonneoplastic disease; in wedge resection margins of a peripheral carcinoma; in random sections of a lobe with another, discrete carcinoma; and as suspected nodules of multifocal tumor along with at least one other documented peripheral ACA. To develop some understanding of the importance of

Ch058-F06861.indd 734

atypical lesions, several points must be kept in mind. First, inasmuch as most AAAH lesions are found in patients undergoing resection of an obvious cancer, it is an almost insurmountable challenge to arrive at any conclusions concerning their biology. This is so because the outcome of these cases will be determined by the characteristics of the macroscopically obvious tumors. AAAH lesions tend to be multifocal throughout both lungs but may be inapparent on gross examination and can easily be missed, even with current radiologic imaging techniques. Therefore, short of bilateral lung transplantation, it is impossible to say what would constitute adequate surgical resection of such lesions. Given these realities, it is best for pathologists to be pragmatically conservative in the diagnosis of clinically inapparent AAAH as small BACs, despite the above-cited conceptual considerations. It is important to emphasize, however, that such lesions can be multifocal and have a relationship with subsequent multicentric BAC, underscoring the need for close follow-up to identify the possible appearance of metachronous tumors. On the other hand, proliferations that represent grossly observed lesions with compellingly atypical cytology indeed need to be designated as outright carcinomas.

Adenocarcinomas Associated With Scars Until recently, it was taught that fibrous scarring in the lung— seen as a consequence of pneumonia, interstitial fibroproliferative disease, or pneumoconiosis—predisposed to ACA and had a directly causative role in the genesis of that tumor type.60 However, several investigators have now concluded that the central fibrosis seen in scar adenocarcinomas is formed after initiation of the carcinoma and is the product of the tumor cells themselves (Shimosato et al, 1993).61-63 At a practical level, there is no reason to suspect that fibrosing conditions in the lung are, in and of themselves, preneoplastic. With particular reference to asbestosis and silicosis,

1/21/2008 12:12:55 PM

Chapter 58 Pathologic Features of Carcinoma of the Lung

735

special forms of pulmonary interstitial fibrosis, our synthesis of the aggregated literature leads to the conclusion that carcinomas of the lung arise only in patients with those conditions who also are, or have been, cigarette smokers. In that scenario, it is further believed that smoking is the principal carcinogenic factor. Maeshima and associates64 showed that an increasing level of scar-like fibrosis in peripheral ACAs is associated with progressively worsening prognosis.

Adenosquamous Carcinoma Morphogenesis and Morphologic Findings Adenosquamous carcinoma (ASC) is a composite tumor exhibiting simultaneous squamous and glandular differentiation in the same mass. It accounts for no more than 5% of all lung cancers in most surgical series (Ishida et al, 1992).65-67 The clinical, radiographic, and gross pathologic attributes of ASC are most similar to those of pure ACAs of the lung.68 A point of contention in regard to this lesion is whether it is synonymous with high-grade mucoepidermoid carcinoma of the salivary glandular type. Our opinion is that those two neoplasms typically can be separated from one another. Salivary gland analogue tumors in the lung tend to arise in the large central airways, in contrast to the propensity for ASC to be peripheral. In addition, foci of lower-grade mucoepidermoid carcinomas are often present in the former, but not the latter, of these tumor types. The prognosis of pulmonary ASC is said to be rather adverse. In several series, the survival of patients with adenosquamous tumors has been statistically worse than that of individuals with pure ACAs or squamous cell carcinomas (Ishida et al, 1992).65,67,69,70

Large Cell Undifferentiated Carcinoma Morphogenesis LCUCs account for approximately 15% of all lung cancers.71 As mentioned earlier, diagnostic use of the term non–smallcell carcinoma has produced some confusion between poorly differentiated SCC, poorly differentiated ACA, poorly differentiated ASC, and true LCUC. Accordingly, it has been suggested that the designation large cell carcinoma be employed restrictively as a synonym for LCUC.

Morphologic Findings LCUCs are typically larger than 5 cm in maximum dimension, have a white-gray cut surface (which may be lobulated and resemble fish flesh, thus potentially simulating the appearance of a sarcoma or a hematolymphoid lesion), and are rarely multicentric. Internal necrosis is a relatively common feature. Approximately 50% demonstrate a connection to a large tubular airway. Histologically, LCUCs show a composition of large polygonal cells with vesicular chromatin, prominent nucleoli, discernible cytoplasmic borders, and a lack of glandular differentiation or keratinization (Fig. 58-8). They are typically arranged in sheets or large clusters, potentially exhibiting foci of central necrosis. Two distinctive subtypes of large cell carcinoma exist: giant cell carcinoma and clear cell carcinoma.

Ch058-F06861.indd 735

FIGURE 58-8 Large cell undifferentiated carcinoma of the lung, composed of polygonal cells with prominent nucleoli and no evidence of lineage-related differentiation.

Giant cell carcinoma was initially thought to be a separate clinicopathologic entity,72,73 but that philosophy is no longer thought to be valid (Travis et al, 2004).2,74 Microscopically, this variant of LCUC is composed of extremely pleomorphic large tumor cells, which are often multinucleated. There is a regular admixture of polymorphonuclear leukocytes with the neoplastic elements, even in the absence of necrosis, suggesting tumoral synthesis of leukocyte cytokines such as granulocyte colony-stimulating factor.75 (This phenomenon can also be associated with systemic neutrophilia in association with giant cell LCUC.) Neoplastic cannibalism may also be observed, wherein the giant tumor cells appear to engulf one another microscopically. Primary clear cell carcinoma of the lung (CCCL) is a diagnosis of exclusion. That is so because a number of other clear cell neoplasms of the lung, including some carcinoids, the so-called benign sugar tumor, metastatic renal cell carcinoma, and metastatic balloon cell melanoma, must be considered before making an interpretation of CCCL.21,76-80 This can be accomplished by a combination of radiographic, electron microscopic, and immunohistologic evaluations, which need to be done invariably in each instance. The overall clinicopathologic attributes of CCCL are comparable to those of LCUC, not otherwise specified. It has been suggested that a subset of pulmonary large cell carcinomas that show neuroendocrine differentiation (as detected by electron microscopy or immunohistology) needs to be nosologically separated from truly undifferentiated large cell tumors.81-84 Hence, the terms exocrine large cell carcinoma (another synonym for LCUC) and endocrine large cell carcinoma have entered use.83 In our opinion, endocrine large cell carcinomas are best specified as either large cell neuroendocrine carcinomas (LCNECs) or large cell carcinomas with occult neuroendocrine differentiation.

1/21/2008 12:12:56 PM

736

Section 3 Lung

Sarcomatoid Carcinomas (Including Carcinosarcomas and Blastomas) Morphogenesis Neoplasms of the lung with histologic appearances featuring the presence of fusiform and pleomorphic cells, like those of sarcomas, are uncommon. A review of malignant pulmonary tumors seen during a 12-year study period at our institution showed that roughly 2400 such neoplasms were treated overall; sarcomatoid carcinomas (SCs) accounted for 1% of these cancers (Nappi et al, 1994).85 (We use the initials SC to encompass lesions called carcinosarcomas [CSs] or pulmonary blastomas [PBs] by others.) During the same interval, however, only one example of well-documented primary pulmonary sarcoma was observed, excluding Kaposi’s sarcoma in patients with the acquired immunodeficiency syndrome (AIDS). Therefore, one can rightly conclude that a diagnosis of carcinoma is far more likely than one of true mesenchymal neoplasia86-89 when confronted with a primary spindle cell and pleomorphic tumor of the lung. SCs, PBs, and CSs all show a male-to-female ratio of 2 : 1. The age range at presentation of the tumors is 44 to 78 years, with a mean of 65 years. Virtually all patients with such lesions are cigarette smokers, and they usually complain of cough, dyspnea, or hemoptysis. The anatomic distribution of these lesions potentially includes all of the pulmonary lobes; they may be either central or peripheral, although PB is typically a centrifugal tumor and may even be subpleural. Radiographically, the neoplasms are represented by irregularly marginated (often spiculated) masses that range in maximum dimension between 1.5 and 12 cm. A minority show variable internal roentgenologic attenuation consistent with the presence of intratumoral hemorrhage or necrosis.

Morphologic Findings Grossly, most CSs, PBs, and SCs are large lesions that often exhibit internal necrosis and hemorrhage, as well as an irregular permeative interface with the surrounding lung parenchyma. Occasionally tumors of this type are small (<3 cm) and peripherally located, suggesting the appearance of usual pulmonary ACAs. Some examples of CS and SC have a discernibly polypoid endobronchial component, whereas PB is usually a peripheral lesion. Microscopically, one observes a range of histologic appearances in such neoplasms, including monodifferentiated spindle cell and pleomorphic lesions that closely simulate the appearance of sarcomas; biphasic tumors comprising recognizable carcinoma morphotypes admixed with nondescript spindle cell elements; other biphasic lesions in which the sarcoma-like components demonstrate heterologous (osteosarcoma-like, chondrosarcoma-like, angiosarcoma-like, or rhabdomyosarcoma-like) differentiation (these are the lesions still called carcinosarcomas by some other observers90,91) (Fig. 58-9); biphasic neoplasms showing admixtures of fetal-like glands and nondescript blastema-like small cells (traditionally called blastomas [Koss, 1995]92-94); and still other proliferations that are deceptively bland and simulate the appearance of inflammatory pseudotumors of the lung (Wick et al, 1995).95 Several authors also have described examples of

Ch058-F06861.indd 736

FIGURE 58-9 Carcinosarcoma (sarcomatoid carcinoma) of the lung, in which foci of recognizable poorly differentiated squamous carcinoma (center of figure) are admixed with sarcoma-like spindle cells.

composite rhabdoid tumors of the lung,96,97 in which elements resembling malignant rhabdoid tumor of other sites are admixed with ordinary ACA of the lung. These neoplasms probably represent additional examples of sarcoma-like change in pulmonary cancers. Despite its relative rarity, sarcomatoid pulmonary carcinoma has been the object of intense interest for many decades. Several papers have been written on the clinicopathologic features of CS, PB, and spindle cell carcinoma of the lung, with histologic descriptions of such entities paralleling those provided here. Although it was suggested in early communications that CSs were merely carcinomas showing pseudomesenchymal metaplasia, other authors appear to have adopted the premise that such lesions are collision tumors with truly sarcomatous components.98 Some definitions of CS have not mandated the presence of heterologous mesenchymal elements, so that neoplasms simply showing admixtures of overt carcinoma and spindle cell foci have been included in this nosological category. Recent reports on CS, PB, and SC have revealed four reproducible observations that link these proliferations together conceptually. First, it is relatively common to find areas in all three tumor types where obviously epithelioid foci merge imperceptibly with others having sarcomatoid patterns, providing that the lesions are sampled thoroughly. Second, conjoint immunoreactivity for several potential markers of carcinomatous differentiation has been seen in both of the components just mentioned. Third, microscopically obvious carcinomas have been identified that appear to lack keratin production (at least as detected in routinely processed tissues), providing a link to those examples of SC with a similar immunophenotype. Fourth, there are few if any differences in the biologic behaviors of pulmonary SC, PB, and CS, regardless of the histologic nuances of such tumors.99 There is growing evidence that carcinomas undergoing divergent sarcomatoid evolution may demonstrate immuno-

1/21/2008 12:12:57 PM

Chapter 58 Pathologic Features of Carcinoma of the Lung

histologic co-labeling for epithelial and mesenchymal markers in the same cell populations, some of which may have acquired a mesenchymal-like phenotype (e.g., of myogenous or chondro-osseous tissue) microscopically.98 In view of these findings, other authors have suggested that CS and SC are merely points in the same neoplastic spectrum of lung tumors, the basic nature of which is epithelial.100,101 We strongly endorse this construct. Moreover, in our desire to eliminate confusing diagnostic terminology whenever possible, we suggest that the terms biphasic sarcomatoid carcinoma and monophasic sarcomatoid carcinoma be adopted to replace CS/PB and spindle cell carcinoma, respectively. Using this paradigm, biphasic neoplasms may or may not display evidence of a divergent cell line on conventional microscopy, ultrastructural studies, or immunohistology. Such proliferations may be regarded as examples of clonal evolution, as acknowledged in so-called dedifferentiated malignancies of various types.90,102 This general concept can also be implemented to explain the existence of pulmonary tumors with mixed-carcinomatous (e.g., adenosquamous or mixed small cell/non–small cell) phenotypes, as mentioned earlier.

CLINOCOPATHOLOGIC FEATURES OF NEUROENDOCRINE NEOPLASMS OF THE LUNG The concept of a diffuse neuroendocrine system is not a new one. Feyrter103 developed this paradigm in 1938, in a philosophical attempt to unify tumors in several anatomic locations that had potential secretory functions and similar morphologic characteristics. Pearse104 refined and renamed this cellular network 35 years later, coining the designation of amine precursor uptake and decarboxylation (APUD) system to describe its shared biochemical attributes. Inherent in the latter scheme was the presumption that all APUD cells—and tumors deriving from them (i.e., APUDomas)— emanate from the remnants of the neural crest. There is, perhaps, no other single aspect of neuroendocrine pulmonary neoplasia that is as exasperating as the pathologic terminology that has been used to describe it. Such terms as bronchial adenoma, carcinoid, atypical carcinoid, Kulchitsky cell carcinoma, argentaffinoma, APUDoma, atypical endocrine carcinoma, oat cell carcinoma, small cell carcinoma, large cell neuroendocrine carcinoma, and large cell carcinoma with neuroendocrine features have all been employed in this context.105 A crucial concept in understanding the categorization and clinical behavior of neuroendocrine neoplasms is that all of them are at least potentially malignant tumors. Therefore, it follows logically that the modifier benign should never be applied in conjunction with any of the above-cited diagnostic terms. For example, in reference to classic bronchial carcinoids—generally regarded as defining the low end of the spectrum of biologic behavior in this context—there are many well-documented examples of metastasizing lesions in the literature. The following sections consider discrete members of the family of neuroendocrine lung tumors, as defined by the World Health Organization.

Ch058-F06861.indd 737

737

Classic Carcinoid Morphogenesis Pulmonary carcinoids were initially labeled as adenomas of the bronchus,106 a term that unfortunately persists, to some extent, in current clinical usage. Their similarity to gastrointestinal carcinoids (carcinoma-like tumors) was noted many decades ago. Although the majority of classic carcinoids are centrally located, a small minority are found in the periphery of the lung.107,108 The criterion commonly used to distinguish these two locations is the relationship of the lesion to a cartilaginous airway; tumors that are so associated are considered central, whereas those without such a relationship to a tubular airway are considered peripheral.

Morphologic Findings Carcinoids with classic histology rarely present a diagnostic dilemma. They typically grow as polypoid intraluminal masses, with an intact overlying epithelium or one demonstrating squamous metaplasia. This pattern explains the usual clinical presentation, which is largely that of localized obstruction manifested by wheezing, cough, or pneumonia. These patients almost never present with the carcinoid syndrome; rarely, patients have associated Cushing’s syndrome or other endocrinopathies. Localized obstruction also dominates the radiographic picture, with evidence of localized pneumonia or atelectasis. Rarely, a central mass growing with a dumbbell–like configuration is seen on plain films, and CT scans usually demonstrate a lesion within and adjacent to a large airway. Men and women are approximately equally affected, and young to middle-aged adults account for most of the cases. The lesions are thus usually seen in patients who are substantially younger than those with ordinary bronchogenic carcinomas. Gross features include a lesional size of 2 to 4 cm. Carcinoids are usually tan to dark red and lack obvious necrosis or hemorrhage. Both central and peripheral tumors display a wide variety of growth patterns, including trabecular, ribbon-like, nested, and solid sheets (Fig. 58-10). The cytoplasm is relatively abundant and may be strikingly oncocytic. Spindle cell change is rarely noted in central lesions and is more usual in peripheral carcinoids109; it must be emphasized that fusiform cells are not, in and of themselves, evidence of more aggressive biologic potential. Mitotic activity is very limited, and necrosis is absent (Travis et al, 1998).110 The behavior of central and peripheral carcinoids of the lung is generally good. Complete excision is the treatment of choice, which may necessitate lobectomy or a more complicated sleeve resection. Endobronchial excisions are associated with an unacceptable rate of local recurrence. Rates of metastasis vary from 1% to 20%; a figure of about 5% to 10% is probably closest to the true incidence, and, when present, secondary deposits are usually seen in adjacent peribronchial or hilar lymph nodes.111-113 It is this observation that leads us to consider these lesions as undeniable carcinomas. Moreover, distant metastases of prototypical grade I pulmonary neuroendocrine carcinomas (NECs) have been well documented, although they are rare.114 These show a tendency for involve-

1/21/2008 12:12:58 PM

738

Section 3 Lung

A

B

FIGURE 58-10 Classic carcinoid of the lung, represented by an endobronchial mass (A) manifesting organoid growth of uniform tumor cells with minimal mitotic activity and no necrosis (B).

A

B

FIGURE 58-11 Atypical carcinoid of the lung, represented by a peripheral lesion (A) showing central en masse necrosis and brisk mitotic activity (B).

ment of the skin, bones, liver, or brain. Overall, survival is in excess of 90% to 95% at 5 years.

Atypical Carcinoid Morphogenesis Very few areas of pathology arouse such a combination of angst, confusion, and controversy as the discussion surrounding the proper labeling of atypical carcinoid. That term was first used by Arrigoni and colleagues115 in 1972. They reviewed 216 pulmonary carcinoids and found 23 with unusual features including pleomorphism, increased mitotic activity, hyperchromatic nuclei, high nucleocytoplasmic ratios, and evidence of spontaneous necrosis or hemorrhage. In this original series, 70% of the lesions metastasized, and 7 patients (30%) died of their tumors.

Morphologic Findings The following criteria are currently used to define atypical carcinoid: a mitotic rate of 5 or more mitoses per 10 high-

Ch058-F06861.indd 738

power fields; at least moderate nuclear pleomorphism; spontaneous necrosis; and at least focal loss of the organoid growth pattern associated with low-grade neuroendocrine carcinomas of the lung (Fig. 58-11). As indicated by Yousem,116 a requirement for two or more of these criteria to be met before the designation of atypical is used is reasonable, to avoid overgrading. Atypical carcinoids are slightly larger than their typical relatives, often more than 3 cm in diameter. Lymph node metastases are present at diagnosis in 30% to 50% of cases, and roughly 25% have remote metastatic disease.112

Small Cell Carcinoma Morphogenesis Small cell carcinoma (SmCC) is probably the best-recognized neoplasm in the family of neuroendocrine lung tumors, accounting for about 20% of all pulmonary carcinomas (Cook et al, 1993).117-122 Most SmCCs arise in the large central airways, but peripheral examples are also well documented.

1/21/2008 12:12:58 PM

Chapter 58 Pathologic Features of Carcinoma of the Lung

tumors, their small-cell nature may not be obvious in limited biopsy material.124,125

Morphologic Findings The classic morphologic appearance of this lesion features small, hyperchromatic, molded cells; almost no visible cytoplasm; inconspicuous or absent nucleoli; single-cell necrosis; and a relative absence of stromal desmoplasia117 (Fig. 58-12). En masse (coagulative) necrosis is not uncommon, and the tumor cells of SmCC may be focally pleomorphic as well. A difficulty that may be encountered is the identification of cells that have the appearance of small cell carcinoma in a fine-needle aspirate of an apparently solitary peripheral lung nodule. As mentioned earlier, peripheral lesions of this type account for 10% of cases.123 Another problem relating to SmCC is that, although they are definable as high-grade

Large Cell Neuroendocrine Carcinoma Morphogenesis and Morphologic Findings The diagnosis of LCNEC is relatively new to the nomenclature of pulmonary carcinomas. Travis and colleagues (Travis et al, 1998)110,126 proposed that this term be used for tumors that have obvious features of neuroendocrine differentiation by light microscopy but that do not fit into the diagnostic categories of carcinoid, atypical carcinoid, or small cell carcinoma. The histologic attributes in question include a cell size at least three times that of small cell NEC; the presence of an organoid growth pattern; cellular palisading or rosettelike areas; geographic necrosis; a high mitotic rate (approximating that of small cell NEC); and a variably granular chromatin pattern2 (Fig. 58-13). The clinical features of LCNECs are distinctive (Doddoli et al, 2004; Travis et al, 1998).110,126-130 These lesions almost always occur in heavy smokers, as does small cell NEC. Although a few of these tumors manifest as central masses, most are located in the more peripheral lung parenchyma. Many examples of LCNEC are T1 or T2 tumors pathologically, and yet the aggressive potential of these lesions cannot be overstated. Only 10% of patients with LCNEC are alive after 2 years, despite the fact that most of them have stage I tumors. All patients in one series (Doddoli et al, 2004; Travis et al, 1998) 110,126 were dead of disease or had distant metastases at 2 years’ follow-up. We have studied a group of 36 patients with LCNEC, in which the survival rate for stage I cases was 20% at 40 months. Thus, the behavior of LCNEC is significantly worse than that of poorly differentiated ACA, poorly differentiated squamous carcinoma, or LCUC. Surprisingly, the survival of patients with resected, low-stage small cell NECs is better than that of individuals with LCNEC.131

FIGURE 58-12 Small cell neuroendocrine (oat cell) carcinoma composed of sheets and nests of tumor cells with little cytoplasm and abundant mitoses.

A

739

B

FIGURE 58-13 Large cell neuroendocrine carcinoma (A), demonstrating an organoid growth pattern and geographic necrosis (center of figure). The tumor cells (B) have dispersed chromatin and inconspicuous nucleoli, and they are much larger than those of small cell carcinoma.

Ch058-F06861.indd 739

1/21/2008 12:13:00 PM

740

Section 3 Lung

PRIMARY VERSUS SECONDARY CARCINOMAS IN THE LUNG A difficult problem in thoracic surgery is the management of solitary intrapulmonary masses in patients who have had a prior carcinoma.132 A proportion of such lesions prove to be benign (and usually granulomatous), but the ability of pathologists to distinguish between new primary tumors and metastases is variable in the remaining cases. That is especially true with regard to examinations of frozen sections and other modes of intraoperative pathologic consultation. Statistically, the incidence of second primary lung carcinoma in current or former cigarette smokers is 1% to 4% per patient-year.133 In addition, patients with squamous carcinoma of the oropharynx, hypopharynx, or larynx are particularly prone to develop lung cancer of the same cell type.134 Quint and coworkers132 specifically examined the relative likelihood of a primary versus a secondary nature for solitary carcinomatous nodules in the lung, in patients who had had extrapulmonary malignancies in the past. In cases of prior carcinoma of the head and neck, bladder, breast, cervix, biliary tract, esophagus, ovary, prostate, or stomach, a new lung nodule was much more likely to be a primary bronchogenic neoplasm than a metastasis. Patients with previous carcinoma of the salivary glands, adrenal gland, intestine, kidney, thyroid, thymus, or uterus demonstrated a roughly equal chance of having a new primary lesion instead of a metastatic one in the lung. Finally, individuals who had had a melanoma, sarcoma, or malignant germ cell tumor were more likely to have a solitary lung mass prove to be a metastasis. This issue is easily resolved if the histologic features of the two tumors in question are clearly dissimilar (although that can be determined only if the first of the two lesions is made available for the pathologist’s examination). Moreover, some ACAs in selected anatomic sites have sufficiently distinctive features that they can be separated from primary pulmonary ACA by means of special studies.135,136 Molecular profiling is a promising new technique for determining whether two neoplasms share identity with one another,137-139 but that procedure is time-consuming and expensive. Practically speaking, it would appear that there are few drawbacks to surgical removal of a new and pathologically problematic pulmonary nodule, using an approach that would be acceptable for treatment of a primary lung cancer. Data on excision of solitary pulmonary metastases from

carcinomas of the breast, oropharynx and larynx, and kidney indicate that survival is probably improved by such an approach.140-142

STYLIZED SURGICAL PATHOLOGY REPORTS ON CARCINOMA OF THE LUNG Obviously, not all pulmonary carcinomas are resectable. Colby and Deschamps143 have nicely summarized the clinicopathologic features of these tumors, including that subset which is surgically approachable (Table 58-2). For those lesions that can be completely excised, pathology organizations such as the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology (ADASP) have published guidelines for the reporting of morphologic findings (Nash et al, 1995).144,145 In our opinion, the most tenable system is that provided by the ADASP, which is reproduced in slightly modified form in Box 58-1.

COMMENTS AND CONTROVERSIES In this excellent revision of a chapter from the previous edition, Drs. Wick and Ritter have provided an in-depth, practical review of the pathologic features of carcinoma of the lung. A number of important points deserve special emphasis. The authors point out the high frequency of mixed histologic cell types and illustrate the difficulty in establishing a clear histologic diagnosis from the small tissue specimens provided by minimally invasive biopsy techniques. In this era of surveillance CT imaging, the authors provide a forthright description of the controversy surrounding AAAH and BAC. Notwithstanding the theoretical differences that have been widely published recently, the authors state that distinguishing AAAH from BAC is “conceptually arbitrary and probably fallacious.” Their recommendations for the practical management of these lesions are sound and are consistent with the practice of most thoracic surgeons. The authors address head-on the exasperating muddle of terminology that has previously been used to describe neuroendocrine neoplasms of the lung. They clearly point out that these lesions are not benign, having well-documented features of local invasion and nodal metastases. The clearly described terms classic carcinoid, atypical carcinoid, LCNEC, and small cell carcinoma—or the alternative terminology of grade I, II, and III neuroendocrine carcinoma of the lung and small cell carcinoma of the lung—need to be in common usage. The designation of LCNEC or, alternatively, large

TABLE 58-2 Comparison of Clinicopathologic Features of Carcinoma of the Lung by Histologic Type Tumor Type

Cases (%)

Smokers (%)

Central Lesions (%)

Localized (%)

5-Year Survival (%)

Squamous cell

30

98

64

21.5

15.4

Adenocarcinoma

31

82

5

22.2

16.6*

Small cell carcinoma

19

99

74

Other†

15

95

42

8.2 15

4.6 11.5

*Bronchioloalveolar carcinomas are associated with a 5-year survival rate of 42%. Statistics in this group encompass large cell “undifferentiated” carcinoma, large cell neuroendocrine carcinoma, and sarcomatoid carcinoma. Modified from Colby TV, Deschamps C: The lung and pleura. In Banks PM, Kraybill WG (eds): Pathology for the Surgeon. Philadelphia, WB Saunders, 1996, pp 155-168. †

Ch058-F06861.indd 740

1/21/2008 12:13:03 PM

Box 58-1 Suggested ADASP Reporting Format for Resected Lung Carcinomas A. Gross Description 1. How the specimen was received—fresh, in formalin, opened, unopened, and so on. 2. How the specimen was identified—labeled (with name, number) and designated as, for example, right upper lobe. 3. Part(s) of lung included—with measurements in three dimensions, weights, and description of other attached structures (e.g., parietal pleura, hilar lymph nodes). 4. Tumor description. —Tumor location, including relationship to lobe(s), segment(s), and, if pertinent, major airway(s) and pleura. Involvement of lobar or main stem bronchus needs to be specified. —Proximity to bronchial resection margin and to other surgical margins (e.g., chest wall soft tissue, hilar vessels) as appropriate. —Tumor size (three dimensions if possible). —Presence or absence of satellite tumor modules. 5. Description of nontumorous lung—presence or absence of postobstructive changes or other abnormalities (e.g., bronchiectasis, mucous plugs, obstructive pneumonia, atelectasis). B. Diagnostic Information 1. Site of tumor (i.e., side, lobe, and specific segment if appropriate) and surgical procedure (i.e., segmentectomy, lobectomy, or pneumonectomy) including portion of lung resected. 2. Histologic type—A modified World Health Organization (WHO) classification* is recommended. Although the WHO classification is based on light microscopic criteria, the results of ancillary studies (i.e., histochemistry, immunohistochemistry, electron microscopy) need to be reported if appropriate (e.g., large cell neuroendocrine carcinoma). —Squamous cell carcinoma (keratinization and/or intercellular bridges). Variant: spindle cell (squamous carcinoma). —Adenocarcinoma (tubular, acinar, or papillary growth pattern, and/or mucus production; acinar adenocarcinoma (i.e., adenocarcinoma, not otherwise specified); papillary adenocarcinoma; solid carcinoma with mucus formation; and variants including bronchioloalveolar adenocarcinoma and spindle cell adenocarcinoma. —Large cell carcinoma (large nuclei, prominent nucleoli, abundant cytoplasm, without characteristic features of squamous cell, small cell, or adenocarcinoma) including variants of giant cell carcinoma and clear cell carcinoma (large cell carcinomas composed extensively [>90%] of large cells with clear or foamy cytoplasm without mucin; clear cell features also can be prominent in squamous cell carcinomas and adenocarcinomas and in metastatic renal cell carcinomas). —Adenosquamous carcinoma. —Neuroendocrine tumors including carcinoid tumor, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma. Variants can be mixed small cell/large cell carcinoma or composite small cell carcinoma (typical small cell carcinoma intimately admixed with areas of squamous cell carcinoma or adenocarcinoma). —Bronchial gland (salivary gland analogue) carcinomas (adenoid cystic carcinoma, mucoepidermoid carcinoma, acinic cell carcinoma). —Other specific carcinoma types. 3. Histologic grade—WHO classification (i.e., well, moderately, or poorly differentiated) recommended for squamous cell carcinoma and for adenocarcinomas of acinar (i.e., adenocarcinoma, not further specified) or papillary type. 4. Histologic assessment of surgical margins—Include comment regarding the involvement of lobar or main stem bronchi by invasive or in situ carcinoma and the microscopic relationship of tumor to bronchial and/or vascular margin(s). 5. Pleural involvement—Specify whether tumor invades into but not through visceral pleura without involving parietal pleura (T2), or into parietal pleura (T3) (elastic tissue stains can be helpful in defining the limiting elastic layer of visceral pleura). 6. Lymph node metastases—Indicate the number of involved nodes and the total number of nodes received. (Precise node counts may be difficult for fragmented specimens such as those received from mediastinoscopy.) The nodal groups (N) need to be specifically identified using the American Joint Committee on Cancer intraoperative staging system for regional lymph nodes.† N2 lymph nodes (with the exception of level 11 interlobar nodes) are generally received separately and must be appropriately identified by the submitting surgeon; these are to be reported separately. Pneumonectomies are usually accompanied by attached N2 lymph nodes, which must be specifically identified by location. If the nodal involvement is only by direct extension, this feature needs to be noted. 7. Non-neoplastic lung—Any significant abnormalities (e.g., granulomas, pneumonia) need to be recorded. C. Optional Features The following features are considered optional in the final report because they represent specific institutional preferences or are considered inconclusive in regard to prognostic significance. 1. Stage—Surgical pathology reports containing the information listed here will contain all of the necessary data to establish the International TNM Staging System for lung carcinoma. It must be emphasized that pathologic tumor stage may be based on incomplete information and therefore may differ from clinical tumor stage. 2. Angiolymphatic invasion—Whenever possible, it must be specified whether the structures involved are blood vessels or lymphatic vessels and whether the involved blood vessels are muscular arteries, elastic arteries, or veins. 3. Perineural invasion. 4. Presence or absence of extranodal (extracapsular) tumor invasion. 5. Results of ancillary investigations (e.g., molecular pathology evaluations). *Travis WD, Colby TV, Corrin B, et al: Histological Typing of Lung and Pleural Tumours (International Histological Classification of Tumours). Geneva, World Health Organization, 1999, pp 1-55. † Fleming ID, Cooper JS, Henson DE, et al (eds): American Joint Committee on Cancer—Cancer Staging Manual, 5th ed. Philadelphia, Lippincott-Raven, 1997, pp 127-137.

Ch058-F06861.indd 741

1/21/2008 12:13:03 PM

742

Section 3 Lung

cell carcinoma with occult neuroendocrine differentiation, is not an insignificant designation because, in our own experience and that of others, these lesions have, stage for stage, very poor prognosis in comparison to other non–small cell carcinomas of the lung. There is often a dilemma in the characterization of pulmonary lesions with spindle cell features. The authors point out the rarity of so-called pure sarcoma of the lung, recognizing that most of these lesions are carcinomas rather than pure mesenchymal lesions. They also have developed a very practical approach to the differentiation of primary versus secondary pulmonary neoplasms. Finally, the authors completed their contribution with a detailed description of a stylized surgical pathology report on carcinoma of the lung, providing a template for a complete pathology report which every patient undergoing resection for lung cancer deserves. Such accurate and complete staging information is vital for proper decision making regarding estimate of prognosis and case management, as well as necessary research and registry purposes. G. A. P.

KEY REFERENCES Attanoos RL, Gibbs AR: “Pseudomesotheliomatous” carcinomas of the pleura: A 10-year analysis of cases from the Environmental Lung Disease Research Group, Cardiff. Histopathology 43:444-452, 2003. Clayton F: Bronchioloalveolar carcinomas: Cell types, patterns of growth, and prognositc correlates. Cancer 57:1555-1564, 1986. Cook RM, Miller YE, Bunn PA Jr: Small cell lung cancer: Etiology, biology, clinical features, staging, and treatment. Curr Probl Cancel 17:69-141, 1993. Doddoli C, Barlesi F, Chetaille B, et al: Large-cell neuroendocrine carcinoma of the lung: An aggressive disease potentially treatable with surgery. Ann Thorac Surg 77:1168-1172, 2004. Fraire AE, Cooper SP, Greenberg SD, Buffler PA: Carcinoma of the lung: Changing cell distribution and histopathologic cell types. Prog Surg Pathol 12:129-149, 1992. Ishida T, Kaneko S, Yokohama H, et al: Adenosquamous carcinoma of the lung: Clinicopathologic and immunohistochemical features. Am J Clin Pathol 97:678-695, 1992. Koss MN: Pulmonary blastomas. Cancer Treat Res 72:349-362, 1995. Manning JT Jr, Spjut HJ, Tschen JA: Bronchioloalveolar carcinoma: The significance of two histopathologic types. Cancer 54:525-534, 1984.

Ch058-F06861.indd 742

Nakanishi K: Alveolar epithelial hyperplasia and adenocarcinoma of the lung. Arch Pathol Lab Med 114:363-368, 1990. Nappi O, Glasner SD, Swanson PE, Wick MR: Biphasic and monophasic sarcomatoid carcinomas of the lung: A reappraisal of “carcinosarcomas” and “spindle cell carcinomas.” Am J Clin Pathol 102:331-340, 1994. Nash G, Hutter RVP, Henson DE: Practice protocol for the examination of specimens from patients with lung cancer. Cancer Committee Task Force on the Examination of Specimens from Patients with Lung Cancer. Arch Pathol Lab Med 119:695-700, 1995. Ritter JH, Wick MR, Reyes AR, et al: False-postive interpretations of carcinoma in exfoliative respiratory cytology: Report of two cases and a review of underlying disorders. Am J Clin Pathol 104:133-140, 1995. Roggli VL, Vollmer RT, Greenberg SD, et al: Lung cancer heterogeneity: A blinded and randomized study of 100 consecutive cases. Hum Pathol 16:569-579, 1985. Shimosato Y, Norguchi M, Matsuno Y: Adenocarcinoma of the lung: Its development and malignant progression. Lung Cancer 9:99-108, 1993. Sorenson JB, Hirsch FR, Gazdar A, Olsen JE: Interobserver variability in histopathologic subtyping and grading of pulmonary adenocarcinoma. Cancer 71:2971-2976, 2003. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (eds): World Health Organization Classification of Tumors: Tumors of the Lung, Pleura, Thymus, and Heart. Geneva, IARC Press, 2004, pp. 10-124. Travis WD, Rush W, Flieder DB, et al: Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its spearation from typical carcinoid. Am J Surg Pathol 22:934-944. 1998. Volpino P, Cavallaro A, Cangemi R, et al: Comparative analysis of clinical features and prognostic factors in resected bronchioloalveolar carcinoma and adenocarcinoma of the lung. Anticancer Res 23:49594965, 2003. Wick MR: Immunophenotyping of malignant mesothelioma. Am J Surg Pathol 21:1395-1398, 1997. Wick MR, Ritter JH, Nappi O: Inflammatory sarcomatoid carcinoma of the lung: Report of three cases and clinicopathologic comparison with inflammatory pseudotumors in adult patients. Hum Pathol 26:10141021, 1995. Yesner R, Seydel G, Asbell SO, et al: Biopsies of non-small cell lung cancer: Central review in cooperative studies of the radiation therapy oncology group. Mod Pathol 4:432-440, 1991.

1/21/2008 12:13:03 PM

chapter

59

EARLY DETECTION AND SCREENING OF LUNG CANCER Robert J. Korst David F. Yankelevitz Claudia I. Henschke Nasser K. Altorki

Key Points ■ Historical efforts at lung cancer screening using chest radiographs

and sputum cytologic examination detected more lung cancers but failed to demonstrate a reduction in lung cancer–specific mortality in the randomized setting. However, it is widely accepted that these studies were methodologically limited. ■ Interest in lung cancer screening has experienced resurgence in recent years due to the increased sensitivity of computed tomography (CT) compared with plain radiographs in detecting pulmonary nodules and early lung cancer. ■ The use of low-dose CT in the screening setting has allowed the identification of a novel form of lung cancer, represented by localized, persistent nonsolid nodules, also referred to as ground-glass opacities, that are not seen on plain chest radiographs. ■ Molecular screening techniques continue to be investigated as novel biomarkers for lung cancer are identified; however, none of these approaches is currently applicable to lung cancer screening.

BRIEF HISTORICAL NOTE During the first half of the 20th century, the cigarette industry experienced unrelenting growth in the United States, in part due to advances in mechanized production, lack of restriction, and innovative advertising. Following these industrial advancements, a corresponding increase in the incidence of carcinoma of the lung and bronchus began to emerge in the 1920s.1 Although oropharyngeal malignancies had been associated with tobacco use as early as the mid-1800s, an association of lung cancer with smoking was not formally reported until the 1950s.2-5 Interest in a lung cancer screening test for this newly defined group of high-risk individuals came shortly thereafter in the form of the plain chest radiograph (CXR). The first mass-screening project was conducted in London from 1960 to 1964 and set the stage for future screening interventions for this deadly disease.6

INTRODUCTION Efforts at early detection in patients with non–small cell lung cancer (NSCLC) are based on the fact that long-term survival after treatment of early-stage disease is significantly better than that observed for advanced disease.7,8 Because most early-stage lung cancers cause no symptoms, it follows that

their detection can come about only through the process of screening asymptomatic, high-risk individuals. Given the high rates of lung cancer mortality worldwide in patients with symptomatic disease, screening for lung cancer has been, and continues to be, the subject of intense investigation. Unlike screening for cancers of the uterine cervix, colon, and breast, screening for lung cancer is not a generally accepted practice. Indeed, no major professional organization officially endorses lung cancer screening of any kind. Although it is now documented that CT screening more commonly leads to early diagnosis, and it is accepted that early-stage lung cancer is more curable than late-stage lung cancer, these organizations have not considered these facts sufficient to provide evidence of a benefit of screening. Reduction in cancer-specific mortality determined as a result of a randomized controlled trial (RCT) is considered to be the gold standard and has not been demonstrated. The question that arises is how can increased detection combined with increased curability not automatically result in a decrease in mortality? This issue is now the focus of ongoing debate within the scientific community, with one of the major concerns being that there is a tendency for the traditional RCT design to underestimate the potential benefit of screening, possibly yielding misleading results.9 The primary basis for this concern relates to two features of the screening RCT as it has been traditionally performed.10 The first is that RCTs have generally involved a limited number of screening rounds with longterm follow-up. This approach was developed as a cost-saving measure because actual screening rounds are more expensive than the follow-up. However, for screening to reach its full effectiveness, it needs to be continued over many rounds because limiting the number of screening rounds may dilute the potential cumulative benefit of screening. The second feature is a lack of appreciation of the duration of elapsed time required before screening achieves its desired goal (i.e., a reduction in disease-specific mortality). In a traditional RCT design, the total number of deaths throughout the entire study is used to estimate mortality. However, preventable deaths from screening cannot be expected to occur in the first few years. The early cancers that are found by screening would have led to death only years into the future. This feature also has the effect of diluting the measured benefit. In the remainder of this chapter, we review the current guidelines for screening and then turn to some of the more influential studies that have contributed to these recommendations. We then review ongoing studies, and finally we look at promising approaches that are being developed. 743

Ch059-F06861.indd 743

1/21/2008 12:14:06 PM

744

Section 3 Lung

CURRENT GUIDELINES The United States Preventive Services Task Force (USPSTF) is a group of health experts sponsored by the Agency for Healthcare Research and Quality in the Department of Health and Human Services to conduct rigorous, impartial assessments of scientific evidence regarding preventive health care. Recommendations by this group are often used to help guide public policy. In April 2004, the USPSTF published an update of their recommendation regarding screening for lung cancer.11 The group reversed its previous recommendation on lung cancer screening, giving it an “I” rating, indicating that “The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that [the service] is effective is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.” In the past, “D” recommendations were given in 1985 and 1996, indicating that “The USPSTF recommends against routinely providing [the service]. The USPSTF found at least fair evidence that [the service is ineffective] or that harms outweigh benefits.”12 In an accompanying article,13 a detailed description of the evidence used for the current recommendation was given. The data consisted of one randomized trial of CXR in conjunction with a multiphase screening program, five RCTs of CXR with or without sputum cytology, six case-controlled studies of CXR and sputum cytology, one nonrandomized controlled trial of CXR, four older cohort studies of CXR, and six recent cohort studies using CT. The controlled trials took place over a period of 44 years and included more than 200,000 participants, and the cohort studies took place over 53 years and involved more than 2 million subjects. The USPSTF placed most emphasis on information from RCTs, with nonrandomized controlled trials, case-controlled studies, and cohort studies receiving less emphasis. They also rated the quality of the studies on a three-point scale: good, fair, and poor. Notably, none of the controlled trials (randomized or not) and none of the case-controlled studies received a good rating. The fact that the USPSTF did not rate a single lung cancer screening study as “good” is simply extraordinary given the effort and resources spent on this question over the past half century. The following conclusions were reached by the USPSTF: “Current data do not support screening for lung cancer with any method. These data, however, are also insufficient to conclude that screening does not work, particularly in women.”11 In an accompanying article, a summary written to allow for better patient understanding stated the following: “If screening is being considered, doctors should discuss the pros and cons of screening before going ahead with x-ray, CT scan, or sputum cytological examination to screen for lung cancer.”14 This recommendation appears to be totally consistent with their “I” recommendation, and it is consistent with the Principle of Patients’ Autonomy in the recently advanced Charter on Medical Professionalism.15 However, it is unclear how a patient and physician should be able to reach a rational decision regarding screening when the USPSTF, after exhaustive analysis of all the currently available data, cannot give

Ch059-F06861.indd 744

any guidance. The USPSTF also stated that “Two randomized trials of screening with chest radiography or low-dose CT are currently under way and will better inform lung cancer screening decisions.”11 However, these studies are fundamentally no different in design from their predecessor studies, the concern being that they also may ultimately be found to be methodologically limited.

CHEST RADIOGRAPH AND SPUTUM CYTOLOGY After the initial London lung cancer screening trial conducted in the 1960s, interest in lung cancer screening was renewed in the 1970s, when the National Cancer Institute (NCI) funded three randomized trials focused on the use of both CXR and sputum cytology to accomplish this goal.16-18 These studies were driven by the success that had been achieved in cervical cancer with Papanicolaou (PAP) smears, and it was thought that similar success against lung cancer would be possible with sputum cytology. Two of these trials (the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Cancer Center trial) focused on the addition of sputum cytologic examination to interval CXRs (Table 59-1) (Melamed et al, 1984).16,17 In both studies, patients were randomly assigned to either annual CXR alone or annual CXR plus the addition of sputum cytologic assessment. Therefore, in neither of these studies was the CXR independently assessed. Although the studies did demonstrate that cancers could be detected by sputum cytology alone, and that some of these were early stage, they failed to demonstrate a mortality benefit. The third of the three NCI trials was the Mayo Lung Project (Fontana et al, 1984).18 It was designed differently from the other two and focused on the combined impact of CXR and sputum cytology in screening for lung cancer (Table 59-2). Patients were randomly assigned to undergo CXR as well as sputum cytologic assessment every 4 months for 6 years (the screened group) or to follow the standard Mayo Clinic recommendations, which at that time were to undergo both of these examinations annually (unscreened group). Although the study demonstrated that an increased number of early-stage cancers were detected in the screened arm and that these patients had improved survival relative to the unscreened group, a significant mortality benefit was not observed. Another randomized trial was conducted in Czechoslovakia in the late 1970s which also focused on the combined effects of CXR and sputum cytologic examination for lung cancer screening (see Table 59-2).19,20 In that trial, patients in the screened group underwent CXR and evaluation of sputum cytology every 6 months for 3 years, whereas those in the unscreened group had an initial CXR and sputum cytologic examination, both of which were repeated at the end of the 3-year period. After the initial screening period, both groups underwent annual CXR and sputum assessment for an additional 3 years. Similar to the results of the Mayo Lung Project, more lung cancer was diagnosed in the screened group compared to the unscreened group, but no difference was appreciated in lung cancer–specific mortality.

1/21/2008 12:14:06 PM

Chapter 59 Early Detection and Screening of Lung Cancer

745

TABLE 59-1 Randomized Controlled Trials Evaluating the Role of Sputum Cytologic Examination for Lung Cancer Screening Parameter

Memorial Sloan-Kettering16

Johns Hopkins17

Years of accrual

1974-1982

1973-1982

Screened arm Sample size Protocol No. cancers (baseline) No. cancers (repeat screen) Lung cancer mortality*

4968 Annual CXR; sputum cytology every 4 mo 30 114 2.7

5226 Annual CXR; sputum cytology every 4 mo 39 194 3.4

Unscreened arm Sample size Protocol No. cancers (baseline) No. cancers (repeat screen) Lung cancer mortality*

5072 Annual CXR 23 121 2.7

5161 Annual CXR 40 202 3.8

*Per 1000 person-years. CXR, plain chest radiography. From Melamed MR, Flehinger BJ, Zaman MB, et al: Screening for early lung cancer: Results of the Memorial Sloan-Kettering study in New York. Chest 86:44-53, 1984; and Tockman M: Survival and mortality from lung cancer in a screened population: The Johns Hopkins study. Chest 89:325s-326s, 1986.

TABLE 59-2 Randomized Controlled Trials Evaluating the Role of Chest Radiography Combined With Sputum Cytologic Examination for Lung Cancer Screening Parameter

Mayo Clinic18

Czechoslovakia19,20

Years of accrual

1971-1983

1976-1980

Screened arm Sample size Protocol No. cancers (baseline) No. cancers (repeat screen) Lung cancer mortality†

4618 CXR and sputum cytology every 4 mo for 6 yr Data not available 206 3.2

3172 CXR and sputum cytology every 6 mo for 3 yr* Data not available 39 3.6

Unscreened arm Sample size Protocol No. cancers (baseline) No. cancers (repeat screen) Lung cancer mortality*

4593 Advised to have annual CXR and sputum cytology Data not available 160 3.0

3174 CXR and sputum cytology initially and after 3 yr* Data not available 27 2.6

*Followed by annual CXR and sputum cytology for an additional 3 yr. † Per 1000 person-years. CXR, plain chest radiography. From Fontana RS, Sanderson DR, Taylor WF, et al: Early lung cancer detection: Results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis 130:561-565, 1984; Kubik AK, Parkin DM, Zatloukal P: Czech Study on Lung Cancer Screening: Post-trial follow-up of lung cancer deaths up to year 15 since enrollment. Cancer 89(11 Suppl):2363-2368, 2000; and Kubik A, Polak J: Lung cancer detection: Results of a randomized prospective study in Czechoslovakia. Cancer 57:2427-2437, 1986.

The interpretation of these four randomized trials continues to be a source of controversy into the 21st century. The controversy involves primarily two main topics. The first asks how it is possible that more early-stage cancers were detected, yet this did not lead to a reduction in mortality. The second relates to the standard explanation given to account for the increased number of cancers detected—that is, that they were overdiagnosed. In regard to the first issue, the Mayo Clinic trial is considered to be the most influential of these trials. It is now generally accepted that the Mayo Clinic trial was limited in its methodology and therefore was an imper-

Ch059-F06861.indd 745

fect study on which to base public policy.21 In particular, there was a lack of contrast between the two arms of the study; with almost 50% of the patients in the control arm having received at least one CXR in the last year, and almost 75% in the last 2 years. This study therefore can be viewed as, in essence, a contrast of high-intensity versus low-intensity screening. In addition, the study was underpowered to detect a small difference in mortality. It was designed to detect a 50% reduction in mortality and was underpowered to detect more subtle differences (19% chance of detecting a 10% decrease in mortality).22

1/21/2008 12:14:06 PM

746

Section 3 Lung

In regard to the second issue, the idea of overdiagnosis has been particularly troublesome for the clinician to accept, given that lung cancer is generally considered one of the most lethal of all cancers. Overdiagnosis falls into two broad categories: cases in which the subject dies of a competing cause of death and cases in which the tumor is, in essence, indolent.23 In the context of RCTs, these two causes of overdiagnosis are grouped together and cannot be evaluated separately. The challenge is whether it is reasonable to consider the subject with an aggressive, life-threatening cancer who happens to die of another cause as not having a genuine case of cancer. This would imply that cancer is genuine only if the person actually dies from it, and otherwise it is overdiagnosed. The second proposed mechanism of overdiagnosis, the indolence of cancers detected by CXR screening, may not be credible after careful scrutiny of the data. For example, cancers detected in all three NCI studies were on the order of 2 cm in diameter at the time of detection, were not visible on the initial screen, and were seen only on subsequent screening rounds.24 The calculated growth rates of these tumors were typical of symptomatic lung cancers, and, among those subjects who refused surgery, these tumors were almost uniformly fatal. To those involved in the care of patients, it would be hard to consider cancers with this profile representative of indolent disease. Other completed CXR screening studies are the five Japanese case-controlled studies (all rated as fair) used by the USPSTF in making their most recent recommendations. These studies did demonstrate a small but significant benefit and were the basis for the change in their guidelines.13 The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is an ongoing, NCI-sponsored, multicenter trial (10 sites) that has accrued 148,000 subjects (Gohagan et al, 2000).25 Men and women, ages 55 to 74 years, were randomly assigned to undergo either an annual CXR for 3 years (smokers) or 2 years (nonsmokers) or routine medical care (unscreened group). The trial was designed to determine whether a smaller mortality benefit might be found with CXR

screening, and it has an 89% power to detect a 10% reduction in lung cancer–specific mortality. The study started in 1993 and is not expected to be completed until 2014. There are several concerns that have arisen in regard to this trial. The technology being evaluated is already outdated, with multislice CT screening trials underway and the expectation that there will be many more advances before 2014. Nationally, given the wide availability of CT scanners, it is likely that individuals in the screened group may be subjected to a CT scan at some point during their long follow-up. The trial also has few rounds of screening with long-term follow-up. Finally, the study does not mandate a specific diagnostic protocol; all diagnostic and therapeutic decisions are left to the discretion of each participating site.26 All of these features may combine to limit the prospects of a successful result.

LOW-DOSE COMPUTED TOMOGRAPHY CT of the chest was introduced into routine clinical practice in the early 1980s and has been demonstrated to be more sensitive than CXR for the detection of pulmonary nodules (Hensche et al, 1999).27-34 Further, the sensitivity of CT for the detection of small pulmonary nodules is not compromised even with significant reductions in the radiation dose.35 Low-dose, thin-section helical scans are now being performed during a single breath-hold.29,36,37 With these advances, a new era of lung cancer screening using low-dose CT has emerged. In the early 1990s, a group of investigators in the United States (Early Lung Cancer Action Project [ELCAP]) and in Japan independently began projects to evaluate the potential of CT for screening.38,39 Since that time, several other groups in North America, Europe, and Asia (Table 59-3) have published both baseline (prevalence) and repeat screening (incidence) results.27-32,36,37,40-42 The end points assessed in these trials include the number, size, and radiographic characteristics (including calcification) of nodules detected, as well as the number and stage of cancers detected. Nodule detection

TABLE 59-3 Results of Observational Studies Using Low-Dose Computed Tomography for Lung Cancer Screening Parameter

Mayo36,37

Shinshu31,32

ELCAP27,29

ALCA30

Munster28,42

Milan41

Hitachi40

Prevalence No. subjects Abnormal CT result* No. cancers on CXR No. cancers on CT Stage 1 NSCLCs detected*

1520 51% NA 26 79%

5483 35% 1 19 84%

1000 23% 7 27 85%

1611 11.5% 5 14 71%

817 43% NA 11 64%

1035 19% NA 11 55%

7956 26% NA 37 82%

Incidence No. subjects No. cancers on CT Stage 1 NSCLCs detected† Interval cancers‡

1438 10 67% 2

4781 37 86% NA

1184 7 82% 2

1180 19 79% 3

668 10 70% 5

1035 11 100% 0

5568 4 100% 0

CT, computed tomography; CXR, plain chest radiography; NA, not assessed; NSCLC, non–small cell lung cancer. *One or more noncalcified nodules. † Percentage of total NSCLCs detected. ‡ Cancers not detected by screening CT.

Ch059-F06861.indd 746

1/21/2008 12:14:06 PM

Chapter 59 Early Detection and Screening of Lung Cancer

was usually followed by an algorithm for further workup; these were similar and were usually based on the size, number, radiographic characterization, and growth rate of detected nodules. As demonstrated in Table 59-3, consistent results were obtained across all studies. First, a large percentage of subjects were found to have noncalcified pulmonary nodules on low-dose CT, ranging from 11% to 51%. Second, far fewer lesions required additional workup. Current protocols required additional CT scans on only 15% of subjects in the baseline round and 6% in the repeat rounds.43,44 Cancer was diagnosed in 0.4% to 2.7% of the subjects on the baseline round of screening. Third, the majority of cancers detected in all studies were stage I. Finally, in the three programs in which CXR was also performed, low-dose CT was far more sensitive than CXR in detecting lung cancer. An extension of the initial ELCAP study is the I-ELCAP study, which has now enrolled more than 30,000 subjects worldwide.45 Using a novel design, the study evaluates the two component issues of screening separately (i.e., the diagnostic component and the therapeutic component).38 This contrasts with the traditional screening RCT, which combines the two components and studies them jointly. Potentially, there are many advantages to this design, including fewer subjects, shorter time to completion, lower cost, and adaptability to changes in technology and protocols. Based on the promising results of the ELCAP and certain Japanese studies, the NCI decided to initiate a large RCT with a mortality end point to assess the benefit of CT screening.46 This study has completed its enrollment of 50,000 subjects, and participants randomly assigned to either CT or CXR. The trial has an 80% power to detect a 20% reduction in mortality.46 Participants will undergo three rounds of screening with an average of 4.5 years of follow-up. This trial is being conducted by two independent groups, the American College of Radiology Imaging Network (ACRIN) and the PLCO group, each accruing half of the subjects. As with the other traditional RCTs, there are limited rounds of screening with long-term follow-up. However, there are additional concerns in regard to this trial. First is the choice to use CXR as the control arm, which may limit the contrast between the two arms of the study. Second, the diagnostic protocol is well defined for the ACRIN group but is left to the discretion of the investigator for the PLCO group. There is also a concern about possible lack of compliance, particularly for the group designated to receive CXR. For example, subjects in the CXR arm may not return for subsequent rounds or may obtain CT scans outside of the study. Although the trial results are not yet available, the pilot study for the National Lung Screening Trial (NLST), the Lung Screening Study (LSS), reported that 20% of the subjects in the CXR arm did not return for their first annual repeat screen.33 Because patients will need to be screened over many years to reap the benefits of screening, a 20% yearly decrease in protocol compliance may be problematic. Final analyses for the NLST are currently scheduled for 2009. Additional CT screening studies using the traditional RCT design that are ongoing include the NELSON trial in the Netherlands and a French study that has recently completed a pilot phase.47

Ch059-F06861.indd 747

747

NONSOLID AND PART-SOLID NODULES In the course of these CT screening studies, a novel type of pulmonary abnormality, best described as a nonsolid nodule, also referred to as a ground-glass opacity, has been identified. These are localized, hazy parenchymal densities that preserve normal bronchovascular anatomy, are invisible on plain CXR, and are frequently multifocal (Fig. 59-1).48 Although some of these lesions disappear after a course of antibiotics, persistent nonsolid nodules discovered during the course of screening frequently represent either the bronchioloalveolar variant of adenocarcinoma (BAC) or a mixed subtype with a large BAC component.49 Among cases with a combination of solid and nonsolid components (part-solid), the invasive component tends to be confined to the solid portion (see Fig. 59-1). The radiographic appearance correlates with extent of the invasiveness (Watanabe et al, 2002).49,50 Optimal treatment for nonsolid cancers is currently unknown, given that little is known about their natural course. It remains unclear what percentage of small nonsolid cancers will progress to invasive carcinoma. Further data need to be collected regarding these lesions before anatomic resection, limited resection, or merely observation can be recommended.

COMPUTED TOMOGRAPHIC SCREENING IN PATIENTS WITH PREVIOUSLY RESECTED NSCLC (SURVEILLANCE CT) Patients who have undergone previous curative resection for NSCLC represent the highest risk group for the development of a new lung cancer (Fig. 59-2). This risk is estimated to be approximately 2% per patient per year of follow-up, accumulating over time (Johnson, 1998).51,52 Although many clinicians, including our own group, obtain CT scans of their patients in the surveillance setting, few data have been published to support this practice. We recently examined our experience with surveillance CT in patients with completely resected NSCLC and made several observations.53 First, approximately two thirds of postoperative, surveillance scans are abnormal with regard to defined criteria, including pulmonary nodules, adenopathy, and/or pleural fluid. Second, fewer than one third of these abnormal scans were considered suspicious for recurrent or new primary lung cancer by the clinician. Third, when the clinician deemed a surveillance scan to be suspicious and subjected the patient to further diagnostic testing, metachronous lung cancer was diagnosed in 50% of the cases. Fourth, all scan-detected new primary lung cancers were pathologically stage I. These findings imply that surveillance CT has the ability to detect new primary lung cancer in its early stages; however, because many postoperative scans are abnormal, well-defined management protocols will be required to avoid unnecessary workups in the majority of patients. Further evaluation of this approach is needed in the form of large-scale clinical trials.

SPUTUM ANALYSIS The examination of expectorated sputum using standard cytologic techniques is generally regarded as insensitive in screening for lung cancer, based on the results of the Memorial

1/21/2008 12:14:07 PM

748

Section 3 Lung

Non-solid component Solid component

A

B

FIGURE 59-1 Persistent, localized nonsolid nodules (ground-glass opacities) detected on screening with low-dose CT scans. A, A pure nonsolid nodule (arrow) is a hazy abnormality that preserves normal bronchovascular anatomy. B, A part-solid nodule contains a radiographically solid component, which is usually a harbinger of invasive cancer.

FIGURE 59-2 Surveillance chest CT revealed a suspicious right lower lobe nodule (arrow) in a patient who had previously undergone right upper lobectomy for non–small cell lung cancer. Biopsy confirmed the existence of a second primary lung cancer.

Sloan-Kettering and Johns Hopkins Lung Projects, which randomized subjects to either annual CXR alone or CXR plus sputum cytologic evaluation every 4 months (see Table 59-1).16,17 Those trials demonstrated that examination of expectorated sputum did not decrease lung cancer–specific mortality in the populations studied. The quality of the sputum specimen remains a cause of some of the insensitivity associated with evaluation of sputum for the presence of

Ch059-F06861.indd 748

malignant cells. As a result, some recent investigations have focused on the development of technology to enhance the quality of sputum specimens. Potential advances include the high-frequency chest wall oscillation vest54 and the use of inhaled uridine 5′-triphosphate (UTP), a compound that stimulates salt and water transport and increases cilia beat frequency in airway epithelium.55 More sophisticated assays are also being investigated to improve the sensitivity of sputum analysis as a screening tool. In a retrospective analysis of archived sputum specimens containing moderately atypical cells from the Johns Hopkins Lung Project, 64% of specimens possessing positive immunostaining for the heterogeneous nuclear ribonucleoprotein, hnRNP A2/B1, were from patients who eventually developed lung cancer, whereas 88% of patients with negative staining did not develop cancer.56 However, despite further prospective data supporting this technique, more refinements are necessary before this reagent can be applicable to large-scale lung cancer screening (Thunnissen, 2003).57 Other sputum-based investigational approaches to lung cancer early detection, and potentially to screening, include use of the polymerase chain reaction (PCR) to detect mutations in expectorated bronchial epithelial cells and the detection of malignancy-associated changes (MACs). Although PCR is a very sensitive assay (detecting 1 mutated cell among more than 100,000 normal cells), and mutations in genes including KRAS (K-ras) and TP53 (p53) have been detected in the sputum of patients with lung cancer using PCR,58 at the present time the utility of this technique remains unclear because these mutations are also found in the sputum of smokers without cancer, and many different mutations can exist for a particular gene (e.g., TP53).59,60

1/21/2008 12:14:07 PM

Chapter 59 Early Detection and Screening of Lung Cancer

MACs are subtle, subvisual changes in DNA that are present in nontransformed cells. These changes in chromatin pattern are thought to be induced merely by the presence of neighboring malignant cells. Further, these changes can be quantified with the use of computer-assisted imaging technology.61-63 In a retrospective analysis using archived sputum specimens from the Mayo Lung Project, MACs were found to be present in 74% of the specimens from patients who went on to develop cancer.64 One advantage of this technology is that a positive result is not dependent on the presence of malignant cells in the sputum, which may serve to offset some of the inefficiencies of the sputum induction process. The clinical application of image cytometry continues to be the subject of ongoing investigation. Abnormal methylation of the promoter region of a variety of specific genes may be responsible for the inhibition of gene expression seen in multiple tumor types (e.g., tumor suppressor genes).65 These epigenetic changes also have been shown to occur in lung cancers and can be demonstrated in the sputum of lung cancer patients.65-68 More than 40 genes involved in methylation in lung cancer have been reported to date.69 As an example, a recent study demonstrated aberrant methylation of both the TP16 and the O6-methylguanine DNA methyltransferase (MGMT) genes in 100% of squamous cell cancers and their corresponding sputum specimens.66 However, as with the detection of genetic changes (mutations), false-positive results were relatively common, with aberrant methylation being demonstrable in almost one of every four long-term smokers without cancer.66 Evaluation of RNA in sputum by means of reverse transcriptase—PCR is also beginning to be investigated in lung cancer patients. In one study, transcripts for preprogastrinreleasing peptide were detected in the sputum of 5 of 23 patients with small cell lung cancer (SCLC).70 Sputum RNA analysis is still in an early developmental stage, however, and more data are required before large-scale clinical investigation can begin.

MOLECULAR DETECTION OF CIRCULATING TUMOR CELLS Molecular diagnostic techniques are also beginning to be evaluated for the detection of circulating tumor cells in the bloodstream of patients with lung cancer. Studies examining the role of circulating biomarkers include the use of methylation-specific PCR, which has revolutionized the detection of circulating, epigenetic alterations (aberrant promoter methylation).65 Numerous genes have now been found to be abnormally methylated in both SCLC and NSCLC specimens, including TP16, DAPK1, GSTP1, MGMT, adenomatous polyposis coli (APC), and the retinoic acid receptor–beta.65,71-73 Significantly, identical aberrant methylation is often found in the serum of patients from whom these tumor specimens are obtained, but not in the serum of patients whose tumors have unmethylated DNA, nor in serum from normal subjects. Other detectable alterations in the blood of patients with lung cancer (mainly SCLC) include microsatellite alterations

Ch059-F06861.indd 749

749

and levels of preprogastrin-releasing peptide messenger RNA, the latter being detected using reverse transcriptase–PCR.74,75 Whether these findings, as well as changes in promoter methylation, will play a role in screening of patients for lung cancer remains to be determined.

FLUORESCENCE BRONCHOSCOPY Conventional, white-light bronchoscopy has an overall sensitivity of only approximately 40% for the detection of preinvasive lung cancer (carcinoma in situ).76 Fluorescence bronchoscopy (FB) relies on the difference in autofluorescence spectra between normal and malignant airway epithelia. Under the helium-cadmium laser (442 nm), normal epithelium fluoresces green, whereas malignant tissue fluoresces brown/red. In a recent review of the published literature regarding the use of FB for detection of preinvasive lesions, Lam and colleagues76 found that the addition of FB to conventional bronchoscopy improved the detection rate from 40% to 80%. A European prospective, multicenter trial recently randomized 1173 patients to bronchoscopy followed by FB or to bronchoscopy alone.77 The prevalence of early malignant findings in the group undergoing FB was 1.4-fold higher than in the control group. Future work regarding FB will entail the design and evaluation of thinner bronchoscopes because the major limitation of this modality is the size of the instrument.

SUMMARY After early disappointment resulting from the randomized trials evaluating CXR and sputum cytology, lung cancer screening has experienced a resurgence of interest with the use of low-dose CT and molecular techniques. Multiple studies have documented the increased sensitivity of low-dose CT compared with CXR for detection of early lung cancer. Several large studies with varying designs are underway, and much additional information will become available in the next several years. Already, diagnostic algorithms are evolving, and new treatment strategies for the small cancers and novel types of cancer found with CT screening are being developed. Finally, technologies are being developed in the laboratory that may possess utility in the detection of preclinical lung cancer. These include assays for molecular alterations in sputum and peripheral blood and novel imaging techniques, including FB and computer-assisted imaging of expectorated sputum cells. Whether any of these new technologies will play a role in the future of lung cancer screening remains to be determined.

COMMENTS AND CONTROVERSIES The authors are internationally recognized for their contributions to the early detection of lung cancer, especially through the use of screening CT scans. Given the worldwide epidemic of lung cancer, its mortality rate, and its accepted association with cigarette smoking, it is astonishing that no major organization, government or otherwise, endorses lung cancer screening. The authors clearly describe the dilemma of screening for lung cancer: the limited

1/21/2008 12:14:08 PM

750

Section 3 Lung

number of screening rounds and duration of time before screening reaches its goal of decreased lung cancer–specific mortality. The methodologic defects and criticisms of major prior and current massive screening trials are discussed. Not insignificant is the changing technology, which renders most imaging studies or molecular assays obsolete before screening trials are ever completed. The speed and accuracy of CT imaging improves annually. Promising new data are emerging regarding the use of new molecular techniques in the evaluation of the serum of lung cancer patients. Even the age-old technique sputum cytology is being rehabilitated as methods are developed to improve the quality of the submitted specimens and to apply molecular genomic and epigenetic assays in their analysis. G. A. P.

KEY REFERENCES Bach PB, Kelley MJ, Tate RC, et al: Screening for lung cancer: A review of the current literature. Chest 123(1 Suppl):72S-82S, 2003. Fontana RS, Sanderson DR, Taylor WF, et al: Early lung cancer detection: Results of the initial (prevalence) radiologic and cytologic screen-

Ch059-F06861.indd 750

ing in the Mayo Clinic study. Am Rev Respir Dis 130:561-565, 1984. Gohagan JK, Prorok PC, Hayes RB, et al: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: History, organization, and status. Control Clin Trials 21(6 Suppl):251S-272S, 2000. Henschke CI, McCauley DI, Yankelevitz DF, et al: Early Lung Cancer Action Project: Overall design and findings from baseline screening. Lancet 354:99-105, 1999. Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90:1335-1345, 1998. Melamed MR, Flehinger BJ, Zaman MB, et al: Screening for early lung cancer: Results of the Memorial Sloan-Kettering study in New York. Chest 86:44-53, 1984. Strauss GM, Gleason RE, Sugarbaker DJ: Screening for lung cancer: Another look—a different view. Chest 111:754-768, 1997. Thunnissen FB: Sputum examination for early detection of lung cancer. J Clin Pathol 56:805-810, 2003. Watanabe S, Watanabe T, Arai K, et al: Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography. Ann Thorac Surg 73:1071-1075, 2002.

1/21/2008 12:14:08 PM

chapter

60

DIAGNOSIS AND STAGING OF LUNG CANCER Mark W. Onaitis Thomas A. D’Amico

Key Points ■ The diagnosis and staging of lung cancer is a process that involves

clinical, radiographic, and pathologic information. ■ The TNM staging system is used to define extent of disease,

assess prognosis, and assign therapy for patients with non–small cell lung cancer. ■ Clinical staging alone frequently underestimates the extent of disease. ■ Radiographic studies must be judiciously employed to accurately define the preoperative stage, to include patients appropriate for surgical resection, and to exclude patients from surgery who would not benefit. ■ In the future, molecular biologic analysis may improve prognostic stratification and the results of therapy.

The diagnosis and staging of lung cancer may be influenced by clinical symptoms, physical examination, radiographic evaluation, and pathologic results. The optimal staging system achieves accurate assessment of the extent of disease, effective prognostic stratification, and selection of appropriate therapy. The current TNM staging system for non–small cell lung cancer (NSCLC) provides a framework for the assessment of prognosis and the assignment of therapy for patients with a new diagnosis of lung cancer using the histopathologic evaluation of the primary tumor (T), lymph nodes (N), and metastatic disease (M). In the future, molecular biologic characteristics of the tumor may improve the classification and the outcomes of patients with lung cancer.

DIAGNOSIS The clinical symptoms of NSCLC are varied. If the examiner is patient and thorough, symptoms and signs of the tumor may be elicited in the majority of patients. Because of the highly aggressive nature of these cancers, two thirds of patients exhibit symptoms resulting from metastatic or systemic disease.1 Perhaps with improving radiologic detection measures and lung cancer screening strategies, more asymptomatic patients with lung cancer will be detected in the future. Clinical symptoms can be categorized simply as pulmonary, extrapulmonary thoracic, and extrathoracic symptoms.

Cough Although cough is the most frequent presenting symptom of NSCLC, occurring in 75% of patients,2 the finding is nonspecific and is frequently present in cigarette smokers. The finding of a new, unremitting cough, especially in patients older than 50 years of age who have a significant tobacco history, warrants further investigation.

Dyspnea Dyspnea is present in 50% to 60% of patients with NSCLC.2 The etiology of dyspnea is diverse, including obstructive and compressive factors. Central airway obstruction may result from endobronchial disease, usually squamous cell carcinoma. Extrinsic bronchial compression by a large central tumor or malignant mediastinal adenopathy can cause dyspnea, which is common with patients with small cell lung cancer (SCLC). In addition, parenchymal compression may be caused by a significant malignant pleural effusion. Dyspnea may be caused by large pericardial effusions or by vena caval obstruction. Rarely, a large or infiltrative tumor burden limits alveolar function (e.g., diffuse bronchoalveolar carcinoma).

Wheeze/Stridor As with dyspnea, compression of the bronchus by the tumor itself or by enlarged lymph nodes can cause wheezing if peripheral bronchi are affected or stridor if the trachea or main bronchi are involved.

Hemoptysis Hemoptysis is usually not massive in NSCLC and may occur in 25% to 40% of patients. This presentation occurs more commonly with centrally located tumors such as squamous cell tumors and SCLC.

Pneumonic Symptoms Almost all of the pulmonary symptoms of NSCLC can be mimicked by a postobstructive pneumonia. In addition, postobstructive atelectasis and pneumonia can cause fever, chills, sputum production, and pleuritic chest pain. Finally, lung abscess may be the end result of a chronic postobstruction pneumonia.

Extrapulmonary Thoracic Symptoms Pulmonary Symptoms Pulmonary symptoms are varied and include cough, dyspnea, wheeze, stridor, hemoptysis, and pneumonic symptoms.

Direct invasion of chest wall or mediastinal structures by either the tumor or enlarged lymph nodes may lead to diagnostic symptoms. 751

Ch060-F06861.indd 751

1/21/2008 12:14:59 PM

752

Section 3 Lung

Chest Wall Pain Peripheral tumors may extend through the visceral pleura to invade the parietal pleura, intercostal muscles or nerves, or ribs. Pain may result from invasion of any of these structures. Visceral pleural invasion leads to pleuritic pain, and invasion of the chest wall structures leads to somatic gnawing pain. Invasion of a neurovascular bundle may lead to radicular pain. A special case of chest wall invasion is the superior sulcus (Pancoast) tumor, which involves the thoracic outlet. This invasion can cause any of the classic triad of symptoms, including shoulder pain from direct muscle or rib invasion, radicular arm pain from invasion of C8 and T1 nerve roots, and Horner’s syndrome (ipsilateral ptosis, miosis, and facial anhidrosis) from invasion of the stellate sympathetic ganglion.

Symptoms From Mediastinal Involvement Mediastinal involvement of lung cancer causes specific symptoms based on the structure involved. Direct invasion of the phrenic nerve can cause either chronic hiccups or frank diaphragmatic paralysis. Also, because of its origin from C3-C5, phrenic nerve involvement can cause referred shoulder pain. Involvement of the recurrent laryngeal nerve occurs most commonly on the left due to the proximity of the nerve to lymph nodes in the aortopulmonary window. This may lead to subtle voice alteration or to hoarseness. Chronic recurrent laryngeal nerve paralysis contributes to lung dysfunction because of recurrent aspiration secondary to inability to adequately protect the airway. Extensive tumor involvement of right mediastinal lymph nodes may result in superior vena caval syndrome, which is characterized by a plethoric appearance, distention of the venous drainage of the arm and neck, and edema of the face, neck, and arms. Vena caval obstruction usually progresses gradually over time, allowing the development of collateral venous drainage that is detectable on physical examination. SCLC is more often the cause, rather than NSCLC. Pericardial involvement may lead to symptomatic effusion and even tamponade. Esophageal compression sometimes occurs because of compression by enlarged mediastinal lymph nodes. Finally, vertebral bodies may be involved by posterior tumors, leading to back pain.

Extrathoracic Symptoms Paraneoplastic Syndromes Paraneoplastic syndromes—symptoms or findings that are related to the primary tumor or its metastases by hormonal intermediates—may accompany lung cancer. Although paraneoplastic syndromes are unusual, the resulting symptoms may predate thoracic manifestations of a curable primary tumor. Systemic manifestations of NSCLC include cachexia, parathyroid-like hormone secretion with concomitant hypercalcemia, hypertrophic pulmonary osteoarthropathy, and various neurologic syndromes. Weight loss and anorexia occur in up to one third of patients. Even in noncachectic patients, however, increases in protein turnover, glucose production, and muscular catabolism may be demonstrated.3

Ch060-F06861.indd 752

Paraneoplastic syndromes are frequently associated with SCLC, and they are more often present at the time of diagnosis in patients with SCLC than in those with NSCLC. In addition to weight loss, anorexia, and neuromyopathies, paraneoplastic syndromes may result from tumor elaboration of antidiuretic hormone, adrenocorticotropin (ACTH), calcitonin, or parathyroid hormone.

Skeletal Manifestations Skeletal syndromes include hypertrophic pulmonary osteoarthropathy (HPO) and clubbing. HPO is a proliferation of periostitis of the ends of long bones. Affecting primarily the tibia, fibula, and radius, the periostitis causes tenderness and swelling. Unlike many of the other paraneoplastic syndromes, HPO is more common in NSCLC than in SCLC. Alkaline phosphatase levels are often elevated, but hepatic enzymes are normal. HPO is always associated with clubbing of the digits, but the converse is untrue. Clubbing occurs in 35% of NSCLC patients.4

Endocrine Manifestations The syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurs in up to 46% of patients with SCLC,5 but also may occur, less frequently, in NSCLC. Symptoms include those of hyponatremia: anorexia, nausea, vomiting, confusion, lethargy, and seizures. These same signs and symptoms may be present with secretion of atrial natriuretic peptide (ANP), which may also be secreted by SCLC. The distinction between the two conditions may be made by measurement of serum ADH. In SCLC, the treatment is chemotherapy. Hypercalcemia develops in 10% of patients with lung cancer. However, only 15% of these cases are caused by the production of parathyroid hormone or other humoral substances.6 For this reason, metastatic bone disease must be ruled out in these patients by bone scan or by positron emission tomography (PET). The most frequent lung tumor that produces parathyroid hormone is squamous cell cancer. These tumors are often resectable, and, after complete resection, the calcium level normalizes. However, tumor recurrence after resection is common and may manifest as recurrent hypercalcemia. Ectopic production of an ACTH-like substance may lead to Cushing’s syndrome. This is much more common in SCLC than in NSCLC. The resulting cortisol production is not suppressible by dexamethasone. Because of the rapidity of the ACTH elevation, physical signs of Cushing’s syndrome are usually absent, and the symptoms that do appear are primarily caused by metabolic consequences. Among these are hypokalemia, metabolic alkalosis, and hyperglycemia. Neurologic paraneoplastic syndromes are most commonly associated with SCLC and squamous cell cancer and are thought to be immune mediated. The cancer cells may express antigens that are normally expressed only by nervous system tissues.7 Unlike patients with the endocrine paraneoplastic syndrome, these patients tend to exhibit their symptoms later in the disease process. Symptoms resulting from this immune process range from sensory, sensorimotor, and

1/21/2008 12:14:59 PM

Chapter 60 Diagnosis and Staging of Lung Cancer

autonomic peripheral neuropathies to the central neuropathies of cerebellar degeneration, dementia, brain stem encephalitis, and encephalomyelitis. Weight loss often accompanies these symptoms, making workup of metastatic disease essential. The peripheral neuropathies are the most common paraneoplastic syndromes associated with lung cancer, occurring in up to 16% of patients. Of these, 56% have SCLC, 22% have squamous cell cancers, 16% have large cell cancers, and 5% have adenocarcinomas.8 Lambert-Eaton myasthenic syndrome is most frequently seen in SCLC and may lead to proximal muscle weakness and fatigability (particularly of the thighs), a waddling gait, and dry oral mucosa. This syndrome is produced by immunoglobulin G (IgG) antibodies, which target voltage-gated calcium channels that function in the release of acetylcholine from presynaptic sites at the motor endplate. These antibodies are generated through an immune response to similar channels present on tumor cells.9 These symptoms often occur before the onset of symptoms of the primary tumor and may precede radiologic evidence of the tumor by up to 4 years.10 As with most of the paraneoplastic syndromes, treatment of the primary tumor may lead to dramatic symptomatic improvement.

Metastatic Symptoms Lung cancer most frequently metastasizes to the brain, spinal cord, bones, liver, adrenal glands, lungs, and skin/soft tissues.

Central Nervous System Metastases Central nervous system (CNS) metastases are present in approximately 10% of patients at diagnosis. Over time, 10% to 15% of the other patients will develop CNS lesions. Although these metastases are frequently asymptomatic, symptoms of increased intracranial pressure (headache, nausea, vomiting, altered level of consciousness) predominate. More focal symptoms, such as weakness/numbness or seizures, are less common.

Bone Metastases Twenty-five percent of lung cancer patients develop bony metastases. Of these, 55% occur in the axial skeleton (spine, pelvis, sternum, ribs).11 These patients complain of pain at the affected area.

Hepatic and Adrenal Metastases Hepatic metastases are usually asymptomatic and are found on follow-up computed tomographic (CT) scans. Adrenal metastases are often found on a staging CT scan or PET scan and are also usually asymptomatic. Addison’s or Conn’s disease rarely is present, even in the presence of bilateral metastases.

Skin and Soft Tissue Metastases Skin and soft tissue metastases are present as late-stage findings in 8% of lung cancer patients. These lesions are usually subcutaneous and painless. Occasionally, they erode through

Ch060-F06861.indd 753

753

the skin and cause a chronic wound, which may require excision.

Nonspecific Metastatic Symptoms Anorexia, weight loss, fatigue, and malaise are poorly understood symptoms of metastatic lung cancer. All patients with lung cancer need to be queried regarding such symptoms, and their presence initiates a search for metastatic disease.

SCREENING This subject is covered in more detail in Chapter 59; however, a brief review is pertinent to this discussion of diagnosis. The purpose of screening is to identify lung cancers at an early stage, before signs and symptoms develop. Achieving this goal would increase the number of patients who are eligible for curative surgical resection, improving overall survival and resource utilization. In order for CT-based screening programs to improve on programs based on plain chest roentgenography (CXR), a significant relationship must be identified between smaller size of a tumor and lower stage and subsequently better survival. Analysis of the Surveillance, Epidemiology and End Results (SEER) registry focusing on 84,152 cases of lung cancer diagnosed before autopsy revealed a significant correlation between small size and low stage.12 Although this finding is encouraging, no assessment of symptoms was available, limiting its applicability to screening. The Mayo Lung Project randomly assigned men aged 45 years or older who had smoked 1 pack a day for the previous year to either screening with CXR and sputum cytology every 4 months for 6 years or recommendation of annual CXR and sputum cytology.13 Although the incidence of lung cancer in the screened population was lower than in the control population (4.5% versus 3.5%), the lung cancer–specific mortality and all-cause mortality were unaffected by screening. This study has been criticized for the statistical design to detect a 50% difference in mortality, for nonadherence to the assigned screening strategy (50% of controls received more than just an annual CXR), and for poor screening technique, detecting only 45 (22%) of 206 resectable tumors. The Czechoslovakian lung cancer screening study randomly assigned male smokers aged 40 to 64 years with a 20.5 packyear average tobacco history to either CXR and sputum cytology every 6 months for 3 years or a single CXR at the end of 3 years.14 Both groups then underwent CXR annually for 3 additional years. At 3 years, the 5-year survival rate was better in the screened group, but lung cancer–specific mortality was higher in the screened group. At 6 years, an insignificant difference in lung cancer mortality existed between the groups. Both the Johns Hopkins15 and the Memorial SloanKettering16 trials randomly assigned male smokers older than 45 years of age to either annual CXR and sputum cytology every 4 months or annual CXR. Both groups were screened in these studies, and the 5-year survival rate of those developing lung cancer was 35%, better than the 13% national average. However, the groups that received sputum cytologic

1/21/2008 12:14:59 PM

754

Section 3 Lung

analysis enjoyed no lung cancer–specific mortality advantage in either study. Taken together, these studies quashed enthusiasm for the staging of lung cancer in the 1990s. However, as a more recent review17 noted, they may inform our understanding of screening trials in general before discussion of the more modern trials. First, methodologic problems can lead to poor results. These studies were relatively underpowered to show significant differences, and groups may not have been well matched despite randomization. Second, and more important, is the question of bias.18 Why, for instance, did the trials produce screened groups that had more cancers detected at earlier stages but exhibited no advantage in cancer-specific mortality? Possible answers include lead-time bias, length-

time bias, and overdiagnosis bias (Fig. 60-1). Lead-time bias occurs when screening hastens diagnosis but does not change the time of death. This bias is particularly evident when survival time is used as an end point. Length-time bias involves detection of biologically indolent tumors more frequently than those that are more aggressive. Overdiagnosis bias occurs if screening detects tumors that would not cause death in the patient’s lifetime. The end point of lung cancer–specific mortality is unaffected by these biases. None of the trials described earlier achieved improvements in lung cancer–specific mortality rates. The Matsumoto study from Japan19 investigated smokers and nonsmokers aged 40 to 74 years who were already part of a national screening program employing yearly CXR and

Length-Time Bias Aggressive tumors

Onset of tumor

Tumor detectable

Symptoms

Lead-Time Bias Survival time

Onset of tumor

Time Screened group

Diagnosis confirmed

Patient dies

Tumor detectable

Symptoms

Lead time Onset of tumor

Survival time

Tumor detectable

Symptoms

Indolent tumors

Time Control group

Symptoms

Diagnosis confirmed

Patient dies

A

Time

B Overdiagnosis Bias

Time Screened group

Diagnosis confirmed

Patient dies

Natural death

Time Control group

Symptoms Diagnosis Patient Natural confirmed dies death

C FIGURE 60-1 Lead-time, length-time, and overdiagnosis biases. A, Lead-time bias. The diagnosis is made earlier in the screened group, resulting in an apparent increase in survival time (lead-time bias), although the time of death is the same in both groups. B, Length-time bias. The probability of detecting disease is related to the growth rate of the tumor. Aggressive tumors have a short potential screening period (interval between possible detection and the occurrence of symptoms). Unless the screening test is repeated frequently, patients with aggressive tumors are more likely to present with symptoms. Tumors that grow more slowly have a longer potential screening period and are more likely to be detected when they are asymptomatic. As a result, a higher proportion of indolent tumors is found in the screened group, causing an apparent improvement in survival. C, Overdiagnosis bias: The detection of very indolent tumors in the screened group produces an apparent increase in the number of cases of lung cancer (in this example, three cases in the screened group and one in the control group). There is also an apparent increase in survival: two of three patients in the screened group were treated and died of natural causes, without evidence of disease (66% survival), and the one patient in the control group did not survive (0% survival). However, there is no effect on mortality (one death from lung cancer in each group) because two patients in the control group died with undiagnosed lung cancer that did not affect their natural life span. (FROM PATZ EF, GOODMAN PC, BEPLER G: SCREENING FOR LUNG CANCER. N ENGL J MED 343:1627-1633, 2000.)

Ch060-F06861.indd 754

1/21/2008 12:14:59 PM

Chapter 60 Diagnosis and Staging of Lung Cancer

sputum cytology. Each of the 3967 patients who underwent both CT and CXR was matched with two controls from the same population who underwent CXR only. When abnormalities were found, the patients underwent high-resolution CT and transbronchial biopsy if possible. Of the 3967 patients in the experimental group, 223 underwent further testing, and 19 cancers were found. Of these, 16 were stage I and 3 were stage IV. The positive predictive value for helical CT in this study was a disappointing 8.5%. The incidence of lung cancer was 5 per 1000 patients (2.5-fold higher than in the general male population, and 15.7-fold higher than in the general female population) and was not different in smokers versus nonsmokers. Mortality data have not yet been published. The Early Lung Cancer Action Project (ELCAP) study screened 1000 smokers (≥10 pack-years) who were asymptomatic and deemed fit for thoracotomy with CXR and helical CT.20 Noncalcified nodules were identified in 233 patients by helical CT and in 68 patients by CXR. These 233 subjects then underwent conventional CT, and 28 were biopsied, with 27 cancers diagnosed. Of these, 23 were stage I and 26 (96.3%) were resectable. The incidence in this study was 31 per 1000 subjects. Mortality data were not yet available in this preliminary report. Although the increased incidence of lung cancer found in these studies is encouraging, maturation and publication of mortality data will be important to rule out lead-time bias. The Mayo Clinic screened 1520 smokers (>20 pack-years) older than 50 years of age with annual spiral CT for 5 years.21 This trial found noncalcified nodules in 74% of the patients. Of these, 66 were found to be lung cancer. However, despite 61% of the diagnosed cancers being stage I, lung cancer– specific mortality was 1.6 per 1000 person-years, not significantly better than that found in the first Mayo trial, described earlier. Several explanations have been posited to account for the lack of success of these screening trials. Beyond the biases described previously, negative effects of screening and treatment of lung cancer may negate survival improvements created by screening programs. Patients with lung cancer are usually smokers, who are known to have a much higher incidence of chronic obstructive lung disease and coronary artery disease than nonsmokers. In patients who are overdiagnosed, screening leads to increased survival, but operative mortality increases the mortality rate in the screened group.22 Another issue in widespread acceptance of screening is the potential cost to the health care system. Assuming charges of $250 for a screening CT scan and $600 for a high-resolution follow-up CT scan, one estimate of cost for the first 2 years of screening the at-risk population of the United States was $20 billion.22 The advent of molecular biologic approaches to assay overexpression of tumor markers may lead to sputum, bronchoalveolar lavage, or serum screening of high-risk individuals.23-27

The Solitary Pulmonary Nodule Just as indeterminate lung nodules found during sensitive screening studies create a significant clinical problem, so do

Ch060-F06861.indd 755

755

nodules found incidentally in asymptomatic patients (Table 60-1). A solitary pulmonary nodule is defined as one that is less than 3 cm in diameter and is surrounded by pulmonary parenchyma; in follow-up, these are found to be malignant up to 70% of the time.28,29 Of the benign lesions, 80% are infectious granulomas, and 10% are hamartomas. Characteristics of nodules on chest CT may help disclose malignancy. First among these is the border of the lesion. Margins of a lesion may be classified as smooth, lobulated, or irregular (speculated). Smooth nodules are generally benign, although 21% of malignant nodules have smooth borders.30 A lobulated contour may signify the uneven growth of a malignancy, but it may also occur in up to 25% of benign nodules.31 Spiculated nodules have a corona radiata appearance and are highly likely to be malignant (Gurney, 1993).31-35 Internal characteristics and density of a nodule may also help to diagnose malignancy. Homogeneous attenuation is seen in 55% of benign lesions but also in 20% of malignant lesions.31 Cavitation may occur in both benign and malignant nodules. However, benign nodules tend to have thin walls, whereas malignant nodules tend to have thick and irregular walls.34 Most nodules with a wall thickness greater than 16 mm are malignant, and most of those with wall thickness less than 4 mm are benign.36 Certain characteristics may also help with specific diagnoses: pseudocavitation for bronchoalveolar carcinoma37,38 and intranodular fat for hamartoma.39 Finally, calcification helps to diagnose benign nodules. Central, diffuse solid, and laminated calcifications are seen in loci of prior infections, whereas so-called popcorn calcification is seen in hamartoma. However, up to 63% of benign nodules are not calcified, and calcification may also occur in up to 6% of lung cancers.40 TABLE 60-1 Differential Diagnosis of the Solitary Pulmonary Nodule Category

Diagnosis

Neoplastic/Malignant

NSCLC/SCLC Lymphoma Carcinoid

Neoplastic/Benign

Hamartoma Chondroma

Infectious

Granuloma Nocardia infection Round pneumonia Abscess

Inflammatory

Rheumatoid nodule Wegener’s granulomatosis nodule

Vascular

Arteriovenous malformation Infarct Hematoma

Congenital

Bronchial atresia Sequestration

Other

External object (nipple, mole) Pseudotumor (fluid in fissure) Pleural plaque/mass

NSCLC, non–small cell lung cancer; SCLC, small cell lung cancer.

1/21/2008 12:15:00 PM

756

Section 3 Lung

In like manner, the solidity of a nodule may be important. A nonsolid nodule is defined as a density through which aerated lung is visible. This type of nodule has a relatively low (15%) risk of cancer; however, as size increases to greater than 15 mm, the risk of malignancy increases. A part-solid nodule contains a solid portion that obliterates aerated lung in addition to a nonsolid portion, and these nodules carry a much higher risk of malignancy (40%-50% even for nodules smaller than 15 mm). Again, the risk of cancer increases with the size of the nodule, but it also increases as the solid component increases.41 Of small solid nodules, only approximately 15% are malignant. However, because most small nodules (<1 cm) are solid, most cancers are diagnosed in solid nodules. A progression from nonsolid to part-solid to solid nodules may occur. Assessment of growth rate may also allow prediction of malignancy. Volume-doubling time for malignant nodules is between 30 and 400 days and correlates with a 26% increase in diameter.42 Because of this, stability of a nodule’s size over 2 years has generally been considered to be reliable for benignity.43 This rule is easier to apply and probably more accurate for larger lesions rather than small ones.44 Bayesian analysis allows precise determination of the probability of malignancy by calculating a likelihood ratio (the number of malignant nodules with a given feature divided by the number of benign nodules with the same feature) for each characteristic and then taking the product of these ratios.32,45 The probability of malignancy based on various clinical and radiologic characteristics is shown in Table 60-2 and the recommended imaging follow-up in Table 60-3. ELCAP data provide some interesting perspectives on this problem. The circumstance of the CT scan is important. In the ELCAP series of 1000 screening CTs, 23.3% of scans showed one to six noncalcified nodules; of these, 12% contained cancer.20 However, on repeat screening 1 year later, only 2.5% of scans contained new nodules. Twelve of these

TABLE 60-2 Association of Clinical and Radiographic Features With the Likelihood of Malignancy Feature

Likelihood Ratio

Spiculated margin

5.54

Size >3 cm

5.23

Age <70 years

4.16

Malignant growth rate

3.40

Smoker

2.27

Upper lobe location

1.22

Size <1 cm

0.52

Smooth margins

0.30

Age 30-39 years

0.24

Never smoked

0.19

Age 20-29 years

0.05

Benign calcification

0.01

Benign growth rate

0.01

Ch060-F06861.indd 756

nodules resolved 4 to 6 weeks later; of the 18 nodules that did not resolve, 39% had lung cancer (Henschke et al, 2001).46 These data indicate that, although new nodules are more common on screening studies, false-positive results are much more common on baseline screening than on 1-year interval screening studies. Although degree of smoking is clearly important in estimating lung cancer risk in a solitary nodule,47 some subtleties have emerged. Whereas cessation of smoking clearly limits lung cancer risk, the risk may level off rather than decline.48 The trend toward lower-tar, filtered cigarettes has corresponded with a shift from central lesions to peripheral adenocarcinomas as the predominant cancers found.49 CT may be the test of choice to identify these peripheral nodules.

STAGING Diagnosis and staging of lung cancer are often performed concurrently. Therefore, before discussion of the various diagnostic modalities, a description of the staging system is necessary. The purposes of any staging classification are the assessment of prognosis and assignment of therapy. As with other cancers, the staging system for lung cancer is based on a tumor-node-metastasis (TNM) system (Tables 60-4 and 60-5). Before operation, patients are assigned a clinical stage; after surgery, a pathologic stage is obtained. Because the pathologic stage allows more careful assessment of the primary tumor and nodes, survival rates based on pathologic stage are higher than those based on clinical stage. In 1974, the American Joint Committee for Cancer (AJCC) introduced a lung cancer staging system based on the TNM system.50 Shortly thereafter, Naruke and colleagues51 put forth an anatomic lymph node map. This schema was subsequently modified by the American Thoracic Society52 and by Mountain and Dresler (Mountain and Dresler, 1997).53 The current regional lymph node map is presented in Figure 60-2 (Mountain and Dresler, 1997).53 In the United States, this TNM system was used for staging for several years. In Europe, the Union Internationale Contre de Cancer (UICC) has used a separate system since 1978. In 1986, Mountain, with the backing of these groups as well as Japanese and German groups, applied a TNM staging system to a database of 3000 patients with NSCLC from M.D. Anderson Cancer Center and the Lung Cancer Study Group.54 This study TABLE 60-3 Recommended Imaging Based on Likelihood of Malignancy in a Solitary Nodule Likelihood of Cancer

Recommended Imaging

Very low Nodule <1 cm Nodule >1 cm

CXR/CT at 6, 12, 24 mo CT at 3, 6, 12, 24 mo PET

Intermediate Nodule <1 cm Nodule >1 cm

CT at 3, 6, 12, 24 mo PET

High

Staging workup

CT, computed tomography; CXR, plain chest radiography; PET, positron emission tomography.

1/21/2008 12:15:00 PM

Chapter 60 Diagnosis and Staging of Lung Cancer

757

TABLE 60-4 Staging Parameters for Non–Small Cell Lung Cancer: TNM Descriptors Classification

Description

Primary Tumor (T) T0 No evidence of primary tumor T1 Tumor <3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus T2 Tumor >3 cm in greatest dimension; or involving the main stem bronchus >2 cm from the carina; or invading the visceral pleura; or associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T3 Tumor of any size that invades the chest wall, diaphragm, mediastinal pleura, or parietal pericardium; or tumor in the main stem bronchus <2 cm from the carina without invading the carina; or associated atelectasis or obstructive pneumonitis of the entire lung T4 Tumor of any size that invades mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina; or tumor with a malignant pleural or pericardial effusion; or tumor with satellite nodule(s) within the same lobe Regional Lymph Nodes (N) N0 No regional lymph node metastasis N1 Metastasis to ipsilateral peribronchial or ipsilateral hilar lymph nodes and intrapulmonary nodes involved by direct extension of the primary tumor N2 Metastasis to ipsilateral mediastinal or subcarinal lymph nodes N3 Metastasis to contralateral mediastinal, contralateral hilar, or ipsilateral or contralateral scalene/supraclavicular nodes Distant Metastases (M) M0 No distant metastasis detected M1 Distant metastasis present From Mountain CF: Revisions in the international system for staging lung cancer. Chest 111:1710-1717, 1997; and Mountain CF, Dresler CM: Regional lymph node classification for lung cancer staging. Chest 111:1718-1723, 1997.

TABLE 60-5 Staging Subgroups and Survival Stage

TNM Subset

5-Year Survival (%)

IA

T1 N0 M0

67

IB

T2 N0 M0

57

IIA

T1 N1 M0

55

IIB

T2 N1 M0 T3 N0 M0

39 38

IIIA

T3 N1 M0 T1-3 N2 M0

25 23

IIIB

T4 Any N M0 Any T N3 M0

5

IV

Any T Any N M1

1

From Mountain CF: Revisions in the international system for staging lung cancer. Chest 111:1710-1717, 1997.

demonstrated 5-year survival curves for each stage, which verified the TNM system. The applicability of the system was confirmed by subsequent studies by Naruke55 and Watanabe56 and their colleagues. In 1997, Mountain (Mountain, 1997)57 analyzed an additional 1524 patients from M.D. Anderson and outlined changes in the staging system designed to group together patients with similar prognoses. This study demonstrated the disparate prognoses of T1 N0 M0 and T2 N0 M0 tumors and classified them as stage IA and stage IB, respectively. In similar manner, T1 N1 M0 and T2 N1 M0 cancers were split from stage II into stage IIA and stage IIB, respectively. Finally, T3 N0 M0 was noted to have similar prognosis to T2 N1 M0

Ch060-F06861.indd 757

and was moved from stage IIIA to stage IIB. These changes were ratified by both the AJCC and the UICC. Staging is usually carried out in a centripetal manner. Distant disease is ruled out first, so that patients who are not surgical candidates may be spared invasive procedures. Next, noninvasive methods to stage mediastinal nodes are performed before invasive tests are undertaken. The T stage is then assessed and is often not precisely defined until operation and pathologic assessment.

Diagnostic Modalities Chest Roentgenogram The CXR has been an integral tool since its inception and is believed by many to be the most important test in the diagnosis of lung cancer. If lung cancer is suspected based on clinical criteria, a posterior-anterior and lateral CXR is the first test ordered (Fig. 60-3). Lung masses are also often seen on CXR performed for other reasons. For a lesion to be visible on CXR, it must be at least 7 to 10 mm in diameter.58 The posterior-anterior and lateral CXR also allows assessment of peripheral versus central location of the tumor, presence of atelectasis due to bronchial obstruction, presence of effusion from malignant spread or from exudate, and presence of hemidiaphragm elevation due to phrenic nerve involvement. On occasion, a large degree of hilar lymphadenopathy is visible on the CXR.

Computed Tomography If an abnormal nodule is suspected on CXR, the next step in diagnosis is usually high-resolution chest CT. The CT scan confirms the presence, size, and location of the primary

1/21/2008 12:15:00 PM

758

Section 3 Lung

Brachiocephalic (innominate) artery

Superior Mediastinal Nodes 1 Highest mediastinal 2R

2 Upper paratracheal 3 Pre-vascular and retrotracheal

Ao 4R

Azygous vein

4 Lower paratracheal (including azygos nodes)

4L 10R

N2 = Single digit, ipsilateral N3 = Single digit, contralateral or supraclavicular

PA 7

11R

11L 8

10L

5 Subaortic (A-P window)

9

12,13,14R

Aortic Nodes

12,13,14L Inferior pulmonary ligament

6 Para-aortic (ascending aorta or phrenic)

Inferior Mediastinal Nodes 7 Subcarinal Ligamentum arteriosum

3

Left pulmonary artery

8 Paraesophageal (below carina) 9 Pulmonary ligament

Phrenic nerve

N1 Nodes 10 Hilar

Ao 5 PA

11 Interlobar 12 Lobar 13 Segmental 14 Subsegmental

FIGURE 60-2 Regional lymph node map. Ao, aorta; A-P, anterior-posterior; L, left; PA, pulmonary artery; R, right. (FROM MOUNTAIN CF, DRESLER CM: REGIONAL LYMPH NODE CLASSIFICATION FOR LUNG CANCER STAGING. CHEST 111:1718-1723, 1997.)

nodule, and it may also provide important information regarding the risk of malignancy of the primary tumor (Fig. 60-4). In addition, the CT scan assesses the contiguous structures, hilar lymph nodes and mediastinal lymph nodes, the status of the remaining pulmonary parenchyma and pleura, and the presence of distant metastases (particularly in the liver and adrenal glands). As noted in the discussion of the solitary lung nodule, the margin of the lesion, the internal characteristics of the lesion, the rate of growth, the circumstance of the CT, the presence or absence of calcification, and the smoking history of the patient are all extremely important in assessing the risk of cancer in a lung nodule. Assessment of mediastinal lymph nodes is also aided by chest CT. Size greater than 1 centimeter in the shorter axis is the usual criterion for defining adenopathy. In a 143-patient prospective study in which CT findings were tested by surgi-

Ch060-F06861.indd 758

cal pathology, the sensitivity of chest CT for mediastinal lymph node positivity was found to be 64%, and the specificity was 62%.59 Meta-analysis of 3438 patients in 20 studies revealed a lower sensitivity of 57% but a higher specificity of 82% (Toloza, Harpole, and Detterbeck, 2003; Toloza, Harpole, and McGory, 2003).60,61 Clearly, positive lymph nodes in the mediastinum by chest CT require histologic confirmation. Chest CT may also diagnose non-nodal metastatic disease. It provides detailed information regarding synchronous second nodules as well as satellite nodules. In addition, because routine chest CT includes the upper abdomen to the level of the adrenal glands, unsuspected metastases may be documented in the liver and in the adrenal glands. Rates of positive findings are 3% to 6% in the liver and 3% to 7% in the adrenals.62 These patients are then spared unnecessary thoracotomy.

1/21/2008 12:15:00 PM

Chapter 60 Diagnosis and Staging of Lung Cancer

Positron Emission Tomography PET uses fluorodeoxyglucose (FDG), a D-glucose analogue that is labeled with positron-emitting fluorine 18. This agent is taken up by cells and phosphorylated but is not metabolized further. Because malignant cells are more metabolically active than normal cells, the 18F-labeled agent preferentially accumulates in these cells. Whole-body imaging allows visu-

FIGURE 60-3 Chest roentgenogram demonstrating prominent right upper lobe mass.

759

alization of malignant cells at primary, nodal, and distant sites (Fig. 60-5). For diagnosis of cancer in a solitary pulmonary nodule, FDG-PET is accurate. Multiple studies have revealed a sensitivity of 96%, specificity of 88%, and accuracy of 94% in these nodules.63-67 False-positive results may occur with infectious and inflammatory processes. False-negative results may occur with small tumors or with less aggressive pulmonary malignancies such as carcinoid or bronchoalveolar carcinoma. Also, the results of PET scans in patients with lesions smaller than 1cm in diameter on chest CT may not be reliable because few such patients were included in the PET studies described earleir.68 Although FDG-PET is expensive, it has been shown to be cost-effective in a strategy combined with chest CT if the pretest probability of malignancy is 12% to 69%. With probabilities lower than 12%, observation is more costeffective, and above 69%, resection is more cost-effective.69

FIGURE 60-4 CT demonstrating small left upper lobe nodule.

FIGURE 60-5 A, Positron emission tomogram (PET) scan demonstrating hypermetabolic activity in the primary left upper lobe tumor and mediastinal lymph nodes. PET scan with activity in the primary tumor (B) and in the left sacrum (C).

A

Ch060-F06861.indd 759

B

C

1/21/2008 12:15:03 PM

760

Section 3 Lung

The success of PET in the diagnosis of malignancy in a primary nodule led to much enthusiasm in the assessment of mediastinal nodes. In one of the most quoted studies evaluating PET, Pieterman and colleagues70 prospectively compared PET versus conventional staging in 102 patients who underwent staging of the mediastinum. PET improved sensitivity from 75% to 91% compared to CT, and it improved specificity from 66% to 86%. The combination of the two approaches had a sensitivity of 94% and a specificity of 86%. Initial studies documented improved accuracy for FDG-PET compared to chest CT, with an increase or decrease in TNM stage in 21% to 40% of patients (Pieterman et al, 2000).70,71 In addition, the combined use of CT and PET was found to be cost-effective.72 However, much as in the assessment of malignancy in a primary nodule, false-positive results may occur. In the mediastinum, this occurs most often with infection, inflammation, hyperplasia, sarcoidosis, and anthracotic nodes.71,73,74 Because the identification of mediastinal nodal disease precludes resection, false-negative results are also a large problem. Because of these issues, controversy has arisen over whether PET can obviate the need for invasive staging of the mediastinum. A recent European prospective randomized trial assessing the role of PET in staging was the PET in Lung Cancer Staging (PLUS) trial, which randomized 188 patients to either PET or conventional staging.75 The end point of the trial was futile thoracotomy (defined as thoracotomy without resection, thoracotomy with mediastinal nodal involvement, or recurrence within 1 year after resection). Although the PET group had a significantly lower rate of futile thoracotomy compared to the conventional staging group (21% versus 41%), criticisms of this study have focused on inadequacy of the conventional staging (few studies despite 24% of patients having stage III disease) and sloppiness of the clinical evaluation (15% with weight loss and 9% with poor performance status). Toloza and colleagues (Toloza, Harpole, and McCrory, 2003),61 in their recent meta-analysis, found a false-positive rate of 22% for PET in assessment of mediastinal involvement. Another recent meta-analysis demonstrated a 30% rate of malignancy in CT-documented enlarged mediastinal lymph nodes when the PET was negative.76 More recent studies also call into question the accuracy of PET in mediastinal nodal assessment. A recent retrospective review from Duke University assessed 202 patients who underwent PET followed by mediastinoscopy; PET was found to have 64% sensitivity, 77% specificity, and 74% accuracy for mediastinal disease (Gonzalez-Stawinski et al, 2003).77 In this study, the false-positive rate was 32% and the falsenegative rate was 12%. The American College of Surgeons Oncology Group (ACOSOG) recently published the results of their Z0050 trial, which sought to assess the utility of PET in staging of operable patients (Reed et al, 2003).78 Of the 303 patients randomized, 84% had clinical stage I or II disease, and 16% had clinical stage IIIA lung cancer. The sensitivity of PET for mediastinal nodal involvement was found to be 61%, with a specificity of 84%, a negative predictive value of 87%, and a positive predictive value of 56%. Taken together, these data demonstrate that PET lacks the accuracy to replace invasive staging for assessment of medi-

Ch060-F06861.indd 760

astinal nodal disease in NSCLC. A negative PET scan in the mediastinum does not preclude N2 or N3 disease, and a positive PET result needs to be verified pathologically. PET has been studied in the assessment of unsuspected distant metastatic disease. In patients who have symptoms of systemic metastases (e.g., fatigue, weight loss, anorexia), PET allows total-body imaging with one study. Pieterman and associates (Pieterman et al, 2000)70 found undiagnosed metastases in 11% of patients. In the ACOSOG Z0050 study (Reed et al, 2003),78 the sensitivity of PET for metastatic disease was 83%, and the specificity was 90%; the negative predictive value was 99%, but the positive predictive value was only 36%. Therefore, a negative result in an asymptomatic patient obviates further attempts to stage patients as M1 before resection. However, a positive result requires histologic confirmation. In excluding metastatic disease, PET has proved more accurate in some areas than in others. Because of high FDG uptake in normal gray matter, PET has not been useful for identification of brain metastases.79 For adrenal metastases, PET was found to be 100% sensitive in three studies.80-82 As results of these and other studies mature, the appropriate roles for PET in NSCLC will continue to be defined.

Sputum Cytology Analysis of sputum cytology can be a powerful method of diagnosing lung cancer. Its accuracy depends on several factors. Specimens may be induced by saline or collected as a 3-day sample of morning sputum that is preserved in 50% ethanol/2% polyethylene glycol or 70% ethanol. In a recent meta-analysis of 16 studies of unselected patients, the overall sensitivity was 66%, and the overall specificity was 99%.83 However, an earlier study of patients presumed clinically to have lung cancer revealed a sensitivity of 87% and a specificity of 90%.84 Another factor of importance in optimizing accuracy is the number of samples obtained. Several authors have shown optimal accuracy with three samples per patient.85-87 Sputum cytology is also more sensitive for central versus peripheral lesions.83 Finally, larger tumors, tumors associated with atelectasis/obstruction, and lower lobe tumors may have higher yield.88 Because false-positive results may occur, albeit infrequently, positive results require clinical correlation.

Bronchoscopy The availability and ease of performance of flexible bronchoscopy have made this an indispensable test in the diagnosis of lung cancer. It may be performed transnasally, transorally, or via laryngeal mask airway or endotracheal tube. Methods of obtaining cells or tissue include direct biopsy, brushing, bronchoalveolar lavage, and transbronchial biopsy. If endobronchial tumor can be visualized, direct biopsy/brushing has been shown to have a sensitivity of 80% to 100%. As with sputum cytology, bronchoscopy is much more likely to be successful in diagnosis of central lesions compared with peripheral lesions.89 The combination of bronchoscopy with CT abnormalities may also increase diagnostic accuracy. The presence

1/21/2008 12:15:04 PM

Chapter 60 Diagnosis and Staging of Lung Cancer

of an endobronchial lesion on CT is strongly associated with a positive tissue diagnosis on bronchoscopy.90 In addition, the presence of a bronchus within or leading to a lesion on CT increases the yield of bronchoscopy.91 Transbronchial needle aspiration was originated in 1958 by Schiepatti.92 In the early 1980s, Wang and Terry93 used a 20to 22-gauge rigid needle to perform transbronchial needle aspiration. Experience with this technique has led to a sensitivity of 50% and a specificity of 96%.91 Addition of fluoroscopy may lead to higher diagnostic yield.94 Although this technique is useful in establishing a diagnosis, it is limited in mediastinal staging because of the inability to determine whether a node or bronchial lesion or both was included in the specimen. The discussion so far has applied to bronchoscopy performed with a standard white light. More recently, green or blue light has been used in a technique called autofluorescence bronchoscopy. Because normal, dysplastic, and malignant cells show differences in autofluorescence when exposed to green or blue light, this technique may allow earlier detection of premalignant and malignant lesions. The best known system is the Light Induced Fluorescence Endoscopy (LIFE) device, which uses a helium-cadmium laser to produce 442-nm light.95 Use of this procedure enhances the ability to detect preinvasive lesions and carcinoma in situ 1.5- to 6.3-fold.96-99 Limitations to the procedure include applicability only to squamous cell cancer, lack of evidence that eradicating premalignant lesions produces a survival advantage, and cost. Despite these factors, the technique may be useful as a screening study in high-risk patients.

Transthoracic Needle Aspiration Percutaneous transthoracic fine-needle aspiration is used to make a tissue diagnosis in patients in whom immediate surgery is undesirable. Both fluoroscopically guided and CTguided approaches are available, but CT has become preferred because of superior anatomic precision and improved diagnostic yield. In addition, CT may allow biopsy of nonnecrotic portions of masses.100 Transthoracic biopsy is 90% sensitive, with a 98% specificity.101 The size of the lesion may be important in sensitivity, with a trend toward lower sensitivity for smaller lesions (as low as 78% for lesions <1.5 cm in diameter).102 The type of needle is also important, in that use of a cutting needle, as opposed to a fine needle, allows more specific diagnosis of nonmalignant lesions.103,104 Nevertheless, questions remain about the negative predictive value of transthoracic needle aspiration in an operable individual.101 Although a positive test allows an earlier treatment plan, it does not lead to avoidance of surgery. The main complications of this procedure are pneumothorax and hemoptysis. Pneumothorax requiring intervention occurs approximately 1.6% to 17% of the time, and chronic obstructive pulmonary disease is an important risk factor.105-107 Most pneumothoraces are apparent 1 hour after the procedure,108 and fewer than 20% of patients require chest tube placement.109,110 Hemoptysis is rarer, occurring in 5% to 10% of cases. Because of the small-gauge needles used, massive hemoptysis is extremely rare.111,112

Ch060-F06861.indd 761

761

Mediastinoscopy/Mediastinotomy Acquisition of mediastinal lymph nodal tissue is useful for both diagnosis and staging of lung cancer. Cervical mediastinoscopy is a technique that needs to be in the armamentarium of all practicing thoracic surgeons. First described by Carlens in 1959, the technique involves placing a rigid lighted scope through a transverse suprasternal incision into the avascular pretracheal space.113 This allows forceps biopsy of nodal stations 2R, 2L, 4R, 4L, and 7 (see Fig. 60-2). Great care must be taken to avoid the azygos vein when assessing 4R, the innominate artery when assessing 2R and 4R, and the right pulmonary artery when assessing 4R and 7.114 If injury to a large vessel occurs, the area is packed, and immediate median sternotomy or right thoracotomy is performed. Despite these high-risk areas, cervical mediastinoscopy has proved to be extremely safe. A review of 2137 patients revealed a morbidity rate of 0.6%, with 0.05% mortality (Hammoud et al, 1999).115 Cervical mediastinoscopy has proved to be the most accurate method of staging the mediastinal lymph nodes. A recent meta-analysis of 5687 patients with lung cancer demonstrated a sensitivity of 81% and a specificity of 100%.60 In addition, negative mediastinoscopy predicts a 93% rate of complete resection.116 Although mediastinoscopy is both safe and effective, many do not advocate its routine use. Most surgeons agree that mediastinoscopy is clearly indicated for lymphadenopathy greater than 1 cm on CT and for positive mediastinal nodes on PET; relative indications include T2 or T3 tumor, adenocarcinoma histology, and large-cell histology. Left anterior mediastinotomy was popularized by McNeill and Chamberlain to biopsy enlarged lymph nodes at either level 5 or level 6 in left upper lobe tumors.117 This technique involves a transverse incision over the 2nd rib. After removal of the 2nd costal cartilage, blunt dissection of the pleura reveals the para-aortic space, and nodal tissue may be biopsied. Many surgeons do not remove the costal cartilage, instead using a mediastinoscope to visualize the area for forceps biopsy. Review of the literature on this technique reveals it to be effective and safe, with low morbidity (8%) and no mortality.118 Another option for assessment of level 5 and level 6 nodes in left upper lobe tumors is extended cervical mediastinoscopy, in which blunt dissection creates a space posterior to the innominate vein and anterior to the aorta between the left carotid and innominate arteries. The mediastinoscope is passed into this space, and biopsy may be performed.119 This procedure is avoided in patients with calcified or postoperative ascending aortas and aortic arches.

Endoscopic Ultrasonography/Fine-Needle Aspiration Another diagnostic technique that has gained popularity is fine-needle aspiration through an esophagogastroscope using endoscopic ultrasound (EUS) guidance. Because EUS can easily visualize lymph nodes that are in proximity to the esophagus, this technique allows sampling of nodes in the posterior mediastinum, which may not be accessible via mediastinoscopy. Several prospective studies demonstrate a

1/21/2008 12:15:04 PM

762

Section 3 Lung

sensitivity of 88% to 96% and a specificity of 80% to 100% for detection of posterior mediastinal metastases.120-126 A recent study demonstrated the utility of EUS-guided fine-needle aspiration to verify PET hot spots in the lower mediastinum and retroperitoneum. In this study, 62% of patients were spared mediastinoscopy and thoracoscopy/ thoracotomy.127

Video-Assisted Thoracoscopic Surgery Video-assisted thoracoscopic surgery (VATS) has become an invaluable tool in the diagnosis of lung cancer. It allows high-quality visualization of the thorax and biopsy of tissue through small incisions without painful rib spreading. Development of fiberoptics and laparoscopic equipment that may also be used in the chest allows expansion of this approach. This approach requires general anesthesia and a dual-lumen endotracheal tube. We use a standard technique for VATS procedures in which the thoracoscope is placed through a port placed in the 8th or 9th intercostal space in the posterior axillary line. A larger utility incision is placed in the 4th or 5th intercostal space just lateral to the nipple. This utility incision allows multiple conventional instruments to be placed simultaneously. Others place more ports in different locations with equal success, validating the flexibility of the approach. Many studies have demonstrated the ability of VATS lung biopsy to effectively diagnose indeterminate lung nodules with a sensitivity and specificity nearing 100%.128-130 Failure has occurred mainly with small nodules situated deep in the lung parenchyma. However, with experience in correlating CT images with thoracoscopic anatomy, these nodules can almost always be excised thoracoscopically. In addition to resection of indeterminate nodules, mediastinal lymph nodes that are inaccessible by other methods may be sampled thoracoscopically.131,132

Thoracotomy If less invasive diagnostic procedures have failed, open thoracotomy may be required. It is usually performed through the 5th or 6th intercostal space and allows manual assessment of the lung and other intrathoracic structures. A tumor may be biopsied with a Tru-cut needle or, more commonly, resected as a wedge for frozen section analysis before formal anatomic resection if cancer is diagnosed.

Organ-Specific Scanning for Diagnosis of Distant Metastatic Disease Several studies have demonstrated low yield in routine multiorgan scanning for distant metastatic disease in asymptomatic patients.133,134 The frequency of such findings was 2.7% to 15%. A large meta-analysis revealed a high negative predictive value (89%-95%) for the clinical evaluation using head CT, abdominal CT, and bone scan as gold standards.135 Many clinicians believe that routine multiorgan scanning is indicated in the presence of significant comorbidities that would make resection hazardous, T2 or T3 tumors, or stage IIIA disease.

Ch060-F06861.indd 762

Brain CT produces a false-positive result in 11% of patients.136 Routine imaging of the brain in asymptomatic patients with early-stage lung cancer is not a cost-effective strategy; the risk of brain metastasis is low, and the sensitivity of head CT is also low. All patients with suspicious neurologic symptoms or with locally or distantly advanced disease have imaging of the brain. In patients with neurologic symptoms, a magnetic resonance imaging (MRI) of the brain is often performed in place of brain CT. Although some practitioners routinely order MRI of the brain, this staging strategy is not cost-effective in patients with early-stage disease. Bone scanning has been useful in the past because of high sensitivity, but these scans are notorious for lower specificity. One study noted a false-positive rate of 40%133 and another demonstrated that only 50% of solitary foci of uptake represented metastases.137 Routine bone scans in asymptomatic patients with early-stage lung cancer is not a cost-effective strategy. All patients who have suspicious symptoms of pain, locally or distantly advanced disease, or elevated serum calcium or alkaline phosphatase concentrations need to have a bone scan. Abdominal CT scanning may identify the adrenal adenomas that are present in 2% to 8% of the population.138 Although not particularly accurate in detecting brain metastases, PET scanning has allowed improved detection of distant metastases.

Molecular Biologic Staging The power of a staging system, based on large databases, in predicting prognosis is self-evident. Nevertheless, there is an inherent inaccuracy in this staging process. According to the TNM system, the predicted 5-year survival rate after complete resection for T1 N0 M0 NSCLC (stage IA) is only 67%.54 Therefore, 33% of patients with stage IA NSCLC are incorrectly staged at presentation. Even with optimal therapy, these patients will die of their disease, predominantly from the development of metastatic disease not detected at the time of diagnosis and initial therapy, despite the use of standard staging procedures. Similarly, a significant fraction of all patients with stage IB or II disease are incorrectly staged, resulting in inaccurate assessment of extent of disease, prognostic stratification, and selection of therapy. Molecular biologic substaging—the use of molecular markers as a strategy for risk stratification—has been validated in retrospective studies (D’Amico et al, 1999)139-146 and is under evaluation prospectively. Assessment of the primary tumor with molecular techniques may improve the prognostic stratification of patients with NSCLC by predicting which patients are most likely to experience recurrence after surgical resection. In addition, the profile of the primary tumor may be used to assess its sensitivity to selected adjuvant therapy. Characterization of the primary tumor may be made using various molecular markers. The use of a panel of markers may improve the effectiveness of this approach because expression of individual oncogenic markers is low in NSCLC: TP53 (p53) and the epidermal growth factor receptor (EGFR) are

1/21/2008 12:15:04 PM

Chapter 60 Diagnosis and Staging of Lung Cancer

expressed in approximately 43% and 52% of tumors, respectively (D’Amico et al, 1999).141 In one study of 408 stage I patients who underwent complete resection and no adjuvant therapy, multivariable analysis demonstrated significantly elevated risk for the following molecular markers: TP53 (hazard ratio 1.68; P = .004); angiogenesis factor VIII (1.47; .033); ERBB2 (1.43; .044); CD44 (1.40; .050); and Rb (0.747; .084). Each of these factors improved the stratification independently, and, as a composite, molecular substaging identified groups of patients with 5-year survival rates ranging from 37% (five negative prognostic markers) to 80% (one negative prognostic marker). The identification of these factors also can establish potential therapeutic strategies, such as blockade of the ERBB2 receptor in patients with overexpression of ERBB2, the administration of normal TP53 in patients with TP53 mutations, or antiangiogenic therapy in patients with a high level of angiogenesis factor VIII. The expression of molecular markers may be used to identify specific oncogenic pathways that may characterize treatment sensitivity or resistance. In one study, the expression of a panel of potential molecular markers of chemoresistance was prospectively evaluated in a population of patients with pathology-confirmed stage III NSCLC to determine the prognostic value of each marker in relation to response to chemotherapy or survival.146 Immunohistochemical staining was performed on histologically positive mediastinal nodal specimens obtained from 59 patients without evidence of distant metastatic disease who were treated with Navelbinebased chemotherapy and external-beam radiation therapy between 1996 and 2001. Included were markers for apoptosis (TP53, BCL2), drug efflux/degradation (ABCB1[MDR], GSTP1), growth factors (EGFR, ERBB2), and mismatch repair (hMLH1, hMSH2). After chemotherapy, patients underwent radiologic evaluation for response measured by standard criteria. Multivariable analysis of marker expression associated the overexpression of TP53 and low expression of hMSH2 with poor treatment response and cancer death. In addition, there was a significant difference in median survival for patients who expressed none (>60 months), one (18 months), or two (8 months) of the negative prognostic markers (P < .003).146 Molecular biologic staging in patients with stage I NSCLC may have the potential to alter therapy, in addition to improving risk stratification. The ability of molecular biologic markers to predict results of chemotherapy would enable the clinician to design therapy based on the individual tumor. In addition, identifying and understanding the mechanisms of treatment resistance offers another pathway to intervene, by blocking or reversing the mechanism of resistance. Furthermore, understanding of the molecular mechanism of receptor activity and DNA repair enables the study of pharmacologic targeting with chemotherapy or biologic agents. The ultimate power of molecular biologic staging depends on the ability to alter therapy and improve outcome, which has not yet been demonstrated. However, with current technology, it would be possible to biopsy a patient with clinical stage I NSCLC and determine the relative prognosis, based on molecular

Ch060-F06861.indd 763

763

staging. Patients with strong negative prognostic markers and patients with occult metastases in the bone marrow or serum might be treated with induction biologic therapy or chemotherapy, and the choice of agents would be determined by the biological characteristics of the tumor.

COMMENTS AND CONTROVERSIES The authors have thoroughly reviewed the important issues in the diagnosis and staging of lung cancer. They have appropriately stated the importance of a thorough history and physical examination in the evaluation of these patients. Thoracic surgeons now have at their disposal a host of imaging and procedural strategies to improve the accuracy of clinical staging. Technological advances continue to improve this accuracy. However, imaging is far from 100% accurate for clinical diagnosis or staging. For peripheral nodules, characteristic features of malignancy on CT and PET imaging can also be present in benign lesions such as granulomas. The authors point out the problems of false-negative and falsepositive CT and PET imaging in the evaluation of mediastinal lymph nodes. This is a problem, and not only in regions with endemic granulomatous disease such as the Mississippi River Valley. At present, accurate staging of mediastinal lymph nodes is ultimately dependent on histologic proof from biopsy or excised lymph node stations. Molecular imaging and staging are in their infancy. However, both strategies offer real hope for greater accuracy in staging and also for estimation of prognosis in patients with bronchogenic carcinoma. G. A. P.

KEY REFERENCES D’Amico TA, Massey M, Herndon JE, et al: A biological risk model for stage I lung cancer: Immunohistochemical analysis of 408 patients with use of ten molecular markers. J Thorac Cardiovasc Surg 117:736743, 1999. Gonzalez-Stawinski GV, Lemaire A, Merchant F, et al: A comparative analysis of positron emission tomography and mediastinoscopy in staging non-small cell lung cancer. J Thorac Cardiovasc Surg 126:19001905, 2003. Gurney JW: Determining the likelihood of malignancy in solitary pulmonary nodules with Bayesian analysis. Radiology 186:405-413, 1993. Hammoud ZT, Anderson RC, Meyers BF, et al: The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg 118:894-899, 1999. Henschke CI, Nadich DP, Yankelevitz DF, et al: Early Lung Cancer Action Project: Initial findings on repeat screenings. Cancer 92:153159, 2001. Mountain CF: Revisions in the international system for staging lung cancer. Chest 111:1710-1717, 1997. Mountain CF, Dresler CM: Regional lymph node classification for lung cancer staging. Chest 111:1718-1723, 1997. Pieterman RM, van Putten JWG, Meuzelaar JJ, et al: Preoperative staging of non-small cell lung cancer with positron-emission tomography. N Engl J Med 343:254-261, 2000.

1/21/2008 12:15:04 PM

764

Section 3 Lung

Reed CE, Harpole DH, Posther KE, et al: Results of the American College of Surgeons Oncology Group Z0050 Trial: The utility of positron emission tomography in staging potentially operable nonsmall cell lung cancer. J Thorac Cardiovasc Surg 126:1943-1951, 2003.

Ch060-F06861.indd 764

Toloza EM, Harpole L, Detterbeck F, et al: Invasive staging of non-small cell lung cancer: A review of the current evidence. Cancer 123:157S166S, 2003. Toloza EM, Harpole L, McCrory DC: Noninvasive staging of non-small cell lung cancer: A review of the current evidence. Chest 123:137S146S, 2003.

1/21/2008 12:15:04 PM

chapter

61

SURGICAL MANAGEMENT OF NON–SMALL CELL LUNG CANCER Benjamin D. Kozower G. Alexander Patterson

Key Points ■ Completely remove the tumor and all intrapulmonary lymphatic

drainage. ■ Take care not to transgress the tumor during resection in order to

avoid tumor spillage. ■ Make an effort to perform en-bloc resection of adjacent or invaded

structures rather than discontinuous resection. ■ Perform frozen section analysis on the bronchial margin and any

other margins in close proximity to the tumor. ■ Remove or sample all accessible mediastinal lymph node stations

for pathologic evaluation.

This is a revision of a chapter in the previous edition of this text written by Robert Ginsberg and Nael Martini. Drs. Ginsberg and Martini were recognized as international leaders in the investigation, education, and treatment of lung cancer. We are honored to update a contribution made by two of the leading figures in the field. The American Cancer Society projected a lung cancer incidence of 171,613 new cases for the year 2005.1 Lung cancer is the leading cause of cancer death worldwide. Non–small cell lung cancer (NSCLC) accounts for 80% of newly diagnosed cases.2 Most patients ultimately die of their disease; for those with limited disease, surgical resection is the most effective method of controlling the primary tumor and provides the best opportunity for cure. Therefore, every patient with locoregional NSCLC is approached as a surgical candidate. However, even with appropriate staging and physiologic evaluation, only 35% of patients diagnosed with NSCLC are eligible for resection. The surgical goal is complete resection of localized tumors (stages I and II) as the definitive primary therapy. Selected patients with mediastinal nodal metastases (stages IIIA and IIIB) are considered for multimodality therapy, ideally as part of a clinical trial. Patients with distant metastatic disease (stage IV) are not candidates for curative surgical resection. Recent years have brought impressive contributions to the understanding of tumor biology in NSCLC. However, the long-term survival of only 70% of patients with stage I, completely resected tumors leaves enormous opportunity for improvement. This chapter reviews the surgical treatment of NSCLC and the changes in surgical paradigm involving types and extent of resection and stage-dependent therapy.

HISTORICAL NOTE Although surgery for lung cancer was first discussed in the late 1800s, it did not become a reality until the first successful pneumonectomy was performed by Graham and Singer in 1933.3 Subsequent advances were made to preserve lung parenchyma while improving operative mortality. The first successful one-stage lobectomy was reported by Brunn in 1929, but this procedure did not replace pneumonectomy as the standard anatomic resection until the development of underwater pleural drainage.4 Bronchoplastic procedures were developed to avoid pneumonectomy. The first successful sleeve lobectomy for a bronchial carcinoma was performed by Allison in 1952.5 Lesser resections, such as segmentectomy, were pioneered by Churchill and Belsey and first reported for a patient with bronchiectasis in 1939.6 The techniques of segmentectomy were further popularized by Overholt and Jensik and their coworkers.7,8 Jensik and colleagues8 were the first to report a series of segmental resections performed as an intentional curative procedure for lung cancer. The development of mechanical stapling devices and reliable absorbable suture material facilitated the conduct of pulmonary resections and reduced postoperative morbidity. However, the major advances in management of NSCLC over the past 30 years were the improvements in imaging technology and in the precision of staging. The standard use of highresolution computed tomographic (CT) imaging has greatly improved the accuracy of clinical staging. Positron emission tomography (PET) has become a standard staging modality most useful for the detection of unsuspected distant metastatic disease. Mediastinoscopy remains the gold standard for mediastinal lymph node evaluation, and we continue to use it routinely for diagnosis and staging. These advances in staging have allowed thoracic surgeons to perform a complete resection in almost all of the patients considered to have resectable disease. As laparoscopy has become the standard of care for routine general surgery procedures, thoracic surgeons have pursued the use of video-assisted thoracoscopic surgery (VATS). The first major meeting on VATS pulmonary resection was held in conjunction with the Society of Thoracic Surgeons meeting in 1993.9 The technique has gained popularity and is now the technique of choice for early-stage lung cancer resection in some centers. However, its effects on long-term survival and late outcome are not well established. Finally, limited resections are being revisited as a means of accomplishing an adequate oncologic procedure while preserving lung function. Anatomic segmentectomy and wedge resection with brachy765

Ch061-F06861.indd 765

1/21/2008 12:15:52 PM

766

Section 3 Lung

therapy are the topics of multicenter prospective trials that will help thoracic surgeons determine their appropriate indications.

PREOPERATIVE ASSESSMENT

Mediastinal staging is the main determinant of resectability for patients without distant metastatic disease. Briefly, the most common methods for staging the mediastinum before thoracotomy are CT scan (Fig. 61-2), positron emission tomography (PET), and mediastinoscopy. PET has gained

Staging Accurate staging must be the preeminent concern of the thoracic surgeon in every patient. The international tumornode-metastasis (TNM) staging system has been used since 1986.10 The detailed staging of NSCLC is described elsewhere and only briefly reviewed here. Tumors that are confined to the lung without any local extension or metastases are classified as stage I. Tumors that are associated with hilar or peribronchial lymph node involvement (N1) or with extension to the chest wall, mediastinum, or diaphragm (T3) are classified as stage II. Locally advanced tumors with mediastinal (N2, N3) lymph node metastasis, malignant pleural effusion, or invasion of adjacent unresectable structures (T4) are classified as stage III (Fig. 61-1). Tumors with distant metastasis at presentation and synchronous tumors in different lobes are classified as stage IV. The 5-year survival rate after complete resection (R0) of NSCLC is dependent on the pathologic stage (Table 61-1) (Mountain et al, 1997).11-13 Incomplete resection is not curative. Large clinical series demonstrate that 60% to 70% of patients with T1 N0 resected lung cancer survive 5 years (Martini et al, 1995; Mountain et al, 1997).12-14 Eighty percent of these patients never have a recurrence. Between 15% and 20% die within 5 years after diagnosis from causes unrelated to their NSCLC. At the other end of the spectrum, fewer than 10% of patients treated with surgical resection for stage IIIB NSCLC are cured of their disease.

FIGURE 61-1 Non–small cell lung cancer (NSCLC) invading the carina. Fiberoptic bronchoscopy is mandatory in the evaluation of patients with NSCLC. This tumor was unresectable in a 58-year-old man with obvious carinal involvement (T4) and poor pulmonary function.

TABLE 61-1 Stage-Dependent Survival of Patients With Non–Small Cell Lung Cancer Mountain†

Naruke* Classification

No. Patients

5-Year Survival (%)

Stage I T1 N0 (IA) T2 N0 (IB)

245 291

75 57

Stage II T1 N1 (IIA) T2 N1 (IIB) T3 N0 (IIB)

66 153 106

Stage III T3 N1 (IIIA) T1-3 N2 (IIIA) T1-3 N3 (IIIB) T4 Any N (IIIB) Stage IV Any T M1

No. Patients

Rami-Porta‡

5-Year Survival (%)

No. Patients

5-Year Survival (%)

511 549

67 57

235 817

58 50

52 38 33

76 288 87

55 39 38

31 290 —

66 42 —

85 368 55 104

139 15 0 8

55 344 572 458

38 23 3 6

389 — 138 —

25 — 28 —

293

7

1427

1

27

25

*Naruke T, et al: Prognosis and survival in resected lung cancer based on the new international staging system. J Thorac Cardiovasc Surg 96:440, 1988. † Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:1710, 1997. ‡ Rami-Porta R: The Bronchogenic Carcinoma Cooperative Group, Spanish Society of Pneumonology and Thoracic Surgery. Lung Cancer 29(Suppl 1):133, 2000.

Ch061-F06861.indd 766

1/21/2008 12:15:52 PM

Chapter 61 Surgical Management of Non–Small Cell Lung Cancer

767

Box 61-1 Surgical Principles and Management of NSCLC Surgically curable NSCLC is treated in a systematic manner with adherence to fundamental oncologic principles. The following key points need to be adhered to during resection:

FIGURE 61-2 Chest CT scan of T2 N2 NSCLC. The T2 tumor and enlarged upper right paratracheal lymph node (R2) are shown.

popularity because it is better than CT scanning for detection of mediastinal and distant metastatic disease. The American College of Surgeons Oncology Group (ACOSOG) Z0050 Trial demonstrated that, in patients with suspected or proven NSCLC considered resectable by standard staging procedures, PET can prevent a nontherapeutic thoracotomy in a significant number of cases (6.3%) by demonstrating unsuspected metastatic disease (Reed et al, 2003).15 However, PET has a positive predictive value for mediastinal disease of only 56%. PET-positive lymph nodes need to be confirmed with transbronchial or endoscopic ultrasound-guided needle aspiration or mediastinoscopy before determining that a patient has N2 or N3 disease and is not a candidate for surgical therapy. The role of mediastinoscopy remains controversial. In our view, it remains the gold standard for the evaluation of mediastinal lymph nodes in patients with NSCLC. Indeed, for patients with locally advanced T2, T3, T4 tumors or suspected N1, N2, or N3 nodal disease, it is mandatory. However, for tumors that are clinical stage IA (T1 N0) by CT and PET, mediastinoscopy is not necessary because the overwhelming majority of these patients will not have N2 disease (Meyers et al, 2006).16 Mediastinoscopy is performed for T2, T3, and T4 tumors with negative mediastinal staging by CT and PET because at least 15% of these patients have mediastinal nodal involvement that would preclude curative surgery.

Physiologic Considerations Operability must be determined by careful assessment of both the medical risk of thoracotomy and the risk of removing the involved lung parenchyma. Smoking-induced cardiopulmonary disease is the major cause of morbidity and mortality. Sardari and colleagues used a regression analysis to study the prognostic significance of smoking status on 311 patients who underwent surgery for NSCLC.17 Continued smoking was an independent predictor of poor prognosis, and recent quitters had improved survival compared with continued smokers. Of note, the longer a patient goes without

Ch061-F06861.indd 767

1. Completely remove the tumor and all intrapulmonary lymphatic drainage. The standard procedures for NSCLC resection are anatomic lobectomy, sleeve resection, bilobectomy, and, uncommonly, pneumonectomy. 2. Take care not to transgress the tumor during resection in order to avoid tumor spillage. 3. Make an effort to perform en-bloc resection of adjacent or invaded structures rather than discontinuous resection. 4. Perform frozen section analysis on the bronchial margin and any other margins in close proximity to the tumor. Perform extended resection, whenever possible, if a positive resection margin is encountered. The surgeon needs to play an active role in orienting the pathologist and marking any concerning margins to improve accuracy. 5. Remove or sample all accessible mediastinal lymph node stations for pathologic evaluation. These need to be anatomically and numerically labeled by the surgeon to enable precise pathologic staging in every patient.

smoking preoperatively, the more likely he or she is to remain nonsmoking after surgical resection.18 Pulmonary function testing and arterial blood gas analysis help determine the feasibility of pulmonary resection, and the use of these tests along with other physiologic considerations is discussed in detail in Chapter 3. However, many of the traditional barriers to surgical resection are being challenged. In general, patients with normal function during activities of daily living, regardless of their measured pulmonary function, usually do well after resection. Patients with NSCLC frequently have smoking-induced emphysema. When pulmonary function testing is performed 6 months after lobectomy in patients with mild emphysema, there is no statistical decline in pulmonary function.19 Choong and colleagues20 demonstrated that carefully selected patients with severe emphysema and a tumor located in the most diseased parenchyma actually improved their pulmonary function after resection. In this series of 21 patients with a mean preoperative forced 1-second expiratory volume (FEV1) of 29%, all patients showed improved lung function postoperatively, and the 1- and 5-year survival rates were 100% and 63%, respectively.

SURGICAL RESECTIONS: SELECTION OF OPERATIVE PROCEDURE Box 61-1 presents a summary of surgical principles and management of NSCLC. The goal for the surgical treatment of NSCLC is complete resection. Incomplete resection does not improve survival, may impair the patient’s quality of life, and delays subsequent radiation therapy or chemotherapy. There is a logical

1/21/2008 12:15:53 PM

768

Section 3 Lung

progression in the preoperative workup, from chest radiography, to CT and other relevant imaging, to biopsy of suspected extrathoracic sites of metastatic disease, to invasive staging including mediastinoscopy and VATS. If the tumor is deemed resectable and the patient is physiologically able to tolerate an operation, then the appropriate resection is performed. Every operation for lung cancer has three essential parts: confirmation of the diagnosis and intrathoracic stage, complete resection of the tumor, and systematic sampling or complete dissection of the lymph node stations that drain the primary tumor. If a tissue diagnosis has not been established preoperatively, an intraoperative biopsy is desirable. We typically perform a wedge biopsy for suspicious nodules, with frozen section analysis obtained before performing a completion lobectomy. However, if a wedge resection is not anatomically feasible, a lobectomy may have to be performed without a tissue diagnosis. If a bilobectomy or pneumonectomy is being considered, a tissue diagnosis (Tru-cut needle biopsy) is obtained before resection. After a diagnosis of NSCLC has been made and resectability is established, the appropriate operative procedure is performed. The current standard resections are lobectomy, sleeve lobectomy, bilobectomy, and pneumonectomy. Anatomic lobectomy has traditionally been viewed as the smallest acceptable resection in fit patients, but this view is being challenged by anatomic segmentectomy for small, peripheral tumors. Nonanatomic wedge resection is performed only as a definitive treatment when a patient’s physiologic status precludes anatomic resection or in cases of synchronous or multiple metachronous tumors. The so-called sump lymph nodes that lie on the pulmonary artery between the upper and lower lobes need to be examined. If there is any question that these contain tumor, they are submitted for frozen section analysis. Most surgeons believe that involvement of the sump nodes requires an extended resection: bilobectomy, sleeve resection, or pneumonectomy.

tumors for which the alternative is pneumonectomy. Sleeve lobectomy is used when a negative bronchial margin cannot be achieved with standard lobectomy. Construction of a precise, properly oriented bronchial anastomosis adds to the technical demands of the procedure. Accurate frozen section analysis of the resection margins is mandatory. For tumors that involve the pulmonary artery, pneumonectomy can be avoided by the use of pulmonary arterioplasty. Some authors have reported a high incidence of anastomotic complications22 and increased mortality with bronchoplasty.23 However, surgeons experienced with bronchoplastic techniques have published very favorable results. Suen and colleagues24 demonstrated that sleeve resection for NSCLC can be performed with a low risk of bronchial anastomotic complications: only 3 of 77 patients required intervention for dehiscence or stricture. In a single-institution series of 1230 consecutive patients, Deslauriers and colleagues25 reported that long-term survival and local tumor control are significantly better if complete resection can be achieved by sleeve lobectomy versus pneumonectomy. The 5-year survival rates after sleeve resection and pneumonectomy were 52% and 31%, and the operative mortality rates were 1.6% and 5.3%, respectively. Importantly, it was reported in a decision analysis by Ferguson and colleagues that sleeve lobectomy offers significantly better quality of life than pneumonectomy because of the preservation of pulmonary function.26 Bilobectomy is resection of the right upper and middle lobes or the right lower and middle lobes. It is indicated if a tumor crosses the fissure or approximates an incomplete fissure and in certain cases of interlobar vascular or nodal involvement when a pneumonectomy would not be tolerated. Keller and colleagues reported on 166 bilobectomies, for which the most common indication was tumor extension across a fissure (45%).27 Carbognani and colleagues reported a perioperative mortality rate of 6.5% and a 5-year survival rate of 38%.28 These rates are higher than for lobectomy but significantly lower than for pneumonectomy.

Lobectomy

Pneumonectomy

Lobectomy is the ideal operation for resection of NSCLC confined to a single lobe. The tumor and its lymphatic drainage, both pleural and central, are removed. Lobectomy is generally well tolerated and usually leaves sufficient volume to fill the pleural space. The Lung Cancer Study Group completed a randomized clinical trial of lobectomy versus a lesser resection (wedge resection or segmentectomy) for stage I NSCLC with small peripheral tumors (Ginsberg et al, 1995)21; 247 patients were prospectively evaluated. There was a 3-fold increase in local recurrence in patients treated by lesser resections compared with lobectomy (17.2% versus 6.4%, P = .008). In addition, the overall survival rate was reduced by 30% in the group undergoing lesser resections (P = .09). The significant increase in local recurrence with lesser resection is the primary reason why lobectomy remains the standard resection for tumors confined to a single lobe. Sleeve lobectomy is a parenchyma-saving procedure that involves resection of a lobe with a circumferential segment of the adjacent main stem bronchus. It is indicated for central

Pneumonectomy is typically performed for central tumors and is appropriately performed if lobectomy does not provide complete resection and the loss of an entire lung will be tolerated. Indications for pneumonectomy are extensive involvement of the main stem bronchus; adherence to the proximal, extrapericardial pulmonary artery; and an upper lobe lesion that invades the pulmonary artery to the lower lobe. As mentioned earlier, bronchoplasty can be used to obtain negative margins on the airway and pulmonary artery in order to avoid pneumonectomy. Modifications to a standard pneumonectomy include intrapericardial dissection and ligation of the pulmonary vessels, supra-aortic pneumonectomy on the left, and tracheal sleeve pneumonectomy. The decision to perform a pneumonectomy needs to be made carefully because of the increased morbidity and mortality of the resection. Pairolero and colleagues reported on more than 600 patients treated with pneumonectomy for NSCLC with a perioperative mortality rate of 7%.29 Forty percent of patients in this series had a significant complica-

Ch061-F06861.indd 768

1/21/2008 12:15:53 PM

Chapter 61 Surgical Management of Non–Small Cell Lung Cancer

tion, most often respiratory and cardiovascular complications. Multivariate analysis identified increased age and cardiovascular disease as independent risk factors for morbidity. Completion pneumonectomy is widely known to be associated with even higher morbidity and mortality. It is usually performed for progressive or recurrent benign disease, for recurrence of a malignant tumor, and for complication after lobectomy. The mortality rate for completion pneumonectomy was recently reported to be 21% in a series of 115 patients.30 These results were similar to those of Stoelben and colleagues, who reported on 86 patients requiring completion pneumonectomy.31 Their 30-day mortality rate was 20%, with a 5-year survival rate of 28%.

Segmentectomy Segmentectomy is an anatomic sublobar resection that may increase resection rates in patients with stage I NSCLC and poor pulmonary function. It is technically more difficult than lobectomy because of the lymph node dissection required, the anatomic division of the parenchyma, and the complexity of the procedure for tumors that are larger than 2 cm.32 Segmentectomy remains controversial due to the question of increased local recurrence and reduced survival compared with lobectomy. Although the Lung Cancer Study Group found an increased rate of local recurrence with limited resection compared with lobectomy, the limited resection group in this study was predominantly composed of patients who underwent nonanatomic wedge resection.21 Controversy continues as more surgeons are becoming experienced with segmentectomy and reporting excellent results. Keenan and colleagues33 retrospectively reviewed patients who had undergone lobectomy (n = 147) or segmentectomy (n = 54) for stage I cancer. They found that segmentectomy preserved pulmonary function (FEV1 and maximum voluntary ventilation) without compromising survival. The 4-year survival rates for segmentectomy and lobectomy were 67% and 62%, respectively. Importantly, the segmentectomy group had significantly worse preoperative pulmonary function but equivalent survival. Important work on segmentectomy continues in Japan. Tsubota and colleagues performed a small prospective study evaluating the outcome of extended segmentectomy for T1 tumors smaller than 2 cm.34,35 The parenchyma was divided just beyond the burdened segment, and intraoperative frozen sections of segmental, hilar, and mediastinal nodes were used to confirm N0 status. A lobectomy was performed if the margin or lymph nodes were positive. The 5-year survival rate for this series of 55 patients was 82%, and the local and distant recurrence rates were equivalent to those obtained with lobectomy. However, 25% of these highly selected patients were excluded from the trial because of positive margins or nodal disease. Ultimately, a large, multicenter trial comparing anatomic segmentectomy versus lobectomy for small, peripheral tumors will be required to definitively resolve the controversy. We currently perform segmentectomy for NSCLC on small peripheral tumors, most frequently in the superior segment of the lower lobe, the lingula, and the apicoposterior and anterior segments of the left upper

Ch061-F06861.indd 769

769

lobe. Patients are usually older, have marginal cardiopulmonary reserve, and have peripheral T1 tumors and histologically confirmed N0 nodal status by frozen section.

Wedge Resection Wedge resection is a nonanatomic procedure that is used to accomplish complete resection with minimal sacrifice of pulmonary parenchyma. It is used primarily for patients with limited lung function as a result of intrinsic lung disease (emphysema or interstitial lung disease) and for synchronous or metachronous tumors in patients who would not tolerate a lobectomy. The major problems with wedge resection as the primary treatment for NSCLC are an increase in local recurrence despite negative margins and a trend toward reduced survival. Landreneau and colleagues prospectively studied wedge resection versus lobectomy in a nonrandomized fashion.36 Patients treated with wedge resection were older and had significantly greater preoperative pulmonary dysfunction. This study reported a 5-year survival rate that was significantly lower for the wedge resection group, 58%, compared with 70% for the lobectomy group. However, this difference was the result of a significantly greater non–cancerrelated death rate during the first 5 postoperative years among patients undergoing wedge resection. Postoperative local radiation therapy has been used in an attempt to reduce the local recurrence rate after wedge resection. However, external beam radiation further reduces pulmonary function in this already compromised group of patients. Intraoperative brachytherapy with iodine 125 brachytherapy has been evaluated in recent publications as an adjunct to compromise wedge resection therapy.37,38 Local recurrence can be reduced to 2% in this high-risk group, and survival for those with T1 tumors approaches 70% at 5 years. 125 I brachytherapy is currently being evaluated in a prospective multicenter trial.

Video-Assisted Thoracoscopic Resection VATS has been used with increasing frequency for major lung resections. Two technological advances that made non–ribspreading VATS lobectomy possible were the improvement in optical systems and the advancement of linear staplers. Proponents of VATS lobectomy for small, peripheral tumors state that it decreases pain, preserves pulmonary function, reduces the systemic inflammatory response, and leads to an earlier return to normal activities.39-41 It is important to remember that VATS represents a new approach rather than a new procedure, and it does not change the indications for surgical resection of NSCLC. Several recently published series have reported excellent results with VATS lobectomy for stage I lung cancer (Table 61-2).42-44 Experienced surgeons have a low conversion rate to thoracotomy (<10%) and an operative time between 75 and 130 minutes. Absolute contraindications to VATS lobectomy are inability to tolerate single-lung ventilation, large tumor (>4 cm), a fused pleural space, and established N2 disease. The occurrence of massive bleeding during VATS is rare and can be controlled with direct pressure while converting to open thoracotomy. Tumor implantation at port sites

1/21/2008 12:15:53 PM

770

Section 3 Lung

TABLE 61-2 Large Case Series on VATS Lobectomy for Stage I NSCLC Author

No. Cases

Daniels*

Conversion (%)

30-Day Mortality (%)

Length of Hospitalization (Days)

3.6

3

Stage I 5-Year Survival (%)

110

2

Walker

158

11.2

1.8

6

78

Gharagozloo‡

179

0

0.05

4.1

85

†

NSCLC, non–small cell lung cancer; VATS, video-assisted thoracoscopic surgery. *Daniels LJ, et al: Thoracoscopic lobectomy: A safe and effective strategy for patients with stage I lung cancer. Ann Thorac Surg 74:860, 2002. † Walker WS, et al: Long-term outcomes following VATS lobectomy for non–small cell bronchogenic carcinoma. Eur J Cardiothorac Surg 23:397, 2003. ‡ Gharagozloo F: Video-assisted thoracic surgery lobectomy for stage I lung cancer. Ann Thorac Surg 76:1009, 2003.

has been reported but is rare when wound protectors and commercially available specimen retrieval bags are used. Another important complication of VATS lobectomy has been the increased rate of bilobectomy for right upper lobe lesions due to technical factors with superior vein branch dissection.44 However, with experience, this seems to be a very uncommon occurrence. The true advantage of VATS lobectomy over muscle-sparing thoracotomy is debatable, but patient expectations continue to drive the development of less invasive approaches for the resection of NSCLC.

Lymph Node Dissection The role of complete mediastinal lymph node dissection versus lymph node sampling remains controversial. Complete mediastinal lymph node dissection is the most accurate way to stage a patient’s disease and to determine which patients might benefit from adjuvant treatment. However, Little and colleagues presented a disturbing report from the American College of Surgeons.45 They surveyed 729 hospitals to retrieve information on the patterns of surgical care provided to patients with NSCLC. The report included more than 11,000 patients with major pulmonary resections and showed that only 58% of mediastinoscopy specimens contained any lymph node tissue. Even more surprising, 40% of surgically treated patients never had any mediastinal lymph node biopsy performed. This means that almost half of patients reported in this study did not have any attempt at accurate pathologic staging as part of their operative treatment for NSCLC. Many surgeons do not perform complete mediastinal lymph node dissection because it has not been proven to improve survival and because of their concerns about increased morbidity (e.g., recurrent laryngeal nerve injury, thoracic duct injury). However, a recent prospective randomized trial of more than 1000 patients from the ACOSOG, Z0030, demonstrated that complete lymphadenectomy does not increase the morbidity or mortality of surgical resection.46 If complete lymphadenectomy is being performed for a rightsided tumor, the right paratracheal, pretracheal, subcarinal, and inferior pulmonary ligament nodes are dissected. For a left-sided resection, the preaortic, aortopulmonary window, subcarinal, and inferior pulmonary ligament nodes are dissected. The definitions for various types of lymph node dissections and proposed guidelines for intraoperative medi-

Ch061-F06861.indd 770

Box 61-2 Lymph Node Dissection: Definitions Selected Lymph Node Biopsy: No systematic nodal dissection or biopsies are performed. Only suspicious lymph nodes are biopsied to prove N1 or N2 disease. The procedure is justified only to document metastatic disease when resection is not justified. Lymph Node Sampling: One or more lymph nodes are removed, guided by preoperative or intraoperative findings that are thought to be representative. Systematic sampling means that a predetermined sampling of the anatomic lymph node stations is performed. Systematic Nodal Dissection: The mediastinal tissue containing lymph nodes is dissected and removed systematically within anatomic landmarks. Lobe-Specific Systemic Lymph Node Dissection: The mediastinal tissue containing specific lymph node stations is excised, depending on the lobar location of the primary tumor. Radical Lymph Node Dissection: For right-sided tumors, all mediastinal tissue containing lymph nodes is dissected and removed within anatomic landmarks. For left-sided tumors, the aortic arch needs to be mobilized to obtain access to the high and low paratracheal nodes. Extended Lymph Node Dissection: Bilateral mediastinal and cervical lymph node dissection is performed through median sternotomy and cervicotomy. Lardinois D, De Leyn P, Van Schil P, et al: ESTS guidelines for intraoperative lymph node staging in non–small cell lung cancer. Eur J Cardiothorac Surg 30:787, 2006.

astinal staging were recently proposed by the council of the European Society for Thoracic Surgeons (ESTS)47 and are presented in Box 61-2. The other side of the debate is that mediastinal lymph node dissection is performed for patients with a locally advanced, surgically resectable NSCLC (N1, N2) to obtain complete resection.48 The Eastern Cooperative Oncology Group (ECOG) compared complete mediastinal lymph node dissection versus systematic sampling (at least one node from each major station) for stages II and IIIA NSCLC.49 This nonrandomized, prospective trial of 373 patients demon-

1/21/2008 12:15:53 PM

Chapter 61 Surgical Management of Non–Small Cell Lung Cancer

STAGE I DISEASE (T1 N0, T2 N0) Fewer than 25% of patients with lung cancer present with early-stage disease. Most stage I lesions are detected as incidental findings on imaging studies performed for unrelated conditions. These lesions have a myriad of radiographic appearances (discrete nodules, ground-glass opacities, and air space infiltrates). The presentation of these lesions and their investigation are covered in Chapter 36. Diagnostic CT scans of the chest and upper abdomen are routinely performed to assess the remainder of the lungs, mediastinum, liver, and adrenal glands. Meyers and colleagues16 recently demonstrated that patients with clinical stage I NSCLC (negative mediastinal nodes) staged by CT and PET derive little benefit from cervical mediastinoscopy. Their decision analysis determined that mediastinoscopy added 0.01 years of life expectancy at a cost of $200,000 per life-year gained. Reed and colleagues reported the prospective multi-institutional findings on the utility of PET in staging potentially operable NSCLC.15 The greatest value of PET in lung cancer staging is in the identification of hematogenous metastatic disease. PET identified metastatic disease in 6% of patients not identified by conventional CT scanning. However, a positive PET finding requires histologic confirmation because 19 (6.6%) of the 297 cases of distant disease detected by PET were subsequently proven to be benign. PET is also significantly better than CT scanning for the detection of mediastinal lymph node metastases (42% versus 13%, P = .02). The negative predictive value of PET for mediastinal node disease is 87%, but the low positive predictive value mandates biopsy confirmation of mediastinal nodal metastases. If the patient is medically fit and has good lung function, surgical resection is the treatment of choice for stage I NSCLC. At the time of thoracotomy, systematic lymph node dissection or sampling is carried out to ensure that no hilar or mediastinal nodal metastasis is present. The standard resection for stage I lung cancer in patients with adequate cardiopulmonary reserve remains lobectomy because of the increased local recurrence rates of lesser resections.21

Ch061-F06861.indd 771

However, controversy regarding the treatment of small (T1 N0) peripheral tumors remains. Some authors have demonstrated excellent results with segmentectomy.33-35 Other recent reports, such as that from the Mayo Clinic,52 have demonstrated that lobectomy remains superior to segmentectomy for the treatment of NSCLC lesions smaller than 1 cm. This series of 100 patients demonstrated a significant improvement in survival and fewer recurrences among those patients treated with lobectomy. The 5-year survival rate of patients with stage I lung cancer is only 50% to 75% in large series.11 Patients with small T1 tumors that are less than 3 cm in diameter, confined to the parenchyma, and without evidence of local or regional spread have a 5-year disease-free survival rate of 60% to 80% when treated by surgical resection alone.14,53 Patients with T2 tumors that fall into stage IB have a 5-year survival rate of only 50% to 60%. This relatively poor result for the earliest stage of lung cancer is probably related to undetected systemic occult metastasis.54 Traditionally, most patients with completely resected stage I or II NSCLC have not received adjuvant chemotherapy.55 However, multiple trials have been performed to determine whether adjuvant chemotherapy improves the survival of patients with early-stage lung cancer.56,57 An important recent prospective randomized controlled trial demonstrated that adjuvant chemotherapy improves survival among patients with completely resected early-stage NSCLC.58 This trial evaluated 482 patients with stage IB (T2 N0) and stage II completely resected NSCLC and demonstrated a significant improvement in recurrencefree and overall survival in the group of patients receiving adjuvant vinorelbine plus cisplatin (Fig. 61-3). There were two deaths (0.8%) resulting from chemotherapy. Fewer than 10% of patients treated with chemotherapy experienced severe toxicity, but only half were able to tolerate the complete treatment regimen. The standard use of adjuvant che-

100 80 Probability (%)

strated that the two methods were equivalent for detecting N1 and N2 disease. However, complete mediastinal lymph node dissection identified more levels of N2 disease and suggested a survival advantage for stages II and IIIA NSCLC. This result was corroborated by a Chinese study of 471 patients with stages I to IIIA NSCLC.50 The median survival times were 59 months in the complete dissection group and 34 months in the nodal sampling group (P < .05). For patients with small tumors (T1) and early disease (N0), it has been suggested that mediastinal lymph node dissection is unnecessary. This issue was addressed by a small randomized study for peripheral tumors smaller than 2 cm. Complete ipsilateral mediastinal lymph node dissection offered no survival advantage or local control benefit over intraoperative node sampling.51 Whether a complete mediastinal lymph node dissection truly improves long-term survival awaits the results of the ACOSOG multicenter trial. The follow-up from this study is likely to take another 5 years to mature before the results are known.

771

Vinorelbine plus cisplatin

60

Observation

40 20 P ⬍ 0.001 0 0

2

4

6

8

10

37 41

10 9

0 0

Years No. at Risk 240 Observation 242 Vinorelbine plus cisplatin

131 174

78 101

FIGURE 61-3 Recurrence-free survival for early-stage lung cancer treated with adjuvant chemotherapy. (FROM WINTON T, ET AL: VINORELBINE PLUS CISPLATIN VS. OBSERVATION IN RESECTED NONSMALL CELL LUNG CANER. N ENGL J MED 352:2589, 2005, FIG. 1A.)

1/21/2008 12:15:54 PM

Section 3 Lung

motherapy after completely resected early-stage lung cancer represents a large paradigm shift. The 15% survival advantage offered by adjuvant chemotherapy for early-stage NSCLC in this study is more than that observed for many other cancers for which adjuvant chemotherapy has become routine. However, questions remain regarding the benefit of adjuvant chemotherapy in early-stage disease for elderly patients and those with comorbidities. Between 20% and 30% of patients with completely resected stage I disease develop a recurrence. Most relapse with distant metastasis, with more than 20% of these being solitary brain metastases. It has been impossible to determine which patients with resected stage I disease will do well. Most authors advocate close follow-up to detect recurrent disease and second primary lung cancers. Carbone and colleagues59 retrospectively studied 545 patients with tumors greater than 3 cm (T2, T3, and T4) to demonstrate the importance of tumor size. They found that T2 tumors (stage IB) larger than 5 cm produce a 5-year survival rate of only 35% and might be more appropriately staged as T3. Battafarano and colleagues60 studied 451 patients with resected stage I NSCLC to determine the effect of comorbidity on lung cancer survival. They adjusted for age, T status, and tumor histology and found that the severity of comorbidity was a much more reliable predictor of long-term survival. As the mean age in patients with NSCLC increases and sicker patients are treated with surgical resection, this may help to explain the lower than expected survival for patients with completely resected early-stage NSCLC.

than 5 cm carried a worse prognosis. Furthermore, the number of lymph nodes involved was significant. The 5-year survival rate for patients with a single positive lymph node was 45%, compared with 31% for patients with multiple lymph node involvement (Fig. 61-4). The incidence of local and regional recurrence after complete resection of stage II lung cancer is reduced by the postoperative administration of radiation therapy. However, radiation therapy has no impact on survival.63 Many studies have failed to demonstrate a significant improvement in survival with adjuvant chemotherapy. However, a recent prospective randomized trial demonstrated that patients with stage II completely resected NSCLC have a large survival advantage when treated with postoperative vinorelbine plus cisplatin.58 The median survival time for stage II patients was 41 months in the observation group and 80 months in the chemotherapy group (P = .004) (Fig. 61-5). These multi-

Proportion Surviving

772

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

(P ⫽ .016)

0

12

24

STAGE II DISEASE Tumors that are confined to the lung or bronchus with involvement of hilar or bronchopulmonary lymph nodes as the sole site of tumor spread (T1-2 N1 disease) account for 10% of resected lung cancers. A review from the Memorial SloanKettering Cancer Center evaluated 214 patients who had completely resected stage II lung cancer and mediastinal lymph node dissection.61 Lobectomy is the procedure of choice for stage II disease and was performed for 68% of the patients in this series. Lobectomy resulted in complete resection for 34 of the 35 T1 N1 lesions. However, 30% of stage II patients required a pneumonectomy to obtain a complete resection. Fifty percent of patients had a single N1 node involved, and 85% of patients had nodal involvement at a single N1 level. These authors believe that a complete lymph node dissection should be performed for stage II disease because occult mediastinal metastases occur with increasing frequency. This view remains a topic of debate. The 5-year survival rate after resection for this group of patients is 40% to 55%. A recent review by Khan and colleagues examined the prognostic significance of a number of histologic features after complete resection of T1-2 N1 NSCLC.62 Multivariate analysis demonstrated that vascular invasion, nonsquamous histology, and visceral pleural involvement were associated with a worse prognosis. Martini and colleagues61 demonstrated that there was no difference in survival between T1 and T2 tumors but that tumors larger

Ch061-F06861.indd 772

36 Months

48

FIGURE 61-4 Survival for completely resected stage II non–small cell lung cancer depends on the number of N1 nodes. (FROM MARTINI N, ET AL: INCIDENCE OF LOCAL RECURRENCE AND SECOND PRIMARY TUMORS IN RESECTED STAGE I LUNG CANCER. J THORAC CARDIOVASC SURG 109:120, 1995.)

100 80 Probability (%)

T1-2 N1

1 0.9 0.8 0.7 0.6 45% 0.5 0.4 0.3 31% 0.2 0.1 0 60

Single (n ⫽ 107) Multiple (n ⫽ 107)

Vinorelbine plus cisplatin

60 40

Observation 20 P ⫽ .004 0 0

2

4

6

8

10

18 24

5 4

0 0

Years No. at Risk 132 Observation 131 Vinorelbine plus cisplatin

91 100

37 56

FIGURE 61-5 Adjuvant chemotherapy improves overall survival for stage II lung cancer. (FROM WINTON T, ET AL: VINORELBINE PLUS CISPLATIN VS. OBSERVATION IN RESECTED NON-SMALL CELL LUNG CANCER. N ENGL J MED 352:2589, 2005, FIG. 1D.)

1/21/2008 12:15:54 PM

Chapter 61 Surgical Management of Non–Small Cell Lung Cancer

institutional data strongly suggest that medically fit patients with completely resected stage II NSCLC should receive adjuvant chemotherapy.

T3 N0 T3 tumors are lesions of any size that invade the chest wall, diaphragm, mediastinal pleura, or parietal pericardium or are located within 2 cm of the carina without carinal involvement. Because of the favorable survival after surgical resection of T3 N0 tumors, they have been reclassified as stage IIB disease. If lymph node involvement is present, the overall survival after resection of T3 tumors is reduced; for this reason, T3 N1-2 tumors remain in the stage IIIA category.

Chest Wall Invasion Hilar or mediastinal lymph node metastases are less likely to occur in T3 patients with chest wall invasion because most of these lesions are peripheral in location. These tumors extend to invade the parietal pleura, and local invasion can involve the muscles and ribs of the chest wall (Fig. 61-6). Even with chest wall invasion, many of these patients are candidates for en-bloc resection. Factors that influence survival in this group of patients include completeness of resection, extent of chest wall invasion, and the presence of regional lymph node metastasis.64 The results of two large series of lung cancers with chest wall invasion are shown in Table 61-3.65,66 The Memorial Sloan-Kettering series evalu-

FIGURE 61-6 Chest computed tomographic scan of a T3 N0 left upper lobe non–small cell lung cancer with chest wall invasion.

773

ated 334 patients; 50% of them had a complete resection, and the 5-year survival rate was 50% for T3 N0 disease. The Mayo Clinic series had a similar result, with the best survival being in women with T3 N0 disease (61% at 5 years). Controversy exists regarding the significance of depth of penetration and whether en-bloc resection of chest wall is required for adequate resection (compared with parietal pleura only). There are no randomized data to answer this question, and surgeons use their personal experience and large published series to guide their practice. The Lung Cancer Study Group attempted a study in the early 1980s that closed prematurely because of poor accrual. With only 5% to 8% of all NSCLCs involving chest wall invasion, it is unlikely that phase III data will ever be available.67 The Memorial Sloan-Kettering data do not support the idea that depth of invasion influences survival.65 These authors suggest that a significant number of patients whose tumors are confined to the parietal pleura can be treated by extrapleural mobilization of the tumor. If the resection margins are negative, they do not perform an en-bloc resection of the adjoining ribs and chest wall. However, 50% of patients in their series had positive margins. Pairolero and colleagues have a different approach and stress the need for routine fullthickness chest wall resection.66,68 Their intraoperative approach is to assess the degree of involvement by manual palpation. If the tumor is adherent to pleura, they resect the overlying ribs and intercostal muscle en bloc, with a margin of 1.0 to 2.0 cm. Extrapleural resections are performed only if there are flimsy adhesions to the chest wall. Because chest wall resection does not add significantly to morbidity or mortality, this approach is reasonable. However, the current series by these authors does not indicate the percentage of complete resections, and their 5-year survival rate of 44% with routine chest wall resection for T3 N0 disease does not appear to be better than that achieved by selective use of extrapleural resection. The use of adjuvant or neoadjuvant radiation therapy for lung cancers invading the chest wall is discussed in Chapter 62, but the majority of studies have not demonstrated any improvement in survival.69,70 Little information exists on the use of adjuvant chemotherapy for lung cancers invading the chest wall. Although induction chemoradiation therapy has been demonstrated to improve resectability and overall survival in patients with Pancoast tumors, no comparable data exist to suggest that it improves survival for lung cancers invading the chest wall away from the apex of the chest.71

TABLE 61-3 Results After Resection of NSCLC Involving the Chest Wall Institution (Author)

No. Patients

30-Day Mortality (%)

Memorial Sloan-Kettering Cancer Center (Downey*)

334

6

Mayo Clinic (Burkhart†)

95

6.3

Complete Resection (%) 50 100

5-Year Survival (%) 32 (R0 resection) 39 (all patients)

NSCLC, non–small cell lung cancer. *Downey RJ, et al: Extent of chest wall invasion and survival in patients with lung cancer. Ann Thorac Surg 68:188, 1999. † Burkhart HM, et al: Results of en bloc resection for bronchogenic carcinoma with chest wall invasion. J Thorac Cardiovasc Surg 123:670, 2002.

Ch061-F06861.indd 773

1/21/2008 12:15:54 PM

774

Section 3 Lung

The need for chest wall reconstruction depends on the size and location of the defect. The main reasons to reconstruct the chest wall are to protect vital underlying structures and to prevent paradoxical chest wall motion and respiratory compromise. For large defects with chest wall instability, a combination of Marlex and methyl methacrylate works well.72,73 For smaller defects, less than three ribs or less than 5 cm, a taut Marlex mesh or a Gore-Tex patch closure is adequate.68 Very small defects of one to two ribs, and defects located posteriorly beneath the scapula, usually do not require reconstruction. However, if a posterior chest wall resection extends to the 5th rib or lower, chest wall reconstruction is performed to prevent the scapula from falling into the chest.

Superior Sulcus Tumors Superior sulcus tumors (Pancoast tumors) are apical bronchogenic carcinomas with chest wall invasion. Because of their location in the pleural apex, these lesions frequently invade the brachial plexus, subclavian vessels, or spine. The anatomic location and extension of the tumor determine the presenting symptoms and signs. Most patients with superior sulcus tumors present with shoulder or chest wall pain. These tumors may invade the lower brachial plexus (C8-T1), and patients present with radicular pain or neurologic findings of the ulnar hand. Hand swelling is a sign of subclavian or brachiocephalic vein compression. Horner’s syndrome may be present as a result of invasion of the stellate ganglion. Posterior-anterior and lateral chest radiographs may demonstrate nothing more than apical pleural thickening because

tumors can hide behind the 1st rib. However, CT and MRI can detect small lesions and provide excellent anatomic detail. The preoperative evaluation is very important to determine the extent of disease and the chance for complete resection (Fig. 61-7). Most superior sulcus tumors are diagnosed by transcutaneous needle biopsy performed under CT or fluoroscopic guidance. Transbronchial biopsy is less useful because the lesions are usually too peripheral. The great majority of tumors are NSCLC, but up to 5% are small cell carcinomas with vastly different therapeutic options. A preoperative tissue biopsy is also important because induction therapy has become the standard of care for superior sulcus tumors.71 Before resection, we routinely perform mediastinoscopy as well as supraclavicular lymph node biopsy to rule out N2 or N3 disease, which would preclude surgical resection. Surgical resection is usually performed 4 to 6 weeks after induction therapy, after restaging rules out distant metastatic disease. Absolute contraindications to resection include N2 or N3 disease, extensive vascular invasion, brachial plexus involvement more extensive than C8 and T1, and multiplelevel vertebral involvement with extension into the spinal canal. Different operative approaches are useful depending on the location of the primary tumor. The goal of the operation is en-bloc resection of the upper lobe along with involved ribs and other structures including transverse processes, the lower roots of the brachial plexus, the stellate ganglion, and the upper dorsal sympathetic chain. Three approaches are most commonly employed. The posterior approach, described by Shaw and Paulson,74 is ideal for lesions situated posteriorly. The anterior cervicothoracic approach, described by Dartevelle

FIGURE 61-7 Positron emission tomographic scan of a superior sulcus tumor demonstrates increased activity in the right apex and some moderate activity in the mediastinal brown fat. No mediastinal lymphadenopathy was identified.

Ch061-F06861.indd 774

1/21/2008 12:15:55 PM

Chapter 61 Surgical Management of Non–Small Cell Lung Cancer

and colleagues,75 is ideal for management of anterior lesions. The hemiclamshell approach is less commonly employed, but it is useful for anterior or posterior lesions. We believe that, if the posterolateral approach is selected, an initial cervical exploration is warranted to evaluate the scalene fat pad for nodal metastases and the extent of tumor invasion into the subclavian vessels and brachial plexus. Such findings can eliminate the possibility of an incomplete resection before subjecting the patient to the morbidity of the high posterolateral thoracotomy only to discover an unresectable situation. The initial results with superior sulcus tumors were quite poor until Shaw and Paulson demonstrated that preoperative irradiation facilitated surgical resection and improved the 5-year survival rate to 30%.76,77 Rusch78 reported the largest series (225 patients) operated on for superior sulcus tumors. The 5-year survival rate was 46% for T3 N0 (stage IIB) disease and less than 15% for stage III. Survival was influenced by T and N status and by completeness of resection. However, a pathologic complete resection was achieved in only 64% of T3 N0 and 39% of T4 N0 tumors, with locoregional disease being the most common form of relapse. This prompted the Southwest Oncology Group (SWOG) to perform a prospective, multi-institutional trial of induction chemoradiation therapy.71 A total of 111 patients with mediastinoscopy-negative T3-4 N0-1 superior sulcus tumors received two cycles of cisplatin and etoposide concurrent with 45 Gy of radiation. Patients with stable or responding disease (83/111) underwent thoracotomy 3 to 5 weeks later. One third of patients had a complete pathologic response, and 92% had a complete resection. This preliminary report demonstrated that induction chemoradiation is feasible in a multi-institutional setting, improved resectability, and improved the 2-year survival rate to 70% for those with a complete resection (76/83 patients). A recent study from the University of Maryland retrospectively evaluated 36 patients treated with induction chemoradiation followed by surgery.79 Platinum-based combination chemotherapy was given concurrently with 45 Gy of conformal radiation therapy. The complete resection rate was 97.3%, with an operative mortality of less than 3%. A pathologic complete response rate was achieved in 40% of the patients. The median survival time for the whole group was 2.6 years, and for the complete response group it was 7.8 years. Some surgeons continue to offer primary surgery for superior sulcus tumors clinically staged as T3 N0. However, we believe that induction chemoradiation therapy is very beneficial because it helps select patients who will benefit from surgery and greatly improves the rate of complete resection.

Tumors in Proximity to the Carina Another subset of patients with stage IIB NSCLC who benefit from surgical resection are those who have central tumors within 2 cm of the carina but without actual carinal involvement. Most of these lesions are resectable, but mediastinal nodal disease must be ruled out preoperatively with mediastinoscopy. Pneumonectomy is the most common resection

Ch061-F06861.indd 775

775

offered for these T3 tumors, but sleeve lobectomy needs to be considered whenever it can accomplish a complete resection. Sleeve resection preserves pulmonary function and reduces morbidity and mortality compared with pneumonectomy. There are no direct data comparing pneumonectomy with sleeve lobectomy for T3 tumors. However, these resections have been compared for N1-2 disease, and the results demonstrate that sleeve lobectomy does not compromise survival.80 Pitz and colleagues81 reported on 75 patients with T3 NSCLC, with a 5-year survival rate of 40% for proximal bronchial tumors. Riquet and colleagues82 reported on a retrospective series of 261 T3 tumors and analyzed the prognosis of the T3 subgroups (mediastinal, chest wall, proximity to the carina). Two thirds of patients were treated by pneumonectomy. The overall 5-year survival rate was 28%, with a rate of 35% for tumors close to the carina. Neither the T3 subgroup nor the type of resection influenced survival.

Tumors Invading the Mediastinum Patients presenting with tumors that invade the mediastinal pleura have a relatively poor prognosis when treated by surgery alone. A retrospective report from Burt and colleagues83 evaluated 225 patients who had undergone thoracotomy for mediastinal T3 disease. Only 22% of the patients had a complete resection with surgery alone, and the 5-year survival rate for the whole group was only 9%. However, two thirds of the patients with mediastinal invasion by the primary tumor were stage III due to mediastinal lymph node metastases. When the mediastinal T3 N0 tumors were evaluated separately (n = 102), the 5-year survival rate was 19%. Riquet and colleagues82 reported a slightly better 5-year survival rate of 31% in their retrospective evaluation of 68 tumors with mediastinal involvement. These data highlight the importance of performing mediastinoscopy before surgical resection of T3 tumors. Radiation therapy has been used as adjuvant therapy after both complete and incomplete resection of T3 NSCLC. No prospective study has demonstrated a survival advantage for adjuvant radiation therapy.84,85 However, postoperative radiation therapy does improve local control after incomplete resection and/or positive regional lymph nodes.86,87 Improved rates of local control have also been suggested in patients with N2 disease.85

STAGE III DISEASE The majority of lung cancers at presentation for therapy are advanced tumors. When distant metastases are absent but patients have lymphatic metastases to the mediastinum, the NSCLC is classified as stage III disease. Patients with ipsilateral mediastinal lymph nodes and T3 tumors or less have stage IIIA disease. Stage IIIB disease includes multiple tumors in the same lobe and tumors that invade adjacent mediastinal organs (T4). Stage IIIB also includes contralateral mediastinal lymphatic spread (N3). The 5-year survival rate for stage III disease is less than 15%, and most patients are treated without surgery. The importance of accurate staging cannot be overemphasized to determine which of these patients with locally

1/21/2008 12:15:55 PM

776

Section 3 Lung

advanced disease, particularly T4 or N2, are amenable to surgical resection or combined-modality therapy that includes surgery.

Stage IIIA Disease (N2) Metastasis to ipsilateral mediastinal lymph nodes (N2) is the most frequent deterrent to cancer cure despite an apparent localized presentation. Mediastinal metastasis is present in almost one half of all patients presenting with NSCLC. Many view this group of patients as having a nonsurgical disease because the best efforts of surgery do not cure metastatic disease. However, the optimal treatment for this challenging group of patients remains to be defined. A recent retrospective series from M.D. Anderson Cancer Center reported the results of 353 patients with pathologically staged IIIA disease.88 Approximately equal numbers of patients were treated with surgery alone, surgery plus external-beam irradiation, and surgery plus chemotherapy with or without irradiation. Preoperative staging over the 16-year study period included CT (99%), mediastinoscopy (25%), and PET (3%). The 5-year survival rate during the second half of the study period improved to 25%. A complete (R0) resection was performed in 87% of patients. Independent predictors of survival included female gender, complete resection, upper lobe tumor location, and single-station N2 disease. The authors concluded that multimodality treatment appears to contribute to improved outcomes over time in patients with resected stage IIIA (N2) NSCLC.

Clinically Undetected N2 Disease—Resectable Despite enormous effort to accurately stage patients preoperatively, many of those with clinically negative N2 nodes are discovered to have positive N2 nodes at the time of thoracotomy. Most surgeons believe that, if a complete resection is possible, surgery should proceed because the patient has already incurred the morbidity of the thoracotomy. Martini and colleagues89 reported on 706 patients with N2 disease, with only 21% completely resectable. Those patients with a complete resection had a 5-year survival rate of 30%, but this represented only 1 of every 5 patients. This study and several others also confirmed that patients with single-station nodal disease have better outcomes than do patients with multiple positive nodal stations.90-92 Keller and colleagues93 analyzed data from the ECOG 3590 trial. They demonstrated that patients with single-level N2 nodal disease have a survival rate similar to that of patients with N1 disease. Keller has also suggested that complete mediastinal lymph node dissection should be performed to limit recurrence and improve survival in patients with stage II and stage IIIA NSCLC.49 Ferguson94 and other surgeons do not support the decision to proceed with resection if N2 nodes are discovered during thoracotomy. Ferguson used a decision analysis to compare initial resection with termination of the procedure. The analysis was performed from the perspective of the medical center, using survival, quality-adjusted life years survival, and cost-effectiveness as outcomes. The analysis supported delaying resection until after neoadjuvant therapy to improve survival and cost-effectiveness.

Ch061-F06861.indd 776

If N2 disease is discovered by the pathologist, adjuvant therapy may be considered after resection. However, chemotherapy is often poorly tolerated after major pulmonary resection. Pisters and colleagues reported that patients received less than 60% of the full adjuvant regimen.95 The Non–Small Cell Lung Cancer Collaborative Group performed a large meta-analysis of 14 trials that included 4357 patients.56 This meta-analysis of platinum-based chemotherapy suggested a modest improvement in survival of 5% at 5 years. The International Adjuvant Lung Cancer Trial (IALT) was a multicenter prospective study that reported similar results, with a 4% improvement in overall survival.57 Unfortunately, adjuvant chemotherapy offers only a modest survival advantage for stage III NSCLC, with considerable morbidity after a major resection. As mentioned in the discussion of stage II disease, external-beam radiation therapy can reduce locoregional recurrence but does not affect survival.63

Clinically Evident N2 Disease—Unresectable The goal of preoperative staging is to determine which patients will benefit from initial surgery and to identify patients that may benefit from induction therapy and subsequent resection. A combination of CT, PET, and mediastinoscopy is important to identify patients with stage IIIA disease. These patients have an 80% rate of incomplete resection with initial surgery and a 15% survival rate at 5 years. CT scanning is the most common mediastinal staging modality. It correlates fairly well (80% accuracy) with negative nodes less than 1 cm on transverse diameter.96,97 PET is slightly better than CT for mediastinal staging as reported by ACOSOG Z0050.15 PET has a negative predictive value of 87% but a poor positive predictive value of only 56%. It is imperative to confirm mediastinal lymph nodes that appear positive by CT or PET because 30% to 50% of them are histologically negative for malignancy. Mediastinoscopy remains the gold standard for mediastinal staging, and we routinely use it for all patients except those with T1 tumors and a negative mediastinum by CT and PET.16 Hammoud and colleagues98 reported on 2137 patients who had cervical mediastinoscopy performed at Washington University. The procedure is extremely safe, with only one procedure-related death and a complication rate of less than 1%. Only 76 (8%) of 947 lung cancer patients had a negative mediastinoscopy but were found to have N2/N3 disease during surgical resection. The low false-negative rate of mediastinoscopy is significantly better than for PET or CT and helps prevent a noncurative thoracotomy. If N2 disease is discovered preoperatively, most patients receive definitive chemoradiation. However, if the nodal disease and primary tumor appear to be resectable, induction therapy may be considered because the result of primary resection is poor even for well-selected patients. The full details of induction therapy for stage IIIA disease are discussed in Chapter 62. The SWOG 88-05 trial used cisplatin and etoposide with 45 Gy of concurrent thoracic irradiation for patients with stage IIIA or IIIB disease.99 Patients with a response to induction therapy or with stable disease went on to surgery. The overall 3-year survival rate was 26%, and the

1/21/2008 12:15:56 PM

Chapter 61 Surgical Management of Non–Small Cell Lung Cancer

operative mortality rate was 6%. Patients with disease progression, incomplete resection, or residual disease in resected lymph nodes received additional chemoradiation. Importantly, patients with a significant response to induction therapy were the best candidates for surgery, and those with a complete pathologic response in the mediastinum had a 3-year survival rate of 44%. Two small, early phase III trials of induction chemotherapy also suggested an improvement in survival.100,101 However, two additional small trials did not show any survival advantage.102,103 Two prospective trials by the Radiation Therapy Oncology Group (RTOG 0412 and 0229) have recently opened to further investigate the role of induction chemoradiation therapy followed by surgery for N2 disease. The treatment of stage IIIA NSCLC remains controversial. Two important points must be emphasized. First, suspicious mediastinal lymph nodes found on staging workup (CT scan or PET) need pathologic confirmation because of the significant false-positive rate. Second, survival after induction chemotherapy and surgical resection is dependent on the completeness of the resection and the status of the mediastinal lymph nodes (Fig. 61-8). Lorent and colleagues104 demonstrated that complete resection is more likely in patients with a significant response to induction chemotherapy than in those with stable disease without progression. There are several strategies to assess the mediastinal lymph nodes before and after induction therapy. Our practice has been to offer induction therapy to healthy patients with single-station nodal disease confirmed by mediastinoscopy. Patients are carefully restaged by CT and PET after induction therapy and proceed to surgery only if they show a response to treatment and are free of distant metastatic disease. Cerfolio and colleagues demonstrated that endoscopic ultrasound-guided fine-needle aspiration is safe and accurate for the confirmation of positive mediastinal lymph nodes detected by CT and PET.105 This strategy reserves cervical mediastinoscopy for restaging the mediastinum after induction therapy. If the mediastinal nodes are positive, completion chemoradiation is administered. If the cervical mediastinos-

100 Survival with complete resection (CR) (89) Survival with incomplete or no resection (IR) (47)

Percent Survival

80

3 yr 5 yr Median CR 41% 26% 27 mos IR 05% 05% 12 mos

60

40

20

0 0

1

2 3 4 Years From Diagnosis

5

6

FIGURE 61-8 Impact of complete resection on survival after induction therapy for stage IIIA non–small cell lung cancer.

Ch061-F06861.indd 777

777

copy does not show persistent disease, formal resection is performed. For those patients who proceed to surgery after induction therapy, we perform a complete mediastinal node dissection for the stations that were positive preoperatively and systematically sample the remainder of the lymph node stations. In addition, we routinely cover the bronchial stump with a vascularized flap of pleura, pericardial fat pad, or intercostal muscle to reduce the risk of bronchopleural fistula.

Stage IIIB Disease (T4 or N3) Patients presenting with supraclavicular or contralateral mediastinal lymph node metastases (N3); invasion of the spine, trachea, carina, esophagus, great vessels, or heart (T4); satellite lesions within the same lobe (T4); or malignant pleural effusion (T4) have stage IIIB disease. The overall 5year survival rate for patients with stage IIIB NSCLC is less than 10%, and most patients are considered inoperable. Occasionally, patients are found at thoracotomy to have completely resectable T4 disease because they were clinically understaged preoperatively. This group comprises most of the reported long-term survivors. A real concern is clinical overstaging of these T4 patients. Before a patient is assigned to a T4 or N3 category on clinical grounds, there needs to be incontrovertible evidence to support this involvement. If invasive approaches are not used for staging, inappropriate (nonsurgical) therapy may frequently be prescribed for completely resectable tumors. Furthermore, not all T4 subgroups have the same survival characteristics; the results of surgical treatment for each subgroup are discussed later in this chapter.106 Importantly, complete resection may be possible in highly selected patients with T4 disease and may provide improved survival.

T4 Disease: Carinal Involvement Lesions that extend up to and invade the carina have a much poorer prognosis than those in the main stem bronchi. Pneumonectomy with tracheal sleeve resection and direct reanastomosis of the trachea to the contralateral main stem bronchus is the only option to obtain a complete resection. This is a technically demanding operation and is reserved for younger patients with few medical comorbidities. Mediastinoscopy is essential to identify those patients whose cancer is completely resectable. De Perrot and colleagues107 recently reported a large, single-center, French experience with 100 carinal resections for bronchogenic carcinoma over a 23-year period. The 5- and 10-year survival rates were 44% and 25%, respectively. The 5-year survival was significantly better with N0/N1 disease (n = 73) than with N2/N3 disease (n = 27), 53% versus 15%. The operative mortality rate was 8% and was highest after right carinal pneumonectomy. Postoperative complications occurred in 50% of patients, and the incidence of anastomotic complications was 10%. These results are similar to those in previously reported series despite the fact that they operated on 25% of patients with positive mediastinal disease.108-110 Induction chemotherapy has been used to improve the complete resection rate and does not appear to increase operative mortality.109

1/21/2008 12:15:56 PM

Section 3 Lung

Satellite Nodules Although satellite nodules in the same lobe are now considered T4 lesions, the 5-year survival rate after resection is significantly better than for other stage IIIB disease. Battafarano and colleagues111 reported 66% survival at 3 years for T4 (satellite nodule) patients. In many instances, the satellite lesion is discovered only at the time of pathologic examination. Furthermore, it may be difficult to conclude that a satellite nodule seen on CT scanning represents cancer and not an inflammatory lesion. We strongly believe that, unless there is evidence of metastatic disease, the approach for this group of patients needs to be surgical. Although other reports have shown satellite nodules to be a poor prognostic factor, the outcome for these patients approaches the survival rates of those with early-stage lung cancer.112,113 In the future, the T4 descriptor for these lesions may be adjusted to more accurately reflect survival.

Organ Involvement Lung cancers that invade mediastinal structures such as the vertebrae, pulmonary artery, superior vena cava, esophagus, and atrium can be resected en bloc in certain circumstances. As with other central tumors, it may be difficult to determine the status of mediastinal lymph nodes by CT or PET, and cervical mediastinoscopy is essential. Osaki and colleagues113 reported on 26 patients with mediastinal organ involvement. The 5-year survival rate was 18%. The important prognostic factors for survival are completeness of resection and lymph node status. Pitz and colleagues114 reported 5-year survival rates of 46% for complete resections and only 10% for incomplete resections. Rendina and colleagues reported that induction therapy may down-stage such patients and allow less radical resections.109 However, some of these patients were probably overstaged by noninvasive preoperative clinical staging. Other authors, such as Dartevelle and colleagues,75 approach such lesions without preoperative treatment, using imaging and invasive staging to assess operability and resectability of the involved adjacent structure. Cardiopulmonary bypass may be used to facilitate a complete resection for a large central tumor. We have used bypass on several occasions to help reconstruct the main pulmonary artery and left atrium. Although it adds to the complexity of the procedure, it facilitates exposure and hemodynamic stability for large central resections.

patients were identified preoperatively, and the remainder were identified at the time of thoracotomy. There were no complete resections and no survivors after 5 years.

N3 Disease Contralateral mediastinal lymph node metastases represent N3 disease. Patients with N3 disease have a very poor prognosis, and long-term survival is extremely rare. N3 disease is an absolute contraindication to surgery except as part of an investigational protocol. Recently, induction therapy has been evaluated in the treatment of N3 disease. However, the effects were difficult to determine because the trials were small and included mixed T4 and stage IIIA disease. Albain and colleagues99 reported the initial phase II trial of induction chemoradiation (cisplatin/etoposide plus radiation) for 75 stage IIIA patients and 51 stage IIIB patients. Eighty percent of the stage IIIB patients underwent resection, with a 3-year survival rate of 24%. Grunenwald and colleagues115 performed a more recent phase II induction therapy trial for stage IIIB NSCLC. Thirty patients had a T4 lesion, and 18 had N3 disease. The 5-year overall survival rate for patients with N3 disease was 17%. Importantly, survival was directly related to the postinduction lymph node status (Fig. 61-9). A multivariate analysis demonstrated that postinduction lymph node status was the only prognostic factor for survival and relapse. The true value of induction chemoradiation for N3 disease remains unknown. Phase II trials have shown it to be relatively safe, and it may improve locoregional failure, which is a major problem for these patients.116 We routinely perform mediastinoscopy preoperatively and do not operate on patients with N3 disease.

Probability of Survival

778

T4 Pleura Tumors with a malignant pleural effusion have an extremely poor outcome after surgical resection. Pleural effusions detected by staging evaluation must be investigated. Thoracentesis with cytologic examination or pleuroscopy can prevent a nontherapeutic resection. If an effusion is discovered at the time of thoracotomy, the fluid is sent for urgent analysis. The problem with surgery for this disease is that complete resection is almost impossible. There are a few small case series describing experience with parietal pleurectomy and extrapleural pneumonectomy, but the results have been extremely poor. Osaki and colleagues113 recently reported on 16 patients with T4 pleural disease. Three

Ch061-F06861.indd 778

Patients

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Post-induction N0N1/complete resection Post-induction N2N3/complete resection Unresected

P ⬍ 0.0001 0

12

24

36 Months

48

60

15

10

10

9

8

6

8

6

3

1

1

1

17

5

1

FIGURE 61-9 Postinduction lymph node status predicts survival after induction therapy and surgery for stage IIIB non–small cell lung cancer. (FROM GRUNENWALD DH, ET AL: BENEFIT OF SURGERY AFTER CHEMORADIOTHERAPY IN STAGE IIIB [T4 AND/OR N3] NON-SMALL CELL LUNG CANCER. J THORAC CARDIOVASC SURG 122:796, 2001, FIG. 3, P 800.)

1/21/2008 12:15:56 PM

Chapter 61 Surgical Management of Non–Small Cell Lung Cancer

STAGE IV DISEASE The vast majority of patients with NSCLC exhibiting distant metastasis are not curable by surgery, and the 5-year survival rate is less than 7%. However, surgery may be appropriate for highly selected patients with resectable lung cancer and evidence of a solitary metastasis on complete organ scanning. These patients may be considered for a combined approach, with removal of the primary tumor and then the solitary metastasis. Thorough staging is imperative, and the use of PET along with mediastinoscopy has become the standard of care.15 Isolated lesions in the brain and in the adrenal glands and synchronous tumors in a different lobe are discussed in the following sections.

Solitary Brain Metastases Almost 25% of patients with stage IV NSCLC have brain metastases. The survival time for patients treated with steroids alone is 2 months; this improves to almost 6 months with whole-brain irradiation.117 Aggressive treatment of solitary brain metastases may involve either surgical resection or radiosurgical ablation. The two techniques produce similar rates of survival, local control, morbidity, and mortality.118 Patients may be considered for treatment if they are medically fit, have completely resectable brain metastases, have no evidence of other systemic disease, and have primary NSCLC confined to the lung. The 5-year survival rate for patients with completely resected NSCLC and brain metastases approaches 20%.106,119 A recent study from Maryland reported the results of 72 patients treated with gamma knife stereotactic radiosurgery.120 The 5-year actuarial survival rate was only 10%, and the median survival time was 16 months. The presence of a metachronous versus a synchronous brain metastasis was the only significant prognostic factor in univariate and multivariate analyses. Postoperative whole-brain irradiation is frequently used to help sterilize the tumor bed. However, the data are conflicting and insufficient to make this a standard procedure.

Isolated Adrenal Metastases Solitary adrenal metastases are detected with increasing frequency because of preoperative CT and PET scanning. Highly selected patients have undergone resection of adrenal metastases from NSCLC with curative intent. The overall 5-year survival rate approaches 20%.121 Survival is improved in N0 patients, but tumor histology, synchronous versus metachronous presentation, and ipsilateral versus contralateral location do not affect survival. Because of the paucity of evidence, there are no firm recommendations at the current time for the treatment of isolated adrenal metastases. However, an increasing number of patients are being considered for surgery,122 and outcome data for a larger number of patients with longer follow-up will become available.

Lung Metastases The optimal management of multifocal NSCLC remains controversial. Preoperatively, it is often difficult to determine whether multiple lesions represent separate primary lung

Ch061-F06861.indd 779

779

cancers or intrapulmonary metastases. This difficulty may persist even after resection if the histology is the same. The American Joint Committee on Cancer (AJCC) staging manual assigns the M1 descriptor to both synchronous primary lung cancers and intrapulmonary metastases. The importance of distinguishing between the two is debated, but most reports show improved survival for synchronous primary tumors. This is not an uncommon dilemma because the incidence of multifocal primary lung cancer is approximately 5% in many surgical series.111,123 Battafarano and colleagues111 reported on 44 patients with multifocal NSCLC who underwent resection, with a 3-year survival rate of 61%. Okada and colleagues reported similar results for completely resected synchronous primary lung cancers, with a 5-year survival rate of 70%.124 Our practice has been to perform complete resection of both lesions using a median sternotomy or staged thoracotomies. Mediastinoscopy is essential to ensure that there is no N2/N3 disease.

PALLIATIVE RESECTION Surgery is rarely indicated for the palliation of patients with unresectable tumors. Most patients can receive palliation from chemotherapy and/or radiation therapy. However, three indications for palliative resection are an unremitting lung abscess, massive hemoptysis, and painful invasion of the chest wall.

Lung Abscess An unresolving lung abscess can result from a necrotic tumor (usually squamous cell cancer) or from a lung abscess distal to an obstructing bronchial tumor. These lesions rarely require surgery and can usually be managed with percutaneous drainage of the abscess. The obstruction can be relieved with the use of rigid bronchoscopy to clear the lumen or endobronchial laser therapy followed by external-beam irradiation. However, for unresolving abscesses that can be completely resected, palliative surgery may be warranted.

Massive Hemoptysis Massive uncontrolled hemoptysis is a rare feature of lung cancer. It is usually caused by the development of a fistula after radiation therapy. The pulmonary artery, aorta, or eroded bronchial vessels can be the source of severe bleeding. Occasionally, patients present with persistent hemoptysis that requires treatment. It is usually from bronchial arteries and is best localized by bronchoscopy and CT. If it is severe, every effort needs to be made to maintain patency of the contralateral lung and avoid suffocation. It may be necessary to place a bronchial blocker or double-lumen endotracheal tube to stabilize the patient for transport. The most common definitive treatments are selective bronchial artery embolization and laser coagulation. If the bleeding cannot be controlled by any of these techniques, surgery may be useful. Occasionally, the lesion is resectable, and this usually controls the bleeding. More frequently, the lesion is not completely resectable, and hilar division of all bronchial vessels can be performed.

1/21/2008 12:15:56 PM

780

Section 3 Lung

Chest Wall Invasion Patients can present with severe pain from chest wall invasion. If the tumor is unresectable due to extensive nodal involvement or distant metastatic disease, surgery is avoided. External-beam irradiation is the most common treatment modality, and patients with continued pain may benefit from seeing a pain service for local or regional block anesthesia. In the rare circumstance where surgery is performed, the duration of palliation is determined by the amount of time before the disease recurs. The most common indication for palliative resection is to protect the spinal cord when the primary tumor invades the thoracic vertebrae and causes extradural compression. En-bloc resection of the tumor and vertebral body may protect the spinal cord from high-dose radiation and prevent paralysis. However, these patients have prolonged hospital stays and significant morbidity from the resection.

COMMENTS AND CONTROVERSIES The surgical management of NSCLC continues to evolve. More comprehensive physiologic assessment has enabled more accurate estimation of postoperative functional capacity in potential candidates for resection. Constant improvements in imaging technology, principally CT and PET imaging, have markedly increased the accuracy of diagnosis and staging. Operative approaches and techniques have been refined for both early-stage and locally advanced tumors. Limited resection by segmentectomy or extended segmentectomy has been repopularized in many centers. Video-assisted lobectomy has become the procedure of choice for early-stage lesions. Muscle-sparing incisions are routinely used for open resections. Surgeons have had to become more knowledgeable in the multidisciplinary management of these cancers because adjuvant chemotherapy has become routine for patients undergoing resection

Ch061-F06861.indd 780

for stage IB and stage II disease. In addition, surgeons are evaluating an ever-increasing number of patients as candidates for induction chemotherapy followed by resection. These patients present an entirely different set of intraoperative technical challenges. However, despite these advances, the principles of resectional surgery for NSCLC have not changed. Well-selected patients must be accurately staged and completely resected. G. A. P.

KEY REFERENCES Ginsberg RJ, et al: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60:615, 1995. Hammoud ZT, et al: The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg 118:894, 1999. Lung Cancer Study Group: Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 315:1377, 1986. Martini N, et al: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109:120, 1995. Meyers BF, et al: Cost-effectiveness of routine mediastinoscopy in CT- and PET-screened patients with stage I lung cancer. J Thorac Cardiovasc Surg 131:822, 2006. Epub 2006 Mar 2. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:1710, 1997. Reed CE, et al: Results of the American College of Surgeons Oncology Group Z0050 Trial: The utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thorac Cardiovasc Surg 126:1943, 2003. Rusch VW: Induction chemoradiation and surgical resection for nonsmall cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 121:472, 2001. Winton T, et al: Vinorelbine plus cisplatin vs. observation in resected non-small cell lung cancer. N Engl J Med 352:2589, 2005.

1/21/2008 12:15:56 PM

chapter

62

INDUCTION AND ADJUVANT THERAPY FOR OPERABLE NON–SMALL CELL LUNG CANCER Jeffrey D. Bradley Ramaswamy Govindan

Key Points ■ Recent randomized trials show an overall survival benefit with the

addition of adjuvant chemotherapy for patients with resected T2 primaries and/or those with N1 or N2 disease. ■ Randomized trials also have demonstrated a survival benefit for neoadjuvant chemotherapy before surgery in patients with stage IIA disease. It appears that neoadjuvant chemoradiation therapy also may provide a survival benefit for patients with resectable N2 disease. However, patients requiring a pneumonectomy, especially a right pneurmonectomy, have a much higher operative mortality rate following neoadjuvant chemoradiation. ■ Neoadjuvant chemoradiation appears to provide a benefit to patients with resectable superior sulcus tumors.

Despite adequate surgical resection, a significant proportion of patients with stage I-III non–small cell lung cancer (NSCLC) die from recurrent disease. The 5-year survival rate for patients with stage I disease ranges from 60% to 70%, and for stage II from 35% to 40%.1,2 Very few patients with stage III NSCLC are cured with surgical resection alone. Systemic relapse outside the chest is the common mode of recurrence, most likely because of micrometastatic disease present even at the time of surgical resection. Systemic therapy offers the potential to increase the cure rate by eradicating micrometastatic disease. Two approaches have been pursued—a neoadjuvant or induction therapy, in which systemic chemotherapy, thoracic irradiation, or a combination of chemotherapy and radiation is administered before surgical resection, and adjuvant therapy, in which the same modalities are administered after surgical resection. The first section of this chapter focuses on published studies involving the neoadjuvant approach, and the second section reviews the emerging data on adjuvant therapy in patients with completely resected NSCLC.

NEOADJUVANT THERAPY There is no clear existing consensus for the management of operable N2 NSCLC. The options include surgery followed by adjuvant therapy, neoadjuvant therapy followed by surgery, and nonsurgical chemoradiation therapy. Despite these management options, the survival rate for patients with stage III lung cancer remains poor, in the range of 13% to 21%, based on randomized trials. Surgery alone has been shown to result in poor outcome for patients with N2 disease.3,4 However, there may be a survival advantage to induction therapy fol-

lowed by surgery for selected patients with stage IIIA disease (Albain et al, 2005).5 One of the principal reasons for poor outcome in patients with N2 NSCLC is the tendency to develop metastatic disease. Therefore, chemotherapy is employed to decrease the risk of distant metastases. Both adjuvant and neoadjuvant chemotherapy have been shown to improve survival in patients with resectable NSCLC (Rosell et al, 1994; Roth et al, 1998; Strauss and Herndon, 2004; Winton and Livingston, 2004).6-12 Other trials have demonstrated that induction (neoadjuvant) chemoradiation before surgery is an effective treatment strategy (Albain et al, 2005; Rusch et al, 2001).5,13 Induction chemoradiation therapy has also been effective in the management of patients with superior sulcus carcinomas by reducing the tumor away from critical structures and rendering it more easily resectable. This chapter discusses the role of both induction and adjuvant therapy in patients with resectable NSCLC.

Induction Chemotherapy Four randomized trials designed to compare induction chemotherapy followed by surgery versus surgery alone have involved (or included) patients with resectable stage IIIA lung cancer (Table 62-1). Two of these studies, initially published in the mid-1990s, were small, randomized trials that showed an overall survival (OS) advantage for patients with stage III NSCLC who received induction chemotherapy compared with surgery alone (Rosell et al, 1994; Rosell et al, 1999; Roth et al, 1998).9,10,14 A third randomized trial, designed by the Japan Clinical Oncology Group, was prematurely terminated because of a failure to complete accrual.15 This study showed no statistical difference between the induction chemotherapy and surgery arms. The lack of statistical power makes it difficult to draw conclusions from this trial. A fourth randomized trial, from France, was much larger, included patients with stages I through IIIA NSCLC, and also showed an advantage to induction chemotherapy.16 Roth and colleagues reported the results of a phase III prospective randomized trial completed at the University of Texas M.D. Anderson Cancer Center (Roth et al, 1998; Roth et al, 1994).10,17 The trial enrolled 60 patients between 1987 and 1993 and randomly assigned them to either three cycles of cyclophosphamide, etoposide, and cisplatin followed by surgery or surgery alone. If tumor regression was documented by imaging studies after the initial three cycles of chemotherapy, the patient received three additional cycles of chemotherapy before surgery. The trial was terminated early because of the demonstrated survival advantage in favor of 781

Ch062-F06861.indd 781

1/21/2008 12:16:51 PM

782

Section 3 Lung

TABLE 62-1 Phase III Trials of Induction Chemotherapy Versus Surgery Alone Median Survival Time (Months) Authors (Year)

No. Patients

Surgery Only

Induction Plus Surgery

Surgery Only

Induction Plus Surgery

19 (3 yr) 15 (5 yr)

43 (3 yr) 36 (5 yr)

5 (3 yr) 0 (5 yr)

20 (3 yr) 17 (5 yr)

Roth et al10,17 (1994, 1998)

60

11 (14 on longer follow-up)

64 (21 on longer follow-up)

Rosell et al9,14 (1994, 1999)

60

8 (10)

26 (22)

26 (overall) 18.9 (N2)

37 (overall) 25 (N2)

Depierre et al16 (2002)

355

Overall Survival (%)

41.2 (3 yr, overall) 39.6 (3 yr, N2) 35.3 (4 yr)

51.6 (3 yr, total) 37.1 (3 yr, N2) 43.9 (4 yr)

Note: Nagai et al, 2003, closed early due to poor accrual.

1.0

100

80

0.6

0.4 Perioperative chemotherapy N = 28 0.2

0

20

40

60

80

100

120

40 Preresectional chemotherapy N = 30

Surgery N = 30

140

Months FIGURE 62-1 Overall survival curves comparing perioperative chemotherapy vs. surgery alone for stage IIA NSCLC. (FROM ROTH JA, ATKINSON EN, FOSSELLA F, ET AL: LONG-TERM FOLLOW-UP OF PATIENTS ENROLLED IN A RANDOMIZED TRIAL COMPARING PERIOPERATIVE CHEMOTHERAPY AND SURGERY WITH SURGERY ALONE IN RESECTABLE STAGE IIIA NON–SMALL-CELL LUNG CANCER. LUNG CANCER 21:1-6, 1998.)

the chemotherapy arm. The major clinical response rate (complete or partial response) after the initial three cycles of chemotherapy was 35%. Median survival times were 64 months on the induction arm and 11 months in the surgeryonly arm (P < .008) at the time of initial publication. With longer follow-up, the median survival times dropped to 21 and 14 months, respectively. The estimated 3-year survival rates were 43% in the group receiving preoperative chemotherapy and 19% in the group receiving surgery alone; the 5-year survival rates were 36% and 15%, respectively (P = .048 at 3 years; P = .056 at 5 years) (Fig. 62-1). Rosell and colleagues from Spain reported a similar phase III prospective trial in patients with stage IIIA NSCLC comparing induction with mitomycin, iphosphamide, and cisplatin for three cycles followed by surgery versus surgery alone.9,14 The trial enrolled 60 patients with pathologic evidence of N2 disease between 1989 and 1991. Both patient groups received mediastinal irradiation to 50 Gy after surgery. An interim analysis after 24 months of accrual showed a

Ch062-F06861.indd 782

60

20

Surgery N = 32 0

Proportion Surviving

Probability of Survival

0.8

0 0

12

24

36

48

60

72

84

96

108

Months Since Randomization FIGURE 62-2 Overall survival curves comparing perioperative chemotherapy vs. surgery alone for stage IIA NSCLC. (FROM ROSELL R, GOMEZ-CODINA J, CAMPS C, ET AL: PRERESECTIONAL CHEMOTHERAPY IN STAGE IIIA NON–SMALL-CELL LUNG CANCER: A 7-YEAR ASSESSMENT OF A RANDOMIZED CONTROLLED TRIAL. LUNG CANCER 26:7-14, 1999.)

significant survival difference in favor of the chemotherapy arm, and the trial was stopped. Of the 30 patients receiving induction chemotherapy, 60% had either a partial response or a complete response (CR). One patient developed liver metastases during chemotherapy. Median survival times were 22 and 10 months, respectively, for the groups receiving induction chemotherapy versus surgery alone (P < .001). The 3-year OS rates were 20% and 5%, respectively, in the induction and surgery-only arms, and the 5-year OS rates were 17% and 0%, respectively (P < .001) (Fig. 62-2). These two widely publicized randomized trials from Roth and Rosell have been criticized on several points. First, neither study required pathologic nodal staging before randomization, leading to possible imbalances on the treatment arms. Second, the complete pathologic response rates were less than 5%. Third, there was a poorer surgical outcome than expected. There were no long-term survivors on the surgeryalone arm of the Rosell trial and only 15% long-term survivors

1/21/2008 12:16:51 PM

Chapter 62 Induction and Adjuvant Therapy for Operable Non–Small Cell Lung Cancer

on the Roth trial. Both are considered substandard results for a favorable group of patients with stage IIIA disease. A fourth prospective phase III randomized trial comparing induction chemotherapy followed by surgery versus surgery alone was carried out by the French Thoracic Cooperative Group for patients with resectable NSCLCs.16 This was a larger trial, enrolling 355 patients. Tumor stages were similar on both arms, with roughly 35% to 40% having stage I (T2 N0) disease, 14% to 18% stage II, and 45% to 50% stage III. There was a statistical trend toward more patients with N2 disease on the chemotherapy arm; other patient factors were evenly distributed. Patients on the induction arm received two cycles of mitomycin, ifosfamide, and cisplatin. If there was a complete or partial response, two additional cycles were delivered postoperatively. Patients in both arms who had pathologic T3 and/or N2 disease received 60 Gy of mediastinal radiation therapy (RT) postoperatively. There was a slightly higher postoperative mortality in the chemotherapy arm (6.7%) than in the surgery arm (4.5%); this difference was not statistically significant. There were no differences between arms in the type of surgery performed. The objective response rate on the chemotherapy arm was 64%. Ten (6%) of 179 patients developed progressive disease on chemotherapy (6 locoregional and 4 metastatic lesions). The median follow-up of this trial was 80 months. Median survival times were 25 and 18.9 months in the induction and surgery-alone arms, respectively (P = .15). The 4-year survival rates were 43.9% and 35.3%, respectively. Although no statistical advantage to preoperative chemotherapy on OS was demonstrated for the entire group, patients with stage I or II disease did have a survival benefit from chemotherapy (P = .027). The postoperative death rate in the trial was higher in the chemotherapy arm (10.0% versus 4.5%).

Surgery Versus Radiation Therapy After Induction Chemotherapy The European Organization for Research and Treatment of Cancer (EORTC) recently reported the results of a phase III trial comparing surgery with lymph node dissection versus 60 Gy of RT after induction cisplatin-based chemotherapy for patients with stage IIIA (N2) NSCLC.18 The results are available only in abstract form at this time. The trial enrolled 572 patients, who received three cycles of induction chemotherapy. A total of 333 patients were randomized (167 to surgery and 166 to RT) and monitored for a median of 72 months. Of the 154 operated patients, 15% underwent exploratory thoracotomy, 51% had a radical resection, and 39% received postoperative RT. Definitive RT consisted of 40 Gy to the elective mediastinal nodes and 60 Gy total tumor dose for 155 patients completing treatment. The median survival time, 2-year OS, and 5-year OS for patients randomized to surgery versus RT were 16.4 versus 17.5 months, 35% versus 41%, and 16% versus 13%, respectively (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.751.19). The difference between arms was not significant. Though these results are interesting, the rates of attrition between registration and definitive therapy in this study are

Ch062-F06861.indd 783

783

concerning. Additional data are needed to draw conclusions from this trial.

Induction Radiation Therapy Randomized trials have failed to show a survival benefit for preoperative RT compared with surgery alone. Many of the trials are fairly outdated, and modern noninvasive and intraoperative staging techniques were not used. In the Lung Cancer Study Group trial (LCSG 881), patients received preoperative irradiation to 44 Gy or preoperative cisplatin, mitomycin, and vinblastine in a randomized phase II trial of patients with pathologically proven stage IIIA disease. However, the median survival time was only 12 months, and a pathologic CR was seen in only 2 of 57 patients (1 in each arm).19 Despite more modern methods, preoperative RT does not appear to increase survival.

Induction Chemotherapy and Radiation Therapy Combined trimodal approaches aim to apply one of two rationales to improve patient survival. The first is to convert inoperable and marginally operable cases to operability by some combination of induction chemotherapy and RT. The second rationale is to improve on the results of surgery in patients deemed to be operable at presentation by the addition of preoperative chemoradiation. Clearly, the morbidity of trimodality therapy is considerable (see later discussion). Although surgical strategies remain a priority for patients with resectable and marginally resectable stage III disease, it remains uncertain whether the addition of surgery is superior to chemoradiation alone because of the high risk of distant failure. Chemotherapy given with RT for patients with inoperable stage III lung cancer has been shown to reduce distant metastatic failures and improve survival.20-23 The objective of these trials was to use primary RT, aided by chemotherapy radiosensitization, to shrink the primary tumor and bulky N2 disease and to use the chemotherapy to sterilize distant micrometastases. Based on these experiences in unresectable disease, we can reasonably expect chemotherapy to reduce the incidence of distant metastases in resectable NSCLC. Induction chemoradiation therapy has long been the standard for patients with operable superior sulcus NSCLC. Rusch and colleagues13 published the results of a prospective phase II Intergroup experience (Southwest Oncology Group [SWOG] 9416/Intergroup 0160) in which patients with T34 N0-1 superior sulcus carcinomas received two cycles of induction cisplatin and etoposide chemotherapy concurrent with RT to 45 Gy. Patients with stable or responding disease went on to thoracotomy 3 to 5 weeks later. The trial enrolled 111 patients; 102 patients (92%) completed induction therapy. Of the 95 patients eligible for surgery, 83 underwent thoracotomy and 76 (92%) had a complete resection. Pneumonectomy was required in only 3 patients. Two patients died postoperatively. Fifty-four thoracotomy specimens (65%) demonstrated either a pathologic CR or minimal microscopic residual disease. The 2-year survival rate was 55% for all eligible patients and 70% for patients with a complete resection (Figs. 62-3 and 62-4).

1/21/2008 12:16:51 PM

Section 3 Lung

100

100

80

80 Percentage

Percentage

784

60 40 20 0

N 110

Median Death in months not reached 38

60 40 Median N Deaths in months 76 18 not reached

20 0

0

12

24

36

48

Months After Initial Registration FIGURE 62-3 Overall survival of all eligible patients with follow-up.

SWOG 8805 demonstrated the feasibility of surgery after two cycles of preoperative cisplatin and etoposide and RT (45 Gy) in patients with stage IIIA/B NSCLC.24 Resectability was 85% and 80%, and the 2-year survival rates were 27% and 24% for stage IIIA and stage IIIB patients, respectively. Subsequently, numerous phase I/II and retrospective studies have investigated various combinations of neoadjuvant chemotherapy and RT.25-36 These studies have demonstrated the safety and feasibility of this approach, although there is an indication of higher operative morbidity than without neoadjuvant treatment. Outcomes were variably reported, and the studies tended to focus on those patients who were resected, with less information regarding the outcomes of patients who were unable to have surgery. Response rates (CR plus partial response) to induction therapy ranged from 42% to 93%. Median survival time ranged from 11 to 52 months, and longterm OS was in the range of 11% to 56%. In general, good responses to neoadjuvant treatment (variously defined as CR, only microscopic residual disease, N2 nodes converted to negativity, and so on) were associated with significantly better outcomes (median survival time, 35-36 months; long-term OS, 48%-54%) compared with poor responses (median survival time, 11-14 months; long-term OS, 9%-24%). It appears from these data that many patients with CR or near-CR are cured. Their likely outcome with definitive chemoradiation without surgery is unknown. On the other hand, it appears that few poor responders are cured by surgery after induction therapy. A German phase III study of stage IIIA/B NSCLC randomized 558 patients to preoperative chemotherapy (cisplatin/etoposide) followed by concurrent hyperfractionated chemoradiation (45 Gy; 2 × 1.5 Gy/day with carboplatin and vindesine) or to preoperative cisplatin/etoposide alone. Patients on each arm proceeded to surgery.37 After surgery, patients in the induction/concurrent chemoradiation arm received postoperative RT only if they had less than an R1 or R2 resection, whereas all patients in the induction chemotherapy alone arm received postoperative RT. There were no survival differences (3-year survival rate, 24% versus 23%; P = .89). All the patients in this trial received RT either preoperatively or postoperatively. Therefore, this study is of

Ch062-F06861.indd 784

0

12

24

36

48

Months After Surgery Registration FIGURE 62-4 Overall survival after surgery for eligible patients with complete resection.

interest because it reports a large phase III cooperative group experience of patients treated with trimodality therapy for stage III disease. However, because patients on both arms received RT, this trial does not address the role of induction RT in the surgical setting. The Radiation Therapy Oncology Group (RTOG) 93-09 trial was a phase III randomized study designed to address the role of surgery in combined-modality therapy.5 Patients with T1-3, pN2, M0 (p meaning pathologic) tumors were eligible if resection was technically feasible at registration. A total of 429 randomized patients received induction with cisplatin and etoposide for two cycles and daily RT to 45 Gy starting day 1. Patients in Arm 1 then had a resection if there was no progression, followed by two more chemotherapy cycles. Patients in Arm 2 had uninterrupted RT to 61 Gy with two more cycles of chemotherapy. The results have been reported only in abstract form at this time. There were more early noncancer deaths in the surgery arm, and the OS curves crossed at the median (Arm 1, 22.1 months; Arm 2, 21.7 months). There was no difference in OS between arms (38% versus 33%; P = NS) (Fig. 62-5). More deaths occurred during treatment on Arm 1 (15 versus 4). Fourteen deaths occurred in patients who had a pneumonectomy, including 11 deaths among 29 patients undergoing right pneumonectomy. Progression-free survival was superior on Arm 1 (logrank P = .02); the median survival times were 14.0 versus 11.7 months, and the 3-year survival rates were 29% versus 19% (Fig. 62-6).5 These initial results raise the question of how to balance a greater number of early deaths against better outcomes in patients who survive beyond treatment. It is possible that better surgical technique can reduce operative morbidity and mortality and that centers with more experience with combined-modality therapy would have fewer treatment-related deaths. Patient selection is critical to the success of this trimodality strategy. Nearly all of the deaths in the operative arm were associated with pneumonectomy after induction chemoradiation. Patients who are candidates for a lobectomy might be expected to tolerate trimodality therapy better. The decision regarding resectability of tumors is highly individualized. In general, studies enroll patients with the best performance status and minimal

1/25/2008 3:35:50 PM

Chapter 62 Induction and Adjuvant Therapy for Operable Non–Small Cell Lung Cancer

100

Alive Without Progression (%)

Alive Without Progression (%)

100

785

Dead/Total 75

CT/RT/S 145/202 CT/RT 155/194

50

25

Failed/Total 75

CT/RT/S 159/202 CT/RT 172/194

50

25

Log rank P = .24 Hazard ratio = 0.87 (0.70, 1.10)

Log rank P = .017 Hazard ratio = 0.77 (0.62, 0.96) 0

0 0

12

24

36

48

60

Months From Randomization

0

12

24

36

48

60

Months From Randomization

FIGURE 62-5 Overall survival by treatment arm.

FIGURE 62-6 Progression-free survival by treatment arm.

weight loss. For these reasons, it is unclear how to generalize the results of this study to the care of average patients, both at tertiary referral centers and in the community. The RTOG and the SWOG initiated a multi-institutional trial testing induction chemotherapy versus induction chemoradiation therapy (RTOG 0412). The objective of this trial was to determine the benefit of adding induction RT to chemotherapy for patients with operable or marginally operable stage III (N2) NSCLC. Unfortunately, this trial closed prematurely due to poor accrual.

studies using this drug combination in patients with lung cancer have been conducted in Japan. A large meta-analysis of 14 trials that included 4357 patients, performed by the Non–Small Cell Lung Cancer Collaborative Group, reported a modest benefit to the use of cisplatin-containing regimens (HR, 0.87; P = .08) and an absolute benefit of 5% at 5 years from adjuvant therapy (Anonymous, 1995).51 These observations, along with the introduction of novel second-generation chemotherapy regimens and improved supportive care, have prompted re-evaluation of adjuvant chemotherapy by the cooperative groups in the United States and Europe. These large, prospective studies are discussed in detail here (Tables 62-2 and 62-3).

THE ROLE OF ADJUVANT THERAPY IN RESECTED NSCLC Adjuvant Chemotherapy Historical Perspective Adjuvant chemotherapy administered after surgical resection is a logical approach to eradicate micrometastatic disease and improve cure rates. However, several randomized studies conducted in the past 3 decades failed to reveal any significant survival advantage with adjuvant chemotherapy in patients with resected NSCLC.38-43 These studies had several problems, including small sample size, poor compliance, poor drug delivery, and excessive toxicities with rather ineffective antiemetics. It is not surprising that these studies uniformly reported disappointing results with adjuvant chemotherapy. The combination of uracil-tegafur (UFT) has been studied extensively in Japan as adjuvant therapy after resection of NSCLC.44-49 Tegafur is a prodrug that is converted to fluorouracil in the liver by the cytochrome P450 enzyme. Uracil increases the serum concentration of fluorouracil by inhibiting a key metabolic enzyme, dihydropyrimidine dehydrogenase. Although individual studies have reported conflicting results on the utility of this agent in the adjuvant setting, a recent meta-analysis of all published studies suggested a survival benefit with postoperative administration of UFT (5year OS HR, 0.77; 95% CI, 0.63-0.94; P = .011).50 UFT is not available in the United States, and all of the adjuvant

Ch062-F06861.indd 785

Recent Adjuvant Chemotherapy Studies Adjuvant Lung Project Italy. The Adjuvant Lung Project Italy (ALPI) study randomized 1209 patients with completely resected stage I-IIIA NSCLC to adjuvant chemotherapy or observation (Scagliotti et al, 2003).52 Those assigned to adjuvant chemotherapy received mitomycin (8 mg/m2 on day 1), vindesine (3 mg/m2 on days 1 and 8), and cisplatin (100 mg/m2 on day 1) every 3 weeks for three cycles. Adjuvant RT was allowed after the completion of chemotherapy or immediately after surgery for those assigned to observation. The investigators planned to accrue 1300 patients, to provide 80% power to detect a 20% relative reduction in overall mortality. This study, conducted from January 1994 to January 1999 in 71 institutions in Europe, was closed prematurely when it accrued only 1209 patients. The final data analyses were performed on only 1088 patients because of data integrity concerns from a single site that required the exclusion of almost 100 patients. The proportions of patients with stage I, II, and III disease were 39%, 33%, and 28%, respectively, in the final analyses. Most patients in this study were men. The most common histology was squamous cell carcinoma (50%), followed by adenocarcinoma (37%). Pneumonectomy was performed for 25% of the patients. Postoperative RT (50-54 Gy) was delivered to 43% of the

1/21/2008 12:16:52 PM

786

Section 3 Lung

TABLE 62-2 Summary of Prospective Adjuvant Chemotherapy Studies: Demographics Study

No. Patients

% Women

ALPI

1088

14

IALT

1867

% Stage I

% Stage II

% Stage III

38.5

32.5

29

19.5

36.4

24.2

39.4

JBR10

482

35

14.5

85.5

0

CALGB

344

34

100

0

0

ANITA

840

14

35

30

35

ALPI, Adjuvant Lung Project Italy; ANITA, Adjuvant Navelbine International Trialists Association Study; CALGB, Cancer and Leukemia Group B Study; IALT, International Adjuvant Lung Cancer Trial; JBR10, National Cancer Institute of Canada Adjuvant Study.

TABLE 62-3 Summary of Prospective Adjuvant Chemotherapy Studies: Outcome 5-Year Relapse-Free Survival (%)

5-Year Overall Survival (%)

Study

Chemotherapy Delivery (%)

Treatment

Observation

Treatment

Observation

ALPI

69

43

38

47

45

IALT

75

39

34

45

40

JBR10

48

60

49

70

55

CALGB

85

61

50

71

59

ANITA

Not reported

51

43

51

43

ALPI, Adjuvant Lung Project Italy; ANITA, Adjuvant Navelbine International Trialists Association Study; CALGB, Cancer and Leukemia Group B Study; IALT, International Adjuvant Lung Cancer Trial; JBR10, National Cancer Institute of Canada Adjuvant Study.

patients assigned to chemotherapy and 43% of those assigned to observation. Only 69% of patients completed the chemotherapy regimen, and half of those who completed three cycles required dose reduction or omission. There were three treatment-related deaths in the group of patients assigned to chemotherapy. The ALPI study did not show any improvement in median OS with the use of chemotherapy (55 months) compared with observation alone after resection (48 months; P = .0589). The numerically longer median progression-free survival with the use of chemotherapy (37 versus 29 months) was not statistically significant. The lack of any survival benefit seen in the ALPI study with the use of chemotherapy is probably due to the use of a toxic triple-drug regimen (seldom used in the United States in the treatment of lung cancer) and a substantially high level of postoperative RT. The International Adjuvant Lung Cancer Trial. The International Adjuvant Lung Cancer Trial (IALT) randomized patients with stage I-IIIA to observation or cisplatin-based chemotherapy (LeChevalier and Investigators, 2003).53 This study was designed to detect a 5% improvement in 5-year survival from 50% to 55% (α = .05, β = .83, two-sided), with an anticipated accrual goal of 3300 patients. This study also was terminated before completion of the planned enrollment in view of poor accrual early, which was attributed to increasing interest in neoadjuvant therapy. Etoposide was administered with cisplatin to 56% of the patients; others received vinorelbine, vinblastine, or vindesine in combination with cisplatin. Of the 1867 enrolled patients, 36% had stage I,

Ch062-F06861.indd 786

25% stage II, and 39% stage III NSCLC. With a median follow-up period of 56 months, the 5-year survival rate improved from 40% to 44% in the treated group (relative risk [RR], 0.83; 95% CI, 0.76-0.98; P < .03), and there was improvement in disease-free survival as well, from 34% to 39% (RR, 0.86; 95% CI, 0.74-0.94; P < .003). The treatmentrelated mortality was less than 0.8%. Postoperative RT was administered to 27.7% of the patients assigned to observation and 22.9% of those who received postoperative adjuvant chemotherapy. The modest improvement in survival after cisplatin-based adjuvant therapy is similar to what was seen in the large meta-analysis. Cancer and Leukemia Group B Study. The Cancer and Leukemia Study Group B (CALGB) randomized 344 patients with T2 N0 M0 NSCLC to either observation or four cycles of paclitaxel and carboplatin after complete resection.11 Adjuvant chemotherapy resulted in significant improvement in 4-year survival (59% versus 71%; P = .026), with a 38% RR reduction in mortality. Although 85% of patients received the planned four cycles of chemotherapy, only 55% received all four cycles of chemotherapy without dose reduction or delay. There were no treatment-related deaths. National Cancer Institute of Canada Adjuvant Study. A randomized phase III study from the National Cancer Institute of Canada, JBR10, studied the role of cisplatin and vinorelbine after resection of stage I-II NSCLC (stage IB, 45%; stage IIA, 15%; stage IIB, 40%) (Winton and Livingston, 2004).12 This study randomized 482 patients to adjuvant therapy with cisplatin (50 mg/m2 on days 1 and 8 every 4

1/21/2008 12:16:52 PM

Chapter 62 Induction and Adjuvant Therapy for Operable Non–Small Cell Lung Cancer

weeks for four cycles) and vinorelbine (25 mg/m2 weekly for 16 weeks) or to observation after surgery. Postoperative RT was not allowed in this study. Almost 20% of patients had pneumonectomy. More than half of the patients did not complete the planned four cycles of chemotherapy, and there were two treatment-related deaths. However, the study demonstrated a significant 15% absolute improvement in 5year survival with adjuvant cisplatin and vinorelbine (54% versus 69%; P = .012) after resection. Adjuvant Navelbine International Trialists Association Study. In an Adjuvant Navelbine International Trialists Association (ANITA) phase III study, 840 patients with completely resected stage I-IIIA NSCLC were randomized to four cycles of adjuvant chemotherapy or observation (Douillard, 2005).54 Patients receiving chemotherapy were treated with cisplatin (100 mg/m2 every 4 weeks for four cycles) and vinorelbine (30 mg/m2 weekly for 16 weeks). Postoperative RT was allowed in this study. Approximately 30% of patients had pneumonectomy. With very mature follow-up data (median, >70 months), the 5-year survival rate was significantly higher in the group assigned to receive chemotherapy (51% versus 43%). Even though a substantial number of patients had grade 3 or 4 neutropenia (86%), only 9% had febrile neutropenia. There were five deaths (1%) attributed to chemotherapy.

Adjuvant Radiation Therapy Postoperative RT is discussed for specific categories of resected disease, including patients with incomplete resections (close or positive margins), node-negative disease, positive hilar metastases (N1), and positive mediastinal metastases (N2). Postoperative RT has been advocated for positive or close surgical margins. Eradication of local cancer is a prerequisite for cure. As with any other tumor site, if surgical margins are

787

close or positive, postoperative RT is clearly indicated for improvement of local tumor control. The definitions of positive, close, and clear surgical margins are rather arbitrary. In general, if tumor cells are found at the surgical margins (usually inked), these are called positive surgical margins. If less than 0.5 cm of normal tissue is present adjacent to the tumor edge, the surgical margin is usually considered close; more than 1 cm of normal tissue is considered a clear surgical margin. Close or positive bronchial surgical resection margins can occur with peripherally located tumors, often attached to the chest wall, or with centrally located tumors. In these situations, a course of postoperative RT of 60 to 66 Gy in 2-Gy fractions is usually recommended. If, during thoracotomy, a complete and thorough resection of mediastinal nodes is performed and all nodes are negative, the course of postoperative RT for positive or close surgical margins can be directed only to a small volume related to the primary tumor. We have not treated the lymph-bearing areas prophylactically in this situation. A great deal of controversy exists regarding the role of postoperative adjuvant therapy for patients with resected N1 or N2 disease. The rationale for adjuvant RT or chemotherapy, or both, stems from data reporting patterns of failure after resection alone (Table 62-4). In general, the rate of systemic failure is double that of local failure. Numerous retrospective institutional reports have been published on the potential benefits of postoperative adjuvant RT or chemotherapy and RT.55-61 Supporting data from controlled prospective randomized trials proving its efficacy are few. There have been many randomized trials comparing surgery with or without adjuvant RT.55,59,62-67 None has shown a survival advantage in favor of RT, although selected studies have demonstrated improvements in local control.65,67 The prospective trials comparing surgery with or without postoperative RT span the past 50 years and include hypofractionated regimens, orthovoltage, and cobalt 60 therapies.

TABLE 62-4 Pattern of Failure After Surgery for Lung Cancer Author/Study (Year)

Tumor Stage

Kotlyarov and Rukosuyev72 (1991)

All

Martini and Beattie73 (1977)

T1-2 N0 T1-2 N0 T1-2 N1

Immerman et al

74

(1981)

No. Patients

Local Failure (%)

Distant Failure (%)

542

12

18

110

0

18

77 22

12 41

27 23

Pairolero et al75 (1984)

T1 N0 T2 N0 T1 N1

170 158 18

6 28 9

15 23 39

Feld et al76 (1984)

T1 N0 T1 N1 T2 N0

162 32 196

9 11 20

17 22 30

Lung Cancer Study Group77 (1986)

N1-2

108

20

30

Ludwig Lung Cancer Study Group78 (1987)

T1-2 N0-1

1012

17

22

Medical Research Council Lung Cancer Working Party79 (1996)

T1-2 N1-2

154

47

67

The Groupe d’Etude et de Traitemant des Cancers Bronchiques80 (1999)

T1-3 N0-2

355

28

26

Ch062-F06861.indd 787

1/21/2008 12:16:52 PM

788

Section 3 Lung

Data for patients with node-negative disease come from a randomized trial. Van Houtte and colleagues66 reported that postoperative RT after resection of node-negative T1-3 primary tumors reduced the locoregional recurrence rates from 18% to 13%. However, irradiated patients experienced shorter survival times as a result of late toxicity. Problems with RT technique in this study include the use of 60Co, large field sizes, and the lack of computed tomography–based treatment planning capability. Recommending postoperative RT for surgically resected primary tumors with negative surgical margins and positive mediastinal nodes is less controversial. The LCSG conducted a randomized study to evaluate postoperative RT in patients with completely resected stage II-IIIA squamous cell carcinoma of the lung.67 Only patients with hilar (N1) or mediastinal (N2) lymph node metastasis were included in the study. Patients on the adjuvant radiation arm were administered 50 Gy over 5 weeks. No difference in OS was detected. However, patients receiving RT had reduced local recurrence rates, especially those with N2 disease. There were four significant fallacies in the design and conduct of this study: only squamous cell carcinoma was included; 11% of the patients had no regional node metastasis and therefore would not have been advised to have postoperative RT; only 74% of those assigned to postoperative RT received within 5% of the total dose prescribed; and no other comments were made about the adequacy of the irradiation volume. The British Medical Research Council (MRC) conducted a randomized trial for patients with completely resected T12 N1-2 M0 tumors.65 Patients randomized to the radiation arm received 40 Gy in 15 fractions, although 10% did not initiate such therapy. Results were reported by intention to treat. No survival advantage was seen for either group. However, adjuvant RT reduced local recurrences and the development of distant metastases, specifically bone metastases. On subgroup analysis, patients with N2 disease experienced less local recurrences, less distant metastases, and prolonged survival with the addition of RT. Patients with N1 disease did not benefit from RT. There are widely publicized reports of the detrimental effects of RT for patients with resected lung cancers. A prospective, multicenter randomized trial from Europe comparing postoperative RT versus observation for patients with stages I, II, and III lung cancer showed excessive mortality in the treated group.62 Patients received 60 Gy in 6 weeks. The first 40 Gy was delivered in fractions of 2.5 Gy; this was followed by a 20-Gy boost after a 2-week interruption. Field arrangements consisted of anteroposterior/posterior administration, initially followed by an opposed oblique pair. Computerized dosimetry was recommended but not required. Intercurrent deaths were attributed to excess respiratory and cardiac complications. In a recent meta-analysis reported by the Postoperative Radiotherapy (PORT) Meta-analysis Trialists Group,68 postoperative RT resulted in a decrement in survival for patients with resected N0, N1, and N2 disease. A total 2128 patients from nine trials were included. Subgroup analysis limited the adverse effects to patients with N0 or N1 disease. There are many criticisms of this trial, mostly relating to the beam energies and technique of RT from a

Ch062-F06861.indd 788

prior era. Although these data may not apply to modern RT techniques, they are further evidence that patients with resected N0 or N1 disease should not routinely receive RT. Megavoltage energies, conventional fraction sizes, and imagebased treatment planning must be applied carefully to selected patients to minimize late complications.

Adjuvant Chemotherapy and Radiation Therapy for NSCLC The previously discussed trials demonstrating a survival advantage favoring adjuvant chemotherapy after resection have rekindled interest in adjuvant chemotherapy and RT combinations. If adjuvant RT is recommended, the question of sequential or concurrent chemoradiation approaches remains unsettled. An Intergroup trial (ECOG 3590) randomized 488 patients with completely resected stage II (T12 N1 M0) or stage IIIA (T1-2 N2 M0 or T3 N1-2 M0) NSCLC to adjuvant RT with or without concomitant cisplatin and etoposide.40 The intrathoracic recurrence rate was not affected by the addition of chemotherapy (12% versus 13%, respectively), nor was there a difference in survival between the arms. Adverse side effects were more frequent in the chemoradiation therapy arm. The RTOG conducted a phase II trial (RTOG 9705) that tested adjuvant carboplatin and paclitaxel with concomitant RT for patients with resected stage II or IIIA disease.69 The median survival time was 56.3 months, and the 3-year survival rate was 61%, comparing favorably with results from the chemoradiation therapy arm of ECOG 3590. Toxicity was acceptable. Randomized trials are needed to determine the optimal sequence of chemotherapy and RT in the adjuvant setting. The CALGB study that randomized patients with resected stage IIIA disease to observation or thoracic RT after four cycles of adjuvant chemotherapy was discontinued because of poor accrual.

Practical Issues in the Adjuvant Therapy of Resected NSCLC The prospective studies mentioned earlier mandated enrollment within 2 months after curative surgery, and only of patients with good performance status. We do not advocate the use of adjuvant chemotherapy for patients who have poor performance status or unresolved postoperative complications at 2 months after surgical resection. Cisplatin-based doublets were studied in all the adjuvant chemotherapy trials mentioned earlier with the exception of the CALGB study that included only patients with stage IB disease. Carboplatin-containing doublets are more commonly used in the United States in patients with advanced NSCLC, compared with cisplatin-containing doublets. A prospective study demonstrated superiority of a cisplatin-containing regimen over a carboplatin-containing regimen in advanced NSCLC70; this difference was considered relatively insignificant in advanced NSCLC and has not changed the practice pattern in the United States. However, it remains to be seen whether carboplatin-containing regimens can consistently produce results similar to those of cisplatin-containing regimens in the setting of adjuvant therapy in early-stage NSCLC.

1/21/2008 12:16:52 PM

Chapter 62 Induction and Adjuvant Therapy for Operable Non–Small Cell Lung Cancer

The cisplatin and vinorelbine doublet is the best studied regimen in this setting. Based on the prospective studies, it is reasonable to offer three to four cycles of adjuvant chemotherapy with a cisplatin-containing regimen for patients who have recovered within 2 months after surgery and have a good performance status.

789

trials. Less than rigorous standards were employed for the surgical staging of mediastinal nodes. Therefore, we can be less than certain of the pathologic stage of many of the seemingly early-stage patients entered into these trials. G. A. P.

KEY REFERENCES

FUTURE DIRECTIONS There are no reliable clinical or molecular predictors of relapse in patients with resected NSCLC. Several approaches, including genomic and proteomic approaches, are being considered to identify those at high risk for relapse. Despite the use of adjuvant chemotherapy, 40% to 50% of patients with stage I-II disease eventually die from recurrent NSCLC. Clearly, novel approaches are required. The addition of bevacizumab, a monoclonal antibody directed against the vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improved response rates, time to disease progression, and OS in patients with advanced NSCLC.71 This promising study has led to the development of a North American Intergroup study incorporating bevacizumab in the adjuvant setting along with platinum-based chemotherapy.

COMMENTS AND CONTROVERSIES The results of surgical resection alone for early-stage NSCLC are suboptimal, and for more advanced (stage II-III) disease they are poor. Most patients die of locally recurrent or distant metastatic disease; hence, the great interest in the application of chemotherapy and/or RT in the induction or adjuvant postresection setting. Drs. Govindan and Bradley outline the results of available trials—some conclusive, some not. They give a balanced appraisal, based on years of experience, of the strengths and weaknesses of each trial and the evidence-based application of adjuvant and induction therapies stage for stage. In some areas, progress has clearly been made. For example, it is clear that good-performance status patients with stage IB or stage II completely resected lesions derive survival benefit from postoperative adjuvant chemotherapy. The difference is not great, but it is statistically significant. In addition, it seems clear that patients with resectable superior sulcus tumors benefit from induction chemotherapy and RT. However, the benefit of this strategy for patients with N2 disease, widely applied in clinical practice, is not clear, especially if there is a poor response. It is incumbent on thoracic surgeons to be critically aware of the strengths and weaknesses of various trials that advocate or criticize the use of adjuvant or induction therapy. For example, recent studies used to justify the routine administration of adjuvant chemotherapy to patients with completely resected stage IB and II lung cancer call into question the accuracy of staging in patients entered into these

Albain K, Swann R, Rusch V, et al: Phase III study of concurrent chemotherapy and radiation therapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol (Proc ASCO) 2005, A7014. Anonymous: Chemotherapy in non-small cell lung cancer: A metaanalysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group (see comments). BMJ 311:899-909, 1995. Douillard JY: Adjuvant chemotherapy for non-small cell lung cancer: Which agents for which patients? Rev Mal Respir 8S:118-123, 2005. Le Chevalier T, Investigators FtI: Results of the Randomized International Adjuvant Lung Cancer Trial (IALT): Cisplatin based chemotherapy vs no chemotherapy in 1867 patients with resected non-small cell lung cancer. J Clin Oncol (Proc ASCO) 22:2, 2003. Rosell R, Gomez-Codina J, Camps C, et al: Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: A 7-year assessment of a randomized controlled trial. Lung Cancer 26:7-14, 1999. Rosell R, Gomez-Codina J, Camps C, et al: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 330:153-158, 1994. Roth JA, Atkinson EN, Fossella F, et al: Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 21:1-6, 1998. Roth JA, Fossella F, Komaki R, et al: A randomized trial comparing preoperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst 86:673680, 1994. Rusch VW, Giroux DJ, Kraut MJ, et al: Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 121:472-483, 2001. Scagliotti GV, Fossati R, Torri V, et al: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small cell lung cancer. J Natl Cancer Inst 95:1453-1461, 2003. Strauss G, Herndon J: Randomized clinical trial of adjuvant paclitaxel and carboplatin following resection of stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. J Clin Oncol 22:621s, 2004. Winton T, Livingston R: A prospective randomized trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage IB and II non small cell lung cancer (NSCLC): Intergroup JBR.10. J Clin Oncol 22:621s, 2004.

tahir99-VRG vip.persianss.ir

Ch062-F06861.indd 789

1/21/2008 12:16:52 PM

chapter

63

POSTRESECTION FOLLOW-UP FOR NON–SMALL CELL LUNG CANCER Joe B. Putnam, Jr.

The need for postresection follow-up and improved postresection screening for recurrence is evident in the limited survival found after primary treatment of primary non–small cell lung carcinoma (NSCLC). Lung cancer is a significant public health problem in the United States and the world. Despite optimal resection, 5-year survival for stage I NSCLC is 57% to 80%, and for stage II disease it is 45%.1-4 In patients with mediastinal (N2) lymph node metastasis (stage IIIA), the 5-year survival may be only 20% even with aggressive treatment (Table 63-1). Although local and systemic interventions may improve survival after primary therapy in these patients, additional survival advantage from treatment of recurrent disease or from treatment of a second primary is less clear.5 Molecular changes that predispose to the development of lung cancer may provide strategies for chemoprevention or other treatments directed at genetic alterations in the cancer itself. Currently, numerous prospective protocols are ongoing in an attempt to better understand and evaluate various combinations of multidisciplinary treatments. Postresection follow-up of a thoracic malignancy requires a careful balance of clinical examination, diagnostic imaging examination, and cost-effectiveness. After resection for earlystage lung cancer, second lung cancers develop at a rate of 2% to 5% per year.6,7 The clinician must evaluate those factors that will provide for the patient and the health care system an advantage, in health and cost, for those services provided. For that reason, multiple scans to identify early recurrence or metastasis may not be consistently effective and may yield false-positive examinations requiring further costly evaluation or surgical intervention. The optimal postresection follow-up protocol has not been defined, and this is complicated by other medical and social needs of the patient and the patient’s family. A balance of specialty care from the thoracic surgeon and general medical care by the patient’s regular physician appears to optimize the specific needs of the patient after resection of lung cancer. Postresection follow-up of the patient begins in the immediate postoperative period with the patient’s normal convalescence from surgery. The in-hospital recovery phase, including the first 30 days after surgery, is usually considered the early follow-up period from which surgical morbidity and mortality (defined as ≥30 days after resection, or <30 days if the patient has been continuously in hospital) are calculated. Routine follow-up usually begins about 1 month after discharge (5-6 weeks after the date of surgery). New symptoms or sequelae of early events related to the operation, or those noted during the in-hospital convalescence, are evaluated and treated. Typically, the first postresection follow-up visit

includes an interim history, a physical examination, and a baseline chest radiograph (posteroanterior and lateral). The following is a discussion of the various options available to the physician and the patient for postresection follow-up after resection of thoracic malignancy and the value of such follow-up.

THE NEED FOR POSTRESECTION FOLLOW-UP Postresection follow-up not only benefits the patient but also assists the thoracic surgeon in evaluating the benefits as well as the disadvantages of a particular operation. With followup, the surgeon can determine the value of a specific operation and evaluate the need for changes or modifications in the operation. This process of continuous self-education and improvement (by the thoracic surgeon’s personal evaluation of his or her patients) is critical to the specialty of thoracic surgery and thoracic surgical oncology. Although larger multiinstitutional studies may be required to prove the advantage of one operation over another, for the individual surgeon, close follow-up provides immediate feedback on the relative value of specific operations. For example, resection for lung cancer should consist of anatomic resections such as lobectomy and mediastinal lymph node dissection. The value of lobectomy over a more limited resection (wedge resection or segmentectomy) was shown by a prospective study performed by the Lung Cancer Study Group, which evaluated lobectomy or limited resection with mediastinal lymph node dissection in patients with stage T1 N0 lung cancer. Patients with lesser resections tended to have a greater number of local recurrences (which were not second primary cancers), more second primary cancers (P = .079), more frequent locoregional metastases, and a trend (P = .094) toward increased likelihood of death from cancer. The study validated the concept of lobectomy as the procedure of choice in patients with lung cancer.8 Frequently, tumors occur in the lung after resection of primary lung cancer. This recurrence may be a second primary lung cancer, a local recurrence, or metastatic disease to the lung. In the presence of limited disease, a physiologically fit patient, and a clinical stage I or II tumor, resection may be considered. If it is detected early, these patients may be subsequently cured of their recurrent lung cancer. The location of recurrent disease may be modified by radiation therapy or surgery techniques. Recurrence patterns may vary depending on the treatment provided. In the North American Intergroup Trial 3590, postoperative adjuvant therapy was given to patients with completely resected stages II and IIIA NSCLC. The patients had concomitant adjuvant

790 tahir99-VRG vip.persianss.ir

Ch063-F06861.indd 790

1/21/2008 1:15:40 PM

Chapter 63 Postresection Follow-up for Non–Small Cell Lung Cancer

TABLE 63-1 Postresection Survival in Patients With Primary Non–Small Cell Lung Cancer

791

TABLE 63-2 Signs and Symptoms of Local Recurrence

Mountain2 (1997)

Naruke3 (1988)

Subset

No. Patients

% 5-Year Survival

No. Patients

% 5-Year Survival

T1 N0 M0

511

67

245

75.5

T2 N0 M0

549

57

241

57.0

T1 N1 M0

76

55

66

52.5

T2 N1 M0

288

39

153

40.0

T2 N0 M0

87

38

106

33.3

T3 N1 M0

55

25

85

39.0

Any N2 M0

344

23

368

15.1

TNM

therapy with four cycles of cisplatin plus radiotherapy over radiotherapy alone. Sites of intrathoracic recurrences were similar in both groups: 42% in the combination arm and 49% in the radiotherapy arm.

Second Primary Lung Cancer After curative (R0) resection with pathologically negative margins and no involved lymph nodes, a new lesion in the lung may well represent a second primary tumor, which may occur at any time in the patient’s postresection course. Generally, when the same histology occurs within a 2-year period, this is classified as a metastasis. Still, resection is frequently offered to these patients, because a second primary tumor cannot be absolutely excluded. When doubt exists, the benefit is given to the patient and the patient is treated for the most favorable stage of the disease, that is, early-stage second primary lung cancer. Histologic diagnosis and appropriate clinical staging are critical in the planning of subsequent treatment. Second primary tumors have been defined as follows: 1. A different histologic cell type 2. A tumor-free interval of 24 months 3. Location in the contralateral lung, or a new tumor in a separate and distinct ipsilateral lobe for tumors within the same thorax In a study from Memorial Sloan-Kettering, the cases of 118 patients who had survived 10 or more years were reviewed. Second primary lung cancers developed in 16% (19/118) of patients between 6 and 22 years after resection. Thirteen of these had a different histology.9 The results of treatment of these tumors were recently reviewed. This study evaluated second thoracotomy in 114 patients with second primary tumors of the lung. Eighteen patients underwent thoracotomy for a third primary lung cancer. Of 132 thoracotomies, a conservative resection was emphasized to minimize postoperative complications reflected in the 73 sequential resections performed. Operative mortality was 8.8% (10/114) for second primary tumors and 5.5% for those undergoing a third resection. Cumulative survival rates for 114 patients with

Chest pain—localized or pleuritic

Pleural effusion

Thoracic rib or vertebral/ back pain

Phrenic nerve paralysis

Cough

Superior vena cava obstruction

Hoarseness

Weight loss

Horner’s syndrome

Anorexia

Dysphagia

Fatigue Decreased performance status

metachronous tumors were 33% at 5 years and 20% at 10 years. The authors recommend early detection and resection as a means of enhancing survival.10

ROUTINE FOLLOW-UP: AN EVOLVING PROCESS The thoracic surgeon requires a simple, consistent, and costeffective method of evaluating the patient. Various outcomes must be identified and catalogued. Although the patient’s regular physician can conduct routine health care, the thoracic surgeon’s knowledge of various oncologic and physiologic variables after resection and the myriad presentations of normal and abnormal events are critical to the patient’s health and well-being. Each follow-up visit should include discussion with the patient as to his or her general health and whether problems exist. Follow-up to these questions by the discerning physician may elicit symptoms of early local or regional recurrence or, potentially, the presence of metastatic disease. The patient may also describe other problems related to the surgery or other new medical problems. These problems should be evaluated further by the surgeon and communicated appropriately to the patient’s primary or referring physician. The signs and symptoms of local recurrence are shown in Table 63-2. Evaluation of the patient’s physical condition includes a physical examination, with note taken of changes in weight and changes in performance status. The history should include the onset or persistence of specific symptoms and the presence or occurrence of late events. Other evaluation for a new primary tumor, or for recurrent disease, typically includes a screening chest radiograph that should be reviewed by the surgeon. Often the surgeon has clinical information, personally obtained, that may not be available to the radiologist interpreting the films. Most commonly, patients have stopped smoking over the months after the re-resection of a thoracic neoplasm. If this has not occurred, aids to this smoking cessation, including smoking cessation clinics and counseling, biofeedback, nicotine patches, nicotine gum, pharmaceuticals, and physician counseling, should be offered. Symptoms of local recurrence are shown in Table 63-2. Nonspecific symptoms such as anorexia, malaise, fatigue, and weight loss may occur in up to 70% of patients. Paraneoplas-

tahir99-VRG vip.persianss.ir

Ch063-F06861.indd 791

1/21/2008 1:15:40 PM

792

Section 3 Lung

tic syndromes are distant manifestations of lung cancer (not metastases) as revealed in extrathoracic nonmetastatic symptoms (Table 63-3). Lung cancer affects these extrathoracic sites by producing one or more biologic or biochemical substances. These various effects are grouped into paraneoplastic syndromes.

be evident only after review of two or three sequential chest radiographs; however, the abnormality may not be identified within the most recent films. If abnormalities are identified, the patient may require further evaluation directed by the patient’s history, physical examination, signs and symptoms, or other findings.

PHYSICAL EXAMINATION AND ROUTINE RADIOGRAPHIC STUDIES

SCREENING STUDIES

Physical Examination

The value of routine screening studies beyond chest radiography is not known, but they do not appear to be helpful, nor do they contribute to the patient’s overall care. Falsepositive findings are occasionally found and may be a source of significant anxiety to the patient and to the family. Still, various screening studies are being developed in an attempt to identify recurrent disease that may be more effectively treated, with improved survival. Investigations by other screening modalities for patients at high risk for lung cancer may be of even greater benefit for patients after resection of lung cancer. Initial favorable reports on CT screening for patients at high risk for lung cancer have suggested a significant cost benefit. Patients with previous lung cancer are at the most increased risk for developing a second lung cancer. Use of CT in patients after pulmonary resection of lung cancer may be effective in identifying recurrences at an earlier (and potentially curable) stage of disease, but this requires further study. Spiral CT scanning is a technique that allows a lowresolution image of the entire thorax to be obtained during a single breath-hold with low radiation exposure. Various centers throughout the world are now involved in evaluating large numbers of patients with screening CT. The purpose of screening CT is to increase the frequency of curable lung cancer. A criticism of screening CT is that small benign nodules are identified with increasing frequency. These observations may result in increased numbers of surgical procedures for benign disease, increased cost of care, and complications as a result of this care. Patients involved in such a screening program after curative therapy should continue to be evaluated by traditional methods for comparison purposes to assess the value of these studies for improved survival, reduced recurrence rate, and improved health. An evaluation of 1500 patients with no prior diagnosis of lung cancer but at high risk (<50 years of age, smoking history of 20 or more pack-years, and no prior cancer within the past 5 years [except skin, localized prostate cancer, or cervical carcinoma in situ]) is being conducted by physicians at the Mayo Clinic. They are evaluating the possibility of detecting 75% or more of lung cancers while they are at stage I.11,12

A limited physical examination with specific attention to the cervical and supraclavicular nodal beds may demonstrate the presence of metastatic disease in these lymph nodes. Additional examination of the surgical wound for healing or local recurrence, as well as those areas influenced or changed by the operation, should also be performed.

Chest Radiography The standard chest radiograph and computed tomography (CT) of the chest and upper abdomen (including the adrenals) are the most frequent diagnostic imaging studies performed in patients with lung cancer. Routinely, a plain chest radiograph is obtained at the first postoperative visit and at every visit thereafter. The purpose of this chest radiograph is to serve as a baseline for future changes within the chest. With the plain posteroanterior and lateral chest radiographs the surgeon can evaluate the postoperative appearance and can assess for local, regional, or metastatic disease. After the first visit, chest radiographs are reviewed as serial films in time order (e.g., 2000, 2001, 2002, and so on). This serial comparison may enable detection of subtle changes that may

TABLE 63-3 Manifestations of Extrathoracic Paraneoplastic Syndromes General Fatigue Malaise Other constitutional symptoms Endocrine Cushing’s syndrome Inappropriate antidiuretic hormone secretion (hyponatremia) Carcinoid syndrome Hypercalcemia Hypoglycemia Skeletal Clubbing Hypertrophic pulmonary osteoarthropathy Neuromuscular (more common with small cell lung carcinoma) Polymyositis Eaton-Lambert syndrome (myasthenia-like syndrome) Peripheral neuropathy Subacute cerebellar degeneration Encephalopathy Vascular Vascular thrombophlebitis Thrombosis

Serial Computed Tomography of the Chest

Sputum Cytology In the absence of smoking, most patients do not produce sputum. In the postresection follow-up period with the absence of spontaneous sputum production or hemoptysis, induced sputum cytologic studies are frequently negative and are not cost efficient. Sputum cytology may yield a diagnosis if the patient is a poor operative risk or has symptoms suggestive of cancer or

tahir99-VRG vip.persianss.ir

Ch063-F06861.indd 792

1/21/2008 1:15:40 PM

Chapter 63 Postresection Follow-up for Non–Small Cell Lung Cancer

if a transthoracic needle biopsy may cause increased risk. A fine-needle aspiration via a transthoracic route may be approximately 95% accurate in patients with a poor operative risk, or it may be used to obtain a biopsy before definitive therapy. Screening of patients at high risk of lung cancer by sputum cytology does not consistently provide a sensitive examination for the presence of small resectable lung cancer.

METASTATIC DISEASE FROM PRIMARY LUNG CANCER Metastatic disease is common after curative resection of lung cancer and may occur in up to two thirds of patients.1 Most patients with recurrent or metastatic disease have symptoms; only a minority are identified with asymptomatic recurrence. Even fewer patients with asymptomatic recurrence have isolated localized recurrence amenable to resection. Criteria for nonresectability are presented in Table 63-4. If neurologic problems, jaundice, or other suspected signs or symptoms of metastatic disease are present, the patient should be screened for the presence of metastatic disease in all areas. Typically, this screening consists of bone scintigraphy, CT of the abdomen and the chest, and a CT evaluation or magnetic resonance imaging (MRI) of the brain. More recently, these scans have been suggested as a means of postresection follow-up for individuals having prior radiation therapy or those in whom an infectious process or other process cannot be completely excluded. Surgical resection of metastasis from lung cancer generally is a curiosity, although many patients with resectable brain

TABLE 63-4 General Criteria for Nonresectability Recurrent laryngeal nerve paralysis Superior vena cava syndrome Involvement of main pulmonary artery Contralateral or supraclavicular node involvement

793

metastases do quite well. After excision, patients with a solitary brain metastasis may have up to a 15% five-year survival.13

POSTRESECTION FOLLOW-UP GUIDELINES In general, the routine visits to the thoracic surgeon should be straightforward, simple, and consistent. The postresection follow-up guidelines suggested by the University of Texas M.D. Anderson Cancer Center are shown in Table 63-5. The frequency of the postoperative follow-up depends on the extent of the resection and whether the resection was complete or incomplete. An incomplete resection may be defined as R1 (microscopic) or R2 (gross tumor). If all identifiable disease, including lymph nodes, is completely resected, then the extent of resection may be defined as complete (R0). An incomplete resection leaves a positive margin, which predisposes to earlier local, or locoregional, recurrence. These patients may have received adjuvant therapy to decrease local or locoregional recurrence, to prevent worsening systemic metastasis, or to improve quality of life. Follow-up for early-stage lung cancer (stages I and II) includes a history, a limited regional physical examination, and screening chest radiography (after baseline) every 6 months for 2 years and then yearly thereafter. For later-stage lung cancer that has been resected, these patients are often on a clinical protocol that prescribes the required follow-up period—usually every 3 or 4 months with a chest radiograph and blood work for the first 2 years, every 6 months for the next 3 years, and every year thereafter. These recommendations have been incorporated into the guidelines of care for patients with lung cancer as published by the University of Texas M.D. Anderson Cancer Center (see Table 63-5). A recent comparison was made between postresection follow-up guidelines developed by the National Comprehensive Cancer Network (NCCN) and those developed by the American Society of Clinical Oncology (ASCO).14 The premise of the author’s paper was that guidelines would be reproducible if “two groups of experts, presented with the same evidence and methods, derive a similar set of recommendations.” The authors point out that current medical

Ipsilateral mediastinal nodes if high (2R) Malignant (or bloody) pleural effusion Malignant pericardial effusion Phrenic nerve paralysis (relative contraindication) Extrathoracic metastatic disease typically involving the brain, bone, adrenals, or liver Involvement of trachea, heart, great vessel Insufficient pulmonary reserve Tracheoesophageal fistula Other signs may suggest a more advanced tumor Chest wall pain Horner’s syndrome Compression of the splanchnic nerve with unilateral ptosis, miosis, anhidrosis, and enophthalmos Esophageal compression with dysphagia from extrinsic compression from enlarged subcarinal lymph nodes

TABLE 63-5 Surveillance for Non–Small Cell Lung Cancer After Resection Stage I and II Postoperative visits every 6 months for 2 years, then annually. Chest radiograph annually. Stage III History and physical examination, chest radiograph, and laboratory tests every 3 months for 2 years, then every 6 months for 3 years, and then annually. Chest radiograph with each visit. Stage IV (not on treatment or in-home hospice) History and physical examinations, chest radiograph, complete blood cell count, and other tests as clinically indicated every 2-3 months. From the postresection follow-up guidelines as suggested by The University of Texas M.D. Anderson Cancer Center (Houston) for non–small cell lung cancer.

tahir99-VRG vip.persianss.ir

Ch063-F06861.indd 793

1/21/2008 1:15:40 PM

794

Section 3 Lung

knowledge is incomplete and cannot provide the hard data on which to base recommendations. The role of expert opinion may be to fill the gap where hard evidence is not available. Combinations of medical care, clinical need, patient demands, medicolegal responsibilities, general health care issues, family concerns, and cost effectiveness must all be weighed during the physician’s care of the patient. A mathematical model complex enough to solve this multivariable equation would require data from a large number of patients, objectively defined, prospectively collected, and analyzed in a valid manner. Unfortunately, these data do not exist. Therefore, comparison of guidelines may be considered an appropriate alternative. The National Comprehensive Cancer Network recommended monitoring including a history and physical examination every 4 months for the first 2 years and then every 6 months for the next 3 years. A chest radiograph would be obtained at each visit during this period generally, and annual chest radiographs would be obtained thereafter. This panel did not recommend any additional scans. The American Society of Clinical Oncology panel recommended a history and physical examination every 3 months for the first 2 years and then every 6 months for the next 3 years. A chest radiograph was recommended on an annual basis. The guidelines proposed by ASCO recommended fewer chest radiographs. Neither group recommended screening CT of chest or abdomen, nor MRI brain imaging, as part of the surveillance program.

ing for second primary tumors (either aerodigestive tract or other) in patients with completely resected early-stage disease was suggested. Thirty-five patients developed 36 new malignancies. About half of these patients had aerodigestive tract cancers. Of all patients in the study, 80 of 358 patients had additional primary malignancies either before or after the index pulmonary resection for cancer. Physical examination detected a recurrence in only 2 of 33 asymptomatic patients. The charge associated with curative treatment was $1256/ month, compared with $859/month for palliative care. Median survival was 27.7 months for patients treated with curative intent and 18.3 months for patients treated with palliative intent (P = .03). This study suggests that follow-up of patients with pulmonary resection may not be a costeffective clinical practice given the end points of survival and identification of recurrent disease; still, other outcomes of care were not measured. In addition, the financial impact of identification and management of new or concurrent medical problems, the improvement in our understanding of the biology of lung cancer or the effectiveness of certain treatments, and the evaluation of the effectiveness of specific operations cannot be quantified. A nonrandomized comparison of intensive versus symptomrelated follow-up in patients with NSCLC did not identify a significant difference in median survival after diagnosis of recurrent disease (7.9 versus 6.6 months, respectively).16

EVALUATION OF EFFECTIVENESS OF POSTOPERATIVE FOLLOW-UP

No generally accepted blood study or molecular characteristic is being routinely used to diagnose a patient’s recurrent tumor or metastasis, although various serum and molecular characteristics exist that are negatively associated with survival. Postresection survival may be modified by specific molecular characteristics of the patient’s individual tumor. Although clinical stage and lymph node status are strong predictors of survival, other clinical and cancer-related factors are associated with poorer stage-for-stage outcome; these include male gender, weight loss, decreased performance status, and increased age. Adenocarcinoma tends to have a poorer survival than squamous cell carcinoma. Molecular alterations in lung cancer include increased expression of specific oncogenes (upregulation of MYC, RAS, C-ERB, and BCL-2) and decreased expression of specific tumor suppressor genes (e.g., downregulation of TP53, RB). Kwiatkowski evaluated 244 resected stage I tumors and noted that predictors of diminished (poor) cancer-free survival included age older than 60, male gender, limited resection of lung (wedge resection), large tumor size (>4 cm), adenocarcinoma with mucin subtype, lymphatic invasion, KRAS mutation, TP53 expression, and lack of HRAS expression.17 D’Amico and associates18 evaluated 408 early (stage I) lung cancers with immunohistochemical staining of 10 common molecular markers. Markers associated with increased risk of recurrence and death include TP53 (associated with apoptosis), factor VIII (angiogenesis), ERB-B2 (growth regulation), CD44 (adhesion), and radiation bronchitis (cell cycle regulation). In other studies evaluating stage

Guidelines for the appropriate follow-up of lung cancer patients after surgery have been proposed; however, few studies exist in which the value of this follow-up has been evaluated. In a retrospective study of 358 patients undergoing complete resection of lung cancer, recurrence, secondary primary, and survival were studied.15 Median follow-up was 76 months. The authors found that recurrences developed in 135 patients—local only in 32, distant only in 90, and local and distant in 13. Most patients (n = 102) were symptomatic, and only 33 were asymptomatic. New primary tumors developed in 35 patients. Asymptomatic diagnosis was most commonly made by chest radiography. Ninety-five patients were treated palliatively, and only 40 were treated with curative intent with radiation or surgery. Surprisingly, median survival from time of recurrence was 8 months for symptomatic patients and 16 months for asymptomatic patients. Multivariate analysis revealed that longer disease-free interval (<12 months) was the most favorable predictor of survival. The authors concluded that although a lead-time bias was noted, survival was not significantly affected by early detection of lung cancer. In addition, they concluded that frequent follow-up and radiologic evaluations may be unnecessary. Problems with this study include the retrospective nature of the analysis and the exclusion of patients with incomplete resection, superior sulcus tumors, mixed tumor histology, or follow-up outside of the home institution. A role for screen-

MOLECULAR PREDICTORS OF RECURRENCE AND SURVIVAL

tahir99-VRG vip.persianss.ir

Ch063-F06861.indd 794

1/21/2008 1:15:40 PM

Chapter 63 Postresection Follow-up for Non–Small Cell Lung Cancer

I lung cancer tumors from patients with histologically negative lymph nodes, early relapse and decreased survival could be predicted by immunostaining techniques for TP53 protein19 and for cytokeratin.20 Molecular assays may be more advantageous and more sensitive than immunostaining techniques in predicting postresection survival or recurrence. TP53 mutations, KRAS mutations, CDKN2A methylation, and microsatellite markers in tumor cells were found by molecular techniques in 53% of patients who underwent bronchoalveolar lavage at the time of surgical resection. Sputum cytology is not a sensitive test for occult lung cancer; however, DNA biomarkers may indicate premalignant changes.21-24

SUMMARY Follow-up after resection for lung cancer should be directed toward identifying those patients with recurrent disease in the earliest stage possible, in the most cost-efficient manner possible. The techniques of low-dose spiral CT of the chest and molecular markers either in primary lung cancer or in sputum cytology specimens may prove to be more efficient and sensitive means of identifying recurrent lung cancer than the more traditional methods of history (symptoms), physical examination, and chest radiography. Although some studies have failed to demonstrate an objective improvement in survival with clinical follow-up by retrospective analysis, prospective confirmation of this finding has not been confirmed nor attempted, and may be medically inappropriate. Techniques identified by population screening in patients without prior history of lung cancer may provide clues that enable us to more efficiently identify patients at high risk of recurrence after resection of lung cancer. Follow-up of patients after resection of lung cancer requires a simple, consistent clinical protocol to optimize the health of the patient. Improvements in survival as a result of improved primary therapy are required to lessen the need for postoperative follow-up. Improved survival will result from better understanding of the molecular events leading to lung cancer and modulation of those events. Until then, routine clinical follow-up of the lung cancer patient and evaluation of new screening techniques for those patients at increased risk of recurrence will be required to optimize survival and decrease recurrence.

795

COMMENTS AND CONTROVERSIES Dr. Putnam reviews in detail the reasons for postresection follow-up, its limitations, and the arguments suggesting it has no practical value either for the care of the patient or economically. One of the most important aspects of postresection follow-up is that it enables surgeons to evaluate their treatment strategies over the long term. Surgeons who simply perform the pulmonary resection and never follow the patient cannot learn from their successes or errors. Whether postresection follow-up benefits the patient is very questionable, at least in retrospective studies that have addressed this question. A recent analysis suggests that follow-up by family physicians is less expensive than that performed by thoracic surgeons and, for economic reasons, patients should be offered this type of follow-up. Despite all the uncertainties, on occasion, second primary tumors are discovered early and solitary sites of metastases are aggressively treated with beneficial results for the patient because of the follow-up performed by the thoracic surgeon. How to quantitate this is unclear. With regard to spiral CT screening for follow-up of surgically resected lung cancer patients, an ACOSOG trial is planned to evaluate this. At the moment, the standard recommendation remains chest radiography only. R. J. G.

ADDITIONAL COMMENTARY This chapter has not been revised from the previous edition. Many of the points Dr. Putnam made in the previous edition are still valid. However, there are a number of areas of controversy. I do not believe that positron emission tomography plays any role in the routine follow-up of lung cancer patients who have undergone a complete resection. The use of CT in postresection follow-up is also controversial. There are several instances in which routine CT is of help in follow-up. There are a group of patients whose cancer was identified in a surveillance CT program. These patients will never be satisfied with follow-up by chest radiography alone. I generally follow patients who have undergone resection for bronchoalveolar cancer by routine CT. If they are to develop multifocal disease, it is much more likely to be identified by CT. I also rely on periodic CT in patients who have undergone pneumonectomy because chest radiography is a completely unreliable method of evaluating the pneumonectomy space or that portion of the remaining lung that has shifted across the midline. G. A. P.

tahir99-VRG vip.persianss.ir

Ch063-F06861.indd 795

1/21/2008 1:15:40 PM

chapter

64

ALTERNATIVES TO SURGICAL RESECTION FOR NON–SMALL CELL LUNG CANCER Hiran C. Fernando Ghulam Abbas

Key Points ■ Ablative techniques and stereotactic surgery for lung tumors are

key alternatives for freatment of NSCLC. ■ Microwave ablation is the most recent development in tumor abla-

tion techniques.

Lung cancer is a significant public health problem, with approximately 170,000 new cases diagnosed annually in the United States.1 Surgical resection remains the mainstay of therapy for early-stage non–small cell lung cancer (NSCLC) and provides the best opportunity for cure. However, many patients present with advanced disease, and many of those with resectable early-stage disease are unable to tolerate pulmonary resection because of compromised cardiopulmonary function. It has been estimated that more than 20% of patients diagnosed with stage I or II NSCLC do not undergo operation.2 Lung cancer continues to be a leading cause of death for both men and women. Since the results of the randomized study of lobectomy versus sublobar resection by the Lung Cancer Study Group were published,3 the preferred operation for NSCLC has been lobar resection. Because of the threefold increased incidence in local recurrence after sublobar resection reported in that study, most surgeons reserve wedge or segmental resection for those patients who are believed to have increased risk with lobectomy but could still tolerate a smaller pulmonary resection. Most local recurrences occur within the first 24 months after surgery, and they have been reported in 17% to 22% of patients after sublobar resection (Ginsberg and Rubenstein, 1995).3,4 External-beam radiation therapy (EBRT) is typically used for patients for whom any pulmonary resection is believed to carry too high a risk. However, the treatment results are inferior to those obtained with resection, and the chance for cure is small. In a study of 71 node-negative patients who received at least 60 Gy to their cancers, the 3- and 5-year survival rates were 19% and 12%, respectively.5 A more recent report described results after radiation therapy in 60 patients with stage I or II NSCLC.6 Local progression occurred in 53% of the patients, with a median progression-free survival time of 18.5 months and an overall median survival time of 20 months. Another concern with EBRT is the issue of radiation injury to surrounding tissues because it is difficult to deliver a precise area of radiation to a target area due to lung movement with respiration. Radiation pneumonitis is a

potentially life-threatening problem, particularly for a patient with severely impaired pulmonary function who is not a candidate for resection (the type of patient usually referred for nonoperative therapy). In the series described earlier,6 radiation pneumonitis occurred in 8.3% of patients treated with definitive radiotherapy. New alternatives to resection or standard EBRT are now entering clinical practice for the treatment of lung cancer or limited pulmonary metastases. The two principal modalities that are being offered by many centers around the world are radiofrequency ablation (RFA) and stereotactic radiosurgery (SRS). Another ablative modality, microwave ablation (MWA), also is being introduced into practice, although currently the clinical experience is very small. This chapter reviews these therapies and their roles in clinical practice.

RADIOFREQUENCY ABLATION Systems and Mechanism of Action RFA is widely used for the treatment of liver tumors. It is being used either as an adjunct to resection or as a primary therapy, and because of its lower rate of complications, it has largely replaced other, less invasive modalities.7,8 A large international, multicenter study of 2320 patients who received percutaneous RFA for liver malignancies reported a periprocedural mortality rate of 0.3% and an overall complication rate of 7.1%.9 Several centers around the world have now published reports of RFA for the lung. These reports primarily demonstrate the safety and feasibility of this technique for lung tumors.10,11 RFA involves the application of high-frequency electric current to heat and coagulate target tissue. RFA consists of an alternating current, which moves from an active electrode that is placed within the tumor to dispersive electrodes (Bovie pads) placed on the patient. RFA systems therefore have three components: a generator, an active electrode, and a dispersive electrode (Fig. 64-1). As the radiofrequency energy moves from the active electrode to the dispersive electrode and then back to the active electrode, ions within the tissue oscillate in an attempt to follow the change in the direction of alternating current. This results in frictional heating of the tissue; as the temperature within the tissue rises to more than 60ºC, instantaneous cell death begins due to protein denaturation and coagulation necrosis. Typically when RFA is performed, the local temperature in the ablated tumor rises to the range of 90ºC to 100ºC. Animal models have been used to investigate the efficacy and feasibility of this technique in lung tissue and have helped

796 tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 796

1/21/2008 1:16:51 PM

Chapter 64 Alternatives to Surgical Resection for Non–Small Cell Lung Cancer

797

FIGURE 64-1 Components of a radiofrequency ablation system: active electrode in tumor, dispersive electrodes (Bovie pads), and generator.

in the development of the treatment algorithms for humans. In a study by Goldberg and associates,12 the authors generated a model of lung tumors by infiltrating the pulmonary parenchyma of 11 rabbits with VX2 sarcoma cell suspensions. Seven lesions were treated with RFA for 6 minutes at 90º C, and the remaining four tumors were left untreated as controls. The authors noted computed tomographic (CT) evidence of coagulation necrosis surrounding the tumor, manifested by increased opacity enveloping the lesion. This was followed by central tissue attenuation with peripheral hyperattenuation surrounding the treated site. Histologic analysis revealed that at least 95% of the tumor nodules were necrotic, although some rabbits (43%) had residual tumor nests at the periphery of the tumor. Pneumothorax was the only procedure-related complication, and it occurred in 29% of the treated rabbits and 25% of the controls. In another study, Miao and colleagues13 implanted VX2 tumor tissue in the lungs of 18 rabbits (12 treated and 6 controls), and the lesions were then treated with RFA using a cooled-tip electrode for 60 seconds. Efficacy of therapy was assessed with magnetic resonance imaging (MRI), microangiography, and histopathology. Absolute tumor eradication was achieved with RFA in 33% and a partial response in 41.6% of rabbits that survived longer than 3 months. MRI evaluation of the lesion after RFA demonstrated an early hyperintense peritumoral rim on T1- and T2-weighted images, which led to a homogeneous signal and decreased lesion size with time. Microangiography revealed no perfusion to the ablated lesion. On histopathologic evaluation, the ablated lesion retained its tissue architecture but exhibited changes consistent with coagulation necrosis with surrounding edema and inflammation of normal surrounding lung. After 1 to 3 months of treatment, the ablated tumor became an atrophied nodule of coagulation necrosis within a fibrotic capsule. The timing and progression of these postablation changes become an important issue when evaluating treatment response and is discussed in more detail later in this chapter. Some investigators have performed RFA ablation followed by resection to evaluate the efficacy of the ablation in the resected specimen. In one multicenter study of 15 patients, ablation was possible in 13 cases.14 In these 13 patients, median tumor kill was 70%, with 7 patients achieving a 100% ablation. There appeared to be a learning curve effect because 5 of the last 6 patients in this study achieved 100% ablation.

FIGURE 64-2 Boston Scientific (BOS) electrode.

More recently, Nguyen and coworkers15 published the results of an ablate and resect study wherein supravital staining was used to assess tumor cell viability. In seven tumors studied with this technique, greater than 80% nonviability was demonstrated. Only three patients had 100% nonviability in their ablated tumors, and all three of these tumors were smaller than 2 cm in diameter. However, only a single ablation, with either a 3-cm or a 3.5-cm active electrode, was performed, so some of the larger tumors may have been inadequately ablated. These studies demonstrated that, although RFA can produce effective ablation, 100% cell death is not guaranteed in every case, and, at the present time, resection is the preferred approach for patients suitable for surgery.

Available Devices The U.S. Food and Drug Administration has approved three devices: the Boston Scientific (BOS) (Natick, MA), RITA Medical (Fremont, CA), and Valley Lab (VL) (Boulder, CO) systems. With the impedance-based BOS device (Fig. 64-2), the end point of treatment is determined by a significant rise in impedance, which indicates that the tumor has been ablated, resulting in cell necrosis that prevents further conduction. The RITA (Fig. 64-3) and VL (Fig. 64-4) systems are temperature-based devices that rely on raising the tumor temperature to high levels for specified periods of time, depending on the device used and the size of tumor being ablated. The BOS and RITA active probes both consist of an expandable needle system, whereas the VL system uses either a single needle or three parallel needles placed into the tumor. The VL electrode consists of a proximal insulated portion and a distal noninsulated active tip. The electrode is irrigated with a continuous infusion of ice water, and for this reason it is sometimes referred to as a so-called cool-tip electrode. Currently, no clinical studies have evaluated the differences among these probes. One animal study has evaluated these probes in both in vivo and ex vivo settings in pig and calf livers.16 In this study, the expandable probes resulted in a more reproducible spherical ablation (measuring 3942 cm3), whereas the cooled-tip electrodes tended to produce a more ovoid ablation lesion with a smaller volume (29 cm3).

tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 797

1/21/2008 1:16:51 PM

798

Section 3 Lung

FIGURE 64-4 Valley Lab (VL) probe.

FIGURE 64-3 RITA electrode.

Patient Selection As discussed later, we have found that the efficacy of RFA falls when nodules greater than 5 cm in diameter are treated.17 Additionally, one of our patients developed a massive hemoptysis 19 days after ablation of a central lung nodule.17 For these reasons, we do not recommend RFA for lesions greater than 4 to 5 cm or for central lesions. In NSCLC, RFA can be used for patients with stage I disease who are believed to be at increased risk for any kind of pulmonary resection or who refuse surgery. Occasionally, RFA is a reasonable therapy for patients with more advanced cancer, such as those with stage IIIB disease (based on a second nodule within the same tumor lobe) or stage IV disease based on a satellite nodule within another lobe. Tumors such as these are a subgroup of advanced-stage tumors that may be more appropriately treated with resection as long as the cancer is localized to the lung.18 For those patients who are believed to be at increased operative risk, RFA is a good alternative. Other patients who may be considered for treatment with RFA include those

with advanced-stage disease who have responded to definitive irradiation and chemotherapy but have a persistent solitary peripheral focus of cancer and those who present with a recurrent isolated cancer after previous lung resection. RFA is also a suitable option for some patients with limited peripheral pulmonary metastases. As with resection, this treatment is reserved for those patients who have a limited number of metastases, disease localized to the chest, and a primary cancer that is either controlled or controllable. As with lung cancer, RFA is reserved for those patients who are believed to be at increased operative risk for resection of their pulmonary metastases. Situations may also occur in which complete resection of all pulmonary metastases is not possible; RFA of some nodules may be an alternative. We have certainly found RFA to be of use in cases in which a wedge resection of a peripheral nodule was performed and resection of a second, deeper nodule would have required a lobectomy or pneumonectomy. In order to preserve pulmonary parenchyma, the central tumors were treated with RFA. Table 64-1 outlines suggested selection criteria to help determine when to use RFA in preference to pulmonary resection.

Operative Approach Initially, we performed these procedures via open thoracotomy. Although this approach provides the most controlled method for RFA application, few patients are candidates because resection is preferable in most situations in which thoracotomy can be performed. However, situations may arise, such as that described earlier, in which a patient presents with a deeper tumor that is treated with RFA and a peripheral tumor treated with wedge resection. Although the video-assisted thoracic surgery (VATS) approach may be attractive because of its minimally invasive nature, in practice the RFA technique is not easily compatible with VATS. The main reason is that it is important to obtain optimal needle deployment within the tumor. When VATS is performed, the lung is collapsed to allow visualization within the pleural space, and the tumor (particularly if it is deep to the visceral pleural surface) may not be seen. In an open thoracotomy,

tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 798

1/21/2008 1:16:52 PM

Chapter 64 Alternatives to Surgical Resection for Non–Small Cell Lung Cancer

799

TABLE 64-1 Selection Criteria for Radiofrequency Ablation (RFA) Inclusion Criteria

Exclusion Criteria

Stage I or II* NSCLC; poor surgical candidate

Tumor abutting hilum or large pulmonary vessel

Stage IIIB (satellite nodule in same lobe) or IV (nodule in another lobe or lung); poor surgical candidate

Malignant effusion

Stage IIIA or IV with solitary pulmonary nodule remaining after standard therapies

Pulmonary hypertension

Pulmonary metastases; primary disease controlled or controllable; poor surgical candidate

>3 Tumors in one lung

Target lesion ≤5 cm

Target lesion >5 cm

NSCLC, non–small cell lung cancer. *Patients with stage II NSCLC should receive additional therapy, because N1 disease is not treated with RFA.

the tumor can easily be palpated to place the active electrode; this is not the case with VATS. The most common method used for pulmonary RFA is a percutaneous CT-guided approach. This has the advantage of being truly minimally invasive, an important factor for the higher-risk patients who are treated with this modality. Either general or local anesthesia can be used when performing CTguided RFA. Our preference has been to use general anesthesia. This allows needle deployment, ablation, and biopsies (if required) to be performed in a more controlled manner. Additionally, some patients with cardiopulmonary compromise have difficulty in lying flat for a prolonged period, and general anesthesia is better tolerated in this situation. Patient positioning is also very important during CT-guided RFA. We prefer to position the patient in such a way that the target lesion is accessed with minimal penetration of normal lung parenchyma. This decreases the risk of hemorrhage and prolonged air leak. In our center, thoracic surgeons perform the CT-guided RFAs for lung cancer.

FIGURE 64-5 Lobectomy specimen after prior radiofrequency ablation. More than 90% of the tumor was ablated, but a focus of cancer is seen inferiorly at the periphery of the tumor.

Determination of Treatment Response Determination of treatment response is perhaps one of the most challenging issues with RFA. In contrast to pulmonary resection, a residual mass may be present after RFA. It can be difficult to determine whether the mass represents scar or viable cancer. This is illustrated in Figure 64-5, which shows a pathologic specimen from a patient who had a left upper lobe cancer treated initially with RFA (surgery was contraindicated because of a recent myocardial infarction). After an uneventful recovery, the patient underwent lobectomy several months later because of concerns of tumor growth. Final pathologic analysis demonstrated a small focus of viable cancer at the edge of the ablated tumor. After RFA, there is an inflammatory response, which may persist for up to 3 months. For this reason, the mass may initially appear larger and then start to decrease in size with time. In our experience, ablated lesions may demonstrate central cavitation (Fig. 64-6) or develop bubble lucencies, which are indicative of effective ablation. Other centers have been using CT densitometry protocols to help evaluate for persistent or recurrent disease.19 Densitometry involves the injection of contrast material, with CT images of the ablated nodule obtained at 0, 45, 180, and

300 seconds after the injection. Lesions greater than 9 mm that enhance at 15 HU or greater compared to baseline within 1 minute are believed to be suspicious for cancer. These densitometry techniques are time-consuming and are of value only for those patients with single tumor nodules. Furthermore, no data are available on long-term follow-up or after resection of these areas, so all nodules still need longterm imaging follow-up. We have modified a group of radiologic criteria, referred to as the Response Evaluation Criteria in Solid Tumors (RECIST), to monitor our patients (Fernando et al, 2005).20 CT scans are obtained at 3-month intervals and analyzed for evidence of tumor growth. Whenever possible, positron emission tomographic (PET) scans are also obtained to help in the determination of tumor response. The modified RECIST criteria are outlined in Table 64-2. The American College of Surgeons Oncology Group recently opened a multicenter study of RFA in high-risk patients with stage IA NSCLC. This study (Z4033) will address issues such as response assessment by standardizing the follow-up protocol in the study sites. Follow-up assessment will include CT (size criteria and densitometry) as well as serial PET scans.

tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 799

1/21/2008 1:16:53 PM

800

Section 3 Lung

A

B FIGURE 64-6 CT scans of right lower lobe tumor before (A) and 4 months after (B) radiofrequency ablation.

TABLE 64-2 Modified RECIST Criteria for Follow-up After Radiofrequency Ablation Criteria Response (No. of Criteria Required)

Mass Size by CT

Mass Quality by CT

PET Findings

Complete response (two)

Lesion disappearance (scar) <25% of original size

Cyst/cavity formation; low density of entire lesion

SUV <2.5

Partial response (one)

>30% decrease in LD of target lesion

Central necrosis or central cavitation with liquid density

Decreased SUV or area of FDG uptake

Stable lesion (one)

<30% decrease in LD of target lesion

Mass solid appearance, no central necrosis or cavitation

Unchanged SUV or area of FDG uptake

Progression (two)

Increase of >20% in LD of target lesion

Solid mass, invasion of adjacent structures

Higher SUV or larger area of FDG uptake

CT, computed tomography; FDG, fluorine 18–labeled fluorodeoxyglucose; LD, largest diameter of lesion; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors; SUV, standard uptake value of FDG on PET scan.

Clinical Results In our initial experience with RFA, we treated 33 tumors in 18 patients.17 Tumor pathologies included metastatic carcinoma (n = 8), sarcoma (n = 5), and NSCLC (n = 5). The mean age was 60 years (range, 27-95 years). There was one death from massive hemoptysis, which occurred 19 days after RFA of a central metastatic tumor. The same patient had also undergone recent brachytherapy for an endobronchial metastasis. Although it was unclear what specifically caused the massive hemoptysis, we do not recommend percutaneous RFA for tumors abutting mediastinal structures. Another key finding from this study was the lack of effectiveness for tumors larger than 5 cm. Using the RECIST criteria, we found a radiographically determined response in 66% of tumors measuring 5 cm or smaller, compared with only 33% in tumors larger than 5 cm. A report from seven centers around the world summarized results of 493 patients undergoing RFA of pulmonary

nodules.21 As with many other reports, this was primarily a discussion of periprocedural mortality and morbidity. The authors concluded that RFA was safe, with negligible mortality (2 of 493 patients) and morbidity and a gain in quality of life. Although we agree with the authors’ comments about the safety of the procedure, their conclusions about quality of life cannot be substantiated. Quality of life was not measured as an outcome, and in most patients small pulmonary nodules are relatively asymptomatic. Importantly, this study did not address response or durability of RFA as a cancer treatment. More recently, we have reported on the results of RFA in 18 patients with NSCLC.20 A total of 21 tumors were treated. Most patients (n = 9) had stage I NSCLC. Four patients had stage IV cancer, including three with recurrence after previous lobectomy and one patient with a synchronous solitary liver metastasis that was also treated with RFA. The median tumor diameter was 2.8 cm (range, 1.2-4.5 cm). Although morbidity occurred in 55.6% of patients, it was minor in most

tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 800

1/21/2008 1:16:54 PM

Chapter 64 Alternatives to Surgical Resection for Non–Small Cell Lung Cancer

801

cases. The most common complication (38.9%) was a pneumothorax noted during the procedure that resolved with immediate pigtail catheter drainage within 24 hours in most cases. At a median follow-up of 14 months, 83.3% of the patients were alive. Local progression occurred in 38.1% of the ablated nodules. For stage I cancer, the mean progressionfree interval was 17.6 months; the median progression-free interval was not reached. Although this was a small study, the results compare favorably with those obtained by standard methods of EBRT, in which local progression is seen in more than 50% of cases.6 However, they do not approach the results of surgical wedge resection, underscoring the importance of careful surgical evaluation before consideration of RFA.

STEREOTACTIC RADIOSURGERY Background and Techniques Radiation therapy is commonly used when resection for NSCLC is not possible. However, 5-year survival rates are usually poor and have been reported to range from 10% to 30%.22-25 Qiao and associates25 summarized results from 18 studies reporting on EBRT for stage I NSCLC. The mean 3and 5-year survival rates were 34% and 21%, respectively. Local tumor progression has been shown to be a major cause of failure after EBRT.22 As discussed earlier, this can occur in up to 53% of patients.6 Higher radiation doses appear to enhance local tumor control.26 In one study, patients receiving doses greater than 70 Gy had better local control and cancer-specific survival than those treated with lower doses.27 Dose escalation is limited because increased doses of radiation result in increased toxicity and damage to surrounding pulmonary parenchyma. The major toxicity encountered in treatment of lung tumors is pulmonary toxicity.28 Radiation fibrosis seems to depend on the volume of lung irradiated above a threshold of 20 to 30 Gy.28 SRS is a relatively new approach that enables the selective delivery of an intense dose of high-energy radiation to destroy a tumor with precision targeting. The improved accuracy is achieved by very precise spatial localization of the tumor and delivery of multiple cross-fired beams of radiation to converge on the tumor, minimizing injury to surrounding normal tissue. This technology has become standard treatment in many centers for intracranial tumors, but respiratory motion creates difficulties for the precise delivery of radiation to lung tumors. Respiratory displacements are greatest near the diaphragm and are less significant near the lung apex and adjacent to the carina. Only relatively recently have respiratory gating techniques become available that minimize the effects of respiratory motion on radiation delivery. One simple approach to SRS is to use breath-holding techniques, sometimes in combination with an abdominal compression device to limit the ability of the diaphragm to move caudally.29 The Cyberknife Stereotactic Radiosurgery System (Accuray, Sunnyvale, CA) is a frameless SRS system that has been used at the University of Pittsburgh and a number of other centers in the United States.30 The Cyberknife system consists of a linear accelerator radiation source that is mounted on a

FIGURE 64-7 Cyberknife Stereotactic Radiosurgery System.

FIGURE 64-8 Gold fiducials such as this one are placed close to the tumor to facilitate stereotactic radiosurgery.

robotic arm (Fig. 64-7). Before treatment is initiated, 2 to 4 small gold fiducials (Fig. 64-8) are percutaneously placed close to the tumor under CT guidance. At the time of therapy, cameras on the Cyberknife system use these markers to localize the tumor in space. Additionally with the addition of the Synchrony respiratory gating option, breathing movements of a patient’s chest are recorded and combined with the radiographs of the fiducials to facilitate delivery of radiation during any point of the respiratory cycle. A major advantage with this system over those involving breath-holding and immobilization techniques is that the treatment times are shorter and therefore better tolerated by patients, who frequently have some degree of cardiopulmonary compromise.

Patient Selection Patient selection is virtually identical to that for RFA. However, an advantage of SRS is that centrally based tumors can be treated. There are some concerns about increased complications with central RFA, which are discussed earlier. Additionally, we have found that some osteosarcomas are

tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 801

1/21/2008 1:16:54 PM

802

Section 3 Lung

extremely difficult to penetrate with a needle, as would be required for RFA. With SRS, fiducials need only be placed close to the tumor, rather than in the tumor. In the case of metastatic osteosarcoma, SRS may be a technically favorable therapy, but few clinical data are available to support its efficacy.

Results As with RFA, long-term studies are required. Most published series to date have been small and with relatively short follow-up. Assessment of response to therapy is also challenging because of the difficulty in differentiating scarring and fibrosis after irradiation from viable cancer. Whyte and colleagues (Whyte et al, 2003)31 published the first results of SRS for the lung using the Cyberknife system. This study included 23 patients from two institutions. Respiratory gating was used in 14 patients and breath-holding in 9. A single fraction of 15 Gy was used. Three patients developed a pneumothorax after fiducial placement. There was no radiation esophagitis or clinically apparent radiation pneumonitis. At a mean follow-up of 7 months, 2 patients (8.6%) had a complete response, 15 (65.2%) had a partial response, 4 (17.4%) had stable disease, and 2 (8.7%) had evidence of progression. In our initial experience from the University of Pittsburgh, 32 patients (27 with NSCLC and 5 with pulmonary metastases) were treated with SRS using the Cyberknife System.30 Patients were treated with 20 Gy in a single fraction. Note that the radiobiology of SRS because of the high-energy, single, focused dose, is different from that of EBRT. The biologically effective dose (BED) is much higher (Timmerman and Papiez, 2004).32,33 With SRS, it is estimated that 42 Gy delivered in three fractions is equivalent to a BED of 100.8 Gy by standard irradiation.33 In our study, the 20-Gy dose was equivalent to a BED of 60 to 70 Gy with standard techniques (Whyte et al, 2003).31 After SRS in our 32 patients, an initial complete response was seen in 7 (22%), a partial response in 10 (31%), stable disease in 8 (25%), and progression in 6 (19%). At a median follow-up of 9 months, only 6 patients (19%) were progression-free. Both of these studies demonstrated the safety and feasibility of SRS; however, the results with these fractions were still inferior to those of pulmonary resection. One question that is being investigated is whether increasing the SRS dose will improve outcomes. Timmerman and associates29 recently reported the results of a dose escalation study in 37 patients with stage I NSCLC. A breath-holding technique with abdominal compression was used. In this series, the dose was escalated from 20 to 60 Gy in three fractions. A complete response was seen in 27% of patients, and a partial response in 60%. At a median follow-up of 15 months, 6 patients (16.2%) had experienced local failure. All 6 received less than 18 Gy, supporting the concept of dose escalation. The same group recently published a follow-up study.34 Stage I NSCLC patients were stratified into those with T1 tumors (19 patients) and those with T2 tumors (28 patients). Doselimiting toxicity included bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4 (21%)

of the T1 tumors and 6 (21%) of the T2 tumors. Eight (42%) of the patients with T1 tumors had regional or distant recurrences (or both). Among those with T2 tumors, 6 (21%) had regional or distant recurrence. Longer follow-up and standardization of response criteria are needed to better define the value of SRS. The issue of optimal radiation dose also needs to be determined. Currently, a limited-access, multicenter dose escalation study using the Cyberknife system with respiratory gating in all patients is being performed and needs to address some of these issues. There are discussions underway to consider a randomized multicenter study of SRS for stage I NSCLC (personal communication, Jack Roth, MD, M.D. Anderson Cancer Center).

RADIOFREQUENCY ABLATION AND STEREOTACTIC RADIOSURGERY: COMBINATION THERAPY Both RFA and SRS have benefits and limitations. The larger lesions have less desirable responses with either of these techniques. Recently, we have been placing fiducial markers during RFA for larger lesions or asymmetric lesions when a uniform ablation cannot be achieved. During follow-up, if persistent tumor is suspected, it can be treated with either repeat RFA or SRS. Additionally, SRS is more effective in this situation because the lesion may be smaller than the original lesion due to the prior RFA treatment.

MICROWAVE ABLATION MWA is the most recent development in the approaches to tumor ablation. The mechanism of MWA is dielectric heating (frictional heating of water molecules in tissue). Microwave radiation is in the 900 to 2450 MHz wavelength of the electromagnetic spectrum. Because microwave radiation interacts with water molecules, the polarity of these molecules changes, resulting in heating and eventually leading to cell death.35,36 As with RFA, most clinical experience with MWA has been in the liver.37,38 It has been suggested, although not proved, that MWA offers some advantages compared with RFA.36 Unlike RFA, MWA is not limited by tissue boiling and charring of the tissue. This may allow intratumoral temperatures to be driven higher, resulting in a larger ablation zone in a shorter time. MWA was compared with RFA (using the RITA system) in a hepatic porcine model in 19 pigs. The pigs were sacrificed at 0, 2, and 28 days after ablation. To assess the heat sink effect of blood vessels on ablation, the investigators created a deflection score. This was defined by measuring the diameter of the zone of ablation at a blood vessel (>3 mm) and the diameter of the ablation zone next to the same blood vessel. The percentage difference between these diameters was the deflection score. The deflection score was significantly less (P < .02) after MWA (3.6%) than after RFA (17%). The ablation zones were significantly greater in the long axis (P < .01) after MWA (3.6 cm) than after RFA (2.2 cm). There were no differences in short-axis measurement or in tumor volume. The differences in length of ablation may have been related to the protocol design: for MWA a 3.6 cm electrode

tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 802

1/21/2008 1:16:56 PM

Chapter 64 Alternatives to Surgical Resection for Non–Small Cell Lung Cancer

was used, whereas for RFA only a 3 cm deployment of the RITA probe was used. Shibata and colleagues37 performed a randomized comparison of MWA (n = 36) and RFA (n = 36) for small hepatocellular carcinomas. There were no significant differences noted in the rates of initial therapeutic effect, complications, or residual disease. Clinical experience with MWA for the lung is limited at this time. Feng and coworkers39 reported on MWA of 28 tumors in 20 patients. A response of 50% or greater was noted in 13 nodules (46.4%), and a complete response in 3 (10.7%). No significant complications were noted. An ablate and resect study was performed by Simon and colleagues.36 Patients undergoing elective lung resection had MWA before their resection. The mean tumor diameter was 3 cm (range, 2-5.5 cm), with an average tumor volume of 7.1 cm3. The maximum ablation achieved was 4 cm (range, 3-5 cm), with a tumor volume of 23.4 cm3.

SUMMARY We have discussed three alternative modalities for the treatment of NSCLC. At this point, MWA is the least welldeveloped modality. Although the treatment times and heat-sink effect may be less with MWA compared to RFA, larger trials are needed to better understand its effectiveness and safety. The heat-sink effect may in fact be protective, minimizing the necrosis of large blood vessels and subsequent fatal hemoptysis. As experience with MWA increases, this may be become an issue limiting the application of this therapy. It is unclear whether RFA or SRS is more effective. One advantage of RFA is that it is much cheaper to introduce to an institution than SRS. RFA can be performed in one treatment session, whereas it now appears that SRS is more effective if larger doses of radiation are administered in two or three fractions. RFA is not recommended for centrally based tumors. There are also some tumors (e.g., small apical tumors, posteriorly based tumors close to the diaphragm, tumors close to the scapula) in which it is difficult to percutaneously place an active electrode. Such tumors will be more optimally

803

treated with SRS. In a few cases, we have treated patients for whom RFA has failed with SRS (and vice-versa). Future studies need to address long-term outcomes using standardized assessments of treatment response between centers. Comparisons of different RFA systems and ablation modalities need to be undertaken. Again, given the absence of long-term data and the uncertainty of achieving a 100% tumor kill with a surrounding margin, surgical resection needs to be offered to all patients who are fit for surgery in preference to any of these new alternative therapies.

COMMENTS AND CONTROVERSIES The authors present a balanced overview of three new techniques to ablate pulmonary malignancies. Currently, it is clear that surgery offers a better chance of local control. However, as the technology improves, this surgical advantage may diminish, leading more patients to seek these less invasive approaches. Therefore, it is imperative that thoracic surgeons investigate these new techniques and incorporate them into their practices as clinically indicated. With screening CT scans, suspicious lung lesions at a subcentimeter size will continue to be discovered in an ever-aging population seeking less invasive options. The thoracic surgical community is best positioned to understand all options, deliver a nonbiased opinion, and ultimately provide treatment individualized to each patient that is based on efficacy and not simply on one approach. J. D. L.

KEY REFERENCES Fernando HC, De Hoyos A, Landreneau RJ, et al: Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates. J Thorac Cardiovasc Surg 129:261-267, 2005. Ginsberg RJ, Rubenstein LY: Randomized trial of lobectomy versus limited resection for TIN0 non-small cell lung cancer: Lung Cancer Study Group. Ann Thorac Surg 60:615-622, 1995. Timmerman RD, Papiez L: The Song/Kavanagh/Benedict et al. article reviewed. Oncology 18:1430-1435, 2004. Whyte RI, Crownover R, Murphy MJ, et al: Sterotactic radiosurgery for lung tumors: Preliminary report of a phase I trial. Ann Thorac Surg 75:1097-1101, 2003.

tahir99-VRG vip.persianss.ir

Ch064-F06861.indd 803

1/21/2008 1:16:56 PM

chapter

65

DEFINITIVE MANAGEMENT OF INOPERABLE NON–SMALL CELL LUNG CANCER David J. Adelstein Gregory M. M. Videtic Tarek Mekhail

Key Points ■ Nonoperative management of locoregionally confined non–small

cell lung cancer may still be potentially curative. ■ Long-term disease-free survival is possible after single-modality

■

■ ■ ■

radiation therapy alone, particularly in patients with early tumors that are medically inoperable. In patients with anatomically inoperable stage III disease, survival is improved when concurrent chemotherapy is given along with a full course of radiation therapy. In patients with recurrent disease or distant metastases, radiation therapy can have significant palliative benefit. Systemic chemotherapy improves survival in patients with advanced non–small cell lung cancer. Molecularly targeted therapies are being actively investigated and have already been demonstrated to be of benefit.

It is important to note that nonoperative management for inoperable lung cancer may still be potentially curative. In patients with stage III, locoregionally confined disease, the historical standard of care has been radiation therapy (RT) alone, an approach with demonstrated curative potential. With the recent incorporation of chemotherapy into RTbased approaches, the prospects for these patients have significantly improved. These approaches are reviewed in this chapter. Patients with stage IIIB disease due to a malignant pleural effusion, and patients with extrathoracic metastases (stage IV) are not considered curable. The palliative role of RT and the favorable impact of chemotherapy on overall survival are discussed. The newer systemic treatments directed at defined molecular targets, as well as some of the specific treatment approaches appropriate for selected metastatic sites, are also reviewed.

THERAPY WITH CURATIVE INTENT The definition of inoperability in a patient with non–small cell lung cancer (NSCLC) has both anatomic and medical considerations. Anatomically, stage I-II disease is considered resectable with curative intent, whereas stages IIIB and IV are usually considered not resectable. For stage IIIA tumors, however, there is considerable variability from surgeon to surgeon in the definition of resectability. Evidence-based recommendations are nonetheless possible. As detailed by Andre and colleagues,1 patients with microscopic single nodal station N2 involvement have a 5-year survival of 34% after primary surgical therapy. On the other hand, patients with clinical evidence of mediastinal lymph node involvement or with multiple positive lymph nodes identified at surgery have a poor prognosis, with a 5-year survival after surgery of 11% or less. Historically, such patients have not been considered appropriate candidates for surgical intervention. The recent development of successful induction chemotherapy and chemoradiotherapy treatment regimens,2,3 as well as the benefit demonstrated after postoperative adjuvant chemotherapy,4,5 suggest that more such patients with stage IIIA disease now merit surgical resection. Continued investigation into the optimal approach for these patients is required. This chapter discusses the nonoperative management options for those patients with stage III or IV NSCLC who have been deemed inoperable, in general, for anatomic reasons. Similar approaches may be appropriate for those deemed medically inoperable, although these medical considerations often mandate a more individualized approach.

Definitive Radiotherapy Inoperable Early-Stage Disease Recognizing that surgical resection is the treatment of choice for early-stage NSCLC,6 patients whose tumors are technically resectable may be considered inoperable due to concurrent medical comorbidities, advanced age, or refusal of surgery. In this setting, definitive external-beam radiotherapy (EBRT) is considered the standard of care.6,7 Conventional EBRT is delivered as daily doses (fractions) of 2 Gray (Gy), with total doses up to 70 Gy in 35 daily fractions administered over 7 weeks for early-stage disease.7 Because one of the most common underlying causes for medical inoperability is compromised lung function, treatment is typically administered only to the tumor. Careful consideration is given to the total volume of non–cancer-bearing lung parenchyma exposed to radiation, reflecting caution about causing excessive lung morbidity from the treatment. For the same reason, prophylactic (or so-called elective) mediastinal and hilar nodal irradiation is often avoided in these patients.7 In the large number of series reporting on RT for early lung cancer, 5-year survival rates ranged widely but averaged between 20% and 30%. Representative studies8-14 are presented in Table 65-1. The generally inferior outcomes with RT compared to surgery most likely reflect a variety of factors: the medically unfavorable population treated; the clinical heterogeneity of patients; clinical as opposed to pathologic determination of tumor stage; insufficient RT administered for the

804 tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 804

1/21/2008 1:18:16 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

disease stage; exacerbation of comorbidities by RT; lack of phase III studies examining comparable patients undergoing surgery versus RT; and the retrospective and single-institution nature of most reported series. Variations in RT delivery are being explored in an effort to improve outcomes in early-stage NSCLC. These include increases in total dose, alterations in fractionation schedules, and introduction of new delivery techniques.7 The rationale for treating early-stage disease with total doses greater than 70 Gy using conventional fractionation has been prompted by data showing that improved outcome is a function of increasing dose. For example, Martel and associates15 stated that more than 84 Gy is required to achieve greater than 50% local control. Narayan and colleagues16 from the University of Michigan reported safe delivery of 92.4 Gy and 102.9 Gy, in a phase I trial of dose escalation for early-stage lung cancer, by minimizing the effective treatment volume as a proportion of the total lung volume. They reported that 68% of the patients were free from local progression at 3 years, and the 3-year overall survival rate was 33%. Administering RT more than once daily and in smaller fractional doses may allow greater dose delivery without greater toxicity (hyperfractionation). Jeremic and coworkers12 reported on 49 stage I patients treated with 1.2 Gy twice daily to a total dose of 69.6 Gy. The results compared favorably with those of other studies employing conventional radiation, with a 5-year survival rate of 30%. Grills and colleagues17 studied the potential for reduced toxicity and dose

escalation in the treatment of inoperable NSCC by carrying out a comparison of intensity-modulated radiation therapy (IMRT), three-dimensional conformal radiation therapy (3DCRT), and conventionally planned RT with elective nodal irradiation. 3D-CRT and, in particular, IMRT are dose-delivery tools that may permit enhanced dose escalation while maximizing sparing of normal tissue. In this study of 18 patients, in which 2 patients had stage I disease and 5 had stage II, the authors found IMRT to be of limited additional value (compared with 3D-CRT) in node-negative early-stage cases. Another approach in modifying RT involves the use of larger-than-conventional (>2 Gy) daily fractionation (hypofractionation). This produces a shorter RT schedule, with equivalent or higher biologic activity with respect to cancerkill, although it does potentially increase the rates of late side effects. Cheung and colleagues13 at the University of Toronto treated 33 patients using 48 Gy in 12, once-daily fractions without elective nodal irradiation and reported a 54% overall survival rate and a 40% recurrence-free survival rate at 2 years, with acceptable toxicity. A recent development in RT technology is extracranial stereotactic body radiotherapy (SBRT), which has been applied to the management of early-stage inoperable lung cancer. Modeled after the principles of stereotactic radiosurgery used in the treatment of brain tumors, SBRT delivers radiation, with very high doses (e.g., 5-20 Gy) per fraction, to a small target in the chest, either as a single dose or in a brief fractionated regimen (three to five fractions).18 This technique requires rigid patient immobilization and methods of managing target instability through tumor tracking, restriction of tumor motion, or control of respiratory excursion. To date, the results are promising with respect to local control rates and tolerability. Representative studies and results19-23 are provided in Table 65-2. Although it appears that SBRT for early-stage disease NSCLC is safe and effective, randomized studies are needed to demonstrate a survival benefit for this approach, compared to doses similarly achieved with more conventional conformal RT or to the gold standard of surgery.18

TABLE 65-1 Definitive Radiotherapy for Inoperable Early-Stage Lung Cancer

Author (Year)

No. Patients

Haffty et al8 (1988) 9

Zhang et al (1989) Ono et al

10

(1991)

5-Year Overall Survival (%)

43

21

44

32

38

42

Gauden et al11 (1995)

347

27

Jeremic et al12 (1997)

49

33

203

16

113

20

13

Cheung et al

(2000)

Lagerwaard et al14 (2002)

805

Inoperable Locally Advanced Disease The role of RT as sole treatment for inoperable locally advanced (LA) NSCLC has been defined by a limited number

TABLE 65-2 Selected Results of Stereotactic Body Radiotherapy for Early-Stage Non–Small Cell Lung Cancer

Author (Year)

No. Patients

Dose

Any Grade 3 Toxicity (%)

Median Follow-up (Months)

Local Control (%)

Uematsu et al19 (2001)

50

30-76 Gy (5-15 F)

0

36

100

24

92

20

(2004)

245

18-75 Gy (1-22 F)

2.4

21

(2003)

23

15 Gy (1 F)

0

7

87

37

24-60 Gy (3 F)

5

15

87

45

48-60 Gy (8 F)

2

17

80

Onishi et al

Whyte et al

Timmerman et al22 (2003) 23

Onimaru et al

(2003)

F, fractions.

tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 805

1/21/2008 1:18:16 PM

806

Section 3 Lung

of randomized studies. The Veterans Administration Lung Group conducted a randomized clinical trial that tested RT against placebo in patients with LA-NSCLC.24 Published in 1968, the study demonstrated an improvement in median survival time with RT. Although there were ultimately no 2-year survivors in either arm, this “benefit” in survival time suggested that an intervention could alter the course of what had otherwise been considered an incurable condition. In contrast, a phase III study from the 1980s suggested no survival benefit after thoracic RT in LA-NSCLC.25 In that study, patients were randomized to RT alone, RT plus vindesine (a chemotherapy drug with limited single-agent activity), or vindesine alone. Although no survival benefit was observed for the RT-alone arm, there was substantial treatment crossover from vindesine to RT in the trial, leading some authors to question the validity of the conclusions.26 Reinfuss and colleagues27 reported on a contemporary Polish trial of RT versus best supportive care (BSC) in 1999. In this three-arm study, patients were randomized to receive either 50 Gy at 2 Gy per fraction, a split course of 40 Gy in 10 fractions (two segments of 20 Gy in 5 fractions), or observation with palliative RT when severe local symptoms developed. The 2-year overall survival rates were 18% for the 50 Gy arm, 6% for the split course schedule, and 0% for the observation arm. Subsequent randomized studies of RT alone have shifted from comparisons with BSC to studies of dose and efficacy. In 1980, Perez and coauthors (Perez et al, 1980)28 published results from the landmark Radiation Therapy Oncology Group (RTOG) four-arm phase III trial (RTOG 73-01), which compared several radiation dose and fractionation schedules for treatment of inoperable NSCLC. Four hundred patients were randomly assigned to receive 40 Gy, 50 Gy, 60 Gy, or 40 Gy as a split course, all with daily fractionation of 2 Gy. The result of this trial favored the 60-Gy arm, which produced a significantly better 3-year survival rate of 15%. The intrathoracic failure rate was reported as 33% at 3 years. Although providing only a modest survival benefit, this phase III study defined 60 Gy as the “gold standard” for RT treatment of unresectable LA-NSCLC. Seeking to improve on this result, RTOG 8311 was designed as a randomized phase I/II dose-seeking study of dose escalation through hyperfractionation. The dose per fraction was reduced to 1.2 Gy, and two fractions were given daily, with an interfraction interval of 4 to 6 hours (Cox et al, 1990).29 Total doses were increased incrementally from 60 to 79.2 Gy. In this study of 828 patients, 69.6 Gy was declared “optimal,” not because of an overall survival advantage but based on a subset analysis of the results in favorable patients. A three-arm phase III trial conducted by the RTOG and the Eastern Cooperative Oncology Group (ECOG) allowed for a comparison between conventional and hyperfractionated RT by randomizing patients to either conventionally fractionated RT to 60 Gy alone, hyperfractionated RT to 69.6 Gy, or induction chemotherapy followed by standard RT to 60 Gy (Sause et al, 2000).30 Overall survival was statistically superior for the patients receiving chemotherapy plus standard RT, compared with the other two arms of the study. Notably, the survival of patients given twice-daily RT

was better but not statistically superior to that of patients given standard RT. One of the most frequently cited studies of RT alone in the definitive management of LA-NSCLC is the Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) trial from Great Britain. This was a phase III trial of 563 patients in whom the RTOG standard of 60 Gy was compared with 54 Gy prescribed as 1.5-Gy fractions given three times a day over 12 consecutive days without interruption.31,32 A statistically significant survival benefit at 2 years favored CHART over conventional treatment (29% versus 20%). This improvement in survival resulted from both a significant improvement in local tumor control and a reduction in metastases. There was no overall difference in late morbidity between the two groups. Despite this increase in survival, the logistics of CHART have made it difficult to implement, especially in North America, due to the time and machine demands that this regimen places on patients and institutions. Modifications of this treatment schedule, such that weekends are without treatment, have been attempted in the United States (Hyperfractionated Accelerated Radiation Therapy [HART]) and in Europe (CHART–weekend less [CHARTWEL]). A German randomized trial comparing the equivalence of CHART and CHARTWEL (ARO 97-1) will require 665 patients and remains in progress.33 The major challenge for the radiation therapist in improving survival of patients with LA-NSCLC remains achieving greater control of the primary disease site. This continues to be an area suited for further improvements in RT delivery. The local control rates of approximately 60% first reported after 60 Gy in RTOG 73-01 were overly optimistic, reflecting a limited ability to accurately measure failure in that era.26 This was validated by the post-RT bronchoscopic studies of Lechevalier and associates,34 which demonstrated that complete response rates at a primary site receiving doses in the range of 60 Gy were less than 20%. Furthermore, although altered fractionation (e.g., CHART) improves RT efficacy, almost 60% of the CHART patients died of local regional failure. The difficulty in LA-NSCLC lies in adequately irradiating the necessary volume of disease without causing excessive damage to normal tissue. Technological improvements have been suggested to maximize the efficacy of dose escalation and achieve better control. The development of sophisticated computing technology as well as the widespread use of computed tomographic (CT) scanning in the 1980s permitted the development of 3D-CRT and, later, IMRT techniques for the planning and delivery of RT. The principle underlying these forms of planning is that precise anatomic delineation of the target and identification of the surrounding normal critical structures permits the design of multiple RT portals and allows maximum delivery of dose to the target while minimizing irradiation of the normal structures.6 In the recent study by Grills and coworkers,17 IMRT appeared to be beneficial in cases of LA-NSCLC, especially in targets close to the esophagus. For given levels of toxicity, IMRT was reported capable of delivering doses 25% to 30% greater than 3D-CRT and 130% to 140% greater than traditional RT with elective

tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 806

1/21/2008 1:18:17 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

807

tion with RT has the potential to improve on the results achieved with RT alone. A number of treatment schedules have been explored. The earliest multimodality approaches used sequential chemotherapy followed by definitive RT. The rationale for this approach recognized the increased efficacy of chemotherapy in previously untreated patients. It was hoped that any tumor shrinkage achieved after chemotherapy might allow for better locoregional control by irradiation, and that the systemic chemotherapy might also decrease the risk of distant metastases. Initial attempts were hampered by the limited efficacy of the alkylating agent–based chemotherapy regimens. With the advent of cisplatin-based treatment schedules, however, a modest survival benefit was observed. Table 65-3 lists five of the largest randomized trials conducted to test this approach, all completed more than a decade ago (Sause et al, 2000).30,34,38-42 The results achieved with the treatment regimens based on cyclophosphamide and Adriamycin did not justify the addition of chemotherapy to RT in these studies. However, when a vinca alkaloid and cisplatin regimen was employed in conjunction with full-dose RT, a modest but nonetheless statistically real improvement in survival was observed. Both the Dillman trial, from the Cancer and Leukemia Group B (CALGB),40,41 and the Sause study, from the RTOG,30,42 confirmed the benefit of a relatively short course of vinblastine and cisplatin induction therapy, followed by a full course of definitive RT. An alternative approach to the sequential use of chemotherapy in definitive management has been the use of concurrent treatment. There is good in vitro evidence, and evidence from other malignancies, that chemotherapy is radiosensitizing and can improve on the locoregional benefit achieved with RT alone.43,44 Many of the early approaches to the use of concurrent chemotherapy and RT used chemotherapy schedules which, although considered suboptimal for systemic disease control, were potentially effective in radiosensitization. Table 65-4 lists six randomized trials that tested what might be considered suboptimal chemotherapy and concurrent RT regimens in comparison to RT alone.45-50 A survival benefit was again demonstrated, particularly when the RT

nodal irradiation. Despite the widespread interest and use of these technologies, to date there has been no phase III trial demonstrating clinical superiority or a survival advantage compared with conventional delivery systems. An RTOG trial of dose intensification using 3D-CRT with chemotherapy in patients with LA-NSCLC remains ongoing. Ancillary technologies are also being actively explored as a means of improving outcomes with RT. Positron emission tomography (PET)-based imaging is playing an increasing role in RT planning and may allow a more precise definition of the target volume. This would decrease the risk of a geographic miss of the tumor, and in some patients it would reduce the target volume and lower the risk of complications.35 Other techniques being investigated for improving RT delivery include breath-holding techniques and gating RT to tumor motion.35,36 These efforts to compensate for respiration effects and tumor movement might limit irradiation of normal lung parenchyma, which would then allow RT dose escalation with decreased morbidity. Clinical data demonstrating benefit from these new modalities remain to be published. Biologic approaches may also facilitate RT dose escalation. In particular, the use of amifostine as a radioprotectant is being explored in the treatment of NSCLC. Amifostine is an organic thiophosphate that is in clinical use as a selective cytoprotective agent for normal tissues against the toxicities of chemotherapy and RT. Clinical data are emerging to suggest that amifostine has potential radioprotective activity against acute radiation esophagitis and radiation pneumonitis (acute and chronic) in NSCLC patients treated with RT with or without concurrent chemotherapy.37

Definitive Chemotherapy and Radiotherapy The success achieved with single-modality RT for patients with locoregionally confined but inoperable disease has been limited, and this has led to intensive investigation into the potential role of systemic chemotherapy. Although chemotherapy as a single-treatment modality is of only modest benefit in patients with advanced disease, its use in conjunc-

TABLE 65-3 Randomized Phase III Trials Comparing Sequential Induction Chemotherapy Followed by Radiotherapy With Radiotherapy Alone for Locoregionally Confined Unresectable Non–Small Cell Lung Cancer Median Survival Time (Months) Author

No. Patients

Chemotherapy

RT

Induction

No Induction

Survival Benefit

238

CAP*

55 Gy (split)

11.0

10.4

No

Morton

114

MACL*

60 Gy

10.6

10.4

No

Lechevalier et al34

353

Vd CPL*

65 Gy

12.0

10.0

Yes

155

VbP

60 Gy

13.7

9.6

Yes

13.2

11.4

Yes

Mattson et al38 39

40,41

Dillman et al

30,42

Sause et al

458

VbP

†

60 Gy

A, Adriamycin (doxorubicin); C, cyclophosphamide; L, lomustine; M, methotrexate; P, cisplatin; RT, radiotherapy; Vb, vinblastine; Vd: vindesine. *Chemotherapy was also given after RT. † In the third arm of this study, 69.6 Gy of hyperfractionated RT resulted in a median survival time (12 mo) equivalent to that after 60 Gy of conventional RT without chemotherapy.

tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 807

1/21/2008 1:18:17 PM

808

Section 3 Lung

TABLE 65-4 Randomized Phase III Trials Comparing Concurrent Radiotherapy and Chemotherapy With Radiotherapy Alone for Locoregionally Confined Unresectable Non–Small Cell Lung Cancer Median Survival Time (Months) Author

No. Patients

Chemotherapy

RT

Concurrent Therapy

RT Alone

Survival Benefit

Soresi et al45

95

P weekly

50 Gy

16

11

No

Trovó et al46

173

P daily

45 Gy

10.3

10.0

No

Schaake-Koning et al

331

P weekly

55 Gy (split)

19%*

13%*

No

P daily

55 Gy (split)

26%*

13%*

Yes

Blanke et al48

240

P q 3 wk

60-65 Gy

11.5

10.8

No

49

Jeremic et al

169

CbE on wk 1,3,5

65 Gy (HF)

13

8

No

Jeremic et al50

131

47

CbE weekly

65 Gy (HF)

18

8

Yes

CbE daily

69 Gy (HF)

22

14

Yes

Cb, carboplatin; E, etoposide; HF, hyperfractionated radiotherapy; P, cisplatin; RT, radiotherapy. *2-Year survival rate.

TABLE 65-5 Randomized Phase III Trials Comparing Concurrent With Sequential Chemotherapy and Radiotherapy for Locoregionally Confined Unresectable Non–Small Cell Lung Cancer Median Survival Time (Months) Author

No. Patients

Chemotherapy

RT

Concurrent Therapy

Sequential Therapy

Survival Benefit

320

VdPMi

56 Gy

16.5

13.3

Concurrent

Curran et al

408*

VbP

60 Gy

17

14.6

Concurrent

Zatloukal et al54

102

VrP

60 Gy

16.6

12.9

Concurrent

Furuse et al51 52,53

Mi, mitomycin; P, cisplatin; RT, radiotherapy; Vb, vinblastine; Vd, vindesine; Vr, vinorelbine. *In this study, the results from a third arm using concurrent cisplatin, etoposide, and 69.6 Gy of hyperfractionated radiotherapy were not statistically different from those of either of the other two arms.

was given in full doses using an uncompromised schedule. However, even a treatment regimen using concurrent daily low-dose cisplatin and a split course of RT resulted in a significant improvement in overall survival.47 This survival benefit came as a result of better locoregional control. The rate of distant metastases was not improved by this radiosensitizing low-dose chemotherapy schedule. As experience accumulated with these multimodality treatment regimens, so did recognition of the importance of uncompromised chemotherapy dosing. The use of full-dose chemotherapy in combination with RT added the potential for improvement in the control of distant metastatic disease, the major cause of treatment failure, in addition to the observed improvement in locoregional control. The question remained as to whether full systemic doses of chemotherapy would be better administered before RT in a sequential fashion or concurrent with the RT. Table 65-5 lists three of the randomized trials that have addressed this question (Furuse et al, 1999).51-54 All three employed a full course of RT, either sequentially after induction chemotherapy or concurrent with chemotherapy, using a vinca-alkaloid and cisplatin–based treatment regimen. All three studies demonstrated a consistent survival benefit favoring the concurrent treatment approach. These three randomized trials allow us to

make a firm, evidence-based recommendation that treatment for patients with locoregionally confined but unresectable NSCLC includes uncompromised RT with concurrent cisplatin-based chemotherapy given in full systemic doses (Pfister et al, 2004).55 Despite the relative success of these concurrent treatment approaches, distant metastases continue to be the predominant reason for treatment failure. This has led to attempts to use additional chemotherapy in conjunction with concurrent chemoradiotherapy in an effort to further improve survival by decreasing distant metastatic disease. The two approaches explored have been concurrent chemoradiotherapy followed by consolidation chemotherapy and induction chemotherapy followed by concurrent treatment. It appears that the schedules using consolidation chemotherapy after concurrent treatment have had more success. Table 65-6 lists four trials that have come from work initiated by the Southwest Oncology Group (SWOG) that explored the use of full-dose concurrent RT, cisplatin, and etoposide, followed by consolidation chemotherapy with either additional cisplatin and etoposide or single-agent docetaxel.56-60 Note that the SWOG 901956 and SWOG 950458,59 trials were restricted to patients with stage IIIB disease. The 9504 protocol resulted in a median survival time of 26 months and

tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 808

1/21/2008 1:18:17 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

809

TABLE 65-6 Selected Phase II and Phase III Trials of Concurrent Chemotherapy and Radiotherapy Followed by Consolidation Chemotherapy in Patients With Locoregionally Confined Unresectable Non–Small Cell Lung Cancer and Good Prognosis*

Author

Group/Study

No. Patients

Stage

Concurrent Chemotherapy

RT

Consolidation Chemotherapy

Median Survival Time (Months)

5-Year Survival (%)

Albain et al56

SWOG 9019

50

IIIB

PE

61 Gy

PE

15

17

57

Albain et al

INT 0139 (Control Arm)

194

IIIA

PE

61 Gy

PE

22

20

Gandara et al58,59

SWOG 9504

83

IIIB

PE

61 Gy

D

26

29

SWOG 0023

575

IIIA/B

PE

61 Gy

D

19

N/A

60

Kelly et al

D, docetaxel; E, etoposide; INT, North American Intergroup; N/A, not available; P, cisplatin; RT, radiotherapy; SWOG, Southwest Oncology Group. *Patients in all four studies were required to have a pretreatment 1-second forced expiratory volume (FEV1) >2 L or an FEV1 >800 mL in the contralateral lung.

a 5-year survival rate of 29%, results numerically superior to those of most other studies. This experience was reproduced by SWOG 0023,60 a randomized trial that failed to demonstrate a benefit from the addition of maintenance gefitinib to this regimen. The INT 0139 experience was the nonsurgical control arm of a study addressing the role of surgery after concurrent chemoradiotherapy in patients with potentially resectable stage IIIA tumors.57 The results appeared to be consistent with those of the other SWOG studies. It must be recognized that the trials in Table 65-6 were restricted to patients with a relatively good prognosis. An eligibility requirement for all four studies was a pretreatment 1-second forced expiratory volume (FEV1) greater than 2 L, or at least 800 mL in the contralateral lung. This defined a more limited patient population than had generally been included in other studies of this stage of disease, and the better prognosis of these patients may well explain some of the additional benefit observed. Nonetheless, the apparent doubling of median survival time, from 13.7 months in the sequential Dillman study40,41 to 26 months in the Gandara58,59 study, is of considerable interest, particularly because all patients in the Gandara study had stage IIIB disease. Other investigators have conducted similar investigations in less homogeneous patient populations. Jeremic and colleagues61 reported on a series of stage III patients treated with concurrent daily multiagent chemotherapy using carboplatin and paclitaxel and a hyperfractionated RT course to 67.6 Gy. A median survival time of 28 months with a 5-year survival rate of 26% was reported, again suggesting an improvement with more aggressive treatment regimens. The alternative approach, induction chemotherapy followed by chemoradiotherapy, appears to have been less successful. The CALGB reported a study of three different cisplatin-based induction regimens followed by concurrent chemotherapy and RT; the median survival time for all patients was 17 months.62 When this cooperative group compared a concurrent carboplatin and paclitaxel chemoradiotherapy regimen with induction carboplatin and paclitaxel followed by the same concurrent chemoradiotherapy, median survival increased only from 11.4 months to 14 months, a difference that was not statistically significant.63

Similar results were noted by Choy and colleagues64 in the Locally Advanced Multimodality Protocol (LAMP) study from the American College of Radiology. This was a randomized phase II trial comparing these arms: 1. Induction carboplatin and paclitaxel followed by RT alone 2. Induction carboplatin and paclitaxel followed by concurrent chemoradiotherapy with the same agents 3. Concurrent carboplatin/paclitaxel chemoradiotherapy followed by consolidation carboplatin and paclitaxel Although the study was not sufficiently powered to allow statistical comparisons among the three treatment arms, the third regimen (concurrent chemoradiotherapy followed by consolidation chemotherapy) produced a median survival time of approximately 16 months, compared with 12.5 months for the first regimen (sequential induction) and 11 months for the third (induction followed by concurrent chemoradiotherapy). Although the results of these randomized studies suggest that induction chemotherapy is not the optimal treatment strategy, the numerically inferior results obtained from these schedules compared with the SWOG data may merely reflect selection criteria in the patient population studied. They might also reflect the fact that the concurrent schedules from both of these groups used weekly chemotherapy treatments, a schedule choice that may have been suboptimal. It is therefore difficult to be terribly dogmatic about the strength of the evidence-based recommendations that can be made. Although concurrent treatment regimens using full doses of cisplatin-based chemotherapy seem to provide the best treatment platform on which to build, much work remains to be done. Comparisons of the results obtained in different patient populations are hazardous, and, although the regimens employing consolidation chemotherapy after concurrent chemoradiotherapy appear promising, they have not yet been subjected to randomized phase III testing. Further investigation is required to optimize both the chemotherapy combination used and the RT administered. The incorporation of targeted agents remains a promising avenue for further investigation, particularly given the recent benefit reported

tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 809

1/21/2008 1:18:17 PM

810

Section 3 Lung

when bevacizumab was added to a treatment regimen used for patients with more advanced disease.65

THERAPY WITH PALLIATIVE INTENT Palliative Radiation Therapy Principles and Indications Most lung cancer patients are not candidates for curative therapy but rather are treated to relieve symptoms and improve their quality of life (QOL). The reason is that most lung cancer patients present with either locally advanced or metastatic disease, or they experience a relapse after initial treatment.66 When palliation becomes the treatment goal, RT is often the treatment modality of choice because it is quick and effective in relieving local symptoms. This kind of palliative care is not defined as merely an end-of-life measure, however, but rather as an endeavor that can positively influence the course of the illness. The goal of any palliation is to provide rapid relief of suffering. This fits well with the ability of palliative RT to be administered quickly and effectively with a course of a few large daily radiation fractions (e.g., 30 Gy in 10, 3-Gy fractions over 2 weeks). Moreover, palliative treatment is not limited by the potential development of delayed radiationinduced side effects.67 Historically, palliative RT regimens have been empirically based, reflecting close patient observation, personal judgment and training, and even cultural variations (e.g., between the United States and the United Kingdom). Until the 1980s, there was little systematic research into the use of palliative thoracic RT.66 However, current approaches emphasize formalized assessment of palliative benefits, accomplished mainly through the use of clinical trials and validated QOL tools to measure end points.68 Outcomes that are often evaluated include the number and relief of symptoms, toxicities of treatment, and improvements in performance status. Although QOL measures of palliation can elicit methodologic concerns regarding the validity of clinical trial results,68 the reality is that there now exists a wealth of peer-reviewed evidence that is useful in recommending specific palliative RT regimens for clinical practice. The most common means by which palliative RT for thoracic symptoms is delivered is EBRT, either by a linear accelerator or, in many countries still, by a cobalt unit. Although a variety of RT planning tools may refine the form of delivery (3D-CRT, IMRT) depending on clinical need, most treatment plans and set-ups for patients are simple and easily administered, in keeping with the palliative principles of ease and efficacy. Another means of palliating with radiation is through placement of radioactive sources close to or into tumor sites (brachytherapy). This is often indicated in the re-treatment of patients who have exhausted their capacity to tolerate further EBRT or when the clinical scenario favors highly focused treatment (e.g., endobronchial lesions).69 Although palliative EBRT is most often a single-modality treatment, clinicians have combined it with surgical interventions (e.g., stenting) or medical interventions (e.g., chemotherapy) as determined by patient need.

Chest symptoms related to primary lung cancer are most commonly caused by tumor compression, obstruction, or invasion. Therefore, respiratory compromise in various forms, such as dyspnea, cough, stridor and wheezing resulting from airway narrowing, postobstructive pneumonia, and atelectasis, are among the primary symptoms relieved by a course of palliative RT. In contrast, RT is relatively ineffective for respiratory symptoms arising from other presentations of advanced disease, such as pleural effusion, lymphangitic carcinomatosis, or extensive multilobar disease.69 Pain syndromes are usually attributable to visceral or bone involvement and are also amenable to palliation with RT. Bleeding or hemoptysis is often a symptom requiring urgent medical attention. It usually indicates tumor erosion into vasculature and can be one of the indications for emergency palliative RT. Less common complaints include altered swallowing from primary tumor or metastatic lymph node involvement or impingement on the esophagus. Although these symptoms may potentially be palliated by a rapid course of RT, the time course to relief can be prolonged.67

Palliative Thoracic Radiation Therapy— Evidence-Based Approach Since 1985, 13 phase III trials of palliative RT for thoracic symptoms27,70-81 have been reported in the medical literature as either abstracts or full papers (Table 65-7). As previously described, the end points in most of these trials have been symptom control, with a secondary focus on specific treatment-related toxicities (e.g., esophagitis) and overall survival. Although varieties of RT prescriptions have been investigated in these clinical studies, in many the experimental arm has been designed as an ultrarapid course of treatment (e.g., two fractions of 8 Gy), in contrast to standard arms with more conventionally administered RT (5-10 fractions of 3-4 Gy). In a recent comprehensive review of randomized palliative RT trials, Macbeth and Stephens66 used recognized radiation conversion factors and equations to translate RT doses, schedules, and fractionations into radiobiologically equivalent (RBE) prescriptions that would then allow for meaningful comparisons among trials (Table 65-8). Three broad categories of studies were created: class I studies, in which RBE regimens randomized patients with any performance status (PS); class II studies, in which RBE regimens randomized only patients with poor PS; and class III studies, in which non-RBE regimens randomized only patients with good PS. Their analysis led to the following conclusions. For class I, no significant difference was found among trials with respect to outcomes, regardless of PS. A median survival time of 6 months for all trials was determined. For class II, symptom control and palliation were equivalent; less esophagitis was noted in single-fraction regimens. An improved median survival time in patients with better PS was found in one class II study by Bezjak and colleagues.80 In class III, a trend to longer survival in patients with better PS receiving higher RT doses was reported. In particular, a U.K. Medical Research Council (MRC) trial comparing 39 Gy administered in 13 fractions versus 17 Gy administered in 2 fractions demonstrated a significant difference, with 2-year survival rates of

tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 810

1/21/2008 1:18:17 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

Author (Year)

RT Doses

Simpson et al70 (1985)

40 Gy/20 F vs 40 Gy/10 F (split) vs 30 Gy/10 F

thoracic symptoms at 6 months. Follow-up examinations were given at 1, 2, 4, and 6 months. The results showed no difference between the two arms at any time point: 28% of “immediate” RT patients versus 26% of “delayed” RT patients met the end point of 6 months. The overall survival was the same for both arms. Hence, there appears to be no advantage to early versus late palliation.

Teo et al71 (1988)

45 Gy/18 F vs 31.2 Gy/4 F (4 wk)

Palliative Radiation Therapy—Brachytherapy

Medical Research Council Lung Cancer Working Party72 (1991)

30 Gy/10 F vs 17 Gy/2 F

Medical Research Council Lung Cancer Working Party73 (1992)

10 Gy/1 F vs 17 Gy/2 F

Abratt et al74 (1995)

34 Gy/10 F vs 45 Gy/15 F

Macbeth et al75 (1996)

36-39 Gy/12-13 F vs 17 Gy/2 F

Rees et al76 (1997)

17 Gy/2 F vs 22.5 Gy/5 F

Reinfuss et al27 (1999)

50 Gy/25 F vs 40 Gy/10 F (split) vs 20-25 Gy/5 F (delayed)

Nestle et al77 (2000)

36 Gy/15 F (twice daily) vs 60 Gy/30 F

Senkus-Konefka et al78 (2001)

16 Gy/2 F vs 20 Gy/5 F

Gaze et al79 (2001)

10 Gy/1 F vs 30 Gy/10 F

Bezjak et al80 (2002)

10 Gy/1 F vs 20 Gy/5 F

Despite previous thoracic EBRT and other attempts at palliation, a significant percentage of patients may need relief of symptoms when obstruction or bleeding develops in the major airways. A number of local (i.e., endobronchial) therapies are clinically available for primary or recurrent disease in the trachea or bronchi. Brachytherapy, in which the radiation source is placed at a short distance from the target area, is one such local treatment. Various rates of dose delivery are feasible, of which the most common currently is a high-doserate (HDR) approach that reduces patient discomfort and inconvenience through speedy dose delivery.83 Treatment is usually administered in one to six fractions over intervals of 1 to 3 weeks.67 Brachytherapy involves endoscopic placement of a treatment catheter followed by introduction of the radioactive source into the patient for a prescribed application of dose. Complications appear to develop with single-fraction treatments greater than 15 Gy.84 There are numerous singleinstitution reports and retrospective studies validating the effectiveness of brachytherapy as a stand-alone therapy, but the single phase III study conducted did not demonstrate its superiority over EBRT.85 Current evidence, instead, favors its application as a complimentary therapy to EBRT.69

Sundstrom et al81 (2004)

17 Gy/2 F vs 42 Gy/15 F vs 50 Gy/25 F

Palliative External-Beam Radiation Therapy Compared With Other Modalities

TABLE 65-7 Randomized Studies of Palliative Radiotherapy for Thoracic Symptoms in Patients With Lung Cancer

F, fractions; RT, radiotherapy.

13% and 9%, respectively.75 Macbeth and Stephens’ overall assessment66 was that patients with poor PS are not well served by prolonged palliative regimens, in terms of either palliation or survival, and they recommended one- or twofraction RT schedules for this group. For patients with good PS, small survival benefits, without improved palliative results, might justify a more prolonged palliative course (e.g., 10 fractions) at the expense of more esophagitis. Clinicians may be unsure when to offer palliative thoracic RT when assessing patients with metastatic disease who present with minimal symptoms. The question is, are there advantages to “preventative” palliation in order to prevent progression to symptoms? This was explored by an MRC study reported by Falk and associates.82 A total of 230 patients with untreated, incurable NSCLC were randomly assigned to receive either 17 Gy in two fractions or 10 Gy in one fraction at presentation (immediate) or at symptom development (delayed). The end point in this study was the proportion of patients who were alive and free of moderate or severe

811

Given that palliative thoracic RT is most commonly administered externally, there have been a number of studies exploring the effectiveness of EBRT compared with other palliative techniques. Stout and coworkers85 compared EBRT versus palliative brachytherapy alone in a randomized trial involving 99 patients with advanced untreated NSCLC. Endobronchial brachytherapy (15 Gy at 1 cm, delivered in one fraction) was compared with EBRT (30 Gy, 10 fractions) for symptom relief and duration. The result showed equivalent symptom relief, although the duration of symptom control was longer with EBRT. There were fewer retreatments with EBRT: 28% of EBRT patients had subsequent brachytherapy, and 51% of brachytherapy patients required subsequent EBRT. Overall survival was reported as “better” with EBRT (9.5 versus 8.3 months), but the difference was not statistically significant. Comparing “surgical” palliation to EBRT was the purpose of a 1999 randomized MRC trial.86 In this study, EBRT was to be compared with either brachytherapy, laser resection, or cryotherapy, with the choice of the “surgical” method left to the discretion of the clinician or hospital. This study was closed due to poor accrual because only 75 out of a necessary 400 patients were enrolled. To date, there have been no phase III trials of EBRT versus endobronchial stents alone.

tahir99-VRG vip.persianss.ir

Ch065-F06861.indd 811

1/21/2008 1:18:17 PM

812

Section 3 Lung

TABLE 65-8 Randomized Trials of Palliative Thoracic Radiotherapy Categorized by Radiobiologic Equivalency and Patient Performance Status

Author (Year) Class I—RBE, any PS Medical Research Council Lung Cancer Working Party72 (1991) Rees et al76 (1997) Senkus-Konefka et al78 (2001) Sundstrom et al81 (2004)

Class II—RBE, Poor PS Medical Research Council Lung Cancer Working Party73 (1992) Gaze et al79 (2001) Bezjak et al80 (2002)

Regimen

No. Patients, PS, and Age

30 Gy/10 F vs 17 Gy/2 F

Symptom Control

Esophagitis

Survival

369, any PS 71% >65 yr

No difference

No difference

No difference

17 Gy/2 F vs 22.5 Gy/5 F 16 Gy/2 F vs 20 Gy/5 F 17 Gy/2 F vs 42 Gy/15 F vs 50 Gy/25 F

216, any PS 77% >65 yr 100, any PS mean 66 yr 407, any PS NA

No difference

NA

No difference

No difference

Worse for 20 Gy

No difference

No difference

NA

No difference

10 Gy/1 F vs 17 Gy/2 F

235, PS 2-4 73% >65 yr

No difference

Worse with 17 Gy

No difference

10 Gy/1 F vs 30 Gy/10 F 10 Gy/1 F vs 20 Gy/5 F

148, NA NA 230, PS 0-3 median 70 yr

Possibly better for 30 Gy Possibly better for 20 Gy

NA

No difference

No difference

Better for 20 Gy

509, PS 0-1 59% >65 yr 84, PS 0-2 mean 60 yr 152, KPS >50 median 66 yr

No difference

Worse with 39 Gy

No difference

Worse with 45 Gy

No difference (poor data)

Worse with 60 Gy

Better for 39 Gy: 9% vs 12% at 2 yr No difference: 40% vs 37% at 1 yr No difference

316, KPS >60 56% 60-70 yr

No difference

NA

No difference

273, any PS mean 62 yr 407, any PS NA

Better with 45 Gy (P = .012) No difference

NA

No difference

NA

No difference

Class III—Non-RBE, Good PS Macbeth et al75 (1996) 36-39 Gy/12-13 F vs 17 Gy/2 F Abratt et al74 (1995) 35 Gy/10 F vs 45 Gy/15 F Nestle et al77 (2000) 36 Gy/15 F (twice daily) vs 60 Gy/30 F Simpson et al70 (1985) 40 Gy/20 F vs 40 Gy/10 F (split) vs 30 Gy/10 F Teo et al71 (1988) 45 Gy/18 F vs 31.2 Gy/4 F (4 wk) Sundstrom et al81 (2004) 17 Gy/2 F vs 42 Gy/15 F vs 50 Gy/25 F

F, fractions; KPS, Karnofsky performance score; NA, not available; PS, performance status; RBE, radiobiologic equivalent. Adapted from Macbeth F, Stephens R: Palliative treatment for advanced non-small cell lung cancer. Hematol Oncol Clin North Am 18:115, 2004.

The role of palliative chemotherapy administered with palliative RT was explored in a phase III Australian study. Ball and colleagues87 randomized 200 patients with incurable NSCLC to EBRT (20 Gy, five fractions) versus the same RT plus continuous infusion of 5-fluorouracil (5-FU). The results revealed no difference in symptom palliation or survival with the addition of 5-FU. Higher toxicity was reported in the chemoradiotherapy arm, in the form of higher rates of nausea and vomiting, esophagitis, and skin rash. The authors concluded that the combined treatment was inferior to EBRT alone. Palliative RT, especially in the form of EBRT, remains a major component of the management of advanced lung cancer. Especially for those patients with poor PS, there is no evidence from randomized trials that prolonged or protracted regimens offer better symptom management than shorter courses of treatment do. This conclusion is in accord with the reality of the dismal median survival times in patients

Ch065-F06861.indd 812

with incurable or advanced disease. In that regard, regimens of two fractions not only offer patients efficacy and convenience but also appear to maintain QOL. For the minority of patients with good PS, and for those with unusually indolent disease, higher doses given over more protracted periods may produce a small survival benefit and reduce potential longterm morbidity from the therapy.

Palliative Systemic Treatments Systemic Chemotherapy Many patients presenting with inoperable advanced stage III and IV NSCLC are candidates for palliative chemotherapy, a treatment modality that has been demonstrated to have activity in advanced NSCLC in multiple studies over the past 20 years.88,89 Chemotherapy Versus Best Supportive Care. A large number of randomized studies have compared combination

1/21/2008 1:18:17 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

813

TABLE 65-9 Chemotherapy Versus Best Supportive Care Author

Chemotherapy

No. Patients, BSC/Chemotherapy

Median Survival Time (Weeks), BSC/Chemotherapy

P Value

Rapp et al95

CAP, VdP

50/43/44

17/25/33

.0001

ELVIS

Vr

81/80

21/28

.03

Spiro (BLT)99

P-based

361/364

23/32

.0006

98

BSC, best supportive care; CAP, cyclophosphamide, Adriamycin, cisplatin; P-based, cisplatin-based; VdP, vindesine, cisplatin; Vr, vinorelbine.

or single-agent chemotherapy with BSC in patients with advanced NSCLC (Rapp et al, 1988).90-101 Most of these studies showed a small but statistically significant survival benefit in favor of chemotherapy. In those studies in which QOL outcomes were prospectively assessed, lung cancer– related symptoms were, in general, improved. Table 65-9 summarizes the results of three representative, often cited trials. Several meta-analyses have been performed to assess the survival benefit from chemotherapy compared with BSC in patients with advanced NSCLC. All have suggested a survival benefit for chemotherapy (Non–Small Cell Lung Cancer Collaborative Group, 1995).102-104 A landmark 1995 metaanalysis, using updated individual patient data, included 9387 patients enrolled on 52 randomized trials comparing chemotherapy and BSC (Non–Small Cell Lung Cancer Collaborative Group, 1995).103 At 1 year, an absolute survival benefit of 10% was noted with chemotherapy (26% versus 16%), and median survival time increased by 2 months (6 versus 8 months). These differences were highly statistically significant (P = .00007). The benefit was limited, however, to patients receiving cisplatin-based chemotherapy. Alkylating agent–based chemotherapy was associated with a detrimental effect on both median and 1-year survival. During the 1990s, several new agents were shown to be active in the treatment of advanced NSCLC, including paclitaxel, docetaxel, vinorelbine, and gemcitabine.105 Many questions needed to be answered. Would the addition of these newer agents to platin (i.e., doublet versus single-agent therapy) add to the benefit of the platin? Which platin doublet is better? Is carboplatin, a better tolerated platin, equivalent to cisplatin? Do we even need a platin? Can we do better with the addition of a third agent to the mix (triplet therapy)? These questions are addressed in the following sections. Doublet Versus Single-Agent Therapy. Multiple randomized trials have compared cisplatin-containing combination regimens with single-agent therapy in advanced NSCLC (Table 65-10).106-117 Most have demonstrated higher response rates for the combination regimens, but only some have shown a survival benefit.106,108-110 In one study where the doublet was associated with no statistically superior survival in the overall study population, a benefit with the doublet was noted in patients with an ECOG performance status of 2.110 At least three meta-analyses have been conducted to compare monotherapy versus polychemotherapy for treatment of advanced NSCLC.118-120 Lilenbaum and associates119

Ch065-F06861.indd 813

included 5156 patients enrolled on 25 trials comparing a variety of single agents versus combination therapy. Overall, combination chemotherapy produced an almost twofold increase in response rate compared with single-agent chemotherapy (relative risk, 1.93; 95% confidence interval [CI], 1.54-2.42). However, combination chemotherapy also increased toxicity significantly, including a 3.6-fold increase in the risk of treatment-related death. Survival at 6 months and 12 months was modestly superior with combination chemotherapy when all trials were included. However, if the single agent was a platinum analogue or vinorelbine, this difference was no longer statistically significant. The authors concluded that combination chemotherapy increased objective response and toxicity rates, compared with single-agent chemotherapy. Survival was prolonged only modestly with combination chemotherapy, but not significantly so when the more active single agents were used. Marino and colleagues120 demonstrated that the estimated pooled odds ratio (OR) of death at 1 year with polychemotherapy, compared with monotherapy, was 0.8 (95% CI, 0.6-1.0). The largest of the meta-analyses included 65 trials of monotherapy versus twodrug or three-drug polychemotherapy and a total of 13,601 patients.118 In the trials comparing a doublet regimen versus monotherapy, doublet therapy was associated with a significantly higher objective tumor response (OR, 0.42; 95% CI, 0.37-0.47, corresponding to a twofold increase in the response rate, from 13% to 26%) and a significantly higher 1-year survival rate (OR, 0.8; 95% CI, 0.70-0.91, corresponding to an increase in 1-year survival from 30% to 35%). The median survival ratio was 0.83 (95% CI, 0.79%-0.89%), corresponding to a 17% improvement in median survival. In summary, there appears to be a trend toward better survival when platinum-containing doublets are used.121,122 Single-agent treatment is recommended for patients who are unable to tolerate combination chemotherapy. Is There an Optimal Chemotherapy Regimen? Many randomized trials have compared doublets containing the newer chemotherapy agents (taxanes, gemcitabine, vinorelbine, and irinotecan) plus either cisplatin or carboplatin to older doublets (vindesine, etoposide) plus cisplatin or to other new nonplatinum doublets.123 The results of these trials are summarized in Table 65-11 (Schiller et al, 2002).106,122,124-131 In most of these studies, the newer twodrug combinations produced response rates, median survival times, and long-term survival rates almost identical to those of the older doublets. The most important trial comparing modern cisplatinbased combinations was a four-arm randomized study

1/21/2008 1:18:17 PM

814

Section 3 Lung

TABLE 65-10 Randomized Studies Comparing Doublet Versus Single-Agent Chemotherapy Author (Year)

No. Patients

Chemotherapy

Response Rate (%)

Overall Survival (Wk)

P Value

Lechevelier et al106 (1994)

612

C/V

30

40

RR (C/V vs V): P = .02 OS (C/V vs V): P = .001

C/Vind V

19 14

32 31

C/V

26

32

C

12

24

162

C/Eto C

22 19

26 22

NS

216

C/Eto

25.8

32

RR: P = .005 OS: NS

C

7

24

Wozniak et al108 (1998)

107

Klastersky et al

(1989)

Rosso et al111 (1990)

112

Einhorn et al

415

RR: P = .002 OS: P = .0018

(1986)

124

C/Vind C/Vind/M Vind

27 20 14

26 17 18

NS

Luedke et al113 (1990)

435

C/Vind

19

24.7

OS (C/Vind vs Vind): P = .06

C/Vind/M Vind

27 <1

20.4 14.8

30.4

36.4

Sandler et al109 (2000)

552

C/G C

11.1

30.4

Lilenbaum et al110 (2005)

661

T/Cp

30

35.2

T

17

26.8

D/C

36.5

42

C

21.7

32

26

34.4

Georgoulias et al

Gatzemeier et al

117

114

(2004)

319

RR: P < .0001 OS: P = .004 RR: P = .0001 OS: NS RR: P = .004 OS: NS RR: P = .028 OS: NS

(1998)

414

T/C C

17

32.4

Sederholm et al115 (2002)

335

G/Cp G

29.6 11.5

47.7 39

OS: P = .016

Masuda et al116 (1999)

380

I/C Vind/C I

44 32 21

50 46 46

NS

C, cisplatin; Cp, carboplatin; D, docetaxel; Eto, etoposide; G, gemcitabine; I, irinotecan; M, mitomycin; NS, not significant; OS, overall survival; RR, response rate; T, paclitaxel; V, vinorelbine; Vind, vindesine.

conducted by the Eastern Cooperative Oncology Group (ECOG) that compared gemcitabine plus cisplatin, docetaxel plus cisplatin, and paclitaxel plus carboplatin versus a reference arm of cisplatin plus 24-hour infusion paclitaxel (Schiller et al, 2002).125 Overall response rates (approximately 19%), median survival times (average 7.9 months), and 1-year survival rates (33%), as well as 2-year survival rates, were similar in all four groups. None of the four regimens was superior. Although platin doublets have been the standard of care for first-line treatment of metastatic lung cancer, recent trials comparing nonplatin doublets versus platin-containing doublets have also revealed no statistically different difference in response rate or median survival time.122,126-128 A metaanalysis was performed to compare the activity, efficacy, and toxicity of platinum-based versus non–platinum-based che-

Ch065-F06861.indd 814

motherapy in patients with advanced NSCLC. Subgroups of trials using third-generation agents were compared. Thirtyseven assessable trials were identified, involving 7633 patients, comparing first-line palliative platinum-based chemotherapy versus the same regimen without platinum or versus platinum replaced by a nonplatinum agent. A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46-1.8; P < .0001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% versus 29%; OR, 1.21; 95% CI, 1.09-1.35; P < .0003). Platinum-based regimens produced significantly higher hematologic toxicity, nephrotoxicity, and nausea and vomiting, but not neurotoxicity, febrile neutropenia, or toxic death.132 Therefore, despite the large number of completed randomized trials, no single regimen has emerged as the best choice

1/21/2008 1:18:18 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

815

TABLE 65-11 Randomized Trials Comparing Doublet Chemotherapy Regimens

Chemotherapy

Response Rate (%)

408

Vinorelbine/cisplatin Paclitaxel/carboplatin

29 25

8 8

36 38

NS

1172

Paclitaxel/cisplatin Gemcitabine/cisplatin Docetaxel/cisplatin Paclitaxel/carboplatin

21 21 17 15

7.8 8.1 7.4 8.2

31 36 31 35

NS

Smit EF et al (EORTC 08975)122

479

Paclitaxel/cisplatin Gemcitabine/cisplatin Paclitaxel/gemcitabine

31 36 27

8.1 8.8 6.9

35 33 26

NS

Georgioulias et al126

317

Docetaxel/cisplatin Docetaxel/gemcitabine

30 33

12 11

46 41

NS

Kosmidis et al127

253

Paclitaxel/carboplatin Paclitaxel/gemcitabine

29 37

10.7 12.3

41 51

NS

Satouchi et al128

112

Irinotecan/docetaxel Docetaxel/cisplatin

35 41

9.0 7.8

NR NR

NS

Fossella et al129

1218

Vinorelbine/cisplatin Docetaxel/cisplatin Docetaxel/carboplatin

NR NR NR

42 47 38

NS

Scagliotti et al130

612

Gemcitabine/cisplatin Paclitaxel/carboplatin Vinorelbine/cisplatin

30 32 30

9.8 9.9 9.5

37 43 37

NS

Kubota et al131

332

Docetaxel/cisplatin Vindesine/cisplatin

37 21

11.3 9.6

47.7 24.4

0.02

Lechevalier et al106

612

Vinorelbine/cisplatin Vindesine/cisplatin

30 19

40 32

NR NR

0.04

Author/Study Kelley et al (SWOG)124 Schiller et al (ECOG 1594)125

No. Patients

Median Survival Time (Mo)

10 11 9

1-Year Survival (%)

P Value

ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; NR, not reported; NS, not significant; SWOG, Southwest Oncology Group.

for treatment of advanced NSCLC. All regimens seem to have equivalent efficacy, but their toxicity varies. Cisplatinbased regimens are complicated by the length of administration, need for hydration, nausea, and renal toxicity. Paclitaxel regimens are associated with an increased risk of peripheral neuropathy. Vinorelbine, docetaxel, and gemcitabine have been more frequently associated with bone marrow toxicity. Therefore, the choice between the available combination regimens can best be made based on the toxicity, convenience of administration, and cost. The use of platinum-based chemotherapy is recommended for patients with metastatic NSCLC and good PS. Non–platinum-containing doublets also represent an acceptable option in patients who would not be able to tolerate a platin doublet. Triplet Versus Doublet Therapy. Only a few randomized trials have been conducted to determine whether three-drug combinations are superior to two-drug combinations or to alternating combinations.133-135 There has been no clear evidence of an improvement in survival, and the three-drug combinations are more toxic. Currently, there is no evidence that a three-drug combination or an alternating twodrug combination regimen is preferred over a two-drug combination.

Ch065-F06861.indd 815

Optimal Duration of Therapy. Two trials have assessed the optimal duration of chemotherapy.136,137 In one trial specifically designed to answer this question, 230 patients with advanced NSCLC were randomly assigned to either of the following136: 1. Four courses of paclitaxel plus carboplatin followed by salvage therapy with single-agent paclitaxel at the time of progression 2. Continuous treatment with both agents until radiographic progression Compared with continuous combination therapy, overall response rates were similar when treatment was limited to four cycles (22% versus 24%), as were median survival times (6.6 versus 8.8 months) and 1-year survival rates (28% versus 34%). Although QOL did not differ significantly between the two groups, the incidence of treatment-related grade 2 neurotoxicity more than doubled (20% versus 43%) between cycles 4 and 8 on the continuous treatment arm. Similar results were found in a trial comparing three versus six courses of MVP chemotherapy (mitomycin, vinblastine, and cisplatin).137 The objective response rate was slightly higher with longer treatment duration (38% versus 31%), but

1/21/2008 1:18:18 PM

816

Section 3 Lung

survival was similar.137 QOL parameters suggested less fatigue and a trend toward less nausea and vomiting with three compared to six cycles of therapy. Guidelines for treatment of unresectable NSCLC from The American Society of Clinical Oncology (ASCO) recommend that first-line chemotherapy be limited to four to six cycles for patients with stage IV disease, and that it be discontinued in patients who do not have a response after four cycles.55 Second- and Third-line Treatments. Second-line treatment should only be considered for selected patients with a good PS. Response rates tend to decline with each subsequent treatment regimen.138 Docetaxel was the first drug to be approved by the U.S. Food and Drug Administration for second-line treatment of metastatic NSCLC. The benefit of docetaxel was shown in a trial in which 103 patients with previously treated stage IIIB or IV NSCLC were randomly assigned to docetaxel monotherapy (100 mg/m2 or 75 mg/m2) or BSC.139 Patients undergoing chemotherapy had a better median survival (7.5 versus 4.6 months) and 1-year survival (37% versus 11%). Side effects such as febrile neutropenia were less common in patients treated with the lower-dose regimen. This result was associated with improved pain control and significantly less deterioration in QOL in those receiving chemotherapy.140 Single-agent docetaxel (100 or 75 mg/m2 once every 3 weeks) was directly compared to vinorelbine (30 mg/m2 weekly) or ifosfamide (2 g/m2 daily for 3 days, every 3 weeks) in a randomized trial of second-line chemotherapy for 373 patients for whom a first-line platinum-containing regimen had failed.141 The median survival times were similar in all groups (5.6 months); however, 1-year survival rates favored docetaxel 75 mg/m2 (32% versus 21% for docetaxel 100 mg/m2 and 19% for vinorelbine or ifosfamide). Pemetrexed was approved for salvage therapy based on its therapeutic noninferiority to docetaxel and a more favorable toxicity profile. A phase III trial was conducted comparing docetaxel 75 mg/m2 and pemetrexed 500 mg/m2 (supplemented with folic acid [350 to 1000 µg daily], vitamin B12 [1000 µg every 9 weeks], and dexamethasone) in 571 patients with recurrent NSCLC.142 Although the objective response rate (9%) and median survival time (8 months) were similar for both agents, pemetrexed was associated with significantly less fever, neutropenia, hair loss, and neuropathy. Patients receiving docetaxel were three times more likely to require hospitalization during therapy. Erlotinib and gefitinib are small-molecule tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) and have both been approved for patients with advanced NSCLC for whom prior regimens have failed. The roles of these agents are discussed in the next section.

Novel Therapies The transformation of a normal cell into a tumor cell is now considered to be dependent on mutations in gene products that are important for integrating extracellular and intracellular signals to the cell cycle and cell death machinery, and

Ch065-F06861.indd 816

on those gene products involved in directly controlling cellcycle progression. Loss of either type of function leads to loss of regulatory cell growth signals. The discovery of oncogenes in the 1970s and their overexpression or increased activity in tumor cells led to the suggestion that the abnormality in tumor cells was the presence of too much signal that pushed the cell through the cell cycle. The discovery of tumor-suppressive genes in the 1980s added to this model by suggesting that the growth abnormality of tumor cells resulted from a combination of too few cell-cycle brakes (tumor suppressors) and too many cell-cycle accelerators (oncogenes). An extracellular signal often triggers a robust array of intracellular signaling pathways that simultaneously communicate a multitude of signals. This process is known as signal transduction. Cell signaling is vital to the life cycle and biologic function of all cells and is critically important in governing such processes as proliferation and differentiation. The desire to provide less toxic therapeutic alternatives for patients with advanced NSCLC and the limited success of conventional chemotherapy have led to the exploration of novel targeted therapies. Because targeted therapies are meant to differentiate between malignant and nonmalignant cells, they lack many of the side effects associated with systemic chemotherapy. Furthermore, they presumably do not share the same pathways of drug resistance, and many may have synergistic or additive effects when added to conventional chemotherapeutic agents. Major components of cell signaling pathways (e.g., protein tyrosine kinases, protein kinase C, and RAS/mitogenactivated protein kinase [RAS/MAPK]) and components of the normal cell cycle (cell survival pathways) are frequently altered in lung cancer cells through either overexpression or mutation. A number of these dysregulated pathways have been identified as potential therapeutic targets. In addition, tumor-associated antigens have become a focus for immunotherapy approaches, and angiogenesis, the process by which tumors establish their own blood supply, has also been targeted using specific antiangiogenic therapies. Here we present an overview of the most promising novel therapeutic approaches for the treatment of NSCLC. Tyrosine Kinases. There are more than 90 known protein kinase genes in the human genome; 58 encode transmembrane receptor TKs, and 32 encode cytoplasmic, nonreceptor TKs.143 In normal cells, the activity of protein TKs is tightly regulated. However, perturbation of protein kinase signaling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation.144 As with normal cells, tumor growth and progression depends largely on the activity of cell surface membrane receptors that control the intracellular signal transduction pathways regulating proliferation, apoptosis, angiogenesis, adhesion, and motility. One such family of cell surface receptors are the receptor tyrosine kinases (RTKs), which include EGFR (also called HER1 or ERBB1), ERBB2 (also called HER-2/neu), ERBB3 (HER-3), and ERBB4 (HER-4). These receptors are glycoproteins that possess an N-terminal extracellular ligand-binding domain, a single anchoring transmembrane alpha helix, and a cytosolic C-terminal domain with TK activity. Ligand binding to the extracellular domain of the

1/21/2008 1:18:18 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

RTK results in dimerization of the receptor, activation of the cytosolic TK domain with autophosphorylation of the receptor, and activation of downstream signaling molecules such as phospholipase C and RAS/MAPK. Whereas RTK activity is tightly controlled in normal cells, the genes encoding these receptors escape from their usual inhibitory intracellular mechanisms in malignant cells through amplification, mutation, or structural rearrangement.145 The EGFR is a transmembrane receptor TK of the ERBB family that is abnormally activated in many epithelial tumors. Several mechanisms lead to aberrant receptor activation, including receptor overexpression, gene amplification, activating mutations, overexpression of receptor ligands, and loss of negative regulatory mechanisms. Receptor activation leads to recruitment and phosphorylation of several intracellular substrates, which, in turn, engage mitogenic signaling and other tumor-promoting activities.144 More than 20 years ago, Mendelsohn and colleagues proposed that the EGFR was a potential target for cancer therapy.146,147 This hypothesis has been confirmed, and there are now two classes of anti-EGFR agents with established clinical activity in cancer. These are the monoclonal antibodies directed at the extracellular domain of the receptor and the small-molecule, adenosine triphosphate (ATP)-competitive inhibitors of the receptor’s TK.148 The small-molecule TKIs compete with ATP binding to the TK domain of the receptor, which inhibits TK activation and subsequently leads to blockade of EGFR signaling pathways. A significant number of this class of agents are currently under clinical development. They differ mainly in their potency against the various members of the HER-receptor family and their capacity to preferentially inhibit a single receptor type or to inhibit other HER receptors or other TKreceptor families.144 Two TKIs are currently commercially available for use in metastatic NSCLC: gefitinib (also known as ZD1839 or Iressa), and erlotinib (OSI-774, or Tarceva). Both are orally administered and generally well-tolerated. Although, as a class, they are not myelosuppressive, they share dermatologic toxicity (predominantly dry skin and an acneiform rash), presumably because of high levels of EGF expression in the basal layer of the epidermis. The occurrence

817

and severity of rash during treatment may correlate with efficacy.149,150 Based on the early clinical activity observed in the phase I studies, anti-EGFR TKIs were preferentially studied in patients with advanced NSCLC. The documentation of clinical responses observed in the large monotherapy trials with the EGFR TKIs gefitinib and erlotinib generated a high degree of enthusiasm.151-153 This enthusiasm, however, was followed by disappointment when a series of large phase III studies failed to show additional benefit when erlotinib or gefitinib was given in combination with conventional chemotherapy.154-157 Results of these trials are summarized in Table 65-12. Interest was renewed by a series of new findings that will have a profound impact on the potential role of these agents in the treatment of patients with NSCLC. First, the results of two well-powered, placebo-controlled, randomized studies with single-agent erlotinib (BR.21) (Shepherd et al, 2005)158 and single-agent gefitinib (Iressa Survival Evaluation in Lung Cancer [ISEL])159 have become available (Table 65-13). Second, EGFR gene mutations have been discovered in the receptor TK domain that are associated with a high response rate to these small-molecule inhibitors. The first reported randomized trial of single-agent therapy versus placebo was the BR.21 study (Shepherd et al, 2005).158 Patients with NSCLC after first- or second-line chemotherapy were randomly assigned to receive erlotinib 150 mg/day or placebo (2 : 1 randomization). The primary end point was survival, with secondary end points of progression-free survival (PFS), response, toxicity, and QOL. A total of 731 patients entered the study and were heavily pretreated: 49% had received two prior chemotherapy regimens, 93% had received platinum, and 37% had received prior taxanes. Overall response to erlotinib was 8.9% (95% CI, 6.6%-12.0%; P < .001). Statistically significant differences were observed for overall survival (6.7 versus 4.7 months; P = .001) and PFS (2.2 versus 1.8 months; P < .001) (Shepherd et al, 2005).158 A similar study with gefitinib (ISEL) has also been conducted. In this large study, 1692 patients were randomly assigned to receive gefitinib 250 mg/day or placebo. Although the response rate was similar to that observed with erlotinib

TABLE 65-12 Randomized Studies of Chemotherapy Plus Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors Versus Chemotherapy Alone Author/Study

Treatment

Median Survival (Mo)

1-Year Survival (%)

Giaccone et al (INTACT 1)154

G + P + placebo G + P + gefitinib 250 mg/day G + P + gefitinib 500 mg/day

10.9 9.9 9.9

44 41 43

Herbst et al (INTACT 2)155

T + C + placebo T + C + gefitinib 250 mg/day T + C + gefitinib 500 mg/day

9.9 9.8 8.7

42 41 37

Herbst et al (TRIBUTE)156

T + C + placebo T + C + erlotinib 150 mg/day

10.6 10.8

NR NR

Gatzemeier et al (TALENT)157

G + P + placebo G + P + erlotinib 150 mg/day

10.2 9.9

NR NR

C, carboplatin; G, gemcitabine; NR, not reported; P, cisplatin; T, paclitaxel.

Ch065-F06861.indd 817

1/21/2008 1:18:18 PM

818

Section 3 Lung

TABLE 65-13 Randomized Studies of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors Versus Placebo Author/Study

Treatment

Median Survival (Mo)

Hazard Ratio

Shepherd et al (BR.21)158

Erlotinib 150 mg/day Placebo

6.7 4.7

0.76 (P < .001)

Thatcher et al (ISEL)159

Gefitinib 250 mg/day Placebo

5.6 5.1

0.89 (P = .11)

in BR.21, gefitinib failed to statistically prolong patients’ survival in comparison to placebo (hazard ratio [HR] = 0.89; P = .11; median, 5.6 versus 5.1 months).159 The reason for the discordance between these two studies is unknown. One potential explanation is that these two agents may have different activity profiles. A second, not mutually exclusive, possibility is that they were used at doses with different biochemical potency against the EGFR. In transient transfection studies, phosphorylation of the wildtype EGFR was inhibited 50% by 0.1 µmol/L and 100% by 2.0 µmol/L gefitinib, whereas the respective concentrations for mutant EGFR (L858R and del747-752) were approximately 0.015 and 0.2 µmol/L.160 Of note, the steady-state plasma levels of gefitinib (250 mg/day) and erlotinib (150 mg/ day) are less than 1 and 3 µmol/L, respectively.149,161 Although at these doses both small molecules would have attained adequate plasma concentrations sufficient to block mutant EGFR signaling, a 250-mg dose of gefitinib might be insufficient to completely inhibit the activated wild-type EGFR. However, this speculation is countered by the fact that, in the monotherapy trials with 250 or 500 mg/day gefitinib (IDEAL 1 and IDEAL 2), the response rate in patients with chemotherapy-refractory NSCLC was identical regardless of the dose.151,152 Whether the difference in outcome of these two trials can be explained by the fact that erlotinib was used at a higher equivalent dose than gefitinib remains unknown.144 In all the studies, there was a strong indication that a subset of patients with NSCLC has a substantially greater benefit from therapy with gefitinib or erlotinib. Patients with bronchioloalveolar carcinoma (BAC), never-smokers, females, and Japanese patients had a higher response rate and greater clinical benefit. This could suggest the existence of a subpopulation of patients with EGFR-dependent tumors. Recently, mutations in exons 18 through 21 encoding the TK domain of the EGFR were discovered and found to be predicative of response to gefitinib and erlotinib.160,162-164 These mutations are more frequent in tumors from neversmokers (92/181, or 50.8%) as opposed to former/current smokers (39/ 434, 9.0%),163,164 from females (81/216, 37.5%) as opposed to males (55/422, 13.0%),163,164 from adenocarcinomas (142/453, 31.3%) as opposed to other NSCLC histologies (7/306, 2.3%),160,162-164 and from patients of East Asian origin (122/419, 29.1%) as opposed to non–East Asian patients (27/340, 7.9%).160,162-164 The incidence of these mutations among patients from the United States is 9.5% (25/262).160,162-164 EGFR mutations may also appear more commonly in tumors with features of BAC histology.160,162,164 Using the strict World Health Organization definition of BAC as a com-

Ch065-F06861.indd 818

pletely noninvasive adenocarcinoma of the lung with lepidic growth,165 the incidence of EGFR mutations was low.163 However, using a less stringent histologic criteria in which adenocarcinomas containing any areas of BAC growth are included,163 almost all tumors sensitive to gefitinib or erlotinib and harboring mutations have features of BAC.163 This is consistent with the clinical observation that the response rate to erlotinib in pure BAC may be somewhat lower than that of mixed tumors or BAC variants.166 This difference in mutation frequency between pure BAC and adenocarcinomas with areas of BAC features raises questions as to whether these entities arise via distinct mechanisms of pathogenesis. There is a suggestion that the clinical benefit observed with anti-EGFR TKIs is not restricted to those patients harboring EGFR gene mutations. Although patients with receptor mutations may have an increased response rate to an EGFR TKI and have a longer survival time, the relatively small fraction of patients with tumor responses in BR.21 is unlikely to sufficiently explain the observed survival benefit. The implication is that factors other than EGFR mutations may have played a role in the observed clinical benefit in BR.21. This is not surprising because other molecular mechanisms, such as EGFR gene amplification and receptor ligand overexpression, can also endow the receptor with a “gain of function” potentially leading to EGFR dependence and, in turn, sensitivity to single-agent EGFR TKIs. In a subset analysis of BR.21 with a limited number of tumor samples, the survival benefit was greater for those patients with higher levels of EGFR expression. Furthermore, EGFR gene amplification has been recently reported in NSCLC and has been shown to correlate with high levels of receptor expression.151 Preliminary data suggested a strong correlation between EGFR gene amplification and response to gefitinib in NSCLC.152,167 Whether amplification of the EGFR locus correlates with the mutations reported in NSCLC is unknown. Studies are currently underway to correlate EGFR gene amplification and clinical benefit from anti-EGFR therapies, as occurs in the case of ERBB2amplified tumors and response to the anti-HER2 monoclonal antibody (MoAb) trastuzumab in patients with breast cancer. MoAbs have also been developed against the extracellular domain of EGFR; many of these are currently in clinical trials. One agent commercially available is cetuximab (IMCC225, Erbitux), a human/mouse chimeric antibody that binds to EGFR in a fashion similar to EGF and competitively inhibits activation of the EGF RTK, causing cell cycle arrest in G1.168 Anti-EGFR antibodies have shown clinical activity in a variety of solid tumors, including colon cancer, head and

1/21/2008 1:18:18 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

neck cancer, NSCLC, and renal cell carcinomas. Single-agent clinical trials have been conducted in these tumor types, and a substantial proportion of studies have also incorporated anti-EGFR MoAbs in commonly used combination chemotherapy regimens. In NSCLC, a randomized phase II study compared the use of a conventional chemotherapy regimen (cisplatin and vinorelbine) given alone or in combination with cetuximab.169 Patients treated with cetuximab had a higher response rate (31.7% versus 20.0%) and a more prolonged time to disease progression (4.7 versus 4.2 months) than patients treated with chemotherapy alone. This activity is currently being confirmed in a large phase III study. Angiogenesis. The growth and development of solid tumors is critically dependent on a functional vascular supply. In the absence of this blood supply, tumors remain dormant.170-172 Initiation of angiogenesis (i.e., new blood vessel formation) is believed to be reliant on an angiogenic ‘‘switch,’’ which leads to a complex series of events, starting with the release of tumor-related proangiogenic factors that result in endothelial cell activation and capillary tube formation.173,174 Control of the switch relies on the balance of intrinsic proangiogenic versus antiangiogenic factors.175 In healthy adults, angiogenesis is well controlled and limited to normal physiologic processes such as wound healing and proliferation of cells in the ovary and uterus. However, in order to develop and metastasize, solid tumors secrete a range of proangiogenic factors that tip this balance in favor of angiogenesis. The role of angiogenesis is well established in the progression of lung cancers. High microvessel density has been identified as a prognostic factor predictive of metastasis and poor survival.176-180 Vascular endothelial growth factor (VEGF) has been identified as the most potent and specific mitogen for endothelial cells, with a key role in activating the angiogenic switch. As with many tumor types, high levels of VEGF have been correlated with poor prognosis in patients with lung cancer, and high VEGF levels have been identified as an independent prognostic factor.181-183 The inhibition of tumor angiogenesis is, therefore, a key therapeutic strategy that holds great promise for the advancement of lung cancer management. Many of the most successful antiangiogenic agents are aimed at inhibiting the proangiogenic effects of VEGF, and a wide range of agents designed to interfere with specific stages of the angiogenic process are currently in development. Bevacizumab (Avastin) is a humanized MoAb that acts by binding and neutralizing all VEGF-A isoforms. Bevacizumab became the first clinically available agent that specifically targets the angiogenesis pathway. Clinical trials first demonstrated a survival advantage when this agent was used in combination with chemotherapy, and compared to chemotherapy alone, in patients with metastatic colon cancer.184 The efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel has also been assessed in patients with advanced or recurrent NSCLC.185 In this study, 99 patients received either bevacizumab (7.5 or 15 mg/kg) plus carboplatin (area under the curve = 6 mg/mL · min) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone.185 The addition of bevacizumab (15 mg/kg)

Ch065-F06861.indd 819

819

resulted in a longer median time to progression (7.4 months) compared with the lower-dose bevacizumab arm (4.3 months) or the combination chemotherapy regimen alone (4.2 months); there was also a trend toward increased survival (17.7, 11.6, and 14.9 months, respectively). Although the statistical power of the study precluded a definitive conclusion, these results suggest that the higher dose of bevacizumab (15 mg/kg) had superior efficacy compared with the lower dose (7.5 mg/kg). However, bevacizumab therapy was associated with an increased risk of bleeding. Six patients experienced life-threatening pulmonary hemorrhage, and four of them died. This event did not appear to be dosedependent because all but one of these six cases occurred in the low-dose bevacizumab arm. Bleeding arose from centrally located tumors close to major blood vessels, and cavitation or necrosis had occurred in most cases. Multivariate analysis identified squamous cell histology as a risk factor.185 A later phase II/III NSCLC study of bevacizumab (15 mg/ kg) plus carboplatin and paclitaxel versus carboplatin and paclitaxel alone included only patients with nonsquamous histology who had no brain metastasis and no need for anticoagulation. The trial was conducted by the ECOG (study E4599) and enrolled 842 patients. In this trial, the addition of bevacizumab produced a significant increase in overall survival compared with chemotherapy alone (12.5 versus 10.2 months; P = .007).65 These data will likely result in the addition of bevacizumab to chemotherapy as the standard of care for patients with nonsquamous advanced NSCLC who do not have brain metastasis and are not in need of anticoagulation.65

Management of Selected Metastatic Sites Most patients who have been diagnosed with metastatic disease have multiple sites of metastases, and their survival is limited despite chemotherapy. Nevertheless, there is a definite subset of patients with a primary resectable lung tumor and an isolated site of metastatic disease who may benefit from synchronous resection of both the primary lung tumor and the metastatic lesion. Although the possibility of having a sole site of extracranial metastasis in a patient with otherwise operable lung cancer is low, as many as 7% of patients with metastatic lung cancer in one series were found to have a solitary metastasis after full evaluation.186

Solitary Brain Metastasis Twenty percent of NSCLC patients eventually develop brain metastases, with the brain being the only site of metastasis in 6.7% of patients.187 In almost half of these cases, a solitary lesion is found.188 Patients with solitary brain metastasis who undergo resection of the primary tumor and brain metastasectomy can achieve survival rates between 15% and 30%.189-191 A retrospective analysis of 185 patients undergoing resection of brain metastasis from NSCLC at Memorial Sloan-Kettering Cancer Center reported a survival of 55% at 1 year, 27% at 3 years, and 18% at 5 years.189 Complete resection of the primary lung cancer was the major determinant of survival in these patients. In two smaller retrospective reviews, the 5-year survival rates were 30% and 21%.190,191

1/21/2008 1:18:18 PM

820

Section 3 Lung

In a randomized study by Patchell and colleagues (Patchell et al, 1990)192 comparing surgical resection followed by RT versus RT alone in patients with solitary brain metastasis (predominantly of lung origin), survival was superior in the surgery arm (40 versus 15 weeks). A second study193 compared whole-brain irradiation (WBI) alone versus surgical resection with postoperative WBI in 66 patients; improved median survival time was reported in the surgically treated group (10 versus 6 months). A third trial194 randomized 95 patients (57 with NSCLC) who underwent complete resection of solitary brain metastasis to either postoperative WBI (50.4 Gy in 28 fractions) or no further treatment. The addition of postoperative WBI resulted in substantially better control of tumor in the brain, with less frequent recurrence of tumor anywhere in the brain in the RT group compared to the observation group (18% versus 70%; P < .001). Patients in the RT group were less likely to die of neurologic causes than were patients in the observation group (14% versus 44%; P = .003). There was, however, no significant difference between the two groups in overall survival or in the length of time that patients remained functionally independent. Nonetheless, at present there exists substantial evidence to recommend resection or radiosurgical ablation of isolated brain metastases from NSCLC, followed by WBI.195

Isolated Adrenal Metastasis Another frequent site of metastasis from NSCLC is the adrenal gland. Adrenal metastasis can be found in 5% to 10% of NSCLC patients undergoing staging abdominal CT.196 Cases have been reported of highly selected patients who underwent resection of an isolated adrenal metastasis with curative intent.197-200 Luketich and coworkers186 conducted a retrospective analysis of the management of 14 patients with isolated adrenal metastases. Eight patients were treated surgically, and six received only chemotherapy. Median survival time in the surgical group was 22 months, compared with 8.5 months in the chemotherapy group (P = .03). It is generally recommended that patients with isolated adrenal metastasis from NSCLC are considered for curative surgery if a careful search does not reveal other metastases.195

Bone Metastasis The standard management of bone metastasis is RT for pain control or prevention of pathologic fractures and observation for asymptomatic patients. In addition, orthopedic surgical procedures are used to prevent or correct pathologic fractures in weight-bearing areas. Recently, osteoclast function inhibitors, including the bisphosphonates and gallium nitrate, have been shown in clinical trials to decrease bone-related complications, and the bisphosphonates have now become an integral part of the management of bone involvement in patients with myeloma or breast cancer. In 2003, Tchekmedyian and colleagues201 reported results of a phase III trial assessing long-term safety and efficacy of zoledronic acid, a bisphosphonate, in reducing skeletal complications in patients with bone metastasis from solid tumors other than breast or prostate cancer. The majority (57%) of the study population had lung cancer. There was a 31% risk

Ch065-F06861.indd 820

reduction for development of a skeletal-related event with zoledronic acid compared to placebo. This was the first trial to demonstrate the long-term safety and efficacy of bisphosphonate therapy in patients with bone metastasis from lung cancer. Although RT and bisphosphonates can both provide pain relief, neither has been shown to prolong survival. New treatments are needed for known bone metastasis and for patients who are at high risk of developing such metastasis.

SUMMARY Although surgery remains the most effective treatment modality in the management of NSCLC, reasonable treatment options remain for those patients not amenable to surgical resection. Locoregionally confined disease can be approached with curative intent using aggressive combinations of chemotherapy and RT. Patients with malignant pleural effusions or extrathoracic disease can still achieve significant survival prolongation and/or symptomatic palliation with the appropriate use of RT and chemotherapy. Intensive exploration of a number of novel targeted therapies is likely to result in significant progress in the management of inoperable NSCLC in the future.

COMMENTS AND CONTROVERSIES Most patients with NSCLC are not candidates for surgical resection and therefore must be evaluated for definitive or palliative care using nonoperative strategies. The authors have provided a detailed review of the current status of definitive nonoperative management for patients with NSCLC. The appropriate roles of RT and chemotherapy, as well as various combinations of these modalities, are discussed in detail. Recent advances in EBRT have markedly increased response rates and local control. Particularly exciting is the recent development of stereotactic irradiation (SBRT), which offers significant prospects for local control and cure, particularly in patients with localized parenchymal lesions who, by virtue of limited pulmonary function, are not candidates for surgical resection. In recent years, great strides have been made in the application of chemotherapy, using a variety of drugs in combination. The multiple clinical trials evaluating various drug combinations are discussed in detail. The reader is provided with an excellent review of first- and second-line chemotherapy options for those who are not candidates for surgical resection. Also important is a concise review of the current status of palliative treatment options for patients with metastatic disease. G. A. P.

KEY REFERENCES Non–Small Cell Lung Cancer Collaborative Group: Chemotherapy in non–small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899, 1995. Cox JD, et al: A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: Possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non–small-cell lung carcinoma. Report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 8:1543, 1990.

1/21/2008 1:18:18 PM

Chapter 65 Definitive Management of Inoperable Non–Small Cell Lung Cancer

Furuse K, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non–small cell lung cancer. J Clin Oncol 17:2692, 1999. Patchell RA, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494, 1990. Perez CA, et al: A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non–oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 45:2744, 1980. Pfister DG, et al: American Society of Clinical Oncology treatment of unresectable non–small cell lung cancer guideline: Update 2003. J Clin Oncol 22:330, 2004.

Ch065-F06861.indd 821

821

Rapp E, et al: Chemotherapy can prolong survival in patients with advanced non–small-cell lung cancer: Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633, 1988. Sause W, et al: Final results of phase III trial in regionally advanced unresectable non–small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 117:358, 2000. Schiller JH, et al: Comparison of four chemotherapy regimens for advanced non–small cell lung cancer. N Engl J Med 346:92, 2002. Shepherd FA, et al: Erlotinib in previously treated non–small cell lung cancer. N Engl J Med 353:123, 2005.

1/21/2008 1:18:19 PM

chapter

66

THORACIC SURGERY: A PALLIATIVE CARE SPECIALTY Bill Nelems

Most will agree that perhaps the greatest challenge facing all of medicine is the development and implementation of truly comprehensive standards of care. In trying to provide all patients with “access to a uniformly high quality of care in the community or hospital wherever they may live and to ensure maximum possible cure rates and best quality of life,”1 one could well use thoracic surgical practice as a proxy for developing the principles that govern standards of care. Thoracic surgeons have excelled in developing high standards in diagnostic procedures, in disease staging, and in the execution of treatments intended for cure. In general, however, thoracic centers have not kept stride with the allinclusive palliative needs of their patients. This is somewhat surprising because 80% of the thoracic surgeon’s caseload relates to malignant disease and 80% of those patients will not survive the illnesses for which they have sought help.2 Even while performing more palliative procedures than curative ones, thoracic surgeons have not kept abreast of the emerging paragons of palliation. The shift needed in thoracic surgery practice is philosophical rather than technical or academic. Traditionally, thoracic surgeons, like most conventional practitioners, have concerned themselves with diseases and their potential cure. Newer paradigms of care, however, are moving from a biomedical focus to a psychosocial-economic one, one that considers the patient in his or her cultural and social setting rather than offering strictly diseased-focused care.3 Palliative or hospice care has long since moved from terminal palliation to very comprehensive supportive care philosophies; it is time for thoracic surgeons to view themselves as integral members of the palliative process. In conducting end-of-life narrative interviews with my patients, I have learned that, for the patient, the journey their illness takes them on becomes more important than the disease itself or its treatment. Grateful as the patient may be for the therapy received, their life’s journey is consistently more important than the role played by their surgeon. When conventional therapies are withdrawn, it matters not what particular disease eventually leads to the patient’s death or what treatments could or should have been used at earlier stages; impending death sets its own priorities. What matters most to the patient facing death is whether their various symptoms will be adequately controlled and whether they will have time to reconcile their spiritual journey and to gather their family and loved ones to their bedside. As a thoracic surgeon now comfortable with end-of-life narrative counseling, I am humbled by these insights, which are inadequately taught at medical school and seldom role-modeled during surgical training.

HISTORICAL NOTE Although the concept of compassionate care for the elderly and the infirm is deeply embedded in indigenous cultures and espoused by the teachings of all major religions, the formal acceptance of care for the dying as a medical discipline is relatively new. Key events include: ■

■

■

■

1967—Dr. Cicely Saunders becomes the first physician to chronicle the lives of the dying, founding the first modern hospice unit, St. Christopher’s, in London. Named a dame of the British Empire in 1980, she died in 2005, aged 87, at the hospice unit that she founded.4 1969—Dr. Elizabeth Kübler-Ross publishes her groundbreaking book On Death and Dying,5 introducing the lay public to the concept of palliative care. Numerous other lay publications followed, including the recent Tuesdays With Morrie, by sports columnist Mitch Albom.6 1974—Dr. Florence Wald, dean of nursing at Yale University, founds the first American hospice, in Branford, Connecticut.7 1974—The first Canadian hospice is established at St. Boniface General Hospital in Winnipeg8; the following January, Dr. Balfour Mount opens a hospice unit at Montreal’s Royal Victoria Hospital.9

Throughout the 1980s and early 1990s, as hospice/palliative care became widely accepted as a societal movement that was reforming health delivery, various health care systems began characterizing care with titles such as acute, chronic, geriatric, or palliative. These new terms reflected those systems’ identification of specialized needs and required definition. Today, nearly every country in the world has established hospice houses and has formed palliative care societies. With the advent of the worldwide HIV/AIDS pandemic, these developments have been timely, never more so than in sub-Saharan Africa where, in some countries, as much as 34% of the population is believed to be infected with this immunity-sapping retrovirus.10 Awareness of the concept of care for the dying has grown rapidly, leading to a number of significant governmental and World Health Organization (WHO) initiatives. In 1990, the U.S. government enacted the Patient Self-Determination Act (PSDA).11 This document mandated all American hospitals, nursing homes, hospices, and health maintenance organizations receiving federal funds to incorporate advance directives (e.g., do not resuscitate orders) on patients’ charts. Although revolutionary in concept, a 1993 study showed that measures taken to meet PSDA requirements “increased patient awareness of living wills, but . . . failed to increase the

822

Ch066-F06861.indd 822

1/21/2008 1:19:12 PM

Chapter 66 Thoracic Surgery: A Palliative Care Specialty

number of patients who act on this awareness, [indicating that] simply informing patients about their right of selfdetermination [was] insufficient to meet the intended goals of the legislation.”12 By 1997, the PSDA was widely perceived as having failed to meet its objectives.13 Further international awareness of palliative care issues was aroused when in 1990 the WHO published a document entitled, “Cancer Pain Relief—a Guide to Opioid Availability.”14 In 1995, the Calman-Hine Report, published by the chief medical officers for England and Wales,1 tabled 44 recommendations and conclusions with respect to comprehensive standards of care for cancer patients. This report acknowledges the value of surgical treatment and accreditation and demands the provision of comprehensive care for the palliative patient. This report is currently at various stages of implementation within Great Britain and is a model for the rest of the world to emulate. In June 2000, a Canadian Senate Standing Committee released a landmark report entitled “Quality End-of-Life Care: The Right of Every Canadian,”15 which recommended that the federal government, in collaboration with the provinces, develop a national strategy for end-of-life care and establish a 5-year plan for its implementation. The 2005 Terri Schiavo case in the United States drove home the need for clearer guidelines regarding living wills and advanced care planning. Before Ms. Schiavo, a young woman in a persistent vegetative state, could have her feeding tube removed and be allowed to die (Schiavo’s husband insisted that she had expressed her wishes not to be kept on life support systems), her case underwent the following: ■ ■ ■ ■

■ ■

Fourteen appeals and numerous motions, petitions, and hearings in the Florida courts Five suits in federal district court Florida legislation struck down by the Supreme Court of Florida A subpoena by a committee of the United States Congress (in an attempt to qualify her for the federal Witness Protection Program) Federal legislation (Palm Sunday Compromise) Four denials of certiorari16 from the Supreme Court of the United States17

Philanthropic organizations such as the Soros Foundation as well as federal and other granting agencies have now moved decisively to support research into palliative care.18 Highquality randomized trials are now producing solid evidence as to how symptoms are best controlled in the palliative patient.19

WHERE DO WE GO FROM HERE? There has been an inexorable developmental progression over the past 40 years in palliative care. Once an all-too-desperate scramble to provide palliative care for patients in their last few hours of life, it has become a far broader provision of supportive care, one that is provided to all patients from the time of first diagnosis to either cure or death, as the patient’s illness dictates. This comprehensive approach extends beyond the patient to include such initiatives as bereavement support for the patient’s family should the patient die.

Ch066-F06861.indd 823

823

The thoracic surgical community must remain firmly focused on providing prompt access to care, on diagnosis, on surgical treatments, and on the training and accreditation of young surgeons. In addition, our community must continue to adapt to the changing philosophies regarding comprehensive care; in the Internet era, society demands no less. Of all the international working groups, perhaps the Sheffield palliative care studies group (SPCSG) is one of the most impressive. The group represents “an active collaboration between researchers, teachers, and—crucially—clinicians. The fact that many members of SPCSG work in hospital-, hospice-, and community-based palliative care services ensures that their academic activities are constantly informed by, and in turn influence, regular clinical care.”20 Their Sheffield model conceptualizes how palliative care can be best delivered in modern health care settings. For some patients, treatment may be of curative intent, but, for the greater majority, therapy will be palliative. The model, however, generally uses the term supportive rather than palliative, a simple change in language and attitude that better enables physicians to coalesce the significant contributions from stakeholders, including primary care teams, pain clinics, oncology teams, social workers, and information providers. Patient needs always develop long before a formal diagnosis is made. Early activation of the stakeholder community means supportive care can begin with the patient’s first step along his or her illness journey. In this way, family members can become involved early in the process, thus facilitating their bereavement needs when loved ones die. In most modern societies, and even in some developing countries, significant stakeholder groups already exist. It behooves us, as thoracic surgeons, to activate these groups early on and then remain connected to the patient to help with surgical palliation needs as they arise. Next, issues relating to advanced care planning, advanced care directives, and living wills must be addressed. Randomized controlled studies have shown that the deployment of living wills or advance directives has the power to significantly reduce health costs, without sacrificing mortality or quality of care.21 No published population-based research data exist to indicate whether living wills have been systematically deployed with lung or esophageal cancer patients at the time of initial diagnosis. Such research is needed and can best be done by surgical teams because they see the patients at the early, investigative stage of illness. Data from such studies will inform and improve ongoing clinical care.

SURGICAL PROCEDURES SPECIFICALLY DESIGNED TO PALLIATE SYMPTOMS Thoracic conditions that commonly require palliation, literature citations as to investigative and treatment options, and my preferences for therapy are listed in Table 66-1.22-43 Potentially curative therapies are not included. Future generations of thoracic surgeons will be more comprehensively trained; they will have had exposure to the broader philosophical perspectives needed to provide more all-embracing care than we, their teachers, have been able to provide.

1/21/2008 1:19:12 PM

824

Section 3 Lung

TABLE 66-1 Thoracic Conditions Commonly Requiring Palliation: Investigation/Treatment Options Thoracic Condition

Investigation/Treatment Literature Citation

Author’s Comments

Malignant esophageal obstruction

Brachytherapy22 External-beam radiotherapy23 Chemotherapy24 Intubation25 Palliative resection26

In general I do not favor palliative esophageal resection but prefer the use of modern stenting devices.

Tracheobronchial obstruction

External-beam radiation Brachytherapy Laser treatments27 Photodynamic therapy28 Stenting29

Airway obstruction is one of the most taxing conditions to manage. All of the modalities listed are valuable in individual cases.

Malignant pleural effusions

Pleurodesis30 Pleuroperitoneal shunt31

Talc pleurodesis is my preferred technique. Shunting is beneficial in managing “trapped lung” syndrome.

Superior vena caval (SVC) obstruction

Mediastinoscopy32 Radiation Endovascular shunts33

Mediastinoscopy is not contraindicated in SVC obstruction. Radiation most often suffices to control symptoms. In treatment of refractory cases, endovascular stenting is helpful.

Hemoptysis (malignant etiology)

Radiation Photodynamic therapy

Radiation controls hemoptysis in most cases.

Major pulmonary hemorrhage

Bronchial embolization34 Resection35

In general, embolization is preferred to resection. Resection in the presence of hemoptysis can tax the best of surgeons.

Metastatic chest wall recurrences

Resection36 Radiation

Clinical judgment on a case-by-case basis. Prosthetic patches and plastic surgery myocutaneous flaps allow for wide chest wall resections.

Cerebral metastases

Radiation Resection37

Short-term relief occurs in 70%+ cases.

Bone metastases

Radiation

Ninety percent of patients with symptomatic bone pain obtain relief with low-dose radiotherapy. Lytic lesions should be treated prophylactically.

Mesothelioma

Extrapulmonary pneumonectomy38 Pleurectomy/decortication39 Clinical trials40

We await better outcomes from results. Considering complication rates and poor outcomes with treatments, I believe that cases should be referred to clinical trials whenever possible.

Malignant pericardial effusion

Subxiphoid pericardial window41 Thoracotomy with window and sclerosis42 Pericardiocentesis with sclerosis43

The pros and cons of these methods have been well argued in the literature. My preference is for left limited fourth interspace thoracotomy without rib spreading, pericardial window formation, and talc ablation of pericardial and pleural spaces.

Experiences with population-based research, advanced care planning, the routine use of living wills for those with lifethreatening disease, and comprehensive supportive care programs will contribute to the paradigm shifts that will evolve over time, and our patients will be better served.

COMMENTS AND CONTROVERSIES Given that much of the work of a thoracic surgeon focuses on malignant disease, the editors were convinced that a chapter

Ch066-F06861.indd 824

focused on palliative care would strengthen this textbook. Dr. Nelems proves us correct. Palliative care has long been an interest of his, as it should be for all thoracic surgeons. In this chapter, Dr. Nelems outlines the progress made internationally in palliative care. He also points out the critical need for development of standards of care in this regard. Finally, he provides a synopsis (in tabular format) of his own perspective for the management of various palliative care scenarios commonly encountered by thoracic surgeons. G. A. P.

1/21/2008 1:19:12 PM

chapter

67

SMALL CELL LUNG CANCER Natasha B. Leighl Frances A. Shepherd

Key Points ■ Small cell lung cancer (SCLC) represents approximately 15% of

lung cancer cases. ■ Despite high response rates to initial chemotherapy and radiation,

more than 80% of patients relapse and die within 1 to 2 years. ■ There are two stages of SCLC, limited (LSCLC) and exten-

■ ■

■

■ ■ ■

■

■

sive (ESCLC); limited-stage disease is that confined to one hemithorax. Median survival time without treatment is 12 to 17 weeks in LSCLC, 5 to 6 weeks in ESCLC. Optimal treatment for LSCLC includes combination chemotherapy (e.g., etoposide/cisplatin) with early, concurrent thoracic radiotherapy, followed by prophylactic cranial irradiation (PCI) in responding patients; this is associated with a long-term survival rate of 15% to 20%. Standard therapy for ESCLC is chemotherapy (e.g., four to eight cycles of etoposide/cisplatin); responding patients may be considered for PCI. Median survival time with treatment is 8 to 10 months, and the 2-year survival rate is less than 5%. More than 80% of SCLC patients relapse and die within 2 years; median survival time at relapse is approximately 25 weeks. Second-line chemotherapy (e.g., topotecan, CAV) may modestly prolong survival and improve symptoms. Patients with resected SCLC, any stage, must be offered adjuvant chemotherapy (e.g., four cycles of etoposide/cisplatin). Surgical intervention is not considered standard in the management of SCLC, but there may be a potential role for surgery in selected scenarios: to decrease local failure rates, for mixedhistology tumors (10%-15%), for second primary tumors (often non-SCLC), and for very limited disease SCLC (pathologic stage I). Age alone must not affect the decision to treat. Fit, older patients must be treated with combination chemotherapy and can tolerate thoracic radiation.

EPIDEMIOLOGY AND ETIOLOGY Lung cancer remains the most commonly diagnosed cancer in the world, and it is responsible for the largest number of cancer-related deaths annually. There are 10.9 million new cases of cancer each year worldwide, of which 1.35 million are lung cancer, and 1.18 million lung cancer deaths each year.1 Small cell lung cancer (SCLC) now represents approximately 13% to 15% of lung cancer cases, with 45,000 new cases per year in North America.2 SCLC is a rapidly progressive cancer with high rates of response to initial chemother-

apy and radiation. Despite the response to initial therapy, more than 80% of patients relapse and die within 1 to 2 years. The 5-year survival rate for SCLC is 10% at best. The rates of SCLC incidence parallel those of cigarette smoking, with a time lag reflecting the changing smoking patterns. The incidence rates of SCLC have fallen among men living in developed countries since the decline in cigarette smoking in men. However, among women, the incidence of SCLC is increasing, in accord with a recent peak in the prevalence of smoking among women.3 Whereas men previously comprised the majority of SCLC patients, the ratio between men and women is decreasing. More than 98% of SCLC cases are attributed to smoking, and fewer than 2% to other causes, most commonly radon exposure, often as a consequence of mining.4

PATHOLOGY The diagnosis of SCLC is primarily based on histologic appearance by light microscopy. SCLC is one of a group of neuroendocrine tumors that includes large cell neuroendocrine carcinoma and typical and atypical carcinoid tumors. SCLC has a distinct pattern of clinical behavior and is characterized by small cells (smaller than three lymphocytes), scant cytoplasm, finely granular chromatin, absent nucleoli, and prominent nuclear molding. The mitotic count is typically high, cells have a high nuclear-cytoplasmic ratio, and the granular chromatin may be described as having a so-called salt and pepper appearance. Current classifications include small cell carcinoma and combined small cell carcinoma, in which small cell carcinoma is combined with an additional component of non–small cell carcinoma (NSCLC), such as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. It may also be seen in association with spindle cell or giant cell carcinoma. Combined small cell carcinoma has been identified in approximately 10% to 25% of cases of SCLC. Previous classifications have used names such as oat cell carcinoma, small cell anaplastic carcinoma, and undifferentiated small cell carcinoma, as well as intermediate cell type and mixed small/large cell carcinoma.5 The cell of origin for SCLC remains unknown, but it is believed that there is a pluripotent bronchial precursor cell that can differentiate into the various histologic types of lung cancer.6,7 Among the neuroendocrine tumors, there are greater similarities between small cell and large cell neuroendocrine carcinomas, based on morphology and genetics, than there are between typical and atypical carcinoid tumors. It is important to remember that these histologic types all have different clinical behaviors. 825

Ch067-F06861.indd 825

1/21/2008 1:20:18 PM

826

Section 3 Lung

Immunohistochemistry Electron microscopy shows neuroendocrine granules in two thirds of cases, and most tumors are positive for CD45, chromogranin, and synaptophysin (neuroendocrine markers). Staining for thyroid transcription factor-1 (TTF-1) is also positive in 90% of cases, compared with approximately 70% of NSCLC. Fewer than 10% of SCLC tumors are negative for all neuroendocrine markers.

Differential Diagnosis The diagnosis of SCLC is based on histology using light microscopy and requires preserved tumor cells. The differential diagnosis includes NSCLC, other neuroendocrine tumors, so-called small round blue cell tumors such as Ewing’s sarcoma, and lymphoid infiltrates. Crush artifact, common with SCLC, can also be seen with carcinoid tumors, inflammatory lymphocytic infiltrates, lymphoma, and poorly differentiated NSCLC. Carcinoid tumors typically do not have the same degree of necrosis and mitotic activity as is seen with small round blue cell tumors, including primitive neuroectodermal tumors. These also are not cytokeratin or TTF1 positive, and Merkel cell carcinoma is negative for cytokeratin 7 and TTF-1 but positive for cytokeratin 20.5 To help differentiate between SCLC and other lung cancers, SCLC typically is positive for low-molecular-weight keratins with a punctate staining pattern, negative for TP63 (p63), positive for CD56 with a membranous staining pattern, and positive for TP16 (p16). Squamous cell carcinoma, by contrast, is usually positive for high-molecular-weight keratin, positive for TP63, usually negative for CD56 (if positive, diffusely so), and negative for TP16 (Dr. W. Geddie, personal communication).

Cytogenetics and Molecular Alterations SCLC is characterized by numerous mutations. These are aneuploid tumors, with a high incidence of chromosomal deletions in 3p, 4, 5q, 10q, 13q, and 17p. DNA gains may be seen in 3q, 5p, 6p, 8q, 17q, 19, and 20q. Abnormalities in 3p are almost universal in SCLC. When comparing SCLC and carcinoid tumors, despite many similarities, SCLC has higher rates of TP53 mutation, thought to be related to cigarette smoking, whereas carcinoid tumors have mutations in the menin gene. NSCLC has a greater frequency of RAS mutations and COX2 overexpression, whereas SCLC is characterized by MYC amplification7 and methylation of caspase 8. Inactivation of RB and E2F1 overexpression are also seen in SCLC, but rarely in NSCLC. Other molecular abnormalities seen in SCLC include overexpression of BCL2, activation of autocrine loops through bombesin-like peptides, and KIT (formerly c-kit). Upregulation of telomerase, matrix metalloproteinase (MMP) inhibitors, and vascular endothelial growth factor (VEGF) is also seen. Insulin-like growth factor, gastrin-releasing peptide, and transferrin may be growth factors for SCLC,7-9 as well as granulocyte colony-stimulating factors (G-CSF and GMCSF). Despite in vitro evidence that G-CSF enhances SCLC growth, its administration has not produced a clear negative effect clinically, except in one randomized trial of GM-CSF

Ch067-F06861.indd 826

in limited-stage SCLC treated with chemoradiation.10-13 The value of G-CSF in SCLC therapy is discussed later in the chapter. Gene expression profiling indicates that several neuroendocrine genes are markers for SCLC, including chromogranins B and C, insulinoma-associated gene 1, human achaete-scute homolog 1 (hASH1, now called ASCL1), and others.3 However, the relevance of many of these genetic changes remains unclear with respect to improving the diagnosis or directing therapy for this disease. Studies to explore the prognostic significance of these molecules in small series suggest that the presence of MMP-2 and MMP-9 carries an adverse prognosis.14 Overexpression of KIT has been shown to be an adverse prognostic factor in some series, but not in all.15

STAGING Definitions Cancer staging in SCLC is essential for prognostication and treatment planning. The traditional tumor-node-metastasis (TNM) classification is less helpful in SCLC because most patients have stage III or IV disease at diagnosis, and surgery is seldom performed. The Veterans Administration Lung Cancer Study Group (VALG) divided SCLC into two stages, limited and extensive, and this classification was subsequently revised by the International Association for the Study of Lung Cancer (IASLC). Limited-stage disease (LSCLC) is seen in up to 40% of patients at presentation. As defined by the VALG, limited stage comprises disease restricted to one hemithorax, with ipsilateral regional and supraclavicular lymph node involvement, in which the primary tumor and regional nodes can be adequately treated and totally encompassed in the radiation port.16 Patients with metastases outside the hemithorax, seen in 60% of cases, are classified as having extensive-stage disease (ESCLC). Without treatment, median survival time is approximately 12 to 17 weeks for patients with LSCLC, and 5 to 6 weeks for those with ESCLC.16-18 Malignant ipsilateral pleural effusions and contralateral regional nodes (mediastinal and supraclavicular) remain areas of controversy. However, the IASLC has revised the classification, with the definition of limited stage approximating stages I to III by the revised TNM criteria, and extensive stage reflecting stage IV disease (Stahel et al, 1989).19 Thus, the IASLC classification of limited disease includes patients with disease restricted to one hemithorax who have regional node metastases including ipsilateral and contralateral hilar, mediastinal, and supraclavicular nodes, as well as ipsilateral pleural effusions independent of positive or negative cytology. Stahel and colleagues19 recommended that ipsilateral effusions and pleural metastases be considered limited stage because patients with these features have superior survival to those with distant metastatic disease. As many as 21% of patients may have extensive-stage disease based on the VALG criteria yet limited stage according to the IASLC criteria. A small study of 109 patients suggested that survival in patients downstaged by IASLC criteria (291 days) did not differ significantly from that in

1/21/2008 1:20:18 PM

Chapter 67 Small Cell Lung Cancer

patients with limited disease by VALG criteria (385 days for VALG limited stage; P = .422); this confirmed the discriminatory power of the IASLC staging on prognosis.20 It is worth recalling, however, that most published trials in SCLC use the VALG staging system, and only a few use the IASLC staging system. Furthermore, these systems were developed before the more sensitive scanning techniques of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) were in routine use.

Very Limited Disease The subgroup of patients with very limited disease (VLD) has been further defined by the University of Toronto Oncology Lung Group and groups in Japan. Tumors in this subgroup are often small, without adenopathy or pleural effusions, and are associated with a good prognosis, T1 or 2 N0 by TNM staging. These patients often present with peripheral disease, and, given the lack of systemic metastases, may potentially benefit from further study of more aggressive local therapies (e.g., surgery). In a review of 180 consecutive patients with LSCLC, 33 (18%) fit the definition of VLD, and they had a projected 5-year survival rate of 25%.21

Staging Investigations Given that the common metastatic sites for SCLC include the mediastinum and regional lymph nodes, contralateral lung, liver, brain, bone, and adrenal glands, initial staging investigations encompass these areas. Recommended imaging includes full imaging of the chest and upper abdomen, with chest and abdominal CT, brain imaging (MRI may be more sensitive than CT brain), and a total-body bone scan. Because approximately 10% of patients present with brain metastases, brain imaging is a reasonable test to perform at diagnosis. Bone marrow metastases are also common in ESCLC, but bone marrow biopsy has been found to upstage only 2% to 5% of patients and therefore is no longer considered a routine part of staging.22 It is considered, however, for cases in which the complete blood count is abnormal. Finally, procedures such as lumbar puncture may still be considered standard in the staging of patients with LSCLC at some centers, although, increasingly, MRI with gadolinium enhancement may eliminate the need for this procedure in the setting of a normal neurologic examination. Although patients often have repeat assessments to ensure response or lack of progression, there is little evidence to support duplicating the staging workup in LSCLC patients with complete response documented by chest radiography.23 The most valid argument for systemic restaging at the end of therapy is to confirm the completeness of the response, to enable further treatment decision making regarding prophylactic cranial irradiation (PCI). The value of fluorodeoxyglucose (FDG)-PET in the routine staging of SCLC remains unclear, and it is not recommended at present. In a large series of 120 patients with SCLC, FDGPET was performed after conventional staging, with 100% sensitivity in locating the primary tumor.24 However, PET was concordant or accurate in 40% of cases, and not correct in 8%, and accuracy was not clarified in 7%. Ten patients (8%)

Ch067-F06861.indd 827

827

were upstaged, and 3 (2.5%) were downstaged with PET. Although PET appeared to be more sensitive and more specific for extrathoracic disease and metastases outside of brain, MRI or CT brain scans were better than PET for cranial imaging. In a series of 45 patients, the sensitivity of PET was compared with that of conventional staging with CT chest/ abdomen, brain MRI, and bone scan.25 There was no difference in the staging accuracy between the two techniques. In another small study of 24 patients with LSCLC, PET upstaged 8.3% to ESCLC and revealed unsuspected mediastinal node metastases in 25% of patients, affecting radiation treatment planning. Therefore, although the utility of PET is not entirely clear, it may be helpful in the upstaging of patients who have occult metastatic disease by current staging techniques, and its value in radiotherapy treatment planning must be further explored.

CLINICAL PRESENTATION A smoking history is present in 98% of patients with SCLC. Lesions tend to be central and bulky, with associated hilar adenopathy. Peripheral SCLC lesions represent fewer than 10% of the cases. More than half of patients present with disseminated or extensive-stage disease. With a rapid doubling time, patients often develop symptoms and deteriorate quickly, over a period of weeks to a few months. Paraneoplastic syndromes may also be seen, including the syndrome of inappropriate antidiuretic hormone (SIADH) in 5% of patients, ectopic adrenocorticotrophic hormone (ACTH) production in 3%, and neurologic syndromes including Lambert-Eaton myasthenic syndrome (LEMS) and peripheral polyneuropathies, often mediated by anti-Hu and anti-Jo antibodies. Cerebellar syndromes are also seen, including cerebellar degeneration. Except for SIADH, the presence of a paraneoplastic syndrome suggests an adverse prognosis. SIADH is easily correctable with treatment of the underlying disease within approximately 6 weeks.26 Other paraneoplastic syndromes may be improved or corrected with treatment of the SCLC,27 but they may also require additional efforts, such as steroids and/or plasmapheresis for LEMS or corticosteroid replacement and ketoconazole for paraneoplastic Cushing’s syndrome.28 Finally, it is important to note that the presence of malignancy and the paraneoplastic syndrome may not be synchronous, although the syndrome often heralds malignancy.

PROGNOSTIC FACTORS Key prognostic factors in this disease are stage or anatomic disease extent, performance status (PS), and the pretreatment serum concentration of lactate dehydrogenase (LDH).19,29-32 Weight loss within the preceding 6 months, similar to that seen in NSCLC, is a poor prognostic factor,33,34 and other factors, including baseline neutrophil count and hemoglobin, appear to be important for response and survival.35 Gender is also prognostic, with several studies demonstrating that women with SCLC have better response and survival with therapy.27,30,33,36 An analysis of National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) trials found that women with SCLC experienced more chemotherapy-related

1/21/2008 1:20:18 PM

828

Section 3 Lung

toxicity than men but still had high rates of treatment compliance.37 In addition, this study confirmed that, despite greater toxicity, women had higher rates of response and better survival than their male counterparts. Although no molecular marker has been sufficiently validated, small series suggest that expression of MMP-2, MMP-9, and KIT may be prognostic, although some studies have not confirmed this finding.14,15 Deregulation of MYC and elevated neuronspecific enolase (NSE) may also be important.38 The prognostic impact of age on patient outcome in SCLC has been debated in the literature. Some cooperative groups found that age greater than 70 years has a negative impact on survival (hazard ratio [HR] for mortality, 1.3)32,39,40; however, when recursive partitioning and amalgamation techniques were used, age either became nonsignificant as a prognostic factor or was applicable only in certain patient subsets, most commonly LSCLC. Other groups, such as the NCIC-CTG, have found that age is not prognostic after correction for stage and PS (Siu et al, 1996).41 Additionally, Quon and colleagues42 showed that age does not restrict patients with good PS from receiving chest radiotherapy as part of combination therapy for LSCLC.

Biomarkers Although the serum LDH level is a useful pretreatment biomarker for prognostication,19,29,31 it often returns to normal if the patient responds to therapy. Carcinoembryonic antigen (CEA) may correlate with disease stage and be an independent prognostic factor, although it is elevated in only one third of patients.43 Other markers remain of investigational interest, such as circulating tumor cells, NSE, and C-terminal flanking peptide of the gastrin-releasing peptide.44,45

colleagues from the Princess Margaret Hospital were among the first to test the hypothesis that chemotherapy might add to the effects of local radiotherapy, and they showed a modest survival advantage for patients treated with single-agent lowdose cyclophosphamide.50 The British Medical Research Council (MRC) Lung Cancer Working Party undertook a similar trial in which patients were randomized prospectively to receive 30 Gy radiotherapy delivered in 15 fractions, or the same radiotherapy with systemic chemotherapy (cyclophosphamide, CCNU [lomustine]). A significant prolongation of progression-free survival was seen for patients in the chemotherapy arm, although a long-term survival benefit was not demonstrated.51 A partial list of the single agents with greatest activity in SCLC is shown in Table 67-1. These include etoposide (VP-16), cisplatin, cyclophosphamide, doxorubicin (Adriamycin), and vincristine. Newer agents include gemcitabine, with a response rate of 27%52; the camptothecins irinotecan and topotecan, which inhibit topoisomerase I activity53-55; and the taxanes docetaxel and paclitaxel, with response rates of 31% to 50%.56-58 Common side effects seen with the various treatment modalities for SCLC are listed in Table 67-2. Combining chemotherapy agents resulted in higher response rates (70%-90% in LSCLC, 55%-75% in ESCLC), with improvement in median survival times. As the number of agents used increases, response rates also increase, although many studies show that adding more drugs does not yield

TABLE 67-1 Established Active Single Agents in the Treatment of Small Cell Lung Cancer Agent

Approximate Activity (%)

LIMITED-STAGE DISEASE

Bis-chloroethyl-nitrosourea (carmustine)

20

Outcomes for patients with LSCLC have improved over the past 3 decades. An analysis by Janne and colleagues showed improved median survival of patients treated in randomized trials between 1972 and 1981 from 12.0 months to 17.0 months for those treated between 1982 and 1992 (P < .001).46 Over a similar period, there was a 6.4-month increase in the median survival time of patients with LSCLC listed in the database of the Surveillance Epidemiology and End Results (SEER) program of the U.S. National Cancer Institute (P < .0001), and the 5-year survival rate increased from 5.2% to 12.1% (P = .0001). Treatment advances such as thoracic and cranial irradiation may explain some of the improvement in survival, but there may also be a contribution from stage migration with more accurate staging investigations, as well as advances in supportive care.

Carboplatin*

40

Cisplatin*

15

Cyclophosphamide*

40

Chemotherapy Before the use of chemotherapy in this disease, 1-year survival rates were less than 10%.47 Single-agent chemotherapy treatment results in response rates of 20% or higher, and almost every class of chemotherapy agent demonstrates single-agent activity.48,49 In initial studies of single-agent therapy, cyclophosphamide was compared with placebo and produced a doubling of median survival time.18 Bergsagel and

Ch067-F06861.indd 828

Doxorubicin*

30

Epirubicin (high-dose)

50

Etoposide (VP-16), intravenous*

40-50

Etoposide oral*

50

Gemcitabine

27

Hexamethylmelamine (altretamine)

30

Ifosfamide*

40-50

Irinotecan*

30-40

Methotrexate

35

Nitrogen mustard

35

Paclitaxel*

35-50

Teniposide

40-50

Topotecan*

30-40

Vincristine*

35

Vindesine

30

*Agents most commonly used today.

1/21/2008 1:20:18 PM

Chapter 67 Small Cell Lung Cancer

829

TABLE 67-2 Early and Possible Late Toxicities in Patients With Small Cell Lung Cancer Therapy

Early Toxicities

Possible Late Toxicities

Chemotherapy

Nausea and vomiting Alopecia Peripheral neuropathy Myelosuppression with possible bleeding (cisplatin) Anemia Constipation Electrolyte disturbances Cardiotoxicity Nephrotoxicity and ototoxicity Hemorrhagic cystitis Mucositis Hypotension, hypertension (etoposide) Bronchoesophageal fistulae

Unusual infections (e.g., herpes zoster) Anthracycline-induced cardiomyopathy Pulmonary fibrosis CNS toxicity (especially with PCI) Second malignancies Second lung primaries (including NSCLC) Other solid tumors Acute leukemia

Esophagitis ± stricture Pneumonitis Cardiac toxicity

Pulmonary fibrosis Late cardiac effects Myelitis ? Predisposition to second malignancy

Cranial

Erythema of the scalp Otitis externa Prolongation of myelosuppression

Somnolence, confusion, cognitive impairment (e.g., memory loss) Tremor, dysarthria, slurred speech, ataxia Dementia

Surgery

Postoperative death Pain at thoracotomy incision site Bronchopleural fistulae

Chronic pain at incision site Bronchopleural fistulae Respiratory failure from loss of functioning lung

Radiation Therapy Thoracic

CNS, central nervous system; NSCLC, non–small cell lung cancer; PCI, prophylactic cranial irradiation.

significant improvements in survival compared with two- or three-drug regimens, but does increase toxicity. At least 21 randomized trials have been undertaken comparing various chemotherapy regimens in LSCLC. A meta-analysis was updated recently in an attempt to determine the optimal combination of chemotherapy regimens to be used in limitedstage disease (Laurie et al, 2004).59 The majority of studies included etoposide/cisplatin (EP), although high activity was also seen with cyclophosphamide/doxorubicin/vincristine (CAV) or with alternating treatment with both of these regimens (CAV/EP). Randomized trials suggested similar activity overall, with one trial suggesting superiority of CAV/EP over CAV or EP alone.60 On balance, no regimen appeared to have clearly outperformed EP, and EP can be safely combined with early thoracic irradiation. By contrast, the incremental radiosensitizing effects of CAV with thoracic irradiation, which results in higher rates of esophagitis, have made firstline CAV problematic in the setting of LSCLC.61 Most centers use EP as standard first-line therapy with thoracic irradiation for LSCLC, although first-line anthracycline-based regimens remain of interest in some European countries. More recent studies have confirmed that platinum-based regimens may be superior. A Norwegian trial in which 436 patients were randomly assigned to receive either CEV (cyclophosphamide, epirubicin, vincristine) or EP for five cycles showed similar results in all patients, but in those with LSCLC the median survival time favored the EP arm (14.5 versus 9.7 months).62

Ch067-F06861.indd 829

Although etoposide/carboplatin can be used instead of EP,63 the evidence from randomized trials supports use of cisplatin to improve response and survival in SCLC,64 along with evidence from other tumor types that cisplatin may have better efficacy in the curative setting. Therefore, carboplatin should not be substituted in the curative setting unless there is concern for patient safety.

Dose Intensification Given the high relapse rate and chemosensitivity of SCLC, dose intensity has been a widely examined strategy. The interest comes from studies correlating dose intensity (amount of drug administered per unit of time) with patient outcome in other tumor types, such as lymphoma. Klasa and colleagues65 were able to correlate response and median survival with dose intensity during the first 6 weeks of therapy for SCLC (P = .07 for CAV in ESCLC). Several studies of dose intensification have demonstrated higher tumor response but not survival improvement, with one exception.66 In that study, despite several negative similar studies, Arriagada and colleagues gave higher doses only in cycle 1 of treatment, and this resulted in better median and 2-year survival. It is important to note that the control arm is variable in the published literature, with some studies using lower than standard doses as the control arm, with suboptimal results. In an analysis of randomized studies, an association was seen between the relative dose intensity of

1/21/2008 1:20:18 PM

830

Section 3 Lung

doxorubicin and response rate, but not survival. Similar associations were seen for etoposide-containing regimens, again confirming higher response rates with higher dose intensity but without translation to better patient outcomes. A recent meta-analysis assessed the value of G-CSF and GM-CSF in maintaining dose intensity, accelerated chemotherapy with increased dose intensity, and also increased dose density (similar total dose of chemotherapy delivered in shorter time interval). Berghmans and colleagues (Berghmans et al, 2002)67 found 12 trials, including 2107 randomized patients, that overall showed no benefit in the routine use of CSFs in SCLC. In particular, CSF administration appeared to be associated with a decreased response rate when used to maintain dose intensity (relative risk, 0.92; 95% confidence interval [CI], 0.87-0.97), but with similar survival. No

clear impact on response or survival in accelerated chemotherapy delivery was observed, and a lesser survival was seen with the delivery of dose-dense chemotherapy in SCLC. One trial from the British MRC Working Party compared standard ICE or CAE therapy administered every 3 weeks (Table 67-3) to administration every 2 weeks of the same chemotherapy with G-CSF support for 6 cycles in 403 patients with good PS who had limited- or extensive-stage disease.68 Although the response rates were similar, patients treated with dose-dense chemotherapy survived longer (47% and 39% at 12 months, 13% and 8% at 24 months for dose-dense and standard arms respectively; HR, 0.80; P = .04). Both arms had similar toxic death rates, quality of life scores, and metastasis-free survival times, although patients in the dose-dense arm received more transfusions. However, these results were

TABLE 67-3 Frequently Used Chemotherapy Combinations for Small Cell Lung Cancer Regimen

Dose Range, Route, and Days of Administration

Frequency

CAV Cyclophosphamide Adriamycin (doxorubicin) Vincristine

1000-1200 mg/m2 IV on day 1 45-50 mg/m2 IV on day 1 1.4 mg/m2 (maximum dose 2 mg) IV on day 1

Every 3 wk

CAVE Cyclophosphamide Adriamycin (doxorubicin) Vincristine Etoposide

750-1000 mg/m2 IV on day 1 45-50 mg/m2 IV on day 1 1.4 mg/m2 (maximum dose 2 mg) IV on day 1 80-100 mg/m2 IV on days 1-3

Every 3-4 wk

1000-1200 mg/m2 IV on day 1 45-50 mg/m2 IV on day 1 50 mg/m2 IV on days 1-5 OR 80 mg/m2 IV on days 1-3

Every 3-4 wk

80-100 mg/m2 IV on days 1-3 75-100 mg/m2 IV on day 1 OR 25 mg/m2 IV on days 1-3

Every 3 wk

100-120 mg/m2 IV on days 1-3 300 mg/m2 IV on day 1 OR 100 mg/m2 IV on days 1-3

Every 3 wk

ICE Etoposide Carboplatin Ifosfamide

180 mg/m2 on days 1 and 2 300 mg/m2 on day 1 5 g/m2 over 24 hours on day 1

Every 3 wk

CODE Cisplatin Vincristine (Oncovin) Doxorubicin (Adriamycin) Etoposide

25 mg/m2 weekly × 8 1 mg/m2 on weeks 1, 2, 4, 6, and 8 40 mg/m2 q2wk × 5 80 mg/m2 IV on day 1 and PO on days 2 and 3 q2wk × 5

IP (two versions) (JCOG)116 Irinotecan Cisplatin

60 mg/m2 on days 1, 8, and 15 60 mg/m2 on day 1

Every 3 wk

Hanna et al117 Irinotecan Cisplatin

65 mg/m2 on days 1 and 8 30 mg/m2 on days 1 and 8

Every 3 wk

CAE or CDE Cyclophosphamide Adriamycin (doxorubicin) Etoposide

EP Etoposide Cisplatin

EC Etoposide Carboplatin

Ch067-F06861.indd 830

1/21/2008 1:20:19 PM

Chapter 67 Small Cell Lung Cancer

not confirmed in a subsequent study from this group, in which ICE (ifosfamide, cisplatin, and etoposide) given every 4 weeks (see Table 67-3) was compared with dose-dense ICE given every 2 weeks with G-CSF and autologous stem cell support.69 There was similar survival in both groups, with more hematologic toxicity but less febrile neutropenia in the dose-dense arm. Although G-CSF use can decrease the risk of febrile neutropenia, its general use in patients with SCLC is not costeffective, costing up to 240 c per percentage decrease in the risk of febrile neutropenia.70 Whether it is used to accelerate dose delivery (dose-dense therapy), to intensify chemotherapy doses, or to add additional agents (three-drug versus two-drug regimens), G-CSF allows delivery of planned treatment, but to date studies have not shown significantly improved outcomes using these strategies.67,71,72 However, there may be special populations or indications in which the use of G-CSF could be helpful, such as maintaining standard doses of therapy in older patients rather than using attenuated dosing,73 or other indications using American Society of Clinical Oncology guidelines.74

Duration of Chemotherapy There have been six randomized trials looking at the optimal duration of therapy in LSCLC.59,75-80 Four examined prolonged administration strategies (≥9 treatment cycles), and two examined shorter durations of therapy (4 cycles), compared to 6 or 8 cycles. None of these trials demonstrated a benefit for prolonged chemotherapy, and one study in patients with LSCLC found that maintenance chemotherapy was associated with poorer survival,76 in addition to the expected increase in toxicity and detriment to quality of life. Finally, the two studies examining shorter courses of treatment did not find any differences between four versus more cycles of therapy, suggesting that four cycles may be sufficient in SCLC, although the number of trials examining this question is small.

Advances in Chemotherapy for Limited-Stage Disease Several studies have looked at adding additional agents to EP with concurrent thoracic irradiation or substituting agents. Most phase II studies have examined the use of paclitaxel and irinotecan, demonstrating the clear feasibility of combining these drugs (with or without EP) with thoracic irradiation, with high response rates.81-87 Mavroudis and colleagues88 randomly assigned 133 patients with SCLC to either EP or EP plus paclitaxel with G-CSF support. This study was terminated early because of the increase in toxic deaths and toxicity with triplet therapy, without substantial prolongation of survival. Reck and colleagues randomized 614 patients with limited- or extensive-stage disease to EP combined with either vincristine or paclitaxel on one day every 3 weeks.89 Median survival was slightly longer in the paclitaxel/etoposide/carboplatin arm, 12.7 versus 11.7 months (P = .02), with no significant increase in toxicity and better symptom control.90 Long-term survival remained superior in the paclitaxel arm, 14% versus 6% at 5 years. To improve outcome by

Ch067-F06861.indd 831

831

adding a fourth drug to triplet therapy, Thatcher and colleagues randomized patients with SCLC (85% limited-stage) to either ICE plus vincristine (ICE-V) or standard therapy (CAE for 77%), with thoracic and cranial irradiation after chemotherapy.91 Median survival time was 15.6 months for the four-drug regimen, compared to 11.6 months for standard therapy, with 20% and 11% of patients, respectively, surviving at 2 years. The main criticism of these new regimens is that their outcomes are not superior to the current standard of EP with early concurrent thoracic radiotherapy and PCI, which is associated with long-term survival rates of 20% (Murray and Turrisi, 2006).92

Thoracic Radiotherapy Many of the recent advances improving survival in SCLC have resulted from radiotherapy interventions. Pignon and colleagues have conducted a meta-analysis of 13 randomized trials with 2140 patients, confirming a modest survival benefit with the addition of thoracic radiotherapy to systemic chemotherapy in limited-stage disease (Pignon et al, 1992).93 They demonstrated an improved 3-year survival rate, from 8.9% with chemotherapy alone to 14.3% with the addition of thoracic irradiation (HR, 0.86, P = .001).93 Radiation also improved local control, with a 2-year local failure rate of 23% in the radiation-treated patients, compared with 48% among those treated with chemotherapy alone (P = .0001). The trade-off is toxicity, with higher rates of esophagitis and pneumonitis, and a small increase in treatment-related mortality (1%).

Radiotherapy Timing Although Pignon and coworkers were not able to draw conclusions about optimal timing of thoracic radiation (i.e., concurrent or sequential, early versus late), most trials using concurrent chemoradiation showed better survival compared to a minority of those using a sequential approach (Murray and Turrisi, 2006; Pignon et al, 1992).92,93 The Cochrane Collaboration performed a meta-analysis examining the timing of thoracic irradiation with chemotherapy in LSCLC (DeRuysscher et al, 2006).94 Early radiation treatment was defined as treatment starting within 30 days after the first day of chemotherapy, and seven trials with a total of 1706 patients were included (Table 67-4).95-101 If the one trial that used non–platinum-based chemotherapy concurrent with thoracic irradiation is excluded,98 there was a clear survival benefit in favor of early thoracic irradiation at 5 years (HR, 0.64; P = .02). Among those studies that delivered the radiation within a 30-day treatment period, the 5-year survival figures further improved (HR, 0.56; P = .006). Including all seven trials, however, the results were not statistically significant, although a reduction in mortality at 2 and 5 years was seen with early irradiation (0.84 at 2 years, 95% CI 0.561.28; 0.80 at 5 years, 95% CI 0.47-1.38). Esophageal and pulmonary toxicity were worse with early concurrent irradiation and chemotherapy, although leukopenia was more common in the late radiotherapy group.94 One relevant factor may be that some trials included an LSCLC population with a worse prognosis, and this may have

1/21/2008 1:20:19 PM

832

Section 3 Lung

TABLE 67-4 Randomized Trials of Early Versus Late Thoracic Irradiation With Chemotherapy Author (Year)

No. Patients

Chemotherapy

Dose, Fractions, Time

Timing: Early/Late

PCI

Murray et al95 (2003)

332

CAV/EP

40 Gy/15 F/3 wk

Day 21/105

Yes (if CR)

96

Work et al

199

EP/CAV

40-45 Gy/15 F/3 wk

Day 1/126

Yes (if CR)

Jeremic et al97 (1997)

(1997)

107

ECb

54 Gy/36 F/3.6 wk (1.5 Gy bid)

Day 1/42

Yes (if CR or PR)

Perry et al98 (1987)

426

CEV, CAV

50 Gy/25 F/5 wk

Day 1/64

Yes

99

Skarlos et al

(2001)

Takada et al100 (2002) 101

James et al

(2003)

ECb

45 Gy/30 F/3 wk (1.5 Gy bid)

Day 1/56

Yes (if CR)

231

86

EP

40 Gy/15 F/3 wk

Day 2/85

Yes (if near-CR)

325

EP

40 Gy/15 F/3 wk

Day 21/105

Yes (if CR)

A, Adriamycin (doxorubicin); C, cyclophosphamide; Cb, carboplatin; CR, complete response; E, etoposide; F, fractions; P, cisplatin; PCI, prophylactic cranial irradiation; PR, partial response; V, vincristine.

diluted the ability for early thoracic irradiation to demonstrate a long-term survival impact.92 Those trials confirming a benefit from early chemoradiation95,97,100 all had longer median survival times than those trials not showing a benefit96,98,101 (18.6-30 months versus 11.2-14.3 months). Therefore, selecting patients with good prognostic features for early concurrent chemoradiation is important. Another important predictor of outcome from the meta-analysis of radiotherapy timing was the interval between the start of any treatment and the end of radiotherapy, designated SER.102 Patients treated within a SER of 30 days or less had better survival (HR, 0.62; P = .0003), although worse esophagitis. Delivering early concurrent chemoradiotherapy in a timedense fashion may result in better outcomes because of decreased ability of tumor cells to repopulate after initial chemotherapy, whereas later administration of radiotherapy may be less active due to repopulation triggered by neoadjuvant chemotherapy.103 Therefore, early concurrent thoracic radiation, ideally completed within 30 days, with platinumbased chemotherapy such as EP, is considered for all fit patients with limited-stage SCLC.

Dose and Fractionation There are variations in practice patterns according to the radiotherapy dose delivered as part of concurrent chemoradiation. Some groups administer less than 50 Gy for reasons of cord tolerance (e.g., 40 Gy in 15 daily fractions, NCI Canada95), but other groups use newer conformal and shielding technology to escalate to doses as high as 70 Gy,104 although no evidence yet exists that higher doses yield a superior outcome. Hyperfractionation has been of great interest in SCLC, given its sensitivity to radiation even at small doses. With hyperfractionation, or delivery of multiple small doses of radiation over time, it is possible to kill SCLC cells effectively while reducing late toxicity to normal tissues. Turrisi and colleagues (Turrisi et al, 1999)105 randomly assigned 417 patients with LSCLC to receive either 45 Gy in 25 once-daily fractions of 1.8 Gy over 5 weeks or 30 twice-daily fractions of 1.5 Gy over 3 weeks, administered concurrently with EP for four cycles (irradiation started within 24 hours of chemotherapy start). When the results were initially presented in

Ch067-F06861.indd 832

1996, response rates were identical between the two arms (87%), and median survival time was not significantly different (18.6 versus 22.7 months for once- and twice-daily treatment, respectively; P = .126),106 although there were nonsignificant differences in 2- and 3-year survival favoring the twice-daily arm. With continued follow-up to a median of 8 years, the survival difference between the two arms became statistically significant. Patients treated with oncedaily irradiation had a median survival time of 19 months, a 2-year survival rate of 41%, and a 5-year survival rate of 16%, compared with those treated with twice-daily radiation—23 months, 47%, and 26%, respectively (HR for once-daily treatment, 1.2; 95% CI, 1.0-1.6; P = .04 by log-rank test). More patients treated with hyperfractionated radiation suffered grade 3 esophagitis (27% versus 11%; P < .001). Treatment with hyperfractionated radiation did not improve relapse-free survival significantly, (29% twice-daily versus 24% once-daily relapse-free at 2 years; P = .10) but showed a trend to improvement in local control, with a local failure rate of 56% for patients treated with once-daily radiation, compared with 36% for the group treated twice-daily (P = .06). Although 45 Gy delivered in 30 twice-daily fractions over 3 weeks is accepted as the current standard radiotherapy regimen, critics have highlighted that the comparator arm might be considered substandard, with many other groups using higher daily doses and/or higher total doses of radiation in this setting. The North Central Cancer Treatment Group performed a confirmatory study of hyperfractionated (twicedaily) versus once-daily treatment; however, both arms had delayed initiation of chemoradiation until after induction chemotherapy.107 The study did not demonstrate a survival benefit and has been criticized for the delay in appropriate therapy (i.e., concurrent chemoradiation), even though lower rates of esophagitis were seen with this design. These findings further highlight the importance of timely completion of the radiotherapy as part of combined-modality therapy in LSCLC.

Radiotherapy Target Volume With respect to radiotherapy target volume, especially with the use of higher doses, target size is often limited to the primary tumor and involved nodal stations. Treatment of

1/21/2008 1:20:19 PM

Chapter 67 Small Cell Lung Cancer

uninvolved nodal areas may not be required and will cause toxicities such as esophagitis and pneumonitis. Defining a feasible target volume can be a challenge in patients with bulky limited disease, commonly seen in SCLC. If the bulk is too large to encompass safely in one radiation port, sometimes one or two cycles of induction chemotherapy are used, with replanning of treatment based on shrinkage of the primary tumor and nodes. Whereas there are limited supporting data, the Mayo Clinic has not demonstrated a clear hazard in using this approach, although a clinical trial has not been undertaken. According to Turrisi (Turrisi et al, 1999),105 an acceptable target for therapy would include nodal structures larger than 1 cm on CT and palpable nodes in the supraclavicular fossae in addition to the primary tumor, and elective irradiation of uninvolved nodes is not recommended.

Prophylactic Cranial Irradiation Although only 10% of patients present with brain metastases initially, the brain is an important site of relapse in patients with SCLC. Within 2 years, 50% to 70% of patients relapse with brain metastases. Given the relative protection of central nervous system (CNS) tissue from chemotherapy by the blood-brain barrier (sanctuary site), PCI was developed as a way to prevent central CNS relapse. In patients with responding limited- or extensive-stage disease without brain metastases, PCI is an important measure to prevent their development. A meta-analysis of 10 of 17 published trials, including 987 patients, demonstrated a clear improvement with PCI (Auperin et al, 1999).108 Patients receiving PCI had a lower risk of mortality (HR, 0.84; P = .01), with an absolute improvement in survival of 5.4% at 3 years (15.3% with observation versus 20.7% with PCI). This difference persisted beyond 3 years and has established PCI as the standard of care in patients with limited or extensive disease and a good response to initial induction therapy. PCI also decreased the risk of brain metastases by half (HR, 0.46; P < .001), from 58.3% to 33.3%, in the meta-analysis of these randomized trials. In addition, PCI improved disease-free survival, but without impact on local or other distant recurrences (HR, 0.75). There appeared to be a trend to greater efficacy with higher doses, but this effect did not reach statistical significance in these trials. Toxicities of PCI include short-term alopecia, fatigue, skin erythema and desquamation, otitis externa, and myelosuppression. Long-term changes can include cognitive dysfunction, including memory and visual changes, dementia, and neurologic changes such as ataxia, dysarthria, and tremors. However, studies have demonstrated that most patients with SCLC who are eligible for PCI have baseline evidence of significant cognitive dysfunction, and this does not appear to deteriorate with PCI treatment.109,110 The preexisting cognitive dysfunction is likely multifactorial because most SCLC patients are heavy smokers, with chronic hypoxemia and arteriosclerosis. The optimal dose of PCI remains to be determined, with the aim of maximizing CNS tumor development while minimizing toxicity. A standard dose currently being used is 25

Ch067-F06861.indd 833

833

Gy in 10 fractions. Fractionation schedules of 36 Gy in 18 fractions and 36 Gy in 24 twice-daily fractions are being explored.

Summary—Limited-Stage Disease Current standard therapy for LSCLC includes EP chemotherapy for 4 to 6 cycles, early concurrent thoracic irradiation, and, in patients with responding or stable disease, PCI. This is associated with long-term survival of 15% to 20% (Auperin et al, 1999).108

EXTENSIVE-STAGE DISEASE Approximately 60% of patients present with ESCLC. Fiveyear survival remains rare. Median survival for untreated patients with ESCLC is approximately 5 weeks.16-18 In both first-line and second-line settings, systemic chemotherapy for ESCLC yields a modest survival benefit, and median survival time with treatment is approximately 8 to 10 months with 2-year survival rates of less than 5%.18,111,112 Since the discovery of activity of cyclophosphamide and superior activity of combination regimens, combination chemotherapy has been the mainstay of therapy for ESCLC. Potential regimens include EP, CAV, and other options. EP remains one of the most commonly used regimens, for approximately four to eight cycles. Many of the chemotherapy studies described earlier included both limited and extensive-stage cases, and many of the issues discussed there apply in the setting of both LSCLC and ESCLC. There are only limited data supporting use of triplet or quadruplet regimens, high-dose administration, and dose-dense approaches in ESCLC. For example, the NCIC-CTG and the SWOG compared a dose-dense regimen, CODE, with alternating CAV/EP (see Table 67-3).113 Despite a higher response rate (87% CODE, 70% CAV/EP; P = .006), survival was similar in both groups, and the study was stopped early because of a higher toxic death rate in the dose-dense CODE arm. Additional studies of ESCLC have confirmed that increasing dose results in increasing toxicity, without clear improvements in survival.114,115 Given the palliative goals of therapy in patients with extensive-stage disease, many centers continue to use EP as standard therapy in ESCLC. The most recent agents of interest in SCLC are the camptothecins, irinotecan and topotecan. Irinotecan/cisplatin (IP) has been studied in two randomized trials, in comparison with EP, and a third trial (SWOG) is ongoing. In the first trial, from the Japanese Clinical Oncology Group (JCOG),116 treatment with IP yielded response rates of 84%, compared to 67% with EP, and better overall survival (12.8 versus 9.4 months; P = .002). Also, 2-year survival was 19.5% for the IP arm, compared with 5.2% for the standard arm. A subsequent trial conducted in North America, using a different dose and schedule of IP and EP (see Table 67-3), did not confirm this difference, and outcomes between the two arms were similar,107 save for toxicity differences. Treatment with IP was associated with less febrile neutropenia (3.7% versus 10.4%; P = .06) but more grade 3 or 4 vomiting (12.5% versus 3.8%; P = .04) and less diarrhea (21.3% versus 0%). A third trial, identical to the original JCOG study, is ongoing through

1/21/2008 1:20:19 PM

834

Section 3 Lung

SWOG, and will examine pharmacogenomic differences in a North American study population and the association with toxicity and efficacy. Studies with other agents have suggested equivalence, including a randomized trial of EP versus oral topotecan plus cisplatin that included 859 patients118 and a randomized trial from the London Lung Cancer Group of gemcitabine/carboplatin versus EP.109 In both studies, the main differences between regimens were differing toxicity profiles. There have been two published randomized trials in which a third drug was added to EP—one using ifosfamide, and the other paclitaxel plus G-CSF support.72,120 The addition of ifosfamide prolonged survival (9.0 versus 7.3 months; P = .045) and 2-year survival (13% versus 5%) without increased admissions for febrile neutropenia and no increase in toxic deaths.120 However, there were higher rates of anemia and myelosuppression, and the regimen has not been adopted as standard, most likely because of the perception of greater toxicity, the small magnitude of survival benefit, and the palliative goals of treatment. In another study, the Cancer and Leukemia Group B (CALGB) randomized 406 patients to standard EP or EP plus paclitaxel and G-CSF.72 There were no differences in median survival and 1-year survival; there was an increase in nonhematologic toxicity with the triplet regimen, as well as a higher toxic death rate. Therefore, EP remains standard as palliation in extensive-stage disease. Maintenance therapy has also been explored in ESCLC, after completion of initial chemotherapy. Schiller and colleagues121 randomly assigned 223 patients who had not progressed after four cycles of EP to either intravenous (IV) topotecan or observation until progression. There was a modest improvement in progression-free survival with maintenance chemotherapy (3.6 versus 2.3 months) but no difference in overall survival or quality of life, and there was increased toxicity in the chemotherapy arm. Another trial randomized 144 patients with stable or responding disease after four cycles of etoposide/cisplatin/ifosfamide to oral etoposide or observation until progression.122 Again, an improvement in progression-free survival was seen with maintenance chemotherapy (8.2 versus 6.5 months; P = .002), but there was no survival benefit. Although systemic chemotherapy is usually sufficient for rapid symptom palliation in ESCLC, palliative radiotherapy may also be helpful to improve symptom control in certain areas or if chemotherapy is unsuccessful.

Summary—Extensive-Stage Disease Chemotherapy with EP remains standard, for four cycles or more if appropriate. In addition to systemic therapy, radiation therapy may be used (e.g., for brain metastases) to palliate symptoms.

Currently accepted standards include CAV or topotecan. Other options include single-agent paclitaxel, gemcitabine, and the incorporation of other drugs, such as liposomal doxorubicin (Davies et al, 2004).123,124 This is an area of intense study, with more than 80 phase II studies in this setting. For patients who have been relapse- and progression-free for longer than 12 months since completion of platinum-based therapy, re-treatment with the same platinum combination (e.g., EP) may be a consideration and can yield acceptable response rates of up to 60%.125,126 Factors that may predict response include time to relapse (with >3 months, or 90 days from last chemotherapy, considered sensitive), prior history of response, good PS, and lesser extent of disease. Those whose SCLC either progressed during or did not respond to first-line therapy are said to have refractory disease; cancer that may have initially responded but relapsed or progressed within 90 days of therapy is said to be resistant. CAV and topotecan were compared in a randomized trial of 211 patients in the second-line setting (Von Pawel et al, 1999).127 Both treatments had similar response rates (24%), median survival times (25 weeks), and progression-free survival times. Several quality-of-life domains favored topotecan over CAV, but patients receiving topotecan required significantly more red cell transfusions (52.3% versus 26.9%) and platelet transfusions (19.6% versus 1.9%). IV and oral topotecan have recently been demonstrated to have similar activity as second-line therapy for patients in sensitive relapse.128 In a small phase II randomized trial, 106 patients were assigned to either oral or IV topotecan; the two groups had similar response rates and median survival times (23% and 32 weeks oral; 15% and 25 weeks IV). Severe neutropenia was twice as common in the IV treatment arm (67% versus 35%; P = .001). O’Brien and colleagues112 randomized 141 patients, who were not considered eligible for second-line IV chemotherapy, to best supportive care (BSC) with or without oral topotecan, administered daily for 5 days every 3 weeks at a dose of 2.3 mg/m2/day. Approximately half of the patients had resistant or refractory disease. The response rate in the chemotherapy arm was 7%, with better survival than in the BSC-alone arm (26 versus 14 weeks; HR, 0.64; P = .01). Quality of life deteriorated more quickly in those patients not treated with chemotherapy, strengthening the rationale for palliative benefit of second-line therapy in SCLC. For patients with a late relapse of disease or with lung-only recurrence or progression, consider repeat biopsy of the lesion. There is a 10% incidence of second primary cancers in this population, related to field cancerization effects, as well as the possibility of a residual NSCLC component of the tumor to explain progression or lack of response (Ginsberg and Shepherd, 1995).129

RELAPSED DISEASE

ROLE OF SURGERY

More than 80% of patients who are diagnosed with SCLC relapse and die of their disease within 1 to 2 years. The median survival time after relapse in treated patients is 25 weeks. There are several regimens that may be of potential benefit in the setting of relapsed disease, but none is curative.

Surgical intervention in the management of SCLC is not considered standard. However, there may be a role for surgery in highly selected scenarios for SCLC patients.129 The majority of patients with SCLC present with locally advanced or metastatic disease, precluding surgical intervention. Before

Ch067-F06861.indd 834

1/21/2008 1:20:19 PM

Chapter 67 Small Cell Lung Cancer

835

TABLE 67-5 Survival of Patients With SCLC Treated With Surgery Alone 5-Year Survival (%) Author

No. Patients

Shah et al137

28 135

Stage I 57.1

Stage II 0

Stage III

Overall

55.5

43.5

Sorensen et al

77

12

13

0

8

Shore and Paneth136

40

—

—

—

25

Mountain133

368

—

—

—

(Only 1 patient)

132

Lennox et al

275

—

—

—

7 (pneumonectomy), 18 (lobectomy)

Hayata et al134

106

—

—

—

(Only 1 patient)

71

—

—

—

(Only 1 patient)

131

Fox and Scadding (British MRC)

MRC, Medical Research Council; SCLC, small cell lung cancer.

the widespread use of chemotherapy, even for patients with resectable disease, 5-year survival rates were less than 10% for patients with SCLC because of the high metastatic potential of this disease130-137 (Table 67-5). A prospective randomized trial was undertaken by the British MRC in which 70 patients were randomized to undergo surgical resection and 73 to receive so-called radical radiation therapy, 30 Gy or higher over 20 to 40 days.130 Patients treated with radiotherapy had a higher median, 5year, and 10-year survival than those treated with surgical resection (median, 300 days versus 199 days, respectively; 3/73 versus 1/70 alive at 5 years; 3/73 versus 0/70 alive at 10 years).131 Although neither treatment was very effective, radiation treatment was at least preferable to surgery. Thus, any consideration of a local treatment such as surgery or radiation must be incorporated into standard approaches with systemic chemotherapy as appropriate. There are, despite the highly metastatic potential of this disease, some scenarios in which surgical resection can be considered. The first is in the setting of a peripheral nodule without local nodal involvement, thought to be SCLC based on cytology results, which may in fact be typical or atypical carcinoid tumors. The second is to improve local control of SCLC compared to chemoradiation alone. There is significant interest in the very limited disease (VLD) subgroup, including T1/2N0 tumors. This is a good prognostic group, and the addition of adjuvant or preoperative chemotherapy (and radiotherapy) to surgery may improve local control. Patients with mixed small non–small cell histology tumors also may benefit from the addition of surgery to chemoradiation, as well as patients with localized tumors refractory to chemoradiation. Finally, patients with a late isolated local relapse or second primary cancer (often NSCLC) can be considered for surgical intervention (Ginsberg and Shepherd, 1995).129 In a review of surgical results for SCLC in the Veterans Administration Surgical Oncology Group (VASOG), a subgroup of patients with very low TNM stage was identified; this characteristic may be prognostic for SCLC patients undergoing surgery, and adjuvant chemotherapy may prolong survival after surgery.138 The Toronto Lung Group reported that, among 63 patients receiving adjuvant chemotherapy after surgical resection, median survival time was 83 weeks

Ch067-F06861.indd 835

TABLE 67-6 Survival of Patients Treated With Adjuvant Chemotherapy After Surgical Resection of SCLC, by Pathologic Stage 5-Year Survival (%) No. Patients Stage I Stage II Stage III Total

Author Shields et al138

132

51

20

3

28

134

72

26

17

0

11

Meyer et al

30

>50

50

0

Osterlind et al143

36

22

—

—

25 (3-yr)

Maassen and Greschuchna144

124

34

21

11

20 (3-yr)

63

48

24

24

31

157

61

35

35

? (4-yr)

Macchiarini et al

42

52

—

13

36

Hara et al146

37

64

42

10.7

—

Davis et al147

32

50

35

21

36

Wada et al

17

37 (Stages I & II) 33

32

Lucci et al149

92

46

15

9

33

Cataldo150

Hayata et al

142

Shepherd et al139 140,141

Karrer et al

145

148

—

60

46

36

15

—

151

Suzuki et al

62

64* 76†

50* 38†

17* 40†

57

Badzio et al152

67

—

—

27

—

*Clinical stage. † Pathological stage. SCLC, small cell lung cancer.

and the projected 5-year survival rate was 31%.139 Similar results were reported in Europe and Asia, with a projected 4-year survival rate of 61% for patients with stage I SCLC.140,141 These and other studies are further described in Table 67-6.134,138-152 Given comparable results to chemoradiation in limited-stage disease, it is recommend that all patients who have resection of SCLC be offered adjuvant chemotherapy, most commonly with four cycles of EP.

1/21/2008 1:20:19 PM

836

Section 3 Lung

Because local failure is a problem in 25% to 35% of patients after chemotherapy for limited-stage disease,153 the value of additional local therapy has been further explored. The feasibility of surgery after induction chemotherapy in patients with responding disease has been investigated in a number of single-institution series (Table 67-7) (Shepherd et al, 1991).146,148,154-166 Surgical eligibility after induction chemotherapy ranged from 27% to 79%, with median survival times of up to 2 years and 5-year survival projections of 60% to 80% for patients with pathologic stage I tumors.154,158 In addition, most authors reported that 10% to 15% of patients had tumors with mixed histology and a NSCLC component on resection. Of interest, the two approaches, induction or adjuvant chemotherapy plus surgery, yielded low local relapse rates in phase II trials, although patient selection confounds any comparison with local relapse rates after radiotherapy. Ten trials of 420 patients with LSCLC treated with surgical resection and adjuvant chemotherapy report a pooled relapse rate of 56%.139,142,145-7,149,150,152,167-9 Among the patients with relapse, 16% had local recurrences, half with both local and distant recurrence. In 10 studies of patients treated with induction chemotherapy followed by surgery, 250 patients underwent resection, and 210 (84%) had complete resection.146,154-156,158-160,165,166,170 Of 116 patients who relapsed, 26% had local failure; in two thirds of those patients, this was their only site of recurrence.

The Lung Cancer Study Group initiated a prospective randomized trial in 1983 in which patients were treated with CAV induction chemotherapy, and responding patients were randomized to either surgical resection followed by irradiation or radiotherapy alone.171 Of 328 patients enrolled on the study, 44% (146) were later randomized: 70 to surgery/ radiotherapy and 76 to radiotherapy alone. The majority of patients who were not randomized either did not respond to induction chemotherapy or declined randomization to receive thoracotomy. Sixty of the 70 randomized patients underwent thoracotomy, as did 8 patients off trial protocol. Seventy-seven percent had complete resection of their tumor. Complete pathologic response was seen in 19%, and 9% were found to have residual NSCLC. No difference was observed between the surgical and nonsurgical arms, with a median survival time of 16 months in both. The results of this trial do not support the addition of pulmonary resection to the multimodality treatment of SCLC. However, patients with peripheral nodules were excluded from this study, thus the value of surgery in maximizing local control remains an important question in the group with very limited disease. Although surgical resection is not routine in the management of SCLC, it remains of interest for patients with T1-2 N0 tumors after induction chemotherapy or as initial management, with adjuvant chemotherapy to follow. As tumor stage increases, the potential value of surgical intervention is less

TABLE 67-7 Prospective Phase II Trials of Induction Chemotherapy Followed by Surgery for LSCLC Clinical Stage Author

No. Patients

Prager et al154

I

II

III

Chemotherapy

RR/pCR (%)

25

CAVE × 2-4

88/5

39

2

12

Thoracotomy/CSR (%) 1/8 (21)

5-Year Survival (%) —

Williams et al

38

—

—

—

CAE × 3

82/11

25/21 (55)

—

Johnson et al156

24

3

7

14

CAV × 6 ± EP

100/37

23/15 (62)

—

Baker et al157

37

—

—

—

CAE × 2

54/5

20/20 (54)

58 (2-yr)

155

72

21

16

35

CAV × 6 ± EP

80/4

38/33 (36)

36

Benfield et al159

8

—

5

3

CAEV × 2

88/0

8/8 (100)

—

160

25

10

1

24

COPE × 3

96/20

14/10 (40)

—

Shepherd et al

158

Zatopek et al 146

Hara et al

17

4

6

7

Eberhardt et al161

46

6

2

38

Fujimori et al162

22

11

4

7

53

—

—

—

33

0

1

32

Various

?/13

Rea et al

163

Gridelli et al164 Wada et al

148

17 165

Lewinski et al

75

Muller et al166

27

6* —

Various

82/?

17/17 (100)

33

EP

94/24

32/23 (50)

46

CAV

96/25

21/21 (96)

64 (3-yr)

Various

—/—

38/37 (70)

20

Car, Ep, E

90/9

5/4 (12)

9 (4-yr)

—

31

12*

17*

EP × 3

75/16

46/35 (47)

29

—

27

Various

?

48/45 (94)†

34

*Stage reported only for surgical patients Includes patients who had surgery before chemotherapy A, Adriamycin (doxorubicin); C, cyclophosphamide; Car, carboplatin; CSR, complete surgical resection; E, etoposide; Ep, epirubicin; LSCLC, limited-stage small cell lung cancer; O, vincristine; P, cisplatin; pCR, pathologic complete response; RR, overall response rate; V, vincristine. †

Ch067-F06861.indd 836

1/21/2008 1:20:19 PM

Chapter 67 Small Cell Lung Cancer

clear, although it becomes less likely (e.g., for stage III SCLC). Another group who may benefit from surgical resection after chemotherapy and irradiation are the 10% to 15% of patients with combined SCLC and NSCLC tumors. Surgical resection can be considered after initial management of the SCLC component to resect residual disease that is resistant to chemotherapy and/or radiotherapy. Patients with residual tumors after chemoradiation can be considered for repeat biopsy to rule out a mixed NSCLC component and possible surgical salvage. For example, the Toronto Lung Group identified 10 of 28 patients who had residual NSCLC after surgical salvage for SCLC.172

TREATMENT IN THE ELDERLY Although there are large numbers of elderly patients with lung cancer, including SCLC, there are few data on how treatment for this group of patients differs or should differ from that of younger patients. Until recently, elderly patients were excluded from many clinical research trials, and there have been few studies designed specifically for the elderly population. Goodwin and colleagues reported that, whereas 31% of all adult patients with cancer were older than 70 years of age, only 7% of all patients enrolled in SWOG trials were in that age group.173 In SWOG lung cancer trials, only 18% of the patients were older than age 65 years, and only 9% were older than 70. The Toronto Lung Group reported that, between 1976 and 1988, only 63% of patients aged 70 years or older were treated with chemotherapy (78 of 123 patients, only one third of them older than 80 years of age), and 20% (25/123) received no treatment at all.174 The most important determinant in the treatment decision-making process was PS. Of the patients with PS 0 to 2, 66% received therapy, compared with 38% of those with PS 3. Similar observations were made in the Netherlands, where 52% of patients older than 70 years of age were offered no treatment, compared with 14% of those in their 50s and 22% of those in their 60s.175 Factors that affect the decision to not treat older patients include concern regarding the presence of comorbid conditions, the potential for worse toxicity, and less benefit in older patients. However, analyses of cooperative group databases, although limited in the number of older patients included, indicate that stage remains the most important prognostic factor, followed by PS, gender, and baseline LDH.30,40 In the SWOG database, age older than 70 years was also found to be a significant prognostic factor, and in a retrospective review of the CALGB database, patients with limited-stage disease who were older than 60 years had higher rates of mortality than younger patients (P < .008).39 Sagman and colleagues analyzed 614 patients in the University of Toronto database and found that patients older than 70 years of age had poorer survival, although this factor was not significant in multivariate analysis.40 In an analysis of the NCIC-CTG database of patients with limited-stage disease, age was of modest prognostic significance as a continuous variable (P = .02), but survival of patients older than 70 years was similar to those younger than 70.41 The patients with the worst prognosis

Ch067-F06861.indd 837

837

were those age 75 and older. Pignon examined the impact of age in the meta-analysis of thoracic radiation added to systemic chemotherapy in limited-stage disease and found that patients appeared to benefit more if they were younger than 55 years of age compared to 70 years or older. In fact, the relative risk of death was increased, at 1.07 (95% CI, 0.701.64) in patients older than 70 years of age when radiotherapy was added to chemotherapy (10.2% survival at 3 years with radiotherapy versus 8.7% without it).93 Toxicity rates in older patients do not appear to be higher than in younger patients, but older patients appear to receive fewer cycles of treatment.41 In the NCIC-CTG BR.3 and BR.6 trials, 69% of older patients and 82% of younger patients completed six cycles of chemotherapy (P = .01). Despite a lesser dose of chemotherapy administered to older patients, their response rates, median survival times, and 5-year survival rates were similar to those of younger patients. Additional studies are shown in Table 67-8.41,174,176-182 However, more prospective data are needed. Findlay and colleagues180 reviewed older patients who had been treated with either of the following: 1. Combination chemotherapy or single-agent therapy 2. Reduced doses of combination therapy Median survival time was longer in the standard arm (36 versus 16 weeks), especially in limited-stage disease (43 versus 26 weeks). Therefore, underdosing of fit patients on the basis of chronologic age alone may disadvantage outcomes in SCLC. There have been several trials looking at single agents in older patients, including teniposide, with response rates ranging from 23% to 90%, and toxic deaths ranging from none to an unacceptably high rate of death during the first cycle of treatment.183-185 The most informative trials in older patients have been from the United Kingdom. The MRC Lung Cancer Working Party randomized patients with poor PS to oral etoposide 50 mg given twice daily for 10 days or to one of two standard combination treatments, CAV or IV etoposide/vincristine.186 The median age of the patients was 67 years (range, 35-83 years), and those treated with combination therapy did better (median survival time, 183 versus 130 days; P = .03). The single agent group had more life-threatening toxicity (19% versus 10%; P = .05), prompting early closure of the study after recruitment of 339 patients. The London Lung Cancer Group compared etoposide 100 mg given twice daily for 5 days to alternating combination therapy (CAV/EP) in patients who were older than 75 years of age or had poor PS with limited- or extensive-stage SCLC.187 Response rate, median survival time, and 1-year survival rate were all superior in the combination arm (39% versus 61%, 4.8 versus 5.9 months, and 9.8% versus 19.3%, respectively, for oral etoposide versus combination therapy; P < .05). Except for short-term nausea and vomiting associated with IV therapy, all other domains of quality of life and symptom control were worse in the oral etoposide arm. Therefore, combination therapy remains standard in older patients, and dose delivery may be enhanced by such measures as supportive G-CSF.73 There have also been several studies looking at ways to modify current regimens to decrease toxicity and improve treatment delivery in

1/21/2008 1:20:20 PM

838

Section 3 Lung

TABLE 67-8 Summary of Retrospective Analyses of Response, Survival, and Toxicity in Elderly Patients Treated With Chemotherapy for Small Cell Lung Cancer* No. Patients Author

Young

Shepherd et al174

0

Old 78

Response (%)

Median Survival Time

Toxic Death

Chemotherapy

Young

Old

Young

Old

Young

Old

CAV or EP

NA

62

NA

11.9 mo (LD) 5.2 mo (ED)

NA

0

12

4

9

4

Dajczman et al176

231

81

CAV or EP

50

51

∼9 mo

6 mo

Siu et al41

520

70

CAV and EP

78

82

15 mo (11% 5-yr)

13 mo (8% 5-yr)

0

20

Various

NA

NA

10 mo

NA

1

19

10

0

3

177

Clamon et al

178

Poplin et al

Kelly et al179 180

Findlay et al Nou181

Tebbutt et al182

50

164

49

CAE

60 (LD) 44 (ED)†

75 (LD) 40 (ED)†

—

∼12 mo

62

34

Various

NR

NR

27 wk

25 wk

0

64

235

110

73

29

†

†

Various

NA

67

NA

25 wk

NA

3

CAV or CME

NR

NR

10.9 mo

7.4 mo

15

9

CAV or EC

71 (LD) 65 (ED)

(68) LD (38) ED

45 wk (LD) 39 wk (ED)

36 wk (LD) 23.5 wk (ED)

0

3

*Results summarized only for patients treated with chemotherapy in each series. † Only complete remission rates reported. CAE, cyclophosphamide, doxorubicin, and etoposide; CAV, cyclophosphamide, doxorubicin, and vincristine; CME, CCNU (lomustine), methotrexate, and etoposide; EC, etoposide and carboplatin; ED, extensive disease; EP, etoposide and cisplatin; LD, limited disease; NA, not applicable; NR, not reported.

this population; these approaches look promising but have yet to be tested in randomized trials.188,189 With respect to thoracic irradiation in older patients, Quon and colleagues42 examined the NCIC-CTG database in patients with LSCLC and identified 88 of 608 patients aged 70 years or older. Although patients could have sequential or alternating radiation, early or late timing, and doses ranging from 25 Gy in 10 fractions to 40 Gy in 15 fractions, there were no differences in treatment completion rate, time to complete radiation, total dose delivery, or incidence of acute and late toxicities between older and younger patients. Radiation oncologists used similar field sizes in older patients, with no increase in pulmonary toxicity or esophagitis. Therefore, PS and general condition remain better predictors of thoracic irradiation tolerance than age, as confirmed by Pignon and colleagues (Pignon et al, 1992).93 In summary, fit elderly patients need to be offered optimal treatment with combination chemotherapy and irradiation after an informed discussion of the potential benefits and risks of therapy. Age must not be used as a limiting factor in treatment planning for SCLC.

ALTERNATIVE APROACHES Immunotherapy Given the poor outcome with conventional therapy for SCLC, a number of alternative approaches have been investigated. Immunotherapy has been widely explored, following the observation that patients with postoperative empyemas had superior survival to patients without infection.190,191 Interferon has been studied in at least five randomized trials as adjuvant therapy after initial response to chemotherapy.192-196

Ch067-F06861.indd 838

No benefit has been seen with the addition of interferon, and two trials were associated with a decrease in survival in the experimental arms. Also, given the significant rate of toxicity associated with interferon treatment, the majority of patients were unable to comply with the intended course of therapy. Two of the studies reported a trend toward better 2-year survival for patients with LSCLC who had a complete response at time of randomization.192,196 Vaccines are a resurgent focus of activity in cancer, including SCLC. One study showed that patients with antibodies against autologous tumor cell proteins had prolonged survival. Potential targets include gangliosides, including CM2, GD2, and GD3, which are distributed in almost all SCLC cell lines. A large randomized trial of the Bec2 vaccine, which can induce anti-GD3 antibodies, was conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and recently reported.197 A total of 515 patients with LSCLC who had a response to chemoradiation were randomly assigned to receive either five vaccinations over 10 weeks or observation. Progression-free survival and overall survival were similar, with no evidence of benefit in the vaccine arm. Other ganglioside vaccines remain under clinical development, such as BMS-248967, a bivalent vaccine of gangliosides GM2 and GD2 and immunoadjuvant StimulonR. Phase II trials are ongoing and will look at the serologic response after six vaccinations, as well as safety, anti-KLH (keyhole limpet hemocyanin) antibody titers, progression-free survival, and overall survival.198

Anticoagulants Anticoagulants remain of interest, with preclinical data suggesting a potential for reduction in metastatic potential

1/21/2008 1:20:20 PM

Chapter 67 Small Cell Lung Cancer

through reduction in the coagulant activity of tumor cells. Trials in SCLC using warfarin, heparin, and aspirin have been conducted. The CALGB treated patients with extensive SCLC with combination chemotherapy: methotrexate, doxorubicin, cyclophosphamide, and lomustine (MACC) or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC.199 Patients were randomized to warfarin or control, and warfarin was administered to maintain a prothrombin time of 1.5 to 2 times the control values. Response rates were higher for patients treated with MACC plus warfarin, and that study arm also had a trend to better failure-free survival and overall survival. However, there were more hemorrhagic events in that arm, including lethal bleeding in 2% of patients, and life-threatening bleeding in 4%. This trial has not been repeated. Lebeau and colleagues conducted two trials with heparin.200,201 Patients with limited- or extensive-stage disease were randomized to sequential chemotherapy or alternating chemotherapy. Subcutaneous heparin was administered to patients three times a day (500 IU/kg/day) for 5 weeks, and those treated with heparin had a higher complete response rate (37% versus 23%). The overall response rates were similar (67% and 73%), and overall survival was better in the heparin-treated group (P = .012). In subset analyses, the survival benefit with heparin was associated with LSCLC rather than ESCLC. The second study compared full-dose heparin given two to three times daily with prophylactic doses of low-molecular-weight heparin given once daily. Survival was similar in all groups, even in patients with limited-stage disease. A further study was done examining the role of aspirin.202 Patients with LSCLC or ESCLC were treated with combination chemotherapy (lomustine, cyclophosphamide, doxorubicin, and etoposide), and patients were randomized to receive aspirin (1 g/day) or control. Response rates were similar (77% and 76%), as were median survival times. Despite initially promising results with these studies of warfarin and one of heparin, this approach has not been pursued in the past decade.

quality-of-life scores. One third of patients required dose reduction of the marimastat, and 32% discontinued the drug for toxicity reasons, most commonly joint toxicity. This is related to the broad-spectrum effects of MMP inhibitors on sheddase enzymes, which results in significant arthritis, tendonitis, and joint pains. Vascular endothelial growth factor (VEGF) and its receptor-mediated signaling are important in the development and survival of cancer. High microvessel density and VEGF overexpression have been shown to be poor prognostic factors in SCLC,204 as well as NSCLC. Bevacizumab, a monoclonal antibody targeting VEGF, is being studied in two phase II trials as first-line therapy in ESCLC; the bevacizumab is added to EP in Eastern Cooperative Group trial E3501, and irinotecan/cisplatin in CALGB trial 30306. Other agents are also being studied. Sorafenib, a multi-kinase inhibitor (including RAF kinase, VEGF receptors 2 and 3, and platelet-derived growth factor receptor-β), is being studied in SWOG S0435 as a single agent for second-line therapy. AZD2171, a broadspectrum VEGF receptor tyrosine kinase inhibitor, is being studied through the California Cancer Consortium. And vandetinib, a dual epidermal growth factor receptor (EGFR) and KDR (VEGF receptor 2) tyrosine kinase inhibitor, is being examined as maintenance therapy in a randomized phase II trial through the NCIC-CTG BR.20 trial. Pending signal of activity, this last study may proceed to a phase III trial for maintenance vandetinib versus placebo. Studies with thalidomide, a known antiangiogenic agent, have been conducted in the United Kingdom and in France. The London Lung Cancer Group study 12 of EP with or without thalidomide has completed accrual and awaits analysis. The French have recently reported results from a maintenance trial in which patients with extensive-stage disease responding to first-line combination chemotherapy were treated with an additional four cycles of chemotherapy and randomized to either thalidomide (400 mg daily) or placebo.205 Although the study closed early due to poor accrual, improved survival was seen in patients treated with maintenance thalidomide (11.7 versus 8.7 months; HR, 0.48; P = .03).

Antiangiogenic Agents

Other Compounds

Angiogenesis has been a target of tremendous interest in all solid tumors. Recently developed antiangiogenic agents are potentially the most promising agents moving forward in drug development in SCLC. The MMPs are important enzymes because they are proteins capable of digesting extracellular matrix and basement membrane components, facilitating angiogenesis. Overexpression of MMPs is seen in the setting of tumor growth and metastasis, and Michael and colleagues demonstrated that overexpression of MMP-11 and MMP-14 is associated with poorer survival in SCLC.14 There have been three randomized trials of MMP inhibitors in SCLC. The NCICCTG and the EORTC randomized 532 patients with limitedor extensive-stage SCLC, after complete or partial response to initial therapy, to receive marimastat or placebo for up to 2 years.203 There was no difference in survival between the two groups, and patients treated with marimastat had poorer

N-901 is a monoclonal antibody combined with blocked ricin that targets the neural cell adhesion molecule, CD56, which is present on almost all SCLC cells. In a phase I study of N-901 as a single agent in patients with relapsed or refractory SCLC, a response was seen in 1 of 21 patients.206 In a subsequent phase II study, patients developed severe problems with capillary leak syndrome, limiting further development of this drug.207 BB-10901 also targets CD56 and is being studied in combination with a microtubule-inhibiting agent, maytansinoid. A phase II trial is currently ongoing, and 2 of 10 patients have had a response to single-agent therapy.208 SCLC cells commonly express KIT, which is prognostic in some series but not all.15 Imatinib mesylate is a smallmolecule tyrosine kinase inhibitor that targets the KIT receptor and blocks KIT-mediated signal transduction. Because of the frequent overexpression of KIT in SCLC tumors, imatinib has been studied both as a single agent and in combina-

Ch067-F06861.indd 839

839

1/21/2008 1:20:20 PM

840

Section 3 Lung

tion with chemotherapy in SCLC. Two phase II trials, both selecting only patients with evidence of tumor expression of KIT, failed to demonstrate any activity of imatinib as a single agent in pretreated SCLC patients.209,210 Imatinib has also been combined with irinotecan/cisplatin in several phase I studies, but all studies were complicated in the dose escalation phase by significant diarrhea and neutropenia in patients given the combination.211

Apoptosis Given the high expression of BCL2, an anti-apoptotic protein, in SCLC and its potential role in chemoresistance, a number of inhibitors of BCL2 have been studied. Oblimersen sodium, a second-generation antisense oligonucleotide, has been shown to downregulate BCL2. Rudin and colleagues212 successfully combined oblimersen with EP in the first-line treatment of ESCLC, with a response rate of 86% and median time to progression of 5.9 months. Interestingly, levels of BCL2 in peripheral blood mononuclear cells did not drop with administration of the antisense oligonucleotide. A randomized trial will be required to determine whether oblimersen adds to first-line chemotherapy in SCLC. Another trial of second-line paclitaxel plus oblimersen demonstrated no responses in 12 patients, a disappointing result given the potential for single-agent activity with paclitaxel alone.213

FUTURE DIRECTIONS There are many potential targets for improving outcome in patients with SCLC. Increasing the doses of radiation is a strategy being explored in a proposed intergroup trial, which will examine the effect of doses of 70 Gy using conformal radiation techniques compared with standard twice-daily fractionation to a total dose of 45 Gy. Attempts to improve chemotherapy are ongoing, such as the incorporation of irinotecan in the setting of limited-stage disease, while results of the confirmatory SWOG trial using irinotecan in extensive-stage disease are pending. Novel therapies, including angiogenesis inhibitors as maintenance therapy or perhaps concurrent with systemic therapy, hold great promise, with recent positive results in a randomized trial of thalidomide and several ongoing trials of potent antiangiogenic agents. Finally, surgery continues to be a potential option for highly selected patients and remains an interesting therapy for testing in randomized trials. In addition to therapeutic improvements, prevention through smoking cessation has been highly effective in decreasing the incidence of SCLC in North American men, and it is hoped that, with renewed focus on primary prevention, rates of SCLC will continue to fall.

COMMENTS AND CONTROVERSIES SCLC comprises approximately 15% of all lung cancers. The incidence in North America appears to be falling in men and rising in women, coincident with changing smoking patterns. Current staging modalities separate patients into limited (LSCLC) and extensive (ESCLC) disease categories. Although prognosis is poor, there are long-term survivors and a cure rate of approximately

Ch067-F06861.indd 840

20% in the limited-stage group. Paraneoplastic syndromes (except possibly SIADH) are associated with poor prognosis. First-line chemotherapy is EP (four to six cycles). Other regimens or prolonged chemotherapy offer no advantage. Cisplatin is superior to carboplatin in the curative setting. Early concurrent thoracic irradiation improves survival and should be offered to all LSCLC patients with good PS. There is a clear benefit from PCI in patients who have had a response to initial chemoradiation. Survival is enhanced, and subsequent relapse in the brain is reduced significantly by PCI. There is no clear role for primary surgical resection in SCLC. However, use of surgery for very limited disease (T1-2N0 tumors), either before or after chemotherapy or chemoradiation, remains of interest. A variety of novel or targeted therapies based on known molecular markers of SCLC are currently under study and may improve survival rates for this challenging lung cancer. G. A. P.

KEY REFERENCES Auperin A, Arriagada R, Pignon J-P, et al: Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. N Engl J Med 341:476-484, 1999. Berghmans T, Paesmans M, Lafitte JJ, et al: Role of granulocyte and granulocyte-macrophage colony-stimulating factors in the treatment of small-cell lung cancer: A systematic review of the literature with methodological assessment and meta-analysis. Lung Cancer 37:115123, 2002. Davies AM, Evans WK, Mackay JA, Shepherd FA: Treatment of recurrent small cell lung cancer. Hematol Oncol Clin North Am 18:387416, 2004. De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al: Systematic review and meta-analysis of randomized, controlled trials of the timing of chest radiotherapy in patients with limited-stage, smallcell lung cancer. Ann Oncol 17:542-552, 2006. Ginsberg RJ, Shepherd FA: Surgery for small cell lung cancer. Semin Radiat Oncol 5:40-43, 1995. Laurie SA, Logan D, Markman BR, et al: Practice guideline for the role of combination chemotherapy in the initial management of limitedstage small-cell lung cancer. Lung Cancer 43:223-240, 2004. Murray N, Turrisi AT: A review of first-line treatment for small-cell lung cancer. J Thorac Oncol 1:270-278, 2006. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:16181624, 1992. Shepherd FA, Ginsberg RJ, Patterson GA, et al: Is there ever a role for salvage operations in limited small-cell lung cancer? J Thorac Cardiovasc Surg 101:196, 1991. Siu L, Shepherd FA, Murray N, et al: Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 14:821-828, 1996. Stahel RA, Ginsberg R, Havemann K, et al: Staging and prognostic factors in small cell lung cancer: A consensus report. Lung Cancer 5:119-126, 1989. Turrisi AT, Kyungmann K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999. Von Pawel J, Schiller JH, Shepherd FA, et al: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658-67, 1999.

1/21/2008 1:20:20 PM

chapter

68

RARE PRIMARY MALIGNANT NEOPLASMS OF THE LUNG Robert J. Downey Maureen Zakowski Andre L. Moreira

Key Points ■ A host of rare malignancies can occur as primary pulmonary

tumors. ■ Most of these lesions have non-specific imaging features that are

difficult to distinguish from non–small cell carcinoma. ■ Staging is critical. ■ When localized, the majority of these lesions should be resected.

Most primary pulmonary malignant neoplasms are bronchogenic carcinomas. The uncommon primary malignant neoplasms that arise in the lung are of disparate histogenesis and include pulmonary blastoma, thymoma, carcinosarcoma, epithelioid hemangioepitheliomas, melanomas, teratomas, sarcomas, and lymphoreticular disorders. In this chapter, we review the available literature concerning each of these rare malignant neoplasms.

OVERVIEW OF CLINICAL PRESENTATIONS Most rare primary pulmonary malignant tumors have clinical features that mimic those of non–small cell lung cancer (NSCLC). Most patients (50%-85%) are symptomatic, most commonly with cough, dyspnea, chest pain, or hemoptysis and less often with wheezing, fever, fatigue, and weight loss. Investigation of these symptoms leads to radiographs that, with the exception of patients with lymphoreticular disorders and epithelioid hemangioendothelioma, typically demonstrate a solitary pulmonary nodule. Although the diagnosis may be suspected or, rarely, made before surgical exploration, the histologic diagnosis of a rare malignant primary lung tumor is most commonly made during surgery with the intent of resecting locoregional disease. On the whole, management after diagnosis of most rare primary pulmonary malignancies should follow the guidelines for those of patients with NSCLC.

PULMONARY BLASTOMA Pulmonary blastomas are malignancies that are composed of a mixture of malignant mesenchymal and epithelial cells that morphologically resemble embryonal lung. As such, these tumors are held to be dysembryonic or dysontogenetic neoplasms, other examples of which are hepatoblastoma, neuroblastoma, and Wilms’ tumors. Pulmonary blastoma is unique within this group as the only tumor to occur consistently in adulthood rather than childhood.

The first description of pulmonary blastoma was made in 1945 by Barrett and Barnard.1 They described a 40-year-old woman with influenza, fatigue, weight loss, anemia, and a chest radiograph demonstrating “a circumscribed opacity of even density in the middle of the right lung about as large as a small grapefruit” that was removed by pneumonectomy. In 1952, a follow-up report by Barnard revealed that “the patient has had no further trouble attributable to the tumor since its removal in 1943.” The microscopic appearance was described, and the tumor labeled an embryoma of lung.2 In 1961, Spencer described three additional cases and coined the term pulmonary blastoma because of the similarity of this lesion to nephroblastoma (Wilms’ tumor) and suggested that the tumor arose from primitive blastomatous cells.3 Recent immunologic evidence to support this view has been provided by Yousem and colleagues,4 who found a remarkable resemblance between the antigenic profile of blastoma and embryonic lung, as others have found between nephroblastoma and fetal kidney.5 Microscopically, this tumor shows a biphasic pattern, that is, it contains a mixture of epithelial and mesenchymal components, either of which may be dominant. Hemorrhage and necrosis are common features. The epithelial component may be arranged on branched tubules that resemble fetal lung; the mesenchymal component is represented by spindle or polygonal stromal cells. The stroma may show heterologous elements with cartilaginous, osseous, or skeletal muscle (rhabdoid) differentiation, as well as their malignant counterparts (e.g., chondrosarcoma, osteosarcoma). Metastases may be epithelial, stromal, or both.6,7 Fine-needle aspiration biopsy may characterize the lesion in sufficient detail to allow diagnosis.8 Pulmonary blastomas are uncommon. Jacobsen and Francis9 reviewed their experience at one hospital in Sweden over the 8-year period from 1971 to 1978 and found 11 cases, representing 0.5% of all lung neoplasms seen during that period. More recently, by reviewing the English language literature since the first reported case in 1945, two comprehensive reports by Larsen and Sorensen10 and Berho and colleagues11 summarized 156 cases of pulmonary blastoma. The largest report from a single institution was by Koss and colleagues12 from the Armed Forces Institute of Pathology (AFIP), who described 52 patients with pulmonary blastoma. Since the two summaries,10,11 there have been additional case reports.13-24 The following discussion summarizes the available information concerning presentation, therapy, and survival contained in these reports. Of the 156 patients described in the literature reviews, 102 (66%) were male and 54 (34%) were female, for a ratio 841

Ch068-F06861.indd 841

1/21/2008 1:21:16 PM

842

Section 3 Lung

of 1.9 : 1. The age at diagnosis ranged from neonatal to 80 years (median, 40 years). The distribution of left (45%) versus right (54%) lung was as expected. At presentation, many patients (40%) were asymptomatic. In the report from the AFIP, of the symptomatic patients, 33% presented with cough, 31% with chest pain, 20% with hemoptysis, 14% with dyspnea, 12% with weight loss, 8% with fever, and 4% with recurrent pneumonia. Most pulmonary blastomas were peripheral and ranged from 1 to 28 cm in diameter (median, 7-8 cm). The majority of patients (80%) were smokers. Details regarding treatment and results achieved are difficult to extract coherently from the literature. Series often combine patients with pulmonary blastoma, pleuropulmonary blastoma, a mesenchymal tumor of childhood, and welldifferentiated fetal adenocarcinoma of the lung, since these tumors were originally thought to represent histologic variations of the same malignant neoplasm. But today they are classified as separate tumors by the World Health Organization classification of tumors of the lung.25 Therefore, in reports before the current classification, most reports grouped these three distinct entities when discussing therapy and did not separate the effects of surgery, chemotherapy, and irradiation, which were often co-administered. However, it appears that most patients who present with evidence of locoregional disease underwent only pulmonary resection. Of the patients not undergoing resection, approximately one half had unresectable locoregional disease (i.e., pleural effusion) and the other half had distant disease. Because of the heterogeneous nature of the reports in the literature, pathologic staging cannot be summarized other than to note that there were reports describing hilar and mediastinal nodal metastases. The histologic differential diagnosis of pulmonary blastomas includes other biphasic tumors such as pleomorphic carcinomas and carcinosarcomas, pleuropulmonary blastoma, and well-differentiated fetal adenocarcinoma. Pleomorphic carcinoma, carcinosarcoma, and pulmonary blastoma of the lung are classified under the group of sarcomatoid carcinoma. Pleomorphic carcinoma is a poorly differentiated non–small cell carcinoma that is composed of a clearcut epithelial component such as squamous cell carcinoma or adenocarcinoma in association with spindle cells (sarcomatoid component). In contrast to pulmonary blastoma and carcinosarcoma, both parts of pleomorphic carcinoma (epithelial and spindle cells) stain for cytokeratins, therefore indicating their epithelial origin. There are no heterologous elements in pleomorphic carcinoma. This latter feature is the differentiating point between pleomorphic carcinoma and carcinosarcoma. Carcinosarcoma, as stated earlier, is differentiated from pleomorphic carcinoma by the presence of a sarcomatous differentiation. Rhabdomyosarcoma is the most often encountered, followed by osteosarcoma and chondrosarcoma. In contrast to pulmonary blastoma, carcinosarcomas are poorly differentiated tumors—the epithelial element does not resemble fetal lung. Pleuropulmonary blastoma is a true sarcoma of the lung, without a malignant epithelial component, and it is a disease of childhood. Pleuropulmonary blastoma is discussed separately later in this chapter.

Ch068-F06861.indd 842

Well-differentiated fetal adenocarcinoma is classified as a subtype of adenocarcinoma. It has no mesenchymal component but enters in the differential diagnosis of pulmonary blastoma because it is composed entirely of epithelial cells that resemble fetal lung epithelium. In the current classification, the term fetal adenocarcinoma is preferred because poorly differentiated fetal adenocarcinomas have been described. Like non–small cell carcinomas, the prognosis of pulmonary blastoma is dependent on the clinical stage of the disease. However, it has been suggested that these tumors have a worse prognosis, stage by stage, compared with the most common non–small cell carcinomas. Most patients who experience recurrences after resection do so with distant metastases, with many of them occurring in the brain. In summary, pulmonary blastoma behaves much like an NSCLC. Given the incomplete information available, the evaluation, indications for surgery, and extent of pulmonary resection probably best follow those of a patient with suspected or proved NSCLC; there is insufficient information available to support recommendation of regimens of chemoradiation therapy.

PRIMARY PULMONARY CARCINOSARCOMA The term carcinosarcoma denotes a biphasic malignancy containing both malignant epithelial and mesenchymal components. This allows a distinction to be drawn between carcinosarcoma and sarcomatoid (pleomorphic) carcinoma, with the latter being a carcinoma demonstrating spindling of the epithelial component without the presence of a true sarcomatous element. Virchow considered carcinosarcoma a “manifestation of the multipotentiality of the mother tissue,” such that the “sarcoma and carcinoma grow side by side like two branches of the same tree.”26 The simultaneous development of separate but comixing epithelial and stromal malignancy is another possibility, but less likely than differentiation of the cells of a malignant tumor into two or more divergent pathways from a single primitive neoplastic cell. Given the evolution in the pathologic understanding of this disease, older reports must be interpreted with caution. The first case report of carcinosarcoma is attributed to Kika,27 as cited by Herxheimer and Reinke,28 but there is no information available concerning the patient. Bergmann and colleagues26 reviewed eight cases of carcinosarcoma of lung and described the first two cases that were successfully resected, both by pneumonectomy by Dr. Evarts Graham. These two patients represented 0.8% of the 258 resected bronchopulmonary tumors at Barnes Hospital in St. Louis at that time. Recently, several reviews containing larger numbers of patients have become available.29,30 Of the patients with carcinosarcomas of the lung, a disproportionate number are men (male-to-female ratio, 7.25 : 1), are heavy smokers, and have an overall mean age of 65 years. If the tumor lies in the periphery of the lung, the patients tend to be asymptomatic whereas patients with tumors involving the major airways presented with cough, hemoptysis, wheezing, dyspnea, chest pain, or pulmonary infections. Central disease is more common than peripheral location, and endobronchial disease diagnosed by bronchoscopy is

1/21/2008 1:21:16 PM

Chapter 68 Rare Primary Malignant Neoplasms of the Lung

present in 62%. Chest radiographs generally demonstrate well-circumscribed lesions, with approximately two thirds being in the upper lobes and one third in the lower lobes. Of the patients reported in the literature, approximately 90% presented with evidence for local disease only and underwent pulmonary resection. The 5-year actuarial survival rates are reported as being 21% with a median of 12 months.31 Patients who have recurrences after resection do so in a pattern similar to that of patients with NSCLC, with distant metastases predominating. Metastases to the lung, liver, adrenal gland, brain, bone, and heart have been described. Histologically, carcinosarcomas can show significant necrosis, especially when peripheral in location. The most frequent epithelial component is squamous cell carcinoma (46%), then adenocarcinoma (31%), and, least commonly, adenosquamous carcinoma (19%). Small cell carcinoma has not been reported in these tumors.6 The mesenchymal component may be made up of undifferentiated spindle cells, but the sarcomatous elements have included rhabdomyosarcoma, osteosarcoma, and chondrosarcoma, and pleomorphic areas resembling malignant fibrous histiocytoma have been reported.6,32 Metastases, which may be present at the time of diagnosis, may be sarcomatous, epithelial, or both. Because it appears that its pattern of locoregional spread and distant metastasis mimics that of NSCLC, the evaluation and treatment of carcinosarcoma of the lung should be similar to that of NSCLC. However, strong recommendations on combined modality therapy cannot be made based on the limited material available in the literature.

PRIMARY PULMONARY THYMOMA A total of 22 cases of thymoma arising from the lung have been reported in the English literature since the first report in 1951 (Veynovich et al, 1997).33-43 Of these, 19 are well summarized in the recent case report and review by Veynovich and coworkers (Veynovich et al, 1997).40 The mean age at presentation was 55 years (range, 19-79 years) with discovery being based on an asymptomatic radiographic finding in most and less often with symptoms including chest pain, cough, hemoptysis, and, in two women, myasthenia gravis. The gross appearance is that of a well-demarcated lesion within the lung, with reported sizes reaching 12 cm in diameter. As with mediastinal thymomas, the histologic appearance of the tumor is diverse and can be classified similarly. The most common histologic types of pulmonary thymomas are type A (spindle cell thymoma), type B1 (lymphocyte predominant), type B2 (mixed cellularity), and type B3 (epithelioid predominant) as per the World Health Organization classification. Distinguishing lymphocyte-predominant thymoma from primary pulmonary lymphoma and epithelioid-predominant thymoma from disease metastatic to the lung can be difficult. The origin of these lesions is unknown. It has been suggested that intrapulmonary thymoma may arise from ectopic descent of thymic tissue during embryogenesis39 (although the respiratory primordium develops before the descent of the thymic primordium) or from pluripotent cells within the lung parenchyma that could also give rise to other unusual lung neoplasms (e.g., intrapulmonary meningioma).

Ch068-F06861.indd 843

843

Treatment is by surgical resection, with postoperative irradiation to be considered if the lesion is found to be unresectable or, as with mediastinal thymomas, if gross or microscopic extension of thymic tissue beyond the capsule is noted. There is no defined role for chemotherapy.

PULMONARY EPITHELIOID HEMANGIOENDOTHELIOMA Pulmonary epithelioid hemangioendothelioma ([EHE] and formerly called intravascular bronchioalveolar tumor [IVBAT]) is a rare malignant tumor of the lung first described by Dail and coworkers in 1975 in an abstract and later in a full report detailing 20 patients (Dail et al, 1983).44 In early reports, EHE was thought to be a peculiar form of bronchioloalveolar carcinoma with a high rate of vascular involvement. Recent electron microscopic and immunologic studies (Dail et al, 1983) 44-48 have demonstrated diffuse cytoplasmic staining of the malignant cells with factor VIII–related antigen; therefore, this tumor is now held to be of endothelial, not alveolar, cell origin. EHE is a tumor of multicentric origin that can arise from bone, soft tissues, liver, skin, and lung either simultaneously or sequentially. The lung is rarely involved, but, if it is, the tumor is typically multifocal and there is some evidence to suggest that the multiple foci arise synchronously.49 Radiographically, the appearance is that of multiple nodules that are perivascular and may be either well demarcated or poorly defined. Grossly, the well-demarcated pulmonary nodules of EHE have a firm cartilaginous surface when cut, and, microscopically, the almost acellular central portion of the tumor is surrounded by a cellular periphery that consists of an intra-alveolar collection of plump spindle cells and looser myxomatous tissue. The interstitial tissue can become hyalinized and sclerotic, and calcification and ossification can occur. The tumor can extend to adjacent alveoli and into peribronchial lymphatic channels. This tumor is probably best categorized as a low-grade sarcoma.6 A review of the English literature yielded 36 patients reported before 1998 (Dail et al, 1983),44-59 at which time Kataichi and coworkers published the results of a survey of 230 Asian Hospitals, during which they collected data on 21 patients with pulmonary EHE (10 of whom had been previously reported).60 In their study, Kataichi and coauthors found a slight female predominance (62%) and an overall mean age at diagnosis of 42 years (range, 14-69). Seventy-six percent of patients were asymptomatic, with the remainder demonstrating a variety of pulmonary complaints. A solitary lesion was found in only 4 patients, with unilateral multiple lesions being seen in 2 patients and multiple bilateral lesions seen in 15 patients. Eight patients underwent resection with curative intent. At a mean time after diagnosis of 73 months, 16 of 21 patients are alive (76%). Chemotherapy was administered to an unclear number of patients, but the authors note that chemotherapy “had no apparent beneficial effects.” Spontaneous regression of tumors was noted in 3 patients. EHE is a low- to intermediate-grade malignancy. High-grade epithelioid tumors of vascular origin are classified as angiosarcomas (epithelioid angiosarcomas). Angiosarcomas are distinguished from EHE by high cytologic atypia and mitotic rate.

1/21/2008 1:21:16 PM

844

Section 3 Lung

Recommendations about therapy are difficult to make based on the literature. EHE should be considered in the differential diagnosis of any patient with multiple bilateral pulmonary nodules, especially if the patient is a young woman. The disease tends to be indolent, with death usually resulting from slowly progressive pulmonary compromise secondary to replacement of the lung parenchyma by the tumor, although death due to systemic metastases can occur.58 There is no known effective treatment. Varying chemotherapeutic regimens have been attempted but usually only in symptomatic patients near death (Dail et al, 1983).44,60 Radiation therapy was unsuccessful in two patients.45,58 Patients with disease that can be resected should be considered for surgery.

PRIMARY PULMONARY MELANOMA Primary melanoma at any site except the skin and juxtacutaneous mucous membranes, eye, and leptomeninges is very uncommon, and primary malignant melanoma of the lung is very rare. It is well established that cutaneous melanoma can undergo spontaneous regression, and approximately 5% of patients newly diagnosed with melanoma will present with what appear to be metastases without an obvious primary site of disease in the locations where the disease normally originates.61 Distinguishing such patients from the apparently rare phenomenon of primary lung melanoma is difficult, and suggested criteria for the diagnosis of a primary pulmonary melanoma include the following62: 1. The absence of a current or previous primary melanoma elsewhere or the absence of a previously resected or cauterized cutaneous lesion of unknown type 2. No ocular tumor resection 3. Solitary tumor in the surgical specimen from the lung 4. Tumor morphology consistent with a primary melanoma 5. No demonstrable melanoma in other organs at time of operation 6. Autopsy findings without primary malignant melanomas being demonstrated elsewhere The first reported case of primary malignant melanoma of the lung has been attributed to Todd, in 1888, with subsequent cases reported by Kunkel and Torrey,63 Carlucci and Schleussner,64 and Allen and Spitz,65 but others have contended that there was not enough evidence provided by these reports to support the diagnosis. The first published case meeting the criteria just listed for a primary melanoma of lung was reported by Salm in 1963.66 The histologic appearance of malignant melanoma of the lung is identical to that of a melanoma at any site. Large pleomorphic cells, sometimes with prominent nucleoli, are seen; intranuclear inclusions may be present, and a search for pigment should be made. Immunohistochemical stains are helpful in establishing the diagnosis. Because cutaneous or mucosal malignant melanoma can spontaneously regress,67 some authors believe that the diagnosis of primary pulmonary melanoma of the lung cannot be made unless the lesion is located in the bronchial epithelium only (Bagwell et al, 1989).68 Other investigators suggest that melanoma can be primary within the lung parenchyma, suggesting derivation

Ch068-F06861.indd 844

from cells of the primitive foregut that migrate to the tracheobronchial tree in fetal life.62,66,69,70 The pathologic issues involved in the diagnosis of primary pulmonary melanoma have been recently reviewed by Wilson and Moran.71 By 1999, Ost and associates72 recorded 20 additional cases of primary malignant melanoma of the lung reported in the English language literature since Salm’s report in 196366; and since 1999, there have been a few additional case reports,73-77 as well as two series.61,71 Reviewing these reports suggests that the male-to-female ratio is even and that the median age at diagnosis is approximately 60 years. Approximately 75% of patients were symptomatic, with cough, hemoptysis, chest pain, dyspnea, or pneumonia being reported. There is no apparent predilection for side or upper or lower lobes. Approximately a fourth was evident endobronchially. de Wilt and associates61 performed a detailed survival analysis of 15 patients seen with melanoma in the lung without current or prior evidence for disease at any other site. There were 12 men and 3 women with a median age of 59 years. The melanoma was solitary in 11 and in multiple sites in the lung in 4. Lymph node sampling or dissection was performed in 12 patients, none of whom were found to have lymph node involvement. All patients underwent resection (lobectomy in 10 and less than a lobectomy in the others). The median disease-free survival was 17 months, and the overall survival was 32 months. At the time of the report, 4 patients were alive without evidence of disease at a median postoperative interval of 74 months (range, 32-132 months). They suggest that this survival exceeds that of patients with melanoma metastatic to the lung who undergo resection, and, therefore, resecting patients with apparently primary pulmonary melanoma is reasonable. Based on these data, after a histologic diagnosis of melanoma in the lung has been made, an exhaustive examination of the skin, eyes, and mucosa (including the pharynx, vagina, esophagus, and anal canal) and careful radiographic evaluation (probably including positron emission tomography) should be performed in an attempt to detect other sites of disease. If no other site can be found, then it is reasonable to proceed with lung resection if feasible.

PRIMARY MALIGNANT GERM CELL TUMORS Primary malignant germ cell tumors of the lung are exceedingly rare. Two types have been described: malignant teratoma and choriocarcinoma.

Malignant Teratoma Teratomas are tumors composed of endoderm-, ectoderm-, and mesoderm-derived tissue usually in a cystic mass. Teratomas are usually classified as mature, which are tumors composed of benign normal tissue or immature teratomas, when primitive elements, most often neuroepithelial tissue, are present. Mature intrapulmonary teratomas78 are exceedingly uncommon, with only 20 cases documented by 1978,79-81 and primary immature teratomas of the lung are very rare. Intraparenchymal tumors are more common than endobronchial tumors.78 A review of the literature yielded only 5 cases with enough information to confirm the diagnosis

1/21/2008 1:21:16 PM

Chapter 68 Rare Primary Malignant Neoplasms of the Lung

of a malignant intrapulmonary teratoma (Pound and Willis, 1969).81-85 The case of Barrett and Barnard1 has been recorded in multiple reviews as a malignant teratoma, but it has been classified by Spencer3 as a pulmonary blastoma. In the report of Ruland,84 little clinical information is presented. The patient of Schiodt and Jensen85 was a 66-year-old man who underwent an apicoposterior segmentectomy of the left upper lobe for a walnut-sized malignant teratoma. The patient had a recurrence locally and died approximately 1 year after the operation. The case of Gautam82 was that of a 68-year-old man who underwent a pneumonectomy for a 5-cm malignant teratoma with an endobronchial component completely obstructing the left upper lobe bronchus. No follow-up after discharge was presented. The case of Pound and Willis (Pound and Willis, 1969)83 was that of a 10-month-old boy who presented with supraclavicular lymphadenopathy that on biopsy revealed an undifferentiated large cell carcinoma. There was complete opacification of the right chest. He died 6 days after admission, and the autopsy revealed a 9-cm malignant teratoma within the right lower lobe, with associated hilar and mediastinal lymph node metastases. The patient reported by Kakkar and colleagues81 was that of a 20-year-old man who presented with recent onset of hemoptysis and a longer history of fever and cough. Radiographs revealed consolidation of a portion of the right lung; the patient died shortly thereafter, with final pathologic diagnosis being consistent with elements from all the germ cell layers as well as yolk sac components. Like other germ cell tumors, primary intrapulmonary malignant teratoma is exceptionally rare and little information is available to guide management. Most malignant teratomas have been treated as one would treat germ cell tumors in other sites.

Choriocarcinoma Choriocarcinoma is a germ cell tumor secreting β-human chorionic gonadotropin (β-hCG) and containing syncytiotrophoblastic cells. It may be misdiagnosed as adenocarcinoma. Staining for β-hCG or α-fetoprotein (or the presence of serum elevation of these proteins) may assist in making the diagnosis; elevation of β-hCG in patients with lung tumors is not uncommon, but primary pulmonary choriocarcinoma is rare. Approximately 175,000 patients are diagnosed with primary bronchogenic carcinoma of the lung in the United States each year, and secretion of β-hCG occurs in approximately 6% of these lung cancers.86-90 Primary extragonadal choriocarcinoma of the lung, by comparison, is extremely uncommon; in a review of the literature in 1962, Fine and colleagues90a did not record a single case of primary pulmonary choriocarcinoma in 109 reported cases of primary extragonadal choriocarcinoma in male patients. The first reported case of primary choriocarcinoma of the lung was by Gerber in 1935,91 and from then to 1999 there were an additional 36 cases reported and then reviewed by Ikura and coworkers.92 Since 1999, 4 additional cases have been reported.93-96 Of these 41 cases, 27 were male (male-to-female ratio, 0.65), with ages ranging from 4 months to 77 years (median,

Ch068-F06861.indd 845

845

54 years). Six patients (14%) were asymptomatic, with the remainder demonstrating pulmonary symptoms and hormonal problems such as male gynecomastia, precocious puberty, or postmenopausal vaginal bleeding. Treatment was by a variety of combinations of surgery and chemotherapy. At an approximately median time of 14 months after diagnosis, 15 of these 41 (36%) patients were recorded as being alive, of whom 10 underwent combined modality therapy (surgery and chemotherapy), 3 had chemotherapy alone, and 2 had surgery alone. Combined modality therapy with chemotherapy and surgery appears reasonable.

PRIMARY SARCOMA OF THE LUNG Primary malignant mesenchymal tumors (sarcomas), although rare, can arise in the lung, just as they do in all other anatomic sites. Most reports of primary sarcomas of the lung describe soft tissue sarcomas, but primary chondrosarcomas and osteosarcomas, although even more rare, do occur. The area has been extensively reviewed by Suster.97

Chondrosarcoma Primary extraskeletal chondrosarcoma of the lung is an extremely uncommon entity. Because most chondrosarcomas are metastatic to the lungs, a careful search of the skeletal system must be carried out before the diagnosis of primary chondrosarcoma of the lung can be made. It is believed that primary chondrosarcoma of the lung can be derived from tracheobronchial cartilage, but an origin from bronchial chondroma or hamartoma is possible.6 Grossly, the tumor may appear to be a round, lobulated mass within the lung.98 The histologic appearance is of plump, somewhat pleomorphic chondrocytes, some showing binucleation. Calcification or ossification may be present.98 By using the strict criteria of Morgan and Salama,98 approximately 12 well-documented cases were available for review (Yellin et al, 1983).99-109 There was a slight male predominance (male-to-female ratio, 0.7), with ages ranging from 23 to 74 years (median, 44 years). Most patients presented with a cough. Two had hemoptysis, and two had chest pain. All presented with a solitary, usually large pulmonary mass. Of the 12 patients, 3 received no therapy and died of locoregional disease between 6 and 20 months after the onset of symptoms. Nine patients underwent resection (2 by pneumonectomy, 4 by lobectomy/bilobectomy, 2 by wedge resection, and 1 by endobronchial resection). Of those who underwent resection, 1 died of metastatic disease to the lung 24 months after the lobectomy. The remaining 8 patients were alive and well 1 to 48 months after resection. Two patients (16%) had metastases to their mediastinal lymph nodes. If diagnosed preoperatively, these tumors should be resected because resection appears to translate into long-term survival. Because these tumors have metastasized to mediastinal lymph nodes, a mediastinal lymph node dissection at the time of resection appears to be advisable.

Osteosarcoma Primary osteosarcoma of the lung is also extremely rare because a metastasis from the skeletal system must be ruled

1/21/2008 1:21:16 PM

846

Section 3 Lung

out for the diagnosis of this entity; in two of the largest series of extraosseous osteosarcomas, not a single case of primary osteosarcoma of the lung was reported.110,111 In a review of the literature, only 14 reports containing 27 cases that were considered primary osteosarcoma of the lung were found (Colby et al, 1989).102,112-124 Histologically, spindle cells with myxoid, chondroid, or osteoid tissue are present. The osteoid tissue must be cytologically malignant for the diagnosis of osteosarcoma. Radiographically, the lesions are solitary, large, and calcified. Intense uptake on technetium-99m methylene diphosphonate (99mTcMDP) bone scintigraphy in the lung lesions is seen. Of the reported patients, the male-to-female ratio was nearly 1 : 1, with ages ranging from 33 to 77 years (median, 62 years). Most patients presented with pulmonary or chest wall symptoms. All lesions were solitary by chest radiography, and all were greater than 4 cm in maximal diameter (range, 418 cm). Patients have been treated with a variety of single and combined modality therapies. The prognosis of these patients is poor, with many dying within 1 year of diagnosis. Primary osteogenic sarcoma of the lung occurs as a large solitary lesion on chest radiography. If no distant disease is documented, resection appears to be the treatment of choice. The efficacy of adjuvant or neoadjuvant chemotherapy is unknown.

OTHER SARCOMAS In a review of the experience at Memorial Sloan-Kettering Cancer Center (MSKCC), Martini and colleagues125 reported on 22 patients with primary pulmonary soft tissue sarcomas who were evaluated over a 42-year period (1926-1968). During that time, 5714 patients with primary lung cancer were seen, a relative incidence of primary pulmonary sarcoma to lung cancer of 0.4%. In the literature, the descriptions of patients with “primary sarcoma of the lung” before 1975 are confusing; for example, reports such as those of Hochberg and Crastnopol126 include the lymphoproliferative disorders under the term lymphosarcoma. In this 1955 review of 77 “primary sarcomas of the bronchus and lung,” 44 (57%) were soft tissue sarcomas, 26% were lymphoproliferative disorders (including Hodgkin’s disease, lymphosarcoma, malignant lymphoma, and dendritic cell sarcoma), 5 (6%) were carcinosarcomas, and 2 (3%) were chondrosarcomas. However, since 1931, approximately 300 primary soft tissue sarcomas of the lung have been reported.119,126-171 The number of patients per report is small, ranging from 1 to 42 patients per report, with a median of 1. The largest single report was by McCormack and Martini (McCormack and Martini, 1989).172 The raw data from the 42 patients in this report from Memorial Sloan-Kettering Cancer Center were re-analyzed and, because they are representative of other reports in the literature, they are presented in the following paragraph. Of the 42 patients with primary sarcomas of the lung, 19 were male and 23 were female (male-to-female ratio, 0.8); ages ranged from 1.5 to 78 years (median, 52 years). Approximately 25% of the patients were asymptomatic, and the lesions detected by routine chest radiograph. Seven patients

Ch068-F06861.indd 846

(17%) presented with hemoptysis. The remaining patients presented with cough, dyspnea, chest pain, or systemic symptoms, such as fatigue, malaise, fever, or weight loss. All lesions were solitary masses, the diameter of which ranged from 1 to 17 cm (median, 5.5 cm). The histologic subtypes of sarcomas in these 42 patients were leiomyosarcoma (16), rhabdomyosarcoma (6), spindle cell carcinoma (13), angiosarcoma (2), malignant fibrous histiocytoma (3), fibrosarcoma (2), hemangiopericytoma (1), and blastoma (1). Although not specified, the sarcomas probably contained a number of malignant peripheral nerve tumors. Twenty-nine (69%) of these patients underwent resection of their primary pulmonary sarcomas (lobectomy, 15; pneumonectomy, 7; wedge resection, 6; and segmentectomy, 1). Of those whose lungs were not resected, 5 received no therapy, 6 received radiation therapy, and 2 received irradiation and chemotherapy. These 42 patients with primary sarcomas of the lung experienced overall 1-, 3-, and 5-year survival rates of 55%, 31%, and 25%, respectively, with a median survival of 13 months. In a report from the Mayo Clinic,119 size was thought to affect survival; in the Memorial Sloan-Kettering Cancer Center experience there was a trend, although not significant, toward improved rate of survival in patients with tumors 5 cm or smaller. Leiomyosarcoma is the most common histologic subtype, with approximately 41 reported in the MSKCC series. It is likely that a certain proportion of these arise from unrecognized leiomyosarcoma of the uterus in women, particularly if the patient has undergone a hysterectomy for the diagnosis of fibroids in the past. Having said this, the male-to-female ratio in the series was 2.5 : 1. The reported cases presented primarily as a solitary mass, with even distribution among the regions of the lung. Treatment has consisted mainly of surgical removal. Malignant fibrous histiocytoma is the most common soft tissue sarcoma, but it is only a subgroup of tumors arising in the lung and has been well reviewed by Yousem and Hochholzer.170 The histologic classification of this sarcoma is controversial: many tumors classified as malignant fibrous histiocytoma are classified today as fibrosarcomas, leiomyosarcomas, and myxoid fibrosarcomas. However, the diagnosis of malignant fibrous histiocytoma is still made. Four histologic subtypes are described173: 1. 2. 3. 4.

Storiform pleomorphic Myxoid Giant cell Inflammatory

Storiform pleomorphic is the type most commonly found in the lung.170 It consists of bundles of spindle cells arranged in a cartwheel, or storiform, pattern. Present in this background are pleomorphic, often giant, cells with many mitotic figures. The most important predictor of survival is complete resection of the primary tumor. The patients undergoing resection survived significantly longer (36% alive at 5 years) than those receiving radiation therapy or no therapy (no one survived longer than 2 years).

1/21/2008 1:21:16 PM

Chapter 68 Rare Primary Malignant Neoplasms of the Lung

MISCELLANEOUS MALIGNANT TUMORS 174

There have been case reports of primary ependymoma, Ewing’s sarcoma,175 lymphoepithelioma-like carcinoma,176 and pseudomesotheliomatous carcinoma177 of the lung. Because of the scarcity of data concerning these extraordinarily rare primary malignant tumors of the lung, the reader is referred to the reference section for more information.

PRIMARY MALIGNANT LYMPHORETICULAR DISORDERS OF THE LUNG All the components of the lymphoreticular system are found in the normal lung and can give rise to primary tumors of the lymphoreticular system. Although extremely uncommon, primary Hodgkin’s disease, non-Hodgkin’s lymphoma, and plasmacytoma of the lung are seen and are estimated to be approximately 0.5% of all primary lung tumors. Involvement of the lung as one site of disease in a patient with extrapulmonary Hodgkin’s or non-Hodgkin’s lymphoma is, of course, much more common and has been reported to be found in 40%178 and 49% (Mentzer et al, 1993),179,180 respectively. In this section, we focus on primary Hodgkin’s disease, nonHodgkin’s lymphoma, and plasmacytoma of the lung.

Solitary Plasmacytoma Plasma cell malignancies are a group of related disorders characterized by the proliferation of plasma cells, which are immunoglobulin-secreting B cells. The most common is multiple myeloma. Of patients with plasma cell malignancies, 4% present with a solitary malignant plasma cell neoplasm of the soft tissues (called an extramedullary plasmacytoma).181 Most extramedullary plasmacytomas occur in the nasopharynx, the upper respiratory tract, or the oropharynx; a primary plasmacytoma of the lung is extremely uncommon. In a review of six collected series, only 4% of extramedullary plasmacytomas were found to occur in the lung.182-186 The first reported case of an extramedullary plasmacytoma of the lung was noted by Gordon and Walker.187 A review of the English literature since then revealed 15 cases for which sufficient data were available for analysis (Joseph et al, 1993).188-200 Primary plasmacytoma of the lung occurs more frequently in men, with a male-to-female ratio of 2 : 1. Patient age ranges from 3 to 72 years (median, 43 years). Of these patients, 13 were treated with pulmonary resections (10 lobectomies and 3 pneumonectomies); in 3 of them, radiation therapy was added, and in 1, chemotherapy. Two patients underwent biopsy followed by medical therapy alone. The overall 5-year survival rate was approximately 40% (although it should be noted that only limited follow-up was reported). It is notable that 2 patients (17%) developed multiple myeloma at intervals of 7 and 26 months after resection. Primary pulmonary plasmacytoma can present as a parenchymal lesion or within the airway as an endotracheal or endobronchial lesion with airway obstruction.197 Microscopically, specimens demonstrate sheets of atypical plasma cells, similar to multiple myeloma. Ossification can be seen,201 and amorphous eosinophilic material representing immunoglobulin or amyloid may be present.202 This type of tumor must be distinguished from other lymphoproliferative disorders

Ch068-F06861.indd 847

847

such as plasmacytoid B-cell lymphoma. In addition, neuroendocrine tumors also enter the histologic diagnosis of plasmacytoma. Carcinoid and atypical carcinoid tumors are also composed of plasmacytoid cells and show occasional nuclear atypia or binucleation that can be seen in plasmacytomas. Poorly differentiated plasmocytomas may mimic poorly differentiated carcinomas. Immunohistochemical stains are helpful in establishing the correct diagnosis. Most pulmonary plasmacytomas are not associated with abnormal serum or urine immunoglobulin levels.6 If the tumor is diagnosed at thoracotomy, a complete resection of all apparent disease should be performed. If no other sites of disease are found, if serum electrophoresis is normal, and if Bence Jones proteinuria is absent, such a patient may be followed expectantly.182-186

Hodgkin’s Disease The occurrence of Hodgkin’s disease as extranodal disease is extremely uncommon,203 and primary extranodal Hodgkin’s disease was found to represent only 0.6% of all patients with Hodgkin’s disease seen at Yale–New Haven Hospital from 1980 to 1987204 and 0.07% of 1470 patients seen at Stanford Medical Center from 1960 to 1980.205 To be defined as primary pulmonary Hodgkin’s disease, the following criteria must be met169,205,206: 1. Histologic features of Hodgkin’s disease 2. Restriction of the disease to the lung, with no nodal involvement (although some authors accept minimal local nodal involvement)204 3. Clinical or pathologic exclusion of disease at distant sites According to the Ann Arbor staging system,207 a patient with primary pulmonary Hodgkin’s disease would be either stage IE (involvement of a single extranodal site) or IIE (localized involvement of an extranodal site and its contiguous lymph node chain). To summarize the presentation, therapy, and outcome, a literature search revealed reports detailing 65 patients with sufficient data to be analyzed.169,178,208-215 The excellent reviews of Radin204 and Habermann and associates216 are the sources of much of the data presented subsequently. Of 65 patients with primary Hodgkin’s disease of the lung, 40% were male, with ages ranging from 12 to 82 years (median, 37 years). Of these 65 patients, 15% were asymptomatic; 85% had symptoms, in decreasing frequency, of cough, weight loss, chest pain, dyspnea, hemoptysis, fatigue, rash, night sweats, and wheezing. Of those with symptoms, approximately 50% had the B-type symptoms of Hodgkin’s disease (weight loss, fever, and night sweats). The location of the finding on chest radiograph was unilateral in 50 patients (77%) and bilateral in 15 (23%). Two patients with normal chest radiographs had endobronchial Hodgkin’s disease diagnosed by bronchoscopy. All bilateral disease demonstrated multiple nodules; unilateral disease presented as a single nodule in 85% and as multiple nodules in 15%. Of the solitary nodules, 31% demonstrated cavitation.

1/21/2008 1:21:16 PM

848

Section 3 Lung

Intrathoracic Hodgkin’s disease, either primary or with contiguous mediastinal spread, is most often of the nodular sclerosing type. The histologic appearance of primary pulmonary Hodgkin’s disease is identical to that seen in extrapulmonary sites6 and is characterized by the presence of Reed-Sternberg cells (or their variants) in the appropriate background of inflammatory cells, such as lymphocytes, plasma cells, histiocytes, and eosinophils. Granulomas may also be present. In all but 1 patient reviewed, tissue was obtained by thoracotomy, with either open biopsy (59%) or resection (41%) by pneumonectomy (n = 9), lobectomy (n = 11), segmentectomy (n = 2), or wedge resection (n = 3). The remaining patient was diagnosed at autopsy. A diagnosis of Hodgkin’s disease can be made by percutaneous transthoracic needle biopsy or bronchoscopy, but the accuracy of these methods is debated by pathologists.217-219 There are reports of the diagnosis being made by sputum cytology.220 The therapy for patients with primary Hodgkin’s disease of the lung has varied considerably by decade and institution. Of the 64 patients reviewed, approximately 40% underwent complete resection of their intrathoracic disease, 40% had radiotherapy, and 50% had chemotherapy. Many patients with primary Hodgkin’s disease of the lung may have their disease diagnosed during thoracotomy for a so-called coin lesion. It is reasonable to subject these patients to formal pulmonary resections with mediastinal lymph node dissection if it appears that all evident disease can be removed. Other patients present with multiple bilateral or unilateral nodules; and although an attempt at diagnosis by less invasive methods may be made, most undergo open biopsy because of concerns that the transthoracic needle biopsy or bronchoscopy may not be sufficiently accurate. Once a diagnosis of pulmonary Hodgkin’s disease has been made by biopsy or resection, a search for other sites of disease should be performed. If no other disease is found (patient’s disease stage is IE or IIE), radiation therapy is added to the treatment. It is debatable whether chemotherapy should also be given for patients with unilateral disease; patients with bilateral disease could be considered as having stage IV disease, and they should be offered chemotherapy in the hope of long-term survival.

Non-Hodgkin’s Lymphoma Although primary extranodal non-Hodgkin’s lymphoma is not uncommon (10% of 380 untreated patients with nonHodgkin’s lymphoma at Tufts University School of Medicine between 1966 and 1976),221 primary non-Hodgkin’s lymphoma of the lung is rare. In the Tufts series there were no cases of primary extranodal pulmonary non-Hodgkin’s lymphoma. Another large series found that 3.6% of extranodal non-Hodgkin’s lymphoma occurred in the lung.222 The series from Memorial Sloan-Kettering Cancer Center (1949-1982) reported 36 cases of primary non-Hodgkin’s lymphoma of the lung (L’Hoste et al, 1984).223 During this period, 5030 patients with non-Hodgkin’s lymphoma were seen; thus, the estimated frequency of this lymphoma arising in the lung was 0.34% of all cases (L’Hoste et al, 1984).223

Ch068-F06861.indd 848

More recently, a review of the Mayo Clinic experience has been published.224 Patients were believed to have primary pulmonary non-Hodgkin’s lymphoma if the following criteria were met: 1. Unilateral or bilateral pulmonary parenchymal or bronchial involvement without mediastinal adenopathy 2. No history of previously diagnosed extrathoracic lymphoma 3. No evidence for extrathoracic disease on physical examination, CT of the chest, abdomen, and pelvis, as well as examination of peripheral blood and bone marrow 4. No evidence for extrathoracic disease for 6 months after diagnosis of pulmonary disease One hundred and six patients met these criteria and were diagnosed with pulmonary non-Hodgkin’s lymphoma between 1979 and 1994 of a total of 10,046 cases of newly diagnosed non-Hodgkin’s lymphoma. Primary pulmonary non-Hodgkin’s lymphomas most commonly arise from mucus-associated lymphoid tissue (MALT) of the bronchi (which has alternately been called the marginal zone or BALT as an acronym for bronchus-associated lymphoid tissue by some authors) and have been included in the most recent World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues225 under “extranodal marginal zone lymphomas of mucosaassociated lymphoid tissue.” This classification reflects the view that pulmonary MALT lymphomas may be similar to other MALT lymphomas, which can be associated with autoimmune diseases or chronic inflammation, and that they would have a generally indolent course and spread to other MALT-containing tissues.224 Grossly, the parenchymal lesions of lymphoma are white to tan and may be well defined or diffuse. The malignant cells are found predominantly in interstitial tissues,6 and extension into the pleura can occur. Tumor necrosis is uncommon. Information about the presentation and management of patients with primary pulmonary lymphoma can be assembled from these various series. First, in the Memorial SloanKettering Cancer Center series of 36 patients published in 1984 (L’Hoste et al, 1984),223 44% were asymptomatic, with the abnormality first being detected by incidental chest imaging. The appearance is that of a nodule with poorly demarcated borders and possibly containing air bronchograms. Of the symptomatic patients, 30% had cough, 11% had chest pain, 11% had malaise, and 7% had diagnoses of pneumonia. There were 18 men and 18 women, with ages ranging from 12 to 75 years (mean, 53 years). The AFIP report (Koss et al, 1991)226 enumerated the radiographic findings in 124 patients with primary non-Hodgkin’s lymphoma of the lung: a solitary nodule in 58%, a solitary infiltrate in 27%, multiple nodules in 9%, and multiple infiltrates in 6%. In one of the Mayo Clinic series (Ferraro et al, 2000)227 of 48 patients with primary pulmonary nonHodgkin’s lymphoma, a MALT type of lymphoma was found in 35 patients (73%) and a non-MALT type in 13 (27%). Complete surgical resection was performed in 19 patients (40%). With a median follow-up of 4.2 years (range, 1 month-

1/21/2008 1:21:17 PM

Chapter 68 Rare Primary Malignant Neoplasms of the Lung

16 years), 27 (56%) patients were alive without disease, 4 (8%) were alive either with disease or with unknown disease status, and 17 (36%) had died. The 5-year actuarial survival was 68% and did not differ between the MALT and the nonMALT groups. After a histologic diagnosis of non-Hodgkin’s lymphoma is made, the patient should be thoroughly evaluated for any evidence of extrathoracic disease. Once this is completed, the patient’s disease is then staged according to a modification of the Ann Arbor staging system (L’Hoste et al, 1984)207,223 as follows: Stage IE: Lung only involved Stage II1E: Lung and hilar nodes involved Stage II2E: Lung and mediastinal nodes involved Stage II2EW: Lung and adjacent chest wall or diaphragm involved Although the disease in patients with primary nonHodgkin’s lymphoma of the lung must have a histologic classification, a simpler approach is to group the disease in patients with primary non-Hodgkin’s lymphoma of the lung into small cell–predominant and large cell–predominant groups. This terminology is used mostly in cytologic material (aspiration biopsy). The group composed of predominantly small lymphocytes includes tumors such as small lymphocytic lymphoma, MALT lymphoma, follicular lymphoma grade I and II, and mantle cell lymphoma. The group composed of large lymphocytes includes diffuse large B-cell lymphoma, anaplastic large cell lymphoma, and follicular lymphoma grade III, among others. In the Memorial SloanKettering Cancer Center experience (L’Hoste et al, 1984),223 58% of the patients could be classified as having small cell lymphoma and 42% as having large cell lymphoma. Of those with small cell lymphomas, 90% underwent complete resection and 10% had a biopsy only; 35% received chemotherapy, and 40% experienced recurrence. In the large cell non-Hodgkin’s lymphoma group, 33% underwent resection and 67% underwent biopsies alone; 89% received chemotherapy. The overall recurrence rate was 50%. Overall, 5-year survival rates can be anticipated to be approximately 85% and 45% for patients with primary small cell and large cell non-Hodgkin’s lymphoma, respectively, with treatment (Koss et al, 1991).222,226,228,229 The prognosis is directly related to the final histologic classification of the tumor. Overall, primary non-Hodgkin’s lymphoma of the lung usually presents as a symptomatic ill-defined pulmonary nodule in a 40- to 60-year-old patient. Histologic diagnosis of lymphoma can be difficult to make by fine-needle aspiration, and many patients will require a surgical procedure or flow cytometric analysis of the aspirate to confirm clonality and classification based on surface markers. For MALT lymphomas, molecular analysis for gene rearrangement study is very often necessary to establish the diagnosis. If an extentof-disease evaluation, as outlined earlier, fails to disclose other sites of disease, it is reasonable to suggest complete resection rather than an incisional biopsy. Specific treatment of lymphomas is based on histologic classification of the tumor and staging.

Ch068-F06861.indd 849

849

COMMENTS AND CONTROVERSIES This chapter provides the ultimate compendium of information on these types of tumors because of the extensive bibliography. In the course of practice, a surgeon undoubtedly will encounter a few of these rare primary malignancies diagnosed preoperatively or intraoperatively. If diagnosed preoperatively, some of these tumors may be best treated by primary chemotherapy, for example, myeloma and B-cell lymphoma (although surgery may be the treatment of choice when the lesion is solitary). In most cases the diagnosis is made at the time of surgery, and because of inadequacies of frozen section the true diagnosis may not be available in the operating room. For this reason, these lesions, if believed to be solitary or within one lung, should be resected and a lymph node dissection should be accomplished. This approach may seem radical, but the ultimate diagnosis may not confirm the frozen section diagnosis. An example of this dilemma is seen in pulmonary lymphomas. Although surgeons continue to offer resection to these patients when they have been diagnosed preoperatively, it is unknown whether surgical resection is required to effect the best therapy. Like lymphomas elsewhere, these tumors are responsive to chemotherapy and to irradiation. However, because of lack of firm evidence to the contrary, it appears that, when possible, total surgical excision remains the mainstay of treatment. Unfortunately, the reports in the literature are so few that once resection has been performed, the prognosis of an individual patient is difficult to estimate. Adjuvant therapy must be considered on a per-patient basis because there is very little to guide the practitioner. In most instances one must look to other sites where these primary lesions occur and follow the examples of treatment at these sites. Most important, however, is that at the time of surgery a complete resection should be accomplished whenever possible. R. J. G.

KEY REFERENCES Bagwell SP, Flynn SD, Cox PM, Davison JA: Primary malignant melanoma of the lung. Am Rev Respir Dis 139:1543, 1989. ■ This is a case report of one patient with primary malignant melanoma of the lung. It is also the best review of the literature available. Colby TB, Bilbao JE, Battifora H, Unni K: Primary osteosarcoma of lung: A reappraisal following immunohistologic study. Arch Pathol Lab Med 113:1147, 1989. ■ This report from the Mayo Clinic describes three patients with primary osteosarcomas of the lung and reviews the limited literature in detail. Dail DH, Liebow AA, Gmelich IT, et al: Intravascular, bronchiolar, and alveolar tumor of the lung (IVBAT): An analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer 51:452, 1983. ■ This report summarizes the collected series of 20 patients with epithelioid hemangioepithelioma from the AFIP. It is the largest report in the literature. Davis MP, Eagan RT, Weiland LH, Pairolero PC: Carcinosarcoma of the lung: Mayo Clinic experience and response to chemotherapy. Mayo Clin Proc 59:598, 1984. ■ This is the largest report about carcinosarcomas of the lung from a single institution. It describes the clinical findings in 17 patients from the Mayo Clinic and details the clinical presentation, therapy, and outcome. Ferraro P, Trasteck VF, Adlakha H, et al: Primary non-Hodgkin’s lymphoma of the lung. Ann Thorac Surg 69:993, 2000.

1/21/2008 1:21:17 PM

850

Section 3 Lung

■ This report details one institution’s experience with the surgical management of 48

patients with primary non-Hodgkin’s lymphoma of the lung, emphasizing the diffuse nature of presenting symptoms and the lack of prognostic factors. Joseph G, Pandit M, Korfhage L: Primary pulmonary plasmacytoma. Cancer 71:721, 1993. ■ This case report and review of the literature succinctly summarizes the literature. Koss MN, Hochholzer L, O’Leary T: Pulmonary blastomas. Cancer 67:2368, 1991. ■ This is the largest report about pulmonary blastomas from a single institution. It describes the clinical and pathologic findings in a collected series of 52 patients from the AFIP. L’Hoste RJ, Filippa DA, Lieberman PH, Bretsky S: Primary pulmonary lymphomas: A clinicopathologic analysis of 36 cases. Cancer 54:1397, 1984. ■ This report, which is the largest reported series from a single institution, describes the presentations, therapies, and clinical outcomes of 79 patients seen at Memorial Sloan-Kettering Cancer Center. McCormack PM, Martini N: Primary sarcomas and lymphomas of lung. In Martini N, Vogt-Moykopf I (eds): Thoracic Surgery: Frontiers and Uncommon Neoplasms. Vol 5, St. Louis, CV Mosby, 1989, p 269. ■ This report from Memorial Sloan-Kettering Cancer Center reviews the clinical presentation, therapy, and outcome of 42 patients with primary soft tissue sarcomas of the lung. Mentzer SJ, Reilly JJ, Skarin AT, Sugarbaker DJ: Patterns of lung involvement by malignant lymphoma. Surgery 113:507, 1993. ■ This retrospective review details one institution’s experience with both primary pulmonary lymphomas and secondary lung involvement; correlation between the anatomic pattern of lung involvement and patient outcome is described.

Ch068-F06861.indd 850

Pound AW, Willis RA: A malignant teratoma of the lung in an infant. J Pathol 98:111, 1969. ■ In this report, the literature concerning primary malignant teratoma of the lung, of which there are few reports, is reviewed. Sridhar KS, Saldana MJ, Thurer RJ, Beattie EJ: Primary choriocarcinoma of the lung: Report of a case treated with intensive multimodality therapy and review of the literature. J Surg Oncol 41:94, 1989. ■ This report describes one patient with primary choriocarcinoma of the lung. It also is an excellent review of the sparse data available in the literature. Veynovich B, Masetti P, Kaplan PD, et al: Primary pulmonary thymoma. Ann Thorac Surg 64:1471, 1997. ■ This report summarizes very well the available literature, describing 18 patients, to which they add 1 of their own. In particular, the authors provide detailed suggestions for distinguishing primary pulmonary thymoma from either primary pulmonary lymphoma or malignancies metastatic to the lung. Yellin A, Schwartz L, Hersho E, Lieberman Y: Chondrosarcoma of the bronchus: Report of a case with resection and review of the literature. Chest 84:224, 1983. ■ This report describes a patient with a primary chondrosarcoma of the lung and reviews the limited literature available concerning this rare neoplasm. Yousem SA, Weiss LM, Colby TV: Primary pulmonary Hodgkin’s disease: A clinicopathologic study of 15 cases. Cancer 57:1217, 1986. ■ This report from Stanford University is the largest single institutional series of primary Hodgkin’s disease of the lung. The clinical data from 15 patients are reviewed, as is the literature.

1/21/2008 1:21:17 PM

chapter

69

SURGICAL RESECTION OF PULMONARY METASTASES Ugo Pastorino Dominique Grunenwald

HISTORICAL ASPECTS Pulmonary metastasectomy is a potentially curative surgical procedure, with predictable clinical outcome in a variety of solid tumors, and has gradually become a standard treatment in properly selected patients over the past 30 years. Nonetheless, the role of surgical resection of pulmonary metastases is still disputed by many oncologists on the grounds that systemic disseminated disease is already present at the time of diagnosis. The first resection of a single lung metastasis was reported by Weinlechner in 1882, during intraoperative assessment for a chest wall sarcoma.1 In the following 50 years, elective surgery has been offered very occasionally2 to patients presenting with single pulmonary metastases and or a long disease-free interval.3 The high risk of widespread end-stage disease and the substantial limitations of cancer imaging at that time restricted the indication for surgical therapy to those patients with solitary metastases occurring many years after the initial tumor. With the improvement of surgical techniques and the proven safety of limited pulmonary resections, metastasectomy gained greater popularity. Nonetheless, it was only in selected departments of oncology that metastasectomy was offered systematically to patients with multiple or bilateral lesions on the basis of favorable results achieved in metastatic sarcomas.4,5 A major proof of the curative potential of metastasectomy was achieved in the management of childhood osteosarcoma, in which fatal lung metastases occurred in 80% of patients after amputation of the primary tumor.6 In a consecutive series of 27 patients presenting with lung metastases from osteosarcoma, systematic lung resection resulted in complete eradication of the disease in more than 80% of cases and a 45% survival rate at 5 years.7 New chemotherapy regimens, which were potentially more effective on micrometastatic foci but unable to totally eradicate the component of disease that is clinically detectable, have further expanded the role of adjuvant or salvage surgery aimed at excising the residual tumor after induction chemotherapy or confirming a complete pathologic remission.

BASIC MECHANISMS The basic mechanisms controlling the process of metastatic spread remain largely unknown. Research on angiogenesis and growth factors has provided a new insight in some aspects of tumor progression, but a proper biologic explanation of the selectivity and specificity of distant metastases is still lacking.

Studies performed on large series of autopsies demonstrated that the lung was the second most common metastatic locus in 29% of those patients who died of malignancies.8 Weiss and Gilbert9 showed that the lungs were the sole site of detectable cancer in 20% of autopsied patients. Clinical incidence of isolated pulmonary metastases varies with the primary tumor site. Lung metastases represent the main reason for treatment failure in 50% to 80% of osteosarcomas10,11 and in 30% to 50% of soft tissue sarcomas.12-14 In the experience of the National Cancer Institute,15 the median survival time of patients with unresected lung metastases from soft tissue sarcomas was 7.4 months. For most patients with pulmonary metastases, resection may represent the sole chance of permanent cure, but the number of surgical candidates is relatively small. The proportion of cases that are amenable to surgical resection depends largely on the site of the primary tumor and is determined by a number of clinical factors, such as the risk of metastases in other organs, the sensitivity to chemotherapy or hormone treatment, and the probability of new primary tumors (Table 69-1). Many patients presenting with lung metastases from sarcomas and germ cell or pediatric malignancies may be candidates for metastasectomy, but in most epithelial cancers only a small fraction of patients (1%-2%) may be so treated because most present with concurrent distant metastases in other organs.16,17 The efficacy of chemotherapy against pulmonary metastases varies with the primary tumor site. In germ cell tumors and osteogenic sarcomas, systemic therapy may sometimes achieve complete eradication of the disease. Radiotherapy has a very limited role in the management of pulmonary metastases and is usually reserved for palliation of local symptoms.

SURGICAL RESECTION FOR PULMONARY METASTASES Diagnosis and Staging The probability of detecting pulmonary metastases depends on the modality and intensity of clinical follow-up after primary tumor management. If the risk of pulmonary metastases and the chance of salvage therapy are high (germ cell tumors and sarcomas), a more frequent surveillance of patients is justified by repeated computed tomography (CT) of the chest. Lung metastases may manifest with symptoms that mimic those of primary lung cancer, such as pain due to pleural or chest wall extension, cough and hemoptysis secondary to bronchial or vessel erosion, and mediastinal syndrome from nodal metastases. Extensive pulmonary dissemination, pleural 851

Ch069-F06861.indd 851

1/21/2008 1:22:08 PM

852

Section 3 Lung

effusion, or central airway obstruction can cause dyspnea, whereas severe shortness of breath with a limited radiologic picture is suggestive of lymphangitic spread. Nonetheless, most pulmonary metastatic lesions are detected on routine chest radiography in otherwise asymptomatic patients (Fig. 69-1). CT is the appropriate instruTABLE 69-1 Rationale of Metastasectomy in Various Primary Tumors Primary Site

Aim of Metastasectomy

Application

Sarcomas

Permanent cure

Systematic

Teratoma

Confirm CR, residual teratoma

Systematic

Colon-rectum

Permanent cure ± liver resection

Selective

Kidney

Occasional cure

Highly selective

Melanoma

Occasional cure, new primary

Only single lesion

Breast

Hormone receptors, new primary

Only single lesion

CR, complete resection.

TABLE 69-2 Relevant Questions in Clinical Staging Probability of a false-positive result Single versus multiple lesions Unilateral versus bilateral disease Lung primary or single metastasis Involvement of hilar or mediastinal lymph nodes Total required volume of resection

ment to clarify the nature of any suspicious nodular density found on chest radiography. It provides accurate information on the number, dimension, and site of each individual lesion (Table 69-2). First-generation CT can identify up to 80% of all pulmonary nodules greater than 3 mm detected at surgical exploration (25% more than linear tomography).18-20 In the multi-institutional review made by the International Registry of Lung Metastases (IRLM), covering four decades of surgical metastasectomy and various radiologic techniques, the overall accuracy in the radiologic assessment of the number of lung metastases was only 61%, with 25% of cases showing more metastases at the time of surgery and 14% showing fewer lesions than those detected preoperatively (Pastorino et al, 1997).21 The accuracy of radiologic assessment was only 37% in the subset of patients who had bilateral surgical exploration, and the real number of metastases was underestimated in 39%. Spiral CT scanning has greatly improved the diagnostic yield of radiologic staging, in terms of both the minimum size of parenchymal nodules (<3 mm) and the recognition of suspicious hilar or mediastinal adenopathies. However, a recent evaluation of the accuracy of single or multidetector helical scanners on 28 consecutive patients with osteosarcoma who underwent 54 thoracotomies at Memorial SloanKettering Cancer Center between 1996 and 2004 showed that the number of metastatic lesions was underestimated in 35% of thoracotomies, and therefore one third of patients would have been left with tumor in the chest without manual palpation by open thoracotomy.22 With new 16-slice CT scanners, the accuracy of imaging has improved so dramatically that low-dose examination of the chest without intravenous contrast can provide images of

FIGURE 69-1 Follow-up chest radiographs of a patient who has undergone radical resection for colon cancer show a solitary lesion on the right lung (A). However, the chest CT scan demonstrates, in addition to the lesion in the right upper lobe (B), a larger metastasis in the left lower lobe (C).

Ch069-F06861.indd 852

1/21/2008 1:22:08 PM

Chapter 69 Surgical Resection of Pulmonary Metastases

853

FIGURE 69-2 The routine CT scan of the chest performed in a patient treated for endometrial cancer revealed a 2-cm lesion in the right lower lobe, as well as two small lesions smaller than 1 cm in the right (A) and left (C) upper lobes. All of these metastases were detected by positron emission tomography and pathologically confirmed at thoracotomy.

less than 1 mm slice thickness in a single breath-hold (12 seconds), allowing for immediate three-dimensional reconstruction along axial, coronal, and sagittal planes, and highly consistent volume calculation for subsequent assessment of growth, if relevant for management.23,24 Extensive investigation on early lung cancer detection in heavy smokers has boosted clinical research on nodule detection by computerassisted diagnoses (CAD) software, which may prove useful also in the staging of pulmonary metastases. With such a high sensitivity, however, the rate of false-positive lesions also has increased, and concurrent presence of multiple metastatic deposits and benign lesions such as fibrotic nodules, granulomas, or intrapulmonary lymph nodes may represent a challenge for surgical management.25 In a recent report from the University of North Carolina, based on 34 patients who underwent 41 metastasectomies after helical CT assessment, malignant nodules were missed by CT in 22% of cases, and false-positive benign lesions were detected by CT in 37%, resulting in an overall CT accuracy of only 41%.26 Particularly in patients with multiple pulmonary lesions, a liver ultrasound and a CT or magnetic resonance imaging (MRI) scan of the brain needs to be part of preoperative staging. In sarcomas and gastrointestinal tumors in which the probability of local relapse is high, full examination of the primary tumor site, including CT, MRI, or endoscopy, may be necessary to exclude local recurrence or assess its resectability before undertaking lung metastasectomy. Where tumor markers are available, they, too, must be assessed (e.g., germ cell or gastrointestinal). In the past 10 years, positron emission tomography (PET) has become essential in the differential diagnosis of pulmo-

Ch069-F06861.indd 853

nary nodules27 and pretreatment staging of lung cancer,28 being able to reduce the probability of useless surgery for advanced disease in a randomized trial.29 The data on specificity of PET are promising also for lung metastasectomy, particularly in epithelial tumors, which have a higher risk of extrapulmonary deposits or locoregional relapse (Fig. 69-2), even though the minimum size of detectable lesions remains approximately 5 mm. We evaluated the role of preoperative PET staging in 86 consecutive patients with previously treated malignancy and proven or suspected lung metastases, deemed resectable at CT scan, of whom 68 underwent surgical resection and 54 proved to be lung metastasis.30 In 19 cases (21%), lung surgery was excluded on the basis of PET scan results due to extrapulmonary metastases (11 cases), primary site recurrence (2), mediastinal adenopathy (2), or benign disease (4). All mediastinal node metastases (7 cases) were detected by PET, which had a sensitivity, accuracy, and negative predictive value for mediastinal staging of 100%, 96%, and 100% respectively, compared with 71%, 92%, and 95% for the CT scan. In the group of patients who underwent lung resection, PET sensitivity for detection of lung metastasis was 87% (Table 69-3). This study essentially confirmed the experience matured in lung cancer, proving that the PET scan is a useful staging procedure in patients with clinically resectable lung metastasis and may change the therapeutic management in a high proportion of cases. A solitary lesion seen on a chest radiograph is not considered a metastasis unless it is histologically confirmed. A primary lung cancer or a benign lesion is not uncommon in middle-aged patients and is more frequent in smokers. As

1/21/2008 1:22:09 PM

854

Section 3 Lung

TABLE 69-3 Sensitivity of Positron Emission Tomography in Lung Metastasis

Parameter

PET Positive

PET Negative

Sensitivity (%)

TABLE 69-4 Probability of a New Primary Cancer Versus Metastasis in Patients Presenting With a Solitary Lung Opacity After Prior Treatment for Malignant Tumor

P Value* Prior Tumor

Overall

47

7

87

Nodule size† (mm) ≤10 2 11-20 18 ≥21 27

3 2 2

40 90 93

Histology Colon Urologic Sarcoma Head and neck Other

2 1 3 0 1

92 86 75 100 87

22 6 9 3 7

.00149

.51

*Fisher exact extension associated probability value. † Maximum nodule size in patients with multiple lesions PET, positron emission tomography. Modified from Pastorino U, Veronesi G, Landoni C, et al: Fazio FDGPET improves preoperative staging of resectable lung metastasis. J Thorac Cardiovasc Surg 126:1906-1910, 2003.

illustrated in Table 69-4, the probability that a new solitary lesion is a new primary cancer is related to the type, and also the stage, of the previous primary cancer.31 On the other hand, solitary lung metastases from colorectal cancer may be radiologically indistinguishable from primary lung cancer.32 A recent study based on 50 nodules in 44 patients investigated with high-resolution CT showed that 58% of colon metastases presented with irregular shape, spiculation, or pleural tags indicative of primary disease.33 In germ cell tumors, specific tumor markers can help to confirm the diagnosis. Preoperative tissue diagnosis, through bronchoscopy, percutaneous needle aspiration biopsy, or thoracoscopy, may be useful in choosing the best surgical approach and the appropriate resection volume for a solitary lesion that may be a primary cancer, and also in the presence of multiple pulmonary lesions, when systemic chemotherapy may be considered before resection.

Selection of Patients The selection criteria for pulmonary metastasectomy are listed in Table 69-5. Adequate control of the primary tumor is an essential requirement. In the case of synchronous metastases, lung surgery may be done first if complete metastasectomy is a prerequisite to justify a radical approach to the primary tumor (e.g., limb amputation). If lung metastases are associated with local recurrence of the primary tumor, the resectability of the local relapse must be assessed before lung resection is undertaken. A full clinical restaging, based on the nature of the primary site, must be completed before pulmonary resection to exclude the presence of extrapulmonary metastases. However, in primary colon carcinoma occurring with liver and lung metastases, resection of both sites has been successful,

Ch069-F06861.indd 854

New Primary Cancer (%)

Metastasis

Total

Wilms

0 (0)

8

8

Sarcoma

5 (8)

55

60

Melanoma

7 (19)

29

36

Testis

6 (33)

12

18

Kidney

11 (55)

9

20

Colon-rectum

30 (58)

22

52

Breast

40 (63)

23

63

Ovary

6 (66)

3

9

Uterus

32 (74)

11

73

Bladder

25 (89)

3

28

Lung

47 (92)

4

51

Head and neck

158 (94)

10

168

Other*

140 (100)

0

140

Total

507 (73)

189

696

*Esophagus, prostate, stomach, pancreas, skin, lymphoma, and leukemia. Modified from Cahan WG, Shah JP, Castro EB: Benign solitary lung lesions in patients with cancer. Ann Surg 187:241-244, 1978.

TABLE 69-5 Selection Criteria for Resection of Pulmonary Metastases The primary tumor is controlled or is controllable. No extrapulmonary tumor exists. No better method of proven treatment value is available. Adequate medical status for the planned resection exists. Complete resection is possible based on computed tomographic evaluation.

achieving long-term survival in a significant proportion of cases.34-36 In chemosensitive tumors such as germ cell tumors, firstor second-line chemotherapy is considered before pulmonary resection. The evaluation of a patient for metastasectomy always includes an assessment of the risk-benefit ratio of surgery alone versus chemotherapy or combined modalities. For less chemosensitive tumors, such as osteosarcoma, clinical decision making is more difficult because complete disappearance of pulmonary metastases is uncommon, and relapse at multiple lung sites is frequent after chemotherapy stops. In patients presenting with multiple bilateral lesions at CT scan, in whom resectability is questionable and prognosis poorer, the absence of new pulmonary metastases during the previous 2 months may represent a further selection criterion. The medical condition of the patient must be assessed in terms of ability to tolerate general anesthesia, adequate

1/21/2008 1:22:09 PM

Chapter 69 Surgical Resection of Pulmonary Metastases

cardiac and renal function, and sufficient lung reserve with respect to the anticipated resection volume. The final requirement is that all visible lesions on the CT scan must be resectable with adequate margins. Incomplete resections yield little benefit for the patient.

INDICATIONS FOR SYSTEMIC THERAPY In some tumor types, such as osteogenic sarcoma, induction chemotherapy has proved moderately effective. In osteogenic sarcoma, primary tumor regression after chemotherapy contributes to limb-sparing surgery in a high proportion of cases. Similarly, chemotherapy eradicates many, if not all, lung metastases, and residual disease can be resected, with longterm survival in about 30% of cases.37,38 The outcome of metastatic testicular carcinoma has changed in the past 3 decades as a consequence of highly effective chemotherapy.39 Complete clinical remission of lung metastases can be achieved in most patients, and resection of residual pulmonary lesions shows the presence of viable tumor in only 20% to 25% of cases. For these reasons, in cases of osteosarcoma or testicular carcinoma with pulmonary metastases at presentation, chemotherapy is given initially. If a complete remission is achieved, as observed on CT scan, surgical metastasectomy can be avoided in germ cell tumors, whereas in osteosarcoma a thoracotomy may still be considered to confirm pathologic remission and prevent later relapses. On the other hand, in most epithelial tumors and softtissue sarcomas induction chemotherapy has proved ineffective, with the possible exception of metastases from colon cancer. The value of adjuvant systemic therapies after lung metastasectomy is not well established. In tumors in which chemotherapy shows definite activity for disseminated disease (e.g., breast cancer, colorectal cancer), adjuvant systemic treatment is a logical option after metastasectomy, unless the same therapy was fully exploited before lung surgery. In patients who have not undergone pretreatment, if the risk of relapse is high because of multiple resected lesions, adjuvant therapy may be considered as part of the treatment plan. Adjuvant radiotherapy may be indicated if incomplete resection occurs at a single site, such as chest wall or mediastinal adenopathy, particularly if the primary tumor has proved sensitive to radiation.

855

time, it is appropriate to test innovative treatment policies with prospective clinical trials.

Unilateral Thoracotomy Posterolateral thoracotomy has long been the standard approach to pulmonary metastasectomy. Two sequential operations were used for bilateral lesions in the past, during one or two hospitalizations.18 In the 1990s, more conservative approaches, combining limited skin incision and musclesparing thoracotomy, became popular. Compared with posterolateral thoracotomies, this approach produces less functional damage of thoracic muscles and nerves, lessens postoperative pain, facilitates early mobilization of the patient, and reduces pleural adhesions, thus facilitating future reoperation, if needed.40

Median Sternotomy The median sternotomy incision as an alternative approach for the resection of bilateral metastases has some distinct advantages: both lungs can be examined at the same time; the midsternal split prevents surgical damage of thoracic muscles and nerves and disruption of the chest wall parietal pleura; and it causes less pleural adhesions—all features that prove useful if reoperation must be performed.18,41 In sarcoma, sternotomy allows the exploration of both lungs, even in cases of single or unilateral metastases. In fact, median sternotomy revealed bilateral lung metastases in 30% to 50% of cases presenting with unilateral lesions.5,41-43 Most cases of metastatic sarcomas can be treated surgically through the median approach, although this incision is best for superficial nodules located anteriorly in the lungs. A left lower lobe segmentectomy or lobectomy, if required, is technically demanding with this approach because the necessary mobilization of the lung may trigger transient arrhythmias.

Bilateral Anterior Thoracotomies In patients presenting with numerous or centrally located lesions involving both lungs, or hilar/mediastinal adenopathies, a sequential lateral approach may facilitate resection and prevent acute lung injury. Bilateral anterior thoracotomy with or without transverse sternotomy, also called the clamshell incision, may be preferred in very selected cases to combine the advantages of the sternotomy, which allows access to both lungs, with those of the lateral thoracotomy, which provides adequate exposure to all lobes of both lungs.44

SURGICAL APPROACHES The surgical approach to metastasectomy remains controversial. Two main questions still have to be answered: what is the relative value of open versus thoracoscopic surgery in epithelial tumors, and what is the relative value of bilateral versus unilateral exploration in sarcoma? Long-term survival has been obtained using radical metastasectomy techniques, but no randomized trial has demonstrated an advantage of early resection of occult disease. On the other hand, it is possible that spiral CT and PET will improve the accuracy of clinical staging and patient selection to the extent that intraoperative assessment will lose most of its relevance. At this

Ch069-F06861.indd 855

TECHNIQUES OF RESECTION The objective for lung metastasectomy with curative intent is excision of all detectable lesions, allowing clear surgical margins and preserving as much functional tissue as possible. Particularly in sarcomas or multiple pulmonary lesions, the surgeon must be able to palpate the lung, in both the inflated and the deflated state, to identify and remove any radiologically occult lesions and thereby achieve a macroscopically complete resection. The segmental or hilar lymph nodes are examined, and they are sampled if involvement is suspected.

1/21/2008 1:22:09 PM

856

Section 3 Lung

sionally help in choosing the proper resection volume. The presence of nodal metastases may require a lobectomy or even a larger volume of resection, but this is uncommon. Pneumonectomy is an exceptional indication for metastasectomy and is considered only if preoperative pulmonary function tests guarantee a good quality of life after surgery. Nonetheless, in properly selected cases, long-term survival can be achieved after pneumonectomy for a metastasis.47-49 A review from the IRLM database confirmed this concept: among 133 patients treated by pneumonectomy as their first metastasectomy, 84% achieved a complete resection, with a survival rate of 20% at 5 years.50

The appropriate resection volume depends on the number, site, and dimensions of the lung lesions. A sublobar resection (an atypical tangential or wedge resection) is generally adequate because most metastatic lesions are small and peripherally located. It is usually sufficient to resect 1 cm of normal lung around the palpable tumor. A variety of mechanical staplers are available to achieve a quick and easy resection. However, the so-called precision resection may be more volume-effective in cases of multiple or deeper metastases (Fig. 69-3).45 This technique consists of cutting out a uniform layer (5-10 mm) of normal lung tissue around the nodule, usually by making a cone-shaped excision with the larger base on the pleural surface, using a diathermy needle or a laser (yttrium-aluminum-garnet [YAG]) or argon beam. Small intrapulmonary vessels and bronchi that are encountered during such a precision resection may easily be controlled by electrocautery or metal clips. Recent experiences suggest a potential technical improvement with the latest generation of lasers, which allow radical excision of large and deeply located metastases that would otherwise require lobectomy. In a series of 328 patients, 3267 nodules were resected by lateral thoracotomy with a new Nd: YAG laser device, which delivers 20 KW/cm, 1318-nm power densities with 400-mm fibers and a focusing handpiece.46 Pathologic assessment revealed malignant deposits in 2546 (78%) of resected lesions, with sizes ranging from 3 to 80 mm. Complete resection was achieved in 85% of patients, with a lobectomy rate of only 7%, no reported 30-day mortality, and adequate 5-year survival (41% after complete resection). These results appear very promising, although they need to be confirmed by other series. For multiple metastases that are centrally located and for solitary lesions suggestive of a primary lung tumor, anatomic segmentectomy or lobectomy may be necessary to obtain a complete resection (Fig. 69-4). A frozen section may occa-

A

En-Bloc Resections If a pulmonary metastatic lesion invades adjacent structures and these structures are completely resectable, do not be deterred from offering a surgical excision if the other criteria for metastasectomy can be satisfied. En-bloc resections of chest wall, pericardium, or diaphragm during lung metastasectomy are still associated with satisfactory long-term survival.

Video-Assisted Thoracic Surgery Video-assisted thoracic surgery (VATS) gained popularity during the last decade of the 20th century as a safe alternative to open thoracotomy when performing small resections because it allows for small incisions and less subsequent pain.51-53 However, the majority of thoracic surgeons, believing that a thorough palpation of the entire lung is necessary to perform a complete metastasectomy, have maintained substantial skepticism about the advantages and safety of the thoracoscopic approach.54 There is little question that creating adequate surgical margins requires palpation of the lesion so that the stapler may be placed properly, and open manual

B

FIGURE 69-3 A precision resection with electrocautery or laser may be more effective to achieve radicality and preserve functional tissue for a centrally located metastasis in the right lower lobe. A, CT image. B, Surface of the lung at the end of resection.

Ch069-F06861.indd 856

1/21/2008 1:22:09 PM

Chapter 69 Surgical Resection of Pulmonary Metastases

857

FIGURE 69-4 A-D, These large and centrally located metastases from breast carcinoma required a left lower lobectomy for radical excision.

B

C

A

suture or precision dissection may better fit the size and location of the nodule. Moreover, small nodules located deeper in the lung parenchyma are frequently missed by VATS. As demonstrated by McCormack and colleagues,55 in patients who underwent thoracoscopy followed by immediate thoracotomy, open surgical exploration allowed resection of additional metastases in 56% of the cases. Despite the constant improvement of pulmonary imaging, radiologically occult lesions are detected by open surgery in 25% to 35% of sarcomas and 15% of nonsarcomatous lesions, and careful palpation of the lung remains the gold standard in most cases.22,26 The aim of lung metastasectomy is not cytoreduction or debulking but complete removal of detectable disease. This fundamental principle applies to any type of salvage surgery with curative intent, and it is critical in pulmonary metastases, for which preoperative staging is grossly inaccurate. Retrospective, nonrandomized comparisons of small series of patients, with a follow-up of only 2 years, cannot provide any proof of equivalence between thoracoscopic and open metastasectomy.56 The combination of thoracoscopy with manual lung palpation through median substernal57 or lateral subcostal transdiaphragmatic58 incisions has been proposed to circumvent the problem of open surgery. All of these approaches, however, strongly limit the feasibility of metastasectomy to the use of mechanical staplers, losing the valuable option of lung-sparing precision resections.46 In addition, as was observed for primary lung cancer and mediastinal tumors, thoracoscopic metastasectomy carries a substantial risk of intraoperative pleural dissemination of the disease.59 Complete resection of all metastatic nodules is the only operation that will help the patient. However, current pro-

Ch069-F06861.indd 857

D

spective trials employing VATS may resolve the issue and indicate its value in pulmonary metastasectomy.

RESULTS OF SURGERY In experienced hands, morbidity rates after pulmonary metastasectomy are low, and overall perioperative mortality ranges between 0% and 2% (Pastorino et al, 1997).21 The history of this surgery indicates that permanent cure can be achieved in fewer than one third of cases. Five-year survival results vary with the primary site and depend on the site and the pattern of metastases. The IRLM analyzed a total of 5206 patients who underwent lung metastasectomy, from 18 departments of thoracic surgery in Europe, the United States, and Canada; 4572 (88%) achieved complete surgical resection.21 Despite the large numbers, this is clearly a highly selected series of patients, and the denominator population is not known. In the experience of the IRLM, the actuarial survival rate after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median survival time, 35 months) (Table 69-6). The corresponding values for incomplete resection were 13% at 5 years and 7% at 10 years (median, 15 months). The overall 30-day mortality rate after complete resection was only 0.8%.

Prognostic Factors Appropriate selection for metastasectomy based on the prediction of a successful outcome can be difficult in an individual patient. A number of adverse prognostic factors have been suggested, but the number of patients analyzed in each series has been relatively small, giving rise to conflicting results.60

1/21/2008 1:22:10 PM

858

Section 3 Lung

TABLE 69-6 Long-Term Survival After Complete Resection (IRLM) Survival (%) Prognostic Factors

No. Patients

5-Year

10-Year

Median Survival Time (Mo)

Overall

4572

36

26

35

Disease-free 0-11 12-35 36+

Interval (mo) 1384 33 1662 31 1416 45

27 22 29

29 30 49

31 24 19 17

43 31 27 26

No. of Metastases 1 2169 2-3 1226 4+ 1123 10+ 342

43 34 27 26

TABLE 69-7 IRLM System of Prognostic Grouping Group

Characteristics

I

Resectable, no risk factors: DFI ≥36 mo and single metastasis

II

Resectable, 1 risk factor: DFI <36 mo or multiple metastases

III

Resectable, 2 risk factors: DFI <36 mo and multiple metastases

IV

Unresectable

IRLM, International Registry of Lung Metastases.

IRLM, International Registry of Lung Metastases.

Tumor doubling time based on serial chest radiographs has been suggested in the past by a number of investigators. This calculation, however, may prove impractical when assessable radiographs are not available and tumor growth rates are not constant.61 The disease-free interval (DFI), defined as the time from treatment of the primary to the appearance of metastases, correlates differently with survival in various series. Depending on the series, DFIs from as little as 8 months to as long as 5 years have been significant positive prognostic factors. On the whole, results are inconclusive. The number of metastases was initially considered a very important variable to predict outcome. However, in the past 20 years, a number of authors have reported long-term survival after resection of multiple lesions in both lungs (Pastorino et al, 1991).18,62,63 The probability of survival tends to decrease proportionally with the number of resected lesions, but a firm cutoff beyond which resection is useless has not been defined. The data of Institut Montsouris in Paris showed that the survival of 44 patients who underwent resection of eight or more pulmonary metastases was not significantly different from that of the other 412 patients operated on during the same period.64 The prognostic value of the number of pulmonary metastases seemed to be more dependent on associated resectability than on the number per se. Similarly, the results of Memorial Sloan-Kettering on metastatic colorectal cancer suggested that complete resection provided the only significant variable.65 In a very recent series, the 5-year survival rate was 28% for patients with 10 or more resected metastases, and 26% for those with 20 or more lesions.46 Occasionally, at thoracotomy, patients are found to have widespread dissemination of multiple small nodules in the lung. This is an obvious contraindication to metastasectomy. With recent improvements in CT technology, this scenario of intraoperative discovery of such dissemination becomes very infrequent. The occurrence of hilar or mediastinal lymph node metastasis varies with the primary tumor and has only rarely been

Ch069-F06861.indd 858

identified in the metastasectomy reports. The prognostic influence of this type of lymphatic spread is unknown. The role of concurrent lymph node dissection, together with pulmonary metastasectomy, is under investigation. A recent review of the Mayo Clinic experience included 70 cases of complete lymphadenectomy, representing only 8% of all metastasectomies: nodal metastases were detected in 29% of patients and were associated with significant reduction in survival (38% versus 69% at 3 years; P < .001).66 The IRLM was established with the specific purpose of defining by multivariate analysis the prognostic factors for the various primary tumors. In their analysis (Pastorino et al, 1997),21 described in the previous section, disease-free interval, number of metastases, and tumor type were highly significant independent prognostic variables at univariate as well as multivariate analysis. However, the achievement of a macroscopically complete resection was the most important independent prognostic factor. Such a large series of patients represented a unique opportunity to build up a system of prognostic grouping that could take into account all the relevant prognostic factors simultaneously. As a result of the IRLM analysis (Pastorino et al, 1997),21 a novel classification was proposed (Table 69-7), combining three prognostic indicators (disease-free interval, number, and radicality). Figure 69-5 shows the actuarial survival of the four prognostic groups. Median survival time was 61 months for group I, 34 months for group II, 24 months for group III, and 14 months for group IV (P < .00001). The discriminatory power of this prognostic grouping was tested in terms of the various primary tumors and proved to be highly significant in each specific tumor type (see Fig. 69-5BF). It was also confirmed by the independent analysis of a surgical series not included in the Registry.67 Other potential tumor-specific prognostic factors have been proposed and now must be investigated by prospective studies: grading and local recurrence in soft tissue sarcomas; persistent malignant disease and elevated β-human chorionic gonadotropin after induction therapy in teratoma; carcinoembryonic antigen (CEA) and liver resection in colorectal cancer; hormone receptors in breast cancer; and vascular invasion, vascular endothelial growth factor (VEGF), and E-cadherin expression in colorectal cancer.68-72

1/21/2008 1:22:11 PM

Chapter 69 Surgical Resection of Pulmonary Metastases

All Sites

100

1 2 3 4

60

80

60

40

40

20

20

0

0 0

24

48

72

96

0

120

A

24

48

72

96

120

96

120

96

120

B

100

Colon Cancer

100

Soft Tissue Sarcomas

80

80

60

60

40

40

20

20

0

0 0

24

48

72

96

0

120

C

24

48

72

D

100

100

Breast Cancer

80

80

60

60

40

40

20

20

0

Melanoma

0 0

E

Osteosarcoma

100

80

859

24

48

72

96

0

120

24

48

72

F

FIGURE 69-5 A-F, Long-term survival in months for five primary tumor types, according to the four prognostic groups defined by the International Registry of Lung Metastases (IRLM) classification system. The IRLM classification is based on the risk factors of disease-free interval shorter than 36 months and multiple metastases (see Table 69-7).

Ch069-F06861.indd 859

1/21/2008 1:22:11 PM

860

Section 3 Lung

Relapse After Metastasectomy and Surgical Rescue The pattern of relapse after lung metastasectomy depends on the histology of the primary tumor as well as the extent of pulmonary disease. A significant proportion of these patients may be suitable for surgical rescue. As an example, in the historical series of 22 highly selected children with metastatic osteosarcoma treated at Memorial Sloan-Kettering, four of the six 10-year survivors lived more than 19 years after as many as nine thoracotomies, and three of them developed second primary cancers during the second decade of follow-up.73 In the experience of the IRLM, a recurrence was documented in 53% of patients after complete lung metastasectomy, with a median time to recurrence of 10 months. The probability of relapse (all sites) was higher for sarcomas and melanoma (64%) than for epithelial (46%) or germ cell (26%) tumors. Limited intrathoracic relapse accounted for 66% of recurrences in sarcomas, 44% in epithelial tumors, and only 27% in melanomas. The proportion of relapsed patients who underwent a second metastasectomy was higher in those with sarcomas than in those with epithelial tumors (53% versus 28%), and the median interval was shorter (10 versus 17 months). The long-term survival rate of patients undergoing a second metastasectomy was 44% at 5 years and 29% at 10 years, little different from that seen after initial metastasectomy. Analogous favorable results have been reported after repeated liver, or liver and lung, salvage metastasectomy for colorectal cancer.74 Clinical follow-up after pulmonary resection is tailored to the expected time and site of relapse, including chest radiographs every month and a chest CT scan every 3 months during the first year, followed by radiographs every 3 to 4 months up to the third year. In patients with sarcoma, for which salvage surgery is more commonly needed and the size of the pulmonary lesions is a critical factor for resectability, a more intense follow-up may be appropriate after primary tumor treatment if the risk of relapse is high. This may include, in selected cases, a routine chest radiograph every 2 to 3 months and a chest CT scan every 6 months for a prolonged period.

MANAGEMENT OF SPECIFIC CANCERS The purpose and applicability of lung metastasectomy varies with the primary tumor according to a number of clinical factors, such as the risk of metastases in other organs, the sensitivity to chemotherapy or hormone treatment, and the probability of new primary tumors. Carcinomas as a group have a different metastatic pattern of spread from sarcomas, and within this group each major primary site has a distinctive behavior. The IRLM results for the main primary tumor sites are summarized in Table 69-8.

Sarcoma Osteosarcoma metastasizes mainly to the lungs, and in the days before effective chemotherapy, 80% of patients treated by radical resection of their primary tumors developed lung metastases.6,10 A surgical approach was therefore advocated

Ch069-F06861.indd 860

TABLE 69-8 Long-Term Survival After Pulmonary Metastasectomy by Primary Tumor (IRLM) Survival (%) Tumor Type

No. Patients

5-Year

10-Year

Median Survival Time (Mo)

Epithelial Overall Colorectal Breast Kidney

1894 653 411 402

37 37 37 41

21 22 21 24

40 41 37 41

Sarcoma Overall Osteosarcoma Soft tissue

1917 734 938

31 33 30

26 27 22

29 40 27

Melanoma

282

21

14

19

Germ Cell

318

68

63

—

IRLM, International Registry of Lung Metastases.

by Marcove, and a strategy of resection was introduced at Memorial Sloan-Kettering with encouraging results (a 30% 5-year survival rate).7 More recently, the pattern of metastasis appears to be changing, with bone and other sites occurring more commonly. Despite the efficacy of intensive chemotherapy, lung metastases have remained the main reason for failure in 40% to 50% of osteosarcomas.75,76 More recent studies have provided further evidence that systematic surgical resection of pulmonary metastases, rather than the use of salvage chemotherapy, may contribute to the sustained improvement of survival.76 In a consecutive series of 174 primary childhood osteosarcomas treated at the Instituto Nazionale Tumori of Milan, we reported that the total proportion of patients who underwent complete resection of their pulmonary metastases rose to 55% in the years 1982 to 1988, after the introduction of systematic bilateral metastasectomy, compared with 17% in the years 1970 to 1981 (Pastorino et al, 1991).62 This change of strategy led to an improvement in the 5-year survival rate of all patients with metastases, from 0% to 28%, with a 47% survival rate after complete metastasectomy in the latter period (Fig. 69-6). Patients presenting with metastases at the time of initial diagnosis may still be eligible for metastasectomy. The best timing for metastasectomy is unclear. In most centers, control of the primary tumor takes priority while the response of the metastases to chemotherapy is assessed. Other centers have advocated immediate operation, if possible. Lung exploration may rule out false-positive lesions, avoid unnecessary amputation in case of disseminated disease, and possibly improve the chance of permanent eradication of disease. In the IRLM analysis, 108 osteosarcoma patients with synchronous lung metastases showed a 5-year survival rate of 38% after complete resection. Such a relatively favorable prognosis of osteosarcoma with synchronous metastases at presentation was confirmed by the Japanese Musculoskeletal Oncology Group, which reported

1/21/2008 1:22:11 PM

Chapter 69 Surgical Resection of Pulmonary Metastases

100

27

26

1982–1988

80 Percentage

20 15

21

60

12

Resected 8

6

6

4

40

20

P
.001

8

2

4

1

1

Unresected 0

0 0

20

40

60

861

of London, complete resection was achieved in 123 cases (87%); pathologic analysis showed viable malignant elements in 46 patients (32%), necrosis or fibrosis in 32, and differentiated teratoma in the remaining 63.81 The overall survival rate was 77% at 5 years and 65% at 15 years; survival time was significantly shorter in patients with malignant teratomatous elements. However, in the latter group, metastasectomy still achieved a 51% survival rate at 5 years. Very similar results were reported by researchers at Memorial SloanKettering based on 157 patients (Liu et al, 1998).82 They also demonstrated a better 5-year survival rate in patients diagnosed after 1985 (82% versus 62% overall), as well as the adverse prognosis of metastases to nonpulmonary visceral sites.

Months FIGURE 69-6 Lung metastasectomy in a consecutive series of childhood osteosarcomas: overall survival from detection of pulmonary metastases, according to salvage surgery, in the years 1982 to 1988. The numbers of patients alive at each time point and the median survival times (vertical dotted lines) are shown for patients with resection or no resection of pulmonary metastases.

a 5-year survival rate of 18% for this group, compared with 0% or 6% for lung metastases occurring during induction or adjuvant chemotherapy, and 31% for those occurring after completion of the whole therapy.77 Primary soft tissue sarcomas also produce both synchronous and metachronous metastases to the lungs, although the incidence is lower. Chemotherapy has a less important role in the management of these tumors than in cases of osteogenic tumor. Therefore, metastasectomy may be very important for eligible patients. A meta-analysis of the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group, based on 255 patients, showed a 5-year survival rate of 30%.68 These figures were confirmed by the IRLM data (see Table 69-8). No controlled trials exist that compare metastasectomy with no treatment, or with chemotherapy or radiation therapy alone. However, the data on the results of untreated lung metastases suggest that they are usually fatal in 2 years.15,63,78 Poor median survival may, to some extent, be biased by the number of patients with more advanced disease (unresectable), but observed survival beyond 3 years is unlikely to be influenced by such a selection bias.

Germ Cell Tumors Germ cell tumors are very sensitive to chemotherapy, and the use of cisplatin-based regimens has greatly improved the cure rate, from approximately 10% in the 1960s to the current 85% to 90%79 even in the presence of metastatic disease. Resection of any residual disease after chemotherapy is of considerable importance because there is no reliable way to predict the histology (necrosis, mature teratoma, persisting tumor), and survival depends on the elimination of active disease.80 In a recent analysis of 141 patients who underwent resection of thoracic metastases at the Royal Brompton Hospital

Ch069-F06861.indd 861

Colorectal Tumors Metastatic spread of colorectal cancer typically involves regional lymph nodes, liver, and lung. However, lung metastases may occur in the absence of disease below the diaphragm. Primary rectal tumors show the distinct capability of bypassing the liver through an alternative venous drainage and producing direct metastases to the lungs. For patients with isolated pulmonary metastases, chemotherapy can provide palliation and a small survival benefit. However, it cannot provide permanent cure. In the experience of Memorial Sloan-Kettering, including 144 carefully selected patients undergoing lung metastasectomy, the 5-year survival rate was 44% and the 10-year survival rate was 25%.83 Chemotherapy alone for colorectal metastases to lung without metastasectomy had no survivors beyond 24 months.35,69 In the report of the Institut Montsouris in Paris, survival was significantly better in patients with normal CEA at the time of metastasectomy,69 whereas in the series of Memorial Sloan-Kettering, CEA levels did not have any prognostic significance. Three recent papers have confirmed the prognostic value of preoperative CEA, with a cutoff of 5 ng/mL84,85 or 10 ng/mL.86 Five-year survival ranged from 43% to 58% for patients with normal CEA values and from 0% to 23% for those with elevated CEA. Nonetheless, at multivariate analysis, the stage of colorectal tumor (Dukes A versus B-D) and the extent of lung metastases (unilateral versus bilateral) showed a stronger effect on survival.87 Given the reported good results from an aggressive approach to simultaneous liver and lung metastases, such an approach is worth considering in selected individuals.88,89 However, better survival is to be expected with metachronous lesions, and the prognosis of lung metastases detected 12 or more months after liver resection is similar to that observed in patients without liver metastases.86.87

Breast Tumors Breast cancer metastases to the lungs are rarely amenable to resection with curative intent. In this disease, pulmonary spread is likely to occur through the internal mammary or mediastinal lymph nodes, rather than through limited hematogenous deposits. Bone, pleura, or liver metastases are often associated. Solitary or few nodules have been resected with good results,90 but they represent fewer than 1% of all

1/21/2008 1:22:11 PM

862

Section 3 Lung

mammary carcinomas. For the majority of patients with lung metastases, it is not certain to what extent a surgical approach may be better than medical management only. Almost 50% of solitary pulmonary nodules in patients with a prior breast cancer represent not metastasis but secondary primary lung malignancy or benign disease. Often, a clear distinction between primary and secondary tumors is impossible even after surgery because pathologic features are ambiguous. Therefore, resection is warranted in the case of solitary lesions, and long-term survival rates approach 40%. In the IRLM series, based on 467 patients, the survival rates were 38% at 5 years, 22% at 10 years, and 20% at 15 years.91 Among the 167 patients with favorable prognosis according to the IRLM classification system, survival was 50% at 5 years and 26% at 15 years (median survival time, 59 months).

Hypernephroma Metastatic renal cancer shows very limited sensitivity to systemic chemotherapy or immunotherapy. In the few selected cases in which no other distant or nodal metastases can be detected, lung metastasectomy may contribute to long-term survival. However, lung metastases are often multiple and not suitable for complete resection at the time of initial diagnosis. In a recent report from the Cleveland Clinic Foundation, of 417 patients with pulmonary metastases from renal cell carcinoma diagnosed between 1986 and 2001, 92 (22%) underwent pulmonary metastasectomy.92 Spontaneous regression of these metastatic foci may rarely occur, but the probability is so low that the event has no clinical relevance. Only 67 cases are reported in the world literature by Freed and colleagues93 and Fairlamb.94 Of these cases, only 12 have documented 5-year follow-up. Lung metastases may occur very late in renal cancer, and pulmonary resection can reveal metastatic deposits even 25 years after nephrectomy.95 The survival rates reported in the literature after metastasectomy for hypernephroma range between 24% and 44% at 5 years.96 Solitary lesions appear to have better results, but repeat surgery yields similar results in selected candidates.97,98 The overall results of the IRLM (see Table 69-8) and the value of its prognostic grouping have been confirmed by recent reports from single institutions.92,99

Head and Neck Tumors The occurrence of a pulmonary opacity in patients previously treated for head and neck tumors is a common event. If the pulmonary nodule is solitary, it is virtually impossible to distinguish metastases from primary lung tumors. These patients have a very high risk of multiple aerodigestive tract malignancies, due to their long smoking history, and are prone to develop second primary lung tumors. In all such cases, if the lesion is resectable, it needs to be treated as a primary lung tumor, with curative intent. If multiple pulmonary nodules are detectable on CT scans, a needle aspiration or thoracoscopic biopsy will usually demonstrate a metastatic squamous cell carcinoma. The real efficacy of pulmonary metastasectomy for metastatic head and neck carcinoma is unclear. A study from Memorial Sloan-Kettering reported a

Ch069-F06861.indd 862

5-year survival rate of 34% for squamous type compared to 64% for glandular type of head and neck origin.100 Patients with salivary gland or thyroid tumors may present with solitary lesions in the lung. As with other head and neck tumors, one must differentiate between a primary lung cancer and a solitary metastasis. Radioisotope studies or needle aspiration biopsy can be helpful. Most of these patients present with multiple, deeply located, bilateral metastases, and truly complete resection is often unfeasible.101 Despite good prognosis and a 5-year survival rate in excess of 80% from metastasectomy, none of the resected patients remain free of disease, and it is difficult to estimate to what extent metastasectomy can improve their life expectancy in comparison with conservative management.100 Surgical metastasectomy for thyroid carcinoma is rarely requested, and removal of thoracic deposits is more frequent for mediastinal adenopathies than for parenchymal lesions. In these occasional cases of resectable residual disease, usually after repeated radioactive iodine ablation, median survival can be very long.102

Melanoma Clinical behavior of metastatic melanoma is often unpredictable. Metastatic foci can be stable for many years and then give rise to disseminated spread, through both the hematogenous and the lymphatic route. Systemic chemotherapy and immunotherapy are still being used with mixed results (Harpole et al, 1992).103 Approximately one quarter of patients affected by malignant melanoma develop pulmonary metastases, but the role of metastasectomy is controversial. Resection of pulmonary metastases has been advocated by some for solitary metastases, but the overall results did not appear significantly better than with other treatment modalities.5,104,105 The data of the IRLM revealed a favorable outcome for patients with less than two risk factors according to their proposed classification system: the 5-year survival rate was 29% for group I patients (solitary lesion, long DFI) and 20% for group II (multiple lesions or short DFI).106

FUTURE PROSPECTS Future prospects for better management of pulmonary metastases still rely on more effective systemic therapy to prevent their occurrence. At present, induction and adjuvant systemic therapies play a small role in managing resectable and unresectable metastases, but innovative and possibly targeted systemic treatments will become available in the near future. Antimetastatic agents, such as antibodies against VEGF or tyrosine kinase inhibitors such as antagonists of epithelial growth factor receptors (EGFR), are very promising drugs that may be applied as adjuvant or neoadjuvant therapy in this set of patients. Intra-arterial infusion of high-dose chemotherapy agents directly into the pulmonary artery, after isolation of the lung in order to increase the dose without toxicity, has shown some encouraging results in animal models.107-109 Present human experience has demonstrated the feasibility of isolated lung perfusion of resectable lung metastases, with absence of mortality or significant morbidity, but its value in

1/21/2008 1:22:11 PM

Chapter 69 Surgical Resection of Pulmonary Metastases

preventing pulmonary recurrence remains to be proven.110,111 Currently, the best therapeutic results can be obtained by surgical resection of pulmonary metastases in properly selected candidates. Treatment is offered to patients who appear likely to benefit from this aggressive approach. The classification proposed by the IRLM combines essential indicators of tumor biology (DFI), anatomic extent (number), and radicality of treatment into a simplified system that reliably predicts long-term survival of patients with various tumor types. This classification may be useful in the future to stratify patients into randomized trials to test new systemic treatments and to further define the role of surgery in the treatment of pulmonary metastases.

COMMENTS AND CONTROVERSIES Pulmonary metastasectomy is a simple term to describe a wide variety of operative procedures in a host of different circumstances. In some situations, such as childhood osteosarcoma, its use has proved effective. For some epithelial malignancies, such as colorectal or renal metastases, pulmonary metastasectomy appears to offer benefit to selected patients. However, for breast or melanoma metastases, the benefit of pulmonary metastasectomy is not at all clear. We are all aware of the parameters necessary for success: control of the primary tumor, no other metastatic disease, limited number of pulmonary metastases so that a complete resection can be accomplished using lung-sparing techniques, and no other available therapy. Other factors, such as DFI and tumor doubling time, are of uncertain value in selecting patients for resection. Of course, the limitation with all of these approaches is that success is determined by a myriad of unknown factors constituting the biology of the tumor and the patient. A number of questions remain unanswered: Is nodal staging necessary before resection of epithelial metastases? Is VATS an acceptable operative strategy? Is a unilateral exploration and resection acceptable? For bilateral lesions, should exploration and resection be performed by bilateral synchronous or staged unilateral procedures? All of these questions are addressed by the authors in this excellent chapter. The IRLM has accumulated a large experience and reported interesting results as described by the authors. This group has proposed a novel prognostic classification that may well shed some light on a confusing situation and ultimately help in the selection of patients for pulmonary metastasectomy. G. A. P.

863

■ A total of 86 patients with pulmonary metastases from colorectal cancer underwent

102 metastasectomies, resulting in a 24% probability of survival at 5 years and 20% at 10 years. In their experience, besides completeness of resection and number of metastases (solitary versus multiple), a normal preoperative level of carcinoembryonic antigen (CEA) appeared to be a favorable prognostic factor (60% versus 4% 5-year survival). Harpole DH Jr, Johnson CM, Wolf WG, et al.: Analysis of 945 cases of pulmonary metastatic melanoma. J Thorac Cardiovasc Surg 103:743, 1992. ■ Pulmonary metastases were documented in 945 patients with melanoma, and the overall survival from detection was 30% at 1 year and only 4% at 5 years. Predictors of survival at multivariate analysis were complete surgical resection, disease-free interval, solitary versus multiple lesions, and nodal metastases. These retrospective data indicated that patients who underwent metastasectomy showed a better 5-year survival (20% versus 4%) and suggested benefit for the selective use of pulmonary metastasectomy in patients with malignant melanoma. Liu D, Abolhoda A, Burt ME, et al: Pulmonary metastasectomy for testicular germ cell tumors: A 28-year experience. Ann Thorac Surg 66:1709-1714, 1998. ■ This 28-year experience of the Memorial Sloan-Kettering Cancer Center is based on 157 patients who underwent pulmonary resection for suspected metastases from germ cell tumors. Complete resection was achieved in 155 cases (99%), and pathology showed viable malignant elements in 70 patients (44%); 41 patients (26%) had metastases to other sites. The overall 5-year survival was 68% and was higher in patients diagnosed after 1985 (82%); viable carcinoma in the specimen and metastases to nonpulmonary visceral sites were associated with adverse prognosis. Pastorino U, Gasparini M, Tavecchio L, et al.: The contribution of salvage surgery to the management of childhood osteosarcoma. J Clin Oncol 9:1357-1362, 1991. ■ The authors report their experience with 174 consecutive children treated for primary osteosarcoma. During the period of observation, the proportion of patients who underwent complete resection of their pulmonary metastases rose from 17% to 55%. As a consequence, the overall 5-year survival of patients developing lung metastases improved from 0% to 28%, with 47% survival after complete metastasectomy in the latter period. These results are attributed to the improvement of chemotherapy for this disease combined with aggressive salvage surgery. Pastorino U, Buyse M, Friedel G, et al: The International Registry of Lung Metastases: Long-term results of lung metastasectomy: Prognostic analyses based on 5,206 cases. J Thorac Cardiovasc Surg 113:37-49, 1997. ■ The International Registry of Lung Metastases, by pooling the unselected cases and extensive follow-up of major thoracic oncology centers worldwide, has clarified in a definitive way that pulmonary metastasectomy is a procedure of proven therapeutic value in properly selected patients, and that permanent cure can be achieved in about one third of cases. Disease-free interval (DFI), number of lesions, and completeness of resection have emerged as significant independent predictors of patient outcome. The combination of anatomic (number, resectability) and biologic (DFI) elements results in a simple and innovative system of classification in four groups, which has proved effective to assess prognosis in all tumor types (with the only exception being testicular cancer).

KEY REFERENCES Girard P, Ducreux M, Baldeyrou P, et al: Surgery for lung metastases from colorectal cancer: Analysis of prognostic factors. J Clin Oncol 14:2047-2053, 1996.

Ch069-F06861.indd 863

1/21/2008 1:22:11 PM

Surgical Techniques chapter

PNEUMONECTOMY

70

Paul F. Waters

Key Points ■ Pneumonectomy is reserved for patients in whom lesser resection

is not possible.

and other nonmalignant conditions is uncommon in modernday pulmonary medicine following the advances in antibiotics.4 There is a growing sense of pneumonectomy as an operation to be avoided if lesser resection is at all possible.

■ Individual ligation of hilar structures is done. ■ Management of the post-pneumonectomy space is essential.

HISTORICAL NOTE The first successful one-stage pneumonectomy was performed by Graham and Singer in 1933 in a patient with bronchogenic carcinoma.1 This followed the first pneumonectomy in multiple stages in a patient with tuberculosis and empyema, which was achieved by Macewen in 1895.2 Earlier attempts had not met with success. In 1910, Kummel performed a pneumonectomy for lung cancer by clamping the pedicle and leaving the clamps in situ; that patient survived 6 days. The first individual hilar ligation was accomplished by Hinz in 1922, and that patient succumbed to heart failure on the third postoperative day. Churchill, in 1930, Archibald, in 1931, and Ivanissevich, in 1933, also attempted removal of a whole lung but no patient survived longer than a few days.2 Churchill left a tube in the residual bronchus, bringing it out through the chest wall. Reinhoff first described the modernday technique of individual ligation of the pulmonary vessels and suturing of the bronchus.3 By the 1940s, the standard operation for resectable lung cancer became pneumonectomy. HISTORICAL READINGS Abbey Smith R, Nigam BK: Resection of proximal left main bronchus carcinoma. Thorax 43:616, 1979. Graham EA, Singer JJ: Successful removal of an entire lung for carcinoma of the bronchus. JAMA 101:1371, 1933. Meade RH: A History of Thoracic Surgery. Springfield, IL, Charles C Thomas, 1961.

INDICATIONS Historically, removal of an entire lung was the suggested therapy for all bronchogenic carcinomas, although in many cases lesser resections such as lobectomy or segmentectomy could be considered appropriate. It is generally accepted that with careful patient selection and staging, pneumonectomy is the correct treatment for lung cancer that cannot be removed by lobectomy or lesser resection. Pneumonectomy for inflammatory lung disease, bronchiectasis, tuberculosis,

INCISION The most common incision used for the removal of the lung is a posterolateral thoracotomy with access to the pleural cavity via the fifth intercostal space. This approach allows access to all areas of the lung, both posterior and anterior, and therefore is the most popular. Although many surgeons routinely remove a rib, this is not necessary. If the rib is excised, then in the rare instance when empyema and infection cause dehiscence of the thoracotomy incision, it may be difficult to eventually close the incision because of the loss of tissue the rib represents. Also, removal of a rib may hamper the use of the intercostal muscle, if needed, to protect the bronchial stump. Posterior thoracotomy with the patient in the prone position was popular in the early days of thoracic surgery, when control of airway secretions was a major problem in the removal of lungs for septic inflammatory diseases such as tuberculosis. The techniques of airway control with reliable endobronchial intubation and one-lung anesthesia are such that the prone position is not necessary. Moreover, access to the vascular structures of the hilum is less convenient, such that the approach is very rarely employed. Anterolateral thoracotomy with the patient in a supine position results in an incision that is poorly tolerated cosmetically, and access to the necessary hilar structures is suboptimal. This approach also is rarely employed for pneumonectomy. Median sternotomy carries with it the advantage of less postoperative compromise of pulmonary function, and some practitioners favor it for that reason. It allows good access to the hilar structures for right pneumonectomy. It can be very difficult and sometimes impossible to perform left pneumonectomy through this approach because the heart prevents access to the inferior vein. Although it is preferred by some surgeons, there is also the theoretic risk of sternal infection, which might be increased when this approach is used for clean contaminated cases such as those involving pulmonary resection.5,6 Video-assisted thoracoscopic surgery (VATS) has been employed in a limited manner to perform pneumonectomy. There are only a few scattered reports in the literature.7-10 Thoracoscopy can provide better visualization of the necessary structures in some cases. An additional thoracotomy incision is by definition required to remove the specimen

864

Ch070-F06861.indd 864

1/21/2008 1:33:13 PM

Chapter 70 Pneumonectomy

865

once the resection is complete. This has been accomplished using a limited standard thoracotomy incision—the so-called utility thoracotomy. The VATS approach has been more widely applied for lesser resections and has been met with mixed enthusiasm. The expected decrease in pain, length of hospital stay, and subsequent costs have not lived up to expectations. Therefore, VATS pneumonectomy cannot be recommended for widespread use, given the current state of the technology. Experience with thoracoscopic lobectomy is increasing and demonstrates good results both from the point of view of postoperative morbidity and mortality but also of cancer survival. There is no reason to expect that thoracoscopic pneumonectomy will be any different.

ANESTHESIA It is very important for the surgeon performing thoracic surgery and pulmonary resections to maintain very clear communication with the attending anesthesiologist. It is also important that the anesthesiologist be experienced in thoracic anesthesia and be comfortable with the various techniques of one-lung anesthesia. Careful monitoring of blood pressure (using an arterial line), of blood gases, of end-tidal carbon dioxide, and of pulmonary arterial pressures with a Swan-Ganz line, as well as urine output measurement and pulse oximetry, will all be required depending on the preoperative condition of the patient. Certainly, Swan-Ganz catheters are rarely required. Single-lung anesthesia is best provided with the use of a standard disposable Robertshaw double-lumen endotracheal tube. Some surgeons prefer to use either a bronchial blocker in combination with a standard endotracheal tube or one of the newer commercially available tubes that have a built-in blocker, especially for left pneumonectomy. It is also quite possible to perform this procedure with a single-lumen tube if the usual endobronchial catheter cannot be placed for whatever reason.

OPERATIVE TECHNIQUE Often, the decision to perform pneumonectomy has been made preoperatively on the basis of the type or location of the pathology, based on imaging or endoscopic findings. On other occasions, the need for pneumonectomy is determined intraoperatively. In either situation, the possibility of performing a lesser resection without compromising the intended purpose of the procedure always must be kept in mind. It is not uncommon, for example, to find a situation in which a bronchoplastic sleeve resection with or without a concomitant vascular sleeve resection can be performed instead of pneumonectomy. This determination may sometimes not be possible until the intraoperative assessment is made. Once thoracotomy has been performed, a determination of the extent of the disease, its resectability, and the appropriate resection is made.10,11 If the need for pneumonectomy is confirmed, the approach to the resection needs to be flexible, depending on the circumstances of each particular case. In any event, the hilum is first dissected to identify the pulmonary artery and the two (inferior and superior) pulmonary veins to assess resectability (Fig. 70-1).

Ch070-F06861.indd 865

Inferior pulmonary vein

FIGURE 70-1 The hilum of the right lung has been dissected completely, showing an anterior view of the right main stem bronchus, the right pulmonary artery, and the pulmonary veins.

PULMONARY VEINS Although theoretically (for oncologic reasons) the division of the veins needs to occur early in the procedure and before the division of the artery, this may not always be possible, depending on the intraoperative situation.12 In my opinion, much of the dissection is best performed bluntly with an “educated” finger to complete the vessel identification. The inferior pulmonary veins are best exposed by retracting the lung anteriorly and superiorly. When not involved with tumor, they are easily dissected and isolated. I prefer to staple or oversew the main trunks. Other surgeons doubly ligate or suture-ligate branches separately. The superior pulmonary vein is in close proximity to the pulmonary artery anteriorly on both sides and is handled similarly to the inferior vein. Although the vessels may be closed in various ways, the most popular method seems to be the use of vascular staples, which are especially designed for this purpose. They are safe and extremely convenient. Before the veins are manipulated in central tumors, the veins are gently palpated to be sure they do not contain extension of the tumor. If tumor is present, a determination is made rapidly as to its extent and resectability. Tumor released from such veins can result in a potentially disastrous tumor embolus. When suspected, it is best to examine the

1/21/2008 1:33:13 PM

866

Section 3 Lung

FIGURE 70-2 The left pulmonary hilum has been totally exposed intrapericardially. The ligamentum arteriosum can be divided to provide further length on the left main artery. The recurrent nerve must always be protected.

Left phrenic nerve Ligamentum arteriosum

Left vagus nerve Left recurrent laryngeal nerve Left pulmonary artery

Pericardium

Left upper lobe

Left superior pulmonary vein

intrapericardial portion of the veins to make this determination using a pericardiotomy anterior to the veins. If necessary, several millimeters of atrium may be encompassed in the resection (see Fig. 70-4). Under these circumstances, I prefer to use an atrial clamp rather than mechanical staples, oversewing the atrium with a running vascular suture following its division. As the clamp is applied to the atrium in such circumstances, venous return from the contralateral lung may be compromised, rapidly resulting in hemodynamic instability requiring a less central application. Under these circumstances, the clamp is applied for 1 or 2 minutes before any incision in the vessels is made, so that if instability is noted the clamp can be reapplied. Although there is sufficient atrium on the left side, on the right side mobilization of the interatrial groove may be required to provide adequate atrium to apply a clamp.

PULMONARY ARTERY Where the tumor is close to the origin of the pulmonary artery, it may not be possible to obtain enough length to safely apply a vascular stapler. In this situation, use of a proximal atraumatic vascular clamp, with oversewing of the vessel in a more traditional way, is perfectly acceptable. When possible, division of the first branch of the pulmonary artery on either the left side or the right side allows greater length for ultimate division of the main trunk. When the tumor is not very central, dissection of the pulmonary artery is not difficult and can be carried out intrapericardially. With the occasional use of Swan-Ganz catheters, it is important to ensure the device is not included in the artery when it is divided. The pulmonary artery is weakened by applica-

Ch070-F06861.indd 866

tion of staples in continuity. It is, therefore, important to avoid traction on the vessel once it has been stapled but before it is divided. Difficulty can occur when the tumor is tight on the pulmonary artery and obtaining sufficient length for safe control presents a problem. There are a few techniques available to deal with this. On either side, the pericardium is opened anterior to the pulmonary artery, and the intrapericardial portion of the pulmonary artery is identified.13 This maneuver will produce 1 or 2 cm of additional length. It is important to avoid injury to the phrenic nerve when doing this and also to ensure that adequate hemostasis on the pericardiotomy is secured. Postoperative bleeding from this area can be troublesome and can result in unacceptable blood loss requiring reexploration and may cause pericardial tamponade. The size of the pericardial defect is considered at the end of the procedure and the necessary steps taken to prevent cardiac herniation and compromise to venous return. A patch using Gore-Tex (or other suitable material) can be placed to prevent this, if necessary. On the left side, dissection may be continued proximally and the remnant of the ductus (ligamentum arteriosum) divided to obtain additional length on the left main pulmonary artery (Fig. 70-2). The left recurrent laryngeal nerve is vulnerable here, and care is taken to avoid injury to it, cautery to nearby structures, or traction on the nerve. As one proceeds centrally, it is possible to divide the left pulmonary artery at its origin (Fig. 70-3). Care must be taken to avoid compromise to the contralateral right pulmonary artery when the vessel is divided. It is also wise to position a vessel loop around the main right or left pulmonary artery during the dissection. This will allow control of a potentially lethal

1/21/2008 1:33:20 PM

Chapter 70 Pneumonectomy

867

Bronchus intermedius

Left atrium

Tumor

FIGURE 70-3 After division of the ligamentum arteriosum, a Satinsky clamp is applied just distal to the pulmonary conus. Care always must be taken not to impinge on the right pulmonary artery.

problem and salvage the situation if the artery is entered or torn. When extensive intrapericardial dissection is contemplated, the possibility of requiring cardiopulmonary bypass needs to be considered. This is exceedingly rare, but the surgeon needs to be prepared to institute it quickly, if necessary. On the right side, control of the intrapericardial artery may require mobilization of the superior vena cava and dissection of the artery that is medial to it, allowing a greater length of artery for control. The pulmonary artery is unforgiving and does not tolerate undue traction or rough handling. The veins are much tougher, and inadvertent injury is less frequent. On occasion, when the bulk of tumor is anterior and large, the vessels may be divided after isolation and division of the main bronchus (Fig. 70-4). Resectability is determined with certainty before this approach is used, although considerable experience is sometimes required to make such a judgment. Once the great pulmonary vessels have been divided, the suture or staple lines are carefully examined for satisfactory hemostasis. Where the dissection has been very central, the site of division may retract, and small amounts of bleeding may not be readily apparent.

BRONCHUS The handling of the main left or right bronchus is also a function of experience and personal preference. Dissection of the

Ch070-F06861.indd 867

Inferior vena cava

Interatrial groove

Right atrium

FIGURE 70-4 The right lung is retracted anteriorly, exposing the right main stem bronchus. With difficult hilar dissection, often the bronchus can be dissected first and divided, exposing the pulmonary artery from behind. With a tumor approximating the pulmonary veins, greater length can be obtained by opening up the interatrial groove (dotted lines) with careful sharp dissection.

bronchus proximal to the resection margin is kept to a minimum to preserve as much as possible of its blood supply. The goal of the process is to divide the main stem bronchus as proximally or close to its origin as possible to avoid the problem of a long bronchial stump. On the right side, it is very easy to judge the point of bronchial division in relation to the trachea and avoid a long stump. It is a little more difficult on the left side, and particular care must be taken to follow the left main bronchus centrally to the carina. Sometimes this requires an initial distal division of the bronchus, removal of the specimen, and a subsequent revision, taking the bronchus a little more proximally. If staplers are not available, possible, or desired, the bronchus may be closed by standard suturing techniques. Nonabsorbable suture material is to be avoided because of the incidence of suture granuloma and troublesome hemoptysis later. I prefer to use Vicryl or a similar suture. Sutures are interrupted, in an anteroposterior orientation. They are placed approximately 1 mm apart, encompassing the first cartilaginous ring. At the completion of the bronchial closure, the suture line is tested under water for air leaks, with the anesthesiologist’s help. A Valsalva

1/21/2008 1:33:28 PM

868

Section 3 Lung

maneuver with 30 to 35 cm H2O static airway pressure is sufficient. If there are any air leaks, they are dealt with and obliterated. This may require additional suture or additional tissue depending on the circumstances. Additional tissue implies the mobilization of neighboring vascularized tissues such as the pleura, the pericardium, the pericardial fat, the omentum, or an intercostal bundle, to suggest a few possibilities. The routine use of additional tissue to patch the bronchial suture line is controversial. Some believe it is necessary in every case; others think that it provides an enclosed area to encourage local infection. I do not routinely cover the bronchus.

POSTPNEUMONECTOMY SPACE Before closure, the usual checklist is covered: check for satisfactory hemostasis, the absence of air leak, and the condition and size of any pericardial defect, and, if applicable, search for possible esophageal or thoracic duct injuries. The phrenic nerve must not be crushed or otherwise intentionally damaged unless it is involved with the tumor. The thoracotomy is closed in standard fashion, with consideration to the location of the mediastinum. If the incision has been a posterolateral thoracotomy, the mediastinum will fall away during the procedure with resulting compromise of contralateral lung function and even possible impairment of venous return. Once the chest is closed and the patient is supine, steps are taken to evacuate air from the operated hemithorax to return the mediastinum to the midline.14 Once the patient is placed supine, a sterile needle can be introduced into the chest in the operating room, and air can be evacuated until the sensation of resistance to evacuation is obtained. I have left a 16-gauge soft catheter in the hemithorax during the closure, bringing it out through the front of the incision. The catheter is positioned and the closure conducted in such a way to allow immediate removal of the catheter without a defect in the chest wall. With the catheter in place, a member of the surgical team and the necessary equipment (a so-called Christmas tree, 50-mL syringe and three-way stopcock) remain sterile while the patient is returned to the supine position. Sufficient air is then evacuated in a sterile fashion to accomplish the goal; this is usually about 1 L of air in the average adult patient. The changes in position may be accompanied by arrhythmia and hypotension; therefore, it is necessary for a senior member of the surgical team to remain in the operating room for this. Some surgeons leave a chest tube in the hemithorax after pneumonectomy to achieve balancing of the mediastinum and to announce promptly any significant blood loss. This tube, if used, receives no more than 5 cm H2O suction, and personnel caring for the patient are warned that additional suction may have disastrous consequences. Alternatively, commercially available pneumonectomy drainage systems allow for balanced drainage, maintaining the pneumonectomy space at −1 cm H2O. Other surgeons leave the tube clamped after the mediastinum has been repositioned. The tube is removed within 12 to 24 hours of the surgery. I have not used

Ch070-F06861.indd 868

a tube because of the risk of introducing microorganisms via this route, with subsequent infection.

COMMENTS AND CONTROVERSIES Dr. Waters reviews the surgical steps involved in the performance of a pneumonectomy. Most important is the actual decision to perform a pneumonectomy rather than a more limited procedure such as a sleeve resection of the bronchus or pulmonary arterioplasty. Pneumonectomy carries a significantly higher operative morbidity and mortality than lesser resections but may not facilitate a better oncologic resection than accomplished by sleeve resection. The patient must undergo a thorough intraoperative evaluation to determine the possibility of bronchoplasty or pulmonary arterioplasty before committing the patient to the potential morbidity of pneumonectomy. The sequence of hilar structure division can be flexible. We do not hesitate to open the pericardium to gain additional length of pulmonary artery. Intrapericardial pneumonectomy is often much safer in patients with central lesions. If the pericardium is opened, the defect is always closed even if the opening appears small, because cardiac herniation can occur and will usually prove fatal if it occurs into the right chest. We prefer to utilize vascular stapling devices for pulmonary veins and pulmonary artery. The vascular staple line must always be inspected before vessel division. However, for completion or intrapericardial pneumonectomy, there is often not enough space for staple placement. A central clamp permits division with ample cuff for oversewing with polypropylene suture. There is a difference of opinion regarding the use of a bronchial stapler to seal the main bronchus. If the bronchus is not calcified, staples provide effective closure. However, if the bronchial cartilage is calcified or if the staple line impinges on the tracheal carina, a hand-sewn technique is used. My own bias is to cover all pneumonectomy stumps (especially after right pneumonectomy) with local viable tissue. The soft tissue immediately posterior to the divided pulmonary artery can be incorporated with the pericardium to nicely cover the bronchial stump. On the right side, the azygos vein or a generous flap of pericardium over the ascending aorta can be raised and reflected over the stump. Pedicled flaps of pericardial fat or muscle are also effective. Also controversial is the use of pleural space drainage. We typically utilize a single chest drain connected to a balanced drainage system. The tube is removed 12 to 24 hours postoperatively so as to limit the risk of pleural space infection. Alternatively, the pleural space can be aspirated after chest closure to balance the mediastinum. Dr. Waters describes this technique fully in this chapter. G. A. P.

KEY REFERENCES Grismer JT, Read RC: Evolution of pulmonary resection techniques and review of the bronchus-first method. Ann Thorac Surg 60:1133-1137, 1995. Ochsner A: Technique of pneumonectomy. Arch Surg 74:297-304, 1957.

1/21/2008 1:33:41 PM

chapter

71

ROLE OF SUBLOBAR RESECTION (SEGMENTECTOMY AND WEDGE RESECTION) IN THE SURGICAL MANAGEMENT OF NON–SMALL CELL LUNG CANCER Brian Pettiford Rodney J. Landreneau

Key Points ■ The increased application of high-resolution CT scanning is identi-

fying a greater number of small peripheral lung nodules. ■ Sublobar resection with margins at least equal to the diameter of

■ ■

■

■

the tumor can be effective in the primary management of peripheral adenocarcinomas measuring less than 2 cm and without endobronchial involvement. Local recurrence patterns may be addressed by the use of adjunctive radiation therapy such as brachytherapy mesh. Tumor biology and incomplete staging may account for survival differences between patients undergoing lobectomy and those undergoing sublobar resection. Randomized trials such as the ACOSOG Z4032 may help define the role of sublobar resection with adjuvant intraoperative brachytherapy in the treatment of stage la NSCLC. The proposed CALGB sponsored intergroup trial comparing sublobar resection to lobectomy for peripheral lung cancers less than 2 cm in diameter may help to further define the role of sublobar resection alone in the management of stage I NSCLC.

The use of sublobar resection as definitive management of resectable non–small cell lung cancer (NSCLC) has been a controversial topic throughout the history of surgery for lung cancer. Most thoracic surgeons continue to consider pulmonary resection less than lobectomy as inadequate for the management of lung cancers that are anatomically confined to a single lobe of the lung. Accordingly, sublobar resection is considered a so-called compromise operation by many surgeons, one that is employed only for the management of small peripheral lung cancers present in patients with significant impairment in cardiopulmonary reserve who cannot withstand the physiologic rigors of lobectomy. The increasingly common finding of new subcentimeter malignant lesions identified through surveillance computed tomographic (CT) chest scanning efforts has led many surgeons to reassess the need for total lobectomy for the management of smaller peripheral NSCLCs. In this setting, a question frequently asked today is, “Could anatomic segmentectomy or extended nonanatomic wedge resection be adequate for cure of the patient’s lung cancer?” We review the clinical information that is available today to the physician who is formulating an opinion regarding the appropriate use of sublobar resection for the small, peripherally located NSCLC. The technical details of the most commonly performed segmental resections are described in Chapter 73.

HISTORICAL NOTE Pulmonary segmentectomy was originally used for the resection of focal bronchiectasis and tuberculosis. Both of these pulmonary disease processes are commonly anatomically localized to discrete bronchopulmonary segments, and the common bilateral involvement encourages the use of parenchymal-sparing resection techniques. The first reported use of segmentectomy for the management of bronchiectasis is credited to Churchill and Belsey in 1939.1 Kent and Blades’ advocacy of individual ligation of bronchial and vascular hilar structures, coupled with Overholt and Langer’s 1947 description of the technique for resection of each bronchopulmonary segment in the treatment of bronchiectasis, established the use of anatomic segmentectomy for discrete sublobar pathology.2,3 Total pneumonectomy was still regarded as the only appropriate surgical option for the treatment of primary lung cancer during that period.4 The dreadfully high mortality rate (40%) associated with pneumonectomy at that time led to the use of lobectomy as the preferred approach to resection of peripheral lung cancers.5 The use of anatomic segmentectomy for the management of peripheral lung cancers was explored by some thoracic surgeons.6-9 However, the relative complexity of the operative approach, compared with lobectomy, and the increased morbidity related to prolonged air leak and local recurrence deterred the enthusiasm of most surgeons for this approach to lung cancer.10 The use of segmentectomy, and sublobar resection in general, was relegated as a so-called compromise procedure for patients with significant impairment in cardiopulmonary reserve who had peripheral lung lesions confined within segmental anatomic boundaries (Ginsberg and Rubenstein, 1995; Landreneau et al, 1997).10-15 An increasing body of evidence is emerging to suggest that sublobar resection with accurate nodal staging may be an adequate resection for the small peripheral NSCLC. Surgical marginal status after sublobar resection continues to be an important concern, and measures to enhance marginal clearance continue to be explored.16-32

CONTROVERSIES REGARDING THE USE OF SUBLOBAR RESECTION The use of anatomic segmentectomy is generally accepted for the management of benign disease processes and metastatic carcinoma to the lung confined to an anatomic segment. Sublobar resection, and segmentectomy in particular, has been accepted as a reasonable approach for resection in 869

Ch071-F06861.indd 869

1/21/2008 1:34:39 PM

870

Section 3 Lung

A

B FIGURE 71-1 A and B, CT roentgenographic images of small peripheral T1 lesions ideal for sublobar resection.

A

B

FIGURE 71-2 A and B, CT roentgenographic images of lesions for which adjuvant brachytherapy is used if sublobar resection is being considered (T2 lesions confined to anatomic boundaries of the pulmonary segment).

patients with significant impairment in cardiopulmonary reserve. The primary controversy over the years among thoracic surgeons has concerned the use of segmentectomy as primary management of peripheral primary NSCLC in patients who are physiologically fit to undergo lobectomy. In the following sections, we review representative pertinent clinical investigations addressing the appropriateness of sublobar resection in the primary management of NCSLC. We must first clarify that we believe sublobar resection is inappropriate for the management of most clinical NSCLC beyond that of stage I disease. For the most part, we favor the use of segmentectomy without adjuvant local therapy for small stage IA lesions that are less than 2 cm in diameter without endobronchial extension and within anatomic segmental boundaries (Fig. 71-1). Larger lesions are necessarily

Ch071-F06861.indd 870

associated with anatomic margins of resection that are more prone to local recurrence unless adjuvant therapeutic measures are considered (Figs. 71-2 and 71-3), as discussed later.

Concerns About Compromise of Patient Survival The use of sublobar resection for stage I attracted international attention with the initiation of the randomized trial of sublobar resection versus lobectomy for good-risk patients with stage IA disease conducted by the now-defunct North American Lung Cancer Study Group during the late 1980s and early 1990s (Ginsberg and Rubenstein, 1995).11 This study was inspired by the survival results seen among women undergoing less than total mastectomy for small primary

1/21/2008 1:34:40 PM

Chapter 71 Role of Sublobar Resection in the Surgical Management of Non–Small Cell Lung Cancer

FIGURE 71-3 Lesion for which lobectomy is required due to central lobar location that limits marginal clearance of the tumor.

breast cancers and by Erret’s 1986 report of equivalent survival results among stage I NCSLC patients with impaired cardiopulmonary reserve undergoing sublobar resection compared to physiologically fit stage I patients undergoing lobectomy (Erret et al, 1985).33,34 The results of the Lung Cancer Study Group’s efforts were reported in 1995 (Ginsberg and Rubenstein, 1995).11 Primary findings of this study were that survival in patients undergoing sublobar resection compared with lobectomy was not significantly different, but local recurrence was three times greater when sublobar resection was used. As an aside observation, the study also found no difference in loss of pulmonary function between lobectomy and sublobar resection when patients were assessed 1 year after surgery. This important conclusion regarding postoperative function caught the attention of many thoracic surgeons who were already convinced that lobectomy was the superior operation even for small, stage I NSCLCs. This conclusion regarding postoperative physiologic equivalency between resection approaches was made despite the fact that more than one third of the patients in the study were not available for pulmonary function testing 1 year after surgery. Subsequent analyses of the late effects of relative pulmonary function preservation have countered the conclusions of the LCSG in favor of sublobar resection.18,19 In any case, many thoracic surgeons continue to regard lobectomy as the gold standard treatment for earlystage NSCLC. In Japan, large CT radiologic screening programs in place for well over a decade have exposed an increased number of small, peripheral, early-stage lung cancers.35 Programs using fast CT scanners to screen high-risk populations (older patients with significant smoking history and impairment in pulmonary function) are underway now in North America and Europe.36 Renewed interest in sublobar resection and emerging enthusiasm for nonsurgical percutaneous management of small peripheral lung cancers identified through

Ch071-F06861.indd 871

871

these efforts are now seen (Fernando et al, 2005; Okada et al, 2001).18-25, 29-32,37-40 Analyses that have compared sublobar resection with lobectomy identify patient age and the size of the resected tumor as the primary determinants of survival. Mery and colleagues20 examined the effects of age and type of surgery on survival in patients with early-stage NSCLC. Their analysis of the Surveillance, Epidemiology, and End Results (SEER) Database categorized survival after resection of stage I NSCLC in three age groups: younger than 65 years, 65 to 74 years, and older than 75 years. A statistically greater number of elderly patients underwent limited resections, which included wedge resection. Two years after surgery, better survival was shown among young patients undergoing lobectomy as opposed to sublobar resection, but no such survival time difference was demonstrated in the elderly population. Furthermore, the statistically significant long-term survival advantage favoring lobectomy versus sublobar resection for younger patients was lost among patients older than 70 years of age. Okada and coworkers21 conducted a retrospective analysis of 1272 consecutive patients who underwent complete resection with complete lymph node staging of NSCLC and stratified them in four groups according to tumor size: 10 mm or smaller, 11 to 20 mm, 21 to 30 mm, and larger than 30 mm. The cancer-specific 5-year survival rates were 100%, 83.5%, 76.5%, and 57.9%, respectively, for the four groups. No difference in cancer-specific survival was seen between patients undergoing lobectomy and those undergoing segmentectomy for cancers smaller than 30 mm in diameter. The authors identified tumor size as an independent prognostic factor and suggested that segmentectomy, with systematic nodal staging to avoid stage shift bias, be considered as primary therapy for tumors 20 mm or less in size. El-Sherif and colleagues25 evaluated a 13-year experience in the management of resectable stage I NSCLC at our institution. The recurrence patterns and survival of 784 patients who underwent resection of stage I NSCLC (577 lobectomies and 207 sublobar resections, primarily wedges) were evaluated. No significant differences were observed in diseasefree survival between sublobar resection and lobectomy for patients with stage IA disease; however, disease-free survival was slightly worse for stage IB patients undergoing sublobar resection compared with lobectomy (58% versus 50% diseasefree at 5 years). Sublobar resection was also associated with a lower overall 5-year survival rate compared with lobectomy (40% versus 54%).16 The authors suggested that this reduced overall survival after sublobar resection may have been related to the generally poorer functional status and comorbidities of the patients chosen for resection rather than lobectomy at their institution.

Concerns About Local Recurrence Although disease-free survival remains the most critical parameter in the assessment of any treatment modality for lung cancer, local recurrence after primary therapy is also an important concern. Local recurrence can result in significant morbidity, such as invasion into the chest wall or vital medi-

1/21/2008 1:34:40 PM

872

Section 3 Lung

astinal structures, malignant pleural effusion, and problems related to airway obstruction and hemoptysis. It is generally established that the risk of local recurrence is increased with the use of sublobar resection for the management of stage I NSCLC. Primary factors related to local recurrence are the surgical marginal distance of resection and the related presence of microscopic extension of disease or in-transit local metastases. Recent investigations have noted that molecular immunohistochemical assessment of the tissue margin may assist in predicting the risk for local recurrence after sublobar resection.17 Such pathologic assessment of surgical margins may aid in decision making regarding local adjuvant treatment measures or re-resection to obtain clearance of disease. The present recommendations for sublobar resection are to establish a margin at least that of the diameter of the pulmonary lesion resected.16 Adjuvant radiotherapy has been considered as a possible option to be used in conjunction with sublobar resection to possibly reduce local recurrence. Miller and Hatcher12 reported a significant decrease in local recurrence in followup studies of a small group of sublobar resection patients undergoing postoperative focal external-beam so-called postage stamp radiation, compared with an earlier group of patients who had sublobar resection alone. However, radiation treatment planning problems created by the unpredictable three-dimensional course of staple lines, respiratory variation, the risk of local radiation injury to the treated remaining lobar segments of the lung, and the transportation difficulties associated with a several-week course of radiation therapy after thoracic surgery have resulted in little enthusiasm for adjuvant external-beam radiation therapy. Others have used intraoperative brachytherapy as an adjunctive local control measure after lung resection associ-

ated with close or positive margins of resection. Adjuvant intraoperative brachytherapy was primarily used in the setting of locally advanced lung cancer where margins could not be reliably sterilized and in an effort to provide immediate potential salvage therapy without the intrinsic delays associated with initiation of external-beam radiotherapy after thoracotomy.26 d’Amato and colleagues27 were the first to report the use of intraoperative iodine-125 (125I) brachytherapy as a local measure after sublobar resection of peripheral stage I lung cancers when pathologically clear surgical margins had been obtained. They described the fabrication of a radiation implant based on a polyglycolate hernia mesh template in which polyglycolate suture with (125I) pellets incorporated at 1-cm intervals along its length was woven into the mesh to create a treatment grid with pellets at 1 cm2 intervals (Fig. 71-4). This mesh template was then introduced into the chest and sutured onto the lung parenchymal surface at the suture line of resection to provide at least a 2-cm lateral margin coverage from the staple line. Usually 40 to 60 125I pellets within four to five lines of suture material were used with each brachytherapy implant. The total delivered radiation dose to the local tissues was calculated to be 10,000 cGy at a depth of 1 cm. In essence, this very high-intensity local therapy effectively extended the margin of resection by another centimeter. Santos and colleagues28 subsequently reported a longitudinal follow-up of the use of intraoperative 125 I brachytherapy from the same institution. Local recurrence after sublobar resection appeared to be significantly reduced, compared with historical control cases of sublobar resection. On this further analysis, no local important radiation fibrosis, implant migration, or unexpected decline in postoperative pulmonary function was noticed among patients receiving intraoperative 125I brachytherapy (Fig. 71-5).

A

FIGURE 71-4 Fabrication of brachytherapy implant. A, Brachytherapy implant template. B, Radiation oncologist fabricating radioactive iodine brachytherapy implant.

Ch071-F06861.indd 872

B

1/21/2008 1:34:41 PM

Chapter 71 Role of Sublobar Resection in the Surgical Management of Non–Small Cell Lung Cancer

873

Oncology Group (ACOSOG) is conducting a randomized trial (Z04032) of sublobar resection alone (by anatomic segmentectomy or extended wedge resection) versus similar sublobar resection with intraoperative 125I brachytherapy for stage IA NSCLC. More than 200 patients are to be accrued for study. Cancer and Leukemia Group B (CALGB) is in the final phase of preparation of a randomized investigation of surgical resection of small (<2 cm in diameter) stage IA NSCLCs by either lobectomy or sublobar resection with segmentectomy or wedge resection. More than 800 patients will be enrolled. The results of these investigations should aid in establishing the role of sublobar resection in the future management of stage I NSCLC.

PREOPERATIVE EVALUATION BEFORE SUBLOBAR RESECTION FIGURE 71-5 Typical dosimetry calculation after use of brachytherapy implant.

Other retrospective reports of the use of intraoperative 125I brachytherapy after sublobar resection have been encouraging and have helped to further define the use of this adjuvant therapy approach aimed at reducing local recurrence. Fernando and associates29 reported a retrospective multicenter analysis of 291 patients that compared outcomes after lobectomy (n = 167) versus sublobar resection (n = 124). Almost one half of the sublobar resection group (n = 60) received adjuvant 125I brachytherapy. The rate of local recurrence in the sublobar resection group was decreased from 17.2% to 3.3% with the use of adjuvant 125I brachytherapy. Finally, Birdas and coworkers30 retrospectively compared the outcomes of sublobar resection with brachytherapy versus lobectomy for patients with pathologic stage IB NSCLC. A total of 167 stage IB patients (126 lobectomy, 41 sublobar resection) were evaluated for local recurrence, disease-free survival, and overall survival. Local recurrence in the group receiving sublobar resection with 125I brachytherapy (4.8%) was similar to that in the group receiving lobectomy (3.2%). There was no statistically significant difference in disease-free survival or overall survival between the two groups.30 These investigators concluded that sublobar resection with intraoperative 125I brachytherapy provided equivalent local control and disease-free and overall survival outcomes similar to those obtained with lobectomy for stage IB NSCLC. In accordance with other investigators’ concern that close surgical margins lead to increased risk for local recurrence,16 they emphasized the potential utility of intraoperative 125I brachytherapy in theoretically extending the margin of resection when larger (T2) tumors are chosen for sublobar resection.30

Future Investigative Efforts Much of the information provided here has been the product of retrospective reviews of collected clinical experiences with sublobar resection. Randomized studies currently in progress or in conception will do much to define the role of sublobar resection and the use of adjuvant local control measures after these resections. Presently, the American College of Surgeons

Ch071-F06861.indd 873

Patients being considered for nonanatomic extended wedge resection or anatomic segmentectomy for the primary management of stage I NSCLC have usually been those with potentially important impairments in cardiopulmonary reserve. As mentioned, this may include borderline or marginal pulmonary function physiology that prohibits formal lobectomy. Predicted postoperative pulmonary function based on the volume of functional pulmonary parenchyma to be resected may dictate the resection options for the patient with underlying pulmonary impairment. Most patients present to the thoracic surgeon with an abnormal chest CT scan. This CT scan includes imaging of the liver and adrenal glands. Special attention is focused on the mediastinum and the size and segmental location of the pulmonary parenchymal lesion in question. Mediastinoscopy is performed, if indicated based on enlarged mediastinal lymph nodes (>1 cm in diameter) or focal uptake of fluorodeoxyglucose (FDG) within the mediastinum on positron emission tomographic (PET) scanning. The thoracic surgeon must also carefully evaluate the anatomic characteristics of lesions being considered for sublobar resection, as manifested through preoperative CT imaging and preoperative bronchoscopic evaluation. It is generally appreciated that lesions chosen for sublobar resection by extended wedge resection, via either open thoracotomy or video-assisted thoracic surgery (VATS) approaches, are located within the outer third of the lung parenchyma, smaller than 3 cm in diameter, and without evidence of endobronchial involvement. These concepts must be honored to minimize the possibility of inadequate margins of resection, staple line dehiscence and associated air leak or bleeding problems, and distortion of the remaining parenchyma of the lung resulting from deep application of stapling devices during the course of a deep nonanatomic wedge resection. A complete physiologic evaluation of the patient being chosen for sublobar resection is important. One must remember that the individual usually chosen for sublobar resection as definitive management of a peripheral malignant lesion is usually one whose cardiopulmonary functionality is in question. Thorough pulmonary function evaluation is indicated. This must include formal pulmonary spirometry, arterial blood gas analysis, and assessment of the carbon monoxide diffusion capacity. Split-lung ventilation/perfusion nuclear

1/21/2008 1:34:42 PM

874

Section 3 Lung

scintigraphic assessment and maximum oxygen consumption exercise testing may be selectively considered before surgery based on general functional concerns. Importantly, if there is little to no perfusion of the lobe under consideration for sublobar resection, one must question the rationale for segmentectomy in this setting, in particular for lesions within the emphysematous upper lobes of prior smokers. Cardiac functional assessment using standard or pharmacologic stress testing and two-dimensional echocardiography with estimates of pulmonary arterial pressures are considered. Once the patient has been deemed a candidate for anesthesia and sublobar resection, radiation oncology consultation is obtained if adjuvant intraoperative 125I brachytherapy is being considered as part of the treatment plan.

OPERATIVE CONSIDERATIONS FOR SUBLOBAR RESECTION Anesthetic Airway Control and Thoracotomy Incision At the time of operation, laterality is marked. After intubation with a single-lumen endotracheal tube, a flexible bronchoscopy is performed in the standard fashion to ensure the absence of endobronchial extension of the malignant process, which would preclude the use of sublobar resection. A double-lumen tube is then inserted, and the patient is positioned on the side. It is mandatory that the thoracic surgeon confirm proper positioning of the endotracheal tube after initial placement and after patient positioning to ensure the adequacy of selective contralateral lung ventilation and ipsilateral pulmonary atelectasis for the procedure. These actions can reduce the occurrence of time-consuming intraoperative problems associated with inadequate selective airway control with double-lumen intubation.

FIGURE 71-6 Usual three-stick intercostal access approach used for excision of small peripheral pulmonary lesions. A, Line drawing demonstrates triangulation approach for instrumentation and endoscopic camera. B, Intraoperative application of three-stick intercostal access. The surgeon’s right hand holds the endostapler and the left hand holds the thoracoscope with endoscopic camera. C, Endostapling device typically used for excision of small peripheral lung lesions. Insert demonstrates stapler head with 3.5-mm stapling cartridge.

Lesion Identification and VATS Sublobar Resection Approach Some important strategies for lesion localization and intercostal access for VATS instrumentation need to be discussed when diagnostic sublobar resection of suspicious indeterminant nodules (before anatomic resection) or sublobar resection as definitive management of peripheral NSCLC is being considered. The intercostal orientation established for access of the thoracoscope and instrumentation facilitate exploration of the entire cavity and identification of target lung pathology as determined through careful preoperative review of the chest radiograph and CT images. Generally, the initial intercostal access is achieved for the thoracoscope at the seventh intercostal space in the midaxillary line. Endosurgical instrumentation and the stapling device are introduced through intercostal access at the fifth or sixth interspace along the posterior axillary line and at the fourth or fifth interspace on the anterior axillary line. These intercostal access locations allow for good video imaging and also triangulation of most lesions being considered for VATS wedge resection. The position of the thoracoscope and endoscopic grasper/endostapler may be alternated as needed to facilitate exposure to important visual angles and application of the surgical stapler to facilitate wedge resection (Fig. 71-6). Careful examination of the surface of the lung in the region of the suspected lesion identified by preoperative CT scan-

B

A

Ch071-F06861.indd 874

Whenever possible, we prefer the VATS approach for the performance of sublobar resection. With appropriate selection of lesions for this approach, we find VATS to be advantageous with regard to reduction in postoperative morbidity and equivalent in utility to open thoracotomy approaches.41-44

C

1/21/2008 1:34:42 PM

Chapter 71 Role of Sublobar Resection in the Surgical Management of Non–Small Cell Lung Cancer

875

FIGURE 71-7 A-C, Drawings of endostapler application across pulmonary parenchyma. D, Photograph of sublobar resection specimen.

A

B

C

D

ning of the chest often reveals local visceral pleural scarring or retraction in the case of malignancy. Once full atelectasis of the lung in the region of the lesion is obtained, localization can usually be achieved through effacement of the nodule against the surrounding collapsed lung. Gentle palpation of the lung in the area in question with a sponge forceps or endoscopic grasper can also identify the lesion when videoscopic inspection is less rewarding. Issues related to resection of the indeterminant pulmonary nodule necessarily also apply to resection of the known small peripheral lung cancer chosen for primary VATS sublobar resection. Certainly, all efforts are centered on obtaining a clear surgical margin of resection. This does require a conscientious effort on the part of the surgeon through each step of the endosurgical stapled extended wedge resection. Once the lesion is identified, it is important to assess and estimate the thickness of the parenchymal margin of resection. For small subpleural lesions, a simple wedge resection can be accomplished with adequate surgical margins, as illustrated in Figure 71-7 with line drawings of endostapler application across the pulmonary parenchyma and a photograph of a sublobar resection specimen. The visceral surface of the lung is grasped with forceps, and an initial firing of the endostapler

Ch071-F06861.indd 875

is applied beneath the elevated, atelectatic lung tissue deep to the subpleural lesion. The staple line is inspected for parenchymal closure, and then the endostapler is introduced through an alternate intercostal access site to complete a standard V wedge resection with adequate margins. After completion of the resection, the lung is inspected for adequate pneumostasis. For deeper lesions, the surgeon must determine whether the required depth and thickness of the resection will preclude a safe and effective wedge resection of the lesion. This can be assessed by grasping the lung parenchymal surface near the lung lesion and applying an endoscopic grasping forceps (Masher Forceps, Starr Medical, NY) across the line of possible parenchymal resection. If the tissue can be thinned beneath the lesion without compromising resection margins, as determined by this tissue thickness approximating technique, the 45- or 60-mm length endostapler with thick-tissue staples (3.5-4.8 mm staple height) may be used to transect the parenchymal tissue for the wedge resection. The relationship of the pulmonary lesion to the line of resection is reassessed before each subsequent stapler application with the aid of the Masher Forceps estimation of lung parenchymal thickness. The resection is continued with successive applica-

1/21/2008 1:34:44 PM

876

Section 3 Lung

A

B FIGURE 71-8 Endoscopic image of staple line progression during the course of resection.

tions of the endostapler along the waist of pulmonary parenchyma deemed adequate for a clear resection margin (Fig. 71-8). Several techniques have been described for localization of pulmonary nodules that are not thought to be easily identifiable at the time of VATS sublobar resection. Beyond careful preoperative assessment of the CT images of the chest to determine the segmental location of the lesion, preoperative injection of methylene blue or use of a needle localization technique (or both) to identify the soft small, subpleural nodule has been described. Intraoperative ultrasonography has also been used with variable success.45 At completion of the sublobar resection, the pulmonary specimen is removed from the chest in a endoscopic specimen retrieval bag, to avoid chest wall contamination by a potentially malignant lesion within the specimen. Alternatively, a sterile operating room latex glove can be introduced into the chest through an intercostal access site to be used as a retrieval bag. After removal of the specimen, the lung is partially expanded, and the resection staple line margin is reexamined for hemostasis and air-leak control. A single chest tube is inserted through one of the lower intercostal access sites and positioned under thoracoscopic guidance toward a posterior apical position. The other intercostal access sites are closed primarily. The chest tube is removed after drainage is minimal and the air leak has resolved. This is customarily accomplished on the second or third postoperative day.

Minithoracotomy Approach to Sublobar Resection We prefer to use a vertical axillary muscle-sparing minithoracotomy incision, when the VATS approach is not chosen, for most sublobar pulmonary resections.46 For upper lobe and middle lobe sublobar resections, the incision is placed at the lower border of the axillary hairline in the midaxillary plane and extended distally for 8 cm (Fig. 71-9A). The pectoralis minor muscle is reflected anteriorly. The muscle fibers of the

Ch071-F06861.indd 876

FIGURE 71-9 A, Axillary vertical muscle-sparing thoracotomy through the bed of the 3rd rib, used to approach upper and middle lobe lesions. B, Midthoracic vertical muscle-sparing minithoracotomy through the bed of the 4th rib, used to approach lower lobe lesions.

serratus anterior muscle overlying the 3rd rib are split. The lateral aspect of the 3rd rib is resected subperiosteally, and a 2-cm portion of the 4th rib is also resected to further enhance minithoracotomy exposure. Two pediatric rib spreaders are inserted and positioned at right angles to each other for exposure. For lower lobe sublobar minithoracotomy resections, the skin incision is begun approximately 3 cm inferior to the axillary hairline along the posterior axillary line, near the anterior border of the latissimus dorsi muscle, and a similar 8-cm incisional length is used for thoracotomy (see Fig. 719B). The latissimus dorsi is reflected posteriorly, and the serratus anterior is detached along a segment of its inferior muscular origin. The 4th rib is resected subperiosteally, and a 2-cm portion of the 5th rib is removed. We have found that these vertical minithoracotomy approaches allow for adequate exposure with minimal chest wall trauma.47 This vertical incisional approach also increases versatility in accessing a number of segments of the lung, and it is relatively cosmetically appealing compared with lateral thoracotomy. A final concern regarding the performance of sublobar resection relates to the handling of parenchymal staple lines when performing a stapled resection across severely emphysematous or indurated pulmonary tissues. The most important consideration is careful handling of the pulmonary parenchymal tissue and gentle manipulation of the open or endostapling devices across the pulmonary parenchyma. The use of staple line–bolstering material and/or topical sealants

1/21/2008 1:34:48 PM

Chapter 71 Role of Sublobar Resection in the Surgical Management of Non–Small Cell Lung Cancer

may be helpful in obtaining pneumostasis when the pulmonary parenchyma is emphysematous or indurated.48,49

Intraoperative Brachytherapy To reduce the likelihood of local recurrence, we commonly employ adjuvant 125I brachytherapy in patients who have undergone anatomic segmentectomy or extended wedge resections as definitive management of NSCLC. We conform to the technical details for creation of the brachytherapy implant and insertion described by d’Amato and colleagues,27 which were detailed earlier in this chapter. An alternative approach, described by Lee and associates,50 involves direct suturing of the polyglycolic acid suture with the incorporated 125 I pellets directly to the lung surface, without the use of the polyglycolic acid hernia mesh template. The relative merits of these approaches will be one of the points of analysis in the ACOSOG Z04032 study mentioned earlier.

Thoracoscopic Approach to Formal Segmentectomy The VATS approach for segmental resections is similar to that for VATS lobectomy. The intercostal access that we use for VATS anatomic segmentectomy is slightly different (Fig. 71-10), but the intrathoracic technical details of VATS lobectomy are the same as those detailed in Chapter 80 of this text. The performance of VATS segmentectomy does add a new dimension to the hilar dissection that is not appreciated with VATS lobectomy. The details of the dissection are basically the same as those described for segmentectomy per-

X

X

FIGURE 71-10 Intercostal access and intramammary utility incision, used to accomplish thoracoscopic anatomic segmentectomy.

Ch071-F06861.indd 877

formed through open approaches (see Chapter 73). The application of a brachytherapy implant is also easily accomplished with the VATS approach, if this adjuvant measure is believed to be an important complement for local control of the lung cancer.27

SUMMARY Segmentectomy demands a thorough knowledge of the threedimensional bronchovascular anatomy of the lung. The anatomic detail makes segmentectomy significantly more challenging than lobectomy. Several principles must be applied when performing segmental lung resection: 1. Avoid dissection in a poorly developed fissure. 2. Use the transected bronchus as the base of the segmental resection during division of the lung parenchyma in the intersegmental plane. 3. Consider the use of endostapler division of the pulmonary parenchyma, to reduce the air-leak complications related to finger fracture dissection of the intersegmental plane. 4. Consider the use of adjuvant 125I brachytherapy as a means of reducing local recurrence after sublobar resection. Increasing evidence supports the use of anatomic segmentectomy in the treatment of primary lung cancer for appropriately selected patients. This resection approach appears most appropriate for management of small (<2 cm in diameter), peripheral, stage I NSCLCs for which a generous margin of resection can be obtained. Accurate intraoperative nodal staging is important to estimate the relative utility of these approaches compared with more aggressive resections and to determine the need for adjuvant systemic therapy if metastatic lymphadenopathy is identified. Future investigations comparing the results of sublobar resection versus lobectomy will more clearly define the role of segmentectomy among good-risk patients with clinically stage I NSCLC. At the present time, it appears that sublobar resection is an appropriate therapy for the management of stage I NSCLCs identified in elderly patients and those with significant cardiopulmonary dysfunction, and for the management of peripheral, low-volume, metastatic disease to the lung. Because the primary disadvantage of sublobar resection is local recurrence, intraoperative adjuvant 125I brachytherapy may be considered to minimize this risk.

COMMENTS AND CONTROVERSIES X

–

877

The authors have presented an excellent review of the controversies surrounding limited resection for primary NSCLC. This is a timely discussion because smaller and smaller peripheral lung nodules are being discovered by CT screening, and, although the best management for these lesions is yet to be determined, it is likely that strategies involving less than lobectomy will emerge. Important considerations include local recurrence rates and survival. One important issue that needs to be considered when contemplating less than a lobectomy is the functional status of the lobe that harbors the lesion. For example, upper lobes in smokers tend to have little perfusion and function, and this fact, in conjunction with previous findings that upper lobe removal or reduction may actually improve lung function, must not be ignored. Therefore, we must

1/21/2008 1:34:49 PM

878

Section 3 Lung

keep in context the effort that is being considered to salvage part of a lobe that may not be functional. On a final note, it is important that thoracic surgeons continue to investigate and perform clinical trials of nonoperative interventions for the treatment of NSCLC. Chapters on radiofrequency ablation and stereotactic radiosurgery are presented elsewhere in this text and are recommended readings. J. D. L.

KEY REFERENCES

Fernando HC, Santos RS, Benfield JR, et al: Lobar and sublobar resection with and without brachytherapy for small stage IA NSCLC. J Thorac Cardiovas Surg 129:261-267, 2005. Ginsberg RJ, Rubenstein LV: for the Lung Cancer Study Group: Randomized trial of lobectomy vs. limited resection for T1N0 non-small cell lung cancer. Ann Thorac Surg 60:615-623, 1995. Landreneau RJ, Sugarbaker DJ, Mack MJ, et al: Wedge resection versus lobectomy for stage I (T1N0M0) non-small cell lung cancer. J Thorac Cardiovasc Surg 113:691-700, 1997. Okada M, Yoshikawa K, Hatta T, et al: Is segmentectomy with lymph node assessment an alternative to lobectomy for non-small cell lung cancer of 2 cm or smaller? Ann Thorac Surg 71:956-961, 2001.

Erret LE, Wilson J, Chiu RC-J, Munro DD: Wedge resection as an alternative procedure for peripheral bronchogenic carcinomas in poor-risk patients. J Thorac Cardiovasc Surg 90:656-661, 1985.

Ch071-F06861.indd 878

1/21/2008 1:34:49 PM

chapter

LOBECTOMY

72

David P. Mason

Key Points ■ Lobectomy is the gold standard for localized lung cancer. ■ Understanding the three-dimensional relationship among bron-

chus, artery, and vein are critical to safe surgery.

tomy is carried out. This chapter focuses on basic, open techniques. The nuances of video-assisted lobectomy (VATS lobectomy) are beyond the scope of this chapter. Nonetheless, the anatomic features and principles of VATS lobectomy are identical to those of the standard approaches.

■ Meticulous technique to prevent air leak reduces pleural space

problems and patient length of stay.

HISTORICAL NOTE Today, performing a lobectomy is commonplace. The technique includes dissection of the hilar structures and serial transection of segmental vasculature, airway, and lung parenchyma. It is difficult to realize that the first dissection lobectomy was not performed until 1912 by Davies. Unfortunately, the patient died of an empyema 8 days postoperatively.1 Subsequently, in 1950, Churchill performed the first successful lobectomy with dissection and division of the hilar structures for bronchogenic carcinoma (Churchill et al, 1950).2 Based on Churchill’s success, lobectomy with systematic lymph node dissection of the hilum and mediastinum became the standard operation for lung cancer by the 1960s.3 As developments in technique and instrumentation progressed, it was hoped that lesser resections, including wedge resection and segmentectomy, could provide oncologic outcomes comparable to those of lobectomy but with preservation of lung function.4 In the 1980s, however, a sentinel study undertaken by the North American Lung Cancer Study Group compared limited resection with lobectomy for T1 N0 non–small cell lung cancer (NSCLC) in a randomized clinical trial, and the results showed that limited resection resulted in a higher cancer recurrence rate and a 50% increase in the observed death rate with cancer (Ginsberg and Rubinstein, 1995).5 The findings of this study made lobectomy the gold standard for patients with localized, resectable lung cancer and adequate pulmonary reserve. Most commonly performed for malignancy, lobectomy is occasionally indicated in other benign conditions that require anatomic lobar excision. In the properly selected patient, it can be performed safely and with low mortality. Although thoracic surgical approaches vary and there is some movement toward minimally invasive techniques, the basic principles of anatomic resection remain clear and constant. Anatomic resection requires division of the appropriate branches of the pulmonary artery, pulmonary vein, and lobar bronchus, as well as division of the lung parenchyma that forms any incomplete fissures. In addition, a lymphadenec-

INDICATIONS Patients with stage I-II NSCLC are candidates for primary surgical resection. In selected cases, patients with stage III disease may also be surgical candidates. Suitable candidates are typically treated with a multimodality approach: induction chemotherapy or chemoradiation therapy followed by surgery with possible consolidation therapy postoperatively (Albain et al, 1995).6,7 Our institutional bias is for accelerated hyperfractionated radiation therapy and concomitant chemotherapy followed by surgery and consolidation chemoradiation.8 The advantage of this regimen is completion of therapy within 3 months. There is no clear consensus on the best regimen for stage III disease, although it is increasingly accepted that neoadjuvant therapy combined with surgery is the preferred approach.9 In addition to malignancy, benign indications for lobectomy include carcinoid tumors,10 fungal and bacterial infections,11,12 chronic bronchiectasis,13 tuberculous infection of the lung,14 and congenital malformations.15 However, the most common indication for lobectomy remains bronchogenic carcinoma.

PREOPERATIVE EVALUATION Before resection, the clinical stage is confirmed using computed tomography (CT), positron emission tomography (PET), and brain magnetic resonance imaging (MRI). The patient’s fitness to tolerate surgery is determined by history, physical examination, electrocardiography, and pulmonary function tests. In general, patients with good performance status and pulmonary function tests that demonstrate a predicted postresection 1-second forced expiratory volume (FEV1) greater than 40% of predicted are candidates for lobectomy. Because no established parameters indicate a firm cutoff for pulmonary function tests that preclude resection, it may be more pertinent to rely on the patient’s performance status, global fitness, and exercise tolerance. Provocative pulmonary testing and quantitative ventilation-perfusion scans better define pulmonary reserves and indicate resection for many patients for whom initial pulmonary function test results would seemingly prohibit surgery.16 Given the significant comorbidities and advanced age of many patients, cardiac stress-testing and echocardiography are used liberally in preoperative evaluation. 879

Ch072-F06861.indd 879

1/21/2008 1:35:35 PM

880

Section 3 Lung

Careful review of the imaging studies helps determine the extent of resection. Adequate pulmonary reserve must be confirmed for patients in whom tumor location might necessitate bilobectomy or pneumonectomy.

POSITIONING Cervical mediastinoscopy on all patients with diagnosed or suspected bronchogenic carcinoma is preferred because present noninvasive staging modalities, including PET scanning, have unacceptable sensitivity and specificity in the evaluation of the mediastinum for lymphatic metastases.17 Mediastinoscopy minimizes the chances of finding unexpected N2 disease at thoracotomy. In addition, the procedure is quick and carries low morbidity.18 Combined bronchoscopy, mediastinoscopy, and thoracotomy for lung cancer is more efficient than staged procedures, as measured by shortened operative times and reduced overall costs.19 Every procedure begins with the patient in a supine position. Bronchoscopy is done through a single-lumen tube to evaluate the anatomy of the airway, verify the location of endobronchial tumor, and clear all airway secretions. The patient is then prepared and draped with a transverse roll between the shoulders; the cervical mediastinoscopy is carried out. While lymph nodes are evaluated by frozen section, hemostasis is established and the mediastinoscopy wound is closed. Once the lymph nodes are confirmed negative for metastatic disease, the patient is reintubated with a double-lumen endotracheal tube and placed into the lateral decubitus position. An axillary roll is placed in the axillary space of the downside arm; the upside arm is carefully placed onto an arm rest that minimizes any arm stretch that could cause a brachial plexus injury. The chest is prepared posteriorly, starting at the midline from the nape of the neck down to the iliac crests, and anteriorly, all the way to the midline. This ensures immediate access in the event that the incision needs to be extended for added exposure (Fig. 72-1).

INCISIONS Limited, muscle-sparing, posterolateral thoracotomy can be performed safely and effectively on most lobectomies. Latissimus and serratus muscles are mobilized and spared. The fifth interspace is the most functional for most lobectomies, although an interspace higher or lower may be preferable for an upper or lower lobe, respectively. “Shingling” of a rib prevents painful rib fractures caused by the rib spreader. Occasionally, a subperiosteal rib resection is performed for better exposure. The intercostal muscles are undercut anteriorly and posteriorly to minimize or avoid rib fractures during rib spreading. Standard-size and smaller, pediatric-size rib spreaders are used to reflect the mobilized serratus and latissimus muscles (Fig. 72-2). Axillary, lateral, and anterior thoracotomies are reasonable surgical alternatives, but the posterolateral thoracotomy gives the best overall exposure to the hilum of the lung and is the most commonly used approach. The anesthesiologist isolates the lung, and the pleural space is entered cautiously to avoid any air leaks from inadvertent parenchymal injury.

SURGICAL PROCEDURE Exploration and Mobilization of the Lung The chest is carefully explored to identify any unexpected pleural metastasis. All lobes of the lung are palpated to identify the location of the lesion, confirm its resectability, and

FIGURE 72-1 Body positioning in the lateral decubitus position with axillary roll. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND

FIGURE 72-2 View of fissure through thoracotomy. (REPRINTED WITH

CLINIC FOUNDATION.)

THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Ch072-F06861.indd 880

1/21/2008 1:35:35 PM

Chapter 72 Lobectomy

rule out any other lesions. The inferior pulmonary ligament is taken down using electrocautery, and the hilum of the lung is freed up circumferentially with division of the mediastinal pleura. Electrocautery can be used on the posterior aspect of the hilum, but care must be taken anteriorly to avoid thermal injury to the phrenic nerve.

Management of the Hilar Vessels Hilar dissection begins with identification and dissection of the three primary vascular structures: the pulmonary artery, the superior pulmonary vein, and the inferior pulmonary vein. Venous drainage of each lobe is confirmed, and any anatomic anomalies are identified. The order of dissection and transection is classic. Branches of the pulmonary artery are divided first, followed by those of the vein and airway. Although some espouse dividing the vein first, to prevent dissemination of malignant cells during the manipulation of the tumor, it is unclear whether this affects outcome. Sequential transection of artery, followed by vein, followed by airway is the safest method. This prevents inadvertent injury to the pulmonary artery during encirclment of the airway and prevents traction injury to a small tethering vessel. The location and size of the tumor, however, may dictate variations in the surgical approach and in the order of division of the hilar structures. If dissection is particularly difficult because of inflammation on the segmental pulmonary artery branches or a bulky tumor, the pulmonary artery is controlled proximally by encircling the main pulmonary artery and placing umbilical tape around it. A vascular clamp can be quickly placed on it if bleeding occurs. Similarly, the pulmonary veins are encircled and isolated to minimize back-bleeding. Dissection of the pulmonary artery is facilitated by cutting down sharply to the appropriate plane, exposing the “egg-shell white” of its surface. Adequate lengths are mobilized in this plane to prevent injury during division and ligation. Pulmonary veins can be dissected out by blunt dissection and do not require the same meticulous dissection as the artery does. It is preferable to divide most of the larger vessels with the use of an endoscopic stapler with a vascular insert. Smaller vessels are divided using 2-0 silk ligatures and double ligation on the proximal end. The endoscopic stapler can go through a chest tube incision to obtain the best angle around the vessel and prevent torque during division.

881

of bronchus; therefore, if the tumor is particularly close to the lobar orifice, the airway is sharply cut with a scalpel and a bronchoplasty is performed using interrupted 3-0 vicryl suture to ensure a negative margin. Frozen section evaluation of the bronchial margin or any close parenchymal margin must be performed routinely. Options to cover the bronchial stump include a pleural flap, azygous vein, pedicled pericardial flap, or pericardial fat pad, depending on availability and quality. Intercostal muscle flaps are preferred if chemoradiation preceded surgery. The stump is tested by inflation to 30 cm of water pressure by the anesthesiologist. If an air leak is present, it is oversewn with interrupted Vicryl suture.

Management of the Fissure Whether a fissure is complete or incomplete makes the difference between a very simple resection and a tedious and difficult one. Complete fissures allow identification of the pulmonary artery as a landmark to begin dissection. This minimizes the amount of lung parenchyma divided bluntly or with electrocautery that predisposes to air leak. Fissures are divided early if doing so facilitates dissection and manipulation of the lobe. Otherwise, the fissures are divided after the vascular supply has been transected and before division of the bronchus. In poor-quality, emphysematous lung, division is performed with a thick tissue GIA stapler buttressed with pericardial strips. Care must be taken to align serial staple fires to produce a smooth, linear staple line, minimizing tearing and air leak. The staple line is tested for air leak and oversewn, if necessary. Lung sealants are rarely required.

Lymphadenectomy The role and extent of lyphadenectomy in lung cancer has been widely debated. The survival advantage of lymphadenectomy versus lymph node sampling has not been clearly demonstrated. Accurate staging relies on careful lymph node sampling, and prognosis may be improved by extensive lymphadenectomy.20-22 Therefore, ipsilateral lymphadenectomy with careful cleanout of all lobar, hilar, and mediastinal lymph node stations is recommended. Mediastinal stations include levels 4R, 3, 7, 8, and 9 through the right chest and levels 5, 6, 7, 8, and 9 through the left.

SPECIFIC ANATOMIC RESECTIONS Right Upper Lobectomy

Management of the Bronchus Management of the airway is greatly simplified with the use of stapling devices. After dissection of the bronchus, all peribronchial lymph nodes are swept up bluntly into the specimen to avoid lymph node contamination of the bronchial margin. Minimizing cautery and skeletonization of the airway avoids devascularization of the bronchial stump, which could lead to breakdown and bronchopleural fistula. After the airway is completely exposed, a right-angled, heavy wire stapler is closed over it. The anesthesiologist inflates the operative lung to confirm no impingement on the remaining airways. Only after adequate ventilation of the remaining lobes has been confirmed is the stapler fired and the specimen excised. The stapling technique does require a longer length

Ch072-F06861.indd 881

After circumferential opening of the mediastinal pleura, the surgeon begins the operation anteriorly by dissecting out the right main pulmonary artery in its entirety as it emerges from beneath the superior vena cava. Superior and inferior borders of the right main pulmonary artery are dissected out, allowing clear identification of the truncus anterior branch. Only after the borders of the right main pulmonary artery have been identified are the fragile bifurcation of the truncus and the ongoing pulmonary artery dissected out. This can be a difficult area to repair if injured. The superior border of the truncus anterior is dissected out, and the vessel is encircled with a blunt-tipped, right-angled clamp. The vessel is then transected with an endoscopic vascular stapler, which is best positioned through a chest tube port in the midaxillary line

1/21/2008 1:35:39 PM

882

Section 3 Lung

FIGURE 72-4 Posterior view of the right upper lobe with the airway divided. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 72-3 Anterior view of right hilum with the lung retracted posteriorly and the vein to the upper lobe divided. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

to achieve the appropriate angle. The upper lobe branch of the superior pulmonary vein is then carefully encircled to preserve the middle lobe vein. The ongoing pulmonary artery that lies directly posterior to the vein must be carefully avoided. The vein is also transected with the use of an endoscopic stapler through the chest tube port (Fig. 72-3). With the vein divided, the ongoing pulmonary artery can be dissected out distally, which allows identification of the posterior ascending branch of the pulmonary artery. This branch is variable and may also come off the superior segmental artery. It is fragile and easily injured. Typically, the vessel is ligated at this point, using silk ligature from an anterior exposure. If it is difficult to reach the posterior ascending artery from this angle, it can be done later in the dissection, after transection of the right upper lobe bronchus or completion of the oblique fissure. This maneuver provides added room and mobility. The airway is addressed next. The pulmonary artery is dissected free of the airway, and all lymphatics swept off the bronchus and up into the specimen. The lung is reflected anteriorly to visualize the posterior hilum and the crotch between the upper lobe takeoff and bronchus intermedius (Fig. 72-4). At this point, either the bronchus can be divided

Ch072-F06861.indd 882

or the fissures completed. If the oblique fissure is almost complete and the posterior aspect of the ongoing pulmonary artery has been identified, it is usually easier to now complete the fissure with the GIA stapler. The minor fissure between the upper and middle lobes can be divided with serial fires of the endoscopic GIA stapler by rotating the lung posteriorly, grasping the upper and middle lobes gently, and firing the stapler from the anterior aspect while aiming just superior to the middle lobe vein. Finally, the bronchus is encircled; the stapler is closed over the upper lobe takeoff, flush to the bronchus intermedius. The lung is inflated, and middle and lower lobe inflation is confirmed. Care must be taken not to constrict the bronchus intermedius and the takeoff of the right middle lobe airway. If the fissure is thick and incomplete, the order for completion of the fissures and division of the bronchus is reversed. In this case, the bronchus is transected first, leaving the lobe entirely on its fissural attachments. The fissure is transected by reflecting the lobe caudally, bringing the stapler beneath it, and completing the fissure using serial staple fires. The middle lobe can be tacked to the lower lobe with interrupted Vicryl sutures if the fissure between the middle and lower lobes is complete and the middle lobe appears to be prone to torsion.

Right Middle Lobectomy The right middle lobe is the smallest lobe and the site of the least common lobectomy. Dissection is initiated at the junction of the oblique and major fissures; the pulmonary artery is identified. This is dissected out both proximally and distally, and the middle lobe artery branch or branches are

1/21/2008 1:35:39 PM

Chapter 72 Lobectomy

883

the endovascular stapler. The inferior pulmonary vein is encircled and transected with the endovascular stapler. The bronchus to the lower lobe lies directly behind the transected pulmonary artery. The fissures can now be completed with the GIA stapler anteriorly and posteriorly, using the airway as the most medial aspect of the staple line. At this point, the lobe remains tethered only by its bronchus. With the stapler brought down over the airway, the bronchus is transected after inflation of the lung to ensure that the middle lobe bronchus is not compromised. Occasionally, the superior segmental bronchus requires transection with a separate staple fire if the takeoff is high and cannot be incorporated into the staple line with the trunk to the basilar segments.

Bilobectomy

FIGURE 72-5 View of the dissected right pulmonary artery in the fissure. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

identified (Fig. 72-5). Gentle anterior retraction on the lobe places tension on the segmental vessels that are serially ligated. The lung is reflected posteriorly to bring to view the anterior hilum. The middle lobe vein or veins are identified and similarly ligated. Attention is again returned to the fissure. The right middle lobe bronchus is identified just posterior to the ligated pulmonary artery branches. The bronchus is divided with a stapler, and the fissures are completed with the use of the GIA stapler. An alternative approach to middle lobectomy is to initiate dissection from the anterior aspect of the hilum. The middle lobe vein is transected first, followed by the bronchus that lies just posterior to the vein. The pulmonary artery branches lying posterior to the bronchus are now exposed and can be divided. Finally, the fissures are completed.

Right Lower Lobectomy After transection of the inferior pulmonary ligament and opening of the mediastinal pleura, the dissection is initiated at the junction of the major and minor fissures. The pulmonary artery is identified in the fissure. If the dissection is difficult, proximal control is obtained at the right main pulmonary artery. The arterial trunk to the basilar segments is identified. Similarly, the superior segmental artery, which usually lies just proximal to this, is identified. Branches to the middle lobe artery are identified and carefully spared. The trunk to the basilar segments is then encircled and transected with the use of an endovascular stapler. The superior segmental artery is encircled and is either doubly ligated or transected with

Ch072-F06861.indd 883

If the tumor location crosses the boundary of two lobes, bilobectomy is performed on the right side. Most common is bilobectomy of the middle and lower lobes. This procedure is necessary if tumor crosses the fissures between the right lower and middle lobes, if there is a large tumor involving the bronchus intermedius that is not amenable to a sleeve resection, or if significant lymph node disease of the lower lobe involves the middle lobe as well. Dissection is initiated at the junction of the major and minor fissures. The pulmonary artery is transected just proximal to the middle lobe arteries. Care is taken to preserve the posterior ascending branch. The middle lobe branch of the superior pulmonary vein is then ligated, followed by transection of the inferior pulmonary vein. The lung is rotated anteriorly; the bifurcation between the upper lobe takeoff and the bronchus intermedius is dissected out. The fissure between the upper and middle lobes is completed anteriorly with serial fires of the GIA stapler. Completion of the fissure is performed between the superior segment and the upper lobe. At this point, the middle and lower lobes remain only by their bronchial attachment. The bronchus intermedius is transected just distal to the right upper lobe takeoff, carefully minimizing stump length. The stump must be gently covered with vascularized tissue to minimize the risk of bronchopleural fistula. Intraoperative air-leak control is critical given that a postoperative pleural space issue makes management difficult. Bilobectomy of the upper and middle lobes is less common and involves more steps than does a bilobectomy of the middle and lower lobes. Arterial blood supply must be divided sequentially with preservation of the lower lobe. The steps of the operation parallel those for a right upper lobectomy. The truncus anterior is transected, and the fissure is opened up widely to expose the posterior ascending artery as well as branches to the middle lobe. The superior pulmonary vein, including the branch to the middle lobe, is transected in a single staple fire of a vascular stapler. This helps expose the course of the ongoing pulmonary artery. Arterial branches are serially ligated to identify and preserve the superior segmental artery. The lung is reflected anteriorly, and the bifurcation of the upper lobe bronchus and the bronchus intermedius dissected out. The upper lobe bronchus is then divided, followed by the middle lobe bronchus. The length of the oblique fissure is completed using serial fires of a GIA stapler.

1/21/2008 1:35:43 PM

884

Section 3 Lung

FIGURE 72-6 Posterior view of the left hilum, showing the left main pulmonary artery, arch of aorta, and left main bronchus. (REPRINTED

FIGURE 72-7 Anterior view of the left hilum, showing the divided superior pulmonary vein and apical pulmonary artery branches.

WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

(REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Left Upper Lobectomy Because the left upper lobe has the most variable arterial blood supply, lobectomy here must be undertaken with caution. It is the largest of the lobes and the most prone to postoperative space problems. Hilar mobilization is performed. Dissection is initiated, with the lung reflected anteriorly on the left main pulmonary artery as it courses below the arch of the aorta (Fig. 72-6). Care must be taken to avoid the recurrent laryngeal nerve, which lies in close proximity to the dissection. To avoid thermal injury to the nerve, no electrocautery is used in this region. The apical pulmonary artery branches are variable here, but in general there is a short, large anterior branch and an apicoposterior trunk, or separate apical branch and posterior branches (Fig. 72-7). Because these branches are prone to traction injury, retraction must be done with caution. The lung is reflected anteriorly and caudally at this point, to ligate and divide these apical branches. With all apical branches divided, the pulmonary artery is dissected further out into the fissure, to identify and divide the lingular branches which come off more distally. Although there can be several lingular branches, there are usually two (Fig. 72-8).

Ch072-F06861.indd 884

Next, the superior pulmonary vein is divided with a vascular stapler, and the fissure is completed. The lobe is now only on its bronchial attachment. The bifurcation between the upper and lower lobes is dissected out, and the stapler is brought down and closed, with the lobe reflected posteriorly. The lung is inflated to ensure no compromise to the lower lobe. The bronchus is transected.

Left Lower Lobectomy After the lung is mobilized by division of the inferior pulmonary ligament and opening of the mediastinal pleura, dissection is initiated at the junction of the major and minor fissures. The pulmonary artery is identified in the fissure. If the dissection is difficult, proximal control is obtained at the left main pulmonary artery. The arterial trunk to the basilar segments is identified. Similarly, the superior segmental artery, which usually lies just proximal to this, is identified. Arterial branches to the lingula are identified and carefully spared. The trunk to the basilar segments is then encircled and transected with the use of an endovascular stapler. The superior segmental artery is encircled and either doubly ligated or transected with the use of the endovascular stapler. The inferior pulmonary vein is then encircled and transected with

1/21/2008 1:35:45 PM

Chapter 72 Lobectomy

885

more than the initial injury. To prevent thrombosis if full vascular occlusion of the lung is performed, 2500 U of IV heparin is given. Repair can then be performed under optimal conditions with vascular control.

Space and Air Leak Air leaks after lobectomy go hand and hand with space problems. Every effort must be made to ensure that there are no air leaks when the patient leaves the operating room. Staple lines are carefully inspected and oversewn if they are not pneumostatic. Carefully test the bronchial stump under saline for air leaks. Techniques to help prevent air leaks include careful creation of the fissures with a clean, straight staple line and buttressing of this line with bovine pericardium, particularly when working with fragile, emphysematous lungs. Finally, lung sealants have demonstrated some efficacy and are occasionally used in selected cases. Unless there is an accompanying air leak, a space issue is not generally a problem because the space will close or become slowly filled with fluid over time. Several techniques to minimize space are creation of a pleural tent at the apex of the chest, injection of the phrenic nerve with local anesthetic and placement of a subphrenic catheter to inject air, and creation of a pneumoperitoneum to elevate the hemidiaphragm. Thoracoplasty or re-creation of the diaphragm is rarely necessary. The importance of air leak prevention cannot be overemphasized.23 FIGURE 72-8 View of the dissected left pulmonary artery in the fissure. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

the endovascular stapler. The bronchus to the lower lobe lies directly behind the transected pulmonary artery. The fissures can now be completed with the GIA stapler, using the airway as the most medial aspect of the staple line. At this point, the lobe remains tethered only by its bronchus. The stapler is brought down over the airway, and, after inflation of the lung to ensure that the left upper lobe bronchus is not compromised, the bronchus is transected. Occasionally, if the takeoff is high and cannot be incorporated into the staple line with the trunk to the basilar segments, the superior segmental bronchus will need to be transected with a separate staple fire.

SPECIAL CONSIDERATIONS Major Bleeding Although major bleeding from the pulmonary artery during pulmonary resection is uncommon, it can rapidly become life-threatening if not immediately controlled. As a general rule, direct gentle pressure with a finger or Kitner can temporarily control most bleeding of the pulmonary artery. Proximal and distal control are obtained with either vascular clamps or vascular tapes. Intrapericardial dissection must be carried out if control cannot be obtained extrapericardially. Resist the urge to directly suture the fully pressurized pulmonary artery before obtaining control because the fragile pulmonary artery may tear, compounding the problem far

Ch072-F06861.indd 885

Middle Lobe Torsion The narrowly pedicled middle lobe can be subject to torsion after right upper lobectomy, although torsion of any lobe can occur.24 To prevent this, the middle lobe can be tacked to the lower lobe using suture or a staple fire. The best prevention, however, is to be sure that the middle lobe is well inflated and positioned within the chest on closing. Atelectasis of the middle lobe predisposes it to torsion, but a fully inflated lobe is unlikely to twist. Should the diagnosis of middle lobe torsion be made later in the postoperative period, a middle lobectomy is performed expeditiously.

Chemoradiation Neoadjuvant therapy with chemotherapy and high-dose radiation is being given with increasing frequency. Although lobectomy and pneumonectomy can be performed with reasonable morbidity and mortality, these patients must still be approached with caution.25,26 Some form of restaging after treatment, but before surgery, using CT scan or repeat PET scan to rule out tumor progression or new metastatic disease, is recommended. In the operating room, 125 mg of SoluMedrol is given; the anesthesia team keeps the inhaled oxygen concentration to a minimum while minimizing the amount of intravenous (IV) fluid to prevent postoperative adult respiratory distress syndrome (ARDS).27 To optimize exposure, the incision must be larger than that of a standard lobectomy. Hilar dissection can be challenging because of adhesions and the obliteration of the usual planes around vessels. For this reason, vascular control is obtained early. Before the rib retractor is inserted, an intercostal muscle pedicle is taken

1/21/2008 1:35:48 PM

886

Section 3 Lung

down to avoid crushing it; it is used to cover the bronchial stump.28

Chest Tube Management Individually, thoracic surgeons have strong feelings about chest tube management after lobectomy. In general, chest tubes must be adequate to re-expand the lung and to evacuate air and fluid. Chest tube size, number, time for placement to water seal, and time of removal are all subject to debate. Our policy is to use two chest tubes after lobectomy. For an upper lobe, two straight 28 Fr chest tubes are used, one anterior and one posterior to the remaining lung, and directed to the apex. For a lower lobe, a posterior apical 28 Fr chest tube and a 28 Fr angled chest tube are placed below the lung and over the diaphragm. Insertion of two chest tubes contributes to symmetrical re-expansion of the lung; the tubes are connected to −20 cm H2O of suction for the first night and water sealed the following morning. Cutoff for removal is 250 mL of drainage a day.

Atrial Fibrillation and Deep Venous Thrombosis or Pulmonary Embolism Atrial fibrillation and venous thromboembolism are frequent occurrences after thoracotomy for malignancy.29-32 Either complication can cause significant morbidity, increase the risk of mortality, prolong length of stay, and add to hospital cost. It is recommended that each hospital have a prophylaxis policy for both atrial fibrillation and venous thromboembolism. Our regimen is aggressive: β-blockade to prevent atrial fibrillation and a combination of subcutaneous unfractionated heparin, pneumatic compression stockings, and early ambulation to prevent venous thromboembolism.33

The author has written the chapter largely from the perspective of the surgeon favoring muscle-sparing posterolateral thoracotomy. The sequence of exposure and vision of vessels and airway is not always uniform (i.e., artery, vein, bronchus). Tumor size or location sometimes mandates a different approach. For large, upper right tumors, it is often easier to divide the bronchus posteriorly, followed by the arterial branches and, subsequently, the anteriorly positioned superior pulmonary vein. Surgeons favoring an anterior or axillary approach will be familiar with initial division of the vein, followed by artery and bronchus. Sometimes, when using an anterior approach, it is easier to divide the fissure as the final step. Dr. Mason emphasizes a number of important technical points: gentle handling of the pulmonary artery, especially when a small defect is created in the wall; use of endoscopic vascular staplers introduced through chest tube site ports; and covering of the bronchial stump after bilobectomy. However, it is important to remember that, for bronchial closure, mechanical staplers offer no advantage, except perhaps time, over simple suture closure. G. A. P.

KEY REFERENCES Albain KS, Rusch VW, Crowley JJ, et al: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stage IIIA (N2) and IIIB. J Clin Oncol 13:1880-1892, 1995. Churchill ED, Sweet RH, Sutter L, Scannel JG: The surgical management of carcinoma of the lung: A study of cases treated at the Massachusetts General Hospital from 1930-1950. J Thorac Cardiovasc Surg 20:349-365, 1950. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60:615-623, 1995.

COMMENTS AND CONTROVERSIES This chapter provides an in-depth review of the preoperative patient evaluation and technical conduct of anatomic pulmonary lobectomy.

Ch072-F06861.indd 886

1/21/2008 1:35:50 PM

chapter

SEGMENTAL RESECTION

73

Stanley C. Fell

Key Points ■ For early-stage lung cancer, segmentectomy is a satisfactory

oncologic procedure. ■ When segmentectomy is being performed for cancer, frozen

section analysis of segmental nodes is mandatory to ensure a complete resection. ■ Segmentectomy is often the procedure of choice for limited bronchiectasis.

Anatomic segmental resection is the excision of one or more bronchopulmonary segments of a lobe, with individual ligation and division of the corresponding bronchovascular structures. Although portions of lobes may be excised with the use of clamps, stapling devices, cautery, or lasers, these nonanatomic methods are properly classified as wedge resections.

HISTORICAL NOTE Clinical application of the known detailed knowledge of human bronchovascular anatomy did not occur until Kramer and Glass originated the term bronchopulmonary segment in their study of lung abscess in 1932.1 Segmental resection was first proposed and performed in 1939 by Churchill and Belsey, who stated that “the bronchopulmonary segment may replace the lobe as the surgical unit of the lung (Churchill and Belsey, 1939).”2 The surgical and anatomic study of Kent and Blades in 19423 popularized the technique of individual ligation of hilar structures. Subsequently, Overholt and Langer4 systematized the operative methods for resection of all bronchopulmonary segments in 1949. Segmental resection was developed for the surgical management of tuberculosis and bronchiectasis. Both are often multisegmental and bilateral diseases. Segmental resection made it possible to extirpate irreversible disease with minimal loss of functioning lung parenchyma. An additional advantage claimed for segmental resection in cases of tuberculosis was that it minimized compensatory hyperinflation of the residual lung, a phenomenon believed (erroneously) in the preantibiotic era to accelerate the reactivation of quiescent residual disease. Segmental resection has more recently been applied to the surgical therapy of primary or metastatic lung cancer. Supported by the Feldesman Fund for Thoracic Surgery at the Montefiore Medical Center.

PRINCIPLES OF SEGMENTAL RESECTION General Considerations Segmental resection is technically more difficult than lobectomy, requiring intimate three-dimensional knowledge of the relevant bronchoarterial relationships and possible arterial anomalies. Preoperative bronchoscopy is required to ensure that segmental bronchi are free of disease. After thoracotomy, lysis of adhesions, and hemostasis, complete mobilization of the lung is necessary to facilitate the exposure required for resection and subsequent pulmonary re-expansion. In cases of lung cancer, sampling of hilar and mediastinal lymph nodes with frozen section analysis is mandatory to determine the applicability of segmentectomy. Ideally, the tumor is 2 cm or less in diameter and deeply seated in the segment with surrounding normal lung tissue. Subpleural tumors near the edge of a lobe are usually amenable to generous wedge resection with a stapling device. Visual examination and palpation is used to determine whether the residual segments are of sufficient volume to warrant their preservation. In surgery for inflammatory disease, for example, a shrunken fibrotic basilar segment is usually associated with compensatory hypertrophy of the superior segment, which makes salvage of this segment worthwhile. In carcinoma, this phenomenon is not noted. The most reliable landmark of a segment is its bronchus, which is rarely anomalous. Identification of the segmental bronchus may be facilitated by repeated traction on the tumor and finger palpation in the hilar area for the resultant tautening of the segmental bronchus. The segmental bronchi of the right upper and lower lobes and left lower lobe are usually identifiable before the division of any segmental arteries. This situation does not occur in the left upper lobe, in which the segmental bronchi are obscured by the segmental arteries. The order of division of the segmental hilar structures may vary; in general, the arterial branches are divided first, which allows identification of the segmental bronchus. The segmental veins may then be identified. Because the venous drainage may not be readily apparent, venous ligation is best performed last, after the intersegmental plane has been delineated and developed. The intersegmental veins define the perimeter of a bronchopulmonary segment and drain contiguous segments. Dissection in the intersegmental plane, sparing the intersegmental vein and thus preserving the venous drainage of adjacent segments, is a stringent requirement of segmental resection if complications are to be avoided. Identification and separation of the intersegmental plane is performed by differential inflation, in which occlusion of the 887

Ch073-F06861.indd 887

1/21/2008 2:11:53 PM

888

Section 3 Lung

Apical segmental artery

Apical segmental vein

Anterior segmental vein

Posterior and inferior segmental veins Middle lobe vein Azygos vein

Apical segmental bronchus

RUL RML

Posterior segmental bronchus

FIGURE 73-1 The apical segmental artery and vein have been ligated and divided. (Head of patient is at left.) RML, right middle lobe; RUL, right upper lobe.

FIGURE 73-2 After medial retraction of the right upper lobe, the apical segmental bronchus is dissected.

segmental bronchus in a deflated lung is followed by expansion of the lung. The excluded segment remains airless and can be readily delineated. Occasionally, collateral ventilation fills the diseased segment. The reverse procedure may then be employed: the lung is expanded, and then, after occlusion of the segmental bronchus, the lung is deflated. The expanded, diseased segment is thereby demarcated. The bronchus is transected, leaving a stump of sufficient length so that closure will not occlude other segmental orifices. Manual closure of the segmental bronchus, using a few fine polyglactin or silk sutures, is preferred. Stapling devices are often difficult to apply at the tertiary hilum, and their application may compromise adjacent segmental orifices or leave a long stump. A right-angled clamp is applied to the specimen end of the bronchus, elevated, and retracted under the left thumb (by a right-handed surgeon). Traction is applied to the clamp with the lung partially inflated. Dissection of the segmental plane by scissors is commenced inferior to the bronchus. Fine fibrous strands, possibly representing tiny bronchi or veins, that impede the development of the intersegmental plane are clipped and divided. Finger dissection along the path of least resistance completes the intersegmental plane to the pleura, using the intersegmental vein as a guide. Alternatively, the bronchus clamp is held by the left thumb and pressure is applied to the pleural surface of the segment using the fingers of the left hand, thus everting the deep surface of the segment along the intersegmental plane. Again, the fibrous strands that impede the progress of the dissection are individually clipped and divided. The segmental vein, if not conveniently demonstrated and divided earlier in the procedure, is now readily identified and ligated. Pressure applied with a gauze pad to the raw lung surface for several minutes usually is sufficient to control bleeding; if not, cautery is used. Small air leaks are controlled with fine sutures. Air leaks may also be controlled by suturing the raw surface down to a contiguous segment, but this method may induce distortion and kinking of bronchi and thereby limit

re-expansion of the residual segments, a major goal of segmental resection. A pedicled pleural flap applied to the raw surface also may be useful, particularly after resection of apical or superior segments. The description to this point has been that of segmental resection as classically performed; however, the development of stapling devices has added a new dimension to the technique. The prevalence of obstructive emphysema in cancer patients mandates stringent control of air leak, for which staples have no equal at this time. Biologic adhesives are not readily available and require further evaluation. If stapling devices are to be used, they are best applied along the intersegmental plane in the partially inflated lung after division of the segmental artery and bronchus to avoid excessive distortion of the residual lobe. Stapling facilitates extending the resection into an adjacent subsegment, if necessary, to obtain an adequate margin about the tumor. Two large-bore intercostal catheters are inserted before closure, one placed apical and anterior and the other placed posterolaterally, lying on the diaphragm. The anterior tube is sutured to the apical pleura to ensure continued evacuation of air leak. Suction of 20 cm H2O is applied to the drainage apparatus. If necessary, nasotracheal suction and bronchoscopy are performed to achieve complete expansion of the residual lung, to prevent late pleural space problems. Prolonged air leak is the most common complication of segmental resection, occurring in approximately 10% of cases; its management depends on the severity of the leak, the extent of lung expansion, and the condition of the patient. Small alveolopleural fistulas may seal, leaving a so-called neutral air space, which usually reabsorbs with gradual lung expansion. If empyema supervenes, drainage and later obliteration of the space by muscle flap transposition or limited thoracoplasty will be required. A large air leak associated with radiographic evidence of opacification of the residual lobe suggests that complete lobectomy may be indicated.

Ch073-F06861.indd 888

1/21/2008 2:11:53 PM

Chapter 73 Segmental Resection

889

Apical segment Intersegmental vein

A

B

FIGURE 73-3 A, Dissection of the intersegmental plane between apical and posterior segments is commenced. B, Finger dissection of intersegmental plane, preserving the intersegmental vein.

Technical Considerations Right Upper Lobe Apical Segment. The mediastinal pleura is incised about the hilus of the right upper lobe, the incision extending from the superior pulmonary vein anteriorly and continuing about the branches of the right upper lobe to its lower border. Anteriorly, the superior pulmonary arterial trunk is demonstrated; the apical segmental artery is its uppermost branch (Fig. 73-1). The lower branch is the anterior segmental artery, which is crossed by the apical segmental vein. The apical segmental vein and artery are ligated and divided. If the artery is short, additional length may be obtained by dissecting with a right-angle clamp into the pulmonary parenchyma and dividing the parenchyma with cautery. Scissors dissection exposes the posterior surface of the lobar bronchus. Several branches of the bronchial artery require division. Pledget dissection will demonstrate the posterior aspects of the segmental bronchi (Fig. 73-2). The apical segmental bronchus arises from the upper portion of the right upper lobe bronchus. Traction on the segment and palpation of the bronchus, as well as bronchial occlusion and differential inflation, confirm that the appropriate bronchus has been isolated. Closure of the bronchus and excision of the segment are performed as previously described (Figs. 73-3 and 73-4). Posterior Segment. The posterior segment is often removed with the apical segment of the right upper lobe in resections for inflammatory disease. The posterior segmental bronchus arises from the midportion of the right upper lobe bronchus. The posterior portion of the major fissure is opened to demonstrate the origin of the posterior segmental artery from the anterior aspect of the interlobar artery, just above the origin of the superior segmental artery. Rarely, the superior segmental artery of the lower lobe gives rise to the posterior segmental artery of the upper lobe. If it is not possible to complete the major fissure readily, the posterior segmental

Ch073-F06861.indd 889

Anterior segment

FIGURE 73-4 Completed apical segmentectomy.

artery may be demonstrated after division of the posterior segmental bronchus. Dissection of the bronchus must be performed with great care because the artery lies directly anterior to it and is vulnerable to injury. Elevation of the stump of the divided bronchus will demonstrate the posterior segmental artery. Traction on the distal stump of the bronchus and differential inflation will demonstrate the line of demarcation between the posterior and the anterior segments. The posterior segmental vein is best identified and divided after completion of the retrograde dissection, so that injury to the anterior and inferior segmental veins is avoided. Anterior Segment. Dissection of the anterior segment is the most technically difficult of all segmental resections. The anterior segmental bronchus is not easily accessible from the posterior aspect because it is obscured by the posterior segmental vein. Dissection of the arterial supply and preser-

1/21/2008 2:11:57 PM

890

Section 3 Lung

vation of the venous drainage of contiguous segments is tedious. The mediastinal pleura is incised about the anterior aspect of the hilus of the right upper lobe to below the level of the middle lobe vein. The superior trunk of the pulmonary artery is identified; its lower branch, crossed by the apical vein, is the anterior segmental artery. The apical segmental vein joins the anterior segmental vein to form the upper trunk of the superior pulmonary vein and must be preserved. It is usually convenient to ligate and divide the anterior segmental vein prior to ligation and division of the segmental artery. The interlobar pulmonary artery is closely applied to the undersurface of the vein, and careless dissection can be disastrous. The middle lobe vein originating at the lower border of the superior pulmonary vein is identified and preserved. The inferior segmental vein is ligated and divided, with care taken to avoid injury to the posterior segmental vein lying deep to it. The horizontal fissure is then completed with the use of a stapling device. The interlobar pulmonary artery is visualized. Occasionally, accessory arteries to the anterior segment are noted and require division. The anterior segmental bronchus, originating near the lower border of the lobar bronchus, is then divided and closed, and the segment is excised. Given the setting of a voluminous anterior segment and small apical and posterior segments, lobectomy may be preferable to segmental resection. Lobectomy is technically easier, and the patient’s postoperative course is likely to be smoother.

RUL

Interlobar artery

Basilar arteries

Ligated superior segmental artery

Superior segmental bronchus

RLL

FIGURE 73-5 The oblique fissure has been opened, and the interlobar pulmonary artery has been exposed. The superior segmental artery has been ligated and divided. RLL, right lower lobe; RUL, right upper lobe.

RLL

RUL

Right Lower Lobe Superior Segment. The oblique fissure is opened to expose the interlobar pulmonary artery, which is deeply situated in the region where the oblique and horizontal fissures meet (Fig. 73-5). The middle lobe artery originates from the anteromedial surface of the interlobar artery, whereas the superior segmental artery originates posterolaterally at a slightly lower level. Rarely, the posterior ascending artery to the upper lobe originates from the superior segmental artery, and occasionally there are two superior segmental branches. The basal segmental arteries may have a short common trunk from which two branches originate, or all four basal segmental arteries may originate separately distal to the middle lobe artery. After division of the superior segmental artery, the superior segmental vein, which is the uppermost tributary of the inferior pulmonary vein, is divided (Fig. 73-6). It lies at a slightly lower level than, and posterior to, the superior segmental bronchus. The superior segmental bronchus is divided, leaving a stump that is long enough that ventilation of the middle lobe bronchus is not compromised. The segment is then excised as previously described (Figs. 73-7 and 73-8). Basal Segments. The exposure and anatomy are as described earlier. The basal segmental bronchi follow the arterial distribution closely, being situated posterior and medial to their respective segmental arteries. After division of the basal segmental arteries, the inferior pulmonary ligament is divided. Three or four basal segmental

Superior segmental bronchus Ligated superior Inferior segmental vein pulmonary vein FIGURE 73-6 Posterior aspect of right lower lobe hilum. The superior segmental vein has been divided, and the superior segmental bronchus has been identified. RLL, right lower lobe; RUL, right upper lobe.

FIGURE 73-7 Traction on the specimen bronchus and finger dissection of the intersegmental plane, sparing the intersegmental vein.

tahir99-VRG vip.persianss.ir

Ch073-F06861.indd 890

1/21/2008 2:12:05 PM

Chapter 73 Segmental Resection

891

veins join the inferior pulmonary vein, either individually or via two trunks. After division of the basal segmental veins, the basal bronchi are divided and sutured distal to the superior segmental bronchus, and the segment is excised.

Anteromedial Middle lobe segmental artery artery

Left Upper Lobe

Posterolateral segmental artery

FIGURE 73-8 Completed superior segmentectomy.

Inferior lingular artery

Superior lingular artery

Posterior segmental artery

LUL

Basilar arteries LLL FIGURE 73-9 The oblique fissure has been opened, and the branches of the interlobar pulmonary artery have been demonstrated. (Head of patient is to the right.) One lingular artery has been ligated. LLL, left lower lobe; LUL, left upper lobe.

Lingular arteries

Commonly performed segmental resections involving the left upper lobe are excision of the apicoposterior segment, upper division (apicoposterior and anterior segment) resections, and lingulectomy. The key to segmental resection of the left upper lobe is control of the left pulmonary artery. It is best dissected in its subadventitial plane and encircled with a Silastic loop for proximal control. Isolation of the left pulmonary artery allows easier dissection of its apical and anterior segmental branches, which are often short and broad and, therefore, susceptible to injury. Anterior and inferior to the pulmonary artery, the superior pulmonary vein and its tributaries are demonstrated: the superior venous trunk drains the apicoposterior segment, the middle trunk drains the anterior segment, and the lowermost trunk drains the lingula. The oblique fissure is completed by sharp dissection or by the use of a stapling device with the pulmonary artery visualized. Dissecting the pulmonary artery from its perivascular sheath over the midpoint of its presenting surface as it enters the fissure facilitates this dissection. Additional posterior segmental arteries may be demonstrated, as well as the lingular arteries arising as terminal branches from the upper border of the interlobar pulmonary artery. The segmental bronchi of the left upper lobe are concealed by arteries. Because of possible anatomic variations, no arteries to the apicoposterior segment are divided until all arteries to the left upper lobe have been demonstrated. Traction on the tumor and the distal bronchus will demonstrate which arteries require division. Division of the appropriate segmental arteries exposes the segmental bronchus, which is then divided and sutured. Traction is applied to the specimen end of the bronchus, and the intersegmental plane is delineated as previously described. The venous drainage is usually best divided when it is most easily identified—that is, after the segmental dissection has been completed.

Lingula

Lingular bronchus

FIGURE 73-10 After the division of the lingular arteries, the lingular bronchus is dissected.

The oblique fissure is open for its entire length, and the interlobar pulmonary artery is exposed (Fig. 73-9). As noted earlier, in the presence of a fused or incomplete fissure, the pulmonary artery is at risk of injury, and proximal isolation of the main pulmonary artery is indicated. The lingular arteries, usually two in number, are identified and divided. The bronchus is readily isolated and divided, leaving sufficient length so that its closure does not compromise ventilation of the upper division bronchi (Fig. 73-10). Retrograde dissection is then performed as previously described (Fig. 73-11). The lingular vein, which is the lowest tributary of the superior pulmonary vein, is identified and transected as the final step (Fig. 73-12).

tahir99-VRG vip.persianss.ir

Ch073-F06861.indd 891

1/21/2008 2:12:09 PM

892

Section 3 Lung

Pulmonary vein to lingula

Lingular bronchus ligated

Superior segmental artery

A

B FIGURE 73-11 A and B, Traction on specimen bronchus and dissection of the intersegmental plane.

Ligated lingular vein

Intersegmental vein

and sutured, and the segment is removed as previously described. Basal Segments. The dissection proceeds as described for the superior segment. After the superior segmental and lingular arteries have been demonstrated, the basal arterial trunk with its three branches is dissected and divided. Posteriorly, basal segmental veins are divided, with care taken to preserve the superior segmental vein. After division of the vein, the basal bronchi are divided and sutured, and the segment is excised.

SUMMARY

FIGURE 73-12 Completed lingulectomy. The divided lingular vein is demonstrated.

Left Lower Lobe Superior Segment. The posterior mediastinal pleura is incised medial to the vagus nerve; the inferior pulmonary ligament is divided; and the oblique fissure is opened. Dissection of the pulmonary artery commences where it enters the oblique fissure. The superior segmental artery arises from the posterolateral surface of the interlobar artery at a slightly lower level than the posterior segmental artery to the upper lobe. There may be two superior segmental arteries. They are divided after demonstration of the lingular arteries originating anteriorly and the basal arterial trunks. The uppermost tributary of the inferior pulmonary vein is the superior segmental vein, which lies slightly inferior to the bronchus. It crosses the basal bronchus to enter the inferior pulmonary vein. After division of the vein, the bronchus is readily divided

Segmental resection was designed for and is admirably suited to the surgical management of bronchiectasis and tuberculosis, which are benign diseases with multisegmental and bilateral distribution. Salvage of functional parenchyma is of paramount importance in such cases. These diseases have largely disappeared from thoracic surgery services in developed nations because of improvements in social hygiene and the availability of antibiotics. Considering also the dismal reality that thoracic surgery training is an atrophied appendage to many cardiothoracic programs and the attrition in the ranks of thoracic surgeons who have mastered segmental resection, McElvein’s5 comment that “few of these resections are now being performed and many thoracic surgeons are not familiar with this method” is understandable. Fortunately, a few major teaching institutions have kept the technique of segmental resection alive and have used it not only for patients with compromised respiratory reserve but also for patients who could tolerate lobectomy. The development of single-lung anesthesia and improved stapling devices has made wedge resection an almost irresistible alternative to anatomic segmental resection. Huge wedges of parenchyma may be excised without regard to anatomic

tahir99-VRG vip.persianss.ir

Ch073-F06861.indd 892

1/21/2008 2:12:18 PM

Chapter 73 Segmental Resection

planes. Despite warnings that distortion of residual parenchyma might lead to pleural complications such as empyema and bronchopleural fistula, documentation of these events is lacking in the surgical literature. Commonly, the stapled residual lobe has a grotesque appearance in the open chest, but the postoperative radiograph is quite satisfactory.6 Ravitch and Steichen7 stated that, “with the advent of mechanical sutures, the classic anatomical segmental resection has become a technique of the past.” They acknowledged, however, that preliminary ligation of the segmental artery and the bronchus may still be useful. It is our opinion that stapling devices are a useful adjunct to the classic technique of segmental resection, especially in patients with marginal pulmonary function. It is in this group that avoidance of prolonged air leak is critical. Careful sequential application of a stapler along the demonstrated intersegmental plane of a partially expanded lobe minimizes distortion and loss of volume of the remaining lobar segments. If air leak is controlled and the bronchi are patent, pleural space problems are unlikely to occur. There is general agreement that patients with compromised pulmonary function caused by intrinsic lung disease or prior resection are offered limited resection, if this is feasible. Miller and Hatcher (Miller and Hatcher, 1987)8 defined the criteria: maximum breathing capacity greater than 35% of predicted, forced expiratory volume in 1 second (FEV1) greater than 0.6 L, and forced expiratory volume between 25% and 75% of expiration (FEV25-75) greater than or equal to 0.6 L. If pulmonary function values are less, the patient is not considered a candidate for limited resection. Local recurrence after segmental resection has been reported in 12% to 35% of cases and commonly occurs in patients in whom the tumor has crossed an intersegmental plane (Miller and Hatcher, 1987).8 Jensik9 reported a 55% 5-year survival rate with a 12% local recurrence rate. In some of these cases, completion lobectomy was possible, which suggests that lobectomy could have been tolerated at the initial operation. The incidence of local recurrence after segmental resection has led to controversy regarding its applicability for patients who could tolerate lobectomy. Proponents of segmental resection reason that incomplete fissures between lobes do not afford lobectomy a wider margin about the tumor than does segmental resection.4 Nevertheless, the 12% local recurrence rate for T1 N0 lung cancer (with tumor size <3 cm) is disturbing. Martini and others (Ginsberg and Rubenstein, 1995)10,11 reported a local recurrence rate of 19% after segmental resection or wedge excision and no local recurrences after lobectomy. Since the preparation of this chapter from the previous edition of this text, a spate of reports on the use of segmentectomy for small (<2 cm) carcinomas has appeared, notably from Japan. In one of them (Okada et al, 2005),12 the 5-year

893

cancer-specific survival rate in stage I disease with a tumor size of 2 cm or less was 96.7% after segmentectomy, 92.4% after lobectomy, and 85.7% after wedge resection. With tumors 21 to 30 mm in diameter, the survival rates were 87.4% after lobectomy, 84.6% after segmentectomy, and 39.4% after wedge resection. With tumors larger than 30 mm in diameter, the 5-year cancer-specific survival rates were 81.3% after lobectomy, 62.9% after segmentectomy, and 0% after wedge resection. The inferior results noted with wedge resection are evident in other series.13 In fact, the inclusion of wedge resection with segmental resection in series of limited resections may be responsible for the inferior results reported (Ginsberg and Rubenstein, 1995).11 Intraoperative brachytherapy has been combined with segmental resection in small (<2 cm) stage IA cases of non–small cell lung cancers; in one study,14 the local recurrence rate was reduced from 17.2% to 3.3%. As advances in imaging technology allow for earlier diagnosis of lung cancer, the indications for segmental resection may expand beyond its current applications to benign tumors, metastases, and inflammatory lesions, as well as lung cancers 2 cm or less in diameter.

COMMENTS AND CONTROVERSIES There is general consensus that anatomic lobectomy is the resection of choice for most patients with early-stage lung cancer. However, segmental resection remains an important parenchymasparing procedure. It has a particular role in the operative management of inflammatory lung disease, where sparing useful lung is a paramount consideration. The technical details of the various segmental resections are precisely described and beautifully illustrated. Of particular interest are the recent reports of Okada’s group, noted by the author, describing segmental sleeve resection for the management of small stage I lung cancers. Operative results and long-term survival are excellent, certainly equivalent to previously published experience with lobectomy. G. A. P.

KEY REFERENCES Churchill ED, Belsey R: Segmental pneumonectomy in bronchiectasis. Ann Surg 109:481-499, 1939. Miller JI, Hatcher CR: Limited resection of bronchogenic carcinoma in the patient with marked impairment of pulmonary function. Ann Thorac Surg 44:340-343, 1987. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1N0 non small cell lung cancer. Ann Thorac Surg 60:615-623, 1995. Okada M, Nishio W, Sakamoto T, et al: Effect of tumor size on prognosis in patients with non–small cell lung cancer: The role of segmentectomy as a type of lesser resection. J Thorac Cardiovasc Surg 129:8793, 2005.

tahir99-VRG vip.persianss.ir

Ch073-F06861.indd 893

1/21/2008 2:12:27 PM

CHAPTER 73 REFERENCES 1. Kramer R, Glass A: Bronchoscopic localization of lung abscess. Ann Otol Rhinol Laryngol 41:1210,1932. 2. Churchill ED, Belsey R: Segmental pneumonectomy in bronchiectasis. Ann Surg 109:481-499, 1939. 3. Kent EM, Blades B: The anatomic approach to pulmonary resection. Ann Surg 116:782, 1942. 4. Overholt RH, Langer L: The Technique of Pulmonary Resection. Springfield, MO, Charles C Thomas, 1951. 5. McElvein RB: Commentary on Landreneau SR, Johnson JA, Hazelrigg SR: Neodymium:yttrium-aluminum garnet laser-assisted pulmonary resections. Ann Thorac Surg 51:973, 1991. 6. Kittle CF: Atypical resections of the lung: Bronchoplasties, sleeve resections, and segmentectomies—their evolution and present status. Curr Probl Surg 26:57-132, 1989. 7. Ravitch MM, Steichen FM: Atlas of General Thoracic Surgery. Philadelphia, WB Saunders, 1988, p 200. 8. Miller JI, Hatcher CR: Limited resection of bronchogenic carcinoma in the patient with marked impairment of pulmonary function. Ann Thorac Surg 44:340-343, 1987.

9. Jensik RJ: The extent of resection for localized lung cancer: Segmental resection. In Kittle CF (ed): Current Controversies in Thoracic Surgery. Philadelphia, WB Saunders, 1986. 10. Martini N, McCaughan BC, McCormack PM, et al: The extent of resection for localized lung cancer: Lobectomy. In Kittle CF (ed): Current Controversies in Thoracic Surgery. Philadelphia, WB Saunders, 1986. 11. Ginsberg RJ, Rubenstein LV: Randomized trial of lobectomy versus limited resection for T1N0 non small cell lung cancer. Ann Thorac Surg 60:615-623, 1995. 12. Okada M, Nishio W, Sakamoto T, et al: Effect of tumor size on prognosis in patients with non-small cell lung cancer: The role of segmentectomy as a type of lesser resection. J Thorac Cardiovasc Surg 129:87-93, 2005. 13. Cerfolio RJ, Allen MS, Trastek VF, et al: Lung resection in patients with compromised pulmonary function. Ann Thorac Surg 62:348351, 1996. 14. Fernando HC, Santos RS, Benfield JR, et al: Lobar and sublobar resection with and without brachytherapy for small stage IA nonsmall cell lung cancer. J Thorac Cardiovasc Surg 129:261-267, 2005.

1 tahir99-VRG vip.persianss.ir

Ch073(R)-F06861.indd 1

1/21/2008 1:36:18 PM

chapter

74

BRONCHOPLASTY François Tronc Jocelyn Grégoire Jean Deslauriers

Key Points ■ Bronchoplasty is a parenchyma-saving operation in which a

segment of main bronchus is removed in continuity with a lobe. ■ Bronchoplasty is an adequate cancer operation for both compro-

mised and uncompromised lung cancer patients. ■ In all reported series, lesions located in the hilum of the right upper

lobe are the most common indications for bronchoplasty. ■ All lobes and individual segments may, on occasion, be involved

with tumors that are amenable to bronchoplastic procedures. ■ Good knowledge of the topographic anatomy of the tracheobron-

chial tree and of its blood supply is necessary to reduce postoperative morbidity. ■ Bronchoplasty can be carried out with low operative mortality and morbidity even after induction therapies. ■ In lung cancer patients, survival after bronchoplasty is highly dependent on the surgeon’s ability to perform a complete resection of the tumor. ■ In lung cancer patients with similar cancer stages, bronchoplasty provides long-term survival figures comparable or even better than those observed after pneumonectomy.

Bronchoplasty was first described as a compromised operation for lung cancer patients whose pulmonary reserve was considered inadequate to permit pneumonectomy. Since then, however, several authors have suggested that bronchoplasty may provide as good if not better results than pneumonectomy in selected cases of primary lung cancer involving the proximal bronchial tree. A review of the literature identifies an increasingly large number of clinical series suggesting that this operation has now been widely adopted in major centers throughout the world and that all pulmonary lobes or even segments are amenable to some form of lung-sparing bronchoplastic procedure. As a general statement, bronchoplasties should be considered in any case of lung cancer that can be completely resected by these techniques.

HISTORICAL NOTES In 1947, Sir Clement Price Thomas, surgeon to the Westminster and the Brompton hospitals in London, performed a circumferential resection of the right main bronchus for an adenoma projecting out of the origin of the right upper lobe bronchus and occluding the main bronchus.1 The operation,

which was done in a young flying cadet who was awaiting his commission in the Royal Air Force, was a success and the patient was able to resume his work as a pilot in active flying duties. In 1952, Price Thomas carried the concept further in the treatment of a patient with a tuberculous stricture of the left main bronchus associated with a destroyed left upper lobe.1 This case in which the lower lobe was saved by resecting the stricture and anastomosing the divided ends of the main bronchus showed that when two ends of a bronchus are sewn together they can unite in the same way as two pieces of intestine.2 Shortly thereafter, in 1956, Allison2 reported the first case of bronchogenic carcinoma treated by right upper lobectomy, sleeve resection of the right main bronchus, as well as partial elliptical resection of the right main pulmonary artery. The first significant and comprehensive report on the clinical use of bronchoplasty is that of Paulson and Shaw, in 1955,3 who reviewed 18 patients in whom sleeve resection had been done for a variety of benign and malignant bronchial processes. In that article, the authors showed that bronchoplastic procedures were feasible and they stressed the importance of preserving functional lung in cancer operations often performed in patients with limited reserve due to chronic obstructive pulmonary disease. A follow-up article by the same authors4 showed that in cases of lung cancer, bronchoplastic procedures could be done deliberately in uncompromised individuals. In 1959, Johnston and Jones5 from the Brompton Hospital and the London Chest Hospital, London, and the Baguley Hospital in Manchester reported a series of 98 patients with lung cancer treated by sleeve resection. They concluded that bronchoplasties were safe operations (operative mortality of 8%) and that the early follow-up results were no worse than the results achieved by more conventional types of pulmonary resections. In 1984 and 1986, Faber and Jensik and their colleagues6,7 described their extensive experience and provided the most comprehensive reports on sleeve lobectomy that had yet to be published. They concluded that sleeve lobectomy was a safe procedure and when technically feasible should be considered the procedure of choice for bronchogenic carcinoma. The last historically significant series popularizing sleeve lobectomy was that of Vogt-Moykopf and coworkers, which was published in 1986.8 In that article the authors reviewed indications, surgical techniques, and results of bronchoplastic

894 tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 894

1/21/2008 1:37:19 PM

Chapter 74 Bronchoplasty

895

operations that they suggested should be done more liberally than ever before. HISTORICAL READINGS Allison PR: Personal communication, quoted by Johnston JB, Jones PH: The treatment of bronchial carcinoma by lobectomy and sleeve resection of the main bronchus. Thorax 14:49, 1959. Faber LP, Jensik RJ, Kittle CF: Results of sleeve lobectomy for bronchogenic carcinoma in 101 patients. Ann Thorac Surg 37:279-285, 1984. Jensik RJ, Faber LP, Kittle CF: Sleeve lobectomy for bronchogenic carcinoma: The Rush-Presbyterian–St-Luke’s Medical Center experience. Int Surg 71:207-210, 1986. Johnston JB, Jones PH: The treatment of bronchial carcinoma by lobectomy and sleeve resection of the main bronchus. Thorax 14:48-54, 1959. Paulson DL, Shaw RR: Preservation of lung tissue by means of bronchoplastic procedure. Am J Surg 89:347-355, 1955. Paulson DL, Shaw RR: Results of bronchoplastic procedures for bronchogenic carcinoma. Ann Surg 151:729-740, 1960. Price Thomas C: Conservative resection of the bronchial tree: A lecture delivered before the fellows of the college in October 1955. J R Coll Surg (Edinb) 1:169-186, 1956. Vogt-Moykopff I, Fritz TH, Meyer G, et al: Bronchoplastic and angioplastic operation in bronchial carcinoma: Long-term results of a retrospective analysis from 1973 to 1983. Int Surg 7:211-220, 1986.

FIGURE 74-1 Anterior view of the distal trachea, carina, and right and left bronchial tree. Note that on the right side the presence of the bronchus intermedius makes it easier to perform right upper lobe sleeve resections.

ANATOMY Topographic Anatomy of the Tracheobronchial Tree The trachea originates below the cricoid cartilage and extends from front to back to the carina, which is located at about the level of the fourth thoracic vertebra. At that point, the trachea bifurcates into right and left main stem bronchi. The right main bronchus is in direct line with the trachea, and its length from carina to upper lobe takeoff varies between 1.5 and 2.0 cm. Distal to the right upper lobe bronchus, the primary bronchus becomes the bronchus intermedius, which has a length of approximately 2 cm. The presence of the bronchus intermedius (Fig. 74-1) explains, in part, why sleeve resections are more frequently done in association with right upper lobectomies (Box 74-1). The middle lobe bronchus arises from the anterior surface of the bronchus intermedius almost in direct line with the origin of the superior segmental bronchus of the lower lobe, which arises from the posterior wall of the bronchus intermedius. In some cases of right upper lobe bronchoplasties, the distal bronchotomy may fall close to the takeoff of these two segmental bronchi, and care must be taken to preserve them while doing the reconstruction. The left main bronchus arises from the carina at a more oblique angle than the right main bronchus. It is 4 to 6 cm long (versus 1.5 cm for the right main bronchus), and it passes under the aortic arch to lie posteriorly in the left hilum. It then bifurcates to form the upper and lower lobe bronchi. The greater length of the left main bronchus gives the surgeon increased possibilities for left upper lobe sleeve resection, but the adjacent aorta often interferes with proper exposure for the anastomosis. The lower lobe bronchus gives

Box 74-1 Topographic Anatomy of the Bronchial Tree ■ On the right side, the presence of a bronchus intermedius makes

a sleeve resection technically easier. ■ The greater length of the left main bronchus gives increased pos-

sibilities for left upper lobe sleeve resections, but the aorta may interfere with proper mobilization and exposure for anastomosis. ■ The left recurrent nerve is vulnerable during bronchoplasties involving the left main bronchus. ■ Anastomosis between main bronchi and lobar bronchi may be more difficult because of greater caliber mismatch.

off its first segmental bronchus, the superior segmental bronchus, posteriorly 0.5 cm from the left upper lobe orifice. The absence of bronchus intermedius and this particular arrangement of segmental bronchi make reconstruction of the bronchial tree after sleeve resection on the left side more difficult than on the right side. Indeed, the distal bronchial section after left upper lobe sleeve resection is often dictated by the level of the orifice of the bronchus to the apical segment of the left lower lobe. Because of its anatomic location, the left recurrent laryngeal nerve is vulnerable during bronchoplasties involving the proximal left main bronchus. The left recurrent laryngeal nerve originates close to the ligamentum arteriosum, where it courses from front to back around the aorta before ascending in the neck in the tracheoesophageal groove (Fig. 74-2). During bronchoplasties, it is vulnerable on opening of the mediastinal pleura and dissection of the aortopulmonary region.

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 895

1/21/2008 1:37:19 PM

896

Section 3 Lung

Right vagus nerve (X)

Left vagus nerve (X)

Right intercostal artery

Right intercostal artery

Right recurrent laryngeal nerve

Right bronchial artery

Left bronchial artery

Left recurrent laryngeal nerve

Ligamentum arteriosum

FIGURE 74-2 Anatomy of the left and right recurrent laryngeal nerves. (COURTESY OF DR. CLEMENT A. HIEBERT.)

FIGURE 74-3 The most common bronchial artery anatomy is one right artery arising from an intercostal artery and two left arteries with separate origins. The next three most common bronchial arterial arrangements are shown at the bottom of the figure. (COURTESY OF DR. THOMAS RICE.)

There is sometimes a significant difference in airway diameter between main bronchi (greater diameter), bronchus intermedius, and lobar bronchi. On the right side, the difference in diameter between main bronchus and bronchus intermedius is minimal, thus making an end-to-end anastomosis fairly easy. Anastomosis between main bronchus and lower bronchi such as is necessary after sleeve bilobectomies or sleeve lower lobectomies with reimplantation of the upper lobe may, however, be more difficult because of greater caliber mismatch.9

Blood Supply and Innervation of the Lower Trachea and Bronchi Because most anastomotic complications occurring after bronchoplasties are directly related to the disruption of the systemic mucosal blood flow at the level of the anastomosis,10,11 operating surgeons must have a clear understanding not only of the topographic anatomy of the vascular supply to the bronchi but also of the rich network of anastomosis and interconnections that exist between the systemic bronchial circulation and the pulmonary arterial system (Box 74-2). Most importantly, they must understand potential risk

Box 74-2 Blood Supply of the Bronchi ■ Most anastomotic complications are due to the disruption of sys-

temic blood flow. ■ More commonly there are two bronchial arteries on the left side

and one on the right side. ■ At the level of lobar and segmental bronchi there is a rich anasto-

motic network between bronchial and pulmonary circulations.

factors such as extensive peribronchial dissection,12 radical lymphadenectomy,13 or high-dose preoperative irradiation10 that may have an effect on the tracheobronchial circulation and thus on anastomotic healing. Although the level of origin, number, and distribution of bronchial arteries is quite variable,14,15 most arise separately from the anterolateral aspect of the descending thoracic aorta or from intercostal arteries located within 2 to 3 cm distal to the left subclavian artery. Most commonly, there are three bronchial arteries, two on the left side and one on the right side (Fig. 74-3).

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 896

1/21/2008 1:37:19 PM

Chapter 74 Bronchoplasty

This particular arrangement is one of the reasons why the right main bronchus is more susceptible to ischemia than its left counterpart. The bronchial arteries circulate posteriorly to the airway where they lie on the membranous portion of main stem bronchi and where they eventually divide to supply lobar and segmental bronchi. On the right side, the single bronchial artery runs parallel to the azygos vein by which it is overlapped. One interesting feature of the bronchial circulation system is the rich anastomotic network interconnecting it with the pulmonary arterial circulation.16 This network is not significant at the level of the carina or main bronchi, but more distally, such as at the level of the lobar or segmental bronchi, the pulmonary circulation may account for up to 75% to 90% of the airway blood supply. This arrangement becomes an important consideration when selecting the level of the distal bronchotomy in cases of sleeve resections. Indeed, distal bronchial transection should always be made as close as possible to the origin of lobar bronchi. In an interesting experimental study conducted several years ago, Kiriluk and Merendino17 were able to demonstrate that healing of bronchial anastomosis was not influenced by the manner of interruption of the bronchial vascular supply and that proximal and distal bronchi could be transected transversely or obliquely in any plane. Thus, after sleeve resection, both bronchial ends can be tailored in such a way as open ends of equal size are available for end-to-end anastomosis. Most of the venous drainage from the bronchial arterial system empties into the pulmonary veins, while the rest empties into bronchial veins located around the segmental

Trachea

Right pulmonary artery

897

and subsegmental bronchi.18 These bronchial veins subsequently empty into the azygos and hemiazygos systems.

Topographic Anatomy of the Pulmonary Arterial System The main pulmonary artery originates from the right ventricle (Fig. 74-4), and its axis is oriented in an anteroposterior direction, slightly upward and to the left. Below the aortic arch, it bifurcates into right and left main pulmonary arteries. The right pulmonary artery runs horizontally (Fig. 74-5A) to the right behind the ascending aorta and superior vena cava and below the carina. More than three fourths of its length is inside the pericardium. As it leaves the pericardium, it lies anterior to the right main bronchus and it is at that particular level that most bronchovascular fistulas have been reported after sleeve resection (Tedder et al, 1992).19-21 Circumferential wrapping of the anastomosis with viable tissue flaps will provide a mechanical cushion between the anastomosis and the pulmonary artery, thus lowering significantly the risk of such a complication. Shortly after having given off its first branch, the truncus anterior (superior division of the pulmonary artery), the right pulmonary artery curves inferiorly between the bronchus intermedius posteriorly and the superior pulmonary vein anteriorly. The left pulmonary artery passes inferiorly and posteriorly (see Fig. 74-5B) before exiting the pericardium under the aortic arch (aortopulmonary window). It then lies above the left main bronchus and will curve around three fourths of

FIGURE 74-4 Anteroposterior view of the pulmonary artery branching and its relationship to the bronchial tree. (COURTESY OF DR. ERINO A.

Apicoposterior branch

RENDINA.)

Left main bronchus Apical and posterior bronchi Left Anterior pulmonary bronchus artery Anterior branch

Right main bronchus Superior division of the pulmonary artery Upper lobe bronchus

Lingular bronchi

Apicoposterior branch

Lingular branches

Middle lobe branch

Basilar branches

Basilar branches

Pulmonary trunk Bronchus intermedius Middle lobe bronchus

Upper lobe bronchus Basilar bronchi

Basilar bronchi

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 897

1/21/2008 1:37:22 PM

898

Section 3 Lung

B

A

Apicoposterior branch

Superior division of the pulmonary artery

Trachea

Upper lobe bronchus

Right main bronchus

Anterior branch

Left main bronchus

Right pulmonary artery Apicoposterior branch

Superior segmental bronchus

Lingular Superior branches segmental artery

Left pulmonary artery

Superior segmental bronchus

Middle lobe branch Pulmonary trunk

Basilar branches

Upper lobe bronchus

Basilar branches

Lingular bronchus Middle lobe bronchus

FIGURE 74-5 A, Lateral view of the right pulmonary artery. B, Lateral view of the left pulmonary artery. (COURTESY OF DR. ERINO A. RENDINA.)

the circumference of the left upper lobe bronchus. In the interlobar fissure, the left main pulmonary artery gives rise to the lingular artery (anteromedially) and superior segmental artery (posterolaterally) before ending in the arteries of the basal segments. Because the left pulmonary artery curves around 60% to 75% of the circumference of the origin of the left upper lobe bronchus, left upper lobe sleeve resection combined with resection of the pulmonary artery is the most common type of bronchovasculoplasty.

Oncologic Anatomy of Lung Cancer Applicable to Bronchoplasties In 1956, Nohl22 reported the results of a detailed analysis of the lymphatic and vascular spread of bronchogenic carcinoma in which he emphasized the predictability of upper lobe lymphatic drainage. He showed that right upper lobe carcinomas may metastasize to nodes located below the right upper lobe bronchus (sump of Borrie) but seldom involve nodes located below a line drawn from the middle lobe bronchus to the bronchus of the superior segment of the lower lobes, thus justifying the use of sleeve lobectomy in such instances. Similarly, left upper lobe tumors give rise to nodal metastasis in the fissure above the apical branch of the lower lobe bronchus but generally do not infiltrate nodes below that level.

INDICATIONS In all reported series, lesions in the hilum of the right upper lobe represent the most common indication for sleeve lobectomy. This relates to the anatomic structure of the right main bronchus and the relatively long bronchus intermedius. The

left upper lobe is the next most common site of sleeve resection. As a general rule, all lobes and even segments23 of the lung may on occasion be involved with tumors that are amenable to some form of lung-sparing bronchoplastic procedure.

Noncompromised Patients Sleeve resection is an accepted operation for patients who could tolerate a pneumonectomy but in whom the surgeon judges that a complete resection is possible with a bronchoplastic procedure. It is ideal for tumors of low or intermediate grade such as typical carcinoids24-27 and for benign post-traumatic or tuberculous bronchial strictures.28 During the past 20 years, there has been an increasing acceptance for the application of bronchoplasties as the best elective operation in selected cases of lung cancer patients without compromised function and capable of tolerating any extent of resection. In one interesting study, Martin-Ucar and associates29 showed that the rate of pneumonectomy decreased significantly with increasing experience with parenchyma-sparing surgery. They concluded that pneumonectomy can be avoided in a large proportion of patients with centrally located non–small cell lung cancer without adversely affecting outcome but with preservation of lung function. The use of sleeve resections when the carcinoma has spread to bronchopulmonary or hilar nodes (N1 disease) is more controversial, with the argument in favor of pneumonectomy in this setting being that tumor cells may involve peribronchial lymphatics and that, in such cases, pneumonectomy may afford better curability rates. There is some evidence, however, that such is not always the case and that N1 disease does not always mandate pneumonectomy when a sleeve

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 898

1/21/2008 1:37:24 PM

Chapter 74 Bronchoplasty

resection can achieve complete resection of the neoplasm (Rendina et al, 2002).30,31 In a nonrandomized study, Okada and colleagues32 paired 60 patients undergoing sleeve lobectomy with 60 patients undergoing pneumonectomy and concluded that sleeve lobectomy should be performed instead of pneumonectomy in patients with non–small cell lung cancer regardless of the nodal status providing that a complete resection could be achieved. In yet another paper, Okada and coworkers33 also suggested that extended sleeve lobectomies should even be considered because these lungsaving operations are safer than pneumonectomies and are equally curative. In most thoracic surgery centers, bronchoplastic techniques are currently used in 5% to 8% of patients with resectable lung cancer (Lowe et al, 1982; Rendina et al, 2002).31,34

Compromised Patients On occasion, sleeve resections can be indicated for patients with severe respiratory impairment that contraindicates pneumonectomy. In this group, the incidence of both anastomotic dehiscences and operative mortality is higher than when the operation is done in uncompromised patients. In addition, Weisel and colleagues35 have reported a 5-year survival of 18% in compromised patients who could undergo complete resection, but there were no survivors among patients who had incomplete resections.

SELECTION OF PATIENTS Preoperative Assessment Preoperative assessment is very important not only to adequately delineate tumor extent but also to estimate the functional status of the residual lung. Flexible bronchoscopy is thus a critical part of the evaluation, and it is the procedure that usually defines sleeve resection as a possible option at thoracotomy. In every such case, it is highly desirable that the thoracic surgeon himself carries out the preoperative bronchoscopy. The usual finding that identifies possible candidates for sleeve resection is the location of the tumor, which extends from distal segmental bronchi to the lobar origin or sometimes into the lumen of the main bronchus. During bronchoscopy, the operator must also observe bronchial motion during voluntary breathing and coughing because stiffness of the bronchial wall may indicate the presence of significant peribronchial tumor infiltration (Rendina et al, 2002).31 Computed tomography (CT) is a useful complement to bronchoscopy because this imaging modality is able to define tumor location and size as well as the extent of extraluminal growth. On occasion, magnetic resonance imaging, with its ability to provide direct images in multiple planes, can clarify equivocal CT findings.36 Ultimately, selective pulmonary arteriography may be required to accurately delineate the pulmonary arterial anatomy at the lobar level.37 Such information may be critically important in compromised patients in whom one wants to avoid an unnecessary thoracotomy. Regardless of the interpretation of the mediastinal nodes by CT, mediastinoscopy should be done in every patient in

899

whom sleeve lobectomy is contemplated because the presence of N2 disease at the tracheobronchial angle, even in microscopic amounts, will usually indicate the need for pneumonectomy. In patients with benign and long-standing obstructions, one must be certain that the lung to be preserved is healthy; and, in these instances, CT and isotopic ventilation-perfusion scans are of value.

Intraoperative Assessment Probably the most difficult aspect of bronchoplasties is to determine their feasibility at thoracotomy based on intraoperative findings such as extraluminal growth of the tumor, presence of N1 nodes at the bronchopulmonary or hilar levels, or even evidence of cancer at the resection margin of the bronchus after standard lobectomy. Indeed, the feasibility of a sleeve resection is often determined only after full mobilization of the involved bronchi and pulmonary artery (main and lobar branches) and pathologic examination of lobar and hilar nodes. Frozen section evaluation of bronchial resection margins is a critical feature of the operation because the definition of complete resection is essential to the decision to carry out a bronchoplastic procedure. For lung cancer operations, a tumor-free margin of 1 cm on both sides of the origin of the lobar bronchus is generally considered to be sufficient,38 whereas for low-grade malignancies, a 5-mm margin is adequate.39 The presence of positive nodes at the origin of the lobar bronchus is not a contraindication to sleeve resection, but the presence of metastatic nodes along the bronchus intermedius in cases of right upper lobe carcinomas may require that the middle lobe be included in the sleeve. On the left side, nodal involvement in the oblique fissure often requires left pneumonectomy for adequate tumor clearance.

SURGICAL TECHNIQUES General Principles of Circumferential Sleeve Bronchoplasties (Box 74-3) Sleeve resections are usually done through a standard posterolateral thoracotomy, and split lung ventilation through the use of double-lumen tubes or endobronchial blockers is desirable. During the opening of the chest, a pedicled intercostal muscle flap can be mobilized for later use as a reinforcement around the anastomosis (Rendina et al, 2002).31 After the thorax has been opened, the surgeon must confirm the preoperative findings, including the location and extent of the primary tumor and the status of the lymphatic spread. Despite the fact that this part of the operation may be difficult because of the presence of a large central mass impairing access to the hilum, the surgeon must be careful during the dissection to preserve systemic vessels entering the distal lobe. Once the lobe to be removed has been fully mobilized in an oncologic fashion, the pulmonary artery branches and pulmonary veins are ligated and divided in a standard fashion. The next step is to carefully divide circumferentially the involved bronchi to achieve adequate margins (Fig. 74-6), and

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 899

1/21/2008 1:37:25 PM

900

Section 3 Lung

Box 74-3 General Surgical Principles for Circumferential Bronchoplasty ■ Posterolateral thoracotomy is the preferred incision. ■ Split lung ventilation is desirable. ■ Confirmation of preoperative findings including extent of the tumor

and lymph node status must be done first. ■ Preservation of systemic vessels entering the hilum of the distal

lobe is important. ■ Pulmonary artery branches and pulmonary vein are divided in

standard fashion. ■ Proximal bronchial division is made as close as possible to the

origin of the main bronchus. ■ Distal bronchial division is close to lobar segmental subdivision. ■ The status of bronchial margins should be checked with intraop-

erative frozen section analysis. ■ Adequate mobilization of the distal lobe is necessary.

FIGURE 74-6 Diagram showing division of the distal bronchial margin away from the tumor. (COURTESY OF DR. R. J. GINSBERG.)

■ Approximation of bronchial ends can be achieved with interrupted

or running absorbable sutures. ■ Luminal disparity is corrected by uneven spacing of sutures (see

Box 74-4). ■ Air tightness of the anastomosis is checked by inflating the distal

lung. ■ The anastomosis should be covered with a viable tissue flap

(pleura, intercostal muscle, pericardial flap). ■ Bronchoscopy is always done before extubation to check the

anastomosis and aspirate residual blood and mucus from the distal lobe.

the status of the bronchial margins should be checked with intraoperative frozen section analysis. In the event of a positive resection margin either proximally or distally, the resection should be extended accordingly. As a general statement, the distal bronchus should be divided close to its segmental subdivisions to obtain the most robust pulmonary collateral circulation16 while the proximal bronchus should be divided as close as possible to the origin of the main bronchus to benefit from the most generous bronchial artery systemic supply. Before reconstructing the airway, the distal lung must be mobilized to ensure a tension-free anastomosis, and this usually involves release of the inferior pulmonary ligament in cases of upper lobe sleeve resections. The anastomosis is then constructed by careful end-to-end approximation of the two divided ends of the bronchi. This can be achieved in an interrupted fashion with sutures applied transmurally and knots tied outside (Fig. 74-7) the bronchial lumen or through a running technique.40 Although a variety of suture materials have been used in the past, most surgeons now recommend the use of absorbable sutures because this type of suture material minimizes complications such as anastomotic narrowing, expectoration of sutures, or granuloma formation.41,42 Any luminal disparity between bronchi of different sizes can easily be corrected by stretching the smaller lumen to the size of the larger one through space-suturing techniques (Box 74-4; Figs. 74-8 and 74-9). Other methods that have been described to circumvent this problem include excision

FIGURE 74-7 Anastomosis constructed in an interrupted fashion with sutures applied transmurally and knots tied outside the bronchial lumen. (COURTESY OF DR. R. J. GINSBERG.)

Box 74-4 Techniques for Correction of Luminal Disparity Between Bronchial Ends ■ Uneven spacing of sutures ■ Excision of a small wedge of the cartilaginous part of the larger

bronchus ■ Plication of the cartilage-membrane junction of the larger

bronchus ■ Correction at the level of the membrane portion of the

anastomosis ■ Telescoping technique

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 900

1/21/2008 1:37:25 PM

Chapter 74 Bronchoplasty

of a small wedge of the cartilaginous part of the proximal bronchus to reduce its diameter,43 plication of one of the cartilage-membrane angles,35 or correcting the disparity at the level of the membranous part of the anastomosis by taking larger bites on the side of the larger bronchus.6 On occasion a telescoping technique can also be used for the end-to-end anastomosis9 if there is an important mismatch in diameters between proximal and distal bronchus. Before completion of the anastomosis, catheter aspiration of the dependent lung should be done; and once completed, the anastomosis should be carefully checked for air tightness by asking the anesthetist to inflate the distal lung. Most authors recommend that the anastomosis be covered with some type of autogenous tissue (usually a pleural or intercostal pedicle flap44) to provide a mechanical cushion

FIGURE 74-8 Completed anastomosis; any luminal disparity has been corrected through uneven suture spacing. (COURTESY OF DR. R. J. GINSBERG.)

A

B

901

between the bronchial anastomosis and the adjacent branches of the pulmonary artery. This cushion will not only prevent bronchovascular fistulas but will also augment the development of a systemic circulation across the anastomosis. Once the operation is completed and the patient is ready to be extubated, flexible bronchoscopy should be done to make sure that the anastomosis is technically perfect and to aspirate residual blood and mucus from the distal lobe(s).

Specific Types of Circumferential Bronchoplasties Lobes of the Right Lung Most bronchoplasties are carried out on the right side, and right upper lobectomy with circumferential sleeve resection of the main bronchus is the most common of these operations (Fig. 74-10). In such cases, the hilum of the right upper lobe is first dissected and all attachments of the lobe are divided in a standard fashion, including the truncus anterior and posterior ascending branches of the pulmonary artery and the upper lobe vein preserving the middle lobe vein. The anterior and posterior surfaces of the right main bronchus and intermediate bronchus are then dissected and freed, and umbilical tapes are passed around them to be used for traction. The proximal bronchotomy (Fig. 74-11A) is made 4 to 5 mm from the origin of the main bronchus underneath the arch of the azygos vein (usually preserved), and the bronchus intermedius is divided at the orifice of the middle lobe to obtain bronchial ends of approximately the same caliber and to avoid having to use a long bronchus intermedius with poor vascular supply. Tumor extension across the horizontal fissure (minor fissure) to the middle lobe implies the removal of the middle lobe as well as the upper lobe. This can be done by extending the division of the bronchus intermedius distal to the orifice of the middle lobe bronchus (see Fig. 74-11B) or by dividing separately the middle lobe bronchus instead of including it in the main bronchial sleeve (see Fig. 74-11C).45 On rare occasions, a middle lobectomy with sleeve resection of the bronchus intermedius will be indicated (see Fig. 74-11D). In cases of right lower lobe proximal tumors, most surgeons will remove both the lower lobe and middle lobe and salvage

C

FIGURE 74-9 Alternative techniques that can be used to correct luminal disparity. A, Wedge resection of cartilage of larger bronchus. B, Plication of cartilage-membrane angle. C, Correction at the level of the membranous portion of the anastomosis.

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 901

1/21/2008 1:37:27 PM

902

Section 3 Lung

FIGURE 74-10 Possible indications for sleeve resection in patients with bronchogenic carcinomas of the right upper lobe. A, Central tumor located at the origin of the right upper lobe where standard lobectomy is not possible. B, Peripheral tumor with metastatic nodes at the lobar or hilar level. C, Larger tumor with direct contiguous invasion of lobar nodes.

A

B

C

FIGURE 74-11 Sleeve resections of the right lung. A, Right upper lobe. B, Upper and middle lobe by extending the division of the bronchus intermedius distal to the origin of the middle lobe bronchus. C, Upper and middle lobe by separate division of the middle lobe bronchus. D, Middle lobectomy with sleeve resection of the bronchus intermedius.

A

B

C

D

the upper lobe (Fig. 74-12A). In such cases, the upper lobe bronchus must be properly aligned with the main bronchus so that the pulmonary artery vascular supply and pulmonary venous drainage to the upper lobe is not compromised by kinking of these structures. In some cases, especially when the tumor is located more distally in the lower lobe (at the level of the basal segments), some authors46,47 are advocating the preservation of middle lobe that can be reimplanted in the bronchus intermedius (see Fig. 74-12B). Size disparity can be corrected by oblique division of the middle lobe bron-

chus or by a small wedge incision of the membranous portion of the middle lobe orifice.46

Lobes of the Left Lung Sleeve resections of the lobes of the left lung are done less commonly than on the right side not only because left pneumonectomy, which is the alternative, is better tolerated than right pneumonectomy but also because the topographic anatomy of the left bronchial tree and pulmonary artery

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 902

1/21/2008 1:37:28 PM

Chapter 74 Bronchoplasty

branches make the operation technically more difficult (no bronchus intermedius on the left side) and perhaps tumor clearance less than optimal. In cases of left upper lobectomy (Fig. 74-13A) with sleeve resection of the main bronchus, the greater length of the left main bronchus gives the surgeon increased possibilities for sleeve resection but the adjacent aorta often prevents effective mobilization and proper exposure for the anastomosis.

903

In addition, the absence of bronchus intermedius dictates the site of the distal bronchotomy, which often has to be done at the level of the orifice of the superior segmental bronchus of the left lower lobe. In general, the anastomosis is easier to construct by placing a tape around the pulmonary artery and retracting it anteriorly (the anastomosis is done posterior rather than anterior to the pulmonary artery). Left lower lobectomies with sleeve resection of the main bronchus and reimplantation of the upper lobe (see Fig. 7413B) are seldom indicated but are rather easy to do. Like the same operation on the right side, care must be taken to avoid misalignment of the pulmonary artery and especially of the upper lobe vein to avoid kinking with secondary obstruction.

Main Stem Bronchi

A

B FIGURE 74-12 Sleeve resections of the right lung. A, Lower and middle lobe. B, Salvage of the middle lobe by reimplantation in the bronchus intermedius.

Main stem bronchial sleeve resection is defined as the circumferential resection of either main stem bronchus without resecting any pulmonary parenchyma.48 The indications for operation are similar to those for sleeve lobectomy; and in one series of 22 patients, resection was for cancer in 15 patients (68%), benign stricture in 5 (23%), and impacted broncholith in 2 (9%).48 The operation is done through a posterolateral thoracotomy with the use of single-lung ventilation. After careful assessment of the resectability of the tumor, the operative technique involves full mobilization of the distal trachea and ipsilateral main bronchus, circumferential transection of the main bronchus proximal and distal to the lesion, removal of the main bronchial sleeve, and reconstruction in the same way as was described for sleeve lobectomies. On the left side, adequate exposure is more difficult owing to the aortic arch, which sometimes has to be partially mobilized and retracted upward and laterally. Some authors49 have stressed the importance of tracheal and bronchial traction to improve operative exposure. In cases of right main bronchus resections, a traction tape is placed around the trachea, whereas for left main bronchus resections, traction tapes are placed around both the distal trachea and right main bronchus. On the left side, the inferior pulmonary ligament has to be mobilized to release tension on the anastomosis whereas for right main bronchus resection, tension is generally not a

FIGURE 74-13 Sleeve resections of the left lung. A, Left upper lobe. B, Left lower lobe.

A

B

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 903

1/21/2008 1:37:29 PM

904

Section 3 Lung

problem, given the short length of the right main bronchus.49 In all cases of left main bronchial sleeve resection, the left recurrent nerve, which arises from the vagus nerve to the left of the aortic arch, must be carefully identified and preserved.

Segments Other types of bronchoplasties with segmental resection or anastomosis between a segmental bronchus and main bronchus can also be done in patients with centrally located early lung cancer or low-grade lung cancer.22,50,51 The most common of these operations involves the resection of the superior segments of the lower lobes, the lingula, or the superior truncus of the left upper lobe (Fig. 74-14). Once the dissected segment has been removed, the technique of anastomosis is the same as that described for lobar sleeve resection with spacing of the sutures if there is a disparity in lumen diameters between the bronchi to be anastomosed. Although segmental bronchoplasties are seldom indicated because most lung cancers cannot be completely resected by these techniques, the operation itself is fairly easy to do and the healing of the anastomosis is better than with sleeve lobectomies because there is less tension at the anastomosis and better blood supply from both pulmonary and systemic circulation and the site of the anastomosis is completely surrounded by lung tissue, which acts as a well-vascularized protecting flap.23 The negative pressure within the lung parenchyma also tends to pull the anastomosis in an outward direction, thus widening its diameter.

Wedge and Flap Reconstruction of the Bronchus Wedge resection of the main bronchus instead of a full circumferential bronchial sleeve has been reported infrequently as an alternative technique for preservation of lung tissue.52,53 In such cases, the wedge resection is carried out longitudi-

FIGURE 74-15 Wedge bronchoplasties. A, With right upper lobectomy (RUL). B, With left upper lobectomy (LUL). C, With left lower lobectomy (LLL). (REDRAWN

nally along the bronchus and the bronchial defect is reapproximated transversely53 (Fig. 74-15). In cases of flap bronchoplasties, a lobectomy and partial main bronchus wall resection is made in such a way that 2 to 3 cm of the unaffected lobar bronchus is preserved. This lobar remnant is spread out and used as a flap to cover the defect in the main bronchus53 (Fig. 74-16). Most surgeons believe, however, that both tumor and nodal clearance is less satisfactory with these procedures than it is LMBr

B1 + 2

1 2 3 4

B3

Ling Br LLBr FIGURE 74-14 Sleeve resection of the superior truncus of the left upper lobe preserving the anterior segment and the lingula segments. B1 + 2, bronchus to apicoposterior segment; B3, anterior segment; Ling Br, lingular bronchus; LLBr, left lower lobe bronchus; LMBr, left main bronchus. (REDRAWN WITH PERMISSION FROM TSUBOTA N: BRONCHOPLASTY AT THE LEVEL OF THE SEGMENTAL BRONCHUS. SEMIN THORAC CARDIOVASC SURG 18:96-103, 2006.)

RUL LUL

WITH PERMISSION FROM KHARGI K, DUURKENS VAM, VERSTEIGH MMI: PULMONARY FUNCTION AND POSTOPERATIVE COMPLICATIONS AFTER WEDGE AND FLAP RECONSTRUCTION OF THE MAIN BRONCHUS. J THORAC CARDIOVASC SURG 112:117-123, 1996. COPYRIGHT 1996, THE AMERICAN ASSOCIATION FOR THORACIC SURGERY.)

LLL

A

B

C

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 904

1/21/2008 1:37:30 PM

Chapter 74 Bronchoplasty

FIGURE 74-16 Flap bronchoplasties. A, With right upper lobectomy. B, With right lower lobectomy. C, With middle lobectomy. Ap, apical segment of upper lobe; A, anterior segment of upper lobe; AB, anterior basal segment of lower lobe; MB, medial basal segment of lower lobe; LB, lateral basal segment of lower lobe. (REDRAWN FROM KHARGI K,

RUL Ap RUL A

ML ML

AB LB

RLL

MB RLL

A

B

with full circumferential sleeve bronchoplasties. In addition, postoperative complications such bronchostenosis, bronchial deformity, and pneumonia have been reported to be more common, especially after wedge bronchoplasties.53

PERIOPERATIVE AND POSTOPERATIVE CARE In general, the postoperative care of the bronchoplasty patient is the same as that of any other patient who has had a more standard form of pulmonary resection. A good sense of observation, competency in the interpretation of clinical and radiologic signs, and experience in the supervision of postoperative patients are important attributes that the staff providing postoperative care must possess. Special attention must be given to adequate pain control usually through the use of spinal narcotics, proper fluid management, and use of other pharmacologic interventions when necessary. The problem of secretional retention, which may occur more often after sleeve resections, can be minimized by attention to postoperative posturing and chest physiotherapy, which is the mainstay of all regimens intended to prevent atelectasis and physically aid in the expulsion of retained endobronchial secretions. Breathing exercises, such as inhaling deeply before coughing, are meant to increase total lung capacity and, therefore, cough force. Patients should also be encouraged to use maneuvers and devices (incentive spirometry) that will intermittently maximize lung inflation (sighing). When patients are unable to raise sputum, they should undergo bedside flexible bronchoscopy, which is the preferred method to aspirate mucus plugs under direct vision. In some centers, fiberoptic bronchoscopy is routinely done on the first postoperative day to observe the anastomosis and to aspirate sputum even if the patients have no abnormal symptoms.54 The use of corticosteroids during the early postoperative period to reduce the inflammatory response and edema at the site of the anastomosis is controversial and probably unnecessary. In one prospective randomized clinical trial55 to assess the safety and efficacy of corticosteroid administration

905

DUURKENS VAM, VERSTUGH MMI, ET AL: PULMONARY FUNCTION AND POSTOPERATIVE COMPLICATIONS AFTER WEDGE AND FLAP RECONSTRUCTION OF THE MAIN BRONCHUS. J THORAC CARDIOVASC SURG 112:117-123, 1996. COPYRIGHT 1996, THE AMERICAN ASSOCIATION FOR THORACIC SURGERY.)

C TABLE 74-1 Postoperative Complications of Sleeve Resection Sputum retention and secondary atelectasis Bronchovascular fistulas Anastomotic complications Edema Dehiscence Bronchopleural fistulas

in 20 patients undergoing sleeve lobectomy, it was found that low doses of methylprednisolone (10 mg) given intraoperatively and postoperatively associated with aerosolized hydrocortisone improved bronchial healing. The authors55 also concluded that the anti-edema effect of corticosteroids was beneficial because it reduced secretion retention and atelectasis and minimized the risk of dehiscence and granuloma formation at the level of the anastomosis.

RESULTS Postoperative Morbidity and Mortality Complications peculiar to sleeve resections (Table 74-1) are an increased incidence of retained secretions and atelectasis, bronchovascular fistulas, and the potential for anastomotic complications, such as edema, dehiscence, or bronchopleural fistulas. Distal atelectasis occurs in 5% to 6% of patients after sleeve resection,19 and it is due to sputum retention secondary to inability to cough, edema at the level of the anastomosis, and mucociliary dysfunction secondary to mucosal interruption and denervation of the distal lung. It is seen more often after sleeve resection of the lower lobes, where kinking of the anastomosis is potentially the greatest, and less often after sleeve resection of the upper lobes, where the distal lumen is made wider to meet the size of the proximal lumen. In sleeve resections of the right upper lobe, the high reimplantation of the bronchus intermedius into the proximal

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 905

1/21/2008 1:37:31 PM

906

Section 3 Lung

main bronchus also tends to reduce the degree of middle lobe kinking with secondary obstructive atelectasis. Bronchovascular fistula is almost always a lethal complication due to erosion of the adjacent pulmonary artery into the bronchial tree across the anastomosis. This complication, which is very rare (0%-1% in recent reviews) can be minimized by applying the principles for a healthy bronchial anastomosis (tension free, maintenance of circulation), by avoiding suture material with hard knots or ends, and by using a pedicled flap around the completed anastomosis. The incidence of anastomotic dehiscence with secondary bronchopleural fistula is in most series below 5%56 and because this complication is essentially technical, it can be prevented intraoperatively by preserving an adequate blood supply to the anastomosis. This can be achieved by avoiding too much dissection and overaggressive lymph node removal, by avoiding unnecessary devascularization, especially of the distal bronchus, and by performing careful approximation of the two ends of the bronchus. Wrapping of the anastomosis is considered by most authors to be an efficient maneuver to prevent dehiscence, especially when one uses a pedicled intercostal flap.57 A pleural flap can also be used58 efficiently to prevent this complication. In one interesting study,59 looking at risk factors for the development of postoperative complications inclusive of airway complications after bronchial sleeve resection for malignancy, the combination of respiratory and cardiovascular risk factors (P = .012, OR = .165) was predictive for overall complications and the authors concluded that comorbidity significantly influences the postoperative complication rate after bronchoplasties. In most series, the operative mortality after sleeve resection is below 5% (Tables 74-2 and 74-3), and the causes of death are usually related to the complications described previously.

plication is in the range of 2% to 5%, although in one series the incidence of early and late stricture formation was 23%.66 When this problem occurs, treatment should be, at least initially, conservative with bronchoscopic dilatation of the stricture and removal of granulomatous tissue to reestablish an adequate bronchial lumen. Tsang and Goldstraw66 have also shown that endobronchial stenting with a Silastic prosthesis may be a valid option in the treatment of this complication. In some rare cases, treatment will have to be surgical with resection of the stricture and reanastomosis or by completion pneumonectomy.

Long-Term Complications at the Level of the Anastomosis

Another potential issue with sleeve resection is whether local control of the cancer is as good as it is after pneumonectomy (Table 74-4).32,67,68 This issue is, however, difficult to appreciate in retrospective series because the definition of locoregional recurrence is often unclear as well as the steps that have been taken to demonstrate if local failure was present or not at the time of recurrence. Despite these methodologic difficulties, it appears that the incidence of locoregional recurrence is at least not worse after sleeve lobectomies than

Late anastomotic strictures are mainly related to interrupted bronchial blood supply to the distal bronchial segment, especially when there has been extensive nodal dissection or to anastomotic partial dehiscence with secondary granuloma formation. In most recent series, the incidence of this com-

Survival Results Most major reports document a 5-year survival of 45% to 50% (see Table 74-254,60-63) after bronchoplasties done for lung cancer; and in most of these reports, survival is adversely affected by the nodal status, particularly in N2 cases. The survival according to nodal status from recent studies is summarized in Table 74-3.54,64,65 The relationship between long-term survival after bronchoplasties and lymph node involvement remains, however, controversial; although many surgeons agree that sleeve lobectomy should be considered in any case of lung cancer that can be completely resected by the technique, some still believe that this approach is only applicable to N0 tumors and that pneumonectomy may be a better suited operation for patients with N1 or N2 disease. The argument in favor of a more extended resection in this setting is that tumor cells may involve peribronchial lymphatics and that, for those patients, pneumonectomy may afford better curability rates. There is some evidence, however, that N1 or N2 disease does not necessarily mandate pneumonectomy when a bronchoplasty can achieve complete resection (Rendina et al, 2002).31

Local Recurrences

TABLE 74-2 Operative Mortality and Survival Results After Sleeve Resection

No. Patients

Author (Year) Watanabe et al60 (1990) 61

Van Schil et al

5-Year Survival Rate (Overall) (%)

1.3

45

TABLE 74-3 5- and 10-Year Survival Rates After Sleeve Resection for Lung Cancer by Lymph Node Status 5-Year Survival (%)

10-Year Survival (%)

Author (Year)

No. Patients

N0

N1

N2

N0

N1

N2

145

4.8

46

Rea et al54 (1997)

217

6.2

49

Rea et al54 (1997)

179

72

36

22

59

27

14

Tronc et al (2005)

300

2.7

54

Icard et al64 (1999)

110

57

29

33

26

18

33

145

62

29

31

53

21

6

300

66

50

19

45

28

15

62

Nagayasu et al 63

Yildizeli et al

(1996)

94

Operative Mortality (%)

(2006)

(2007)

65

118

5.9

56

Van Schil et al

218

4.1

53

Tronc et al (2005)

(2000)

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 906

1/21/2008 1:37:31 PM

Chapter 74 Bronchoplasty

it is after pneumonectomy (see Table 74-4). In one series that looked specifically at local control of disease after bronchoplastic lobectomies, 22.5% of patients developed a locoregional recurrence after sleeve lobectomy but only 4.5% of patients died of isolated local recurrences.69

Functional Results and Quality of Life In 1974, Wood and colleagues70 reported the results of an experimental study that was conducted in mongrel dogs to compare pulmonary function after lobectomy with that after lobectomy plus sleeve resection. They found that oxygen uptake in the ipsilateral lung was deficient in the early postoperative period after sleeve resection but that this uptake improved in a few weeks time to approximate levels found after simple lobectomy. They were also able to demonstrate that perfusion was deficient in the immediate postoperative period after sleeve resection. In another study,71 comparison of preoperative and postoperative FEV1/FVC ratios in an unselected group of six patients showed that lobectomy with sleeve resection caused little impairment of lung function. Our own studies72 of postoperative lung function after sleeve lobectomy done in 19 patients, 5 or more years after the operation showed that the reimplanted lobe or lobes contribute significantly to the overall remaining function. Further-

TABLE 74-4 Local Failure Rates in Lung Cancer Treated by Sleeve Resection in Comparison to Pneumonectomy Local Relapse After Sleeve Lobectomy

Author (Year) Okada et al32 (2000) Kim et al

67

(2005)

Bagan et al

68

(2005)

Tronc et al (2005)

After Pneumonectomy

8%

10%

24%

9%

5%

8%

16%

35%

907

more, the operation resulted in no measurable functional loss when we compared preoperative and postoperative data. Other authors have showed complete recovery of the reimplanted lung lobes after sleeve lobectomy.73,74 In 2003, Ferguson and Lehman (Ferguson and Lehman, 2003)75 reported the results of a meta-analysis of results of sleeve lobectomy and pneumonectomy published in English between 1990 and 2003. For their analysis, a decision model was developed with 5-year survival, quality-adjusted life years (QALY), and cost effectiveness as the outcomes. In that model, sleeve lobectomy was strongly favored over pneumonectomy when the reward was QALY (1.53 QALY advantage).

SPECIAL ISSUES Sleeve Lobectomy Versus Pneumonectomy for Lung Cancer There have been several institutional studies (Table 74-5)30,32,58,67,76-79 that have compared survival results between sleeve lobectomy and pneumonectomy. All are retrospective because a randomized prospective trial is not possible, not only because of the small number of cases that would be available for study but also because of the definition of eligibility. Although each of these studies has obvious bias related to its retrospective nature, collectively they provide the most reliable information. All of them have shown that survival after sleeve resection appears to be no different or is even better than survival after pneumonectomy, provided that a complete resection can be achieved. In all of these series survival is adversely affected by the nodal status, but this is not considered a valid reason to extend the indication for pneumonectomy, again provided that complete resection is possible. In our own series30 there was no significant difference in survival between sleeve lobectomy and pneumonectomy for patients with N2 or stage III disease, indicating that even in higher-stage tumors, a more radical operation such a pneumonectomy is not a more appropriate procedure and does not necessarily lead to better survival figures.

TABLE 74-5 Comparison of Survival Between Sleeve Lobectomy and Pneumonectomy 5-Year Survival Author (Year)

No. Patients

Gaissert et al76 (1996) Yoshino et al Suen et al

58

77

(1997)

(1999)

Okada et al32 (2000) 30

Deslauriers et al Ludwig et al

78

(2004)

(2005)

Sleeve Lobectomy

Pneumonectomy

128

42% (N = 72)

44% (N = 56)

58

65.7% (N = 29)*

58.8% (N = 29)*

200

37.5% (N = 58)

35.8% (N = 142)

120

48% (N = 60)

28% (N = 60)

1230

52% (N = 184)

31% (N = 1046)

310

39% (N = 116)

27% (N = 194)

Kim et al67 (2005)

249

53.7% (N = 49)

59.5% (N = 200)

Takeda et al79 (2006)

172

54% (N = 62)

33% (N = 110)

*These are 3-year survival figures.

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 907

1/21/2008 1:37:32 PM

908

Section 3 Lung

Sleeve Lobectomy and Adjuvant Therapies 80

Paulson and colleagues were the first to suggest that preoperative radiotherapy could have a beneficial effect by downsizing the tumor and sterilizing the lymphatics. In their series of 20 patients who underwent sleeve resection after preoperative irradiation, only 1 developed a local recurrence. Jensik and coworkers81 also suggested that preoperative irradiation may be of value especially for compromised patients who could not tolerate a pneumonectomy and in whom they wanted to downsize the tumor so that a sleeve resection would be possible. There is currently, however, no evidence that this strategy has any impact on survival after bronchoplastic procedures. Several authors82-85 have reported that bronchoplastic techniques can be performed with low morbidity and mortality after induction therapy. In 2004, Rendina and associates82 reported on 53 patients treated with induction therapy followed by sleeve resection. In that series there was no operative mortality; no bronchopleural fistulas were reported, and the 5-year survival was 31%.

SUMMARY Sleeve resection is now widely accepted as an appropriate operation in patients with uncompromised pulmonary function who could tolerate a pneumonectomy. The surgical technique is not particularly difficult, but some intraoperative steps are important if one wants to avoid postoperative complications or local recurrences. For most patients, functional results after sleeve resection are significantly better than those observed after pneumonectomy.

COMMENTS AND CONTROVERSIES Bronchoplastic procedures, most commonly sleeve resection, are underutilized procedures. It could be said that the knowledge, expertise, and technical ability to appropriately apply sleeve resection for benign and malignant disease is a defining characteristic of the expert thoracic surgeon. Dr. Deslauriers and his colleagues have a long-standing reputation for scholarly contributions in this area. They carefully reviewed the relevant anatomic considerations. The appropriate selection criteria are outlined, especially the need for mediastinoscopy in any patient undergoing sleeve resection for bronchogenic cancer.

I believe that the surgical margins recommended by the authors (1 cm for lung cancer and 5 mm for low-grade malignancy) are often not practical or necessary. The proximal resection margin for sleeve resection can be at the level of the tracheal carina, that is, much more proximal than practical for pneumonectomy. This provides sleeve resection with an oncologic advantage over standard pneumonectomy. The technical points are all important and worthy of study. The anastomotic reconstruction must be precise. A pedicled flap should be used to cover the anastomosis to limit the likelihood of bronchovascular fistula. However, care must be taken to avoid a bulky flap, which can compress the pulmonary artery, impede pulmonary arterial flow, and result in subsequent distal airway infarction. It is important to remember that the bronchial artery flow is interrupted by the resection and the distal airway is supplied by collateral pulmonary vascular flow and systemic arterial collaterals through the pericardium. If a pericardial release is required to gain mobility and reduce tension, the pericardial incision should be limited so as to minimize disruption of collateral flow. Sleeve resection is an oncologically satisfactory procedure in wellselected patients. The operation provides superior functional results than pneumonectomy. It should be in the operative repertoire of every thoracic surgeon. G. A. P.

KEY REFERENCES Ferguson M, Lehman AG: Sleeve lobectomy or pneumonectomy: Optimal management strategy using decision analysis techniques. Ann Thorac Surg 76:1782-1788, 2003. ■ Meta-analysis comparing the results of sleeve resection versus those of pneumonectomy. Lowe JE, Bridgman AH, Sabiston DC: The role of bronchoplastic procedures in the surgical management of benign and malignant pulmonary lesions. J Thorac Cardiovasc Surg 83:227-234, 1982. ■ Excellent review article. Rendina EA, Venuta F, de Giacomo T, et al: Parenchymal sparing operations for bronchogenic carcinoma. Surg Clin North Am 82:589-609, 2002. ■ Addresses in details all issues pertinent to bronchoplasties. Tedder M, Anstadt MP, Tedder SD, Lowe JE: Current morbidity, mortality, and survival after bronchoplastic procedures for malignancy. Ann Thorac Surg 54:387-391, 1992. ■ Excellent review of the status of sleeve resection for lung cancer.

tahir99-VRG vip.persianss.ir

Ch074-F06861.indd 908

1/21/2008 1:37:32 PM

chapter

RECONSTRUCTION OF THE PULMONARY ARTERY

75

Erino A. Rendina Federico Venuta

Key Points ■ Oncologically complete resection should be primarily pursued. ■ Use of magnifying loops (2.5×) is essential. ■ Do not insist on wedge resection or patch reconstruction when a

sleeve with end-to-end anastomosis can ensure a larger caliber and a straight arterial axis. ■ Test the arterial axis and suture oozing after reinflation of the residual lobe; torsion of the arterial axis may cause oozing or torsion of the artery.

The pulmonary artery (PA) can be infiltrated by primary lung tumors or by metastatic hilar-mediastinal lymph nodes with extracapsular extension. The right and left PAs can be involved to various extents. Partial infiltration of the arterial wall may be limited and require only simple, tangential resection and direct suture. This technique is regarded as a variation of standard lobectomy and is not considered in this chapter. More extensive defects of the PA (Table 75-1) may require reconstruction by a patch (of various materials), sleeve resection and reconstruction by end-to-end anastomosis, or sleeve resection and reconstruction by a prosthetic conduit. If the main PA is infiltrated by advanced lung cancer, the reconstruction requires the use of cardiopulmonary bypass.

HISTORICAL NOTE The first report concerning resection and reconstruction of the PA in a patient with lung cancer was made by Allison in 1952. The vessel was partially infiltrated by tumor, and the technique employed was tangential resection and direct suture. Later, scanty descriptions of PA reconstructive procedures came from Thomas in 1956, Petrovsky and Perelman in 1966, and Wurning in 1967. The first study focusing on PA sleeve resection appeared in 1967; Gundersen described two patients with left upper lobe tumors that infiltrated the artery who were treated by PA sleeve resection and end-toend anastomosis, without complications. In 1971 Pichlmeier and Spelberg reported four successful cases of combined bronchial and vascular sleeve resections, and in 1974 VogtMoykopf published his first series of 39 angioplastic procedures of various types (Vogt-Moykopf, 1974). During the following decade, a limited number of cases were reported in different series (Bennett et al, 1978; Lowe, 1982; Weisel, 1979); however, no real breakthrough was made in PA reconstruction. Thoracic surgeons were concerned about technical difficulties and perioperative complications. Long-term survival did not seem to be advantageous, and pneumonectomy

was still considered oncologically more appropriate. The series of 37 PA sleeve resections published by Vogt-Moykopf in 1986 demonstrated that the operation was feasible with acceptable complications and good long-term survival, but it was not until very recently that lobectomy associated with resection and reconstruction of the PA has been demonstrated to be an advantageous alternative to pneumonectomy. HISTORICAL READINGS Allison PR: Course of thoracic surgery in Groningen. Quoted by: Jones PH: Lobectomy and bronchial anastomosis in the surgery of bronchial carcinoma. Ann R Coll Surg Engl 25:20, 1959. Bennett WF, Abbey-Smith R: A twenty-year analysis of the results of sleeve resection for primary bronchogenic carcinoma. J Thorac Cardiovasc Surg 76:840, 1978. Gundersen AE: Segmental resection of the pulmonary artery during left upper lobectomy. J Thorac Cardiovasc Surg 54:582, 1967. Kittle FC: Atypical resections of the lung: Bronchoplasties, sleeve resections, and segmentectomies—Their evolution and present status. Curr Probl Surg 26:57, 1989. Lowe JE, Bridgman AH, Sabiston DC Jr, et al: The role of bronchoplastic procedures in the surgical management of benign and malignant pulmonary lesions. J Thorac Cardiovasc Surg 83:227, 1982. Petrovsky B, Perelman M, Kuzmichev A: Resection and plastic surgery of bronchi. [Translated from the 1966 edition by L. Askenova.] Moscow, MIR Publishers, 1968. Thomas CP: Conservative resection of the bronchial tree. J R Coll Surg Edinb 1:169, 1956. Vogt-Moykopf I: Gefäβplastiken bei bronchusmanschettenresektion. Prax Klin Pneumol 28:1030, 1974. Vogt-Moykopf I, Frits TH, Meyer G, et al: Bronchoplastic and angioplastic operation in bronchial carcinoma: Long-term results of a retrospective analysis from 1973 to 1983. Int Surg 71:211, 1986. Weisel RD, Cooper JD, Delarue NC, et al: Sleeve lobectomy for carcinoma of the lung. J Thorac Cardiovasc Surg 78:839, 1979. Wurning P: Technische Vorteile bei der Hauptbronchusresektion rechts und links. Thorax Chir 15:16, 1967.

SURGICAL ANATOMY The main PA originates in the pericardial sac from the right ventricle, and its axis is oriented in an anteroposterior direction, slightly upward and toward the left. Below the aortic arch, the main PA divides into its right and left branches. The right PA (Figs. 75-1 and 75-2) runs horizontally to the right, behind the ascending aorta and the superior vena cava (SVC) and in front of the carina. Lateral to the SVC, the right PA lies in front of the right main bronchus, and it almost immediately gives rise to its first branch, to the right upper lobe (Boyden trunk). Shortly thereafter, the vessel curves 909 tahir99-VRG vip.persianss.ir

Ch075-F06861.indd 909

1/21/2008 1:37:59 PM

910

Section 3 Lung

TABLE 75-1 Techniques of Reconstruction of the Pulmonary Artery Partial infiltration

Patch reconstruction Autologous pericardium Bovine pericardium Azygos vein Synthetic

Complete circumferential infiltration

Pulmonary artery sleeve End-to-end anastomosis Pericardial conduit Prosthesis

Infiltration of main pulmonary artery

Reconstruction via cardiopulmonary bypass

inferiorly between the bronchus intermedius posteriorly and the superior pulmonary vein anteriorly. At this level, the artery is closely applied to the undersurface of the vein, and careless dissection may be hazardous. Subsequently, the interlobar PA turns posteriorly behind the origin of the middle lobe bronchus. In this portion, one or two ascending arteries originate posterior to the segment of the upper lobe and the middle lobe artery. The middle lobe artery arises from the anteromedial surface of the interlobar artery, and the ascending arteries originate posteromedially at a slightly lower level. Distal to the latter is the origin of the artery to the apical segment of the lower lobe, and, subsequently, the PA branches into the arteries to the basal pyramid.

Trachea

Left main bronchus

Right pulmonary artery Right main bronchus

Left pulmonary artery

Superior division of pulmonary artery

Apicoposterior branch

Apical and posterior bronchi Anterior bronchus Anterior branch Ligular bronchi

Upper lobe bronchus

Lingular branches

Apicoposterior branch Middle lobe branch

Basilar branches

Basilar branches

Bronchus intermedius

Middle lobe bronchus

Pulmonmary trunk

Upper lobe bronchus

Basilar bronchi

Basilar bronchi FIGURE 75-1 Anteroposterior view of the pulmonary artery branching and its relationship to the bronchial tree.

tahir99-VRG vip.persianss.ir

Ch075-F06861.indd 910

1/21/2008 1:37:59 PM

Ch075-F06861.indd 911

Superior division of pulmonary artery

Trachea

Right main bronchus Upper lobe bronchus

Apicoposterior branch Left main bronchus

Anterior branch Lingular branches

Right pulmonary artery

Left pulmonary artery

Apicoposterior branch

Superior segment artery

Superior segment artery

Middle lobe branch

Basilar branches

Lingular bronchus

Pulmonary trunk

Upper lobe bronchus

Middle lobe bronchus

A

B FIGURE 75-2 A, Lateral view of the right pulmonary artery. B, Lateral view of the left pulmonary artery.

Basilar branches

911

1/21/2008 1:38:01 PM

Chapter 75 Reconstruction of the Pulmonary Artery

Superior segment bronchus

Superior segment bronchus

912

Section 3 Lung

FIGURE 75-4 MRI of an intrapericardial tumor with infiltration into the left pulmonary artery. FIGURE 75-3 A CT scan with injection of contrast material of the left pulmonary artery. Extrapericardial tumor infiltration involves the left interlobar pulmonary artery and its branches to the left upper lobe.

The left PA (see Figs. 75-1 and 75-2) is shorter than its right counterpart; at its origin is the ligamentum arteriosum, and its relationship with the aortic arch continues posteriorly. At this level (the so-called aortopulmonary window) are the recurrent laryngeal nerve and several mediastinal lymph nodes. The left PA lies above the left main bronchus and surrounds three fourths of the circumference of the left upper lobe bronchus. In fact, the PA abuts the superior, posterior, and inferior aspects of the upper lobe bronchus, leaving its anterior surface in contact with the superior pulmonary vein. The first branches, the apical and the anterior segmental arteries, arise anteriorly and superiorly to the upper lobe bronchus, and posteriorly and superiorly to the superior pulmonary vein. These arteries are often short and broad and, therefore, susceptible to injury. They are often best exposed after division of the superior pulmonary vein. Throughout its course around the upper lobe bronchus, the interlobar PA delivers branches to the upper lobe that are highly variable in number and location and are usually surrounded by lymph nodes. The most distal of these branches is the lingular artery, which usually arises distally or at approximately the same level as the artery that leads to the superior segment of the lower lobe. The lingular artery arises from the anteromedial surface of the interlobar PA, and the superior segmental artery originates posterolaterally. The PA axis is then oriented anteriorly, and the vessel branches into the arteries to the basal segments.

INDICATIONS Reconstructive surgery of the PA, often associated with sleeve resection of the bronchus, is intended to obtain complete resection of lung cancer, avoiding pneumonectomy. This is a reasonable approach, not only in patients who cannot tolerate pneumonectomy because of impaired cardiopulmonary function, but also in any patient in whom the procedure is feasible. Complete resection being the primary goal, extensive use

Ch075-F06861.indd 912

FIGURE 75-5 A three-dimensional reconstruction by angio-MRI showing caliber reduction of the left pulmonary artery.

of frozen section histology must be made on all resection margins, and if tumor infiltration persists, pneumonectomy is performed without hesitation. It is difficult to establish the indication for a PA reconstruction preoperatively. PA angiography, computed tomography (CT) scan with injection of contrast material (Fig. 75-3), and magnetic resonance imaging (MRI) of the blood vessels (angio-MRI) (Figs. 75-4 and 75-5) can all contribute to clarification of the pattern of infiltration, but the decision is usually made intraoperatively. The primary indication is direct infiltration of the interlobar PA by the primary tumor (Fig. 75-6); however, extracapsular nodal extension into the vessel can also be treated effectively by this technique. After induction therapy, the PA can be involved to a various extent either by residual tumor

1/21/2008 1:38:05 PM

Chapter 75 Reconstruction of the Pulmonary Artery

FIGURE 75-6 Typical pattern of a pulmonary artery tumor infiltration requiring pulmonary artery resection and reconstruction. The left upper lobe tumor involves the artery in the interlobar fissure; often, the lingular artery is free of tumor and can be ligated and resected separately, as shown in this figure. (REDRAWN FROM RENDINA EA, VENUTA F, DE GIACOMO T, ET AL: SAFETY AND EFFICACY OF BRONCHOVASCULAR RECONSTRUCTION AFTER INDUCTION CHEMOTHERAPY FOR LUNG CANCER. J THORAC CARDIOVASC SURG 114:830, 1997.)

or by desmoplastic reaction, scarring tissue, or fibrosis. The concern about an increased complication rate in these patients has been proved to be excessive, and, in our experience, PA reconstructive techniques can be performed in this setting safely and effectively. Approximately 70% of all PA reconstructions are performed for left upper lobe tumors and 20% for right upper lobe lesions. The remaining 10% entail procedures performed on the main PA or on the lower lobes bilaterally. Reconstruction of the main PA via cardiopulmonary bypass is applicable only for patients with left T4 lung cancer. On the right side, the anatomic relationship of the PA to the SVC, right atrium, and ascending aorta makes these tumors invariably unresectable. The long-term results of this approach are uncertain, although the development of effective multimodality protocols for locally advanced lung cancer (i.e., induction therapy) may rejuvenate its use.

OPERATIVE TECHNIQUE General Principles The resection phase of the operation and the preparation of the operative field can present pitfalls and difficulties. The first step consists of achieving full control of the PA proxi-

Ch075-F06861.indd 913

913

mally and is described in detail later. On both sides, the exposure of the PA and its first branches can be facilitated by division of the superior pulmonary vein. In general, however, the transection of any vessel or bronchus is postponed until the feasibility of the procedure is ascertained. The vein is nevertheless dissected and retracted as much as possible. Once all the elements involved in the resection are duly prepared (main and distal PA; main and distal bronchus; both pulmonary veins), the resection phase begins. The superior pulmonary vein (in the instance of upper lobe tumors) is transected first; subsequently, 1500 to 2400 U of heparin sodium are injected intravenously, and the main PA is occluded by insertion of a Satinsky clamp from the assistant’s side of the table. The artery is not occluded distally, and the backflow is arrested by clamping the inferior pulmonary vein. Moderate back-bleeding is easily controlled by suction. As a result, both clamps will be out of the surgeon’s way during suturing, and the fragile distal stump of the artery will not be traumatized. The reconstructive phase of the operation is usually simple, and judicious employment of three basic techniques (patch, end-to-end, and conduit) warrants straightforward reconstruction of the arterial lumen. In fact, the only PA defect that would be too extended for reconstruction is one for which pneumonectomy is mandatory to achieve complete tumor resection. The various techniques for reconstruction are described in detail later. After the suture is completed, the venous clamp is removed before the suture is tied, and backflow is restored to allow air drainage. The suture is then tied, and the arterial clamp is removed, but heparin is not reversed by protamine. Before closing the chest, it is very important to check the suture line for oozing sites, which might pass unnoticed because of low PA pressure. Secondly, lung re-expansion is carefully tested to ascertain that no kinking or folding of the PA occurs. At the end of the procedure, especially if a bronchial sleeve was also performed, it is advisable to interpose viable tissue between the artery and the bronchus. Our preference is an intercostal muscle flap. In the postoperative period, low-dose anticoagulation therapy (6000 U/day heparin [Seleparin] subcutaneously) is administered for 7 to 10 days.

Arterial Mobilization Left Upper Lobe If the tumor involves only the interlobar artery (see Fig. 753), the main PA can be prepared extrapericardially, but in the more common case in which the artery is infiltrated close to its origin (see Figs. 75-4 to 75-6), the pericardium must be opened. The pericardium is incised longitudinally behind the phrenic nerve, and a finger is introduced to palpate the PA. The origin of the left PA may be free of tumor (Fig. 75-7), and it can be encircled by an umbilical tape. Sometimes, tight adhesions below the aortic arch require further dissection before resectability can be ascertained (Fig. 75-8). The aortopulmonary window needs to be carefully dissected, dividing the ligamentum arteriosum and the pericardial duplication, and sometimes mobilizing the aortic arch. During this maneuver, the recurrent laryngeal nerve can be injured. If the

1/21/2008 1:38:06 PM

914

Section 3 Lung

B A FIGURE 75-7 Surgical anatomy of the interlobar left pulmonary artery from a posterolateral view.

tumor infiltrates the artery very proximally, the posterior aspect of the vessel is invariably dissected blindly. This maneuver has to be carried out very carefully. In fact, the traction applied on the hilum elevates the main PA bifurcation, and the tip of the clamp passed behind the left PA may injure the right PA with disastrous results. Usually, the anatomic location of the tumor is such that the posterior aspect of the pulmonary hilum, and, in particular, the main bronchus is free of disease (Fig. 75-9). However, if the interlobar PA is infiltrated by tumor behind the upper lobe bronchus, the dissection planes between the posterior mediastinal pleura and the descending aorta might be obliterated. This area must, therefore, be carefully dissected before the hilum can be elevated and the main bronchus exposed and prepared. Once proximal control of the PA is obtained, the interlobar fissure is approached. Clamping the PA proximally may facilitate the dissection in this area. It is important at this stage to expose the artery to the superior segment of the lower lobe arising posterolaterally and the artery to the anterior basal segment of the lower lobe, which continues anteriorly along the curve of the interlobar artery. If these two vessels are tumor-free, the vasculature to the lower lobe can be preserved. All along the curve of the PA around the upper lobe bronchus, branches to the upper lobe can arise. These can be separately ligated and transected if tumor-free, as is often the case for the lingular artery.

Left Lower Lobe Tumors in the left lower lobe or infiltrative metastatic lymph nodes located between the lower lobe branches may involve the inferior aspect of the interlobar artery (Fig. 75-10). The procedure is much simpler than that involving the upper lobe because the proximal PA is free from tumor. After the hilar structures have been prepared and the viability of the lingular artery has been ascertained, the inferior pulmonary vein is transected and the main PA and superior pulmonary vein are

Ch075-F06861.indd 914

FIGURE 75-8 Full-circumference infiltration of the pulmonary artery requiring sleeve resection. A, Surgical anatomy of the interlobar artery from a posterolateral view. B, The infiltrated pulmonary artery from a lateral view.

FIGURE 75-9 A posterolateral view of the left hilum after upper lobectomy associated with sleeve resection of the pulmonary artery and the bronchus. Note that the distal stump of the pulmonary artery is not clamped; backflow is avoided by occlusion of the lower pulmonary vein.

clamped. The interlobar artery is then incised obliquely, in an anteroposterior and inferosuperior direction, and subsequently reconstructed by a tissue patch. The elastic retraction of the arterial wall in this setting is such that the patch must be very carefully trimmed to the appropriate size to preserve the patency of the lingular artery and properly reconstruct the dead-end of the PA. This technique can also be employed during harvesting of the left lower lobe in living donor for lobar transplantation.

Right Upper Lobe The anatomy of this region makes proximal tumors often unresectable because of invasion of the SVC and right atrium.

1/21/2008 1:38:09 PM

Chapter 75 Reconstruction of the Pulmonary Artery

915

Left inferior pulmonary vein

A

B

FIGURE 75-10 Infiltration of the pulmonary artery (PA) by a left lower lobe tumor. A, The tumor involves the distal PA before its lower lobe branching; the lingular artery is, however, free of disease. B, After resection of the lower lobe, the lower pulmonary vein is sutured, and the upper pulmonary vein and main PA are clamped. The PA defect will be reconstructed by a pericardial patch.

A

B

A

B

FIGURE 75-11 Partial tumor infiltration of the right pulmonary artery requiring patch reconstruction of the vessel. A, The right upper lobe tumor partially infiltrates the artery. B, After the resection, the ensuing arterial wall defect can be reconstructed by a patch.

FIGURE 75-12 Full-circumference infiltration of the right pulmonary artery requiring sleeve resection. A, The right upper lobe tumor involves the pulmonary artery. B, After the resection, the ensuing defect can be reconstructed by end-to-end anastomosis.

PA reconstruction is usually feasible for tumors or lymph nodes that are located on the anterior or inferior aspect of the upper lobe bronchus and involve the PA between the superior trunk and the posterior ascending fissural arteries (Figs. 75-11 and 75-12). Although transection of the superior pulmonary vein would greatly facilitate the exposure at this level, this maneuver is discouraged unless the feasibility of the reconstruction has been ascertained or the patient can withstand right pneumonectomy. Proximal control of the PA can usually be obtained extrapericardially

after anterior and medial retraction of the SVC. Alternatively, the PA can be exposed transpericardially between the SVC and the ascending aorta. Distally, it is important to demonstrate the integrity of the arteries to the middle lobe and to the superior segment of the lower lobe. For anatomic reasons, the arterial wall defect resulting after resection is usually extended longitudinally but does not involve the full circumference of the vessel. Sleeve resection is therefore rarely indicated, and a tissue patch is often adequate for reconstruction.

Ch075-F06861.indd 915

1/21/2008 1:38:14 PM

916

Section 3 Lung

Right Lower Lobe This is a very unusual situation, similar to its left counterpart. The harvesting of the right lower lobe for living donor lobar transplantation also presents similar features.

RECONSTRUCTION Partial Resection and Patch Reconstruction Patch reconstruction is very versatile and can be used in a variety of circumstances (Fig. 75-13). These range from limited infiltration involving the origin of segmental arteries to large defects extended longitudinally on one aspect of the PA. The only necessary condition is that the opposite side of the circumference of the PA be free from tumor. If this is not the case, sleeve resection with end-to-end anastomosis or conduit interposition is performed. After the resection, an oval defect oriented along the PA axis ensues (Fig. 75-14A), even if the resected portion was round in shape because of the tension applied on the vessel by the lower lobe. The patch, therefore, is tailored on the resected portion rather than on the PA defect. Various patches can be used; our preference is for biologic materials because of better biocompatibility. Azygos vein patches, although adequate, have a number of disadvantages. First, the azygos vein is available only on the right side, where the need for a PA patch is less likely to occur, and harvesting of other venous patches requires a separate procedure. In addition, the amount of tissue is limited. We recommend the use of autologous or bovine pericardium, both of which have none of the aforementioned limits. Autologous pericardium is fresh and unpreserved, cost-free, and biocompatible; it is, however, difficult to use. Conversely, bovine pericardium is less cost effective and less biocompatible, but very easy to use. The autologous pericardium is harvested anteriorly to the phrenic nerve, and the pericardial defect is left open. The arterial reconstruction is performed before the bronchial

B A FIGURE 75-13 Posterolateral (A) and lateral (B) views of the typical indications for patch reconstruction of the pulmonary artery on the left side.

Ch075-F06861.indd 916

anastomosis to reduce the arterial clamping time. The patch is trimmed appropriately and secured to the artery by two stay sutures (see Fig. 75-14B). The inferior stay suture is not tied; it is used only to keep the patch in place and will be removed when the suture line reaches its level. Some degree of tension is desirable at this stage; it shows that the patch is not exceedingly long, and tension will disappear after declamping (see Fig. 75-14B). Suturing (see Fig. 75-14C) must be done very carefully because the edge of the pericardium tends to shrink and curl, and sutures that are too wide apart may result. The pitfalls of harvesting, trimming, and suturing the autologous pericardium are overcome by the use of bovine pericardium, which displays little if any elasticity and has even and stiff edges. The patch is sutured using running 5-0 or 6-0 monofilament nonabsorbable material. The right-handed surgeon proceeds from top to bottom, “artery first,” on the right side, while the assistant grasps and stretches the patch, and then continues from bottom to top, “patch first.”

Sleeve Resection and Reconstruction by End-to-End Anastomosis When transecting the artery, both proximally and distally, regular and even margins are desirable, even at the cost of some loss of tissue (see Fig. 75-9). This allows proper placement of the stitches and yields an even inside lumen. In addition, regular suture borders facilitate the correction of the large caliber discrepancy that usually occurs. Because of the elasticity of the arterial wall, caliber discrepancy is never a problem. The PA reconstruction is usually performed after completion of the bronchial anastomosis, to minimize the manipulation of the vessel (Fig. 75-15A). In addition, the exposure of the bronchial stumps is optimal when the artery is divided. If the vascular and bronchial procedures are done simultaneously, the bronchial axis is shortened, and the PA stumps are almost always opposable with acceptable tension (see Fig. 75-15B). On completion of the bronchial anastomosis, the distance between the two arterial ends will be markedly decreased, and it can be further reduced by elevating the lower lobe while suturing. Restoration of blood flow and removal of the proximal clamp almost always relieves any residual tension (see Fig. 75-15C and D). If the distance between the arterial stumps is deemed excessive, the interposition of a prosthetic conduit is indicated. The anastomosis is performed by running 5-0 or 6-0 monofilament nonabsorbable material; especially if some degree of tension exists, it is safer to complete the posterior portion of the suture and subsequently parachute the two stumps together while lifting the lower lobe. Sometimes the distal end of the PA shrinks so that the first branch (apical segmental artery on the left; middle lobe artery on the right) appears almost separate from the rest of the vessel. The reconstruction is still feasible, but the sutures are placed very carefully to avoid stenosis.

Sleeve Resection and Reconstruction by a Prosthetic Conduit In the very unusual case of extended circumferential defects in which end-to-end anastomosis is not feasible, a prosthetic conduit of synthetic or biologic material can be used. We

1/21/2008 1:38:22 PM

Chapter 75 Reconstruction of the Pulmonary Artery

917

Graft

B

A

C

D FIGURE 75-14 Patch reconstruction. A, After upper lobectomy and partial resection of the pulmonary artery, an oval defect ensues, caused by the tension applied to the vessel by the lower lobe. B, The patch is held in place by two stay sutures. Some degree of tension on the patch is desirable at this stage, to show that the patch is not too long; tension will disappear after declamping. C, The lower stay suture is not tied but simply keeps the patch in place. The right-handed surgeon would proceed from top to bottom, “artery first,” on the right side and then continue bottom to top, “patch first.” D, Completed patch reconstruction of the pulmonary artery. The pericardial defect is left open. The ligated stump of the lingular artery can also be seen. (A AND D REDRAWN FROM RENDINA EA, VENUTA F, DE GIACOMO T, ET AL: SAFETY AND EFFICACY OF BRONCHOVASCULAR RECONSTRUCTION AFTER INDUCTION CHEMOTHERAPY FOR LUNG CANCER. J THORAC CARDIOVASC SURG 114:830, 1997.)

prefer the autologous pericardium because other materials might increase the risk of thrombosis. The conduit interposition may be useful when a left upper lobe tumor infiltrates the PA extensively, but the lobar bronchus is not involved and, therefore, a bronchial sleeve is not indicated. This unusual situation (PA sleeve without bronchial sleeve) may produce a long bronchial segment separating the two widely spaced PA stumps, so that an end-to-end anastomosis is not possible (Fig. 75-16A). The autologous pericardium is trimmed to rectangular shape, wrapped around a 28 Fr chest tube with the epicardial surface inside, and sutured longitudinally with 6-0 monofilament nonabsorbable material. A pericardial conduit of approximately 1 to 2 cm is thus created. When sizing the conduit, two points must be considered: the PA stumps can be approximated closer than it seems, and the

Ch075-F06861.indd 917

conduit will stretch more than predicted. It is advisable to tailor the length of the conduit on the basis of the resected arterial segment because the elasticity of the two tissues is comparable. The proximal anastomosis is performed first with running 5-0 monofilament suture (see Fig. 75-16B). The distal anastomosis is performed last, after the conduit has been trimmed to the appropriate length by overlapping the suture margins. It is advisable to parachute the distal end of the conduit, folding it over on itself to obtain some degree of tension, which will disappear after declamping (see Fig. 75-16C). When the blood flow is restored, the dimension of the conduit will increase by approximately one third. Care must be taken to avoid lengthening of the PA, which may cause kinking of the vessel, impaired blood flow, and, ultimately, thrombus formation.

1/21/2008 1:38:24 PM

918

Section 3 Lung

B

A

C

D FIGURE 75-15 Sleeve resection with end-to-end anastomosis. A, The arterial anastomosis is performed after the bronchial suture to minimize manipulation of the vessel. B, Regular and even arterial margins facilitate proper placement of the stitches. When the bronchial and pulmonary artery sleeves are associated, the pulmonary artery stumps will reach with acceptable tension. C, After completion of the end-to-end anastomosis, caliber discrepancy is compensated by the elasticity of the pulmonary artery. D, A posterior view of the left hilum after bronchial and pulmonary artery sleeve resection. The inferior pulmonary vein is visible on the left side. (A AND B REDRAWN FROM RENDINA EA, VENUTA F, DE GIACOMO T, ET AL: SAFETY AND EFFICACY OF BRONCHOVASCULAR RECONSTRUCTION AFTER INDUCTION CHEMOTHERAPY FOR LUNG CANCER. J THORAC CARDIOVASC SURG 114:830, 1997.)

Ch075-F06861.indd 918

1/21/2008 1:38:27 PM

Chapter 75 Reconstruction of the Pulmonary Artery

919

B

A

C FIGURE 75-16 Sleeve resection and reconstruction by a prosthetic conduit. A, The need for a pulmonary artery (PA) sleeve without bronchial sleeve produces a long bronchial segment separating the two widely spaced PA stumps, so that end-to-end anastomosis is not possible. B, The proximal anastomosis between the PA and the conduit is performed first. C, The distal anastomosis is performed last, overlapping the suture margins to create tension, which will be relieved by declamping. (C REDRAWN FROM RENDINA EA, VENUTA F, DE GIACOMO T, ET AL: SAFETY AND EFFICACY OF BRONCHOVASCULAR RECONSTRUCTION AFTER INDUCTION CHEMOTHERAPY FOR LUNG CANCER. J THORAC CARDIOVASC SURG 114:830, 1997.)

Resection and Reconstruction of the Main Pulmonary Artery via Cardiopulmonary Bypass Cardiopulmonary bypass is instituted via median sternotomy, and the main PA is separated from the ascending aorta and clamped. The right PA is clamped between the aorta and the SVC because tumor does not allow placement of the clamp on the left side of the aorta (Fig. 75-17A). Alternatively, the right heart can be emptied by bicaval cannulation, thus making PA clamping unnecessary. The left PA and part of the main and right PA are resected en bloc with the left lung. The defect is then reconstructed by a tissue patch (see Fig. 75-17B).

Ch075-F06861.indd 919

PITFALLS AND COMPLICATIONS Although the postoperative course of bronchial sleeve resection depends to some extent on patient compliance and judicious clinical management, the short-term results of PA reconstruction depend mostly on operative judgment and technique. If the operation has been correctly performed, specific complications might be expected in no more than 5% of the patients. These essentially consist of leakage from the suture line and thrombosis. Bronchoarterial fistula is much more likely to be associated with bronchial sleeve resection and can be effectively prevented by interposing the intercostal muscle between the two structures.

1/21/2008 1:38:32 PM

920

Section 3 Lung

Aorta

Right pulmonary artery

Left pulmonary artery Graft

Pulmonary trunk

A

B

FIGURE 75-17 Resection and reconstruction of the main pulmonary artery (PA) via cardiopulmonary bypass (CPB). A, The tumor infiltrates the left and main PA. CPB is instituted, and the main and right PA are clamped. B, After left pneumonectomy and en-bloc resection of the main PA, the defect is reconstructed by a pericardial patch. (REDRAWN FROM RICCI C, RENDINA EA, VENUTA F, ET AL: RECONSTRUCTION OF THE PULMONARY ARTERY IN PATIENTS WITH LUNG CANCER. ANN THORAC SURG 57:627, 1994.)

Because the PA is a low-pressure vessel, leakage from the suture line may pass unnoticed intraoperatively. Also, the bleeding may start on the first or second postoperative day after a patch reconstruction. A blood loss of up to 800 to 1000 mL daily may occur after 1 or 2 days of no drainage. This may last for 1 or 2 days and then stop spontaneously, independently from anticoagulation. A possible explanation is that the autologous pericardium shrinks and curls markedly after harvesting, and it is difficult to place the suture bites at the appropriate distance. After declamping and distention, bites too wide apart may result. These would not cause bleeding immediately because the PA is stretched downward by the atelectatic lower lobe, and simple apposition of the tissue edges is enough to counteract the low PA pressure. However, in the postoperative period when the re-expansion of the lower lobe elevates the hilum, the rotation and kinking of the PA may distort the suture line and reopen the bleeding site. It is, therefore, very important, especially when using autologous pericardial patches, to carefully check the suture line and test the PA position after re-expansion of the residual lobe. The latter maneuver is also important to prevent thrombosis. After a patch reconstruction of the PA associated with a bronchial sleeve, the bronchial axis is shortened, and the length of the artery remains stationary. Some of the discrepancy is compensated by the elasticity of the vessel, but the PA may tend to kink and fold over on itself. The aforementioned repositioning of the PA caused by the re-expansion of the lower lobe further increases this risk. Impairment of

Ch075-F06861.indd 920

blood flow may ensue, and thrombosis may be facilitated. Under these circumstances, it is better to cut the distorted segment away and proceed to an end-to-end anastomosis. The pitfalls of sleeve resection and end-to-end anastomosis are of a different nature. Sometimes the procedure is anatomically impossible, such as in cases of left upper lobe tumors infiltrating the concave surface of the PA from its origin down to the anterobasal artery. On the right side, the same problem may arise when the posterolateral aspect of the PA is infiltrated from the upper division artery to the artery for the superior segment of the lower lobe. Conversely, sleeve resection is sometimes excessive, if the artery is only partially infiltrated. Additionally, the end-to-end anastomosis can be technically difficult, owing to unexpected traction between the stumps and caliber discrepancy. Tears on the arterial wall made during suturing are difficult to repair, and failure to do so may produce disastrous results. The main pitfall of the use of a conduit is sizing its length. Application of the aforementioned technical insights will prevent this problem.

LONG-TERM RESULTS Mid-term and long-term evaluation of patients undergoing PA reconstruction are based on three issues: 1. Patency of the PA and perfusion of the residual lobe 2. Right heart function 3. Analysis of survival

1/21/2008 1:38:35 PM

Chapter 75 Reconstruction of the Pulmonary Artery

921

TABLE 75-2 Reconstruction of the Pulmonary Artery in the Literature Author (Year)

No. Patients

Complete (%)

Technically Complete (%)

Mortality (%)

5-Year Survival (%)

Rendina (1999)

52

13.4

1.9

0

38.3

Icard (1999)

16

NS

NS

NS

39*

Shrager (2000)

33

NS

NS

46.6

Lausberg (2000) Okada (2000)

6.1

4

NS

0

NS

61.9*

21

NS

0

0

48*

*Comprehensive survival of arterial and bronchial sleeve resection. NS, not significant.

FIGURE 75-18 Tangential resection and direct suture of the pulmonary artery. Postoperative angio-MRI shows marked caliber reduction and narrowing of the right pulmonary artery (arrow).

FIGURE 75-19 Postoperative angio-MRI after patch reconstruction of the left pulmonary artery.

Immediately after the operation, patency problems occur in fewer than 5% of cases. Newer, noninvasive techniques such as angio-MRI provide outstanding imaging of the PA (Figs. 75-18 to 75-20) and may be very useful in demonstrating patency problems even in the immediate postoperative period. However, once the normal blood flow through the PA has been restored and the new orientation of the PA caused by the re-expansion of the residual lobe has taken place without kinking in the early postoperative period, patency impairment is very unlikely to occur. In the absence of clinical symptoms, pulmonary angiograms in addition to perfusion lung scans are redundant. In the long term, CT with injection

Ch075-F06861.indd 921

FIGURE 75-20 Postoperative angio-MRI after sleeve resection with end-to-end anastomosis (arrows) of the left pulmonary artery.

of contrast material has proved to be a versatile, noninvasive diagnostic tool that is useful to evaluate both PA patency and distal PA branching, as well as the overall oncologic status of the patient. Standard electrocardiography and echocardiography are useful to confirm the advantages in terms of right heart function and morphology obtained by the preservation of a normally perfused lobe. These tests confirm that, in contrast to pneumonectomy, the right ventricular size and motility remain normal, and pulmonary hypertension does not tend to develop. These findings parallel those of spirometry, which indicates that bronchial sleeve lobectomy equals standard lobectomy in terms of pulmonary function. Because the reports on PA reconstructions have been rare in the literature so far (Table 75-2), the long-term survival of these patients has been uncertain. Recently, it has been demonstrated that the survival of patients undergoing PA reconstruction is comparable, stage-by-stage, to that reported in the major reviews on lung cancer surgery and sleeve resection in the literature (Fig. 75-21). The impact of nodal status on survival is also comparable to that reported for bronchial sleeve and standard resection. In the face of N1 or N2 involvement, once the decision to resect the disease with intent to cure is taken, PA reconstruction can also be proposed as an adequate procedure in this setting. Moreover, there is no statistically significant difference between PA

1/21/2008 1:38:40 PM

922

Section 3 Lung

FIGURE 75-21 Five-year survival by stage of 52 patients undergoing pulmonary artery reconstruction. (FROM

p ⫽ 0.01

90

83%

80 Percentage surviving

RENDINA EA, VENUTA F, DE GIACOMO T, ET AL: SLEEVE RESECTION AND PROSTHETIC RECONSTRUCTION OF THE PULMONARY ARTERY FOR LUNG CANCER. ANN THORAC SURG 68:995, 1999.)

100

70 56%

60 50 40 30

Stage I Stage II Stage IIIA Stage IIIB

20 10 0

0

12

22% 11%

24

36

48

60

72

Mo

reconstruction alone or PA reconstruction associated with bronchial sleeve. This suggests that even complex lung-sparing operations can be pursued with intent to cure, so long as a complete anatomic resection is achieved.

Acknowledgment We are greatly indebted to Professor G. Furio Coloni, Chief of Thoracic Surgery, University “La Sapienza” Roma, for his support and advice.

COMMENTS AND CONTROVERSIES Drs. Rendina and Venuta have made many significant contributions to the field of general thoracic surgery. None is more significant than their efforts to develop and refine the techniques of pulmonary arterioplasty as a strategy in the operative management of non– small cell lung cancer. As was the case with bronchoplastic procedures 10 to 15 years ago, pulmonary arterioplasty has come into more widespread use to achieve R0 resections while preserving lung parenchyma in patients with central primary cancers or metastatic N1 disease. The authors clearly describe the anatomic considerations and technical maneuvers necessary to safely perform these PA reconstructive procedures while at the same time accomplishing cancer resections that provide results functionally superior and oncologically equivalent to those of pneumonectomy. These techniques need to be in the operative repertoire of all thoracic surgeons. G. A. P.

Icard P, Regnard JF, Guibert L, et al: Survival and prognostic factors in patients undergoing parenchymal saving bronchoplastic operation for primary lung cancer: A series of 110 consecutive cases. Eur J Cardiothorac Surg 15:426-432, 1999. Lausberg HF, Graeter TP, Wendler O, et al: Bronchial and bronchovascular sleeve resection for treatment of central lung tumors. Ann Thorac Surg 70:367-371, 2000; discussion 371-372. Lowe JE, Bridgman AH, Sabiston DC Jr, et al: The role of bronchoplastic procedures in the surgical management of benign and malignant pulmonary lesions. J Thorac Cardiovasc Surg 83:227, 1982. Okada M, Yamagishi H, Satake S, et al: Survival related to lymph node involvement in lung cancer after sleeve lobectomy compared with pneumonectomy. J Thorac Cardiovasc Surg 119(4 Pt 1):814-819, 2000. Rendina EA, Venuta F, De Giacommo T, et al: Safety and efficacy of bronchovascular reconstruction after induction chemotherapy for lung cancer. J Thorac Cardiovasc Surg 114:830, 1997. Rendina EA, Venuta F, De Giacomo T, et al: Sleeve resection and prosthetic reconstruction of the pulmonary artery for lung cancer. Ann Thorac Surg 68:995, 1999. Ricci C, Rendina EA, Venuta F, et al: Reconstruction of the pulmonary artery in patients with lung cancer. Ann Thorac Surg 57:627, 1994. Shrager JB, Lambright ES, McGrath CM, et al: Lobectomy with tangential pulmonary artery resection without regard to pulmonary function. Ann Thorac Surg 70:234-239, 2000. Vogt-Moykopf I, Frits TH, Meyer G, et al: Bronchoplastic and angioplastic operation in bronchial carcinoma: Long-term results of a retrospective analysis from 1973 to 1983. Int Surg 71:211, 1986. Weisel RD, Cooper JD, Delarue NC, et al: Sleeve lobectomy for carcinoma of the lung. J Thorac Cardiovasc Surg 78:839, 1979.

KEY REFERENCES Bennett WF, Abbey-Smith R: A twenty-year analysis of the results of sleeve resection for primary bronchogenic carcinoma. J Thorac Cardiovasc Surg 76:840, 1978.

Ch075-F06861.indd 922

1/21/2008 1:38:41 PM

chapter

76

POSTERIOR APPROACH TO SUPERIOR SULCUS TUMORS Kacy Phillips Garrett L. Walsh

Key Points ■ History and physical examination are the most important compo-

nents of the workup.

this chapter is on superior sulcus tumors, which by definition are T3 or T4 lesions by virtue of their chest wall or vertebral body invasion, and on the outcomes and controversies of multimodality treatment options.

■ CT, MRI, and CT/PET are essential and routinely used for all radio-

graphic workups and surgical planning. ■ Mediastinoscopy or EBUS is required to rule out N2 disease before

proceeding with resection. ■ N3 disease, including ipsilateral supraclavicular and scalene lymph nodes, behaves biologically like N1 disease and is considered locoregional resectable disease. ■ Stage T3 and T4 superior sulcus tumors are considered resectable.

Superior sulcus tumors are bronchogenic carcinomas, usually of non–small cell histology, that typically produce unrelenting pain in the distribution of the eighth cervical and first and second thoracic nerve roots and are associated with Horner’s syndrome (ptosis, miosis, and anhidrosis) and motor deficits of the intrinsic hand muscles. This compilation of symptoms is known as Pancoast’s syndrome. The apical location of these tumors, tendency to cause severe pain, and functional deficits from their locally invasive nature and distant metastases make these lesions complex surgical challenges for evaluation and management. For the patient with a superior sulcus tumor, the treatment options vary depending on the anatomic site of the lesion, involvement of surrounding thoracic inlet structures, and the presence or absence of distant metastases. Ideally, complete surgical resection with negative margins is the goal in these patients. However, these tumors are more often found at a locally advanced stage or have invaded contiguous structures, such as vertebrae, subclavian vessels, or the chest wall. Although radiation and chemotherapeutic agents continue to be mainstay treatments for unresectable disease, these two treatments are now used in tandem with surgical resection to address the more locally invasive and destructive tumors. Perioperative radiation, chemotherapy, and aggressive surgical resections have changed the previously defined parameters of resectability. For instance, induction chemoradiotherapy can now be used to reduce tumor burden in patients with T3-T4 N0-N1 disease. Subsequently, responding tumors can be resected with a high likelihood of negative margins. Ongoing trials are intended to optimize all three options to treat patients with this relatively infrequent entity. The focus in

HISTORICAL NOTE Over a century before treatment protocols were developed, superior sulcus tumors were yet to be fully characterized. In 1838, Edwin Hare described a patient presenting with the constellation of an apical chest mass, shoulder pain, and signs of an ulnar neuropathy in the London Medical Gazette.1 In 1924, Henry Pancoast, a radiologist, described seven patients with similar clinical presentations and small apical opacities on their radiographs.2 Early on, these lesions were believed to be infectious or remnants of an embryonic rest.3 However, in 1932 Tobias was the first to correctly identify these apical masses as malignancies of bronchogenic origin.4 Throughout the 1930s and 1940s, superior sulcus tumors were believed to be unresectable, radioresistant, and uniformly fatal. These opinions were ultimately proven to be false. To 1946, there were no documented cases of 5-year survivors, with death usually occurring within 10 to 14 months from the time of diagnosis.5 In 1954, Haas described the first patient to survive 3 years after radiotherapy, with equally important palliation and relief of the classic Pancoast syndrome symptoms.6 This served as the basis for early multimodal therapy. In 1956, Chardack and MacCullum published the first successful report of combined modality (surgery followed by 65-Gy radiation therapy) treatment of a patient.7 Within a decade, advances in external-beam radiation technology allowed for higher dosages and wider portals to be used, including the mediastinum, vertebral bodies, and supraclavicular fossae. During this time frame, reports of 5year survivors emerged after radiation therapy alone. Building on these medical advances, Shaw and Paulson developed the standard model for radiation and surgery to treat superior sulcus tumors. In 1961, Shaw described a patient with an advanced lesion who had a 50% decrease in tumor volume after an initial 30 Gy of radiation therapy.8 The tumor that was previously considered unresectable was subsequently removed surgically. This patient lived for another 27 years without local recurrence of disease. Paulson popularized this approach of neoadjuvant radiotherapy followed by surgical resection. Over the next 30 years this approach became the standard model for many medical centers.9 Due to the evolution of surgical techniques, involvement of spine surgeons, and creation of synthetic grafting materials, tumors 923

Ch076-F06861.indd 923

1/21/2008 1:39:43 PM

924

Section 3 Lung

involving the subclavian vessels and vertebral bodies are now resected with acceptable morbidity and mortality.10

PATIENT SELECTION Like many other illnesses, the most important component of patient evaluation involves the initial history and physical examination. The progressive loss of motor function to the intrinsic hand muscles, wrist, and the arm itself usually indicates direct brachial plexus infiltration and is an absolute contraindication to surgery. Therefore, this finding is important in deciding whether to proceed with surgical evaluation or resection. Sensory changes, however, can represent displacement or upward compression on the brachial plexus rather than direct invasion. This scenario represents a resectable situation. The physical examination, therefore, should elicit the extent of disease by evaluating atrophy of the affected hand, limb, and shoulder girdle. An apical mass seen on a chest radiograph with shoulder pain, Horner’s syndrome, and Pancoast symptoms suggests a superior sulcus bronchogenic tumor. However, it is important to rule out infectious causes. For instance, fungal and bacterial agents such as Staphylococcus, Cryptococcus, Echinococcus, and Actinomyces can mimic this clinical and radiographic presentation. Thus, tissue diagnosis is critical before considering treatments. Fine-needle aspiration results in a positive diagnostic yield in more than 90% of patients.11 Non–small cell histology is the predominant cell type of superior sulcus tumors (90%-95% of cases). Small cell type (2%-5%) can rarely produce this presentation, which would be treated with chemotherapy (with or without radiation therapy) rather than surgical resection. Fiberoptic bronchoscopy adds little to the pathologic diagnosis of superior sulcus tumors because they are so peripherally located and beyond the limits of the scope.12 This peripheral location is also responsible for the lack of typical pulmonary symptoms, such as coughing, dyspnea, or hemoptysis, that are seen in more centrally located bronchogenic malignancies. Imaging of superior sulcus tumors is critical in planning a resection. On chest radiography, the classic Pancoast tumor is visible as a small mass or pleural thickening in the apex of the lung. These lesions can be nonspecific and are often missed on routine radiographs. Larger upper lobe tumors that extend into the apex of the chest may present with similar symptoms but are not representative of the classic Pancoast tumor as originally described. Unlike chest radiographs, CT and MRI are usually ideal for tumors more cephalad in the thoracic cavity. The thin slices provide information of the tumor relation to bronchi, great vessels, subclavian vessels, vertebral column, and clinical lymphatic (N) staging. While the CT scan imaging is excellent for detection of vertebral body bony invasion by the tumor (Fig. 76-1), MRI is the preferred modality to ascertain neuroforminal, dural sac, or spinal cord extension of these tumors (Fig. 76-2). The posterior arc of the ribs and posterior chest wall invasion can also be demonstrated more clearly through the use of MRI. Axial, coronal, and sagittal MR images provide superior imaging of the region of the brachial plexus and its relationship with the subclavian and vertebral vessels.

Ch076-F06861.indd 924

A

B FIGURE 76-1 A, CT image of a typical posteriorly positioned superior sulcus tumor with chest wall invasion but no evidence of vertebral body invasion. B, CT image of a more anteriorly positioned superior sulcus tumor.

Fused CT/PET would now also be considered routine baseline imaging for superior sulcus tumors, with a specific focus on nodal and extrathoracic sites of fluorodeoxyglucose (FDG) uptake. PET has also been used to detect tumor recurrence after definitive treatment, but small areas can remain hot in the treated tumor bed for a significant period after definitive external-beam radiation therapy. When surgical resection is being considered, it is important that the disease be accurately staged. Overstaging the disease clinically, with a higher T or N status, can misdirect therapy

1/21/2008 1:39:43 PM

Chapter 76 Posterior Approach to Superior Sulcus Tumors

925

ment portends a poor survival outcome, those patients with ipsilateral N3 disease have a better prognosis. At Memorial Sloan-Kettering Cancer Center, Ginsberg published a 14% 5-year survival in patients with N3 disease as opposed to 0% in patients with N2 disease.15

POSTERIOR RESECTION TECHNIQUE Anesthesia and Patient Positioning

FIGURE 76-2 Coronal MR image demonstrating multilevel vertebral body invasion by a superior sulcus tumor. TABLE 76-1 Absolute Contraindications to Tumor Resection Motor loss of arm and/or MRI evidence of direct infiltration of the brachial plexus Esophageal and/or tracheal invasion Tumor spread to mediastinal structures (great vessels, atria, ventricles) Histologically confirmed N2 disease or contralateral N3 disease Extrathoracic disease

toward palliative care options rather than curative modalities. Similarly, understaging can subject a patient to an unnecessary thoracotomy and delay definitive radiation and chemotherapy. Precise imaging is desired in each case, but radiologic data frequently underestimate the true pathologic stage. Cangemi and coworkers reported an accuracy of 91% and 27% for staging T3 and T4 lung cancer by CT, respectively.13 Other studies have demonstrated the accuracy for staging T3 and T4 cancers of only 50%.14 As mentioned earlier, PET may improve radiologic staging due to its ability to detect micrometastatic disease. However, assessing the mediastinal nodes by endobronchial ultrasound (EBUS) or mediastinoscopy is mandatory for staging patients because it confirms or excludes N2 mediastinal disease. The presence of mediastinal nodal disease is such a strong predictor of future systemic failure that pathologically confirmed N2 disease would be considered an absolute contraindication to resection (Table 76-1). An ipsilateral supraclavicular (technically N3 or IIIB disease by the staging system), on the other hand, with the high apical chest location of the superior sulcus tumors, biologically behaves like a locoregional N1 node and as such would be considered potentially resectable for cure at the time of the pulmonary resection. A standard neck dissection from an anterior approach would be performed in such patients. Whereas any lymph node involve-

Ch076-F06861.indd 925

After bronchoscopy through a single-lumen tube or laryngeal mask airway, EBUS or mediastinoscopy is performed. If the nodes are negative, a double-lumen tube is placed and positioned under bronchoscopic guidance. The patient is placed in a lateral decubitus position, taking care to pad all of the important sites that could result in nerve injury from prolonged positioning on the operating table. The axillary roll is placed to protect the brachial plexus. The head is stabilized with cervical tongs if the tumor is suspected or known to involve the vertebral column, and care is taken to align the cervical, thoracic, and lumbar spines. The patient is placed in a perfectly perpendicular orientation and is secured in this position with an inflated beanbag. Supplemental taping is used to further prevent any rotation of the torso during the case or during the resection of the chest wall. Care is taken to prep and drape the patient from the occiput beyond the midline posteriorly and to the sternum anteriorly.

Posterolateral Thoracotomy Incision If it is anticipated that the patient will require a posterior spinal instrumentation, then it is important for the extended posterolateral thoracotomy incision to meet the planned midline incision at a right angle to minimize any risk of acute angulation and skin flap ischemia. This can be an extremely important aspect of dealing with the complex superior sulcus tumors that invade the vertebral body. A breakdown of these skin flaps may subsequently result in exposed posterior hardware, which can become an extremely complicated surgical problem to deal with. Initially, a limited posterolateral thoracotomy is performed by the division of the latissimus dorsi muscle and reflection of the serratus anterior muscle (Fig. 76-3). Based on CT, MRI, and clinical palpation of the upper rib interspaces, a decision is made to enter at least one or two rib spaces below the tumor. The initial opening of the chest needs to be at least at the midpoint of the rib or more anteriorly for larger tumors. With a limited opening sufficient to palpate the inside of the chest cavity, a decision is made to either extend along the top of the fourth rib or the top of the fifth rib, provided there is no visible or palpable evidence of intrathoracic dissemination of the tumor through the more limited exposure. Ideally, the interspace is chosen to minimize floating ribs at closure. If it is possible to maintain the 5th through 12th ribs intact as a unit, this will improve the patient’s postoperative chest wall mechanics.

Assessment of Resectability Once the interspace has been entered, the initial rib retractor is placed to permit further palpation of the lung in its entirety

1/21/2008 1:39:44 PM

926

Section 3 Lung

FIGURE 76-3 A limited posterolateral thoracotomy for fourth or fifth interspace exploration of the pleural space to determine resectability and extent of resection.

FIGURE 76-4 The thoracotomy incision is extended posteriorly and superiorly to the level of the spinous process of C7 or T1. Division of the trapezius and rhomboid muscles permits elevation of the scapula and exposure of the apical chest wall.

Brachial plexus 2

3

4

2

3

4

Bond transverse junction Tumor Paraspinous muscle FIGURE 76-5 The surgeon’s hand is shown inside the chest cavity to determine the extent of resection, number of involved ribs, as well as anterior and posterior margins of chest wall resection.

FIGURE 76-6 An additional third interspace incision is depicted along with anterior division of the third and second ribs. The posterior paraspinous muscles are elevated, and the costal transverse process joints are exposed.

and a more extended examination of the pleural and diaphragmatic surfaces, again, to rule out intrathoracic metastatic spread. Once this has been ascertained to be clear, then the initial limited posterolateral thoracotomy is extended to a full posterolateral thoracotomy, with the incision continuing to the midline at the base of the neck, at least to the level of the T1 spinous process (Fig. 76-4). The extended posterolateral thoracotomy requires the division of the trapezius muscle and rhomboids to the base of the neck. A Burford retractor with a shallow and a deep blade is positioned with the crank on the assistant’s side of the table. The large blade is positioned beneath the scapula, and the shallower blade is placed on the lower rib. This permits elevation of the scapula away

from the thoracic inlet, freeing up the assistant to help the surgeon with the dissection without any need for manual scapular retraction. With progressive elevation of the scapula, this provides an excellent view of the entire apex of the chest cavity. The lung is now deflated. Care is taken to minimize the barotrauma on the down (ventilated) lung and to reduce the concentration of inspired oxygen. Simultaneously, the patient’s oxygen saturations must be maintained and measured by a continuous O2 saturation monitor. With the lung deflated, a hand is inserted along the inside of the chest cavity to ascertain the extent of chest wall involvement by the tumor (Fig. 76-5).

Ch076-F06861.indd 926

1/21/2008 1:39:44 PM

Chapter 76 Posterior Approach to Superior Sulcus Tumors

927

Subclavian artery First rib

Subclavian artery

Brachial plexus

2

3

Right angle clamp under posterior scalene FIGURE 76-7 The scalenus posterior muscle is divided from its attachments with the second rib through tumor-free margins.

Chest Wall Resection An additional superior interspace incision is usually necessary to preserve uninvolved ribs. The initial chest wall division is directed to the anterior aspect of the ribs to be resected (Fig. 76-6). At least a 3- to 5-cm margin is taken anteriorly. The ribs are divided in sequence. The rib of the interspace that was entered is initially divided with clipping, ligation, or cautery of the intercostal vessels. The ribs are divided with rib shears, and small segments of the anterior rib edges are removed and sent as margins for permanent sectioning. This also permits better visualization and mobility of the chest wall during the rest of the resection of the anterior portions of the ribs. The scalenus posterior muscle is divided from its insertion with the second rib (Fig. 76-7). For superior sulcus tumors that extend through the chest wall, a greater margin of the scalene posterior muscle is taken in case the tumor should extend into this muscle. The first rib is identified, and the periosteum is gently scored with electrocautery. With the use of a Cobb elevator, a subperiosteal dissection of the first rib is performed. Again, depending on the anterior extent of this posteriorly situated tumor, it may be necessary to divide the insertion of the scalenus anterior muscle as it inserts into the tubercle of the first rib. The subclavian vessels are gently swept superiorly by blunt digital dissection. Care must be taken to completely clear all soft tissues away from the proposed site of division of the first rib (Fig. 76-8). The first rib is divided with hooked first-rib shears or a Gigli saw (Fig. 76-9). When using a Gigli saw, it is important to protect the soft tissue superiorly to avoid any inadvertent injury to the subclavian vessels or brachial plexus. Injury to the subclavian vessels at this point would be problematic, because proximal control and repair may be difficult. The paraspinal musculature is dissected away from the junction of the ribs and transverse process. For tumors that are more extensive and by MRI are shown to extend into the paraspinal musculature, an en-bloc resection of the muscles

Ch076-F06861.indd 927

FIGURE 76-8 The first rib is encircled at the site of proposed division with the subclavian vessels swept superiorly.

Brachial plexus

Gigli saw

First rib

FIGURE 76-9 A Gigli saw or angled rib cutter is an effective way to divide the first rib anteriorly.

with the tumor is performed. The typical posterior superior sulcus tumor often involves the first and second ribs and the paraspinal musculature, which can be included en-bloc with tumor resection. Using electrocautery, the costotransverse ligaments are identified and divided with electrocautery. Sequentially, the rib heads are disarticulated from the transverse processes, from the more caudal to cephalad ribs. A Cobb elevator is utilized to lift the rib head and neck away from the transverse process and vertebral body (Fig. 76-10). One should never lever on the transverse process itself. This maneuver is similar to the techniques of an anesthesiologist intubating a patient with a laryngoscope. The force is a lifting motion to elevate the larynx rather than lever

1/21/2008 1:39:50 PM

928

Section 3 Lung

2

3

2

3

Transverse processes

Intercostal nerves

Third transverse junction FIGURE 76-10 An elevator is used to lift the neck and head of the rib away from the transverse process and vertebral body.

FIGURE 76-11 With anterior rotational pressure by the first assistant, the costal transverse joints are opened, enabling identification and division of the ligated or clipped intercostal nerves and vessels.

A B FIGURE 76-12 A, As ribs are disarticulated from inferior to superior, the T1 nerve root can be seen immediately below the neck of the first rib. B, An operative photograph shows the neck of the first rib between the forceps tips and the T1 nerve root lying immediately inferior.

the blade of the laryngoscope on the upper incisors. Force is always directed away from the neural foramina to avoid any risk of inadvertent entry into the neural foramina with possible spinal cord injury. Tumor involvement can destroy the bone and weaken this area and cause a serious neurologic injury if these principles are not adhered to. The assistant applies rotational pressure anteriorly to rotate the ribs away from the transverse process as the surgeon elevates the rib away from the vertebral body. This rotational pressure permits opening of the costotransverse joints. As

Ch076-F06861.indd 928

these joints open, the intercostal nerves and vessels can be identified and ligated or clipped (Fig. 76-11).

Dissection of the Brachial Plexus As the ribs are disarticulated from inferior to superior, special attention must be placed in the region of the first and second ribs. The neck of the first rib courses immediately between the very large T1 nerve root and the C8 nerve root. The T1 nerve root can be identified as a very broad structure that is

1/21/2008 1:39:53 PM

Chapter 76 Posterior Approach to Superior Sulcus Tumors

FIGURE 76-13 The T1 nerve root can be readily divided without sacrificing function. All efforts need to be made to preserve the C8 nerve root. A neurolysis along C8 will often enable an R0 resection with preservation of the C8 nerve root.

coursing anteriorly and superiorly from the surgeon’s view at an angle of approximately 60 degrees at which it joins the C8 root just beneath the neck of the first rib (Fig. 76-12). The T1 root has both a motor and a sensory component. Tumoral invasion is most commonly limited to the T1 nerve root. If this occurs, the nerve root is divided as it emerges from the intervertebral foramen while keeping the C8 component intact. The disarticulation of the first rib is technically the most difficult rib and carries with it the greatest risk of injury to the nerve roots. The first rib is almost a hook that must be gently rotated out of its joint through the use of a small Cobb elevator that is gently placed in the joint with slight rotation to loosen the ligaments that are attached. A distinct sensation can be appreciated when the rib has been loosened. The neck of the first rib is grasped with a Kocher clamp, which facilitates the outward rotation of the first rib, again taking care to avoid injury to the C8 and T1 nerve roots. With the rib now rotated out of the joint, the soft tissues superiorly are cauterized to free up the most posterior insertion of the scalene muscles. Neurolysis occurs along the C8 root, and the junction between C8 and T1 is closely observed. The T1 root may be simply compressed by the superior sulcus tumor, in which case a neurolysis is all that is required to free up the T1 root. Often, however, the T1 root is involved with tumor and must be resected with specimen. The T1 root can be sacrificed with very little change in hand function. The root is sharply divided with its junction with the C8 root. Care is taken to avoid sacrificing of the C8 root if at all possible because this will significantly impair the intrinsic hand function of the

Ch076-F06861.indd 929

929

patient (Fig. 76-13). After either neurolysis of the C8 and T1 roots or division of the T1 root, the sympathetic chain is next divided along with some ligation of intercostal veins. If the upper portion of the stellate ganglion can be salvaged and is not involved by tumor, then Horner’s syndrome can be avoided postoperatively. Posteriorly situated superior sulcus tumors, however, frequently have already infiltrated the ganglion, which will therefore require en-bloc resection. Care must also be taken at this point to avoid injury to the vertebral artery. The vertebral artery courses posteriorly from the subclavian artery and loops downward before turning cephalad to enter the foramen in the transverse process of the C6 vertebra. The dissection is extended with an apical pleurectomy and, as well, dissection of Sibson’s fascia as it extends up into the neck. The pleural dissection is also extended onto the anterior portion of the vertebral body to include the prevertebral fascia. Once a clear margin is identified, then the pleura and prevertebral fascia are incised with electrocautery and extended up toward the neck. Often the longus colli muscle may also be infiltrated, and this can be dissected high into the neck as well from the posterior approach. This maneuver now completed fully mobilizes the lobe and its attached chest wall component.

En-bloc Resection At this point, for small apical tumors, the chest wall and tumor can be separated from the lobe with a series of GIA stapler firings. The specimen can be handed off and can be processed for frozen section analysis by the pathologist while a completion lobectomy and mediastinal lymphadenectomy is performed. Removal of the chest wall at this point minimizes some of the weight of the specimen that could result in a torsional injury to the delicate hilar vessels during the dissection of the hilum. Tumors that extend more centrally cannot be removed before the formal anatomic dissection. Care must be exercised during the hilar dissection of the pulmonary artery when a bulky tumor requires manipulation, because retraction of the tumor and attached chest wall to expose the vessels for ligation can result in avulsion of the branches from the pulmonary arterial tree. A full mediastinal lymph node dissection is performed after the specimen has been removed. At this point, the vertebral bodies are closely examined. If there is any suggestion of involvement of the vertebral body or neural foramina, consultation with a spinal surgeon is obtained at this point about whether to perform a foraminotomy or a partial or complete vertebrectomy through this extended posterolateral thoracotomy exposure. Extended resections including resections of vertebral bodies at several levels with anterior and posterior stabilizations may be required for very complex lesions. Provided no vertebral body work needs to be done, the chest wall defect can be closed. Although the overlying scapula provides adequate coverage, the tip of the scapula can often become entrapped with movement of the shoulder girdle. In addition, patients can develop poor chest wall mechanics due to the loss of scalene attachments. These two

1/21/2008 1:39:57 PM

930

Section 3 Lung

conditions can be minimized with proper chest wall reconstruction. Two-millimeter polytetrafluoroethylene (PTFE) or a double layer of high-density polyethylene mesh can be used. The prosthetic mesh is anchored to the transverse processes posteriorly, pulled taut anteriorly, and placed into the second, third, and fourth or fifth ribs anteriorly. The patient is positioned in reverse flexion to elevate the legs, and a very taut closure is then performed to the remaining ribs inferiorly. Also, the mesh or PTFE can be extended to cover any posterior hardware that is at risk for exposure and infection. Smaller resections do not require prosthetic closure of the chest wall because the overlying scapula and chest wall musculature are sufficient protection despite the posteriorly resected ribs. If a mesh reconstruction is not used, then a partial scapular tip resection needs to be performed to avoid scapular tip entrapment, which results in a “shoulder” dislocation-type presentation of arm pain and immobility.

Closure of the Thoracotomy Incision Chest tubes are placed before the closure of the thoracotomy incision. Meticulous closure of this large defect is required to reduce postoperative complications. Individual muscle layers such as paraspinous muscles must be reapproximated to cover any vertebral hardware. The skin must be appropriately sutured to prevent wound dehiscence that could have serious consequences for any underlying prosthetic mesh or hardware that may become exposed.

Complications Resecting an apical tumor mass has its share of risks. Hemothorax and chylothorax can occur with any extensive thoracic or vertebral dissection. Care must be taken to ensure detailed and extensive ligation of paravertebral veins and intrathoracic lymphatic vessels. Cerebrospinal fluid leakage is a potential complication that may occur during rib disarticulation in which a tear in the dura mater at the axilla of the nerve root may occur. Prolonged cerebrospinal fluid leakage can lead to severe headaches, meningitis, or an infection of vertebral hardware. More importantly, if there are air leaks from the fissural dissection of the lung, this could lead to patient confusion and seizures from pneumocephalus because air can track into the subarachnoid space, ventricles, and central canal of the brain and spinal cord. Also, Horner’s syndrome, if not already a presenting symptom, can develop postoperatively with manipulation or division of the sympathetic chain. Patients undergoing this surgery are at increased risk for respiratory failure that may require an extended period of mechanical ventilator support. Factors that may contribute to respiratory problems include the pain control of the patient in the immediate postoperative period, the number of pulmonary segments removed, the size and location of the chest wall defect (including the extent of scalene musculature resection), the preoperative FEV1 of the patient, and possible phrenic nerve sacrifice for anteriorly situated tumors with extension into the scalene anterior muscle. All of these factors can result in abnormal, paradoxical, or dyskinetic chest wall and/or diaphragmatic movements that can contribute to poor respiratory mechanics, secretion retention, atelectasis, and pneumonia.

Ch076-F06861.indd 930

Vertebral Body Tumors Despite the success of the this procedure, resection of superior sulcus tumors becomes exponentially more difficult when the brachial plexus, subclavian vessels, or vertebral column is involved. This resection involves coordination of thoracic, orthopedic, and neurosurgical teams, which has been shown to improve resectability and local control.16 Bone involvement was identified by Paulson as an indicator of poor prognosis.9 At that time, subclavian and vertebral invasion were considered contraindications to surgery. Advanced resection techniques and neoadjuvant therapy have changed this perspective, although vertebral involvement continues to be a poor prognostic indicator. Komaki and colleagues at the University of Texas M. D. Anderson Cancer Center reported direct vertebral extension of superior sulcus tumors to be a significant negative prognostic factor with disease-free survivals at 2 years of 15% and 40%, with and without vertebral invasion, respectively.17 This study confirmed the role of local control, with 2-year survivals of 52% and 13% with and without local control, respectively. At Memorial SloanKettering Cancer Center, Ginsberg and coworkers showed the 5-year survival of completely resected patients to be 41%, as opposed to 9% with incomplete resection.15 Although the number and complexities of possible surgical approaches has increased, superior sulcus tumors continue to be challenging resections. For tumors involving the subclavian vessels, Dartevelle popularized an approach originally described by Mathey and Cormier.18 This anterior transcervical approach allows better exposure of the extreme lung apex, brachial plexus, and subclavian vessels. It involves incisions of the sternocleidomastoid and retraction of the clavicle. Dartevelle’s approach has lower morbidity than the previously described posterior approach. However, the osteomuscular resections alter shoulder mobility and cause deformities to the cervical posture. To avoid this, Grunenwald and colleagues at the Institut Mutualiste Montsouris devised a technique that combines the anterior cervicothoracic transmanubrial and posterior median spinal approaches. This procedure maintains the sternoclavicular joint, yet still allows for secure control of the subclavian vessels. In addition, this approach facilitates upper lobectomy, superior mediastinal lymph node dissection, and division of the thoracic wall beyond the tumorous elements. For vertebral resections, Grunenwald and colleagues perform an en bloc extratumorous resection. The anterior vertebral body plane is separated from the posterior mediastinal structures. After stabilization of the contralateral vertebral body with a plate and transpedicular screws, the ipsilateral vertebral body is excised so that the attached pulmonary lobe, superior sulcus tumor, and vertebral body are resected en bloc. This procedure respects oncologic principles and avoids violation of the tumor block. Despite its complexity, data from this group’s 8-year experience proves its merits. Of the 19 patients who underwent en-bloc resection, the 1- and 5-year survivals were 59% and 14%, respectively.16 Unlike Grunenwald and colleagues, the M. D. Anderson group separately resects the involved vertebrae after the tumor with disarticulated ribs and chest wall have been removed. This is an endolesional approach that has been

1/21/2008 1:39:59 PM

Chapter 76 Posterior Approach to Superior Sulcus Tumors

utilized by M. D. Anderson spine surgeons in over 2000 cases for metastatic tumors involving the spine, which is faster, is more direct, and permits optimal anterior stabilization of the spine after the resection. For stabilization, the vertebral column is supported by an anterior methylmethacrylate column or cage and lateral titanium plating. Data from this experience from 1990 to 1998 showed an actuarial 2-year survival of 54%, with locoregional recurrence noted in 6 of 17 patients.19 The 2-year survival was 80% in the 11 patients with negative margins, as opposed to 0% for the six patients with positive margins. There were no perioperative deaths, and complication rates were similar (42% versus 53%) between the two groups.

Multimodal Therapy For patients with advanced superior sulcus tumors, their best chance of survival involves multimodal therapy. The neoadjuvant protocol established by Paulson 30 years ago has become the gold standard of treatment. Reported in the early 1980s, Paulson’s series totaled 131 patients.20 Complete resection was achieved in 60% of patients, and the survival rates for those completing combined treatment were 31% at 5 years, 26% at 10 years, and 22% at 15 years. For those without nodal involvement at operation, the survival rates were 44% at 5 years, 33% at 10 years, and 30% at 15 years. There have been other series involving preoperative radiation and surgical resection. Martini and colleagues treated 145 patients over a 36-year period, with 29 patients treated by external radiation alone, 68 by operation without preoperative radiation, and 48 by preoperative radiation followed by resection.21 The mean survivals were 6 months with radiation alone, 30 months with preoperative radiation followed by resection, and 10 months with operation alone. Other reports by Anderson and Ricci both showed 5-year survival rates of 34%.22 Although radiation followed by subsequent resection resulted in 60% complete resection, the major determinant of overall survival is residual micrometastatic disease. The success of combined-modality therapy for stage IIIa (N2) non–small cell lung cancer (NSCLC) during the 1980s and 1990s led to the development of a novel treatment strategy. Rusch and the Southwest Oncology Group (SWOG) conducted a prospective multicenter trial in which patients with T3-T4, N0-N1 superior sulcus NSCLC underwent induction chemoradiotherapy (two cycles of cisplatin and etoposide concurrently with 45 Gy of radiation) followed by resection.23 Results from this study showed that pathologic complete response (CR) or minimal microscopic disease occurred in 56% of resection specimens. The 5-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 disease. A major finding was that any amount of residual disease, even when completely resected, is associated with a significantly worse survival than when a pathologic complete response occurs. The overall 5year survival was better with induction chemoradiotherapy followed by resection compared with patients who did not receive chemotherapy. Furthermore, the 5-year survival for patients with residual disease treated by the SWOG regimen surpassed the approximate 30% survival reported for patients

Ch076-F06861.indd 931

931

treated with the classic induction radiation followed by resection. Despite the promise of induction chemoradiotherapy, some thoracic surgeons prefer resection initially, followed by radiotherapy. In 1993, Dartevelle and colleagues reported 2and 5-year survival rates of 50% and 31%, respectively, with a median follow-up time of 2.5 years.24 Fourteen percent of these patients had surgery alone; 86% had surgery followed by postoperative radiation, whereas none of the patients received preoperative irradiation. These patients had extensive disease of the superior sulcus, but their resectability rates were high owing to the anterior transcervical and thoracic approach and accurate staging by modern imaging studies. A report by Komaki and coworkers revealed that combined therapy improved superior sulcus tumor control and increased survival rates as opposed to use of either modality alone.25 In this study, 43 patients with stage IIIA disease and 42 patients with stage IIIB disease underwent treatment. Surgery was more frequently performed on those with stage IIIA than stage IIIB disease, who were offered chemotherapy. The patients with stage IIIA disease who underwent surgery had a 1-year survival of 46.5% compared with 21% for the patients with stage IIIB disease. Furthermore, with surgery, 52% (13/25) lived longer than 2 years compared with 22% (13/60) when radiation therapy was used for unresectable tumors. These data support the belief that resection needs to be used whenever possible for superior sulcus tumors and that uninterrupted high-dose radiation needs to be offered to those with unresectable lesions. With the exclusion of chemotherapy, the data are equivocal in relation to neoadjuvant or adjuvant radiotherapy for the treatment of superior sulcus tumors. No randomized prospective trials have been performed to compare the following: 1. 2. 3. 4.

Preoperative radiation followed by surgical resection Surgical resection followed by postoperative radiation Surgery alone Radiotherapy alone

At the University of Texas, M. D. Anderson Cancer Center, an ongoing treatment protocol consists of tumor resection followed by uninterrupted concurrent radiation and chemotherapy. Specifically, patients receive a segmentectomy or lobectomy with en-bloc resection of the involved chest wall or vertebrae, followed by radiation therapy and concomitant chemotherapy. The radiation regimen consists of 60 Gy in 50 fractions for negative margins and 64.8 Gy in 54 fractions for positive margins. Chemotherapy involves the platinum analogue cisplatin, 50 mg/m2 intravenously on days 1 and 8, and etoposide on days 1 to 5 and days 8 to 12. This cycle is repeated on day 29. The exact role of chemotherapy is still unclear in the treatment of superior sulcus tumors. Prior to completion of the aforementioned study, preliminary work from the SWOG yielded an impressive 50% complete pathologic response rate and approximately 50% 3-year survival rate in patients with T3-T4 N0 M0 Pancoast tumors.26 This work serves as the basis for the present study being conducted at M. D. Anderson Cancer Center, which has accrued 40 patients to date.

1/21/2008 1:39:59 PM

932

Section 3 Lung

Some studies have shown that up to 44% of patients surviving more than 2 years will develop brain metastases.27 In addition, brain metastases are more common in patients with poorly differentiated or undifferentiated lesions. Therefore, prophylactic cranial irradiation is offered at the completion of chest irradiation in the previously described trial.

SUMMARY Superior sulcus tumors are unique lung cancers in which location and tumor biology continue to be a challenge for the thoracic surgeon. Their location at the apex of the lung and their often advanced stage at diagnosis have resulted in technically complex resections. The important key to a beneficial outcome starts with a thorough initial workup including history and physical examination, tissue diagnosis, and modern imaging studies, including the routine use of CT, MRI, and fused CT/PET. These patients require mediastinoscopy or EBUS to rule out N2 disease, sparing patients an unnecessary thoracotomy. Those with T3 chest wall or T4 vertebral disease are now offered resection after full exposure to the thoracic inlet, posterior mediastinum, and vertebral column through an extended posterolateral thoracotomy. Radiation therapy and chemotherapy continue to play important roles in either the preoperative or the postoperative setting. Although the standard approach has been neoadjuvant radiotherapy followed by resection, some groups choose postoperative radiotherapy because of its uninterrupted schedule

Ch076-F06861.indd 932

and the ability to give higher doses of treatment. The role of chemotherapy is unclear, although the use of these agents has been shown to downstage tumors and may provide immediate treatment of subclinical metastatic disease. Besides platinum agents and semisynthetic agents, other drugs aimed at inhibition of angiogenesis such as vascular endothelial growth factor or tyrosine kinase inhibitors may play a future role in patient survival and potential chronic maintenance therapy for patients with treated superior sulcus tumors.

COMMENTS AND CONTROVERSIES The posterior approach to a superior sulcus tumor provides superb exposure, particularly for the more posteriorly positioned tumors. Basically the entire chest wall, brachial plexus, and subclavian artery dissection is conducted outside the pleural space. Unfortunately the patient must be exposed to an extensive operative procedure before the thoracic inlet and the tumor attachments to surrounding structures are visualized. Occasionally, the circumstance of an incomplete resection will be encountered only after subjecting the patient to major surgical trauma. It is my practice to conduct a primarily supraclavicular dissection. This enables the surgeon to evaluate the extent of tumor from its superior aspect without exposing the patient to major operative insult. Involvement of subclavian vein, artery, brachial plexus, scalene muscle, and supraclavicular lymph nodes can be determined before posterolateral thoracotomy and skeletal chest wall division. G. A. P.

1/21/2008 1:39:59 PM

chapter

ANTERIOR APPROACH TO SUPERIOR SULCUS TUMORS

77

Benjamin D. Kozower G. Alexander Patterson

Key Points ■ Thorough staging is imperative to exclude patients with mediastinal

nodal involvement (stage III) and systemic disease (stage IV). We perform mediastinoscopy before all resections. ■ The anterior approach to superior sulcus tumors is best suited for tumors located in the anterior and middle compartments of the thoracic inlet. We believe that posterior compartment tumors are better approached by a high posterolateral thoracotomy. ■ Induction chemoradiation therapy improves complete resection rates and improves survival. We believe that it needs to be the standard of care for superior sulcus tumors. ■ The key to a successful operation is en-bloc exenteration of the tumor with negative margins.

Oncology Group (SWOG) to perform a prospective, multiinstitutional trial of induction chemoradiation therapy (Rusch, 2001).6 A total of 111 patients with mediastinoscopynegative T3-4 N0-1 superior sulcus tumors received two cycles of cisplatin and etoposide concurrent with 45 Gy of radiation. Patients with stable or responding disease proceeded to thoracotomy 3 to 5 weeks later. One third of resections showed a complete pathologic response, and 92% had a complete resection. This preliminary report demonstrated that induction chemoradiation was feasible in a multiinstitutional setting, improved resectability, and improved the 2-year survival rate to 70% for those with a complete resection (76 of 83 patients).

SURGICAL ANATOMY

HISTORICAL NOTE Pancoast described the importance of careful radiologic assessment of superior sulcus tumors in 1924.1 Pancoast’s syndrome is the combination of shoulder and arm pain in the distribution of the C8-T2 nerve roots, Horner’s syndrome, and weakness and atrophy of the hand muscles. The most common cause for this syndrome is local extension of an apical lung tumor at the thoracic inlet. Pancoast mistakenly believed that these tumors emanated from epithelial rests of the fifth branchial cleft. It was Tobias who correctly identified bronchopulmonary tissue as the origin of the Pancoast-Tobias syndrome.2 Superior sulcus tumors may extend through the visceral pleura into the parietal pleura and the surrounding structures of the thoracic inlet and supraclavicular region. These tumors were considered inoperable until Shaw and Paulson demonstrated that preoperative irradiation facilitated surgical resection and improved the survival rate at 5 years to 30% (Paulson, 1975; Shaw et al, 1961).3,4 The operation consisted of an extended en-bloc resection of the chest wall, including the first three ribs and their transverse processes, the intercostal nerves, the lower trunk of the brachial plexus, and the involved lung. Rusch reported the largest series of 225 patients operated on for superior sulcus tumors.5 The 5-year survival rate was 46% for T3 N0 (stage IIB) disease and less than 15% for stage III. Survival was influenced by T and N status and completeness of resection. However, a pathologic complete resection was achieved for only two thirds of T3 tumors and 40% of T4 tumors. Importantly, locoregional disease was the most common form of relapse. This prompted the Southwest

The anatomy of the superior sulcus is complex, and a thorough understanding of its contents and their spatial relationships is imperative for the thoracic surgeon. The insertion of the anterior, middle, and posterior scalene muscles on the 1st and 2nd ribs divides the thoracic inlet into three compartments (Fig. 77-1). The anterior compartment lies in front of the anterior scalene muscle. It contains the platysma, sternocleidomastoid muscles, jugular veins, inferior belly of the omohyoid muscle, the subclavian vein, and the scalene fat pad. The middle compartment lies between the anterior and middle scalene muscles. It contains the anterior scalene muscle with the phrenic nerve on its anterior aspect, subclavian artery, brachial plexus, and the middle scalene muscle. The posterior compartment is behind the middle scalene muscle. It includes the long thoracic nerve and external branch of the spinal accessory nerve, posterior scapular artery, sympathetic chain, and vertebral bodies.

CLINICAL FEATURES Superior sulcus tumors of non–small cell histology account for fewer than 5% of all bronchogenic carcinomas.7 Most superior sulcus tumors are peripherally located, and pulmonary symptoms such as cough, hemoptysis, and dyspnea are rare. The clinical features are influenced by tumor location and type of invasion of the thoracic inlet.8 Tumors located in the anterior compartment usually manifest with chest wall pain due to invasion of parietal pleura, overlying ribs, and associated intercostal nerves. Many patients are incorrectly treated for cervical osteoarthritis or bursitis, delaying the correct diagnosis. Hand or arm swelling suggests subclavian or brachiocephalic vein invasion. The phrenic nerve may be involved as it crosses the anterior scalene muscle. Tumors located in the middle compartment frequently invade the 933

Ch077-F06861.indd 933

1/21/2008 1:40:47 PM

934

Section 3 Lung

Right anterior dissection Thyroid gland (reflected)

Internal jugular vein Common carotid artery

Middle cervical sympathetic ganglion

Ascending cervical artery Phrenic nerve

Vagus nerve (X)

Anterior scalene muscle Vertebral artery Inferior thyroid artery Common carotid artery

Transverse cervical artery

Recurrent laryngeal nerve

Suprascapular artery Dorsal scapular artery

Brachiocephalic trunk

Costocervical trunk

Internal jugular vein (cut)

Thyrocervical trunk Subclavian artery and vein

FIGURE 77-1 Anatomy of the right thoracic inlet. (FROM NETTER FH: ATLAS OF HUMAN ANATOMY, 3RD ED. TETERBORO, NJ, ICON LEARNING SYSTEMS, 2003, PLATE 29.)

brachial plexus. They usually manifest with pain and parasthesias radiating to the shoulder and arm. These tumors tend to spread along the fibers of the middle scalene muscle. Tumors invading the posterior compartment may manifest with the signs and symptoms of the Pancoast-Tobias syndrome. They are usually located in the costovertebral groove. Posterior compartment tumors initially manifest with abnormal sensation and pain in the axilla and medial aspect of the upper arm along the territory of the intercostobrachial nerve. They also result in weakness and atrophy of the intrinsic muscles of the hand, caused by tumor extension into the C8 and T1 nerve roots. Posterior tumors lead to Horner’s syndrome by extension into the stellate ganglion. They extend through the intervertebral foramina in 5% of patients, resulting in spinal cord compression and paraplegia. In addition, vertebral bodies may be involved by direct extension.

DIAGNOSIS The majority of cases of Pancoast’s syndrome are caused by non–small cell lung cancer. However, the differential diagnosis for Pancoast’s syndrome and superior sulcus lesions is diverse8 (Table 77-1). The most sensitive diagnostic procedure is a transthoracic needle biopsy under radiologic guidance. A diagnostic yield of greater than 95% has been reported. The radiologic findings can be subtle because these lesions are often hidden behind the 1st rib and clavicle. Posteroanterior and lateral chest radiographs have a low sensitivity for

Ch077-F06861.indd 934

TABLE 77-1 Etiology of Pancoast’s Syndrome and Superior Sulcus Lesions Neoplasm Primary bronchogenic carcinoma Other primary thoracic neoplasms Mesothelioma, adenoid cystic carcinoma, sarcomas Metastatic neoplasms Hematologic neoplasms Plasmacytoma, lymphoma Infectious Processes Bacterial Pneumonia, actinomycosis Fungal Aspergillosis, cryptococcosis, allescheriasis Tuberculosis Parasitic Hydatid cyst Miscellaneous Causes Cervical rib syndrome Pulmonary amyloidoma

early lesions. Computed tomography (CT) provides precise localization of the tumor and its local extension. Magnetic resonance imaging (MRI) appears to be even more accurate than CT for the detection of tumor extension into the brachial plexus, subclavian vessels, vertebral bodies, and spinal canal.9

1/21/2008 1:40:47 PM

Chapter 77 Anterior Approach to Superior Sulcus Tumors

935

STAGING AND PREOPERATIVE ASSESSMENT All patients undergo a thorough search for mediastinal and distant metastases. Positron emission tomography (PET) is a routine part of our evaluation to assess regional lymph node involvement and distant metastatic disease. We perform mediastinoscopy on all patients with superior sulcus lesions because they are at least T3 tumors, and N2 or N3 mediastinal lymph node involvement precludes surgery. Our initial investigation also includes preoperative cardiopulmonary function tests and other standard investigations required for major pulmonary resection. Determination of specific nerve root involvement is important to predict resectability and functional outcome after resection. T1 invasion produces pain and paresthesia in the medial aspect of the upper arm. C8 invasion is associated with loss of intrinsic muscle strength, lack of thumb opposition, and numbness in the small finger and medial half of the ring finger. However, resection of C8 and T1 will leave a severely impaired so-called ulnar hand. These observations can be confirmed by electromyography, but clinical examination is usually sufficient. Phrenic nerve invasion is detected by elevation and immobility of the ipsilateral diaphragm. Vascular invasion is usually apparent by high-quality contrast CT scanning, but additional information may be obtained from MRI. It is important to remember that apposition of a tumor to major structures does not confirm invasion or preclude surgical exploration to determine resectability. Absolute contraindications to resection include N2 or N3 disease, extensive vascular invasion that is not resectable, brachial plexus involvement more extensive than C8 and T1, and multiple-level vertebral involvement with extension into the spinal canal. Subclavian vein or arterial invasion is not a contraindication to resection. The subclavian vein can be resected without reconstruction. Subclavian artery resection requires primary reconstruction or interposition grafting. Importantly, vascular invasion indicates a T4 lesion and predicts decreased long-term survival. Limited involvement of the vertebra (transverse process or partial vertebral body involvement) is not a contraindication to resection. More extensive vertebral involvement may be resectable due to recent advances in vertebral resection and spinal stabilization. Limited experience with such resections has been reported from a small number of specialized centers, but the early results are encouraging.

OPERATIVE TECHNIQUE Anterior Transcervical-Thoracic Approach (Dartevelle Approach) The anteror transcervical-thoracic (Dartevelle) approach is well suited for anterior lesions but requires a great deal of expertise to perform an en-bloc resection without making a thoracotomy. Dartevelle first reported his surgical technique and results with this approach in 1993 (Dartevelle et al, 1993).10 The patient is placed in the supine position with the shoulders elevated, the neck hyperextended, and the head turned away from the involved side. The operative field extends from the mastoid down to the xiphoid process and between the axillary lines.

Ch077-F06861.indd 935

FIGURE 77-2 The L-shaped cervicotomy. Anterior transcervicalthoracic approach for radical resection of lung tumors invading the thoracic inlet.

An L-shaped incision is made that includes an oblique, presternocleidomastoid incision extended horizontally below the clavicle and lateral to the deltopectoral groove (Fig. 77-2). However, to perform the entire resection through this incision and avoid making a separate thoracotomy, the horizontal portion of the incision is lowered to the second or third intercostal space. A subplatysmal flap is raised laterally to expose the supraclavicular fat pad. This tissue is resected to rule out supraclavicular N3 disease. The sternocleidomastoid muscle is separated from the clavicle and manubrium to create a myocutaneous flap. The flap is reflected back to expose the neck and the thoracic inlet. The inferior belly of the omohyoid muscle is transected, and the scalene fat pad is dissected and sent for frozen section examination. Superior mediastinal invasion is assessed by inserting a finger along the lateral aspect of the tracheoesophageal groove. Extension of the tumor into the thoracic inlet is carefully assessed. Resection through this approach requires visualization of the thoracic inlet immediately posterior to the medial clavicle. Dartevelle and colleagues described resection of the medial half of the clavicle.10 However, medial clavicular resection can limit shoulder mobility and result in significant postoperative morbidity. A number of authors have described techniques to preserve the sternoclavicular joint and elevate the entire clavicle from the medial to lateral direction. After resection is complete, the clavicle-sternal unit is rigidly fixed back to the sternum.

Dissection of the Subclavian Vein Division of the internal, external, and anterior jugular veins facilitates excellent visualization of the venous confluence at the origin of the innominate vein. On the left side, the

1/21/2008 1:40:49 PM

936

Section 3 Lung

FIGURE 77-3 Dissection of the subclavian vein. Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet.

thoracic duct is identified, ligated, and divided. Division of the internal jugular vein improves exposure of the subclavian vein. If the subclavian vein is involved, it is resected after proximal and distal control have been obtained. The phrenic nerve is identified on the surface of the anterior scalene muscle and preserved whenever possible (Fig. 77-3). The anterior scalene muscle is then divided, either at its insertion on the scalene tubercle of the 1st rib or well away from the tumor. If the tumor has invaded the superior aspect of this muscle, the muscle is divided at the insertion on the anterior tubercles of the transverse processes of C3 through C6.

FIGURE 77-4 Dissection of the subclavian artery. Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet. (FROM DARTEVELLE P, CHAPELIER A, MACCHIARINI P, ET AL: ANTERIOR TRANSCERVICAL APPROACH FOR RADICAL RESECTION OF LUNG TUMORS INVADING THE THORACIC INLET. J THORAC CARDIOVASC SURG 105:1025, 1993.)

Dissection of the Subclavian Artery The subclavian artery is mobilized by dividing branches as necessary (Fig. 77-4). The vertebral artery is sacrificed only if it is involved and provided that no significant extracranial occlusive disease was detected on preoperative Doppler ultrasound examination. The artery can usually be dissected away from the tumor in a subadventitial plane. If the artery is invaded, it is resected and reconstructed primarily or with an interposition graft (Fig. 77-5).

Dissection of the Brachial Plexus The middle scalene muscle is divided above its insertion on the 1st rib or higher, as indicated by the extension of the tumor. The nerve roots of C8 and T1 are then easily identified and dissected until they coalesce to form the lower trunk of the brachial plexus. The prevertebral muscles are then detached along with the dorsal sympathetic chain and stellate ganglion from the anterior surface of the vertebral bodies of C7 and T1 (Fig. 77-6). This permits visualization of the

Ch077-F06861.indd 936

FIGURE 77-5 Reconstruction of the subclavian artery. Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet. (FROM DARTEVELLE P, CHAPELIER A, MACCHIARINI P, ET AL: ANTERIOR TRANSCERVICAL APPROACH FOR RADICAL RESECTION OF LUNG TUMORS INVADING THE THORACIC INLET. J THORAC CARDIOVASC SURG 105:1025, 1993.)

1/21/2008 1:40:50 PM

Chapter 77 Anterior Approach to Superior Sulcus Tumors

937

FIGURE 77-7 Chest wall resection. Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet. FIGURE 77-6 Dissection of the brachial plexus. Anterior transcervicalthoracic approach for radical resection of lung tumors invading the thoracic inlet. (FROM DARTEVELLE P, CHAPELIER A, MACCHIARINI P, ET AL: ANTERIOR TRANSCERVICAL APPROACH FOR RADICAL RESECTION OF LUNG TUMORS INVADING THE THORACIC INLET. J THORAC CARDIOVASC SURG 105:1025, 1993.)

intervertebral foramina. The T1 nerve root, if involved, is divided proximal to the tumor at the level of the T1 intervertebral foramen. Although the tumor may extend well superior into the brachial plexus, neurolysis is usually achieved without division of any nerve roots above T1. Damage to the lateral and long thoracic nerves are avoided to prevent a winged scapula.

Chest Wall Resection The anterolateral arch of the 1st rib is divided at the costochondral junction, whereas the 2nd rib, unless involved more anteriorly, is divided at the level of its middle arch. The 3rd rib is scraped on the superior border toward the costovertebral angle (Fig. 77-7). The specimen is slowly freed as the ribs are disarticulated from the transverse processes of the first two or three thoracic vertebrae.

Pulmonary Resection The procedures described create a chest wall defect through which an anatomic, en bloc, upper lobectomy can be performed. The exposure mandates resection from an anterior to a posterior direction. On the right side, the order of division is superior pulmonary vein, pulmonary arterial branches, and bronchus. On the left side, the order of division is superior pulmonary vein, upper lobe bronchus, and then the pulmonary arterial branches. In experienced hands, it is

Ch077-F06861.indd 937

uncommon to reposition the patient and complete the lobectomy through a standard posterolateral thoracotomy. However, it is very difficult, if not impossible, to visualize the inferior pulmonary ligament and divide it safely through this anterior superior defect without video thoracoscopic equipment.

Chest Wall Closure If the medial clavicle is resected, the sternocleidomastoid muscle is fixed to the upper edge of the sternum. If the anterior 2nd and 3rd ribs are also resected, a chest wall prosthesis is advised. Marlex-methylmethacrylate, Gore-Tex, or Prolene mesh is a useful substitute. Standard closure and chest drainage are employed.

Hemiclamshell Approach The hemiclamshell approach for superior sulcus tumors was reported by Korst and Burt in 1998 (Korst et al, 1998).11 It provides excellent exposure for resection of these tumors. We have increased our use of this approach for tumors of the anterior and middle compartments. Although it may be used for posterior tumors, we prefer a standard Shaw-Paulson approach for those lesions. The patient is positioned supine with the ipsilateral arm tucked by the side and the contralateral arm abducted. The neck is extended, and the head is turned away from the operative side (Fig. 77-8). An anterolateral thoracotomy is made from the sternum to the anterior axillary line in the fourth intercostal space. The pleural cavity is explored to be sure there are no pleural metastases, nodal metastases, or contraindications to resection. Medially, the incision is carried

1/21/2008 1:40:51 PM

938

Section 3 Lung

superiorly over the sternum and up the anterior border of the ipsilateral sternocleidomastoid muscle. A partial sternotomy is made from the suprasternal notch down to the fourth interspace. The internal thoracic vessels are ligated, and a sternal retractor is placed to elevate the chest wall and clavicle, exposing the mediastinum and ipsilateral hemithorax. Dissection is continued in the neck in a similar fashion to the Dartevelle approach. The hemiclamshell approach provides excellent exposure of neurovascular structures running

from the neck down into the thorax (Fig. 77-9). The cervical portion of the dissection is shown in detail in Figure 77-10. The tumor present in the cervicothoracic junction can now be readily dissected free from the surrounding neurovascular structures. En-bloc resection of neighboring involved structures such as vertebral bodies, ribs, veins, arteries, nerves, and thyroid is now possible because of this wide exposure. The pulmonary hilum is also safely and easily dissected, allowing for various anatomic lung resections to be performed without the need for a separate thoracotomy incision. After resection of the tumor, chest tubes are placed, the sternum is reapproximated with wires, and pericostal sutures are placed to close the intercostal space. The remainder of the closure is performed in standard fashion.

COMPLICATIONS Patients undergoing resection of a superior sulcus tumor are at risk for the standard complications of pulmonary resections. Several specific complications after resection are discussed here. A cerebrospinal fluid leak can be catastrophic. It can lead to meningitis or be the source for an air embolus to travel from the pleural space to the brain or spinal cord. If a leak is identified intraoperatively, it needs to be sealed with an intercostal muscle flap or adjacent pleura. Postoperatively, cerebrospinal fluid leakage is suspected whenever clear fluid drains from the chest tubes. Reoperation is mandatory, and repair may require neurosurgical consultation, foraminotomy, and direct dural repair. The possibility of Horner’s syndrome and nerve deficits secondary to division of the nerve roots is discussed with the patient preoperatively. Resection of the lower trunk of the

FIGURE 77-8 Hemiclamshell incision. (REPRINTED FROM KORST RJ, ET AL: CERVICOTHORACIC TUMORS: RESULTS OF RESECTION BY THE “HEMI-CLAMSHELL” APPROACH. J THORAC CARDIOVASC SURG 115:286, 1998. WITH PERMISSION FROM ELSEVIER.)

Right vagus nerve Internal jugular vein

Common carotid artery Recurrent laryngeal nerve

Subclavian artery

Right brachiocephalic artery

Pherenic nerve Right brachiocephalic vein

Left brachiocephalic vein

Right lung

A

B

FIGURE 77-9 A and B, Exposure provided by the hemiclamshell approach. (REPRINTED FROM KORST RJ, ET AL: CERVICOTHORACIC TUMORS: RESULTS OF RESECTION BY THE “HEMI-CLAMSHELL” APPROACH. J THORAC CARDIOVASC SURG 115:286, 1998. WITH PERMISSION FROM ELSEVIER.)

Ch077-F06861.indd 938

1/21/2008 1:40:51 PM

Chapter 77 Anterior Approach to Superior Sulcus Tumors

Right vagus nerve

939

Common carotid artery

Internal jugular vein

Longus colli muscle

Phrenic nerve

Spine Vertebral artery

Recurrent laryngeal nerve Subclavian artery Right brachiocephalic artery

A

B

FIGURE 77-10 A and B, Cervical dissection. (REPRINTED FROM KORST RJ, ET AL: CERVICOTHORACIC TUMORS: RESULTS OF RESECTION BY THE “HEMI-CLAMSHELL” APPROACH. J THORAC CARDIOVASC SURG 115:286, 1998. WITH PERMISSION FROM ELSEVIER.)

brachial plexus (C8 and T1) results in atrophic paralysis of the forearm and intrinsic muscles of the hand (KlumpkeDéjérine syndrome). This is very debilitating and is avoided whenever possible. A hemothorax may occur after the chest wall resection because of the difficulty of securing small veins at the level of the intervertebral foramina. Chylothorax is more common after left-sided resections because the thoracic duct may be injured during the cervical portion of the resection. It can be avoided by ligation of the thoracic duct and its branches. If a chylothorax is identified and does not respond to conservative therapy, thoracic duct ligation via a right thoracotomy may be required. If the subclavian vein has been resected, the ipsilateral forearm needs to be elevated to facilitate venous drainage and minimize edema. If a portion of the subclavian artery has been resected, the radial pulse must be monitored to assess the patency of the repair.

SUMMARY Resection of superior sulcus tumors is one of the most technically demanding procedures in thoracic surgery. The outcome of these resections depends on the completeness of resection and the presence of N2 disease. Regardless of the approach, the key is to properly stage these patients and perform a complete, en-bloc resection. We believe that the anterior approaches detailed here are very useful for anterior and middle superior sulcus tumors. For posterior tumors, we prefer the traditional Shaw-Paulson posterolateral thoracotomy. Before a traditional posterior approach, we use a supra-

Ch077-F06861.indd 939

clavicular exploration to assess resectability and dissect the subclavian vessels and the brachial plexus. It is important to note that, in Dartevelle’s original report, a subsequent posterolateral thoracotomy was required in almost 50% of patients. Their group has gained a large experience and is now able to resect the majority of tumors using the anterior approach alone. However, surgeons with less experience may prefer the hemiclamshell approach for anterior lesions. It provides excellent exposure, preserves the clavicle, and facilitates an anatomic pulmonary resection. The SWOG demonstrated that induction chemoradiation improved the rate of complete resection, pathologic complete response, local recurrence, and 2-year survival, compared to historical controls treated with induction radiotherapy.6 A recent study from the University of Maryland retrospectively evaluated 36 patients treated with induction chemoradiation followed by surgery (Kwong et al, 2005).12 Platinum-based combination chemotherapy was given concurrently with 45 Gy of conformal radiation therapy. The complete resection rate was 97%, with an operative mortality of less than 3%. A pathologic complete response rate was achieved in 40% of patients. The median survival for the whole group was 2.6 years, and for the complete response group it was 7.8 years. Some surgeons continue to offer primary surgery for superior sulcus tumors clinically staged as T3 N0. However, we believe that induction chemoradiation therapy needs to be the standard of care for superior sulcus tumors. It helps select patients who will benefit from surgery and significantly improves the rates of complete resection and survival.

1/21/2008 1:40:53 PM

940

Section 3 Lung

COMMENTS AND CONTROVERSIES The optimal approach for resection of superior sulcus tumors must be tailored to the specific situation of the individual patient. The anterior cervicothoracic approach and the hemiclamshell approach both offer superb exposure of the thoracic inlet. Technical modifications of the anterior cervicothoracic approach enable preservation of the sternoclavicular joint and the medial half of the clavicle. The hemiclamshell approach avoids this problem. Either approach enables complete resection of most lesions without synchronous posterior thoracotomy. Either approach can be used in conjunction with a posterior midline approach for resection of tumors with localized vertebral body involvement. G. A. P.

KEY REFERENCES Dartevelle PG, Chapelier AR, Macchiarini P, et al: Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet. J Thorac Cardiovasc Surg 105:1025-1034, 1993.

Ch077-F06861.indd 940

Korst RJ, Burt ME: Cervicothoracic tumors: Results of resection by the “hemiclamshell” approach. J Thorac Cardiovasc Surg 115:286-294, 1998. Kwong KF, Edelman MJ, Suntharalingam M, et al: High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long term survival. J Thorac Cardiovasc Surg 129:1250-1257, 2005. Paulson DL: Carcinomas in the superior pulmonary sulcus. J Thorac Cardiovasc Surg 70:1095-1104, 1975. Rusch VW, Parekh KR, Leon L, et al: Factors determining outcome after surgical resection of T3 and T4 lung cancers of the superior sulcus. J Thorac Cardiovasc Surg 119: 1147-1153, 2000. Rusch VW, Giroux DJ, Kraut MJ, et al: Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 121:472-483, 2001. Shaw RR, Paulson DL, Kee JL: Treatment of the superior sulcus tumor by irradiation followed by resection. Ann Surg 7:29-40, 1961.

1/21/2008 1:40:54 PM

chapter

EXTENDED PULMONARY RESECTIONS

78

Felix G. Fernandez G. Alexander Patterson

Key Points ■ Surgical resection remains an important part of therapy for select

patients with locally advanced lung cancer. ■ Bronchogenic cancers invading the chest wall may be treated with

en-bloc resection and chest wall reconstruction. ■ Modern bronchoplastic techniques, anesthesia, and postoperative

care allow for the resection of some bronchogenic cancers invading the tracheal carina. ■ Collaboration between thoracic surgeons and orthopedic or neurosurgical colleagues allows for the en-bloc resection and subsequent reconstruction of certain bronchogenic tumors invading thoracic vertebrae. ■ Superior vena cava reconstruction utilizing either an autologous or a prosthetic interposition graft allows for the resection of bronchogenic cancers invading the superior vena cava.

As neoplasms of the lung grow they may infiltrate tissues or contiguous organs and structures. The most commonly invaded structures are the chest wall, the vertebral bodies, the diaphragm, the aorta, the left atrium, the pericardium, the esophagus, and the superior vena cava. In those situations in which invasion of lung carcinomas extends beyond the visceral pleura, the ability to resect the contiguous invaded structure or organ varies greatly. The prognosis is directly related to the completeness of the resection and the presence of nodal metastases. Resection techniques for each structure are discussed later.

HISTORICAL NOTE Carcinoma of the lung is the most frequent cause of cancer deaths in both men and women. Lung cancers invade the chest wall in 5% of cases, which amounted to 8250 cases in 1992. Between 1% and 2% invade the vertebral bodies, diaphragm, pericardium, esophagus, and superior vena cava. In 1899, Parham was the first to describe a successful resection of a chest wall tumor in the American literature.1 He stressed leaving an intact parietal pleura, lest the normal respiratory function be interrupted and death result. In 1943, Graham and colleagues produced a thoracic surgical manual that standardized the surgical approach for chest wall injuries on the basis of experience gained during World War I.2 The gravity of a sucking chest wound was recognized, and immediate closure to maintain ventilation was urged. Surrounding soft tissues were used to close the defect. These

authors also recommended tube thoracostomy for drainage and ventilation purposes. Brewer chronicled his experience during World War II, applying these principles and improving their application.3 Resection of a portion of the lung in continuity with the chest wall invaded by the tumor is now commonplace. Early chest wall resections were performed when the resulting defect was small. This defect was bridged by a variety of materials, including dura mater, fascia lata, or fascia, and, more recently, Marlex mesh. Rigid materials, including autogenous ribs and metal struts, have also been used. If a large defect occurred, the Marlex mesh and fascia-like materials did not prevent a respiratory flail and patients remained on respirator support for prolonged periods. This changed in 1974 with the introduction of the Marlex mesh/polymethyl methacrylate (PMMA) prosthesis. Reconstruction techniques using materials that are readily available are adaptable to any size and contour needed and are integrated by the body tissues with little reaction. Low infection rates were reported by McCormack and coworkers in 1981 using a mesh with PMMA.4 Sundaresan and others, in 1985, described the technique and results of resections of a vertebral body in continuity with a lung cancer.5 This requires collaboration among neurosurgeons and orthopedic and thoracic surgeons. Complete sleeve resections of the vena cava, with reconstruction by varying techniques, uniformly failed until Chu and colleagues,6 in 1974, and Doty, in 1982,7 described the construction of a spiral vein graft. Long-term patency rates improved, but the intrinsic complexity of this technique prevented widespread acceptance. Dartevelle and associates, in 1987, detailed the use of a polytetrafluoroethylene (GoreTex) graft with proven patency if used as a venous substitute when resecting the superior vena cava because of tumor.8 In 1991, Dartevelle and associates used a Gore-Tex graft for vena cava reconstruction combined with a right pneumonectomy in six patients with lung cancer (Dartevelle et al, 1991).9 Two of the six lived 16 and 51 months, respectively; the median survival of the four others was 13 months. All grafts remained patent in this series.

CHEST WALL INVASION The most reliable predictor of chest wall invasion is chest pain. Radiographic demonstration of the chest wall invasion is not reliable unless clear evidence of chest wall soft tissue or bony invasion is demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI) (Fig. 78-1). 941

Ch078-F06861.indd 941

1/21/2008 1:42:06 PM

942

Section 3 Lung

FIGURE 78-1 CT scan shows obvious extension of a primary bronchogenic carcinoma through full-thickness chest wall. Note the convexity of the tumor mass outside the skeletal chest wall. Also note the large right paratracheal lymph node. In this patient, mediastinoscopy revealed N2 disease, contraindicating any attempt at resection.

Occasionally, involved ribs will enhance on nuclear bone scan. If resection is contemplated, accurate staging is essential. N2 disease must be excluded. Several authors have demonstrated that long-term survival will not be achieved in patients undergoing resection of T3 tumors in the presence of N2 disease.10-12 Therefore, mediastinoscopy is mandatory if chest wall invasion is suspected. The goal of surgery when lung cancer invades the chest wall is complete resection and reconstruction of the chest wall when necessary. Frequently, reconstruction is not required because the chest wall defect is often beneath the scapula or chest wall musculature and does not require reconstruction for cosmesis or chest wall stability. However, for anterolateral or anterior defects, standard techniques of reconstruction are employed. These are thoroughly discussed in Chapter 107.

Surgical Assessment In cases in which chest wall invasion is suspected, the chest initially is explored through an aspect of the incision that is away from the area of suspected invasion. Careful digital palpation of the pleural surface will confirm the location and extent of the tumor. Chest wall invasion is usually evident by the degree of fixation of the primary tumor to the chest wall. If fixation is not firm, the adhesion is likely due to inflammatory fibrosis. In this situation, an extrapleural plane can easily be developed over the area of adherence. If the parietal pleura dissects away easily, tumor invasion farther into the chest wall is usually not present. Frozen section examination of the pleural surface under suspicion is essential to confirm tumor-free margins on the outer pleural surface.

Technical Considerations If rigid fixation is present, if an extrapleural plane is difficult to accomplish, or if there is any doubt, chest wall invasion is assumed and an en-bloc chest wall resection is performed. It

Ch078-F06861.indd 942

is usually easier from a technical point of view to conduct the chest wall resection first from outside-in with a minimum of 3-cm margins. When the chest wall detachment is complete, the anatomic resection of lung can then be conducted either through the chest wall defect or through the initial exploration thoracotomy. Lesser pulmonary resections by wedge or segmentectomy are associated with an increased likelihood of local recurrence.13 The anatomic pulmonary resection is accompanied by a thorough lymph node sampling or dissection to accurately stage the tumor. For lesions involving the lateral chest wall, resection of one rib above and one rib below plus 3 to 5 cm anterior and posterior to the tumor is resected to maximize the opportunity for complete resection. Frozen section confirmation of complete resection also is obtained. Invasion of rib cancellous bone is not an indication for complete resection of the affected rib because the margins described above are generally sufficient to provide an R0 resection, although this has never been studied. For posterior and lateral defects beneath the scapula, chest wall reconstruction is not required. However, if the fifth rib is removed, some sort of prosthetic replacement using Marlex, Gore-Tex, or Dacron is employed to prevent the scapular tip from falling into the chest over the top of the posterior sixth rib. If reconstruction is undertaken for posterior superior defects, curved chest contour is not required. However, for more anterior or lateral defects, a contoured rigid reconstruction is preferable and can be accomplished by a combination of Marlex and methylmethacrylate, which has been described by several authors. Others believe that a taut 2-mm Gore-Tex graft is sufficient. Unless this type of patch is overlaid by a myocutaneous flap, it will cause a deformity. It also will cause a temporary flail segment. In the Mayo Clinic experience, in which Gore-Tex grafts were used exclusively, a significant number of patients postoperatively required ventilation; and, in fact, the mortality rate of the Mayo Clinic experience was extremely high (Fig. 78-2).

Results Several reports have demonstrated acceptable long-term survival in patients undergoing resection of bronchogenic carcinoma with chest wall invasion. Patterson and colleagues reported a 5-year survival rate of 32.9%.11 Trastek and colleagues reported a 5-year survival figure of 39.7%.12 The Memorial Sloan-Kettering Cancer Center reported their experience in 198514: in 125 patients, 5-year survival was directly related to completeness of resection (42% versus 0%), the absence of lymph node metastasis (56% versus 20%), and depth of chest wall invasion (50% versus 16% for those with full-thickness chest wall invasion). Chapelier and colleagues reported their experience in 100 consecutive patients who underwent radical en-bloc resection of lung and chest wall.10 Survival was less satisfactory than it was in other reports, with 5-year survival for patients with N0 and with N1 and N2 disease being 22.9% and 0%, respectively. In this report, histologic differentiation and depth of chest wall invasion were the major factors affecting long-term survival. Finally, Doddoli and coworkers reported the largest present

1/21/2008 1:42:06 PM

Chapter 78 Extended Pulmonary Resections

series of chest wall resections for non–small cell lung cancer including 309 patients (Doddoli et al, 2005).15 They found that in this series the presence of lymph node metastases had a significant impact on survival, with 5-year overall survival for stage IIB and IIIA disease being 40% and 12%, respectively.

943

VERTEBRAL INVASION In the minds of most thoracic surgeons, vertebral involvement by bronchogenic carcinoma (Fig. 78-3) has represented a specific contraindication to resection because of the low likelihood of complete margins and the associated morbidity

FIGURE 78-2 Chest wall reconstruction. A, Radiograph of a resected chest wall tumor. B, Spreading methylmethacrylate over mesh. Continued

Ch078-F06861.indd 943

1/21/2008 1:42:06 PM

944

Section 3 Lung

C

FIGURE 78-2, cont’d C, Prosthesis sutured in place. D, Omentum sutured over prosthesis. E, Myocutaneous flap sutured to skin.

of vertebral resection. However, technical developments have been made that overcome most of the concerns regarding morbidity. However, limited survival suggests that the problem of incomplete resection has not been resolved. Vertebral invasion is usually documented clearly by CT and MRI. Vertebral invasion by lung cancer most frequently involves the upper thoracic spine above the level of T5 and occurs most often in the setting of superior sulcus tumors. Invasion of cortical bone is likely not a specific contraindication to attempt at radical resection. However, cancellous invasion

Ch078-F06861.indd 944

makes resection a contentious issue. Before DeMeester and colleagues reported a series of 12 patients who underwent vertebral resection for locally advanced lung cancer, such a resection had been reported only sporadically.16

Technical Considerations DeMeester and colleagues’ description of a vertebral resection involves a posterolateral thoracotomy with extension to the base of the neck.16 The pleural cavity is entered one rib

1/21/2008 1:42:07 PM

Chapter 78 Extended Pulmonary Resections

below the caudal extent of the tumor, and the paraspinous muscles are dissected off the transverse processes to the midline. Their technique of partial vertebral resection is depicted in Figure 78-4. The technical approach to total vertebrectomy and one method of reconstruction is indicated in Figure 78-5. There have been many variations of the methods of resection and reconstruction, which are always done in conjunction with orthopedic surgeons and neurosurgeons. The vertebral resection can be performed piecemeal (versus en bloc), although the oncologic result of this is unknown. An en-bloc hemiver-

945

tebrectomy or total vertebrectomy is ideal as described by Grunenwald and colleagues17 (Fig. 78-6). In a subsequent communication, the same group reported experience with an anterior cervicothoracic and median posterior approach eliminating the need for posterolateral thoracotomy.18 However, the survival in Grunenwald’s original report is less than satisfactory: among four patients who underwent resection for bronchogenic carcinoma, two were alive without disease and two had died within a short time after resection. In an invited commentary on this report, Dartevelle and colleagues cautioned against widespread application of this technique without very careful patient selection.19 In their experience with partial vertebral resection, five of six patients were alive and free of disease with a median follow-up of 10 months. They argued strongly that spinal canal invasion was an absolute contraindication to resection. Most surgeons agree with their opinion and consider invasion of the spinal canal a definite contraindication for attempt at curative resection (Fig. 78-7). Gandhi and coworkers from the M. D. Anderson Cancer Center report what is probably the largest experience with resection of superior sulcus tumors with vertebral invasion (Gandhi et al, 1999).20 This group’s approach is through an extended posterolateral thoracotomy with occasional addition of a posterior midline incision for tumors with significant vertebral involvement. They also advocate an endolesional approach to resection in which the tumor is resected off the vertebral body, allowing a more careful evaluation of the extent of vertebral involvement, even though this is a clear

FIGURE 78-3 CT scan shows invasion of a primary lung cancer into an upper thoracic vertebral body.

A Dissection Costotransverse foramen

Lung OSTEOTOMY Transverse process

Rib

Osteotomy

B

C Costotransverse foramen

Lung

Costotransverse foramen

Lung

FIGURE 78-4 Transverse section of the thoracic vertebra showing a fixed lung tumor. The costotransverse foramen is free of disease. A, The broken line shows the plane of dissection posterior to the rib. B, The site of osteotomy of the transverse process and rib. C, The plane of the tangential osteotomy of the vertebral body. Access to the vertebral body is through the costotransverse foramen. (FROM DEMEESTER TR, ALBERTUCCI M, DAWSON PJ, ET AL: MANAGEMENT OF TUMOR ADHERENT TO THE VERTEBRAL COLUMN. J THORAC CARDIOVASC SURG 97:373, 1989.)

Ch078-F06861.indd 945

1/21/2008 1:42:09 PM

946

Section 3 Lung

violation of standard oncologic principles. Seventeen patients underwent preoperative radiation (3000 cGy) and postoperative radiation to a total dose of 5400 cGy plus postoperative adjuvant therapy with cisplatin and etoposide. Seven patients underwent total vertebrectomy, 7 patients had partial vertebrectomy, and 3 patients had resection of the neuroforamen and transverse process. There was no operative mortality, and, at the time of the report, all patients were ambulatory. Two-year actuarial survival was 54%. Once again, the importance of complete resection is emphasized in this report. Only 1 of 11 patients with negative margins had local recurrence, whereas all 6 patients with positive margins developed locally recurrent disease.

vertebral substance was utilized.20 Spinal fixation was accomplished with a combination of anterior locking plate and screw construct as well as posterior fixation with hooks and rods (Fig. 78-8). Methylmethacrylate was used to reconstruct vertebral bodies (Fig. 78-9). Errico and Cooper have described a useful technique to control the delivery of methylmethacrylate into the vertebral body above and below the defect while at the same time filling the interval defect with methylmethacrylate21 (Fig. 78-10). Expandable titanium cages are increasingly being used for spinal reconstruction after vertebral resection.22 These cages are quicker to insert, may be tailored to the patient’s anatomy, and may be filled with bone chips to facilitate bony fusion (Fig. 78-11).

Reconstruction Methods

AORTIC INVASION

Many strategies to accomplish spinal fixation have been reported. In Gandhi and associates’ report, a novel strategy of spinal fixation consisting of methylmethacrylate to replace

Involvement of the aorta is not uncommon for left-sided lung cancers. Aortic invasion can be suspected when the tumor is in apposition to the aorta, when it is more than 25% of aortic Text continued on p 950

FIGURE 78-5 Vertebral body reconstruction. A, Tumor (arrow) invading the vertebral body. B, After resection of the tumor and vertebral body (arrow, spinal cord).

A

B

Ch078-F06861.indd 946

1/21/2008 1:42:10 PM

Chapter 78 Extended Pulmonary Resections

947

FIGURE 78-5, cont’d C, Steinmann pins inserted into intact vertebral bodies above and below resection (spinal cord visible). D, Methylmethacrylate injected around Steinmann pins to replace resected vertebral body. E, Completed reconstruction of resected vertebral body.

C

D

E

Costotransverse foramen

Lung

A

C

Ch078-F06861.indd 947

Esophagus

B

FIGURE 78-6 A, The technique of total vertebrectomy with the patient in the ventral position after the chest wall and lung have been sectioned in tumor-free margins. B, A laminectomy is performed at the level of the lesion extending one level above and below the involved vertebra. C, The lateral dissection is continued to the point of the dissection through the previous thoracotomy and cervicotomy. D, Mobilization of the vertebral bodies and transection of the vertebral body end plate using a Gigli saw completes the resection.

D

1/21/2008 1:42:12 PM

948

Section 3 Lung

FIGURE 78-9 Operative photograph demonstrating posterior rod fixation. The vertebral body defect is filled with methylmethacrylate (arrows). (FROM GANDHI S, WALSH GL, KOMAKI R, ET AL: A FIGURE 78-7 Coronal (A) and axial (B) MR images demonstrating extensive multilevel vertebral body involvement by a right apical superior sulcus tumor. Obvious invasion of the spinal canal is present.

Brachial plexus

MULTIDISCIPLINARY SURGICAL APPROACH TO SUPERIOR SULCUS TUMORS WITH VERTEBRAL INVASION. ANN THORAC SURG 68:1778, 1999. COPYRIGHT ELSEVIER 1999.)

Vagus nerve

T2, T3 Nerve root

C5 C6 C7 C8 Nerve root T1 Nerve root Spinal cord (dura mater)

T4

T5

FIGURE 78-8 Multilevel thoracic vertebrectomy and laminectomy, reconstruction with methylmethacrylate, placement of anterior locking plate and screw construct, and posterior fixation with hooks and rods. (FROM GANDHI S, WALSH GL, KOMAKI R, ET AL: A MULTIDISCIPLINARY SURGICAL APPROACH TO SUPERIOR SULCUS TUMORS WITH VERTEBRAL INVASION. ANN THORAC SURG 68:1778, 1999. COPYRIGHT ELSEVIER 1999.)

Ch078-F06861.indd 948

1/21/2008 1:42:15 PM

Chapter 78 Extended Pulmonary Resections

A

C

949

FIGURE 78-10 A, The involved vertebral body is resected with decompression of the spinal canal. The lateral aspect of the vertebral bodies above and below is left intact, and the cancellus bone is excavated with either angled curets or an angled drill. B, A Silastic tube is fashioned to fit into the vertebral body above as well as below. A hole is made with a rongeur in the lateral portion of the tube to accept a syringe filled with methylmethacrylate in a highly liquid phase. Holes are fashioned at the ends of the tube as shown to facilitate extrusion of the cement. C, The cement is pressurized into the tube until it is seen to exude out of the bodies above and below. Care is taken to avoid migration of the cement into the spinal canal. Cement is then packed all around the tube until it is flush with the lateral aspects of the vertebral bodies. D, In the lumbar spine, a threaded rod is placed between the two KostuikHarrington screws or Zielke screws that are inserted into the bodies above and below. Cement is packed around the rod, thus incorporating the rod and the Silastic tube into a single construct. (FROM ERRICO TJ, COOPER

B

D

PR: A NEW METHOD OF THORACIC AND LUMBAR BODY REPLACEMENT FOR SPINAL TUMORS: TECHNICAL NOTE. NEUROSURGERY 32:678, 1993.)

FIGURE 78-11 A lateral thoracic spine radiograph demonstrates posterior spinal instrumentation with pedicle screws and an anterior expanding titanium cage that locks into the vertebral bodies above and below the defect without the need for drilling. (FROM MARTIN LW, WALSH GW: VERTEBRAL BODY RESECTION. THORAC SURG CLIN 14:241-254, 2004.)

Ch078-F06861.indd 949

1/21/2008 1:42:21 PM

950

Section 3 Lung

FIGURE 78-12 CT scan depicting a left lower lobe superior segment non–small cell carcinoma with extensive apposition to the descending thoracic aorta. The fat plane between the tumor and the aorta is obliterated. This lesion was resected by subadventitial resection through tumor-free margins.

circumference, or when the fat plane is lost between the aorta and the tumor (Fig. 78-12). In most patients, resectability cannot be determined until the time of exploration. It may be possible to develop a plane of dissection within the aortic adventitia and to accomplish a complete resection. Full-thickness involvement of the aortic wall is generally considered a contraindication to resection. Unfortunately, determination of such involvement is very difficult before resection. For such central lesions, direct aortic invasion and frequent nodal metastasis make complete resection and cure unlikely. In addition, there are a limited number of reports available in the literature from which to draw conclusions.

Surgical Technique The methods for resecting tumors that invade the aortic area include a subadventitial dissection, a partial resection with patch, or a total tubular resection with reconstruction. The latter approach requires at least partial bypass or other techniques to maintain distal circulation. Klepetko and colleagues described a small experience in 7 patients undergoing resection of lung tumors involving the aorta.23 Six of these seven resections were conducted with the assistance of cardiopulmonary bypass, and in 1 patient a temporary interposition graft was employed. Aortic reconstruction was accomplished by tube graft or pericardial patch for small noncircumferential defects. Long-term survival was limited, with only 2 of the 7 patients alive without disease. In another report, Tsuchiya and associates from the National Cancer Center Hospital in Tokyo reported a large experience of resection for tumors involving the aorta in 28 patients.24 Twenty-one of these patients underwent a subadventitial resection, and 7 patients underwent full-thickness resection and aortic replacement. Only 1 of these 7 patients with fullthickness resection was a long-term survivor. Interestingly, among the 21 patients with aortic adventitial resection, 11 had incomplete resections and all of these patients did poorly.

Ch078-F06861.indd 950

Ten patients had a complete subadventitial resection, but 4 of these patients developed recurrent disease. In another report, Nakahara and colleagues reported results in 3 patients who underwent en-bloc resection of left-sided lung cancers and the aorta.25 Two of these patients died of metastatic disease within 1 year. In their experience, there was only one intermediate-term survivor. Ohta and associates also evaluated the results of combined resection of the thoracic aorta and primary lung cancer in 16 patients26: there were six left pneumonectomies, nine left upper lobectomies, and one partial lung resection. Cardiopulmonary bypass was utilized in 10 cases, and a shunt between the ascending and descending aorta was used in 4 cases. Operative morbidity was 31%, and the mortality rate was 12.5%. Five-year survival was 70% for patients with N0 disease and 16.7% for those with N2 or N3 disease.

LEFT ATRIAL INVASION There are limited reports of curative resection for bronchogenic carcinoma involving the left atrium. However, there are techniques described to permit complete and potentially curative resection of selected lesions invading the left atrium. On the right side, the anterior left atrial wall can be lengthened significantly by opening the interatrial groove, thus increasing the margin of resection and the likelihood of an adequate cuff for primary atrial closure. Tsuchiya and colleagues reported on their experience with 44 patients who underwent resection of the left atrium alone or in combination with other major vascular structures.24 All of these resections were conducted without cardiopulmonary bypass using vascular clamps. The fact that primary repair was conducted in all cases suggested that the extent of atrial wall resection was limited in this series. In one of these patients, a pedunculated tumor growing into the left atrial lumen was grasped from outside with a central clamp. The atrial wall was opened laterally, and the tumor mass was flipped out while the central clamp was secured. A more conventional and safer technique would have been to place the patient on cardiopulmonary bypass, fibrillate the heart, create an atriotomy for resection under direct vision, and use primary closure. Spaggiari and coworkers reported on 15 patients undergoing partial resection of the left atrium for lung cancer, all without cardiopulmonary bypass.27 Three-year probability of survival was 39% with no postoperative mortality and two minor morbidities (atrial arrhythmias). Their technique is demonstrated in Figures 78-13 and 78-14. Ratto and colleagues performed left atrial resections on 19 patients over a 12-year period.28 Cardiopulmonary bypass was not used in this series. They reported a 5-year overall survival rate of 14% with a median survival of 25 months. Ferguson and Reardon reported a single case in which a “complete” resection was conducted including left atrium, atrial septum, and right atrial wall29 (Fig. 78-15). Of course, cardiopulmonary bypass was required for this procedure. Primary reconstruction was accomplished. At the time of this report, the patient’s survival was 24 months without any evidence of disease.

1/21/2008 1:42:25 PM

Chapter 78 Extended Pulmonary Resections

FIGURE 78-13 During a right pneumonectomy for lung cancer with extension into the left atrium a large Satinsky clamp is placed centrally on the left atrium after dissection of the interatrial groove. (FROM SPAGGIARI L, D’AIUTO M, VERONESI G, ET AL: EXTENDED PNEUMONECTOMY WITH PARTIAL RESECTION OF THE LEFT ATRIUM, WITHOUT CARDIOPULMONARY BYPASS, FOR LUNG CANCER. ANN THORAC SURG 79:234-240, 2005, WITH PERMISSION FROM THE SOCIETY OF THORACIC SURGEONS.)

951

FIGURE 78-14 Resection of left atrial extension of a lung cancer and reconstruction with double running sutures of 2-0 polypropylene. (FROM SPAGGIARI L, D’AIUTO M, VERONESI G, ET AL: EXTENDED PNEUMONECTOMY WITH PARTIAL RESECTION OF THE LEFT ATRIUM, WITHOUT CARDIOPULMONARY BYPASS, FOR LUNG CANCER. ANN THORAC SURG 79:234-240, 2005, WITH PERMISSION FROM THE SOCIETY OF THORACIC SURGEONS.)

SUPERIOR AND INFERIOR VENA CAVA Surgical Technique Bronchogenic carcinoma can involve the superior vena cava by direct extension of the primary tumor or by nodal metastasis. There are two possible techniques for resecting the superior vena cava. It may be performed en bloc with the pulmonary resection. For minimal involvement, a side-biting clamp can be applied and the vena cava simply oversewn or patched if the lumen is compromised. Patches can include Gore-Tex or pericardium. For full reconstruction, the preferable method is a ringed Gore-Tex sleeve patch as outlined by Dartevelle and colleagues30 (Fig. 78-16). Although the ideal approach for superior vena caval reconstruction is a sternotomy or hemiclamshell, often this is encountered at the time of thoracotomy; and the incision is appropriately extended to allow appropriate control of vessels. A right pneumonectomy or right upper lobectomy is typically performed en bloc with the superior vena cava. A

Ch078-F06861.indd 951

FIGURE 78-15 CT image of the chest with intravenous contrast medium demonstrating a central right hilar mass (m) with involvement of the posterior aspect of the left atrium (la). ra, right atrium. (FROM FERGUSON ER JR, REARDON MJ: ATRIAL RESECTION IN ADVANCED LUNG CARCINOMA: UNDER TOTAL CARDIOPULMONARY BY-PASS. TEX HEART INST J 27:110, 2000.)

1/21/2008 1:42:25 PM

952

Section 3 Lung

FIGURE 78-16 Caval invasion. A, Illustration of a tumor invading the superior vena cava. B, Reconstruction with a polytetrafluoroethylene graft.

A

B

truncular replacement of the vena cava requires that the confluence of both innominate veins be tumor-free. An interposition graft of Gore-Tex is then placed between this confluence and the proximal superior vena cava stump. Alternatively, if the confluence of the innominate veins is involved with tumor, then either the right, left, or both innominate veins may be revascularized with individual ringed Gore-Tex grafts from the right atrium. Clamping the superior vena cava can be associated with several adverse consequences, including decreased cardiac output resulting from decreased venous return and increased venous pressures in the cerebral territories. Consequently, venous clamp times are kept as short as possible. Strategies for prevention of venous cross-clamp effects include shunt procedures, maintenance of blood pressure with volume and vasoconstrictors, and a targeted surgical strategy in which the vascular resection and reconstruction is performed before any airway procedures. Anticoagulation therapy is generally recommended after replacement of the vena cava with a prosthetic graft.

Results In 1987, Dartevelle and colleagues first reported a technique of caval reconstruction using Gore-Tex grafts8 (Fig. 78-17). Subsequently, they reported a larger series of patients who had undergone caval resection and replacement, only 6 of whom had primary bronchogenic carcinoma (Dartevelle et al, 1991).9 Among these patients, 2 patients with N1 disease were alive at 16 and 51 months and 1 patient with N1 disease died at 38 months. There were no long-term survivors among patients with N2 disease. In a more recent report of his experience, Dartevelle described a total experience of 14 patients who underwent caval resection for non–small cell carcinoma.31 Eleven patients had squamous cancer. Most patients required extended pneumonectomy, six of which were sleeve pneumonectomies. Overall survival was 31%, with 5 of 14 patients still alive and free of disease 3 to 65 months after resection. Spaggiari and colleagues described their experience in 25 patients who underwent resection of the superior vena caval

Ch078-F06861.indd 952

FIGURE 78-17 Central right hilar non–small cell carcinoma with invasion of the proximal right main bronchus and lateral vena cava. This lesion was resected by tracheal sleeve pneumonectomy and vena cava replacement.

system for non–small cell lung cancer.32 Seven patients had complete resection of the superior vena cava with graft interposition. Twelve patients underwent tangential resection of the superior vena cava, and 1 patient had a pericardial patch. Five patients underwent resection of the right innominate and subclavian veins without vessel reconstruction. Most patients had N2 disease, and 20% of patients had an incomplete resection. Operative mortality was 12%, median survival was 11.5 months, and 5-year actuarial survival was 29%. There were only 4 patients alive at 5 years. The central location of non–small cell lung cancers involving the vena cava often mandates extended resections of other structures, including the airway (Fig. 78-18). In addition to Dartevelle and colleagues’ description of vena caval and tracheal sleeve resection, Spaggiari and

1/21/2008 1:42:29 PM

Chapter 78 Extended Pulmonary Resections

953

FIGURE 78-18 A, MR image of the thoracic apex showing vertebral body involvement of T2 before induction chemotherapy. Note that there is no involvement of the spinal canal or spinal cord compression. MR image (B) and CT scan (C) of the thoracic apex after three cycles of chemotherapy showing a slight decrease in tumor size and persistent vertebral body involvement. Note the abnormal bone structure of the body of T2. (FROM GRUNENWALD D, MAZAL C, BALDEYROU P, ET AL: EN BLOC RESECTION OF LUNG CANCER INVADING THE SPINE. ANN THORAC SURG 61:1878, 1996.)

Pastorino have reported a small experience in six patients who underwent combined superior vena cava resection and tracheal sleeve resection.33 Muscle-sparing thoracotomy was performed in four patients, and a hemiclamshell approach was used in two patients. There were no postoperative deaths. However, three patients had major postoperative complications. Median survival in this small experience is 14.5 months, with a range of 3 to 17 months. Invasion of the inferior vena cava by resectable bronchogenic carcinoma is exceedingly rare. Roberts and coworkers reported their experience with an interesting patient who presented with a lesion involving the right lower lobe diaphragm and intrapericardial inferior vena cava.34 The patient underwent resection and primary replacement of the vena cava without cardiopulmonary bypass and was alive and well 8 months after the procedure.

Ch078-F06861.indd 953

TRACHEAL CARINA The technical details of tracheal carinal resection are covered in detail in Chapter 33. In the past, sleeve pneumonectomy or carinal resection in treating lung cancer was associated with significant operative mortality that often exceeded any possibility of 5-year survival. However recent advances in anesthetic, operative, and postoperative care have resulted in a dramatic reduction in operative mortality in most published series. Most reported series include all resections, no matter what the underlying disease is. Roviaro and colleagues reported an experience with 27 right tracheal sleeve resections.35 There was only one postoperative death in this series. de Perrot reported the experience of the Dartevelle group with carinal resections in a larger number of patients (de Perrot et al, 2006).36 Among

1/21/2008 1:42:31 PM

954

Section 3 Lung

119 patients undergoing carinal resection for carcinoma, there were nine deaths occurring in the hospital or within 30 days of the operation. Overall operative mortality was 7.6%. Mitchell and coworkers determined that postoperative mechanical ventilation, length of resected airway, and development of anastomotic complication were all significant predictors of postoperative mortality after carinal resection.37 The largest series of carinal resections come from Porhanov and associates, who reported on 231 carinal resections, 151 of which were performed for bronchogenic carcinoma.38 Operative mortality was 16% and was mostly related to respiratory distress syndrome, and anastomotic complications and complications were observed in 35%. Mortality and complications were correlated to the length of resection, laryngeal nerve injuries, and the mode of intraoperative ventilation (jet ventilation). Several strategies have been developed to maintain viability of the remaining proximal and distal airway and reduce tension on the airway anastomosis. Most authors advocate coverage of the airway anastomosis with vascularized pericardial fat pad, pericardium, or omentum. Despite these advances, long-term survival remains limited. In Roviaro’s report, among 27 patients undergoing resection there were only 7 patients alive at 4 years and 1 at 5 years.35 In de Perrot’s report (de Perrot et al, 2006),36 the 5- and 10-year survivals were 44% and 25%, respectively, for patients with bronchogenic carcinoma. Not surprisingly, long-term survival was significantly influenced by nodal status. Among the 27 patients with N2 or N3 disease, 5-year survival was 15%. Promising results were also reported by Mitchell and associates, who found a 5-year overall survival rate of 42% in 60 patients.37 Parhanov and coworkers also found that nodal status significantly impacted 5-year survival (N0-N1 = 32%, N2 = 7.5%).38

DIAPHRAGM INVASION Diaphragmatic invasion by otherwise resectable non–small cell lung cancer is exceedingly rare. As a result there are a limited number of reports from which thoracic surgeons can draw conclusions. Diagnosis of isolated diaphragmatic invasion is difficult. Symptoms are usually absent, and imaging is of limited value in determining diaphragmatic invasion. Thoracoscopic examination has been suggested as a means to detect diaphragmatic invasion in suspected cases. The available literature suggests a poor prognosis after resection, perhaps because of vascular and lymphatic invasion within the diaphragm. Weksler and associates from the Memorial Sloan-Kettering Cancer Center reported only 8 patients with diaphragmatic invasion from a total experience of 4668 (17%) patients explored for non–small cell carcinoma.39 Seven of these 8 patients had squamous cancers, and 4 had N2 disease. Primary repair was accomplished in 7 of 8 patients. There was only one long-term survival. All patients with N2 disease developed fatal recurrence. In a subsequent report, Rocco and colleagues reported a dual-institution experience with 15 patients.40 Overall, 5year actuarial survival was 20% and only 27% for patients without nodal metastasis. Interestingly, these authors found

Ch078-F06861.indd 954

a correlation between need for prosthetic diaphragmatic replacement and survival, suggesting that wider margins of resection conferred some survival benefit. Two multi-institutional retrospective reviews have been published. The Japanese group described an experience with 63 patients who underwent resection of T3 lung cancers invading the diaphragm.41 Five-year survival after complete resection was only 22.6%. There was no long-term survival in patients undergoing incomplete resection. For patients with T3 N0 disease, survival was only 28.3% and 18% if nodal metastases were discovered. In this report, depth of invasion was of prognostic importance. Minimal invasion (parietal pleura or subpleural tissue) had a survival of 33% in comparison with the 14.8% survival noted in patients with deeper invasion (muscle or peritoneum). In the French multi-institutional report there were 68 patients who underwent exploration for T3 cancers involving the diaphragm.42 Eight patients had exploration; surprisingly, long-term survival was significantly influenced by nodal status. Among the 12 patients with N2 disease, there were no survivors beyond 46 months. Localized diaphragmatic invasion by lung cancer is amenable to wide resection in a few selected cases. In light of reports of dismal overall survival, the T3 descriptor assigned to primary tumors with diaphragmatic invasion is inaccurate. These tumors behave much more like T4 tumors. The difficulty of establishing a preoperative diagnosis without thoracoscopic examination makes consideration of induction therapy impractical in most of these patients.

PERICARDIAL INVASION The pericardium is in contact with the lung over most of its medial surface. Nonetheless, invasion of the pericardium in otherwise resectable lung cancers is somewhat unusual. For medially positioned tumors, if pericardial adherence is noted, the pericardium is opened away from the phrenic nerve. The phrenic nerve is spared if at all possible. Digital and visual exploration of the pericardium provides an accurate assessment of the extent of tumor and the magnitude of pericardial resection required. If a pneumonectomy is performed, any pericardial defect is closed to prevent cardiac torsion or herniation. A variety of patch materials can be used, including Marlex, Gore-Tex, Dacron, bovine pericardium, or Vicryl. Tamesue and colleagues describe the use of a pedicled flap of the central tendon of the diaphragm to reconstruct a pericardial defect.43 Interestingly, a complete defect of the pericardium on the left side probably does not need repair because there is little chance of herniation or torsion. Occasionally, for central tumors that do not involve the pericardium, an intrapericardial dissection will greatly facilitate resection, providing central exposure to the pulmonary vein or pulmonary artery.

ESOPHAGEAL INVASION Occasionally, the esophagus can be involved by primary bronchogenic carcinoma, although it is far more commonly involved by metastatic spread to periesophageal or subcarinal lymph nodes. Resection of a portion of the muscular wall of

1/21/2008 1:42:32 PM

Chapter 78 Extended Pulmonary Resections

the esophagus leaving the mucosa intact is an appropriate strategy for such central tumors. However, long-term prognosis in these patients is poor because most have extensive disease, and complete resection is not probable. Similarly, resection of the esophagus en bloc with a pulmonary resection, although technically feasible, cannot be justified by the experience of any reported series.

EXTENDED RESECTION AFTER INDUCTION THERAPY Recent enthusiasm for the use of induction chemotherapy and radiation therapy has led some groups to study the use of this modality in patients with locally advanced tumors. Several reports suggest that there may be a place for induction chemoradiation prior to resection in patients with T4 tumors. Arguments for the use of induction therapy include measurement of tumor response, decrease of tumor size to facilitate or reduce the magnitude of subsequent resection, increase in the likelihood of negative surgical margins, and treatment of micrometastatic disease. Macchiarini and his colleagues reported an experience in 23 patients with T4 non–small cell lung cancer.44 These patients received two courses of cisplatin-based chemotherapy with or without radiation (median dose, 4500 cGy). Twenty-one of these 23 patients underwent subsequent complete resection. There were 2 patients who had incomplete resections. Complete pathologic response was noted in 13 patients. Postoperative complications occurred far more commonly in patients who had combination chemoradiation in comparison with those who received chemotherapy alone. Projected 3-year survival was 54%. In a subsequent report, Rendina and associates describe their experience with 57 patients who presented with T4 non–small cell lung cancer.45 Patients received three cycles of cisplatin, vinblastine, and mitomycin. Forty-two patients (73%) responded to therapy and underwent exploration. Eleven patients did not obtain a response, and 4 patients had major chemotherapy-related toxicity. Thirty-six patients (63% of the entire group) had a complete resection. Only 4 patients had a complete pathologic response. Overall survival at 1 and 4 years was 61.4% and 19.5%, respectively. The 36 patients who had complete resection had a 4-year survival of 30.5%. In another report, Stamatis and colleagues reported their experience with an intensive regimen of cisplatin and etoposide chemotherapy and preoperative irradiation (4500 cGy) in patients with stage IIIB lung cancer.46 Among patients who had T4 N0-N1 lesions, complete resections were conducted in 80% of patients, and 50% of patients experienced complete pathologic response. Median survival was 26.5 months, and 5-year actuarial survival was 37.5%. Galetta and colleagues reported on 39 patients with stage IIIB (T4) non–small cell lung cancers who received induction therapy with cisplatin and 5-flurouracil along with 50.4 Gy of radiation.47 Twenty-one responders and 1 patient with stable disease went on to surgery. A radical resection was possible in 21 of these patients, with a 5-year overall survival of 23% in that group. In another study by Ichinose and coworkers, 27 patients with stage IIIB lung cancer were given

Ch078-F06861.indd 955

955

induction therapy with uracil, tegafur, and cisplatin along with 40 Gy of thoracic radiation. At least a partial response was obtained in 93% of patients. All underwent surgical resection, and 3-year survival was estimated at 56%. Rusch and colleagues reported the results of the SWOG 9416 trial investigating the use of induction chemoradiation for superior sulcus tumors.48 Their regimen included two cycles of cisplatin and etoposide along with 45 Gy of radiation. There were 32 patients with T4 tumors, and median survival in this group was 25 months. Despite the small number of patients in these phase II studies, a number of speculations can be made. First, treatment toxicity is significant, particularly with concurrent chemoradiation. Postoperative morbidity is increased significantly in patients who receive concurrent chemoradiation in comparison with those receiving chemotherapy alone. T4 lesions can be downstaged, increasing the possibility of complete resection. Unfortunately, there are no phase III data on which to base any conclusion regarding the merits of this approach with respect to long-term survival.

COMPLETION PNEUMONECTOMY Completion pneumonectomy entails the removal of the remaining lung after a previous resection of a portion of that same lung. The indications for a completion pneumonectomy have expanded with the increased incidence of lung cancer, increased survival of patients undergoing previous lung resections, increased survival in patients with long-term pulmonary infections, and an increased demand for repeat resection of metastatic disease to the lungs. A completion pneumonectomy is technically demanding and is associated with significant morbidity and mortality. Operative mortality is greater than the 6.2% mortality for a pneumonectomy reported by the lung cancer study group.49 The operative mortality also appears to vary with the indication for the procedure, with benign disease having worse outcomes. Previous resections, radiation therapy, or past infections or inflammatory processes may obliterate the pleural and pericardial spaces and lead to a difficult operation. Intrapericardial control is optimal if adhesions and scarring involve the hilar vessels. Mobilization of the pulmonary artery can be particularly dangerous in this setting. In cases of obliteration of the pericardial space, the pulmonary artery may be exposed posteriorly by first dividing the bronchus, as has been described by Mansour and Downey.50 On the right the pulmonary artery may also be isolated by dividing the posterior pericardium between the superior vena cava and the ascending aorta. Miller and colleagues from the Mayo Clinic reported on 115 patients undergoing completion pneumonectomy over a period of 13 years.51 The indication for pneumonectomy was benign disease in 49.6%, lung cancer in 44.3%, and metastatic disease in 6.1%. The mortality rates were 26.3%, 17.6%, and 0% for benign disease, lung cancer, and metastatic disease, respectively. They identified advanced age, preoperative use of corticosteroids, and a low preoperative hemoglobin value as factors adversely affecting mortality. Fujimoto and coworkers reported on 66 completion pneumonectomies.52 The indication was malignancy in 49 patients

1/21/2008 1:42:32 PM

956

Section 3 Lung

months, and the probability of 3-year survival was 46%. Subsequently, Lewis and Caccavale reported a single case utilizing video-assisted technology with an excellent early result.57 Donington and colleagues reported on 24 patients undergoing resection of a contralateral lesion after a pneumonectomy.58 Operative mortality was 8% in this series. The 5-year overall survival was 40%, with a survival of 50% for the 14 patients in the series who had metachronous lesions. There were 20 wedge resections, 3 segmentectomies, and 1 lobectomy.

COMMENTS AND CONTROVERSIES

FIGURE 78-19 CT image demonstrating a metachronous primary non–small cell lung cancer after left pneumonectomy. (FROM LEWIS RJ, CACCAVALE RJ: PULMONARY RESECTION AFTER PNEUMONECTOMY. ANN THORAC SURG 64:583, 1997.)

and benign disease in 17. Intrapericardial vessel ligation was done in 62% of cases. Operative morbidity rate was 71% for benign disease and 49% for malignant disease. Five-year actuarial survival was 65% for benign indications and 54% for malignant disease. Guggino and associates reported on 55 consecutive completion pneumonectomies (42 for malignancy and 13 for benign disease).53 An intrapericardial approach was used in 89% of cases. Operative mortality was 11.9% for malignant disease and 30.8% for benign disease.

CONTRALATERAL RESECTION AFTER PNEUMONECTOMY Metachronous primary lung cancers occur at a rate of 1% to 3% per year in patients who have undergone prior curative resection for lung cancer (Fig. 78-19). If the prior resection was pneumonectomy, resection of a subsequent contralateral lesion is often contraindicated because of the extent of the lesion. General indications for lung cancer resection after a pneumonectomy include clinical stage I disease, resectability by wedge or segmentectomy, and adequate pulmonary reserve present. Kittle and colleagues reported an experience among 15 patients who underwent resection of pulmonary malignancies after prior pneumonectomy.54 At the time of their report, only 3 patients were alive without disease, with a range of follow-up that was 18 to 70 months. Westermann and coworkers reported their experience with resection after contralateral pneumonectomy in 8 patients.55 There was one postoperative death due to pulmonary embolism. Resection included one right upper lobectomy, five segmental resections, and two wedge resections. Only 4 of these patients were alive, 1 of whom has locally recurrent tumor. Spaggiari and associates have reported a series of 13 patients who underwent resection of a new lesion after prior pneumonectomy.56 Three patients underwent segmentectomy, 7 patients had wedge resection, 2 patients had multiple wedge resection, and 1 patient was explored without resection. There was no operative mortality. Median survival was 19

Ch078-F06861.indd 956

The purpose of this chapter is to discuss the surgical options for those locally advanced tumors not covered in other specific chapters. Most of these cancers are staged T3 or T4. Therefore, it is mandatory that all patients undergo extensive staging, including mediastinoscopy, before an attempt at resection. Operative planning is critical because only a complete resection provides the patient with any opportunity for cure. The technical details regarding each extended resection are noted. For chest wall resection, all involved ribs must be resected, but including the rib above and rib below obvious involvement is sometimes excessive. Good margins can usually be achieved by resecting periosteum of the uninvolved rib above and below. Intraoperative frozen section of margins is mandatory. Recent innovative strategies for vertebral body resection and reconstruction have been developed and are being increasingly applied worldwide. Long-term follow-up data are sparse. Invasion of aorta, vena cava, or left atrium is usually an indication of an unresectable tumor. However, for selected patients, complete resection may be possible. For these tumors, operative exploration and a tedious intrapericardial dissection are usually necessary to ultimately determine resectability. The results of carinal resection and sleeve pneumonectomy have improved with better patient selection and improved surgical technique. Diaphragmatic invasion confers a poor long-term survival. In these patients it is critical to rule out invasion in abdominal structures, particularly direct extension into the liver. Completion pneumonectomy is a procedure in increasing use. This may be even more the case in the future because lesser resections, commonly employed at the present, may result in higher incidence of local recurrence. G. A. P.

KEY REFERENCES Dartevelle PG, Chapelier AR, Pastorino U, et al: Long-term follow-up after prosthetic replacement of the superior vena cava combined with resection of mediastinal-pulmonary malignant tumors. J Thorac Cardiovasc Surg 102:259-265, 1991. de Perrot M, Fadel E, Mercier O, et al: Long-term results after carinal resection for carcinoma: Does the benefit warrant the risk? J Thorac Cardiovasc Surg 131:81-89, 2006. Doddoli C, D’Journo B, Le Pimpec-Barthes F, et al: Lung cancer invading the chest wall: A plea for en-bloc resection but the need for new treatment strategies. Ann Thorac Surg 80:2032-2040, 2005. Gandhi S, Walsh GL, Komaki R, et al: A multidisciplinary surgical approach to superior sulcus tumors with vertebral invasion. Ann Thorac Surg 68:1778-1784, 1999; discussion 1784-1785.

1/21/2008 1:42:32 PM

chapter

79

MEDIASTINAL LYMPH NODE DISSECTION Steven M. Keller Ricardo A. Bello

Key Points ■ The common patterns of lymphatic drainage and metastasis must

■ ■

■ ■

be recognized so that the principles of surgical staging can be applied properly. Familiarity with the various revisions of the staging system is necessary to correctly report new data and interpret published results. Complete mediastinal lymph node dissection or systematic sampling is performed in all patients undergoing curative surgery. Either procedure can be performed rapidly and with no increase in operative morbidity. Complete mediastinal lymph node dissection may be associated with improved survival. Sentinel lymph node mapping and thoracoscopic staging are experimental procedures.

Intraoperative staging is an essential component of the surgical treatment of lung cancer. Although the “T” category of the primary tumor is readily apparent to both surgeon and pathologist, the presence or absence of tumor within the intrathoracic lymph nodes is frequently not obvious. Indeed, the lymph nodes themselves may not be apparent and must be diligently sought. Microscopic assessment is required to determine accurately the “N” status. Furthermore, because histologic staging is completely dependent on the material submitted during the operative procedure, the surgeon must accurately identify and properly label the requisite specimens. Knowledge of lung cancer metastatic patterns provides the rationale for lymph node dissection. Lymph node level definitions and lymph node dissection techniques are best appreciated in their anatomic and historical perspectives. Finally, the utility of mediastinal lymph node dissection can be fully comprehended only through review of the accompanying risks and benefits.

RATIONALE FOR LYMPH NODE DISSECTION Appropriate staging of lung cancer can be accomplished only with accurate and thorough lymph node dissection. In the absence of precise staging, comparison of results from different institutions is impossible, as is the conduct of multiinstitutional trials. Although many authors believe that the value of mediastinal lymph node dissection accrues from detailed staging, some investigators believe that removal of all lymph nodes in the likely drainage pathways results in improved survival (Hata et al, 1990; Keller et al, 2000; Wu et al, 2002; Yang et al, 2004).1-7

Critical assessment of the published literature relating survival to pathologic stage in patients with non–small cell lung cancer (NSCLC) requires knowledge of the investigator’s intrathoracic staging technique. In general, sampling means that only those lymph nodes that were obviously abnormal were removed. Systematic sampling refers to routine biopsy of lymph nodes at levels specified by the author. Complete mediastinal lymph node dissection indicates that all lymph node–containing tissue was routinely removed at those levels indicated by the investigators (Keller et al, 2000).5,8,9 Gaer and Goldstraw10 reported the results of the only study that has directly compared intraoperative visual evaluation of lymph nodes with pathologic examination. Based on inspection and palpation of the lymph nodes after dissection, the surgeon recorded his impression regarding the presence or absence of metastatic tumor in 95 consecutive patients with NSCLC who underwent pulmonary resection and mediastinal lymph node dissection. A total of 287 nodal levels were removed (Table 79-1). Sensitivity was 71%, and the positive predictive value was 64%. If only tactile inspection of the nodal levels through unopened mediastinal pleura had been performed, these values would presumably have been lower. The need for routine intraoperative systematic lymph node sampling was further demonstrated by Graham and associates,11 who reported the results of systematic sampling of right levels 2 through 4 and 7 through 10 or left levels 4 through 10 in 240 patients with clinical T1-3 N0 NSCLC. Mediastinoscopy was performed before thoracotomy if the computed tomographic (CT) scan demonstrated mediastinoscope-accessible lymph nodes larger than 1.5 cm. No patient with documented N2 disease underwent thoracotomy. Mediastinal lymph node metastases were demonstrated in 20% of patients, the majority of whom had T1 or T2 tumors. Haiderer and colleagues12 reported the results of routine mediastinal lymph node dissection performed as part of their operation for NSCLC. Enlarged mediastinal lymph nodes were found in 34 (41%) of 83 patients. However, only 19 (56%) contained metastatic disease. Micrometastatic disease was found in 2 (4.1%) of the 49 patients with normalappearing mediastinal lymph nodes. Supporting data are contained in a publication by Bollen and coworkers,13 who found that the discovery ratio (calculated in a fashion similar to the more familiar relative risk ratio) of N2 disease in patients with NSCLC who underwent mediastinal lymph node dissection was 2.1 (confidence interval, 0.9-4), when compared with those patients whose lymph nodes were removed only if they appeared or felt abnormal. 957

Ch079-F06861.indd 957

1/21/2008 1:43:44 PM

958

Section 3 Lung

TABLE 79-1 Intraoperative Assessment of Lymph Nodes Assessment

No. Node Stations

No. Patients

True negative

238

88

True positive

25

16

False positive

14

11

False negative

10

9

Total number of resections

95

Accuracy, 91.6%; positive predictive value, 25/(25 + 14) = 64.1%; negative predictive value, 238/(238 + 10) = 96.0%. From Gaer JAR, Goldstraw P: Intraoperative assessment of nodal staging at thoracotomy for carcinoma of the bronchus. Eur J Cardiothorac Surg 4:207, 1990.

A number of investigators have evaluated the extent of mediastinal biopsy necessary to obtain accurate staging information. Bollen and coworkers13 found that systematic sampling of mediastinal lymph nodes was as successful as mediastinal lymph node dissection in identifying N2 disease (discovery ratio, 2.7; confidence interval, 1.04-4.2). Izbicki and colleagues14 conducted a randomized prospective trial containing 182 patients that compared the two techniques. The number of N2-positive levels was greater in the patients who had full lymph node dissections, although the percentage of patients found to have N1 or N2 disease was not significantly different between the two study arms. Keller and associates (Keller et al, 2000),5 in a study of 373 patients with stage II or IIIA NSCLC, showed similar results regarding the staging efficacy of complete mediastinal lymph node dissection. In their study of 115 patients with clinical T1 N0 tumors smaller than 2 cm in diameter, Sugi and colleagues (Sugi et al, 1998)15 found mediastinal metastases in 12% of the dissection group and in 14% of the sampling group (P = NS). However, in a randomized trial of 471 patients, Wu’s group (Wu et al, 2002)6 found fewer stage I and more stage IIIA patients in the group of those undergoing complete mediastinal lymph node dissection, suggesting that systematic sampling provides less accurate staging than does complete lymph node dissection. Biopsy of the sentinel lymph node has been proposed as a selective method for directing mediastinal lymph node staging. Little and colleagues16 injected each quadrant of lung tissue surrounding the tumors of 36 clinically N0 patients with isosulfan blue dye. After pulmonary resection, systematic sampling was performed. A sentinel lymph node was identified in 17 patients. Each of the five sentinel lymph nodes found in the mediastinum contained tumor, whereas only 3 of 12 found within the pleural reflection harbored metastatic cancer. Among the 19 patients in whom no sentinel lymph node could be found, 5 patients proved to have N1 disease, and 1 patient had N2 disease. Liptay and colleagues17 reported on 91 patients with resectable NSCLC who underwent sentinel lymph node mapping (technetium99m [99mTc]-sulfur colloid), anatomic resection, and complete mediastinal lymph node dissection. A sentinel lymph node was found in 78 patients (86%). In 21 (27%) of 78

Ch079-F06861.indd 958

patients, the sentinel node contained metastatic disease, and in 9 patients it was the only positive node. Serial sectioning or immunohistochemistry was required to detect the disease in seven of the nine patients, and all seven were upstaged. Interestingly, the sentinel node was found in the mediastinum (N2) in 16 patients with an identifiable sentinel node, without concomitant disease in the intrapulmonary lymph nodes (N1). In 9 (15%) of the 78 patients, the sentinel node was declared to be free of tumor in the presence of disease in other lymph nodes. Schmidt and associates18 studied 31 patients with clinical stage I or II NSCLC who underwent sentinel lymph node mapping (99mTc-sulfur colloid and/or isosulfan blue), pulmonary resection, and complete mediastinal lymph node dissection. Sentinel nodes were sought only in the mediastinum and were identified in 25 patients. The sentinel node was commonly demonstrated by both methods, but occasionally the sentinel node contained only dye or radiotracer. Therefore, it appears that using both dye and radiotracer increases the likelihood of finding a sentinel node. In three patients, tumor was found in the sentinel node; two of these patients also had tumor in the hilar lymph nodes. One patient demonstrated skip metastases. No immunohistochemistry or serial sectioning was employed, so it is not known whether the 22 negative sentinel nodes contained micrometastases. However, in those cases, no tumor was found in the more distant mediastinal nodes. The authors concluded that the presence of a mediastinal sentinel node or nodes free of disease may obviate the need for a mediastinal lymph node dissection. Investigations by Melfi,19 Faries,20 and Nomori21 and their colleagues resulted in similar conclusions in patients with clinical stage I NSCLC. A sentinel lymph node was identified in 81% to 100% of patients when a radiotracer was used for detection. The presence of bulky tumor or emphysema disrupted intrapulmonary lymphatic drainage sufficiently to preclude detection of a sentinel node. The sentinel node or nodes were found to be free of disease when, in fact, metastases were detected in other nonsentinel nodes in only 2.3% to 3.8% of patients. Tumor was present in the sentinel lymph node in 18% to 36% of patients, and skip metastases were observed in 13% to 28%. All three studies suggested that patients without disease in the hilar and mediastinal sentinel lymph nodes may not require a complete mediastinal lymph node dissection. Data regarding long-term survival in patients undergoing sentinel lymph node mapping to determine the need for mediastinal lymph node dissection are not available. The efficacy of this procedure has yet to be proved in randomized trials, and, as such, it is still considered experimental. The Cancer and Leukemia Group B has opened a multicenter study (protocol 140203) to investigate the role of sentinel lymph node mapping in the treatment of earlystage NSCLC.

EVOLUTION OF THE NODAL STAGING SYSTEM The stumbling block of accurate lung cancer staging has been the “N” of the TNM system. Disagreement about the stage to which lymph node levels are assigned (e.g., level 10), as

1/21/2008 1:43:44 PM

Chapter 79 Mediastinal Lymph Node Dissection

contiguous level 4 lymph nodes? Similarly, the precise limits of the superior mediastinal lymph nodes (levels 1 through 4) and aortic lymph nodes (levels 5 and 6) allowed some investigators to report multilevel metastases where others reported only single nodal level involvement. The American Thoracic Society (ATS) attempted to ameliorate the confusion by issuing an official statement in which the vague terms “hilar” and “mediastinal” were discarded in favor of nodal level definitions based on constant anatomic structures identified in the operating room.23 For instance, right level 4 lymph nodes were defined as those lymph nodes found “to the right of the midline of the trachea between the cephalic border of the azygous vein and the intersection of the caudal margin of the brachiocephalic artery with the right side of the trachea.” No decision was made regarding whether level 10 lymph nodes need to be considered as N1 or N2.

well as competing definitions for a number of the N levels (e.g., levels 2-4), have caused much confusion. The realization that clinical outcome varied with the location of the tumor-containing lymph node influenced the definitions of the N category. The lymph node mapping schema proposed by Naruke and coworkers22 and accepted by the American Joint Committee for Cancer Staging and End Results Reporting (AJCC) achieved universal acceptance after its publication in 1978 (Fig. 79-1). However, interinstitutional as well as intrainstitutional interpretation of lymph node levels varied because of the lack of precise anatomic definitions. For instance, the term hilar was used for level 10. Were these lymph nodes within the pleural reflection, or were they located in the mediastinum? If they were located outside the pleural reflection, why were they included in the N1 category, and how could they be differentiated from the

FIGURE 79-1 Lymph node map originally proposed by Naruke. 1, Superior mediastinal or highest mediastinal; 2, paratracheal; 3, pretracheal, retrotracheal or posterior mediastinal (3p), and anterior mediastinal (3a); 4, tracheobronchial; 5, subaortic or Botallo; 6, para-aortic (ascending aorta); 7, subcarinal; 8, paraesophageal (below carina); 9, pulmonary ligament; 10, hilar; 11, interlobar; 12, lobar (upper lobe, middle lobe, and lower lobe); 13, segmental; 14, subsegmental. (FROM

1

2

2 3 4 14

6

4

5

10

10

7 13 14

14

12 11

10

13

10

13

12

14

11 11

8

14

NARUKE T, SUEMASU K, ISHIKAWA S: LYMPH NODE MAPPING AND CURABILITY AT VARIOUS LEVELS OF METASTASIS IN RESECTED LUNG CANCER. J THORAC CARDIOVASC SURG 76:832, 1978. COPYRIGHT ELSEVIER 1978.)

13

12 12

8

13 14

13 14

13 13

13

959

14 14

9

9

1 3p

2

1 3

3a

3a

3

2 3p

4 6

4

5

8 8

9 9

Ch079-F06861.indd 959

1/21/2008 1:43:44 PM

960

Section 3 Lung

TABLE 79-2 American Joint Committee on Cancer and Union Internationale Contre le Cancer 1996 Lymph Node Level Definitions

From Mountain CF, Dresler CM: Regional lymph node classification for lung cancer staging. Chest 111:1718, 1997.

This determination was deferred until survival data for patients who had accurate and thorough intraoperative lymph node dissections could be collected and analyzed. The ATS nodal definitions were not officially accepted by the AJCC, though they were commonly used. The Lung Cancer Study Group initially employed the AJCC lymph node definitions but later adopted and modified the ATS definitions.24,25 Level 10 lymph nodes were unequivocally placed in the N2 category. In 1986, a revised international staging system for lung cancer was adopted by the AJCC and the Union Internationale Contre Cancer (Table 79-2).26 Lymph node level definitions remained unchanged, although the components of the N2 nodal group were altered, and an N3 category was created. The staging system and lymph node level definitions were again significantly modified in 1997 (Mountain, 1997; Mountain and Dresler, 1997).27,28 The new mediastinal lymph node level definitions were created to enable accurate and reproducible clinical staging and are based on structures readily identified by CT scans (Figs. 79-2 and 79-3). Unfortunately, the intraoperative identification of some of the lymph node

Ch079-F06861.indd 960

levels has been rendered more difficult (e.g. right levels 2 and 4) because the revised definitions use structures that are not easily identified during surgery. Level 10 lymph nodes were defined as those nodes found along the anterior surface of the main stem bronchus distal to the pleural reflection and were place in the N1 category. Mountain and colleagues29 emphasized the importance of identifying the nodal and stage definitions used by different authors when interpreting and comparing published results. The new revised staging system is used in studies presently being conducted under the aegis of the various American national cooperative oncology groups.

PATTERNS OF METASTATIC SPREAD Harvey and Zimmerman30 documented the development of the pulmonary lymphatics within the human embryo. The definitive description of the locations of the extrapulmonary intrathoracic adult human lymph nodes was written by Rouviere.31 Superb summaries of the common intrapulmonary lymphatic anatomy were published by Borrie32 and Weinberg.33

1/21/2008 1:43:45 PM

Chapter 79 Mediastinal Lymph Node Dissection

961

Left level 2

Right level 2

Left level 4

Right level 4 superior

Left level 6

Left level 5

Right level 4 inferior Left level 10 Right level 12 Left level 12 Right level 8

Left level 8

Right level 9

Left level 9 Subcarinal level 7

FIGURE 79-2 Graphic representation of current lymph node level definitions. (COURTESY OF STEVEN M. KELLER, MD.)

FIGURE 79-3 Details of the current lymph node definitions in the left hemithorax. (COURTESY OF STEVEN M. KELLER, MD.)

The patterns of lung cancer dissemination within the intrapulmonary lymphatics of resected specimens were investigated by Borrie.32 He found that right upper lobe tumors metastasized to the lymph nodes surrounding the right upper lobe bronchus and to those lymph nodes “in the angle between the upper and middle lobe bronchus and also along the medial surface of the right main bronchus.”32 The latter region became known as the lymphatic sump of Borrie. Metastases from right upper lobe tumors were not found below the level of the middle lobe bronchus. Lymph nodes surrounding the middle lobe bronchus and proximal to the previously described bronchial sump were the sites of metastases from right middle lobe tumors. Tumors within the right lower lobe metastasized to the peribronchial lymphatics, the lymph nodes contained within the inferior pulmonary ligament, and the sump of Borrie. Metastases to the lymphatic sump were found to correlate with the presence of endobronchial tumor in the middle or lower lobe orifices.34 Left upper lobe cancers metastasized to lymph nodes surrounding the left upper lobe bronchus and to those surrounding the apical and basilar segmental bronchi of the left lower lobe. Sites of lymphatic metastases of left lower lobe tumors included nodes surrounding the left lower lobe bronchus, the inferior pulmonary ligament, and the left upper lobe bronchus. These observations were confirmed and extended by NohlOser35,36 to include the patterns of mediastinal spread. The locations of nodal specimens from 749 patients with stages I through IV NSCLC who underwent mediastinoscopy, scalene node biopsy, or mediastinal lymph node dissection were included in the analysis. Histology was not stated. Right upper lobe tumors spread rarely to the subcarinal region (1%) or to the contralateral scalene nodes or mediastinum (3%), but they commonly spread to the ipsilateral mediastinum (50%). Tumors within the right lower lobe metastasized to the contralateral scalene nodes or mediastinum infrequently

(4%), but they commonly spread to the subcarinal region (13%) and the ipsilateral mediastinum (29%). Insufficient numbers of right middle lobe tumors were present to allow analysis. Left upper lobe tumors metastasized to the subcarinal region (5%) and contralateral mediastinum (7%). Tumors originating within the left lower lobe metastasized to the subcarinal region (3%), as well as the contralateral mediastinum. Greschuchna, cited by Nohl-Oser,37 documented a much higher prevalence of subcarinal lymph node metastases from upper lobe tumors and a greater occurrence of paratracheal disease from lower lobe neoplasms. More recently, Asamura and coworkers38 documented the patterns of intrathoracic lymph node metastases in 166 patients with proven N2 disease (Table 79-3). All patients had undergone complete mediastinal lymph node dissections at the time of pulmonary resection. He found that upper lobe tumors rarely metastasized to the subcarinal lymph nodes, particularly in the absence of concomitant paratracheal lymph node metastases. He suggested, therefore, that subcarinal node dissection is unnecessary in the absence of documented metastases at lymph node levels 1 to 4. The intrathoracic metastatic patterns of 124 patients with N2 NSCLC who underwent pulmonary resection and mediastinal lymph node dissection were reported by Watanabe and colleagues.39 In contradistinction to Nohl-Oser35 and Asamura,38 Watanabe found frequent metastases from right upper lobe tumors to the subcarinal lymph nodes (36%). He also demonstrated that tumors originating in the right middle and lower lobes commonly (28%) spread to the ipsilateral paratracheal region (level 4). The subcarinal lymph nodes were a common site of metastases from tumors of the left upper (20%) and left lower (38%) lobes. Kotoulas and coworkers40 conducted a retrospective review of 557 patients who underwent pulmonary resection and lymph node dissection. Their results were in general agreement with the findings of Nohl-Oser35 and Asamura.38 In addition, centrally located tumors from all lobes were more

Ch079-F06861.indd 961

1/21/2008 1:43:45 PM

962

Section 3 Lung

TABLE 79-3 Pattern of Intrathoracic Metastases in Patients With N2 Disease* Lymph Node Levels

Right Upper Lobe (n = 54)

Right Lower Lobe (n = 41)

Left Upper Lobe (n = 44)

Left Lower Lobe (n = 19)

1-4

75

46

27

11

10-14

30

36

37

7

7

7

24

9

11

8

0

0

0

1

9

0

4

0

5

5

—

—

26

3

6

—

—

14

1

*Metastases may be present at more than one lymph node level. From Asamura H, Nakayama H, Kondo H, et al: Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg 117:1102, 1999.

FIGURE 79-4 The width of each line corresponds to the relative frequency of lymphatic drainage. A, Apical and dorsal segments of the right upper lobe. B, Middle lobe and superior segment of the lower lobe. C, Basal segments of the lower lobe. Four routes of drainage were identified from the left lung: D, through the subaortic lymph nodes and then dividing to run proximally, either along the vagus nerve to the scalene nodes or along the recurrent laryngeal nerve to the mediastinal nodes; E, by way of the phrenic nerve to the scalene nodes; F, along the main stem bronchus to the paratracheal nodes; G, under the main stem bronchus to the subcarinal lymph nodes. (FROM HATA E, HAYAKAWA K, MIYAMOTO H, HAYASHIDA R: RATIONALE FOR EXTENDED LYMPHADENECTOMY FOR LUNG CANCER. THEOR SURG 5:19, 1990.)

likely to metastasize to the subcarinal nodes than were peripherally located tumors. This may explain the unexpected findings of Watanabe.39 Experimental support for these results was provided by Hata and associates.2 Lymphoscintigraphies were performed in 179 patients who had no evidence of lymph node involve-

Ch079-F06861.indd 962

ment by transbronchoscopic injection of antimony sulfide or rhenium colloid labeled with technetium 99m into the submucosa of each segment. Gamma camera scanning demonstrated patterns of lymphatic drainage that recapitulated the clinical findings of Greschuchna37 and Watanabe and colleagues (Fig. 79-4).39

1/21/2008 1:43:46 PM

Chapter 79 Mediastinal Lymph Node Dissection

TECHNIQUES OF LYMPH NODE SAMPLING AND DISSECTION The earliest detailed description of a thorough intrathoracic lymph node dissection as part of an operation for lung cancer was given in 1951 by Cahan and colleagues,41 although Brock42 indicated that it was a routine part of his operative procedure for lung cancer a number of years earlier. En-bloc removal of the lymphatics and lung was emphasized. Other authors43-48 soon published their techniques describing the lymph node locations in general anatomic terms. Numbers were first assigned to the lymph node regions by Weinberg.43 Martini49 detailed the mediastinal lymph node dissection technique developed at the Memorial Sloan-Kettering Cancer Center. During a right thoracotomy the right paratracheal and subcarinal regions are routinely cleared of all lymphatic tissue, whereas during a left thoracotomy the subcarinal and aorticopulmonary window lymph nodes are removed. Lymph nodes were not resected in continuity with the pulmonary specimen. Level numbers were assigned according to Naruke.22 Extensive lymphadenectomies have been devised by those surgeons who believe that removal of regional lymphatics offers a survival advantage. These have included contralateral mediastinal lymph nodes and, in some cases, supraclavicular lymph nodes. Watanabe and colleagues1 transected the azygos vein to gain access to the upper mediastinal lymph nodes (Naruke levels 1 through 4) during a right thoracotomy. Nodes anterior to the superior vena cava (SVC) with associated thymic tissue were also removed. In addition, left levels 2 through 4 were resected by continuing the dissection to the contralateral aspect of the trachea. All lymph nodecontaining tissue was cleared from the subcarinal region. Both ipsilateral and contralateral levels 8 and 10 lymph nodes were removed. An equally aggressive lymph node dissection is possible in the left hemithorax. However, such an approach requires mobilization of the arch of the aorta and a portion of the descending aorta. Watanabe’s left mediastinal lymph node dissection involved transection of several intercostal arteries. In this fashion, left levels 3 and 4 as well as portions of level 2 could be resected.1 Watanabe and colleagues1 further modified his operative procedure to permit more thorough dissection of all left mediastinal lymph nodes. After completion of pulmonary resection by means of a standard posterolateral thoracotomy, a mediansternotomy was performed. This permitted complete dissection of all left levels 1 through 4 as well as access to contralateral levels 1 through 4 and 10. This approach was also investigated by Mitsuoka and colleagues.50 Nakahara and associates3 used a similar approach for treatment of right lung cancers. A mediansternotomy was not, however, employed for left lung tumors. Rather, the ligamentum arteriosum was transected, the aorta encircled with a catheter, and traction applied caudally. The pleura between the left common carotid and subclavian arteries was opened, and the trachea and left main stem bronchus were exposed, permitting dissection of left node levels 2 through 4.

Ch079-F06861.indd 963

963

Hata and colleagues (Hata et al, 1990)2,4 pursued an even more aggressive approach, extending the right lymphadenectomy performed during posterolateral thoracotomy to include ipsilateral scalene lymph nodes if the most cephalad right paratracheal lymph nodes (Naruke levels 1, 2, and 4) contain metastatic cancer. Hata advocated broadening the supraclavicular dissection to include the left scalene lymph nodes if anterior mediastinal lymph node (Naruke level 3) involvement is suspected. The extent of the left lymphadenectomy was determined by both tumor histology and stage. Mediastinal lymph nodes of patients with stage I squamous cell cancers were removed via a left posterolateral thoracotomy. Although the authors did not specifically state the operative details, they appeared to include division of the ligamentum arteriosum and mobilization of the aortic arch. Patients with more advanced stages and other histologies underwent mediansternotomy followed by anterior and bilateral paratracheal lymphadenectomy (levels 1-4). Exposure was obtained by retracting the ascending aorta to the left and the SVC to the right. The subcarinal nodes were exposed by caudal retraction of the right main pulmonary artery. The left lobe of the thymus was resected to uncover the aortopulmonary window lymph nodes, which were removed to the ligamentum arteriosum. Left upper lobectomy and pneumonectomy were performed via sternotomy, and a left lower lobectomy was accomplished through an additional anteroaxillary thoracotomy. Hata and colleagues (Hata et al, 1990)2,4 recommended a cervical dissection if metastatic disease is found in the highest mediastinal, supraclavicular, or scalene lymph nodes. A cervical collar incision was made, and the sternocleidomastoid muscles were retracted laterally and the strap muscles divided. The fascia over the internal jugular vein was opened, and the vein was skeletonized. The recurrent laryngeal nerve was gently retracted forward, and the cervical paraesophageal lymph nodes were removed. Although the extended dissections described here provide for thorough inspection of the mediastinum, these procedures have never gained widespread acceptance because of their significant invasiveness. Recently, Kuzdzal and colleagues51 described a transcervical, video-assisted mediastinoscopic technique that allowed for dissection of levels 1, 2R/L, 3a, 4R/L, 5, 6, 7, and 8, obviating the need for a mediansternotomy. The mediastinum was approached via a 5- to 6-cm collar incision, and exposure was achieved with the aid of a sternal elevating retractor. A success rate of 62% to 100% for complete dissection at the intended N2 levels was reported.

COMPLETE MEDIASTINAL LYMPH NODE DISSECTION Right Hemithorax Mediastinal lymphadenectomy can readily be accomplished via either a posterolateral thoracotomy or a vertical musclesparing skin incision. Entry into the chest through the fourth or fifth interspace provides access to the necessary lymph node locations. Although mediastinal lymph node dissection is commonly performed after completion of the pulmonary

1/21/2008 1:43:47 PM

964

Section 3 Lung

Internal mammary artery Internal mammary vein

Phrenic nerve

Internal mammary vein

Level of aortic arch

Level of aortic arch

Innominate artery

Vagus nerve

Trachea

Azygos vein Azygos vein FIGURE 79-5 Exposure of right superior mediastinum with mediastinal pleura intact. (COURTESY OF STEVEN M. KELLER, MD.)

resection, if the presence of tumor within the lymph nodes will change the operative procedure the lymph node resection is performed before lung removal. The superior mediastinum encompassed by the trachea, SVC, and azygos vein is exposed by retracting the lung inferiorly (Fig. 79-5). The phrenic nerve is identified on the lateral border of the SVC. The vagus nerve traverses the superior mediastinum and is usually visible through the unopened mediastinal pleura more posteriorly. The mediastinal pleura cephalad to the azygos vein (between the trachea and the SVC) is grasped with a forceps and incised to the level of the innominate artery. The pleural edge over the trachea is retracted and, with the use of a peanut sponge, rolled tightly on a clamp; the mediastinal fat pad is dissected off the anterolateral tracheal surface (Fig. 79-6). Traction is placed on the pleural edge over the SVC, and the mediastinal fat pad is gently dissected from the junction of the SVC and azygos vein to the level of the innominate artery. A small vein draining from the mediastinal fat pad directly into the SVC is frequently present. The mediastinal fat pad is removed from the SVC to the trachea, and from the cephalad border of the azygos vein to the caudal border of the innominate artery. Hemostatic clips are used liberally. Right level 2 lymph nodes are located between the cephalic border of the aortic arch and the cephalic border of the innominate vein. Lymph nodes distal to the aortic arch and proximal to the azygos vein are labeled right level 4 superior nodes (Fig. 79-7). A vein retractor is used to elevate the azygos vein, and the lymph nodes located between its cephalic border and the origin of the right upper lobe bronchus are removed (Fig. 79-8). During dissection of these level 4 inferior lymph nodes, care must be taken not to injure the pulmonary artery. Dissection between the esophagus and the membranous portion of the trachea reveals level 3 posterior nodes (Fig. 79-9). Level 3 anterior lymph nodes are found anterior and medial to the SVC at the insertion of the azygos vein. Right level 10 lymph nodes are located along the anterior border of the bronchus intermedius distal to the pleural

Ch079-F06861.indd 964

FIGURE 79-6 The internal mammary vein drains into the approximate juncture between the right and left innominate veins as they combine to form the superior vena cava and is a reliable structure with which to differentiate the division between level 2 and level 4 lymph nodes. The dashed line represents the aortic arch. (COURTESY OF STEVEN M. KELLER, MD.)

Innominate artery

Vagus nerve

Azygos vein

FIGURE 79-7 The lymphadenectomy may be extended to the contralateral lymph node levels (not shown). Care must be taken not to injure the left recurrent laryngeal nerve, which is found in the tracheoesophageal groove. (COURTESY OF STEVEN M. KELLER, MD.)

Right upper lobe bronchus

Azygos vein

Right mainstem bronchus FIGURE 79-8 Division of the azygos vein is rarely necessary. (COURTESY OF STEVEN M. KELLER, MD.)

1/21/2008 1:43:47 PM

Chapter 79 Mediastinal Lymph Node Dissection

965

Right level 10 lymph nodes

Retrotracheal level 3P lymph nodes

Prevascular level 3A lymph nodes

Bonchus intermedius

Esophagus Right upper lobe bronchus

FIGURE 79-9 The location of the membranous portion of the trachea and the phrenic nerve must be determined before clips are applied. (COURTESY OF STEVEN M. KELLER, MD.)

Pulmonary artery

Level 12 lymph nodes

Right upper lobe bronchus

FIGURE 79-11 A peanut is used to dissect the level 12 lymph nodes and include them with the specimen. Cautery is employed to transect soft tissue because a clip might interfere with the application of a stapling device. (COURTESY OF STEVEN M. KELLER, MD.)

Right mainstem bronchus Azygous vein

Subcarinal level 7 lymph nodes Esophagus FIGURE 79-12 The esophagus and membranous portion of the bronchus must not be injured when applying clips. (COURTESY OF STEVEN M. KELLER, MD.)

Ch079-F06861.indd 965

Pulmonary artery

FIGURE 79-10 Exposure of the level 10 lymph nodes is accomplished by retracting the pulmonary artery anteriorly. (COURTESY OF STEVEN M. KELLER, MD.)

reflection (Fig. 79-10). Level 11, interlobar, lymph nodes are found in the sump of Borrie and are exposed by retracting the lung posteriorly. Level 12 nodes are adjacent to the distal lobar bronchus and are removed with the specimen (Fig. 79-11). The level 7 subcarinal region is exposed by retracting the lung anteriorly (Fig. 79-12). The mediastinal pleura is opened, and the edge overlying the esophagus is grasped with a rightangle clamp. The esophagus is retracted posteriorly, and the subcarinal lymph node packet is grasped with a ring clamp and elevated from the pericardium. Before transection, the attachments to the right and left main stem bronchi are clipped. Vessels course along the anterior border of the trachea and enter the subcarinal lymph nodes from the region of the carina. These arteries and veins must be identified and controlled before transection. The inferior pulmonary ligament contains the easily visualized level 9 lymph nodes, which are grasped with a ring forceps and removed with cautery or clips. Paraesophageal, level 8, lymph nodes are not always present.

Left Hemithorax The aortopulmonary (levels 5 and 6) and subcarinal (level 7) lymph nodes are exposed via a fifth interspace thoracotomy. Beginning at the level of the aortopulmonary window, the pleura is incised in a cephalad direction, midway between and parallel to the vagus and phrenic nerves (Fig. 79-13). The ligamentum arteriosum is not usually seen but is readily palpated. The pleural edge closest to the phrenic nerve is grasped, and the lymph node–containing fat pad anterior to the ligamentum arteriosum is removed. Dissection of the level 6 lymph nodes is best accomplished with blunt instruments. To avoid electrical injury to the nearby nerves, vessels are controlled with clips or ties. The location of the phrenic nerve must be constantly known, to avoid iatrogenic diaphragm paralysis. Level 5 lymph nodes are located posterior

1/21/2008 1:43:48 PM

966

Section 3 Lung

Phrenic nerve

Highest intercostal vein

Left pulmonary artery

Vagus nerve Descending aorta Level 6 lymph nodes

Ligamentum arteriosum

Level 5 lymph nodes

Subcarinal level 7 lymph nodes

Recurrent laryngeal nerve Inferior pulmonary ligament Level 9 lymph nodes

Esophagus FIGURE 79-14 The subcarinal lymph nodes are more difficult to expose in the left hemithorax than in the right hemithorax. A malleable retractor is used to retract the aorta and esophagus posteriorly. (COURTESY OF STEVEN M. KELLER, MD.)

Level 12 lymph nodes FIGURE 79-13 The left superior mediastinum before the mediastinal pleura is opened. Exposure of level 2 or 4 lymph nodes would require mobilization of the aortic arch. (COURTESY OF STEVEN M. KELLER, MD.)

to the ligamentum arteriosum and exposed with blunt dissection. Vocal cord paralysis is a potential, albeit rare, complication. Therefore, the recurrent laryngeal nerve and the proximal vagus nerve must be zealously protected. The level 7 subcarinal lymph nodes are approached with the lung retracted anteriorly (Fig. 79-14). The left main stem bronchus is identified, and the pleura is opened anterior and parallel to the aorta. The lymph nodes are grasped with a ring clamp, and clips are liberally applied before removal of the nodal packet. The arterial vessel that commonly enters the lymph nodes from the anterior border of the trachea at the level of the carina must be identified and clipped to avoid postoperative hemorrhage. Level 11 interlobar lymph nodes are best visualized with the lung retracted anteriorly. The pulmonary artery is located immediately anterior and must be avoided when clips or cautery is used. Level 12 lymph nodes are located along the distal lobar bronchus, near its junction with the main stem bronchus, and are removed with the specimen (Fig. 79-15). Level 9, pulmonary ligament, lymph nodes are identified within this structure and removed with cautery or clips. The esophagus courses posteriorly, and injury to it must be avoided. If the resected specimens are not correctly labeled, even the most detailed lymph node dissection will provide little information. To ensure that each level is reported separately and that levels are not lumped together as “mediastinal lymph nodes,” each level must be sent from the operating room as a discrete specimen.

Complications Some surgeons are hesitant to perform a complete mediastinal lymph node dissection for fear of complications that might arise from interruption of the blood supply to the

Ch079-F06861.indd 966

Left upper lobe bronchus FIGURE 79-15 As the soft tissue is cleared to permit application of the stapling device, the nodes are pushed distally with a peanut. (COURTESY OF STEVEN M. KELLER, MD.)

bronchial stump or from removal of a large portion of the intrathoracic lymphatics. The postoperative complications of 155 patients with NSCLC who underwent no mediastinal lymph node dissection or sampling (n = 70), complete mediastinal lymph node dissection (n = 65), or systematic mediastinal lymph node sampling (n = 20) were reported by Bollen and colleagues.13 Intraoperative blood loss or the need for transfusion was not significantly different among the groups. Three patients (5%) who underwent complete nodal dissection suffered unintentional left recurrent laryngeal nerve injury. Chylothoraces developed in two additional patients. One patient who underwent node dissection required reoperation for bleeding not related to the lymphadenectomy. Bronchopleural fistulas developed in two patients who had not undergone node dissection. Hata and colleagues (Hata et al, 1990)2 reported two left recurrent laryngeal nerve injuries and one phrenic nerve paralysis in 50 patients who underwent extensive mediastinal dissection. The morbidity and mortality associated with systematic mediastinal sampling and mediastinal lymph node dissection were compared in a randomized prospective study (n = 182) conducted by Izbicki and coworkers (Izbicki et al, 1994).52 Though mediastinal lymph node dissection extended the operative procedure by approximately 20 minutes, there was

1/21/2008 1:43:49 PM

Chapter 79 Mediastinal Lymph Node Dissection

no increase in blood loss, mortality, or need for reoperation. One chylothorax occurred in each group. Six patients who underwent systematic sampling and five patients who underwent mediastinal lymph node dissection had recurrent laryngeal nerve injury. Chest tube drainage and hospitalization were similar in both groups. In a prospective nonrandomized trial of 373 patients, Keller and colleagues5 found no difference in blood loss, transfusion requirement, or duration of operation between patients who underwent either systematic sampling or complete mediastinal lymph node dissection. Manser and colleagues (Manser et al, 2005),53 in a pooled analysis of Sugi (Sugi et al, 1998)15 and Izbicki (Izbicki et al, 1998)54 and their colleagues, found an increased risk of air leak persisting for more than 5 days in patients undergoing complete mediastinal lymph node dissection (relative risk [RR], 2.94). Wu and associates (Wu et al, 2002)6 reported a similar finding. Sugi and colleagues (Sugi et al, 1998) 15 also found that complete dissection required 42 minutes more than systematic sampling did. The American College of Surgery Oncology Group (ACS-OG) randomized 1111 patients to either systematic sampling or complete mediastinal lymph node dissection. There was no difference in morbidity, mortality, or hospital length of stay. Complete mediastinal lymph node dissection was associated with statistically significant, but clinically insignificant, increases in blood loss (18 mL), chest tube drainage (48 mL), and operating room time (14 minutes) (Allen et al, 2006).55 There was no difference between the two groups with regard to atrial arrhythmia, chest tube drainage lasting longer than 7 days, air leak lasting longer than 7 days, respiratory complications, chylothorax, recurrent nerve injury, or mean hospital length of stay.

LYMPH NODE DISSECTION AND SURVIVAL In addition to the diagnostic and staging superiority of systematic sampling and complete mediastinal lymph node dissection over sampling, several studies have reported a survival benefit with these two techniques. Gajra and coworkers56 compared the overall and disease-free survival rates in 442 patients who underwent pulmonary resection and lymph node dissection for stage I NSCLC. Systematic sampling and complete mediastinal lymph node dissection provided an overall and disease-free survival advantage at 5 years, compared with random sampling (84% versus 56% and 80% versus 51%, respectively). Increased overall survival and disease-free survival were observed when more than six lymph nodes were harvested or when three or more levels were sampled. In a prospective randomized trial of 169 patients with a median follow-up of 47.5 months, Izbicki and colleagues (Izbicki et al, 1998)54 showed that there was no difference in overall or disease-free survival between sampling and dissection when all patients were considered. Subgroup analysis demonstrated that mediastinal lymph node dissection tended to improve survival (70% versus 38%) and prolonged disease-free survival (59% versus 21%) in patients with pN1 or limited (single-node) pN2 disease. In a nonrandomized study of 373 patients with stage II and IIIA disease, Keller and colleagues (Keller et al, 2000)5 showed a statisti-

Ch079-F06861.indd 967

967

cally significant survival benefit with complete mediastinal lymph node dissection (median survival time, 66.4 versus 24.5 months) in patients with tumors of the right lung. Wu and associates (Wu et al, 2002)6 conducted a prospective randomized trial of 471 patients with stages I through IIIA NSCLC who underwent pulmonary resection and either complete mediastinal lymph node dissection or sampling. The 5-year overall survival rate was 48% in the mediastinal lymph node dissection group and 37% in the sampling group. A survival benefit for patients who underwent mediastinal lymph node dissection was also seen when patients were compared by stage. In addition, mediastinal lymph node dissection reduced the rate of local recurrence and distant metastasis. Yang and coworkers (Yang et al, 2004)7 have presented in abstract form a meta-analysis of randomized trials comparing systematic sampling with mediastinal lymph node dissection published since 1995. Analysis of 997 patients from four studies showed a survival benefit at 5 years (odds ratio for death, 0.67) in favor of mediastinal lymph node dissection (Fig. 79-16). Although Sugi and colleagues (Sugi et al, 1998)15 found no difference in survival between sampling and dissection, Manser and associates (Manser et al, 2005)53 found a statistically lower risk of death (hazard ratio [HR], 0.78) and recurrence (RR, 0.79) with complete mediastinal lymph node dissection in a pooled analysis of the work of Sugi (Sugi et al, 1998),15 Izbicki (Izbicki et al, 1998),54 and Wu (see Fig. 79-16) (Wu et al, 2002).6 In a nonrandomized study of 465 patients, Doddoli and colleagues57 reported an increased 5year survival (HR = 1.43) in favor of lymphadenectomy. However, nonstandard definitions for complete mediastinal lymphadenectomy (≥10 lymph nodes and ≥2 levels sampled) and sampling (<10 lymph nodes or <2 levels sampled) were used. Most recently, Lardinois and colleagues58 compared systematic sampling with complete dissection in 100 consecutive patients with T1-3 N0-1 NSCLC. There were 50 patients in each arm, with assignment based on surgeon preference. Although there was no difference in overall survival, improvements in recurrence rate (13% versus 45%) and disease-free survival (60.2 versus 44.8 months) in patients with stage I disease were noted. Therefore, it appears that systematic lymph node sampling is as accurate as mediastinal lymph node dissection for staging NSCLC. Evidence suggesting a survival benefit associated with complete mediastinal lymph node dissection is now starting to emerge. The ACSOG has completed a trial (Z0030) designed to compare the diagnostic and survival differences between systematic sampling and complete mediastinal lymph node dissection. Longterm results are not yet available. Five-year survival of patients with N2 disease after pulmonary resection and mediastinal lymph node dissection, performed in a fashion similar to that described earlier, is reported to range from 9% to 40% (Keller et al, 2000).5,38,49,58-64 After bilateral mediastinal lymph node dissection via sternotomy, a 5-year survival rate of 66% in 15 patients with N2 disease and 35% in 13 patients with N3 (contralateral mediastinal) disease was reported by Hata and colleagues.4 Five-year survival was 33% in 12 patients with scalene or supraclavicular N3 disease who underwent sternotomy and cervical dissection. Nakahara

1/21/2008 1:43:52 PM

968

Section 3 Lung

Study

Hazard ratio (Fixed) 95% CI

log [Hazard ratio] (SE)

Weight (%)

Hazard ratio (Fixed) 95% CI

Izbicki 1998

–0.25 (0.25)

13.4

0.78 [0.48, 1.27]

Sugi 1998

–0.06 (0.55)

2.7

0.94 [0.32, 2.79]

Wu 2002

–0.26 (0.10)

83.9

0.77 [0.63, 0.93]

100.0

0.78 [0.65, 0.93]

Total (95% CI) Test for heterogeneity chi-square ⫽ 0.13 df ⫽ 2 p ⫽ 0.94 I ⫽ 0.0% 2

Test for overall effect z ⫽ 2.80 p ⫽ 0.005 0.2 0.5 Favors dissection

A

1

2 5 Favors sampling

Weight (%)

Relative Risk (Random) 95% CI

Study

Lymphadenectomy n/N

Node sampling n/N

Izbicki 1998

42/76

61/93

53.6

0.84 [0.66, 1.08]

Sugi 1998

6/59

6/56

2.9

0.95 [0.33, 2.77]

Wu 2002

61/240

82/231

43.5

0.72 [0.54, 0.95]

100.0

0.79 [0.66, 0.95]

Relative Risk (Random) 95% CI

375 380 Total (95% CI) Total events: 109 (Lymphadenectomy), 149 (Node sampling) Test for heterogeneity chi-square ⫽ 0.88 df ⫽ 2 p ⫽ 0.64 I2 ⫽ 0.0% Test for overall effect z ⫽ 2.55 p ⫽ 0.01

B

0.1 0.2 0.5 1 2 5 10 Favors dissection Favors sampling

FIGURE 79-16 Comparison of (A) 4-year survival and (B) recurrence rates in a pooled analysis of patients from three randomized trials undergoing either systematic sampling or mediastinal lymph node dissection. (FROM MANSER R, WRIGHT G, HART D, ET AL: SURGERY FOR EARLY STAGE NON-SMALL CELL LUNG CANCER. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS, 2005, CD004699. DOI: 10.1002/14651858. CD004699. PUB2.)

and associates3 documented a 3-year median survival for 13 patients with N2 disease who also underwent bilateral mediastinal lymph node dissection. However, no patient with N3 disease survived longer than 14 months (n = 4). Watanabe and colleagues1 claimed significantly improved survival in a retrospective study of patients with left upper lobe tumors who underwent bilateral lymph node dissections, compared with those patients who had only suspicious lymph nodes removed. These reports need to be interpreted with some degree of skepticism because they contain small numbers of patients. Indeed, Mitsuoka and colleagues50 found no significant survival advantage for patients with pathologic stage IIIA left lung NSCLC who underwent sternotomy and nodal dissection, compared with those patients who had resection and node dissection via thoracotomy only. Furthermore, no patients with N3 disease survived 3 years.

THORACOSCOPIC LYMPH NODE DISSECTION The use of the thoracoscope in the diagnosis and treatment of chest diseases was introduced by Jacobaeus.65 Though the reported advantages of video-assisted thoracic surgery (VATS)

Ch079-F06861.indd 968

include smaller incisions, decreased blood loss, decreased postoperative pain, improved postoperative immunologic and pulmonary function, decreased length of stay, and decreased hospital costs, skepticism remains regarding the oncologic adequacy and safety of this technique.66-71 Several retrospective reviews can be found in the literature. However, only two small prospective trials have directly compared VATS and thoracotomy approaches with regard to mediastinal lymph node dissection. In a prospective randomized trial of 100 consecutive patients with clinical stage I NSCLC, Sugi and associates72 compared lobectomy by VATS and open thoracotomy. Fifty patients were assigned to each arm, but two patients randomized to the VATS arm required conversion to thoracotomy. The number of lymph nodes harvested did not differ, with a mean of 8 hilar and 13 mediastinal lymph nodes being removed in both groups. The actuarial 5-year survival rates were 85% and 90% for the open and VATS groups, respectively. Locoregional recurrence was observed in 19% of the open group and 10% of the VATS group; these results were not significantly different. In another prospective trial, Sagawa and colleagues73 studied 35 patients with clinical stage I lung cancer who

1/21/2008 1:43:52 PM

Chapter 79 Mediastinal Lymph Node Dissection

underwent VATS lobectomy with mediastinal lymph node dissection through two port sites and a small thoracotomy. After the thoracoscopic part of the procedure, a different surgeon performed a thoracotomy to assess the completeness of the lymph node dissection. Lobectomy could not be completed thoracoscopically in 6 of the 35 patients. An average of 40.3 lymph nodes were harvested by VATS from the right hemithorax, and an additional 1.2 (range, 0-6) were removed by thoracotomy. An average of 37.1 lymph nodes were removed by VATS from the left hemithorax, with an additional 1.2 (range, 0-4) resected by thoracotomy. Survival and recurrence data were not presented.

FUTURE DIRECTIONS The ACS-OG has recently completed a prospective trial designed to evaluate the influence of the type of lymph node dissection on patient survival. After histologic documentation of the absence of N2 disease, patients with T1-2 N0-1 NSCLC were randomized intraoperatively to either complete lymph node dissection or lymph node sampling (ACOSOG Z0030). Long-term results are not yet available. A companion study (ACOS-OG Z0040) addressing the issue of micrometastatic lymphatic disease has completed accrual of approximately 1200 patients, but no results are yet available.

COMMENTS AND CONTROVERSIES Evaluation of the importance of mediastinal lymph node dissection as part of the routine operative management of patients undergoing curative resection for lung cancer has been hampered by a lack of consistency in the definition of lymph node stations and by variability of operative technique. This chapter clarifies both points very well. The operative technique of complete lymph node dissection is well standardized for all pulmonary resections. The technique was successfully employed by numerous surgeons in a multicenter randomized trial recently completed by the ACS-OG. Initial reports from this study indicated that morbidity and operative time were not significantly increased by complete lymph node dissection, compared with lymph node sampling. As the authors point out, long-term results with respect to survival are not yet available. However, a number of reports indicate that patients who have routine lymph node dissection are more accurately staged. Consequently, the

Ch079-F06861.indd 969

969

improved survival among patients undergoing node dissection in a number of these reports may be a result of the well-described phenomenon of stage migration. Equally important is the precision required in labeling resected lymph nodes. The anatomic and numeric localization of mediastinal, hilar, and bronchopulmonary node stations is essential, not only for the appropriate management of the individual patient but for accurate entry and stratification of patients in clinical trials. G. A. P.

KEY REFERENCES Allen MS, Darling G, Pechet T, et al: Morbidity and mortality of major pulmonary resections in patients with early stage lung cancer: Initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81:1013-1020, 2006. Hata E, Hayakawa K, Miyamoto H, Hayashida R: Rationale for extended lymphadenectomy for lung cancer. Theor Surg 5:19, 1990. Izbicki JR, Passlick B, Pantel K, et al: Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: Results of a prospective randomized trial. Ann Surg 227:138, 1998. Izbicki JR, Thetter O, Habekost M, et al: Radical systematic mediastinal lymphadenectomy in non-small cell lung cancer: A randomized controlled trial. Br J Surg 81:229, 1994. Keller SM, Adak S, Wagner H, Johnson DH: Mediastinal lymph node dissection improves survival in patients with stages II and IIIa nonsmall cell lung cancer. Eastern Cooperative Oncology Group. Ann Thorac Surg 70:358, 2000. Manser R, Wright G, Hart D, et al: Surgery for early stage non-small cell lung cancer. The Cochrane Database of Systematic Reviews 2005, CD004699. DOI: 10.1002/14651858. CD004699.pub2. Mountain CF: Revisions in the system for staging lung cancer. Chest 111:1710, 1997. Mountain CF, Dresler CM: Regional lymph node classification for lung cancer staging. Chest 111:1718, 1997. Sugi K, Nawata K, Fujita N, et al: Systematic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg 22:290, 1998. Wu Y, Huang ZF, Wang SY, et al: A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer 36:1, 2002. Yang H, Wu Y, Yang X, Chen G: A meta-analysis of systematic lymph node dissection in resectable NSCLC [Abstract 7190]. J Clin Oncol (Proc ASCO) 22(14S), 2004.

1/21/2008 1:43:52 PM

chapter

VIDEO-ASSISTED PULMONARY RESECTIONS

80

Alan D. L. Sihoe Anthony P. C. Yim

Key Points ■ Video-assisted thoracic surgery (VATS) pulmonary resection differs

■ ■ ■

■

from open resection in that a minimal access approach is used, but otherwise it is the same operation using the same surgical principles. The principles of safe surgery and adequate resection must never be compromised to maintain minimal access. Avoidance of rib spreading is the distinguishing feature of VATS and must be observed. There is now good evidence that pulmonary resection by the VATS approach is superior to the open approach in terms of postoperative pain, preservation of pulmonary function, quality of life, shoulder function, and degree of immunosuppression. Intermediate and long-term survival rates for lung cancer patients receiving VATS lung resection are as good as or even better than the rates for patients receiving thoracotomy.

The thorax is ideally suited for minimally invasive surgery. With the lung collapsed, the pleural space is a large, open space that allows free access to all regions with a thoracoscope and instruments, even from a limited number of ports. The collapsed lung is easy to mobilize and manipulate. The chest wall is fixed, obviating the need for carbon dioxide insufflation and valved ports. This not only saves costs compared to laparoscopic surgery, but it allows digital examination of thoracic contents as well as the use of conventional thoracic surgical instruments through well-placed stab wounds.

HISTORICAL NOTE Hans Christian Jacobaeus from Stockholm is generally recognized to have pioneered thoracoscopic therapy. Toward the end of the 19th century, he first used a modified cystoscope to examine the pleural cavity under local anesthesia. He primarily used this technique of direct thoracoscopy to lyse adhesions in order to collapse the lungs because this was the prevailing treatment for tuberculosis at the time. This technique was adopted throughout Europe in the early decades of the 20th century. Nevertheless, the introduction of streptomycin, in 1945, and ever-improving medical treatment of tuberculosis spelled the end of this first period of enthusiasm for therapeutic thoracoscopy. It is only in the past 2 decades that interest in minimally invasive thoracic surgical therapy has been rekindled by two technological developments. First, the marriage of the thoracoscope with solid-state video systems and microcameras in

the early 1980s allowed a panoramic view of the hemithorax, instead of the previous tunnel-like vision with direct thoracoscopy. Second, the availability of new endoscopic instruments such as the linear mechanical stapler opened up new vistas for a spectrum of diagnostic and therapeutic procedures. From these advances, video-assisted thoracic surgery (VATS) was born. The video-thoracoscope unit with its own light source provides a well-illuminated, magnified operative view of the thorax, offering very high resolution for details surpassing even that provided by the conventional headlight and magnifying loops. Although initially used for simpler diagnostic purposes, the tremendous success of laparoscopic cholecystectomy in the mid-1980s gave impetus to surgeons to apply VATS for treatment of intrathoracic conditions. The first major meeting on VATS was held in January 1993 in San Antonio, Texas, in conjunction with the Society of Thoracic Surgeons meeting; this represented the baptism of a newborn technique. Since then, VATS has become established and developed in many centers in North America, Asia, Europe, Australia, and South America. Its applications as a diagnostic approach and as a therapeutic modality for benign thoracic diseases have now been firmly incorporated into mainstream thoracic surgery. These aspects of VATS are dealt with elsewhere in this book. With growing experience with the technique, it was inevitable that more complex pulmonary operations would be performed using VATS. Although VATS major pulmonary resection, particularly for primary cancer, met with much initial skepticism, there is now a growing body of evidence that VATS pulmonary resections offer significant advantages to patients, compared with conventional open approaches. Perhaps the most important advantage of the VATS approach is its potential for reducing postoperative morbidity and pain. For one whole century since the first lung resection was performed in 1891 by Tuffier, the posterolateral thoracotomy—and, less frequently, the median sternotomy and the clamshell incisions for bilateral pulmonary procedures— have been the preferred modes of surgical access. Although these incisions generally provide good surgical exposure, they are also among the most painful incisions in all of surgery. The trauma of access is often described as worse than that of the procedure itself. It has been reported that 5% to 80% of patients experience significant levels of pain at 2 months or more after a standard thoracotomy.1 This pain can persist in up to 30% of patients at 4 to 5 years after surgery. Once this chronic pain is established, it becomes a difficult condition to treat effectively by conventional analgesic modalities. Ideally, such morbidity is precluded by using surgical techniques that avoid causing this pain. It has previously been

970

Ch080-F06861.indd 970

1/21/2008 1:44:45 PM

Chapter 80 Video-Assisted Pulmonary Resections

suggested that the pain can result from a combination of skin incision, muscle splitting, rib fracturing, costochondral dislocation, pleural injury, diathermy burning, neuroma formation at the wound, and so on. Above all, many surgeons believe that the single most important element is the forcible spreading of the ribs during thoracotomy. The rationale for VATS pulmonary resection is that, by using video technology to minimize the surgical access required, most of these paincausing elements can be reduced, particularly rib spreading. Much of this chapter focuses on our own technique of anatomic major lung resections. However, with the growing acceptance of VATS pulmonary resections worldwide, we recognize that the fine technical details will vary from one unit to the next. We shall then briefly discuss nonanatomic VATS lung resections and recent variations on video-assisted, minimally invasive techniques for pulmonary resections. We emphasize throughout that, compared with open surgery, VATS represents a different mode of access, but the basic principles of pulmonary resection are unchanged. HISTORICAL READINGS Braimbridge MV: Thoracoscopy: A historical perspective. In Yim APC, Hazelrigg SR, Izzat MB, et al (eds): Minimal Access Cardiothoracic Surgery. Philadelphia, WB Saunders, 2000, pp 1-10. Jacobaeus HC: Ueber die Möglichkeit die Zystoskopie bei Untersuchung seröser Höhlungen anzuwenden. München Med Wchenschr 57:2090-2092, 1910. Lewis RJ, Kunderman PJ, Sisler GE, Mackenzie JW: Direct diagnostic thoracoscopy. Ann Thorac Surg 21:536-539, 1976. Mack MJ, Hazelrigg SR, Landreneau RJ, Naunheim, KS (eds): The First International Symposium on Thoracoscopic Surgery. Ann Thorac Surg 56:605-806, 1993. Meade RH: A history of thoracic surgery. Springfield, Charles C Thomas, 1961.

VATS MAJOR PULMONARY RESECTIONS Definition of VATS It is important to point out that VATS major resection is not a unified technique; several variations do exist.2 This is not surprising because the procedure was developed almost simultaneously at different centers around the world, with each unit having its own characteristics. For example, how long of an incision does one allow for minithoracotomy before it becomes a thoracotomy? How often should one operate by peeking through the minithoracotomy instead of looking at the video monitor? How much rib spreading can occur before the benefits of minimal access surgery are lost? We believe that the most significant component of pain after thoracotomy is in the spreading of the ribs. To achieve the objective of minimizing surgical access trauma, we therefore define VATS pulmonary resection as a video-assisted, minimal-access approach in which the surgeon operates primarily by watching the television monitor and uses no rib spreading throughout the entire procedure. Note that the emphasis is not so much on whether one “peeks” through the wound on occasion, but rather on the eschewing of rib spreading. For those surgeons who use rib-spreaders, regardless of whether they operate primarily by looking at the monitor or

Ch080-F06861.indd 971

971

through the minithoracotomy wound, we suggest that their technique be described as minithoracotomy with video assistance or video-assisted thoracotomy (see later discussion). Although it may at first appear pedantic, this strict definition has important implications. In recent years, there have been clinical research papers that apparently fail to confirm or reproduce the excellent results initially reported for VATS lung resection and claim to have found no advantage of “VATS” over open surgery in terms of postoperative morbidity. As a consequence, some surgeons have concluded that the early promise of VATS has died out. However, closer scrutiny of the operative technique used in these studies sometimes reveals that rib spreading was used. Hence, strictly speaking, video-assisted minithoracotomy rather than true VATS was performed.

Patient Selection VATS represents a new approach and not a new procedure. Therefore, the indications for VATS major resections remain the same as for conventional open resection. In our institution, approximately 80% of the resections are for early, primary lung cancer, with the remaining ones being performed for metastatic lung cancer and benign diseases such as localized bronchiectasis or multidrug-resistant tuberculosis.3 For primary lung cancer, accurate preresectional staging (including mediastinoscopy) remains a critical step in cancer management, and it is just as important when selecting patients for VATS resections as for open resections. However, in this regard, VATS affords excellent access to many ipsilateral hilar and mediastinal lymph nodes. Hence, it is entirely feasible to perform VATS sampling of suspicious nodes detected by computed tomography (CT) or positron emission tomography (PET) scanning for accurate staging just before and in the same sitting as the lung resection. In general, the same physiologic criteria for selecting patients for conventional open lung resection also apply for VATS pulmonary resection. However, the reduced trauma and postoperative morbidity potentially offered by VATS may allow recruitment of older and sicker patients with multiple comorbidities for major lung resections.4,5 In conjunction with VATS, improvements in modern anesthetic techniques and specialist perioperative pulmonary physiotherapy and rehabilitation can further enable such patients, who are otherwise not candidates for a conventional thoracotomy approach, to receive potentially curative surgery. The criteria for selecting patients for major lung resection are therefore evolving in response to advances in operative and perioperative care. The lowest limits in lung function parameters that would still be considered acceptable for VATS lobectomy have not yet been scientifically defined.6 Currently, patient selection for VATS pulmonary resection depends to a certain degree on the surgeon’s judgment and experience and the contribution of the excised lobe to overall lung function. For example, upper lobe lesions in patients with bullous emphysema or isolated middle lobe pathology are favorable for resection. In particular, patients with pulmonary emphysema undergoing lung cancer resection can effectively receive a combined VATS lobectomy with lung

1/21/2008 1:44:45 PM

972

Section 3 Lung

Box 80-1 Contraindications to VATS Major Resections Absolute Contraindications Inability to tolerate single-lung ventilation Established mediastinal (N2) lymphadenopathy T3 tumor (main stem bronchial involvement) Planned sleeve resection Relative Contraindications Previous surgery (VATS or thoracotomy) Prior irradiation to the hilum Pleural adhesions Fused interlobar fissures Established hilar (N1) lymphadenopathy Large tumor (>4 cm maximal diameter)

volume reduction.7 We have recently performed VATS lobectomies on 13 patients whose forced expiratory volume in 1 second (FEV1) was less than 0.8 L, or less than 50% of predicted, with no mortality and only two cases of postoperative pulmonary complications (air leakage and atelectasis). Patients who are not candidates for an anatomic resection could still be considered for VATS wedge resection as either a compromised curative procedure or a palliative procedure (see later discussion). There are few contraindications specifically applicable to VATS pulmonary resections, and they are listed in Box 80-1. With growing experience, there are fewer and fewer examples of absolute contraindications to VATS lung resections. The inability to tolerate single-lung ventilation still represents a major contraindication to VATS. We previously described a simple technique of selective lobar collapse that may allow VATS in patients who cannot tolerate collapse of an entire lung.8 Further development may permit VATS pulmonary resections to be carried out with the use of this technique. The current, available data do not yet support the concept that a complete mediastinal lymphadenectomy can be faithfully reproduced through VATS. Therefore, patients with N2 disease that has been pathologically established (either through cervical mediastinoscopy or intraoperatively by frozen section) are treated through an open surgical approach. However, the debate over the relative merits of complete mediastinal nodal dissection versus nodal sampling is still ongoing, and it is notable that Naruke switched several years ago to favor systematic lymph node sampling instead of lymphadenectomy for stage I cancer.9 Lobectomy with enbloc chest wall resection through the VATS approach for primary cancer with chest wall invasion has been reported.10 However, more complex T3 tumors with main stem bronchial involvement requiring pericarinal dissection, as well as pathology requiring sleeve resections, still require open surgery. We have reported our experience on repeat VATS surgery,11 and we now consider prior thoracic surgery a relative rather than an absolute contraindication to VATS resection. Similarly, true pleural symphysis that leads to abandonment of

Ch080-F06861.indd 972

the VATS approach is uncommon in our experience, and normally pleural adhesions are only a relative contraindication. With most cases of pleural adhesions, once the correct plane in the interpleural space is entered, endoscopic adhesiolysis can proceed quickly and safely. Fused interlobar fissures present a technical challenge in VATS pulmonary resections, but not necessarily an absolute contraindication. In difficult cases, if the surgeon remains flexible in the sequence of dissection, he or she may find, for example, that division of the pulmonary vessels and the bronchus before completion of the fissure by endoscopic stapling or suturing may be an easier option. We previously did not recommend VATS resections for tumors larger than 4 cm, primarily because rib spreading may have to be used during specimen retrieval, negating the benefits of minimal-access surgery. However, we have since achieved retrieval of larger tumors by resecting a short segment of rib at the utility minithoracotomy, improving access while causing no more pain than rib spreading (see later discussion). Hence, we no longer regard larger tumors as an absolute contraindication to VATS. Nevertheless, we would stress that, even for the experienced VATS surgeon, a low threshold for converting to an open procedure must always be maintained whenever one is faced with difficulties during surgery. The basic principles of safe surgery are, under no circumstances, sacrificed for the sake of maintaining minimal access.

Operative Technique There are two fundamental concepts that every VATS surgeon needs to follow. First, VATS pulmonary resection is the same operation as an open pulmonary resection except for the minimal access approach. Compared with conventional surgery, VATS pulmonary resection does demand a new set of eye-hand coordination skills because one operates looking at a video monitor rather than where the hands are. However, all the basic principles regarding anatomy, tissue handling, and basic surgical techniques are unchanged. If the surgeon uses these same familiar principles for open surgery when performing VATS pulmonary resection, the duration of the learning curve is usually short.12 Second, the need for safe, effective surgery must never be compromised by the desire to maintain minimal access. If any operative difficulty arises, or if adequacy of the resection seems doubtful, the surgeon must never hesitate to convert to a full thoracotomy.

Anesthesia The procedure is carried out with the patient under general anesthesia, using selective single-lung ventilation. This is usually accomplished by use of a double-lumen endobronchial tube. Because of anatomic considerations, a left-sided intubation is usually preferred, unless a left pneumonectomy is anticipated. We prefer double-lumen tubes over the bronchial blocker systems used with single-lumen endotracheal tubes because the bronchial occlusion caused by the blocker makes it potentially difficult to collapse the lung, especially in patients who have emphysema. More recently, we described a technique of positioning a nonocclusive tube to a lobar

1/21/2008 1:44:45 PM

Chapter 80 Video-Assisted Pulmonary Resections

bronchus via a standard single-lumen endotracheal tube, selectively collapsing the target lobe for VATS.8 There is currently no double-lumen endobronchial tube commercially available for young children. For pediatric cases, we use a single-lumen endotracheal tube and position its tip into the appropriate main stem bronchus.13 Readers are referred to specific reviews on VATS anesthesia for details.14,15

973

lation of the camera. The second video monitor is positioned on the surgeon’s side of the bed so that the first assistant can comfortably view it instead of having to twist around to view the main monitor. If a second assistant is available, he or she stands directly across from the surgeon and assists in lung retraction, usually via the posterior instrument port.

Instruments Patient and Surgeon Positioning

We prefer a 10-mm thoracoscope and a three-chip camera system (e.g., the Stryker 884TE, Kalamazoo, MI) for major pulmonary resection. We use a 30-degree lens for most pulmonary resections, which gives excellent visualization of the lateral chest wall, hilum, and mediastinal surfaces for all required dissections and for lymph node sampling at all ipsilateral stations. However, manipulation of the 30-degree lens is an acquired skill, and if an experienced assistant is not available, a 0-degree lens may suffice for lower and middle lobe resections. It is crucial that the assistant is reminded to avoid torquing the thoracoscope via the camera port. Because of the leverage, even slight torquing could result in significant pressure on the intercostal nerve, causing postoperative neuralgia.16 If necessary, the rigid camera port can be slid back along the thoracoscope out of the wound, allowing more flexibility of the thoracoscope in the chest with less torquing. We generally do not use rigid plastic or metal ports except for the thoracoscope and for introducing mechanical staplers.18 This is done not just to save money, but because the presence of a rigid port makes it difficult to use conventional thoracic instruments.19 Conventional forceps and needle-

Anesthetic machine Anesthesiologist

r

ito

on

2nd Assistant

m

r er ito int on e pr er m g rd TV ima eco rce r u o de eo so Vi Vid ight L

TV

The patient is turned into a full lateral decubitus position and positioned and secured exactly as for an open thoracotomy. We advocate flexing the operating table at the level of the nipples. This allows the utility thoracotomy that is to be made to naturally “gap,” rendering rib retraction unnecessary (Fig. 80-1). The flexion of the table further opens up the intercostal spaces for insertion of the thoracoscope and instruments.16 Because rib spreading is not used, patient positioning is particularly important during VATS to enable optimal instrumentation. We would stress that it is the surgeon’s own responsibility, rather than that of other operating room staff, to ensure satisfactory patient positioning before scrubbing. Occasionally, the tip of the endotracheal tube is displaced after positioning. If there is any doubt, the endotracheal tube position is reconfirmed at this time using a fine-bore flexible bronchoscope. The skin is then prepared and the patient draped as for an open thoracotomy. Our operating room is set up as shown schematically in Figure 80-2. The surgeon stands in front of the patient. Because we prefer the utility thoracotomy to be made slightly anterior to the midaxillary line, this position allows much easier instrumentation by the surgeon. The main video monitor is then positioned along a straight line from the surgeon through the utility thoracotomy. This allows the surgeon to look straight ahead when he or she operates and provides the best ergonomic position for the surgeon.17 The first assistant is the “camera man” who controls the videothoracoscope and stands opposite the surgeon so that there is minimal interference to the surgeon’s hands from manipu-

Surgeon

Nurse

y

rm

he

at

Di

1st Assistant

FIGURE 80-1 Patient positioning for VATS pulmonary resection. With flexion of the operating table to 30 degrees at the level of the nipple, the intercostal spaces naturally open up, obviating the need for rib spreading.

Ch080-F06861.indd 973

Instrument trolley

FIGURE 80-2 Schematic view of our operating room setup. The surgeon stands facing the patient. The first assistant holds the camera.

1/21/2008 1:44:45 PM

974

Section 3 Lung

holders, for example, cannot be opened through such ports. A limited resection of an ellipse of the superior aspect of the rib at each wound has been described to reduce the likelihood of intercostal nerve injury during instrumentation.20 In our own experience, the practice of avoiding rigid ports and introducing instruments directly through each wound adequately minimizes such intercostal trauma. Although complete sets of dedicated thoracoscopic instruments—both disposable and reusable—are commercially available (e.g., those designed respectively by Kaiser, and by Landreneau and Lewis), our preference is still to use conventional instruments. We typically use Rampley sponge holding forceps for lung manipulations and retraction, and DeBakey forceps and Metzenbaum scissors for dissections. For diathermy within the chest, we use either long monopolar diathermy forceps or long-blade monopolar diathermy. Such open thoracotomy instruments are easy to use, universally available, and cheap.21 Moreover, because these instruments are already familiar to surgeons performing open surgery, they allow for the learning curve for VATS to be shortened and for the surgeon to quickly become accustomed to the “feel” of tissues through palpation with the instruments.

FIGURE 80-3 The utility thoracotomy is made in an anterolateral position, and the skin is retracted with a Weitlaner retractor. The flexion of the table at the level of the nipples opens up the rib spaces at the utility thoracotomy, and rib spreading is not required.

Ports Strategy We employ a three-port strategy for VATS pulmonary resections. The first incision is for the camera port. We usually place this incision in the seventh or eighth intercostal space over the midaxillary to anterior axillary line, depending on the body build of the patient and the location of the pathologic lesions. From this position, a panoramic view of the hemithorax is obtained with the video-thoracoscope, allowing exploration of the entire thoracic space for any evidence of inoperability. Suspected pleural or lymph node metastases can be biopsied for frozen section. For the former, we use an endoscopic biopsy forceps inserted either coaxially, alongside the thoracoscope through the camera port or through a second port. If a suspicious-looking mediastinal lymph node is detected, we would biopsy it and perform a frozen section. Confirmation of N2 disease may mandate conversion to open surgery for complete mediastinal lymphadenectomy or referral for neoadjuvant therapy. If there is no contraindication to proceed, a utility thoracotomy (usually 4-8 cm in length) is placed in the anterolateral chest (Fig. 80-3). This incision is made so that the utility thoracotomy opens directly at the level of the interlobar fissure to be dissected, facilitating hilar dissection. The exact level is guided by the video-thoracoscopic view from inside the chest and is typically at the fourth intercostal space. We prefer the incision to be slightly anterior to the midaxillary line because the anterior intercostal space is wider, providing more room for instrumentation and facilitating later retrieval of the specimen. The location of this wound usually means that only a small portion of the latissimus dorsi muscle (if any) needs to be divided. The serratus anterior muscle is split along the direction of its fibers. Division of the intercostal muscles then permits access into the pleural cavity. In women, the skin incision can be made (if the anatomy allows) over the inframammary fold for cosmesis. The soft tissue and skin

Ch080-F06861.indd 974

FIGURE 80-4 Postoperative picture of a typical patient who underwent VATS major resection (a left pneumonectomy in this case). Note the three-port strategy used with the anterolateral utility minithoracotomy; the lower, anterior camera port for the thoracoscope (arrowhead); and the posterior instrument port (arrow).

at the utility thoracotomy can be held open with Weitlaner retractors, and again we stress that rib spreading is to be avoided. The third incision is a posterior instrument port. A 5- to 10-mm incision is made in the seventh or eighth intercostal space in the posterior axillary line (Fig. 80-4). Again, the

1/21/2008 1:44:48 PM

Chapter 80 Video-Assisted Pulmonary Resections

exact location of the incision is guided by the use of the video-thoracoscope from the inside. Care must be taken to avoid positioning this wound too close to the utility thoracotomy, thereby predisposing to “sword-fighting” between instruments. Two Rampley sponge holding forceps, one through the utility thoracotomy and the other through the posterior instrument port, can then be used to manipulate the collapsed lung. Any pleural adhesions can be released by long-blade diathermy via either port.

Routine VATS Exploration Before Resection Before proceeding with lung resection, the videothoracoscope may be used to survey the ipsilateral thorax for lung or pleural metastases. The entire exploration takes only minutes. With the use of a 30-degree lens, the entire lateral chest wall (often difficult to directly visualize even with open thoracotomy) can be fully examined. Assessment can be made of the location and extent of the primary lesion to exclude extensive mediastinal or chest wall involvement and confirm suitability for VATS. A search is also made for associated pathology, such as satellite lung nodules, or mediastinal lymphadenopathy (missed by CT or deemed suspicious by PET). In this exploration, we emphasize the importance of digital palpation. Contrary to laparoscopic surgery (which usually does not allow digital palpation because of the need to use valved ports to sustain carbon dioxide insufflation), digital palpation through the utility thoracotomy is entirely feasible. The sponge holding forceps, inserted via the posterior port, can be used to bring the lung toward the palpating finger placed through the utility thoracotomy and vice-versa. If further lung mobilization is required, the pulmonary ligament can be released at this point (see later discussion). Virtually the entire lung can be palpated in this way. This is important because small, deep nodules (<0.5 cm) would almost certainly go undetected by visual examination alone. Furthermore, there is growing interest in the use of intraoperative pleural lavage for cytologic study to determine the presence of microscopic pleural metastases. This role can be accomplished by VATS. The routine use of VATS exploration to evaluate patients with known primary lung cancer before resection has been studied by several authors, including ourselves, and the results are summarized in Table 80-1. Among a total of more than 650 patients who were clinically staged as resectable before surgery, about 7% were found to have inoperable disease by VATS (pleural metastasis or direct invasion to vital structures) and were thereby spared unnecessary thoracotomy.22 VATS exploration adds very little time to the cancer operation and can yield important information that markedly alters the treatment strategy. We therefore recommend the routine use of VATS exploration in all surgical cases of pulmonary malignancy, including those for whom open thoracotomy is planned from the outset.23

Hilar Dissection Our normal operative sequence for the various major resections is summarized in Box 80-2. However, we would stress that dogmatic adherence to this sequence is unnecessary. As

Ch080-F06861.indd 975

975

TABLE 80-1 Routine Use of VATS Exploration in Lung Cancer Patients With Clinically Resectable Lesions Author (Year)

No. Patients

Inoperable (%)

Wain22 (1993)

43

5.0

Yim23 (1996)

63

3.3

151

11.9

286

5.7

116

4.3

24

Loscertales 25

Roviaro

(1996)

(1996)

Asamura26 (1997)

Modified from Sonett JR, Krasna MJ: Thoracoscopic staging for intrathoracic malignancy. In Yim APC, Hazelrigg SR, Izzat MB, et al (eds): Minimal Access Cardiothoracic Surgery. Philadelphia, WB Saunders, 2000, pp 183-193.

Box 80-2 Operative Sequence for VATS Resection of Various Lobes Left Upper Lobe Lingular PA Superior PV Anterior ascending PA Bronchus Posterior PA (variable number)

Right Middle Lobe Middle lobe PA Middle lobe tributary to superior PV Fissure Bronchus

Left Lower Lobe Descending PA to LLL (before division into apical and basal branches) Inferior PV Fissure Bronchus

Right Lower Lobe Descending PA to RLL (apical and basal branches may have to be taken separately) Inferior PV Fissure Bronchus

Right Upper Lobe Anterior ascending segmental PA Superior pulmonary vein Anterior trunk (before division into apical and posterior segmental PA) Fissure Bronchus

Left Pneumonectomy Superior PV PA Inferior PV Left main bronchus Right Pneumonectomy Superior PV PA Inferior PV Right main bronchus

LLL, left lower lobe; PA, pulmonary artery; PV, pulmonary vein; RLL, right lower lobe.

with open lung resections, the actual sequence used depends to a large degree on intraoperative findings and circumstances and on the surgeon’s judgment. For example, if dissection of an artery proves difficult, it is entirely acceptable to tackle the vein first and come back to the artery later. For this reason, the description provided here does not delve into the specific details and sequences for dissection of each lobe or lung, but rather presents our general technique of VATS dissection.

1/21/2008 1:44:50 PM

976

Section 3 Lung

Hilar dissection is often a cause of anxiety for surgeons starting to learn VATS pulmonary resection because of the apparent lack of normal tactile feedback during dissection. In addition to digital palpation, described earlier, experienced VATS surgeons have learned to “feel” with the tips of their instruments. One important reason why we advocate the use of conventional open instruments is because they are familiar to the surgeons and generally provide the same tactile feedback during VATS as during open surgery. The decrease in tactile information during VATS is compensated for by the superiority in visual information. The video-thoracoscope is freely mobile within the chest and provides a greater range of visual angles than even open surgery, especially with a 30degree lens. The lens can be “zoomed” in or out, providing magnified views of the operative field with higher resolution for details than is possible with open surgery. Subtle displacement of a structure during dissection (which usually is not noticeable in conventional open surgery) provides important clues to an experienced VATS surgeon. We prefer to use conventional Metzenbaum scissors and DeBakey forceps introduced through the utility thoracotomy for sharp dissection of the hilum. The sponge holding forceps from the posterior instrument wound is used to provide appropriate traction and to position the lobes so that the hilum can be easily accessed through the utility thoracotomy. The second assistant can then hold the sponge holding forceps, maintaining the retraction while the surgeon’s hands are freed to proceed with the dissection. The key to the dissection is appropriate traction and countertraction across the dissected tissue. As dissection proceeds, the site and angle of retraction can be constantly but subtly readjusted to optimize this balance. If the interlobar fissure is complete or almost complete, hilar dissection can begin by sharp incision of the visceral pleura at the interlobar hilum. A combination of sharp dissection with scissors and gentle blunt dissection using a dental pledget mounted on a conventional curved clamp (e.g., a Roberts forceps) can then allow identification and isolation of the pulmonary vessels. If the fissure is not complete, we find a monopolar diathermy forceps (Olsen Electrosurgical, Concord, CA) at a low setting useful for hemostasis when dividing interlobar adhesions and/or lung parenchyma to access the hilar vessels. Particularly fused fissures can be divided with endoscopic staplers, or between a pair of vascu-

lar clamps, with the two sides sutured. As mentioned earlier, particularly difficult fissures may sometimes be tackled out of sequence, and attention may be focused on hilar dissection from another angle before being returned to fissure completion. Dissecting around a pulmonary vessel is basically the same as in conventional, open surgery. We use a right-angle Mixter clamp (Downs Surgical, Surrey, UK) to go around behind a vessel, and then loop it with a heavy silk ligature (Fig. 80-5). With light traction on the silk sling, a small dental pledget mounted on a right-angle Mixter clamp is used to gently dissect the undersurface of the vessel. Usually, if sufficient space is created to allow the pledget to pass around behind the vessel easily, there should be enough space for the stapler to pass through. A mechanical stapler (e.g., the EndoGIA30, Autosuture, United States Surgical, Norwalk, CT) is then introduced through one of the ports (chosen according to the alignment) to staple-transect the vessel. The surgeon needs to be flexible when choosing which port to use to pass the stapler; if the camera port is used, the thoracoscope can be repositioned to view through the utility thoracotomy. Appropriate traction on the lung using a sponge holding forceps via another port, and on the vessel using the silk sling, is crucial in aligning the vessel with the stapler for staple-transection. A less costly alternative to staple-transection is to simply ligate the vessels as for an open procedure. In many cases, the vessels can be reached and knots tied directly by hand via the utility thoracotomy. For deeper vessels out of reach of the surgeon’s finger, ligation can be performed with extracorporeal knots and the use of a knot-pusher. Although many commercial knot pushers are available, we use one of our own design, which better allows the surgeon to control the tension on the ligature (Fig. 80-6).28 We staple-transect the lobar bronchus using a standard endoscopic linear stapler with a built-in blade (EndoGIA30). For a main stem bronchus, we normally use a different stapler that requires manual transection (Roticulator 30, Autosuture, United States Surgical, Norwalk, CT). The specifications of these mechanical staplers are summarized in Table 80-2.

Release of the Pulmonary Ligament Release of the inferior pulmonary ligament is required as part of a lower lobectomy, and it is also frequently performed

TABLE 80-2 Specifications of Some Mechanical Staplers (Autosuture, United States Surgical, Norwalk, CT) Staples Specificity

Device

Color Code

EndoGIA30

Blue

Applications Lung parenchyma, lobar bronchus

Cut Line (mm)

Staple Line (mm)

Leg Length (mm)

Crown Length (mm)

Approximate Wire Closed Staple Diameter Height (mm) (mm)

No. Staggered Rows*

27.5

32.5

3.5

3

1.5

0.21

3

EndoGIA30V

White

Pulmonary vessel

27.5

32.5

2.5

3

1.0

0.21

3

Roticulator 30

Green

Main stem bronchus

Manual

31.5

4.8

4

2.0

0.28

2

*Refers to the number of staggered rows of staples left in patient.

Ch080-F06861.indd 976

1/21/2008 1:44:50 PM

Chapter 80 Video-Assisted Pulmonary Resections

A

B

C

D

977

FIGURE 80-5 Management of the left main pulmonary artery (PA) in a VATS pneumonectomy to illustrate our technique of hilar vessel dissection. A, Under thoracoscopic vision, a conventional right-angle clamp was used to go around behind the PA. A No. 2 silk tie was passed to be pulled around the vessel (arrowhead). B, With gentle traction on the silk sling, a dental pledget mounted on a right-angle clamp was used to open up the space behind the PA. C, A vascular stapler (EndoGIA30V, Autosuture, United States Surgical) was used to staple-transect the PA. D, Three rows of staples were left on either side of the staple-transected PA. The final diagnosis in this patient was a T2 N0 M0 (stage IB) squamous cell carcinoma. He was discharged on postoperative day 3 and returned to his country of origin by airplane the following week. This was the same patient as in Figure 80-4.

after an upper and/or middle lobectomy to reduce the problem of a large residual air space. In our experience, we have often found that release of the pulmonary ligament from the outset, before hilar dissection, yields greater lung mobility for the initial exploration and for optimal positioning for hilar dissection. Sponge holding forceps can be used via the posterior instrument port to retract the lower lobe in an apicolateral direction, straightening the ligament. A combination of long-blade diathermy and gentle blunt dissection with a dental pledget via the utility thoracotomy can then be used to release the ligament fully. Although this is usually a straightforward maneuver using VATS, the positions of the ports and minithoracotomy mean

Ch080-F06861.indd 977

that paradoxical motion sometimes occurs. Paradoxical motion is generated when the camera and instruments are facing each other. Although several tricks have been described to overcome this problem, we have found that, by turning the camera 180 degrees, a normal spatial relationship is restored for the operator.29 This simple maneuver allows the surgeon to use the camera and existing ports to the best ergonomic advantage.

Retrieval of Specimen The resected lobe is removed via the utility thoracotomy. Wound protection is essential to prevent tumor implantation

1/21/2008 1:44:50 PM

978

Section 3 Lung

A

B

FIGURE 80-6 A, A knot pusher was made by engraving a groove on the outside of a right-angle Mixter clamp. B, The device is used to slide down an extracorporeal knot. The original idea came from Dr. Tsuguo Naruke. (REPRODUCED WITH PERMISSION FROM YIM APC, LEE TW: “HOMEMADE” KNOT PUSHER FOR EXTRACORPOREAL TIES. AUSTRAL N Z J SURG 65:510-511, 1995, FIGURES 2 AND 3. BLACKWELL PUBLISHING.)

at the utility thoracotomy. We use a sterile plastic bag with the bottom cut open to create a plastic bag “tunnel,” which is inserted across the utility thoracotomy (Fig. 80-7). The lobe is grasped by two or more sponge holding forceps and pulled out through this plastic bag tunnel, using a gentle backand-forth rocking motion to avoid tearing the lobe as it passes through the intercostal space. If the primary tumor is smaller than 4 cm in diameter, a mechanical rib spreader usually is not needed for retrieval of a resected lobe, or even an entire lung. A very brief moment of manual rib retraction may occasionally be needed as a larger tumor is pulled through the rib space. Increasingly, however, we are eschewing even this brief rib retraction in favor of resecting a short segment of rib at the utility thoracotomy. This reduces the risk of uncontrolled rib fractures and disruption of the posterior costovertebral elements and anterior costosternal cartilages. We have found that controlled resection of a short rib segment may be no more painful than brief rib spreading, and it has the advantage of allowing even larger tumors and pneumonectomy specimens to be easily retrieved via the small utility thoracotomy incision.

Systematic Lymph Node Sampling The debate over the relative merits of lymph node sampling versus lymph node dissection after lung cancer resection is ongoing and is beyond the scope of this chapter. In our unit, after pulmonary resection by either VATS or open thoracotomy, the ipsilateral mediastinal lymph nodes are systematically sampled. Although all the accessible nodal stations are sampled, the concept of sentinel lymph nodes and the patterns of pulmonary lymphatic drainage mean that some stations are more likely to be involved for tumor originating from a particular lobe, and these stations must be preferentially sampled in a lobe-specific manner.30 Naruke9,31 previously published his recommendations on lymph node sampling: right upper lobe (prevascular and retrotracheal 3 and lower paratracheal 4R); right middle lobe (3 and subcari-

Ch080-F06861.indd 978

FIGURE 80-7 Retrieval of the resected lung through the minithoracotomy. Note the use of a wound protector and only a soft tissue retractor. Forceful rib spreading was not necessary.

nal 7); right lower lobe (7); left upper lobe (subaortic 5, and para-aortic 6); and left lower lobe (7). After lobectomy, the extra space inside the chest allows even more room for lymph node sampling. The remaining lung can be retracted away if necessary, using sponge holding forceps. The soft tissue or mediastinal pleura over a nodal station can be grasped with a Roberts or DeBakey forceps and opened with long-blade diathermy. An exposed lymph node can then be excised in the same manner as during an open thoracotomy procedure. If extensive lymph node dissection for complete mediastinal lymphadenectomy is considered necessary, our current practice is to perform this through an open thoracotomy.

1/21/2008 1:44:53 PM

Chapter 80 Video-Assisted Pulmonary Resections

However, there are surgeons who now advocate routine VATS radical lymphadenectomy.32 There is growing evidence that the adequacy of VATS radical lymphadenectomy approaches that of open surgery in terms of both number and mass of nodal tissue removed (Sagawa et al, 2002).33,34 Nonetheless, the benefits of VATS mediastinal lymphadenectomy in terms of survival have yet to be proven.

Completion of the Procedure The entire hemithorax is then copiously irrigated with warm sterile saline or water. The lavage helps to remove debris and to identify sources of bleeding. The value of such lavage in reducing intracelomic spread of tumor cells has been speculated upon but not proven. Before suctioning of all the fluid, the anesthetist is asked to inflate the remaining lung on the operative side and to sustain an airway pressure. In this way, the integrity of the bronchial stump is tested to 30 to 40 cm of sustained airway pressure underwater. If there is any bronchial stump air leak (rare) or significant parenchymal air leak, we would perform repair by endoscopic suturing with conventional 3/0 Prolene on a 25-mm curved needle through the utility thoracotomy. We have found a dedicated “doubleaction” needle holder (originally designed by Carpentier for mitral valve surgery) to be especially useful for facilitating endoscopic suturing via small VATS ports (Fig. 80-8). We routinely perform intercostal blockade with 0.5% bupivacaine injected at two levels above and below the minithoracotomy using a spinal needle (Becton Dickinson & Co, Franklin Lakes, NJ) inserted through the minithoracotomy and guided by the video-thoracoscope. We place one or two 20 or 24 Fr chest tubes through the previous camera and/or instrument wounds. Smaller chest tubes are acceptable in pediatric or smaller patients. There is still controversy regarding the size and number of chest tubes used, but thus far there has been no convincing evidence to suggest whether fewer or smaller drains can reduce the degree of postoperative pain. Layered closure of the minithoracotomy wound

979

completes the operation (see Fig. 80-4). Postoperatively, we employ the same protocols for postoperative observations, chest drain management, resumption of feeding, and chest physiotherapy as we use for open lung resections.

Mortality and Morbidity Some of the larger published series on VATS major resections are summarized in Table 80-3. Despite slight variations in individual techniques, the results have universally ranged from good to excellent. The overall surgical mortality of 0% to 2% for VATS compares favorably to the conventional technique, although it must be pointed out that the VATS group was selected patients. Morbidity in minimally invasive thoracic surgery is often indicated by certain perioperative indexes, including rates of conversion to an open procedure, operating times, intraopera-

FIGURE 80-8 A specially designed, “double jointed” needle holder useful for endoscopic suturing in minimal access surgery. This was originally designed by Carpentier for use in mitral valve surgery (Model 56615-28, Delacroix-Chevalier, Paris, France).

TABLE 80-3 Results of Large Case Series on VATS Lobectomy Author (Year)

No. Patients

Conversion (%)

Postoperative Mortality (%)

Follow-up (Mo)

Survival Stage I (%)

Kaseda32* (1998)

145

11.7

0.8

48

94

212

7.0

0.5

28.9

76

266

19.5

0.5

26

95

250

—

0

34

92

79

21.5

0

36

94

(2001)

125

10.4

0

36

90

Walker39 (2003)

159

11.2

1.8

60

78

179

0

0.05

60

85

257

22.2

0

60

64

106

10.4

1

36

97

238

7.1

1.4

60

87

35

McKenna 36

Yim

(1998)

(1998)

Lewis37 (1999) Naruke31 (2000) 38

Solaini

40

Gharagozloo 41

Roviaro

(2003)

(2004)

Ohtsuka42 (2004) 33

Watanabe * (2005)

*Routine mediastinal lymphadenectomy was included.

Ch080-F06861.indd 979

1/21/2008 1:44:54 PM

980

Section 3 Lung

tive blood loss, and postoperative length of stay in the hospital. The rate of conversion to open thoracotomy is sometimes unreliable in this regard, and it varies considerably depending on each surgeon’s thresholds for conversion (see Table 80-3). Such thresholds, in turn, are based on the individual surgeon’s experience with “difficult” cases, strategies to deal with mediastinal lymph nodes, and so on. In our unit, with increasing experience and a policy of routine systematic mediastinal lymph node sampling, the conversion rate has fallen from 19.5%, reported in 1998, to well under 10%. In previous studies, VATS has been consistently shown to take similar operating times as open surgery, to produce similar or lower levels of blood loss, and to result in significantly shorter hospital stays (Sugiura et al, 1999).5,43 A recent systematic review concluded that the evidence is excellent that figures for operative time, intraoperative blood loss, postoperative air leak, and postoperative length of stay after VATS and open thoracotomy pulmonary resections are statistically similar.44 In return for the advantages it provides, VATS takes no longer to perform and produces no more morbidity than open thoracotomy. Major complications and postoperative morbidity from VATS resections are relatively uncommon.45,46 Both our group and others have experienced mechanical failure of endoscopic staplers that resulted in massive bleeding.18,47 This was controlled by pressing on the bleeder with a sponge stick and immediately converting to a thoracotomy. Note that these are anecdotal cases and that the mechanical staplers available today are generally very reliable. Having acquired additional skill and experience in endoscopic suturing, we now feel comfortable using this technique in the unlikely event of minor to moderate bleeding from the pulmonary vasculature, hence avoiding the need for a conversion. Tumor implantation after VATS has been reported.48 In one series of VATS wedge resections for cancer in which specimen retrieval with wound protection was carried out in only 24% of cases, port site recurrence was noted in only 0.26%.49 This already low figure could be further minimized by routine use of a wound protector, gentle handling of tissue, and copious irrigation of the hemithorax before closure. Persistent air leak beyond 7 days was the most common morbidity in our earlier experience.50 This was almost certainly related to hilar dissection when the fissures were incomplete. However, like most technical issues, it improved with experience. As described earlier, we have found endoscopic suturing of parenchymal leaks at the end of the procedure to be a great asset in preventing such air leaks.

Benefits Over Conventional Surgery VATS major lung resection was not well received initially. A survey of members of the General Thoracic Surgery Club in 1995 showed that most considered this application unacceptable.51 In particular, several concerns were raised. First, the safety of fine anatomic dissection of the hilum in an essentially closed chest was questioned. Second, there was skepticism about the adequacy of clearance for oncologic lung resections with curative intent. Third, although the short-

Ch080-F06861.indd 980

term benefits of VATS to patients were intuitively obvious, its long-term advantages over conventional surgery remained unclear. Fourth, the relatively high cost of the endoscopic equipment and VATS-related consumables cast doubt on the cost-effectiveness of this procedure. However, since that time, growing experience with VATS lung resections has produced a sizable body of evidence that has largely dispelled such early doubts. Instead, current evidence suggests that VATS pulmonary resections may hold a number of significant advantages over conventional open surgery.

Postoperative Pain It is now well established that patients who undergo resections via the VATS approach experience less immediate postoperative pain than those having the thoracotomy approach. This has been documented in several large case-controlled studies, either by objective assessment in terms of analgesic requirements50,52 or by subjective assessment in terms of pain scoring, usually in the form of a visual analogue scale.5,50,53 A trend for reduced postoperative analgesic requirements was also seen in an early randomized, prospective study comparing VATS with a limited thoracotomy for lobectomy.54 The lack of statistical significance in that study was probably a result of the small sample sizes and consequent low statistical power. In the longer term, Landreneau and colleagues (Landreneau et al, 1994)55 reported that the incidence of chronic postoperative pain at 1 year after VATS was not different from that after thoracotomy. This cross-sectional, questionnaire-based study (containing 36 patients in the VATS long follow-up arm) has often been quoted to suggest that the benefits of VATS may not extend to the long term. However, this has not been our experience when the maneuvers described earlier to minimize surgical access trauma have been adhered to—particularly the strict avoidance of rib spreading. Sugiura and coworkers (Sugiura et al, 1999)43 later noted a lower incidence of chronic post-thoracotomy pain syndrome after VATS compared with thoracotomy.

Preservation of Pulmonary Function There is emerging evidence that VATS causes less depression of pulmonary function after lung resection surgery than does thoracotomy. Kaseda and colleagues56 reported that both the FEV1 and the forced vital capacity (FVC) measured at 3 months postoperatively were significantly better preserved relative to preoperative values in patients who underwent lobectomy by a VATS approach, compared with a thoracotomy approach (P < .0001). In another similar study, postoperative arterial oxygen tension (PaO2), arterial oxygen saturation (SaO2), peak flow rates, FEV1, and FVC were all found to be better on postoperative days 7 and 14 in patients who had VATS rather than thoracotomy for lung resection.57 Blood oxygenation, lung diffusion capacities, 6-minute walk test results, and recovery of vital capacity and cardiopulmonary function after surgery all tend to be better after VATS than after various forms of open thoracotomy for pulmonary resections.58-60 Such evidence gives further weight for the argument, discussed earlier, that patients with poor lung

1/21/2008 1:44:54 PM

Chapter 80 Video-Assisted Pulmonary Resections

Quality of Life Although the success of surgery for lung cancer resections has traditionally been measured in terms of survival rates, there is increasing realization that postoperative quality of life (QOL) is at least as important to the patient. It has been shown that patients tend to be more concerned about postoperative functional status and performance in activities of daily living than about abstract survival statistics.61 As more evidence is emerging that VATS pulmonary resections confer survival outcomes as good as those of open resections (discussed later), the advantages of VATS in terms of improved postoperative QOL become increasingly difficult for the surgeon and patient to ignore. Using a six-item questionnaire, Sugiura and colleagues (Sugiura et al, 1999)43 showed that patients who underwent VATS lobectomy for early cancer were able to return to preoperative activities significantly earlier than patients who underwent thoracotomy (2.5 versus 7.8 months; P = .03). It was also noted that significantly fewer patients who received VATS lobectomy were taking analgesics on a regular basis on follow-up, and there was a trend for greater satisfaction with the scar and with the operation overall in the VATS group. Demmy and Curtis5 compared VATS to conventional major resection in high-risk patients and also found an earlier return to work in the VATS group (2.2 versus 3.6 months). More recently, Li and coauthors (Li et al, 2002)62 conducted a more detailed survey using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-LC13 questionnaires, which were designed to assess QOL in lung cancer patients, supplemented by a self-designed, nine-item surgery-specific questionnaire. The survey was conducted on patients who received lung resections with curative intent for early-stage lung cancer, either by a VATS approach (median follow-up time, 33.5 months) or by an open thoracotomy approach (39.4 months). Statistically comparable levels of QOL and functional status were noted, although there was a trend for the VATS group to show better QOL scores and lower incidences of fatigue, dyspnea, coughing, and pain.

Shoulder Function An important but often overlooked measure of both postoperative pain and QOL after thoracic surgery is impairment of shoulder function. Shoulder function can be impaired after a thoracotomy by a combination of neurologic injury during patient positioning, division of shoulder girdle muscles, direct injury to the long thoracic nerve, and the significant postoperative pain from the wound. By reducing such surgical trauma and postoperative pain, VATS lung resections may reduce the incidence of postoperative shoulder dysfunction. Landreneau and colleagues (Landreneau et al, 1994)55,63 reported that the strengths of the latissimus dorsi and serratus anterior muscles measured on a dynamometer were significantly better preserved after VATS versus thoracotomy, both at 3 weeks and at 1 year after surgery. In a prospective

Ch080-F06861.indd 981

study, Li and coworkers64 reported that short-term shoulder strength and range of movement were significantly better in patients who received VATS pulmonary resection than in those who received thoracotomy.

Long-Term Survival The success of any cancer operation is judged by the longterm survival of patients. The published results to date from several centers on VATS major resection for stage I lung cancer consistently show that intermediate to long-term survival is at least as good as, if not superior to, that seen with the conventional thoracotomy approach (see Table 80-3). Five-year survival rates are now being consistently reported at 70% to 95% for VATS lobectomy for stage I non–small cell lung cancer. Kaseda and Aoki65 reported an 8-year survival rate of 92.7% for stage IA lung cancer patients receiving VATS lobectomy. In a recent nonrandomized study, Watanabe and colleagues33 reported that the 5-year actuarial recurrence-free survival rate and cumulative survival rate of pathologic stage IA cases were 88.6% and 92.9%, respectively, among patients who had VATS lobectomy, compared with 92.4% and 86.5% among those who had thoracotomy (although comparability between the two study arms could not be strictly demonstrated in this study). There have been few prospective randomized trials directly comparing long-term survival of VATS versus thoracotomy lung resections for lung cancer. In 2000, Sugi and coworkers66 reported a trial involving 100 patients with stage IA lung cancer randomized to receive curative resection by VATS (n = 48) versus thoracotomy (n = 52). The respective survival rates were 90% versus 93% at 3 years and 90% versus 85% at 5 years. We prospectively studied our pathologic stage I lung cancer patients who underwent either the VATS or thoracotomy and found that there was a trend toward improved disease-free survival in favor of the former (Fig. 80-9). We are not drawing any premature conclusions regarding survival advantages for VATS pulmonary resections until

1

Proportion free of disease

function who are deemed unfit for open surgery may yet benefit from VATS lung resections.

981

VATS

0.8

0.6 Open 0.4

0.2

0 0

20

40

60

80

100

Postoperative follow-up (in months) FIGURE 80-9 Disease-free survival of patients with pathologic stage I non–small cell lung cancer who underwent either VATS or open surgery at Prince of Wales Hospital, Hong Kong (1994-1999).

1/21/2008 1:44:54 PM

982

Section 3 Lung

further results from large, prospective, randomized studies with long follow-up times become available.

Immune Function There is now a wealth of literature showing that the body’s immune function is better preserved after laparoscopic surgery compared with its open counterparts in general abdominal surgery. Few similar publications exist in the thoracic surgical literature. We prospectively studied two groups of patients with clinical stage I lung cancer who underwent either VATS or conventional resection through a thoracotomy. Significantly reduced postoperative release of both proinflammatory cytokines (interleukins 6 and 8) and anti-inflammatory cytokines (interleukin 10) in the plasma was found in the VATS group compared with the control group (Yim et al, 2000).67 Our findings were consistent with those of a similar but smaller Japanese study, which showed significantly reduced cytokine release (interleukins 6 and 8) into the pleural fluid in the VATS lobectomy group compared with the open thoracotomy group.68 Leaver and colleagues69 from Edinburgh showed in a small randomized, prospective study that VATS lobectomy was associated with a lesser effect on the postoperative fall in circulating CD4-positive T cells and natural killer (NK) cells. Lymphocyte oxidation was also less suppressed by VATS compared with open surgery. In another randomized trial following up on this study, the same group found that a range of acute phase responses—including C-reactive protein, interleukin 6, tumor necrosis factor, P-selectin, and oxygen free radical activity—were also significantly less among the patients undergoing VATS.70 In independent studies in our unit, we found that NK cell levels were suppressed to similar degrees on the first postoperative day after both VATS and thoracotomy lung resections for non–small cell lung cancer, but T lymphocyte numbers were significantly more reduced after thoracotomy.71 The levels of NK cells subsequently rose more quickly in the VATS group. These results suggest that the VATS approach was associated with less, and quicker recovery from, postoperative immunosuppression after lung resection surgery, compared with the thoracotomy approach. In essence, there is evidence now that VATS is associated with less perturbation in both the humoral and cellular immune functions compared with open surgery, at least in the short term.72,73 So far, there have been no reports demonstrating that VATS pulmonary resection confers a lower incidence of postoperative infection than the open approach. It has also been hypothesized that, because immunosurveillance may play an important role in the progression of cancer, surgically induced immunosuppression may predispose to increased tumor growth or recurrence. Whether better preservation of the immune system by VATS may lead to improved long-term survival is unclear but certainly deserves further investigation.73 On the other hand, caution was raised in a study by Yamashita and colleagues.74 They used reverse transcriptase polymerase chain reaction techniques to study carcinoembryonic antigen messenger RNA (CEA mRNA), a tumor marker,

Ch080-F06861.indd 982

in the peripheral blood of patients with early lung cancer. They found that, among patients with no detectable preoperative CEA mRNA, the proportion of patients who were found to have elevated CEA mRNA during lung resection was higher for those undergoing VATS lobectomy compared with an historical group of patients who underwent conventional resection. The significance of this observation is unclear, and thus far VATS has not been associated with more distant metastasis than conventional surgery for clinical stage I cancer. However, as with all lung cancer surgery, appropriate caution must be taken to avoid excessive intraoperative tumor manipulation that might cause tumor cell dissemination.

Cost-effectiveness The high cost of the consumables is a serious concern and represents a major deterrent to the adoption of VATS in developing countries. However, by choosing the right patients for this technique, using mainly conventional instruments, and relying on ligation and suturing in preference to staplers wherever possible, the consumable costs can be minimized.21 In experienced hands, VATS major resection can also be a quick operation because little time is needed to open and close the chest. Our average time for a VATS pneumonectomy or lower lobectomy together with mediastinal sampling is less than 1 hour, and it is only slightly longer for an upper lobectomy. This represents significant cost savings in terms of operating room time. One study comparing VATS with open resections for cancer showed that the overall hospital charges were lower for the former approach.75

LIMITED PULMONARY RESECTIONS Indications VATS nonanatomic resections (which include wedge resection and nodulectomy) and anatomic sublobar resections (i.e., segmentectomy) are indicated for selected groups of patients: ■

■

■ ■

Patients with diffuse pulmonary infiltrates or indeterminate solitary lung nodules for diagnosis (dealt with elsewhere in this book). Patients with early lung cancer whose pulmonary function or comorbidities do not permit a lobectomy.5 It was previously believed that limited resections in these situations represent an acceptable but compromised therapy,76 but more recent evidence tends to suggest that the oncologic result in stage IA patients may approach that of complete lobectomy.77 Selected patients with pulmonary metastasis for therapeutic resections.78 Patients with end-stage emphysema for lung volume reduction surgery.79

A detailed discussion of each of these indications is beyond the scope of this chapter, which is primarily intended to focus on surgical technique.

Localization of the Pathology It is often a source of concern for surgeons that a small, deep lesion may prove very difficult to find during VATS. This is

1/21/2008 1:44:55 PM

Chapter 80 Video-Assisted Pulmonary Resections

believed to be especially likely because palpation with more than one finger is impossible, so that one cannot “feel” a lesion in the lung tissue rolled between two fingers. Suzuki and colleagues80 estimated that, if the target lesion was more than 5 mm beneath the pleural surface or was 10 mm or smaller in size, the probability of failure to detect it was 63%. They recommend that preoperative localization be performed for all such cases before VATS. In practice, however, the experienced VATS surgeon seldom has problems finding a target lesion. The first step is careful study of the CT scans to locate the lesion, especially in relation to the fissures and lung edges. Intraoperatively, visceral pleura changes (e.g., abnormal vascularity, puckering), overlying pleural adhesions, and sometimes gentle instrument palpation can give important clues as to the position of the lesion. Above all, the need for meticulous digital palpation cannot be overemphasized. One finger is inserted via a wound to palpate. The other hand then uses a sponge holding forceps to “deliver” the part of the lung to be explored into the reach of the palpating finger. If necessary, pleural adhesions and even the pulmonary ligament may be released to fully mobilize the lung to facilitate this examination. During this manipulation, rough handling of the lung is avoided because swelling and bruising of the parenchyma can mask a small, deep lesion, making detection even more difficult. With this technique, our incidence of failure to detect a lung lesion or of needing to convert to a larger wound is very low. In the rare cases in which particular difficulty in locating a lesion is foreseen, preoperative measures to “mark” the lesion may be considered. In virtually all cases, this is done by CTguided (or, rarely, fluoroscopy-guided) placement of a hooked wire into or adjacent to the target lesion. For obvious reasons, the placement is done as close to the time of the operation as possible (ideally on the same morning). The outer end of the wire is conventionally cut outside the skin and taped down to the skin or cut flush with the skin. If the former method is used and the tape is forgotten and not removed, there is a chance that the wire may be pulled out of the lung as it is collapsed in preparation for VATS. For this reason, we prefer the latter method (although dislodgement can still occur). Intraoperatively, the wire embedded in the lung at the target is usually easily identified. In recent years, some centers have reported CT-guided placement of radio-opaque markers that can be detected intraoperatively by fluoroscopy. We believe that fluoroscopy tends to cause unnecessary interruption to the operation, and we have not yet found instances when this technique has been necessary in our practice. In our unit, we have also tried CT-guided subpleural injection of methylene blue to mark the target lesion. However, the dye quickly spreads across the pleura, so localization is poor, and our experience with this method has so far proved unsatisfactory.

Operative Technique The technique for a VATS wedge resection or nodulectomy follows the same basic principles as described earlier for VATS major pulmonary resection. Anesthesia, patient posi-

Ch080-F06861.indd 983

983

tioning, and operating room setup are identical. Because the extent of resection is limited, patients undergoing a limited VATS resection often have poorer lung function than those undergoing VATS anatomic resections. If a patient cannot tolerate single-lung ventilation, alternatives include intermittent collapse and reventilation of the lung on the operative side or the selective lobar collapse technique we have previously described.8 For VATS limited resections, we do not require the surgeon to stand in front of the patient, but rather in a position from which to triangulate the working ports and the site of pathology according to the classic VATS “baseball diamond” concept.17 For our port strategy, we use three ports (one camera, two instruments), usually with 5- to 10-mm incisions. We do not dogmatically adhere to any predetermined sites for the ports. Instead, we stress flexible port locations sited according to the “baseball diamond” concept. With the target pathology at “second base,” the camera port is sited close to the surgeon at “home base” facing the lesion, and the instrument ports are placed at the “first” and “third” bases to allow easy triangulation wherever the exact site of the incisions may be. Again, the wounds are not placed too close to one another, to prevent “sword fighting” between the instruments. With this strategy, very often the first assistant holding the videothoracoscope stands on the same side as, and slightly behind, the surgeon (Fig. 80-10). After taking down any pleural adhesions, the target lesion is located as described earlier. As with VATS major lung resections, we manipulate the lung primarily using sponge holding forceps. Care must be taken not to directly grasp the target lesion because this could cause tumor cell dissemina-

FIGURE 80-10 For VATS limited pulmonary resections, surgeon positioning and port site locations must be flexible to allow good triangulation on the target lesion according to the “baseball diamond” strategy. The target lesion and the video monitor are in the same line, straight ahead of the surgeon. The instrument ports are comfortably spaced to either side and triangulate on the lesion. Having the assistant hold the camera standing slightly behind the surgeon often makes it easier for the assistant to manipulate the camera and avoid paradoxical movement.

1/21/2008 1:44:55 PM

984

Section 3 Lung

Box 80-3 Techniques for VATS Nonanatomic/ Limited Pulmonary Resections Mechanical stapling Sharp or diathermy resection with endoscopic suturing Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser Harmonic scalpel Saline-enhanced thermal sealing

FIGURE 80-11 A TissueLink floating ball device (TissueLink Medical, Dover, NH) designed for endoscopic nodulectomy using salineenhanced thermal sealing technology.

Anatomic sublobar resection (segmentectomy)

tion. Instead, the tissue adjacent to the lesion may be gently grasped. If mechanical staplers are to be used, we normally define the line of stapling first by closing the sponge holding forceps on the lung along the intended staple line below the lesion. With the sponge holding forceps closed on the line, digital palpation is used to confirm that the entire lesion is well above the line with a good margin. On removal of the sponge holding forceps, the lung remains indented along the line, allowing the stapler to easily follow the same line and ensuring that the lesion is resected with an adequate margin. Once the lesion has been identified and demarcated, several techniques may be used to resect the wedge. These are listed in Box 80-3. Mechanical staplers remain the most frequently used device for VATS wedge resection. They are ideal for small nodules situated in the lung periphery, especially if they are close to a free edge. If the lung parenchyma is particularly emphysematous or fragile, bovine pericardial strips can be used to buttress the staple lines. For bigger nodules (>3 cm) lying beneath a flat lung surface and for lesions lying particularly deep within the lung parenchyma, wedge resections using endoscopic staplers are often technically difficult or even hazardous. Forced attempts at large wedge resections may result in sacrificing more functional lung tissue than would be necessary for the procedure, or leaving areas of remaining lung cut off from vascular or bronchial supply. This could have a major impact on the recovery of patients who are elderly, are frail with multiple comorbidities, or have poor lung function. In such situations, and if the lesions must be resected, the surgeon may consider the feasibility of proceeding to either a lobectomy or a Perelman enucleation procedure.81 Although the neodymium:yttrium-aluminum-garnet (Nd: YAG) laser has been advocated for resection of these nodules in conjunction with a mechanical stapler,82 the former requires specialized equipment and high upfront costs. The new technology of saline-enhanced thermal sealing was recently made available (TissueLink Medical, Dover, NH) and, when powered by a conventional diathermy generator, may prove less costly than a laser and perhaps a harmonic scalpel. The technique can be applied either by a floating ball probe (Fig. 80-11) or by a two-bladed grasper. With this technology, an endoscopic wedge resection or Perelman enucleation procedure can be carried out with a high level of precision, with the thermal sealing hemostasis and pneumostasis to the cut

Ch080-F06861.indd 984

lung surface without the need for suturing or staples. This device differs from the conventional electrocautery in that it generates less smoke and does not char tissue. The first clinical trial of this device for nodulectomy was carried out in our unit, and preliminary results have proved satisfactory.83 The cheapest alternative is to simply resect the lesion by cutting the lung with scalpel, scissors, or diathermy. A wedge resection or Perelman resection can be performed in this way. If diathermy is used, the smoke generated can quickly cause fogging of the video-thoracoscope lens. We have found that this can be circumvented by using a fine plastic catheter connected to wall suction, inserted coaxially with the camera or one instrument via one of the wounds, to remove the smoke. Use of a 10-mm rigid port at another instrument wound to allow a flow of air into the thoracic space prevents the suction from reinflating the lung. The cut edge or surface of the lung can be repaired by endoscopic suturing, which, we stress, is an essential skill for the VATS surgeon. In addition to the nonanatomic resections described, anatomic segmentectomy has also been demonstrated to be feasible by the VATS approach.84 This represents extremely fine dissection that may prove to be an extreme test of the surgeon’s skill, and there is no convincing evidence at this time that perseverance with a difficult VATS segmentectomy has any advantages over an open segmentectomy or a VATS wedge resection with brachytherapy in the treatment of malignant disease. Regardless of the type of resection, we deliver the resected specimen via the most anterior port using wound protection. The anterior port is again chosen because it naturally provides the widest intercostal space for easier retrieval. If necessary, the incision can be widened slightly to facilitate retrieval. For wound protection, very small specimens can sometimes be retrieved via a rigid port placed through one of the wounds. For larger specimens, we use a sterile bag inserted entirely into the chest. The mouth of the bag is opened inside the chest with the sponge holding forceps, the resected specimen is delivered deep into the bag, and the bag is then retrieved via the anterior wound mouth first, with the mouth held closed by the forceps.

VARIATIONS IN MINIMALLY INVASIVE PULMONARY RESECTION TECHNIQUES Simultaneous Stapling Technique In the early days of VATS in the early 1990s, Lewis proposed that VATS lobectomy need not follow the pattern of indi-

1/21/2008 1:44:56 PM

Chapter 80 Video-Assisted Pulmonary Resections

vidual dissection and ligation of the hilar vessels and bronchi, and instead described a technique of simultaneous stapletransection of all the hilar pulmonary vessels and bronchus with a mechanical stapler.85 This represented not only a new approach but a new operation altogether. Initial results published by Lewis and coworkers37 were impressive. In a series of 400 VATS lobectomies using this technique, they reported no mortality, bronchopleural fistulas, need for blood transfusion, or cases of tumor involving the bronchial margin. Operating times, incidence of postoperative complications, and lengths of hospital stay were comparable to those of “conventional” VATS lung resections, and the overall costs were said to be half those of an open lobectomy. Survival of patients with stage I disease was 92% with a mean follow-up time of 34 months. Nevertheless, skeptics have dismissed this technique as simply turning a lobectomy into a large wedge resection. Worries over its not conforming to conventional oncologic principles have largely kept the procedure from becoming mainstream practice at present. We believe that simultaneous stapling technique has a role in selected cases. These include resection of nonmalignant disease and cases of severe lung trauma requiring prompt resection. In our practice, we follow all the steps for anesthesia, positioning, and port strategy as described earlier for VATS major lung resection. Adhesions and the pulmonary ligament are released to mobilize the lung, and enough clearance of the hilar soft tissue is performed to allow passing of the mechanical stapler across the hilar structures with adequate resection margins on either side. For lower lobe resections, we use a modified version of Lewis’ technique, performing staple-transection of the pulmonary vein first, followed by simultaneous stapling of the pulmonary artery with the bronchus. With this technique, a lobectomy can sometimes be performed in less than half an hour.

Video-Assisted Thoracotomy There is currently some confusion about the nomenclature in the field of VATS. Some authors loosely apply the term VAT to describe any thoracic surgery in which a videothoracoscope is prepared, often for little more than illumination of the thoracic space while the operation is performed essentially via an open approach.2 They then have to invent another term, complete VATS, to describe surgery in which the surgeon uses the video monitor primarily while operating. As emphasized earlier, we reserve the term VATS to specifically describe thoracic surgery in which a video-thoracoscope is used for visualization inside the thoracic space, thereby allowing the surgeon to operate without rib spreading. This strict adherence to the original definition ensures that all published results of studies on VATS refer to the same operation, past and present. For all other techniques in which a videothoracoscope is used but rib spreading is not avoided, we prefer the term “video-assisted thoracotomy” or “minithoracotomy with video assistance,” which emphasizes that the ribs are nevertheless spread as in an open procedure. It is not our intention to disparage surgeons who choose to practice video-assisted thoracotomy or who “peek” through the wound. Video assistance has a role to play even in open

Ch080-F06861.indd 985

985

surgery. Use of the illumination provided by the videothoracoscope can help with difficult adhesiolysis in the lung apex or base, or with difficult resections of posteriorly located lung nodules during median sternotomy for bilateral lung resections. Such video-assisted thoracotomy/sternotomy procedures could also serve as an intermediate step for surgeons to acquire skills in VATS. In our own practice, video-assisted thoracotomy retains only a very limited role in selected patients in whom VATS is contraindicated but for whom a smaller skin incision may be desirable for cosmetic or other reasons. Because of the current confusion over nomenclature, it is not easy to distinguish evidence that may demonstrate any advantage of video-assisted thoracotomy over conventional posterolateral thoracotomy. In one of the few studies to address this issue, Nomori and colleagues86 demonstrated that patients receiving curative lung cancer resection by a video-assisted minithoracotomy experienced reduced blood loss, chest drainage duration, postoperative pain, and pulmonary dysfunction when compared with case-matched patients receiving anterolateral or posterolateral thoracotomy. In a later follow-up report, these same authors suggested that their video-assisted minithoracotomy approach gave postoperative vital capacity and 6-minute walk test results similar to those of VATS and superior to those of open thoracotomy.59,60

“Muscle-Sparing” Thoracotomy It has been hypothesized that the division of the latissimus dorsi and serratus anterior muscles during a thoracotomy may be partly responsible for the significant levels of pain patients experience after an open approach for lung resection. The idea of a muscle-sparing incision was first conceived as the “French incision” in the 1950s, but it was largely overshadowed in popularity by the better exposure of the posterolateral thoracotomy.87 However, with increasing realization of the morbidity caused by the latter approach, various newer muscle-sparing approaches have been devised, using a limited thoracotomy with either a vertical or an oblique anteroaxillary incision through the skin, followed by retraction rather than division of these muscles.88 Proponents of the muscle-sparing approach point to the combined advantages of reduced trauma compared with a thoracotomy plus the ability to access the thoracic space with the entire hand for palpation and fine hilar dissection. In a series of 713 major pulmonary resections performed with the muscle-sparing approach and using mechanical stapling of the hilar vessels, Szwerc and coauthors89 reported no mortality, one conversion to thoracotomy, and seven intraoperative vascular complications. However, one of the problems of the muscle-sparing approach is that chest wall seromas have been reported in 15% to 25% of patients. Also, because the wound is small, the operative field is markedly restricted, and this has been shown to prolong operative times in at least one study.90 The overhead operating room light may fail to satisfactorily illuminate the entire thoracic cavity through the small wound, and this was one of the reasons for the lack of success of the earlier French incision. The video-

1/21/2008 1:44:56 PM

986

Section 3 Lung

thoracoscope can be used to assist in illumination during muscle-sparing approaches (hence blurring the line between the muscle-sparing and video-assisted minithoracotomy approaches). Results of the muscle-sparing technique tend to indicate a reduction in acute postoperative pain compared with a standard posterolateral thoracotomy. In a prospective, randomized study, Hazelrigg and coworkers88 noted significantly less postoperative pain in the muscle-sparing group in terms of requirement for analgesics and visual analogue scale scores. A more recent study suggested that, although acute pain was reduced in the muscle-sparing group, this advantage over posterolateral thoracotomy was lost by 1 month after surgery.91 Other studies failed to show any differences between the two approaches in terms of acute or chronic pain, although there may be less shoulder dysfunction with the muscle-sparing approach.92,93 This last finding is not surprising given that, by definition, this approach avoids division of the latissimus dorsi and serratus anterior muscles, both major shoulder girdle muscles. Studies directly comparing the muscle-sparing and VATS approaches are few. An early prospective, randomized trial found that VATS resulted in significantly less postoperative pain than the muscle-sparing technique for major pulmonary resection.53 However, in a later randomized trial, Kirby and coauthors54 could find no significant differences between the two groups in terms of operating time, intraoperative blood loss, duration of chest tube drainage, or length of hospital stay. There was a trend for lower analgesic requirements in the VATS group, although no statistical significance was reached with the sample sizes involved. However, a significantly higher rate of postoperative complications (mostly prolonged air leaks) was observed in the muscle-sparing thoracotomy group. At present, we believe that the choice between the VATS and muscle-sparing approaches is again a matter of surgeon preference. The muscle-sparing thoracotomy potentially gives a restricted field of vision and illumination through a limited thoracotomy, but it may be a technically more familiar, and hence easier, technique for surgeons who are uncomfortable operating while looking at a video monitor. For those conversant with the hand-eye skills required, VATS may provide better visualization of the thoracic cavity and more flexible instrumentation.

TRAINING IN VATS PULMONARY RESECTION It is undeniable that a learning curve exists when one first attempts VATS.94 The difficulty that faces many surgeons is the need to adapt from open surgery, which features direct vision and “hands on” contact with the thoracic contents, to looking at a monitor and operating almost entirely through instruments. Familiarity with open surgical techniques makes the switch to a new set of hand-eye coordination skills awkward and indeed may be a relative impediment to the acquisition of VATS skills. Techniques such as video-assisted thoracotomy or minithoracotomy with video assistance have proved to be useful “stepping stones” to bridge the gap between the open and VATS approaches. Some surgeons

Ch080-F06861.indd 986

have been satisfied with the results of these intermediate approaches and see no advantage in advancing further along the path of minimal invasiveness to non–rib-spreading VATS. Paradoxically, coming generations of thoracic surgeons may encounter fewer difficulties in learning VATS pulmonary resections. Despite a traditional emphasis on the need to learn the “basic” skills of open surgery,95 the current generation of trainees is being brought up in an age where VATS pleurodesis and VATS diagnostic procedures are commonplace treatments of choice, and these are very likely to be among the first operations they learn. The required hand-eye skills for VATS are therefore being acquired alongside the training in open surgical skills: a parallel approach that we encourage.12 As we have emphasized, the basic surgical principles and skills for VATS are essentially the same as those for open surgery. Therefore, the training in VATS and training in open techniques are complementary rather than antagonistic. Whereas experienced surgeons may have previously required years to hone their VATS technique, we are now witnessing trainees in our unit who are already proficient in performing VATS lung resections by the final year of their training.

SUMMARY Initially viewed as a heresy, VATS pulmonary resection has matured to become an established, alternative approach to conventional open surgery for selected patients.96 VATS major resection has been shown to be a safe operation in experienced hands. Postoperative pain is significantly less after VATS than after open surgery. Other documented advantages include better preservation of pulmonary function in the early postoperative period, earlier return to full activities, and better QOL. Older and sicker patients may thus be recruited for surgery. Intermediate to long-term survival rates for stage I lung cancer patients who undergo VATS resection appear at least as good, if not superior, to those of patients undergoing open surgery. As the established benefits of VATS resections become increasingly well recognized by both surgeons and patients, it is becoming ever more difficult to justify not using VATS as the surgical approach of choice in selected patients.

COMMENTS AND CONTROVERSIES The authors have presented a comprehensive overview of the state of the art of minimally invasive pulmonary resections. On a technical note, the approach by the authors to the hilar dissection differs to some degree from that of Tommy D’Amico,1 Robert Mckenna,2 Rod Landreneau, and others from our group, in that they describe entering the fissure as one of the first steps and also list the incomplete fissure as a possible contraindication to VATS lobectomy. In contrast, the surgeons mentioned all have described approaching the fissure, in general, as the last step, with the incomplete fissure no longer posing a significant obstacle. Therefore, I think it would be important for readers to take the time to read summaries by many different surgeons on the approach to VATS lobectomy and to consider these when formulating their own approaches to the VATS lobectomy. Personally, I have done it many times both ways and

1/21/2008 1:44:56 PM

Chapter 80 Video-Assisted Pulmonary Resections

have found the lateral approach to the ligation of the pulmonary vessels and bronchus first, with the fissure as generally the final step, to be the easiest and most reproducible approach. Briefly, the technical steps to VATS lobectomy have been summarized by D’Amico3 and include the following: Left Upper Lobectomy—With the thoracoscope in the midaxillary incision, the horizontal and oblique fissures are inspected, and the presence of the tumor in the left upper lobe is confirmed. The lung is retracted posteriorly, and the superior pulmonary vein is identified and mobilized. The left superior pulmonary vein is then encircled using a curved clamp; dissection behind the superior pulmonary vein allows identification of the pulmonary artery. The stapling device is then applied, and the superior pulmonary vein is divided, exposing the pulmonary artery. The pulmonary artery is mobilized, focusing on the apical and anterior branches, which may then be stapled and divided. Subsequently, the branches of the posterior and lingular arteries are stapled. Finally, the fissures are completed and the specimen is retrieved. Right Upper Lobectomy—This is slightly more difficult than left upper lobectomy because both the horizontal and the oblique fissures must be managed. With the thoracoscope in the midaxillary incision, the horizontal and oblique fissures are inspected, and the presence of the tumor in the right upper lobe is confirmed. The right lung is retracted posteriorly, and the superior pulmonary vein is identified and mobilized, to identify the division between middle lobe and upper lobe venous branches. The upper lobe branches are encircled using a curved clamp; dissection behind the superior pulmonary vein allows identification of the pulmonary artery. The stapling device is then applied, and the vein is divided, exposing the pulmonary artery. The pulmonary artery is mobilized, and the apical anterior trunk (truncus anterior) may then be stapled and divided. The right bronchus is now exposed, and the upper lobe bronchus may be stapled and divided. Subsequently, the posterior ascending arterial branch is stapled. Finally, the fissures are completed and the specimen is retrieved. Right Middle Lobectomy—With the thoracoscope in the midaxillary incision, the horizontal and oblique fissures are inspected, and the presence of the tumor in the middle lobe is confirmed. The lung is retracted posteriorly, and the superior pulmonary vein is identified and mobilized, to identify the division between middle lobe and upper lobe venous branches. The middle lobe vein is encircled and stapled, exposing the middle lobe bronchus and artery. Retraction of the middle lobe laterally and posteriorly optimizes exposure of the bronchus. At this point, the bronchus is encircled and stapled, further exposing the middle lobe artery. The middle lobe artery is then stapled and divided as well, allowing completion of the fissures. Lower Lobectomy (Right or Left)—The strategy for lower lobectomy is similar to that for the right and left sides. With the thoracoscope in the midaxillary incision, the presence of the tumor in the lower lobe is confirmed. The lung is retracted anteriorly, and the pleura is incised between the lung and the esophagus. The lung is then retracted laterally and superiorly to incise the pleura overlying the inferior pulmonary vein, which may then be encircled and stapled, after ascertaining that the superior segment branch is included in the dissection. Further superior retraction of the lower lobe improves exposure of the bronchus, at the bifurcation of the lower lobe bronchus and the middle lobe bronchus (right lung) or lingular bronchus (left lung). The lower lobe bronchus is then encir-

Ch080-F06861.indd 987

987

cled and stapled, exposing the lower lobe arterial trunk, which is then stapled and divided. Finally, the fissure is completed and the specimen is retrieved. The authors have referred briefly to VATS pneumonectomy as a potential VATS procedure, and I agree this is technically feasible. The main concern our group has about this procedure is actually the detailed decision tree that one goes through during an open thoracotomy in attempts to avoid pneumonectomy. For example, in many cases a sleeve resection or other parenchyma-sparing technique can be accomplished. A number of cases have been referred to us as potential pneumonectomies in which careful hilar dissection and palpation have led to the ability to spare a lobe. Therefore, we cannot enthusiastically recommend the VATS approach for most tumors that might require pneumonectomy. Especially given the higher morbidity and mortality of pneumonectomy, we recommend in most cases an open thoracotomy and thorough evaluation of the technical steps that might allow one to avoid a pneumonectomy. 1. Onaitis MW, Petersen R, Balderson SS, et al: Thoracoscopic Lobectomy Is a Broadly Applicable and Safe Procedure for Patients with Suspected Stage I Lung Cancer. Presented at a meeting of the American Surgical Association, Boston, MA, April 20-21, 2006. 2. McKenna RJ Jr, Houck W, Beeman Fuller C: Video-assisted thoracic surgery lobectomy: Experience with 1,100 cases. Ann Thorac Surg 81:421-426, 2006. 3. Onaitis M, D’Amico TA: Lung cancer: Minimally invasive approaches. In Sellke FW, del Nido PJ, Swanson SJ (eds): Sabiston and Spencer Surgery of the Chest, 7th ed. Philadelphia, Elsevier, 2005, pp 277-284.

J. D. L.

KEY REFERENCES Yim APC, Hazelrigg SR, Izzat MB, et al (eds): Minimal Access Cardiothoracic Surgery. Philadelphia, WB Saunders, 2000. ■ This remains the most authoritative textbook on minimally invasive cardiothoracic surgery, covering all aspects of VATS and its controversies in detail. Sagawa M, Sato M, Sakurada A, et al: A prospective trial of systematic nodal dissection for lung cancer by video-assisted thoracic surgery: can it be perfect? Ann Thorac Surg 73:900-904, 2002. Gharagozloo F, Tempesta B, Margolis M, Alexander EP: Video-assisted thoracic surgery lobectomy for stage I lung cancer. Ann Thorac Surg 76:1009-1015, 2003. Ohtsuka T, Nomori H, Horio H, et al: Is major pulmonary resection by video-assisted thoracic surgery an adequate procedure in clinical stage I lung cancer? Chest 125:1742-1746, 2004. Roviaro G, Varoli F, Vergani C, et al: Long-term survival after videothoracoscopic lobectomy for stage I lung cancer. Chest 126:725-732, 2004. ■ The previous four large case series are representative of the growing evidence for the efficacy of VATS pulmonary resection in treating lung cancer. Landreneau RJ, Mack MJ, Hazelrigg SR, et al: Prevalence of chronic pain after pulmonary resection by thoracotomy or video-assisted thoracic surgery. J Thorac Cardiovasc Surg 107:1079-1086, 1994. Sugiura H, Morikawa T, Kaji M, et al: Long-term benefits for the quality of life after video-assisted thoracoscopic lobectomy in patients with lung cancer. Surg Laparosc Endosc 9:403-408, 1999. Yim APC, Wan S, Lee TW, Arifi AA: VATS lobectomy reduces cytokine responses compared with conventional surgery. Ann Thorac Surg 70:243-247, 2000. Li WWL, Lee TW, Lam SSY, et al: Quality of life following lung cancer resection: Video-assisted thoracic surgery vs thoracotomy. Chest 122:584-589, 2002.

1/21/2008 1:44:56 PM

988

Section 3 Lung

■ The previous four entries are a few examples of the many papers suggesting the

advantages of VATS pulmonary resection over open approaches in many clinical parameters. Yim APC: Minimizing chest wall trauma in video assisted thoracic surgery. J Thorac Cardiovasc Surg 109:1255-1256, 1995.

Ch080-F06861.indd 988

Yim APC: VATS major pulmonary resection revisited: Controversies, techniques, and results. Ann Thorac Surg 74:615-623, 2002. ■ The previous two reviews present the rationale for the authors’ VATS technique and discuss the current controversies in VATS pulmonary resection.

1/21/2008 1:44:56 PM

ROBOTIC-ASSISTED VIDEO-ASSISTED THORACIC SURGERY LOBECTOMY

chapter

81

Bernard J. Park Raja M. Flores Valerie W. Rusch

Key Points ■ Robotic assistance is an adjunct to the video-assisted thoracic

surgery (VATS) lobectomy technique. ■ Advantages provided by robotics include enhanced three-

dimensional visualization and improved dexterity of instrumentation. ■ Implementation of robotic technology for complex thoracoscopic

pulmonary resection is feasible and safe.

Telerobotic minimally invasive surgical techniques are relatively new and continue to evolve as technology advances. Robotic assistance during VATS lobectomy provides access to binocular, three-dimensional (3D) imaging and enhanced dexterity of instrumentation for dissection. We have developed a technique that is feasible, safe, and reproducible.

HISTORICAL NOTE The technique of VATS pulmonary lobectomy was first reported in the early 1990s simultaneously by several authors.1-4 Since then, the practice of VATS lobectomy for primary surgical therapy of early-stage non–small cell lung cancer (NSCLC) has been slowly increasing because of indications that the procedure is safe and oncologically acceptable in patients with stage I disease (McKenna, 2005).5-11 Limitations of minimally invasive surgical approaches for performance of major thoracic procedures include two-dimensional imaging, an unsteady camera platform, and limited maneuverability of instruments used through small, non–ribspreading incisions. In an effort to improve standard minimally invasive surgical techniques, telerobotic surgery evolved. The first generation of surgical robots focused primarily on the issue of the unstable camera platform. In 1994, the AESOP (Automated Endoscopic System for Optimal Positioning; Computer Motion, Santa Barbara, CA), a voice-activated robotic camera holder, was approved by the U.S. Food and Drug Administration (FDA) for clinical use in abdominal surgery. A more recently approved device, the Endo-Assist (Armstrong Healthcare Ltd. [now Prosurgics], Loudater, High Wycombe, UK), allows the operating surgeon to control camera movement through natural head movement (Ballantyne, 2002).12 The newest generation of surgical robots was designed to address issues beyond the camera platform by employing telerobotic technology, in particular the ability of the operating surgeon to control the surgical robot and its instruments through the use of a remote computer console. The da Vinci

Surgical System (Intuitive Surgical, Sunnyvale, CA) is an FDA-approved telerobotic system that is currently the most commonly employed robot in minimally invasive surgical techniques. It is a master/slave device consisting of four components: the robotic arms; the surgeon’s console; the Insite vision system with a true 3D endoscope providing a high-resolution, binocular view of the surgical field; and the EndoWrist instrument system capable of seven degrees of freedom and two degrees of axial rotation (Fig. 81-1). The advanced articulation of the robotic instruments allows human wrist-like movements and is clearly its greatest potential improvement over straight instruments employed in conventional VATS procedures. For this reason, the da Vinci system was initially implemented in closed-chest cardiac surgery, and the earliest experience was in the area of coronary artery bypass grafting.13 Since then, robotic assistance for a wide array of minimally invasive surgical procedures has been described. Currently, the most common procedure performed robotically is the laparoscopic prostatectomy,14 and it is in this arena that the largest published series exist. In the field of general thoracic surgery, the majority of the literature consists of a few case reports of procedures employing robotic assistance (Melfi et al, 2002).15-17 For VATS anatomic pulmonary resection, there is only one published series detailing a robotic-assisted technique or its feasibility in a meaningful cohort of patients (Park et al, 2006).18

PATIENT SELECTION AND ROBOTIC TRAINING Patients with suspicious or biopsy-proven clinical stage IA or small (≤4 cm in diameter) stage IB NSCLC or other pathologic tumors that are peripheral and confined to the lung are considered eligible for a VATS lobectomy approach at our institution. We consider the definition of robotic assistance to be use of the da Vinci Surgical System during a VATS lobectomy for individual dissection, isolation, and ligation of the pulmonary hilar structures, as well as mediastinal lymph node dissection. Informed consent for the use of robotic assistance during VATS lobectomy is obtained as a separate portion of the procedure.

Robotic Training and Technique Development Before implementation of robotics into clinical practice, we attended, along with our operating room team of nurses, surgical technicians, and surgical physician assistants (PAs), an intensive, 2-day certifying course given by Intuitive Surgical. Use of a human cadaver model and additional modifications in our institutional dry laboratory allowed for 989

Ch081-F06861.indd 989

1/21/2008 1:45:58 PM

990

Section 3 Lung

A

B

C

C

D

FIGURE 81-1 The da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA). A, Surgical cart. B, Surgeon’s console. C, Insite vision system. D, EndoWrist instrument system.

Ch081-F06861.indd 990

1/21/2008 1:45:58 PM

Chapter 81 Robotic-Assisted Video-Assisted Thoracic Surgery Lobectomy

991

implementation of robotic assistance into our established VATS lobectomy technique. Once the entire surgical team became proficient with the da Vinci Surgical System, it was incorporated into treatment of patients. The initial 10 cases were performed with a dedicated minimally invasive surgical PA and at least two members of the attending staff working together, one as operating surgeon at the surgeon’s console, and the other as first assistant at the operating room table with the patient. Once each surgeon became comfortable with the procedure, surgical fellows were incorporated as first assistants. All procedures are now performed with one attending surgeon, a surgical fellow, and a surgical PA.

A

OPERATIVE TECHNIQUE (THREE-ARM ROBOT) Preparation of the Robot The operating room technical staff sets up the da Vinci Surgical System (robot, surgeon’s console, Insite vision system) in the room. In the beginning of the case, the nursing staff power up the system, run the appropriate diagnostics, and drape the robotic arms and camera. This requires two individuals and typically takes 20 to 30 minutes for staff who are trained and familiar with the process; meanwhile, the patient undergoes induction of anesthesia and positioning.

Initial Exploration and Positioning of the Robot For the intrathoracic portion of the case, the patient is placed in a maximally flexed, lateral decubitus position after singlelung ventilation is established. Initial thoracic exploration is conducted with conventional thoracoscopy to verify tumor location, establish a tissue diagnosis if necessary, assess resectability and appropriateness of a VATS approach, and establish the VATS lobectomy access incisions. We perform VATS lobectomy via a technique that employs two 1- to 1.5-cm access incisions and a 4-cm or smaller non–rib-spreading utility incision. The incision for the camera is placed in the seventh or eighth intercostal space at the posterior axillary line. The next incision is placed just above the diaphragm, posterior to the tip of the scapula. The lung is retracted posteriorly to identify the hilar structures. The location of the main utility incision varies depending on the lobe of interest. For upper lobectomy, it is placed at the level of the superior vein in the midaxillary line. For middle and lower lobectomies, the incision is placed one interspace lower. Once the incisions have been made, no additional dissection is performed. The conventional VATS instrumentation is removed, and the da Vinci robot is brought into position from the posterior aspect of the patient with the center column at an angle of approximately 45 degrees with respect to the longitudinal axis of the patient (Fig. 81-2). This allows for the field of dissection to include the hilar structures and the majority of the chest. A 12-mm trocar is placed through the anterior inferior access incision, and the camera arm is attached to the trocar. The 3D, 30-degree scope is introduced through the trocar and secured to the camera arm. The positioning of the instrument arms with attached trocars through the two remaining access incisions is accomplished under direct vision both from outside the patient and from within the patient’s thorax.

Ch081-F06861.indd 991

B FIGURE 81-2 Robot positioning. The robot is brought in from the posterior aspect of the patient at a 45-degree angle. A, Overhead view. B, Magnified overhead view.

FIGURE 81-3 Final robot position. The arms must have full range of motion without colliding with one another or with the patient.

Care must be taken to ensure that each instrument arm has full range of motion and does not collide with another instrument or with any portion of the patient (Fig. 81-3). Once the surgical instruments have been introduced under direct thoracoscopic vision, the operating surgeon moves to

1/21/2008 1:46:07 PM

992

Section 3 Lung

the surgeon’s console. One or two assistants are required for robotic-assisted VATS lobectomy, depending on which lobe is to be removed. For upper lobectomy, the first assistant stands at the anterior aspect of the patient and provides additional retraction of the lung and suctioning through the main utility incision. The second assistant is positioned at the posterior access incision and passes the endoscopic stapling devices when required. For middle and lower lobectomies, one assistant is usually sufficient because exposure and passage of stapling devices can be achieved through the utility incision alone.

is confirmed, either preoperatively or intraoperatively, we are in the practice of beginning the procedure with mediastinal lymph node dissection (Figs. 81-4 and 81-5). If indicated, the nodes are sent for frozen section to rule out occult stage III disease.

Hilar Dissection If there are no contraindications to lobectomy, individual isolation of the hilar structures proceeds, with dissection around the hilar vessels and bronchi performed through a combination of cautery and sharp and blunt dissection. Complete removal of all regional nodal tissue is performed. After a vessel or bronchus has been mobilized sufficiently, two blunt-tipped Cadiere forceps are used to isolate the structure; the seven degrees of freedom allow articulation of the instruments at near-right angles to do so (Figs. 81-6 and 81-7). For upper and middle lobectomy, individual ligation

Mediastinal Lymph Node Dissection Dissection is initiated with a blunt-tipped forceps in the left arm (Cadiere or Maryland) and the permanent spatula attached to electrocautery in the right arm. If the procedure is being performed for NSCLC, once the pathologic diagnosis

RUL

AzV

T

SVC PhN

H

N

FIGURE 81-4 Right paratracheal lymph node dissection. The mediastinal pleura is incised, and the entire nodal packet between the trachea (T) and superior vena cava (SVC) is excised. AzV, azygos vein; H, hilum; N, node; PhN, phrenic nerve; RUL, right upper lobe.

Ch081-F06861.indd 992

1/21/2008 1:46:08 PM

Chapter 81 Robotic-Assisted Video-Assisted Thoracic Surgery Lobectomy

C

E

AzV

993

FIGURE 81-5 Subcarinal lymph node dissection from the right chest. All lymph nodes between the main carina, esophagus, and pericardium are removed. AzV, azygos vein; B, bronchus; C, carina; E, esophagus; N, node; RUL, right upper lobe.

RUL

B

N

and division of the hilar structures are performed with endoscopic staplers introduced via the posterior access incision. This requires temporary repositioning of the left instrument arm. In contrast, for lower lobectomy, division of the hilar structures is best performed by placing the stapling devices through the anterior utility incision, which requires repositioning of the right instrument arm.

Division of the Fissure Completion of the fissure is performed last, just before removal of the specimen. After isolation and division of all of the hilar structures, the robot is removed, and conventional thoracoscopy is re-established to complete the fissure. For upper lobectomy, the entire fissure is divided with endoscopic staplers (Fig. 81-8); for middle and lower lobectomies, the anterior portion of the fissure is often divided with electrocautery in the course of dissection of the hilar structures. The remaining posterior portion of the fissure is then completed using the endoscopic staplers.

INITIAL RESULTS AND EXPERIENCE Between November 2002 and January 2006, there were 48 consecutive patients at our institution who underwent attempted robotic-assisted VATS lobectomy employing the three-arm da Vinci Surgical System. The patient characteristics and perioperative results are listed in Table 81-1. Patients were selected for a robotic-assisted approach based on the following criteria:

Ch081-F06861.indd 993

1. Presence of a localized, peripheral lung lesion without evidence of nodal or extrathoracic spread 2. Adequate cardiopulmonary reserve to tolerate a lobectomy Eight patients had no preoperative tissue diagnosis and underwent wedge resection during initial VATS exploration, and eight patients had mediastinoscopy also in the same setting. The majority of patients had NSCLC, one patient had a typical carcinoid tumor, and one had a primary pulmonary lymphoma. Those with NSCLC all were clinical stage I preoperatively. Only one patient had had any therapy prior to resection. This patient was diagnosed with Hodgkin’s lymphoma and NSCLC simultaneously and was treated at an outside institution with chemotherapy directed at both before resection. Robotic-assisted VATS lobectomy was completed in 44 patients. Robotic assistance for individual isolation and ligation of all hilar structures was performed in 38 patients. In 6 of the first 20 patients, robotic assistance was used for a portion of the hilar dissection, followed by conventional thoracoscopy. Conversion to thoracotomy was required in four patients (8%)—three for bleeding and one secondary to loss of single-lung isolation. None of these patients required blood transfusion intraoperatively or postoperatively. Operative time was measured from the start of VATS to skin closure. Median operative time was 215 minutes (range, 143-350). Median room time, defined as the total time the patient was in the room, was 295 minutes (range, 204-433).

1/21/2008 1:46:11 PM

994

Section 3 Lung

PhN SVC

RUL

H

RA

SPV

SPV

TA

PA SPV FIGURE 81-6 Right superior hilar vessel dissection. A blunt-tipped forceps is used to isolate the vessels, which are divided by endovascular staplers. H, hilum; PA, pulmonary artery; PhN, phrenic nerve; RA, right atrium; RUL, right upper lobe; SPV, superior pulmonary vein; SVC, superior vena cava; TA, truncus arteriosus.

Ch081-F06861.indd 994

1/21/2008 1:46:14 PM

Chapter 81 Robotic-Assisted Video-Assisted Thoracic Surgery Lobectomy

RULBr

995

AzV

PA

RULBr

PA

MLA

SPV

FIGURE 81-7 Right upper lobe bronchus dissection. After individual ligation and division of the vasculature, the bronchus is isolated, stapled, and divided, completing the hilar dissection required to resect the right upper lobe. AzV, azygos vein; MLA, middle lobe artery; PA, pulmonary artery; RULBr, right upper lobe bronchus; SPV, superior pulmonary vein.

Every type of lobectomy was done, and mediastinal lymph node dissection was performed in each instance. The median number of lymph node stations dissected in patients undergoing successful robotic-assisted VATS lobectomy was 5.0 (range, 2-7). Most of the patients with NSCLC had pathologic stage IA disease (32/46, 70%). The median size of the lesions pathologically was 2.0 cm (range, 0.8-5.0). The remaining 14 patients had more locally advanced disease, based on size or on microscopic nodal metastases. The median chest tube duration for the entire group was 3.0 days (range, 2-19), and the median length of stay was 5.0 days (range, 2-20). The complication rate for all patients was 31% (15/48). The most common complication was supraventricular tachycardia. Based on the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE), the grades of complications ranged from 1 to 3. One patient with a history of coagulopathy had postoperative

Ch081-F06861.indd 995

hemorrhage requiring re-exploration with no clear source of bleeding identified. There were no in-hospital deaths, and the 30-day mortality rate was 0%. Since the initial series in the early 1990s describing the technique, VATS lobectomy has not gained widespread acceptance as a standard approach to early-stage lung cancer. This may be due, in part, to wide variations in technique, even among its busiest practitioners, and to the lack of a large, randomized trial demonstrating equivalency to a standard thoracotomy approach for treatment of resectable NSCLC. However, with ongoing refinements in minimally invasive techniques and instrumentation and with detection of primary lung cancers at smaller sizes and earlier stages, the use of minimally invasive VATS techniques for anatomic pulmonary resections is likely to become more commonplace. One of the newest advances in minimally invasive surgery is the development of telerobotics. With its advanced 3D optics, stable camera platform, and instrumentation that allows for

1/21/2008 1:46:18 PM

996

Section 3 Lung

FIGURE 81-8 Division of right upper lobe fissure. The fissure between the right upper, middle, and right lower lobes is completed with multiple fires of the endoscopic stapler. The resected lobe is placed in a laparotomy sac and removed via the utility incision. RML, right middle lobe; RUL, right upper lobe. RML

RUL

RML

seven degrees of freedom of motion, the da Vinci Surgical System can provide useful technical advantages when performing complex minimally invasive surgical thoracic procedures. There are several issues that most be kept in mind when attempting to incorporate use of the robot. First, one of the major challenges is determining the optimal positioning of the surgical cart and the instrument arms. Having the patients in a lateral decubitus position limits the available surface area on which to position the camera and instrument arms. Close attention must be paid to the spacing and range of motion of the arms so that they do not collide with one another or cause undue pressure on any portion of the patient, particularly the upper extremities. We have found that bringing the robot toward the patient from an angle of approximately 45 degrees results in optimal movement of the three-arm system. Newergeneration robots have four arms and may require modifications of the positioning should the operating surgeon wish to employ all of the arms available. Second, it is critical to have assistants at the operating table who are familiar with conventional VATS lobectomy techniques, especially with regard to retraction and exposure of

Ch081-F06861.indd 996

pertinent anatomic structures and placement of vascular stapling devices. This is particularly true because the operating surgeon is seated at the surgeon’s console, away from the patient. Third, although there is excellent visual feedback with the 3D robotic video system, there is no tactile feedback during traction and dissection with robotic instrumentation. The same technology that eliminates tremor also eliminates any sensation of the tissue planes. Fourth, choosing the appropriate robotic instruments to employ during dissection is critical. In doing so, one needs to remember that most of the instruments were designed for use on coronary vessels. The instruments we use are by no means the only ones that need to be considered. Each individual surgeon must evaluate and test the equipment to determine those instruments that are safe and effective for dissection. Lastly, because of the reasons listed and with any new procedure, we encourage a graded process of developing experience with the technique, employing the robot in stages before completing an entire dissection robotically. What are the advantages in employing telerobotic surgery during VATS lobectomy? First, the 3D Insite camera system results in a superior, stable image for the operating surgeon.

1/21/2008 1:46:22 PM

Chapter 81 Robotic-Assisted Video-Assisted Thoracic Surgery Lobectomy

TABLE 81-1 Patient Characteristics and Perioperative Results (N = 48) Median age

69.0 years (range, 12-85)

Male:female ratio

18:30

Tumor location RUL LUL LLL RLL RML

21 13 5 8 1

Median tumor diameter

2.0 cm (range, 0.8-5.0)

Tumor histology NSCLC Typical carcinoid MALT

46 1 1

Pathologic stage (NSCLC, n = 46) T1 N0 M0 (IA) T2 N0 M0 (IB) T1 N1 M0 (IIA) T2 N1 M0 (IIB) T1 N2 M0 (IIIA)

32 7 5 1 1

Median operative time

215 min (range, 143-350)

Median room time

295 min (range, 201-433)

Median chest tube duration

3.0 days (range, 2-19)

Median length of stay

5.0 days (range, 2-20)

Postoperative complications (n = 15, 31%) Supraventricular arrhythmia Hemorrhage Myocardial infarction Prolonged air leak Pneumothorax Empyema Acute renal insufficiency

6 1 1 3 1 1 1

LLL, left lower lobe; LUL, left upper lobe; MALT, mucosa-associated lymphoid tissue; NSCLC, non–small cell lung cancer; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe.

Second, the seven degrees of freedom of the EndoWrist robotic instruments allows for truly intuitive bimanual dissection of the hilar structures. However, in the end, proving an improvement in the technical ease of a procedure is quite difficult. Currently, use of this new technology increases

Ch081-F06861.indd 997

997

operating room time and adds cost for use of the robotic instrumentation. The technique is certainly still evolving and requires further study in clinical trials before it can be routinely adopted in clinical practice. The future directions for study of this technology include further refinement of the technique, validation of the adequacy of the oncologic results, and determining methods to compare it with conventional VATS techniques.

Acknowledgments We would like to acknowledge Hugh Thomas for providing the artwork for the figures.

COMMENTS AND CONTROVERSIES The authors are to be congratulated on a succinct review of the topic of robotic lobectomy and an unbiased, objective assessment of robotic surgery in the field of general thoracic surgery. It is clear that this technology is still looking for its place in the field of surgery. Certain niches, such as robotic prostatectomy, seem to be gaining momentum, but widespread acceptance is not yet present. In other areas, such as esophagectomy, the multifield requirement makes the robotic choice a bit cumbersome for repositioning. Some groups have suggested that robotic mediastinal cases represent an area worth exploring, but their relative uncommon place in most thoracic practices make the learning curve difficult. It is clear that it is only through innovative, specialized practices such as the group at Memorial Sloan-Kettering Cancer Center that this field has any hope of moving forward. The current status and any advantages for robotic lobectomy over VATS lobectomy remain somewhat limited, but the prospects for future robotic innovations and newer, user-friendly improvements in technology are bright and can take place only through surgeon-driven investigation. G. A. P.

KEY REFERENCES Ballantyne GH: Robotic surgery, telerobotic surgery, telepresence and telemonitoring. Surg Endosc 16:1389-1402, 2002. McKenna RJ Jr: New approaches to the minimally invasive treatment of lung cancer. Cancer J 11:73-76, 2005. Melfi FM, Menconi GF, Mariani AM, et al: Early experience with robotic technology for thoracoscopic surgery. Eur J Cardiothorac Surg 21:864-868, 2002. Park BJ, Flores RM, Rusch VW: Robotic assistance for video-assisted thoracic surgical lobectomy: Technique and initial results. J Thorac Cardiovasc Surg 131:54-59, 2006.

1/21/2008 1:46:25 PM

Introduction chapter

82

ANATOMY AND PHYSIOLOGY OF THE PLEURAL SPACE Reza John Mehran Jean Deslauriers

Key Points ■ The pleura is made of two serosal membranes, one covering the

■

■ ■ ■

lung (visceral pleura) and one covering the inner chest wall and mediastinum (parietal pleura). The visceral pleura is devoid of somatic innervation, whereas the parietal pleura is innervated through a rich network of somatic, sympathetic, and parasympathetic fibers. Pleural fluid is constantly secreted, mostly by filtration from the microvessels in the parietal pleura. The resorption of pleural fluid may be through lymphatic stomata in the parietal pleura rather than through the visceral pleura. The pleural pressure, which is subatmospheric, is proportional to the pressure developed within the lung.

ANATOMY The pleura is formed of two serosal membranes, one covering the lung (the visceral pleura) and one covering the inner chest wall (the parietal pleura). The surfaces glide over each other, facilitating proper lung movements during the various phases of respiration. The pleural space is the space delimited by the two layers. Under normal conditions, it contains only a small amount of liquid that functions mainly as a lubricator. The total amount of pleural fluid ranges between 0.1 and 0.2 mL/kg, with a thickness of about 10 µm.1 The two pleural cavities are independent of each other, but in some conditions the parietal pleura of each side is in contact anteriorly behind the sternum. The transition between the parietal and visceral pleurae is at the level of the pulmonary hilum. At this level, the reflection covers the constituents of the hilum, except inferiorly, where the reflection extends down to the diaphragm. The overall shape of this reflection is a racquet, the handle of which forms the pulmonary ligament, also known as the triangular ligament of the lung. The limits of the triangular ligament are listed: 1. Medially, the esophagus on the right, the aorta on the left, and the pericardium 2. Superiorly, the inferior pulmonary vein 3. Inferiorly, the diaphragm The ligament contains a few small arteries and veins that have little clinical significance and lymph nodes that drain the inferior lobe.

EMBRYOLOGY During the end of the third week of gestation, the embryonic mesoderm differentiates into the para-axial mesoderm, the intermediate mesoderm, and the lateral plate (Figs. 82-1 to 82-4). The lateral plate forms two different layers: the somatic mesoderm or somatopleure and the splanchnic mesoderm or splanchnopleure. Gradually, the somatic mesoderm progresses to meet in the midline, in the ventral portion of the embryo, closing the intraembryonic coelom from the extraembryonic coelom. The somatic mesoderm becomes the parietal layer, and the splanchnic mesoderm becomes the visceral layer of the intraembryonic coelomic sac. By the end of the seventh week, the diaphragm separates the pleuropericardial and peritoneal spaces. Meanwhile, the separation of the serosal cavities of the chest starts with the medial growth of the pericardial folds. The folds contain the phrenic nerves and the common cardinal veins (Cuvier’s duct), the precursors of the superior vena cava. The folds coalesce in the midline during the fifth week, separating the pericardial from the pleural space. During the same period, the pulmonary buds grow and contribute to the formation of the final shape of the pleural and pericardial cavities (see Figs. 82-3 and 82-4). By the third month, the pleural cavities have expanded cranially, caudally, and ventrolaterally to surround the pericardium.

ADULT PLEURAL SAC Visceral Pleura The visceral pleura covers the surface of the lung and extends into the fissures. The visceral pleura is thin, transparent, and tightly adherent, via elastic fibers, to the underlying alveolar wall elastica (Fig. 82-5). Disruption of these elastic fibers results in the formation of pleural blebs.2

Parietal Pleura The parietal pleura is more complex anatomically. This layer covers almost completely the inner surface of the thoracic wall and the medial aspect of the mediastinum. The attachment of the parietal pleura to these structures is via a fibrous layer known as the endothoracic fascia (see Fig. 82-5). The endothoracic fascia is a cleavage layer from which the parietal pleura can be separated from the chest wall. The thickness and strength of the endothoracic fascia vary with location. The fascia is strongest over the inner surface of the ribs. Posterior to the sternum and over the pericardium, the endothoracic fascia is almost nonexistent. This makes the detachment of the pleura in these locations impossible. At 1001

Ch082-F06861.indd 1001

1/21/2008 1:51:00 PM

1002

Section 4 Pleura

Amniotic cavity

Amniotic cavity Lateral plate

Somatopleure

Yolk sac Intra-embryonic coelomic cavity

Splanchnopleure FIGURE 82-1 Differentiation of the lateral plate into the somatopleure and the splanchnopleure, the precursors of the parietal and visceral pleura, respectively (early third week of gestation).

Lung bud

FIGURE 82-2 The creation of the intraembryonic coelomic cavity by ventral migration of the somatopleure toward the midline.

Pleuropericardial fold Lung

Pleural cavity

Phrenic nerve

Common cardinal vein

FIGURE 82-3 Creation of the lung bud and the pleuropericardial folds (about the fifth week). Large arrow indicates movement of the lung bud during growth of the fecus.

Pleuropericardial membrane FIGURE 82-4 Midline fusion of the pleuropericardial folds, with separation of the pleural cavity from the pericardial sac. Expansion of the pleural cavity (fifth week to third month).

the level of the thoracic inlet, the fascia is again strong and forms a diaphragm called the fibrous cervicothoracic septum3 or the cervicothoracic diaphragm of Bourgery.4 This diaphragm is supported by a number of suspensory ligaments to surrounding structures in the thoracic inlet.

In only one order of mammal, the Proboscidea, which includes the elephant, the fetal pleural cavities are replaced by elastic tissue.5 In humans, the stretching capacity of the pleura is seen after a pneumonectomy: the remaining lung expands into the contralateral pleural space.

Pericardial cavity

Pleural Sinuses The parietal pleura can be divided into the costal, mediastinal, and diaphragmatic pleurae. The transition between each segment is done at the level of the pleural sinuses. The pleural sinuses include the following: 1. Anterior and posterior costomediastinal sinuses 2. Costophrenic sinus 3. Mediastinophrenic sinus The parietal pleurae in the sinuses, especially in the posterior costophrenic sinus, are in contact at rest, but the sinuses fill with lung during inspiration.

Ch082-F06861.indd 1002

Pleural Topography The projection of the pleural sinuses over the chest wall is fairly similar on the right and on the left. Anteriorly, the lung extends no lower than the 6th rib in the midclavicular line, whereas the pleural costophrenic sinus extends to the 7th rib. Laterally in the midaxillary line, the lung descends to the eighth rib, and the lateral costophrenic sinus descends to the 9th rib. Posteriorly, the lung extends to the 11th rib and the pleura to the 12th rib. Superiorly, the pleural space and the lung extend above the bony limits of the thoracic inlet.

1/21/2008 1:51:00 PM

Chapter 82 Anatomy and Physiology of the Pleural Space

1003

5

11

9

1

2 3 4 6 7

10

8

FIGURE 82-5 The layers of the parietal and visceral pleurae: 1, endothoracic fascia; 2, subpleural connective tissue layer; 3, superficial elastic layer; 4, parietal mesothelial layer; 5, lymphatic stoma; 6, pleural space; 7, visceral mesothelial layer; 8, deep elastic layer; 9, interlobular septa; 10, connective fiber; 11, interlobular lymphatics.

Blood Supply The blood supply of the parietal pleura comes exclusively from the systemic arteries. The costal pleura is supplied by intercostal arteries and branches from the internal mammary arteries; the mediastinal pleura is vascularized by bronchial, upper diaphragmatic, and internal mammary arteries. The blood supply to the cervical pleura (pleural dome) comes from subclavian arteries. For the most part, venous blood drains into peribronchial veins or directly into the venae cavae. In contrast, the visceral pleura is vascularized by both the systemic circulation (through the bronchial arteries) and the pulmonary circulation. Venous blood is drained into the pulmonary venous system. Gilbert and Hakim6 observed that the relative contribution of the systemic circulation through the branches from the bronchial arteries is increased at the subpleural level.

Lymphatic Drainage The pleural space is on the boundary of two lymphatic systems, both of which play a major role in the removal of fluid, cells, and foreign particles from the pleural space. In the subpleural space of the visceral pleura, large lymphatic capillaries form a meshed network that drains into the pulmonary lymphatic system. These capillaries are more abundant over the lower lobes and are connected to the deep pulmonary plexuses located in the interlobular and peribronchial spaces. The lymphatic drainage of the parietal pleura is more elaborate, with direct communication between the pleural space and the parietal pleural lymphatic channels. These communications, called stomata (see Fig. 82-5), are 2 to 6 µm in diameter and predominate over the lower portions of the mediastinal, diaphragmatic, and costal pleura. They have endoluminal valves and drain into a network of submesothelial lymphatic lacunae. Over the costal pleura, these collecting vessels run parallel to the ribs to reach the internal mammary nodal chain anteriorly and the intercostal nodal chain posteriorly. At the level of diaphragm, the drainage is to the retrosternal, mediastinal, and celiac nodes.7 The

Ch082-F06861.indd 1003

transdiaphragmatic anastomoses allow for the passage of fluid and foreign particles from the peritoneal cavity into the pleural space. The subpleural lymphatics play an important role in the reabsorption of fluid and the removal of proteins, particles, and cells from the pleural space.

Innervation The visceral pleura is devoid of somatic innervation; in contrast, the parietal pleura is innervated through a rich network of somatic, sympathetic, and parasympathetic fibers. At the level of the costal pleura, these fibers travel through the intercostal nerves. Pain stimuli from the diaphragm are transmitted through the phrenic nerve.

MICROSCOPIC ANATOMY The visceral and parietal pleural membrane consists of a single layer of mesothelial cells resting on connective tissue. Mesothelial cells are stretchable, and their size and shape may vary, depending on their location. Abundant microvilli cover their surface. The presence of a rich endoplasmic reticulum points to some secretory capacity. By expanding the cell surface, microvilli favor phagocytosis and fluid absorption (transcytosis). The epithelium lies over a basal membrane, which is formed of various amounts of collagen and elastic fibers. It contains blood vessels, nerve endings, and lymphatic channels. In the visceral pleura, this underlayer is directly connected to the fibroelastic network of the lung and thus helps to distribute mechanical stress evenly throughout the structure. The parietal pleura contains two particular features that are not present in the visceral pleura. A rich network of lymphatic vessels is concentrated in the posterior and inferior portion of the chest. As described earlier, these vessels communicate directly with the pleural space through openings, or stomata, in the parietal pleura. Kampmeier foci, or milky spots, are found in the lower portion of the mediastinal pleura and are covered with slightly different, cuboidal, mesothelial cells. They consist of an aggregate of macrophages, lymphocytes, histiocytes, plasma

1/21/2008 1:51:01 PM

1004

Section 4 Pleura

cells, mast cells, and undifferentiated mesenchymal cells encircling thick blood capillaries and lymphatic channels. Kanazawa8 demonstrated that Kampmeier foci participate in the defense of the pleural space in various ways. They exhibit phagocytic activity, trap macrophages and particles, appear to exert some focal suction, and have the capacity to produce leukocytes under the stimulus of inflammation, not unlike the lymphoid tissue in the tonsils.

MECHANICAL PROPERTIES The visceral pleura has a double mechanical action: volume limitation of the lung and the generation of elastic recoil pressure. The pleural contribution to lung elastic recoil pressure originates from the elastic network, which returns back to its resting position when inspiratory pressures become negligible.9 Hills10 demonstrated that the pleural surfaces contain a phospholipid coating, which is electrically charged. The two pleural surfaces, therefore, repulse each other, which prevents friction and adhesion. This graphite-like antiwear property is comparable to the best lubricants. During normal respiration the two pleural surfaces move together. The relative sliding velocity can be approximately 10 cm/sec in humans.11 The elastic properties of the visceral and parietal pleurae are similar.12 This suggests that the shearinduced pressures generated during breathing deform the chest wall and lung surfaces to an equal extent, preventing tissue damage and promoting spatial uniformity and pleural fluid thickness. The mechanisms that hold the lung close to the chest wall are complex and depend mainly on two physiologic processes, those that ensure a constant removal of pleural fluid and those that prevent the accumulation of free gas in the pleural space. These mechanisms involve the interplay of different pressures.

Pleural Pressure The pressure in the pleural cavity (PPL) results from the mechanical properties of the respiratory system (Fig. 82-6) and can be derived by the following equation:

PRS




PL



PW

PRS = PL + PW

where PRS is the pressure of the respiratory system, PL is the pressure exerted by the lung, and PW is the pressure developed in the chest wall. The pressures measured at the boundaries of these structures are the alveolar pressure (PALV), the pleural pressure (PPL), and the ambient barometric pressure (PBAR). The PPL is equal to the difference between the alveolar and the transpulmonary pressure (PL) as shown in the following equation: PPL = PALV − PL

In static conditions, the alveolar pressure is equal to zero, and the equation becomes PPL = −PL

This equation demonstrates that the pleural pressure is proportional to the pressure developed in the lung. When the pulmonary volume is at its functional residual capacity, the elastic forces of the lung and thorax are in equilibrium, and the pleural pressure equals −2 to −5 cm H2O. As the pulmonary volume increases during inspiration to the vital capacity, the pleural pressure becomes progressively more negative, −25 to −35 cm H2O. In any condition in which the elastic recoil of the lung is increased, such as interstitial fibrosis, edema, atelectasis, or resection of the parenchyma of the lung, the pleural pressure becomes more subatmospheric. In situations in which airway resistance is increased, such as chronic obstructive pulmonary disease, bronchial stenosis, or obstruction by a foreign body or secretions, the negativity of the pleural pressure increases further during inspiration.

Vertical Gradient of Pleural Pressure The pleural pressure is not uniform around the surface of the lung. Minor local variations of pleural liquid pressure occur in relation to variations in the thickness of the pleural space, but these are of no practical consequence. More important, a vertical pleural pressure gradient exists from the top to the bottom of the thoracic cavity. The mechanisms responsible for this gradient were reviewed by Agostoni.11 The effect of gravity on the lung is one important determinant. Other factors include the size, volume, shape, and position of the lung. The pleural pressure changes by approximately 0.25 cm H2O per centimeter of height and is more negative at the apex (−7 to −9 cm H2O) than at the base (0 to −2 cm H2O) of the lung in an upright subject. This is one reason why the upper portion of the lung usually collapses more with a pneumothorax.

Gas Pressures

PALV

PPL

PBAR

FIGURE 82-6 This model represents the pressures involved in the mechanics of the respiratory system. PRS is the total respiratory system pressure plus the sum of PL, the pressure developed in the lung, and PW, the pressure developed in the chest wall. PALV, alveolar pressure; PBAR, ambient barometric pressure; PPL, pleural pressure.

Ch082-F06861.indd 1004

Given that the hydrostatic pleural pressure is subatmospheric, there is a theoretical risk that gases dissolved in the blood and interstitial fluid could be freed into the pleural space. The pleural space is influenced by the partial pressures of gases prevailing in the arterial and venous blood that irrigates the pleura. The cascade of partial pressure changes from the atmospheric pressure to the venous blood is summarized in Table 82-1. Oxygen and carbon dioxide are exchanged during respiration. Nitrogen is neither consumed nor pro-

1/21/2008 1:51:02 PM

Chapter 82 Anatomy and Physiology of the Pleural Space

1005

TABLE 82-1 Partial Pressures of Gases in Air and Blood* Partial Pressure Water

Atmosphere

Alveolar Gas

Arterial Blood

Pleural Space

Venous Blood

47

47

47

47

150

102

95

40

0

39

40

45

Nitrogen

563

572

575

575

Total

760

760

757

Oxygen Carbon dioxide

703 [Gradient + 54 mm Hg]

*All pressures in millimeters of mercury, assuming temperature at 37°C, saturated in water vapor.

duced during respiration. However, because the respiratory quotient is less than 1, the amount of oxygen consumed is greater than the amount of carbon dioxide rejected in the alveoli. As a consequence, the partial pressure of nitrogen increases slightly, from 563 mm Hg in the inspired gas to 572 mm Hg in the alveolar gas. The partial pressure of nitrogen in the blood equals 575 mm Hg and is close to equilibrium with the alveolar gas.13 The situation is different with oxygen and carbon dioxide. As a result of cellular respiration, the contents of the blood change at the capillary level. The oxygen content decreases, and the carbon dioxide content increases. The repercussions of these gas exchanges on partial pressure are different for the two gases because the dissociation curves of oxygen and carbon dioxide in the blood are not the same. A partial oxygen pressure of 95 mm Hg in arterial blood drops to 40 mm Hg in venous blood, a 55-mm Hg difference. The partial carbon dioxide pressure goes from 40 to 45 mm Hg, a corresponding gain of only 5 mm Hg. The total pressure of dissolved gases in venous blood is 703 mm Hg, 54 mm Hg (or 72 cm H2O) lower than the 757 mm Hg in arterial blood and the pleural space. This pressure gradient protects the pleural space against the spontaneous formation of gas if the hydrostatic pressure does not exceed −72 cm H2O. It ensures also that air collected in the pleural space, as in the pneumothorax, will be reabsorbed by the venous side of the circulating blood.

Box 82-1 Composition of Normal Pleural Fluid Volume: 0.1-0.2 mL/kg Protein: 10-20 g/L Albumin: 50%-70% Glucose: As in plasma Lactic dehydrogenase: <50% of plasma level Cells/mm3: 4500 Mesothelial cells: 3% Monocytes: 54% Lymphocytes: 10% Granulocytes: 4% Unclassified: 29% pH: 7.38 (mixed venous blood + 0.02) Partial pressure of carbon dioxide: 45 mm Hg (= mixed venous blood) Bicarbonate: 25 mmol/L (= mixed venous blood) From Agostini B: Mechanics of the pleural space. In American Physiological Society: Handbook of Physiology, vol 3, sec 3, part 2. Bethesda, MD: American Physiological Society 1986.

Box 82-2 Starling’s Equation Applied to Pleural Fluid Dynamics F = K × [(PCAP − PPL) − (πCAP − πPL)]

PLEURAL FLUID DYNAMICS Normal Fluid Only a small amount of fluid can be recovered from the pleural space under normal conditions (Box 82-1). A volume of 0.1 to 0.3 mL/kg may be extrapolated from experimental data in animals.14 The protein content is low, 10 to 20 g/L, a fact that led Staub and colleagues1 to question and study the mechanisms of fluid reabsorption and turnover.

Pleural Fluid Turnover Pleural fluid is constantly secreted, mostly by filtration from the microvessels in the pleurae, mainly in the less dependent regions of the cavity.15 A quantitative assessment of the amount of pleural fluid production in humans is difficult to obtain, and most documented values are obtained from animal studies. Pistolesi and colleagues16 showed a wide range

Ch082-F06861.indd 1005

σ = Reflection coefficient where: F is fluid movement across the pleura; K is permeability coefficient; PCAP is hydrostatic capillary pressure; PPL is hydrostatic pleural pressure; πCAP is osmotic capillary pressure; and πPL is osmotic pleural pressure.

of values from 0.02 to 2 mL/kg/hr. Comparative mammalian studies reveal that pleural fluid turnover relatively decreases with increasing animal size.17 In large mammals such as elephants, there is no production of pleural fluid, and the pleural space is actually nonexistent. Agostoni and colleagues18 proposed that the balance of hydrostatic and osmotic pressures could explain the mechanism of pleural fluid exchange. The Starling equation (Box 82-2) states that the flow of fluid through a semipermeable

1/21/2008 1:51:02 PM

1006

Section 4 Pleura

FIGURE 82-7 The mechanisms of pleural fluid exchanges at the level of the parietal and the visceral pleura. P is the hydrostatic pressure, and π is the osmotic pressure (both in centimeters of water). The arrows indicate the direction of flow. In areas in which the pleura is vascularized by the systemic circulation, the net balance of pressures, according to Starling’s equation, favors the filtration of fluid toward the pleural space. Capillary hydrostatic pressures are lower in the capillaries of the pulmonary circulation, and the balance of pressures favors pleural fluid resorption through the visceral pleura. Other mechanisms of fluid transport in animal species are transcytosis of proteins and electrolytedependent transport. However, most of the resorption occurs through the lymphatic channels of the parietal pleura.

Visceral pleura

P
26

P
5

P
26

␲
29

␲
4

␲
29

Systemic capillaries (bronchial arteries)

Systemic capillaries

Pleural space

Pulmonary lymphatic

P
12 ␲
29 Lymphatic vessels

Pulmonary capillaries

Transcytosis

Electrolyte-dependent transport

membrane such as the pleura depends on three factors: the permeability coefficient of the pleura, the difference in hydrostatic pressures, and the difference in osmotic pressures across the pleura. However, recent data show that the system of diffusion of fluids across the parietal pleura is more complicated than the principles of the Starling equation can explain. Rather, the parietal pleura is a complex membrane that allows selective passage of proteins and solute. This can explain the low protein concentration of the pleural fluid compared with the extrapleural interstitium.14 A tentative explanation of the most important mechanisms of fluid transport across the pleurae is presented in Figure 82-7. The net effect of the Starling equation on the parietal pleura is an influx of fluid into the pleural space; for the visceral pleura it is the opposite. Both pleural surfaces are also equipped with electrolytecoupled liquid removal. The most important appear to be a luminal Na+/H+-Cl−/HCO3− double exchange, and a Na+glucose cotransport coupled to a basolateral Na+/K+-ATPase. This is an active transport of solutes and liquids that is independent of hydrostatic pressures (Zocchi, 2002).19 Furthermore, mesothelial cells lining the pleural surfaces, as described earlier, are able to provide vesicular flow and protein transcytosis across the cell layer, a major mechanism for the transport of particles with large molecular size. There is also direct drainage through the lymphatic stomas. The parietal pleural lymphatics, through their contractile wall, are able to create a negative pressure, sucking in the pleural fluid.20 The predominance of the lymphatic stomata in the

Ch082-F06861.indd 1006

Parietal pleura

Transcytosis

Electrolyte-dependent transport

most dependent portion of the chest also creates a flow of pleural fluid from the area of production in the upper chest to the lower portion of the chest cavity. The balance of drainage of the mechanisms described is toward a net absorption of pleural fluid through the parietal pleura.21 If the filtration rate exceeds the maximum absorption rate or if one of the primary absorptive mechanisms is altered, fluid accumulates in the pleural space. The causes of pleural effusion may be subdivided into three categories: 1. Those impairing the balance in transpleural pressures 2. Those impairing lymphatic flow 3. Those producing mesothelial and capillary endothelial permeability Factors affecting the Starling forces are usually extrapleural in nature. Those affecting the lymphatic drainage may be of pleural or extrapleural origin. Those causing loss of membrane selectivity involve the pleural mesothelium. Other, less clear factors involve the direct passage of fluids and protein into the pleural space, as is seen in experimental models of congestive heart failure and chemically induced pulmonary edema.22-24 Peritoneal fluid may also leak into the chest through pores in the diaphragm in patients with ascites or in those who are undergoing peritoneal dialysis. Obstruction or narrowing of the lymphatic trunks draining the diaphragm lymph in an experimental rat model caused a hydrothorax, indicating that there is at least one other mechanism causing fluid accumulation during chronic ambulatory dialysis and diseases with ascites.25

1/21/2008 1:51:02 PM

Chapter 82 Anatomy and Physiology of the Pleural Space

If the pathologic process results in more leakage of protein into the pleural space, the effusion will become an exudate; otherwise, it is a transudate. The clinical differentiation between the two is usually obtained with the criteria presented by Light and associates,26 described elsewhere in this textbook.

Ch082-F06861.indd 1007

1007

KEY REFERENCES Lai-Fook SJ: Pleural mechanics and fluid exchange. Physiol Rev 84:385410, 2004. Zocchi L: Physiology and pathophysiology of pleural fluid turnover. Eur Respir J 20:1545-1558, 2002.

1/21/2008 1:51:02 PM

chapter

83

PLEURA IMAGING David S. Gierada

Key Points ■ Chest radiography and computed tomography (CT) are the primary

imaging modalities for evaluating pleural disease. ■ The radiologic appearance of pleural fluid and air collections vary

depending on their size, presence of loculations, and patient positioning. ■ Typical imaging features of pleural masses include a peripheral location, sharp or partly sharp interface with the lung, and obtuse angles with the chest wall. ■ Pleural malignancy should be suspected if multiple masses are present, or if parietal pleural thickening is greater than 1 cm, nodular, or circumferential or involves the mediastinal pleural surface.

Pleural abnormalities often are first discovered or suspected on chest radiographs. CT provides greater sensitivity in detecting and specificity in characterizing pleural disease and may help discriminate pleural, chest wall, and peripheral pulmonary processes in certain cases. The excellent spatial resolution now obtainable with multiplanar reformatting from multidetector CT scanning has further improved the CT depiction of anatomic regions more optimally evaluated by coronal and sagittal planes, such as the superior sulcus and the diaphragm. Magnetic resonance imaging (MRI) of pleural diseases provides diagnostic capabilities largely similar to those of CT, without the need for ionizing radiation. However, MRI requires greater time and expense and provides far less concomitant information about the lung parenchyma. Ultrasonography is used primarily to confirm the presence of pleural fluid and to provide imaging guidance for pleural fluid aspiration or percutaneous biopsy of pleural masses.

cular tree, the location of the fissures on CT also may be identified as relatively avascular zones of decreased attenuation along the interface between lobes; this can be a useful means of identifying the fissures on relatively thicker CT slices (= 5 mm) and of localizing the horizontally oriented minor fissure on scans reconstructed in the transverse plane. The major fissures are incomplete in at least half of patients, and the minor fissure even more frequently, and therefore may not extend all the way to the hilum.2,4,7,8 This may allow air, infection, and neoplastic disease to extend between lobes. Accessory fissures between pulmonary segments are seen in a small percentage of patients radiographically9 and are detectable in more than 20% of patients by thin-section CT.2,10,11 These include the inferior accessory fissure,11,12 which separates the medial basal segment from the rest of the lower lobe, usually on the right; the left minor fissure, which separates the lingula from the left upper lobe;10,11,13-15 the azygos fissure,16,17 which separates a variably sized portion of the medial right upper lobe apex from the rest of the lobe, with the azygos vein coursing in the fissure’s inferior extent; and the superior accessory fissure,11,18 which separates the superior segment of the lower lobe from the basilar segments, usually on the right. Other accessory fissures have been described.10,14 The bronchovascular supply of accessory lobes is normal. The inferior pulmonary ligaments, representing union at the hilum of the parietal pleura lining the mediastinum and the visceral pleura of the lung, course inferoposteriorly from the inferior pulmonary veins. When visible, they are seen on CT as short, thin lines or septae extending laterally into the lung from the posterior mediastinal pleural margins, adjacent to or slightly anterior to the esophagus.19

PLEURAL DISEASE

ANATOMY

Pleural Effusion

The pleura comprises a single surface layer of mesothelial cells and underlying loose connective tissue, blood and lymphatic vessels, and nerves.1 The visceral pleura covers the lung and is continuous with the parietal pleura, which lines the mediastinum, chest wall, and diaphragm. The apposed visceral pleural surfaces at the interfaces of the various lobes of the lungs form the interlobar fissures. The interlobar fissures are seen as thin, hyperattenuating lines on radiographs when tangent to the x-ray beam. Depiction of fissures on CT scans improves as the slice thickness is decreased.2-6 Because the pleural surfaces represent the periphery of the lobes at the end of the pulmonary vas-

The radiographic appearance of freely flowing fluid in the pleural space varies with the position of the patient and the volume of fluid present. On erect radiographs, small amounts of fluid first become visible in the posterior costophrenic sulcus on the lateral radiograph, then in the lateral sulcus on the frontal radiograph, causing so-called blunting or a meniscus (i.e., a concave upward contour of the normally sharp costophrenic angles).20,21 The side of a unilateral effusion seen only on the lateral radiograph in the posterior sulcus usually can be determined by distinguishing the right from the left hemidiaphragm. The left posterior sulcus may be identified by its contiguity with the left hemidiaphragm, which usually

1008

Ch083-F06861.indd 1008

1/21/2008 1:51:50 PM

Chapter 83 Pleura Imaging

A

1009

B

FIGURE 83-1 A, Frontal chest radiograph in an 81-year-old woman following drainage of a persistent left pleural effusion 6 weeks after coronary bypass surgery shows no evidence of residual pleural effusion. Mild atelectasis is present in the left lung (white arrows), and there is a calcified mitral valve annulus (open arrows). B, Lateral chest radiograph shows a sharp posterior costophrenic angle (white arrow) continuous with the left hemidiaphragm that becomes indistinct anteriorly at the heart, indicating complete drainage of the left effusion. The blunted posterior costophrenic angle due to a small pleural effusion (arrowhead) is continuous with the right hemidiaphragm, which is visible farther anteriorly. Also note that the posterior ribs contiguous with the effusion are more magnified than those contiguous with the sharp costophrenic angle on this left lateral projection (left hemithorax closer to the image receptor), confirming that the effusion is on the right. There is a calcified mitral valve annulus (open arrows).

is not visible as far anteriorly as the right hemidiaphragm, the left being obscured anteriorly by the heart (Fig. 83-1). Determining the side of any subphrenic stomach or colon gas on the corresponding frontal projection also often helps distinguish the posterior sulci on the lateral view. In addition, on left lateral radiographs (i.e., with the left side of the patient closest to the image receptor, the conventional position) obtained in slight obliquity, the ribs on the right side are magnified more than those on the left, so the right posterior sulcus can be identified by following the posterior pleural margin along the more magnified right ribs inferiorly. Costophrenic angle blunting also can be caused by pleural thickening or scarring. As the size of a pleural effusion increases, the fluid level and resultant opacification rise to become visible on both frontal and lateral radiographs and obscure the hemidiaphragm, becoming higher laterally and posteriorly.21 Fluid accumulating between the base of the lung and the diaphragm (subpulmonic pleural effusion) may simulate hemidiaphragm elevation (Fig. 83-2). This situation should be suspected if the peak of the apparently elevated hemidiaphragm dome appears more lateral than usual and there is fluid in the posterior costophrenic angle.22-24 On the left, an increase in the distance between the base of the lung and the top of the gastric air bubble may be seen.24,25 If a hemithorax is completely opacified, it may be difficult from chest radiographs to determine the relative contributions of pleural effusion, parenchymal consolidation, and lung collapse. Mediastinal shift to the contralateral side favors a large pleural effusion

Ch083-F06861.indd 1009

or a large mass, whereas mediastinal shift to the ipsilateral side favors a predominance of collapse. The distinction is readily made with CT, particularly with administration of intravenous contrast material. On supine and semi-erect radiographs, pleural fluid layering posteriorly may produce an ill-defined increase in haziness of the lower or entire hemithorax, often obscuring the hemidiaphragm margin.24,26 At times, this can be difficult to discriminate from atelectasis or an infiltrative process in the lungs (Fig. 83-3). In addition, patient obliquity can produce asymmetry in the overall opacity of the hemithoraces, which may mimic a posteriorly layering effusion. The presence of pleural fluid is more confidently determined on radiographs if there is associated blunting of the costophrenic angle or widening of the pleural margin by fluid between the chest wall and the lung, or if apical capping is present; these signs increase in frequency with increased size of the effusion.26 Pleural fluid on supine radiographs also may cause widening of the left paraspinal pleural line,27 or it may track into the major fissure to produce an increase in opacity laterally that is bordered medially by a sharp interface between the fluid and the aerated lower lobe.28 However, even moderate pleural effusions may be undetectable, and pleural effusion size may be underestimated, on supine radiographs.29 Pleural fluid loculated within the interlobar fissures may simulate a mass lesion, resulting in a pseudotumor, phantom tumor, or vanishing tumor, most commonly described in heart failure.30 On radiographs, a biconvex or elongated shape along a fissure in at least one projection, sometimes with an

1/21/2008 1:51:51 PM

1010

Section 4 Pleura

A

FIGURE 83-2 A, Frontal chest radiograph shows the typical appearance of a subpulmonic right pleural effusion, with apparent elevation of the right hemidiaphragm and a laterally positioned peak. B, Right lateral decubitus radiograph demonstrates dependent layering of the moderate pleural effusion.

B

incompletely sharp border, and a tail extending along the fissure usually allows identification of the intrapleural location (Fig. 83-4).25 Pleural fluid loculated between the lung and chest wall also may simulate a pleural or extrapleural mass. The concomitant presence of nonloculated pleural fluid in a dependent location, or the rapid appearance and transient nature of such opacities, may suggest the correct radiographic diagnosis of loculated fluid. Most pleural effusions, whether loculated or free-flowing, transudative or exudative, are of homogeneous, near-water attenuation on CT. Although CT is of limited value in distinguishing transudates from exudates,31,32 high-density fluid and thickening of the parietal pleura almost always indicate that an effusion is an exudate.33 With transudates, pleural thickening and/or enhancement is not typically seen on CT. Distinction between transudative and exudative pleural effusions on the basis of MRI signal characteristics presently cannot be accomplished.34 Thoracentesis remains a requirement for determining the composition of most pleural effusions and for establishing whether the pleural space is infected or contains blood or malignant cells. Ultrasound guidance for drainage of small pleural effusions significantly reduces the frequency of complications35 and has been found useful in the surgical intensive care unit.36 Pleural fluid with an attenuation on CT similar to or higher than that of soft tissue is suggestive of a hemothorax (Fig. 83-5). Hemothoraces may be inhomogeneous in attenuation and may contain fluid levels of different attenuation, with hyperdense areas reflecting the high hemoglobin content of

retracted clot or sedimented blood.37 Causes include trauma, malignancy, hypercoagulable states, pulmonary infarction, ruptured aortic dissection, aneurysm, arteriovenous malformation, and pleural endometriosis.38 Chylothorax refers to an effusion containing lymphatic fluid, which has a high triglyceride content.39 About half of chylothoraces are related to tumors, mostly lymphoma. Surgery is the most common traumatic cause. The predominantly right-sided course of the thoracic duct explains why traumatic chylothorax usually occurs on the right.40 Leakage from pleural lymphatics may be the cause of chylothorax in lymphangioleiomeiomyomatosis and in thoracic duct obstruction.41 Chylothorax can produce fluid having a CT attenuation less than that of water (Fig. 83-6).42 Occasionally, lymphography may be useful for surgical planning if ligation of the thoracic duct is contemplated for persistent chylothorax.43 Pseudochylous fluid,41,40,44 which contains lipid but is nonchylous, may be seen in chronic pleural effusions. Tuberculous empyema and rheumatoid disease are the most common causes. Impaired resorption of cholesterol from degenerated red and white blood cells due to chronic pleural thickening is the suggested mechanism. If milky pleural fluid is associated with pleural thickening on CT, pseudochylothorax should be suspected because chylothorax is usually not associated with pleural thickening. Urinothorax is of water attenuation and may result from dissection of a retroperitoneal urinoma in patients with a urinary tract obstruction45; it is typically unilateral.

Ch083-F06861.indd 1010

1/21/2008 1:51:52 PM

Chapter 83 Pleura Imaging

L

L

E

A

FIGURE 83-3 A, Portable chest radiograph in a 72-year-old woman who had recent adhesiolysis and bowel resection for a small bowel obstruction shows diffuse haziness of the mid- and lower hemithoraces, suggestive of a posteriorly layering pleural effusion, with or without pulmonary edema. B, Image from an abdominal CT scan performed on the same day for a suspected abscess reveals the cause of the radiographic haziness to be moderate bilateral pleural effusions (E) with associated passive atelectasis of the lower lobes (L). C, CT image at the same level as the image in B at lung window settings reveals normal aeration of the right middle lobe and lingula, with no pulmonary edema.

Empyema An empyema is a grossly purulent exudative pleural effusion (white blood cell count >5000/mm3) that may be positive on culture or Gram staining.31,46 Empyemas most commonly occur as the result of an infected parapneumonic effusion after pyogenic bacterial pneumonia, but they can be seen with tuberculosis,47 with fungal infections, or as a complication of a lung abscess, septic pulmonary infarction, surgery, or trauma.48,49 Infection also may spread to the pleura from osteomyelitis of the spine or a subdiaphragmatic abscess. Other iatrogenic causes include thoracentesis or percutaneous needle aspiration.

Ch083-F06861.indd 1011

1011

E

B

C

Chest radiography, sometimes in conjunction with decubitus positioning, generally suffices to diagnose a loculated pleural fluid collection and possible empyema. Ultrasonography can also be extremely helpful in corroborating pleural fluid and in guiding aspiration. At times, however, definitive distinction between a loculated pleural collection and parenchymal opacification may not be possible with conventional radiographic techniques (Fig. 83-7). This can be more definitively accomplished by CT, which may depict the loculated pleural fluid and thickening of the adjacent visceral and parietal pleura in empyemas and frequently reveals associated edematous inflammation of the extrapleural tissues. As an empyema develops, the pleural surfaces become organized

1/21/2008 1:51:53 PM

1012

Section 4 Pleura

FIGURE 83-4 A, Posteroanterior chest radiograph obtained in a patient after coronary bypass grafting reveals blunting of the left costophrenic angle, compatible with a small pleural effusion, and a mass-like opacity in the left mid-lung zone that has a partly sharp and partly unsharp interface with the lung and tapering margins, suggestive of fluid loculated in the major fissure. B, Lateral chest radiograph confirms location within the major fissure (arrows), consistent with a pseudotumor. Note tapering superior margins. A small amount of fluid is also present in the left posterior sulcus (arrowheads).

A

B

B

A FIGURE 83-5 A, CT image in a patient with a falling hematocrit after chest tube removal demonstrates a large right hemothorax. The pleural collection is of heterogeneous attenuation, including areas of low attenuation and areas of attenuation higher than that of the chest wall muscles, consistent with blood. B, Hemothorax in a different patient is characterized by a fluid-fluid level on the left (arrows), with the dependent blood having higher attenuation. A simple pleural effusion is present on the right, and there is enhancing passive atelectasis (arrowheads) adjacent to the effusions bilaterally.

Ch083-F06861.indd 1012

1/21/2008 1:51:53 PM

Chapter 83 Pleura Imaging

1013

FIGURE 83-6 CT image from a patient after left pneumonectomy shows a large left chylothorax with a fluid-fluid level (arrows) shifting the mediastinum toward the right. The nondependent component has attenuation lower than water, characteristic of chylous fluid.

A

B

L

*

C

Ch083-F06861.indd 1013

FIGURE 83-7 A, Posteroanterior radiograph reveals a poorly defined opacity projecting over the left lung base. B, Lateral radiograph shows this to be a posterior, pleural-based, lenticular opacity (arrows) suspicious for a pleural process. C, CT scan shows a loculated pleural fluid collection with thickening and enhancement of visceral (arrows) and parietal (arrowheads) pleura (split pleura sign), representing an empyema. Note enhancing adjacent atelectatic lung (L) and a small amount of free pleural fluid (∗).

1/21/2008 1:51:55 PM

1014

Section 4 Pleura

with fibrosis and vascular ingrowth, resulting in increased attenuation and marked contrast enhancement of the thickened pleura around the margins of the pleural fluid; this is termed the split pleura sign (Fig. 83-8; see Fig. 83-7). This circumferential enhancement, seen in more than two thirds of empyemas, is a useful sign in identifying infected pleural fluid collections (Stark et al, 1983).50 Pleural neoplasm and inflammatory disease also may produce this sign.31,33,51,52 Lack of pleural thickening or enhancement does not exclude infection of a pleural fluid collection. In the absence of preceding surgery, trauma, or percutaneous intervention, the presence of an air-fluid level in a loculated pleural collection (Fig. 83-9) strongly suggests an empyema with bronchopleural fistula. Air within an empyema also may result from thoracentesis, from thoracostomy tube drainage, or, rarely, from gas-producing organisms. A peripheral location of an air-fluid level and unequal lengths of the air-fluid interface on posteroanterior and lateral views, when present, are signs confirming that a collection is located within the pleural space rather than in the lung. In equivocal cases, CT usually allows ready distinction. Accurate diagnosis is critical because of the disparate treatments for these serious infections. Proper treatment of an empyema requires thoracostomy tube drainage, whereas a lung abscess is appropriately managed by the use of antibiotics and postural drainage, with percutaneous or bronchoscopic drainage or surgical resection reserved in case antibiotic treatment fails.53-56 CT allows evaluation of pleural rind thickness, the presence of

L

FIGURE 83-8 CT scan in a patient with an empyema shows a multiloculated fluid collection with pleural enhancement (arrowheads) compressing the adjacent enhancing, atelectatic lung (L).

FIGURE 83-9 A, Frontal radiograph in a patient with an empyema demonstrates multiple air-fluid levels on the right (arrows). B, CT image reveals a large air and fluid collection in the right pleural space with thickened, enhancing margins caused by the empyema. The empyema was secondary to a lung abscess (arrow), which is visible as mixed fluid attenuation and gas within the compressed, atelectatic lung.

A

Ch083-F06861.indd 1014

B

1/21/2008 1:51:56 PM

Chapter 83 Pleura Imaging

radiographically occult loculations, the effectiveness of chest tube drainage, and the presence of unexpanded, so-called trapped lung after drainage.46 Inadequate treatment of an empyema may result in progressive organization of the fibrin lining the visceral and parietal pleura surrounding the loculated pleural fluid, leading to a chronic empyema. The pleura may eventually calcify, particularly if the cause of the empyema was tuberculous infection.47 Neither calcification nor fibrosis in chronic empyema indicates quiescent disease, and the presence of fluid in the pleural rind may be secondary to an active ongoing infection. Once fibrosis of the pleural surfaces has occurred, effective therapy requires surgical pleural decortication. Serial CT can be used to help determine the need for decortication because fibrinous pleural peels may resolve after thoracostomy tube drainage rather than progress to organized fibrosis.57 In tuberculosis, fibrothorax without pleural effusion suggests inactive disease.44 Several malignancies have been reported in association with chronic empyema. The most common is lymphoma, followed by squamous cell cancer, mesothelioma, and various sarcomas.58 CT or MRI should be considered to look for a mass or chest wall invasion if radiographs or symptoms suggest that an underlying malignancy may be present.

1015

absence of a known risk factor or trauma. These occur more frequently in tall, thin men in the third to fourth decade, often as a result of rupture of subpleural blebs. Chest radiography is the principal technique for detecting and evaluating pneumothoraces. A pneumothorax is typically identified on radiographs as air lucency peripheral to the inwardly displaced visceral pleural margin of the partially collapsed lung. The visceral pleural margin usually maintains the smooth, curved contour of the lung, parallel to the curve of the chest wall. Pulmonary vascular markings are absent in the pneumothorax space, which is hyperlucent relative to the adjacent lung. Although expiratory radiographs are often recommended to enhance pneumothorax detection, experimental evidence for this is lacking; in fact, inspiratory and expiratory radiographs have been found to be equally sensitive and specific.59 Different approaches to assessing whether upright or decubitus radiographs are more sensitive for pneumothorax detection have produced conflicting results.60,61 A small pneumothorax may be undetectable on semi-erect or supine radiographs if the pleural air is located anteriorly and does not cause displacement of the apical, lateral, basilar, or medial lung margin. Therefore, occasionally the only evidence of pneumothorax on supine radiographs is a relative increase in lucency overlying the inferior thorax and upper quadrant of the abdomen (Fig. 83-10), lucency outlining the inferior margin of the anterior costophrenic sulcus,62 and lucency within the lateral costophrenic sulcus (deep sulcus sign).63 Even less frequently, pneumothorax may collect in the posteromedial pleural space in the supine position (Tocino et al, 1985)64 or produce a sharply lobulated contour of the pericardial fat over the cardiac apex.65 If supine radiographs raise suspicion of a pneumothorax but are not definitive, upright or decubitus radiographs should be obtained. A lateral

Pneumothorax There are numerous causes or predisposing conditions for pneumothorax, including blunt or penetrating trauma, percutaneous interventions, thoracic surgery, barotrauma from mechanical ventilation, pneumonia, cystic or obstructive lung disease, malignancy, and, rarely, endometrial pleural implants (catamenial pneumothorax). A primary spontaneous pneumothorax can occur in otherwise healthy individuals in the

P

B

A

Ch083-F06861.indd 1015

FIGURE 83-10 A, Supine chest radiograph in a man who was assaulted with a baseball bat shows relatively greater lucency and paucity of vascular markings overlying the right lower lung and upper abdomen. B, CT image confirms anterior right basilar pneumothorax (P).

1/21/2008 1:51:57 PM

1016

Section 4 Pleura

radiograph may provide supplemental information if findings on the frontal view of a two-view, erect chest radiograph are equivocal, so they also should be closely inspected if available; pneumothoraces on lateral radiographs are most often seen anteriorly or posteriorly, though an air-fluid level may be the only sign.66 Hemidiaphragm depression on the side of a pneumothorax and mediastinal shift toward the contralateral side should be looked for when a pneumothorax is present because these findings may indicate a tension pneumothorax with hemodynamic compromise. CT can be useful in complex cases and in selected cases when erect or decubitus images cannot be obtained. For example, CT may be helpful to evaluate for a coexistent pneumothorax when extensive subcutaneous air obscures findings on chest radiographs, to distinguish a medial pneumothorax from pneumomediastinum, or to differentiate a large bulla from a pneumothorax suspected on a conventional radiograph. Identification of even a small pneumothorax can be important in trauma patients about to undergo mechanical ventilation or general anesthesia for surgery. For this reason, and because of the recognized low sensitivity of supine portable radiographs, the most cephalad scans from all abdominal CT examinations obtained during trauma evaluation should be examined with lung window settings to identify an otherwise occult pneumothorax.67 CT also may be useful in detecting apical subpleural blebs, bullae, and paraseptal emphysematous lesions, which may warrant resection with

unresolving or recurrent spontaneous pneumothorax (Fig. 83-11).68-70 However, a visceral pleural defect may not be visible. Persistent air leaks, whether loculated or not, raise suspicion of a malpositioned chest tube or a bronchopleural fistula. Chest tube position is readily and more accurately determined by CT than by chest radiography. Chest tubes not within the pleural space (i.e., intraparenchymal or in the chest wall) may need to be replaced or repositioned. Whether tubes in the interlobar fissures provide adequate drainage of pneumothorax or pleural effusions has been controversial.71,72 Occasionally, intrafissural thoracostomy drainage tubes appear intraparenchymal on CT, particularly if thicker sections are obtained or if the tube is in the minor fissure.71 Bronchopleural fistulas may result from necrotizing pneumonia (often leading to empyema), lung resection (Fig. 83-12), malignancy, trauma, barotrauma, bronchiectasis, or infarction. Although tiny openings in the visceral pleural surface may not be identifiable, direct communication between a peripheral airway and the pleural space often can be depicted by CT.73 Identification of a bronchopleural fistula by CT, in the absence of peripheral bullae, suggests a greater likelihood of a need for surgical management.74 Persistent pneumothorax also may occur due to failure of trapped lung to re-expand after drainage of a large pleural effusion in the presence of pleural malignancy or pleural thickening due to chronic empyema.46

B

A

FIGURE 83-11 A, Frontal chest radiograph in a 42-year-old man with sudden onset of dyspnea and chest pain reveals a large right pneumothorax with almost total collapse of the right lung. B, Frontal chest radiograph after chest tube placement reveals a persistent moderate right pneumothorax; arrowheads indicate the margin of the incompletely re-expanded right lung. C, CT scan reveals a ruptured right apical bleb (arrow) as the cause of the ongoing air leak.

Ch083-F06861.indd 1016

C

1/21/2008 1:51:58 PM

Chapter 83 Pleura Imaging

1017

Pleural Thickening Pleural thickening may be focal or diffuse, and it is usually the result of a preceding inflammatory or infectious process. Apical lung fibrosis and adjacent pleural thickening are commonly seen as an apparent senescent change, possibly related to the relative ischemia of this region, or as a result of prior granulomatous infections such as tuberculosis or histoplasmosis. Extensive, circumferential fibrous pleural thickening, usually caused by an organizing effusion, hemothorax, or pyothorax, is referred to as a fibrothorax. Other benign causes of diffuse pleural thickening include prior surgery, trauma, radiation therapy, asbestos exposure, drug reactions, and collagen vascular diseases. Pleural thickening is seen on radiographs as soft tissue density separating the lung from the chest wall or diaphragm (Fig. 83-13). However, the radiographic appearance is not specific and is often caused by extrapleural fat. Blunting of the costophrenic angles can be caused by pleural thickening or pleural fluid. In contrast, CT allows distinction between pleural thickening, fat, and fluid (Fig. 83-14). Malignant neoplasms, including metastases, mesothelioma, and lymphoma, also can manifest as thickened pleura (Leung et al, 1990).75 If nodularity, parietal pleural thickness greater than 1 cm, circumferential pleural thickening, or mediastinal pleural involvement is seen, a malignant cause should be suspected (Fig. 83-15) (Leung et al, 1990).31,75-77 Tuberculous pleurisy, which can involve the mediastinal pleura if extensive, is the main exception to this rule.31,76 These features of malignant pleural thickening are much more readily depicted by CT than by radiography. Expansion of the extrapleural fat

FIGURE 83-12 CT image from a patient with a history of right upper lobectomy for atypical mycobacterial infection who developed a persistent pneumothorax shows a fistulous communication (arrow) between the bronchial stump and the pleural space. The subcutaneous gas developed after chest tube placement.

B

A

Ch083-F06861.indd 1017

FIGURE 83-13 A, Frontal chest radiograph in a 34-year-old man with unrelenting chest pain shows smooth thickening of the mid- to lower left lateral pleural margin. B, CT image shows smooth pleural thickening of soft tissue attenuation, sparing the mediastinal surface, and contraction of the left hemithorax. Open biopsy revealed benign chronic sclerosing pleuritis (fibrothorax) of undetermined cause, and decortication was performed.

1/21/2008 1:51:59 PM

1018

Section 4 Pleura

A

B

FIGURE 83-14 A, Frontal chest radiograph shows smooth thickening of the mid- to lower lateral pleural margins on both sides. B, CT image shows that the thickened pleura has the same attenuation as subcutaneous and mediastinal fat and therefore represents abundant extrapleural fat (arrows).

A

B

FIGURE 83-15 A, Frontal chest radiograph in a 55-year-old man with metastatic melanoma reveals extensive nodular pleural thickening on the left. B, CT image shows circumferential involvement that includes the mediastinal pleural surface, with extension into the major fissure (arrows) and diminished left lung volume. Subcutaneous metastases are also present (arrowheads).

layer adjacent to thickened pleura strongly suggests a chronic, benign process. Percutaneous biopsy with CT guidance can be useful in determining the cause of diffuse pleural thickening. Adhesions between the visceral and parietal pleura may form as a result of inflammatory or malignant pleural disease. Pleural adhesions can make open or thoracoscopic thoracic surgery difficult and increase operative morbidity. CT findings that suggest the presence of adhesions include pleural

Ch083-F06861.indd 1018

thickening greater than 3 mm; high-attenuation or enhancing bands in pleural fluid or crossing a pneumothorax; pleural fluid loculation; subpleural interstitial disease with visceral pleural retraction or pleural thickening; and the split pleura sign. However, these signs have been found to be only moderately sensitive and specific.78 The presence of pleural thickening does not necessarily mean that the visceral and parietal pleura are fused, and adhesions may be present even if the pleural margins appear normal.

1/21/2008 1:52:00 PM

Chapter 83 Pleura Imaging

1019

V

A

B

FIGURE 83-16 A, Frontal chest radiograph in a patient with a remote history of tuberculosis reveals sheets of calcification overlying the right lung and pleural thickening and calcification laterally. B, CT scan shows diffuse right pleural thickening and calcification, sparing the mediastinal surface. Calcified right hilar (white arrow) and subcarinal (black arrowhead) lymph nodes are also present. V, superior vena cava.

Pleural Calcification Unilateral pleural calcification is most commonly caused by prior infection or hemorrhage, usually is associated with pleural thickening, and is relatively specific for benign disease.76,79 A prior tuberculous empyema can cause dense unilateral pleural thickening with extensive calcification (Fig. 83-16), often accompanied by substantial associated parenchymal disease and volume loss. Rarely, hypercalcemic states can cause pleural calcifications,80 and high-density (about 160 HU) areas of pleural thickening may occur in patients undergoing amiodarone therapy.81 Talc instilled into the pleural space for pleurodesis may simulate pleural calcification (Fig. 83-17). Bilateral, symmetrical disease, particularly with calcified plaques on the diaphragm, is almost pathognomonic of asbestos-related pleural disease.

Asbestos-Related Benign Pleural Disease Persons exposed to asbestos dust have a substantially increased incidence of benign and malignant abnormalities, including pleural plaques, thickening, effusions, pulmonary fibrosis, and malignant neoplasms of the lung and pleura (Roach et al, 2002).82-88 Benign effusions are probably the earliest manifestation. They are thought to be uncommon, and they may be asymptomatic, transient, and recurrent.89 There are no specific diagnostic features, so attributing a pleural effusion to asbestos exposure requires exclusion of other causes of exudative effusions (Roach et al, 2002).87,90 A pleural effusion may be the harbinger of a malignant pleural or pulmonary neoplasm in a patient with substantial asbestos exposure, and this should be the initial consideration. However, a pleural

Ch083-F06861.indd 1019

FIGURE 83-17 CT scan in a 72-year-old woman with a history of talc pleurodesis for a malignant pleural effusion secondary to metastatic ovarian cancer shows high-density material resembling calcification along the posterior pleural margin (solid arrow). Also note high-density pleural thickening anterolaterally (arrowhead) and thickening of the major fissure (open arrow).

1/21/2008 1:52:01 PM

1020

Section 4 Pleura

effusion related to asbestos exposure can be benign in nature; it is typically an exudate and may be hemorrhagic.91 Focal plaque formation is the most frequent manifestation of asbestos exposure.92-94 The latent period between the initial asbestos exposure and radiologic demonstration of plaques is approximately 20 years. Pleural plaques have little or no effect on lung function.88,95 They do not undergo malignant degeneration, but they signify exposure to asbestos and suggest an increased risk for the development of lung cancer, malignant mesothelioma,96 and possibly interstitial lung disease. Radiographically, pleural plaques appear as nodular or irregularly shaped opacities along the anterior and posterior ribs of the midthorax, with or without calcification (Fig. 83-18). Like other pleural or extrapleural masses, their borders often are partly sharp and partly ill-defined when viewed en face. Calcifications appear linear when seen in profile, and a socalled holly leaf configuration of calcification may be seen en face with larger, more extensive plaques.93 Calcified diaphragmatic pleural plaques are virtually pathognomonic of previous asbestos exposure. Asbestos-related pleural plaques are typically bilateral, although they may be unilateral. Oblique radiographs increase the sensitivity for detecting pleural plaques.97 Large calcified plaques can simulate parenchymal disease and present a confusing appearance on chest radiographs. CT is far more accurate than radiography in identifying asbestos-related pleural plaques, especially in depicting involvement of the mediastinal and paravertebral pleura.88,98 CT is particularly useful for problem solving, such as distinguishing pleural plaques from lung nodules (Fig. 83-19) or determining whether the observed pleural-based changes are caused by plaques, extrapleural muscles, or abundant extrapleural fat.98-100 On CT, asbestos-related plaques have sharp

A

margins and usually range in thickness from 2 to 15 mm.94 They may be of soft tissue attenuation, completely calcified, or partially calcified. Calcified and noncalcified plaques frequently coexist. Asbestos exposure also can result in diffuse pleural thickening, anywhere from the apex to the base.87,92,94 Unlike pleural plaques, this radiologic appearance is nonspecific. If it is extensive, marked restrictive lung disease may be produced.101-103 Visceral pleural thickening is uncommon and should raise the suspicion of a mesothelioma104; it is indistinguishable from parietal pleural thickening except when it is seen in the interlobar fissures or when the pleural layers are separated by fluid. CT is far superior to radiography in determining whether there is associated interstitial lung disease. The term asbestosis is reserved for the pulmonary parenchymal fibrosis caused by asbestos exposure and should not be used to describe asbestos-related pleural abnormalities. Although there is a correlation between the severity of pleural disease and presence of asbestosis, most patients with plaques do not have interstitial pulmonary disease.105,106 MRI plays little role in asbestos-related pleural disease, though it may aid in determining the extent of possible malignancy. Rounded atelectasis is a unique form of peripheral masslike pulmonary collapse that may simulate a bronchogenic carcinoma.87,107,108 It is most commonly associated with prior asbestos exposure but may develop as a result of tuberculosis or other causes of an exudative pleural reaction (e.g., after trauma or cardiac surgery).109 Rounded atelectasis usually occurs on the posterior surface of a lower lobe and is always associated with adjacent pleural thickening.107,108,110,111 Possible mechanisms include formation of adhesions over the pleural surface when the lung is atelectatic in the presence of an exudative pleural effusion, which prevents the lung

B

FIGURE 83-18 Posteroanterior (A) and lateral (B) chest radiographs in a patient with asbestos-related pleural plaques reveal numerous irregularly shaped opacities, with partly sharp and partly ill-defined borders, overlying the lungs. Pleural thickening (arrows) is seen medially, laterally, and posteriorly, and there are calcified plaques along the diaphragmatic pleura (arrowheads).

Ch083-F06861.indd 1020

1/21/2008 1:52:02 PM

Chapter 83 Pleura Imaging

A

C

from re-expanding when the effusion resolves; and pleuritis with localized fibrosis, which leads to contraction and folding of the visceral pleura with collapse of underlying lung parenchyma.112 Patients usually are asymptomatic, and the finding is often discovered incidentally on chest radiography or a CT examination performed for other reasons. Rounded atelectasis typically appears as a rounded or oval mass that abuts thickened pleura, is variable in size (usually 3-5 cm in diameter), and forms an acute angle with the chest wall (Fig. 83-20).107,108,111,113 The mass may contain air bronchograms or central lucency on CT as a result of slightly aerated atelectatic lung parenchyma.114 The adjacent lung may demonstrate compensatory hyperinflation, and there may be other signs of volume loss.112 The most characteristic

Ch083-F06861.indd 1021

1021

B

FIGURE 83-19 Posteroanterior (A) and lateral (B) chest radiographs reveal numerous irregularly shaped opacities characteristic of asbestosrelated pleural plaques, along with a focal opacity projecting in the left lower lobe (arrows), suspicious for a mass. C, CT image reveals a left lower lobe mass (arrow), which proved to be a lung cancer, and multiple calcified pleural plaques (arrowheads).

finding on CT, also described on MRI, is curved bronchi and vessels entering and obscuring the margin of the mass closest to the hilum, producing a so-called comet tail appearance.108,115,116 However, this feature is occasionally absent in rounded atelectasis, and it is uncommonly present with malignant or consolidative lesions.110 For equivocal cases in which the distinction between rounded atelectasis and a lung tumor is difficult, fluorodeoxyglucose positron-emission tomography (FDG-PET) may prove useful. A high specific uptake value would support performing a biopsy for diagnosis; low uptake would support close observation by serial follow-up CT scanning. Percutaneous needle biopsy for tissue evaluation may be required to help corroborate the diagnosis and should be considered in equiv-

1/21/2008 1:52:03 PM

1022

Section 4 Pleura

A

FIGURE 83-20 A-C, Cephalocaudal CT images show rounded atelectasis as a peripheral, posterior right lower lobe, mass-like opacity adjacent to focal pleural thickening with internal lucency and swirling margins, with vessels curving into and obscuring the hilar side of the mass.

ocal cases,108,112 although pathologic interpretation may be difficult.46 Occasionally, small subpleural, curvilinear, streaky opacities may be seen adjacent to chronic pleural thickening; they most likely represent an incomplete form of rounded atelectasis.

Pleural Tumors The features useful in localizing a focal lesion to the pleura include the following: 1. A lenticular or crescent shape 2. An obtuse or tapering angle at the chest wall interface 3. Margins that are partly sharp and partly ill-defined when viewed en face on radiographs, or sharp and well-defined margin when seen in profile on radiographs or on CT Extrapleural lesions may have a similar appearance, although an associated extrapleural soft tissue mass, bone destruction, or displaced extrapleural fat may be visible on

Ch083-F06861.indd 1022

B

C

CT and help determine the site of origin.117 Although lesions forming an acute angle with the chest wall are typically parenchymal in origin, larger or pedunculated pleural lesions may sufficiently indent the pulmonary parenchyma to simulate a parenchymal lesion. A less frequent exception occurs if a parenchymal lesion such as bronchogenic carcinoma infiltrates the pleura, creating an obtuse rather than an acute angle with the chest wall. Therefore, overlap in the appearance of extrapleural, pleural, and peripheral parenchymal lesions sometimes occurs. Imaging features of diffuse pleural disease favoring malignancy over a benign process include pleural thickening greater than 1 cm, nodularity, circumferential pleural involvement, and mediastinal pleural involvement (Leung et al, 1990).31,75-77 Definitive diagnosis usually requires cytologic/histologic analysis. The most common benign tumors involving the pleura are lipomas and localized fibrous tumors. Metastases are the most common form of malignancy involving the pleura. They may be of hematogenous origin, or they may form by direct exten-

1/21/2008 1:52:04 PM

Chapter 83 Pleura Imaging

sion, such as from bronchogenic carcinoma, invasive thymoma, or chest wall tumors. Primary pleural tumors, such as mesothelioma, account for fewer than 5% of malignant pleural neoplasms.118

Benign Tumors Lipoma Benign pleural and extrapleural lipomas are usually asymptomatic and incidental findings. On radiographs, a lipoma appears as a nonspecific mass of pleural or extrapleural origin, with a peripheral location, lenticular shape, and smooth borders that may be partly indistinct (Fig. 83-21). Some extend from the chest wall into the pleural space, protruding into the lung to simulate a peripheral pulmonary lesion on

A

B

C

FIGURE 83-21 A, Posteroanterior chest radiograph in a 31-year-old man with nondescript chest pain reveals a poorly defined opacity overlying the right lower lung. B, Lateral chest radiograph shows that the opacity is pleural-based posteriorly (arrows), with sharp borders, a lenticular shape, and obtuse angles with the chest wall, characteristic of a pleural or extrapleural mass. C, CT image confirms the obtuse margins of a pleural or extrapleural lesion and demonstrates the homogeneous fat attenuation of a lipoma.

Ch083-F06861.indd 1023

1023

radiography.119 CT allows a definitive diagnosis based on the characteristic fat attenuation, which is usually homogeneous (see Fig. 83-21).120 A few linear soft tissue strands or septations or tiny calcifications may be present. On MRI, lipomas are high in signal on T1-weighted images and intermediate on T2-weighted images, identical to subcutaneous fat, and their signal can be nulled on fat-suppression sequences. Although a well-differentiated liposarcoma also can contain macroscopic fat, this tumor is exceedingly rare and is typically more heterogeneous in appearance, with concomitant areas of soft tissue.121

Fibrous Tumors of the Pleura Fibrous tumors of the pleura account for fewer than 5% of all pleural neoplasms.122,123 Less common than malignant mesothelioma, fibrous tumors were known as benign mesothelioma in the past; the name was changed because they do not arise from the mesothelial cells but rather from the underlying mesenchymal connective tissue,124-126 and they may not behave in a benign fashion. In contrast to mesothelioma, fibrous pleural tumors are unrelated to asbestos exposure.127-129 Patients with large tumors may present with a cough, chest pain, or dyspnea. A small percentage of patients exhibit the classically associated clinical findings of hypertrophic pulmonary osteoarthropathy, clubbing, or symptomatic hypoglycemia118,122,127,129,130; tumor production of highmolecular-weight insulin-like growth factor II has been suggested as the cause of the latter.131 However, most fibrous tumors are asymptomatic and are discovered incidentally on chest radiographs.122,130 Chest radiographs usually show a mass with smooth, rounded margins contacting the pleura (Fig. 83-22). Almost all have an acute angle with the chest wall on at least one side, possibly because they are usually relatively large at the time of clinical presentation (Rosadode-Christenson et al, 2003).132 Because these tumors arise at the interface of the lung and other structures, they may simulate pulmonary masses such as peripheral bronchogenic carcinoma, anterior mediastinal masses such as thymoma, posterior mediastinal masses such as neurogenic tumors, or diaphragm abnormalities such as elevation or eventration (Fig. 83-23).133 Masses arising in a fissure may simulate pulmonary nodules on chest radiographs.118,130,134 The lesions can grow to be very large, almost filling a hemithorax. Most fibrous tumors (about 80%) arise from the visceral pleura.11 8,124,127,129,135 These tumors are usually sessile or lobulated, but some are attached to the pleural surface by a pedicle or stalk. This allows mobility so that they may change shape on inspiration and expiration, during fluoroscopy, or between CT examinations.122,130,136,137 Demonstration of a pedicle is pathognomonic and is highly suggestive of the benign variety of the tumor and a favorable prognosis.122,127,130 CT can be useful in determining the origin and etiology of fibrous pleural tumors, but the features are nonspecific (see Figs. 83-22 and 83-23). Findings that suggest the diagnosis include a solitary, sharply defined, sometimes lobulated, soft tissue, pleural-based mass without evidence of chest wall invasion; tapering margins may be noted if the lesion is in the

1/21/2008 1:52:05 PM

1024

Section 4 Pleura

B

A

L

FIGURE 83-22 A and B, Posteroanterior and lateral chest radiographs in an 82-year-old man with a localized fibrous tumor of the pleura demonstrate a well-circumscribed, pleuralbased mass laterally in the inferior right hemithorax (arrows). The superior aspect of the mass forms an obtuse angle with the chest wall. C, CT image shows a soft tissue mass with slight heterogeneous enhancement, compressing adjacent hyperenhancing right lower lobe (L).

fissure.122 Although smaller lesions typically make an obtuse angle with the chest wall, larger lesions usually form an acute angle.130,136 Smaller lesions typically appear homogeneous, whereas larger lesions may have low attenuation areas within them due to cystic necrosis or hemorrhage.128,130 Enhancement may be homogeneous or heterogeneous, equal to or greater than that of other soft tissues, but is not invariable (Rosadode-Christenson et al, 2003).128,130,132,136 A minority of fibrous pleural tumors have associated pleural effusions, which may be more common in the malignant variety.132 Small foci of calcification within fibrous pleural tumors have been seen in up to 26% of cases.124,132,136

Ch083-F06861.indd 1024

C

With MRI, localized fibrous tumors have predominantly low to intermediate but heterogeneous signal intensity on both T1- and T2-weighted images. Areas of high signal are more frequently present on T2-weighted images, possibly related to degeneration, necrosis, and hypercellular components (Rosado-de-Christenson et al, 2003).132,136,138 Enhancement with gadolinium is also heterogeneous and intense (Rosado-de-Christenson et al, 2003).132,138 Multiplanar MRI or multidetector CT with multiplanar reformatting may be helpful in localizing these masses, and in demonstrating their full extent and relationship to the diaphragm or mediastinal structures.

1/21/2008 1:52:06 PM

Chapter 83 Pleura Imaging

1025

A

B

C

Rarely, localized fibrous tumors can invade the chest wall and cause bone destruction,136 or they can manifest as multiple lesions.139 However, the radiologic appearance usually is not reliable for determining whether an individual lesion will behave in a benign or malignant manner. Obtaining a complete excision confers the best prognosis (Rosado-deChristenson et al, 2003).129,132,139 Recurrence can happen as late as 15 years after resection.130 Follow-up imaging is advised after resection to evaluate for recurrent disease, which also can be resected (Rosado-de-Christenson et al, 2003).132,140 Malignant tumors may rarely metastasize (Rosado-deChristenson et al, 2003).127,129,132

Ch083-F06861.indd 1025

FIGURE 83-23 Posteroanterior (A) and lateral (B) chest radiographs in a patient with a localized fibrous tumor of the pleura demonstrate a large, left apical mass with smooth, rounded borders forming acute angles with the chest wall. C, CT image shows heterogenous enhancement of the mass and a few small calcifications. The radiologic features are nonspecific, and the differential diagnosis includes neurogenic tumor and superior sulcus lung carcinoma.

Calcifying Fibrous Pseudotumor Calcifying fibrous pseudotumor of the pleura141 is a rare, benign lesion that differs from the localized fibrous tumor of the pleura. Like other pseudotumors,142 these lesions are thought to result from previous inflammation. The pleural variety contains extensive psammomatous calcification and may be solitary or multifocal. They appear as well-marginated pleural soft tissue masses, with visible calcification on CT.141 In contrast to localized fibrous tumors of the pleura, calcifying fibrous pseudotumors occur in children and young adults. Recurrence after resection is rare.

1/21/2008 1:52:07 PM

1026

Section 4 Pleura

Thoracic Splenosis Thoracic splenosis is the result of the displacement of ectopic splenic tissue into the thorax after a diaphragm injury.143,144 The splenic fragments become supplied by the pleural vessels and manifest as pleural nodules and masses on imaging studies. The radiographic and CT appearances (Fig. 83-24) are nonspecific, although the enhancement pattern is typical of splenic tissue. A history of appropriate traumatic injury and concomitant CT evidence of splenectomy or peritoneal splenosis support the diagnosis. Characterization of pleural nodules as splenic tissue can be accomplished with radiolabeled sulfur colloid or heat-damaged red blood cell scintigraphy.145-147

Malignant Tumors Pleural Metastases Metastases constitute the overwhelming majority of malignant neoplasms involving the pleura. Pleural metastases usually involve both the visceral and parietal pleural surfaces, and they almost always cause an associated effusion.148 Adenocarcinoma is the most likely cell type to metastasize to the pleura. Lung cancer, breast cancer, lymphoma, and ovarian cancer together account for more than three quarters of pleural metastases.149,150 Lung and breast cancer and invasive thymoma may invade the pleura by direct spread. Pleural metastasis also may occur as a result of hematogenous spread

A

FIGURE 83-24 A, Frontal chest radiograph in a patient with a remote history of traumatic rupture of the left hemidiaphragm shows multiple soft tissue masses along the periphery of the inferior left lung, present medially, along the left hemidiaphragm, and laterally. Note multiple healed left rib fractures. B, CT image through the inferior thorax reveals multiple nodular left pleural masses (arrows). C, CT image through the inferior sulci and upper abdomen shows additional left pleural masses (arrows) and surgical absence of the spleen. The history and imaging findings are most consistent with thoracic splenosis.

Ch083-F06861.indd 1026

B

C

1/21/2008 1:52:08 PM

Chapter 83 Pleura Imaging

A

1027

B

FIGURE 83-25 A, Frontal chest radiograph in a 45-year-old man with a thymoma reveals multiple lenticular masses along the pleural margins (arrows). The anterior mediastinal mass is not visible. B, CT image shows the primary anterior mediastinal tumor (arrow) and multiple pleural drop metastases (arrowheads), probably caused by direct seeding of tumor into the pleural space.

from tumor emboli lodged in distal branches of the pulmonary arteries.148 Pleural effusion is the first manifestation of pleural metastasis in most cases, though an effusion may be absent. Pleural metastases usually appear as relatively small, nodular lesions or lenticular masses that have obtuse margins with the chest wall (Fig. 83-25). Pleural implants also may occur as solitary lesions along the chest wall, mediastinum, diaphragm, or interlobar fissures.118 The soft tissue component often enhances on CT after contrast administration, allowing or improving differentiation from any adjacent nonenhancing pleural effusion. CT may reveal pleural-based nodules radiographically obscured by the pleural fluid (Fig. 83-26). As the disease progresses, nodularity and pleural thickening may encase the lung and extend into the fissures (see Fig. 83-15). Although inflammatory pleural diseases, such as infection or asbestos-related pleural disease, often produce pleural thickening, they rarely produce the nodular and irregular appearance of metastatic disease, and they rarely involve the mediastinal pleura. Pleural metastases may be difficult to distinguish from malignant mesothelioma; both may result in pleural effusions, isolated pleural nodules, diffuse or nodular thickening, and, in some cases, encasement of the lung.

Pleural Lymphoma Both Hodgkin’s and non-Hodgkin’s lymphoma can involve the pleura. Pleural lymphoma is seldom the solitary initial

Ch083-F06861.indd 1027

L

FIGURE 83-26 CT image in a 35-year-old woman with metastatic breast cancer and a large right pleural effusion allows distinction between multiple enhancing soft tissue lesions (arrowheads) along the parietal pleural surface and the lower-attenuation fluid. Note collapsed right lower lobe (L).

manifestation of the disease151,152; rather, it represents recurrence (Fig. 83-27) or occurs in addition to thymic or mediastinal nodal and sometimes pulmonary parenchymal disease. A paraspinal location is common. Lymphomatous involvement of the lymphatic channels and lymphoid aggregates found beneath the visceral pleura of the lung may manifest

1/21/2008 1:52:09 PM

1028

Section 4 Pleura

B

A

as subpleural nodules or plaques.152,153 Lymphoma also may involve the pleura by direct extension from the mediastinum154 or chest wall. In addition to nodules and effusions, imaging findings include areas of pleural thickening and diffuse pleural involvement indistinguishable from those of other pleural malignancies (Leung et al, 1990).75 Pleural involvement in patients with lymphoma may significantly affect radiation therapy planning, and unrecognized disease increases the risk of treatment failure.155

Malignant Mesothelioma Mesothelioma is a highly malignant, locally aggressive tumor of the pleura. Eighty percent of patients presenting with malignant mesothelioma have had occupational exposure to asbestos,156-159 a link first established in 1960.160 Other risk factors include radiation therapy, chronic inflammation (including tuberculosis and chronic empyema), genetic predisposition, and exposure to other nonasbestos mineral fibers (erionite, zeolite), organic chemicals (e.g., polyurethane, ethylene oxide, polysilicone), or simian virus 40.135,161,162 Although smoking is synergistically associated with asbestos in relation to lung cancer risk, it is not associated with the development of mesothelioma. Clinical symptoms are typically a late finding and include chest pain, dyspnea, cough, weakness, and weight loss.135,157,163,164 Unlike with localized fibrous pleural tumors, hypertrophic pulmonary osteoarthropathy and intermittent hypoglycemia are infrequent.135 Almost all patients with mesothelioma develop an ipsilateral pleural effusion.156,157,159,162 Effusions are variable in size but may be large and may obscure the pleural tumor on chest radiographs (Fig. 83-28).164-166 Nodular pleural thickening or discrete pleural masses may be visible in areas not obscured by pleural fluid.162,166 On CT, as with pleural metastases, the

Ch083-F06861.indd 1028

FIGURE 83-27 A, Frontal chest radiograph in a patient with recurrent Burkitt’s lymphoma shows lobulated pleural thickening around the right upper lobe extending to the apex. B, CT scan shows mildly enhancing pleural thickening and lobular masses along the margins of the right lung apex, including the mediastinal pleura. The radiologic appearance is indistinguishable from other forms of malignant pleural disease.

fluid typically has a lower attenuation than adjacent enhancing tumor. Because there is so much overlap in imaging features, it is often impossible to differentiate malignant mesothelioma from metastatic adenocarcinoma by CT or MRI. With mesothelioma there is often evidence of asbestos exposure, including pleural thickening and pleural plaques (Fig. 83-29),166-168 but concomitant interstitial lung disease (asbestosis) is relatively uncommon.169 Calcification of the tumor is extremely rare, although calcified pleural plaques may become incorporated into the tumor.170 Both CT and MRI provide greater detail than radiography on the presence and extent of the pleural masses and pleural effusion.79,164,166,171,172 These cross-sectional imaging methods usually demonstrate that the neoplasm is more extensive than appreciated on conventional radiographs.164,171 The disease is often advanced at the time of diagnosis, with circumferential involvement of the lung producing ipsilateral volume loss and fixation of the mediastinum (Fig. 83-30).104,157,162,166,167,169,170 This may limit shifting of the mediastinum toward the contralateral side if a large pleural effusion is present. Both the visceral and parietal pleura are involved, and extension into the fissures and along the mediastinal pleural surface is common.167,168 As the tumor progresses, it may invade the lung, pericardium, heart, esophagus, mediastinum, ipsilateral chest wall, and, occasionally, the contralateral chest.170,173-176 It may penetrate the diaphragm and involve the peritoneal cavity or retroperitoneum.169,170 Loss of normal fat planes, extension into mediastinal fat, and encasement of more than half of the circumference of a structure (e.g., great vessels, heart, trachea, esophagus) are features that suggest invasion on either CT or MRI.170 Mediastinal lymph node and distant metastases are possible.87,177 However, the accuracy of CT for identifying lymph node metastases is limited because size is the sole criterion for evaluation but is not highly specific. The

1/21/2008 1:52:11 PM

Chapter 83 Pleura Imaging

A

1029

B

FIGURE 83-28 A, Frontal chest radiograph in a patient with mesothelioma shows presentation as a moderate right pleural effusion. B, CT scan through the right inferior sulcus shows the pleural effusion and slightly nodular thickening and enhancement of the pleura (arrowheads), representing the tumor.

E

A

B

FIGURE 83-29 A, CT image in a patient with mesothelioma shows a lobulated pleural mass (arrow), representing a portion of the tumor, along with multiple calcified pleural plaques (arrowheads) as evidence of previous asbestos exposure. B, More caudal CT image demonstrates nodular enhancing pleural masses invading the pericardium (arrows), loculated pleural effusion (E) surrounded by smooth, enhancing pleural thickening, and calcified pleural plaque (arrowheads).

extent of disease in early chest wall involvement may be underestimated by CT.178,179 Death is usually caused by the progression of local disease. For mesothelioma, CT is recommended as the first tomographic imaging study. Multiplanar MRI may add value in assessing chest wall, diaphragm, and mediastinal involvement in very select patients with mesothelioma for whom resection is being considered.172,178 Multidetector CT with multiplanar reformatting may further improve the CT depiction of tumor

Ch083-F06861.indd 1029

extent in these regions, although it has not been extensively studied.87,170 An international staging system based on TNM (tumor extent, nodal metastasis, and distant metastases) features was developed in 1995 by the International Mesothelioma Interest Group.180,181 The “T” descriptor depends on the extent rather than the size of the tumor. T1 through T3 tumors are potentially resectable, although they may be locally advanced; T4 tumors are technically unresectable because of diffuse chest

1/21/2008 1:52:12 PM

1030

Section 4 Pleura

A

B

C

D

FIGURE 83-30 A, Frontal chest radiograph in a patient with mesothelioma shows diffuse, smooth and lobular pleural thickening encasing the left lung. Note diminished left lung volume. B and C, CT scans through the upper and lower thorax confirm near-complete encasement of the left lung by tumor, with extensive involvement of the mediastinal surface (and probably the pericardium) and extension into the major fissure (arrows). D, FDG-PET scan reveals a rind of increased uptake by the tumor around the margins of the left lung.

wall, peritoneal, contralateral pleural, mediastinal organ, spine, or internal pericardial surface involvement. The “N” and “M” descriptors are the same as those used in the International Lung Cancer Staging System.182 As with lung cancer staging, discrepancies between imaging and surgical staging of mesothelioma exist, particularly in the evaluation of chest wall, diaphragmatic, mediastinal, and nodal involvement. However, this TNM staging system is potentially applicable to CT or MRI, which have similar accuracy in staging (Heelan et al, 1999),183 and could be used to stratify patients in trials that do not include surgical intervention.180,181 Malignant mesothelioma has a very poor prognosis. It is virtually always fatal, with median survival times after diag-

Ch083-F06861.indd 1030

nosis usually less than 1 year, and with fewer than 10% of patients surviving longer than 3 years after the onset of symptoms.135,156,158,165,166,181 Surgical resection via pleurectomy or extrapleural pneumonectomy, radiation therapy, and chemotherapy all are used for treatment of malignant mesothelioma, but with little impact on survival.156,157,163,184 Imaging criteria for unresectability include tumor encasement of the diaphragm; invasion of extrapleural soft tissue or fat; invasion, displacement, or separation of ribs by tumor; and invasion or encasement of essential mediastinal structures.135,178 However, false-negative and false-positive imaging findings do occur, and mild pleural spreading of mesothelioma may be impossible to detect by CT or MRI.162,178 Both CT and MRI may

1/21/2008 1:52:13 PM

Chapter 83 Pleura Imaging

be used to detect recurrence after surgical management and to monitor response to chemotherapy.

Other Primary Pleural Neoplasms Other primary pleural malignancies are extremely rare. The pleura has been reported as an atypical site of origin for Castleman’s disease,185 post-transplantation lymphoproliferative disorder,186 angiosarcoma,187 liposarcoma,121,188 synovial sarcoma,189,190 and epithelioid hemangioendothelioma, the latter having an aggressive clinical course with widespread metastasis when arising in the pleura.191 Soft tissue sarcomas developing after radiation therapy or chemotherapy also may arise from the pleura.192 With the possible exception of fat in a well-differentiated liposarcoma, there are no specific imaging findings that allow distinction from other primary or secondary pleural malignancies.

PLEURODESIS Sclerosis and fusion of the pleural surfaces, or pleurodesis, can be effective therapy for a malignant pleural effusion, unresolving or recurrent pneumothorax, chylothorax, or idiopathic or other recurrent pleural effusion. Pleurodesis may be accomplished by instillation of sclerosing agents or by mechanical pleural abrasion. Chemical sclerosing agents such as doxycycline or bleomycin have long been used, but talc appears to be more effective.193-195 With the increased popularity of talc, possible complications of empyema, reexpansion edema, and acute respiratory distress syndrome have been recognized and may be dose dependent.193-196 Systemic absorption of intrapleural talc has been identified and may be a causative factor in the development of acute respiratory distress syndrome.193,196 Pleural fluid loculations of variable size are common after pleurodesis, with multiple air-fluid levels often seen. As fluid is resorbed, a variable degree and distribution of pleural thickening and nodularity is typical. The high density of talc instilled into the pleural space resembles pleural calcification (see Fig. 83-17); the appearance is clustered and nodular with talc slurry and seen as fine linear deposits with talc poudrage.197

POSTPNEUMONECTOMY SPACE After pneumonectomy, there is volume loss of the ipsilateral hemithorax, with mediastinal shift and elevation of the hemidiaphragm. Serial radiographs in the immediate postpneumonectomy period show gradual gas resorption and fluid filling of the pneumonectomy space as a rising air-fluid level across the thoracic cavity over weeks to months.198 Smaller, loculated air-fluid collections that gradually opacify completely also may be seen. A decrease in height of the air-fluid level or development of an air-fluid level in a previously opacified thorax heralds the development of a bronchopleural fistula, so the fluid level should be monitored closely in the postoperative period.199 Some of the fluid in the postpneumonectomy space is eventually resorbed, and the space is gradually reduced in size.200 However, in only about 20% of patients does it become completely obliterated and occupied by relocated mediastinal structures.

Ch083-F06861.indd 1031

1031

The complete opacification of the hemithorax makes evaluation of the postpneumonectomy space and ipsilateral mediastinum extremely difficult with conventional radiography. Recurrent tumor or infection can be detected radiographically only when it is so gross that, for example, mediastinal shift occurs or an air-fluid level develops in the postpneumonectomy space. CT and MRI are more sensitive for detecting recurrent neoplasm or another complication at an earlier stage.201-203 Recurrence of bronchogenic carcinoma most commonly occurs near the bronchial stump or in the mediastinal lymph nodes. Sometimes, pleural metastases can be identified as soft tissue density nodules projecting into the lowerattenuation postpneumonectomy space. Palliative radiation therapy may be targeted to the recurrent tumor. CT also may be of value in diagnosing infection in the postpneumonectomy space, which may occur soon or years after surgery.201,204 Straightening or convex expansion of the concave mediastinal border or development of an air-fluid level may occur with a complicating empyema, with or without shifting of the mediastinum toward the contralateral side. Other features identifiable on CT include an increase in the baseline postoperative thickening, enhancement of the residual parietal pleura, and empyema necessitatis.201 The mediastinal shift that occurs after a pneumonectomy may be so extreme in children or thin adults that the distal trachea and remaining left main bronchus are partially compressed between the aorta and left pulmonary artery, resulting in dyspnea or recurrent lung infections (postpneumonectomy syndrome) (Fig. 83-31).205 Although most cases occur after right pneumonectomy, or after left pneumonectomy in patients with a right aortic arch,206 the syndrome can also occur after left pneumonectomy in patients with a left arch.207 Effective management is obtained by placement of a space-occupying prosthesis, such as a breast prosthesis or tissue expander, into the pleural cavity to return the mediastinum to its normal position; because bronchomalacia may be associated with the syndrome, insertion of a bronchial stent may be required.207

COMMENTS AND CONTROVERSIES Although pleural disorders are common in the practice of thoracic surgery, their assessment can be problematic. Clinical history, physical examination, and imaging of the pleural space represent first-line investigation. The diagnosis of pneumothorax is best confirmed by erect chest radiograph, although expiratory films on occasion are useful to demonstrate a small pneumothorax that may have been missed on a standard film. Quantification of the size of a pneumothorax could potentially be useful for making a therapeutic decision; however, the methods used for this quantification vary greatly and lack standardization. In patients with advanced emphysema and secondary pneumothorax, standard chest radiographs may be difficult to interpret because of the increased radiolucency of the peripheral lung. In such cases, CT scanning is useful to confirm the diagnosis and to distinguish between a large bulla and a pneumothorax. Imaging is the mainstay of the evaluation of patients with pleural effusions. CT scanning not only facilitates the detection of small amounts of pleural fluid, but it is also helpful to detect loculated

1/21/2008 1:52:14 PM

1032

Section 4 Pleura

P

A

B

FIGURE 83-31 A, CT image in a 62-year-old woman with progressive cough and shortness of breath after right pneumonectomy demonstrates marked mediastinal shift into the right pneumonectomy space, with narrowing of the left main bronchus (arrow) between the pulmonary artery and descending aorta. B, CT image obtained after insertion of a saline breast prosthesis (P) into the right pneumonectomy space shows return of the mediastinum to the midline and increased diameter of the left main bronchus (arrow).

collections or to distinguish pleural lesions from parenchymal processes. In the hands of a dedicated radiologist, ultrasonography is complementary to CT in detecting small amounts of pleural fluid (3-5 mL). It is also useful to characterize the effusion and to guide thoracentesis. Imaging modalities are also helpful for diagnosis and staging of empyemas. Indeed, the classic image of an empyema is that of a posteriorly located, inverted D-shaped density (pregnant lady sign) seen on the lateral film. CT scanning is useful to ascertain the underlying lung and to demonstrate the presence of loculations, the thickness of the pleura, and the presence or absence of a trapped lung. In recent years, ultrasonography has become the best technique to demonstrate loculations. There is no valid radiologic finding that allows one to differentiate between a chylothorax and pleural effusions due to other causes. Bipedal lymphangiograms and radionuclide imaging with technetium 99m–antimony sulfide colloid can demonstrate obstruction to lymph flow, but they are limited in localizing the site of chyle leakage. In the investigation of a pleural disorder, it is important to have a methodical and structured approach, reduce the costs of investigation, and minimize morbidity. One must begin with simple methods, such as careful history taking, standard chest radiographs, CT scanning, and ultrasound-guided thoracentesis, rather than proceeding immediately with more invasive techniques such as thoracoscopy. J. D.

KEY REFERENCES Heelan RT, Rusch VW, Begg CB, et al: Staging of malignant pleural mesothelioma: Comparison of CT and MR imaging. AJR Am J Roentgenol 172:1039-1047, 1999. ■ This report from the prospective staging of 95 patients found that MRI was slightly better at identifying chest wall and diaphragm invasion; because this does not affect

Ch083-F06861.indd 1032

surgical treatment, and CT and MRI were otherwise equivalent for determining tumor extent, the authors recommend using CT because of its lower cost. Leung AN, Müller NL, Miller RR: CT in differential diagnosis of diffuse pleural disease. AJR Am J Roentgenol 154:487-492, 1990. ■ The authors evaluated the CT scans of 74 consecutive patients with diffuse pleural disease to determine the specificity for malignancy of numerous CT signs. Although the sensitivity was low (36%-56%), the presence of circumferential thickening, nodular thickening, parietal pleural thickening greater than 1 cm, and mediastinal pleural involvement were highly specific (88%-100%) for malignant pleural disease (metastases, mesothelioma, or lymphoma). Roach HD, Davies GJ, Attanoos R, et al: Asbestos: When the dust settles—An imaging review of asbestos-related disease. Radiographics 22:S167-S184, 2002. ■ This article reviews the imaging findings related to all of the pleural and pulmonary diseases that result from asbestos exposure. Rosado-de-Christenson ML, Abbott GF, McAdams HP, et al: From the archives of the AFIP: Localized fibrous tumor of the pleura. Radiographics 23:759-783, 2003. ■ This article describes the imaging features of 82 localized fibrous tumors of the pleura, both benign and malignant. The authors present a comprehensive analysis that includes clinical presentation, radiography, CT, MRI, and gross and microscopic pathology. Stark DD, Federle MP, Goodman PC, et al: Differentiating lung abscess and empyema: Radiography and computed tomography. AJR Am J Roentgenol 141:163-167, 1983. ■ This study established the high accuracy of CT for distinguishing lung abscess and empyema and described the utility of the split pleura sign and compression of adjacent lung for making the diagnosis of empyema. Tocino IM, Miller MH, Fairfax WR: Distribution of pneumothorax in the supine and semirecumbent critically ill adult. AJR Am J Roentgenol 144:901-905, 1985. ■ In this study, 30% of 112 pneumothoraces present on supine or semi-erect radiographs were missed. The authors emphasize the importance of being familiar with the appearances of basilar pneumothorax in the severe trauma and intensive care settings.

1/21/2008 1:52:14 PM

chapter

84

DIAGNOSTIC PROCEDURES FOR PLEURAL DISEASES Brian E. Louie Eric Vallières

Key Points ■ Diagnosis of pleural diseases is based on a comprehensive history

and physical examination. ■ Simple, minimally invasive techniques such as thoracentesis can

provide fluid, cells, and tissue for analysis, which lead to diagnosis in the majority of cases. ■ VATS or pleuroscopy can aid in diagnosis when less invasive techniques fail to yield a diagnosis. More invasive procedures such as thoracotomy are rarely required.

Diseases of the pleural space are common in a thoracic surgical practice, and although their management may seem simple, their diagnosis often presents a challenge. In patients presenting with pleural problems, a thorough history and physical examination remain the basis for the physician’s initial assessment and differential diagnosis. Radiography is helpful in providing clues to a diagnosis by distinguishing between pleural fluid and a mass and by allowing evaluation of the adjacent lung and pleura. A definitive diagnosis, however, usually requires a diagnostic procedure to provide fluid, cells, or tissue for analysis and microscopic review. This chapter reviews the range of pleural diseases in relation to the diagnostic procedures, their indications, and techniques. Although a wide range of diseases can involve the pleura and the pleural space, these can be narrowed down to two forms: pleural fluid and pleural mass or masses (Table 84-1). Pleural effusions are the most common disturbances of the pleural space. Effusions may be secondary to increased capillary permeability (inflammation, infection, tumor implants); decreased oncotic pressure (liver failure, malnutrition); increased hydrostatic pressure (congestive heart failure, renal failure); increased intrapleural pressure (atelectasis); or decreased lymphatic drainage (carcinomatosis, tumor compression, radiation). Often, the effusion results from a combination of mechanisms. As a result, these processes produce fluid that may be serous, sanguineous, chylous, or purulent. Less commonly, a solid process or tumor may involve the pleural surfaces. Masses in the pleural lining are predominantly malignant. Of these, secondary malignancies are more common, most frequently from lung, breast, ovarian, or gastrointestinal primaries. Primary malignancies of the pleura and mesothelioma are seen with increasing frequency, and most cases are related to a remote asbestos exposure. Benign lesions of the pleural surface may be pleural plaques or solitary fibrous tumors.

HISTORY AND PHYSICAL EXAMINATION A thorough history and physical examination is the initial diagnostic procedure in understanding a pleural problem. The past history may identify clues that lead to a list of potential causes for the underlying pleural pathology. Additional historical factors focus on a previous or current history of cancer and its associated treatments. Known diseases associated with pleural effusions include heart failure, end-stage renal disease with or without dialysis, cirrhosis, and global hypoalbuminemia. A recent history of upper respiratory tract infection may uncover an undiagnosed pneumonic infection complicated by a parapneumonic effusion or frank empyema. Patients presenting with deep venous thrombosis and pulmonary embolism may have recently traveled or suffered lower extremity trauma or surgery. Exposures to asbestos and tuberculosis (TB) are associated with pleural processes that may require additional workup. Dyspnea at rest or on exertion is the most common symptom of patients with pleural diseases. The degree of shortness of breath may relate to the extent of the pleural process or underlying related pulmonary issues but may also reflect a combination of the pleural process, the patient’s preexisting comorbidities, and the rapidity with which the problem developed. Massive but slowly progressive accumulation of fluid in an otherwise healthy person with normal underlying lung function can result in minimal symptoms. Pain is another common symptom. It may be pleuritic from pleural irritation, somatic from direct invasion of the chest wall, or more of a pressure-type discomfort from the fluid accumulation. Diaphragmatic irritation may cause shoulder pain. Finally, patients may complain of a cough, usually dry, often relieved by evacuation of the pleural space. The physical examination adds little to the diagnostic aspect of management except when palpable adenopathy is identified or a warm, red, fluctuant chest or flank mass is identified with empyema necessitatis (Fig. 84-1). Wound or skin nodules found in recent biopsy sites raise the suspicion for mesothelioma, a malignancy that has a strong tendency to grow in needle tracts and incisions. Much of the physical examination is accomplished with thoughts of planning a diagnostic procedure. Percussion of the chest wall is used to identify a relative area of dullness on the affected side. The affected side will also have an absence of breath sounds, and the trachea may be shifted away from the affected side with a large tension hydrothorax or toward the affected side if there is significant ipsilateral loss of lung volume associated with the pleural process. Radiographs are used to confirm the clinical impression, refine the differential diagnosis, and plan 1033

Ch084-F06861.indd 1033

1/21/2008 1:53:10 PM

1034

Section 4 Pleura

Necissitatis

A

B

Thoracotomy scar

Mild redness with bulge

FIGURE 84-1 Empyema necessitatis. Thirty years after right pneumonectomy, this patient presented with new and increasing right chest wall and arm erythematous mass. A, Computed tomography scan. B, Clinical picture.

TABLE 84-1 Diseases of the Pleura and Pleural Space Fluid Effusion Congestive heart failure Hepatic failure Renal failure Hypoalbuminemia Hemothorax Chylothorax Empyema and parapneumonic effusion Bacterial Fungal Tuberculous Malignant effusion Mass Mesothelioma Metastatic malignancy Solitary fibrous tumor Pleural plaques

a diagnostic procedure. Further information on the radiology of the pleural space is contained in Chapter 83.

DIAGNOSTIC PROCEDURES The goal in any diagnostic pleural procedure is to obtain fluid, cells, and/or tissue that may lead to a diagnosis using the least invasive and safest method. Often, thoracentesis, which is the least invasive procedure, provides a diagnosis. The addition of pleural biopsy, either closed or thoracoscopic, increases the success of diagnosis. In 2006, open thoracotomy is rarely needed to obtain a diagnosis. Bronchoscopy and mediastinoscopy can be used selectively as adjunct procedures.

Ch084-F06861.indd 1034

Thoracentesis Bowditch1 reported on three cases of so-called paracentesis thoracis as a diagnostic and therapeutic procedure in 1852. The technique was described to him and first used in the United States by Wyman of Cambridge. He described the procedure as a puncturing of the thoracic cavity by means of an exploring trocar and removal of the accumulated fluid or air by suction catheter. A bleeding diathesis is the only absolute contraindication to thoracentesis. Relative contraindications include an uncooperative patient and a small amount of fluid.2 Ultimately, the goal of a diagnostic thoracentesis is to provide fluid, cells, and tissue for analysis.

Technique of Thoracentesis Krausz3 described thoracentesis with the patient seated with arms resting comfortably on a table and leaning forward slightly. After clinical and radiographic confirmation of the patient’s effusion, an appropriate site in the midscapular line on the affected side is selected, opposite to the level of the clinically identified diaphragm on the contralateral side. Alternatively, the site may be localized by bedside thoracic ultrasonography. Under sterile conditions, local analgesia is instituted; a needle or angiocatheter is advanced perpendicular to the skin at the superior edge of the rib. Negative pressure is applied with suction as the needle is advanced. Loss of resistance and return of fluid confirm access to the effusion. The soft angiocatheter is advanced over the needle, and the needle is withdrawn. The angiocatheter is temporarily occluded with a finger while a three-way stopcock is connected to the angiocatheter on one end and to drainage tubing with a volume regulator on the other. The volume regulator controls the rate of evacuation, avoiding a rapid evacuation of fluid. We prefer either gravity drainage into a collection

1/21/2008 1:53:10 PM

Chapter 84 Diagnostic Procedures for Pleural Diseases

bag or drainage into vacuumed sterile bottles to allow for ease of transportation of the specimen to the laboratory. This technique has been modified by the use of central venous catheters,4 Tuohy loss-of-resistance needles,5 or intravenous tubing and drip bottles. Patients may experience distress and severe coughing spells if too much fluid is drained too fast. This can be avoided by controlling the rate at which the effusion is drained. To avoid the rare but potentially lethal complication of re-expansion pulmonary edema (RPE), seen after rapid evacuation of chronic large pleural collections, we recommend limiting the amount of fluid drained to a volume of about 1 L per session (see later discussion). For smaller effusions, we prefer to evacuate the majority of the fluid rather than to limit the thoracentesis to small volumes used solely for diagnostic purposes. If the patient develops a cough, chest tightness, or discomfort, the procedure needs to be terminated. With this approach, the complications are minimal and the occurrence of RPE is eliminated. After the fluid has stopped draining or if the patient develops persistent cough and discomfort, the drainage tubing is clamped and removed. Gentle pressure is applied to the site for several minutes to prevent bleeding. We routinely obtain a postprocedure chest radiograph. The presence of a pneumothorax after thoracentesis does not always equate to the presence of a lung injury and air leak. Often, particularly if a chronic effusion was tapped, pneumothorax reflects failure of the lung to re-expand. A follow-up radiograph obtained a few hours later may help differentiate these two scenarios. The entire volume of fluid is sent for analysis, usually to four different laboratories. For undiagnosed effusions, we request the following tests: ■ ■ ■ ■

Biochemistry for lactate dehydrogenase (LDH), protein, pH, and glucose Microbiology for Gram staining and cultures (including fungal and TB cultures) Hematology for cell counts and differential Cytology

Additional tests may be requested, depending on the character of the fluid and the patient’s clinical presentation; these may include measurements of amylase, lipase, cholesterol, and triglycerides.

Results Overall, thoracentesis provides clinically useful information in 92% of pleural effusions if pleural fluid analysis is combined with the clinical presentation (Collins and Sahn, 1987).6 Empyema, chylothorax, and hemothorax are easily identified with simple tests. Distinguishing between other nonmalignant and malignant effusions requires cytologic and biochemical analysis to determine the nature of the effusion. For malignant pleural disease, the diagnostic results of thoracentesis vary with the underlying cancer. Pleural fluid analysis has historically established a diagnosis in 50% to 87% of cases. Prakash and Reiman7 showed that cytology analysis is superior to pleural biopsy alone. Newer technologies, such as immunocytochemistry,8 tumor marker identification, fluores-

Ch084-F06861.indd 1035

1035

cence in situ hybridization (FISH),9 and reverse transcriptase– polymerase chain reaction (RT-PCR),10 have improved the pathologist’s ability to determine the origin of the cells. The rate of success of pleural fluid cytologic analysis depends on several factors: 1. Tumor type 2. Specimen examination 3. Number of specimens submitted It has long been known that certain tumors are more likely to be detected in the pleural space. Cytology is more effective in patients with metastatic adenocarcinomas of breast, ovary, colon, and lung origins; it is less effective in patients with lymphomas, squamous cell carcinomas, and mesotheliomas.11 Central squamous cell carcinomas of the lung have a lower likelihood of positive pleural fluid,12,13 because the effusion seen with these cancers is paramalignant and relates to bronchial or lymphatic obstruction rather than direct pleural involvement. Historically, malignant mesotheliomas were very difficult to differentiate from metastatic adenocarcinomas on the basis of pleural fluid cytology alone. Today, immunohistochemical evaluation of the cells allows better diagnostic differentiation. Still, immunohistochemical analysis of pleural biopsy specimens is often needed, and occasionally electron microscopy is required, to confirm a diagnosis of mesothelioma.14 The method by which the pleural fluid is processed and prepared is often overlooked in its ability to be diagnostic. In general, effusive samples are prepared by one of two methods, the cell block or the smear technique, after centrifugation of the specimen. Separately, these methods have equivalent results. But, when cell blocks and smears were compared with smear cytology alone in diagnosing malignant effusions, the use of both methods doubled the identification of malignant cells.15 Logic would dictate that, when using the concentrating techniques to process effusive samples, sending larger volumes of fluid should provide greater yield. This, however, has not been supported by retrospective studies,16 and the optimal amount of fluid required for retrieval and subsequent diagnosis remains unproven. Currently, amounts from as little as 10 mL17 to several hundred milliliters2 have been reported as having a 56% to 60% success in diagnosing a malignant effusion, yet many cytology departments request more volume for analysis. The number of specimens examined also improves the diagnostic accuracy of cytology studies. Pleural fluid cytology is diagnostic in only 60% of patients with one specimen. This rate is improved by 27% with a second specimen and by another 5% with a third specimen (Light, 1999).18,19 Repeated examination after therapeutic thoracentesis has the potential advantage of providing newly shed and better preserved cells for analysis.20 Biochemical pleural fluid analysis is paramount in determining the exact cause of the effusion. Pleural effusions seen annually in the United States are predominantly secondary to congestive heart failure and pneumonia (Table 84-2). Light’s criteria (Box 84-1) can be used to separate transudates from exudates (Romero-Candeira et al, 2002).21 If the clinical suspicion suggests a transudative effusion but Light’s

1/21/2008 1:53:12 PM

1036

Section 4 Pleura

TABLE 84-2 Annual Incidence of Pleural Effusions in the United States Cause

Incidence

Congestive heart failure

500,000

Pneumonia

300,000

Malignant disease

200,000

Pulmonary embolism

150,000

Viral illness

100,000

Post heart surgery

60,000

Cirrhosis with ascites

50,000

Gastrointestinal disease

25,000

Collagen vascular disease

6,000

Tuberculosis

3,000

From Light RW: Update on Pleural Diseases. Presentation to the Washington Thoracic Society. September 27, 2005. Seattle, Washington.

Box 84-1 Light’s Criteria for Exudative Effusion An exudative effusion meets one or more of the following criteria (a transudate meets none): Pleural fluid-to-serum protein ratio 0.5 Pleural fluid-to-serum lactate dehydrogenase (LDH) ratio 0.6 Pleural fluid LDH >2/3 of upper normal limit for serum

the same technique was used with ultrasound guidance, the rate of pneumothorax was 0%. RPE is a rare but significant and potentially lethal complication that is usually unilateral, at times becomes bilateral, and develops within 12 to 24 hours after drainage. Two clinical factors are thought to predispose to the occurrence of this problem: 1. The chronicity (>3 days) of the lung collapse, whether it is secondary to an effusion or an undrained pneumothorax 2. The rapidity with which re-expansion is allowed to occur26,27 The pathophysiology of RPE is believed to be an increased capillary leakiness resulting from the mechanical stress applied to the re-expanding lung and also possibly an ischemiareperfusion–type injury. The treatment of RPE is supportive, and at times intubation and mechanical ventilation are required. If the patient survives beyond the first 48 hours, full recovery is the norm. Prevention is really the key. Even though most patients can withstand rapid evacuation of large effusions without sequelae, it is probably prudent to adopt a universal approach to these large effusions and avoid one-time large-volume thoracentesis. One approach is to limit the rapidity with which the effusions are drained, to limit the volume drained in one continuous period (e.g., stop draining for a period of 1-2 hours with every liter of fluid evacuated), and to terminate the procedure if the patient develops chest discomfort, distress, or a cough.26

Percutaneous Pleural Biopsy criteria are weakly positive in favor of an exudate (protein ratio <0.65, LDH ratio <0.9, or LDH less than the upper limit of normal), a serum-to-pleural fluid protein gradient of greater than 3.1 g/dL confirms the presence of a transudate (Romero-Candeira et al, 2002).21 The presence of a pleural fluid N-terminal, pro-brain natriuretic peptide (BNP) level elevated to greater than 1500 pg/mL is diagnostic of a transudate secondary to congestive heart failure (Porcel et al, 2004).22 The diagnosis of pleural TB is often made with pleural biopsy, but there are pleural fluid markers such as adenosine deaminase (ADA), γ-interferon, and PCR that can be used to diagnose TB pleuritis and thereby avoid the need for pleural biopsy.23 Of these, ADA is most accessible and levels greater than 45 IU/L are almost always related to TB (Light, 1999).19 High levels can also be seen in patients with empyema or rheumatoid arthritis, however. Patients with levels less than 40 IU/L usually have a nontuberculous effusion.

Complications Complications from thoracentesis are generally thought to be uncommon. However, three studies of thoracentesis performed at university teaching hospitals using needles or needle catheters reported major complication rates of 14% in 1986,24 20% in 1987 (Collins and Sahn, 1987),6 and 19% in 1990.25 The majority of these were pneumothoraces. When

Ch084-F06861.indd 1036

Percutaneous or closed pleural biopsy was introduced by De Francis and colleagues28 in 1955 using a Vim-Silverman needle to diagnose pleural TB. This was followed by the development of similar needles by Cope29 and Abrams.30 The designs of these needles are similar, with a needle inside a trocar and a side hole to purchase the parietal pleura. Each needle has proved to be successful at obtaining parietal pleura without inadvertently damaging the underlying lung. Currently, VimSilverman, Cope, and Abrams needles are used with equal success that is more dependent on the operator than on the type of needle. Pleural biopsies are indicated in patients with exudative pleural effusions that remain undiagnosed after biochemical and cytologic analysis. Frequently, biopsies are used to diagnose pleural TB, mesothelioma, and other tumors of the pleura.

Technique Although the technique for closed pleural biopsy depends on the needle selected, the general approach is the same. Often, but not always, the pleural biopsy is done in tandem with thoracentesis. After local anesthesia is provided, a small nick is made in the skin over the selected site. The cannula and needle are inserted until pleural fluid is aspirated. After the needle is withdrawn slightly, the trocar is advanced into the thoracic cavity, thus exposing the notched part of the trocar.

1/21/2008 1:53:12 PM

Chapter 84 Diagnostic Procedures for Pleural Diseases

While the needle is being withdrawn, gentle angled or lateral pressure is applied on the trocar to catch the parietal pleura in the notch. When the parietal pleura is engaged, a slight resistance is felt. The needle is readvanced and twisted to perform a cutting motion and excise a 2-mm portion of pleura and underlying muscle. Gentle skin pressure is applied to tamponade any bleeding. Pleural fluid may be aspirated before or after the pleural biopsy, remembering that a small amount of pleural fluid may provide a small safety cushion between the underlying lung and the needle.

Results The rate of diagnosis with closed pleural biopsies varies with the disease. In cases of malignancy, closed pleural biopsies yield a diagnosis in approximately 60% (range, 38%-67%) of patients.2 It is important to emphasize that a nondiagnostic or normal pleural biopsy does not rule out malignancy. Nance and colleagues31 reviewed 385 undiagnosed effusions and compared cytologic examination and pleural biopsy. Pleural fluid cytology was superior to blind pleural biopsy in making a diagnosis of malignancy in a ratio of nearly 2:1. The addition of closed pleural biopsies to pleural fluid analysis in the diagnosis of malignancy provided only a slight benefit over cytologic examination alone. Pleural TB is the best process to evaluate by closed pleural biopsy; yields of up to 90% have been reported (Poe et al, 1984).32 In pleural TB, this technique is clearly superior to cytologic examination (Poe et al, 1984).32-34 This high diagnostic return simply reflects the fact that pleural TB is a diffuse process that affects the entire pleural surface. Moreover, when pleural specimens are cultured, the diagnostic yield for pleural TB is enhanced.33 Occasionally, patients with rheumatoid arthritis, systemic lupus erythematosus, or sarcoidosis have granulomatous pleuritis on pleural biopsies. Negative culture for TB reliably rules out TB pleuritis in these patients (Poe et al, 1984).32 Pleural-based and juxtapleural tumors can successfully be diagnosed with percutaneous biopsies. In recent years, imageguided percutaneous biopsies have replaced the blind bedside approach and carry a much better diagnostic accuracy. In one series, ultrasound-guided biopsies of 91 pleural and juxtapleural lesions of 2 cm or more in size were performed with virtually no complications.35 Diagnostic specimens were obtained in 85% of cases, and 100% of patients with mesothelioma were accurately diagnosed. Although this technique is accurate to make a diagnosis of mesothelioma, identification of the specific subtype is limited by the size of the specimen and usually requires multiple pleural samples.14 In a randomized trial, Maskell and colleagues36 compared blind Abrams needle biopsy to Abrams needle biopsy under CT guidance in patients with unilateral, undiagnosed, exudative pleural effusions who had previously undergone at least one negative cytologic examination. CT-guided biopsy had a sensitivity of 87%, compared with 47% for blind Abrams needle biopsy. The benefits of image-guided biopsy are obviously the possibilities of targeting the biopsy and of accessing narrow areas such as the costophrenic recesses, where malignancy is preferential.37

Ch084-F06861.indd 1037

1037

Complications Complications of closed needle pleural biopsy are infrequent when the procedure is performed by or supervised by a welltrained specialist (Poe et al, 1984).32 Overall complication rates are less than 10% (Poe et al, 1984).31,32 Pneumothorax is the most common complication and accounted for the majority of complications in all reported series. Hemothorax and subcutaneous hematoma were also reported. In the series of 414 consecutive biopsies reported by Nance and associates in 1991, the liver was biopsied twice and the kidney once. In this series, there were two deaths, both related to massive hemothorax.31

Recent Innovations Two innovative variations using the tools of closed pleural biopsy have been reported. Emand and Rezaian38 reported on a novel approach using a cytologic brush introduced into the pleural cavity via the cannula of a pleural biopsy needle. With fluoroscopic guidance, a cytology brush is advanced into the chest through a Cope needle. The brush is then moved back and forth three times to obtain specimens. Closed pleural brushing was compared with pleural fluid cytology and closed pleural biopsy in 43 patients with suspected malignant effusion. Brushing was positive for malignant cells in 91%, 67%, and 58% of cases, respectively. Complications were more frequent with brushing and included hypotension, arrhythmia, cough, and pain. There were no pneumothoraces in the brushing group. In a similar fashion, Uthaman and colleagues39 advanced an 8 Fr Bioptome via a 9 Fr sheath placed into the thoracic cavity by the Seldinger technique. Using fluoroscopy, the Bioptome can be advanced and curled back on itself to biopsy multiple sites. They reported an average of 14 Bioptome biopsies per patient in 28 patients undergoing the procedure. Sixty-eight percent of biopsies yielded a diagnosis of either tuberculous pleuritis (n = 18) or malignancy (n = 1); 9 patients had nonspecific pleuritis as an initial diagnosis, and on follow-up two of these turned out to be malignant. Complications included cough, pain, and subcutaneous emphysema.

Pleuroscopy and Thoracoscopy Thoracoscopy was first described in 1910 by Professor H. C. Jacobaeus in Sweden.40 Over the next 15 years, he used the thorakoscope to make two entry points to access and lyse pleural adhesions in the creation of artificial pneumothorax for the treatment of TB. The term pleuroscopy was coined by Fourestier and Duret in their report on the diagnosis of pleural malignancies using pleuroscopy.41 After a brief period of disuse, Boutin and colleagues repopularized the use of diagnostic thoracoscopy in 1981, reporting on its use in 1000 cases of chronic pleurisy.42 Innumerable instruments have been used to perform thoracoscopy over the years. They range from flexible and rigid bronchoscopes to simple or video-assisted mediastinoscopes. Currently, most thoracic surgeons have adapted the laparoscopy equipment for use in the thoracic cavity. We prefer to use the term pleuroscopy for single-port exploration of the pleural space and reserve the term thoracoscopy to denote

1/21/2008 1:53:12 PM

1038

Section 4 Pleura

the use of multiple ports and video equipment to visualize the thoracic cavity. Direct visualization of the pleural space for the purposes of biopsy for diagnosis is required in about 20% of patients with pleural effusions who have not had a diagnosis made after cytologic examination and closed pleural needle biopsy. Indications for diagnostic thoracoscopy are listed in Table 84-3.43,44

Technique of Pleuroscopy Pleuroscopy is usually performed through the intercostal space with the patient under local, regional, or general anesthesia. Most patients undergoing pleuroscopy are positioned supine, with a roll under the operative side to raise that side of the thoracic cavity. The ipsilateral arm can be supported on an arm board, above the head or dangled across the chest. Our current preference is to use the mediastinoscope with or without video with the patient under general anesthesia (Fig. 84-2). An alternative is to use a single-port

TABLE 84-3 Indications for Diagnostic Pleuroscopy or Thoracoscopy Unexplained pleural effusion Pleural mass biopsy Thoracic malignancy and pleural effusion Mesothelioma Unexplained pericardial effusion

working thoracoscope. Depending on our goals, a single- or double-lumen endotracheal tube is used. Because lung collapse is not mandatory for this technique, it is ideal for patients who are too compromised to tolerate double-lumen intubation and single-lung ventilation but require exploration and drainage of a complicated pleural collection. If a singlelumen endotracheal tube is used, ventilation may need to be held periodically to allow for adequate visualization above the costophrenic recesses and other difficult angles. Unless there is a definite target site identified by imaging, our incision usually corresponds to the fifth or sixth interspace in the anterior axillary line, along the line of an eventual posterolateral thoracotomy. After complete drainage of the pleural fluid, the pleural surfaces are examined for abnormalities. With the videomediastinoscope, the entire thoracic cavity can be examined through a single port. There are potential advantages of this single-port approach in the evaluation of patients who potentially may have mesothelioma and may be considered for extrapleural pneumonectomy as part of future treatment plans. First, each port site is at risk for tumor implantation and growth. Second, every area where the parietal pleura has been breached is prone to technical difficulties at the time of extrapleural dissection. For the same technical reasons, it is probably best to site the single port along the potential incision line for extrapleural pneumonectomy, thus facilitating resection of the tract and access to the extrapleural plane. At the completion of the procedure, a chest tube can be guided into place through the scope and the incision closed tightly around the secured drain.

Pneumothorax Traumatic hemithorax

Technique of Thoracoscopy

Foreign body—intrapleural

Standard thoracoscopy is performed with the patient in full lateral decubitus position, with the bed flexed to drop the ipsilateral hip to a point parallel to or below the chest (Fig. 84-3). A double-lumen endotracheal tube is always used. We prefer to have two lenses available: a 5-mm and a 10-mm 30-degree scope. Unless there is a targeted area or specific area of interest, we often use our potential chest tube site as

To facilitate unusual thoracotomy incision To evaluate mediastinal lymph nodes (stations 5 or 6) Adapted from Deslauriers J, Carrier G, Vallieres E: Diagnostic procedures for pleural diseases. In Pearson FG et al (eds): Thoracic Surgery. Philadelphia, Churchill-Livingstone, 2002, pp 1140-55.

A

B

Pleural metastasis

FIGURE 84-2 A and B, Using the mediastinoscope for pleuroscopy to identify a pleural metastasis.

Ch084-F06861.indd 1038

1/21/2008 1:53:13 PM

Chapter 84 Diagnostic Procedures for Pleural Diseases

the port of entry, anteriorly. One or two additional ports, as necessary, are placed after complete drainage of the pleural fluid and initial assessment of the thoracic cavity. Over the years, we have moved our port sites anteriorly as much as possible: the intercostal spaces are wider in the front, and there is less chest wall discomfort that way during recovery. At either pleuroscopy or thoracoscopy, finger palpation of the adjacent parietal pleura is first completed and then a thorough examination of the thoracic cavity is performed, with particular attention paid to the paravertebral gutter and the costophrenic recesses. These dependent areas often harbor pathologic changes.45 Any abnormal areas are biopsied

X

X X

FIGURE 84-3 Right lateral decubitus position with patient flexed for video-thoracoscopy. X denotes potential port site placements.

1039

and sent to the pathology and microbiology laboratories, asking for bacterial cultures, TB testing, and fungal studies. Frozen section evaluations are recommended so that adequate samples can be taken and the yield of the procedure increased. In addition, confirmation of a malignancy by frozen section allows completion of the procedure with a talc poudrage in appropriate situations. To minimize the risks of postoperative air leaks, biopsies of the visceral pleura need to be restricted to situations in which no other sites are likely to return a diagnosis. If no abnormalities are felt or seen, blind parietal pleural biopsies need always be performed in the areas of greatest risk, such as the gravity-dependent paravertebral gutter and costophrenic angles. The normal pleural space reveals only a trace of fluid on exploration and is lined with a translucent membrane that readily allows for identification of all anatomic structures (Fig. 84-4A). In patients with pleural disease, the most common finding is that of a nonspecific pleuritis where there is increased vascularization, redness, and edema (see Fig. 844B). The translucency is lost, and the pleura is thickened. With increasing chronicity, the pleura becomes whitish, opaque, and thicker. Benign pleural plaques and granulomas are readily identifiable. Metastatic lesions appear as small nodules, masses, or polypoid lesions (Fig. 84-5). They can also appear as whitish plaques across the lower half of the thoracic cavity. Occasionally, a gelatinous morass remains after drainage of pleural fluid. This so-called jellyfish46 can be processed by frozen section or permanent paraffin section to yield a malignant diagnosis. The appearance of mesothelioma varies with the stage at presentation. Biopsies of normal pleura or benign-looking pleural plaques, particularly over the diaphragm or in the

3rd rib

B

A

Sympathetic chain

FIGURE 84-4 A, Normal pleura. Note the translucency with the sympathetic chain and vessels. B, Nonspecific pleuritis. Note the erythema and loss of translucency.

Ch084-F06861.indd 1039

1/21/2008 1:53:14 PM

1040

Section 4 Pleura

Tumor

TABLE 84-4 Complications of Thoracoscopy Bleeding (entry site, adhesions, biopsy site) Prolonged air leak Subcutaneous emphysema Empyema Cardiac arrhythmia Entry site implant or metastasis Persistent pain

FIGURE 84-5 Metastatic pleural disease from an ovarian carcinoma.

a collective review of 1500 thoracoscopies performed at different centers, a diagnostic accuracy of more than 90% and an associated morbidity rate of less than 3%. In 1995, Harris and coworkers44 reviewed 182 patients undergoing thoracoscopy at The Cleveland Clinic. They estimated that thoracoscopy directly influenced treatment in 85% of the patients. Complications were seen in 20% of patients, and the operative mortality rate was 0.5%. In experienced hands, diagnostic thoracoscopy is a safe procedure with few complications. Common complications are listed in Table 84-4. Empyemas are related to prolonged placement of chest tubes and are usually associated with incomplete re-expansion of the lung and persistent fluid drainage. Early chest tube removal in these situations, despite failure of re-expansion and persistent drainage, minimizes the risk for infection. A problematic complication is that of port site recurrence, particularly with mesothelioma. Boutin and colleagues showed that a single-dose prophylactic radiation treatment to the port site eliminates this complication completely.48

Recent Advances A recent report by Mohamed and associates49 described the use of pleural space lavage with 300 mL of normal saline in 50 patients with exudative pleural effusions as a complement to thoracoscopy after evacuation of the pleural space. The diagnostic accuracy of the lavage returns was 22% better than that of fluid cytology alone and almost as good as that of direct thoracoscopic biopsies. Although this technique is described as an adjunct to thoracoscopy, it could potentially be adapted as an adjunct to bedside diagnostic thoracentesis via an angiocatheter or central venous line. FIGURE 84-6 Mesothelioma.

OTHER PROCEDURES Open Thoracotomy

costophrenic angles, have often returned a diagnosis of malignancy. More often, the pleura is studded with small, friable, vascular lesions and thick viscous fluid. In late presentations, the tumor mass is whitish and friable (Fig. 84-6).

Results Despite the assertion that direct examination of the pleural space has utility, there is a surprising dearth of literature on the topic. Two series have provided a good evaluation of the procedure. In 1991, Menzies and Charbonneau47 reported, in

Ch084-F06861.indd 1040

Open thoracotomy is rarely indicated in the evaluation of the pleura and pleural space diseases in the current environment of video-assisted thoracoscopy.50 Statistically, the odds of establishing a diagnosis at thoracotomy after a complete evaluation including a thorough thoracoscopic examination (with blind biopsies, if no abnormality is seen) are quite low. In 1981, Ryan and colleagues51 reported on the outcomes of 51 patients who underwent open thoracotomy for undiagnosed effusion: 61% had resolution of their effusion, 25% were diagnosed with malignancy between 12 days and 6 years after

1/21/2008 1:53:18 PM

Chapter 84 Diagnostic Procedures for Pleural Diseases

thoracotomy, and 13% remained undiagnosed. Close followup of such patients, with repeat evaluation and thoracoscopy if needed, is probably the best approach, compared with submitting them to a thoracotomy. Occasionally, thoracotomy is required for diagnosis in the presence of abnormal pleura and a completely fused and obliterated pleural space that renders thoracoscopy impossible. If this is the case, a small incision with or without resection of a short segment of rib, potentially targeted with CT correlation, is usually all that is required to obtain parietal pleural tissue.

Bronchoscopy The role of bronchoscopy in the evaluation of undiagnosed pleural disease is controversial. In a group of 28 patients with an undiagnosed effusion but no mass or lobar atelectasis on chest radiography, bronchoscopy was diagnostic in only 4% of cases.52 In one report, Chang and Perng53 reviewed 140 patients with undiagnosed pleural effusions. Patients were grouped according to their chest radiographic findings, and all underwent bronchoscopy. In patients who had additional radiographic findings beyond that of a pleural effusion, bronchoscopy was definitely more likely to be helpful. Another report, by Williams and Thomas,54 described a diagnostic rate for bronchoscopy of 1 in 7 for patients with an undiagnosed pleural effusion and no other radiographic evidence of a mass lesion or atelectasis. Therefore, in the presence of an undiagnosed effusion and chest radiographic abnormalities other than the effusion, we believe that bronchoscopy is indicated. In the absence of additional radiographic abnormalities, bronchoscopy contributes very little, but it is simple to obtain at the time of pleuroscopy or thoracoscopy and adds very little risk and morbidity.

Mediastinoscopy There is no role for routine mediastinoscopy in the evaluation of pleural disease. However, if associated mediastinal adenopathy is identified by imaging, this outpatient procedure may potentially yield a diagnosis and avoid the need for pleuroscopy/thoracoscopy, particularly in situations in which pleural fluid evacuation is not required and attempts at chemical pleurodesis are not planned.

SUMMARY If a patient presents with a pleural abnormality on clinical examination that is confirmed by plain chest radiographs, the clinician has a variety of diagnostic techniques to establish a diagnosis. History and physical examination are the cornerstones in the evaluation of a patient with pleural abnormalities. Thoracentesis with biochemical fluid analysis and repeated cytologic fluid examination yields a diagnosis in most cases. The addition of closed pleural biopsies, particu-

Ch084-F06861.indd 1041

1041

larly for tuberculous pleuritis, and directed pleural biopsies via pleuroscopy or thoracoscopy can increase the diagnostic yield to almost 100%. Recent innovations such as pleural lavage and closed pleural brushing show great promise but require confirmatory studies before widespread use. A carefully structured diagnostic plan based on the patient’s history can provide a diagnosis with minimal cost and patient morbidity.

COMMENTS AND CONTROVERSIES One of the most important aspects of the investigation of pleural effusions is assessment of the clinical setting in which the effusion has occurred. A patient who develops an effusion in conjunction with a pneumonia, for instance, is likely to have a parapneumonic effusion. Likewise, a patient with known congestive heart failure who develops a right-sided effusion or a woman who develops a new pleural effusion after having been treated for breast cancer is likely to have a diagnosis related to the clinical history. If the cause of the effusion is not clinically obvious, thoracentesis is the next step, and the procedure is usually performed under ultrasound guidance. It is diagnostic in 50% to 60% of cases, with higher yields for processes such as empyema (turbid or purulent fluid), hemothorax (bloody fluid), and chylothorax (clear milky fluid). With the advent of video-thoracoscopic examinations, percutaneous pleural biopsies with the Abrams or Cope needles are seldom indicated or done. Thoracoscopy allows direct access to 90% to 100% of the pleural surfaces, and in experienced hands it has a diagnostic accuracy of almost 100% while being associated with minimal morbidity. Very seldom, open thoracotomy is indicated if the pleural space is obliterated or if one wishes to proceed immediately with a surgical procedure such as decortication or pulmonary resection. While investigating a pleural effusion, it is most important to have a methodical approach, which will not only reduce the costs of investigation but also minimize patient morbidity. J. D.

KEY REFERENCES Collins TR, Sahn SA: Thoracocentesis: Clinical value, complications, technical problems, and patient experience. Chest 91:817-822, 1987. Light RW: Useful tests on the pleural fluid in the management of patients with pleural effusions. Curr Opin Pulm Med 5:245-249, 1999. Poe RH, Israel RH, Utell MJ, et al: Sensitivity, specificity, and predictive values of closed pleural biopsy. Arch Intern Med 144:325-328, 1984. Porcel JM, Vives M, Cao G, et al: Measurement of pro-brain natriuretic peptide in pleural fluid for the diagnosis of pleural effusions due to heart failure. Am J Med 116:417-420, 2004. Romero-Candeira S, Hernandez L, Romero-Brufao S, et al: Is it meaningful to use biochemical parameters to discriminate between transudative and exudative pleural effusions? Chest 122:1524-1529, 2002.

1/21/2008 1:53:20 PM

chapter

85

PLEURAL EFFUSION: BENIGN AND MALIGNANT Valerie W. Rusch

Key Points ■ Pleural effusions are a common clinical problem. ■ Transudative effusions should be distinguished from exudative

effusions because of differences in etiology and treatment. diagnosis may require thoracoscopy and pleural biopsy. ■ Transudative effusions respond to management of underlying etiology. ■ Exudative effusions, especially if cancer-related, are usually managed by pleurodesis. ■ Definitive

Pleural effusions are a common and significant clinical problem. During the past 2 decades, several advances have made possible a more systematic approach to their management, and research, based primarily on animal models, has provided a better understanding of their pathophysiology.1-3 Characterization of the biochemical characteristics of pleural fluid has improved our ability to diagnose the cause of an effusion by using the relatively noninvasive approach of thoracentesis (Light, 1983).4,5 The advent of computed tomography (CT) in the late 1970s also dramatically improved the noninvasive evaluation of pleural disease. Thoracoscopy, which was always a popular procedure in Europe (Deslauriers and Lacquet, 1990),6,7 is now widely practiced in North America for the diagnosis and treatment of pleural disease because of the development of video-assisted technology in the early 1990s. Patients who previously were subjected to multiple thoracenteses and percutaneous pleural biopsies are now offered thoracoscopy if the initial noninvasive evaluation is not diagnostic. Finally, pleurodesis for malignant pleural effusions, which was often performed in a highly individualized manner, has been evaluated in well-designed prospective trials. A better understanding of pathophysiology, better imaging, faster and more accurate methods of diagnosis, and the careful assessment of therapy have improved the diagnosis and treatment of pleural effusions. This chapter covers the current approach to the management of pleural effusions, focusing on malignant pleural effusions, which are the most common problem seen by surgeons.

PATHOPHYSIOLOGY The anatomy and physiology of the pleural space were described in detail in Chapter 82. Pleural effusions develop because of a disturbance in the mechanisms that normally

move 5 to 10 L of fluid across the pleural space every 24 hours and resorb it, leaving only 5 to 20 mL present at any time.3,8 Increased capillary permeability (inflammation or tumor implants), increased hydrostatic pressure (congestive heart failure), decreased oncotic pressure (hypoalbuminemia), increased negative intrapleural pressure (atelectasis), and decreased lymphatic drainage (lymphatic obstruction by a tumor or radiation-induced fibrosis) can all cause a pleural effusion. In patients with cancer, several different mechanisms often contribute to the formation of an effusion (Table 85-1). These mechanisms may relate directly to the presence of the tumor (e.g., obstruction of lymphatic channels), may reflect underlying medical problems (e.g., congestive heart failure, hypoalbuminemia), or may be a combination of both.

CLINICAL PRESENTATION AND DIAGNOSIS Small pleural effusions are asymptomatic. Larger pleural effusions cause dyspnea, cough, and chest discomfort. Dullness to percussion and diminished breath sounds are present on the physical examination. The clinical diagnosis is confirmed by chest radiography. Small pleural effusions cause blunting of the costophrenic angle. If the pleural space is free, larger effusions produce the classic picture of a fluid level with a meniscus sign (Fig. 85-1). A lateral decubitus radiograph confirms freely flowing fluid (Fig. 85-2). Massive effusions cause a complete opacification of the hemithorax. Rarely, they manifest as a tension hydrothorax, with a mediastinal shift, respiratory distress, and hemodynamic instability. Loculated pleural effusions are harder to diagnose on a standard chest radiograph. They manifest as opacities of varying size and shape that can be hard to distinguish from a pulmonary parenchymal process such as atelectasis or dense consolidation (Fig. 85-3). Lateral decubitus radiographs do not show layering of the fluid. Ultrasonography detects a loculated fluid collection and can help determine the proper site for thoracentesis, but the most useful examination under these circumstances is a CT scan. This helps direct therapy by outlining the size and location of fluid collections and by distinguishing underlying parenchymal disease from pleural fluid and thickening (Fig. 85-4). Thin-section CT, with images at intervals of 2 to 5 mm, is more accurate in identifying pleural metastases than standard CT because it detects very small pleural nodules.9 The clinical setting in which an effusion occurs influences the approach to diagnosis and therapy. A patient who develops a small effusion in conjunction with pneumonia but is improving while receiving antibiotics is likely to have a para-

1042

Ch085-F06861.indd 1042

1/21/2008 1:54:07 PM

Chapter 85 Pleural Effusion: Benign and Malignant

1043

TABLE 85-1 Interaction Among Pathogenetic Mechanisms and Contributing Factors Favoring the Accumulation of Pleural Fluid

Pathogenetic Mechanisms

Impaired Lymphatic Drainage

Increased Pleural Permeability Pressure

Increased Capillary Pressure

Increased Venous Pressure

Pleural implants

+

+

+

−

Lymphatic metastases Mediastinal nodes Lymphangitis

+ +

+ +

− −

− −

Tumor cell suspension

+

+

+

−

Contributing syndromes Superior vena cava syndrome Congestive heart failure Pericarditis or effusion Infection Mediastinal irradiation Ascites Hypoalbuminemia

+ + + + + + −

+ + + + + + +

− − − + − − −

+ + − − − + −

+, contributes; −, does not contribute. Data from Roth JA, Ruckkdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, WB Saunders, 1989, p 596; and Harper GR: Pleural effusions in cancer. Clin Cancer Briefs 1:1, 1979.

FIGURE 85-1 Posteroanterior chest radiograph of a patient with widely disseminated lung cancer and a left pleural effusion. The retrocardiac region is opacified, and there is a fluid level with a typical meniscus sign (arrow).

pneumonic effusion and could be treated expectantly. The same would be true of a patient with known cirrhosis and ascites who has a small pleural effusion. These effusions are known to occur in the absence of primary intrathoracic disease and are related to the presence of peritoneopleural communication.10 In contrast, a woman who develops a new pleural effusion several years after treatment for a nodepositive breast cancer merits intensive investigation. Before

Ch085-F06861.indd 1043

FIGURE 85-2 The lateral decubitus chest radiograph of the patient shown in Figure 85-1 shows that the pleural effusion layers easily and is, therefore, free flowing.

any invasive workup is initiated, the patient with a pleural effusion needs to have a careful history and physical examination so that all subsequent evaluation is directed toward the clinically likely causes (Box 85-1). Knowledge of the most common causes of pleural effusions is also helpful in defining etiology. The four most common causes of pleural effusions in North America are congestive

1/21/2008 1:54:07 PM

1044

Section 4 Pleura

FIGURE 85-3 A, Loculated right pleural effusion in a patient who underwent decortication of the right lung for empyema. There is a hazy density in the right midlung field with a fluid level at its upper margin (arrow). B, CT scan of the patient shown in A, taken in the prone position, demonstrates a loculated fluid collection with an air-fluid level (arrow). C, Posteroanterior chest radiograph of the same patient after percutaneous catheter drainage of the fluid collection shows clearing of the hazy density that was seen on the initial chest radiograph.

heart failure, bacterial pneumonia, malignancy, and pulmonary emboli. Viral pneumonia, cirrhosis with ascites, gastrointestinal disease, collagen-vascular disease, and tuberculosis are less common causes.4 The most common causes of malignant pleural effusion are lung cancer, breast cancer, and lymphoma. However, the frequency of the type of cancer responsible for a pleural effusion depends on the patient’s gender. Lung cancer, lymphoma, and gastrointestinal cancer are the three most common causes in men; breast cancer, gynecologic cancer, and lung cancer are the most common ones in women (Tables 85-2, 85-3, and 85-4). If the diagnosis is not clinically obvious, a thoracentesis needs to be performed and the character of the fluid noted. Bloody fluid occurs with pulmonary emboli, malignancy, or trauma. Clear milky fluid is strongly suggestive of a chylothorax; turbid or purulent fluid is indicative of an empyema. Send the pleural fluid for cytologic examination, culture, and cell count. Obtain simultaneous determinations of pleural fluid and serum glucose, protein, and lactic dehydrogenase

Ch085-F06861.indd 1044

levels. Effusions are classified as exudative or transudative based on the levels of protein and lactic dehydrogenase (LDH). An effusion is considered an exudate if the pleural fluid-to-serum ratio of protein is greater than 0.5, the LDH ratio is greater than 0.6, or the absolute pleural LDH level is greater than two thirds of the normal upper limit for serum.5 The most common cause of transudative effusions is congestive heart failure. There are many causes of exudative effusions, but the most common ones are malignancy, infection, and pulmonary emboli. The pleural fluid concentration of glucose is also helpful because a level less than 60 mg/dL is seen only in four conditions: malignancy, tuberculous pleuritis, parapneumonic effusions, and rheumatoid pleural effusion.11-13 Therefore, a patient who has a bloody exudative effusion with a low glucose level is likely to have a malignancy. Several other biochemical tests are helpful in specific clinical situations. The amylase level is elevated in three conditions: esophageal perforation, pancreatitis, and malignant effusions. Obtain a triglyceride level if a chylothorax is sus-

1/21/2008 1:54:08 PM

Chapter 85 Pleural Effusion: Benign and Malignant

1045

FIGURE 85-4 A, Another example of a loculated pleural effusion that is extremely difficult to distinguish from underlying parenchymal disease in a patient who had severe radiation-induced fibrosis. The posteroanterior chest radiograph shows a hazy density in the midlateral aspect of the left lung with an underlying air bronchogram. B, CT scan of the same patient at the level of the carina shows dense consolidation of the left upper lobe with an air bronchogram. There is no pleural fluid at this level. C, CT scan of the same patient at the level of the midheart shows a large free-flowing right pleural effusion and a multiloculated left pleural effusion (arrows). This combination of parenchymal disease and multiloculated pleural effusion accounts for the abnormalities seen on the plain chest radiograph in A. It would be hard to interpret the chest radiograph and make a determination of whether drainage of the pleural effusion would be appropriate without the aid of the CT scan.

pected. A level greater than 110 mg/dL is considered diagnostic. Pleural fluid pH and glucose levels have been used in the evaluation of parapneumonic effusions. Light reported that a pH less than 7.00 in conjunction with a glucose level less than 60 mg/dL indicates that a parapneumonic effusion will progress to a frank empyema.4 However, other authors have not found the pH and glucose levels to be as reliable in the management of parapneumonic effusions. Complement, rheumatoid factor, and antinuclear antibody levels are often elevated in collagen-vascular disease and need to be obtained if this is being considered in the differential diagnosis.4 Other tests have been used to determine the cause of pleural effusions and particularly to ascertain whether an effusion is malignant. The level of carcinoembryonic antigen (CEA) has been the most widely used pleural fluid marker.

Ch085-F06861.indd 1045

Levels of this antigen higher than 5.0 ng/mL are a specific but relatively insensitive marker of malignancy.14-17 Creatine kinase isoenzyme BB, adenosine deaminase, and galactosyltransferase have been reported to distinguish benign from malignant effusions in small series of patients.18-20 Various immunohistochemical stains have been used to identify malignant cells and to distinguish them from reactive mesothelial cells.21 Flow cytometry is relatively inaccurate in diagnosing malignancy because cytologically positive pleural effusions do not always contain aneuploid cells.22 Cytogenetic techniques can diagnose malignant pleural effusions, but they are labor intensive and do not consistently add to the standard cytologic examination.23-26 Uptake of technetium 99m phosphate in malignant pleural effusions has been anecdotally reported in patients undergoing bone scans to search for

1/21/2008 1:54:09 PM

1046

Section 4 Pleura

Box 85-1 Differential Diagnosis of Pleural Effusions I. Transudative pleural effusions A. Congestive heart failure B. Cirrhosis C. Nephrotic syndrome D. Peritoneal dialysis E. Glomerulonephritis F. Myxedema G. Pulmonary emboli H. Sarcoidosis II. Exudative pleural effusions A. Neoplastic diseases 1. Metastatic disease 2. Mesothelioma B. Infectious diseases 1. Bacterial infections 2. Tuberculosis 3. Fungal infections 4. Parasitic infections 5. Viral infections C. Pulmonary embolization D. Gastrointestinal disease 1. Pancreatitis 2. Subphrenic abscess 3. Intrahepatic abscess 4. Esophageal perforation 5. Diaphragmatic hernia E. Collagen-vascular diseases 1. Rheumatoid pleuritis 2. Systemic lupus erythematosus

3. Drug-induced lupus 4. Immunoblastic lymphadenopathy 5. Sjögren’s syndrome 6. Familial Mediterranean fever 7. Wegener’s granulomatosis F. Drug-induced pleural disease 1. Nitrofurantoin 2. Dantrolene 3. Methysergide 4. Bromocriptine 5. Procarbazine 6. Methotrexate 7. Practolol G. Miscellaneous diseases and conditions 1. Asbestos exposure 2. Postpericardiectomy or postmyocardial infarction syndrome 3. Meigs’ syndrome 4. Yellow nail syndrome 5. Sarcoidosis 6. Uremia 7. Trapped lung 8. Radiation therapy 9. Electrical burns 10. Urinary tract obstruction 11. Iatrogenic injury H. Hemothorax I. Chylothorax

From Light RW: Pleural Diseases. Philadelphia, Lea & Febiger, 1983, p 62, with permission.

TABLE 85-2 Primary Organ Site or Neoplasm Type in Male Patients With Malignant Pleural Effusions

TABLE 85-3 Primary Organ Site or Neoplasm Type in Female Patients With Malignant Pleural Effusions

Primary Site or Tumor Type

No. Patients

Lung

140

49.1

Breast

70

37.4

Lymphoma/leukemia

60

21.1

Female genital tract

38

20.3

Gastrointestinal tract

20

7.0

Lung

28

15.0

Genitourinary tract

17

6.0

Lymphoma/leukemia

14

8.0

Melanoma

%

Primary Site or Tumor Type

No. Patients

%

4

1.4

Gastrointestinal tract

8

4.3

Miscellaneous less common tumors

10

3.5

Melanoma

6

3.2

Primary site unknown

31

10.9

Urinary tract

2

1.1

285

100.0

Total

From Johnson WW: The malignant pleural effusion: A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 56:905, 1985.

Miscellaneous less common tumors Primary site unknown Total

3

1.6

17

9.1

187

100.0

From Johnson WW: The malignant pleural effusion: A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 56:905, 1985.

Ch085-F06861.indd 1046

1/21/2008 1:54:10 PM

Chapter 85 Pleural Effusion: Benign and Malignant

1047

TABLE 85-4 Primary Tumor Site in Patients With Malignant Pleural Effusion Primary Tumor Site

Salyer141 (n = 95)

Chernow142 (n = 96)

Johnston143 (n = 472)

Sears144 (n = 592)

Hsu145 (n = 785)

Total (%)

Lung

42

32

168

112

410

764 (37.5)

Breast

11

20

70

141

101

343 (16.8)

Lymphoma

11

−

75

92

56

234 (11.5)

Gastrointestinal tract

−

13

28

32

68

141 (6.9)

Genitourinary tract

−

13

57

51

70

191 (9.4)

Other

14

5

26

88

15

148 (7.3)

Unknown primary

17

13

48

76

65

219 (10.7)

From Antunes G, et al: BTS Guidelines for the management of malignant pleural effusions. Thorax 58(Suppl II):ii29-ii38, 2003. Reproduced with permission from the BMJ Publishing Group.

osseous metastases.27,28 Although this is not likely to be useful as a routine diagnostic test, remember its clinical significance as an incidental finding. More recently, molecular biologic techniques have been applied to the diagnosis of pleural effusions. These include the development of a sensitive and specific assay, based on the reverse transcriptase–polymerase chain reaction (RTPCR), to detect epithelial tumor cells that potentially increase the diagnosis of malignancy in cytologically negative effusions.29 The detection of specific molecular alterations, such as KRAS mutations, may also enhance the diagnosis of malignancy in pleural effusions.30 Telomerase activity is frequently observed in malignant effusions but also is occasionally seen in some inflammatory conditions such as tuberculosis.31,32 The precise benefit of molecular techniques in the diagnosis of pleural effusion requires further investigation. The long list of tests that can be performed on pleural effusions to pinpoint a cause are of academic rather than practical interest. The character of the fluid (e.g., bloody versus serous), a determination of whether it is an exudate or a transudate, measurement of the glucose level, and culture and cytologic examination are the most important initial tests.33-35 Additional biochemical or molecular analyses are used selectively, based on the clinical setting. If the examination of the pleural fluid is nondiagnostic, consider a percutaneous or thoracoscopic pleural biopsy. A percutaneous pleural biopsy alone yields a diagnosis of malignancy in 40% to 69% of cases. When pleural fluid cytologic findings and pleural biopsy results are combined, the yield increases to 80% to 90%.36-39 Pleural biopsy can also diagnose some benign diseases, such as tuberculous effusion or amyloidosis, in situations in which the pleural fluid analysis is uninformative.40-42 Patients whose effusions remain undiagnosed after a thoracentesis with or without percutaneous pleural biopsy undergo a CT scan of the chest and abdomen, a bronchoscopy, and a thoracoscopy. If the effusion is large, do the CT scan after the fluid has been evacuated so that the lung can be imaged when it is fully expanded. The CT detects underlying pulmonary parenchymal and abdominal disease that may not be evident otherwise. Bronchoscopy diagnoses endo-

Ch085-F06861.indd 1047

bronchial tumors (primary or metastatic) that may be responsible for an effusion due to postobstructive atelectasis. Thoracoscopy is performed to obtain a tissue diagnosis by directed pleural biopsy and to do a pleurodesis, usually by talc poudrage. Several large series have reported a diagnostic accuracy of 80% to 100% for thoracoscopy, depending on the reasons for which thoracoscopy was performed. In almost all patients, it is the definitive way of diagnosing a malignancy involving the pleura.43-51 The exceptions are patients in whom thoracoscopy cannot be performed because of a fused pleural space. The development of video-assisted thoracoscopy (VATS) significantly expanded the diagnostic potential of this technique by making lung and lymph node biopsies possible.52,53 In the past, patients often underwent multiple thoracenteses and percutaneous pleural biopsies in an effort to avoid a thoracotomy for diagnosis. Thoracoscopy, widely used in Europe for a long time, was a largely forgotten procedure in North America for the diagnosis of pleural disease.54 With the popularization of VATS, patients with undiagnosed pleural effusions are now referred sooner for this minimally invasive and highly diagnostic procedure.

MANAGEMENT General Principles Transudative pleural effusions are managed by treatment of the underlying disease and usually resolve after it has been controlled.4,55 Occasionally, additive intervention is required, either because the effusion is symptomatic or because the underlying medical problem is refractory to maximal medical treatment. For example, tube thoracostomy might be necessary to drain a large effusion secondary to a pulmonary embolus, or a pleurodesis or pleuroperitoneal shunt might be required to control a symptomatic effusion in a patient with medically refractory ascites. Some exudative effusions also resolve after treatment of the underlying disease. This is true of effusions caused by gastrointestinal disease, drugs, collagen vascular disease, and nonbacterial infections.4,6,42 Some exudative effusions caused by malignancy are also best managed in this manner if the

1/21/2008 1:54:10 PM

1048

Section 4 Pleura

tumor is highly responsive to chemotherapy or irradiation. The classic example is an effusion or chylothorax caused by a lymphoma, which usually resolves quickly after chemotherapy or irradiation alleviates the lymphatic obstruction.35 Effusions caused by solid tumors, such as breast cancer and ovarian cancer metastases, for which effective chemotherapy is available, also may resolve spontaneously after chemotherapy is instituted.6,55,56 The most difficult management problem is the malignant pleural effusion caused by a tumor that is refractory to chemotherapy. Traditionally, these have been treated by some form of pleurodesis. Before proceeding with pleurodesis, however, it is important to make certain that the patient does not have “trapped” lung with a fixed pleural space. The lung is often encased by a peel of visceral pleural tumor that causes chronic collapse of the lung and prevents the parietal and visceral pleural surfaces from coming into apposition with each other. Effective pleurodesis under these circumstances is obviously impossible. Partial entrapment of the lung with smaller loculated effusions is also common in patients with cancer. Sometimes this is not caused by a pleural tumor but is the result of a chronic effusion that contains a lot of protein and fibrinous debris, which create a limited fibrothorax. A trapped lung is readily recognized by lack of expansion of the lung after therapeutic thoracentesis or chest tube insertion (Fig. 85-5). Complete or near-complete expansion of the lung and evacuation of the pleural space is documented on a chest radiograph before proceeding with pleurodesis.

Pleurodesis for Malignant Effusions At one time, it was believed that malignant pleural effusions could be controlled by serial thoracentesis or tube thoracostomy alone without pleurodesis. Although Lambert and colleagues reported a recurrence rate of only 17% for effusions managed by tube thoracostomy alone, subsequent experience

with this approach demonstrated that virtually all patients experienced a rapid reaccumulation of their effusion.57,58 Today, drainage of the effusion without pleurodesis (usually by serial thoracentesis) is considered appropriate only for terminally ill patients who are unwilling or unable to tolerate other therapies. A large number of agents have been used intrapleurally to try to control malignant pleural effusions. These agents can be classified in two broad categories, according to their modes of action: 1. Cytostatic agents: Presumably control the effusion by reducing the tumor volume 2. Sclerosants: Produce a chemical pleuritis that leads to the formation of adhesions and subsequent obliteration of the pleural space59 Radioactive colloids and some chemotherapeutic agents (nitrogen mustard, doxorubicin, and bleomycin) may combine both modes of action when administered intrapleurally. However, with the exception of cisplatin and perhaps thiotepa and 5-fluorouracil, most chemotherapeutic drugs act predominantly as sclerosants. The early experience with pleurodesis for malignant pleural effusions was comprehensively reviewed.60,61 Nitrogen mustard controlled the effusions in approximately one third of cases but caused significant pleuritic pain and fever and was associated with bone marrow depression.58,62 Thiotepa and 5-fluorouracil have fewer side effects but are no better at controlling effusions.55 Response rates as high as 80% have been reported for intrapleural doxorubicin, but the associated problems of pain, fever, and nausea and vomiting preclude its routine use.63-65 Quinacrine was an effective sclerosant that controlled effusions in up to 80% of patients but caused severe pleuritic pain, fever, nausea, and occasionally, hypotension, hallucinations, and seizures.66,67 These agents were abandoned, either because of their ineffectiveness or because of

FIGURE 85-5 A, Posteroanterior chest radiograph on a patient with malignant mesothelioma who underwent a thoracoscopy for diagnosis. The lung was clearly trapped at thoracoscopy. The initial postoperative portable chest radiograph shows evacuation of the pleural space with an unexpanded lung. B, The chest radiograph obtained on the following day, after removal of chest tube, shows this more clearly. There is a fixed pleural space (arrows) and lack of re-expansion of the underlying lung. This patient would not be an appropriate candidate for pleurodesis.

Ch085-F06861.indd 1048

1/21/2008 1:54:10 PM

Chapter 85 Pleural Effusion: Benign and Malignant

significant toxicity. Radioactive colloids including radioactive zinc (63Zn), gold (198Au), and chromium phosphate (Cr32PO4) were associated with little toxicity but were successful in only 50% to 60% of patients.61,68 They were also expensive and inconvenient because of the need to shield hospital personnel from radioactivity and therefore are no longer routinely used. Experience with these agents, however, established that pleurodesis was more likely to be successful if the pleural space was fully evacuated by tube thoracostomy before instillation of the sclerosant and the chest tube was left in place after the pleurodesis until the drainage was minimal. This remains an important principle in performing a pleurodesis. Tetracycline pleurodesis was introduced in 1972. It had the advantage of being inexpensive, easily available, and relatively nontoxic. Its major side effect was severe pleuritic pain, which was often difficult to control even with appropriate systemic premedication and the use of intrapleural lidocaine.69-71 Success rates ranging from 39% to 83% were reported with tetracycline in several prospective studies comparing it with other agents (Table 85-5). The effectiveness of tetracycline depended on the dose and technique. Tetracycline had so many advantages over other sclerosants that it rapidly became the agent of choice, even though it did not always result in a successful pleurodesis. Bleomycin also became a popular sclerosant.72-74 Its success rate was at least as good and perhaps better than that of tetracycline, and it caused less pain.75 A prospective randomized trial that compared pleurodesis with 1 g of tetracycline versus 60 units of bleomycin found that the median time to recurrence or progression of the effusion was 32 days for tetracycline and 46 days for bleomycin. The recurrence rate within 90 days after instillation was 30% with bleomycin and 53% with tetracycline. Toxicity was similar for the two agents.75 Although bleomycin usually is well tolerated, it can occasionally cause nephrotoxicity in patients with underlying renal insufficiency. Bleomycin is also expensive. In the early 1990s, the manufacture of tetracycline was discontinued, and in North America this led to a resurgence in the use of talc, a sclerosant first used by Bethune in 1935 that was always popular in Europe.76 Because talc is insoluble, it is administered either as a powder, by insufflation at thoracoscopy or thoracotomy (“talc poudrage”), or as a suspen-

TABLE 85-5 Results of Tetracycline Pleurodesis in Pleural Effusions No. Successful/Total Patients

Success Rate (%)

10/12

83

7/7

100

10/12

83

53/60

80

15/25

60

101/108

94

Adapted from Boutin C, Viallat JR, Aelony Y: Practical Thoracoscopy. Berlin, Springer-Verlag, 1991, p 68.

Ch085-F06861.indd 1049

1049

sion, via tube thoracostomy (“talc slurry”).77-79 This approach has become increasingly popular, and the success rates with talc slurry approximate those achieved by VATS and talc poudrage.80,81 Experimentally, talc was shown to cause an intense chemical pleuritis that exceeds that caused by other agents.59,77 Table 85-6 summarizes some of the published experience with talc. Its reported success rate has consistently been 90% or better.82-98 Several randomized trials showed that talc is superior to tetracycline or bleomycin.7,87,99-101 Iodine was sometimes added to the talc to keep the talc sterile and to intensify the pleuritis,79,102 but this is clearly not necessary in light of the high success rate of noniodized talc. Fever and pleuritic pain occur after the administration of talc, although pain seems to be far less common and less severe than with tetracycline. There have been rare reports of adult respiratory distress syndrome developing after talc pleurodesis,103,104 but given the thousands of patients treated with talc over several decades, the risk of this complication appears to be low.105 It has been hypothesized that the development of adult respiratory distress syndrome may be related to the amount of talc used or to contaminants within the talc preparation.106 However, published series report using widely varying amounts of talc (usually at least 5 to 10 g), and some do not specify the amount of talc used at all. Moreover, when a talc poudrage is performed, it is hard to estimate the amount of talc remaining in the pleural space because some of it is dissipated into the air during the procedure. There was some concern in the past that talc pleurodesis might lead to a significant decrease in pulmonary function and predispose to the development of malignancy. A mild restrictive defect was seen as a late sequela in patients who underwent talc pleurodesis for spontaneous pneumothorax.107 Long-term followup (14-40 years) by the British Thoracic Association of 210 patients who underwent pleurodesis disclosed no increased incidence of lung cancer or mesothelioma.108 The risk of carcinogenesis from talc may have been related to contamination of the talc preparations with asbestos. Talc prepared for medical use today is asbestos free. Neither one of these issues is important for patients with malignant pleural effusions, who usually have a life expectancy of less than 1 year and who need pleurodesis to palliate their dyspnea. Several early collective reviews55,60,61 attempted to assess the relative merits of the various agents used as sclerosants (Table 85-7). This was difficult because many of the published series were retrospective and uncontrolled. Prospective trials have often been poorly designed because they are based on small numbers of patients and loosely defined eligibility and response criteria. Follow-up is usually short, and a central review of chest radiographs to verify the response data is rare.109 In addition, patients with malignant pleural effusions represent a difficult patient population in which to carry out clinical trials. They have a limited life expectancy, with about half of the patients dying within 3 months of therapy. Therefore, large numbers of patients must be entered into a study to have statistically adequate numbers available to analyze response rates and toxicity. Many patients require ongoing radiation therapy or chemotherapy, which can make it hard to evaluate the effect and morbidity of pleurodesis.

1/21/2008 1:54:11 PM

1050

Section 4 Pleura

TABLE 85-6 Results of Studies of Talc Pleurodesis for Malignant Pleural Effusions Author (Year)

Method of Administration

Chambers (1958)

Suspension, chest tube

17/20 (85)

Camishion et al (1962)

Poudrage, thoracotomy

30/31 (97)

Roche (1963)

Poudrage, thoracoscopy

6/6 (100)

Pearson and MacGregor (1966)

Poudrage, thoracotomy or trocar

Adler and Rappole (1967)

Poudrage, thoracoscopy

4/4 (100)

Jones (1969)

Poudrage, thoracoscopy

22/23 (96)

Shedbalkar et al (1971)

Not stated

22/28 (96)

Adler and Sayek (1976)

Suspension, chest tube

41/44 (93)

Harley (1979)

Poudrage, thoracoscopy

41/44 (93)

Austin and Flye (1979)

Suspension, chest tube

38/41 (91)

Todd et al (1980)

Poudrage, thoracotomy or trocar

Scarbonchi et al (1981)

Poudrage, thoracoscopy

70/77 (91)

Migueres et al (1981)

Poudrage, thoracoscopy

15/26 (58)

Sorensen et al (1984)

Suspension, chest tube

9/9 (100)

Ladjimi et al (1985)

Poudrage, thoracoscopy

66/78 (85)

Viallat et al (1986)

Poudrage, thoracoscopy

23/25 (92)

Fentiman et al (1986)

Poudrage, thoracoscopy

11/12 (92)

Boniface and Guerin (1989)

Poudrage, thoracoscopy

233/254 (92)

Ladjimi et al (1989)

Poudrage, thoracoscopy

192/218 (88)

Hamed et al (1989)

Poudrage, thoracoscopy

10/10 (100)

Daniel et al (1990)

Poudrage, thoracoscopy

18/20 (90)

Ladjimi et al (1991)

Poudrage, thoracoscopy

18/21 (84)

Aelony et al (1991)

Poudrage, thoracoscopy

23/28 (82)

Engeler (1992)

Poudrage, thoracoscopy

19/20 (95)

Ohri et al (1992)

Poudrage, thoracoscopy

35/37 (95)

Webb et al (1992)

Suspension, chest tube

37/37 (100)

Hartman et al (1993)

Poudrage, thoracoscopy

22/25 (88)

Underlying pleural or pulmonary disease and minor degrees of entrapment of the lung confuse the interpretation of the response on chest radiographs. Assessment of symptoms is rarely meaningful because patients often have multiple reasons to feel dyspneic (e.g., pleural effusion plus lymphangitic spread of the tumor). Only recently has there been an attempt to develop well-designed clinical trials that include an adequate number of patients. A recent Cochrane review110 critically examined a total of 36 randomized clinical trials with 1499 subjects available for meta-analysis and concluded that the available evidence supported the use of chemical sclerosants for successful pleurodesis.

Intrapleural Cytotoxic Agents Several different agents have been used in attempts to control pleural effusions by cytotoxicity rather than sclerosis. Some of these are thought to act indirectly by immunomodulation; others exert direct cytotoxicity. Corynebacterium parvum

Ch085-F06861.indd 1050

No. Controlled/No. Treated (%)

17/19 (89)

158/163 (97)

enjoyed a period of popularity as an intrapleural agent after it was found to have antitumoral activity in an animal model.111-113 Success rates ranging from 56% to 100% were reported, but at least one study found the incidence of pain and fever to be greater than with tetracycline.114 Tetracycline is not used routinely because the same or better results can be achieved with sclerosants that are more easily available. Intrapleural interleukin-2 was found to control effusions in a small number of patients in whom it induced lymphokineactivated killer cells.115,116 The expense and systemic toxicity of interleukin-2 limit its routine use, and its role outside the research setting remains to be shown. Cisplatin is the drug that has been the most widely used for intracavitary chemotherapy. Multiple studies of intraperitoneal cisplatin, primarily for the treatment of ovarian cancer, showed that it acts through cytotoxicity rather than sclerosis and that the local pharmacologic advantage achieved by intracavitary administration can lead to tumor regression when systemic treatment has failed.117,118 The depth of pen-

1/21/2008 1:54:11 PM

Chapter 85 Pleural Effusion: Benign and Malignant

TABLE 85-7 Results of the Principal Randomized, Controlled Studies of Pleurodesis in the Treatment of Pleurisy No. Patients

Agents Used

Success Rates (%)

25

Quinacrine/Thiot

64/27

22

TCN/quinacrine

83/90

25

TCN/bleomycin

58/54

21

Cory/mustine

56/42

24

TCN/drainage

72/36

37

Mustard/talc

56/90

24

TCN/drainage

77/22

21

Talc/drainage

100/60

40

Talc/TCN

32

Cory/TCN

88/79

41

Talc/TCN

92/48

32

Cory/bleomycin

65/13

34

TCN/bleomycin

39/31

30

Talc/doxycycline

90/63

90/50

Cory, Corynebacterium parvum; TCN, tetracycline; Thiot, thiotepa. Adapted from Boutin C, Viallat JR, Aelony Y: Practical Thoracoscopy. Berlin, Springer-Verlag, 1991.

etration of drugs given by the intracavitary route appears to be 5 mm or less; therefore, they are not effective in the setting of bulky tumor.119 Cisplatin-based chemotherapy has also been administered intrapleurally,120,121 and the pharmacokinetic properties were found to be analogous to those obtained with the intraperitoneal route of administration.122 One study of cisplatin-based intrapleural chemotherapy for malignant pleural effusions reported a 49% response rate.123 Intrapleural cisplatin carries the potential of significant toxicity because a significant amount is absorbed systemically122; therefore, it is unlikely to be used routinely for the management of malignant pleural effusions. Rather, it may be useful in clinical trials designed to maximize the local intrathoracic effects of chemotherapy.124

TECHNIQUES OF ADMINISTRATION Administration of Sclerosing Agents by Tube Thoracostomy Good and Sahn believed strongly that the technique of administration of tetracycline affected the success of pleurodesis.125 They recommended insertion of a chest tube in the eighth or ninth intercostal space in the posterior axillary line and drainage of the effusion for 24 hours. Complete drainage of the pleural effusion and full expansion of the lung was documented by chest radiography. A dose of 15 to 20 mg/kg of tetracycline mixed in 75 mL of sterile water was then instilled through the chest tube into the pleural space. This was followed by 200 mL of air to facilitate contact of the tetracycline with both visceral and parietal pleural surfaces. The chest tube was clamped, and the patient was

Ch085-F06861.indd 1051

1051

rotated to the left and right lateral decubitus, prone, and supine positions every 30 minutes to disperse the tetracycline solution throughout the pleural cavity. At the end of 2 hours, the chest tube was unclamped and placed back on suction. It was removed when the drainage was less than 150 mL per 24 hours. The methods proposed by Good and Sahn became widely accepted guidelines for the administration of any sclerosing agent by tube thoracostomy.125 However, in practice there are some variations in the precise technique used with respect to drug dose and the amount of fluid in which it is mixed. The length of time that the chest tube is left to drainage before instillation of the intrapleural agent also varies. There is not clear evidence that the amount of chest tube drainage should be allowed to decrease to 100 to 150 mL per 24 hours before instillation of the intrapleural agent (Antunes et al, 2003).126 Instillation can occur as soon as the pleural space is completely evacuated, usually within 48 hours after insertion of the chest tube. Some physicians remove the chest tube 24 hours after pleurodesis; others leave it in place until the drainage is less than 150 mL per 24 hours. However, the principles to be considered in performing a pleurodesis by tube thoracostomy remain as follows: First, for a pleurodesis to be effective, the lung must be fully expanded so that the parietal and visceral pleural surfaces are in apposition. Second, there must be good dispersion of the agent throughout the pleural space. This is less likely to occur if the chest tube has been in place for several days and loculations have begun to form around the tube. Third, the pleural surfaces must be kept in close apposition after instillation of the agent for the chemical pleuritis to progress to pleural symphysis. This is most likely to happen if the chest tube is left in place and on suction until drainage is minimal.

Talc Poudrage Talc is often insufflated by poudrage. Traditionally, asbestosfree talc was dry heat sterilized by hospital pharmacies and stored in sterile glass containers (test tubes or Petri dishes) in 5- to 10-g aliquots. It was then transferred to a bulb syringe or powder blower and insufflated at thoracoscopy or thoracotomy. Attaching the bulb syringe to a red rubber catheter facilitates insufflation at thoracoscopy. Insufflation by a powder blower can also be done by attaching it to a source of pressurized air or oxygen, just as with an atomizer. This produces a finer and more uniform coverage of the pleura than does hand insufflation with a bulb syringe, but either method seems to produce a satisfactory pleurodesis. A spray can containing 4 g of sterile asbestos-free talc is now commercially available. This eliminates many of the logistic problems previously faced by hospitals in the preparation of sterile talc. Talc produces a rapid pleural symphysis, and it is helpful to insert two chest tubes (28 Fr anterior and posterior tubes or 28 Fr anterior and 32 Fr right-angle diaphragmatic tubes) to prevent loculated fluid collections. If these develop during the immediate postoperative period, they usually are resorbed over the subsequent 1 to 2 months. A recent multicenter randomized clinical trial compared the use of talc slurry via tube thoracostomy with VATS talc

1/21/2008 1:54:11 PM

1052

Section 4 Pleura

poudrage. In 482 eligible randomized patients, efficacy and risk for these two approaches were similar, but better results were obtained after VATS poudrage in patients with a lung or breast primary (Dresler et al, 2005).127

Administration of Cytotoxic Agents A technique similar to that described by Good and Sahn for tetracycline is used for the administration of cytotoxic agents intrapleurally, but different considerations apply for cytotoxic than for sclerosing agents. Cytotoxic agents are left in the pleural space longer to maximize contact with the pleural tumor. The length of instillation time is dictated by the pharmacokinetic properties of the individual drug. Cisplatin is left in the peritoneal or pleural space for 4 hours because by that time it has been almost totally absorbed into the systemic circulation.122,128 The chest tube can be immediately removed after instillation of a cytotoxic drug because there is no need to produce pleural symphysis. However, full expansion of the lung before instillation of the drug needs to be documented because an effusion caused by a trapped lung is no more effectively treated by cytotoxic than by sclerosing agents.

MANAGEMENT OF AN EFFUSION IN PATIENTS WITH A TRAPPED LUNG Patients who have a trapped lung are not candidates for therapy with sclerosants and are unlikely to benefit from intrapleural cytotoxic agents because they have bulky tumor. Even though they have a collapsed, unexpandable lung, some of these patients experience a relief of dyspnea and chest discomfort when the effusion is evacuated, perhaps because this alleviates mediastinal compression. Some patients have a lung that can re-expand partially and experience a definite improvement in pulmonary function with drainage of the effusion. The insertion of a pleuroperitoneal shunt is one way to palliate such patients.129-132 The device used for this procedure, the Denver pleuroperitoneal shunt (Codman and Shurtleff, Randolph, MA) is a single-unit silicone rubber conduit consisting of a unidirectional valved pumping chamber located between fenestrated pleural and peritoneal catheters. One catheter is introduced into the pleural space with the use of a Seldinger technique and directed toward the posterior costophrenic sulcus. The other catheter is placed into the peritoneal cavity via a small upper quadrant muscle-splitting incision. The pumping chamber is positioned in a subcutaneous pocket created over the anterolateral costal margin that provides a stable base for shunt compression.133 Pleuroperitoneal shunting is also a therapeutic option for patients with pleural effusions secondary to intractable ascites, and it has sometimes been combined with peritoneovenous shunting for such patients. However, active participation by the patient or family is required for the shunt to function because the pumping chamber must be actively compressed approximately 25 times every 4 hours. Patients who are unable to cooperate with this routine should not have a shunt implanted. In properly selected patients, pleuroperitoneal shunting provides good palliation with minimal morbidity. The risk of infection is minimal, but shunt occlusion as a result of fibrin deposition over the ends of the catheter

Ch085-F06861.indd 1052

occurs occasionally and may require replacement of the shunt. Another alternative for patients who have a symptomatic pleural effusion and a trapped lung is intermittent drainage via an indwelling catheter (Pleurx; Denver Biomaterials, Golden, CO). The catheter is inserted under local anesthesia and can be used by the patient and family at home as needed to drain pleural fluid whenever the effusion becomes symptomatic. The efficacy and safety of this approach were shown in both a retrospective study and a prospective multiinstitutional trial (Putnam et al, 1999; Putnam et al, 2000).134,135 Intermittent drainage via an indwelling pleural catheter is now the easiest and most accepted management option for patients with a symptomatic effusion in the presence of a trapped lung.

PLEURECTOMY Pleurectomy with or without decortication was one of the early approaches used for malignant pleural effusions. Jensik and associates reported a series of 52 pleurectomies, 15 of which were associated with decortication.136 The immediate mortality rate was 6%, and the 30-day mortality rate was 18%. Two patients developed recurrent effusions, and the average survival time was only 10.4 months. Subsequently, Martini and colleagues reported on a series of 106 patients whose malignant pleural effusion was treated by pleurectomy.137 Most patients required two to three units of blood transfusion intraoperatively, and the overall 30-day mortality rate was 10%. In both of these series, which antedate modern chemotherapeutic regimens, patients with breast cancer had the longest survival. More recently, Fry and Khandekar reported the results of pleurectomy and decortication performed via axillary thoracotomy in 24 patients who did not respond to standard treatment for malignant pleural effusion. Three patients died postoperatively, for an overall mortality rate of 12.5%, and the other 21 patients all experienced control of their recurrent effusions.138 The high operative mortality rates undoubtedly reflect the poor performance status and limited reserve of patients who have malignant pleural effusions. With less morbid therapeutic options now available, thoracotomy and pleurectomy for the palliation of malignant pleural effusions has largely been abandoned. However, VATS pleurectomy is associated with a much lower risk. Waller and colleagues reported 19 patients who underwent VATS parietal pleurectomy.139 The procedure required less than 1 hour to perform, and there were no postoperative deaths or episodes of respiratory failure. Therefore, VATS pleurectomy can be considered an option in patients who are not candidates for simpler approaches such as talc pleurodesis.

SUMMARY Patients who present with a pleural effusion first undergo a thorough clinical evaluation to try to identify the likely cause. The size and location of the effusion and the determination of whether it is free flowing is made on posteroanterior, lateral, and lateral decubitus chest radiographs. CT is helpful in characterizing effusions that appear loculated and in detect-

1/21/2008 1:54:11 PM

Chapter 85 Pleural Effusion: Benign and Malignant

ing underlying pulmonary or intra-abdominal disease that may be responsible for the effusion. Thoracentesis with biochemical analysis of the pleural fluid, culture, and cytologic examination is then performed to determine whether the effusion is a transudate or an exudate, to establish whether it is malignant, and to direct further evaluation. Ultrasonography and CT can localize loculated effusions for thoracentesis. If the cytologic findings are negative and malignancy is suspected, percutaneous pleural biopsy, or repeat thoracentesis, or especially thoracoscopy is indicated to establish a definitive tissue diagnosis. Transudative effusions are managed by treatment of the underlying medical condition. Exudative effusions are also treated in this manner if they are not malignant. Patients with malignant effusions must have a determination made as to whether the lung will fully re-expand after evacuation of the effusion. If the lung expands completely, the effusion can be managed by sclerosis. Talc is probably the most effective sclerosant currently available, although tetracycline, doxycycline, and bleomycin have also been popular. Intrapleural cytotoxic agents are still considered investigational. If the lung is trapped and the patient is symptomatic, intermittent drainage via an indwelling pleural catheter is the simplest and most effective option. However, the recent reviews from the American and British Thoracic Societies and from the Cochrane Collaboration now support the systematic approach to management of pleural effusion, as outlined in this chapter, and provide guidelines for pleurodesis (Fig. 85-6) (Antony et al, 2000; Antunes et al, 2003).110,126,140

COMMENTS AND CONTROVERSIES A pleural effusion arises when there is a disruption between the formation and reabsorption of pleural fluid. Its presence can be diagnosed by conventional imaging, and its cause can be documented by means of thoracentesis with biochemical analysis, culture and cytologic examination of the pleural fluid, percutaneous pleural biopsy, or thoracoscopic examination with biopsy. As discussed by Doctor Rusch, initial thoracentesis is useful to determine whether the effusion is a transudate or an exudate, whether the effusion is hemorrhagic, and whether the effusion is purulent. Patients whose effusions remain undiagnosed after one or more thoracenteses may have a percutaneous needle biopsy. Unfortunately, this procedure has a low diagnostic yield in malignant neoplasms because of the patchy distribution of disease. Thoracoscopic examination of the pleural space is the most definitive diagnostic technique, with an accuracy greater than 95%. The procedure allows direct access to 90% to 100% of both the visceral and parietal surfaces and, for most patients, clarifies whether the effusion is caused by a malignant process. At the time of thoracoscopy, a pleurodesis can also be achieved, should it be necessary. Because of such techniques, the cause of most pleural effusions can be established accurately and in a timely fashion, and few circumstances occur in which open thoracotomy is necessary. Finally, it is important to remember that, in a patient with a current malignant disease or a history of a previously treated neoplastic disorder, the likely cause of the effusion might be obvious. It will also be obvious in patients with bacterial pneumonia who have an asso-

Ch085-F06861.indd 1053

1053

Proven malignant effusion

Recurrence/ symptomatic?

NO Observe

YES Seek specialist opinion from a member of the thoracic malignancy multidisciplinary team

Intercostal tube insertion and drainage

Consider: Chest radiograph: complete lung re-expansion?

NO

1. Thoracoscopy 2. Long-term indwelling catheter 3. Pleuroperitoneal shunt

YES Chemical pleurodesis Consider:

Recurrence of effusion?

NO

YES

1. Repeated pleurodesis 2. Thoracoscopy 3. Long-term indwelling catheter 4. Pleuroperitoneal shunt 5. Palliative repeated thoracentesis

STOP FIGURE 85-6 Algorithm for the management of pleural effusions. (ADAPTED FROM ANTUNES VB, ET AL: BTS GUIDELINES FOR THE MANAGEMENT OF MALIGNANT PLEURAL EFFUSIONS. THORAX 58[SUPPL II]: II29-II38, 2003; REPRODUCED WITH PERMISSION FROM BMJ PUBLISHING GROUP.)

ciated effusion and in patients with known congestive heart failure who develop a right-sided effusion. The clinical setting in which a pleural effusion occurs is therefore important in trying to identify its cause. J. D.

KEY REFERENCES Antony VB, Loddenkemper R, Astoul P, et al: Management of malignant pleural effusions. Official statement of the American Thoracic Society. Am J Respir Crit Care Med 162:1987-2001, 2000.

1/21/2008 1:54:11 PM

1054

Section 4 Pleura

Antunes G, Neville E, Duffy J, Ali N, for the BTS Pleural Disease Group: BTS guidelines for the management of malignant pleural effusions. Thorax 58(Suppl II):ii29-ii38, 2003. ■ Both of these papers provide succinct evidence-based guidelines for the management of pleural effusions Deslauriers J, Lacquet LK: Thoracic Surgery: Surgical Management of Pleural Diseases. St. Louis, CV Mosby, 1990. ■ This is a multiauthored text that provides an in-depth review of the pathophysiology and management of pleural diseases. Dresler CM, Olak J, Herndon JE II, et al: Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest 127:909-915, 2005. ■ This paper reports a large prospective randomized trial that established talc slurry administered via tube thoracostomy as a standard treatment for malignant pleural effusion.

Ch085-F06861.indd 1054

Light RW: Pleural Diseases. Philadelphia, Lea & Febiger, 1983. ■ This is a comprehensive reference on the diagnosis and treatment of pleural effusions with emphasis on the biochemical characteristics of pleural fluid. Putnam JB Jr, Light RW, Rodriguez RM, et al: A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer 86:19921999, 1999. Putnam JB Jr, Walsh GL, Swisher SG, et al: Outpatient management of malignant pleural effusion by a chronic indwelling pleural catheter. Ann Thorac Surg 69:369-376, 2000. ■ These two papers report the feasibility and efficacy of indwelling pleural catheters in the management of malignant pleural effusions.

1/21/2008 1:54:11 PM

Benign Pleural Diseases chapter

86

EMPYEMA AND BRONCHOPLEURAL FISTULA Daniel L. Miller

Empyema thoracis can be defined as a purulent pleural effusion. Although this infection usually originates from the lung, it may enter through the chest wall or from sources below the diaphragm or within the mediastinum. Complications from elective thoracic surgery or from post-traumatic hemithoraces are other possible causes. Most empyemas are, however, parapneumonic, and infection occurs when the host reaction is overwhelmed by the number and virulence of the inoculum. Although the normal pleural space is resistant to infection, the abnormal space, such as one containing air, blood, or other fluids, is highly susceptible to empyema formation. The therapy for empyema depends on a clear understanding of the pathogenesis of the pleural infection. In this chapter, some of the most controversial issues concerning pathogenesis, diagnosis, and management of postpneumonic empyemas are addressed. The problems associated with posttraumatic or postoperative empyemas are covered extensively in other sections of this textbook.

HISTORICAL NOTE Empyema of the pleural cavity was recognized approximately 2400 years ago when Hippocrates made the distinction between empyema and hydrothorax.1 Prior to his description, the terms were used interchangeably; and before the principles of asepsis were defined by Semmelweis and Lister, infection from unsterilized instruments (used to evacuate fluid) occurred often in the treatment of serous pleural effusions. Hippocrates diagnosed empyema based on its clinical presentation. Fever was constant but mild during the day and increased at night. Patients’ coughs were nonproductive. Eyes were hollow, and cheeks showed red spots. When the patient was shaken by the shoulders, splash succussion sounds could be heard from the thorax, depending on the presence of air and fluid. In his book on chest auscultation, Laënnec translated Hippocrates’ description that distinguished hydrothorax from empyema: “When applying the ear on the ribs, during a certain time you hear a noise like boiling wine gar, which suggests that the chest contains water and no pus.”2 Sometimes, the noises were not heard, depending on the quantity and physical characteristics of the intrathoracic liquid. Hippocrates is also credited with the first drainage operation for empyema by using the cautery or doing the trephination of a rib. As reported by Paget, Hippocrates opened the chest where the pain and swelling were most evident.3 He packed the wound with a strip of linen cloth, which was changed every day. He observed that this packing allowed fluid to escape around the strip but prevented air into the

space. Daily irrigations with “warm wine and oil” cleaned the lung surfaces, and when the empyema had healed, metal rods were used to close the wound. He clearly understood the natural history of undrained empyemas when he wrote in a treatise on pleurisy and peripneumonia: “Patients with pleurisy who, from the beginning, have sputum of different colors or consistencies die on the third or the fifth day, or they become suppurative by the eleventh day.”4 Hippocrates also wrote: “When empyemas are opened by the cautery or by the knife, and the pus flows pale and white, the patient survives, but if it is mixed with blood, muddy, and foul smelling, he will die.” In the 19th century, aspiration of acute pleural effusions was introduced. Wyman and his colleague Bowditch are credited with establishing this procedure.5,6 Wyman described the first therapeutic thoracentesis in a letter addressed to Sir William Osler: “With Dr. Homans’ advice and assistance, the chest was punctured with an exploring trocar and cannula between the sixth and seventh ribs about six inches from the spine, and twenty ounces of straw colored serum drawn off slowly with great relief of the symptoms.” Needles used for pleural aspiration, cannulas, devices preventing the entry of air, and suctioning systems were developed during the 19th century.7 Thoracentesis was modified by the description of closedtube thoracostomy by Playfair8 (Fig. 86-1) and Hewitt,9 who performed drainage with a trocar, placing a rubber tube through the cannula into the pleural space. The rubber drain was connected to a glass tube that went through a cork into a bottle with a sealing level of antiseptic solution. It acted like a unidirectional valve, allowing the liquid to leave the thoracic cavity but keeping air from entering the space. The sealing level could be adjusted depending on the type and amount of fluid being drained. This system constituted a true siphon drainage system that also allowed pleural irrigation. In 1891, Von Bulau popularized the underwater drainage system throughout Europe. His name is still associated with this “no suction” method of pleural drainage.10 The consequences of open pneumothorax and the importance of closed-tube drainage were not truly appreciated until a clear understanding of the pathogenesis of pleural infection was provided by Graham and Bell.11 They were members of the U.S. Army Medical Corp (USAMC) and of the World War I Empyema Commission, and most of their work was done in Europe during the severe influenza epidemic due to hemolytic Streptococcus. Prior to their report, acute empyemas were managed by rib resection and open drainage; unfortunately, mortality rates averaged 30%. Death frequently occurred within 30 minutes of the procedure and 1055

Ch086-F06861.indd 1055

1/21/2008 1:57:02 PM

1056

Section 4 Pleura

FIGURE 86-2 Dr. Leo Eloesser. FIGURE 86-1 Water seal drainage of the pleural space as described by Playfair in 1875. “The end of the tube was placed in a vessel of water under the bed.” This system was used mostly for children with empyema. (FROM HOCHBERG LA: THORACIC SURGERY BEFORE THE 20TH CENTURY. NEW YORK, VANTAGE PRESS, 1960, P 244.)

was attributed to the open pneumothorax and mediastinal instability rather than to the empyema itself. Soon after Graham and Bell recommended closed rather than open drainage to treat early empyemas, the mortality rates decreased from 30% to 5% to 10%.12,13 The principles of empyema management as described by Graham and Bell include (1) careful avoidance of open pneumothorax during the acute stage; (2) prevention of chronicity by rapid sterilization and obliteration of the space; and (3) careful attention to the patient’s nutritional status. Open drainage is indicated only when fibrotic changes have occurred within the space. In 1935, Eloesser (Fig. 86-2) described a tissue flap for the treatment of acute pleural tuberculosis. This flap was constructed as a one-way valve, allowing the exit of pus but preventing the entry of air (Fig. 86-3).14 As thoracic surgery evolved rapidly during the end of the 19th century, procedures such as thoracoplasty15,16 and decortication17-19 were introduced. These procedures described the obliteration of space either by collapsing it over the lung or by attempting to re-expand the lung itself. The results were not always good but, in 1901, Fowler stated that decortication was applicable to all patients with non-tuberculous empyemas who could tolerate the procedure.18 He even said that “decortication could be used instead of Estlander’s operation in most cases and should replace the Schede’s thoracoplasty in all.” In 1923, Eggers reported on 146 patients who submitted to decortication, and he described in full details the procedure as it is still used today.20 At the end of the 20th century, another modality was introduced for the diagnosis and treatment of empyema: thoracoscopy or video-assisted thoracoscopic surgery (VATS).

Ch086-F06861.indd 1056

A

B

C

FIGURE 86-3 The original Eloesser flap.

Wakabayashi first used thoracoscopy for the drainage of an empyema.21 Today VATS is the modality of choice for the diagnosis and treatment of early empyema.22 With the onset of the antibiotics era, the incidence of pneumococcal and streptococcal empyemas fell sharply and the mortality rate also declined dramatically. Subsequently, the increasing significance of anaerobic infection and the development of new generations of drug-resistant organisms led to a new spectrum of problems. In addition, the increasing frequency of the acquired immunodeficiency syndrome (AIDS) and of patients undergoing active chemotherapy has somewhat modified the natural history of the disease because patients are no longer able to produce the inflammatory reaction that is so important to localize the empyema and obliterate the space.23 HISTORICAL READINGS Atwater EC: Morrill Wyman and the aspiration of acute pleural effusion, 1850 [Letter]. N Engl Bull Hist Med 36:235, 1972. Bowditch HI: On pleuritic effusions and the necessity of paracentesis for their removal. Am J Med Sci 22:320, 1852. Chadwick J, Mann WN: The Medical Works of Hippocrates. Springfield, IL, Charles C Thomas, 1950.

1/21/2008 1:57:03 PM

Chapter 86 Empyema and Bronchopleural Fistula

Delarue NC: Empyema: Principles of management—an old problem revisited. In Deslauriers, Lacquet LK (eds): International Trends in General Thoracic Surgery. St. Louis, Mosby–Year Book, 1990. Delorme E: Nouveau traitement des empyèmes chroniques. Gaz Hôp 67:94, 1894. Eggers C: Radical operation for chronic empyema. Ann Surg 77:327, 1923. Eloesser L: An operation for tuberculous empyema. Surg Gynecol Obstet 60:1096, 1935. Estlander JA: Résection des côtes dans l’empyème chronique. Rev Med Chir (Paris) 3:156, 1879. Fowler GR: A History of Thoracic Surgery (quoted by R. Meade). Springfield, IL, Charles C Thomas, 1961. Gossot D, Stern JB, Galetta D, et al: Thoracoscopic management of postpneumonectomy empyema. Ann Thorac Surg 78:273, 2004. Graham EA: Some Fundamental Considerations in the Treatment of Empyema Thoracis. St. Louis, CV Mosby, 1925. Graham EA, Bell RD: Open pneumothorax: Its relation to the treatment of acute empyema. Am J Med Sci 156:939, 1918. Hewitt LF: Thoracentesis: The place of continuous aspiration. BMJ 1:317, 1876. Hurt R: The diagnosis and treatment of empyemas. In Hurt R (ed): The History of Cardiothoracic Surgery. New York, Parthenon, 1996. Lain-Entralgo P: Clásicos de le Medicina: Laënnec. Madrid, CSIC, Instituto Arnaldo de Vilanova, 1954. Major RH: Classic Descriptions of the Disease. London, Balliere, Tindall & Cox, 1945. Paget S: Empyema. In Paget S (ed): The Surgery of the Chest. New York, EB Treat, 1897, pp 204-229. Peters RM: Empyema thoracis: Historical perspective. Ann Thorac Surg 48:306, 1989. Playfair GE: Case of empyema treated by aspiration and subsequently by drainage: Recovery. BMJ 1:45, 1875. Schede M: Die Behandlung der Empyema. Verh Dtsch Ges Imm Med 9:41, 1890. Von Bulau G: Fur die Heber Drainage bei Behandlung der Empyema. Z Klin Med 18:31, 1891.

1057

Wakabayashi A: Expanded applications of diagnostic and therapeutic thoracoscopy. J Thorac Cardiovasc Surg 102:721, 1991. Yeh TJ, Hall DP, Ellison RG: Empyema thoracis: A review of 110 cases. Am Rev Respir Dis 88:785, 1963.

STAGES OF EMPYEMA PROGRESSION An empyema is a collection of pus in a natural body cavity. One of the most common varieties of empyema is empyema thoracis, which can be localized (i.e., encapsulated) or can involve the entire pleural space.24 The American Thoracic Society, in 1962, divided the formation of an empyema into three distinct stages, indicative of disease progression in the pleural space (Table 86-1). These usually occur over a 3- to 6-week period. For management purposes, two stages are recognized: an acute process and an organizing phase. During the exudative phase (stage I), the pleural membranes swell considerably and discharge a thin exudative fluid. Fibrin is deposited over all pleural surfaces and, despite early angioblastic and fibroblastic proliferation that extends outward from the pleura, the peel is not thickened enough to prevent complete lung re-expansion once the space is emptied. During the fibrinopurulent phase (stage II) (Fig. 86-4), there are heavy fibrin deposits over all pleural surfaces, more over the parietal pleura than over the visceral

TABLE 86-1 Pathologic Findings of Empyema Stage

Phase

Stage I

Exudative (acute phase)

Stage II

Fibrinopurulent (transitional phase)

Stage III

Organizing (chronic phase)

FIGURE 86-4 Posteroanterior (A) and lateral (B) chest radiographs of postpneumonic empyema during the fibrinopurulent stage.

Ch086-F06861.indd 1057

1/21/2008 1:57:03 PM

1058

Section 4 Pleura

pleura. The pleural fluid is turbid or frankly purulent and has a large number of polymorphonuclear white cells. At this stage, the pleura is still relatively intact, and the lung, although less mobile, can be re-expanded. Loculations form during this stage (Fig. 86-5). Usually within 3 to 4 weeks, organization (stage III) begins with massive ingrowth of fibroblasts and formation of collagen fibers over both parietal and visceral surfaces. The pus is very thick, and the lung, which at this stage is virtually functionless, is imprisoned within a thick fibrous peel (Fig. 86-6). The lung can no longer expand without being decorticated. Within 6 weeks, arterioles infiltrate the peel. In a 10-year retrospective analysis of 101 patients with empyema, Renner and associates found that 17 patients had stage I empyema, 8 were in the purulent stage, and 76 (75%) had an organized empyema.25

COMPLICATIONS Complications can occur at any time during the formation of an empyema, but they are more likely to develop during the chronic stage of the disease process (Table 86-2). One of the

most common, but often unrecognized, complications is increased fibrosis and scar tissue in the lung, which produce pulmonary fibrosis. Scar tissue can also penetrate the parietal pleura and reach the intercostal spaces, which become narrowed and contracted, giving the chest wall the appearance of a carapace.24 In extreme cases, the shape of the ribs is altered and, on cross-section, they appear triangular. In other instances, calcifications may develop in the fibrous tissue and bone may be formed. Empyema necessitatis (Fig. 86-7) is characterized by the dissection of pus through the soft tissues of the chest wall and eventually through the skin. Similarly, the sudden appearance of purulent sputum signals the onset of a bronchopleural fistula with spontaneous drainage of pus into the bronchial tree (Fig. 86-8). In a series of 77 patients with bronchopleural fistula presented by Hankins and colleagues (Hankins et al, 1978),26 spontaneous fistula (n = 28) was secondary to tuberculosis in 23 patients and to bacterial pneumonia or lung abscess in 5. Unusual complications include rib or spine osteomyelitis, pericarditis, mediastinal abscesses, or transdiaphragmatic drainage of the empyema into the peritoneal cavity.

Parapneumonic Effusions Patients with bacterial pneumonia may have an associated pleural effusion, which is called a parapneumonic or a postpneumonic effusion. Uncomplicated effusions are nonpuru-

TABLE 86-2 Complications of Empyema Pulmonary fibrosis Contraction of the chest wall Spontaneous drainage through the skin: Empyema necessitatis Spontaneous drainage through the bronchus: Bronchopleural fistula

FIGURE 86-5 CT scan showing a multiloculated empyema.

FIGURE 86-6 Thickened fibrous peel that was resected from the visceral pleura to re-expand the lung.

Ch086-F06861.indd 1058

Others Osteomyelitis (rib, spine) Pericarditis Mediastinal abscess Subphrenic abscess

FIGURE 86-7 Patient with empyema necessitatis that has eroded through the soft tissues of the chest wall.

1/21/2008 1:57:04 PM

Chapter 86 Empyema and Bronchopleural Fistula

1059

TABLE 86-3 Pathogenesis of Empyema Contamination from a source contiguous to the pleural space (50%-60%) Lung Mediastinum Deep cervical Chest wall and spine Subphrenic Direct inoculation of the pleural space (30%-40%) Minor thoracic interventions Postoperative infections Penetrating chest injuries Hematogenous infection of the pleural space from a distant site (<15%)

FIGURE 86-8 Bronchopleural fistula. Chest radiograph shows an airfluid level–containing space.

lent, have a negative Gram stain and culture, and do not loculate in the pleural space. They resolve spontaneously with antibiotic treatment of the underlying pneumonia.27 Complicated effusions are either empyemas or loculated parapneumonic effusions that require surgical drainage for adequate resolution. According to Light and colleagues,28 the pleural fluid, pH, lactate dehydrogenase (LDH), and glucose levels appear to be useful to differentiate uncomplicated from complicated parapneumonic effusions.

PATHOGENESIS Most empyemas are the result of bacterial suppuration in organs that are contiguous with the pleural surface. Among these, the lungs are the most common source. In such cases, empyema occurs by direct bacterial spread across the visceral pleura or by free intrapleural rupture of microscopic and peripherally located lung abscesses. In a classic description of putrid empyemas, Maier and Grace29 showed that most were associated with bronchiectasis, pulmonary abscess, and suppurative pneumonia. In most series, empyemas are secondary to bronchopulmonary infections in 50% to 60% of cases (Table 86-3), and nearly all of the so-called primary empyemas are due to subclinical pneumonic processes.19,30,31 In 1971, Vianna showed that several patients with postpneumonic empyemas had various underlying conditions, such as alcoholism or chronic pulmonary disease.32 Inactive pulmonary tuberculosis, diabetes mellitus, long-term corticosteroid therapy, and various malignancies are other common predisposing conditions. Substance abusers and immunosup-

Ch086-F06861.indd 1059

pressed individuals, such as patients with AIDS, are also at risk for bacterial and aspiration pneumonia and other pulmonary infections.33 These may lead to parenchymal destruction with subsequent contamination of the pleural space, which results in either simple empyema or complex infections, including bronchopleural fistula. Other potential sources of contamination should be sought when the cause of empyema is unclear. Rupture of the esophagus, for instance, nearly always results in empyema formation. Rare causes of contamination include infection in the deep posterior region of the neck and, more infrequently, infections in the chest wall or thoracic spine. Although subphrenic abscesses can occasionally contaminate the pleural space through direct transdiaphragmatic erosion, most effusions associated with these abscesses are sterile exudates. Le Roux showed that lymph drainage from subphrenic spaces can travel cephalad through the diaphragm, and this is the likely route of transferral of subphrenic infections to the pleural space.34 He also noted that silent paracolic abscesses can occasionally erode through the diaphragm and infect the pleural space. Virtually all post-traumatic empyemas are associated with penetration of the chest wall or the presence of a hemothorax. In a large series of trauma patients seen between 1972 and 1996, Mandal and Thadepalli reported a 1.6% incidence of empyema.35 In penetrating thoracic injuries, empyema formation is mostly the result of organic foreign bodies being carried into the pleural space.36 In an interesting study, Ogilvie showed that the nature of the missile (e.g., shell splinters, bullets, or bayonets) played little part in determining the rate of infection in empyemas secondary to penetrating injuries.37 In blunt thoracic injuries, hemothoraces become secondarily infected via contamination through the chest tube or from an infection in the adjacent lung. Risk factors for empyema formation are shown in Table 86-3. In 1977, Arom and colleagues made a distinction between post-traumatic empyemas and infected organizing hemothoraces (clotted hemothoraces) in which masses of blood clot became secondarily infected.38 Ogilvie showed that air in the pleural space that is associated with blood is more likely to get infected than is a pneumothorax or a hemothorax alone.37 In an experimental model for empyema thoracis, Mavroudis and

1/21/2008 1:57:04 PM

1060

Section 4 Pleura

colleagues showed that a concomitant hemothorax increased the incidence of empyema and early death after Staphylococcus was inoculated in the pleural space.39 In rarer cases, traumatic empyemas follow blunt esophageal rupture, acute diaphragmatic hernia with bowel strangulation and/or necrosis, or aspiration of a foreign body with perforation of the lung.40 Direct inoculation of the pleural space can occur as a result of minor thoracic interventions, such as thoracentesis, thoracic biopsies, or chest tube drainage. Postoperative empyemas are seen almost exclusively after operations in which the esophageal or bronchial lumina have been entered. The incidence of this complication is in the range of 2% to 4% after pulmonary resection. In recent years, prophylactic use of antibiotics during the postoperative period and improved surgical technique has played a significant role in lowering the incidence of these events. There is little evidence that hematogenous infection of the pleural space can occur from a distant infection site (classically, osteomyelitis) without an intermediate lung infection, which then contaminates the pleural space. In Sherman and colleagues’ series, only four cases represented true metastatic hematogenous seeding of the pleural space.31

BACTERIOLOGY In the preantibiotic era, the predominant organisms recovered from empyemas were pneumococci and Streptococcus pneumoniae.41,42 In summarizing a total of 3000 empyemas reported from 1934 to 1939, Ehler noted that pneumococci was found in 64% of cases, Streptococcus pyogenes in 9%, and Staphylococcus aureus in 7%.43 He concluded that other organisms were found rarely and should be considered curiosities. The incidence of empyema was greater (80%) with streptococcal pneumonia than with other types of pneumonia because of greater lung destruction associated with the causative organism. In those cases, myriad tiny lung abscesses occurred along the lymphatic channels and discharged the infecting organisms into the effusion in great quantities; this converted the effusion into an empyema within a matter of hours.44 The introduction and increasing use of antibiotics was accompanied not only by a marked reduction in the incidence and mortality rates of empyemas but also by a change in the spectrum of causative organisms. In a study on the changing etiology of acute bacterial empyema, Finland and Barnes showed that although the incidence of streptococcal pneumonia generally declined from 1950 to 1953, it still continued to occur in community-acquired empyemas.45 The incidence of S. aureus–related empyemas increased, and it became the most frequently found organism in empyemas in 1955. It declined to its original levels after 1965, but gramnegative rods increased in importance. The predominant isolates in recent years have been S. aureus (29%-69% of culture-positive cases) and enteric gramnegative bacilli (29%-60% of culture-positive cases).46 In a report by Vianna, 41 patients with bacterial pneumonia complicated by empyema were studied and S. aureus was the most common causative organism isolated (34%).32 Gramnegative bacteria were isolated in 64% of empyemas that complicated some other underlying disease, probably owing

Ch086-F06861.indd 1060

to previous antibiotic therapy. The incidence of S. aureus– induced empyema has also increased in children. From 1955 to 1958, it was the causal organism in 92% of cases in children younger than 2 years, as reported by Ravitch and Fein.47 In countries in which the introduction of new antibiotics and of new techniques of administration was delayed, the changes in the bacteriology of empyemas were seen at a later date. The recovery rates of anaerobes isolated from empyema vary from 19% to 76%.47,48 These microorganisms are normal inhabitants of the mouth, intestine, and female genital tract. They reach the lung by aspiration from the mouth or bacteremic spread from the intestines or areas of pelvic suppuration. In a series reported by Sullivan and colleagues, 226 culture-proven empyemas were analyzed and anaerobes were isolated in 44 patients. More than 50 anaerobic bacteria were identified, but the most common was Streptococcus.48 In the series by Bartlett and colleagues, 76% of patients with empyemas had either anaerobes alone (35%) or in combination with aerobic agents.46 In most cases, the flora were complex, with an average of three different species of bacteria per case. According to these authors, the paucity of anaerobic isolates in most reports of empyema is due to inadequate methods to preserve oxygen-sensitive forms during transfer to the laboratory and lack of adequate anaerobic culture technique. Often a culture of empyema fluid does not establish a microbiologic diagnosis. In the series of Le Roux, a causative organism could not be isolated in 80% of patients.34 In other series, the percentage of negative cultures varied from 25% to 60%.49,50 In general, negative cultures are due to inadequate culture techniques or to very effective antibiotics that can penetrate the empyema and prevent bacterial growth. When empyema necessitatis occurs, the pathogens recovered do not necessarily represent the microorganism responsible for the disease because the skin fistula may be contaminated with skin flora or hospital pathogens (Bergeron, 1990).49

DIAGNOSIS The diagnosis of an empyema is made on clinical grounds, the presence of leukocytosis, characteristic findings on chest radiographs, and the recovery of purulent fluid from the pleural space. In several cases, however, the real problem is to distinguish between a noninfected parapneumonic pleural effusion and a true empyema or to correlate radiographic findings and fluid analysis with the stage of empyema. An empyema should be suspected in patients with acute respiratory illnesses with associated pleural effusion. Typical symptoms, such as pleuritic chest pain, high fever, cough, tachypnea, tachycardia, toxicity, or local tenderness, are often present. Other symptoms include generalized malaise, anorexia, and weight loss. These symptoms can occur very acutely or develop insidiously over a period of a few days or even weeks. Physical examination nearly always shows diminished mobility of the involved hemithorax, decreased breath sounds, and dullness to percussion. In the series by Varkey and colleagues of 72 cases of empyema, the most common initial manifestations were dyspnea (82%), fever (81%), cough (70%), and chest pain (67%).51 In addition, a major underlying disease was present

1/21/2008 1:57:05 PM

Chapter 86 Empyema and Bronchopleural Fistula

in 45 patients. Because the symptoms are related to the cause and stage of empyema, the amount of pus in the pleural space, the status of the host’s defense mechanisms, and the virulence of the microorganisms involved, patient experience may vary from a few symptoms to several with severe toxicity. Symptoms may also vary with the cause of the empyema. Patients with parapneumonic empyemas, for instance, often present with cough and purulent sputum, whereas the symptoms of patients with empyemas secondary to subphrenic abscesses may be exclusively abnormal complaints. On the basis of the clinical history, Maier and Grace divided cases of putrid anaerobic empyemas into one of two groups.29 In the first group, expectoration of foul sputum indicated the presence of a pulmonary anaerobic process or of an anaerobic empyema with a bronchopleural fistula. In the second group, the foul sputum was absent and the symptoms suggested ordinary pneumonia. Most patients with an empyema have leukocytosis with a shift of the cell count to the left. Chest radiographs show a pleural effusion with or without underlying pneumonia or lung abscess. On lateral radiographs, the empyemas are nearly always posterior and lateral and most extend to the diaphragm. The classic image is that of a posteriorly located, inverted D-shaped density (pregnant lady sign) as seen in the lateral chest film or computed tomography (CT) scan (Fig. 86-9). Decubitus views are useful to determine if the collection is free flowing in the pleural space (stage I) or if it is loculated (stage II). Because it is often difficult to differentiate between lung consolidation and pleural fluid, CT scanning is used to ascertain the underlying pulmonary pathologic condition. CT is also useful to stage the empyema as determined by the presence of loculations, thickness of the pleura, and presence or absence of a trapped lung. As reported by Stark and colleagues, visualization of thickened and separated pleural surfaces, compression of the parenchyma, and pleural thickening are specific CT signs of empyema.52 In 1991, Herna and colleagues described the “split pleura sign,” which is indicative of the presence of pleural fluid between the thickened visceral and parietal pleura (Fig. 86-10).53 Ultrasonography may be used to document the presence of fluid or to distinguish between pleural fluid, pleural thickening, or parenchymal consolidation. It is also useful for guided pleural needle aspiration of fluid, especially when the position of the diaphragm cannot be documented with certainty on standard radiographs. As described by Moran (Moran, 1988)54 and Orringer,55 an empyemogram can be done by injecting contrast material at the time of initial thoracentesis and then obtaining posteroanterior and lateral chest films and decubitus views. Although this technique has seldom been used since the advent of CT, it may provide information about the extent of the empyema cavity and the presence or absence of loculations within the space. After the presence of pleural fluid has been confirmed, diagnostic thoracentesis should be done and the aspirate should be sent for cytologic study, biochemical analysis, Gram stain, and aerobic and anaerobic studies, including bacterial sensitivity tests. Orringer showed that the gross appearance and odor of pleural fluid are among the most significant items of information obtainable by thoracentesis.55 Thin fluid, even with posi-

Ch086-F06861.indd 1061

1061

FIGURE 86-9 CT scan of a postpneumonic empyema during the fibrinopurulent stage. This image is of a posteriorly located inverted Dshaped density (pregnant lady sign).

FIGURE 86-10 CT scan of the chest showing a large empyema compressing the underlying lung.

tive bacteriologic findings, may respond to selective antibiotic therapy and thoracentesis; thick pus requires formal surgical drainage. Anaerobic pus is usually foul; aerobic pus has no offensive odor. Several authors have shown that to recover anaerobes careful attention must be paid to the technique. Varkey and colleagues noted that the variability in the reported incidence of anaerobic empyemas may be caused by differences in the methods of transportation and processing of the pleural fluid specimens.51 In addition to standard bacteriologic examinations, pleural fluid should also be sent for viral, tubercular, and fungal cultures. The relevance of pleural fluid analysis in empyema diagnosis is controversial especially regarding its biochemistry (Table 86-4). Some authors28,56,57 believe that pleural effusions with low fluid pH (<7.0), low glucose concentration (<50 mg/dL), and high LDH contents (>1000 IU/L) should be drained because these parameters indicate a complicated effusion or impending empyema. These changes can be detected before

1/21/2008 1:57:05 PM

1062

Section 4 Pleura

TABLE 86-4 Analysis of Pleural Effusions and Empyema

TABLE 86-5 Regrouping of Patients With Empyema Into Diagnostic Classes

Specimen

Simple Parapneumonic Effusion

Complicated Parapneumonic Effusion

Empyema

Pleura

Thin, leaky

Fibrin deposition/ loculi

Thick granulation tissue

Fluid appearance

Clear

Opalescent

Pus

White blood cell count

PMN+

PMN++

PMN++

Bacteria

−/Sterile

+/−

+/+

pH

>7.3

<7.1

<7.1

Lactate dehydrogenase (U/L)

<500

>1000

>1000

Glucose (mg/dL)

>60

<40

<40

Drainage: closed-tube drainage, VATS drainage, open thoracotomy

Fluid/serum glucose (U/L)

>0.5

<0.5

<0.5

Antibiotics: appropriate selection

Type

Characteristics

Class I

Low pH pleural effusion

Postpneumonia effusion, pleural fluid, pH < 7.2, negative pleural fluid cultures

Class II

Classic empyema

Positive pleural fluid culture, absence of multiple loculations, chest radiograph visualization

Class III

Complicated empyema

Multiple loculations on chest radiograph, initially or subsequently, or trapped lung

TABLE 86-6 Principles of Therapy for Acute Empyemas

organisms are found on Gram stain or culture, and they usually occur concomitantly. In uncomplicated effusions, the pH is greater than 7.3, the glucose level is higher than 60 mg/ dL, and the LDH concentration is less than 1000 IU/L; these effusions do not need to be drained (Light, 1985).58 If the patient has free-flowing, nonpurulent fluid with borderline biochemical parameters, Sahn and Light recommend appropriate antibiotic therapy and repeated thoracentesis 12 hours later.59 If the pleural fluid measurements are stable or improving, continued antibiotic therapy is warranted, but if there is worsening of these measurements, chest tube drainage is generally necessary for resolution. In a series by Potts and colleagues, three categories of parapneumonic effusions were characterized.60 The pH was greater than 7.3 in all 10 benign effusions, and spontaneous resolution occurred in each case. All 10 empyemas and the four loculated effusions had pH levels that were less than 7.3. Physiologically, these biochemical changes are explained by an increased leukocytic activity and acid production in the pleural fluid. Based on all these diagnostic parameters, Van Way and colleagues proposed a method of regrouping patients with empyemas by diagnostic class.61 Patients with class I empyemas (n = 12) were treated with short-duration chest tubes, and there were no deaths. Patients with class II empyemas (n = 28) were treated with chest tubes, and there were 2 deaths (7%). There were 40 patients with class III empyemas, and most required some form of surgical intervention (Table 86-5). Despite the usefulness of all of these tests, the proper clinical staging of parapneumonic effusions remains difficult. How does one differentiate simple inflammatory reaction likely to respond to antibiotics and drainage from early organization? How does one differentiate between the very acute stage in which pleural fluid is thin and the purulent stage in which fibrin is deposited over pleural surfaces? Values of pleural fluid chemistry, such as pH less than 7.2, correlate

Ch086-F06861.indd 1062

Class

Enzymes: intrapleural fibrinolytic enzymes (streptokinase or urokinase) Supportive measures: respiratory care, nutrition, therapy for comorbid conditions Therapy: underlying cause of empyema VATS, video-assisted thoracoscopic surgery.

with loculated effusions but not necessarily with the presence of frank empyema.62 In experienced hands, CT and ultrasonography provide significant information by detecting loculations and thickness of the fibrinous deposits encasing the lung.63 During the investigation of patients with empyema, it is also important to look for the causative process. Sullivan and colleagues, for instance, showed that decayed teeth, retained foots, or advanced periodontal disease were present in 17 of 24 patients with anaerobic empyemas of pulmonary origin.48 Bronchoscopy should be performed to rule out foreign bodies or endobronchial tumors, especially if the patient requires surgery.

MANAGEMENT As emphasized by Cohen and colleagues, empyema management depends on its cause, clinical stage, state of the underlying lung, presence or absence of a bronchopleural fistula, and the patient’s clinical and nutritional status.64

Acute Empyema In acute empyema (Table 86-6), antibiotics are used to control the infection, and intercostal tube drainage is both simple and effective to drain and obliterate the space. Repeated thoracentesis, in conjunction with antibiotic therapy, may be indicated when the fluid is thin and the toxicity is well controlled. According to Moran, antibiotics and thoracentesis can be curative in a large proportion of parapneumonic effusions if the mode of therapy is instituted early enough.65 Conversely, Personne suggests that performing thoracentesis alone is usually a mistake because the

1/21/2008 1:57:05 PM

Chapter 86 Empyema and Bronchopleural Fistula

chances of complete success are minimal.66 It often leads to the formation of multiloculated pockets, which eventually become difficult to drain. Ferguson67 noted that “although simple drainage and antibiotic therapy remain the norm, an enlarging group of patients, particularly those with complicated or postoperative empyemas, will require aggressive surgical intervention. Early recognition of these patients and institution of surgical intervention, as primary therapy rather than as a last resort, will likely result in improved survival and shortened hospital stay.” Open drainage plays no role in the therapy of acute empyemas.

Drainage Surgical removal of pus by proper pleural space drainage remains the gold standard of empyema management. This procedure not only evacuates the pus but also allows for the apposition of pleural surfaces, a feature that eventually leads to obliteration of the space and resolution of the infection. The timing of the surgical drainage and the choice of a drainage procedure must be tailored to the individual patient.54 Pleural drainage can be accomplished by closed-tube thoracostomy, by pigtail catheter, by VATS, or by open thoracotomy. The technique of intercostal tube drainage is simple and well described in every textbook of thoracic surgery. When inserting a chest tube without proper visualization of the space, the surgeon must be careful not to penetrate the diaphragm, which is often retracted upward. The chest tube (28-36 Fr) is connected to an active suction system, usually with a pressure of −20 cm H2O. If the lung expands well, the chest tube is left under suction drainage for a period of 5 to 7 days or until the space is permanently obliterated. This is likely to have occurred when the daily amount of drainage is low (<100 mL/day), when there are no up-and-down movements of fluid in the tubing, or when no pneumothorax develops if the tube is opened to atmospheric pressure. At this point, the tube can simply be removed, or closed drainage can be changed to open drainage by cutting it close to the chest wall. The tube is then shortened at the rate of about 1 inch per week or until granulation tissue and fibrosis lead to its spontaneous expulsion from the pleural space (Fig. 86-11).

1063

When the lung expands well with tube drainage and there is no persistent empyema cavity, intrapleural irrigation of antibiotics does not appear to provide additional advantages.68-70 Intrapleural irrigations were required in 96 of 236 patients (44%) with empyema reported by Blasco and colleagues.71 In these individuals, initial drainage was inadequate either because fibrin clots occluded the chest tube or because persistent loculations and adhesions prevented adequate lung re-expansion. Several patients (n = 36) required more than one chest tube for these irrigations. In that series, the overall mortality was low (2%), and only 20 patients had permanent radiologic sequelae. Another option for closed pleural space drainage is to use small-based, pigtail catheters positioned with ultrasound or CT guidance. This technique is less traumatic, but often these patients will need several CT scans and replacement of blocked or misplaced catheters. Lee and colleagues72 and Crouch and coworkers73 have reported success rates ranging from 70% to 90%, but these were for very early disease. Pigtail catheters should not be used when thick pus is likely to clog these small-bore tubes. The use of pigtail catheters should be reserved for patients who are not surgical candidates because of comorbidities or contraindications to surgery for other reasons. In 1991, Wakabayashi reported on expanded applications of therapeutic VATS.21 In his series, 20 patients underwent thoracoscopic débridement of chronic empyema; the lungs re-expanded in 18 patients, in whom the duration of empyema had been less than 2 months, and failed to re-expand in 2 patients who had empyema for 4 and 7 months, respectively. Since then, several authors have used this technique as a primary method to drain acute empyemas (Striffeler et al, 1998).63,74-77 After ultrasound or CT delineation of the location and size of the collection, VATS techniques are used to evacuate the pus, disrupt the loculations containing fibrin clots and membranes, remove the fibrinous membranes, reexpand the lung, and position the chest tubes in the most dependent portion of the space. Because it is minimally invasive, VATS is also an ideal procedure for most of these critically ill patients, who are at high surgical risk not only because of their illness but also because of a prior debilitating condition or immunosuppressed status. Deslauriers believes that

FIGURE 86-11 A, A chest tube being shortened by approximately an inch weekly. B, A safety pin is used to prevent the tube from falling out or back into the space.

Ch086-F06861.indd 1063

1/21/2008 1:57:06 PM

1064

Section 4 Pleura

TABLE 86-7 Thoracoscopic Treatment of Empyema Author (Year)

No. Patients

Mackinley et al76 (1996) 74

Landreneau et al

(1995)

Striffeler et al77 (1998) 63

Cassina et al 79

Luh et al

(1999)

(2005)

Wurnig et al80 (2006) 81

Solaini et al

(2007)

Stage

Success (%)

Complications (%)

Mortality (%)

31

II

90

16

19

76

II, III

83

3

0

67

II

72

4

6

45

II, III

82

11

0

210

II, III

86

25

3

130

II, III

97

9

0

II

97

11

0

80

VATS débridement of fibrinopurulent empyemas represents one of the best indications of therapeutic VATS techniques.78 In 1996, Mackinley and colleagues reported 64 cases of fibrinopurulent empyemas treated by formal thoracotomy (n = 33) or thoracoscopy (n = 31).76 The mortality was similar in both groups (3%), but VATS techniques had substantial advantages over thoracotomy in terms of resolution of the disease, hospital stay, and cosmetic outcome. In 1999, Cassina and colleagues presented a prospective, selected single-institution series of 45 patients with pleural empyema who underwent operation.63 In 37 patients (82%), VATS débridement was successful, and there were no complications during the procedure. At follow-up (n = 35), with pulmonary function tests, 86% of the patients treated by VATS showed normal values. A summary of the world’s literature on thoracoscopic treatment of empyema is shown in Table 86-7.63,74,76,77,79-81 Overall, these techniques are safe and efficient for stage II empyemas but inefficient for organized disease. Before the advent of VATS techniques, several authors33,61,65,81 proposed early open thoracotomy to drain acute empyemas that could not be adequately evacuated by tube thoracostomy because of multiple loculations or inaccessible purulent collections.39 This procedure was incorrectly called “early decortication” by many of these authors.35,82,83 With the patient under general anesthesia, a small incision is made over the cavity and a short segment of rib is resected. The empyema is then completely evacuated and, through a separate incision, a large-bore chest tube is secured in the most dependent portion of the space. In Fishman and Ellertson’s series, six of eight immunosuppressed patients survived early decortication and were discharged 3 to 6 weeks after the operation.84 Morin and colleagues also reported excellent results with early thoracotomy in 23 patients with posteriorly located, D-shaped densities seen on lateral chest radiograph.83 Miller85 and Pothula and Krellenstein86 also advocate early aggressive surgical approach when the standard chest tube does not relieve the loculated fluid because the surgical risk is low and the expected outcome is good in more than 95% of patients. Of 52 patients reported by Pothula and Krellenstein, there were no operative deaths, and good results were obtained in 50 of 52.86 In substance abuse patients, exploration thoracotomy is recommended within 24 to 48 hours if the patient has toxic manifestations despite drainage or if there is evi-

Ch086-F06861.indd 1064

dence of parenchymal destruction, multiple loculations, or trapped lung.33

Antibiotics Several factors, such as the pathogen involved, the stage of the empyema, and the immune status of the host, determine the response to antibiotics. Concentrations of antibiotics in the infected pleural space must be high enough to neutralize the pathogens, a feature possible during the exudative phase of disease but less likely during the fibrinopurulent or organization stages (Bergeron, 1990).49 Initially, and while awaiting the results of antibiotic susceptibility, a semisynthetic penicillin, such as methicillin, or clindamycin should be given if the empyema has been acquired in the community or if the Gram stain reveals clusters of gram-positive cocci that are compatible with S. aureus (Bergeron, 1990).49 A guide to the choice of antibiotics is given in Table 86-8. In patients with anaerobic, gram-negative empyema, penicillin is the antibiotic of choice; clindamycin can also be used. It is generally agreed that antibiotics should be continued for a period of 2 to 4 weeks.

Intrapleural Enzymes and Talc During the transitional stage of empyema progression, fibrin is deposited in the pleural space, and fibrin strands develop between visceral and parietal pleura, forming loculi and preventing lung re-expansion despite well-placed chest tubes. During that period, the use of intrapleural fibrinolytic enzymes has been described as a method to break up these strands and to improve drainage. The use of intrapleural streptokinase for the therapy for acute empyemas was first described by Tillett and Sherry in 1949.86a However, allergy and bleeding complications, probably owing to impure preparations and prolonged dwelling times, prevented adoption of these techniques.87 In 1977, Bergh and colleagues showed that streptokinase at the dose of 250,000 U diluted in 100 mL of physiologic saline solution stimulates the liquefaction of fibrin clots and, in some cases, facilitates the subsequent drainage of the pleural space.88 In 1994, Robinson and colleagues presented a series of 13 consecutive patients with fibrinopurulent empyemas who had incomplete drainage (Robinson et al, 1994).89 Streptokinase (250,000 U in 100 mL of 0.9% saline solution) or urokinase (100,000 U in 100 mL of 0.9% saline solution) was instilled daily into the chest tube, and

1/21/2008 1:57:06 PM

Chapter 86 Empyema and Bronchopleural Fistula

TABLE 86-8 Choice of Antibiotics for Empyema Organism

First Choice

Gram-Positive Bacteria Streptococcus Penicillin pneumoniae Clindamycin Ceftriaxone Staphylococcus Penicillin aureus (BL−) S. aureus (BL+) Oxacillin S. aureus (methicillin resistant) S. epidermidis (BL−)

Vancomycin Teicoplanin Penicillin

S. epidermidis (BL+)

Oxacillin

S. epidermidis (methicillin resistant) Streptococcus faecalis

Vancomycin Ampicillin Gentamicin

Gram-Negative Bacteria Pseudomonas Ceftazidime aeruginosa

Escherichia coli Proteus mirabilis Haemophilus influenzae

Bacteroides fragilis

Cefazolin Cefuroxime Cefamandole

Amoxicillin Clavulanate Clindamycin Metronidazole

Alternative

Erythromycin

Cefazolin Clindamycin Cefazolin Clindamycin Ciprofloxacin Aminoglycosides Cefazolin Clindamycin Cefazolin Clindamycin Cefazolin Clindamycin Vancomycin

Imipenem Aminoglycoside Piperacillin Ticarcillin Ciprofloxacin Cefamandole Cefoxitin Ampicillin (if sensitive) Cefuroxime Ampicillin (if sensitive) Amoxicillin Clavulanate Cefoxitin

the tube was clamped for 6 to 12 hours, followed by suction. This regimen was completely successful in 10 of 13 patients (77%), with resolution of the empyema, eventual withdrawal of the chest tubes, and no recurrence. In 1997, Davies and colleagues reported the benefits of this technique in a randomized, controlled trial.90 Twenty-four patients with infected, community-acquired parapneumonic effusions were studied, and all had either frankly purulent or Gram-stain– positive pleural fluid. These patients were treated by drainage and either intrapleural saline flushes or intrapleural streptokinase given as 250,000 IU in 20 mL of saline with a 2-hour dwelling time daily for 3 days. The streptokinase group drained more fluid and showed greater improvement on chest radiograph at discharge. Surgery was required in three control patients but in none in the streptokinase group. Another randomized trial of empyema therapy by Wait and colleagues compared pleural drainage and fibrinolytic therapy with VATS with regard to efficacy and duration of hospitalization.91 In patients with loculated, complex, fibrinopurulent, parapneumonic empyema, this study showed that a primary treatment strategy of VATS was associated with a higher efficacy, shorter hospital duration, and lower cost. Currently streptokinase is not available for patient use in the United States.

Ch086-F06861.indd 1065

1065

Urokinase, an enzyme isolated from human urine and acting through activation of plasminogen, can also be used for the lysis of loculated pleural effusions.92,93 In a prospective, double-blind study, Bouros and colleagues concluded that urokinase could be the thrombolytic of choice given the potential of dangerous allergic reaction to streptokinase and the relatively small cost of urokinase.94 In a series by LopezRivero and colleagues, 22 patients with empyema were treated by intrapleural instillation of urokinase (200,000 IU) three times a day.95 Depending on the clinical and radiologic response, this treatment was continued for 48 hours, sometimes with lower dosage. Ninety-five percent of empyemas were completely drained after an average dose of 900,000 IU, and only one patient had to undergo surgery because of treatment failure. The use of talc has also been described by Weissberg and Kaufman.96 They reported on five patients with fibrinopurulent empyema who did not respond to conventional therapy and in whom intrapleurally insufflated talc powder led to pleurodesis. Although no side effects were observed, this technique should clearly be restricted to a few selected patients. Currently, talc is not recommended in patients with culture-proven or suspected infected pleural space.

Supportive Measures Supportive measures, including proper respiratory care with therapy of associated respiratory infection and obstructive pulmonary disease and maintenance of nutrition by enteral feedings, are essential for the successful management of early empyemas. Active chest physiotherapy is particularly important to promote lung re-expansion and prevent chest wall contraction. Because nearly 50% to 60% of patients have a major associated medical illness, it is imperative that this condition is diagnosed and appropriately managed.

Chronic Empyema Usual causes of chronicity include a delay in diagnosis, inadequate antibiotic therapy, improper drainage during the acute phase, continuing reinfection (e.g., that which occurs with a bronchopleural fistula or lung abscess), presence of a foreign body, or presence of a specific infection (e.g., tuberculosis or fungal infection). Chronicity is diagnosed by persistent or increasing fever and chest pain, thick pleural fluid, unresolving radiologic findings, and incomplete re-expansion of the lung after closed drainage.97 When the empyema has reached this stage, simple forms of therapy, such as rib resection, open drainage, or window thoracostomy, may be useful initially, but they are, as a rule, ineffective for definitive space obliteration. Decortication of the lung, space filling by muscle transplants, space collapse, and space sterilization are alternative therapeutic options that should be considered before a final decision is made. It is most important to weigh all options before a decision is reached so that nonreversible procedures are not performed.

Rib Resection Drainage and Open Thoracic Window The first therapeutic priority is to provide adequate drainage of the empyema. In poor-risk patients, this can be done either by inserting a large drainage tube or by the creation of an

1/21/2008 1:57:06 PM

1066

Section 4 Pleura

open thoracic window. Lemmer and colleagues noted that early rib resection, especially for postoperative empyemas and for empyemas that have occurred in immunosuppressed patients, was likely to result in fewer therapeutic failures.98 In their series, control of the empyema was obtained in 10 of 11 patients treated by this method. Rib resection drainage is a relatively minor procedure, but it should be done only at a time at which sufficient adhesions have formed between the visceral and parietal pleura. When the pleural fluid consists of 75% sediment, the empyema can be considered to be in a chronic stage, and rib resection with open thoracic window can be safely performed. It is primarily indicated for debilitated, poor-risk patients and for patients with small residual spaces that are expected to obliterate early.99 Rib resection is usually performed with the patient under general anesthesia. It requires the resection of a short segment of rib over the most dependent part of the cavity, the opening and deloculation of the space, and the insertion of a large multifenestrated tube into the cavity. If the visceral pleura is thin and “stretchable,” space obliteration may eventually occur through lung re-expansion, contraction of the space, and filling by granulation tissue. With this technique, the recovery period is long and frequent dressing and tube changes are usually needed. In Conlan and colleagues’ series, 50 patients with chronic empyema without bronchopleural fistula were treated with rib resection, closed-tube drainage, and twicedaily instillation of 2% taurolidine solution into the empyema space through the drainage tube.100 Forty-one patients underwent further therapy, which consisted of drain removal, decortication, or open-window thoracostomy. A more permanent form of drainage can be established by the creation of an open-window thoracostomy. This was first described by Samuel Robinson from the Mayo Clinic in 1916 in a patient with nontuberculous empyema.101 However, this technique of open-window thoracostomy is usually credited to Dr. Leo Eloesser in 1935 and bears his name; he described it as a drainage procedure for acute, tuberculous empyemas.16 This open thoracic window is particularly useful for patients in whom long-term drainage may be required.102 The advan-

FIGURE 86-12 Open thoracic window that closed spontaneously by re-epithelization from the skin flaps.

Ch086-F06861.indd 1066

tages of the technique are that the cavity can be easily irrigated and cleaned and that the dressings can be changed daily on an outpatient basis. Given time, some of these windows close spontaneously, either by filling of the space with granulomatous tissue or by complete re-epithelialization from the skin flaps (Fig. 86-12). Free skin grafts can also be used to stimulate faster closure. In most cases, however, the space is too large for spontaneous closure to occur (Fig. 86-13). In these cases, the window may have to be left open permanently or it may be closed at a later stage with a muscle interposition flap on a pedicle. More recently Thourani and colleagues from the author’s institution reported a series of patients who underwent a modified Eloesser flap for chronic empyema.103 The flap differed from the original flap in that it was an inverted U shape flap of skin and subcutaneous tissue (Figs. 86-14 to 86-19). This modification was originally described by Symbas and colleagues in 1971.104

Space Sterilization Sterilization of chronic persistent empyema cavities was originally described as a therapeutic option for parapneumonic empyema spaces. According to Virkkula and Eerola,102 Heuer, in 1929,105 first described space sterilization techniques when he discussed the therapy in 24 patients with chronic empyemas, some of which were of tuberculous origin. He used drainage and sterilization of the empyema cavities with antiseptic chemicals. In a number of the patients, he tried, in addition to space sterilization, operative maneuvers that involved the parietal pleura. One of the most important contributions to the therapy of chronic empyema was made by Clagett and Geraci in 1963, when they reported a technique of sterilization for the treatment of postpneumonectomy empyemas.106 This technique has been effective in 50% to 70% of patients who do not have an associated bronchopleural fistula.107,108 More recently an updated series from Dr. Clagett’s former institution, the Mayo Clinic, reported on 84 patients who underwent a Clagett procedure consisting of open pleural drainage, serial

FIGURE 86-13 CT scan of a large open window thoracostomy.

1/21/2008 1:57:06 PM

Chapter 86 Empyema and Bronchopleural Fistula

1067

Left lung

Infected left lower lobe space

FIGURE 86-14 Left chronic empyema.

Proposed inverted ‘U’ incision

FIGURE 86-15 Proposed incision for modified Eloesser flap. The proposed inverted-U incision is in the left chest.

Ribs to be resected

Ribs resected

Tongue flap

Tongue flap

FIGURE 86-16 Incision performed with tongue flap reflected and proposed ribs to be resected identified.

FIGURE 86-17 Incision performed with tongue flap reflected and proposed ribs resected.

operative débridements, and eventual chest closure after filling the pleural cavity with a débridement antibiotic solution containing gentamicin, neomycin, and polymyxin B.109 Modification of the procedure was performed if a bronchopleural fistula was present. The bronchial stump would be isolated in the mediastinum and re-closed at the carina with interrupted polypropylene suture. The re-closed stump is

reinforced with an intrathoracic transposition of extrathoracic skeletal muscle, usually the serratus anterior muscle if available. In the Mayo Clinic series, a bronchopleural fistula was present in 55 patients (65%) and was successfully closed in all patients.109 Overall, 81% of patients had a healed chest cavity without evidence of recurrent infection at a median follow-up of 1.5 years. The bronchopleural fistula remained

Ch086-F06861.indd 1067

1/21/2008 1:57:07 PM

1068

Section 4 Pleura

closed in all patients. An intrathoracic muscle transposition flap is essential for successful and persistent closure of a postpneumonectomy bronchopleural fistula as previously described by Pairolero and colleagues.110 Patients younger than 65 years of age and an interval between pneumonectomy and empyema of greater than 15 weeks were independent predictors of long-term survival. Space sterilization techniques can also be used in patients who have empyemas but no previous pneumonectomy.111,112 In Weissberg’s series,112 open-window thoracostomy was created in 12 patients with empyema and sepsis after conventional therapy with antibiotics and drainage had failed. Complete obliteration of the empyema cavity by granulation tissue occurred in 11 of 12 patients within 1 to 8 months; the time variation depended on the size of the space. SmolleJuttner and colleagues113 also showed that open-window thoracostomy is worthwhile because of its potential for rapid and low-risk control of severe, life-threatening, septic conditions in desperate cases of pleural empyema.

Completed procedure with tongue flap sewn down

Space-Filling Procedures

FIGURE 86-18 Completed modified Eloesser flap with tongue flap sewn to the base of the empyema cavity.

Left lung

Drained empyema cavity

Skin flap attached to base of empyema cavity Skin flap

Diaphragm

FIGURE 86-19 Cross-sectional view of the drained empyema cavity and the completed modified Eloesser flap with tongue flap sewn to the base of the empyema cavity.

Ch086-F06861.indd 1068

Decortication and Empyemectomy. Decortication is defined as the removal of a constricting peel over the lung, and empyemectomy is the complete excision of the empyema space and of its contents without entering it. In empyemectomy, both visceral and parietal peels are excised together, avoiding contamination of either the thoracotomy wound or the free pleural space. Although decortication is the procedure most commonly used, both operations are performed to encourage lung re-expansion in the hope of filling the space. In general, decortication is seldom required because most patients with parapneumonic empyemas are treated before the disease process reaches the chronic organizing stage. In Blasco and colleagues’ series, only 8 of 236 patients required decortication.71 Personne also emphasized that decortication should be reserved for patients with obvious treatment failures.66 The timing of decortication in relation to the diagnosis of chronic empyema remains somewhat controversial. Many authors believe that it is best to wait 3 or more months after diagnosis to achieve maximal functional respiratory recovery.66,86 Others recommend decortication at an earlier stage when the peel of the empyema is not excessively adherent to the lung and therefore may be removed without important blood losses or parenchymal tears.114 In addition, when decortication is performed before significant ingrowth of fibrous tissue into the lung has occurred, the visceral pleura does not need to be removed, thus minimizing the likelihood of lung injuries. The success rates of decortication depend on an intact visceral pleura, a lung that is expandable, and, most importantly, a space that can be completely obliterated by pulmonary re-expansion. In a series of 94 patients reported on by Sensenig and colleagues, the results of decortication for chronic, nontuberculous empyema were as follows: good, 79; passable, 9; and poor, 2.115 Four patients died; all were older than 45 years of age. In another report of 25 patients with chronic empyemas, Martella and Santos showed that decortication should be the preferred treatment of chronic post-

1/21/2008 1:57:10 PM

Chapter 86 Empyema and Bronchopleural Fistula

pneumonic empyemas because it was the only procedure that permitted complete débridement of the space and full re-expansion of the affected lung.116 To eradicate any potential source of chronic infection completely, it is occasionally necessary to resect a segment of lobe of the lung adjacent to the empyema. In a few cases when the lung is completely destroyed, total pleuropneumonectomy may be necessary. Several authors have also noted that significant functional improvement cannot be achieved after decortication in patients with significant underlying lung disease.117-119

Muscle Transposition Since first reported by Abrashanoff in 1911 and Robinson in 1915 and 1916, transposing muscle flaps on pedicles has been used extensively for the therapy for residual, infected pleural spaces, whether closed or in the form of open-window thoracostomies.119-130 The indications for muscle transposition include obliteration of persistent pleural spaces and reinforcement of the bronchial stump after closure of an associated bronchopleural fistula.125 Viable tissue in the cavity is essential for successful surgery. The muscle selection should be based not only on its availability but also on the location, size, and shape of the empyema space. The blood supply, innervation, and bulk of the muscle must be preserved, and it must fill the entire space because empyema is likely to recur if a residual space is left. No attempt to close small bronchopleural fistulas (<2 mm) should be made; however, large fistulas must be débrided and closed. The space should always be drained during the first 10 to 12 postoperative days.

Thoracoplasty The concept of resecting ribs to decrease the size of the thorax and collapse infected spaces was first described by Estlander in 1879 and Schede in 1890.15,16 In 1937, Alexander redefined some of these principles.131 He proposed a posterior extramusculoperiosteal approach through which residual spaces could be collapsed in most cases. During the last 30 years of the 20th century, collapse therapy lost much of its popularity because it is considered by many to be a mutilating and poorly tolerated operation. Two studies have shown, however, that extrapleural thoracoplasty is an excellent therapeutic option for selected patients. In the Hopkins and colleagues series of 30 patients, the operative mortality was 10% and permanent space closure was obtained in 82% of the survivors.132 Gregoire and colleagues showed that in 17 patients who underwent one-stage thoracoplasties for the therapy for postpneumonectomy empyemas, there were no operative deaths, and immediate control of the empyema was obtained in 15 (88%) patients.133 In 1989, Nakaoka and colleagues presented the cases of 22 patients with chronic empyema thoracis who underwent decortication.134 In 11 of them, decortication alone did not achieve sufficient lung re-expansion, and the parietal wall was collapsed, without rib resection, to contact the surface of the decorticated lung. All 11 patients had a one-stage cure, and in all, pulmonary function was well preserved. In another

Ch086-F06861.indd 1069

1069

series, Laisaar and Ives described the use of partial thoracoplasty with omental transplant as a method to treat postpneumonectomy empyemas.135 In 5 patients there were no recurrences of the empyema, and the authors emphasized that the procedure was a one-stage operation without openwindow thoracostomy.

SPECIAL PROBLEMS Bronchopleural Fistula Bronchopleural fistulas aggravate the course of empyemas and present a major therapeutic challenge. The presence of a bronchopleural fistula indicates persistent contamination of the pleural space, difficulties in the re-expansion of the lung, and possible aspiration in the remaining lung. For many patients with empyema, the presence or absence of a fistula makes the difference between recovery, chronicity, or death.

Incidence and Pathogenesis Bronchopleural fistulas usually follow pulmonary resection. In the series of Malave and colleagues, 1307 resections were performed and 35 patients (2.7%) developed bronchopleural fistulas.136 In another study by Vester and colleagues, the overall incidence of postresection fistulas was 1.6% (35 of 2243 resections) and approximately two thirds of the patients with postoperative fistulas had undergone preoperative radiotherapy, chemotherapy, or both.137 Postoperative bronchopleural fistulas can be either at the bronchial or at the peripheral level (alveolar peripheral air leak). Pertinent etiologic factors include endobronchial tuberculosis or infection, contamination of the pleural space during the procedure, devascularization of the bronchus, long bronchial stump, poor surgical technique, or concomitant illnesses. Patients are considered to have a spontaneous fistula if no previous pulmonary resection has been carried out.26 These usually occur in association with tuberculosis, bacterial pneumonia, or lung abscesses. They also occur with spontaneous pneumothoraces, especially those secondary to chronic obstructive lung disease, or to AIDS. In a series by Crawford and colleagues, 44 patients with AIDS were treated for spontaneous pneumothorax, and in 14 of them, a bronchopleural fistula that persisted for more than 10 days developed.138

Clinical Presentation and Diagnosis The most common presenting symptoms of postoperative bronchopleural fistulas are the coughing up of serosanguineous fluid or pus, fever, malaise, and general symptoms of toxicity. On chest radiograph, a previously small space may be enlarging or a newly formed air-fluid level may be noted. Other radiologic signs include lowering or sudden disappearance of a pleural effusion or a mediastinal shift toward the contralateral side. A drop of at least two intercostal spaces is considered significant to suggest a bronchopleural fistula. The diagnosis of a bronchopleural fistula is usually made by bronchoscopy or by observing persistent air leak through the chest tube. Occasionally, late-occurring fistulas and empyema are overlooked until they drain spontaneously through the skin

1/21/2008 1:57:12 PM

1070

Section 4 Pleura

of the chest wall (empyema necessitatis) or they are misdiagnosed as a cancer recurrence.

Management The management of patients with postresection fistulas depends on the reason why the bronchial stump or lung tissue failed to hold the sutures.139 Primary failures result from poor closure technique, persistent pathologic changes in the bronchus, or impaired healing, such as that seen in patients who have undergone radiotherapy. In these cases, the therapy may be conservative, with suction drainage of the pleural cavity and possible use of fibrin sealants applied through the rigid bronchoscope140 or through the flexible fiberoptic bronchoscope.141-143 In some cases, re-closure of the bronchus, reamputation of the stump, additional sealing of the pulmonary sutures, or additional resection may be advisable.139 Secondary failures occur in empyemas in which the bronchial stump reopens because of local pressure by the purulent collection.139 In this situation, drainage should be done initially, followed by definitive management, which consists of bronchial re-closure, muscle flap, or thoracoplasty. These patients are usually very ill, and definitive therapy should be delayed until the empyema has become chronic and the patient’s overall medical condition has improved. Puskas and colleagues showed that direct surgical repair of chronic bronchopleural fistulas may be achieved in most patients by suture closure and aggressive transposition of vascularized pedicle flaps.144

Immunocompromised Patients and Transplant Recipients Immunocompromised patients, defined as individuals with impaired immunity from any cause, are at high risk for infectious complications.145 They include not only patients with AIDS or transplant recipients but also patients on chronic corticosteroid use, patients with malignancies, malnourished patients with congenital or acquired immunoglobulin deficiencies, postoperative patients, and others. The prevalence of pleural effusion in patients with human immunodeficiency virus (HIV) infections ranges from 1.7% in the series of Joseph and colleagues146 to 18.3% in the series of Labadibi and colleagues.147 In 1995, Gil Suay and colleagues studied 983 patients with community-acquired pneumonia and compared 99 patients infected with HIV to 884 patients who had not been infected with HIV.148 Parapneumonic effusions were significantly more common in patients infected with HIV (21/99 [21%]) than patients who were not infected with HIV (116/884 [13%]) (P < .005). In addition, the clinical course of patients with HIV was more severe with higher rates of bacteremias (58% versus 18%). Pleural fluid from the group infected with HIV showed significantly lower glucose levels, and S. aureus was the most common microorganism isolated. Finally, chest tube drainage was required more often in patients with HIV (71%) than in patients who were not infected (44%). There are relatively few actual documented HIV-associated empyemas that have been reported. In 1994, Ambrosi and colleagues described 18 cases that occurred

Ch086-F06861.indd 1070

after chest surgery was done in patients infected with HIV.149 Fifty percent of patients included in that cohort were treated by tube drainage alone, whereas the other patients required formal decortication. In 1998, Hernandez and colleagues reviewed 23 empyemas that occurred in 419 patients with HIV infections seen between 1985 and 1993.150 These were diagnosed by purulent pleural fluid, positive bacteriology, or biochemical abnormalities (pH < 7.10; LDH > 1000 L; glucose <40 mg/dL). Twenty-one patients developed their empyema secondary to community-acquired pneumonia, and parenteral drug abuse was a predominant risk factor. A single species of bacteria was isolated from 10 patients (52%), whereas multiple organisms grew in the remaining nine positive cultures. The most common organisms were S. aureus (23%) and gram-negative bacilli (36%). It is interesting to note that only 10 patients had been previously diagnosed as HIV patients when the diagnosis of empyema was made. The treatment of empyema in patients with HIV infection is similar to that described in patients with non-HIV empyemas. Early closed-tube drainage, specific antibiotics, and intrapleural enzymes should be a part of the therapy in patients with stage I and stage II empyemas. In the series of Hernandez and colleagues, 18 patients had tube drainage and none required surgery.150 Eleven complications developed in 9 patients, and 5 of these 11 complications were related to chest tubes. The mean duration of hospital stay was 26 days. Patients with empyema and HIV infection require prolonged hospitalization for bacteremias. Prolonged air leaks are more common in patients with HIV than in patients who are not infected with HIV. Patients who have undergone transplants are more likely to have virulent respiratory infections and empyemas than are individuals who have not undergone transplantation. Pleural empyemas have been reported after renal,151,152 cardiac,153 and lung154-158 transplantation. Recipients of lung transplants are likely to have pleural complications, mostly because of the prolonged and intense manipulations that occur during surgery. In these cases, the empyema is secondary to bacterial pneumonia or lung abscess. The most common organisms isolated are S. aureus and Pseudomonas aeruginosa. Empyemas secondary to bacterial pneumonia are often preceded by graft dysfunction and prolonged periods of postoperative mechanical dysfunction. Empyema is also more common in patients for whom lung transplant was performed for septic lung disease such as cystic fibrosis or chronic bronchiectasis. In a study by Paris,159 8 of 120 lung transplant patients had postoperative empyemas and all recovered after treatment with closed-tube drainage and specific antibiotic therapy. In 1995, Herridge and colleagues reported pleural complications (seven empyemas) in 30 of 138 patients who had lung transplantation.154 They emphasized that pleural complications are expected in transplant patients for several reasons: 1. The pleural space is completely exposed. 2. Patients receive immunosuppressive agents. 3. Patients may have had previous pleural procedures and complications.

1/21/2008 1:57:12 PM

Chapter 86 Empyema and Bronchopleural Fistula

4. Some patients already have bronchopulmonary infections. 5. Frequent transbronchial biopsies are part of transplant surveillance protocols. In that series, all empyemas occurred after double-lung transplant, and the authors found no significant differences in the incidence of postoperative empyemas between patients with previous septic lung disease and patients with noninfected native lungs. Open thoracotomy was necessary in 2 patients, and 3 of the 7 patients with empyemas eventually died.

SUMMARY Empyema thoracis has been a major medical concern throughout recorded medical history. During the 20th century and particularly over the past 2 decades, management has been influenced by the identification of a spectrum of new and more virulent pathogens and by the increasing incidence of immunologically compromised hosts. New antibacteriologic agents have contributed to major advances in the therapy of these infectious problems. In many centers, early decortication by thoracoscopic techniques is also performed to reexpand the lung and prevent the more serious complications associated with chronicity. The overall mortality rate associated with empyemas continues to decline. Most deaths occur in elderly patients or from conditions that predispose patients to the empyema, rather than from the empyema itself. Other important factors include the cause of the empyema, the bacteria involved, the correct use of antibiotics, and the immunologic status of the host.

COMMENTS AND CONTROVERSIES Every thoracic surgeon needs to have an excellent understanding of the pathophysiology and management of empyema and bronchopleural fistula. In this chapter the author reviews the historical contributions of many surgeons who developed strategies to safely evacuate the pleural space, achieve re-expansion of the lung, or otherwise fill the pleural space. The management of bronchopleural fistula provides special complicating factors. Closure of the fistula and subsequent eradication or sterilization of the cavity is often done sequentially. I believe it is nearly impossible to safely close a large bronchopleural fistula and eradicate the cavity simultaneously. New strategies for empyema management are coming into widespread use. Of particular importance is the acceptance of video-

Ch086-F06861.indd 1071

1071

assisted thoracoscopic surgery as the procedure of choice for the effective evacuation and débridement of the pleural space in early empyema. In addition, Weder has described an aggressive open re-exploration strategy for the management of postpneumonectomy empyema. This strategy of repeated trips to the operating room for débridement and packing ultimately followed by definitive closure within a week creates an effective strategy to avoid the need for chronic pleural space drainage. G. A. P.

KEY REFERENCES Barrett NR: The treatment of acute empyema. Ann R Coll Surg Engl 15:25, 1954. ■ This is an excellent discussion of various therapies that have been applied to acute empyema over the years. Bergeron MG: The changing bacterial spectrum and antibiotic choice in thoracic surgery: Surgical management of pleural diseases. In Deslauriers J, Lacquet LK (eds): International Trends in General Thoracic Surgery. St. Louis, Mosby–Year Book, 1990, pp 197-207. ■ This is a classic review of the bacteriologic findings in empyema and of the principles to follow when selecting antibiotic therapy. Hankins JR, Miller JE, Alter S, et al: Bronchopleural fistula: Thirteenyear experience with 77 cases. J Thorac Cardiovasc Surg 76:755, 1978. Light RW: Parapneumonic effusion and empyema. Clin Chest Med 6:55, 1985. ■ This is a complete review from a medical standpoint of the pathophysiology, investigation, and management of empyemas. Moran JF: Surgical management of pleural space infections. Semin Respir Infect 3:383, 1988. ■ This is a good review article on the surgical management of empyemas. The authors analyze all surgical options to manage empyemas in the acute or chronic form. Robinson LA, Moulton AL, Fleming WA, et al: Intrapleural fibrinolytic treatment of multiloculated empyemas. Ann Thorac Surg 57:803, 1994. ■ This article analyzes the indications, techniques, and results of the intrapleural use of fibrinolytic agents. The authors provide an excellent review of the principles involved in empyema management. Striffeler H, Gugger M, Imhof V, et al: Video-assisted thoracoscopic surgery for fibrinopurulent empyema in 67 patients. Ann Thorac Surg 65:319, 1998. ■ The authors review the indications for early débridement of fibrinopurulent empyemas by thoracoscopic technique. They conclude that VATS is safe and efficient in stage II empyemas but that open decortication should be performed during the organizing stage.

1/21/2008 1:57:12 PM

chapter

TUBERCULOUS PLEURAL DISEASE

87

Paula A. Ugalde Sérgio Tadeu L. F. Pereira

Key Points ■ Pleural tuberculosis occurs 3 to 7 months after primary pulmonary

■ ■ ■ ■ ■

■ ■ ■

tuberculosis and is usually secondary to the rupture of a subpleural caseous focus. Pleural tuberculosis is self-limited, with 80% of patients achieving complete remission without treatment. If pleural tuberculosis is left untreated, 65% of patients will develop active (pulmonary or extrapulmonary) disease within 5 years. Pleural needle biopsy of pleural tuberculosis for histologic and microbiologic study has 80% to 90% sensitivity. Treatment of pleural tuberculosis consists of 6 months of chemotherapy. Tuberculous empyema results from the rupture of a parenchymal pulmonary tuberculous focus with a large number of organisms spilling into the pleural space. In acute tuberculous empyema, bronchopleural fistula is usually present. Chronic tuberculous empyema may develop if an acute empyema is not recognized or is not properly treated. The treatment goals for tuberculous empyema are to clean the pleural cavity until the space is sterile and to obliterate the residual pleural space.

HISTORICAL NOTE To understand the current management of pleural tuberculosis (TB), one must have a background against which presentday concepts can be brought into focus. More than 100 years ago, TB was treated in sanatoria with bed rest, saving all of the patients’ energy to fight the disease.1 Then, from about 1900 until World War II, so-called collapse procedures became the only active approach for patients who failed to respond to rest treatment.2 The principle of the collapse therapy was to fix the chest wall and shrink the lung so that the cavities would stay closed and the tuberculous tissue would progressively turn into scar tissue.3 It started with induced pneumothorax, but the considerable burden of pneumothorax and the infectious risk from repeated puncture led rapidly to the conception of more aggressive surgical techniques. Thoracoplasty with plombage became the main surgical collapse treatment.4 Tuberculous empyema was a common complication of pulmonary TB in the prechemotherapy era. It resulted either from progressive pulmonary TB or from complications of a surgical intervention.5 In 1950, two types of pleural TB empyema were identified: one pure and one mixed. The pure

one was exclusively caused by Mycobacterium tuberculosis infection, and antituberculous chemotherapy with regular thoracentesis was the standard treatment.6 At treatment completion, if significant pleural thickening remained, decortication was indicated.6 In the mixed empyema type, antibiotics were added to the previous scheme to treat the associated bacterial infection. In this case, residual pleural thickening was managed in accordance to the underlying lung illness. If this was severe, a pleuropneumonectomy was indicated. Otherwise, simple pleural drainage was installed.1 The advent of antituberculous chemotherapy in 1945 revolutionized the management of TB.7 Today, we no longer operate on patients for asymptomatic shadows. Contrary to older notions, tuberculous residual disease can be accepted as a sequela with no malignant consequences.

TUBERCULOUS PLEURAL DISEASE The World Health Organization (WHO) estimates that, each year, more than 8 million new cases of TB occur and approximately 3 million people die from the disease.8,9 One third of the world’s population is infected with M. tuberculosis, primarily in the less economically developed countries, where 95% of all cases occur.10 Since the introduction of antituberculous agents, the incidence of TB has decreased significantly in the developed world. Yet, since 1990, this trend has progressively inverted as a result of poor social situations and the increasing prevalence of acquired immunodeficiency syndrome (AIDS).9,11 Among the extrapulmonary presentations of TB, the pleura is the most commonly affected site.12,13 To understand the physiopathology and clinical presentation of pleural TB, it is fundamental to distinguish tuberculous primary infection from chronic tuberculosis infection. The primary infection occurs at the first invasion of the M. tuberculosis bacilli, mostly in young people, and has, in general, a clinically benign course.14-16 Chronic pleural tuberculosis occurs in older persons, usually secondary to recrudescence of dormant residuals of a primary infection, and in general it culminates with pleural empyema.14-16 For a better organization, this chapter has been subdivided into sections dealing with tuberculous pleural effusion, tuberculous empyema, and long-term complications of collapse therapy.

TUBERCULOUS PLEURAL EFFUSION Definition and Pathology Pleural infection due to M. tuberculosis occurs in approximately one third of patients with coexisting pulmonary TB,15 but this incidence can differ among countries.17 Most often,

1072

Ch087-F06861.indd 1072

1/21/2008 1:58:03 PM

Chapter 87 Tuberculous Pleural Disease

pleural TB is a side phenomenon of primary infection, and it seldom requires an operative intervention. Tuberculous effusion originates from the rupture of a small, subpleural caseous focus,18 which allows tuberculous protein to enter the pleural space.19 There, mycobacterium antigens interact with T cells that were previously sensitized to this organism in the primary infection.19 A delayed hypersensitivity reaction is initiated and is responsible for an increased permeability of the pleural capillaries to proteins. As a result, an exudative pleural effusion starts to accumulate (Rich, 1951).19,20 In general, this takes place 3 to 7 months after the primary lung infection (Valdes et al, 1998).21 In this case, pleural primary infection is a fairly benign, self-limited form, with 80% of patients achieving complete remission without treatment.22 However, if it is left untreated, 65% of all infected patients will develop active (pulmonary or extrapulmonary) tuberculous disease within 5 years (Roper and Waring, 1952).23 In adults, when tuberculous pleural effusion occurs in the absence of radiologically apparent pulmonary TB, it may represent the late effect of a primary infection or a reactivation of the disease.24 Reactivation can occur at any time, weeks or decades after primary infection,15,25 mostly if the patient’s immunity is diminished.26 Pleurisy resulting from bacillary spillage from mediastinal lymph nodes or a hematogenous dissemination (miliary TB) is an unusual event.25 Table 87-1 describes the usual mechanisms of tuberculous pleural effusion.

Pleural Cellular Response Once the hypersensitivity reaction has started, an initial neutrophilic response is necessary for the subsequent mononuclear influx.27 Macrophages are the predominant mononuclear cells in the pleural effusion until day 4, with lymphocytes predominating thereafter.28 The local release of cytokines probably induces the sequential expression of specific cell adhesion molecules in vascular endothelium that direct the inflow of the various inflammatory cells. Because of selective enrichment of cells with the helper/inducer (CD4) phenotype, the proportion of T lymphocytes in humans with tuberculous pleuritis is higher in pleural fluid than in blood.28

1073

Clinical Presentation The clinical presentation of TB pleurisy can be subtle or abrupt and severe (Haa, 2000).29 Asymptomatic effusions are thought to be rare.30 Pleuritic chest pain, nonproductive cough, fever, dyspnea, night sweats, and weight loss are the classic symptoms without an elevation in the peripheral white blood cell (WBC) count.31 Median duration of symptoms before consultation is about 14 days if the effusion is secondary to primary pulmonary TB and 60 days if secondary to reactive disease.15 In the elderly, silent disease is not uncommon. The symptoms most commonly reported in published series are cough (71%-94%), fever (71%-100%), chest pain (78%-82%), and dyspnea.30 In the chronic evolution, lowgrade fever, weakness, and weight loss are usually present. Coinfection with human immunodeficiency virus (HIV) has changed the clinical presentation of tuberculosis. First of all, AIDS patients with TB have greater proportion of pleural involvement that in the general population.32 Also, data from Tanzania show that patients with tuberculous pleural effusion and HIV seropositivity have a longer period of symptoms, are more symptomatic, and have a greater incidence of hepatosplenomegaly and lymphadenopathy, compared with seronegative patients.33

Diagnosis Tuberculous pleurisy is considered in any patient with an exudative pleural effusion. The diagnosis depends on the demonstration of acid-fast bacilli in the sputum, pleural fluid, or pleural biopsy specimen or the demonstration of granulomas in the pleura. In most cases, however, fluid samples are paucibacillary due to the dilution factor secondary to the hypersensitivity reaction.19 Pleural needle biopsy has proved to be a useful, safe, and simple technique that secures both fluid and pleural tissue and has up to 90% sensitivity (Mestitz et al, 1958).34 Establishing the diagnosis of this infection can sometimes be difficult because the classic findings may not be present. Not rarely, in inconclusive cases, clinicians must rely more heavily on clinical judgment and offer empiric treatment.35

Diagnostic Tests Tuberculin Skin Test or PPD Testing TABLE 87-1 Pathogenesis of Pleural Tuberculosis Pleural Involvement

Mechanism

Rupture of pulmonary subpleural caseous focus

Primary tuberculosis with delayed hypersensitivity pleural reaction

Pleural reactivation

Immunosuppression resulting in recrudescence of dormant residuals of a primary infection

Miliary tuberculosis

Massive spread of bacilli to the bloodstream culminating into the pleura

Tuberculous mediastinal node

Ch087-F06861.indd 1073

Delayed hypersensitivity reaction with consequent exudative pleural effusion

Fifty years ago, the purified protein derivative (PPD) test was an important diagnostic tool. Currently, a negative test can be found in up to 43% of immunocompetent patients36 and in 50% of HIV-infected patients.31,37 With routine bacille Calmette-Guérin (BCG) vaccination and high TB prevalence in some countries, the PPD test in isolation has no diagnostic value.

Pleural Fluid and Tissue Pleural fluid smears are rarely diagnostic,29,38,39 but culture can be positive in approximately 40% of patients.40 Biochemical laboratory studies of the pleural effusion are nonspecific and in general do not help to define the diagnosis.17 Table 87-2 describes the biochemical characteristics of tuberculous

1/21/2008 1:58:03 PM

1074

Section 4 Pleura

TABLE 87-2 Biochemical Characteristics of Tuberculous Pleural Fluid Characteristic of Pleural Effusion

Comment

Exudate21

Protein >3.0 g/dL, LDH >500 IU/L25,31

Low glucose concentration can occur

More characteristic of tuberculous empyema

Low pH can occur

pH 7.40-7.30, pH < 7.30 in 20% of cases

LDH >500 IU/L

Inflammatory pleural reaction is present in 75% of cases21,25,31,37

Lymphocytes predominate40 Hypersensitivity reaction Mesothelial cells in low concentration46

<5% in pleural fluid

Eosinophils in low concentration46

>10% excludes tuberculous pleuritis

LDH, lactate dehydrogenase.

pleural fluid. The pleural effusion is citrine in more than 80% of cases,40 although it may be slightly bloody.41 Pleural tissue can be obtained either via closed percutaneous needle biopsy or by thoracoscopy. In Boutin’s practice, thoracoscopy plays no significant role in diagnosis unless the disease is accidentally found during an investigation of indeterminate pleural effusion.42 The two techniques are believed to have comparable sensitivities, and the needle biopsy is generally preferred in areas where tuberculous pleuritis is common.43,44 The presence of granulomas on histologic examination of the pleura is virtually diagnostic of TB because TB is the cause in more than 95% of patients with pleural granulomatosis, although other disorders, such as sarcoidosis and rheumatoid lung disease, can also cause pleural granulomas.13 Several biopsy specimens (at least three for histologic studies and one for culture) are obtained.45 Tissue culture can be positive even if no granulomas are seen on histologic examination. Therefore, with one procedure we combine histology, microbiology, and cultures, and this provides 80% to 90% efficacy for M. tuberculosis confirmation (Mestitz et al, 1958).34,46 Repeated biopsies are performed if the first is negative and TB is highly suspected.47 Cultures require 2 to 6 weeks, but the use of the radiometric mycobacterium culture system (BACTEC, BD Biosciences, Sparks, MD) could overcome the delay, with results usually available within 18 days.48

Radiology Studies Tuberculous pleural effusions are unilateral in 95% of cases (Figs. 87-1 and 87-2) and occur slightly more often on the right side. Typically, they are small to moderate in size, so a massive effusion favors a nontuberculous etiology (Valdes et al, 1998).21 The size and side of the effusion do not bear on prognosis,41 and the effusion occurs virtually always on the same side as the parenchymal infiltrate.31 Chest radiographs demonstrate tuberculous and pleuroparenchymal disease together in 50% of patients37; however, in pathology analyses, both are almost always present.39

Ch087-F06861.indd 1074

FIGURE 87-1 Radiograph showing left tuberculous pleural effusion with apparently normal right lung.

FIGURE 87-2 Radiograph showing left tuberculous pleural effusion after thoracentesis.

Computed tomographic (CT) scanning is more sensitive in showing interstitial disease and yields more information about the pleural thickening, effusion, and eventual mediastinal involvement. In three fourths of patients with pleural TB, the parenchymal infiltration is located in the upper lobes, which suggests reactivation disease. In the remaining patients, the disease is located in the lower lobes and resembles primary disease.

Adenosine Deaminase Test Two recent meta-analyses with a total of 71 studies on the measurement of adenosine deaminase (ADA) in pleural TB yielded a joint diagnostic sensitivity of 92% to 93%.49,50 Falsepositive results can occur with lymphoma, rheumatoid arthritis, systemic lupus erythematosus, and, rarely, adenocarcinoma (Riantawan et al, 1999).21,51-53

1/21/2008 1:58:03 PM

Chapter 87 Tuberculous Pleural Disease

Pleural fluid lysozyme concentrations are greater than 15 mg/ dL in more than 80% of tuberculous pleural effusions.53,55 The limitation to this test is the overlap between TB and malignant pleural effusions. Also, the highest concentrations of lysozyme are found in pleural empyemas.55

Residual pleural thickening is the most frequent complication of pleural TB regardless of whether adequate antituberculous treatment is used.17 It occurs in up to 50% to 70% of patients.62,63 Usually, the biochemical characteristics of the effusion are high levels of lactate dehydrogenase (LDH)63 and lysozyme and low levels of glucose and pH.64 With these findings, a chest radiograph is obtained every 2 months as routine follow-up. This residual pleural disease is a threat for reactivation disease or further development of a bronchopleural fistula (BPF). Persistence or progression of diffuse pleural thickening leading to entrapment of the lung is an indication for a CT scan (Fig. 87-3). Thereafter, decortication is considered.

Polymerase Chain Reaction Test

Drainage

Surprisingly the polymerase chain reaction (PCR) test has a sensitivity for TB of only 42% to 81% and has a high cost.38,56

Routine complete drainage of pleural fluid at the time of diagnosis does not appear to improve long-term outcomes, even though it might ameliorate the clinical condition of the patient.65 Therapeutic thoracentesis is indicated only for dyspneic patients. Lai and colleagues66 demonstrated that pigtail drainage of newly diagnosed tuberculous pleural effusions did not improve outcome. However, it was uniquely associated with a faster resolution of dyspnea. In their work, pulmonary function and the degree of residual pleural thickening seen on chest radiography were similar in both groups at the end of the study.66 A thoracoscopic decortication for pleural residue can be indicated in the absence of fibrous or calcifying pleural thickening.67,68 This technique is successful to evacuate pleural contents such as fibrin, peels, loculations, and pus and also to fully re-expand the lung.13,67,69 However, waiting until the drug treatment is completely finished before attempting any surgery might be a wise decision. In TB, the resolution of parenchymal and pleural disease is a gradual process requiring months (Ali et al, 1996).70

Sputum Analyses Smears of sputum and cultures are rarely positive in primary cases.29 Cultures have 20% to 50% positive results in the presence of parenchymal disease.18,25,31,37,54 Induced sputum has a sensitivity of up to 52% for M. tuberculosis.54

Lysozyme Test

Management The treatment of tuberculous pleuritis is the same as that of pulmonary TB. The disease is common, its cause is well characterized, and it is, by the current state of the art, both preventable and curable with inexpensive and nontoxic medications.57 It is important that proper treatment be initiated once the diagnosis is established because its administration reduces the incidence of subsequent TB.31 Moreover, in patients in whom the bacilli could not be isolated but the diagnosis is considered most likely because of the clinical spectrum and high local prevalence, empiric treatment is offered. Table 87-3 outlines the goals of treatment for TB pleuritis. Ferrer58 suggested that, in the context of indeterminate pleural effusion that is predominantly lymphocytic and a positive PPD, the high negative predictive value of ADA is very valuable. He advises not to treat if the ADA is less than 45 U/L. Otherwise, antituberculous chemotherapy is recommended. Also, in countries with high prevalence of TB, the finding of a lymphocytic pleural effusion with high ADA level allows empiric treatment, provided that lymphoma and arthritis are not part of the differential diagnosis.

1075

TUBERCULOUS EMPYEMA Definition and Pathology Tuberculous empyema represents an active pleural infection (Sahn and Iseman, 1999)71 and results from a large number

Response to Therapy Within the first 2 weeks of therapy, most patients become asymptomatic and pleural fluid starts to be reabsorbed.59 In a few cases, it can take up to 2 months to control symptoms, and 4 months for fluid absorption. In selected patients, the administration of corticosteroids can shorten the duration of fever and the time required to reabsorb the effusion, although their precise risk and benefit in this setting have not been well defined.60,61 TABLE 87-3 Goals of the Treatment for Tuberculous Pleuritis Prevent subsequent development of active tuberculosis Relieve the patient’s symptoms Prevent the development of fibrothorax

Ch087-F06861.indd 1075

FIGURE 87-3 CT showing residual pleural thickening after 6 months of antituberculous chemotherapy.

1/21/2008 1:58:03 PM

1076

Section 4 Pleura

of bacilli spilling into the pleural space. In 90% of cases, it originates from the rupture of an adjacent parenchymal focus with leak of caseous material, which is responsible for an acute clinical presentation.5 In the remaining 10%, it is caused by reactivation of caseous pleural lesions, in which case the evolution tends to be more chronic, with extensive residual pleural scarring and sometimes even pleural calcification (fibrothorax).39,72,73 This last presentation occurs in severely ill, undernourished, and alcoholic patients and progresses with shrinkage of the chest wall and consequent loss of lung function.26,39 Independently of its physiopathology, TB empyema rarely occurs in patients who received adequate medical treatment, and its management still lies in the surgical principles proposed by Graham73: drainage of the empyema cavity and obliteration of the pleural space.

Tuberculous Empyema With Bronchopleural Fistula In the acute case of tuberculous empyema, BPF is usually present and is a devastating complication. In this context, the pleural fluid has a mixed infection, pyogenic and mycobacterial. Patients clinically present with cough, fever, and increase in their sputum production, which turns yellowish or green. The diagnosis is suggested by classic parenchymal tuberculous lesions and an air-fluid level in the pleural space, which could culminate with hypertensive pneumothorax if not rapidly and properly managed (Figs. 87-4 and 87-5).74 Further treatment depends on the response to drainage, the fistula size, the amount of disease in the lung, the sensitivity of the organisms, and other poorly understood factors. The institution of definitive surgical therapy is delayed until control of the TB infection has been accomplished, as evidenced by sputum and pleural fluid conversion to negative on culture.75

Management of Acute Empyema Current management of tuberculous empyema is eminently surgical. It includes appropriate chemotherapy and antibacterial agents if a BPF is also present (Ali et al, 1996).70 The

FIGURE 87-4 Radiograph showing tuberculous empyema with pneumothorax secondary to a bronchopleural fistula.

Ch087-F06861.indd 1076

primary objective is to clean the purulent material from the pleural cavity until it becomes sterile. Then, the secondary objective is to fully obliterate the residual space, ideally with the least invasive method, through complete pulmonary reexpansion (Al-Kattan, 2000).76 Unfortunately, this group of patients has poor surgical status because of their overall clinical condition (Fig. 87-6).30 A simple pleural drainage can be a life-saving procedure; not only can it control the infection and the patient’s septic state (Ali et al, 1996),70 but it can also prevent contralateral pulmonary aspiration of bacilli content. It is important to allow the pleural drainage to work, along with the specific antituberculous chemotherapy, before taking any major surgical decisions (Ali et al, 1996).70 In the series of Treasure and Seaworth of 12 patients with acute pleural empyema and BPF, tube thoracostomy was the definitive surgical therapy in one third of the cases.75 Once drainage has been accomplished, the following questions must be answered: Has the lung expanded? How compromised is the underlying lung parenchyma? and Is this multiresistant TB? If total lung re-expansion was achieved with a chest tube, this simple method is the definitive treatment. Otherwise, if the cavity is not reducible, most probably the underlying lung is severely affected or there is a BPF, or both (Al-Kattan, 2000).76 In this case, some prefer to maintain the chest tube for several months, whereas others convert this closed drainage system to an open drainage (window thoracostomy) once mediastinal fixation is assured. With associated medical treatment, the fistula may close, and, in addition, most of the pleuroparenchymal disease may heal, and consequently the lung will be released to expand fully. The indication of continuous suction and/or pleural washing through the chest tube is controversial.3 Probably, in a chronic condition with important pleural thickening, neither procedure will benefit the clinical evolution. Only an adequate, well-placed, large chest tube will be effective.

FIGURE 87-5 Radiograph showing tuberculous empyema with a pleural chest tube installed. The significant residual space confirms the lung encasement.

1/21/2008 1:58:04 PM

Chapter 87 Tuberculous Pleural Disease

1077

FIGURE 87-7 Radiograph showing a case of tuberculous empyema successfully treated with pleurostomy (open-window thoracostomy).

A

B FIGURE 87-6 A, Radiograph showing pulmonary tuberculosis with bilateral lung commitment and massive left pleural effusion. B, After the thoracentesis, significant pleural thickening with loss of left lung volume can be seen. Pleural fluid showed empyema.

Open-window thoracostomy can be a good and wise option for the management of tuberculous empyema, even though it implies resection of a portion of one or two ribs and at least 6 months of commitment. In severely compromised patients, this period can be precisely the time to improve their clinical state and their thoracic muscular condition.77 Pleurostomy offers therapeutic efficacy and causes minimal anatomic and functional damage77; however, it jeopardizes the possibility of subsequent decortication. Ali and coworkers (Ali et al,

Ch087-F06861.indd 1077

1996)70 described a series of 47 cases of tuberculous pleural empyema. All patients were initially submitted to chest tube drainage and subsequently to pleurostomy. Twenty-eight achieved complete re-expansion, 11 were in various stages of re-expansion, and 8 did not have any re-expansion at all. In the last group, major lung destruction with fibrosis, bronchiectasis, and pleural adhesions was the rule (Ali et al, 1996).70 So, in cases of poor general health status, an inoperable patient, or extensive calcifications, this type of management is a reasonable alternative for decortication, which is unsuitable (Fig. 87-7). In cases of a residual pleural space after completion of chemotherapy, a two-stage approach, as suggested by Garcia-Yuste and colleages,77 is necessary. Regarding the optimum time to close the thoracostomy, we must consider whether the BPF is still open, whether the pleural cavity is sterile, and the underlying lung condition. Before taking this step, it is wise to finish the antituberculous drug treatment. As in any other pleural infectious collection, the infection is treated first, and then the residual pleural space. The infectious collection and the pleural space can be dealt with at the same time, with one-step surgery, only if, preoperatively, we are certain of lung re-expansion and full obliteration of the pleural cavity.78

Management of Pleural Residual Space Once the pleural infection is under control and the cavity is sterile, it is time to consider several factors—the size of the residual space, the thickening of the pleura, the presence or absence of a BPF, and the illness of the underlying lung parenchyma—in order to determine a rational surgical approach to obliterate the cavity according to the patient’s clinical condition. Only a complete and definitive obliteration of the pleural space will prevent further relapse of the infection. At this point, a bronchoscopy and a CT scan are done. The first is to rule out endobronchial obstruction, and the second is to identify the thickness of the parietal and visceral pleura

1/21/2008 1:58:04 PM

1078

Section 4 Pleura

and the state of the underlying lung parenchyma, now in a maximum state of expansion (Al-Kattan, 2000).76 The classic principle, to convert sputum cultures to a negative status with chemotherapy before resection, is still applied, as recommended by Treasure and Seaworth.75 Considering all these factors, we present here the classic surgical options for management of the pleural residual space.

Decortication Pleural decortication is an established method for obliterating an abnormal pleural space, using the lung as a natural prosthesis to fill the space. It is the best choice once we are sure that the underlying lung is expandable (Al-Kattan, 2000).76 This technique combines removal of the thickened pleura and empyema pocket with an opportunity to improve respiratory function, allow the mediastinum to return to the normal position, and permit resection of the diseased segments of the lung, if indicated.79 Three factors are important to estimate the likelihood of success—the nature of the pleural disease, the underlying parenchymal condition, and the duration of the pleural process—because pleural fibrosis can extend into the lung, withholding its expansion.80 Only in preserved lung can a significant improvement in the respiratory status be achieved.79,81 Technically, the parietal pleura and lung are mobilized in the extrapleural plane, using the fingers as dissectors. It is necessary to remove the thick parietal pleura entirely, to get good movement of the lung and chest wall. This is not feasible with calcified pleural disease. Special care is taken to prevent damage to any mediastinal structures. The visceral pleura is never as thick as the parietal one, but the ease with which it strips varies. The therapeutic aims of this technique are listed in Table 87-4. It is important that the lung be fully expanded at the earliest possible time and kept so until all air leaks have ceased postoperatively. The classic contraindications to this surgery are listed in Table 87-5. Persisting TABLE 87-4 Therapeutic Aims of Pleural Decortication Release and expansion of collapsed lung from encasement Re-establishment of intrathoracic spatial relationships of the lungs and mediastinal structures Control of infection by evacuation and obliteration of the pleural space Proper treatment of any underlying parenchymal disease From Carroll D, McClement J, Himmelstein A, Cournand A: Pulmonary function following decortication of the lung. Am Rev Tuberc 63:231-251, 1951.

TABLE 87-5 Contraindications to Pleural Decortication Stenosis of a main bronchus

pleural spaces after decortication may be managed with pneumoperitoneum, muscle plombage, or thoracoplasty.

Modified Clagget Technique Clagett and Geraci82 described a therapeutic surgery for residual pleural cavities without BPF sterilized by openwindow thoracostomy. In this procedure, a closure of the thoracostomy was performed after the sterilized empyema cavity was filled with an antibiotic solution. This technique was originally designed for postpneumonectomy empyema cavities, but, as a possible means of decreasing morbidity, it can be applied in any residual empyematic pleural cavity. Stafford and Clagett83 reported a success rate higher than 80% in patients with pyogenic empyema. Therefore, in a patient who had undergone open thoracostomy and has a residual sterile cavity, the modified Clagget technique might be a good, less invasive option.

Thoracoplasty or Thoracomyoplasty For the prime purpose of obliterating the pleural space, thoracomyoplasty has also provided satisfactory results.84 It can be done as a unique treatment option, at the same time with a decortication or months after, in case of decortication failure,84 or as plombage to a cavity previously treated by thoracostomy.77 A muscular flap from extrathoracic skeletal muscle might be added to close the BPF and fill the empyema space. Always keep in mind that thoracoplasty is an aggressive, mutilating surgery that implies the removal of several ribs with consequent loss of pulmonary function.85 This procedure is restricted to patients who have either space problems after decortication or diffuse and heavy calcifications obliterating the extrapleural dissection plane. Preoperatively, patients must have good clinical and respiratory performance.

Pneumonectomy or Pleuropneumonectomy If the underlying lung is severely damaged, treatment includes lung resection (Al-Kattan, 2000).76 Pneumonectomy or pleuropneumonectomy often remains as the only curative treatment modality for lung and pleural extensive suppurative disease (i.e., tuberculous empyema associated with an entire damaged lung) (Ali et al, 1996).70,86 Surgery in these cases is better performed after sterilization of the empyema with conversion to negative TB cultures.75 Therefore, as soon as the infection is under control, the definitive lung resection is undertaken (Al-Kattan, 2000).76,87 These procedures require specialized centers to reduce the associated high mortality and morbidity.88 In Shiraishi’s series of 94 patients submitted to pleuropneumonectomy for the treatment of empyema with destroyed lung, operative mortality was 8.5%, and the rate of postoperative empyema was 9.6%.87

Severe uncontrolled disease in the underlying lung

Chronic Tuberculous Empyema

Severe contralateral disease making an operation on the side with the thickened pleura functionally impossible

Chronic empyema may develop because an acute empyema was either not recognized or not properly treated. In some cases, months or even years may elapse before clinical evidence or recurrent infection manifests.89 Patients often come

From Savage T, Fleming HA: Decortication of the lung in tuberculous disease. Thorax 10:293-308, 1955.

Ch087-F06861.indd 1078

1/21/2008 1:58:05 PM

Chapter 87 Tuberculous Pleural Disease

to attention at the time of a routine chest radiograph or after the development of BPF or empyema necessitatis.5,90 Chest radiography and CT show a thick, calcified pleural rind and rib thickening surrounding a loculated pleural fluid. The fluid collection is grossly purulent, thick, and cloudy (Sahn and Iseman, 1999)71 and usually has a high lymphocytic WBC count.39 It may also have an appearance of chyle if cholesterol is present. Laboratory confirmation is necessary to ensure the absence of chylomicrons and high levels of triglycerides.39 Resistant acid-fast bacilli are commonly found on direct examination.72 Acid-fast smear and mycobacterial cultures are also usually positive (Sahn and Iseman, 1999),30,39,48,71 which makes pleural biopsy unnecessary.39 Fluid analysis is done routinely after the beginning of treatment to monitor its effectiveness.13 When chronic empyema has existed for many months or years, the parietal wall becomes so thick and rigid that it cannot easily be brought into apposition with the visceral pleura. These are clear signs of lung entrapment. In this circumstance, an early open-window thoracostomy not only sterilizes the pleural cavity but also identifies those patients who are most likely to succeed with lung expansion. After at least 6 to 12 months of drug treatment, if a pleural cavity persists and the patient has good clinical performance with an underlying expandable lung, empyemectomy or a modified Clagget technique (in the absence of BPF) is a suitable option to obliterate the residual pleural space. Otherwise, if no expansion at all is obtained, a more aggressive procedure is necessary. Thoracoplasty with myoplasty or omentoplasty is the best option.

intracavitary tension, the devitalized ribs offer little or no resistance to the plombage, which may directly erode the ribs.95 In case of hemoptysis, attention must be given because it can be a serious warning of vascular erosion.95 The development of pleural and lung carcinoma in patients submitted to extrapleural pneumonolysis has also been described.94,96 Standard antituberculous treatment in this context is controversial because in the majority of cases the infection is pyogenic.82 Surprisingly, the pleural fluid is sterile on culture in more than half of the patients, and the proven incidence of confirmed TB is relatively low.97 Schmid and DeHaller start chemotherapy until the result of culture is obtained.98 The exudative fluid accumulation is often not of tuberculous origin, and conservative treatment may lead to clinical stabilization.98 Otherwise, the infection in the pleural space is the primary treatment goal, and an approach similar to that used for a chronic TB empyema can be taken. A more aggressive mode of treatment was described by Massard and associates in cases of late empyema in the plombage pleural space. Because, in general, these patients have a trapped lung below an armor of fibrotic scar tissue, they suggested lung decortication to remove all the plombage and a combined thoracoplasty if lung expansion incompletely fills the pleural space.95,99

Acknowledgment The authors wish to acknowledge the contribution of Dr. Cesar Araujo, Assistant Professor at the Federal University of Bahia, Brazil, who has provided all radiographs that are displayed in this chapter.

LONG-TERM PLEURAL COMPLICATIONS OF COLLAPSE THERAPY

COMMENTS AND CONTROVERSIES

Until the early 1940s, when antituberculous chemotherapy became available, the only active treatment for TB was the so-called collapse procedure.2 The main objective of this technique was to collapse the cavitated lung tissue and to obtain scarring of the diseased area in progressive stages. At the first surgical stage, the periosteum was stripped from all the ribs that involved the tuberculous part of the lung, then a pack of prosthetic material (usually Lucite balls) was placed between the denuded ribs and the intercostal bundles, separating the lung from the inside of the rib cage.4 Technically, the lung was separated from the inside of the rib cage, and the space so created was maintained by refills of prosthetic material (extraperiosteal plombage). In his original description, Woods used Lucite balls as plombage and planned a second-stage surgery to remove the prosthesis after the chest wall was stable.4 Not all surgeons followed his suggestions,91,92 which is why patients with plombage are still seen. Several late complications within the plombage space of patients who are still alive have been well documented in the literature.92-94 A number of substances used as plombage for extrapleural pneumonolysis, including Lucite balls, Fiberglas, Teflon, air, oil, plastic bags, and paraffin,4,91,92 have been responsible for late infectious and noninfectious complications. Empyema necessitatis with BPF can be the initial clinical presentation of the infected fluid collection. Owing to the

Involvement of the pleura is a common manifestation of pulmonary tuberculosis thought to be secondary to the rupture of peripheral caseous lesions into the pleural space. It can appear at anytime during the course of the disease, and it can be associated with both primary and reactivation processes. The pleural fluid is usually exudative and the diagnosis can be substantiated by pleural biopsies which will yield acid-fast bacilli or show granulomas in 75% to 80% of patients. The management of tuberculous pleural effusion is essentially medical with antituberculous drugs. Surgical drainage of the pleural space is not indicated unless the effusion is very large and symptomatic. Indeed ill-advised surgical drainage can result in a mixed empyema due to bacterial contamination of the pleural space, a problem which complicates enormously patient management. Late sequelae of uncomplicated tuberculous pleural effusions are uncommon, and most do not require surgical intervention. As discussed by the authors, a bronchopleural fistula usually results from the rupture of a tuberculous cavity into the pleural space. All such patients have a mixed empyema and although the definitive treatment of this condition often has to be individualized, initial management must consist of tube drainage of the pleural space and antibiotic therapy. Definitive therapy, which may at times only consist of permanent open-window thoracostomy, must be delayed until sepsis is under control and tuberculosis is adequately treated with specific antituberculous drugs for several months. J. D.

Ch087-F06861.indd 1079

1079

1/21/2008 1:58:06 PM

1080

Section 4 Pleura

KEY REFERENCES Al-Kattan KM: Management of tuberculous empyema. Eur J Cardiothorac Surg 17:251-254, 2000. Ali SM, Siddiqui AA, McLaughlin JS: Open drainage of massive tuberculous empyema with progressive reexpansion of the lung: An old concept revisited. Ann Thorac Surg 62:218-224, 1996. Haa DW: Mycobacterial disease. In Mandell GL, Douglas RG, Bennett JE, Dolin R (eds): Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 5th ed. Philadelphia, Churchill Livingstone, 2000. McDonald RJ, Reichman LB: Tuberculosis. In Baum GL, Crapo JD, Celli BR, Karlinsky JB (eds): Textbook of Pulmonary Disease, 6th ed. Philadelphia, Lippincott-Raven, 1998, pp 603-630.

Ch087-F06861.indd 1080

Mestitz P, Purves MJ, Pollard AC: Pleural biopsy in the diagnosis of pleural effusion: A report of 200 cases. Lancet 2:1349-1353, 1958. Rich AR: Application of principles of the pathogenesis. In Rich AR (ed): The Pathogenesis of Tuberculosis, 2nd ed. Springfield, IL, Charles C Thomas, 1951. Roper WH, Waring JJ: Primary serofibrinous pleural effusion. Trans Annu Meet Natl Tuberc Assoc 48:150-156, 1952. Sahn SA, Iseman MD: Tuberculous empyema. Semin Respir Infect 14:82-87, 1999. Valdes L, Alvarez D, San Jose E, et al: Tuberculous pleurisy: A study of 254 patients. Arch Intern Med 158:2017-2021, 1998.

1/21/2008 1:58:06 PM

chapter

88

RARE INFECTIONS OF THE PLEURAL SPACE Jorge Nin Vivó Mario Brandolino Ismael A. Conti Díaz Key Points

■ Pleural hydatidosis is a significant health problem in regions where

sheep and dogs are raised and cohabit. ■ Pleural hydatidosis is always secondary to the rupture of hydatid

cysts located in organs adjacent to the pleura. ■ Treatment of the initial accident in pleural hydatidosis should be

pleural hydatidosis and hydatid pneumothoraces.7 In 1945, he described patients in whom surgery had been performed with good results, and in 1946 he published his technique for the treatment of hydatid cysts of the lung.8 The technique consisted of enucleation of the intact hydatid cyst with resection of the emergent pericyst layer. In 1947, Barret described a similar technique.9

done on an urgent basis with tube drainage of the pleural space. ■ Pleuropulmonary contamination is the most common complication

of amebic hepatic abscesses. ■ All pleural effusions secondary to amebiasis should be drained. ■ Pleural actinomycosis is usually secondary to lung infection, which is mostly due to aspiration. ■ Pleural aspergillosis is an extremely serious illness that cannot be eradicated unless the infected space is obliterated.

PLEURAL HYDATIDOSIS Hydatid pleural disease is always secondary to the rupture of hydatid cysts located in organs adjacent to the pleura such as the lung, the liver, or, less commonly, the pericardium, spleen, or chest wall (ribs, spine, or diaphragm). Invasion of the pleural space will eventually develop into so-called secondary pleural hydatidosis.

Historical Note In 1885, Davies Thomas reported 32 hydatid cysts of the lung that were treated by surgery.1 The surgical technique was pleurotomy, cyst puncture, incision, and marsupialization of the pericyst and evacuation of the contents, leaving a chest tube inside the thoracic cavity. Four years later he reported a series of 38 patients treated by this technique with 32 good results. Three hydatid cysts of the lung that ruptured in the pleura were treated by pleurotomy.2 At about the same time, many cases of hydatidosis of the lung were seen in Argentina and Uruguay, where there were two different schools of thought. Some surgeons performed one-stage procedure: fixation of the lung before the opening of the pleural space, cyst evacuation, and pericyst and lung suture, without drainage of the chest cavity.3 In 1910, Lamas and Mondino4 began to perform this surgery in two stages, first inducing pleural adhesions and then evacuating the parasite through these adhesions, thereby avoiding operative pneumothoraces.5 In 1937, Dévé reported 11 cases of secondary pleural hydatidosis; 3 of them were complications from surgery.6 Previously, Armand Ugón also reported cases of secondary

HISTORICAL READINGS Armand Ugón CV: Neumotórax hidático. Archivos Internacionales de la Hidatidosis 1:143, 1935. Montevideo. Armand Ugón CV, et al: La lobectomía en el tratamiento de las secuelas del quiste hidático del pulmon. Bol Soc Cir Montevideo Tomo 17(912):465, 1946. Barret NR: The treatment of pulmonary hydatid disease. Thorax 1:21, 1947. Davies Thomas J: The treatment of pulmonary cysts by the establishment of large openings into the sac, and subsequent free drainage. BMJ 2:692, 1885. Davies Thomas J: The Operative Treatment of Hydatid Cyst of the Liver and Lungs. Melbourne, Stillwell & Co., 1889, p 80. Dévé E: L’échinococcose secondaire de la plèvre. J Chir (Paris) 49:497, 1937. Fossati A: Quistes hidaticos de pulmon: Metodo de Lamas y Mondino/ Tecnica (Personal y breve comentario). An Fac Med (Montevideo) 28:793, 1943. Lamas A: Quelques details a propos du traitement chirurgical au kyste hydatique du poumon. J Chir (Paris) 41:406, 1933. Posadas A: Toracoplastia Temporaria y Parcial. Buenos Aires, Peuser, 1898.

Pathology Pleural Complications of Hydatid Cysts of the Lung Hydatid cysts of the lung are slowly progressive lesions. Their pericyst layer is weak. They can give rise to two varieties of pleural lesions: parahydatid and hydatid pleural complications (Fig. 88-1). In parahydatid complications, the cyst itself is not ruptured and the clinical manifestations are related either to a pneumothorax (periadventitial complication) or to a serofibrinous pleurisy secondary to mechanical or allergic pleural irritation. Hydatid pleural complications are produced by the rupture of both the hydatid and the pericyst layer, giving rise to a hydatid hydropneumothorax. When a bronchoadventitial pleural fistula is also present, secondary infection of the cavity will produce a hydatid pyopneumothorax. Occasionally, the lung will remain collapsed for some time and its surface will be covered by a fibrinous coat that gives rise to loculated 1081

Ch088-F06861.indd 1081

1/21/2008 1:58:50 PM

1082

Section 4 Pleura

1

2

A

5

3

4

B

6

7

C

8

D

FIGURE 88-1 Different presentations of hydatid pleural disease. A, 1, Pyopneumothorax (membrane retention); 2, pneumothorax. B, 3, Heterotopic pleural primitive hydatidosis; 4, pyopneumothorax (water-lily sign). C, 5, Hydatid thorax of hepatic origin; 6, pneumohydatid thorax. D, 7, Hydatid implant; 8, mixed form (hydatid thorax and hydatid pleural implant).

collections of hydatid fluid, air, or pus. With these types of effusions, scolices will grow to become hydatids. This phenomenon is called hydatid thorax. If the bronchopleural fistula closes and the lung re-expands, scolices will remain between the pleural surfaces and eventually grow as independent hydatids. In this form of secondary pleural hydatidosis, which is called hydatid pleural implant (the form most commonly encountered in clinical practice), cysts are mainly located in dependent areas and at the sites of pleural reflections. Infrequently, ruptured lung hydatid cysts will simultaneously contaminate both the pleural space and the bronchus, giving rise to secondary pleural hydatidosis and bronchogenic secondary pulmonary hydatidosis, the so-called massive pleuropulmonary hydatidosis.7 Accidental surgical rupture of a hydatid cyst of the lung may also produce a secondary

Ch088-F06861.indd 1082

pleural hydatidosis. Additionally, there is a rare variety of secondary pleural hydatidosis called heterotopic pleural primitive hydatidosis, in which isolated pericyst rupture allows passage of the intact hydatid into the pleural cavity.

Pleural Complications of Hepatic Hydatidosis Pleural complications of hepatic hydatidosis develop in two different stages: the plastic and the perforative stages. During the plastic stage, the liver cyst, which is normally located posteriorly and superiorly, will grow upward, and the diaphragm will progressively become thinner with areas of relative ischemia. During this process, infection is common because roughly one third of hepatic hydatid cysts have already ruptured in the biliary tract. During the perforative stage, the pathologic process involves the cyst, the diaphragm,

1/21/2008 1:58:51 PM

Chapter 88 Rare Infections of the Pleural Space

the pleura, and the lung; negative intrapleural pressure elevates the cyst toward the chest, a process helped by the obstructive biliary hypertension. When the diaphragm is perforated (the site of perforation usually does not exceed 2 cm), hydatic content reaches the pleural space, producing a hepatic, thoracic, transdiaphragmatic pleural hydatidosis.

Pleural Complications Originating as Osseous Echinococcosis In the spine, the parasite can invade the bone, producing necrosis and destruction of trabeculations and generating new spaces in which it will eventually grow in an irregular and asymmetric form. If this occurs, the hydatic content may invade adjacent tissues such as the pleura and become pleural hydatidosis.

1083

Diagnosis The initial accident is often a dramatic clinical event with sudden and acute thoracic pain, cardiovascular collapse (sometimes leading to shock), and symptoms of hydatid allergy (urticaria, bronchospasm, and fever). Often the patient will have a tension hydropneumothorax with mediastinal shift. When the lung cyst is accidentally ruptured during a surgical procedure, there are no symptoms, although occasionally the patient will show symptoms of allergy. The patient with hepatic, thoracic, transdiaphragmatic hydatidosis may present in an acute condition, with epigastric pain, cough, fever, shortness of breath, biliary phthisis, and anaphylactic reactions. With secondary pleural hydatidosis, symptoms often appear years after the initial accident (Fig. 88-2). Hydatid pleural

FIGURE 88-2 Secondary pleural hydatidosis. A, Standard chest radiograph taken during the initial accident shows a right pyopneumothorax. The patient underwent thoracotomy, pleural drainage, and cavity treatment. Three years later, chest radiograph (B) and CT scan (C) show hydatid pleural implants. D, CT scan taken after treatment with albendazole. Note that the contents of one cyst were expectorated.

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1083

1/21/2008 1:58:53 PM

1084

Section 4 Pleura

implant is often asymptomatic or produces mild symptoms, whereas hydatid cysts located in the thoracic vertex can produce symptoms of mediastinal compression. In the hydatid thorax form, the clinical presentation depends on whether secondary infection is present. Clinical and radiologic diagnoses of pleural hydatidosis are usually presumptive because only the expectoration of hydatid debris or the identification of hydatid elements by thoracentesis are pathognomonic of the disease. The rate of positive results in immunologic testing (indirect hemagglutination, immunofluorescence, electrosyneresis, and double diffusion) varies between 40% and 85%. Immunoelectrophoresis testing is also useful, but Casoni’s reaction, Weinberg’s test, and eosinophils count are less specific. Chest radiographs may show a blurred hemidiaphragm or a loculated pleural effusion. In the hydatid pleural implant, the lung may be riddled with multiple rounded opacities projecting into the pleural space. In heterotopic pleural primitive hydatidosis, a hydatid pneumothorax with or without pleural effusion and a so-called wanderer cyst changing its location with different radiologic positions can be seen. Ultrasonography and CT of the thorax and liver may demonstrate the presence of cystic lesions.

Management Treatment of the initial accident is on an emergency basis, and drainage of the pleural contents is mandatory. Definitive therapy, which is delayed until the anaphylactic reaction is over, consists of removing the parasites, evacuating all pleural contents, and treating the affected lung by meticulous bronchial suturing and capitonnage of the adventitial cavity. The procedure is always completed by profuse pleural swabbing with hydrogen peroxide. Hydatid pleural implant is a diffuse pleural process (Fig. 88-3) in which cysts can be few or many and can be localized, widespread, or even included in thick and fibrous areas of pachypleuritis. Often this arrangement makes the exploration of the whole pleural cavity very difficult. Because few of these cysts can be enucleated, most have to be treated by aspiration followed by injection of a parasiticide solution into the cyst. Thoracotomy alone or with laparotomy is performed electively when the hydatid thorax has originated from a hepatic thoracic transdiaphragmatic hydatidosis. The pleural cavity is first totally evacuated and cleaned. An anterolateral radial diaphragmatic incision is then made in a way that trauma to the vena cava and suprahepatic veins is avoided but a distance from infected tissues is maintained. The contents of the hydatid hepatic cyst are suctioned away with a trocar, and the hepatic cavity is opened wide, totally evacuated, cleaned, and drained by two large-bore tubes, which are inserted through a separate abdominal incision. If there is an associated obstruction of the common bile duct, it is decompressed and drained by simultaneous laparotomy or by endoscopic retrograde cholangiography with papillotomy. Only occasionally do the hepatic cysts need to be treated by hepatic resection. Mebendazole and albendazole are useful

FIGURE 88-3 CT scan showing several pleural implants.

during the postoperative period to prevent seeded scolices from growing.

Clinical Series In 1988, we reviewed the 1841 patients who had been operated on in the Saint Bois Thoracic Department in Montevideo since 1947 for thoracic hydatidosis and the 77 with pleural complications who had been seen.10 A subsequent series included patients who were seen between 1970 and 2004. A total of 464 patients were operated on for thoracic hydatidosis, and 49 had pleural complications (Fig. 88-4), which originated in the lung in 23 patients, in an organ located below the diaphragm in 21, in the spine in 3, in the pericardium in 1, and in the diaphragm in 1. Among the 23 patients who previously had hydatid cysts of the lung, 10 had pleural complications that never progressed to secondary pleural hydatidosis, 11 developed true secondary pleural hydatidosis, and 2 developed heterotopic pleural primitive hydatidosis. Among the 21 patients with abdominothoracic, transdiaphragmatic pleural hydatidosis, this complication originated in the liver in 18, in a subphrenic hydatid cyst in 2 (peritoneal hydatidosis), and in a splenic cyst in 1. All 21 patients reached the stage of secondary pleural hydatidosis: 2 with thoracic vertebral hydatidosis and 1 with secondary pericardial hydatidosis also developed secondary pleural hydatidosis. The diaphragmatic cyst secondarily produced a parahydatid pleural effusion. Of the patients who eventually developed secondary pleural hydatidosis, 17 had previously undergone surgery. There was no operative mortality during this period, and early complications, which included empyemas, wound infections, biliary fistulas, and hemorrhage, were all successfully treated. In all patients with prior hydatic pleural disease, it is important that follow-up is done at regular intervals because of the possibility of a recurrence of the hydatid disease. In this series, the 3 patients with secondary pleural hydatidosis of vertebral origin required laminectomy, cord decompression, and vertebral resection, and 1 of them had permanent paraplegia.

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1084

1/21/2008 1:58:53 PM

Chapter 88 Rare Infections of the Pleural Space

1085

Thoracic Hydatidosis 464

Pleural Lesions 49

HPPH

SPH

No Recurrence

2

35

12

FIGURE 88-4 Thocacic hydatidosis series 1970-2004: incidence and evolution of pleural lesions. HPPH, heterotopic pleural primitive hydatidosis; SPH, secondary pleural hydatidosis.

At present, the number of new cases is considerably lower, not only because of the efficient work in prevention by the Uruguayan Committee that fights against hydatidosis but also because the Saint Bois Thoracic Surgery Department, which was the reference center in this pathology for more than 40 years, has been closed.

Case Study This clinical case was chosen to illustrate what Armand Ugón (1947) described as massive pleuropulmonary hydatidosis (Fig. 88-5).11 A 21-year-old man presented who had dyspnea of acute onset, right-sided chest pain, cough, fever, and vomiting of foul-smelling liquid. Initial chest radiographs showed a pleural effusion with the so-called water-lily sign, and thoracentesis confirmed the diagnosis of pleural hydatidosis. A chest tube was inserted, and hydatid membranes with pus were evacuated from the pleural space. The patient had a good recovery, but 18 months later, while he was in ostensibly good health, the follow-up radiographs showed rounded opacities consistent with the diagnosis of secondary pleural hydatidosis. He then underwent thoracotomy with excision and formolization of 32 hydatid cysts, and 10 days later he had a third-space, anterolateral thoracotomy with extrapleural excision of 20 additional cysts. Sixteen months later, he developed cough, hemoptysis, and abundant expectoration of hydatid membranes and a mass was noted over the sixth intercostal space. Because of his poor medical status, hydatid debris and pus were evacuated by pleurotomy. However, 2 months later, a right pleuropneumonectomy was required and the postoperative course was uneventful.

PLEURAL AMEBIASIS Pathology Amebiasis is a parasitic infection produced by an amoeba called Entamoeba histolytica. Approximately 500 million people worldwide are infected, and as many as 10% will eventually develop the disease. The expected mortality rate is 0.75 per 100,000 infected persons.12 The parasite is mainly transmitted by fecal-oral mechanisms. Once absorbed through the portal system, it migrates

FIGURE 88-5 Standard chest radiograph showing several pulmonary and pleural hydatid cysts. In the vertex and over the mediastinum there are several hydatid pleural implants.

to the liver, where it produces abscesses or periportal fibrosis. Amebic liver abscesses contain an acellular, proteinaceous material, and the trophozoites are located in the periphery of the abscess, where they further invade adjacent tissues. Although periportal fibrosis is common, only 5% of patients with symptomatic amebiasis develop true hepatic abscesses. When the abscess ruptures or if it extends to the surrounding tissues, it can produce pleuropulmonary or pericardial complications. As reported by Ochsner and DeBakey13 pleuropulmonary contamination is the most common complication of amebic hepatic abscesses. In their series of over 181 patients with amebiasis-induced hepatic abscesses, 26 had a pleuropulmonary complication (17 pulmonary and 9 pleural) and 1 had a pericardial complication. Most amebic hepatic abscesses develop over the superior and posterior surfaces of the right lobe. As the abscess enlarges, it includes the diaphragm in its wall. If the abscess develops slowly, it may produce a pleural reaction that will generate adhesions at the base of the right lung and sometimes produce a hepatobronchial fistula. However, if the abscess enlarges rapidly, it may rupture in the pleural cavity with consequent empyema. Amebic hepatic abscesses can also rupture in the pericardial cavity, but this is uncommon.

Diagnosis The most common symptom of pleural amebiasis is rightsided chest pain with radiation to the shoulder. The cough,

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1085

1/21/2008 1:58:55 PM

1086

Section 4 Pleura

initially unproductive, is nearly always followed by production of abundant, purulent expectorations that resemble chocolate sauce and are pathognomonic of an amebic hepatobronchial fistula. At this stage, sputum examination can reveal the parasite and establish the diagnosis. Fever is more pronounced with pleural involvement, and often there is general malaise, weakness, anorexia, and weight loss. Rupture into the pericardium must be suspected when the patient presents with epigastric pain that radiates to the base of the neck, severe dyspnea, and fever. Occasionally, acute filling of the pericardial sac produces symptoms of cardiac tamponade. Characteristically, standard chest radiographs show an elevation of the right hemidiaphragm, a pleural effusion, and, in the adjacent lung, areas of consolidation with or without cavitation. CT, ultrasonography, and MRI are mainly used for the detection of hepatic abscesses. The pleural fluid is generally exudative, but it can become secondarily infected by other pathogens. Pleural biopsy or needle biopsy of the wall of the hepatic abscess may reveal E. histolytica. When there is a pericardial effusion, needle aspiration often yields a fluid that is serofibrinous or contains “chocolate sauce” pus. Serologic techniques are very important in the diagnosis of amebiasis because frequently the parasite cannot be isolated. Serology is positive in most thoracic complications. The most commonly used techniques are the indirect hemagglutination test and the enzyme-linked immunosorbent assay. Double diffusion and counterimmunoelectrophoresis (electrosyneresis) are also useful. Agglutination with latex is a simple test but often gives false-positive results. In most cases erythrocyte sedimentation rate is elevated, and there is a moderate leukocytosis. In pulmonary complications, careful sputum analysis may sometimes reveal the parasite.

Management The most useful drugs to treat amebiasis are emetine, chloroquine, and metronidazole. Because of its possible cardiotoxicity, emetine must be given with great caution and under electrocardiographic monitoring. Metronidazole is a more effective drug and is less toxic. The usual dosage is 750 mg given three times a day (1500-2000 mg/day) for 5 days. If necessary, 1000 mg/day is given for 5 more days. When it is combined with drugs such as paromomycin, cures are often seen within 10 days of the beginning of treatment. In hepatobronchial fistulas, postural drainage is useful and all pleural effusions or empyemas must also be drained. Pericardial effusions may require urgent decompression. Steroids and immunosuppressor drugs are contraindicated.

ACTINOMYCOSIS Pleural actinomycosis is mainly caused by Actinomyces israelii, but three other species of Actinomyces and the related Arachnia propionica can also cause actinomycosis with pleural involvement. Thoracic actinomycosis has no anatomic boundaries and often involves the lung, pleura,

mediastinum, and chest wall. In at least 50% of thoracic actinomycosis cases, there is pleural involvement.

Pathology Actinomycetes are normal inhabitants of the oropharynx, but they are especially abundant in septic dental processes. From these sites the bacteria travel to the thorax through aspiration, by local contiguous spreading, or via the bloodstream (hematogenously). Once the disease has reached the lung, it propagates by contiguity, tending toward externalization through the chest wall or extension to subdiaphragmatic areas. In 17 cases of thoracic actinomycosis reported by MingJang and colleagues,14 the chest wall and pleura were involved in 7 patients. In 8 cases reported by Ibañez-Nolla and associates,15 the pleura was involved in 4 cases and the chest wall in 3 additional cases.

Diagnosis The symptoms of pleural actinomycosis are entirely nonspecific. Chest pain reflects pleural involvement and can be accompanied by dyspnea, fever, cough, hemoptysis, or weight loss, all symptoms that can wrongly be interpreted as those of tuberculosis. Poor dentition or skin lesions in the area of the jaw or in the neck may suggest the diagnosis of actinomycosis. Unfortunately, previous treatment with antibiotics can change the evolution of the process and complicates diagnosis. Chest radiographs and CT scans often show lung masses that may resemble lung cancer or that may be cavitated, with adjacent pleural thickening and pleural effusion. Chest wall involvement, sometimes with destruction of ribs or vertebrae, is common. In most cases, however, the definitive diagnosis can be made only by study of the resected specimen.16 Pleural fluid may be either serous or purulent, and typical sulfur granules of 1 to 2 mm in diameter can be found. These granules are conglomerates of filamentous organisms with characteristically clubbed peripheral radiations. Actinomycosis organisms must be cultured anaerobically. Sulfur granules can also be isolated from sputum, bronchial washings, or pus from dental abscesses or infected cutaneous tracts. In general, the erythrocyte sedimentation rate and leukocyte count are elevated. An eosinophil count of 13% was found in a patient with a hydatid cavity in which lung actinomycosis had developed with secondary actinomycotic empyema.17

Management Treatment consists of penicillin in doses of up to 30 million U/day given for 5 weeks. In the presence of sepsis and empyema, longer periods of treatment may be required. Erythromycin and tetracyclines have also been successfully used in patients with penicillin allergy. When the pleural effusion is only an exudate, there is usually a good response to antibiotic treatment, but when the pleural fluid is infected, pleural drainage must be instituted. Late sequelae consisting of lung abscesses and chest wall fistulas determine the need for lung or chest wall resections.

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1086

1/21/2008 1:58:55 PM

Chapter 88 Rare Infections of the Pleural Space

NOCARDIOSIS Nocardia species are normal inhabitants of the soil, and in tropical countries they constitute the principal cause of foot mycetoma. N. asteroides is the organism responsible for pleuropulmonary infections that are clinically and radiologically similar to actinomycosis. It often invades immunosuppressed patients, and up to 25% of patients with lung nocardiosis also have pleural involvement, with effusion, empyema, or bronchopleural fistula. Hematogenous dissemination from the lung frequently affects the central nervous system. Nocardia species identification is not enough to establish a diagnosis of nocardiosis because these bacteria can be found in the respiratory tree as saprophytes. Response to treatment with antibiotics is important.18

Diagnosis The diagnosis of nocardiosis may be confirmed by identification of the bacteria in the pleural fluid, sputum, or bronchial washings. Because N. asteroides is slightly acid fast, it can be incorrectly identified as Mycobacterium tuberculosis. Smears of pathologic materials are always stained by Gram and Kinyoun methods. Definitive identification of Nocardia species requires cultures under aerobic conditions on blood agar in which Nocardia species will grow.

Management Sulfonamides are the drugs of choice. Sulfadiazine is usually used, but trimethoprim-sulfamethoxazole can also be used with similar results. In severe infections and in immunosuppressed patients, use of ampicillin or erythromycin with sulfonamide therapy is also recommended. These drugs are given for at least 6 weeks and are continued for 1 year in immunosuppresesd patients. The only role of surgery is to drain the pleural space in cases of empyema.

PLEURAL TUBERCULOSIS Tuberculosis, a disease seldom seen in many areas of the world, frequently occurs in underdeveloped countries. The amount of tuberculosis bacilli spilling in the pleura and the delayed hypersensitivity of the pleura seem to play dominant roles in determining which disease pattern will occur. Tuberculous pleurisy generally results from rupture of a subpleural focus of caseous necrosis of the lung. Less commonly, it is secondary to the spillage of a tuberculous node in the pleura; in this process, the contamination is light but there is a pleural hypersensitivity reaction with a secondary scarce-to-moderate aqueous effusion. Most of the time, the effusion will regress over 1 to 2 months without treatment. It is the most common form of extrapulmonary tuberculosis and usually occurs within 6 months of the primary infection. Tuberculous pleurisy as a manifestation of primary tuberculosis is more common in adults who are between 25 and 45 years of age than it is in older adults, and it is rarely seen in children. In tuberculous empyema, the pleural contamination is massive, the pleural fluid is purulent, and it is common to find resistant acid-fast bacilli on direct examination or culture

1087

of the pleural fluid. Tuberculous empyemas may be pure empyemas or pyopneumothoraces. In mixed tuberculous and pyogenic empyemas, bacterial superinfection is produced by a persistent bronchopleural fistula, or it occurs secondary to thoracentesis or chest tube drainage.

Diagnosis Tuberculous Pleurisy In two thirds of cases, patients with tuberculous pleurisy have an acute infection with low-grade fever, a nonproductive cough, pleuritic chest pain, and general malaise. When both cough and pleuritic chest pain are present, the pain usually precedes the cough. In the remaining one third of patients, the clinical presentation is more insidious and nonspecific, with asthenia, anorexia, weight loss, and nocturnal sweats as the main symptoms. Respiratory symptoms such as cough and chest pain appear only later. The peripheral white blood cell count is often normal, but the tuberculin skin test is positive in 70% to 80% of patients. However, a negative skin reaction does not exclude the diagnosis because during the acute stage of tuberculous pleuritis, circulating adherent cells suppress the specifically sensitized circulating T lymphocytes. Because those cells are not present in the pleural space,19 this effect explains why in some cases there is pleural hypersensitivity to the tuberculosis bacillus with cutaneous anergy. Apart from the moderate and usually unilateral pleural effusion, chest radiographs may be normal. Pulmonary foci are frequently not seen because they are small and peripheral; when present, they are always ipsilateral. In those cases with minimal findings, thoracic CT scan20 or thoracoscopy may be more useful in demonstrating the pulmonary lesions. In general, the presence of a massive effusion favors a nontuberculous etiology. Once a pleural effusion has been diagnosed, fluid must be sampled for analysis. In tuberculous pleurisy, the pleural fluid is yellow or sometimes serohemorrhagic with little or no opalescence. The presence of a frankly hemorrhagic effusion eliminates the possibility of tuberculous pleurisy. The fluid is exudative, with a protein content of more than 3 g/dL and frequently more than 5 g/dL. The remainder of the biochemical workup on the pleural fluid is of little help. Fluid with a pH below 7.3 or with a low glucose level is nonspecific and can be seen in other pathologic processes, including rheumatoid arthritis and carcinoma. High levels of lactic acid are also nonspecific and not very useful in making the diagnosis of tuberculous pleurisy. Piras and colleagues21 showed that the more sensitive and useful biochemical markers for tuberculous pleurisy were an increase of the adenosine deaminase level to more than 30 IU/L and an increase in the pleural/serum lysozyme ratio. Lymphocytes are nearly always predominant in the cell count of the pleural fluid (they usually are in the range of 50%70%), although in the first 2 weeks of tuberculous pleurisy, polymorphonuclear leukocytes may predominate.22 When lymphocytes are in excess of 50% to 70%, lymphoma is suspected. Mesothelial cells are seldom above 5%; and if eosinophils are found, they are never in excess of 10%. Acid-fast

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1087

1/21/2008 1:58:56 PM

1088

Section 4 Pleura

bacilli are seldom identified by direct analysis of the pleural fluid or by culture. To enhance the chances of isolating acid-fast bacilli, it is advisable to centrifuge all obtained fluid; but even with this technique, only 20% to 30% of patients will have positive fluid. Percutaneous pleural biopsy with the Cope or the Abrams needle is one of the better diagnostic methods because it reveals the presence of granulomas in the parietal pleural fluid in 60% to 80% of patients. Identification of areas of caseous necrosis or of acid-fast bacilli is helpful but is not absolutely necessary to make the diagnosis. Pleural biopsies are always complemented by fluid evacuation; but because chest tubes can promote infection, their use is discouraged. Thoracoscopic biopsies are considered when other methods have failed. This technique has the advantage of providing visualization of all surfaces so that proper areas can be selected for biopsy. In our personal series of 312 thoracoscopies performed for undiagnosed pleural effusions, only 5 were related to pleural tuberculosis. A presumptive diagnosis of tuberculous pleural effusion is often enough to initiate treatment. This diagnosis is based on the combination of a positive tuberculin skin test and a predominantly lymphocytic reaction in the pleural fluid. A biopsy showing caseating or noncaseating epithelioid granulomas is further proof of underlying tuberculosis. However, only direct identification of acid-fast bacilli or culture of these organisms on biopsy specimens provides definitive documentation of tuberculous pleural disease.

FIGURE 88-6 Standard chest radiograph of a patient with a tuberculous empyema.

Tuberculous Empyema Tuberculous empyema is less common than tuberculous pleurisy. In 90% of cases, it originates from a focus of tuberculous primary infection; and in the remaining 10%, it is due to reactivation of cavitated or fibrocaseous lesions. Clinically, patients with tuberculous empyemas have a productive cough, fever, and dyspnea, with the severity of symptoms being related to the volume of the empyema. Erythrocyte sedimentation rates are classically above 60 mm/hour and are accompanied by leukocytosis and moderate anemia. Resistant acid-fast bacilli are found in the sputum and in the pleural fluid in over 70% of patients (Fig. 88-6).

Mixed Empyema Mixed empyemas are the result of pleural fluid contamination by thoracentesis, chest tube insertion, or bronchopleural fistula. Symptoms are those of the primary tuberculous effusion associated with those of empyema or pyopneumothorax.

Management Tuberculous Pleurisy In the therapy of tuberculous pleurisy, the objectives are to avoid tuberculosis from becoming active and to prevent longterm pleural sequelae. In the face of a presumptive diagnosis of pleural tuberculosis with a positive purified protein derivative (PPD) skin test and a predominantly lymphocytic pleural effusion, treatment for 6 to 9 months with a regimen that

includes two to four antituberculous drugs is suggested. If the skin test is negative at the start of therapy, the drugs can be stopped after 2 months. In our clinic, we prefer to document the presence of acidfast bacilli either in the sputum or in the gastric contents or to identify tuberculous granulomas by pleural biopsy before initiating drug therapy. Antituberculous treatment is then given for a total of 7 months starting with the four drugs isoniazid, rifampicin, ethambutol, and pyrazinamide during the first 2 months. During the following 5 months, twice-weekly doses of isoniazid and rifampicin are given. Patients with persistent large effusions or intense toxic reactions after adequate antituberculous drug treatment and pleural evacuation may need systemic or intrapleural corticotherapy. Lung decortication is seldom needed because the pleural process usually resolves with adequate treatment.

Mixed and Tuberculous Empyema Pleural drainage is indicated in tuberculous empyemas with large effusions and in all mixed empyemas, especially if there is a bronchopleural fistula with its inherent risks of contralateral aspiration. Luizy and colleagues23 described a pleural irrigation technique consisting of continuous aspiration and washing. When the lung does not expand after drainage, or if there is a residual fibrothorax, the condition of the underlying lung needs to be determined before planning decortication because

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1088

1/21/2008 1:58:56 PM

Chapter 88 Rare Infections of the Pleural Space

the presence of fibrotic lesions, cavities, or bronchiectasis can make decortication difficult, impossible, or inadvisable. In those cases, pulmonary resection with decortication may be required. A review of all available radiographs is important because they will often indicate the topography and evolution of pulmonary lesions. CT is also useful to determine the nature and extent of pulmonary lesions and to differentiate them from pleural lesions. If pulmonary resection is contemplated, bronchoscopy is imperative in documenting the presence or absence of active endobronchial tuberculosis. In a classic study, Hood and associates24 divided these patients into two groups. The first group included patients with only pleural involvement, and the second group included those with significant associated parenchymal disease. In the first group, decortication was considered when the constrictive pleuritis extended to 25% to 30% of the pleural space or when 25% of predicted pulmonary function was lost. Occasionally, smaller collections were also treated surgically because they entailed the risks of tuberculous perforation into the bronchus (bronchopleural fistula) in addition to sometimes interfering with pulmonary function. Decortication was performed when there was no longer evidence of clinical toxicity and tuberculosis was medically controlled. Ideally, the sputum was negative for 4 months preoperatively; and if it had always been negative, antituberculous drug treatment was given for 4 to 6 months before surgery. In Hood’s second group, patients had severe parenchymal lesions in addition to pleural tuberculosis; and to eradicate the disease as well as to prevent reactivation, these patients required pulmonary resection and decortication. If the empyema is small or loculated, it can be enucleated by the procedure called empyemectomy.25 In most cases, however, pleural decortication is necessary, and it is advisable to decorticate both parietal and visceral surfaces. The diaphragm must also be freed to allow for better mobility; and if the lung does not expand, an individualized thoracoplasty of usually no more than three to five ribs may have to be added to the decortication. In general, tuberculous lesions predominate in upper lobes, and, therefore, this is the most common type of resection performed in association with decortication. Thoracoplasty may also have to be added if there is any doubt about pulmonary re-expansion. Pleuropneumonectomy is rarely indicated and is generally reserved for patients with destroyed lung, empyema, or bronchopleural fistula. In all those cases, special care must be taken to protect the bronchial stump, and pleural drainage with daily irrigations must be maintained for 1 to 3 weeks postoperatively. Open thoracostomy is indicated when the empyema cannot be managed by closed thoracostomy and when the patient is medically unstable or, more importantly, is not considered a candidate for resection. The window thoracostomy is initiated in a dependent position; and in patients without important pulmonary lesions, pleural space obliteration can be achieved in 6 to 9 months. For these individuals, open thoracostomy is more comfortable than a chest tube, with the

1089

added advantage of allowing pleural washing to be performed more easily. If there is a bronchopleural fistula, pleural washings must be done carefully, with the patient always in the upright position and the solution introduced slowly (Fig. 88-7). Calcified fibrothoraces, which sometimes occur as late sequelae of tuberculous empyemas or of prior therapeutic pneumothoraces, must not be operated on unless absolutely necessary. Decortication is usually neither desirable nor possible, and sometimes these patients will develop secondary pyogenic empyemas with or without bronchopleural fistula years later (Fig. 88-8), for which they may require pleuropneumonectomy (Fig. 88-9).

NONTUBERCULOUS MYCOBACTERIOSIS The main causative organisms of nontuberculous mycobacteriosis are Mycobacterium kansasii, seen in the urban population, and M. intracellulare, seen more often in rural areas. The symptoms are similar to those seen in association with tuberculosis, although they may be somewhat attenuated. The PPD test is negative, but the pleural fluid may have elevated proteins and lymphocytes. Fluid glucose concentration is normal or even decreased, and, occasionally, cultures of the biopsy specimen will identify Mycobacterium. Therapy for atypical mycobacterial disease consists of administration of drugs such as rifampicin, ethambutol, and isoniazid until the disappearance of the effusion or until the bacteriology is negative for 6 months.

FIGURE 88-7 A tuberculous empyema treated by open thoracostomy.

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1089

1/21/2008 1:58:56 PM

1090

Section 4 Pleura

blue, or Gomori on biopsy specimens, spheroid or ovoid formations of 10-µm average diameter can be seen surrounded by a clear halo that corresponds to the typical capsule of Cryptococcus.

Management Drug treatment consists of amphotericin B and flucytosine. Fluconazole can also be used, with the same effectiveness but with fewer side effects on kidneys, liver, and bone marrow. In immunosuppressed patients, the treatment must be continued for 6 to 12 months to avoid extrapulmonary dissemination. Pleural drainage is generally not necessary. If a previously undiagnosed pulmonary nodule is found at operation to be cryptococcosis, resection must be followed by drug treatment.

ASPERGILLOSIS

FIGURE 88-8 Standard chest radiograph showing an empyema with a bronchopleural fistula that has developed in an area of calcified pleural sequelae (arrow). This patient was treated by open thoracotomy.

CRYPTOCOCCOSIS Cryptococcosis is a disease of universal distribution produced by an opportunistic fungus, Cryptococcus neoformans. This organism is widely distributed in nature, its principal reservoir being dry pigeon excreta. Cryptococcosis is the most common fungal pulmonary infection in the acquired immunodeficiency syndrome (AIDS). The portal of entry is believed to be the respiratory tract. In the early 1950s, 25% of patients with cryptococcosis had pulmonary lesions. More recently, Wasser and Talavera reported that in 5 of 11 patients with cryptococcosis and AIDS, pulmonary lesions were the initial manifestation and that 3 had a pleural effusion (2 with pleural fluid positive for Cryptococcus).26 Pleural cryptococcosis is usually produced when a subpleurally located lung nodule extends into the pleura. The main symptoms are fever, cough, pleuritic chest pain, dyspnea, and weight loss.

Diagnosis Although chest radiographs and CT scans may show pulmonary infiltrates or nodules, mediastinal masses, and pleural effusions, the diagnosis of cryptococcosis can only be made by isolating the organism from pulmonary cavities, pleural fluid, or bronchial secretions. By using staining techniques such as hematoxylin and eosin, periodic acid–Schiff, Alcian

Aspergillosis is a disease caused by the opportunistic fungus Aspergillus fumigatus, which lives in soil and in organic matter. Humans become infected by inhalation of the conidia, which are suspended in the air. Aspergillus may initiate several pathologic processes in the lung, such as fungal balls, invasive aspergillosis, and allergic bronchopulmonary aspergillosis. Pleural aspergillosis usually develops over preexisting pathologic processes; it may be a sequela of therapeutic pneumothoraces (intrapleural or extrapleural), residual pleural cavities following pleural or pulmonary surgery, or other pleural diseases (e.g., chronic hemothoraces, pneumothoraces, pleural tuberculosis, or pleural hydatidosis).27 In those situations, Aspergillus pleural contamination is often secondary to a bronchopleural fistula, which initiates suppuration and Aspergillus infection of the pleural residual cavity. Sometimes the fungus may be isolated from the pleural fluid or biopsy specimens of the pulmonary tissues. Serologic studies identifying antibodies against Aspergillus are also useful for diagnosis except in immunosuppressed patients, in whom these studies are negative. In 1992, Massard and colleagues28 reported a series of 77 patients with pleuropulmonary aspergillomas, of whom 16 had pleural aspergillosis. In 10 of these 16 patients aspergillosis developed after lobectomy; in 1 it developed in a residual space after exploratory thoracotomy; in 3 it followed collapse therapy; and in 2 it followed a spontaneous bronchopleural fistula. Chest radiographs showed thickening of the pleura in 10 patients and a pleural effusion that turned out to be an empyema in 6 others. Thirteen patients with pleural aspergillosis were treated by surgery; 2 died. The risk is higher in symptomatic patients. Patients with pleural aspergillosis must be carefully selected for surgery, and, whenever possible, radical and aggressive operation is avoided. We prefer to use closed pleural drainage or, preferably, open thoracotomy with or without added thoracoplasty. Amphotericin B is given for several months when necessary. Nebulized liposomal amphotericin B and oral itraconazole have been used with good results in the treatment of A. fumigatus empyemas.29

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1090

1/21/2008 1:58:57 PM

Chapter 88 Rare Infections of the Pleural Space

1091

FIGURE 88-9 A, Standard chest radiograph showing a chronic mixed tuberculous empyema with bronchopleural fistula and an unexpandable lung. B, The pleuropneumonectomy specimen shows the lung, pleura, and peel. C, The portion of the diaphragm that had to be resected to avoid contamination of the space. D, The inside of the cavity. E, Postoperative chest radiograph showing partial filling of the space.

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1091

1/21/2008 1:58:57 PM

1092

Section 4 Pleura

HISTOPLASMOSIS

BLASTOMYCOSIS

Histoplasmosis is the most important fungal disease involving the respiratory system, but pleural involvement is unusual. It is produced by Histoplasma capsulatum, a dimorphic fungus living in the soil. Pleural lesions originate from a contiguous pulmonary focus or by hematogenous dissemination.30 The most common symptoms associated with pleural histoplasmosis are pleuritic pain, fever, malaise, and signs of a pleural effusion. Diagnosis is based on the identification of the fungus either in the pleural fluid or on biopsy specimens. In 1966, Schub and associates31 reported four patients with pleural histoplasmosis. In two of them, Histoplasma was identified by open pleural or pulmonary biopsies; in a third, Histoplasma was cultured in the pleural fluid; and in the fourth the diagnosis was made by a histoplasmin sensitivity test and elevation of antibody titer. In 1997, Richardson and George32 reported a patient with empyema, bronchopleural fistula, and a granulomatous process in the lower lobe of the right lung. Cultures demonstrated H. capsulatum both in the pleural fluid and in the pulmonary parenchymal process. Small or moderate-size effusions do not need specific therapy. Amphotericin B therapy is reserved for immunosuppressed patients or for patients with chronic pulmonary histoplasmosis and secondary pleural effusion.

Blastomycosis is a fungal infection produced by a dimorphic fungus called Blastomyces dermatitidis. This fungus is present in nitrogen-rich soils. The disease exists in the United States, Canada, and Africa. Blastomycosis is a less common mycotic infection than either coccidioidomycosis or histoplasmosis. It is acquired through inhalation of conidia into the lungs. The symptoms are similar to those seen with other acute fungal infections and include cough, fever, myalgia, erythema nodosum, chest pain, and pleural effusion. In the chronic form of the disease, pleural involvement produces a pleural effusion or an empyema, often without specific symptoms. Diagnosis can be made by the identification of the fungus in bronchial secretions, pleural fluid, or on pleural biopsies. These are frequently positive either on smears or by culture. Pleural biopsy may also show granulomas, with stains and cultures of the material defining the etiology. Serologic and skin tests are of limited value. Acute blastomycosis with pleural effusion does not generally require specific therapy. Pleural involvement associated with chronic pulmonary infection must be treated with amphotericin B and tube drainage when necessary. In 1995, Failla and coworkers36 reported 7 cases of pulmonary blastomycosis, 2 of them with pleural effusions. In 18 children with culture-proven, acute pulmonary blastomycosis reported by Alkrinawi and associates,37 pleural effusions were seen in 3 patients.

COCCIDIOIDOMYCOSIS Coccidioidomycosis is a fungal disease produced by a dimorphic fungus called Coccidioides immitis. This fungus, first described in Argentina,33 grows in the environment as a mycelium that eventually develops into arthrospores that are inhaled in the lungs. The incidence of pleural effusion in coccidioidomycosis is about 7%.34 Pleural effusions may be associated with acute primary coccidioidomycosis. In 1976, Lonky and colleagues34 reported on a series of 28 patients with coccidioidal pleural effusion. In 90%, it was secondary to a direct spread from a contiguous pulmonary infection site. C. immitis was identified in the effusion of only 3 of 15 patients, but in all 8 patients who had pleural biopsies, cultures were positive. In acute disease, the prognosis is excellent, often without specific therapy. Pleural effusion may also be secondary to chronic pulmonary coccidioidomycosis. In these cases, coccidioidal cavities rupture in the pleural space, where they may produce a pneumothorax, an empyema, or a bronchopleural fistula. Rapidly, a pleural peel will develop and entrap the lung. The definitive diagnosis can be made by the identification of the fungus in the pleural fluid, by needle biopsy, or by culture. A serologic diagnosis can also be obtained by precipitin and complement fixation tests, which are accurate and relatively specific.24 When a positive diagnosis of pleural coccidioidomycosis is made, specific drug therapy with amphotericin B is indicated. Surgical management also includes tube drainage of pneumothoraces or empyemas and lung decortication, or it includes pulmonary resection to manage a bronchopleural fistula.

ZYGOMYCOSIS Zygomycosis is a group of diseases produced mainly by zygomycetes of the order Mucorales. Spores from the environment are inhaled, causing several clinical types of diseases in patients with diabetes or immunosuppression. The principal clinical forms are rhinocerebral, pulmonary, cutaneous, and disseminated. Pleural effusions are relatively common in pulmonary zygomycosis. Diagnosis of the pulmonary form is difficult because of the necessity of performing lung biopsies for further histopathologic studies and cultures. Therapy with amphotericin B is always indicated.38

COMMENTS AND CONTROVERSIES A variety of rare pleural infections that are seldom encountered in North America are discussed in this chapter. Pleural aspergillosis is particularly difficult to manage and carries a significant mortality both with conservative nonsurgical management and after operation. Surgical indications depend largely on the patient’s overall medical status, but, whenever possible, the infected space must be obliterated either by muscle transplant or by thoracoplasty. When these procedures are carried out, prolonged postoperative treatment with antifungal drugs is also imperative. If these principles are not followed, the risks of recurrent pleural aspergillosis and death are very significant. J. D.

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1092

1/21/2008 1:58:58 PM

Chapter 88 Rare Infections of the Pleural Space

KEY REFERENCES Armand Ugón CV: Neumotórax hidático. Archivos Internacionales de la Hidatidosis. 1:143, 1935. Armand Ugón CV, et al: La lobectomía en el tratamiento de las secuelas del quiste hidático del pulmón. Bol Soc Cir Montevideo Tomo 17(912):465, 1946.

1093

Barret NR: The treatment of pulmonary hydatid disease. Thorax 1:21, 1947. Hood RM, Antman K, Boyd A, et al: Surgical Disease of the Pleura and Chest Wall. Philadelphia, WB Saunders, 1986.

tahir99-VRG vip.persianss.ir

Ch088-F06861.indd 1093

1/21/2008 1:58:58 PM

chapter

89

SPONTANEOUS PNEUMOTHORAX AND PNEUMOMEDIASTINUM Gilles Beauchamp Denise Ouellette

Key Points ■ Primary spontaneous pneumothoraces occur in young patients

■ ■ ■

■ ■

■

■

■ ■

■

without lung disease; secondary spontaneous pneumothoraces occur in patients with chronic obstructive pulmonary disease (COPD). The most common cause of a primary spontaneous pneumothorax is the rupture of small subpleural blebs. Pneumothoraces are considered small if they measure less than 3 cm and large if they measure more than 3 cm. Conventional tube thoracostomy with underwater seal drainage remains the procedure of choice for the initial management of moderate to large pneumothoraces. Surgery is indicated if there is recurrence after a first episode. Surgery is indicated at the time of the first episode if the pneumothorax is complicated by persistent air leak, hemothorax, or failure of the lung to re-expand. Resection of blebs and bullae and obliteration of the pleural space by pleurectomy or pleural abrasion, alone or in combination, are the two major goals in the surgical treatment of spontaneous pneumothoraces. With video-assisted thoracic surgery (VATS), analgesic requirements and length of hospital stay are reduced, but the recurrence rate is slightly higher. Rarely, surgeons use chemical pleurodesis as first-line treatment for recurrences of pneumothorax. Spontaneous pneumomediastinum (SPM) is defined as nontraumatic presence of free air in the mediastinum in a patient with no known underlying disease. After specific causes of mediastinal emphysema have been excluded, primary SPM can be treated expectantly.

Pneumothorax is defined by the presence of air in the intrapleural space, with secondary lung collapse. Although such air may originate from various sources, rupture of the visceral pleura with air leakage from the lung parenchyma is by far the most common cause. Pneumothoraces can be classified as spontaneous, posttraumatic, and iatrogenic (Table 89-1). Whereas primary spontaneous pneumothoraces occur in young patients without lung disease, secondary spontaneous pneumothoraces occur in patients with clinical or radiographic evidence of underlying lung disease, most often COPD. Posttraumatic pneumothoraces are the result of blunt injuries to the bronchi, the lung, or the esophagus. An open pneumothorax happens when a penetrating trauma induces a disruption of the chest wall. Iatrogenic pneumothoraces may occur during a diagnostic or therapeutic procedure in the hospital environment.

Artificial therapeutic pneumothorax refers to the historical treatment for tuberculosis. Most patients with a spontaneous pneumothorax seek medical attention because of sudden chest pain and dyspnea. If the spontaneous pneumothorax progresses to become under tension, the symptoms are more severe, and significant hemodynamic and respiratory instability may develop and require urgent treatment.

HISTORICAL NOTE Boerhaave in 1724 was the first to identify the presence of abnormal air in the chest cavity, and Meckel (1759) was the first to describe a tension pneumothorax at the time of a postmortem examination.3 The term pneumothorax was introduced by Etard in 1803, but it was Laennec (1819) who first described the clinical signs and symptoms accompanying a spontaneous pneumothorax (Killen and Gobbel, 1968).1,2 For a long period, tuberculosis was considered as the principal cause of pneumothoraces. Kjaergaard (1932) was the first to propose rupture of isolated blebs located at the apex of the lung as the most common cause of spontaneous pneumothorax in young healthy adults.3 Currently, COPD and diffuse interstitial lung disease are among the leading causes of the secondary pneumothoraces in the aging population.4,5 Secondary spontaneous pneumothoraces are also found in other lung diseases such as acquired immunodeficiency syndrome (AIDS) and severe acute respiratory syndrome (SARS) (Table 89-2).6,7 Before intercostal tube thoracostomy became the treatment of choice, several weeks of bed rest was the only treatment for these patients.8 Thoracotomy for the resection of apical blebs was suggested by Bigger in 1937 and adopted by Tyson and Crandall, who reported their results a few years later.9,10 Churchill (1941) was the first to suggest gauze abrasion of the parietal pleura to generate pleural adhesions in order to reduce recurrences.2 Gaensler and later Thomas and Gebauer proposed parietal pleurectomy as the best method for an effective pleurodesis.11,12 There has been some debate over the years about the best method to reduce recurrences. Clagett did not agree with pleurectomy, which he thought was too aggressive for the treatment of a benign disease.13 He recommended pleural abrasion, and Youmans and colleagues, in 1970, provided additional clinical and experimental evidence of the efficacy of pleural abrasion.14 Deslauriers and associates were the first to report very low recurrences with a combination of blebectomy and limited apical pleurectomy performed through a transaxillary incision.15 This proved to be an ingenious way to deal effectively

1094

Ch089-F06861.indd 1094

1/21/2008 1:59:45 PM

Chapter 89 Spontaneous Pneumothorax and Pneumomediastinum

TABLE 89-1 Classification of Pneumothorax Spontaneous Primary Secondary (underlying pulmonary disease) Chronic obstructive pulmonary disease infection Neoplasm Catamenial Posttraumatic Blunt penetrating Iatrogenic Inadvertent Diagnostic Therapeutic

with the disease and reduce the morbidity related to a standard thoracotomy. Levi and coworkers introduced videoassisted thoracic surgery (VATS) for the surgical treatment of spontaneous pneumothorax.16 With the development of minimally invasive surgery, the VATS approach has gradually replaced the transaxillary approach (Table 89-3).

TABLE 89-2 Historical Landmarks Author (Year)

Landmark

Boerhaave (18th century)

Ruptured esophagus associated with presence of air in the pleural cavity

Meckel (18th century)

Postmortem description of a tension pneumothorax

Etard (19th century)

Autopsy description; introduction of the term pneumothorax

Laennec (19th century)

Description of clinical signs and symptoms

Kjaergaard (1932)

Rupture of lung blebs replacing tuberculosis as the most frequent cause of primary spontaneous pneumothorax

Getz and Beasely (1983)

Chronic obstructive lung disease as a frequent cause of pneumothoraces

Wait and Estrera (1992)

Pneumocystis carinii pneumonia, cytomegalovirus pneumonia, and atypical mycobacterial infections associated with AIDS are common causes of pneumothorax

BASIC SCIENCE Anatomy of the Pleural Space The visceral pleura covers the entire surface of the lung and has no plane of dissection with the parenchyma; the parietal pleura is a serous membrane that covers the inner surfaces of the mediastinum, the chest wall, the diaphragm, and the apex of the chest cavity. The presence of the endothoracic fascia between the pleura and the chest wall provides a plane of dissection that makes it easy for surgeons to perform a parietal pleurectomy. The parietal pleura is vascularized through branches originating from intercostal arteries and the apical pleura through branches of the subclavian artery. The parietal pleura, unlike the visceral pleura, has somatic innervation, and pain stimuli are transmitted through the intercostal and phrenic nerves.17

Physiology of the Pleural Space When a patient is at rest (i.e., at functional residual capacity), the elastic forces of the chest wall and lung tend to separate the parietal pleura from the visceral pleura, creating a negative pressure with respect to atmospheric and alveolar pressure. This negative intrapleural pressure is not uniform throughout the pleural space; a gradient exists between the apex and the base of the lung. At the apex, the pressure is more negative than at the base; this difference tends to favor greater distention of the apical alveoli. In tall individuals, this gradient may be even greater and probably contributes to the development of pneumothoraces through the rupture of apical blebs.

Physiologic Changes Secondary to a Pneumothorax Uncomplicated Pneumothorax When a communication develops between the lung and the pleural space, the positive pressure of intra-alveolar air makes

Ch089-F06861.indd 1095

1095

TABLE 89-3 Evolution of Therapy Author (Year)

Therapy

Tyson and Crandall (1941)

Thoracotomy, resection of blebs

Gaensler (1956) Thomas and Gebauer (1958)

Subtotal parietal pleurectomy

Deslauriérs et al (1980)

Axillary thoracotomy, bleb resection, and apical pleurectomy

Levi et al (1990)

Video-assisted thoracoscopic surgery for bleb resection, pleural abrasion, or pleurectomy

the air flow from the lung into the pleural space until there is no difference between the intrapleural pressure and the atmospheric pressure (Fig. 89-1). The same mechanism of pressure equilibration occurs when there is a communication between the opened chest wall and the pleural cavity. Alveolar hypoventilation and hypoxemia are the consequences seen in patients with any significant (>25%) pneumothorax.18 According to Moran and coauthors, hypoxemia is related to an alteration of the ventilation-perfusion ratio.19 Anatomic shunting also contributes to the low arterial oxygen pressure.20 Anthonisen suggested that the ventilation mismatch often seen in pneumothorax was secondary to the airway closure at low lung volumes.21 A pneumothorax also affects the mechanics of the lung and leads to reductions in lung compliance, vital capacity, total capacity, and functional residual capacity.22 Finally, the normal

1/21/2008 1:59:45 PM

1096

Section 4 Pleura

↑ ↓ ↓ ↓ ↓ ↓

Air flow until no pressure difference Apex to base pressure gradient Lung compliance Functional residual capacity Ventilation Oxygenation Slight shunt

↑ ↑ ↑ ↓ ↑ ↓ ↑ ↑

Continuous air flow (one-way valve) Intrapleural pressure Mediastinal shift (alteration of lung mechanics) Ventilation Shunt Oxygenation Cardiac stroke volume Heart rate

FIGURE 89-1 Some of the physiologic characteristics of spontaneous pneumothorax.

FIGURE 89-2 Physiologic characteristics of a tension pneumothorax.

gradient of pressure between apex and base in the pleural space tends to disappear (see Fig. 89-1).23

by simple diffusion and equilibration. The rate of resorption of a pneumothorax is related to the quality of the pleural membrane. With a fibrotic pleura, for instance, the rate of resorption is slower than with a normal pleura. The rate of resorption is also proportionate to the total surface area of the pleura and to the amount of residual gas in the pleural cavity. The greater the amount of gas, the longer it takes for resorption. In pneumothoraces, the pressure gradient between the gas in the pleural space and the gas in the subpleural venous system is the driving force directing this diffusion process. Each gas is resorbed independently of the other. Gas resorption from the pleural space takes place gradually and in successive phases. During the first phase, there is equilibration of oxygen and carbon dioxide partial pressures; during the second phase, there is a progressive resorption of the remaining intrapleural gases. Gradually, the intrapleural pressure recovers its negative pressure favoring lung reexpansion. If the lung does not re-expand, a transudate fills the pleural cavity.27 Finally, the composition of gases in the pleural space can also vary. For example, oxygen is more diffusible and soluble, and its transfer from pleura to circulation is faster than that of carbon dioxide or nitrogen.

Tension Pneumothorax During an episode of tension pneumothorax, a positive intrapleural pressure builds up during the expiration phase. This is because the air flow accumulates in the pleural space without any possibility of evacuation from a closed chest cavity. It was long believed that a tension pneumothorax induces mediastinal compression and a decrease in venous return to the heart that ultimately decreases the cardiac output.24 According to Gutsman and colleagues, however, only a fraction of the increase in intrapleural pressure is transmitted to the mediastinum, suggesting that mediastinal compression by accumulated air is not the sole explanation for the cardiovascular changes observed in a tension pneumothorax.25 In an experimental model, Hurewitz and associates showed that a fall in cardiac stroke volume as well as a progressive reduction in systemic oxygen transport and tissue oxygenation occurred during an episode of tension pneumothorax.26 The insufficient tissue oxygenation of the heart resulted in the inability to increase the cardiac output. Tension pneumothorax can also induce a shunt and thereafter reduce oxygenation and cardiac output (Fig. 89-2).

PRIMARY SPONTANEOUS PNEUMOTHORAX Etiology and Epidemiology

Resorption of Pleural Gas The normal pleural space is free of gas. The pleural membrane is a semipermeable structure through which gases move

Ch089-F06861.indd 1096

The most common cause of a primary spontaneous pneumothorax is the rupture of small subpleural blebs. This may occur when a patient is at rest or during exertion, and it is

1/21/2008 1:59:46 PM

Chapter 89 Spontaneous Pneumothorax and Pneumomediastinum

seen stereotypically in young, healthy, thin and tall male smokers.28,29 With the increased incidence of smoking, women are now also at risk.30 In North America, the incidence varies from 6 to 7 per 100,000 in men and from 1 to 2 per 100,000 in women.28 A familial incidence has been reported.31 According to Brooks, primary spontaneous pneumothorax occurs more commonly on the right side.32 Bilateral pneumothoraces occur in fewer than 10% of patients.33 In addition to smoking, other explanations for the development of a spontaneous pneumothorax are still open to discussion. Exertion is probably not a major factor, but change in atmospheric pressure is considered an important cause.34 In one study, the rate of hospital admission for spontaneous pneumothorax was significantly greater during the first 48 hours after a fall in the atmospheric pressure.35 Studies on flight personnel with prior episodes of pneumothorax also showed that small apical bullae increase in size when subjected to decreasing atmospheric pressure in altitude chambers.36

Histopathology Blebs are small (<2 cm) subpleural collections of air contained within the visceral pleura. They result from ruptured alveoli with air trapping between the elastica interna and externa of the visceral pleura. Blebs are usually found at the apex of the upper lobes or over the superior apices of the lower lobes.37 Blebs are well demarcated from the remaining normal lung, although they are still attached to it by a narrow neck. They are considered to represent the paraseptal variety of emphysema, which can occur independently of widespread centriacinar or panacinar emphysema. Blebs are often accompanied by apical fibrosis of the lung.38 The formation of blebs is associated with the degradation of elastic fibbers. This process of elastolysis, in which neutrophils and macrophages play a role, is caused by imbalances between proteases and antiproteases and between oxidants and antioxidants.39-42 Bullae are found in secondary pneumothoraces. Bullae usually result from the alveolar wall destruction typically seen in diffuse emphysema.43 In 1966, Reid proposed a classification of the types of bullae found in the lung.44 Type I bullae have thin walls made of pleura and connective tissue with few blood vessels. These bullae are located at the apices of upper lobes or over the edges of other lobes. They correspond to overinflation of a small volume of parenchyma and communicate with the lung by a narrow neck. Blebs are type I bullae. In type II bullae, the mesothelial cells are relatively well preserved but alveolar structures are destroyed at their base. The diseased alveoli are in continuity with the bullae through a broad neck. In type III bullae, the base of the bulla is large and extends deep into the lung.

1097

steady pain. The symptoms of dyspnea and chest pain usually decrease gradually and resolve during the 24 hours following the episode.45 Occasionally, patients have a nonproductive cough. Most episodes occur while the patient is at rest. Physical findings may be totally absent if lung collapse is minimal, but when a significant pneumothorax is present, there is often a decrease in chest wall movement on the affected side. On percussion, the chest cavity may be hyperresonant, and at auscultation, breath sounds are diminished or absent. A pleural friction rub can sometimes be heard, and tachycardia is almost invariably present. The diagnosis of pneumothorax is best confirmed by erect posteroanterior (PA) and lateral chest radiographs through identification of the visceral pleura, which normally is not recognizable, and the presence of abnormal air in the pleural cavity (Fig. 89-3). Expiration films are useful in demonstrating a small pneumothorax that may have been missed on a standard film (Fig. 89-4). Lateral decubitus views may be advantageous in confirming the presence of a pneumothorax.46 Pseudopneumothoraces such as skin folds or chest wall alterations must always be ruled out. Occasionally, a pulmonary cyst or emphysematous bulla may also be mistaken for a pneumothorax. The diagnosis of a tension pneumothorax is suggested by complete collapse of the lung with contralateral shift of the heart and mediastinum and inversion of the hemidiaphragm (Fig. 89-5).

Size of the Pneumothorax The American College of Chest Physicians defines small pneumothoraces as those in which the visceral pleura is less

Diagnosis and Staging The severity of symptoms such as chest pain and dyspnea usually, but not always, correlates with the degree of lung collapse. Chest pain is very common and can be quite severe. It is often described as an early sharp pain followed by a

Ch089-F06861.indd 1097

FIGURE 89-3 A pneumothorax is identified by finding the location of the visceral pleura (arrows).

1/21/2008 1:59:46 PM

1098

Section 4 Pleura

A

B FIGURE 89-4 A, Spontaneous pneumothorax (regular film). B, Increased evidence with expiration film.

FIGURE 89-5 Chest radiograph showing a tension pneumothorax with mediastinal shift and deviated trachea. The trachea is outlined. Arrows indicate location of visceral pleura.

Ch089-F06861.indd 1098

than 3 cm from the chest wall; in large pneumothoraces, the distance is greater than 3 cm.47 However, according to Light, measuring the average diameter of the collapsed lung and of the involved hemithorax provides a better approximation of the size of the pneumothorax.48 One must understand that the lung is in a three-dimensional space, and the volume of a pneumothorax approximates the ratio of the cube of the lung diameter to the hemithorax diameter. If a pneumothorax is measured to be 1 cm from the apex to the bottom on the chest radiograph, it occupies approximately 25% of the hemithorax volume. Similarly, in a 2-cm radiographic pneumothorax, approximately 49% of the volume of the hemithorax is occupied by abnormal air. According to the British Thoracic Society guidelines, a pneumothorax of more than 2 cm represents a condition that needs immediate attention.49 Considering the three dimensions of the pleural cavity, we define a small pneumothorax as one with a diameter of less than 3 cm if located solely at the apex or one in which there is less than a 2-cm rim of air between the lung and the parietal pleura. For a large pneumothorax, the space between the lung and the parietal pleura is greater than 2 cm from the apex to the bottom of the pleural cavity. Computed tomographic (CT) scanning is the most precise method to estimate the size of a pneumothorax, especially in patients with emphysema or other underlying diseases.50-52 A detailed description of the number, size, and location of the blebs by CT scanning is also useful for predicting contralateral occurrences (Fig. 89-6).53

1/21/2008 1:59:47 PM

Chapter 89 Spontaneous Pneumothorax and Pneumomediastinum

A

B FIGURE 89-6 A, Chest radiograph showing left-sided pneumothorax and normal right lung. B, CT scan of the same patient showing ipsilateral and contralateral bullae with left-sided pneumothorax.

Patients with pneumothoraces can also have abnormal electrocardiographic readings. For example, in patients with a left-sided pneumothorax, the electrocardiogram may show changes such as a right-sided shift of the QRS axis with a decrease in precordial R-wave voltage and QRS amplitude and a precordial T-wave inversion; these changes usually resolve with re-expansion of the lung.54 If a large pneumothorax is present, the interposition of air between the heart and the electrodes may also lead to a decrease in QRS amplitude as well as that of the R and T waves, simulating an anterior myocardial infarction.55

COMPLICATIONS OF SPONTANEOUS PNEUMOTHORAX A tension pneumothorax is a serious complication that occurs when alveolar air continuously accumulates in the pleural space.56 The patient usually shows signs of respiratory distress, with tachycardia, anxiety, dyspnea, and chest pain.

Ch089-F06861.indd 1099

1099

Occasionally, the patient rapidly becomes hypotensive, with peripheral cyanosis and tracheal deviation. It is a lifethreatening situation. Immediate decompression of the pleural space with a needle, chest drain, or other instrument is imperative. Pneumomediastinum is secondary to the dissection of air along the bronchi and vascular sheets of pulmonary vessels. Usually, it has no clinical significance; however, in certain circumstances, an injury to major airways or perforation of the esophagus needs to be ruled out. Pneumoperitoneum secondary to a pneumothorax is uncommon. In this situation, a perforated abdominal hollow viscus must be ruled out.57 Interstitial emphysema and subcutaneous emphysema, which often accompany secondary pneumothorax, are usually of no clinical consequence. Rarely, massive subcutaneous emphysema causes respiratory embarrassment that may require a tracheal intubation and cutaneous incision on the chest wall for decompression. Hemopneumothoraces occur rarely and are more frequent in men than in women. The hemorrhage is caused by a torn vascular adhesion between the parietal and visceral pleura or, less frequently, by a rupture of vascularized blebs or bullae. Although lung re-expansion may help tamponade the bleeding site, early surgery is often warranted.58,59 Bilateral pneumothoraces occur in 10% to 15% of cases. Although these may be synchronous, more often they are sequential.60 Recurrence after initial treatment is probably the most frequent complication of primary spontaneous pneumothorax; it occurs in approximately 10% to 15% of the cases. Most recurrences are seen within 2 years of the first episode, and the majority are ipsilateral; after a second pneumothorax, the risk of having a third one increases to 40% to 50%.61,62 The most frequent complications after the initial treatment of a pneumothorax are listed: 1. An air leak that does not resolve after 48 to 72 hours in an apparently well-drained chest cavity 2. An incomplete re-expansion of the lung after suction has been applied to the chest tube 3. An important air leak that cannot be controlled successfully with a chest tube In the aforementioned conditions, surgery is often required to solve the problem.

MANAGEMENT Management of the First Uncomplicated Episode At the time of a first episode, various therapeutic strategies such as observation, aspiration, chest tube drainage, and surgery may be used, depending on the size of the pneumothorax and the presence of symptoms.

Observation Asymptomatic patients in good health who have a small pneumothorax may be treated expectantly if there is no clinical or radiographic evidence of progression.63

1/21/2008 1:59:48 PM

1100

Section 4 Pleura

Air resorption from the pleural space is estimated to be 1.25% of the volume of the pneumothorax per 24 hours (50 to 70 mL/day).64 Administration of oxygen, which is reabsorbed faster than room air, is an effective method to enhance the rate of resolution.65 It may avoid the need for a chest tube drainage in a small pneumothorax.66 Patients who are treated expectantly are observed very closely, especially if they are sent home. Before hospital discharge, they are instructed about the potential hazards of developing a tension pneumothorax, and they must be monitored with weekly chest radiographs until the pneumothorax has completely resolved. This method of treatment exceeds tube thoracostomy in duration. In addition, one must remember that mortality secondary to unrecognized tension pneumothorax can happen in patients treated by observation alone.67 Nevertheless, careful observation remains a valid therapeutic option for patients with small pneumothorax.

Aspiration Aspiration of the pneumothorax with a 16-gauge intravenous canula connected to a three-way stopcock and 60-mL syringe is a treatment option that is successful in approximately 50% of patients.68 According to the British Thoracic Society, it is the method of choice for treatment of the first episode of a spontaneous pneumothorax.49 It is successful in 83% of patients without lung disease but in only 33% of patients with preexisting lung disease. Those who appear to benefit from this approach are patients younger than 50 years of age whose pneumothorax is smaller than 50%.69,70 Because of a 20% to 50% recurrence rate with this method, small-caliber catheters are often used to decompress iatrogenic pneumothoraces.71 Since the introduction of the dart technique for the emergency treatment of pneumothoraces, several devices have become commercially available. The McSwain dart is a 16 Fr, 15-cm polyethylene catheter with a winged flange attached to a flutter valve, and the thoracic vent is a small-bore 13 Fr urethane catheter trocar with a one-way valve connected to a suction apparatus or underwater seal system.72 Chest tubes smaller than 9 Fr are often associated with malfunction and occlusion.

Tube Thoracostomy Conventional tube thoracostomy with underwater seal drainage remains the procedure of choice for the initial management of moderate to large pneumothoraces. Significant symptoms, radiographic progression, complete collapse of the lung, tension pneumothorax, contralateral pulmonary disease, and failure of re-expansion after aspiration are all indications for tube thoracostomy. With proper tube drainage, the lung re-expands rapidly, and in most patients the air leak stops within 48 hours. Although underwater seal drainage is sufficient for most cases, we personally prefer to use negative pressure (−10 to −20 cm of H2O) on the chest tube to maintain lung re-expansion during the first 24 hours. The chest tube is removed after the air leak has stopped for at least 24 hours and preferably 48 hours. A radiologic control is always recommended before the patient is dis-

Ch089-F06861.indd 1100

charged. In spite of satisfactory lung re-expansion, immediate relapse after removal of the chest tube is not uncommon. Although most of our patients are kept in the hospital for 24 hours with underwater seal drainage and suction, in selected cases we use the Heimlich valve. The Heimlich flutter valve is a passive, one-way, ambulatory chest tube drainage system.73 It has been shown to be safe and efficient for the outpatient treatment of primary spontaneous pneumothorax.74 In our experience, it is installed only after underwater seal drainage has been in place for several hours to allow for a full re-expansion of the lung. After the lung is re-expanded and if air leak is minimal, a Heimlich valve is installed, and the patient is discharged from the hospital. If, during the early follow-up period, the lung does not reexpand, the patient is admitted to the hospital for underwater seal drainage.

Indications for Surgery at the Time of the First Episode Complicated Pneumothorax Surgery may be indicated at time of the first episode if the pneumothorax is complicated by persistent air leak, hemothorax, or failure of the lung to re-expand. Bilaterality, tension pneumothorax, and complete pneumothorax may also be indications for surgery (Table 89-4). In contrast, surgery is rarely indicated for psychological reasons such as fear of pain related to the chest tube insertion.75 A prolonged air leak lasting longer than 4 days is probably the most frequent indication for surgery at the time of the first episode. Most air leaks in patients with primary spontaneous pneumothorax seal within 24 to 48 hours after the insertion of a chest tube. Only 3% to 5% of patients have a persistent air leak. Today, there are very few good reasons for prolonged chest tube drainage.76 Considering the efficacy and the low morbidity of surgery, as well as the low recurrence rate, early surgical intervention is advocated.77 The occurrence of simultaneous bilateral pneumothoraces is uncommon, but when it occurs it is followed by definitive surgery, at least on one side but preferably on both sides. TABLE 89-4 Indications for Surgery in Primary Spontaneous Pneumothorax First Episode Early complications Prolonged air leak Non–re-expansion of the lung Bilaterality Hemothorax Tension Complete pneumothorax Potential hazards Occupational hazard Absence of medical facilities in isolated areas Associated single large bulla Psychological Second Episode Ipsilateral recurrence Contralateral recurrence after a first pneumothorax

1/21/2008 1:59:49 PM

Chapter 89 Spontaneous Pneumothorax and Pneumomediastinum

Patients with a significant hemothorax may need urgent surgery for definitive control of the bleeding site. Large clotted hemothoraces (>1000 mL), if inadequately drained, may lead to complications such as empyema and fibrothorax and therefore needs to be evacuated. Patients at risk of developing pneumothoraces in relation to their occupation (e.g., airline personnel, scuba divers) may be treated with surgery at the time of the first episode.78 Patients living in isolated areas and patients who travel frequently, especially those with evidence of bullae on chest radiographs, may also be candidates for early surgery. The management of a pneumothorax that occurs in a pregnant woman during the first trimester or near parturition needs to be conservative. A first episode of a tension pneumothorax is an indication to proceed with surgery before the patient leaves the hospital. If a single large bulla or multiple blebs are identified on chest radiography or CT at the time of a spontaneous pneumothorax, surgery is also recommended.

Uncomplicated Pneumothorax The option for surgery at the time of a first uncomplicated episode is now a matter of debate.79-82 The choice for surgery is based on patient preference in certain cases but more often on economic concerns such as potentially decreased duration of work disability and decreased overall medical costs.83-85 The argument against surgery is that most patients (80%) will not have any recurrence after the first episode and therefore would undergo unnecessary surgical risk.86-88 We maintain that easy access to VATS does not modify the indications for surgery at the time of the first episode.

Management of Recurrences The most frequent reason for considering surgery for a spontaneous pneumothorax is recurrence after conservative treatment. Approximately 20% of the patients have a recurrence within 2 years after a first episode. After three or more episodes of spontaneous pneumothorax, the incidence of recurrence in the following 2 years increases up to 50%, and in our opinion surgery is the only good option for these patients. If a recurrence occurs during pregnancy, surgical treatment may be carried out safely during the second trimester.89

Surgical Strategies Resection of blebs and bullae and obliteration of the pleural space by pleurectomy or pleural abrasion, alone or in combination, are the two major goals in the surgical treatment of spontaneous pneumothorax.90 If apical blebs are present, wedge resection of the blebs is necessary.91,92 Multiple wedge resections may be required if there are blebs at several sites. Anatomic segmentectomies or lobectomies are rarely indicated. Blebs are not always found at the time of surgery. A single bleb may have ruptured and therefore is no longer visualized.93 In addition, there are several patterns of the disease. In the first pattern, which occurs in about 30% to 40% of the patients, the lung is normal. In the second pattern, in 12% to 15% of patients,

Ch089-F06861.indd 1101

1101

the lung appears normal but there are pleuropulmonary adhesions, suggesting previous pneumothoraces. It is in the third group, comprising 30% to 40% of patients, where one finds single or multiple blebs. Finally, in 5% to 10% of patients, one finds multiple bullae larger than 2 cm. Retrospective studies showed that apical stapling reduced the recurrence rate from 23% when no resection was made to 1.8% when resection was accomplished.94,95 Resection of the apex decreased the rate of recurrence even if no abnormalities were found.96 Although resection of the apex of the lung where the blebs are located is very effective to prevent recurrences, obliteration of the pleural space by pleurectomy, pleural abrasion, or pleurodesis is a second maneuver to ensure the lowest possible recurrence rate. Obliteration of the pleural space can be accomplished by parietal pleurectomy or mechanical abrasion of the parietal pleura because each of these methods creates an inflamed surface with secondary fixation of the lung to the endothoracic fascia. Parietal pleurectomy limited to the apex creates sufficient adhesions to prevent recurrences. Gaensler found no evidence of any respiratory functional restriction after pleurectomy.11 The morbidity associated with apical pleurectomy is low, although significant complications such as hemorrhage can occasionally happen.97 When used as the sole procedure, pleurectomy produces excellent results, with a recurrence rate varying from 1% to 5%.15,98-100 Pleural abrasion also produces effective obliteration of the pleural space. It has the advantage of preserving the entire pleura and resulting in fewer hemorrhagic complications than pleurectomy.101,102 In nine reported series reviewed by Weeden and Smith, the recurrence rate of pneumothorax after pleural abrasion alone was 2.3%.97 It appears that a combination of resection of the blebs and pleurodesis is a safer treatment.103 We routinely proceed with a wedge resection of the apex, followed by an apical pleurectomy and pleural abrasion of the rest of the parietal pleura. Occasionally, the inferior pulmonary ligament is taken down. A single 28 Fr chest tube is left in the pleural place and can often be removed within 48 hours after surgery. Most patients are discharged from the hospital by the third or fourth postoperative day.

Surgical Approaches A full posterolateral thoracotomy is seldom necessary for the surgical treatment of spontaneous pneumothorax. The apex of the lung can be resected, and a pleurectomy or pleural abrasion can easily be performed through a less invasive and more cosmetically acceptable axillary incision15,98 or a limited thoracotomy. The standard VATS with three ports is very popular and is currently the technique of choice in the surgical community. Uniportal VATS has recently been proposed as an alternative to reduce the neurologic complications.104 VATS is performed with the patient under general anesthesia with a double-lumen endotracheal tube. Three ports of entry are usually necessary to introduce a rigid telescope with video attachment and instruments to perform the blebectomy, pleurectomy, or pleural abrasion. Proper port place-

1/21/2008 1:59:49 PM

1102

Section 4 Pleura

ment is essential to produce the triangulation that is required to fully access all lung zones and to eliminate criss-crossing of instruments. Selection of the appropriate intercostal spaces for placement of trocars is adjusted according to the patient’s morphologic form. Blebs are best resected with an endoscopic linear stapler, and this is followed by pleural abrasion or subtotal parietal pleurectomy.

Treatment for Bilateral Disease Some surgeons select simultaneous bilateral thoracotomy or single-stage bilateral transaxillary thoracotomies even if the pneumothorax is unilateral.105 VATS is a good option for performing bilateral bleb excisions during the same procedure, but the surgical risk needs to be weighed against the benefits.106 To avoid incisions on both sides, an ipsilateral VATS with surgery on the contralateral lesion has been described.107 A median sternotomy has been advocated when bilateral disease is identified before surgery.108 We prefer bilateral staged operations if bilateral disease is present.109

Morbidity of VATS Most patients have minimal postoperative morbidity and discomfort; however, chronic postoperative pain requiring analgesic medication is always possible after any VATS procedure. Postoperative chest wall pain can be very distressing. The pain is secondary to trocar insertion and manipulation of the instruments in the intercostal space, which contributes to injury of the intercostal nerves. Placing the incisions anteriorly in wider intercostal spaces for the bigger trocars and using the posterior trocar for smaller instruments (5-7 mm) may help prevent postoperative pain. The postoperative chest wall pain that occurs after VATS is not negligible and may represent a significant problem in young patients.95

Results of VATS In a retrospective study, Cole and coworkers failed to demonstrate any advantage of VATS over axillary thoracotomy in terms of hospital stay or morbidity.85 Kim and colleagues found no advantage of VATS over axillary thoracotomy with regard to operating time, amount of analgesics used during the first postoperative day, duration of chest tube drainage, and number of postoperative recurrences.110 Horio and colleagues showed that the recurrence rate after VATS was double that seen after limited axillary thoracotomy.111 In 1997, Dumont and associates compared the results of axillary thoracotomy with thoracoscopy and found no major differences between the two groups with regard to chest tube duration or hospital stay.112 The overall morbidity rate was 16% in the axillary thoracotomy group and 11% in the thoracoscopy group. In a prospective randomized study comparing VATS with axillary thoracotomy, Freixenet and coauthors found no significant difference for postoperative blood loss, respiratory function (maximum inspiratory and expiratory pressures, forced expiratory volume in the first second, and forced vital capacity), postoperative pain (analogue visual scale), supplementary doses of analgesics, postoperative complications, hospital stay, or resumption of normal activity.113 In a prospective, controlled randomized study, 60 patients with spontaneous pneumothorax were treated by VATS or

Ch089-F06861.indd 1102

posterolateral thoracotomy.114 Patients undergoing VATS had significantly longer operative time, but patients who had a thoracotomy had more severe alterations of their postoperative pulmonary functions. No differences were found in duration of chest tube drainage, treatment failure, recurrence, or operative mortality. VATS appears to be superior to thoracotomy because of lower postoperative analgesic requirements and decreased duration of hospitalization.114 In 1997, Jiménez-Merchan and coworkers reported the results of a retrospective analysis comparing 110 patients with pneumothorax treated by VATS with 627 patients treated by thoracotomy. The VATS group has decreased postoperative pain, faster recovery, and shorter length of hospital stay.115 In a recent systematic review of randomized clinical trials comparing VATS with conventional strategy, it was found that use of pain medication and length of hospital stay were reduced, but the recurrence rate was slightly higher, averaging 5%.116 Most of the series reported in the literature represented the early period of experimentation with VATS. We are convinced that the future will show the superiority of the VATS approach. The operation is easy for a single operator, fast, and cosmetically acceptable with a minimum of residual pain, and the results are as good as with the other approaches. The learning curve is probably completed for most thoracic surgeons in practice today, thus the posterolateral thoracotomy must be abandoned as a routine approach in favor of VATS.

Management of Recurrence After VATS There is very little experience with the surgical management of recurrence after VATS. Many surgeons would consider that VATS is not a good option for reoperation because of the presence of postoperative pleural adhesions. However, Cardillo and colleagues, in a small series of 19 patients undergoing repeat VATS who were monitored for 32 months, reported no recurrences. The conversion rate was 5.2%.117 VATS was also used with success in patients who had talc pleurodesis for the treatment of recurrent spontaneous pneumothorax.118 VATS is an acceptable approach for recurrence after a previous VATS. However, one should not hesitate to convert to full posterolateral thoracotomy if VATS becomes difficult.

Other Treatment Options Medical Thoracoscopy and VATS for Pleurodesis Alone In Europe, medical thoracoscopy has long been used for the diagnosis and treatment of spontaneous pneumothoraces.93,119 According to its proponents, the technique allows for proper staging of the disease followed by treatment. According to Verschoof and associates, thoracoscopy needs to be performed routinely at the time of the first episode of a spontaneous pneumothorax to classify the patients in one of three categories: 1. No obvious abnormalities 2. Small apical blebs 3. More generalized bullous disease

1/21/2008 1:59:49 PM

Chapter 89 Spontaneous Pneumothorax and Pneumomediastinum

Treatment is then selected according to the findings.120 A chemical pleurodesis is used in the first two groups, and surgery is offered to patients with generalized bullae.120 Talc poudrage is an acceptable technique for patients who present with a secondary spontaneous pneumothorax, but it is controversial in the management of primary spontaneous pneumothorax.

Chemical Pleurodesis Rarely, surgeons use chemical pleurodesis as first-line treatment for recurrences of pneumothorax. Many agents, such as quinacrine, autologous blood, and bleomycin as well as tetracycline and talc, have been used for this purpose.127-130 Talc is a powder of hydrous magnesium silicate containing various contaminants that has been shown to be effective in treating malignant pleural effusions and spontaneous pneumothoraces. Commercially available purified talc is free of asbestos and is considered safe for therapeutic use. It is effective in inducing pleural fibrosis and adhesions, but the morbidity associated with its use includes fever and pain. The most compelling concern about using talc is the risk of inducing respiratory failure in a young patient. Because of this possible complication, the maximum dose recommended for intrapleural use is 5 g. Talc may be injected through a chest tube in suspension form (2-5 g diluted in 50-250 mL of normal saline) or sprinkled with a syringe over the entire pleural surface during the VATS procedure. It may also be insufflated in its powder form through a thoracoscope or with a talc insufflator. A recent series involving a large number of patients treated by videothoracoscopic talc poudrage showed a high success rate and a low morbidity.119 Some surgeons are concerned by the use of chemopleurodesis in patients who may eventually require a thoracotomy because it may be associated with higher morbidity rates. At present, chemical pleurodesis is used only in selected cases of surgery. In our opinion, chemical pleurodesis in primary spontaneous pneumothorax is not recommended except in exceptional situations. Aerosol of fibrin glue nebulized over the lung surface under thoracoscopic control has been used with a success rate of 80%.121 We think surgery can offer better results. Electrocautery, using laser or the argon beam electrocoagulator for ablation of the blebs with the VATS approach, has become an option in the management of pneumothoraces.122-126

Outcome After Treatment Although most of the studies evaluating the results are retrospective, they show a low incidence of recurrences whether pleurectomy or pleural abrasion was used. In surgical series, including 977 patients from 1957 to 1993, the recurrence rate after a follow-up of between 5 and 10 years was 1.5%.131 Patients treated with bed rest, needle aspiration, and chest tube drainage had a recurrence rate of 30%.

Ch089-F06861.indd 1103

1103

TABLE 89-5 Common Causes of Secondary Spontaneous Pneumothorax Airway and Pulmonary Disease Chronic obstructive pulmonary disease (bullous or diffuse emphysema) Asthma Cystic fibrosis Interstitial Lung Disease Pulmonary fibrosis Sarcoidosis Infectious Disease Tuberculosis and other mycobacterial infections Bacterial infections Pneumocystis jiroveci (P. carinii) infection Parasitic infections Mycotic infections Acquired immunodeficiency syndrome (AIDS) Neoplastic Disease Bronchogenic carcinoma Metastatic disease (lymphoma or sarcoma) Catamenial (endometriosis) Miscellaneous Marfan’s syndrome Ehlers-Danlos syndrome Histiocytosis X Scleroderma Lymphangiomyomatosis Collagen diseases

SECONDARY SPONTANEOUS PNEUMOTHORAX Spontaneous pneumothorax can occur secondary to a variety of pulmonary and nonpulmonary disorders (Table 89-5).

Chronic Obstructive Pulmonary Disease COPD is the most common cause of secondary pneumothorax. It almost always occurs in patients older than 50 years of age and represents a troubling episode in the evolution of a patient with COPD. A spontaneous pneumothorax is a marker of the severity of the disease and a predictor of survival. Each pneumothorax occurring in these patients increases the chance of dying by almost fourfold.132 The explanation for the development of blebs and bullae was suggested by several studies to be a combination of inflammation provoked by smoking and resulting in an endobronchial obstruction. It is believed that endobronchial obstruction by inflammatory cells and peribronchial fibrosis are among the causes for the generation of bullae by increasing the pressure in the alveolar tissue. The result is rupture of pulmonary parenchyma and the development of bullae. Clinical diagnosis of a pneumothorax can be difficult in these patients, who already have dyspnea. They often show increased dyspnea and acute respiratory distress with hypoxia, hypercarbia, and acidosis. Because of their limited pulmonary function, patients with COPD often show little tolerance to even a small pneumothorax. Diagnosis can be made by chest radiography, but again it can be difficult to interpret the radiographs because of the increased radiolucency of the

1/21/2008 1:59:49 PM

1104

Section 4 Pleura

diseased lung. CT scanning is often helpful to confirm and localize the pneumothorax.133,134 More than 40% to 50% of patients will develop a second pneumothorax if pleurodesis is not performed at time of the first event. Because of decreased lung vascularization, patients with COPD and pneumothorax are more likely to have prolonged air leak; they also have a higher incidence of in-hospital infection and of empyema.135 A persistent bronchopleural fistula may necessitate early aggressive treatment. The choice of therapy is based on the severity and duration of symptoms, severity of the underlying parenchymal disease, number of previous episodes, medical comorbidities of the patient, and experience of the surgical team. Patients with secondary spontaneous pneumothorax have, as a first line of therapy, a chest tube with underwater seal drainage. Negative pressure on the chest tube must always be used with caution. Major operative risks tend to justify this prolonged conservative treatment before a surgical decision is made. However, surgery needs to be considered early, before the patient may contract a nosocomial infection or an empyema as a result of prolonged chest tube drainage. Chemical pleurodesis is not always possible or effective in these patients, in whom it is impossible to clamp the chest tube if the air leak is important.136,137 It may even be dangerous because it could convert it into a tension pneumothorax. Medical thoracoscopy and talc poudrage are options that have been proposed, but we believe that, whenever possible, VATS performed under general anesthesia with a double-lumen intubation is preferable.138,139 For many surgeons, a thoracotomy remains the safest approach because it allows a better vision in patients with COPD and large emphysematous bullae. We limit the resection with staplers to the site of the leak unless we plan to proceed with a lung volume reduction at the same time. We normally do not resect all the bullae because we fear it may result in an unfilled pleural space and too many leaks from suture lines. We always add an extensive parietal pleurectomy and a chemical pleurodesis with talc poudrage. The operative mortality rate may reach 10%, and the morbidity can be significant. In 1994, Waller and associates reported an operative morbidity rate of 23%, a mortality rate of 9%, and a mean postoperative stay of 9 days in a series of 22 patients who had undergone VATS for secondary pneumothorax.139 Other surgical procedures, such as electrocautery, carbon dioxide laser, or neodymium : yttrium-aluminum-garnet (Nd : YAG) laser, have been used to deal with the bullae, but we think resection with the endostaplers is the safest and most effective approach. In individuals with poor overall physical condition in whom anesthesia may be too risky, alternative options such as tube chemical pleurodesis or permanent drainage with a Heimlich valve is considered for a prolonged air leak. More than 40% to 50% of patients with a pneumothorax in the context of COPD eventually develop a second pneumothorax. It is then time to perform a chemical pleurodesis before the chest tube is removed.

Ch089-F06861.indd 1104

Cystic Fibrosis Pneumothorax occurs in about 10% of patients with cystic fibrosis. It may lead to a life-threatening situation in patients with poor lung function. Although conservative therapy is associated with a high rate of recurrence, the possibility of subsequent lung transplantation must be considered before a decision is made about surgery and pleurodesis.140 The best surgical option is probably a thoracoscopic approach with lung resection and limited pleurodesis.141 Localized apical thoracoscopic talc poudrage is also an option.142

Infection Pneumothorax can be secondary to pulmonary infection (bacterial, viral, mycotic, or parasitic), pleural infection (empyema), or intra-abdominal infection (subphrenic abscess). Cavitary pulmonary infections are particularly prone to rupture with secondary pneumothoraces. Pulmonary tuberculosis, for instance, is known to be associated with pneumothoraces that often require prolonged tube drainage. Surgery is not undertaken until these patients have received adequate systemic antituberculosis therapy.

Acquired Immunodeficiency Syndrome Since the early 1980s, several reports have described the association of spontaneous pneumothorax, pneumomediastinum, and AIDS.143 DeLorenzo and associates reported a 6% incidence of pneumothorax in the AIDS population, with pneumothorax occasionally being the initial manifestation of the disease.144,145 In AIDS patients, the pneumothorax may remain small and asymptomatic, but it may also increase rapidly and become under tension, causing severe respiratory failure. In the AIDS population, there is an increased incidence of synchronous bilateral pneumothoraces and bronchopleural fistulas, as well as higher rates of ipsilateral and contralateral recurrences. The high incidence of pneumothorax in AIDS patients is probably the result of cystic lesions that are most common at the apices and consist of subpleural air spaces filled with eosinophilic exudates, Pneumocystis jiroveci (P. carinii) organisms, fibrous material, and macrophages. Histologic studies suggested that such lesions are the result of infection associated with tissue destruction and fibrosis. Whenever possible, the initial management needs to be conservative; sometimes, small pneumothoraces resolve with observation alone. However, most patients have large and persistent air leaks that eventually require tube thoracostomy.146 On occasion, these patients may be treated on an outpatient basis with a one-way flutter valve.147 To prevent recurrences, chemical pleurodesis has been used, but not always with good results.148 Surgical resection of the diseased area with pleurectomy remains the most effective mode of therapy. Although significant operative mortality rates have been reported, AIDS patients can tolerate surgery reasonably well, and most do not require mechanical ventilation during the postoperative period.149 Treatment with VATS and talc poudrage may also be used to control the pneumothorax and associated air leak.150 The introduction of

1/21/2008 1:59:49 PM

Chapter 89 Spontaneous Pneumothorax and Pneumomediastinum

new medical therapies for AIDS has led to a decrease in the incidence of related pneumothoraces.

Severe Acute Respiratory Syndrome Spontaneous pneumothorax occurs as a complication in 1.7% of patients with SARS.7 Clinically, all patients are usually very dyspneic with high oxygen requirements and show extensive radiologic manifestations of the disease. Such an extensive pulmonary injury is a predisposing factor for the development of pneumothorax in this category of patient. Regarding the management of pneumothorax, conservative measures appear to offer adequate treatment in most symptomatic patients. Chest tube drainage is used first, before one recommends video-assisted thoracoscopy for prolonged or persistent air leak. One must be careful not to rush into surgery with these very fragile patients.151

Neoplasia Occasionally, bronchial obstruction by a lung cancer leads to a pneumothorax. A pneumothorax may also develop as the result of pleural space rupture of an ischemic primary tumor or metastasis. Pneumothoraces may also occur during chemotherapy or radiotherapy.152 Pneumothoraces are more commonly associated with metastatic sarcomas but have also been described with teratomas, Wilms’ tumors, melanomas, carcinomas of the kidney and pancreas, gynecologic malignancies, lymphomas, choriocarcinomas, and lymphangiomatosis.153-158 In these patients, chest tube drainage is the therapy of choice; surgery is seldom indicated. Chemical pleurodesis may be used to prevent recurrences.159

Catamenial Pneumothorax Pneumothoraces occurring within 48 to 72 hours after the onset of menstruation were first described by Maurer and Schall.160 According to Nakamura, catamenial pneumothorax may afflict 3% to 6% of women between 20 and 30 years of age.30 Most catamenial pneumothoraces are on the right side, and they may be recurrent over several years before being diagnosed. They are usually small, and patients present with chest pain and dyspnea.160 The pathogenesis of catamenial pneumothorax is still unclear.161 Air may reach the pleural space from the cervix and abdomen through congenital diaphragmatic defects, or there may be focal thoracic endometrial implants on the visceral pleura or in the lung, with air leakage occurring during menstruation. Endometrial implants may also obstruct bronchioles, causing distal hyperinflation and alveolar rupture.162 Increased levels of prostaglandin F2 tromethamine at the time of menses may also cause bronchial and vascular constriction, leading to alveolar rupture and subsequent pneumothorax. It is likely that several of these mechanisms are involved simultaneously in the development of catamenial pneumothoraces. Management is similar to that for other types of pneumothoraces. Small and asymptomatic episodes may be treated conservatively, whereas large and symptomatic episodes

Ch089-F06861.indd 1105

1105

require chest tube drainage. The management of recurrence is more controversial, and several options are possible: 1. Treatment of each episode with tube thoracostomy 2. Use of oral contraceptives or weak androgens to suppress ovulation 3. Chemical pleurodesis 4. Hysterectomy and bilateral oophorectomy 5. Thoracotomy with pleural abrasion or pleurectomy163 In 1990, Fleisher proposed a treatment algorithm taking into consideration whether hormonal therapy is contraindicated and whether or not pregnancy is desired. Resection of blebs and pleurectomy or pleural abrasion are indicated if pregnancy is desired or if laparoscopic tubal ligation is contraindicated.164 The postoperative outcome may be influenced by the presence of diaphragmatic defects with or without endometriosis. Surgery is performed during menstruation for optimal visualization of pleurodiaphragmatic endometriosis. Coverage of the diaphragmatic surface with polyglactin mesh to prevent recurrence of catamenial pneumothorax, even when the diaphragm appears normal, is an option.165 The use of talc poudrage is debatable in these young patients.

Miscellaneous Other diseases that have sometimes been associated with pneumothorax include Marfan’s syndrome, Ehlers-Danlos syndrome, histiocytosis X, pulmonary infarction, interstitial fibrosis, eosinophilic granuloma, sarcoidosis, and tuberous sclerosis.166

PRIMARY SPONTANEOUS PNEUMOMEDIASTINUM Spontaneous pneumomediastinum (SPM) is defined as the nontraumatic presence of free air in the mediastinum in a patient with no known underlying disease. SPM is a rare condition with an incidence of 1 per 7000 to 12,000 hospital admissions. It has long been recognized as a self-limited, benign condition in young men. According to Munsell, pneumomediastinum was first recognized in the 17th century by a midwife to the Queen of France.167 The first reported case in the modern era was by Louis Hamman in 1939.168 This entity develops as a result of the increased pressure in the intrabronchial and intra-alveolar space associated with a Valsalva maneuver, coughing, straining, or vomiting or during artificial ventilation. It is also linked to other causes, such as bronchial asthma, diabetic ketoacidosis, inhalation of drugs, and childbirth. According to Macklin and Macklin, SPM results from the rupture of terminal alveoli into the lung interstitium.169 The air dissects along the pulmonary vasculature toward the hilum, centrally along the bronchoalveolar trunks, through the peribronchial space, or within the lymphatics, toward the mediastinum. The air can also dissect along the perivascular connective tissue into the pulmonary parenchyma, resulting in interstitial emphysema. The clinical presentation of SPM can be subtle, and the diagnosis can be missed or delayed. A high index of suspicion is necessary for prompt diagnosis. The most frequent signs

1/21/2008 1:59:49 PM

1106

Section 4 Pleura

and symptoms are pain in the chest and neck, exertional dyspnea, subcutaneous emphysema (40%-100% of the cases), hypotension, dysphagia, and cough. Hamman described the mediastinal crunch sign, consisting of crunch-like sound over the left hemithorax anteriorly. It is reported in about 50% of patients.170 The initial differential diagnosis of SPM is broad and includes cardiac, pulmonary, musculoskeletal, and esophageal causes. Most of these can be excluded with a thorough history, detailed physical examination, the use of electrocardiographic examination, and radiographic or endoscopic assessment as indicated. CT scanning of the thorax may be required for more precision. The diagnosis is confirmed by chest radiography, which shows streaky gas densities along the fascial planes of the mediastinum. The lateral display helps to obtain 100% accuracy. The most important differential diagnosis to be excluded is an esophageal perforation. That is why an esophagogram is often performed during the initial investigation of these patients. However, these patients are often overinvestigated.171 After specific causes of mediastinal emphysema have been excluded, primary SPM can be treated expectantly. Tension pneumomediastinum arises when air in the lung and mediastinum causes compression of pulmonary and mediastinal vessels and interferes with respiration by the splinting action of air in the interstitial tissues of the lung. Its clinical characteristics are dyspnea, cyanosis, prominent veins in the neck, tachycardia, and hypotension. It may mimic cardiac tamponade. Fatalities have been reported. The treatment of malignant pneumomediastinum aims to reduce the high pressure in the alveoli by evacuating the air in the mediastinum with the use of multiple subcutaneous aspirations or incisions. Cervical mediastinotomy rarely may be necessary. In conclusion, SPM is an uncommon and self-limited clinical entity. It is usually a benign condition that can be treated expectantly.172 Recurrence is rare. Hospitalization and an aggressive approach are limited and individualized.

COMMENTS AND CONTROVERSIES Primary spontaneous pneumothorax occurs in young, apparently healthy individuals. In such patients, radiographic signs of lung disease are absent, but the apical blebs that are the cause of the pneumothorax can usually be identified on CT scanning. Why these young and usually thin and tall people have apical blebs is a matter of controversy, but one of the most prevalent theories is that the lung becomes stretched during its growth, leading to areas of relatively diminished vascular supply (arterial and pulmonary) at the apices (i.e., farthest from the hilum). This, in turn, leads to bleb formation. It is generally agreed that the first episode, if uncomplicated, can be managed by observation alone if the pneumothorax is small (≤20%) or by intercostal tube drainage if the pneumothorax is larger (>20%). If the first episode is complicated by tension, persistent air leakage (3%-5% of patients), or hemothorax (5% of patients) or if the pneumothorax is recurring (10%-12% incidence after a first episode), further measures are necessary. These involve resection

Ch089-F06861.indd 1106

of the offending blebs (blebectomy) and obliteration of the pleural space. It is worth noting that, in spontaneous pneumohemothoraces, the bleeding, which can be quite severe, usually results from a torn adhesion between the parietal and visceral pleura. Because the vessels contained in such adhesions have thin walls, they do not retract after disruption and therefore bleed actively in the empty, negative-pressure pleural space. Most controversies concerning the surgical treatment of primary spontaneous pneumothoraces revolve around which surgical approach is best and which method should be recommended to achieve pleurodesis. Both of these issues are well discussed in this chapter. At present, the relative merits of the thoracoscopic approach (VATS) versus those of the limited axillary incision are still debated, although in most series the incidence of further recurrences is higher after VATS than what has been reported after transaxillary operations. Pleurodesis, which is the most important part of the operation, can be accomplished by either parietal pleurectomy or mechanical abrasion, the latter technique having the advantage of preserving the extrapleural plane should further surgery be required. Both procedures result in effective pleurodesis, although many surgeons believe that pleurectomy stimulates the formation of denser and more complete and permanent adhesions. If a pneumothorax still recurs after blebectomy and pleurodesis, it is more often caused by the inadequacy of the pleurodesis rather than the formation of new blebs. The problems associated with pneumothoraces secondary to COPD are different because almost all patients are older and have associated comorbidities. Because of their limited pulmonary reserve, these patients may also show little tolerance to even a small pneumothorax, and they can present with acute respiratory distress, hypoxia, hypercapnia, and respiratory acidosis. Chances of recurrence are much higher in this group (30%-50%) than in patients with primary spontaneous pneumothorax (10%-12%). Because of the significant incidence of prolonged air leaks, the high risk of recurrence, and the potential fatality of this condition, surgical intervention should be considered at the time of first occurrence. The emergence of VATS techniques has considerably changed the magnitude of the operation, which can now be done with low operative morbidity and mortality even in high-risk cases. If the operative risks are considered prohibitive, management should consist of prolonged tube drainage with or without administration of sclerosing agents through the tube. J. D.

KEY REFERENCES Boutin C, Viallat JR, Aelony Y: Practical Thoracoscopy. Berlin, SpringerVerlag, 1991. ■ This book has an excellent chapter on the thoracoscopic management of pneumothoraces. Deslauriers J, Lacquet LK: Surgical management of pleural diseases. In Deslauriers J, Lacquet LK (eds): International Trends in General Thoracic Surgery, Vol. 6. St. Louis, Mosby-Year Book, 1990. ■ In this volume devoted to the pleural space, there are several good chapters written on the management of various types of pneumothoraces. Hood MR, Antman K, Boyd A, et al: Surgical Diseases of the Pleura and Chest Wall. Philadelphia, WB Saunders, 1986.

1/21/2008 1:59:49 PM

Chapter 89 Spontaneous Pneumothorax and Pneumomediastinum

■ This book is devoted to the surgical approach to pleural diseases and includes a

well-written chapter on pneumothoraces. Killen DA, Gobbel WG: Spontaneous Pneumothorax. Boston, Little, Brown, 1968. ■ Although published more than 20 years ago, this book remains a classic in the understanding of pneumothoraces and is the most complete review of the history of pneumothoraces.

Ch089-F06861.indd 1107

1107

Light RW: Pleural Diseases, 4th ed. Philadelphia, Lea & Febiger, 2001. ■ A complete review of the diagnosis and treatment of pleural diseases is provided with a good chapter on primary and secondary pneumothoraces.

1/21/2008 1:59:50 PM

chapter

90

THE THORACIC DUCT AND CHYLOTHORAX Dalilah Fortin Richard I. Inculet Richard A. Malthaner Key Points

■ Chylothorax is an infrequent but important cause of pleural

effusion. ■ The most common causes are postoperative and neoplastic. ■ After the diagnosis is confirmed by analysis of the pleural fluid, early

therapy must be instituted to prevent complications related to the ongoing chylous leak. ■ Basics of conservative therapy include drainage of the effusion, nothing by mouth (NPO), and parenteral nutrition (TPN). ■ Prompt surgical ligation of the thoracic duct needs to be done if nonsurgical modalities fail.

THORACIC DUCT Historical Note Aristotle and the anatomists Herophilos and Erasistratos are said to have described the lymphatic system in approximately 300 BC. In the 16th century, Vesalius, professor of anatomy and surgery at Padua, named the thoracic duct the vena alba thoracis because of the milky white fluid that it contained. In an illustration of the lymphatic channels in the mesentery of the dog, Aselli1 traced these vessels into the abdominal receptaculum chyli but mistakenly believed that they ended in the liver. In 1651, Pecquet of Paris observed the intestinal lacteal channels that empty into the receptaculum chyli, then into the thoracic duct, and eventually into “the whirlpool of the heart.” He confirmed these observations in an autopsy of the body of a criminal who had eaten a large final meal. In 1653, Bartholin named these vessels lymphatics. In 1784, William Hunter,2 with his assistants at the Hunterian School, Hewson and Cruikshank, recognized that the lymphatic vessels are the same as the lacteal vessels and “that these altogether with the thoracic duct constitute one great and general system dispersed through the whole body for absorption.” In 1878, Claude Bernard’s3 conception of the mammalian milieu intérieur and Starling’s4 work (1896) on hydrostatic and colloid osmotic pressure further illuminated the role of the lymphatic channels. In 1931, Drinker and Field5 measured protein flux from the capillaries to the tissues. They confirmed the notion that the lymphatic channels and the thoracic duct act as vessels that return protein molecules to the central circulation. Reports on the chylothorax were rare before the 19th century. From the medical literature dating back to 1691, Bargebuhr6 compiled a review of 40 patients with nontrau-

matic chylothorax. All had neoplasms of the abdomen and thorax. Although the first traumatic chylothorax was reported by Quincke7 in 1875, Zesas’ review8 stated that Longelot in 1663 was probably the first to describe a traumatic chylothorax. In this collected series of 24 patients, 12 died. In 1922, on the basis of his review of the literature and personal experimental work on ligation of the thoracic duct, Lee9 concluded that injuries need to be treated by direct repair if possible and, if not, by ligation. This represented the first challenge to the accepted dogma that the duct was essential to life. Blalock and colleagues10 noted chylothorax after ligation of the superior vena cava. Their attempts at complete lymphatic blockage by duct ligation were successful in only 3 of 72 animals because collateral lymph channels developed rapidly and relieved the obstruction. Heppner,11 in 1934, first pointed out that progressive obliteration of the pleural space around the opening, rather than healing of the injured duct, was the mechanism of spontaneous resolution of thoracic duct fistulas. Daily thoracenteses were advocated, and many attempts at pleurodesis subsequently failed. Intravenous (IV) injection of aspirated chyle was tried in the early 1900s by Oeken but was abandoned after several anaphylactic reactions.12 Readministering chyle by mouth or rectum was also found to be unhelpful. Phrenic nerve sectioning also proved to be unsuccessful. Although Crandall and coworkers13 successfully treated a thoracic duct fistula in the neck by direct thoracic duct ligation, it was Lampson in 1948 who ligated the thoracic duct in the chest and marked the turning point in the therapy of chylothorax.14 The mortality rate at that time was almost 100% in nontraumatic chylothorax and 50% in traumatic chylothorax, with the latter figure suggesting that one half closed spontaneously. In 1951, Schumacker and Moore suggested feeding cream to infants preoperatively to help localize the duct.15 Soon after, Klepser and Berry16 introduced intraoperative visualization of the duct with lipophilic dyes and early ligation. Their approach, through the right chest at the level of the diaphragm regardless of the side of injury, has become one of the most commonly used approaches today for thoracic duct injuries. HISTORICAL READINGS Aselli G: De Factibus Sive Lacteis Verris, Quarto Vasorum Mesdarai Corum Genere Novo Invento. Milan, JB Bieldellium Mediolani, 1627. Bernard C: Leçons sur les Phénomènes de la vie Communs aux Animaux et aux Végétaux, Vol 1. Paris, JB Bailliere et Fils, 1878.

1108

Ch090-F06861.indd 1108

1/21/2008 2:00:46 PM

Chapter 90 The Thoracic Duct and Chylothorax

Blalock A, Cunningham RS, Robinson CS: Experimental production of chylothorax by occlusion of the superior vena cave. Ann Surg 104:359, 1936. Lampson RS: Traumatic chylothorax: A review of the literature and report of a case treated by mediastinal ligation of the thoracic duct. J Thorac Cardiovasc Surg 17:778, 1948. Lee FC: The establishment of collateral circulation following ligation of the thoracic duct. Bull Johns Hopkins Hosp 33:21, 1922.

Basic Science Anatomy Davis17 characterized the anatomy of the thoracic duct as “constant only in its variability.” The thoracic duct is the left main collecting vessel of the lymphatic system and is far larger than the right terminal lymphatic duct (Fig. 90-1). The duct originates from the cisterna chyli in the abdomen but may be absent in 1 of 50 people. The cisterna chyli is a globular structure that is 3 to 4 cm long and 2 to 3 cm in diameter. It is found along the vertebral column at the level of L2, but it may be found anywhere between T10 and L3

Left jugular vein Right jugular vein Right subclavian vein

Right lymphatic duct

Thoracic duct Left subclavian vein

Aorta Intercostal lymphatics

Collateral lymphatics

Thoracic duct

Azygos vein

Diaphragm

Embryology

Cisterna chyli

Left lumbar trunk

FIGURE 90-1 Surgical anatomy of the thoracic duct.

Ch090-F06861.indd 1109

on the right side of the aorta. From the cisterna chyli, the thoracic duct ascends along the spine to enter the thorax through the aortic hiatus at the level of T10 to T12, just to the right of the aorta. It ascends extrapleurally along the right anterior surface of the vertebral bodies, posterior to the esophagus, between the aorta and the azygos vein and anterior to the right intercostal arteries. At the level of T5 to T7, the duct crosses behind the aorta to the left posterior side of the mediastinum and ascends on the left side of the esophagus, beneath the pleural reflection and posterior to the left subclavian artery. In this region, the duct is vulnerable during operations involving the aortic arch, left subclavian artery, or esophagus. At 4 cm above the clavicle, the duct turns laterally behind the carotid sheath and jugular vein, anterior to the inferior thyroid and the vertebral arteries, subclavian artery, and phrenic nerve. At the medial margin of the anterior scalene muscle, it turns inferiorly, entering the venous system at the subclavian-internal jugular vein junction on the left, although it may empty into the left innominate, left internal jugular, left vertebral, or even the right internal jugular vein. The duct contains a variable number of valves throughout its course, with one consistent bicuspid valve at the lymphaticovenous junction that protects it against the reflux of blood.18 Variability is common, with 40% to 60% of individuals having anomalous collaterals communicating with the azygos, intercostal, and lumbar veins.19,20 Also, it was found that 25% to 33% of individuals have multiple ducts at the level of the diaphragm, which has implications if an operation is considered.21 The right duct is small (2 cm in length) and is rarely visualized. It drains lymph from the right side of the head, neck, and chest wall through the jugular trunk and from the right lung, heart, and lower half of the left lung through the bronchomediastinal trunk. Lymph from the dome of the liver, the right diaphragm, and the right upper anterior chest drains through the right internal mammary trunk to the right duct. These anatomic relationships explain why injury to the duct below the level of T5 to T6 usually results in a right chylothorax, and injury above this level results in a left chylothorax. The collateral communications also explain why the duct can be ligated at any point in the chest or neck without impairing the delivery of lymph to the central circulation.

Esophagus

Inferior vena cava

Right lumbar trunk

1109

The thoracic duct is a bilateral structure, and it can have many varied anatomic patterns. The lymphatic system begins to develop at the end of the fifth week, about 2 weeks later than the cardiovascular system. Sabin22 showed that the original lymph sacs arose from the endothelium of the adjacent veins. She described six original lymph spaces (Fig. 90-2). The two jugular sacs arise from the anterior cardinal vein, and the two iliac sacs arise near the junction of the iliac veins and the posterior cardinal veins. The single retroperitoneal sac is situated in the root of the mesentery on the posterior abdominal wall, and the primitive cisterna chyli arises from the mesonephric vein and the veins at the dorsomedial edge of the wolffian bodies. The cisterna chyli is then formed by

1/21/2008 2:00:46 PM

1110

Section 4 Pleura

Internal jugular vein (anterior cardinal vein)

Jugular lymph sac

Retroperitoneal lymph sac

Inferior vena cava

Cisterna chyli

Iliac lymph sac

A

Iliac vein Right lymphatic duct Lymph node

Internal jugular vein Subclavian vein

Superior vena cava Anastomosis Thoracic duct Left and right thoracic ducts Lymph node

Cisterna chyli Retroperitoneal lymph sac Iliac lymph sac

B

C

FIGURE 90-2 Embryologic origin of the lymphatic channels and the thoracic duct in the human embryo. A, Left side of a 7-week-old embryo with the six lymph sacs. B, Ventral view at 9 weeks showing the paired thoracic ducts. C, Later stage showing the formation of the adult thoracic duct and the right lymphatic duct. (FROM MOORE KL, PERSAUD TVN: THE DEVELOPING HUMAN, 5TH ED. PHILADELPHIA, WB SAUNDERS, 1993.)

the union of two lumbar lymphatic trunks and the intestinal trunk within the abdomen. Lymphatic buds appear from the original sacs and follow the tissue planes of least resistance, principally along veins, toward the periphery. The thoracic duct is formed from a downward growth of the left jugular sac and an upward growth of the right thoracic duct from the cisterna chyli. Initially, the duct is represented by a bilateral symmetrical plexus of lymph vessels, each side attached to the jugular sac and each with several anastomoses between them. The azygos and the intercostal veins also

Ch090-F06861.indd 1110

contribute to the formation of a major portion of the duct. This explains the multiple connections between the duct and these vessels that allow chyle to be carried into the bloodstream when the duct is ligated. With maturation, the upper one third of the right duct and the lower two thirds of the left duct are obliterated, but the main communication between them persists to give the adult thoracic duct configuration. If the upper portion on the right side is not obliterated, a right lymphatic duct prevails.

Histology Lymphatic capillaries consist of single layers of flat endothelial cells, slightly larger and thinner than blood capillary cells. The basement membrane is absent or vestigial, which allows large molecules to permeate the walls easily. The lymphatic capillaries can be distinguished from blood capillaries by the absence of the basement membrane and blind endings and the lack of arterial and venous connections. Lymphatic capillaries do not have associated pericytes, but they do have anchoring filaments that attach to the surface of the endothelial cells and extend out into the connective tissue around the capillary. These filaments seem to hold the capillaries open during times when the surrounding edematous pressure might cause them to collapse. The thoracic duct, however, contains a well-developed basement membrane and has three layers within the wall: intima, media, and adventitia. The intima contains elastic fibers. The media is well developed, consisting of smooth muscle fibers supported by connective tissue containing elastic fibers. It is this well-developed layer that contracts rhythmically to aid in lymph flow. The adventitia is supplied by the vasa vasorum and contains smooth muscle fibers running both longitudinally and obliquely. The thoracic duct and all lymphatic channels, except the smallest ones, have valves. The valves have two leaflets consisting of folds of intima with delicate connective tissue in the middle covered with endothelium. They are more numerous and closer together than the valves of veins. The valves are so close together that a distended lymphatic vessel appears beaded because of the dilated sections between the valves.

Physiology The principal function of the thoracic duct is the transport of digestive fat to the venous system. Small fatty acids with less than 10 carbon atoms are absorbed directly into the portal system, whereas larger lipids are absorbed into the intestinal lymphatic vessels as micelles.23 The transport time of absorbed fat, from the mouth until it appears in the venous blood, is less than 1 hour after ingestion, with peak absorption 6 hours after ingestion. The volume of lymph flow is estimated to be 1.38 mL/kg of body weight per hour. Volumes up to 2500 mL of chyle in 24 hours have been collected from the cannulated human thoracic duct. The flow of lymph in the thoracic duct ranges from 0.38 mL/min at rest to 3.9 mL/min after a meal or during abdominal massage.13 It was found that 95% of the volume comes from the liver and intestinal lymphatic channels, although the amount from the extremities is negligible.

1/21/2008 2:00:47 PM

Chapter 90 The Thoracic Duct and Chylothorax

Lymphatic flow in amphibians, reptiles, and some birds is propelled by lymph hearts, whereas mammals have more complex mechanisms. The forward flow of chyle from the abdomen in humans is influenced by four factors. 1. Vis a tergo, from the Latin (“force exerted from the back”), is the transmission of pressure to the cisterna chyli from the intestinal lacteal vessels by the absorption of lymph. This force comes from the inflow into the lacteal system of chyle produced by the intake of food and liquid meals and intestinal movement. It is proportional to the volume of the food and independent of the external pressure or wall pressure. 2. There is a pressure gradient. Negative intrathoracic pressure and positive intra-abdominal pressure create a gradient favoring the flow of lymph toward the central circulation. 3. Muscular contractions by the duct itself are probably the most important factor in propelling lymph forward; the valves within the duct prevent retrograde flow. Contractions occur every 10 to 15 seconds and are independent of respiratory movements.24 The intraductal pressure ranges from 10 to 25 cm H2O and may rise to 50 cm H2O with obstruction.25 Acetylcholine produced by fibers of the vagus nerve constricts the duct; epinephrine dilates it.26 4. There is a Bernoulli suction effect produced by the flow of blood past the lymphaticovenous junction, which creates a vacuum.27 The lymphatic vessels perform the vital functions of collecting and transporting tissue fluid, extravasated plasma proteins, absorbed lipids, and other large molecules from the interstitial space to the intravascular space. Most of the body’s lymphocytes are circulated through the duct.

CHYLOTHORAX Definition Chylothorax is the accumulation of excess lymphatic fluid in the pleural space, usually as a result of a leak from the thoracic duct or one of its major branches. The term chyle comes from the Latin chylus, meaning “juice,” and usually connotes the milky appearance of intestinal lymph caused by the presence of emulsified fats. (Note that chyme is the semifluid mass of partly digested food found in the small intestine.)

Basic Science Etiology The prevalence of chylothorax ranges from 0.5% to 2.0% in selected series.28 Chylothorax is thought to result from either an obstruction or a laceration of the thoracic duct. The most common causes are neoplasms, trauma, tuberculosis, and venous thrombosis.29,30 A classification adapted from DeMeester31 is shown in Box 90-1. Congenital chylothorax is the leading cause of pleural effusion in the neonate.29 Fifty percent of newborns with chylothorax develop symptoms in the first 24 hours. The fluid is

Ch090-F06861.indd 1111

1111

Box 90-1 Causes of Chylothorax Congenital Atresia of thoracic duct Thoracic duct–pleural space fistula Birth trauma Traumatic Blunt Penetrating Surgical Cervical Excision of lymph nodes Radical neck dissection Thoracic Ligation of patent ductus arteriosus Coronary bypass surgery Excision of coarctation Esophagectomy Resection of thoracic aortic aneurysm Resection of mediastinal tumor Pneumonectomy or lobectomy Left subclavian artery operations Sympathectomy

Abdominal Sympathectomy Radical lymph node dissection Diagnostic Procedures Lumbar arteriography Subclavian vein catheterization Left-sided heart catheterization Neoplasms Benign Malignant Infections Tuberculous lymphadenitis Nonspecific mediastinitis Ascending lymphangiitis Filariasis Miscellaneous Venous thrombosis Left subclavian or jugular vein Superior vena cava Secondary to chylous ascites Pancreatitis Spontaneous

From DeMeester TR: The pleura. In Sabiston DC, Spencer FC (eds): Surgery of the Chest, 4th ed. Philadelphia, WB Saunders, 1983.

initially clear, but it quickly turns turbid when milk feeding begins. The cause is not always clear, but birth trauma or congenital defects in the duct, or both, may be precipitating factors. Increased venous pressure during a difficult delivery can cause rupture of the thin walls of the thoracic duct. Chylothorax has been associated with a variety of syndromes, including Noonan’s syndrome, Down syndrome, Gorham’s syndrome, Adams-Oliver syndrome, hereditary lymphedema (Nonne-Milroy-Meige syndrome), yellow nail syndrome, Behçet’s disease, and tracheoesophageal fistula.32-37 Malformations of the lymphatic system are rare causes of congenital chylothorax. The anomalous duct may be absent or atretic, or it may have multiple dilated lymphatic channels with abnormal communications between the duct and pleural space. Anomalies of the thoracic duct may be associated with polyhydramnios or lymphedema.

Traumatic Chylothorax Traumatic injury to the thoracic duct may occur with blunt or penetrating trauma or during surgery.38 Injury can occur at any point along the course of the duct, making localization difficult. The most common mechanism of nonpenetrating injury is sudden hyperextension of the spine, which results in rupture of the duct just above the diaphragm. It is thought

1/21/2008 2:00:48 PM

1112

Section 4 Pleura

that this is caused by a shearing of the duct by the right crus of the diaphragm or by sudden stretching over the vertebral bodies.27 Costal fractures are not necessary to produce this injury, especially after a meal. Penetration by gunshot or stab wounds is rare. These injuries are usually overshadowed by life-threatening damage to other structures. Ductal injury, however, is considered during the evaluation of a thoracotomy for trauma. Surgical injury to the thoracic duct has been reported after almost every thoracic surgical procedure, especially those performed in the upper part of the left side of the chest. Surgical injury is possible during procedures involving the heart, lungs, aorta, esophagus, sympathetic chain, and subclavian vessels. The duct is most vulnerable in the upper part of the left chest during mobilization of the aortic arch, the left subclavian artery, or the esophagus.39 Chylothorax after coronary bypass surgery is usually reported as the consequence of harvesting the left internal mammary artery.40 Injury has also been reported after radical neck dissection and scalene node biopsy. Operations in the abdomen, such as sympathectomy and radical lymph node dissection, also result in damage to the thoracic duct. Diagnostic procedures, such as translumbar aortography and central venous line placement in the jugular or subclavian vein, also cause thoracic duct injuries.

Neoplasms The thoracic duct can be involved with benign and malignant tumors, lymphatic permeation, direct invasion, or tumor embolus. The most frequently found tumors are lymphomas, lymphosarcomas, and primary lung carcinomas. Unilateral or bilateral chylothorax results from the rupture of distended tributaries or erosion into the duct. Benign lesions of the thoracic duct include lymphangiomas, mediastinal hygromas, and pulmonary lymphangiomyomatosis. Lymphangiomyomatosis occurs in young women and is associated with pneumothorax and hemoptysis.41,42 It is characterized by proliferation of smooth muscle in the peribronchial, perivascular, and perilymphatic regions of the lung, resulting in obstruction of the lymphatic channels. Dyspnea is the major symptom, and these women usually die of pulmonary insufficiency within 10 years after diagnosis.43 Tumors cause more than 50% of chylothoraces in adults. Lymphomas are found 75% of the time.30 A chylous effusion is always evaluated as a possible signal for an unsuspected mediastinal or retroperitoneal malignancy. Malignant obstruction may occasionally cause leakage of chyle into the pericardium, producing signs and symptoms of cardiac tamponade.

occur after such minor trauma, the possibility of an underlying malignancy must be considered. Thrombosis of the great veins into which the thoracic duct drains can produce a chylous effusion.45 Chylous effusions in the chest can be the result of chylous ascites, which is usually caused by a malignancy, commonly lymphoma. Primary fistulas and lymphatic disease in children can cause intraperitoneal chylous accumulation. Exudative enteropathy caused by congenital intestinal lymphatic and chylous leaks from the lumen of the bowel is another cause. Amyloidosis can be complicated by chylothorax if the disease process causes ductal obstruction. Chylous ascites also occurs after various abdominal operations and with pancreatitis.46

Composition of Chyle Thoracic duct lymph is not pure chyle but a mixture of lymph originating in the lungs, the intestine, the liver, the abdominal wall, and the extremities. Most chyle is produced in the intestine, and the amount of lymph originating from the extremities is negligible under normal circumstances. Chyle is characteristically milky white, odorless, and alkaline. The ductal lymph is clear during fasting and becomes milky after a fatty meal.47 It is strongly bacteriostatic and contains lipids, proteins, electrolytes, lymphocytes, and various other elements. The normal composition of chyle is shown in Table 90-1.

Lipids The main component of chyle is fat. Chyle contains from 14 to 210 mmol/L total fat, including neutral fat, free fatty acids, sphingomyelin, phospholipids, cholesterol, and cholesterol esters. Between 60% and 70% of ingested fat is absorbed by the intestinal lymphatic channels and conveyed to the blood by the thoracic duct. Neutral fat in lymph is transported as chylomicrons measuring 0.5 mm in diameter.45 Fatty acids with less than 10 carbon atoms are absorbed directly by the portal venous system. This is the basis for using medium-chain triglycerides (MCT) as the oral diet in the medical management of chylothorax. The triglyceride content greatly exceeds the cholesterol content.

Protein The lymphatic vessels are the main pathways for the return of extravascular proteins to the vascular space. The protein content is approximately one half of the plasma concentration, ranging from 21 to 59 g/L.45,48 The albumin concentration ranges between 12 and 41.6 g/L, and the globulin concentration is between 11 and 30.8 g/L.

Infections

Electrolytes

Infectious causes of chylothorax include tuberculosis, fungal diseases, lymphangiitis, filariasis, and nonspecific mediastinitis, which result in lymph node enlargement and obstruction.44

The electrolyte composition of chyle is similar to that found in plasma; the glucose concentration ranges from 2.7 to 11.1 mmol/L. The predominant ions include sodium, potassium, chloride, calcium, and inorganic phosphorus.

Other Causes of Chylothorax

Cellular Elements

Vomiting or violent coughing can cause a spontaneous rupture, especially if the duct is full after a fatty meal. If rupture does

Lymphocytes are the main cellular elements in the thoracic duct lymph; they arise from the peripheral lymphatic chan-

Ch090-F06861.indd 1112

1/21/2008 2:00:48 PM

Chapter 90 The Thoracic Duct and Chylothorax

1113

TABLE 90-1 Normal Characteristics and Composition of Chyle Characteristics and Composition

Concentration in Chyle

Characteristics Milky appearance with a creamy layer that clears when fat is extracted by alkali or ether pH 7.4-7.8 (alkaline) Odorless Specific gravity 1.012-1.025 Sterile and bacteriostatic Fat globules staining with Sudan III Lymphocytes 400-6800 × 106/L Erythrocytes 0.050-0.6 × 109/L Composition Total protein Albumin Globulin Fibrinogen Antithrombin globulin Prothrombin Fibrinogen Total fat Triglycerides Cholesterol Glucose Urea Electrolytes Pancreatic exocrine enzymes Lipoprotein electrophoresis Cholesterol/triglyceride ratio

nels and lymphoid organs. Ninety percent of the lymphocytes are T lymphocytes, and they react differently to antigenic stimulation than blood lymphocytes do.49 There is a continuous circulation of cells from blood to lymph and back again. Prolonged drainage can deplete the lymphocytes and impair the immune system. In clear lymph, there are 0.05 × 109 erythrocytes per liter, but this may rise to 0.6 × 109/L in postabsorptive states.25

Miscellaneous Elements Other components of chyle include fat-soluble vitamins, antibodies, urea nitrogen, and enzymes, including pancreatic lipase, alkaline phosphatase, aspartate transaminase, and alanine transaminase.

Pathophysiology Chylothorax results from a tear or rupture in the thoracic duct. It can cause cardiopulmonary abnormalities and metabolic and immunologic deficiencies. Lymph commonly accumulates in the posterior mediastinum until the mediastinal pleura ruptures, usually on the right side at the base of the pulmonary ligament. The accumulation of chyle in the chest can compress the underlying lung and compromise pulmonary function, resulting in shortness of breath and respiratory distress. Empyema is a rare complication of chylothorax because of the bacteriostatic actions of lecithin and fatty acids. Sterile chyle is nonirritating and therefore does not cause pleuritic pain or a fibrotic inflammatory reaction.

Ch090-F06861.indd 1113

21-59 g/L 12-41.6 g/L 11-30.8 g/L 0.16-0.24 g/L >25% plasma concentrate >25% plasma concentrate >25% plasma concentrate 14-210 mmol/L Greater than plasma value Plasma value or lower 2.7-11.1 mmol/L 1.4-3.0 mmol/L Similar to plasma Present Chylomicron band <1

Normal Plasma Concentration

1500-4000 × 106/L 4500-6500 × 109/L 65-80 g/L 40-50 g/L 25-35 g/L 1.5-3.5 g/L

0.84-2.0 mmol/L 4.4-6.5 mmol/L 2.5-4.2 mmol/L 3.0-7.0 mmol/L

Although fat is the most conspicuous constituent of chyle, the loss of protein and vitamins is more important in terms of serious metabolic and nutritional defects. Loss of protein, fat-soluble vitamins, lymphocytes, and antibodies from a persistent chyle leak can lead to immunodeficiency, coagulopathy, malnutrition, inanition, and death.25

Diagnosis Clinical Features The onset of chylothorax is usually insidious, and rapid accumulation, tachypnea, tachycardia, and hypotension can occur. There is often a latent interval of 2 to 10 days before the chylothorax becomes clinically evident because many injured or postsurgical patients receive a restricted diet. Clinical manifestations of chylothorax are initially the result of mechanical compression of the ipsilateral lung and mediastinum, which causes dyspnea, fatigue, and heaviness. The problems of protein, fat-soluble vitamin, and antibody loss can be accentuated by repeated thoracenteses or chronic tube drainage. Fluid losses can reach 2500 mL of chyle per day and result in cardiovascular instability if they are not replaced. Death is inevitable if supportive treatment fails, unless the fistula closes spontaneously or is ligated surgically.

History A pleural effusion in a patient with any of the diagnoses associated with chylothorax is always evaluated for chyle. A history of trauma after a heavy meal or a recent surgical procedure in the distribution of the thoracic duct should raise the suspicion of chylothorax.

1/21/2008 2:00:48 PM

1114

Section 4 Pleura

Laboratory Studies Laboratory studies of blood chemistry and hematologic parameters are often normal immediately after traumatic injury to the duct. Chronic effusion or chylothorax in infancy may cause hypoproteinemia, decreased triglyceride levels, and lymphocytopenia.

Radiologic Studies There are no valid radiologic findings to differentiate chylothorax from other pleural effusions. Bipedal lymphangiograms can be useful in diagnosing thoracic duct laceration28 (Fig. 90-3). In this procedure, 10 mL of ethiodized oil is injected into lymphatic vessels on the dorsum of the foot, followed 1 to 2 hours later by radiography of the abdomen and chest. This technique can cause pulmonary edema, lymphangiitis, or, rarely, cerebral oil embolism. Radionuclide imaging with technetium 99m–antimony sulfide colloid injected subcutaneously yields images within 3 hours. The radionuclide technique can demonstrate obstruction, but it is limited in localizing the site of leakage.50 Computed tomography (CT) also has limited use in localizing the site of leakage but may demonstrate a mediastinal mass, enlarged lymph nodes, or a primary lung carcinoma.

Fluid Analysis Chylothorax is suggested by the presence of nonclotting milky fluid obtained from the pleural space at thoracentesis

or chest tube drainage. The characteristics of chyle are listed in Table 90-1. The diagnosis is confirmed by finding free microscopic fat, a fat content that is higher than that of the plasma, and a protein content that is less than one half of the plasma level. The fat globules clear with alkali or ether and stain with Sudan III. Chyle may be mistaken for pus, but there is no odor, and cultures are negative. Gram staining is helpful because the cells in chyle are lymphocytes rather than polymorphonuclear leukocytes, and no bacteria are seen. It is important to recognize that chyle is milky white only when fat is being transported from the gut. A finding of clear or bloody fluid does not rule out a chylous leak. Traumatic injury to the duct in the fasting state may yield chyle that initially appears blood stained; it may eventually become clear and serous. Lymphocytes are the predominant cells in chyle, and a 90% lymphocyte count is virtually diagnostic. In traumatic effusions, there is an admixture of erythrocytes and other blood elements. The diagnosis may be delayed in patients receiving parenteral nutrition and nasogastric suction. Before an effusion is evident, patients may show a widening of the superior mediastinum caused by a chyloma or accumulation of chyle within the mediastinal pleural envelope. The chyloma may drain into the pleural space and develop into chylothorax, and there is often a decrease in the leukocyte count as a result of a selective decrease in lymphocytes. Another useful hint is the rate of fluid accumulation in the chest. A disproportionately high volume of fluid drainage from the chest, averaging 700 to 1200 mL/day in a patient who has suffered a hyperextension injury or has undergone esophagectomy or thoracic aortic surgery needs to be evaluated for a chylous leak. Chyle has a cholesterol/triglyceride ratio of less than 1, whereas nonchylous effusions have a ratio greater than 1.51 If the fluid has a triglyceride level that is greater than 1.24 mmol/ L, there is a 99% chance that the fluid is chyle. If the triglyceride content is less than 0.56 mmol/L, there is only a 5% chance that the fluid is chyle.51 An intermediate value requires lipoprotein electrophoresis, and the presence of chylomicrons is specific for the diagnosis of chylothorax.52 The main diagnostic tests are listed in Box 90-2. Methylene blue dye may be injected into the lymphatic channel to help visualize the duct and fistula at surgery. Ductal visualization can also be enhanced by preoperative ingestion of cream or instillation of methylene blue into the stomach.53,54

Differential Diagnosis

FIGURE 90-3 Bipedal lymphangiogram showing the site of a chylous leak with resulting chyloma (arrow). (COURTESY OF B. R. BOULANGER, MD.)

Ch090-F06861.indd 1114

In the differential diagnosis of milky effusions, pseudochylothorax and cholesterol pleural effusions need to be considered. Long-standing chronic pleural effusions may have a chylous appearance. These cholesterol effusions are seen in tuberculosis or rheumatoid arthritis and are related to the high cholesterol content of the fluid.55 They do not contain fat globules or chylomicrons on electrophoresis. The presence of cholesterol crystals on smears of the sediment is diagnostic of pseudochylothorax.56 Pseudochyle occurs with the thickened or calcified pleura in patients with malignant tumors or infections; it is milky

1/21/2008 2:00:48 PM

Chapter 90 The Thoracic Duct and Chylothorax

because of the presence of a lecithin-globulin complex.57 There is only a trace of fat, and fat globules cannot be seen with Sudan III. Pseudochyle contains less cholesterol and protein than does chyle. A complex pleural effusion exists when a thoracic duct leak is present in addition to some other cause of pleural effusion (e.g., congestive heart failure, infection, tumor, trauma). The analysis may be misleading because of a dilutional effect. In summary, thoracentesis and fluid analysis for cell count, Gram staining, and lipid levels are diagnostic in the majority of cases.

Management The first step in the management of chylothorax is prevention. Potential injury to the thoracic duct needs to be recognized or anticipated intraoperatively. Ductal ligation at the aortic hiatus is easily accomplished at the time of esophageal or thoracic aortic dissection. Routine ligation of the thoracic duct needs to be considered if an extensive lymphadenec-

Box 90-2 Diagnostic Tests for Chyle Gram stain

Cholesterol/triglyceride ratio <1

pH

Triglyceride level >1.24 mmol/L

Sudan III stain

Chylomicrons on electrophoresis

1115

tomy or posterior mediastinal node dissection is carried out. In the event that a chylothorax is recognized postoperatively or is simply not related to a surgical procedure, the diagnosis must be established in a timely fashion and promptly treated. Untreated chylothorax can lead to respiratory compromise, dehydration, malnutrition, and immune deficiency. A variety of modalities have been described for treatment and are divided in two general categories: conservative (nonsurgical) and surgical. Most often, a combination of modalities is used to address five important principles of therapy: support of respiratory function, re-expansion of the lung and obliteration of the pleural space, prevention of dehydration and malnutrition, reduction of chyle production, and, in certain cases, treatment of the underlying cause (Table 90-2).

Conservative Management Most cases are initially managed conservatively. Overall, up to 50% of patients have a response. Conservative treatments are frequently used as adjuncts to surgical management. Drainage and Obliteration of the Pleural Space. Drainage, re-expansion of the lung, and obliteration of the pleural space is the basic treatment of any pleural effusion. Drainage can be achieved by thoracentesis, tube thoracostomy, or pleuroperitoneal shunt. Thoracentesis often needs to be repeated, rarely achieves complete pleural evacuation, and can result in loculated effusions, hemothorax, pneumothorax, or empyema. Tube thoracostomy allows rapid continuous drainage and

TABLE 90-2 Chylothorax: Principles and Modalities of Treatment Conservative Management Principles

Medical

Interventional

Respiratory care

Chest physiotherapy Drainage of effusion

Mechanical ventilation

Drainage of pleural space with lung re-expansion Obliteration of pleural space

Thoracentesis Chest tube thoracostomy Pleuroperitoneal shunt Chemical pleurodesis via thoracostomy tube

VATS or thoracotomy Lung decortication Pleurectomy Pleuroperitoneal shunt Chemical pleurodesis

VATS or thoracotomy Direct ligation of thoracic duct Mass ligation of thoracic duct Duct anastomosis to azygos vein (?) Fibrin glue (?) Laparotomy: Mass ligation of thoracic duct

Prevention of dehydration and malnutrition

Chyle infusion (?) MCT diet (?) TPN

Reduction of chyle production

NPO

Thoracic duct embolization

Somatostatin (?) Octreotide (?) Etilefrine (?)

Mechanical ventilation with PEEP (?)

Treatment of cause

Surgical Management Minimally Invasive or Open

Radiation therapy Chemotherapy

MCT, medium-chain triglycerides; NPO, nothing by mouth; PEEP, positive end-expiratory pressure; TPN, parenteral nutrition; VATS, video-assisted thoracoscopy.

Ch090-F06861.indd 1115

1/21/2008 2:00:49 PM

1116

Section 4 Pleura

timely monitoring of fluid losses, achieves lung re-expansion, and is the most widely used method. The pleuroperitoneal shunt is generally considered a conservative treatment in patients who would not tolerate a more invasive surgical procedure. Pleuroperitoneal shunting with the double-valve Denver shunt has been reported in high-risk patients.58-60 Success rates of 75% to 90% have been reported in pediatric chylothorax.61-63 The shunt is relatively simple to place and drains the pleural space. It also can reduce the nutritional, fluid, and cellular losses seen with external drainage. Patient compliance is required to compress the pump chamber periodically. Shunt occlusion with fibrin, which necessitates shunt replacement, occurs in 10% of the cases. Chylous ascites does not appear to be a significant problem, but its presence remains a contraindication to shunt placement. Chemical pleurodesis via the thoracostomy tube with talc, nitrogen mustard, or bleomycin have all been described to help with the obliteration of the pleural space. Although often unsuccessful by its own, pleurodesis is usually added to other conservative modalities for high-risk patients in whom surgery is not an option. For the surgical candidate, chemical pleurodesis can also be used after thoracic duct ligation. Respiratory Care. Institution of necessary measures to support adequate respiratory function cannot be overemphasized. Many patients already have precarious respiratory status induced by their underlying pathology (e.g., lymphoma, thoracic trauma) or by their postoperative state (e.g., sternotomy, thoracotomy, high abdominal incision). Further compromise by accumulation of chylous fluid in the pleural space with secondary atelectasis may precipitate acute respiratory failure. Re-expansion of the lung by drainage of the pleural space and aggressive chest physiotherapy are the main modalities used. If those fail, support must be provided by mechanical ventilation, which, despite its own related complications, may reduce the chylous leak.64 Prevention of Dehydration and Malnutrition. The most important aspects of chylothorax management are preventing dehydration, maintaining adequate nutrition, and correcting fluid and electrolyte imbalances (Bessone et al, 1971).65 Fluid losses via the thoracostomy tube must be monitored properly and volume replacement instituted aggressively to prevent hypovolemia. IV injection of chyle was used in the 1930s and then abandoned in the 1940s because of anaphylactic reactions.12,66 Chyle was successfully reinfused with the use of a 40-µm blood filter and a volumetric pump.67 A small test dose was recommended to avoid anaphylaxis. Although it is attractive, this treatment has not gained popularity, most likely because of its technical complexity and the possible risk of infection with manipulation. Maintenance of nutrition is usually done by using the MCT diet or parenteral nutrition (TPN). Enteral formulas with a low fat content supplemented with MCT have been recommended but rarely work. Long-chain fatty acids (>10 carbon atoms) undergo a second esterification and pass into the lymph as chylomicrons. Medium-chain fatty acids, however, pass directly into the portal vein bound to albumin.23 Despite this preferential uptake of MCT directly into the portal circulation, intestinal triglycerides are derived from endogenous

Ch090-F06861.indd 1116

as well as exogenous sources. Eighty percent of chylous triglycerides have been found to be non-MCTs despite an MCT diet.68 Although the MCT diet is certainly effective to maintain nutrition, it more often does not abolish chyle production completely. Any oral intake, in fact, increases chyle production.69 Therefore, TPN and NPO are the most effective methods for decreasing chyle production and supporting nutrition.70 Reduction of Chyle Production. The most effective way to decrease chyle production is to completely avoid any oral intake. Recently, additional conservative measures have been employed in an attempt to reduce chyle output. The use of somatostatin, octreotide, etilefrine, mechanical ventilation with positive end-expiratory pressure (PEEP), and percutaneous embolization of the thoracic duct have been described. The first use of somatostatin to decrease chylous leak was described in 1990.71 More recently, a significant decrease in drainage and earlier fistula closure with octreotide was demonstrated in a canine model.72 The exact mechanism by which the drug exerts its effects is unknown. Somatostatin and octreotide decrease splanchnic blood flow and intestinal motility and inhibit many gastrointestinal hormones or peptides. It is believed that a combination of those effects limits gastrointestinal secretions, absorption, and, subsequently, chyle flow.73 The use of somatostatin, or octreotide in IV continuous infusion, has been reported in several pediatric case reports for the treatment of postoperative or congenital chylothorax, including use in the premature infant.74 Doses ranged from 1 to 5 µg/kg/hr for continuous IV infusion and from 10 to 70 µg/kg/day divided in three doses for octreotide injected subcutaneously.73 Most reports found a decreased amount and duration of chyle leak. The use of octreotide for the treatment of chylothorax in the adult population is certainly less well documented, and the effectiveness of the treatment seems to be more debated.75,76 The subcutaneous route has generally been used, with a dosage of 300 µg/day divided in three doses. More reports on the use of octreotide for the treatment of chylothorax in the adult are needed to better define which drug is more effective (somatostatin or octreotide), the proper dosage, and its proper place in the armementarium.77 Etilefrine, a sympathomimetic drug used in the management of postural hypotension, was also described in one case report as an adjunct to conservative therapy.78 The postulated mechanism for reduction of chyle flow is smooth muscle contraction of the thoracic duct. A decrease in chyle drainage associated with ventilation therapy was observed many years ago.79,80 More recently, a canine model was used to demonstrate that thoracic lymph flow was reduced by 50% when mechanical ventilation with PEEP of 7.5 was applied.64 The use of mechanical ventilation with PEEP in the treatment of chylothorax has been reported mostly in the treatment of traumatic chylothorax, when ventilation therapy was also needed for other reasons. A decrease in chyle production can certainly be a welcome side effect of mechanical ventilation when it is already in use to support respiratory failure.81 The use of percutaneous transabdominal catheterization of the cisterna chyli to embolize the thoracic duct was first

1/21/2008 2:00:49 PM

Chapter 90 The Thoracic Duct and Chylothorax

described in 199882 and was subsequently reported by others.83,84 Under local anesthesia and sedation, unipedal or bipedal lymphography is performed with iodinated oil to opacify the cisterna chyli. With the use of a percutaneous approach through the anterior abdominal wall, the cisterna chyli or other large (>2-3 mm) retroperitoneal lymphatics are cannulated under fluoroscopic guidance and then embolized. A success rate of 70% was achieved in 42 patients with unresolving chylothorax, with no complications related to the technique.85 Treatment of Underlying Cause. In chylothorax not related to trauma or surgery, the cause must be determined and appropriately treated. Chylous fistulas that result from obstruction by malignancies respond poorly to conservative modalities or surgical ligation unless the underlying disease can be treated effectively. For lymphomas or other malignancies, radiation, chemotherapy, or both often form an integral part of the treatment. Combination with other modalities (e.g., TPN, NPO, surgical ligation, pleurodesis) is often needed to achieve control. Twenty Gy of radiation was also successfully used in the treatment of postoperative chylothoraces in four patients.86 Other obstructive causes (infection, vein thrombosis) also are addressed and might improve the success of other modalities. Results of Conservative Management. The results with conservative modalities depend on many factors, including the underlying cause, the severity of chylous leak, and the various treatments done. It is usually recognized that 25% to 50% of chyle leaks will close spontaneously within 2 weeks of conservative management. If spontaneous closure is thought to have occurred, a high-fat challenge meal needs to be given before the chest tube is removed.

Surgical Management Lampson14 was the first to introduce thoracic duct ligation for the treatment of chylothorax, decreasing the mortality rate of this condition from 50% to 15%. Nontraumatic chylothorax at that time had a mortality rate of almost 100%. As a principle, perform surgical intervention to ligate the thoracic duct before the debilitating complications of the chyle leak itself or its therapy are manifested. Timing of Surgery. There is no consensus as to the length of time that conservative therapy should be tried before instituting a surgical approach. Fourteen days has been suggested as the maximum limit of conservative management before proceeding with surgical ligation.87,88 Between 25% and 50% of leaks close spontaneously during this interval, and the remainder require surgical intervention. A shorter course of nonsurgical management is recommended, especially in neonates and in debilitated patients who are severely compromised by the lymphocyte, antibody, and protein loss resulting from an active thoracic duct fistula. Dugue and coauthors89 reviewed their experience with postesophagectomy chylothorax and looked at variables that could predict success or failure of conservative therapy (NPO and TPN). A chylous output of less than 10 mL/kg on the fifth day after the onset of leakage reliably predicted success of nonoperative treatment (sensitivity, 86%); a higher output

Ch090-F06861.indd 1117

1117

was seen in all patients who ultimately required reoperation (specificity, 100%). Others also reviewed postesophagectomy chylothorax and suggested early operative therapy, after 2 days if the volume of drainage is more than 2 L/24 hr at that time, reporting a high rate of failure with conservative management in those patients.90 Operative Techniques. Surgical intervention for chylothorax addresses two important principles of treatment: reducing the chylous leak and providing good lung re-expansion and obliteration of the pleural space (see Table 90-2). Surgery is usually augmented by the conservative modalities. Several surgical techniques for repairing chylothorax have been described, all historically done through an open approach via thoracotomy or laparotomy. Direct ligation of the thoracic duct, supradiaphragmatic mass ligation of the thoracic duct, infradiaphragmatic mass ligation, anastomosis of the duct to the azygos vein, and fibrin glue application have all been performed in an attempt to stop chylous leaks. Lung decortication, pleurectomy, chemical pleurodesis, and pleuroperitoneal shunting have been described to improve lung expansion, obliterate the pleural space, and hopefully control the leak (Cevese et al, 1975).91 These techniques are typically used in addition to direct control of the duct, or on their own if the site of leakage is not found. Almost all of them can be performed with the use of a video-assisted thoracoscopy (VATS) approach. Preparation for Surgery. Ongoing chest physiotherapy is often rewarded by fewer postoperative pulmonary complications. Electrolyte imbalance needs to be corrected and fluid status optimized. Preoperative consultation with the anesthesia service is recommended. Routine prophylactic antibiotic coverage is provided only for the first 24 hours. Thromboprophylaxis is provided. A preoperative lymphangiogram may be done to localize the site of leakage. This is seldom necessary, and it is reserved for specific cases or after failure of a first surgery. Most patients have been NPO for a few days, and the leak of clear chyle is not always obvious at the time of surgery despite high output. Instillation of 100 to 200 mL of olive oil 2 to 3 hours before the operation through the nasogastric tube has been suggested.45 This fills the duct with a milky chyle and allows its easy recognition. Similarly, the preoperative administration of 60 mL of cream 30 minutes before thoracotomy has been recommended.15 However, knowing that the transport time of absorbed fat from ingestion to venous blood is about 1 hour, with a peak at about 6 hours, it is not surprising that administration of a small amount within a short interval before surgery has not been consistently successful. Orringer92 suggested using 60 to 90 mL/hr of cream in a nasogastric or jejunostomy tube for 6 hours before surgery and waiting for a sustained flow of milky drainage through the chest tube before performing thoracotomy. Some have used a meal of cream stained with Sudan black to help localization.93 Any residual oil or cream is aspirated from the stomach before the induction of anesthesia. An alternative method is injection of 1% aqueous Evans blue dye into the leg. The dye stains the duct within 5 minutes and lasts about 12 minutes. The disadvantage of this method is that other tissues may also be stained. Filling the thorax with

1/21/2008 2:00:49 PM

1118

Section 4 Pleura

saline intraoperatively may help in the detection of milky chyle leaking from the duct. Control of Chylous Leak. Avoiding injury or prophylactic thoracic duct ligation at the time of the initial thoracotomy is important whenever an extensive mediastinal dissection is performed or if a chyle leak is suspected because of a continuous accumulation of watery fluid in the thorax. For patients without prior surgery or those diagnosed postoperatively, many surgeons prefer to perform a thoracotomy on the side of the chylothorax and directly ligate the site of the suspected leak with suture material. The use of tissue or felt pledgets often helps with the fixation ligatures. Some believe that the best method for chylothorax repair is to find the leak and close it with nonabsorbable sutures and Teflon pledgets, allowing the main portion of the duct to remain patent.60 If the leak cannot be found, extensive dissection needs to be avoided. Mass ligation of all tissue between the aorta and azygos vein is performed above the diaphragm.14,16,54,58,88,94 The duct is a single structure from T12 to T8 in more than 60% of patients19; in almost 40%, there is duplication of the mediastinal thoracic duct in its caudal portion. Mass ligation is important to avoid missing a major channel. Duct ligation can be performed through either a right (preferred) or left thoracotomy. Accessing the duct through the left side can be technically difficult, depending on the variable position of the descending aorta. On the right side, a short posterolateral thoracotomy incision is used. The fibrin deposits on the pleura are removed, and the inferior pulmonary ligament is released. A biopsy is performed on thickened pleura or enlarged nodes to rule out a malignant process causing the chylothorax. The esophagus is elevated off its bed. All the tissue beneath the esophagus and between the azygos vein and the aorta is ligated with nonabsorbable suture material. No attempt is made to close the fistula directly (Fig. 90-4). On the left side, the lower 10 cm of esophagus is mobilized to the left. The tissue to the right of the aorta is dissected until the azygos vein is identified. Mass ligation of all tissue between the aorta and the azygos vein is then performed. The minor lymphaticovenous anastomoses between the duct and the azygos, intercostal, and lumbar veins quickly compensate for this localized interruption. Even if the duct cannot be found, mass ligation is successful in 80% of patients.94 In infants, a transient edema of the legs and ascites may be seen for several days and usually then resolves. It is helpful to preoperatively detect whether the aorta is ectatic in its location above the diaphragm on a CT scan. A supradiaphragmatic aorta that is located to the right of the vertebral body makes access to the thoracic duct by way of a right thoracotomy difficult; in such cases, a left-sided approach is preferred. An approach through an upper midline abdominal incision has also been described.95 Mass ligation of the duct is done just below the hiatus after identification of the cisterna chyli on the right of the aorta. Reimplantations of the divided duct into a vein or other anastomoses are complicated and unnecessary. Success using fibrin glue to seal the leaking duct has been reported.96,97 Lung Re-expansion and Obliteration of the Pleural Space. If the lung is trapped, decortication may be neces-

Ch090-F06861.indd 1118

Azygos vein Esophagus Thoracic duct

Right bronchus

Double ligation of thoracic duct

Diaphragm

FIGURE 90-4 Therapy for chylothorax using mass ligation of the supradiaphragmatic thoracic duct.

sary. Some suggest that parietal pleurectomy to achieve pleurodesis is the most successful treatment if no distinct chylous leak can be found.98 Pleurectomy may also be used as an adjunct to duct ligation; however, some argue that pleurectomy should be avoided because of the risk of injury to intercostal lymph vessels.93 Chemical pleurodesis done at the time of surgery was reported many years ago99 and has been used since then as a primary treatment or, more often, as an adjunct to other procedures. Pleuroperitoneal shunting allows lung re-expansion and is generally reserved as a more conservative treatment for high-risk patients. Minimally Invasive Surgical Techniques. The use of VATS for the management of chylothorax has been evolving in the past decade and is now more frequently reported. Almost all previously described surgical techniques have been successfully attempted with this minimally invasive approach. In 1991, Shirai and colleagues were the first to report repair of a ductal fistula by thoracoscopy.100 Shortly thereafter, thoracoscopic duct ligation was performed,101 and it was later reported by many others. Ultrasonic coagulation of the duct has been used more recently.102,103 Intrapleural fibrin glue application97 and chemical pleurodesis104 have also been described using VATS. It is recommended that the initial surgical approach be performed with the use of VATS. Results of Surgical Management. The success of various surgical modalities varies with the underlying cause of the

1/21/2008 2:00:49 PM

Chapter 90 The Thoracic Duct and Chylothorax

chylothorax. Overall reported success varies between 60% and 100%. At time of surgery, even if the duct cannot be found, mass ligation is successful in 80% of patients.94

1119

thoracotomy remains the standard. It is often easier for the patient than a prolonged course of hyperalimentation. This is particularly true for infants and children, in whom central lines are associated with significant morbidity rates.

Overall Management Postoperative Chylothorax

An approach to managing chylothorax is summarized in Figure 90-5. If the chest tube drainage is consistently greater than 500 mL/day for longer than 1 week, surgical intervention is necessary. If a lung is entrapped, malignancy is suspected or multiple loculations are present, and early surgical intervention is appropriate.105,106 Surgery, however, should be avoided in patients in whom the risk is outweighed by other considerations, such as unstable vertebral fractures, unresectable tumors, or multiple organ injuries. Although the repair of a ductal fistula can be accomplished by thoracoscopy, the open procedure for ligating the duct through a small right

Chylothorax is uncommon after thoracic surgical procedures.107 The incidence appears to be higher after esophagectomy with mediastinal lymphadenectomy than after pulmonary resection (3% and 0.4%, respectively), and surgical ligation is often required. Conservative management with drainage, hyperalimentation, and lung re-expansion generally seals the leak after lobectomy. Chylothorax after pneumonectomy is difficult to diagnose. It is suggested by rapid filling of the pneumonectomy space and is confirmed by analysis of the fluid obtained by thoracentesis. Most cases probably

FIGURE 90-5 Algorithm for the treatment of chylothorax. NPO, nothing by mouth; VATS, videoassisted thocacoscopy.

Thoracentesis (Confirm diagnosis)

Conservative management ADJUNCTS Somatostatin/Octreotide Etilefrine Mechanical ventilation when indicated

NPO Parenteral nutrition Thoracostomy tube

Thoracic duct embolization

Wait 5 days

Drainage persists ⬎500mL/day OR ⬎10 mL/kg/day

Drainage decreases ⬍250 mL/day OR ⬍10 mL/kg/day

Feed orally or tube feeds

Drainage increases

Drainage stops

Remove chest tube VATS ligation

Malignant/infection

Definitive therapy Radiation/chemotherapy

Consider chemical pleurodesis if high risk

Drainage persists Consider surgery

Thoracotomy Duct ligation (direct or mass ligation) Decortication/pleurectomy/chemical pleurodesis

Ch090-F06861.indd 1119

1/21/2008 2:00:51 PM

1120

Section 4 Pleura

remain undiagnosed unless the patient develops hemodynamic problems. Stable patients with no mediastinal shift may be simply observed. However, rapid opacification of the pneumonectomy space accompanied by a mediastinal shift to the contralateral side requires urgent tube thoracostomy drainage.108 Subsequent management is controversial but is guided by the response to conservative therapy and the size of the leak.109 Persistent chyle drainage for longer than 1 week needs to be surgically explored, and the duct needs to be ligated.

Pediatric Chylothorax A review of 26 postoperative chylothoraces in pediatric patients revealed a spontaneous cessation rate of 73% with drainage and hyperalimentation.110 Failure of conservative management was associated with venous hypertension resulting from elevated right-sided cardiac pressures or central venous thrombosis. The authors suggested that the elevated pressure is transmitted to the lymphatic system and hinders closure; they recommended thoracotomy on the affected side with duct ligation if conservative treatment fails.

Summary A chylothorax, if unrecognized or not treated in a prompt fashion, can lead to devastating consequences. Treatment strategies include surgical and nonsurgical approaches and are often used in combination. VATS techniques are recommended.

COMMENTS AND CONTROVERSIES As discussed in this excellent chapter, comprehensive management of chyle leaks demands an understanding of the anatomy and physiology of the thoracic duct as well as of the metabolic, nutritional, and immunologic consequences of continuous chyle depletion. It also demands an understanding of the combined aspects of medical and surgical treatment modalities, including space drainage, dietary management, and surgical reintervention. Most chylothoraces are the result of surgical injuries to the thoracic duct occurring during pulmonary or esophageal resection. During pulmonary resection, the main duct can be lacerated, but often the injury is to accessory lymphatic-venous connections located around the azygos vein and carina. In such cases, extensive pleural adhesions, significant local tumor extension, and radical mediastinal lymphadenectomy are associated with increased risk for the complication. Although it is possible to diagnose these injuries during operation, it is usually difficult, not only because lymph is a low-pressure and low-flow system but also because chyle is clear in fasting patients, making it difficult to see during surgery. The clinical diagnosis of postoperative chyle leak is often delayed until the patient has resumed oral intake. Initially, the pleural fluid draining from chest tubes is straw colored or blood stained, but as soon as the patient starts drinking or eating, this fluid becomes milky white, making it easy to recognize. If the diagnosis is still in doubt, one can administer a high-fat diet followed by careful observation

Ch090-F06861.indd 1120

of drainage, which will rapidly increase in volume and become milky white. Bearing in mind that chyle has electrolyte concentrations similar to those of plasma and that lymph flow averages 60 to 80 mL/hr, the potential for extracellular fluid losses is significant, and such losses can rapidly lead to hypovolemia, hypotension, or even shock. Electrolyte imbalances are also likely to occur. Because the protein content of chyle is between 22 and 60 g/L, protein depletion can also arise within a short time, with hypoalbuminemia and significant weight loss. Indeed, a typical feature of chylothorax is that patients still lose weight even if replacements appear to be adequate. Once the diagnosis of chylothorax has been confirmed, a trial of conservative management is recommended, with the objectives being to drain the lymph collection, to re-expand the lung fully, to prevent dehydration and electrolyte imbalance, to maintain nutrition, and to minimize chyle formation. Although options to minimize chyle formation include enteral feedings with low-fat diets and MCT, we agree with the authors that early implementation of parenteral feedings is more likely to achieve resolution of the chylothorax. The decision to continue on with conservative management or to undertake surgical intervention must be based on the duration of fistula and daily amount of chyle drainage, the severity of nutritional and immunologic complications, and the nature of the operation that was done initially. It is generally agreed that a continuous chyle leak in excess of 1 L/day for 7 days or a leak greater than 500 mL/day for 2 weeks in patients with complete cessation of oral intake (including water) is an absolute indication for reoperative intervention. Results of reintervention with direct ligation of the fistula site or with thoracic duct ligation above the right hemidiaphragm are excellent, with low rates of complications and late sequelae. If the thoracic duct cannot be identified, mass ligation of all tissues posterior to the esophagus and between the azygos vein and the aorta just above the diaphragm is also effective. J. D.

KEY REFERENCES Bessone LN, Ferguson TB, Burford TH: Chylothorax. Ann Thorac Surg 12:527-550, 1971. ■ This is a classic in-depth review of the anatomy, pathophysiology, and management of chylothorax. It contains 133 references and remains the most complete review of the subject. Cevese PG, Vecchioni R, Cordiano C, et al: Surgical techniques for operations on the thoracic duct. Surg Gynecol Obstet 140:957-965, 1975. ■ This is an excellent compilation of the surgical approaches and techniques related to thoracic duct pathologic conditions. Although simpler methods have been advised, the background is an essential element in the armamentarium of the thoracic surgeon. DePalma RG: Disorders of the lymphatic system. In Sabiston DC (ed): Textbook of Surgery, 13th ed. Philadelphia, WB Saunders, 1987, p 1479. ■ This chapter summarizes the lymphatic system with respect to the historical and basic science aspects. It is concise and well written and has 124 references.

1/21/2008 2:00:51 PM

Malignant Pleural Diseases chapter

91

PLEURAL TUMORS Christopher T. Ducko David J. Sugarbaker

Key Points ■ Primary pleural tumors, whether benign or malignant, are rare. ■ About 75% of all pleural lesions represent distant metastatic foci

of other primary cancers. ■ Benign pleural primary tumors, such as the solitary fibrous tumor,

are exceedingly rare. ■ The most common malignant pleural primary tumor is diffuse

malignant pleural mesothelioma (DMPM), which carries a poor prognosis. ■ The treatment approach to benign primary pleural tumors is surgical excision, which is curative with complete (R0) resection. ■ Treatment recommendations for DMPM, for which there is currently no cure, follow a multimodal approach, consisting of a combination of surgery, radiation, and chemotherapy. ■ Numerous innovative diagnostic studies and treatments for DMPM are currently being explored.

Primary tumors of the pleura are rare. The diagnostic process often reveals the suspicious density to be a metastatic focus of other primary cancers, principally lung, breast, or lymphoma. In fact, 75% of suspected pleural tumors are found to be distant metastatic deposits. Occasionally, the diagnosis rests on one of several benign pleural entities, which include solitary fibrous tumor, lipoma, endothelioma, angioma, pleural cysts, plaques, amyloidosis, or endometriosis, but these benign pleural primaries are extremely rare. By far the most common malignant primary pleural tumor is mesothelioma. Malignant pleural mesothelioma (MPM) is a highly aggressive and currently incurable neoplasm. More has been written about this devastating malignancy than about all other pleural entities combined.

PLEURAL ANATOMY AND PHYSIOLOGY The pleura is a thin, two-layer membrane that surrounds and separates the lungs from the diaphragm, mediastinum, and chest wall. It is derived from the mesoderm, and during embryogenesis it develops into two serosal surfaces. The visceral surface fuses with the endoderm to form the splanchnopleure, which covers the lungs, whereas the parietal pleura or somatopleure fuses with the ectoderm and covers the chest wall, mediastinum, and diaphragm. The visceral and parietal pleurae fuse at the hilar reflection, creating a space between the two layers called the pleural space. This space normally contains a small amount of fluid for lubrication during respiration. The blood supply to the visceral pleura

is derived from two sources. The bronchial arteries supply systemic circulation, and the pulmonary arteries supply the pleura with blood from the pulmonary circulation. Blood supply for the parietal pleura is derived exclusively from the systemic circulation via branches from the subclavian, internal thoracic, intercostal, and phrenic arteries. Lymphatic drainage stems from the parietal pleura and follows its blood supply. The visceral pleura is devoid of somatic innervation, whereas the parietal pleura has a rich network of somatic, sympathetic, and parasympathetic neural fibers (e.g., intercostal or phrenic nerves). Each pleural membrane is composed of a single layer of mesothelial cells, which is covered with microvilli and rest on a basement membrane of connective tissue. The parietal pleura contains lymphatic vessels, which reabsorb fluid and remove particles. The cells of the parietal pleural membrane also exhibit phagocytic activity and can produce leukocytes under certain conditions. There is a physiologic balance between hydrostatic and oncotic forces in the visceral and parietal pleural vasculature and lymphatic drainage system. When the dynamics of the pleural space are altered, fluid accumulates, producing a pleural effusion, which may be benign or malignant.

BENIGN PLEURAL PROCESSES Solitary Fibrous Tumors One of the earliest reports of a primary pleural tumor is credited to Wagner in 1870.1 In 1931, Klemperer and Rabin described many distinguishing features of primary pleural neoplasms and separated them into localized or diffuse types.2 The diffuse type is now more commonly known as mesothelioma. Mesothelial tumors are malignant and generally associated with asbestos exposure (80% of cases), and they almost uniformly portend a poor prognosis. In contrast, localized pleural tumors are more likely to be benign. They are not associated with asbestos exposure and generally demonstrate a favorable response to therapy. Solitary fibrous tumors are found equally in men and women, with a peak incidence after the fifth decade. Patients are usually asymptomatic and commonly give no history of asbestos exposure. The lesions are often detected incidentally on a plain chest radiograph. Representative radiologic images are shown in Figure 91-1. Compressive symptoms may arise if the tumor grows large enough to invade local structures. The symptoms can include cough, chest pain, or dyspnea. Extrathoracic symptoms may be encountered and include weight loss, hypoglycemia (Doege-Potter syndrome), digital clubbing, and hypertrophic pulmonary osteoarthropathy.3 1121

Ch091-F06861.indd 1121

1/21/2008 2:01:42 PM

1122

Section 4 Pleura

B

A

FIGURE 91-2 Pathology specimen from a patient with a solitary fibrous tumor of the pleura (the same patient as in Fig. 91-1). Intersecting fascicles composed of bland spindle cells and thick bands of collagen are characteristic features of solitary fibrous tumors. Immunohistochemically, the spindle cells in this specimen were positive for CD-34. No necrosis is present (hematoxylin and eosin [H&E] stain, 400×). (COURTESY OF LUCIAN CHIRIEAC, MD, BRIGHAM AND WOMEN’S HOSPITAL.)

The cell of origin of these tumors has been controversial for many years, as revealed by the varied nomenclature used to describe these lesions. Historically, these tumors were called localized mesotheliomas, localized fibrous tumors, fibrous mesotheliomas, pleural fibromas, or submesothelial

Ch091-F06861.indd 1122

FIGURE 91-1 Appearance of a solitary fibrous tumor of the pleura on chest radiograph (A) and CT scan (B).

fibromas. As a result of electron microscopic and immunohistochemical studies, they have been shown to be mesenchymal in origin rather than mesothelial; hence, the term localized mesothelioma has been abandoned (de Perrot et al, 2002).4 The pleuripotent mesenchymal cells are responsible for producing solitary fibrous tumors. The tumor cells usually originate in the visceral pleura from submesothelial mesenchymal cells. The lesions are usually pedunculated and grow into the pleural space without invading adjacent tissues. Grossly, these tumors are lobulated and firm, with a graywhite to yellow-white appearance. The microscopic features include whorls of fibroblasts with collagen and elastin, without any organized or distinctive pattern (Fig. 91-2). These tumors are well circumscribed and have a low mitotic rate, rare atypia, and no necrosis. There may be nests of cuboidal mesothelial or bronchoalveolar cells interspersed in predominantly connective tissue and fibroblasts. Invasion into adjacent tissues is a characteristic of a malignant tumor such as mesothelioma.5 The protein antigen CD-34 is expressed in most solitary fibrous tumors and is believed to be a definite marker.6 These tumors also stain positively for vimentin, but they are negative for carcinoembryonic antigen (CEA), S-100, and cytokeratin.7 A classification system has been proposed (Table 91-1) (de Perrot et al, 2002).4 Although the majority of malignant tumors are larger than 10 cm, histologic signs of malignancy appear to be more prognostic than size. The treatment of solitary fibrous tumors is local resection. This can be done via a standard thoracotomy, but video-

1/21/2008 2:01:43 PM

Chapter 91 Pleural Tumors

TABLE 91-1 Classification of Solitary Fibrous Tumors of the Pleura Stage

Description

0

Pedunculated tumor without signs of malignancy*

I

Sessile or “inverted” tumor without signs of malignancy

II

Pedunculated tumor with histologic signs of malignancy

III

Sessile or “inverted” tumor with histologic signs of malignancy

IV

Multiple synchronous metastatic tumors

*The signs of malignancy include high cellularity with crowding and overlapping of nuclei, cellular pleomorphism, high mitotic count (>4 per high-power field), necrosis, and stromal/vascular invasion. Adapted from De Perrot M, Fischer S, Brundler M, et al: Solitary fibrous tumors of the pleura. Ann Thorac Surg 74:285-293, 2002.

assisted thoracic surgery (VATS) resection has also been described.8 The resection should be complete (R0) and the specimen removed en bloc with a margin of normal lung. Occasionally, extrapleural dissection or chest wall resection may be needed, as may a wedge, lobar, or total lung resection. Adjuvant chemotherapy may also be necessary, and, if resection is incomplete, external radiation therapy with or without chemotherapy has been recommended.9

Pleural Plaques Pleural plaques are benign deposits of hyalinized collagen that are found on the parietal pleura in up to 10% of the population. These lesions are a hallmark of asbestos exposure, but they are asymptomatic and have no malignant potential. They are less than 5 mm thick, up to 10 cm in diameter, and most commonly occur over the lower ribs and along the diaphragm, sparing the apices and costophrenic recesses.10 These plaques can be multiple and can occur bilaterally, presumably as a result of mechanical trauma by asbestos fibers.11 However, plaque size is not necessarily related to cumulative asbestos exposure.12 When viewed intraoperatively, pleural plaques are hard, white, flat or nodular lesions that are usually free of adhesions to adjacent structures. Computed tomography (CT) scanning is useful for further evaluation of lesions seen on plain films.13 Pleural biopsy is done for suspicious lesions to rule out malignancy. Otherwise, no specific treatment is necessary.

Pleural Cysts Pleural cysts arise in the parietal pleura, usually as a consequence of aberrant fusion at the pleuropericardial recess during development.14 Many patients are asymptomatic, but some may present with compressive symptoms or cystic infectious complications.15 The plain chest radiograph serves as the initial diagnostic modality. CT and magnetic resonance imaging (MRI) can provide supplemental data. Surgical intervention via aspiration or resection is usually warranted to confirm a definitive histologic diagnosis and avoid local complications.16 A thoracoscopic approach to avoid thoracotomy is the treatment of choice.17

Ch091-F06861.indd 1123

1123

Calcifying Fibrous Pseudotumors Calcifying fibrous pseudotumors are rare benign lesions that were first described in the pleura by Pinkard and associates.18 They are usually seen in the first three decades of life and are slow growing. Calcifying fibrous pseudotumors are characterized by the presence of abundant hyalinized collagen with psammomatous or dystrophic calcifications and a lymphoplasmacytic infiltrate.19 Calcifications may be evident on radiographic imaging.20 Although re-resection may be necessary, these tumors do not have malignant potential, and excision is curative.21

MALIGNANT PLEURAL DISEASE Metastatic Implants Primary malignant tumors of the pleural space, other than malignant mesotheliomas, are extremely rare. Most have been described in case reports only. They include thymomas, sarcomas, nerve sheath tumors, and pseudomesotheliomas. The majority of pleural tumors are secondary to malignancies elsewhere in the body that have metastasized. These lesions spread via hematogenous dissemination, by pleural invasion (as in T3 bronchogenic cancers), or by direct pleural seeding (as in so-called drop metastases from a thymoma). Symptoms may include dyspnea from the associated pleural effusion or pain from direct tumor extension. Diagnosis is aided by a healthy suspicion when evaluating patients with these signs and symptoms. Thoracoscopy can be both diagnostic and therapeutic when combined with pleurodesis.

Thymic Tumors Thymic tumors usually originate in the anterior mediastinum, but they can spread to the pleural space with diffuse involvement or with drop metastases.22 Several cases of a primary pleural thymoma without a mediastinal component have been described.23 A CT scan from a patient with thymic carcinoma of the pleura is shown in Figure 91-3. Thoracoscopy is used to establish a tissue diagnosis and often reveals a biphasic population of lymphoid and epithelial cells (Fig. 91-4). Pseudomesotheliomatous adenocarcinoma describes a metastatic adenocarcinomatous disease, usually emanating from the lung, with an extensive pleural involvement that mimics pleural mesothelioma.24 The microscopic appearance of these lesions often leads to misdiagnosis as a mesothelioma, when in actuality there is tubulopapillary growth with a desmoplastic reaction. The differentiation between these two tumor types must be made with immunohistochemical stains.25 It is suggested that this variety of adenocarcinoma is derived from type II pneumocytes, also known as Clara cells.26

Sarcomas Liposarcoma is rarely found in the chest. Of the 1067 cases recorded at the Armed Forces Institute of Pathology, 29 involved the chest.27 The majority of these tumors were located in the mediastinum; only nine cases were attributed to the pleural space. These tumors tend to be very large at

1/21/2008 2:01:44 PM

1124

Section 4 Pleura

B

A FIGURE 91-3 Appearance of a thymic carcinoma of the pleura on chest radiograph (A) and CT scan (B).

FIGURE 91-4 Pathology specimen from a patient with thymic carcinoma (the same patient as in Fig. 91-3). The section demonstrates a poorly differentiated carcinoma. There are pleomorphic tumor cells with hyperchromatic nuclei and high nuclearto-cytoplasmic ratios invading into parietal pleura and chest wall. The tumor is separated by septa of dense fibrous tissue (H&E, 200×). (COURTESY OF LUCIAN CHIRIEAC, MD, BRIGHAM AND WOMEN’S HOSPITAL.)

presentation, with CT scan characteristics of an inhomogeneous tumor with vague margins, fat infiltration, and occasionally calcification (Fig. 91-5). Wide resection with adjuvant radiation is required. Synovial sarcoma can uncommonly involve the pleural space.28 Sarcomas can comprise poorly differentiated spindle cells alone, or they can be biphasic, composed of both spindle and epithelial cells (Fig. 91-6). The

Ch091-F06861.indd 1124

FIGURE 91-5 Appearance of sarcoma of the pleura on CT scan. The lesion shown was adjacent to the liver (posteriorly) but was resectable.

immunohistochemistry can be similar to that of mesothelioma, despite the differences in gross appearance. Smooth muscle tumors of the pleural space have been described, including three leiomyosarcomas and two smooth muscle tumors of indeterminate malignant potential.23 These commonly occur in patients younger than 50 years of age, and most patients present with large tumors (>10 cm). Vascular tumors involving the pleural space have also been described. One such series included 14 cases of hemangioendothelioma and angiosarcoma.29 These may also mimic mesotheliomas.30 Endothelial origins are suggested by the presence of arbor-like vessel formation; strong expression of vimentin,

1/21/2008 2:01:44 PM

Chapter 91 Pleural Tumors

the lung in tumor.32 Rarely, it may manifest as a local pleural mass.33 MPM can demonstrate a wide range of mesenchymal differentiation, with fibrosarcomatous, malignant fibrous histiocytoma–like, chondroid, osteoblastic, and liposarcomatous forms.34 These can occur alone or in concordance with epithelial differentiation. Distinguishing between benign mesothelial hyperplasia and malignant mesothelial proliferations can be a challenge. Guidelines have been established to aid in making the definitive diagnosis.5 In general, the diagnosis of MPM depends less on cytologic atypia and more on the architectural features of the tumor and the demonstration of invasion beyond the pleura into fat, skeletal muscle, or lung.35 The incidence of MPM is believed to parallel the industrial use of asbestos. Between the 1920s and 1950s, numerous medical journals published articles pertaining to asbestosrelated cancer, and an association between occupational asbestos exposure and risk of cancer began to emerge.36-38 In 1960, Wagner and colleagues reported a series of mesothelioma cases clustered around the South African asbestos mines.39 It was not until the late 1960s and 1970s, when Selikoff and colleagues published reports from the United States, that a clear link between asbestos exposure and MPM was established.40,41 The recognition of a cause-and-effect relationship between asbestos and cancer caused a series of regulatory measures to be implemented, albeit at various rates, across the world. Despite these regulatory efforts, the incidence of mesothelioma in the United States has been rising since 1980. Between 2000 and 3000 new cases are diagnosed each year, usually among patients in the fifth to seventh decade of life. This is equivalent to 14 cases per 1 million population for men and 3 cases per million for women.42 The disease pattern is expected to peak in 2020 as a result of increased awareness and government regulation of asbestos exposure by the 1970s, coupled with the inherent latency period of 20 to 50 years.

CD-31, and CD-34; and the absence of cytokeratin (Fig. 91-7).31

MALIGNANT PLEURAL MESOTHELIOMA Malignant mesothelioma is a rare tumor of the pleura. Mesotheliomas arise from mesothelial cells and can occur in any body cavity covered by mesothelial cells, including the peritoneum, pericardium, tunica vaginalis of the testis, and ovary. The pleura, however, is the most common site of involvement, and there may be diffuse visceral and parietal thickening. The tumor grows preferentially over the serosal surfaces, penetrating the interlobar fissures and completely encasing

FIGURE 91-6 Pathology specimen from a patient with sarcoma (same patient as in Fig. 91-5) demonstrating spindle cell sarcoma, unclassified, high grade. Note the characteristic tumor cells with highgrade pleomorphic nuclei arranged in a spindle-like pattern invading into adjacent soft tissue (H&E, 400×). (COURTESY OF LUCIAN CHIRIEAC, MD, BRIGHAM AND WOMEN’S HOSPITAL.)

A

1125

B

FIGURE 91-7 Pathology specimen of a patient with hemangioendothelioma. A, The tumor is composed of epithelioid cells arranged in solid nests and anastomosing vascular channels embedded in a myxohyaline matrix. Tumor cells have pink to densely eosinophilic cytoplasm with focal vacuolization and a signet ring–like appearance, features characteristic of epithelioid hemangioendothelioma (H&E, 400×). B, The epithelioid cells diffusely express CD-31 (CD-31 stain, 400×). (COURTESY OF LUCIAN CHIRIEAC, MD, BRIGHAM AND WOMEN’S HOSPITAL.)

Ch091-F06861.indd 1125

1/21/2008 2:01:45 PM

1126

Section 4 Pleura

However, with the massive exposure to asbestos resulting from the fall of the World Trade Center towers during the September 11th tragedy, there may be a new mode of disease distribution in this population.43 Conversely, not all patients with MPM necessarily have a known history of asbestos exposure.44 Only about 80% of mesotheliomas are associated with a known asbestos exposure, leaving roughly 500 patients per year in the United States with non–asbestos-related mesothelioma. Although the mechanisms involved in the process of MPM are multifactorial (e.g., genetic predisposition, environmental, asbestos mineral fibers, or pleural scarring), one interesting link is between exposure to the simian virus 40 (SV40).7 Carbone and associates found SV40-like fragments in 60% of human pleural mesothelioma samples.45 This virus was inadvertently transmitted to humans in the 1950s, when polio vaccines contaminated with SV40 were used to inoculate millions of children and adults in the United States. It is thought that SV40-induced transformation may act in synergy with DNA damage induced by asbestos. Chromosomal deletions and loss of tumor suppressor genes have also been implicated in human mesothelioma disease.46,47 Before embarking on therapy directed at mesothelioma, it is imperative to first confirm the diagnosis. This begins with the clinical history and radiographic imaging. The most frequent presenting symptoms are dyspnea and nonpleuritic chest pain.48 The physical examination may be normal but usually reveals evidence of unilateral pleural effusion. The chest radiograph typically reveals a large pleural effusion, often with evidence of pleural-based masses. Chest CT scanning is more accurate than plain films in delineating the extent of disease.49 A representative CT scan in a patient with mesothelioma is shown in Figure 91-8. This mode of imaging is also useful for serial evaluations during and after a course of therapy.50 MRI is generally superior to CT when evaluating

FIGURE 91-8 Appearance of mesothelioma on CT scan. There is circumferential pleural involvement, as well as disease extending into the fissure.

Ch091-F06861.indd 1126

for diaphragmatic or mediastinal invasion.51 However, neither mode is 100% accurate, mandating operative exploration if resectability is in question. Recently, integrated positron emission tomography–CT (PET-CT) imaging with coregistration of anatomic and functional imaging data was shown to increase the accuracy of MPM staging.52 In a series of 29 patients evaluated for extrapleural pneumonectomy (EPP) for mesothelioma, surgery was precluded in 11 patients as a direct consequence of additional staging information provided by the fusion scanning. The information provided by PET-CT included evidence of extrathoracic spread of disease not detected from routine clinical and conventional radiologic evaluation in seven cases. Overall, PET-CT scans are 91% sensitive and 100% specific in differentiating benign from malignant pleural disease.53 However, PET-CT scans cannot distinguish mesothelioma from adenocarcinoma, and false-positive findings are possible with benign inflammatory pleural processes. If the clinical presentation raises the concern of MPM, the next step in the evaluation is to obtain tissue for diagnosis. Because most patients often have a thoracentesis performed for symptomatic relief, cytologic analysis of the pleural fluid is commonly done. However, the yield from this type of sample is relatively poor at only 62%.54 The yield from pleural needle biopsy is somewhat improved at 86%.55 Although standard thoracotomy may sometimes be required, thoracoscopy has been shown to be an effective method of enhancing the diagnosis of MPM, and it allows biopsy of selected areas of parietal, visceral, and diaphragmatic pleura.56 Extensive sampling is still often needed, but collection in this fashion is diagnostic in 98% of patients. Tissue samples are evaluated histologically, taking care to differentiate between benign proliferative mesothelial processes and malignant mesothelioma. It is also difficult to determine differences between epithelial mesothelioma, sarcomatoid mesothelioma, and sarcoma. Definite stromal invasion is the most reliable indicator of malignancy in both epithelial and spindle cell neoplasms.5 Densely packed mesothelial cells in the pleural space are consistent with a benign disease process, but if they are found within the stroma it is more suggestive of malignant mesothelioma. Malignant mesothelioma is classified histologically into three subtypes, according to the relative proportions of epithelial and spindle cells: epithelioid, sarcomatoid (spindle), and mixed (Fig. 91-9). The epithelioid subtype accounts for more than 50% of tumors and needs to be carefully differentiated from adenocarcinoma.57,58 Electron microscopy may aid in this differentiation. The basement membrane underlying adenocarcinoma cells has a more complete structure than that underlying mesothelioma cells.59 Mucopolysaccharide stains (i.e., periodic acid–Schiff, Mayer’s mucicarmine stain) are strongly positive in adenocarcinoma and usually absent in mesothelioma. Conversely, the presence of hyaluronic acid strongly supports the diagnosis of mesothelioma. Epithelioid mesotheliomas are further characterized not only by their architectural pattern, including tubular, tubulopapillary, papillary, solid, and microcystic types, but also on the basis of their cytologic features, including small cell, large cell, deciduoid, and clear cell types.60

1/21/2008 2:01:48 PM

Chapter 91 Pleural Tumors

A

B

C

D

1127

FIGURE 91-9 Pathologic classification is based on the histologic pattern and has prognostic value. Diffuse malignant mesothelioma is categorized as epithelioid, sarcomatoid (a poor prognostic indicator in clinical trials), or biphasic (mixed) epithelioid mesothelioma. A, Epithelioid subtype (H&E, 400×). This is a typical photomicrograph of epithelioid mesothelioma. The cells are arranged in a tubular pattern. B, Immunostaining pattern of malignant mesothelioma, epithelioid subtype. Note the more solid pattern of cells highlighted with cytokeratin immunostaining (AE1/AE3, 400×). The photomicrograph also demonstrates invasion of tumor cells into the chest wall adipose tissue. C, Sarcomatoid subtype (H&E, 400×). Spindle-shaped cells are arranged in sheets or fascicles that form nonspecific architectural patterns resembling those seen in the various sarcomas. D, The biphasic or mixed subtype is characterized by the presence of both epithelioid and sarcomatoid components (H&E, 400×). (COURTESY OF LUCIAN CHIRIEAC, MD, BRIGHAM AND WOMEN’S HOSPITAL.)

The sarcomatoid subtype accounts for 15% to 20% of tumors and must be distinguished from sarcoma.27,61 Although no single immunohistochemical marker is sufficiently sensitive and specific to differentiate mesothelioma from adenocarcinoma, sarcoma, or reactive mesothelial hyperplasia, a panel of markers is currently used to aid in this distinction.62 The antibody calretinin demonstrates good specificity for mesothelial cells, whereas CEA is highly specific for adenocarcinoma.63 Low-molecular-weight cytokeratin is a general marker of mesothelioma, whereas the high-molecular-weight cytokeratins favor epithelioid mesothelioma in particular.64 Thyroid transcription factor-1 (TTF-1) and E-cadherin stains also help differentiate mesothelioma from adenocarcinoma, whereby mesotheliomas are negative for TTF-1 and adenocarcinomas are positive for E-cadherin.25 These two markers

Ch091-F06861.indd 1127

serve as the front-line immunohistochemical staining regimen for mesothelioma; they can be followed, if necessary, by a secondary panel of antibodies including BerEP4, Leu M1, calretinin, cytokeratin 5/6, and N-cadherin. Bueno and colleagues investigated the role of a technique involving microarray RNA profiling to help distinguish between mesothelioma and adenocarcinoma.65 This work uses gene product ratios and represents a novel approach to diagnosing MPM, with an accuracy of 95% to 99%.

Staging Just as in lung cancer, accurate staging in MPM is important in determining the best therapy for any given patient. Staging is equally important in assessing the effectiveness of new

1/21/2008 2:01:48 PM

1128

Section 4 Pleura

therapies, and it ensures that proper comparisons are being made between treatment groups. As with any staging system, one must be sure to understand the differences between clinical and pathologic staging when study results are reported or used in comparisons. There is lack of consensus for a single mesothelioma staging system, and several different systems are in use today. These include the Butchart staging system,66 the TNM staging system set forth by the Union Internationale Contre le Cancer (UICC),67 the International Mesothelioma Interest Group (IMIG) staging system based on TNM status,68 and the Brigham and Women’s Hospital/Dana-Farber Cancer Institute (BWH) staging system (Sugarbaker et al, 1999).69 Butchart’s classification, described in 1976, was the first to be introduced. In Butchart’s scheme, stage I tumors are confined to the parietal pleura; stage II disease invades the chest wall, esophagus, heart, or contralateral pleura with or without thoracic lymph node involvement; stage III tumors invade through the diaphragm or have extrathoracic lymph node involvement; and stage IV disease is associated with distant metastasis. This staging system is quite simple but fails to provide any prognostic information because any tumor higher than stage I is considered unresectable in Butchart’s system. The UICC staging system was described in 1990 and is based on the tumor-node-metastasis (TNM) classification system used for non–small cell lung cancer (NSCLC). Because of the nature of mesothelioma tumor growth within the pleural space, the T variable, as it is described in terms of NSCLC, is not always applicable in patients with mesothelioma. Furthermore, although the N nodal description is the same as in NSCLC, in mesothelioma it is often difficult to evaluate nodal stations because the pleural space is completely filled with tumor or effusion. In addition because of the short overall survival time in mesothelioma, patients do not routinely live long enough for metastatic disease (M) to be found. Once again, clinically, this staging system falls short in terms of correlating patient survival with prognosis. In 1994, another staging system was proposed by the IMIG (Table 91-2). This classification attempts to account for the unique features of mesothelioma while working within the accepted T and N status indicators. In it, T1A tumors involve the ipsilateral parietal pleura with or without diaphragmatic involvement, and T1B tumors involve the visceral pleura. T2 disease invades the lung parenchyma, and lung resection would be necessary for complete removal of tumor. These tumors are associated with a pleural effusion. T3 tumors are locally advanced but still amenable to resection, in that there is involvement of endothoracic fascia, mediastinal fat, localized chest wall, or pericardium. T4 disease is technically unresectable and involves invasion of tumor into the chest wall, through the diaphragm into the peritoneum, or into the contralateral pleura, mediastinal organs, spine, internal pericardial surface, or myocardium. Nodal involvement is similar to that in NSCLC staging. Stages IA and IB correlate with T1A N0 and T1B N0, respectively. Stage II includes T2 N0 tumors. Stage III is any T3 or any N1 or N2 disease, and stage IV involves any T4, N3, or M1 disease. The BWH classification is simpler than the TNM-based systems (Table 91-3) and offers better prognostic value for

Ch091-F06861.indd 1128

patients treated with different modalities. Stage I disease is resectable without lymph node involvement. Stage II tumors are also confined to the pleural envelope but include positive lymph node (N1 or N2) involvement. Stage III disease is unresectable, with locally aggressive tumors invading the mediastinum, diaphragm, or chest wall. Stage IV tumors are associated with extrathoracic metastases. This system stratifies patients according to survival and accounts for resectability, tumor histology, and nodal status, and its validity was confirmed in an analysis of a series of 120 patients.70

Prognosis MPM is a rare but highly aggressive tumor of the pleura that has defied a standard approach to treatment. Without treatment, the median survival time ranges from 4 to 12 months.71-73 Recommended treatment strategies are based on the same principles applied to other solid tumors and include chemotherapy, radiation, surgery, and combinations of each. Assessment of response to treatment can be measured according to certain criteria.74 However, mesothelioma tumors have a unique growth pattern which makes application of conventional response criteria sometimes difficult.75 A modification of these criteria for tumor response correlates with survival and lung function and can be used to measure outcome of mesothelioma treatments.76 In addition to tumor stage, several independent prognostic variables are important and have been defined in two scoring systems.77,78 These include age, performance status, and histologic subtype. Less important variables are chest pain, dyspnea, presence of pleural effusion, asbestos exposure, weight loss, anemia, leukocytosis, thrombocytosis (platelet count >400,000/µL), and elevated lactate dehydrogenase (LDH >500 IU/L). The prognostic value of these scoring systems was confirmed in a retrospective review of an independent cohort of patients.79 Tumors with epithelioid histology carry a better prognosis.80

Treatment To date, there are no evidence-based consensus guidelines on the management of MPM. Given its rare incidence, there have been no randomized controlled trials comparing different surgical approaches with one another or surgery with alternative treatments. The cumulative evidence in the literature lies in retrospective case series reports and prospective, noncontrolled studies. These data are further confounded by the changing classification and staging systems for mesothelioma.

Radiation Therapy Mesothelioma cells have a modest sensitivity to radiation, less so than small cell lung cancer but more than NSCLC.81 Effective treatment with an intact lung is largely limited by the collateral damage to vital organs within the necessary radiation field.82 It is difficult to assess the value of radiation therapy because no large study has compared radiation therapy versus no treatment at all. In a small series of 23 patients reported by Ball and Cruickshank, those patients who received less than 40 Gy did not have effective palliation, whereas those receiving higher doses were better palliated.83

1/21/2008 2:01:51 PM

Chapter 91 Pleural Tumors

1129

TABLE 91-2 International Mesothelioma Interest Group (IMIG) Staging System Classification

Description

T T1 T1A

Primary Tumor and Extent Tumor limited to ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura; no involvement of the visceral pleura Tumor involving the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura; scattered foci of tumor also involving the visceral pleura Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic pleura; scattered foci or tumor also involving the visceral pleura) with at least one of the following features: • Involvement of diaphragmatic muscle • Confluent visceral pleural tumor (including the fissures) or extension of tumor from visceral pleura into the underlying pulmonary parenchyma Locally advanced but potentially resectable tumor; tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features: • Involvement of the endothoracic fascia • Extension into mediastinal fat • Solitary, complete resectable focus or tumor extending into the soft tissues of the chest wall • Nontransmural involvement of the pericardium Locally advanced, technically nonresectable tumor; tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features: • Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction • Direct transdiaphragmatic extension of the tumor to the peritoneum • Direct extension of tumor to the contralateral pleura • Direct extension of tumor to one or more mediastinal organs • Direct extension of tumor into the spine • Tumor extending through the internal surface of the pericardium, without or without a pericardial effusion, or tumor involving the myocardium

T1B T2

T3

T4

N Nx N0 N1 N2 N3

Lymph Nodes Regional lymph nodes cannot be assessed No regional lymph node metastases Metastases in ipsilateral bronchopulmonary or hilar lymph nodes Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes, including the ipsilateral internal mammary nodes Metastases in contralateral mediastinal, contralateral internal mammary, or ipsilateral or contralateral supraclavicular scalene lymph nodes

M Mx M0 M1

Metastases Presence of distant metastases cannot be assessed No (known) metastasis Distant metastasis present

Stage Grouping A B II III IV

T1A N0 M0 TB N0 M0 T2 N0 M0 Any T3 M0, any N1 M0, any N2 M0 Any T4, any N3, any M1

TABLE 91-3 Brigham and Women’s Hospital/Dana-Farber Cancer Institute (BWH) Revised Staging System Stage I

II III

IV

Ch091-F06861.indd 1129

Description Disease confined to the capsule of the parietal pleura; ipsilateral pleura, lung, pericardium, diaphragm, or chest-wall disease limited to previous biopsy types All stage I with positive intrathoracic (N0, N1) lymph nodes Local extension of disease into chest wall or mediastinum, heart, or through diaphragm into peritoneum, with or without extrathoracic or contralateral (N2, N3) lymph node involvement Distant metastatic disease

Radiation therapy has been shown to be effective in the prevention of local recurrence after thoracentesis or thoracoscopic biopsy.84 However, radiation is usually ineffective in controlling disease after partial surgical resections. Dosages must be limited to 20 Gy due to toxicity to the remaining lung. If a patient can undergo EPP, adjuvant radiation can help reduce local recurrence, which can occur in the ipsilateral hemithorax more than 60% of the time. In one nonrandomized study that did not reach statistical significance, 31% of patients treated with radiation after EPP had local recurrence, compared with 45% of patients not treated with adjuvant radiation.84 Those patients with negative margins did not show any decrease in local recurrence after postoperative

1/21/2008 2:01:51 PM

1130

Section 4 Pleura

irradiation, whereas postoperative radiation therapy was found to possibly benefit those with positive resection margins. External beam radiation therapy, previously based on chest radiographs, has evolved to include intensitymodulated regimens based on three-dimensional field planning.85 With careful intraoperative marking by the surgeon and postoperative planning by the radiation oncologist, intensity-modulated radiation beams maximize targeting of the tumor bed and avoid toxicity to surrounding vital structures.86 However, recent anecdotal follow-up has called into question the observed toxicity profile of this mode of radiation delivery despite its theoretical benefits.86a

Chemotherapy Mesothelioma is relatively chemoresistant, with response rates to single agents of less than 20% and no effect on overall survival. The antimetabolites, anthracyclines, and platinum compounds seem to be the most active in mesothelioma. Methotrexate showed a 37% response rate in a phase II trial of 63 patients87; however, toxicity was seen in 58% of the patients. Detorubicin showed a greater response than doxorubicin in 35 patients, in whom a response rate of 26% was found.88 Cisplatin was demonstrated to have a 14% response rate in a Southwest Oncology Group study.89 With a higher dosing schedule, a 36% response rate was seen.90 However, there were significant side effects, prompting discontinuation of the treatment in 34% due to toxicity. Carboplatin showed a similar response rate of 11% and is somewhat better tolerated than cisplatin.88 Vinorelbine also has single-agent activity against mesothelioma, with a low incidence of serious side effects.91 Partial response with 50% reduction in tumor thickness was seen in 24% of patients, whereas 55% had stable disease (neither 25% increase nor 50% decrease in tumor thickness). Gemcitabine has limited activity when used alone.92 Pemetrexed showed some encouraging results in single-agent therapy in 64 patients, 14% of whom experienced a partial response.93 Response rates are increased for combination therapies compared with single-agent treatments.94 Therefore, single-agent treatment has given way to combination regimens. The results reported by Vogelzang and colleagues showed superior survival time, time to progression, and response rate for patients treated with pemetrexed plus cisplatin versus cisplatin alone.95 This was a randomized, multicenter, phase III trial in 456 patients. Epithelial histology dominated in more than two thirds of the patients, and stage III or IV disease was seen in 78%. Median survival time was 12.1 months in the combined group versus 9.3 months for cisplatin alone, with response rates of 41.3% versus 16.7%, respectively. With this combination generally accepted as the standard treatment for mesothelioma patients,96 investigation into second-line chemotherapy regimens has begun.97

Surgery Patients must be suitable surgical candidates for thoracotomy before being considered for pleurectomy/decortication (P/D) or EPP. Age and functional status are the first markers to assess. Cardiopulmonary function is closely studied. Left and right ventricular function must be preserved (>45%).

Ch091-F06861.indd 1130

TABLE 91-4 Eligibility Criteria for Extrapleural Pneumonectomy Issue

Criterion

Karnofsky performance

>70

Renal function

Creatinine <2

Liver function

AST < 80 IU/L, total bilirubin <1.9 mg/dL, PT < 15 sec

Pulmonary function

Postoperative FEV1 > 0.8 L as per · · PFTs and quantitative V/Q scans

Cardiac function

Normal ECG and echocardiogram (EF > 45%)

Extent of disease

Limited to ipsilateral hemithorax, with no transdiaphragmatic, transpericardial, or extensive chest wall involvement

AST, aspartate aminotransferase; ECG, electrocardiogram; EF, ejection fraction; FEV1, forced expiratory volume in 1 second; PFTs, pul· · monary function tests; PT, prothrombin time; V/Q, lung ventilation/ perfusion quotient.

Pulmonary hypertension (>45 mm Hg) is a contraindication to EPP. A marginal preoperative value for forced expiratory volume in 1 second (FEV1) warrants a quantitative radionuclide perfusion scan to predict the postoperative pulmonary capacity.98 CT and MRI are used to define the anatomic extent of the tumor, and PET-CT and cervical mediastinoscopy provide additional staging for extrathoracic disease and lymph node involvement. The eligibility criteria for EPP are listed in Table 91-4.7,45,66,99-104 Patients who do not meet these criteria may still be candidates for pleurectomy. Extrapleural Pneumonectomy. With routine hemodynamic monitoring, epidural anesthesia, and a double-lumen endotracheal tube in position, a posterolateral thoracotomy is made. The incision begins midway between the posterior scapula and the spine and extends under the scapular tip along the course of the sixth rib to the costochondral junction (Zellos et al, 2006).105 The latissimus and serratus muscles are divided. In general, any prior thoracoscopy port sites or incisions are excised, and they are incorporated into the thoracotomy incision if feasible. The sixth rib is carefully identified and removed from just anterior to the paraspinal ligament posteriorly to the costochondral junction anteriorly. This sets up the start of the extrapleural dissection plane, which is established next. The fused pleura is dissected away from the chest wall until there is room to insert a retractor. Then, the dissection proceeds in an organized manner, packing off any dissected planes to prevent bleeding during mobilization elsewhere. Blunt dissection using a sponge stick or the surgeon’s finger complements sharp dissection with scissors. Careful attention is given to the subclavian vessels superiorly; the contralateral pleural space and internal thoracic vessels medially; the azygos vein, superior vena cava, and esophagus posteriorly on the right side; and the aorta, intercostal arteries, and esophagus posteriorly on the left side. Continuous reorientation helps avoid inadvertent injury, as does palpation of a properly positioned nasogastric tube.

1/21/2008 2:01:51 PM

Chapter 91 Pleural Tumors

At this point, a determination is made as to the resectability of the tumor. Once this has been confirmed, the diaphragm is dissected at the anterior border with the chest wall and pericardium. The diaphragm is avulsed from the chest wall by careful manual traction, as opposed to sharp dissection, which can lead to more bleeding. Care must be taken to ensure removal of all gross tumor, but it is necessary to leave a rim of the diaphragmatic crus intact for later patch reconstruction. The peritoneum is left intact if at all possible. Next, the pericardium is opened caudally. It is incised anteromedially toward the phrenic nerve and the hilar vessels. The pulmonary veins are divided intrapericardially. The pulmonary artery is taken in similar fashion on the right, but extrapericardially on the left. Each vascular division is done using the endoleader technique and the endoscopic stapling device. Posteriorly, the pericardium is opened at the level of the esophagus on the right and the aorta on the left. The subcarinal lymph nodes are then removed, and the bronchus is divided last, using a heavy-wire stapler. The ability to visualize this bronchoscopically during the dissection aids in achieving the proper bronchus length. A short, nearly flush bronchial stump reduces the sumping of airway secretions and helps minimize stump breakdown.

1131

Once the specimen has been removed, additional lymph node stations are sampled, and the bronchial stump is leak tested. At this point, a chemical wash is performed, followed by intracavitary heated chemotherapy if not contraindicated. Then, the omentum is mobilized for use as a bronchial stump buttress. Alternatively, the stump can be covered with a pericardial fat pad or chest wall muscle buttress, such as latissimus or seratus. Next, the diaphragm and pericardium are reconstructed using 2-mm and 1-mm expanded polytetrafluorethylene (e-PTFE) patches, respectively (Gore-Tex MicroMesh, W. L. Gore & Associates, Flagstaff, AZ) (Fig. 91-10). A series of nine stitches is used to secure the patch circumferentially from the posterior paraspinous ligament around to the sixth costal cartilage anteriorly. Gore-Tex buttons or bumpers are used to keep the sutures from pulling through the chest wall (Fig. 91-11). The dynamic two-piece diaphragm patch is then sewn to the base of the pericardium from the anterior costophrenic angle posteriorly toward the esophagus and inferior vena cava (right) or aorta and crus (left) (Fig. 91-12). The impermeable nature of the patch prevents peritoneal fluid from freely crossing into the pleural space postoperatively. The pericardial patch is fenestrated and sewn in place posteriorly first. It is then secured to the diaphragmatic patch

FIGURE 91-10 Creation of the diaphragmatic patch. Two pieces of 2-mm impermeable PTFE are overlapped, stapled together, and trimmed as shown, creating a so-called dynamic patch with reduced tension along its edges. Once the patch is securely implanted, a separate elliptical opening, through which the omental buttress passes, is created and properly sized. This should be large enough to avoid vascular compromise of the pedicle, yet sufficiently small to avoid herniation at this site. The two patches are also reefed together across the middle as needed to prevent the patch from being too lax and to avoid internal herniation. Nine holes are made along the periphery of the patch to receive the sutures. (FROM ZELLOS L, JAKLITSCH MT, BUENO R, SUGARBAKER DJ: TREATMENT OF MALIGNANT MESOTHELIOMA: EXTRAPLEURAL PNEUMONECTOMY WITH INTRAOPERATIVE CHEMOTHERAPY. IN ZELLOS L, JAKLITSCH MT, BUENO R, SUGARBAKER DJ [EDS]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY: A COMPARATIVE ATLAS, VOL 11, ISSUE 1. SPRING 2006, PP 45-56, FIGURE 9. COPYRIGHT ELSEVIER 2006.)

Ch091-F06861.indd 1131

1/21/2008 2:01:51 PM

1132

Section 4 Pleura

FIGURE 91-11 Diaphragmatic reconstruction. Sutures are placed through the nine holes shown in Figure 91-10. These sutures are pulled through the chest wall, from the paraspinous ligament posteriorly to the sixth rib anteriorly, with an awl and securely tied to the chest wall. PTFE buttons or bumpers are used to prevent the sutures from pulling through the chest wall. A portion of omentum can be mobilized and carefully pulled through the patch to serve as a buttress on the bronchial stump to help prevent bronchopleural fistula. (FROM ZELLOS L, JAKLITSCH MT, BUENO R, SUGARBAKER DJ: TREATMENT OF MALIGNANT MESOTHELIOMA: EXTRAPLEURAL PNEUMONECTOMY WITH INTRAOPERATIVE CHEMOTHERAPY. IN ZELLOS L, JAKLITSCH MT, BUENO R, SUGARBAKER DJ [EDS]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY: A COMPARATIVE ATLAS, VOL 11, ISSUE 1. SPRING 2006, PP 45-56, FIGURE 10. COPYRIGHT ELSEVIER 2006.)

inferiorly and to the residual pericardium anteriorly and superiorly. It is not made too tight because this may constrict filling of the heart, causing a tamponade effect. This is more important on the right side, given the potential of the heart to turn about the axis of the cavae and herniate. In fact, the left-sided pericardium does not have to be patched routinely. Once the patches have been placed, a slit is made in the diaphragmatic patch, and the omentum is pulled through this opening. It is secured to the bronchus, primarily, with additional bites taken along the surrounding tissues to minimize direct tension. The diaphragmatic patch can be reefed up between the two pieces that make up the dynamic patch, with care taken not to make the neodiaphragm too tight. Additional bites are taken to secure this patch to the chest wall and diaphragmatic crura posterolaterally. Thorough hemostasis is achieved with an argon beam coagulator. The thoracotomy is closed in standard fashion, with care taken to make it watertight. A 12 Fr red rubber catheter is left in place for use in balancing the mediastinum intraoperatively. In

Ch091-F06861.indd 1132

men, 1000 mL is removed initially after a right EPP (750 mL from the left); in women, 750 mL is taken from the right chest (500 mL from the left). Additional air is removed in the postoperative setting as needed based on the chest radiograph or pleural manometry, with the intention of removing the catheter altogether by the third day. Pleurectomy. Pleurectomy is a palliative debulking procedure that is combined with decortication in mesothelioma patients whose pulmonary function or physiologic status contraindicate pneumonectomy. The incision and initial dissection are identical to those described for an EPP. Once the parietal pleura has been dissected free, the tumor itself is incised down to the visceral pleura for an internal pleurectomy. Bleeding can be controlled with an argon beam coagulator or hilar clamping, if needed. It is important to remove as much tumor tissue as possible, especially that extending into the fissures, for a macroscopic complete resection.106 On the right side, reconstruction of the diaphragm is not always needed because the liver is there and the lung is left in place. Postoperative Management. Key points in successful recovery of patients in the postoperative setting include pain management, careful fluid balance, and early vigilance for, and diagnosis of, common postoperative complications. These include deep venous thrombosis, pulmonary embolism, vocal cord paralysis, chylothorax, empyema, bronchopleural fistula, and mediastinal shift (Sugarbaker et al, 2004).107 Pain is controlled with a thoracic epidural and a patient-controlled analgesia (PCA) pump when needed. Proper pain control and vigorous ambulation (after an initial 48-hour period of equilibration) are critical to prevent contralateral lung atelectasis. Patients are kept NPO with a nasogastric tube for the first 48 hours. Diet and activity are then advanced as tolerated. There is a low threshold to evaluate the vocal cords in any patient with a voice change or signs of aspiration because aspiration can have devastating consequences in this patient population. Fluid restriction and liberal use of diuretics are employed to help achieve proper fluid balance because pulmonary edema is a dreaded complication of pneumonectomy. Perioperative β-blockade is administered for prophylaxis against atrial fibrillation. Aggressive prophylaxis for deep venous thrombosis is carried out in every patient. Those receiving intraoperative heated chemotherapy are routinely screened perioperatively via noninvasive lower extremity venous duplex scanning. These patients are also carefully hydrated in the immediate perioperative period to protect against the nephrotoxicity associated with cisplatin. Adjuncts such as sodium thiosulfate and amifostine are also used to reduce the incidence of postoperative renal failure.108 Operative Results. Several large studies of pleurectomy for mesothelioma have been reported. A series from the Memorial Sloan-Kettering Cancer Center listed a mortality rate of 1.8%, a complication rate of 25%, and a 1-year survival rate of 49% in 64 patients.109 In Germany, Achatzy and associates reviewed 245 partial and complete pleurectomy cases and showed a 30-day mortality rate of 8.5% with a median survival time of 9.2 months.110 In 1991, Brancatisano described a series of 45 pleurectomy patients with a mortality rate of 2.2%, a morbidity rate of 16%, and a median survival time of 16 months.111 Allen and colleagues reported on a series of 56

1/21/2008 2:01:52 PM

Chapter 91 Pleural Tumors

1133

FIGURE 91-12 Completion of patch reconstruction. The posterior or mediastinal edge of the diaphragmatic patch is sutured to the inferior cut edge of the pericardium. Care is taken to avoid constriction of the inferior vena cava (right side), slitting the patch if necessary, and to avoid intraabdominal herniation (left side) with healthy bites along the crus and posterior chest wall. The pericardial patch is secured to the cut edges of pericardium posteriorly first, then anteriorly and superiorly. Inferiorly, it is sutured to the diaphragmatic patch itself. Depending on patient size, it may be necessary to splice in an additional patch to avoid cardiac or caval constriction. Displacement of the heart into the pneumonectomy space after closure needs to be taken into account when sizing the pericardial patch during implantation. The pericardial patch should be fenestrated before reconstruction to reduce the chance of pericardial tamponade from fluid accumulation behind the patch. A portion of omentum can be mobilized and carefully pulled through the patch to serve as a buttress on the bronchial stump to help prevent bronchopleural fistula. (FROM ZELLOS L, JAKLITSCH MT, BUENO R, SUGARBAKER DJ: TREATMENT OF MALIGNANT MESOTHELIOMA: EXTRAPLEURAL PNEUMONECTOMY WITH INTRAOPERATIVE CHEMOTHERAPY. IN ZELLOS L, JAKLITSCH MT, BUENO R, SUGARBAKER DJ [EDS]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY: A COMPARATIVE ATLAS, VOL 11, ISSUE 1. SPRING 2006, PP 45-56, FIGURE 13. COPYRIGHT ELSEVIER 2006.)

patients with a perioperative mortality rate of 5.4%, a morbidity rate of 26.8%, and a 1-year survival rate of 30%.112 More recently, Richards and colleagues reported a retrospective analysis of patients under protocol for a combined regimen of cytoreduction surgery (pleurectomy or EPP) plus intraoperative intracavitary chemotherapeutic lavage with hyperthermic cisplatin.106 In a subgroup of patients undergoing pleurectomy at two different doses of hyperthermic drug (50-150 versus 175-250 mg/m2), the study found that the subset of patients receiving high-dose chemotherapy demonstrated an apparent survival benefit warranting further investigation. The EPP arm of the study is completing accrual. EPP carries a higher mortality rate than pleurectomy in most series. The perioperative mortality rate in Butchart’s original series was 30%, which was comparable to contemporary studies in the 1970s.66 Since then, experience from high-volume centers has enabled a significant reduction in mortality from EPP, to rates of less than 10%. DaValle and associates113 published a mortality rate of 9%, and Rusch and associates114 reported a rate of 6%. Recently, Sugarbaker’s group reported a perioperative mortality rate of 3.8% and a morbidity rate of 25%.70

Mulitmodality Therapy Early efforts to treat MPM with single therapies failed to significantly affect patient survival (Table 91-5). Because of these failures, a multimodality strategy evolved. The multidisciplinary approach for surgical candidates includes P/D or

Ch091-F06861.indd 1133

TABLE 91-5 Therapeutic Options in Malignant Pleural Mesothelioma Single-Modality Therapy Debulking surgery (P/D or EPP) Radiation (external beam, brachytherapy)83 Chemotherapy (single- or double-agent approach); doxorubicin, cyclophosphamide, cisplatinum; gemcitabine, pemetrexed, and cisplatin95,140 Multimodality Therapy Surgery and adjuvant radiation Surgery and adjuvant chemotherapy Surgery adjuvant chemoradiotherapy Innovative Therapies Under Investigation Intracavitary lavage with hyperthermic chemotherapy Photodynamic therapy (PDT) Gene therapy Anti angiogenesis Immunogenic EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication.

EPP, external-beam radiation to the hemithorax, and systemic combined chemotherapy. Treatment plans involving two modalities, such as chemotherapy and surgery, radiation and surgery, or chemotherapy and radiation, have shown some improvement over single-modality treatments in nonrandomized studies. Chemotherapy and radiation without surgery has had very limited success.115 Surgery, either as P/D or EPP, combined with chemotherapy or radiation has produced some improvement in survival in comparison to his-

1/21/2008 2:01:53 PM

1134

Section 4 Pleura

torical controls. Rusch and colleagues from Memorial Sloan-Kettering reported on a series of 105 patients with MPM who underwent P/D combined with intraoperative brachytherapy plus adjuvant external-beam radiation.67 Median survival time was 12.5 months, with local relapse the most common site of treatment failure. In another study from the same institution, 28 mesothelioma patients underwent P/D, this time in conjunction with intrapleural and adjuvant systemic chemotherapy.116 The overall survival rate was 68% at 1 year and 40% at 2 years, with locoregional disease being the most common site of relapse. A seminal article in 1980 by Antman and coauthors advocated a multimodality approach to malignant mesothelioma after a retrospective review suggested an advantage to aggressive intervention.117 Antman initiated a prospective multimodality protocol that included EPP followed by adjuvant chemoradiation. In 1991, Sugarbaker and colleagues reported their first case series of 31 patients who underwent EPP in a trimodality setting. The mortality rate was low (6%), and this study identified trends toward improved survival in the subset of patients with negative histologic margins.118 During this period, other centers produced case series with improved mortality rates after EPP.73,113 A prospective trial by Rusch and associates noted a longer progression-free survival time with EPP but showed no difference in overall survival compared with patients who underwent less radical procedures or nonsurgical treatment.114 Allen and coauthors published a retrospective case series of patients who underwent either pleurectomy or EPP with adjuvant chemotherapy or radiation therapy.112 There was a trend toward higher median survival in those who underwent EPP, but this was not statistically significant. Sugarbaker’s group described a substantial reduction in operative mortality (4.6%), and in 1993 the BWH combined cancer treatment program identified a subset of patients with epithelioid histology and node-negative status that exhibited improved survival.119,120 The next update in the Brigham series reported a median survival time of 21 months in 120 patients.70 Based on the BWH staging system, median survival was 22 months for stage I, 17 months for stage II, and 11 months for stage III disease. These data were subsequently updated in 183 patients using the revised BWH staging system, in which N2 disease was reclassified as stage III (instead of stage II) disease, beyond the pleural envelope (Sugarbaker et al, 1999).69 This reclassification was in response to a multivariate analysis which showed that the most important predictor of poor outcome after EPP in a trimodal setting was histologic subtype (nonepithelioid), N2 nodal disease, and positive resection margins. During this time, the IMIG consortium, led by Rusch, developed another staging system (see Table 91-2).68 TNM staging designates the majority of patients as stage III, coalescing patients with different tumor characteristics and obscuring survival benefits associated with prognostic markers. Nonetheless, the TNM staging system continues to be more widely used. Rusch68 published a prospective, noncontrolled study of a cohort of mesothelioma patients treated with either EPP or pleurectomy followed by adjuvant treatment. Tumor stage had a significant impact on overall survival when

Ch091-F06861.indd 1134

considered across all stage groups: stage I, median survival 30 months; stage II, 19 months; stage III, 10 months; and stage IV, 8 months. Although there was no significant difference in survival based on type of surgical resection, note that pleurectomy was performed in patients with minimal visceral pleural tumor, whereas those with more locally advanced tumors underwent EPP.68 It is important to recognize such a selection bias in operative planning when interpreting results. Because there is much controversy as to the importance of type of surgical resection (P/D versus EPP), this issue is likely to remain unresolved in the absence of randomized controlled trials comparing the two approaches. A recent case series by Stewart and colleagues supported the benefit of EPP over P/D by demonstrating a longer progression-free survival time and longer time to local disease progression with EPP.121 Studies of patterns of failure after multimodality therapy have implicated locoregional recurrence as the most common site of treatment failure. Baldini and colleagues revealed the ipsilateral hemithorax to be the most common site (35%), followed by the abdomen (26%) and the contralateral hemithorax (17%).122 Distant recurrence was rare (8%). This study highlighted the locally aggressive nature of MPM and strongly argued for adjuvant strategies to achieve maximal local control of this disease.

Innovative Adjunctive Therapies Intraoperative Heated Chemotherapy. Intracavitary chemotherapy has been studied in abdominal malignancies as a means of improving locoregional control.49,123 With intracavitary administration, the chemotherapy agent enters the tumor cells directly by way of diffusion. This minimizes the toxicity associated with systemic chemotherapy delivery. It is important to achieve macroscopic complete resection before the administration of intracavitary chemotherapy to ensure complete exposure of the chemotherapeutic agent to all surfaces that may harbor cancer cells.106 The optimal timing of chemotherapy lavage is in the operating room immediately after tumor resection but before the development of adhesions. This allows maximal drug exposure to occur before tumor cells become entrapped in fibrinous exudates and loculated adhesion pockets. In addition, drug delivery is optimal immediately after resection, when the volume of residual tumor cells is small enough to be penetrated by the chemotherapy drug. Furthermore, hyperthermia increases cell permeability, alters cellular metabolism, and improves membrane transport of drugs.124 Because of the potential for local recurrence within the hemithorax, as well as for regional relapse in the abdomen, the practice of bicavitary intraoperative heated chemotherapy is now used in conjunction with EPP or P/D as part of a multimodality treatment approach in patients with mesothelioma. Antiangiogenic Therapy. Angiogenesis plays a central role in tumor growth and therefore lends itself as a treatment target. The three antiangiogenesis inhibitors currently under trial are thalidomide, SU5416, and bevacizumab. Thalidomide is one of the few orally available antiangiogenic agents.

1/21/2008 2:01:54 PM

Chapter 91 Pleural Tumors

It has shown promise in prolonging disease stabilization with a relatively mild toxicity profile.125 Studies of the other two drugs involve the vascular endothelial growth factor (VEGF), and end points include time to progression of disease and tumor response rate. SU5416 is an inhibitor of the VEGF-1 receptor FLK1 and is being studied by the National Cancer Institute, whereas bevacizumab is a recombinant anti-VEGF monoclonal antibody under investigation at M. D. Anderson Cancer Center, the University of Chicago, and the University of Pennsylvania.126 Photodynamic Therapy. Photodynamic therapy (PDT) is a two-step process that first involves the administration of a photosensitizing agent, such as Photofrin or Foscan. These compounds are preferentially taken up by tumor cells. The second step involves the exposure of the affected tumor tissue to light at a specific wavelength. This light catalyzes a cellular reaction in which free radicals are produced and ischemic necrosis occurs. These events lead to damage from both direct cytotoxic effects on cellular membranes and vascular occlusion. Because the depth of tissue penetration of the light is limited, PDT is well suited for use as an intraoperative adjunct after surgical debulking. Applications of this therapy in mesothelioma patients have been ongoing at a few centers.127-129 Takita and his group studied Photofrin in 40 patients from 1991 to 1996.129 Patients underwent pleurectomy or EPP for removal of all gross disease or debulking to a depth of less than 0.5 cm, followed by intraoperative PDT. Median survival time for patients in stages I and II was 36 months, and for those in stages III and IV patients it was 10 months. Because of its better profile in terms of increased oxygen singlet production and decreased duration of skin photosensitivity, the photosensitizer Foscan was studied in 26 patients undergoing P/D or EPP in a phase I trial from 1997 to 2001.127 Median progression-free survival and overall survival times were each 12.4 months. These preliminary results will likely lead to a phase II trial. Immunotherapy. Several studies have suggested that mesothelioma cells are susceptible to destruction by immunologic means.131 Boutin and coworkers described the activity of intrapleural recombinant γ-interferon against malignant mesothelioma in 1991.132 His group has also made use of an implantable access system for prolonged administration of the immunotherapy agents directly into the affected hemithorax, reducing the toxicity and allowing treatment on an outpatient basis.133 A recent prospective multicenter study in 89 patients with early-stage disease showed an overall response rate of 20%, and the treatment was well tolerated.134 The exact mechanism of action is not clear. However, it may relate to a γ-interferon–mediated inhibitory effect on production of interleukin-6 (IL-6) that may abrogate the systemic manifestations associated with mesothelioma cells.135 Other work has been done using the cytokine IL-2, which is known to stimulate proliferation of T cells, natural killer cells, and lymphokine activated killer cells. Repeated intrapleural instillation of IL-2 was given twice weekly for 4 weeks in a phase II trial involving 31 patients, 22 of which were in stage I.136 Pleural fluid collections were effectively treated in

Ch091-F06861.indd 1135

1135

90% of patients, and the median overall survival time was 15 months. In another study, treatment with IL-2 yielded a overall response rate of 47% in a phase I trial and 55% in phase II testing.137 Monti and associates demonstrated the in situ activation of CD-8+ T cells and macrophages after the administration of γ-interferon.138 Despite the theoretical considerations, a phase II trial using an infusion of activated macrophages and γ-interferon did not show an improvement in antitumoral activity.139 Gene Therapy. Gene transfer techniques can be used to alter cells to enhance immunogenicity. This can be done in several ways, including transfection and expression of genes for various cytokines and costimulatory molecules.140 In a murine model of mesothelioma, flank tumors were treated with adenovirus encoding β-interferon.141 Treatment before debulking increased long-term tumor-free survival and resulted in twofold to sixfold smaller foci of implanted tumor cells at 2 weeks postoperatively. It was postulated that elimination of residual tumor cells occurred owing to an amplification of the cytotoxic T-lymphocyte antitumor response mediated by adenovirus encoding β-interferon. Recently, a small study (21 patients with mesothelioma) used high-dose therapy with vector encoding the herpes simplex virus thymidine kinase.142 A spectrum of clinical responses was observed, including two patients who were alive 6 years after gene transfer therapy. It is thought that augmentation of the immune effects of gene transfers may lead to increased numbers of therapeutic responses.

COMMENTS AND CONTROVERSIES Pleural fibromas are uncommon neoplasms, with no more than 400 cases having been recorded in the world literature. They are intriguing tumors because their biology and epidemiology are largely unknown and because they can reach enormous proportions while still being relatively asymptomatic. Classically, these tumors originate from the visceral pleura and are associated with digital clubbing. The treatment of pleural fibromas is local resection, which usually is not possible by thoracoscopic techniques because of the large size of the tumor. Indeed, one often must resect a rib to extract the lesion from the pleural space. Although these tumors are known for their potential to recur locally, this is relatively rare if complete resection has been done in the first place. The problems associated with management of malignant mesotheliomas are vastly different. For the past 30 years, scientists and surgeons have attempted to deploy multimodality therapies that usually included some form of surgery, whether it was parietal pleurectomy, tumor debulking, or pleuropneumonectomy. In this chapter, Ducko and Sugarbaker give a clear and concise review of a disease that is frequently complex because each patient may present with unique features. Most often, MPMs are associated with asbestos exposure, but, contrary to occupational asbestosis, which is related to the duration of exposure, MPM is associated with the intensity of exposure as well as the type of asbestos fibers to which the worker was exposed. Indeed, the first reported cases were those of young men who had worked for short periods in South African asbestos mines. As a rule of thumb, the late Doctor Nael Martini used to say that 50% of cases were clearly associated with asbestos exposure, 25% were possibly

1/21/2008 2:01:55 PM

1136

Section 4 Pleura

associated, and in 25% no such association could be demonstrated. Before embarking on therapy, the diagnosis of MPM, which can be suspected on standard radiographs showing a pleural effusion with contraction of the involved hemithorax, must be substantiated, preferably by thoracoscopic examination of the pleural space. Once the diagnosis is made, extensive clinical staging must be carried out, and we have found that PET scanning provides useful information. Whether mediastinoscopy should be done in patients for whom pleuropneumonectomy is contemplated is still controversial. The exact role of pleuropneumonectomy in the management of early-stage MPM is probably the most controversial issue, and this operation must be considered as part of multimodality therapy rather than primary treatment of the disease. Most importantly, familiarity with and understanding of the local anatomy, as well as experience with the procedure and postoperative management, are necessary to avoid difficult situations and catastrophic complications. J. D.

KEY REFERENCES

de Perrot M, Fischer S, Brundler M, et al: Solitary fibrous tumors of the pleura. Ann Thorac Surg 74:285-293, 2002. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al: Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: Results in 183 patients. J Thorac Cardiovasc Surg 117:5465, 1999. Sugarbaker DJ, Jaklitsch MT, Bueno R, et al: Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 128:138-146, 2004. Sugarbaker DJ, Strauss GM, Lynch TJ, et al: Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 11:1172-1178, 1993. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:26362644, 2003. Zellos L, Jaklitsch M, Bueno R, Sugarbaker D: Treatment of malignant mesothelioma: Extrapleural pneumonectomy with intraoperative chemotherapy. In Zellos L, Jaklitsch MT, Bueno R, Sugarbaker DJ (eds): Operative Techniques in Thoracic and Cardiovascular Surgery: A Comparative Atlas, Vol 11, Issue 1. Spring 2006, pp 45-56.

Antman KH, Blum RH, Greenberger JS, et al: Multimodality therapy for malignant mesothelioma based on a study of natural history. Am J Med 68:356-362, 1980.

Ch091-F06861.indd 1136

1/21/2008 2:01:55 PM

chapter

92

MANAGEMENT OF MALIGNANT PLEURAL EFFUSIONS Paula A. Ugalde W. Fred Bennett Jean Deslauriers

Key Points ■ Pathologic substantiation of malignant pleural effusions can be

obtained by simple techniques. ■ Thoracoscopic examination has a diagnostic yield of 95% to 100%

in malignant pleural effusions. ■ Expedient and effective palliation of dyspnea and improvement in

quality of life are the main objectives of therapy. ■ Bedside chemical pleurodesis is an excellent option to control the

reaccumulation of pleural fluid. ■ The decision to use chemical pleurodesis is based on practical

considerations such as availability, cost, effectiveness, comfort of the patient, and incidence of side effects. ■ A prerequisite for successful chemical pleurodesis is radiologic evidence that the underlying lung can re-expend. ■ Patients with trapped lungs can be helped through the use of semi-permanent pleural drainage units. ■ Management strategies need to take into account the age of the patient and his or her overall medical condition and life expectancy as well as the type and extent of the underlying malignancy.

A malignant pleural effusion results from the disruption of the dynamic formation and reabsorption of pleural fluid. In health, the flow of pleural fluid depends on the permeability coefficient of the pleura, difference of hydrostatic pressures and difference of osmotic pressures across the pleural space. In patients with malignant pleural effusions, deposition of malignant cells onto the pleural surfaces and tumor invasion of the pleural mediastinal lymphatics disrupt this balance and a malignant pleural effusion results. Malignant pleural effusions are a common clinical problem that often leads to significant morbidity and impairment of quality of life in patients already affected by advanced cancer. Although all malignancies have the potential to generate malignant pleural effusions, lung and breast cancers account for the majority of such effusions. Median survival of these patients is approximately 6 months, but it can be exceeded in individuals with non–small cell lung cancer (NSCLC), breast cancer, and ovarian cancer. Such survival data must be kept in mind while selecting treatment and indeed expedient and effective palliation of symptoms such as chest pain and dyspnea is the main objective of therapy. Treatment strategies also need to aim at avoiding repeated procedures and hospitalizations, causing little discomfort, having minimal side effects, and above all preventing recurrence of the effusion.

HISTORICAL NOTE The use of talc was first reported in 1935 by Norman Bethune as an agent to produce adhesions as a preliminary to lobectomy.1 Bethune was a Canadian thoracic surgeon who at the time was working at McGill University under the directorship of Edward Archibald. In addition to the reporting of the first use of talc in humans, Bethune reported the first animal experiments as well (Sahn, 1998).2 The use of talc in the management of malignant pleural effusions dates back to 1958 when Chambers3 published data on 20 patients who received talc slurry via chest tubes. Other investigators4,5 subsequently reported the use of both talc slurry and poudrage as an effective means of pleurodesis in animal models.2 HISTORICAL READINGS Bethune N: Pleural poudrage: A new technique for the deliberate production of pleural adhesions as a preliminary to lobectomy. J Thorac Surg 4:251-261, 1935. Chambers JS: Palliative treatment of neoplastic pleural effusion with intercostal intubation and talc instillation. West J Surg Obstet Gynecol 66:26-28, 1958. Hanrahan EM, Adams R, Klopstock RJ: The role of experimentally produced intrapleural adhesions in extrapleural pneumolysis and in the prevention of surgical atelectasis in animals. Thorac Surg 10:284299, 1941. Kennedy L, Rusch VW, Strange C, et al: Pleurodesis talc slurry. Chest 106:342-346, 1994. Singer JJ, Jones JC, Tragerman LJ: Aseptic pleuritis experimentally produced. J Thorac Surg 10:251-283, 1941.

BASIC SCIENCES Malignant and Paramalignant Pleural Effusions Pleural effusions containing malignant cells are called malignant pleural effusions (Table 92-1).1 They result from the cumulative effects of increased capillary permeability secondary to tumor implants on pleural surfaces (increased fluid production) and impaired fluid resorption due to tumor invasion of the pleuromediastinal lymphatics (Table 92-2). Interference with the integrity of the lymphatic system is particularly important2 because it is now recognized that a significant feature of the circulation of pleural fluid through the pleural space is its resorption by lymphatic lacunae located between parietal pleural mesothelial cells3 and that these lacunae drain directly into the mediastinal nodes via intercostal trunk vessels.4 Direct invasion of the parietal 1137

Ch092-F06861.indd 1137

1/21/2008 2:02:44 PM

1138

Section 4 Pleura

pleura by lung cancer or less commonly by primary pleural tumors such as malignant mesotheliomas is yet another mechanism that can increase fluid production. Other possible mechanisms include increased capillary permeability resulting from local pleural inflammation5 and increased production of vascular endothelial growth factor (VEGF), which is a promoter of endothelial permeability and is produced in significant amounts by diseased pleural tissues.6-8 Hemorrhagic malignant pleural effusions are the result of direct invasion of pleural blood vessels or are related to tumor-induced angiogenesis. With neoplastic infiltration of the deepest layers of the pleura, occlusion of small vessels may also occur, resulting in vascular engorgement with secondary hemorrhage through their endothelial surfaces.9 Overall, one third of patients with a malignant pleural effusion will have a hemorrhagic effusion. Paramalignant pleural effusions are cancer-related effusions in which no malignant cells are found in the pleural fluid. In lung cancer patients, most such effusions are associ-

ated with bronchial obstruction and distal pneumonitis and their significance is that patients can still undergo complete and curative resection of their tumor. Other causes of paramalignant effusions are those related to prior mediastinal irradiation and those secondary to trapped lung or hypoalbuminemia (Antony et al, 2000) (Table 92-3).10 Concurrent nonmalignant diseases such as congestive heart failure or renal failure may also be the cause of pleural effusions in cancer patients.

Etiology of Malignant Pleural Effusions Although nearly all types of malignancies can be the cause of malignant pleural effusions, approximately two thirds of these effusions are accounted for by lung cancer, breast cancer, and lymphomas (both Hodgkin’s disease and nonHodgkin’s lymphomas) (Dresler et al, 2005) (Table 92-4).9,11-23 In 10% to 15% of patients, the site of the primary lesion remains unknown despite extensive investigation.24 When the etiology of a malignant pleural effusion is correlated with the cell type of the primary tumor, 75% are of carcinomatous origin; and among them, adenocarcinomas are the most common, being responsible for nearly 50% of all cases.12 Surprisingly, squamous cell tumors are responsible for only 5% of malignant pleural effusions. In general, the parietal pleura is less frequently involved by the metastatic process than the visceral pleura, both in lung cancer and extrapulmonary carcinomas. Indeed, postmortem studies are suggesting that most pleural metastasis arise from tumor emboli to visceral pleural surfaces with secondary seeding of the parietal pleura.9,11

TABLE 92-1 Malignant and Paramalignant Pleural Effusion Malignant Pleural Effusions Diagnosis based on finding malignant cells in the effusion Cumulative result of increased capillary permeability and impaired lymphatic drainage Two thirds are accounted for by lung cancer, breast cancer, lymphoma Site of primary lesion unknown in 15% of patients Paramalignant Effusions No malignant cells in effusion Due to local or systemic effects of tumor or complications of therapy Majority accounted for by lung cancer Do not affect operability of lung cancer

DIAGNOSIS AND EVALUATION Clinical Presentation Typical symptoms associated with malignant pleural effusions include dyspnea, cough, and chest discomfort. The dyspnea is due to a combination of reduction in ipsilateral lung volume and contralateral shift of the mediastinum. Its severity often

From Deslauriers J, Mehran R: Handbook of Perioperative Care in General Thoracic Surgery. Philadelphia, Elsevier Mosby, 2005, p 496.

TABLE 92-2 Interaction Among Pathogenetic Mechanisms and Contributing Factors Favoring the Accumulation of Pleural Fluid in Patients With Cancer

Pathogenetic Mechanisms

Impaired Lymphatic Drainage

Increased Pleural Osmotic Pressure

Increased Capillary Permeability

Increased Venous Pressure

Pleural implants

+

+

+

−

Lymphatic metastases Mediastinal nodes Lymphangitis

+ +

+ +

− −

− −

Tumor cell suspension

+

+

+

−

Contributing conditions Superior vena cava obstruction Congestive heart failure Pericardial effusion Infection Mediastinal irradiation Hypoalbuminemia

+ + + + + −

+ + + + + +

− − − + − −

+ + − − − −

+, Contributes; −, does not contribute.

Ch092-F06861.indd 1138

1/21/2008 2:02:44 PM

Chapter 92 Management of Malignant Pleural Effusions

TABLE 92-3 Common Causes of Paramalignant Pleural Effusions

TABLE 92-4 Most Common Neoplasms Associated With Malignant Pleural Effusions

Local Effects of Tumor Endobronchial obstruction with distal atelectasis/pneumonitis Lymphatic or superior vena cava obstruction Trapped lung

Site of Primary Tumor Lung

790 (35.4%)

Systemic Effects of Tumor Hypoalbuminemia

Breast

722 (32.4%)

Gastrointestinal

177 (7.9%)

Gynecologic

134 (6.0%)

Lymphoma

130 (5.8%)

Complications of Therapy Prior mediastinal irradiation with secondary mediastinal fibrosis or constrictive pericarditis Secondary to chemotherapy-related toxicity Concurrent Nonmalignant Conditions Congestive heart failure, renal failure Adapted from Antony VB, et al: Management of malignant pleural effusions. Am J Respir Crit Care Med 162:1987-2001, 2000.

depends more on the rate of fluid accumulation than on the total amount of fluid present in the pleural space. Chest pain is usually related to involvement of the parietal pleura, ribs, and other intercostal structures.4,25 Because of the advanced stage of their disease, several patients also have constitutional symptoms related to generalized illnesses, such as weight loss and cachexia. In several large series,26,27 25% of patients had no or only minimal symptoms. The clinical setting in which an effusion occurs is always helpful in determining its origin. A lung cancer patient with N2 disease who develops a pleural effusion, for instance, is likely to have a malignant effusion. Similarly, a woman who develops an effusion months or years after treatment of a breast cancer is also likely to have a malignant effusion. Interestingly, 10% to 15% of patients have no history of prior malignancy and the pleural effusion will be the first manifestation of their disease.26-29 Because most malignant effusions are in excess of 500 mL, physical findings such as decreased breath sounds and dullness to percussion are usually present.

Imaging Conventional imaging is the mainstay of the evaluation of these patients. Small effusions (200-500 mL) cause blunting of the costophrenic angle whereas larger effusions produce the classic meniscus sign. Massive effusions cause a complete opacification of the hemithorax. In one study, malignancies were the most common cause of massive exudative effusions and they were associated with worse survival independent of age and histologic subgroup.30 Computed tomography (CT) is useful to detect small amounts of pleural fluid. It is also helpful to distinguish pleural lesions from parenchymal masses31 and to establish the presence of pleural thickening or irregularities.32 Furthermore, CT-guided biopsies appear to be superior to conventional closed pleural biopsies for diagnosing malignant pleural disease.33 Positron emission tomography (PET) may offer some additional information,34-36 but this information does not replace histologic diagnosis, which is needed in most cases.37 In one series reported by Toaff and colleagues,34 PET/ CT parameters considered to be significant in identifying

Ch092-F06861.indd 1139

1139

No. Patients (%)

Genitourinary

77 (3.5%)

Unknown primary Total

200 (9.0%) 2230 (100%)

Data from 14 series of malignant pleural effusions; references 9,11-23.

TABLE 92-5 Diagnosis of Malignant Pleural Effusions Clinical setting is important in determining possible etiology. Most hemorrhagic effusions are malignant. Fifty percent are diagnosed by one fluid cytologic analysis. Seventy percent are diagnosed by a combination of thoracentesis and closed pleural biopsy. Ninety-five percent are diagnosed by video-assisted thoracoscopic examination.

malignant pleural effusions included focal increased uptake of fluorodeoxyglucose in the pleura (P < .001) and the presence of solid pleural abnormalities on CT (P < .002). The sensitivity was 66% and 71%, respectively, and the specificity was 90% for each of those two parameters. Ultrasonography is helpful to guide thoracentesis in patients with small effusions, and in one study Grogan and colleagues38 showed that ultrasonography was also helpful in decreasing the incidence of complications associated with blind percutaneous pleural biopsy.

Thoracentesis and Biopsy Procedures If the diagnosis of malignant pleural effusion is not clinically obvious, thoracentesis under CT or ultrasonographic guidance is performed (Table 92-5). Most malignant pleural effusions are exudative (85%-95%), and indeed the presence of an exudative effusion in the setting of a known malignancy is highly suggestive of a malignant effusion and indicates the need for additional investigations.39 Approximately one third of malignant pleural effusions will have a pH lower than 7.3, which is often associated with glucose values of less than 60 mg/dL.40,41 Such values indicate that the effusion has been present for some time42 and are often associated with a large tumor burden and fibrosis of the pleura.43 Because of such associations, malignant pleural effusions with low pH and low glucose concentrations are generally thought to have a higher initial diagnostic yield by cytologic examination,13 a worse overall survival (when associated with lung cancer),44 and a

1/21/2008 2:02:44 PM

1140

Section 4 Pleura

worse response to pleurodesis45 than those with pH and glucose of normal values.13,21,43 Aelony and colleagues,41 however, reported that thoracoscopic talc poudrage was effective to control malignant pleural effusions even when the pleural pH was low. In two other studies, pleural fluid pH as not found to be a predictor of survival46,47 or of a good response to pleurodesis.47 An elevated pleural fluid amylase level in the absence of esophageal perforation or pancreatic disease greatly increases the likelihood that the effusion is malignant, most commonly an adenocarcinoma of the lung, pancreas, or ovary.27,42,48 High levels of tumor markers in the pleural fluid may represent a helpful adjunct to rule in malignancy as the probable cause of an undiagnosed pleural effusion.49,50 Pleural fluid cytology is the simplest method for obtaining a diagnosis of malignant pleural effusion, but because the yield is highly dependent on the extent of disease and nature of the primary tumor, the incidence of positive findings can be quite variable.51-54 Approximately one half of malignant pleural effusions will be diagnosed on the basis of the first pleural fluid cytologic study whereas a second and a third thoracentesis increase the likelihood of positive findings to 65% to 70%.55-56 Patients whose effusions remain undiagnosed after thoracentesis may have a blind percutaneous needle biopsy, but this technique has a low yield (∼50%) in malignant neoplasms because of the patchy distribution of disease. Combining fluid cytology and pleural biopsy, however, increases the diagnostic yield to 75%.13,26,57 Obviously, blind percutaneous needle biopsy is ideal for patients whose physical condition excludes the possibility of more invasive diagnostic procedures, such as thoracoscopy.58 If the cause of the effusion is still unclear after thoracentesis and needle biopsy, the patient should undergo diagnostic thoracoscopy.59 The procedure allows direct access to all surfaces of both the visceral and parietal pleura, and most times it will clarify whether the effusion is due to a benign or malignant process. Several large series and review articles60-64 have reported a diagnosis accuracy of 90% to 100%; and, in experienced hands, diagnostic thoracoscopy, particularly when limited to inspection and biopsy, is a safe procedure with few complications. In addition to providing a diagnosis, thoracoscopy also allows, when indicated, prompt initiation of treatment with intraoperative pleurodesis.65-67 Thoracoscopy can be done under local anesthesia and sedation (medical thoracoscopy),20,68-69 which has the advantage of being performed in an endoscopy suite and requiring less than 24 hours of hospital stay, or under general anesthesia with videoassisted technology. With the development of thoracoscopic techniques, few circumstances occur in which open thoracotomy is necessary. It may be indicated when the pleural space is obliterated or when one wishes to proceed immediately with a surgical procedure such as decortication or pulmonary resection. The diagnostic yield of bronchoscopy is low in patients with undiagnosed pleural effusions, although it may be useful in patients with hemoptysis and in those with radiologic features suggestive of bronchial obstruction, such as atelectasis and ipsilateral mediastinal shift.

Ch092-F06861.indd 1140

MANAGEMENT The presence of a malignant pleural effusion invariably indicates advanced cancer status. Metastatic disease in other organ systems is frequently present, and these patients are usually compromised due to the systemic nature of their illness or to previous treatments. Expedient and effective palliation of symptoms is thus the primary objective of therapy, with judicious selection of treatment based on both general considerations and anticipated life expectancy. Although the primary goal of treatment is relief of dyspnea, secondary benefits also include improvement of other symptoms, such as chronic cough and thoracic discomfort. Ultimately, treatment may improve the patient’s quality of life. As a rule, the choice of therapy aims at avoiding unnecessary hospitalizations, minimizing hospitalization times and expenses, and ensuring fewer treatment-related complications.

General Principles In some situations in which the underlying malignancy is likely to be sensitive to systemic chemotherapy, this option is exploited initially. This is the case, for instance, of patients with breast carcinomas, small cell lung cancers, lymphomas,69 or ovarian carcinomas. In such patients, treatment of the primary tumor may be effective in eliminating the effusion and avoiding further interventions. For most patients, however, palliative treatment of the malignant effusion will be necessary to improve symptoms and quality of life; and the choice of therapy is based on factors such as age, site of the primary tumor, morphologic measurements of disease status and progression, and expected survival. In an interesting study, Burrows and colleagues14 were able to demonstrate that the Karnofsky Performance Scale (KPS) score at the time of thoracoscopy was the only variable predictive of survival in patients with malignant pleural effusions. In their study, patients with KPS scores greater than 70 had significantly better prognosis and were thus more likely to derive benefits from pleurodesis. Observation alone can be recommended in asymptomatic patients and in those without recurrence of symptoms after initial thoracentesis. Waiting too long for pleurodesis may, however, be detrimental because more significant neoplastic thickening of the pleural surfaces is likely to occur and the development of multiple pleural loculations due to repeated thoracentesis may prevent effective subsequent pleural symphisis.16 It may therefore be reasonable to recommend treatment at an earlier stage once the malignant nature of the pleural effusion has been documented. The great variety of possible treatment options such as repeated thoracentesis, chemical pleurodesis, use of indwelling pleural catheters, and pleuroperitoneal shunting highlights the fact that no procedure is distinctly superior or appropriate for all patients.

Management Options Repeated Thoracentesis Thoracentesis provides a rapid and satisfactory relief of symptoms in the majority of cases but almost inevitably the

1/21/2008 2:02:44 PM

Chapter 92 Management of Malignant Pleural Effusions

TABLE 92-6 Advantages and Disadvantages of Repeated Thoracentesis Advantages Provides immediate relief of respiratory distress Good option for terminal patients with survival expected to be less than 1 to 2 months Good option for patients with slowly reaccumulating pleural fluid Disadvantages Ineffective to prevent reaccumulation of fluid Results in patient’s increased anxiety and discomfort Repeated hospital or clinic visits Repeated exposure to risks and complications of procedure (pneumothorax, empyema, loculations) Predisposes to development of fibrous peel, limiting subsequent re-expansion From Deslauriers J, Mehran R: Handbook of Perioperative Care in General Thoracic Surgery. Philadelphia, Elsevier Mosby, 2005, p 496.

effusion will recur (Table 92-6). It is thus not a reasonable option for long-term management even if the procedure can easily be done in an outpatient setting and requires minimal equipment. Thoracentesis often results in a patient’s increased anxiety and discomfort in addition to exposure to the risks and complications of the technique, such as pneumothoraces and empyemas. In patients with longer life expectancies it may also cause problems prejudicial to effective later palliative treatment, such as the development of hydropneumothoraces with subsequent encasement of the lung. However, in patients judged to have a limited life expectancy measured in weeks,6,10 in patients with acute respiratory distress, and in patients with slowly reaccumulating effusions, it may be a suitable and indeed the only available option. The volume of fluid that can be safely removed from the pleural space during thoracentesis is unknown, but the American Thoracic Society10 recommends removal of 1.0 to 1.5 L of fluid at one sitting, as long as the patient does not develop dyspnea, chest pain, or severe cough. It has been shown that the mechanisms of patient’s improvement after thoracentesis include increases in total lung capacity and forced vital capacity70 and improvement in pulmonary gas exchange.71

Chemical Pleurodesis The objective of chemical pleurodesis is to produce adhesions between visceral and parietal pleurae, thus obliterating the potential pleural space. A variety of chemicals72,73 can be used to achieve this objective, but there are prerequisites, as well as indications and contraindications (Table 92-7), to the success of this approach.74-76 Indications, Prerequisites, and Contraindications. The presence of significant symptoms, such as dyspnea and chest pain, that are clearly related to the effusion is the main indication for chemical pleurodesis. This symptom-effusion relationship is best documented by removing 1.5 to 2.0 L of fluid and assessing its effect on breathlessness. If the dyspnea does not improve, other possible causes, such as bronchial obstruction with distal atelectasis or lymphangitic carcinomatosis,

Ch092-F06861.indd 1141

1141

TABLE 92-7 Indications for and Contraindications to Chemical Pleurodesis Indications Tumors unlikely to be responsive to systemic therapy Effusion must be symptomatic and symptoms must be clearly related to the effusion Should be evidence of complete re-expansion of underlying lung Pleural effusion must be recurrent Contraindications Patients with limited anticipated life span Patients with incomplete re-expansion of underlying lung From Deslauriers J, Mehran R: Handbook of Perioperative Care in General Thoracic Surgery. Philadelphia, Elsevier Mosby, 2005, p 496.

must be considered before proceeding with chemical pleurodesis. Such problems are frequently seen in the presence of primary pulmonary neoplasms or extensive intrapulmonary metastatic disease. Another prerequisite for successful chemical pleurodesis is radiologic evidence that the underlying lung can re-expand and is not trapped by a fibrous or neoplastic peel lying on its visceral surface or by a main stem endobronchial tumor preventing air entry into the parenchyma. Other factors that may prevent lung re-expansion also include irregular scattered adhesions, loculations of the pleural space by fibrin, and loss of pulmonary elasticity.77 Failure of re-expansion is often best documented by inserting a chest tube, evacuating the pleural fluid, and obtaining a chest radiograph, which will demonstrate whether the lung can re-expand. Chemical pleurodesis in the presence of a nonexpanded lung may induce fibrosis of the visceral pleura, which will further restrict the expansion of the underlying lung. Patients selected for chemical pleurodesis must also have an effusion that is recurrent, and the recurrence must correlate with symptoms. One possible exception is the patient who lives at a distance from the treatment center and in whom the effusion has a high likelihood of recurring. The selection of a patient for chemical pleurodesis must finally be predicated on a reasonable anticipated life span, in general at least 1 to 2 months. Chemicals Used for Pleurodesis. The list of chemicals and other products that have been or are still used to produce pleurodesis is long and ranges from antibiotics to antineoplastic, physical, and immunologic agents.78 As a rule, chemotherapy agents have been found ineffective as sclerosing compounds in addition to adding very little in terms of local antitumor activity.39,79,80 In general, the selection of a sclerosing agent is made easier by practical considerations of availability, cost, effectiveness, comfort of the patient, and incidence of side effects (Table 92-8). The ideal sclerosing agent is, in theory at least, highly effective, easy to administer, inexpensive, virtually free of adverse effects, and not associated with serious adverse events.81,82 One must understand, however, that sclerosing agents will produce some degree of pleural inflammation and fibrosis and that the more potent of these agents will inevitably induce more significant acute pleuritis with associated pain and

1/21/2008 2:02:45 PM

1142

Section 4 Pleura

fever, an unfortunate “No pain, no gain” situation as described by Lee and colleagues.83-85 Biologically, sclerosing agents used for pleurodesis have a high molecular weight, locoregional but rapid systemic clearance, and a steep dose-response curve.6 Criteria used to assess the efficacy of chemical pleurodesis are not universally accepted, but the procedure is generally considered to be successful if there is no recurrence of the effusion on radiographic controls done 30 days after the pleurodesis. TETRACYCLINE. In the past, tetracycline instilled via an intercostal tube was the most widely used pleural sclerosing agent, with an average success rate of 65% and an excellent safety profile.5 It was well tolerated and side effects were infrequent, mild, and transient. Since the production of tetracycline was discontinued in 1992 in the United States, it is no longer used as a pleurodesis agent.86 TALC. Talc is the oldest and still most effective agent used for pleurodesis.87-89 It is a naturally occurring magnesium sheet silicate that is mined in many parts of the world.90 Although talc ores are frequently associated with other minerals, such as asbestos, the product that is used for chemical TABLE 92-8 Chemicals Commonly Used for Pleurodesis Talc

Doxycycline*

Bleomycin

Availability of product

Wide

Wide

Wide

Cost

Minimal

Minimal

High

Effectiveness

>90%

50%-75%

60%-85%

Inconvenience (adverse effects‡)

++

+ + + (chest pain)

++

Toxicity (morbidity)

Minimal

Minimal

Minimal

†

*Doxycycline is a tetracycline analogue. Thirty-day success rate in controlling effusion. ‡ Most common adverse effects are nausea and vomiting, pleuritic pain, and fever. From Deslauriers J, Mehran R: Handbook of Perioperative Care in General Thoracic Surgery. Philadelphia, Elsevier Mosby, 2005, p 498. †

pleurodesis is free of asbestos.91 It is not packaged in a sterile manner by the manufacturer, but limitation on the number of microorganisms is part of USP specification and talc can be sterilized with heat (132ºC for 6 hr) or ethylene oxide gas (130ºC for 1.75 hr) techniques.81 Because of the filtration process, talc has variable particle sizes, although most of these particles are less than 50 µg. Talc is inexpensive and can be ordered from chemical companies worldwide. Most importantly, talc controls malignant pleural effusions in over 90% of patients. In a literature search of Englishlanguage medical journals that reported treatment of malignant pleural effusions, Walker-Renard and coworkers78 identified 1168 patients with malignant pleural effusions who were reviewed for the efficacy of pleurodesis. In that cohort, the success rate of pleurodesis agents varied from 0% with etoposide to 93% with talc. The authors concluded that talc appears to be the most effective and least expensive agent. Other reports76,90,92-96 have also confirmed the superiority of talc over other available products. The most common adverse events associated with talc pleurodesis are transient fever, characteristically occurring 4 to 12 hours after instillation and lasting no longer than 72 hours and chest pain, which is generally minimal.16,78 Talc can be administered through the chest tube as a slurry (bedside administration), or it can be insufflated during thoracoscopy (Table 92-9). Although it is generally thought that talc insufflation over a collapsed lung is associated with better results, two recent prospective randomized trials have shown that talc insufflation was not a superior approach when compared with talc slurry instilled through the chest tube at bedside and that both methods were similar in efficacy.18,97 In an animal model, Cohen and associates98 have also shown that effective pleurodesis could be obtained with either talc slurry or thoracoscopic talc insufflation. When talc is used as a slurry, 5 g of asbestos-free purified talc is mixed with 100 mL of normal saline solution and 10 mL of 1% lidocaine to form a suspension that is instilled directly into the chest tube. Major advantages of this procedure are that it is simple and safe, that it can be done at bedside, and that it is associated with high success rates

TABLE 92-9 Talc Pleurodesis Talc Slurry (Bedside)

Talc Insufflation (Thoracoscopic)

Product used and technique

5% of talc diluted in 100 mL of saline instilled in chest tube

5% of talc insufflated with atomizer over visceral and parietal pleura

Advantages

Simplicity Performed at bedside Local anesthesia

Complete evacuation of pleural space ensured Multiple biopsies can be performed Homogeneous distribution of talc over all lung surfaces Loculations of fluid can be broken down Visual placement of chest tubes

Success rate

High (>90%)

High (>90%)

Disadvantages

Occasionally associated with pneumonitis Chest tube more likely to become occluded by talc particles

Additional costs General anesthesia and one-lung anesthesia

From Deslauriers J, Mehran R: Handbook of Perioperative Care in General Thoracic Surgery. Philadelphia, Elsevier Mosby, 2005, p 500.

Ch092-F06861.indd 1142

1/21/2008 2:02:45 PM

Chapter 92 Management of Malignant Pleural Effusions

(>90%). Disadvantages include possible transient ipsilateral pneumonitis and the possibility of chest tube occlusion by clumping of the substance in the tube. Thoracoscopic talc insufflation is also an effective and popular technique. Major disadvantages are the requirement for general anesthesia and one-lung ventilation, the additional costs associated with the use of an operating room, and the fact that all studies have shown results that are no better than when talc is given as a slurry. One clear advantage of videoassisted thoracoscopy insufflation is that biopsy of the pleura is possible for pathologic confirmation of the malignant neoplasm. In general, 5 g of talc is insufflated through the use of an atomizer. The issue of respiratory complications after talc pleurodesis whether done by talc slurry tube instillation or by talc insufflation has received much attention in recent years. While in some reviews this problem is hardly mentioned,77,99 several cases have been reported worldwide.90,100-103 In an interesting study, Rehse and coworkers101 reported that patients developed respiratory complications after 27% (24 of 89) of talc pleurodesis procedures and that these complications included hypoxia, dyspnea, re-expansion pulmonary edema, and bilateral pulmonary edema (ARDS), which occurred after 8 procedures in 7 patients, for an overall incidence of 9%. The exact mechanism or mechanisms by which talc produces acute lung injury is still unknown, but according to Light,104,105 it is possibly related to the systemic absorption of talc, with subsequent production of inflammatory mediators. Recent data in lower mammal studies using equivalent doses of talc per kilogram have also shown distribution of talc particles beyond the lung to distant organs such as the kidneys and the brain.106-108 Other possible explanations include reexpansion pulmonary edema, excessive dosage of talc, and sepsis due to bacterial contamination of the talc.81 In a study reported by York and coworkers,109 pneumonitis was reported in 8 cases of a series of 125 patients who underwent talc slurry pleurodesis but only 5 patients had radiologic features consistent with ARDS and only two required assisted mechanical ventilation. DOXYCYCLINE. Doxycycline is a tetracycline analogue that has a success rate of 50% to 75% when used as a sclerosing agent.110-114 It is administered at bedside through the chest tube in a suspension that has 500 mg of doxycycline diluted in 50 to 100 mL of 0.9% saline solution. From 10 to 20 mL of lidocaine 1% is added to the solution because pleuritic pain is a common adverse effect of doxycycline pleurodesis. In some cases, more than one instillation may be necessary113 to achieve effective pleurodesis. BLEOMYCIN. Bleomycin is a chemotherapy agent that has been shown to have similar or higher success rates when compared with tetracycline39,75,115 but lower success rates when compared with talc.78,95,116,117 The major drawback of bleomycin pleurodesis is the cost, which amounts to approximately $800 for 60 units. Bleomycin is administered through the chest tube, and the sclerosing dose is 60 units diluted in 50 to 100 mL of 0.9% saline solution. The administration of a second dose of bleomycin to patients not responding to the first one appears to improve the overall outcome of the treatment.118

Ch092-F06861.indd 1143

1143

Techniques of Chemical Pleurodesis BEDSIDE PLEURODESIS. A thoracostomy tube (small-bore [8-16 Fr]2,15,110,119,120 or standard [28 Fr]) is first inserted under local anesthesia and the pleural fluid evacuated, a process that is done slowly because re-expansion pulmonary edema due to vascular stretching may occur,121 especially if the lung has been compressed for prolonged periods of time. The recommended way to evacuate the pleural space is to remove 200 mL hourly until the space is completely emptied. The chest tube is then connected to an active suction system, and a radiograph is obtained to ensure that the pleural space has indeed been emptied and that the lung has re-expanded. The actual pleurodesis can be carried out when the amount of pleural fluid drainage is less than 150 to 200 mL/day, although this criteria is probably not as relevant as having confirmation of lung re-expansion on chest radiography.122 About 20 to 30 minutes before the pleurodesis, the patient is premedicated. The suspension (always prepared at the hospital pharmacy) is then instilled into the chest tube, which is clamped for 3 to 4 hours after the instillation. The chest tube is then unclamped, reconnected to an active suction system (−20 cm H2O), and left in until the daily output decreases to below 3 to 5 mL/kg. At such a time, the chest tube is removed. In the past it was thought that the patient should be turned in different positions during clamping time so that the solution could be distributed uniformly over all pleural surfaces. Recent studies using radiolabeled tetracycline have shown, however, that the sclerosing agent is dispersed throughout the pleural space within seconds in a fairly uniform fashion6,123 without having to turn or rotate the patient. Other subsequent randomized trials have also found no significant differences in the success rates between rotated and nonrotated patients.124,125 THORACOSCOPIC PLEURODESIS. One of the prerequisites for thoracoscopic pleurodesis126 is the ability of the patient to tolerate a general anesthetic. The procedure is performed with selective one-lung ventilation with the patient in the lateral decubitus position. One or two access ports are used. Initially, the pleural fluid is aspirated, the space is inspected, loculations are broken down, and biopsy samples are taken. Five grams of purified talc is then insufflated with an atomizer in such a way as to cover all visceral and parietal pleural surfaces. We recommend leaving two thoracostomy tubes (28 Fr), which are positioned under direct vision and connected to an active suction system. These tubes are removed as described earlier in the section on the technique of bedside pleurodesis.

Ambulatory Management by Indwelling Pleural Catheters The use of a semi-permanent outpatient indwelling pleural catheter such as the Pleurx (Scientific Medics, Denver Biomaterials Inc., Golden, CO)127-136 or of a small-bore pigtail catheter137 or Port-a-Cath138 has been described for the management of malignant pleural effusions. The Pleurx catheter is inserted percutaneously on an outpatient basis, and either the patient, a relative, or a home care

1/21/2008 2:02:45 PM

1144

Section 4 Pleura

visiting nurse can drain the pleural space with the supplied vacuum bottle system, usually every day at the beginning. When not in use, the catheter is coiled under a dressing, thus avoiding the need to carry around a drainage system. The main advantage (Table 92-10) of using an indwelling catheter is that the entire technique can be done on an outpatient basis, thus substantially reducing treatment costs. In addition, there are no adverse effects or morbidity because chemical pleurodesis is not used. Interestingly, a substantial number of patients will achieve spontaneous pleurodesis over time and at that point the catheter can be removed.131,132 One of the disadvantages of indwelling pleural catheters is the possible need for repeated drainage of the effusion if spontaneous pleurodesis does not occur. Another disadvantage is that it may become costly if the patient has to replace the vacuum bottle systems and dressing kits at her or his own expense. In 1999, Putnam and colleagues129 reported the results of a multi-institutional randomized trial designed to compare the effectiveness and safety of an indwelling pleural catheter (Pleurx) with doxycycline pleurodesis in the treatment of cancer patients with malignant pleural effusions. One hundred and forty-four patients were randomized, and the median hospitalization time was 1.0 day for the catheter group and 6.5 days for the doxycycline group. The degree of symptomatic improvement in dyspnea and quality of life was comparable in each group, but 6 of 28 patients who received doxycycline (21%) had a late recurrence of their effusion as opposed to 12 of 91 patients who had in indwelling catheter (13%). Of the 91 patients sent home with the pleural catheter, 42 (46%) achieved spontaneous pleurodesis at a median time of 26.5 days.

Often, however, treatment failure is related to the patient’s having a trapped lung. In those individuals, dyspnea is secondary to compression of the mediastinum and contralateral lung; consequently, these patients can be helped by emptying the pleural space (even if the ipsilateral lung is trapped). This can be achieved by the use of an indwelling pleural catheter or by insertion of a pleuroperitoneal shunt.

Because the use of pleuroperitoneal shunts requires significant patient participation, he or she must be in generally good condition, alert, and well motivated. The principle of the pleuroperitoneal shunt139-142 is that it transfers pleural fluid from the pleural space into the peritoneum where it is reabsorbed. Placement of the shunt usually requires general anesthesia and the advantages and disadvantages of the technique are listed in Table 92-11. The main disadvantages are that the patient’s cooperation is needed (must pump 250-400 times/day [1 mL of pleural fluid is transferred each time]) and that, over time, shunt failures will occur in approximately 15% of patients. Most shunt failures require shunt removal and replacement.

Management of Refractory Malignant Pleural Effusions

Malignant Pleural Effusions in Specific Diseases Lung Cancer

In some patients, initial failure of chemical pleurodesis is the result of suboptimal technique. In such cases, a repeated attempt at sclerosis can be carried out with a different product or approach.

Lung cancer is the leading cause of malignant pleural effusions, which will occur in 7% to 15% of all patients at some time during their evolution.10 The presence of a pleural effusion is indeed a sign of advanced disease even if the pleura is not actually involved by the tumor.144 In some cases, the effusion will be related to obstructive pneumonitis (parama-

Pleuroperitoneal Shunt

Open Thoracotomy Open thoracotomy for pleural tumor decortication to reexpand the lung is seldom an option because it carries significant morbidity and mortality (6%-10%) rates, making it difficult to justify as a palliative procedure. Using videoassisted techniques may be a safer alternative,143 although this type of surgery is still hard to justify for palliative purposes except maybe for patients with malignant mesotheliomas.

TABLE 92-10 Advantages and Disadvantages of Drainage by Indwelling Pleural Catheters Advantages Does not require hospitalization No adverse effects, toxicity, or morbidity often associated with chemical pleurodesis Low cost because of no hospitalization Effective to palliate dyspnea Possibility of spontaneous pleurodesis

TABLE 92-11 Advantages and Disadvantages of Pleuroperitoneal Shunt for Malignant Pleural Effusions Advantages Single intervention Reliable and effective palliation of symptoms Avoids prolonged hospitalization

Disadvantages May be more expensive for patient who has to pay for vacuum bottles Possible need for repeated drainage of the effusion Patient needs the catheter for prolonged period of time (versus chemical pleurodesis)

Disadvantages High cost of device Requires general anesthesia Requires patient cooperation and motivation Late complications (15% of cases) may require shunt removal and replacement

From Deslauriers J, Mehran R: Handbook of Perioperative Care in General Thoracic Surgery. Philadelphia, Elsevier Mosby, 2005, p 502.

From Deslauriers J, Mehran R: Handbook of Perioperative Care in General Thoracic Surgery. Philadelphia, Elsevier Mosby, 2005, p 503.

Ch092-F06861.indd 1144

1/21/2008 2:02:45 PM

Chapter 92 Management of Malignant Pleural Effusions

lignant effusion) and the patient will still be able to undergo surgical resection of the primary tumor with curative intent. According to some authors,145 the prognosis of patients with non–small cell lung cancer and paramalignant effusions is comparable to that of those in the same stage category without pleural effusions.10 Unfortunately, the revised TNM classification146 is not very clear with regard to the tumor (T) status of patients with paramalignant cytologically negative pleural effusions. These are fairly rare occurrences, however, and most patients with NSCLC and a pleural effusion have advanced and inoperable disease. Management of these patients with reference to their effusion follows the guidelines previously described. Pulmonary resection in the presence of a malignant pleural effusion even if the effusion is considered to be minor is not beneficial for the survival of patients with NSCLC.147

Malignant Mesotheliomas Malignant mesotheliomas are locally growing tumors of the pleura that are generally associated with poor survival (median survival, 12-24 months after diagnosis). The clinical presentation of these patients is often insidious, and dyspnea that is related to the presence of a pleural effusion is the predominant symptom. Unfortunately, the treatment of patients with malignant mesotheliomas is not standardized and more often than not it will be palliative. Patients with malignant pleural effusions are usually treated by talc pleurodesis done at the time of diagnostic thoracoscopy148 or by indwelling pleural catheter.149 Other more experimental options include intrapleural chemotherapy, immunotherapy, or gene therapy.149

Breast Carcinoma Breast carcinoma is the second-ranking cause of malignant pleural effusions,10 and 7% to 11% of patients with breast carcinoma will develop a malignant pleural effusion during the course of their disease.150,151 In many cases, the effusion will be the first sign of disease or it will occur years after treatment when the patient appears to be in complete remission. The pathogenesis of malignant pleural effusions associated with breast cancer is usually that of involvement of lymphatics of the chest wall152 or, more frequently, that of hematogenous spread to the pleura. An interesting feature of malignant pleural effusions associated with breast carcinoma is that the yield of thoracentesis with cytologic analysis is usually higher than in patients with malignant effusions due to other primary tumors,153 so that thoracoscopic examination is seldom required. Recommended treatment of metastatic pleural effusion with associated breast carcinoma differs from that of others types of tumors, and chemotherapy with cytotoxic agents or with hormonotherapy may be effective.10,154-156 If these approaches do not relieve symptoms, local nonsurgical options with chemical pleurodesis must be considered.157

Gynecologic Malignancies Pleural effusions associated with gynecologic malignancies are nearly always antedated by peritoneal metastasis and

Ch092-F06861.indd 1145

1145

ascites.158 In these cases, talc sclerotherapy appears to be effective even in the presence of ascites.159

Hematologic Malignancies Malignant pleural effusions are not uncommon in patients with lymphomas, and indeed approximately 10% of all malignant pleural effusions are associated with a hematologic malignancy. In the majority of patients, the effusion is present at the time of diagnosis and it is part of widespread disease chiefly associated with mediastinal involvement,160-162 direct pleural infiltration by the tumor, or mechanical obstruction of the thoracic duct.69 It can also be treatment related and be secondary to mediastinal fibrosis or constrictive pericarditis secondary to mediastinal irradiation. Pleural effusions associated with lymphomas are generally exudates, and they can be serous, hemorrhagic, or chylous. Indeed non-Hodgkin’s lymphomas are the most common cause of noniatrogenic chylothoraces.163,164 The treatment of choice of lymphoma patients with pleural effusions is that of systemic chemotherapy with or without mediastinal radiation therapy165 when there is mediastinal node involvement. Patients with chylothoraces are treated with parenteral hyperalimentation associated with chemical pleurodesis. Thoracic duct ligation is seldom necessary under such circumstances. In one study,160 it was shown that, when appropriately treated, the finding of a pleural effusion at the time of presentation of patients with intermediate-grade nonHodgkin’s lymphomas did not have an adverse effect on survival.

SUMMARY Patients suffering from malignant pleural effusions require careful clinical examination, and a reasonable estimate of life expectancy is also mandatory to determine the most appropriate form of intervention. By following these guidelines, a significant palliative benefit with resultant improved quality of life can be obtained with minimal morbidity in carefully selected patients. KEY REFERENCES Antony VB, Loddenkemper R, Astoul P, et al: Management of malignant pleural effusions. Am J Respir Crit Care Med 162:1987-2001, 2000. ■ Official statement of the American Thoracic Society on management of malignant pleural effusions. Dresler CM, Olak J, Herndon JE, et al: Phase III Intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest 127:909-915, 2005. ■ In this prospective randomized trial, talc poudrage and talc slurry were found to be similar in efficacy to control malignant pleural effusion. Putnam JB, Light RW, Rodriguez RM, et al: A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer 86:1992-1999, 1999. ■ This multi-institutional study showed that indwelling pleural catheters were effective treatment for patients with malignant pleural effusions.

1/21/2008 2:02:45 PM

1146

Section 4 Pleura

Sahn SA: Malignancy metastatic to the pleura. Clin Chest Med 19:351361, 1998. ■ Excellent overall review of pathogenesis, investigation, and management of patients with malignant pleural effusions. Shaw P, Agarwal R: Pleurodesis for malignant pleural effusions (review). The Cochrane Database of systematic reviews 1:CD002916, 2004.

Ch092-F06861.indd 1146

■ Review done to ascertain the optimal technique of pleurodesis in cases of malignant

pleural effusion. Walker-Renard PB, Vaughan LM, Sahn SA: Chemical pleurodesis for malignant pleural effusions. Ann Intern Med 120:56-64, 1994. ■ Studies including 1168 patients with malignant pleural effusions were reviewed for efficacy of the pleurodesis agent.

1/21/2008 2:02:45 PM

Surgical Techniques chapter

93

CLOSED DRAINAGE AND SUCTION SYSTEMS Robert James Cerfolio

Key Points ■ Placement of a chest tube at the bedside requires careful prepara-

tion for both the physician and the patient.

leaving the chest open was 28%, compared with 4% for closed pleural drainage. Based on these findings, closed pleural space drainage became the standard of care in the early 20th century, and the concept of underwater seal was born.

■ Water seal is superior to suction for most air leaks. ■ Evidence-based medicine from scientific studies should be used

to manage chest tubes and the pleural space, not “unproven dogma learned in training.”

Terms such as pleural space, negative intrathoracic pressure, and underwater seal represent a convoluted web of phrases and concepts to many physicians, particularly those in nonsurgical specialties. Management of chest tubes and the pleural space is a well-protected bastion for the thoracic surgeon, and we should continue to protect it as our own. We should be the ones who insert chest tubes, manage the tube settings, decide when and how to remove them, and manage the pleural space. The key concepts that are needed to make these decisions should be based on scientific data gleaned from published peer-reviewed studies and not on hard-held opinions derived from where and by whom we were trained. Unfortunately, these decisions are too often based on handed down doctrines and training preferences, few of which have any scientific evidence to support them. It is this fact that further confuses our medical colleagues. One surgeon recommends suction, but his weekend-covering partner changes the management to water seal. This commonplace management change erodes the faith others have in our strategy. Medical physicians make most of their decisions based on peer-reviewed scientific data, as should thoracic surgeons. The facts needed to make chest tube decisions are presented in this chapter.

HISTORY Hippocrates is credited as being the first to drain the pleural space, but he did not have a closed system to attach to his pleural drainage tube. Playfair in 1875, and Hewett in 1876, reported an underwater seal drainage system to help evacuate empyema. However, Gotthard Bülau (Fig. 93-1) is credited as the originator of the first closed water seal drainage system. The improved outcome of using a closed system over the more popular open drainage system (i.e., rib resection with open drainage or Eloesser flap) is derived from data accumulated by the United States Army. They reported their extensive experience from the battlefield and elsewhere. The mortality rate for empyema treated with rib resection and

INDICATIONS FOR BEDSIDE CHEST TUBE PLACEMENT In general, the indication to insert a chest tube into the pleural space is the presence of air or fluid in the pleural space (Table 93-1). The pleural space is meant to be a potential space only, and when foreign material enters it, it usually should be drained. However, the decision as to whether that space needs to be drained or just carefully monitored by chest roentgenography is based on the specific situation of each patient. The decision as to whether it is best to drain an effusion or air at the bedside instead of in the operating room via video-assisted techniques is another part of the decision tree that again is best made based on each patient’s individual clinical status and history. Trauma patients, those who are bleeding postoperatively, and those with spontaneous pneumothorax from large blebs all present special situations that deserve particular attention and are discussed elsewhere in this textbook.

DEVELOPMENT AND TYPES OF CHEST TUBES Chest tubes come in various sizes and types. In general, there are only two shapes for chest tubes—a straight and a right angle. Most commonly, a right-angle tube is used to drain fluid from the inferior hemithorax, and a straight tube is used to control the upper hemithorax. There are few data to support the use of one tube over another. In my institution, we almost never use a 32 Fr tube and prefer a 28 Fr tube. It is large enough to drain blood without getting occluded from clot, yet it is small enough to limit the pain of rubbing against the intercostal nerve. Tubes can be soft or more rigid. Again, there is no solid data to support one over the other. Many surgeons have changed to soft, pliable tubes that are large enough not to clot and may cause less pain. We have had some problems with kinking if the tube is too soft.

TECHNIQUE OF INSERTION OF BEDSIDE CHEST TUBE Once the decision to place a chest tube has been made, the next decision is where to perform the placement. If one chooses to place the chest tube at the bedside, careful planning is needed. Forethought and good communication among the surgeon, the nurse, and the patient are mandatory. Chest tube placement is probably the most difficult bedside 1147

Ch093-F06861.indd 1147

1/21/2008 2:03:31 PM

1148

Section 4 Pleura

FIGURE 93-1 Gotthard Bülau (1836-1900) of Hamburg, Germany, originator of the method of closed water seal drainage of the chest. (FROM NISSEN R, WILSON RHL: PAGES IN THE HISTORY OF CHEST SURGERY. SPRINGFIELD, IL, CHARLES C THOMAS, 1960.)

TABLE 93-1 Indications for Tube Drainage Pneumothorax Spontaneous (primary, secondary) Open pneumothorax Tension pneumothorax Traumatic Iatrogenic (central venous access procedure, thoracentesis, pleural biopsy, needle biopsy of lung, positive-pressure ventilation) Hemothorax Empyema Parapneumonic effusions Frank empyemas Pleural Effusion Chylothorax Postoperative Drainage Thoracic procedures Cardiac surgery

procedure that is performed, and it is an art. The final position of the tube and the eventual chest roentgenogram are not more important than the patient’s comfort during the procedure. Both should be maximized. We prefer the patient to have a blood pressure cuff that can be cycled so that blood pressure can be monitored continuously and a test dose of intravenous sedation given. Liberal but safe doses should be

Ch093-F06861.indd 1148

administered by the patient’s nurse during the procedure, and the nurse should be present throughout. The patient is best positioned on the side, with the affected side up and the arm over the head. This maneuver helps to open the space between the ribs. The patient’s face should never be covered, and the nurse or another assistant should be present at all times to talk to the patient in a calm voice. There are several possible locations that can be chosen for the incision. This decision may be influenced by the patient’s history or the location of the material to be evacuated. In general, if the pleural space is free, we prefer a location inferior to the breast and anterior to the midaxillary line, so as to maximize patient comfort after placement. The skin site is carefully anesthetized with a small 25-gauge needle; only a small incision is needed, and it should be made over the thinnest part of the chest wall, so that the underlying rib can be palpated. Tunneling the tube superiorly one or two rib spaces is not needed and in our opinion makes the insertion unnecessarily more difficult. We prefer entering the chest with a blunt instrument, such as a Kelley clamp. The pleura that is to be opened should be anesthetized before insertion. Once the space is entered, the surgeon’s index finger should be used to explore the pleural space. If dense adhesions are palpated, these should be taken down only with great care if they are filamentous. If the adhesions are dense or if there is complete pleural symphysis, then a blind pneumolysis at the bedside is ill-advised and can cause bleeding. In such cases, the bedside procedure should be abandoned, and tube placement should be done in the operating room, depending on the patient’s clinical status. However, this situation is quite rare, especially if the tube is being placed for fluid or air because the mere fact that either has accumulated in the pleural space means by definition that some part of the pleural space is free.

COMPLICATIONS Many complications can occur from a bedside chest tube placement. As described earlier, bleeding is the most serious complication and can be almost eliminated with careful insertion if one ensures that the patient is not coagulopathic. The creation of an air leak secondary to injury to the pulmonary parenchyma is the second most common complication and can usually be managed with nonoperative measures. The placement of a tube in the peritoneal cavity or into an abdominal solid organ viscera below the diaphragm can usually be avoided. This latter complication often occurs when the surgeon forgets that the diaphragm may be elevated after a previous thoracotomy or pulmonary resection or in a patient with ascites or cirrhosis. Another devastating but rare complication is cardiac injury. Once the tube is safely in the pleural space, it needs to be securely attached to the connector, then to the hosing, and then to a self-contained modern three-bottle system.

CLOSED DRAINAGE SYSTEM: THE THREE BOTTLE SYSTEM The development of the pleural drainage device is a fascinating story. It is a story most recently dominated by industry,

1/21/2008 2:03:32 PM

Chapter 93 Closed Drainage and Suction Systems

and there still exists serious competition between manufacturers. An abridged version of this story is presented here. The most basic pleural drainage system unit is a threebottle system as shown in Figure 93-2. A one-bottle system was used initially; however, as the fluid or blood that drained from the patient rose in the bottle, it increased the resistance to further drainage. Moreover, the mixture of air in the bottle and blood from the patient caused a foamy effluent to build in the bottle, again impeding further drainage. For those reasons, a two-bottle system was quickly adopted. The second bottle allowed the fluid to drain into the first bottle only, while the air escaped into the second bottle. This prevented the foam from forming, and the two-bottle system had to be drained less frequently. The problem with this system was that the added length of the tubing increased the dead space, adding significant resistance. Some patients actually had reversal of flow in the tubing, such that the chest tube effluent would start to go back up the tube into the patient. For that reason, we finally arrived at the famed three-bottlesystem. The third bottle provides a way to add suction to the system. This active suction prevents the chest tube effluent from going back toward the patient. Essentially, all commercial systems use this technology now.

Wet Versus Dry Suction Once it was noted that an active suction system led to the best design clinically, companies began to come up with ways to add all three bottles into one compact, user-friendly system. Initially, the suction that was added was “wet,” meaning that there is a continuous bubbling of suction and the system requires a water level. These systems are safe because it is difficult to exert greater than a −15 or −20 cm H2O pressure, but they allow inadequate air flow in patients with a large leak. More recently, manufacturers have become incredibly creative. Now there are one-way valves that prevent spillover, one way valves to help regulate suction, and systems that allow the physician to dial in the desired amount of negative intrathoracic pressure to be exerted. The dry systems are superior because they feature mechanical manometers and eliminate the noise of the constant bubbling,

1149

which was a very annoying feature of the wet systems for patients who were sleep-deprived already. After pneumonectomy, most surgeons do not want to add suction to the patient’s emptied pleural space, for fear of causing a mediastinal shift and hypotension. Although this concern is theoretical in selected patients, we have witnessed hypotension when suction was applied to the postpneumonectomy chest tube. Our practice is to use a specially designed pneumonectomy balanced drainage system, if available. This system allows fluid to drain so that postoperative bleeding is noted before the development of hypotension, yet it does not add the risk of mediastinal shifting because the space sees little negative pleural pressure. Alternatively, a regular drainage system may be used, with a large sign taped to the system stating, “Do Not Apply Suction.”

Connectors Although this detail can be overlooked, a perfectly placed chest tube attached to an ideal pleural drainage system is of no use if the tubing that connects the two falls off. For this reason, we have switched, over the past decade, to the use of a banding system. The heavy-duty plastic band has almost eliminated this problem. Usually, the attachment of the hose to the pleural drainage system is secure because of the connectors provided by the pleural drainage system manufacturers.

CHEST TUBE MANAGEMENT Once the tube is secured, it should be managed based on scientific data derived from peer-reviewed articles. Air leaks or alveolar-pleural fistulas remain the most common complications after pulmonary resection. Until the past 7 years, there was little scientific evidence as to the best way to manage tubes to help seal them. In this section, we review some of the newer developments, which have also been summarized in a more in-depth review (Cerfolio, 2005).1 Air leaks have many different causes, including spontaneous, iatrogenic, traumatic, and postresectional types. The most common clinical setting for the occurrence of air leaks is after

FIGURE 93-2 Three-bottle water seal unit in which the third bottle is used to regulate the amount of suction applied through the entire system. A, Tube from the patient; B, collecting bottle; C, water seal; D, vent tube; E, connection to wall suction.

Ch093-F06861.indd 1149

1/21/2008 2:03:32 PM

1150

Section 4 Pleura

pulmonary resection. Because of the homogeneity of this type of air leak, it has been the only type to have been truly scientifically studied in clinical prospective trials and therefore is the focus of this review. However, the principles learned from these studies are applicable to any patient with an air leak from any cause. Surgeons and pulmonologists have been called upon for years to manage chest tubes in patients with an air leak. Most such decisions have been based on individual training experiences, as opposed to objective facts gleaned from review of the most recent scientific literature. Nonetheless, recent studies have provided important data to help guide these decisions.

Definition One of the biggest problems with air leaks is the confusion of terms.2 Very frequently, physicians call alveolar-pleural fistulas bronchopleural fistulas. An alveolar-pleural fistula is a communication between the pulmonary parenchyma distal to a segmental bronchus and the pleural space. A bronchopleural fistula is defined as a communication between a main stem, lobar, or segmental bronchus and the pleural space. The two terms refer to completely different clinical problems. This distinction is not merely academic. The majority of air leaks after elective pulmonary resection are alveolar-pleural fistulas, not bronchopleural fistulas. The latter cannot occur unless the patient has had a pneumonectomy, lobectomy, or segmentectomy (unless there has been an iatrogenic injury or trauma to the airway from a suction catheter or double-lumen tube, or a deceleration or missile injury, all of which are exceedingly rare). The proper classification of an air leak as one or the other is important because the treatment and natural history of the two types of fistulas is drastically different. Bronchopleural fistulas almost always require reoperation or some type of surgical intervention. They usually require a muscle or omental flap or occasionally can be treated, if very small, with glue injection into the sidewall of the bronchus. These types of fistulas have significant morbidity. In contrast, alveolar-pleural fistulas almost never require reoperation. Time and patience are usually all that is needed. With patience, almost all of these leaks seal, and even if they do not, the tubes can be removed within a few weeks and the pleural space adhesions will prevent a tension pneumothorax.3

Incidence Alveolar-pleural fistulas are extremely common and are reported to occur in most large series in about 33% of patients after elective pulmonary resection (Brunelli et al, 2004),3-6 depending on how they are defined. Several risk factors have been shown to increase the chance of having an air leak. These include wound healing problems such as steroid use, emphysematous qualities such as a low forced expiratory volume in 1 second (FEV1), and large resections that leave a large pleural space deficit. These concepts are all further expanded in the next section. Many of these patients’ characteristics are also found in those who present with a spontaneous pneumothorax. The principles presented here, which are obtained from randomized trials on patients undergoing

Ch093-F06861.indd 1150

pulmonary resection, are applicable to these patients as well. Both the air leak and the pleural space need to be controlled, but the latter need not be overtreated, as has occurred in the past.

Risk Factors for Air Leaks Brunelli and colleagues (Brunelli et al, 2004)5 performed a retrospective analysis of a prospective database on 588 patients who underwent lobectomy and identified predictors of prolonged air leak. The authors defined prolonged air leak as a leak that persists for longer than 7 days after resection. A low predicted postoperative FEV1, the presence of pleural adhesions, upper lobectomy, and bilobectomy were all identified as factors that increase the risk of a prolonged leak. Bilobectomy (the removal of two lobes on the right side) is an operation that removes a large amount of pulmonary parenchyma and leaves only one lobe in a large pleural space, with little chance of apposition of parietal to visceral pleura. Our prospective randomized trail showed that the creation of a pneumoperitoneum is a safe technique and one that decreases the incidence of air leak in these patients.7 This can be performed on patients with prolonged leaks who have not undergone surgery but have a leak and a basilar pneumothorax. In a separate article, Brunelli and colleagues8 showed in a prospective trial that the creation of a pleural tent, a technique that brings the parietal pleura of the upper chest wall down to the remaining pulmonary parenchyma after upper lobectomy, is another surgical technique that helps reduce the duration of air leaks. This technique addresses upper hemithorax pleural space problems. Both of these techniques highlight the importance of pleural-pleural apposition as a critical component in the sealing of air leaks. However, it is not a necessary component. Some patients have a fixed pleural space deficit. This is defined as a nonresolving pneumothorax in a patient with a fully expanded lung and patent chest tubes that connect the pneumothorax to suction. This space is best left alone and not overtreated. If the patient does not have an air leak, the tubes should be removed, and the space will fill with fluid. The largest series of predictors of air leak was published by our group. It was a retrospective review of an electronic prospective database comprising 688 patients.3 We found that steroids, male gender, a leak with a pneumothorax, and lobectomy were all risks for having a prolonged leak. In that series, we defined a prolonged leak as one that is present on postoperative day 4.

Initial Evaluation of an Air Leak: Is It Real? If confronted with an alveolar-pleural fistula (air leak), the clinician at the bedside must ensure that the leak is real and is not a system leak. All connections between the chest tube and the drainage system should be checked. If the leak is confirmed as coming from inside the patient’s chest and not from the system, it should be classified. Careful observation at the bedside reveals that the natural history of air leaks is based on two main features, the type of air leak (i.e., the qualitative aspect of the system, determined by when the air leak occurs during the respiratory cycle) and the size of the

1/21/2008 2:03:32 PM

Chapter 93 Closed Drainage and Suction Systems

air leak (the quantitative aspect of the classification system). We have developed9 and refined10 a classification system for alveolar-pleural fistulas. It has been formally referred to as the Robert David Cerfolio Classification System for Air Leaks (named in honor of my father, a practicing surgeon), or The RDC System for short. Because it helps guide treatment, it is briefly presented here. This system may be replaced in the near future with a digital air leak score that is less subjective but as yet untested or proven.

Qualitative Aspect of the Classification System There are only four types of air leaks. The largest and most uncommon type of leak is a continuous (C) air leak. These leaks are present throughout the entire respiratory cycle. When the physician asks the patient to breathe in and out, there is continuous bubbling in the air leak chamber. This type of leak is rare and is usually seen only in patients who are on a ventilator or who have a bronchopleural fistula. If the patient is on a ventilator, the bubbling occurs continuously during the inspiratory and expiratory phase of the mechanically delivered breath. The second largest type of air leak, which is also uncommon, is an inspiratory (I) air leak. These leaks are present only during inspiration. They too are almost exclusively seen in ventilated patients who have a sizeable alveolar-pleural fistula or a small bronchopleural fistula. These leaks are most commonly seen in patients with severe emphysema who have developed a spontaneous pneumothorax from a ruptured bleb. The third and fourth types of air leak are much more common than C or I leaks. The third largest leak is called an expiratory (E) air leak. An E leak is present only during expiration (it is also evident during forced expiration). When the physician at the bedside asks the patient to take deep breaths in and out, bubbling is seen in the leak chamber (or in the air leak meter) only during expiration. This type of leak is commonly seen after pulmonary surgery, and it suggests a parenchymal air leak (alveolar-pleural fistula). Finally, if a patient is asked to take deep breaths in and out and no air leak is seen in the leak meter chamber, the patient should then be asked to cough. If a leak is present only with coughing, it is referred to as a forced expiration (FE) leak. FE leaks are also very common. More than 98% of air leaks after elective pulmonary surgery in nonventilated patients are E or FE leaks. As leaks begin to resolve or heal, they usually change from an E leak to an FE leak.

Quantitative Aspect of the Classification System The other feature of air leaks that was critical to the development of the classification system is the size of the air leak. A commercially available air leak meter is contained within the Sahara S1100a Pleur-evac Chest Drainage System (Genzyme Corporation, Fall River, MA). The air leak meter features a chamber in which the leak is measured on a scale from smallest (1) to largest (7). Each chamber has a different size, hence a different resistance. The air leak meter is a reliable and accurate way of quantifying the size of air leaks. The RDC system is simple to use and teach. Air leaks are scored based on qualitative and quantitative criteria. For

Ch093-F06861.indd 1151

1151

example, a leak may be called an expiratory 2 air leak or a forced expiratory 3 air leak, referred to as an E2 or an FE3, respectively. Medical students, residents, and fellows learn this system in 10 to 15 minutes. It facilitates communication among physicians about patients’ air leaks without having to be at the bedside. This information has allowed more efficient chest tube management and contributes to fast-tracking of patients after pulmonary resection, which enables patients to be discharged routinely with a high degree of satisfaction by postoperative day 3 or 4. Armed with this system, we are able to review the most recent literature.

Recent Literature Over the past several years, we and others have studied the problem of alveolar-pleural fistulas (air leaks) using prospective randomized trials or predetermined algorithms in an attempt to bring some science to what has always been a subjective art form. The first prospective study, which was from our group at the University of Alabama at Birmingham (UAB), found that most air leaks occurred during expiration (Cerfolio et al, 1998).9 We also reported in that first study that pulmonary function testing results consistent with emphysema increased the risk of having an air leak after pulmonary resection. Our study showed that placing chest tubes on water seal was not only safe for air leaks but appeared to be superior to suction at stopping leaks. It provided safety data to perform a prospective randomized study. The second study on air leaks was also from UAB. It was a prospective, randomized trial involving 140 patients, 33 of whom had air leaks.10 This study showed that patients who had their tubes placed on water seal instead of wall suction were more likely to have their leaks stopped. Water seal also made air leaks smaller. However, water seal did not stop large expiratory (E) leaks. The classification system for air leaks was further refined and validated with the use of blinded observers. The classification system has become a critical component for the management of chest tubes. It helps guide treatment. For example, if a patient has an E5 leak, the tubes are best left on suction and not placed to water seal because an enlarging pneumothorax is probable. Marshall and associates from The University of Pennsylvania reported, in another prospective randomized study,11 that placing chest tubes on water seal after pulmonary resection shortens the duration of air leaks and decreases the time the chest tubes remain in place. However, Brunelli and colleagues recently published a series12 of selected patients, many of whom had undergone pleural tenting. As described earlier, this technique decreases the incidence and duration of air leaks. The authors did not conclude that water seal was a better chest tube setting than suction, although the advantages of water seal can be seen in their data. However, the authors reported that those patients for whom water seal was used had more complications than those treated with suction. This finding needs to be further explored. Other reports have found that, if patients have large E6 or E7 air leaks on postoperative day 1, they will continue to have an air leak by postoperative day 4 regardless of the chest tube management.3 These patients are discharged home

1/21/2008 2:03:32 PM

1152

Section 4 Pleura

(if otherwise ready for discharge) on a Heimlich valve. Because of the accuracy and reliability of the classification system, these patients can be informed about the need for discharge with an indwelling tube early in their hospital course. This allows the patient, the family, nurses, and physicians to prepare both mentally and physically for discharge to home on a Heimlich valve. Moreover, this information has helped us care for patients with spontaneous pneumothoraces. For a patient who has experienced a first spontaneous pneumothorax, we usually place a chest tube only and observe the patient. But if the air leak is large, E4 or greater, we now know that the natural history of that leak is prolonged. Therefore, we now offer video-assisted thoracoscopic surgery (VATS) early in the hospital stay, instead of waiting for the leak to resolve. In our most recent manuscript on leaks, we showed that water seal is safe for patients who have an air leak and a pneumothorax.13 However, if the leak is large (>E4) or the pneumothorax is large (>8 cm on a measurement scale defined in that paper), the seal is not safe. Many studies have evaluated the efficacy of using pulmonary sealants to prevent leaks.4,14-16 However, the only pulmonary sealant approved by the U.S. Food and Drug Administration (FDA) is no longer commercially available. Several companies are currently in phase II and III studies trying to develop the ideal sealant.

Treatment of Persistent Air Leaks We define a persistent air leak as one that prolongs hospitalization. If, on the third postoperative day, the leak is larger than an FE3, it will not seal overnight. For that reason, the patient’s chest tubes are connected to a Heimlich valve, and the other end of the valve is connected to a urinary leg bag or a compact portable drainage system. A chest roentgenogram is obtained after 24 hours on the Heimlich valve, and if no new subcutaneous emphysema or new or enlarging pneumothorax is seen, the patient is discharged home on postoperative day 4 or 5. If the radiograph identifies a problem, the patient must be returned to water seal or −10 cm H2O of suction, whichever is needed to alleviate the pneumothorax. This process is repeated again in 2 days. If a second pneumothorax occurs, the alternative is to perform a bedside chemical pleurodesis. If a bedside pleurodesis using doxycycline is performed, the tubing cannot be clamped. Tubing should be hung about 6 feet off the ground. An extra length of rubber tubing is often needed to accomplish this height. With this technique, the sclerotic agent is able to stay in the chest while air escapes.

chest tube placement. These adhesions prevent a pneumothorax from developing because the rest of the lung is stuck, even though part of the lung is still leaking. In conclusion, air leaks are a very common clinical problem. The management of tubes and drains and air leak can be studied with randomized trials and objective data. A validated, objective classification system is now available and helps to guide treatment. This system and randomized studies have shown that placing chest tubes to water seal is superior to suction and better helps stop air leaks. However, large leaks (>E4) will probably fail to heal with water seal, and patients may develop a pneumothorax or enlarging subcutaneous emphysema. In these patients, some suction is best. Prolonged air leaks are more common in patients with emphysematous lungs and in those who have undergone pulmonary resections that removed large amounts of lung. A pneumothorax is not an indication for suction. Finally, patients can safely go home with an air leak and with chest tubes. The tubes can be managed on an outpatient and then removed, even if the patient still has an air leak, so long as there is no subcutaneous emphysema or a symptomatic pneumothorax. Further randomized studies are needed.

OUTPATIENT SYSTEMS Because of continued cost constraints, and because patients prefer to be home as opposed to in the hospital, we and others have studied the use of discharging patients who have a persistent small air leak to home with chest tubes in place. In summary, we have demonstrated that this technique is safe and effective when a Heimlich valve is used (Fig. 93-3). We usually apply it in the hospital and observe the patient for at least 6 hours. If the patient tolerates the Heimlich valve without developing a symptomatic pneumothorax or subcutaneous emphysema, discharge home after patient and family education is safe. Neither a pneumothorax nor subcutaneous emphysema occurs unless the air leak is large (greater than an E4 in our classification system). We have shown that the chest tube can be removed in these patients after 2 weeks, almost without exception, even if a leak is still present. Provocative chest tube clamping can be performed, as described earlier, if the leak is worrisome. More recently, we have switched from the Heimlich valve system to a compact, selfcontained device that can be strapped to the belt; it contains fluid and can even apply some suction when patients are home. We have had excellent success with this system. It allows better capturing of the effluent and is more compact, cleaner, and more user-friendly than the Heimlich valve hooked to a Foley bag.

Provocative Chest Tube Clamping While a patient is home with a Heimlich valve, a chest roentgenogram is obtained every week. If the air leak resolves, the tube can be removed. If the air leak is still present after 2 weeks at home on a Heimlich valve, the tubes can still be removed safely. The safety of this method has been demonstrated3 by a technique called provocative chest tube clamping, which was first described by Kirschner.17 The reason it is safe to remove a chest tube despite the presence of a leak is probably that the pleural space develops adhesions as a result of

Ch093-F06861.indd 1152

FIGURE 93-3 Heimlich one-way flutter valve.

1/21/2008 2:03:32 PM

Chapter 93 Closed Drainage and Suction Systems

WHEN TO REMOVE CHEST TUBES Air leaks are not the most common limiting factor that prevents tubes from being removed. Many surgeons use unnecessarily strict criteria for the amount of drainage a tube can have before removing it. Patients often have had chest tubes left in because the drainage was “greater than 150 mL/day” or “greater than 50 mL per shift.” This practice is very common even though there are no data to support it. We have liberalized our criteria over the past several years and have used 450 mL/day as a threshold below which we will remove a tube. We have practiced this way in over 6000 patients and are aware of only 2 patients who have had to return to the hospital because of a pleural effusion. And both of these cases were suspect as the real cause of readmission. Perhaps an even higher number could be used as the accepted threshold; this requires further study. In our experience, a criterion of 450 mL/day as the cutoff point for removal of a tube with no air leak allows patients to leave the hospital safely on postoperative day 3 or 4.

HOW TO REMOVE A CHEST TUBE Before removing a tube, the physician should be certain that it is ready to be taken out. He or she should have seen the chest radiograph, double-checked the character and quantity of the effluent, and ensured there is no chylothorax or any other contraindications to removal. The physician as well as the patient should then be prepared for the procedure. Many patients are quite anxious about tube removal, and they should be reassured and premedicated. Precut tape, a Vaseline gauze, and a small sponge should all be within arm’s reach and ready at the bedside before tube removal. The patient, the proper disposable bags, the surgeon, and the nurse should be comfortable and ready. Interestingly, the ideal way to remove a chest tube has not been well studied. One study evaluated the two most commonly used techniques: (1) asking the patient to take a deep breath and hold it as the tube is removed and the site is covered and taped, and (2) asking the patient to blow out as much air as possible and then hold the breath as the tube is removed. Either technique is safe, but we prefer the former. The technique chosen is not as important as the way in which it is done and the preparation. Finally, the amount of tape used over the tube insertion site should be minimized and should be a little more than the skin puncture. It should not be placed over the skin closure of the thoracotomy.

SUMMARY Although the insertion, management, and removal of chest tubes are often delegated to junior residents, these procedures should not be taken lightly. The art of bedside chest tube insertion is not easily mastered. The management of tubes needs to be based on daily observations at the bedside and should take into account patient characteristics and the operation performed. With diligent care and the application of scientific data gathered from prospective randomized studies, surgeons can have a uniform plan. This will lead to outstanding patient results and satisfaction.

Ch093-F06861.indd 1153

1153

COMMENTS AND CONTROVERSIES Tube thoracostomy is often considered a minor surgical procedure. It can, however, result in considerable morbidity if the operator does not have intimate knowledge of chest wall and pleural space anatomy, a clear understanding of the technique to be used, and, most importantly, the experience to safely carry out the procedure. Whether all chest tubes should be inserted by thoracic surgeons remains a controversial and practical issue, not only because most hospitals do not have thoracic surgeons on hand but also because most general surgeons and even radiologists and intensivists are now well trained in pleural space drainage techniques. In addition, the availability of user-friendly “disposable drainage kits” has made the procedure somewhat easier and safer, especially if one is dealing with a free pleural space. In all cases, the exact site of the collection (air or fluid) being drained should be well documented through the use of imaging modalities. As discussed by Dr. Cerfolio, it is also most important that patients be well informed about the technique because fearful and anxious patients can immensely complicate the procedure. The ideal site of insertion is almost always the third or fourth intercostal space in the anterior or midaxillary line, immediately behind the pectoralis fold (thinner part of the chest wall). Anterior insertion (second space, midclavicular line) is no longer used because it necessitates dissection through the pectoralis major muscle, which may be painful and cause hemorrhage and may leave a highly visible scar. The tube insertion technique is well described in this chapter, and I would only re-emphasize the importance of entering the pleural space with a blunt instrument rather than using the trocar method with its inherent risk of injury to the underlying lung or other intrathoracic structures. Chest tubes can be removed when drainage is minimal—the exact amount is controversial (100-400 mL/24 hr)— and the air leak has stopped for 24 hours. Many surgeons favor clamping the tube for 12 to 24 hours before removal, especially if the air leak has been persistent for several days or is still questionable. To seal the thoracostomy incision at the time of removal, we prefer tying down a U stitch placed at the time of tube insertion. Surgical emphysema sometimes develops after tube insertion or during the following days. It is always secondary to improper drainage of the pleural space because air exits in the subcutaneous tissues through the perforated pleura at the site of thoracostomy rather than through the tube itself. Common causes include improper location of the tube, occlusion or kinking of the tube or connecting tubes, accidental tube pullback in the soft tissues of the chest wall, or a large air leak inadequately absorbed by the drainage unit. If surgical emphysema occurs, the drainage system and thoracostomy site should be carefully checked. If the whole system is air-tight and the tube is functioning well, the level of suction can be increased. If this does not solve the problem, the tube can be pulled back 2 to 3 cm or another tube inserted. Despite the claims of many manufacturers, no currently available system is perfect or has complete versatility to be adapted to every pathologic condition of the pleural space. Overall, drainage systems must be able to evacuate air or fluid completely from the pleural cavity, collapse and obliterate residual spaces, and ensure complete re-expansion of the lung. Their design must be straightforward so that their functioning can be thoroughly understood by the entire team. Disposable “dry systems” are currently used in most institutions. These units are compact, light, and easy to assemble and

1/21/2008 2:03:33 PM

1154

Section 4 Pleura

operate. Outpatient management of patients with spontaneous pneumothorax or even prolonged postresectional air leak appears safe, efficient, and economical. J. D.

Cerfolio RJ: Recent advances in the treatment of air leaks. Curr Opin Pulm Med 11:319-323, 2005. Cerfolio RJ, Tummala RP, Holman WL, et al: A prospective algorithm for the management of air leaks after pulmonary resection. Ann Thorac Surg 66:1726-1731, 1998.

KEY REFERENCES Brunelli A, Monteverde M, Borri A, et al: Predictors of prolonged air leak after pulmonary lobectomy. Ann Thorac Surg 77:1205-1210, 2004.

Ch093-F06861.indd 1154

1/21/2008 2:03:33 PM

chapter

94

OPEN DRAINAGE OF THORACIC INFECTIONS Nirmal K. Veeramachaneni Richard J. Battafarano

Key Points ■ Most pleural infections are successfully treated with closed chest

tube drainage or by surgical decortication. ■ Patients who have localized infection not adequately treated by

insertion of a chest tube and who are too infirm for a more extensive surgical decortication are best treated with an open drainage procedure. ■ Open drainage allows for durable treatment of localized infection with minimal morbidity. ■ Tissue transposition techniques may be used to close the open drainage cavity once the infection is controlled.

Open drainage of established pleural space infections has been described since the time of Hippocrates. It is only in the past 100 years, with the advent of radiographic imaging and antibiotic therapy, that open drainage has become an infrequent tool in the thoracic surgeon’s armamentarium. Most pleural infections are successfully treated with closed suction drainage. In the presence of entrapped lung or multiloculated collection in a patient who is physiologically capable of tolerating an extended thoracotomy, decortication and removal of pleural peel is indicated. However, a small fraction of patients present with chronic empyema and are unable to tolerate extensive thoracotomy. These patients are the optimal candidates for open drainage. Historically, use of open drainage led to unacceptably high mortality rates. It was not until World War I that open drainage early in the course of an empyema was abandoned due to recognition of the hemodynamic consequences of the resulting pneumothorax. The indications for open drainage are as follows: ■ ■

■

■

Open drainage is typically reserved for high-risk patients who may not tolerate more aggressive interventions. The empyema must be localized and the underlying lung be not likely to re-expand with tube thoracostomy or decortication. This may be the result of parenchymal destruction or chronic fibrosis of the underlying lung. Surrounding lung tissue must be well adhered to the surrounding chest wall to prevent complications of open pneumothorax. Postpneumonectomy empyema with or without bronchopleural fistula is particularly amenable to open drainage. Definitive closure of the chest may be performed later, once the infection is controlled and the fistulas have healed.

Computed tomographic (CT) scanning is essential to adequately define the extent of disease, to demonstrate loculations, and to determine the optimal location of the incision. Thickened pleura is noted in most empyemas.1 CT scanning is especially useful in determining the extent of lung parenchymal injury because it can readily differentiate compression or consolidation of adjacent lung tissue from true destruction of the surrounding lung parenchyma. Additionally, careful review of the CT images allows placement of the open drainage incision in a location that will preserve musculocutaneous flaps that may be used for subsequent reconstruction. The original concept, described by Leo Eloesser in his 1935 paper, presented a means of draining acute tuberculous empyema with avoidance of extensive thoracoplasty or closed drainage, which were associated with secondary infection and increased mortality in the preantibiotic era2 (Fig. 94-1). In the original description, a small, U-shaped incision, 2 inches wide and 2.5 inches long, was made over the most dependent portion of the abscess cavity. The chest was entered, and the purulent material was drained after resection of a short segment of rib underlying the flap. The resulting skin flap was then sutured into the chest cavity to prevent the closure of the incision. The lateral edges of the defect were reapproximated with suture to create a one-way valve that allowed egress of air and purulent material while preventing a pneumothorax. The present-day modification of the Eloesser flap maintains the concept of epithelialization of the wound edge to prevent premature closure. This is the only concept true to the original description. A number of incisions have been described, including an inverted U-shaped incision and an Hshaped incision over the most dependent portion of the site of infection. The incision needs to be long enough to permit dressing changes by the caregiver, and a portion of at least two ribs is resected to facilitate drainage and to prevent premature closure. Marsupialization of the open drainage site is accomplished by suturing the skin to the parietal pleural edge with absorbable suture (Fig. 94-2). Because open drainage is performed for localized infection in the setting of chronic empyema, the complication of a pneumothorax is not expected. The cavity may then undergo frequent dressing changes. Over the course of weeks and months, the chronically infected parietal pleural surface is replaced with healthy epithelial tissue. Contraction of the cavity occurs over time and is limited by the rigidity of the bony thorax and the mobility of the surrounding mediastinal structures and lung. In the largest studies of open drainage procedures, the most common indications for the procedure were parapneu1155

Ch094-F06861.indd 1155

1/21/2008 2:04:17 PM

1156

Section 4 Pleura

FIGURE 94-1 A-C, The original Eloesser flap provided a means to drain acute tuberculous empyema. The incision was limited, and a one-way valve was created to permit drainage while preventing a pneumothorax. (FROM ELOEESER LA: AN OPERATION FOR TUBERCULOUS EMPYEMA. SURG GYNECOL OBSTET 60:1096, 1935.)

Ribs resected

Completed procedure with tongue flap sewn down Tongue flap

FIGURE 94-2 The area over the chronic empyema is identified, and an inverted U incision is made. After a flap of soft tissue is created, the underlying ribs are resected and the flap is sewn to the edge of the empyema cavity. Some authors do not create a flap of tissue. Instead, a wide incision is made and the underlying ribs are resected. The skin edge is then sutured to the underlying parietal pleura in a circumferential manner to marsupialize the incision. (ADAPTED FROM THOURANI VH, LANCASTER RT, MANSOUR KA, MILLER JI JR: TWENTY-SIX YEARS OF EXPERIENCE WITH THE MODIFIED ELOESSER FLAP. ANN THORAC SURG 76:401-405, 2003.)

monic effusions and postresection empyema (Fig. 94-3). Open drainage was successful in controlling infection in all patients and was associated with minimal morbidity.3 In a selected patient population, muscle flap coverage may be used to fill the cavity once the infection is controlled and there is evidence of granulation in the wound bed.4 Muscle flap closure was performed approximately 3 months after the original drainage procedure, and in one study it resulted in closure of the cavity within 30 days of the muscle transfer. In the larger series employing this technique, latissimus dorsi, trapezius, and pectoralis major muscles were the most frequently utilized muscle flaps for closure.5 When choosing the appropriate flap, the surgeon must consider the route of entry into the chest and the vascular pedicle of the transposed flap. A separate incision may be required in some instances, and prior incisions may preclude the use of some flaps. For

Ch094-F06861.indd 1156

example, a standard posterolateral thoracotomy in which the latissimus dorsi muscle is divided often prevents its subsequent use as a muscle flap for closure. In the special instance of postpneumonectomy empyema, the treatment has evolved into open pleural drainage of the pneumonectomy cavity, followed by closure of the cavity once the infection has been controlled (typically 1-2 months after the initial procedure); an antibiotic solution is used to obliterate the sterile cavity at the time of closure (Fig. 94-4). Clagett and associates first described this technique in the early 1960s. Since the original description, a number of investigators have demonstrated the efficacy of this technique.6 The most common causes of failure of this technique is the presence of a bronchopleural fistula, which provides a source of continuous contamination. This is best treated by closure of the fistula, if it can be identified, and muscle transposition

1/21/2008 2:04:18 PM

Chapter 94 Open Drainage of Thoracic Infections

A

1157

B

FIGURE 94-3 Radiograph (A) and CT (B) of a 53-year-old man with locally advanced lung cancer of the right lung who was treated with definitive chemoradiation therapy. Months after the completion of treatment, the patient developed a cavitary pneumonia in the anterior portion of the right upper lobe. In an effort to control the infectious process, the patient underwent open drainage.

FIGURE 94-4 Open drainage was done by creating an incision over the 3rd rib. Ribs 2 and 3 were then resected, and the skin edges were reapproximated to the thickened pleura circumferentially. The patient tolerated the procedure well and was managed by serial dressing changes.

to cover the site of the fistula in the initial phase of the Clagett procedure (Fig. 94-5). In their report of 28 patients treated with this technique, Pairolero and colleagues reported an 85% incidence of successful closure of the bronchopleural fistula.7 Furthermore, these investigators used muscle transposition if the empyema occurred early after pneumonectomy, or if the bronchial stump was not well incorporated into surrounding tissue. More recently, other investigators

Ch094-F06861.indd 1157

reported similar success.8,9 In both of these large series, a number of patients were treated by open drainage alone. This resulted in control of the infection, but, because of tumor recurrence, comorbidities, or patient choice, additional steps to close the window or place a muscle flap were not done. This finding illustrates the durability of open drainage alone. As an alternative means of controlling the infection and permitting expedited definitive closure of the chest, some authors have advocated frequent reopening of the incision and débridements in the operating room. Schneiter and colleagues reported a strategy of every-other-day operative débridements until the chest was macroscopically clean. This strategy avoids the need for prolonged dressing changes and a prolonged open wound but requires multiple operative procedures under general anesthesia. Such an aggressive strategy may not be applicable to all patients who require open drainage because these patients may not have the physiologic reserve to tolerate multiple operative procedures.10

COMMENTS AND CONTROVERSIES In 1935, Eloesser described a technique of open drainage that was designed to act as a tubeless one-way valve to drain chronic pleural, often tuberculous, effusions. The only aspect of Eloesser’s operation that still applies today is the concept of providing adequate drainage of an empyema cavity with an epithelialized stoma. It is a valuable option for treating patients with chronic empyemas when long-term or permanent drainage is indicated or seems necessary and for the drainage of postpneumonectomy empyemas. It can also be of value for patients who do not understand or will not cooperate and have a large cavity and for patients who are waiting for a more radical

1/21/2008 2:04:18 PM

1158

Section 4 Pleura

FIGURE 94-5 Latissimus dorsi, serratus anterior, pectoralis major, anterior rectus, and omentum flaps have been described. These photographs depict latissimus dorsi flap creation, with preservation of the thoracodorsal artery pedicle. (PHOTOGRAPHS COURTESY OF TERENCE M. MYCKATYN, MD.)

procedure and may need a period of rehabilitation and correction of nutritional deficiencies. Although creation of an open thoracic window is usually performed under general anesthesia, some surgeons believe that local anesthesia is as well suited, if not better suited, for these patients (often elderly) who are in poor general condition. As indicated by the authors, the site of incision must be planned carefully by review of CT scans and ultrasonographic examinations. It is also important to make the open window in an area that will be comfortable for the patient, where dressing changes can easily be carried out, and where it is not likely to interfere with subsequent procedures. In time, some of these thoracic windows become obliterated, leaving only an indentation over the chest wall. In most patients, however, the cavity is too large to expect spontaneous obliteration, and surgical closure must be performed at a later stage. On occasion, patients live with an open thoracic window for several years or even for the rest of their lives. These patients have adjusted

Ch094-F06861.indd 1158

to a lifestyle of daily dressing changes that often are performed by the spouse, who becomes an important participant in their management. J. D.

KEY REFERENCES Deschamps C, Allen MS, Trastek VF, Pairolero PC: Empyema following pulmonary resection. Chest Surg Clin North Am 4:583-592, 1994. Hurvitz RJ, Tucker BL: The Eloesser flap: Past and present. J Thorac Cardiovasc Surg 92:958-961, 1986. Magovern CJ, Rusch VW: Parapneumonic and post-traumatic pleural space infections. Chest Surg Clin North Am 4:561-582, 1994. Miller JI Jr: The history of surgery of empyema, thoracoplasty, Eloesser flap, and muscle flap transposition. Chest Surg Clin North Am 10:4553, viii, 2000.

1/21/2008 2:04:19 PM

chapter

THORACOPLASTY

95

Jean Deslauriers Jocelyn Grégoire

Key Points ■ Current indications for thoracoplasties include postpneumonec-

tomy empyemas and injected apical spaces. thoracoplasties are performed through a standard posterolateral thoracotomy, which can be extended upward, if necessary. An axillary incision can be used for limited thoracoplasty. Preservation of the first rib is important to maintain the integrity of the neck and shoulder girdle. The second to the eighth ribs are usually resected in an extramusculoperiosteal fashion. Apicolysis is a most important step of the operation. Successful obliteration of the space can be obtained in 80% to 90% of patients.

■ Most

■ ■ ■ ■ ■

Thoracoplasty is a surgical procedure that was originally designed to permanently collapse the cavities of pulmonary tuberculosis by removing the ribs from the chest wall. Until supplanted by effective chemotherapy, it was one of several methods used to put the lung to rest, with the hope of inactivating the disease. Other methods, such as artificial pneumothoraces, intercostal neurectomy, scalenotomy, and phrenic nerve interruption, were also used with variable results for the same purpose. Thoracoplasty is currently being used for the treatment of chronic pleural space infection when the lung cannot be expanded. Since the early 1960s, however, it has lost much of its popularity, not only because it is considered to be a mutilating procedure, but also because of the advent of better techniques of muscle transfer to fill infected spaces. Despite this “bad press,” there remain a few patients with chronic empyema who have no remaining lung or a lung that cannot be expanded because of intrinsic disease, who are potential candidates for thoracoplasty. In this chapter, we describe the important technical points to consider in performing a thoracoplasty. We also attempt to define the role of this procedure in the context of contemporary thoracic surgery.

HISTORICAL NOTE Estlander (1879) was the first surgeon to use the term thoracoplasty to denote removal of ribs for the purpose of bringing the chest wall down to the lung.1 In 1885, de Cerenville of Lausanne also described a technique in which short segments of two or more ribs were resected with the goal of

collapsing the chest wall over areas of apical cavitary tuberculosis. The thoracoplasty described by Schede in 1890 was an operation that included not only multiple rib resections but also the removal of the periosteum, intercostal muscles and nerves, and parietal pleura. In 1896, Paget2 provided a description of the technique of thoracoplasty as described by Schede at the medical conference in Vienna in 1890: Using a large U-shaped incision carried to rib level, a flap of skin and extracostal soft tissue is created and raised. All the ribs over the cavity are resected subperiosteally, from a point a little beyond their angles posteriorly to the costochondral junction anteriorly. The ribs are divided at about their midpoint with bone forceps. The cut ends are drawn apart and broken up. Anteriorly, they break at the costochondral junction, and posteriorly, they always break at or close to the tubercule. According to Kergin,3 the Schede thoracoplasty was formulated on the basis of accurate knowledge of the pathology of chronic empyema, but it had serious disadvantages: It was shocking and mutilating; it involved the resection of intercostal nerves with resulting cutaneous anesthesia; and it left a large open wound, which required a long period of packing and dressing. In 1907, Friedrich, following the suggestion of Rudolph Brauer (an internist) that thoracoplasty must collapse the diseased lung,1 resected full lengths of the second to the ninth ribs with an operative mortality of 43% (four of seven patients survived the operation). Subsequently, Wilms (1913) and Sauerbruch (1925) resected the posterior segments of the first 11 ribs during an operation that became known as the paravertebral thoracoplasty. They pointed out that resection of the posterior ribs would bring about a greater collapse of the underlying lung than would resection of the more anterior segments. All of these procedures evolved into the classic three-stage thoracoplasty popularized in 1925 by John Alexander (1925, 1937), which involved resecting the posterior segments of the ribs and sometimes portions of the transverse processes, but leaving the periosteum, to ensure that new bone formation would maintain long-term collapse of the lung. The following outline of the first stage of Alexander’s thoracoplasty (1937) was given by Langston2: A periscapular incision permitted elevation of the scapula. The upper digitations of the serratus anterior muscle were separated. The third and second ribs 1159

Ch095-F06861.indd 1159

1/21/2008 2:08:41 PM

1160

Section 4 Pleura

were resected subperiosteally from the level of the transverse process to approximately the mid and anterior axillary lines, respectively. The first rib and its cartilage was resected, along with the tip of the transverse process, to the sternum. The second and third transverse processes with the underlying rib were resected to the level of the lamina of the vertebra. The periosteal beds were dried and rubbed with 10% formalin to delay regeneration. The wound was closed without drainage. The second and third stages followed at 3-week intervals. Using this technique, Alexander was able to achieve cavity closure in 93% of survivors, with an operative mortality rate of 10%. In 1934, Semb described an important addition to the technique of thoracoplasty, which he called extrafascial apicolysis.4 His method consisted of extrapleural division of all adhesions between the pleural dome at the apex and the soft tissues around the base of the neck and cervical spine. This dissection, carried out outside the plane of the endothoracic fascia, provided more complete collapse of the lung without requiring resection of the transverse processes of the vertebrae. Because conventional thoracoplasty was considered cosmetically unacceptable, other surgeons described plombage thoracoplasty, introduced by Tuffier in 1891 as a method of extrapleural pneumolysis. By means of this procedure, air was insufflated extrapleurally to maintain lung collapse. Subsequent variations included the use of omentum5 or paraffin extrapleurally or of other products, such as Lucite balls, between the freed periosteum and the ribs. In contemporary thoracic surgery, thoracoplasty is seldom used; indeed, most young surgeons have never seen a single case, let alone performed the procedure.

Tuffier T: État actuel de la chirurgie intrathoracique. Paris, Masson, 1914, pp 90, 163. Wilms M: Die pfeilerresektion der Rippen Zur Verengerung des thorax bei lungentuberculose. Ther Gegenhwart 54:17, 1913. Young WG, Moor GF: The surgical treatment of pulmonary tuberculosis. In Sabiston DC, Spencer FC (eds): Gibbon’s Surgery of the Chest, 3rd ed. Philadelphia, WB Saunders, 1976, p 567.

BASIC SCIENCE Although the techniques of thoracoplasty in current use are numerous and varied in their details (Peppas et al, 1993,6 the principles involved in the operation remain as described by Alexander7: 1. There is a better chance that thoracoplasty will be successful in patients whose empyema is not postresectional. 2. A tailoring thoracoplasty performed concomitantly with pulmonary resection has a high likelihood of failure because of poor chest wall mechanics during the postoperative period. 3. The chances for a successful response to thoracoplasty are characteristically increased if the procedure is preceded by large open-window drainage for which the tube has been inserted through a hole created by resection of a portion of rib. 4. It is especially critical that the first rib be resected for apical space obliteration, as well as a portion of the transverse process if the space is posterior. 5. Preoperative preparation is especially important, including complete control of tuberculous infection and the use of at least one additional antitubercle drug to cover potential activation during the surgical procedure. 6. Thoracoplasty of any type is not used in so-called undefined desperation cases in which uncontrolled sepsis is present, cancer persists, or unidentified sites of hemorrhage exist.

HISTORICAL READINGS Alexander J: The Surgery of Pulmonary Tuberculosis. Philadelphia, Lea & Febiger, 1925. Alexander J: The Collapse Therapy of Pulmonary Tuberculosis. Springfield, IL, Charles C Thomas, 1937. de Cerenville EB: De l’intervention dans les maladies du poumon. Rev Med Suisse Normande 5:441, 1885. Estlander JA: Résection des côtes dans l’empyème chronique. Rev Med Chir (Paris) 3:157, 1879. Friedrich PL: Die operative beeinflubsung einseitiger lungphtliser lurch totale brustwandmobilisierung. Arch Klin Chir 27:588, 1908. Kergin FG: An operation for chronic pleural empyema. J Thorac Surg 26:430, 1953. Langston HT: Thoracoplasty: The how and why. Ann Thorac Surg 52:1351, 1991. Paget S: The Surgery of the Chest. Bristol, England, John Wright and Co, 1896. (As reproduced for Classics of Surgery by Grypron Editions, Birmingham, England, 1990, pp 275-279.) Sauerbruch E: Die chirurgie der brustorgane, Vol 12. Berlin, SpringerVerlag, 1925, p 876. Schede M: Die behandlung der empyeme. Verh Long Innere Med Wiesbaden 9:41, 1890. Semb C: Technique of plastic operation of apicolysis. Acta Chir Scand 74:478, 1934.

Ch095-F06861.indd 1160

TYPES OF THORACOPLASTY The various types of thoracoplasty are shown in Table 95-1. A thoracoplasty is total if the posterior segments of the first 11 ribs are removed and partial if only 8 or 9 ribs are resected. An extended thoracoplasty removes, in addition to the posterior segments of the ribs, the anterior extremities of the upper ribs.8 Most thoracoplasties are done subperiosteally because the ribs can regenerate if the periosteum is left in place. When both rib and periosteum are removed, the procedure is called an extraperiosteal thoracoplasty. A pedicled myoplasty may be added to the thoracoplasty (thoracomyoplasty) if the space to be obliterated is large or if it appears that an associated bronchopleural fistula is unlikely to close with collapse alone.9-11

Intrapleural Thoracoplasty As described by Schede in 1890, intrapleural thoracoplasty involves multiple rib excisions as well as resection of the parietal pleura, periosteum, intercostal muscles, and intercostal neurovascular bundles. Only the skin and thoracic muscles remain to collapse over the residual lung or space; a large

1/21/2008 2:08:41 PM

Chapter 95 Thoracoplasty

open wound is left, with packing required to fill the space. To prevent bleeding from the posterior intercostal arteries, Schede compressed each vessel between “thumb and forefinger first” before cutting and ligating it afterward.2 The Schede thoracoplasty was performed mostly in those patients in whom the walls of the space were so thick that rib resection alone would be insufficient to appropriately collapse the cavity. The procedure, which is no longer done, was considered a mutilating operation; this was further compounded by severe cutaneous anesthesia and abdominal wall

TABLE 95-1 Types of Thoracoplasty Authors (Year)

Description

Intrapleural Thoracoplasty Schede (1890) Resection of ribs, parietal pleura, intercostal muscles, and neurovascular bundles Heller13 (1934) Preservation of intercostal muscles Excision of parietal pleura and fibrous Kergin3 (1953) tissue from intercostal muscles Horrigan and Snow Limited rib resection (1990) Extrapleural Thoracoplasty Alexander (1937) Resection of ribs but retention of periosteum, intercostal muscles, and parietal pleura Semb17 (1935) Extrafascial pneumolysis Björk18 (1954) Osteoplastic thoracoplasty Plombage Thoracoplasty Tuffier5 (1891) Modern version (19491950): Andrews’ thoracomyoplasty29 (1961), Sawamura’s technique28 (1985)

Extrapleural plombage Extrafascial and extraperiosteal plombage

Limited and Tailoring Thoracoplasties

1161

paresis, which eventually led to chest wall instability, paradoxical respiration, and even cardiac exposure in some instances (Barker, 1994).12 Modifications of the technique were therefore proposed by Heller13 and Wangensteen.14 These surgeons described an operation in which, after removal of the ribs overlying the cavity, the rib beds were incised to create a series of ribbons, each consisting of an intercostal muscle with the accompanying vessels, nerve, parietal pleura, and fibrous tissue.3 These ribbons were dropped into the cavity to act as space fillers. Grow15 and Kergin3 described an operation by which the parietal pleura and fibrous tissue was excised from those ribbons so that they became more flexible in adapting to all corners of the empyema cavity (Fig. 95-1). The main advantages of the Kergin thoracoplasty were that the intercostal nerves were preserved and the ribs were able to regenerate, thereby giving stability to the chest wall. In addition, the space was filled with living tissue with an excellent vascular supply. Horrigan and Snow16 used a similar technique but confined the rib removal below the third rib to the more posterior aspect of the chest. They used adjacent trapezius, latissimus, serratus, or rhomboid muscle to reinforce the fistula closure and fill the space. The results were good, and severe deformity was avoided in most patients.

Extrapleural Thoracoplasty The extrapleural thoracoplasty was popularized by Alexander as a procedure that retained the periosteum of the ribs, the intercostal muscles, and the parietal pleura. It provided lateral collapse of the lung. Because the apex is often held up at the level of the cervical spine by strong muscular and fibrous bands, Semb17 proposed the operation of extrafascial apicolysis, by which vertical relaxation was obtained to complement lateral relaxation. The difficulty inherent in this technique is that the fibrous bands that must be divided to free the apex often surround the subclavian artery and vein, along with the lower trunk of the brachial plexus.

FIGURE 95-1 After resection of the parietal wall, the muscle bundles are laid in the cavity. (FROM KERGIN FG: AN OPERATION FOR CHRONIC PLEURAL EMPYEMA. J THORAC SURG 26:430, 1953.)

Ch095-F06861.indd 1161

1/21/2008 2:08:42 PM

1162

Section 4 Pleura

In 1954, Björk described his osteoplastic technique of thoracoplasty, whereby a new roof of the thorax was obtained by resection of posterior portions of the ribs in increasing lengths from above downward.18 The ribs were then bent into the costal cartilages and fixed to the posterior end of the uppermost intact rib with stainless steel sutures (Fig. 95-2). With this technique, a stable chest wall was obtained, and the lung was prevented from re-expanding above the new roof. A similar technique was described by Barclay and Welch.19

Plombage Thoracoplasty Plombage thoracoplasty was initiated in 1891 by Tuffier, who described the merits of performing and maintaining an extrapleural pneumothorax to collapse the lung.5 The method was simple, and initially Tuffier left the extrapleural space empty. He later inserted air, omentum, or “fresh lipomas” for this purpose.20 However, material placed in this plane often eroded into the underlying lung parenchyma and either was expectorated or created a bronchopleurocutaneous fistula. In the late 1940s and early 1950s, several articles appeared reporting the same operation but with an extrafascial (outside the endothoracic fascia) and extraperiosteal, rather than an extrapleural, pneumothorax. Initially, the collapse was maintained by paraffin (paraffin plombage thoracoplasty), which

was associated with an infection rate of 15% and an extrusion rate of 30% (Barker, 1994).12 Subsequently, at least 29 different materials were used to maintain collapse of affected areas of the lung, including gauze sponge, silk, wax, various oils and gelatin, rubber balloons, drawing crayons, and lead bullets.20,21 These products were inserted between the endothoracic fascia and periosteum on one side and the ribs on the other. In 1946, Wilson reported his experience using balls made of polymethyl-methacrylate (Lucite) for plombage22 (Fig. 95-3). These plombage operations had the advantage of providing good selective collapse without paradoxical respiration but the disadvantage of making the patient more prone to infection. Advantages of the Lucite balls over other products included the fact that they were relatively nonirritating and were of light weight and radiolucent.23 Plombage is no longer used by thoracic surgeons, and the last report appears to be the one by Mayer and associates,24 who described the use of a silicone mammary prosthesis in a patient with hemoptysis and tuberculosis. In recent years, several articles have reported late complications occasionally seen after plombage thoracoplasty.20,25-27 In 1985, Iioka and colleagues28 described a technique whereby the parietal pleura, periosteum, and intercostal muscles were collapsed without rib resection (technique of Sawamura), thereby obliterating the empyema cavity. This collapse created an extraperiosteal space, which filled with the patient’s own blood and serum. Ultimately, this exudate,

2

4

6

8

10 12

FIGURE 95-2 The posterior ends of the upper five ribs are resected in increasing lengths. (FROM BJÖRK VO: THORACOPLASTY: A NEW OSTEOPLASTIC TECHNIQUE. J THORAC SURG 28:194, 1954.)

Ch095-F06861.indd 1162

FIGURE 95-3 Plombage thoracoplasty with Lucite balls. No ribs have been resected.

1/21/2008 2:08:42 PM

Chapter 95 Thoracoplasty

which served as an extraperiosteal filler, was reabsorbed. The authors reported a good result in 60 of 65 patients treated with this technique. They recommended that the procedure be reserved for individuals who, because of their general condition, could not sustain a more formidable decortication or extended thoracoplasty. They also noted that their tech-

1163

nique tends to better preserve pulmonary function and precludes deformity. Thoracomyoplasty was described by Andrews in 1961 as a method for treating tuberculous empyemas often complicated by bronchopleural fistula.29 The technique involved the following steps (Fig. 95-4):

A

B

C

D

E

FIGURE 95-4 Andrews’ thoracomyopleuroplasty. A, The ribs over the cavity are resected. B, The cavity is entered through a costal bed and curetted. C, Curettage of the visceral and mediastinal pleura is performed. D, A U-type stitch is used to obliterate the cavity. E, All stitches are tied up. (FROM ANDREWS NC: THORACO-MEDIASTINAL PLICATURE: A SURGICAL TECHNIQUE FOR CHRONIC EMPYEMA. J THORAC SURG 41:806, 1961.)

Ch095-F06861.indd 1163

1/21/2008 2:08:44 PM

1164

Section 4 Pleura

TABLE 95-2 Results of Andrews Thoracomyopleuroplasty Outcome Author (Year)

No. Patients

No. Operative Deaths (%)

Immediate Cure

Late Cure

Failure

Andrews29 (1961)

35

1 (3%)

28

5

1

73

4 (5.4%)

58

9

2

29

1 (3.5%)

21

4

3

40

Cornet et al

(1980)

Icard et al41 (1999)

1. Rib resection over the empyema space, strictly adjusted to the size of the cavity without resection of the head and neck of the rib or the transverse process of the spine 2. Opening of the cavity through an incision overlying a rib bed 3. Evacuation of the contents of the space and cartilage of the parietal wall until it becomes pliable and can be collapsed over the peel covering the lung or mediastinum 4. Placement of the pleuromusculoperiosteal flap in juxtaposition to the lung (which is secured with absorbable sutures to obliterate the space) Associated bronchopleural fistulas were separately closed by means of primary suturing or by covering the site of the fistula with an intercostal muscle that had been freed from the parietal wall. The subscapular extramusculoperiosteal space was drained temporarily, but the drains were removed as soon as possible. No chest drain was left inside the collapsed chest wall. The results of this procedure are presented in Table 95-2.

Limited and Tailoring Thoracoplasties A limited thoracoplasty is a procedure that is restricted to the removal of only a few ribs for the purpose of eliminating an infected space. A limited tailored thoracoplasty or tailoring thoracoplasty is done in association with a pulmonary resection in which a space problem is anticipated. In 1959, Melloy and coworkers30 reported the effectiveness of preresection upper rib limited thoracoplasty in reducing the overall incidence of postresection empyema. According to Barker (Barker, 1994),12 preresection tailoring thoracoplasty is seldom indicated in contemporary thoracic surgery and is used only for patients in whom it is believed, after careful evaluation, that the amount of lung left after resection would be too small to fill the space. Even under those circumstances, reduction of pleural space boundaries by means of simple maneuvers such as pleural tent or pneumoperitoneum is almost always sufficient to prevent postoperative spaces. These procedures can be done at the time of resection, and they are not associated with paradoxical respiration. Therapeutic pneumoperitoneum can also be initiated postoperatively if a residual space is likely to become infected.

INDICATIONS FOR THORACOPLASTY Despite the decline in the popularity of thoracoplasty, four recent studies have shown that it is an excellent therapeutic option for selected patients. In the series of Hopkins and

Ch095-F06861.indd 1164

TABLE 95-3 Current Indications for Thoracoplasty Persistent space after lung resection or other thoracic procedures Infected apical space after upper or upper and middle lobectomies Postpneumonectomy empyema Unresolving chronic empyema unrelated to resection Apical empyema Empyema in a space after previous therapeutic pneumothorax Pleural aspergillosis Tailoring thoracoplasty done before or concomitantly with lung resection

associates (1985), 30 patients were treated with thoracoplasty over a 14-year period (Hopkins et al, 1985).31 The surgery was performed to close a persistent pleural space in 28 patients, and to adapt the thoracic cavity for diminished lung volume concomitantly with pulmonary resection in the other 2 patients. Among the 28 patients with persistent infected spaces, 24 had an associated bronchopleural fistula, and in 19 infection had occurred after an operation. In our own series, 17 patients underwent thoracoplasty for a postpneumonectomy empyema, and 7 had an associated bronchopleural fistula.32 In 1990, Horrigan and Snow16 reported on a series of 13 patients who underwent thoracoplasty between 1976 and 1989. Five of these patients had chronic apical empyema spaces without prior resection of lung, and all had extensive destruction of upper lobe tissue. Eight patients had undergone prior pulmonary resection and had infected postoperative residual spaces. In the series of Peppas and colleagues (1993), 19 patients underwent the operation to control complications of resection for lung cancer, and 18 patients had the operation during the course of management of disease not related to lung cancer (Peppas et al, 1993).6 Current indications for thoracoplasty are summarized in Table 95-3. It is worth noting that, contrary to what can be achieved with infected apical spaces, thoracoplasty is almost never indicated for the treatment of basal spaces such as those sometimes seen after right and middle lower lobectomies. These lower spaces are better managed with open thoracic window drainage or by filling of the space with muscle flaps. In patients with postpneumonectomy empyema, thoracoplasty presents specific advantages over space-filling or space-sterilization methods,33 and treatment failures are uncommon.32 In nonresectional apical empyemas with destroyed upper lobes, or in an empyema that has developed in an apical space after previous therapeutic pneumothorax, decortication is inadvisable and almost inevitably results in failure because of the underlying lung disease (see Chapter

1/21/2008 2:08:45 PM

Chapter 95 Thoracoplasty

1165

FIGURE 95-5 A, Standard posteroanterior chest radiograph of a 60-year-old man with bilateral aspergillomas and massive hemoptysis. B, After left upper lobectomy and apical segmental resection of the lower lobe, the patient had a residual apical space with positive culture for aspergillosis (pleural aspergillosis). C, Standard posteroanterior chest radiograph after axillary thoracoplasty shows complete obliteration of the space.

96). In these situations, thoracoplasty may be indicated to collapse the space. Thoracoplasty may also be indicated in the management of complicated pleuropulmonary aspergillosis34 (Fig. 95-5). Finally, tailoring thoracoplasty may be indicated after pulmonary resection if it appears that the remaining lobe or lobes will be unable to completely fill the space.

Ch095-F06861.indd 1165

TECHNIQUE Incisions and Surgical Access All thoracoplasties are performed under one-lung anesthesia maintained with a double-lumen tube. The use of this type of tube is very important for preventing aspiration of the empyema contents into the contralateral lung.

1/21/2008 2:08:46 PM

1166

Section 4 Pleura

Thoracoplasty can be done through a posterior or a posterolateral approach or through an axillary incision. The posterior approach was commonly used during the early years of thoracoplasty, but it has now been largely abandoned because it involves division of both the trapezius (superficial layer) and the rhomboid (deep layer) muscles, which unite the spine with the lateral border of the scapula. These muscles are important for elevating the scapula and preventing it from floating free. To prevent this problem, Brock35 and others have shown that the muscles must be divided close to the spine, thereby preventing injury to either the spinal nerve or the posterior spinal artery. In recent years, most thoracoplasties have been performed through a standard posterolateral thoracotomy, which can be extended vertically upward to enable adequate access to the upper ribs (Peppas et al, 1993).6 The posterior division of the latissimus dorsi and the division of the serratus anterior muscles completely free the scapula, which can then be elevated to expose the ribs. Maintenance of this exposure is achieved by inserting a chest retractor (Finochetto) between a lower rib and the tip of the scapula. The axillary incision can be used for limited thoracoplasties. It has the advantage of providing good and easy access to the rib cage; its disadvantages are that the scapula cannot be mobilized, and access to the most posterior portion of the ribs is difficult to attain.

Conventional Posterolateral Thoracoplasty (Alexander Type) The conventional procedure consists of extramusculoperiosteal resection of a sufficient number of ribs to enable complete collapse of the space. As originally described by Alexander, it involved the resection of 10 or 11 ribs and it was done in three stages to prevent paradoxical respiration. Today, most spaces requiring thoracoplasty are the result of postoperative infections; these can be treated in one stage and with the use of a more limited number of rib resections. If the operation is done in stages, the interval between stages varies from 10 to 30 days. The second to the eighth ribs are usually resected (Fig. 95-6); it is best to start with resection of the third rib, fol-

lowed by the second and then the fourth to the seventh or eighth ribs. The extent of resection is regulated by the pathologic extent of disease; as a rule of thumb, rib resection is extended to one rib below the most inferior area of disease. Sloping resection of the anterior portion of the ribs, with progressively less anterior rib being removed, preserves the normal configuration of the anterolateral thoracic wall. This maneuver also helps to decrease the paradox and prevent collapse of the healthy lung, which is usually located anteriorly. Posteriorly, the ribs are taken through their neck or head, or even completely disarticulated from the costovertebral joint. To maximize paravertebral collapse and accentuate transverse compression of the lung, part or all of the transverse processes may also have to be resected. If the sixth rib is resected, the tip of the scapula may be moving onto and off of the seventh rib, producing unpleasant sensations. If this is anticipated, the problem can be prevented by resecting either the seventh rib or the lower third of the scapula. There is some controversy as to whether the first rib should be resected. Jaretzki10 summarized well the changing attitudes toward resection of the first rib: When the classic ten-rib Alexander thoracoplasty was performed in the treatment of tuberculosis, removal of the first rib was necessary to obtain adequate collapse therapy [Fig. 95-7]. However, in performing a limited thoracoplasty to assist in the elimination of an infected space, or a limited tailored thoracoplasty in association with a pulmonary resection where a space problem is anticipated, the first rib should not be removed. As was shown by Grégoire,32 Mansour,36 and others, preservation of the first rib is important for maintaining the integrity of the neck, shoulder girdle, and upper thorax (Fig. 95-8). Whether or not the first rib is resected, apicolysis is a most important step in the operation of thoracoplasty. It can be done extrapleurally, as described by Holst and colleagues,37

FIGURE 95-7 Alexander’s version of the suspensory role of the first rib in thoracoplasty. A, All ribs have been removed except the first, and the collapse is incomplete. B, The first rib has been removed, with more adequate collapse. (FROM ALEXANDER J: THE COLLAPSE FIGURE 95-6 Operative photograph showing rib resection and collapse of the space during thoracoplasty.

Ch095-F06861.indd 1166

THEORY OF PULMONARY TUBERCULOSIS. SPRINGFIELD, IL, CHARLES C THOMAS, 1937.)

1/21/2008 2:08:46 PM

Chapter 95 Thoracoplasty

1167

FIGURE 95-8 Chest radiograph (A) and photographs (B and C) of a 53-year-old woman 6 months after right-sided thoracoplasty for a postpneumonectomy empyema. Structural integrity of the neck and shoulder girdle is maintained by retaining the first rib.

Ch095-F06861.indd 1167

1/21/2008 2:08:47 PM

1168

Section 4 Pleura

A

B

FIGURE 95-9 Extrapleural apicolysis (A) and extrafascial apicolysis (B). (ADAPTED FROM FEY B, MOCQUOT P, OBERLIN S, ET AL: TRAITÉ DE TECHNIQUE CHIRURGICALE, VOL 4. PARIS, MASSON, 1955.)

or extrafascially4 (Fig. 95-9). The purpose of apicolysis is to bring the apex of the lung and other soft tissues downward to obliterate the space. It involves division of upper intercostal muscle bundles and fibrous tissue close to the spine, as well as separation of all apical attachments to the chest wall. If the apicolysis is done extrapleurally with the first rib intact, the periosteum over the rib is incised with the use of diathermy and is stripped from its superior surface. Once the rib is freed, the space is collapsed by digital pressure and scissor division of fibrous tissue posteriorly. There is also some controversy as to whether a bronchopleural fistula, if present, should be closed. It has been our policy not to close small bronchopleural fistulas (<2 mm) because collapse of the space almost always results in spontaneous closure.32 If a large fistula is present, a posteriorly pedicled intercostal muscle flap is brought down through the space to cover the bronchial stump. Peppas and coworkers (Peppas et al, 1993)6 and others have suggested that all fistulas, whether small or large, should be closed by direct suture or by apposition of a myoplastic flap. Adequate postoperative intrapleural and extrapleural drainage is mandatory. The intrapleural drain, which is usually in place before the thoracoplasty is performed, is left until complete obliteration of the space is achieved. The extrapleural drain, which is located in the noninfected extrapleural space, can be removed within 4 to 5 days after surgery.

FIGURE 95-10 A, Severe scoliosis seen after extensive six-rib thoracoplasty. Note that the first rib has been removed. B, Less extensive scoliosis seen after thoracoplasty with first-rib preservation.

Ch095-F06861.indd 1168

1/21/2008 2:08:48 PM

Chapter 95 Thoracoplasty

RESULTS Morbidity and Mortality In most recent series, the operative mortality rate associated with thoracoplasty has ranged from 0% to 10%. Postoperative complications include failure to heal, failure to obliterate the space, failure to control infection, failure to close the bronchopleural fistula, and respiratory failure. Late results show successful collapse and obliteration of the space in 80% to 90% of patients.

Complications Related to Specific Types of Thoracoplasties Most thoracoplasties produce some degree of chest wall and shoulder deformity. Progressive scoliosis (Fig. 95-10) may develop if the transverse processes of the spine and the first rib have been resected. Patients may also have chronic postoperative chest pain and hyperanesthesia of the chest wall. With intrapleural types of thoracoplasties such as the Schede type, patients have a greater number of thoracic deformities, in addition to having cutaneous anesthesia and paresthesias over the lower thoracic and upper abdominal walls. Patients may demonstrate restriction of shoulder motion on the involved side because the scapula becomes adherent to the chest wall,16 especially if a portion of that bone has been resected; the appearance is that of a frozen shoulder. Gaensler and Struder38 showed that some patients develop progressive respiratory failure. They reported permanent functional loss

Ch095-F06861.indd 1169

1169

of approximately 27% of the preoperative vital capacity and 21% of maximal voluntary ventilation of the contralateral lung. In a study of 24 patients studied 3 to 27 years after prior thoracoplasty, Powers and Himmelstein39 also presented evidence that the development of scoliosis after thoracoplasty results in a marked decrease in ventilatory function. They attributed the scoliosis to the detachment of muscles that normally act in opposition in the two hemithoraces. After thoracoplasty, the muscles on the opposite side are unopposed and may undergo contracture, with a resulting rotoscoliosis. Most of these problems can be avoided by limiting the size of the thoracoplasty and avoiding resection of the first rib; meticulous surgical technique and early postoperative rehabilitation are also helpful. KEY REFERENCES Barker WL: Thoracoplasty. Chest Surg Clin North Am 4:593, 1994. ■ This is a complete review of indications, techniques, and results of thoracoplasty. Hopkins RA, Ungerleider RM, Staub EW, Young WG: The modern use of thoracoplasty. Ann Thorac Surg 40:181, 1985. ■ Excellent review describing modern indications and results of thoracoplasty. It describes the Alexander principles of thoracoplasty. Peppas G, Molnar TF, Jeyasingham K, Kirk AB: Thoracoplasty in the context of current surgical practice. Ann Thorac Surg 56:903, 1993. ■ This is a review of 37 patients who underwent thoracoplasty between 1975 and 1991. It presents a good discussion of the various types of thoracoplasty and their indications.

1/21/2008 2:08:49 PM

chapter

FIBROTHORAX AND DECORTICATION

96

Gaetano Rocco Claude Deschamps Jean Deslauriers

Key Points ■ The principles behind using decortication to improve lung function

and expansion date back more than 100 years. ■ In selected patients, early decortication prevents the development

of fibrothoraces. ■ Early and complete drainage of the pleural space is the best way

to prevent a fibrothorax and to prevent decortication. ■ Video-assisted thoracoscopy (VATS) is a reasonable alternative to

open thoracotomy for deloculation of early stage empyema.

Under normal conditions, the pleural space is a virtual cavity interposed between the chest wall and the lung. The visceral and parietal linings of this cavity are 1 to 2 mm thick and serve as permeable membranes for transport of cells and fluid. Under pathologic conditions, these relationships may be altered, leading to the development of chronic infections, trapped lung, and severely impaired respiration. Although infrequently encountered, these pathologic conditions must be well understood, not only because they are of historical interest but also because they present challenging management problems.

HISTORICAL NOTE Between the years 1892 and 1894, Delorme in France1 and Fowler2 in America described an operation designed to substitute for the mutilating thoracoplasty of Schede (1890).3 The purpose of the operation was to promote lung reexpansion instead of letting the chest wall collapse to fill in the space. This procedure was called decortication. The exact sequence of these descriptions is still somewhat controversial despite some clarifications offered by Violet (1904).4 In a sealed letter deposited at the French Academy of Medicine in 1892 and at a surgical meeting in 1893, Delorme, professeur au Val-de-Grace, described his method for the treatment of chronic empyemas. In a patient with a large chest wall abscess, he performed a scalpel and scissors dissection of the wall of the abscess, which was 1 cm thick and covered the left lung and pericardium. He concluded that he had freed the lung from this “fausse membrane.” The apparent success of this procedure and further autopsy work, in which he was able to decorticate encased lung (“decortiquer une membrane resistante comme du cuir”) and subsequently re-expand healthy lung (“poumon sain, crepitant et extensi-

ble”), further confirmed his belief that this procedure could be useful for patients with large, residual, infected intrathoracic spaces.1 In 1894, Delorme performed the first planned decortication, and 4 days later he reported the case at the Academy. At a French surgical meeting in 1896, he presented 26 cases of pulmonary decortication and reached the following conclusions: 1. It is possible to free a lung from the membrane that holds it down even long after an operation for an empyema. 2. The method is applicable not only on the right but also on the left side. 3. It is better than the Estlander operation5 because it expands and tends to restore the function of an otherwise useless lung.6 In 1893, Fowler2 also described the operation of decortication, which he had performed for the first time that year on a 35-year-old woman who had had an empyema with a fistula for 10 years. He dissected out the scar tissue surrounding the fistulous tract and removed the entire mass of fibrous tissue from the diaphragm and lung. He was surprised to discover that the lung began to re-expand as soon as the thick scar tissue was peeled from it.7 His method was applicable to the treatment of chronic empyemas, in which he thought that failure of the lung to re-expand was mostly due to encasement by an inexpandable fibrous peel. According to Lund,6 the credit for the operation belongs to Delorme because he apparently had a definite plan to accomplish what he was after, as opposed to Fowler, who had no special plan, apparently, of allowing the lung to expand by removal of the tough, fibrous covering over the lung. According to Mayo and Beckman,7 Fowler was indeed “surprised to discover that the lung began to re-expand as soon as this thick scar tissue was peeled from it.” In 1906, Ransahoff8 advised making multiple incisions at right angles to each other through this thickened pleura down to the lung, thus allowing the lung to re-expand at numerous points. During the early 20th century and until some years after World War I, the procedure was used sporadically, and, finally, because it carried a high fatality rate that results did not appear to justify, it encountered increasing disapproval. Several factors accounted for this lack of enthusiasm, including inadequacy of anesthesia, lack of antimicrobial agents in the presence of infection, lack of blood transfusion ability, and lack of technical expertise.9 It was often a prolonged and

1170

Ch096-F06861.indd 1170

1/21/2008 3:23:35 PM

Chapter 96 Fibrothorax and Decortication

shocking operation. Expansion soon after operation was frequently lost owing to wound breakdown from infection. Re-expansion did not always follow successful decortication because of underlying defects such as parenchymal fibrosis, fistulas, or other active diseases.10 In 1911, Lund reported the experience of Lloyd (1908), who had stated that in the treatment of old empyemas, it was not necessary to remove the pulmonary pleura but simply to break up the adhesions at the borders of the cavity between the parietal and visceral pleurae. Lund presented the cases of seven patients and described the operation performed in the first case: “On splitting this membrane with the scissors and separating it carefully from the surface of the lung, the lung began to expand, and when the child coughed at the close of the operation, the red, velvety lung blew up like a soap bubble and came up against the chest wall, where it remained.”6 In 1915, Lilienthal also treated nontuberculous suppurations with decortication.11 He reported on 23 such patients, among whom there was an operative mortality of 17% (4 of 23) and a good result in all survivors. He insisted on the importance of full lung mobilization and called attention to the dangerous hemorrhage that may follow the tearing away of tough adhesions between the lung and the chest wall. Other early contributions were those of Mayo and Beckman (1914)7 and Eggers (1923),12 who reported shortly after World War I on 146 patients who had undergone decortication for chronic empyemas. He correctly identified the objective of decortication as excision of the peel holding the lung rather than removal of the visceral pleura itself. The advances in management of thoracic trauma that occurred during and after World War II placed further emphasis on decortication of the lung after clotted traumatic hemothorax. Impressive results and new applications of the procedure were reported by Samson and Burford (1946, 1947),13-15 who formulated the newer concept of early and total decortication of the lung. Samson and associates (1946)14 showed that complete pulmonary mobilization (decortication) must not be deferred for the length of time usually necessary to transfer the patient to a specialty center (in the “interior” zone in military situations). In those cases, early decortication results in immediate pulmonary re-expansion and prevents the development of fibrothoraces. Other investigators such as Patton and colleagues (1952)16 showed that decorticated lungs actually regained function if the underlying parenchyma was free of disease.

1171

Himmelstein A, Miscall L, Kirschner PA: Decortication in tuberculosis. Surg Clin North Am 28:1601, 1948. Lilienthal H: Empyema: Exploration of the thorax with primary mobilization of the lung. Ann Surg 62:309, 1915. Lund FB: The advantages of the so-called decortication of the lung in old empyema. JAMA 57:693, 1911. Mayo CH, Beckman EH: Visceral pleurectomy for chronic empyema. Am Surg 59:884, 1914. Milfield DJ, Mattox KL, Beal AC: Early evacuation of clotted hemothorax. Am J Surg 136:686, 1978. Patton WE, Watson TR, Gaensler EA: Pulmonary function before and at intervals after surgical decortication of the lung. Surg Gynecol Obstet 95:477, 1952. Ransahoff J: Discussion of the pleura in the treatment of chronic empyema. Ann Surg 43;502, 1906. Samson PC, Burford TH: Total pulmonary decortication: Its evolution and present concepts of indications and operative technique. J Thorac Surg 16:127, 1947. Samson PC, Burford TH, Brewer LA, Burbank B: The management of war wounds of the chest in a base center: The role of early pulmonary decortication. J Thorac Surg 15:1, 1946. Schede M: Die Behandlung der Empyeme. Proceedings of the Ninth Congress of Internal Medicine. Wiesbaden, Germany, 1890, vol 9, p 41. Violet D: De la decortication pulmonaire dans l’empyeme chronique. Arch Gen Med 81:657, 1904.

FIBROTHORAX Fibrothorax is characterized by the presence of abnormal fibrous tissue within the pleural space, a feature that usually complicates clotted hemothoraces, pleural tuberculosis, or chronic empyemas. As a result of this fibrosis, the lung becomes entrapped and the hemithorax contracts, resulting in reduced mobility. Eventually, there is a marked loss of function in the collapsed lung. Over the years, several terms (Table 96-1) have been used in reference to fibrothoraces. In some cases, the visceral peel has been wrongly thought to be thickened pleura,7 and this has contributed to perpetuation of some misunderstandings about this disease. The so-called lung en cuirasse seen in restrictive pleurisy associated with asbestos-associated diffuse pleural thickening,17 or the visceral pleural fibrosis related to coronary bypass graft surgery, drug-induced pleuritis, rheumatoid pleurisy, or uremic pleurisy18 also need to be distinguished from the “peel” seen in fibrothoraces because the latter does not represent thickened pleura. TABLE 96-1 Commonly Used Terminology Referring to Fibrothorax

HISTORICAL READINGS Burford TH, Parker EF, Samson PC: Early decortication in the treatment of post-traumatic empyema. Ann Surg 122:163, 1945. Delorme E: Nouveau traitement des empyemes chroniques. Gaz Hop 67:94, 1894. Eggers C: Radical operation for chronic empyema. Ann Surg 77:327, 1923. Estlander JA: Sur la resection des côtes dans l’empyeme chronique. Rev Mens 8:885, 1897. Fowler G: A case of thoracoplasty for removal of a large cicatricial fibrous growth from the interior of the chest, the result of an old empyema. Med Rec 44:838, 1893.

Ch096-F06861.indd 1171

Trapped lung Encased lung Unexpanded lung Restrictive pleurisy Constrictive pleurisy/pleuritis/peel Organizing hemothorax/empyema Frozen chest Lung en cuirasse Pleural constriction

1/21/2008 3:23:36 PM

1172

Section 4 Pleura

Decortication, a term derived from Latin, literally means stripping or peeling off of the “bark” from the lung.6 It is a surgical procedure that consists of removing a restricting fibrotic membrane from the visceral pleural surface of the lung. Its purpose is to free the trapped lung as well as to obliterate the pleural space. It is a different operation from the early thoracotomy done for deloculation of the pleural space in cases of fibrinopurulent empyemas19,20 or hemothoraces.21 Deloculation consists of cleaning out a cavity littered with fibrous membranes to improve on closed drainage. It is not a decortication in the true sense of the word because a mature peel has not yet formed over the lung. Some authors also call this procedure débridement of the byproducts of fibrinopurulent exudation seen in stage II empyemas. In this setting, débridement is similar to the limited decortication or early deloculation described for the management of pediatric empyema.22 Finally, decortication is also different from empyemectomy, which is the complete excision of the empyema and its contents without entering the cavity itself, the purpose being to avoid soiling the interior of the hemithorax.23

Causes The causes of fibrothorax are listed in Table 96-2. In the early 20th century, most fibrothoraces were seen in association with tuberculosis, and they resulted from therapeutic pneumothoraces in which the lung became unexpandable or from untreated or unresponsive tuberculous pleurisy or empyema. In recent years, classic examples have been those of a trapped lung secondary to chronic empyema, clotted hemothorax, or neglected pleural effusion. In each of these situations, the pleural collections of pus, blood, or fluid precipitate into fibrin, which eventually becomes fibrous tissue and is deposited over the pleural surfaces and the diaphragm. Rare causes of fibrothoraces include uncommon bacterial and parasitic diseases of the pleural space, chylothoraces,24 and pleural complications of pancreatitis.25 In some patients with fibrothoraces, no specific cause can be identified either by clinical history or at the time of thoracotomy.

Pathophysiology Although it was originally thought that the fibroblastic reaction in the pleural space was a specific response to the

TABLE 96-2 Causes of Fibrothorax Common Causes Traumatic or nontraumatic hemothorax Chronic empyema Chronic pneumothorax Sequelae of tuberculosis Therapeutic pneumothoraces Tuberculous pleurisy or empyema Neglected pleural effusion Uncommon bacterial and parasitic diseases of the pleural space Rare Causes Chylothorax Pancreatic diseases Talc poudrage

Ch096-F06861.indd 1172

presence of blood, it became apparent that any insult to the pleura would result in the same reaction.26 Any undrained or untreated pleural collection of fluid, pus, blood, or chyle is always followed by precipitation of fibrin on the exposed surfaces. As the process evolves into the stage of organization, fibroblasts and angioblasts proliferate and the exudate eventually becomes a mature peel, which is composed of adult tissue rich in collagen but relatively poor in blood supply, cells, and elastic fibers. As the peel further thickens, the underlying lung is covered and entrapped and its normal expansion is impeded. Wachsmuth and Schautz27 and Rudström and Thoren28 have shown that the fully developed parietal peel consists of three poorly defined layers: 1. A layer of comparatively vascular, loosely organized tissue nearest the parietal pleura 2. A layer of connective tissue containing few vessels and cells, which forms the main bulk of the peel 3. An inner layer bounding the central cavity and consisting of necrotic tissues, fibrinoid masses, and detritus with or without bacteria As the peel ages even more, the fibrotic component increases and the loose layer nearest the pleura becomes thinner and finally disappears. In addition to the peel there are almost always dense adhesions between the lung, chest wall, pericardium, diaphragm, and mediastinum. As shown by Williams,29 these adhesions restrain the lung and are important in the production of the pulmonary collapse associated with fibrothorax. Pleurolysis is, therefore, an essential part of decortication. The parietal peel is always thicker than the visceral peel, possibly 2 cm or more. Calcifications are common over the inner surface of the peel (Fig. 96-1), and they are usually associated with chronic exudative effusions, hemothoraces, or tuberculous empyemas. Unless the lung has been damaged by tuberculosis or other parenchymal disease, neither the visceral nor parietal pleura becomes thickened, and both remain largely normal membranes. In patients with small hemothoraces (<200 mL), the continuous movement of the heart and lungs may defibrinate the blood, which will be reabsorbed in a fluid state by the pleural lymphatics. If, however, the hemothorax is larger, if there is continued bleeding, or if air30 or bacteria are also present, a clot with multiple pockets containing air or fluid will form, and eventually this clot will become organized into a peel that will encase the lung. In empyemas, the rapidity of organization varies according to factors such as proper antibiotic treatment, immunologic status of the host, and type of bacteria.22 Ultimately, the lung is compressed by the pleural contents, imprisoned by the peel, and restrained by the pleural adhesions (Williams, 1950).29 Although these factors are not equally important in maintaining the lung in its collapsed state, to be successful the decortication operation must evacuate the pleural contents, remove the peel, and completely mobilize the lung by freeing the adhesions.

Physiologic Consequences There are many functional consequences of a fibrothorax. Several authors have shown that loss of pulmonary function

1/21/2008 3:23:36 PM

Chapter 96 Fibrothorax and Decortication

A

B FIGURE 96-1 A and B, Idiopathic pleural and pericardial calcification causing pericardial tamponade and restrictive pulmonary physiology.

1173

be associated with profound alterations in ventilation and blood flow to the entire lung.32-34 In 1959, Autio showed that localized costophrenic pleuritis could decrease ventilation to the affected lung by an average of 23%, and when the disease was clearly visible, ventilation was reduced well over 50%.32 The physiologic aberrations in pulmonary function seen in patients with fibrothoraces are those of a restriction producing decreased lung volumes, diffusion capacity, and expiratory flows, although no single parameter can be used to explain them.35 Patton and coworkers16 studied pulmonary function before and at intervals after surgical decortication of the lung. In 8 patients, the average maximum breathing capacity was reduced to 68% of the predicted normal and the average vital capacity to 65%. The almost equal reduction of maximum breathing capacity and vital capacity indicated that the ventilatory defect was of the restrictive type. Bronchospirometric observations showed the ventilatory insufficiency to be almost entirely owing to extensive collapse of the involved lung. Similar abnormalities in pulmonary function have been reported by Carroll and colleagues36 and Siebens and associates.37 Diffusion on the affected side is invariably low. This is likely due to a reduction in the available alveolocapillary gas exchange surface. Because of mechanical limitations of pulmonary vasculature and of hypoxic vasoconstriction, ipsilateral lung perfusion is also decreased. Characteristically, perfusion is decreased disproportionately to ventilation38; this reduction is adaptive to the reduced ventilation and is not accompanied by structural arterial changes. This adjustment in the pulmonary blood flow prevents the arterial hypoxia that would otherwise develop.39 In patients studied with xenon-133, Davidson and Glazier40 also provided some evidence that the mechanical function of both lungs could be affected in unilateral disease. In 1966, Robin and associates34 reported four patients in whom severe pulmonary hypertension was associated with chronic constrictive pleuritis, and they speculated about a possible pulmonary vasoconstrictive substance originating in lung tissue, which markedly reduced but still maintained perfusion. Bolliger and de Kock41 have shown that when the movement of the chest wall is impaired by fibrothorax and the lung tissue is not involved, the flow-volume curve has a relatively characteristic pattern, which can be differentiated from that of pure restrictive lung disease. Another difference between fibrothorax and restrictive parenchymal disease that is revealed in pulmonary function studies is the lack of elevation of maximal static pulmonary recoil pressure observed in patients with fibrothorax.31 After blunt trauma, an unrecognized empyema and the resulting fibrothorax can be responsible for the respiratory failure leading to prolonged ventilator dependency.42

Diagnosis bears no relationship to the degree of pleural thickening as seen on chest radiographs. In other words, a thick pleural peel does not necessarily imply reduced ventilation and perfusion any more than a thin peel.31 Other authors have also demonstrated that even a relatively localized pleural restriction may

Ch096-F06861.indd 1173

The clinical presentation of a fibrothorax may vary according to the cause and extent of the process and the presence or absence of underlying parenchymal disease and associated conditions. The most common complaint is that of dyspnea on exertion, which is typically progressive over a protracted

1/21/2008 3:23:36 PM

1174

Section 4 Pleura

period of time. Occasionally, the patient may experience pain. Right ventricular failure with clinical signs of cor pulmonale may also occur in extreme cases. Physical examination reveals a unilateral fixation of the chest with limited respiratory excursion and atrophy of the overlying musculature. Palpation shows decreased fremitus with dullness to percussion, and auscultation identifies diminished or absent breath sounds. Fibrothoraces due to tuberculosis may represent a complication of parenchymal disease. Those caused by chronic empyema may be associated with their own complications, such as empyema necessitatis, chondritis, rib osteomyelitis, bronchopleural fistula, pericarditis, or mediastinal abscesses.43 In those cases, signs and symptoms of infections may dominate the clinical picture and the patient may present with fever, toxicity, and weight loss. The diagnosis and pathogenesis of a given fibrothorax are always substantiated by careful review of past medical history and by comparison of old and current chest films and CT scans. Pulmonary and pleural malignancies must be ruled out because they often mimic benign fibrothoraces. Diagnostic techniques such as bronchoscopy, ultrasonography, MRI, angiography, percutaneous pleural biopsy, and thoracoscopy will usually serve that purpose. Standard chest radiographs with posteroanterior and lateral views often provide clues to the presence of a fibrothorax. The pleura may appear uniformly thickened, initially over the diaphragmatic and lateral surfaces. This may be visible as a markedly increased water density surrounding the lung in an antigravity distribution.44 Later in the process, the entire pleural surface may be obliterated and other signs of advanced fibrothorax, such as narrowing of the intercostal spaces, diminished size of the involved hemithorax, and ipsilateral displacement of the mediastinum may be present. Mottled calcifications may be seen over the inner aspect of the parietal peel. These may be used to determine the actual thickness of the parietal peel. Radiography may contribute to the identification of the causative process in addition to giving clues as to the status of both the involved and the contralateral lung. This evaluation is important because functional improvement after decortication does not occur if extensive parenchymal disease is present. Morton and colleagues45 have demonstrated that absence of underlying parenchymal disease is the best assurance that there will be significant improvement in pulmonary function after operation. CT is essential in assessing the extent and anatomic characteristics of the fibrothorax. Important information concerning the underlying parenchyma may also be obtained by CT, which can identify tuberculous lesions, bronchiectasis, fibrosis, or other conditions that could affect the result of decortication. Kim and associates46 have described a positive correlation between the forced vital capacity and forced expiratory volume in 1 second (FEV1) and the volume of the empyema and extent of lung atelectasis determined on CT scan. Conversely, Roberts47 found that preoperative CT scan could not yield useful elements to help the surgeon decide for a video-assisted thoracoscopic (VATS) decortication over thoracotomy.

Ch096-F06861.indd 1174

MRI has not shown any advantage over CT and has no precise role in the evaluation of fibrothoraces. Bronchoscopy, either flexible or rigid, must be performed to ensure the integrity on the bronchus in the entrapped lung (Scannell, 1990).48 A concomitant carcinoma must be ruled out, and the bronchus of the lung to be decorticated must be free of both active endobronchial tuberculosis and cicatricial post-tuberculous bronchial stricture. Pulmonary function studies, including spirometry, diffusion studies, and exercise tolerance testing are useful in quantifying the degree of respiratory impairment. They also provide for postoperative comparison. Isotope perfusion lung scanning is helpful in determining the contribution of each lung to overall function. In general, anatomic and functional evaluation is useful in predicting whether decortication will improve dyspnea, whether the decorticated lung will reexpand, and whether the re-expanded lung will function in a satisfactory manner. Nutritional assessment may finally be necessary to identify chronic hypovolemia, anemia, and hypoalbuminemia and to institute appropriate supportive measures.

Management Fibrothorax is best treated by prevention. When the potential for pleural effusion is recognized, the patient is treated by early and complete drainage of the pleural space. In one series of 478 patients treated for traumatic hemothorax,49 only 8 eventually required decortication and in each there had been some error in management. Villalba and colleagues50 also recognized that decortication can be prevented by early recognition of hemothorax or pneumothorax; early tube thoracostomy with complete evacuation of blood and expansion of the lung; careful daily monitoring of subsequent fluid accumulation; and prompt evacuation when such fluid accumulates.

DECORTICATION The objectives of decortication are twofold: (1) to re-expand the trapped lung and restore lung, diaphragm, and chest wall function and (2) to obliterate the space and control the infection. In some patients with tuberculosis or chronic empyemas, functional recovery may be a secondary consideration to space obliteration,51 because a lung that is re-expanded after a long period of compression may have impaired ventilation but still be able to fill the space.52 In those cases, decortication may obviate the need for more extensive procedures such as thoracoplasty or pleuropneumonectomy. If decortication is performed for an organizing hemothorax, the objectives are to recover function and prevent late suppurative complications. Mayo and associates53 have described three conditions that are critical to the optimal success of decortication: 1. It needs to be the primary surgical procedure. 2. It must be performed at the earliest opportunity. 3. All elements of the intrathoracic peel must be removed to ensure complete lung re-expansion and both chest wall and diaphragmatic mobility.

1/21/2008 3:23:36 PM

Chapter 96 Fibrothorax and Decortication

Indications Indications for and optimal timing of surgery are described in Table 96-3.

Indications for Early Deloculation in the Adult Early deloculation is indicated in cases of multiloculated empyemas or of hemothoraces when lung expansion cannot be promoted by closed tube thoracostomy alone. Van Way and colleagues54 reported 40 patients with stage III complicated empyemas with multiple loculations. Limited thoracotomy for drainage and placement of tubes was performed in 22 patients, all of whom had resolution of the empyema with no additional procedures. They recommended limited thoracotomy immediately or during the first week of treatment for all multiloculated and complex empyemas (Figs. 96-2 to 96-4). Similarly, Fishman and Ellertson55 advocated early decortication for empyemas in immunosuppressed patients. Their approach was based on the following therapeutic principles: 1. Early, thorough evacuation of the abscess cavity 2. Obliteration of the cavity by removal of the peel, allowing the restricted lung to inflate 3. Avoidance of a chest wall sinus tract Personne56 also recommended that thoracotomy be avoided beyond the third week because at this stage the empyema is not well organized and the peeling of the lung will lead to tearing, bleeding, and prolonged air leaks. He suggested waiting at least 3 months and then proceeding with full decortication. Culinear and colleagues,57 Beall and coworkers,21 and Milfield and associates9 have shown that early evacuation of clotted hemothoraces decreases mortality, morbidity, and hospital stay and prevents the development of post-traumatic empyema. In the series of Milfield and colleagues,9 10 patients underwent evacuation of a clotted hemothorax within 5 days of admission, with no mortality and an average hospital stay of 10 days. Among the 41 patients who underwent decortication more than 5 days after injury there was one death (2.4% mortality) and the average period of hospitalization was 25 days. At an early stage, simple removal of clots is all that is required, whereas if organization is allowed to occur, formal decortication becomes necessary.21 In a study of 452 patients with traumatic hemothorax, Wilson

TABLE 96-3 Indications for Decortication Space Deloculation (1-3 weeks) Inadequately drained multiloculated empyema Early clotted hemothorax Early Decortication (4-12 weeks) Organizing hemothorax Unresolving pleural effusion Empyema Late Decortication (>3 months) Posttraumatic fibrothorax Chronic empyema Idiopathic fibrothorax Pleural tuberculosis

Ch096-F06861.indd 1175

1175

and associates58 concluded that early open operative intervention to remove residual blood clot is usually not necessary and that the emphasis of therapy needs to be on prompt and adequate pleural drainage.

Indications for Early Deloculation and Decortication in Children The need for a different approach to pediatric empyemas has been emphasized in the recently published guidelines by the British Thoracic Society.59 The main difference between adulthood and childhood pleural infections lies in the rarity of concomitant parenchymal involvement. In addition, although causing significant morbidity, pediatric empyemas rarely cause mortality. Mayo and colleagues53 reported 21 pediatric patients who had acute or mature empyemas and were treated by open thoracotomy and decortication. There were no deaths or complications, and the authors concluded that early thoracotomy and decortication yielded uniformly good results. It is, therefore, appropriate to recommend early space deloculation in empyema patients in whom closed thoracostomy does not bring about adequate drainage and lung re-expansion. More recently, management protocols including intrapleural administration of tissue plasminogen activator (tPA) followed by VATS (in the event of tPA failure) and thoracotomy (in the event of VATS failure) have been proposed in the pediatric group.60,61

Indications for Decortication in the Adult The decision to proceed with decortication in adult patients with organized fibrothoraces depends on several factors. Because many conditions associated with acute pleural swelling may resolve spontaneously, decortication is only considered if the pleural thickening has been present for several weeks or months, if the patient’s lifestyle is significantly compromised by exertional dyspnea, and if there is evidence of reversible physiologic impairment of the underlying lung (Fig. 96-5). Samson and colleagues14 found that patients with chronic hemothoraces for whom surgery is indicated are those in whom there is at least 50% compression or the lung, especially if the apex is collapsed; those in whom aspiration has been unsuccessful; and those in whom there has been no appreciable pulmonary expansion at the end of 4 to 6 weeks after injury. In those cases, one can expect full recovery of function because the lung parenchyma is less likely to have been involved in the disease process. It is important to decorticate early (3-5 weeks) in patients with hemothoraces because in time fibrosis may extend into the lung and limit re-expandability. It is also possible that with time, the plane between the visceral pleura and peel will be lost. In patients with chronic empyemas, the therapeutic aims are as follows: 1. To release and expand the collapsed lung if there is marked restriction. The amount of pulmonary restriction that constitutes an indication for decortication is variable, but Petro and colleagues62 considered that this operation must not be done unless there is a reduction of the vital capacity in the order of 30%.

1/21/2008 3:23:37 PM

1176

Section 4 Pleura

FIGURE 96-2 Deloculation for an acute empyema. A, Chest radiograph of a 52-year-old man admitted for fever, cough, and right-sided chest pain. B, Chest radiograph after a minithoracotomy for deloculation of the empyema. C, Chest radiograph taken 1 year later and showing complete lung re-expansion and obliteration of the space.

2. To re-establish the intrathoracic spatial relationship so that false re-expansion, characterized by overdistention of the contralateral lung with mediastinal shift, elevation of the diaphragm, and contraction of the chest wall, does not occur. 3. To control infection by evacuation and obliteration of the pleural space (see Figs. 96-2 to 96-4).

Ch096-F06861.indd 1176

Villalba and colleagues50 recommended that once a posttraumatic empyema becomes well established and refractory to standard modalities, decortication with evacuation of the empyema cavity are performed as soon as possible. It is worth noting again that most patients with hemothoraces, pleural effusions, or empyemas will never need decortication if they are properly treated at the onset of disease.

1/21/2008 3:23:37 PM

Chapter 96 Fibrothorax and Decortication

A

B

C

FIGURE 96-3 A and B, Large hydropneumothorax and lung compression associated with undrained postpneumonic empyema. C, Early post-decortication image demonstrates excellent lung reexpansion and a small residual anterolateral empyema drained by a short-term pleural space tube.

In a series of 19 patients, Young and colleagues63 reported that in each patient an error in management had been made or a complication had occurred during therapy. They concluded that strict adherence to the principle of complete drainage may require insertion of several chest tubes but is

Ch096-F06861.indd 1177

1177

necessary if the incidence of trapped lung is to be decreased. In pleural tuberculosis, therapy is primarily medical and surgical treatment is only used to eliminate or correct those residua of disease that cannot be further altered by

1/21/2008 3:23:37 PM

1178

Section 4 Pleura

FIGURE 96-4 Operative photographs showing a multiloculated empyema with multiple pockets of fluid and fibrin (A); inflammatory peel being removed from the visceral pleura (B); and complete re-expansion of the lung (C). (COURTESY OF JEAN MORIN, MD.)

antibiotic therapy.43,64 In those cases, decortication is performed when evidence of toxicity is no longer present, when thoracentesis fails to yield fluid, or when fluid removal fails to alter the radiographic appearance. The extent of pleural involvement is taken into consideration and needs to be equivalent to one third to one fourth of the hemithorax and cast a clearly discernible shadow on the lateral projection.64 Decortication may finally be indicated for patients with mixed tuberculous empyemas and for patients with unexpandable lungs secondary to therapeutic pneumothoraces.43,65-68

TABLE 96-4 Contraindications to Decortication Absolute Extensive disease in the collapsed lung Bronchial stenosis Relatively Absolute Uncontrolled invasive infection Significant operative risk Debilitation Contralateral disease Relative Minimal symptoms Little evidence of physiologic impairment

Contraindications Although extensive disease or fibrosis of the lung represents a major obstacle to successful decortication and may contraindicate its use (Table 96-4), the only absolute contraindication to the procedure is stenosis of a major bronchus feeding the lobe or lung to be decorticated.69 O’Rourke and colleagues70 have shown that major pulmonary lesions, especially those of tuberculous nature, are also contraindications to decortication, owing to their detrimental effect on re-

Ch096-F06861.indd 1178

expansion of the lung and to the risk of a flare-up of the original process. According to Thurer71 and Magdeleinat and colleagues,72 absent or greatly diminished perfusion to the involved lung contraindicates decortication. Other relatively absolute contraindications include uncontrolled invasive infection in the lung or pleura, significant operative risk, and debilitation. It may also be inappropriate

1/21/2008 3:23:38 PM

Chapter 96 Fibrothorax and Decortication

1179

FIGURE 96-5 Decortication for a chronic empyema. Standard posteroanterior (A) and lateral (B) chest radiographs of a 49-year-old man admitted for cough, hemoptysis, and purulent sputum of 4 months’ duration. Note on the lateral radiograph the inverted D-shaped density typical of a chronic empyema. This patient was treated by complete lung decortication.

to decorticate a lung when there is significant contralateral disease. Relative contraindications include asymptomatic or minimally symptomatic patients and patients with little evidence of physiologic impairment.

Operative Technique With few exceptions, the operative technique described by Samson and Burford,13 Samson,26 and Williams29 is still being followed. For an excellent description of the procedure, the readers need to refer to the classic article written by Witz and Whilm in 1991.73 The operation requires establishment of a plane between the peel and the visceral pleura, freeing of the lung from all adhesions, and decortication of the diaphragm. Decortication is performed through a sixth or seventh interspace posterolateral thoracotomy because incision at this lower level offers better exposure of the diaphragm where adhesions are often denser than those encountered elsewhere29 or worse than preoperatively assessed on chest radiographs. Excision of the sixth rib is not always necessary but may improve exposure, especially when the intercostal spaces have been narrowed by the contractile process of the thickened pleura. After the intercostal space has been entered, the parietal pleura is separated for a distance of several centimeters on

Ch096-F06861.indd 1179

each side of the incision so that a rib spreader can be inserted. If a space is present, it is opened and its contents are thoroughly evacuated. If the contents are purulent, contamination of the operating field will be unavoidable, but this is of little consequence if adequate lung re-expansion is later achieved. When there is no free space, the peel must first be freed from the parietal pleura, starting over the mediastinal surface anteriorly toward the pericardial reflection of the parietal pleura, where it is usually free from adhesions (Fig. 96-6). As the next step, the peel is elevated from the visceral pleura. This is done by incising it with a scalpel until the visceral pleura, which is thin and pliable, is reached. The edges of the peel are then grasped with forceps and separated from the visceral pleura by gentle, blunt dissection with either a “pusher” or a gauze-covered finger. The initial incision in the peel may be vertical or horizontal or several incisions may be made to start the decortication. Gentle re-expansion of the lung by the anesthetist often facilitates separation of the peel, which must be removed over the entire surface of the lung, including the interlobar fissures. If thick adhesions to the visceral pleura are encountered, they may be left in situ to avoid trauma to the lung or the opening of old tuberculous foci. The ease of stripping is unpredictable, and a number of tears to the underlying lung will be made. Large tears can be

1/21/2008 3:23:39 PM

1180

Section 4 Pleura

FIGURE 96-6 A schematic drawing showing the regions where decortication is started in cases of partial (left) or total (right) lung collapse. Often it is easier to start freeing the lung at the reflection between the mediastinal and the parietal pleurae where there is less inflammatory reaction. (MODIFIED FROM LEBRIGAND H: NOUVEAU TRIATÉ DE TECHNIQUE CHIRURGICALE: APPAREIL RESPIRATOIRE, MÉDIASTIN, PAROI THORACIQUE, VOL 3. PARIS, MASSON, 1973, P 404.)

oversewn, whereas most small tears will heal easily once the lung has achieved complete re-expansion. Sometimes, sealants mixed with antibiotics to reduce the risks of local infection can also be used to help reduce air leakage from the decorticated lung.74 More recently, Macchiarini and colleagues75 have reported the use of a new synthetic absorbable sealant, polymerizing polyethylene glycol (Focal Inc., Lexington, KY) to avoid the immunogenicity and risks of disease transmission inherent to fibrin or collagen-based products. If the formation of the peel is secondary to an inflammatory process in the lung, separation almost always presents greater difficulties because the loose subendothelial layer of the visceral pleura is replaced by fibrous, organized granulation tissue.28,75 In extreme cases, it is necessary to remove the visceral pleura to achieve complete lung re-expansion (Fig. 96-7). Unfortunately, this excision leaves a hemorrhagic and air-leaking lung surface, which greatly increases postoperative discomfort and the duration of chest tube drainage. Complete pleurolysis with mobilization of the lung from the diaphragm, pericardium, chest wall, and mediastinum is done next (Fig. 96-8). The diaphragm must be decorticated down to the costophrenic angles, which can prove difficult because fibrosis can be very dense at that level and a plane for dissection is seldom found. Although it is important to restore the mobility of the diaphragm, it is sometimes better to leave plaques of thickened pleura than to damage the muscle. The removal of the parietal peel is controversial. Arguments against performing this step include the possibility that heavy bleeding may occur because the endothoracic fascia may be very vascular and the fact that complete pulmonary re-expansion achieved by visceral decortication may set the stage for resorption of even the thickest of parietal peels. Proponents of removing the parietal peel argue that this is important to restore the full motion of the thoracic cage76

Ch096-F06861.indd 1180

FIGURE 96-7 An operative photograph showing the surface of the lung after excision of the visceral pleura. Note the hemorrhagic and air-leaking lung surface.

and achieve the best functional results. The parietal peel can be excised at the beginning of the operation or after visceral decortication has been completed. When this is done, the plane of dissection is between the parietal pleura and the endothoracic fascia (the parietal pleura cannot be freed from the peel), and in addition to an increased blood loss, technical difficulties can be encountered over the lung apex and mediastinum. At the apex, dense adhesions between the upper lobe and the first two ribs may be present, so that pleurolysis or parietal decortication may be difficult. In some cases, cavities may have penetrated beyond the pleural layer so that to excise them a resection of the costal chest wall, in part at least, may be required.64 Care must be taken not to injure the lower trunk of the brachial plexus, the vagus nerve and subclavian artery on the left side, and the sympathetic chain.

1/21/2008 3:23:39 PM

Chapter 96 Fibrothorax and Decortication

A

FIGURE 96-8 The step of pleurolysis is illustrated in the coronal section (A) and the cross section (B). The visceral peel has been divided at its periphery, and the lung is being fully mobilized. In B, all the adhesions have been divided and the lung is ready for inflation and decortication. (FROM

A

B

WILLIAMS MH: THE TECHNIQUE OF PULMONARY DECORTICATION AND PLEUROLYSIS. J THORAC SURG 20:652, 1950.)

C B

A

B

Over the mediastinum, the dissection is usually considerably easier, but care must be taken to avoid injury to the esophagus, thoracic duct, phrenic and recurrent nerves, and hilar blood vessels. It is remarkable that not even old and thick peels are bound to large vessels, which usually are surrounded by a layer of loose tissue.28 At the end of the procedure, two properly placed chest tubes must be left in the pleural space. In Williams’ technique of decortication,29 complete pleurolysis is first performed, mobilizing the lung from the diagram, pericardium, chest wall, and mediastinum. Once pleurolysis has been completed, the lung is inflated by the anesthetist with the peel still in place and the decortication is carried out as described earlier (see Fig. 96-8). According to Williams,29 this technique facilitates removal of the peel, which is done in a vertical rather than a horizontal plane. Occasionally, selective decortication can be achieved leaving a plaque of peel over some areas of lung disease. Leaving small islands of densely attached pleura may also help to reduce postoperative air leaks.48 If there is a pulmonary lesion (a situation commonly seen with tuberculosis or its sequelae), resection of lung parenchyma may be necessary in addition to decortication. The resort to extrapleural pneumonectomy in selected cases has been described.77 In such cases, complete filling of the residual space with the remaining lung must be ensured. If this is not possible, addition of a small tailoring thoracoplasty with preservation of the intercostal muscles or collapse of the parietal wall without rib resection may obliterate the space.43,78 This has also been used to provide closure of permanent thoracic sinuses.79 Muscle flaps, such as the latissimus dorsi flap mobilized at the time of decortication, or omental pedicled flaps may also be used, thus avoiding the need for thoracoplasty.43,80 Furthermore, the preventive use of intrathoracic muscle flap transposition has been described in conjunction with subtotal pulmonary resection for tuberculosis.81

Ch096-F06861.indd 1181

1181

Obviously, the addition of these procedures is likely to negate the gain in pulmonary function that may have otherwise been obtained.

Thoracoscopy and Decortication The choice of the surgical technique for chronic empyema depends on the stage of the pleural infection.82 The differentiation between stage II (fibrinopurulent) and III (organizing) empyemas can be at times difficult, thereby rendering somehow arbitrary the choice of the surgical approach (open versus VATS). The use of VATS for deloculation of early-stage empyemas is no longer a matter of debate.83 Hutter and colleagues84 reported the use of thoracoscopy for deloculation and débridement of 12 empyemic cavities. After lavage of the cavity, the thoracoscope helped in the placement of irrigation drains under direct vision; this resulted in the complete cure of 11 of the 12 patients within an average of 20 days after the procedure. One patient required a second thoracoscopy and drainage course but also eventually healed. In 1991, the same group85 reported on a total of 30 patients with a cure rate of 60%. In an effort to avoid the significant thoracotomyrelated morbidity, Rodriguez and colleagues86 have successfully used VATS deloculation in children with stage II empyemas. When compared with thoracotomy, VATS deloculation induces less postoperative discomfort and pain.87 Recently, a single-port technique has been proposed to treat early empyemas in pediatric patients.88 Crucial to the success of VATS débridement in stage II empyemas is the promptness of the surgical referral.89 Longer referral time is associated to increasing rate of conversion to thoracotomy and prolonged hospital stay.90 VATS is particularly useful in the management of empyemas seen in early stages,91 wherein the cavity can be deloculated under direct vision; the lung can be re-expanded;

1/21/2008 3:23:40 PM

1182

Section 4 Pleura

and chest drains can be properly placed at dependent sites. It is also useful for deloculation of postpneumonectomy empyemas because the whole cavity can be explored and débrided and chest tubes can be placed at appropriate sites for lavage and attempted sterilization of the space. In cases of organized stage III empyemas, it may be difficult to obtain a good endothoracic image, and true VATS decortication of the lung is hazardous, traumatic, and of limited value. Furthermore, the pulmonary decortication that is often required in these situations may not be in the field of expertise of most clinicians performing thoracoscopies. Decortication using the VATS technique has been reported, although no details about the operative techniques have been given.92-94 Nevertheless, some investigators have supported the view that VATS decortication is feasible in chronic, organized empyema despite a limited success rate (58%) attributed by the authors to a steep learning curve.89 In their VATS patients, operative time and postoperative stay were shorter than their thoracotomy group. However, a common denominator of early experiences with VATS for chronic empyemas were the limited number of surgically treated patients.95,96 Conversely, Lardinois and associates97 have identified the following predictors for conversion from VATS to thoracotomy in presumed stage II empyema: age, sex, time interval between onset of symptoms and surgery, involved microorganisms, and underlying cause of empyema. In their series of 328 patients, conversion to thoracotomy was deemed necessary when a stage III empyema was detected. In fact, among the 178 patients undergoing VATS treatment, only 56% were successfully managed through the thoracoscopic approach while the others required conversion to thoracotomy, with the highest likelihood observed for postpneumonic, gramnegative empyemas and in patients referred after 2 weeks from the onset of the infection. The adoption of an intraoperative decision making strategy for VATS versus thoracotomy has been also advocated by Roberts.47 The suggested criterion was the lack of lung mobilization from the chest wall and the diaphragm, which would indicate the need for an open technique. A routine preliminary VATS exploration of the chest cavity is warranted in the event of doubt.82 Recently, the use of an endo-shaver in 70 patients with pleural empyemas, irrespective of their stage and with 98% success rate, has been described by Kim and coworkers.98 Suzuki and associates99 have postulated that, in debilitated patients, full decortication to facilitate lung re-expansion may not be needed based on two cases with history of therapeutic pneumothoraces successfully treated by VATS débridement and prolonged chest drainage. While the indication for VATS in fibrinopurulent empyemas is consolidated, consensus exists as to the need for open thoracotomy in stage III; by observing this principle, the conversion rate from VATS to thoracotomy is reduced to 3%.100,101 The use of VATS after either blunt or penetrating chest injuries in hemodynamically stable patients has been introduced as a valid diagnostic and therapeutic tool.83 In cases with retained clotted hemothorax, VATS has been proposed

Ch096-F06861.indd 1182

as a useful method to achieve pneumonolysis, superior to intrapleural fibrinolysis.102

Results Operative Morbidity and Mortality In most series, the operative mortality varies between 0% and 5%. In a recent prospective study on 40 patients, Melloni and coworkers103 have reported no mortality and a 12% postoperative morbidity of which 7% was due to sepsis requiring mechanical ventilation. In this series, morbidity was predicted by three prognosticators: the presence of comorbidities, prolonged medical treatment (>30 days), and symptom duration (>60 days). Postoperative morbidity after VATS treatment of empyemas is significantly reduced compared with thoracotomy (6% versus 20%82). The addition of VATS pleurectomy to decortication resulted in a higher incidence of postoperative bleeding requiring re-exploration of the chest cavity.47 Major postoperative complications include sepsis from a residual empyema or from wound infection, bronchopleural fistula, or peripheral bronchoalveolar air leaks and hemorrhage. The incidence of these complications can be lessened by meticulous surgical technique with intraoperative control of air leaks and hemorrhage, achievement of optimal pulmonary re-expansion, and proper tube drainage. The incidence of major complications is substantially increased in patients who require combined pulmonary resection and decortication. Diaphragmatic avulsion during decortication has been reported by Mayo and associates.53 The surgical treatment of post-tuberculous empyemas is performed through one- or two-stage operations43 and carries a significant morbidity and mortality, especially if associated with resectional lung surgery.77,104,105 In these patients, dissemination of tuberculosis or development of tuberculous sinuses is uncommon if patients are given antituberculous drugs.

Functional Results Re-expansion of the lung with obliteration of the space is almost always achieved if the underlying parenchyma is normal. This result is usually permanent and is accompanied by objective improvement, particularly if decortication takes place early in the process of traumatic hemothorax or empyema.20,50 Wright and associates39 were the first to report elaborate preoperative and postoperative studies in two patients who underwent decortication. Preoperative respiratory deficiency was shown by marked diminution of maximum breathing capacity and vital capacity, and bronchospirometry demonstrated that the abnormal findings occurred because of a lack of participation of the involved lung. Postoperative studies showed almost normal overall function. In 1958, Samson and colleagues reported the results of decortication for the pleural complications of pulmonary tuberculosis.26 Among 104 patients in whom decortication was the main operation, 4 (3.8%) died; 79 (77%) had a good to excellent result, with prompt pulmonary re-expansion, clear costophrenic sulcus, adequate motion of diaphragm and thoracic cage, and satisfactory improvement in pulmonary function; and 21 (20%)

1/21/2008 3:23:41 PM

Chapter 96 Fibrothorax and Decortication

had a fair to poor result, in almost every case owing to prior disease involving fibrosis of the lung. More recently, LeMense and colleagues106 reported excellent results in 21 of 22 patients with an empyema. In that series, there was no associated mortality and minimal morbidity. Although some authors have reported no or minimal improvement in individual cases,107,108 decortication is usually followed by improved ventilation and increased lung volumes, measured as improvements in vital capacity, total lung capacity, and maximum breathing capacity. Partial recovery of normal pulmonary blood flow to the diseased side may also be seen.45 In Toomes and colleagues’ series,108 in which the indication for decortication was an empyema, the procedure was not followed by significant improvement in pulmonary function. The authors only noted a mean increase of 13.8% in vital capacity for patients who had preoperative reduction of more than 40%. In Gordon and Welles’ series107 of patients who underwent decortication for pleural tuberculosis, complete studies of pulmonary function before and after operation were given in four cases of re-expansion and little or no improvement was shown. Of note, three of these four patients had been subjected to thoracoplasty before decortication. Swoboda and colleagues109 studied pulmonary function and scintigraphic lung perfusion before and after decortication in nine patients treated for chronic pleural empyema. Preoperatively, vital capacity ranged between 40% and 78% of predicted (mean, 60%), FEV1 averaged 65% of predicted value, and perfusion of the affected side was reduced by 22% (range, 10%-42%). After decortication (3 months-4 years), all parameters were improved. The vital capacity improved by 78.5% (range, 60%-95%), the FEV1 by 60% to 95% (mean, 79.5%), and the postoperative lung perfusion of the affected side increased by 26% to 48% (mean, 37.8%). Magdeleinat and colleagues72 reviewed 25 patients submitted to decortication for empyema (mean follow-up time of 54 months). In 8 patients studied preoperatively and postoperatively, vital capacity improved by 40% (15%-66%). Vital capacity remained stable in 6 patients, and in 1 patient it showed a 25% reduction (this last patient was a smoker with chronic bronchitis). The authors concluded that pulmonary decortication is an effective (23 of 24 patients with complete lung re-expansion) but relatively major operation to treat chronic encysted empyemas. Rzyman and colleagues,110,111 while confirming the reported improvements of perfusion and spirometric values after decortication, observed a persistent and significant impairment of the overall pulmonary function 28 weeks after decortication in 53.6% of the patients. In 1952, Patton and coworkers16 reported the pulmonary function of 14 patients with unilateral constrictive disease, who were studied before and at intervals up to 3 years after surgical decortication. Restoration of function was closely related to the presence or absence of preexisting disease, and there was a progressive gain in function during the entire period of observation. The ultimate gain of preexisting disease, and there was a progressive gain in function, was not influenced by the preoperative duration of collapse or by the presence or absence of infection in the pleural fluid, but it bore a close relationship to the amount of re-expansion seen in the chest films. Patients in

Ch096-F06861.indd 1183

1183

whom visceral decortication was performed showed improvement comparable with that seen in patients who underwent complete visceral and parietal decortication.16 Other investigators such as Barker and associates112 and Carroll and colleagues36 have shown similar results—rises in vital capacity and maximum breathing capacity and improved oxygen uptake being observed postoperatively. Barker and associates112 documented apparent improvement in ventilatory function in the uninvolved lung after contralateral simple decortication. However, contrary to the data and opinion of Patton and coworkers,16 several investigators have shown that the best results seen after decortication are obtained in patients with pleural disease of short duration.36,45,113 Longterm results of decortication in children with empyema showed no limitations of function at intervals of 12 to 18 years after the procedure.53 After elaborate studies of pulmonary function, Patton and coworkers16 observed that pulmonary function seldom returns to the predicted normal postoperatively. This is partly due to loss of parietal elasticity, which persists to some degree even after the most satisfactory decortication. It also relates to other irreversible changes such as overdistention of the good lung, shift of the mediastinum, elevation of the diaphragm, and decrease in size of the hemithorax.

Causes of Failure Failure to control the infection and obliterate the space led to a recurrence of the empyema with or without bronchopleural fistula and to possible deterioration of pulmonary function. In all such cases, it is likely that further surgery will be required. The main causes of failure after decortication are listed in Table 96-5. They are numerous, but most are avoidable with adequate preoperative selection and meticulous surgical technique. The importance of underlying parenchymal disease (Figs. 96-9 and 96-10), especially in cases of decortication performed for tuberculous pleural disease, has been well identified by Gurd,114 who stated, When it comes to applying the principles of decortication to typical pulmonary tuberculosis

TABLE 96-5 Causes of Failure After Decortication Underlying parenchymal disease Tuberculosis (active, fibrosis, bronchiectasis, bronchial stricture) Other parenchymal diseases limiting re-expansion Long duration of lung collapse Technical difficulties Difficulties in removing the peel Air leakage Poor re-expansion of the lung Inadequate postoperative space drainage Associated pulmonary resection Trauma to the phrenic nerve Others Parietal peel not removed over the diaphragm or chest wall Postoperative complications

1/21/2008 3:23:41 PM

1184

Section 4 Pleura

associated with a draining empyema of tuberculous or mixed infection, I would like to sound a note of warning. The prognosis depends chiefly on the extent and severity of the underlying intrapulmonary disease, and is frequently hopeless.

FIGURE 96-9 Fibrothorax. Standard posteroanterior chest radiograph showing an organized left-sided fibrothorax secondary to undrained pleural bleeding after an aortocoronary bypass. Note the trapping of the left lung, which appears otherwise normal.

Mulvihill and Klopstock65 also described a case of failure to re-expand owing to marked fibrosis of the lung. In the 1952 series of Patton and coworkers,16 patients with advanced parenchymal disease had a maximum breathing capacity that was 6% less and a vital capacity that was 16% less than before decortication. By contrast, patients with little parenchymal disease ultimately showed a mean increase of 47% in maximum breathing capacity and a 31% increase in vital capacity. Siebens and colleagues37 have also shown that, in the absence of extensive parenchymal disease, a lung that contributes negligibly to respiration preoperatively may show striking improvement postoperatively. The duration of lung collapse can also play a role in the failure of decortication, and it is generally acknowledged that decortication needs to be done at the earliest possible time. In a group of 111 patients who underwent lung decortication, Morton and colleagues45 concluded that patients with pleural disease of short duration demonstrated more improvement after decortication than did those who had had thickened pleura for prolonged periods of time. This is due to the pleural fibrosis that eventually extends into the lung, thus limiting further its expandability.

FIGURE 96-10 Severe fibrothorax with the destroyed lung. Chest radiograph (A) and CT scan (B) of a patient with extensive post-tuberculous fibrothorax. Note the severe trapping of the left lung and the absence of peripheral blood vessels, indicative of low perfusion.

Ch096-F06861.indd 1184

1/21/2008 3:23:41 PM

Chapter 96 Fibrothorax and Decortication

Technical difficulties are probably the most common cause of failure after decortication. Sometimes there is inflammatory thickening of the visceral pleura, which makes peel removal very difficult. This condition is likely to be seen in tuberculous lungs or in lungs that have been the site of pneumonic processes. In those cases, there will be several sites of air leakage and of bleeding on the lung surface, which may compromise lung expansion. If this occurs, the lung must be decorticated very gently, all large tears must be repaired, and the lung must be fully mobilized from all adhesions so that it can re-expand. Bleeding from the surface of the lung is seldom a major problem; but if the lung does not re-expand or if the pleural space is inadequately drained, collections of fluid may occur in the space, with secondary formation of a new fibrothorax. In all cases, the phrenic nerve must be identified so that diaphragmatic function is preserved. This is usually fairly easy because the mediastinum is almost always free of adhesions. Associated pulmonary resections are also a cause of failure, not only because they indicate the presence of lung disease but also because they increase the magnitude of the procedure and reduce the amount of parenchyma available for space filling. In Okano and Walkup’s series,52 major complications occurred in 35% of patients treated by combined decortication and pulmonary resection. Other factors considered to be potential factors for failure of decortication are nonremoval of the parietal peel over the diaphragm and thoracic wall, which may impair the mechanics of breathing, and the occurrence of postoperative complications such as empyemas or bronchopleural fistulas. Okano and Walkup52 reported significant ventilatory function improvement and no complications in most of their patients who underwent decortication. On the other hand, patients who had postoperative bronchopleural fistula and empyema requiring thoracoplasty had variable changes and some had a diminution in function. Whatever the reason for the failure of decortication, the alternative therapeutic options are meant primarily to provide adequate drainage of the chest cavity.115,116 The Eloesser flap or an open-window thoracostomy can serve this purpose in debilitated patients with “recalcitrant,” stage III empyemas.117 Subsequently, the obliteration of chest cavity may follow by using the available muscle flaps, the omentum, or a limited thoracoplasty.117

Ch096-F06861.indd 1185

1185

COMMENTS AND CONTROVERSIES The management of fibrothorax represents a real challenge to the thoracic surgeon. Prevention is as usual the best form of management. Appropriate drainage of the pleural space after surgical intervention or trauma resulting in hemothorax, early drainage of empyema, and use of VATS to deal with multiple loculated pleural fluid collections will usually eliminate lung entrapment, fibrothorax, and the need for decortication. Of course there are uncommon causes of calcific pleuritis and fibrothorax that occur without a primary pleural fluid collection. These are often challenging cases because the patients usually have extensive parenchymal pulmonary disease (usually restrictive) that limits the likelihood of lung reexpansion and clinical success after decortication. The authors have clearly outlined the indications and contraindications for decortication. In the management of empyema there is always a place for open drainage. The ideal situation for open drainage is in a critically ill patient. This procedure is planned as a temporizing maneuver, allowing the patient to stabilize and recovery adequately to endure the subsequent decortication. G. A. P.

KEY REFERENCES Patton WE, Watson TR, Gaensler EA: Pulmonary function before and at intervals after surgical decortication of the lung. J Thorac Surg 95:477, 1952. ■ The authors provide an excellent review of the mechanisms involved in improving pulmonary function after decortication. Scannell JG: The captive lung: Indications for and techniques of decortication. In Deslauriers J, Lacquet LK (eds): International Trends in General Thoracic Surgery, Vol 6, The Pleural Space. St. Louis, Mosby–Year Book, 1990. ■ This is an excellent overview of the indications and techniques of decortication. Williams MH: The technique of pulmonary decortication and pleurolysis. Thorac Surg 20:652, 1950. ■ This article describes the technique of decortication and emphasizes the importance of pleural adhesions in the production of the pulmonary collapse. Witz JP, Whilm JM: Problemes chirurgicaux poses par les pleuresies purulentes. In Techniques Chirurgicales: Thorax. Paris, Encycl Med Chir, 1991. ■ Excellent description of the technique of decortication.

1/21/2008 3:23:41 PM

chapter

97

TECHNIQUE OF EXTRAPLEURAL PNEUMONECTOMY FOR MALIGNANT PLEURAL MESOTHELIOMA Valerie W. Rusch

Key Points ■ Preoperative evaluation includes computed tomographic (CT)

■ ■ ■

■ ■

■

scanning of the chest and upper abdomen, positron emission tomography (PET)-CT scanning, pulmonary function tests, quanti. . tative ventilation/perfusion ( V/Q ) scanning, and radionuclide stress testing. Thoracotomy is performed via an extended S-shaped posterolateral incision with resection of the sixth rib. The pleural tumor is mobilized away from the chest wall and mediastinum with careful attention to hemostasis. The diaphragm is partially or completely resected. Depending on the extent of the tumor, pericardial resection may or may not be required. After subcarinal node dissection, the main stem bronchus then the hilar vessels are ligated or divided. The diaphragmatic reconstruction should be placed at the same level as the native diaphragm. Pericardial defects should also be reconstructed. Postoperative care should emphasize meticulous pulmonary toilet and fluid management, with transfusion as required and prophylaxis of supraventricular arrhythmias.

The surgical management of malignant pleural mesothelioma (MPM) is controversial because of uncertainty about whether complete resection improves long-term outcome and because of the potential risks of resection. However, given the current limitations of radiation and chemotherapy, surgery remains a mainstay of treatment for MPM. Operations for MPM can be classified into two categories—those performed for palliation and those performed with curative intent. With respect to palliative procedures, video-assisted thoracic surgery (VATS) with talc pleurodesis is an effective way to control pleural effusions in patients whose overall medical condition precludes definitive resection. In such cases, thoracotomy and partial pleurectomy is indicated only if the pleural effusion is loculated and cannot be evacuated by VATS. The operations performed with curative intent are extrapleural pneumonectomy (EPP) and pleurectomy with decortication. This chapter addresses the preoperative evaluation and surgical technique for EPP.

PREOPERATIVE EVALUATION The goals of preoperative evaluation are to determine whether the patient has disease that is potentially amenable to complete resection and whether he or she has sufficient cardiopulmonary reserve to undergo an EPP.

The extent of disease in patients with MPM is primarily determined by imaging studies.1 CT scanning of the chest and upper abdomen, preferably with intravenous contrast, is the chief means of assessing the extent of the primary tumor, of potentially diagnosing disease that extends into the chest wall or through the diaphragm, and of identifying metastatic disease in the peritoneum or in the contralateral lung and pleura.2 Some institutions advocate the routine use of magnetic resonance imaging (MRI) to determine whether the primary tumor invades the chest wall or diaphragm.3 However, based on our experience from a prospective clinical trial at Memorial Sloan-Kettering Cancer Center (MSKCC) comparing CT with MRI, we do not use MRI, because we found that it does not add significantly to the accuracy of CT in preoperative staging (Heelan et al, 1999).4 Positron emission tomography (PET) has recently been shown to add to CT for the initial staging of MPM. Our initial experience indicated that PET detected metastatic disease not identified by CT in approximately 10% of patients.5 These findings were subsequently confirmed by investigators from the M. D. Anderson Cancer Center, who examined the use of PET-CT and found that extrathoracic metastases were identified in 7 of 29 patients. Compared with CT alone, additional information was obtained from PET-CT that precluded EPP in 11 of 29 patients.6 The greater amount of information obtained from PET-CT in this study, compared with ours, may reflect recent technological improvements in PET and the now-routine availability of PET-CT rather than PET alone. In addition, our experience at MSKCC has shown that the standardized uptake value (SUV) on PET is an independent prognostic factor for overall survival in MPM and is therefore useful in selecting patients for surgery and combined-modality therapy (Flores et al, 2006).7,8 As a result of these studies, we now use PET-CT routinely in the initial evaluation of patients with MPM. Mediastinoscopy has also been advocated as a routine staging evaluation before EPP, because the presence of mediastinal nodal metastases (N2 disease) is an adverse prognostic factor in MPM (Sugarbaker et al, 1999).9,10 Imaging studies, including CT, MRI, and PET, are known to be inaccurate in detecting nodal disease (Rusch and Venkatraman, 1996).11 However, mediastinoscopy fails to identify N2 disease in 8% to 90% of patients, because the pattern of nodal metastases of MPM differs from that of lung cancer (Rusch and Venkatraman, 1996).11-13 This is probably related to the presence of direct lymphatic drainage from the pleura to lymph nodes in the internal mammary, paravertebral, and peridiaphragmatic areas (Rusch and Venkatraman, 1996).11 In addition, N2 disease is only one of several important prognostic

1186

Ch097-F06861.indd 1186

1/21/2008 3:24:38 PM

Chapter 97 Technique of Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

1187

FIGURE 97-1 Initial approach for an extrapleural pneumonectomy (EPP). An extended posterolateral thoracotomy or thoracoabdominal incision is performed. A parallel counterincision in the 10th intercostal space, with or without separate skin incision, can be added to improve exposure to the diaphragm.

factors in MPM and does not uniformly identify all patients who have a poor prognosis. Therefore, at the current time, we do not routinely perform mediastinoscopy as part of the initial staging evaluation for MPM. Limited abdominal exploration or laparoscopy has also been advocated as a staging maneuver before EPP (Chang and Sugarbaker, 2004).13-15 Laparoscopy is a low-risk procedure that easily identifies transdiaphragmatic tumor extension and intra-abdominal metastases. Imaging studies usually suggest the presence of such disease, which occurs most frequently in patients who have a locally advanced primary tumor. Routine abdominal exploration is not required for patients whose imaging studies show earlier-stage tumors and no intraabdominal abnormalities. The assessment of cardiopulmonary reserve is a pivotal part of the preoperative evaluation for EPP. Complete pulmonary function testing (PFTs) should be performed, including a measurement of the carbon monoxide diffusing capacity of the lung (DLCO), because patients who have had asbestos exposure often have underlying interstitial lung disease that causes a decrease in the DLCO out of proportion to their decrease in the forced expiratory volume at 1 second (FEV1). At MSKCC, our pulmonary function laboratory also routinely measures arterial blood gases (ABGs) with the patient at rest and during exercise. Although these analyses are not strictly required, the difference between the exercise and resting ABG values provides a qualitative estimate of cardiopulmonary . . reserve. Certainly, a quantitative ventilation/perfusion ( V/Q) lung scan should also be done, so that the patient’s pulmonary function after EPP can be accurately calculated. Most patients with MPM are older and have medical comorbidities, especially underlying cardiovascular disease. An EPP places patients at high risk for myocardial ischemia because of intraoperative blood loss and postoperative fluid

Ch097-F06861.indd 1187

FIGURE 97-2 Example of the S-shaped thoracotomy incision used for EPP. This patient previously had a videothoracoscopy performed (3 incisions also outlined on chest wall). Unfortunately none of these incisions was placed in a way that they could be incorporated into the thoracotomy incision.

shifts. Therefore, a stress test of some type is advisable, even if the patient does not have a history of coronary disease. At MSKCC, we originally used stress testing selectively before EPP. However, after several patients with no preoperative history of cardiovascular disease sustained myocardial ischemia perioperatively, we instituted radionuclide stress testing as a routine part of our preoperative evaluation. As a result, we have not had any patients during the past decade who experienced ischemic events postoperatively. In summary, our routine preoperative evaluation of patients with MPM who are being considered for EPP includes a CT scan of the chest and upper. abdomen, a PET-CT scan, com. plete PFTs, a quantitative V/Q scan, and radionuclide stress testing. Additional evaluations, such as MRI, laparoscopy, or nodal biopsies, are performed selectively, depending on the results of the initial evaluation.

SURGICAL TECHNIQUE Preparation, Positioning, and Incision An epidural catheter is placed preoperatively by the anesthesiologist for postoperative analgesia. After the induction of general anesthesia in the operating room, a double-lumen endotracheal tube is inserted. For left-sided resections, some surgeons prefer to use a bronchial blocker (Chang and Sugarbaker, 2004),15 but at MSKCC we prefer the more reliable single-lung ventilation provided by a double-lumen endotracheal tube and have the anesthesiologist withdraw the tube into the trachea when we are ready to transect the left

1/21/2008 3:24:38 PM

1188

Section 4 Pleura

FIGURE 97-3 The extrapleural plane is opened after resection of the sixth rib.

FIGURE 97-4 The parietal pleura is bluntly dissected away from the endothoracic fascia.

main stem bronchus. In addition to standard intraoperative monitoring (arterial line, pulse oximetry), we place a central venous pressure line because of the fluid shifts that occur perioperatively. The patient is then placed in a standard lateral decubitus position. An extended S-shaped posterolateral thoracotomy incision is made (Fig. 97-1). The curved extension of the thoracotomy incision down toward the costal margin is critical to provide exposure for diaphragmatic resection and reconstruction. Some surgeons recommend adding a second small posterior thoracotomy incision at the level of the 11th rib to provide exposure to the costophrenic sulcus.16 However, this second incision increases postoperative pain and chest wall edema and is not required for exposure to the diaphragm if the extended posterolateral thoracotomy incision is used. Ideally, previous incisions used for thoracoscopic pleural biopsy are incorporated into the thoracotomy incision or reutilized for chest tube insertion, but if these incisions were not properly placed (Fig. 97-2), they should be bypassed by the thoracotomy incision. Both the latissimus dorsi and the serratus anterior muscles are divided. If there is doubt about whether the patient’s disease is completely resectable, exploration can be performed via a standard thoracotomy first, with the incision extended only when it is clear that all tumor can be removed. Some authors recommend using a median sternotomy rather than a thoracotomy. In a small series of 10 patients, 7 had the procedure completed without additional thoracotomy access.17 However, this approach is unlikely to provide adequate exposure for resection and reconstruction of the posterior aspect of the diaphragm.

Technique of Resection The sixth rib is excised to facilitate exposure to the extrapleural plane (Fig. 97-3). Care is taken to resect the rib subperiosteally, preserving the intercostal muscles for reclosure

Ch097-F06861.indd 1188

FIGURE 97-5 After the parietal pleura has been mobilized from the chest wall, a chest retractor is inserted, and the mediastinal pleura is freed from the mediastinal structures under direct vision using a combination of sharp and blunt dissection.

1/21/2008 3:24:40 PM

Chapter 97 Technique of Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

1189

FIGURE 97-7 Intraoperative view of the peritoneum and remaining strands of diaphragmatic muscle after resection of the hemidiaphragm during extrapericardial pneumonectomy. The pericardium is also visible in the lower righthand corner of the photograph.

FIGURE 97-6 The tumor has been bluntly mobilized out of the costophrenic sulcus. Strong traction is placed on the pleural tumor and underlying lung, and cautery is used to dissect the diaphragmatic surface of the tumor away from the diaphragmatic muscle or peritoneum.

at the end of the operation. This approach is slightly lower than that of a standard pulmonary resection, because the greatest bulk of tumor is usually in the lower half of the hemithorax. Blunt dissection is begun in the extrapleural plane between the parietal pleura and the endothoracic fascia and is continued with a sweeping motion of the hand up to apex of the chest (Fig. 97-4). A similar dissection is then performed inferiorly, from the intercostal incision down to the diaphragm. The dissection is carried anteriorly to the pericardium and posteriorly to the spine. It is important to pack each section of the chest sequentially as this dissection is performed, because there can otherwise be a substantial blood loss. Previously, we used the Argon Beam Electrocoagulator (ConMed Corporation, Englewood, CO) to control this diffuse chest wall bleeding. However, our recent experience has shown the Tissue Link (Tissue Link Medical, Dover, NH) to be vastly more hemostatic. After the parietal pleura has been mobilized away from the chest wall, a chest retractor is inserted. Dissection is continued under direct vision, mobilizing the pleura away from the mediastinum superiorly, anteriorly, and posteriorly (Fig. 97-5). On the left side, care must

Ch097-F06861.indd 1189

be taken to identify the esophagus, the plane between the adventitia of the aorta and the tumor, and the origins of the intercostal vessels. On the right side, dissection along the superior vena cava must be performed very gently. After this portion of the dissection is finished, the pleura and lung will have been completely mobilized in the upper half of the chest, exposing the superior and posterior aspects of the hilum. A standard en-bloc dissection of the subcarinal lymph nodes is performed for staging purposes and to expose the main stem bronchus. The lymph nodes are submitted separately, appropriately labeled, to the pathologist. In some patients, there is a clean plane of dissection between the mediastinal pleura and the pericardium, also allowing exposure of the anterior aspect of the hilum. In other patients, this plane is obliterated and the anterior mediastinal pleura must be resected en bloc with the pericardium later in the operation. Attention is then turned to the resection of the diaphragm. There is always a palpable edge between the tumor and normal diaphragmatic muscle or peritoneum. This plane can be entered and the tumor mobilized along the diaphragmatic surface by blunt dissection, much as one would perform a Kocher maneuver. Once the tumor is mobilized from the posterior costophrenic angle, it is rotated up into the thoracotomy incision, rolling it back on itself and placing strong traction on the diaphragm. The depth of dissection varies considerably from one patient to the next. If the involvement of the diaphragm is extensive, the entire thickness of the diaphragm is removed, peeling it away from the peritoneum. If the involvement of the diaphragm is superficial, dissection can be carried through the diaphragmatic muscle with the use of the electrocautery (Fig. 97-6). Every effort is made not to enter the peritoneum because of the propensity of MPM to produce tumor implants. This is most difficult at the level at the central tendon, and often a small opening in the peritoneum is unavoidable, but it should be immediately reclosed. The diaphragmatic portion of the tumor is completely mobilized back to the pericardium medially (Fig. 97-7). If resection of the pericardium is required, it is entered

1/21/2008 3:24:40 PM

1190

Section 4 Pleura

FIGURE 97-8 The pericardium is opened after the tumor has been completely mobilized from all other directions, including the diaphragm.

only after the tumor has been mobilized as fully as possible from all other directions, because traction on the pericardium causes arrhythmias and hemodynamic instability (Fig. 97-8). The hilar structures are divided in whatever sequence is technically easiest and requires the least manipulation of the large tumor mass. Usually, this means dividing the main stem bronchus first, followed by the inferior pulmonary vein, the superior pulmonary vein, and, lastly, the main pulmonary artery. If the pericardium is being resected, it is gradually opened as this portion of the dissection is carried out. Traction sutures are placed on the pericardium to prevent it from retracting toward the opposite hemithorax. The traction sutures minimize changes in the position of the heart and reduce hemodynamic instability (Fig. 97-9). The specimen, consisting of pleura, lung, and diaphragm with or without pericardium, is removed en bloc (Fig. 97-10). Sampling or dissection of the paratracheal lymph nodes, if the operation is on the right, or of the aortopulmonary window nodes, if the operation is on the left, is performed for staging purposes. Again, these nodes are submitted separately and with appropriate labeling to the pathologist.

Reconstruction of the Diaphragm and Pericardium Reconstruction of the diaphragm is then performed (Fig. 97-11). On the right side, Dexon mesh may be used, because the underlying liver assists in preventing herniation of the intra-abdominal contents. On the left side, Gore-Tex (W. L. Gore & Associates, Flagstaff, AZ) is used, because a heavier, nonabsorbable material is required to prevent herniation. If the diaphragmatic muscle has been completely resected back

Ch097-F06861.indd 1190

FIGURE 97-9 The hilar vessels have been divided intrapericardially. Traction sutures were placed on the edge of the pericardium as it was opened, to prevent it from retracting into the contralateral hemithorax.

FIGURE 97-10 Example of an extrapericardial pneumonectomy specimen after en-bloc removal of the pleura, lung, and portions of the pericardium and hemidiaphragm. The forceps is holding the bronchus.

to its costal insertion, the prosthesis is secured by placing sutures around the ribs laterally (Fig. 97-12). Posteriorly, it is sutured to the crus or gently tacked with fine sutures to the wall of the esophagus. Medially, it is sewn to the edge of the pericardium. It is extremely important to place the diaphragmatic reconstruction at the same level as the native diaphragm, namely at the 10th intercostal space posteriorly and at the 8th and 9th intercostal spaces anteriorly and laterally. Placing the reconstruction any higher than this makes it difficult to deliver adjuvant radiation safely, especially to the posterior costophrenic sulcus, and increases the risk of radia-

1/21/2008 3:24:41 PM

Chapter 97 Technique of Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

1191

FIGURE 97-13 Intraoperative view of a partially completed pericardial reconstruction using Dexon mesh. The photograph is taken from the anterior aspect of the incision. The esophagus and spine are visible in the upper part of the photograph.

FIGURE 97-11 The pericardial and diaphragmatic defects are reconstructed with prosthetic material. Reconstruction of the diaphragm is not always necessary, especially on the right side.

abdominal contents at an appropriate level for postoperative radiotherapy. To date, flaps are not widely used for reconstruction. If the pericardium has been resected, it is reconstructed with Dexon mesh (Fig. 97-13). This prevents cardiac herniation into the empty hemithorax and facilitates postoperative irradiation of the hemithorax by maintaining the heart in a central position. Some surgeons prefer to use a 1-mm thick Gore-Tex patch, fenestrating it for pericardial reconstruction. However, this is more difficult to size for the pericardial defect, compared with Dexon mesh, and it is associated with a risk of epicarditis and pericarditis.19 Meticulous attention is given to obtaining hemostasis throughout the operation, and particularly before closure of the chest. A chest tube, usually a 32 Fr right-angle tube, is inserted and placed on the diaphragmatic reconstruction to drain the blood that inevitably oozes from the chest wall dissection. The thoracotomy incision is closed in the usual manner, taking care to reapproximate the intercostal muscles in order to prevent leakage of fluid from the pleural space.

Important Aspects of Postoperative Care

FIGURE 97-12 The completed pericardial and diaphragmatic reconstruction. If the diaphragm was detached from its costal insertion, the prosthetic material can be secured by sutures that are placed around the ribs laterally.

tion hepatitis after right-sided resections or radiation gastritis after left-sided resections. Some surgeons recommend reconstruction of the diaphragm with a latissimus dorsi reverse flap.18 Although this technique is reported to be easy and reliable, it is unclear how well it could maintain the intra-

Ch097-F06861.indd 1191

Careful fluid management is important after EPP. Transfusion is best started early during the operation. Ongoing fluid shifts during surgery make it difficult to use the hemoglobin value as a guide to transfusion. Transfusing the patient according to measured intraoperative blood loss is more appropriate and, in our experience, will avoid perioperative hypotension. This is also true during the first 24 hours postoperatively. Gradual intravascular equilibration and hemodilution during the first 4 days postoperatively is common, and transfusions also may be required at that time. Monitoring of the central venous pressure during the first 24 hours postoperatively is helpful in assessing fluid management. As for any pneumonectomy, administration of intravenous crystalloid solution should be minimized.

1/21/2008 3:24:43 PM

1192

Section 4 Pleura

The chest tube is placed to gravity drainage, using a balanced drainage system to equilibrate the mediastinum. Leaving the chest tube in place for 24 to 72 hours, until drainage becomes serosanguineous, avoids the accumulation of a large hemothorax in the operated pleural space after EPP. A purse-string suture should be placed around the chest tube and tied on removal of the tube, to prevent leakage of pleural fluid from the chest tube site. Supraventricular arrhythmias, particularly atrial fibrillation, occur in approximately one third of patients after EPP. Therefore, we routinely start diltiazem prophylactically in these patients on the first postoperative day and continue it for up to 6 weeks. Careful attention should be paid to the position of the mediastinum after the chest tube has been removed. Because the pleural space usually fills with fluid faster than air is resorbed from it, the mediastinum often shifts away from the operated side during the first 5 days postoperatively. Mediastinal shift can cause refractory atrial arrhythmias which respond immediately to aspiration of air from the pleural space but are not controlled by medication. Prophylactic aspiration of the pleural space, performed as soon as the tracheal silhouette is seen to shift even slightly on chest radiography, prevents these arrhythmias and also relieves the sense of dyspnea experienced by patients when the mediastinum is compressed. Aspiration of the pleural space can be performed by inserting an intravenous catheter via the first or second intercostal space at the midclavicular line under sterile conditions with local anesthesia while the patient is sitting upright. The catheter is attached to a threeway stopcock and a 50-mL syringe. No more than 500 mL of air and/or fluid is aspirated at one time, to avoid rapid shift of the mediastinum. Postoperative care after EPP is otherwise identical to that provided after a standard pneumonectomy.20 Respiratory insufficiency (atelectasis, retained secretions, pneumonia, and acute lung injury) is the most common complication, and great attention is given to early ambulation and to the maintenance of pulmonary toilet. Venous compression boots are used intraoperatively and during the first 24 hours after surgery, and subcutaneous heparin is started on the first postoperative day to reduce the risk of venous thromboembolism.

Follow-up Care After Discharge From the Hospital Early follow-up care is similar to that after any pulmonary resection. An initial postoperative visit occurs 2 to 4 weeks after discharge from the hospital for a wound check, chest radiograph, and adjustment of medications. Referral to the radiation oncology department for planning of adjuvant hemithoracic radiotherapy should be made immediately, so that treatment can commence 4 to 6 weeks postoperatively. The skin reaction and chest wall edema caused by radiation exposure are painful, and pain medications are typically required until these symptoms abate, about 1 month after completion of radiotherapy. CT of the chest and upper abdomen is performed for radiation treatment planning, at about 1 month after radiation therapy, and then every 4 to 6 months for the

Ch097-F06861.indd 1192

first 2 to 3 years postoperatively, after which annual CT will suffice. CT detects most of the sites of disease progression after EPP and adjuvant radiation therapy, which are usually the peritoneum and the contralateral lung or pleura. We do not use PET-CT routinely for follow-up, because it is expensive and yields false-positive results.

COMMENTS AND CONTROVERSIES MPMs are highly malignant tumors that arise from the pleura and are associated with a 90% death rate within 2 years after diagnosis. Optimal treatment is still undefined, and over the years, surgery, radiation therapy, and chemotherapy have been used singly or in combination. As discussed by Dr. Rusch, the surgical approach to MPM includes procedures done for palliation and those performed with a curative intent. Palliative operations are mostly indicated to control recurrent pleural effusions and chest pain, although, in earlier series, parietal pleurectomy was also associated with improved survival. Radical surgery in the form of EPP is based on the concept that MPMs tend to remain localized within the pleural space, so that cure can possibly be achieved by en-bloc removal of the parietal pleura, lung, pericardium, and diaphragm with as wide a margin of tumor clearance as possible. In general, EPP is reserved for early-stage tumors still confined to the ipsilateral pleural space. In such cases, the diagnosis of MPM must have been made ahead of surgery, so that one does not have to rely on frozen sections to decide whether to embark on an EPP. This is best achieved by obtaining large pieces of pleura, usually through a thoracoscopic approach. Clinical staging is also of utmost importance, and each patient must be individually evaluated for consideration of surgery. We agree with Dr. Rusch about the routine use of PET scanning to detect metastatic disease, which is often located in the contralateral pleural space; however, in my opinion, mediastinoscopy should also be routine, because the presence of metastatic nodes in the superior mediastinum would clearly contraindicate EPP. The technique of EPP is well described in this chapter. The costal pleura can usually be stripped easily from the endothoracic fascia over the chest wall and at the apex, whereas both the pericardium and the diaphragm must be removed en bloc, because at those levels there is no plane of dissection between mediastinal pleura and pericardium or between diaphragmatic pleura and diaphragm. With the pericardium opened widely and pulled posteriorly, the hilar structures can be accessed in a standard fashion. Like Dr. Rusch, I prefer to divide the bronchus first and then move inferiorly. Reconstruction of the diaphragm usually necessitates the use of a prosthetic mesh, whereas I prefer to use bovine pericardium to repair the pericardial defect. Although the operative mortality rate of EPP varies from 0% to 30%, a rate of 6% to 10% is achieved by experienced surgeons. J. D.

KEY REFERENCES Chang MY, Sugarbaker DJ: Extrapleural pneumonectomy for diffuse malignant pleural mesothelioma: Techniques and complications. Thorac Surg Clin 14:523-530, 2004.

1/21/2008 3:24:44 PM

Chapter 97 Technique of Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

Flores RM, Akhurst T, Gonen M, et al: Positron emission tomography predicts survival in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 132:763-768, 2006. Heelan RT, Rusch VW, Begg CB, et al: Staging of malignant pleural mesothelioma: Comparison of CT and MR imaging. Am J Radiol 172:1039-1047, 1999. Rusch VW, Rosenzweig K, Venkatraman E, et al: A phase II trial of surgical resection and adjuvant high dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 122:788795, 2001. Rusch VW, Venkatraman ES: Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg 68:1799-1804, 1999.

Ch097-F06861.indd 1193

1193

Rusch VW, Venkatraman E: The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 111:815-826, 1996. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al: Resection margins, extrapleural nodal status, and cell type determine postoperative longterm survival in trimodality therapy of malignant pleural mesothelioma: Results of 183 patients. J Thorac Cardiovasc Surg 117:54-65, 1999.

1/21/2008 3:24:44 PM

Introduction chapter

98

ANATOMY AND PHYSIOLOGY OF THE CHEST WALL AND STERNUM WITH SURGICAL IMPLICATIONS Joseph I. Miller, Jr. Ayesha Bryant Jean Deslauriers

Key Points ■ The anatomy of chest wall and sternum is important from a surgical

standpoint. ■ Knowledge of the thoracic inlet and outlet of thorax, knowledge

and understanding of the importance of the extrathoracic muscles of the chest wall, and knowledge of chest wall mechanics are prerequisites in the training of the cardiothoracic surgeon. ■ Various muscle flaps may be used to provide coverage, wrapping, and filling of defects.

The anatomy and physiology of the chest wall and sternum are completely intertwined (Graeber, 1986).1 The musculoskeletal structure of the chest wall and sternum serve to protect the lungs and thoracic viscera. Surgeons must have a thorough knowledge of the external bony landmarks, the muscles of the chest wall, and their intertwined workings to appreciate the physiology of respiration and anatomic movement.

SURFACE ANATOMY The skeletal framework of the thorax consists of 12 pairs of ribs and their cartilages, 12 thoracic vertebrae, the intervertebral discs, and the sternum (Netter, 1979).2 These are illustrated in Figure 98-1. This illustration also includes the clavicle and scapula because they serve as important attachments for some of the muscles involved in respiration. An understanding of the surface anatomy enables identification of bony and prominent structures as well as the position of deep related structures. The sternum is made up of three parts: the manubrium, the body, and the xiphoid process.2 The manubrium and body are not in quite the same plane and therefore form the sternal angles at their junction, where the cartilage of the 2nd rib articulates with the sternum, as illustrated in Figure 98-1. This is a significant anatomic landmark for the surgeon because it corresponds to the level of the aortic arch and the tracheal bifurcation and is approximately 25 cm from the start of the esophagus. It also defines what is frequently called the upper one third of the thoracic cage. The superior border of the sternum is slightly concave; forming what is called the suprasternal notch. The suprasternal notch on the superior aspect of the manubrium is palpable between the prominent medial ends of the clavicle and it lies opposite the lower border of the body of the second thoracic vertebra. The sternal angle lies opposite the lower border of the fourth thoracic vertebral body. The body of the sternum

runs from the level of the sternal angle to its junction with the xiphoid sternal process, known as the xiphoid process. There are 12 pairs of ribs. They are divided into the upper seven, which are called true ribs because they form a complete loop between the vertebral body and the sternum, and the lower five ribs, which fail to reach the sternum.3 The costal cartilages of the 8th, 9th, and 10th ribs, called false ribs, are usually attached to the cartilage of the ribs above, whereas the ventral ends of the cartilages of the 11th and 12th ribs, which are called floating ribs, have no direct skeletal attachment.2 All of the ribs articulate dorsally with the vertebral column in such a way that they are ventral to it and, together with the sternum, can be raised slightly, as occurs on inspiration. The articulations of the cartilage with the sternum, except for the 1st rib, are true or synovial joints, which allows more freedom of movement than would usually be seen with this type of articulation. The scapula overlies the posterior lateral aspect of the thorax, from the 2nd to the 7th ribs, and serves as a protective barrier to the upper dorsal surface of the thorax. It is held with muscles attached to it there. The scapula’s only bony articulation is between the acromion process and the lateral end of the clavicle; this acts as a strut to hold the lateral angle of the scapula away from the thorax. On the dorsal aspect of the scapula, a spine protrudes and continues laterally into the acromion process. The central end of the spine flattens into a smooth triangular surface with a base of the triangle at the vertebral border. The three borders of the scapula are described as superior, lateral, and medial or vertebral. On the superior border there is a notch or incisura, and lateral to this is the coracoid process, which protrudes anteriorly. The lateral angle of the scapula presents a slight concavity, the glenoid fossa, for articulation with the head of the humerus. The clavicle articulates at the medial end with the superior lateral aspect of the manubrium of the sternum, and its lateral end with the medial edge of the acromion process of the scapula. Its medial two thirds are curved slightly anteriorly, and its lateral third is curved posteriorly. Muscular attachments to the medial and lateral aspects of the clavicle leave its medial portion less protected and thus readily subject to fracture.2

Rib Characteristics and Costovertebral Articulations A typical rib has a head, a neck, and a body, as illustrated in Figure 98-2. The head articulates with one or two vertebral 1197

Ch098-F06861.indd 1197

1/21/2008 3:25:34 PM

1198

Section 5 Chest Wall and Sternum

Jugular notch

Anterior view

Manubrium Acromion

1

Angle

Coracoid process

2

Glenoid cavity

Scapula

Neck

Xiphoid process

3

Scapular notch

Sternum

Body

4

Subscapular fossa

5 Clavicle

6

True ribs (1–7)

11

7

Costal cartilages

8

False ribs (8–12)

12

9 Floating ribs (11–12)

10

Clavicle

Head

Posterior view

1 2

Neck Rib

Tubercle Angle

Body

3

Acromion

4

Supraspinous fossa

5

Spine

6

Infraspinous fossa

Scapula

7 True ribs (1–7)

8 9 10

False ribs (8–12)

11 Floating ribs (11–12)

12

FIGURE 98-1 Anterior and posterior views of the bony thorax. (FROM NETTER FM: THE CIBA COLLECTION OF MEDICAL ILLUSTRATIONS. VOL 7: RESPIRATORY SYSTEM. ARDSLEY, NY, CIBA-GEIGY CORPORATION, 1979, P 4.)

Ch098-F06861.indd 1198

1/21/2008 3:25:34 PM

Chapter 98 Anatomy and Physiology of the Chest Wall and Sternum

1st rib viewed from above

Grooves for subclavian vein and artery

Subclavius muscle

Scalenus anterior muscle

Head

Red = muscle origins

Neck Tubercle

Blue = muscle insertions Head Neck Tubercle

Scalenus medius

1199

Head Tubercle

Angle

Neck

1st digitation; Scalenus 2nd digitation posterior of serratus anterior muscle

2nd rib viewed from above

Superior; inferior Articular facet for transverse process

Angle

Articular facets for vertebrae

Costal groove

Transverse process (cut off)

A middle rib viewed from behind

Radiate ligament Costotransverse (neck) ligament Lateral costotransverse (head) ligament Superior costotransverse (neck) ligament Intertransverse ligament Radiate ligament Interarticular ligament Superior articular facet Costovertebral ligaments viewed from right posterior

Costovertebral ligaments viewed from above

Synovial cavities

Superior costotransverse ligament (cut off)

Lateral costotransverse (head) ligament Costotransverse (neck) ligament FIGURE 98-2 Rib characteristics and costovertebral articulations. (FROM NETTER FM: THE CIBA COLLECTION OF MEDICAL ILLUSTRATIONS. VOL 7: RESPIRATORY SYSTEM. ARDSLEY, NY, CIBA-GEIGY CORPORATION, 1979, P 5.)

Ch098-F06861.indd 1199

1/21/2008 3:25:37 PM

1200

Section 5 Chest Wall and Sternum

bodies. A tubercle at the lateral end of a relatively short neck articulates with the transverse process of the lower of the two vertebrae with which the head articulates. As the body is followed anteriorly, the angle of the rib is formed. At the inferior border of the body is the costal, or subcostal, groove, which contains the intercostal artery, nerve, and vein. Each rib is continued anteriorly by a costal cartilage, by which it is attached either directly or indirectly to the sternum; the exceptions are the 11th and 12th ribs, which have no sternal attachment.2 The 1st and 2nd ribs differ from the typical rib. The 1st rib, which is the shortest and most curved of all the ribs, is quite flat, and its horizontal surfaces are roughly superior and inferior. On its superior surface are intertubercular grooves for the subclavian artery and subclavian vein, which are separated by a tubercle for the attachment of the scalenus anterior muscle. The 2nd rib is longer than the 1st, but its curvature is very similar. Its angle, which is close to the tubercle, is not at all marked. It articulates with the sternum at the angle of Louis.2 Knowledge of the basic anatomy of the ribs, the costovertebral joints between the heads of the ribs and the vertebral bodies, and the costotransverse joints between the tubercles and the transverse processes, is a prerequisite to understanding the two types of respiratory movements.

The Sternum and the Ribs The sternum is an elongated, flat bone that lies in the anterior midline. It is approximately 15 to 20 cm long and is formed from the cartilaginous precursors that ossify separately to form its three components—the manubrium, the body, and the xiphoid process.4 The manubrium is about 5 cm wide in its upper half and 2.5 to 3 cm wide in its lower half. Its upper border is thickened and is marked on either side by a notch for articulation with the clavicle. Ventrally, an indentation is present, which, together with the sternal ends of each clavicle, forms the jugular or suprasternal notch. The widest portion of the manubrium is marked by bilateral indentations, the costal incisura, to accommodate articulation of the first costal cartilage.4 The body, or longest portion of the sternum, is slightly more than twice the length of the manubrium. It is slanted at a steeper angle than the manubrium, and its articulation with that bone forms the angle called the sternal angle. The lateral margins of the body exhibit segmental incisura for articulation of costal cartilages 2 to 7. The body of the sternum ends at about the level of the 10th or 11th thoracic vertebra, where it forms a cartilaginous joint with the xiphoid process. The xiphoid is a cartilaginous process that is usually ossified by middle age. It is the shortest and thinnest part of the sternum and may occasionally be bifid or perforated. The anatomic features of the thorax provide firm structural support by the sternum, the 10 pairs of ribs with their cartilages, 2 pairs of ribs without cartilages, and the 12 thoracic vertebrae and their intervertebral discs. The anatomic entrance into the thoracic cavity is known as the thoracic inlet. The inlet is surrounded by the manubrium of the

Ch098-F06861.indd 1200

sternum, the 1st ribs, and the 1st thoracic vertebra. Its anterior border lies about 1 inch below its posterior limits. The inlet is roofed by a bilateral, thickened endothoracic fascia known as Sibson’s fascia. The outlet of the thorax is formed by the xiphoid process, the fused costal cartilages of ribs 7 to 10, the anterior portions of the 11th rib, the shafts of the 12th rib, and the body of the 12th thoracic vertebra. The anterior margin of this outlet is at the level of the 10th thoracic vertebra (see Fig. 98-1).

BLOOD SUPPLY The arterial supply to the chest wall arises from the subclavian arteries and the aorta itself. Intercostal arteries, which run under each rib, supply the posterior and lateral aspects of the chest wall. The internal thoracic artery and the intercostal arteries combine to provide the arterial supply to the anterior portion of the chest wall, as illustrated in Figure 983. The internal thoracic artery and the highest two intercostal arteries typically arise from the subclavian artery. The lower 10 intercostals arrive from the descending thoracic aorta and course anteriorly, under the ribs and the neurovascular bundle. Major contributions to the blood supply of the anterior chest wall, and particularly the sternum, are the paired internal thoracic arteries. Each of these vessels arises from the subclavian artery and courses distally along the internal periosteal aspect of the chest (see Fig. 98-3). Distally, the internal thoracic artery bifurcates into two major branches. The direct extension becomes a superior epigastric artery after it exits the thoracic cavity through the space between the sternal and costal slips of the diaphragm and the superior epigastric arises from the direct extension of the internal thoracic artery once the internal mammary has gone through the potential foramen of Morgagni. The venous drainage of the chest wall consists of numerous intercostal veins that course with the intercostal arteries under their respective ribs. These vessels drain to the hemizygos and azygos systems, depending on their anatomic position.

INNERVATION The intercostal nerves provide the primary motor and sensory innervation of the entire chest wall. They arise within the spinal canal, exit through the intervertebral foramina and course anteriorly under the inferior margin of each rib.2 The important anatomic features of these nerves need to be mentioned. The sympathetic trunk conveys sympathetic fibers to the nerves just after the nerves exit the spinal canal. The nerves lie most distal among the three structures of the neurovascular bundle under each rib. The intercostal vein is most cephalad, followed progressively by the intercostal artery and finally the intercostal nerve. The first six to seven intrathoracic nerves supply the sensory innervation and dermatomes ranging from the posterior aspect of the back around to the midline of the sternum. The eighth intercostal nerve supplies the anterior wall for sensory fibers around the region of the xiphoid process. The ninth intercostal nerve supplies the upper portion of the epigastrium.

1/21/2008 3:25:40 PM

Chapter 98 Anatomy and Physiology of the Chest Wall and Sternum

Sternothyroid muscle Sternohyoid muscle Internal jugular vein Anterior scalene muscle Subclavian artery and vein

1201

Manubrium of sternum Common carotid artery Inferior thyroid artery Vertebral artery Brachiocephalic trunk Subclavian artery and vein

Clavicle (cut) Brachiocephalic vein

Brachiocephalic vein

Phrenic nerve and pericardiacophrenic artery and vein

Internal thoracic artery and vein Anterior intercostal arteries and veins and intercostal nerve

Internal thoracic artery and vein Anterior intercostal arteries and veins and intercostal nerve

Internal intercostal muscles

Perforating branches of internal thoracic artery and vein and anterior cutaneous branch of intercostal nerve

Innermost intercostal muscles

Transversus thoracis muscle

Collateral branches of intercostal artery and vein Body of sternum Sternocostal triangle

Diaphragm Slips of costal origin of diaphragm Musculophrenic artery and vein

Transversus abdominis muscle

Transversus abdominis muscle Sternal part of diaphragm Xiphoid process

Internal thoracic artery and veins Superior epigastric artery and veins

FIGURE 98-3 Internal view of the anterior thoracic wall. (FROM NETTER FM: THE CIBA COLLECTION OF MEDICAL ILLUSTRATIONS. VOL 7: RESPIRATORY SYSTEM. ARDSLEY, NY, CIBA-GEIGY CORPORATION, 1979, P 8.)

Ch098-F06861.indd 1201

1/21/2008 3:25:40 PM

1202

Section 5 Chest Wall and Sternum

ANATOMY OF THE SUPERIOR AND INFERIOR OUTLETS OF THE THORAX The inferior thoracic aperture lies at the boundary between the chest and the abdomen. The anatomy of the diaphragm and the inferior rim of the musculoskeletal attachments are discussed elsewhere in this text. The superior thoracic aperture has unique anatomic features that govern surgical procedures in this region. The main muscles of this region are the sternocleidomastoid and the scalene muscles. The sternocleidomastoid originates on the temporal bone of the skull and courses inferiorly and anteriorly to insert on the manubrium of the sternum and on the medial third of the clavicle. Its action is to rotate the skull to the opposite side. It also functions as an accessory muscle of respiration in that it elevates the head of the sternum and causes minimal elevation of the clavicle. Of the three scalene muscles, the middle and posterior are also accessory muscles of respiration, in that they elevate the 1st and 2nd ribs and raise them somewhat anteriorly in the respiratory mechanism (Fig. 98-4). The three scalene muscles originate on the cervical vertebrae and insert on the first two ribs. The anterior and middle scalene muscles insert on the dorsal aspect of the 1st rib. The posterior scale muscle inserts on the cephalad aspect of the 2nd rib. The major vessels of the head and upper extremities, as well as the trachea and esophagus, exit the thorax through the superior thorax inlet, as illustrated in Figure 98-4. The subclavian vein is the most anterior vascular structure. The subclavian vein becomes the axillary vein once it passes between the clavicle and the 1st rib. The three great arteries exit the chest through the superior thorax inlet (see Fig. 98-3). The first is the innominate artery, which gives rise to the right carotid and right subclavian artery. The second branch of the aortic arch exiting through the superior thoracic aperture is the left carotid artery. The third great vessel to arise from the aortic arch, the left subclavian artery, courses medially and cephalad to the apex

of the chest and exits over the left 1st rib, just under the clavicle. The major trunks of the brachial plexus course posterior to the subclavian artery and travel over the 1st rib to reach the upper extremity (see Fig. 98-4).

EXTRATHORACIC MUSCLES OF THE CHEST WALL Figures 98-5, 98-6, and 98-7 are schematic diagrams showing the extrathoracic muscles of the chest wall. They are principally important from an anatomic and surgical reconstructive point of view. Each of these muscles is briefly discussed here, with a summary presented in Table 98-1.5

FIGURE 98-4 Anatomy of the superior thoracic outlet. (FROM SAUNDERS RJ, HAUG CE: ANATOMY OF THORACIC OUTLET. IN SAUNDERS RJ, HAUG CE: THORACIC OUTLET SYNDROME. PHILADELPHIA, JB LIPPINCOTT, 1991, P 36.)

TABLE 98-1 Muscles of the Anterior Chest Wall Muscle

Neurovascular Supply

Origin

Insertion

Latissimus dorsi

1: Thoracodorsal nerve, artery, vein 2: Artery to serratus anterior

T6-S3, posterior crest of ileum

Intratubular groove of the humerus

Pectoralis major

1: Thoracoabdominal nerve, artery, vein 2: Internal mammary and intercostal arteries

Sternum, clavicle, ribs 1-7

Tricipital groove of the humerus

Rectus abdominis

1: Superior and inferior epigastric arteries

Pubic crest

Rib cartilages 5-7, xiphoid

Serratus anterior

1: Serratus branch of thoracodorsal artery 2: Long thoracic artery

1: Outer surface and scapula tip, superior border of ribs 8-10 2: Intercostal fascia

—

External oblique

1: Lower thoracic intercostal artery, nerve, vein

External surface and inferior border of ribs 4-12

Iliac crest, lower abdominal process

Trapezius

1: Transverse cervical artery, nerve, vein 2: Occipital branches and intercostal perforators

Occipital bone, C7-T12 spinous processes

1: Posterior and lateral third of clavicle 2: Superior lip of scapular spine, acromion

Ch098-F06861.indd 1202

1/21/2008 3:25:45 PM

Chapter 98 Anatomy and Physiology of the Chest Wall and Sternum

Sternothyroid muscle Sternohyoid muscle Omohyoid muscle

Sternocleidomastoid muscle Posterior triangle of neck Trapezius muscle

1203

Invested by cervical fascia

Clavicle

Perforating branches of internal thoracic artery and anterior cutaneous branches of intercostal nerves

Subclavius muscle invested by clavipectoral fascia Thoracoacromial artery (pectoral branch) and lateral pectoral nerve

Pectoralis major muscle

Costocoracoid ligament

Cephalic vein Acromion

Coracoid process

Deltoid muscle

Medial pectoral nerve

1 2 3 4 5

Long thoracic nerve and lateral thoracic artery

Pectoralis minor muscle invested by Clavipectoral fascia

6

Latissimus dorsi muscle 7 Digitations of serratus anterior muscle

Digitations of serratus anterior muscle

8

Lateral cutaneous branches of intercostal nerves and posterior intercostal arteries

9 10

External oblique muscle

External intercostal membranes anterior to internal intercostal muscles External intercostal muscles Body and xiphoid process of sternum

Anterior layer of rectus sheath

Internal oblique muscle

Sternalis muscle (inconstant) Linea alba

Rectus abdominis muscle Cutaneous branches of thoracoabdominal (abdominal portions of intercostal) nerves and superior epigastric artery

FIGURE 98-5 Anterior thoracic wall. (FROM NETTER FM: THE CIBA COLLECTION OF MEDICAL ILLUSTRATIONS. VOL 7: RESPIRATORY SYSTEM. ARDSLEY, NY, CIBA-GEIGY CORPORATION, 1979, P 6.)

Ch098-F06861.indd 1203

1/21/2008 3:25:47 PM

1204

Section 5 Chest Wall and Sternum

Superior nuchal line

Splenius capitis muscle

External occipital protuberance

Accessory nerve (XI) Levator scapulae muscle

Posterior triangle of neck

Rhomboid minor muscle

Sternocleidomastoid muscle

Rhomboid major muscle

Trapezius muscle

Supraspinatus muscle

Spine of scapula

Infraspinatus muscle

Infraspinous fascia

Spine and Acromion of scapula

Deltoid muscle

T1

Teres minor muscle

Teres minor muscle

Teres major muscle

Teres major muscle

T6 Spinous processes of thoracic vertebrae Latissimus dorsi muscle (cut) Lower digitations of serratus anterior muscle

Latissimus dorsi muscle

T12 Digitations of external oblique muscle

External oblique muscle

Lumbar triangle (Petit) with internal oblique muscle in its floor Serratus posterior inferior muscle Iliac crest

Thoracolumbar fascia over deep muscles of back (erector spinae) Medial Lateral

Posterior cutaneous branches (from medial and lateral branches of dorsal rami of thoracic spinal nerves)

FIGURE 98-6 Posterior thoracic wall. (FROM NETTER FM: THE CIBA COLLECTION OF MEDICAL ILLUSTRATIONS. VOL 7: RESPIRATORY SYSTEM. ARDSLEY, NY, CIBA-GEIGY CORPORATION, 1979, P 9.)

Ch098-F06861.indd 1204

1/21/2008 3:25:50 PM

Chapter 98 Anatomy and Physiology of the Chest Wall and Sternum

Thoracoacromial artery

Lateral thoracic artery

Pectoralis major

Rectus abdominis

Thoracodorsal artery

Superior epigastric artery

Serratus anterior Latissimus dorsi

Omental graft

Epiploic branches of left gastroepiploic artery FIGURE 98-7 Muscles of the anterior chest wall that may be used for muscle flaps. (FROM MILLER JI: MUSCLE FLAPS AND THORACIC PROBLEMS: APPLICABILITY AND UTILIZATION FOR VARIOUS THORACIC PROBLEMS. IN KITTLE CF [ED]: CURRENT CONTROVERSIES IN THORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 1986, P 235.)

Latissimus dorsi: The latissimus dorsi is most frequently used for lateral and anterior defects. It is supplied by the thoracodorsal neurovascular bundle, and it also receives blood from the branches supplying the serratus anterior and can be based on this vascular pedicle. Excellent musculocutaneous collaterals allow significant skin to be taken with this muscle. The largest is an extrathoracic flap (25 × 35 cm) with a skin area of 30 × 40 cm. It has a large pedicle and a wide arc of rotation. It arises from T6 to T12, L1 to L4, S1 to S3, and the posterior crest of the ileum, and it has its insertion on the intertubercular groove of the humerus. The donor site rarely acquires any morbidity but may require a skin graft. Pectoralis major: The second most frequently utilized extrathoracic muscle flap in clinical situations is the pectoralis major. It is appropriate for anterior and midline thoracic wall defects. Its primary blood supply is the thoracoacromial neurovascular bundle arising at the mid-clavicle. Its second blood supply is from the internal mammary artery, lateral intercostal arteries, and lateral thoracic perforators. It is the second largest muscle (15 × 23 cm), with a potential skin area of 20 × 28 cm. Its origin is from the sternum, the clavicle, and the first seven ribs. Its insertion is on the bicipital groove of

Ch098-F06861.indd 1205

1205

the humerus. It may be used as a pedicle graft based on the primary blood supply or as a turnover flap if a secondary supply is used. Harvest must take into account the possible displacement of the breast and loss of adduction and medial rotation of the arm. It is of excellent reliability. Rectus abdominis: The third most frequently used muscle flap, which is appropriate for lower anterior chest wall repairs, is the rectus abdominis. It has two predominant vascular pedicles: the superior epigastric artery supply and the deep inferior epigastric. If the flap is based on the superior epigastric, the inferior epigastric must be divided; therefore, adequate blood flow through the superior epigastric by way of the internal mammary must be ensured. Anterior chest wall irradiation may damage the internal mammary artery; therefore, angiography is sometimes required. The muscle presents a smaller surface area of 6 × 25 cm, with a potential skin area of 21 × 14 cm. Along the pedicle, the skin flap may be oriented vertically or horizontally. Vertical orientation preserves more musculocutaneous perforators and therefore is safer. Its origin is from the pubic crest, and its insertion is on the cartilages of ribs 5, 6, 7 and the xiphoid. Some atrophy of the muscle may occur due to the loss of innervation prerequisite in its harvest. Serratus anterior: The serratus anterior has been called the workhorse of endothoracic surgery. It is less frequently used for extrathoracic reconstruction. It is located between the latissimus and pectoralis major and the midaxillary line. It is a small muscle, best suited as an intrathoracic flap, but it may be used in combination with the latissimus or pectoralis to supplement blood supply of the cutaneous segments of these larger flaps. The primary blood supply is the serratus branch of the thoracodorsal pedicle. Its secondary blood supply is the long thoracic artery. It arises from the outer surfaces and superior borders of the upper 8th, 9th, and 10th ribs and from intercostal fascia. Its insertion is into the tip of the scapula. The blood supply is reliable, but the bulk of the muscle is small, limiting its usefulness as an extrathoracic muscle flap. External oblique: The external oblique is infrequently used, but it may be used for upper abdomen and lower thoracic defects as far as the inframammary fold. Its primary blood supply is from the lower thoracic intercostal vessels. It arises from the external surface and inferior border of the lower eight ribs, and its insertion is into the iliac crest and abdominal fascia. Trapezius: The trapezius muscle is infrequently used in extrathoracic muscle wall surgery. It is occasionally used for upper chest and neck defects. It is most useful for the base of the neck and thoracic outlet defects. Its major pedicle is the transverse cervical by way of the thyrocervical trunk. Its secondary blood supply includes occipital branches and intercostal perforators. It is of moderate size and bulk, 34 × 18 cm, with a potential skin island of 20 × 80 cm, making it a good muscle for use in the upper thoracic area. It arises from the occipital bone and the spinous processes of the seventh cervical and all the thoracic vertebrae. Its insertion is in the posterior and lateral third of the clavicle, the acromion process, and the superior lip of the spine of the scapula.

1/21/2008 3:25:53 PM

1206

Section 5 Chest Wall and Sternum

CHEST WALL AND DIAPHRAGM PHYSIOLOGY Knowledge of the basic anatomy of the ribs, costovertebral joints between the heads of the ribs and the vertebral bodies, and the costotransverse joints between the tubercles and the transverse processes, is a prerequisite to understanding the two types of respiratory movements: inspiration and expiration. The mechanics of the chest wall are described by a pressure-volume curve that differs in the upright and supine positions due to displacement of abdominal contents into the thoracic cavity when supine. In the upright position, the resting volume of the chest wall alone is at approximately 55% of vital capacity (VC); below this volume, the rib cage

Muscles of inspiration

recoils outward, and above this volume, the rib cage recoils inward. The resting volume of the respiratory system as a whole, taking into account not only the mechanical properties of the chest wall but also the inward recoil of the lung, is at approximately 35% of VC.1,2 The excursion of the chest wall depends on complex interactions among its components. The motion of the ribs depends on their attachments to the sternum and to the vertebral column and is influenced by the adjoining muscle groups. The parasternal and scalene muscles insert on ribs 1 through 6; the costal portion of the diaphragm inserts on the sternum and on ribs 7 through 12. Flexion and extension of the spine can result in displacement of the rib cage and abdominal wall to account for as much as 50% of VC (Fig. 98-8).

Muscles of expiration

Accessory

Quiet breathing

Sternocleidomastoid (elevates sternum)

Expiration results from passive recoil of lungs and rib cage

Scalenes Anterior Middle Posterior (elevate and fix upper ribs)

Principal

Active breathing

External intercostals (elevate ribs, thus increasing width of thoracic cavity)

Internal intercostals, except interchondral part

Interchondral part of internal intercostals (also elevates ribs)

Diaphragm (domes descend, thus increasing vertical dimension of thoracic cavity; also elevates lower ribs)

Abdominals (depress lower ribs, compress abdominal contents, thus pushing up diaphragm) Rectus abdominis External oblique Internal oblique Transversus abdominis

FIGURE 98-8 Muscles of respiration. (FROM NETTER FM: THE CIBA COLLECTION OF MEDICAL ILLUSTRATIONS. VOL 7: RESPIRATORY SYSTEM. ARDSLEY, NY, CIBA-GEIGY CORPORATION, 1979, P 47.)

Ch098-F06861.indd 1206

1/21/2008 3:25:55 PM

Chapter 98 Anatomy and Physiology of the Chest Wall and Sternum

The diaphragm is innervated by the phrenic nerve and affects the rib cage through changes in abdominal and pleural pressures as well as through direct effects upon the ribs on which it inserts. The muscles of the abdominal wall are important muscles of expiration, and contraction of these muscles can also have a significant effect on lung volume. The movements of the diaphragm and chest wall aid in respiration (see Fig. 98-8). During tidal volume inspiration, the diaphragm contracts and moves downward, thus creating a negative intrapleural pressure, and air moves into the alveoli. Tidal volume is about 600 to 800 mL per breath. During maximal inspiratory effort, or forced ventilation, the chest wall muscles, such as the scalene muscles, aid inspiration by elevating the uppermost part of the ribcage. The sternomastoid muscle elevates the sternum and lifts the ribs, thereby slightly enlarging the anteroposterior and longitudinal dimensions of the chest, and the external intercostal muscles elevate the ribs.2 Use of these muscles allows an increased volume of 1500 to 1800 mL per breath.2 During normal expiration or tidal volume respiration, the diaphragm relaxes and the lung returns to its resting position due to passive intrinsic recoil forces. However, during maximal respiratory effort, internal intercostal muscles depress the ribs, decreasing the intercostal distances. Additionally, the abdominal muscles depress the ribs and displace the abdominal contents into the thoracic cavity, forcing the diaphragm upward. Maximal respiratory effort permits movement of 600 to 800 mL beyond tidal volume, per breath. Only reserve volume remains in the lung at this point. Some of the conditions that affect the forces acting on the mechanical structure of chest wall and affecting the lung volumes are discussed in the following paragraphs. Ankylosing spondylitis is a chronic inflammatory disease affecting joints of the axial skeleton with resultant fibrosis and ossification of the ligaments of the spine (“bamboo sign”), sacroiliac joints, and rib cage. Patients present with chronic low back pain and often with limited spinal range of motion, bilateral sacroiliitis on plain radiographs, and positive serology for the human leukocyte antigen HLA-B27. Ankylosing spondylitis causes fixation of the chest wall through fusion of the costovertebral joints due to inflammation.6 Pectus excavatum is a congenital deformity of the chest wall that is characterized by a concave depression, which may be a broad, shallow defect or a narrow central pocket. Infants and young children usually have no symptoms, but older patients may complain of mild dyspnea on exertion and pain in the area of rib deformity after exercise. Symptoms result from compression of lung tissue by the abnormal chest wall. Cardiac effects from compression of the sternum include decreased stroke volume in the upright position, mitral valve prolapse and associated arrhythmias, and a systolic ejection murmur after exercise. Poland’s syndrome occurs in 1 of every 30,000 live births and encompasses other abnormalities, including aplasia or hypoplasia of the sternocostal portion of the pectoralis major muscle. Flail chest describes an unstable chest wall, which usually results from blunt trauma (e.g., steering wheel hitting the chest) that causes double rib fractures in more than one site

Ch098-F06861.indd 1207

1207

(i.e., three sequential rib fractures, or fracture of ribs plus sternum). The rib fractures detach parts of the chest wall from the rib cage, and this segment is thereafter subjected to unopposed pleural pressures, resulting in paradoxical motion. Fibrothorax results from fibrotic scarring around the visceral pleura of the lung. In severe cases, the fibrotic process can invade the chest wall, destroy the intercostal structures, replace the endothoracic fascia, and cause thickening of the periosteum of the ribs. Ultimately, the ribs fuse, and calcification of collagen can occur, resulting in a limitation of respiratory excursion.

APPLIED SURGICAL IMPLICATIONS OF ANATOMY OF THE CHEST WALL AND STERNUM Various surgical approaches are used for specific problems within the thorax. A thorough knowledge of the anatomy is mandatory for the surgeon to achieve optimal visualization in the surgical approach. A specific examples is video-assisted thoracoscopic surgery (VATS). Depending on which side is to be entered, a low port is usually placed in the 7th intercostal space on the midaxillary line. This space can be identified from the external standpoint in the lateral thoracotomy position: the tip of the scapula usually lies over the 7th intercostal space. In addition, two other ports are typically applied: one for a grasper and one for a stapler if a lung biopsy is being performed. These ports are frequently placed in the 4th intercostal space in the anterior axillary line and in the posterior axillary line of the 3rd or 4th intercostal space. If one is performing an endothoracic off-pump coronary artery bypass (OPCAB) procedure, the incision is usually made over the left 2nd intercostal space, with or without resection of the 2nd costal cartilage. This anatomy is confirmed by knowing the angle of Louis and knowing that this is at the 2nd rib. If one is doing minimally invasive valve surgery, the incision is frequently made over the 2nd or 3rd intercostal space, identified by locating the sternal manubrium and counting the ribs below. These areas can then be resected and provide quite adequate visualization for minimally invasive valve surgery. The extrathoracic wall musculature can be used in a number of different ways. The muscles can be used in sternal reconstruction. The extrathoracic muscle flaps can be used for filling numerous types of defects and may be used extensively in chest wall reconstruction. The extrathoracic flaps can be used in the treatment of postpneumonectomy empyema; in the treatment of bronchopleural fistula after lobectomy; in tracheal resection for coverage of anastomotic areas; in the gastrointestinal tract as wrapping of anastomoses; after repair of certain defects in the great vessels to wrap the heart or the great vessels; in total sternal reconstruction; and in the treatment of postoperative open heart mediastinitis. A thorough knowledge of muscle flaps is a prerequisite in the training of any cardiothoracic surgeon.

COMMENTS AND CONTROVERSIES A thorough knowledge of the anatomy of the chest wall and sternum is a prerequisite for any well-trained cardiothoracic surgeon. To

1/21/2008 3:25:57 PM

1208

Section 5 Chest Wall and Sternum

determine a surgical approach for a specific procedure, knowledge of defined anatomic points is a must. Knowledge of extrathoracic muscle flaps is helpful in determining which flaps are useful in a given clinical situation. J. D.

KEY REFERENCES Graeber GM: Embryology, anatomy and physiology of the chest wall. In Seyfer AK, Graeber GM, Wind GG (eds): Atlas of Chest Wall Reconstruction. Rockville, MD, Aspen, 1986, p 11. Graeber GM, Szwerl MF: Anatomy and physiology of the chest wall and sternum. In Pearson FG, Cooper JD, Deslauriers J, et al: Thoracic Surgery, 2nd ed. Philadelphia, Churchill Livingstone, 2001, chapter 48.

Ch098-F06861.indd 1208

Miller JI: Muscle flaps and thoracic problems: Applicability and utilization for various conditions. In Kittle CF (ed): Current Controversies in Thoracic Surgery. Philadelphia, WB Saunders, 1986, pp 235-240. Netter FM: Atlas of Human Anatomy. Ardsley, NY, Ciba-Geigy Corporation, 1989. Netter FM: The Ciba Collection of Medical Illustrations. Vol 7: Respiratory System. Ardsley, NY, Ciba-Geigy Corporation, 1979. Sanders RJ, Haug CE: Thoracic Outlet Syndrome. Philadelphia, JB Lippincott, 1991, p 36. Seyfer AK, Graeber GM, Wind GG (eds): Atlas of Chest Wall Reconstruction. Rockville, MD, Aspen, 1986. West JB: Mechanics of breathing. In West JB (ed): Best and Taylor’s Physiologic Basis of Medical Practice, 12th ed. Baltimore, Williams & Wilkins, 1991, p 550.

1/21/2008 3:25:57 PM

chapter

99

CHEST WALL AND STERNUM IMAGING David S. Gierada

Key Points ■ Computed tomography (CT) and magnetic resonance imaging

(MRI) are the primary imaging modalities for evaluating most nontraumatic chest wall abnormalities. ■ Imaging is useful for determining the extent of chest wall infections, identifying abscesses, and evaluating for mediastinal involvement. ■ Imaging features of nonlipomatous chest wall masses may suggest whether the etiology is more likely benign or malignant and help define the extent of the mass, but biopsy is usually required to make a specific diagnosis.

Although the focus of most thoracic imaging examinations is on the lungs and mediastinum, the bones and soft tissues of the chest wall also should be inspected whenever imaging of the chest is performed. Chest radiography is often useful in evaluating the osseous structures for fractures in the setting of trauma and for calcifications in bone lesions, and it can reveal gross bone destruction and intrathoracic extension of chest wall masses. However, radiography is of limited value in the detection and characterization of more subtle bone lesions, and even relatively large soft tissue masses of the chest wall may not produce radiographic abnormalities. CT and MRI are far more sensitive in identifying chest wall pathology and in some patients have complementary roles (Tateishi et al, 2003)1-6: CT has better spatial resolution and depicts cortical bone disruption better, whereas better soft tissue characterization and flow-sensitive pulse sequences are advantages of MRI. MRI and multidetector CT both allow multiplanar evaluation of anatomic regions more optimally depicted by coronal and sagittal planes, such as the superior sulcus and the diaphragm.

DEVELOPMENTAL AND CONGENITAL ANOMALIES One of the more common anomalies of the chest wall is the pectus excavatum, or funnel chest deformity. This consists of an inward depression of the middle and lower sternum and anterior chest wall, which may reduce the prevertebral space and cause leftward displacement and rotation of the heart and mediastinal structures.7,8 The sternum is often also rotated or tilted. This deformity may cause an indistinct increase in opacity over the medial right lung base on frontal radiographs, simulating pneumonia (Fig. 99-1). A lateral radiograph suffices to confirm the diagnosis. Pectus carina-

tum, or pigeon breast, is characterized by convex outward protrusion of the sternum. It is less common than pectus excavatum,8 and there is associated congenital heart disease in half of the cases.9 The sternum is often wider and longer than normal,8,10 and there is an associated emphysematous appearance to the lungs, with increased anteroposterior diameter.11 CT12 or MRI may be of benefit in pectus deformities if operative correction is contemplated. Cervical ribs are observed in about 1% of chest radiographs,13,14 and they may be unilateral or bilateral. Cervical ribs are almost always incidental, but a small percentage are associated with thoracic outlet syndrome. The diagnosis of thoracic outlet syndrome usually is made clinically, without imaging. In some cases, CT angiography in thoracic outlet syndrome can confirm positional vascular compromise15 (Fig. 99-2). Postural arterial compression also can be evaluated by magnetic resonance angiography16 or ultrasound.17 However, neural impingement by cervical ribs or abnormal C7 transverse processes seen on CT do not appear to allow discrimination between symptomatic and asymptomatic sides.18 Imaging evaluation is most useful to identify other conditions that may cause similar symptoms rather than to establish or confirm a diagnosis of thoracic outlet syndrome.19 Supernumerary intrathoracic ribs are rare congenital anomalies; they have the structure of a typical rib, but with an aberrant location and orientation. Although they are adequately characterized by chest radiography in most cases, CT is even more definitive for distinguishing intrathoracic ribs from abnormalities such as pleural plaques, scimitar syndrome, or foreign bodies.20,21 Anomalous rib fusions, articulations, and bifid ribs occur uncommonly and are of little or no clinical importance.22 Fibrous dysplasia is a developmental anomaly of bone that is more often monostotic than polyostotic. It often involves the ribs, producing fusiform expansion with cortical thinning or thickening, increased trabeculation, and a so-called ground-glass homogeneous increase in density (Tateishi et al, 2003)3,23,24 (Fig. 99-3). These lesions must not be mistaken for neoplasms requiring biopsy or resection because the diagnosis can be made by imaging, and no treatment is needed. Although it is not a primary chest wall abnormality, rib notching25 may develop secondary to congenital or acquired conditions. The most common cause is aortic coarctation, which causes inferior rib notching due to collateral flow through the dilated internal mammary and intercostal arteries which supply the aorta distal to the coarctation. Coarctation proximal to the left subclavian artery produces unilateral right rib notching, whereas coarctation distal to the left subclavian artery produces bilateral rib notching. Rarely, inferior 1209

Ch099-F06861.indd 1209

1/21/2008 3:26:56 PM

1210

Section 5 Chest Wall and Sternum

A B

FIGURE 99-1 A, Posteroanterior chest radiograph in a 44-year-old woman with a history of asthma and bronchitis shows ill-defined opacification of the medial right lung base, with poor visualization of the right heart border. Also note slight shifting of the heart into the left hemithorax. B, Lateral radiograph reveals that the posteroanterior radiograph findings are secondary to a pectus excavatum deformity, with inward displacement of the sternum (arrows at posterior edge). C, CT image shows that the cause of the right-sided opacity on the frontal radiograph is asymmetrically greater anteroposterior thickness (arrows) of the inwardly depressed anterior chest wall on the right. No pneumonia is present.

C

rib notching is seen in cardiovascular disorders associated with reduced pulmonary blood flow, such as the tetralogy of Fallot or pulmonary atresia. Ipsilateral inferior rib notching also may occur after a subclavian-to-pulmonary artery shunt (Blalock-Taussig shunt) performed for tetralogy of Fallot. Superior rib notching is even less common than inferior notching, but it can occur as a result of poliomyelitis, connective tissue diseases, neurofibromatosis, localized pressure

from rib retractors or chest tubes, or hyperparathyroid states. Poland’s syndrome occasionally is seen incidentally on cross-sectional imaging as congenital unilateral absence of the sternal head of the pectoralis major muscle and the pectoralis minor muscle. Associated anomalies may include underdevelopment of the breast or nipple on the affected side, ipsilateral rib aplasia or hypoplasia, lung hernia, a small and elevated

Ch099-F06861.indd 1210

1/21/2008 3:26:56 PM

Chapter 99 Chest Wall and Sternum Imaging

1211

B A

FIGURE 99-2 A, Chest radiograph in a 20-year-old man with left arm pain due to thoracic outlet syndrome shows a left cervical rib (arrow) and developmental deformity of subjacent ribs. B, Three-dimensional CT (3D-CT) image with the left arm and clavicle elevated shows an occluded segment of the left subclavian artery (arrows) due to compression by the clavicle and anomalous ribs. C, 3D-CT image with the left arm down shows return to normal caliber of the left subclavian artery, with slight dilation of the segment immediately distal to the point of positional occlusion (arrows). (IMAGES COURTESY OF SANJEEV BHALLA, MD.)

C

scapula (Sprengel deformity), cervical vertebrae fusion (Klippel-Feil syndrome), syndactyly, and renal anomalies; malignancies including leukemia, lymphoma, cervical cancer, and lung cancer also have been associated.26 The soft tissue deficiency may result in asymmetrically greater lucency of the involved side on chest radiography. CT (Fig. 99-4) and MRI readily depict the absence of the pectoralis musculature and may be useful in assessing for concomitant latissimus dorsi hypoplasia if reconstructive surgery is planned.27

TRAUMA

FIGURE 99-3 Preoperative chest radiograph in a 47-year-old man with polyostotic fibrous dysplasia demonstrates fusiform expansion of multiple ribs bilaterally.

Ch099-F06861.indd 1211

Portable radiographs are often the first imaging examinations obtained in the trauma setting. They can reveal rib, clavicle, and scapula fractures. A flail chest, with paradoxical respiratory movement of the flail portion, may occur with fractures of five or more adjacent ribs or with multiple fractures of three or more ribs.28 Sternal fractures are usually caused by steering wheel and seat belt injuries (Franquet et al, 1997).29,30 They are not usually identifiable on frontal radiographs but are readily depicted by CT (Fig. 99-5). If sternal fractures are identified, the possibility of cardiac and mediastinal vascular injuries is considered. Although seldom needed primarily for the evaluation of fractures, CT is more sensitive than radiography in their identification28 and is also better for demonstrating associated hematoma, lung contusion, pneumothorax, soft tissue gas, and pleural effusion. Occasionally, CT is useful for distinguishing between a healing rib fracture and a pulmonary nodule when radiographs are inconclusive.

1/21/2008 3:26:57 PM

1212

Section 5 Chest Wall and Sternum

* *

* V A

FIGURE 99-4 CT image of a 69-year-old man incidentally reveals findings of Poland’s syndrome, with congenital absence of the right pectoralis major and minor muscles. Right serratus anterior muscle (asterisk) appears smaller than left (open square). Also note normal left pectoralis major (open circle) and minor (filled circle) muscles.

In most cases of sternoclavicular dislocation, the clavicular head is displaced anteriorly, which may be diagnosed clinically because of the usually obvious anterior chest wall deformity. Posterior dislocation, although far less common, is difficult to diagnose both clinically and radiographically and is a much more serious disorder. The medial end of the clavicle may injure adjacent mediastinal vascular structures such as the brachiocephalic veins, cause compression or displacement of the trachea, and result in esophageal injury.31-33 Rarely, superior dislocation of the clavicular head may occur. CT is the preferred imaging procedure; it allows rapid definition of the relationship between the clavicular head and sternum (Fig. 99-6), definitive diagnosis and distinction among the different types of dislocation, and identification and evaluation of any associated vascular or soft tissue injuries.31,34,35 Dislocations, abnormalities of adjacent soft tissues, and occult vascular injuries also can be evaluated with MRI.31 Infrequently, severe blunt trauma results in protrusion of the lung into the chest wall.32,36,37 Rarely, such lung hernias also may occur after thoracic surgery,38,39 spontaneously (following coughing or sneezing),39-43 or congenitally.39,41,44 With rare exception, lung hernias are intercostal (about two thirds of cases) or cervical (about one third).45 They may manifest clinically as a focal bulging of the chest wall or neck that appears or changes in size with breathing, coughing, straining, or lifting.36 Apical lung hernias may cause tracheal deviation.42 The diagnosis of lung hernia is often apparent on chest radiography as a bulging intercostal lucency into the chest wall or supraclavicular region, and it is even more readily made or confirmed by CT. Lung hernias are usually asymptomatic, and surgical repair is often unnecessary, but pain or hemoptysis may indicate strangulation.

Ch099-F06861.indd 1212

FIGURE 99-5 CT image of a 21-year-old man after a high-speed motor vehicle accident demonstrates a comminuted fracture of the manubrium (arrow). Adjacent mediastinal hemorrhage (asterisks) is separated from the top of the aortic arch (A) by a normal fat plane. There was no aortic injury. V, right brachiocephalic vein.

POSTSURGICAL CHANGES Thoracotomy Radiographic changes in the chest wall after lobectomy or pneumonectomy include decreased intercostal spaces secondary to volume loss and associated rib defects. Synthetic graft material used to cover larger defects resulting from chest wall resections can be delineated by CT,46 along with any abnormal postoperative fluid collections. Open-window thoracostomy for drainage of chronic pleural space infections produces a large chest wall defect that may have a dramatic appearance on CT, particularly after pneumonectomy (Fig. 99-7). Awareness of any tissue flaps used or packing material inserted is important if tumor recurrence is a potential concern. CT is effective in demonstrating any complications of open-window thoracostomy, including fluid collections and necrosis of tissue flaps.47 Thoracoplasty performed to collapse the lung in patients with tuberculosis in past decades, or to reduce the pleural space after lung resection, results in marked deformity of the rib cage, with fracture and inward displacement of multiple ribs (Fig. 99-8).

Median Sternotomy Sternal healing after sternotomy may not be apparent on CT until more than 3 months after surgery.48 Fluid, edema, and inflammatory changes normally may be seen in the soft tissues adjacent to the sternum and in the anterior mediastinum for

1/21/2008 3:26:58 PM

Chapter 99 Chest Wall and Sternum Imaging

1213

C V

B

A

FIGURE 99-6 A, Chest radiograph in a 24-year-old man after a motor vehicle accident shows a widened mediastinum, slight leftward deviation of the trachea, and subtle inferior displacement of the right clavicular head. B, CT image reveals posterior dislocation of the right clavicular head (C), which abuts the right brachiocephalic artery (arrow) and lies adjacent to the right brachiocephalic vein (arrowhead). Mediastinal widening is explained by the increased attenuation of the mediastinal fat, representing hematoma around the clavicular head and to the right of the trachea, which slightly compresses the right brachiocephalic vein (arrowhead). V, left brachiocephalic vein. C, Arteriogram shows minimal extrinsic compression of clavicle on right brachiocephalic artery (arrow) but no arterial injury.

C

several weeks, and air for up to 1 week, after median sternotomy.10,49-51 After healing, segmental gaps, uneven alignment, and mild impaction are commonly seen. Lateral migration of sternal wire fragments can be identified readily by chest radiography. CT allows precise localization when more distant migration occurs; rarely, serious complications, including erosion of wire fragments into the aorta, pulmonary artery, and bronchus, and fatal mediastinal hemorrhage, have been reported.52-54 Sternal dehiscence, an infrequent but serious postoperative complication of median sternotomy, may occur with or without infection or mediastinitis.55 Risk factors for sternal dehiscence include chronic obstructive pulmonary disease, obesity, diabetes, internal mammary bypass grafting, prolonged bypass time, reoperation for bleeding, prolonged

postoperative ventilation, and off-center sternal incision or inadequate fixation.51,53,56 Although dehiscence is usually detected clinically by sternal instability, sternal abnormalities including wire displacement, rotation, and fracture and a radiolucent midsternal stripe are identifiable on chest radiographs in most cases (Fig. 99-9), and radiographic detection may sometimes precede the clinical diagnosis.56,57 Sternal wire fractures are relatively common after sternotomy and alone are usually not related to sternal dehiscence. Though radiographs are useful for detecting sternal wire abnormalities in dehiscence, they are of limited value in the depiction of inflammatory changes and mediastinal fluid collections. CT or MRI may provide information regarding the cause of mediastinal widening seen postoperatively, such as high-attenuation hemorrhage (>30 HU), or may help to

Ch099-F06861.indd 1213

1/21/2008 3:26:59 PM

1214

Section 5 Chest Wall and Sternum

A

C

B

D

FIGURE 99-7 A, Frontal chest radiograph, in a 62-year-old man with an open-window thoracostomy and serratus muscle flap for bronchial stump dehiscence after pneumonectomy for squamous cell carcinoma, shows the thoracostomy defect in the left lateral chest wall and lobulated soft tissue in the left hemithorax. Mottled opacity is due to packing material. B and C, CT scans show soft tissue, representing the serratus anterior muscle flap (arrows), abutting the mediastinum and left hilar region. D, CT scan at a more caudal level demonstrates the large thoracostomy defect.

Ch099-F06861.indd 1214

1/21/2008 3:27:00 PM

Chapter 99 Chest Wall and Sternum Imaging

1215

determine whether a poststernotomy infection is limited to the presternal tissues or involves the anterior mediastinum.50,51,58,59 Localized mediastinal fluid collections and mediastinal air persisting for longer than about 2 weeks are more specific for a mediastinal abscess or mediastinitis.10,50,60 Aspiration may be needed to determine whether a mediastinal fluid collection is infected.61 CT can reveal sternal osteomyelitis with findings of demineralization, cortical erosion, bone destruction, new periosteal bone, and sclerosis (Novick and Fishman, 2003).51,62

COLLATERAL VESSELS Enlarged collateral vessels may be seen in the chest wall in patients with superior vena cava obstruction63 or occlusion of another major vein in the thorax or abdomen. They appear on CT as round or tubular structures that enhance after intravenous (IV) contrast administration (Fig. 99-10). Transient enhancement of normal thoracic wall veins on the side of contrast injection, particularly in the periscapular and supraclavicular regions, may be seen because of retrograde flow in chest wall veins resulting from compression of the subclavian veins during hyperabduction of the arms and the increased contrast flow rates produced by the use of a power injector. FIGURE 99-8 Frontal chest radiograph in a 72-year-old man previously treated with thoracoplasty for tuberculosis shows inward depression of multiple right ribs with consequent right upper lobe volume loss.

A

B

CHEST WALL INFECTIONS Inflammation, cellulitis, fasciitis, and abscesses of the chest wall may occur as a result of surgery, trauma, or direct exten-

C

FIGURE 99-9 A, Chest radiograph after coronary bypass grafting, taken at the time of discharge, shows normal alignment of median sternotomy wires. B, Chest radiograph taken several weeks later shows malalignment of sternal wires characteristic of dehiscence. C, CT image shows one of the wires pulled into the sternal incision (arrow), along with a tiny wire or bone fragment (open arrow), surrounded by fluid (arrowheads), extending into the mediastinum.

Ch099-F06861.indd 1215

1/21/2008 3:27:00 PM

1216

Section 5 Chest Wall and Sternum

*

A

C

sion from pulmonary, pleural, or mediastinal infections, or from extraosseous extension of osteomyelitis.10,64 The extent and severity of chest wall infections may be difficult to assess by physical examination alone. Plain radiographic findings are often absent, subtle, or nonspecific, such as focal soft tissue swelling. In addition, pulmonary infiltrates or pleural effusions may obscure osseous detail. CT and MRI are far more useful, with the capability of demonstrating inflammatory infiltration of chest wall fat planes, fluid collections, and gas. CT best depicts small areas of bone destruction, periosteal reaction, and gas,65 whereas soft tissue inflammation is better demonstrated with MRI.66 Although diffuse or focal chest wall infections may appear mass-like and indistinguishable from a neoplastic process by CT or MRI alone, an associated

Ch099-F06861.indd 1216

B

FIGURE 99-10 A, Chest CT scan in a patient with a history of Hodgkin’s disease, a right internal jugular port catheter, and face and neck swelling shows a thrombosed superior vena cava (asterisk) with enhancement of numerous collateral veins in the chest wall on the side of the contrast injection. B, CT scan at a more caudal level demonstrates collateral pathways through the medial segment of the left hepatic lobe (arrows) to reach the inferior vena cava (arrowhead). C, Maximum-intensity projection of CT scan data shows extensive chest wall collateral venous network.

empyema, fluid collection, or air-fluid level within the subcutaneous tissues, or skin fistulas, may provide imaging clues to the infectious nature of a chest wall process. Empyema necessitatis occurs when infected pleural fluid ruptures into the chest wall, often manifesting as a subcutaneous mass. Most often, this occurs secondary to tuberculosis, but it also may occur as a consequence of actinomycosis of blastomycosis or even after thoracentesis of a pyogenic empyema.10,67-69 With actinomycosis, swelling, draining sinus tracts and fistulas, periosteal reaction, and bone destruction are common.66,70 Individuals with poor dental hygiene and immunosuppression are predisposed. CT (Fig. 99-11) can demonstrate contiguity or proximity of the subcutaneous abscess with a pleural space collection and may show areas

1/21/2008 3:27:02 PM

Chapter 99 Chest Wall and Sternum Imaging

1217

*

A

FIGURE 99-11 CT image in a 48-year-old man with empyema necessitatis shows extensive pleural soft tissue thickening on the right in the inferior sulcus around the liver, an adjacent anterior chest wall fluid collection with rim enhancement (arrows), and adjacent soft tissue thickening. This patient had had several nondiagnostic percutaneous pleural and bronchoscopic lung biopsies during a 5month history of fevers, chills, night sweats, cough, and chest pain before development of a fluctuant right chest wall mass. Actinomyces was identified after drainage of the chest wall abscess and empyema. (MODIFIED FROM GIERADA DS, SLONE RM: PLEURA, CHEST WALL, AND DIAPHRAGM. IN LEE JKT, SAGEL SS, STANLEY RJ, HEIKEN JP [EDS]: COMPUTED BODY TOMOGRAPHY WITH MRI CORRELATION, VOL 1, 4TH ED. PHILADELPHIA, LIPPINCOTT WILLIAMS & WILKINS, 2006.)

of lung destruction beneath the pleural disease that were obscured on conventional radiographs.67,71 In osteomyelitis, three-phase bone scintigraphy provides detection in most cases; it may be supplemented by gallium 67 or radiolabeled white blood cell scanning in equivocal cases or to improve specificity in the setting of trauma, orthopedic prostheses, or diabetes.65,72 Any cortical destruction, periosteal proliferation, or soft tissue extension in osteomyelitis is much more reliably detected by CT than by radiography.72 Marrow changes in chest wall osteomyelitis are well depicted by MRI as decreased signal intensity on T1-weighted images, increased signal on T2-weighted images, and focal enhancement.1,73 However, other processes, such as bone contusion, healing fracture, and metastasis, can produce similar signal abnormalities, so the clinical context must be considered.72 Bone destruction, sequestra, and surrounding soft tissue abscesses with rim enhancement are common findings in tuberculous chest wall infection, which may affect the rib shaft, costovertebral joint, or costochondral junction and infrequently may involve the sternum.62,74-78 Osteomyelitis of the sternum is rare and is usually a complication of surgical median sternotomy. In anterior chest wall infections (including sternoclavicular infections), anterior mediastinal extension can occur;

Ch099-F06861.indd 1217

B FIGURE 99-12 A, CT image in a 74-year-old man with diabetes and Staphylococcus aureus bacteremia reveals a right sternoclavicular joint fluid collection (arrow) with an associated right pectoralis abscess (asterisk). B, In a slightly more caudal image, the fluid collection extends to the anterior extrapleural space (arrowheads) and into the anterior mediastinum (arrows). (MODIFIED FROM GIERADA DS, SLONE RM: PLEURA, CHEST WALL, AND DIAPHRAGM. IN LEE JKT, SAGEL SS, STANLEY RJ, HEIKEN JP [EDS]: COMPUTED BODY TOMOGRAPHY WITH MRI CORRELATION, VOL 1, 4TH ED. PHILADELPHIA, LIPPINCOTT WILLIAMS & WILKINS, 2006.)

increased density and stranding in anterior mediastinal fat, fluid collections, and mass effect on the great vessels may be seen on CT.62 The sternoclavicular joint is a common site for septic arthritis.79 An increased incidence of sternal and sternoclavicular joint infection has been associated with IV drug abuse.8,29 There are multiple additional predisposing conditions, including infection at a distant site, diabetes, and trauma, although up to one quarter of patients have no predisposing factors.80 Radiography may show soft tissue swelling and bone erosion or periosteal reaction, but it is relatively insensitive. CT (Fig. 99-12) and MRI are helpful in evaluating for sternoclavicular joint fluid collections, osteomyelitis, and chest wall or mediastinal abscess.80-82 Other common causes of painful sclerosis and swelling of the medial end of the clavicle, namely osteoarthritis and condensing osteitis, are usually distinguishable from sternoclavicular infection by CT or MRI.83 Costochondritis resulting from a bacterial or fungal infection can cause fragmentation and destruction of costal cartilage with soft tissue swelling, low-attenuation cartilage, and

1/21/2008 3:27:02 PM

1218

Section 5 Chest Wall and Sternum

localized peripheral calcification.84,85 Tietze syndrome, an inflammatory condition that includes chest pain as well as tenderness and swelling of the costal cartilage, can clinically mimic a chest wall mass. Although it usually involves a solitary costal cartilage, it can be multifocal.85 CT is useful primarily to exclude tumor, although mild focal cartilaginous enlargement is sometimes seen.10,86 Diffuse enlargement of costal cartilages also occurs in rickets and acromegaly.85

TUMORS OF THE CHEST WALL Both benign and malignant primary tumors may arise from any of the soft tissues or bones of the chest wall. Neoplasms such as bronchogenic and breast carcinoma, thymoma, lymphoma, and mesothelioma may involve the chest wall by direct extension. In addition, almost any primary malignancy can produce hematogenous metastases to the soft tissues or bones of the chest wall. Although patients frequently present with a painful or palpable mass, some are asymptomatic, and the tumor is discovered incidentally.87 Chest radiography is of limited value in identifying and characterizing chest wall tumors. Masses that project into the thoracic cavity or cause bone destruction may be detected radiographically, but masses confined to the chest wall soft tissues generally are not visible on radiographs unless they are so large that they cause gross asymmetry of the chest wall soft tissues. Both CT and MRI provide superior contrast, can delineate the extent of soft tissue infiltration, and help assess bone involvement by chest wall tumors. As with infectious processes, MRI is more sensitive in detecting bone marrow involvement and the extent of soft tissue involvement by chest wall tumors and is better for tissue characterization, whereas CT is better at identifying calcified tumor matrix and cortical bone destruction.4,66 Occasionally, it may be difficult to determine whether a mass arises from the chest wall or from the pleura because both can form lenticular masses along the lung margin. Bone destruction is definitive evidence of chest wall involvement, and extension between ribs is highly suggestive on crosssectional imaging. Benign lesions typically cannot be distinguished definitively from malignant lesions, however, so biopsy is frequently required.

Bone Tumors The thorax is an uncommon site for primary bone tumors, accounting for about 5% to 10% of all resected cases.88-90 The vast majority arise in the ribs.87,88,90,91 Primary rib tumors are about as frequently benign as malignant in some series,90-92 but in others malignant tumors are more common.87,89 Tumors of the sternum are overwhelmingly malignant.88,87

Benign Bone Tumors Chest radiographs often suffice for the assessment of nonaggressive or multiple thoracic bone lesions (see Fig. 99-3). CT may provide additional reassurance that a lesion is clearly a benign developmental, degenerative, or posttraumatic abnormality. Osteochondromas (exostoses), the most common benign tumors of cartilage and bone,6,8 are benign exophytic projections of bone. In the ribs, they frequently occur at the

Ch099-F06861.indd 1218

costochondral junction; they are usually lobulated with a cartilaginous cap,91 although continuity between the cortex and medulla often is not visible in rib lesions on CT or MRI images.3 Pain, bone erosion, irregular calcification, and thickening of the cartilaginous cap of more than 2 cm raises suspicion of malignant transformation to chondrosarcoma3,6,84; the risk is greatest in multiple hereditary exostoses (0.5%2.0%),84 an autosomal dominant condition. Benign bone islands appear as small sclerotic foci and commonly occur in the cancellous bone of the ribs, shoulder girdle, and spine. Occasionally, CT reveals that a suspected pulmonary nodule actually represents a bone island (Fig. 99-13), osteochondroma, or other lesion. Enchondromas are benign bone lesions that typically are well defined, lobulated, and expansile and contain diffuse, stippled, or cartilage matrix calcification.84,91 Although they are benign, complications can include pathologic fracture and an increased risk for malignant degeneration if the lesions are multiple and diffuse, as in Ollier’s disease (enchondromatosis) or Maffucci syndrome (enchondromatosis, hemangiomas).84 Aneurysmal bone cysts manifest as expansile lytic lesions, sharply demarcated by a thin shell of periosteum.91 They contain multiple blood-filled cysts and have the potential to extend beyond their sclerotic margin into adjacent soft tissues, which may make them hard to distinguish from sarcomas.3 Fluid-fluid levels may be seen on CT or MRI because of the hemorrhagic cyst contents, but these are not specific because they also can occur in simple bone cysts, giant cell tumors, chondroblastomas, telangiectatic osteosarcomas, and other tumors.3,93,94 Eosinophilic granuloma is a benign destructive bone lesion of unknown etiology that frequently involves the ribs and sternum.6,95 It typically appears as a geographic lytic defect with well-defined margins. There may be some expansion.91 Hemangioma manifests as an expansile lesion with internal trabeculations and an intact cortical margin.96 CT can reveal typical so-called honeycomb, soap bubble, or sunburst appearances; both CT and MRI can show lipomatous portions.6 Giant cell tumors are usually found in young adults, after epiphyseal closure. They are rare in the thorax97 but can arise in the sternum, clavicle, and ribs as osteolytic, expansile lesions with cortical thinning.3 Although considered benign, they may be locally aggressive, with recurrence rates of 30% to 50%.98 Other rare benign bone tumors that have been described in the chest wall include chondroblastoma84 and chondromyxoid fibroma.3 Both lesion types are radiolucent and well defined.

Malignant Bone Tumors Destructive lesions of the ribs or sternum are usually caused by metastases or myeloma. Both processes generally appear as areas of subtle or complete lytic destruction of the cancellous and cortical bone (Figs. 99-14 to 99-16).66,99 A soft tissue mass may accompany the bone destruction and is visible on CT or MRI. Widespread lytic metastatic disease or myeloma also may manifest as a diffuse, mottled appearance of the thoracic skeleton. Sclerosis may be seen in myeloma, more frequently in healing fractures or after treatment.4 Metasta-

1/21/2008 3:27:04 PM

Chapter 99 Chest Wall and Sternum Imaging

A

1219

B

FIGURE 99-13 A, Posteroanterior chest radiograph in a 58-year-old man who had a positive tuberculin skin test shows a small nodular opacity in the left mid lung zone (arrow). B, CT scan reveals that the opacity corresponds to a well-circumscribed sclerotic focus in the posterior sixth rib (arrow), characteristic of a bone island. No pulmonary nodule was identified.

FIGURE 99-14 Enlargement of a portion of the chest radiograph in a patient with right clavicular pain and hematuria shows a focal lytic lesion of the right clavicle (arrows). Additional imaging revealed a left renal mass, leading to a diagnosis of renal cell carcinoma with bone metastasis.

Ch099-F06861.indd 1219

ses from thyroid and renal cancer are invariably lytic; lung, breast, and colorectal cancer usually produce lytic or mixed lytic and blastic lesions; and blastic metastases are usually produced by prostate and neuroendocrine carcinomas, which can cause diffuse sclerosis.64 Metastatic involvement also may occur by direct spread, such as from lung cancer; bone destruction provides unequivocal evidence of chest wall invasion (Fig. 99-17). Primary malignant tumors of the thoracic skeleton include chondrosarcomas, osteosarcomas, fibrosarcomas, and round cell tumors. Chondrosarcoma is the most common primary malignant tumor of the chest wall; it more frequently arises from the anterior ribs near the costochondral junction (Fig. 99-18) than from the sternum, clavicle, or scapula.84,99 Peaks of prevalence occur before 20 years of age and at about 50 years of age.84,99 Most are primary, but some arise from benign lesions, such as osteochondroma or enchondroma.4,84 Chondrosarcomas often manifest as large, lobulated tumors with associated cortical bone destruction and internal calcifications.8,91,100 Secondary chondrosarcomas may be lytic.84 On MRI, typical chondrosarcomas have signal intensity similar to muscle with T1 weighting, similar to or higher than fat with T2 weighting, and heterogeneous enhancement with gadolinium; myxoid variants lack calcification and may have very high signal intensity on T2-weighted images.3,101 Osteosarcomas usually produce a mixed lytic and sclerotic pattern, depending on the amount of bone production by the tumor; the parosteal form attaches to the outer margin of the cortex.8 Chest wall tumors previously known as primitive

1/21/2008 3:27:04 PM

1220

Section 5 Chest Wall and Sternum

*

6 3

A

*

*

C

B FIGURE 99-15 A, Posteroanterior chest radiograph in a 50-year-old man with subacute chest, right shoulder, and back pain demonstrates destructive lesions of the posterior right sixth (6) and anterior left third (3) ribs with surrounding hazy opacities. B, CT scan reveals a right upper lobe mass that proved to be a primary lung cancer (arrow) and a large mass (asterisk) replacing a portion of the left third rib, consistent with metastasis. Enlarged lymph nodes are present anterior to the right upper lobe bronchus. C, More caudal CT image shows additional rib metastases (asterisks).

neuroectodermal or Askin tumors are aggressive forms of Ewing’s sarcoma (Tateishi et al, 2003).4,5 These small cell tumors occur most often in children and young adults. They usually arise in the rib, scapula, clavicle, or sternum but may be extraskeletal. Masses may be large, with inhomogeneous CT attenuation due to areas of hemorrhage or necrosis, with or without calcification. MRI features of both osteosarcomas and Ewing’s sarcoma are nonspecific and include signal intensity similar to or greater than muscle on T1-weighted images, enhancement with gadolinium, and heterogeneous high signal on T2-weighted images (Tateishi et al, 2003).4

Soft Tissue Tumors Primary chest wall soft tissue tumors are typically of mesenchymal origin and may arise from the fat, fibrous, vascular,

Ch099-F06861.indd 1220

neural, muscular, or dermal tissues. Chest radiography may show the mass if it is large, bulges into the thoracic cavity, or causes bone destruction but provides little detail. Although CT and MRI rarely allow a specific diagnosis of masses other than lipomas and hemangiomas, these modalities can play an important role in determining the extent of the tumor and involvement of adjacent structures. Distinction between benign and malignant masses with CT and MRI is not reliable, though a capsule or pedicle, smooth margins, and homogeneous signal intensity on MRI are more suggestive of a benign lesion, whereas irregular or ill-defined margins, heterogeneous signal intensity on MRI, and muscle, bone, or vascular invasion favor a malignant lesion. However, chest wall infection and hematoma also may have irregular margins and heterogeneous signal, mimicking a malignant lesion (Fortier et al, 1994).102 Because of its greater soft tissue contrast, MRI

1/21/2008 3:27:05 PM

Chapter 99 Chest Wall and Sternum Imaging

1221

B

A

FIGURE 99-16 CT images showing destructive sternal masses in three different patients. A, Plasmacytoma. B, Metastatic thyroid cancer. C, Undifferentiated sarcoma, involving the left pectoralis major and extending into the anterior mediastinum.

generally is the preferred radiologic modality for evaluating the extent of soft tissue tumors, although CT has greater spatial resolution and can better detect calcifications and bone destruction.

Benign Soft Tissue Tumors Lipomas are the most common soft tissue tumor involving the chest wall. They may be subcutaneous, intramuscular, or extrapleural; rarely, they are infiltrating and diffuse and the term lipomatosis of the chest wall is most appropriate. If a lipoma occurs in the extrapleural fat along the lung margin, it can displace pleura inwardly and mimic a pleural or pulmonary mass on conventional radiography. Lipomas are easily diagnosed on CT by their characteristic, relatively homogeneous fat attenuation (−80-−90 HU) (Fig. 99-19). They follow the signal intensity characteristics of subcutaneous fat on all MRI sequences, demonstrating high signal intensity on T1-weighted images, intermediate signal on T2-weighted images, and low signal intensity with short tau inversion recovery (STIR) and fat saturation techniques (Fig. 99-20). Lipomas usually have sharply defined margins, exhibit very little architecture except for a thin capsule or septations, and occasionally contain small calcifications. In comparison, lipo-

Ch099-F06861.indd 1221

C

sarcomas are typically inhomogeneous, containing soft-tissue attenuation components in addition to or instead of fat in the stroma, and are generally large and infiltrating. They are usually distinguished confidently from a benign lipoma on CT or MRI. If thickened septa, nodules, or soft tissue components are present within masses of predominantly fat composition, a well-differentiated liposarcoma is suspected, although such features may also have benign causes such as fat necrosis, fibrosis, myxoid change, or a variant such as chondroid lipoma, angiolipoma, or lipoleiomyoma.103-105 Neurogenic tumors, including schwannomas and neurofibromas, can be seen in the chest wall involving the intercostal nerves and spinal nerve roots. Extension into a neural foramen is evidence of a neurogenic origin. Schwannomas (neurilemomas, neurinomas) (Tateishi et al, 2003)3 are usually slow growing and often are incidentally discovered on chest radiographs obtained for unrelated reasons. These tumors are typically well circumscribed, round, ovoid, or lobulated masses (Fig. 99-21). On CT, they usually have attenuation similar to or slightly lower than muscle, and they enhance mildly with contrast. Any areas of cystic degeneration are lower in attenuation and unenhancing. On MRI, schwannomas have a signal intensity similar to or slightly higher than that of muscle with T1 weighting, and markedly higher than muscle with T2

1/21/2008 3:27:06 PM

1222

Section 5 Chest Wall and Sternum

7

A

C

weighting. The nerve of origin may be seen tapering from a margin of the mass (Fig. 99-22). Small tumors tend to enhance uniformly with gadolinium, whereas larger tumors may enhance heterogeneously (Tateishi et al, 2003).3 Neurofibromas are most commonly (but not always) associated with type 1 neurofibromatosis or multiple plexiform neurofibromas (Tateishi et al, 2003).3 They are slightly low in attenuation on CT and enhance heterogeneously with IV contrast. On MRI, many neurofibromas have characteristic peripheral high signal intensity and central lower signal intensity on T2-weighted images, related to central cellularity and peripheral stromal material, which results in central contrast enhancement.3 Plexiform neurofibromas may extensively infiltrate the chest wall. Intramuscular neurofibromas may be

Ch099-F06861.indd 1222

B

FIGURE 99-17 Posteroanterior (A) and lateral (B) chest radiographs in a 75-year-old man with right-sided rib pain subsequently found to have lung cancer show destruction of the posterior right seventh rib (7) with surrounding, ill-defined, pleural-based opacity (arrows). C, CT scan reveals a soft tissue mass in the periphery of the right lower lobe, invading the chest wall and replacing the rib.

difficult to delineate with CT because of limited soft tissue contrast discrimination, but their chest wall extent is readily evaluated with MRI because of their high signal on T2weighted images.8 The intraspinal extent of a neurogenic tumor usually can be depicted with MRI, obviating contrast myelography. There is a risk of malignant degeneration of neurofibromas,3 as much as 10% to 20% in neurofibromatosis, but lesions may still be benign even if inhomogeneous attenuation is seen. Cavernous hemangiomas are benign vascular tumors found in the skin, soft tissues, and bones of the chest wall. CT reveals a soft tissue mass of heterogeneous attenuation depending on the vascular, fat, and fibrous components and can depict characteristic phleboliths if they are present

1/21/2008 3:27:06 PM

Chapter 99 Chest Wall and Sternum Imaging

1223

*

FIGURE 99-19 CT image in a 73-year-old man with small cell cancer of the lung reveals an incidental right subscapular, intermuscular lipoma (asterisk). The mass is of homogeneous fat attenuation. Enlarged right hilar and subcarinal lymph nodes are present.

plasm.113 As the lesion matures, identification of a peripheral rim of calcification and ossification around a more lucent region may suggest the true nature of the lesion; MRI correlates include a low-signal-intensity border and a central area containing fat or high T2 signal intensity.114 FIGURE 99-18 CT image in an 82-year-old woman reveals a predominantly low-attenuation mass with minimal internal enhancement arising from the anterior costal cartilage, representing a chondrosarcoma with myxoid matrix and foci of dedifferentiation.

(Tateishi et al, 2003).3 Hemangiomas contain tortuous vessels that enhance after contrast administration. The finding of a network of tortuous vessels containing phleboliths is considered specific for hemangioma.106 The excellent soft tissue contrast of MRI best demonstrates the extent of hemangiomas. Signal intensity varies depending on the proportion of vascular, fat, and fibrous components, as well as the presence of thrombus, hemosiderin, and old blood.1 Lymphangiomas manifest as masses that may be confused with hemangiomas.107 These masses are usually cystic and smoothly marginated, being composed of sequestered ectatic lymphatic tissue separated from the lymphatic drainage system.107 They arise most frequently in the neck; may extend into the mediastinum, chest wall, or axilla; and often require surgical resection. They typically appear as near-water attenuation cystic masses on CT, though may be of higher attenuation due to hemorrhage, proteinaceous substance, or hemangiomatous elements.108-111 Preoperative planning involves careful evaluation of the full extent of the lymphangioma to minimize the risk of recurrence. Lymphangiomas are best evaluated by MRI, which is better suited to define the extent and degree of infiltration of adjacent tissues; water signal intensity on all pulse sequences is typical,1 although intermediate signal in some lymphangiomas on T1- and T2weighted images also has been reported.111 Sebaceous cysts are commonly encountered as lowattenuation, circumscribed lesions within the subcutaneous fat. Glomus tumors can occur in the chest wall and are much more often benign than malignant (Tateishi et al, 2003).3,112 CT findings are nonspecific. Myositis ossificans is unusual in the chest wall and may be mistaken for a malignant neo-

Ch099-F06861.indd 1223

Malignant Soft Tissue Tumors Soft tissue sarcomas of the chest wall, including desmoid tumor (Fig. 99-23), malignant fibrous histiocytoma, fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma (Fig. 99-24), malignant peripheral nerve sheath tumor, synovial sarcoma, and other less common sarcomas, all have a similar appearance on CT.8 The findings are those of nonspecific soft tissue masses, with or without low-attenuation areas of necrosis and variable, often heterogeneous, enhancement. Occasionally, the presence of fat allows distinction of a well-differentiated liposarcoma from other tumor types. There is enough overlap with benign lesions, however, that benign and malignant lesions usually cannot be distinguished with complete certainty by CT or MRI. Bone, vessel, or muscle invasion; intrathoracic extension; or pulmonary metastases occasionally provide clues to the malignant nature of a chest wall sarcoma. Desmoid tumors are considered low-grade fibrosarcomas.1,4 They are a diagnostic and therapeutic challenge because they tend to be locally aggressive and to recur if inadequately excised,87,115 although they do not metastasize.4,8 They lack a capsule and may infiltrate extensively into surrounding tissue and even intrathoracically. Wide surgical resection is required to try to prevent recurrence.115 On CT scans (see Fig. 99-23), desmoid tumors are of nonspecific soft tissue attenuation with variable enhancement. On MRI, they have signal intensity similar to muscle with T1 weighting. With T2 weighting, they are mostly intermediate in signal intensity but may have areas of very low (due to collagen) or very high signal intensity.4,115,116 They may cause pressure erosions on bone but do not usually invade bone.4 Lymphoma involves the chest wall in 10% to 15% of patients and can arise from interpectoral or lateral thoracic lymph nodes, from internal mammary nodes, or by extension of contiguous mediastinal or pleuropulmonary disease.10,117 Primary muscle lymphoma tends to be infiltrative without confinement to muscle compartments.118 Lymphoma typi-

1/21/2008 3:27:07 PM

1224

Section 5 Chest Wall and Sternum

*

*

S

S

L

L

B

A

*

S

L

C

Ch099-F06861.indd 1224

FIGURE 99-20 A-C, MRIs in a 46-year-old woman with chest wall pain during arm movement demonstrate a right chest wall mass (asterisk) between the latissimus dorsi (L) and serratus anterior (S) muscles, with homogeneous signal intensity identical to fat on T1- (A) and T2- (B) weighted images and signal loss identical to subcutaneous fat on T1weighted image with fat saturation (C), consistent with a lipoma, which was subsequently resected. Comparison with a CT scan from 4 years earlier had revealed interval growth.

1/21/2008 3:27:08 PM

Chapter 99 Chest Wall and Sternum Imaging

A

C

Ch099-F06861.indd 1225

1225

B

FIGURE 99-21 A, Posteroanterior chest radiograph in a 33-year-old woman who had left-sided chest pain shows a mass with sharp inferior (arrows) and indistinct superior borders, with associated inferior rib notching (arrowhead) suggesting an extrapleural origin. B, Lateral radiograph shows smoothly marginated mass (arrows) abutting the posterior chest wall. C, CT image reveals pleural-based soft tissue mass forming obtuse angles with the chest wall. Biopsy and resection revealed an intercostal schwannoma.

1/21/2008 3:27:08 PM

1226

Section 5 Chest Wall and Sternum

*

B

A

*

C

D

FIGURE 99-22 A, Posteroanterior chest radiograph in a 78-year-old man with a schwannoma shows a left apical mass with smooth inferior border (arrows). B, Coronal T1-weighted MRI demonstrates intermediate signal intensity of the mass (asterisk), which arises from a thickened left first thoracic nerve root (arrow). High-signal-intensity fat plane between the mass and the lung confirms the extrapleural location of the mass. C, Sagittal T2-weighted MRI with fat saturation reveals high signal intensity of the mass (asterisk). D, Axial T1-weighted MRI with gadolinium shows mild heterogeneous enhancement of the mass (arrows), which abuts the left subclavian artery (arrowheads).

cally has CT attenuation similar to muscle and enhances slightly after IV contrast administration4 (Fig. 99-25). MRI, on which lymphomas generally appear similar to or higher than fat in signal intensity on T2-weighted images, is more sensitive than CT for detecting chest wall involvement by lymphoma.118-120 Hematogenous metastases (Fig. 99-26) also can involve the soft tissues of the chest wall.

Ch099-F06861.indd 1226

Chest Wall Invasion Primary pulmonary or pleural neoplasms may secondarily involve the parietal pleura and chest wall. The only reliable sign of chest wall invasion by a mass contacting the parietal pleura is rib or spine destruction (see Fig. 99-17). Abnormal soft tissue extending external to the margin of the ribs on CT

1/21/2008 3:27:09 PM

Chapter 99 Chest Wall and Sternum Imaging

FIGURE 99-24 CT image without IV contrast in a 66-year-old woman with a history of breast cancer treated with lumpectomy and radiation therapy 7 years previously demonstrates a nonspecific soft tissue mass in the lower left anterior chest wall, extending from the anterior costal margin to the skin. This proved to be a pleomorphic leiomyosarcoma, possibly induced by the previous radiation therapy.

FIGURE 99-23 CT image in a 36-year-old woman who felt a palpable lump reveals a nonspecific soft tissue mass located inferiorly in the anterior chest wall, abutting the left costal cartilage. Open biopsy revealed a desmoid tumor. A full-thickness resection of the mass and chest wall was performed, with chest wall reconstruction.

A

1227

B

FIGURE 99-25 A, Posteroanterior chest radiograph in a 31-year-old man with recurrence of a sarcomatoid variant of Hodgkin’s disease shows a vague increase in opacity overlying the right upper lung, with lytic destruction of the anterior second and third ribs. B, CT scan reveals a large, slightly hypoenhancing soft tissue mass in the anterior right chest wall, replacing the pectoralis muscles and anterior second rib and bulging into the right hemithorax.

also supports chest wall invasion.121 CT findings such as obtuse angles of the mass with the chest wall, more than 3 cm of contact of the mass with the pleural surface, pleural thickening adjacent to the mass, abnormal extrapleural fat attenuation, and asymmetry of the chest wall soft tissues often occur with invasion by lung cancer but can also be caused by inflammatory changes, scarring, or asymmetric patient positioning.10,122 Therefore, in most cases, CT is of fairly limited value in identifying chest wall invasion. The accuracy of MRI in identifying chest wall invasion by lung cancer has been found to be equal to (Webb et al,

Ch099-F06861.indd 1227

1991)123 or greater than that of CT.1,124,125 Signs of chest wall invasion include tumoral signal intensity in the chest wall soft tissues (Fig. 99-27), ribs, or spine and interruption of the extrapleural fat plane by tumoral signal intensity. However, abnormal chest wall signal may be caused by inflammation and is not always reliable. Preoperative identification of chest wall invasion may aid surgical planning. For tumors in the superior sulcus, it is important to determine whether invasion extends into the chest wall to involve the brachial plexus or subclavian artery (Fig. 99-28). In some cases, shrinking an invasive superior

1/21/2008 3:27:10 PM

1228

Section 5 Chest Wall and Sternum

sulcus tumor through the use of neoadjuvant chemotherapy and radiation therapy allows resection to be performed (Fig. 99-29). Advances in chest wall reconstruction have facilitated potentially curative resections.87 Postoperatively, chest wall prostheses of Marlex mesh molded to the chest wall contour with methyl methacrylate are not visible radiographically but are easily depicted by CT, having attenuation greater than that of bone.46

tissue contrast. Lesions are typically of low signal intensity with T1 weighting and of high signal intensity with T2 weighting. Radiation fibrosis, primary and metastatic lung cancer, and metastatic breast cancer account for almost three fourths of nontraumatic cases of brachial plexopathy.131 Primary tumors are relatively uncommon. Benign varieties include neurofibromas and schwannomas and, even more rarely, lipomas, lymphangiomas, hemangiomas, and ganglioneuromas.129,131-134 Plexiform neurofibromas occur in patients with type I neurofibromatosis. Malignant tumor types are mostly fibrosarco-

AXILLA The axilla contains the axillary artery and vein, branches of the brachial plexus, and lymph nodes and is well demonstrated on conventional chest CT or MRI examination. CT may detect enlarged axillary lymph nodes that are not palpable on physical examination, particularly in patients with breast cancer, lymphoma, upper extremity melanoma, or infection.126,127 Because size is the primary criterion for evaluating lymph nodes, the sensitivity and specificity of CT and MRI are limited; lymph nodes of normal size may contain metastases, and enlarged lymph nodes greater than 1 cm in the short axis may occur in reaction to nonmalignant processes.

BRACHIAL PLEXUS MRI is the procedure of choice for evaluating the brachial plexus (Rapoport et al, 1988).128-131 CT also can depict the brachial plexus, but artifacts from the adjacent shoulder bones and from inflowing concentrated IV contrast sometimes limit anatomic detail, and MRI provides better soft

FIGURE 99-26 CT scan showing numerous soft tissue nodules throughout the subcutaneous fat caused by metastatic melanoma.

3

4

4

A

B

FIGURE 99-27 A, T1-weighted MRI in a 68-year-old woman with lung cancer reveals invasion of the large right upper lobe tumor into the chest wall (arrows) between the third (3) and fourth (4) ribs. B, Slightly more caudal T1-weighted image taken after administration of IV gadolinium demonstrates enhancing tumor within the chest wall (arrows) surrounding the fourth rib (4). The central portion of the tumor does not enhance, suggesting necrosis.

Ch099-F06861.indd 1228

1/21/2008 3:27:11 PM

Chapter 99 Chest Wall and Sternum Imaging

mas and malignant neurofibromas and schwannomas but also include lymphomas and synovial sarcomas.129,131,133,134 The MRI features of benign and malignant neurogenic tumors overlap, as do those of schwannomas and solitary neurofibromas.135,136 All tend to be isointense to muscle on

T1-weighted images, hyperintense on T2-weighted images, and usually show significant contrast enhancement. One characteristic described for benign neurogenic tumors is the target sign, which refers to central low signal on T2-weighted images, possibly due to organized collagen.135,136 Larger, more heterogeneous masses with irregular margins are findings more suggestive of malignancy. Secondary neoplastic involvement can occur from metastatic breast cancer; or by direct extension of soft tissue tumors such as superior sulcus lung carcinoma (Pancoast tumor) (see Fig. 99-28), lymphoma, myeloma, desmoid tumor, or chest wall sarcoma; or from distant primaries.129-131 The lesser accuracy of CT compared with MRI for evaluating chest wall invasion in superior sulcus tumors124 may be improved by the technological advances of helical scanning and multiplanar reformatting, but the relative advantages of greater contrast resolution and reduced shoulder region artifacts with MRI still exist. Combined PET-CT scanning also may prove useful (see Fig. 99-29). Radiation fibrosis, most commonly from treatment of breast cancer, may be diagnosed on MRI with the appropriate history and hypointense signal on T1- and T2-weighted images,130,131,137 although tumors with desmoplasia can have similar signal characteristics. Diffuse thickening of the nerves may be seen. Radiation-induced changes alone may enhance with gadolinium and may be of high signal intensity on T2weighted images, making their distinction from recurrent tumor difficult.130,131,136,138,139 A focal mass is suspicious for recurrent tumor and is the most reliable means of distinction from radiation fibrosis by MRI.129,130,136,139,140 In the absence of brachial plexus abnormalities, MRI may reveal other causes for symptoms, such as myositis, synovitis, or bone metastasis.140

*

FIGURE 99-28 T1-weighted coronal MRI demonstrates extension of a superior sulcus carcinoma into the chest wall, surrounding and indistinct from the proximal nerves of the brachial plexus (asterisk).

A

1229

B

FIGURE 99-29 A, Fluorodeoxyglucose (FDG)-enhanced positron emission tomography–CT (PET-CT) image in a patient with superior sulcus carcinoma shows a soft tissue mass in the posterior right lung apex. Increased FDG uptake is seen in the medial portion of the mass and in the adjacent rib. B, A follow-up scan obtained after neoadjuvant chemoradiation therapy reveals a decrease in size of the mass and no FDG uptake. Pathology after resection revealed microscopic foci of poorly differentiated carcinoma and radiation artifact in the primary mass, with no evidence of chest wall tumor.

Ch099-F06861.indd 1229

1/21/2008 3:27:12 PM

1230

Section 5 Chest Wall and Sternum

Trauma involving the proximal nerves may result in nerve root avulsion and formation of a pseudomeningocele, which can be readily demonstrated by MRI.129,136,141-143 The most common cause in adults is motorcycle accidents. Compared with conventional MRI techniques that may be limited by motion artifacts and partial volume averaging, CT myelography is more reliable for assessing nerve root integrity.129,135,144 With a thin-section, overlapping oblique coronal technique, however, MRI has been found comparable to CT myelography in determining nerve root avulsion.145 Brachial neuritis, or Parsonage-Turner syndrome, may be caused by a viral infection or its sequelae; or may occur as a complication after use of a vaccine, antibiotic, or other drug; or may be idiopathic. Nerve thickening, increased nerve signal with T2-weighting, and gadolinium enhancement of the nerves, or else normal nerves with shoulder muscle atrophy and increased T2 signal of muscle due to denervation and neurogenic edema, may be seen on MRI.129,130,135,136,138,141,146

COMMENTS AND CONTROVERSIES The chest wall, including the sternum, may be affected by a wide variety of processes that include congenital deformities, trauma, primary and secondary malignancies, and infections. In all of these processes, CT scanning and MRI assist in the evaluation and diagnosis and have complementary roles. Not only is CT useful to delineate the extent of bone and soft tissue involvement, but it also readily shows small calcifications as well as areas of bone destruction. CT signs that suggest malignancy include rapid increase in tumor size, cortical bone destruction, and involvement of surrounding structures. MRI is helpful in determining compression or invasion of major vascular structures. It is also the best imaging technique to demonstrate soft tissue involvement and invasion of the spine. Additional useful diagnostic techniques include ultrasonography, to document the tumor’s relationship to the pleura and lung, and nuclear bone scanning, which is not specific but may help identify other sites of disease or distant metastases. In chest wall tumors, CT and MRI may be specific enough to avoid the need for histologic confirmation by closed or open biopsy. In all of these patients, conventional chest radiographs are still of considerable value, especially if one takes the time to compare new and old radiographs. Chest fluoroscopy is another imaging modality that has fallen out of popularity but can still be useful to distinguish

Ch099-F06861.indd 1230

a lesion located in the periphery of the lung from a lesion of the chest wall. J. D.

KEY REFERENCES Fortier M, Mayo JR, Swensen SJ, et al: MR imaging of chest wall lesions. RadioGraphics 14:597-606, 1994. ■ This study of the MRI features of chest wall masses in 45 patients demonstrates that, although certain features tend to be associated with a benign or malignant etiology, most chest wall lesions other than lipoma and arteriovenous malformation cannot be classified as benign or malignant solely by MRI characteristics. Franquet T, Gimenez A, Alegret X, et al: Imaging findings of sternal abnormalities. Eur Radiol 7:492-497, 1997. ■ Comprehensive, well-illustrated overview providing examples of the radiographic, CT, MRI, and scintigraphic assessment of sternal neoplasms, infection, and trauma. Novick SL, Fishman EK: Anterior mediastinal extension of primary chest wall infections: Role of spiral CT in detection and management. Crit Rev Comput Tomogr 44:79-93, 2003. ■ This case series of anterior chest wall infections unrelated to surgery demonstrates the high efficacy of CT scanning in the assessment of mediastinal involvement. Rapoport S, Blair DN, McCarthy SM, et al: Brachial plexus: Correlation of MR imaging with CT and pathologic findings. Radiology 167:161165, 1988. ■ This article demonstrated the advantages of MRI in evaluating the brachial plexus in the setting of neoplasm, trauma, and inflammation, supporting its role as the imaging procedure of choice. Tateishi U, Gladish GW, Kusumoto M, et al: Chest wall tumors: Radiologic findings and pathologic correlation. Part 1: Benign tumors. Radiographics 23:1477-1490, 2003. ■ Comprehensive, illustrated review of CT, MRI, and pathologic findings in benign bone and soft tissue tumors of the chest wall. Tateishi U, Gladish GW, Kusumoto M, et al: Chest wall tumors: Radiologic findings and pathologic correlation. Part 2: Malignant tumors. Radiographics 23:1491-1508, 2003. ■ Comprehensive, illustrated review of CT, MRI, and pathologic findings in malignant bone and soft tissue tumors of the chest wall. Webb WR, Gatsonis C, Zerhouni EA, et al: CT and MR imaging in staging non-small cell bronchogenic carcinoma: Report of the radiologic diagnostic oncology group. Radiology 178:705-713, 1991. ■ This multicenter, prospective study determined that CT and MRI are equivalent for evaluating chest wall invasion by lung cancer and confirmed that both have limited sensitivity and specificity.

1/21/2008 3:27:13 PM

chapter

100

DIAGNOSTIC STRATEGIES FOR A CHEST WALL MASS Nirmal K. Veeramachaneni Richard J. Battafarano

Key Points

sify chest wall masses by site of origin or by biologic behavior. Masses may be inflammatory or neoplastic (Table 100-1).

■ Chest wall masses may arise from bone or muscle, by extension

from underlying structures, or from metastatic disease. ■ Most primary chest wall neoplasms are benign. ■ Rapid growth of a mass or symptoms of pain suggest malig-

nancy. ■ Most malignant chest wall masses are a result of metastatic

disease. ■ Computed tomographic (CT) scanning and magnetic resonance

imaging (MRI) accurately delineate a chest wall mass and in some cases establish the diagnosis. ■ Tissue diagnosis is essential because some masses benefit from preoperative chemotherapy or radiation.

Chest wall masses present unique diagnostic challenges to the treating physician. The advent of improved cross-sectional imaging techniques over the past 2 decades has improved our diagnostic acumen greatly. Physicians are no longer limited to plain radiographs, which may demonstrate radiolucent or calcified masses and provide little other information. The combination of CT scanning, MRI, and metabolic studies such as fluorodeoxyglucose positron emission tomography (FDG-PET) have given us the ability to distinguish aggressive from nonaggressive lesions and inflammatory or infectious processes from neoplastic growth. In some circumstances, these imaging modalities have eliminated the need for tissue biopsy to formulate diagnosis. Other chapters in this textbook specifically address the diagnosis and management of specific neoplasms of the sternum and chest wall, as well as radionecrosis and infectious complications of the chest wall in greater detail. This chapter focuses on the differential diagnosis of chest wall masses and strategies to evaluate the etiology of these masses. Because the underlying cause of a given chest wall mass can range from a posttraumatic hematoma that will resolve without intervention to a high-grade sarcoma requiring multimodality therapy, a thorough evaluation of any chest wall mass must be performed before initiating any treatment. A careful history concerning the growth of the mass, the presence or absence of pain, and any history of trauma must be obtained. Systemic signs and symptoms of fever, night sweats, and weight loss is also sought. Masses of the chest wall may arise from any of its components: bone, muscle, or underlying structures (Faber et al, 1995).1 Additionally, they may arise as a result of metastatic disease (Fig. 100-1). One may clas-

INFLAMMATORY CHEST WALL MASSES The soft tissue injury associated with trauma and infection may lead to discreet inflammatory chest wall masses. Although a careful history may elicit the cause, some patients deny an antecedent event to implicate trauma or minimize constitutional symptoms such as fever. Comparison of current radiographic studies with prior studies may demonstrate stability of a lesion and thereby avoid the need for biopsy. However, in many patients, a tissue diagnosis is needed to guide therapy. Inflammatory masses associated with tuberculosis may manifest with bone destruction, a soft tissue cystic mass, or a soft tissue mass with peripheral calcification.2 Similarly, fungal infections involving the lung or pleural space, such as blastomycosis, candidiasis, coccidioidomycosis, and actinomycosis, may have an indolent course and manifest with direct extension through the chest wall. Osteomyelitis may be the result of secondary infection after surgical intervention or trauma, or it may result from direct hematogenous seeding of the bone marrow after bacteremia. Characteristic findings include the new onset of a mass, periosteal elevation of the afflicted bone, and loss of deep soft tissue planes (Tateishi et al, 2003) (Fig. 100-2).3

BENIGN NEOPLASTIC LESIONS The majority of primary chest wall neoplasms are benign and originate in cartilaginous structures. Benign tumors tend to be slowly growing and asymptomatic (Burt, 1994).4 Osteochondroma comprises 50% of all nonmalignant rib tumors. Chondroma and fibrous dysplasia represent the majority of the remaining benign neoplasms of the chest wall bone structures.5 A number of less common masses originating from peripheral nerves may yield symptoms of pain, or show bone erosion, without lytic destruction.6 These peripheral nerve tumors typically have a characteristic appearance on CT and MRI. Similarly, tumors such as lipomas have a characteristic uniform appearance on CT and MRI (Fig. 100-3). With the appropriate clinical history and imaging, these benign lesions may often be observed.

MALIGNANT NEOPLASTIC LESIONS Unlike benign chest wall masses, malignant chest wall masses tend to be rapidly growing and to cause chest pain (Anderson and Burt, 1994).7 Although more than 50% of malignant chest wall tumors result from metastasis or direct invasion of 1231

Ch100-F06861.indd 1231

1/21/2008 3:28:03 PM

1232

Section 5 Chest Wall and Sternum

TABLE 100-1 Differential Diagnosis of a Chest Wall Mass Inflammatory Traumatic Healing rib fracture Soft tissue contusion Hematoma Infectious Osteomyelitis Tuberculosis Blastomycosis Candidiasis Coccidioidomycosis Actinomycosis Aspergillosis

FIGURE 100-1 A 36-year-old woman with a history of transitional cell carcinoma of the bladder was noted to have a mass originating from the left fourth rib on a screening chest radiograph. She was asymptomatic. Core biopsy and resection revealed adenocarcinoma of unknown origin.

FIGURE 100-2 A 67-year-old man previously diagnosed with prostate cancer presented with a slowly growing mass on his sternum. CT scanning demonstrated an ill-defined lesion. Excision of the mass revealed chronic osteomyelitis.

tumor from adjacent structures, most primary chest wall neoplasms are soft tissue sarcomas derived from bone, muscle, or cartilage. The most common primary malignant neoplasm of the chest wall and sternum is chondrosarcoma.5 This tumor often manifests as a painful mass arising from the rib or scapula with equal predilection for either sex.7 Additional malignant tumors of the bony structures include osteogenic sarcoma, synovial sarcoma,8 and a constellation of primitive neuroectodermal tumors (PNET) that includes Ewing’s sarcoma (Carvajal and Meyers, 2005).9 Ewing’s sarcoma and PNET

Ch100-F06861.indd 1232

Noninflammatory Metastatic Disease Primary Benign Bone and cartilage Osteochondroma Chondroma Fibrous dysplasia Enchondroma Granular cell tumor Eosinophilic granuloma Aneurysmal bone cyst Soft tissue Fibroma Lipoma Neurilemmoma Fibrolipoma Primary Malignant Bone and cartilage Chondrosarcoma Plasmacytoma Osteosarcoma Ewing’s sarcoma Soft tissue Desmoid Fibrosarcoma Malignant fibrous histiocytoma Leiomyosarcoma Hemangiosarcoma Primitive neuroectodermal sarcoma

are the most common primary chest wall tumors of children and young adults (Fig. 100-4). Most investigators believe that PNET requires multimodality therapy because radical local resection alone has been associated with a high rate of local and distant recurrent disease. Plasmacytomas, which often manifest as rib lesions in older men, are a local manifestation of multiple myeloma.10 For this reason, patients are treated with systemic therapy directed against myeloma; treatment of the rib lesion by local resection or radiation therapy is reserved for patients with persistent symptoms. Primary malignant fibrous histiocytomas of the chest wall occur infrequently and have been associated with previous chest wall radiation therapy (e.g., adjuvant therapy for breast cancer). Primary soft tissue sarcomas represent 20% of primary malignant chest wall masses. These tumors are classified by histology (fibrosarcoma, leiomyosarcoma, liposarcoma, or

1/21/2008 3:28:03 PM

Chapter 100 Diagnostic Strategies for a Chest Wall Mass

A

1233

B

FIGURE 100-3 A teenager presented with a slowly growing mass on her upper back. MRI showed the classic appearance of a large lipoma. A fatty subscapular mass was noted to be insuating the spaces above and below the third rib, with distortion of the pleural surface. The mass was stable on follow-up over the subsequent 3 years. A, T1-weighted image of a large subscapular mass. B, The same section as a T2-weighted image.

sites, these tumors are better classified as low-grade fibrosarcomas because of their locoregional involvement and biologic behavior.12

RADIOGRAPHIC EVALUATION OF A CHEST WALL MASS AND ITS LIMITATIONS

FIGURE 100-4 A 19-year-old man previously treated for Hodgkin’s lymphoma presented with a new left flank mass. CT imaging demonstrated extensive destruction of the 10th rib. Core biopsy revealed Ewing’s sarcoma. After chemotherapy, the patient underwent en-bloc resection of the diaphragm and lung.

neurofibrosarcoma), and prognosis is determined by grade and distant metastasis (Walsh et al, 2001).11 Desmoid tumors, unlike other sarcomas, tend to affect women and have a high rate of local recurrence. Although desmoid tumors are often considered benign because they do not metastasize to distant

Ch100-F06861.indd 1233

Whereas plain radiographs may be diagnostic for traumatic injury to the ribs and sternum, use of CT or MRI has become the mainstay of thoracic chest wall mass imaging. CT imaging has the advantage of detecting calcification or ossification of a tumor (Tateishi et al, 2003).3,13 Although MRI imaging is more time-consuming, it is superior to CT for delineating soft tissue planes and assessing involvement of nerves and vascular structures.14 Edema and hemorrhage may mimic malignant infiltration on MRI, but gadolinium contrast can improve this distinction.15 Furthermore, because of the presence of a pseudocapsule of compressed parenchyma, a tumor may appear sharply demarcated on MRI when in actuality there is tumor invasion. Although MRI and CT scanning are accurate in determining the nature of certain lesions such as lipoma, cyst, or arteriovenous malformations, imaging studies alone cannot distinguish benign from malignant masses. Although large size, presence of neurovascular involvement, and edema suggest malignancy, recent studies16,17 have shown that the sensitivity and specificity are not high enough to exclude the need for tissue diagnosis. Because many tumors, such as Ewing’s sarcoma, plasmacytomas, and those representing distant metastases, require systemic chemotherapy, tissue diagnosis is mandatory before considering resection.

1/21/2008 3:28:04 PM

1234

Section 5 Chest Wall and Sternum

FIGURE 100-5 The patient presented in Figure 100-2 underwent PET-CT imaging. A large mass concerning for malignancy was noted on his anterior chest. Excision revealed osteomyelitis.

Before planning any surgical resection, the absence of distant metastasis must be verified. In addition to standard CT and technetium 99m bone scans, recent data suggest that positron emission tomographic (PET) imaging may have the advantage of predicting recurrence based on metabolic activity of the tumor,18,19 as well as predicting the potential benefit of adjuvant therapy.20 Furthermore, a number of authors have documented improved specificity of PET compared with standard bone scans (Cheran et al, 2004).21,22 However, PET imaging is not able to distinguish inflammatory processes such as osteomyelitis from a primary chest wall malignancy because of the markedly increased uptake of fluorodeoxyglucose (FDG) by leukocytes (Fig. 100-5).19,23,24

SUMMARY Modern imaging and biopsy techniques have lessened the role of exploratory surgery and resection in the evaluation and diagnosis of a chest wall mass. Often, CT and bone scans are enough to fully characterize a lesion and to evaluate for metastatic disease. MRI is a useful adjunct in the evaluation of lesions that involve the brachial plexus or whose characteristics suggest a benign lesion such as a lipoma. Tissue diagnosis, usually by carefully planned core biopsy, is required before any resection because some tumors benefit from preoperative chemotherapy or irradiation.

COMMENTS AND CONTROVERSIES TISSUE DIAGNOSIS The standard methods for tissue diagnosis are fine-needle aspiration, core-needle biopsy, incisional biopsy, and wide local excision of small lesions. Care must be taken to orient biopsy tracts so that they do not violate unnecessary tissue planes and can be completely excised at the time of definitive resection. If the lesion cannot be palpated, ultrasound image guidance may be invaluable in planning the biopsy tract. The accuracy of core biopsy has supplanted the need for incisional biopsy and needs to be the primary modality (Welker et al, 2000).25,26

Ch100-F06861.indd 1234

Patients with chest wall masses present diagnostic problems that are unique because these masses can originate from soft tissues, cartilage, bone, or even an underlying structure. The lesion can be asymptomatic, or, more often, it can manifest as a painful mass. In many cases, the pain is initially misinterpreted as being nonspecific, only to be associated with a mass after months or even years of observation. In all such cases, the assessment aims at determining the site, size, and nature of the mass, as well as the degree of involvement of adjacent structures. In many instances, age is important in narrowing down the differential diagnosis. Plasmocytomas, for example, always occur in

1/21/2008 3:28:04 PM

Chapter 100 Diagnostic Strategies for a Chest Wall Mass

elderly people. By contrast, Ewing’s sarcoma and Askin’s tumor are fast-growing tumors seen exclusively in young patients. In general, the two clinical features that suggest that a chest wall mass is or has become malignant are pain and rapid increase in size. Conventional chest radiographs are still of value, especially if new and old radiographs can be compared to detect tumor growth rate. CT and MRI have complementary roles in evaluating chest wall masses. CT is useful to delineate the extent of bone, soft tissue, and mediastinal involvement, whereas MRI is useful to define vascular and spinal invasion. As pointed out by the authors, these imaging modalities can sometimes eliminate the need for tissue biopsy. Biopsy options include fine-needle aspiration, which has a poor diagnostic yield, core-needle biopsy (accuracy of 95%), and incisional and excisional biopsy. Excisional biopsy is appropriate for small lesions (2-4 cm) and for lesions that appear benign on imaging. Less invasive biopsy procedures are preferable for larger tumors and tumors for which treatment is unlikely to be surgical. These include Ewing’s sarcomas, plasmacytomas, and metastases to the chest wall. Having a preoperative diagnosis is also important for tumors that are likely to require major chest wall resection or multimodality therapy. If surgery for a chest wall mass is contemplated, chest wall reconstruction may warrant consultation with a plastic surgeon or a neurosurgeon if the tumor is abutting the spine. J. D.

Ch100-F06861.indd 1235

1235

KEY REFERENCES Anderson BO, Burt ME: Chest wall neoplasms and their management. Ann Thorac Surg 58:1774-1781, 1994. Burt M: Primary malignant tumors of the chest wall. The Memorial Sloan-Kettering Cancer Center experience. Chest Surg Clin North Am 4:137-154, 1994. Carvajal R, Meyers P: Ewing’s sarcoma and primitive neuroectodermal family of tumors. Hematol Oncol Clin North Am 19:501-25, vi-vii, 2005. Cheran SK, Herndon JE 2nd, Patz EF Jr: Comparison of whole-body FDG-PET to bone scan for detection of bone metastases in patients with a new diagnosis of lung cancer. Lung Cancer 44:317-325, 2004. Faber LP, Somers J, Templeton AC: Chest wall tumors. Curr Probl Surg 32:661-747, 1995. Tateishi U, Gladish GW, Kusumoto M, et al: Chest wall tumors: Radiologic findings and pathologic correlation. Part 1: Benign tumors. Radiographics 23:1477-1490, 2003. Tateishi U, Gladish GW, Kusumoto M, et al: Chest wall tumors: Radiologic findings and pathologic correlation. Part 2: Malignant tumors. Radiographics 23:1491-1508, 2003. Walsh GL, Davis BM, Swisher SG, et al: A single-institutional, multidisciplinary approach to primary sarcomas involving the chest wall requiring full-thickness resections. J Thorac Cardiovasc Surg 121:4860, 2001. Welker JA, Henshaw RM, Jelinek J, et al: The percutaneous needle biopsy is safe and recommended in the diagnosis of musculoskeletal masses. Cancer 89:2677-2686, 2000.

1/21/2008 3:28:05 PM

Benign Conditions chapter

101

CHEST WALL DEFORMITIES Charles B. Huddleston

Key Points ■ Pectus excavatum and carinatum are by far the most common

chest wall deformities. ■ These common chest wall deformities are benign conditions,

but they often produce symptoms, which can be improved with repair. ■ Other congenital chest wall deformities, such as Jeune’s syndrome and ectopia cordis, are rare but carry a very high mortality.

A variety of chest wall anomalies occur in children. By far the most common of these is pectus excavatum, which occurs in approximately 1 of every 200 live births. For the most part, chest wall anomalies pose no major health risk to these children, although they are often symptomatic. However, a few of these deformities, such as ectopia cordis and asphyxiating thoracic dystrophy (Jeune’s disease), are life-threatening.

PECTUS EXCAVATUM Pectus excavatum appears four times more commonly in males than in females. It is rarely seen in African Americans or Hispanics. It is the most common chest wall anomaly. It is usually noted at or soon after birth.1 Although some cases of spontaneous resolution may occur, the overwhelming majority of children have no change or worsening of the deformity over time. It commonly worsens during periods of rapid growth, which for boys is between the ages of 12 and 15 years. This lesion is characterized by posterior angulation of the lower third or half of the sternum with posterior curvature of the attached costal cartilages, commonly the fifth through eighth ribs. In some instances, the sternal depression extends up to the insertion of the second rib (Fig. 101-1). The deformity may be asymmetric, with the depression more marked toward the right, so that the sternum is both rotated to the right and angled posteriorly. The costal margins usually flare outwardly. The severity varies considerably from patient to patient and can be assessed in a number of ways. Perhaps the most practical and simplest method is to measure the ratio of the transverse chest diameter to the smallest distance from the posterior aspect of the sternum to the anterior surface of the spine. This is referred to as the pectus index.2 It can be calculated from either the routine chest radiograph or a computed tomographic (CT) scan of the chest (Fig. 101-2). The average for normal individuals is approximately 2.5; for those with pectus excavatum, it is typically 3.5 to 5.0 but may

range as high as 12. Other indexes exist which are more complicated to compute. The Welch index, for example, requires measurements of the horizontal distance from the spinous process of the third thoracic vertebral body to the anterior aspect of the sternum, the distance from the anterior aspect of the ninth vertebral body to the posterior aspect of the sternum, and the angle of the ribs to the horizontal, and the cardiothoracic ratio.1 Yet another proposed mathematical representation of the severity involves a ratio of the vertebral body diameter and the distance from the xiphisternal junction and the posterior border of the vertebral body.3 These measurements can all be made from the chest radiograph, but they become more complex and less reproducible than a simpler ratio and provide no additional insight into the severity of the deformity beyond that provided by the pectus index. The cause of this deformity is unknown. Some have suggested that it is a result of intrauterine pressure, rickets, or abnormalities of the diaphragm.4,5 The diaphragmatic anomalies include congenital diaphragmatic hernia and agenesis of the diaphragm. Repair of these abnormalities may result in posterior traction on the sternum as the presumed cause of the deformity. It seems much more likely that there are inherent abnormalities in the biochemical or connective tissue properties of the costal cartilages. There is certainly a strong association with other skeletal abnormalities, particularly scoliosis, which may be present to some degree in 20% of all those with pectus excavatum.1 The association of Marfan’s syndrome and pectus excavatum (as well as pectus carinatum) suggests an abnormality in the components of the skeletal system as the underlying mechanism for this malformation. Approximately 65% of all patients with Marfan’s syndrome have anterior chest wall deformities, most commonly pectus excavatum.6 Only about 2% of all patients presenting for treatment of pectus excavatum have Marfan’s syndrome, however. Although no clear pattern of inheritance has emerged, up to 40% of patients have a family member with a chest wall deformity. The incidence of congenital heart disease in association with pectus excavatum is similar to the incidence of congenital heart disease in the general public. The same is true for cardiac lesions, with ventricular septal defects being the most common cardiac lesion seen. Symptoms associated with pectus excavatum include dyspnea with exertion or poor stamina, pain, and a sense of embarrassment over the appearance. Some patients complain of palpitations, asthma, and frequent respiratory infections, although a clearcut link to pectus excavatum is difficult to prove. The chest radiograph in children with pectus excavatum often is suggestive of an infiltrate in the right middle

1236

Ch101-F06861.indd 1236

1/21/2008 3:28:56 PM

Chapter 101 Chest Wall Deformities

RA

RV

FIGURE 101-1 This image of a patient with pectus excavatum demonstrates a depression from near the angle of Louis to the xyphoid process.

FIGURE 101-2 This is a representative film from a CT study of a patient with pectus excavatum. The pectus index is calculated by taking the ratio of the transverse dimension of the chest (T) divided by the distance from the back of the sternum to the anterior aspect of the spine at its closest point (AP).

lobe, although no true infiltrate is actually present. This socalled pseudoinfiltrate is somehow a reflection of the deformity of the soft tissues present. Exertion-related symptoms and the physiologic impact of this chest wall deformity have been studied extensively. Most patients with pectus excavatum and limited tolerance to exertion derive benefit from repair of the deformity, including a sense of improved stamina and improved ability to keep

Ch101-F06861.indd 1237

1237

LA

LV

FIGURE 101-3 This is an image from an echocardiogram performed on a patient with a severe pectus excavatum deformity. Note the depression of the sternum against the anterior wall of the right atrium (RA) and, to a lesser extent, on the right ventricle (RV). LA, left atrium; LV, left ventricle.

up with peers during athletic endeavors. Pulmonary function tests in patients with pectus excavatum generally show a mild to moderate restrictive pattern with a forced vital capacity of approximately 85% of predicted (Morshuis et al, 1994).7,8 Repair of the chest wall deformity does not result in any significant improvement in these values. What does appear clear is that cardiac function during upright exercise in children with pectus excavatum is less than that seen in otherwise normal children, presumably because of the compression of the anterior wall of the right ventricle by the depressed sternum9 (Fig. 101-3). This compression reduces filling of the right ventricle during periods of extreme exercise, so that the stroke volume is reduced. Repair of the deformity results in improvement in stroke volume and cardiac output during exercise approaching that seen in normal individuals (Beiser et al, 1972).10 The work of breathing during exercise is also increased in these patients, in part related to the restrictive defect noted on pulmonary function studies. It may also be related to impaired mechanics of breathing induced by the deformity. Some contend that the improved work of breathing and relief of the restriction on cardiac filling during exercise result in improved exercise tolerance.11 However, others are skeptical that this perceived improvement in exercise tolerance is a consequence of repair of the skeletal deformity. There are studies of cardiorespiratory performance that do not demonstrate any changes after repair in patients who subjectively feel better.12,13 The preponderance of evidence does, in fact, support the notion that correction of pectus excavatum provides a positive impact on cardiac function during upright exercise.

1/21/2008 3:28:56 PM

1238

Section 5 Chest Wall and Sternum

FIGURE 101-4 A and B, These photographs show a patient with chondrogladiolar type of pectus carinatum. The lower ribs are somewhat concave in the anterolateral position, whereas the sternum protrudes anteriorly.

A

B

The psychological impact of pectus excavatum or any other chest wall deformity is not easily measured. There is little doubt, however, that the self-image of teenagers and adolescents is adversely affected by this deformity.14,15 Swimming is avoided, as is any situation in which the shirt would be removed in front of others. These sorts of feelings can extend to lowered self-esteem and social anxiety. In many cases, this is the driving force behind the desire for repair.

PECTUS CARINATUM Pectus carinatum is characterized by outward protrusion of the sternum and parasternal ribs, usually involving the lower half of the sternum. The Latin word, carinatum, refers to a shape similar to the keel of a ship. The deformity is often asymmetric, with the left side bulging up and twisting the sternum to the right. Some authors have described three types of sternal protrusion within the broad category of pectus carinatum (Shamberger and Welch, 1987).16 These include chondrogladiolar, mixed carinatum/excavatum, and chondromanubrial. The chondrogladiolar is the most common. The sternum angles outward to a point corresponding to the inferior tip of the body of the sternum, with the xiphoid process angling posteriorly (Fig. 101-4). The lower ribs in the anterolateral region often have some degree of concavity, giving the impression that the chest has been squeezed on the sides, forcing the sternum to bulge outwardly and giving a wedge-shaped appearance to the chest. There can be a mixed deformity, with both anterior protrusion of the upper chest and backward depression of the lower portion of the sternum (Fig. 101-5). In some instances, the parasternal ribs seem to bulge outward, usually on only one side, effectively rotating the sternum. The other side is often a bit concave. The actual position of the sternum may be appropriate, but it is twisted around. This deformity occurs much less frequently than pectus excavatum, accounting for approximately 10% of chest wall

Ch101-F06861.indd 1238

FIGURE 101-5 This photograph shows a patient with a mixed type of pectus carinatum/excavatum. The superior portion of the sternum projects outwardly and then, at the midpoint, angles sharply posteriorly.

deformities. Males are affected four times as often as females. It often presents later in life than pectus excavatum, usually in the preteen years or slightly later (Shamberger and Welch, 1987).16 The cause is unknown. About one in four patients has a positive family history of chest wall deformities. It is occasionally associated with other skeletal anomalies, particularly scoliosis. Excessive growth of the ribs may account for the deformity. What triggers this is unknown, however. Some children appear to have early fusion of the sternal growth plates, leading to foreshortening of the sternum and mixed carinatum/excavatum deformities. The incidence of congeni-

1/21/2008 3:28:57 PM

Chapter 101 Chest Wall Deformities

tal heart disease in this group of patients is reported to be 20%.17 As with pectus excavatum, the pectus index can be measured from standard chest radiographs by dividing the transverse chest diameter just above the diaphragm by the distance from the back of the sternum to the anterior aspect of the spine. The normal ratio is approximately 2.5.2 Patients with pectus carinatum have a pectus index of 1.5 to 1.9.18 Patients with pectus carinatum present with symptoms similar to those of pectus excavatum, including pain, breathing difficulties, and embarrassment over the appearance of the chest. The pain is generally in the area of greatest protrusion. Some children inadvertently bump into objects, such as a desk while sitting in class at school. It may also be painful to sleep prone. The breathing problems include exerciseinduced asthma, relative intolerance to exercise, and frequent respiratory infections. Embarrassment over the appearance of the chest results in avoidance of exposure of the chest in public, as in those with pectus excavatum. For many children, this translates to no longer swimming, reluctance to dress-out for gym class with other students, and reluctance to shower with others.14 The physiologic impact of pectus carinatum is difficult to assess, and opinions on its effects vary. Some have noted a pattern of breathing described as restrictive excursion related to the relatively narrow chest.19 Some patients have a restrictive defect noted on pulmonary function studies, but there is no consistent pattern. Those patients with restrictive patterns often also have other deformities of their skeletal system to account for this, such as scoliosis. Exercise testing using upright cycle ergometry has demonstrated increased work of breathing in patients with pectus carinatum.20 Longterm follow-up of patients undergoing repair has consistently shown clinical improvement in virtually all respiratory symptoms.18,21,22 However, some authors contend that there is no physiologic basis to claims that the chest wall deformity is responsible for the respiratory symptoms and that repair is based only on a desire to alter the outward appearance of the chest.23 This controversy is not likely to be sorted out in the near future.

POLAND’S SYNDROME Poland’s syndrome is named for the individual (a medical student at the time) who first offered a description of this chest wall deformity in English medical literature. In the mid-1800s, he described a patient with absence of the pectoral muscles of the chest wall.24 This syndrome consists of deficiency of a variable amount of tissue from the anterior chest wall, usually on the right side (Fig. 101-6). This deficiency of tissue almost always includes the pectoral muscles but may also include absence of breast tissue, ribs, and axillary hair.25 The chest wall depression can be quite marked and is particularly noticeable in women. The lack of subcutaneous tissue is also remarkable, because it often appears that there is little between the skin and the anterior surface of the ribs. The incidence is around 1 in 30,000 live births, and the condition is occasionally familial.26,27 The underlying cause is unknown. It is occasionally associated with unilateral

Ch101-F06861.indd 1239

1239

palsy of the abducens oculi muscle and facial muscles.28 Abnormalities of the hand are relatively common and include syndactyly, hypoplasia of the thumb, hypoplasia or aplasia of the middle phalanges, and, rarely, complete absence or hypoplasia of the hand and forearm (Ireland et al, 1976).29,30 The degree of rib/chest wall deformity varies from normal appearance of the ribs to aplasia.31 For the most part, these children have no functional respiratory deficit unless there is significant depression of the chest wall or absence of ribs.

STERNAL DEFECTS Sternal defects are extraordinarily rare chest wall deformities that have such a dramatic appearance that they are not soon forgotten. All or part of the beating heart or inflating lungs may be visible through a thin layer of skin. These defects range from a relatively simple cleft in the sternum to absence of the sternum and chest wall, creating ectopia cordis. The presumed underlying embryologic cause is failure of ventral fusion of the sternum. The resulting entities are sternal clefts, thoracic ectopia cordis, and thoracoabdominal ectopia cordis with an associated abdominal wall defect.

Cleft Sternum Sternal cleft almost always involves only the upper portion of the sternum, whereas ectopia cordis involves the lower portion of the sternum. Although the defect is readily palpable, often it is noted initially when the infant cries and the lungs create a distinct and obvious bulge in the upper anterior chest. The sternal separation may involve the upper half of the sternum or extend to the xiphoid process. The heart is covered by pericardium and the overlying skin and subcutaneous tissue. It is also usually in the normal position within the chest. The lungs are likewise covered by pleura, subcutaneous tissue, and skin medially. The diaphragm is typically normal. There are usually no associated anomalies of the heart, and omphaloceles do not occur. There is an association with hemangiomas in the neck and face,32 as well as scarlike bands that extend from the umbilicus to the point of fusion of the sternum or from the that point to the mandible.33 These children usually have no significant compromise to their ventilatory mechanics and have a relatively normal life expectancy. However, it is believed that repair is warranted to provide coverage and protection to the underlying chest structures.

Ectopia Cordis Although technically the term ectopia cordis means only that the heart is out of its normal position, it usually refers to the heart’s being positioned in whole or part outside the body, without any covering of skin or other overlying somatic structures (Fig. 101-7). A defect in the sternum is obviously a necessary component of this anomaly and may run the entire length of the sternum or for only a small portion thereof. The apex of the heart is typically pointed straight anteriorly. Intracardiac anomalies are the rule rather than the exception. Tetralogy of Fallot is the most common associated cardiac defect; others are listed in Table 101-1.34 Although not readily apparent, the volume of the chest cavity is generally small,

1/21/2008 3:28:57 PM

1240

Section 5 Chest Wall and Sternum

Sternum

Costal cartilage

A

C

B

D

FIGURE 101-6 Degrees of chest wall deficiency in patients with Poland’s syndrome. A, Normal chest contour. B, There is some hypoplasia of the chest with inward displacement of the ribs. C, There is relatively severe depression of the affected side, with rotation of the sternum and buckling outward of the contralateral chest wall. D, There is actual deficiency of ribs, with only soft tissue separating the lung from the outside.

because the lack of presence of the heart within the thorax prevents the normal development of this cavity.30 This has obvious implications with respect to surgical repair.

Thoracoabdominal Ectopia Cordis As opposed to thoracic ectopia cordis, thoracoabdominal ectopia cordis has the following characteristics: 1. 2. 3. 4.

The heart is covered by a thin membrane The heart is not rotated anteriorly There is a defect in the abdominal wall There is a defect in the diaphragm

Ch101-F06861.indd 1240

The thin membrane or pigmented skin that covers the heart is often extremely thin, to the point of being almost transparent. The defect in the abdominal wall may be an omphalocele, ventral hernia, or diastasis recti, most often omphalocele.34 Intracardiac anomalies are also very common and are similar in type to those of thoracic ectopia cordis. The one obvious difference is the very high incidence of diverticulum of the left ventricle (see Table 101-1). This diverticulum may be the only component of the heart protruding through the diaphragmatic and abdominal wall defect. The relative importance of this diverticulum is unclear. At times it appears to be dyskinetic with the remaining portion

1/21/2008 3:28:58 PM

Chapter 101 Chest Wall Deformities

1241

Divided sternum

LV diverticulum

Sternal defect

FIGURE 101-7 Photograph taken during repair of ectopia cordis. A diverticulum of the left ventricle (LV) was protruding through a circular defect in the sternum. This portion of the heart was not covered by skin or any other tissue.

TABLE 101-1 Congenital Cardiac Lesions Associated With Ectopia Cordis

Tetralogy of Fallot

Thoracic (N = 58)

Thoracoabdominal (N = 100)

13

13

Diverticulum of left ventricle With Tetralogy of Fallot With VSD ± ASD

0

29 1 13

TGA with pulmonary stenosis or atresia or VSD

5

4

Patent ductus arteriosus

6

0

VSD ± ASD

13

14

VSD with pulmonary stenosis

0

2

Truncus arteriosus

3

4

Coarctation of the aorta ± ASD

3

0

Single ventricular anomalies

6

8

Cor biloculare

3

4

Cor triatriatum

2

0

Double-outlet left ventricle

2

2

Double-outlet right ventricle

1

2

Aortic stenosis, VSD

0

1

Eisenmenger complex

0

1

Aberrant right subclavian artery

1

0

Bilateral superior venae cavae

1

1

Normal

2

4

ASD, atrial septal defect; TGA, transposition of the great arteries; VSD, ventricular septal defect.

Ch101-F06861.indd 1241

FIGURE 101-8 Chest radiograph of a patient with Jeune’s syndrome. Note the horizontal orientation of the ribs, the elongated thoracic cavity, and the narrow transverse dimension of the thoracic cavity.

of the left ventricular cavity during systole. However, it may be an important component of the left ventricular volume and function. Care must be exhibited in deciding to remove this diverticulum in the process of closing the body wall defect. Occasionally, the heart is located completely within the abdominal cavity. In this circumstance, the great vessels penetrate through the diaphragmatic defect to enter the chest and run to the pulmonary hilum and aortic arch.

OTHER THORACIC WALL DEFORMITIES Jeune’s Syndrome (Asphyxiating Thoracic Dystrophy) Jeune’s syndrome35 is characterized by a restrictive chest wall that limits pulmonary development and excursion with respirations. A narrow, bell-shaped chest is seen radiographically, with horizontal ribs and costochondral junctions that are displaced laterally to the midaxillary line (Fig. 101-8). The horizontal orientation of the ribs is a manifestation of the very short length of the ribs and results in poor chest wall excursion with respirations. Microscopic examination of the costochondral junctions demonstrates poorly progressing endochondral ossification, which presumably is responsible for the very short rib length noted. Other skeletal anomalies include a small pelvis with square iliac bones and short extremities. Although this disorder is generally held to be fatal early in infancy, some patients have survived for prolonged periods.36 Histologic examination of the lungs usually shows normal bronchial development with limited alveolar development, suggesting that the respiratory compromise observed in these infants is more complex than just limited chest wall excursion.37 An acquired form of this disease has been reported as a late complication of repair of pectus excavatum.38 In this series, the patients underwent rather extensive repair at a very young age. Poor chest wall growth,

1/21/2008 3:28:58 PM

1242

Section 5 Chest Wall and Sternum

presumably related to the early surgery, produced a significant restrictive ventilatory problem. Surgical repair by effective lengthening of the ribs resulted in improved respiratory mechanics.

Jarcho-Levin Syndrome (Spondylothoracic Dysplasia) The Jarcho-Levin anomaly is characterized by close approximation of the ribs with very narrow intercostal spaces, resulting in poor lung development. The very close approximation of the ribs is related to multiple alternating hemivertebrae that primarily affect the thoracic and lumbar spine. The vertebral bodies are almost all very abnormal and very short, so that the ribs of necessity originate very close to one another. This inevitably results in death due to complications of pneumonia or respiratory insufficiency.39,40

COMMENTS AND CONTROVERSIES This chapter provides an excellent review of current knowledge about anterior chest wall deformities. As stated, pectus excavatum is not only the most common of these deformities but also the most intriguing. Its embryogenesis is obscure, although most people think that the malformation is secondary to an overgrowth of costal cartilages that pushes the sternum inward. Indeed, in all pectus deformities, the sternum itself is quite normal. Pectus excavatum is also reported to be more common in males than in females; however, young girls may not seek medical attention as often because the deformity is advantageous for the general appearance of their anterior chest wall (i.e., the breasts appear bigger because of the central depression of the sternum). In our experience, pectus excavatum is usually asymmetrical, and, in all such cases, the sternum is rotated in a counterclockwise direction (i.e., the anterior sternum faces the right side of the thorax). This particular feature, which is the result of asymmetrical over-

Ch101-F06861.indd 1242

growth of costal cartilages, must be taken into consideration when surgically correcting the deformity. As described by Dr. Huddleston, the severity of most cases of pectus excavatum increases until early adolescence and then stops once the bony skeleton of the thorax has reached maturity (age 18-22 years). During adolescence, most patients also experience a worsening of their posture, with the shoulders being bent more forward and the abdomen becoming more protuberant. One major area of controversy in chest wall deformities is the relationship between pectus excavatum and potential anomalies of cardiopulmonary function. In the past, most investigators believed that cardiopulmonary function remained normal even with severe deformities, and they thought that the heart was displaced to the left rather than being compressed. Such observations were based on static measurements of cardiopulmonary function such as vital capacity, expiratory volumes, resting right heart pressures, and cardiac output. It has now been shown that pectus excavatum has a negative impact on right ventricular filling and stroke volume if these indices are measured during exercise. This is certainly one of the reasons (the other being psychological) why patients feel better, eat better, and have a better tolerance to exercise after correction of their deformity. J. D.

KEY REFERENCES Beiser GD, Epstein SE, Stampfer M, et al: Impairment of cardiac function in patients with pectus excavatum, with improvement after operative correction. N Engl J Med 287:267-272, 1972. Ireland DCR, Takayama N, Flatt AE: Poland’s syndrome: A review of forty-three cases. J Bone Joint Surg Am 58A:52-58, 1976. Morshuis W, Folgering H, Barentsz J, et al: Pulmonary function before surgery for pectus excavatum and at long-term follow-up. Chest 105:1646-1652, 1994. Shamberger RC, Welch KJ: Surgical correction of pectus carinatum. J Pediatr Surg 22:48-53, 1987.

1/21/2008 3:28:59 PM

RADIONECROSIS AND INFECTION OF THE CHEST WALL AND STERNUM

chapter

102

Mark S. Allen

Key Points ■ Infection or radionecrosis accounts for about 20% of chest wall

resections and reconstructions. ■ Careful preoperative planning with a plastic surgeon is critical. ■ All irradiated and infected tissue are removed. ■ Reconstruction with muscle or myocutaneous flaps yields good

results.

Radionecrosis and infection of the chest wall are relatively uncommon problems, yet they are difficult to manage without experience. These lesions usually occur in patients that are debilitated and immunodepressed from a protracted illness. Radionecrosis is an iatrogenic illness. This chapter describes the pathophysiology of radiation necrosis and chest wall infections and explains the management of this difficult problem.

HISTORICAL NOTE Chest wall resection and reconstruction techniques have been described for more than 100 years, but only recently have these techniques been used to treat complex chest wall infections or radionecrosis of the chest wall. In 1899, Parham wrote the first paper in North America concerning resection of the chest wall; however, this was for neoplasms.1 He described two patients, the first of whom became hypoxic after a rent in the pleura developed. The surgeons were unable to remove more tissue and had to close the defect; however, the patient did survive the therapeutic attempt. A similar catastrophe occurred in the second patient when the pleura was opened, but the tumor was successfully resected. Parham commented about the pneumothorax that occurred: Suddenly was presented to our anxious view one of the most startling clinical pictures that the surgeon can ever be called upon to witness. . . . [N]o wonder the old surgeons discountenanced such operations. . . . [S]o sudden in my case was the pneumothorax and so striking were the manifestations of profound shock, threatening almost instant dissolution before our eyes, that I resolved to acquaint myself more thoroughly with the dangers of thoracic surgery.1 From these early endeavors, the need to prevent an open pneumothorax was recognized. After these initial attempts, the technique of staged preoperative pneumothorax was

used: the parietal and visceral pleura were fused, allowing resection of the chest wall without the complication of a pneumothorax. Dollinger described the successful use of this technique in 1906.2 Other techniques included the Sauerbruch technique, in which the operation was carried out with the patient’s body in a negative-pressure enclosure, to prevent pneumothorax when the pleural space was entered. All of these techniques predated the development of the endotracheal tube, which solved the problem of intraoperative pneumothorax.3-5 Throughout history, war, with its associated traumatic injuries, has necessitated the development of new methods of managing chest wall injuries, and these methods have been applied to management of infections and radionecrosis of the chest wall. One of Napoleon’s surgeons, named Laney, applied a bandage to a soldier with a serious chest wound, not to treat the wound but to hide it from other soldiers, so they would not see that the combatant was going to die.6 To the surgeon’s surprise, the patient survived what usually was a uniformly fatal injury. The fact that he had converted an open to a closed pneumothorax with the dressing was not recognized by the treating surgeon, but the practice of covering chest wounds continued. During World War II, Graham, Bigger, Churchill, and Eloesser collaborated on a manual on the treatment of thoracic wounds.6 By this time, surgeons had recognized the need to close the pleura and cover the defect in the chest wall. They described mobilizing local tissue, including muscle, to cover a defect in the chest wall and using diaphragmatic transposition or suturing of the pulmonary parenchyma to the chest wall to treat the pneumothorax that resulted from an open chest wall after injury. They also developed the principles of tube thoracoscopy, pleural débridements, tension-free closure, and pleural drainage systems. Muscle and myocutaneous flaps were also brought into vogue during World War II and the Korean War to close large chest wall wounds. In 1956, Kiricuta introduced omental transposition as a method to close vesicovaginal fistulas and, later, to repair chest wall defects.7 The latissimus dorsi musculocutaneous flap was initially described in 1906 by Tansini and was subsequently used by Campbell in 1950 for chest wall reconstruction.8,9 The description of the method was ignored for almost 20 years until it was revived in a modified form by others. The pectoralis muscle, originally described in 1946 by Shaw and Payne,6 was used extensively by Arnold and Pairolero to repair chest wall defects.10 Two Japanese surgeons also described using upper abdominal wall flaps to control chest wall infections.6 The Emory group, led by Dr. Maurice J. Jurkiewicz, trained many young energetic plastic 1243

Ch102-F06861.indd 1243

1/21/2008 3:29:50 PM

1244

Section 5 Chest Wall and Sternum

surgeons in the use of muscle and myocutaneous flaps to reconstruct the chest wall; these surgeons disseminated this knowledge to programs throughout North America, making these techniques the standard of care (Arnold and Pairolero, 1984).11

RADIONECROSIS On March 27, 1845, in Lennep, Germany, Wilhelm Conrad Roentgen was born. By the time he was 30 years old, he was a professor of mathematics and physics at the college of agriculture in Hohein, Germany. On November 11, 1895, he saw an unusual phenomenon while performing experiments with a Cooke tube. When current was passed through the tube, a thin line appeared on a piece of barium platinocyanide paper that was on a nearby bench. This phenomenon persisted even when the tube was covered with black cardboard. The so-called rays were investigated by Roentgen and were found to pass through almost all materials, including the human body. He found he could make photographs using the rays, which we know as radiation today, to create images of the inside of the body. Radiation therapy was shortly thereafter found to be useful for treatment of cancer, and the field of radiation medicine quickly developed. The first report of radiation therapy for laryngeal malignancies was given by Coutard and Hautant in 1922 at a meeting in Paris.12 The dangers of radiation were quickly discovered as well. The first known death from radiation occurred in 1904, just 9 years after Roentgen’s discovery. The victim was Clarence Dally, an early radiation worker, who developed a fatal squamous cell carcinoma of the skin secondary to radiation exposure.13 Radiation therapy to the chest wall causes changes that are most easily appreciated in the overlying skin. Acute skin changes occur during the first 70 days of radiation therapy and include erythema, hyperpigmentation, epilation, and desquamation. Then a variable period of time passes before the late effects are seen; telangiectasia appears as early as 6 months after radiation exposure. This is followed by dense dermal fibrosis, sebaceous gland atrophy, loss of hair follicles, altered melanin deposition, and skin ulceration.14 The pathophysiology of these lesions involves destruction of the microvasculature under the skin. Ulcerated lesions of the chest wall after radiation therapy need to be differentiated from recurrent cancer, new primary skin cancer, and other systemic diseases such as systemic sclerosis, lupus erythematosus, stasis dermatitis, and lichen sclerosis et atrophicus. It is difficult to determine the frequency with which these severe lesions occur on the chest wall. Patients often die from the original malignancy and therefore do not live long enough to develop these lesions, and the long latency period between radiotherapy and the development of radionecrosis clouds the assignment of blame for the lesion. Factors that affect the probability of developing radionecrosis include total radiation dose, fraction size, duration of time during which the dose was delivered, the rate at which radiation dose was given (dose rate), and the volume treated. Late skin and chest wall toxicities are thought to increase when the dose delivered is 25 cGy or greater. A recent review suggested that the therapeutic dose of radiation therapy needs to be raised, from the

Ch102-F06861.indd 1244

FIGURE 102-1 Radiation ulcer in sternal and supraclavicular area after radiation therapy for breast cancer. (COURTESY OF PETER PAIROLERO, MD.)

typical 50 to 60 cGy currently used to 70 to 74 cGy, implying that side effects may be more common in the future.15 Treatment with orthovoltage and cobalt machines in the past was associated with more skin toxicity than is the case with modern linear accelerators because there was virtually no skin sparing with the older techniques. Despite new techniques, complications still result from chest wall irradiation, and as thoracic surgeons we are asked to see these patients (Fig. 102-1). Radiation therapy injuries may result from errors in dose calculation, errors in machine calibration, and/or field misalignment. Inappropriate overlap in treatment fields can lead to an unintentionally high dose to an area. Use of computed tomography (CT) to plan fields has probably reduced the error in field placement, although this has not been shown in a randomized trial. Despite all the recent advances in radiation oncology, a problem still exists, as was noted by Arnold and Pairolero: “Although radiation therapy has been highly refined and rendered much safer . . . we continue to see some rather astonishing associated wounds.”16(p809) When the skin and soft tissue are damaged, an ulcerated, fungating wound can rapidly develop. These wounds are difficult to manage and are quite disabling for the patient. When tissue has been irradiated and the microvasculature is damaged, infections will not heal without appropriate surgical intervention.

INFECTIONS The most common infection of the chest wall is an infected median sternotomy after cardiac surgery; this is discussed in Chapter 103 of this textbook. Other causes of serious infections of the chest wall that necessitate resection include infection after radiotherapy, as discussed earlier, and necrotizing soft tissue infections. Necrotizing infections of the soft tissue are highly lethal and usually involve the abdominal wall, perineum, and lower extremities. Involvement of the chest wall is rare. In a review of the literature, only 20 welldocumented cases were identified.17 Most of the patients were in the fifth or sixth decade of life, and 13 were men. Significant predisposing conditions were present in most

1/21/2008 3:29:51 PM

Chapter 102 Radionecrosis and Infection of the Chest Wall and Sternum

1245

patients. Thirteen of the 20 infections occurred after a surgical procedure, usually insertion of a chest tube for an empyema. The causative bacteria were group C streptococcus in 20%, group A streptococcus in 25%, and polymicrobial in 55%. Clinical features of a necrotizing chest wall infection are similar to those seen at other anatomic locations: excessive pain, blisters, crepitus, foul-smelling discharge, and a rapid deterioration of the patient’s condition.18-21 Diagnosis is difficult, but positive Gram staining on skin puncture or the finding of air in the soft tissue may lead to the diagnosis. Unfortunately, the diagnosis is usually late, accounting for the high mortality rate of this rare disease. Nonsurgical treatment of this disease is not successful; only aggressive débridements offer the chance at recovery. The mortality rate in the reported series is 60%. FIGURE 102-2 Locally fungating and weeping ulcer with recurrent cancer after radiotherapy for breast cancer. (COURTESY OF PETER

PREOPERATIVE EVALUATION OF PATIENTS WITH CHEST WALL NECROSIS OR INFECTION

PAIROLERO, MD.)

Preoperative evaluation includes thorough physiologic assessment. This includes cardiovascular and pulmonary function

TABLE 102-1 Large Series of Chest Wall Resections and Reconstructions Indication (%) Institution (Years)

% Males

Median Age (Range)

Mayo Clinic16 (1977-2000)

500

57.2

55 yr (1 day-85 yr)

23.8

6.0

3

21

Emory University22 (1975-2000)

200

53

54 yr (13-86 yr)

15

16

7

18

MSKCC23 (1992-2002)

113

77.9

58 yr (19-88 yr)

9.7

10.6

4

11.5

Radionecrosis

Infection

Mortality Rate (%)

Length of Hospital Stay (Days)

No. Patients

MSKCC, Memorial Sloan-Kettering Cancer Center.

TABLE 102-2 Flaps Used for Soft Tissue Reconstruction*

Institution

Pedicle Flap

Free Flap

Latissimus Dorsi

Mayo Clinic16

—

—

23

Emory University

22

MMSK23

TRAM 2.9

Pectoralis

Serratus

Deltoid

Trapezius

58†

4

—

1

Omentum 8.3

External Oblique 4.9

48

9

20

17

16

9

2

2

10

13

12

17

33

33

22

4

1

—

5

—

*Percentage of patients who had the particular flap; because patients may have had none, one, or more flaps, the percentages may add to more than 100%. † Infected median sternotomy was included in this series. MSKCC, Memorial Sloan-Kettering Cancer Center; TRAM, transverse rectus abdominis muscle.

TABLE 102-3 Material Used to Reconstruct the Skeletal Chest Wall Polypropylene Mesh

Vicryl Mesh

Autologous Rib

Methyl Methacrylate

—

26

—

—

31

6

—

6

11

51

—

55

—

45

Institution

Gore-Tex

Mayo Clinic16

32

11

1

25

—

—

—

Emory University22 MMSK23

Marlex Mesh

None

MMSK, Memorial Sloan-Kettering Cancer Center.

Ch102-F06861.indd 1245

1/21/2008 3:29:51 PM

1246

Section 5 Chest Wall and Sternum

FIGURE 102-3 Blood supply of the pectoralis major. (USED WITH PERMISSION.)

testing, as well as an assessment of the nutritional status. The latter is particularly important. Often, patients with chest wall radionecrosis or infection require multiple trips to the operating room, with repeated days of withholding oral alimentation, and nutritional depletion can rapidly ensue. Preoperative baseline measurements of nutrition including total serum protein and albumin, a history of recent weight loss, and dietary review may be helpful. A careful explanation of postoperative nutritional plans are discussed with the patient and the family. Patients are also warned of the magnitude of the resection. Often, there are serious psychological problems with body image when a large chest wall defect is present. Patients often develop depression as a result of the chronic pain or chronic disease or a feeling of hopelessness after being told by others that there is nothing that can be done for their chest wall lesion (Fig. 102-2). A critical preoperative necessity is to have a full discussion with plastic surgery colleagues for assistance in planning the reconstruction. Together, as a team, this group discusses what has to be resected and makes a primary plan for reconstruction. Backup plans also are discussed, in case the first reconstruction efforts fail. Collaboration with plastic surgery specialists cannot be overly emphasized; it is vitally important. The lifestyle, work, and family situation of the patient are also clarified. These factors provide important input in making a decision on how best to treat the patient. Finally, it is not possible to cure every chest wall infection or radiation ulcer; however, removal

Circumflex scapular artery and vein Subscapularis muscle Serratus anterior muscle

Subscapular artery and vein Teres major muscle (insertion)

Serratus branch Thoracodorsal nerve Thoracodorsal artery and vein Latissimus dorsi muscle Trapezius muscle

Teres major muscle

External oblique muscle

Thoracolumbar fascia

FIGURE 102-4 Blood supply of the latissimus dorsi muscle. The latissimus dorsi muscle and its immediate neighbors are shown in cutaway fashion to demonstrate the dominant thoracodorsal neurovascular pedicle and relationships at the origin and insertion of the muscle. (USED WITH PERMISSION.)

Ch102-F06861.indd 1246

1/21/2008 3:29:52 PM

Chapter 102 Radionecrosis and Infection of the Chest Wall and Sternum

1247

FIGURE 102-5 Radiation necrosis of the anterior chest wall after radiation therapy for breast cancer. (COURTESY OF CRAIG JOHNSON, MD.)

of a foul-smelling gangrenous ulcerated lesion will improve the quality of life for the period of time the patient has remaining in his or her life. FIGURE 102-6 Latissimus muscle raised and ready to be transferred to the anterior chest wall. (COURTESY OF CRAIG JOHNSON, MD.)

SURGICAL MANAGEMENT OF CHEST WALL NECROSIS OR INFECTION The incidence of surgery to correct radionecrosis and chest wall infections can be gleamed from several large series in the literature. The most notable report of chest wall resection and reconstruction is from Arnold and Pairolero, who described more than 500 chest wall resections from 1977 to 1995.16 The indications for surgery among these 500 patients were mostly tumors and infected median sternotomies. However, 10% of their patients had a chest wall resection and reconstruction for radiation necrosis, 12% of the surgeries were for a tumor that had received radiation therapy, and 6% were for infections. Another large series of chest wall resections and reconstructions was reported by Mansour and colleagues from Emory University.22 This report included 200 consecutive chest wall resections performed over the past quarter century. Radiation necrosis of the chest wall accounted for 15% of their patients, and chest wall infection for 16%. As with Pairolero and Arnold’s review, the most common indication for surgery was a chest wall tumor. Chang and associates from Memorial Sloan-Kettering Cancer Center has also reported a large series of chest wall resections.23 Among their series of 113 patients, radionecrosis was the indication for surgery in 10% and infection in 11%. Therefore, although they are not the most common reason, radionecrosis and chest wall infections make up about 20% of the indications for chest wall resection and reconstruction. These three large series revealed other information in addition to the indications for surgery (Table 102-1). The disorder was fairly evenly distributed between men and women, and most patients presented at about 55 years of age. In addition, although the mean length of hospitalization was long (2-3 weeks), implying that this is a difficult procedure to recover from, the operative mortality rate was relatively low (3%-

Ch102-F06861.indd 1247

FIGURE 102-7 Latissimus muscle transferred to cover anterior chest wall defect. (COURTESY OF CRAIG JOHNSON, MD.)

1/21/2008 3:29:57 PM

1248

Section 5 Chest Wall and Sternum

FIGURE 102-8 Close up of latissimus dorsi muscle in place to cover reconstructed chest wall. (COURTESY OF CRAIG JOHNSON, MD.)

FIGURE 102-9 Lower anterior chest wall ulcerated lesion caused by radionecrosis. (COURTESY OF PETER PAIROLERO, MD.)

7%). Review of these series also unveils many similar management principles among the authors. They all advocated close collaboration with plastic surgery. The description of the reconstruction was the major portion of the text of each manuscript. Removal of all devitalized, irradiated, or infected tissue was another common recommendation. All reconstructed the skeletal chest wall if necessary, but by a variety of different methods (Table 102-2). In all three series, clean, well-vascularized soft tissue was used to cover the defect. Once the chest wall has been resected and all infected or irradiated tissue has been removed, the skeletal chest may need reconstruction. Rigid chest wall reconstruction prevents physiologic flail and helps protect the underlying viscera. Skeletal reconstruction need not be performed if the defect is small (i.e., <5 cm) or if it is covered by the scapula. A variety of materials can be used to reconstruct the skeletal

chest wall (Table 102-3). The choice is based on the surgeon’s preference. Gore-Tex, Marlex mesh, Prolene mesh, and methylmethacrylate were compared by Deschamps and colleagues, who reported no difference in the outcome of the operative procedure.24 There are differences in cost of the material, radio-opaqueness, ease of use, and water tightness. However, in the long run, all of these materials, when used properly, satisfactorily accomplish the goal of rigid chest wall fixation. After the skeletal chest wall has been reconstructed, it must be covered by viable tissue. Myocutaneous or muscle flaps accomplish this goal (see Table 102-2). Pairolero and Arnold have beautifully summarized their 25-year experience with more than 600 flaps for chest wall coverage.16 The pectoralis major is well suited to defects in the anterior chest wall, especially in the upper portion. It is mobilized and

FIGURE 102-10 Resected costal arch from patient in Figure 102-9.

FIGURE 102-11 Defect resulting from resection of the affected chest wall. (COURTESY OF PETER PAIROLERO, MD.)

(COURTESY OF PETER PAIROLERO, MD.)

Ch102-F06861.indd 1248

1/21/2008 3:29:59 PM

Chapter 102 Radionecrosis and Infection of the Chest Wall and Sternum

1249

FIGURE 102-12 Line drawing showing the chest wall defect and the location of the external oblique muscle. (COPYRIGHT © 1979, MAYO CLINIC.)

5 6 7 8 Defect excised

External oblique muscle

Incision

MAYO CLINIC.)

Skin flap

External oblique muscle Blood supply

FIGURE 102-13 Line drawing illustrating the elevation of the external oblique. (COPYRIGHT © 1979,

Rectus abdominis Internal muscle oblique muscle

External oblique muscle

Skin Internal oblique muscle

CROSS SECTION

transposed on the thoracoabdominal neurovascular leash, which maintains its function and viability (Fig. 102-3). Basing it on the internal mammary perforators may lead to compromise if infected or necrotic cartilage must be removed at a later date. Another muscle, the latissimus dorsi, is very useful for reconstruction, either as a muscle or as a musculocutaneous flap (Fig. 102-4). It is indicated for defects in the anterior or anterolateral chest wall. By transposing the muscle on its dominant thoracodorsal neurovascular leash, almost two thirds of the back can be transposed to the front of the chest if necessary. The use of this muscle to reconstruct a left chest wall lesion secondary to radiation therapy is shown in Figures

Ch102-F06861.indd 1249

102-5 to 102-8. The serratus anterior muscle is usually used for intrathoracic mobilization, but occasionally it can be used in conjunction with the latissimus dorsi muscle to get even more skin to the front of the chest. For anterior chest wall reconstruction, the rectus abdominis muscle or myocutaneous flap is valuable. This muscle is not as robust as the latissimus dorsi and does not possess as reliable a blood supply as either the latissimus dorsi or the pectoralis muscle. The external oblique muscle or musculocutaneous flap is effective for the lower anterolateral chest up to the inferior mammary fold. The use of this muscle is shown in Figures 102-9 to 102-18. Finally, the omentum can be used as a

1/21/2008 3:30:01 PM

1250

Section 5 Chest Wall and Sternum

FIGURE 102-14 Line drawing showing the transfer of the external oblique myocutaneous flap to cover the inferior chest wall defect. (COPYRIGHT © 1979, MAYO CLINIC.)

Skin flap External oblique muscle

Incision Inguinal ligament

Skin graft

The postoperative management after surgical treatment of chest wall necrosis or infection is often surprisingly uncom-

plicated. Chest tubes can be removed after the drainage has decreased to an acceptable level, usually less than 300 mL in a 24-hour period. There should be no air leak if the lung has not been resected and the chest wall defect is properly covered. Flap drains can be removed after the drainage is low. If artificial material is used for skeletal reconstruction, drains are removed earlier (if used at all), to reduce the possibility of infection. If an infection does develop with artificial material in place, it most likely will have to be removed. Usually, with time, a thick fibrous peel develops over the lung, and removal of the artificial material will not result in a pneumothorax. The resulting defect can be covered with a myocutaneous flap to obtain a healed wound. Flap loss is quite rare, but its possibility reinforces the idea of careful preoperative planning, including a backup plan.

FIGURE 102-15 Intraoperative photograph of the elevated external oblique. (COURTESY OF PETER PAIROLERO, MD.)

FIGURE 102-16 Intraoperative photograph of the external oblique placed over the anterior chest wall defect. (COURTESY OF PETER

means to supply a vascularized bed to place a skin graft. It can reach anywhere on the anterior chest wall and readily accepts a skin or bone graft. The omentum has the advantage of bringing a new blood supply to damaged tissue, and it can be used for very large areas that need to be reconstructed. However, is not useful if full-thickness chest wall must be taken because it is not as robust as a myocutaneous flap. An example of the use of the omentum to cover a large anterior chest wall wound is shown in Figures 102-1 and 102-19 to 102-22.

POSTOPERATIVE MANAGEMENT

PAIROLERO, MD.)

Ch102-F06861.indd 1250

1/21/2008 3:30:02 PM

Chapter 102 Radionecrosis and Infection of the Chest Wall and Sternum

1251

FIGURE 102-17 Intraoperative photograph of the external oblique myocutaneous flap in place with a fenestrated skin graft covering the donor site. (COURTESY OF PETER PAIROLERO, MD.)

SUMMARY Resection for chest wall infections and/or radionecrosis can be done very successfully, with little mortality. Adherence to well-developed principles is important. Careful preoperative planning, in conjunction with plastic surgeons, is critical for success. In the operating room, removal of all infected and irradiated tissue is required, and careful reconstruction of the skeletal wall and soft tissues will yield a healed wound in most patients. Some of these patients may have an incurable malignancy, yet removal of a painful, foul-smelling wound will greatly improve their quality of life. By building on what others have learned and developed, the thoracic surgeon needs to be able to achieve an excellent outcome. However, “Good judgment comes from experience, and experience comes from bad judgment.”25

COMMENTS AND CONTROVERSIES Pathologic processes that involve the chest wall include a variety of congenital anomalies, infectious and inflammatory diseases, and

FIGURE 102-19 Intraoperative photograph of resultant defect after resection of nonvital skin and subcutaneous tissue. (COURTESY OF PETER PAIROLERO, MD.)

Ch102-F06861.indd 1251

FIGURE 102-18 Postoperative photograph of the healed chest wall lesion after resection and reconstruction with external oblique myocutaneous flap. (COURTESY OF PETER PAIROLERO, MD.)

neoplastic conditions. In developed countries, infections are seldom seen by thoracic surgeons because they are uncommon and can often be controlled with systemic antibiotics. Radionecrosis is also uncommon and usually can be prevented with improved techniques of radiotherapy. This is not necessarily the case in underdeveloped countries where hygiene is poor, bacteria are resistant, and new technologies are unavailable. In North America, better control of tuberculosis with systemic antibiotics has virtually eliminated tuberculous cold abscesses of the chest wall, but in underdeveloped countries such abscesses are still seen with regularity. Other than infected sternums after open heart surgery, chest wall infections occur mostly in immunodepressed individuals, including those with acquired immunodeficiency syndrome (AIDS), and in individuals with other predisposing conditions such as diabetes mellitus and poor

FIGURE 102-20 Intraoperative photograph of omentum after harvesting for transfer to cover the anterior chest wall defect. (COURTESY OF PETER PAIROLERO, MD.)

1/21/2008 3:30:04 PM

1252

Section 5 Chest Wall and Sternum

FIGURE 102-21 Intraoperative photograph of skin graft placed on the omentum after transfer to the anterior chest wall defect. (COURTESY

FIGURE 102-22 Postoperative photograph of healed anterior chest wall defect. (COURTESY OF PETER PAIROLERO, MD.)

OF PETER PAIROLERO, MD.)

nutritional status. Infections of the sternoclavicular joint, for example, are almost always seen in such debilitated patients. As discussed by Dr. Allen, surgical resection of infectious processes of the chest wall or of areas of radionecrosis may be indicated, and in such cases, the patient must be well prepared both physiologically (nutritional status must be optional) and psychologically. The type of resection required must be planned long before the day of surgery, with the understanding that all infected or radionecrotic tissues need to be resected if one wants to avoid recurrence of the infection. A consultation with a plastic surgeon is necessary so that the operating surgeon has assistance in selecting the most appropriate flap for soft tissue coverage. Indeed, none of these operations, whether for radionecrosis or for infection, should be done without the assistance of an experience plastic surgeon.

Ch102-F06861.indd 1252

Skeletal reconstruction with a prosthesis is always risky in an infected area, and we have found, especially in patients with radionecrosis, that the chest wall is often rigid enough so that, despite fairly extensive rib resection, it is not necessary to use a prosthesis to prevent physiologic flail. J. D.

KEY REFERENCES Arnold PG, Pairolero PC: Chest wall reconstruction: An account of 500 consecutive patients. Plast Reconst Surg 98:804-810, 1996. Mansour KA, Thourani VH, Losken A, et al: Chest wall resections and reconstructions: A 25-year experience. Ann Thorac Surg 73:17201725, discussion 1725-1726, 2002.

1/21/2008 3:30:06 PM

chapter

103

COMPLICATIONS OF MIDLINE STERNOTOMY Francis Robicsek Alexander A. Fokin

Key Points ■ Complications of midline sternotomy could be of noninfectious or

■ ■

■

■

■ ■

■

■

■ ■

infectious origin. Within those categories, the reunited sternum could be stable or unstable. Perioperative instability is termed dehiscence, whereas later separation is known as non-union. Instability begets infection and infection begets instability. Preexisting conditions such as obesity, diabetes, osteoporosis, and immunocompromised status require thorough preoperative planning to reduce the risk of dehiscence and poststernotomy mediastinitis. Preventive interventions such as normalization of glucose levels and hemoglobin concentration, surgical breast reduction, and screening for and prophylactic treatment of methicillin-resistant Staphylococcus aureus, especially in high-risk patients, are to be considered. Normal and exaggerated breathing movements of the thorax act against the cohesive force of different sternal closure techniques. Risk factors (modifiable and non-modifiable) relative to sternal instability, such as an impaired sternal blood supply after internal thoracic artery harvesting, asymmetrical sternotomy, and so on, may endanger the healing of the sternotomy. Sternomediastinitis is the most significant complication and is associated with high morbidity and mortality rates. Re-entry for bleeding, cardiopulmonary resuscitation, concomitant infections, prolonged mechanical ventilation, and early tracheostomy increases the risk of deep sternal wound infection. If necessary, percutaneous or minitracheostomy with meticulous isolation of the sternal area is recommended. Keen clinical observation with an active search for early signs of sternal infection and instability in conjunction with CT imaging and, if necessary, aggressive surgical treatment, are key elements for success. Open treatment of poststernotomy mediastinitis should be kept as brief as possible. Small signal hemorrhages often precede a major bleed, and if they occur, urgent reoperation should be considered. Parasternal weaving remains the gold standard technique for the repair and/or prevention of sternal dehiscence. Vacuum-assisted closure and muscle flaps are proven methods for the treatment of sternomediastinitis.

In the early years of cardiac surgery, areas of the heart were exposed through conventional anterolateral or posterolateral thoracotomies. As cardiac interventions became more complex, these incisions were often extended across the sternum into the contralateral pleural cavities (so-called

clamshell incision). Midline axial sternotomy, first described by Milton in 1887, was popularized by Julian and colleagues in the mid-1950s1 and offered a more extended exposure of the heart. Although changes in cardiac surgery, such as the off-pump and other types of minimally invasive methods, including port access and robotic surgery, revived some of the old incisions and introduced new ones (Fig. 103-1), midline axial sternotomy still remains a popular technique due to its ultimate exposure, quick and easy performance, minimal blood loss, and little if any functional impairment. Despite its unsurpassed advantages, however, this approach also carries a potential for complications, which may result in significant morbidity and mortality as well as increased costs of treatment.2 In this chapter, the complications of sternotomy are discussed in two principal categories: noninfectious and infectious. Within each of these categories, the discussion is subdivided according to whether the sternum is stable or unstable.

NONINFECTIOUS COMPLICATIONS OF STERNOTOMY Noninfectious Complications of Sternotomy Without Sternal Instability General Surgical Complications Superficial noninfectious wound problems, such as hematomas, skin separation, and seroma formation, are handled according to the general rules of surgical practice. Postpericardiotomy syndrome, an inflammatory reaction (possibly an autoimmune response) of the pericardium, is manifested in fever and pericardial inflammation and effusion. It usually responds to corticosteroids, nonsteroidal antiinflammatory agents, or, ultimately, drainage of effusions. The development of arteriovenous fistula of the internal thoracic vessels may result from direct needle injury or from erosion by a wire suture.3,4 It is best treated by either ligation or transcatheter embolization.5-7 Subxiphoid incisional hernia occurs in about 0.5% of sternotomies.8 The presence of infection, either deep or superficial, substantially increases the risk of subxiphoid hernia. Patients who have undergone transplantation and are receiving immunosuppressive therapy are at greater risk for wound infection and subsequent hernia development, as are obese patients and those with previous abdominal operations.8 To prevent this complication, the rectus abdominis muscle is not detached from the sternum, and the linea alba is restored at the time of wound closure, using nonabsorbable sutures. 1253

Ch103-F06861.indd 1253

1/21/2008 3:31:03 PM

1254

Section 5 Chest Wall and Sternum

C

F

D

G

E

H

A

B

FIGURE 103-1 Sternotomy incisions used to expose the heart. A, Midline axial sternotomy. B, Lazy S midline sternotomy. C, Modified trap-door incision. D, Clamshell incision. E, Anterior thoracotomy with transverse sternotomy. F, T-shaped lower sternotomy. G, Manubriotomy with transverse sternotomy. H, Transxiphoid exposure.

Laparoscopic repair with mesh reinforcement is the recommended treatment. Because the midsternal skin incision crosses Lange’s tension lines, the resulting scar is less cosmetic than a transverse incision and could result in the formation of an unsightly keloid. The latter may require the attention of a plastic surgeon. However, a comparative study of patients’ attitudes toward various scars showed that adults who have undergone cardiothoracic surgery are more likely to have a negative attitude toward lateral thoracotomy scars than toward sternotomy scars.9

Neurologic Complications Numbness of the skin alongside the suture line is a common complaint, reported in 47% of the patients (Francel and Kouchoukos, 2001).10 Chronic pain frequently occurs in and around sternotomy incisions. In contrast to recurrent angina, poststernotomy pain is typically associated with tenderness around the surgical incision and is induced by the action of the chest wall muscles and those of the shoulder girdle. Poststernotomy pain usually responds to common pain medications but not to nitroglycerin and seldom requires special measures.

Ch103-F06861.indd 1254

There are, however, several types of so-called stubborn pain syndromes, with distinctly different pathogeneses. The remainder of this section describes these syndromes. Poststernotomy neuralgia is most often caused by scarentrapped neuromas of the anterior terminal branches of the intercostal nerves. It may be treated by local analgesics such as bupivacaine or aqueous phenol or by injection of alcohol.11 Sternal wire sutures may also be sources of chronic chest wall pain, especially if a knot or a broken end lies against the skin. Another type of chronic pain that is caused by sternal wires may appear from 2 months to several years after the sternotomy. It is described as a sharp, stabbing, deep-seated ache and is induced by excessive fibrous tissue reaction to wire sutures. Serial sections of the fibrous tissue usually reveal entrapment of sensory nerve fibers.12 The fact that biologic sensitivity to stainless steel occasionally becomes a surgical problem has also been documented with pacemakers and orthopedic implants.13 By definition, stainless steel contains at least 50% iron and 11% chromium. Other metals may also be added to form alloys to resist corrosion. Such alloys could cause hypersensitivity reactions. Nickel has been implicated most frequently; chromium and cobalt have also been shown to induce hypersensitivity. A particular symptom of sensitivity to wire alloy is persistent itching in the scar. It has been observed that the culprit wires often have elevated electrical potentials and that their removal usually relieves the pain and tenderness. Poststernotomy brachial plexopathy occurs in about 5% of the cases. It may be caused by hyperabduction of the arm during anesthesia or by overstretching of the sternal halves with retractors during surgery, with consequential first rib fracture. The severity of plexopathy varies from a simple dysesthesia and numbness to a full-blown radiculopathy in the C8-T1 area, involving the entire arm. Motor signs range from mild clumsiness to marked weakness of all intrinsic muscles. Plexopathy usually responds to physiotherapy and pain relievers. Brachial plexus injury in connection with open heart surgery may also occur during traumatic cannulation of the internal jugular vein.14,15 In aseptic osteochondritis, tenderness and sometimes swelling are usually localized to one or two parasternal costal cartilages. Osteochondritis is often associated with sternochondral separation, in which case the patient experiences a feeling of “clicks” and pain that is more intense during deep inspiration or when the shoulder is moved. Initial treatment consists of infiltration of the tender area with local anesthetics or steroids. If symptoms persist, especially if there is continued pathologic mobility, removal of 3 to 4 cm of the involved cartilage almost always relieves the pain and discomfort by eliminating the rubbing-together of the separated edges. Because the costal cartilage is nourished by diffusion from the perichondrium, surgical stripping makes it especially vulnerable to aseptic necrosis. The involved area may be indurated and is painful on palpation. Because the necrotic portion of the rib acts as a foreign body, healing can occur only after the sequestrated bone or cartilage either discharges spontaneously or is removed surgically.

1/21/2008 3:31:03 PM

Chapter 103 Complications of Midline Sternotomy

1255

(alteration in the axis of the wire compared with its previous orientation), disruption, or unraveling (Fig. 103-2). These signs may precede clinical symptoms of dehiscence by 1 to 8 days.18,19 The so-called midsternal stripe sign (vertical sternal lucency in the area of the sternotomy), identified in 20% of patients with sternal dehiscence, may also help in the diagnosis, especially if it is wider than 3 mm.18,20

Sternal Instability in the Absence of Infection Sternal instability may be caused by trauma, or it may occur after radical resection of a tumor, but most such cases that a surgeon sees in daily practice are sternal wound complications occurring after cardiac surgery. Perioperative sternal instability is termed dehiscence or disruption. Sternal separation observed in the late postoperative period is known as non-union. The separation of the sternal halves may be total, involving the entire sternal suture line, or partial, limited to a portion (usually the lower) of the sternotomy. These conditions are characterized by chronic discomfort as well as by clicking and a feeling of abnormal motion.16 Although the consequences are certainly not lifethreatening, pain associated with rubbing of the bony surfaces against one another may be most uncomfortable. Sternal nonunion without infection occurs in approximately 0.3% of the patients.17 Sternal disruption per se causes neither flail chest nor paradoxical breathing. The latter occurs only when the integrity of the sternocostal cage is interrupted along at least two vertical lines instead of only one, such as in sternal separation combined with linear fracture of the costal cartilages. However, respiratory embarrassment may still develop without flail chest, due to a cycle of pain, rapid and shallow breathing, and inadequate air exchange. The main significance of sternal instability, especially in the early postoperative period, is that, if it is not treated in a timely fashion, it more often than not develops into an infectious sternomediastinitis.

Factors Involved in Sternal Instability Sternal Blood Supply Any discussion concerning sternal dehiscence and infection is incomplete without considering the particularities of the sternal blood supply, the main source of which are the internal thoracic arteries and their branches. There is also supplemental nourishment to the costal cartilages by diffusion.21,22 The blood supply of the distal sternum and the xiphoid process is relatively scarce, which is possibly one of the reasons why dehiscence most often begins there. A midline sternotomy disrupts only a few vascular arcades and has no significant effect on the sternal blood supply. The use of the internal thoracic arteries for coronary artery bypass grafting deprives the sternum of a significant portion of its normal blood flow. There are three main methods of harvesting: pedicled, semiskeletonized, and skeletonized. The skeletonized approach spares the collateral branches and thus disturbs the sternal blood supply less than the other two techniques. Our data have shown that, even if harvesting is done by the skeletonized technique, the intercostal and pectoral segmental branches cannot immediately substitute for the internal thoracic arteries, and therefore the sternum is rendered acutely ischemic (Fokin et al, 2005) (Figs. 103-3 and 103-4).22 This condition usually resolves within 1 month.23 Several technical considerations are based on these findings. First, wire sutures are placed as close as possible to the sternum to prevent damage to the nonharvested internal thoracic artery. Second, wire sutures cut through the sternum more often on the harvested side. Third, extensive distal mobilization of the internal thoracic artery may aggravate the ischemia of the distal sternum.

Diagnosis Sternal disruption may be diagnosed by simple physical examination, especially using bimanual chest compression and feeling the mobility of the sternal halves. Not infrequently, however, especially in obese patients or if the separation of the sternal halves is incomplete, additional measures are needed to confirm the diagnosis. Conventional radiographs often reveal early signs of wiresuture abnormalities such as displacement (shift of one or more wires in relation to others in the vertical row), rotation

FIGURE 103-2 Radiographic signs of sternal dehiscence. A, Normal appearance of wire suture. B, Wire rotation. C, Wire disruption (unraveling). D, Wire displacement. E, Midsternal stripe sign (vertical sternal lucency).

A

B

C

D

E

Normal

Rotation

Disruption (unraveling)

Displacement

Gaping lucent midsternal stripe

Ch103-F06861.indd 1255

1/21/2008 3:31:03 PM

1256

Section 5 Chest Wall and Sternum

38.0°C

LI01 LI02

35

30

25 22.0°C

A

38.0°C

35 LI01 LI02

30

25

B

22.0°C

FIGURE 103-3 Thermographic image of sternal halves after midline sternotomy. Temperatures measured along Line 1 (LI01) and Line 2 (LI02). A, Similar temperatures exhibited by both sternal halves, with the xiphoid process being the coolest sternal segment. B, Lower temperature of the semisternum on the side of harvested internal thoracic artery. (FROM FOKIN AA, ROBICSEK F, FOKIN A JR, ANDERSON JE JR: CHANGES IN STERNAL BLOOD FLOW AFTER DIFFERENT METHODS OF INTERNAL THORACIC ARTERY HARVESTING. THORAC CARDIOVASC SURG 52:334-337, 2004, COPYRIGHT GEORG THIEME, VERLAG KG, STUTTGART, NEW YORK, WITH PERMISSION.)

Biomechanical Considerations In the early postoperative period, the sole cohesive force acting on the reunited sternum is the holding power of the sternal sutures. On one hand, the tighter the wire sutures, and the smaller the area on which they act, the more reliable is the closure. On the other hand, the tauter and narrower the wire sutures, the more likely they are to cut into the bone. The sutures then become loose, the sternal halves begin to separate, and, with the respiratory motions of the chest, the loose wires soon saw the sternum into segments. Coughing and sneezing may exacerbate this process considerably. Forces leading to sternal disruption also include the action of the respiratory muscles. The rhythmic inspiratory expansion of the thoracic cage, which acts primarily in the lateral direction, is one of the primary disruptive forces (Fig. 103-5). The same force also has an anteroposterior component acting as the longest displacement of the distal sternum. There is also pivoting of the sternotomy suture line in the anteroposterior direction (Fig. 103-6). Another force hostile to the reunited sternum is the lateral pull of the pectoralis major muscles. Mobility of one sternal half in relation to the other in the axial direction may also be induced if only one of the two

Ch103-F06861.indd 1256

3e+5

2e+5

1e+5

0

1e+5

2e+5

3e+5

FIGURE 103-4 Reduced radioactivity (after intravenous injection of technetium 99m microparticles) of the sternal segments after midline sternotomy on the side of harvested internal thoracic artery. (FROM FOKIN AA, ROBICSEK F, MASTERS TN, ET AL: STERNAL NOURISHMENT IN VARIOUS CONDITIONS OF VASCULARIZATION. ANN THORAC SURG 79:1352-1357, 2005, WITH PERMISSION FROM THE SOCIETY OF THORACIC SURGEONS.)

rectus abdominis muscles is detached from the sternum (see Fig. 103-6). This may occur in rectus abdominis flap transposition. In the cadaver studies of McGregor and colleagues,24 four types of disrupting forces, as well as a simulated Valsalva force, were applied within physiologic limits (<400 Newtons [N]) in the lateral, anteroposterior, and rostral-caudal directions. As expected from clinical observations, sternum separation occurred as a result of the wires’ cutting into the bone rather than wire fractures. The minimally effective force needed to cause disruption was that which occurred in the lateral direction (220 ± 40 N), followed by anteroposterior (263 ± 74 N) and by rostral-caudal (325 ± 30 N) forces. Additional findings were as follows: 1. Increased intrathoracic pressure produced the most motion in the lateral direction. 2. Lateral force across the sternotomy during coughing was estimated to be as high as 400 to 1200 N, thus exceeding physiologic limits.25 3. The lower part of the sternum proved most vulnerable for disruption. This last point was also confirmed by clinical observations and was attributed to pivoting at the xiphoid level. This finding

1/21/2008 3:31:04 PM

Chapter 103 Complications of Midline Sternotomy

FIGURE 103-5 Biomechanics of the movement of the thoracic cage. A, Bucket handle movement of the rib cage in the lateral direction during inspiration/ expiration cycle. B, Pump handle movement of the sternum in the anteroposterior direction with maximum displacement at the distal end.

1257

1st rib during inspiration

Bucket handle

1st rib during expiration Rib movement A

Sternum during inspiration Sternum during expiration

Pump handle

Sternal movement B

7th rib during inspiration

7th rib during expiration

FIGURE 103-6 Disruptive forces acting on the sternotomy. A, Lateral pull by the pectoralis muscles. B-D, Forces that may be generated by Valsalva action. E, Uneven pull exerted by the rectus abdominis muscle.

A

B

C

D

makes stabilization of the distal sternum with additional wire sutures advisable.26

Intraoperative Measures That May Decrease the Likelihood of Sternal Disruption Intraoperative events that may increase or decrease the likelihood of sternal instability relate to how the sternum is divided, how it is spread, and the manner in which it is reunited. The instruments used to divide the sternum (i.e., Lebsche knife; oscillating, rotating, or reciprocating saws) seem to be less important than the method by which they are

Ch103-F06861.indd 1257

E

applied.27-29 Before the sternum is divided, the midaxial line is marked by electrocautery. If the sternotomy does not precisely follow this line, especially if the sternum is narrow, as is often the case in women of small stature, the corresponding sternal half may be enfeebled to such a degree that it will not hold sutures. Also, more vascular arcades are disrupted, thus reducing blood supply to the interior of the divided sternum. For the same reasons, the so-called lazy S, helical, and arched sternotomies, which are advocated to prevent longitudinal misalignment, are, for the most part, avoided. The application of sternal spreaders needs to be gentle and gradual. Spreaders with a single pair of narrow blades can

1/21/2008 3:31:05 PM

1258

Section 5 Chest Wall and Sternum

of fibrin- or collagen-based sealants in lieu of bone wax is more appropriate.31-33

cause fragmentation and therefore are avoided whenever feasible, in favor of instruments with wider blades that distribute the spreading force along the sternal length. If a retractor having only one pair of narrow blades is used, it needs to be inserted into the lower end of the divided sternum, never in the middle. Overspreading of the sternum is avoided regardless of the type of retractor used (Fig. 103-7). In our experience, beeswax applied to the divided sternal edges not only failed to reduce total blood loss but, when tested in the canine model, also embolized to the lungs.30 Considering its role as a foreign body, it is likely that it also enhances the likelihood of infection. Therefore, application

A

C

Ch103-F06861.indd 1258

Closure of the Sternotomy For sternal closure, most surgeons use interrupted transverse wire sutures, either by passing them through the bone (using needles, awls, gimlets, or drills) or, preferably, by encircling the sternal body.34 These sutures are made of varieties of stainless steel, a strong and relatively inert metal against which other materials used to unite the sternum are compared. Surprisingly, however, analysis of explanted fractured

B

FIGURE 103-7 Application and misuse of sternal retractors. A, Wide-grip retractor distributes the spreading force over a wide area. B, Single-pair retractor may break the sternum if applied in the middle of the sternum. C, Placement in the lower third of the sternum prevents damage.

1/21/2008 3:31:05 PM

Chapter 103 Complications of Midline Sternotomy

1259

pylene or metal instead of wires,40,41 has been suggested. Late results of these studies were not impressive. To eliminate the palpable and painful knots often seen in thin individuals, especially children, the knots are not left in the midline but pulled laterally and bent to the sternal edge. For the same reason, replacement of wires with absorbable materials such as polyglycolic and polydioxanone sutures has also been proposed.42,43 However, in the early stage, the sole force holding the sternal halves together is the suture, so we do not recommend absorbable materials because they carry a higher potential of disruption. A number of publications have also advocated more complex methods for sternal closure and tools, such as plates, screws, pins, rod-compression systems, and various orthopedic paraphernalia.44-46 None of these techniques has shown superiority over properly applied simple wire sutures.47 A common technical shortcoming in closing the divided sternum is the misalignment of the sternal halves. Radiographic studies by VanLeeuw in the early postoperative period commonly revealed displacement of the sternal halves in the anteroposterior or longitudinal direction, as well as sternal spacing in the majority of patients. Sternal approximation was judged perfect in only 15% of patients in whom sternal wires were used and in none of those in whom the sternum was united with bands.48 These findings indicate that there is still room for improvement, and that future innovations contributing to sternal stability are needed. For example, the addition of absorbable sternal pins to routine wire closure could increase sternal stability in both anteroposterior and cranial-caudal directions.49 In high-risk individuals, it is wise to use additional measures of prevention, such as parasternal weaving, a technique we have found to be most effective in preventing as well as repairing sternal disruption (Robicsek et al, 1977).50,51 Retention sutures are recommended in obese patients, especially

wires often reveals corroded pits, transgranular cracking, diminution of nickel concentration, and metallic remnants in macrophages. Such findings indicate not only that some wire sutures may be of inferior quality but also that the synergistic effects of stress and environment may lead to material failure.35 In addition to the choice of material of which the wire is made, its thickness is also important because heavier wires are less likely to break.36 However, because it is more difficult to twist heavier wires tightly and their bulkiness may contribute to wound problems, it makes sense to compromise by applying medium-strength (No. 5 or 6) sutures. Also, when placing the suture, one does not tie the knots under excessive tension but asks the assistant to cross and pull temporarily the untied sutures, both above and below the suture being tied, to hold the sternum halves together. The same may be accomplished with an approximator or by simple towel-clips. Studies have shown that twists are stronger than knots and that commercial devices provide firmer and more reproducible twists than do ordinary pliers. A minimum of six or seven evenly spaced transverse wires are needed to safely close the sternum of an average adult, and more for that of a heavy-set person. If there is a load exceeding 15 kg per wire, the risk of dehiscence increases. Therefore, the axiom of Stoney, that one wire is placed for every 10 kg of body weight, is a sound one.37,38 There is a wide variety of wiring techniques, ranging from single peristernal or transsternal to figure-of-eight peristernal or pericostal sutures (Fig. 103-8). The latest studies confirm that single transverse peristernal or alternating peristernal and transsternal wire sutures are superior to any other wiring techniques.25,39 The failure rate of figure-of-eight pericostal closure was found to be especially high.25 To eliminate the occurrence of wire cutting into the bone, application of bands of different materials, such as polypro-

FIGURE 103-8 Types of wire sutures most commonly used for the closure of midline sternotomy: A, single transverse peristernal; B, single transverse transsternal; C, alternating transsternal and peristernal; D, figure-of-eight peristernal; E, figure-of-eight pericostal.

A

B

D

Ch103-F06861.indd 1259

C

E

1/21/2008 3:31:10 PM

1260

Section 5 Chest Wall and Sternum

women with pendulous breasts.52 If the tension on the soft tissues is very severe, sternal closure (preferably weaving) may be combined with bilateral breast reduction.53 Postoperatively, the strain of coughing and sneezing is controlled by hugging a pillow or other soft object (teddy bears preferred). The arms are crossed in a self-hugging posture whenever the patient is being turned or moved. The use of various commercially available harnesses after surgery has been also advised. Dyspnea is treated appropriately. In extreme cases, the patient may have to be maintained on assisted respiration.

Repair of Noninfected Sternal Dehiscence Instability of the sternum is self-perpetuating, and even if the sternal separation is moderate at the beginning, the loose wires eventually will either break or cut through the bone. Concomitantly, fluid accumulates, the skin dehisces, and a situation that could have been easily handled by timely intervention ends in a surgical disaster (Fig. 103-9). If the skin remains intact, there is usually ample time for intervention; however, the sternal disruption needs to be corrected before the skin breaks and the wound inevitably becomes infected. Such an event may be heralded by increasing amounts of serous drainage or the appearance of bubbles at the lower edge of the incision. Even if the skin is unbroken and the patient does not exhibit any signs of septicemia, sternal disruptions after the first 3 to 4 postoperative days is regarded as potentially contaminated. Gram stains are obtained during sternal repair; only if they show no bacteria can the wound be tentatively regarded as noninfected. Cultures and sensitivity swabs are also obtained and the results considered in further planning. If the wires are found to be broken but the disrupted sternum is without visible damage, reclosure of the sternum by the same technique may not be sufficient to prevent repeated disruption. After a minor débridement, a more extensive procedure is performed to minimize the possibility of a second episode. The safest and easiest way to accomplish this is to buttress the outer sternal edges with a parasternal weave.50,51

Parasternal Weave In the course of the procedure, which we named parasternal weaving, continuous, returning No. 6 stainless steel wire sutures are placed parallel to and on both sides of the sternum. Each suture begins at the lowest chondrosternal junction and then is passed alternately anterior and posterior to the costal cartilages, up to and around the second rib. The suture is then reversed and led caudally, posterior where it had been anterior and vice versa, and then tied. After both sides of the sternum have been so reinforced, six to eight interrupted transverse peristernal sutures are placed in the usual manner and tied taut (Figs. 103-10 and 103-11). Attention is given to placing these sutures lateral to the weaving suture line, to avoid injury to the internal thoracic arteries. About 40 modifications of this method have been published, none of which were found to offer significant advantages over our original technique. If the sternotomy was inadvertently made off-center, leaving only a narrow strip of bone on one side, or if, in extreme cases, the costal cartilages are completely sheared off, the weaving on that side is directed, not around, but through the costal cartilages (Fig. 103-12).

Pectoralis Muscle Padding In the course of this procedure, both pectoralis major muscles are detached from the sternal edges by electrocautery. Then, with blunt rather than sharp technique, the muscles are dissected off the rib cage bilaterally, not more than a length of 4 to 5 cm—just enough to be sutured together presternally without tension. The sutures uniting the muscles are placed to bury the knots (Fig. 103-13). This maneuver reverses the disrupting lateral force of the pectoralis muscles and converts it into a cohesive one.54 The muscles are not separated from the subcutaneous layer. If one of the internal thoracic arteries was harvested for grafting, the extent of muscle detachment on that side is sparing. An additional advantage of presternal padding is that the sternotomy is covered with well-vascularized muscle, which is beneficial for both healing and preventing infection. This method is especially recommended for disruption-prone

FIGURE 103-9 Types of sternal disruption: A, broken wires; B, wires cutting into the bone; C, sternal fragmentation; D, off-side sternotomy.

A

Ch103-F06861.indd 1260

B

C

D

1/21/2008 3:31:10 PM

Chapter 103 Complications of Midline Sternotomy

A

1261

B

FIGURE 103-10 Parasternal weaving I. A, The suture begins at the level of the second-lowest sternochondral junction and is passed alternately anterior and posterior to the costal cartilages, up to the level of the second costosternal junction. B, The suture is then reversed and led caudally, posterior where it had previously been anterior and vice versa, and then tied.

A

FIGURE 103-11 Parasternal weaving II. After the weaving is completed, transverse, encircling sutures are placed lateral to the weave (A), then tied (B).

obese patients and for those patients with scarce subcutaneous tissues, in whom the pad of muscle between the sternotomy and the skin covers otherwise palpable wire sutures. This padding can be used either in conjunction with a routine sternotomy closure or in combination with parasternal weaving.54 A modified sternal weave may be applied to repair chronic sternal non-unions in which the manubrium is well healed, but the sutures intended to unite the body of the sternum are broken and the separated lower sternum forms an upturned letter Y. Instead of pulling together the disrupted halves under tension or reopening the sternotomy in its entire length, the surgeon mobilizes only the separated lower part

Ch103-F06861.indd 1261

B

and then, at the highest level of separation, cuts transversely through one of the sternal halves. This allows easy approximation of the two halves, which can then be reunited by three or four peristernal transverse wire sutures buttressed over a parasternal weave (Fig. 103-14).55 Besides weaving, other methods of buttressing have been recommended, such as intrasternal clips and Kirschner wires.56 Again, we have found most of these techniques to be less effective than simple weaving. Kirschner wires and other rods have also been reported to dislodge and enter vital organs, such as the heart, lung, or aorta.57 There are reports of the use of metal plates, autologous bone,58 and homografts59 with various results. Homologous Achilles tendon

1/21/2008 3:31:11 PM

1262

Section 5 Chest Wall and Sternum

pretreated with glutaraldehyde has also been applied for sternal closure.60

INFECTIOUS COMPLICATIONS OF STERNOTOMY Infectious Complications Without Sternal Instability Superficial Infection The rate of superficial infection after midline sternotomy is 0.8% to 2.1%.10,17,61 These infections may be treated by removal of a few skin sutures, dressing changes, and admin-

Skin suture

Mammary vessels FIGURE 103-12 If the line of sternotomy is off-center, or if the cartilages are sheared off, the initial part of the weaving suture is directed, not around, but through the costal cartilages on the weakened side.

A

Pectoralis muscle

(Mammary vessels dissected)

FIGURE 103-13 Cross-sectional view of presternal suturing of the advanced pectoralis major muscles. Note that the advancement is more sparing on the side on which the internal thoracic artery has been harvested.

B

FIGURE 103-14 A, Repair of chronic partial sternal separation. B, Repair is accomplished by mobilizing the right half of the sternum by a transverse incision at the highest level of separation. This eases approximation and suturing over parasternal weaving.

Ch103-F06861.indd 1262

1/21/2008 3:31:14 PM

Chapter 103 Complications of Midline Sternotomy

istration of antibiotics. More advanced cases may require reopening part of the wound, packing it with moist gauze, and then allowing spontaneous healing by granulation. Continued fever, malaise, and elevated white cell count suggest deeper penetration, as does abnormal mobility of the sternum, drainage of pericardial effusion through the sternotomy incision, a so-called sucking wound, or the appearance of bubbles. Such events require radical and timely intervention.

Sternal Infection With Instability: Poststernotomy Mediastinitis The incidence of poststernotomy mediastinitis is reported to be between 0.7% and 1.5% (Lu et al, 2003).17,61-63 The mortality rate varies dramatically, depending on treatment options, patient selection, the time elapsed since surgery, and the clinical manifestation of the infection. It has been reported to be as low as 0% and as high as 52.8% (Sjögren et al, 2005),64,65 averaging between 4% and 10%. Poststernotomy mediastinitis is also associated with a marked increase (more than double) in long-term mortality rates after coronary surgery.63,66,67 In children, the incidence of sternomediastinitis was reported to be 0.2% to 1.4%, with gram-positive organisms identified in two thirds of the cases.68,69

Risk Factors for Poststernotomy Mediastinitis The array of multivariant risk factors for poststernotomy mediastinitis are classified as modifiable versus nonmodifiable or preexisting, intraoperative, and postoperative. Because instability begets infection and infection begets instability, all of the risk factors listed for sternal instability are risk factors for sternal infection as well. Also, in cases of deep-seated infections, if the sternum is not disrupted initially, it soon will be because the infected bone will not hold wire sutures. For this reason, most patients with poststernotomy mediastinitis also need to be treated for sternal instability. In addition to the risk factors already described for noninfectious sternal instability, the following preexisting conditions may enhance the development of infectious sternomediastinitis. Patients with advanced age (>75 years), low preoperative hemoglobin concentrations (<140 g/L), and female gender are all at a higher risk for complications, including infections. Obesity (body mass index >30 kg/m2) doubles the probability of sternal wound complications in general, and dehiscence in particular. Diabetes with glucose levels higher than 200 mg/dL is associated with an increased incidence of sternal wound infection and therefore requires thorough perioperative control. New York Heart Association (NYHA) class 3 patients are more likely to need a longer period of postoperative ventilation, thus increasing the risk of complications. Smoking, osteoporosis, large breasts, chronic obstructive pulmonary disease, immunosuppressed state, renal failure, history of radiation, and medications such as steroids have also been identified as risk factors for poststernotomy mediastinitis.63,70

Preoperative Preventive Measures The importance of a clean environment and meticulous sterile technique cannot be emphasized enough. Facilities must be

Ch103-F06861.indd 1263

1263

kept painstakingly clean, and infection control measures must be kept up to date. Preparation for surgery includes showering with chlorhexidine. Body hair is removed with clippers or depilatory cream rather than with a razor. The studies of Bryan71 and DeGeest72 and their colleagues showed that, by tightening the rules of operating room asepsis, the infection rate may be reduced from 7.5% to 0.8%. The issue of prophylactic antibiotics is a matter of continued debate. The most commonly used approach is to administer prophylactic antibiotics for a short term, the night before and during surgery. Currently, the most common causative microorganism, isolated in about two thirds of the cases, is methicillin-sensitive Staphylococcus aureus. Coagulase-negative Staphylococcus, gram-negative rods such as Escherichia coli, Pseudomonas, Enterococcus, Enterobacteria, and Staphylococcus epidermidis are also often identified.73 In the selection of antibiotics, individual surgeons need to consider the pathogens that most commonly cause infections in their own patients and hospital. Routine and extended prophylactic administration of antibiotics leads to an increase in infections with methicillinresistant S. aureus (MRSA), which could account for about one third of the pathogens recovered from patients with sternomediastinitis.74 Such infections have a higher mortality rate, require a longer hospital stay, and incur increased costs compared with methicillin-sensitive infections.75-77 The risk of MRSA infection is increased in patients with diabetes, female gender, and age greater than 70 years.78 Previous hospitalization has also been shown to represent a significant risk for MRSA poststernotomy mediastinits.74 For this reason, it is advisable to obtain a nasal swab culture in all previously hospitalized patients. Nasal carriers of MRSA need to be treated with intranasal mupirocin and with vancomycin.

Intraoperative Measures to Decrease the Risk of Poststernotomy Mediastinitis Time-conscious and aseptic surgical technique that inflicts minimal trauma to the tissues is the cornerstone of prevention of poststernotomy infections. During the course of surgery, the exposed edges of the sternum are protected with pads soaked in povidone-iodine or antibiotic solution. Local gentamicin application produces high antibiotic concentrations in the wound and has been shown to reduce sternal wound infections.79 The length of cardiopulmonary bypass and the amount of transfused blood, especially infusion of mediastinal shed blood with 6 hours of surgery,80 was found to be related to occurrence of infections.80,81 Harvesting of the internal thoracic artery, especially if done bilaterally, also increases the risk of sternal infection,23,82,83 especially in male and obese diabetics.84 In this particular patient population, bilateral internal thoracic artery harvesting is avoided if clinically feasible. Shifting a pedicled pericardial fat pad to the back side of the sternotomy suture line has been proposed to bring live, vascularized tissue close to the reunited sternotomy.85,86 For the same purpose, we have found presternal padding using

1/21/2008 3:31:18 PM

1264

Section 5 Chest Wall and Sternum

the pectoralis muscles (described earlier) to be much simpler and more effective.54

Postoperative Measures Postoperative risk factors for sternomediastinitis include reentry for bleeding, concomitant infections at other sites, cardiopulmonary resuscitation, and prolonged mechanical ventilation.81,86 The last factor was found to be particularly associated with increased rates of septicemia and sternal infections.65 For this reason, depending on their clinical status, early extubation is considered for all patients after cardiac surgery. Tracheostomy performed in the early postoperative phase increases the risk of deep sternal wound infection fivefold; therefore, it is delayed whenever possible.87 Lower rates of infection may be achieved by performing a minitracheostomy and/or a percutaneous instead of standard tracheostomy and by meticulous isolation of the sternal area. The latter may be best accomplished by placing the tracheostomy somewhat higher than usual, avoiding extensive paratracheal dissection, and covering the sternotomy incision with a plastic drape for a minimum of 6 days.

Diagnosis of Poststernotomy Mediastinitis In the diagnosis of poststernotomy mediastinitis, the introduction of new technology does not diminish the importance of a keen clinical eye. In the presence of obvious local signs of infection, such as redness, fluctuation, or purulent discharge, one must not waste time but proceed with appropriate drainage and wound care. Similarly, proof of sternal instability, alone, sends the patient into the operating room. In cases of deep-seated, smoldering infections, however, these classic diagnostic signs may be absent, and establishing the presence of sternomediastinitis may be difficult. Therefore, it is most important that the clinician exhibit a high degree of suspicion: In the postoperative setting after sternotomy, a septic state indicates the presence of mediastinitis unless proven otherwise. There are a number of special diagnostic measures the surgeon may take. Radiologic findings that suggest sternal disruption also raise a high suspicion of sternomediastinitis, especially in the presence of general signs of infection. Retrosternal gas, when the previous films demonstrated none, is diagnostic for mediastinal infection. This needs to be distinguished from air left in after surgery, which could remain for days or even weeks after the operation. Infection may also manifest as presternal emphysema and soft tissue swelling.20 Computed tomography (CT) may be used both to diagnose and as a follow-up of poststernotomy mediastinitis. Its sensitivity is close to 100%, although its specificity varies from 33% to 100%.88 CT may detect a periosteal reaction, loss of integrity of soft tissue, signs of abscess formation, pericardial and pleural fluid collections, and progressive widening of the space between the sternal halves, and it may also reveal the depth of sinus tracts.89 Most of these findings are nonspecific; however, the greater the number of manifestations present,

Ch103-F06861.indd 1264

and the longer they exist, the higher the probability of retrosternal infection. CT scans may also be useful in the planning of additional surgical treatment by revealing details of the retrosternal anatomy, such as adhesion of the right ventricle to the sternum (occurring in ∼40% of the patients), or determining whether there is a safe distance between the sternum and the ascending aorta.90 These data may be valuable in avoiding catastrophic hemorrhage due to injury to the heart, aorta, or grafts during sternal reentry, which is estimated to occur in approximately 1% of the cases.91,92 After débridement and reconstructive repair of the sternum with omental or muscle flaps, CT imaging may detect dehiscence, outline irregular bony fragments, or show lack of cortical definition, dislocation of the muscle flaps, midline soft tissue masses, hematomas, herniation of the bowel, or the presence of abscess formation within the flaps. Prolonged edema, new or increasing fluid or air collections, and attenuation of contours seen on CT imaging suggest the presence of infection, especially if they persist for longer than 1 month after surgery.93,94 Radiolabeled blood cell imaging, using leukocytes tagged with radioactive substances such as indium 111, has been recommended for identification and localization of mediastinal inflammation processes. The sensitivity, specificity, and accuracy are 86%, 97%, and 95%, respectively.95 Application of technetium 99m-labeled monoclonal granulocyte antibody scintigraphy has an accuracy of diagnosis of almost 100% and also can show the extent of sternal wound infections. Positron emission tomography (PET) scanning may be applied in the late postoperative course to diagnose and localize inflammatory processes. In low-grade, smoldering mediastinal infections with vague or absent clinical signs, we have found thermography extremely useful. Demonstration of temperature rise at the sternotomy site more than 2 weeks after surgery yields a 100% sensitivity and specificity in differentiating infections from postpericardiotomy syndrome–like situations (Fig. 10315). For infections that have already been diagnosed, thermography has also proved to be useful in monitoring the efficiency of both surgical treatment and antibiotic therapy.96 The most important confirmation of the diagnosis of sternomediastinitis is microbiologic proof. In all patients with continued temperature elevation in whom obvious sources cannot be identified, we recommend multiple aspiration of the peristernal area, including the retrosternal space through the suprasternal notch. Grossly purulent fluid can sometimes be found in wounds that appear to be healing normally.97 The attempt may be enhanced by injection and reaspiration of a few milliliters of normal saline. If simple aspirations fail, a CT-guided retrosternal tap may be attempted. In an effort to obtain microbiological proof, we have found cultures of temporary epicardial pacing wires most rewarding, both for confirmation of infection and for early and specific antimicrobial therapy. For this reason, whenever the temporary pacer wires are removed from a patient with suspected mediastinal infection, or from a patient who is considered to be

1/21/2008 3:31:18 PM

Chapter 103 Complications of Midline Sternotomy

1265

FIGURE 103-16 The positions of irrigation and drainage catheters during closed treatment of sternomediastinitis. (FROM BLANCHARD A,

FIGURE 103-15 Thermographic image of a normally healing (A-C) and an infected (D-F) sternotomy. A, Preoperative thermography shows “cool” chest. B, One week after surgery, the incision is “warm,” owing to the healing process. C, Two weeks after surgery, the normally healing incision is “cool” again. D, In case of infection, the skin remains “hot” past 2 weeks. E and F, Temperature continues to increase in the infected sternotomy.

at higher than usual risk for mediastinal infection, the tips of the wires need to be cultured.98 Naturally, a positive blood culture may serve as a tool to obtain an early diagnosis in patients with suspected sternomediastinitis and to provide guidance in antibiotic treatment.

Surgical Management of Poststernotomy Mediastinitis The goals for the surgical management of poststernotomy mediastinitis are twofold: (1) bring the infectious process under control in the shortest possible time, and (2) ensure sternal stability. Historically, cardiac surgeons managed sternomediastinitis with the open technique. This involved reopening the sternum, caring for the wound, and waiting for spontaneous closure by granulation. The latter usually required 40 to 60 days. Because of its associated high mortality rate, this method was largely replaced in the early 1970s with initial drainage followed by primary closure of the sternum and irrigation.27,70 Fenestrated drainage and infusion catheters71 and antibiotic or antiseptic solutions99 with either passive drainage or suction (Fig. 103-16) were applied with varying

Ch103-F06861.indd 1265

HURNI M, RUCHAT P, ET AL: INCIDENCE OF DEEP AND SUPERFICIAL STERNAL INFECTION AFTER OPEN HEART SURGERY: A TEN YEAR RETROSPECTIVE STUDY FROM 1981 TO 1991. EUR J CARDIOTHORAC SURG 9:153-157, 1995.)

success. Because the mortality rate still remained high, about 12.5%,100 and because of the readily evident shortcomings of this treatment, such as creation of potential dead spaces, the possibility of catheter erosion into vital organs, and the likelihood of systemic absorption of irrigation fluids, surgeons were soon looking for alternative methods.101 Modern surgical management of poststernotomy mediastinitis is based on differentiation and classification of the various types and stages of the disease. The grouping of El Oakley and Wright,102 which is based on the time of first presentation, presence of risk factors, and success of initial treatment, may be useful to evaluate outcomes; however, this system yields little guidance as to what kind of approach to use in an individual case. In this regard, we found the classification of Pairolero and associates,103 which is based on clinical rather than microbiologic features, to be the most practical. In their system, there are three major types of sternomediastinitis. Type I sternomediastinitis manifests with serosanguineous drainage within a few days after sternotomy. Pus, osteomyelitis, and chondritis are notably absent. Mediastinal tissues are still soft and pliable. Bacterial cultures are initially negative or yield staphylococci. In such cases, the sternotomy is reopened, all blind pockets eliminated, and the mediastinum irrigated. This type of infection is best managed by reinsertion of drainage tubes, reclosure of the sternum over parasternal weaving, and aggressive antibiotic treatment. Type II sternomediastinitis is a fulminant process that occurs 1 to 3 weeks after surgery. In addition to reopening,

1/21/2008 3:31:18 PM

1266

Section 5 Chest Wall and Sternum

A

B

C FIGURE 103-17 A-C, Creation of a retrosternal omental flap. (MODIFIED FROM MADDERN IR, GOODMAN LR, ALMASSI GH, ET AL: CT AFTER RECONSTRUCTIVE REPAIR OF THE STERNUM AND CHEST WALL. RADIOLOGY 50:1019-1023, 1993.)

drainage, and irrigation, these patients also require débridement of necrotic soft tissue, bone, and cartilage. This may be done initially, when the wound is reopened, but may be delayed if the patient is septic or if his or her general condition too critical to allow a major intervention. An effort is made to remove all foreign materials such as felt-pledgets and pacer wires. Exposed suture lines are reinforced with autologous tissue, such as fascia lata, or covered with muscle flaps. The wound is then kept open and treated with daily dressing

change, irrigation with normal saline, and antibiotic or povidone-iodine solution. After the drainage ceases and septicemia subsides, the sternotomy wound is closed using muscle or omental flaps and covered with subcutaneous tissue and skin. Type III sternomediastinitis occurs 1 month to 1 year after surgery. The patient typically presents with chronic draining sinus tracts that lead to the infected sternum, cartilages, or retained foreign bodies. Repair requires wide exposure, extensive débridement, often total sternectomy, and flap coverage using autologous tissues. The autologous tissues most commonly used in mediastinal reconstruction are omental and muscle flaps, both of which are eminently suitable to cover surfaces and fill up space with living, well-vascularized tissue. The omentum has a long and distinguished history in the management of infections in cardiovascular surgery (Fig. 103-17).104 Transfer of omental pedicles, with or without muscle flaps, is the technique preferred by many surgeons, especially if synthetic or homograft material is exposed. Muscle flaps were introduced for the treatment of sternomediastinitis by Jurkiewicz and colleagues105 to eliminate potentially infected hollows of the mediastinum and to cover the damaged sternum. This method, combined with adequate débridement, irrigation, appropriate antibiotics, and good supportive care, improved the clinical results significantly and at the same time decreased the length and cost of hospitalization. Of the muscles applied, the pectoralis major most easily covers the upper two thirds of the sternum (Figs. 103-18 and 103-19). Owing to its excellent blood supply from the thoracoacromial vessels and its length, it is the preferred muscle for creating flaps. It may be applied as a single flap, or, if necessary, both pectoralis muscles can be used. To cover more extensive defects, pectoralis flaps may also be combined with rectus abdominis muscle flaps. The latissimus dorsi muscle is

FIGURE 103-19 Creation of pectoralis and rectus abdominis muscle flaps. (MODIFIED FROM MADDERN IR, GOODMAN LR, ALMASSI GH, ET AL: FIGURE 103-18 The blood supply to the pectoralis major muscle.

Ch103-F06861.indd 1266

CT AFTER RECONSTRUCTIVE REPAIR OF THE STERNUM AND CHEST WALL. RADIOLOGY 50:1019-1023, 1993.)

1/21/2008 3:31:19 PM

Chapter 103 Complications of Midline Sternotomy

1267

usually used as a myocutaneous flap to ensure tension-free skin closure.106 The sternocleidomastoid muscles are occasionally applied to fill gaps in the upper mediastinum. The bipedicle flap107,108 is made of the superiorly based pectoralis muscle left in continuity with the inferiorly based rectus abdominis (Fig. 103-20). If the patient’s breasts are large and pendulous, it may be necessary to combine the application of muscle flaps with reduction mammoplasty.53,103 In cases of larger skin defects, the muscle flaps may be covered with split-thickness skin. The same problem may be addressed by creating myocutaneous island flaps.109 Definite drawbacks of muscle-plasties are as follows110: 1. Repeated débridements and revision of flaps are often necessary. 2. About half of the patients notice considerable discomfort long after the intervention. 3. Many patients also continue to experience abnormal sternal motion, as well as clicking and rubbing during coughing or sneezing.

FIGURE 103-20 The pectoralis–rectus abdominis bipedicular flap. (MODIFIED FROM SOLOMON NP, GRANICK MS: BIPEDICLE MUSCLE FLAPS IN STERNAL WOUND REPAIR. PLAST RECONSTR SURG 101:356-360, 1998.)

Reduction in the strength of the shoulder girdle muscles is also seen in about 20% of the patients.10,97 Bulging and herniation of the abdominal wall has been reported in one third of patients.110 If omentum or rectus abdominis flaps are used, there is a potential for herniation of abdominal organs, especially the colon, into the mediastinum.111,112 The latter could be prevented or treated with the use of synthetic materials; unfortunately, however, this may not be advisable in a contaminated environment. In connection with muscle flaps, concern has also been raised regarding possible deterioration of respiratory function, especially in patients who were already compromised before surgery. In the study of Kohman and colleagues,113 however, postoperative pulmonary function tests were found to be unchanged compared with preoperative results, and only patients who were dyspneic before cardiac surgery were short-winded after flap repair. Others found that muscle flap transposition resulted in only mild restrictive impairment of lung function, with the results favoring a pectoralis major rather than a rectus abdominis muscle flap. Francel found a 50% reduction in pulmonary function that returned to preoperative values within 3 months.10

The Open Sternum (Hanuman Syndrome) Closure of the sternotomy incision may be delayed for hemodynamic reasons because of uncontrollable coagulopathy, to accommodate temporary cardiac assist devices, or, most commonly, for drainage, irrigation, and delayed débridement as part of the management of florid mediastinitis. The gaping sternotomy and exposed heart is referred to as the Hanuman syndrome after Hanuman, the Monkey King of Indo-Siamese mythology, who, to demonstrate his goodwill, opened his chest to show his heart to the god Rama (Fig. 103-21). The cardinal issues in the management of patients with Hanuman syndrome follow: FIGURE 103-21 Hanuman, the monkey king of Indo-Siamese mythology.

Ch103-F06861.indd 1267

1. Prevention of contamination if the field is sterile 2. Management of infection, if present 3. Minimization of additional bacterial colonization

1/21/2008 3:31:21 PM

1268

Section 5 Chest Wall and Sternum

4. Prevention of additional complications, primarily hemorrhage from the exposed heart.114 If the field is not contaminated, every effort is made to keep it sterile. Even if the sternum is left open, the skin edges are approximated whenever the situation allows. Drains and other tubes are placed through separate stab wounds. The mediastinum may be packed with sponges soaked in normal saline solution or in povidone-iodine. The edges of the sternum are covered with wet sponges or laps soaked in povidone-iodine, and the entire field is shielded with antiseptic film-adhesive. To ensure drainage and at the same time prevent compression of the heart in cases of hemodynamic compromise, the sternal edges are never overly approximated. This may be achieved by packing or by the use of commercially available99 or improvised115 stents. Methylmethacrylate plates34 were also applied successfully as indwelling stents to spread the sternal edges. In nonseptic pediatric cases in which the sternum could not be closed for hemodynamic reasons or because a conduit was inserted, various materials, including plates made of ceramic or of hydroxyapatite (coral), were recommended as permanent sternal inserts.116 With an open sternum, some patients can maintain a reasonable respiratory state on their own; however, in the acute stage (first 1-2 weeks) the patient is heavily sedated, intubated, and also paralyzed. The principal reason for this is to prevent the occurrence of exsanguinating hemorrhage from the heart, the most dreaded complication of the open method of treating sternal infection, which carries a mortality rate of 19% to 53%.117,118 Although such a hemorrhage may also be caused by direct injury from left-in wires, by the jagged edges of the sternum, or by the infectious process attacking exposed suture lines, there is a special form of life-threatening bleeding that is particular to the Hanuman syndrome. While the patient is at rest, the heart more or less stays away from the opened sternotomy site. If, however, the patient coughs or strains and the heart is forced against the window of the open sternotomy incision and meets the edge of the sternum, the bone may cut deeply into the myocardium and cause severe, often fatal, hemorrhage (Fig. 103-22). The occurrence of such a Valsalva maneuver–like situation may be best prevented by paralyzing the patient and instituting controlled ventilation.114 If bleeding does occur, pressure is applied for initial control, and then the patient immediately is returned to the operating room with cardiopulmonary bypass available. The latter is best instituted through the femoral vessels. If the bleeding is caused by a tear on the heart, usually on the right ventricle, it may be closed with sutures buttressed with autologous tissue, then covered with a patch of pericardium attached with biologic or cyanoacrylate glue.119 Bleeding from suture lines is always infectious in origin and is handled by additional sutures and simultaneous muscle flap or omental coverage. Because small signal hemorrhages often precede a major one, any bleeding from the exposed mediastinum, however small, should be taken most seriously. To prevent the devastating complication of hemorrhage from the exposed heart, every effort is made to keep the

Ch103-F06861.indd 1268

A

B

C

D

FIGURE 103-22 Mechanisms of hemorrhage of the exposed heart in the course of open management. A, Spread of the infectious process. B, Injury caused by a jagged edge of the sternum. C, Increased intrathoracic pressure forcing the heart against the sternal window. D, Tear on the heart caused by dense adhesions to the anterior chest wall.

period during which the mediastinum is exposed as short as possible. Whenever the condition, either hemodynamic or infectious, that made the exposure necessary has been brought under reasonable control, the mediastinum is closed without undue delay. If the sternum was left open for hemodynamic reasons, it can usually be closed primarily. If Hanuman syndrome was created to treat sternomediastinitis, closure is accomplished with the use of muscle flaps. Hemorrhage as a consequence of sternomediastinitis may occur even if the heart is not fully exposed. Major bleeding is reported to occur in 0.07% to 0.14% of all cardiac surgery patients.117,120,121 The frequency of this complication in cases of sternomediastinitis is approximately 5%.117,120 Because of the presence of dense adhesions, bleeding seldom occurs into the mediastinum, but rather through partially exposed areas or through chronic fistulas. Recommendations for the prevention and treatment of mediastinal bleeding may be summarized as follows: 1. Aggressive and early surgical treatment of mediastinitis as soon as the diagnosis is established 2. Dissection of adhesions of the right ventricle to the posterior sternum during débridement 3. Stabilization of the sternal edges by VAC foam or stent 4. Protection of the exposed heart by placement of a dressing or a layer of pericardium between the sternal edges and the heart 5. Immediate institution of cardiopulmonary bypass 6. Wide application of muscle and/or omental flap A major development in the management of poststernotomy mediastinitis was vacuum-assisted closure (VAC). Application of negative (subatmospheric) pressure for treatment of various soft tissue wounds and ulcers was pioneered in the 1970s.122,123 VAC for treatment of poststernotomy mediastinitis was first described by Obdeijn and colleagues in 1999.124 The method consists of filling the gaping sternal wound after it has been adequately drained and débrided with reticulated polyurethane foam of 400 to 500 µm pore

1/21/2008 3:31:23 PM

Chapter 103 Complications of Midline Sternotomy

To suction Adhesive drape Skin Subcutaneous tissue

Muscle Rib

Sternum

Foam

Protective mesh

-125 -50 -200 mmHg

Heart FIGURE 103-23 A schematic illustration of vacuum-assisted closure.

size, sealing the wound with adhesive drape, and placing it under suction with a range of −50 to −200 mm Hg, using a tube positioned inside the foam (Fig. 103-23). Currently, suction of −125 mm Hg is most commonly recommended. VAC was also successfully applied in pediatric cases with an intermittent suction of −50 mm Hg.125 During VAC treatment, care is taken to prevent adherence of the sternum to the right heart by using a mesh-like dressing impregnated with Vaseline/paraffin. Delay in changing the dressing beyond 3 days may result in the ingrowth of granulation tissue into the foam and wound damage during consequent dressing changes.126 Fluid balance is carefully monitored throughout VAC to prevent toxic shock syndrome and renal failure due to the excessive loss of extracellular fluid and hypovolemia.127 VAC may be combined with separate drainage of pleural effusion.128 The duration of VAC therapy with either continuous or intermittent regimens varies from 4 to 49 days.124,129 The beneficial effects of VAC treatment have been attributed to several factors: 1. 2. 3. 4. 5.

Stimulation of tissue granulation Augmentation of blood flow Increased penetration of antibiotics Decreased bacterial colonization Removal of metalloproteinases and harmful enzymes from the wound 6. Immediate stabilization of the opened sternum by vacuum sponge, which, in turn, reduces the threat of right ventricular damage and bleeding VAC also raises the partial pressure of oxygen and the lactate level in the wound, which in turn stimulates transcription and deposition of collagen, production of vascular endothelial growth factor, and, ultimately, angiogenesis.130 VAC treatment proved most effective in promoting rapid healing of infected sternotomy wounds by dramatically reducing mortality, shortening hospitalization time and cost, and occasionally eliminating the need for myocutaneous flap. It could be used as first-line therapy or, in other cases, as a bridge to plastic surgery.131 Concerns raised in connection with VAC are that it may impair right ventricular performance, especially in patients with marginal cardiac function.132 However, recent studies confirmed that VAC therapy with vacuum in the range of −50 to −175 mm Hg, given

Ch103-F06861.indd 1269

1269

appropriate foam application between and above the sternal level, does not disturb central hemodynamics. It has been hypothesized that VAC may even exert a favorable effect on cardiac function by increasing cardiac contractility and venous return.131 Rupture of the right ventricle was reported in two patients undergoing VAC. Reducing the strength of the suction and freeing the right ventricle from adhesions during the initial débridement are recommended to avoid this complication.133 VAC is disconnected at the first signs of mediastinal bleeding.128 Late complications of sternomediastinitis include mycotic pseudoaneurysm formation from suture lines of the heart and aorta. This can cause severe, sometimes exsanguinating hemorrhage.134 Another delayed complication of sternotomy infections is septic costochondritis and osteomyelitis with sinus tract formation.103 In such cases, all necrotic tissue must be removed. If the sinus tract leads into the mediastinum, there is usually retained foreign material, which also is extricated. Radicality rather than conservatism is appropriate. In stubborn or extensive processes, sternectomy may become a necessity.129 After débridement, the wound is left open and a delayed closure is performed, preferably with the use of muscle flaps.103 The effect of sternomediastinitis on the patency of the aortocoronary grafts has not been completely clarified; however, there are reports that mediastinal infections do not adversely affect graft patency.135-137

Antibiotic Management In uncomplicated cases, antibiotic administration is usually limited to the immediate perioperative period. Culturespecific antibiotics are continued, however, if the patient is known to have a chronic infectious process that was not eradicated before the operation. If the postoperative course is septic and there are no clinical signs indicating a specific focus of infection, blood, sputum, and urine cultures are obtained and the patient is given intravenous broad-spectrum antibiotics. Antibiotic management is modified according to the culture results. There is a continued search for the source of the infection, primarily in the sternomediastinum. If the infectious process indeed turns out to be sternomediastinitis, the surgical treatment is closely coordinated, not only with antibiotic sensitivity studies of the respective microorganisms but also with the clinical response to treatment and possible side effects of the antibiotics themselves. Sternomediastinitis is a life-threatening condition. Consultation and assistance of an infectious disease specialist is considered, especially if the infection does not respond to treatment in a timely fashion.

General Measures Besides disease-specific surgical and antibiotic treatment, sternomediastinitis, like any other life-threatening infection, requires thorough and sometimes extensive supportive measures, for the details of which the reader is referred to the appropriate chapters of this book. Although this task is more

1/21/2008 3:31:23 PM

1270

Section 5 Chest Wall and Sternum

often than not shared by different disciplines, the cardiac surgeon maintains the responsibility he or she acknowledged when accepting the patient for the primary surgery and continues in a leading/coordinating capacity. The morbidity and mortality of poststernotomy mediastinitis have improved dramatically during the past 2 decades. The condition, however, still remains potentially lethal. Our future task is to further decrease its occurrence to the absolute minimum, and to invent and apply even more effective approaches for its treatment. KEY REFERENCES Fokin AA, Robicsek F, Masters TN, et al: Sternal nourishment in various conditions of vascularization. Ann Thorac Surg 79:1352-1357, 2005.

Ch103-F06861.indd 1270

Francel TJ, Kouchoukos NT: A rational approach to wound difficulties after sternotomy: The problem. Ann Thorac Surg 72:1411-1418, 2001. Lu JCY, Grayson AD, Jha P, et al: Risk factors for sternal wound infection and mid-term survival following coronary artery bypass surgery. Eur J Cardiothorac Surg 23:943-949, 2003. Pairolero PC, Arnold PG, Harris JB: Long-term results of pectoralis major muscle transposition for infected sternotomy wounds. Ann Surg 213:583-590, 1991. Robicsek F, Daugherty HK, Cook JW: The prevention and treatment of sternum separation following open-heart surgery. J Thorac Cardiovasc Surg 73:267-268, 1977. Robicsek F, Fokin A, Cook J, Bhatia D: Sternal instability after midline sternotomy. Thorac Cardiovasc Surg 48:1-8, 2000. Sjögren J, Gustafsson R, Nilsson J, et al: Clinical outcome after poststernotomy mediastinitis: Vacuum-assisted closure versus conventional treatment. Ann Thorac Surg 79:2049-2055, 2005.

1/21/2008 3:31:24 PM

THORACIC OUTLET SYNDROMES

chapter

104

Susan E. Mackinnon Christine B. Novak G. Alexander Patterson Harold C. Urschel, Jr.

Key Points ■ In patients with predominantly neurogenic symptoms and no intrin-

sic muscle atrophy, the diagnosis of TOS is a clinical diagnosis based on reproduction of patient symptoms with provocation testing (arm elevation) and exclusion of other conditions that can cause similar symptoms. ■ Conservative management should include modification of activities (at home and at work) to decrease patient symptoms, postural correction, and physical therapy to address the problems of nerve compression and cervicoscapular muscle imbalance. ■ Patients with severe vascular compression and brachial plexus compression with intrinsic muscle atrophy will likely require surgical decompression. ■ The majority of patients with brachial plexus compression and no intrinsic muscle atrophy will be successfully managed with an appropriate program of physical therapy and very few patients require surgical decompression.

DEFINITION Thoracic outlet syndrome, a term coined by Rob and Standover,1 refers to compression on the subclavian vessels and brachial plexus at the superior aperture of the chest. It was previously called scalenus anticus, costoclavicular, hyperabduction, cervical rib, or first thoracic rib syndrome, depending on the presumed cause. The various syndromes are similar, and the compression mechanism is often difficult to identify. Most compressive factors operate against the first rib (Fig. 104-1).2,3

HISTORICAL NOTE Until 1927, the cervical rib was commonly thought to be the cause of symptoms of the thoracic outlet syndrome. Galen and Vesalius first described the presence of a cervical rib.4 Hunauld, who published an article in 1742, is credited by Keen5 as being the first to describe the importance of the cervical rib in causing symptoms. In 1818, Cooper treated symptoms of cervical rib with some success,6 and in 1861, Coote performed the first cervical rib removal.7 Sir James Paget, in 1875 in London,8 and von Schroetter, in 1884 in Vienna,9 described the syndrome of thrombosis of the axillary-subclavian vein (Paget-Schroetter syndrome). Halsted10 stimulated interest in dilation of the subclavian

artery distal to cervical ribs, and Law11 reported the role of adventitious ligaments in the cervical rib syndrome. Naffziger and Grant12 and Ochsner and associates13 popularized section of the scalenus anticus muscle. Falconer and Weddell14 and Brintnall and associates15 incriminated the costoclavicular membrane in the production of neurovascular compression. Wright16 described the hyperabduction syndrome with compression in the costoclavicular area by the tendon of the pectoralis minor. Rosati and Lord17 added claviculectomy to anterior exploration, scalenotomy, resection of the cervical rib (if present), and section of the pectoralis minor and subclavian muscles as well as of the costoclavicular membrane. The role of the first rib in causing symptoms of neurovascular compression was recognized by Bramwell in 1903.18 Murphy19 is credited with the first resection of the first rib, and in 1916 a collective review of 112 articles related to compression from the cervical ribs was published.20 Brinckner and Milch,21 Brinckner,22 Telford and Stopford,23 and Telford and Mottershead24 suggested that the first rib was the primary problem. Clagett2 emphasized the first rib and its resection through the posterior thoracoplasty approach to relieve neurovascular compression. Falconer and Li25 reported the anterior approach for first rib resection, whereas Roos26 introduced the transaxillary route for first rib resection and extirpation. Krusen27 and Caldwell and coworkers28 introduced the measurement of motor conduction velocities across the thoracic outlet in diagnosing thoracic outlet syndrome. Urschel and associates29 popularized reoperation for recurrent thoracic outlet syndrome and thrombolysis with prompt transaxillary rib resection for Paget-Schroetter syndrome. Wilborn30 emphasized the controversial nature of neurogenic thoracic outlet syndrome without intrinsic muscle wasting. Mackinnon and Novak31-34 stressed the merits of appropriate physical therapy and recognition of associated distal entrapment neuropathies in the management of thoracic outlet syndrome.

BASIC SCIENCE Surgical Anatomy At the superior aperture of the thorax, the subclavian vessels and the brachial plexus traverse the cervicoaxillary canal to reach the upper extremity.35 The cervicoaxillary canal is divided by the first rib into two sections: the proximal one, composed of the scalene triangle and the costoclavicular space (the space bounded by the clavicle and the first rib), 1271

Ch104-F06861.indd 1271

1/21/2008 3:32:17 PM

1272

Section 5 Chest Wall and Sternum

Scalenus anticus and medius muscles Pectoralis minor muscle and costocoracoid ligament Costoclavicular membrane Subclavius muscle

Cervical rib First rib anomalies Long transverse process Clavicle abnormalities

COMPRESSION First rib

VASCULAR Subclavian vein

NERVE

Subclavian artery

Sympathetic

Peripheral

Raynaud’s phenomena

Pain Paresthesias Motor weakness

Pain Color and temperature change Ischemia Trophic change Edema Venous distention Paget-Schroetter syndrome

Loss of pulse Claudication Thrombosis

FIGURE 104-1 The relation of muscle, ligament, and bone abnormalities in the thoracic outlet that may compress neurovascular structures against the first rib.

and the distal one, composed of the axilla (Fig. 104-2). The proximal division is the more critical for neurovascular compression. It is bounded superiorly by the clavicle, inferiorly by the first rib, anteromedially by the costoclavicular ligament, and posterolaterally by the scalenus medius muscle and the long thoracic nerve. The scalenus anticus muscle, which inserts on the scalene tubercle of the first rib, divides the costoclavicular space into two compartments: the anteromedial compartment, which contains the subclavian artery and the brachial plexus, and the scalene triangle, which is bounded by the scalenus anticus anteriorly, the scalenus medius posteriorly, and the first rib inferiorly. This region of neurovascular compression is correctly termed the thoracic inlet and not the thoracic outlet.36

Functional Anatomy The cervicoaxillary canal, and in particular its proximal segment, the costoclavicular area, normally has ample space for passage of the neurovascular bundle with compression. This space narrows during functional maneuvers. It narrows during abduction of the arm because the clavicle rotates backward toward the first rib and the insertion of the scalenus anticus muscle. In hyperabduction, the neurovascular bundle is pulled around the pectoralis minor tendon, the coracoid process, and the head of the humerus. During this maneuver, the coracoid process tilts downward and thus exaggerates the tension on the bundle. The sternoclavicular joint, which ordinarily forms an angle of 15 to 20 degrees, forms a smaller angle when the outer end of the clavicle descends (as in drooping of the shoulders in poor posture), and narrowing of the costoclavicular space may occur.17 Normally, during inspiration, the scalenus anticus muscle raises

Ch104-F06861.indd 1272

the first rib and thereby narrows the costoclavicular space. This muscle may cause an abnormal lift of the first rib, as in cases of severe emphysema or of excessive muscular development typically seen in young male adults. The scalene triangle, which is normally located between the scalenus anticus anteriorly, the scalenus medius posteriorly, and the first rib inferiorly, permits passage of the subclavian artery and the brachial plexus, which are in direct contact with the first rib. The triangle is 1.2 cm at its base and approximately 6.7 cm in height. There is little space between the neurovascular bundle and this triangular space. Anatomic variations may narrow the superior angle of the triangle, cause impingement on the upper components of the brachial plexus, and produce the upper type of scalenus anticus syndrome, which involves the trunk-containing elements of C5 and C6. If the base of the triangle is raised, compression of the subclavian artery and the trunkcontaining components of C7, C8, and T1 results in the lower type of scalenus anticus syndrome. Both types have been described by Swank and Simeone.37

Compression Factors Many factors can cause compression of the neurovascular bundle at the thoracic outlet, but the most important factor is specific anatomy in this area17 (Box 104-1). Bony abnormalities are present in approximately 10% of patients, in the form of a cervical rib, a bifid first rib, fusion of first and second ribs, or clavicular deformities or as the result of previous thoracoplasties. These abnormalities can be visualized on the plain posteroanterior chest radiograph, but special radiographic views of the lower cervical spine may be required in some cases to visualize the cervical ribs.

1/21/2008 3:32:18 PM

Chapter 104 Thoracic Outlet Syndromes

1273

FIGURE 104-2 Hyperabduction of the right arm with anatomic structures as noted.

Biceps muscle (short head) Coracobrachialis muscle

Anterior Middle Posterior

Subclavius muscle Clavicle Acromion Coracoid process

Scalene muscles

Brachial plexus Costoclavicular ligament

Brachial artery and vein Head of humerus Axillary artery Subclavian artery Attachment of anterior scalene muscle Subclavian vein Pectoralis minor muscle First rib

Diagnostic maneuver for pectoralis minor or humeral head syndrome

Box 104-1 Neurovascular Compression Factors Anatomic Potential sites of neurovascular compression Interscalene triangle Costoclavicular space Subcoracoid area

Enlarged transverse process of C7 Omohyoid muscle Anomalous course of transverse cervical artery Brachial plexus after repair Flat clavicle

Congenital Cervical rib and its fascial remnants Rudimentary first thoracic rib Scalene muscles Anterior Middle Minimus Adventitious fibrous bands Bifid clavicle Exostosis of first thoracic rib

Traumatic Fracture of clavicle Dislocation of head of humerus Crushing injury of upper thorax Sudden, unaccustomed muscular efforts involving shoulder girdle muscles Cervical spondylosis and injuries to cervical spine

Ch104-F06861.indd 1273

Atherosclerosis

1/21/2008 3:32:18 PM

1274

Section 5 Chest Wall and Sternum

Histopathology of Chronic Human Nerve Compression Knowledge of the pathogenesis of chronic nerve compression is important to the understanding of thoracic outlet syndrome because a significant component of patient symptoms results from compression of the brachial plexus. There are very few studies providing any documentation of the histopathology of human chronic nerve compression because nerve compression is treated with surgical release rather than with surgical excision. Experimental rodent and primate models have been developed that reliably produce changes similar to those seen with human chronic nerve compression (Mackinnon and Dellon, 1988).38-40 These models have been useful in demonstrating the histopathology of chronic nerve compression and in evaluating current treatment modalities. From these experimental studies, several key points relating to the histopathology have been determined:

1. The histopathology spans a broad spectrum—from initial blood-nerve barrier changes, to epineural and perineural thickening, to segmental demyelination, and finally to Wallerian degeneration (Fig. 104-3). 2. These changes are slowly progressive and are influenced by the degree of compression and the duration of nerve compression. 3. Within the compressed nerve, histologic changes vary from fascicle to fascicle (Figs. 104-4 and 104-5). These histopathologic findings have significant clinical implications: 1. Just as the histopathology spans a broad spectrum from mild to severe neural changes, patient symptoms and clinical findings vary along a similar continuum (Fig. 104-6).

FIGURE 104-3 The histopathology of chronic nerve compression progresses across a broad spectrum—from blood-nerve barrier changes, to connective tissue changes, to focal nerve fiber changes, and finally to Wallerian degeneration. (FROM MACKINNON SE, DELLON AL: SURGERY OF THE PERIPHERAL NERVE. NEW YORK, THIEME, 1988.)

Ch104-F06861.indd 1274

1/21/2008 3:32:20 PM

Chapter 104 Thoracic Outlet Syndromes

1275

FIGURE 104-4 A, A normal myelinated fiber population. B, With chronic nerve decompression, segmental demyelination occurs. The large myelinated fibers are associated with only a thin ring of myelin. (FROM MACKINNON SE, DELLON AL: CHRONIC HUMAN NERVE COMPRESSION: A HISTOLOGICAL ASSESSMENT. NEUROPATHOL APPL NEUROBIOL 12:547, 1986.)

2. With continuation of the precipitating factors that contribute to chronic nerve compression (e.g., positions of provocation or activity, systemic disease), the patient will develop progressive symptomatology associated with nerve compression. 3. The fact that one fascicle within a compressed nerve may be normal while another demonstrates significant histologic changes corresponds with the situation in which the unaffected fascicles are reflected in normal electrical studies while the patient’s symptomatology is related to the fascicles demonstrating nerve damage. In a fresh cadaver study, the roots (C5 through Tl) and trunks of the brachial plexus were sampled. In C8, T1 nerve roots and the lower trunk, we noted the same histomorphologic changes of chronic nerve compression (epineurial thickening, demyelination, a loss of large myelinated fibers, and Renaut’s bodies) as were found in other human and experimental studies of chronic nerve compression (Figs. 104-7 and 104-8).

Double and Multiple Crush Syndromes In their report of the double crush syndrome in 1973, Upton and McComas stated that a proximal source of nerve compression renders the distal nerve segment more susceptible to a second site of compression.41 They hypothesized that one site alone might not cause clinical disturbance, but that the summation of two sites of compression would produce symptomatology. This hypothesis is directly applicable to brachial plexus compression in that several anatomic structures may compress the brachial plexus by amounts that, on their own,

Ch104-F06861.indd 1275

would not be enough to cause symptoms. Similarly, the recognized association between the carpal and cubital tunnel syndromes and the thoracic outlet syndrome is supported by the double crush hypothesis (Fig. 104-9). In our series of patients with thoracic outlet syndrome who were receiving workers’ compensation, all patients had clinical evidence of either carpal or cubital tunnel syndrome, but only 24% had electrical evidence of these syndromes.42 A clinical entity associated with an increase in occupations requiring repetitive activity and previously termed cumulative trauma disorder or repetitive stress disorder is now termed work-related upper extremity musculoskeletal disorder. A significant component of this disorder relates to multiple-level nerve compression. Specific anatomic structures and particular positions of the extremity increase the pressure around the nerve and ultimately produce symptomatic nerve compression. (If the wrist is in a position other than neutral, pressures increase around the median nerve in the carpal tunnel; elbow flexion produces increased pressure around the ulnar nerve in the cubital tunnel; and elevation of the arms overhead theoretically increases pressure around the lower trunk of the brachial plexus.) Patients with symptoms associated with repetitive activity frequently have bilateral multiple-level nerve compression. Hand surgeons who are trained to focus on the distal portion of the extremity must evaluate their patients for concomitant thoracic outlet syndrome. Similarly, cardiothoracic surgeons treating patients with thoracic outlet syndrome will find a significant association between this syndrome and common distal sites of nerve compression such as carpal and cubital tunnel syndromes. We now recognize that both upper

1/21/2008 3:32:23 PM

1276

Section 5 Chest Wall and Sternum

FIGURE 104-5 A, A cross-section of a compressed median nerve in a primate demonstrates increased vascularity and increased epineural connective tissue. B, A fascicle demonstrating Wallerian degeneration and severe histologic changes; arrowheads indicate perineurial thickening. C, Fascicles (*) adjacent to those seen in B show a more normal histologic pattern and normal blood vessels (arrows). (FROM MACKINNON SE, DELLON AL, HUDSON AR: A PRIMATE MODEL FOR CHRONIC NERVE COMPRESSION. J RECONSTR MICROSURG 1:185, 1985).

extremities work together as a single functional unit and that difficulties in one extremity can be associated with complaints in the contralateral extremity due to secondary compensatory overuse. (Similarly, physicians recognize that pathology at an ankle joint can eventually result in pathology at the contralateral hip joint.) The patient is evaluated for pathology at all points in this circle (wrist, elbow, shoulder, and neck), all components of which are interrelated (Fig. 104-10). Initial conservative management can be directed at several components of the circle. Surgery directed at distal problems in the extremity can result in an improvement in overall function without necessitating proximal surgical inter-

Ch104-F06861.indd 1276

vention. However, if significant pathology exists in the region of the cervical spine or thoracic outlet, distal procedures may improve symptoms but will not completely relieve the patient’s symptoms.34

DIAGNOSIS Symptoms and Signs The symptomatology of thoracic outlet syndrome depends on whether neural or vascular structures (or both) are compressed in the cervicoaxillary canal. Symptoms associated with nerve compression are observed more frequently than

1/21/2008 3:32:23 PM

Chapter 104 Thoracic Outlet Syndromes

1277

HISTOPATHOLOGY

Breakdown blood-nerve barrier

Connective tissue thickening

Localized Wallerian degeneration

Fiber demyelination Diffuse

CLINICAL FINDINGS Pressure position

SYMPTOMS

Positive provocative tests

Intermittent paresthesia/ weakness Persistent paresthesia/ weakness

Threshold tests/ weakness Abnormal 2 pd/ muscle atrophy

Numbness/ paralysis

FIGURE 104-6 The continuum of chronic nerve compression is illustrated. The histopathologic changes begin with breakdown of the blood-nerve barrier and conclude with Wallerian degeneration. The patient’s presentation, including subjective symptoms and clinical evaluation, parallels the histopathology of the nerve damage. 2pd, two-point discrimination.

A

B

Ch104-F06861.indd 1277

symptoms associated with vascular compression. Patient complaints include pain and paresthesias, which are present in approximately 95% of cases, as well as motor weakness and, rarely, atrophy of the intrinsic hand muscles, which occurs in fewer than 5%. The symptoms occur most commonly in areas supplied by the lower trunk of the brachial plexus (C8-T1), which include the medial aspects of the arm and hand and the fourth and fifth digits. The onset of discomfort and pain is usually insidious and commonly involves the neck, shoulder, arm, and hand. The paresthesias may be precipitated by strenuous physical exercise or by sustained physical efforts with the arm in an elevated position. Symptoms may be initiated by raising the arms above the head. In other cases, trauma to the upper extremities or the cervical spine is a precipitating factor. Physical findings usually consist of hypesthesia along the medial aspects of the forearm and hand. Atrophy is rarely present; if it is evident, it is present in the intrinsic muscles and is associated with clawing of the fourth and fifth digits. If pure ulnar nerve atrophy is present (hypothenar, interosseous muscles) without wasting of the thenar muscles, compression of the ulnar nerve at the elbow (cubital tunnel syndrome) or wrist is suspected. If both median and ulnar innervated muscles are involved, the compression is localized proximally to the lower brachial plexus

FIGURE 104-7 Photomicrographs of cross-section of nerve roots C5 (A) and T1 (B). Note increased epineural (EP) thickening, especially in T1, and fiber fallout in T1 (asterisks). (Toluidine blue, ×88.)

1/21/2008 3:32:24 PM

1278

Section 5 Chest Wall and Sternum

A

B FIGURE 104-8 Higher-power micrographs of nerve roots C5 (A) and T1 (B). Note perineurial (P) thickening in C5 and marked fiber fallout in T1. EP, epineurium. (Toluidine blue ×140.)

or cervical disc level. In the upper type of thoracic outlet syndrome, in which components of C5 and C6 nerves are involved in compression, pain may radiate to the deltoid area and the lateral aspects of the arm. The presence of this pain indicates testing to exclude a herniated cervical disc.17 In these cases, Spurling’s test43 will be positive. Similarly, rotator cuff tendinitis needs to be excluded in patients with shoulder and lateral arm pain. Components of the C5-T1 nerves can be compressed at the thoracic outlet because of a cervical rib and can produce symptoms of varying degrees in the distribution of these nerves. In some patients, the pain is atypical, involving the anterior chest wall or parascapular area, and is termed pseudoangina because it simulates angina pectoris. These patients may have normal coronary arteriograms. The shoulder, arm, and hand symptoms that usually provide clues for the diagnosis of thoracic outlet syndrome initially may be absent or minimal compared with the severity of the chest pain. The diagnosis of thoracic outlet syndrome is frequently overlooked; many of these patients are committed to becoming so-called cardiac cripples without an appropriate diagnosis, or they may develop severe psychological depression if told that their coronary arteries are normal and that they have no significant cause for their pain.44

Ch104-F06861.indd 1278

FIGURE 104-9 The double crush hypothesis can be extrapolated to a multiple crush hypothesis. At the left, carpal tunnel syndrome is associated with median nerve compression in the forearm and cervical disc disease. At the right, thoracic outlet syndrome is associated with cubital tunnel syndrome and ulnar nerve compression in Guyon’s canal.

FIGURE 104-10 The upper extremities and the cervical thoracic region work as a single unit. Pathology anywhere along this ring or circle will predispose some other area for overuse. The overcompensation can produce symptoms at new sites. Evaluation of patients with upper extremity complaints should include examination for problems at all points on the circle.

1/21/2008 3:32:25 PM

Chapter 104 Thoracic Outlet Syndromes

Symptoms of arterial compression include coldness, weakness, and fatigue of the arm and hand and diffuse pain.3,45 Raynaud’s phenomenon is noted in approximately 7.5% of patients with thoracic outlet syndrome.3 Unlike Raynaud’s disease, which is usually bilateral, symmetrical and elicited by cold, Raynaud’s phenomenon in neurovascular compression is usually unilateral and is more likely to be precipitated by hyperabduction of the involved arm, turning of the head, or carrying of heavy objects. Sensitivity to cold may also be present. Symptoms include sudden onset of coldness and blanching of one or more fingers, followed slowly by cyanosis and persistent rubor. Vascular symptoms in neurovascular compression may be precursors of permanent arterial thrombosis.17 Arterial occlusion, usually of the subclavian artery when present, is manifested by persistent coldness, cyanosis or pallor of the fingers, and, in some cases, ulceration or gangrene. Palpation in the paraclavicular area may reveal prominent pulsation, which indicates poststenotic dilation or aneurysm of the subclavian artery. Less frequently, the symptoms are those of venous obstruction or occlusion, commonly recognized as effort thrombosis or Paget-Schroetter syndrome. The condition characteristically results in edema, discoloration of the arm, distention of the superficial veins of the limb and shoulder, and some degree of aches and pains. In some patients, the condition is observed on waking; in others, it follows sustained efforts with the arm in abduction. Sudden backward and downward bracing of the shoulders, heavy lifting, or strenuous physical activity involving the arm may constrict the vein and initiate venospasm, with or without subsequent thrombosis. In cases of definite venous thrombosis, there is usually moderate tenderness over the axillary vein on examination, and a cord-like structure may be felt, corresponding to the course of the vein. The acute symptoms may subside in a few weeks or days as the collateral circulation develops. Recurrence follows if the collateral circulation is inadequate.17 Objective physical findings are more common in patients with primarily vascular rather than neural compression. Loss or diminution of the radial pulse and reproduction of symptoms can be elicited by the three classic clinical maneuvers: the Adson or scalene test,46 the costoclavicular test, and the hyperabduction test47 (Fig. 104-11).

Diagnostic Methods The diagnosis of thoracic outlet syndrome includes the patient history, physical and neurologic examination, chest and cervical spine radiographs, electromyogram, and nerve conduction studies. In some cases with atypical manifestations, other diagnostic procedures, such as cervical magnetic resonance imaging (MRI), peripheral48 or coronary arteriography, or phlebography,49 need to be considered. A detailed history and physical and neurologic examinations provide the diagnosis of neurovascular compression.

Clinical Evaluation The clinical evaluation is based on the patient history and physical findings of reproduction of symptoms. Because no one test has been universally accepted as diagnostic of tho-

Ch104-F06861.indd 1279

1279

racic outlet syndrome, it is necessary to exclude the diagnoses that may mimic symptoms associated with thoracic outlet syndrome. Provocation tests are used to elicit symptoms of neurovascular compression, particularly in those patients who are asymptomatic at rest. These include percussion of the nerve (Tinel’s sign) and pressure and positional provocative tests. It is necessary to examine and identify all sites of nerve compression in the upper extremity that may be contributing to the patient’s symptoms, particularly if thoracic outlet syndrome is suspected (Mackinnon and Novak, 2005).50 These distal sites of compression are often overlooked and, if left untreated, may result in ongoing patient symptoms despite appropriate treatment at the thoracic outlet. Therefore, tests of provocation are performed at the common nerve entrapment sites in the upper extremity (carpal tunnel, median nerve in the forearm, cubital tunnel, and brachial plexus). A Tinel sign is performed by percussing over the nerve with four to six taps in the region of entrapment, with the presence or absence of a tingling sensation within the distribution of that nerve being recorded. Movement and pressure provocative tests are applied for a total of 60 seconds and are considered positive if paresthesia, numbness, or pain occurs in the appropriate nerve distribution. Movement provocative tests include arm elevation42 (brachial plexus), elbow flexion51 (cubital tunnel), and wrist flexion (Phalen’s sign for carpal tunnel).52,53 The pressure provocative tests include direct pressure with the examiner’s fingertip on the brachial plexus,42 on the ulnar nerve in the cubital tunnel,51 and on the median nerve at the proximal forearm and also just proximal to the carpal tunnel (Fig. 104-12).54 A rest period of approximately 1 minute is included between each test to allow a return to the asymptomatic state. Provocation tests that combine movement with pressure elicit symptoms more quickly. A positive response is indicated if the symptoms are provoked in the appropriate neural distribution. For the classic thoracic outlet syndrome maneuvers, a positive response is recorded with the obliteration of the radial pulse. This may be useful in patients with vascular compression, but it is of limited value in patients with symptoms arising from compression of the brachial plexus. Because the majority of patients with thoracic outlet syndrome have symptoms related to brachial plexus nerve compression, we prefer to use reproduction of symptoms as indicative of a positive response in patients with suspected neurogenic thoracic outlet syndrome. 1. The Adson or scalene test6 (see Fig. 104-11A) consists of a maneuver that tightens the anterior and middle scalene muscles and thus decreases the interspace, magnifying any preexisting compression of the subclavian artery and brachial plexus. The patient is instructed to take and hold a deep breath, extend the neck fully, and turn the head toward the side. Obliteration or decrease of the radial pulse suggests compression.17,55 2. In the costoclavicular (Halsted) test (see Fig. 104-11B), the shoulders are drawn downward and backward (military position). This maneuver narrows the costoclavicular space by approximating the clavicle to the first rib and

1/21/2008 3:32:26 PM

1280

Section 5 Chest Wall and Sternum

FIGURE 104-11 A, The Adson maneuver occludes the pulse when the head is turned toward the affected side and the patient inspires deeply. Others have modified this test by turning the head to the unaffected side and requiring reproduction of the patient’s symptoms. B, The Halsted maneuver puts the patient in a military position with the shoulders braced down to the side to obliterate the pulse. The test is now considered positive if the symptoms are reproduced. C, Wright described a hyperabduction maneuver to obliterate the pulse, with reproduction of the patient’s symptoms being considered a positive test result. Wright suggested that the elbows should be flexed. We have modified this test to keep the elbows extended because elbow flexion will reproduce symptomatology with ulnar nerve compression in the cubital tunnel. We consider reproduction of the patient’s symptoms after 1 minute of arm elevation to be a positive test result. The time required for a positive test can be decreased by placing digital pressure over the brachial plexus in the supraclavicular fossa. D, Roos’ test has been modified by Roos to add a 3-minute stress test of rapidly opening and closing the hand. The test is positive if the patient’s symptoms are reproduced. (FROM LUOMA A, NELEMS B:

A

B

C

D

THORACIC OUTLET SYNDROME: THORACIC SURGERY PERSPECTIVE. NEUROSURG CLIN NORTH AM 2:187, 1991.)

FIGURE 104-12 A, Pressure provocative tests can be used to reproduce symptomatology; in particular, pressure over the median nerve just proximal to the carpal tunnel produces paresthesia in the distribution of the median nerve within a few seconds if carpal tunnel syndrome is present. A similar test can be used to evaluate cubital tunnel syndrome with pressure over the ulnar nerve in the cubital tunnel. B, Pressure over the brachial plexus and supraclavicular fossa produces paresthesia in the hand in patients with thoracic outlet syndrome. Symptoms can be accelerated by combining this pressure with elevation of the upper extremities above the head.

Ch104-F06861.indd 1280

1/21/2008 3:32:26 PM

Chapter 104 Thoracic Outlet Syndromes

therefore tends to compress the neurovascular bundle. Changes in the radial pulse with production of symptoms indicate compression.17,55 3. In the hyperabduction test (Wright) (see Fig. 104-11C), the arm is hyperabducted to 180 degrees, which pulls the components of the neurovascular bundle around the pectoralis minor tendon, the coracoid process, and the head of the humerus. If the radial pulse is decreased, compression is suspected.17,55 4. Roos26 described a test of 90 degrees of abduction with external rotation of the shoulder to reproduce symptoms. He later modified this test by incorporating a 3-minute stress test of rapidly closing and opening the hand (see Fig. 104-11D). 5. Mackinnon, Patterson, and Novak42 emphasized reproduction of symptoms in 1 minute with arm elevation. The arm position is similar to that described by Roos except that the elbows are extended to avoid provocation from the ulnar nerve at the cubital tunnel, and the wrists are in a neutral position to avoid eliciting symptoms from the median nerve at the carpal tunnel. Digital pressure in the supraclavicular interscalene region on the brachial plexus decreases the time to onset of symptoms. Because many patients have multiple levels of nerve compression, it is important to provoke symptoms from only one entrapment site during evaluation. Provocation of multiple sites may reproduce a patient’s symptoms but does not assist in isolating the sites of compression that are producing the symptoms. The clinical diagnosis of neurogenic thoracic outlet syndrome is based on clinical history, alteration of sensation to the hands with arm elevation provocation, scalene tenderness, and exclusion of other pathologies that may produce similar symptoms, including distal sites of nerve compression. Compression of the nerves may contribute to only a portion of a patient’s symptoms, and we believe that the discomfort in the cervicoscapular region is usually of muscular origin. Many patients with thoracic outlet syndrome have concomitant postural abnormalities that contribute to muscle imbalance in the cervicoscapular region. The common posture seen is the head positioned anterior to the thorax with scapular abduction and shoulder internal rotation. This results in chronic muscle length changes, which adversely affects muscle strength.56,57 Decrease in the strength of some muscles causes other muscles to compensate for this lack of strength, resulting in overuse and hypertrophy. Continuous use of these muscles perpetuates the cycle of muscle imbalance, particularly in the scapular muscles. Evaluation should also include the cervical, scapular, and shoulder region. Cervical range of motion should be evaluated, with notation of the degree of movement and associated pain or discomfort. Shoulder evaluation begins with active range of motion, noting the degree of motion and associated discomfort, and should also include the scapular movements associated with shoulder motion to assess for abnormal scapular movement and weakness in the scapular muscles. Particularly with shoulder flexion and abduction, weakness of the serratus

Ch104-F06861.indd 1281

1281

anterior and trapezius may be evident. Patients should also be assessed for associated rotator cuff tendinitis, which is not uncommon in patients with thoracic outlet syndrome.

Pain Evaluation A significant component of symptoms in patients with thoracic outlet syndrome is pain. It is often challenging to understand a patient’s pain because of the difficulty in verbalizing these symptoms. A pain evaluation questionnaire can be useful to document symptoms in patients with diffuse pain and many symptoms. Our pain evaluation questionnaire,40,58 which is continuing to be modified, is composed of parts of the McGill questionnaire59 and Hendler’s back pain questionnaire60,61 and consists of 10-cm visual analogue scales (VAS) addressing pain, stress and coping, a body diagram, pain adjectives, and questions regarding work, medications, activities, symptom onset, and so on. Patients who score high on the questionnaire, use more than three pain adjectives, and draw a body diagram outside the normal anatomic distributions are referred for further psychological assessment.

Sensory Testing The histopathology of chronic nerve compression spans a broad spectrum, and patient symptoms and clinical findings parallel the changes in the nerves. Initially, patients may be completely asymptomatic at rest and become symptomatic only with positional or pressure provocative maneuvers. With time and increased compression, patients may have persistent subtle abnormalities in the sensory system, which can be detected only with sensitive tests that determine the threshold of the system by vibratory or pressure threshold measurements. With an increased duration of nerve compression, nerve injury and loss of nerve fibers occurs, with loss of discriminatory function as measured by the two-point discrimination test. Recent efforts have been directed toward developing tests to evaluate sensory function in the hand, and the correlations between these tests and the fiber receptor system are understood. Quantitative and qualitative sensory changes can be measured with examination of the sensory thresholds. The threshold of the rapidly adapting fiber receptor system can be assessed by several instruments used to evaluate vibration thresholds (Fig. 104-13A,B), either qualitatively with a tuning fork or quantitatively with a vibrometer. Qualitatively, vibration sense is evaluated by placing the wrong end of a vibrating 256-cps tuning fork against the skin of the distal digit pulp. This end of the tuning fork is used because it has a larger amplitude of vibration and the stimulus may be more easily perceived. The patient is asked to compare the vibration sensation to the sensation on the contralateral hand. This assessment depends on the consistency of the examiner in applying the same amplitude of stimulus and cannot be assessed in patients with bilateral hand involvement. To quantify the threshold of the quickly adapting fibers, a fixedfrequency (120-cps), variable-amplitude vibrometer, such as the Vibratron II (Sensortek, Clifton, NJ) can be used. The vibrating portion of the Vibratron II is placed against the skin,

1/21/2008 3:32:28 PM

1282

Section 5 Chest Wall and Sternum

FIGURE 104-13 A, Threshold testing includes vibration and pressure assessment. Response to vibration can be measured qualitatively with a tuning fork. B, Vibration thresholds can be measured quantitatively with a fixedfrequency, variable-amplitude vibrometer. C, Pressure thresholds are measured with Semmes-Weinstein monofilaments. (FROM MACKINNON SE, DELLON AL: SURGERY OF THE PERIPHERAL NERVE. NEW YORK, THIEME, 1988.)

and the smallest stimulus perceived is identified as the baseline vibration threshold and recorded in microns of motion. A variable-frequency, variable-amplitude vibrometer may also be used and provides a vibrogram of the patient’s response to a number of frequencies of vibration.62,63 Because the higher frequencies of vibration are more sensitive to nerve compression, such an instrument is potentially of interest in evaluating patients with thoracic outlet syndrome. Pressure thresholds can be assessed quantitatively with Semmes-Weinstein monofilaments.64 These nylon monofilaments are applied perpendicular to the cutaneous surface, and pressure is applied until bending of the monofilament is observed. Filaments of increasing diameter filaments are used, and the probes range from 1.65 to 6.65, a value that represents the logarithm of 10 times the force in tenths of a milligram that is required to bow the monofilament. The lightest probe that elicits perception and localization of pressure is recorded as the pressure threshold (see Fig. 104-13C). Assessment of innervation density provides an indication of the number of innervated receptors. The innervation density of the slowly adapting receptors is measured by a static two-point discrimination test, and that of the rapidly adapting receptors is measured by a moving two-point discrimination test. Moving and static two-point discrimination are assessed with a Disk-Criminator (Neuroregen, Baltimore, MD).65,66 The moving discrimination test is carried out by

Ch104-F06861.indd 1282

slowly moving the prongs of the Disk-Criminator longitudinally with just enough pressure to elicit a response. The subject is then asked to indicate whether one or two prongs were felt. The smallest spacing at which the subject is able to correctly identify two prongs in two of three trials is recorded in millimeters (Fig. 104-14). The simple analogy shown in Figure 104-15 helps to describe and understand the relationship between innervation density and threshold and the tests used to measure sensibility. In a prospective study, we evaluated 50 patients whom we believed to have thoracic outlet syndrome.42 The physical examination included tests of provocation (positional, percussion [Tinel], and compressive) and sensory evaluation (baseline and postprovocation vibration thresholds and twopoint discrimination). In 47 (94%) of these patients, provocative position and compression tests were positive (see clinical test No. 5 listed earlier) (Fig. 104-16), and two-point discrimination was normal in 49 (98%). Measurements of sensory thresholds after provocation of symptoms were significantly elevated in the small finger, compared with thresholds measured at rest.

Radiographic Findings Chest and cervical spine radiographs are helpful in revealing bony abnormalities, particularly cervical ribs, prolonged transverse processes, and bony degenerative changes. If

1/21/2008 3:32:28 PM

Chapter 104 Thoracic Outlet Syndromes

1283

FIGURE 104-14 A, Two-point discrimination is measured with a Disk-Criminator. B, Moving two-point discrimination is measured by moving the two prongs of the Disk-Criminator across the surface of the skin. (FROM MACKINNON SE, DELON AL: SURGERY OF THE PERIPHERAL NERVE. NEW YORK, THIEME, 1988.)

A

B

C FIGURE 104-15 A, A simple analogy helps to describe the relationship between innervation density and threshold. If each person in the audience is considered as a single-fiber sensory receptor unit, the number of people present in the audience can be considered the innervation density. A test of threshold evaluates the status, health, or well-being of the individuals. If all the seats in the auditorium are full and the individuals in the audience are awake and content, all testing for fiber receptor function (both innervation density and threshold tests) will be normal. B, Threshold testing will be abnormal (vibration and Semmes-Weinstein monofilament tests) if the individuals, although present, are not awake and content but rather asleep or unhappy. It will take more effort (e.g., greater pressure, larger amplitude) to wake up these sleepy receptors. Moving and static two-point discrimination tests remain normal because all members of the audience are present and eventually will respond to stimulation. C, If individuals vacate the auditorium, the results of innervation density testing (two-point discrimination) will be abnormal. If the remaining individuals are other than awake and content, the threshold tests will be abnormal as well. (FROM MACKINNON SE: PERIPHERAL NERVE INJURIES IN THE HAND. IN VISTNES LM [ED]: HOW THEY DO IT: PROCEDURES IN PLASTIC AND RECONSTRUCTIVE SURGERY. BOSTON, LITTLE, BROWN, 1991, P 321.)

Ch104-F06861.indd 1283

1/21/2008 3:32:28 PM

1284

Section 5 Chest Wall and Sternum

100

100 30 seconds 60 seconds

90

80 70

70 60 50 40

60 50 40

30

30

20

20

10

10 0

0 Elevation Elbow flexion

A

30 seconds 60 seconds

90

Patients (%)

Patients (%)

80

Wrist Elevation Elbow Wrist flexion flexion flexion UNAFFECTED HAND AFFECTED HAND

B

Brachial Cubital Carpal Brachial Cubital Carpal plexus tunnel tunnel plexus tunnel tunnel UNAFFECTED HAND AFFECTED HAND

100 90

Patients (%)

80 70 60 50 40 30 20 10 0 Brachial Cubital Forearm Carpal plexus tunnel tunnel

C

AFFECTED HAND

Brachial Cubital Forearm Carpal plexus tunnel tunnel UNAFFECTED HAND

FIGURE 104-16 A, Distribution of positive provocative movement, showing the percentage of patients who exhibited positive signs with each provocative movement (arm elevation to reproduce thoracic outlet symptoms, elbow flexion to reproduce cubital tunnel symptoms, and wrist flexion to reproduce carpal tunnel symptoms), within 30 seconds and within 60 seconds (total). Both affected and unaffected hands are illustrated. B, Distribution of positive pressure provocative movement, showing the percentage of patients who exhibited positive signs provoked with pressure of common nerve entrapment sites, within 30 seconds and within 60 seconds (total) for both affected and unaffected hands. C, Distribution of positive Tinel’s sign, showing the percentage of patients who exhibited a positive Tinel’s sign at entrapment sites in the upper extremity (carpal tunnel, forearm, cubital tunnel, and brachial plexus) in both affected and unaffected hands. (FROM NOVAK CB, MACKINNON SE, PATTERSON GA, ET AL: EVALUATION OF PATIENTS FOR THORACIC OUTLET DECOMPRESSION. J HAND SURG AM 18:292, 1992, WITH PERMISSION.)

osteophytic changes and intervertebral space narrowing are present on plain cervical radiographs, cervical computed tomography (CT) or MRI should be performed to rule out bony encroachment and narrowing of the spinal canal and the intervertebral foramina.67

nature of this compressive neuropathy by suggesting that SSEP assessment be performed in both neutral and stressed positions. In our evaluation of patients with thoracic outlet syndrome, we have not found SSEPs to be useful in the diagnosis.71

Electrodiagnostic Testing Somatosensory Potentials

Nerve Conduction Velocities

Somatosensory evoked potentials (SSEPs) have been described in the diagnosis of thoracic outlet syndrome to deal with the proximal location of the compressive problem. Machleder and associates68 demonstrated in a group of 80 patients with thoracic outlet syndrome that 74% of the patients had abnormal SSEPs. Similarly, Yiannikas and Walsh69 found SSEPs to be useful in the diagnosis. By contrast, Borg and colleagues70 found SSEPs to be abnormal only in patients with positive clinical signs. Both Borg and colleagues70 and Machleder and associates68 stressed the dynamic

Ch104-F06861.indd 1284

Determination of nerve conduction velocities is a test used in the differential diagnosis of arm pain, tingling, and numbness with or without motor weakness of the hand. Such symptoms may result from compression at various sites: in the spine; at the thoracic outlet; around the elbow, where it causes ulnar nerve palsy; or on the volar aspect of the wrist, where it produces carpal tunnel syndrome. One of us (HCU) relies on the ulnar nerve conduction velocity for diagnosis of thoracic outlet syndrome,72 whereas the other three do not. For completeness, it is reviewed here in detail. For diagnosis and localization of the site of compression, cathodal stimula-

1/21/2008 3:32:30 PM

Chapter 104 Thoracic Outlet Syndromes

tion is applied at various points along the course of the nerve. Motor conduction velocities of the ulnar, median, radial, and musculocutaneous nerves can be measured reliably.73 Caldwell and associates28 improved the technique of measuring ulnar nerve conduction velocity for evaluation of patients with thoracic outlet compression. Conduction velocities over proximal and distal segments of the ulnar nerve are determined by recording the acting potentials generated in the hypothenar or first dorsal interosseous muscle. The points of stimulation are the supraclavicular fossa, middle upper arm, below the elbow, and at the wrist.72 Electromyography is usually normal in thoracic outlet syndrome. Measuring Equipment. Electromyographic examination of each upper extremity and determination of conduction velocities are performed with the Meditron 201 AD or 312 electromyograph; a coaxial cable with three needles or surface electrodes is used to record muscle potentials, which appear on the fluorescent screen. Technique. The conduction velocity is determined by the Krusen-Caldwell technique.28 The patient is placed on the examination table with the arm fully extended at the elbow and in about 20 degrees of abduction at the shoulder, to facilitate stimulation over the course of the ulnar nerve. The ulnar nerve is stimulated at four points by a special stimulation unit, which imparts a 350-V electrical stimulus, which is approximately equivalent to 300 V in view of the patient’s skin resistance of 5000 ohms. Supramaximal stimulation is used at all points to obtain maximal response. The duration of the stimulus is 0.2 msec, except for muscular individuals, for whom it is 0.5 msec. The times of stimulation, conduction delay, and muscle response appear on the electromyograph screen; time markers occur each millisecond on the sweep. The latency period to stimulation from the four stimulation points to the recording electrode is obtained from the digital recorder or calculated from the tracing on the screen. Calculation of Velocities. After the latencies (which are expressed in milliseconds) are obtained, the distance in millimeters between two adjacent sites of stimulation is measured with a steel tape. The velocities, which are expressed in meters per second, are calculated by subtracting the distal latency from the proximal latency and dividing the distance between two points of stimulation by the latency difference (Fig. 104-17), according to the following formula:

Velocity (m/sec) =

distance (mm) difference in latency (msec)

Normal Ulnar Nerve Conduction Velocities. The normal values for ulnar nerve conduction velocities, according to the Krusen-Caldwell technique,28 are 72 m/sec or greater across the outlet; 55 m/sec or greater around the elbow; and 59 m/ sec or greater in the forearm. Wrist delay is 2.5 to 3.5 msec. Decreased velocity in a segment of increased delay at the wrist indicates compression, injury, neuropathy, or neurologic disorders. Decreased velocity across the outlet is consistent with thoracic outlet syndrome, and decreased velocity

Ch104-F06861.indd 1285

1285

FIGURE 104-17 Technique for stimulating and recording during the evaluation of nerve conduction velocities.

around the elbow signifies ulnar nerve entrapment or neuropathy. Increased delay at the wrist is encountered in carpal tunnel syndrome.

Angiography Simple clinical observations usually suffice to determine the degree of vascular impairment in the upper extremity. Peripheral angiography48,74 is indicated in some cases, as in the presence of a paraclavicular pulsating mass, the absence of radial pulse, or the presence of supraclavicular or infraclavicular bruits. Retrograde or antegrade arteriograms of the subclavian and brachial arteries should be obtained to demonstrate or localize the pathology (Figs. 104-18 and 104-19). In cases of venous stenosis or obstruction, as in Paget-Schroetter syndrome, phlebograms are used to determine the extent of thrombosis and the status of the collateral circulation.

Differential Diagnosis The diagnosis of thoracic outlet syndrome should be differentiated from various neurologic, vascular, cardiac, pulmonary, and esophageal conditions.17,44 Neurologic causes of pain in the shoulder and arm are more difficult to recognize and may arise from involvement of the nerve roots, the brachial plexus, or the peripheral nerves. A common neurologic cause of pain in the upper extremities is a herniated cervical intervertebral disc. The herniation almost invariably occurs at the interspace between the fifth and sixth or between the sixth and seventh cervical vertebrae and produces characteristic symptoms. Onset of pain and stiffness

1/21/2008 3:32:30 PM

1286

Section 5 Chest Wall and Sternum

FIGURE 104-18 In a patient with symptoms of vascular compression in the left upper extremity, an arteriogram with both arms elevated demonstrated a patent subclavian artery in the right arm (A) and occlusion of the subclavian (arrowheads) in the left arm (B). (COURTESY OF P. M. WEEKS, MD, WASHINGTON UNIVERSITY SCHOOL OF MEDICINE, ST. LOUIS.)

FIGURE 104-19 Evaluation of vascular thoracic outlet syndrome using an arteriogram may demonstrate unusual findings such as this aneurysm (A) (arrowhead), which was excised at surgery (B). (COURTESY OF J. J. MCDONOUGH, MD, CINCINNATI, OH.)

Ch104-F06861.indd 1286

1/21/2008 3:32:31 PM

Chapter 104 Thoracic Outlet Syndromes

of the neck is manifested with varying frequency. The pain radiates along the medial border of the scapula into the shoulder, occasionally into the anterior chest wall, and down the lateral aspect of the arm, into the fingers. Numbness and paresthesias in the fingers may be present. The segmental distribution of pain is a prominent feature. A herniated disc between the C5 and C6 vertebrae, which compresses the C6 nerve root, causes pain or numbness primarily in the thumb and to a lesser extent in the index finger. The biceps muscle and the radial wrist extensor may be weak, and the reflex of the biceps muscle is reduced or abolished. A herniated disc between the C6 and C7 vertebrae, which compresses the C7 nerve root, produces pain or numbness in the index finger and weakness of index finger flexion and ulnar wrist extension; the triceps muscle is weak, and its reflex is reduced or abolished. Any of these herniated discs may cause numbness along the ulnar border of the arm and hand due to spasm of the scalenus anticus muscle. Rarely, pain and paresthesias in the ulnar distribution may be related to herniation between the C7 and T1 vertebrae, which causes compression of the C8 nerve root. Compression of the C8 and T1 nerve roots produces weakness of intrinsic hand muscles.17,27 Although rupture of the fifth and sixth discs produces hypesthesia in this area, only rupture of the seventh disc produces pain down the medial aspect of the arm.17 The diagnosis of a ruptured cervical disc is based primarily on the history and physical findings; lateral radiographs of the cervical spine reveal loss or reversal of cervical curvature, with the apex of the reversal of curvature at the level of the disc involved. Electromyography and MRI can localize the site and extent of the nerve root irritation. Another condition that causes upper extremity pain is cervical spondylosis, a degenerative disease of the intervertebral disc and the adjacent vertebral margin that causes spur formation and the production of ridges into the spinal canal or intervertebral foramina. Radiographs, a CT scan of the cervical spine, and electromyography help in making the diagnosis of this condition. Several arterial and venous conditions can be confused with thoracic outlet syndrome; the differentiation can often be made clinically.17 In atypical patients who present with chest pain alone, it is important to suspect the thoracic outlet syndrome in addition to angina pectoris. If there is a high index of suspicion of angina pectoris, exercise stress testing and coronary angiography may exclude coronary artery disease.44,55

MANAGEMENT Principles of Management The initial method of management in most patients with thoracic outlet syndrome is nonoperative, particularly in those patients with neurogenic symptoms. Successful nonoperative therapy depends on treatment of all sites of nerve compression and concomitant pathology, including muscle imbalance, rotator cuff tendonitis, cervical root impingement, or degenerative disc disease (Novak, 1999).50,75-77 Treatment of only one site of nerve compression or other pathology may alleviate symptoms that result from that site

Ch104-F06861.indd 1287

1287

but will do little to relieve overall symptoms in the patient with multiple sites of nerve compression and other sites of pathology. Our approach begins with patient education regarding positions and postures that provoke and alleviate symptoms. Patient should begin by modifying postures and activities that exacerbate symptoms. We do not recommend that patients stop working or discontinue all activities, but rather that they adapt their postures to spend less time in positions that are contributing to their symptoms. Typically, activities that require overhead activity, heavy lifting, repetitive motions, or use of vibratory tools aggravate symptoms arising from thoracic outlet syndrome. Rest periods with the arms down are recommended at intervals during the day. A large period of time is spent sleeping, and therefore sleeping postures and positions should be modified if the patient is awakening at night with pain or paresthesia/numbness or awakens in the morning with these symptoms, headaches, or neck stiffness. It is necessary to decrease irritation of structures that are contributing to symptoms in the cervicoscapular region or other sites of nerve compression at night: arms above the head, aggravating the thoracic outlet syndrome; elbows flexed, aggravating the cubital tunnel syndrome; or wrist flexion or extension, provoking carpal tunnel symptoms. These sleeping patterns are described to patients and their partners, and patients are encouraged to develop sleeping patterns with arms by the sides (Fig. 104-20). We have found that patients report good relief of cervical symptoms from the use of soft cervical rolls at night. These rolls are made from two rolls of stockinette stuffed with soft gauze padding. If patients have concomitant carpal or cubital tunnel syndrome, conservative management is also directed toward these problems; resting wrist splints at night are used to maintain the wrist in a neutral position, and soft elbow pads to cushion the ulnar nerve and block extreme elbow flexion are recommended.

Physical Therapy Many of the symptoms of thoracic outlet syndrome are a consequence of both brachial plexus nerve compression and muscle imbalance in the cervicothoracic region. These neuromuscular difficulties result from faulty posture, typically a relaxed forward posture with the head anteriorly displaced in relation to the thorax.56 McKenzie’s approach78 to the cervical spine recognizes three factors that are associated with pain in this region and are applicable to patients with thoracic outlet syndrome: faulty posture, an increased frequency of cervical flexion, and loss of extension. Janda79,80 described a proximal crossed syndrome in the upper extremity in patients with thoracic outlet syndrome in which the pectoralis major and minor, upper trapezius, scalene, and sternocleidomastoid muscles become tight. Weakness occurs in the scapular stabilizers, including the middle and lower trapezius, rhomboid, and serratus anterior muscles. Tightness of the scalene muscles is well recognized as a major contributor to nerve compression of the brachial plexus. Muscles that exhibit decreased range of motion or strength can be evaluated for the presence of hyperirritability.

1/21/2008 3:32:31 PM

1288

Section 5 Chest Wall and Sternum

A

B FIGURE 104-20 A, Certain positions of the extremities put particular nerves at risk for increased pressure. Especially at night, patients assume these postures. Flexion or extension of the wrist aggravates carpal tunnel syndrome, elbow flexion aggravates cubital tunnel syndrome, and elevation of the arms above the head aggravates thoracic outlet symptoms. The sleeping positions illustrated put the nerves at risk for compression. B, Patients should be advised to train themselves to sleep with their arms by their sides and their wrists in neutral position.

Treatment begins with postural correction, although many patients cannot assume the ideal posture due to the restriction of tight muscles, and placing these muscles on stretch exacerbates their pain. Therefore, many patients require stretching exercises to regain normal muscle length to allow pain-free postural correction. To regain full cervical range of motion, we follow McKenzie’s approach78 and begin with repetitive retraction exercises in a supine position, progressing to full cervical extension. Tightness of the sternocleidomastoid and scalene muscles not only compresses the brachial plexus; these muscles and other shortened muscles also contribute to movement abnormalities. Patients often also have tightness to the upper trapezius, levator scapulae, and suboccipital muscles. Prolonged positioning of the scapulae in abduction will result in elongation of the middle and lower trapezius muscles and shortening of the serratus anterior. These changes in muscle length contribute to weakness, muscle imbalance, and scapular movement abnormalities.56,57 Postures that contribute to short tight muscles also result in neural connective tissue tightness, and tightness in the neural structures restricts neural mobility. Therefore, it is

Ch104-F06861.indd 1288

important to regain optimal neural length and mobility. To avoid exacerbation of symptoms, segmental stretches in the cervical, scapular, and shoulder regions should be initially instituted, with progression to comprehensive stretches over multiple joints in the upper extremity.81,82 With relative pain control and restoration of range of motion, strengthening exercises should be instituted to regain muscle balance. Typically, patients with thoracic outlet syndrome require strengthening of the serratus anterior and middle and lower trapezius muscles, and these exercises should begin in gravity-assisted positions to provide the opportunity to recruit the appropriate muscles and to avoid exacerbation of pain. Other factors that may contribute to symptoms in patients with thoracic outlet syndrome include poor aerobic conditioning, obesity, and, in some women, breast hypertrophy. Poor aerobic conditioning and poor posture can compromise respiratory function, which then increases the use of the accessory respiratory muscles, particularly the scalene, sternocleidomastoid, and upper trapezius muscles. Education regarding diaphragmatic and lateral costal breathing assists the patient to decrease the use of the accessory muscles.83 Postural correction in an upright position decreases thoracic flexion and permits better chest expansion and excursion of the diaphragm during inspiration. Improved aerobic condition also assists patients to decrease the overuse of the scalene muscles during quiet normal respiration. In most cases, this begins as a walking program, with emphasis on the correct breathing technique. Obesity and breast hypertrophy aggravate thoracic outlet syndrome, and weight loss plans are recommended. Occasionally, breast reduction surgery may be indicated, and it has been reported to dramatically improve patient’s symptoms.84 After a diagnosis of thoracic outlet syndrome, patients should be directed to physical therapy for instruction in an appropriate exercise program. The goals of therapy are to decrease brachial plexus nerve compression; restore neural mobility; regain cervical, scapular, and shoulder range of motion; and correct muscle balance. Modification of activities at home and work, as well as sleep postures, may also be necessary to ameliorate patient symptoms. If symptoms continue after appropriate physical therapy for proximal neurovascular compression and conservative management of any associated distal entrapments, surgery may be considered. Surgical correction of associated distal entrapments is frequently preferable to first rib resection because there are fewer potential complications and the procedure may be successful in alleviating symptoms in those patients with multiple levels of nerve compression.50,85 If conservative management and surgical treatment of distal entrapments fails to relieve symptoms, surgical resection of the first rib and the cervical rib (if present) should be considered (Sanders and Haug, 1991; Urschel and Razzuk, 1998).26,45,86-89

Paget-Schroetter Syndrome (Effort Thrombosis) Effort thrombosis of the axillary subclavian vein (PagetSchroetter syndrome) is usually secondary to unusual or

1/21/2008 3:32:32 PM

Chapter 104 Thoracic Outlet Syndromes

excessive use of the arm, in addition to the presence of one or more compressive elements in the thoracic outlet.90,91 Sir James Paget in 1875 in London8 and von Schroetter in 1884 in Vienna9 described this syndrome of thrombosis of the axillary subclavian vein. The word effort92 was added to thrombosis because of the frequent association with exertion, producing either direct or indirect compression of the vein. The thrombosis is caused by trauma93,94 or by unusual occupations that require repetitive muscular activity, as has been observed in professional athletes, linotype operators, painters, and beauticians. Cold and traumatic factors such as carrying skis over the shoulder tend to increase the proclivity for thrombosis.95 Elements of increased thrombogenicity also increase the incidence of the problem and exacerbate its symptoms on a long-term basis. Adams and DeWeese90 and DeWeese and coworkers96 reported long-term results in patients treated conservatively with elevation and warfarin (Coumadin). There was a 12% incidence of pulmonary embolism. Occasional venous distention developed in 18%, and late residual arm symptoms of swelling, pain, and superficial thrombophlebitis were noted in 68% of the patients (deep venous thrombosis with postphlebitic syndrome). Phlegmasia cerulea dolens was present in one patient. For many years, therapy included elevation of the arm and use of anticoagulants, with subsequent return to work. If symptoms recurred, the patient was considered for a first rib resection, with or without thrombectomy,96,97 as well as resection of the scalenus anterior muscle and removal of any other compressive element in the thoracic outlet, such as the cervical rib or abnormal bands.98-100 Availability of thrombolytic agents, 101,102 combined with prompt surgical decompression of the neurovascular compressive elements in the thoracic outlet,103 has reduced morbidity and the necessity for thrombectomy and has substantially improved clinical results, including the ability to return to work (Urschel and Razzuk, 2000).104 One advantage of urokinase over streptokinase is the direct action of urokinase on the thrombosis distal to the catheter, producing a local thrombolytic effect.105-107 Streptokinase produces a systemic effect, which may increase the risk of potential complications. Heparin decreases the need for thrombectomy after use of the thrombolytic agent followed by aggressive surgical intervention; this is another advantage because some of the long-term disability is related to morbidity from thrombectomy as well as to recurrent thrombosis.108-110 The natural history of Paget-Schroetter syndrome suggests moderate morbidity111 with conservative treatment alone. Bypass with vein or other conduits112-114 has limited application. Causes other than thoracic outlet syndrome must be treated individually.115 Intermittent obstruction of the subclavian vein116 can lead to thrombosis, and decompression should be employed prophylactically.113,114

Surgical Management Several surgical approaches have been described for operative treatment of patients with thoracic outlet syndrome, includ-

Ch104-F06861.indd 1289

1289

FIGURE 104-21 Results of the three primary operations for thoracic outlet syndrome. (FROM SANDERS RJ: THORACIC OUTLET SYNDROME: A COMMON SEQUELA OF NECK INJURIES. PHILADELPHIA, JB LIPPINCOTT, 1991.)

ing posterior, transaxillary, supraclavicular, infraclavicular, transthoracic, and through the bed of the resected clavicle. A definitive review of the surgical management of thoracic outlet syndrome was published by Sanders.87 Sanders concluded that transaxillary first rib resection, scalenotomy, and supraclavicular first rib resection with scalenotomy result in essentially the same patient outcome (Fig. 104-21). Coupled with the appropriate preoperative and postoperative management, it is likely that any of these approaches can result in excellent patient outcome, and, similarly, any of these approaches can result in poor outcome. The success in the surgical management of patients with thoracic outlet syndrome depends on correct patient selection, meticulous surgical technique, and appropriate postoperative management, including early motion to promote optimal neural mobility.

SUMMARY Thoracic outlet syndrome is recognized in approximately 8% of the population. Its manifestations may be neurologic, vascular, or both, depending on the component of the neurovascular bundle that is predominantly compressed. The diagnosis is suspected by reproduction of symptoms with arm elevation and the exclusion of other causes. Treatment is initially nonoperative, but persistence of significant symptoms, which occur in only 5% of patients with diagnosed thoracic outlet syndromes, is an indication for surgical intervention. KEY REFERENCES Mackinnon SE, Dellon AL: Surgery of the Peripheral Nerve. New York, Thieme Medical Publishers, 1988. Mackinnon SE, Novak CB: Compressive neuropathies. In Green DP, Hotchkiss RN, Pederson WC, Wolfe SW (eds): Operative Hand Surgery. New York, Churchill Livingstone, 2005, p 999. Mackinnon SE, Novak CB: Thoracic outlet syndrome. Curr Probl Surg 39:1057, 2002. Mackinnon SE, Patterson GA: Thoracic outlet syndrome: Supraclavicular first rib resection and brachial plexus decompression. In Neuro-

1/21/2008 3:32:32 PM

1290

Section 5 Chest Wall and Sternum

surgical Operative Atlas, vol 3. Baltimore, Williams & Wilkins, 1993, pp 185-191. Novak CB: Conservative management of thoracic outlet syndrome. Chest Surg Clin North Am 9:747, 1999. Roos DB: Transaxillary approach for first rib resection to relieve thoracic outlet syndrome. Ann Surg 163:354, 1966. Sanders RJ, Haug CE: Thoracic Outlet Syndrome: A Common Sequela of Neck Injuries. Philadelphia, Lippincott, 1991.

Ch104-F06861.indd 1290

Urschel HC Jr, Razzuk MA: Neurovascular compression in the thoracic outlet: Changing management over 50 years. Ann Surg 228:609, 1998. Urschel HC Jr, Razzuk MA: Paget-Schroetter syndrome: What is the best management? Ann Thorac Surg 69:1663, 2000.

1/21/2008 3:32:32 PM

chapter

105

NEOPLASMS OF THE CHEST WALL Geoffrey M. Graeber David R. Jones Peter C. Pairolero

Chest wall tumors encompass a kaleidoscopic panorama of bone and soft tissue pathologic conditions. Included are primary and metastatic neoplasms of both the bony skeleton and soft tissues and the primary neoplasms that invade the thorax from adjacent structures, such as the breast, lung, pleura, and mediastinum (Box 105-1; Table 105-1). Nearly all of these neoplasms have at one time or another been irradiated, and it is fairly common for these patients to present with postradiation necrotic ulceration. The thoracic surgeon is asked to evaluate all of these patients. Most are seen to establish a diagnosis, some to treat for cure, and a few to manage necrotic, foul-smelling, chest wall malignant ulcers. Primary chest wall neoplasms previously considered unresectable because of their size or extension into adjacent structures are now being resected, and the chest wall is reconstructed with little morbidity. In many patients, surgical extirpation is often the only remaining modality of therapy. This may be compromised by an incorrect diagnosis or an inability to reconstruct large chest wall defects (Pairolero and Arnold, 1985).1

HISTORICAL NOTE Because primary chest wall neoplasms are uncommon, relatively few series have previously been reported. Moreover, most reports have included only patients with bone tumors.2-4 When bone neoplasms are combined with primary soft tissue tumors, however, the soft tissues become a major source of chest wall neoplasms and account for nearly one half of these tumors treated surgically (Graeber et al, 1982; King et al, 1986).1,5,6 The incidence of malignancy in these tumors is variable and has been reported to range from 50% to 80%. The higher malignancy rates are found in those series that include soft tissue tumors. When combined, malignant fibrous histiocytoma (fibrosarcoma), chondrosarcoma, and rhabdomyosarcoma are the most frequent primary malignant neoplasms that the thoracic surgeon is asked to manage. Cartilaginous tumors (osteochondroma and chondroma) and desmoid tumors are the most common primary benign tumors. HISTORICAL READINGS Groff DB, Adkins PC: Chest wall tumors. Ann Thorac Surg 4:260, 1967.

Pascuzzi CA, Dahlia DC, Clagett OT: Primary tumors of the ribs and sternum. Surg Gynecol Obstet 104:390, 1957. Stelzer P, Gay WA Jr: Tumors of the chest wall. Surg Clin North Am 60:779, 1980.

CLINICAL FEATURES The mean age at presentation for a patient with a benign tumor of the chest wall is approximately 15 years younger than for those with primary malignancies. The average patient age for benign tumors is 26 years old; for malignant tumors, the average age is 40 years old.7 The male-to-female ratio is approximately 2 : 15,8,9 for most tumors, with the exception of the desmoid tumors, which have a 1 : 2 male to female preponderance.8,10 Chest wall tumors generally present as slowly enlarging masses. Most are initially asymptomatic, but with continued growth, pain invariably occurs. At first, the pain is generalized and the patient is frequently treated for a neuritis or musculoskeletal complaint. The incidence of a chest wall mass is 70%, and pain is seen in 25% to 50% of patients.6,8 These chest wall masses may be large and have been present for long periods. The size of these tumors may rarely prevent the patient from dressing and thus cause the patient to seek therapy. Pain is more common in malignant tumors but cannot be used to exclude the diagnosis of benignity because one third of patients with benign chest wall neoplasms have associated pain. Less common symptoms include weight loss, fever, lymphadenopathy, and brachial plexus neuropathy.

DIAGNOSIS The evaluation of patients with suspected chest wall tumors includes a careful history and physical and laboratory examination, followed by conventional plain and tomographic chest radiography. Old chest radiographs are important to determine the growth rate. Computed tomographic scans (CT) are obtained to delineate soft tissue, pleural, mediastinal, and pulmonary involvement. The role of magnetic resonance imaging (MRI) is not yet fully known, but preliminary evaluation indicates still further enhancement of tissue pathologic findings, which may make it the diagnostic modality of choice in the future. A bone survey is done if metastases are suspected. Pulmonary function testing is also obtained. Most primary chest wall neoplasms are diagnosed by excisional biopsy. The reasons for excisional biopsy include the following: 1291

Ch105-F06861.indd 1291

1/21/2008 3:33:20 PM

1292

Section 5 Chest Wall and Sternum

Box 105-1 Primary Chest Wall Neoplasms Malignant Myeloma Malignant fibrous histiocytoma Chondrosarcoma Rhabdomyosarcoma Ewing’s sarcoma Liposarcoma Neurofibrosarcoma Osteosarcoma Hemangiosarcoma Leiomyosarcoma Lymphoma Benign Osteochondroma Chondroma Desmoid Lipoma Fibroma Neurilemmoma

BENIGN TUMORS Benign chest wall tumors require diagnostic studies similar to those for malignant tumors. Radiographic studies may suggest the diagnosis of benignity, but histologic evidence is necessary. The more common benign chest wall tumors are discussed earlier. Less common benign tumors include lipomas, osteomyelitis, mesenchymomas, fibroxanthomas, hemangioendotheliomas, and some neural tumors.

TABLE 105-1 Estimates of Number of New Cases of Primary Malignant Chest Wall Tumors in the United States in 1993 Tumor

All Sites (No.)

Chest Wall (No.)

Soft tissue sarcoma

6000

360

Chondrosarcoma

400

60

Ewing’s sarcoma

300

45

Solitary plasmacytoma

125

25

Osteosarcoma Total

600

18

7425

508

1. Removal of the entire mass 2. Adequate tissue sampling to establish the tumor’s histologic type 3. Earlier administration of adjuvant therapy if necessary Cavanaugh and associates11 recommended a limited incisional biopsy to establish the diagnosis and allow appropriate management plans to be made that are based on the histologic type. In this series, 73% of the lesions were benign and no further surgery was performed. In most series, however, the rate of malignancy is 50% to 80%, and all require en-bloc resection.1,5,6 Incisional biopsies may confuse the histologic diagnosis because certain tumors, particularly chondrosarcomas, have areas that histologically appear benign and other areas in which frank malignancy is present.5 Clinical decisions based on the wrong pathologic diagnosis may be catastrophic. If an incisional biopsy is performed, it is made in such a way that the definitive excision will not be compromised. No flaps or extensive dissection is used to prevent tumor cell seeding. Needle biopsy of a lesion in a patient with a known prior malignancy may be helpful. Ayala and Zornosa12 demonstrated a 79% accuracy rate in the diagnosis of primary bone

Ch105-F06861.indd 1292

tumors with percutaneous needle biopsy. Most thoracic surgeons still prefer excisional biopsy whenever possible. Laboratory analysis and diagnostic studies include liver function tests, alkaline phosphatase levels, and a CT or MRI of the chest. Many of these tumors metastasize to the lungs or involve the lung. Involvement of the underlying lung does not preclude resection, but it is associated with a worse prognosis, particularly in a patient with high-grade sarcomas.6,13 Ultrasonography of chest wall tumors helps to localize the tumor’s relationship to the pleura and lung parenchyma.14 If the tumor is confined to the chest wall, its movement during respiration is synchronous with the chest wall movement and not with the lung parenchyma.

Chondroma Chondroma is the most common benign tumor of the chest wall.5,9,15 They usually arise in the ribs near the costochondral junction anteriorly. These patients present with a mass that may be painful. Radiographically, the lesion has a lobulated radiodense appearance, which frequently displaces the bony cortex but does not penetrate it (Fig. 105-1). Calcification may be diffuse or focal with a stippled pattern. Histologically, there is mature hyaline cartilage with foci of myxoid degeneration and calcification. These lesions may grow to enormous size if untreated, and the therapy of choice is wide local excision with 2-cm margins.

Fibrous Dysplasia Fibrous dysplasia occurs in young adults and presents as a painless, asymptomatic mass. It can arise anywhere on the chest wall but occurs frequently in the posterior ribs.16 There is an association with trauma. Radiographs show a central, fusiform, expanded mass with thinning of the cortex and absence of calcification.9 Cortical bone erosion is not uncommon. Histologically, there is a characteristic fishhook configuration of the trabeculae and lack of transformation of the coarse bony fibers to lamellar bone. This suggests that fibrous dysplasia represents a maturation defect. Excision of this lesion is curative.

Osteochondromas Osteochondroma is a rare chest wall tumor that occurs in the first or second decade of life. The radiographic appearance is typical. The lesion, which is usually located in the metaphysis, grows in a direction opposite to that of the adjacent joint (Fig. 105-2). Infrequently, it has a focal radiolucent area surrounded by osteosclerotic tissue.9 Grossly, the tumor consists of mature bone trabeculae covered by a cartilaginous cap.

1/21/2008 3:33:21 PM

Chapter 105 Neoplasms of the Chest Wall

1293

FIGURE 105-1 CT image of a 42-year-old man with a lobulated chondroma arising near the costochondral junction in the left fourth rib. The tumor was resected with adequate margins of excision.

FIGURE 105-2 A representative CT scan of a solitary osteochondroma of the posterior left scapula with displacement of the third rib anteriorly. The patient complained of dull posterior chest wall pain.

Most lesions are greater than 4 cm in diameter but may become larger if untreated. Solitary osteochondromas are benign and rarely may degenerate into malignancy. Multiple osteochondromas have a higher incidence of malignancy.16 The therapy is wide local excision.

Eosinophilic Granuloma Eosinophilic granuloma is a disease of the lymphoreticular system and not a true bone tumor. It may be solitary or multifocal and is a unifying feature of the conditions designated as histiocytosis X. Microscopically, there is an abundance of Langerhans cells, giant cells, eosinophils, and neutrophils. The peak incidence is between 5 and 15 years. It occurs in either the metaphysis or diaphysis of the bone and has no malignant potential. These lesions show osteolytic activity with adjacent osteosclerosis by radiography. They are frequently confused with Ewing’s sarcoma or osteomyelitis. The therapy consists of either resection or radiotherapy.

Ch105-F06861.indd 1293

Desmoid Tumor Desmoid tumors occur most commonly in the third to fourth decades of life and have a 2 : 1 female to male predominance. The desmoid tumor is frequently difficult to differentiate from the low-grade fibrosarcoma. Histologically, the desmoid tumor contains sheets of fibroblasts with well-differentiated abundant collagen, which lacks encapsulation. The fibrosarcoma is usually well encapsulated with a herringbone pattern and distinct mitoses.10 Although one third of patients with Gardner’s syndrome have desmoid tumors, only 2% of patients with a desmoid tumor have Gardner’s syndrome.17 Desmoids have also been reported to occur after trauma and to be associated with estrogen-induced growth.10,17 The clinical presentation is usually one of a dull, aching mass, which may be fixed to the underlying tissues but not to the skin.18 The growth of the mass is slow, and it does not metastasize. There are no characteristic radiographic findings, and the diagnosis is made by excisional biopsy.

1/21/2008 3:33:21 PM

Section 5 Chest Wall and Sternum

FIGURE 105-3 Survival rates in patients with malignant neoplasms of the chest wall. The total number of patients used to generate this graph was 44 rather than 47 because 2 patients with fibrosarcomas were lost to follow-up and an 84year-old man with a massive chondrosarcoma of the chest wall was not considered a candidate for resection. (ADAPTED FROM GRAEBER GM, SNYDER RJ, FLEMING AW, ET AL: INITIAL AND LONG-TERM RESULTS IN THE MANAGEMENT OF PRIMARY CHEST WALL NEOPLASM. ANN THORAC SURG 34:664, 1982.)

Percentage surviving

1294

100 90 80 70 60 50 40 30 20 10 0 1

2

3

4

5

Years after diagnosis and therapy Chondrosarcoma (N = 9) Osteogenic sarcoma (N = 4) Ewing’s sarcoma (N = 6)

The therapy is wide local excision with margins of at least 4 cm. Because desmoids may spread along fascial planes well beyond the primary lesion, the wider resection margins are recommended. The recurrence rates for desmoid tumors after excision range from 4% to as high as 50%.10,19 The recurrence rates were directly related to resection margin status in a study by McKinnon and coworkers,10 and 45% of patients with positive resection margins had recurrences. Only 4% with negative resection margins had relapses. In patients with recurrence or gross residual disease, radiotherapy is effective for local control.20,21 The recommended radiation doses of 50 to 60 Gy at 1 : 8 Gy/fraction prevent the dose-related complications of radiotherapy.21 Chemotherapy plays no role in the therapy for desmoid tumors. Because of the hormonal influence on the desmoid’s growth, tamoxifen has been reported to decrease both the size and symptoms of these tumors.22 The actual survival rates after wide local excision are 90% at 10 years, with a cause-specific survival rate of 100%.5 Local recurrence remains the most difficult challenge for this locally aggressive, benign tumor.

Fibrosarcoma (N = 17) Multiple myeloma (N = 8)

FIGURE 105-4 This photomicrograph presents a characteristic field from a histologic section of a chondrosarcoma. The histologic characteristics of this tumor include a cartilaginous neoplasm, which has anaplastic cells with one or more bizarre, hyperchromatic nuclei. This malignant neoplasm is also known to have frequent variations in the grade of tumor cells present throughout the presenting mass (H&E, ×200).

MALIGNANT TUMORS Malignant primary chest wall tumors can be cured if certain surgical principles are followed. These tumors may require extensive chest wall resection, but with the aid of muscle flaps, chest wall reconstruction is successful. Adjuvant therapy has become increasingly important in the management of these tumors. The most common primary malignant chest wall tumors were shown previously. Less common malignant tumors include neurofibrosarcomas, malignant hemangioendotheliomas, and leiomyosarcomas. The survival rates after therapy for these tumors vary, but all histologic subtypes have some long-term survivors (Fig. 105-3).

Chondrosarcoma Chondrosarcoma is the most common primary chest wall malignant tumor. It accounts for 50% of the malignant neoplasms and 25% of all primary chest wall tumors.9 Eighty percent of these tumors arise in the ribs, and 20% arise in the sternum (McAfee et al, 1985).23 Most of these tumors

Ch105-F06861.indd 1294

are solitary and have been present an average of 18 months before presentation.23 The conventional radiographic findings of a chondrosarcoma include a lobulated mass that arises in the medullary portion of the rib or sternum, often with cortical bone destruction. Calcification of the tumor is missed in 45% of chest radiographs but detected on chest CT scan. A stippled calcification pattern is most common, but rings and arcs of calcification may be present.24 The diagnosis of these tumors is made by an excisional biopsy. The incisional biopsy has no place in the diagnosis of these lesions because the histologic findings vary from a poorly differentiated cellular appearance to an extremely well-differentiated lesion that is indistinguishable from a benign chondroma (Fig. 105-4).9,23 The incidence of chondrosarcomatous change in a solitary osteochondroma is reportedly 1% to 2%.25 The natural history of these tumors is one of slow growth, with frequent local recurrence and late

1/21/2008 3:33:21 PM

Chapter 105 Neoplasms of the Chest Wall

metastasis. Chondrosarcomas have been related to previous chest wall trauma in 12.5% of patients.23 The therapy of choice is wide local excision, including several partial ribs above and below the lesion, with surgical margins of at least 4 cm. If the lesion originates in the sternum, a sternotomy with a corresponding resection of the costal arches bilaterally is performed.26 Chest wall reconstruction is frequently necessary. Chondrosarcomas are extremely radioresistant and chemoresistant. The prognostic factors include the tumor’s grade, diameter, and location. Tumors less than 6 cm and sternal tumors have a better patient prognosis. The 10-year survival rates are 96% with wide local excision, 65% with local excision, and 14% with palliative excision.23 The local recurrence rate is higher with local excision (50%) than wide local excision (17%). The possibility of late local recurrences of chondrosarcomas necessitates long-term follow-up of these patients.5

1295

FIGURE 105-5 This photomicrograph shows a characteristic sample taken from a Ewing sarcoma. The histologic characteristics of this tumor include closely packed, small, round cells, which are infiltrating muscle fibers (H&E, ×200).

Ewing’s Sarcoma and Askin’s Tumor Ewing’s sarcoma is a small, round tumor with characteristics of a primitive neuroectodermal tumor (PNET) and a neural histogenesis, as indicated by experimental studies.27 It is the most common primary chest wall malignancy in children and occurs in 8% to 22% of malignant chest wall lesions in adults.5,6,9,28 The differential diagnosis of small, round cell malignant tumors includes neuroblastomas, embryonal rhabdomyosarcomas, and lymphomas in addition to Ewing’s sarcomas.29 A highly malignant alternative to Ewing’s sarcoma is the PNET, which was first described by Askin and colleagues.30 PNET is considered similar to Ewing’s sarcoma because of a common neuroectodermal differentiation and a frequently seen translocation between the long arms of chromosomes 11 and 22 [t(11:22)(q24:q12)].31,32 PNET and Ewing’s sarcoma are grouped together because the diagnosis and therapy of each are similar. Most patients are between 5 and 30 years old and present with progressive chest wall pain with or without the presence of a mass. Some patients have a modest leukocytosis and elevated erythrocyte sedimentation rate. The typical radiographic picture is the characteristic onion-peel appearance, which is produced by multiple layers of periosteal new bone formation.9 Bony destruction, sclerosis of the widened cortex, and a widened medulla are also common radiographic findings. The tumor may involve several ribs but usually is confined to one rib. The diagnosis may be made with percutaneous needle biopsy,12 but, as with other primary chest wall malignancies, an excisional biopsy is best (Fig. 105-5). The preoperative workup includes standard chest imaging and bone marrow aspiration. These patients are best treated through a multimodality approach. The entire marrow cavity of the rib is considered to be at risk for malignancy; therefore, the entire involved rib is removed along with a partial rib resection above and below the lesion.28 Postoperative external-beam irradiation to the tumor bed provides excellent local control. If complete surgical resection and irradiation are performed, local control rates of 93% have been reported.33

Ch105-F06861.indd 1295

Chemotherapy is used to control distant disease and has been shown to decrease the incidence of distant metastases and improve survival rates.33,34 Doxorubicin, dactinomycin, cyclophosphamide, and vincristine are the four drugs used in combination most frequently. Failure to include doxorubicin in this combination has detrimental results.35 Preoperative chemotherapy has been reported to facilitate subsequent local therapy, but its use is not well established.28,36 The survival rate was improved with multimodality therapy to 52% at 5 years in one study.17 Patients with distant metastasis rarely survive 5 years. The complications of extensive chest wall resections in children with Ewing’s sarcoma include scoliosis and restrictive pulmonary disease.37,38 Harrington rod fusion may be necessary for severe scoliosis. The restrictive pulmonary function usually does not result in any long-term respiratory difficulties.

Osteosarcoma Osteosarcomas occur between the ages of 10 and 25 years and again after age 40 years in association with several other disease processes. They frequently present as a painful mass with a duration of symptoms before presentation that lasts from weeks to months. Most osteosarcomas arise de novo and are located in the metaphyseal portion of the long bones, such as the femur, the tibia, and the humerus. They do, however, account for a small but significant number of rib-based malignancies (Fig. 105-6).5 There is an association between the development of osteosarcomas and previous irradiation, Paget’s disease, and chemotherapy.39-41 The latency period for the development of osteosarcoma after irradiation is approximately 10 years.42 The preoperative evaluation of a patient considered to have an osteosarcoma includes an excisional biopsy to confirm the diagnosis. An elevated serum alkaline phosphatase level may be present by laboratory analysis, but this is nonspecific. One study showed that tumors associated with a serum elevation

1/21/2008 3:33:22 PM

1296

Section 5 Chest Wall and Sternum

prognosis), and unifocal osteosarcoma. The addition of multidrug chemotherapy to the therapy for osteosarcoma has increased 5-year disease-free survival rates to greater than 50%.47

Plasmacytoma

of this enzyme had increased metastatic rates.43 Radiographically, the classic “sunburst” pattern of new periosteal bone formation is frequently seen.7,16 Triangular elevation of the periosteum secondary to reactive new bone formation also may be evident on a radiograph and is known as Codman’s triangle sign. Histologically, we see eosinophilic staining and a glassy appearance with irregular contours of the osteoid. Interspersed with the osteoblastic cells are foci of fibroblastic and chondroblastic cells, which help divide osteosarcomas into those three subtypes (Fig. 105-7).44 The therapy for osteosarcoma of the chest is preoperative chemotherapy, which usually consists of a combination of doxorubicin, high doses of methotrexate, and cisplatin.45 This is done to shrink the tumor before resection and to evaluate the tumor’s response to chemotherapy. Tumors with a significant amount of tumor necrosis after chemotherapy are associated with better patient survival rates.43 Preoperative intra-arterial chemotherapy with cisplatin has produced significant disease-free survival rates in patients who have a complete or partial response.46 Radiotherapy is usually ineffective for osteosarcomas. The prognostic factors include the response to preoperative chemotherapy, an association with Paget’s disease (worse

Solitary plasmacytomas that arise in bone account for 10% to 30% of primary chest wall malignancies.5,7 They are more common in male patients and usually occur later in life, with a mean age of 60 years.5 The most common chest wall location is the ribs, followed by the clavicle and sternum. Soft tissue invasion from bone lesions may occur. The radiographic appearance of the plasmacytoma demonstrates an osteolytic process with several paracostal opacities frequently present.48 Confirmation that the plasmacytoma is localized to the chest wall requires several studies. The patient undergoes a bone marrow aspiration, skeletal radiographs, and immunoelectrophoretic examination of the serum and urine. A patient with a solitary plasmacytoma usually has a normal calcium level and is not anemic. Evidence of monoclonality of one of the immunoglobulins with normal levels of the other circulating immunoglobulins strongly suggests that the plasmacytoma is solitary. Serum β2-microglobulin levels are usually normal in the solitary plasmacytoma. Most bone lesions show a predominance of immunoglobulin reactivity; upper respiratory tract lesions are predominantly immunoglobulin.44 The diagnosis of a solitary plasmacytoma is made only if all studies for disseminated disease have negative findings. Microscopically, plasmacytomas are composed of sheets of plasma cells and are often hypervascular. The nucleoli are prominent and have a characteristic pinwheel appearance. Amyloid may be present in 25% of the lesions (Fig. 105-8).49 The role of surgery is to establish the diagnosis by excisional biopsy. High-dose radiotherapy (5000-6000 cGy) has been shown to be successful for the local control of solitary plasmacytomas.50 If the lesion is refractory to radiotherapy,

FIGURE 105-7 This photomicrograph shows a characteristic section taken from an osteosarcoma. The histologic characteristics include anaplastic osteoblasts in an osteoid matrix with atypical calcification (H&E, ×200).

FIGURE 105-8 This is a representative photomicrograph taken from a plasmacytoma. The characteristic features of this neoplasm include a large field of well-differentiated plasma cells that have eccentric nuclei that are surrounded by an adjacent “halo” (H&E, ×200).

FIGURE 105-6 Osteosarcoma. CT scan of a right third rib–based osteosarcoma with destruction of the bone is shown. The diagnosis was confirmed by an excisional biopsy.

Ch105-F06861.indd 1296

1/21/2008 3:33:22 PM

Chapter 105 Neoplasms of the Chest Wall

then a more extensive surgical excision can be done. Systematic chemotherapy is only given for evidence of disease progression.7 Local recurrence is uncommon for plasmacytomas. Spontaneous regression of a chest wall plasmacytoma has been reported, but this is rare.51 After they are treated for a solitary plasmacytoma, in 35% to 55% of patients, multiple myeloma develops, often 10 to 12 years after the initial diagnosis.49 The presence of nuclear immaturity with prominent nucleoli may have a positive predictive value for the development of multiple myeloma. The presence of a monoclonal protein in the serum or urine has no predictive value for the development of multiple myeloma.44 The 10-year survival rate for all bony locations of solitary plasmacytoma is 68%.52 A 25% to 37% 5-year survival rate after therapy for primary chest wall plasmacytomas is expected.5,8 Close follow-up of these patients with frequent urine and serum electrophoretic studies is necessary because the development of multiple myeloma is fairly common.

Soft Tissue Sarcoma Primary soft tissue sarcomas of the chest wall are uncommon, and few centers have treated extensive series of these tumors. The more common tumors include fibrosarcomas, liposarcomas, malignant fibrous histiocytomas, rhabdomyosarcomas, dermatofibrosarcoma protuberans, and angiosarcomas.5,8 These tumors comprise nearly 50% of all primary chest wall sarcomas.15,40 The factors that may predispose the patient to the development of soft tissue sarcomas include a history of previous irradiation and syndromes such as von Recklinghausen’s disease (neurofibromatosis), Gardner’s syndrome, and Werner’s syndrome.53,54 Fibrosarcomas are large, painful masses that occur in all age groups and often involve adjacent structures (Fig. 105-9).16 The radiographic findings show a large irregular mass with frequent destruction of the bone. The therapy includes wide local excision, with tumor-free margins for low-grade sarco-

FIGURE 105-9 Photomicrograph showing a representative sample of a fibrosarcoma. The histologic characteristics of this tumor show malignant spindle cells, which are arranged in a “herringbone” fashion. This alignment is characteristic of the tumor (H&E, ×200).

Ch105-F06861.indd 1297

1297

mas and the addition of chemotherapy for high-grade lesions.8 The difficulty in treating this neoplasm is related to the significant incidence of local recurrence and a propensity for the tumor to metastasize to the lungs.5 The 5-year survival rate is 53% to 86% after surgery, with or without adjuvant therapy.5 Rhabdomyosarcoma is a rare primary chest wall tumor. It accounts for 4% to 26% of primary malignant tumors. These tumors arise from undifferentiated mesoderm and are usually diagnosed after an incisional biopsy. Microscopically, the tumor cells are small and spindle shaped (Fig. 105-10). There are highly cellular regions that surround blood vessels and alternate with abundant parvicellular regions of muscle intercellular material. Immunocytochemical analysis of the tissue has been very useful in the diagnosis of rhabdomyosarcoma. The markers used include myoglobin, desmin, myosin, actin, and antiskeletal muscle antibody from myasthenic patients. The therapy is wide surgical excision and multidrug chemotherapy. Radiotherapy is usually not effective in this tumor. Malignant fibrous histiocytoma (MFH) is an uncommon primary tumor to the chest wall. These tumors arise from tissue histiocytes and have the potential to produce collagen (Fig. 105-11).55 CT aids in the operative planning and in the evaluation of metastatic disease. The therapy is by wide local excision for primary and locally recurrent tumors.56 MFH frequently has local recurrence and distant metastasis. However, MFH is generally resistant to chemotherapy. Adjuvant brachytherapy for soft tissue sarcomas has been shown to be beneficial if the patients are undergoing resection for locoregional recurrence in a previously irradiated site.57 Postoperative external-beam radiation may be effective, particularly if the resection margins are inadequate.56,57 Liposarcoma accounts for 15% of primary chest wall soft tissue sarcomas.8 Most (70%) are low grade, and en-bloc resection is the therapy of choice. Local recurrence was found in 33% of patients in the study by Greager and colleagues,58 and was treated by wide local excision alone. The presence

FIGURE 105-10 Photomicrograph depicting some of the histologic characteristics associated with a rhabdomyosarcoma. Included in the field are large, elongated tumor cells that have abundant eosinophilic cytoplasm, racket cells, and more primitive rhabdomyoblasts (H&E, ×200).

1/21/2008 3:33:23 PM

1298

Section 5 Chest Wall and Sternum

100

Free from recurrence (%)

P < .06 80

60 > 4 cm margin 40

20 2 cm margin 0 0

2

4

6

8

10

Time (yr) FIGURE 105-11 This photomicrograph shows a representative field from a malignant fibrous histiocytoma. The characteristics of this neoplasm include a pleomorphic tumor, which has many large, bizarre-shaped cells in a fibrous stroma (H&E, ×200).

of local recurrence has no significant effect on the overall survival rate.8 Radiotherapy may be effective in the control of local recurrence, but its role is unclear. The 5-year survival rate is 83%.5 The prognostic indicators for primary tissue sarcomas include the tumor grade, presence of distant metastases, and positive surgical resection margins.5,8,13 Tumors that are low grade are associated with a 90% 5-year survival rate; highgrade sarcomas have a 49% 5-year survival rate.40 Positive resection margins negatively affect both the disease-free survival and overall survival rates in high-grade sarcomas, which emphasizes the importance of negative margins.13 Radiotherapy and chemotherapy have no prognostic value for highgrade sarcomas in the adult patient. Because sarcomas tend to metastasize to the lungs, CT scans of the chest are performed. However, up to 50% of lung parenchyma nodules discovered at surgery are not seen on preoperative CT scans.59 The presence of these synchronous pulmonary metastases is associated with a worse prognosis.13

SURGERY Chest Wall Resection Wide resection of primary malignant chest wall neoplasm is essential to successful management. However, the extent of resection must not be compromised because of an inability to close a large chest wall defect.1,60-63 Opinions differ as to what constitutes wide resection. In a report from the Mayo Clinic,6 in which the effect of the extent of resection on the long-term survival of patients with primary malignant chest wall tumors was analyzed, 56% of patients with a 4-cm or greater margin of resection remained free from recurrent cancer at 5 years compared with only 29% for patients with a 2-cm margin (Fig. 105-12). For many surgeons, a resection margin of 2 cm would be considered adequate. Although this margin may be adequate for chest wall metastases, benign tumors, and certain low-grade malignant primary neoplasms

Ch105-F06861.indd 1298

FIGURE 105-12 Percentage of patients with malignant chest wall tumors free from recurrent tumors by extent of resection margin. Zero time on the abscissa represents the day of the chest wall resection. (FROM KING RM, PAIROLERO PC, TRASTEK VH, ET AL: PRIMARY WALL TUMORS: FACTORS AFFECTING SURVIVAL. ANN THORAC SURG 41:597, 1986.)

such as chondrosarcoma, a 2-cm resection margin is inadequate for more malignant neoplasms, such as osteogenic sarcoma and malignant fibrous histiocytoma, which have the potential to spread within the marrow cavity or along tissue planes, such as the periosteum or parietal pleura. Consequently, all primary malignant neoplasms initially diagnosed by excisional biopsy undergo further resection to include at least a 4-cm margin of normal tissue on all sides. High-grade malignancies also need to have the entire involved bone resected. For neoplasms of the rib cage, this would include removal of the involved ribs, the corresponding anterior costal arches if the tumor is located anteriorly, and several partial ribs above and below the neoplasm. For tumor of the sternum and manubrium, resection of the entire involved bone and corresponding costal arches bilaterally is indicated. Any attached structures, such as the lung, thymus, pericardium, or chest wall muscles, are also excised.

Chest Wall Reconstruction The ability to close large chest wall defects is of prime importance in the surgical therapy of chest wall neoplasms. The critical questions of whether the reconstructed thorax will support respiration and protect the underlying organs must be answered when we consider that both the extent of resection and dependable reconstruction are the mandatory ingredients for successful therapy. These two important items are accomplished most safely by the joint efforts of a thoracic and a plastic surgeon.61 Reconstruction of chest wall defects involves a consideration of many factors (Box 105-2). The location and size of the defect are of the utmost importance, but the medical history and local conditions of the wound may drastically alter a reconstructive choice. Primary closure remains the best option available if possible. If full-thickness reconstruction is required, which is usually the situation in most primary

1/21/2008 3:33:23 PM

Chapter 105 Neoplasms of the Chest Wall

Box 105-2 Consideration for Reconstruction of Chest Wall Defects

Box 105-3 Autogenous Tissue Available for Chest Wall Reconstruction

Location Size Depth Partial thickness Full thickness Duration Condition of local tissue Irradiation Infection Residual tumor Scarring General condition of patient Chemotherapy Corticosteroid Chronic infection Lifestyle and type of work Prognosis

Muscle Latissimus dorsi Pectoralis major Rectus abdominis Serratus anterior External oblique Trapezius Omentum

neoplasms that have not been previously treated, consideration must be given to both the structural stability of the thorax and the soft tissue coverage.

Skeletal Reconstruction Reconstruction of the bony thorax is controversial. Differences of opinion exist both as to which patients should undergo reconstruction and what type of reconstruction should be done. The decision not to reconstruct the skeleton depends on the size and location of the defect and whether the wound is infected. In general, infected wounds are not reconstructed simultaneously. Similarly, defects less than 5 cm in greatest diameter anywhere on the thorax are usually not reconstructed. Likewise, high posterior defects less than 10 cm do not require reconstruction because the overlying scapula provides support. However, if the defect is located near the tip of the scapula, the defect, even if 5 cm or less, is closed to avoid impingement of the tip of the scapula into the chest with movement of the arm. Alternatively, the lower half of the scapula could be resected. Finally, all larger defects located anywhere on the chest need to be reconstructed, and either autogenous tissue or prosthetic material may be used. Stabilization of the bony thorax is best accomplished with prosthetic material, such as Prolene mesh (Ethicon, Somerville, NJ) or 2-mm-thick Gore-Tex (polytetrafluroethylene) soft tissue patch. When either of these materials is placed under tension, the rigidity of the prosthesis is improved in all directions. Currently, the Gore-Tex soft tissue patch is superior because this material has the added advantage of preventing movement of fluid and air across the reconstructed chest wall. Marlex mesh (Davol, Providence, RI) is used less frequently because when it is placed under tension, this material is rigid in one direction only. Reconstruction with rigid material, such as methylmethacrylate-impregnated meshes is not necessary.

Ch105-F06861.indd 1299

1299

All large, full-thickness skeletal defects that result from the resection of a neoplasm in both the sternum and lateral chest wall are reconstructed if the wound is not contaminated. If the wound is contaminated from previous radiation necrosis or necrotic neoplasm, reconstruction with prosthetic material is not advised because the prosthesis may subsequently become infected, which would result in obligatory removal. In this situation, reconstruction with a musculocutaneous flap alone is preferred. Similarly, resection of fullthickness bony thorax in a patient who has been previously irradiated may not require skeletal reconstruction because the lung is frequently adherent to the underlying parietal pleura and pneumothorax may not occur with chest wall resection.

Soft Tissue Reconstruction Both muscle and omentum can be used to reconstruct soft tissue chest wall defects (Box 105-3). Muscle can be transposed as muscle alone or as a musculocutaneous flap and is the tissue of choice for closure of most full-thickness soft tissue defects. All major chest wall muscles can be mobilized on a single axis of rotation and transposed to another location of the chest wall (McCraw and Arnold, 1986).64 If muscle is not available because of previous radiation damage or an operation, free muscle flaps from another location can be reimplanted with the expectation of dependable long-term coverage. The omentum is reserved for partial-thickness reconstruction or as a back-up procedure when muscle either is not available or has failed in a previous full-thickness repair.

Latissimus Dorsi The latissimus dorsi is the largest flat muscle in the thorax. Its dominant thoracodorsal neurovascular leash has an arc of rotation that allows coverage of the lateral and central back and the anterolateral and central front of the thorax.65,66 Its dependable, musculocutaneous vascular connections permit it to be used also as a reliable musculocutaneous flap. This muscle flap can cover huge chest wall defects because virtually one half of the back can be elevated on the blood supply of a single latissimus dorsi in the uninjured, nonirradiated patient. The donor site posteriorly may require skin grafting when large musculocutaneous flaps are elevated, but this represents a minor disadvantage when we consider that large,

1/21/2008 3:33:24 PM

1300

Section 5 Chest Wall and Sternum

robust flaps can be transposed to either the anterior or the posterior chest for full-thickness reconstruction. If the dominant blood supply has been compromised by previous trauma or surgery, the muscle can still be transposed dependably on the branch of the adjacent serratus anterior.67

Pectoralis Major The pectoralis major is the second largest flat muscle on the chest wall and in many respects is the mirror image of the latissimus dorsi. Its dominant thoracoacromial neurovascular leash, which enters posteriorly about midclavicle, allows both elevation and rotation centrally of the muscle as either a muscle or a musculocutaneous flap.60 The pectoralis major flap is as reliable as the latissimus dorsi flap. It is of major benefit in the reconstruction of anterior chest wall defects, such as those that result from sternal tumor excisions.26,63,68 Generally, only the muscle without the overlying soft tissue and skin is transposed, which thus avoids the distortion created by a centralization of the breast. Reconstruction in this manner is more symmetrical and more aesthetically acceptable. If sternal skin must be excised, the symmetry of the breast can still be maintained because the transposed muscle readily accepts and supports a skin graft. If necessary, the muscle may also be transposed on its secondary blood supply through the perforators from the internal mammary vessels.

Rectus Abdominis Use of the rectus abdominis for chest wall reconstruction is based on the internal mammary neurovascular leash. The inferior epigastric vessels must be divided to allow rotation to the chest wall. This muscle can be mobilized and moved either as a muscle or as a musculocutaneous flap, with the skin component oriented either horizontally, vertically, or both. The vertical skin flap, however, is more reliable because it is oriented along the long axis of the muscle and thus maintains more musculocutaneous perforators. The donor site is usually closed primarily. The rectus abdominis is most useful in the reconstruction of lower sternal wounds. Either muscle can be used because their arc of rotation is identical. Care must be taken to choose the muscle that has patent and uninjured internal mammary vessels. Angiographic demonstration of vessel patency may be helpful to determine which musculocutaneous unit would be the most reliable, particularly in previously irradiated patients or in patients who had prior coronary artery bypass surgery.

Serratus Anterior The serratus anterior is a smaller, flat muscle that is located along the midaxillary chest wall. Its blood supply comes from the serratus branch of the thoracodorsal vessels and from the long thoracic artery and vein. Although this muscle can be used alone, it is more commonly utilized in chest wall reconstruction as an adjunctive muscle in tandem with either the pectoralis major or the latissimus dorsi to close larger defects. The muscle also augments the skin-carrying ability of either

Ch105-F06861.indd 1300

adjacent muscle.69 This muscle is particularly useful as an intrathoracic muscle flap.69,70

External Oblique The external oblique muscle may also be transposed as either a muscle or a musculocutaneous flap, and it is most useful in closing defects of the upper abdomen and lower thorax. It reaches the inframammary fold without tension but does not readily extend higher.71 The primary blood supply is from the lower thoracic intercostal vessels. The advantage of this muscle is that lower chest wall defects can be closed without a distortion of the breast.

Trapezius The trapezius muscle is useful to close defects at the base of the neck or the thoracic outlet, but it is not a consistently useful muscle as far as the remainder of chest wall reconstruction is concerned. Its primary blood supply is the dorsal scapular vessels.

Omentum Omental transposition has been useful in the reconstruction of the partial-thickness chest wall defects that may occur with certain soft tissue neoplasms or radiation necrosis.72,73 In the latter situation, the skin and soft tissue are débrided down to what remains of the thoracic skeleton, which may be either bone or cartilage but frequently is only irradiated ischemic scar. The transposed omentum, with its excellent blood supply from the gastroepiploic vessels, adheres to the irradiated wound and readily accepts and supports an overlying skin graft. Because the omentum has no structural stability on its own, it is not useful in full-thickness defects because additional support with fascia lata, bone, or prosthetic material would be necessary. Omental transposition is exceedingly helpful in situations in which planned muscle flaps have been used but have failed because of partial necrosis. Generally, this results in only a soft tissue defect, and a pleural seal with respiratory stability is not required, which thus allows a most threatening situation to be salvaged.

Late Results During the past 10 years, more than 60 chest wall resections for primary neoplasms were performed at the Mayo Clinic by one team of surgeons (unpublished data). Nearly two thirds of these neoplasms were malignant. Malignant fibrous histiocytoma and chondrosarcoma were the most common malignant neoplasms, and desmoid tumor was the most common benign tumor. The patients’ ages ranged from 12 to 80 years (median, 43.5 years). An average of 3.9 ribs were resected. Total or partial sternectomies were performed in 13 patients. Skeletal defects were closed with prosthetic material in 2 patients and with autogenous ribs in 5. Fiftyfour patients underwent 68 muscle transpositions; these included 24 pectoralis major, 23 latissimus dorsi, 6 serratus anterior, 3 external oblique, 2 rectus abdominis, 2 trapezius, and 8 other. The omentum was transposed in 8 patients. The

1/21/2008 3:33:24 PM

Chapter 105 Neoplasms of the Chest Wall

(17)

100

(10)

(6)

Chondrosarcoma survival (%)

Wide resection

FIGURE 105-13 Survival of patients with chest wall chondrosarcomas by extent of operation. Zero time on the abscissa represents the day of chest wall resection. (FROM MCAFEE MK, PAIROLERO PC, BERGSTRAHL EJ, ET AL: CHONDROSARCOMA OF THE CHEST WALL: FACTORS AFFECTING SURVIVAL. ANN THORAC SURG 40:535, 1985.)

80 (15) (13) 60

1301

(8) Local excision

(8) 40

20

(2)

P < .0001

Palliative excision

0 0

3

6

9

12

15

Years after operation

SUMMARY The key to successful therapy of primary chest wall neoplasms remains early diagnosis and aggressive surgical resection. This procedure can generally be performed in one operation, with minimal respiratory insufficiency and with low operative mortality rates. When combined with current methods of reconstruction, potential cure is likely for most patients with primary chest wall neoplasms.

100 Chondrosarcoma 80

Survival (%)

median hospitalization was 9 days. There were no 30-day operative deaths. The patients were generally extubated during the evening of the operation or on the following morning. Two patients required tracheostomy. Most other patients had only minor changes in pulmonary function.74 The long-term survival of patients with primary chest wall malignant neoplasms is dependent on the cell type and the extent of chest wall resection. In the Mayo Clinic series, the overall 5-year survival rate was 57%.6 Wide resection for chondrosarcoma resulted in a 5-year survival rate of 96%23 compared with only 70% for patients who had local excision (Fig. 105-13). The 5-year overall survival rate for patients with either chondrosarcoma or rhabdomyosarcoma was 70%,6 in contrast to a rate of only 38% for patients with malignant fibrous histiocytomas (Fig. 105-14). Recurrent neoplasm, however, was an ominous sign; only 17% of patients in whom recurrence developed survived 5 years.

60 Rhabdomyosarcoma 40 Malignant fibrous histiocytoma 20 P < .05 0 0

2

4

6

8

10

Time (yr) FIGURE 105-14 Survival for patients with chondrosarcomas and rhabdomyosarcomas compared with those with malignant fibrous histiocytomas. Zero time on the abscissa represents the day of chest wall resection. (FROM KING RM, PAIROLERO PC, TRASTEK VH, ET AL: PRIMARY WALL TUMORS: FACTORS AFFECTING SURVIVAL. ANN THORAC SURG 41:597, 1986.)

pathologists currently accept the desmoid tumor as a low-grade fibrosarcoma and not a benign disease.19,75 M. E. B.

COMMENTS AND CONTROVERSIES As documented by Drs. Graeber, Jones, and Pairolero, primary malignant tumors of the chest wall are relatively uncommon. Approximately 500 new cases of primary malignant chest wall tumors will be diagnosed yearly in the United States. Because it is estimated that there will be 1,170,000 new cases of cancer diagnosed in the United States yearly, primary malignant tumors of the chest wall comprise only 0.04% of all new cancers. Because primary malignant tumors of the chest wall are relatively uncommon, data to support therapy options are sparse, but nicely outlined in this chapter. There is only one area of disagreement, and that is the classification by the authors that chest wall desmoid tumors are benign. Many

Ch105-F06861.indd 1301

KEY REFERENCES Graeber GM, Snyder RJ, Fleming AW, et al: Initial and long-term results in the management of primary chest wall neoplasms. Ann Thorac Surg 34:664, 1982. ■ These authors present the Armed Forces Institute of Pathology’s experience with 110 patients with primary chest wall neoplasms. Included are both soft tissue and bone neoplasms. The roles of chemotherapy and radiotherapy for each type of malignant neoplasm are discussed. King RM, Pairolero PC, Trastek VF, et al: Primary chest wall tumors: Factors affecting survival. Ann Thorac Surg 41:597, 1986. ■ This series represents a 20-year experience of chest wall tumors treated at the Mayo Clinic from 1955 to 1975 and includes both soft tissue and bony tumors. Both

1/21/2008 3:33:24 PM

1302

Section 5 Chest Wall and Sternum

chondrosarcoma and rhabdomyosarcoma had a better prognosis than did malignant fibrous histiocytoma. McAfee MK, Pairolero PC, Bergstralh EJ, et al: Chondrosarcoma of the chest wall: Factors affecting survival. Ann Thorac Surg 40:535, 1985. ■ These authors present a single institution’s experience (96 patients) with chondrosarcoma of the chest wall. This series is the largest series of chest wall chondrosarcoma reported to date and clearly demonstrates that the natural history of chondrosarcoma is one of slow growth and local recurrence. McCraw JB, Arnold PG: McCraw and Arnold’s Atlas of Muscle and Musculocutaneous Flaps. Norfolk VA, Hampton Press, 1986. ■ The anatomy, indications for, and technique of commonly used muscle flaps in all areas of the body are each summarized, illustrated by color photographs of fresh

Ch105-F06861.indd 1302

cadaver dissections, and then supplemented by appropriate intraoperative color photographs of clinical cases. This atlas should be read by every surgeon interested in the reconstruction of the chest wall. Pairolero PC, Arnold PG: Chest wall tumors: Experience with 100 consecutive patients. J Thorac Cardiovasc Surg 90:367, 1985. ■ This series represents a single team of surgeons’ experience in the management of 100 consecutive patients with chest wall tumors. This series of patients demonstrates that aggressive resection for a chest wall tumor with reliable reconstruction can be accomplished safely and that early wide resection is potentially curative therapy.

1/21/2008 3:33:24 PM

Surgical Techniques chapter

106

DORSAL SYMPATHICOTOMY FOR HYPERHIDROSIS King F. Kwong Mark J. Krasna

Key Points ■ Intrathoracic visual and tactile orientation is the key first step in the

operation. ■ Identification of rib levels leads to the appropriate sympathetic

chain level. ■ Recognizing the anatomic landmarks neighboring the stellate

ganglion helps in identifying its location. ■ The second thoracic ganglion is usually found within the second

intercostal space, and so on.

Hyperhidrosis is a medical condition that has significant physical, psychological, and social consequences for those who are afflicted with moderate or severe symptoms. Nonoperative treatments are only occasionally effective for these patients, in contrast to surgery’s better results. Thoracoscopic sympathicotomy yields equivalent clinical results to that of the historical sympathectomy procedure (Kwong et al, 2005).1-3 The thoracoscopic sympathicotomy operation permits the identification of the thoracic sympathetic nerve chain and division of the dorsal thoracic sympathetic nerve for alleviating the symptoms of hyperhidrosis. The thoracoscopic surgical approach offers a minimally invasive operation, resulting in quicker patient recovery from surgery and less surgical trauma compared with an open approach.

TECHNIQUE General anesthesia with double-lumen endotracheal intubation is commonly used to perform the operation. Alternatively, single-lumen endotracheal intubation may be used, but it is then necessary to insufflate carbon dioxide gas into the chest cavity for adequate visual exposure of the thoracic sympathetic chain as it courses in the superior aspect of the hemithorax. The patient is placed into a semi-Fowler position on the operating table, and the arms are abducted to expose the axillae bilaterally. Both axillary regions are prepared and draped for sequential bilateral thoracoscopic procedures to be completed in the same anesthetic setting. A single skin incision is made in each axilla, just lateral to the lateral border of the pectoralis musculature (Fig. 106-1), and a 10-mm thoracoscopic port is placed through the second or third intercostal space. The use of an operating thoracoscope simultaneously allows excellent visualization of the intrathoracic anatomy and permits the introduction of long thoracoscopic surgical instruments through the endoscope to perform the operation. Alternatively, multiple 2- or 3-mm–sized incisions may be used to conduct this operation; the main draw-

back is the potential for anatomic disorientation from using much smaller endoscopes which provide more limited visual fields of the thoracic cavity during the operation. The postoperative course of patients with single versus multiple microincisions is not significantly different. We prefer the superior operative visual exposure with the incrementally larger endoscope. The thoracic sympathetic nerve chain is located longitudinally in the paraspinal region, often overlying the rib heads as it courses in a cephalad-caudal orientation (Fig. 106-2). The stellate ganglion is located in its apicoposterior location, often surrounded and covered by several fat pads, and is left undisturbed in surgery conducted solely for hyperhidrosis. Although the sympathetic chain is often depicted as a vertical straight-line anatomic structure in medical illustrations, in living anatomy, the nerve chain’s course can meander somewhat from the apex of the chest down to the level of the pulmonary hilum. A blunt thoracoscopic probe can be used to provide tactile feedback in locating the sympathetic chain in vivo as it courses beneath the pleural covering. Identification of the level of the sympathetic chain to be divided is guided by recognition of the appropriate rib levels. The second sympathetic ganglion is often situated at the lower edge of the second rib or within the second intercostal space. Once the appropriate level has been established, the pleura overlying the posterior rib is divided for 2 to 3 cm lateral to the nerve chain, in order to expose and visualize any accessory nerves of Kuntz (Fig. 106-3). The parietal pleura that overlies the sympathetic chain is then divided, and the nerve chain is dissected circumferentially free from its surrounding tissue. The sympathetic nerve chain itself is then divided, using intermittent electrocautery with a thoracoscopic hook instrument, and the ends of the divided chain are gently distracted apart (Fig. 106-4). An alternative to electrocautery is the use of the harmonic scalpel. The levels of sympathetic nerve division for hyperhidrosis are dependent on the preoperative symptomatology of the patient and continue to evolve as thoracic sympathetic surgeons seek to improve the clinical results of this operation.4,5 Care must be taken to avoid disturbing the nearby, often large, venous tributaries. In the left hemithorax, due attention must be given to the location of the often prominently visible left subclavian artery, aortic arch, and descending thoracic aorta to avoid inadvertent injury. In addition, division of the chain occurs at the level of the midpoint of the rib bed, to avoid the more inferiorly located intercostal blood vessels. After completion of the intended sympathicotomies (Fig. 106-5), the lung is re-expanded by the anesthesiologist. A 1303

Ch106-F06861.indd 1303

1/21/2008 3:34:12 PM

1304

Section 5 Chest Wall and Sternum

2nd rib

Incision in 3rd ICS lateral to pectoralis muscles

3rd rib

FIGURE 106-1 The patient is placed into the semi-Fowler position, with the arms abducted. Both axillary regions are prepared and draped to accommodate bilateral sequential surgeries in the same anesthetic setting. ICS, intercostal space. (FROM KWONG KF, KRASNA MJ: THORACOSCOPIC SYMPATHICOTOMY. IN PATTERSON GA [ED]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY. NEW YORK, WB SAUNDERS, 2004.)

Subclavian vessels Ganglia FIGURE 106-3 The pleura overlying the second rib bed is divided to expose any accessory nerves of Kuntz, as is the partial pleura overlying the sympathetic chain medially. (FROM KWONG KF, KRASNA MJ: THORACOSCOPIC SYMPATHICOTOMY. IN PATTERSON GA [ED]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY. NEW YORK, WB SAUNDERS, 2004.)

2nd rib

IVC 3rd rib

pediatric chest tube is used to evacuate the intrapleural air and is then removed before complete closure of the surgical incision. A long-acting local anesthetic agent is administered to the peri-incisional subcutaneous tissues to minimize immediate postoperative pain. After bilateral thoracoscopic sympathicotomy surgeries, the patient recovers in the postanesthetic care unit and then is discharged home with outpatient follow-up.

TERMINOLOGY At times, operative nomenclature may vary among surgeons. A uniform terminology needs to be considered by surgeons in describing sympathetic nerve operations. Although there

FIGURE 106-2 Common anatomic location of the thoracic dorsal sympathetic chain as seen during right-sided thoracoscopy. IVC, inferior vena cava. (FROM KWONG KF, KRASNA MJ: THORACOSCOPIC SYMPATHICOTOMY. IN PATTERSON GA [ED]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY. NEW YORK, WB SAUNDERS, 2004.)

Ch106-F06861.indd 1304

1/21/2008 3:34:13 PM

Chapter 106 Dorsal Sympathicotomy for Hyperhidrosis

1305

2nd rib 2nd rib

3rd rib 3rd rib

FIGURE 106-4 The sympathetic chain is dissected free from surrounding tissues with the use of the thoracoscopic hook instrument, in preparation for electrocautery division. (FROM KWONG KF, KRASNA MJ: THORACOSCOPIC SYMPATHICOTOMY. IN PATTERSON GA [ED]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY. NEW YORK, WB SAUNDERS, 2004.)

is no absolute correct or incorrect language, a reasonable set of definitions can be proposed for sympathetic nerve surgery. For example, a T2 level sympathicotomy refers to division of the sympathetic chain overlying the second rib, and a T3 sympathicotomy means chain division overlying the third rib. A T2-T3 sympathicotomy, therefore, means division of the sympathetic chain over both the second and the third ribs, without extirpation or ablation of the intervening ganglion. The use of more uniform terminology will greatly improve our ability to understand and extrapolate the clinical results among different surgical groups.

OUTCOME Thoracoscopic sympathicotomy yields dramatic improvements in the quality of life of patients with palmar hyperhidrosis and of selected patients with severe axillary symptoms.6 In our experience, the operation can be conducted with excellent results and low morbidity. Careful patient selection and frank preoperative discussion with prospective patients regarding possible side effects and complications are also important contributing factors in determining overall success-

Ch106-F06861.indd 1305

FIGURE 106-5 The next lower level sympathicotomy is performed in order to isolate the targeted sympathetic ganglion. (FROM KWONG KF, KRASNA MJ: THORACOSCOPIC SYMPATHICOTOMY. IN PATTERSON GA [ED]: OPERATIVE TECHNIQUES IN THORACIC AND CARDIOVASCULAR SURGERY. NEW YORK, WB SAUNDERS, 2004.)

ful outcome for sympathetic surgery in hyperhidrosis patients. KEY REFERENCES Kwong KF, Cooper LB, Bennett LA, et al: Clinical experience in 397 consecutive thoracoscopic sympathectomies. Ann Thorac Surg 80:1063-1066, 2005. ■ This paper describes one of the first North American centers to report significant quality of life improvements supported with a quantified methodology in a large patient series. Kwong KF, Hobbs JL, Cooper LB, et al: Stratified analysis of clinical outcomes in thoracoscopic sympathicotomy for hyperhidrosis. Ann Thorac Surg 2008 (in press). ■ Specific levels of sympathicotomies performed are correlated to clinical outcomes in this paper describing more than 600 thoracoscopic sympathicotomies for hyperhidrosis. Rex LO, Drott C, Claes G, et al: The Boras experience of endoscopic thoracic sympathicotomy for palmar, axillary, facial hyperhidrosis and facial blushing. Eur J Surg 580(Suppl):23-26, 1998. ■ This is one of the first publications detailing a large patient cohort undergoing the modern-day version of sympathetic surgery for hyperhidrosis.

1/21/2008 3:34:39 PM

chapter

107

CHEST WALL AND STERNUM RESECTION AND RECONSTRUCTION Geoffrey M. Graeber

Key Points ■ Surgical resection of disease processes of the chest wall should

■ ■ ■ ■

■

be undertaken with a full understanding of the pathology afflicting the patient. Thorough evaluation of the entire patient should take place before the resection. Chest wall stabilization will be required in only a few selected instances after the chest wall pathology has been removed. Pedicle flap reconstruction will offer the key to soft tissue coverage of any defect in the chest wall. Occasionally, more than one flap will be necessary to cover large defects. With careful attention to detail, the morbidity and the mortality from resection of chest wall pathology and reconstruction should be low. The outcome in most patients should be satisfactory and will depend on the type of disease process that has been resected from the chest wall.

Chest wall resection is usually performed for one of five reasons: 1. 2. 3. 4. 5.

Removal of neoplasms Eradication of entrenched infection Excision of radiation injuries Débridement of traumatic wounds Correction of congenital defects

These indications for chest wall resection are not mutually exclusive because infection can be a major complication for each of the others. Recurrent tumor and infection together can complicate radiation injuries. The following discussion delineates the essential surgical principles governing chest wall resection for each of the five major indications. Before any major resection, the surgeon should make a thorough and accurate assessment of the patient to avoid major complications.1,2 In the trauma patient the resection may have to proceed even in victims who are poor operative risks because allowing devitalized material to remain invites catastrophic infection.3

RESECTION FOR NEOPLASMS Before embarking on a biopsy of any chest wall neoplasm, the surgeon must take a complete history and conduct a thorough physical examination with the intent of identifying any history of chest wall trauma and of uncovering any malignancy that could spawn a chest wall metastasis. Metastatic

lesions and healing rib fractures are far more prevalent than all primary chest wall neoplasms combined.4,5 Either a healing rib fracture or a chest wall metastasis may have many of the same radiographic features as a primary chest wall neoplasm. The age of the patient, the presentation of the tumor, its physical location and characteristics on the chest wall, and its radiographic appearance will strongly suggest the true character of the neoplasm. The evaluation of a suspected primary chest wall tumor includes standard chest radiographs plus a computed tomographic (CT) scan of the thorax that completely images all ribs, the totality of both leaves of the diaphragm, and the entire base of the neck. The treating surgeon should seek several consultations before embarking on a biopsy.5,6 The first consultation should be with a radiologist who specializes in imaging of the thorax. After the chest radiographs and CT scan have been reviewed by the surgeon and radiologist together, they should determine whether specialized diagnostic imaging techniques could be useful in providing more information about the neoplasm. These specialized studies should be undertaken before any diagnostic biopsy is conducted. The surgeon should also consult with a medical oncologist and a radiation therapist to see if any specialized studies need to be conducted on tissue obtained at the time of biopsy. Finally, a pathologist who regularly reads pathologic specimens containing musculoskeletal neoplasms should be consulted. The pathologist usually suggests how much tissue is necessary to perform the tests required to achieve a proper diagnosis. Continuing consultation with the pathologist at the time of surgery is mandatory. Frozen sections are generally of limited value in assessing chest wall neoplasms because so many of them have bony or cartilaginous components. The surgeon and the pathologist should work together to obtain enough appropriate material at the time of biopsy to ensure an accurate diagnosis on subsequent permanent sections. In many instances, specialized stains will be necessary to determine the final diagnosis. The question of how much tumor needs to be sampled remains controversial.4,5 The technique of biopsy and how much tumor is removed depends on the suspected type of tumor and the pathologist. At one extreme is the needle biopsy, a technique that has proved particularly effective for the group at the University of Texas M. D. Anderson Cancer Center in evaluation of children with Ewing’s sarcoma of the chest wall.7 In one study of primary bone tumors, needle biopsy accurately diagnosed 83% of malignant and 64% of benign neoplasms.8 Incisional biopsy is indicated if the needle biopsy is not diagnostic or if the pathologist needs more tissue to make a definitive diagnosis. Conduct of the incisional

1306

Ch107-F06861.indd 1306

1/21/2008 3:35:52 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

biopsy should be governed by the anticipation of possible radical resection if the tumor proves to be malignant. The surgeon should bear in mind that 5 cm of clear skin from the margin of the biopsy site should be resected with radical surgical extirpation.6 Meticulous surgical technique is mandatory because hematoma within the wound predisposes to tumor extension. The biopsy site ideally should be closed without a drain because a drain increases the chance of infection, which would complicate definitive resection and reconstruction. Excisional biopsy is indicated for smaller lesions (2-3 cm) and also for chondromatous lesions because these neoplasms may well include benign as well as malignant areas within the same neoplastic mass.5 Wide excision of osteochondromas and neurofibromas is also indicated, particularly in patients suffering from the familial syndromes of multiple osteochondromas and neurofibromatosis because malignant degeneration has been recorded in both entities.9 Once the true nature of the primary chest wall neoplasm has been established, definitive therapy can be undertaken. Proper resection of benign neoplasms consists of surgical

excision with preservation of the overlying skin and surrounding musculature. In the event that the benign neoplasm falls into one of the categories of chondromatous lesions noted previously, wider excision should be conducted.7 Although there has been some variance in reporting, the generally accepted rate of malignancy for primary chest wall neoplasms is 50%.5,10,11 The most common malignancies in most series are the chondrosarcomas, with the incidence of fibrosarcoma not far behind. Adjuvant chemotherapy and radiation therapy have a role in treating some primary chest wall malignancies. For this reason preoperative consultation with a radiation therapist and a medical oncologist is indicated before conducting a radical chest wall resection in any patient suffering from a chest wall neoplasm. The most common primary chest wall malignancy, chondrosarcoma, is resistant to both chemotherapy and radiotherapy.7 Appropriate radical resection with tumor-free margins of at least 5 cm has yielded excellent results.5,12-15 Survival is related to the tumor’s histologic grade and size and to the adequacy of resection (Figs. 107-1 to 107-6). In one series, patients with grade I lesions had a 10-year survival rate of 70% and patients with a tumor less than 6 cm in greatest dimension had an 87% 10-year survival.15 On the other hand, the same series noted that patients with grade III or dedifferentiated chondrosarcomas had very poor survival. Primary fibrosarcomas of the chest wall are usually treated with aggressive surgical resection.5,9 Most chemotherapeutic

FIGURE 107-1 Large anterior lateral chest wall neoplastic mass, such as would be seen with a chondrosarcoma. The tumor has obvious physical margins. The dotted line represents the planned area of resection around the tumor, which includes resection of an adequate, approximately 5-cm margin of healthy tissue around the tumor itself. This is the best way to eliminate local recurrence, which is the most common cause of treatment failure in chondrosarcomas.

FIGURE 107-2 Method for determining resection of recurrent cancer in an irradiated field. Note that the line of resection, denoted by the heavy dotted line, is drawn at the margin of skin showing any radiation change. The chest wall excision should include all tissue that is apparently damaged even though the defect may be large. Healing will be better if the flaps are approximated to healthy tissues. (FROM

(FROM SEYFER AE, GRAEBER GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

SEYFER AE, GRAEBER GM, WIND GG: THE RECTUS ABDOMINIS MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1307

1307

1/21/2008 3:35:52 PM

1308

Section 5 Chest Wall and Sternum

FIGURE 107-3 A, The patient has been placed in a supine position on the operating table, and the anticipated margins of resection have been drawn on the chest wall. The dotted lines on the extremities show the preparation of the patient. In this case, a transverse musculocutaneous rectus abdominis (TRAM) flap based on the left rectus muscle will be used to reconstruct the defect. The solid line on the lower abdomen depicts the skin island that will be taken with the flap. Preparation of the patient for resection includes a double preparation, the first of which is directed at cleaning the ulcerated wound on the chest. Once this has been closed and covered with a gauze sponge impregnated with povidone-iodine solution, which is covered with a piece of plastic or a section of rubber after being placed in the wound, a second preparation can be conducted over the entire area. B, Close-up of the way the ulcer is filled with the gauze sponge in the defect. Note that the rubber patch, a portion of a sterile glove, or a piece of sterile impermeable drape is stapled in place so that the entirety of the ulcer is excluded from the field during the second preparation. (A FROM SEYFER AE, GRAEBER GM, WIND GG: THE RECTUS ABDOMINIS MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986; B FROM SEYFER AE, GRAEBER GM, WIND GG: THE OMENTUM. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

FIGURE 107-4 Patient with severe chest wall wound that has been treated in accordance with the principles of military medicine as dictated in the early part of the 20th century. Note that the wound has been débrided widely and allowed to granulate. Some patients treated in this manner, including soldiers wounded in World War I, survived despite their wounds. The wound continued to granulate and remain superficially infected, causing severe nutritional depletion of the patient. Hence, the patient looked quite cachectic because depletion occurred slowly over time. Few of these individuals survived the long term. (FROM SEYFER AE, GRAEBER GM, WIND GG: SOME HISTORICAL ASPECTS OF CHEST WALL RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

agents have relatively little effect on these malignancies. Some success has been reported with the use of radiotherapy for lower-grade fibrosarcomas (desmoids) of the chest wall.7 Preoperative and postoperative chemotherapy appears to be beneficial in treating primary chest wall osteosarcomas.7 Although most series are small, primary radical surgical resection can yield long-term survivors.5 Preoperative chemotherapy causes a degree of necrosis in the primary tumor, which may aid in selecting postoperative agents.9 Cisplatin and doxorubicin, either alone or in combination with other agents, appear to be effective.7

Ch107-F06861.indd 1308

1/21/2008 3:35:52 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

FIGURE 107-5 Closure of wounds in World War II usually consisted of mobilization of local slips of muscle for closure over the previously débrided defect. This drawing depicts one of the attempts at closure, which was conducted on a patient suffering an anterior thoracic wall wound during World War II. Note that the area had been débrided widely and that closure was attempted only when all evidence of infection had receded. (FROM SEYFER AE, GRAEBER GM, WIND GG: SOME HISTORICAL ASPECTS OF CHEST WALL RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ewing’s sarcoma generally presents in the second decade of life and is unusual in the ribs.7 When it presents as a chest wall tumor, it generally has a worse prognosis than when it is a primary lesion in a long bone of an extremity because metastases to the lungs occur in about half of the cases.7 When Ewing’s sarcoma is localized to the chest wall, the patient is treated with CyVADIC (cyclophosphamide-vincristine-Adriamycin–imidazole carboxamide) induction chemotherapy for two to five cycles before undertaking resection of the primary tumor. In general, the goals of the resection are to excise the primary tumor with minimal soft tissue margins and with the entirety of the affected rib(s).7 CyVADIC is then continued for seven to eight cycles postoperatively without administration of radiation therapy.7 Although some survivors have been reported with surgery alone, the prudent use of neoadjuvant and adjuvant chemotherapy for treating primary Ewing’s sarcoma of the chest wall is strongly indicated.5,7 Radiotherapy is reserved only for patients who have residual disease after definitive therapy.7,16

CHEST WALL STABILIZATION The first step in chest wall reconstruction is preservation of function through stabilization. In some cases the resection itself does not sufficiently compromise chest wall function, and thereby also respiratory mechanics, to warrant stabilization. If stabilization is necessary, a number of materials have been used successfully to preserve chest wall integrity and

Ch107-F06861.indd 1309

1309

FIGURE 107-6 Placement of chest tubes as they would be situated for an anterolateral thoracic wound. In placing the tubes, care is taken to remain away from the wound site itself so that the tubes do not traverse the area of the open chest wall. One tube is placed over the apex of the chest to drain any air that may be remaining within the pleural cavity; the other tube is placed low and posterior so that it will evacuate any blood or tissue fluids that may collect in the posterior costophrenic sinus. (FROM SEYFER AE, GRAEBER GM, WIND GG: RESECTION AND DÉBRIDEMENT OF THE CHEST WALL. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

respiratory mechanics. Some have remained useful and have earned a secure place in chest wall reconstruction, whereas others have proved marginally or minimally successful and have been abandoned. The indications for chest wall stabilization as a part of an integrated reconstruction are reviewed; the materials, both biologic and synthetic, that have been used in this capacity are listed; and the most popular methods used by surgeons today are summarized.

Indications Chest wall reconstruction is generally viewed as a procedure with two aspects, chest wall stabilization and soft tissue reconstruction. In some cases the consistency of the soft tissue reconstruction affords satisfactory stabilization to preserve respiratory mechanics,17,18 whereas in others the flaps used in providing soft tissue coverage have little intrinsic consistency (e.g., omentum flaps) and usually need stabilization.19,20 Each case must be assessed and handled individually because respiratory mechanics must be preserved. The final decision on whether chest wall stabilization is necessary involves consideration of multiple factors, the most impor-

1/21/2008 3:35:53 PM

1310

Section 5 Chest Wall and Sternum

Box 107-1 Biologic Materials Used for Chest Wall Stabilization Human Tissues Autogenous Fascia lata Bone grafts Ribs, whole and longitudinally split Tibia Fibula Iliac crest Composite Preserved Dura mater Fascia Pericardium Preserved Animal Tissues Dura mater Pericardium Ox fascia

tant of which are the general condition and respiratory capabilities of the patient, the size and location of the resection performed, the integrity and quality of the structures overlying the defect, and the intrinsic qualities of the flaps used for soft tissue coverage. The final goal is to provide a reconstruction that has minimal if any paradoxical chest wall motion during respiration so that the patient can be weaned from ventilatory support as soon as possible after reconstruction.17,18,21 Satisfactory cosmesis is an important secondary goal that merits careful consideration.17,18 The general condition and respiratory capabilities of the patient are major factors in determining whether chest wall stabilization is required as a part of chest wall reconstruction.22 The operating surgeon carefully must evaluate the patient who will undergo chest wall resection to determine just how much respiratory embarrassment the patient can tolerate and yet still be able to be weaned from a respirator early in the postoperative period. A reasonable guiding principle is that any patient who is able to tolerate a pulmonary lobectomy based on pulmonary function studies, arterial blood gas determination, and exercise testing will also be able to tolerate a major chest wall resection.2 Special consideration should be given to the unusual patient who needs a pulmonary resection in conjunction with a major chest wall resection and reconstruction. Obviously, a younger, more robust patient with excellent nutrition will tolerate a large resection and reconstruction better than a frail, elderly patient who suffers from cachexia. The location and size of the chest wall resection are major determinants of whether chest wall stabilization is required as a part of successful reconstruction. Small defects (5-7 cm in greatest diameter) seldom need stabilization, since the amount of paradoxical motion is small and can be tolerated by most patients.21,23 Larger defects almost always need some form of chest wall stabilization to preserve respiratory function.2,23 Location of the resection is important because major

Ch107-F06861.indd 1310

structures of the ipsilateral upper extremity may provide the necessary overlying support. The scapula is an example of such a structure posteriorly, but its relation to the defect may impinge on the margin, requiring partial resection of the inferior scapular pole.23 Anteriorly, the pectoralis major muscle, if it and its overlying skin and subcutaneous tissues are left intact, may provide sufficient support that chest wall stabilization is not necessary. Resections that are lateral and inferoanterior generally require stabilization because major muscles and bones do not overlie the chest wall in these regions. The size of the flap employed in soft tissue reconstruction and its intrinsic consistency have direct bearing on whether chest wall stabilization is required. As noted previously, the omentum usually is very flaccid, with little intrinsic rigidity; hence, stabilization is almost always required when the omentum is used. In contrast, a large musculocutaneous flap (e.g., latissimus dorsi) has an intrinsic robust quality, which may allow coverage of a defect without stabilization. All flaps, like any other surgically manipulated tissues, generate edema within 48 hours of the procedure. Because edema tends to make tissues more rigid, the flap has less paradoxical motion on the second through fourth postoperative days. The flap becomes less robust as the edema fluid is mobilized later in the postoperative period, but usually the patient has been weaned from the ventilator by this time.

Materials Used in Chest Wall Stabilization A host of materials have been used to stabilize the chest wall and preserve respiratory mechanics since the inception of the chest wall resection and reconstruction (Box 107-1). An excellent review by McCormack21 has summarized most of these and should be consulted. The following discussion is based on experiences recorded in the literature by other authors and on personal observations recorded during major reconstructions performed on patients by myself and colleagues at our respective university institutions. This section presents a classification of materials that have been used to stabilize the chest wall. The last section of this review highlights the major methods used in chest wall stabilization that are practiced regularly because of ease in handling, durability, relative radiographic permeability, and superior performance. The first major category is biologic implants. The assets of autogenous tissues are availability and biocompatibility. Their liabilities include poor resistance to infection, increased operating time, substantially increased patient discomfort, and relative flaccidity when compared with synthetic materials.17,21 Their presence in a wound can be disastrous if infection supervenes. Fascia lata is devascularized tissue, which acts as a perfect culture medium for bacteria. Bone chips added to fascia lata provide no stabilization because they are resorbed.17 Their presence on fascia lata compounds the problem of infection because they act as yet another source of devascularized tissue on which microorganisms can thrive. For all the aforementioned reasons, fascia lata alone or in conjunction with bone chips has fallen into disfavor. Bone grafts can be used judiciously in selected instances for chest wall stabilization. Although portions of tibia, fibula,

1/21/2008 3:35:54 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

and iliac crest have been used successfully, their harvesting adds another operative site, with its associated discomfort and potential for complications.17,21 Rib grafts have the advantage of being more likely to follow the natural curvature of the chest wall, but they have significant liabilities. If they are harvested in a subperiosteal fashion, the resultant chest wall instability may be consequential and the rib may regenerate from the remaining periosteum poorly or not at all. Ribs that are partially resected by using a longitudinal line of resection leave a compromised rib in place at the donor site while providing a graft that is particularly frail. The result is suboptimal chest wall stabilization at both the donor and recipient sites. The use of rib grafts by my colleagues and me has been limited to carefully selected patients who need protection for vital intrathoracic structures (e.g., the heart and great vessels) while maintaining an acceptable cosmetic contour to the reconstruction. The patient must have relatively good pulmonary function because the discomfort from the donor site, when compounded with that of the reconstruction, can produce a serious decrease in respiratory function. Placement of an epidural catheter to maintain regional anesthesia in the immediate postoperative period has decreased patient discomfort in our experience, so that early weaning from the ventilator is the rule. If rib grafts are placed properly, marrow from the intact ribs at the margins of the resection grow into and vascularize the marrow of the graft, ensuring its prolonged viability (Fig. 107-7).17 Rib grafts in any position are dependent on surrounding tissues, particularly on the rib to which they are attached, for postoperative viability.24 If a rib graft or any bone graft does not receive a new blood supply, the graft is resorbed by the body, leaving only a fibrous remnant.21,24 Preserved tissues, human or animal, were mostly used before synthetic cloth and sheeting became available and proved so successful.17,21 There have been some devoted proponents of these tissues for chest wall stabilization.25 Although these membranes may provide substantial initial stability, they may become flaccid with time, owing to peripheral stress on anchoring tissues as well as to intrinsic weakening of structural proteins. The patient’s body reacts to these materials as it does to any foreign body, with an intense fibrous reaction. This fact, plus the relatively inferior resistance of biologic materials to infection, has led to a decrease in their use. The rise in the use of synthetic materials for chest wall stabilization has been fostered by their variety and availability, their perceived inert nature, and their general ease of handling.17,21 At the outset, any surgeon should realize that absolutely no material is completely inert when placed in a patient. The patient’s natural healing process will at least respond to any foreign material with fibrous reaction to form a pseudocapsule. Rigid materials have had some popularity in chest wall reconstruction, but they have some liabilities, which have limited their application.17,21 Because the chest wall is a dynamic structure, which is constantly active in respiration, rigid materials have a tendency to migrate and fracture. Migration, when it is external, finally causes dermal erosion,

Ch107-F06861.indd 1311

1311

FIGURE 107-7 Use of rib grafts in anterior chest wall stabilization. Note that the grafts, as well as the ribs, are notched so that they can be secured with transfixing permanent sutures. Notching also allows a greater area of interface between the rib and the graft marrow cavities. The greater interface of the two marrows increases the likelihood that the bone graft will survive because the marrow of the graft is dependent on the ingrowth of cellular material from the end of the rib. (FROM SEYFER AE, GRAEBER GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

which exposes the rigid material. Infection of the entire capsule surrounding the rigid support ensues quickly, requiring removal of the foreign material. If the rigid bar or strut erodes internally, major viscera (e.g., the lung) and great vessels may be entered, producing serious if not lethal hemorrhage.21 Metallic struts are for the most part currently limited to stabilization of the sternum after repair of a severe pectus deformity.26,27 In most cases these struts are not permanent but are removed after the chest wall has become stable (Fig. 107-8). Most synthetic materials used for human implantation are produced as sheets or as meshes (Box 107-2). Many of these have been employed, with varying degrees of success, as stabilizing membranes in chest wall reconstruction.13,21,23,28 Each has its assets and liabilities. For example, Marlex mesh can be stretched along one axis while it is rigid along the perpendicular axis. Prolene mesh is a double-stitch knit, which is rigid along all axes. Gore-Tex, which is very malleable as a soft tissue patch, is impervious to air and water but is most difficult to contour and sew in place tightly. Although each of these materials is relatively inert, they all provoke an intense fibrous reaction when placed in the chest wall. Even polypropylene, which has been touted as quite unreactive, was found to provoke an intense fibrous reaction from the lung and pleura in one experimental model.24

1/21/2008 3:35:54 PM

1312

Section 5 Chest Wall and Sternum

A number of synthetic materials can be produced with variable degrees of firmness. Success has been reported with acrylic, silicone, Silastic, and methylmethacrylate prostheses.29-32 They may be used alone or in composites as prosthetics in chest wall reconstruction.33 Although such techniques have been available since well before the early 1980s, recent concerns about silicone, particularly as it has been used in mammary implants, indicate extreme caution in its use.34,35 Current U.S. Food and Drug Administration guidelines for implanting silicone should be consulted before embarking on such a reconstruction. In current practice, customized prostheses are used for both chest wall stabilization and partial chest wall reconstruction only in selected cases in which standard stabilization and flap reconstruction either has failed or offers exceptionally limited options.33 Such individualized prostheses may be created to reconstruct complex defects with rounded contours; however, they are difficult to secure to the chest wall, require sophisticated, computerized techniques to generate, and are subject to all the recognized liabilities of a firm foreign body in the dynamic chest wall. Excellent long-term results have been recorded in carefully selected patients with very special reconstructive needs.33 McCormack and associates have had particularly beneficial experience with composite prostheses generated in the operating room from Marlex mesh and methylmethacrylate monomer.21,36 A customized prosthesis is made by measuring the size of the defect on the patient, laying a piece of Marlex mesh over a surface of similar contour, applying the methylmethacrylate to the Marlex to match the size and shape of the defect as determined by the previously measured pattern, and then applying another layer of Marlex over the still soft methylmethacrylate so that the Marlex bonds to it. The

resulting prosthesis has a firm, contoured center of polymethylmethacrylate, which lies between two layers of Marlex. The 5-cm rim of Marlex that extends beyond the hard central polymethylmethacrylate prosthesis acts as a sewing ring for securing it to the chest wall defect. The prosthesis has several assets: it has an absolutely rigid center, conforms well to the anticipated curve of the chest wall, and has a pliable sewing ring. One of its true liabilities arises with its creating: the reaction leading to the hardening of the methylmethacrylate is extremely exothermic, often reaching temperatures near 140˚ F. Appropriate curvature may be obtained by shaping the prosthesis over a chest tube collection bottle or over the patient’s thigh, which can be protected with towels to prevent the exothermic reaction from causing thermal tissue injury. Once in place, the prosthesis is subject to all the problems, as noted previously, attendant on rigid prostheses in a dynamic environment. Investigators working at the National Cancer Institute have identified another problem associated with methylmethacrylate prostheses.37 In their method for creating the prosthesis, the lung is dropped away from the defect in the chest wall and the prosthesis is actually created on the patient from Marlex, steel mesh, and methylmethacrylate. After the prosthesis has been created, the lung is re-expanded against the prosthesis. A metabolic acidosis, which is secondary to anion replacement with methylmethacrylate, ensues. This has to be corrected during the reconstruction.

METHODS OF IMPLANTATION Chest wall stabilization is necessary to provide a firm surface on which to set the soft tissue flaps that complete the recon-

Box 107-2 Alloplastic and Synthetic Materials Used in Chest Wall Stabilization Plates and Struts Metal Tantulum steel Stainless steel Other materials Lucite Fiberglass Synthetic Materials Sheets and meshes Polytetrafluorethylene (Teflon) sheeting and patch Nylon Polypropylene Prolene mesh Vicryl mesh FIGURE 107-8 Use of a Steinmann pin in stabilizing a repaired sternum as part of a correction for pectus excavatum. The pin is secured to the ribs lateral to the repair. It will be removed in most cases after the repair has healed. (FROM SEYFER AE, GRAEBER GM, WIND GG: CONGENITAL DEFECTS: POLAND’S SYNDROME, PECTUS DEFORMITIES AND STERNAL CLEFTS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1312

Solid and Firm Prosthetics Acrylic Teflon Silastic Silicone Composite Marlex mesh combined prosthesis

1/21/2008 3:35:54 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

struction. The key point to remember is that stabilization is directed at reducing paradoxical motion of the chest wall and maintaining its contour. Technical aspects of the three most popular methods of stabilization are discussed subsequently. Creativity is necessary in all aspects of chest wall reconstruction to achieve a desirable cosmetic result. There are several important points to consider in implanting the polymethylmethacrylate “sandwich.” The prosthesis has a central rigid area, which follows the chest contour and is extremely rigid. The sewing ring, which consists of the 5cm rim of Marlex around the central hard prosthesis, is used to join the prosthesis to the chest wall. If sutures have to be placed through the central, hard portion of the prosthesis, a tunnel has to be created with a drill to allow passage of the needle because the methylmethacrylate sets to the same consistency as a football helmet. Stabilization with either mesh or screening requires creative tailoring to suture the material to the chest wall (Fig. 107-9). The margin of resection should be palpated to determine the most stable point, which is usually a rib or a remaining portion of the sternum. A horizontal mattress suture of braided, permanent synthetic material is placed through the edge of the patch or the screening and periosteum of the bone and is tied in place. A second suture is placed through the synthetic material so that it can be secured firmly to the most stable point 180 degrees opposite the original suture. Another set of sutures is placed through the prosthetic material at the edge of the resection so that the material is drawn tight and secured to the periosteum along an axis perpendicular to the line between the first two sutures. Sutures are then

FIGURE 107-9 A successful method for securing synthetic mesh or sheeting to a chest wall defect to achieve stabilization. Note that the sutures are placed on the cephalad aspect of the ribs to avoid the neurovascular bundles that course along the caudad surfaces of the ribs. Sutures are placed starting at one point in the defect and are placed sequentially and radially to achieve a relatively taut surface on which to place the flap(s) used to reconstruct the soft tissue defect. (FROM SEYFER AE, GRAEBER GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1313

1313

placed in a radial fashion so that the material is drawn tightly across the wound. Once the entirety of the prosthesis has been adjusted in place, any excess margins are trimmed. An alternative method is to start with the firmest point on the margin of resection and secure the prosthesis to the periosteum. Sutures are then placed sequentially in a radial fashion around the defect, drawing the synthetic material progressively tighter. Tailoring cuts are made in the prosthetic material after each suture so that the material will tuck underneath the edges of the margin neatly. If the sutures are placed appropriately by either method, a firm, taut surface for accepting the soft tissue flaps is created. In some patients with very difficult reconstructive problems, a customized prosthesis can be made to achieve chest wall stabilization and replace the soft tissue defect (Fig. 107-10). In such cases there has to be soft tissue coverage of the prosthesis after it is in place. Usually, the soft tissue placed over the prosthesis is the native tissue remaining at the site, but in some cases a musculocutaneous flap is necessary to form sufficient coverage. The customized prosthesis is generated via computer: the opposite side of the patient’s

FIGURE 107-10 Composite prosthesis with two components: a hard Silastic posterior segment, which replaces the upper anterior thoracic wall, and a soft gel prosthesis, which gives contour and shape to the absent breast. Note that there are three integral plastic tabs on the margins of the prosthesis. These plastic tabs are used to secure the prosthesis to bones on the thoracic wall and thereby prevent migration. (FROM HOCHBERG J, ARDENGHY M, GRAEBER GM, MURRAY GF: COMPLEX RECONSTRUCTION OF THE CHEST WALL AND BREAST UTILIZING A CUSTOMIZED SILICONE IMPLANT. ANN PLAST SURG 32:524, 1994.)

1/21/2008 3:35:54 PM

1314

Section 5 Chest Wall and Sternum

chest wall is surveyed, measurements are taken, a mirror image of the chest wall is created through a computer model, the dimensions of the model are printed, and a plaster model is created.33 In the case illustrated in Figure 107-10, the patient also needed a breast prosthesis. A silica gel prosthesis was added to the heavy Silastic contoured model of the chest wall. The composite model is custom manufactured, and the prosthesis is sterilized by the manufacturer and delivered to the surgeon for implantation in the patient. Implantation of this model is dependent on integral plastic tabs, which may be seen in Figure 107-10. These tabs are sutured to stable skeletal structures so that the prosthesis does not migrate. In the case cited, the three tabs were secured respectively to the sternum medially, the clavicle superiorly, and the ribs laterally. Heavy, braided synthetic sutures were placed through the plastic tabs and though the periosteum of the bony structures noted. In some situations, as with the clavicle or the sternum, the sutures may actually be placed around the entire structure to provide added security. One final point cannot be overemphasized. Each reconstruction must be individualized and creative to achieve an excellent contour and reduce paradoxical motion in the chest wall to a minimum.

P

L O

R

SOFT TISSUE RECONSTRUCTION Soft tissue reconstruction of the chest wall has been revived and expanded since the early 1970s. The concept of pedicled flap reconstruction has been the mainstay of this movement since its inception. Tissue reconstruction has continued to grow, with delineation of new applications of pedicled flaps to repair increasingly complex defects. Free flap transfer has had some limited applications in carefully selected cases. The following discussion presents the major considerations in planning soft tissue coverage of a chest wall defect, the salient characteristics of the pedicled flaps, and the complications associated with specific reconstructions. Several major works have focused on this field, with comprehensive treatments of all aspects of chest wall reconstruction (McCraw and Arnold, 1986; Seyfer and Graeber, 1989).38-40 Surgeons contemplating chest wall reconstruction should consult these texts for a thorough understanding of the complexities associated with successful thoracic reconstruction.

Planning the Reconstruction Pedicled reconstruction of chest wall defects may be conducted on any anatomic region of the chest wall. Certain areas have more options for reconstruction than others. Selection of appropriate flaps is mandatory because tension on a flap’s margin or its pedicle spells disaster. Designation of secondary flaps in each instance is essential because one flap may not cover the entire defect without introduction of supplemental tissue and because rotation of replacement flaps may become necessary if the primary flap proves unsuitable.1,17 Coverage of the anterior and anterolateral chest wall offers the most options because several pedicled flaps may be rotated successfully.1,41 Major pedicled flaps that may be used

Ch107-F06861.indd 1314

FIGURE 107-11 Anterior and anterolateral areas of the chest wall and the pedicled flaps that may be used to reconstruct these areas. The sternum has been divided into upper, middle, and lower sections. The area over the pectoralis major muscle has been designated by a solid line extending from the shoulder around the clavicle to the sternum and to just below the breast; this is the upper lateral region. The lower lateral region is directly below this area and covers the rest of the thoracic cage from the anterior axillary line to the sternum. The areas of transfer for each muscle are shown by arrows: the first choice for coverage of a given area is designated by a solid arrow, the second choices by dashed arrows, and the third choices by dotted arrows. Each of the flaps is designated by a letter: L, latissimus dorsi; O, omentum; P, pectoralis major; R, rectus abdominis. (FROM SEYFER AE, GRAEBER GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

in this area include the pectoralis major, rectus abdominis, and latissimus dorsi muscular and musculocutaneous flaps as well as the omentum (Fig 107-11). The serratus anterior muscular flap may be used in some limited applications. The lateral chest wall has more limited options for pedicled reconstruction.1,17 The latissimus dorsi muscular and musculocutaneous flap is the first choice (Fig. 107-12). The rectus abdominis muscular or musculocutaneous flap is the second choice for these areas, and the omentum is the third choice. The serratus anterior flap and abdominal wall flaps have limited roles in this region, but they may be used if the main options have been exhausted or if their rotation is not possible.38 Reconstruction of the chest wall posteriorly is more difficult because of limited options (Fig. 107-13). The latissimus

1/21/2008 3:35:55 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

1315

T L

L

O

R

FIGURE 107-12 The lateral areas of the chest wall may be reconstructed with either latissimus dorsi or rectus abdominis muscular or musculocutaneous flaps or the omentum. The two distinct areas, which are outlined by solid lines, represent an upper and a lower region. Note that the latissimus dorsi (L) is the primary pedicled flap for reconstruction in both areas, the rectus abdominis (R) is the secondary flap, and the omentum (O) is the tertiary flap for reconstructing these areas. The heavy black arrows designate the latissimus as the primary flap for reconstruction in both areas, the dashed arrows indicate the rectus as the secondary flap, and the dotted line, associated with the omentum, indicates that it is the third choice. (FROM SEYFER AE, GRAEBER GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

FIGURE 107-13 The limited options for reconstruction of the posterior aspect of the chest wall are delineated. Note that there are two areas for reconstruction: the upper spinous and the paraspinous area and the lower, larger area that encompasses most of the back. The primary flap for reconstruction of the upper area is the trapezius muscle (T). The latissimus dorsi (L) is the muscle and musculocutaneous flap that can be used most effectively to cover most of the back. (FROM SEYFER AE, GRAEBER GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

be dissected maximally and the size of the flap may extend to its extreme to achieve coverage. Such reconstructions using combined latissimus dorsi and rectus abdominis flaps to close large contralateral defects have been reported.41

Flaps for Reconstruction dorsi muscular and musculocutaneous flap is clearly the best choice for cephalad rotation. On the upper chest, the trapezius muscle may be rotated to cover spinal and paraspinal defects. In extreme cases, free flap transfer may be used as long as suitable arterial and venous supply is maintained, the pedicle is not placed under tension, and the margins of the flap are not overextended. Occasionally, a defect may be so large that more than one flap may be necessary to provide for adequate soft tissue coverage.1,17 In such cases, secondary and tertiary flaps may be rotated to achieve satisfactory soft tissue coverage without tension on the pedicle(s) or on the margins of the flaps. In some extreme circumstances, the pedicles of the flaps may

Ch107-F06861.indd 1315

Each of the flaps used in reconstruction of the chest wall has assets and liabilities as well as a defined arcs of rotation. Transposition of any of the flaps requires precise understanding of the blood supply. Successful rotation of any flap depends on preservation of the blood supply and prevention of any tension on the pedicle and on the margins of the flap. Previous surgical procedures and pathologic conditions may preclude successful rotation of specific flaps.

Pectoralis Major Muscle One of the most frequently used muscular and musculocutaneous flaps is the pectoralis major. The utility and durability of this flap has been shown in several series.5,23,42 Because

1/21/2008 3:35:56 PM

1316

Section 5 Chest Wall and Sternum

Thoracoacromial artery

Internal thoracic artery

Perforating branch Lateral thoracic artery

FIGURE 107-14 The primary and secondary blood supply for the right pectoralis major muscle. Note that the thoracoacromial artery and vein constitute the primary supply, with the major vessel directed from cephalad to caudad. The next most abundant vascular supply to the muscle consists of the internal thoracic artery and vein, which course along the lateral aspect of the sternum to give rise to perforators, which penetrate the intercostal spaces and give blood to the pectoralis major muscle. The tertiary supply consists of some random branches of the lateral thoracic artery and of the intercostal arteries as they give rise to small vessels that perforate the muscle. Pedicled flaps have been described that are based on the thoracoacromial neurovascular bundle and on the internal thoracic artery and its penetrating branches that supply the medial aspect of the pectoralis major muscle. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE PECTORALIS MAJOR MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

of its primary and secondary blood supply, it can be transferred as a pedicled flap based on the thoracoacromial neurovascular bundle or on the perforators arising from the ipsilateral internal mammary artery (Fig. 107-14).17,43 It is particularly well suited for use in repairing defects of the upper anterior chest wall and in the upper part of the ipsilateral pleural space.12,44 Major assets of the pectoralis major muscle and musculocutaneous flap are its ability to be based on two different blood supplies and thus allow successful transfer and its intrinsic ability to be divided into segments so that structure and function may be preserved while maintaining the natural contour of the thoracic wall (Fig. 107-15). It may be moved into the upper portion of the pleural space, into a dehisced median sternotomy incision, or into the head and neck for reconstruction depending on the pathology present.43,45 It has relatively few problems, which can be addressed successfully if they are appreciated prior to reconstruc-

Ch107-F06861.indd 1316

FIGURE 107-15 The arc of rotation of the pectoralis major muscular and musculocutaneous flap when based on the thoracoacromial neurovascular bundle. Note that the origin and the insertion of the muscle have been cut and have retracted toward the center. The muscle may be rotated over the entire anterolateral chest wall and into the head and neck region. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE PECTORALIS MAJOR MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

tion.43,45 One is elimination of a pedicle due to trauma or removal of the primary blood supply for a pedicle. These complications are quite rare for the primary pedicle, the thoracoacromial neurovascular bundle. They are not uncommon, unfortunately, for the secondary pedicle, the internal thoracic (mammary) artery. If the ipsilateral internal thoracic artery has been harvested for revascularization of the myocardium, rotation of the pectoralis based on the secondary pedicle (ipsilateral internal thoracic artery) is contraindicated because the muscle pedicle would be based on the tertiary blood supply, the intercostal vessels. Under these conditions, the viability of the flap would be extremely questionable. The blood supply to the flap can also be compromised by a sternal wire that perforates the internal thoracic vessels. Hence, closure of a dehisced median sternotomy incision with pectoralis major muscular flaps based on the ipsilateral internal thoracic artery and vein must be undertaken only after thorough evaluation of the integrity of these vessels. One of the most common indications for use of the pectoralis major muscular flap is the reconstruction of the dehisced median sternotomy.46-48 One method describes

1/21/2008 3:35:56 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

A

1317

B

FIGURE 107-16 A, Mobilization of the pectoralis major flaps for reconstruction of the upper anterior thorax. Both muscles have been pedicled on their respective thoracoacromial arteries and veins. Note that the origins of both muscles as well as the insertions have been transected. B, Muscles reconstructed over the sternal defect. Note that the pectoralis major muscles join together in the midline to add support to the wound. (FROM SEYFER AE, GRAEBAR GM, WIND GG: THE PECTORALIS MAJOR MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

FIGURE 107-17 The pectoralis major muscular flap may be based on the internal thoracic perforators arising along the origin of the muscle just lateral to the sternum. In this dissection, the inferior part of the muscle is saved to preserve function and cosmesis. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE PECTORALIS MAJOR MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1317

advancement of the pectoralis major muscular flaps into the wound based on their primary pedicles, the thoracoacromial neurovascular bundles. In such cases both muscles in their entirety are dissected free of their origins and insertions and are advanced into the wound together to reconstruct the wound closure (Fig. 107-16).45 An alternative is to base the flaps on the perforators arising from the respective internal thoracic arteries, divide the thoracoacromial vessels, and turn the flaps over into the dehisced median sternotomy wound (Fig. 107-17).49,50 Variations of these two approaches based on the segmental anatomy of the pectoralis major muscle have been described in which the first method is used on one side and a variation of the second is used on the contralateral side.43,46 In addition to reconstruction of the anterior chest wall after tumor resection and reconstruction of the dehisced median sternotomy, the pectoralis major muscular and musculocutaneous flap has been useful in reconstruction of the radiation-damaged chest wall, in treating bronchopleural fistulas and their associated empyemas, and in repairing tracheoesophageal fistulas. In the experience at the Mayo Clinic, the pectoralis major and latissimus dorsi flaps have been the most commonly used in treating patients with radiation damage of the chest wall.51 The pectoralis major muscular flap has been successful in treating high bronchopleural fistulas and their associated empyemas.52 For this application the flap has been based on the thoracoacromial neurovascular bundle in most cases.52 Reconstruction of tracheoesophageal fistulas has also been successfully performed by using this flap.53 A skin island appended to the flap may be used to

1/21/2008 3:35:57 PM

1318

Section 5 Chest Wall and Sternum

reconstruct the membranous trachea or, alternatively, a meshed, split-thickness skin graft may be used for this purpose and for epithelializing any exposed portions of the muscle (Fig. 107-18).

Rectus Abdominis Muscle The rectus abdominis muscle has been important in chest wall reconstruction both as a muscular and as a musculocutaneous flap. It is a large muscle, with the capacity to carry substantial islands of tissue to repair defects on the chest wall and in the thorax. It can have both a longitudinal and a transverse cutaneous island. Its blood supply is particularly favorable in that it usually has a balance between the superior and inferior epigastric arteries. The intercostals, which end in the rectus sheaths along the abdominal wall, are the tertiary blood supply. Flaps may be constructed based on the superior or inferior epigastric artery. In some cases involving particularly large defects of the chest wall, flaps have been rotated based on both rectus muscles and both internal thoracic arteries.54 Accurate, comprehensive descriptions of the methodologies for rotating these muscular and musculocutaneous flaps are available.55,56 This muscle, and particularly its musculocutaneous flap, has been quite useful in reconstruc-

FIGURE 107-18 The pectoralis major musculocutaneous flap has been placed over the repaired esophagus, which is posterior. The skin island is being joined to the open area of the trachea so that the membranous portion is being replaced. Any exposed portion of the muscle that remains after the reconstruction will be covered with meshed, split-thickness skin grafts. (FROM SEYFER AE, GRAEBER GM, WIND GG: TRACHEOESOPHAGEAL AND BRONCHOPLEURAL/CUTANEOUS FISTULAS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1318

tion of the breast, with several authors presenting extensive experiences with this muscle for breast reconstruction.57-60 The rectus abdominis muscle has a large arc of rotation, which allows it or its musculocutaneous flap to be rotated onto most of the anterior, anterolateral, and lateral thoracic wall.55 The domain of the flap for chest wall reconstruction is extensive and covers virtually all of the anterior and lateral thorax (Fig. 107-19). Besides its significant use in reconstruction of the breast, it has been particularly effective in repair of the dehisced median sternotomy. It must be used carefully in this capacity because its blood supply is dependent on the integrity of the internal thoracic artery (see later). Because of the amount of tissue that can be transferred, the rectus abdominis muscle and musculocutaneous flap have been particularly useful in the reconstruction of anterior and lateral chest wall defects after resection of malignant tumors. These flaps have also been used extensively in reconstruction of the chest wall after radiation injuries, particularly those associated with breast cancer therapy.

FIGURE 107-19 The rectus abdominis muscle and musculocutaneous flap are particularly useful in reconstruction of the anterior and lateral chest wall. In all instances of this application, the pedicle is based on the superior epigastric vessels, which are continuations of the internal thoracic (mammary) artery and vein. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE RECTUS ABDOMINIS MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

1/21/2008 3:35:59 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

The blood supply to the rectus abdominis muscle allows rotation of the entire muscle and an associated subcutaneous and cutaneous island along with the flap onto the greater part of the chest wall.61 The superior epigastric vessels, which are the direct extensions of the internal thoracic artery and vein, are the principal vessels in the pedicle on which this muscular and musculocutaneous flap is based for rotation onto the anterior and lateral thoracic wall.62,63 Because of the rich vascular plexus within the muscle, the entire length of the rectus abdominis may be transferred cephalad with the superior epigastric vessels used as the sole pedicle (Figs. 107-20 and 107-21). In some very rare cases, both rectus abdominis muscles and a large associated subcutaneous and cutaneous island may be rotated onto the anterior thorax based on both pairs of epigastric vessels.64 This flap must be rotated with great care because the blood supply must be preserved. Obviously, previous abdominal incisions can have a deleterious effect on the blood supply to the muscle and hence to

the flap. Incisions that may modify or preclude the use of this flap include the paramedian, midline, and upper transverse incisions (Fig. 107-22). The upper transverse incisions, which cross either rectus abdominis muscle, almost always interrupt the superior epigastric vessels so that the muscle distal to the incision becomes dependent on the inferior epigastric vessels for its viability. Cephalad rotation based on the superior epigastric vessels is therefore not indicated because the distal portion of the muscle will die under these circumstances. A midline incision limits the amount of subcutaneous tissue and skin that may be transferred on the distal portion of the flap because the subcutaneous and cutaneous blood supply will be interrupted lateral to the midline incision. Under these circumstances, any soft tissue that is lateral to the midline incision and is transferred with the flap will most likely succumb. Paramedian incisions generally disrupt the entire vascular plexus and preclude successful rotation. There are several methods for using this muscular and musculocutaneous flap in chest wall reconstruction. The

FIGURE 107-20 The rectus abdominis muscle may be based on either the superior or the inferior epigastric vascular pedicles. The rich anastomosis between the vessels, which is in the center portion of the muscle, ensures the viability of the distal portion of the flap when it is based on either pedicle. (FROM SEYFER AE, GRAEBER GM, WIND GG:

FIGURE 107-21 This anatomic dissection shows the direct dependence of the superior epigastric vessels on the extension of the internal thoracic artery and vein. The rectus abdominis has been divided in its midportion to show the rich plexus of penetrating vessels, which allow viability of the skin when transferred with the muscular flap. (FROM SEYFER AE, GRAEBER GM, WIND GG: BLOOD

BLOOD SUPPLY TO THE SKIN OF THE CHEST WALL. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE MD, ASPEN PUBLISHERS, 1986.)

SUPPLY TO THE SKIN OF THE CHEST WALL. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1319

1319

1/21/2008 3:36:00 PM

1320

Section 5 Chest Wall and Sternum

FIGURE 107-22 Whenever the rectus abdominis muscle is contemplated for reconstruction of the thorax, the surgeon must analyze the previous incisions on the abdomen. In this instance, an upper right subcostal incision precludes the use of the rectus based on the superior epigastric vessels. If a flap based on these vessels were to be rotated, any tissue distal to the line of incision would die because all this tissue has become dependent on the inferior epigastric vessels after the transverse incision. (FROM SEYFER AE, GRAEBER GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

muscle itself may be transposed to fill a dehisced median sternotomy incision. The muscle itself may also be rotated to close a particularly low fistula within the thorax. Most frequently, the rectus is rotated into the chest as a musculocutaneous flap with either a transverse or a longitudinal orientation. The transverse rectus abdominis musculocutaneous (TRAM) flap is very popular for reconstruction of the breast and of radiation injuries of the anterior chest wall (Figs. 107-23 and 107-24).57-60 The TRAM flap has been used in many creative ways to reconstruct absent breasts (Figs. 107-25 and 107-26). The longitudinal musculocutaneous flap is particularly beneficial in repairing a severely dehisced median sternotomy incision. The longitudinal island may be rotated with the flap to completely fill a severe defect associated with the severe dehiscence of a median sternotomy wound, such as those more frequently seen in diabetic patients (Fig. 107-27). If one of the internal mammary arter-

Ch107-F06861.indd 1320

FIGURE 107-23 The potential viability of skin and subcutaneous tissues when transferred with the rectus abdominis as a transverse musculocutaneous rectus abdominis (TRAM) flap is depicted. The skin and subcutaneous tissues directly overlying the rectus muscle have the highest probability of viability after transfer. These are denoted by the crosshatched area. Other areas that are directly juxtaposed to this well-vascularized tissue may remain viable but can still suffer necrosis under certain conditions. These areas are denoted by the vertical and the oblique lines. The soft tissue that is far distal to the main flap is of questionable viability and should not be used; this area is represented by the stippled area on the right anterior abdominal wall. This drawing depicts a left rectus flap; if a right rectus flap were contemplated, the areas of tissue viability would be the mirror image of that shown here. (FROM SEYFER AE, GRAEBER GM, WIND GG: BLOOD SUPPLY TO THE SKIN OF THE CHEST WALL. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

ies has been harvested for myocardial revascularization, the rectus abdominis musculocutaneous flap used for repair of a dehisced median sternotomy should be rotated based on the opposite superior epigastric vessel. If both mammaries have been harvested for myocardial revascularization, the rectus abdominis should not be rotated into the wound, since the muscular or musculocutaneous flap will most likely die in this situation. The use of the rectus abdominis has been extended by free transfer and by creative vascular anastomoses. Free flap transfers of the rectus abdominis muscle, the omentum, and the latissimus dorsi have been reported in the management of complex intrathoracic problems.65 These free flaps have been most useful in repairing bronchopleural cutaneous fistulas. The rectus itself may have its blood supply enhanced and its vertical configuration of tissue transfer enlarged by anastomosing the inferior epigastric artery and vein to their axillary counterparts.66 Flaps enhanced in this manner have been particularly useful in filling large anterior wall defects.

1/21/2008 3:36:01 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

1321

FIGURE 107-24 A TRAM flap being harvested to repair a radiation defect of the right anterior chest wall. Note that the flap is based on the left rectus abdominis muscle and that the distal transverse subcutaneous and cutaneous skin island is being transferred in continuity with the rectus muscle. (FROM SEYFER AE, GRAEBER GM, WIND GG: BLOOD SUPPLY TO THE SKIN OF THE CHEST WALL. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

FIGURE 107-25 A musculocutaneous flap based on the left rectus abdominis muscle has been completed and is ready for transfer into the thoracic defect in the right chest wall. Note that the muscle, the attached subcutaneous tissue, and the skin can all be transposed into the defect by rotation underneath the bridge of intact soft tissue on the upper abdominal wall. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE RECTUS ABDOMINIS MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1321

1/21/2008 3:36:02 PM

A

B

FIGURE 107-26 A, Planned reconstruction of the right breast using a left rectus abdominis TRAM flap. There is no associated radiation ulcer of the chest wall. B, The completed left rectus abdominis TRAM flap rotated up into the thoracic defect. The lower abdominal incision can then be closed with preservation of the umbilicus. The flap may be tailored to provide for adequate reconstruction of the breast. (FROM SEYFER AE, GRAEBER GM, WIND GG: RECONSTRUCTION OF THE BREAST FOLLOWING MASTECTOMY. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

A

B

FIGURE 107-27 A, The rectus abdominis myocutaneous flap may be used in reconstructing defects of the sternum and the dehisced median sternotomy as long as the ipsilateral internal thoracic vessels are intact. A longitudinal musculocutaneous flap has been fashioned for anterior wall reconstruction in this drawing. B, The completed longitudinal musculocutaneous flap ready to be rotated based on the superior epigastric vessels. The longitudinal flap will be laid into the defect and adjusted to the edges. The blood supply to the musculocutaneous flap must be scrupulously maintained. The viability of the internal thoracic artery for this type of reconstruction is absolutely mandatory. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE RECTUS ABDOMINIS MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

1322

Ch107-F06861.indd 1322

1/21/2008 3:36:03 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

The Latissimus Dorsi Muscle Pedicled muscular and musculocutaneous flaps based on the latissimus dorsi muscle have found wide application in chest wall reconstruction because this muscle has an extensive arc of rotation when the pedicle is based on the thoracodorsal neurovascular bundle (Fig. 107-28).67,68 When a latissimus dorsi muscular or musculocutaneous flap has been based on its primary blood supply, the flap can be used to cover defects on the anterior, lateral, and posterior aspects of the thorax.69 When the pedicle of a latissimus dorsi flap is based on its secondary blood supply (the ipsilateral 9th through 11th intercostal arteries and their perforators), the flap’s arc of rotation is more limited, and the flap is best suited for posterior intrathoracic applications.67 The primary blood supply to this large, flat muscle located on the posterolateral aspect of the chest wall is the thoracodorsal artery and its associated veins.70 In the vast majority of cases, the axillary artery gives rise to the subscapular artery, which divides to create the thoracodorsal artery and the

A

1323

artery or arteries to the serratus anterior muscle.70 In 74% of cadavers studied by Rowsell and coworkers,70 the artery to the serratus anterior was single; in 24% it was represented by two or more branches. The thoracodorsal artery, which is a direct extension of the subscapular artery in most cases, descends to the body of the latissimus dorsi, where it most commonly divides into two branches (Fig. 107-29). The more anterior branch descends parallel to the lateral border of the muscle; the medial branch usually traverses more horizontally in the body of the muscle. Both branches form collaterals with the secondary blood supply (the 9th through the 11th intercostal arteries and their perforators) in the body of the muscle. The blood supply to the latissimus dorsi has allowed some creativity with the primary pedicle. When the subscapular artery has been divided by previous surgery, a latissimus dorsi muscular or musculocutaneous flap may still be rotated by basing it on the continuity of the arteries from the serratus anterior muscle to the thoracodorsal.67,71 When the pedicle for rotation has been created in this fashion, the integrity of

B

FIGURE 107-28 A, Arc of rotation over the anterior chest for latissimus dorsi muscular and musculocutaneous flaps based on the thoracodorsal neurovascular pedicle. The tape measure depicts the length of the flap and its rotation when the posterior aspect of the tape is held against the anticipated pedicle. Note that this flap has a great ability to reconstruct defects in the lateral, anterior, and superior aspects of the chest wall. This flap is not recommended for covering defects in the region of the distal sternum and xiphoid process. B, The arc of rotation of the latissimus dorsi muscle when it is pedicled on the thoracodorsal neurovascular bundle. This muscular and musculocutaneous pedicle is the most useful one for covering defects of the posterior thoracic wall. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE LATISSIMUS DORSI MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

Ch107-F06861.indd 1323

1/21/2008 3:36:04 PM

1324

Section 5 Chest Wall and Sternum

FIGURE 107-29 Arterial supply to the latissimus dorsi based on the thoracodorsal artery. Note that the subscapular artery originates from the axillary artery. The subscapular artery divides into two branches: a branch that courses medially to the serratus anterior, and the thoracodorsal artery, which is the direct extension of the subscapular artery. Once the subscapular artery enters the latissimus dorsi muscle, it divides into a lateral and a medial branch. The dotted line represents the maximal domain of the cutaneous island that may be carried with this muscle. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE

FIGURE 107-30 If the patient has had a previous posterolateral thoracotomy incision, the distal portion of the latissimus dorsi muscle and any cutaneous elements that may overlie the muscle receive their blood supply from the secondary vessels that penetrate the lumbodorsal fascia. If the entire muscle were raised on a pedicle based on the thoracodorsal vessels, the distal portion of the muscle beyond the incision would undergo necrosis. Rotation of the entire muscle based on the thoracodorsal pedicle after a posterolateral thoracotomy incision is contraindicated. (FROM SEYFER AE, GRAEBER

LATISSIMUS DORSI MUSCLE AND MUSCULOCUTANEOUS FLAPS. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

GM, WIND GG: PLANNING THE RECONSTRUCTION. IN SEYFER AE, GRAEBER GM, WIND GG]: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

the arteries from the serratus anterior must be maintained scrupulously. As might be expected, the arc of rotation in this situation is more limited by the need to preserve the vessels to the serratus anterior. Some serious limitations to the use of latissimus dorsi muscular and musculocutaneous flaps based on the thoracodorsal pedicle have been found to exist.67,68 Previous radiation to the axilla can cause constriction of the thoracodorsal vessels, which limits blood supply and rotation. Probably the most common cause of this problem has been radiation to the chest wall and axilla during therapy for breast carcinoma.67 Another serious problem with use of a latissimus dorsi flap arises when a full posterolateral thoracotomy has been performed.67,68 Division of the muscle and the thoracodorsal vessels causes the distal part of the muscle to become

dependent on the secondary blood supply. If the entire muscle is raised as a flap based on the thoracodorsal vessels, the tissues distal to the scar undergo necrosis. Hence, the entire muscle can no longer be transferred to reconstruct chest wall defects or to repair intrathoracic problems such as bronchopleural cutaneous fistulas (Fig. 107-30). A number of authors have favored the use of musclesparing thoracotomies so that the blood supply to the latissimus dorsi and the serratus anterior is preserved. The necessity for muscle-sparing incisions is particularly apparent in the pediatric population.72,73 Despite these limitations, the latissimus dorsi pedicled muscular and musculocutaneous flaps have found wide appreciation for reconstruction of all types of chest wall defects.67,68 The use of these flaps in repairing posterior and spinal defects

Ch107-F06861.indd 1324

1/21/2008 3:36:05 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

1325

FIGURE 107-32 The omentum enjoys a dual blood supply, which is based on the right and left gastroepiploic vessels. This drawing represents the arcades that are usually found in the omentum. The main arterial arcade runs along the greater curvature of the stomach and is continuous between the right and left gastroepiploic arteries. There are usually two secondary arterial arcades that descend into the omentum. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE OMENTUM. FIGURE 107-31 The arc of rotation of the omentum is quite large when the pedicle is based on the epiploic vessels. This shows the potential realm of application for the omentum in reconstruction of chest wall defects. The omentum is particularly useful in treating contaminated and infected defects of the anterior and lateral chest wall. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE OMENTUM. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

is well recognized.69 Even though radiation may have been applied to the axilla in treating mammary or other malignancies, these flaps may still be used quite effectively in breast reconstruction, closure of defects secondary to resection of radiation-induced chest wall necrotic tissue, and reconstruction of the axilla.74 This musculocutaneous flap may have its capacity for closing defects enhanced by tissue expansion.75

Omentum The omentum may be used in chest wall reconstruction. It has tremendous ability to reach all portions of the anterior and lateral chest wall as well as both pleural spaces.19,20 Indeed, the omentum has been lengthened so that it has been used to repair cervical and cranial defects as well (Fig. 10731). It has the distinct asset of being able to contain infection well. Since the omentum has no dermal covering, it must be covered to achieve cutaneous continuity; probably the most efficacious method of doing so is application of a meshed, split-thickness skin graft. When the mesh remains small, the continuity of the skin graft follows promptly and provides for a smooth surface.

Ch107-F06861.indd 1325

IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

The blood supply of the omentum is based on the right and left gastroepiploic arteries and veins.76 These vessels create a continuous arcade, which runs along the greater curvature of the stomach. A pedicled flap may be created that is based on either the right or the left gastroepiploic artery or on both. The caliber of the right and left gastroepiploic arteries may vary from individual to individual. One artery may be larger than the other and therefore may be more suitable as a pedicle on which to base an omental flap. The omentum in any given individual is subject to variation of the blood supply. The most common anatomic variation has two arcades that are continuous with one another (Fig. 107-32). The omentum may be lengthened by judicious division of the arcades (Fig. 107-33).77 Great care should be taken to maintain pulses distally in the omentum when the arcades are divided. Appropriate blood supply may be maintained by testing with a Doppler ultrasound device before the division of any of the arcades. The point of division of each of the arcades should be occluded by soft vascular clamps before the actual division. If the pulse remains good distal to the anticipated points of division, there is a high probability that the distal portion of the omentum will remain viable. The blood supply to the omentum also allows free flap transfer to new positions to achieve soft tissue coverage and repair. The omentum has been used as a free flap to cover defects on the extremities or on the head and neck and to repair intrathoracic problems such as bronchopleural fistu-

1/21/2008 3:36:07 PM

1326

Section 5 Chest Wall and Sternum

FIGURE 107-33 One of the most beneficial aspects of the omentum is that it may be tailored to fit irregular defects and lengthened on the basis of the vascular supply. This drawing depicts one of the possible lengthening procedures based on the right gastroepiploic artery. Note that the entire omental arcade has been dissected from the stomach, which is cephalad. The secondary arcades have been divided so that there is continuity of blood flow throughout the omentum. Obviously, because there is variation in the arcades, a continuous pulse must be ascertained before dividing any one of the arcades. Use of fine vascular clamps and Doppler ultrasound allows precise division of these arcades with assurance of good distal arterial supply. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE OMENTUM. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

A

B

FIGURE 107-34 A, Arterial supply to the left serratus anterior muscle. The major arterial pedicle comes from the subscapular artery at the origin of the thoracodorsal. Other arteries enter the cephalad aspect of the muscle from the axillary artery. B, Because the serratus anterior is often spared in performing a posterolateral thoracotomy, this muscle may be used effectively in repairing bronchopleural fistulas after pulmonary resection. This line drawing depicts the use of the muscle developed on its primary blood supply arising from the subscapular artery. The muscle has been introduced into the chest through the second intercostal space. Portions of the second and/or third rib may be resected to facilitate transposition of the muscle into the pleural space. As with all muscle transpositions, there should be no tension on the muscle itself or its primary blood supply.

Ch107-F06861.indd 1326

1/21/2008 3:36:08 PM

Chapter 107 Chest Wall and Sternum Resection and Reconstruction

las.78,79 Unique aspects of its blood supply, its ability to contain infection, and its malleable nature have allowed creative transfer and sculpting of the omentum to fill complex defects. A number of liabilities may be associated with pedicled omental flaps when they are used for chest wall reconstruction.20,80 Previous abdominal surgery or abdominal infection may preclude use of the omentum. Gastric surgery, in particular, may have interrupted the arcades and may eliminate many possibilities for omental transfer. Previous infection may have caused so many adhesions that the omentum cannot be harvested without jeopardizing portions of it. The omentum can also be a channel for spreading infection from the chest to the abdomen; although this complication is rare, it has been documented.80 Finally, there is the ever-present complication of chest wall or diaphragmatic hernia associated with thoracic reconstruction using the omentum. The omentum has to be brought to the anterior chest wall through an epigastric hernia. Most often, an iatrogenic anterior defect has to be created in the diaphragm to allow the omentum to pass into either pleural space. Such defects offer the potential for herniation of abdominal viscera into the thoracic cavity. Obviously, an epigastric hernia may be filled with more than omentum as the healing process progresses. More recently, laparoscopic harvesting has been advocated to reduce such complication.81 Despite its liabilities, the greater omentum has been used to cover virtually all possible types of chest wall defects.80 It has been particularly helpful in repairing dehisced median sternotomies and in repairing radiation injuries to the chest wall.47,74 In such applications its ability to contain infection and to fill irregular defects has proved most useful.

Serratus Anterior The serratus anterior muscle has found some specific applications in thoracic reconstruction. The most common one is transposition into the thoracic cavity for control of bronchopleural fistulas.52 Because this muscle is often spared with a lateral or posterolateral thoracotomy, it may be transposed intact with its cephalad blood supply to close chest wall or intrathoracic defects. It has a rather limited arc of rotation because the pedicle must be based on the artery to the serratus anterior, which arises from the subscapular artery (Fig. 107-34). When the serratus anterior is introduced into the chest, the secondary blood supply, which consists of small arteries arising from the axillary artery and some perforators from the intercostals, must be transected. The muscle may be brought through an intercostal space; however, a portion of the second or third rib may be resected to facilitate intrathoracic transposition (see Fig. 107-34).

Trapezius Although posterior defects are generally infrequent, the trapezius muscle offers an option for closure of such defects. The muscle may be used in conjunction with the pedicled latissimus dorsi flap or may be used alone to cover selected defects. This musculocutaneous flap is most useful in covering defects around the shoulder, the suprascapsular region,

Ch107-F06861.indd 1327

1327

FIGURE 107-35 The trapezius muscle may be used to reconstruct defects in the region of the shoulder or the spine. Its limited domain of rotation includes the area of the scapula, the apex of the shoulder, and the vertebral region. It is an excellent muscle for closing small defects in these areas. It may be used alone or in addition to a latissimus dorsi flap. (FROM SEYFER AE, GRAEBER GM, WIND GG: THE TRAPEZIUS MUSCLE AND MUSCULOCUTANEOUS FLAP. IN SEYFER AE, GRAEBER GM, WIND GG: ATLAS OF CHEST WALL RECONSTRUCTION. ROCKVILLE, MD, ASPEN PUBLISHERS, 1986.)

and the perispinous region. It is usually rotated on the descending branch of the transverse scapular artery.20 The muscle also finds some limited use in correcting defects at the extreme apex of the pleural space (Fig. 107-35).

Acknowledgment The author would like to thank Ms. Nancy Myers for her excellent preparation of the manuscript. KEY REFERENCES McCraw JB, Arnold PG: McCraw and Arnold’s Atlas of Muscle and Musculocutaneous Flaps. Norfolk, VA, Hampton Press Publishing, 1986. ■ This is an excellent atlas that depicts the development and use of all the major pedicled flaps. Excellent dissections are provided to show the major aspects of constructing each flap, and the text is supplemented by clear photographic illustrations of all the flaps. Since most of the flaps were constructed on cadavers, the anatomic landmarks, blood supply, and individual characteristics of each flap are clearly depicted.

1/21/2008 3:36:10 PM

1328

Section 5 Chest Wall and Sternum

Seyfer AE, Graeber GM (eds): Chest wall reconstruction. Surg Clin North Am 69:142-145, 1989. ■ This monograph addresses all the major aspects of chest wall reconstruction. A number of authors who have contributed much to the field of thoracic reconstruction have written major chapters. The entire monograph is richly illustrated; the reference lists are extensive; and the text is clear and conveys all major points concerning chest wall reconstruction in a sequential fashion.

■ This atlas specifically delineates the methods used in chest wall reconstruction. It

covers most aspects of chest wall reconstruction, starting from the evaluation of the patient and continuing through postoperative care. Major emphasis is placed on pedicled flap reconstruction and on specific problems afflicting the chest wall. The illustrations depict all the major steps necessary in each of the reconstructions cited.

Seyfer AE, Graeber GM, Wind GG: Atlas of Chest Wall Reconstruction. Rockville, MD, Aspen Publishers, 1986.

Ch107-F06861.indd 1328

1/21/2008 3:36:11 PM

chapter

108

SURGERY OF PECTUS DEFORMITIES John C. Kucharczuk Larry R. Kaiser

Key Points ■ Pectus excavatum is the most common of the congenital chest

wall deformities. ■ Pectus deformities result from abnormal costal cartilage growth. ■ Open repair techniques are modifications of the original Ravitch

technique differing only in the amount of cartilage removed and the stabilizing techniques employed. ■ The Nuss procedure is a minimally invasive procedure that relies on cartilage remodeling rather than resection.

The congenital anterior chest wall deformities encompass a wide variety of abnormalities. They range in severity from minor cosmetic defects to life-threatening conditions with cardiopulmonary compromise. Although the diagnosis is readily made by examination, the indications for and timing of surgical intervention remain debated in all but the most dramatic cases. Included among these abnormities are pectus excavatum, pectus carinatum, Poland’s syndrome, and sternal clefts.

PECTUS EXCAVATUM Historical Note The pectus excavatum deformity has been recognized for centuries. Surgical intervention, however, did not enter into the picture until the early 20th century. The first reported surgical repair was performed by Meyer in 1911.1 Shortly thereafter, the famed German thoracic surgeon Ferdinand Sauerbruch reported a cohort of children in whom he had resected the rib edges and elevated the sternum with external silk traction sutures suspended above the bed.2 In 1939, DeBakey and Ochsner theorized that the causative factor in the development of pectus excavatum was abnormal cartilage growth.3 Although, the underlying molecular mechanisms involved in the development of this deformity are not understood, it is clearly an abnormality of cartilage growth rather than sternal bone development. Based on this concept, Dr. Mark Ravitch of Johns Hopkins Hospital described a detailed operative procedure for correction of pectus excavatum in 1949 (Ravitch, 1949).4 The main tenet of the Ravitch operation was resection of all involved costal cartilages including the perichondrium, a transverse sternal osteotomy with overcorrection of the deformity, and fixation of the sternum in the corrected position. Ravitch described the use of both Kirschner wires placed through the body of the sternum and suture for sternal stabilization. Presently, all open corrective

procedures for pectus excavatum are some type of modification of the original Ravitch procedure. The most commonly applied modification is that proposed by Baronofsy5 and Welch6 that emphasize preservation of the perichondrium during resection of the costal cartilages. Various sternal stabilization techniques have also been described. These include the use of a retrosternal bar7 or Marlex mesh8 and application of modern orthopedic fixation plates with screws. In 1998, Donald Nuss presented a 10-year experience with a minimally invasive technique he had developed for the correction of pectus excavatum deformities in children (Nuss et al, 1998).9 The Nuss procedure involves the percutaneous placement of a temporary U-shaped bar to elevate the sternum. The technique differs radically from the open technique in that it relies on cartilage remodeling over time for success rather than cartilage resection. The majority of minimally invasive corrective procedures performed today represent some variation of the original Nuss procedure.

Background Pectus excavatum is the most common congenital anterior chest wall deformity seen in clinical practice. It is thought to occur in 1 of 400 live births,10 with a 5 : 1 male-to-female ratio.11 Although several familial cohorts have been reported, the majority of cases are sporadic and a genetic basis has not been established. This disorder is often accompanied by other congenital abnormalities. The incidence of associated musculoskeletal abnormalities in a series of 704 patients was 18%.12 Scoliosis is the most common associated abnormality and affects about 15% of patients. Concomitant congenital cardiac abnormalities also occur and should be considered for simultaneous correction when pectus repair is planned.13 The diagnosis of pectus excavatum is based on the clinical examination. It is characterized by a so-called funnel chest, and the severity of the deformity can be quite variable. Almost all of these defects are recognized within the first year of life. The deformity is well tolerated from a physiologic standpoint through childhood, and most patients are asymptomatic. During rapid growth phases the deformity becomes more pronounced. This is especially evident around puberty. Despite decades of study, no consistently reproducible cardiopulmonary measurements have documented preoperative impairment or postoperative improvement after surgical repair.14-16 Nevertheless, the literature is replete with reports of significant symptomatic improvement, both physically and psychologically after repair. The indications for open repair of pectus excavatum remain elusive. In our practice most candidates for open repair 1329

Ch108-F06861.indd 1329

1/21/2008 3:37:05 PM

1330

Section 5 Chest Wall and Sternum

present around puberty. Almost all patients are asymptomatic. A number of classification systems have been proposed to assist in grading the severity of the deformity and selecting patients for operative repair. The Congenital Heart Surgery Nomenclature and Database Project classifies deformities of less than 2 cm in depth as mild, those 2 to 3 cm in depth as moderate, and those greater than 3 cm as severe.17 No clearcut surgical recommendations based on this classification have been established. The most commonly used classification system is based on the mean severity index. The index is calculated by dividing the inner width of the chest at its widest point by the distance between the posterior table of the sternum and the spine. The measurements can be taken from either anteroposterior and lateral chest radiographs or a CT scan of the chest.18 A severity index score of greater than 3.2 suggests severe disease that should be corrected. Although these classification systems are useful when classifying and comparing among series of patients reported in the literature, we have not found them helpful in determining which patient to offer corrective surgery. At present, we offer repair to all patients with pectus excavatum who present with pain, perceived exercise intolerance, or dissatisfaction with appearance, although insurance coverage frequently is the deciding factor for many because many carriers view this procedure as cosmetic as opposed to reconstructive. The optimal age for correction of pectus excavatum also remains unclear. Corrective procedures involving cartilage resection are clearly easier in children between 2 and 5 years of age, but concern exists over subsequent malformation of the chest wall with resultant chest wall constriction.19,20 Open repair in young children was far more common in the past, but the incidence of chest wall restriction has significantly decreased the performance of this operation in the

Skin incision

B

A Skin incision FIGURE 108-1 Incisions used for pectus repair. A, Inframammary incision. B, Vertical midline incision providing good exposure but an inferior cosmetic result.

younger age group. In general, open operative repair is offered to patients older than age 10 years.

Open Operative Repair We obtain anteroposterior and lateral chest radiographs for preoperative and postoperative comparison, but we do not routinely calculate radiographic indexes of sternal depression, finding them to have little use in clinical decision making. The diagnosis is confirmed on physical examination. Assessment of spinal curvature is also undertaken. Other associated conditions such as Marfan’s syndrome are ruled out clinically. The patient and the parents are counseled as to the details of the procedure and the expected outcomes. The open repair is performed under general anesthesia with the patient in the supine position. The arms are tucked

Elevation of pectoral flaps

3

4

To develop plane between pectoralis muscle and intercostal muscle

Right angle under pectoralis muscle

A

B FIGURE 108-2 A, Creation of pectoralis muscle flaps to provide exposure of the anterior surface of the costal cartilage. B, The use of small retractors to establish the appropriate plane between the pectoralis major and intercostal muscles.

Ch108-F06861.indd 1330

1/21/2008 3:37:05 PM

Chapter 108 Surgery of Pectus Deformities

Retracted pectoralis major

1331

Manubrium

2 Gladiolus 3 Divide cartilage junction over perichondrial elevator

4 Perichondrial incision 5

6

Xiphoid

7

A

B

Excise costal cartilage leaving growth plate

Bed of 3rd cartilage 2

3

4

C

4

D

FIGURE 108-3 Technique for subperichondrial resection of the costal cartilages from the third through seventh ribs. A, The dotted line demonstrates the intended incision through the perichondrium for subperichondrial resection. B, A small periosteal elevator is use to establish the plane between the perichondrium and costal cartilage. The cartilage is divided sharply with a knife. C and D, Once divided, the cartilage is grasped and removed from the perichondrial sheath.

Ch108-F06861.indd 1331

1/21/2008 3:37:06 PM

1332

Section 5 Chest Wall and Sternum

FIGURE 108-4 Costal cartilage resected during a routine modified Ravitch-type repair of a pectus excavatum deformity.

at the side. The procedure can be performed through a vertical midline or an inframammary transverse incision (Fig. 108-1). We prefer the inframammary incision because we believe it provides superior cosmetic results. In prepubescent girls care is taken to keep the incision in the inframammary folds to avoid disturbance of future breast development. Skin flaps are raised with electrocautery to the sternal notch superiorly, the anterior axillary line laterally, and the costal margin inferiorly. The pectoralis muscles are elevated off the sternum

and anterior chest wall with electrocautery and reflected laterally to expose the involved costal cartilages (Fig. 108-2A). All dissection is superficial to the intercostal muscles to avoid inadvertent entrance into the pleural cavity, especially in thin patients. The use of small retractors aids in establishing the dissection planes (see Fig. 108-2B). The pectus excavatum deformity usually spares both the first and second costal cartilages. The cartilage resection is begun at the level of the third costal cartilage with the intent to remove the abnormal cartilage in a subperichondrial fashion, leaving the perichondrial sheath relatively intact. The anterior perichondrium is scored with electrocautery as shown in Figure 108-3A. The edge of the perichondrial sheath is grasped with fine mosquito clamps. The plane between the perichondrium and costal cartilage is developed with a Freer perichondrial elevator (see Fig. 108-3B). Once both the superior and inferior edge of the perichondrium has been mobilized the cartilage is divided at its lateral aspect with a knife and removed. The cartilage division is facilitated and done more safely by passing a Matson periosteal elevator posterior to the cartilage and cutting through the cartilage down to the elevator. A similar technique is used to remove all remaining abnormal costal cartilages bilaterally down through the costal margin (see Fig. 108-3C). The costal cartilages removed during a routine open pectus excavatum repair are shown in Figure 108-4. Once the costal cartilage resection is complete, the xiphoid process is excised from the lower edge of the sternum. A bone hook is used to elevate the lower sternum, allowing establishment of the retrosternal space (Fig. 108-5). This is

Osteotome

Osteotomy Retract lower sternum upward and forward

5 6 7

Retrosternal space

2

3

Wedge osteotomy

2

3

Divide xiphoid 4

4

Rectus sheath

FIGURE 108-5 The xiphoid process is divided, and the tip of the sternum is elevated. The thin attachments to the pleural reflections and the pericardium are gently swept away. Care is taken to avoid entrance into either pleural space. When the pleural cavity is entered, the resultant pneumothorax can often be aspirated through a red rubber catheter; tube thoracostomy usually is not required.

Ch108-F06861.indd 1332

FIGURE 108-6 A wedge osteotomy is created in the anterior table of the sternum. The posterior table is gently fractured but not separated from the rest of the sternum.

1/21/2008 3:37:07 PM

Chapter 108 Surgery of Pectus Deformities

1

1

2

2

Closure

3 4

3 4 5

5

6

6

7

7 30°–35°

Before

After

FIGURE 108-7 The sternum is rotated anteriorly into a slightly overcorrected position, a move that is allowed by the newly created wedge osteotomy.

1333

accomplished by gently sweeping away the pericardium and pleural membranes. An anterior wedge osteotomy is performed on the sternum between the insertion of the second and third costal cartilages. The osteotomy violates only the outer table of the sternum. Gentle upward pressure is applied to the distal end of the sternum to provide anterior sternal rotation (Fig. 108-6). The sternum is overcorrected, as shown in Figure 108-7, because reapproximation of the pectoralis muscle results in attenuation of the correction angle. A number of sternal fixation techniques have been reported. These include use of a temporary retrosternal strut, the socalled pectus bar (Fig. 108-8A). This technique is probably the most common technique employed in clinical practice. We prefer the use of modern orthopedic fixation techniques with microfragment stainless steel or titanium plates and screws (see Fig. 108-8B and C). Unlike traditional pectus bars the plates do not require removal and have not broken or migrated. We believe they provide more stable fixation, allowing for earlier mobility and return to activity. If there is a significant rotational component to the lower part of the sternum it can be de-rotated. This is accomplished by making a full-thickness osteotomy across the lateral 50% of the sternum, de-rotating it, and then plating it in place to provide stabilization and fixation.

Plate fixation 2 3 4 5

B

A

FIGURE 108-8 Various sternal fixation/stabilization techniques have been developed. A, The pectus bar is probably the most commonly used method in clinical practice. It is a temporary strut and requires removal. B and C, Use of a stainless steel or titanium fixation plate. The plate is shaped in the operating room with a bender to provide a semicustom fit. The plate provides excellent stabilization and fixation and does not require removal. It has become our preferred method of stabilization.

Ch108-F06861.indd 1333

C

1/21/2008 3:37:08 PM

1334

Section 5 Chest Wall and Sternum

Pectoralis major muscle approximated over sternum

Complete closure of rectus sheath to pectoralis muscle

B

A

C

D

FIGURE 108-9 A, The rectus muscles are reattached to complete the repair. The skin is closed with a subcuticular suture. B, Completed repair. Anteroposterior (C) and lateral (D) postoperative chest radiographs. Note the fixation plate in good position.

The pectoral muscles are brought together in the midline with running 0 Vicryl suture. The rectus sheath is secured to the inferior aspect of the pectoralis muscle with interrupted 0 Vicryl sutures (Fig. 108-9A). A No. 10 Jackson-Pratt drain is brought out through the skin and placed under the skin flaps. The remaining portions of the wound are closed in layers. The skin is closed with a subcuticular stitch. Figure

Ch108-F06861.indd 1334

108-9B shows the completed repair. Figure 108-9C and D shows the postoperative chest radiograph with the microfixation plate in good position. Fonkalsrud and colleagues reported on their experience with open repair of pectus excavatum involving minimal cartilage resection.21 The technique again involves extensive modification of the technique described by Ravitch and

1/21/2008 3:37:09 PM

Chapter 108 Surgery of Pectus Deformities

FIGURE 108-10 The Nuss procedure is performed by creating a tunnel between the anterior pericardium and the point of maximal sternal depression. The sternal bar is passed through the tunnel with its convexity pointing posteriorly. The passage is facilitated and made safer by passing it under direct vision using the videothoracoscope.

begins with the elevation of skin flaps and reflection of the pectoralis muscles. Small pieces of cartilage (~5 mm) are removed adjacent to the sternum from the involved levels of cartilage. Another small piece of cartilage is removed from each level laterally just near or beyond the costochondral junction. Care is taken to preserve the perichondrium at each location where cartilage is resected. The xiphoid and lower two perichondrial sheaths only are detached from the lower sternum, with the other sheaths remaining attached. The retrosternal space is mobilized for 4 to 5 cm, and the right pleural space intentionally is opened for drainage. A transverse wedge osteotomy is made across the anterior table of the sternum at the level where the sternum is depressed posteriorly and the posterior table is fractured. A stainless steel strut is placed posterior to the sternum and the costal cartilages and used to elevate the sternum and anterolateral chest to the desired level. The strut is attached to the rib with wire. The sternal bar is removed in a second procedure approximately 6 months after the repair.

Minimally Invasive Repair The minimally invasive repair was popularized in children by Dr. Donald Nuss. His procedure forms the basis of minimally invasive repair techniques. The hallmark of the Nuss procedure is that it does not require cartilage incision or resection. Correction of the cartilaginous growth abnormalities are achieved by remodeling over time. This is accomplished by the minimally invasive implantation of a semi-customized bar to forcefully move the sternum into a normal anatomic position. Nuss originally applied his technique to children younger than 15, although older patients now are being offered this procedure as well. The Nuss procedure is performed with the patient under general anesthesia and placed with the arms extended. A Lorenz tunneler (Walter Lorenz Surgical, Inc., Jacksonville,

Ch108-F06861.indd 1335

1335

FIGURE 108-11 The sternal bar is flipped so that the convexity now points anteriorly, moving the depressed sternum to a normal anatomic position.

Bar attached to rib

FIGURE 108-12 The Nuss procedure is completed by securing the bar laterally to a rib on each side to prevent migration. The small skin incisions are closed.

FL) is inserted through a small lateral incision and passed either blindly across the mediastinum or with videothoracoscopic guidance to create a tunnel. The tunnel is positioned behind the sternum and anterior to the heart at the point of maximal sternal depression. The tunneler is brought out through a lateral incision on the other side. An umbilical tape is pulled back through the tunnel and used to guide the insertion of a convex bar. The bar must be customized to each individual chest by making a series of small bends from the center of the bar outward. The customized bar is guided through the tunnel by the umbilical tape with the convexity facing posteriorly (Fig. 108-10). Once in place the bar is rotated 180 degrees with the aid of a Lorenz flipper, which results in anterior movement of the sternum (Fig. 108-11). Later, crosspieces are attached and the structure is secured to the soft tissue to avoid bar migration. The completed procedure is depicted in Figure 108-12. The most commonly

1/21/2008 3:37:10 PM

1336

Section 5 Chest Wall and Sternum

TABLE 108-1 Complications With the Nuss Procedure for Pectus Excavatum Repair in 322 Patients Complications

No.

% of Total

Pneumothorax Spontaneous resolution Needle aspiration Chest tube Percutaneous catheter drainage

24 11 4 1* 8

7.5

Bar displacement Major (flipped bar) Minor

11 4 7(3)†

3.4

Wound seroma

10

3.1

Pleural effusion

8(1)

†

2.5

Pericardial effusion (pericarditis)

8(5)†

2.5

3

0.9

Pneumonia Hemothorax Cardiac perforation Total complications Early complications Late complications

3(3)

†

0.9

1

0.3

61 49 12

18.9 15.2 3.7

*Tension pneumothorax. † Late complication. From Park HJ, Lee SY, Lee CS, et al: The Nuss procedure for pectus excavatum: Evolution of techniques and early results on 322 patients. Ann Thorac Surg 77:289-295, 2004.

series have supported these open procedures as the gold standard producing acceptable results with very low complication and recurrence rates.23,24 Fonkalsrud and Mendoza reported on 275 patients operated on with their minimal cartilage resection procedure over a 3-year period (Fonkalsrud and Mendoza, 2006).25 All but 5 patients had results that were very good to excellent, and there were no major complications or deaths. The most common intraoperative complication from any of the open procedures is pneumothorax due to inadvertent entrance into the pleural cavity. Usually this is resolved with aspiration and a formal chest tube is not required. Common postoperative complications include wound infection and seroma formation. These almost always respond to conservative measures. The results for the Nuss procedure have also been excellent, with patient satisfaction rates as high as 95%26 and a low complication rate (Park et al, 2004) (Table 108-1).27 Initial application of the Nuss procedure was in the pediatric population; whether it has application in adults is unclear. Most of the major complications associated with the Nuss procedure occur early in reported series, suggesting a learning curve similar to that seen for other minimally invasive procedures. It is likely that children with symmetrical deformities will have excellent results with the Nuss procedure whereas older patients with asymmetric deformities probably benefit from undergoing an open repair.

PECTUS CARINATUM used modification of the Nuss procedure is the application of thoracoscopy to guide the creation of the substernal tunnel. This greatly reduces the chance of catastrophic cardiac injury. The bar usually remains in place for 1 to 2 years and then is removed during a short second surgical procedure. Whether this procedure is suitable for correction of pectus deformity in adults remains to be determined once the results of longer follow-up studies have been reported.

Prosthetic Reconstructions Patients with pectus excavatum are evaluated by a number of different specialists, including pediatric surgeons, thoracic surgeons, and plastic surgeons. Although addressing the underlying deformed cartilage remains the standard, a number of purely cosmetic techniques have been reported. These techniques center around the design, construction, and implantation of a custom-made solid silicone prosthesis. A plaster of Paris moulage of the deformity is made and used to manufacture the prosthesis. The prosthesis is placed into position via a remote lateral incision in a subpectoral pocket. This technique may be an alternative to corrective surgery in adults with mild deformities,22 but overall the cosmetic result is less acceptable than that achieved by a definitive correction.

RESULTS Open repairs based on modifications of the original technique as described by Ravitch provide excellent results. Several

Ch108-F06861.indd 1336

Pectus carinatum represents a collection of anterior chest wall deformities characterized by anterior projection of the sternum. The two most distinct types are chondrogladiolar (chicken breast), representing about 90% of carinatum deformities, and chondromanubrial (pigeon breast). Pectus carinatum is much less common than pectus excavatum. The etiology of the deformity is poorly understood, and the underlying molecular events leading to its development are unknown. Although pectus excavatum is usually diagnosed at birth, the diagnosis of pectus carinatum is made later, often at puberty. Most patients present for surgical consideration between the ages of 11 and 15 years. The initial operative repair for pectus carinatum was described by Ravitch in 1952 for correction of a chondrogladiolar carinatum deformity.28 The currently available techniques for open repair of pectus carinatum are modifications of the initial Ravitch procedure.

Operative Repair Because of the many variations of pectus carinatum, flexibility and an aesthetic eye are required for successful surgical repair. The procedure is performed with the patient under general anesthesia in the supine position with the arms tucked. We utilize a transverse inframammary incision with a slight upward orientation in the midline similar to that employed for excavatum repairs. Skin flaps are raised, and the pectoralis muscles are reflected to expose the costal cartilage. Limited subperichondrial resection of the costal cartilages is performed. In patients with pectus carinatum the

1/21/2008 3:37:11 PM

Chapter 108 Surgery of Pectus Deformities

1337

with a hypoplastic serratus and external obliques.32 Patients may also have absence of the anterior ribs, with lung herniation and a number of upper extremity abnormalities on the affected side. The syndrome is rare, with a reported incidence of 1 in 32,000 live births.33 The first surgical repairs were reported by Ravitch in 1952.34 The current indications for surgical intervention include psychological consideration due to the cosmetic defect, paradoxical chest wall movement with lung herniation, and unilateral breast aplasia in females.

deformity often involves the second costal cartilages as well as all inferior costal cartilages. Once all the deformed cartilage has been resected, an anterior wedge-shaped osteotomy is made with an osteotome. The size, shape, and orientation of the osteotomy depend on the type of carinatum deformity being corrected. To correct the symmetrical chondrogladiolar deformity, the most common type of pectus carinatum, a simple wedge osteotomy is made to allow for posterior displacement of the sternum (Fig. 108-13A). Most authors provide stabilization with a bar placed anterior to the sternum and anchored to the ribs laterally. We utilize a microfragment plate and screws to provide stabilization. For patients with asymmetric chondrogladiolar deformities, a triangular osteotomy is performed to produce depression of the sternum with rotation. Again, we prefer microfragment plates for stabilization. Finally, in patients with the chondromanubrial deformity a high, broad osteotomy is made (see Fig. 10813B).29 The procedure is completed with reapproximation of the pectoralis muscles and subcuticular skin closure over a closed suction drain.

Surgical Repair Procedures to correct Poland’s syndrome usually are performed in conjunction with a plastic reconstructive surgeon because of the concomitant breast abnormality. The precise steps of surgical repair depend on the nature of the defect and its severity. In children with lung herniation, especially girls, the chest wall defect is corrected early as a first stage, with split rib grafts (Fig. 108-14). A second operation is performed after the onset of puberty that includes breast reconstruction utilizing a variety of techniques, including prosthetic implantation and pedicled muscle transposition. In adults, correction is with a single-stage operation that includes repair of the chest wall defect with a polypropylene mesh and methylmethacrylate prosthesis, pedicled latissimus dorsi muscle transfer for soft tissue coverage, and creation of a breast in female patients.

Results The cosmetic results for pectus carinatum repair by a variety of modified Ravitch techniques currently used are excellent. Over 90% of patients report excellent results with little or no morbidity.30,31

POLAND’S SYNDROME

Results

Poland’s syndrome represents a variety of anterior chest wall anomalies all characterized by absence of the sternocostal head of the pectoralis major muscle. Poland’s 1843 description included the absence of the sternocostal portion of the pectoralis major muscle and absence of the pectoralis minor,

No large series exist to comment on the short- or long-term results. A review of 27 patients presents a good description of the variety of techniques used for reconstruction and the potential complications involved (Fokin and Robicsek, 2002).35

1

Wedge osteotomy

Osteotomy

1

2 1.5 cm 3

2 4

2 3

5 6

4

4

5 6

5 6

7

7

A

3

B

7

Overcorrection

°

35

FIGURE 108-13 Repair of pectus carinatum. A, The symmetrical chondrogladiolar deformity is corrected with an anterior wedge-shaped osteotomy. B, The less common chondromanubrial deformity is corrected with a high broad osteotomy through the fused sternal-manubrial junction.

Ch108-F06861.indd 1337

1/21/2008 3:37:11 PM

1338

Section 5 Chest Wall and Sternum

1

FIGURE 108-14 Split rib grafts are used for reconstruction of the chest wall agenesis with lung herniation in growing children with Poland’s syndrome. Female patients return after puberty for breast reconstruction. In adults with uncorrected Poland’s syndrome the entire procedure can be done in a single stage with prosthetic chest wall reconstruction, pedicle muscle flap transfer, and breast reconstruction when indicated.

1

2

2

3

4

3

Rib grafts

4 5

Harvest rib from contralateral side and split for grafts

5 6 6 7 7

CLEFT STERNUM Midline incision

Clavicle

Cleft sternal abnormalities are rare. In a large review from Argentina only 8 of 5182 patients (0.15%) with anterior chest wall malformations had a sternal cleft.36 The defect results from a failure of fusion of the sternal bars during the eighth week of development. It is evident at birth and is dramatically evident during crying. The skin, pericardium, diaphragm, and position of the heart are all normal. These features distinguish sternal clefts from the other rarer sternal defects, which include cervical ectopia cordis, thoracic ectopia cordis, and thoracoabdominal ectopia cordis.

1 2 3

4

Bifid sternum 5

Surgical Repair

6

Sternal clefts should be repaired in infancy because the flexibility of the newborn chest allows for primary closure. A midline incision is made over the length of the deformity. The posterior aspects of the sternal bars are freed from the endothoracic fascia by blunt dissection. In patients with a total cleft the sternal bars are brought together with nonabsorbable suture. In patient with a partial superior cleft, a wedge-shaped osteotomy at the inferior aspect of the defect assists in closure (Fig. 108-15).

A

7

Tevdek sutures or PDS Undermine

Results The surgical results for sternal clefts are gleaned from a number of small case reports and series. Daum and Zachariou report very good results in six patients undergoing surgical correction over a 34-year period.37 In this series the patients underwent correction between the first hour of life and 4 weeks.

SUMMARY As a group, the congenital chest wall abnormalities constitute a broad range of pathology. Demonstration of physiologic

Ch108-F06861.indd 1338

± Wedge

B

C

FIGURE 108-15 Technique for repair of sternal cleft. A, A midline incision is used. B, The sternal bars are mobilized from the underlying endothoracic fascia. C, The sternal bars are reapproximated in the midline. PDS, polydioxanone sutures.

1/21/2008 3:37:11 PM

Chapter 108 Surgery of Pectus Deformities

impairment caused by these defects is difficult except in very extreme cases. A number of surgical techniques, as outlined in this chapter, are available to provide correction with acceptable cosmetic outcome.

1339

repair versus observation without repair need to be carried out to clarify these issues. J. D.

KEY REFERENCES

COMMENTS AND CONTROVERSIES The authors have provided the readers with an excellent overview of the surgical options and results for pectus deformities. The minimally invasive procedures such as the Nuss, appear promising, and the short-term results are encouraging that similar outcomes may be achieved without open surgery in selected cases. One area of significant controversy is the pathophysiologic negative impact of some of these deformities and objective documentation of this versus the obvious cosmetic and self-mage impact on psychosocial development. In my practice I continue to have insurance carriers who deny these procedures. Further research and clinical outcomes both on the physiologic effects and psychosocial impact of surgical

Ch108-F06861.indd 1339

Fokin AA, Robicsek F: Poland’s syndrome revisited. Ann Thorac Surg 74:2218-2225, 2002. Fonkalsrud EW, Mendoza J: Open repair of pectus excavatum and carinatum deformities with minimal cartilage resection. Am J Surg 191:779-784, 2006. Nuss D, Kelly RE, Croitoru DP, et al: A 10-year review of a minimally invasive technique for the correction of pectus excavatum. J Pediatr Surg 33:545-552, 1998. Park HJ, Lee SY, Lee CS, et al: The Nuss procedure for pectus excavatum: Evolution of techniques and early results on 322 patients. Ann Thorac Surg 77:289-295, 2004. Ravitch MM: The operative treatment of pectus excavatum. Ann Surg 129:429, 1949.

1/21/2008 3:37:12 PM

chapter

109

COMPLICATIONS OF PECTUS DEFORMITY REPAIR Francis Robicsek Alexander A. Fokin Larry T. Watts

Key Points ■ Specific complications of pectus deformity repair may be divided

■

■

■

■

■

■

■

into (1) acute life-threatening conditions resulting from injury to the heart and great vessels and (2) residual/recurrent deformities caused by inadequate surgical repair. Preexisting conditions, such as disposition to keloid formation, scoliosis, and congenital cardiac or pulmonary abnormalities, as well as a detailed family history together with genetic counseling, should be carefully evaluated before surgical correction of pectus deformities. Careful planning of the timing of the procedure and method of surgery, along with prolonged sternal support, should be exercised in patients with pectus deformities associated with connective tissue disorders, such as Marfan’s syndrome. Simultaneous aortic surgery and pectus deformity repair in such patients could be considered. To prevent the development of acquired restrictive thoracic dystrophy, the extirpation of deformed cartilages, as well as substernal suturing of the rib’s perichondrium, should be avoided, especially in young patients. During resection of deformed rib cartilages, the growth centers at the costochondral junctions should be spared to allow further growth of the thorax. The synovial joints at the sternochondral junctions should also be spared to allow mobility of the anterior chest wall. Surgical experience and familiarity with different techniques should allow adequate correction of deformities at any age, even in cases in which there is no functional impairment, but repair is done in order to prevent future psychological distress. In older patients, especially those with severe and asymmetric deformities, a surgical correction that includes resection of the rib cartilages is more appropriate. The diagnosis of pectus excavatum should take into account the degree of the concavity, asymmetry, and progression, and should be distinguished from other congenital chest abnormalities, such as Poland’s syndrome or Pouter pigeon breast.

Surgical trials to treat pectus excavatum began as early as 1911, when Meyer attempted to correct congenital sternal depression by sternocostal resection.1 However, surgical treatment of this deformity became popular only after Ravitch in 1949 and our group in the 1960s recognized the pathophysiologic features of this disease and laid down the basic principles of surgical correction.2-4

Although these original techniques are still practiced by many, a plethora of new methods—most of them based on modification of the same techniques—have also been introduced. As it usually happens, new operations led to new complications, some of which were never before seen. These complications ranged from support-rod dislodgement to acquired restrictive thoracic dystrophy and, last but not least, so-called true recurrence of the previously existing anomaly. More often than not, these complications were directly linked to particular faults in the technique of surgical repair. The purpose of this chapter is to discuss the cause, prevention, consequences, and treatment of these iatrogenic conditions. Postoperative complications that are not specific to pectus deformity repair, such as incisional site infections, are not included in this chapter. Complications occurring after pectus deformity repair can be classified as shown in Box 109-1.

INJURY TO THE HEART AND GREAT VESSELS Although intraoperative penetration of the heart by metal rods may occur in the course of the Nuss procedure (Moss et al, 2001; Park et al, 2004),5,6 cardiac or aortic injuries after Ravitch-type repair are more likely to happen postoperatively due to migration of the metal support.7-9 The addition of thoracoscopy to the Nuss operation and improvements in introducer design, as well as extrapleural submuscular bar placement using bilateral thoracoscopy, may reduce the chance of such an event (Nuss, 2005).5,10,11 Concerns have also been raised about the potential difficulties in cardiopulmonary resuscitation after the Nuss procedure in patients who still have a transverse steel bar inside their thorax. The standard anterolateral positioning of defibrillator paddles places them close to the metal bar and results in diversion of the current from the myocardium, thus reducing the chances of successful defibrillation.12 The effectiveness of chest compressions is also of concern because of the rigidity and convexity of the metal bar. Current recommendations include appropriate identification of these patients, anteroposterior placement of the defibrillation paddles, and consideration of early internal cardiac massage.12

RESIDUAL DEFORMITY Residual deformity is usually the result of inadequate cartilage resections (in length or number) or, less often, insufficient sternal support. The condition is identified more often than not at the end of the surgical correction. Even in cases

1340

Ch109-F06861.indd 1340

1/21/2008 3:37:55 PM

Chapter 109 Complications of Pectus Deformity Repair

1341

Box 109-1 Complications After Pectus Deformity Repair Injury to the heart and great vessels Residual deformity Sternal rotation Acquired pectus carinatum Pneumothorax and/or hemothorax Asymmetry and/or retarded growth of the breasts Specific wound complications Floating sternum Sternal sequestration Keloid formation Psychological effects Peri-incisional numbness/pain Dislodgement or fracture of the substernal rods Allergy to metals Pericarditis-like syndrome Acquired thoracic scoliosis Thoracic outlet syndrome True recurrence of the pectus deformity Acquired restrictive thoracic dystrophy

FIGURE 109-1 Lateral radiograph of a patient after minimally invasive repair of pectus excavatum. The retrosternal bar fails to hold the sternum in the appropriate position. There is visible depression of the sternum.

in which the deformity is limited, it is advisable to be radical rather than conservative; otherwise, it may easily happen that, after the closure of the skin or, even worse, during the first postoperative visit, it will become apparent that part of the deformity is left uncorrected. It is a good practice to pull the skin edges temporarily together after correction of the anomaly and cast a critical look to see whether additional corrective steps are required before permanent closure of the skin is undertaken. Naturally, a residual deformity may occur after the Nuss procedure if the substernal rod fails to raise the sternum to the appropriate height (Fig. 109-1).

STERNAL ROTATION Congenital malrotation of the sternum along its axis, which is usually clockwise and involves more the sternal body than the manubrium, is common in asymmetrical chest deformities. If such malrotation is not addressed during surgery, it could worsen considerably afterward.6 After cartilage resection, malrotation may be corrected by deepening the transverse sternotomy on the depressed side, manually twisting the sternum away from the depression, and securing the corrected sternal position with a figure-of-eight suture (Fokin and Robicsek, 2005; Robicsek, 2000; Robicsek and Fokin, 1999) (Fig. 109-2).13-16 Sternal malrotation may also be caused entirely by the surgery itself. This usually occurs in patients with asymmetrical pectus carinatum when the surgeon performs extensive costochondral resection on the involved side, but leaves the cartilages intact on the so-called normal side. In such a situation, the cartilages on the nonresected side may push the sternum anteriorly and create a unilateral protrusion (Fig. 109-3).17 This can be readily prevented or corrected by performing a conservative cartilage resection on the contralateral normal side, as well.

Ch109-F06861.indd 1341

FIGURE 109-2 Correction of sternal rotation with figure-of-eight suture. (FROM FOKIN AA, ROBICSEK F: MANAGEMENT OF CHEST WALL DEFORMITIES. IN FRANCO KL, PUTNAM JB JR [EDS]: ADVANCED THERAPY IN THORACIC SURGERY, 2ND ED. HAMILTON, ONTARIO, BC DECKER, 2005, PP 145-162, WITH PERMISSION.)

1/21/2008 3:37:56 PM

1342

Section 5 Chest Wall and Sternum

ACQUIRED PECTUS CARINATUM

PNEUMOTHORAX AND HEMOTHORAX

Overcorrection of pectus excavatum may result in protrusion of the sternum. Such so-called acquired pectus carinatum could also be brought about by overbending the rods used for posterior support and further exaggerated by overzealous removal of costal cartilages. Because the anomaly is readily evident at the completion of surgery, it can and must be promptly and easily corrected by adjusting the rod to bring the sternum down to the appropriate level. This complication may also occur if external traction is applied using excessive force (Fig. 109-4). If the protrusion is significant and correction is delayed, the patient may require a full-fledged pectus carinatum repair, which may be difficult due to fibrosis, adhesions, and altered anatomy of the anterior chest wall.

Pneumothorax develops during dissection of the posterior surface of the sternum in about 2% to 18% of the patients18,19 in the course of Ravitch-type operations or during positioning of the retrosternal support bar in 3% to 52% of the patients during the Nuss procedure.6,10,19-21 Because of the anatomy of the thorax, this complication usually occurs on the right side. Residual pneumothoraces are usually small, but they may still require aspiration or placement of a chest tube. Hemothorax, occasionally seen after pectus repair, is most often caused by injury to the internal thoracic vessels and may be avoided by careful peristernal dissection and meticulous hemostasis. For obvious reasons, in patients with a history of pectus surgery for whom coronary bypass is planned, the patency of the internal thoracic arteries needs to be assured at the time of coronary imaging.

ASYMMETRY OR RETARDED GROWTH OF THE BREASTS

FIGURE 109-3 Asymmetrical pectus deformity repair. In a unilateral resection for correction of asymmetrical pectus deformity, the contralateral ribs may move the unrestrained sternum forward, creating a new deformity. (FROM ROBICSEK F: SURGICAL TREATMENT OF PECTUS CARINATUM. CHEST SURG CLIN N AM 10:357-376, 2000, WITH PERMISSION.)

A

Pectus excavatum is sometimes associated with asymmetrical and unequally developed breasts. This irregularity may become exaggerated after correction of the pectus deformity. Asymmetry of the nipples is easily corrected in the course of pectus repair with the use of a triangular skin plasty (Fig. 109-5).15 If inequality of the areolae is unsightly enough, the larger areola may be shared in a variety of ways, one of which is the use of an excised circumferential rim. If the patient has underdeveloped breasts, this may be addressed by breast augmentation after puberty. To prevent surgery-induced growth retardation of the breasts, a submammary skin incision outside the area of the

B

FIGURE 109-4 A, Patient with acquired pectus carinatum caused by overcorrection of pectus excavatum. Reduced and restricted thorax with protrusion of the anterior chest wall. B, Radiograph of the same patient showing protrusion of the distal sternal segments. (FROM FOKIN AA, ROBICSEK F: ACQUIRED DEFORMITIES OF THE ANTERIOR CHEST WALL. THORAC CARDIOVASC SURG 54:57-61, 2006. COPYRIGHT GEORG THIEME VERLAG KG STUTTGART, NEW YORK, WITH PERMISSION.)

Ch109-F06861.indd 1342

1/21/2008 3:37:56 PM

Chapter 109 Complications of Pectus Deformity Repair

1343

FIGURE 109-6 Mediastinal drainage in pectus excavatum repair is accomplished by deliberate connection of the retrosternal space with the right pleural cavity and insertion of a chest tube.

FIGURE 109-5 Correction of nipple asymmetry in the course of pectus excavatum repair (white arrow indicates the direction in which the breast will be repositioned). (FROM ROBICSEK F: SURGICAL TREATMENT OF PECTUS EXCAVATUM. CHEST SURG CLIN N AM 10:277296, 2000, WITH PERMISSION.)

developing breast is used in young female patients. Injury to gland tissue is to be avoided.

WOUND COMPLICATIONS A small skin incision, combined with the extensive dissection necessary to expose the sternum and adjacent cartilages, predisposes patients to accumulation of serum or blood under the flap of skin and muscle. This may occasionally lead to infection and could threaten the outcome of an otherwise successful surgical intervention. Insertion of drains under the flap will decrease, but certainly not eliminate, its occurrence. The most effective method of preventing such complications is to deliberately open the right pleura, connect the retrosternal space with the right thoracic cavity, and insert a chest tube (Fig. 109-6). Such transpleural drainage often yields 200 to 300 mL of blood in a 24- to 48-hour period, all of which otherwise might have accumulated in the mediastinum or underneath the flap. This simple step dramatically decreases the occurrence of various wound problems. Dermatitis and seroma may also develop at the sides of the chest after the Nuss procedure because of the continuous pressure by the support bar.6,10,22 Predisposing factors are the size of the stabilizer and slenderness of the patient. Infection, which may also develop at this site, is usually stubborn and

Ch109-F06861.indd 1343

FIGURE 109-7 Patient with local infection after minimally invasive repair of pectus excavatum. Notice the scar from the substernal bar placement and residual deformity.

requires surgical removal of the bar and drainage of the seroma (Fig. 109-7).

FLOATING STERNUM If the surgeon fails to provide adequate support to the sternum after bilateral resection of the costal cartilages and deep transverse sternotomy, the patient may end up with an abnormally mobile (floating) sternum. Detachment of the

1/21/2008 3:37:57 PM

1344

Section 5 Chest Wall and Sternum

perichondrial and intercostal strips of the sternum may also be a contributing factor. Such a situation may occur even if the surgeon provides substernal support, such as a metal rod, that, due to complications, is removed or dislodges in the early postoperative period. Although this situation is seldom life-threatening, the hypermobile sternum, which induces paradoxical respiratory movement, moves with every heartbeat, is often painful, is poorly tolerated by the patient and, more often than not, requires repair.23 This consists of reconstruction of the anterior chest wall, which includes mobilization of the sternum away from any fibrous adhesions, and the use of a bone graft, metal strut, or prosthetic mesh for substernal support. The chance of developing floating sternum may be decreased by limiting the extent of costal cartilage resection and by reattaching the perichondrial strips to the sternum.

STERNAL SEQUESTRATION In most methods for the repair of pectus deformities, the perichondrial and intercostal strips, which contain the principal sources of blood supply, are detached from the sternum. This creates sternal ischemia, which is further aggravated by a transverse osteotomy, which decreases the blood flow through the periosteum and the bone marrow. Sternal ischemia is especially severe in the sternal turnover procedure without vascular pedicle, in which the sternum is removed from the body, hammered flat, then turned over and reinserted.24 Surprisingly, sternal sequestration is rare even with this radical approach. This is in stark contrast to complications attributed to sternal ischemia after bilateral internal thoracic artery harvesting done in the course of coronary bypass operations. In such situations, vascular sternal necrosis may occur in diabetic obese patients25-27 (see Chapter 103). The treatment of vascular sternal necrosis includes removal of the sequestrated sternum and restoration of the anterior chest wall with Marlex mesh (Bard Inc., Cranston, RI), followed by pectoralis major muscle flap advancement. Such an operation may be safely performed even in the presence of a coexisting chronic infection.

with complaints of incisional pain. On closer questioning, such patients readily admit to a plethora of other symptoms, ranging from being short of breath to having extensive headaches, dissatisfaction with the length and appearance of the scar, and so on. Alleviation of these symptoms is always difficult and often impossible. If the tenderness is localized, one may inject the area with local anesthetics. In selected cases, psychological consultation may be appropriate. We recognize two principal forms of functional complaints after pectus repair. The juvenile form is manifested in late puberty. These patients typically are experiencing discord with their parents and complain of chest pain. Simple reassurance is often effective. The other form usually occurs in adults and represents projection of life frustration onto the surgery site. These patients usually have been operated on as young adults. For this reason, we recommend that, unless special circumstances exist, surgery is offered to adults only if the deformity is severe. If the deformity is moderate and the adult patient insists on correction for cosmetic reasons, the situation may be best handled by the use of Silastic implants.28,29

DISLODGEMENT OR FRACTURE OF SUBSTERNAL RODS Metal rods, placed behind the sternum for sternal support, are known to dislodge (Fig. 109-8). Kirschner wires are especially notorious for wandering to other body areas.30 There are also several reports of other metal supports that were retrieved after dislodgement only after having inflicted severe, life-threatening injuries to vital organs such as the heart or

KELOID FORMATION Keloids are most common when the repairs are performed via a vertical midline skin incision instead of a submammary transverse skin incision. Because the former violates Lange’s tension lines, it is less cosmetic and more likely to lead to keloid formation. Some patients, however, are keloid-formers and develop keloids regardless of the type of incision used. If the keloids are unsightly enough to disturb the patient, the services of a plastic surgeon may become a necessity.

PSYCHOLOGICAL EFFECTS Pectus deformities may have a crippling effect, not only physiologically, but also psychologically. A good number of patients undergo surgery for cosmetic reasons only, not to improve their functional state. In most of these individuals, repair of the unsightly deformity corrects the psychological problem. In some cases, however, the patient remains emotionally unstable and may present at the surgeon’s office

Ch109-F06861.indd 1344

FIGURE 109-8 Chest radiograph indicating dislodgement of the supporting rod after pectus repair. (FROM ROBICSEK F: SURGICAL TREATMENT OF PECTUS EXCAVATUM. CHEST SURG CLIN N AM 10:277296, 2000, WITH PERMISSION.)

1/21/2008 3:37:59 PM

Chapter 109 Complications of Pectus Deformity Repair

lungs.9 Remote injuries may also occur after migration of the rod into the abdominal cavity.31 Unnoticed injury to the left diaphragm during the Nuss procedure may result in an incarcerated diaphragmatic hernia.32 Appropriate fixation of the rods to the respective ribs with multiple, heavy, nonabsorbable sutures decreases, but certainly does not eliminate, the occurrence of such mishaps. To prevent this complication, the patient needs to avoid impact sports and any vigorous physical activities while the supporting bar is still in place.33 Dislodgement is especially common after the Nuss procedure. The incidence of such bar shifting ranges from 0.8% to 33%, with an average from 3.4% to 9.2% (Kim et al, 2005).6,10,20,34,35 The occurrence of this complication varies depending on the method of bar stabilization (e.g., threepoint fixation, lateral stabilizer), surgical experience, and patient selection, with the degree of the asymmetry and advanced age being important risk factors.22,35 Patients with retrosternal rods are monitored, not only clinically but also radiologically. In case of dislodgement, the rod is either reattached to the appropriate rib or removed if the anterior chest wall is sufficiently stabilized. Supporting struts may also fracture or become infected— events that obviously necessitate their removal.36-38 The most reliable method of prevention is to not apply such rods at all, but instead to use prosthetic mesh. In our practice, Marlex mesh provides substernal support superior to metal rods, with the added advantage of avoiding a second operation for rod removal.13,15,39,40

ALLERGY TO METALS Nickel allergy, especially if a steel bar is implanted for a long duration (currently recommended up to 4 years after a Nuss procedure), may result in rash and hyperesthesia. If topical steroids are ineffective, then removal, or replacement of the support made of nickel alloy with a titanium bar, is considered.10,20,22

PERICARDITIS-LIKE SYNDROME Pericarditis or pericarditis-like syndromes, which occur in 0.4% to 2.5% of the cases, are seen occasionally after minimally invasive pectus excavatum repair.6,34,41 They probably reflect inflammatory or autoimmune responses, and they manifest in fever, pericardial or pleural effusion, dyspnea, and chest pain.11 These symptoms usually respond to nonsteroidal anti-inflammatory medications; however, because of the tendency for recurrence, steroid therapy of 2 weeks or longer is most appropriate.42 In some cases, effusion drainage becomes necessary.

ACQUIRED THORACIC SCOLIOSIS Thoracic scoliosis is often present in patients with pectus excavatum. Worsening of a preexisting scoliosis or onset of a new one may occur after minimally invasive repair due to unbalanced pressure by the unresected, deformed cartilages on the chest wall and on the paraspinous muscles.22,43 For obvious reasons, evaluation and documentation of the thoracolumbar spine is performed before pectus repair in all patients.43

Ch109-F06861.indd 1345

1345

THORACIC OUTLET SYNDROME In rare cases, patients without preexisting positional abnormalities of the first or second rib may develop thoracic outlet syndrome after pectus repair due to the additional displacement of the ribs. The symptoms are usually not severe and consist mainly of paresthesia in the upper extremities. This may occur after both Ravitch-type and Nuss procedures, but it may also occur as the result of hyperabduction of the arm during surgery.5,44 Patients usually respond to the removal of supporting rods and administration of anti-inflammatory medications. Minor signs of neurovascular compression caused by latent thoracic outlet syndrome are documented before pectus surgery.

TRUE RECURRENCE OF THE PECTUS DEFORMITY True recurrence of pectus excavatum is reported in about 5% of the cases, even after an initially successful surgical repair. In patients with connective tissue disorders such as Marfan’s syndrome, the recurrence rate could reach 10%.45,46 Some authors also believe that patients who are operated on at a very young age have a higher incidence of recurrence than those operated on in their teens or later.46,47 We do not follow such delaying tactics and believe that repair of pectus deformities may be safely carried out at any age without increasing the risk of recurrence, even in children 2 to 4 years old, provided the appropriate surgical technique is used. In fact, it is our preference to perform the repair before school age, when the chest wall is still pliable and its growth may be more easily directed toward normal. We have also found that psychological problems occur more frequently if the repair of the deformity is delayed until the patient reaches the teen years. Patients with Marfan’s syndrome and related anomalies demand special attention. They are tall, asthenic, and flatchested. In an effort to obtain acceptable long-lasting results and no recurrence, one must weigh the limitations imposed by their corporal build when considering the choice and extent of the surgical repair. In Marfan’s patients, surgery is preferably delayed until the teen years, when the chest is fairly well developed. The patient and the family need to understand that the surgery may bring the level of the sternum to that of the anterior chest wall, but it will not change the underlying flat-chestedness. Resection of the cartilages is conservative, and substernal (preferably mesh) support is implemented for a long duration. Simultaneous aortic surgery, if needed, may be safely carried out with pectus repair.48,49 The best way to avoid recurrence of pectus deformities, naturally, is prevention. Faulty initial repair, by inadequate resection of the deformed cartilages and failure to correct the sternal depression, cannot be disguised as recurrence. True recurrences are also caused by less than satisfactory stabilization of the sternum. We also have found that methods that do not provide posterior support to the sternum but rely on manipulation of the cartilages or intercostal strips—or, as in the classic Ravitch repair, on sutures of the sternal periosteum—are prone to recurrence (Ravitch, 1977).15,50 One

1/21/2008 3:37:59 PM

1346

Section 5 Chest Wall and Sternum

Marlex mesh

A FIGURE 109-9 The method we recommend for the repair of pectus excavatum involves subperichondrial bilateral resection of the deformed costal cartilages, transverse sternal osteotomy, detachment of the perichondrial and intercostal strips and the xiphoid process of the sternum, and bending of the sternum forward, with posteriorly applied Marlex mesh (Bard Inc., Cranston, RI) to support it in the correct position. (FROM FOKIN AA, ROBICSEK F: MANAGEMENT OF CHEST WALL DEFORMITIES. IN FRANCO KL, PUTNAM JB JR [EDS]: ADVANCED THERAPY IN THORACIC SURGERY, 2ND ED. HAMILTON, ONTARIO, BC DECKER, 2005, PP 145-162, WITH PERMISSION.)

must also provide support for a minimum of several months, until the sternum is permanently stabilized by the neo-growth of the anterior chest wall. Such stabilization may be accomplished by the use of various rods or, as we prefer, a nonabsorbable mesh (Fig. 109-9). Since the introduction of the mesh technique into our practice, we have all but eliminated recurrences.13,15,39 As far as pectus carinatum is concerned, substernal support is seldom, if ever, necessary (Figs. 109-10 and 109-11).14,16 Interventions for all forms of pectus deformities are complemented by pre-sternal suturing of the pectoralis major muscles (Fig. 109-12). If the recurrence is severe, one must start over and perform a full pectus repair. This may be complicated by the altered anatomy and the fact that the surgeon has to deal with a fibrous plate of newly formed ribs and cartilages. Resection

Ch109-F06861.indd 1346

B

C

FIGURE 109-10 In the repair of pectus carinatum, the axis of the sternum is corrected, without detaching the perichondrial and intercostal strips, by resecting a portion of the most distal part of the sternal body. (FROM FOKIN AA, ROBICSEK F: MANAGEMENT OF CHEST WALL DEFORMITIES. IN FRANCO KL, PUTNAM JB JR [EDS]: ADVANCED THERAPY IN THORACIC SURGERY, 2ND ED. HAMILTON, ONTARIO, BC DECKER, 2005, PP 145-162, WITH PERMISSION.)

of this parasternal plate is conservative. If the depression is limited to the sternum, one may choose the method of sternal halving—that is, dissect the sternum free, perform an axial sternotomy, and spread the two sternal halves, resting them on the parasternal plate (Fig. 109-13).51

ACQUIRED RESTRICTIVE THORACIC DYSTROPHY Patients with acquired restrictive thoracic dystrophy (ARTD), also known as acquired Jeune’s syndrome or acquired restrictive lung disease, usually seek medical attention in their early teens due to their underdeveloped and deformed chest and impaired respiratory function (Haller et al, 1996).52-54 Because both the pathogenesis and the clinical manifestations of Jeune’s syndrome are different, we prefer to term this condition ARTD.54 The history of patients with ARTD includes pectus excavatum repair at an early age (usually

1/21/2008 3:37:59 PM

Chapter 109 Complications of Pectus Deformity Repair

1347

Marlex mesh

A

B

FIGURE 109-12 Interventions for all forms of pectus deformity repair are complemented by pre-sternal suturing of the pectoralis muscles.

C

FIGURE 109-11 The repair of pouter-pigeon breast, in addition to the standard pectus excavatum repair, also includes a second transverse sternotomy and removal of the protruding angle of Louis. (FROM FOKIN AA, ROBICSEK F: MANAGEMENT OF CHEST WALL DEFORMITIES. IN FRANCO KL, PUTNAM JB JR [EDS]: ADVANCED THERAPY IN THORACIC SURGERY, 2ND ED. HAMILTON, ONTARIO, BC DECKER, 2005, PP 145-162, WITH PERMISSION.)

Pectoralis m usc le Rib

Reg en cartil erate age d

Stern

um

B

Ster

num

FIGURE 109-13 Repair of recurrent pectus excavatum. A, The lower third of the sternum is split, spread, and rested on the regenerated cartilaginous plate. B, A cross-sectional view of the anterior chest wall in recurrent pectus excavatum before surgery. C, A cross-sectional view of the anterior chest wall after repair of recurrent pectus excavatum. (FROM SANGER PW, ROBICSEK F, DAUGHERTY HK: THE REPAIR OF RECURRENT PECTUS EXCAVATUM. J THORAC CARDIOVASC SURG 56:141-143, 1968, WITH PERMISSION.)

C A

Ch109-F06861.indd 1347

1/21/2008 3:38:01 PM

1348

Section 5 Chest Wall and Sternum

Substernal tissue band

B

6th-7th Rib Level Left Right

a1 b1

C

D

FIGURE 109-14 Patient with acquired restrictive thoracic dystrophy 15 years after pectus excavatum repair. Note the reduced, restricted, and deformed thorax with postoperative scar and compromised posture. (FROM FOKIN AA, ROBICSEK F: ACQUIRED DEFORMITIES OF THE ANTERIOR CHEST WALL. THORAC CARDIOVASC SURG 54:57-61, 2006. COPYRIGHT GEORG THIEME VERLAG KG STUTTGART, NEW YORK, WITH PERMISSION.)

younger than 4 years) and progressive dyspnea. The chest is small, narrow, and sometimes keeled (Fig. 109-14). The anteroposterior diameter of the thorax is reduced, and it fails to expand during inspiration. Depending on the severity of the deformity, patients with ARTD have various degrees of dyspnea and difficulty in performing physical activities (Fig. 109-15). Pulmonary function studies reveal severe restrictive lung disease, with significant decreases in forced vital capacity and expiratory volume. Conventional radiography shows a deformed rib cage, often a recurrent pectus deformity, and an abnormally low diaphragm. On CT scan, retrosternal bone or cartilage neoformation can often be seen (Fokin and Robicsek, 2006) (Figs. 109-16 and 109-17).54,55 Patients with ARTD have poor posture, have obvious scars from previous surgery, and often are in need of psychological counseling. Faulty surgical technique without doubt plays a role in the causation of ARTD. By reviewing the literature on the subject and the data of patients we have personally observed, we found that in all cases surgery had been performed with the use of a modified Ravitch approach, in the course of which the costal cartilages, from the first rib down, were radically removed. The extent of the resection included the growth center at the costochondral junctions as well as the costosternal synovial joints. Often, the situation was further aggravated by suturing the left and right perichondrial strips together retrosternally, presumably to create a support for the mobilized sternum.55 This technique creates a nongrow-

Ch109-F06861.indd 1348

A

FIGURE 109-15 Anatomic representation of acquired restrictive thoracic dystrophy (ARTD). A, Three-dimensional view of ARTD. B and C, Reduced anteroposterior and transverse diameter of the thorax. Substernal cartilaginous-osseous growth. Compromised posture. Low-lying diaphragm. D, Narrow torso with absent cartilages. Diaphragmatic dome is flattened. (FROM FOKIN AA, ROBICSEK F: ACQUIRED DEFORMITIES OF THE ANTERIOR CHEST WALL. THORAC CARDIOVASC SURG 54:57-61, 2006. COPYRIGHT GEORG THIEME VERLAG KG STUTTGART, NEW YORK, WITH PERMISSION.)

FIGURE 109-16 Computed tomographic scan of a patient with acquired restrictive thoracic dystrophy (ARTD). Osseous tissue is seen behind the sternum. The thoracic cage is reduced and deformed. Arrows indicate osseous tissue. (FROM FOKIN AA, ROBICSEK F: ACQUIRED DEFORMITIES OF THE ANTERIOR CHEST WALL. THORAC CARDIOVASC SURG 54:57-61, 2006. COPYRIGHT GEORG THIEME VERLAG KG STUTTGART, NEW YORK, WITH PERMISSION.)

1/21/2008 3:38:03 PM

Chapter 109 Complications of Pectus Deformity Repair

A Main growth center

1349

Ca

rti

la

ge

Synovial joints

B

FIGURE 109-17 Computed tomographic scan of a patient with acquired restrictive thoracic dystrophy (ARTD) showing cartilaginous tissue behind the sternum. White arrows indicate cartilaginous tissue. (FROM ROBICSEK F, FOKIN AA: HOW NOT TO DO IT: RESTRICTIVE THORACIC DYSTROPHY AFTER PECTUS EXCAVATUM REPAIR. INTERACT CARDIOVASC THORAC SURG 3:566-568, 2004, WITH PERMISSION.)

ing and immobile thoracic cage and eventually leads to the syndrome we now know as ARTD. Because in all ARTD patients pectus repair was done at a very early age, it has been recommended that surgery is delayed until 6, 8, or even 12 years of age, until the thoracic cage fully develops.53,56 We disagree with this view for two reasons. First, overly radical resection not only harms the young child; it also adversely affects the respiratory function of the young adult. Second, as we have shown in a large number of cases, pectus repair may be safely performed at any age, even in patients younger than 3 years old, if it is done properly.13,15,57 Several operations have been designed to make the life of these patients more tolerable.53,58 These interventions are based on the principles of proposed surgical correction of asphyxiating dystrophy in newborns.59-61 The procedures of Webber and Haller were intended to enlarge the thoracic cavity. Webber’s technique consists of performing an axial sternotomy, spreading the sternal halves, and keeping them distant by placing segments of autologous ribs in between.58 The operation that was applied in 11 patients by Haller consisted of elevating the mobilized sternum and supporting it with metal splints.53 One may expect results obtained by these interventions to be moderate, at best. To prevent the development of ARTD, the two end quarters of the rib cartilages are left in place during cartilage resection. The spared growth center at the costochondral junction allows future enlargement of the thorax, and the preserved sternocostal synovial joints retain mobility of the anterior chest wall and reduce postoperative morbidity. Substernal suturing of the perichondrium of the lower ribs for posterior sternal support needs to avoided. In general, the resection of the cartilages should not be excessive. Removal of the second rib is rarely necessary (Fig. 109-18).55 Some limitations in mobility of the anterior chest wall may occur even if cartilage resections are performed correctly and

Ch109-F06861.indd 1349

C Internal thoracic vessels

D FIGURE 109-18 Possible mechanisms explaining how acquired restrictive thoracic dystrophy (ARTD) may develop after inappropriate pectus excavatum repair and technical considerations for surgical correction of pectus deformity. A, Deformed cartilages resected subperichondrially, preserving the costosternal synovial joints and growth centers at the costochondral junctions. B, Subperiosteal resection within bony parts of the rib with subsequent suturing of the segment in long resections. C, Perichondrium sutured together behind sternum. D, The excess length of perichondrium may fold and unite behind the sternum. (FROM FOKIN AA, ROBICSEK F: ACQUIRED DEFORMITIES OF THE ANTERIOR CHEST WALL. THORAC CARDIOVASC SURG 54:57-61, 2006. COPYRIGHT GEORG THIEME VERLAG KG STUTTGART, NEW YORK, WITH PERMISSION.)

the synovial joints at the sternochondral junctions are preserved.62,63 This moderate reduction of mobility does not decrease pulmonary function and by no means can be compared with the severe changes seen in patients with ARTD. Such anterior chest wall stiffness may also be seen after the Nuss procedure while the supporting bar or bars remain in place substernally (Fig. 109-19).

SUMMARY Complications of pectus deformity repair are an issue to be taken seriously for several reasons. Because most patients seek surgical attention for cosmetic or psychological reasons, the indication for surgical intervention is relative. In such a situation, mortality or even a high rate of morbidity is unac-

1/21/2008 3:38:05 PM

1350

Section 5 Chest Wall and Sternum

FIGURE 109-19 Radiograph of a patient after minimally invasive repair of the pectus excavatum. Notice the restriction of the lower chest by the bar and the formation of an abscess near the bar stabilizer.

ceptable. In addition, most, if not all, complications specific to pectus deformity repair are not random but are caused by identifiable features of the technique applied and are therefore preventable. For these reasons, it is important that a surgeon who is engaged in the practice of pectus surgery needs to be experienced enough to wisely choose among the technical modalities available and to apply them successfully.

COMMENTS AND CONTROVERSIES In this chapter, Dr. Robicsek and colleagues describe a variety of common and uncommon complications of pectus deformity repair. These highlight the fact that surgery needs to be restricted to patients with severe anatomic deformities that are causing cardiopulmonary dysfunction (a rare occurrence) and to those with significant cosmetic or psychological problems, which often become less significant as the patient grows older. Inadequate corrections or recurrences can generally be avoided if the surgeon has a clear understanding of the pathophysiology of pectus deformities, which in most cases are secondary to an overgrowth of the third to the seventh costal cartilages that pushes the sternum posteriorly (pectus excavatum) or anteriorly (pectus carinatum). Therefore, most repair techniques, especially in adults, must include the resection of such abnormal cartilages, and this resection must be done subperichondrially if one wants to allow the reconstitution of new ossified cartilage that will ensure long-term stability of the repair. As pointed out by the authors, pectus deformities are often asymmetrical, and one must avoid the temptation of leaving intact the cartilages located on the normal side because these untouched cartilages will pull the sternum posteriorly, allowing the

Ch109-F06861.indd 1350

corrected side to move anteriorly into a position sometimes worse than before. Another method recommended to ensure stability of the correction is to preserve the xiphoid and its attached rectus abdominis muscles. If a portion of the lower sternum needs to be resected, the xiphoid is resutured to the lower edge of the sternum. Two other common complications of pectus deformity repair are right-sided pneumothoraces, which can be avoided if one routinely drains the right pleural space, and hypertrophic scarring (keloid) of the skin incision. This latter complication is difficult to prevent, especially if one uses a small transverse skin incision, which requires that generous skin flaps be raised in an area with poor cutaneous vascular supply. If pectus deformities are associated with hypodeveloped or asymmetrical breasts, such as in Poland’s syndrome, we recommend that the chest wall deformity be corrected first, with the breast deformity addressed, if necessary, in a second procedure done at a later time. Metal rods that are sometimes used to support the sternum can become dislodged and lead to potentially life-threatening complications such as erosion of the aorta, heart, lung, or diaphragm. Obviously, such complications are unacceptable when the operation is done for cosmetic purposes. Special attention must therefore be given to the position of the steel bar and its proper fixation. More importantly, all patients with retrosternal rods should be radiologically monitored to verify the proper position of the rod. If the rod becomes dislodged, it is either replaced in its original position or removed. J. D.

KEY REFERENCES Fokin AA, Robicsek F: Acquired deformities of the anterior chest wall. Thorac Cardiovasc Surg 54:57-61, 2006. Fokin AA, Robicsek F: Management of chest wall deformities. In Franco KL, Putnam JB Jr (eds): Advanced Therapy in Thoracic Surgery, 2nd ed. Hamilton, Ontario, BC Decker, 2005, pp 145-162. Haller JA Jr, Colombani PM, Humphries CT, et al: Chest wall constriction after too extensive and too early operations of pectus excavatum. Ann Thorac Surg 61:1618-1625, 1996. Kim do H, Hwang JJ, Lee MK, et al: Analysis of the Nuss procedure for pectus excavatum in different age groups. Ann Thorac Surg 80:1073-1077, 2005. Moss RL, Albanese CT, Reynolds M: Major complications after minimally invasive repair of pectus excavatum: Case reports. J Pediatr Surg 36:155-158, 2001. Nuss D: Recent experiences with minimally invasive pectus excavatum repair: “Nuss procedure.” Jpn J Thorac Cardiovasc Surg 53:338-344, 2005. Park HJ, Lee SY, Lee CS, et al: The Nuss procedure for pectus excavatum: Evolution of techniques and early results on 322 patients. Ann Thorac Surg 77:289-295, 2004. Ravitch MM: Pectus excavatum. In: Congenital Deformities of the Chest Wall and their Operative Correction. Philadelphia, WB Saunders, 1977, pp 78-205. Robicsek F: Surgical treatment of pectus excavatum. Chest Surg Clin N Am 10:277-296, 2000. Robicsek F, Fokin AA: Surgical correction of pectus excavatum and carinatum. J Cardiovasc Surg 40:725-731, 1999.

1/21/2008 3:38:06 PM

chapter

110

SUPRACLAVICULAR APPROACH FOR THORACIC OUTLET SYNDROME Susan E. Mackinnon G. Alexander Patterson

Key Points ■ The supraclavicular approach allows direct visualization of the bra-

■ ■

■

■

■

■

chial plexus and, if necessary, the cervical or 1st rib can be safely excised. Loupe magnification, microbipolar cautery, and portable nerve stimulation are used. Care must be taken to remove all portions of the cervical or 1st rib from the spinal attachments to avoid regrowth of any remaining bony segments. At the end of the procedure, the pleura is opened to facilitate drainage of any postoperative bleeding to minimize the collection of blood at the operative site. A bupivacaine infusion pump is used to minimize postoperative pain at the incision site, and a Jackson-Pratt drain is used to eliminate any collection of blood in the region surrounding the brachial plexus. Range-of-motion exercises are started the first day following surgery and full range of motion is anticipated by the second postoperative week. Postoperatively, supervised physical therapy is often necessary to correct the problem of muscle imbalance in the cervicoscapular region.

Several approaches have been described for decompression of the brachial plexus and vascular structures in the region of the thoracic inlet, and major complications have been reported with all surgical approaches.1-4 We believe that the supraclavicular approach allows direct visualization of the brachial plexus and, if necessary, the cervical or 1st rib can be safely excised.5 In those few patients who fail to improve with conservative management and in the appropriately selected patient, we advocate a surgical decompression using the supraclavicular approach.6-9 The supraclavicular approach to relieve thoracic outlet syndrome by decompression of the brachial plexus and excision of the 1st rib releases structures that compress soft tissue in the region of the interscalene portion of the brachial plexus. The lower nerve trunk and C8 and T1 nerve roots can be completely identified and protected as the most posterior aspect of the 1st rib is resected under direct vision. Any cervical ribs or prolonged transverse processes are easily removed by this supraclavicular approach. Loupe magnification (×4.5) and microbipolar cautery are used, and a portable nerve stimulator (Concept 2, Clearwater, FL) is frequently applied throughout the procedure.

A sandbag is placed between the scapula and the neck and extended to the nonoperative side. Long-acting paralytic agents are avoided. An incision in a neck crease, parallel to and 2 cm above the clavicle, is made in the supraclavicular fossa (Fig. 110-1). The supraclavicular nerves are identified just beneath the platysma and mobilized to allow vessel loop retraction (Fig. 110-2). The omohyoid is divided and the supraclavicular fat pad is elevated, after which the scalene muscles and the brachial plexus are easily palpated (Fig. 110-3). The lateral portion of the clavicular head of the sternocleidomastoid is divided, and at the end of the procedure is repaired. The phrenic nerve is seen on the anterior surface of the anterior scalene muscle, and similarly, the long thoracic nerve is noted on the posterior aspect of the middle scalene muscle. The anterior scalene muscle is divided from the 1st rib. The subclavian artery is noted immediately behind this, and an umbilical tape is placed around the subclavian artery. The phrenic nerve is not mobilized (Fig. 110-4), but rather is simply avoided. The upper, middle, and lower trunks of the brachial plexus are easily visualized and gently mobilized. The middle scalene muscle is now divided from the 1st rib. It has a broad attachment to the 1st rib, and care must be taken to avoid injury to the long thoracic nerve, which in this position may have multiple branches and may pass through and posterior to the middle scalene muscle (Fig. 110-5). With division of the middle scalene muscle, the brachial plexus is easily visualized and mobilized, and the lower trunk and the C8 and T1 nerve roots are identified above and below the 1st rib (Fig. 110-6). Congenital bands and thickening in Sibson’s fascia are divided. The 1st rib is then encircled and divided where it is easily visible with bone-cutting instruments, and its posterior segment is removed back to its spinal attachments by rongeur technique (Fig. 110-7). By using a fine elevator, the soft tissue attachments to the 1st rib are separated. Finally, the posterior edge of the 1st rib is grasped firmly with a rongeur, and then a rocking and twisting motion is used to remove the entire aspect of the rib (Fig. 110-8), so that the cartilaginous components of its articular facets with both the costovertebral and costotransverse joints can be identified on the specimen (Fig. 110-9). The anterior portion of the 1st rib is removed in a similar fashion in order to decompress the neurovascular elements (Fig. 110-10). Cervical ribs or long transverse processes are removed by the same technique (Fig. 110-11). We use a technique described by Nelems to open the pleura, facilitating drainage of any postoperative blood collection into the chest cavity rather than allowing the blood to collect in the operative site 1351

Ch110-F06861.indd 1351

1/21/2008 3:38:53 PM

1352

Section 5 Chest Wall and Sternum

FIGURE 110-1

The surgical incision is made parallel to the clavicle.

FIGURE 110-2

The supraclavicular nerves are protected.

FIGURE 110-4 The phrenic nerve is protected, and the scalene anticus is divided. The subclavian artery can now be seen in its location behind the scalene anticus muscle.

FIGURE 110-3 The fat pad has been retracted to identify the phrenic nerve on the scalene anticus muscle and the long thoracic nerve exiting from the posterior border of the scalene medius muscle (blue vessel loop), with the brachial plexus noted in the interscalene position.

Ch110-F06861.indd 1352

1/21/2008 3:38:53 PM

Chapter 110 Supraclavicular Approach for Thoracic Outlet Syndrome

C8

1353

rib T1

FIGURE 110-5 The scalene medius muscle is divided from the 1st rib with care to protect the long thoracic nerve.

FIGURE 110-6 The upper portion of the brachial plexus is retracted to identify the 1st rib. T1 can be seen below the 1st rib.

FIGURE 110-7 The 1st rib is divided where it is easily visualized, and then the posterior and anterior aspects of the rib are removed. The relationship of T1 and C8 to the head of the 1st rib can be seen. C8

T1

FIGURE 110-8 The nerve roots are reflected anteriorly and, with a twisting motion using rongeurs, the posterior aspect of the 1st rib is removed. C8 and T1 are labeled.

Ch110-F06861.indd 1353

1/21/2008 3:38:56 PM

1354

Section 5 Chest Wall and Sternum

FIGURE 110-9 The entire posterior portion of the 1st rib is removed so that no residual 1st rib remains to produce new bone formation and subsequent recurrence of symptoms. The articular facets of the costovertebral and costotransverse joints are noted (asterisks).

FIGURE 110-10 The brachial plexus has been completely decompressed. The phrenic and long thoracic nerves have been protected (blue vessel loops).

*

A

B

FIGURE 110-11 A, Radiograph demonstrating a prominent transverse process on the right (asterisk) and a large cervical rib on the left. The pseudojoint noted in the cervical rib (single arrow) is a frequent finding. The cervical rib can be seen to articulate with the 1st rib (double arrow). B, Operative photograph corresponding to radiograph, demonstrating the relationship between the brachial plexus (BP) and the cervical rib (arrows). Note supraclavicular nerve retracted (asterisk).

around the brachial plexus. When the pleura is opened, care is taken to protect the intercostobrachial nerve, which is noted on the dome of the pleura. Bupivacaine (Marcaine) is injected into the wound, and a bupivacaine-filled pain pump (I-Flow Corporation, Lake Forest, CA) is also used. The wound is closed in a subcuticular fashion, and a simple suction

Ch110-F06861.indd 1354

drain is placed and sealed after wound closure and maximal inflation of the lungs by the anesthetist. Gentle range of motion is begun on the first postoperative day, the pain pump and drain are removed on the second or third postoperative day, and supervised physiotherapy is begun 2 weeks after surgery.

1/21/2008 3:38:58 PM

TRANSAXILLARY FIRST RIB RESECTION FOR THORACIC OUTLET SYNDROME (WITH DORSAL SYMPATHECTOMY)

chapter

111

Harold C. Urschel, Jr. Amit N. Patel

Key Points ■ The transaxillary approach for thoracic outlet syndrome (TOS)

is indicated primarily for nerve compression and venous obstruction. ■ For arterial reconstruction, the supraclavicular approach allows for proximal control of the subclavian artery. ■ Through the transaxillary approach, the 1st rib may be removed without retraction of the axillary-subclavian neurovascular structures, thus producing a lower incidence of injury. ■ The long-term results of the transaxillary approach for TOS are excellent when the 1st rib is completely removed, and this approach provides the best cosmetic result because the majority of patients are women.

When surgery is indicated for thoracic outlet syndrome (TOS), the transaxillary approach is employed for 1st rib resection to decompress the axillary subclavian vein in PagetSchroetter syndrome and to decompress the nerve structures for pain and neurologic deficit. The supraclavicular approach is reserved for arterial obstructions or aneurysms requiring proximal control of the subclavian artery for either bypass or resection. The posterior approach is indicated for reoperation in recurrent TOS. The advantage of the transaxillary approach is that the neurovascular structures are away from the 1st rib, so that it may be resected without retraction of these structures, thus minimizing the chance for injury.

HISTORICAL NOTE Clinical manifestations of TOS have been described since prerecorded history. One of the first cases is recorded in the Bible, in the book of Genesis, Chapter 22, Verse 1. Abraham was planning to sacrifice his son Isaac to prove his devotion to God. As Abraham raised the knife, an Angel of the Lord came to him and, with omniscient compassion, created an “acute thoracic outlet syndrome,” causing Abraham’s arm to become numb and weak. He dropped the knife, sparing Isaac, and forever ending human sacrifice in the Judeo-Christian religions. The earliest recorded references to TOS were the anatomic recognitions of cervical ribs by Galen and Vesalius. The first scientific study of cervical ribs reported in modern literature was published in a French journal by a German anatomist, Hunauld.1

Paget,2 in London in 1875, and von Schroetter,3 in Vienna in 1874, independently described thrombosis of the axillary subclavian vein in the area of the thoracic outlet. The occlusion of the vein is today called the Paget-Schroetter syndrome or effort thrombosis. In 1907, Keene4 reported 42 patients with TOS, 31 of whom were women who developed neurologic paresthesias (in two thirds) and vascular symptoms (in less than one half). He noted that trauma was the probable cause in certain cases. The term thoracic outlet syndrome was first employed by Peet and colleagues5 in 1956 and independently by Rob and Standeven6 in 1958. Various anatomic abnormalities, such as the scalenus anticus, costoclavicular, or neurovascular compression syndromes, were combined into a single term for the purpose of simplification, particularly because they can produce similar symptoms. The 1st rib was recognized as the common denominator against which the axillary subclavian artery and vein or brachial plexus were compressed by the variety of muscles, ligaments, or bone structures (Urschel, 2000).7 In 1962, O. T. Clagett8 presented in his presidential address to the American Association of Thoracic Surgery the posterior so-called high thoracoplasty approach for removal of the 1st rib in TOS. This provided a safe removal of the 1st rib and cervical ribs with minimal injury to the nerves. It had the disadvantage of dividing or splitting the trapezius and rhomboid muscles, producing increased morbidity. Subsequently, Roos,9 in 1966, described the transaxillary approach, following the technique of Atkins10 and Palumbo11 for transaxillary sympathectomy. This procedure was revised by Urschel (Urschel, 1999).12 Neurophysiologic testing was initiated by Caldwell, Crane, and Krusen13 in the 1960s and reported in 1970s.14 They measured nerve conduction velocities across the outlet in the median, ulnar, and musculocutaneous nerves. Conduction velocities across the carpal tunnel or the elbow are easy to measure; however, across the thoracic outlet it is much more difficult to locate Erb’s point and to reproduce consistently reliable readings. This is particularly important in patients with primarily neurologic compression symptoms producing pain. It is important to assess pain objectively, in the same way that angiography does for the blood vessel obstruction.15 In evaluating a patient with recurrent symptoms of TOS after operation, assessment is even more difficult without objective data. The technique is described by Greep and colleagues in a book entitled Pain in Shoulder and Arm.16 A 50-year experience of more than 5000 cases of TOS coming to surgery was presented by Urschel to the American 1355

Ch111-F06861.indd 1355

1/21/2008 3:40:00 PM

1356

Section 5 Chest Wall and Sternum

Surgical Association in 1998, summarizing the changes in diagnosis and management of that disease process over half a century (Urschel and Razzuk, 1998).17 In surgery to relieve TOS, the transaxillary route is an expedient approach for complete removal of the 1st rib with neurovascular decompression and dorsal sympathectomy if indicated. Resection of the 1st rib or cervical ribs can be performed without the need for major muscle division, as in the posterior approach; without the need for retraction of the brachial plexus, as in the anterior supraclavicular approach; and without the difficulty of removing only the posterior segment of the rib, as in the infraclavicular approach. In addition, transaxillary 1st rib resection shortens postoperative disability and provides better cosmetic results than the anterior and posterior approaches do, which is important particularly because 80% of patients are female (Urschel and Cooper, 1995; Urschel and Patel, 2003).18-20

TECHNIQUE The patient is placed in the lateral position with the involved extremity abducted to 90 degrees by traction straps wrapped around the forearm and attached to an overhead pulley. An appropriate weight, usually 2 lb, is used to maintain this position without undue traction. A transverse incision is made below the axillary hairline, between the pectoralis major and the latissimus dorsi muscles, and is deepened to the external thoracic fascia (Figs. 111-1 and 111-2). Care must be taken to prevent injury to the intercostobrachial cutaneous nerve, which passes from the chest wall to the subcutaneous tissue in the center of the operative field. The dissection is extended cephalad along the external thoracic fascia to the 1st rib. With gentle dissection, the neurovascular bundle and its relation to the 1st rib and both scalenus muscles are clearly outlined to avoid injury to its components. In patients with traumatic TOS, the neurovascular structures are often attached to the chest wall with

FIGURE 111-1 A schematic drawing illustrating the relationship of the neurovascular bundle to the scalene muscles, 1st rib, costoclavicular ligament, and subclavius muscle.

adhesions. Careful lysis of the adhesions is necessary to expose the 1st rib. The insertion of the scalenus anticus muscle is identified, and the muscle is divided at the level of the 1st rib at the scalene tubercle (see Fig. 111-2). The scalenus anticus muscle is resected into the neck so that it will not reattach to Sibson’s fascia. The 1st rib is dissected with a periosteal elevator and separated carefully from the underlying pleura to avoid pneumothorax. A triangular segment of the middle portion of the rib is resected, with the vertex of the triangle at the scalene tubercle to avoid vascular injury (Fig. 111-3A). After the costoclavicular ligament is divided, the anterior portion of the rib is resected back to the costochondral junction (see Fig. 111-3B). The scalenus medius muscle is carefully stripped from the 1st rib with a periosteal elevator to avoid injury to the long thoracic nerve, which lies on its posterior margin. The posterior segment of the rib is divided at the articulation with the transverse process (Fig. 111-4). The head and neck of the 1st rib are completely removed with long, Urschel double-action pituitary and Urschel-Lexell rongeurs (reinforced) to avoid injury to C8 and T1 nerve roots (Fig. 111-5). The C8 and T1 nerve roots are carefully protected. If a cervical rib is present, its anterior portion, which usually articulates with the 1st rib, is resected with the middle portion of the 1st rib. The remaining segment of the cervical rib is removed after removal of the posterior segments of the 1st rib. Decompression and removal of bands and adhesions from the axillary-subclavian artery and vein are carried out, and neurolysis of C7, C8, and T1 nerve roots and the brachial plexus is accomplished with magnification. To add dorsal sympathectomy to the procedure, the pleura is separated from the vertebrae and the sympathetic trunk is identified (Fig. 111-6). Clips are placed above the T1 and below the T3 ganglion on the chain and on the gray and white ramus communicans to each nerve root (Fig. 111-7). The sympathetic chain is removed.

Subclavian artery Scalenus anticus

Brachial plexus Subclavian vein

Costal clavicular ligament Scalenus medius First rib

Ch111-F06861.indd 1356

1/21/2008 3:40:01 PM

Chapter 111 Transaxillary First Rib Resection for Thoracic Outlet Syndrome

1357

FIGURE 111-2 A transaxillary incision is made below the axillary hairline, between the pectoralis major and the latissimus dorsi muscles (inset). The scalenus anticus muscle is isolated and divided at its insertion in the 1st rib.

A

B FIGURE 111-3 A, A triangular portion of the rib is removed, with the vertex of the triangle at the scalene tubercle. The scalenus anticus muscle is resected back up into the neck. B, The costoclavicular ligament is divided, and the anterior part of the rib is resected to the costocartilage of the sternum.

Ch111-F06861.indd 1357

1/21/2008 3:40:03 PM

1358

Section 5 Chest Wall and Sternum

A

B FIGURE 111-4 A and B, The axillary subclavian vein and artery are decompressed. The posterior part of the rib is dissected to the transverse process of the vertebra and divided.

FIGURE 111-5 The head and neck of the rib are removed with a special reinforced Urschel pituitary rongeur, with care taken to avoid injury to the C8 and T1 nerve roots. The complete rib is thus excised.

Ch111-F06861.indd 1358

FIGURE 111-6 The dorsal sympathetic chain is identified by sweeping the pleura inferiorly from the T1 nerve root.

1/21/2008 3:40:06 PM

Chapter 111 Transaxillary First Rib Resection for Thoracic Outlet Syndrome

1359

Medical Center wishes to thank Mrs. Rachel Montano for her dedication and commitment to the research and completion of this chapter on transaxillary 1st rib resection for thoracic outlet syndrome with dorsal sympathectomy.

COMMENTS AND CONTROVERSIES Our preferred approach for primary neurogenic and venous compression is the transaxillary route, wherein the rib is proximal and retraction of the brachial plexus or blood vessels is avoided. H. C. U.

KEY REFERENCES Roos DB: Transaxillary approach for first rib resection to relieve thoracic outlet compression syndrome. Ann Surg 163:354, 1966. ■ The transaxillary approach to first rib resection was initially described by Atkins for sympathectomy and was popularized by Roos for first rib removal. Urschel HC Jr: The transaxillary approach for treatment of thoracic outlet syndrome. Chest Surg Clin North Am 9:771-780, 1999. ■ Modified techniques improve outcomes and allow total resection of the first rib, and thus minimizing recurrence. Urschel HC Jr: The history of surgery for thoracic outlet syndrome. Chest Surg Clin North Am 10:183-188, 2000. ■ The history of management of thoracic outlet syndrome is completely and clearly presented. FIGURE 111-7 with the chain.

The T1, T2, and T3 ganglions are removed along

A No. 20 chest tube is used for drainage. Only the subcutaneous tissues and skin require closure because no large muscles have been divided. The patient is encouraged to use the arm for self-care but to avoid heavy lifting until at least 3 months after the operation. It is preferable to remove the 1st rib entirely, including the head and neck, to avoid future regeneration and recurrent symptoms.

Acknowledgments

Urschel HC Jr, Cooper JD: Atlas of Thoracic Surgery. New York, Churchill Livingstone, 1995. ■ All of the improved techniques for treatment of thoracic outlet syndrome are described in this atlas. Urschel HC Jr, Patel AN: Paget-Schroetter syndrome therapy: Failure of intravenous stents. Ann Surg 75:1693-1696, 2003. ■ This paper describes the largest series of patients with Paget-Schroetter syndrome secondary to thoracic outlet syndrome and deprecates the use of intravenous stents. Urschel HC Jr, Razzuk MA: Neurovascular compression in the thoracic outlet: Changing management over 50 years. Ann Surg 228:609, 1998. ■ Fifty years’ experience with more than 15,000 patients is presented with improved methods of diagnosis, therapy, surgical techniques, and outcomes.

The Chair of Cardiovascular and Thoracic Surgical Research, Education and Clinical Excellence at Baylor University

Ch111-F06861.indd 1359

1/21/2008 3:40:10 PM

REOPERATION FOR RECURRENT THORACIC OUTLET SYNDROME THROUGH THE POSTERIOR THORACOPLASTY APPROACH WITH DORSAL SYMPATHECTOMY

chapter

112

Harold C. Urschel, Jr. Amit N. Patel

Key Points

neurovascular structures, as described by Urschel (Urschel and Cooper, 1995).5

■ For recurrent thoracic outlet syndrome, the high posterior thora-

coplasty approach provides excellent exposure. ■ The trapezius and rhomboid muscles are split rather than

divided. ■ The 1st rib remnant and fibrocartilage are removed. ■ Neurolysis of C7, C8, and T1 nerve roots and the brachial plexus, as well as decompression of the axillary-subclavian artery and vein are easily accomplished through this “virgin” incision. ■ Dorsal sympathectomy is added to provide optimal pain relief.

Recurrent thoracic outlet syndrome occurs infrequently. It is most commonly observed in patients in whom the 1st rib was not removed completely at the first procedure. The rib remnant allows osteoblasts and osteocytes to grow from the end of the rib, producing a fibrocartilage that can compress the neurovascular structures. If the initial operation was performed through either the supraclavicular or the transaxillary approach, it is safer to perform the reoperation through the posterior high thoracoplasty approach. This provides a virgin field and allows careful neurolysis of the nerve roots and brachial plexus as well as release of the vascular structures. A dorsal sympathectomy is usually performed because the sympathetic-maintained pain syndrome and causalgia are present in most cases of recurrent thoracic outlet syndrome. Reoperation is indicated if conservative management has failed (Urschel et al, 1976; Urschel, 1986; Urschel and Razzuk, 1998).1-3

HISTORICAL NOTE Initially, Clagett4 recommended the posterior thoracoplasty approach in his presidential address to the American Association for Thoracic Surgery in 1962 as the safest approach for 1st rib resection. Because of the pain and cosmetic effect, the transaxillary approach replaced posterior thoracoplasty as the primary approach to remove the 1st rib in patients with venous or neurologic compression. The supraclavicular approach still is the ideal way to obtain control of the proximal subclavian artery and either perform an interposition or bypass arterial graft. The posterior approach is employed primarily for reoperation, to remove the stump of the 1st rib and fibrocartilage, and to provide adequate neurolysis and decompression of the

TECHNIQUE The patient is placed in the lateral position with an axillary roll under the down side. The upper arm is placed as for a thoracotomy. An incision is made approximately 6 cm in length, with the midpoint at the angle of the scapula.5 It is made halfway between the scapula and the spinous processes (Fig. 112-1A). The incision is carried through the skin and subcutaneous tissue down to the trapezius muscle. After dissection of the appropriate subcutaneous flaps, the trapezius and rhomboid muscles are split in the direction of their fibers (see Fig. 112-1B). The posterior superior serratus muscle is resected, and the 1st rib stump is identified by retracting the sacrospinalis muscle medially (Fig. 112-2). Cautery is used to expose the 1st rib remnant (stump) and to open the periosteum. A periosteal elevator, or joker, is employed to remove the stump subperiosteally (see Fig. 112-2B). The head and the neck of the rib usually have not been removed in the initial operation. The rib shears are used to divide the rib remnant, and the reinforced Urschel-Leksell and Urschel pituitary rongeurs are employed carefully to remove the head and neck of the rib (see Fig. 112-2C). Once the T1 nerve root is identified grossly or with a nerve stimulator, neurolysis is carried out using magnification, a right-angle clamp, a knife, and special microscissors (Fig. 112-3). A nerve stimulator may be helpful if extensive scarring is present. Neurolysis is extended to the C7 and C8 nerve roots and to the brachial plexus. All of the scar is removed as far forward as necessary, so that the nerve roots as well as the upper, middle, and lower trunks of the brachial plexus are free. Care is taken not to injure the long thoracic nerve or any other brachial plexus branch. The axillary subclavian artery and vein are decompressed through the same incision. The 2nd rib is dissected free, and the cautery is used to open the periosteum linearly (Fig. 112-4). A 1-cm segment of the rib is resected posteriorly, medial to the sacrospinalis muscle, in order to perform the dorsal sympathectomy. (This exposure may also help identify the T1 nerve root.) After the head and neck of the 2nd rib are removed, the sympathetic chain is identified on the pleura. The stellate ganglion lies in a transverse rather than vertical position (Fig. 112-5).

1360

Ch112-F06861.indd 1360

1/21/2008 3:40:57 PM

Chapter 112 Reoperation for Recurrent Thoracic Outlet Syndrome Through the Posterior Thoracoplasty Approach

1361

A

B FIGURE 112-1 A, A high thoracoplasty incision is performed halfway between the angle of the scapula and the spine; it extends about 4 cm above and 2 cm below the angle of scapula. B, The incision is carried through the skin and subcutaneous tissue to the trapezius muscle. The trapezius and rhomboid muscles are split along their fiber lines.

C

A D

B E FIGURE 112-2 A, The rib remnant or recurrent piece of the first rib is identified, and a cautery is used to incise the periosteum. B, The rib stump is removed subperiosteally. C and D, The rongeur is used to remove the head and neck of the rib. E, The T1 nerve root is identified and touched with a nerve stimulator.

Ch112-F06861.indd 1361

1/21/2008 3:40:57 PM

1362

Section 5 Chest Wall and Sternum

FIGURE 112-3 Neurolysis of the scar over the T1 nerve root is carefully performed with magnification so that the nerve sheath is not injured.

FIGURE 112-5 The dorsal sympathetic chain and the stellate ganglion are identified.

FIGURE 112-4 The neurolysis is completed on the C8 and T1 nerve roots, and a piece of the 2nd rib is removed posteriorly.

FIGURE 112-6 The T1, T2, and T3 ganglia are removed with the dorsal sympathectomy.

The lower third of the stellate ganglion is incised sharply (T1), and the gray and white rami communicantes are clipped and divided. The T1, T2, and T3 ganglia are removed along with the sympathetic chain using clips on all of the branches. Cautery is employed to effect hemostasis and to minimize sprouting and regeneration of the sympathetic chain (Fig. 112-6). After irrigation with antibiotic solution has been performed, methylprednisolone (Depomedrol) and hyaluronic acid are left on the areas of neurolysis. The wound is closed in layers with interrupted No. 1 nylon sutures in a figure-ofeight fashion (so-called Tom Jones stitch) in each of the muscle layers. Running and interrupted 2-0 Vicryl sutures are

used in the subcutaneous tissue and in the skin. A large, round Jackson-Pratt drain is placed in the area of neurolysis through a separate stab wound made 2 cm below the inferior part of the incision. Care is taken not to incorporate the drain while closing the muscle layers over the top.

Ch112-F06861.indd 1362

Acknowledgments Mrs. Rachel Montano is to be highly commended for her many contributions to the success of this research and reproduction of reoperation for recurrent thoracic outlet syndrome.

1/21/2008 3:41:02 PM

Chapter 112 Reoperation for Recurrent Thoracic Outlet Syndrome Through the Posterior Thoracoplasty Approach

COMMENTS AND CONTROVERSIES Recurrent thoracic outlet syndrome, in our opinion, is best operated on posteriorly with a high thoracoplasty approach and a musclesplitting incision because this method gives excellent exposure in virgin territory. The usual rib remnant and fibrocartilage impinging on the brachial plexus is easier to remove posteriorly. This approach also allows expeditious neurolysis of the brachial plexus and dorsal sympathectomy. The supraclavicular approach may also be used for neurolysis of the brachial plexus; however, it is difficult to remove the rib stump posteriorly without retracting the brachial plexus, and doing so requires great skill and experience. H. C. U.

1363

Urschel HC Jr: Reoperation for thoracic outlet syndrome. In Eschapasse H, Dalarue N (eds): International Trends in General Thoracic Surgery, vol. 2. Philadelphia, CV Mosby, 1986. ■ The largest series of patients having reoperation for recurrent thoracic outlet syndrome describes the diagnosis and management including surgical techniques. Urschel HC Jr, Cooper JC: Atlas of Thoracic Surgery. New York, Churchill Livingstone, 1995. ■ All of the improved techniques for treatment of thoracic outlet syndrome are described in this atlas. Urschel HC Jr, Razzuk MA: Neurovascular compression in the thoracic outlet: Changing management in over 50 years. Ann Surg 228:609, 1998. ■ Fifty years’ experience with more than 15,000 patients is presented with improved methods of diagnosis, therapy, surgical techniques, and outcomes.

KEY REFERENCES Claggett OT: Presidential address: Research and prosearch. J Thorac Cardiovasc Surg 44:153, 1962. ■ This is the first classic reference explaining the anatomic and pathophysiologic basis for first rib resection to alleviate neurovascular compression in the thoracic outlet. The incision is the high posterior thoracoplasty approach, currently employed for reoperation for recurrent thoracic outlet syndrome.

Ch112-F06861.indd 1363

Urschel HC Jr, Razzuk MA, Albers JE, et al: Reoperation for recurrent thoracic outlet syndrome. Ann Thorac Surg 21:19, 1976. ■ The first significant series of patients undergoing reoperation for recurrent thoracic outlet syndrome describes accurately the current technique.

1/21/2008 3:41:07 PM

Introduction chapter

113

DIAPHRAGM: ANATOMY, EMBRYOLOGY, PATHOPHYSIOLOGY Federico Venuta Erino A. Rendina

Key Points ■ The diaphragm is the most important respiratory muscle. ■ The diaphragm has two major components: a central noncontrac-

tile tendon and a periphery consisting of three groups of muscle fibers. ■ Diaphragmatic innervation and blood supply are crucial to decide the incision for any transdiaphragmatic approach. ■ The structure of the diaphragmatic muscle fibers is extremely resistant to fatigue and is able to adapt to different situations, from rest to extreme efforts. ■ Hyperinflation in patients with emphysema causes a loss of the zone of apposition and compromises the anteroposterior and transverse expansion of the rib cage.

The diaphragm is a musculotendinous septum that separates the thoracic from the abdominal cavity. It is the most important muscle of inspiration and is responsible for most of the work of breathing, both in normal individuals and in patients with lung disease. The physiology and pathophysiology of the diaphragm can be easily inferred from the anatomic arrangement of this structure and its embryologic development (Epstein, 1994).1-5

ANATOMY The diaphragm has two major components: a central noncontractile tendon and a periphery consisting of three groups of muscular fibers radiating downward and outward. Although it is often thought of as dome shaped, the diaphragm is more appropriately considered as an elliptical cylindroid structure capped by a dome6 (Fig. 113-1). It arches over the abdominal cavity and on that surface is covered for the most part with peritoneum. On the abdominal (concave) side (Fig. 113-2), the diaphragm is related to the liver, stomach, spleen, kidney, and suprarenal glands. The superior (convex) surface bulges into the thoracic cavity (Fig. 113-3), rising higher on the right side than on the left; it is related to the pericardium and pleurae and, along its margin, to the chest wall. The domelike shape allows important abdominal structures, such as the liver and the spleen, to take advantage of the protection of the lower ribs and chest wall. The highest part, the central tendon, is a roughly trifoliate aponeurosis consisting of interwoven collagenous fibers arranged with the form of a three-leaf clover (anterior, left, and right leaves). The two lateral leaves relate to the parietal pleura superiorly and to the peritoneum inferiorly; the middle leaf is fused to the pericardium superiorly and relates to the

triangular ligament of the liver on the abdominal side. The central tendon is not at all central but is placed nearer to the front than to the back. Consequently, the anterior muscular fibers are shorter and the posterior crural fibers, arising from the vertebral column, are the longest. Nor is the central tendon symmetrical: the right leaf is the largest, the anterior is intermediate in size, and the left is a little narrower. The cylindrical portion surrounding the central tendon consists of a continuous band of muscle fibers, most of which are directly in contact with the inner surface of the lower ribs. The region of contact between the diaphragm and chest wall is known as the zone of apposition (see Fig. 113-1). The muscular part of the diaphragm originates from the entire circumference of the lower six ribs, the lumbar spine posteriorly, and the sternum anteriorly. These three components, which are typically separated from each other by muscle-free gaps, are called the costal (pars costalis), lumbar (pars lumbalis), and sternal (pars sternalis) parts, and they all insert at the central tendon. Diaphragmatic thickness and muscle mass may vary from one person to another, in relation to gender, age, body size, lifestyle, and disease.7

Costal Part (Pars Costalis) The muscular fibers of the costal part of the diaphragm originate from the inner surface and upper margin of the six lower ribs on each side, alternating with the dentations of the transverse abdominis muscle, and radiate into the central tendon. In most cases, a triangle lacking muscle fibers, the lumbocostal triangle (trigonum lumbocostale, or Bochdalek’s gap), exists posteriorly between the lumbar and costal parts of the diaphragm, more commonly on the left than on the right side. In these weak areas, the gap is usually closed only by the pleura, peritoneum, and fascia (transversalis and phrenicopleuralis).

Lumbar Part (Pars Lumbalis) The lumbar part of the diaphragm is the most powerful part. It is located beside the lumbar spine on both sides and forms the right and left crura. The crura are a pair of elongated musculotendinous bundles that arise from the anterior surface of the lumbar vertebrae (the right from L1-L4 and the left from L1-L2 and sometimes L3), the intervertebral disks, and the anterior longitudinal ligament. The right crus is, as a rule, much larger than the left. It spreads out from a thick triangular sheet that is directed upward to its insertion into the middle part of the concave border of the central tendon on both sides of the median plane. Its left margin is directed 1367

Ch113-F06861.indd 1367

1/21/2008 3:42:01 PM

1368

Section 6 Diaphragm

Zone of Apposition

FIGURE 113-1 The human diaphragm. Note the apposition zone to the inner aspect of the lower rib cage.

obliquely upward and to the left in front of the aorta; it splits as it approaches the central tendon, to form an elliptical opening for the passage of the esophagus. The muscular fibers usually meet again and decussate to form the anterior margin of the opening, which is thus separated from the central tendon and surrounded by a sphincter-like arrangement of the muscle. From the right crus, below the esophageal opening, a narrow, detached band of muscle passes forward and downward to the left of the celiac artery; this is the upper portion of the suspensory muscle of the duodenum. The left crus is quite variable in size and attachments but usually is much smaller than the contralateral one; it arises up and farther from the median plane than the right crus does. The main portion of its muscular fibers is directed upward to the left of the esophageal opening, from which it

is separated by the left margin of the right crus. Frequently, a separate bundle passes to the right, between the aortic and esophageal openings, behind the fibers of the right crus, to insert into the central tendon in the neighborhood of the vena caval opening; but as a general rule this bundle takes no part in the formation of the esophageal opening. The medial part of each crus forms at its origin a tendinous funnel; the mouth of each funnel is limited above by a spiral edge that runs downward and laterally from the aortic opening, and from it the muscular part bulges. Each crus is connected with the one of the opposite side by a tendinous band called the median arcuate ligament, which arches between them, in front of the aorta, and gives origin to fibers joining the right crus as it splits to encircle the gullet. The most lateral part of the crus is continuous with the medial end of the medial arcuate ligament. Each crus is frequently divided into two or three distinct portions in relation to the passage of the splanchnic nerves and the sympathetic trunk. Between the crus and the medial edge of the costal portion of the diaphragm, the origin of the lateral part of its vertebral portion is associated with the tendinous structures known as the medial and lateral arcuate ligaments; by means of these ligaments, the origin of the diaphragm is carried across the upper parts of the psoas major and quadratus lumborum muscles. Both of these arches have frequently been described as thickenings of the fascial covering of those two muscles, but one of them is a truly independent structure with which the fascia is fused. The medial arch is essentially a tendinous origin of the diaphragm itself, whereas the lateral arch is a thickened portion of the anterior lamella of the lumbar fascia from which muscular fibers of the diaphragm may secondarily arise. The medial arcuate ligament springs from the side of the body of the second lumbar vertebra; it is continuous with the lateral part of the crus and arches obliquely over the upper part of the psoas muscle, behind the lateral border of which it passes downward and medially to attach to the transverse process of the first or second lumbar vertebra near the tip. The lateral end of the ligament furnishes a direct tendinous origin of the diaphragm from the transverse process to which Pars sternalis

Inferior vena cava

Esophagus

Right crus

Aortic opening

Left crus

FIGURE 113-2

Pars costalis Central tendon

Psoas muscle

Ch113-F06861.indd 1368

Inferior vena cava

Esophagus

The diaphragm from below.

Aorta

FIGURE 113-3

Pars lumbalis

The diaphragm from above.

1/21/2008 3:42:01 PM

Chapter 113 Diaphragm

it is attached, and the part of the arch that lies in front of the psoas gives rise to a thin sheet of muscle which fills the interval between it and the origin of the crus. The lateral arcuate ligament stretches from the transverse process of the first or second lumbar vertebra across the upper part of the quadratus lumborum to be attached laterally to the 12th or 11th rib. Between the lateral margin of the quadratus and the costal attachment, the ligament is continuous below with the posterior aponeurosis of the transverses abdominis, and it corresponds to similar, smaller arches existing between the ends of the 12th and 11th and of the 11th and 10th ribs. A broad band of muscular fibers sweeps upward from this ligament to insert into the medial and posterior border of the lateral portion of the central tendon. This band is overlapped toward its insertion by the edge of the costal portion of the diaphragm, and it may or may not completely fill the interval between the edge of the psoas and the last rib.

Sternal Part (Pars Sternalis) The sternal part of the diaphragm originates with two small dentations, from the posterior layer of the rectus sheath and from the back of the xiphoid process of the sternum, which soon insert at the central tendon of the diaphragm. Bilaterally, between the sternal and costal parts, a narrow gap of varied shape and size is usually closed only by connective tissue. These gaps are named the right and left sternocostal triangles (trigonum sternocostale), or Morgagni’s and Larrey’s gaps. The superior epigastric and lymphatic vessels pass through these gaps. The diaphragm has three major apertures: the openings for the esophagus, the inferior vena cava, and the aorta (Fig. 113-4). It also has a number of small ones. The esophageal hiatus, elliptical in shape, is located at the level of T10, just left of the midline and anterosuperior to the aortic hiatus. It transmits the esophagus, the vagi and sympathetic trunks,

8

Inferior vena cava

10

Esophagus 12 Aorta

FIGURE 113-4 Cross-section of the diaphragm showing the three openings for major structures. The inferior vena cava passes most anteriorly, at the level of T8; the esophagus is at an intermediate position, at the level of T10; and the aorta is the most posterior, in the midline at the level of T12.

Ch113-F06861.indd 1369

1369

esophageal branches of the left gastric vessels, and lymphatic vessels. The right crus forms the esophageal hiatus in 64% of individuals; however, it is not uncommon that fibers of the left crus take part in the formation of the right side of the esophageal orifice. The right crus arises from the lateral surface of the first three lumbar vertebrae, sweeps around the esophageal hiatus, and inserts anterior to the aorta in the median or arcuate ligament. Also, in 2% of individuals, the left crus makes up the major part of the esophageal hiatus.8 The fascia on the inferior surface of the diaphragm extends upward into the opening in a conical fashion and is attached to the wall of the esophagus about 2 cm above the gastroesophageal junction. This fascial expansion limiting the upward displacement of the esophagus is known as the phrenoesophageal ligament. In this way, the esophagus is attached to the hiatus by reflections of the peritoneum in the abdomen and of the pleura in the chest. Arising from these, as well as from the crus, are the fascial fibers of Laimer,9 which make up the phrenoesophageal membrane of Allison. The length of the so-called canal extending from where the esophagus first enters the abdomen to its entry into the stomach is 2 to 3 cm. The inferior vena cava traverses the right leaf of the central tendon of the diaphragm at the level of the T8-T9 intervertebral disk; this orifice is stretched during diaphragmatic contraction, facilitating venous flow toward the chest during inspiration. Also, small branches of the right phrenic nerve and a few lymphatic vessels cross the border between the two cavities through this orifice. The aortic aperture is an osseoaponeurotic opening located anterior to the lower border of T12, between the crura and behind the median arcuate ligament; it transmits also the azygos vein, the thoracic duct, and lymphatic vessels that ascend from the cisterna chyli to the thorax. There are also two smaller orifices in each crus, for the greater and lesser splanchnic nerves. Other structures that pass between abdomen and thorax through the diaphragm or posterior to it are the superior epigastric vessels (between the sternal and costal origins of the diaphragm), the musculophrenic vessels (between the diaphragmatic origins at the level of the T7-T8 cartilages), the lower five intercostal nerves (at the level of the T7 cartilage inferiorly), the sympathetic trunk (deep to the medial arcuate ligament), and the inferior hemiazygos vein. The Morgagni and Bochdalek gaps, although physiologically present, are certainly loci minoris resistentiae and therefore could be the site of development of congenital or acquired transdiaphragmatic hernias (described elsewhere in this textbook). Along with the physiologic openings, the diaphragm may rarely present other defects that are known as the various porous diaphragm syndromes.10 The defects are usually located in the tendinous portion of the diaphragm or, less commonly, in the muscular portion. They may be single, multiple, and even cribriform. They range in size from a tiny pinhole to 1 cm or more in diameter, and they are certainly more frequent in the right hemidiaphragm. Some defects may be congenital, but many of them are acquired. Clinically, patients usually present with thoracic findings such as pleural effusion, pneumothorax, hemothorax, or emphysema.

1/21/2008 3:42:03 PM

1370

Section 6 Diaphragm

DIAPHRAGMATIC BLOOD SUPPLY AND PERFUSION The diaphragm has an extremely rich blood flow reserve. The diaphragmatic circulation is supplied by several sources11: the phrenic artery, the musculocutaneous branches of the mammary artery, and the intercostals. The anastomosis between the phrenic arteries and the internal mammary arteries forms an internal arterial circle along the central tendon-muscular junction. Anastomosis of branches from the internal arterial circle with intercostal arteries forms costophrenic arcades along the costal part of the diaphragm. There are also minor contributions from the pericardiophrenic arteries that run with the phrenic nerves, entering the diaphragm where the nerve penetrates. The pericardiophrenic artery, the musculophrenic artery, and the superior phrenic arteries extend to the cranial side of the diaphragm. Small, direct branches from the aorta vascularize the dorsal part. The inferior side is supplied by the inferior phrenic arteries, which give the major vascular support to the diaphragm (Fig. 113-5). They branch off in the aortal hiatus directly from the aorta or from the celiac trunk. In rare cases, the right inferior phrenic artery originates from the right renal artery. The inferior phrenic arteries are much stronger than the superior arteries and are the main route for arterial blood supply. They usually bifurcate posteriorly, near the dome of the diaphragm, and the branches course along the margins of the central tendon. The smaller posterior division is directed laterally, above the dorsal and lumbocostal origin of the diaphragm, where it has collateral anastomoses with the lower five intercostal arteries. The larger anterior division runs anterosuperiorly to the edge of the central tendon, where it anastomoses freely with the pericardiophrenic artery. The diaphragmatic veins follow the arteries, but the major venous drainage passes through the inferior phrenic veins, which enter the inferior vena cava just below the hepatic vein; they may also communicate with the hepatic veins through the left triangular and coronary ligaments of the liver. The veins usually course along the posterior aspect of the

Esophageal hiatus Right inferior phrenic artery

Left inferior phrenic artery

central tendon before joining the inferior vena cava. On the other side of the diaphragm, the venous drainage is via the azygos and hemiazygos veins. The role of blood perfusion of the diaphragm, both at rest and under effort, has been widely explored. Flow is proportional to the phase of the respiratory cycle and to the grade of exercise of the subject. Resistive loading increases diaphragmatic blood flow much more than does unobstructed ventilation.12 Resistance breathing in experimental animal models resulted in a 26-fold increase in diaphragmatic blood flow; blood flow to other inspiratory and expiratory muscles increased to a lesser degree and only with greater work loads.13 The duty cycle (duration of contraction of the diaphragm as a proportion of the total duration of the respiratory cycle) is an extremely important variable in determining diaphragmatic blood flow. During contraction of the muscle, the blood flow to the diaphragm is either partially or completely interrupted, with flow restored during the relaxation phase.14 The diaphragmatic blood flow (Qdi) is clearly related to the transdiaphragmatic pressure generated (Pdi) multiplied by the duty cycle.15-17 This mathematical product is called the tension (or pressure)–time index (TTdi), and it has been extremely useful for defining the physiologic behavior of the loaded diaphragm. It describes a parabolic relation between TTdi and Qdi. The endurance time of the diaphragm when breathing against resistance is also related to the product of the force developed and the duty cycle; the time to task failure is highly predictable and is related to perfusion. If breathing is held at a TTdi of 0.20 or lower, the endurance time is about 1 hour, but at a TTdi of 0.30, it is about 15 minutes. There are studies stressing the importance of diaphragmatic perfusion pressure15 to maintain contractility; in fact, respiratory muscle endurance varies at a given TTdi with the perfusion pressure: if perfusion pressure is increased, endurance is prolonged. Respiratory rate can also affect respiratory muscle perfusion. Faster frequencies increase perfusion for a given TTdi because in humans Qdi is linearly related to the respiratory muscle’s oxygen consumption. Other conditions, such as hypoxemia, may influence diaphragmatic perfusion18,19; hypoxemia increases blood flow to the diaphragm and seems to be adaptive in patients with chronic obstructive pulmonary disease (COPD), in whom both a fast respiratory rate and a lower tidal volume may help to preserve muscle performance.

LYMPHATIC SYSTEM OF THE DIAPHRAGM

Right suprarenal gland

Aorta

Left suprarenal gland

FIGURE 113-5 Vascular distribution of the inferior phrenic arteries to the lower surface of the diaphragm. (MODIFIED FROM ANDERSON JE: GRANT’S ATLAS OF ANATOMY, 8TH ED. BALTIMORE, WILLIAMS & WILKINS, 1983, FIG. 2-117A.)

Ch113-F06861.indd 1370

A network of lymphatic vessels can be appreciated on the thoracic and abdominal sides of the diaphragm; the superior and inferior lymphatic frames are interconnected through the diaphragm with multiple anastomoses. The lymphatic drainage of the diaphragm and satellite lymph nodes have not yet been completely understood. There are three different groups of lymph nodes involved in this system on each side. The anterior group includes two or three lymph nodes located behind the xiphoid process and drains into the parasternal lymphatic chain. There is a second group of two or three lymph nodes located on both sides

1/21/2008 3:42:04 PM

Chapter 113 Diaphragm

close to the pericardium, where the phrenic nerve enters the diaphragm; these lymph nodes drain to the groups of the posterior mediastinum. The last group of lymph nodes is located posteriorly, behind the crura, and drains to the lateral aortic and posterior mediastinal lymph nodes.

1371

The right phrenic nerve reaches the diaphragm just lateral to the inferior vena cava, whereas the left one enters the diaphragm lateral to the left border of the heart, in a slightly more anterior plane than on the right. Both nerves divide at the level of the diaphragm or just above it into several terminal branches (Fig. 113-7), the right phrenic nerve being the

INNERVATION OF THE DIAPHRAGM The diaphragm is innervated by the phrenic nerves (Fig. 113-6), which arise from the cervical roots C3 to C520; C4 is the main contributor. They originate at the level of the upper border of the thyroid cartilage, at the lateral border of the scalenus anterior, under the sternomastoid muscle. They descend on the muscle beneath and though fascial investment, crossing the muscle from its lateral to its medial border on the way to the thoracic outlet. The C5 nerve root usually joins the nerve trunk on the surface of the scalenus anterior; however, it may descend into the thorax before joining the main nerve at the level of the upper border of the thyroid cartilage. This is an important consideration in diaphragmatic pacing. At the root of the neck, the phrenic nerve is crossed by the transverse cervical and suprascapular arteries; the left phrenic nerve is crossed also by the thoracic duct. At the apex of the thorax, the right phrenic nerve lies behind the innominate vein and crosses the internal mammary artery anteriorly, with a lateromedial direction. The right phrenic nerve descends on the front of the first portion of the subclavian artery to enter the thorax. In the thorax, the right phrenic nerve descends along the right side of the innominate vein and the superior vena cava, and then along the side of the pericardium anterior to the hilum of the lung. It then passes along the upper border of the inferior vena cava to just above the diaphragm, where it branches. The left phrenic nerve descends between the left common carotid and subclavian arteries, crossing in front of the left vagus nerve, then passing lateral to the arch of the aorta and continuing down the side of the pericardium, where it branches.

Sternal branches LEFT HEMIDIAPHRAGM Antero-lateral branch

Phrenic nerve Accessory branch from the fifth cervical nerve Deep root from under the cervical nerves

Accessory branch from the fifth cervical nerve

Main trunk of the phrenic nerve

Branches to the diaphragm

Branches to the diaphragm

FIGURE 113-6

Removed phrenic nerves. (FROM ELEFTERIADES JA, QUIN JA: DIAPHRAGM PACING. CHEST SURG CLIN N AM 8:331-357, 1998. COPYRIGHT ELSEVIER 1998.)

RIGHT Sternal HEMIDIAPHRAGM branch Antero-lateral branch

Central Tendon IVC aperture Esophageal hiatus

Phrenic nerve

FIGURE 113-7 Branches of the phrenic nerve at the diaphragm. IVC, inferior vena cava. (FROM PLESTIS KA, FELL SC: ANATOMY, EMBRYOLOGY, PATHOPHYSIOLOGY AND SURGERY OF THE PHRENIC NERVE AND DIAPHRAGM. IN PEARSON FG, COOPER JD, DESLAURIERS J, ET AL [EDS]: THORACIC SURGERY, 2ND ED. PHILADELPHIA, CHURCHILL LIVINGSTONE, 2002, FIG. 56-5.)

Accessory posterolateral branch Postero-lateral branch

Ch113-F06861.indd 1371

Crural branch

Aorta

Postero-lateral branch

1/21/2008 3:42:05 PM

1372

Section 6 Diaphragm

mirror image of the left. Two or three of these terminal branches are very fine and are distributed to the serosal surfaces of the diaphragm. Three muscular branches arise directly from the phrenic nerve; one is directed anteromedially toward the sternum, another is directed laterally anterior to the lateral leaf of the central tendon, and the third one is directed posteriorly. The last-mentioned ramus divides into a branch that runs posterior to the lateral leaf of the tendon and a branch that runs posteriorly and medially to the region of the crus. These four branches are named the sternal or anterior branch, the anterolateral branch, the posterolateral branch, and the crural or posterior branch, respectively. They are usually located deep within the muscle rather than lying exposed on the undersurface of the diaphragm as is described in anatomic texts. The right crus of the diaphragm, whose fibers divide to the right and left of the esophageal opening, is innervated by both the right and left phrenic nerves. Although the crural fibers are not innervated separately from the rest of the diaphragm, there is some evidence that this

FIGURE 113-8 Development of the diaphragm. Top, Embryo at approximately 6 weeks after conception. Middle, Embryo at approximately 12 weeks after conception. Bottom, Fully developed fetus.

Septum transversum

(FROM LANGER JC: CONGENITAL DIAPHRAGMATIC HERNIA. CHEST SURG CLIN N AM 8:295-314, 1998. COPYRIGHT ELSEVIER 1998.)

Pleuroperitoneal membrane

part of the muscle contracts slightly before the costal part.21

EMBRYOLOGY The diaphragm originates embryologically from four structures: an unpaired ventral portion (the septum transversum); two paired dorsolateral portions (the pleuroperitoneal membranes or folds); and an irregular medial dorsal portion (the dorsal mesentery) (Figs. 113-8 and 113-9). The body wall muscles contribute to the development of the diaphragm. These various components are not delineated precisely as a morphologic entity in the definitive diaphragm. The septum transversum is composed of mesoderm, which lies between the pericardium and the abdomen after ventral folding of the embryo during the 3rd to 4th week of gestation. This structure eventually will form the central tendon of the diaphragm, but at this stage it incompletely separates the pericardial region from the rest of the body cavity. It is

Inferior vena cava Pericardioperitoneal canal

Esophagus Aorta

Mesentery of esophagus

Septum transversum

Pleuroperitoneal membrane

Body wall Mesentery of esophagus

Central tendon Inferior vena cava Esophagus Pleuroperitoneal membranes (site of Bochdalek diaphragmatic hernia) Aorta Crura Musculature of the diaphragm

Ch113-F06861.indd 1372

1/21/2008 3:42:06 PM

Chapter 113 Diaphragm

1373

Phrenic nerves Pericardial cavity Trachea

Esophagus Pleural coelom sac Site of the pleuroperitoneal membrane

Site of the septum transversum Abdominal coelom

Umbilical coelom

FIGURE 113-9 Relationships of pericardium, right pleura, and peritoneum in a 6-week embryo; the pleuroperitoneal channel is closed. The pleural sac is still very small in comparison with the pericardial sac. (MODIFIED FROM GRAY SW, SKANDALAKIS JE [EDS]: EMBRYOLOGY FOR SURGEONS: THE EMBRYOLOGICAL BASIS FOR THE TREATMENT OF CONGENITAL DEFECTS. PHILADELPHIA, WB SAUNDERS, 1972, P 360, FIG. 13.2.)

initially located at the level of the occipital and upper cervical somites (C3) and shows a dorsocaudal inclined frontal orientation22,23; it then progressively descends distally, reaching the final position at about 8 weeks. Caudally and laterally, at the beginning it is connected to the body wall, and the cranial edge ends in the open midgut. During the downward migration, the septum transversum progressively passes by the third, fourth, and fifth segments of the neck; myogenous stem cells migrate from these somites into the septum transversum, but myoblasts can also differentiate locally in the tissue of the posthepatic plate of mesenchyme.24-27 The pleuropericardial membranes are located laterally on either side of the septum transversum, at the level where the cardinal veins swing around to enter the sinus venosus of the heart. These folds extend medially and somewhat caudally to join the septum transversum and the dorsal mesentery, completing the development of the diaphragm at about the 7th week. The dorsal mesentery attaches the developing foregut to the dorsal body wall and ultimately forms the crura of the diaphragm. The last component of the diaphragm comes from the mesenchyme of the lateral abdominal wall, which grows in to join the other components about 12 weeks after conception. During the 5th week of gestation, nerves sprout from the fourth and fifth cervical segments of the spinal cord and penetrate through the pleuropericardial folds into the septum transversum,28 where they form the phrenic nerves. Because the pleuropericardial folds ultimately detach from the somatopleure to form the pericardium, the phrenic nerve remains located between the pericardium and the mediastinal pleura. At the beginning of the 6th week of gestation, the developing diaphragm is located in the region of the thoracic somites; 2 weeks later, it is at the level of L1. During the

Ch113-F06861.indd 1373

Intercostal nerves

FIGURE 113-10 Nerve supply to the diaphragm. The phrenic nerves are usually the sole motor nerve to each half of the diaphragm; they are also sensory to their own half, including the pleura and the peritoneum below. The lower intercostals nerves add innervation to the peripheral fringe of the diaphragm.

caudal descent, the phrenic nerves are progressively pulled to their final length. At this stage, the liver parenchyma increases in size and consistency, turning from a frontal to a transverse axis, and the diaphragm turns in a ventrodorsal direction. The septum transversum does not immediately close the pleuroperitoneal cavity; the cavities remain open and in communication and are called the pleuroperitoneal ducts. At approximately the 8th week of gestation, the right and left pleuroperitoneal membranes close and definitively separate the thoracic and abdominal sides from one another; the right pleuroperitoneal canal closes earlier than the left. In addition to these modifications, the body wall participates in the formation of the lateral portion of the diaphragm. In fact, between the 9th and 12th weeks of gestation, the pleural cavities reach the lateral part of the body and penetrate into the wall; the body wall is then split into two layers—the outer one, which later will develop into the thoracic wall, and the inner layer, which eventually will be incorporated into the diaphragm. This configuration explains the observation that peripheral parts of the diaphragm receive innervation by the lower six intercostal nerves (Fig. 113-10). The entry of the pleural cavity into the primitive body wall also results in the formation of the costodiaphragmatic recesses. During the 10th week of gestation the intestines return from the yolk sac to the abdominal cavity, and at about 12 weeks they rotate and become fixed. It is easy to understand how the embryologic development of the diaphragm is the key to interpreting the congenital and some of the acquired disorders of this musculomembranous membrane. A delay or variation in the described timetable may result in a variety of congenital hernias, with or without the hernial sac. Errors of growth of the septum transversum or other embryologic elements usually result in an absent diaphragm. Vascular, pulmonary, and heart anomalies may be associated

1/21/2008 3:42:06 PM

1374

Section 6 Diaphragm

with defects of the diaphragm on the basis of fusion and formation timetable variations (Fig. 113-11).

SURGICAL CONSIDERATIONS RELATED TO DIAPHRAGMATIC ANATOMY Appropriate information about diaphragmatic anatomy is extremely important in choosing the correct surgical approach and preventing complications. Incisions into the diaphragm must be made so as to avoid injury to the major branches of the phrenic nerves. However, because of the rapid diminution in size of the phrenic nerve rami, it is practically impossible to delineate areas in the diaphragm where incisions can

Right lung

Intrathoracic liver

Incomplete right hemidiaphragm

FIGURE 113-11 Incomplete right hemidiaphragm with intrathoracic liver and hypoplastic right lung. Heart-lung and diaphragm block fixed in formalin.

be made absolutely safely. Incisions made in the central tendon rarely cause diaphragmatic paralysis, but they provide only minimal exposure to the adjacent abdominal compartment. However, a diaphragmatic incision that goes backward from the front to the esophageal hiatus (septum transversum incision), as described by Sicular29 (Fig. 113-12), has the advantage of a rapid performance but carries some risk of trauma to the left phrenic nerve. A circumferential incision at the periphery of the diaphragm (Fig. 113-13) allows a much better exposure, with little or no possibility of injury to any major branch of the ipsilateral phrenic nerve. On the left, the incision may be started at the esophageal hiatus and carried from behind forward circumferentially, about 3 cm away from the diaphragmatic attachment to the chest wall. The cut edges of the diaphragm are grasped with Allis clamps and elevated, facilitating further incision. Bleeding is usually managed by cautery, but large branches of the phrenic arteries are better controlled with suture ligatures. The posterior branch of the phrenic nerve may be divided with this incision, but this is of little consequence. However, with this incision the main branch of the left inferior phrenic artery may be encountered; if so, it is ligated and divided. When a combined abdominothoracic approach is used, the incision in the diaphragm may be extended medially, between the pericardial attachment to the diaphragm and the entrance of the phrenic nerve into the muscle, severing only the small sternal division of the nerve. The incision is then carried to the apex of the esophageal hiatus; if a tumor is adherent to the diaphragm, extended en-bloc resection can easily be performed with this approach. However, if the diaphragmatic incision is made in association to antireflux procedures, it is preferable to use the anterolateral two thirds of the diaphragm instead of carrying the incision posteriorly to the level of the esophageal hiatus. This gives ample exposure to the abdomen and simplifies management of the vasa brevia and the gastrohepatic ligament (Fell, 1998).30 This incision allows for the crura to be repaired in the abdomen and a fundoplication to be performed before closure of the diaphragm.

FIGURE 113-12 Septum transversum incision for transdiaphragmatic exposure of the cardia. (FROM PLESTIS KA, FELL SC: ANATOMY, EMBRYOLOGY, PATHOPHYSIOLOGY AND SURGERY OF THE PHRENIC NERVE AND DIAPHRAGM. IN PEARSON FG, COOPER JD, DESLAURIERS J, ET AL [EDS]: THORACIC SURGERY, 2ND ED. PHILADELPHIA, CHURCHILL LIVINGSTONE, 2002, PP 1499-1507, FIG. 56-8.)

Incision

Outline of base Esophagus of pericardium

Left phrenic nerve

Aorta

Ch113-F06861.indd 1374

1/21/2008 3:42:07 PM

Chapter 113 Diaphragm

The radial incision in the diaphragm from the costal margin to the esophageal hiatus results in almost total diaphragmatic paralysis, and it needs to be avoided. The radial incision was a major cause of postoperative morbidity and mortality in patients subjected to thoracolaparotomy; it resulted in ineffective cough, lower lobe atelectasis, and associated pneumonia. Nevertheless, it is still described in the literature. Diaphragmatic incisions are closed with two layers of sutures: a first layer of interrupted mattress sutures, followed by a continuous suture. The proximity of the phrenic nerves to the internal mammary artery puts them at risk for injury during harvest of the artery for coronary artery bypass procedures. Nerve injury in these cases is the result of thermal or stretch injury during dissection.

PHYSIOLOGY The diaphragm is the most important respiratory muscle; the physiologic role of this muscle is related to its inspiratory action on the lungs, which accounts for most of the inspired volume of air.31 However, the diaphragm has several other important functions, such as providing anatomic stability to thoracic and abdominal organs and sustaining increases in intra-abdominal pressure that are necessary for postural stability of the torso; the diaphragm also lends additional power to all expulsive efforts, such as defecation, micturition, and parturition.32 This muscle is also involved in activities such as coughing, talking, singing, sneering, laughing, and crying; however, these activities are only phasic and occasional. In addition, the diaphragmatic lymphatic drainage system has a major role in the absorption of material from the peritoneal cavity.33 As a dividing structure between the pleural and peritoneal cavity, the diaphragm is able to vary the volume of both cavities. Contraction of the diaphragm draws the central tendon downward, displacing the abdominal viscera. This part of the muscle progressively becomes a fixed point due to the increase

Pericardial attachment Left Hemidiaphragm

B

Right Hemidiaphragm

1375

in abdominal pressure, while the surrounding muscular fibers continue to contract, producing an inflationary action of the lower ribs through the zone of apposition. This widens the costodiaphragmatic recess, giving the lung additional volume to expand. However, this simple description of diaphragmatic activity has a complex physiologic and evolutionary background. The diaphragm is engaged in a continuous rhythmic activity that does not allow any pause; for this reason, the muscle fibers of this structure must be very resistant to fatigue and must be able to adapt to the different situations, from rest to extreme efforts. Strength and endurance are different but related properties of any striated muscle. Muscle strength is determined by adequacy of the neural drive, innervation, neuromuscular transmission, number and density of actomyosin filaments, fiber type distribution, and the length-tension and forcevelocity relationships. Relative endurance, the ability to sustain repeated contractions at a specific fraction of maximum strength, is determined by fiber type distribution, mitochondrial density, myoglobin content, delivery of oxygen and other nutrients to the contracting muscle, and removal of the products of energy metabolism. Absolute endurance is the ability to sustain contractions at a specific tension; it depends both on strength and on all the factors that determine relative endurance. Because breathing is an endurance task that depends on repeated generation of inspiratory muscle forces that are determined primary by work load, absolute endurance is clearly the most important characteristic of respiratory muscles in resisting to ventilatory failure. Respiratory muscle strength and absolute endurance usually change in parallel,34-37 but certain neuromuscular disorders, such as myasthenia gravis and metabolic myopathies, tend to reduce endurance more than strength; some other conditions, such as steroid myopathy,38 malnutrition,39,40 and disuse atrophy,41 appear to reduce strength more than endurance. An evolutionary adaptation to this continuous demand is seen morphologically because the diaphragm is mainly com-

FIGURE 113-13 Diaphragm incisions: A, radial incision; B, circumferential incision; C and D, incisions in safe areas. (FROM PLESTIS KA, FELL SC: ANATOMY, EMBRYOLOGY, PATHOPHYSIOLOGY AND SURGERY OF THE PHRENIC NERVE AND DIAPHRAGM. IN PEARSON FG, COOPER JD, DESLAURIERS J, ET AL [EDS]: THORACIC SURGERY, 2ND ED. PHILADELPHIA, CHURCHILL LIVINGSTONE, 2002, FIG. 56-6.)

A

C D B

Ch113-F06861.indd 1375

1/21/2008 3:42:09 PM

1376

Section 6 Diaphragm

posed of fatigue-resistant muscle fibers. According to the classification of skeletal muscle fibers of Brooke and Kaiser,42 slow oxidative fibers (type I) account for approximately 55% of the diaphragmatic muscle mass, rapid oxidative fibers (type IIA) for 21%, and rapid glycolytic fibers (type IIB) for 24% (Lieberman et al, 1973).43 The fiber composition of the diaphragm progressively changes during gestation and in the early postnatal period. Recent studies44 have provided a comprehensive view of the mechanism behind the developmental increase in contractile force of rat diaphragm. Three distinct factors interplay: the increased density of myosin per sarcomere, the replacement of slow and neonatal myosin with fast myosin, and the higher force developed by individual myosin molecules in fibers expressing fast myosin. It is likely that similar mechanisms could be relevant also for the human diaphragm, where the replacement of neonatal myosin with adult slow and fast myosin occurs rapidly in the perinatal period; during this time, the proportion of slow fibers increases from 9% at 27 weeks to 25% at term and reaches the adult level during the second postnatal year.45 The increase in slow myosin expression is accompanied by an increase in oxidative capacity evaluated by reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase activity, producing enhanced resistance of the diaphragm to fatigue.45 The presence of slow and fast fibers in respiratory muscles, and in particular within the diaphragm, reflects their functional tasks. In fact, although quiet breathing uses mainly slow fibers, fast muscle fibers are recruited specifically when the breathing rate increases. This recruitment shift has been confirmed experimentally.46,47 The increased level of aerobic oxidative metabolism in respiratory muscles results in the increased resistance to fatigue required by the continuous rhythmic activity. Fatigue in respiratory muscles limits physical performance, as shown in athletes and in patients with COPD.48,49 There is also another peculiar aspect of the muscular structure of the diaphragm: in this muscle, fibers have a smaller cross-sectional area than in other skeletal muscles. Because the number of capillary vessels surrounding each fiber is similar, in the diaphragm the diffusion distance is reduced, which makes the oxygen supply more efficient. An inverse relation has been reported between aerobic oxidative enzyme activity and cross-sectional area.50 This may contribute to improved oxygen diffusion and increased diaphragmatic resistance to fatigue. Two basic principles control all the muscles subjected to physiologic stimuli, including also the structures involved in respiration. The first is the relationship between the length of a muscle and its capacity to generate force (force-length relationship). A muscle generates more force as it lengthens, until it reaches an optimal length. Stretching the muscle beyond that point causes a decrease in strength, until the fiber breaks. If the resting length of the muscle shortens (as in the diaphragm of patients with hyperinflation due to emphysema), the force-generating capacity for a given electrical stimulus decreases. Therefore, there is an optimal fiber length at which maximal nerve stimulation results in a maximal active tension. The exact in vivo position of the diaphragm on its length-tension relationship has not been determined in humans; however, studies have shown that

Ch113-F06861.indd 1376

transdiaphragmatic pressure obtained with a supramaximal stimulation of the phrenic nerve decreases almost linearly with increasing lung volume, as the operating diaphragmatic fiber length shortens.51,52 These concepts are extremely important in understanding normal diaphragmatic function and its modification under stress or in certain pathologic conditions. In normal humans, the resting position of diaphragmatic fibers on their length-tension relationship is modified according to posture. In the supine position, abdominal content exerts a physiologic stretch on diaphragmatic fibers; conversely, fibers are least stretched in the standing and erect sitting positions. Erect positions result in reduced diaphragmatic efficiency by shortening fiber length and increasing diaphragmatic radius curvature. The decrease in muscle efficiency is compensated by a reflex increase in the intensity of phrenic nerve impulses. The reflex causes augmentations of diaphragmatic electromyographic potentials when normal subjects go from a supine position to a standing or erect sitting position53,54 and results in preservation of the transdiaphragmatic pressure when switching from one position to the other. The second principle is the inverse relationship between the velocity of muscle contraction and force-generating capacity. As the velocity of contraction increases (e.g., during increased respiratory rate), the capacity to generate force decreases.55 The diaphragm assists lung inflation through several mechanisms. The piston-like downward movement certainly increases thoracic volumes, and the cephalocaudal orientation of its fibers and the curvature of its shape contribute to optimize this modification.5 The curvature of the diaphragm approximates the shape of a hemisphere with a radius r. Laplace’s law for a sphere states that P = 2 T/r, where P is the pressure inside the sphere and T is the intramuscular tension. If T is constant and the diaphragm flattens, its curvature will decrease, r will increase, and, by definition, P must decrease. Finally, the diaphragm transmits the increase in abdominal pressure during contraction to the rib cage, through the zone of apposition, using the abdomen as a fulcrum against which it leans4,5,56; this has a second expansive action on the rib cage with an outward swing of the last ribs. Therefore, during inspiration, the diaphragmatic fibers shorten; the central tendon is pulled down, expanding the chest volume with a piston-like action; and the dome of the diaphragm descends, increasing the intra-abdominal pressure. The pressure is transmitted across the zone of apposition and pushes the lower ribs outward, resulting in rib cage expansion.57 In vivo, diaphragmatic force can be assessed only indirectly by measuring pressure changes generated in the thoracic and abdominal cavities during contraction.58 This force is termed transdiaphragmatic pressure (Pdi), and it equals the difference between the abdominal (Pab) and pleural (Ppl) pressures (Pdi = Pab − Ppl). It can be measured in the respiratory physiology laboratory. Under normal circumstances, a pressure gradient is created, and the transdiaphragmatic pressure equals the difference between the absolute values of the two pressures. As a consequence of the normal curvature and piston-like movement of the diaphragm, transdiaphragmatic pressure is not equivalent to the tangential tension (Tdi)

1/21/2008 3:42:10 PM

Chapter 113 Diaphragm

generated by the contraction of the diaphragm itself, but rather is the result of conversion of Tdi to Pdi according to the aforementioned Laplace’ s law. However, in reality, the diaphragm is far from having a perfect semicircular shape and therefore possesses many radii of curvature, making application of Laplace’s law virtually impossible in vivo.32 Nevertheless, the equation is conceptually useful to understand the effects of increasing lung volume on pressure: the more flattened the diaphragm, the greater is the radius of curvature, and the less efficiently is tangential tension converted into negative pleural or transdiaphragmatic pressure, which most closely represents the physiologically active force inflating the lungs. During quiet breathing, contraction of the diaphragm draws the central tendon downward with an excursion of about 1.5 cm. With this movement, the curvature of the diaphragm is scarcely altered; the cupola moves slightly downward and a little forward, almost parallel to the original position, and the dome flattens to some extent. Deep inspiration is associated with more relevant modifications. Between residual volume and total lung capacity, a full inspiratory contraction of the diaphragm causes up to 40% shortening of its fibers and increases thoracic diameters in three axes: cephalocaudad, anteroposterior, and transverse.59 The first of these modifications is the mere consequence of lowering displacement of the floor of the chest, with the contracting diaphragm descending in the abdomen while the normal relaxation of the anterior abdominal musculature shifts the intraperitoneal organs inferiorly and anteriorly. Anteroposterior and transverse expansions result from the interaction of several simultaneous mechanisms. During inspiration, the diaphragm moves against the abdominal content, which is incompressible; the associated downward displacement of the abdominal viscera is allowed by the extensibility of the abdominal wall,60 but the limit of this is soon reached with an increase in abdominal pressure. In this situation, the movement of the central tendon is arrested by the abdominal viscera; this part of the diaphragm becomes a fixed point from which the surrounding muscular fibers continue to contract. This causes tension on the lower rib cage that is directed superiorly because the cephalocaudal orientation of the apposition zone is maintained by the abdominal content opposing the descent of the diaphragmatic dome.52,61,62 As a result of the nature of rib cage attachment on the thoracic vertebrae, this translates into combined increases in anteroposterior and transverse thoracic dimensions; this mechanism is usually described and referred as the bucket handle movement of the rib. The increase in abdominal pressure during inspiration produces also an inflationary action on the lower rib cage through the zone of apposition. Thus, increases in thoracic dimensions brought on by inspiratory diaphragmatic contraction result not only from lowering of the thoracic floor, even if this is certainly the most important contributor to inspiration,59 but also from anteroposterior and transverse expansion. The right cupola of the diaphragm, which lies on the liver, has a greater resistance to overcome than the left, which lies over the stomach; in compensation for this, the right crus and the fibers of the right side are more substantial than those on the left. These diaphragm and chest wall movements

Ch113-F06861.indd 1377

1377

cause the pleural pressure to become more negative, favoring inspiration. From the mechanical point of view, the muscular portion of the diaphragm could be considered as being composed of two distinct muscles: the costal and crural diaphragms. These two parts form a continuous sheet through a common site of insertion on the central tendon (De Troyer et al, 1981).63-65 The costal diaphragm originates from the costal margin of the muscle, and the crural diaphragm arises from the spinal column and the medial and lateral arcuate ligaments. The two parts have different embryologic origins, different segmental innervations, and different actions on the rib cage. Although they both cause diaphragmatic dome descent and outward abdominal displacement during inspiratory contraction, only the costal diaphragm, with its zone of apposition, causes elevation and expansion of the rib cage. Conversely, the contraction of the crural part alone causes a paradoxical inward displacement of the rib cage. Under normal circumstances, both parts are mechanically functioning in parallel, and the total inspiratory force generated by them equals the sum of the forces developed by each part. On the other hand, the forces developed by the two muscles arranged in series are not additive because the tension generated by one muscle must be matched by the other to be transmitted to the point of insertion.65 Such a mechanical arrangement can occur in emphysema because of the effects of hyperinflation on the diaphragm. In normal subjects, at functional residual capacity (FRC), lung and chest wall recoils are directed, respectively, inward and outward, balancing each other and allowing relaxation of inspiratory and expiratory muscles.66 During inspiration, the diaphragm contracts and works against a progressively larger load as the lung compliance decreases, inwardly directed lung recoil increases, and the chest wall recoil directed outwardly decreases. At a volume corresponding to 60% of the vital capacity chest wall recoil becomes directed inward, and total lung capacity is reached when the inspiratory musculature can no longer exceed inward recoil forces.66,67 Therefore, at progressively larger lung volume, more diaphragmatic work is required to maintain (or generate) inspiration.

ASSESSMENT OF DIAPHRAGMATIC FUNCTION Specific assessment of diaphragmatic function can be performed by physical examination, radiographic techniques, transdiaphragmatic pressure measurements, and electrophysiologic studies.

Physical Examination Percussion of the chest allows estimation of the diaphragmatic position and excursion during inspiration and expiration. The normal diaphragmatic contraction favors its descent into the abdomen with an outward movement of the abdominal wall. If the diaphragm is paralyzed, the negative intrathoracic pressure draws the diaphragm upward and the abdomen inward. In patients with bilateral diaphragm paralysis, there is often a marked reduction in chest expansion in the supine position compared to the upright position (Pacia and Aldrich, 1998).68 This paradoxical motion can be appreciated in the supine position; however, if the diaphragm is only weak or

1/21/2008 3:42:10 PM

1378

Section 6 Diaphragm

fatigued but not paralyzed, the paradoxical motion may be present only intermittently. In the upright position, patients with diaphragmatic weakness or paralysis may have seemingly normal diaphragmatic function because they compensate with active expiratory muscle contraction to push lung volume below FRC. During the next inspiration, the abdominal muscles relax and the abdominal anteroposterior diameter increases, assisted by gravity.

Radiography Chest radiography may be useful to discover diaphragmatic paralysis, but it cannot be completely relied upon, and elevated hemidiaphragm can be interpreted as a sign of unilateral paralysis. Both false-negative and false-positive results may occur.69 Fluoroscopy may show diminished or paradoxical movement of the affected diaphragm during sniffing70; if an inspiratory elevation greater than 2 cm is present, it is probably pathologic. Diaphragmatic movements can also be assessed by comparing radiographs obtained during inspiration and expiration and with the use of ultrasound or magnetic resonance imaging.

Electromyography There are direct and indirect methods to record the electrical activity of the diaphragm. Direct methods include insertion of needle electrodes subcostally or through the lowest intercostal space, just below the pleural reflection71,72; this procedure has been demonstrated to be reasonably safe in humans and is able to produce a neuropathologic diagnosis.71 Indirect methods include the use of chest wall and esophageal electrodes.73 Recordings made through chest wall electrodes show some limitation due to interference from other muscles and problems related to the complete lack of standardization for electrode positioning. Esophageal electrodes are mounted on a catheter, inserted through the nose, and placed at the level of the crural diaphragm.68 Distal balloons are used as stabilizers to reduce movement artifacts. This limits motion relative to the esophagus but does not control diaphragmatic movements. Power spectral analysis of the diaphragm electromyograph (EMG) provides information about the frequency content of the signal,74 with a spectrum recorded via esophageal electrodes usually between 25 and 250 Hz. Bandpass filtering may be effective to remove motion but not cardiac artifacts. Muscle fatigue is associated with a shift toward lower frequencies in the EMG power spectrum, quantified either as a reduction in the mean frequency or as a reduction in the ratio of power at high frequencies to power at low frequencies. However, despite the many studies already published, diaphragmatic EMG is not yet of extensive clinical utility and remains mainly a research tool.

Transdiaphragmatic Pressure Pressures in the chest and abdomen, above and below the diaphragm, can be measured by balloon catheters placed in the esophagus and stomach; they are connected to pressure transducers. The force generated by diaphragmatic contrac-

Ch113-F06861.indd 1378

tion is approximately proportional to the pressure difference generated across the muscle by diaphragmatic contraction minus any change in transdiaphragmatic pressure that occurs as a result of change in thoracic volume.60 The pressure is most frequently measured during a maximal static inspiratory effort against a closed airway. However, these measurements highly depend on voluntary effort, which may not always be maximal on demand. Transdiaphragmatic pressure is nonlinearly and inversely related to lung volume. Therefore, it must be evaluated while taking lung volumes into account. Optionally, it can be measured at various lung volumes and a curve can be constructed relating pressure to volume.

PATHOPHYSIOLOGY OF THE DIAPHRAGM IN PATIENTS WITH EMPHYSEMA Pulmonary emphysema offers the most diffuse and wellknown example of how diaphragmatic physiology can be modified and adapt to compensate for abnormal conditions. Briefly, in emphysema, air-flow obstruction, loss of elastic recoil due to parenchymal destruction, air trapping, and, eventually, hyperinflation coexist. The hyperinflation may initially compensate for the impairment in respiratory mechanics, but at the most advanced stage of the disease it is highly detrimental to the inspiratory function of the diaphragm. During hyperinflation, flattening of the diaphragm occurs, the zone of apposition is lost, and a more horizontal orientation of fibers arising from the inner chest wall is seen (Fig. 113-14). The result of these modifications is that the mechanical linkage between the costal and crural parts of the diaphragm is no longer in parallel, and the volume displaced toward the abdomen by each part becomes additive.65 In this way, the two muscles are arranged in series, and they can exert only as much force as the weakest part of the two. In addition, the loss of the zone of apposition compromises the anteroposterior and transverse expansions of the lower part of the rib cage. If hyperinflation is severe, the rib cage corresponding to the previous zone of apposition may even show paradoxical inward movement during inspiration; this phenomenon is known as Hoover’s sign, and it is related to the more horizontal configuration of the costal fibers of the diaphragm at their site of origin from the ribs.62 Hyperinflation increases the radius of curvature of the diaphragm and reduces the ability to convert tangential tension into effective transdiaphragmatic pressure (Minh et al, 1976).75,76 At extremely high volumes, there is no descent toward the abdomen, and diaphragmatic contraction leads only to inward movement of the lower rib cage. Hyperinflation modifies also the length-tension relationship within diaphragmatic fibers; in fact, they become significantly shorter than optimal length and are activated on a less efficient portion of their force-length relationship curve, leading to an increase of neural stimuli and energy consumption to produce the same amount of work, with a decreased efficiency. This has been confirmed by transdiaphragmatic pressure measurements: there is an almost linear decrease of pressure obtained for a given stimulation of the phrenic

1/21/2008 3:42:10 PM

Chapter 113 Diaphragm

Outward thoracic recoil

Normal fiber length and near vertical orientation

Zone of apposition

Normal diaphragmatic radius of curvature (Rdi)

A Minimal or no outward thoracic recoil

1379

nerves with the increase in lung volumes, both in normal subjects and patients with COPD.51,77,78 The increased energy demand is probably more critical; an impaired perfusion of the diaphragm has also been described in COPD patients. This finding is probably related to a decreased diaphragmatic perfusion pressure from added extrinsic load on the diaphragm and increased vascular resistance from greater vessel tortuosity in a shortened muscle.79 Acidosis, hypoxemia, and malnutrition, characteristic of severe COPD, may further reduce diaphragmatic performance. The inspiratory work is overall dramatically increased; severe hyperinflation creates a situation in which every inspiratory effort is initiated and maintained against inwardly directed lung and chest wall elastic recoils. Therefore, a larger amount of inspiratory work is necessary to generate the same negative pressure and to produce air flow. The inspiratory muscles are no longer assisted by the elastic recoil of the chest but must work against it.

COMMENTS AND CONTROVERSIES Shorter fiber length and more horizontal orientation

Reduced or absent zone or apposition

Drs. Venuta and Rendina have provided an excellent review of the embryology, anatomy, and physiology of the diaphragm. This is essential information for any surgeon contemplating surgery on or about the diaphragm. Diaphragmatic physiology is concisely outlined and is complemented by a review of the pathophysiology of the diaphragm. T. W. R.

KEY REFERENCES Larger diaphragmatic radius of curvature (Rdi)

B FIGURE 113-14 The diaphragm and chest wall at functional residual capacity in health (A) and in emphysema (B). Consequences of the emphysema and hyperinflation include flattening of the diaphragm, loss of the zone of apposition, shorter operational length and more horizontal orientation of diaphragmatic muscle fibers, increased diaphragmatic radius of curvature, and loss of outward thoracic recoil.

Ch113-F06861.indd 1379

De Troyer A, Sampson M, Sigrist S, et al: The diaphragm: Two muscles. Science 213:237-238, 1981. Epstein S: An overview of respiratory muscle function. Clin Chest Med 15:619-639, 1994. Fell SC: Surgical anatomy of the diaphragm and the phrenic nerve. Chest Surg Clin N Am 8:281-294, 1998. Lieberman DA, Faulkner JA, Craig AB, et al: Performance and histochemical composition of guinea pigs and human diaphragm. J Appl Physiol 34:233-237, 1973. Minh VD, Dolan GF, Kopka RF, et al: Effect of hyperinflation on inspiratory function of the diaphragm. J Appl Physiol 40:67-73, 1976. Pacia EB, Aldrich TK: Assessment of diaphragmatic function. Chest Surg Clin N Am 8:225-236, 1998.

1/21/2008 3:42:10 PM

chapter

114

IMAGING OF THE DIAPHRAGM David S. Gierada

Key Points ■ The substantial variability in the normal position of the diaphragm,

related in part to age, weight, and anteroposterior thoracic dimension, should be kept in mind when assessing whether the diaphragm is depressed or elevated. ■ Multidetector computed tomography (CT) and multiplanar magnetic resonance imaging (MRI) are the primary imaging modalities for confirming and determining the contents of diaphragmatic hernias. ■ Traumatic rupture of the diaphragm usually occurs in the setting of multiple traumatic injuries, and herniation may not be present initially, so diagnosis often requires a high index of suspicion and close radiographic surveillance. ■ Fluoroscopy is the quickest, easiest, and most efficient means of evaluating for diaphragm paralysis.

The thin structure and complex shape of the diaphragm present an ongoing challenge for diagnostic imaging. Abnormalities that affect the diaphragm are often first detected on chest radiographs as an alteration in position or shape. Crosssectional imaging studies, primarily CT and occasionally MRI, can depict structural defects and intrinsic and adjacent pathology in greater detail. Fluoroscopy is the primary radiologic means of evaluating diaphragm motion, although MRI and ultrasound also are capable of this function. This chapter illustrates the normal appearance of the diaphragm and the role of imaging in specific conditions, including congenital and acquired hernias, diaphragm paralysis, and diaphragm masses.

THE NORMAL DIAPHRAGM On chest radiographs, the superior margin of each hemidiaphragm with overlying parietal pleura forms a dome-shaped interface between the thorax and abdomen. The heart, with subjacent pericardium and fat, forms a relative depression between the two hemidiaphragms, obscuring the central and anteromedial portions of the diaphragm. A scalloped or polyarcuate contour of the diaphragm is a normal variation, most frequently seen on the right.1 Several signs help distinguish the right from the left hemidiaphragm on the lateral radiograph (see Fig. 83-1 in Chapter 83). The entire anteroposterior extent of the right hemidiaphragm is usually visible because of its interface with the

lung, whereas a variable segment of the anterior left hemidiaphragm is usually obscured by the adjacent heart and mediastinal fat. Gas in the stomach or splenic flexure of the colon beneath the left hemidiaphragm often can be used to identify this side on the lateral projection; interposition of the colon between the liver and right hemidiaphragm, although seen in fewer than 1% of patients,2 may provide a similar clue. Finally, in a left lateral radiograph (left side of the patient in contact with the image receptor) that is slightly oblique, the right ribs are more magnified than the left. Therefore, the hemidiaphragm that arises from the margin of the larger ribs can be identified as the right hemidiaphragm, and vice versa. On CT and MRI, the muscular diaphragm is best seen where it is surrounded by lower-attenuation fat (Fig. 114-1A).3 Segments of the diaphragm that are in contact with liver or spleen may be visible because the diaphragm muscle enhances to a lesser degree with intravenous contrast (see Fig. 114-1B).4 Occasionally, short segments are sufficiently thick to allow distinction from the adjacent liver without contrast.3 Nodularity of the muscular diaphragm is often seen (see Fig. 114-1C) and is often more pronounced in elderly individuals. The previously recognized relative advantage of direct multiplanar imaging with MRI has been reduced by the development of multidetector CT and the ability to quickly generate multiplanar reformations with excellent resolution. The diaphragmatic crura arising from the anterior aspects of the first through third lumbar vertebral bodies on the right and from the first and second lumbar vertebral bodies on the left5 are routinely depicted on CT and MRI. The crura sometimes have a nodular appearance, which is distinguishable from retroperitoneal lymph nodes by the tapering of the crura onto the lumbar vertebral bodies on consecutive cephalocaudal scans. The larger right crus decussates around the esophagus to form the esophageal hiatus, which may be seen on CT or MRI when appropriately oriented in the axial plane (see Fig. 114-1C). The aortic hiatus, which lies posterior to the esophageal hiatus, and the inferior vena caval hiatus, which passes through the central tendon, are not well depicted in the axial plane but may be seen in coronal or sagittal planes. One or both of the inferior pulmonary ligaments,6-8 which are frequently visible on CT as thin septa extending into the lungs from the pleural margin near the esophagus, may be seen extending to the diaphragm. The diaphragm also can be seen by means of ultrasonography. However, because of stomach and bowel gas, which block sound waves on the left, evaluation is generally limited

1380

Ch114-F06861.indd 1380

1/21/2008 3:43:00 PM

Chapter 114 Imaging of the Diaphragm

1381

f L St

M

L m Sp

A

B

C

f St L E A Sp

C

to the right side. In addition, the field of view with ultrasound is limited, and the diaphragm is more difficult to see in obese patients because the liver is positioned higher up under the rib cage. Hence, ultrasound is used infrequently in clinical evaluation.

ABNORMALITIES AFFECTING THE DIAPHRAGM Abnormalities of Diaphragm Position The normal position of the diaphragm on erect posteroanterior chest radiographs obtained in full inspiration varies substantially among individuals.9-11 The right hemidiaphragm dome usually projects between the level of the top of the T10 vertebral body and the top of the T12 vertebral body,

Ch114-F06861.indd 1381

FIGURE 114-1 A, CT image through the upper abdomen in a 30-yearold man reveals portions of the diaphragm (arrows) that have adjacent low-attenuation fat (f) or aerated lung. Segments of the diaphragm that are in contact with structures having similar attenuation, such as liver (L), spleen (Sp), or skeletal muscle (M), are not separately visible. St, stomach. B, CT image in a 78-year-old man demonstrates the diaphragm (short arrows) enhancing less than the liver (L) but similarly to skeletal muscle (m). The slightly nodular appearance of the right crus (long arrow) is of no significance. C, CT image in a 76-year-old man demonstrates multiple normal nodular folds or muscle bundles of both hemidiaphragms (arrows). Esophagus (E) passes through the hiatus created by the crural components of the diaphragm. A, aorta; C, colon; L, liver; Sp, spleen; St, stomach. (FROM GIERADA DS, SLONE RM, FLEISHMAN MJ: IMAGING EVALUATION OF THE DIAPHRAGM. CHEST SURG CLIN N AM 8:237, 1998.)

although it is slightly higher in obese individuals.11 The left hemidiaphragm usually projects about half of a vertebral level lower,11 although in 5% to 10% of normal subjects it is at the same level as the right or slightly higher.1,12 The diaphragm tends to be lower in persons with a more narrow anteroposterior dimension of the thorax11 and with increased age,11,13 and it tends to be higher with increased weight (Bellemare et al, 2001).11,13 Hemidiaphragm elevation or apparent elevation has numerous causes (Table 114-1), including lung volume loss; pleural disease (see Fig. 83-2 in Chapter 83); eventration (Fig. 114-2); phrenic nerve dysfunction or paralysis (Figs. 114-3 and 114-4); inspiratory pain (splinting); weakness due to various neuromuscular, metabolic, endocrine, or connective tissue disorders14,15; and abdominal distention or mass

1/21/2008 3:43:01 PM

1382

Section 6 Diaphragm

(Fig. 114-5). The causes of hemidiaphragm depression (Table 114-2) include diseases that produce lung hyperinflation (Fig. 114-6), positive-pressure ventilation, tension pneumothorax, and, in children, congenital lobar emphysema and foreign body aspiration.

TABLE 114-1 Causes of Hemidiaphragm Elevation Unilateral Volume loss (atelectasis, lobar collapse, partial lung resection, radiation fibrosis, congential pulmonary hypoplasia, pleural encasement by tumor) Eventration Abdominal disease (dilated stomach or colon, hepatomegaly, splenomegaly, subphrenic abscess) Phrenic nerve paralysis Splinting (rib fracture, pneumonia, infarction, abscess, cholecystitis, peritonitis) Mimics (subpulmonic pleural effusion, large pleural mass, diaphragmatic hernia) Single-lung transplantation for pulmonary fibrosis Phrenoplasty Bilateral Volume loss (suboptimal inspiration, supine positioning, atelectasis, lung resection, pulmonary fibrosis) Abdominal mass effect (obesity, pregnancy, marked bowel dilation, ascites, hepatosplenomegaly, large abdominal tumor) Eventration Subpulmonic pleural effusion (mimics hemidiaphragm elevation) Neuromuscular disease (quadriplegia, multiple sclerosis, amyotrophic lateral sclerosis, Guillain-Barré syndrome, myasthenia gravis, Eaton-Lambert syndrome, muscular dystrophy, steroid or alcohol myopathy, rhabdomyolysis) Connective tissue disease (fibrosis in rheumatoid arthritis, scleroderma, and ankylosing spondylitis; weakness in systemic lupus erythematosus, polymyositis) Endocrine and metabolic disorders (hypothyroidism, hyperthyroidism, Cushing’s disease, hypokalemia, hypophosphatemia, hypomagnesemia, metabolic alkalosis) Phrenic nerve paralysis

A

Congenital Hernias Bochdalek Hernia Bochdalek hernias result from incomplete closure of the embryonic pleuroperitoneal membrane. Despite the name, they typically occur through posterolateral defects in the diaphragm that are separate from the foramen of Bochdalek.16 The defects also occur medially and may be small or large. These hernias are seen more commonly on the left than on the right, an observation that has been attributed to earlier closure of the right pleuroperitoneal membrane17 and the protection of right-sided defects by the liver.18 A small defect may contain only retroperitoneal fat, whereas larger defects can contain abdominal viscera such as stomach, intestine, spleen, kidney, or liver.17,19 In the neonatal period, a large Bochdalek hernia (congenital diaphragmatic hernia) is a surgical emergency.20 Newborns present with severe respiratory distress and a scaphoid abdomen. The initial chest radiograph usually reveals opaci-

TABLE 114-2 Causes of Hemidiaphragm Depression Unilateral Large pneumothorax Asymmetrical bullous emphysema Large pleural effusion Foreign body aspiration Congenital lobar emphysema Single-lung transplantation for emphysema Bilateral Chronic obstructive pulmonary disease (emphysema, asthma) Deep inspiration (young, thin person) Bilateral large pneumothorax Bilateral large pleural effusion Mechanical ventilation at high pressures Cystic fibrosis Pulmonary histiocytosis X Lymphangioleiomyomatosis

B

FIGURE 114-2 Posteroanterior (A) and lateral (B) radiographs in a 42-year-old man reveal a broad, upwardly bulging segment (arrows) of the anteromedial right hemidiaphragm, characteristic of partial eventration.

Ch114-F06861.indd 1382

1/21/2008 3:43:01 PM

Chapter 114 Imaging of the Diaphragm

M

M

A

1383

B

FIGURE 114-3 Posteroanterior (A) and lateral (B) radiographs demonstrate an elevated left hemidiaphragm associated with a paramediastinal left upper lobe mass (M) caused by bronchogenic carcinoma. Fluoroscopy revealed left hemidiaphragm paralysis, consistent with phrenic nerve invasion. (FROM GIERADA DS, SLONE RM, FLEISHMAN MJ: IMAGING EVALUATION OF THE DIAPHRAGM. CHEST SURG CLIN N AM 8:237, 1998.)

FIGURE 114-4 Radiograph obtained 1 month after left carotid endarterectomy shows left hemidiaphragm elevation. The elevation had been persistent since the immediate postoperative radiograph, which was suspicious for cervical phrenic nerve injury. Fluoroscopy confirmed left phrenic nerve paralysis.

Ch114-F06861.indd 1383

fication of the hemithorax and a contralateral shift of the mediastinum, caused by herniation of the abdominal contents into the chest. As air is swallowed, bowel loops in the chest become filled with gas and produce multiple lucencies (Fig. 114-7). Morbidity and mortality are related to the degree of underlying pulmonary hypoplasia. Prenatal diagnosis is possible with the use of fetal ultrasonography.21 In the adult, a Bochdalek hernia is usually asymptomatic and discovered incidentally by chest radiography or CT as a soft tissue mass of variable size bulging upward through the posterior aspect of a hemidiaphragm. Such incidental hernias remaining undetected until adulthood may even be more frequent on the right than on the left.22 The hernia contents usually can be defined without difficulty on CT or MRI, which also can demonstrate the diaphragmatic defect (Fig. 114-8). Other radiologic studies also may demonstrate the hernia contents: barium studies may reveal herniated bowel loops; intravenous urography may reveal a herniated kidney; and technetium 99m–sulfur colloid scintigraphy may demonstrate herniation of the liver or spleen. If bowel or organs are involved, there may be a risk of strangulation.23 Small, focal diaphragmatic defects or discontinuities, with or without herniated fat or viscera, may be seen in more than 5% of adults on CT (Gale, 1985).24,25 Their increasing incidence with age and emphysema strongly suggests that most such abnormalities are acquired and are not true congenital Bochdalek hernias.25

1/21/2008 3:43:02 PM

1384

Section 6 Diaphragm

A

B

rc

E

lc T

la T

T A

C

D

FIGURE 114-5 Posteroanterior (A) and lateral (B) radiographs show left hemidiaphragm elevation and a right retrocardiac mass. C and D, Cephalocaudal CT images reveal that the radiographic findings are due to a large tumor (T) of mixed fat and soft tissue attenuation, representing a liposarcoma, which extends through the esophageal hiatus (curved arrow in D). Short arrows in D point to the left (lc) and right (rc) crus of diaphragm. A, aorta; E, esophagus; la, left atrium.

Morgagni Hernia Foramen of Morgagni hernias are related to maldevelopment of the embryologic septum transversum with failure of fusion of the sternal and costal fibrotendinous elements of the diaphragm.17,19 In contrast to the true Bochdalek hernia, a hernia sac of peritoneum and pleura surrounds the contents of a Morgagni hernia.26 Morgagni hernias are most often rightsided, probably because left-sided defects are covered by the heart and pericardium, and are often associated with obesity.

Ch114-F06861.indd 1384

The hernia sac usually contains omentum but may contain transverse colon or, rarely, stomach, small bowel, or liver.17 Although some Morgagni hernias produce epigastric pressure or discomfort and may rarely cause strangulation or obstruction of contained portions of the gastrointestinal tract,18 they usually come to clinical attention as asymptomatic right cardiophrenic angle masses detected on chest radiographs (Fig. 114-9). Gas-filled intestinal loops may be present. The CT finding of omental vessels coursing across the parasternal diaphragmatic defect facilitates CT diagnosis

1/21/2008 3:43:03 PM

Chapter 114 Imaging of the Diaphragm

1385

12

A

B

FIGURE 114-6 A, Posteroanterior radiograph in a 59-year-old man with emphysema reveals hyperinflation of the lungs, with depression of the diaphragm inferior to the level of the 12th thoracic vertebra (12). B, Posteroanterior radiograph in a 36-year-old man with emphysema demonstrates asymmetrical bullous disease that is more severe on the right, causing greater right hemidiaphragm depression and contralateral shifting of the mediastinum.

(Fig. 114-10). The actual defect may be difficult to identify because of its typically small size. CT readily permits distinction from other causes of cardiophrenic angle masses, such as pericardial cysts, pericardial fat pads, and pleural or parenchymal masses, by revealing omental fat, omental vessels, and abdominal viscera peripheral to the diaphragm in the lower anterior chest. As with Bochdalek hernias, multiplanar MRI is occasionally useful.

Acquired Hernias Hiatal Hernia

FIGURE 114-7 Frontal radiograph in a newborn infant with a congenital diaphragmatic hernia, obtained 4 hours after birth, reveals shifting of the mediastinum to the right and numerous cystic and tubular lucencies filling the left hemithorax, consistent with herniated bowel.

Ch114-F06861.indd 1385

Hiatal hernia is the most frequently encountered type of diaphragmatic hernia in adults. Acquired enlargement of the esophageal hiatus and laxity of the phrenoesophageal ligament are etiologic factors, often associated with conditions resulting in increased intra-abdominal pressure, such as obesity and pregnancy.17,26 Sliding hiatal hernias are much more common than the paraesophageal variety, in which the stomach herniates up alongside the lower esophagus. On chest radiography, hiatal hernias are depicted as lower posterior mediastinal, retrocardiac soft tissue masses, often containing air and fluid. The diagnosis is easily confirmed by a barium esophagogram, although this is rarely necessary. Very large hernias can become incarcerated or undergo vol-

1/21/2008 3:43:04 PM

1386

Section 6 Diaphragm

A

B

C C

C

D

FIGURE 114-8 Posteroanterior (A) and lateral (B) chest radiographs obtained in the emergency department to evaluate for possible pneumonia in a 92-year-old woman reveal an ovoid lucency inferiorly in the posterior left hemithorax. An air-fluid level is seen on the lateral view (arrows). C, CT image shows loops of colon (C) and surrounding fat in the posterior sulcus of the right hemithorax. D, Slightly more caudal CT image demonstrates the colonic loops and fat passing through a defect (arrows at margins of defect) in the posterolateral right hemidiaphragm posterior to the liver and kidney, consistent with an incidental Bochdalek hernia.

vulus (Fig. 114-11A).27 Hiatal hernias are frequent incidental findings on CT scans. Extension of a portion of the proximal stomach into the lower mediastinum is seen, and an abnormally wide esophageal hiatus may be identified. Incomplete distention of the stomach lumen within the hernia may simulate wall thickening of the gastric fundus on CT and raise suspicion of neoplasm; prone position scanning to distend the proximal stomach28 or further evaluation by endoscopy or barium fluoroscopy may be indicated in suspicious cases. Multidetector CT or multiplanar MRI can be useful to define the contents of large hiatal hernias when operative repair is planned (see Fig. 114-11B).

Traumatic Hernia Traumatic diaphragmatic hernia usually results from either blunt or penetrating injury. Diaphragm rupture is recognized

Ch114-F06861.indd 1386

in 0.5% to 6% of blunt trauma survivors in various series.29-32 It more often affects the left hemidiaphragm, possibly because of protection of the right hemidiaphragm by the liver or because of inherently greater weakness of the left hemidiaphragm; infrequently, bilateral rupture occurs.29-35 Blunt traumatic tears can involve any portion of the diaphragm,36 although they usually involve the posterior central aspect of a hemidiaphragm and extend radially, or they can result in disruption of the posterolateral attachments.29,37 Blunt traumatic defects are usually large, often more than 10 cm in length.19,31,34,38 Penetrating trauma due to stab wounds most often affects the left hemidiaphragm because most people are right-handed, whereas gunshot wounds affect both sides with equal frequency.34 Penetrating wounds are usually less than 2 cm in length.38 Though exceedingly rare, diaphragm rupture and hernia may occur spontaneously from sudden increases in abdominal pressure, such as with vomiting, par-

1/21/2008 3:43:04 PM

Chapter 114 Imaging of the Diaphragm

1387

A

B

C

turition, coughing, and vigorous physical exertion,39 or after thoracoabdominal surgery.40 Herniation through a traumatic defect most frequently involves the stomach on the left and the liver on the right, but it can also involve the large or small bowel, omentum, liver, or spleen.29-31 In virtually all cases, traumatic rupture of the diaphragm is associated with multisystem injuries which more directly determine survival in the acute setting,29,31,32,34,36 and there are no reliable clinical signs or symptoms.30 In addition, conservative management of patients whose abdominal injures can now be monitored by CT or ultrasound precludes the identification of diaphragmatic tears that would have been detected during exploratory laparotomy. The diagnosis of diaphragm rupture therefore may be overlooked and requires a high degree of suspicion.32,41 Early diagnosis is important because the pleuroperitoneal pressure gradient can

Ch114-F06861.indd 1387

FIGURE 114-9 Posteroanterior (A) and lateral (B) chest radiographs in a 52-year-old woman with acute nausea and vomiting demonstrate a large right cardiophrenic angle mass. C, CT image reveals that the mass comprises transverse colon and fat extending from the parasternal region, consistent with a Morgagni hernia. There were no inflammatory changes to suggest strangulation, and no bowel dilation to suggest obstruction.

cause defects to enlarge over time,34,42 with eventual bowel incarceration, strangulation, and obstruction.36,41,43-45 Numerous studies have found the chest radiograph to be the most valuable test in the preoperative diagnosis of diaphragm rupture. However, the range of reported sensitivities is wide, from 20% to 71%.29-32,34,35 Herniation of hollow viscera into the chest and identification of a nasogastric tube in the intrathoracic stomach (Fig. 114-12) are the most specific radiographic signs. Diaphragm rupture should be suspected whenever radiographs reveal apparent elevation of a hemidiaphragm (Fig. 114-13), although this can be caused by atelectasis, eventration, diaphragm paralysis, or subpulmonic pleural effusion. Because nonspecific apparent elevation of the hemidiaphragm is usually the only sign of right hemidiaphragm rupture, right-sided rupture is more difficult to detect radiographically. Data from one small study suggest

1/21/2008 3:43:05 PM

1388

Section 6 Diaphragm

A

B L

St A Sp

C

that elevation of the apparent right hemidiaphragm by 4 to 5 cm or more relative to the left should be considered highly suspicious for right-sided rupture in the setting of blunt trauma.40 Evidence of rupture may not be present on the initial radiograph but may develop on subsequent studies, so serial radiographs can be helpful in diagnosis.30,31,35,41 Other plain radiographic findings of diaphragm injury include hemothorax, basal lung opacity, and abnormal contour of a hemidiaphragm. Rarely, herniated omental fat can simulate pleural fluid on chest radiographs.46 Radiographic findings are absent or nonspecific in most penetrating injuries, and early diagnosis typically requires direct inspection.47 The accuracy of CT in diagnosing traumatic diaphragmatic hernias has been variable, with sensitivity and specificity on

Ch114-F06861.indd 1388

FIGURE 114-10 Posteroanterior (A) and lateral (B) radiographs in a patient with a large right Morgagni hernia demonstrate numerous bowel loops in the right lower hemithorax. C, Early arterial phase, contrastenhanced CT image demonstrates enhancing mesenteric arteries, unenhancing veins, and mesenteric fat extending from the parasternal portion of the diaphragm to the herniated bowel loops filling the right lower hemithorax. The arrows indicate the anterior left hemidiaphragm. A, aorta; L, liver; Sp, spleen; St, stomach.

retrospective studies in the range of 61% to 100% and 77% to 100%, respectively, and better for left- than for right-sided ruptures.48-51 The numerous findings indicative of traumatic disruption40,48-55 include the following: 1. Contact of the upper third of the liver on the right or the stomach or bowel on the left with the posterior ribs (dependent viscera sign) (Fig. 114-14; see Figs. 114-12 and 114-13) 2. Identification of abdominal structures external to the diaphragm (see Fig. 114-14) 3. Focal constriction of the hernia contents (collar or hourglass sign) (Fig. 114-15; see Figs. 114-12 and 114-14) 4. A focal bulge of the liver (hump sign, a variation of the collar sign) (Fig. 114-16; see Fig. 114-15)

1/21/2008 3:43:06 PM

Chapter 114 Imaging of the Diaphragm

1389

H

F V

SB SB C

P SB A St

A

B

FIGURE 114-11 A, Image from an upper gastrointestinal series in a 45-year-old man demonstrates a large paraesophageal hernia, with a completely intrathoracic stomach. The gastric fundus (F) is on the right, consistent with organoaxial rotation. B, CT image in a 74-year-old woman obtained to evaluate the contents of a large hiatal hernia reveals stomach (St), colon (C), small bowel (SB), and pancreas (P) within the lower mediastinum. A, aorta; H, heart; V, inferior vena cava.

5. Linear lucency across the liver along the torn edge of the hemidiaphragm (band sign) 6. Abrupt discontinuity of the diaphragm (see Fig. 114-16), with or without visceral herniation (this sign should be interpreted cautiously because similar small defects are frequently seen in asymptomatic persons scanned for indications other than trauma) 7. Inability to identify the diaphragm (absent diaphragm sign) in an area where it does not contact another organ and should normally be seen 8. Acute arterial extravasation of contrast at the level of the diaphragm 9. Asymmetrical thickening of the diaphragm (see Fig. 114-15) The presence of any one of these signs indicates a substantial chance of diaphragm rupture.51 Intrapericardial herniation occurs rarely but may be demonstrated by CT.56,57 With penetrating trauma, CT signs of diaphragm injury include contiguous organ injury on either side of the diaphragm; herniation of fat through the diaphragmatic defect; a wound track extending to the diaphragm; thickening of the diaphragm due to blood or edema; and an isolated focal defect without herniation.55 Isolated small defects from penetrating trauma, in the absence of other injuries, may be difficult to detect by imaging in the absence of herniation. Such small defects may result in delayed herniation if they are not detected and repaired (see Fig. 114-16); therefore, laparoscopic or thoracoscopic evaluation may be indicated with certain injuries.58,59 If hemidiaphragm elevation is only mild and a defect is not seen on CT, additional or follow-up imaging may be indicated. Spiral CT with multiplanar reformatting (see Fig. 114-12) can be helpful,52 although it may not always be

Ch114-F06861.indd 1389

definitive or provide additional information,49 and it can be misleading (Larici et al, 2002).50 Direct coronal or sagittal MRI also may be helpful in diagnosing traumatic diaphragmatic hernias, which may be more readily recognized in these planes. These views can be of particular value in depicting the secondary sign of a focal bulge or mushrooming in the diaphragmatic contour, particularly on the right, where diagnosis can be difficult (see Fig. 114-15). Use of MRI is generally limited to non–critically ill and hemodynamically stable patients in whom a delayed diagnosis is sought.32,60-63 In the nonacute setting, imaging studies that may be performed for other indications sometimes depict a traumatic diaphragmatic hernia. Ultrasound can be of value in assessing the right hemidiaphragm by depicting the free edge of the diaphragm as a flap within pleural fluid or by demonstrating liver herniated into the chest.64 Scintigraphy can demonstrate traumatic herniation of the liver or spleen. Contrast studies of the upper or lower gastrointestinal tract may demonstrate herniated segments, particularly in delayed presentations.

Paralysis of the Diaphragm Paralysis of the diaphragm may result from an abnormality at any point along its neuromuscular axis, may be unilateral or bilateral, and has numerous potential causes.15,17,65-67 Invasion by a malignant neoplasm (see Fig. 114-3) and phrenic nerve trauma related to surgery (stretch, crush, or transection) (see Fig. 114-4) are common causes, although many cases are idiopathic. Central nervous system conditions, such as multiple sclerosis, Arnold-Chiari malformation, syringomyelia, neurofibromatosis, and high cervical quadriplegia, also have been associated with bilateral hemidiaphragm paralysis. Hypothermic injury of the phenic nerve related to the use of cold topical cardioplegia during coronary artery bypass

1/21/2008 3:43:07 PM

1390

Section 6 Diaphragm

A

B

C

surgery can lead to hemidiaphragm paralysis, usually on the left, which may persist for longer than 1 year.66 Multiple other causes have been implicated, including mediastinal masses such as lymphadenopathy, aortic aneurysm, and substernal goiter; diabetes; vasculitis; herpes zoster; and birth injury. Diaphragm weakness without paralysis can be found in numerous conditions, including myopathies, connective tissue diseases, and various endocrine and metabolic disorders (see Table 114-1). Fluoroscopy is the simplest, quickest, and most practical method of assessing diaphragm motion. Diaphragm motion also can be assessed by ultrasound or MRI and by comparing radiographs obtained in full inspiration and expiration. In most studies, the average maximal excursion of the hemidiaphragm domes is 3 to 5 cm (range, 2-10 cm).68-71 Normal

Ch114-F06861.indd 1390

FIGURE 114-12 A, CT image in a 20-year-old man after a motor vehicle accident reveals a dilated stomach in the left hemithorax. The stomach contacts the posterior chest wall, constituting the dependent viscera sign of a traumatic diaphragmatic hernia. There is a small amount of subcutaneous gas in the left chest wall. B, Coronal CT reconstruction demonstrates gross herniation of the stomach, which is narrowed where it passes through the diaphragm (collar sign) (arrows). Note the large left pneumothorax and left lung partial opacification, most likely caused by contusion and atelectasis. C, Frontal chest radiograph after nasogastric tube placement shows the tube coiled in the intrathoracic stomach.

excursion is usually greater than 2.5 cm, but excursion of less than 3 cm is fairly frequent18,69,72,73 and can be seen in healthy persons with a normal vital capacity.72 Unequal excursion of the hemidiaphragms is common; the difference is usually less than 1.5 cm and may be greater on either side.71,72 Asynchronous motion of the hemidiaphragms is not unusual.10,12,71 Fluoroscopy is typically performed with the patient erect, but supine positioning stresses the diaphragm by removing the aid of gravity during inspiration and may increase the sensitivity of the test. In unilateral paralysis, a paralyzed hemidiaphragm paradoxically moves upward on inspiration and downward on expiration, passively following changes in intrapleural and intra-abdominal pressure.10,17 In bilateral paralysis, both hemidiaphragms move upward on inspiration, concomitant with inward rather than normal outward move-

1/21/2008 3:43:07 PM

Chapter 114 Imaging of the Diaphragm

A

1391

B

FIGURE 114-13 A, Frontal chest radiograph in a 22-year-old woman who was in a high-speed car accident shows apparent elevation of the left hemidiaphragm. B, CT image reveals that the stomach fills the left lower hemithorax. Contact of the stomach with the posterior chest wall (dependent viscera sign) indicates traumatic diaphragmatic hernia rather than hemidiaphragm elevation.

A

B

St

A a St

C

Ch114-F06861.indd 1391

FIGURE 114-14 A, Initial frontal radiograph obtained in a man who fell 30 feet from a balcony shows normal position of both hemidiaphragms. B, Frontal radiograph obtained 1 hour later shows new apparent elevation of the left hemidiaphragm suspicious for interval development of a diaphragmatic hernia. C, CT image reveals herniation of the stomach (St) through a traumatic defect in the medial left hemidiaphragm (arrows at margins of defect). Note constriction of stomach by the defect (collar sign) and contact of herniated portion of stomach with posterior chest wall (dependent viscera sign). Absence of the inferior vena cava and the enlarged azygos system veins (a) passing behind the aorta (A) are due to congenital azygos continuation of the inferior vena cava.

1/21/2008 3:43:08 PM

1392

Section 6 Diaphragm

A

B

C

D

E

Ch114-F06861.indd 1392

FIGURE 114-15 A, Frontal chest radiograph in a 24-year-old woman after a car accident shows bilateral parenchymal lung opacities consistent with contusion and/or aspiration. Diaphragm position is within normal range bilaterally. B, CT image obtained on admission shows thickening of the right crus (arrows), a nonspecific finding that can be interpreted as an indirect sign of traumatic rupture. C, Frontal radiograph obtained approximately 1 week later, after the patient had been extubated, reveals a new upward bulge of the apparent right lateral hemidiaphragm (hump sign) suspicious for traumatic hernia. Coronal (D) and sagittal (E) MRIs confirm herniation of the liver, with narrowing (arrows) at the level of the diaphragm defect (collar sign).

1/21/2008 3:43:09 PM

Chapter 114 Imaging of the Diaphragm

1393

B

A

* St

St

St

C

D

FIGURE 114-16 Posteroanterior (A) and lateral (B) chest radiographs in a 33-year-old man who had sustained a left upper quadrant stab wound almost 2 years earlier and presented with chest pain radiating to the back and upper abdomen shows apparent focal elevation of the anterolateral left hemidiaphragm (hump sign). C, CT image through the lower chest reveals elevation of the stomach (St) and a small left pleural effusion. D, More caudal CT image shows the stomach (St) passing through defect in left hemidiaphragm (arrows at margins of defect). Ingested oral contrast material within the abdominal portion of the stomach has not entered the herniated portion of the stomach. The most distal portion of the stomach (asterisk) remains on the abdominal side of the diaphragm defect. Note edema within fat adjacent to the anterior margin of the defect. A strangulated hernia was found at surgery, and partial gastrectomy was performed, with repair of the diaphragm.

ment of the abdominal wall.74 However, a paralyzed hemidiaphragm may show a slight descent on slow, deep inspiration due to passive stretching as the rib cage expands. The sniff test is used to confirm that abnormal hemidiaphragm excursion is caused by paralysis rather than unilateral weakness. For the sniff test, the patient inhales rapidly and forcefully through the nose with the mouth closed. This normally produces a rapid, brief descent of both hemidiaphragms.

Ch114-F06861.indd 1393

Paradoxical upward motion of an entire hemidiaphragm (in oblique or lateral projection) of greater than 2 cm is consistent with hemidiaphragm paralysis (Alexander, 1966).68 Several potential difficulties may limit the fluoroscopic assessment of diaphragm paralysis. Diaphragm motion may be diminished due to inflammatory processes such as pneumonia, pleuritis, pleural effusion, peritonitis, and subphrenic abscess, so fluoroscopic assessment is best delayed until such

1/21/2008 3:43:09 PM

1394

Section 6 Diaphragm

reversible conditions that may affect the diaphragm have resolved. Complete eventration may be difficult or impossible to distinguish from diaphragm paralysis,18 and severe weakness or fatigue may appear identical to bilateral paralysis on fluoroscopy.17 Although some patients with bilateral paralysis show the typical paradoxical upward motion of both hemidiaphragms during a deep inspiration or sniff, normal inspiratory descent of the diaphragm can be mimicked in those patients who perform a compensatory maneuver of actively exhaling below functional residual capacity using their abdominal muscles, then inhaling by relaxing the abdominal muscles, which causes passive descent of the diaphragm.75 This effect can be detected by carefully observing abdominal motion during breathing,76 and it can be minimized by performing the examination with the patient in the recumbent position, which eliminates the assistance of gravity.77 The diagnosis of diaphragm paralysis also can be difficult in patients with severe hyperinflation due to chronic obstructive pulmonary disease, in whom the normal diaphragm moves very little, or in weak, debilitated patients who cannot produce a strong inspiratory effort or forceful sniff. In some patients with phrenic nerve injury, even though fluoroscopy demonstrates paralysis, the paralysis may not be permanent. Regeneration of phrenic nerve fibers may lead to partial or complete recovery of diaphragm function over time. Based on the normal rate of peripheral nerve regeneration, this usually occurs within 1 year.78

and cystic masses such as bronchogenic89,90 and teratoid91 cysts have been reported most frequently.92 Most malignant tumors are sarcomas of fibrous or muscular origin.92 Numerous other tumors have been reported, including schwannoma,93 chondroma,94 pheochromocytoma,95 endometriosis,96 and hemangiopericytoma.97 Tumors of the diaphragm that are large enough for radiographic detection produce a focal bulge or contour abnormality and can resemble a diaphragmatic hernia, eventration, or a pleural lesion. Because the diaphragm is a thin structure, the diaphragmatic origin of a mass may be difficult to confirm as separate from lung, pleura, or abdominal viscera, even on CT, MRI, or ultrasonography. Small masses of fat density are occasionally seen on CT within the diaphragm muscle; they may represent lipomas that are too small for clinical or radiographic detection or age-associated fat containing diaphragmatic defects.25 The CT appearance of nonlipomatous soft tissue tumors usually is not specific. Thoracic or abdominal tumors may secondarily involve the diaphragm by direct extension. Such tumors include bronchogenic carcinoma, mesothelioma and other primary or secondary pleural or chest wall malignancies, hepatic malignancies, peritoneal carcinomatosis, and tumors of the stomach, kidney, adrenal gland, colon, ovary, or retroperitoneum, as well as lymphoma and peritoneal carcinomatosis.17 However, if thoracic or abdominal masses abut the diaphragm without traversing it on imaging studies, definitive diagnosis of invasion cannot be made.

Accessory Diaphragm

COMMENTS AND CONTROVERSIES

An accessory, or duplicated, diaphragm is a rare congenital anomaly in which a thin, fibromuscular membrane is attached to the diaphragm anteriorly and courses posteriorly and cephalad to attach to the posterior rib cage.79-81 Most reported cases have occurred on the right. The accessory diaphragm may follow a fissure or divide the lower lobe. On imaging studies, the affected hemithorax is usually small due to the accompanying pulmonary hypoplasia, and the mediastinal border is indistinct and blurred by a hazy increase in opacity. The lateral radiograph reveals a retrosternal band of increased opacity produced by loose areolar connective tissue filling the space between the anterior chest wall and the small lung.79 The findings closely resemble those of right upper and middle lobe atelectasis or left upper lobe atelectasis, or alternatively, primary pulmonary hypoplasia.79,80,82,83 A thickened, oblique septum may be seen extending posteriorly and cephalad from the diaphragm to the posterior chest wall. CT or MRI may be helpful in suggesting the diagnosis and identifying associated pulmonary vascular anomalies84,85; there is frequently an association with other congenital anomalies, particularly pulmonary hypoplasia, partial anomalous arterial supply or venous drainage, congenital heart disease,79,82 or congenital pulmonary venolobar (so-called scimitar) syndrome.86

Imaging of the diaphragm is difficult because of its complex shape, thin profile, and broad extent. The importance of the chest radiography and fluoroscopy should not be overlooked. When faced with differentiating eventration from herniation or paralysis, crosssectional studies are essential. Dynamic imaging may further define the problem. Primary diaphragmatic tumors are uncommon, and secondary involvement is much more common. In this setting, metabolic imaging may prove useful. T. W. R.

Tumors of the Diaphragm Primary tumors of the diaphragm are very rare. Benign tumors are equal to or greater in frequency than malignant tumors, and the right and left sides are equally affected.87 Lipomas88

Ch114-F06861.indd 1394

KEY REFERENCES Alexander C: Diaphragm movements and the diagnosis of diaphragmatic paralysis. Clin Radiol 17:79-83, 1966. ■ This paper established the guidelines used for fluoroscopic diagnosis of diaphragm paralysis and is a common literature reference for the topic. Bellemare JF, Cordeau MP, Leblanc P, et al: Thoracic dimensions at maximum lung inflation in normal subjects and in patients with obstructive and restrictive lung diseases. Chest 119:376-386, 2001. ■ This study quantifies the variation in normal diaphragm position; the association of position with age, height, and body mass index; and alterations in position that occur in chronic obstructive pulmonary disease, cystic fibrosis, and restrictive lung disease. Gale ME: Bochdalek hernia: Prevalence and CT characteristics. Radiology 156:449-452, 1985. ■ This retrospective case review of more than 900 chest and abdomen CT cases found a 6% prevalence of small posterior diaphragmatic, Bochdalek-type hernias, illustrating that these abnormalities are relatively frequent, incidental, asymptomatic findings on CT.

1/21/2008 3:43:10 PM

Chapter 114 Imaging of the Diaphragm

Larici AR, Gotway MB, Litt HI, et al: Helical CT with sagittal and coronal reconstructions: Accuracy for detection of diaphragmatic injury. AJR Am J Roentgenol 179:451-457, 2002. ■ Although typically retrospective, this blinded analysis of 25 surgically proven diaphragm injuries and 22 surgically confirmed uninjured diaphragms serves as one

Ch114-F06861.indd 1395

1395

of the better demonstrations of the usefulness of multiple CT signs for evaluating the diaphragm after blunt, penetrating, right-sided or left-sided trauma. The sensitivity and specificity overall were 84% and 77%, respectively, and were greater for left than right hemidiaphragm injury.

1/21/2008 3:43:10 PM

chapter

115

EVALUATION AND MANAGEMENT OF ELEVATED DIAPHRAGM Clemens Aigner Walter Klepetko

Key Points ■ Elevated diaphragm is a rare indication for surgery in adult

patients. ■ Clinical key symptoms are dyspnea and orthopnea. ■ Complete diagnostic workup is crucial in treatment planning. ■ Surgery yields good results in carefully selected patients.

When discussing the evaluation and management of diaphragmatic elevation, it is necessary to distinguish between congenital conditions of diaphragmatic eventration or diaphragmatic hernias and acquired elevation of the diaphragm. Congenital diaphragmatic pathologies are discussed in separate chapters; this chapter focuses on acquired conditions in which patients present with an elevated diaphragm (Table 115-1). In most adult patients, elevation of the diaphragm is primarily detected on chest radiography.1 Patients are often asymptomatic or present with only mild symptoms. Further confirmation and evaluation of the underlying mechanism may be gained by computed tomography (CT),2 ultrasonography,3 or, in rare cases, magnetic resonance imaging (MRI); MRI is, however, useful in detecting paradoxical motion (Iwasawa et al, 2002).4-6 The underlying pathologies for unilateral or bilateral diaphragmatic elevation encompass a wide spectrum. The cause may be supradiaphragmatic, diaphragmatic, or subdiaphragmatic. Frequently, the exact cause of an elevated diaphragm is difficult to determine even after complete surgical exploration.7 It remains a point of discussion in the literature whether an underlying occult malignant process is a likely cause.8 The main symptoms of an elevated diaphragm are respiratory problems.9 The underlying mechanism is a restrictive breathing pattern. The severity obviously depends on the degree of diaphragmatic elevation.10 In addition to restriction, various degrees of compressive atelectasis with decreased ventilation and perfusion in the affected lung base have been described.11 Another important factor influencing respiratory function is the paradoxical movement of a paralyzed diaphragm. There is paradoxical deflation of the lung during inspiration, caused by elevation of the diaphragm, and during expiration there is paradoxical inflation of the lung, resulting in rebreathing of dead air space. The normal diaphragm creates a negative intrapleural pressure, which is absent in a diseased elevated diaphragm, resulting in paradoxical movement.12

ETIOLOGY Supradiaphragmatic Causes The most frequently encountered reason for unilateral hemidiaphragm elevation is lung volume loss. Additional signs accompanying unilateral lung volume loss may be ipsilateral shifting of the mediastinum and narrowing of the intercostal spaces. Bilateral lung volume loss may also be responsible for bilateral diaphragmatic elevation. Underlying causes include atelectasis (Fig. 115-1), pulmonary fibrosis (Fig. 115-2), partial lung resection, lobar collapse, and encasement by tumor formation, as seen in mesothelioma patients (Fig. 1153).13-15 Also, the diaphragm is frequently elevated after pneumonectomy. Obviously, all diseases leading to loss of pulmonary volume can eventually lead to diaphragmatic elevation. Additionally, osseous alterations such as rib fracture and scoliosis may provoke elevation of the diaphragm. Such cases are mainly related to mechanical factors.16 With an intact phrenic nerve, they are usually associated with normal diaphragmatic function or only temporary paralysis, with full recovery expected.

Diaphragmatic Causes Diaphragmatic elevation is frequently caused by diaphragmatic eventration, in which a portion or the entire hemidiaphragm is elevated with a marked decrease in muscular fibers,17 yet retains an unbroken continuity with normal attachments to the costal margins. In such cases, the abnormally thin diaphragm is stretched and displaced by the abdominal organs. Aside from congenital eventration, which is caused by incomplete muscularization of the pericardioperitoneal membrane,18 the incidence of eventration, especially of the right hemidiaphragm, increases with age, suggesting an acquired process. Eventration frequently does not affect the entire hemidiaphragm but is incomplete. The most commonly involved part is the anteromedial right hemidiaphragm.19 In some cases, a congenital eventration that remained unrecognized during childhood becomes symptomatic with decreasing pulmonary function. Also, blunt trauma can lead to diaphragmatic elevation with an abnormally thin and elevated diaphragm, with the macroscopic aspect of eventration.20,21 A major cause leading to diaphragmatic paralysis, a condition in which the diaphragm still has its normal muscular basis even if it is atrophic, is phrenic nerve paralysis. Involvement of the phrenic nerve can be classified in posttraumatic, iatrogenic, neoplastic, related to infectious or neuromuscular disease, or, if no underlying pathology is found, idiopathic.22

1396

Ch115-F06861.indd 1396

1/21/2008 3:43:59 PM

Chapter 115 Evaluation and Management of Elevated Diaphragm

1397

TABLE 115-1 Frequent Causes of Acquired Elevated Diaphragm Supradiaphragmatic Pulmonary resection Pulmonary fibrosis Atelectasis Pleural tumor Pneumonia Pulmonary abscess Pulmonary infarction Rib fracture Diaphragmatic Eventration Blunt trauma Phrenic nerve palsy Traumatic Iatrogenic (surgery, chest tubes, central venous catheter) Infectious (poliomyelitis, diphtheria, tuberculosis, herpes zoster, influenza, syphilis, echinococcus, subphrenic abscess, pericarditis) Neoplastic (N2 disease, mediastinal tumors) Dystrophia myotonica Lead poisoning Idiopathic Infradiaphragmatic Obesity Pregnancy Bowel dilation Hepatosplenomegaly Abdominal tumors Ascites

FIGURE 115-1 Right lower lobe atelectasis with consecutive elevation of the right hemidiaphragm. (COURTESY OF DR. BÖHM, DEPARTMENT OF RADIOLOGY, ST. ELISABETH HOSPITAL, LINZ, AUSTRIA.)

Systemic Disease Neuromuscular disorders (quadriplegia, multiple sclerosis, amyotrophic lateral sclerosis, Guillain-Barré syndrome, EatonLambert syndrome, myasthenia gravis, muscular dystrophy, steroid myopathy, alcohol myopathy, rhabdomyolysis) Connective tissue disease leading to pulmonary fibrosis (rheumatoid arthritis, scleroderma, ankylosing spondylitis) or diaphragmatic weakness (systemic lupus erythematosus, polymyositis) Endocrine and metabolic diseases (hypothyroidism, hyperthyroidism, Cushing’s syndrome, low potassium or phosphate or magnesium, metabolic alkalosis)

Injuries to the phrenic nerve are a potential complication of any type of thoracic or cardiac surgery, as well as neck surgery. A higher risk seems to be associated with correction of congenital cardiovascular anomalies (Joho-Arreola et al, 2005).23-26 The use of ice slush to achieve topical hypothermia in adult cardiac surgery also leads to a higher incidence of temporary postoperative phrenic nerve paralysis (Efthimiou et al, 1991).27,28 The use of ice slush is also a potential source of phrenic nerve injury in lung transplantation. Diabetes mellitus and grafting of the internal thoracic artery have been described as risk factors for postoperative phrenic nerve paralysis.29 Phrenic nerve palsy has also been described after insertion of chest tubes30-32 and central venous catheters.33-35 Numerous neuromuscular and infectious diseases, including tuberculosis, diphtheria, poliomyelitis, herpes zoster, syphilis, influenza, dystrophia myotonica, pericarditis, sub-

Ch115-F06861.indd 1397

FIGURE 115-2 Bilateral diaphragmatic elevation in a patient with pulmonary fibrosis. (COURTESY OF DR. BÖHM, DEPARTMENT OF RADIOLOGY, ST. ELISABETH HOSPITAL, LINZ, AUSTRIA.)

phrenic abscess, echinococcal liver infection, Lyme disease, and lead poisoning, have been reported to be associated with phrenic nerve palsy and elevated diaphragm.36-41 Phrenic nerve injury can also be caused by neoplastic involvement. Mainly malignant mediastinal masses, such as enlarged N2 lymph nodes in bronchogenic carcinomas, or

1/21/2008 3:43:59 PM

1398

Section 6 Diaphragm

EVALUATION AND DIAGNOSTIC EXAMINATIONS

FIGURE 115-3 Unilateral diaphragmatic elevation caused by malignant pleural mesothelioma.

primary mediastinal tumors such as thymomas, lymphomas, or germ cell tumors are responsible.42 In diaphragmatic hernia, the regular continuity of the diaphragm is broken, which can mimic diaphragmatic elevation in radiologic examinations. The most common causes of bilateral diaphragmatic elevation are severe obesity and pregnancy. Nonetheless, neuromuscular, connective tissue, and metabolic disorders are important differential diagnoses and must be ruled out.4 In connective tissue diseases such as polymyositis and systemic lupus erythematosus, diaphragmatic weakness causes the elevation, whereas scleroderma, rheumatoid arthritis, and ankylosing spondylitis cause elevation as a result of pulmonary fibrosis.43

Infradiaphragmatic Causes Abdominal disease and pregnancy may also lead to diaphragmatic elevation. Large tumors, fluid collections, subphrenic cysts or abscesses, organomegaly, and gastrointestinal dilation are potential causes.

Usually, the diagnosis is established by posteroanterior and lateral chest radiographs. The diaphragm is unilaterally on the affected side or clearly elevated bilaterally. Additionally, an abnormal position of the stomach may be detected. Diaphragmatic elevation on a chest radiograph does not predict diaphragmatic paralysis, although paralysis is unlikely if no elevated diaphragm is found (Chetta et al, 2005).48 If the phrenic nerve is affected, paradoxical motion of the diaphragm is detectable on fluoroscopy. Additionally, diaphragmatic motion can be depicted on MRI to assess paradoxical movement.5 Phrenic nerve function can be tested by electromyography. Ultrasonography (Gerscovich et al, 2001)49 and CT scanning2,13,15 are further diagnostic modalities used to detect underlying pathologies. However, they are often not able to distinguish between elevated diaphragm with intact continuity and true herniation. A CT scan and, if necessary, other diagnostic workup should be performed to rule out malignancy. MRI primarily has a role in the assessment of congenital or acquired hernias and in the evaluation of paradoxical diaphragmatic movement.4-6,16 A technique that was initially described 1930 is the diagnostic pneumoperitoneum, which can be used to outline the continuity of the diaphragm by induction of air, nitrogen (N2), or carbon dioxide (CO2) into the abdomen, followed by an upright chest radiograph to differentiate between elevation and hernia. Some pathologies can mimic an elevated diaphragm on radiologic examination. Subpulmonal effusion or pleural tumor50 can potentially arouse the impression of an elevated diaphragm. The degree of impact on respiratory function should by documented by spirometry and, eventually, by exercise studies.

CONSERVATIVE MANAGEMENT Unless severe dyspnea, orthopnea, or gastrointestinal problems are clearly related to an elevated diaphragm, eventration should be treated conservatively in most cases. Optimal management of the underlying disease should be sought to avoid progression. As mentioned, the degree of impact on respiratory function should be documented by spirometry, and control spirometries can detect a beginning decline in pulmonary function. Additionally, exercise studies can be performed (Celli, 2002).51

CLINICAL PRESENTATION

SURGERY

The leading symptoms in adult patients with acquired diaphragmatic elevation are respiratory problems.44 Because the diaphragm is the main respiratory muscle, most patients complain about dyspnea or orthopnea and, less commonly, about cough and retrosternal or epigastric pain. In case of underlying lung disease or reduced pulmonary reserve, this may lead as far as complete respiratory failure (Simansky et al, 2002).45,46 Other possible symptoms include a variety of digestive tract symptoms such as nausea, vomiting, gas bloat, belching, or abnormally increased bowel noises.47

Surgery for elevated diaphragm is indicated in relatively few cases. A careful evaluation of symptoms potentially related to the elevated diaphragm should be performed. The surgical technique of plication of the diaphragm was described in the early 20th century by Wood,58 and later by Morrison.59 The goal of the operation is to immobilize the diaphragm in a lower, relatively flat position, to reduce compression of the lung and mediastinum and eventually reduce paradoxical movement. Functional recovery is potentially possible if there is an adequate muscular reserve.

Ch115-F06861.indd 1398

1/21/2008 3:43:59 PM

Chapter 115 Evaluation and Management of Elevated Diaphragm

1399

TABLE 115-2 Results of Operative Plication for Acquired Elevated Diaphragm Improvement (%) Author (Year)

No. Patients

Mouroux53 (2005)

12

(2003)

Higgs61 (2001)

Hines

60

62

Ribet

(1992) 63

Graham

(1990)

Wright64 (1985) 7

Donzeau-Gouge (1982) 65

Pastor

(1982)

NcNamara1 (1968)

Mortality (%)

Clinical

Radiographic

Functional

0

110

100

100

5

0

100

100

Not stated

15

0

93.3

Not stated

100

11

0

90.9

Not stated

Not stated

17

0

100

100

100

7

0

100

100

100

9

11.1

Not stated

Not stated

15

0

86.6

100

Not stated

13

0

92.3

Not stated

Not stated

Initially, plication was performed through a posterolateral approach, whereas now it can also be performed through a less invasive anterolateral approach (Lai et al, 1999)52 or by a video-assisted technique.53,54 An abdominal approach, which may also be laparoscopic, is recommended if there is infradiaphragmatic involvement or a gastric volvulus requiring repositioning.55 The repair may be performed without incising the diaphragm by a simple plication with various suture materials or even endostaplers,56 or by excising part of the elevated diaphragm. Surgical reanastomosis of the phrenic nerve after transection has been reported in patients as late as 4 months after the lesion. Sural or intercostal nerve can be used as autologous grafts to bridge a gap between intact portions of the phrenic nerve. A success rate of 75% can be expected; however, full recovery usually takes months because of slow nerve growth.57 Various clinical studies have reported on series of patients undergoing diaphragmatic plication. Most of the studies required patients to have dyspnea interfering with everyday life, orthopnea, and respiratory function tests demonstrating impairment. A complete thoracic and abdominal diagnostic workup was recommended to rule out other correctable causes. An overview is given in Table 115-2. All studies concluded that plication is a safe and effective procedure. However, surgical correction of bilateral eventration seems to be associated with a higher operative mortality rate due to associated malformations and hypoplasia of the lung. More recent papers describing endoscopic techniques stress the reduction of operative trauma and shorter recovery period as advantages in choosing this approach.

SUMMARY Indication for surgery in acquired elevated diaphragm in adults should be determined very cautiously, after thorough evaluation of the patient and after exclusion of other potential causes for respiratory problems. In many cases, conservative measures such as weight loss, respiratory hygiene, optimal

Ch115-F06861.indd 1399

87.5

treatment of the underlying disease, and physiotherapy are sufficient to improve symptoms. For patients presenting with only gastrointestinal symptoms, the indication should be made even more restrictively. Yet, growing evidence exists that carefully selected patients show substantial benefit in lung function and respiratory symptoms after plication of the diaphragm. Less invasive techniques, such as video-assisted thoracic surgery (VATS) or minithoracotomy, help in minimizing the operative trauma.

COMMENTS AND CONTROVERSIES The elevated diaphragm is a common finding in the thoracic surgery clinic. The variable position of the normal diaphragm and the effects of age and body habitus on its position must be remembered to prevent misdiagnosis. A thorough history, including prior surgery, trauma, malignancy, and so on, is essential in the determining the cause of an elevated diaphragm. The authors’ useful classification of etiologies into supradiaphragmatic, diaphragmatic, and subdiaphragmatic brings to attention and reminds the clinician that the problem may not exist in the diaphragm or phrenic nerve. The presence of a mass or fluid collection may change the contour of the diaphragm and be misinterpreted as an elevated diaphragm. Simple investigations such as posteroanterior and lateral chest radiographs, decubitus radiography, and fluoroscopy are very helpful and should not be overlooked in the evaluation. Multidetector CT and multiplanar MRI are essential in problematic cases of elevated diaphragm. T. W. R.

KEY REFERENCES Celli BR: Respiratory management of diaphragm paralysis. Semin Respir Crit Care Med 23:275-282, 2002. Chetta A, Rehman AK, Moxham J, et al: Chest radiography cannot predict diaphragm function. Respir Med 99:39-44, 2005. Efthimiou J, Butler J, Woodham C, et al: Diaphragm paralysis following cardiac surgery: Role of phrenic nerve cold injury. Ann Thorac Surg 52:1005-1008, 1991. Gerscovich EO, Cronan M, McGahan JP, et al: Ultrasonographic evaluation of diaphragmatic motion. J Ultrasound Med 20:597-604, 2001.

1/21/2008 3:44:00 PM

1400

Section 6 Diaphragm

Iwasawa T, Kagei S, Gotoh T, et al: Magnetic resonance analysis of abnormal diaphragmatic motion in patients with emphysema. Eur Respir J 19:225-231, 2002. Joho-Arreola AL, Bauersfeld U, Stauffer UG, et al: Incidence and treatment of diaphragmatic paralysis after cardiac surgery in children. Eur J Cardiothorac Surg 27:53-57, 2005.

Ch115-F06861.indd 1400

Lai DT, Paterson HS: Mini-thoracotomy for diaphragmatic plication with thoracoscopic assistance. Ann Thorac Surg 68:2364-2365, 1999. Simansky DA, Paley M, Refaely Y, Yellin A: Diaphragm plication following phrenic nerve injury: A comparison of paediatric and adult patients. Thorax 57:613-616, 2002.

1/21/2008 3:44:00 PM

Benign Conditions chapter

CONGENITAL DIAPHRAGMATIC MALFORMATIONS

116

Éric Fréchette Salam Yazbeck Jean Deslauriers

Key Points ■ Congenital diaphragmatic malformations include congenital dia-

phragmatic hernia (CDH) and diaphragmatic eventration (DE). The eventrated diaphragm, which is an abnormally thin diaphragm, results from an abnormal development of its muscular component. It must be differentiated from diaphragmatic paralysis. ■ The standard of care for newborns presenting with CDH is delayed surgical repair after that the patient has been stabilized. During that time, nitric oxide, high-frequency jet ventilation, and extracorporeal membrane oxygenation may be used. ■ Surgery is rarely needed for DE in the pediatric population. It may be indicated in symptomatic patients or when a large eventration will potentially interfere with postnatal lung growth. ■ An elevated diaphragm in the adult population is attributed to congenital diaphragmatic malformation only after other etiologies have been excluded. Indications for surgery in adults are rare and are almost limited to previously unrecognized diaphragmatic hernias. Clinicians must be careful before recommending diaphragmatic plication for respiratory or digestive symptoms thought to be related to eventration.

Congenital disorders affecting the diaphragm may be divided into congenital diaphragmatic hernia (CDH) and diaphragmatic eventration (DE). Contrarily to CDH, in which the diaphragm has lost its continuity or sometimes its normal attachments to the costal margin, the eventrated diaphragm is complete and unbroken. DE is defined as an abnormally thin and fibrous diaphragm secondary to incomplete development of a part or the totality of muscular components (Box 116-1). Its inability to contract normally causes its distention and elevation toward the chest, which explains its name, eventration (e, “out of”; venter, “abdomen”). It must be differentiated from a diaphragmatic paralysis, which can present similarly on the chest roentgenograms and be responsible for similar physiologic disturbances. In this chapter, the origin, diagnosis, and treatment of congenital diaphragmatic malformations are discussed. Indications for surgical treatment and methods of surgical correction are emphasized, in both pediatric and adult populations.

HISTORICAL NOTE Although a description of CDH can be found as early as in the 16th century, it was only in 1848 that Vincent Bochdalek, an anatomist of Prague, described a bowel herniation through

a posterolateral hernia and gave his name to the CDH most commonly seen. In 1769, Giovanni Battista Morgagni, an anatomist at the University of Padua, reported his observations about an anterior diaphragmatic defect through the space of Larrey, named in honor of Napoleon’s surgeon, who described a retrosternal approach to the pericardium. The first successful repair of a CDH was reported by Gross in 1946 in a newborn patient with Bochdalek hernia.1 The first series was reported by Harrington in 1948. In this series, only 1.5% of patients had a Morgagni hernia.2 Concerns about the possibility that diaphragmatic agenesis is a different clinical entity where raised by Bingham in 1959 but were not confirmed by more recent works.3,4 Although the use of extracorporeal membrane oxygenation (ECMO) in infancy was first described by Bartlett in 1976, German reported the first survivor in a series of four patients with severe respiratory insufficiency who were placed on ECMO after surgical repair of a CDH.5,6 ECMO has been used as a method of stabilizing the patients preoperatively since the late 1980s. DE was first recognized in 1774 by Jean-Louis Petit in his Oeuvres Médicales Posthumes.7 In 1829, however, Pierre Augustin Béclard, anatomist in Paris, first introduced the term eventration of the diaphragm.8 About a century later, Wood expanded further on DE and made a plea that this condition must not be confused with CDH.9 He further suggested that surgical plication could be done if symptoms were sufficiently disabling and distressing.10 Before the use of radiography, the diagnosis of DE was difficult to make, and Korn in 1921 was able to collect only 65 cases in the world literature.11 By 1935, only 183 cases had been published.12 In 1951, a report by Nylander and Elfving identified localized DE that was sometimes encountered on mass chest surveys.13 Bilateral DE in infants and children has since been reported.14,15 In 1923, Morrison performed the first successful repair of DE, and he described the surgical principles that are still used today. He plicated the diaphragm of a 10-year-old girl, with immediate relief of symptoms.16 In infants, there were only 11 cases of DE described before the first successful repair was made by Bisgard in a 6-week-old boy.17 DE still remains a rare condition for which surgery is seldom indicated. In a 1954 review article, Arnheim found that 300 surgical cases were reported but only a few patients had been operated on.18 HISTORICAL READINGS Fine R, Borrero E, Stone A: Bochdalek hernia in adulthood. N Y State J Med 87:516-518, 1987. 1401

Ch116-F06861.indd 1401

1/21/2008 3:44:44 PM

1402

Section 6 Diaphragm

Box 116-1 Anatomic Classification of Eventration Total Partial (localized) Anterior Posterolateral Medial Modified from Thomas TV: Non-paralytic eventration of the diaphragm. J Thorac Cardiovasc Surg 55:586, 1968.

Harrington SW: Various types of diaphragmatic hernias treated surgically: Report of 430 cases. Surg Gynecol Obstet 86:735, 1948. Laxdal OE, McDougall H, Mellin GW: Congenital eventration of the diaphragm. N Engl J Med 250:401-408, 1954. Thomas TV: Congenital eventration of the diaphragm. Ann Thorac Surg 10:180-192, 1970. Wayne ER, Campbell JB, Burrington JD, et al: Eventration of the diaphragm. J Pediatr Surg 9:643-651, 1974.

may have a similar embryogenesis to Bochdalek hernia but occurs at a slightly later stage during gestation.25 According to Thomas, a premature return of the viscera to the abdominal cavity after their rotation, and the absence of ingrowth of striated muscle to the pleuroperitoneal membrane from the septum transversum, may also be factors involved in the embryogenesis of DE.9 Based on this theory, the premature return of the viscera to the peritoneal cavity might prevent complete development of the diaphragm by a stretching action. This concept is further supported by the observation that both DE and Bochdalek hernias occur more frequently on the left side and that the diaphragm generally has an intact anterior muscular rim.12,25 As shown by Revillon and Fekete, DEs occur in any location over the dome of the diaphragm, such as underneath the heart. They can be partially central, partially peripheral, or complete.26 Bilateral eventrations in infants and children were reported by Avnet and Lundstrom, and multiple eventrations on the same side have also been described.14,15,27 Bilateral eventrations are mostly seen within the context of polymalformations.28 DEs are usually classified as total, partial, unilateral, or bilateral.9,29

BASIC SCIENCE Embryogenesis and Anatomy

Incidence

Beginning at the end of the 6th week of gestation, the diaphragm is made from fusion of the septum transversum, the pleuroperitoneal membranes, the dorsal mesentery of the esophagus, and the body wall. A defective formation or a failure of fusion of any of these structures may be responsible for the development of a CDH.19 The embryogenesis of Bochdalek hernia, for instance, is related to a failure development or fusion of the pleuroperitoneal membranes, which usually occurs around the 8th week of gestation.20 In Morgagni hernia, the herniation occurs in the sternocostal hiatus, through which the superior epigastric vessels pass from the abdomen to the retrosternal area.19 According to most authors, DEs are always derived from a congenital defect in the musculature of one portion or the entire central part of the diaphragm.21,22 Bochdalek hernias occur in the posterolateral portion of the diaphragm and are left-sided in 90% of cases. The hernia size ranges from a small defect to a complete absence of diaphragm. Although most Bochdalek hernias (90%) do not have a true hernia sac, Salacin stated that a sac could be found in up to 38% of cases.23 On the left side, the contents of the hernia most commonly include stomach, spleen, and colon. Small bowel, liver, and kidney may also be involved. The less common right-sided Bochdalek hernias contain part of the liver, kidney, or omentum. Morgagni hernias are much less common than Bochdalek hernias. Because they are more common on the right side, it was postulated that the presence of the pericardium has a protective effect on the left hemidiaphragm.24 All Morgagni hernias have a sac, and they usually contain omentum. Colon, small bowel, and stomach may also have herniated. DE results from an incomplete migration of myoblasts from the cervical somites into the pleuroperitoneal membrane during the 4th week of embryologic development.19 McNamara and colleagues also suggested that the anomaly

The incidence of CDH is often reported to be between 1 in 3000 and 1 in 5000 live births, but this number does not include the cases of in utero fetal deaths or of infants born dead.30 According to Graham and associates,31 the true incidence is probably about 1 in 2200. Although female predominance has been reported by some authors, males are probably affected as often as females.32,33 Most cases are sporadic, familial cases having been identified in fewer than 5% of cases.34 In a study done in California, Torfs and coworkers identified CDH in 237 infants out of a population of 718, 208 live births, for an overall incidence of 3.30 per 10,000.35 In that cohort, 95% of infants had a Bochdalek hernia, 5% a Morgagni hernia, and 2% had bilateral hernias. In another study done over a 10-year period, Stege and colleagues were able to identify 185 cases of CDH from the Northern Region Congenital Abnormality Survey database in the United Kingdom.36 In that series, 70% of cases were observed in live birth situations, 24% after elective termination of pregnancy, 3% after spontaneous abortion, and another 3% in cases in which the fetus was already dead at delivery. From a similar registry of 396,577 births over a 5-year period (1995-2000), Tonks and associates reported an incidence of 2.9 per 10,000 births.37 Most cases of Bochdalek hernia (85%-90%) occur on the left side. Although the true incidence of DE is unknown, Chin and Lynn reported that the Southampton and Portsmouth mass radiography units had diagnosed only 32 cases of eventration in 412,000 subjects over a 5-year period (1949-1954).21 In that series, DE occurred nine times more often on the left side than on the right. In another series reported by Christensen, 38 among 107,778 persons examined were found to have a DE, for an incidence four times greater than in the Chin and Lynn report.38 In another study, Kinser and Cook identified an abnormally elevated diaphragm in 31 of 412,149 radiographs.39 In neonates and young children, the true inci-

Ch116-F06861.indd 1402

1/21/2008 3:44:45 PM

Chapter 116 Congenital Diaphragmatic Malformations

dence of DE is even harder to pinpoint. In a review of 2500 chest radiographs of neonates, Beck and Motsay documented some degree of diaphragmatic weakness in 4% of 2500 chest radiographs, but only 3 patients had severe symptoms, indicating that the true incidence may have been overestimated.40 Overall, males are affected more often than females, and the left hemidiaphragm is involved more commonly than the right.21,41 Congenital eventration of the diaphragm accounts for 5% of all diaphragmatic anomalies.42

Pathology The diaphragm of patients with CDH exhibits a congenital defect in the musculature of one portion or sometimes in the entire diaphragm, but, as reported by Dietz and Pongratz, the morphology of the muscle is normal.43 A true hernia sac is found in all cases of Morgagni hernia but is absent in the most cases of Bochdalek hernia. The pathogenesis and pathology of CDH may be different in the adult and pediatric populations. As reported by Mullins, congenital diaphragmatic malformations diagnosed in adults are more common in females and are found more commonly on the right side (68%), both features being different from what is observed in a pediatric population.32 In such situations, CDH may not be secondary to a defect of muscularization but rather to a malformation of the amuscular mesenchymal components.44 Salacin and colleagues even suggested that hernias discovered in adults may have developed from a small congenital defect enlarging over time secondarily to an increase in intra-abdominal pressure caused by physical exertion, childbirth, obesity, and so on.23 In many cases of CDH diagnosed in adults, a traumatic cause is difficult to rule out.

1403

In DE, the eventrated diaphragm is thin and has a membranous appearance, whereas the rest of the diaphragm is still muscular, having normal attachments to the chest wall and spine. Indeed, Wright and associates pointed out that there is little difficulty at thoracotomy in distinguishing DE with its membranous appearance from diaphragmatic paralysis, in which the elevated portion, even if somewhat atrophic, is still partly muscular.22 Microscopically, the attenuated portion of the eventrated diaphragm is made of fibroelastic tissue with some muscle fibers. Nerve bundles are seldom seen, and there is no evidence of degeneration of the phrenic nerve.45 Revillon and Fekete showed that, microscopically, the abnormal area always contained some muscular fibers, although these were fewer than normal in number and were dispersed in every direction.26 Often, muscular fibers are replaced by fibrous tissue rich in collagen and leukocytic infiltrate. As shown in Box 116-1, partial DE can be divided into three types, based on location: anterior (Fig. 116-1), posterolateral, and medial. Table 116-1 illustrates the main differences between true congenital eventration and those conditions related to paralysis secondary to phrenic nerve lesions.

Physiologic Consequences of Congenital Diaphragmatic Malformations In CDH, the defective diaphragmatic muscle allows a variable volume of intra-abdominal content to be present within the thoracic cavity during fetal life, with secondary associated lung hypoplasia. To fully understand the physiologic derangements associated with CDH, notions of lung maturation, alveolar and vascular development, and left heart function must be added to this simple mechanical concept.46 New-

FIGURE 116-1 A, Standard posteroanterior chest radiograph showing an asymptomatic congenital eventration of the right hemidiaphragm diagnosed in an adult. B, Lateral view showing the incomplete anterior nature of the eventration.

Ch116-F06861.indd 1403

1/21/2008 3:44:45 PM

1404

Section 6 Diaphragm

TABLE 116-1 Differences Between Diaphragmatic Eventration and Paralysis Feature

Eventration

Paralysis

Incidence

Rare

Common

Etiology

Congenital anomaly in formation of the diaphragm

Acquired lesion

Associated congenital anomalies

Yes

No

Phrenic nerve

Intact

Often abnormal

Appearance of the diaphragm

Marked decrease in muscular fibers; membranous appearance

Atrophic but still muscular

Sniff test

Decreased motion but no paradoxical motion

Paradoxical motion

borns with CDH often present with respiratory difficulties, or even respiratory failure, and this appears to be related to pulmonary hypoplasia. In such patients, the absolute number of terminal bronchioles has been shown to be lower than in nonaffected patients; because each terminal bronchiole has a predetermined number of alveoli, the end result is an overall decreased number of alveoli.47,48 Furthermore, in patients with CDH, maturation of the lung parenchyma is probably incomplete on the affected side, a finding suggested by decreased phospholipid levels in neonates with CDH as well as histologic and biochemical findings similar to those found in infants with respiratory distress syndrome.49,50 In patients with CDH, there is also some degree of pulmonary vascular hypoplasia associated with a hyperreactive and thickened media in the preacinar arterioles. Left cardiac ventricular hypoplasia has also been described and may be related to a decrease in fetal lung perfusion.51 All these factors are implicated in the etiology of the pulmonary hypertension, decreased pulmonary compliance, and, eventually, persistence of fetal circulation through an open ductus arteriosus and foramen ovale.52 CDH is associated with other congenital anomalies in 45% to 50% of live births and up to 72% of stillborns.53 The presence of such associated anomalies worsens the prognosis very significantly, with a mortality rate of almost 80%.54 The most significant physiologic derangement associated with DE is respiratory because the diaphragm normally contributes to a large proportion of the tidal volume.55,56 Indeed, several authors have documented a restrictive pattern characterized by a reduction in lung volumes and mild hypoxemia, all changes made worse when measurements are obtained with the patient in a supine position.31 In the group of patients reported by Wright and colleagues, there was a moderate level of hypoxia, and the total lung capacity (TLC), vital capacity (VC), and expiratory reserve volume (ERV) were lower than predicted with the patients seated, falling further away from predicted values with the patients in the supine position.22 This restrictive pattern is generally more severe in cases of complete DE, but it can be nonexistent in cases of partial or mild DE. Many authors have also shown various degrees of compressive atelectasis with decreased ventilation and perfusion in the involved lung base.57-59 DE is far more clinically significant in newborn infants or young children than it is in adults because infants depend mainly on diaphragmatic excursion for their tidal exchange. Therefore,

Ch116-F06861.indd 1404

newborns with DE may develop acute respiratory distress requiring endotracheal intubation with positive-pressure ventilation.60 Patients with elevation of the diaphragm can also present with digestive symptoms related to the rotation of the gastric fundus underneath the diaphragm, or even to a complete volvulus of the stomach with outlet obstruction. According to Laxdal and colleagues, the stomach may lie in any one of the following positions, all of which are the result of an elevation toward the chest10,61-64: 1. Normal position, with the fundus rising unusually high under the diaphragm 2. Inversion with the greater curvature lying adjacent to the undersurfaces of the diaphragm 3. Inversion with partial or complete volvulus Associated anomalies, such as abnormal pulmonary segmentation, congenital heart disease, or chromosomal anomalies, are common in patients with DE and ultimately may affect the prognosis and the results of treatment.65

DIAPHRAGMATIC EVENTRATION IN PEDIATRIC PATIENTS In DE, the diaphragmatic continuity is present but the incomplete and abnormal development of the muscle leads to an inability to contract normally. It differs from CDH, in which diaphragm continuity has been lost. Modern imaging modalities, such as magnetic resonance imaging (MRI), have made it possible to clearly define diaphragmatic continuity and differentiate the two entities.66,67 The diagnosis can be made at birth, particularly if the newborn has a complete eventration and presents in respiratory distress. Other symptoms that may occur at an early age include failure to thrive, nausea, heartburn, and even symptoms related to complete gastric volvulus.68 In the pediatric age group, 20% of gastric volvulus cases are associated with eventration.69,70 The prenatal differentiation between CDH and DE may be important because of the significant difference in postnatal management and prognosis. The accepted criterion for the diagnosis of DE on a chest radiograph is the presence of a hemidiaphragm at least two intercostal spaces higher than on the other side (Fig. 116-2).71 This radiologic sign can be difficult to observe if the patient is being ventilated, only to become obvious after extubation.

1/21/2008 3:44:45 PM

Chapter 116 Congenital Diaphragmatic Malformations

1405

FIGURE 116-2 Preoperative (A) and postoperative (B) chest radiographs of a child with incomplete eventration of the right hemidiaphragm. Surgical plication was carried out to maximize development of the underlying lung.

Although the finding is not specific, pulmonary function studies may show a restrictive pattern with reduction in lung volumes and mild hypoxemia.31 Asymptomatic patients do not require treatment. Some authors suggest that large eventrations, even if asymptomatic, may interfere with postnatal lung growth and that some consideration needs to be given to their correction.65,72 It is unlikely, however, that patients with such large defects would remain asymptomatic, as was shown in the series of 25 patients with total DE reported by Tsugawa and coworkers, in which only 4 were asymptomatic. In this series, 17 patients presented with respiratory distress, 9 of them with severe distress, and 3 presented with gastrointestinal symptoms (Tsugawa et al, 1997).72 In DE, the aim of surgery is to plicate the hemidiaphragm in a flattened position two intercostal spaces lower than its initial position.73 The noncontracting part of the diaphragm is folded in a mediolateral direction and sutured with nonabsorbable sutures. Care must be taken to avoid injury to the phrenic nerve, or to intra-abdominal organs if the surgical approach is transthoracic. The plication is done through a laparotomy if the eventration is bilateral or if the presence of a gastric volvulus mandates stomach reduction and fixation. The abdominal approach is also preferred in patients with previous cardiac surgery who may have intrapleural adhesions. Diaphragmatic plication can be done safely by minimally invasive techniques, either thoracoscopy or laparoscopy.74,75 In most series, the clinical results of diaphragmatic plication are dramatic, allowing patients to be extubated within a few hours or a few days. In a series of 33 pediatric patients, all symptomatic since birth, Yazici and associates reported 31 successes and 2 deaths due to cardiorespiratory complications (Yazici et al, 2003).76

Ch116-F06861.indd 1405

In a 2005 paper, Koivusalo and colleagues assessed the long-term quality of life in adults after repair of congenital diaphragmatic defects.77 In that series of 69 patients (45 with CDH and 24 with congenital DE), 20% had symptoms of gastroesophageal reflux, 7% of recurrent intestinal obstruction, and 12% of recurrent abdominal pain. The quality-oflife index was lower than normal in 25% of patients. Some cases of diaphragmatic rupture have been reported after plication, and those are thought to be the result of a high tension on the repair leading to secondary rupture.78 Symptomatic pediatric patients with DE benefit from early surgical plication of the diaphragm, whether their symptoms are respiratory, gastrointestinal, or both, because the results of surgical treatment are generally excellent (Table 116-2).

CONGENITAL DIAPHRAGMATIC HERNIA IN PEDIATRIC PATIENTS With the increase in the number of ultrasound examinations done during the course of pregnancy, more fetuses with diaphragmatic hernia are being diagnosed early. For this reason, a prenatal diagnosis of CDH does not carry as bad a prognosis as it did 2 decades ago. Some investigations have attempted to identify prognostic factors based on prenatal ultrasound and MRI findings, to better select patients who could potentially benefit from fetal intervention. MRI also allows better differentiation of the lung from the herniated liver, although there is currently no consensus about the significance of the presence of the liver in the chest.79,80 Another commonly assessed prognostic factor is the ratio of contralateral lung area to head circumference (LHR). Although some authors consider the LHR to be an absolute

1/21/2008 3:44:45 PM

1406

Section 6 Diaphragm

TABLE 116-2 Results of Plication for Diaphragmatic Eventration in the Pediatric Population Improvement (%) No. Patients

Author (Year) Stauffer and Rickham120 (1972) Revillon and Fekete

26

(1982)

8

Operative Mortality (%)

Length of Follow-up (Yr)

Clinical

Radiographic

Functional

0

Up to 11

100

100

—

Unknown

—

95

—

1-7

—

100

—

28

4

Stone et al121 (1987)

11

36

Kizilcan et al122 (1993)

25

0

1.5-11

92

75

83

Total

83

6

—

97

91

83

A

B

FIGURE 116-3 Preoperative (A) and postoperative (B) chest radiographs of a newborn with a left Bochdalek hernia. The involved chest was not drained postoperatively, to reduce the amount of the barotrauma on the lung.

predictor of survival, others question the validity of this measurement (Smith et al, 2005).81-83 Fetal lung volume assessed by three-dimensional sonography, abdominal circumference, and size of the pulmonary artery have also been reported to be prognostic factors for clinical outcome in fetuses with CDH.84-86 The overall survival associated with CDH is difficult to pinpoint, however, because of the socalled hidden mortality related to stillbirths and deaths of newborns in the period before transportation to a tertiary care center. Among live births, the mortality is directly related to the age at which the newborn presents with signs of respiratory distress, the prognosis being worse for neonates whose symptoms are immediately present in the delivery room. In addition to the clinical symptoms related to respiratory distress and hypoxia, newborns with CDH often have a scaphoid abdomen, and the heart sounds can be heard over the right side when the hernia is on the left side (>80% of patients). Radiologically, there are gas-filled loops of bowel in the chest (Fig. 116-3), and, if a nasogastric tube has been placed in the stomach to decompress the gastrointestinal tract, it may be seen above the diaphragm.

Ch116-F06861.indd 1406

Between 5% and 20% of CDH cases are diagnosed after the perinatal period, and in such cases, the diagnosis may be difficult to obtain, not only because of the variability of symptoms, but also because of atypical radiographic findings. In such cases, the diagnosis may be made incidentally on a chest radiograph done for another reason, or the abnormality may be discovered during a surgical procedure. The diagnosis of CDH is sometimes made only at postmortem examination. On occasion, children present with acute gastrointestinal symptoms caused by incarceration of bowel loops in the chest or with more chronic symptoms, such as failure to thrive, vomiting, or recurrent abdominal pain. Among infants and young children with CDH, standard chest radiographs confirm the diagnosis in approximately half of the patients; in the other half, other imaging modalities, such as CT, MRI, or ultrasonography, are necessary to confirm the diagnosis and rule out pneumothorax or pneumonia. Sixteen percent of patients in a literature review of late-presenting CDH in children had a chest radiograph that was interpreted as normal. In such cases, a diaphragmatic defect present at birth, associated with a visceral herniation occurring later, may be suspected.87

1/21/2008 3:44:46 PM

Chapter 116 Congenital Diaphragmatic Malformations

If a prenatal diagnosis of CDH has been made, the delivery needs to take place in a center where advanced neonatal care, including pediatric surgery, is available. Several studies have shown that the results of CDH treatment are significantly better in centers that have a volume of more than 5 patients per year.88-90 At birth, a neonate with respiratory difficulties and suspected CDH is immediately intubated. Mask bagging is avoided because it increases the distention of the herniated stomach and intestine and therefore compromises the ventilation even more. Stabilization of the patient and delayed surgical repair is now the standard of care for newborns with CDH. During the stabilization period, inhaled nitric oxide (NO), high-frequency oscillatory ventilation (HFOV), and ECMO are often used to correct the hypoxia, although a Cochrane review on NO and HFOV use could not demonstrate any clear benefit for the use of these techniques.91 Because barotrauma to the lungs is a significant cause of mortality and morbidity, Wung and associates proposed in 1985 a protocol of so-called gentle ventilation with permissive hypercapnia, designed to minimize barotrauma with limited peak inflation pressures.92 The general rule is to maintain the preductal oxygen saturation greater than 85% while tolerating increases in arterial partial pressure of carbon dioxide (PaCO2) of up to 60 mm Hg. With this type of mechanical strategy, considered to be the most significant advance in CDH management in recent years, survival rates of up to 80% have been reported.93,94 Indeed, this new approach has led to a steady decline in the use of ECMO.95,96 ECMO therapy for newborns with respiratory failure became widely available in the 1980s. The initial goal of ECMO was to allow the lung to rest during the time necessary to obtain homeostasis, patient stabilization, and even resolution of pulmonary hypertension.5 Over the years, ECMO techniques were modified in several centers tat switched from a venoarterial to a venovenous circuit. ECMO was generally used according to inclusion and exclusion criteria described by Rothenbach (Table 116-3). Currently, the role of ECMO remains controversial in patients with CDH who require ventilatory support because of limited survival improvement and significant morbidity associated with the technique, particularly in centers that use it less frequently (Harrington and Goldman, 2005).95-99 In a recent series of 24 patients reported by Cortes and colleagues, ECMO was used in only 1 patient.100 Open fetal repair of CDH has been limited because of unsolved technical challenges (e.g., induction of premature labor). The fetal technique of tracheal occlusion also seemed promising, but a randomized trial sponsored by the National Institutes of Health showed no survival benefit compared with elective delivery with optimal postnatal CDH care.101 The role of fetal surgery in the treatment of fetuses with CDH remains to bedefined.102 However, this avenue is still pursued in Europe. In a recent series, Deprest and colleagues reported the results of percutaneous fetoscopic endoluminal tracheal occlusion in 20 fetuses with poor prognosis due to liver herniation and LHR less than 1. Survival in this group was 50%, instead of the predicted 8%.81

Ch116-F06861.indd 1407

1407

TABLE 116-3 Inclusion and Exclusion Criteria for the Use of ECMO in Newborns With Congenital Diaphragmatic Hernia Inclusion Criteria A-a gradient >600 mm Hg for 4 hr Oxygen index >40 PaO2 < 40 and/or pH < 7.15 for 2 hr Exclusion Criteria Newborns weighing <2 kg (because of cannula size) Newborns with <34 wk gestation (increased risk of intracranial hemorrhage) Associated lethal fetal malformation A-a, alveolar-arterial; ECMO, extracorporeal membrane oxygenation; PaO2, arterial partial pressure of oxygen.

As discussed earlier, CDH patients are brought to the operating room only after stabilization, although in some cases surgery can be performed in the neonatal intensive care unit.103 A sudden deterioration of vital signs at any time before or after surgery can be related to a contralateral pneumothorax, which needs to be drained immediately. The correction of the diaphragmatic defect is performed through a subcostal incision. The herniated viscera are returned to the abdomen, and, in the rare case in which a hernia sac is present, it is excised. Any small diaphragmatic defect is closed with interrupted nonabsorbable sutures. For larger diaphragmatic defects, or in complete absence of the hemidiaphragm, a polytetrafluoroethylene (PTFE) membrane is used and can sometimes be sutured to the ribs anteriorly and posteriorly. The medial edge of the prosthesis can be sutured safely to the contralateral hemidiaphragm. To avoid negative intrapleural pressure that increases the risks of barotrauma and alveolocapillary membrane damage, a chest tube is not left in the ipsilateral pleural space. If respiratory excursion appears to be compromised by a tight abdominal closure, a PTFE prosthesis can be used. Skin closure over a fascia layer left open is also commonly done, with the ventral hernia that is deliberately created being closed at a later time. Recurrent herniation can be a significant postoperative complication, particularly if a large CDH is present, in which it has been reported to occur in up to 56% of cases. Cortes and associates showed that a significant number of patients require oxygen supplementation for 2 years postoperatively and that 44% need pulmonary medication during that period.100 Trachsel and colleagues studied pulmonary function in adolescents who had been treated for CDH in the neonatal period (Trachsel et al, 2005).104 Twenty-two percent of patients had symptoms of asthma, and many had a reduced inspiratory muscle strength and mild to moderate airway obstruction with decreased maximum minute ventilation. Forty-eight percent of patients were responsive to bronchodilators. However, these patients had minimal compromise of their daily activities. Other respiratory complications have been reported, and repeated respiratory tract infections may be the cause of failure to thrive in such patients.105 In 1996, Vanamo and colleagues reported on the long-term gastrointestinal morbidity in 60 patients with CDH who had undergone surgical repair during infancy.106 Gastroesophageal

1/21/2008 3:44:46 PM

1408

Section 6 Diaphragm

Sometimes the cause of diaphragmatic elevation is difficult to determine. In 1982, Donzeau-Gouge and coworkers reported on a series of 20 patients for whom no clear etiology could explain the elevation of the diaphragm, even after full surgical exploration.108 In those cases, diaphragmatic elevation may be the early manifestation of a malignant disease or of a neuromuscular disorder. In 1982, Piehler and colleagues reported a study of 247 patients evaluated at the Mayo Clinic between 1960 and 1980 for elevation of one hemidiaphragm.109 In 142 of these 247 patients, the initial evaluation failed to suggest any etiologic cause. Because a neoplasm was eventually discovered in only 5 of these patients (3.5%) during a follow-up period ranging from 5 months to 20 years, the authors concluded that patients with unexplained diaphragmatic elevation were unlikely to have an underlying occult malignant process. They also stated that recovery of the normal diaphragmatic position was unlikely to occur. In an interesting study of the prevalence of incidental Bochdalek hernias in an adult population, Mullins and colleagues were able to document 22 cases in a review of 13,138 abdominal CT scans, for an incidence of 0.17%.32 Most of these patients (89%) were females, and 68% of hernias were right-sided. In that series, 3 patients (14%) were found to have bilateral hernias, which is an incidence higher than what should be expected. In the adult population, symptoms related to DE are predominantly respiratory, mainly dyspnea, cough, and retrosternal pain. In other patients, the symptomatology is mostly digestive and consists of gas bloat, nausea, vomiting, heartburn, and frequent uncontrollable belching. The same symptoms might be present in patients with diaphragmatic hernia, whereas chest pain, constipation, and crampy abdominal pain

reflux (GER) was documented in 18% of patients, but 63% of patients complained of symptoms suggestive of GER at the time of the survey. Endoscopy showed macroscopic esophageal pathology in 29% of cases, including four patients with Barrett’s esophagus. On biopsy, 37% of patients had abnormal findings, including three patients with gastric metaplasia of the lower esophageal epithelium. Symptoms of intestinal obstruction occurred in as many as 20% of patients.

CONGENITAL DIAPHRAGMATIC MALFORMATIONS IN ADULTS In the adult, abnormalities of the diaphragm are usually found incidentally on routine chest radiographs in asymptomatic or mildly symptomatic patients. In some patients, focal diaphragmatic abnormalities are the result of a diaphragmatic hernia, either congenital or traumatic, and the diagnosis can be made easily. In other patients, the diagnosis is more difficult to document. In some cases of elevated diaphragm, the diagnosis is clearly a congenital eventration that has gone unnoticed during childhood, only to become symptomatic with decreased pulmonary function caused by obesity, chronic obstructive lung disease, or any other pulmonary disorder. In most other adult patients with an elevated diaphragm, the disorder is acquired and associated with either an intact or abnormal phrenic nerve. According to Naunheim, CDHs are seldom found in adults because they are diagnosed during the first year of life in more than 90% of patients.107 In fact, CDH is the cause of fewer than 1% of the diaphragmatic hernias treated by an adult thoracic surgeon (Fig. 116-4).

A

B

FIGURE 116-4 A, Standard posteroanterior chest radiograph showing a Morgagni hernia containing colon and omentum in an adult presenting for intermittent chest pain. B, Lateral view showing the anterior location of the hernia.

Ch116-F06861.indd 1408

1/21/2008 3:44:46 PM

Chapter 116 Congenital Diaphragmatic Malformations

may be related to other causes. A more dramatic presentation may be seen with incarcerated hernias, containing colon, spleen, or stomach volvulus; perforation has been described. The diagnosis of an elevated diaphragm can usually be made on standard posteroanterior and lateral chest films (Fig. 116-5). In such cases, the diaphragm is in a higher position than normal, and it forms a round, unbroken line arching from the mediastinum to the costal arch.10 If there is involvement of the phrenic nerve, true paradoxical motion of the diaphragm will be observed on fluoroscopy. Fluoroscopic examination may also be useful to rule out pericardial cysts or excessive mediastinal fat located at the cardiophrenic angle that may simulate DE. Although rarely done, diagnostic pneumoperitoneum might be useful to distinguish between an elevated diaphragm and frank herniation, despite the fact that, in chronic hernias, adhesions would prevent air from reaching the pleural space. The original technique described by Zeitlin involved the introduction of air, nitrous oxide, or carbon dioxide into the peritoneal cavity, followed by an upright chest radiograph to outline the diaphragmatic continuity.110 CT scanning and ultrasound are not very helpful in differentiating between elevated diaphragm and true herniation.111 MRI allows one to acquire high-quality images in transverse, coronal, and sagittal planes and therefore to evaluate the entire diaphragm. The ability of MRI to identify areas of diaphragmatic discontinuity has been reported by many authors, particularly in cases of blunt or penetrating diaphragmatic trauma.112,113 While investigating a patient with an elevated diaphragm, it is important to rule out a

1409

thoracic (pulmonary or mediastinal) malignancy affecting the phrenic nerve (see Table 116-1). The presence of a lung cancer, for instance, may have to be ruled out by CT scanning and/or bronchoscopy. It is also important to document by pulmonary function studies and exercise testing the consequences of the elevation of the diaphragm on the pulmonary function. Most cases of eventration diagnosed in adult life are treated conservatively unless severe dyspnea interfering with normal activities, orthopnea, or gastrointestinal symptoms are clearly related to the high position of the diaphragm. Indications for surgery in adults are uncommon, and the clinician must be very careful before recommending plication for respiratory or digestive symptoms thought to be related to elevation of the diaphragm. The operation is usually carried out through a posterolateral approach, the repair consisting of a simple plication without opening the diaphragm, or the excision of a central ellipse of aponeurotic diaphragm followed by double breast suturing. In all cases, the objectives of surgery are to immobilize the diaphragm in a lower flat position, to reduce its compression of the ipsilateral lung and mediastinum, and possibly to recover function if there is adequate residual muscle under the costal arch. A transabdominal approach is preferred in cases of bilateral eventrations, if there is an infracardiac component to the eventration, or if there is a gastric volvulus that requires repositioning.114 Diaphragmatic plication can also be done through a video-assisted thoracic surgery (VATS) approach, as was described by Mouroux and coworkers in 1996 (Fig.

FIGURE 116-5 A, Standard posteroanterior chest radiograph of a 55-year-old woman with an eventration of the left diaphragm. At fluoroscopy, the diaphragm moved very little but there was no paradoxical motion. No cause could be found to explain the anomaly. Spirometric studies showed a restrictive pattern with a vital capacity of 72% of predicted. B, Standard chest radiograph taken 4 years before A and considered normal.

Ch116-F06861.indd 1409

1/21/2008 3:44:47 PM

1410

Section 6 Diaphragm

Port 1 5th ICS Port 2 5th ICS

9th ICS

A

C

B

D

FIGURE 116-6 A, Position of the two thoracoscopic ports. A minithoracotomy is made over the ninth intercostal space (ICS) for the suturing of the diaphragm. B, With the use of Duval forceps, the apex of the eventration is pushed down toward the abdomen. C, The newly created transverse fold of diaphragm is sutured with nonabsorbable material. D, Completed operation. (FROM MOUROUX J, PADOVANI B, POIRIER NC, ET AL: TECHNIQUE FOR THE REPAIR OF DIAPHRAGMATIC EVENTRATION. ANN THORAC SURG 62:905, 1996.)

116-6).75 With this technique, the eventrated diaphragm is pushed down by endoscopic long clamps and then plicated by the use of two superimposed transverse continuous sutures. The first line of sutures holds the diaphragm down and keeps the excess tissue within the abdomen, while the second suture line completes the repair by placing the desired tension over the dome. The main advantage of this technique is the minimal access type of surgery, which facilitates postoperative recovery and respiratory re-education. Table 116-4 summarizes the results obtained after surgical correction of an elevated diaphragm in the adult. In Graham’s series of 17 patients (mean age, 53.7 years) who underwent plication of the diaphragm, all patients showed both subjective and objective improvement (Table 116-5).31 Six patients were reassessed 5 or more years after plication, and the noted improvement was maintained. In that series, indications for surgery included dyspnea interfering with normal activities,

Ch116-F06861.indd 1410

orthopnea, and, in some cases, respiratory function studies showing a significant restrictive pattern. In Wright’s series, seven adult patients underwent plication of the diaphragm for dyspnea.22 There were no postoperative complications, and all patients’ symptoms were improved after surgery. Significant increases in PaO2 and all lung volumes except residual volume were also noted. The authors concluded that diaphragmatic plication is a safe and effective procedure. Similarly, Ribet and Linder reported good results in 11 adults who were followed up for a mean of 8.5 years after plication.115 In that series, surgery was recommended if there were symptoms that could not be related to another cause after complete thoracic and abdominal workup. Contrary to DE, most cases of CDH diagnosed in adults are addressed surgically because of the potential for catastrophic complications secondary to organ volvulus and perforation. Sometimes, a totally asymptomatic patient can be

1/21/2008 3:44:47 PM

Chapter 116 Congenital Diaphragmatic Malformations

1411

TABLE 116-4 Results of Plication for Diaphragmatic Elevation in the Adult Population Improvement Author (Year)

No. Patients

Graham et al31 (1990)

17

22

Wright et al

(1985)

Operative Mortality (%) 0

Length of Follow-up (Years)

Clinical

Radiographic

Functional

5-7

6/6

6/6

6/6

7

0

0.3-4

—

7/7

7/7

Ribet and Linder115 (1992)

11

0

8.5 (mean)

—

—

—

Pastor et al123 (1982)

15

0

1-15

13/15

15/15

—

Donzeau-Gouge et al

108

9

10

0.4-10

7/8

—

—

McNamara et al25 (1968)

(1982)

13

0

1-5

12/13

—

—

Total

72

1.3

—

92%

100%

100%

TABLE 116-5 Dyspnea Scores and Physiologic Measurements Before and After Unilateral Diaphragmatic Plication (N = 17) Parameter

Before Operation

After Operation

P value

Dyspnea score

7.4 ± 0.8

3.3 ± 0.9

<.001

FVC (liter) Sitting Lying

2.7 ± 0.7 1.9 ± 0.5

3.2 ± 0.5 2.7 ± 0.6

<.001 <.001

TLC (liter) Sitting Lying

4.1 ± 1.6 3.4 ± 0.8

4.5 ± 1.7 4.2 ± 1.7

<.002 <.002

FRC (liter)

2.5 ± 0.2

2.9 ± 0.2

<.01

ERV (liter)

0.6 ± 0.2

0.9 ± 0.2

<.01

RV (liter)

1.9 ± 0.2

2.0 ± 0.7

NS

DLCO (% predicted)

85 ± 4.5

100 ± 6.9

<.05

PaO2 (mm Hg)

73.1 ± 10.9

85.6 ± 13.2

<.001

PaCO2 (mm Hg)

39.8 ± 6.7

38.4 ± 6.1

<.001

DLCO, diffusion capacity for carbon monoxide; ERV, expiratory reserve volume; FRC, functional residual capacity; FVC, forced vital capacity, NS, not significant; RV, residual volume; TLC, total lung capacity. From Graham DR, Kaplan D, Evans CC, et al: Diaphragmatic plication for unilateral diaphragmatic paralysis: A 10-year experience. Ann Thorac Surg 49:248-251, 1990.

observed, especially when surgical risk is high or when the omentum is the only herniated organ. In all other cases, surgical repair is recommended because these hernias tend to increase in size over time.116-118 An abdominal approach is preferred because it allows a complete inspection of the abdominal organs that may have been injured by incarceration, strangulation, or the reduction procedure itself. A bowel preparation is obtained before all elective procedures. If present, the hernia sac is resected. Although, the defect can sometimes be closed primarily without tension, a polypropylene or polytetrafluoroethylene mesh is typically used. Since 1991, laparoscopic repair of CDH has been reported by many authors to be a feasible and safe procedure, especially for the repair of Morgagni hernias.117-119 Good results can be obtained, but the rarity of congenital hernias in adults has limited the

Ch116-F06861.indd 1411

number of large series. In 1999, Hüttl and colleagues118 reported on a series of three patients who underwent laparoscopic repair of Morgagni hernia without perioperative complications. Follow-up ranging from 10 to 72 months revealed no residual symptoms and no hernia recurrences. More recently, Yavuz and associates reported the largest series of laparoscopic Morgagni hernia repair.117 Five patients underwent surgery between 2002 and 2004. The mean hospital stay was 4 days, and there were no perioperative complications. A mean follow-up of 7 months revealed no short-term recurrences.

SUMMARY Congenital diaphragmatic malformations include CDH and DE. These are different from acquired diaphragm paralysis, but they share similarities in presentation in the adult population. In newborns, the treatment of CDH is evolving, and surgical repair after a period of stabilization is now the standard of care. Theses hernias are rarely seen in the adult population, but when they are present they mandate surgical treatment. On the other hand, DE rarely requires surgical correction, except when respiratory or digestive symptoms are clearly related to the malformation, or when a large DE is thought likely to interfere with lung development in an infant. Other causes of elevated hemidiaphragm must always be ruled out when assessing these patients.

COMMENTS AND CONTROVERSIES It is amazing to review the complex growth of the diaphragm in utero and realize that developmental abnormalities are not more common. However, an active adult thoracic surgeon will see the spectrum of congenital diaphragmatic malformations. Careful review of chest CT periodically demonstrates small asymptomatic Bochdalek defects. Morgagni hernia, an uncommon problem seen almost exclusively in adults, is easily managed by minimally invasive techniques. DE requires careful diagnosis; it may be difficult to differentiate from other causes of diaphragmatic elevation, and it infrequently requires surgical management in the adult. Bochdalek hernia (CDH) in a newborn requires intense multidisciplinary care to successfully repair the defect. The physiologic consequences for respiratory, pulmonary, vascular, and gastrointestinal development may be significant and permanent. Dr.

1/21/2008 3:44:51 PM

1412

Section 6 Diaphragm

Fréchette and colleagues have provided an excellent review of these malformations and their treatment. T. W. R.

KEY REFERENCES Deslauriers J: Eventration of the diaphragm. Chest Surg Clin N Am 8:315-330, 1998. Harrington KP, Goldman AP: The role of extracorporeal membrane oxygenation in congenital diaphragmatic hernia. Semin Pediatr Surg 14:72-76, 2005. Smith NP, Jesudason EC, Featherstone NC, et al: Recent advances in congenital diaphragmatic hernia. Arch Dis Child 90:426-428, 2005.

Ch116-F06861.indd 1412

Trachsel D, Selvadurai H, Bohn D, et al: Long-term pulmonary morbidity in survivors of congenital diaphragmatic hernia. Pediatr Pulmonol 39:433-439, 2005. Tsugawa C, Kimura K, Nishijima E, et al: Diaphragmatic eventration in infants and children: Is conservative treatment justified? J Pediatr Surg 32:1643-1644, 1997. Vanamo K, Rintala RJ, Lindahl H, et al: Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects. J Pediatr Surg 31:551-554, 1996. Yazici M, Karaca I, Arikan A, et al: Congenital eventration of the diaphragm in children: 25 Years’ experience in three pediatric surgery centers. Eur J Pediatr Surg 13:298-301, 2003.

1/21/2008 3:44:51 PM

PRENATAL INTERVENTION FOR CONGENITAL DIAPHRAGMATIC HERNIA

chapter

117

Jan Deprest Jacques Jani Dominique Van Schoubroeck Mieke Cannie Anne Debeer Maissa Rayyan Lourenço Sbragia Tim Van Mieghem Marc Van de Velde Elise Doné Leonardo Gucciardo Toni E. M. R. Lerut

Key Points ■ Prenatal imaging can diagnose congenital diaphragmatic hernia,

may rule out frequently associated anomalies, and can determine prognosis. ■ Fetuses with liver herniation into the thorax and a small lung (lungto-head ratio <1.0) have a poor prognosis when managed with standard postnatal therapy. ■ Fetal endoscopic tracheal occlusion (FETO) may improve survival in the latter group, with results dependent on preoperative lung size.

Congenital diaphragmatic hernia (CDH) is a surgically correctable anatomic defect with unknown etiology (Box 117-1). It sporadically occurs with an incidence of 1 of every 2500 live births, or 1 in 5000 newborns if stillbirths are included. Less than 2% of cases are familial, and the recurrence rate of isolated CDH is 2%. Eighty-four percent of lesions are left-sided (LCDH), 13% are right-sided (RCDH), and 2% are bilateral. Complete agenesis, herniation of the central tendineous part, and eventration (thinning of the muscle) are other rare manifestations. In about 40% of cases, there are associated anomalies; this is an independent predictor of neonatal death, with fewer than 15% of babies surviving in this group (Stege et al, 2003).1-3 We refer to the literature for current concepts on the embryology and molecular and genetic mechanisms behind this disease.4 This chapter focuses on fetuses with isolated CDH. The defect arises in the embryologic period of lung development, and herniating viscera interfere with all further lung development stages. CDH-affected lungs have fewer alveoli, thickened alveolar walls, increased interstitial tissue, and markedly diminished alveolar air space and gas-exchange surface area. Parallel to the airway changes, the pulmonary vasculature is abnormal, with a reduced number of vessels, adventitial thickening, medial hyperplasia, and peripheral

extension of the muscle layer into the smaller intra-acinary arterioles. Both lungs are affected, but the ipsilateral lung more than the contralateral one. These morphologic changes have a tremendous functional impact in the postnatal period. Pulmonary hypoplasia leads early on to ventilatory insufficiency, and vascular alterations lead to variable degrees of pulmonary hypertension. Actual survival rates in isolated CDH are a matter of debate. With advances in neonatal care, one would intuitively expect neonatal survival rates to improve accordingly. Larger surveys, however, estimate the mortality rate in antenatally diagnosed cases of isolated CDH in live-born infants at about 30%, even today.3,5 Specialized centers for neonatal care, however, easily quote survival rates of 80% and higher (Downard et al, 2003).6,7 There are several reasons for this apparent difference in statistics from different sources. First, fetal medicine specialists start counting numbers from the moment of prenatal diagnosis. Their statistics therefore include spontaneous in utero deaths, a number of terminated pregnancies, and immediate postnatal deaths, constituting the “hidden mortality.”8 Neonatal or surgical studies start counting once the baby is born or admitted (hence, alive) into the neonatal ward or when the infant is operated on.9 Because surgeons are often not familiar with data from the prenatal period, we quote a few recent population-based studies. These also demonstrate that CDH is still often missed. The population-based study from Western Australia reported outcomes on 116 babies with CDH collected over a 10-year period.5 In utero diagnosis was made in 53% of cases, and half underwent termination of pregnancy (TOP), mainly because of associated problems. The number of TOPs in isolated CDH was 8% (3/37), as good as can be assessed from the paper. The survival rate was 33% for prenatally diagnosed, live-born fetuses, but only 16% for all prenatally diagnosed fetuses. Among those babies who were eventually referred for neonatal surgery, 80% survived, and survival beyond 1 year of age was 92% for those who underwent operation. In another recent population-based study from 1413

Ch117-F06861.indd 1413

1/21/2008 3:45:38 PM

1414

Section 6 Diaphragm

France (n = 51), in utero diagnosis was made in 57% of the cases. There were 29 cases of isolated CDH, and 16 (55%) of those patients survived. Prenatal diagnosis was made in only 13 cases (45%), of whom 5 (38%) underwent TOP. There was one in utero death in which a postnatal diagnosis of isolated CDH was the only abnormal finding.10 From these reports, it is clear that there are strong regional or cultural differences regarding the attitude toward TOP for (isolated) CDH. Further, some obstetric studies are interventional and not representative of the natural history of the disease (because termination is being done). This is a double-edged sword: it increases prenatal loss rates, but if cases with dismal prognosis are more likely to be offered TOP, that practice may cause an apparent improvement in survival for this condition.

PRENATAL DIAGNOSIS OF CONGENITAL DIAPHRAGMATIC HERNIA Modern ultrasound allows prenatal diagnosis of CDH (Box 117-2). The diaphragm can be visualized with high-resolution equipment already in the first trimester (Fig. 117-1). Its absence is usually suggested by the intrathoracic presence of abdominal viscera and, as a consequence, the displacement, compression, and maldevelopment of thoracic organs. On longitudinal scanning, a defect in the posterior aspect of the diaphragm may be seen, at least for the most common posterolateral (Bochdalek) type of hernia. For left-sided lesions, mediastinal shift and rightward displacement of the heart can be seen, and in most cases a fluid-filled stomach, or later on bowel, is present within the thoracic cavity (Fig. 117-2). An important feature to look for is whether the liver is confined to the abdomen or herniates into the thorax (Fig. 117-3). Doppler interrogation of the umbilical vein and hepatic vessels may be helpful in this respect. With right-sided

Box 117-1 Introductory Concepts Congenital diaphragmatic hernia arises in the embryologic period, resulting in pulmonary hypoplasia. Associated problems are common. For isolated prenatally diagnosed cases, there is a 30% to 40% mortality rate in the neonatal period, based on population-based studies. Nonsurvivors die from the consequences of poor lung development leading to respiratory failure, pulmonary hypertension, or complications of neonatal intensive care.

Box 117-2 Prenatal Diagnosis of CDH The diaphragm can be visualized at the time of screening ultrasound; therefore, the defect needs to be picked up before birth. Associated anomalies and abnormal karyotype are ruled out. Additional imaging techniques, in particular fetal MRI, may be used. Patients must be referred to tertiary care centers that are familiar with multidisciplinary management of this condition.

A

B

C

Ch117-F06861.indd 1414

FIGURE 117-1 Prenatal ultrasound images of the normal diaphragm at 15 weeks (A) and 21 weeks (B) of gestation in longitudinal sections. C, A cross-section through the thorax is taken in the four-chamber view, and one of the lungs is measured, as would be done for cases of congenital diaphragmatic hernia.

1/21/2008 3:45:38 PM

Chapter 117 Prenatal Intervention for Congenital Diaphragmatic Hernia

1415

FIGURE 117-2 Measurement of the lung-to-head ratio in a section obtained through the so-called four-chamber view, both schematically (left) and on ultrasound images (right). In the top pair of images, a two-dimensional measurement of the contralateral lung (opposite the side of the lesion) is obtained by the “longest axis method”: the lung’s longest axis is multiplied by the longest measurement made perpendicular to it. This lung area value is compared with the head circumference (bottom images), which is measured in the standard biparietal view, showing two symmetrical hemispheres, the septum cavum pellucidum one third of the way from the front to the back, and the posterior horns of the lateral ventricles. FIGURE 117-3 Axial (A) and sagittal (B) T2-weighted magnetic resonance images of a fetus with a left congenital diaphragmatic hernia at 24.1 weeks of gestation with intrathoracic liver herniation. H, heart; L, lung; Li, liver; S, stomach; Sb, small bowel. C, Ultrasound image of the liver, its contour marked by the dotted line. Vessels (solid line) are landmarks and can be visualized with the use of Doppler imaging. D, Slice in axial plane, used for volumetric measurements.

B A

C

Ch117-F06861.indd 1415

D

1/21/2008 3:45:39 PM

1416

Section 6 Diaphragm

lesions, the right lobe of the liver usually herniates into the chest, and there is also a mediastinal shift to the left. A high proportion of fetuses with CDH have associated anomalies, and the sonographer needs to look for these. In descending order, these include cardiac, renal, central nervous system, and gastrointestinal anomalies. Chromosomal anomalies usually coincide with a range of structural anomalies, but CDH can also be part of a range of monogenic and other as yet undefined syndromes. Genetic amniocentesis and consultation is therefore mandatory. Parents base their perception of any congenital anomaly on its initial communication. The physician making the first diagnosis must refrain from premature, potentially imprecise comments. Expecting parents must be referred immediately to a tertiary center specializing in this condition, where they will receive further diagnostic evaluation followed by comprehensive multidisciplinary counseling based on prognostic indicators. Structural ultrasound may for that purpose be complemented by fetal magnetic resonance imaging (MRI) and/or three-dimensional ultrasound.

for isolated cases. This has not been easy because there are some unique aspects when evaluating a yet unborn fetal patient. First, the lung is a nonfunctional organ in utero; therefore, predictions rely mainly on anatomic rather than functional measures. Second, the pattern of lung growth throughout gestation is not equal over all time periods. In brief, predictions are more likely to be more accurate late in gestation. The lung grows more in the second half of pregnancy, and there is less overlap between normal and abnormal at that time. Clinically, however, late prediction is not helpful; it needs to be done early enough to allow the parents the option of termination as well as fetal therapy (Deprest et al, 2005).11 In general, prediction relies on the presence or absence of liver herniation but mainly measurement of lung size—which is a proxy for the degree of disturbance in lung development. Just as the pathologist looks at the proportion of lung weight to body weight in defining pulmonary hypoplasia, the fetal medicine specialist measures lung dimensions and compares these with a biometric variable not affected by the condition. The lung-to-head ratio (LHR) was first proposed by Metkus

PRENATAL COUNSELING AND PROGNOSIS Counseling consists of accurate description of the nature of the anomaly, the measured impact on lung development, and the expected natural history in the individual case (Box 117-3). The need for planned delivery and perinatal management in a specialized neonatal intensive care unit, as well as other prenatal options depending on the severity of the disease, is discussed. The expected neonatal course and the potential morbidity must be covered (Fig. 117-4). The most dramatic change in the past decade is that prenatal imaging techniques can now be used to predict survival

FIGURE 117-4 Flow chart of decision making in case of early diagnosis of congenital diaphragmatic hernia (CDH). Prenatal therapy (FETO) is offered as an alternative to postnatal therapy or termination. “Good” or “intermediate” status depends on the lung-to-head ratio (LHR) and the position of the liver. TOP, termination of pregnancy. (ADAPTED FROM DEPREST J, JANI J,

Box 117-3 Prenatal Counseling and Prognosis Lung development can be measured in the prenatal period. The best validated predictors of postnatal death are the presence of liver herniation and a lung-to-head ratio of less than 1.0. Volumetric measurements are expected to replace these soon; preliminary studies show that survival chances are minimal when lung volumes are less then 35% of normal and the liver is in the thorax. Prediction of morbidity is still in its infancy.

Prenatal diagnosis of CDH

Nature of associated anomalies

Isolated CDH/Position of liver and measurement of LHR

GRATACOS E, ET AL, AND THE FETO TASK GROUP: FETAL INTERVENTION FOR CONGENITAL DIAPHRAGMATIC HERNIA. SEMIN PERINATOL 29:94-103, 2005.)

Multidisciplinary counseling

“Severe”
LHR 1.0 and liver “up”

“Good” or “intermediate”

Serious anomalies

FETO 26–28 weeks Unplug 34 weeks

Expectant

TOP

In utero transfer and optimal postnatal therapy

Ch117-F06861.indd 1416

Postnatal counseling

1/21/2008 3:45:41 PM

Chapter 117 Prenatal Intervention for Congenital Diaphragmatic Hernia

1417

TABLE 117-1 Neonatal Outcome as a Function of LHR in Fetuses With LCDH and Liver Herniation, After Expectant Management or FETO Therapy Clinical Category LHR <1.0 Extreme hypoplasia Severe hypoplasia

{

N

0.4-0.5 0.6-0.7 0.8-0.9

2 6 19

0 (0%) 0 (0%) 3 (15.8%)

27

3 (11.1%)

23 19

14 (60.9%) 13 (68.4%)

1.0-1.1 1.2-1.3

n.a. n.a.

11 6

8 (72.7%) 5 (83.3%)

1.4-1.5 ≥1.6

n.a. n.a.

Subtotal (LHR <1.0) LHR ≥1.0 Intermediate or moderate hypoplasia Mild hypoplasia

1.0-1.1 { 1.2-1.3 1.4-1.5 { ≥1.6

Total (any LHR)

Expectant Management*

FETO Therapy†

LHR

86

LHR

N

0.4-0.5 0.6-0.7 0.8-0.9

6 13 9

1 (16.7%) 8 (61.5%) 7 (77.8%)

28

16 (57.1%)

43 (50%)

100

100

90

90

80

80

70

70

Survival rate (%)

Survival rate (%)

LCDH, left-sided congenital diaphragmatic hernia; LHR, lung-to-head ratio; n.a., not applicable. *Data from Jani J, Cos T, Benachi A, et al: Lung volume assessment at midgestation with 3D ultrasound to predict pulmonary hypoplasia in fetuses with isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 26:402, 2005. † Data from Jani JC, Nicolaides KH, Gratacos E, et al, and the FETO Task Group: Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Am J Obstet Gynecol 195:1646-1650, 2006. Modified from Jani J, Keller RL, Benachi A, et al: Prenatal prediction of survival in isolated left-sided diaphragmatic hernia. Ultrasound Obstet Gynecol 27:18-22, 2006.

60 50 40 30

60 50 40 30

20

20

10

10

0

0 0.4–0.5 0.6–0.7 0.8–0.9 1.0–1.1 1.2–1.3 1.4–1.5

A

1.6

Lung area-to-head circumference ratio with herniation of liver

0.4–0.5 0.6–0.7 0.8–0.9 1.0–1.1 1.2–1.3 1.4–1.5

B

1.6

Lung area-to-head circumference ratio without herniation of liver

FIGURE 117-5 Survival rate according to the ratio of fetal lung area to head circumference in fetuses with isolated left-sided congenital diaphragmatic hernia (LCDH) with (A) and without (B) intrathoracic herniation of the liver. Observations on 184 cases of isolated LCDH were made at 22 to 28 weeks. (FROM JANI J, KELLER RL, BENACHI A, ET AL: PRENATAL PREDICTION OF SURVIVAL IN ISOLATED LEFT-SIDED DIAPHRAGMATIC HERNIA. ULTRASOUND OBSTET GYNECOL 27:18-22, 2006.)

and colleagues, who observed a relationship of this proportional value to survival.12 LHR is the two-dimensional measurement of the lung contralateral to the lesion (the “better” one). There is a relationship not only between LHR and survival but also between liver herniation and survival.13 Prediction seems best when both parameters are combined. We validated this fact in a retrospective chart review including 184 fetuses with isolated LCDH, assessed between 22 and 28 weeks, who were expectantly managed and born live after 30 weeks (Jani et al, 2006).14 Liver herniation and LHR mutually affected each other. Whereas LHR correlated with survival, the predictive value of LHR was much better if the

Ch117-F06861.indd 1417

liver was herniated also (Table 117-1; Fig. 117-5). A fetus that had an LHR between 1.0 and 1.6 had a 66% chance to survive. With an LHR of 1.6 or higher, this increased to 83% or more. Fetuses with an LHR of less than 1.0 as well as liver herniation had only an 11% chance of survival, and not a single fetus with an LHR between 0.4 and 0.7 survived. This study showed that the current critical margin of viability in fetuses with liver herniation lies somewhere between an LHR of 0.7 and an LHR of 1.0. It is intuitively much more logical to measure both lungs rather than one, and three-dimensional lung volume rather than a single two-dimensional cross-section. Three-

1/21/2008 3:45:41 PM

1418

Section 6 Diaphragm

dimensional measurements can easily be obtained today, by either ultrasound or MRI. Nomograms of three-dimensional ultrasound lung volumes are already available, and current research efforts are dedicated to validation of those measurements as a predictor of survival. Such measurements provide reproducible volumetric estimations that relate to outcome as long as the position of the liver is also taken into account. In up to 40% of patients, it is not possible to measure the ipsilateral lung by ultrasound15,16; this is not so for MRI. The fetal lung is primarily composed of water, which provokes a high signal intensity on MRI (see Fig. 117-3). Mathematical algorithms have been developed to measure lung volume on serial sections of the lung. Because the measured absolute volume is meaningless apart from the gestational age of the fetus, measurements are expressed in relation to what a normal matched control should have; this is referred to as the observed/expected (O/E) lung volume ratio.17 “Normal” fetuses can be matches selected on the basis of gestational age or comparable biometric indexes, such as abdominal circumference, liver volume, or, as we have proposed, body volume.18 Body volume has the advantage that uncertain dates or altered fetal growth are discounted. One obtains then a fetal lung-to-body volume ratio, which is probably the best proxy for a ratio of fetal lung to body weight, on which pulmonary hypoplasia is defined by the pathologist. We performed with this method a study in fetuses with suspected lung hypoplasia early in gestation. All fetuses had ultrasound measurement of LHR as well, and an LHR of 1.0 was found to correlate to an O/E ratio of 35% in the third trimester.18

NEONATAL MANAGEMENT OF CONGENITAL DIAPHRAGMATIC HERNIA The previously described morphologic changes have a tremendous functional impact in the postnatal period (Box 117-4). These are two-fold: respiratory insufficiency and pulmonary hypertension. Until the 1990s, the cornerstone of neonatal management was hyperventilation and hyperoxygenation, together with other measures for controlling pulmonary hypertension, and emergency repair of the defect.19 Later, these two tenets were questioned, and today, “gentle ventilation” followed by delayed surgery have been shown to improve results. Gentle ventilation protocols or spontaneous breathing, with permissive hypercapnia and minimal sedation, reduce barotrauma and volutrauma.20,21 High-frequency oscillatory ventilation (HFOV) has been suggested as a primary ventilation mode in cases of lung hypoplasia, but most centers consider it as rescue therapy to be used before

Box 117-4 Neonatal Management of CDH Postnatal repair of the defect is not an emergency. The baby’s condition needs first to be stabilized. Gentle ventilation avoids barotrauma and volutrauma, and pulmonary hypertension is aggressively controlled. The value of administering surfactant, ECMO, and other strategies is a matter of debate. Survivors may have significant morbidity.

Ch117-F06861.indd 1418

extracorporeal membrane oxygenation (ECMO).22,23 Pulmonary hypertension is increasingly and earlier treated by inhaled nitric oxide (iNO).24 Recently, it has been proposed that the ductus arteriosus be kept patent by administration of prostaglandins (PGE1) in cases of severe secondary left ventricular cardiac dysfunction.25,26 Some centers are proponents of a liberal use of ECMO,27 but its role has been criticized because of unproven benefits, its inherent complications, and the fact that it is not widely available. Conceptually, however, ECMO might also be promising when postnatal attempts are undertaken to enhance lung growth, such as by partially filling the lung with perfluorocarbon (although a trial of this therapy was stopped by the U.S. Food and Drug Administration28). This might induce increased lung tissue stretch, following the same rationale as tracheal occlusion in the prenatal period, although obviously application is restricted to the alveolar phase of lung development. Surfactant use has so far no proven benefit in treating CDH, not even in selected subgroups.29 Data from the CDH Study Group registry failed to show any benefit of surfactant on the clinical course of infants receiving ECMO.30 In a retrospective analysis of full-term infants treated with surfactant, no improvement in survival rate, decreased ECMO use, or chronic lung disease was documented.29 The same applies to preterm infants (born before 37 weeks of gestation). In the absence of evidence that one postnatal strategy is any better than another, no true recommendations can be made. However, it is likely that improved results will be obtained by highly specialized, high-volume centers where well considered and well designed treatment protocols are applied.31 This was confirmed in a recent Canadian Neonatal Network study by 17 neonatal intensive care centers. The expected survival rate was calculated based on two parameters, birth weight and Apgar score at 5 minutes. The observed survival rate was higher then the expected rate for all severity groups, with an overall survival rate of 83% (73/88). Hospitals classified as high-volume centers (i.e., with >12 CDH admissions during the 22-month study period) had a 90% overall survival rate, compared with a rate of 77% in the lowvolume centers. This finding demonstrates the importance of turnover. However, the numbers also demonstrated the meaning of selection bias. From these numbers, survival rates would seem to be at least 75%, if not 90%. These are typical postnatal statistics, discounting antenatal and immediate neonatal loss. We clearly are dealing here with neonatal data, assuming live birth (it is based on Apgar), hence discounting antenatal losses. It is therefore impossible to compare absolute percentages of this study to those of series from fetal medicine specialists or population-based studies. Survivors are not free from long-term morbidity. They may have chronic pulmonary problems, feeding difficulties, gastroesophageal reflux and oral aversion, failure to thrive (mainly in the first 2 years of life), hearing problems, and, in a small group, neurodevelopmental problems. Some newer neonatal strategies, such as permissive hypercapnia and tolerance of lower oxygen saturations, may actually contribute to neurodevelopmental problems, although they might improve survival. Morbidity may thus be related not only to the underlying condition but also to the postnatal therapy. More-

1/21/2008 3:45:41 PM

Chapter 117 Prenatal Intervention for Congenital Diaphragmatic Hernia

over, it is dependent on the severity of the pulmonary hypoplasia.32,33 With increasing survival rates (or fetal therapy), we must beware that morbidity does not substitute for mortality. It is obvious that survivors need to be followed up and cared for in a proper long-term multidisciplinary follow-up program.34

CONCEPT AND CLINICAL IMPLEMENTATION OF FETAL THERAPY Current postnatal management strategies do not salvage the underlying limiting factor for survival, which is pulmonary hypoplasia, for which theoretically only one other option— neonatal lung transplantation—is available (Box 117-5). Prenatal interventions that can improve lung development have therefore been conceived. Anatomic repair was emulated first and was shown to be feasible and to improve lung development. However, it cannot be offered to fetuses with liver herniation, who are the actual candidates for fetal therapy: liver reduction would kink the umbilical vein and cause fetal death.35 An alternative is based on an experiment of nature. Congenital high airway obstruction syndrome (CHAOS) induces impressive lung overgrowth. The congenital obstruction or its analogue of surgical occlusion prevents egress of lung liquid, leading to increased pulmonary stretch and accelerated growth of airways and pulmonary vessels.36 The timing and duration of surgical occlusion are crucial for the quantitative and qualitative response and are the subject of intense debate.37 Probably oversimplifying the experimental literature, one could summarize the argument for fetal therapy as follows: ■

■

■

■

■

Tracheal obstruction does cause fluid accumulation, “inflating” the lung. This causes tissue stretch and true lung growth (airways and vessels). The DNA synthesis rate plateaus 48 hours after tracheal obstruction but continues later on. Differentiation and growth are dependent on the duration of tracheal obstruction, but there is more growth if occlusion is maintained longer. The amount of fluid the lung can produce (related to its size) is another determinant of lung response. Sustained tracheal obstruction leads to a decreased number of type II alveolar cells, the surfactant-producing cell in the lung. Temporary tracheal obstruction (created by inserting a balloon in the late canalicular phase and removing it at the transition of saccular to alveolar phase), known as the plug-unplug sequence, is associated with recovery of the type II cells.38,39 Cyclic strain for 47 hours followed by 1 hour release achieves optimal lung growth and duration (normal morphology and type II cell numbers). Its clinical translation is technically not yet feasible.40 Medical adjuncts, such as corticosteroids, surfactant, and yet untested pharmacologic agents, may alter the functional results, but experimental evidence is not clear on what the best scenario would be; therefore, clinical conclusions cannot be drawn.41-43

Ch117-F06861.indd 1419

1419

Clinically, occlusion by tracheal clipping was first performed via laparotomy and hysterotomy.44 Later fetoscopic tracheal dissection and clipping was shown to be associated with frequent local complications.45 Today, clinical fetal endoscopic tracheal occlusion (FETO) is performed via percutaneous 3.0-mm access (rather than laparotomy) and by tracheoscopic balloon occlusion (rather than external clipping)—a procedure we first described experimentally in the late 1990s (Deprest et al, 2004).46,47 Occlusion with an expandable balloon meets the needs of tracheal growth and reversal is technically possible via endoscopic retrieval as well as puncture. This makes vaginal delivery possible, as well as return to the referring treatment center. Reversal also has a beneficial effect on late neonatal survival.48 While the FETO procedure was being introduced in Europe, in the United States a randomized controlled trial sanctioned by the National Institutes of Health compared FETO therapy with standard postnatal care.49 Inclusion criteria were isolated LCDH and normal karyotype. Severity criteria were liver herniation and LHR less than 1.4 at 22 to 28 weeks; patients were further stratified into three severity groups (Table 117-2). Although all procedures were fetoscopic, they were performed via laparotomy to facilitate placement of fetoscopic ports of at least 5 mm in diameter. All fetuses were administered prenatal corticosteroids before restoration of airways by an ex utero intrapartum treatment (EXIT) procedure. Enrollment was stopped after 24 patients because of the unexpectedly high survival rate with standard care. Eight (73%) of 11 fetuses in the FETO group and 10 (77%) of 13 in the standard care group survived to 90 days of age (P = 1.00). Preterm prelabor rupture of the membranes (PPROM) and preterm delivery were the fate of almost all cases treated in utero. The rate of neonatal morbidity did not differ between the groups. Postnatal pulmonary compliance of survivors in the FETO group was a little better, with a lower alveolar-arterial oxygen difference, but the clinical relevance of this finding was questioned.50 The results of this trial were no reason to stop the European program because the latter was aimed only at the worst severity group (LHR <1.0), for whom the randomized controlled trial was actually underpowered to judge upon any effect of fetal therapy.

OPERATIVE FETO TECHNIQUE An ongoing study is being carried out at the University Hospitals of Leuven (Belgium), London (U.K.), and Barcelona (Spain). All sites adhere to a single protocol with the follow-

Box 117-5 Concepts and Clinical Implementation of Fetal Therapy Prenatal intervention aims to induce sufficient lung development before birth to allow survival. Anatomic repair might do so, but it cannot be offered to fetuses with liver herniation. Tracheal occlusion induces lung growth by tissue stretch. In an experimental setting, its effects are dependent on the duration of occlusion and the time point of its effectuation.

1/21/2008 3:45:42 PM

1420

Section 6 Diaphragm

TABLE 117-2 Comparison of Recent Series of Fetal Endoscopic Tracheal Occlusion (FETO) Therapy Study

RCT Harrison et al (2004)*

Deprest et al (2005)†

Criteria

LCDH: Liver up and LHR <1.4

Liver up and LHR <1.0

Treatment

Standard neonatal care (n = 13)

Fetoscopic clip (n = 2) or balloon (n = 9)

FETO therapy (n = 20 L + RCDH)

PPROM

3 (23%) at <32 wk

11 (100%) at <34 wk

7 (35%) at <32 wk 10 (50%) at <34 wk

Gestational age at delivery in weeks (range)

37.0 ± 1.5 (34.0-39.0)

30.8 ± 2.0 (28.0-34.0)

33.2 (27.0-38.5)

Birthweight (kg)

3.03 ± 0.48

1.49 ± 0.36

2.12 ± 0.66

Survival no. (%)

10/13 (77%) at 90 days

8/11 (73%) at 90 days

10/20 (50%) at discharge

LCDH, left congenital diaphragmatic hernias; L + RCDH, left and right congenital diaphragmatic hernias; LHR, lung-to-head ratio; Liver up, liver herniated into the thorax; PPROM, preterm prelabor rupture of fetal membranes; RCT, randomized controlled trial. *Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congential diaphragmatic hernia. N Engl J Med 349:1916-1924, 2003. † Deprest J, Jani J, Gratacos E, et al and the FETO task group. Fetal intervention for congenital diaphragmatic hernia. Semin Perinatol, 29:94-103, 2005.

ing selection criteria: singleton pregnancy with severe CDH in an anatomically and chromosomally normal fetus; liver herniated into the thorax; and LHR less than 1.0, as measured between 26 and 28 weeks, irrespective of the side of the herniation. Treatment is started before 28 weeks 6 days. After FETO therapy (and unless the balloon can be removed before birth), patients may leave our hospital as long as they have access to an institution with permanent facilities for neonatal balloon removal by an EXIT procedure. This is a pragmatic attitude because most patients in Europe want to travel back home for a variety of reasons. Such a decision is not without risk because patients may deliver “ex abrupto,” or referring centers may experience problems organizing balloon removal or during the EXIT procedure. We make the risk clear to patients and remain ready if at any time with prior notification the patient is referred back (Box 117-6). All sonographic evaluations and operative procedures (fetoscopic balloon placement, reversion of occlusion) are performed by a fixed team of fetoscopists, sonographers, and anesthesiologists. Balloon placement is scheduled, whenever possible, at 26 to 28 weeks, and retrieval of the balloon at 34 weeks, time points based on extrapolation of lung developmental stages used in sheep experiments. Operations are performed under (loco)regional anesthesia and prophylactic tocolysis. Fetal analgesia and immobilization are achieved by fetal injection of fentanyl and pancuronium. A 10 Fr cannula (Cook Performa), a 1.3-mm fetoscope (Karl Storz, 11630 AA) within a 3.0 mm sheath, and a detachable balloon occlusion system (GVB16, Acta Vascular Systems, Santa Clara, CA) are the required instruments and devices. Some are still prototypes and may be changed to meet the needs we have experienced, so far as manufacturers are willing to do so (Fig. 117-6). Patients are typically admitted for 48 hours. Balloon retrieval at 34 weeks is done by fetal tracheoscopy or by balloon puncture using an ultrasound-guided 20-gauge needle. Preferentially, this is done in the prenatal period or on an emergency basis after birth. Prepartum removal avoids the performance, risks, and consequences of an EXIT proce-

Ch117-F06861.indd 1420

Box 117-6 Fetal Operative Technique Under sonoendoscopic guidance and through a 3.3-mm cannula, a detachable balloon is fetoscopically positioned between the carina and vocal cords at 26 to 28 weeks. Removal at 34 weeks is typically by fetoscopy, or, if labor starts early, by puncture in the peripartal period. FETO has been shown to improve survival compared with controls of matched severity treated with standard neonatal care.

Box 117-7 Results of Fetal Tracheal Occlusion FETO is a minimally invasive procedure, but it carries an inherent risk for iatrogenic PPROM and, as a consequence, preterm delivery. It increases survival on average from less than 15% to about 50% to 55%.

dure. It also allows in utero referral of the patient back to the local tertiary unit, which has a psychosocial advantage and is more pragmatic in a Europe that still knows boundaries in health care. Postnatal therapy is performed according to per local protocols once the patient is referred back.

RESULTS We published our first experience with a consecutive series of 20 FETO treatments in a paper that aimed to report on the technique and its reproducibility.47 The experience of the consortium now totals more than 100 cases, and some trends can be observed (Box 117-7). With increasing workload, it was possible to move away from a fixed team of the three principal investigators, doing the procedures together at all three locations, to a more workable situation in which each of the three centers has its own fixed team. We also moved away from general anesthesia to combined spinal-epidural anesthesia and even local anesthesia.48 Over the course of the

1/21/2008 3:45:42 PM

Chapter 117 Prenatal Intervention for Congenital Diaphragmatic Hernia

1421

FIGURE 117-6 Left, Fetoscopic images of landmarks during the operation. From left to right beginning at the top, these are the epiglottis, vocal cords, trachea, carina, inflated and detached balloon, and vocal cords about to close over balloon. Not all of these images were from the same patient. (FROM NELSON S, CAMERON A, DEPREST J: FETOSCOPIC SURGERY FOR IN UTERO MANAGEMENT OF CONGENITAL DIAPHRAGMATIC HERNIA. FETAL MATERN MED REV 17:69-104, 2006.). Top right, Deported eyepiece fetoscope. (COURTESY OF KARL STORZ ENDOSKOPE.) Bottom right, Schematic drawing of percutaneous fetal endoscopic tracheal occlusion (FETO) procedure. (FROM DEPREST J, GRATACOS E, NICOLAIDES KH: FETOSCOPIC TRACHEAL OCCLUSION [FETO] FOR SEVERE CONGENITAL DIAPHRAGMATIC HERNIA: EVOLUTION OF A TECHNIQUE AND PRELIMINARY RESULTS. ULTRASOUND OBSTET GYNECOL 24:121-126, 2004. REPRINTED WITH PERMISSION FROM ISUOG AND JOHN WILEY & SONS, LTD.)

initial study, we moved from perinatal retrieval by tracheoscopy or puncture to prenatal balloon removal at 34 weeks, via fetal tracheoscopy or ultrasound-guided puncture. Complete inability to access the trachea is rare and is associated with an unfavorable position (facing posterior); in such cases, we delay the procedure if the fetus cannot be manipulated to a better position by external version. We are not aware of any direct trauma to the pharynx or trachea. The balloon may end up too low or too high, so that it dislodges or needs to be removed, after which another one is inserted. Inflation of the balloon in the bronchus can cause laceration, which heals in about 1 week, after which a new balloon can be inserted. There have been no maternal complications such as hemorrhage, pulmonary edema, or infection. The need for additional tocolysis has been very low. There was one intrauterine fetal death after the operation, for unclarified reasons. In our initial experience,47 15% of patients developed premature prelabor with rupture of the membrane (PPROM) before 28 weeks, and more than 30% did so before 32 weeks, suggesting its iatrogenic nature. This does not mean that the patient will go into labor because it is a sterile trauma presenting as amniorrhexis. It may arrest or, if it persists, the patient is watched closely or admitted for relative rest and monitoring for ascending infection and signs of labor. A balance needs to be made here to determine a reasonable

Ch117-F06861.indd 1421

time point for removal of the balloon before birth. Fortunately, the rate of early iatrogenic PPROM is decreasing, and, as a consequence, delivery is later as experience increases. For instance, in 30 consecutive cases at one center, PPROM before 28 weeks dropped to 4%, and PPROM before 32 weeks to 19%. Mean gestational age at birth was initially 34 weeks (range, 27-38 weeks), with four out of five patients delivering after 32 weeks. This has increased to 35 weeks on average, with almost all patients delivering after 37 weeks. PPROM rates in this European series are therefore lower than in the American study,49 where PROM rates (<37 weeks) were as high as 100% and mean gestational age at delivery was less than 31 weeks. For the FETO procedure in that series, general anesthesia, laparotomy, and uterine puncture with a 5-mm endoscope were used. Follow-up ultrasonography shows, invariably, lung response as increased echogenicity and increased lung size within 48 hours (Fig. 117-7).48 LHR, as well as volumetric lung size, is increased more clearly after 1 week. In our initial series, survival till discharge was 55%.47 In the later report on a homogenous series of LCDH cases, early neonatal survival was 75%, and surgical repair of the diaphragmatic hernia was carried out in 66% (16/24) of the babies.48 More than 90% of the babies required a patch repair, suggesting the severity of the anatomic defect. Late (28 days) neonatal survival was

1/21/2008 3:45:42 PM

1422

Section 6 Diaphragm

A

B

FIGURE 117-7 Coronal T2-weighted magnetic resonance image of a fetus with a left congenital diaphragmatic hernia before tracheal occlusion, at 25.1 weeks of gestation (A), and at 32 weeks of gestation, before unplugging (B). The arrow indicates the tracheal plug. The intrathoracic liver herniation is obvious. Notice the increased intensity of the lung parenchyma at 32 weeks; total volume increase was 74% in this case. C, colon; L, lung; Li, liver; S, stomach.

58%, and survival to hospital discharge was 50%. The mean duration of tracheal occlusion was 42 days; among nonsurvivors, it was much less. In contemporary controls we have seen during the same period more than 90% of neonates dying from pulmonary hypoplasia. The 12 babies in this series with long-term survival (median, 15.7 months) had no apparent developmental problems. Four babies were temporarily oxygen dependent. Postnatal losses were attributed to a variety of causes, but most were still related to the primary problem (i.e., respiratory insufficiency). Death coincided more frequently with extreme prematurity, balloon dislodgment, and a preoperative LHR of less than 0.6. Postnatal deaths in babies with adequate lung function were related either to complications of intensive care or surgery or to prenatally missed associated problems. For instance, coarctation of the aorta caused additional problems, and one baby died from multiorgan failure as part of a deletion in chromosome 8, which apparently was missed on the initial karyotyping at the referring center. Neonatal survival was higher with prenatal versus perinatal balloon retrieval: 83.3% versus 33.3% (P = .013). Survival until discharge showed a similar trend for higher survival (67% versus 33%) in babies if reversal was done before birth; however, this result was not significant. A more detailed analysis of outcomes on the longer term is needed for these babies. However, it seems that the introduction of antenatal therapy for CDH has a few consequences for the neonatologist and pediatric surgeon. First, the births are more likely to be preterm. Second, these babies may also be surfactant deficient if tracheal occlusion could not be reversed before birth. Third, based on the selection criteria, they typically have large diaphragmatic defects, which may increase patch use and may present a pediatric

Ch117-F06861.indd 1422

Box 117-8 Predictors of Survival After Fetal Therapy Survival after FETO can be predicted from the LHR measured at the time of plugging. Preoperative LHR may be used to stratify fetal therapy and/or selection of patients for trials.

surgical challenge. All of these findings prompt, again, the need for follow-up of these cases.

PREDICTORS OF SURVIVAL AFTER FETAL THERAPY The most striking observation is that survival rate after FETO is predictable from the LHR measured before the procedure (Box 117-8; see Table 117-1) (Jani et al, 2006).51 For instance, survival increases from 17% for an LHR of 0.4 to 0.5, to 62% for LHR 0.6 to 0.7, and 78% for LHR 0.8 to 0.9. This observation is logical if one thinks about the physiology of tracheal occlusion: growth is induced by tissue stretch, which is caused by distention and lung liquid production. The degree of lung response to FETO is based on the potential of the lung to produce lung liquid: the larger the lung, the higher its surface area, the more liquid it can produce, and, hence, the greater the biologic response. This observation has prompted us to propose a classification of pulmonary hypoplasia in terms of prognosis after FETO. This classification system can form the basis for antenatal stratification of prenatal therapy of isolated LCDH and liver herniation.

1/21/2008 3:45:43 PM

Chapter 117 Prenatal Intervention for Congenital Diaphragmatic Hernia

1. Fetuses with an LHR of at least 0.6 but less than 1.0 are referred to as having severe pulmonary hypoplasia. The natural history of the disease is a survival rate of less than 15%, as seen today. Our data show that FETO increases survival to 60% or greater. To formally validate this finding, the FETO Task Group has proposed a randomized controlled trial (RCT) of FETO at 26 to 28 weeks and in utero reversal at greater than 34 weeks, compared with standard postnatal care.37 2. Fetuses with an LHR of less than 0.6 are referred to as having extreme pulmonary hypoplasia because their predicted survival rate is close to 0% today. This can raise to 17% if FETO is done at 26 to 28 weeks. However, this increased survival rate is considered clinically irrelevant, and we need to do better. The potential of better lung growth by early tracheal occlusion (<24 weeks) is being explored in a feasibility study, based on the experimental observation that lung growth goes on long after the onset of tracheal occlusion, albeit at a lesser speed than initially. It is hoped that a longer occlusion period will lead to a more achievable lung size. 3. Fetuses with an LHR of 1.0 or greater but less than 1.3 are considered as having intermediate or moderate lung hypoplasia. According to the multicenter studies we have done, they have an expected survival rate of about 60% or greater. As such, they have not been considered eligible for fetal surgery, and the RCT by Harrison and colleagues49 did actually show that (Harrison et al, 2003). However, a survival rate of 60% to 75% is still lower than the greater than 90% survival rate observed in fetuses with an LHR of less than 1.0 but at least 0.8 treated by FETO, who had smaller lungs than this group to start off with. Fetuses in this intermediate or moderate group have larger lungs, a larger lung surface area, and, as a consequence, larger lung liquid production. Tracheal occlusion would in these circumstances be expected to yield a better lung response. These fetuses might need not that much lung growth to do better, and they would actually benefit from the greater growth rate later in pregnancy. FETO could be carried out later (i.e., in the saccular phase), reducing the consequences of iatrogenic PPROM if it occurs. Again, a randomized study comparing late tracheal occlusion versus expectant management in fetuses with intermediate lung hypoplasia has been proposed. Under this proposed classification, fetuses would be evaluated and triaged by LHR at different time points in pregnancy. One must realize that the predictive value of LHR has been validated only in a very narrow window in the transition of second to third trimester. Further, LHR depends on gestational age. For that reason, we propose to work in the future with the observed LHR rather than the LHR one would expect for a matched normal control (O/E LHR). This is at present the subject of a validation study, but it would discount the problem of gestational age when evaluating patients. Obviously, once volumetric methods have proved themselves, predictions and case selection need to be based on those methods. However, none of these techniques would take into account that the lung growth pattern in an individual CDH

Ch117-F06861.indd 1423

1423

case may vary considerably throughout pregnancy and therefore may never be 100% predictable. Another caveat is that any predictive test must take into account that we are dealing with a “moving target”—that is, the results achieved with “standard” neonatal care also change over time, or by geographic location. Ideally each center would need to validate its own selection criteria, provided they have sufficient numbers of cases and prenatal documentation were available. The FETO Task Group is currently negotiating with the European Commission a research project involving instrument development as well as a trial (http://www.EuroCDH. org). Survival is a logical primary outcome measure for the RCT, but morbidity indicators may be as important. Expected confounding factors include our current multicenter setting, and it might be difficult to standardize perinatal management. This has in the past proved to be difficult, but consensus recommendations will be given. At present we cannot conduct an RCT in which therapy is offered free of charge in one or three single centers. In Europe, we lack a uniform health system or funding organization that might support such a trial. Also, patients as well as referring centers would be reluctant to concentrate everything in just one center. Therefore, we propose to work more pragmatically: the trial would test actually whether survival is increased by the addition of antenatal therapy (at a specialized fourth level FETO center) to standard (tertiary care center) postnatal care.

SUMMARY CDH is usually diagnosed at the second trimester screening ultrasound examination. Prenatal imaging techniques allow the prediction of postnatal outcome. Fetuses who have herniation of the liver into the contralateral hemithorax and LHR of less than 1.0 have a poor chance to survive. A prenatal intervention that can reverse pulmonary hypoplasia may be contemplated in these cases. Anatomic repair cannot be offered to fetuses with liver herniation. However, lung growth can be achieved by tracheal occlusion. In 2004, a randomized trial failed to show benefit from prenatal tracheal occlusion, but the study lacked power to document the potential advantage of prenatal therapy in severe cases. Recent advances in minimally invasive techniques have made it possible to achieve percutaneous FETO therapy through a 3-mm access port. An endoluminal balloon is inserted into the trachea with sonoendoscopic guidance at 26 to 28 weeks, and the occlusion is reversed at 34 weeks. FETO increases lung size and yields 75% early neonatal (7 days) survival, 58% late neonatal (28 days) survival, and 50% survival at discharge, which compares favorably to less than 15% survival in contemporary controls. Outcome may be predicted from LHR measured before FETO: 62% survival for LHR of 0.6 to less than 0.8, and 78% for LHR of 0.8 to less than 1.0, compared with 0% and 16%, respectively, in controls treated by standard postnatal care. The procedure carries a significant risk for PPROM and preterm delivery. A randomized trial is needed to demonstrate whether prenatal therapy is truly beneficial.

1/21/2008 3:45:44 PM

1424

Section 6 Diaphragm

Acknowledgment The FETO Task Group is directed by Jan Deprest, Eduardo Gratacos (Hospital Clinic, Barcelona, Spain) and Kypros Nicolaïdes (King’s College Hospital, London, UK), where these procedures are done as well (http://www.EuroCDH. org). We thank these, as well as our colleagues at the different perinatal teams for their contribution to this enterprise. The European Commission supports this work via the 5th and 6th Framework Programme (EuroTwin2Twin, QLG1-CT-200201632 and EuroSTEC; LSHC-CT-2006-037409).

COMMENTS AND CONTROVERSIES Advances in intrauterine diagnosis and treatment of CDH are amazing. However, pulmonary hypoplasia and resultant respiratory failure are still major problems. Intrauterine repair of the diaphragm and postdelivery attempts at fostering lung growth are theoretically promising but clinically disappointing. The good fortune of an “experiment of nature” has allowed intrauterine tracheal occlusion for 6 to 8 weeks early in the third trimester to be used to stimulate lung growth. Modern technology has allowed this to be performed percutaneously with balloon occlusion, thus minimizing risk to the fetus and mother. This experience is incredible, promising, but as yet anecdotal. The authors and other workers in this field should be applauded for their excellent work and encouraged to press on. Hopefully, the cause of this congenital abnormality will be identified, and therapy can then be directed at intrauterine prevention. T. W. R.

KEY REFERENCES

Deprest J, Jani J, Cannie M, et al: Progress in intra-uterine assessment of the fetal lung and prediction of neonatal function. Ultrasound Obstet Gynaecol 25:108-111, 2005. ■ Discussion on methods for prenatal assessment of lung development and difficulties in obtaining good and comparable data. Downard C, Jaksic T, Garza J, et al: Analysis of an improved survival rate for congenital diaphragmatic hernia. J Pediatr Surg 38:729-732, 2003. ■ Retrospective, single-center analysis of actual versus predicted survival rates from the CDH study group risk assessment score. The survival rate was in any case higher than in population-based studies. Jani J, Keller RL, Benachi A, et al: Prenatal prediction of survival in isolated left-sided diaphragmatic hernia. Ultrasound Obstet Gynecol 27:18-22, 2006. ■ The largest series currently available on prediction of outcome in babies with isolated CDH in midtrimester gestation. Jani JC, Nicolaides KH, Gratacos E, et al; the FETO Task Group: Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Am J Obstet Gynecol 195:1646-1650, 2006 (Epub 2006 Jun 12). ■ Outcome after FETO is predicted from pre-FETO LHR measurement. Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congential diaphragmatic hernia. N Engl J Med 349:1916-1924, 2003. ■ Randomized trial showing no benefit of prenatal therapy for fetuses with LHR <1.4 and liver herniation. Stege G, Fenton A, Jaffray B: Nihilism in the 1990s: The true mortality of CDH. Pediatrics 112:532-535, 2003. ■ This recent review reports on data from the United Kingdom showing that CDH is still associated with a high mortality rate. The reasons for that are analyzed.

Deprest J, Gratacos E, Nicolaides KH: Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: Evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 24:121-126, 2004. ■ Initial report on percutaneous FETO.

Ch117-F06861.indd 1424

1/21/2008 3:45:44 PM

chapter

118

SURGICAL APPROACHES TO THE DIAPHRAGM Eugenio Pompeo Tommaso C. Mineo

Key Points ■ Surgery involving the diaphragm can be required for a number of

diaphragmatic and nondiaphragmatic abnormalities. ■ It entails thoracic, abdominal, and combined thoracoabdominal

approaches. ■ Minimally invasive video-assisted thoracoscopic and laparoscopic

approaches are increasingly being employed for a number of benign conditions. ■ The diaphragm can be widely incised with no functional compromise, provided that major branches of the phrenic nerves are respected. ■ Most of transdiaphragmatic surgical procedures can be optimally performed through a circumferential peripheral phrenotomy.

The diaphragm is a musculotendinous structure that provides an anatomic barrier separating the pleural cavities and pericardium from the abdominal cavity. Its muscular characteristics and its ability to sustain wide incision with no functional compromise are often useful to the surgeon. In recent years, surgical management of acquired and congenital abnormalities involving the diaphragm has evolved, and it is now performed more frequently and more safely. A competent surgeon needs to be confident using all of the available surgical modalities, which, aside from the classic thoracic, abdominal, and combined thoracoabdominal open approaches, include minimally invasive thoracoscopic and laparoscopic approaches.

FUNDAMENTAL SURGICAL ANATOMY The diaphragm is the most important muscle of respiration, although the crura surrounding the esophagus have a possible role in lower esophageal sphincteric function. It has a domelike shape with a structure of muscular fibers radiating out from a central tendon. The peripheral muscular portion arises from the lumbar vertebrae, sternum, and lower ribs, whereas the central tendinous portion is contiguous on its superior aspect with the pericardium. The diaphragm presents three true openings: 1. The aortic opening—This orifice lies anterior to the lower border of D12, between the crura and behind the median arcuate ligament. It provides a passage for the aorta, the azygos vein, the thoracic duct, and the lymphatic vessels that descend from the thorax to the cisterna chyli. 2. The vena cava opening—It is located at the level of D8 and allows passage for the inferior vena cava, small

branches of the right phrenic nerve, and a few lymphatic vessels. 3. The esophageal hiatus, or simply the hiatus—It is an oval aperture located within the muscular portion of the diaphragm, behind the central tendon and at the level of D10, anterior to the aortic opening. The hiatus provides a passage for the esophagus, the vagi, and the esophageal branches of gastric vessels. The esophagus is not strictly adherent to the hiatus but lies within an areolar tissue, which allows it a certain mobility that is limited by the fibroelastic membrane of Bertelli. Other potential diaphragmatic openings include the foramen of Morgagni, between the sternocostal portions of the muscular diaphragm, which provides passage to the distal internal thoracic vessels; the retrosternal gap of Larrey, located between the anterior muscles inserting at the xiphoid, through which prepericardial areolar tissue communicates directly with preperitoneal fat; and finally, a gap of muscular fibers that can sometimes be found between the costal portion of the diaphragm and the portion arising from the arcuate ligament bilaterally (i.e., foramen of Bochdaleck). Other structures that pass between the abdomen and the thorax, through the diaphragm or posterior to it, are the musculophrenic vessels between the diaphragmatic origin at the seventh and eighth cartilages, the lower five intercostal nerves from the seventh cartilage inferiorly, the sympathetic trunk, the splanchnic nerves, and the inferior azygos vein. Arterial supply to the diaphragm is mainly via the right and left phrenic arteries, the intercostal arteries, and branches of the internal thoracic artery. Venous drainage is via the inferior phrenic veins, which drain into the inferior vena cava. The nerve supply of the diaphragm is by the phrenic nerves, which give a motor supply to the dome. The crura are supplied by spinal nerves (Fell, 1998).1

SURGICAL APPROACHES Surgical access to the diaphragm can be required for treatment of congenital or acquired diaphragmatic abnormalities, for secondary involvement from neighboring conditions, in surgical procedures involving structures that pass through diaphragmatic openings, to tailor multiuse pedicled diaphragmatic flaps, and to deal with conditions that can be optimally managed through diaphragmatic incisions. In all these instances, an exact knowledge of the anatomy of the diaphragm and the topography of the adjacent and traversing organs is a basic requirement. 1425

Ch118-F06861.indd 1425

1/21/2008 3:46:29 PM

1426

Section 6 Diaphragm

TABLE 118-1 Diaphragmatic Abnormalities and Suggested Surgical Approaches Abnormality

Thoracic

VATS

Abdominal

Laparoscopic

Thoracoabdominal

Diaphragmatic eventration

+

+

±

±

−

Traumatic diaphragmatic injury

+

+

±

+

±

Traumatic diaphragmatic hernia

+

−

+

−

±

Congenital diaphragmatic hernia

−

−

+

−

−

Diaphragmatic hiatal hernias

±

−

±

+

−

Diaphragmatic unusual hernias

+

+

+

+

−

Diaphragmatic tumors

+

−

+

−

±

Pleuroperitoneal communication

±

+

−

−

−

VATS, video-assisted thoracic surgery.

Diaphragmatic surgical procedures can be managed through abdominal, thoracic, or combined thoracoabdominal access, depending on the nature of the lesion, its location, the existence of other thoracic or abdominal abnormalities, and the surgeon’s attitude and preference. Video-assisted thoracoscopic and laparoscopic approaches to the diaphragm have also been developed and are increasingly employed for a number of benign conditions (Table 118-1).

OPEN APPROACHES Thoracotomy On both sides, thoracotomy ensures an optimal access to the diaphragmatic dome from above. It allows thorough visualization of all of the muscular surface and adequate surgical maneuvering, thus facilitating treatment of any diaphragmatic lesion. This approach is performed under general anesthesia, with a double-lumen tube intubation to effect collapse of the ipsilateral lung and allow an unobstructed view of the entire hemidiaphragm and phrenic nerve. The patient is positioned in full lateral decubitus position with a 30% flexed upper third of the table to widen intercostal spaces and a fixed support against the front of the upper chest that allows the upper arm to be drawn forward, thus swinging the scapula anteriorly and facilitating access to selected intercostal spaces. The incision can be performed on either the left or the right hemithorax, in the sixth, seventh, or eighth intercostal space. Our preferred incision is the classic posterolateral thoracotomy in the seventh intercostal space performed through a curvilinear and slightly italic S-like shaped incision that is extended from the mammillary line below the angle of the scapula and then continued cephalad, between the posterior midline over the vertebral column and the medial edge of the scapula. Muscular layers that are routinely incised are the latissimus dorsi and serratus anterior. The intercostal space is gently and progressively divaricated with a thoracic retractor without rib resection. Some surgeons recommend rib division at the level of the costovertebral angle for patients older than 40 years of age, to decrease the incidence of rib fracture. Another incision that can be performed is the

Ch118-F06861.indd 1426

anterolateral thoracotomy. Whatever the type of thoracotomy employed, access to abdominal organs can be achieved, if required, through a peripheral circumferential phrenotomy, which offers the advantage of sparing all the major branches of the phrenic nerve. At the completion of any procedure, the pleural cavity is drained in a classic manner, with placement of one or two chest tubes. Thoracotomy is commonly employed for treatment of diaphragmatic eventration2 and for surgical management of chronic traumatic and iatrogenic diaphragmatic hernias, which are almost invariably associated with adhesions between abdominal and thoracic structures.

Laparotomy The laparotomy approach allows easy access to the crura, the esophageal hiatus, and the anterior insertions of the diaphragm from below. It also facilitates visualization of both domes, which are covered anteriorly by costal arches and inferiorly by the liver, the stomach, the spleen, and the left colic flexure. From a topographic point of view, abdominal incisions entail the median laparotomy; the paramedian transrectal incision; the right, left, or bilateral subcostal incision; and the oblique supraumbilical incision (Fig. 118-1). Access to the diaphragm can be facilitated by use of the upper hand retractor. Drainage of the peritoneal cavity is not necessarily performed, although we usually place a Redon drain below the operated diaphragm dome. Median laparotomy is commonly employed in patients with thoracoabdominal trauma and diaphragmatic rupture because it offers the possibility to diagnose and repair frequently associated intra-abdominal injuries. Laparotomy also provides ideal access to the esophageal hiatus3 and for surgical management of anterolateral diaphragmatic hernias. Congenital diaphragmatic hernias in children are also commonly approached through the abdomen via a subcostal incision.4

Thoracoabdominal Incision Thoracoabdominal access is a wide surgical approach that has the benefit of improved exposure, providing access to both

1/21/2008 3:46:29 PM

Chapter 118 Surgical Approaches to the Diaphragm

1427

A1 C1 B

PP

C

A

FIGURE 118-1 The most frequently employed abdominal incisions are the median laparotomy (A) with thoracic extension (A1); the subcostal incision (B); and the oblique incision (C) with thoracotomy extension (C1).

FIGURE 118-2 Combined thoracoabdominal incision with peripheral phrenotomy (PP).

chest and abdomen, and optimal access to the diaphragmatic leaves. Depending on the surgeon’s preference and requirement, the incision can initially start from the umbilicus and be carried toward the costal arch, subsequently proceeding in the chest wall along the seventh or eighth intercostal space. Also, it can start from thoracotomy and proceed with a laparotomy as required. The subsequent incision of the abdominal muscles (rectus abdominis, obliquus major and minor, and transversus), the chondrocostal cartilage, and the thoracic muscles (serratus anterior and dorsalis major) offers a satisfactory access, which can be widened in the thorax, extending the incision dorsally as needed. Access to intra-abdominal organs can be gained through a peripheral incision in the diaphragm itself. This is performed with the electrocautery 2 to 3 cm away from the costal margin, with complete avoidance of the major branches of the phrenic nerve. On the right side, the dome, the liver surface, the hepatic hilum, the inferior vena cava, and the esophagus are accessible. From the left side, the dome, the stomach, the spleen, the pancreas, the supradiaphragmatic and infradiaphragmatic tract of the aorta, and the distal esophagus also can be widely visualized (Fig. 118-2). At the completion of any procedure, if phrenotomy has been performed, the incision is sutured with interrupted

nonabsorbable 0/0 or 1/0 sutures with consideration of the constant stress on the suture line during respiration. Finally, both the abdominal and the thoracic cavity must be adequately drained. In children, it can be useful to perform separate abdominal and thoracic incisions, leaving intact the chondrocostal cartilage and thus reducing the risk of post-thoracotomy pain sequelae. We usually prefer the left thoracophrenolaparotomy approach for complex esophagogastric procedures, whereas the right approach is used to manage severe hepatodiaphragmatic traumatic injuries. The thoracoabdominal approach is also less frequently employed for exposure of the spine5 and thoracoabdominal aorta.

Ch118-F06861.indd 1427

VIDEO-ASSISTED APPROACHES Thoracoscopy Video-assisted thoracoscopic surgery (VATS) is being employed in an increasing number of surgical instances and has been purported to yield improved magnified vision, reduced postoperative pain and dysfunction, shorter hospital stays, and improved cosmesis. The procedure is performed under general anesthesia with double-lumen tube intubation to allow ipsilateral lung col-

1/21/2008 3:46:29 PM

1428

Section 6 Diaphragm

diaphragmatic injury is suspected. VATS is also an attractive option for treatment of Morgagni6 and Bochdalek7 hernias. Finally, a thoracoscopic transdiaphragmatic approach has been anecdotally advocated, both experimentally and clinically, to perform adrenal biopsy8 and adrenalectomy.9,10 Contraindications for VATS include a history of previous thoracic surgery, pleurodesis, or radiologic signs of dense pleuropulmonary adhesions in the targeted hemithorax and large traumatic diaphragm ruptures with intrathoracic herniation of abdominal organs.

Laparoscopy

FIGURE 118-3 Thoracoscopic approach with flexible trocars inserted.

A

B

C

D

FIGURE 118-4 Thoracoscopic access. A, Anterior view of left diaphragm dome. B, Posterior view of the dome. C, Anterior costophrenic angle. D, Posterior costophrenic angle.

lapse. The stomach is drained with a nasogastric tube. The patient is placed in full lateral position, and the chest is widely prepared for conversion to open thoracotomy if necessary. For standard VATS exploration of diaphragmatic domes, we usually employ a 10-mm flexible thoracoport for the camera in the seventh intercostal space at the midaxillary line. Two other operating thoracoports are placed for instrumentation (Figs. 118-3 and 118-4). At the completion of the procedure, one chest tube is placed through the lowest trocar’s incision. We now always consider VATS for surgical management of diaphragmatic eventration and to explore the diaphragm leaves after thoracoabdominal trauma in which a limited

Ch118-F06861.indd 1428

Laparoscopy offers a wide visualization of both domes to the crura, the esophageal hiatus, and the anterior insertions of the diaphragm from below that is even superior to that achieved through laparotomy. The patient is placed in a 30-degree reversed Trendelenburg position under general anesthesia and single-lumen endotracheal intubation. The surgeon is positioned between the legs of the patient, with one assistant placed on the right side and another on the left side. If the indication is diaphragmatic eventration or hiatal hernia, the pneumoperitoneum can be safely employed with carbon dioxide insufflation through a Veress needle inserted through a paraumbilical incision. On the other hand, if the indication is repair of diaphragmatic injury, gasless laparoscopy is preferred because tension pneumothorax induced by the passage of carbon dioxide into the pleural cavity through the diaphragmatic lesion has been reported. Through the paraumbilical incision, a 10-mm 30-degree angle laparoscope is introduced. Three additional working trocars, two 10-mm trocars and one 5-mm trocar, are inserted, following an ideal semicircle in the right or left middle and upper abdomen under visual control (Fig. 118-5). In all instances, the left hepatic lobe is mobilized first, along the left triangular ligament. Through the laparoscope, each diaphragmatic dome can be easily and widely visualized from below. In some instances, such as the presence of diaphragmatic eventration, retention stitches can be placed transcutaneously to apply extracorporeal traction on the diaphragm domes and thus facilitate surgical maneuvering.11 Laparoscopy is now commonly employed to treat hiatal hernias and other unusual diaphragmatic hernias,12 diaphragmatic injuries,13,14 and eventration of the diaphragm.11

PHRENOTOMY Incisions into the diaphragm must be tailored to avoid injury to major branches of the phrenic nerves. In fact, although ischemic injuries are unlikely to occur due to the rich vascularity of the diaphragm, the incidental transsection of a nerve branch is invariably followed by paralysis of the tributary muscular sector, with possible associated impairment in respiratory function, gastrointestinal troubles, and risk of diaphragmatic eventration. Incision of the central tendon seldom causes functional impairment of the diaphragm, although this incision provides only minimal exposure of the adjacent compartment. Most phrenotomies can be categorized as either circumferential or radial.

1/21/2008 3:46:30 PM

Chapter 118 Surgical Approaches to the Diaphragm

1429

Circumferential incisions anywhere in the periphery offer excellent visualization of adjacent structures with little, if any, loss of diaphragmatic motion because of the rapid reduction in the size of the branches of the phrenic nerve. Radial incisions start centrally and proceed toward the body wall, so that the diaphragm is incised without transection of any of the major branches of the phrenic nerve. Several relatively safe diaphragmatic incisions have been classically described15 (Fig. 118-6), but most transdiaphragmatic surgical procedures can be reliably performed through a peripheral circumferential phrenotomy that is extended anteriorly or posteriorly as required. It is performed with the electrocautery 2 to 3 cm away from the costal margin, to facilitate subsequent suturing of diaphragmatic edges (Merendino et al, 1956). The cut edges are grasped and elevated to facilitate further incision. Bleeding vessels are cauterized or ligated. When diaphragmatic incisions are made in association with antireflux procedures, it is best to use the anterolateral two thirds of the diaphragm and not to carry the incision posteriorly to the level of the esophageal hiatus. For left transthoracic esophagogastric resections, the circumferential incision may be extended up to the esophageal hiatus, although this is seldom necessary. Direct septum transversum incision performed by a linear stapler has been described to replace circumferential phrenotomy in operations on the cardia.16 Incisions in the diaphragm may be closed with one-layer interrupted nonabsorbable 0/0 or 1/0 sutures, with consideration of the constant stress on the suture line during respiration.

OP5 OP10 CP OP10

FIGURE 118-5 Laparoscopic approach showing positions of the camera port (CP), the 10-mm operating ports (OP10), and the 5-mm operating port (OP5).

DIAPHRAGMATIC FLAPS In 1948, Petrovski17 reported the use of diaphragmatic muscle grafts for reconstructive work in both the thorax and

FIGURE 118-6 Diaphragm incisions: A, radial; B, circumferential peripheral; C and D, incisions in safe areas; E, septum transversum incision proposed by Sicular.16 B

C A E

Ch118-F06861.indd 1429

D

1/21/2008 3:46:31 PM

1430

Section 6 Diaphragm

A

margin, starting dorsally from the aortic hiatus to save the origin of the phrenic artery and explore its territory. As an adjuvant maneuver, we normally introduce a cold-light source inside the abdomen through the initial phrenotomy. For this purpose, we have used a flexible fiberoptic cable. By means of translucency, the major branches of the phrenic artery are clearly visualized, and the flap preparation is conveniently performed. We believe that this technique is also helpful to avoid hepatic and splenic lesions and to divide peritoneal adhesions. The length of the flap is never measured; we just make an estimate. As soon as the length of the flap is deemed suitable for the surgical purpose, the direction of the incision is inverted ventrally to draw an arch of variable sharpness. We normally mark the so-called keystone of the flap with a radiopaque clip to facilitate radiographic localization. To provide an adequate and vital flap, the width of the base is approximately one quarter of the entire length. The flap is tailored to be rotated inside the chest cavity, avoiding torsion on the pedicle and allowing sufficient motility and low tension of the remaining muscle. The flap can reach any district of the hemithorax, depending on the specific indication required.

COMMENTS AND CONTROVERSIES

B FIGURE 118-7 A and B, Diaphragm flap employed to repair esophageal rupture.

B abdomen. Diaphragmatic flaps also have been employed for more than 30 years to reinforce esophageal perforations18 and to close chest wall defects.19 We have extensively employed pedicled diaphragmatic flaps for closure of bronchopleural fistulas, protection of bronchial stumps, wrapping of bronchial anastomoses, repair of esophageal lesions, and repair of pericardial defects (Mineo et al, 1999).20,21 The technique of harvesting that we have employed is depicted in Figure 118-7. The blood supply is provided by the phrenic artery, which flows along the inferior surface of the muscle. The flap is prepared by cutting the diaphragm in a U or V shape and folding it along the uncut margin, which works as a hinge. The diaphragm is first divided along the designed posterior

Ch118-F06861.indd 1430

In selecting a surgical approach to the diaphragm, one must consider the portion of the diaphragm that needs to be exposed, the surrounding organs and structures that may hinder this exposure, and what must be accomplished via this approach. This may lead one to a thoracic, abdominal, or combination approach. The potential for a thoracoscopic, VATS, or hybrid approach must not be forgotten or overlooked. Care in selecting the approach and preoperative planning so as to minimize the length and number of incisions in the diaphragm help avoid restrictive respiratory dysfunction. Phrenotomy outside the dome of the diaphragm must be thoughtfully planned and performed to preserve phrenic nerve function. The use of a diaphragmatic flap is considered only if other conventional muscle, omental, pericardial, or pleural flaps are not available. Consequently, I have never had to use a diaphragmatic flap and would choose one only if the lung had been removed from that pleural space. T. W. R.

KEY REFERENCES Fell SC: Surgical anatomy of the diaphragm and the phrenic nerve. Chest Surg Clin North Am 8:281, 1998. Merendino KA, Johnson RJ, Skinner HH, et al: The intradiaphragmatic distribution of the phrenic nerve with particular reference to the placement of diaphragmatic incisions and controlled segmental paralysis. Surgery 39:189, 1956. Mineo TC, Ambrogi V: The diaphragmatic flap: A multiuse material in thoracic surgery. J Thorac Cardiovasc Surg 118:1084, 1999.

1/21/2008 3:46:32 PM

Surgical Techniques PLICATION OF THE DIAPHRAGM chapter

119

Jérôme Mouroux Nicolas Venissac Francesco Leo Daniel Pop Marco Alifano

Key Points ■ Eventration and permanent phrenic nerve injury are indications for

diaphragmatic plication in symptomatic patients. ■ Thoracotomy, laparotomy, and minimally invasive approaches

have all been described and successfully used. ■ Flag, accordion, and invagination techniques using nonabsorbable

suture have been described. ■ Timing of surgery must allow recovery of reversible phrenic nerve

injury. ■ Unfortunately, outcomes and related measures can be only anec-

dotally described.

The goal of diaphragmatic plication is tightening and lowering of the diaphragm. It is a corrective surgery from a both morphologic and a functional point of view and may be applied to the treatment of diaphragmatic eventration and paralysis. The indications and the possible functional benefits have been described by many surgical teams. The procedure is widely performed in pediatric patients and, in particular, in newborns with congenital eventration or acquired diaphragmatic paralysis. On the other hand, some confusion exists in the classification of diseases causing diaphragmatic elevation in adults that might suitable for surgical treatment. Furthermore, the use of thoracotomy (which has become the preferred approach in recent years) for a functional surgery is a deterrent to both patients and physicians. Nevertheless, the possibility of performing the procedure by video-assisted thoracic surgery (VATS), with the obvious adaptation of the methods of plication to this approach, unquestionably has led to a new interest in these pathologies and their surgical treatment. This chapter provides an overview of the diseases involved (classification, epidemiology, etiology, and anatomicoclinical consequences), as well as surgical techniques, indications, and results of diaphragmatic plication.

HISTORICAL NOTE Wood1 is classically credited with having introduced in 1916 the idea of wrinkling the diaphragm in order to reduce the dimensions of the cupola. In 1923, Morrison2 performed the first successful repair of an eventration, and he described the surgical principles that are still used. He plicated the diaphragm of a 10-year-old girl with immediate relief of

symptoms. In 1947, Bisgard3 described precisely the technique of plication employed to treat a 6-week-old baby. Since these first publications, many studies were devoted to this subject in both France (Quenu and Herlemont,4 Perrotin and Moreaux,5 Dor and colleagues6) and the United States (Michelson,7 McNamara and associates8). These studies allowed evaluation of the various surgical techniques (plication by a thoracic or an abdominal approach, with excision followed by suturing), as well as the indications for surgery. The more recent works by Revillon and Fekete,9 DonzeauGouche and colleagues,10 Wright and colleagues,11 Graham and colleagues,12 and Ribet and Linder13 confirmed the improvement of respiratory functions with surgical treatment. Plication by the transthoracic approach has gradually replaced the abdominal approach. Since the appearance of video-assisted technology, several authors have reported their experience on plication using this tool. We initially described a technique of VATS in 1996 (Mouroux et al, 1996).14 More recently, Hüttl and associates15 reported a technique of plication by video-assisted laparoscopy (Hüttl et al, 2004). HISTORICAL READINGS Bisgard JD: Congenital eventration of the diaphragm. J Thorac Surg 16:484-491, 1947. Donzeau-Gouche, Personne CL, Lechien J, et al: Eventrations diaphragmatiques de l’adultes: A propos de vingt cas. Ann Chir Thor Cardiovasc 36:87-90, 1982. Dor J, Richelme H, Aubert J, Boyer R: L’éventration diaphragmatique. J Chir 97:399-432, 1969. Graham DR, Kaplan D, Evans CC, et al: Diaphragm plication for unilateral diaphragmatic paralysis: A 10-year experience. Ann Thorac Surg 49:248-252, 1990. Hüttl TP, Wichmann MW, Reichart B, et al: Laparoscopic diaphragmatic plication. Surg Endosc 18:547-551, 2004. McNamara JJ, Paulson DL, Urschel HC, Razzuk MA: Eventration of diaphragm. Surgery 64:1013-1021, 1968. Michelson E: Eventration of the diaphragm. Surgery 49:410-420, 1961. Morrison JMW: Eventration of diaphragm due to unilateral phrenic nerve paralysis. Arch Radiol Electrother 28:72-75, 1923. Mouroux J, Padovani B, Poirier NC, et al: Technique for the repair of diaphragmatic eventration. Ann Thorac Surg 62:905-907, 1996. Perrotin J, Moreaux J: Chirurgie du Diaphragme VIII. Les Éventrations. Paris, Masson, 1965, pp 221-262. Quenu J, Herlemont P: Du traitement chirurgical de l’éventration diaphragmatique. J Chir 69:101-121, 1953. Revillon Y, Fekete CN: Eventration diaphragmatique chez l’enfant. Ann Chir 36:71-74, 1982. 1431

Ch119-F06861.indd 1431

1/21/2008 3:47:18 PM

1432

Section 6 Diaphragm

There are no radiologic boundaries allowing differentiation between a slight or insignificant diaphragmatic elevation and a relevant one. Nevertheless, an extreme elevation is manifestly pathologic, especially if an abnormal mediastinal shift is present (Fig. 119-1). The incidence of both eventration and paralysis is difficult to estimate. Among newborns, the reported incidence ranges from 1 in 1400 to 1 in 13,000 cases, but elevation of a hemidiaphragm is 10 times more frequently related to phrenic paralysis than to a true congenital eventration.8,19 In adults, the study of Christensen,20 published in 1959, retrieved 38 cases among 107,778 examined persons. No further study was performed to allow actualization of these data. The male predominance of the condition (60%-80% of cases) and the preferential involvement of the left side are well-established characteristics.17,18

Ribet M, Linder JL: Plication of the diaphragm for unilateral eventration or paralysis. Eur J Cardiothorac Surg 6:357-360, 1992. Wood HG: Eventration of the diaphragm. Surg Gynecol Obstet 23:344, 1916. Wright CD, Williams JG, Ogilvie CM, Donnelly RJ: Results of the diaphragm plication for unilateral diaphragmatic paralysis. J Thorac Cardiovasc Surg 90:195-198, 1985.

CLASSIFICATION AND EPIDEMIOLOGY The radiologic finding of an elevated diaphragm has been named in various ways, with subsequent confusion. The medical debate has further contributed to these ambiguities, since the initial description of diaphragmatic eventration by Jean Louis Petit in 1774.16 Terms such as eventration, relaxation, paralysis, and hernia have been frequently used as synonyms.7,17,18 Diaphragmatic eventration is an anomaly defined by the long-lasting or permanent elevation of an entire hemidiaphragm or a portion of it, without defects. The muscular insertions are normal, the normal apertures are sealed, and there is no interruption in the pleural or peritoneal layer. Eventration can be differentiated from hernia (with or without sac) or from rupture because these other conditions involve loss of continuity of one or more of the layers constituting the diaphragm. According to most authors, only congenital eventration needs to be considered as a disease, whereas all other conditions need to be regarded as a syndrome. On the other hand, the terms eventration and paralysis are often confused because paralysis may be the cause of an abnormal elevation of the diaphragm (with degenerative changes in the muscular layer), whereas pure eventration is not always associated with paralysis. In spite of several differences, both eventration and paralysis carry the same physiologic consequences and share most symptoms. Although the management of these two conditions may be substantially different, plication may constitute a treatment option in both cases.

A

ETIOLOGY Eventration and Paralysis in Children In the newborn, diaphragmatic elevation may be related to either a congenital eventration or an acquired diaphragmatic paralysis. The latter is by far the most frequent cause of elevation in children. In the series by Huault and coworkers19 dealing with 202 pediatric patients with diaphragmatic elevation, a phrenic paralysis was observed in 190 cases, whereas a true eventration accounted for only 12 cases.

Congenital Eventration The diaphragm originates from the union of several components. Its development begins in the 4th week of gestation and finishes during the third month. During the 4th week, the septum transversum appears. It is represented by a thick blade of mesoderm that is initially located on the level of occipital and upper cervical somites but is subject to a pro-

B

FIGURE 119-1 A, Left diaphragmatic eventration with mediastinal contralateral shift. B, Same patient, 2 years after plication of the diaphragm.

Ch119-F06861.indd 1432

1/21/2008 3:47:18 PM

Chapter 119 Plication of the Diaphragm

gressive downward migration. During this descent, it is colonized by myogenous stem cells migrating from cervical somites. There is progressive fusion of the septum transversum with the esophageal dorsal mesentery, which in turn gives rise to the diaphragmatic crura. Communication between the thoracic and the abdominal cavity persists up to the 8th week because of the existence of the posterolaterally located pleuroperitoneal ducts. Closure of this communication is achieved by the pleuroperitoneal membrane, which is initially formed by apposition of the two serosal layers (pleura cranially and peritoneum caudally) but secondarily is subject to colonization from myoblasts originating from a lateral muscular burrowing. At the beginning of the 6th week of gestation, the initial structure of the diaphragm reaches the region of thoracic somites, and at the end of the 8th week it can be found at the level of the first lumbar vertebra (L1). Congenital eventration occurs secondarily to an abnormal myoblastic colonization of the diaphragm during fetal development. Macroscopically, the diaphragm has the appearance of a translucid membrane. Microscopic examination shows that the diaphragm consists of two serosal layers separated by rare muscular fibers and fibrotic tissue. Peripheral insertions have a normal muscular aspect. Eventration may be total (usually on the left side) or partial (more frequently observed on the right). Partial eventrations are classified into three different types: anterior, posterolateral, medial. Congenital eventration may be associated with other malformations.8,18,21

(obstetric, vertebral or neck surgery, central venous access, locoregional analgesia, collapse therapy), and infection (herpes virus). Nerve involvement at the mediastinal level is caused by metastatic lymph nodes (especially from lung cancers), mediastinal tumors, tuberculous adenitis, noniatrogenic trauma (penetrating and nonpenetrating), and iatrogenic trauma (lung and cardiac surgery).

Diaphragmatic Paralysis

ANATOMICOCLINICAL CONSEQUENCES

In the newborn, phrenic nerve injury is usually related to a surgical trauma, in most cases occurring during the repair of a congenital cardiovascular anomaly. In the series by Huault and coworkers,19 this cause accounted for 68% of the cases. The incidence of diaphragmatic paralysis after cardiac surgery ranges from 0.3% to 12.8%.22 The second cause of phrenic nerve injury in newborns is obstetric trauma (difficult delivery, use of forceps, intrauterine malposition). In these cases, the identification of an associated nerve injury (brachial plexus, recurrent laryngeal, sympathetic) may help in diagnosis.9

Childhood

Diaphragmatic Elevation in Adults The previously described forms may manifest in adulthood and thus require consideration at the time of diagnostic workup. Apart from these cases, the eventrations are classically divided into those with and without phrenic nerve involvement.6,17,18,23

Eventrations With Phrenic Nerve Involvement This group of eventrations can be classified according to the level of involvement; such a classification allows a better understanding of laboratory investigations useful in the workup. The levels of involvement are spinal cord (amyotrophic lateral sclerosis, trauma, poliomyelitis), radicular (vertebral disc diseases, osteophytosis), and nerve. Phrenic nerve involvement at the cervical level is caused by noniatrogenic trauma (e.g., motor vehicle accident), iatrogenic trauma

Ch119-F06861.indd 1433

1433

Eventrations Without Phrenic Nerve Involvement Eventrations without phrenic nerve involvement may result from thoracoabdominal trauma, disease in neighboring tissues (subphrenic abscess, atelectasis, pleural infection), or idiopathic causes. Despite an exhaustive workup, the cause of diaphragmatic elevation in adults often remains unexplained. In the study of Pielher and colleagues,24 the cause of eventration could not be found in 142 (57.5%) of 247 patients at initial workup, and only in 6 further cases was the etiology identified during the subsequent follow-up. Neoplasms and cervical or thoracic surgery each accounted for 33% of causes among the 105 patients with a defined etiology of diaphragmatic elevation; in the remaining cases, noniatrogenic trauma, infection, or neurologic disease was responsible for the condition. At the time this work was performed, several diagnostic tools were not yet available; nevertheless, in spite of progress in imaging technology, the cause of eventration still sometimes remains uncertain.13

Elevation of the diaphragm reduces the lung volume. This condition is precariously tolerated because of the weakness of accessory muscles and the excessive mobility of the mediastinum, which shifts during inspiration, causing contralateral lung compression. This situation is further worsened by the dorsal decubitus position (with diaphragmatic compression by abdominal viscera) and bronchial collapse caused by inherent softness. Clinical manifestations may appear very precociously: acute respiratory distress, often necessitating a respiratory assistance, is a frequent feature. The need of mechanical ventilation varies between 13% and 72%, according to published series. It is more frequently necessary in children with phrenic paralysis (40%-72%)13,25-27 than in patients with congenital eventration (13%-16%).9,25 In some cases, clinical manifestations appear less precociously, and dyspnea, recurrent bronchitis or pneumonia, vomiting, postprandial suffocation crises, or failure to thrive may constitute the presenting symptoms. Occasionally, the elevation remains asymptomatic and is discovered only in adulthood.

Adulthood Elevation of the diaphragm is better tolerated in adults and sometimes is discovered only when chest radiography is performed for other reasons. Consequences of diaphragmatic elevation may be respiratory, digestive, or cardiac.6,17,18

1/21/2008 3:47:19 PM

1434

Section 6 Diaphragm

■

firmed in the study by Graham and colleagues.12 Ridyard and Stewart29 showed with ventilation-perfusion scanning that both ventilation and perfusion of the ipsilateral lower lobe are diminished in cases of unilateral diaphragmatic paralysis (Fig. 119-2).

Respiratory: The elevation of the diaphragm causes a decrease in lung volumes, which is responsible for a restrictive syndrome and a moderate hypoxemia. Clague and Hall28 showed that this syndrome was worsened by placing the patient in the supine position. This was con-

A

B 244K

C Anterior view

3/4 Posterior left 349K

FIGURE 119-2 Frontal (A) and lateral (B) radiographic views of an adult with elevated hemidiaphragm. C, Computed tomographic scan of the same patient. D, Ventilation-perfusion scan showing the absence of ventilation in the inferior middle right lung.

Ch119-F06861.indd 1434

Posterior view

3/4 Anterior right

D

1/21/2008 3:47:19 PM

Chapter 119 Plication of the Diaphragm

■

■

1435

TECHNIQUES OF DIAPHRAGMATIC PLICATION

Digestive: Elevation of the diaphragm is accompanied by ascension of abdominal organs. On the right side, the liver is primarily involved. In partial eventrations, it insinuates itself into the deformation, giving rise to the classic appearance of a bun on chest radiography. Sometimes, liver can be accompanied by colon or gastric antrum. In total eventration, the whole liver is pushed cranially, inducing the ascension of the pylorus with the lower portion of stomach. The right colic flexure and the median portion of the transverse colon may become interposed between the liver and the diaphragm, resulting in the Chilaiditi syndrome (Fig. 119-3).30 On the left side, the stomach is primarily involved, and it assumes a reversed-U position, with the gastric fundus being pushed posterosuperiorly and the antrum anterosuperiorly. The median portion, which has a horizontal position, is occupied by a new air pocket with the potential for weakening the lower esophageal sphincter, leading to the possibility of a gastroesophageal reflux. Ascension of colon, spleen, and kidney may be associated. Cardiac: Cardiac symptoms are more frequent in leftsided eventration. In this case, cardiac shift (dextrocardia) may be responsible for arrhythmias.

Principles Plication of the diaphragm aims to provide a satisfactory tension to an abnormally flask-shaped dome, while at the same time lowering it. This procedure has obviously no impact on the mobility of the diaphragm in cases of phrenic paralysis. Nevertheless, in anticipation of restoring of phrenic nerve function, the preservation of distal branches of the nerve allows physiologic movement, in contrast to the excision-suture techniques that do not allow this kind of recovery. Anatomic and histologic observations show that the central portion of the dome is more or less slimmed, with various degrees of atrophy or of rarefaction of the muscular fibers, whereas the peripheral portion generally maintains a solid texture. Stitches will find better support on this portion of the diaphragm at the time of the plication.6 Lowering of the cupola, while providing a more physiologic tension, allows re-expansion of the adjacent lung, diminution of the adverse effect of abdominal pressure, elimination of paradoxical movements and of mediastinal shift, and improvement of the actions of intercostal and accessory muscles.13

Conventional Procedures (Box 119-1) Plication Through an Open Transthoracic Approach

As already stated, totally asymptomatic cases are possible. Oligosymptomatic presentations are also possible, including slight dyspnea, sometimes worsened by the supine position; epigastric or upper quadrant pain (spontaneous or induced by the flexion); regurgitation; and painful eructations.6,7,17,18,23 Exceptional presentations include acute respiratory failure31 and diaphragmatic rupture.32

“Flag” Plication. This is the reference technique (Fig. 119-4). It is carried out through a more or less large posterolateral thoracotomy. The location of the thoracotomy incision is variable according to different authors’ experience (from the 6th to 8th intercostal spaces). The lung and mediastinum

B

A

Ch119-F06861.indd 1435

FIGURE 119-3 A, Chilaiditi syndrome: barium swallow showing interposition of the large bowel between the liver and the diaphragm. B, Computed tomographic scan of the same patient.

1/21/2008 3:47:19 PM

1436

Section 6 Diaphragm

are examined to exclude unsuspected disease. Two Babcock forceps raise the slimmed cupola, creating a fold. The direction of the plication (anteroposterior or transverse) is determined by the grossly apparent axis of the eventration. Generally, plication is performed according to a transverse axis. The fold is fixed at its base by a series of U-shaped, nonabsorbable stitches. The plicated area is subsequently folded onto the portion of the diaphragm that appears more weak and fixed close to the costal insertion of the diaphragm by one or several rows of sutures. At the level of the weakened portion, the repaired diaphragm has thus a three-layer thickness. Mechanical stapling of the base of the fold has been proposed to replace the U-shaped stitches. Another variant is represented by splitting of the plication after incision of the apex of the fold. Each of the two aspects of the fold is subsequently folded onto a side of the axis of the plication. This last technique unquestionably weakens the diaphragmatic dome.

Box 119-1 Surgical Techniques Plication is carried out by the transthoracic approach in the absence of indication for an abdominal approach (bilateral or associated intraabdominal disease). Plication is technically feasible by VATS: the operation is bloodless and rapid, and the desired tension can be applied to the plicated diaphragm.

A

“Accordion” Plication. Other techniques of plication have been described. In particular, the technique by Schwartz and Filler33 is often employed by pediatric surgeons. In this technique (Fig. 119-5), the redundant diaphragm is pulled in a radial direction, and pleats are created by the placement of full-thickness horizontal mattress nonabsorbable sutures in the anteromedial to posteromedial direction while avoiding injury to branches of the phrenic nerve. This type of plication gives the diaphragm an “accordion” appearance. In this manner, the diaphragm can be plicated with as many rows of sutures as necessary to tighten it. Some authors have also suggested buttressing the final layers of the sutures with polytetrafluoroethylene pledgets to prevent tearing out of the sutures.12,34

Plication Through an Open Transabdominal Approach Plication by the abdominal approach (Fig. 119-6) is based on the same principles. It is performed through a median or transverse laparotomy.4,5,17 The diaphragm is grasped with two Babcock forceps, and a large fold is drawn downward. Transfixing stitches are applied at the base of the fold, which is subsequently folded over and fixed to the anterior portion of the hemidiaphragm. Inadvertent lung puncture with pneumothorax may complicate this technique. Pleuropulmonary adhesions may render the technique unsuitable and even dangerous. The abdominal approach is currently rarely employed. It can be useful in cases of associated abdominal disease or bilateral eventration.

B

FIGURE 119-4 “Flag” plication. A, The pleat is created and fixed with mattress sutures at the base. B, The pleat is folded down and fixed at its top.

Ch119-F06861.indd 1436

1/21/2008 3:47:20 PM

Chapter 119 Plication of the Diaphragm

A

1437

B

FIGURE 119-5 “Accordion” plication. A, Mattress sutures are placed carefully to avoid major nerve fibers and entry into the abdominal cavity. B, Completed repair.

Plication by Minimally Invasive Surgery Plication by Video-Assisted Thoracic Surgery

FIGURE 119-6 Diaphragm plication by the abdominal approach. The pleat is created with mattress sutures at the base; then it is folded frontally and fixed at the anterior circumference.

Ch119-F06861.indd 1437

The previously described techniques of plication, and in particular the “flag” plication, require a wide surgical approach to allow creation and handling of the diaphragmatic fold. These methods are not compatible with a video-assisted approach. One of us (JM) developed a technique,14 inspired by the Bisgard operation,3 that has the advantage of being compatible with VATS. The diaphragm is invaginated and then stitched, using two superimposed layers of sutures. Technique. The intervention is performed with the use of general anesthesia and selective tracheobronchial intubation to allow single-lung ventilation. Gastric decompression is achieved by placement of a nasogastric tube. The patient is placed in lateral decubitus position as for standard posterolateral thoracotomy, with the surgeon standing behind. The operating table is positioned with the head raised to decrease the abdominal pressure on the diaphragm. Two thoracoports (10 mm or 5 mm) are introduced (Fig. 119-7). The first one is placed in the fifth intercostal space on the posterior axillary line for the introduction of the 0-degree scope (port 1). The second one is inserted in fifth intercostal space on the anterior axillary line (port 2). After exploration of the lung and mediastinum, a 4- to 5-cm thoracotomy is carried out at the level of the eighth or ninth intercostal space on the posterior axillary line. A retractor is not usually necessary. This minithoracotomy allows the introduction of conventional instruments (needle holder, forceps). An endoscopic Duval forceps, introduced through port 2, is used to grasp and push the apex

1/21/2008 3:47:22 PM

1438

Section 6 Diaphragm

FIGURE 119-7 A, Position of the two thoracoscopic ports. A minithoracotomy is made over the ninth intercostal space (ICS) for suturing of the diaphragm. B, With the use of Duval forceps, the apex of the eventration is pushed down toward the abdomen. C, The newly created transverse fold of diaphragm is sutured with nonabsorbable material. D, Completed operation. (FROM MOUROUX J, PADOVANI B, POIRIER NC, ET AL: TECHNIQUE FOR THE REPAIR OF DIAPHRAGMATIC EVENTRATION. ANN THORAC SURG 62:905, 1996.)

of the eventration down into the abdomen. The invagination creates a transverse fold from the minithoracotomy to the cardiophrenic angle behind the phrenic nerve. This fold is closed by a first suture line of nonabsorbable material (Surgipro 3.5, Tyco Healthcare, France), beginning at the periphery of the diaphragm closest to the minithoracotomy. The first stitch is knotted, with the free end held with a forceps. A superficial continuous suture is performed to avoid injury to the subdiaphragmatic organs. Once at the cardiophrenic angle, the sutures are drawn tight while the Duval forceps used to push the diaphragm downward is removed. A row of return stitches is made along the same axis, and the suture is tied with the free end of the first knot. During placement of the return stitches, the suture is followed by the assistant using a gained forceps (to avoid injury to the stitch) introduced through port 2. The tension applied in this manner facilitates grasping of the edges of the fold to be sutured. This

Ch119-F06861.indd 1438

first back-and-forth series of continuous suture places the excess diaphragm in the abdomen, and care is taken to avoid applying tension to the first series of sutures. A second back-and-forth series of continuous suture is carried out similarly, thus burying the first series of suture lines: stitches are inserted through a more peripheral portion of diaphragm to obtain the desired tension of the diaphragmatic dome. At the end of the procedure, a chest tube is inserted through port 2 and connected to an underwater suction drainage system. The nasogastric tube is removed the next day. The chest tube is removed 3 to 5 days postoperatively. Breathing exercises are started on the first postoperative day and continued for 1 month. Comments. As for conventional surgery, video-assisted diaphragmatic plication carries the risk of late recurrence, thus justifying long-term follow-up. In our opinion, two technical

1/21/2008 3:47:26 PM

Chapter 119 Plication of the Diaphragm

aspects of this technique would prevent recurrence: the first back-and forth running suture allows for maintenance of the excess diaphragm within the abdomen while achieving a favorable distribution of tension, whereas the second running suture involves more peripheral portions of the diaphragm, with more resistant tissues, and provides the desired tension on the diaphragmatic dome. For this reason, care needs to be taken to avoid applying tension to the first series of sutures. In our opinion, there are two contraindications to this technique: the existence of extended pleuropulmonary adhesions and the need to reinforce the diaphragm with synthetic material. These situation are rarely predictable preoperatively. The level and extent of the thoracotomy incision and the optimal technical aspects of diaphragmatic repair can be decided only after exploration through port 1 and, if necessary, port 2. Variations. Since our initial work, several authors have reported their experience with both adults and children and suggested technical variations.35-42 Hwang and associates35 performed the diaphragmatic plication by a four-port thoracoscopic approach: an 11.5-mm port for a 0-degree 10-mm rigid thoracoscope is placed in the fifth intercostal space in the midaxillary line; two 5-mm ports are inserted in the eighth and ninth intercostal spaces in the posterior axillary line; and an 11.5-mm port is placed in the sixth intercostal space in the anterior axillary line. On the other hand, Lai and Paterson36 used a 7-cm anterior thoracotomy at the level of the xyphoid cartilage and a posterior thoracoscopic port introduced in the auscultatory triangle. Moon and associates37 used four thoracoports and carry out plication with the use of endoscopic linear staplers. Since the first successful correction of eventration by video-assisted thoracoscopy in a baby weighing 3 kg,39 the technique has gained popularity among pediatric surgeons. Various authors have described modifications to the technique, concerning either the caliber of the thoracoports or the method employed to fix the plication (Hines, 2003).40-42 These limited surgical series testify to the interest in the technique and the possibility of its implementation in children.

Laparoscopic Diaphragmatic Plication Hüttl and associates15 have recently reported a laparoscopic technique of diaphragmatic plication. They treated three patients who had a left-sided diaphragmatic paralysis secondary to cardiovascular surgery. In their technique, the plication is done with the patient in a 30-degree reversed Trendelenburg position under general anesthesia after single-lumen endotracheal intubation. The surgeon is positioned between the legs of the patients, and the two assistants are placed one at each side of the patient. Through a paraumbilical incision, a 30- to 45-degree angle laparoscope is introduced via a 10mm port. Three additional working ports (two of 10 mm and one of 5 mm) are placed in a semicircle in the right or left middle and upper abdomen under visual control. The left hepatic lobe is mobilized along the left triangular ligament. Subsequently, three retention stitches are placed transcutaneously. By application of extracorporeal traction on these

Ch119-F06861.indd 1439

1439

sutures, the diaphragmatic dome is reduced and an intraabdominal fold is created. This fold is used for the laparoscopic diaphragmatic plication with 12 to 15 nonabsorbable U-type sutures that are than tied extracorporally and placed inside the abdomen using the knot pusher. The line of the plication runs from the left dorsal portion of the diaphragm to the ventral medial portion. In the experience of the authors, two minimal splenic injuries occurred, neither requiring splenectomy. No pneumothorax was noted, and satisfactory results were observed on long-term follow-up (at 40, 72, and 84 months).

INDICATIONS FOR PLICATION (Box 119-2) Childhood Congenital Eventration Knowledge about treatment of congenital eventration in children is mainly derived from case reports and relatively small retrospective series.13,17,25 Patients were usually symptomatic, and in most cases they presented with respiratory distress. There are no data comparing surgical treatment to conservative management, and the timing of operation with respect to the onset of symptoms is usually not stated. In these patients, if there is no evidence of phrenic nerve injury, spontaneous recovery is unlikely; therefore, surgical indication is probably indicated in every symptomatic patient. These babies are often severely ill because of the frequently associated comorbidities, and diaphragm repositioning may help restore partial function in a hypoplastic lung.13,17,25 Little is known about the management of eventration with few or no symptoms. Although conservative management is probably sufficient, some authors advocate routine plication to maximize development of the ipsilateral lung.25

Phrenic Nerve Injury Management of phrenic nerve injury in children (postpartum or postsurgical) has been much more extensively studied than management of congenital eventration. The condition is usually suspected because of respiratory distress, failure to thrive, or, in operated patients, difficulty in weaning from mechanical ventilation. If nerve injury is suspected, confirmation is obtained by chest radiography, fluoroscopy, and/or ultrasonography of the chest.13,22,25,26,41,43-45

Box 119-2 Indications Childhood Indication for plication exists in every symptomatic child with congenital eventration. In asymptomatic patients with congenital eventration, there are insufficient data to provide a level of evidence or grade of recommendation as to whether plication is indicated. Adulthood Plication is indicated in adults with long-lasting, symptomatic diaphragmatic elevation.

1/21/2008 3:47:27 PM

1440

Section 6 Diaphragm

The policies at various centers differ in terms of the indications for and timing of surgery. In the retrospective surgical series by Tsugawa and associates,25 including 50 patients aged 4 days to 7 years with diaphragmatic elevation of miscellaneous origin (but secondary to phrenic nerve injury in most cases), respiratory distress was the indication for surgery. Ventilatory support was necessary in 10 of their patients for 2 to 6 weeks before plication. The number of cases managed conservatively during the time frame of the study (19711996) is not stated. This information can be derived from the retrospective experience (1996-2000) of Joho-Arreola and colleagues,22 who reported on 43 pediatric patients with diaphragmatic paralysis complicating cardiac surgery. Twentynine patients underwent plication because of failure to wean from mechanical ventilation or respiratory distress. Among the 14 patients treated conservatively, the mean assisted ventilation time after cardiac surgery was relatively short (5 days), but some patients were mechanically ventilated for several weeks (up to 49 days). Patients ultimately treated by plication received mechanical ventilation for a longer period (mean, 13 days) before the decision for plication was made. Similarly, in the retrospective series by deVries Reilingh and coworkers,26 18 consecutive patients with obstetric injury to the phrenic nerve were evaluated between 1986 and 1997. All required resuscitation immediately after birth, and 14 of them received intubation and mechanical ventilation. Thirteen of the 18 patients were ultimately treated by plication (at an average of 100 days postpartum), and in the remaining 5 patients, spontaneous clinical and radiologic recovery was observed within 1 month. Generally, in the published reports, conservative management is always attempted before surgery is contemplated in children with phrenic nerve injury. There is general agreement that surgery must be performed after stabilization of the clinical condition by gastric decompression, administration of supplemental oxygen, and, if necessary, mechanical ventilation, but the optimal timing of plication is not known. In fact, conservative treatment would permit restoration of diaphragmatic function if the phrenic nerve is not transected, but the time required may be very long (weeks or months), exposing patients to the unacceptable risks associated with prolonged mechanical ventilation. Most authors have proposed that observation and ventilation not be prolonged beyond a period of 2 weeks,13,43 so as to allow extubation and improved ventilation, with diaphragm plication being of course indicated only if there is no other primary cause of respiratory distress. If phrenic nerve injury is recognized during the initial cardiac or mediastinal surgery, immediate plication must be performed (Simansky et al, 2002).44

Adulthood Experience with surgical treatment of eventration in adulthood is much more limited. Most of the experience is derived from case reports, a small number of retrospective series, and a few prospective studies.11-14,46-49 Controversies exist about indications and the optimal timing of surgery; in this context, consideration of the natural history of diaphragmatic elevation is of paramount importance.

Ch119-F06861.indd 1440

Information about spontaneous evolution of nontraumatic diaphragmatic paralysis can be derived from the large retrospective study by Pielher and colleagues24 involving 247 patients. The cause of paralysis could be identified at initial evaluation in 105 patients but remained obscure in the remaining 142 subjects, who were followed-up for a mean of 8.7 years with no attempt at surgical repair. The cause of paralysis became evident in only 6 of these patients during the follow-up. In the remaining 136 cases, the leading symptom (exertional dyspnea) improved in only 34%; improvement in the other manifestations, cough and chest wall pain, was observed in 78% and 82% of cases, respectively. On chest radiography, the diaphragm returned to a normal position in only 12 of 131 patients who had this examination available. Efthimiou and colleagues47 studied the evolution of postsurgical diaphragmatic paralysis. In a prospective observational study enrolling 100 consecutive patients over a 6-month period, they reported a 32% incidence of unilateral paralysis among patients receiving ice/slush topical hypothermia during cardiac surgery, compared with 2% among those not receiving topical hypothermia. All of these patients could be treated conservatively, and paralysis regressed within 1, 6, and 12 months in 25%, 56%, and 69% of cases, respectively. At 2-year follow-up, the paralysis had regressed in all but one patient. Electromyography showed the absence of nervous conduction in all patients within 1 week after cardiac surgery but progressive reappearance of conduction in those patients who experienced restoration of diaphragmatic function. Obviously, in these patients, the phrenic nerve had suffered a thermal injury but had not been transected. In the experience of Deng and associates,48 derived from a retrospective analysis of a prospectively collected database of patients undergoing high free right internal mammary artery harvesting, the incidence of right-sided diaphragmatic paralysis was 4%. In this setting, the phrenic nerve can be either thermally injured (by the proximity of electrocautery dissection) or completely transected. Management included immediate diaphragmatic plication (i.e., during the sternotomy for cardiac surgery), if phrenic nerve transection was identified intraoperatively, or a middle-term observation for postoperatively evidenced paralysis. Conservative management was adopted for the first 3 months after cardiac surgery, after which plication was recommended in the absence of spontaneous regression of paralysis (apparently without regard to the presence of symptoms). Among the 26 patients with postoperative diaphragmatic paralysis, spontaneous regression was observed in 14 cases, and the remaining 12 patients were finally operated on. Information about indications for plication can be derived from some retrospective surgical series evaluating the outcome of adult patients with diaphragmatic eventration treated by surgery.11-13,43,46,49 All of these studies included patients with diaphragmatic paralysis secondary to various conditions and “idiopathic” forms. In almost all instances, the indication for surgery was the presence of respiratory symptoms (mainly dyspnea or orthopnea, but also cough and chest wall pain) or, less commonly, digestive symptoms (dyspepsia or meteorism) that interfered with patients’ normal activi-

1/21/2008 3:47:27 PM

Chapter 119 Plication of the Diaphragm

ties. The mere presence of an elevated diaphragm on chest radiography was not considered an indication for operation (with some exceptions). Because of the retrospective character of these surgical series, conservative management was not evaluated, and the number (and relative proportion) of patients treated by a nonoperative approach in the same time frames in the various institutions was not stated. It is generally believed that there is no indication for surgical treatment of diaphragmatic eventration if the condition is secondary to a neoplastic disease or if there are no symptoms. In our opinion, if a neoplastic origin is excluded on clinical and radiologic grounds, surgery must be considered on the basis of the clinical presentation and the timing of onset of symptoms. If the patient is symptomatic and the diaphragmatic eventration is long-lasting (>2 years), surgery is usually indicated; the operation is planned after clinical conditions have been optimized (e.g., treatment of respiratory infections, appropriate weight loss). If the patient is symptomatic but the diaphragmatic eventration is recent, a period of observation (18-24 months) before surgery is advocated. During this period, physiotherapy is performed and possible issues of excessive weight addressed. In these patients, serial diaphragmatic electromyographies may be suggested to determine possible recovery of phrenic nerve function.50,51 It is noteworthy that spontaneous resolution of a recent eventration is possible. If the patient has no or few symptoms, strict follow-up is performed, so that surgery may be promptly if even slight deterioration of respiratory function occurs. If significant respiratory impairment is already present, a modest chest trauma or a pulmonary infection could precipitate adverse clinical conditions and necessitate mechanical ventilation.49 Finally, diaphragmatic plication is not contraindicated in patients with ventilatory support. In fact, experience has shown that plication done under these circumstances

A

1441

can wean the patient from mechanical ventilation if the causes of respiratory distress are identified and treated (Fig. 119-8).31,43,49 Recently, Smyrniotis and colleagues proposed, in order to decrease the risks of respiratory complications, to perform simultaneous prophylactic diaphragmatic plication during a major abdominal operation in patients with phrenic nerve palsy.52

RESULTS (Box 119-3) Childhood Postoperative Outcome Several studies have evaluated the outcome of pediatric patients treated by diaphragmatic plication, usually for phrenic nerve injury. They are summarized in Table 119-1.

Box 119-3 Results Childhood Diaphragmatic elevation secondary to phrenic nerve injury in children may be satisfactorily managed by plication; in almost all instances, weaning from respiratory support is possible, often with only a short delay. Mortality is generally related to the underlying disease and not to the operation itself. Long-term outcome is determined by the associated comorbidities because the operation allows a permanent improvement in respiratory function. Adulthood Diaphragmatic plication in nonventilated adult patients carries a low morbidity and very low, if any, mortality. Functional results are fully satisfactory in almost all cases.

B

FIGURE 119-8 A, Radiograph of a 59-year-old woman who experienced right-sided eventration secondary to a blunt chest trauma apparently received 10 years previously. A second blunt trauma (fall down stairs) caused rib fractures and precipitated respiratory failure requiring mechanical ventilation. Tracheostomy was performed to facilitate weaning, but it was complicated by a tracheoesophageal fistula. Staged diaphragmatic plication to allow weaning and repair of the fistula was planned. B, Radiograph of same patient 4 years after the plication of the diaphragm.

Ch119-F06861.indd 1441

1/21/2008 3:47:27 PM

1442

Section 6 Diaphragm

TABLE 119-1 Outcome of Plication in Children

Author Tonz et al45

N

Operative Deaths*

Follow-up (Yr)

Weaning From Respiratory Support

Radiologic Improvement

Clinical Improvement

Retrospective

11

0

3.2 (mean)

11/11

10/11

9/9

Study Period

Design

1983-1992 25

Tzugawa et al

1971-1996

Retrospective

25

5

1-25

—

20/20

20/20

deVries Reilingh et al26

1986-1997

Retrospective

14

0

—

9/9

—

14/14

deLeeuw et al44

1985-1997

Retrospective

68

4

—

49/50

—

—

Simansky et al43

1988-2000

Retrospective

10

3

—

7/7†

—

—

—

Retrospective

5

0

—

2/2

5/5

5/5

1996-2000

Retrospective

29

8

1

—

13/21

—

Hines

41

Joho-Arreola et al22

*No deaths were related to plication. † Not taking into account operative mortality. From Alifano M: Plication for eventration. In Ferguson M (ed): Difficult Decisions in Thoracic Surgery. New York, Springer, 2007, pp 356-364.

These studies aimed to evaluate operative mortality, impact of the procedure on weaning the patient from respiratory support, and, in some cases, improvement in clinical and/or radiologic presentation. In the retrospective series by Tsugawa and associates25 dealing with 25 children with phrenic nerve injury treated by thoracotomy plication, weaning from respiratory support (mechanical ventilation or supplemental oxygen) was possible with only a short delay (0-6 days) in 15 of 17 patients; the other 2 patients underwent repeat plication, which was successful in one instance. In the same study, 25 additional patients underwent plication for congenital eventration, including 4 who were mechanically ventilated before the operation. Weaning was possible in all 25 cases, 1 to 61 days postoperatively. Similar results were reported in the retrospective study by Simansky and colleagues.43 Among the 10 children with postsurgical phrenic nerve injury causing respiratory failure who underwent open plication, 7 could be weaned from mechanical ventilation (within 8 days in 6 cases), but the remaining 3 died despite a radiologically successful plication, mainly because of intractable underlying cardiac disease. No deaths were reported in the series by Tonz and coworkers,45 who operated on 11 of 25 patients with postsurgical phrenic nerve injury because of failure to wean from mechanical ventilation or respiratory distress after extubation. The remaining patients could be managed conservatively. Weaning was possible in all the cases (within 1 week in all but two cases), and respiratory distress was managed successfully. A more consistent experience, albeit retrospective, can be drawn from the study by deLeeuw and colleagues,44 also dealing with postsurgical phrenic nerve paralysis. In their experience, 40% of 170 children with this condition underwent open plication. Respiratory insufficiency was the indication in almost all cases, with most patients being mechanically ventilated at the time of plication. The median time to final extubation after plication was 4 days, with a range of 1 to 65 days. Multivariate analysis showed that the independent factors associated with a longer time to extubation were

Ch119-F06861.indd 1442

bilateral paralysis and a longer interval from the initial operation to diagnosis. There were four in-hospital deaths, but none of these was considered related to the procedure. As in all of the pediatric series described here, all of the deaths were considered secondary to the underlying disease. Further evidence that the plication per se is not associated with mortality or major morbidity was provided by the experience of deVries Reillingh and associates,26 who performed the operation by open approach in 13 patients with phrenic nerve injury resulting, in almost all cases, from an obstetric trauma (with no associated cardiac or pulmonary malformations). Respiratory distress necessitating mechanical ventilation was present in most cases. Dramatic improvement was observed in all of the patients, with discontinuation of mechanical ventilation within a few days and return of arterial gas values to normal in all cases. A small series of diaphragmatic plication in children by VATS was recently published.41 The authors reported on five children, weighing 3.2 to 13.2 kg, with congenital or postsurgical diaphragmatic eventration causing respiratory insufficiency or recurrent respiratory infections. Satisfactory clinical and radiologic results were observed in all of the cases. In particular, weaning from mechanical ventilation could be achieved within 3 days in both of the patients who underwent surgery for this indication.

Long-Term Outcome In some surgical series of pediatric patients, information about long-term follow-up is available. Tonz and coworkers45 reported no late deaths related to diaphragmatic paralysis and good radiologic results in 10 of 11 patients. No children had respiratory symptoms at late follow-up. Similarly, Tsugawa and colleagues25 observed fully satisfactory clinical and radiologic results in all of the patients who are available at followup after plication for either phrenic nerve injury or congenital eventration. On the other hand, in the study by Joho-Arreola and associates,22 6 of 21 patients had elevated diaphragm 1

1/21/2008 3:47:28 PM

Chapter 119 Plication of the Diaphragm

1443

TABLE 119-2 Outcome of Plication in Adults (Nonventilated Patients) Improvement Author Wright et al11 12

Study Period

Design

—

Retrospective

N 7

Operative Deaths

Follow-up (Yr)

Clinical

Radiologic

Functional

0

0.3-4

7/7

7/7

7/7

Graham et al

1979-1989

Retrospective

17

0

5-7

6/6

6/6

6/6

Ribet and Linder13

1968-1988

Retrospective

11

0

8.5 (mean)

9/11

6/11

5/5

1988-2000

Retrospective

7

0

7.3 (mean)

7/7

7/7

7/7

Higgs et al

1983-1990

Retrospective

19

0

7-14 (n = 15)

14/15

14/15

15/15

Mouroux et al49*

1992-2003

Prospective

10

0

6.3 (mean)

10/10

10/10

10/10

43

Simansky et al 46

*Operated by video-assisted thoracic surgery. From Alifano M: Plication for eventration. In Ferguson M (ed): Difficult Decisions in Thoracic Surgery. New York, Springer, 2007, pp 356-364.

year postoperatively; the percentage of patients with respiratory symptoms in that study is not stated. Overall, diaphragmatic elevation secondary to phrenic nerve injury in children may be satisfactorily managed by plication; in almost all instances, weaning from respiratory support is possible, often with only a short delay. Mortality is generally related to underlying disease and not to the operation itself. Similarly, long-term outcome is determined by the associated comorbidities because the operation allows a permanent improvement in respiratory function.

Adulthood Because adults with unilateral diaphragmatic elevation usually present with a mild respiratory insufficiency, weaning from mechanical ventilation is a rare indication for plication. In the recent prospective study by one of us (JM), plication by VATS was performed for this indication in only two patients, and both were successfully weaned within 1 week.49 On the contrary, only one among the four mechanically ventilated patients in the series by Simanski and colleagues43 involving patients with phrenic nerve injury could be weaned. When the operation is performed because of less severe respiratory symptoms (or because of digestive problems), satisfactory results are uniformly observed (Table 119-2). In the aforementioned retrospective study by Simansky and colleagues,43 all seven nonventilated patients experienced an improvement in American Thoracic Society (ATS) dyspnea score of 2 or 3 levels at 3-month re-evaluation. At long-term follow-up (11-114 months), all seven were completely asymptomatic from a respiratory point of view. In the experience of Graham and coworkers12 dealing with 17 patients treated by plication via thoracotomy between 1979 and 1989, an improvement was observed in all patients in both subjective (dyspnea score) and objective measurements. In particular, the operation resulted in significant improvement in terms of postoperative forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO), partial pressure of oxygen (PO2), and partial pressure of carbon dioxide (PCO2). These satisfactory results were still present in all of the six patients who could be reassessed at long-term follow-up (>5 years).12 In the retrospective study by Ribet and Linder,13 9 of 11 patients

Ch119-F06861.indd 1443

were persistently asymptomatic after the operation (followup of 3 months to 18 years), 1 patient was mildly dyspneic, and 1 had persistent digestive symptoms. Of note, chest radiographs showed a persistently elevated (though at a lesser extent) diaphragm in 5 of these cases. In this study, only five patients had both preoperative and postoperative functional assessment, and an improvement in both FVC and forced 1-second expiratory volume (FEV1) was observed in all of those cases. In the prospective study at Nice University Hospital dealing with 12 adult patients treated by video-assisted plication for diaphragmatic elevation of miscellaneous origin (posttraumatic in most instances),49 all of the patients experienced a complete disappearance of symptoms shortly after the operation, and no radiologic relapse was observed at a follow-up of 64.4 ± 46 months. A significant improvement in both FEV1 and FVC was observed at late spirometry in all of the cases.

SUMMARY Plication of the diaphragm is a simple and feasible technique. It is frequently employed in pediatric surgery. In the adult population, the indications are still debated. The availability of minimally invasive surgery can, in the future, increase interest in the plication technique.

COMMENTS AND CONTROVERSIES Restoration of size and contour of the diaphragm by plication is simplistic in its appeal and performance. However, it is an uncommon operation, and reports of its approaches, techniques, indications, and outcomes are few and mostly anecdotal. In the extreme, for the infant with congenital eventration or neonatal phrenic nerve damage, this procedure is well described and very successful in permitting weaning from ventilator support. In the asymptomatic adult with phrenic paralysis or a large eventration, the role of plication has not been defined. In any patient, time must be allowed for return of phrenic nerve and diaphragmatic function. All reversible causes of restrictive and obstructive respiratory impairment must be addressed (e.g., smoking, asthma, obesity). Only then plication is considered. T. W. R.

1/21/2008 3:47:28 PM

1444

Section 6 Diaphragm

KEY REFERENCES Dor J, Richelme H, Aubert J, Boyer R: L’éventration diaphragmatique. J Chir 97:399-432, 1969. ■ This article describes all techniques of plication. Graham DR, Kaplan D, Evans CC, et al: Diaphragm plication for unilateral diaphragmatic paralysis: A 10-year experience. Ann Thorac Surg 49:248-52, 1990. ■ This report confirms that diaphragmatic plication is a safe and effective procedure for adult patients with dyspnea resulting from unilateral diaphragmatic paralysis. Hines MH: Video-assisted diaphragm plication in children. Ann Thorac Surg 76:234-236, 2003. ■ The first short series (five patients) of plication by VATS in children.

Ch119-F06861.indd 1444

Hüttl TP, Wichmann MW, Reichart B, et al: Laparoscopic diaphragmatic plication. Surg Endosc 18:547-551, 2004. ■ Description (with very good photographs) and results of diaphragmatic plication by laparoscopy. Mouroux J, Padovani B, Poirier NC, et al: Technique for the repair of diaphragmatic eventration. Ann Thorac Surg 62:905-907, 1996. ■ The first description (with schemas) of the plication by VATS. Simansky DA, Paley M, Refaely Y, Yellin A: Diaphragm plication following phrenic nerve injury: A comparison of paediatric and adult patients. Thorax 57:613-616, 2002. ■ Presents the results of diaphragmatic plication of ventilated versus nonventilated pediatric and adult patients.

1/21/2008 3:47:28 PM

chapter

120

PHRENIC NERVE AND DIAPHRAGM MOTOR POINT PACING Raymond P. Onders

Key Points ■ Although chronic positive-pressure mechanical ventilation is life-

■

■ ■

■

preserving, it not only carries the stigma of the ventilator tubing for patients but also leads to posterior lobe atelectasis, pneumonia, barotrauma, and respiratory complications, which are the leading cause of death among spinal cord–injured patients on ventilators. Patients requiring long-term ventilator support due to spinal cord injury or congenital central hypoventilation are offered phrenic nerve pacing or be involved in a trial of motor point diaphragm muscle pacing. Phrenic nerve pacing or diaphragm motor point pacing requires a functional diaphragm and intact phrenic nerve to be successful. Failure to wean from mechanical ventilation is in part due to rapid onset of diaphragm atrophy, barotrauma, posterior lobe atelectasis, and impaired hemodynamics, all of which would be improved by maintaining a more natural negative chest pressure with temporary motor point diaphragm pacing. Maintaining diaphragm strength and functions with diaphragm motor point pacing in patients with amyotrophic lateral sclerosis can lengthen the time until patients require positive-pressure mechanical ventilation.

Chronic respiratory insufficiency or the inability to independently breathe has a profound impact on the affected individual, his or her family, and the health care community as a whole. The treatment of chronic respiratory insufficiency has been traditionally performed with positive-pressure ventilation through a ventilator. Chronic mechanical ventilation, although life-saving, is expensive, invasive, disruptive, and unreliable at times. Mechanical ventilation is associated with functional limitations such as decreased mobility and difficulty communicating. The tubing of the ventilator increases the difficulty of dressing and transferring patients. Mobility is limited to spaces and places that can accommodate a portable, electrically driven mechanical ventilator and suction device. Ventilator-assisted individuals need a caregiver who is able to use and troubleshoot these devices throughout the day as well as during transport. Noises from the ventilator can interfere with hearing and concentration. Typical speech on a ventilator has long pauses between phrases, short phrases, and poor voice quality.1 These changes in voice can make clear communication difficult or stressful. Inherent complications of mechanical ventilation include infection, tracheal injury, and equipment malfunction.

Ventilator-associated pneumonia is a common occurrence among patients with prolonged use of an artificial ventilator, and pneumonia is the most common cause of death after spinal cord injury.2,3 Tracheomalacia, tracheal stricture, and tracheal erosion or perforation are potential complications associated with prolonged use of an artificial airway. The need for a reliable source of electricity can limit placement of patients with ventilation-dependency. In some geographic regions, it is difficult to find skilled nursing care for mechanically ventilated patients.4 As shown during the hurricanes of 2005, the lack of electricity negatively affects patients on mechanical ventilation, because the batteries last only several hours, whereas the loss of electricity and available generators can last months.5 There are also psychosocial consequences to prolonged mechanical ventilation, with mechanically ventilated patients feeling more insecure, helpless, and dependent compared with nonventilated patients. Fatigue, depressed mood state, and disruptions of sleep-rest patterns among patients with prolonged mechanical ventilation have been reported as common.6 In addition, mechanical ventilation increased feelings of isolation for both patients and their caregivers.7,8 In the field of spinal cord injury research, it is recognized that “improvements in respiration and elimination of ventilator dependence are extremely important to the quality of life and this topic should be at the forefront of research.”9 Electrical activation of the diaphragm muscle, by way of the phrenic nerves or through diaphragm motor point stimulation, offers an alternative to mechanical ventilation, providing an opportunity for improved speech and mobility and reducing many of the problems associated with mechanical ventilation. The two main clinical indications for phrenic nerve or diaphragm pacing have been cervical spinal cord injuries and central hypoventilation syndromes. Although both of these conditions manifest in the individual’s inability to independently breathe, spinal cord injury involves the disruption of the signal pathway from the respiratory center in the brain to the respiratory nerves (primarily the phrenic nerves), whereas central hypoventilation syndromes generally involve a decreased respiratory drive. In the latter case, the signal from the respiratory center to the phrenic nerves is not generated or sent, although the conduction pathway to deliver the signal is intact. The concept of using phrenic nerve stimulation to provide ventilatory support dates back to the 18th century. In the 1940s, Sarnoff and coinvestigators first demonstrated that ventilation could be maintained with percutaneous electrodes in patients with poliomyelitis.10 In the 1960s, Glenn and coworkers made significant technological advances that led to 1445

Ch120-F06861.indd 1445

1/21/2008 3:48:29 PM

1446

Section 6 Diaphragm

the development of modern phrenic nerve pacing systems.11 They developed an implantable electrode/receiver system that could be activated by radiofrequency waves generated by a power source external to the body. These investigators also accumulated a significant clinical experience that defined patient evaluation methods, surgical techniques, and safe parameters of stimulation resulting in optimal diaphragm conditioning via stimulation of the phrenic nerve. In the 1980s, Mortimer and colleagues showed that the diaphragm could be directly stimulated at the motor point to provide ventilation. By the late 1990s, the device had been refined for the initial human studies. Because muscle motor point electrodes can be used for short periods and then removed, Onders and colleagues began investigations for temporary use in other groups of patients. Subsequent studies led to less invasive methods of application, including the possibility of natural orifice transluminal endoscopic surgery (NOTES) techniques (see later discussion) (Onders et al, 2007).12 For a phrenic nerve or diaphragm pacing device to be effective in recruiting diaphragm muscle to provide ventilatory support, the phrenic nerve must be able to provide conduction pathways through the muscle. Therefore, the lower motor neurons in the spinal cord and the phrenic nerve must be intact to avoid muscle denervation and to be able to stimulate the muscle at acceptable levels. A thorough assessment of phrenic nerve function is performed in all patients for whom phrenic nerve or diaphragm motor point pacing is contemplated. Many patients with tetraplegia have sustained injury to the phrenic motor neurons in the spinal cord and/or phrenic rootlets. If phrenic nerve function is absent or significantly reduced, phrenic nerve or diaphragm pacing is not undertaken. Phrenic nerve function is assessed both by measurements of phrenic nerve conduction times and by fluoroscopic evaluation of diaphragm movement during phrenic nerve stimulation. The cervical portion of the phrenic nerves can be electrically stimulated via surface electrodes or monopolar needle electrodes at the posterior border of the sternocleidomastoid muscle at the level of the cricoid cartilage. Our standard technique is to use surface electrodes only. Diaphragm electromyography (EMG) can be monitored with surface recording electrodes positioned between the seventh and ninth intercostal spaces. Electrical current is applied with single pulses of gradually increasing intensity until effect is seen or the highest machine amplitude is reached. Stimulation is associated with coincident outward movement of the abdominal wall due to movement of the diaphragm. Phrenic nerve conduction time is measured as the interval between the applied stimulus and the onset of the compound muscle action potential (CMAP). Because patients who have been maintained on mechanical ventilation for prolonged periods may have variable degrees of diaphragm atrophy, there may be reductions in the magnitude of the CMAP. For this reason and associated technical difficulties associated with EMG recordings (e.g., optimal electrode placement, variable amounts of fatty tissue that may reduce signal amplitude), the magnitude of the diaphragm CMAP and the latency conduction time of the signal are not reliable in determining

Ch120-F06861.indd 1446

the strength of the diaphragm or the amount of time that will be required to recondition the diaphragm. The key aspect is to determine whether the phrenic nerve is intact. In our own experience, phrenic nerve stimulation is associated with both false-positive and false-negative results. Therefore, fluoroscopic examination of the diaphragm during electrical stimulation is also performed. The diaphragm should descend with the stimulation of the phrenic nerve in the neck. In this chapter, the two basic surgical techniques used to provide diaphragm movement, phrenic nerve pacing and diaphragm motor point pacing, are reviewed. The indications and results for appropriate patients with chronic respiratory insufficiency are then reviewed.

SURGICAL TECHNIQUES Phrenic Nerve Pacing Phrenic nerve stimulation was first described to support full time ventilation in 1972 (Glenn, 1978).13 Electrical stimulation of the phrenic nerve produces diaphragm contraction, which results in respiration. More than 1000 electrodes have been implanted on or around the phrenic nerves in high quadriplegics and people with various hypoventilation syndromes.14 Although the concept of artificially stimulating the phrenic nerve to produce respiration is appealing, its application has been limited because of physiologic and clinical problems associated with phrenic nerve stimulation.15 The implant procedure exposes the phrenic nerve to surgical trauma, infection, and other postsurgical complications, which have been reported in 4.5% of implantation procedures.16 In addition, there is hesitation on the part of many physicians to expose patients to the anesthesia and surgical trauma required for such an invasive procedure. With modern surgical techniques such as thoracoscopy, these concerns can be minimized and patient and physician acceptance increased.

Available Systems Presently, three phrenic nerve stimulation systems are available worldwide, and they have a number of features in common. Electrodes are implanted on the phrenic nerves and attached to an implanted stimulator, which is powered by an external controller through the skin via a radiofrequency link (Fig. 120-1). Low levels of electrical current passed through these electrodes excite the nerve, leading to contraction of the diaphragm muscle. The only pacing system that is available in the United States, the Avery system, is discussed later in this section. The Astrostim (Atrotech, Tampere, Finland) system differs from the Avery system in terms of electrode technology. The electrode is made of two identical strips of Teflon fabric with two platinum buttons mounted onto each strip. This fourpole arrangement divides the nerve into four stimulation compartments, each of which is designed to activate a quadrant of the phrenic nerve. During a single stimulation sequence, which consists of four current combinations, each pole in turn acts as a cathode, with the pole on the opposite side as an anode. Consequently, there are four excitation compartments around the nerve. This stimulation pattern is intended to more closely mimic natural activation of the

1/21/2008 3:48:29 PM

Chapter 120 Phrenic Nerve and Diaphragm Motor Point Pacing

1447

Surgical Techniques

Antenna

Transmitter FIGURE 120-1 Patient with an external controller powering the internal phrenic nerve stimulation system through the attached radiofrequency link.

nerve and theoretically should enhance the transformation of muscle fibers into slow-twitch fatigue-resistant fibers, improving endurance characteristics of the diaphragm and shortening the conditioning process. The so-called Vienna phrenic pacemaker (Medimplant, Vienna, Austria) system is also unique in terms of electrode design, involving multiple electrode contacts with the nerve. A microsurgical technique is required to suture four electrode leads to the epineurium of each phrenic nerve. The nerve tissue between each electrode lead provides different stimulation compartments. As many as 16 different electrode combinations can be adjusted individually for each nerve, although only one combination is stimulated during any given inspiration. As with the Atrotech device, only a portion of the nerve is stimulated at any given time, allowing more time for recovery. This form of stimulation, referred to as carousel stimulation, is also thought to reduce the incidence of fatigue when compared with the unipolar design. The Avery Mark IV Breathing Pacemaker System (Avery Biomedical Devices, Commack, NY) is based on the technology and expertise developed by Dr. William Glenn and coinvestigators; it was initially commercialized in the 1960s. Since the initial design, this device has undergone significant refinement, especially with receiver technology. The electrode, which contains a partial trough for nerve placement, consists of a semicircular platinum-iridium ribbon embedded in molded silicone rubber. The current Mark IV transmitter allows greater flexibility in terms of stimulus parameters and has a longer battery life compared with previous models. The only device available in the United States is the Avery device. For that reason, and because the clinical experience with this device is the greatest, the remainder of this section will deal primarily deal with the Avery device.

Ch120-F06861.indd 1447

Surgical implantation of the phrenic nerve pacer can be done via either a cervical or a thoracic approach. Because patients who will be undergoing implantation of phrenic pacers usually have marginal pulmonary function, the cervical approach has the advantage that it avoids the morbidity of bilateral thoracatomies. Cervical electrode placement, although less invasive surgically, is presently discouraged for several reasons. Cervical phrenic nerve stimulation may result in incomplete diaphragm activation if there is an accessory branch from a lower segment of the cervical spinal cord that joins the main trunk of the phrenic nerve in the lower neck region or thorax. Moreover, other nerves in close vicinity to the phrenic nerve may be activated, resulting in pain or undesirable movement. Finally, neck movement may place significant mechanical stress on the nerve/electrode system, increasing the risk of injury. Modern video-assisted thoracoscopic surgery (VATS) can minimize the morbidity of the thoracotomy and allow full nerve stimulation. Electrodes are often placed on each phrenic nerve during a single procedure. Some centers, however, prefer to place each electrode in two separate procedures, with 1 or 2 weeks between each operation. Strict aseptic technique is imperative to prevent infection, and prophylactic antibiotics are recommended. It is useful to obtain surveillance culture before surgery, because these patients have chronic tracheostomies and urinary catheters and may be colonized with pathogenic bacteria or fungi. Pharmacologic muscle blockade during surgery does not allow for adequate system testing during placement, and such paralytics are not used. A potential complication of electrode placement is iatrogenic injury to the phrenic nerve and subsequent pacemaker failure. It is critical that the phrenic nerves be carefully manipulated to avoid stretching and the development of tension on the nerve during surgery. To prevent ischemic injury, the network of blood vessels within the perineurium must be preserved. The electrode is positioned below the nerve and sutured into place, allowing some “slack” to avoid traction tension on the nerve itself. The electrode wires are connected to a radiofrequency receiver, which is usually positioned superficially over the anterior chest wall (Fig. 120-2). The site of receiver placement is selected carefully to ensure easy accessibility. Typical placement is over the anterior rib cage. This position provides a firm surface upon which the receiver can be palpated and external antennas secured in place. The pacing system is tested before closure of the surgical incisions. Threshold current values of each electrode are determined by gradually increasing the stimulus amplitude until a diaphragm twitch is observed or palpated. When values are increased above this level, a smooth, forceful diaphragm contraction occurs. If the threshold values are high, the electrode leads may need to be repositioned. For cervical placement, a transverse skin incision is made lateral to the sternocleidomastoid muscle. The scalene muscles are divided, and the phrenic nerve is identified just anterior to the scalenus medius. A nerve stimulator can be used with fluoroscopic observation of the diaphragm to

1/21/2008 3:48:29 PM

1448

Section 6 Diaphragm

to optimize oxygenation and ventilation while sleeping. Initially, diaphragm pacing results in fatigue (i.e., decreasing diaphragmatic contraction for the same electrical stimulus) after 60 to 90 minutes.Therefore, “aerobic training” of these muscle fibers is required to sustain pacing for the desired 12 to 16 hr/day. Pacing is started at 1 to 2 hr/day and gradually increased by 30 to 60 min/day each week. Thus, a “training period” of up to 3 to 4 months is usually required to achieve full pacing.

Diaphragm Motor Point Pacing System

FIGURE 120-2 Phrenic nerve cuff electrode with attached radiofrequency-powered stimulator.

confirm correct identification. The electrode is placed under the nerve and sutured into place. The connecting wire is then tunneled subcutaneously. The thoracic placement is now routinely done thoracoscopically.17,18 The patient is positioned in a supine clamshell position; rotation of the bed allows surgery to be performed on both sides without repositioning of the patient. The use of a double-lumen endotracheal tube is necessary. Three ports are usually placed (Shaul et al, 2002). This thoracoscopic procedure lends itself to computer-aided robotic techniques, allowing increased visualization and instrument dexterity. Use of the Da Vinci robotic system (Intuitive Surgical, Mountain View, CA) has been described in six patients. The patients were placed in a supine position with the ports in the second, fourth, and sixth intercostal spaces. The phrenic nerve was dissected free from the pericardium at the level of the left pulmonary artery on the left, and at the confluence of the superior vena cava and right atrium on the right. Five of the six patients underwent bilateral implantation with no operative complications and an average hospital stay of only 2 days (Morgan et al, 2003).19 Immediate postoperative care of the pacer system is relatively benign, because the pacer system is not employed until weeks later. After the skin incisions have healed, the most important element of home care is to avoid injury to the subcutaneous pocket where the receiver resides. For this reason, children with congenital central hypoventilation syndrome (CCHS) and a pacer are encouraged to not participate in contact sports. Younger, active children also must be monitored for rough play. Pacing is gradually initiated at least 4 to 6 weeks after placement, which allows for tissue reaction around the electrodes to stabilize. If pacing is begun before fibrosis of the site, changing of settings is frequently required. Both patients ventilated full-time and those ventilated only in the nighttime are admitted to the hospital to establish settings for initiation of pacing. If nighttime pacing is to be used, the initiation of pacing is optimally done in the sleep laboratory,

Ch120-F06861.indd 1448

The Diaphragm Pacing Stimulation (DPS) System, which uses the NeuRx RA/4 external stimulator, was designed after a series of animal and preliminary human investigations at Case Western Reserve University and University Hospitals of Cleveland (DiMarco et al, 2005; Onders et al, 2004).20-28 The NeuRx RA/4 System is a four-channel percutaneous neuromuscular stimulation system. Intramuscular electrodes are implanted laparoscopically in the diaphragm with leads tunneled subcutaneously to an exit site in the chest. An external stimulator is connected to the leads at the percutaneous exit site to deliver the stimulus pulses and provide respiratory timing. The NeuRx RA/4 device with the laparoscopically placed intramuscular electrodes in the motor point of the diaphragm has been used in more than 40 patients to date in two separate Investigational Device Exemption (IDE) trials. There is now more than 60 years of cumulative use of the device, with the initial spinal cord–injured patients having used it continuously for more than 6 years. With almost 200 electrodes implanted, there have been no lead failures. In the multicenter trial of the device for ventilatory assistance in spinal cord–injured patients, more than 30 patients were treated, with a successful implantation rate of 94%. The surgical procedure has been refined to the extent that the implantation is now a standardized outpatient surgical procedure (Onders et al, 2005).29 The spinal cord–injured population has allowed standardization of the operation and technique for the new indications of amyotrophic lateral sclerosis (ALS) and acute diaphragm motor point stimulation (both discussed later).

Surgical Technique The DPS surgery is completed in four phases: exposure, mapping, implantation, and routing. This procedure takes about 2 hours. After the surgery, patients are placed in the hospital in an observational status. Patients are able to eat a regular diet for dinner and have no activity restrictions. 1. The exposure consists of the setup for a standard fourport laparoscopy to visualize the diaphragm. The patient is anesthetized, with care taken not to use any neuromuscular blocking agents. During this phase, any abdominal adhesions are released and gastrostomy tube tracts are removed if they are in the way of implantation of the DPS system. The falciform ligament is divided, which allows easier visualization of the medial aspect of the right diaphragm and easier exit of the pacing electrodes through the epigastric port.

1/21/2008 3:48:31 PM

Chapter 120 Phrenic Nerve and Diaphragm Motor Point Pacing

FIGURE 120-3 Laparoscopic mapping probe. Its suction port is attached to the operating room vacuum so that the contact electrode at its tip can be noninvasively attached to the surface of the muscle. It receives stimuli from an external, computer-controlled stimulator.

FIGURE 120-5 Laparoscopic electrode implantation tool. The electrode is carried in a hypodermic needle that is enclosed in the instrument for insertion into the abdominal cavity. The trigger rotates the needle outward to allow the surgeon to control the angle of insertion into the tissue.

FIGURE 120-4 Mapping probe being used on patient’s left diaphragm. The blue marks indicate the locations at which the strongest contractions were found.

FIGURE 120-6 The laparoscopic implantation needle, housing the electrode, is placed in the diaphragm muscle. Countertraction applied with another laparoscopic instrument helps to deploy the electrode, which has a small barb, into the diaphragm muscles.

2. Mapping involves finding the point on the abdominal side of the diaphragm at which stimulation causes the greatest diaphragm excursion (Onders et al, 2004).30 The mapping instrument has a suction port that allows it to temporarily attach to the diaphragm and deliver an electrical stimulus (Figs. 120-3 and 120-4). Stimulation is applied in either a twitch or a burst mode from the clinical station. Mapping allows qualitative and quantitative data to be obtained. Quantitatively, changes in abdominal pressures are measured. Qualitatively, the diaphragm contraction is directly observed. The stronger the stimulated contraction, the closer to the motor point of the phrenic nerve. During mapping, the entire diaphragm is assessed in grid pattern to be sure the point of maximal contraction is not missed. These locations are recorded on a transparent sheet that is overlaid on the laparoscopic video display. The magnitude of the abdominal pressure change, in response to

the applied stimulus, is recorded for each location. The primary electrode site is identified as the location of maximal pressure change in each hemidiaphragm. A secondary electrode site is identified as either a backup to the primary site or at a location in each hemidiaphragm that recruits another region of the diaphragm (e.g., anterior, lateral, or posterior) at a similar magnitude. 3. Once the primary and secondary electrode sites are identified in each hemidiaphragm, the implantation phase begins. An intramuscular electrode is introduced into the abdominal cavity with the electrode delivery instrument (Fig. 120-5). The electrode is inserted into the diaphragm at an angle, so that the electrode lead travels parallel to the plane of the diaphragm before exit, and the delivery instrument is withdrawn (Fig. 120-6). The electrode is then tested to ensure the desired response to twitch stimuli is achieved, and the procedure is repeated for the

Ch120-F06861.indd 1449

1449

1/21/2008 3:48:32 PM

1450

Section 6 Diaphragm

remaining electrodes. If the response is not adequate when tested, the electrode may be withdrawn and another implanted. A second electrode is implanted at the site previously marked during mapping (Fig. 120-7). At the conclusion of the implantation, a chest radiograph is obtained to be sure that no intra-abdominal air has tracked with the needle to the chest cavity. If such a capnothorax is present, it can be aspirated with a percutaneous catheter at the end of the procedure. 4. The electrode leads are then routed to the percutaneous exit site. These lead wires are tunneled subcutaneously to an area in the upper chest at a site deemed appropriate by the surgeon and patient’s caregivers. An additional indifferent electrode is placed subcutaneously in the upper chest through a separate percutaneous exit site. The electrodes are then retested to make sure that all of the connections have been made properly. An electrocardiographic strip is recorded with all four electrodes active to be sure that there is no capture of the cardiac rhythm. At this time, if the patient needs a gastrostomy, a standard percutaneous endoscopic technique can be performed, and the wires are once again checked. The port incisions are then closed, and the patient is transferred to the recovery unit.

POSTOPERATIVE MANAGEMENT Implant-site infection, diaphragm muscle injury, and capnothorax are potential complications with this implantation technique. Infections at the implant site are always a possibility, but to date they have not been an issue in the 45 patients in whom electrodes have been implanted. If an infection does occur, and it cannot be treated without removal of the electrodes, the study is discontinued and the electrodes are removed. Work done in our facility and others over the past 20 years with spinal cord–injured individuals and thousands of electrode implants suggests that the likelihood of an infection at the percutaneous electrode exit site is extremely low. With regard to our application, laparoscopy is a minimally invasive surgery with an almost negligible infection rate for nongastrointestinal procedures. The diaphragm muscle could be injured by the implantation needle, but this has not occurred to date. Air may track from the abdominal cavity to the pleural space during the procedure, and this is classified as a capnothorax. This occurs commonly during any routine laparoscopic foregut procedure, and we check for it during this procedure with an intraoperative chest radiograph. If a capnothorax is present, it is aspirated at the completion of the procedure. The possibility of phrenic nerve injury is minimal because the electrodes do not come in direct contact with the nerves. Characterization of electrodes and system evaluation is done 7 to 10 days after implantation. This period allows the patient to fully recover from the surgery and allows time for the body’s reaction to the electrodes to stabilize. Electrode evaluation is performed by adjusting individual stimulus parameters (pulse amplitude, width, rate, and frequency) so that a comfortable level of stimulation can be identified for the diaphragm conditioning sessions. The DPS is set to

Ch120-F06861.indd 1450

FIGURE 120-7 Two electrodes have been implanted on the left diaphragm and exit the abdomen through the epigastric port.

provide a tidal volume that is 15% greater than the basal needs (5-7 mL/kg) and that the patient can easily tolerate. The settings are less than 25 for amplitude, less than 20 for frequency, and less than 200 for pulse width. A home-based conditioning program is then begun wherein the DPS is turned on and the ventilator is turned off.31 The patient’s tidal volume is checked initially with a Wright spirometer and then every 5 minutes. The ventilator is turned back on if the patient feels uncomfortable or the tidal volume starts to drop because of diaphragm fatigue. Initially, patients may only tolerate 15 minutes of diaphragm pacing. Due to disuse atrophy and the conversion of muscle fibers to fastfatigueable type during periods of inactivity, patients who have long-standing and significant respiratory paralysis will require conditioning of the diaphragm muscle in order to sustain ventilation. The diaphragm can recover quite rapidly from training, so that patients and their caregivers can repeat a session every hour. The length of time required to achieve more than 4 continuous hours on DPS stimulation depends on the amount of time the patient and caregivers devote to this process. The patients communicate weekly the results of their conditioning at home, and the investigators analyze and direct changes that need to be made. With increasing strength of the diaphragm and subsequent increased tidal volumes, the setting of the DPS unit may need to be decreased to maintain appropriate minute ventilation.

Significant Issues in Weaning From the Ventilator With a Pacer Because most patients have been maintained on mechanical ventilation for a significant period, the transition to phrenic or diaphragm pacing requires gradual conditioning. If the initial pacing period is too prolonged, diaphragm fatigue and secondary respiratory failure will ensue. While on mechanical ventilation, many patients are maintained with large tidal volumes, resulting in chronic hyperventilation and secondary reduction in bicarbonate stores. When switched to the pacing system, which is designed to maintain normal levels of carbon

1/21/2008 3:48:34 PM

Chapter 120 Phrenic Nerve and Diaphragm Motor Point Pacing

FIGURE 120-8 This patient is using an abdominal binder with the Diaphragm Pacing Stimulation (DPS) system.

dioxide (PCO2), they may develop acidosis secondary to the rise in PCO2. As a result, the patient may experience the sensation of dyspnea despite eucapnea. It is advisable, therefore, to make gradual ventilator adjustments to restore PCO2 values to near-normal levels before initiation of pacing. Because the abdominal muscles are also paralyzed in spinal cord–injured patients, the diaphragm muscles will not elongate up into the chest after contraction. This can lead to smaller tidal volumes and respiratory distress. This effect is alleviated to a large extent by use of a snug-fitting abdominal binder that maintains intra-abdominal pressure (Fig. 120-8). After full-time pacing is achieved throughout the day, pacing can be extended to periods of sleep. During sleep, however, upper airway obstruction can occur with paced breaths. In normal spontaneous inspiration, the body’s respiratory center initiates a breath by stimulating the muscles of respiration (diaphragm, intercostals) to contract while coordinating the muscles of the upper airway to maintain patency. When paced, the diaphragm contracts without this centrally coordinated effort, which predisposes a person’s upper airway to collapse. This predisposition is exaggerated in sleep, particularly rapid-eye movement (REM) sleep, when skeletal muscles become more relaxed, making the muscles of the upper airway even more prone to collapse due to intrathoracic pressure created by the diaphragm. To prevent this occurrence, the tracheostomy is capped with a valve such as the Passy-Muir device, which allows airflow through the tracheostomy. Several patients with the DPS system have been able to sleep without any airway obstruction without a tracheostomy or with the tracheostomy tube capped; this is most likely due the ability of the DPS system to modulate a slow, gradual breath by slowly ramping up the pulse width of the stimulation parameters. The tracheostomy tube is capped in most patients during awake periods. Subjects can have intermittent aspiration of food during meals, related again to the large negative airway pressure generated during diaphragm contraction that is uncoordinated with the orophyarynx. This problem can be eliminated by the use of a Passy-Muir valve during meals. Most patients

Ch120-F06861.indd 1451

1451

eventually learn to time swallowing with the set rate of their pacer and do not require the use of a Passy-Muir valve during eating. With any respiratory support device, adequate monitoring needs to be maintained. Because patients with CCHS do not demonstrate signs of respiratory distress when sleeping, a system of apnea monitoring (e.g., pulse oximetry) is used routinely. Pacers maintain set minute ventilation, so that, if a patient becomes acutely ill, positive-pressure ventilation may be needed on a temporary basis. Pacemaker function is monitored on routine basis and also emergently if the patient complains of difficulty breathing. Tidal volume can be easily measured by attachment of a spirometer to the tracheostomy tube. Because stimulus transmitters allow separate stimulation, each hemidiaphragm can be evaluated independently. It is important to note that reductions in inspired volume can occur despite a normally functioning pacemaker system. For example, retained secretions may cause an increase in airway resistance and the development of atelectasis with secondary reductions in lung compliance. Inspired volumes are reduced as a consequence of these mechanical derangements. Removal of the airway secretions results in prompt improvement in volume generation. If pacemaker failure is suspected and inspired volume generation is significantly reduced or absent on either side, the function of the external components is evaluated in sequence. First, the batteries need to be replaced because this is the most common cause of pacemaker malfunction. If function is not restored, the antennae contacts with the skin are checked. If these are secure, the antennae are replaced. If these measures are not successful, the transmitter is replaced with the backup unit. If evaluation of the external components does not resolve the problem, the integrity of the internal components is assessed. The cost of implanting a phrenic nerve pacer is presently greater than $100,000, which includes the actual system, surgery, and hospitalization. The diaphragm motor point stimulation system is presently being implanted for less than $25,000, which includes the system and the outpatient laparoscopic implantation. One of the major reasons for the decreased cost is that the DPS system is percutaneously connected to the stimulator. However, when compared with the monthly cost of maintaining a patient at home with a portable ventilator, including the cost of long-term equipment replacement or rental as well as medical and nursing care, either the phrenic nerve or the diaphragm motor point system is costeffective. Onders and colleagues described a cost savings of $13,000 per month for one patient with spinal cord injury who was successfully weaned off the ventilator to full-time pacing.28

INDICATIONS AND RESULTS Tetraplegia There are an estimated 250,000 to 400,000 patients with spinal cord injury living in the United States. Of 11,000 new injuries each year in that country, slightly more than one half are affected by quadriplegia. For injuries involving cervical levels above C5, profound respiratory dysfunction occurs; for

1/21/2008 3:48:35 PM

1452

Section 6 Diaphragm

injuries involving levels C3 or above, assistance with ventilation is usually required. Mechanical ventilation via tracheostomy is standard therapy in this patient population. However, mechanical ventilation has a myriad of complications, including difficulty with speech, increased secretions and need for suctioning, loss of sense of smell, constant noise, and difficulty with transfers. Also, the need for mechanical ventilation greatly decreases life expectancy. The need for mechanical ventilation affects older persons (an increasingly common group) to an even greater extent; the 45-year-old patient with spinal cord injury has a life expectancy of only 9 additional years. Given the relatively low numbers of phrenic nerve pacemakers implanted worldwide, there are very few recent studies analyzing the success rate of phrenic nerve pacing and the incidence of side effects. In one study of phrenic nerve pacemakers, however, 14 tetraplegics were monitored systematically for as long as 15 years (mean, 7.6 years) (Elefteriades et al, 2002).32 With chronic bilateral lowfrequency stimulation, the threshold and amplitude values required for maximum excursion of the diaphragm and tidal volume generation were unchanged for the duration of followup. Moreover, there was no evidence of nerve injury based on analyses of available pathologic specimens. The DPS system has been implanted in more than 30 individuals with high-level spinal cord injury, resulting in more than 60 years of cumulative active implantation time. The first patient implanted with the DPS system has been using it continuously for more than 7 years as his sole means of respiratory support. With the exception of the second patient, who did not meet our revised inclusion criteria of seeing diaphragm movement with phrenic nerve stimulation, all of the remaining patients have been able to achieve significant tidal volumes greater than 15% of their basal rate with the outpatient DPS system. Based on these results, the DPS system has demonstrated safety and efficacy in patients with high-level spinal cord injury and is now in a phase III multicenter trial. In the DPS system trial, patients have ranged in age from 18 to 72 years (average, 30 years). The age at the time of injury has ranged from 2 to 70 years. The years spent on mechanical ventilation before implantation have ranged from 1 to 25 years (average, 7 years). The amount of time and daily episodes of diaphragm conditioning affect the time required for weaning to DPS ventilation. Age and time since injury directly affect the conditioning time needed to achieve 4 continuous hours with DPS, from less than 1 week for 18to 20-year-olds who have been ventilated for less than 1 year to 14 weeks for 40- to 50-year-olds who have been ventilated for longer than 5 years. Two patients who were older than 65 years of age needed 21 weeks to meet this conditioning goal. Two patients who required surgical correction of scoliosis before implantation have needed prolonged conditioning to achieve adequate tidal volumes. DPS has been demonstrated to work in all innervated diaphragms. Analysis of the results shows that earlier implantation facilitates weaning from the ventilator and decreases the complications deriving from positive-pressure ventilation. Geriatric tetraplegics and patients with significant scoliosis require increased diaphragm conditioning.

Ch120-F06861.indd 1452

Patients were analyzed who participated in home-based conditioning with the diaphragm motor point pacing system. Six patients were admitted for 24 hours for training and onset of conditioning. The protocol was revised, and all subsequent patients were evaluated in an outpatient clinical setting for 4 to 6 hours for training. All patients and caregivers were comfortable with the care and use of the device and the conditioning process at discharge. All patients successfully achieved conditioning in their own home. Five patients achieved fulltime pacing in less than 7 weeks, and two patients in less than 3 weeks. There have been no complications with home-based conditioning.31 After successful implantation and conditioning of the diaphragm to provide at least 4 continuous hours of DPS ventilation, a survey was sent to patients and caregivers to assess the effect of DPS on their activities. This survey was repeated 1 year later, and the answers were analyzed. The response rate was 92% (22/24). All patients were living at home, with the primary caregiver being the mother in 14 patients. Sixtyfour percent of the patients reported fewer secretions, and 68% of the caregivers reporting less suctioning. Eighty-two percent of the patients reported “more normal breathing.” Seventy-seven percent of the caregivers stated that caring for the paced patient was less work than with the mechanical ventilator. Ninety-one percent of caregivers stated that the pacer was easy to use. Other comments included the following: DPS was life-saving during hurricanes and power outages (3); the silence of pacing equipment enabled the patient to sleep well for the first time since the injury (2); attending classes or church was easier, and the patient was able to travel for the first time since injury (1); transfer from the ventilator ward to assisted living or to home was possible (2); and the patient was able to travel by air (4). One hundred percent of patients described an increase in mobility; 95% reported greater freedom and feeling of independence; and 100% would recommend the DPS system to other tetraplegics. The patient satisfaction of being removed from the ventilator is enough by itself to justify implantation for those patients with devastating high tetraplegia. It allows them to return one aspect of life to a little more normalcy. Although there have been no controlled studies comparing patient outcomes between mechanical ventilation and phrenic nerve pacing or diaphragm pacing, the latter may be associated with improved life expectancy by returning patients to natural negativepressure ventilation using their own diaphragm.

Congenital Central Hypoventilation Syndrome CCHS is characterized by absence or failure of the involuntary central respiratory drive, resulting in hypoventilation. CCHS is also known as central sleep apnea or Ondine’s curse, after the German mythologic figure. This term has fallen into disfavor in recent years, and its history has been well described.33 CCHS is a rare diagnosis, affecting 1 in 50,000 live births.34 Patients typically present as newborns, and CCHS is a diagnosis of exclusion. Generally accepted criteria for the diagnosis of CCHS are persistent evidence of hypoventilation during sleep (PaCO2 >60), onset of symptoms during the first year of life, absence of primary pulmonary or neu-

1/21/2008 3:48:35 PM

Chapter 120 Phrenic Nerve and Diaphragm Motor Point Pacing

romuscular disease, and no evidence of cardiac disease. There is increasing evidence of a genetic link to CCHS, with mutations in PHOX2B identified; however, the cause remains unknown.35 CCHS can be associated with autonomic nervous system manifestations, including decreased heart rate variability, baseline bradycardia, vasovagal syncope, poor heat tolerance, esophageal dysmotility, and ocular problems. Between 15% and 20% of children with CCHS have Hirschprung’s disease. Clinical management of CCHS involves ensuring adequate ventilation. Approximately one third of these patients require full-time ventilatory support, and the remainder require mechanical ventilation while sleeping. For many families of CCHS patients, the costs associated with care of the child exceed $100,000 per year. Managing the complications associated with ventilator use—which include the inability to speak and move around and the increased likelihood of infection and pneumonia—often takes a severe emotional toll on the patient and the parents. Children with CCHS require vigilant monitoring perioperatively in an intensive care unit (ICU), because they demonstrate no signs of respiratory depression or distress, such as retractions or labored breathing. They require mechanically assisted ventilation perioperatively until they are fully awake. Even a slight amount of residual anesthetic agent can result in profound respiratory depression in a patient with CCHS. The official statement from the American Thoracic Society regarding diagnosis and management of CCHS supports the consideration of diaphragm pacing when infants become mobile.36 The distinct advantage of full mobility markedly improves quality of life. A study of 196 patients found that 22% of CCHS patients made the transition to diaphragm pacing.37 Patients aged 12 months and younger have been paced with phrenic nerve pacemakers. Also, some patients have not required tracheotomy when receiving phrenic nerve pacing as an adjunct to noninvasive positive-pressure ventilation. The diaphragm motor point pacing system is only beginning to be used in CCHS and may become another option for these children and their families. With the advent of both thorascopic placement of the phrenic nerve system and the newer laparoscopic DPS system, the percentage of children using one of the pacing systems is likely to increase.

FUTURE APPLICATIONS Amyotrophic Lateral Sclerosis ALS, also known as Lou Gehrig’s disease or motor neuron disease, is a progressive neurodegenerative disease of unknown cause. One of the most important effects of progressive neuromuscular weakness in patients with ALS is the effect on respiration. Although ALS has no direct effect on the lung, it has devastating effects on the mechanical function of the respiratory system. ALS affects all of the major respiratory muscle groups: upper airway muscles, expiratory muscles, and inspiratory muscles. Therefore, all patients with ALS are at significant risk for respiratory complications. Progressive inspiratory muscle weakness in ALS inevitably leads to carbon dioxide retention, inability to clear secretions, and hypercar-

Ch120-F06861.indd 1453

1453

bic respiratory failure, the major cause of death in ALS. Pulmonary complications and respiratory failure are reported to be responsible for at least 84% of deaths in patients wih ALS.38 The average life span of untreated patients from the time of diagnosis is approximately 3 to 5 years. Many studies have looked at the prognostic indicators of survival in ALS and have found strong correlations to forced vital capacity (FVC) and the ALS functional rating scale (ALSFRS).39-42 Studies have shown that patients with significant respiratory muscle involvement, as evidenced by an FVC of 50% or less of the predicted value, have a 9-month mortality rate ranging from 60% to as high as 100%.41,43 A number of studies have looked at the rate of decline of vital capacity (VC) or FVC and have identified that a linear model best describes the progression, with rates ranging from 3.3% to 3.5% decline per month.44-47 The practice parameter of the American Academy of Neurology suggests that all patients with ALS and respiratory symptoms or an FVC of less than 50% of predicted be offered noninvasive positive-pressure ventilation (NPPV). NPPV has been shown to decrease dyspnea and improve quality of life, and it may delay the need for invasive mechanical ventilation. NPPV is usually applied at night because of the greater convenience and the high frequency of sleep-disordered breathing that it might ameliorate. Patients often add daytime hours as their disease progresses, and some eventually use NPPV continuously. The fact that NPPV does not require a surgical procedure helps with acceptance, although compliance is an issue and NPPV is a temporary measure. Most patients in Europe and the United States do not receive NPPV; the acceptance rate is reported to be as low as 2% to 15% due to issues with implementation.48,49 At some point, ALS involves the respiratory muscles so severely that bulbar paresis is combined with severe expiratory and inspiratory muscle weakness, and invasive ventilation becomes the only option for survival.50 There is a significant risk of impending respiratory failure or death with an FVC lower than 25% to 30% of predicted.51 Invasive ventilation or mechanical ventilation requires the placement of a tracheostomy that is connected to a ventilator and can prolong life for up to 20 years. The costs of mechanical ventilation to patients and families in both financial and emotional terms are significant. Treatment with mechanical ventilation in the ALS population has increased, especially in hospital settings. The mean cost of maintaining mechanical ventilation is $180,120 per year, with the upward scale reaching $1,080,000. The mean yearly out-of-pocket expense to families for maintaining mechanical ventilation is $10,356.52 There are fewer long-term care facilities that will care for ventilated patients, compared with nonventilated patients. Family members of mechanically ventilated ALS patients living at home report feelings of major stress. Caring for the patient is a major burden, life-altering and costly in time. Family members provide much of the care for these patients at home and may have to relinquish outside jobs to do so. Even so, many patients report a good quality of life while receiving mechanical ventilation. Neither NPPV nor mechanical ventilation for preserving respiratory muscle function is ideal, suggesting that there is

1/21/2008 3:48:35 PM

1454

Section 6 Diaphragm

a significant need for a more physiologic and effective treatment for worsening respiratory muscle function in ALS patients. Diaphragm motor point pacing is now being used, in a phase III trial authorized by the U.S. Food and Drug Administration, in an attempt to maintain and/or augment respiratory muscle function in ALS patients. The rationale for this intervention is supported by previous independent studies using therapeutic electrical stimulation (TES) and by our preliminary data from 10 ALS patients implanted with the device. Previous evidence has suggested that peripheral muscle function can be preserved or improved in ALS patients with a technique of electrical muscle stimulation. A clinical trial of TES of peripheral skeletal muscle in a patient with ALS suggested that upper extremity muscle motion and mass could be increased with TES using intramuscular electrodes.53,54 The morphologic changes shown with computed tomographic imaging on follow-up support the functional improvement of the extremities through a long-term TES application. Extension of this technology to the respiratory muscles may have a similar effect. In our own studies and those of others,55 it has been shown that diaphragm strength and fatigue resistance improve with electrical stimulation of the diaphragm in patients with high-level spinal cord injury. To date, more than 10 ALS patients have been implanted with the DPS system in the same fashion as the spinal cord– injured patients.56 Instead of using the DPS system to wean off the ventilator, the patients are using the device to condition and maintain the strength of their diaphragm through five 30-minute training sessions per day. The study compares the patient’s monthly decline in FVC before implantation to the monthly decline after implantation once the conditioning regimen has begun. A decrease in the slope leads to an increase in survival. There have been no perioperative complications, even with FVC lower than 50% predicted for many patients. Almost half of the patients are simultaneously having a gastrostomy placed, and there has been no increase in infections. There have been no adverse effects on short-form health and well being (SF 36 Health Survey) or ALS revised functional rating scale (ALSFr) quality-of-life scales. Diaphragm thickness, as measured by ultrasonography, has increased. In all patients, greater fluoroscopically observed diaphragm excursion occurs with diaphragm stimulation than under maximal voluntary effort. The ability to cause greater diaphragm movement with DPS is a surprising and beneficial finding. This may be best explained by intact phrenic nerve motor neurons that are no longer controlled by the medullary respiratory center, cerebral cortex, or central or peripheral chemoreceptors but can be stimulated with DPS. DPS may also have a trophic effect on increasing the survival of these motor neurons. DPS also converts the remaining motor units to usable slow-twitch oxidative units. These additional findings of DPS may lead to improved nighttime ventilation, decreasing the incidence of posterior lung lobe atelectasis and subsequent pneumonia. Overall, the most important finding is that DPS in these ALS patients resulted in a decrease in the rate of decline of FVC of 2.8% to 1.0% per month, providing a 20-month improvement in ventilator-free survival. In conclusion, the diaphragm pacing system can be safely implanted and used in patients with ALS. There has been a

Ch120-F06861.indd 1454

documented decrease in the decline of respiratory failure which leads to increased survival. These initial results have resulted in FDA approval for a multicenter phase II pivotal trial which, although it does not provide a cure for ALS, will allow an increased quality of life by delaying the need for mechanical ventilation.

Temporary Diaphragm Pacing in the Intensive Care Unit Diaphragm muscle fatigue as a consequence of mechanical ventilation commonly occurs in ICUs, with 20% to 30% of patients having difficulty weaning from the ventilator.57 Up to 40% of additional ventilated ICU days may be spent trying to liberate a patient from the ventilator once he or she has been receiving ventilator assistance for several days.58 Some of the factors that impede the ability to wean from mechanical ventilation are diaphragm atrophy, barotrauma, posterior lobe atelectasis, and impaired hemodynamics. These detrimental effects of positive-pressure mechanical ventilation might be ameliorated with the use of negative-pressure ventilation through diaphragm pacing, facilitating more rapid weaning from mechanical ventilation (Pavlovic and Wendt, 2003).59 The laparoscopic DPS system has reached a critical mass of knowledge in the small orphan disease populations that it currently serves: patients with spinal cord injury and those with ALS. Because this system is reversible—the electrodes can be removed, similar to temporary cardiac pacing wires—this system may have a role in patients who are temporarily using a ventilator. Current DPS implantation is done laparoscopically in operating rooms. This location may not be convenient for many ICU patients, and, although bedside laparoscopy is done in ICUs, it is still not as accepted or as easy as bedside endoscopy. Because bedside endoscopy is routinely performed for percutaneous endoscopic gastrostomies (PEG), natural orifice transluminal endoscopic surgery (NOTES) may provide a logical segue to facilitate DPS implantation. NOTES technology has been rapidly expanding and may emerge as an alternative to standard laparoscopic or open abdominal procedures (McGee et al, 2006).60-63 Our research group has shown in swine models that diaphragm pacing can be done using NOTES. At least conceptually, diaphragm motor point pacing could be done in the ICU at the time of placement of a PEG tube and tracheostomy for those patients who are unable to be weaned from a ventilator.12,64 In our present human ALS study, with 50% of the patients undergoing simultaneous laparoscopic DPS implantation and PEG placement, there have been no electrode infections to date. Acknowledging that DPS implantation is feasible, questions remain regarding the efficacy of DPS in patients with temporary mechanical ventilation in the ICU. The primary and secondary effects of diaphragm pacing are outlined in Table 120-1 and are each reviewed separately here.

Diaphragm Strengthening Mechanical ventilation causes diaphragm muscle inactivity and unloading, which lead to a loss of diaphragmatic forcegenerating capacity; this is referred to as ventilator-induced

1/21/2008 3:48:35 PM

Chapter 120 Phrenic Nerve and Diaphragm Motor Point Pacing

TABLE 120-1 Primary and Secondary Effects of Diaphragm Pacing in Patients in the Intensive Care Unit Primary Effects

Secondary Effects

Diaphragm strengthening

Maintenance of slow-twitch oxidative muscle fibers Decreased weaning time and length of stay

Reduction in airway pressure

Decreased barotrauma Improved alveolar ventilation

Posterior lobe ventilation

Decreased atelectasis Pneumonia risk reduction

Maintenance of negative chest pressure

Improved venous return Increased cardiac output Reduced third spacing

diaphragmatic dysfunction (VIDD).65 Animal studies have shown that diaphragm atrophy can be identified within 12 hours after institution of mechanical ventilation, and reduced diaphragm mass by 48 hours.66 In baboon studies, short durations of mechanical ventilation led to a significant impairment of diaphragmatic strength and endurance.67 After a sustained period of muscle unloading with mechanical ventilation, resumption of diaphragm muscle activity during weaning leads to an increased vulnerability of muscle fiber injury.68 Use of intermittent DPS may decrease this risk of muscle injury. The use of positive end-expiratory pressure (PEEP) causes displacement of the diaphragm and shortening of the muscle, which exacerbate atrophy and lead to a loss of sarcomeres. Use of the DPS system would decrease chest pressure and cause less shortening of the diaphragm, thereby preventing injury. The human diaphragm is designed for 24-hour use; 70% of the fibers are slow-twitch oxidative fibers (type I), with the remainder being fast-twitch oxidative fibers (type IIa) or glycolytic fibers (type IIb). Mechanical ventilation initially causes a decrease in the size of type I and II fibers, but prolonged ventilation preferentially decreases type I by both atrophy and transformation to type II.65 Functional electrical stimulation (FES) maintains the type I fibers of the diaphragm that are necessary for continuous diaphragm use during and after weaning off from mechanical ventilation. The diaphragm is more vulnerable to disuse activity than limb muscles, yet FES applied to extremity muscles in patients being mechanically ventilated in ICUs was shown to improve muscle strength and the ability to transfer out of bed.69 In our spinal cord–injured patient group, the strength of the diaphragm (i.e., the amount of stimulated tidal volume) increased by 48% with electrical stimulation. There previously had been no minimally invasive option to provide FES to the diaphragm for the purpose of maintaining strength in the ICU setting. In a case report of a spinal cord–injured patient who had a phrenic nerve cuff electrode system for ventilation with only one side functional, it was concluded that FES of only 30 minutes per day was able to suppress pathologic diaphragmatic attenuation and preserve diaphragm thickness and function.70 Further evidence in a rat model showed that as little as 20 minutes a day of diaphragm activity could prevent atrophy but might not maintain diaphragm

Ch120-F06861.indd 1455

1455

force.71 Prolonged mechanical ventilation of greater than 14 days leads to long-term impaired health-related quality of life especially in regard to pain, sleep, energy, emotional reaction, mobility, and pulmonary function.72 Intermittent diaphragm pacing maintains diaphragm strength, which leads to a decrease in time on mechanical ventilation and could improve long-term quality of life.

Reduction in Airway Pressure Positive-pressure mechanical ventilation “pushes” air in, causing an increase in airway pressures, whereas natural breathing “pulls” air in when the diaphragm contracts. Barotrauma, which occurs in more than 10% of mechanically ventilated patients, is associated with peak pressures of greater than 40 cm H2O and includes pneumothorax, interstitial emphysema, and pneumomediastinum. Various alveolar dysfunctions and injuries (including surfactant depletion) are associated with high pressures. According to Boyle’s law (V = k/P), ventilator pressures will be decreased when negative pressure is added to the system to sustain the same volumes. We are already studying the use of diaphragm pacing in synchronization with the ventilator in our Institutional Review Board- and FDA-approved spinal cord–injury protocols. At the completion of the surgical implantation, we assess the function of the system while the patient continues to use the ventilator. A total of five patients were analyzed, and the average pressure for same-volume ventilation went from 21 cm H2O without DPS stimulation to 17 cm H2O with DPS stimulation. These patients had significant muscle atrophy, but we were able to see a decrease in the average ventilator pressures while maintaining the same volume of ventilation. Synchronizing the DPS system with the ventilator can decrease the average pressure required to ventilate patients in the ICU, thereby decreasing barotrauma.

Posterior Lobe Ventilation Mechanical ventilation preferentially ventilates the anterior lobes of the lung, which predisposes the patient to atelectasis and subsequent pneumonia in the posterior lobes.73 PEEP is presently used with mechanical ventilation to prevent alveolar collapse and decreased functional residual capacity (FRC). However, PEEP is limited by barotrauma and by its effect on cardiac preload and cardiac output. Diaphragm pacing in synchronization with a ventilator would improve posterior lobe ventilation and subsequently decrease the incidence of atelectasis and ventilator-associated pneumonia. Ventilatorassociated pneumonia has a direct relationship to time spent on mechanical ventilation and to morbidity and mortality of patients in ICUs. A ventilator-associated pneumonia increases the length of ICU stay, increases the related cost by more than $50,000, and can increase the mortality rate substantially. The data support the idea that decreasing the duration of ventilation decreases the incidence of ventilator-associated pneumonia, and DPS needs to be able to decrease ventilator time.74

Maintenance of Negative Chest Pressure Mechanical ventilation detrimentally affects the cardiovascular system, because increased intrathoracic pressures leads to

1/21/2008 3:48:36 PM

1456

Section 6 Diaphragm

decreased filling pressure in the right ventricle and impedes systemic venous return. As a consequence, low cardiac output appears in accordance with Starling’s law. Significant improvements in hemodynamic function were observed in both animal and human clinical experiments using a transvenous technique to stimulate the phrenic nerve.75 Fourteen people were studied with this technique in the postoperative period after cardiac operations. Values were obtained from patients during standard ventilation and then with ventilation by transvenous stimulation of the phrenic nerve. Diaphragm pacing reduced pulmonary arterial pressure, right atrial pressure, left atrial pressure, and total pulmonary vascular resistance and augmented cardiac output. This technique had significant practical limitations because of the difficulty in pacing both phrenic nerves with a single catheter, the risk of heart arrhythmias, and the predisposition of patients to the risk of vascular thrombosis. With the possibility of diaphragm pacing laparoscopically or with NOTES, these limitations can be overcome; therefore, diaphragm pacing could benefit the ICU patient by increasing venous return, improving cardiac output, and reducing third spacing. In conclusion, we speculate that successful application of these techniques may facilitate more rapid liberation from mechanical ventilation in critically ill ICU patients. The attendant decreases in length of stay, complications, tracheostomy rate, and cost might dictate a paradigm shift in management of difficult-to-wean ICU patients. “Trach and a PEG” management may be replaced in some cases by a bedside NOTES-facilitated DPS system implantation.

SUMMARY With thoracoscopic phrenic nerve and laparoscopic diaphragm motor point pacing now available for spinal cord–injured patients, there is no longer a reason for patients with these devastating injuries to be faced with a life on a ventilator. Thoracic and general surgeons need to be willing to interact with the rehabilitation specialists taking care of these patients. Pacing is the preferred mode of ventilation for these rare patients. These same recommendations hold true for children with CCHS. The impact of liberation from the ventilator with either a phrenic nerve or a DPS system includes increased independence, normalization, and ease of care. These results have been documented in long-term follow-up of patients with the DPS system and are summarized here. 1. Independence: Patients and primary caregivers report an increased sense of independence. Patients feel safe being left alone for periods of time, whereas, on the ventilator, they did not. Patients are able go on some errands without an attendant. During power outages, they are not forced to evacuate from their home or to depend on a generator to breathe. 2. Normalization: Without the noise of the ventilator, activities such as going to the movies or the theater, dining out, and attending church or school are more easily integrated. One of our patients, a former model, was injured 7 years before her implantation. During those years, because of her ventilator, she never left her home. After implantation

Ch120-F06861.indd 1456

of the DPS system, she went on her first vacation since her injury and is now planning a cross-country trip. 3. Ease of care: Transfers and traveling are less cumbersome. Transferring is simplified because there is no excess tubing to be managed. Patients can get onto airplanes with much less difficulty. They are less likely to be considered too high-risk to fly on a commercial airline. One of our patients was able to fly to China after implantation for the first time. The DPS batteries last 500 hours, whereas the ventilator battery last less than 12 hours. The future also holds a promise for a completely implantable system with no external parts at all, as battery technology improves.76 Based on the experience with the DPS system in spinal cord injuries, there is now a possibility of helping patients with ALS or any patient who is temporarily on a ventilator. With these growing indications, there will be an increased need for surgeons to be experienced with surgical techniques and postoperative management of these patients.

COMMENTS AND CONTROVERSIES Dr. Onders and his coworkers at Case Western Reserve University are to be commended for their pioneering work with diaphragm motor point pacing. Respiratory failure in a patient with an intact phrenic nerve and functioning diaphragm is no longer a sentence to lifelong ventilator support. The minimally invasive laparoscopic technique developed by Dr. Onders for electrode placement and pacer implantation avoids phrenic nerve injury, a significant and procedure-limiting complication of direct phrenic nerve pacing. As pointed out, patient selection is critical, and both phrenic nerve stimulation and diaphragmatic fluoroscopy are necessary to correctly identify those patients who will benefit from diaphragmatic pacing. This chapter is full of clinical gems that are invaluable in the intraoperative and postoperative management of these patients. The potential for temporary and permanent pacing are limited only by the patient’s physiology and the doctor’s imagination. Currently, this technology is being used to assist ventilation in patients with ALS in an effort to improve both quantity and quality of life. Simplified implantation techniques, perhaps by transgastric endoscopic surgery, may extend this technology to temporary assistance therapy. T. W. R.

KEY REFERENCES DiMarco AF, Onders RP, Ignangi AI, et al: Phrenic nerve pacing via intramuscular diaphragm electrodes in tetraplegic subjects. Chest 127:671-677, 2005. Elefteriades JA, Quin JA, Hogan JF, et al: Long-term follow-up of pacing the conditioned diaphragm in quadriplegia. Pacing Clin Electrophysiol 25:897-906, 2002. Glenn WW: Diaphragm pacing: Present status. Pacing Clin Electrophysiol 1:357-370, 1978. McGee MF, Rosen MJ, Marks J, et al: A primer on natural orifice translumenal endoscopic surgery: Building a new paradigm. Surg Innov 13:86-93, 2006. Morgan JA, Ginsburg ME, Sonett JR, et al: Advanced thoracoscopic procedures are facilitated by computer-aided robotic technology. Eur J Cardiothorac Surg 23:883-887, 2003.

1/21/2008 3:48:36 PM

Chapter 120 Phrenic Nerve and Diaphragm Motor Point Pacing

Onders RP, Aiyar H, Mortimer JT: Characterization of the human diaphragm muscle with respect to the phrenic nerve motor points for diaphragmatic pacing. Am Surg 70:241-247, 2004. Onders RP, Ignagni AI, Aiyer H, Mortimer JT: Mapping the phrenic nerve motor point: The key to a successful laparoscopic diaphragm pacing system in the first human series. Surgery 136:819-826, 2004. Onders RP, Ignagni AI, DiMarco AF, Mortimer JT: The learning curve of investigational surgery: Lessons learned from the first series of laparoscopic diaphragm pacing for chronic ventilator dependence. Surg Endosc 19:633-637, 2005.

Ch120-F06861.indd 1457

1457

Onders R, Marks J, Schilz R, et al: Diaphragm pacing with natural orifice transvisceral endoscopic surgery (NOTES): Potential for difficult to wean intensive care unit (ICU) patients. Surg Endosc 21:475479, 2007. (Epub 2006 Dec 20.) Pavlovic D, Wendt M: Diaphragm pacing during prolonged mechanical ventilation of the lungs could prevent respiratory muscle fatigue. Med Hypoth 60:398-403, 2003. Shaul DB, Danielson PD, McComb JG, Keens TG: Thorascopic placement of phrenic nerve electrodes for diaphragm pacing in children. J Pediatr Surg 37:974-978, 2002.

1/21/2008 3:48:36 PM

chapter

121

SURGERY OF THE PHRENIC NERVE Alexander S. Krupnick R. Brannon Claytor Susan E. Mackinnon

Key Points

found accessory nerves at operation or cadaver dissection in 15% to 60% of patients (Fig. 121-1).2,3

■ Comprehensive knowledge of phrenic nerve anatomy is essential

to avoid injury. ■ First-degree injury (neurapraxia) and second-degree injury (axonot-

mesis) will resolve in weeks to months; however, more severe injury (third to fifth degree) will not heal. ■ Although it is theoretically possible to repair a transected phrenic nerve, this is uncommonly reported. ■ Diaphragmatic plication and nerve transfers may be necessary for treatment of respiratory compromise after phrenic injury.

BACKGROUND The diaphragm is a skeletal muscle and the only one that is vital to life. Impairment of this muscle can lead to hypoventilation, hypoxia, atelectasis, and infections. Any surgery near the phrenic nerve, such as cardiac, thoracic, or upper abdominal procedures, can injure the phrenic nerve. The cause of pulmonary dysfunction must be identified before any intervention can be planned. The diaphragm is the main inspiratory muscle and can be augmented by accessory inspiratory muscles at times of great exertion or in restrictive lung disease. It undergoes volume displacement between the thorax and the abdomen with supine positioning and with the use of general anesthetics. This can lead to reductions in vital capacity (VC), total lung capacity (TLC), and tidal volume (VT). These changes can decrease the functional residual capacity (FRC), increase ventilation-perfusion mismatch, and increase development of atelectasis. Injury to the phrenic nerve can adversely affect patient outcome. A patient with a limited pulmonary reserve may require prolonged ventilatory support and delays in hospital discharge. Although unilateral damage in a patient with normal pulmonary function may result in little to no clinical significance,1 bilateral phrenic nerve injury translates into significant morbidity necessitating mechanical ventilatory support (Diehl et al, 1994).

ANATOMY Surgical treatment of pulmonary tuberculosis by collapsing the affected lung provided an opportunity to characterize the phrenic nerve anatomy. Attempts to induce unilateral diaphragm paralysis with phreniconeurectomy led to an enhanced understanding of the prevalence of accessory phrenic nerves at the level of the anterior scalene muscle. Various reports

Left Side The main phrenic nerve on both sides originates from the ventral rami of the third to the fifth cervical nerves. It passes inferiorly down the neck to the lateral border of the scalenus anterior. Then it passes medially across the border of scalenus anterior, parallel to the internal jugular vein, which lies inferomedially. At this point, it is deep to the prevertebral fascia, the transverse cervical artery, and the suprascapular artery. At the anteroinferior medial margin of the scalenus anterior, the left phrenic nerve crosses the first part of the left subclavian artery. It receives a pericardiophrenic branch of the internal mammary artery (IMA), which stays with its distal course. Within the thorax, the phrenic nerve continues inferiorly and slightly laterally on the anterolateral aspect of the arch of the aorta, separated from the posterior right vagus nerve by the left superior intercostal vein. The phrenic nerve crosses the subclavian artery at a distance of about 3 cm laterally from the origin of the IMA from the subclavian artery. After about 4 cm, the phrenic nerve crosses the IMA obliquely from the lateral to the medial side, at an approximate distance of 3 to 4 cm distally from the IMA origin. On crossing the IMA, the phrenic nerve, which may be situated either in front or behind the IMA, continues medially and dorsally through mediastinal adipose tissue to the pericardium, running on it caudally toward the diaphragm. Finally, it curves inferiorly and anteriorly to reach the surface of the diaphragm, which it pierces anterior to the central tendon and lateral to the pericardium. It then forms three branches on the inferior surface of the diaphragm: anterior, lateral, and posterior. These ramify out in a radial manner from the point of perforation to supply all but the periphery of the muscle (Fig. 121-2).4

Right Side At the anterior, inferomedial margin of scalenus anterior and superficial to the second part of the right subclavian artery, the right phrenic nerve passes medially to cross the pleural cupola deep to the subclavian vein at the level of the IMA origin. For another 3 to 4 cm, it runs parallel to the IMA, usually along its medial edge. Within the thorax, the right phrenic nerve is in contact with mediastinal pleura laterally. Medially, it passes in succession, from superior to inferior, the right brachiocephalic

1458

Ch121-F06861.indd 1458

1/21/2008 3:59:28 PM

Chapter 121 Surgery of the Phrenic Nerve

vein, superior vena cava, pericardium of the right atrium, and inferior vena cava. From the level of the superior vena cava, it is joined by the pericardiophrenic artery, and both run inferiorly, anterior to the lung root. The right phrenic nerve pierces the diaphragm in its tendinous portion just slightly lateral to the inferior vena caval foramen. It then forms three branches on the inferior surface of the diaphragm: anterior, lateral, and posterior. These ramify out in a radial manner from the point of perforation to supply all but the periphery of the muscle.4 Although these are well-documented observations of phrenic nerve anatomy, one must take caution when dissecting in the vicinity of the

1

3

A1 2

B1

2

1

4

4 1 5 2

4

3

3

3 A2

phrenic nerve because there is no constant relationship among these structures.5,6

Accessory Phrenic Nerve Accessory nerves are those that are separate from the main trunk of the phrenic nerve and usually lie lateral to the main phrenic nerve. The main phrenic nerve usually arises from C4 but can have contributions from C3 and C5. Anatomic variations of the accessory nerve include a phrenic nerve that arises with the nerve to the subclavius rather than directly from C5, one that receives branches from C6 or from cranial nerve XI or XII,7 one that passes in front of the subclavian vein, and one that arises from the ansa cervicalis and thus indirectly from C3.3,8 The accessory nerves coalesce with the main phrenic nerve on the inferior aspect of the clavicle and achieve a single trunk at that level.

BEST DIAGNOSTIC METHODS

1

4

1459

2 B2

FIGURE 121-1 Anatomy of nerves supplying the diaphragm (anterior view) on the right and left sides (A1 and B1, respectively). Insets show posterior views (A2 and B2, respectively). 1, Scalenus anterior muscle; 2, internal mammary artery; 3, phrenic nerve; 4, subclavian artery; 5, accessory phrenic nerve.

Diaphragm paralysis is suspected in any patient who develops ventilatory insufficiency after an intrathoracic operation. Confirming the diagnosis requires that the patient not be mechanically ventilated and be able to initiate spontaneous inspiration and expiration maneuvers. The paralyzed hemidiaphragm will not move down with inspiration and often will move up in a paradoxical fashion. The most sensitive radiologic test is the “sniff” test, in which the paralyzed hemidiaphragm is observed fluoroscopically to move upward during rapid sniffing. Other, more invasive methods of determining phrenic nerve paralysis include phrenic nerve conduction, transdiaphragmatic pressure differential,9 and contrast 10 peritoneography.

CLASSIFICATION OF NERVE INJURIES In 1951, Sir Sydney Sunderland described a classification of five nerve injuries that encompassed the spectrum of nerve

IMA IMA Phrenic nerve

Phrenic nerve

Subclavian vein

Subclavian Vein

Subclavian artery

A

Subclavian artery

Right

B

Left

FIGURE 121-2 Apex of the hemidiaphragm on the right (A) and on the left (B), showing the proximity of the phrenic nerve and internal mammary artery (IMA).

Ch121-F06861.indd 1459

1/21/2008 3:59:28 PM

1460

Section 6 Diaphragm

TABLE 121-1 Classification of Nerve Damage Histopathologic Changes Degree of Injury

Myelin

I Neurapraxia

±

Axon

Endoneurium

Perineurium

Tinel’s Sign Epineurium

Present

Progresses Distally

−

−

II Axonotmesis

+

+

III

+

+

+

IV

+

+

+

+

V Neurotmesis

+

+

+

+

+

+

−

VI

Various fibers and fascicles demonstrate various pathologic changes

+

±

damage (Sunderland, 1951).11 First-degree injury (type I, or neurapraxia) involves a conduction block at a discrete area along the nerve where there is segmental demyelination. There is no axon abnormality, and nerve transmission resumes once the nerve is remyelinated. Recovery can take up to 12 weeks. Second-degree injury (type II, or axonotmesis) involves axonal damage with Wallerian degeneration. The basal lamina is intact and provides a receptive environment for axonal sprouting and regeneration. The rate of regeneration is approximately 1 inch/month, or 1 to 1.5 mm/day, and recovery is usually complete. Third-degree injury is similar to second degree, except that there is additional injury to the basal lamina. Recovery from this injury is often incomplete because axons must regenerate through some scarring. In fourth-degree injury, the nerve is physically in continuity, but the level of scar tissue prevents axonal nerve regeneration across the site of injury. These injuries never show any signs of motor or sensory recovery and are candidates for nerve grafting or nerve transfer. Fifth-degree injury (type V, or neurotmesis) indicates transection of a nerve and requires microsurgical repair or grafting if the zone of injury is sufficiently large to warrant it. Sunderland’s classification was expanded by Mackinnon12 to include a combination of the injuries, which represents a more clinically relevant scenario. This mixed nerve injury can present as a neuroma in continuity, with some normal fascicles alongside fascicles with varying degrees of injury (I, II, III, IV, V). These represent a more challenging scenario because the recovery will be mixed (Table 121-1 and Fig. 121-3). With respect to the phrenic nerve because of its small size, the injury pattern typically is a neurapraxia, which will recover normal function within 3 months. An axonotmetic injury (type II) may fully recover by 1 year, at a rate of 1 inch/month from the level of injury; may recover only partially (type III) over the same span; or, in fact, may never spontaneously demonstrate any recovery (type IV) as with a neurotmetic injury.

ETIOLOGY OF PHRENIC NERVE INJURY Cardiac Surgery Injury to the phrenic nerve with subsequent diaphragmatic impairment is a well-recognized complication of cardiac

Ch121-F06861.indd 1460

+

+

+

+

+

−

surgery (Curtis et al, 1989).13-20 The incidence of diaphragm dysfunction is similar between adults and children (Russell et al, 1993)21,22 and varies between 10% and 85%, depending on which electrophysiologic, radiologic, or other diagnostic method is used (Brown et al, 1985).23,24 Most cases of phrenic nerve injury are due to cold induced by the use of ice slush to protect the myocardium. The first case of this type of injury was reported by Scannell in 1964.25 Subsequently, Mills and colleagues concluded that even mild hypothermia could induce diaphragmatic dysfunction.26 The incidence of ice slush–induced phrenic nerve dysfunction has been reported to be between 27% and 73%.16,25-28 Whereas the left IMA is harvested and the left side of the heart is exposed for bypass grafting, both phrenic nerves are exposed to ice slush. As a result, both phrenic nerves are at risk for cold injury, and the right hemidiaphragm is also subject to paresis.17,29 In prospective randomized trials, Canbaz and associates30 studied the electrophysiology of the left phrenic nerve after hypothermia and cardiopulmonary bypass, and they compared phrenic nerve function following beating-heart coronary artery bypass (Canbaz et al, 2004). None of the phrenic nerves in the beating-heart group showed any signs of increase in conduction latency or loss of amplitude; however, 10.2% of the patients who had cardiopulmonary bypass with hypothermia had compromised left phrenic nerve function. The explanation for why no right-sided phrenic nerve dysfunction was seen in this study may be the emphasis on using the ice slush around the left ventricle and the left portion of the pericardial cavity, with consequent protection of the right phrenic nerve against cold injury. Animal studies on dogs have demonstrated paralysis of the phrenic nerve after topical hypothermia. Phrenic nerves that were exposed to 1 hour of ice slush did not transmit any diaphragmatic response despite maximal stimulation, and, on microscopic examination, they revealed severe demyelination of the sheath and some axon preservation. The cold-induced paralysis was reversible, with phrenic nerve responsiveness returning in 7 to 62 days.31 Clinically, a patient’s recovery from this neurapraxic/axonotmetic type of injury to the phrenic nerve could take between 30 days and 2 years.14 Although 100% of patients undergoing cardiac procedures have some degree of hypoxemia,32 only 10% have unequivocal phrenic nerve paralysis despite a 93% incidence of atelectasis.19 The variables that can account for the difference between mild dysfunction

1/21/2008 3:59:30 PM

Chapter 121 Surgery of the Phrenic Nerve

1461

Connective tissue components Mesoneurium External epineurium

Nerve fiber Axon

Internal epineurium Perineurium

Myelin

Endoneurium

IV

IV I

III III V II

Fascicle

A

VI

B

FIGURE 121-3 A, Diagrammatic representation of the cross-section of a normal peripheral nerve, demonstrating the connective tissue and nerve components. B, Cross-section of a peripheral nerve demonstrating a mixed (sixth-degree) injury pattern (VI). The fascicle at the 11 o’clock position is normal. Moving counterclockwise, the adjacent fascicle demonstrates a first-degree injury (neurapraxia) with segmental demyelination (I). The next fascicle (II) demonstrates a second-degree injury (axonotmesis). This injury involves both the axon and the myelin. The endoneurial tissue is not damaged. The central two fascicles (III) demonstrate a third-degree lesion, with injury to the axon, myelin, and endoneurium. The perineurium is intact and normal. The fascicles at 12 and 1 o’clock demonstrate fourth-degree injury (IV) with marked scarring across the nerve; only the epineurium is intact. In a fifth-degree injury pattern (V), the nerve is not in continuity but is transected.

such as hypoxemia and atelectasis and a true complication such as prolonged ventilation and hospital stays, are a larger number of bypass grafts, longer operative and bypass time, pleurotomy, absence of right atrial drain, cardiac insulating pad, and lower systemic temperature.19,33 Additional types of injuries may occur from direct damage to the phrenic nerve. The dissection of the left IMA for use as a conduit for aortocoronary bypass may result in direct damage to the phrenic nerve, from electrocautery, disruption of the blood supply to the nerve, or even stretching of the nerve.34 The main blood supply of the phrenic nerve comes from pericardial and pleural branches arising from the cephalad 4-cm segment of the IMA. Approximately 70% of the blood supply to the phrenic nerve comes from the IMA, so at least a modest disruption of blood supply is inevitable.4 Harvesting of the right IMA as a free graft provides a better conduit, compared with the saphenous vein,35,36 but carries a risk to the phrenic nerve. The anatomic relationship of the phrenic nerve to the IMA is different on the two sides, with the nerve and artery in closer proximity to each other within the thorax on the right side.37 The nerve is usually posterior to the artery, but it may be anterior. Usually, no attempt is made to identify the nerve, so traction and diathermy injuries are not recognized. High cephalad dissection of the right IMA increases the risk of phrenic nerve injury, but, in contrast to the left IMA dissection, only minimal changes are noted in blood flow after high right IMA mobilization.34 In the study by Deng and colleagues, patients with transection of the right phrenic nerve who underwent immediate diaphragmatic plication had

Ch121-F06861.indd 1461

upright forced vital capacities (FVC) of 0.90, compared with 0.79 for those diagnosed with phrenic nerve dysfunction who had no treatment.37 Comparison of right and left phrenic nerve palsy reveals that, although left phrenic nerve palsy is usually asymptomatic, right phrenic nerve palsy is more likely to result in noticeable respiratory dysfunction. The supine-to-erect FVC ratio of a right-sided injury is approximately 0.8, whereas that of a left phrenic nerve injury is 0.9. The plicated right side achieves a result similar to that of an untreated left side phrenic nerve injury. Plication of the right side is sufficient to alleviate the symptoms of dyspnea and provide improvement in respiratory function.38-40

Other Causes of Injury During Surgical Intervention Phrenic nerve injury can occur after surgical intervention in the neck area as well. Reports in the literature of diaphragm dysfunction secondary to phrenic nerve injury after subclavian revascularization41 showed decreased amplitude and prolonged latency of the phrenic nerve. The clinical symptoms were self-limited, and the patient had gradual recovery of diaphragm function. Other surgeries in the neck that have led to phrenic nerve injury are scalenectomy for thoracic outlet syndrome,42,43 radical neck dissection,44 blunt trauma to the neck,45,46 insertion of central venous lines,47 and regional blocks in the neck.48,49 Abdominal procedures may also result in injury to the phrenic nerve. Right hemidiaphragm paralysis has been

1/21/2008 3:59:30 PM

1462

Section 6 Diaphragm

reported after orthotopic liver transplantation. The injury most likely occurred during the cross-clamping of the suprahepatic vena cava and was present in up to 79% of patients. All patients recovered by 9 months.50

PHRENIC NERVE REPAIR AFTER TRANSECTION Immediate repair of severed nerves is well described and can reliably restore the compromised motor function. Although no reports of transected phrenic nerve are documented in the literature in cases of coronary artery bypass surgery, one case report in the literature, by Merav and associates, detailed the primary repair of a transected phrenic nerve after traumatic laceration due to a stabbing to the left chest. The nerve was repaired 14 days after the initial injury with sural nerve graft. The subsequent follow-up showed return of some diaphragm function 6 months after repair.51 Another case report, by Brouillette and colleagues, detailed successful reinnervation of a phrenic nerve transected during removal of a thoracic teratoma in a 16-month-old patient. After removal of the mass, it was noted that the patient had bilateral diaphragmatic paralysis.52 End-to-end anastomosis of the right phrenic nerve restored diaphragmatic function. It would be our recommendation to perform a primary repair of a transected phrenic nerve at the time of operation if the injury is noted, and to use a graft or nerve conduit, if necessary, to achieve a tensionless repair.

with the exception of FRC.55-57 Plication has been successful in weaning patients with phrenic injuries from ventilatory dependency, and the beneficial effects have been long-lasting. In addition, the plication does not interfere with the return of diaphragmatic function.58 In the pediatric population, paralysis of the diaphragm usually occurs after birth trauma,59 congenital diaphragmatic eventration,60 or pediatric heart surgery.61 Early plication is recommended to facilitate weaning of affected patients from mechanical ventilation. The majority of cases that lead to diaphragm paralysis in adults involve coronary artery bypass surgery. In this population, most patients could be weaned off ventilation without plication. Of those who were plicated, only one of four was weaned off ventilation; the remaining patients died from the progression of their condition while still intubated.62 However, the results in adults with debilitating dyspnea showed high satisfaction, as measured by the American Thoracic Society dyspnea scale (Simansky et al, 2002) (Fig. 121-4).62

PHRENIC NERVE TRANSFER IN BRACHIAL PLEXUS PALSY Brachial plexus injuries with complete nerve root avulsions have no possibility for spontaneous recovery and are not

CONGENITAL ABSENCE OF THE DIAPHRAGM Children with congenital absence of the diaphragm have a high mortality rate. Advances in neonatal care and extracorporeal membrane oxygenation (ECMO) have improved the immediate survival rate for many of these patients; however, recurrent herniation of Gore-Tex patches used for emergency repair results in restriction of pulmonary function and development. An alternative method of treating congenital diaphragmatic absence involves rotation of the ipsilateral latissimus dorsi muscle, based on lumbar perforators, into the thoracic cavity between the interval of the resected 10th rib. It is secured medially on remnants of the hypoplastic diaphragm and is neurotized by a nerve transfer from the phrenic nerve to the cut end of the transposed thoracodorsal nerve.53 In a series by Wallace and colleagues, there were no recurrences of diaphragmatic herniation, and three of five patients had physiologic neodiaphragmatic motion by 2 to 4 years of follow-up.54

A

B

DIAPHRAGM PLICATION For patients with phrenic nerve injury and resultant diaphragmatic paralysis, decreased FVC may require prolonged ventilatory support. To improve respiratory embarrassment and the elevated hemidiaphragm, the diaphragm can be flattened or plicated to restrict its paradoxical movements with respiration. Diaphragmatic plication is intended to decrease lung compression, stabilize the thoracic cage and mediastinum, and strengthen the respiratory action of intercostals and abdominal muscles. After plication, effective diaphragmatic recruitment occurs, leading to increased diaphragmatic strength and maximal voluntary ventilation. Studies have shown that all lung volumes are improved after plication,

Ch121-F06861.indd 1462

C

D

FIGURE 121-4 A and B, Circumferential plication technique. C and D, Central plication technique. Images above each cross-section show the location of the diaphragm before and after the procedure, respectively.

1/21/2008 3:59:31 PM

Chapter 121 Surgery of the Phrenic Nerve

candidates for direct nerve repair. Neurotization, or nerve transfer, is the only option to achieve elbow flexion for flail arms.63 These procedures involve taking normal nerves from less important functional sites and transferring them to reinnervate a more important function. With limited options for nerve transfers, the classification of “less important” sometimes must be extended to included “important but noncritical” nerves. Donor nerves that have been used include the spinal accessory nerve,64 intercostal nerve,65 and phrenic nerve.66,67 Although the spinal accessory and intercostal nerves seem more expendable than the phrenic nerve, there are many instances in which they are not available. The spinal accessory nerve is often used as the nerve transfer for the suprascapular nerve, to provide the critical movement of external rotation of the arm. In addition, with high-velocity injuries, rib fractures often prevent the use of intercostal nerves. This leaves the phrenic nerve as the only option short of a C7 nerve transfer from the contralateral arm.68 The mild deterioration of pulmonary function that occurs when the phrenic nerve is sacrificed may be less detrimental than the risk of downgrading function in the normal arm. Phrenic nerve transfers to the musculocutaneous nerve or the median nerve have produced good functional outcomes for motor function of the arm but have resulted in decreased pulmonary capacity at 1 year of follow-up.66,69 For this reason, use of the phrenic nerve is not recommended for infants, young children, or any patients with cardiopulmonary disease.

NERVE TRANSFERS AND PACING High nerve injuries that compromise the phrenic nerve in a manner that leads to axonal loss prevent the use of implanted diaphragmatic pacing devices. If a patient sustains an injury above the level of C3, the spinal cord anterior horn cell bodies are still intact and the phrenic nerve is still capable of

1463

transmitting electrical impulses. In such cases, electrophrenic respiration may be achieved by implanting a pacing device to elicit diaphragmatic contraction. Patients with long-term mechanical ventilation after spinal cord injuries above the level of C3 have achieved sufficient electrophrenic stimulation as to be freed from mechanical ventilation.70-72 However, patients with injuries involving the C3 to C5 levels do not have spinal cord anterior horn cell bodies, thus the phrenic nerve is unable to transmit electrical impulses due to the loss of axonotmetic signals and Wallerian degeneration with myelin degeneration. This can also occur if there is direct injury to the trunk of the nerve. In both cases, a pacing device will not work to stimulate diaphragmatic contraction. The nerve can no longer carry an electrical impulse. To re-establish electrical transmission through the phrenic nerve, a new source of axonometric input must be established. Nerve transfer is increasingly being used in the treatment of congenital and traumatic injuries to the brachial plexus and extremities. Early work done by Krieger and colleagues showed successful nerve transfer of segments of the brachial plexus to the phrenic nerve in cats.73 Recently, the same authors performed transfers of intercostals to the phrenic nerve in six human subjects who were ventilator dependent due to spinal cord injury at the C3 to C5 level. In this patient population, external stimulation of the phrenic nerve is unreliable in determining whether sufficient axons remain for diaphragmatic pacing. This requires flexibility in the intraoperative decision-making process. If the patient has no diaphragmatic muscle contraction with direct phrenic nerve stimulation at the time of surgery, then a nerve transfer is necessary to provide axonometric input. Simultaneously, the pacing device may be applied distal to the nerve transfer. The fourth intercostal nerve has been suggested as a good donor for nerve transfer to provide ample size and minimal tension (Fig. 121-5). Minimal dissection is needed to achieve

FIGURE 121-5 Surgical anatomy for transfer of intercostal nerves to the phrenic nerve.

4th rib Intercostal nerve (cut) Phrenic nerve (cut) 6th rib

Malleable ratractor folded and placed within thoracic cavity to retract lung and diaphragm.

Ch121-F06861.indd 1463

1/21/2008 3:59:32 PM

1464

Section 6 Diaphragm

transfer to the phrenic nerve 5 cm proximal to its insertion into the diaphragm (Krieger et al, 2000).74,75 All six patients in this study were able to tolerate diaphragmatic pacing as an alternative to ventilatory support. The average interval from surgery to diaphragm response was 9 months. We have used the lower rectus nerve as a donor because it provides a greater number of motor axons. Intercostal or rectus nerve transfers to phrenic nerve can be used to neurotize injured phrenic nerves and provide the axonometric input that allows pacing to return the diaphragm to independent contractile function. This method of treatment may also be used with other types of nerve injury, such as cold-induced injury or direct transection injury if the level of injury is not identifiable for direct repair.

TRANSPLANTATION OF THE DIAPHRAGM As described earlier, injury to the phrenic nerve can result in significant morbidity due to diaphragmatic dysfunction. Certain inherited neuromuscular disorders can also adversely affect diaphragmatic function. Duchenne muscular dystrophy (DMD) is the most common and severe of the human muscular dystrophies, affecting 1 in 3500 live male births. It is characterized by progressive skeletal muscle weakness and death occurring in the late teens to early twenties from respiratory complications secondary to diaphragmatic dysfunction.76 In the late stages of the disease, patients often require home mechanical ventilation. Histologically, DMD causes ongoing myofiber necrosis and regeneration, resulting ultimately in marked fibrosis and fatty infiltration of all limb and respiratory muscles. Since the discovery that the pathologic myofiber defect of DMD results from the absence of dystrophin, tremendous efforts have focused on the systemic replacement or substitution of this protein within skeletal muscle. However, there have been difficulties with methods of protein and gene delivery, immunologic rejection, and toxicity.77 Although myoblast transplantation has been advocated as a novel therapy for congenital myopathies, this therapeutic strategy is limited by the problem of cell dispersal, lack of functional engraftment, and electromechanical coupling.78 Since its introduction several decades ago, solid organ transplantation has had a wide impact as a successful therapy for end-organ failure. Improvements in immunosuppression have resulted in transplantation of not just traditional solid organs, such as the heart and lungs, but complex vascularized and innervated structures such as upper extremity limbs and laryngeal allografts.79,80 It is surprising that, despite the clinical need, no attempts at transplantation of respiratory musculature have been reported. It is even more surprising given that the diaphragm in children plays a critical role in ventilatory support, whereas the accessory muscles of respiration do so in adults. Isolated diaphragmatic paralysis caused by inadvertent phrenic nerve injury in children usually leads to ventilator dependence, whereas, in the adult, accessory muscles of respiration may provide enough support to alleviate the need for chronic mechanical ventilation (Fell, 1998).81,82 The large body of literature supporting phrenic nerve pacing as a method of establishing ventilator independence in patients with high cervical cord injury further emphasizes the impor-

Ch121-F06861.indd 1464

tance of the role of a functioning diaphragm in independence from mechanical ventilation.72,83,84 Based on the clinical need for diaphragmatic replacement therapy in DMD, the Divisions of Plastic and Cardiothoracic Surgery from the Department of Surgery of Washington University in St. Louis, Missouri, have initiated experimental efforts to evaluate the feasibility of diaphragmatic transplantation as a therapeutic strategy for palliation of DMD-induced respiratory failure. Our overall goal is to transplant a donor diaphragm as a muscular free flap to augment the native failing diaphragm.

Rodent Model A mouse model carrying a mutation similar to human DMD is available from a commercial source (Jackson Laboratories, Bar Harbor, ME), but the small size of the vascular pedicles limited successful transplantation of the diaphragm in our early experiments. Based on this limitation, we decided to pursue initial transplantation studies in the rat model. Because the phrenic arteries branch directly off the abdominal aorta and are reported to act as the main source of blood supply85 to the crural and costal diaphragm, along with collateral blood flow from with the musculophrenic artery supplied by the IMA and intercostal vessels, our initial efforts focused on diaphragmatic transplantation of an aortic arterial pedicle. Using inbred Lewis rats as both donor and recipient, we isolated the intra-abdominal aorta by sequentially ligating the arterial and venous blood supply to the visceral organs while leaving the phrenic arteries and veins intact. Starting with the left kidney, including the gonadal vessels; proceeding with splenectomy and removal of the small and large bowel; and ending with the right kidney and gonadal vessels provided the most consistent result, with a high rate of donor hemodynamic stability during the harvest procedure (Fig. 121-6). Careful attention was paid to preserving diaphragmatic venous drainage to the left kidney via the left adrenal vein. The lumbar vessels were then isolated in a similar fashion with three or four 6-0 silk ties and controlled by ligation distal to the ties along the vertebral column. The liver, which is in direct approximation to the inferior vena cava (IVC), cannot be completely separated from this vessel. In the initial experiments, a rather large cuff of liver parenchyma was retained around the vena cava, and hemostasis was achieved by cautery (Bovie High Temperature Cautery, Aaron Medical, St. Petersburg, FL). Eventually, near-complete removal of the liver was accomplished by ligation of the IVC above and below the liver, with only a small remnant of liver left attached to the infradiaphragmatic IVC. The animal was then systemically anticoagulated with 1000 U of heparin, killed by an overdose of pentobarbital, and perfused with cold heparinized saline. Because of the anatomic difficulty of transplanting the whole rodent diaphragm, it was decided, for the purpose of these initial experiments, to transplant only the left hemidiaphragm (Fig. 121-7). After multiple attempts, successful transplantation into an inbred rat recipient was accomplished with the use of dual venous drainage via an end-to-side anastomosis of the donor superior vena cava (SVC) to the recipient suprahepatic IVC and an end-to-side anastomosis of the

1/21/2008 3:59:33 PM

Chapter 121 Surgery of the Phrenic Nerve

Aorta

Mesenteric vessels

Right renal artery and vein

Inferior vena cava Left renal artery and vein

Lumbar vessels

FIGURE 121-6 Schematic diagram showing ligation of the donor vasculature in experimental transfer of the diaphragm in the rat model.

A

1465

donor IVC to the recipient IVC. Arterial inflow was provided by an end-to-side anastomosis of the donor aorta to the recipient aorta (Fig. 121-8). All vascular anastomoses were performed using 9-0 nylon suture. Reinnervation of the transplanted diaphragm was accomplished by anastomosing the donor and recipient phrenic nerves, using three interrupted 10-0 nylon epineural sutures through a separate left thoracotomy. The transplanted left hemidiaphragm was approximated to the native left hemidiaphragm with several interrupted sutures through the central tendon and costal muscle, as well as with BioGlue. Initial evaluation of blood flow within the transplanted graft was confirmed by visible perfusion of the transplanted diaphragm and distribution into the most distal aspects of the costal diaphragm of Evans Blue dye (Sigma Chemical Co., St. Louis, MO) injected intravenously into the recipient rat before closure. Short-term (12-hour) viability of the diaphragmatic graft was confirmed by visual inspection and histologic analysis. After 72 hours in situ, however, visible necrosis of the most distal aspects of the costal diaphragm was evident (Fig. 121-9), and perfusion was limited solely to the crural diaphragm, as evidence by Evans Blue dye injection. Quantitative analysis of graft blood supply using fluorescent microspheres (NuFlow Fluorescent Microspheres, Interactive Medical Technologies Ltd., Irvine, CA) revealed only 10% blood flow compared with the native left hemidiaphragm. We attempted to increase the blood supply to the costal diaphragm and re-establish flow in the musculophrenic artery by restoring continuity of the internal thoracic artery, using an end-to-end anastomosis of the native and donor

B

FIGURE 121-7 A representative donor rat diaphragm after preservation. A, The full diaphragm viewed from the thoracic side, with the superior vena cava (arrow) and phrenic nerve (arrowhead) marked by silk ties. B, The hemidiaphragm viewed from the abdominal side with the right hemidiaphragm removed. Only a small remnant of liver is left attached to the inferior vena cava (arrow). The aorta and the inferior vena cava of the main vascular pedicle (arrowhead) will be prepared for the anastomosis.

Ch121-F06861.indd 1465

1/21/2008 3:59:34 PM

1466

Section 6 Diaphragm

Donor superior vena cava Donor left hemidiaphragm Recipient inferior vena cava

Kidney

Donor aorta Recipient aorta

Donor inferior vena cava

A Recipient diaphragm

Donor diaphragm

Donor vascular pedicle IVC+aorta

C

B FIGURE 121-8 Revascularization of the donor hemidiaphragm in the rat is accomplished through three separate vascular anastomoses. A, First the donor superior vena cava is anastomosed to the recipient inferior vena cava (IVC), and then the donor IVC and aorta are anastomosed to the recipient IVC and aorta, respectively. B, At completion of the transplantation procedure, the donor hemidiaphragm is secured to the native recipient left hemidiaphragm with nylon suture and BioGlue. C, The viscera are returned to the abdominal cavity, and the laparotomy is closed in two layers. Before extubation, the chest is evacuated with a chest tube.

vessels. This was unsuccessful because of the small size of this vessel. We then focused on and were successful in improving collateral flow through transplantation of intercostal arteries along with part of the chest wall (Fig. 121-10). However, the recipient morbidity resulting from the large size of the graft made this approach impractical.

Ch121-F06861.indd 1466

Large Animal Model Despite the failure of the rodent model to serve as a longterm experimental tool for the study of diaphragmatic transplantation, we were able to define the key pitfalls and refine surgical techniques using this model. The canine model offers

1/21/2008 3:59:34 PM

Chapter 121 Surgery of the Phrenic Nerve

Patchy areas of necrosis

1467

transplantation will be performed in the canine model.86,87 We next plan to systematically evaluate regional blood supply, the contribution of collateral vascular channels to the overall blood supply, and the feasibility of diaphragm transplantation as a free flap in the canine model.

COMMENTS AND CONTROVERSIES

FIGURE 121-9 At 72 hours after hemidiaphragm transplantation in the rat, visible necrosis in the distal aspects of the costal diaphragm is evident.

Inadvertent injury to the phrenic nerve is a disastrous complication of any procedure performed in its vicinity. A direct injury such as operative transection or percutaneous laceration may not be immediately evident. Indirect injury (e.g., thermal, ischemic, pressure, traction) may be even more difficult to appreciate. However, the potential for phrenic nerve injury must be realized and considered in any intervention near its course in the neck or chest. This awareness, along with a thorough knowledge of the relevant anatomy, is the best defense against injury. First- and second-degree injuries may heal spontaneously. However, the potential for restoration of function in a permanently damaged nerve is small. Direct surgical corrections of phrenic nerve problems are uncommon and include direct repair and nerve transfer. Frequently, the only option is plication of the denervated diaphragm. Dr. Mackinnon presents an interesting theoretical solution to the problem of phrenic nerve or diaphragmatic dysfunction, endorgan transplantation. Although not yet ready for clinical application, her work on diaphragmatic transplantation is fascinating. T. W. R

KEY REFERENCES

FIGURE 121-10 In the rat model, a large diaphragmatic graft containing more collateral blood flow via the intercostal arteries could be transplanted in a similar fashion to the diaphragm alone. The recipient morbidity resulting from transplantation of such a large graft, which includes the rib cage, made this approach impractical.

several advantages over the rodent: the internal thoracic artery is larger, and other vessels supply collateral flow to the musculophrenic artery and costal margin. Because a homologue of DMD has been identified in a muscular dystrophic golden retriever dog, future experiments studying diaphragm

Ch121-F06861.indd 1467

Brown KA, Hoffstein V, Byrick RJ: Bedside diagnosis of bilateral diaphragmatic paralysis in a ventilator-dependent patient after openheart surgery. Anesth Analg 64:1208-1210, 1985. Canbaz S, Turgut N, Halici U, et al: Electrophysiological evaluation of phrenic nerve injury during cardiac surgery: A prospective, controlled, clinical study. BMC Surg 4:2, 2004. DeVita MA, Robinson LR, Rehder J, et al: Incidence and natural history of phrenic neuropathy occurring during open heart surgery. Chest 103:850-856, 1993. Diehl JL, Lofaso F, Deleuze P, et al: Clinically relevant diaphragmatic dysfunction after cardiac operations. J Thorac Cardiovasc Surg 107:487-498, 1994. Fell SC: Surgical anatomy of the diaphragm and the phrenic nerve. Chest Surg Clin N Am 8:281-294, 1998. Krieger LM, Krieger AJ: The intercostal to phrenic nerve transfer: An effective means of reanimating the diaphragm in patients with high cervical spine injury. Plast Reconstr Surg 105:1255-1261, 2000. Russell RI, Helps BA, Dicks-Mireaux CM, Helms PJ: Early assessment of diaphragmatic dysfunction in children in the ITU: Chest radiology and phrenic nerve stimulation. Eur Respir J 6:1336-1339, 1993. Simansky DA, Paley M, Refaely Y, Yellin A: Diaphragm plication following phrenic nerve injury: A comparison of paediatric and adult patients. Thorax 57:613-616, 2002. Sunderland S: A classification of peripheral nerve injuries producing loss of function. Brain 74:491-516, 1951.

1/21/2008 3:59:35 PM

Introduction chapter

122

ANATOMY OF THE MEDIASTINUM WITH SPECIAL REFERENCE TO SURGICAL ACCESS William H. Warren

Key Points ■ The anatomy of the mediastinum is presented in four compart-

ments. Allocation of a mass to predominantly one compartment influences the clinician in developing a differential diagnosis. ■ Limited surgical access procedures have been devised to obtain diagnostic tissue samples from each of the four mediastinal compartments. Occasionally, complete surgical resections can be performed using these limited access procedures.

This chapter describes the anatomy of the mediastinum with emphasis on issues of practical importance for the surgeon. It discusses the compartments of the mediastinum, as derived from clinical experience, which serve as a framework from which the clinician can develop a differential diagnosis for a given mediastinal mass. It also discusses various limited surgical approaches by which a surgeon can obtain access to the mediastinum, either to obtain diagnostic material or to drain potential mediastinal spaces.

the diaphragm through the esophageal hiatus, which is created by a complex arrangement of muscular slips known collectively as the crural sling. In contrast to the vascular structures, the esophagus can be easily encircled and dissected from the diaphragm in the posterior mediastinum. Indeed, the prevertebral fascial plane continues all the way to the neck as the retropharyngeal fascia. It is this anatomic plane that allows a surgeon to dissect out the esophagus with minimal disturbance of the surrounding mediastinal structures. Through the mediastinum run a portion of the gastrointestinal tract (the esophagus), the tracheobronchial tree (trachea and main stem bronchi), the heart and great vessels, and major portions of the lymphatic system (including tracheobronchial and periesophageal lymph nodes, the thoracic duct, and the thymus gland). The vagus and phrenic nerves also traverse the mediastinum. Each one of these systems is subject to major pathophysiologic disorders. Discussion of the wide array of cardiac and great vessel pathology is beyond the scope of this chapter, except to say that such conditions as a saccular aortic aneurysm or aneurysm of the pulmonary artery need to be considered when formulating the differential diagnosis of a mediastinal mass.

DEFINITIONS The mediastinum is bounded laterally by the pleural spaces. Anteriorly, it abuts the posterior wall of the sternum, and superiorly, the mediastinum reaches the thoracic inlet (also known as the thoracic outlet). The thoracic inlet is bounded by the spine, first ribs, and manubrium. As such, it is obliquely oriented, following the orientation of the first ribs. Superiorly, there is free communication between the mediastinum and the neck, with fascial planes descending in continuity from the neck (see later discussion). There is some controversy about the posterior border of the mediastinum. Anatomists hold to the notion that the posterior border is the anterior longitudinal ligament of the thoracic spine. Clinicians, however, have arbitrarily included the paraspinal sulci as part of the posterior mediastinum. Although the sympathetic chain and intercostal nerves are not strictly considered to be mediastinal structures, tumors deriving from these usually are. For example, a neurogenic tumor located in the paravertebral sulcus is considered by most surgeons to be a posterior mediastinal tumor. Unlike the superior aspect, the inferior aspect of the mediastinum is sharply demarcated by the diaphragm. The inferior vena cava runs through the vena caval foramen, and the aorta passes through the aortic hiatus. At both of these foramina, the diaphragm is adherent to these vascular structures and there is no free plane of dissection. The esophagus traverses

COMPARTMENTS OF THE MEDIASTINUM Given the complexity of structure in the mediastinum, it is understandable that radiologists and surgeons have proposed division of the mediastinum into compartments. The notion of compartments is of practical value whenever one is deriving a differential diagnosis for a given mediastinal mass (Table 122-1). However, it must be emphasized that tumors traditionally found in one compartment are not excluded from surrounding compartments. Thymic tumors are traditionally found in the anterior compartment but not infrequently can be found near the thoracic inlet (superior compartment), or even draped over the pericardium to appear in the middle of the mediastinum (middle compartment). Likewise, a lymphoma can be found anywhere in the mediastinum because lymph nodes are well described in all compartments, including the paravertebral sulci, although lymphoma is most commonly found in the anterior compartment. To compound issues further, several compartment models have been proposed, with no universal agreement on which nomenclature to adopt, and there is little if any anatomic basis for the boundaries between these compartments. Most surgical textbooks adhere to the division of the mediastinum into four compartments (Fig. 122-1). The superior compartment is that mediastinal territory above an imaginary 1471

Ch122-F06861.indd 1471

1/21/2008 4:00:33 PM

1472

Section 7 Mediastinum

TABLE 122-1 Typical Locations of Mediastinal Masses According to Compartment Superior Compartment

Anterior Compartment

Middle Compartment

Posterior Compartment

Retrosternal goiter

Thymoma

Bronchogenic cyst

Neurogenic tumor

Thymoma

Lymphoma

Mediastinal lymphadenopathy

Bony osteophyte

Thymic cyst

Germ cell tumor

Pericardial cyst

Esophageal duplication cyst

Thymic cyst

Saccular aneurysm

Esophageal leiomyoma

Superior

Anterior

Posterior Middle

The middle compartment is bounded anteriorly and posteriorly by the pericardium, and it contains the pericardium and its contents, the carina, and lymph nodes in the subcarinal region, in the tracheobronchial angles, and along the main stem bronchi. A differential diagnosis of lesions in this region includes bronchogenic cyst, paratracheal adenopathy, and pericardial cyst. The posterior mediastinal compartment extends from the posterior aspect of the pericardium to the anterior longitudinal ligament. It contains the esophagus, the descending aorta, the thoracic duct, and, in the paravertebral gutters, the sympathetic chain. Lesions of the posterior mediastinum include leiomyoma of the esophagus, esophageal duplication cyst, and paraesophageal hiatal hernia. Tumors of the paravertebral sulci are predominantly neurogenic tumors (neurofibroma, neurolemmoma), but lesions related to the spine (bony osteophyte, tuberculous abscess, posttraumatic hematoma) must also be considered.

Traditional Three-Compartment Model

FIGURE 122-1 Anatomic location of the four compartments of the mediastinum.

line drawn from the sternomanubrial junction (angle of Louis) to the inferior aspect of the fourth thoracic vertebra. This imaginary line traverses the carina and the aortic arch. It contains all of the structures running through the thoracic inlet (i.e., the upper third of the thoracic esophagus, the great vessels, the trachea, the superior vena cava, and the upper poles of the thymus gland), as well as the peritracheal and paratracheal lymph nodes. It is into this area that a thyroid mass, such as a retrosternal thyroid goiter, can descend. The anterior compartment is bounded anteriorly by the periosteum of the posterior wall of the sternal body (gladiolus) and posteriorly by the pericardium. In this space is found mediastinal fat and the body and lower poles of the thymus. Because germ cell tumors can arise within this region of the mediastinum, germ cell rests are assumed to be present, but they are seldom found in the non-neoplastic state. An aberrant parathyroid is occasionally found in the anterior mediastinum, sometimes imbedded within thymic tissue. The most common tumors in this region are thymoma, lymphoma, germ cell tumor, and parathyroid adenoma.

Ch122-F06861.indd 1472

This traditional three-compartment model is essentially a modification of the four-compartment scheme whereby the anterior and superior compartments are fused into one compartment. The justification for fusing these two compartments is that most of the masses in the superior mediastinum are located anterior to the trachea and have the same differential diagnosis as those in the anterior mediastinal compartment.

Shields’ Three-Zone Model In 1972, Shields suggested a different model whereby the mediastinum is divided into three zones, each extending from the thoracic inlet to the diaphragm.1 The most anterior compartment, called the prevascular zone, is located behind the posterior wall of the sternum and extends to the anterior pericardium and great vessels. The “visceral zone” extends from the anterior reflection of the pericardium to the anterior longitudinal ligament. Note that, in Shields’ model, the visceral zone would include a portion of the posterior compartment as defined by the other two models. Located in this visceral zone are the pericardium and its contents, the great vessels, the trachea and main stem bronchi, the esophagus, and the lymph nodes associated with them. The “retrovisceral zone” includes the paravertebral sulci, the intercostal arteries and veins, the proximal portion of the anterior ramus, the ramus communicans of the intercostal nerves, and the sympathetic trunk and its major branches, as well as lymphatic and connective tissues in this region.

1/21/2008 4:00:33 PM

Chapter 122 Anatomy of the Mediastinum With Special Reference to Surgical Access

SURGICAL MEDIASTINAL ANATOMY Major exposure for the resection of mediastinal masses (e.g., transcervical thymectomy, median sternotomy, thoracotomy, the “clamshell incision”) is beyond the scope of this chapter. Rather, the discussion focuses on limited surgical approaches that are useful in performing a tissue biopsy of a mediastinal mass or in draining mediastinal infections, taking advantage of cervicomediastinal fascial tissue planes. Early on, the clinical importance of these tissue planes was recognized by surgeons studying the pathways of oropharyngeal infections descending into the mediastinum (“descending mediastinitis”).

Limited Surgical Access to the Anterior Mediastinum There are no fascial planes in the anterior mediastinum as there are around the trachea, esophagus, and great vessels. Therefore, descending mediastinitis tends to favor involvement of the middle and posterior compartments over involvement of the anterior compartment. Hyperplastic thymic tissue can be resected via a transcervical incision, but this is not recommended for thymic masses.2 Although some have described cervical mediastinoscopy to biopsy anterior compartment lesions,3 it is generally believed that this procedure is technically difficult, and it has not been widely adopted. Large mediastinal masses and those masses being considered for preoperative or definitive chemotherapy and/or radiotherapy need to have a tissue diagnosis before treatment is commenced. Large mediastinal masses can be biopsied either percutaneously, by anterior mediastinotomy (Chamberlain procedure),4-6 or by video-assisted thoracoscopic surgery (VATS) (De Giacomo et al, 2000; Keleman and Naunheim, 2000; Solanini et al, 1998) (Fig. 122-2).7-9 Smaller tumors that are assessed to be completely resectable

A

1473

can be treated with excisional biopsy by either median sternotomy or VATS.

Limited Surgical Access to the Middle Mediastinum The surgeon must be familiar with limited surgical procedures to access middle mediastinal lesions. Although bronchogenic cysts can be drained using this route, the risk of reformation of the cyst is high unless the entire wall can be excised (which is difficult to accomplish using a limited transcervical approach). Cervical mediastinoscopy allows the surgeon to biopsy pretracheal, paratracheal, and anterior subcarinal nodes (levels 1-4 and anterior level 7) (Kirschner, 1996) (Fig. 122-3).10-12 Posterior subcarinal nodes (posterior level 7), nodes lateral to the arch, and the aortopulmonary window (levels 5 and 6) and paraesophageal nodes (levels 8 and 9) are not accessible by standard cervical mediastinoscopy. A modification of the cervical approach (extended cervical mediastinoscopy), has been used to provide exposure to nodes along the left carotid and subclavian arteries, as well as on the arch (level 6)13-15 (Fig. 122-4). However, there is limited surgical access to the nodes at the aortopulmonary window under the arch (level 5), which is approached by anterior mediastinotomy (Chamberlain procedure)4-6 or VATS (Mentzer et al, 1997) (Fig. 122-5).16-18 A limited surgical approach is also warranted to drain a pericardial effusion.19 Either a subxiphoid approach or VATS can be used to excise a button of pericardium and effect complete drainage. In my experience, the subxiphoid approach has the advantage over VATS in that it can be performed safely with the patient under local anesthesia, making the procedure simpler, faster, and safer. Reaccumulation of the fluid is very uncommon, and the risk of cardiac herniation is avoided.

B

FIGURE 122-2 A, Computed tomographic scan identifying a large, predominantly anterior mediastinal mass. Note that the tumor extends behind the superior vena cava (arrow) into the middle mediastinum. B, Limited approach to biopsy the anterior mediastinal mass, using an anterior mediastinotomy.

Ch122-F06861.indd 1473

1/21/2008 4:00:34 PM

1474

Section 7 Mediastinum

A

B

FIGURE 122-3 A, Computed tomographic scan illustrating mediastinal adenopathy of the right paratracheal nodes (arrow), level 2R and 4R. B, Cervical mediastinoscopy to biopsy paratracheal lymph nodes.

A

B

FIGURE 122-4 A, Computed tomographic scan illustrating a right upper lobe mass with a positron emission tomography (PET)-positive level 6 node (arrow) lateral to the aortic arch. B, Extended cervical mediastinoscopy to biopsy level 6 node.

Limited Surgical Access to the Posterior Mediastinum Limited surgical access is valuable to drain and occasionally to repair a perforation of the pharynx or cervical esophagus. Contamination in this area often descends into the posterior mediastinum from a tonsillar abscess or a pharyngeal or cervical perforation down the prevertebral fascial space (continuous with the buccopharyngeal fascia, retrovisceral space).20 Not infrequently, infections descend down the pretracheal or the prevascular fascial planes as well, limiting the role of cervical drainage alone.21 The prevertebral and periesophageal fascial planes also provide the surgeon a ready route by which

Ch122-F06861.indd 1474

to encircle the esophagus in the neck and facilitate dissection down to the level of the carina (Fig. 122-6). Likewise, the esophagus is encircled transabdominally immediately above the diaphragm, and the surgeon can dissect up to the carina without opening either pleural space. This plane of dissection is one of the principal anatomic factors facilitating transhiatal esophagectomy (Fig. 122-7).22 A discussion of limited approaches to the posterior mediastinum must include VATS. With this approach, the entire intrathoracic esophagus can be mobilized, a leiomyoma in the esophageal wall can be resected, an epiphrenic diverticulum can be resected, and a myotomy can be performed, avoiding the need for a thoracotomy.

1/21/2008 4:00:34 PM

Chapter 122 Anatomy of the Mediastinum With Special Reference to Surgical Access

A

1475

B

FIGURE 122-5 A, Computed tomographic scan demonstrating posterior subcarinal adenopathy (arrow) in a patient with a right lower lobe carcinoma. This node is not accessible via cervical mediastinoscopy. B, Video-assisted thoracoscopy to perform a biopsy of the posterior subcarinal nodes.

FIGURE 122-6 Mobilization of the cervical and upper thoracic esophagus with dissection of the prevertebral fascial plane.

Masses in the paravertebral gutters can be biopsied percutaneously. However, neurogenic tumors, the most common neoplasms found in this area, are characteristically firm, so that needle aspirates provide the pathologist with only scanty material. Tumors of the paravertebral gutter can be biopsied or completely resected using VATS as an alternative to a thoracotomy.

SUMMARY Knowledge of the anatomy of the mediastinum is of pivotal importance for the thoracic surgeon to formulate a differen-

Ch122-F06861.indd 1475

FIGURE 122-7 Mobilization of the lower thoracic esophagus using an abdominal approach.

tial diagnosis of a mediastinal mass. In addition, the thoracic surgeon must be able to assess surgical options and perform procedures (including those described as limited access procedures) to diagnose and treat infections and tumors of the mediastinum.

1/21/2008 4:00:35 PM

1476

Section 7 Mediastinum

COMMENTS AND CONTROVERSIES Thoracic surgeons must have a thorough knowledge of mediastinal anatomy and the various techniques available for surgical access. This chapter is an excellent review of mediastinal anatomy, describing the various classifications of the mediastinal compartments. The most useful of these are the three-compartment models (anterior, middle, and posterior) and Shields’ three-zone classification. The access techniques are all well described and illustrated. These will change as further refinements in video technology occur. The author did not describe the increasing use and effectiveness of transesophageal and transbronchial ultrasound-guided fine-needle aspiration biopsy. These techniques are familiar to thoracic surgeons. Many lesions in the mediastinum, including paratracheal, subcarinal, and paraesophageal lesions, can be easily accessed using these relatively noninvasive endoscopic techniques. G. A. P.

KEY REFERENCES De Giacomo T, Rendina EA, Venuta F, Coloni GF: Diagnostic thoracoscopy for mediastinal masses. In Yim APC, Zahelrigg SR, Izzat RT,

Ch122-F06861.indd 1476

et al (eds): Minimal Access Cardiothoracic Surgery. Philadelphia, WB Saunders, 2000, p 175. ■ This contribution is one of many excellent chapters in this text exploring the use of minimally invasive techniques applied to cardiothoracic surgery. Keleman JJ III, Naunheim KS: Minimally invasive approaches to mediastinal neoplasms. Semin Thorac Cardiovasc Surg 12:301, 2000. ■ An outstanding review with up-to-date references and illustrations outlining the various limited approaches to the mediastinum. Kirschner PA: Cervical mediastinoscopy. Chest Surg Clin N Am 6:1, 1996. ■ An excellent overview on the value of cervical mediastinoscopy. Mentzer SJ, Swanson SJ, Decamp MM, et al: Mediastinoscopy, thoracoscopy and video-assisted thoracic surgery in the diagnosis of lung cancer. Chest 112:239S, 1997. ■ A good review of the options for limited surgical procedures to evaluate mediastinal lesions. Solanini L, Bagioni P, Campanini A, et al: Diagnostic role of videothoracoscopy in mediastinal disease. Eur J Cardiothorac Surg 13:491, 1998. ■ A comprehensive paper reviewing of the use of VATS to obtain diagnostic tissue from mediastinal masses.

1/21/2008 4:00:35 PM

chapter

123

IMAGING OF THE MEDIASTINUM Carolina A. Souza Nestor L. Müller

Key Points ■ Contrast enhanced CT is the most important imaging modality in

the assessment of mediastinal masses. ■ MRI is superior to CT in the evaluation of tumor involvement of the

great vessels and spine and in differentiating vascular, solid, and cystic lesions. ■ FDG-PET imaging, particularly when combined with CT (PET-CT) imaging, is helpful in the staging of lymphoma and in the follow-up of patients with lymphoma and other malignant mediastinal tumors.

Imaging plays an important role in the detection and management of mediastinal disease. The various imaging modalities currently available provide excellent depiction of the mediastinum and its abnormalities. They have high sensitivity in the detection of mediastinal lesions and in determining their relationship to adjacent structures. Each of the various imaging modalities, however, has inherent limitations. The aim of this chapter is to review the characteristic imaging manifestations of the most common mediastinal abnormalities and to outline the role and limitations of imaging.

IMAGING MODALITIES The main imaging modalities used in the evaluation of mediastinal abnormalities are chest radiography, CT, MRI, and, more recently, PET. Mediastinal abnormalities are often first detected on chest radiography. However, because of its limited contrast resolution, the chest radiograph provides limited information about the specific nature of mediastinal abnormalities and their relationship to adjacent structures. Adequate imaging assessment requires CT and/or MRI. CT is indicated when a mediastinal lesion is identified on the chest radiograph or when there is clinical suspicion of such a lesion in a patient with a normal radiograph. The absence of superimposition of structures on CT allows a reliable evaluation of the mediastinal anatomy and the relationship of lesions with adjacent structures.1,2 CT is able to characterize water, fat, and calcium but has limitations in distinguishing various soft tissues. Iodinated intravenous (IV) contrast is an important adjuvant that is routinely indicated in the assessment of vascular abnormalities and in the differentiation of vascular and soft tissue masses (Fig. 123-1). IV contrast-enhanced CT also allows better delineation of

the exact extent of mediastinal tumors and is useful in the characterization of cystic lesions and in the depiction of mediastinal fluid collections.3,4 Spiral CT is currently the radiologic modality of choice in the study of the mediastinum.5-8 The rapid acquisition of the entire thorax during a single breath-hold minimizes motion artifacts and allows optimal vascular contrast enhancement.4,9 The level of detail of spiral CT angiography for pulmonary and systemic vessels is comparable to that of conventional angiography.5,10,11 High-quality multiplanar reformations and three-dimensional (3D) reconstructions can be obtained from the original data with no additional irradiation. These techniques are more accurate than cross-sectional images in the detection of airway stenosis, air leaks, fistulas, and postpneumonectomy syndrome.8,12-14 Early spiral CT scanners had a single row of detectors. Scanners with multiple detector rows were first introduced in the late 1990s. Multidetector spiral CT has several important advantages over single-row spiral CT, including larger anatomic coverage, higher spatial resolution, and more rapid data acquisition, thus markedly reducing the influence of cardiac and respiratory motion artifacts.11,15 MRI is more accurate than CT in assessing tumoral involvement of the great vessels, heart, and chest wall and in differentiating vascular, solid, and cystic lesions.11,16,17 In patients treated for lymphoma or carcinoma, MRI may be useful in distinguishing fibrous tissue from viable tumor in residual masses.18-20 MRI is the method of choice in the evaluation of paravertebral masses and their relationship to the spinal cord.21,22 MRI protocols are individualized according to the information required. As a rule, T1-weighted images are valuable in the anatomic assessment, whereas T1-weighted images after gadolinium administration and T2-weighted images are most valuable in tissue characterization.23,24 The main limitations of MRI compared with CT are inability to depict calcium, lower spatial resolution, and limited availability. Recently, PET using 2-(18F)fluoro-2-deoxy-D-glucose (FDG) has emerged as a valuable method in the evaluation of neoplasms. The increased FDG uptake by hypermetabolic tissues allows identification of tumoral tissue with sensitivity superior to that of CT or MRI. FDG-PET is more accurate in the diagnosis and staging of lung neoplasias and in the detection of viable tumor in residual masses. In addition, whole-body FDG-PET is helpful in the detection of distant metastases.25 It has been shown that FDG-PET scans can alter the management of patients with neoplasias and reduce the number of unnecessary invasive procedures.26,27 Fusion of FDG-PET with CT images (PET-CT) further increases 1477

Ch123-F06861.indd 1477

1/21/2008 4:01:25 PM

1478

Section 7 Mediastinum

NORMAL RADIOLOGIC ANATOMY OF THE MEDIASTINUM The mediastinum is traditionally divided into three compartments: anterior (prevascular), middle (cardiovascular), and posterior (postvascular).30 No fascial or anatomic planes separate the three compartments; this is a didactic approach that facilitates understanding of the normal mediastinum and categorizes abnormalities according to their location. CT and MRI studies are conventionally obtained in cross-section. Therefore, correct interpretation of CT or MR images requires a detailed knowledge of the normal mediastinal anatomy in the transverse plane.

M

Anterior Mediastinal Compartment A

Ao

B FIGURE 123-1 Mycotic aneurysm of ascending aorta. A, Nonenhanced CT scan in a 60-year-old man shows a 9-cm homogeneous anterior mediastinal mass (M) with attenuation (density) similar to that of chest wall muscles. The lesion is causing marked compression of the trachea (arrow). B, On contrast-enhanced CT, the mass is shown to be vascular, representing a mycotic aneurysm of the ascending aorta (Ao). The lumen of the aneurysm has irregular contours, and there is extensive thrombosis adjacent to the aortic wall (arrows). The patient presented with severe dyspnea and hemoptysis and had a previous diagnosis of infective endocarditis.

the accuracy by depicting more precisely the anatomic site of uptake and avoiding misinterpretation of normal hypermetabolic areas as disease.25,26 Conventional ultrasonography has limited value in the evaluation of the mediastinum and it is seldom performed. However, ultrasonography is excellent in differentiating cystic from solid lesions and may be useful in selected cases. Transcutaneous diagnostic or therapeutic procedures can be safely performed under ultrasound guidance. Transesophageal ultrasonography has emerged as a valuable method in the evaluation of esophageal lesions, including local staging of neoplasms and assessment of nodal involvement. In addition, it may guide fine-needle aspiration biopsy and may be used in the aspiration of cystic lesions.28,29

Ch123-F06861.indd 1478

The anterior mediastinum extends vertically from the anterior aspect of the thoracic inlet to the level of the diaphragm and is limited anteriorly by the sternum and posteriorly by the brachiocephalic vessels, aorta, and pericardium. The anterior compartment contains the thymus, internal mammary artery and vein, inferior sternopericardial ligament, lymph nodes, and variable amounts of fat (Fig. 123-2).30 The thymus is located in the superior portion of the anterior mediastinum, between the level of the left brachiocephalic vein and the base of the heart.31 The thymus has two lobes and is normally asymmetric, the left lobe usually being larger than the right. Considerable change in size, morphology, and density of the thymus occurs over the years, leading to different appearances on CT (Fig. 123-3). Awareness of the normal appearance of the thymus and its variability with age is important to prevent misdiagnosis.32-36 In children, the CT appearance of the normal thymus consists of a well-defined, homogeneous soft tissue structure outlined by mediastinal fat. The often larger left lobe extends laterally and lies adjacent to the aortic arch. Initially presenting a quadrilateral shape and convex margins, in older children the gland assumes a more triangular shape with straight margins. The CT density is approximately the same as that of muscle. Although distinction between thymic tissue and vessels is often possible on nonenhanced CT scans, IV contrast optimizes the visualization of the thymus, which typically shows homogeneous enhancement of 20 to 30 Hounsfield units (HU) (see Fig. 123-3A).32,37 On MRI, the normal thymus can be clearly distinguished from adjacent vascular structures, presenting a signal intensity slightly greater than muscle on T1-weighted images and greater than muscle and fat on T2-weighted images. The thymus reaches a maximum size in puberty, after which it involutes, gradually decreasing in size and being replaced by fat (see Fig. 123-3B).32,33,35,38 In young adults, because of fatty replacement, there is a decrease in the CT attenuation (density) of the thymus.38 After 25 years of age, the gland is no longer recognizable as a soft tissue structure, and its appearance is that of strands or wisps of soft tissue density within a background of fat. After complete involution, the retrosternal space is filled with fatty tissue that is slightly denser than subcutaneous fat (see Fig. 123-3C). This appearance represents the actual involuted thymus contained in a fibrous capsule.33-37 On MRI, the normal adult thymus has intermediate signal intensity on

1/21/2008 4:01:25 PM

Chapter 123 Imaging of the Mediastinum

1479

C

C

LBCV

BCV

BCA

CA

BCV

BCA

T

CA rBCV

SA e

SA

B

A

T SVC SVC

AAo

AA Az

TC DAo

C

D

FIGURE 123-2 Normal CT mediastinal anatomy. A, Immediately below the thoracic inlet, the mediastinum has a relatively small anteroposterior diameter. At this level, the brachiocephalic veins (BCV) are seen anteriorly and laterally immediately behind the clavicular heads (c). The large arterial branches of the aorta are seen as rounded structures around the trachea (T), representing from right to left the brachiocephalic (innominate) artery (BCA), the left common carotid artery (CA), and the left subclavian artery (SA). The esophagus (e) is seen as a round, soft tissue structure containing a small amount of air posterior to the trachea. B, At a more caudal level, the right brachiocephalic vein (rBCV) is again seen in its vertical course as a rounded structure posterior to the right sternoclavicular junction, whereas the left brachiocephalic vein (LBCV) crosses the mediastinum horizontally from left to right, anterior to the large aortic branches. At the same level, the BCA is seen in the midline in close proximity to the anterior tracheal wall. The left CA, the smallest of the three great branches, lies to the left and slightly posterolateral to the BCA. The left SA is seen to the left of the trachea. This vessel originates from the most superior aspect of the aortic arch. C, The aortic arch (AA) appears as an elongated structure crossing the mediastinum obliquely from right to left and from anterior to posterior. At this level, the superior vena cava (SVC) is identified lying anterior and to the right of the AA. In the anterior mediastinum, the thymus gland (T) is seen completely replaced by fat in this 51-year-old man. D, Image taken immediately below the AA shows the region of the aortopulmonary window. Volume averaging of the main pulmonary artery is seen (thick arrow), and there is a normal-sized lymph node (arrowhead). The ascending aorta (AAo) and descending aorta (DAo) are visible as separated, round structures in the middle mediastinum. At this level, the tracheal carina (TC) is identified, and the arch of the azygos vein (Az, narrow arrow) is seen draining into the posterior aspect of the SVC. Continued

Ch123-F06861.indd 1479

1/21/2008 4:01:26 PM

1480

Section 7 Mediastinum

PA SVC

AAo

PA SVC AAo

rPA LPA rMB

Az

DAo

LA

iPV

e LMB

AER

e Az

iPV DAo

E F FIGURE 123-2, cont’d E, At the level of the origin of the right and left main bronchi (rMB and LMB, respectively), the main pulmonary artery (PA) bifurcates into its right and left branches. The right pulmonary artery (rPA) arises at an angle of approximately 90 degrees and crosses the mediastinum to the right, between the AAo and the rMB. The left pulmonary artery (LPA) is seen as the posterolateral continuation of the main PA. It crosses to the left and arches over the LMB toward the left hilum. The SVC is located posterior and to the right of the AAo, and the vertical portion of the Az is seen as a round paravertebral structure to the right of the esophagus (e). F, At the level of the base of the heart, the main PA is the most anterior vascular structure. The AAo lies between the main PA and the SVC. The most posterior elongated structure is the left atrium (LA), demonstrated at the level of the confluence of the inferior pulmonary veins (iPV). The round, opacified structure located anterior and to the left of the thoracic spine represents the DAo. The esophagus (e) is seen as a flattened soft tissue structure immediately behind the LA and anterior to the Az. At this level the azygoesophageal recess (AER) is identified with its normal concave contour.

T1-weighted images, being less intense than mediastinal fat but more intense than muscle. With progressive fatty replacement, differentiation from the surrounding mediastinal fat becomes more difficult on T1-weighted images, and by about age 30 years, the distinction may not be possible. Regardless of age, the intensity of the thymus on T2-weighted images is similar to that of fat, making its visualization difficulton on MRI sequences.37,39 The most reliable assessment of thymus size is obtained on cross-sectional CT and MRI scans by measurement of the thickness of the gland (i.e., the dimension measured perpendicular to the longest axis of one lobe) (Fig. 123-4). The maximal normal thickness of the thymus is 1.8 cm in individuals younger than 20 years of age and 1.3 cm in those age 20 years or older.35,38 The most common cause of diffuse enlargement of the thymus is thymic hyperplasia. Thymic tumors usually result in a focal mass.35,40

Middle Mediastinal Compartment The middle mediastinum is defined as the space that contains the heart and pericardium, ascending and transverse portions of the aorta, great arterial branches of the aorta, main pulmonary arteries and veins, brachiocephalic veins, superior vena cava (SVC), inferior vena cava, trachea and main bronchi, phrenic nerves, cephalad portion of the vagus nerves, and lymph nodes (see Fig. 123-2).30

Ch123-F06861.indd 1480

The thoracic aorta is well demonstrated on CT and MRI from its origin in the heart to the level of the diaphragm (see Fig. 123-2C-F). On cross-sectional images, the ascending and descending aorta are seen as round, separated structures in the middle mediastinum (see Fig. 123-2D). The diameter of the ascending portion is normally 1 cm greater than that of the descending aorta. Any significant variation from this raises suspicion of aneurysm.41,42 The aortic arch, defined as the portion of the aorta between the origin of the brachiocephalic artery and the ligamentum arteriosum, is seen on transverse images as an elongated structure crossing the mediastinum obliquely from right to left and from anterior to posterior and gradually diminishing in diameter (see Fig. 123-2C). However, the appearance of the arch may vary depending on its curvature and orientation relative to the CT or MRI scan plane. The large arterial branches of the aorta are seen on transverse images as rounded structures posterior to the brachiocephalic veins. Although they are variable in size, reliable identification of each one of the branches is possible because of their relatively constant position (see Fig. 123-2B). The main pulmonary artery is the most anterior vascular structure arising from the heart; it is located just behind the sternum (see Fig. 123-2F) and bifurcates into its right and left branches at the level of the tracheal carina (see Fig. 123-2E). The main pulmonary artery normally measures less than 30 mm in diameter at this level; its diameter is slightly

1/21/2008 4:01:27 PM

Chapter 123 Imaging of the Mediastinum

1481

m

T T

A

B

T

C

FIGURE 123-3 CT appearance of the normal thymus according to age. A, In a 20-yearold man, the thymus (T) is seen as a well-defined, homogeneous anterior mediastinal structure with density similar to that of the chest wall muscles (m). B, In a 25-year-old man, the thymus has an inhomogeneous appearance, with areas of soft tissue attenuation intermixed with areas of fat attenuation. C, In a 51-year-old man, the thymic tissue has been completely replaced, and the retrosternal space is filled with fatty tissue.

smaller than that of the ascending aorta at the same level.43,44 Increased diameter is seen in patients with pulmonary arterial hypertension and in patients with increased pulmonary arterial blood flow due to left-to-right shunts.43 The aortopulmonary window is defined as the anatomic region immediately below the aortic arch and above the main pulmonary artery, limited medially by the ligament of the ductus arteriosus and laterally by the mediastinal and visceral pleura over the left lung (see Fig. 123-2D).45 It contains lymph nodes, fat, the left recurrent laryngeal nerve, and the ligamentum arteriosum. In patients in whom the main pul-

Ch123-F06861.indd 1481

monary artery lies immediately below the aortic arch, the aortopulmonary window is poorly demonstrated, and distinctions between lymph nodes and volume averaging may be difficult. In these cases, CT performed with thin sections (1-3 mm collimation) and IV contrast administration is helpful. At the level of the aortopulmonary window, an oval or crescentic structure with water attenuation may be identified immediately behind the proximal ascending aorta and represents the superior pericardial recess (Fig. 123-5). The typical location, contacting the posterior aortic wall, and the charac-

1/21/2008 4:01:28 PM

1482

Section 7 Mediastinum

X

T

Y

layering of the contrast within the SVC lumen is common and must not be misinterpreted as thrombus.48 Reliable CT signs of SVC thrombosis include enlargement of the vein, relatively lucent lumen, and enhancement of the wall on contrast-enhanced studies. On cross-sectional CT and MRI, the azygos vein can be seen as an arch as it courses from the paravertebral region to enter the SVC immediately above the level of the origin of the right main bronchus (see Fig. 123-2D).

Posterior Mediastinal Compartment

FIGURE 123-4 Measurement of the thymus on transverse CT. The thymus is divided by a line (X-Y) through the anterior apex of the gland. The thickness (T) of each lobe is then measured.

AAo

PA

FIGURE 123-5 Superior pericardial recess. Nonenhanced CT scan at the level of the aortopulmonary window shows an oval structure (arrow) with water attenuation (3 HU) immediately behind the proximal ascending aorta (AAo). The typical location and attenuation allow differentiation from mediastinal lymph node. PA, pulmonary artery.

teristic low attenuation allow this structure to be differentiated from paratracheal lymphadenopathy.46,47 The SVC is well demonstrated on axial images from its origin at the confluence of the brachiocephalic veins to the level of the right atrium (see Fig. 123-2). It typically has an elliptical shape and is located to the right and posterior to the ascending aorta. On enhanced CT scans, streaming or

Ch123-F06861.indd 1482

The posterior mediastinal compartment is delimited anteriorly by the heart and trachea, laterally by the mediastinal pleura, and posteriorly by the vertebrae. Its contents include the descending thoracic aorta, esophagus, azygos and hemiazygos veins, thoracic duct, autonomic nerves, lymph nodes, and variable amounts of fat (see Fig. 123-2).30 The descending aorta is seen on cross-sectional images as a round or oval structure located anterior to the thoracic spine, usually slightly to the left of the vertebral bodies. The position of the aorta in relation to the midline varies depending on the presence of tortuosity or ectasia. The azygos and hemiazygos veins and their branches are responsible for the drainage of the intercostals veins, lumbar veins, and systemic veins and serve as important collateral pathways when there is obstruction of the brachiocephalic veins or SVC. The azygos vein courses along the right aspect of the spine to join the SVC at the level of the tracheal carina. The vertical portion of the azygos vein is normally demonstrated on cross-sectional images as a round structure anterior and slightly lateral to the thoracic spine.49 The vein forms an arch and crosses anteriorly to join the posterior aspect of the SVC (see Fig. 123-2D-F). Immediately below the arch, the azygos is joined by the right superior intercostal vein. On the left side, the hemiazygos vein is seen parallel and posterior to the descending aorta, adjacent to the spine. It is smaller than the azygos vein and is less commonly seen on CT. The hemiazygos vein terminates in the azygos vein through communicating branches that cross the midline behind the descending aorta, usually at the level of the eighth thoracic vertebral body.50,51 The accessory hemiazygos vein extends cephalad above the level of the hemiazygos. At the level of the aortic arch, it is joined by the left superior intercostal vein, a vessel that is commonly visible on CT as it courses from the anterior to the posterior mediastinum immediately to the left of the aortic arch. The left superior intercostal vein provides an anastomotic channel between the left brachiocephalic vein and the azygos veins. It is seen on frontal plain radiographs in approximately 10% of normal individuals as a focal, 2- to 3-mm, rounded density immediately lateral to the aortic arch, known as the aortic nipple. Enlargement of this vein (“prominent aortic nipple”) is commonly seen in patients with SVC obstruction. The esophagus appears on cross-sectional images as a prevertebral, flattened or round, soft tissue structure. Frequently, a small amount of air is seen within the esophageal lumen. The esophagus is usually anterior and to the left of the ascending portion of the azygos vein (see Fig. 123-2). The

1/21/2008 4:01:28 PM

Chapter 123 Imaging of the Mediastinum

1483

esophagus and azygos vein abut the right lower lobe; the point of contact between these structures is known as the azygoesophageal recess (see Fig. 123-2F). Recognition of the normal appearance of the azygoesophageal recess on chest radiography is important because of its close relationship with structures of the posterior mediastinum. Characteristically, its contour is concave laterally; a convexity in this region needs to raise concern for abnormalities of the esophagus or the azygos vein or lymphadenopathy. Rarely, a normal convex contour is observed, especially in children and in patients with a narrow mediastinum, as a result of a normally prominent esophagus or azygos vein.52

Mediastinal Lymph Nodes Although all three mediastinal compartments contain lymph nodes, nodes are most numerous in the middle mediastinum. Tracheobronchial nodes comprise almost 80% of all intrathoracic nodes. They are responsible for the drainage of the lungs (except for the left upper lobe) and may be classified according to their location into paratracheal (situated anterior to the trachea), retrotracheal, subcarinal, peribronchial (close to the right and left main bronchi), and azygos nodes (medial to the azygos vein). Nodes located in the aortopulmonary window drain the left upper lobe and freely communicate with other nodal stations of the middle mediastinum, mainly the paratracheal nodes.53,54 Prevascular nodes, located anterior to the aorta, drain the majority of the anterior mediastinal structures. The internal mammary lymph nodes lie adjacent to the internal mammary vessels and freely communicate with the prevascular nodes. They drain the anterior chest wall, the anterior diaphragm, and medial portions of the breasts. Diaphragmatic, paracardiac, and cardiophrenic angle nodes lie anterior to or lateral to the heart and pericardium, on the surface of the diaphragm, and are responsible for drainage of the pericardium, lower intercostal spaces, diaphragm, and liver. Normal internal mammary nodes and cardiophrenic angle nodes are seldom visible on CT. Enlargement is most commonly seen in lymphoma and metastatic carcinoma, mainly from breast.55 The most important nodal stations in the posterior mediastinum are located adjacent to the esophagus and descending aorta and medial to the inferior pulmonary ligament. They are responsible for drainage of the medial portions of the lower lobes, pericardium, esophagus, and posterior diaphragm. In the right side, distinction between these nodes and subcarinal nodes is difficult.53 Posterior to the diaphragmatic crura lie the retrocrural lymph nodes, which drain structures of the posterior mediastinum as well as the diaphragm and the liver.30 Normal lymph nodes are demonstrated on CT studies as round or elliptical soft tissue structures surrounded by mediastinal fat (Fig. 123-6). The size of normal nodes is variable. It has been shown that, in cross-sectional images, measurement of the short axis (smallest diameter of the node) is more reliable than measurement of the long axis.56 Mediastinal lymph nodes are considered normal in size if their short axis diameter is 10 mm or less. This rules applies to all mediastinal nodes except subcarinal nodes, which are considered

Ch123-F06861.indd 1483

A

B FIGURE 123-6 Normal middle mediastinal lymph nodes. Nonenhanced CT scans at the level of the aortic arch (A) and aortopulmonary window (B) show well-defined, elliptical soft tissue structures in the prevascular space (straight arrow) and in the right (arrowhead) and left (curved arrow) paratracheal regions, all measuring less than 10 mm in the short axis.

normal up to 12 mm in diameter.56-58 Although CT accurately determines the size and morphology of mediastinal nodes, the capability of tissue characterization is limited.55 The accuracy of MRI in identifying mediastinal lymphadenopathy is comparable to that of CT (Boiselle et al, 1998).55,59 One significant limitation of MRI is the difficulty in detecting

1/21/2008 4:01:29 PM

1484

Section 7 Mediastinum

foci of calcification. Similar to CT, MRI is of limited value in distinguishing neoplastic nodal enlargement from benign nodal hyperplasia.60 It has been suggested that MRI after IV injection of superparamagnetic iron oxide (ferumoxtran-10) may be useful in nodal characterization in patients with cancer.59,61 However, further studies are required to determine the accuracy and cost-effectiveness of this technique. The accuracy of CT and MRI in staging nodal involvement in cancer is low because both modalities assess only nodal size. The reported sensitivity of CT and MRI is 70% to 90%; the specificity is 60% to 90%; and the accuracy is 66% to 90% in the assessment of mediastinal nodal metastases from lung cancer.62,63 Normal-sized nodes may contain tumor, and enlarged nodes may be hyperplastic. Therefore, histologic confirmation is required. CT can be helpful in determining the most appropriate approach for nodal sampling.55,59,62,63 Recently, FDG-PET has emerged as an important method in the evaluation of mediastinal nodes in patients with cancer because it has a higher diagnostic accuracy than CT (Luketich et al, 2001).26,59,63,64 Further gain in accuracy may be obtained by associating FDG-PET to CT scans. This dual modality (PET-CT) is currently the most accurate noninvasive method for mediastinal nodal staging in patients with non–small cell lung carcinoma.26

MEDIASTINAL MASSES Masses Primarily Found in the Anterior Mediastinal Compartment Thymic Neoplasms Thymoma. Thymoma is the most common primary tumor of the anterior mediastinum, accounting for about 15% of all primary mediastinal masses. Thymoma usually affects patients older than 50 years of age and has no gender predilection. Thymomas are classified into noninvasive and invasive types, the latter accounting for approximately 30% of cases. Thymomas can range from 1 to 34 cm in diameter, with most measuring between 5 and 10 cm. Large lesions can be seen on chest radiography, but CT or MRI is required to demonstrate small lesions and to assess the relationship of thymoma to adjacent structures.65,66 CT scans typically demonstrate a well-defined, rounded or lobulated soft tissue mass involving one of the thymic lobes and projecting to one side of the anterior mediastinum (Strollo et al, 1997) (Fig. 123-7).66,67 Most thymomas have homogeneous soft tissue attenuation and enhance homogeneously after IV contrast administration. Focal areas of calcification and areas of low attenuation secondary to hemorrhage, necrosis, or cyst formation may be present, particularly in larger tumors.65-68 On MRI, thymomas have intermediate to low signal intensity (similar to or greater than that of skeletal muscle) on T1-weighted images and increased signal intensity (similar to that of fat) on T2-weighted images. They may have homogeneous or inhomogeneous signal intensity. Lobules and septations of relatively low intensity may occasionally be demonstrated within the tumor.66,69 Cystic areas with high fluid content and areas of hemorrhage characteristically have low signal intensity on T1-weighted images and high signal

Ch123-F06861.indd 1484

T

AAo PA

FIGURE 123-7 Thymoma. Transverse contrast-enhanced CT scan in a 33-year-old woman shows a 12-cm, well-circumscribed soft tissue mass occupying the anterior mediastinum (T) and causing posterior displacement of the adjacent structures. The diagnosis of thymoma was confirmed at surgery. AAo, ascending aorta; PA, pulmonary artery.

intensity on T2-weighted images. The fibrous capsule has low signal intensity on all sequences. Although typically located just anterior to the aortic root and main pulmonary artery, thymomas can occur at any point from the neck to the cardiophrenic sulcus, reflecting the embryologic origin of the thymus gland.66,70 Cervical masses arising from incompletely descended thymus may be correctly diagnosed when a connection with the anterior mediastinum is demonstrated or when the attenuation value on CT or signal intensity on MRI is seen to be similar to that of the normal thymus.71 Regardless of size, some thymomas invade their fibrous capsule, extend into mediastinal fat, and invade adjacent structures, including the great vessels, SVC, airways, lung, and/or chest wall. Contiguous spread along the pleura may also occur, potentially involving the diaphragmatic surface and extending into the abdomen.70,72,73 CT is of limited value in distinguishing invasive from noninvasive thymoma. Although preservation of fat planes around the tumor is most suggestive of noninvasive thymoma, subtle invasion cannot be excluded (Fig. 123-8). On the other hand, absence of cleavage planes with adjacent mediastinal structures is not reliable for the diagnosis of invasion because obliteration of fat planes has been described in noninvasive tumors.66,67,74 Nevertheless, certain CT findings are highly suggestive of tumor invasion, including complete obliteration of fat planes,40 encasement of mediastinal vessels, irregular interface with the adjacent lung, and pleural and pericardial thickening.66,74,75 MRI is also of limited value in distinguishing between invasive and noninvasive tumors. Although a multinodular appearance with low-signal-intensity septations on T2-weighted images has been considered suggestive of invasive thymoma, these findings are nonspecific and may also be seen in noninvasive tumors.69 However, MRI is superior to CT in the assessment of invasion of vascular structures. Thymoma metastases to the pleura (“drop metastases”) result in ipsilateral focal or diffuse pleural thickening (Fig. 123-9). Pleural involvement may progress to circumferential

1/21/2008 4:01:30 PM

Chapter 123 Imaging of the Mediastinum

1485

M

A FIGURE 123-8 Invasive thymoma. Nonenhanced CT scan in a 65year-old man shows a 3-cm, lobulated soft tissue mass in the anterior mediastinum (arrow). Foci of calcification and a small focal area of low attenuation are noted within the mass. Despite the small size of the tumor and the absence of definite obliteration of adjacent fat planes, invasive thymoma was demonstrated at surgery.

encasement of the lung, mimicking the appearance of malignant mesothelioma.73,76 Even with extensive pleural involvement, pleural effusions are uncommon.67,70 Extension into the posterior mediastinum, retrocrural space, and retroperitoneum is well demonstrated on CT.70,73 CT scanning for the evaluation of thymoma includes the upper abdomen to rule out transdiaphragmatic extension. Distant metastases, usually to the lungs and lymph nodes, are rare. Occasionally, CT demonstrates enlarged mediastinal, supraclavicular, and cervical lymph nodes.67,72 Thymic Carcinoma. Thymic carcinomas comprise a heterogeneous group of aggressive epithelial malignancies characterized by early local invasion and widespread metastases. The most common histologic type is squamous cell carcinoma. Most patients are men, with a mean age of 46 years.67,77 The prognosis is poor. On CT, thymic carcinoma typically manifests as a large anterior mediastinal mass with lobulated or poorly defined margins. These lesions may have homogeneous or heterogeneous soft tissue attenuation, depending on the presence of necrosis; foci of calcification are seen in 10% to 40% of cases (Fig. 123-10).67,75,77 MRI demonstrates a mass with signal intensity higher than muscle on T1-weighted images and increased signal intensity on T2-weighted images. Heterogeneous signal reflects the presence of necrosis, hemorrhage, or cystic degeneration. Low-intensity internal septations are seen less commonly than in thymoma.78 Obliteration of adjacent fat planes and evidence of invasion of the pericardium and pleura are seen in most cases on CT and MRI. Invasion of mediastinal vessels, phrenic nerve palsy, and lymph node and distant metastases are much more common in patients with thymic carcinoma than in those with invasive thymoma. Mediastinal lymphadenopathy is

Ch123-F06861.indd 1485

B FIGURE 123-9 Thymoma with pleural seeding. Contrast-enhanced CT scan in a 65-year-old man (A) shows an inhomogeneous anterior mediastinal mass with areas of low attenuation and foci of calcification (M). Left-sided nodular pleural thickening (arrows) and pleural effusion are noted at this level and also on an image taken immediately above the diaphragm (B). The diagnosis of invasive thymoma with left pleural involvement (“drop metastases”) was confirmed at surgery.

seen in approximately 40% of cases, and pleural effusion is common. Distant metastases, most frequently to lung, liver, and brain, are present at diagnosis in 50% to 65% of patients with thymic carcinoma, compared with only 5% of patients with invasive thymoma.75,79 Thymic Carcinoid (Thymic Neuroendocrine Neoplasms). Thymic carcinoid is the most common of the thymic neuroendocrine neoplasms, a group of rare lesions arising from neuroendocrine cells normally present in the thymus. Thymic carcinoids may be well differentiated with benign behavior or, more commonly, poorly differentiated and associated with local invasion and distant metastases. Carcinoids arising in the thymus have a worse prognosis than those arising in bronchi.80 Thymic carcinoid tumors most commonly affect men in their fourth or fifth decade of life. Patients may present with signs and symptoms related to compression or invasion of mediastinal structures or with

1/21/2008 4:01:30 PM

1486

Section 7 Mediastinum

M

FIGURE 123-10 Thymic carcinoma. CT scan after IV contrast administration in a 41-year-old woman shows a 6.5-cm, inhomogeneous enhancing mass with focal areas of low attenuation (M). There is obliteration of adjacent fat planes and narrowing of the superior vena cava (arrow). The diagnosis of thymic carcinoma was obtained at surgery.

A paraneoplastic manifestations, most commonly Cushing’s syndrome.81,82 One third of patients are asymptomatic.80 On CT, thymic carcinoids appear as large, lobulated anterior mediastinal masses, usually heterogeneous in attenuation as a result of hemorrhage or necrosis; homogeneous attenuation has been described in some cases (Fig. 123-11). Their appearance on CT and MRI is similar to that of thymomas. The size may vary from 1 to 25 cm in diameter; functional tumors tend to be smaller because of earlier diagnosis. Punctate or dystrophic calcifications and contrast enhancement may be present. CT evidence of invasion of adjacent mediastinal structures and metastases to lymph nodes and lung are common. Skeletal metastases also occur and are typically osteoblastic.81,83-85 Thymolipoma. Thymolipoma is a rare, slow-growing, benign tumor composed of mature adipose cells and thymic tissue. Although it can be seen at any age, it occurs most commonly in children and young adults.86 Thymolipomas may arise within the thymus or be connected to the gland by a pedicle. Characteristically, they become very large and cause minimal symptoms.67 Although invasion of surrounding structures does not occur, some degree of compression of mediastinal structures is visible in half of the cases.86 The characteristic radiographic appearance consists of a large anterior mediastinal mass that droops into the inferior chest, occupying one or both hemithoraces, typically conforming to adjacent structures (Fig. 123-12A, B). In some cases, the tumor extends inferiorly to the cardiophrenic sulci, simulating cardiomegaly on the frontal radiograph or diaphragmatic elevation on the lateral view. Chest radiography may demonstrate change of shape or position of the mass after changes in decubitus.67,86-88 Only when they are small in size are thymolipomas seen in the expected location of the thymus. In these cases, distinction from other benign lesions of the anterior mediastinum usually is not possible with conventional radiography.86 CT and MRI scans demonstrate the classic combination of fat and soft tissue and may depict the connection between

Ch123-F06861.indd 1486

M

B FIGURE 123-11 Thymic carcinoid tumor. A, Posteroanterior chest radiograph in a 38-year-old man shows a large, lobulated anterior mediastinal mass projecting into the right hemithorax (arrows). The right hemidiaphragm is elevated, suggesting the presence of phrenic nerve involvement. B, Contrast-enhanced CT scan of the same patient shows a 10-cm, lobulated soft tissue mass (M). Note the compression of the superior vena cava (arrow) and the displacement of the mediastinal structures to the left. At surgical biopsy, this proved to be a thymic carcinoid tumor.

the mass and the anatomic region of the thymus, features that strongly suggest the diagnosis. The tumor may manifest with similar amounts of fat and soft tissue or, less commonly, with predominant fatty tissue, resembling a mediastinal lipoma. On CT scanning, areas of soft tissue attenuation are typically seen as linear whorls intermixed with fat or, less frequently, as small, rounded opacities embedded within the fat component (see Fig. 123-12C).87,88 On MRI, the fat is demonstrated as areas of high signal intensity on spinecho T1-weighted images, similar in intensity to subcutaneous fat, intermixed with areas of intermediate signal intensity, reflecting the presence of the soft tissue component.89

1/21/2008 4:01:31 PM

Chapter 123 Imaging of the Mediastinum

1487

A

B M

C

Thymolipomas must be differentiated from other fat-containing masses of the mediastinum, including lipoma and liposarcoma, mediastinal lipomatosis, and mature teratoma.67,86 The characteristic manifestations of thymolipomas on radiography and CT allow a correct diagnosis in most cases. Thymic Cyst. Thymic cysts are rare, accounting for fewer than 3% of all anterior mediastinal masses.17,67,90 They may be congenital or acquired. Congenital cysts are usually incidentally discovered in the first two decades of life and are typically small (<6 cm in diameter), uniloculated or multiloculated, thin-walled lesions. Acquired thymic cysts may occur after radiation therapy for Hodgkin’s disease, in association with neoplasms such as seminoma or thymic carcinoma,91 and after thoracic surgery.17,92 Acquired cysts occur most commonly in adult men and tend to be larger (range, 3-17 cm), multiloculated, and with walls of variable thickness.67,91 Cysts that develop after irradiation or chemotherapy

Ch123-F06861.indd 1487

FIGURE 123-12 Thymolipoma. A, Posteroanterior chest radiograph in a 63-year-old woman shows obliteration of the lower half of the left hemithorax by a large mass (arrows). There is no apparent deviation of the mediastinal structures. B, On the lateral view, the mass is shown to extend to the posterior aspect of the right hemithorax (arrows). C, Contrast-enhanced CT scan shows a large mass with predominant fat attenuation (M) containing linear whorls of soft tissue density (arrow). There is a small left-sided pleural effusion. Incidental note is made of the presence of extensive aortic and mitral anular calcification.

usually have a more prominent soft tissue component.65 Large, multiloculated thymic cysts have been described in children with human immunodeficiency virus (HIV) infection.17 On CT, thymic cysts typically appear as a smoothly marginated, homogeneous mass of water density (0-20 HU) (Fig. 123-13). Multilocular cysts are heterogeneous in attenuation. High-density cysts may be the result of internal hemorrhage or infection, and areas of low attenuation occur in association with lipid deposits within the cyst. Occasionally, internal septations and foci of curvilinear wall calcification are noted, presumably secondary to previous hemorrhage.17,65 Noncomplicated thymic cysts manifest on MRI with the characteristic features of cystic lesions, with low signal intensity on T1weighted images and high signal intensity on T2-weighted images (Fig. 123-14). Hemorrhage or infection results in increased signal on T1- and T2-weighted images.17,39,65 Distinction of thymic cysts from cystic thymic tumors usually is

1/21/2008 4:01:32 PM

1488

Section 7 Mediastinum

T

FIGURE 123-13 Thymic cyst. CT scan without IV contrast in a 68year-old man shows a smoothly marginated, homogeneous mass (T) with imperceptible walls. Measurement of attenuation values demonstrated 5 HU, confirming its cystic nature. The lesion was resected and proved to be a thymic cyst.

M

A

B FIGURE 123-14 Thymic cyst. A, Axial T1-weighted (TR/TE 640/20) spin-echo MRI in a 47-year-old woman shows a well-defined anterior mediastinal mass (M) with signal intensity similar to that of the chest wall muscle. B, Axial T2-weighted (TR/TE 2580/90) spin-echo image shows homogeneous high signal intensity, characteristic of cyst. The diagnosis of thymic cyst was confirmed at surgery.

Ch123-F06861.indd 1488

readily made based on their lack of enhancement after IV administration of contrast on CT and their homogeneous high intensity on T2-weighted MRI scans. Thymic Hyperplasia and Thymic Lymphoid Hyperplasia. Thymic hyperplasia is defined as an increase in size and weight of the thymus gland associated with a normal histologic appearance, whereas thymic lymphoid hyperplasia describes a distinctive histologic pattern seen in patients who have myasthenia gravis.93-97 Although imaging studies are of limited value in distinguishing thymic hyperplasia and from lymphoid hyperplasia, these two entities may be correctly diagnosed when the imaging findings are interpreted in the proper clinical context. Thymic hyperplasia usually is the result of a rebound hyperplasia after atrophy. Atrophy occurs during periods of stress and in patients receiving corticosteroids; the degree of involution depends on the severity and duration of the stress and the patient’s age. Although rebound hyperplasia is most commonly seen in children, it may occur in adults. It is most commonly seen after chemotherapy for lymphoma or germ cell tumors.95,98 Chest radiography is usually normal; CT has higher sensitivity and demonstrates an enlarged thymus with preservation of its characteristic shape and density.95 In patients with extrathoracic neoplasms, rebound hyperplasia seldom causes concern or diagnostic confusion. However, it can be a problem in patients with treated lymphoma, in whom differentiation between recurrent disease and benign hyperplasia is essential. A more detailed discussion on this topic is given in the section on primary mediastinal lymphoma. Similar to thymic hyperplasia, lymphoid thymic hyperplasia seldom causes radiographic abnormalities. The usefulness of CT in the diagnosis of this entity is limited. Because the weight of the thymus is usually within normal limits, no abnormalities are seen on CT scans in approximately 30% to 50% of cases.95 In the remaining patients, CT demonstrates an enlarged thymus, usually normal in shape and attenuation; less commonly, the gland has a nodular appearance, a focal mass, or inhomogeneous attenuation.94-97 Similar to CT, MRI is of limited value in the diagnosis of thymic hyperplasia. The signal intensity in rebound hyperplasia and in lymphoid hyperplasia is similar to that of the normal gland.65 Mediastinal Germ Cell Tumors. Germ cell tumors comprise a heterogeneous group of benign and malignant neoplasms originating from primitive germ cells. Various histologic types are recognized, including mature (benign) and malignant teratoma, seminoma, endodermal sinus tumor, embryonal carcinoma, choriocarcinoma, and mixed types. Approximately 80% of all germ cell tumors are benign, the majority being mature teratomas. More than 90% of malignant tumors occur in men. Germ cell tumors usually affect young adults between 20 to 40 years of age.99,100 The anterior mediastinum is the second most common site of primary germ cell tumors, after the gonads. Those occurring in the mediastinum are histologically identical to their gonadal counterparts. To confirm its primary origin, when a malignant germ cell neoplasm is diagnosed within the mediastinum, a gonadal or retroperitoneal tumor must be excluded.99,100

1/21/2008 4:01:34 PM

Chapter 123 Imaging of the Mediastinum

TERATOMA. Mature teratoma is the most common mediastinal germ cell tumor. It is characterized by the presence of well-differentiated tissues derived from the three primitive germ cell layers (Rosado de Christenson et al, 1992).99,101,102 The combination of different types of tissue leads to the characteristic appearance on imaging studies, allowing distinction from other mediastinal masses such as thymoma and lymphoma. Although the vast majority of teratomas are located in the anterior mediastinum, they may also occur in the middle and posterior compartments, or they may involve multiple compartments in up to 20% of cases. Most teratomas are asymptomatic and incidentally discovered; when large, they may cause compressive symptoms. Typically, mature teratomas are rounded or lobulated, welldefined anterior masses extending to one side of the mediastinum; their size may vary from 5 to 25 cm, with a mean of 10 cm in the largest diameter.65,101,103 On CT, they usually have a multilocular, cystic appearance with walls of variable thickness that usually enhance after IV contrast administration. The combination of soft tissue, fluid, calcium, and/or fat attenuation is highly specific, allowing a presumptive diagnosis in most cases (Fig. 123-15). Although focal areas of soft tissue attenuation are very common, they are rarely the dominant feature. Focal or rim-like calcification is present in 20% to 80% of cases. Areas of fat attenuation are visible on CT scans in half of the cases and strongly suggest the diagnosis. Fat-fluid levels are considered highly specific for teratoma but are uncommon.101,102 The characteristic MRI appearance of mature teratomas is that of a heterogeneous mass with a combination of areas of different signal intensity, depending on the presence of soft tissue, fat, and fluid components. Cystic areas have low signal intensity on T1-weighted MRI scans and increase in signal with T2-weighted images. The fat component has high signal intensity on T1-weighted images with variable intensity on T2-weighted images, similar to that of subcutaneous fat. However, this appearance is not specific for fat and may be

FIGURE 123-15 Benign teratoma. Contrast-enhanced CT scan in a 27-year-old woman shows a round, well-defined anterior mediastinal mass with areas of soft tissue attenuation, fat (arrowhead), and calcification (arrow). These findings are characteristic of teratoma. The diagnosis was confirmed at surgery.

Ch123-F06861.indd 1489

1489

seen in the presence of hemorrhage. Confirmation of the fat component may be obtained by using MRI techniques with fat saturation, such as phase-shift gradient-echo imaging.17 MRI has lower sensitivity for detection of calcification than conventional radiography or CT. Although MRI findings are highly specific for benign teratoma, it provides no additional information to CT.32 Imaging studies have an important role in the recognition of complications related to mediastinal teratomas. When large, these tumors can cause airway compression leading to atelectasis or obstructive pneumonitis. Mature teratoma has a predisposition to rupture into adjacent structures, presumably related to the presence of digestive enzymes secreted within the tumor. CT findings suggestive of rupture include increased inhomogeneity of the internal component of the tumor, adjacent pulmonary consolidation, and atelectasis.17 Rupture of teratoma into the lungs can cause pneumonitis, which is well demonstrated on CT scans; effusion may represent tumoral rupture into the pleural space or pericardium (Fig. 123-16). Occasionally, pleural or pericardial effusions have a fat-fluid level.102,104,105 Rarely, mature teratomas contain areas of carcinoma, sarcoma, or malignant germ cell tumors on histologic studies and are then classified as malignant teratomas or teratocarcinomas. In contrast to mature teratomas, they are typically poorly defined and predominantly solid, with a thick enhancing capsule on imaging studies; cystic areas are common, but a fat component is less commonly identified. In some patients with malignant teratoma, an unusual phenomenon may occur after successful chemotherapy, when an enlarging mass is demonstrated despite the complete eradication of malignant cells and normalization of serum markers. It has been called the mediastinal growing teratoma syndrome and requires surgery if the mass is sufficiently large to cause compression of adjacent structures.106 SEMINOMA. Seminoma is the second most common mediastinal germ cell tumor and the most common malignant subtype. It is most common in men in their third decade of life. Seminomas usually cause local symptoms, and the prognosis is generally good. Primary mediastinal seminomas are typically large, smooth or lobulated masses extending to one or both sides of the anterior mediastinum. They have homogeneous soft tissue attenuation on CT and show slight enhancement after IV contrast administration. Focal areas of low density or foci of rim-like or stippled calcifications are occasionally present. Although obliteration of fat planes is common, evidence of invasion of adjacent structures is rare. Pleural and pericardial effusions and metastases to regional lymph nodes and bones may occur.102,107,108 NONSEMINOMATOUS MALIGNANT GERM CELL TUMORS. Embryonal cell carcinoma, endodermal sinus tumor, choriocarcinoma, and mixed tumors, classified as nonseminomatous tumors, are rare, highly malignant lesions that affect principally young adult men.99 Clinically, they are characterized by serologic markers such as β-human chorionic gonadotropin (β-hCG) and α-fetoprotein in more than 50% of cases.67 The CT and MRI appearance is similar regardless of the histologic subtype. CT typically demonstrates a large,

1/21/2008 4:01:34 PM

1490

Section 7 Mediastinum

M M PA

PV

A

B FIGURE 123-16 Ruptured benign teratoma. A, Contrast-enhanced CT scan in a 28-year-old man shows a round, heterogeneous anterior mediastinal mass (M) containing areas of soft tissue, fluid, and fat attenuation. Note the obscuration of the fat planes anterior to the lesion (arrow). B, CT scan at the level of the heart shows small pericardial effusion (arrow). The diagnosis of benign teratoma with rupture into the mediastinum and pericardial space was confirmed at surgery.

heterogeneous mass with irregular margins containing extensive areas of low attenuation secondary to necrosis, hemorrhage, or cyst formation (Fig. 123-17). Infiltrative appearance with obliteration of fat planes is the rule. Evidence of invasion of adjacent structures and chest wall, and of pleural and pericardial effusion, is relatively common. MRI typically demonstrates a mass with heterogeneous signal intensity and is more sensitive in detecting invasion of adjacent structures. Metastases to regional lymph nodes and distant sites may occur.67,102,108,109

Primary Mediastinal Lymphoma and Hodgkin’s Disease Hodgkin’s disease and non-Hodgkin’s lymphoma commonly manifest as mediastinal masses. Hodgkin’s disease is more

Ch123-F06861.indd 1490

FIGURE 123-17 Nonseminomatous germ cell tumor. Contrastenhanced CT scan in a 28-year-old man shows a large, inhomogeneous anterior mediastinal mass with enhancing areas of soft tissue attenuation and a central area of decreased attenuation (M). There is obliteration of the fat planes (arrowhead) adjacent to the main pulmonary artery (PA) and marked narrowing of the left inferior pulmonary vein (PV).

common and has a tendency to involve the thymus, manifesting as a bulky anterior mediastinal mass.110,111 Paratracheal, hilar, subcarinal, internal mammary, and pericardiophrenic lymph nodes are affected, in decreasing order of frequency. Contiguous involvement of nodal stations is characteristic of Hodgkin’s disease and is observed in approximately 90% of cases.110,112 An anterior mediastinal mass is visible on the initial chest radiograph in more than 60% of patients with Hodgkin’s disease. On CT scans, the enlarged thymus often preserves the normal shape but may have convex borders or a lobulated or nodular contour (Fig. 123-18). The enlarged thymus and lymph nodes in Hodgkin’s disease usually have homogenous density on CT and demonstrate slight enhancement after IV administration of contrast. Cystic areas reflecting the presence of necrosis have been described in 21% to 23% of adults but are uncommon in children.113 Although calcified lymph nodes are relatively common after irradiation, they rarely occur before treatment.114-116 Non-Hodgkin’s lymphoma also manifests as a bulky anterior mediastinal mass, but differently from Hodgkin’s disease; there is often heterogeneous CT attenuation as a result of necrosis (Fig. 123-19).117 On MRI, lymphomatous masses tend to have inhomogeneous signal intensity due to the presence of areas of necrosis, which are best demonstrated on contrast-enhanced T1weighted images. Characteristically, the signal intensity on T2-weighted images changes during the course of the disease: before treatment, increased signal intensity is the rule, reflecting the presence of active inflammation and necrosis; after successful treatment, tumoral tissue is replaced by fibrosis, resulting in decreased signal intensity of the residual mass.18,19,118-122 The pattern of enhancement on MRI after IV administration of gadolinium also changes during the course of the disease, being considerably lower after successful treatment, presumably reflecting the presence of nonenhancing fibrotic tissue.122

1/21/2008 4:01:35 PM

Chapter 123 Imaging of the Mediastinum

1491

M M

P

A

B

M

P

C

Lymphomas may spread beyond the lymph nodes, invading mediastinal structures and the chest wall.123,124 It is worth noting that, in contrast to invasive carcinoma, lymphoma is only rarely associated with invasion of the phrenic nerve and diaphragmatic paralysis.124 Because of its better contrast resolution, MRI is superior to CT for detection of invasion of mediastinal structures and chest wall in lymphoma.123,125 Intrathoracic lymphoma is almost always associated to extrathoracic disease, which facilitates the correct diagnosis; however, if the mediastinum is the sole site of involvement (<5% of cases), differentiation between lymphoma and other anterior mediastinal masses can be difficult.110 The combination of an anterior mediastinal mass with enlarged nodes in other areas of the mediastinum is very suggestive of the diagnosis of lymphoma.

Ch123-F06861.indd 1491

FIGURE 123-18 Lymphoma. A, Transverse CT scan after IV contrast administration in a 23-year-old man at the level of the great aortic branches shows a large anterior mediastinal mass with slightly heterogeneous attenuation (M). The lesion causes posterior displacement of the adjacent structures and compression of the superior vena cava (arrow). A small pleural effusion is noted in the left. Coronal (B) and sagittal (C) reconstructions depict the mass occupying the anterior mediastinum and extending from the thoracic inlet to the level of the pulmonary outflow tract (P). The patient proved to have Hodgkin’s lymphoma.

Frequently, a residual mass is found after treatment for mediastinal lymphoma or Hodgkin’s disease. CT and MRI have an important role in the evaluation of these masses, helping in the diagnosis of residual disease. Increase in size on follow-up studies is currently one of the most valuable indications of relapsing lymphoma. However, it must be emphasized that an enlarging mass does not necessarily imply active disease; it may be caused by rebound thymic hyperplasia. Additionally, it has been shown that a decrease in size does not rule out the presence of viable tumor.18,119,124,126,127 MRI is superior to CT in the detection of foci of viable tumor within residual masses, with a sensitivity ranging from 45% to 90% and a specificity of 80% to 90%.118,128,129 On MRI, persistent lymphoma manifests as areas of high signal intensity on T2-weighted images. Nevertheless, necrosis, edema,

1/21/2008 4:01:36 PM

1492

Section 7 Mediastinum

PA

M FIGURE 123-19 Lymphoma. CT scan in a 38-year-old man shows a large, lobulated anterior mediastinal mass with heterogeneous enhancement after IV contrast administration. The central areas of decreased attenuation (arrow) reflect the presence of necrosis within the tumor. Note the displacement of the adjacent structures and marked narrowing of the superior vena cava (arrowhead) and right pulmonary artery (PA). The patient had a diagnosis of non-Hodgkin’s lymphoma (large B-cell lymphoma).

inflammation, and immature fibrotic tissue, often present up to 6 months after successful therapy, may likewise manifest as focal areas of increased signal on T2-weighted images.18,19,118,119,128 A recent study assessing the value of gadolinium administration in the characterization of residual mediastinal masses demonstrated that contrast-enhanced MRI was more reliable in the detection of viable tumor than T2-weighted images. Lymphomatous tissue was associated with intense and persistent gadolinium enhancement.127 Gallium scintigraphy and PET imaging have proved to be more accurate in the detection of residual lymphoma than CT assessment of changes in size.118,129-131 Studies comparing MRI and gallium scintigraphy demonstrated similar accuracy.127,128 Increased uptake of FDG on PET scans is highly predictive for the presence of active disease.130-132 Conversely, a negative PET scan is highly accurate in excluding residual disease.27,133

Pericardial Cyst Pericardial cysts are uncommon congenital lesions that presumably originate from abnormal fusion of the anterior pericardial recesses. Rare cases of cysts developing years after acute pericarditis have been described, suggesting that some are acquired in origin. Pericardial cysts are usually seen in adults in their fourth or fifth decades of life and rarely cause symptoms or complications (Strollo et al, 1997).134 Approximately 90% of pericardial cysts are located in the anterior mediastinum, contacting the diaphragm, with 65% to 75% occurring in the right cardiophrenic angle. In approximately 10% of cases, they are at more cephalad levels and may be seen as high as the pericardial recesses, at the level of the proximal aorta. Although pericardial cysts are invariable connected to the pericardium, communication with the pericardial space is rare.17,135 Pericardial cysts are smoothly marginated lesions usually measuring between 3 and 8 cm in diameter. CT scans typically demonstrate unilocular, nonenhancing lesions with

Ch123-F06861.indd 1492

A

M

B FIGURE 123-20 Pericardial cyst. A, Coronal T1-weighted (TR/TE 1034/20) spin-echo MRI in a 32-year-old man demonstrates a well circumscribed mass (M) with low signal intensity in the right cardiophrenic angle, contacting the diaphragm. B, On the T2weighted (TR/TE 8571/112) spin-echo image, the lesion has homogeneous high signal intensity, indicating its cystic nature. The typical location and magnetic resonance signals are virtually pathognomonic of pericardial cyst. The diagnosis was confirmed at surgery.

water attenuation and imperceptible walls. Occasionally, higher attenuation values are demonstrated, presumably related to the presence of viscous material; in these cases, a reliable differentiation from solid neoplasms can be difficult on CT.136 On MRI, pericardial cysts have low signal intensity on T1-weighted images and high signal intensity on T2weighted images, findings that confirm their cystic nature (Fig. 123-20).137

Intrathoracic Thyroid Tissue Although ectopic mediastinal thyroid tissue is extremely rare, direct extension of an enlarged thyroid into the mediastinum

1/21/2008 4:01:36 PM

Chapter 123 Imaging of the Mediastinum

SVC

1493

Ao

M

A

A M

S

SVC

T Ao e

B FIGURE 123-21 Retrosternal goiter. A, Posteroanterior chest radiograph in a 75-year-old woman shows increased soft tissue opacity (asterisk) at the level of the thoracic inlet that is causing a shift of the tracheal air column to the right (arrows). B, CT scan after IV contrast administration shows an inhomogeneous retrosternal mass (arrow) with areas of contrast enhancement and foci of calcification. The mass is insinuated between the aorta (Ao) and the trachea, which is deviated to the right (T). CT scans at more caudal levels (not shown) demonstrated connection of the mass with the thyroid gland. e, esophagus; S, sternum; SVC, superior vena cava.

is common.138 In approximately 80% of cases, the enlarged thyroid extends to the anterior or middle mediastinum (Fig. 123-21). In the remaining 10% to 20% of cases, extension occurs behind the trachea into the posterior mediastinum (Fig. 123-22).139 Rarely, the goiter may extend posterior to the esophagus.140

Ch123-F06861.indd 1493

B FIGURE 123-22 Posterior mediastinal goiter. A, Contrast-enhanced CT scan at the level of the aortic arch (Ao) in a 46-year-old man shows an inhomogeneous enhancing mass (M), with areas of low attenuation and foci of calcification, insinuating into the posterior mediastinum between the esophagus and the trachea (arrow), which is deviated anteriorly. SVC, superior vena cava. B, Sagittal CT reconstruction well demonstrates the mass occupying the posterior mediastinum and depicts the connection of the mass (M) with the thyroid gland in the neck (arrow).

On conventional radiography, a retrosternal goiter is identified as a well-defined, smooth or lobulated mass that extends from the lower neck and displaces the trachea laterally and/or posteriorly (see Fig. 123-21A). CT usually allows differentiation between intrathoracic goiter and other anterior mediastinal masses that may have the same appearance on

1/21/2008 4:01:37 PM

1494

Section 7 Mediastinum

radiography. CT features characteristic of thyroid tissue include areas of high attenuation (>100 HU) and strong and prolonged enhancement (>2 minutes) after administration of IV iodinated contrast material. Goiters tend to be inhomogeneous, with cystic areas of low attenuation (see Figs. 123-21 and 123-22). In some cases, curvilinear, punctate, or ring-like calcifications are demonstrated on CT.67,138 Connection with the cervical thyroid is almost always present and is usually visible on CT. Multiplanar reformations of CT images in the coronal and sagittal planes may be helpful in demonstrating the connection of the intrathoracic thyroid tissue with the thyroid gland. CT studies are highly accurate in determining the anatomic localization and extension of intrathoracic goiters, as well as their relationships with adjacent mediastinal structures, and have an important role in the preoperative evaluation of patients undergoing surgical excision.67 Thyroid carcinoma may also extend into the thorax, manifesting as an inhomogeneous anterior or middle mediastinal mass. Marked irregularity of the gland contours raises the suspicion of malignancy; however, thyroid carcinomas frequently have well-defined borders and may mimic a goiter. Evidence of spread with obliteration of fat planes, invasion of mediastinal structures, and presence of cervical or mediastinal lymphadenopathy indicates the diagnosis of thyroid carcinoma. MRI is highly sensitive in the evaluation of intrathoracic extension of thyroid masses, involvement of mediastinal structures, and obliteration of fat planes. However, it is less sensitive than CT in the detection of calcification and offers no additional information on the tissue characteristics of thyroid lesions. The normal thyroid tissue has signal intensity equal to or slightly greater than that of muscle on T1-weighted images and significantly greater signal intensity on T2weighted images. Multinodular goiters are usually hypointense relative to the normal thyroid tissue on T1-weighted images; focal areas of increased signal are seen when foci of hemorrhage or cysts are present within the mass. On T2weighted images, they are heterogeneous, with areas of high signal intensity throughout the mass.141 Scintigraphy has high sensitivity and specificity in the diagnosis of intrathoracic goiter. The majority of goiters show evidence of radionuclide uptake, including iodine 123, technetium 99m (Tc99m), and iodine 131, the last one being the agent of choice. False-positive uptake has been described in association with hiatal hernia and in thymic tissue.142

Lymphangioma Mediastinal lymphangiomas are rare lesions that probably represent developmental anomalies rather than true neoplasms. Pathologically, they consist of focal proliferation of well-differentiated lymphatic tissue present in thin-walled cysts.17 Two different forms of mediastinal lymphangiomas have been described: the first and most common, also called cystic hygroma, is primarily seen in children and originates in the neck, extending into the mediastinum in approximately 10% of cases; the other form is rare, accounting for fewer than 1% of all lymphangiomas, occurs as a primary mediasti-

Ch123-F06861.indd 1494

M

FIGURE 123-23 Lymphangioma. Contrast-enhanced CT scan in a 37-year-old man shows a large, smoothly marginated, homogeneous mass (M) with water attenuation. The lesion insinuates around the adjacent structures and causes displacement of the large aortic branches (arrows). The diagnosis of lymphangioma was confirmed at surgical biopsy.

nal tumor in adults, and is usually located in the anterior mediastinum. The latter form often represents recurrence of incompletely resected tumor from childhood. Because of their soft tissue composition, lymphangiomas seldom cause compressive symptoms, even if they are large. Complications include infection, chylothorax, and chylopericardium.17,67,143-146 Radiographic findings are nonspecific and consist of a welldefined, smoothly marginated mass that displaces adjacent mediastinal structures. On CT scans, the most common appearance is that of a smoothly marginated, homogeneous cystic lesion (Fig. 123-23). In approximately one third of cases, lymphangiomas are multiloculated, with thin or thick septations that may enhance slightly after IV contrast administration. Areas of homogeneous soft tissue attenuation, foci of calcification, and spiculated margins are less commonly identified. Hemorrhage within the tumor may occur, leading to acute increase in the size of the tumor and in the CT attenuation value. Lymphangiomas may reach large size and may have an infiltrative appearance, insinuating around adjacent structures without causing displacement. Direct invasion may also occur. Because of their infiltrative behavior, complete surgical resection can be difficult, and follow-up CT scans are recommended to exclude recurrence.67,146,147 MRI typically demonstrates heterogeneous signal intensity on T1-weighted images and high signal intensity on T2weighted images, reflecting the presence of cysts. MRI is particularly useful in confirming the cystic nature of lesions with high protein content that may resemble soft tissue tumors on CT. Compared with CT, MRI better demonstrates internal septations and invasion of adjacent structures.146

Mediastinal Parathyroid Adenomas Parathyroid adenomas occur primarily in the neck. Approximately 10% have an ectopic location, and half of those occur in the anterior mediastinum near or within the thymus. They

1/21/2008 4:01:39 PM

Chapter 123 Imaging of the Mediastinum

are rounded, encapsulated tumors that, because of their small size (usually <3 cm), are rarely identified on chest radiographs.67,148,149 Preoperative localization of ectopic parathyroid adenomas can be difficult. Ultrasonography and Tc99m-sestamibi scintigraphy are the most accurate methods for localizing parathyroid adenomas in the neck.67 CT and MRI with IV gadolinium enhancement and fat suppression are the methods of choice for the detection of ectopic mediastinal parathyroid adenomas. On CT, parathyroid adenomas resemble lymph nodes; enhancement after IV contrast administration is seen in only 25% of cases. On MRI, parathyroid adenomas have increased signal intensity on T2-weighted images and enhance on T1weighted images after gadolinium administration.149,150 The sensitivity of CT or MRI in the detection of ectopic parathyroid adenomas is approximately 80%. A recent study demonstrated that 11C-methionine PET scanning can be helpful in the preoperative localization of parathyroid adenomas, having a sensitivity of 83%, a specificity of 100%, and an accuracy of 88%.151 This method is helpful in the assessment of those patients for whom conventional imaging techniques have failed.

1495

H

A H

Anterior Diaphragmatic Hernia (Morgagni Hernia) Morgagni hernia is an uncommon type of diaphragmatic hernia that is related to herniation of abdominal contents into the thorax through the foramen of Morgagni or parasternal hiatus. The result is a smooth, well-defined mass, most commonly located in the right costophrenic angle. Patients are usually asymptomatic, but retrosternal pain and respiratory or gastrointestinal symptoms may occur.152 The imaging appearance depends on the herniated content, usually omentum and in some cases parts of liver and bowel. Chest radiography usually demonstrates a right paracardiac, well-defined, homogeneous shadow. Inhomogeneity may be the result of predominant fat content or air in herniated bowel.153 Confident diagnosis can be made on CT and MRI by demonstration of continuity of the herniated fat or omentum with the remaining omentum through the diaphragmatic defect (Fig. 123-24).152,154

Masses Primarily Found in the Middle and Posterior Mediastinal Compartments Bronchogenic Cyst Bronchogenic cysts, the most common congenital foregut cysts, account for approximately 60% of all mediastinal cysts. Their origin is probably related to abnormalities in the development of the tracheobronchial bud during embryogenesis. Distinction from other foregut duplication cysts is based on the presence of pseudostratified ciliated columnar epithelium typical of airways. Although bronchogenic cysts are found in all age groups, they are often diagnosed in young adults in the third decade of life; they may manifest with compressive symptoms, or they may be asymptomatic and incidentally discovered on imaging studies. In children, severe airway obstruction or obstructive pneumonia is common.85,134 Enlargement over several years is the rule; rapid enlargement may indicate hemorrhage or infection and may be associated

Ch123-F06861.indd 1495

B FIGURE 123-24 Morgagni Hernia. A, CT scan in a 49-year-old man shows an anterior mediastinal mass with fat attenuation representing herniated omentum (H). The focal areas of contrast enhancement within the mass represent omental vessels (arrows) and are helpful in the diagnosis. B, CT image at caudal level depicts the anterior diaphragmatic defect (arrow) and omental fat herniating into the thorax (H).

with local pain. Rupture of a cyst into a bronchus, pleura, or pericardium is rare.17 Although bronchogenic cysts may occur in any mediastinal region, most of them affect the middle mediastinum, being located close to the trachea, main bronchi, or carina in approximately 85% of cases (Fig. 123-25).17,85,134 Communication with the tracheobronchial tree is rare. The remaining 15% occur in extramediastinal sites, usually in the lung parenchyma and, rarely, in the pleura or diaphragm.85,134 CT typically demonstrates a round, smoothly marginated, homogeneous lesion with imperceptible walls (Fig. 123-26). The CT attenuation is variable, reflecting the composition of the cyst content, which may be serous, hemorrhagic, or highly viscous. Approximately half are filled with serous fluid and

1/21/2008 4:01:39 PM

1496

Section 7 Mediastinum

Ao

M

T

T

A

T

Ao PA

FIGURE 123-26 Bronchogenic cyst. Transverse contrast-enhanced CT scan in a 60-year-old woman shows a smoothly marginated, homogeneous, nonenhancing mass in the right paratracheal region (M). Measurement of the attenuation value within the mass demonstrated 9 HU (water attenuation). The location and attenuation value are characteristic of bronchogenic cyst. The diagnosis was confirmed at surgery. T, trachea.

MRI is indicated in those cases in which the cystic nature cannot be determined on CT scans or IV iodine contrast is contraindicated. MRI demonstrates characteristic high signal intensity on T2-weighted images regardless of the nature of the cyst content. On T1-weighted images, the signal intensity varies according to the composition of the fluid within the cyst (Fig. 123-27). After IV gadolinium administration, the cystic wall may enhance, but there is no enhancement of the cyst contents.17,85,147,155

Esophageal Diseases

B FIGURE 123-25 Bronchogenic cyst. A, Axial nonenhanced CT scan at the level of the aortopulmonary window shows a wellcircumscribed, oval structure with water attenuation (arrow) between the ascending aorta (Ao) and the trachea (T). B, Sagittal reconstruction depicts the elongated structure (arrow) contacting the distal trachea (T) and extending to the level of the main pulmonary artery (PA). The patient was an asymptomatic 56-year-old man. Ao, aorta.

therefore have characteristic water attenuation (0-20 HU); in the remaining cases, the CT attenuation values resemble those of soft tissue because of the presence of highly proteinaceous fluid. Cysts containing proteinaceous fluid may be difficult to differentiate from a solid mass on CT. Punctate mural calcification has been described in approximately 10% of mediastinal bronchogenic cysts (Kim et al, 2000).17,85,147 The cystic nature may be demonstrated on CT by the lack of enhancement after IV administration of contrast.

Ch123-F06861.indd 1496

Benign and malignant esophageal tumors may manifest as middle mediastinal masses. Subserosal leiomyoma may manifest on CT as a smooth, round, well-defined, homogeneous mass related to the esophagus. When anteriorly placed, the mass separates the esophagus and the trachea; in some of these cases, the exact origin of the mass may be difficult to determine on cross-sectional images. Malignant esophageal tumors may manifest on CT as regular or irregular thickening of the esophageal wall or, in more advanced cases, as an infiltrative mass (Fig. 123-28). Although CT is limited in the evaluation of depth of tumor invasion and in the determination of lymph node status, it is helpful in the staging of esophageal carcinoma.156,157 Esophageal diverticulum, esophageal varices, and megaesophagus can also cause mediastinal masses. The characteristic appearance of each one of these diseases on imaging studies usually allows confident correct diagnosis. Megaesophagus is well demonstrated on plain radiographs as a large, tubular structure in the topography of the esophagus containing air and heterogeneous opacities related to the presence of alimentary residua. Esophageal diverticula are seen on CT scans as air-containing, round or oval lesions that communicate with the esophagus (Fig. 123-29). Esophageal

1/21/2008 4:01:40 PM

Chapter 123 Imaging of the Mediastinum

1497

LA

M S

A FIGURE 123-28 Recurrent esophageal carcinoma. Nonenhanced CT scan in a 67-year-old man with previous esophagectomy for esophageal carcinoma and gastric pull-up shows an infiltrative soft tissue mass in the subcarinal region (arrows) in continuity with the anterior aspect of the pulled stomach (S).

B FIGURE 123-27 Bronchogenic cyst. A, Transverse T1-weighted (TR/ TE 645/20) spin-echo MRI in a 72-year-old woman shows a slightly inhomogeneous mass (M) with signal intensity similar to that of chest wall muscle (arrow). The mass causes compression of the left atrium (LA). B, On T2-weighted (TR/TE 2580/90) fast spin-echo MRI, the lesion has homogeneous high signal intensity, characteristic of cystic lesions. The appearance is indistinguishable from esophageal cyst. The diagnosis of bronchogenic cyst was obtained after surgical resection.

varices are identified as elongated structures around the distal esophagus. Confident diagnosis of esophageal varices usually requires IV administration of a contrast agent.

e

FIGURE 123-29 Esophageal diverticulum. Transverse CT scan obtained after ingestion of oral contrast shows a well-circumscribed structure filled with air abutting the anterior esophageal wall (arrow). The esophagus (e) is opacified and demonstrates normal morphology and caliber.

Esophageal Cyst Esophageal duplication cysts are the second most common type of foregut duplication cysts and are characterized by the presence of gastrointestinal epithelium. Most esophageal duplication cysts are discovered during childhood because of compressive symptoms. Rupture may occur if the cyst is lined by secretory gastric or pancreatic mucosa.17,134

Ch123-F06861.indd 1497

Barium esophageal studies typically demonstrate smooth extrinsic or intramural compression. Communication with the esophageal lumen is rare. Uptake of Tc99m-sodium pertechnetate by the ectopic gastric mucosa within the cyst on radionuclide studies may be helpful in the diagnosis, particularly in children.17

1/21/2008 4:01:41 PM

1498

Section 7 Mediastinum

Except for their different location, the CT and MRI appearance of esophageal duplication cysts is indistinguishable from that of bronchogenic cysts and consists of a unilocular, smooth, thin-walled lesion with homogeneous content. Calcification is rarely seen. Almost all are localized in the lower posterior mediastinum, within the esophageal wall or in contact with the esophagus (Fig. 123-30). Occasionally, they appear as a paraesophageal tubular cystic lesion.134,139,147

Tracheal Diseases Benign and malignant tracheal neoplasms are a rare cause of middle mediastinal masses. They may be difficult to detect on chest radiography but are usually well seen on CT. CT is helpful in the evaluation of the extent of tumor and involvement of mediastinal structures. CT is of limited value, however, in the distinction of mucosal from intramural lesions and benign from malignant tracheal tumors.

M

A

e

Lymph Node Enlargement Middle mediastinal nodes form the final pathway of drainage of the lungs and may be enlarged in a number of benign and malignant pulmonary diseases. Infections (most commonly tuberculosis and histoplasmosis) and neoplasms (most commonly pulmonary carcinoma), as well as inflammatory processes such as sarcoidosis, are the most common causes of enlarged nodes in the middle mediastinum. Extrathoracic neoplasms that have a propensity to metastasize to the middle mediastinal nodes include head and neck tumors, carcinoma of the breast, renal cell carcinoma, and melanoma. Although lymphoma usually involves mainly the anterior mediastinum, involvement of paratracheal nodes is also common (Fig. 123-31).55,147 CT and MRI are accurate in determining the size and morphology of lymph nodes but are unable to distinguish malignant from benign nodal enlargement.59,62 CT may demonstrate the presence of calcification or necrosis. Calcified nodes are most commonly residual from previous tuberculosis, histoplasmosis, or sarcoidosis and also occur in patients with silicosis. Necrotic nodes are identified by their characteristic low attenuation and are seen most commonly in tuberculosis, fungal infections, lymphoma, metastatic carcinoma, and melanoma. On contrast-enhanced CT, necrotic nodes may have diffuse low attenuation, or they may demonstrate a central area of low attenuation surrounded by a rim of contrast enhancement (Fig. 123-32). FDG-PET is more accurate than CT in the assessment of nodal involvement with cancer. PET can differentiate tumor from benign hyperplasia in enlarged nodes and can detect tumoral tissue in normal-sized nodes.55,63,64 A recent metaanalysis including 39 studies demonstrated that FDG-PET is more accurate than CT in the detection of lymph node involvement in patients with non–small cell lung carcinoma (P < .001). The median sensitivity and specificity of PET were 85% and 90%, respectively, whereas the median sensitivity and specificity of CT were 61% and 71%, respectively.158 These results corroborated those of a prior meta-analysis, which demonstrated sensitivity and specificity of 79% and 91% for FDG-PET and 60% and 77% for CT, respectively.159 The important limitation of PET in mediastinal staging is related to the increased uptake of FDG by inflammatory nodes. False-positive results are seen in granulomatous infection, sarcoidosis, and silicosis. This caution is particularly important in populations with a high prevalence of tuberculosis.160,161

B

Paraganglioma

FIGURE 123-30 Esophageal cyst. A, Contrast-enhanced CT scan at the level of the upper thorax shows a well-circumscribed mass (M) in the left paravertebral region. Mild contrast enhancement is noted in the periphery of the lesion. B, On T2-weighted (TR/TE 2368/20) fast spin-echo MRI, the lesion has homogeneous high signal intensity, characteristic of fluid-filled cysts. The diagnosis of esophageal cyst was suggested by the presence of a tongue (arrow) connecting the lesion to the posterior aspect of the esophagus (e). The patient was a 49-year-old man, and the diagnosis of esophageal duplication cyst was confirmed at surgery.

Paragangliomas, also called chemodectomas, are rare neoplasms originating from neuroectodermal cells of the autonomic nervous system. Mediastinal paragangliomas are usually located in the region of the aortopulmonary window (aortic body tumors) or in the paravertebral region. Patients are usually asymptomatic. Symptoms related to catecholamine secretion are more commonly seen in paravertebral paragangliomas than in those located in the middle mediastinum. Approximately 10% of paragangliomas are malignant.162

Ch123-F06861.indd 1498

1/21/2008 4:01:42 PM

Chapter 123 Imaging of the Mediastinum

1499

L

C

A L

L L

B

D

FIGURE 123-31 Massive lymphadenopathy. A, Posteroanterior radiograph shows a well-defined opacity in the right paratracheal region (arrows). CT scans obtained after IV contrast administration at the level of the aortic arch (B) and subcarinal region (C) show a homogeneous mass with soft tissue attenuation (L). Enlarged nodes are also noted in the prevascular (arrow) and axillary (arrowhead) regions. D, Coronal reconstruction well demonstrates the lymphadenopathy in the right paratracheal and subcarinal regions causing compression of the left atrium (arrow). The patient was a 52-year-old man with a diagnosis of non-Hodgkin’s lymphoma.

The appearance on CT consists of a homogeneous soft tissue mass that typically shows marked enhancement after IV contrast administration. Areas of low attenuation and enhanced linear vascular structures within the mass may be seen on contrast-enhanced CT. Angiography confirms the marked hypervascularity of these lesions.147 On MRI, paragangliomas demonstrate very high signal intensity on T2weighted images and characteristic internal serpentine vascular structures on T1- and T2-weighted images.163

Posterior Diaphragmatic Hernias Esophageal Hiatus Hernia. Esophageal hiatus hernia is the most common diaphragmatic hernia and is a common cause

Ch123-F06861.indd 1499

of mediastinal mass detected on imaging studies. Chest radiographs demonstrate a retrocardiac mass, usually containing air or an air-fluid level (Fig. 123-33). Although the typical appearance usually allows a correct diagnosis, barium study or CT is required in some cases (Fig. 123-34). Bochdalek Hernia. Bochdalek hernias are the result of herniation of abdominal contents through the foramen of Bochdalek, located in the posterolateral aspect of the diaphragm. In infants, Bochdalek hernias are the most common and most serious diaphragmatic hernia and are associated with high rates of morbidity and mortality. Herniation occurs through a persistent pleuroperitoneal canal. The herniation is typically large and is frequently associated with hypoplasia of the underlying lung.

1/21/2008 4:01:43 PM

1500

Section 7 Mediastinum

A FIGURE 123-32 Necrotic lymph node. CT scan after IV contrast administration shows an enlarged subcarinal node with central areas of low attenuation surrounded by a rim of contrast enhancement (straight arrow). A non-necrotic, enlarged node is noted in the right hilum (arrowhead). The patient was a 57-year-old woman with history of melanoma.

In adults, Bochdalek hernias are usually small, asymptomatic, and found incidentally on imaging studies. On chest radiographs, they manifest as a posterior focal bulge in the hemidiaphragm or as a paramediastinal mass, usually in the left hemithorax. A correct diagnosis can readily be made on CT, which demonstrates the diaphragmatic defect with herniation of fat or, occasionally, herniation of kidney or spleen (Fig. 123-35).152-154

Paravertebral Masses Neoplasms of neural tissue are the most common cause of paravertebral masses. They may originate from peripheral nerves (neurogenic tumors) or, less commonly, from the sympathetic ganglia. Neurogenic tumors in the thorax usually arise from an intercostal nerve in the paravertebral region and most commonly represent schwannomas. They usually are asymptomatic and are discovered incidentally on chest radiographs or CT scans in young adults. Neurogenic tumors are seen as sharply defined, round, smooth or lobulated, paraspinal masses usually extending for only one or two posterior intercostal spaces. They can have homogeneous or inhomogeneous soft tissue characteristics on CT and MRI (Fig. 123-36). Malignant neurogenic tumors tend to be larger and more heterogeneous, although they may have well-defined smooth margins. Poorly defined infiltrative margins are common, and in these cases MRI is indicated to evaluate the involvement of adjacent structures.134

Ch123-F06861.indd 1500

B FIGURE 123-33 Large hiatus hernia. A, Posteroanterior chest radiograph shows a large soft tissue mass containing an air-fluid level and occupying the inferior portion of both hemithoraces (arrows). B, On the lateral view, the mass is shown to be in the posterior mediastinum (arrows). The patient was a 78-year-old woman with a hiatus hernia and gastric outlet obstruction secondary to pancreatic carcinoma.

1/21/2008 4:01:44 PM

Chapter 123 Imaging of the Mediastinum

1501

T L

IVC

Ao

FIGURE 123-34 Hiatus hernia. A, Transverse CT scan shows an inhomogeneous soft tissue mass in the topography of the esophagus (arrow). CT scans through lower levels (not shown) demonstrated continuity of this mass with the stomach, confirming the diagnosis of hiatus hernia. The patient was an asymptomatic 67-year-old woman. Ao, aorta; IVC, inferior vena cava.

FIGURE 123-35 Bochdalek hernia. Transverse CT scan in a 36-yearold woman shows a focal defect in the posterior aspect of the left hemidiaphragm (arrows), with herniation of retroperitoneal fat and bowel.

Lymphoma, particularly Hodgkin’s disease, may involve posterior mediastinal lymph nodes, causing a fusiform paravertebral mass of soft tissue attenuation. Primary or metastatic tumors of the thoracic spine can also cause paravertebral masses. Other causes include infection, most commonly tuberculosis; hematoma secondary to trauma or aortic rupture; aortic aneurysm; extramedullary hematopoiesis; and intrathoracic meningocele.17,134,152

MEDIASTINITIS Acute Mediastinitis Acute mediastinal infection is a relatively uncommon condition. Most of the cases are related to thoracic surgery, esopha-

Ch123-F06861.indd 1501

FIGURE 123-36 Neurogenic tumor (cystic neurofibroma). Enhanced CT scan in a 45-year-old man shows an 8.5-cm, smoothly marginated, nonenhancing mass (L) in the right upper chest. Measurement of the attenuation values demonstrated water attenuation, indicating its cystic nature. The lesion was causing compression of the trachea (T) and a shift of the upper mediastinal structures to the left. At surgery, the lesion proved to be a cystic neurofibroma.

FIGURE 123-37 Acute mediastinitis. Nonenhanced CT scan in a 65year-old man after recent coronary artery bypass surgery shows widening of the mediastinum with diffuse stranding of the mediastinal fat that produces areas of increased attenuation (arrow). There is dehiscence of the sternotomy, and a small localized fluid collection is seen on the right (arrowhead). Bilateral pleural effusions are also noted.

geal perforation, or spread of infection from adjacent regions, usually from tonsillar abscesses, traumatic rupture of the pharynx, or spondylitis.139 Mediastinal infection may manifest as diffuse mediastinitis or as a localized process resulting in abscess formation. Acute mediastinitis manifests on plain radiography as smooth widening of the mediastinum. CT findings include widening of the mediastinum, with diffuse or streaky infiltration of the mediastinal fat that demonstrates increased density (usually >25 HU), along with focal areas of low attenuation reflecting fluid collections (Fig. 123-37). The presence

1/21/2008 4:01:45 PM

1502

Section 7 Mediastinum

e e Ao

FIGURE 123-38 Acute mediastinitis. CT scan after IV contrast administration at the level of the thoracic inlet shows localized collections of fluid and air in the paravertebral region (arrowheads), consistent with abscess formation. The adjacent mediastinal structures are compressed and displaced anteriorly. Reactive, enlarged nodes are noted in the right paratracheal region (arrows), and there is a right-sided pleural effusion. The patient was a 27-yearold man who was quadriplegic after C3-C4 fracture, with infection related to the fixation hardware. e, esophagus.

FIGURE 123-39 Acute mediastinitis secondary to esophageal perforation. CT scan after IV contrast administration shows pneumomediastinum (arrowheads) and fluid around the esophagus (arrow), which is identified by the presence of a nasogastric tube within its lumen (e), and the aorta (Ao). There are bilateral pleural effusions, larger on the left side. The patient was a 21-year-old man with severe dermatomyositis and esophageal perforation secondary to Mallory-Weiss tear.

of air, identified in approximately half of the cases, is an important diagnostic clue. Compression of mediastinal structures, reactive lymph node enlargement, and pleural and pericardial effusion are often identified.147,164 Mediastinal abscess formation manifests as a localized, fluid-filled collection often containing air and is better visualized after IV contrast administration (Fig. 123-38). Although MRI is highly accurate in the diagnosis and evaluation of the extent of mediastinal infections, it has no advantages over CT and is seldom used in the evaluation of these patients (Akman et al, 2004).165 CT plays an important role in the therapeutic decision, helping to differentiate patients who require surgical intervention from those who can be managed conservatively. Furthermore, CT is helpful in guiding percutaneous aspiration and drainage of mediastinal abscesses.139,165 It must be emphasized that CT findings mimicking those of acute mediastinitis may be present after uncomplicated sternotomy and may persist for up to 3 weeks. These normal postoperative changes include fluid collections, air, and hematoma and are typical of the early postoperative period. Presence of such abnormalities for longer than 3 weeks after surgery suggests the presence of mediastinitis. After esophageal surgery, localized fluid collections without air may represent seroma, and aspiration may be necessary to differentiate them from abscesses. In mediastinitis secondary to esophageal perforation, air is often demonstrated within the mediastinum and in the soft tissues of the neck (Fig. 123-39). Pneumothorax and hydropneumothorax may also be seen, more commonly on the left side. Esophageal perforation can be confirmed by esophagography, which demonstrates extravasation of contrast material into the mediastinum or pleural space. Although some authors have suggested the use of water-soluble contrast medium in patients with known or suspected esophageal perforation, small tears may be missed and aspiration of this material may

lead to severe pulmonary edema. Barium has been considered safest in this clinical setting.166 Although the definitive diagnosis of esophageal perforation is usually made by esophagography or endoscopy, CT has an important role in the diagnosis of this condition and is valuable in assessing the extent of the mediastinal disease. CT manifestations include esophageal thickening, periesophageal areas of soft tissue and fluid attenuation, and presence of extraluminal air and contrast.165 Mediastinitis secondary to esophageal perforation is associated with a poor prognosis.

Ch123-F06861.indd 1502

Fibrosing Mediastinitis Fibrosing mediastinitis (sclerosing mediastinitis) is a rare, benign disorder caused by proliferation of fibrous tissue within the mediastinum. The precise pathogenesis is unknown. The most common cause is an abnormal immunologic response to Histoplasma capsulatum infection.167 In addition, mediastinal fibrosis has been described in association with tuberculosis, trauma, radiation therapy, Hodgkin’s disease, and idiopathic fibrosing diseases.167,168 A great number of cases are idiopathic. Fibrosing mediastinitis most commonly affects young adults, causing symptoms related to compression or obstruction of mediastinal structures, principally the SVC and its tributaries, the pulmonary artery and veins, central airways, and, less commonly, the esophagus. The heart, aorta, and aortic branches are much less frequently involved.169 The clinical course is unpredictable, and both spontaneous remission and exacerbation have been reported. The fibrosis affects most commonly the middle mediastinal compartment, involving the paratracheal and subcarinal regions and the hila. Two distinct patterns of fibrosing mediastinitis have been described. The most common type consists of a relatively localized disease with focal fibrosis, involving mainly the right paratracheal and subcarinal regions and often associated with foci of calcification. This form is typically associated with previous

1/21/2008 4:01:47 PM

Chapter 123 Imaging of the Mediastinum

infection, most commonly histoplasmosis. The second and less common type results in a diffuse infiltrative mass usually noncalcified, affecting multiple mediastinal compartments. This form is usually idiopathic. CT plays an important role in the evaluation of patients with mediastinal fibrosis, in many cases obviating invasive procedures. CT scans demonstrate an infiltrative soft tissue mass that obliterates the mediastinal fat planes and encases adjacent structures.167,170 Foci of calcification are well demonstrated, and their presence suggests the diagnosis because other mediastinal infiltrative diseases rarely calcify. Enhanced CT is accurate in assessing the involvement of mediastinal vessels. Spiral CT angiography better demonstrates the extent of vascular involvement and multiplanar reformation, and 3D techniques allow precise estimation of the site, length, and severity of airway stenosis.170,171 CT images photographed on lung window settings allow detection of parenchymal abnormalities secondary to vascular obstruction, such as areas of oligemia, localized edema, and lung infarct.147 Contrast esophagography is superior to CT in assessing the presence and extent of esophageal involvement. MRI provides little, if any, additional useful information and therefore is seldom used in the assessment of patients with fibrosing mediastinitis. Furthermore, it is inferior to CT in the detection of foci of calcification. Fibrosing mediastinitis has heterogeneous intermediate signal intensity on T1weighted MRI scans. The appearance on T2-weighted images is more variable, presumably reflecting the presence of different stages of fibrosis. Fibrosing mediastinitis may show heterogeneous enhancement after IV gadolinium administration.172 CT remains the method of choice in the evaluation of patients with known or suspected fibrosing mediastinitis. MRI is primarily performed for the assessment of vascular involvement when IV iodine contrast administration is contraindicated. Contrast-enhanced spiral CT and magnetic resonance angiography are highly accurate in the assessment of vascular involvement and have replaced pulmonary arteriography and contrast venography in most cases.170,172

1503

A

PNEUMOMEDIASTINUM Pneumomediastinum refers to the presence of air in the mediastinal space. The most common source is extension of air from the lung. Any cause of alveolar rupture, such as deep respiratory maneuvers, asthma, mechanical ventilation (barotrauma), or thoracic trauma, may lead to passage of air into the perivascular and peribronchial interstitium toward the hilum and the mediastinum.173 Traumatic rupture of the trachea or main bronchi and esophageal perforation are less common but more serious causes of pneumomediastinum. Rarely, gas extension from the neck, usually secondary to trauma or surgical procedures, or from the abdominal cavity, usually after perforation of retroperitoneal hollow viscera, may result in pneumomediastinum. Radiographic signs of pneumomediastinum include lucent streaks and focal bubble-like or large collections of air outlining the heart and mediastinal structures (Fig. 123-40A).

Ch123-F06861.indd 1503

B FIGURE 123-40 Spontaneous pneumomediastinum. A, Posteroanterior chest radiograph in a 20-year-old woman shows a linear opacity parallel to the left cardiac border (arrows), representing the mediastinal pleura displaced by air within the mediastinum. Air is seen outlining the heart and the aortic arch. B, CT scan in a 27-yearold woman shows air within the mediastinum surrounding the right main pulmonary artery (arrows). Both patients presented with abrupt onset of retrosternal pain.

1/21/2008 4:01:47 PM

1504

Section 7 Mediastinum

Pneumomediastinum may result in the “continuous diaphragm sign.” This sign results from the presence of air interposed between the heart and the diaphragm, which allows visualization of the central portion of the diaphragm in continuity with the lateral portions. On lateral projections, lucent streaks of air may be demonstrated outlining the ascending aorta, aortic arch, and pulmonary arteries as well as the thymus and brachiocephalic veins. In some cases, air in the substernal region, anterior to the heart, is the only radiographic sign of pneumomediastinum.174 CT images photographed with lung windows are superior to the chest radiograph in demonstrating air within the mediastinum as well as extension to the neck, spine, and subcutaneous tissue (see Fig. 123-40B). CT is also helpful in identifying ancillary findings that suggest the origin of the pneumomediastinum.

BV BV

BA C

S

MEDIASTINAL HEMORRHAGE Mediastinal hemorrhage most commonly results from trauma and in such cases is usually venous in origin. Less common causes include venous perforation secondary to indwelling catheters, aortic rupture and spontaneous hemorrhage in patients with coagulopathy, mediastinal tumors, and longterm hemodialysis.175,176 On chest radiography, mediastinal hemorrhage results in symmetrical widening of the mediastinum. If the accumulation of blood is localized, the resulting hematoma is identified as a homogeneous mass projecting to one or both sides of the mediastinum from any of the mediastinal compartments, depending on the origin of the bleeding.139 CT is superior to chest radiography in demonstrating the presence of mediastinal hemorrhage and determining the underlying cause. Acute hemorrhage typically manifests with areas of high CT attenuation (Fig. 123-41); after approximately 72 hours, the CT attenuation values gradually decrease to values similar to those of water.177 MRI is also highly accurate in the diagnosis and follow-up of mediastinal hemorrhage. Acute hematomas demonstrate medium to high signal intensity, whereas subacute bleeding manifests high signal intensity on T1-weighted images, allowing differentiation from other mediastinal fluid collections.178,179 Because it is more readily available, CT is the imaging modality most commonly used in the evaluation of patients with suspected mediastinal hemorrhage.

COMMENTS AND CONTROVERSIES In recent years, there have been spectacular developments in imaging. Refinements in CT, MRI, PET, and ultrasound technology have transformed the evaluation of mediastinal disease. Drs. Souza and Müller have provided a detailed description of the role of current imaging modalities in the evaluation of the normal mediastinum and commonly encountered pathologies. In our own practice, we restrict MRI to the evaluation of tumor invasion of great vessels, spine, or spinal canal. The vast majority of mediastinal pathologies can be adequately imaged by contrast CT examinations. Impressive, high-definition images are readily obtained by multiplanar reformation and 3D reconstruction.

Ch123-F06861.indd 1504

FIGURE 123-41 Mediastinal hemorrhage secondary to venous perforation. Nonenhanced CT scan at the level of the thoracic inlet shows extensive areas of increased attenuation within the mediastinum (arrows). Measurement of the attenuation values demonstrated 60 HU. The patient was a 33-year-old woman with a history of left internal jugular vein perforation after attempted insertion of an indwelling catheter. BA, brachiocephalic artery; BV, brachiocephalic vein; C, left common carotid artery; S, subclavian artery.

However, there are pitfalls in the application of PET imaging, particularly for the evaluation of mediastinal lymph nodes in geographic areas endemic for histoplasmosis or other organisms producing granulomatous inflammation. False-positive PET scans are extremely common in such regions. Ultrasonography is an underutilized modality for evaluation of the mediastinum. Transthoracic ultrasonography can be effective for the identification of anterior mediastinal masses and guidance of fineneedle aspiration. Transesophageal ultrasonography reliably images posterior mediastinal lesions. The detailed description of imaging features of mediastinal pathologies and the excellent figures provide an outstanding review of mediastinal imaging. G. A. P.

KEY REFERENCES Akman C, Kantarci F, Cetinkaya S: Imaging in mediastinitis: A systematic review based on aetiology. Clin Radiol 59:573-585, 2004. Boiselle PM, Patz EF Jr, Vining DJ, et al: Imaging of mediastinal lymph nodes: CT, MR, and FDG PET. Radiographics 18:1061-1069, 1998. Kim Y, Lee KS, Yoo JH, et al: Middle mediastinal lesions: Imaging findings and pathologic correlation. Eur J Radiol 35:30-38, 2000.

1/21/2008 4:01:48 PM

Chapter 123 Imaging of the Mediastinum

Luketich JD, Friedman DM, Meltzer CC, et al: The role of positron emission tomography in evaluating mediastinal lymph node metastases in non–small-cell lung cancer. Clin Lung Cancer 2:229-233, 2001. Rosado de Christenson ML, Templeton PA, Moran CA: From the archives of the AFIP. Mediastinal germ cell tumors: Radiologic and pathologic correlation. Radiographics 12:1013-1030, 1992.

Ch123-F06861.indd 1505

1505

Strollo DC, Rosado de Christenson ML, Jett JR: Primary mediastinal tumors. Part 1: Tumors of the anterior mediastinum. Chest 112:511522, 1997. Strollo DC, Rosado de Christenson ML, Jett JR: Primary mediastinal tumors. Part II: Tumors of the middle and posterior mediastinum. Chest 112:1344-1357, 1997.

1/21/2008 4:01:49 PM

chapter

124

DIAGNOSTIC STRATEGIES IN MEDIASTINAL MASS Didier Lardinois Walter Weder

Key Points ■ The location of mediastinal masses—based on the division of the

■

■

■

■

mediastinum into anterior, middle, and posterior compartments— has important implications for diagnostic stragtegies and treatment. Cytohistopathologic diagnosis is often required to confirm a presumed diagnosis based on clinical evaluation and on the radiologic characteristics on CT scan, especially for mediastinal masses located in the anterior mediastinum. Techniques used for diagnosis and therapy of mediastinal masses are strongly related to their availability and to the expertise of the investigators. In general, cystic lesions and well-encapsulated mediastinal masses smaller than 7 cm can be completely removed, resection being diagnostic and therapeutic simultaneously. The recent introduction of new techniques and new instruments has changed the strategic decision about how to manage a mediastinal mass, allowing a more accurate diagnosis and the use of minimally invasive surgical procedures.

The mediastinum is anatomically defined as the space between the two lungs; it is demarcated by the thoracic inlet superiorly, the diaphragm inferiorly, the sternum anteriorly, and by the spine and paravertebral thoracic sulci posteriorly (Duwe et al, 2005).1,2 For practical reasons, it is further divided into anterior, middle, and posterior compartments based on anatomic landmarks seen on lateral radiographs (Fig. 124-1). Because the localization, extent, and radiologic characteristics of a mediastinal mass are best evaluated on computed tomographic (CT) scans, these landmarks are applied there accordingly. This has important implications for diagnosis and treatment of mediastinal masses because specific lesions have a predilection for a certain compartment.3 In adults, 54% of mediastinal tumors develop in the anterior mediastinum, 20% in the middle mediastinum, and 26% in the posterior mediastinum. In children, the percentages are comparable: 43%, 18%, and 39%, respectively. Although more than two thirds of mediastinal masses are benign, predilection for malignancy is greater in the anterior mediastinum (60%), compared with 30% in the middle mediastinum and 15% in the posterior compartment.1,4 In most patients with primary mediastinal tumors, identification of the lesion results from the onset of local symptoms or from a routine chest radiographic examination in an asymptomatic patient. It has been shown that symptomatic patients are more likely to have a malignant process because about 85% of patients with a malignancy are symptomatic at diag-

nosis, compared with 45% of patients with benign lesions.3,4 Most commonly, symptoms are related to local compression or direct invasion of neighboring structures, or they are paraneoplastic systemic symptoms. Nonspecific symptoms such as cough, chest pain or discomfort, and dyspnea may result from local compression. Superior vena cava syndrome, Horner’s syndrome, hoarseness, and neurologic signs are more frequently associated with infiltration of adjacent structures. Systemic symptoms are rare and typically are caused by the release of excess hormones, antibodies, or cytokines.1 In addition to clinical signs, laboratory and/or radiologic findings can help in the elaboration of a presumed diagnosis in some patients. The initial workup of a mediastinal mass includes posterior and lateral chest radiographs. In all patients with normal renal function, complete evaluation proceeds to spiral CT of the chest with iodinated contrast medium, which is important in planning further diagnostic and treatment strategies. Other examinations, such as barium swallow, CT angiography, magnetic resonance imaging (MRI), and nuclear scans, can also be used to further characterize a mediastinal mass. In the following section, the clinical, laboratory, and radiographic features of the most commonly encountered mediastinal masses are reviewed. In the next section, a detailed overview of the various diagnostic methods is presented. The differential diagnosis of mediastinal masses based on their location in the mediastinum is summarized in Table 124-1.

CHARACTERISTICS OF MEDIASTINAL MASSES ACCORDING TO THE LOCALIZATION Anterior Mediastinum Primary tumors in the anterior mediastinum account for half of all mediastinal masses. The most commonly encountered masses localized in the anterior compartment of the mediastinum are thymic tumors, followed by lymphoma, germ cell tumors, mesenchymal tumors, and retrosternal goiters. Carcinoma, sarcoma, lymphangioma, aberrant endocrine tumors, and several types of cystic lesions have also been described.5,6

Thymic Tumors Thymic tumors are the most frequent tumors arising in the anterior mediastinum. Benign tumors include thymic cysts and certain types of thymoma. Malignant tumors include invasive thymoma, thymic carcinoma, and, more rarely, neuroendocrine neoplasms.7-9 Thymoma. Thymoma is the most common tumor of the anterior mediastinum. It is a neoplasm that arises in adults

1506

Ch124-F06861.indd 1506

1/21/2008 4:02:40 PM

Chapter 124 Diagnostic Strategies in Mediastinal Mass

1507

TABLE 124-1 Differential Diagnosis of Most Common Mediastinal Masses According to Location in the Mediastinum

Anterior compartment

Visceral compartment

Paravertebral sulcus

Anterior

Middle

Posterior

Thymoma

Lymph node metastasis Neurogenic tumor

Germ cell tumor

Lymphoma

Bronchogenic cyst

Lymphoma

Granuloma

Enteric cyst

Intrathoracic goiter

Bronchogenic cyst

Meningocele

Thymic cyst

Enteric cyst

Carcinoma

Pericardial cyst

Parathyroid adenoma Lipoma Lymphangioma

with a median age of 50 years with no gender preference.10 Up to 40% of patients have a paraneoplastic syndrome such as myasthenia gravis (30% of all thymomas), pure red cell aplasia, or hypogammaglobulinemia (5%-10%). Other paraneoplastic syndromes, such as systemic lupus erythematosus, Cushing’s syndrome, and syndrome of inappropriate antidiuretic hormone secretion (SIADH), may also be observed. Myasthenia gravis is most frequent in women, and symptoms include diplopia, ptosis, dysphagia, weakness, and fatigue. Because of the high incidence of myasthenia gravis associated

with thymoma, patients with clinically suspected thymic tumors have a serum anti-acetylcholine receptor antibody test even if they are asymptomatic.10,11 At contrast CT, noninvasive thymomas are well encapsulated, have a rounded or slightly lobular shape, and usually manifest as a solid lesion (Fig. 124-2). Often, areas with hemorrhage, necrosis, or cystic degeneration are observed. In contrast, invasive thymomas may show infiltration of the adjacent structures on CT (Fig. 124-3). Irregular margins, areas of low attenuation, and multifocal calcification suggest invasive thymoma.1,12,13 Thymic Carcinoma. Thymic carcinomas have cytologic and histologic features pathognomonic of malignancy and present a strong tendency toward early local invasion (Fig. 124-4) and metastatic spread. They are rare, occurring predominantly in middle-aged men. Calcification is present in 10% to 40% of cases, and mediastinal lymphadenopathy is seen in 40% of patients. Compared with thymoma, paraneoplastic manifestations are rare, and most patients are asymptomatic at diagnosis.14-16

FIGURE 124-2 CT scan of 49-year-old woman with noninvasive thymoma shows a slightly lobulated anterior mediastinal mass; the fat plane between the mass and the vessels is intact.

FIGURE 124-3 CT scan of a 42-year-old man with invasive thymoma shows an ill-defined anterior mediastinal mass with extension of tumor into the right lung and with pleural metastasis.

FIGURE 124-1 Shields’ three-compartment model of the mediastinum (FROM SHIELDS TW: MEDIASTINAL SURGERY. PHILADELPHIA, LEA & FEBIGER, 1991, P 4.)

Ch124-F06861.indd 1507

1/21/2008 4:02:41 PM

1508

Section 7 Mediastinum

Thymolipoma and Non-Neoplastic Thymic Cysts. Thymolipoma is a rare, benign, slowly growing tumor that occurs in young adults of both genders (Fig. 124-5). CT and MRI show a characteristic fat density. Thymic cysts can be congenital or acquired and are associated with inflammation. Radiologically, they appear as simple homogeneous cysts within the thymus (Fig. 124-6).17,18

Germ Cell Tumors The term germ cell tumors refers to a group of tumors with histology identical to that of some neoplasms of the testicle and the ovary, all of which are believed to derive from common primary germ cells. The mediastinum, in particular the anterior compartment, is the most common site for extragonadal localization.19 Overall, germ cell tumors account for 10% to 15% of masses of the anterior mediastinum and include teratoma, seminoma, and nonseminomatous dysembryoma. In most cases, the tumor becomes manifest in young adults in the third to fifth decade. Benign tumors (80%) are mature teratomas, whereas malignant ones include seminomas, nonseminomatous dysembryomas, and some teratomas. In adults, benign lesions are more frequent among women and malignant lesions among men (seminomas).20 A correlation has been reported between germ cell tumors and Klinefelter’s syndrome in 8% of cases. Hematologic malignancies (commonly nonlymphoid leukemia and occasionally malignant histiocytosis) have also been found to be associated, particularly with teratomas. Testing of serum α-fetoprotein and β-human chorionic gonadotropin (β-HCG) is mandatory in the presence of clinical and radiologic suspicion of a malignant germ cell tumor.21,22 Teratoma. In the thorax, teratoma is almost exclusively found in the anterior mediastinum and is often diagnosed in adolescents and young adults (third and fourth decade), with equal distribution between genders. Teratomas may have a solid or cystic appearance.23 Mature teratomas are the most common variant, accounting for 70% of mediastinal germ cell tumors in children and 60% in adults. They are well delimited in relation to the sur-

FIGURE 124-4 CT scan of a 48-year-old man with thymic carcinoma infiltrating pericardium, left atrium, and right lung hilus. Extended right pneumonectomy was performed after induction therapy, and patient was still alive 10 years after resection.

A

B

FIGURE 124-5 In this 31-year-old woman with thymolipoma, a posteroanterior radiographic view of the chest (A) shows a large paracardial mass typically falling away from the superior mediastinum and draping the heart, suggesting cardiomegaly. CT (B) reveals a large mass of fat density with islands of soft tissue density representing thymic tissue.

Ch124-F06861.indd 1508

1/21/2008 4:02:42 PM

Chapter 124 Diagnostic Strategies in Mediastinal Mass

A

1509

B

FIGURE 124-6 A, CT scan of a 73-year-old woman with thymic cyst shows homogeneous water density without displacement of the mediastinal vascular structures. B, Intraoperative view of the cyst, which was thoracoscopically removed.

rounding mediastinal structures and may be cystic. These tumors tend to be incidentally discovered in asymptomatic patients. However, they can reach a remarkable size and can give rise to local symptoms.20 Histologically, mature teratomas consist of irregularly arranged, well-differentiated adult tissues of ectodermal (teeth, hairs), mesodermal (cartilage, bone, fat, smooth muscle tissue), and endodermal origin. At CT, mature teratomas have well-defined, smooth or lobulated margins. They are encapsulated and display heterogeneous attenuation due to the combination of soft tissue, fluid, fat, and calcific components. They are typically multilobulated cystic tumors with walls of varying thickness (Fig. 124-7). Cough productive of hair or sebum is a pathognomonic sign of rupture into the tracheobronchial tree.23 Immature teratomas are made up of the same differentiated tissues as mature forms in association with poorly organized fetal-type tissue. In childhood, prognosis is good, whereas at any other age, their behavior is often aggressive. Teratomas with malignant transformation, teratocarcinomas, contain a malignant component, most commonly sarcoma. These tumors tend to be larger than benign forms and are often found to invade adjacent structures at the time of diagnosis.19 Seminoma. Seminoma is the second most frequent germ cell tumor of the mediastinum. It manifests almost exclusively in men in the third or fourth decade of life and is usually symptomatic (70%-80%). Most seminomas are solid and present a slow growth pattern (Fig. 124-8). Only occasionally can cystic degeneration be observed.24 Gynecomastia, increased estradiol, and elevated levels of β-HCG have occasionally been reported. About 10% of patients with pure seminoma may show increased serum β-HCG but never elevated α-fetoprotein. At CT, they typically display homogeneous density and mild enhancement after administration of contrast medium. They rarely show calcification, and invasion of adjacent structures is very rare.22,25

Ch124-F06861.indd 1509

FIGURE 124-7 CT scan of a 35-year-old woman presenting with dyspnea and chest pain on the left side shows a well-circumscribed, heterogeneous mass with various tissue densities and cystic areas, corresponding to a mature teratoma.

Nonseminomatous Dysembryomas. The nonseminomatous dysembryomas include tumors of the endodermal sinus or yolk sac, choriocarcinomas, and the mixed variant. Other malignant components, including adenocarcinomas, squamous cell carcinomas, and sarcomas, may also be present.19 These tumors are symptomatic (90%) and affect young adults younger than 30 years of age. About 85% of cases occur in men, and Klinefelter’s syndrome is associated in up to 20% of patients. Patients usually have elevated lactate dehydrogenase (LDH) and serum markers: α-fetoprotein in 60% to 80% and β-HCG in 30% to 50% of patients. The radiologic appearance is that of a bulky, irregular mass, often with inhomogeneous areas due to necrosis, hemorrhage, and cystic degeneration (Fig. 124-9). There may be invasion of

1/21/2008 4:02:43 PM

1510

Section 7 Mediastinum

FIGURE 124-8 CT scan of a 38-year-old man shows a small, welldelimited solid tumor in the anterior mediastinum 6 years after left castration for seminoma. Complete resection of the lesion was achieved, revealing a mediastinal metastasis of the seminoma. Adjuvant chemotherapy was then initiated, and the patient was still in complete remission 4 years later.

FIGURE 124-9 CT scan of a 27-year-old man with malignant nonseminomatous germ cell tumor shows a large, inhomogeneous anterior mediastinal mass containing areas of necrosis and hemorrhage. The tumor reaches the left chest wall, and the fat plane between the mass and the pulmonary artery is obliterated. Extended left pneumonectomy was performed after induction chemotherapy, and patient was still free of recurrence 5 years later.

adjacent structures, and pleural and pericardial effusions are common.1,19

Lymphoma Lymphoma is a relatively common mediastinal tumor. It accounts for about 20% of all mediastinal tumors in adults and 50% in children. They are mostly Hodgkin’s lymphomas and seldom are confined only to the mediastinum at diagnosis. The most common variants of non-Hodgkin’s lymphomas that primarily affect the anterior mediastinum are large B-cell lymphoma and lymphoblastic lymphoma.26 Hodgkin’s Lymphoma. Hodgkin’s lymphoma has a bimodal age distribution, with an incidence peak in adolescence and early adulthood and another peak after the sixth decade. Systemic B-symptoms such as fever, weight loss, night sweats, and itching are present in 20% to 30% of cases; however, most subjects have no systemic or local symptoms, and the disease is incidentally discovered at chest radiography.27 The anterior mediastinum and paratracheal lymph nodes are the most frequently involved sites. The most common variant (nodular sclerosing) typically manifests as a wellcircumscribed, lobulated mass. At CT, the mediastinal mass may consist of multiple rounded formations with soft tissue density, a bulky mass, or a solid lesion (Fig. 124-10). Large lesions may have a heterogeneous pattern, with areas of low density referable to necrosis, hemorrhage, and cystic degeneration.28,29 Non-Hodgkin’s Lymphoma. Non-Hodgkin’s lymphomas can affect all age groups. At diagnosis, 85% of patients have advanced disease, usually with systemic symptoms, generalized lymphadenopathy, or extranodal disease.30 Large B-cell lymphoma is often observed in young adults and occasionally in children, with prevalence in females.

Ch124-F06861.indd 1510

FIGURE 124-10 CT scan of a 17-year-old woman presenting with progressive dyspnea reveals a solid bulky mass of the anterior mediastinum that blends with the other mediastinal structures. Compression of the superior vena cava and narrowing of the distal trachea are observed. Diagnosis of Hodgkin’s disease was established by use of parasternal mediastinotomy.

Lymphoblastic lymphoma occurs in the first two decades of life, more often in male adolescents. Both histologic types manifest as a bulky, nonencapsulated mass, which may frankly invade the thymus and the adjacent structures.31

Intrathoracic Goiters The term retrosternal goiter has not been clearly defined, and although most studies include only those patients with more than 50% of the gland within the thorax, others include patients with any part of the gland extending through the

1/21/2008 4:02:44 PM

Chapter 124 Diagnostic Strategies in Mediastinal Mass

1511

nary window. The differential diagnosis includes malignancy (e.g., lymphoma, metastatic spread from lung cancer or other malignancies) and inflammatory lymph node changes due to infection (tuberculosis, histoplasmosis) or granulomatous disease (sarcoidosis). CT scans may show typical patterns such as calcifications (tuberculosis) or necrosis (lymphomas).1

Bronchogenic Cysts

FIGURE 124-11 CT scan of a 55-year-old woman shows a large intrathoracic nodular goiter with displacement of the trachea to the left, causing dyspnea, expiratory stridor, and chronic cough. The mass is lightly lobulated and contains areas of hemorrhage and cystic formation.

Bronchogenic cysts result from abnormal budding of the tracheal diverticulum between the third and sixth weeks of gestation; they account for 5% to 10% of all mediastinal lesions. They are usually found adjacent to the tracheobronchial tree but can be also found in the posterior mediastinum or within the lungs.35 These cysts cause symptoms in adults in 30% to 45% of cases, either at diagnosis or during the course of observation, mainly because of compression and rarely because of infection, hemorrhage, or rupture.36 At CT, bronchogenic cysts are well-defined, round masses with a homogeneous density similar to water (Fig. 124-13). However, density and the heterogeneous aspect can make diagnosis difficult because most bronchogenic cysts have a low number of Hounsfield units, although occasionally the cysts contain turbid mucoid fluid, resulting in high CT numbers, and may appear solid. If there is a direct communication with the tracheobronchial tree, air-fluid levels can be seen.35

Enterogenous Cysts thoracic inlet. Most goiters are euthyroid. CT and MRI are considered to be most useful in evaluating the extent of the euthyroid goiter and defining its relationships to adjacent structures. Most intrathoracic goiters are in continuity with an enlarged cervical thyroid gland. At CT, retrosternal goiters classically show smooth borders, are multinodular and lobulated, and may include coarse calcifications and low-density cystic areas (Fig. 124-11). Patients with retrosternal goiter may present with dyspnea, dysphagia, or hoarseness, although about 50% of patients are asymptomatic at diagnosis.32,33

Mediastinal Parathyroid Adenomas Overall, 20% of parathyroid adenomas develop in the mediastinum, with 80% of those in the anterior mediastinum. These tumors are encapsulated, round, and usually smaller than 3 cm in size. MRI or nuclear scans are most effective for the diagnosis (Fig. 124-12).34

Middle Mediastinum The most common lesions arising in the middle mediastinum are either enlarged mediastinal lymph nodes or mediastinal cysts. The latter include cysts from the foregut (enterogenous cysts and bronchogenic cysts) and pericardial cysts. Other lesions, such as paragangliomas, hemangiomas, lymphangiomas, and ectopic parathyroid adenomas, have been described occasionally.4

Esophageal duplication cysts are located in or are attached to the esophageal wall. Twelve percent of the patients have associated malformations, mostly of the gastrointestinal tract. These cysts are often asymptomatic, but if they contain gastric or pancreatic mucosa, there is an added risk of hemorrhage or rupture. Radiologically, they are more often calcified than bronchogenic cysts.37

Pericardial Cysts Pericardial cysts are benign intrathoracic lesions and constitute 7% of all mediastinal tumors.38 They are typically located at the right cardiophrenic angle (50%-70%) or at the left cardiophrenic angle (30%-40%), or rarely in other mediastinal locations not adjacent to the diaphragm (Fig. 124-14). Their size varies from a few centimeters to 30 cm. They are usually congenital but may also be acquired after cardiothoracic surgery. Although most pericardial cysts are asymptomatic, patients may present with chest discomfort, dyspnea, and cough; rarely, life-threatening complications such as cardiac tamponade have been reported. Definitive diagnosis by use of CT may be challenging. Echocardiography was shown to be a superior noninvasive modality in selected cases to delineate the exact location of the cyst and to differentiate it from other potential diagnoses such as fat pad, ventricular or aortic aneurysm, and solid tumors.38

Posterior Mediastinum Enlarged Lymph Nodes Enlarged lymph nodes are typically located around the tracheobronchial tree, the lower esophagus, or the aortopulmo-

Ch124-F06861.indd 1511

Mediastinal masses localized in the posterior mediastinum are mostly neurogenic tumors or foregut cysts (esophageal duplications, neuroenteric cysts).

1/21/2008 4:02:45 PM

1512

Section 7 Mediastinum

A Anatomic

Physiologic

Fusion

Transaxial

Transaxial

Transaxial

65

51

B FIGURE 124-12 A, CT scan of a 38-year-old patient with prolonged hypercalcemia despite former cervical parathyroidectomy shows a small, solid tumor mass localized within the thymic rest. B, Dual-phase 99mTc-sestamibi (MIBI) scintigraphy shows ectopic parathyroid in the anterior mediastinum.

Neurogenic Tumors Neurogenic tumors comprise approximately 15% to 20% of all mediastinal masses, although 95% occur in the posterior compartment. Between 70% and 80% are benign, and about 50% are asymptomatic and detected incidentally on chest radiography. When present, symptoms consist of compressive

Ch124-F06861.indd 1512

or neurologic symptoms. The intercostal nerve or the sympathetic chain is involved in 95% of cases.39,40 Benign Nerve Sheath Tumors. Benign nerve sheath tumors are often asymptomatic and represent 40% to 60% of neurogenic mediastinal masses; they are mostly schwannomas (75%). Schwannomas are firm and encapsulated.39 Neurofibromas are nonencapsulated, friable, and associated with

1/21/2008 4:02:45 PM

Chapter 124 Diagnostic Strategies in Mediastinal Mass

FIGURE 124-13 CT scan of an asymptomatic 23-year-old woman reveals a well-defined, homogeneous cystic tumor in the middle and posterior mediastinum with 30 Hounsfield units (HU). Typically, the cyst occurs around the tracheal carina in relation to the major airways. Differential diagnosis includes enterogenous cyst and neuroenteric cyst.

1513

FIGURE 124-15 CT of a 19-year-old patient presenting with a sharply demarcated mass in the posterior mediastinum, corresponding to a schwannoma, shows a deformity of the vertebral body. The lesion was completely removed by the video-assisted thoracoscopic surgery (VATS) technique. Differential diagnosis includes neurofibroma.

Autonomic Ganglionic Tumors. Autonomic ganglionic tumors arise from neuronal cells rather than from the nerve sheath. They include various entities ranging from benign encapsulated ganglioneuroma to aggressive malignant nonencapsulated neuroblastoma. Ganglioneuromas occur in the second or third decade and are mostly asymptomatic. These tumors are well-marginated and occur along the anterolateral aspect of the spine, spanning three to five vertebrae. At CT, the mass can be homogeneous or heterogeneous.43 Neuroblastomas occur in young children (<5 years) and are highly aggressive. They are nonencapsulated and often show hemorrhage, necrosis, and cystic degeneration. Symptoms include pain, neurologic deficits, Horner’s syndrome, respiratory distress, and ataxia. They can also produce vasoactive substance that can cause hypotension, flushing, and diarrhea. Neuroblastomas often cause skeletal damage, and 80% have calcification.44 FIGURE 124-14 CT scan of an asymptomatic 32-year-old man shows typical localization of a pericardial cyst in the left cardiophrenic angle with water density.

von Recklinghausen neurofibromatosis. Imaging findings show sharply marginated spherical masses (Fig. 124-15) with possible deformity of the ribs and vertebral bodies. MRI is useful to rule out intraspinal extension (dumbbell tumors).41 Malignant Tumors of Nerve Sheath Origin. The malignant tumors of nerve sheath origin include malignant neurofibromas, malignant schwannomas, and neurogenic fibrosarcomas. They affect men and women equally in the third to fifth decade of life.42

Ch124-F06861.indd 1513

Neuroenteric Cysts Neuroenteric cysts are associated with multiple vertebral anomalies, such as scoliosis, spina bifida, hemivertebra, and vertebral fusion.40

DIAGNOSTIC METHODS OF MEDIASTINAL MASSES Despite the fact that the mediastinum can harbor a large variety of mass lesions, clinical assessment and imaging guide the further management. However, imaging and clinical evaluation often do not allow a conclusion as to final diagnosis in these patients. Therefore, cytohistopathologic diagnosis is often required to confirm a presumed diagnosis and to provide the optimal strategy of therapy.

1/21/2008 4:02:48 PM

1514

Section 7 Mediastinum

A variety of techniques, including endoscopic or percutaneous radiologically guided fine-needle aspiration (FNA) biopsy and core needle biopsy, surgical biopsy through various approaches including parasternal anterior mediastinotomy, videomediastinoscopy, video-assisted thoracoscopic surgery (VATS), and open procedures (median sternotomy, thoracotomy), must be considered to achieve diagnosis and optimal treatment. Which technique is applied depends on the expected diagnosis and planned treatment. This evaluation includes clinical aspects such as the age of the patient, the expected risk for a malignancy, or the risk that the lesion will develop complications, but also the availability of certain techniques with the required expertise of the investigators.

Percutaneous Image-Guided Fine-Needle Aspiration Biopsy FNA biopsy is a minimally invasive procedure that yields a cytologic diagnosis and is performed under the guidance of either CT or ultrasonography. The technique is performed with local anesthesia and light sedation and requires patient compliance. FNA biopsy can be applied for lesions in all compartments but is mainly used for lesions located in the anterior and middle compartments.45 The application of this technique is controversial. Some authors believe that FNA biopsy may confirm presumed diagnosis but is “never adequate to obtain sufficient tissue to establish a precise diagnosis of lymphoma” (Wakely, 2002).46 Sensitivity of FNA biopsy was reported to be as low as 20% or 71% in patients with lymphoma or thymoma, respectively.47 From the opposite point of view, others consider FNA biopsy to be a highly reliable technique with greater than 80% diagnostic accuracy.45,48,49 Regarding primary neoplasms of the mediastinum, the sensitivity, specificity, and overall accuracy of the FNA biopsy were found to be 85%, 100%, and 93%, respectively.50 Considering non-neoplastic lesions, FNA biopsy may provide high sensitivity and specificity (up to 100% and 93%, respectively), especially in thyroid masses and granulomatous lesions. The reason that surgical biopsy is often required for accurate diagnosis is not only the sampling problem (difficult location, small size of the lesion) but also the difficulty in interpretation of the material sampled, especially for those tumors requiring an immunologic classification. Güllüoglu and colleagues showed that, with the on-site presence of a cytologist giving a feedback for adequacy of the aspirated material, inadequate sampling occurs in fewer than 10% of patients.50 However, Watanabe and associates found a correlation between the cytopathologic diagnosis after FNA biopsy and the final diagnosis in only 50% of the patients, although the material was representative in 90%.51 It has been shown that the ability of FNA biopsy to subtype lesions is less than that of tissue biopsy.52 Indeed, because of the broad spectrum of tissue types in the anterior mediastinum and the variety of cell morphologies even within the same lesion, the results are extremely dependent on the area where aspiration is performed. In his report on cytology-histopathology of the mediastinum,46 Wakely mentioned the relatively poor accuracy of FNA biopsy in the following areas: differentiation

Ch124-F06861.indd 1514

between invasive and noninvasive thymoma, differentiation between thymoma and lymphoma, diagnosis of thymic hyperplasia, diagnosis of Castleman’s disease, subtyping of lymphoma, and differentiation among nonseminomatous germ cell tumor, carcinoma, and large cell lymphoma. On the other hand, FNA biopsy is a safe procedure, with low costs and minimal pain, and it allows early mobilization. An advantage of this technique is that immediate radiotherapy or chemotherapy can be performed because there is no surgical wound. It is also indicated if the patient would be at risk for complications of general anesthesia. However, sufficient expertise of both the investigator and the cytopathologist is not available in all institutions. Pneumothorax is the most frequent complication of FNA biopsy, with an incidence ranging between 4.6% and 41%.53 However, insertion of a chest tube drainage is required in only about 5% to 10% of the patients. Implantation of tumor cells in the needle tract has been reported but is extremely rare.54

Percutaneous Core Needle Biopsy Percutaneous core needle biopsy is suitable for large tumors located mostly in the anterior mediastinum. It provides a larger volume of tissue than FNA biopsy does, and the architecture of the material sampled is preserved. This allows for more sophisticated laboratory analysis, such as electron microscopy, flow cytometry, immunocytochemistry, and measurement of surface tumor markers, all of which increase diagnostic specificity.52,55 Percutaneous core needle biopsy is usually performed using an 18-gauge Tru-Cut automatic cutting needle under CT or ultrasonographic control. This needle is designed to obtain core specimens for histologic analysis: a spring-activated mechanism that fires a cutting cannula, which snares a biopsy specimen adequate for histologic examination into a 1.7-cm stylet. An average of two passes is usually performed to obtain representative sampling.55 In a series of 70 patients undergoing percutaneous core cutting needle biopsy for masses of the anterior mediastinum, adequate material was obtained in 89% of the patients, with an overall sensitivity of 92%.53 However, diagnostic accuracy was much lower (25%) in necrotic tumors. Pneumothorax is the most commonly encountered complication (11% of the procedures), and hemoptysis is observed in 1.6% to 3% of the patients. Pain is found in 3.2% to 5% of the patients.53 Uncooperative patients; those with chronic uncontrollable cough, severe pulmonary emphysema, or coagulation disorders; and those who have undergone surgical procedures may not be ideal candidates for this procedure. The advantages of the percutaneous image-guided FNA biopsy and core needle biopsy are that they are minimally invasive, safe, and reproducible; can be done in an outpatient setting; achieve good cosmetic results; and are cost-effective. The disadvantages are the limited yield of application (anterior mediastinum and some lesions of the middle mediastinum); low diagnostic accuracy and higher morbidity in small lesions; unnecessary delay in diagnosis and therapy if not conclusive (thymoma and lymphoma); and the requirement

1/21/2008 4:02:48 PM

Chapter 124 Diagnostic Strategies in Mediastinal Mass

for expertise of the investigator and an experienced cytopathologist.

Ultrasound-Guided Endoscopic Biopsy Endoscopic ultrasound-guided FNA biopsy (EUS) was introduced in the early 1990s. At present, both cytology and histology results can be obtained by EUS, which has broadened the range of applications and allowed for subclassification of the lesions.56 EUS offers a minimally invasive method to biopsy mediastinal masses located adjacent to the tracheobronchial tree or the esophagus by a transbronchial or transesophageal approach (Fig. 124-16). The posterior and middle mediastinum is otherwise relatively inaccessible to percutaneous approaches for tissue diagnosis because it is surrounded by the spine posteriorly, the lungs laterally, and the trachea, heart, and great vessels anteriorly.57 The main indications for

A

Esophagus

Mass

Ao R lung_

Mass

Sp

B FIGURE 124-16 A, Endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA): distal end of the endobronchial ultrasound probe (XBF-UC260F-OL8; Olympus Ltd), showing the convex-array ultrasound transducer with the balloon inflated and a 22-gauge aspiration needle protruding from the biopsy channel. B, Esophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA biopsy): 65-year-old patient with non–small cell lung cancer in the left upper lobe and enlarged lymph nodes in the aortopulmonary window. Ultrasound will guide the sampling of the nodes for tumor staging. Ao, aorta; R, right; Sp, spine.

Ch124-F06861.indd 1515

1515

EUS in the mediastinum are for diagnosis of enlarged lymph nodes of unknown nature, for diagnosis and staging of non–small cell lung cancer (NSCLC), and for differentiation between specific cancers and lymphomas.58,59 Endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA) allows exploration of the middle mediastinum, whereas esophageal ultrasound-guided fine needle aspiration biopsy (EUS-FNA) is rather indicated for lesions located in the posterior and inferior mediastinum. TBNA has been shown to be a safe and useful diagnostic method by which to assess enlarged mediastinal lymph nodes of the superior middle mediastinum (paratracheal, level 2 and 4, right and left) and the subcarinal lymph nodes (level 7). However, this procedure is usually restricted to large subcarinal lymph nodes, with reported sensitivities varying from 38% to 89% reflecting the operator dependency of this “blind” approach.60 In a recent overview, a sensitivity of 76% and a false-negative rate of 29% were reported for conventional TBNA in patients with clinical stage IIIA N2 disease. This high false-negative rate compromises the use of conventional TBNA for routine mediastinal lymph node staging; however, it can be used as a preliminary diagnostic test, complemented in negative cases with surgical staging.60 The diagnostic accuracy of the technique was clearly improved by ultrasound guidance (EBUS-TBNA). Initially, endobronchial ultrasound probes were radial scanning catheter probes passed through the instrument channel of a bronchoscope. They provided images of the wall layers of major airways and tumor invasion but had limited depth of penetration, and nodes could not be sampled. More recently, a convex array probe has been introduced. An electronic convex array ultrasound transducer is mounted at the distal tip and covered by a water-inflatable balloon sheath. Scanning is performed at 7.5 MHz and allows a penetration of up to 50 mm. FNA biopsy is performed using a dedicated 22-gauge needle passed through the airway wall and into the lymph nodes under real-time ultrasound control. The optimal number of passes required in the absence of on-site cytology is estimated to be three to four passes. With experience, the procedure can be completed in approximately 30 minutes.61 EUS-FNA is mainly suitable for the assessment of lymph nodes in the posterior part of levels 4L (left tracheobronchial angle) and 5 (aortopulmonary window), in the subcarinal level 7, and in the inferior mediastinum at levels 8 (lower esophagus) and 9 (pulmonary ligament), as described on the Mountain-Dresler map.56 EUS-FNA is performed using a linear array echoendoscope and usually a 22-gauge aspiration needle. Optimally, the slides are prepared and evaluated immediately to determine adequacy. EUS Tru-Cut biopsy using a 19-gauge needle device can also been used. The TruCut needle may be useful in selected cases of mediastinal lymph nodes or masses for suspected smooth muscle tumors, sarcomas, and lymphomas, or if FNA cytology is nondiagnostic. The overall accuracy rate for diagnosing posterior mediastinal malignancy with EUS-FNA is approximately 93%.59 According to the diagnostic and staging accuracy of EUSFNA in patients with proven or suspected NSCLC, a review of the literature reported a pooled sensitivity of 88%, a specificity of 91%, a positive predictive value of 98%, and a

1/21/2008 4:02:49 PM

1516

Section 7 Mediastinum

negative predictive value of 77% (Annema et al, 2005).57,58,62 In staging of NSCLC, mediastinoscopy and EUS-FNA are considered as complementary diagnostic methods. A recent study by Annema and colleagues in 107 patients with potentially operable NSCLC who were scheduled for mediastinoscopy showed that the combination of mediastinoscopy and EUS-FNA significantly improved sensitivity and negative predictive value, with diagnosis of mediastinal lymph node involvement in 36% compared with 20% after mediastinoscopy and 28% after EUS-FNA alone.63 However, most of the accuracy studies on invasive nonsurgical staging were retrospective and were performed in selected patients with a high suspicion of N2-N3 disease. When the prevalence of involved mediastinal lymph nodes is high as mentioned earlier, an improved sensitivity is to be expected; this does not reflect the accuracy in patients with normal-sized lymph nodes. In a recent meta-analysis including 13 studies in which all EBUSTBNA results were confirmed by surgical biopsies, it was shown that the sensitivity of EBUS-TBNA critically depends on the prevalence of mediastinal lymph node metastases. In populations with a lower prevalence of mediastinal metastases, the sensitivity of EBUS-TBNA was much lower than reported in recent lung cancer guidelines.64 For this reason, it is generally accepted that endoscopic techniques (both EBUS-TBNA and EUS-FNA) are suitable to provide histologic proof of suspicious mediastinal lymph nodes but cannot be used to exclude mediastinal lymph node disease because of the low negative predictive value. In the diagnosis of sarcoidosis, EUS-FNA was shown to be a reliable method, with a sensitivity of 89%, a specificity of 96%, and a diagnostic accuracy of 82%. As for the percutaneous techniques, the on-site presence of an experienced cytopathologist during the procedure is recommended to maximize the yield of EUS-FNA.59 The sensitivity of diagnosing lymphoma can be increased by adding flow cytometry and immunocytochemistry (44%-86%).59 EUS-FNA is safe, with reported complication rates of less than 0.5%.60 Complications are mostly reported as case studies and include infection (mediastinitis) or cyst infection, hemorrhage, and perforation. Because most posterior mediastinal cysts are benign and infection is a recognized complication, it is obvious that posterior mediastinal duplication cysts must not be aspirated with EUS-FNA.62 EUS-FNA was shown to be cost-effective if used initially, instead of initial mediastinoscopy, in patients with lung cancer.65 However, this result must be taken with caution because most of the patients included had enlarged mediastinal lymph nodes. The advantages of the ultrasound-guided endoscopic FNA biopsy are that it is minimally invasive, is safe with low morbidity, can be done in an outpatient setting, and may avoid unnecessary thoracotomies. The disadvantages are as follows: the yield of application is limited to the middle and posterior mediastinum; the procedure can be time-consuming; it requires the expertise of an experienced investigator and cytopathologist; it requires expensive equipment that is available only in some centers; and there is a lack of prospective randomized studies comparing this technique with other

Ch124-F06861.indd 1516

conventional imaging procedures (e.g., positron emission tomography [PET]-CT) or with more invasive surgical approaches.

Parasternal Anterior Mediastinotomy (Chamberlain’s Approach) The parasternal anterior mediastinotomy approach was first described in 1966 by McNeil and Chamberlain.66 The procedure is indicated for large masses located in the anterior mediastinum that have direct contact with the posterior aspect of the sternum or parasternal chest wall and for paraaortic lesions and masses arising from the aortopulmonary window.51,66,67 This technique is usually performed with the patient under general anesthesia. Local anesthesia may be preferred for patients with compression of the distal trachea and main bronchi by the tumor, to avoid airway collapse after induction of anesthesia.51,68 The patient is placed in supine position. The level of incision is based on CT findings. A transverse parasternal skin incision of about 4 cm is made. In young female patients, a more cosmetic, small, submammary incision is used whenever possible. Removal of the costal cartilage is not necessary, and the internal mammary vessels are preserved. It is recommended not to open the pleura, to avoid dissemination of the tumor cells. The target tissue is excised using a scalpel and forceps to ensure that a specimen with a volume of about 1 cm3 is obtained.67 The biopsy specimen includes fragments of the capsule and not only necrotic material, to increase diagnostic accuracy. Immediate pathologic examination is performed to evaluate whether the specimen is representative for diagnosis. Complications such as pneumothorax and injury to the internal mammary vessels with bleeding have been described in 1% to 4% of cases. Watanabe and associates reported that diagnostic accuracy is significantly higher with parasternal anterior mediastinotomy than after needle biopsies.51 This technique has also been used for removal of mediastinal parathyroid tumors.69 The advantages of this technique are that it provides representative material, the diagnostic accuracy is greater than 90%, local anesthesia is possible, and morbidity is low. The disadvantages are that it is an invasive procedure, occasionally general anesthesia must be used, it is applicable only in selected cases of masses in the anterior mediastinum, there is a risk of pleural opening with possible tumor seeding, the cosmetic result is not always satisfactory, and overnight hospitalization may be required according to the center.

Cervical Mediastinoscopy and Videomediastinoscopy (Conventional and Extended) The cervical mediastinoscopy technique was described in 1959 by Carlens and is useful for diagnosis of lesions located in the superior middle mediastinum, pretracheal and paratracheal spaces, and subcarinal lymph nodes.70 This approach is generally used for diagnosis and staging of NSCLC and small cell lung cancer and for diagnosis of lymphoma, sarcoidosis, and tuberculosis. Excision biopsy with definitive therapy can also be achieved in patients with mediastinal lipoma or, very rarely, parathyroid adenoma.34,69

1/21/2008 4:02:49 PM

Chapter 124 Diagnostic Strategies in Mediastinal Mass

anterior mediastinal masses and particularly accurate in the diagnosis of lymphadenopathies in the aortopulmonary window and subaortic region. It is performed with the patient under general anesthesia, using a suprasternal notch incision as in cervical mediastinoscopy. After preparation of the retrosternal space, a dissection is made between the anterior face of the left innominate vein and the posterior face of the sternum. This technique allows entry at the level of the aortic arch at the origin of the innominate artery. The mediastinoscope is then passed by sliding it along the left anterolateral face of the aortic arch until it reaches the subaortic space or aortopulmonary window.80 However, the technique has never gained wide acceptance and is currently used in few centers only. The advantages of videomediastinoscopy are that the biopsies are always representative, the diagnostic accuracy is about 100%, the cosmetic results are good, it can be performed in an outpatient setting, and there is very low morbidity in experienced centers. The disadvantages are that it is an invasive procedure, general anesthesia is required, a short hospitalization (1-2 days) is required according to the center, there is a limited application (superior middle mediastinum and subcarinal space), and life-threatening complications are possible.

Mediastinoscopy is well established as an invasive mediastinal diagnostic and staging procedure for patients with potentially operable NSCLC and allows histologic confirmation or exclusion of N2 or N3 disease in most patients.71-73 This technique provides access to the left and right paratracheal lymph nodes (level 2R, 4R, 2L, 4L) and to the subcarinal lymph nodes (level 7). Access to the aortopulmonary window (level 5) is limited by the aorta and the left main stem bronchus. Technical refinements achieved by using a video-assisted approach (videomediastinoscopy) have contributed to increased acceptance of the procedure because of improved magnification of the dissection field and the possibility of on-line projection of the procedure for teaching purposes.71 Mediastinoscopy has experienced a renaissance due to the introduction of neoadjuvant treatment protocols and recognition of the limitations of noninvasive mediastinal staging by CT. The introduction of fluorodeoxyglucose (FDG)-PET has called into question the role of mediastinoscopy for mediastinal staging. However, recent reports have demonstrated the need for appropriate mediastinal restaging after induction therapy to aid proper selection of patients who are likely to benefit from surgical resection.74,75 This is of additional importance because PET scanning is limited for predicting residual N2 disease after induction therapy.76 In their metaanalysis, Toloza and coworkers found a sensitivity between 85% and 92%, a specificity of 100%, and a diagnostic accuracy of 96% in staging of patients with NSCLC (Toloza et al, 2003).77 Procedure-related complications have been observed in up to 3% to 4% of patients and have included left recurrent nerve palsy, vascular lesions (innominate vein, azygos vein, brachiocephalic trunk), and esophagus injury.68,78 Extended cervical mediastinoscopy was fist performed by Kirschner in 1971 and was later modified by Ginsberg and Lopez and their associates.47,79,80 This technique was shown by the authors to be safe and effective in the diagnosis of

A

1517

Video-Assisted Thoracoscopic Surgery (Conventional and Robotic) VATS permits excellent exposure of the entire mediastinum and allows precise dissection. This technique is a valuable tool, particularly in cases of masses with difficult access that require direct vision, such as tumors with proximity to neurovascular structures or to the vessels or the heart (Fig. 124-17).81,82 The patient is intubated with a double-lumen tube in the lateral decubitus position. One or two monitors are placed to provide the best view to all members of the

B

FIGURE 124-17 A, Thoracoscopic view of a bronchogenic cyst in a 23-year-old woman. Despite strong adhesions between the cyst and the esophagus and trachea, complete resection was possible by use of the video-assisted thoracoscopic surgery (VATS) technique. B, Typical location of a schwannoma in a 19-year-old patient. The tumor was removed thoracoscopically.

Ch124-F06861.indd 1517

1/21/2008 4:02:49 PM

1518

Section 7 Mediastinum

operating team. The first trocar for the camera is introduced along the midaxillary line between the sixth and eighth intercostal spaces, according to the site of the tumor. After exploration of the thoracic cavity and localization of the tumor, two or, rarely, three other operative ports are positioned along the anterior and posterior axillary line between the fourth and sixth intercostal spaces, to provide the best management of the lesion. If the harvesting of a large tumor is required, the anterior port can be widened to about 4 to 5 cm at the end of the procedure. This small incision (utility thoracotomy) is performed anterolaterally along the inframammary fold. This incision may be extended for a thoracotomy if conversion is required. Besides permitting extraction of larger specimens, the utility thoracotomy may allow insertion of conventional instruments to facilitate the resection.81 In addition to the possibility of allowing selective and large biopsies of mediastinal masses, VATS provides a better evaluation of the anatomic relationship of the tumors, detecting tumor invasion or metastatic spread.83-85 Moreover, complete surgical excision (excisional biopsies) of small lesions (<4-5 cm), such as cystic tumors of the middle mediastinum, encapsulated thymic tumors, and benign neurogenic tumors (neurinomas, schwannomas) of the posterior mediastinum, can be accomplished, providing the advantages of minimally invasive surgery and avoiding the disproportionate operative trauma of the open procedures.81,86,87 In case of myasthenia gravis associated with thymic hyperplasia or a small thymoma, total thymectomy and resection of the surrounding fatty tissue can be carried out thoracoscopically (Fig. 124-18). In case of thymic neoplasms, total thoracoscopic thymectomy is limited to masses that are no larger than 5 cm in diameter, with an intact capsule and with sufficient surrounding thymic parenchyma to allow safe endoscopic manipulation.81,87

FIGURE 124-18 Intraoperative view shows clipping of a thymic vein during thymectomy by use of the da Vinci robotic surgical system (Surgical Intuitive, Mountain View, CA). The increased visualization and instrument dexterity afforded by this technology provide a feasible and safe alternative to open approaches and conventional thoracoscopy.

Ch124-F06861.indd 1518

VATS may also play a role in the staging of NSCLC to diagnose and confirm metastases in enlarged or PET-positive lymph nodes that are not reachable mediastinoscopically or by endoscopic techniques, such as lymph nodes in the aortopulmonary window, the superior para-aortic area, or the posterior mediastinum.83 VATS has also been shown to be more accurate then CT-guided biopsy in the pathologic diagnosis of residual mediastinal masses after treatment of lymphoma.88 The method continues to be contraindicated for invasive tumors because the only technically accepted and oncologically correct resections are those accomplished via open surgery. In his series of 118 patients with mediastinal masses who underwent VATS, Roviaro and colleagues used this technique for diagnosis or staging in 40% and for full resection in 60% of the patients.81 In the literature, the diagnostic accuracy of VATS is reported to be between 91.9% and 100%.83,88 When VATS is performed for diagnosis only, the morbidity is minor. In the case of excisional biopsy or complete resection of a lesion, complications such as intraoperative bleeding (2%), injuries to nerves (recurrent nerve palsy, phrenic nerve palsy, Horner’s syndrome; 2.7%), prolonged air leak, injury to the stellate ganglion, infection, and tumor implantation at the site of the trocars have been described.89 The specimen is extracted inside a plastic bag through the trocar or utility thoracotomy incision. In his overview of 150 patients undergoing VATS for mediastinal masses, Akashi and associates reported a conversion rate to conventional thoracotomy of 5.3%. The reasons were bleeding from the internal mammary or intercostal vessels and severe adhesions (cysts). Reoperation for recurrence was observed in 1% to 2% of the patients. No operative or hospital deaths were observed.87 Clearly, this technique limits surgical trauma and postoperative pain compared with open procedures. Chetty and colleagues found significant postoperative benefits over open surgery in regard to mean volume of chest drainage, postoperative pain, and hospital stay.86 However, to guarantee as low a morbidity as possible, complete resection of mediastinal masses using VATS is performed only in experienced centers. Preliminary results with the robotic surgical system (da Vinci, Surgical Intuitive, Mountain View, CA) showed that this technique can be applied safely for resection of selected mediastinal masses.90,91 The main technological advantages of this system are realistic three-dimensional imaging, motionscaling, and tremor filtration. Thus, it facilitates more precise and accurate endoscopic surgery as compared with VATS. Movement of the instruments allows seven degrees of freedom and is therefore superior to a surgeon’s hand in open surgery. The fact that the camera is robotically controlled provides an entirely stable camera image. That has been shown to improve the motion coordination and the dexterity of the surgeon.90 This technique has been used mostly for thymectomies but also for resection of masses in the posterior mediastinum (DeRose et al, 2003).90,92 In the surgery of the thymus, another advantage of the robotic technique is the possibility to perform extended thymectomies from a single-sided approach, which is critical for the conventional thoracoscopic procedure.93

1/21/2008 4:02:50 PM

Chapter 124 Diagnostic Strategies in Mediastinal Mass

As for conventional VATS, a limitation of the robotic approach is the size of the tumor. However, lesions up to 7 to 10 cm can be removed with the robotic approach. A disadvantage of the robotic procedure is the lack of tactile feedback and the high cost. Intraoperative and postoperative complications in the published series were comparable with those of conventional thoracoscopic interventions.90,92,93 The robotic technique provides an alternative to open approaches and so-called conventional thoracoscopy. Nevertheless, the role of robotic systems in thoracic surgery has not yet been clearly defined. Further investigation in large series and long-term follow-up are required to evaluate this approach precisely and to define appropriate indications. The advantages of the VATS technique are that it provides access to most parts of the mediastinum, with excellent exposure; provides the diagnosis in most cases; provides good cosmetic results; and offers the possibility to operate simultaneously in a diagnostic and therapeutic concept. The disadvantages are that it is an invasive procedure, requires general anesthesia, requires 1 to 3 days of hospital stay, results in chronic pain in up to 5% to 10% of patients, is associated with higher morbidity, and has higher costs (especially robotic systems).

1519

middle mediastinum (bronchogenic and enterogenous cysts), for most of the cystic lesions of the anterior mediastinum, and for noninvasive thymomas and mature teratomas. The selected approach to resect the mediastinal mass depends on the experience and expertise of the center. Recent developments in VATS, with the introduction of more precise instruments and techniques (high definition television, robotics), allow the resection of most mediastinal masses by minimally invasive surgery (Fig. 124-19). Only large lesions (>5-7 cm) or technical difficulties (adhesions, obesity) are still an indication for open procedures. Liberal diagnostic puncture of cystic lesions is avoided because of the risk of infection. Pericardial cysts can often be diagnosed by CT and echocardiography, if required, and do not need further therapy if the size is less than 5 to 10 cm (Fig. 124-20).

Open Procedures (Sternotomy, Thoracotomy, or Combination) An open approach is recommended for diagnosis and simultaneous complete resection, such as for residual mediastinal masses after chemotherapy for lymphoma, resectable thymic tumors, germ cell tumors, or tumors in the posterior mediastinum not resectable by VATS.88 Other indications are conversion of a VATS operation (due to adhesions, bleeding, or infiltration) and resection of a large encapsulated mass that is not resectable by use of the minimally invasive surgical techniques.81 Primary use of the open procedures in patients with suspected malignant mediastinal lesions and infiltration of the neighboring structures without previous histology is avoided. Advantages of the open approaches are that they provide excellent exposure, always allow tissue biopsies, provide the only approach to resect large lesions, and provide better control of the resection margins. The disadvantages are that they are invasive procedures, have higher costs, are cosmetically less favorable, require longer hospitalization, and are associated with higher morbidity.

FIGURE 124-19 Intraoperative view of an ectopic mediastinal parathyroid in a 38-year-old patient with persistent hypercalcemia despite repeated cervical parathyroidectomy (same patient as in Fig. 124-12). Complete resection of the tumor was achieved by use of the robotic technique.

STRATEGIC DECISIONS The strategic decisions about how to manage a mass lesion in the mediastinum depend on the location and expected diagnosis, the age and comorbidities of the patient, and the availability of the required equipment and expertise of the investigators. In general, in most patients with cystic lesions or wellencapsulated solid masses without any signs of invasiveness or malignancy, complete resection of the lesion is advisable, being diagnostic and therapeutic simultaneously. This is the case for most lesions located in the posterior mediastinum (neurinomas, schwannomas), for the cystic lesions of the

Ch124-F06861.indd 1519

FIGURE 124-20 Thoracoscopic resection of a pericardial cyst located in the left cardiophrenic angle in a 32-year-old patient (same patient as in Fig. 124-14).

1/21/2008 4:02:51 PM

1520

Section 7 Mediastinum

Lesions adjacent to the tracheobronchial tree or the esophagus that most likely have arisen from lymph nodes are best approached primarily by endoscopic ultrasound-guided FNA biopsy through a bronchoscope or esophagoscope. If the retrieved tissue does not allow a definitive diagnosis, mediastinoscopy for biopsy of enlarged lymph nodes (paratracheal or subcarinal), or VATS for the lower paraesophageal region, the aortopulmonary window, and along the aorta, is applied without unnecessary delay secondary to repetitive use of inaccurate techniques. Major difficulty in achieving precise diagnosis may be encountered in lesions of the anterior mediastinum that are not well circumscribed. The differentiation between lymphomas, poorly delimited thymomas, or thymic carcinomas and large germ cell tumors can be challenging. Integration of clinical signs, laboratory findings, and the radiologic appearance are important, but in practice they are rarely conclusive and are not sufficiently discriminative to decide the best strategy of therapy. Often, a multimodality therapy is required, depending on the disease. Several techniques and approaches can be applied to provide correct diagnosis. Again, the experience and expertise of the surgeons, cytologists, pathologists, and radiologists are keys of success. Primary percutaneous FNA biopsy or, preferentially, core needle biopsy is considered as a first choice but must be quickly switched to more invasive surgical techniques if not conclusive. Surgical techniques have the major advantage of providing a diagnostic accuracy of almost 100%. Parasternal anterior mediastinotomy is recommended for the diagnosis of large retrosternal masses and VATS for all other types of lesions, independent of the location.

COMMENTS AND CONTROVERSIES The authors have provided an excellent perspective of diagnostic strategies for the mediastinal mass. A concise review of mediastinal masses by their respective compartments is provided. In addition, the roles of various diagnostic strategies, FNA under ultrasound or CT guidance, core biopsy, and minimally invasive and open surgical approaches are discussed, along with advantages and disadvan-

Ch124-F06861.indd 1520

tages of each. Also included are important data regarding newly developing strategies of endobronchial and endoesophageal ultrasound-guided biopsy. These strategies and procedures need to be in the armamentarium of every thoracic surgeon. G. A. P.

KEY REFERENCES Annema JT, Versteegh MI, Veselic M, et al: Endoscopic ultrasound fineneedle aspiration in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol 23:8357-8361, 2005. ■ This is a report of one of the first series of any significant number of patients undergoing a new minimal invasive diagnostic and staging technique of NSCLC. The authors describe their results and try to define the place of this new technique in the staging algorithm of NSCLC. DeRose JJ Jr, Swistel DG, Safavi A, et al: Mediastinal mass evaluation using advanced robotic techniques. Ann Thorac Surg 75:571-573, 2003. ■ This report describes one of the first cases of treatment of a mediastinal mass using the da Vinci Robotic Surgical System. It underlines the fact that the videothorascopic techniques have broadened the surgeon’s ability to evaluate or completely resect mediastinal masses using a minimally invasive approach. Duwe BV, Sterman DH, Musani AI: Tumors of the mediastinum. Chest 128:2893-2909, 2005. ■ A comprehensive review of the anatomy of the mediastinum with the different clinical, radiographic, and therapeutic options of the most commonly encountered masses. Toloza EM, Harpole L, Detterbeck F: Invasive staging of non–small cell lung cancer: A review of the current evidence. Chest 123:157S-166S, 2003. ■ This excellent review shows that mediastinal staging of NSCLC can be effectively performed by use of several invasive methods. Mediastinoscopy is considered to have the best performance characteristics as long as no comparative studies with endoscopic techniques are available. Wakely PE: Cytopathology-histopathology of the mediastinum: Epithelial, lymphproliferative, and germ cell neoplasms. Ann Diagn Pathol 6:30-43, 2002. ■ Precise review of the cytologic and histologic aspects of the masses located in the anterior mediastinum, showing the heterogeneity of cell populations and the challenge to obtain accurate diagnosis according to the needle technique used.

1/21/2008 4:02:53 PM

Benign Conditions chapter

125

ACUTE NECROTIZING MEDIASTINITIS Timothy L. Van Natta Mark D. Iannettoni

Key Points ■ Acute necrotizing mediastinitis is a destructive, life-threatening

■

■ ■

■

■

■

condition akin to necrotizing fasciitis and acute necrotizing pancreatitis. Generally arising from an oropharyngeal source, the infection is a polymicrobial mix of aerobes and anaerobes that act synergistically. Diagnostic delay and inadequate surgical drainage lead to inordinate mortality. The cornerstones of diagnosis and treatment include immediate administration of broad-spectrum antibiotics, early contrastenhanced cervicothoracic CT scanning, and aggressive surgical therapy aimed at both the neck and mediastinum. Best results are achieved by a multidisciplinary approach including thoracic surgeons, otolaryngologists, and, with odontogenic infection, oral maxillofacial surgeons. Unless mediastinal involvement is minimal, a thoracic approach must supplement the cervical approach, and serial operations may be required. Tracheostomy is often necessary but should be used selectively.

Acute necrotizing mediastinitis (ANM), also known as descending necrotizing mediastinitis, is a life-threatening condition. Without timely diagnosis and aggressive surgical management, fatal outcome is likely. Surgical mortality exceeded 50% in the preantibiotic era (Pearse, 1938),1 but even after availability of broad-spectrum antibiotics, mortality still approached 40% (Estrera et al, 1983).2 Introduction of contrast medium–enhanced cervicothoracic computed tomography (CT) led to improved outcomes by facilitating diagnosis and directing operative therapy. Mortality reported in case series of two or more patients published from 1990 to present has decreased markedly (Table 125-1). Most recent reports attribute successful management of ANM to earlier diagnosis via improved imaging techniques, immediate institution of appropriate antibiotics, and prompt aggressive surgery with mandatory cervical and transthoracic drainage. However, debate remains as to whether thoracotomy, as well as tracheostomy, should be compulsory.2-12 ANM generally results from odontogenic, peritonsillar, or other pharyngeal infections (Brunelli et al, 1996).3,5-8,10,12 It may also result from iatrogenic oropharyngeal perforation, cervical trauma, epiglottitis, parotitis, sinusitis, sternoclavicular joint infection, and illicit intravenous drug administra-

tion.3,12,13 Cervical esophageal perforation, iatrogenic or otherwise, is thought to represent a distinct condition with a less virulent course.12 Although neck exploration with cervical drainage and operative esophageal repair may be required, progression of disease into the mediastinum, with necrosis, is unusual. Also, ANM must not be confused with generally less threatening mediastinal infections, such as primary abscess, which lack the descending, necrotizing process in which oral flora have become pathogenic. In comparing reports on efficacy of surgical procedures for ANM, it is imperative to verify that patients meet the criteria outlined by Estrera and colleagues in their 1983 report (Table 125-2).2

PATHOPHYSIOLOGY In ANM, infections are polymicrobial, with a mixture of aerobes and anaerobes typically consisting of Streptococcus or Staphylococcus. A synergy exists, wherein aerobes, on gaining access to soft tissues of the neck and inciting small vessel thrombosis, change the tissue redox potential, favoring growth of anaerobes in an otherwise richly oxygenated environment.13 However, even with rapid administration of broadspectrum antimicrobial agents, fatal outcome is likely without immediate and comprehensive surgery. As such, ANM is akin to other virulent soft tissue infections such as necrotizing fasciitis and pancreatic necrosis for which aggressive, and, in most cases, serial, operative débridement and drainage procedures are mandatory.6 Contributing to poor outcome are diagnostic delays and inadequate initial incision and drainage. The cervical infection of ANM is easy to recognize with the associated edema, erythema, and tenderness, as well as symptoms of neck pain, dysphagia, and odynophagia. However, the more protean manifestations of the mediastinal component underlie the frequently delayed recognition of ANM. The disease progresses from a localized oropharyngeal infection into widespread descending cellulitis, abscess formation, tissue necrosis, and systemic sepsis. A surgical approach limited to the neck, despite attempting to drain the mediastinum from above, may prove inadequate to address a process spreading through the chest and even down into the abdomen.5,6,8-10,12,14

Anatomic Considerations Although understanding the microbiology of ANM is valuable, to appreciate the disorder’s pathophysiology one must know the fascial planes of the neck and their communication pathways into the mediastinum (Fig. 125-1). Deep cervical 1521

Ch125-F06861.indd 1521

1/21/2008 4:03:38 PM

1522

Section 7 Mediastinum

TABLE 125-1 Acute Necrotizing Mediastinitis Case Series: 1990-2004 Surgical Treatment Author (Year)

Mean Age

Wheatley et al12 (1990) 8

33

No. 2

M:F 2:0

Cervicotomy 2

Thoracotomy 2

Tracheostomy 2

Survival (%) 100%

†

Marty-Ane et al (1994)

49

6

6:0

6

6

NA

Brunelli et al3 (1996)

44

5

5:0

5

2

2

100%

Ris et al11 (1996)

35

3

1:2

3

3

0

67%

16

Casanova et al

(1996)

Corsten et al5 (1997) 7

Kiernan et al (1998) 9

83%

<35*

2

2:0

2

2

0

100%

46

8

5:3

8

6

1

88%

56

5

2:3

5

1

4

100% †

Marty-Ane et al (1999)

42

12

11 : 1

12

11

NA

Freeman et al6 (2000)

38

10

9:1

10

10

4

100%

Papalia et al14 (2001)

39

13

9:4

13

11

4

77% 83%

10

Mihos et al

(2004)

Makeieff et al13 (2004) Cumulative

55

6

2:4

6

6

1

42

17

16 : 1

17

14

0

43*

89

70 : 19

89

74

83%

82% †

18

87%

*Age of one “young” patient was not included in the manuscript. † Values were not included in the respective publications. M : F, male : female ratio.

TABLE 125-2 Estrera and Colleagues’ Criteria for Acute Necrotizing Mediastinitis 1. Clinical manifestations of severe oropharyngeal infection 2. Demonstration of characteristic roentgenographic features of mediastinitis 3. Documentation of the necrotizing mediastinal infection at operation or postmortem examination or both 4. Establishment of the relationship of oropharyngeal infection with the development of the necrotizing mediastinal process

Omohyoid muscle Pretracheal space Sternothyroid muscle Angle of Sternohyoid muscle dissection Carotid sheath Sternocleidomastoid muscle

Data from Estrera AS, Landay MJ, Grisham JM, et al: Descending necrotizing mediastinitis. Surg Gynecol Obstet 157:545-552, 1983. Buccopharyngeal fascia Retrovisceral space

Prevertebral fascia

FIGURE 125-1 Deep cervical fascial compartments.

fascial layers separate the neck into three compartments: retrovisceral, pretracheal, and perivascular.8,12,15 Each of these spaces can communicate with the mediastinum. The most common pathway is via the retrovisceral space with caudal extension of infection into the posterior mediastinum.7,10,14 Another route extends anteriorly through the pretracheal space in an inferior, retrosternal direction. This can lead to pleural and/or pericardial space involvement, the latter producing purulent pericarditis and even pericardial tamponade.10 The last route of extension is into the perivascular space within the carotid sheath, potentially leading to cranial nerve palsies and massive hemorrhage from vessel erosion.3,7 An important concept in the pathophysiology of ANM is that both gravity and the negative intrathoracic pressure serve to encourage the spread of the inflammatory and infectious process caudally.3

Ch125-F06861.indd 1522

RADIOLOGIC EVALUATION Determination of the degree of mediastinal involvement is difficult. Contrast-enhanced cervicothoracic CT is vital because it demonstrates the extent and location of mediastinal involvement, which is often not apparent on physical examination and plain films. In ANM (Figs. 125-2 to 125-4), CT is likely to show soft tissue edema with distortion of normal fascial planes. Commonly there are fluid collections that may or may not contain air bubbles.3,8,10,14 Pericardial and pleural fluid collections may be present, and caudal spread of infection into the peritoneum or retroperitoneum may be seen.6 Liberal use of CT before and even after surgical exploration has been advocated by several authors.3,5-12,14 Estrera and colleagues2 recommended addition of thoracotomy to

1/21/2008 4:03:38 PM

Chapter 125 Acute Necrotizing Mediastinitis

1523

cervicotomy whenever the inflammatory process descends to the level of the carina anteriorly or the T4 vertebra posteriorly. Noting that infection may progress despite a seemingly comprehensive operation, Freeman and associates advocate repeated cervicothoracic and abdominal CT scans for any postoperative clinical deterioration as well as surveillance scanning every 48 to 72 hours until the infectious process has clearly abated (Freeman et al, 2000).6

INITIAL TREATMENT

FIGURE 125-2 Contrast-enhanced CT scan in patient with acute necrotizing mediastinitis demonstrating upper mediastinal tissue edema and distortion of tissue planes.

Treatment of ANM begins with intravenous administration of a broad-spectrum antibiotic, such as piperacillin-tazobactam, which would be expected to cover both aerobes and anaerobes of oropharyngeal origin. However, antimicrobial therapy serves only an adjunctive role to emergent surgical therapy. There appears to be a consensus that an aggressive cervical approach (cervicotomy) should be undertaken, either through a transverse collar incision or by unilateral or bilateral longitudinal incisions along the anterior border of the sternocleidomastoid muscle.3,5-12,14,16 For those cases of ANM having an odontogenic source, concomitant maxillofacial surgery is required to control the infection process. For the mediastinal component, some authors favor a selective approach with an attempt to drain upper anterior mediastinal collections through the cervicotomy, adding transthoracic approaches only when the mediastinal infection descends below the carina and/or the T4 vertebra.2-4,7 In the majority of case series from 1990 on, however, some form of thoracic drainage is considered mandatory to achieve survival in ANM over 80%.

Literature Review

FIGURE 125-3 Contrast-enhanced CT scan at the aortic arch level in a patient with acute necrotizing mediastinitis showing pericardial and bilateral pleural fluid collections.

FIGURE 125-4 Contrast-enhanced CT scan at the carinal level in a patient with acute necrotizing mediastinitis demonstrating an abscess and tissue necrosis with distortion of tissue planes.

Ch125-F06861.indd 1523

A report by Corsten and associates5 in 1997 described their successful management in seven of eight patients meeting Estrera and colleagues’ criteria for ANM (Corsten et al, 1997). They stressed the importance of early operative drainage and débridement of both cervical and mediastinal infection along with prolonged antimicrobial use. Corsten and associates also performed a comprehensive literature review over the era beginning with the availability of CT scans. A MEDLINE search over the period of 1960-1995 yielded 12 case series and 24 additional case reports starting in 1970. These case series were subjected to meta-analysis. The focus was to determine the presence of any statistically significant outcome differences when comparing cervical drainage alone with cervicotomy plus formal mediastinal drainage, using the χ2 test of statistical significance. The largest series among these was Estrera and colleagues’ 1983 report2 on 10 patients. Eight were small series ranging from 2 to 5 patients, and only 4 series exceeded 5 patients. Of the 36 reports analyzed, the total cohort was only 69 patients. This attests to the uncommon presentation of ANM, with even the largest tertiary centers encountering at most a few of these patients annually. Development of a standardized approach to ANM is hindered by its infrequent occurrence, with few surgeons having a substantial experience managing the disorder. The meta-analysis revealed some concepts relating to ANM that seem to persist in subsequent reports.6,8,13 ANM is a

1/21/2008 4:03:39 PM

1524

Section 7 Mediastinum

disease primarily of young men with average age between 35 and 40 years. Whereas women (as well as infants and the elderly) may be afflicted, the male-to-female ratio approximated 6:1. Perhaps the most important meta-analysis finding was that 47% of patients died when surgery was limited to transcervical drainage alone, whereas the mortality rate was only 19% when a thoracic incision of some sort was employed in addition to cervicotomy (P < .05). Although not proving that a transthoracic approach is required in every case, these data do suggest that the threshold for performing a thoracic incision should be a low one, particularly with CT evidence of mediastinal involvement beyond the anterosuperior level. As for the eight patients in the personal series reported by Corsten and associates, seven adults survived. One death occurred in an infant in whom an acute cervical infection progressed, as confirmed at autopsy, to mediastinitis with bilateral purulent pleural fluid collections with multiple pulmonary abscesses and overt pericardial infection. Blood cultures demonstrated Streptococcus pyogenes and Staphylococcus aureus. Death occurred before any surgical intervention. Of the seven survivors, only one was managed surgically via cervicotomy alone. Surprisingly, despite the cervicothoracic CT showing extension of mediastinitis to the level of the diaphragm, transcervical drainage and antibiotics proved adequate. The remaining six survivors underwent at least unilateral thoracotomy in addition to cervicotomy. Two of these underwent bilateral thoracotomy on separate days. One patient, after having first undergone left pleuroscopy and decortication, ultimately required formal right thoracotomy followed by left thoracotomy to clear the thoracic infection. Closed irrigation was used routinely. Two survivors had head and neck squamous cell carcinoma, showing that coexistent malignancy does not necessarily portend a poor prognosis. Tracheostomy was employed in only two of the seven survivors. A number of transthoracic approaches have been described for ANM. Procedures range from percutaneous drainage (thoracostomy tubes, CT-guided drainage of mediastinal abscesses17,18), to limited incisions including subxiphoid or anterior mediastinotomy approaches,8,12 to formal thoracotomy. Examples of the latter include conventional anterolateral or posterolateral thoracotomy,5,6,8-10,12-14 median sternotomy,16,19 clamshell or hemi-clamshell incisions,11 and transsternal transpericardial access.19 On occasion, laparotomy is even required to address spread of ANM into the retroperitoneum or peritoneum proper.6 Wheatley and associates12 were the first to advocate mandatory thoracic incision and drainage of the mediastinal component of ANM (Wheatley et al, 1990). They reported the successful management of two patients and stressed the importance of early cervicothoracic CT, broad-spectrum antibiotics, expert treatment of any odontogenic infection, and aggressive cervical incision and drainage. Furthermore, they considered both tracheostomy and transthoracic drainage essential and warned against attempts to drain the thoracic component from the neck. An excellent pathophysiologic discussion and literature review were presented. Of their patients, one was managed with a right posterolateral thora-

Ch125-F06861.indd 1524

cotomy, the other with thoracentesis and drainage of an anterior mediastinal abscess via a subxiphoid incision with manual substernal manipulation. Regarding tracheostomy, Wheatley and colleagues considered dependence on an endotracheal tube hazardous because cervical and esophageal edema could render reintubation impossible in the event of airway dislodgement. Subsequent authors, however, have successfully managed ANM with a more selective use of tracheostomy3,5,6,10,14 as shown in Table 125-1. In 1994, Marty-Ane and associates8 reported on the management and outcomes in six patients meeting Estrera and colleagues’ criteria for ANM (Marty-Ane et al, 1994). There were five survivors, all of whom received right posterolateral thoracotomy in addition to cervical drainage. Three had odontogenic infections, and three had peritonsillar abscesses as initiating events. The one death occurred in a patient who underwent bilateral cervical incisions but thoracic drainage limited to anterior mediastinotomy and subxiphoid incisions. The importance of routine thoracotomy was stressed. They employed multiple mediastinal chest tubes and irrigation with 0.5% povidone-iodine solution. All patients manifested respiratory compromise at presentation. Microbiology was always polymicrobial (mixed aerobic and anaerobic bacteria). Higher mortality in earlier reports on ANM was attributed in part to diagnostic delay. The authors indicated that chest pain and dyspnea denote mediastinal involvement, and, again, the importance of CT was stressed. Standard posterolateral thoracotomy was favored, providing access to all regions of the mediastinum, including the pericardium, as well as the entire ipsilateral pleural space. Contamination from mediastinum to the pleural space, potentially resulting in empyema, was not considered a major concern because most patients with mediastinitis were believed to have coexistent empyema anyway. Two years later, an ANM report of similar size by Brunelli and colleagues3 further described the treatment of ANM. Five patients, all of whom meeting Estrera and colleagues’ criteria, underwent surgical management. The authors agreed with their report that only when CT demonstrates spread of the ANM process below the carina is thoracotomy necessary. They also favored selective tracheostomy. By utilizing generous cervical incisions, generally left open, combined with antibiotic and anti-inflammatory agent administration, tracheostomy was obviated in the majority of cases (three of five in their study). The two patients requiring tracheostomy manifested clinically obvious upper airway obstruction at presentation. Brunelli and coworkers commend the excellent survival achieved in Marty-Ane’s study but speculate as to whether the same result might have been accomplished with less aggressive surgery, tailored more closely to clinical and CT findings such that thoracotomy might at times be avoided. In a brief follow-up case report, Brunelli and coworkers4 reiterated that thoracotomy may not be mandatory. The patient described, despite having CT findings of bilateral pleural effusions and an anterior mediastinal air-fluid collection with extension to the right arm, was cured with broadspectrum antibiotics, dental surgery, serial cervical incision and drainage (with concomitant anterior mediastinal drainage from above), right upper extremity incision and drainage, and

1/21/2008 4:03:40 PM

Chapter 125 Acute Necrotizing Mediastinitis

left thoracostomy tube placement. The authors advocated for early cervicothoracic CT and cervical incision and drainage, suggesting that this may avoid thoracic incisions in some cases. Ris and colleagues11 described use of the clamshell incision to achieve comprehensive one-stage treatment of ANM in the absence of profound septic shock (Ris et al, 1996). The clamshell (and hemi-clamshell) incision, as described in detail by Bains and associates20 for cancer surgery and pulmonary transplantation, was used by Ris and others for ANM treatment. Such a radical approach was pursued in three patients with ANM and bilateral empyema after initial treatment for severe cervical infection. The approach made possible radical mediastinal débridement, clearance of intrapericardial infection, bilateral empyema evacuation, and formal decortication. One patient with septic shock and with respiratory distress on presentation died. Of the two survivors, neither developed sternal osteomyelitis despite exposure of cancellous bone to overt infection. The authors favored the clamshell approach over median sternotomy because of perceived risks of sternal osteomyelitis and dehiscence with the latter. They also considered conventional bilateral thoracotomies insufficient to effect complete mediastinal débridement. Like some of the foregoing authors, Ris and colleagues favored more conservative surgery for ANM not extending below the T4 vertebra, with débridement and drainage of anterosuperior mediastinal infection via cervical incision alone. In their view, however, one should not hesitate to pursue aggressive thoracic surgery for ANM extending caudally. In addition to concerns about osteomyelitis after median sternotomy, they fault that approach as well for providing inadequate access to the posteroinferior pleural regions. As for the clamshell incision, caution was stressed relative to identification and avoiding stretch of the phrenic nerves. Tracheostomy was unnecessary in their two surviving patients. They cited concern about a propensity toward hemorrhage after tracheostomy from large mediastinal vessels having been encroached upon by the inflammatory process and by surgical dissection. Finally, given their poor experience with the clamshell procedure in the presence of major hemodynamic and respiratory instability, they favored placement of bilateral chest tubes and limited approach to upper mediastinal drainage via cervical incision over the more radical operative procedure. An aggressive surgical approach including median sternotomy was described by Casanova and colleagues in 1997.16 They reported on two patients with ANM after odontogenic infection. In both patients, CT showed extension of the disease process from the cervical area down into the anterior mediastinum and on into the right pleural space. The surgical approach in both consisted of combined cervicotomy and median sternotomy. This was the first such report of approaching the entity in this fashion, citing other reports wherein cervicotomy was combined with lateral thoracotomy. An adjunct in these patients was placement of mediastinal and right pleural irrigation catheters for postoperative continuous irrigation with 0.5% povidone-iodine solution in saline for 11 to 14 days. Neither patient had developed sternal osteomyelitis. Advantages of combined cervicotomy and median sternotomy, according to the authors, is wide access for

Ch125-F06861.indd 1525

1525

débridement of the cervical regions, superoanterior mediastinum, cervicomediastinal routes of spread, and right pleural space. Additionally, the pericardium and left pleural space, which may also be involved, can be easily reached. They believe median sternotomy produces less respiratory embarrassment than does lateral thoracotomy. Casanova and colleagues favored selective over mandatory tracheostomy, stating that the latter “perpetuates the infection and predisposes the patient to development of new and sometimes lethal complications.” They ascribed rapid recovery of their two patients to the early and radical débridement afforded by median sternotomy. Another 1997 report, this one by Roberts and colleagues,21 noted success in treating ANM with cervical drainage in conjunction with right video-assisted thoracoscopy. Preoperative CT scan demonstrated an abscess extending from the neck to the diaphragmatic hiatus. Three ports were utilized, and the abscess was unroofed with cautery from above the azygos vein (which was ligated and divided) caudally. The patient did well and was discharged 2 weeks later. However, the underlying disease process was iatrogenic perforation of the cervical esophagus at endoscopy. Cervical and mediastinal infection with mediastinal abscess resulted, but it is uncertain whether Estrera and colleagues’ criteria for ANM were met. As noted earlier, Wheatley and coworkers12 suggested that iatrogenic perforation represents a less virulent entity than ANM. The case presented by Roberts and colleagues21 may have represented a mediastinal abscess rather than ANM. Since 1997, the thoracoscopic approach to ANM has not appeared prominently in the literature. In 1998, Kiernan and associates7 reported on five ANM cases managed surgically at their institution over an 11-year period ending in 1997, again supporting the notion of early and aggressive surgical therapy guided by advanced imaging methods (Kiernan et al, 1998). After a brief pathophysiologic discussion, they describe their heterogeneous group of five ANM patients, both with regard to presentation and management, including their treatment strategies and outcomes. All five survived. Three of the patients required tracheostomy. Four did not undergo major thoracic incision because the superior mediastinum appeared to have been addressed via cervical incisions. One of these patients required bilateral thoracostomy tubes. A fifth patient ultimately required median sternotomy, pericardiotomy, irrigation and packing, and further mediastinal débridement with rectus muscle flap closure of the anterior central mediastinum. The treatment approach of Kiernan and associates consists of immediate antibiotic therapy in conjunction with aggressive transcervical drainage of the infected sites in the neck and upper mediastinum. They dissect out and drain all three deep cervical fascial spaces and manage the airway expectantly. Although their threshold for performing tracheostomy is low, they acknowledge its use is not always required (three of five in their series). The cervical incisions were along the anterior border of the sternocleidomastoid muscles and extended into the carotid sheath with thorough access to all deep fascial planes. For either overt mediastinal fluid collections seen on CT scan or for lack of clinical improvement after the aforementioned measures, they advised placement

1/21/2008 4:03:40 PM

1526

Section 7 Mediastinum

of multiple thoracostomy tubes and/or pursuing mediastinal débridement through a number of possible thoracic incisions ranging from subxiphoid/substernal approaches, to median sternotomy, to conventional lateral thoracotomy, even to the clamshell incision. They argued that the approach should be tailored to the individual situation. In 1999, Marty-Ane and colleagues9 followed their initial (1994) report with a larger case series (Marty-Ane et al, 1999). This study, composed of 12 patients over 10 years, supports their earlier contention that, irrespective of the level of mediastinal involvement, a transcervical approach alone is inadequate for treating ANM. Commenting on the generally reported ANM mortality rate of 30% to 40%, the authors stressed that only by early and extensive surgical mediastinal drainage is it possible to expect a mortality reduction to the 15% to 20% range (16.5% in their study or 2 deaths in 12 patients). In these 12 patients, all of whom meeting Estrera and colleagues’ criteria, only 1 was treated by transcervical drainage alone. They suggested that, for the minority of cases in which mediastinal disease is quite cephalad and limited, perhaps transcervical drainage would suffice. For the 11 of 12 patients undergoing posterolateral thoracotomy, right lateral thoracotomy predominated. Only 1 patient required bilateral thoracotomies; 2 required ipsilateral reoperative thoracotomy. Requirement for tracheostomy was not addressed in either of their studies. The following year Freeman and associates6 discussed the success of serial operative débridement for ANM, with anticipation of multiple operations closely guided by scheduled postoperative CT scans. Their retrospective study looked at 10 patients treated from 1980 to 1999. There were no deaths. They commented on the 25% to 40% mortality in modern series, not far improved from the 50% rate in the preantibiotic era. In comparing ANM with other necrotizing entities, they questioned why serial operative drainage and débridement, which is commonplace in treatment of other necrotizing infections, had not been widely applied to ANM. Like Corsten and colleagues,5 in addition to reviewing their own study, they performed a comprehensive review of literature from 1970 to 1999 available on a MEDLINE and manual Cumulated Index Medicus search, establishing a historical cohort. In their study, 9 of 10 patients were male, with an average age of 38 years. Inciting infections were of odontogenic or pharyngeal origin. All infections were polymicrobial. Admission cervicothoracic CT was performed on all patients. They assiduously repeated the CT scans every 48 to 72 hours after every operative intervention, as well as for any deterioration in patient status. The average number of CT scans for each patient was 6, about half done for clinical deterioration. This generally led to operative reintervention. Of 46 scans done after the initial radiographic evaluation and surgical treatment, 24 were done for deterioration and 22 as surveillance evaluations. Of the latter, nearly 60% prompted additional surgery. Importantly, all patients underwent both cervicotomy and thoracotomy at the initial operation. A combined approach was the rule, with involvement of otolaryngology and thoracic surgery in each case, and adding a maxillofacial surgeon in the setting of odontogenic disease. Overall, patients

Ch125-F06861.indd 1526

averaged six incisions, with four cervical approaches and two thoracic approaches per patient. Six of the 10 underwent bilateral posterolateral thoracotomy, 5 staged and 1 under the same anesthetic. Tracheostomy was required in 40%. Interestingly, 3 of the 10 patients had sufficient abdominal involvement that laparotomy was required. Surveying the English reports from 1970 to 1999, 49 papers were found, and of these there appeared to be 96 patients meeting Estrera and colleagues’ criteria for ANM. When the data on these patients were combined, the average age was found to be 38 years and 83% were male. Infections were almost exclusively due to multiple organisms. Whereas these 96 patients were considered similar to those in their own series, the authors noted considerably less use of CT and more limited use of surgical exploration vis-à-vis their own experience. In summary, patients in the historical cohort averaged two CT scans, two cervicotomies, and less than one thoracotomy per patient. Seventeen percent required abdominal exploration, and 35% underwent tracheostomy. Freeman and associates reviewed the complications in their own series, and serious complications were common. Mean hospital length of stay was 46 ± 30 days, and every patient had at least one occurrence of serious morbidity. Acute respiratory distress syndrome was seen in 40%, pericardial tamponade occurred in 30%, acute renal failure (requiring dialysis) was noted in 20%, stroke occurred in 20%, and pneumonia was reported in 20%, and one patient had chylothorax. Mortality in their study, however, was 0% versus 29% among the historical controls. The authors commented on the major preantibiotic era study,1 reiterating the 50% mortality for ANM, but added that despite major medical advances (development of antibiotics, improved anesthesia and critical care, CT), high mortality persisted. They also believed that the uncommon occurrence of ANM may contribute to the persistently high lethality, noting that only two reports after 1960, theirs included, have 10 patients or more. Furthermore, they emphasized the importance of CT, in agreement with others.3,5,7,9,10,12,13 Freeman and associates stressed the value of liberally using contrast-enhanced cervicothoracic CT scans for preoperative evaluation, postoperative surveillance, and interrogation in the presence of postoperative deterioration. They cited a preponderance of opinion favoring compulsory transthoracic mediastinal drainage of the mediastinum,5,8-10,12,14 and they noted the meta-analysis of Corsten and colleagues5 with 81% survival when thoracic drainage was included and only 53% survival with a transcervical approach alone. Freeman and associates suggested a treatment algorithm for ANM. Although surgeons in this study considered their initial operative drainage and débridement sufficient, their patients went on to an average of three more transcervical explorations and débridements and one additional thoracotomy. They reviewed the various transthoracic access routes but favor standard posterolateral thoracotomy, agreeing with Marty-Ane and colleagues8,9 that such an approach provides greatest access to the prevertebral and paraesophageal regions while avoiding the sternal osteomyelitis risk that exists with median sternotomy and clamshell incision approaches. They

1/21/2008 4:03:40 PM

Chapter 125 Acute Necrotizing Mediastinitis

supported the claim that posterolateral thoracotomy is reasonably well tolerated in patients with ANM. In summary, encouraged by absence of mortality in their 10 patients, they promulgated their ANM treatment algorithm. This involved immediate application of broad-spectrum antibiotics and prompt contrast-enhanced cervicothoracic CT. Following this is an aggressive surgical approach, including mandatory thoracotomy and then liberal use of CT scans of neck, chest, and abdomen at the first indication of any clinical deterioration as well as empirically every 2 to 3 days after the initial operation (and following any additional operations) until clinical signs of infection recede and CT shows no air-fluid pockets or other signs of ongoing infection. This engenders an expectation that one operation is unlikely to suffice and that one should have the mindset to explore, drain, and débride over and over if necessary, just as for other necrotizing soft tissue infections. Although it is difficult to criticize an ANM study with no mortality, one wonders if the same results might not have been accomplished with fewer procedures. Papalia and coworkers14 presented a relatively large ANM series in 2001 of 13 patients treated at their institution over a 6-year period from 1994 to 2000 (Papalia et al, 2001). Again, mean age was 39 years and 70% were men. All met Estrera and colleagues’ ANM criteria, with odontogenic and peritonsillar abscess underlying ANM in 85% and complication of blunt cervical trauma in 15% (2/13). ANM diagnosis was made in all by neck and chest CT scan. Delay from onset of infection to ANM diagnosis and definitive treatment averaged 6 days. All patients underwent neck exploration, generally via transverse collar incision. The first 3 patients did not undergo thoracotomy, 2 underwent limited upper anterior and posterior mediastinal drainage from the cervical approach, and 1 had an additional subxiphoid approach. The next 10 patients underwent compulsory right thoracotomy, in addition to cervicotomy, at the outset. In contradistinction to Freeman and associates’ study,6 only 6 of 13 required reoperation. Two of these involved left thoracotomy. Tracheostomy was only performed in 4 patients (31%). Their overall mortality rate was 23% (3/13) as a result of septic shock and multisystem organ failure. No patients died due to loss of airway. Thus, neither mandatory repeated operations nor tracheostomy was advocated by the authors on the basis of their study. They did support aggressive use of thoracotomy over minimally invasive approaches. They did not comment, however, on whether the three deaths in their series were influenced by type of incision, lack of thoracotomy, or otherwise. Mihos and colleagues10 agreed that ANM is a “dreaded and the most lethal” mediastinal infectious disease (Mihos et al, 2004). They presented a series of six patients treated over a 10.5-year period. Three had odontogenic, and three had peritonsillar abscesses. All patients underwent aggressive surgical treatment involving unilateral cervicotomy and left thoracotomy. Considering the virulence of ANM, both delay in diagnosis and insufficiently aggressive surgical treatment were assailed as causes of high mortality. In this series, all six patients met Estrera and colleagues’ criteria. Cervicothoracic CT scan secured the diagnosis in each case. All patients had cervical edema and soft tissue infiltration and radiographic

Ch125-F06861.indd 1527

1527

indications of posterior mediastinal involvement, with unilateral pleural involvement in five cases and bilateral pleural space infection in one. Bacteriology was always polymicrobial. Only one patient required tracheostomy. Five of six survived, with one death attributable to multisystem organ failure. With regard to operative approach, posterolateral thoracotomy was considered the gold standard. Advantages cited include excellent exposure of the paraesophageal and prevertebral planes and avoidance of osteomyelitis risk with sternal incision. Despite the severe degree to which a patient with ANM may be ill, Mihos and colleagues believe standard thoracotomy to be well tolerated. Finally, like Freeman and associates,6 they noted that one must rule out involvement of the retroperitoneum and retroperitoneal space. They affirm the importance of working with a multidisciplinary team and reiterate Estrera and colleagues’ view that the virulence of this disease requires (in most cases) “dental extraction, wide open drainage of the oral and cervical process, and thoracotomy.” The largest study yet reported, by Makeieff and associates,13 appeared in 2004 (Makeieff et al, 2004). This was a retrospective study of 17 patients treated at their institution from 1984 to 1998. In 82% of patients (14/17) both cervicotomy and thoracotomy were performed. Three of 17 (18%) patients died. Two patients died of sepsis and multisystem organ failure, and 1 died of tracheal rupture. Intensive care unit time averaged 1 month, with average hospital length of stay 45 days. Their protocol mandated thoracotomy whenever the chest portion of the CT scan demonstrated extension below the carina. They attribute their low mortality (<20%) to the liberal use of thoracotomy, extensive use of CT for surveillance of disease progression, and comprehensive intensive care unit management. A number of technical features was stressed. For those 3 patients in whom thoracotomy was omitted, all had limited anterosuperior mediastinal involvement within reach of the cervical incision(s). Cephalad dissection, after careful identification and preservation of hypoglossal nerves, was performed and débridement was aggressive. Tissues were thoroughly irrigated and scrubbed with “oxygenated and iodized solutions” and drains were employed widely. Cervical wounds were packed open. No patients required tracheostomy, and the authors commented that hyperbaric oxygen therapy was not used. As in Freeman and associates’ study,6 complications in the survivors were the rule. Some long-term complications were also observed, including unilateral vocal cord paralysis in 3 and one case each of subglottic tracheal stenosis and esophageal stenosis. The authors offer an interesting, comprehensive pathophysiologic discussion of ANM. One new surgical approach was reported by Stella and associates.19 For a case of ANM from spread of a left parapharyngeal abscess, they used a transsternal transpericardial approach. Therapy with broad-spectrum antibiotics was begun immediately. After transcervical drainage, the patient remained ill and a chest CT revealed an inflammatory mass surrounding the distal trachea and extending below the carina, with associated bilateral pleural fluid collections. The patient was explored via median sternotomy. After entering the pericardial space, retraction of the aorta and superior

1/21/2008 4:03:40 PM

1528

Section 7 Mediastinum

vena cava allowed access to the posterior pericardium. This was incised, yielding purulent fluid, which was evacuated. Pleural fluid was cleared as well. Extensive mediastinal débridement was carried out, and multiple mediastinal and pleural drains were placed. Tracheostomy was not required, and drains were gradually withdrawn. The patient survived and was discharged 22 days after median sternotomy. Sternal osteomyelitis did not result.

SUMMARY Acute necrotizing mediastinitis is a destructive, life-threatening infectious process usually originating in the oropharyngeal region and extending transcervically into the mediastinum along well-described fascial planes. Although the cervical component is easy to recognize, mediastinal involvement is less obvious, leading to serious delays in diagnosis. The cornerstones of treatment involve prompt institution of broadspectrum intravenous antimicrobial agents intended to cover oropharyngeal aerobes and anaerobes, immediate and liberal use of contrast-enhanced cervicothoracic CT, and urgent surgical therapy directed at both cervical and thoracic components. Tracheostomy should be applied selectively. Occasionally, mediastinal involvement confined to the upper anterior mediastinal aspect may be amenable to drainage via the transcervical approach but the potential for rapid diffuse spread deeper in the mediastinum must be anticipated and dealt with accordingly. The patient is best served by a team of surgeons, including otolaryngologists and thoracic surgeons, with maxillofacial surgeons playing a key role when odontogenic infection is the original source. It is incumbent on the physician evaluating a toxic patient with a progressing oropharyngeal and cervical infection to consider ANM in the differential diagnosis and recognize the urgency of the process as being similar to that for necrotizing fasciitis, acute necrotizing pancreatitis, and other related infections. Once the mediastinum is involved, minimally invasive approaches general prove inadequate and some form of major thoracic access will be required. Adjuncts such as hyperbaric oxygen therapy have not been well studied in ANM and cannot be recommended here. The surgical team must have the mindset that several operative procedures may be required to achieve a successful outcome. The actual method of thoracic drainage will depend on the location of fluid collections and tissue necrosis as determined by helical CT.

provided a thorough review of the subject. The key to management of this frequently fatal condition is prompt diagnosis and aggressive surgical débridement and drainage of all abscess. Quality CT imaging is key. The surgeon must accomplish complete drainage. A transcervical incision will accomplish drainage of all layers of the neck and the upper anterior and posterior mediastinum. However, if the sepsis extends below the level of the carina, a transthoracic approach, usually posterolateral thoracotomy, is indicated. Minimally invasive approaches, although attractive in many other indications, have little to recommend them in the situation of acute necrotizing mediastinitis, in which failure to accomplish complete drainage and débridement will lead to a fatal outcome. G. A. P.

KEY REFERENCES Brunelli A, Sabbatini A, Catalini G, Fianchini A: Descending necrotizing mediastinitis: Surgical drainage and tracheostomy. Arch Otolaryngol Head Neck Surg 122:1326-1329, 1996. Corsten MJ, Shamji FM, Odell PF, et al: Optimal treatment of descending necrotising mediastinitis. Thorax 52:702-708, 1997. Estrera AS, Landay MJ, Grisham JM, et al: Descending necrotizing mediastinitis. Surg Gynecol Obstet 157:545-552, 1983. Freeman RK, Villières E, Verrier ED, et al: Descending necrotizing mediastinitis: An analysis of the effects of serial surgical débridement on patient mortality. J Thorac Cardiovasc Surg 119:260-267, 2000. Kiernan PD, Hernandez A, Byrne WD, et al: Descending cervical mediastinitis. Ann Thorac Surg 65:1483-1488, 1998. Makeieff M, Gresillion N, Berthet JP, et al: Management of descending necrotizing mediastinitis. Laryngoscope 114:772-775, 2004. Marty-Ane CH, Alauzen M, Alric P, et al: Descending necrotizing mediastinitis: Advantage of mediastinal drainage with thoracotomy. J Thorac Cardiovasc Surg 107:55-61, 1994. Marty-Ane CH, Berthet JP, Alric P, et al: Management of descending necrotizing mediastinitis: An aggressive treatment for an aggressive disease. Ann Thorac Surg 68:212-217, 1999. Mihos P, Potaris K, Gakidis I, et al: Management of descending necrotizing mediastinitis. J Oral Maxillofacial Surg 62:966-972, 2004. Papalia E, Rena O, Oliaro A, et al: Descending necrotizing mediastinitis: Surgical management. Eur J Cardiothorac Surg 20:739-742, 2001. Pearse HE: Mediastinitis following cervical suppuration. Ann Surg 108:588-611, 1938. Ris HB, Banic A, Furrer M, et al: Descending necrotizing mediastinitis: Surgical treatment via clamshell approach. Ann Thorac Surg 62:16501654, 1996. Wheatley MJ, Stirling MC, Kirsh MM, et al: Descending necrotizing mediastinitis: Transcervical drainage is not enough. Ann Thorac Surg 49:780-784, 1990.

COMMENTS AND CONTROVERSIES Acute necrotizing mediastinitis is an uncommon sequela of oropharyngeal mucosal disruption and secondary sepsis. The authors have

Ch125-F06861.indd 1528

1/21/2008 4:03:40 PM

CHRONIC MEDIASTINITIS chapter Harold C. Urschel, Jr. Amit N. Patel Maruf A. Razzuk Susan J. Hoover Linda M. Razzuk Rachel Montano

126

Key Points ■ Although chronic mediastinitis can progress from any acute

process, it is usually associated with acid-fast bacteria or fungi that may progress to a denser cicatrix that can cause encroachment or occlusion of visceral structures such as the esophagus, trachea, superior vena cava, or the pulmonary vessels. ■ Early diagnosis is critical to minimize morbidity with prompt medical treatment of the acid-fast bacteria or ketoconazole for the fungi (after an elevation of the complement fixation text is observed). ■ Surgical decompression of any significantly compressed organ should follow medical therapy.

Infections of the mediastinum evoke an inflammatory response that initially affects the soft tissue components as well as the lymph nodes of the mediastinum and may progress from an acute process to a chronic reaction. An inflammatory response caused by Gram-stained bacteria may resolve completely at the cellulitic phase or evolve into a destructive exudative process and result in a chronic condition. Infection caused by acid-fast bacteria or certain fungi (when the hilar and mediastinal lymph nodes are involved) induces a granulomatous response that may progress to a chronic dense cicatrix, which can cause encroachment and occlusion of visceral structures. Chronic mediastinitis encompasses a group of entities with heterogeneous clinical and pathologic manifestations. It can be primary, but on the whole it is secondary to infections originating from a variety of pathologic conditions affecting the esophagus, sternum, oropharynx, neck, spine, lungs, or abdomen. The infecting organisms, in a general way, relate to the etiologic source of mediastinitis. Symptoms of the chronic granulomatous, sclerosing form vary according to the compromised structure, whether superior vena cava (SVC), esophagus, airway, or pulmonary vessels (Urschel et al, 1990).1

HISTORICAL NOTE Since Boerhaave’s 1724 report of a fulminant and fateful case of acute mediastinitis,2 this morbid disorder has gained rec-

ognition because of its aggressive, bewildering, and often fatal chronic course. The severe, often fatal, mediastinal infections descending via the neck from oropharyngeal abscesses triggered early, diligent research to understand how the infection was spread. The first experiments to study the neck compartments were undertaken in the 19th century in Europe, as have been reviewed by Pearse3; early researchers included Bichat in 1801; Henke in 1872; Soltmann, Konig, and Riedle in 1882; Paulsen in 1882; and Schmit in 1893. Essential facts about cervical fascia and the manner of spread of infection were learned from these experiments. In North America, significant contributions to the delineation of the paths of spread of oropharyngeal and cervical infections to the mediastinum were made by Mosher (1929),4 lglauer (1935),5 Coller and Yglesias (1937),6 Furstenberg and Yglesias (1937),7 Pearse (1938),3 and Grodinsky and Holyoke (1938).8 Much was learned from those investigations, including the importance of early recognition of the morbid pathology caused by the infection and the value of well-directed surgical intervention to reduce the severity of a chronic outcome by bringing improvement and even cure. In the preantibiotic era, the chronic forms of mediastinitis were fairly frequent and associated with enormous complications and a high mortality rate. Keefer (1938)9 reported the breakdown of a tuberculous lymph node to be the most frequent cause of mediastinitis. Tuberculosis, peritonsillar abscess (quinsy), and Ludwig’s angina were listed by Pearse (1938)3 as the most common forerunners of chronic mediastinitis. Hemolytic streptococci, staphylococci, and tubercle bacilli were the most frequent offending organisms that can produce mediastinitis.10 Chronic mediastinitis, particularly granulomatous fibrous mediastinitis, was most commonly caused by tuberculosis, syphilis, actinomycosis, and paragonimiasis.9 The first reference to mediastinal granulomatous fibrosis was made by Tonnle, in 1829, who reported a symptomatic case of mediastinal granuloma and a “fibrous mass.” Oulmont, in 1856, described mediastinal fibrosis. Osler, in 1903, reported the disorder in conjunction with SVC obstruction.11 Syphilis, although no longer listed as a cause of granulomatous sclerosing mediastinitis,12 can still cause the condition (Fry and Shields, 1991). The incidence of tuberculous mediastinitis has decreased, although a resurgence is appearing in 1529

Ch126-F06861.indd 1529

1/21/2008 4:04:23 PM

1530

Section 7 Mediastinum

the wake of the acquired immunodeficiency syndrome (AIDS) epidemic.13,14 Medical technology introduced the socalled altered host—a patient who receives cytotoxic and immunosuppressive therapy for cancer and organ transplants. These patients have become vulnerable to opportunistic microbes that are usually innocuous or dormant in normal individuals.15 Fungi that lead to opportunistic infection, such as Aspergillus fumigatus, Mucor, Candida albicans, and Cryptococcus neoformans (although a primary pathogen), have appeared on the list of etiologic organisms of chronic mediastinitis.12,16 Technologic advances with the invention of esophageal endoscopy, bougienage, and dilation have introduced the iatrogenic perforation of the esophagus as a causative factor of acute and chronic mediastinitis (Urschel et al, 1974).17 The introduction of the flexible endoscope may have made esophagoscopy safer; however, the overall rate of esophageal perforation by instrumentation has remained basically unchanged. Esophageal perforation accounts for a small amount of chronic mediastinitis.18,19 The development of both cardiopulmonary bypass and a multitude of cardiac surgical procedures has also contributed to the incidence of chronic mediastinitis resulting from deep sternotomy wound infections. In an ever-changing medical world, the journey of chronic mediastinitis shall continue to be turbulent, especially as genetic diversification leads to the emergence of antibioticresistant bacterial strains.

ANATOMIC CONSIDERATIONS Knowledge of the anatomy of the fascial spaces connecting the pharynx and neck to the mediastinum is of significant clinical importance. Infection travels along these spaces and should be intercepted and drained there. The spaces lie between layers of fascia and the investing fascia of the muscles, glands, and blood vessels as well. Because the system of fascia and spaces is so intricate, this chapter limits the discussion to the anatomic aspects that relate to the spread of infection.

The Fascia The superficial fascia is deep to the subcutaneous fascia. It encircles the neck completely and invests the platysma and sternocleidomastoid and trapezius muscles and then inserts on the spinous processes. Superior to the sternal notch, it splits to form the suprasternal space of Burns. The middle fascia has three layers. The two outermost layers invest the strap muscles and fuse laterally with the superficial fascia, which invests the sternocleidomastoid muscle, opposite the carotid sheath. The outer layer invests the sternohyoid and omohyoid muscles. The middle layer invests the sternothyroid muscle. The visceral layer completely surrounds the thyroid gland, trachea, and esophagus. The posterior fascia is the deepest subdivision of the deep cervical fascia. It consists of two layers: (1) the alar fascia, which lies posterior to the visceral fascial compartment and attaches laterally to the transverse processes and then continues laterally to form the carotid sheath; and (2) the prevertebral fascia, which fuses laterally with the alar fascia at the transverse processes from the base of the skull down to the coccyx (Fig. 126-1).8

Fascial Spaces The spaces formed by these fasciae include the following: 1. A cleft is evident between the superficial fascia and the outer layer of the middle fascia (the sternohyoid-omohyoid layer), termed space 1 by Grodinsky. 2. A second cleft occurs between the outer layer (sternohyoid-omohyoid layer) and the middle layer (sternothyroid layer) of the middle fascia, termed space 2 by Grodinsky and the fascial cleft by Gray (see Fig. 126-1).20 The latter clefts are potential spaces and do not communicate with the mediastinum. 3. A space that is well defined for the most part lies between the sternothyroid fascial layer and the visceral fascia and is termed space 3 by Grodinsky, the perivisceral fascial cleft by Gray, and the previsceral space by Pearse. This

FIGURE 126-1 Diagram of the fasciae of the neck. Transverse section at the level of the sixth cervical vertebra. (FROM GRODINSKY M, HOLYOKE EA: THE FASCIAE AND FASCIAL SPACES OF THE HEAD, NECK AND ADJACENT REGIONS. AM J ANAT 63:367, 1938. REPRINTED WITH PERMISSION OF WILEY-LISS, INC, A SUBSIDIARY OF JOHN WILEY & SONS, INC.)

Cervical vertebra

Retrovisceral space

Space 5

Carotid sheath

Prevertebral fascia Alar fascia Esophagus Space 3

Trachea Thyroid gland Sternocleidomastoid muscle

Middle fascia: a) Visceral layer b) Middle layer c) Outer layer Previsceral space (Space 3) Space 2

Ch126-F06861.indd 1530

Omohyoid muscle Sternothyroid muscle Sternohyoid muscle Pretracheal space Visceral fascia Superficial fascia

1/21/2008 4:04:24 PM

Chapter 126 Chronic Mediastinitis

space is the plane used to expose the thyroid gland during surgery. It lies beneath the strap muscles. Anteriorly, this space extends from the thyroid cartilage to the upper border of the aortic arch (level of fourth thoracic vertebra), where it terminates by adhesions extending from the fibrous pericardium to the posterior surface of the manubrium sterni. These fibrous adhesions form a relative barrier to the downward gravitational spread of infection into the anterior mediastinum.21 Posteriorly, it stretches from the base of the skull down to a level between the sixth cervical and fourth thoracic vertebrae, where it ends (Fig. 126-2). Anteriorly, it is continuous across the midline but terminates laterally by adhesions between the alar fascia and the visceral fascia around the inferior thyroid arteries. Posteriorly, the space becomes attenuated by adhesions between the visceral and alar fasciae (see Fig. 126-1).8 4. The visceral compartment, called the visceral or tracheoesophageal space or compartment, contains the thyroid gland, trachea, and esophagus, each with its own thin fascial capsule. All are enclosed by the visceral fascia. The compartment extends from the larynx to the tracheal bifurcation (level of T4 vertebrae) (see Fig. 126-2). The pretracheal space is a potential space. It is open during mediastinoscopy, thyroid surgery, and tracheostomy and in perforating wounds of the trachea. Should an infection

1531

occur or reach these spaces, it is likely to gravitate into the mediastinum. An important space referred to as the “danger space” because of its relation to the posterior mediastinum has been termed space 4 by Grodinsky, the retrovisceral space by Pearse, and the retropharyngeal fascial cleft by Gray. It extends from the base of the skull through the neck and posterior mediastinum down to the diaphragm. It seals off laterally at the transverse processes (see Figs. 126-1 and 126-2). 5. Between the prevertebral fascia and the vertebral bodies lies a potential space (space 5) that extends from the base of the skull to the coccyx laterally and to the transverse processes bilaterally (see Figs. 126-1 and 126-2).8 Vertebral infections can involve this space.

Oropharyngeal Spaces The pertinent spaces include the following: 1. The lateral pharyngeal space is bounded by the tonsil and pharynx medially, the parotid gland posterolaterally, the mandible anterolaterally, the carotid sheath posteriorly, and the submaxillary gland anteriorly (Fig. 126-3). It does not communicate with the carotid sheath, as was reported by Coller and Yglesias.6 It does, however, communicate with the submandibular space on one side and the previsceral space (space 3) on the other side.8 FIGURE 126-2 Diagram of the fasciae and spaces of the head, neck, and mediastinum in midsagittal section. (FROM GRODINSKY M, HOLYOKE EA: THE FASCIAE AND FASCIAL SPACES OF THE HEAD, NECK AND ADJACENT REGIONS. AM J ANAT 63:367, 1938. REPRINTED WITH PERMISSION OF WILEY-LISS, INC, A SUBSIDIARY OF JOHN WILEY & SONS, INC.)

Pharynx

Visceral fascia

C2 Submandibular space

Alar fascia

Hyoid bone

Prevertebral fascia

Epiglottis

Previsceral space (Space 3)

Superficial layer

Retrovisceral space (Space 4) Space 5

Sternohyoid muscle Sternothyroid muscle

Trachea

T1 Thyroid gland

Esophagus

Visceral fascia

Previsceral space Fibrous adhesions Manubrium sterni

Ch126-F06861.indd 1531

1/21/2008 4:04:25 PM

1532

Section 7 Mediastinum

FIGURE 126-3 Transverse section through the tongue and the palatine tonsil. (FROM GRODINSKY M, HOLYOKE EA: THE FASCIAE AND FASCIAL SPACES OF THE HEAD, NECK AND ADJACENT REGIONS. AM J ANAT 63:367, 1938. REPRINTED WITH PERMISSION OF WILEY-LISS, INC, A SUBSIDIARY OF JOHN WILEY & SONS, INC.)

Cervical vertebra Retrovisceral space Previsceral space Carotid sheath

Parotid gland

Tonsil Pharynx Submaxillary gland Submandibular space

Lateral pharyngeal space Masseter muscle Mandible

2. The submandibular space includes the region of the submental and submaxillary triangles lying between the floor of the mouth and the superficial layer of the deep fascia. The spaces between the layers of the investing fasciae of the muscles of this region (the sublingual and submaxillary spaces) make up the submandibular space, which communicates with the lateral pharyngeal space (see Fig. 126-3).8

a localized form, given the term mediastinal abscess, and a diffuse form termed phlegmonous mediastinitis. In chronic mediastinitis, morphologic patterns of granulomatous lesions can be distinctive in infections with Mycobacterium tuberculosis, Histoplasma capsulatum, and Coccidioides immitis. However, in the scarring stage, the morphologic changes are nonspecific. Mediastinitis can be classified as follows:

The Fascial Anatomy and the Spread of Infection

I.

The fascial planes fail to confine certain infections with virulent organisms, which can freely spread along fascial spaces and through fascial planes.22 Although the fascial planes do not pose an inviolate barrier to the spread of infection, nonetheless they influence the early spread of infection and are important to an understanding of both the evolution of signs and symptoms and the planning of treatment.23 The lateral pharyngeal space is a relay for infections originating in the dental and alveolar borders of the mandible, parotid gland, and tonsils, for peritonsillar abscess or “quinsy,” and for cellulitis of the sublingual and submaxillary spaces (Ludwig’s angina). Infections in these areas can make their way to the lateral pharyngeal space and the connecting previsceral space. Infection in the previsceral space may spread down the neck and into the anterior mediastinum or may break through the alar fascia to reach the danger space (the retrovisceral space) that leads to the posterior mediastinum and retroperitoneum (see Figs. 126-1 and 126-2).

Infectious A. Acute 1. Suppurative a. Localized (abscess formation) b. Compartmentalized 2. “Synergistic necrotizing” (Fig. 126-4) B. Chronic 1. Granulomatous/fibrosing 2. End-stage sclerosing fibrosis II. Idiopathic, seen in association with retroperitoneal fibrosis, Riedel’s struma, or sclerosing cholangitis25 III. Pharmacologic, seen in response to methysergide (a serotonin antagonist used in the treatment of migraine)25 The diagnosis of mediastinitis in its acute form is made on the basis of the clinical course, the gross pathologic finding, the extent of involvement of the mediastinal compartments, and the bacteriologic makeup. In granulomatous mediastinitis, morphologic changes and serologic findings can be helpful in establishing a diagnosis. In this chapter, only the infectious categories of mediastinitis are discussed.

CLASSIFICATION

SCLEROSING FIBROSIS OF THE MEDIASTINUM

A classification of mediastinal infections was previously advanced by Neuhof.24 He grouped these infections into nonsuppurative and suppurative, with the latter subdivided into

Sclerosing fibrosis of the mediastinum refers to a fibrous proliferative inflammatory process that usually involves the superior mediastinum. The fibrosis encases the mediastinal

Ch126-F06861.indd 1532

1/21/2008 4:04:26 PM

Chapter 126 Chronic Mediastinitis

1533

FIGURE 126-4 CT scan from a patient with acute synergistic necrotizing mediastinitis. A, Note left peritonsillar abscess with tissue induration and free air in the tissue (arrow). B, A posterior mediastinal abscess secondary to infection has descended from the peritonsillar abscess (arrow). An associated right pleural effusion is also present.

structures, causing entrapment and compression. Primarily low-pressure structures such as the SVC, azygos vein, innominate veins, pulmonary veins, and pulmonary arteries are involved, although the esophagus and trachea can be affected.1 Similar fibrotic changes have been reported in other sites, referred to as retroperitoneal fibrosis, sclerosing cholangitis, and Riedel’s fibrosing thyroiditis.

Etiology Many etiologic factors have been cited in the causation of chronic fibrosing mediastinitis, including fungal infection (histoplasmosis, aspergillosis, mucormycosis, and cryptococcosis, with histoplasmosis being most common), bacterial infection (tuberculosis, nocardiosis, and actinomycosis), autoimmune disease, sarcoidosis, and drugs (Marchevsky and Kaneko, 1992).26

Pathogenesis Sclerosing fibrosis of the mediastinum is an end-stage and chronic granulomatous inflammation that begins in the lymph nodes and continues as a low-grade smoldering response that may lead ultimately to the scarring stage. A delayed hypersensitivity reaction was proposed to be the central process that leads to the development of progressive fibrosis in granulomatous mediastinitis evoked by tubercle bacilli and Histoplasma.11 This type of inflammatory response can be evoked by a variety of agents, including tubercle bacilli and certain fungi, particularly H. capsulatum. The agents induce delayed-type hypersensitivity reactions that are cell mediated and specifically initiated by sensitized T lymphocytes. The reactions are

Ch126-F06861.indd 1533

characterized by the accumulation of lymphocytes around small veins and venules, producing perivascular “cuffing” and increased microvascular permeability that causes tissue induration. In fully developed lesions, the lymphocyte-cuffed venules exhibit marked endothelial hypertrophy and, in some cases, hyperplasia. Immunoperoxidase staining of the lesions reveals a preponderance of CD4+ (helper) T lymphocytes. With certain persistent nondegradable antigens, such as tubercle bacilli, the initial perivascular lymphocytic infiltrate is replaced by macrophages. The accumulated macrophages often undergo a morphologic transformation into epithelium-like cells referred to as epithelioid cells. An aggregation of epithelioid cells surrounded by a collar of lymphocytes is called a granuloma. A granuloma caused by insoluble particles that are capable of inducing a cell-mediated immune response is referred to as an immune granuloma.27 This type of granuloma differs from foreign body granulomas. Typically, the latter form when inert materials such as talc particles or sutures are large enough to preclude phagocytosis by a single macrophage and so do not incite an inflammatory or immune response. Epithelioid cells and giant cells become opposed to the surface of the foreign body, thus encompassing it.28 The cell-mediated inflammation induced by insoluble particles or nondegradable antigens that is characteristic of type IV hypersensitivity begins with the first exposure of the individual to the agent (e.g., tubercle bacillus). Naïve CD4+ T cells recognize peptides derived from the bacillus in association with class II molecules on the surface of monocytes. This initial encounter drives the differentiation of naïve CD4+ T cells to helper T1 cells. The helper T1 cells are important because the expression of the delayed hypersensitivity depends largely on cytokines secreted by them.

1/21/2008 4:04:26 PM

1534

Section 7 Mediastinum

Why certain antigens preferentially induce the helper T1 response is not entirely clear. Cytokines relevant to the delayed hypersensitivity reaction include interleukin-12 (IL12) produced by macrophages. IL-12 is critical for the induction of the helper T1 cell response, and hence delayed hypersensitivity. On initial encounter with a microbe, the resting macrophages attempt to phagocytose and kill the organism. The resting macrophages are not particularly adept at these functions. Nonetheless, this interaction leads to the production of IL-12, which, in turn, drives the differentiation of naïve CD4+ helper cells to helper T1 cells, which produce IL-2, tumor necrosis factor, and interferon-γ (IFN-γ). IFN-γ is an important mediator of delayed-type hypersensitivity. It is a powerful activator of macrophages, causing them to further secrete IL-2. Activated macrophages have an augmented ability to phagocytose and kill microorganisms. They express more class II molecules on the surface, thus facilitating further antigen presentation. Their capacity to kill tumor cells is enhanced. They secrete several polypeptide growth factors, such as platelet-derived growth factor and transforming growth factor-β (TGF-β), that stimulate fibroblast proliferation and augment collagen synthesis. Thus activated, macrophages serve to eliminate the offending antigen; and if the activation is sustained, fibrosis results.28 The sustained fibrosis is the phase of the granulomatous inflammation encountered in the mediastinum. The delayed hypersensitivity is a major mechanism of defense against a variety of intracellular pathogens, including mycobacteria and fungi.

Pathology With healing of the acute pulmonary infection, fibrocaseous granulomas develop in the lymph nodes connected to the lymphatic channels from the lungs. These include the hilar and subcarinal lymph nodes that drain into the right paratracheal nodes. As the inflammation evolves, more fibrosis develops in the infected areas. Extensive fibrosis within the right paratracheal area involves the SVC and the azygos vein. Subcarinal fibrosis with anterior extension involves the pulmonary veins; with posterior extension, the esophagus is involved; and with lateral extension, the main bronchi and pulmonary arteries are affected. In a study reported by Goodwin and associates,11 29% of patients with mediastinal fibrosis had symptoms of bronchial obstruction; 23% had SVC obstruction; 15% had pulmonary vein obstruction with a clinical picture of advanced mitral stenosis; 14% had pulmonary artery obstruction with symptoms of cor pulmonale; and 8%, had esophageal obstruction, the great majority of whom also had dysphagia. The degree of fibrosis determines the clinical significance of the mediastinal lesions. The fibrosis seems to invade the adjacent structures, a phenomenon not observed in retroperitoneal fibrosis, in which a zone of demarcation exists, with no invasion, between the area of fibrosis and the structure compressed (most commonly the ureters).11 Remnants of the offending organisms have been reported to persist in healed caseous lesions.11 Grossly, the fibrotic reaction creates a picture that resembles concrete. These

Ch126-F06861.indd 1534

uncleared remnants act as the stimulus for the persistence of the inflammatory response, which leads to more fibroblastic proliferation and scar formation. Granulomatous lesions with mild fibrosis are indistinguishable grossly, whether due to Mycobacterium infection or to histoplasmosis. However, lesions with excessive to massive fibrosis are usually due to histoplasmosis.11 Microscopically, the tissues show dense collagen bands with fibroblastic activity and inflammatory cellular infiltrate composed mainly of mature lymphocytes and plasma cells. The collagen bands are interspersed with areas of hyalinization. A striking feature is the presence of arteriolar obliteration caused by intimal hyperplasia and medial thickening that is not due to vasculitis, as evidenced by the absence of necrosis and inflammatory cell infiltrate in the vessel wall1 (Fig. 126-5).

Diagnosis The diagnosis of sclerosing mediastinitis should be considered in the differential diagnosis of patients presenting with signs of SVC syndrome, dysphagia, or dyspnea or with findings suggestive of cor pulmonale or mitral stenosis, particularly when no specific etiology is found to explain these manifestations. A good medical history review and physical examination, standard radiographs, and CT scans of neck, chest, and upper abdomen are recommended. In patients with SVC obstruction, simultaneous bilateral brachial phlebograms should be performed. Esophagoscopy is performed in patients with a history of dysphagia. Bronchoscopy and either cervical or second space mediastinoscopy should be done in all cases. Care should be exercised during the mediastinal exploration to prevent bleeding due to the increased collateral circulation. Bronchial washings and mediastinal tissue biopsy specimens should be obtained and sent for microscopy; stains and cultures should be done for tuberculosis and for certain fungi such as Histoplasma, Coccidioides, Blastomyces, Nocardia, and Actinomyces. Complement fixation studies should be performed for histoplasmosis, coccidioidomycosis, and blastomycosis. Titers of 1:32 or higher strongly suggest the diagnosis.1

FIGURE 126-5 A photomicrograph showing collagen bands interspersed with areas of hyalinization. Arterioles with luminal obliteration can be seen (arrows).

1/21/2008 4:04:27 PM

Chapter 126 Chronic Mediastinitis

Clinical Manifestations

Treatment

Sclerosing fibrosis of the mediastinum can affect any age group. It is more common among young whites, particularly women. Most patients present with nonspecific symptoms such as cough, dyspnea, chest pain, fever, wheezing, dysphagia, or hemoptysis. Approximately 40% of patients are asymptomatic, and the mediastinal fibrosing disorder is discovered as an incidental radiologic finding related to asymmetric widening of the mediastinum with distortion of tissue planes.12,26 Entrapment and compression of the visceral mediastinal structures and the severity of the pathology can lead to an incapacitating morbid clinical picture. The thin-walled, lowpressure structures, especially the SVC, are involved most frequently.1,10 The luminal compromise of the SVC results in SVC syndrome. Symptoms of this syndrome include swelling and edema of the upper extremities, face, and anterior chest wall, as well as an increase in dilated superficial veins and flushing in these areas.1 Symptoms of SVC obstruction may show regression as collateral circulation develops. The SVC syndrome was observed in 59%1 and 23%11 of cases with mediastinal structure involvement. Other compression symptoms occur less frequently. Central nervous system symptoms include headache, nausea, and dizziness with visual disturbance. Dysphagia due to esophageal compression, intermittent stridor and dyspnea secondary to tracheal compression, cardiac tamponade due to pericardial effusion, and cor pulmonale and mitral stenosis–like symptoms secondary to pulmonary vessel compression are observed in this disorder.1 Pulmonary vein obstruction is a serious condition and can end fatally.11

There is no universally accepted therapeutic modality for the treatment of mediastinal granuloma and fibrosing mediastinitis. Surgical intervention is initially indicated in most patients to establish a diagnosis and particularly to rule out neoplasia. Surgery consists of bronchoscopy and either cervical or second space exploration. Bronchial washings and mediastinal biopsy specimens should be obtained for cytologic and microbial testing.1 If the disease presents as a noncalcified mass, which shows no neoplasia on biopsy, concomitant thoracotomy can be performed to debulk the mass by removing as much granuloma as is technically feasible.31 In approximately 25% of patients with localized granulomas, complete excision of the lesion can be achieved. In some cases, excision of local granulomas prevented the development of subsequent progressive fibrosis.26 In a few patients, surgical intervention is necessary to alleviate airway obstruction, esophageal obstruction, vascular obstruction, or cardiac tamponade. Reconstructive surgery for SVC obstruction has been recommended (Doty et al, 1990).1,32 We have used an SVC bypass graft using a reconstructed spiral saphenous vein graft or azygos vein transposition. Administering a prolonged course of oral ketoconazole and repeating it if necessary is suggested if the Histoplasma complement fixation titer is high.1 Pneumonectomy may be required for pulmonary complications resulting from the obstruction.12 Administering corticosteroid or antifungal therapy when no evidence of active infection is present is controversial.26

Radiographic Findings

The prognosis for fibrosing mediastinitis generally is good. However, the health of many surviving patients becomes compromised as a result of disease progression. Also, those patients with occlusion of a major airway or of a pulmonary artery or vein have a poor prognosis. In a series of 71 patients reported by Loyd and associates,33 30% of patients died. Death was due to cor pulmonale or persistent respiratory compromise. The interval between onset of symptoms and death was about 6 years.

On standard radiographs, most patients show a widening of the superior mediastinum with a masslike effect and obliteration of normal tissue planes. Calcified lymph nodes may be evident.12 CT study may further delineate the pathologic changes and degree of compression of the involved structures. It can be helpful in identifying the mediastinal changes, especially when the plain radiographs appear to be within normal limits. Magnetic resonance imaging is useful in demonstrating the extent of involvement of the great vein, especially if there is a history of hypersensitivity to contrast materials.12 CT with contrast medium enhancement may be helpful in delineating the nature of the compression in cases of unusual venous obstruction. Phlebograms should be obtained to assess the venous anatomy and the location of the site of obstruction, as well as the collateral circulation and the status of the azygos vein. The latter can be anastomosed to the inferior vena cava to palliate SVC obstruction symptoms.1 Pulmonary arteriography may be helpful in demonstrating pulmonary vessel obstruction in suspected cases of sclerosing mediastinitis.12,29 In rare instances, pulmonary infarct due to arterial or venous thrombosis may occur. Pulmonary interstitial fibrosis, which can follow a course similar to that of the usual interstitial pneumonitis, has been reported.30

Ch126-F06861.indd 1535

1535

Prognosis

SUMMARY Mediastinitis in its chronic form can be disabling or lethal. Chronic sclerosing mediastinitis is an end stage of a delayed hypersensitivity granulomatous process incited by certain fungi and bacteria. Failure of the reacting cells to clear the infecting agent evokes this cell-mediated response. The fibrosing process of this disorder is responsible for the morbid and disabling obstruction of visceral structures of the mediastinum, namely, the great veins, the pulmonary vessels, the esophagus, and the airways. Diagnosis is established by the clinical picture, radiologic evaluation, serologic assessment, and tissue biopsy. Surgery is necessary to alleviate significant vascular, esophageal, and airway obstruction. Medical therapy should be administered in cases of positive identification of the microbe or in cases of rising serologic titer.

1/21/2008 4:04:27 PM

1536

Section 7 Mediastinum

COMMENTS AND CONTROVERSIES Chronic mediastinitis represents a serious management problem for thoracic surgeons. In areas of the world endemic for causative organisms, such as the Mississippi River Valley for histoplasmosis, it is not an uncommon problem. Patients can present with a host of symptoms as a result of compression or obstruction of major airways or vessels. A variety of palliative strategies have evolved, such as stenting, surgical reconstruction, or bypass. Pulmonary resections are uncommonly required. Such resections when required are technically challenging because the dense fibrosis associated with this pathologic process obliterates all normal planes between vessels, lymph nodes, and airways. Unfortunately the manifestations of this condition are so numerous that no large case series of a particular presentation are available for review. Therefore, important management decisions must be made on empirical or anecdotal evidence alone. The authors suggest that resection of enlarged compressive granulomatous lymph nodes will lessen the likelihood of subsequent progressive fibrosis. In addition, they have suggested that antifungal agents are of value in the management of patients with mediastinal fibrosis as a result of histoplasmosis. Unfortunately, neither of these contentions has ever been studied in a controlled fashion. G. A. P.

KEY REFERENCES Doty D, Doty J, Jones K: Bypass of superior vena cava. J Thorac Cardiovasc Surg 99:889, 1990. ■ Superior vena cava obstruction therapeutic reference. Fry WA, Shields TW: Acute and chronic mediastinal infections. In Shields TW (ed): Mediastinal Surgery. Philadelphia, Lea & Febiger, 1991, pp 101-108. ■ A good review of general chronic mediastinitis. Marchevsky AM, Kaneko M: Surgical Pathology of the Mediastinum, 2nd ed. New York, Raven Press, 1992. ■ Pathologic explanation of chronic mediastinitis. Urschel HC Jr, Razzuk MA, Netto GJ, et al: Sclerosing mediastinitis: Improved management with histoplasmosis titer and ketoconazole. Ann Thorac Surg 50:215-221, 1990. ■ Classic reference for chronic mediastinitis associated with fungi with discussion of appropriate diagnosis and management. Urschel HC, Razzuk MA, Wood RE: Improved management of esophageal perforation: Exclusion and diversion in continuity. Ann Surg 179;587, 1974. ■ Early improvement in management of chronic mediastinitis secondary to esophageal perforation.

Acknowledgment Dr. Urschel is deeply indebted to Mrs. Rachel Montano for her outstanding contributions to the research and writing of this complicated project.

Ch126-F06861.indd 1536

1/21/2008 4:04:27 PM

chapter

PERICARDIAL DISEASE

127

William G. Jones, II

Key Points ■ The pericardium is a serous sac that surrounds, supports, and

protects the heart. ■ Impairment of pericardial compliance or elevation of intrapericardial

pressure may lead to pathophysiologic and hemodynamically significant restriction of cardiac function. ■ Prompt recognition of cardiac tamponade and drainage of pericardial fluid may be lifesaving. ■ Differentiating constrictive pericarditis from restrictive cardiomyopathy is challenging but critical because only constriction is improved by pericardiectomy.

Beck and Griswald (1930)5 subsequently contributed to our understanding of pericardial disease and led to advances in its treatment. Early reports of symptomatic relief produced by pericardiocentesis by Karaeneff (1840)6 introduced the era of treatment of pericardial disease. Rehn (1913)7 and Sauerbruch (1925)8 independently described methods for pericardial resection, followed by modifications by Schmieder and Fischer (1926).9 Based on the successes of these reports, Churchill (1936)10 performed the first pericardiectomy in the United States for constrictive disease in 1929. HISTORICAL READINGS

The pericardium is a serous sac that surrounds, supports, and protects the heart. The smooth pericardial surface adjacent to the heart and the small amount of pericardial fluid normally present within the pericardial sac provide a frictionless chamber for cardiac motion, thus improving the efficiency of myocardial contractions. The pericardium, however, is subject to disease, including inflammation, infection, trauma, and malignancy. Impairment of pericardial compliance or intrapericardial fluid accumulation, resulting in reduction of the relative volume of the pericardial space secondary to disease processes, may lead to pathophysiologic and hemodynamically significant restriction of cardiac function. Prompt recognition and treatment of pericardial disease is often lifesaving.

HISTORICAL NOTE Hippocrates is credited with the first description of the human pericardium in 460 BC. Three hundred years later Galen first described inflammatory changes and effusions in animals with pericarditis. Similar studies of pericardial disease in humans, however, did not occur until the 17th and 18th centuries, when Lower,1 in 1669, first described cardiac tamponade secondary to the accumulation of pericardial fluid and Lancisi and Morgani wrote of the diminution of cardiac function resulting from constrictive pericarditis. The classic pathologic description of the “bread and butter” appearance of acute pericarditis by Laënnec in 18192 was later followed by characterization of the pathology of chronic pericarditis associated with hepatic disease by Pick (1886).3 Knowledge of the pathophysiology of pericardial disease was advanced by the hemodynamic observations of Kussmaul (1873),4 including the description of pulsus paradoxus in association with tamponade. Modern experimental studies by

Beck CS, Griswald RA: Pericardiectomy in the treatment of the Pick syndrome: Experimental and clinical observations. Arch Surg 21:1064, 1930. Churchill ED: Pericardial resection in chronic constrictive pericarditis. Ann Surg 104:516, 1936. Karanaeff P: Paracentese des Brustkastens und des Pericardiums. Med Z 9:251, 1840. Kussmaul A: Ueber schwielige Mediatino-perikarditis und dem Paradoxen Puls. Berl Klin Wochenschr 10:433, 1873. Laënnec RTH: Traité d’Auscultation Médicale et des Maladies du Poumon et du Coeur. Paris, Brosson & JS Chaude, 1819. Lower R: Tractatus de Corde. London, 1669, p 104. Pick F: Ueber chronische, unter dem Bilde der Lebercirrhose Verlaufen der Pericarditis (Pericarditis pseudolebercirrhose) nebst Bemerkungen ueber Zuckergussleber. Z Klin Med 29:385, 1886. Rehn L: Zurexperimentellen pathologic des Herzbeutels. Verh Dtsch Ges Chir 42:339, 1913. Sauerbruch F: Die Chirurgie der Brestorgane. Berlin, 1925, vol II. Schmieder V, Fischer H: Die Herzbeutelentzunchung und ihre Folgezustande. Ergeb Chir Orthop 19:98, 1926.

EMBRYOLOGY The pericardium is derived from membranous partitions that begin to form between the pleural and peritoneal cavities during the third week of fetal development. By the seventh gestational week, these membranes grow to envelop the fetal heart, ultimately fusing to form the complete pericardial sac. As the developing heart moves into the embryonic two-layer pericardial sac, the inner serosal layer evolves into the visceral pericardium or epicardium and then reflects back to become fused with the outer fibrous layer.11 Separating the two 1- to 2-mm layers is the pericardial space, which may contain up to 50 mL of clear amber-colored fluid (Fig. 127-1). Because of their common origins during development, the pericardium remains intimately associated with, and in some areas contiguous with, the pleurae and diaphragm. 1537

Ch127-F06861.indd 1537

1/21/2008 4:05:12 PM

1538

Section 7 Mediastinum

Aorta Right ventricle cavity Left ventricle Right pulmonary artery cavity

Fibrous pericardium Superior pulmonary vein

Serous parietal pericardium Pericardial space

Left atrium

Serous visceral pericardium (epicardium)

Inferior pulmonary vein

Oblique sinus Transverse sinus Ventricular septum FIGURE 127-1 Schematic cross-section of the heart and pericardium demonstrating the fibrous and serosal parietal layers of the pericardium separated by the pericardial space from the serosal visceral (epicardial) layer. (ADAPTED FROM GOLDSTEIN JA: CARDIAC TAMPONADE, PERICARDITIS, AND RESTRICTIVE CARDIOMYOPATHY. CURR PROB CARDIOL 29:505, 2004.)

ANATOMY The parietal pericardium consists of a tough fibrous outer layer composed of multiple collagen layers sandwiched between elastin fibrils,12 with an inner serosal surface composed of cuboidal cells. The serosa of the pericardium is organized into microvilli and cilia, which produce and reabsorb the pericardial fluid. The serosal layer is then reflected into the epicardial surface to form the visceral pericardium and becomes contiguous with the adventitia of the great vessels superiorly. The pericardium is further anchored anteriorly to the sternum by the superior and inferior pericardiosternal ligaments and inferiorly to the diaphragm.13 The phrenic nerves that provide innervation and associated blood supply originating from the internal mammary arteries lie within the anterolateral portion of the pericardial fat pad bilaterally (Goldstein, 2004).14

PHYSIOLOGY The physiologic functions of the normal pericardium include the following14: 1. Mechanical protection of the heart and limitation of movement of the heart within the chest 2. Lubrication of cardiac movement and buffering to minimize perception of normal cardiac contractions 3. Influence of cardiac filling, which assists in the maintenance of balance between right and left ventricular filling and output 4. Prevention of acute chamber dilation 5. Protection of the heart from spread of infection from the lungs and other areas through mechanical, lymphatic, and immunologic barriers The smooth serosal surface of the pericardial sac provides a frictionless chamber, facilitating cardiac contraction, whereas the fibrous outer layer provides protection against the spread of infection from the adjacent mediastinum and

Ch127-F06861.indd 1538

pleural cavities. The fixed pericardium also supports the heart and prevents cardiac torsion by maintaining the heart in a relatively fixed position despite body motion. The pericardium contributes to the maintenance of a functionally optimal cardiac shape, preventing acute overdilation, which may damage the myocardium. Negative pressure within the pericardium may also enhance atrial filling to a small degree (Troughton et al, 2004).15 Normally, 15 to 20 mL of clear, straw-colored fluid is present within the pericardial space. Pericardial fluid is produced by the serosal cells and is an ultrafiltrate of plasma.16 Microvilli on the serosal surface both produce and reabsorb pericardial fluid. Although membrane characteristics of these cuboidal serosal cells favor absorption rather than production of fluid,17 the net turnover of pericardial fluid is determined by a number of factors, including intravascular and interstitial oncotic pressure, volume, and composition and the adequacy of the lymphatic drainage of the pericardium. The pericardial fluid contains prostaglandins with surfactant qualities that help lubricate cardiac movement and prostacyclins that may regulate coronary vasodilation and sympathetic tone.18 Histologic section of the fibrous portion of the pericardium reveals that the collagen bundles are arranged in a wavy, “herringbone” pattern.19 This configuration gives the pericardium compliance, allowing it to be stretched to where the collagen strands become straightened and aligned. The size of the pericardial sac when the collagen fibers are maximally stretched represents the limiting volume of the pericardial space and the point beyond which further distention is impossible.20,21 Thus, because constraint by the pericardium may prevent cardiac chamber dilation, particularly of the thinwalled right ventricle, the pericardium helps to equalize compliance between the left and right chambers despite their differences in muscle thickness. Consequently, abnormalities of the pericardium may alter the relationship between pericardial compliance and ventricular filling.13,22 Chronic stretching of the pericardium over time results in pericardial

1/21/2008 4:05:12 PM

Chapter 127 Pericardial Disease

hypertrophy and increased pericardial compliance, thus producing a rightward shift in the limiting volume. However, adherence of the pericardium on the epicardial surface of the heart diminishes pericardial compliance, reduces the ability of the pericardium to stretch by even small amounts, and may ultimately restrict cardiac filling. The normal pressure within the pericardium is less than atmospheric and is equal to the intrapleural pressure. Inspiration lowers both intrapleural as well as intrapericardial pressure, resulting in increased right atrial and ventricular filling.14 The normal volume of the pericardial sac exceeds the size of the heart by approximately 20%,23 allowing physiologic enlargement of the heart to occur without restriction. Additionally, the compliance or distensibility of the normal pericardium allows relatively large increases to occur in either pericardial fluid volume or cardiac size without an increase in intrapericardial pressure, particularly when such increases occur over time. As pericardial distention approaches the limiting volume, however, intrapericardial pressure begins to rise. Tamponade occurs when the intrapericardial pressure exceeds right ventricular filling pressure. The slope of the pericardial pressure-volume curve and the point at which tamponade occurs thus depend on the rate of pericardial fluid accumulation, pericardial compliance, and the intravascular volume status, which determines right ventricular filling pressure (Shabetai et al, 1970).21,24

DISEASE CONDITIONS Acute Pericarditis Etiology and Pathophysiology Acute pericarditis may often be the early manifestation of a systemic illness such as connective tissue disease or myocardial infarction. As many as half of all cases of acute pericarditis, however, are due to neoplastic disease, are uremic or infectious in origin, or result from unclear processes and are thus termed idiopathic or nonspecific.25 Some degree of histologic pericarditis is present in up to 20% of patients who are positive for infection with human immunodeficiency virus (HIV), but symptomatic pericarditis in these patients is usually the result of opportunistic infection or neoplastic involvement.26-28 Pericarditis after cardiac surgery or postpericardiotomy syndrome occurs in 20% to 25% of patients29 and is equally common among conventional and minimally invasive approaches.30 The incidence of postpericardiotomy syndrome may be increased by the use of preoperative antiplatelet therapy.31 Other less common causes of acute pericarditis are listed in Table 127-1. Symptoms in acute pericarditis result from inflammation of the pericardium as well as from irritation of adjacent tissues. Pathologic examination of the pericardium during acute pericarditis demonstrates inflammatory cell infiltration and fibrin deposition leading to a characteristic “bread and butter” appearance of the serosal surface.

Diagnosis Acute pericarditis is often preceded by a prodrome of fever, myalgias, and malaise that may last for 3 to 7 days. As the

Ch127-F06861.indd 1539

1539

TABLE 127-1 Less Common Causes of Acute Pericarditis Drug/hypersensitivity reactions Procainamide Warfarin Hydralazine Phenytoin Others Aortic aneurysms and dissections Connective tissue diseases Arteritis Rheumatoid arthritis Systemic lupus erythematosus Rheumatic fever Sarcoidosis Secondary to or postmyocardial infarct or cardiac surgery Secondary to or post irradiation Secondary to or post trauma Myxedema Amyloidosis

inflammation in the pericardium worsens, chest pain and leukocytosis ensue. The substernal pain associated with acute pericarditis is excruciating and may be confused with angina, although pain associated with pericarditis is usually more pleuritic, increased by supination or deep inspiration. Dyspnea is common and accompanied by a nonproductive cough with clear lung fields. The classic friction rub associated with acute pericarditis has been described as resembling the “squeak of leather on a new saddle.”32 The cardiac silhouette may appear enlarged on a chest radiograph when pericarditis is complicated by an effusion of greater than 250 mL.13 Electrocardiographic (ECG) changes in pericarditis, consisting of widespread rather than regional saddle-shaped ST-segment elevation without Q waves or T wave inversion,33,34 may be helpful in differentiating pericarditis from an acute myocardial infarction, particularly because pericarditis may rarely result in an elevation of the creatine kinase MB fraction25 and troponin levels reflecting myocardial irritation.35 An echocardiogram should be obtained in most cases of acute pericarditis to determine the size of the associated effusion and to examine for signs of tamponade when indicated. It may also be useful in the detection of intrapericardial lymphoma or metastatic disease. If the etiology of acute pericarditis is unclear, minimal workup should include cultures for an infectious etiology, a renal profile, and antibody titers for collagen vascular disease.

Management In general, acute pericarditis that is not complicated by tamponade should be treated by bed rest and pain control. Narcotic analgesia is usually required in the early phase and should be supplemented with nonsteroidal anti-inflammatory agents. Colchicine is an effective alternative in patients unable to take nonsteroidal anti-inflammatory druges.36 Severe and persistent pain may require corticosteroids for control. Persistent fevers despite therapy warrant pericardiocentesis to

1/21/2008 4:05:12 PM

1540

Section 7 Mediastinum

ensure the proper diagnosis and to examine the pericardial fluid for purulence or signs of an infectious etiology. Other indications for pericardiocentesis are to relieve tamponade and to evaluate the etiology in cases in which the effusion persists beyond 2 to 3 weeks. Infectious pericarditis may result from direct contamination of the pericardial space by penetrating trauma or surgery, from seeding of the pericardium and pericardial fluid during bacteremia, or from rupture of an adjacent infected collection into the pericardial space. Treatment of infectious pericarditis requires control of the primary source of the infection and drainage of the pericardial space. In infectious pericarditis, the effusion develops quickly and is often thick and purulent and associated with multiple intrapericardial loculations. Pericardiocentesis, although helpful in establishing the diagnosis, may provide inadequate drainage, and early pericardiotomy with careful exploration to open all loculated areas may be required, especially in children with Haemophilus influenzae infection.37 Tuberculous pericarditis necessitates triple-drug therapy for at least 9 months.38 Although controversial, addition of corticosteroids to the antituberculous regimen has also been reported to decrease the need for repeated pericardiocentesis procedures to control the associated effusion.39 Early operative intervention should also be considered in tuberculous pericarditis because the dense fibrous pericardial reaction may prevent concentration of antituberculous drugs to eradicate the infection. Furthermore, this fibrous reaction will ultimately produce a thickened, constrictive pericardium.40 Acute pericarditis has been reported to complicate 5% to 15% of all HIV-infected patients at some time during the course of the illness.41 Most cases of pericardial effusion in HIV-positive patients are asymptomatic, and the etiology remains unidentified. In those patients with symptomatic pericardial effusions, two thirds are either infectious or neoplastic in origin and therapy should be directed at the primary cause.27 Uremic pericarditis occurs most often in patients with renal failure who are undergoing hemodialysis. Specific symptoms may be absent until tamponade develops and pericardiocentesis or pericardiotomy is required. Uremic pericarditis without tamponade may respond to more frequent hemodialysis or to a change to peritoneal dialysis.25 Intrapericardial instillation of corticosteroids has also been reported to be successful in selected patients.42 Acute pericarditis develops in 10% to 15% of patients who are receiving radiation therapy and may occur months to years after therapy.43 Radiation-induced pericarditis produces both pericardial effusions and fibrosis and should be treated with systemic corticosteroids. Symptoms of constriction may require pericardiectomy, although great care should be taken to attempt to differentiate constrictive pericarditis from radiation-induced myocardial fibrosis in these patients.44 Idiopathic acute pericarditis will recur with relapsing episodes in 15% to 30% of all cases. Although recurrences are often numerous and may occur over more than 10 to 15 years, the risk of tamponade in recurrent pericarditis is lower than in acute pericarditis.45 Therapy is similar to that for the

Ch127-F06861.indd 1540

initial episode, consisting of bed rest and pain control. Corticosteroids are often useful in producing remission, and some patients require long-term therapy to prevent recurrence. Colchicine has also been reported to be useful in preventing recurrences.46 Pericardiectomy will relieve symptoms in 50% to 80% of cases45,47 but should be reserved for those patients who develop complications from their corticosteroid therapy or who have failed to obtain a lasting remission.

Constrictive Pericarditis Etiology and Pathophysiology Constrictive pericarditis usually results from acute pericarditis that has resulted either from a single intense episode or from multiple recurrences that have progressed to chronic scarring and fibrosis, leading to a thickened, often calcified, and noncompliant pericardium.14 The rigid pericardium in constrictive pericarditis then results in chronic biventricular diastolic dysfunction with right-sided heart failure and low systemic cardiac output.48,49 The most common causes of constrictive pericarditis are neoplastic disease and the effects of mediastinal radiation therapy, chest surgery, or trauma.20 Tuberculous pericarditis, formerly the most common cause of constrictive pericarditis, is now less common in the United States but remains problematic in other areas of the world. Less commonly, constrictive pericarditis may be secondary to uremia and collagen vascular disorders or may follow acute bacterial pericarditis. It is estimated that between 0.02% and 0.3% of all cardiac surgical procedures are complicated by pericardial constriction.50-52 The development of constrictive pericarditis secondary to cardiac surgery may be related to complete closure of the pericardium after the procedure and to irrigation of the pericardial cavity with irritating solutions.53 Constriction occurs when a chronically diseased pericardium restricts cardiac function by limitation of diastolic filling. Thickening, fibrosis, and calcification of the pericardium diminish pericardial compliance and result in a fixed, often somewhat contracted intrapericardial volume. Adhesions often occur between the parietal and visceral pericardium and when diffuse they may lead to obliteration of the pericardial space. Such obliterative pericarditis may then in some cases produce constriction without marked thickening or even histologic abnormalities of the parietal pericardium.54 Although a thickened, calcified pericardium remains the hallmark of diagnosis, normal pericardial appearance and thickness have been reported in 18% of a series of patients undergoing pericardiectomy for significant constriction.55 As the pericardium becomes more rigid and nondistensible, the limiting volume or ultimate limit of pericardial distention decreases. This leads to an abrupt cessation of the early rapid phase of diastolic filling when the limiting volume of the pericardium is reached. Most commonly the fibrotic process affects most of the pericardial surface and produces a uniform restriction of filling of all heart chambers, resulting in both pulmonary and systemic venous congestion, decreased cardiac output, a fall in systemic blood pressure, and exertional intolerance. Localized constriction and compression may also occur if the disease process in the pericardium is limited.

1/21/2008 4:05:13 PM

Chapter 127 Pericardial Disease

Diagnosis Physical examination in constrictive pericarditis reveals evidence of right-sided heart failure, including jugular venous distention, peripheral edema, hepatosplenomegaly, and ascites. Kussmaul’s sign, an inspiratory increase in jugular venous pressure, may be present, but pulsus paradoxus does not usually occur. An early diastolic pericardial knock by auscultation and occasionally by palpation is present and corresponds to the cessation of rapid ventricular filling caused by the diminished limiting volume of the constricted pericardium. Pericardial calcification may be prominent on chest radiography, especially in the lateral view (Fig. 127-2). The ECG may display nonspecific ST-segment changes but is often only remarkable for low QRS voltages. Other diagnostic studies may be helpful in determining the extent of pericardial disease and the degree of impairment of cardiac function. Transthoracic echocardiography may document thickening of the pericardium, although its usefulness in this regard is limited compared with other modalities.14 Transesophageal echocardiography better visualizes the pericardium, and Doppler imaging studies correlated with respiration may demonstrate alterations of inspiratory filling and abnormal diastolic function in association with normal ventricular systolic function that is characteristic of constriction.56,57 Computed tomography (CT) and magnetic resonance imaging (MRI) allow measurement of pericardial thickness and assess-

1541

ment of dilation of the inferior and superior venae cavae and the hepatic veins and are superior to echocardiography at delineating the extent of neoplastic pericardial disease.58 Unlike MRI, CT is able to detect pericardial calcification that may be indicative of constrictive pericarditis. However, differentiating thickened pericardial tissue from pericardial fluid may be difficult using CT.59-61 MRI is more sensitive at detecting pericardial thickening than CT,62 and Gd-DTPA enhanced MRI may be particularly useful in differentiating pericardial thickening from an associated effusion in early effusiveconstrictive pericarditis without the use of an intravenous contrast agent.63 Thickening of the pericardium with or without calcification is suggestive but not diagnostic of constriction, and constriction may uncommonly occur in the absence of a thickened pericardium.14,55 Angiography with intrachamber pressure monitoring will demonstrate the abrupt cessation of ventricular diastolic filling and equalization of left and right ventricular diastolic pressure. Angiography may also be helpful in operative planning in older patients if concurrent significant coronary artery disease is suspected. It may be difficult to differentiate between cardiac dysfunction resulting from constrictive pericarditis and that resulting from a restrictive cardiomyopathy, especially in the patient with disease resulting from prior mediastinal irradiation. Differentiation, however, is crucial because resection of the constrictive pericardium can be expected to produce a marked resolution of symptoms, whereas removal of the

FIGURE 127-2 A, Lateral chest radiograph of a patient with constrictive pericarditis, demonstrating extensive calcification of the pericardium. B, Radiograph of the same patient after pericardiectomy.

Ch127-F06861.indd 1541

1/21/2008 4:05:13 PM

1542

Section 7 Mediastinum

pericardium in patients in whom the primary problem is restrictive cardiomyopathy will be unsuccessful and poorly tolerated.64 Restrictive cardiomyopathy results from an infiltrative process in the myocardium, such as amyloidosis or radiation-induced fibrosis, that produces diastolic dysfunction. The resulting hemodynamic pattern may be indistinguishable from constrictive pericarditis. Restrictive cardiomyopathy may, however, affect the left ventricle more than the right and may be associated with signs of other organ involvement in systemic diseases, such as amyloidosis. Echocardiographic findings that may help to distinguish constriction from restriction include findings of pericardial thickening; increased transmitral, pulmonary vein, and tricuspid flow with inspiration; and preserved indexes of myocardial relaxation.64,65 Noninvasive techniques such as cine MRI have also demonstrated value in the differentiation of constrictive pericarditis from restrictive cardiomyopathy.66 Differential diagnostic accuracy of more than 90% has been reported with MRI based on findings of pericardial thickening in constrictive pericarditis and conical narrowing of the ventricles with atrial dilation and engorgement of the venae cavae in restriction.67,68 At angiography, restrictive cardiomyopathy may be distinguished from constrictive pericarditis by the presence of right ventricular systolic hypertension. Restrictive cardiomyopathy also results in impaired function throughout diastole, whereas only the latter portion of the rapid filling phase is affected in constrictive pericarditis. In patients without pericardial thickening in whom echo and hemodynamic findings are consistent with either diagnosis, endomyocardial biopsy at the time of angiography to examine for histologic abnormalities of cardiomyopathy may be diagnostic of restrictive disease in up to 39% of patients.69 The differentiating features of constrictive pericarditis and restrictive cardiomyopathy are presented in Table 127-2.

adherent to the epicardial surface, obscuring planes of dissection. Operative mortality of up to 5% has been reported.73 Failure to improve after pericardiectomy may result from inadequate resection of the visceral portion of the pericardium, leading to continued constriction, or from underlying myocardial disease, atrophy, or fibrosis (Culliford et al, 1980).74,75 Timing of operative intervention remains controversial. Early pericardiectomy, even before the onset of symptoms, has been recommended in pericardial disease processes in which the likelihood that constriction will develop is high, as in tuberculous pericarditis.40 For most other disease processes, surgery may be delayed until the patient actually begins to demonstrate signs of early constriction. Serial echocardiograms may be helpful in following these patients and planning intervention. Median sternotomy is the standard surgical approach, although some surgeons perform pericardiectomy through a left anterior thoracotomy if the disease process is limited to the anterior pericardium. However, complete resection of the pericardium from beyond the right phrenic nerve to the left pulmonary vessels with preservation of the phrenic bundles bilaterally is to be recommended to decrease the risk of recurrent constriction because reoperation for additional pericardial resection carries a significantly higher morbidity and mortality.74 Careful removal of the visceral portion of the pericardium is also crucial in preventing recurrence. Cardiopulmonary bypass should be available at the time of operation in case it is needed to obtain an adequate pericardial resection, but it should probably be avoided if possible to obviate the need for systemic heparinization with its attendant higher risk of bleeding.

Management

Pericardial effusions result when the net rate of pericardial fluid production exceeds the rate of fluid resorption. The pericardial effusion fluid may be serous, purulent, or hemorrhagic or a combination of the three types. More than 75% of pericardial effusions are secondary to malignancy, most commonly of the lung or breast or lymphoma (Press and Livingston, 1987).76 Benign causes of pericardial effusive disease include acute pericarditis, especially if viral and

Thickening, fibrosis, and calcification of the pericardium in constrictive pericarditis are not reversible and therefore necessitate operative intervention if significant. Adequate resection of the pericardium in these cases leads to both immediate relief of symptoms and a later improvement in exercise tolerance.28,70-72 However, pericardiectomy may be a difficult procedure because the pericardium is often firmly

Pericardial Effusive Disease and Cardiac Tamponade Etiology and Pathophysiology

TABLE 127-2 Differentiating Features of Constrictive Pericarditis and Restrictive Cardiomyopathy Constrictive Pericarditis

Restrictive Cardiomyopathy

Clinical Presentation

Chronic right-sided heart failure

Chronic right-sided heart failure

Echocardiography

Dilated atria, small ventricles, increased filling during inspiration, normal myocardial relaxation indexes

Dilated atria, small ventricles, no inspiratory filling variation, abnormal myocardial relaxation indexes

CT/MRI

Most commonly thickened pericardium (>4 mm) with calcification and often small or loculated pericardial effusion

Normal pericardial thickness (≤2 mm), usually no pericardial effusion

Hemodynamics

Elevated and equalized diastolic filling pressures, right ventricular dip and plateau

Elevated and equalized diastolic filling pressures, right ventricular dip and plateau

Endocardial Biopsy

Normal

Usually abnormal, demonstrating an infiltrative process such as amyloidosis

Ch127-F06861.indd 1542

1/21/2008 4:05:13 PM

Chapter 127 Pericardial Disease

1543

idiopathic in origin or after cardiac surgery; trauma; rupture of an ascending aorta aneurysm or dissection; radiation therapy; and myocardial infarction, particularly in association with anticoagulation. Irritation and inflammation of the pericardial serosa produce an exudative reaction resulting in increased pericardial fluid. Likewise, implantation of metastatic disease in the serosa leads to exudation of fluid into the pericardial space. When the resorptive capacity of the pericardial serosa is exceeded or inflammatory or neoplastic processes begin to obstruct the venous and lymphatic drainage of the pericardium, a significant effusion develops that may result in cardiac tamponade when the limiting volume of the pericardium is reached. The normal function of the heart and circulation is compromised when the presence of fluid under increased pressure within the pericardial space compromises diastolic filling. Because the normally compliant pericardium allows some distensibility, the rate of pericardial fluid accumulation may be as important as the total amount of fluid present in determining the point at which cardiac function will be compromised. Mild cardiac compression may only produce an elevated central venous pressure with normal systemic blood pressure because impaired diastolic function may be adequately compensated by a normal heart and circulation. Severe compression leads to further compromise of diastolic filling beyond the compensatory capabilities of the heart and results in tamponade and ultimately in cardiogenic shock.

Diagnosis Pericardial effusive disease without significant cardiac compromise or tamponade is often asymptomatic. Because the development of a pericardial effusion may not diminish the quality of friction rubs or cause ECG changes in acute pericarditis, a high index of suspicion must be maintained for early diagnosis to be made. A pericardial effusion should be suspected when patients with pericarditis, metastatic neoplasms, or uremia and renal failure requiring hemodialysis develop diminished QRS voltages on ECG or an enlarged cardiac silhouette on chest radiography (Fig. 127-3), especially in association with clear lung fields or an unexplained increase in venous pressure. Acute cardiac tamponade occurs when a pericardial effusion rapidly develops, such as after blunt or penetrating chest trauma, percutaneous coronary intervention or pacemaker insertion, postinfarction ventricular rupture, intrapericardial rupture of an aortic dissection, or from bleeding after cardiac surgery (Fig. 127-4). The central venous pressure markedly increases in association with systemic hypotension. Beck’s triad of distended neck veins, muffled heart sounds, and hypotension is characteristic; and pulsus paradoxus may be detectable. Recognition of tamponade in this setting is crucial and should prompt rapid volume infusion to further raise venous pressure to promote diastolic filling, as well as emergent pericardiocentesis for decompression. Definitive identification and correction of the primary abnormality may then be pursued. Subacute tamponade presents as progressive dyspnea on even minimal activity and should be suspected in hemody-

Ch127-F06861.indd 1543

FIGURE 127-3 Chest radiograph demonstrating an enlarged, smooth-bordered cardiac silhouette in a patient with a large pericardial effusion and impending cardiac tamponade.

FIGURE 127-4 CT scan of the chest demonstrating a large pericardial effusion secondary to perforation of the right ventricle by a pacemaker lead.

namically compromised patients who have pericarditis, aortic dissections, or known or suggested intrathoracic or metastatic neoplasms or who are recovering from chest trauma or cardiac surgery. Hypotension may be present, but the systemic blood pressure may be maintained by elevated peripheral vascular

1/21/2008 4:05:13 PM

1544

Section 7 Mediastinum

FIGURE 127-5 Echocardiogram demonstrating a large pericardial effusion in a patient with metastatic breast cancer that is compressing the right atrium and ventricle at end diastole.

resistance. A narrow pulse pressure accompanied by pulsus paradoxus, distant heart sounds, and an elevated central venous pressure is characteristic. Tachycardia results as a compensatory mechanism to maintain cardiac output, whereas rales are uncommon. Chest radiographs confirm the presence of an enlarged cardiac silhouette with clear lung fields, whereas the ECG demonstrates low QRS voltages and ST-segment alterations. Electrical alternans, or QRS voltages that vary from beat to beat, may also be present; this reflects swinging of the heart in the pericardial fluid during contractions. Regional tamponade occurs when loculated effusions or more commonly localized hematomas after cardiac surgery result in selection chamber dysfunction rather global cardiac effects. Consequently, hemodynamic findings are not typical of classic tamponade and may be quite puzzling if the diagnosis of regional tamponade is not considered. Hypotension and low cardiac output are common; but depending on which of the four chambers is most affected, central venous pressure may not be elevated and there may be no equalization of diastolic filling pressures or signs such as pulsus paradoxicus.14 Echocardiography may be helpful, but a high index of suspicion particularly in the post–cardiac surgery patient with impaired hemodynamics must be maintained because surgical intervention may be lifesaving. Proper diagnosis of tamponade requires demonstration of a pericardial effusion, demonstration of hemodynamic abnormalities attributable to pericardial fluid under pressure, and improvement of these hemodynamic abnormalities after drainage of the pericardial fluid.77 Echocardiography (Fig. 127-5) has proven to be the most helpful adjunct in the diagnosis of pericardial effusive disease and tamponade in the subacute setting. M-mode echocardiography allows diagnosis of pericardial effusion by the demonstration of an echo-free space between the heart and pericardium. The heart may be seen to swing freely in the effusion in association with electrical alternans.78 The effusion may be characterized as small if

Ch127-F06861.indd 1544

present only behind the left ventricle, moderate if also present in front of the right ventricle, and massive if the echo-free area surrounds the heart during all phases of the cardiac cycle.79,80 Furthermore, two-dimensional echocardiograms can quantify the amount and location of the effusion, identify loculations and adhesions, and suggest impending tamponade.81 Hemodynamic compromise and cardiac tamponade may be demonstrated echocardiographically by a decreased right ventricular diameter with compression of the right atrium. Paradoxical septal motion and systolic collapse with inward motion of the right atrial and ventricular walls in early systole suggest severe compromise requiring emergent decompression. Other echocardiographic findings of tamponade may include persistent full distention of the inferior vena cava throughout the entire cardiac cycle and an exaggerated respiratory variation in the velocity of flow through the mitral and tricuspid valves.82

Management Treatment of pericardial effusive disease without evidence of hemodynamic compromise may be directed toward the cause of the effusion alone if the underlying condition is self-limited or responsive to therapy, the effusion does not appear to be enlarging, the patient can be observed for signs of increased effusion or evolving tamponade, and fluid is not necessary to establish a primary diagnosis. The indications for pericardiocentesis in the absence of tamponade are to eliminate the possibility of a purulent effusion that requires operative drainage, to differentiate a neoplastic effusion in patients with malignancy from a reactive effusion after irradiation or chemotherapy, and to obtain fluid for proper diagnosis when the etiology of the effusion is unclear or when an exact diagnosis is necessary in choosing therapy.83,84 Signs of impending tamponade on examination or echocardiography are an indication for emergent pericardial decompression by pericardiocentesis or open drainage. While being prepared for drainage, the patient should be treated by volume expansion with saline solutions despite elevated venous pressures. Volume infusion will increase right atrial pressure without affecting intrapericardial pressure, thus promoting diastolic filling. Infusion of dobutamine may also be helpful in the interim management of these patients before drainage by decreasing heart size through improved inotropy and systemic vasodilation. However, it cannot be overemphasized that emergent decompression of the pericardial space is the only maneuver in impending tamponade that is lifesaving. The choice of pericardiocentesis versus open drainage procedures for tamponade remains controversial and depends on the etiology of the effusion, the condition of the patient, and the available facilities and physician experience. Pericardiocentesis is less expensive than open drainage and requires fewer resources. Placement of a catheter into the pericardial space permits an exact hemodynamic diagnosis and allows pressure monitoring for evaluating the effects of drainage on hemodynamics. Sclerosis may be subsequently performed for treatment of malignant effusions. Pericardiocentesis is associ-

1/21/2008 4:05:14 PM

Chapter 127 Pericardial Disease

ated with morbidity and occasional mortality from errant catheter placement into the heart or inferior vena cava and from bleeding due to laceration of an epicardial or coronary vessel. Although decompression may be obtained, complete drainage of the effusion, especially if loculated or purulent, may be difficult, necessitating repeated taps or open drainage. Even in the patient in whom surgical drainage is anticipated, partial decompression by pericardiocentesis before surgery may temporarily improve hemodynamics so that the procedure may more safely proceed. Pericardiotomy may be performed through either a subxiphoid or a left anterior thoracotomy approach. The choice of operative approach depends on multiple factors, including the experience and preference of the surgeon and anesthesiologist, with each method having its proponents. Open drainage through such incisions is performed under direct vision, allows for exploration of the pericardial space, and permits pericardial biopsy if indicated. The incision may be extended if necessary, and pericardiectomy may be performed. Open drainage has the disadvantages that a fully equipped and staffed operating room is necessary and accurate intraoperative pericardial pressure measurements are difficult to obtain. Furthermore, general anesthesia is necessary, at least for the anterior thoracotomy approach, and anesthetic induction in these hemodynamically compromised patients may be hazardous.

1545

A

OTHER DISEASES OF THE PERICARDIUM Congenital Anomalies Partial or complete absence of the pericardium is rare and usually asymptomatic. An incomplete defect on the left side is the most common finding and is often associated with other congenital cardiac malformations, including patent ductus arteriosus, atrial septal defect, mitral valve stenosis and prolapse, and tetralogy of Fallot.85 No significant pathophysiology accompanies a pericardial defect unless it is large enough to allow herniation of the left side of the heart or torsion of the great vessels. Pericardial cysts and diverticula are smooth and rounded structures usually first found on a routine chest radiograph.86 They most commonly occur in the right cardiophrenic angle anteriorly.87,88 The diverticula differ from the cysts by the persistence of a connection to the coelomic cavity.89 Both uncomplicated cysts and diverticula are asymptomatic but when discovered should be differentiated from neoplasms by CT or MRI (Fig. 127-6).

Pericardial Neoplasms Although metastatic disease of the pericardium is common, primary neoplasms of the pericardium are rare. Mesothelioma is the most common primary pericardial neoplasm; and as with primary pleural mesothelioma, effective therapy producing long-term control is lacking. Pericardial resection may be necessary to control pericardial effusions. Treatment with doxorubicin, cyclophosphamide, and cisplatin has also met with limited success.90 Other reported primary pericardial neoplasms include lymphangiomas, hemangiomas, teratomas, rhabdomyosarcomas, and lipomas.

Ch127-F06861.indd 1545

B FIGURE 127-6 A, CT scan of the chest in a patient with a large congenital cyst of the visceral pericardium overlying the right ventricle. B, CT scan of a patient with pericardial diverticulum extending into the right chest.

Metastatic neoplasms are far more common than primary pericardial tumors. Metastases spread to the pericardium by hematogenous or lymphatic routes or through direct invasion of the pericardium. Common primary tumors that metastasize to or involve the pericardium include lung, breast, colon, esophagus, kidney, ovary, prostate, and stomach neoplasms; leukemia and lymphoma; melanoma; and soft tissue sarcomas.76 The most common presentation of tumor involving the pericardium is a pericardial effusion, and metastatic disease is the most common cause of pericardial effusions. The presence of the pericardial effusion almost invariably indicates unresectability for cure. Treatment should be directed toward systemic chemotherapy and effective palliation and control of the effusion by pericardial drainage.91,92 Sclerosis of the pericardial cavity with doxycycline, talc, or bleomycin may be indicated if the effusion is recurrent, enlarging, or hemodynamically significant.93

1/21/2008 4:05:14 PM

1546

Section 7 Mediastinum

Postpericardiotomy Syndrome As many as 25% to 30% of patients undergoing surgical procedures in which the pericardium is opened experience symptoms that are associated with the postpericardiotomy syndrome. Studies have demonstrated elevated antiheart and viral antibody titers in some of these patients,94 but the etiology and pathophysiology of the syndrome remain poorly understood. Symptoms resemble those of acute pericarditis with pleuritic chest pain and dyspnea, a pericardial friction rub, and, less frequently, fevers and leukocytosis. Most patients are well controlled by administration of nonsteroidal anti-inflammatory agents until symptoms have resolved, although rarely a patient may require pulse corticosteroid therapy to control symptoms. Some patients experience relapse with recurrence of symptoms after cessation of therapy and require more prolonged therapy.

PERICARDIOCENTESIS AND PERICARDIAL SURGERY Preoperative and Anesthetic Considerations Patients undergoing procedures for decompression of the pericardial space for impending tamponade should be volume loaded with saline solutions as preparations for the procedure are being made. Volume expansion is crucial, even with already elevated venous pressures, to maintain hemodynamic stability and promote diastolic filling by increasing right atrial pressure above intrapericardial pressure. A careful history for corticosteroid therapy within the past year for pericarditis or underlying disease should be sought; and if it is found, stress corticosteroid therapy should be administered. Arterial and central venous pressure monitoring is essential for open procedures and highly recommended during pericardiocentesis, although in emergent situations rapid decompression through a subxiphoid incision may be made with only local anesthesia and no invasive monitoring. Safe anesthetic induction in hemodynamically compromised patients is difficult and necessitates close cooperation between the surgeon and the anesthesiologist. Sudden loss of vascular tone due to anesthetic administration in patients with impending tamponade will result in hypotension, further hemodynamic compromise, and cardiac arrest if it is not anticipated and proper precautionary actions are not taken. Induction and intubation should not be begun until after the patient is properly positioned on the surgical table with the head elevated. The patient should be prepared and draped awake, and the surgical team should be prepared to commence the operation as the rapid sequence induction is initiated. Pericardiocentesis and partial decompression before open drainage may also improve hemodynamic stability and response to anesthesia and surgery.

Pericardiocentesis Pericardiocentesis is indicated to establish the diagnosis of pericardial disease by examination of effusion fluid, to treat acute or impending tamponade, to differentiate from constriction in the etiology of elevated venous pressures in association with pericardial disease, and as an interim treatment

Ch127-F06861.indd 1546

before surgical drainage for tamponade to aid anesthetic management.95 The patient is placed in a semiupright position, and the midanterior chest is prepared and draped. A parasternal placement of the catheter through the fourth or fifth intercostal space may be chosen, but the subxiphoid approach is generally easier and safer. An entry point is chosen 2 cm inferior to the xiphoid and to the left of the midline. A 21gauge spinal needle is directed at a 45-degree angle aimed toward the left shoulder. The direction of the needle may also be guided by ECG monitoring, with a watch for deflection as the needle contacts the epicardial surface96; by echocardiography97; or by fluoroscopy with pressure monitoring in an angiography suite. The needle is continuously aspirated as it is advanced, and once fluid is encountered, the needle may be changed over a guidewire to a flexible Silastic catheter. Returned bloody fluid should be examined carefully for clotting to rule out inadvertent cardiac puncture. A pneumopericardium, produced by insufflation of air into the pericardial space, was often used in the past, after completion of drainage of the pericardial fluid, to permit determination of pericardial thickness or the presence of masses by plain chest radiography.98 This technique has largely been supplanted by the widespread use of echocardiography.81 The catheter may also be left in place for subsequent fluid drainage or sclerosis of the pericardial space. Bleeding is the most common complication of pericardiocentesis and may result from inadvertent cardiac entry, cardiac or epicardial laceration, or injury to a coronary artery.99 The risk of cardiac injury and significant hemorrhage is increased in patients with thrombocytopenia, coagulopathies, or small or loculated effusions and when a presumptive effusion is drained without echocardiographic confirmation.100 Vasodilation secondary to rapid decompression of the pericardial space may also occur and should be treated by volume administration. Failure to adequately drain the effusion or the recurrence of fluid may lead to later tamponade. The choice of pericardiocentensis over an open surgical drainage procedure depends on the disease process being treated, the availability of facilities, and the experience of the physician performing the procedure. Open drainage should be favored when the accessibility of the effusion by pericardiocentesis is questionable, in the presence of a coagulopathy or other condition that increases the risk of bleeding, or when constrictive pericarditis, which will need resection, is concomitantly present. Suspicion of the presence of partially clotted blood or purulent fluid within the pericardial space should also prompt an open procedure to ensure adequate drainage.

Pericardiotomy Open pericardial drainage and pericardiotomy are indicated for pericardial effusions containing clotted blood; for effusions associated with a likely cardiac bleeding site, such as a traumatic injury; for suspected purulent or loculated effusion; for effusions that are recurrent or likely to recur, as in uremic pericarditis; or when pericardial biopsy is required for diagnosis.

1/21/2008 4:05:15 PM

Chapter 127 Pericardial Disease

Pericardiotomy may be performed by using either a subxiphoid or left anterior thoracotomy incision. The subxiphoid approach may be used with the patient under local anesthesia. A 3- to 4-cm vertical incision is made in the midline just above and inferior to the xiphoid process. Dissection is continued posteriorly and superiorly to the reflection of the pericardium onto the diaphragm. The pericardial space is entered at that point, and the effusion is drained. The pericardial space is carefully explored to ensure adequate drainage and open loculations. Substernal pericardial tubes are then placed for continued drainage and sclerosis if required. Use of a left anterior thoracotomy approach allows improved visualization, greater exploration of the pericardial space, and a wider resection of the pericardium, establishing a drainage pathway into the left pleural space. It is generally performed in the supine position, and the incision may be extended to perform a pericardiectomy if indicated. However, general anesthesia is required for the anterior thoracotomy, which is also more painful postoperatively than the subxiphoid procedure. Use of video-assisted thoracic surgery (VATS) is now allowing many of the benefits of the thoracotomy approach with reduced postoperative pain and morbidity. Pericardiotomy and partial pericardial resection can easily be performed by a surgeon who is skilled in these techniques, although the ability to explore the pericardial space remains limited and the lateral positioning usually required may not be well tolerated by hemodynamically compromised patients. Furthermore, thoracoscopic pericardiocentesis may also require single-lung ventilation through the use of double-lumen endotracheal tubes or bronchial blockers.

Pericardiectomy Pericardiectomy is indicated for constrictive pericarditis and for selected cases of recurrent pericarditis or recurrent pericardial effusive disease that is unresponsive to medical therapy. A median sternotomy approach is preferred, although some surgeons still favor a left anterior thoracotomy incision. Resection of both the parietal and the visceral pericardium are necessary for adequate treatment of constrictive pericarditis, whereas it is less crucial to remove the visceral layer in the treatment of recurrent effusions. The extent of resection for constrictive disease is usually from the right phrenic nerve to the level of the left pulmonary vasculature anteriorly, to the reflection onto the great vessels superiorly, and to the posterior diaphragm inferiorly. The phrenic nerves and associated blood vessels are preserved bilaterally as 1-cm tissue bridges. The visceral pericardium may then be “teased” from the surface of the epicardium, with care taken to remain in the proper plane of dissection (Fig. 127-7). The pericardium over the left ventricle is resected when possible before that over the right ventricle to minimize early blood loss because the latter is the more easily injured of the two chambers. This sequence also theoretically avoids pulmonary congestion, which might occur if right ventricular output were allowed to increase while the left ventricle remained constricted. After the resection, both pleural

Ch127-F06861.indd 1547

1547

FIGURE 127-7 Surgical technique of “teasing” the visceral pericardium from the epicardial surface during pericardiectomy for constrictive pericarditis.

cavities should be widely opened to allow improved postoperative drainage of blood and exudative fluid. Complications may occur in 10% to 30% of cases.73,74 Bleeding may be profuse and can occur from the raw epicardial surface or from laceration of the right atrium, right ventricle, or coronary vessels. Arrhythmias are common and are due to atrial irritability, manipulation of the heart, or injury to branches of the coronary arteries. Some surgeons have recommended the use of cardiopulmonary bypass during pericardiectomy to facilitate control of cardiac lacerations and hemorrhage and to allow safer manipulation of the heart for more complete resection.28,70,74 However, systemic heparinization may make control of bleeding from the raw epicardial surface more difficult and actually increase operative morbidity. Although the routine use of cardiopulmonary bypass is not indicated, it should be available on a standby basis for all pericardial resections for constrictive disease.

COMMENTS AND CONTROVERSIES Dr. Jones has concisely outlined the challenge of differentiating constrictive pericarditis from restrictive cardiomyopathy. Although pericardiectomy will often benefit those patients with constrictive pericarditis, such a major operative procedure is poorly tolerated and often fatal in a patient with restrictive cardiomyopathy. The surgical options for diagnostic and therapeutic evacuation of pericardial effusion are clearly presented. Pericardial centesis is underemployed as a means to avoid operative intervention. Of the operative approaches, subxiphoid, left anterolateral thoracotomy, or video-assisted thoracostomy are preferences to accomplish a pericardial window by means of a subxiphoid approach. This approach provides easiest access with a minimal amount of preoperative preparation. Arterial lines and single-lung ventilation are not necessary. The subxiphoid approach can be accomplished under local anesthesia, which is a definite advantage in the patient who is hemodynamically unstable. With current available imaging modalities, including computed tomography, magnetic resonance imaging, and echocardiography, the diagnosis of pericardial cysts should never be in doubt and

1/21/2008 4:05:15 PM

1548

Section 7 Mediastinum

surgical resection should never be performed in the asymptomatic patient. G. A. P.

KEY REFERENCES Culliford AT, Lipton M, Spencer FC: Operation for chronic constrictive pericarditis: Do the surgical approach and degree of pericardial resection influence the outcome significantly? Ann Thorac Surg 29:146, 1980. ■ This excellent study and subsequent discussion of surgical treatment of constrictive pericarditis weighs the controversies regarding adequate therapy and surgical technique.

Shabetai R, Fowler ND, Gunthenok WG: The hemodynamics of cardiac tamponade and constrictive pericarditis. Am J Cardiol 26:480, 1970. ■ Pericardial pressure-volume relationships and the hemodynamic consequences of pericardial tamponade and constrictive pericarditis are thoroughly discussed. Troughton RW, Asher CR, Klein AL: Pericarditis. Lancet 363:717, 2004. Goldstein JA: Cardiac tamponade, constrictive pericarditis and restrictive cardiomyopathy. Curr Prob Cardiol 29:503, 2004. ■ These two review articles offer excellent summaries of the current state of the art of pericardial diagnostic and imaging modalities and relate these to the pathophysiology of pericardial disease.

Press OW, Livingston R: Management of malignant pericardial effusion and tamponade. JAMA 257:1088, 1987. ■ A well-organized review of etiology and management of malignant pericardial disease includes both medical and surgical treatment options.

Ch127-F06861.indd 1548

1/21/2008 4:05:15 PM

chapter

SURGERY FOR MYASTHENIA GRAVIS

128

Sunil Singhal Larry R. Kaiser

Key Points ■ Patients with myasthenia gravis can improve or have complete

remission of their disease over several years. ■ Patients with myasthenia gravis and a thymoma should have their

tumors completely resected. ■ Various surgical techniques, including transcervical and transster-

nal approaches, can be used to access the anterior mediastinum and resect thymic tissue. ■ Careful preoperative preparation and selection of patients with myasthenia gravis can result in a safe operation with little postoperative morbidity. ■ Patients with myasthenia gravis should be managed by neurologist and thoracic surgeons together.

Myasthenia gravis is an autoimmune disorder that affects skeletal muscles. Clinical symptoms range from intermittent ocular weakness to debilitating respiratory depression. This disease is primarily managed by neurologists with anticholinesterase agents and immunosuppressive therapies. An alternative treatment is surgical removal of the thymus gland. The rationale for thymectomy in patients with myasthenia gravis relates to observations that the thymus may play a role in the pathogenesis of myasthenia gravis and that many patients with myasthenia gravis have either thymic hyperplasia or thymoma. Thousands of patients in scores of retrospective studies have demonstrated that patients undergoing thymic resection do have improvement or complete remission of their disease. Despite the evidence, there has been no well-performed prospective randomized trial comparing medical versus surgical therapy, ultimately leaving patient care to the decision of the neurologist. Within the surgical community there continues to be debate regarding the best approach to resect the thymus gland and the definition of what constitutes a complete resection. It may not be possible to perform a well-controlled prospective trial across multiple institutions to conclusively settle these controversies owing to the indolent nature, variable clinical course, and diverse classification of this disease.

HISTORICAL NOTE In 1879, Erb described a clinical syndrome characterized by skeletal muscle weakness, later termed myasthenia gravis by Jolly.1 The discovery of the junctional transmission of nervous impulses by chemical agents by Loewi and Dale led Mary Walker to observe a dramatic improvement in muscular

strength in myasthenic patients treated with parasympathomimetic drugs such as physostigmine and neostigmine.1 Edrophonium was introduced around 1950 and pyridostigmine in the mid 1950s. John Simpson’s hypothesis of an autoimmune etiology for myasthenia gravis in 1960 was later proven correct, and subsequent use of immunosuppressive therapy including corticosteroids led to the modern era in management of myasthenia gravis.2 The first observation of the relationship between the thymus gland and myasthenia gravis dates to Oppenheim in 1889 and Weigert in 1901, who found thymic tumors at autopsy in patients with myasthenia gravis.3,4 Up to that point, no defining pathology anywhere in the body had been found to correlate with myasthenia gravis.5 The availability of chest radiography in the first half of the 20th century provided further evidence that enlargement of a gland in the anterior mediastinum was frequently present in patients with skeletal muscle weakness. The first operation for myasthenia gravis occurred on March 6, 1911, and was performed by Sauerbruch.6 Using a transcervical approach, he operated on a 19-year-old girl for myasthenia gravis and coexisting goiter. He removed a 49-g mass of hyperplastic thymus and noted subsequent improvement of her symptoms. Over the next 20 years there were intermittent reports of surgeons performing this operation with good response in terms of symptomatic improvement. However, the modern era of thymic surgery for myasthenia gravis started with Alfred Blalock at Johns Hopkins Hospital in 1936. Blalock performed the successful transsternal removal of a thymic tumor in a patient with myasthenia gravis.7,8 The patient experienced marked and sustained improvement for several years. Blalock suggested that exploration of the thymic region would be indicated in all patients with severe myasthenia gravis. A few years later, in 1941, he applied this theory by introducing thymectomy for nonthymomatous myasthenia and achieved similar improvement.9 By 1944, he had reported his series of 20 patients, thus introducing a new therapeutic option for myasthenia gravis.10 Various developments in surgery made it possible to approach tumors in the anterior mediastinum. The history of the transcervical approach to anterior mediastinal masses dates to the 19th century. In 1896, Ludwig Rehn of Frankfurt operated on a patient for an enlarged anterior mediastinal mass that was obstructing the airway. Using a transcervical approach, he pulled the enlarged mass out of the mediastinum and fixed it to the back of the manubrium.5 Another 60 years would pass until Carlens popularized cervical approaches to the mediastinum in developing mediastinoscopy. Thus 1549

Ch128-F06861.indd 1549

1/21/2008 4:06:21 PM

1550

Section 7 Mediastinum

began the modern era of cervical access to the anterior mediastinum. Although several hundred thymectomies were performed through a collar incision in the first 40 years after Blalock’s work, the overwhelming concern in the surgical community was the risk of inadequate resection in cervical thymectomies. Joel Cooper developed the manubrial retractor, which permitted better visualization of the thymus gland via a minimally invasive approach and made it possible to have a complete thymic resection with excellent visualization of the anterior mediastinum from the neck (Cooper et al, 1988).11 This modification repopularized the transcervical approach to remove the thymus gland. In the last decade of the 20th century, other minimally invasive approaches to thymectomy using video-assisted thoracoscopic surgery (VATS) have been advocated and gained popularity.12,13

TABLE 128-1 Modified Osserman Classification* Class

Symptoms

0

Asymptomatic

1

Ocular symptoms

2

Mild generalized weakness: respiratory symptoms spared. Usually associated with bulbar symptoms.

3

Moderate generalized weakness

4

Fulminant severe weakness: prominent respiratory symptoms

*This is the most widely accepted classification of symptoms and severity of disease. It was initially reported in Osserman KE, Genkins G: Studies in myasthenia gravis: Review of a twenty-year experience in over 1200 patients. Mt Sinai J Med 38:497, 1971. It has subsequently been revised several times to its current scaling.

MYASTHENIA GRAVIS Myasthenia gravis is an autoimmune disease with the cardinal feature being exertional voluntary skeletal muscle weakness and fatigability.14 The weakness tends to increase with repeated activity and improve with rest. The muscle weakness occurs in a classic distribution. Ocular symptoms (ptosis and diplopia) occur early in the majority of patients. In 15% of patients, ocular muscle weakness is the only clinical symptom. When the facial and bulbar muscles are affected, there may be a characteristic flattened smile, nasal speech, and difficulty in chewing and swallowing.15 The majority of the patients progress to generalized weakness. The disease affects the limb muscles, often in a proximal distribution, as well as the diaphragm and the neck extensors. If weakness of respiration becomes severe enough to require mechanical ventilation, the patient is said to be in myasthenic crisis. Myasthenia gravis is caused by antibodies directed against the acetylcholine receptor complex of the motor end plate. This results in a decline in neuromuscular transmission at muscle nicotinic acetylcholine receptors.16 Despite significant advances in our knowledge about the pathophysiology of this disease, the factors that initiate and maintain the autoimmune response in myasthenia gravis are not yet known. Myasthenia gravis occurs with a prevalence of 20 per 100,000. An estimated 60,000 persons in the United States have this disease.17 The incidence is age and sex related, with one peak in the second and third decades affecting mostly women and a peak in the sixth and seventh decades affecting mostly men.18 Overall the disease is more common in women by nearly a 2:1 ratio. On physical examination, the findings are limited to the motor system, without loss of reflexes or alteration of sensation or coordination. The patient’s baseline strength is documented quantitatively for later evaluation of the results of treatment: the most useful quantitative measures include timed forward-arm abduction, vital capacity, and dynamometry of selected muscles.18 Symptoms of myasthenia gravis span the spectrum from insidious to sudden flares.19 The modified Osserman scale is the most widely used system for classification of symptoms and severity of disease (Table 128-1).20 Patients with purely ocular symptoms (diplopia and ptosis) are categorized as

Ch128-F06861.indd 1550

having class 1 disease. Once bulbar symptoms and facial weakness emerge, the disease is said to have progressed to stage 2. With increasing proximal skeletal muscle weakness and respiratory difficulties, patients have class 3 disease; and once patients require ventilatory support and fulminant generalized muscle compromise they have class 4 disease. Ten percent of patients with myasthenia gravis have associated autoimmune or endocrine disorders such as autoimmune thyroiditis, hypogammaglobulinemia, systemic lupus erythematosus, or pure red cell aplasia.21 The clinical course of the disease is variable and unpredictable. Approximately one third of patients will have spontaneous remissions, one third have a stable course, and one third will have acute exacerbations of symptoms that lead to lifethreatening respiratory failure.22,23 The cornerstone of medical treatment for patients with myasthenia gravis includes anticholinesterase agents to increase neuromuscular transmission, immunosuppression, and short-term immunotherapy (plasma exchange and intravenous immune globulin). With aggressive medical management, some clinical improvement can be measured in 80% to 90% of patients. Most patients require life-long therapy with medications to remain in remission. Anticholinesterase agents continue to be used as the first line of treatment for myasthenia gravis.24 These drugs work by decreasing the hydrolysis of acetylcholine at the motor end plate. Pyridostigmine (Mestinon) is the most widely used anticholinesterase agent. Its effect begins within 30 minutes, peaks at about 2 hours, and gradually declines thereafter. Neostigmine, on the other hand, has a much shorter duration of action and more rapid onset, making it the drug of choice in the perioperative period. Although anticholinesterase drugs benefit most patients, the improvement is usually incomplete and often wanes after weeks or months of treatment. Most patients therefore require further therapeutic measures. With disease progression, immunosuppression can be accomplished with corticosteroids, azathioprine, and cyclosporine. The decision to use immunosuppressive therapy for myasthenia gravis can often lead to permanent dependence for patients to control symptoms. Chronic immunosuppression is associated with a multitude of risks, including endo-

1/21/2008 4:06:21 PM

Chapter 128 Surgery for Myasthenia Gravis

crine, metabolic, and immune-related consequences. Patients who are poorly compliant with the medical regimen and follow-up visits or who have other risk factors may not be good candidates for this therapy. Short-term immunotherapy can be used to counter the antibodies produced in myasthenia gravis. Plasmapheresis removes antibodies from the circulation and produces shortterm clinical improvement. It is used primarily to stabilize the condition of patients in myasthenic crisis. The effect of plasmapheresis is rapid, with improvement occurring within days of treatment. Improvement correlates roughly with a reduction in the anti-acetylcholine receptor antibody titers. The beneficial effects of plasmapheresis are temporary, lasting only weeks. Alternative approaches include intravenous immunoglobulins that can be infused to bind anti-acetylcholine receptor antibodies. The risks of these therapies include problems with venous access, recurrent infections of indwelling catheters, hypotension, and pulmonary embolism.

THYMUS GLAND The thymus is an anterior mediastinal organ that weighs 12 to 15 g at birth, reaches maximal weight of 40 g at puberty, then involutes and persists in an atrophic state into old age. The exact relationship between the thymus and myasthenia gravis has not been clearly elucidated. Patients with myasthenia gravis can have a full span of thymic histology from normal thymic tissue, thymolipoma, thymic hyperplasia, or thymoma.23,25 Most patients with myasthenia gravis have some thymic abnormality: hyperplasia is found in 70% to 80% and thymoma in 10% to 15%.18,25,26 The thymus gland has two lobes that are composed of three cell types: epithelial, hematopoietic, and accessory cells. Lymphocytes are attracted to the thymus by chemotactic factors secreted by the epithelial cells. After the lymphocytes approach the epithelium, they are bathed by circulating self-antigens. These antigens enter the thymus by a transcapsular route, a step believed to be critical in the process of learning and of self-recognition. The thymic epithelium provides the principal signals of differentiation by direct cell contact (presentation of major HLA antigens) and is affected by three chief hormones: thymopoietin, thymulin, and thymosin. Thymic hyperplasia commonly is found in patients with myasthenia gravis. Hyperplasia is an increase in the volume of the thymus gland by formation of new cellular elements in a normal microscopic arrangement often with increased numbers of germinal centers. Whether the hyperplasia reflects the increased immunologic activity of the gland in myasthenia gravis or is a response to an external stimulus is unknown. A concept of thymic compartmentalization has been proposed with origin of germinal centers in the perivascular space (extraparenchymal compartment) of the thymus. These germinal centers contain a high percentage of B lymphocytes in contrast to the true thymic parenchyma. Although the significance of germinal centers in the thymus in myasthenia gravis remains controversial, removal of non-neoplastic thymus in this condition is of proven therapeutic value.27,28 Thymoma is an uncommon neoplasm that is derived from the epithelial cells of the thymus. Approximately 50% of

Ch128-F06861.indd 1551

1551

patients with thymoma have myasthenia gravis.26 Thymomas can occur in patients of any age, although they are most common in the 30- to 50-year age range. To date, no specific chromosomal abnormalities have been associated with specific histologic types of thymoma or thymic carcinoma. Although thymomas generally are indolent tumors, they have the ability to be locally invasive. They can spread along the anterosuperior mediastinum, pericardium, pleura, and lung parenchyma. Thymomas can invade the diaphragm by drop metastasis and are known to rarely metastasize to the liver and bones. It has long been suspected that thymoma somehow plays a role in the pathogenesis of myasthenia gravis. The cellular classification of thymoma is based on the classification scheme presented in 1999 by the World Health Organization Committee on the Classification of Thymic Tumors.29-31 They recognized five types of thymomas based on histology that correlated with prognosis: type A (spindle cell, medullary), type AB (mixed), type B1 (lymphocyte rich, predominately cortical), type B2 (cortical), and type B3 (primarily epithelial). Five-year survival rates decrease from 95% to 50% in going from type A to type B3 tumors.30-33 The other commonly quoted classification schema is the Marino and Muller-Hermelink classification, which is based on the presumed origin of the malignant cell (medullary or cortical). In both these classification schema, the medullary thymomas are thought to represent the neoplastic equivalents of normal thymic medullary cells and have a more favorable prognosis than cortical thymomas, in which the neoplastic cells have the appearance of having arisen from the cortex of the normal thymus. Due to the close follow-up care, patients with myasthenia gravis usually have their thymomas discovered earlier and have a better prognosis than those patients without myasthenia gravis.34 Patients discovered to have a thymoma who do not have myasthenia gravis are often discovered to have an incidental anterior mediastinal mass while being evaluated for another problem.35-37 If patients have clinical signs and symptoms, they are related to the size of the tumor and effects on adjacent organs: chest pain, shortness of breath, cough, phrenic nerve palsy, and superior vena cava obstruction. Ten percent of thymomas are associated with a variety of paraneoplastic disorders, many of which are autoimmune or endocrine in nature, such as pure red cell aplasia and hypogammaglobulinemia. The chief staging criteria for thymomas is the Masaoka system (Table 128-2). Stage I refers to disease that is completely encapsulated. In locally invasive (stage II) disease, the tumor has broken through the capsule and invaded the fat or pleura. In extensively invasive (stages III and IVa) disease, the tumor has spread contiguously from the thymus gland to involve other organs in the chest. Spread to organs in the abdomen or metastatic embolic spread (stage IVb) is unusual at the time of presentation. The most important prognostic factor predicting disease-free survival and recurrence is the presence of transcapsular invasion.38 Noninvasive forms have virtually 100% cure. Surgery is the preferred therapy for all patients with Masaoka stage I-IVa disease. The entire thymus gland is

1/21/2008 4:06:21 PM

1552

Section 7 Mediastinum

TABLE 128-2 Masaoka Staging System* Stage

Description

I

Macroscopically, completely encapsulated; microscopically, no capsular invasion

IIa

Macroscopic invasion into surrounding fatty tissue or mediastinal pleura

IIb

Microscopic invasion into capsule

III

Macroscopic invasion into neighboring organs (pericardium, lung, and great vessels)

IVa

Pleural or pericardial dissemination

IVb

Lymphogenous or hematogenous metastases

*This is the most widely used staging system for thymomas.

removed. If there is any suspicion of invasion of adjacent structures, then these organs are resected en bloc with the tumor and the thymus gland. Stage I and II thymomas are treated adequately with a complete resection alone.39,40 Postoperative therapy is recommended for stage III thymomas.41 The optimal treatment of stage IV thymomas is controversial: aggressive therapy with surgical resection, usually with adjuvant radiotherapy and chemotherapy, has been reported to result in long-term survival.42-44 The scientific community continues to make great strides in understanding why myasthenia gravis patients with or without thymomas improve after thymectomy. It is postulated that all patients with myasthenia gravis have B cells that produce anticholinesterase antibodies in the thymus. Patients with myasthenia gravis also produce autoantibodies to titin, a striated muscle antigen. It has been suggested that the concurrent presence of striational antibodies directed against titin are predictive of a thymic epithelial tumor in patients with myasthenia gravis.45,46 Another possible immunologic association has been described between certain HLA loci and thymic pathology.47,48 HLA-A24 and HLA-B8 were significant predictive factors for the presence of thymoma. There is a reduction of anti-anticholinesterase receptor antibodies after thymectomy owing to the reduction of B lymphocytes, especially those that arose from the germinal center in the thymus.49 Furthermore, there is decreased presentation of muscle antigens in the thymus that may account for the reduced antibody titer.

INDICATIONS FOR THYMECTOMY Indications for surgery in patients with myasthenia gravis classically have been (1) all patients with a thymoma and (2) patients without thymoma whose disease is refractory to medical management or who cannot tolerate or are noncompliant with the medical regimen. One can make the argument, however, that any patient with myasthenia gravis should have a thymectomy, especially if the procedure can be performed via a minimally invasive approach with minimal morbidity. There are no randomized, controlled trials of the effectiveness of thymectomy for myasthenia gravis in patients who do not have thymoma, and the efficacy and use of thy-

Ch128-F06861.indd 1552

mectomy in the absence of thymoma is still controversial. In view of the lack of controlled prospective studies, probable limited thymic resections in many instances, and frequent invalid analyses of the available retrospective data, it is not surprising that neurologists hold differing views as to when, and even if, a thymectomy is indicated in the course of treatment of nonthymomatous myasthenia gravis.50,51 For Osserman class 1 and 2 disease, thymectomy is recommended for those relatively healthy patients whose myasthenic symptoms interfere with their lives enough for them to consider undergoing major thoracic surgery.52 Although it is expensive and invasive, thymectomy is the only treatment available that offers a chance of an eventual drug-free remission. For Osserman class 3 disease, there is broad consensus among neurologists that patients who are between the ages of puberty and about 60 years should have surgical thymectomy.52,53 For Osserman class 4 disease and myasthenic crisis, thymectomy rarely, if ever, is performed as an emergency procedure. The role of thymectomy for patients with purely ocular symptoms (Osserman class 1) is controversial.54-58 Neurologists are reluctant to refer patients with ocular symptoms due to the risk of surgery for often benign localized symptoms. However, diplopia and ptosis can seriously impair daily functioning of patients with myasthenia gravis. Furthermore, it causes patients with myasthenia gravis to depend on immunosuppression. There is a chance their disease can progress to more advanced stages, missing the opportunity to undergo a thymectomy while medically optimized. We tend to operate on patients in whom the ocular myasthenia gravis interferes with life style or work and when immunosuppressive or other therapy is contraindicated or not effective. Many attempts have been made to find clinical markers or biomarkers that predict which patients will most benefit from a thymectomy. At this time there is no universal agreement regarding relative advantages of thymectomy in relation to age, sex, or duration of illness.59 Age at the time of surgery has been shown to be a potential factor that predicts clinical outcome. Several authors have demonstrated that young patients have a better clinical outcome compared with elderly patients.57,60-63 The benefit of thymectomy decreases as the adult patient gets older and the risk of surgery increases. The age at which the risks outweigh the potential benefits must be individualized for every patient. Others suggest that marked involution of thymic tissue in patients by the age of 60 indicates that thymectomy will be of no benefit in this age group.64 However, other reports concluded age should not be a limitation for the operation and does not correlate with clinical outcome and disease remission.65-70 Myasthenia gravis is rare in childhood. However, there are increasing data that thymectomy early in the child’s life can alter the course of the disease. The indications for thymectomy in children do not have clear guidelines and remain an area of intense study.71-76 The role of gender in outcome after thymectomy for myasthenia gravis is unclear. In some studies, male patients are noted to more likely achieve disease remission compared with female patients.66 However, others found no significant difference on clinical outcomes with respect to gender59,65

1/21/2008 4:06:21 PM

Chapter 128 Surgery for Myasthenia Gravis

while others have found the opposite result.77 At this point, thymectomy is offered to both genders without preference. Generally, patients who undergo a thymectomy early in their disease once symptoms appear tend to have higher rates of remission. Short duration of illness before surgery has also been touted as a positive predictor for which patients would benefit from surgical intervention.65,78 Surgery later than 1 year after the onset of symptoms is believed to be a predictor of poor response to thymectomy, but this also remains controversial.36 Serum and tissue biomarkers that may predict which patients may benefit from a thymectomy have also been studied extensively but with little success.79-82 The clinical features and rates of remission of thymomatous myasthenia gravis patients with and without elevated acetylcholine receptor antibodies are similar. Some reports that include only small numbers of patients have found that those with various anti-muscle antibodies tend to have similar rates of remission after thymectomy compared with those patients who are seronegative for anti-muscle antibodies.82

SURGICAL TECHNIQUES Various surgical techniques for thymectomy have been advocated. The standard approaches include transcervical, transsternal, and video-assisted thoracoscopic surgery (see Table 128-6). Other more experimental and combined approaches (robotics, mediastinoscopic assistance, combined transcervical and VATS) have been presented.83-87 The debate regarding which technique has the best results has not been resolved. The amount of thymus gland and surrounding tissue that needs to be removed for complete remission from myasthenia gravis has also been a topic of controversy. The extent of thymectomy can vary from removing only the thymus gland proper, extensive thymectomy resecting the thymus and the surrounding anterior mediastinal fatty tissues, and a radical thymectomy that includes skeletonizing all the mediastinal vessels. Although, classically, total thymectomy is the goal of surgery, it has not been conclusively demonstrated that this is necessary nor is it clear that all the resectional techniques achieve this goal. We briefly review and compare these approaches in the following sections.

Transcervical Approach The basic transcervical resection involves an intracapsular extraction of the mediastinal thymus via a cervical incision and is limited to removing the central cervical-mediastinal lobes.67 No other tissue is removed in either the neck or the mediastinum. The extended resection described by Cooper and associates in 1988 employs a special manubrial retractor for improved exposure of the mediastinum.11 All visible mediastinal thymic tissue and fat can be removed with dissection extending in the extracapsular plane. The neck exploration is easily visualized and allows for complete removal of the superior horns of the thymic tissue. In certain situations, a partial median sternotomy can be used to provide increased exposure of the anterosuperior mediastinum. The patient is placed supine on the operating table with the neck maximally extended (Fig. 128-1). A 5-cm incision

Ch128-F06861.indd 1553

1553

is made 1 cm above the sternal notch. After elevating subplatysmal flaps, the sternohyoid and sternothyroid muscles are separated in the midline and the superior poles of the thymus glands are found on the posterior surface of the strap muscles, anterior to the inferior thyroid veins. The superior poles of the gland are dissected out and are followed up to their termination. Silk ties can be used to ligate each superior pole, and subsequently each tie can be used to manipulate the thymus during the remainder of the operation. The substernal plane can be freed by bluntly pushing the anterior mediastinal tissues away from the sternum. The remainder of the operation entails using blunt dissection to lift the thymus gland off the innominate vein, pericardium, and pleura. Individual thymic venous branches that empty into the innominate vein are ligated. Once the gland has been dissected off the innominate vein, the manubrial retractor (Cooper thymectomy retractor) is placed into the sternal notch and can be used to expose the remainder of the anterior mediastinum. The dissection is performed bluntly using two peanut or ball sponges. The goal is to sweep the gland off of the pleural reflections laterally, the sternum anteriorly, and the pericardium posteriorly. One must be cognizant at all times of the location of the phrenic nerve and its proximity to the dissection of the thymus gland. With slow persistence, the gland can be safely mobilized from the mediastinum bringing the inferior aspect of the gland up into the neck. The left lobe usually courses down toward the aortopulmonary window, and this portion of the gland must be followed to its termination, dissected free, and mobilized. Visualization of the anterior mediastinum may be limited if the patient’s neck cannot be maximally extended. The inability to extend the neck limits the ability to carry out this operation. The wound is closed in several layers. If there is any concern of having entered a pleural cavity, a red rubber catheter is placed in the open pleural space for use in reexpanding the lung just before completing the closure when a Valsalva maneuver is performed. Given the minimal pain associated with this operation and avoidance of paralytic agents, the patient is generally ready to be extubated and transferred to the postoperative recovery room. After a chest radiograph confirming bilateral lung expansion, the patient can be discharged to home within 6 hours of arriving for the operation.

Transsternal Approach There are several variations to the transsternal thymectomy approach.88 The standard technique was originally designed to remove the well-defined central cervical-mediastinal lobes. At this time, although a complete or partial sternotomy may be performed, the resection is more extensive than originally described, with removal of all visible mediastinal thymus. Mediastinal fat, varying in extent, may or may not be removed. The cervical extensions of the thymus are removed from below, with or without some adjacent cervical fat. The extended resection removes the entire mediastinal thymus and most of the mediastinal perithymic fat from phrenic nerve to phrenic nerve. The cervical extensions are removed from below, with or without additional tissue, but without

1/21/2008 4:06:21 PM

1554

Section 7 Mediastinum

FIGURE 128-1 A-G, Transcervical thymectomy (see text for details). (FROM SUEN HC, COOPER JD: TRANSCERVICAL APPROACH TO THE THYMUS. IN YIM APC, HAZELRIGG SR, IZZAT MB, ET AL [EDS]: MINIMAL ACCESS CARDIOTHORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 2000.)

a formal neck dissection. The maximal thymectomy, as described by Jaretzki, involves a combined cervicothoracic approach to allow removal of all mediastinal tissue, including that which extends into the anterior cervical triangles. The upper poles of the thymus gland are resected en bloc with

Ch128-F06861.indd 1554

adjacent fatty tissue, and the entire anterior mediastinal contents from phrenic nerve to phrenic nerve are resected. The standard approach is performed by placing the patient supine on the operating table (Fig. 128-2). The chest cavity is opened by a standard median sternotomy. Starting inferi-

1/21/2008 4:06:22 PM

Chapter 128 Surgery for Myasthenia Gravis

1555

B

A

FIGURE 128-2 A-C, Transsternal thymectomy. (FROM URSCHEL HC, COOPER JD: TRANSSTERNAL THYMECTOMY. IN: ATLAS OF THORACIC SURGERY. EDINBURGH, CHURCHILL LIVINGSTONE, 1995.)

orly, the fat and thymic tissue can be lifted off the pericardium. Using a combination of sharp and blunt dissection the organ can be separated from the surrounding anterior mediastinum. Laterally, the phrenic nerves are visualized. There are small lateral arteries that can be cauterized or clipped. As the gland is lifted off the innominate vein, small branches need to be ligated. The thymus gland is traced to the neck and then both superior horns are removed as part of the specimen. A chest tube is left in place, the sternum is reapproximated, and the patient can be extubated at the end of the procedure.

Video-Assisted Thoracoscopic Approach A number of variations in videoscopic technique are being developed to assist in the performance of a thymectomy.89-93 The classic VATS technique employs unilateral videoscopic exposure of the mediastinum (right or left) with removal of the grossly identifiable thymus and variable amounts of anterior mediastinal fat. The cervical extensions of the thymus are usually removed from below. The video-assisted thoracoscopic extended thymectomy (VATET) employs bilateral thoracoscopic exposure of the mediastinum for improved visualization of both sides of the mediastinum. Extensive removal of the mediastinal thymus and perithymic fat is described, with the thymus and fat being removed separately. Modifications to this approach include a cervical incision to

Ch128-F06861.indd 1555

C

remove the cervical thymic lobes and pretracheal fat. There are several reviews that describe this approach, and a discussion of it is beyond the scope of this chapter.90,91,94-96

Selection of Surgical Approaches The goal of surgery for myasthenia gravis is to produce a long-lasting remission of symptoms. Assuming a patient can tolerate the different approaches, the choice of technique is based on which method achieves the longest remission while minimizing morbidity of the operation. Currently, there is no consensus as to whether a transsternal approach is better than less invasive techniques, such as a transcervical or VATS approach. A number of reports have described thymectomy using each approach with good results. Comparison of these techniques, however, has been complicated by the lack of accepted objective definitions of severity of the illness and response to therapy as well as variable patient selection, timing of surgery from diagnosis or onset of symptoms, extent of surgery, and methods of analysis of results. Without resolution of these issues by properly controlled prospective studies, there may be no valid comparison of the various thymectomy techniques. To resolve the issues regarding the choice of thymectomy technique and whether there is a relationship between the resectional technique employed and the rate of remission and improvement, the type of thymic resection used has been

1/21/2008 4:06:22 PM

1556

Section 7 Mediastinum

TABLE 128-3 Thymectomy Classification* Classifier

Operation

T-1

Transcervival thymectomy (a) Basic (b) Extended

T-2

Videoscopic thymectomy (a) Classic (b) Extended

T-3

Transsternal thymectomy (a) Standard (b) Extended

T-4

Transcervical and transsternal thymectomy

*The thymectomy classification by the Myasthenia Gravis Foundation of America is an attempt to standardize different resectional techniques to make comparative studies possible.

defined in as objective terms as possible by the Myasthenia Gravis Foundation of America (MGFA).53 The Thymectomy Classification (Table 128-3) was proposed to standardize the approaches so they could be more easily understood by the predominately neurology community. The techniques are grouped according to the primary approach: T-1 refers to a transcervical approach, T-2 signifies VATS, T-3 is transsternal, and a combination of T-1 and T-3 has been designated T-4. For myasthenia gravis patients without thymoma, the choice of technique has been controversial. No study to date has demonstrated that one technique has significantly better rates of remission of the disease. Advocates of the minimally invasive approaches—transcervical and VATS—argue that given there is no outcome difference, these approaches have less postoperative pain, shorter length of hospital stay, and more cosmetically appealing wounds than the transsternal approach. Also, these minimally invasive approaches cause less chest wall trauma; therefore, they have less pulmonary compromise, which is the most critical aspect of recovery and thus lessens morbidity in myasthenia gravis patients.97 Patients undergo a transcervical approach as an outpatient procedure in our institution. Ideally, the less invasive surgical techniques are desirable, assuming the results are equivalent: the selection must not compromise the therapeutic goals. Currently, for patients with thymomatous myasthenia gravis, the transsternal approach is considered the standard of care. The rationale for a transsternal approach is there are multiple nests of ectopic thymic tissue in the superoanterior mediastinum that need to be resected and can be best visualized through a midline sternotomy. It allows full exploration of the mediastinum into the neck to completely remove all thymic tissue and associated fat. Neurologists tend to prefer this approach for patients with known thymomas. There are reports that consider the transcervical and VATS approaches for patients with thymoma. Kark and Kirschner reported in 1971 on the use of the transcervical approach for seven patients with a high-lying thymoma, but no substantial follow-up was reported.98 The largest experience reported is that of Papatestas and colleagues, which consisted of 46

Ch128-F06861.indd 1556

patients with thymomas resected by transcervical thymectomy alone and another 18 patients in whom a complementary median sternotomy was required for complete resection.99 In most of the patients in this series, the thymomas were not suspected preoperatively. This study noted better survival in the group with occult thymomas operated on through a collar incision compared with preoperatively identified thymomas operated on by sternotomy. Our group has used the transcervical approach with good success in patients with small thymomas.100 In our published series (n = 121), 83% of patients with suspected thymoma had their resection completed transcervically. We had no recurrences with a mean follow-up of 48 months. Although thymoma recurrence could certainly occur beyond this follow-up period, there would be no reason to expect a high rate of late recurrence because none of our Masaoka stage I or II patients had positive resection margins. The hotly debated issue is which patients with suspected thymoma are considered candidates for a transcervical approach. We believe patients with Masaoka stage I and II disease can be approached transcervically. Those with evidence of frank invasion of surrounding structures (stage III) are not approached transcervically. If during the transcervical operation it is believed that the resection may be compromised due to visualization, the incision can be extended down along the sternum at least to the sternomanubrial junction. In our series, although one patient in our thymoma group required extension due to tumor size (5 cm), we did achieve complete excision in another patient with a 5-cm thymoma.100 In no lesion less than 4 cm was conversion required strictly on the basis of the size of the tumor. Based on this experience, we believe that a 4-cm tumor is the appropriate upper limit for attempting the transcervical approach. The limited space between the sternum anteriorly and the innominate vein and mediastinum posteriorly renders safe dissection and delivery of tumors larger than 4 cm in diameter problematic. Even using this size limit there will be occasional conversions to larger incisions owing to adhesions or unexpected invasion of surrounding structures. If during the transcervical thymectomy there is insufficient visualization of the anterior mediastinum and the phrenic nerves, or if there are not clear planes of dissection, then extension of the procedure is performed without hesitation. The relatively high conversion rate in the pathologically proven thymoma cases in this series (36%) reflects the fact that we do not hesitate to extend the incision to a partial or full sternotomy if the safety or completeness of the operation seems to be compromised. It must be emphasized that although 36% of patients with suspected thymoma required an extension of the procedure, conversely, 64% of patients with small thymomas were successfully and, to date known to be, adequately treated with a minimally morbid, outpatient procedure instead of a median sternotomy. There have been several analyses attempting to compare the results of various surgical approaches by comparing studies across institutions using vastly different techniques, indications, and follow-up information (Jaretzki et al, 2004).101-106 These analyses are inherently flawed for several reasons. Most studies do not follow patients beyond 3 years

1/21/2008 4:06:25 PM

Chapter 128 Surgery for Myasthenia Gravis

and often do not have radiographic evidence of disease-free survival.107 Virtually all studies of thymectomy are retrospective and therefore do not address the variability and unpredictability of myasthenia gravis and the differing response to treatment among patients with different subtypes of myasthenia gravis, nor the bias inherent in the selection of patients for thymectomy. The most important clinical parameter that needs to be assessed in surgery for myasthenia gravis is remission from disease. Most studies do not qualitate degree of remission or complete remission. With the Osserman classification, patients can be more carefully categorized. Furthermore, various studies do not account for ongoing corticosteroid dependence as true remission. In comparing results of different techniques, other confounding factors are also frequently ignored, including the following53: 1. Failure to define the length of illness preoperatively 2. Failure to record the length of postoperative follow-up 3. Failure to include an analysis of stable remission versus relapse of disease 4. Inclusion of patients with thymoma 5. Combining two or more series with differing definitions and/or multiple surgical techniques 6. Use of meta-analysis based on mixed and uncontrolled data These highly variable and uncontrolled studies by different surgical groups has led the American Academy of Neurology to state that neither controlled nor uncontrolled trials provide convincing evidence that one thymectomy technique is superior to another (Gronseth and Barohn, 2000).101 Regardless of the surgical approach, surgical expertise and experience are required. The surgeon neeeds to be convinced of the importance of complete removal of the thymus for the best long-term results and be willing to commit the necessary time and care to achieve this goal safely.108 There have been enough anecdotal reports describing return of myasthenia gravis symptoms after what was thought to be a total thymectomy.109-113 On re-exploration of these patients, removal of residual thymic tissue has allowed the patient to go into remission. Although these reports have not been formally reported in a controlled manner, they do suggest the importance of complete removal of all thymic tissue.

PERIOPERATIVE MANAGEMENT Patients with myasthenia gravis can undergo a thymectomy with minimal morbidity with careful preoperative preparation, intraoperative anesthetic diligence, and postoperative vigilance. This requires the combined efforts of specialized teams of neurologists, pulmonologists, anesthesiologists, and surgeons who have had experience in the care of these patients. Detailed surgical evaluation includes information on the duration of symptoms, results with medical management, and assessment of any associated autoimmune or endocrine disorders. Most patients are taking anticholinesterase agents, which continue to the time of surgery. If possible, the patient is weaned from corticosteroids before surgery. If corticoste-

Ch128-F06861.indd 1557

1557

roids are still required, we give a single stress dose of a corticosteroid before induction of anesthesia. Postoperatively, we use vitamin A (retinol) to improve wound healing. All patients being referred to us undergo CT of the chest to evaluate the presence of a thymic tumor. The major postoperative risk is the development of oropharyngeal and respiratory muscle weakness with the potential for aspiration of oral secretions, inability to cough effectively, and respiratory failure.114,115 Patients with a history of advanced symptoms of myasthenia gravis have preoperative pulmonary function testing. Forced vital capacity is a useful preoperative data point that can be used to monitor postoperative progress. This value is helpful in assessing the timing of extubation in those patients who require postoperative ventilatory support. If a patient is scheduled to remain in the hospital, we evaluate forced vital capacity in the recovery room and again the morning after surgery. If these values are severely altered after surgery, appropriate medical intervention would be indicated. However, in our experience, we have never had a patient with acute myasthenic crisis immediately after surgery. If the vital capacity is below 2 L preoperatively, plasmapheresis is carried out before surgery to allow independent respiration in the postoperative period. Any patients with preoperative generalized symptoms, respiratory difficulties, or bulbar symptoms are considered for plasmapheresis before surgery.116 This is usually sufficient to get the patient through the postoperative period. Although patients with myasthenia gravis may develop respiratory failure for several reasons, it is very difficult to predict myasthenic crisis after transsternal thymectomy.115 Several scoring systems for predicting postoperative myasthenic crisis have been designed based on length of disease interval before surgery, history of significant respiratory disease, dependence on anticholinesterase medications, preoperative vital capacity less than 2 L, and levels of antibodies to acetylcholine receptors.117-119 Several other factors that are associated with postoperative myasthenic crisis, or the need for prolonged mechanical ventilation, have been reported. These include preoperative expiratory weakness preoperative bulbar symptoms, history of preoperative myasthenic crisis, and intraoperative blood loss greater than 1 L.115,120,121 Extra vigilance is warranted in the postoperative periods for patients with these poor prognostic factors. Our institution has specialized anesthetic protocols for this patient population. Neuromuscular blocking agents are avoided. Inhaled anesthetic agents, in general, provide sufficient muscle relaxation without resorting to paralytic agents. Patients with myasthenia gravis can be resistant to depolarizing agents such as succinylcholine. Nondepolarizing agents are used in one fifth of the usual dose, and a short-acting drug is recommended. For the majority of patients, postoperative care of these patients is straightforward and uncomplicated if careful preoperative assessment is performed. Most patients are extubated in the operating room. Over 90% of the patients who undergo a transcervical approach are discharged from the recovery room. The patients who undergo a median sternotomy or VATS approach get transferred to a monitored stepdown unit and discharged as soon as their chest tube can be

1/21/2008 4:06:25 PM

1558

Section 7 Mediastinum

TABLE 128-4 Myasthenia Gravis Foundation of America Postintervention Status* Status

Definition

Complete stable remission (CSR)

The patient has had no MG during that time. There is no weakness or any muscle symptoms or signs of MG for at least 1 yr, and the patient has received no therapy on careful examination by someone skilled in the evaluation of neuromuscular disease. Isolated weakness of eyelid closure is accepted.

Pharmacologic remission

The same criteria as for CSR, except that the patient continues to receive some form of therapy for MG. Patients receiving cholinesterase inhibitors are excluded from CSR category because their use suggests the presence of weakness.

Minimal manifestations (MM)

The patient has no symptoms of functional limitations from MG but has some weakness on examination of some muscles. This class recognizes that some patients who otherwise meet the definition of CSR or pharmacologic remission do have weakness that is only detectable by careful examination.

MM-0

The patient has received no MG treatment for at least 1 yr.

MM-1

The patient continues to receive some form of immunosuppression but no cholinesterase inhibitors or other symptomatic therapy.

MM-2

The patient has received only low-dose cholinesterase inhibitors (pyridostigmine, <120 mg/day) for at least 1 yr.

MM-3

The patient has received cholinesterase inhibitors or other symptomatic therapy and some form of immunosuppression during the past year.

Change in Status Improved Unchanged Worse Exacerbation Death

A substantial decrease in pretreatment clinical manifestations or a sustained substantial reduction in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific decrease in quantitative MG score. No substantial change in pretreatment clinical manifestations or reduction in MG medications as defined in the protocol. In prospective studies, this should be defined in terms of a maximal change in quantitative MG score. A substantial increase in pretreatment clinical manifestations or a substantial increase in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific increase in quantitative MG score. Patients who have fulfilled criteria of CSR, pharmacologic remission, or minimal manifestation but subsequently had clinical findings greater than permitted by these criteria. Patients who died of MG, of complications of MG therapy, or within 30 days after thymectomy.

*The clinical status of a patient after medical or surgical intervention as defined by the Myasthenia Gravis Foundation of America. MG, myasthenia gravis.

removed and their postoperative pain sufficiently controlled. This typically takes 3 to 5 days. Postoperatively, high-risk patients are managed in a setting where they can be closely observed by an experienced intensivist. If the preoperative pulmonary status off cholinergic medication is satisfactory, regardless of the surgical approach, the patient is extubated at the end of the case. In our experience, we have not needed to emergently reintubate a patient; however, we do not hesitate to support the patient on the ventilator if he or she shows early signs of fatigue, progressive weakness, or impending respiratory failure. The use of cholinergic medication in the acute setting is ineffective. Historically, there has been a lack of detailed reporting of operative and postoperative complications in association with thymectomy for myasthenia gravis. Overall this is a safe operation and most studies report an operative mortality less than 2%.11,12,55,68,78,91,93,103,122-127 The chief complications include phrenic nerve injury, pneumothorax, hemorrhage, and wound infection. Phrenic nerve injury has been reported after aggressive (2%) as well as more limited resections. The Myasthenia Gravis Foundation of America Morbidity and Mortality Classification has proposed to standardize future reporting.53 If the patient with myasthenia gravis is well prepared preoperatively, thymectomy is a safe procedure and the perioperative mortality is that of a similar procedure in a patient without myasthenia gravis regardless of the thymectomy technique employed. The incidence of postoperative

Ch128-F06861.indd 1558

infections is low, although not well documented. Although the use of immunosuppressive agents may increase this risk, their use is frequently unavoidable.

RESULTS There are several large studies comparing medical versus surgical management of myasthenia gravis. However, there has not been a well-controlled prospective randomized study looking at this controversial topic. Scores of large studies demonstrate that patients who have myasthenia gravis and undergo thymectomy have overall improvement of their disease. Whether this improvement is better than aggressive medical management alone is unknown.128 In all studies to date there are inadequate control groups in deciding whether surgical management is superior to medical management in causing disease remission.55,77,129-131 The improvement in patients undergoing surgery for myasthenia gravis may simply reflect an observational bias: patients who are the sickest receive the most aggressive medical therapy in parallel to surgery. Another problem comparing studies is determining the degree of benefit from surgical intervention. Some papers report patients with only complete remission whereas others report any patient with any decrease in symptoms by Osserman class. Often these studies group patients with remission regardless if they continue to depend on immunosuppression. To overcome some of these problems, the American Academy of Neurology has created

1/21/2008 4:06:25 PM

Chapter 128 Surgery for Myasthenia Gravis

1559

TABLE 128-5 Outcomes in Myasthenia Gravis Patients With Medical Therapy Versus Thymectomy Medical Treatment (n)

Thymectomy (n)

Median Follow-up (yr)

Author (Year)

Institution

Mantegazza et al129 (1990)

Six Italian neuromuscular centers

313

812

4.9

35% of cases were symptom-free (pharmacologic remission, 24%; remission without treatment, 11%). Surgical arm had 1.5 higher rate of remission.

Beghi et al77 (1991)

Three Italian neuromuscular centers

290

544

5.3

The overall probability of complete remission was 1% by 1 year, 8% by 3 years, 13% by 5 years, and 21% by 10 years. Twofold higher results in surgical arm.

Papatestas et al55 (1987)

Mt. Sinai Medical Center, NY

1048

788

—

Multivariate analysis showed that appearance of early remissions among all patients was significantly influenced by thymectomy.

Grob et al130 (1987)

Maimonides Medical Center (Brooklyn)

944

309

18

Too little data to draw conclusions about surgical and medical therapies.

Perlo et al131 (1971)

Two large myasthenia gravis clinics

417

225

—

Threefold improvement in patients symptoms undergoing thymectomy

a new classification to report patient response to intervention (Table 128-4).53 The clinical support for thymectomy for myasthenia gravis initially came from a large report from the Mayo Clinic. Buckingham and colleagues132 analyzed 663 patients who were retrospectively computer matched on the basis of age, sex, severity, and duration of disease and they were treated either medically (n = 459) or surgically (n = 104). Complete remission was found in 35% of surgical patients, and 8% of those patients were treated medically. In follow-up, more patients with surgical management had long-term survival and remission from disease. Subsequently, there have been several large studies that have looked at medical therapy versus thymectomy to treat myasthenia gravis (Table 128-5).55,77,129-131 The Quality Standards Subcommittee (2000) of the American Academy of Neurology recommended that there is an association in most studies between thymectomy and remission of myasthenia gravis.101 The task force performed a literature review of all patients undergoing a thymectomy between 1966 and 1998. They identified 28 key studies in myasthenia gravis patients without thymomas and found that myasthenia gravis patients undergoing thymectomy were more likely to achieve medication-free remission than those who had nonsurgical treatment. The association between thymectomy and improved outcomes achieved significance in 7 of 15 studies describing medication-free remission, in 8 of 12 studies describing asymptomatic patients on or off medication, in 8 of 13 studies describing improvement, and in 4 of 13 studies describing survival.101 In no study that was reviewed was a significant negative association between thymectomy and any outcome described. Comparing the outcome rates of several studies in which patients with myasthenia gravis did not get a thymectomy, myasthenia gravis patients undergoing thymectomy were twice as likely to attain medication-free remission, 1.6 times as likely to become asymptomatic, and 1.7 times as likely to symptomatically improve.

Ch128-F06861.indd 1559

Overall Results

Across these studies, patients were also observed with severe symptoms of myasthenia gravis (defined by Osserman Class 2b, 3, or 4) who benefited the most from thymectomy. For all patients, those with severe myasthenia gravis have worse outcomes when compared with those with mild myasthenia gravis. However, patients with severe myasthenia gravis undergoing thymectomy had higher rates of better outcomes compared with those with severe myasthenia gravis not undergoing thymectomy.101 The benefit of thymectomy is not immediate and remission usually occurs over an extended period of time after surgery (Table 128-6).88,133,134 The majority of the symptom improvement occurs within 5 to 10 years.134 Because of this it is reasonable and prudent to consider the time to remission as a continuous variable, and the best way of expressing results is the probability of achieving a complete remission in the form of a Kaplan-Meier curve. This method of expressing outcome after thymectomy was the recommendation of a consensus panel convened by the MGFA several years ago, yet the literature is filled with studies expressing results in a variety of ways. The median rate of becoming asymptomatic is about 40%, and the median rate of achieving medication-free remission is 25% to 50% at 5 years post thymectomy.12,55,61,126,135,136 In our series (n = 78), 31% and 43% of patients with myasthenia gravis had complete stable remission at 2 and 5 years, respectively123 (Fig. 128-3). Overall, 80% to 90% of patients have improvement by at least one Osserman classification and 50% to 70% of patients have a drug-free remission after thymectomy. The benefits of thymectomy usually are delayed until months to years after surgery. Several large studies have analyzed predictors of outcome and clinical features in patients with myasthenia gravis with and without associated thymoma.137 Some studies demonstrate that the presence of a thymoma is a poor prognostic indicator for disease remission62 whereas others have reported the opposite. Improved survival rate of patients with myasthenia gravis with thymoma may simply reflect improved

1/21/2008 4:06:25 PM

1560

Section 7 Mediastinum

TABLE 128-6 Surgical Techniques for Thymectomy

Surgical Approach

Thymectomy (n)

Author (Year)

Institution

Extended transcervical

Cooper et al11 (1988) DeFilippi et al122 (1994) Shrager et al123 (2002)

Toronto General Hospital University of Chicago University of Pennsylvania

Transsternal

Papatestas et al55 (1987) Hatton et al124 (1989) Mulder et al125 (1989) Nussbaum et al68 (1992) Frist et al78 (1994) Kattach et al126 (2006)

Video-assisted thoracoscopic

Mack et al12 (1996) Mineo et al127 (2000) Savcenko et al93 (2002)

Lin et al103 (2005) Manlulu et al91 (2005)

Mean Follow-up (yr)

Complete Remission (%)

Symptom Improvement (%)

65 53 78

3.4 4.3 4.6

52% 17% 40%

95% 81% 90%

Mt. Sinai Medical Center, NY New England Medical Center University of California (LA) University of Cincinnati Vanderbilt John Radcliffe Hospital

962 52 333 84 46 85

120 3.8 3.0 4.3 6.3 4.5

32% 28% 35% 41% 28% 17%

NA 57% 79% 93% 87% 79%

Columbia Hospital Tor Vergata University Cardiopulmonary Research Science and Technology Institute Changhua Christian Hospital Chinese University of Hong Kong

33 31 38

1.9 3.3 4.4

18% 36% 14%

87% 96% 83%

51 38

4.0 5.8

28% 22%

74% 92%

1.0

78 MG Patients 31% CR rate at 24 months 43% CR rate at 60 months

0.8

Probability of CR

0.7 0.6 0.5 0.4

1.0

Stage I

0.9

Stage II

0.8 Survival Rate

0.9

0.7 0.6 0.5

Stage III

0.4

0.3

0.3

0.2

0.2

Stage IV

0.1

0.1

0

0 ⫺0.1 ⫺0.2

Number being followed for CR n⫽ 49 16

0

12

24

36 48 60 72 84 Months Since Surgery

0

10

15

Patients at Risk 96

108 120

FIGURE 128-3 Kaplan-Meier curve for time to complete stable remission after thymectomy. (FROM SHRAGER JB, DEEB ME, MICK R, ET AL: TRANSCERVICAL THYMECTOMY FOR MYASTHENIA GRAVIS ACHIEVES RESULTS COMPARABLE TO THYMECTOMY BY STERNOTOMY. ANN THORAC SURG 74:320-326, 2002.)

long-term medical care of patients with this disease. The differences in these studies may also reflect the proportion of patients who had medullary versus cortical type thymomas. Patients with medullary thymomas have been demonstrated to have a significantly better prognosis than those with the cortical type.138 Also, patients with thymoma and myasthenia gravis are thought to have a better prognosis and survival than those patients with thymoma and no myasthenia gravis.34,139 Overall, the survival for noninvasive thymoma with and without myasthenia gravis is excellent. Based on several large series, 5-year survival rates range from 95% to 100% for stage

Ch128-F06861.indd 1560

5

Survival Time (yr)

5 I II III IV

35 26 16 21

25 14 9 3

8 4 2 0

6 1 1 0

FIGURE 128-4 Disease-free survival curve after thymectomy according to Masaoka staging system. This Kaplan-Meier survival curve is representative of the survival in patients with thymoma. (FROM KONDO K, YOSHIZAWA K, ET AL: WHO HISTOLOGIC CLASSIFICATION IS A PROGNOSTIC INDICATOR IN THYMOMA. ANN THORAC SURG 77:1183-1188, 2004.)

I disease, 85% to 95% for stage II disease, 55% to 75% for stage III disease, and 10% to 50% for stage IV disease30-33,137 (Fig. 128-4). In a large retrospective study involving 273 patients with thymoma, 20-year survival rates (as defined by freedom from tumor death) according to the Masaoka staging system were reported to be 89% for stage I disease, 91% for stage II disease, 49% for stage III disease, and 0% for stage IV disease.30

1/21/2008 4:06:25 PM

Chapter 128 Surgery for Myasthenia Gravis

Subset analyses have looked at patients with thymoma to determine if the presence of myasthenia gravis is a good or bad prognostic indicator. There is no consensus regarding differences in the prognosis. Several large studies have reported that the presence of myasthenia in thymoma patients is an indicator of poor prognosis.62,140,141 Other reports have demonstrated that the presence of myasthenia indicates a more favorable prognosis in thymoma patients.34,142-144 The improved survival of thymoma patients with myasthenia gravis may be due to the early discovery of associated thymoma. Other studies suggest there is no difference in survival in stage-matched patients with thymoma and presence of myasthenia gravis.139

SUMMARY Myasthenia gravis continues to remain a disease managed by neurologists. The American Association of Neurology Task Force (2000) has attempted to standardize the diagnosis and treatment options for this disease to make future practice easier to review and study. Thymectomy has an important role in the management of this disease; however, the absolute indications remain controversial despite all the years of experience. Thymomas are resected given the neoplastic capabilities of these tumors. Patients with myasthenia gravis but without thymomas ultimately benefit from resection; however, it is unknown if aggressive medical management can accomplish the same objectives. The choice of thymectomy technique remains controversial, ranging from an aggressive maximal transsternaltranscervical thymectomy to a minimally invasive outpatient transcervical incision. Other unanswered questions regarding thymectomy include the appropriate age for the surgery, when it is performed in the course of the disease, and the role of thymectomy in patients with purely ocular disease. Perioperative care for these patients centers around avoiding respiratory compromise. Regardless of the medical versus surgical interventions, clinical remission and symptom improvement occur in the vast majority of patients and will continue to improve as we make strides on both the basic science and clinical fronts.

Ch128-F06861.indd 1561

1561

COMMENTS AND CONTROVERSIES The role of surgery in the treatment of myasthenia gravis provides a number of areas of controversy. There is, of course, the controversy regarding the role of thymectomy in myasthenia gravis without thymoma. There is consensus that thymectomy improves the clinical course in the majority of patients. The surgical approach is also controversial. The authors, having expertise and excellent results with the transcervical approach, discuss all surgical options with a balanced view. Of interest is their institutional preference for transcervical thymectomy for small thymomas. This strategy is adopted only by surgeons with expertise in the transcervical operation. Of particular importance are their comments regarding preoperative preparation of the myasthenia patient, including institution of a proper regimen of anticholinesterase therapy and plasmapheresis for patients with generalized symptoms of myasthenia gravis. G. A. P.

KEY REFERENCES Cooper JD, Al-Jilaihawa AN, Pearson FG, et al: An improved technique to facilitate transcervical thymectomy for myasthenia gravis. Ann Thorac Surg 45:242-247, 1988. ■ A classic paper that made it possible to do an extended thymectomy through a transcervical approach. Gronseth GS, Barohn RJ: Practice parameter: Thymectomy for autoimmune myasthenia gravis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 55:7-15, 2000. ■ This paper describes the standard of care that has been devised by the neurologic community. To understand the current indications and reporting of this disease requires an intimate knowledge of the American Academy of Neurology recommendations. Jaretzki A, Steinglass KM, Sonett JR, et al: Thymectomy in the management of myasthenia gravis. Semin Neurol 24:49-62, 2004. ■ For a detailed examination of the various techniques to perform a thymectomy, Jaretzki’s paper attempts to perform comparisons of various surgical trials using the nomenclature of the American Academy of Neurology.

1/21/2008 4:06:26 PM

Cysts chapter

129

MEDIASTINAL CYSTS AND DUPLICATIONS IN INFANTS AND CHILDREN Priscilla Chiu Jacob C. Langer

Key Points ■ Cystic lesions in infants and children are uncommon. ■ Most cystic lesions in infants and children are benign. ■ Symptoms from the cystic lesions arise from mass effect on

adjacent structures or from infectious and inflammatory complications. ■ Complete surgical excision is required for any symptomatic mediastinal cyst unless there is a common wall with the airway or esophagus of a foregut cyst.

Mediastinal cysts and duplications in infants and children are uncommon. Their true incidence is unknown. However, the prevalence of mediastinal cysts among mediastinal masses is approximately 7.7% in children, significantly lower than that in adults (14.1%), with equal distribution between males and females (Takeda et al, 2003).1 The classification of mediastinal cysts is based on mediastinal compartment or location2 and embryologic derivation (foregut cysts, mesothelial pericardial cysts, thymic cysts, thoracic duct cysts, and meningoceles). In this chapter, cystic lesions derived from the foregut and duplications (also known by the term bronchopulmonary lung bud abnormalities), lymphatic malformations (once known as cystic hygroma), thymic cysts, pericardial cysts, and cystlike lesions are described. A significant proportion of mediastinal cysts do not cause symptoms during childhood, and many present in adulthood.1,3 Some mediastinal cysts may not be confined to the mediastinum but extend from or into the neck, chest, or abdominal cavities. When these cysts cause symptoms, the presenting complaints relate to either mass effect of the cystic structure on adjacent organs or the infectious and inflammatory complications of the cysts. More importantly, mediastinal cysts can cause acute life-threatening respiratory distress in infants requiring emergent management.4 The focus in this chapter is on the cystic lesions of the infant and pediatric mediastinum, based on their embryologic derivation, anatomic location, surgical management, and outcomes. A discussion of mediastinal cysts that present and are managed during adulthood is presented in Chapter 130.

FOREGUT CYSTS Foregut cysts are benign cystic lesions of the respiratory and alimentary tract derived from the primitive foregut that later gives rise to the tracheobronchial tree and the esophagus.

Nowhere in pediatric surgery has the pathologic nomenclature undergone as much deliberation as for foregut malformations. Broadly applied, the spectrum of foregut anomalies encompassed by the terms foregut cyst, foregut malformations, or malinosculation include bronchogenic cysts and esophageal duplication cysts in addition to mixed lesions such as congenital cystic adenomatoid malformations (CCAMs) and bronchopulmonary sequestrations.5 This broad definition means that foregut cysts can occupy any mediastinal compartment, although bronchogenic cysts are most commonly situated in the middle mediastinum and duplication cysts most commonly occupy the posterior mediastinum. The first description of a mediastinal foregut cyst was credited to the Dutch physician and physiologist Blasius in 1674 when he identified a tubular mediastinal structure that proved to be an esophageal duplication cyst. In 1881, Roth described the cystic components of the mediastinum as derived from the respiratory and gastrointestinal tracts, especially the latter in relation to adherent components to spinal structures. The term duplication was originally coined by Fitz in 1884 for what were thought to be omphalomesenteric duct remnants within the abdomen.6 Later, Gross and Holcomb used the term to encompass all cystic anomalies of the gastrointestinal tract.7 The original description of mixed lesions containing pulmonary tissue communicating with the esophagus or stomach was by Klebs in 1874.8 Huber first described the pulmonary lesion associated with anomalous systemic blood supply in 1777. However, it was Pryce who used the term sequestration to define those bronchopulmonary cysts or masses without airway communication associated with a systemic vascular supply.9 Intralobar and extralobar sequestrations were initially thought to be separate entities from other foregut anomalies, as proposed by Smith’s classification,10 but their inclusion and definitive description as part of bronchopulmonary-foregut malformation were reported by Gerle in 1968.11 Bronchogenic cysts were fully described by Maier in 1948.2 The term congenital cystic adenomatoid malformation of the lung was first introduced by Ch’in and Tang in 1949.12 The pathologic features of foregut cysts are characterized by remnants from the primitive foregut and may contain respiratory tract or alimentary tract components. Cysts are lined with at least two types of respiratory epithelium, including ciliated, transitional, columnar, and squamous epithelium, and they may contain organized histologic architecture including heterotopic lung tissue, thyroid stroma, ganglia, gastric mucosa,13 well-differentiated lymphoid aggregates resembling Peyer’s patches,14 or pancreatic tissue.15-17 The cysts

1562

Ch129-F06861.indd 1562

1/21/2008 4:07:28 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

may be spherical or tubular.14 Multiple coincident foregut malformations are less common but have been reported for the entire spectrum of foregut cysts.18-22 In general, foregut cysts should be resected if there is evidence or concern about potential complications such as respiratory distress, including life-threatening events in neonates,4 luminal obstruction, bleeding, infection, perforation, fistula formation, and malignant degeneration. Marsupialization of the cyst, a technique once advocated by Gross, should be avoided to prevent complications.23 Despite the common origins of these mediastinal cysts, their clinical behavior, antenatal management, and postnatal treatment are distinctly different. Therefore, each entity of the lesions comprising foregut cysts is discussed separately.

1563

Bronchogenic Cysts Bronchogenic cysts are rare in the general population but are among the most common cystic lesion of the pediatric mediastinum and lung (Table 129-1),1,24 with males more affected than females. Although the term bronchogenic cyst implies that the cyst originates from the airway distal to the trachea, foregut cysts can arise in any location from the trachea (Fig. 129-1A) to branching bronchi (see Fig. 129-1B). The term bronchogenic is, therefore, applied to all cysts originating from or with physical connection to the tracheobronchial tree. Pathologically, bronchogenic cysts are lined by respiratory tract ciliated columnar or cuboidal epithelium containing mucus glands (Fig. 129-2). The accumulation of mucus

TABLE 129-1 Prevalence of Mediastinal Foregut Cysts Among Pediatric Mediastinal Masses and Cysts No. Patients With Mediastinal Masses or Cysts

No. Patients With Foregut Cysts

No. Patients With Duplication Cysts

93

17

11

6

75

N/A

10

N/A

(1985)

34

N/A

11

23

Takeda et al1* (2003)

130

7

1

6

Author (Year) Bower and Kiesewetter112 (1977) 113

Pokorny and Sherman Snyder et al

34

(1974)

No. Patients With Bronchogenic Cysts

N/A, data not available from the report. *Results reported in this table include only pediatric patients from the series.

A

B

FIGURE 129-1 Bronchogenic cysts. A, An esophagogram with oral contrast shows a radiolucent mass in the mediastinum (arrow) resulting in esophageal displacement caused by a paratracheal bronchogenic cyst that communicated with the trachea. B, Chest radiograph shows a left radiopaque mediastinal lesion (arrow) that was found to be a left bronchogenic cyst. (PHOTOGRAPH COURTESY OF DR. S. H. EIN.)

Ch129-F06861.indd 1563

1/21/2008 4:07:29 PM

1564

Section 7 Mediastinum

C

FIGURE 129-2 Histologic features of bronchogenic cyst. This slide demonstrates the respiratory epithelium lining the bronchogenic cyst (arrows) along with cartilage (C) that is present within the walls of the cyst. (PHOTOGRAPH COURTESY OF DR. S. H. EIN.)

results in the gradual enlargement of noncommunicating bronchogenic cysts. The surrounding tissue is composed of smooth muscle, elastic tissue, and bronchial cartilage. Embryologically, bronchogenic cysts are thought to arise from abnormal budding or branching of the tracheobronchial tree. The location of the cysts within the mediastinum depends on the developmental stage during which the group of epithelial cells separate from the tracheobronchial buds.25 These locations are well described by Maier2 and refer to the position of the cyst in relation to the tracheobronchial tree. The cysts may rarely lie adjacent to the trachea (paratracheal cysts; see Fig. 129-1A) if the error occurred early in foregut development and are typically situated to the right of the trachea. Within the spectrum of foregut cysts, some paratracheal cysts containing respiratory tract epithelium may be attached to the esophagus or even embedded within the esophageal wall. The most common locations of bronchogenic cysts are in the right hilar and subcarinal regions. Cysts in these locations may communicate with the tracheobronchial tree directly or may be attached to the bronchi or carina with a fibrous strand. Occasionally, a bronchogenic cyst may be situated within the lung parenchyma (intraparenchymal cyst) if the developmental error occurs after tracheal separation has completed. If the communicating tract is lost, the cyst may migrate to other regions of the thorax during lung development, including the pericardial, paravertebral, and subpleural regions. Rarely, bronchial cysts may be found in the neck or upper abdomen.

Presentation Bronchogenic cysts, in contrast to other foregut cysts, are not commonly associated with other congenital anomalies. In general, bronchogenic cysts present with obstructive symptoms in the neonate and infectious or inflammatory complications in the older child (Haller et al, 1979).26 Bronchogenic cysts can also be associated with congenital lobar emphysema through external compression of the adjacent bronchus by the cyst.27 In such cases, respiratory distress may be more marked with associated pleural distention and mediastinal shift. Pleural-based lesions with infectious or inflammatory complications may present as chest pain. Large cysts in the paratracheal region may also present as dysphagia. Antenatal diagnosis is usually only possible for large bronchogenic cysts.

Ch129-F06861.indd 1564

FIGURE 129-3 CT scan of a bronchogenic cyst (arrow). Contrastenhanced CT image of a left, subcarinal bronchogenic cyst (chest radiograph of this lesion is shown in Fig. 129-1B). Note the position of this cyst in the middle mediastinum posterior to the heart (lower anterior mediastinum) and lateral to the esophagus and aorta.

The differential diagnosis should include CCAM and congenital lobar emphysema in these cases.

Radiologic and Clinical Investigations The majority of bronchogenic cysts are apparent on plain chest radiographs, presenting as an area of mediastinal opacification if the cyst is autonomous (see Fig. 129-1B) or radiolucent if there is a communication with the airway (see Fig. 129-1A). In particular, a mediastinal mass with an air-fluid level is strongly suggestive of a bronchogenic cyst with communication to the airway. Definitive investigation with computed tomography (CT) is mandatory to determine the size, location, and anatomic relationship of these cysts.23 However, the presence of luminal communication between the cyst and airway may still not be established using this technique. Bronchogenic cysts appear as well-defined cystic lesions of the mediastinum without luminal filling by oral contrast and have a significantly higher density (30-120 Hounsfield units [HU]) compared with thymic and mesothelial cysts (Fig. 129-3). Some studies suggest that magnetic resonance imaging (MRI) is superior to CT in distinguishing between solid and cystic masses.28 Bronchoscopy may be useful in detecting a communication between the cyst and bronchus, but failure to demonstrate this via bronchoscopy does not exclude this possibility.29

Management and Surgical Considerations Symptoms from bronchogenic cysts can range from mild respiratory complaints to acute airway obstruction. Therefore, preoperative consideration of airway management is imperative because there are significant anesthetic risks for patients with mediastinal cysts associated with respiratory

1/21/2008 4:07:29 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

1565

adverse outcomes appear to correlate with unrecognized airway obstruction and infectious complications of bronchogenic cysts. In more recently published series, the operative outcomes after resection of bronchogenic cysts, including lobar resections, have been excellent with no operative mortality. Postoperative complications result from infectious complications, nerve injury, suture dehiscence, and persistent air leak. Long-term complications result mainly from incomplete resection with recurrent bronchogenic cyst. Therefore, given the minimal operative risk of treatment, it is recommended that all bronchogenic cysts be managed by complete resection.

FIGURE 129-4 Open resection of bronchogenic cyst. This bronchogenic cyst was exposed through a posterolateral thoracotomy. Umbilical tapes were used to identify and retract the phrenic nerve along the mediastinal border of the cyst. (PHOTOGRAPH COURTESY OF DR. S. H. EIN.)

distress. In general, the patient with respiratory distress should not undergo induction of general anesthesia without a secure airway. Patients who are asymptomatic are unlikely to encounter significant airway issues on induction. CT assessment of airway caliber before operative procedure may help with anesthetic planning and airway management.30 Recurrent infections can also complicate bronchogenic cysts and increase the risk of perforation. Furthermore, the potential for malignant transformation within these cysts is unknown. Therefore, bronchogenic cysts should be completely excised to treat obstructive symptoms and prevent recurrence and complications whenever possible. Marsupialization should be avoided. If the primary presentation is complicated by infection, the infection should be completely treated before surgical resection to minimize adhesions and postoperative infectious complications.23 Paratracheal, hilar, and subcarinal cysts are amenable to cyst resection, whereas intrapulmonary cysts are best treated by complete lobar resection to prevent recurrence. The usual approach for resection is via posterolateral muscle-sparing thoracotomy (Fig. 129-4), although a cervical approach for upper mediastinal cysts and central lesions accessed via median sternotomy have been described.25 Thoracoscopic approach is feasible for lobar resection of intraparenchymal cysts and subpleural cyst resection where they are easily visualized. However, cysts in the subcarinal and pericardial regions may be difficult to access via the thoracoscopic technique, especially in the infant.31 Resection of cysts adherent to or directly communicating with the bronchi or trachea will necessitate primary repair of the airway defect and should be planned preoperatively with the anesthetic team for selective airway ventilation using either direct bronchial intubation or the insertion of a bronchial blocker.

Outcomes Historical series suggest that there was a significant mortality associated with bronchogenic cysts.2,23 However, these

Ch129-F06861.indd 1565

Esophageal Duplication Incidence Esophageal duplications, a subset of the enteric duplication anomalies, are rare cystic remnants of enteric origin with males and females equally affected.32 Retrospective data accumulated from various centers suggest that duplications comprise a minority of mediastinal masses (see Table 129-1), ranging from 19% to 32% among mediastinal cysts.33,34 Enteric duplication cysts can occur anywhere along the alimentary tract from the mouth to anus and may communicate with the lumen of the gastrointestinal or respiratory tract. Esophageal duplications, which are also known by the terms dorsal enteric cysts, gastroenteric cysts, gastrocytomas, and enterogenous cysts, are typically located in the middle and lower thirds of the esophagus. However, duplication cysts adjacent to the lower esophagus do not necessarily arise from the lower esophagus. Distal duplications such as duodenal or even ileal duplication cysts may extend into the thoracic space through the diaphragm. Similar to other duplications, esophageal duplications typically derive their blood supply from the adjacent esophagus. The size of the cyst can vary widely and may be spherical or tubular, with the former more common than the latter.35 Rarely, the esophageal duplication cyst may extend into the spinal canal, known then as neurenteric cysts (Fig. 129-5). These cysts are thought to arise as a result of endoderm herniation into a gap in the developing notochord, a phenomenon known as the split notochord syndrome.36

Presentation and Associated Findings Foregut duplications are among the congenital lesions identified during routine antenatal ultrasound assessment. In one series, 7 of 39 patients with foregut duplications had antenatal diagnosis of esophageal duplication (18%) with 4 infants symptomatic at birth.16 Such presentations allow for antenatal counseling and early perinatal management for any respiratory complications. Most congenital duplication cysts remain asymptomatic throughout childhood. Some cysts, even extensive foregut cysts,37 can remain asymptomatic until late in adulthood.38 When they present in childhood, the most common presenting symptoms result from airway compression. In one series, 67% of patients with mediastinal duplications presented with respiratory complaints.14 Respiratory symptoms vary from severe respiratory distress in the newborn to mild complaints

1/21/2008 4:07:30 PM

1566

Section 7 Mediastinum

A

FIGURE 129-6 Chest radiograph of an infant with an upper mediastinal foregut cyst (arrow).

B FIGURE 129-5 Neurenteric cyst in the posterior mediastinum in situ (A) and after excision (B), exposing the vertebral column through a posterolateral thoracotomy approach. (PHOTOGRAPHS COURTESY OF DR. S. H. EIN.)

such as cough, wheeze, and stridor.34 Those with airway symptoms tended to have cysts in the perihilar region and to be younger at the time of operative intervention.34 Gastrointestinal complaints such as dysphagia were the second most common presenting complaint.32 Other gastrointestinal symptoms include failure to thrive and vomiting. Peptic ulceration from ectopic gastric mucosa present in the cyst may produce complications of pain, bleeding (and subsequent anemia), and rare perforation.39 Massive bleeding is rarely associated with esophageal duplications. Other presenting complaints include neck swelling from cephalad extension of the cyst.33 Symptoms from neurenteric cysts may arise from the mediastinal or spinal component, the latter giving rise to sensory or motor deficits, gait abnormalities, and back pain.40 Rarely, fistula formation may occur between duplication cyst and adjacent blood vessel with resultant thrombus formation.33 It is worthwhile to note that patients with foregut cysts may have a second duplication cyst, either contiguous or in the distal alimentary tract. The incidence of this association

Ch129-F06861.indd 1566

is variable in the published literature, ranging from 15%39 to one third of patients.32,41 This common association warrants thorough investigation of both thoracic and abdominal compartments before surgical intervention. Foregut duplications are also commonly associated with a wide variety of congenital anomalies, including VACTERL associations. Associated skeletal anomalies occur more frequently in patients with foregut cysts than midgut or hindgut cysts. Approximately one third of patients with isolated foregut duplication32 and all patients with more than one type of duplication have skeletal anomalies.14 The most common skeletal anomalies are spina bifida, hemivertebrae, vertebral fusion, and scoliosis; and all of these defects may be associated with intraspinal pathology. Spinal extension of the duplication cyst should be suspected when vertebral anomalies are present.40 Other anomalies associated with distal enteric duplications such as hindgut anomalies, genitourinary duplications, intestinal malrotation, and atresia are not commonly associated with esophageal duplications. Other esophageal anomalies such as esophageal atresia and tracheoesophageal atresia are occasionally seen with foregut duplications.15 Coincident cardiac anomalies are rare and are prognostic indicators of poor outcome.32

Investigations and Radiologic Findings Duplication cysts should be included in the differential diagnosis of any posterior mediastinal mass in infants and children because they are the second most frequent lesion after neurogenic tumors. Additional investigations should be performed to rule out important differential diagnoses for lesions in the posterior mediastinum, including neural tumors (urinary catecholamines) and germ cell tumors (serum β-

1/21/2008 4:07:31 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

1567

FIGURE 129-7 CT scan transverse image of a duplication cyst (arrow).

A human gonadotropin and α-fetoprotein). The frequent association of esophageal duplication cysts with other anomalies makes it imperative that thorough preoperative clinical assessment and imaging be performed before embarking on any interventions. Imaging should, therefore, be extensive, covering both thoracic and abdominal compartments and soft tissue as well as skeletal regions. The primary objective is to assess both the extent of the primary lesion and possible spinal extension. Associated anomalies should be documented and treatment prioritized based on these associations. The radiologic investigations for airway or esophageal obstructive symptoms should include a routine chest radiograph (Fig. 129-6) and barium swallow study. However, the diagnosis of thoracic duplication by these studies depends heavily on the location and size of the cyst. Older published series suggest that preoperative chest radiography may detect the majority of lesions in the upper or lower mediastinum but noted less than half of perihilar or subcarinal cysts because these lesions were typically obscured by consolidated lung or pneumonia. The combination of mediastinal mass and esophageal compression or displacement was diagnostic in less than half of the patients in this series.34 These results suggest that the utility of chest radiography should be limited to screening patients with symptoms suspicious for duplication cyst and that further imaging consisting of CT or MRI be performed. CT and MRI have revolutionized the investigation of duplication cysts with exquisite sensitivity and specificity. Furthermore, a distinct advantage of CT and MRI studies is the ability to simultaneously assess for the presence of spinal extension, coincident duplication cysts, or associated vertebral anomalies. CT imaging of esophageal duplication typically reveals a smooth, well-defined cystic lesion devoid of calcifications situated in the posterior or middle mediastinum, with homogeneous low attenuation (15-30 HU) and contiguous with the normal esophagus (Figs. 129-7 and 129-8). The peripheral enhancement of the cyst with intravenous contrast medium distinguishes enteric cysts from solid tumors.41 In one series, CT imaging correctly localized lesions in 14 of 15 patients; only one lesion was misread as

Ch129-F06861.indd 1567

B FIGURE 129-8 Three-dimensional CT reconstruction image of a mediastinal foregut cyst (also shown in Fig. 129-7). A, Coronal view. B, Sagittal view.

an abscess.34 One clear disadvantage of CT or MRI is the requirement for anesthesia or sedation, especially in infants, and is a significant problem in those patients with airway obstructive symptoms. In such cases, ultrasound imaging may be particularly useful. Bronchoscopy in the investigation of duplication cysts is not helpful and may even be dangerous in the context of airway obstruction.

Management and Surgical Considerations Surgical treatment is indicated for any symptomatic duplication cyst and cyst identified incidentally for which malignancy cannot be ruled out. Ideally, the cyst should be resected because internal drainage retains the associated ectopic gastric mucosa with the risk of peptic ulcer formation and hemorrhage.14 Isolated, autonomous cysts are easily resectable (Fig. 129-9). However, duplication cysts sharing a common wall

1/21/2008 4:07:32 PM

1568

Section 7 Mediastinum

A

B

FIGURE 129-9 View of an esophageal duplication cyst in situ (A) and after excision (B) through median sternotomy. (PHOTOGRAPHS COURTESY OF DR. S. H. EIN.)

Currently, thoracoscopic resection is the approach of choice for lesions isolated to the mediastinum without evidence of

cervical, abdominal, or spinal extension (Fig. 129-10). Thoracoscopic approach has improved visualization of posterior mediastinal masses as fiberoptic technology with magnification reaches the awkward spots in the pediatric thorax that proved difficult to visualize through the open technique. Large cysts should be initially drained (Fig. 129-11),16 and if the cyst fails to decompress and visualization is impaired, it is always possible to convert to an open procedure because the patient is positioned for thoracotomy. Insertion of a nasogastric tube or bougie may aid in the identification of the esophagus.43 Lateral decubitus positioning is done with proper supports and the arm placed in partially adducted position so that range of motion for trocar and instruments is not limited. For the thoracoscopic approach, visualization of the cyst is aided by any maneuvers that will move the lung away from the posterior mediastinum. The patient should be secured well on the operating table so that he or she can be rolled forward to use gravityassisted retraction of the lung away from the operative field.

FIGURE 129-10 Thoracoscopic view of a mediastinal esophageal duplication cyst.

FIGURE 129-11 Video-assisted drainage of retained mucus and secretions from an esophageal duplication cyst prior to extraction from thoracic cavity.

with the esophagus or bronchus should be retained. In these cases, excision of the mucosa with preservation of the seromuscular layers should be performed to maintain organ integrity while avoiding the secretory function of the ectopic gastric mucosa within the retained structure.4,14 Retained mucosa from communicating cysts may also be ablated by use of the neodymium : yttrium-aluminum-garnet (Nd : YAG) laser, especially if the patient is treated by thoracoscopic resection.42 Thoracoscopic resection is feasible but may be difficult if mediastinal cysts are complicated by past infections because extensive pleural adhesions may form. Subcarinal cysts may be difficult to visualize and access via this approach.31 Tubular cysts are less amenable to resection compared with spherical cysts.

Surgical Approach

Ch129-F06861.indd 1568

1/21/2008 4:07:33 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

Other options are carbon dioxide insufflation via the camera port to 4 mm Hg, which will aid in decompressing lung tissue and increase operative domain in the posterior mediastinum,43,44 or use of retractors through additional trocars.31 Single-lung ventilation may further improve overall visualization. Trocar sites are directed toward the posterior mediastinum and, are, therefore, positioned anteriorly or in the midaxillary line. Once the camera port is placed and the cyst visualized, optimal positioning of the remaining instrument sites can be determined and the principle of triangulation applied. In most circumstances, three trocars are usually required, at least one of which should be a camera port (5-mm trocar) used for carbon dioxide insufflation. The remaining combination of trocars depends on patient size (3-mm trocars inserted via stab incisions for infants; 5-mm trocars in older children). Preoperative knowledge of spinal extension is imperative. If spinal extension of the cyst is suspected or identified from preoperative imaging, the spinal component should be done first via a posterior approach before resection of the mediastinal component. Mobilization is done with sharp dissection using cautery or scissors. Mobilization of lesions located in the upper mediastinum and thoracic apex may result in Horner’s syndrome, thus patients and families should be informed of this possibility preoperatively. Once mobilized, cysts are either morcellized or drained before extraction from the thoracic cavity (see Fig. 129-11). A chest tube may be left in situ,42 although many surgeons avoid chest tubes if no lung tissue was resected or the luminal space was not entered.16

Outcomes Historically, mortality associated with the treatment of duplication cysts resulted from complications of delayed presentation.32,33,39 More recent experience indicates that surgical treatment of duplication cysts is associated with minimal mortality and that morbidity is most commonly related to minor infections.31 Complications including tracheal and esophageal injury can be repaired primarily without further sequelae. Resection of lower esophageal foregut cysts may be complicated by a hiatal hernia postoperatively if the diaphragm was traversed in the complete resection of extensive esophagogastric duplications. Fundoplication may also be required in these cases to prevent post-repair gastroesophageal reflux.

Congenital Cystic Adenomatoid Malformation and Bronchopulmonary Sequestration These two lesions are presented together in this chapter because of the difficulty in definitively distinguishing them on clinical and pathologic bases and natural history. Furthermore, given the frequency with which both lesions are now detected antenatally, these lesions warrant special consideration together for their antenatal diagnosis and management options. CCAMs are hamartomatous lesions characterized by multiple cystic changes and proliferation of bronchioles. The

Ch129-F06861.indd 1569

1569

etiology of CCAM remains unclear but is generally thought to result from the lack of bronchoalveolar development in the presence of pulmonary mesenchyme. The terminology of CCAM has generated some confusion, and it should be reserved to identify the specific pathologic diagnosis with cystic morphology. Unfortunately, the term has also come to loosely encompass all types of cystic lung changes, including congenital lobar emphysema and bronchogenic cysts, that are seen within the context of antenatal assessments. New terminology may be required to clarify the classification of cystic lung lesions especially for antenatal diagnoses.45 Classification of CCAM by Stocker as types 1 to 3 was initially used to describe the cystic, solid, and intermediate morphologies of the lesions.46 However, this classification was expanded to include types 0 and 4 to encompass the complete spectrum of pathologic airway malformations from the tracheobronchial to the distal acinar lesions.47 More importantly, the expanded classification has been applied to better define the CCAM types that might predispose to malignant transformation.48 Sequestrations are noncommunicating pulmonary lesions characterized by a systemic blood supply.49 There are many theories concerning the etiology but the most widely accepted is that sequestrations arise from anomalous lung buds dorsal to the normal lung bud between the fourth and eighth weeks of gestation.50 Sequestrations are classified based on the presence of a pleural covering. An intralobar sequestration is contained within the substance of the adjacent lung tissue. An extralobar sequestration has its own pleural lining and is anatomically separate from the adjacent lung. Extralobar sequestrations are more commonly found in the left side and between the left lung and the diaphragm. In rare cases, the entire lung can be an extralobar sequestration. Sequestrations are not confined to the mediastinum but can present as abdominal and suprarenal masses.51,52 The systemic blood supply originates from the thoracic and abdominal aorta in 80% of lesions, although other systemic vascular sources have been reported; and occasionally more than one blood supply is associated. Venous drainage of extralobar sequestrations is typically to the systemic circulation but up to 25% of drain into the pulmonary circulation. In contrast, almost all intralobar sequestrations drain into the pulmonary venous system. Although pulmonary sequestrations have been considered a separate pathologic and clinical entity from CCAM, it is clear that both lesions can be part of a “hybrid” anomaly in which the pathology is consistent with CCAM but is associated with systemic blood supply53 or is based on the gross and histologic features (Davenport et al, 2004).54 These lesions commonly present together21 or coexist within a single pathologic specimen55-57 and arguably represent stages of foregut malformation rather than distinct pathologic anomalies.20 Further complicating the nomenclature was the addition of a new term to define rare extralobar or intralobar sequestrations that communicate with the esophagus or stomach, known as congenital bronchopulmonary foregut malformation (CBPFM). The etiology of CBPFM is poorly understood, although the doxorubicin (Adriamycin)-induced rat model of foregut malformations exhibits a similar constel-

1/21/2008 4:07:36 PM

1570

Section 7 Mediastinum

lation of pathologic processes.58 CBPFM has been classified into four types depending on the location and level of communication between the alimentary tract and the tracheobronchial tree.59 Right-sided CBPFM is more common, and males and females are equally affected. There are numerous congenital anomalies associated with CBPFM, the most common being skeletal anomalies and tracheoesophageal fistula/esophageal atresia.

Incidence Both CCAMs and sequestrations are rare, constituting less than 15% of pediatric cystic lung lesions,1,60 and are the least common among foregut malformation lesions. The incidence of CCAM has been reported to range from 1 : 25,000 to 1 : 35,000. The reported prevalence of sequestrations ranges from 0.15% to 1.8% in the general population. Intralobar sequestration is three times more common than extralobar sequestration. CBPFM are extremely rare. However, CCAM currently constitutes approximately three fourths of the fetal lung lesions diagnosed antenatally, with the remaining lesions identified as sequestrations.61

A

Presentation Antenatal ultrasonography can routinely make a diagnosis of congenital lung lesions including CCAM and sequestration at 20 to 24 weeks’ gestation. Therefore, antenatal surgical consultation after 20 weeks’ gestation is now commonly encountered. In the context of congenital lung lesions, the development of nonimmune fetal hydrops is the most diagnostic indicator of fetal distress and is associated with a high incidence of fetal demise.54,61 Other markers for poor outcome include low fetal lung to thorax ratio, presence of mediastinal shift, and polyhydramnios.62 Most fetuses with antenatally diagnosed CCAM and sequestration do not develop distress and can be managed expectantly with planned delivery near or at term followed by neonatal intervention if warranted.63 Often, lesions identified earlier in pregnancy gradually shrink in size and some eventually disappear.64 In such cases, postnatal imaging is done and surgery may be recommended later in infancy, although this is an area of controversy (see later). A minority of children with CCAM present with respiratory distress. Children who are asymptomatic at birth may present later with infectious complications. CCAMs are not commonly associated with other congenital anomalies or genetic abnormalities.65 In contrast, extralobar sequestrations have a significant association with congenital anomalies, including diaphragmatic hernias, other lung anomalies, musculoskeletal abnormalities, cardiac anomalies, and enteric duplications. Although the majority of pulmonary sequestrations are asymptomatic, they may present in conjunction with these anomalies or may present as respiratory symptoms, high-output cardiac failure, infectious complications, or hemoptysis. Extralobar sequestrations commonly present within the first 6 months of age as respiratory or feeding difficulties, whereas intralobar sequestrations rarely present before 2 years of age with infectious complications.

Ch129-F06861.indd 1570

B FIGURE 129-12 Chest radiograph (A) and CT scan transverse image (B) of 7-year-old boy with large left-sided macrocystic CCAM (arrow).

Radiologic and Clinical Investigations Antenatal ultrasound features of CCAMs depend on the size of cysts associated with the lesion. CCAMs with multiple cystic lesions 5 mm in diameter or larger appear as a hypoechoic mass, whereas microcystic lesions tend to be echogenic. Extralobar sequestrations tend to appear as welldefined, hyperechoic, homogeneous lesions that may be indistinguishable from microcystic CCAMs, unless the systemic blood supply is identified. The systemic blood supply in sequestrations and “hybrid” lesions can be detected by antenatal Doppler ultrasound or MRI enhanced with intravenous injection of a contrast agent.

1/21/2008 4:07:36 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

1571

variant. The latter diagnosis can be confirmed through demonstration of a communication of the pulmonary cyst with the esophagus or stomach by barium swallow. Ultrasonography is the best screening tool because sequestrations will appear as an echo-dense lesion on either side of the diaphragm and the blood supply can usually be identified (Fig. 129-15). CT best defines the type of cystic lesion (Figs. 12916 and 129-17) and its associated anomalies, although the feeding vessel of a sequestration is not consistently seen (Fig. 129-18). MRI is equally useful and superior to CT in identification of systemic blood supply.

Management and Surgical Considerations

FIGURE 129-13 CT transverse image of a left extralobar sequestration (arrow) associated with mediastinal shift.

FIGURE 129-14 Chest radiograph of a left extralobar sequestration demonstrating the classic triangular, diaphragm-based position and associated mediastinal shift.

Postnatal imaging of a CCAM and sequestration may fail to demonstrate the lesion if the presentation is complicated by atelectasis or pneumonia. A CCAM typically appears as a radiolucent area on a chest radiograph (Fig. 129-12A). Large CCAMs and sequestration can cause mediastinal shift (Fig. 129-13) with esophageal displacement on barium swallow. Extralobar sequestrations are small and may not appear on routine imaging. Intralobar sequestrations may appear as a triangular mass in the base of the lung (Fig. 129-14). An airfluid level is seen in 26% of sequestrations, suggesting either bronchial communication in hybrid lesions or the CBPFM

Ch129-F06861.indd 1571

The management of antenatally diagnosed CCAM and sequestration is dictated by the presence of fetal distress. Clear signs of fetal distress as manifested by nonimmune fetal hydrops before 32 weeks’ gestation are the primary indications for fetal intervention, including thoracoamniotic shunt insertion for macrocystic lesions and fetal CCAM resection for microcystic lesions (Adzick et al, 1998).61 Early delivery should be considered for fetuses of more than 32 weeks’ gestation. Termination of pregnancy may be indicated in the context of severe fetal hydrops and maternal mirror syndrome. Expectant management is recommended if no signs of fetal distress are present. Delivery should be as close to term as possible, and there are no specific indications for cesarean section as the preferred mode of delivery for fetuses with CCAM and sequestration. Antenatal diagnosis of CCAM and sequestration has presented a management conundrum for pediatric surgeons because some lesions found antenatally undergo complete resolution by term and CT may be the only means to demonstrate the lesion not readily seen by plain chest radiography.65 There is considerable debate over the appropriate management of asymptomatic CCAMs. In some centers, routine elective resection of all asymptomatic CCAMs is recommended, with the rationale that the minimal morbidity of resection outweighs the risks of long-term complications such as infection and malignant degeneration. If untreated, long-standing CCAMs have been associated with occult malignancies such as rhabdomyosarcoma,66 pleuropulmonary blastomas,67 and bronchoalveolar carcinoma.68 Inability to maintain long-term follow-up is another strong argument for early resection. However, there are data to suggest that the risk of infection is low and that deferring operative intervention until symptoms develop does not significantly increase morbidity.69 Advocates of expectant management point out that malignancy in an asymptomatic CCAM is extremely rare and does not justify the known risk of lobectomy. Patients with asymptomatic extralobar sequestrations can be observed because infectious complications and malignant potential are minimal. The neonate who presents with acute respiratory distress due to CCAM or intralobar sequestration should undergo lobar resection. Segmental resection may be possible if the lesion is small and well defined, but this approach is associated with an increased risk of recurrence. Extralobar sequestrations can be treated by resection of the lesion alone.

1/21/2008 4:07:36 PM

1572

Section 7 Mediastinum

A

A

B FIGURE 129-15 Ultrasound images of a left extralobar sequestration (A) with identification of the systemic feeding vessel by Doppler imaging (B).

Preoperative localization of the systemic arterial supply will guide operative approach and ensure early control of the artery before the resection of the mass. Infectious complications should be completely resolved before surgical resection. The approach for surgery is via posterolateral thoracotomy, although an increasing number of lesions are now resected using a thoracoscopic approach.70,71 Occasionally, sequestrations associated with cardiac failure may require angiographic ablation of the feeding vessel to stabilize the infant before surgical resection.

Outcomes It is now known that the size of the CCAM, rather than lesion type, and the underlying growth characteristics are the important predictors of outcome. Large and bilateral lesions are associated with poor outcome in utero and require early surgical treatment ex utero. In general, fetal intervention should only be undertaken if the benefits outweigh the risks and in the context of expert care. In contrast, the long-term outcome of surgically treated CCAMs and sequestration is excellent. The current surgical approach is associated with minimal morbidity and mortality and minimal respiratory

Ch129-F06861.indd 1572

B FIGURE 129-16 CT transverse section images of macrocystic (A) and microcystic (B) components of a left CCAM (arrow).

sequelae. Postoperative complications are minimal and include infection, gastroesophageal reflux, and chest wall deformities.

ANTERIOR MEDIASTINAL CYSTS Cystic Lymphatic Malformations Cystic lymphatic malformations (CLMs) are known by a variety of names, including lymphangiomas, congenital pul-

1/21/2008 4:07:37 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

FIGURE 129-17 Coronal section of three-dimensional CT reconstruction of a left CCAM.

1573

by hexagonal cell endothelium derived from lymphatic vessels. The cysts may communicate with each other and contain lymphoid tissue. The cysts tend to be thin walled unless complicated by infection or hemorrhage, which results in a thick-walled and adherent complex. Other cystic lymphatic abnormalities found within the mediastinum include thoracic duct cysts. These present as unilocular lesions in adults73 but are exceedingly rare in infants and children. In children, thoracic duct anomalies typically arise from disruption of lymphatic drainage, resulting in congenital chylothorax or chylous ascites.74 The predilection of CLM for the neck region is consistent with the developmental site of junction of the primitive lymphatic jugular sacs. Although there are several theories as to the origins of CLM, it is clear that these lesions develop some time between the sixth week of gestation when the lymphatic jugular sacs form and the ninth week when the lymphatic channels are complete.75 The lymphatic endothelium in CLMs grows from within the cyst walls, extending into adjacent tissues. These new channels fail to drain into normal lymphatic channels, resulting in the formation of new cavities. This gradually results in a cluster of fluid-filled cysts with deep insinuation into tissue planes. This invasive character was thought to represent a neoplastic process, but these lesions are not true neoplasms in that they do not display any other features consistent with neoplasms, such as increased mitotic activity or nuclear atypia.75 CLMs may also be associated with vascular malformations either in the same lesion or elsewhere in the same patient.

Incidence

FIGURE 129-18 Coronal section of a contrast-enhanced CT with three-dimensional reconstructed images demonstrating a left-sided extralobar sequestration and the feeding systemic vessel arising from the lower thoracic aorta.

monary lymphangiectasis, cystic hygromas, lymphatic cysts, and cystic lymphangiomas. They are congenital lymphatic hamartomas characterized by cysts ranging from millimeters to several centimeters. The first description of a CLM was in 1828 by Redenbacher, but the term cystic hygroma was coined by Wernher in 1843. Sabin identified that the common origin of lymphatic and venous structures was the jugular venolymphatic sacs in 1909.72 It was considered a congenital anomaly by Dowd in 1913 after a review of 137 cases in the literature. Goetsch demonstrated the invasive quality of these lesions in 1938, for which these lesions were erroneously categorized as neoplasms. Although the term CLM is preferable and more exact, most surgeons still use the old descriptor of cystic hygroma to indicate CLM of the head, neck, and chest. By gross and histologic examination, CLMs are unilocular or multilocular cysts filled with clear, colorless or straw-colored fluid, lined

Ch129-F06861.indd 1573

Eighty percent of CLMs are found in the neck (Fig. 129-19), with 5% of neck CLMs having a mediastinal component (“dumbbell” or cervicomediastinal type). Cervicomediastinal CLMs account for less than 1% of all neck masses in one series of 2519 patients.76 CLMs confined to the mediastinum alone (mediastinal type) account for 1% to 2% of all CLMs and 2% to 6% of mediastinal tumors77,78 and are typically found in the anterior mediastinum, although large mediastinal CLMs may occupy any part of the mediastinum or thoracic cavity.79,80 No gender difference has been documented for both types of mediastinal CLM. Other CLM sites include the axilla, groin, retroperitoneum, and oral cavity.

Presentation Large CLMs can be detected on routine antenatal ultrasound and maternal MRI. Antenatal diagnosis of CLM has been associated with poor outcomes owing to the obstructive effects of these malformations as well as associated genetic abnormalities.81 However, spontaneous fetal82 and postnatal resolution of CLMs83 have been reported. In childhood, 65% of CLMs present at birth and 90% present within the first 2 years of life.84 Large cervicomediastinal CLMs can present as acute and even lethal airway obstruction in neonates85 and infants.80 Isolated mediastinal CLMs rarely cause symptoms in children and more commonly present in adults.86 However, obstructive symptoms of the airway, esophagus, and vessels can occur with extremely large mediastinal CLMs. Other

1/21/2008 4:07:38 PM

1574

Section 7 Mediastinum

A

and mediastinum. Ultrasonography may not be useful for imaging retropharyngeal and mediastinal extensions. CT and MRI are useful for distinguishing mediastinal CLMs from other solid and cystic mediastinal masses along with detection of coexisting vascular malformations. Furthermore, these modalities are most helpful in determining the relationship of the CLM to adjacent organs and especially large vessels of the thorax. Cysts in CLMs appear complex and heterogeneous without calcifications on CT and MRI. MRI is now the gold standard for the imaging of cervical, mediastinal, and axillary CLMs (Fig. 129-20).89 T2-weighted MR images provide the best definition of a CLM from surrounding tissues, and T1-weighted images with intravenous gadolinium provide greater sensitivity for determining the extent of these lesions. The utility of lymphangiography to assess cervicomediastinal and mediastinal CLMs is limited and should be reserved for noncystic lymphatic malformations involving the limbs.74

Management and Surgical Considerations

B FIGURE 129-19 Cutaneous manifestation of a vascular malformation (A) in a patient with mediastinal CLM accessed via median sternotomy (B). (PHOTOGRAPHS COURTESY OF DR. S. H. EIN.)

symptoms of CLM include chronic cough, wheezing, dyspnea, fever, hoarseness (secondary to recurrent laryngeal nerve palsy), phrenic nerve palsy, cyanosis, superior vena cava obstruction, chylothorax, chylopericardium, and chylomediastinum.84,87 CLMs have been associated with genetic diagnoses such as Turner’s syndrome, Noonan’s syndrome, trisomy 21, trisomy 18, and trisomy 13 and other congenital anomalies, including vascular malformations (hemangiomas), thyroglossal duct cysts, and congenital cardiac anomalies.88

Radiologic and Clinical Investigations On physical examination, CLMs are soft cystic lesions on palpation compared with the firm quality of soft tissue tumors. Chest radiography as the initial screening tool may reveal a well-defined mass of the neck and upper mediastinum and may be associated with chylothorax, findings that help to distinguish cervicomediastinal CLMs from branchial cleft cysts. Ultrasound imaging is helpful for superficial lesions, where CLMs appear as hypoechoic, heterogeneous complex cysts with septa and deep extension into the neck

Ch129-F06861.indd 1574

Fetuses with large cervical and cervicomediastinal CLMs may display signs of fetal distress with airway and esophageal obstruction. In anticipation of airway obstruction postnatally, some centers have advocated interventions including CLM resection in utero90 and ex utero intrapartum treatment (EXIT) procedure at birth.91 Other interventions include antenatal sclerosis with OK-432 to shrink cysts.92 However, the risks and benefits of antenatal intervention must be carefully weighed because some cases of complicated fetal CLMs can resolve spontaneously.82,93 Postnatally, once a diagnosis of a CLM is clearly made and the lesion thoroughly imaged, surgical resection should be undertaken at the earliest convenience. Surgical excision is simplified if the cysts remain intact and are not complicated by antecedent infection. Presence of infection, previous sclerosis, and recurrent disease contribute to increased technical difficulty with any attempt at resection. If the CLM is infected at presentation, initial treatment with antibiotics for 1 to 2 weeks is required and surgical intervention should be deferred for 2 to 3 weeks to minimize inflammatory edema. The goal of surgical treatment is complete excision of the CLM without sacrificing vital structures. Attempts at radical excision of CLMs have not improved recurrence rates, are disfiguring, and should only be performed for failure to rule out a malignant diagnosis. However, every attempt should be made for complete resection to minimize risks of recurrence and other complications.86 Even then, the lesions tend to be adherent to local structures, including the esophagus, bronchi, and major vessels, and to infiltrate into muscle and subcutaneous tissue. Meticulous dissection into tissue planes while preserving nerve and vascular structures is required. Median sternotomy with cervical extension (“inverted hockey stick”) is the most successful approach for excision of cervicomediastinal lesions,94 because these lesions originate from the C3C5 nerve roots along the jugular vein, extending into the mediastinum along the phrenic nerve and insinuating between the subclavian vessels. Posterolateral thoracotomy may be sufficient for isolated mediastinal CLMs.80 One-stage resec-

1/21/2008 4:07:39 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

A

C

tion preceded by thorough preoperative imaging is now the standard treatment.95 Nonsurgical options should only be considered when surgery is contraindicated for extensive and potentially disfiguring CLMs. These approaches include cyst aspiration and cyst injection with sclerosing agents such as bleomycin, sodium tetradecyl sulfate, OK-432, 22.5% glucose solution, and triamcinolone, provided that the cysts are large and communicating. Cyst injection can be used as a combined approach with surgery for the treatment of extensive lesions (see Fig.

Ch129-F06861.indd 1575

1575

B

FIGURE 129-20 Transverse (A), sagittal (B), and coronal (C) fast spinecho inversion recovery MR images of a giant, complex cystic lymphatic malformation (CLM) in a newborn involving the right and left pleural spaces, mediastinum, chest wall, and left axilla. The large, multicystic CLM extends into the right thoracic space and mediastinum, wrapping anteriorly in the lower mediastinum around the heart, extending out to the chest wall, around to the paravertebral muscles, and into the left axilla. The enormous size and wide breadth of this lesion makes it difficult to determine whether this CLM arose from the axillary region or if it is a mediastinal lesion extending out into the chest wall soft tissue. This lesion was resected when the patient was 21 days of age with residual disease left on the left arm.

129-20). However, caution should be exercised because sclerosant leakage can render the surgical procedure extremely difficult. Radiation therapy has been tried with limited success, with the disadvantage of exposing patients to the adverse effects of neck and upper chest radiation, including hypoplasia of teeth and mandible, tracheitis, esophagitis, and thyroid cancer.88,96 Regardless of treatment approach, vigilant and long-term follow-up of patients is critical due to the high incidence of complications and recurrence associated with diffuse CLMs.

1/21/2008 4:07:40 PM

1576

Section 7 Mediastinum

Outcome Historically, cervicomediastinal CLMs have been associated with high mortality resulting from infection and airway obstruction. However, more recent reports suggest an overall mortality of 2% to 5%83 and low operative mortality.94 For surgically treated CLMs, incomplete resections are associated with a 10% recurrence rate. Complications associated with resection of cervicomediastinal CLMs include infection, recurrence, Horner’s syndrome, other nerve injuries, injury to the esophagus or airway, bleeding, and lymph leak, which can be manifested as chylothorax or persistent lymph drainage from the wound.80,87,88,94 Persistent lymph leak can be a difficult problem and can result in immunosuppression and nutritional complications from long-standing lymphocyte and protein losses. The use of medium chain triglyceride–based infant formulas or complete bowel rest with total parenteral nutrition support may be required to control lymph drainage. Occasionally, thoracic duct ligation may be necessary. Replacement of lymph loss with 5% albumin may be required to prevent severe hypoalbuminemia and edema. In summary, the incidence of CLM is rare and the results of CLM resection are sufficiently morbid that the management of extensive cervicomediastinal CLMs should involve a multidisciplinary approach at specialized centers.

Thymic Cysts The thymus is a cervicomediastinal organ and the primary site of T-lymphocyte development. It is derived embryologically from the third pharyngeal pouch, which is the same embryologic precursor for organogenesis of the inferior parathyroid glands.97 The thymic cortex harbors immature T lymphocytes that undergo a maturational “education” through its migration into the thymic medulla. The thymus reaches its peak size and mass at puberty, weighing 30 g, and typically involutes with fatty infiltration after adolescence. The thymus contains all three germinal layers and can give rise to a variety of anomalies. Thymic lesions are predominantly benign in children, with cystic lesions constituting the predominant subset. Cysts of the thymus are classified according to their etiology: congenital, acquired, or those secondary to neoplasms. Congenital thymic cysts are fluidfilled lesions composed of thymic tissue with Hassall’s corpuscles encased in a lymphocyte-laden wall lined by squamous epithelium. The cysts are thought to originate from remnants of the thymopharyngeal tract that marks the embryologic migration route of the thymus from the third pharyngeal cleft to the anterior mediastinum starting at the seventh week of gestation. This theory nicely explains both the frequent association of thymic cysts with ectopic parathyroid tissue and the location of congenital thymic cysts in the neck, anterior mediastinum, or both.98 An alternative theory suggests that congenital thymic cysts result from the coalescence of degenerated Hassall’s corpuscles, which best explains the pathognomonic histologic features of congenital thymic cysts. Congenital thymic cysts can be multiple or unilocular. These cysts are more commonly distributed in the neck than mediastinum, but 50% of cervical thymic cysts are associated with a mediastinal component. The size of cysts can range from miniscule up to 22 cm.99

Ch129-F06861.indd 1576

Acquired thymic cysts, sometimes known by the term multilocular thymic cysts (not to be confused with congenital thymic cysts with multiple cystic components), are inflammatory thymic lesions lined by several types of epithelium (including squamous, cuboidal, columnar, and ciliated) and often contain thymic tissue or are filled with turbid fluid surrounded by thick, fibrous walls.100 Chronic inflammation within the cysts produces characteristic features, including lymphoid follicles, cholesterol granuloma formation, dystrophic calcifications, and fibrosis.101 These cysts are typically associated with primary infections of the thymus, with the infectious etiology shifting from congenital syphilis (Dubois abscesses) historically to human immunodeficiency virus (HIV) more recently in the pediatric population.102 Given the association of HIV infection with Hodgkin’s lymphoma, the important implication for a thymic lesion in an HIVinfected patient is to rule out the possibility of malignancy. Other etiologic factors include radiation exposure103 and surgical trauma.104 Multilocular cysts may contain a variety of tissues within the stromal component that are thought to give rise to malignant changes within cysts found in adults.105-107 Cystic lesions arising from primary thymoma or other thymic tumors are rare in children, whereas they are more commonly found among oncology patients secondary to chemotherapy-induced changes in mediastinal Hodgkin’s108 and non-Hodgkin’s lymphoma.109 These cysts may appear on CT studies as part of the routine follow-up for mediastinal lymphoma. Post-chemotherapy thymic cysts are generally asymptomatic and do not significantly change in size. However, in such cases in which relapse of the primary malignancy cannot be ruled out, surgical resection of the thymus is warranted. Several clinical features associated with thymic cysts in adults are rarely reported in infants and children. The association of thymic cysts with autoimmune conditions such as Sjögren’s syndrome, myasthenia gravis, systemic lupus erythematosus, and aplastic anemia in adults has not been described in infants. It has been suggested that primary thymic malignancies may arise from stroma within thymic cysts in adults106,110 but has rarely been documented in children, although multilocular thymic cysts can be associated with other primary benign mediastinal tumors in children.111

Incidence Thymic cysts are uncommon and account for 3% of mediastinal masses in children.24,112,113 Congenital thymic cysts represent one third of these lesions and may rarely have a familial association.114 The true incidence is unknown because the majority of small congenital thymic cysts rarely cause symptoms. The incidence of acquired thymic cysts in children is strongly correlated with the prevalence of infectious etiologic factors, such as HIV infection rate among neonates.

Presentation The majority of congenital thymic cysts do not cause symptoms and present as incidental findings during investigations of other symptoms. However, symptomatic thymic cysts present between 2 and 15 years of age, reflecting the growth of the thymus relative to the rest of the mediastinum. The

1/21/2008 4:07:41 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

presenting symptoms range from benign respiratory symptoms115 to life-threatening airway obstruction due to acute expansion from intracystic hemorrhage.116 Congenital thymic cysts with a cervical component may present with a neck mass that fluctuates in size with respiration. The cervical thymic cyst may be associated with local tenderness, dysphagia, hoarseness, and infectious complications.117 Hoarseness resulting from vocal cord paralysis may result from mass compression of the recurrent laryngeal nerve.98 Acquired thymic cysts with infectious etiologies may present as chest pain, dyspnea, fever, or hemoptysis at any age.118 All multilocular thymic cysts associated with HIV infection in two published series were asymptomatic and identified through routine screening.102,119

Radiologic and Clinical Investigations Clinical investigations for a child with an anterior mediastinal mass should always include a thorough workup to rule out malignancies, including lymphoma and teratoma. Testing for levels of serum lactate dehydrogenase, β-human chorionic gonadotropin, and α-fetoprotein should be included along with routine hematology. Patients presenting with infectious signs and fever should be assessed and appropriate cultures sent for analysis. Appropriate serology testing should be obtained with informed consent if HIV infection is suspected. The primary objective of clinical and radiologic investigations is to distinguish benign cystic lesions of the thymus from malignant tumors, although the definitive diagnosis can only be made through excision. Features that help to distinguish anterior mediastinal tumors from thymic cysts include presence of calcifications and central foci of low density suggestive of necrosis. The demonstration of coincident cervical cysts, either separate or by direct extension, is strongly suggestive of congenital thymic cyst rather than other mediastinal cystic tumors or branchial cysts.99 Additional tests may be required to distinguish mediastinal thymic cysts from thyroid cysts, including thyroid scan.98 Routine chest radiography is a useful screening tool to identify large thymic lesions but may be impossible to discern between enlarged thymus due to hyperplasia, tumor, or cyst. The most useful imaging studies to distinguish between solid and cystic lesions of the thymus are ultrasonography and CT,120 with the former as diagnostic as the latter in the neonate. Congenital thymic cysts appear as well-defined, hypoechoic, smooth-walled lesions on ultrasound examination. The echo density of the cyst is increased by complications such as infection and hemorrhage. Similarly, uncomplicated thymic cysts should be well defined in appearance with a radiodensity consistent with water (0-10 HU) on CT unless complicated by infection and hemorrhage. In those cases, the cysts may be radiodense surrounded by a thick enhancing wall. MRI may better distinguish between cystic and solid lesions, and T1- and T2-weighted images may provide better delineation of the lesion from the surrounding tissues.121 Multilocular cysts associated with HIV infection can be distinguished from solid tumors by all imaging modalities.122 Contrast-enhanced CT demonstrates the heterogeneous, multiloculated nature of the lesions. MRI T2-weighted

Ch129-F06861.indd 1577

1577

images similarly demonstrate the septations, as does ultrasound imaging. However, ultrasonography may not be able to completely visualize the entire lesion as windows over the anterior thorax may be limited behind the sternum. Other multilocular thymic cysts unrelated to HIV infection demonstrate similar features.118

Management and Surgical Considerations In general, most acquired cysts associated with HIV infection will respond to medical therapy and rarely reach sizes sufficiently large to cause airway obstructive symptoms. As a result, acquired thymic cysts very rarely require surgical intervention in HIV-infected children.119 However, any thymic cyst associated with respiratory symptoms or when a diagnosis of malignancy cannot be ruled out should be treated by surgical resection. The authors do not recommend percutaneous aspiration of thymic cysts before or in lieu of surgical treatment unless the cyst is clearly associated with acute respiratory distress, for which urgent decompression is required. Needle biopsy is not useful for distinguishing malignant lesions from benign cysts, and cyst fluid associated with chronic infection or hemorrhage may be too viscous to sample by needle aspiration. Multilocular thymic cysts present the greatest challenge in both diagnosis and management because resection is complicated by the presence of chronic inflammation of the mediastinum and incomplete resection can lead to recurrence.100 Symptomatic thymic cysts should be treated by resection. Thymectomy in children has not been associated with any known immunologic sequelae because the T-lymphocyte population is thought to be well established by early infancy.123 The traditional approach to thymectomy is through median sternotomy. This is the approach of choice for all central mediastinal thymic lesions, inflammatory cysts, and any suspected malignant thymic lesions. The blood supply to the thymus from the thyroid artery and internal mammary arteries should be visualized and controlled. Cervical extension is possible to include combined resection of any cervical lesions. Other approaches include cervical thymectomy for small superior mediastinal lesions. Although thoracoscopic resection has been successful and advocated for the treatment of thymic lesions,124 one should be wary of the possibility of malignancy associated with the cyst.110

Outcome There are no data to support the routine resection of asymptomatic thymic cysts. However, the long-term outcomes of thymectomy for symptomatic congenital thymic cysts are excellent with minimal morbidity and mortality. Common complications of surgical treatment include infection, nerve injury, chylothorax, and bleeding.

Pericardial Cysts Pericardial or mesothelial cysts are congenital benign cysts of the pericardium and are thought to result from incomplete obliteration of the distal ventral parietal recesses of the pericardium.125 The first description of a pericardial cyst was by His in 1881. The majority of pericardial cysts are based on the diaphragm in the cardiophrenic angle. Most pericardial

1/21/2008 4:07:41 PM

1578

Section 7 Mediastinum

cysts are located on the right side and may be attached to the pericardium by a vascular pedicle, but as many as 30% lie elsewhere in the mediastinum, cross the midline, or rest directly on the pericardium in the retrosternal space. The cysts are lined by squamous epithelium, can be multilocular, and contain clear fluid. A cyst may communicate with the pericardial cavity and is known as a diverticulum if the communication is large. Rarely, pericardial cysts may arise after acute pericarditis or cardiothoracic surgery and likely represent acquired lesions associated with organizing inflammation. Malignancies are rarely associated with pericardial cysts, although they may mimic mesenchymal tumors, germ cell tumors, and lymphoma by their location and appearance on chest radiography.

Incidence Pericardial cysts account for a significant proportion of adult mediastinal masses but are rarely seen in infancy. Large reviews of mediastinal masses in infants and adults suggest that pericardial cysts constitute only 2.2% of pediatric mediastinal tumors and cysts,126 compared with 15% in adults.127 Increased use of CT may have increased the total reported incidence in recent years.128 Increased detection extends to the antenatal period because pericardial cysts have been detected on routine antenatal ultrasonography.129

Presentation The majority of pericardial cysts are asymptomatic even when associated with large quantities of cystic fluid because the cysts rarely develop acutely to result in tension and cardiac compression. However, symptoms from pericardial cysts can be devastating in an acute presentation. Symptoms range from chest pain, cough, and dyspnea to right ventricular outflow tract obstruction, acute cardiac tamponade, and sudden death.130 Dramatic presentations of pericardial cysts, especially after blunt chest trauma,131 only increase the uncertainty concerning the optimal management of incidentally identified, asymptomatic pericardial cysts.

Radiologic and Clinical Investigations No specific clinical investigations, including cyst aspiration, are completely diagnostic for pericardial cysts. Investigations are mainly to rule out differential diagnoses of malignancy and bronchogenic and thymic cysts, for which treatment of asymptomatic lesions is warranted. On routine chest radiography, pericardial cysts appear as well-defined opacifications in the right cardiophrenic angle. CT of pericardial cysts reveals well-defined cysts with smooth walls and without septa. Cyst contents have low attenuation similar to water (0-10 HU) and do not enhance with intravenous injection of a contrast agent. MRI does not provide more specific diagnostic information compared with CT. In MRI, pericardial cysts have low or intermediate signal intensity on T1-weighted images and homogeneously high intensity on T2-weighted images. Administration of gadolinium does not enhance pericardial cysts. Pericardial cysts located in an atypical location may be difficult to distinguish from thymic cysts and bronchogenic cysts by CT and MRI.132 Barium swallow or CT with

Ch129-F06861.indd 1578

luminal contrast may be required to differentiate a retrosternal pericardial cyst from a Morgagni hernia. Additional transthoracic or transesophageal two-dimensional echocardiography may help distinguish pericardial cysts from other cardiac anomalies.133

Management and Surgical Considerations The acutely symptomatic pericardial cyst should be managed by image-guided percutaneous aspiration because life-threatening presentations result from cardiac compression. Traditional pericardiocentesis via the subxiphoid space may not be therapeutic if the cyst does not communicate with the pericardial sac. In most cases of nonacute presentations, cyst resection is indicated to treat airway or esophageal obstructive symptoms and obtain tissue diagnosis. Pericardial cysts can be resected through thoracotomy or thoracoscopy because the latter approach can be utilized for even the largest cysts facilitated by needle decompression.134 Excision of the pericardial cyst is straightforward because cysts are typically nonadherent and can be “shelled out” of the cardiophrenic angle with no significant vascular supply to control. Occasionally, the chronic pericardial cyst may be adherent to adjacent vessels such as the superior vena cava or azygos vein or to the phrenic nerve. Such cases are treated by resecting the free cyst wall, leaving the attached wall behind. Any communications with the pericardium should be sought out and closed primarily. No drains are required after resection.

Outcome The outcome of surgical treatment of pericardial cysts is excellent. There have been no cases of operative mortality reported for resections of pericardial cysts, and there is minimal morbidity associated with both thoracotomy and thoracoscopic resections. The low risk of surgical intervention for pericardial cysts, especially with video-assisted thoracoscopic surgery, has caused some to advocate an aggressive approach to the treatment of pericardial cysts in contrast to conservative treatment by needle decompression. There are currently no long-term data to substantiate this position, and the management of pericardial cysts should be individualized to the patient’s situation.

MISCELLANEOUS CYSTS AND CYSTLIKE LESIONS OF THE INFANT AND PEDIATRIC MEDIASTINUM Infectious Cysts and Abscesses Abscesses of the mediastinum should always be considered as part of the differential diagnosis of cystic lesions in the pediatric mediastinum. Mediastinal abscesses may arise via lymphatic drainage of primary infections of the head and neck or by direct extension from the pleural cavities. Mediastinitis involving gram-positive bacteria secondary to oropharyngeal infections may result in the formation of cystlike cavities within the upper mediastinum.135 Foreign body ingestion with resultant esophageal perforation and abscess formation should always be considered in the preschool pediatric population.136 Although abscesses secondary to tuberculosis

1/21/2008 4:07:41 PM

Chapter 129 Mediastinal Cysts and Duplications in Infants and Children

are more commonly seen within the pleural cavities, endemic regions have reported tuberculous abscess formation in the anterior and superior mediastinum,137 resembling cysts of the thymus or pericardium. Hydatid cysts from echinococcus infection have occasionally presented as posterior mediastinal cysts.138 Therefore, a high index of suspicion for an infectious etiology of a mediastinal cyst should be exercised, especially in the context of the patient’s age and travel history.

Radiologic and Clinical Investigations A history of fever and respiratory symptoms associated with chest pain should raise the suspicion of either infectious complications or etiology associated with any mediastinal lesion. Symptoms of dysphagia should raise concerns of possible delayed presentation of foreign body ingestion. A thorough physical examination for signs of oropharyngeal or chest infections including lymphadenopathy should be specifically sought. The patient’s travel history should be inquired directly and Mantoux or Casoni’s skin test performed if indicated. Echinococcal infections should be considered if travel from endemic regions is noted and abdominal ultrasonography performed to assess for concomitant liver hydatid cysts. Initial investigations for fever with aerodigestive tract symptoms should include hematology, blood cultures, and chest radiography. Mediastinal and pulmonary hydatid cysts appear on chest radiography as round, homogeneous, and well-defined densities in the absence of associated atelectasis or pneumonia. The diagnosis of a mediastinal mass associated with febrile illness may be aided by CT, although it may still be difficult to distinguish between a recently infected foregut cyst and a mediastinal abscess. The presence of a germinative membrane may be visible in some echinococcal abscesses.138 The absence of an identifiable radiopaque lesion does not rule out the association with a foreign body, and barium swallow should be performed. Early endoscopy may be warranted if clinical suspicion is high.

Management and Surgical Considerations Incision and drainage of mediastinal bacterial abscesses with systemic antibiotic therapy is often sufficient in most cases. Exceptions to this are tuberculous and echinococcal infections for which surgical resections of abscesses are indicated as primary treatment. Chronic tuberculous abscesses should be managed by resection because systemic antituberculous therapy may be insufficient to penetrate and eradicate the infected cavity. The diagnosis of hydatid cyst should be established preoperatively by Casoni’s skin test, indirect hemagglutinin assay, or enzyme-linked immunosorbent assay specific for echinococcal infection. Preoperative anthelmintic therapy should be followed by surgical resection of hydatid cysts, although the extent of surgical resection and use of scolicidal agents are controversial in the pediatric population.139 The main objective in the surgical management of pediatric pulmonary hydatid cysts should be complete cyst resection to control local involvement without rupture of the cyst. In such cases, cyst aspiration followed by cystotomy, removal of the germinative membrane, and closure of any bronchial openings may

Ch129-F06861.indd 1579

1579

be sufficient. Ruptured cysts pose a particularly difficult problem because local control of echinococcal infection by surgical resection is unlikely. In the presence of concomitant mediastinal or pulmonary cysts and liver cysts, treatment of the chest lesions should take priority. Mediastinal abscess resulting from chronic foreign body ingestion and localized perforation requires systemic antibiotic treatment, discontinuation of oral intake, and endoscopic retrieval. If endoscopic attempt at foreign body removal is not successful, right thoracotomy and esophagotomy may be required.

Outcome Infections of the mediastinum warrant thorough investigation and aggressive treatment because mortality is directly related to delayed recognition and undertreatment of mediastinitis. Combined medical and surgical treatment of mediastinal tuberculous and echinococcal infections is associated with good outcomes, but data from long-term follow-up are lacking from endemic regions.

Cystic Tumors Benign and malignant childhood tumors of the mediastinum may present as cystic lesions and create diagnostic confusion. Solid pediatric mediastinal tumors (see Chapter 136) that contain cystic components or have cystic appearance on imaging studies include teratoma, thymic carcinoma, thyroid carcinoma, cystic parathyroid adenoma, lymphoblastic lymphoma, pleuropulmonary blastoma, lipoma, and lipoblastoma (Castellote et al, 1999).140-143 As imaging technologies improve, refinement and accuracy of diagnosis of cystic mediastinal lesions will increase. However, the surgeon may have no choice but to resect the lesion to obtain a diagnosis. Given this diagnostic dilemma, the surgeon should approach all mediastinal cystic lesions with caution and with a constant consideration to a possible malignant etiology when embarking on surgical resection.

COMMENTS AND CONTROVERSIES Mediastinal cysts and duplications can present a diagnostic dilemma. However, recent sophisticated imaging techniques have improved diagnostic accuracy and facilitated operative management. Symptomatic cystic lesions should be excised. Asymptomatic lesions of clear diagnosis (e.g., bronchogenic cysts, pericardial cysts) can be safely observed using currently available imaging techniques. More widespread use of video-assisted thoracoscopic surgical technology in the pediatric age group has lessened the magnitude of operative insult required for resection of many of these lesions. G. A. P.

KEY REFERENCES Adzick N, Harrison M, Crombleholme T, et al: Fetal lung lesions: Management and outcome. Am J Obstet Gynecol 179:884-889, 1998. ■ This paper summarizes the long list of congenital lung lesions that are now routinely diagnosed antenatally. The prenatal ultrasonographic features, indications for fetal intervention, and management options are discussed for all lesions described. The

1/21/2008 4:07:41 PM

1580

Section 7 Mediastinum

brief discussion on the postnatal management of these lesions is controversial because many of these lesions may spontaneously resolve with time.

antenatally diagnosed lesions still warrant postnatal workup because the antenatal and postnatal diagnoses are often discordant.

Castellote A, Vazquez E, Vera J, et al: Cervicothoracic lesions in infants and children. RadioGraphics 19:583-600, 1999. ■ This report provides a good summary of the radiologic tools and findings for the various lesions that are represented among mediastinal cysts in infants and children. The current techniques of contrast-enhanced CT and MRI studies have a high success rate in resolving the identities of many lesions without the need for invasive tests.

Haller J, Golladay E, Pickard L, et al: Surgical management of lung bud anomalies: Lobar emphysema, bronchogenic cyst, cystic adenomatoid malformation, and intralobar pulmonary sequestration. Ann Thorac Surg 28:33-43, 1979. ■ Airway obstruction is the most devastating complication associated with mediastinal cysts in infants and children. This paper details the presentations and surgical approaches for the management of foregut malformations causing acute respiratory distress in the pediatric population.

Davenport M, Warne S, Cacciaguerra S, et al: Current outcome of antenally diagnosed cystic lung disease. J Pediatr Surg 39:549-556, 2004. ■ This is a recently published report of 65 antenatally diagnosed lung lesions and the natural history of these lesions to the time of birth. It also contains a brief literature review of other published series on this subject, with the conclusion that many

Ch129-F06861.indd 1580

Takeda S, Miyoshi S, Minami M, et al: Clinical spectrum of mediastinal cysts. Chest 124:125-132, 2003. ■ This paper is a comprehensive review of the incidence and clinical spectrum of mediastinal cysts in children and adults. The one drawback is that it is a singleinstitution series, as are many of the publications on this topic.

1/21/2008 4:07:41 PM

chapter

130

MEDIASTINAL CYSTS AND DUPLICATIONS IN ADULTS Francis C. Nichols, III Karen Harrison-Phipps

Key Points ■ Mediastinal masses are uncommon, with mediastinal cysts

accounting for 20% of such masses. ■ Confusion regarding mediastinal cysts and duplications is, in large

part, due to the plethora of ambiguous names associated with this entity. ■ Bronchogenic cysts are commonly symptomatic in contrast to esophageal cysts, which are asymptomatic. ■ Complete excision is the treatment of choice and is indicated for increasing size or treatment of symptoms or complications. ■ Resection can often be done using minimally invasive techniques; however, largely due to associated inflammatory changes, open techniques may be necessary.

Mediastinal masses are relatively uncommon disorders that remain an interesting diagnostic and therapeutic challenge to thoracic surgeons. Cysts account for approximately 20% of all such masses. A review of all surgically treated mediastinal masses at the Mayo Clinic over a 40-year period revealed that 18.4% were cystic (Wychulis et al, 1971).1 Similarly, in a series of 400 consecutive patients with primary lesions of the mediastinum, 99 (25%) had a primary cystic lesion.2 Furthermore, these same authors identified a combined total of 2799 patients with mediastinal lesions, and cysts represented 9% to 26% of mediastinal lesions (Davis et al, 1987).2 Finally, Oldham found in a collection of 214 mediastinal cysts from 5 separate authors that 41% were bronchogenic, 35% were pericardial, 10% were enteric, and 14% were nonspecific.3 The terminology describing mediastinal cysts has been plagued by ambiguity, with resulting confusion. Mediastinal cysts have been alternatively called bronchogenic, bronchoesophageal, enteric, enterogenous, esophageal, and duplication cysts.4 Difficulty with the classification arises because theoretically all tissue types within the mediastinum may become cystic, and thus classification based on location alone can be misleading. For example, bronchogenic cysts are usually in the subcarinal or peritracheobronchial areas associated with the major airways, esophagus, or cardiac structures; nevertheless, bronchogenic cysts may also occur within the lung parenchyma. The term duplication is confusing because it is not descriptive of the cyst’s origin. Maier, in 1948, used the cyst’s anatomic location to differentiate these lesions.5 Others have used the histology of the epithelial lining as the defining characteristic. Fallon and associates, in 1954, utilized the cyst’s embryologic origin as well as the anatomic location to classify these lesions.6

This chapter focuses on bronchogenic, esophageal (duplication), neurenteric, pericardial, thymic, thoracic duct, pancreatic, and parathyroid cysts, which will be separately discussed. Because most mediastinal cysts are congenital in origin and embryologic development is an important factor in classification, we will first focus on a brief review of the development of the lung and esophagus.

EMBRYOLOGY The notochord (nervous system) begins forming with the migration of ectodermal cells when the embryo is 18 days old. As the notochord forms, it fuses with endoderm. The vertebral bodies form around the notochord. If some endoderm becomes entrapped in the ectoderm, a split in the notochord develops, known as the split notochord syndrome. This malformation is thought to be the cause of neurenteric cysts. This helps to explain the common association of neurenteric cysts with vertebral body anomalies.7 The primitive respiratory and upper gastrointestinal systems have a common embryologic endodermal origin. Their development starts at 28 days’ gestation with the appearance of a laryngeal groove in the ventral wall of the primitive pharynx. The laryngeal groove deepens to become surrounded with mesenchymal tissue and starts budding. Further branching eventually forms the trachea, bronchi, and alveoli. Abnormal bud separation may lead to cyst formation lined with respiratory epithelium and is known as a bronchogenic cyst. If this separation occurs early, the cyst is associated with the large airways; however, delayed separation may lead to cyst formation within the lung parenchyma. As the lung bud elongates, the tracheoesophageal septum appears and then with further maturation eventually separates the esophagus and laryngotracheal tubes. From the esophageal pouch the esophagus rapidly elongates and by 7 weeks reaches its final relative length of growth. During this time frame the esophageal endoderm proliferates, almost completely occluding the lumen. At 6 weeks, microcystic vacuolization occurs, and it is the ultimate fusion of these vacuoles that results in the esophageal lumen. Persistence of any of these vacuoles may lead to esophageal cyst formation within or adjacent to the esophageal wall.

BRONCHOGENIC CYSTS Cystic pulmonary lesions have been reported since the 17th century; however, it was Mixter and Clifford (1929) who first reported in the American literature a patient with a bronchogenic cyst beneath the tracheal bifurcation.8,9 Several subsequent series have demonstrated that bronchogenic cysts are 1581

Ch130-F06861.indd 1581

1/21/2008 4:08:30 PM

1582

Section 7 Mediastinum

the most frequent cystic lesions found in the mediastinum.1,10 Bronchogenic cysts represent 15% to 20% of all mediastinal masses.11 Even though cysts are relatively common mediastinal masses, they are only occasionally seen by general thoracic surgeons. Supporting this relative rarity is a report from a hospital with 54,000 annual admissions identifying only 6 patients with mediastinal cysts over a 4-year time frame.4 Similarly, Coselli and colleagues reported that bronchogenic cysts were seen in only 1 of 42,000 admissions.12 Because these cysts are the result of abnormal lung budding, their location is variable along the embryologic path of lung development. If the cyst separates early, the resulting bronchogenic cyst is located in the mediastinum; however, if the separation occurs late, the bronchogenic cyst ultimately develops within the lung parenchyma.13,14 St-Georges and colleagues found the location of the bronchogenic cysts was mediastinal in 66 of 86 patients (77%) and intrapulmonary in 20 patients (23%) (St-Georges et al, 1991).15 Additionally, they found the specific mediastinal location to be quite variable. Fifteen (23%) of the cysts were superior to the level of the carina and 51 (77%) were inferior. Of note, bronchogenic cysts can occur anywhere within the body. They have been associated with the esophagus, diaphragm, pericardium, and sternum.15-17 Bronchogenic cysts have been found intradurally and also as a skin lesion with a blind sinus tract.18,19 Although bronchogenic cysts are often isolated findings, they have been reported in association with accessory pulmonary lobes, Down syndrome, and pulmonary sequestration.20-22 Bronchogenic cysts are more common in men and most frequently seen on the right side. Although they may be asymptomatic in 20% to 30% of patients, the majority of patients have symptoms.15,23 In the series by Cartmill and Hughes, 75% of patients were symptomatic.24 Additionally, St-Georges and colleagues found that 66% of symptomatic patients had two or more symptoms.15 In Rice’s series, even if patients were initially asymptomatic, on long-term followup 67% of patients eventually became symptomatic.10 In general, the most common symptoms are pain, cough, dyspnea, recurrent infection, and dysphagia. Substernal pain is the most common symptom for mediastinal bronchogenic cysts. The pain is secondary to pressure on adjacent structures or due to infection. Symptoms secondary to compression vary according to the specific structure that is compressed. Compression is found with 57% of paratracheal cysts, 68% of hilar cysts, but only 16% of infrahilar cysts (Ribet et al, 1995).23 Infants and children may present with signs of rapidly progressive major airway obstruction (wheezing, stridor, and cough). Esophageal compression can lead to dysphagia. Superior vena caval syndrome and left atrial compression have also been reported.25-27 Symptoms may be positional and can be augmented with recumbency. Although symptoms in adults may be less acute in onset, they can nonetheless be quite pronounced. Bronchogenic cysts may become symptomatic secondary to infection. The infection is presumed to be due to the cyst communicating with the bronchial tree. Infected bronchogenic cysts may cause fatigue, chest pain, and fever with or without leukocytosis. If the communication with the bronchus is large enough, patients may cough up cyst debris.

Ch130-F06861.indd 1582

FIGURE 130-1 Posteroanterior chest radiograph of an adult with a bronchogenic cyst adjacent to the aortic arch. Seen here is a smooth, round mass in the medial left hemithorax.

Recurrent pneumonias are possible from intermittent bronchial compression by the cyst. Empyema or hemothorax may occur if an infected cyst ruptures into the pleural space. Physical examination may be nonspecific in a patient with a bronchogenic cyst. If an infected cyst is present, the patient may have fever and tachycardia. With airway compression, wheezing may be present. In general, however, physical examination is unrevealing.

Diagnosis A standard chest radiograph may be diagnostic and show a smooth rounded opacity in the mediastinum (Figs. 130-1 and 130-2). The size of the cyst is variable but can fill an entire hemithorax.28 Calcification of the cyst is unusual, but cysts containing milk of calcium have been reported.29,30 An airfluid level may be present. Since the advent of CT, diagnostic specificity has increased because CT accurately localizes and characterizes the mass (Fig. 130-3). CT usually shows a sharply marginated, homogeneous mass with attenuation values in a range consistent with serous fluid (0-20 Hounsfield units [HU]). With infection, the cyst may appear more dense and inhomogeneous on CT, thus accounting for some bronchogenic cysts having Hounsfield units ranging from 30 to 130. MRI is useful in elucidating the true cystic nature of these lesions. An intense T2-weighted image supports the interpretation of a fluidcontaining structure (Figs. 130-4 and 130-5). MRI is a longer, more uncomfortable, and expensive examination than CT and is rarely necessary in patients with bronchogenic cysts.7 Ultrasonography and transesophageal echocardiography

1/21/2008 4:08:31 PM

Chapter 130 Mediastinal Cysts and Duplications in Adults

A

1583

B

FIGURE 130-4 A, Coronal section of the MR image of the patient in Figure 130-1 with the bronchogenic cyst in the left periaortic region. The bronchogenic cyst appears white and is adjacent to the black void in the aorta. B, Sagittal MR image of the same patient. Again, the mass appears white adjacent to the black void of the aorta.

FIGURE 130-2 Lateral chest radiograph of the patient in Figure 130-1 showing the mass in the mediastinum immediately superior to the hilum.

FIGURE 130-5 Coronal MR image in a patient with a bronchogenic cyst along the right paravertebral area.

Pathology

FIGURE 130-3 CT of the patient in Figure 130-1 showing a left-sided bronchogenic cyst adjacent to the descending thoracic aorta.

(TEE) may be useful in eliciting the cystic nature of the mass. TEE may help in distinguishing bronchogenic from pericardial cysts. Endoscopic ultrasonography has helped in the differentiation of bronchogenic cysts from solid lesions.31 Barium swallow can demonstrate compression of the esophagus by the adjacent cyst. Bronchoscopy is normal in the majority of cases, but abnormalities can include extrinsic compression, secretions from infected cysts, and, rarely, direct communication with the cyst cavity.32

Ch130-F06861.indd 1583

Bronchogenic cysts are usually spherical, unilocular, and may contain internal trabeculations. They may be filled with thin clear fluid or mucoid material, which may be white, yellow, turbid, and occasionally blood stained.33 Microscopically, the lining can be variable, consisting of ciliated, columnar respiratory epithelium, squamous cell epithelium, or a flattened type of epithelium.4 Histologically, the cyst wall may contain glands and, rarely, cartilage, smooth muscle, and elastic and fibrous tissue.

Treatment In the absence of a definitive diagnosis, surgical exploration is recommended for nearly all patients with an abnormal mediastinal mass. This approach is required to establish a tissue diagnosis. Although the risk is minimal, malignancies have been reported to develop in bronchogenic cysts. Moersch and Clagett, in 1947, first reported an adenocarcinoma in a bronchogenic cyst and a squamous cell carcinoma found in a

1/21/2008 4:08:31 PM

1584

Section 7 Mediastinum

ciliated cyst of indeterminate origin.34 Others have reported carcinoid tumors, anaplastic carcinoma, and leiomyosarcoma associated with bronchogenic cysts.35-37 Nonetheless, far more important than the minimal risk of malignancy is the risk of developing complications. Treatment is indicated for all cysts that are increasing in size, symptomatic, or have developed complications. Moreover, St-Georges and colleagues recommended that all presumed bronchogenic cysts seen in adults be resected because they believe the majority of these cysts will eventually become symptomatic or complicated.15 Nevertheless, small asymptomatic bronchogenic cysts can be safely observed. During follow-up, regular imaging studies such as chest radiography or CT are mandatory. If the cyst remains stable in size over time, imaging studies may eventually be done yearly. Complete resection of the bronchogenic cyst is the goal if excision is undertaken, thus minimizing the chance of recurrence and the potential for more serious complications.23,32 Thoracotomy is likely to achieve complete resection, although less invasive treatment modalities have been described. Transbronchial needle aspiration and percutaneous aspiration have been suggested as alternatives to thoracotomy in the management of mediastinal bronchogenic cysts.38-40 Aspiration of mucoid material with cytologic evidence of ciliated columnar epithelial cells is indeed useful in confirming the diagnosis; however, aspiration is not always successful, with cyst recurrence and symptoms developing over a number of years.40 Aspiration is reserved only for patients at high risk for a thoracic surgical procedure or possibly for patients refusing surgical resection. Mediastinoscopic removal of bronchogenic cysts has been described and appears to be safe and effective; however, most descriptions in the literature are only case reports.41-43 A clear advantage of mediastinoscopy is its low morbidity when performed by experienced surgeons. Whether a bronchogenic cyst is amenable to mediastinoscopic removal depends on its anatomic location. Criticism of mediastinoscopic treatment focuses on incomplete cyst excision, which is certainly more likely with complicated and infected bronchogenic cysts. Smythe and colleagues reported on three essentially asymptomatic patients in whom mediastinal cysts were removed utilizing mediastinoscopy (Smythe et al, 1998).43 In all three, 80% to 90% of the cyst wall was excised and at 6-month to 1-year follow-up there were no recurrences. We reserve mediastinoscopic resection for simple, small, and radiograpically classic bronchogenic cysts in the appropriate anatomic locations for mediastinoscopy. For all other cysts, either video-assisted thoracic surgery (VATS) or thoracotomy is the preferred surgical approach. The feasibility and safety of a VATS resection was described in two reports.44,45 Eleven mediastinal cysts, including seven bronchogenic or enteric cysts with a mean diameter of 4.2 cm (range, 2.6-11 cm) were excised with VATS. Cysts were most commonly aspirated first because the authors believed this facilitated resection. Complete resection was possible in all but one patient in whom the cyst wall was adherent to a vital structure. In this patient the mucosal remnant was cauterized.45 No complications or recurrences were reported with a mean follow-up of 6 months. VATS appears to be a reasonable surgical approach for the resection of broncho-

Ch130-F06861.indd 1584

genic cysts; however, because of occasional dense pericystic adhesions of the cyst with adjacent structures VATS may not always be technically possible and open thoracotomy must be undertaken. Ribet and colleagues believed that in their series a bronchogenic cyst’s central location, adhesions, and communication with the tracheobronchial tree would have made VATS resection hazardous in 30% of children and 11% of adults.46 In the 1991 series by St-Georges and colleagues, 83 of their 86 patients had cyst resection through a posterolateral thoracotomy.15 Adhesions of mediastinal bronchogenic cysts to adjacent structures were considered to be a major operative difficulty in 25 patients. Additionally, in St-Georges’ series, resection of pulmonary bronchogenic cysts ultimately required a lobectomy in 13 patients, segmentectomy in 6, and pneumonectomy in 1.15 Complete excision of the intact cyst remains the goal; however, in cases where the cyst wall is densely adherent to adjacent vital structures the cyst is opened, as much of the cyst wall resected as possible, and the remaining lining removed or cauterized. Ultimately, no secreting mucosal surface can be left behind and any communication with the aerodigestive tract must be closed. If these goals are accomplished the outcome is uniformly excellent, the patient’s symptoms are relieved, and recurrence is rare.

ESOPHAGEAL CYSTS Esophageal cysts are very similar to bronchogenic cysts. In fact, some authors group both lesions under the term enterogenous cysts. Palmer required three criteria for characterizing an esophageal cyst: 1. Attachment to the esophagus 2. Epithelium characteristic of some level of the gastrointestinal tract 3. Presence of two layers of muscularis propria47 From 50% to 60% of esophageal cysts contain ectopic gastric mucosa, with some containing pancreatic tissue.48 Despite Palmer’s strict criteria, confusion differentiating esophageal and bronchogenic cysts can exist. For example, when a bronchogenic cyst is intimately associated with the airway and contains respiratory epithelium and cartilage in its wall, there is no difficulty differentiating it from an esophageal cyst. However, if a bronchogenic cyst migrates, becomes associated with the esophagus, and contains squamous epithelium, then classification as either bronchogenic or esophageal becomes problematic. In reality, this differentiation may be of no practical significance because both types of cysts behave similarly and require similar treatment.4 After leiomyomas and benign polyps, esophageal cysts are the third most common esophageal mass, although they remain much less common than bronchogenic cysts. Among all mediastinal cysts, only 5% to 14% are esophageal in origin.1,49 A representative series from the Mayo Clinic revealed that of 246 benign esophageal tumors, only 55 (22%) were esophageal cysts.50 Although esophageal cysts may occur anywhere along the length of the esophagus, they most commonly occur in the lower one third of the esophagus.51 Approximately 94% of esophageal cysts are located in the

1/21/2008 4:08:32 PM

Chapter 130 Mediastinal Cysts and Duplications in Adults

1585

esophagus, more likely to be lower in the mediastinum, and may have thicker walls (Jeung et al, 2002).56 If the cyst communicates with the esophagus, an air-fluid level may be present. Barium swallow usually shows a smooth intramural mass extending into the esophageal lumen. Because gastric mucosa is present in the lining of approximately 50% of esophageal cysts, technetium-99m pertechnetate scans may be positive.7 Esophagoscopy, when performed, will demonstrate a smooth, soft, compressible mass without mucosal abnormality. Endoscopic ultrasonography has proven to be useful in distinguishing cystic from solid esophageal lesions as well as defining which layers of the esophageal wall are involved. The temptation to sample or aspirate the cyst must be resisted because this may lead to infection and increased difficulty in resection. FIGURE 130-6 CT scan in a patient with a large esophageal cyst. The cyst almost fills the right hemithorax with significant compression of the left atrium.

esophageal wall, although the majority do not communicate with the esophageal lumen.52 Patients younger than 16 years of age constitute 70% to 75% of patients with esophageal cysts, and there is a 2 : 1 male predominance.53 Associated conditions may exist and include other intestinal cysts, esophageal atresia, tracheoesophageal fistula, and spinal abnormalities such as scoliosis, hemivertebrae, and fusion. These associated conditions are more common in children.54 Esophageal cysts most commonly present as an asymptomatic finding on CT scans obtained for unrelated reasons. The natural history of esophageal cysts is variable, but if left untreated most will become symptomatic (Fig. 130-6). In adults, dysphagia and pain are the most likely symptoms. Nausea, vomiting, weight loss, anorexia, wheezing, and nonspecific precordial sensations or rhythm disturbances have also been reported.52,54 In children, respiratory symptoms predominate secondary to pressure exerted on surrounding structures. Similar to bronchogenic cysts, esophageal cysts can become infected. Patients can present with symptoms that occasionally are life threatening. Spontaneous hemorrhage within the cyst itself can occur, with resulting hematemesis or hemoptysis if the cyst ruptures into the esophageal lumen or tracheobronchial tree.54,55 Additionally, spontaneous rupture of the cyst into the pleural cavity can occur, causing empyema or hemothorax. Malignant degeneration has been reported but is extremely rare.48,52

Diagnosis The typical appearance of an esophageal cyst on chest radiography is a round mass with smooth borders, although chest radiography may not always show the lesion. CT provides better visualization and localization, with the typical appearance being a round, smooth-bordered, homogeneous, lowattenuation mass. In contrast, leiomyoma is of attenuation similar to muscle. Although the CT or MRI appearance of esophageal cysts is very similar to its bronchogenic counterpart, esophageal cysts are in more intimate contact with the

Ch130-F06861.indd 1585

Pathology Esophageal cysts are usually unilocular and contain mucoid material. The epithelial lining can be squamous, columnar, ciliated columnar, or a combination of these. The wall of the cyst may contain glands, and there may be evidence of an underlying inflammatory reaction even without obvious infection being present. The cyst wall has a two-layer muscularis with a myenteric plexus.4,7

Treatment Similar to bronchogenic cysts, complete excision of an esophageal cyst is the preferred treatment. All symptomatic patients are considered for cyst excision. Historically, asymptomatic patients with coincidentally found cysts were also referred for excision. If the patient is a good surgical candidate, then asymptomatic patients are offered excision. Because of significant advances in diagnostic tests, particularly endoscopic ultrasonography and MRI, when there is diagnostic certainty of an esophageal cyst, careful observation is now being offered to high-risk surgical patients.48 Although aspiration and cyst decompression through a bronchoscope or esophagoscope have been reported, these modalities fail to remove the cyst lining, thus increasing the risk of cyst recurrence and infection.57 These techniques cannot be considered optimal therapy. Surgical approaches for excision of esophageal cysts include VATS and limited thoracotomy. Cyst enucleation and closure of the disrupted esophageal muscle layers without injury to the mucosa is possible utilizing VATS. However, the surgeon always needs to be alert for the identification and repair of any mucosal injury that may occur.45 Conversion to an open thoracotomy is undertaken when necessary. Similar to that for bronchogenic cysts, esophageal cyst excision can be accomplished with little morbidity and no mortality.

NEURENTERIC CYSTS These rare cysts occur early in development, presumably due to the aberrant entrapment of endoderm as the vertebral bodies surround the notochord. Neurenteric cysts are differentiated from other foregut cysts by this association with vertebral anomalies, which can range from a minimal spinal abnormality to cysts that are completely intradural without

1/21/2008 4:08:32 PM

1586

Section 7 Mediastinum

any extraspinal component. In the report by Heimburger and Battersly, only 2 of 45 childhood primary mediastinal tumors were found to be neurenteric cysts.58 Similarly, in a pediatric series of 41 foregut cysts, 6 were described as neurenteric.59 Neurenteric cysts are usually symptomatic and only rarely quiescent until adulthood. Most cases present within the first year of life.60 Presenting symptoms are primarily determined by the cyst’s size, location, and the pressure they exert on adjacent mediastinal and spinal structures. Alrabeeah and colleagues noted that symptoms were most frequently due to the cyst’s compression of the airways.61 Cough, wheezing, and dyspnea are among the most common symptoms. The triad of respiratory symptoms, vertebral anomalies, and a mediastinal mass was present in 70% of patients in the series reported by Ahmed and associates.62 Dysphagia, nausea, and vomiting may also occur due to esophageal compression. Peptic ulceration or hemorrhage may occur owing to the acidsecreting potential of glands in the epithelium.63 Neurologic symptoms of back pain, paresthesias, motor disturbance, and paraplegia may occur. The epithelium of neurenteric cysts is varied and may include squamous, pseudostratified columnar, or cuboidal epithelium. These cysts can contain gastric or small bowel– appearing mucosa.64 When present, the intraspinal component is usually thin walled with a single layer of columnar epithelium.65 This contrasts with the extraspinal portion of these cysts, which tends to be thicker with an outer layer of smooth muscle. Communication of the proximal gastrointestinal tract and the intrathoracic portion of the neurenteric cyst is possible. Although chest radiography may occasionally show the mediastinal cyst and associated vertebral abnormality, CT is usually required to establish the diagnosis. Because of the inferior descent of the esophagus during development, the vertebral abnormality is usually located superior to the cyst and may be located in the lower cervical or upper thoracic vertebrae. Although CT certainly can yield more information on the vertebral abnormality than chest radiography, MRI is ideally suited for the delineation of the vertebral abnormality, in particular the intraspinal component. Prenatal diagnosis via ultrasonography has been described.66 Complete excision is the treatment of choice. When preoperative diagnostic imaging shows no intraspinal extension of the cyst, VATS excision may be possible.67,68 When there is only minimal involvement of the vertebral body, resection might be accomplished with VATS or, more commonly, a standard posterolateral thoracotomy. Neurenteric cysts that transgress the diaphragm may require a thoracoabdominal incision. If the spinal or vertebral abnormality is severe, this portion of the resection is accomplished first by a neurosurgeon or orthopedic surgeon, often through a posterolateral thoracotomy. Once the spinal cord attachments have been removed, the remainder of the cyst can be resected. Some neurenteric cysts may require laminectomy and total microsurgical excision of the cysts through a posterior approach.69 With complete resection, most patients do well. Scoliosis, chest wall deformities, and recurrence, however, have occurred after marsupialization and partial resection.4

Ch130-F06861.indd 1586

PERICARDIAL CYSTS Pericardial cysts are also referred to as mesothelial, pericardial coelomic, pleuropericardial, and springwater cysts.3,70 Embryologically, the merging of primitive pericardial lacunae results in the formation of the pericardial coelom. Failure of these lacunae to merge may result in pericardial cyst formation.71,72 Additionally, persistence of the embryonic ventral parietal recess of the pericardium may explain pericardial cysts most commonly in the cardiophrenic angle.73 They are estimated to occur in 1 per 100,000 persons.74 Of 99 mediastinal cysts, Davis and colleagues found 36 (36%) to be pericardial.2 Similarly, Ochsner and Ochsner found 11 (26%) pleuropericardial cysts out of 42 congenital mediastinal cysts.75 About 70% of pericardial cysts are located in the right cardiophrenic angle, 22% in the left cardiophrenic angle, and 8% in other locations, including the posterior mediastinum, right or left hilar regions, right paratracheal area, or in the vicinity of the aortic arch74 (Fig. 130-7). With the advent of better radiologic imaging (CT and/or MRI), the incidence of atypical pericardial cyst locations appears to have risen (38%).76 Pericardial cysts may range from 3 to 30 cm and have been observed enlarging to where they eventually occupy the majority of the pleural cavity.77 Most pericardial cysts are asymptomatic and discovered coincidentally on chest radiography, CT, or echocardiography. Approximately 20% of patients may, however, present with symptoms including shortness of breath, right-sided heart failure with compression, infection, hemorrhage, and herniation through the chest wall.76,78 Radiographically, pericardial cysts are well-marginated spherical or teardrop-shaped masses that characteristically abut the heart, anterior chest wall, and diaphragm. On CT, these masses appear unilocular and nonenhancing. On occasion, these cysts may be radiographically confused with a

FIGURE 130-7 CT scan of a patient with a right pericardial cyst. The low attenuation in the anterior portion of the right chest is the cyst. The lighter-attenuated round structure is the top of the right hemidiaphragm.

1/21/2008 4:08:32 PM

Chapter 130 Mediastinal Cysts and Duplications in Adults

hernia of the foramen of Morgagni. Echocardiography may help alleviate diagnostic uncertainty especially with regard to other cardiac possibilities such as ventricular aneurysms and pericardial fat pads. Surgical resection has been the preferred treatment particularly for enlarging or symptomatic pericardial cysts.70,74,76,77 Recent series have documented the success in treating pericardial cysts with VATS and, for paratracheal cysts, mediastinoscopy.74,76,77 Mouroux and colleagues had follow-up ranging from 4 to 125 months (mean, 57.7 months) and found no recurrent cysts.76 Aspiration has been reported without recurrence, but long-term data on recurrence are lacking and complications may occur.79,80

PANCREATIC PSEUDOCYSTS

THYMIC CYSTS

PARATHYROID CYSTS

Thymic cysts are uncommon, occurring in approximately 4% of patients with mediastinal masses.2,81 Graeber and associates reported on 39 true thymic cysts out of a total of 46 cystic thymic lesions.82 Thymic cysts can be found anywhere along the thymus’ developmental tract, but most commonly they are located in the anterior mediastinum. Usually, thymic cysts are unilocular, are small, and have thin walls. Unilocular cysts are thought to be congenital. Multilocular thymic cysts can occur, are thought to be acquired, and often are accompanied by inflammation and fibrosis. Multilocular thymic cysts are associated with infection, immunologic disease processes, neoplasia, and trauma. Thymic cysts can become massive.78 In contrast to mediastinal thymic cysts, which are often asymptomatic, cervical cysts can present as an enlarging neck mass with pain.82 Symptoms of mediastinal thymic cysts when present include chest pain, cough, dysphagia, dyspnea, pericarditis, and tamponade. For congenital thymic cysts, CT reveals a homogeneous, low-attenuation mass. CT of acquired multiloculated cysts reveals thick-walled, multicystic lesions, and soft tissue attenuation is present. Malignancy may develop within thymic cysts.83,84 Treatment of thymic cysts is most commonly surgical resection so as to rule out cystic variants of thymoma or lymphoma.10 Surgical resection can be performed by open median sternotomy, VATS, or even robotic minimally invasive techniques.85 The optimal approach remains controversial.

Mediastinal parathyroid cysts are extremely unusual. Shields and Immerman were able to identify only 94 parathyroid cysts in the literature.91 These cysts may arise from embryologic remnants of the third and fourth branchial clefts, develop from existing microcysts, or be the end result of cystic generation of a normal gland or adenoma. The location of the mediastinal parathyroid cyst was the anterosuperior (pretracheal) mediastinum in 56 patients, the middle mediastinum in 26 patients, and the true prevascular anterior mediastinum in 12 patients. Thirty-nine patients (41%) had hyperparathyroidism of varying severity, with 7 patients presenting in hypercalcemic crisis. Local findings and symptoms included a neck mass, respiratory distress, occasional dysphagia, chest pain, recurrent laryngeal nerve palsy, tracheal compression, and innominate vein compression.91,92 The size of the mediastinal parathyroid cyst varies, ranging from 0.5 to 12 cm. Most cysts are thin walled, translucent, and unilocular. Parathyroid tissue may be found within the walls. Diagnosis can be confirmed by cyst aspiration, with high levels of parathyroid hormone found in the fluid.93 The treatment of mediastinal parathyroid cysts is surgical. The surgical approach can be transcervical, VATS, median sternotomy, or thoracotomy. Aspiration is not the preferred treatment.

THORACIC DUCT CYSTS Thoracic duct cysts in the mediastinum are extremely rare and tend to be found in the posterior mediastinum.86,87 In contrast to most other mediastinal cysts, which are asymptomatic, thoracic duct cysts are often symptomatic. A supraclavicular mass may be noted, and patients commonly present with compression of the trachea or esophagus.88 After ingestion of a fatty meal, symptoms may worsen due to increased chyle flow, which causes additional cyst enlargement. If the cyst is suspected preoperatively, the diagnosis can be confirmed with lymphangiography. More commonly, the diagnosis is made at the time of resection of an unknown type of mediastinal tumor.7 Cyst excision is recommended to alleviate symptoms.10 Complications of surgery include chylothorax, and care must be taken to ligate the invariably present communication with the thoracic duct.89

Ch130-F06861.indd 1587

1587

Pancreatic pseudocysts may occasionally enter the chest by traversing the aortic or esophageal hiatus or by erosion directly through the diaphragm. The most common location for mediastinal pancreatic pseudocysts is the posterior mediastinum. If a hernia of the foramen of Morgagni is present, the pseudocyst may pass through this opening and be located anterior to the heart. Diagnosis is by CT or by endoscopic retrograde cholangiopancreatography. Pancreatic pseudocysts may rupture, resulting in a pleural effusion with a high amylase content.90 The preferred surgical approach is transabdominal, not thoracic.

COMMENTS AND CONTROVERSIES This chapter outlines the typical presentation, imaging, and management of cystic lesions of the adult mediastinum. This is an excellent review with state-of-the-art representative imaging and an extensive bibliography. With conventional imaging, the majority of these lesions can be diagnosed accurately before resection. Therefore, the major indications for surgical excision are increasing size, symptoms, or complications. When diagnosis is certain in an asymptomatic patient with a stable cystic lesion, follow-up imaging is a satisfactory strategy for the majority of mediastinal cysts. Resection of these lesions can usually be accomplished by minimally invasive techniques. Bronchogenic cysts are often densely adherent to surrounding structures, and complete excision of the entire wall can be hazardous. In this circumstance, resection of the majority of the lesion, leaving one wall on vital structures such as airway or pericardium, is an acceptable treatment strategy. G. A. P.

1/21/2008 4:08:32 PM

1588

Section 7 Mediastinum

KEY REFERENCES Davis RD, Oldham HN, Sabiston DC: Primary cysts and neoplasms of the mediastinum: Recent changes in clinical presentation, methods of diagnosis, management and results. Ann Thorac Surg 44:229, 1987. ■ This often-cited reference from Duke University Medical Center highlights major changes that occurred in the clinical presentation, diagnosis, and management of primary mediastinal lesions. Four hundred consecutive patients ranging in age from 7 days to 83 years with primary mediastinal lesions are included in the study. Demmy TL, Krasna MJ, Detterbeck FC, et al: Multicenter VATS experience with mediastinal tumors. Ann Thorac Surg 66:187, 1998. ■ This multicenter retrospective review included 48 patients from Cancer and Leukemia Group B (CALGB) thoracic surgeons. There were 6 (12.5%) conversions to an open procedure. Three were related to bleeding or the vascularity of the mass and three were due to tumor size. There were no postoperative deaths or major complications. In carefully selected patients VATS resection of benign particularly middle and posterior mediastinal masses is safe. Jeung M-Y, Gasser B, Gangi A, et al: Imaging of cystic masses of the mediastinum. Radiograpics 22:S79, 2002. ■ The authors provide an excellent assortment of chest radiographs, CT scans, and MR images of bronchogenic cysts, duplication cysts, pericardial cysts, thymic cysts, cystic thymoma, and pancreatic pseudocyst. Ribet ME, Copin MC, Gosselin BH: Bronchogenic cysts of the mediastinum. J Thorac Cardiovasc Surg 109:1003, 1995. ■ A retrospective review of 69 patients ranging in age from 1 day to 64 years treated for mediastinal bronchogenic cysts. The authors recommended resection because

Ch130-F06861.indd 1588

of uncertainties in diagnosis. The operative morbidity was 13.4%. The authors commented on the cysts’ central location, adhesions, and communication of the cyst to the tracheobronchial tree, making thoracoscopic resection hazardous in 30% of children and 11% of adults. Although thoracoscopic resection of bronchogenic cysts has been reported by some authors, none of the series is large. Appropriate judgment of when to convert to open thoracotomy must always be kept in mind. Smythe WR, Bavaria JE, Kaiser LR: Mediastinoscopic subtotal removal of mediastinal cysts. Chest 114:614, 1998. ■ This small series (three cases) reviews mediastinoscopic removal of mediastinal cysts that the authors cite as being even less invasive than VATS. In all cases 80% to 90% of the cyst wall was excised. There were no recurrences; however, follow-up did not exceed 1 year and only included plain radiography. St-Georges R, Deslauriers J, Duranceau A, et al: Clinical spectrum of bronchogenic cysts of the mediastinum and lung in the adult. Ann Thorac Surg 52:6, 1991. ■ This important series is probably the largest series of bronchogenic cysts in adults (86 patients). This paper emphasizes that most bronchogenic cysts either are or become symptomatic. For this reason, the authors advocate resection of all bronchogenic cysts to either alleviate symptoms or prevent complications. Major intraoperative difficulties or complications occurred in 43.9% of the patients. Wychulis AR, Payne WS, Clagett OT, et al: Surgical treatment of mediastinal tumors: A 40-year experience. J Thorac Cardiovasc Surg 62:379, 1971. ■ This classic report from the Mayo Clinic focuses specifically on 1064 patients who required surgery for mediastinal neoplasms and cysts.

1/21/2008 4:08:33 PM

Tumors and Masses chapter

131

THYMIC TUMORS: A REVIEW OF CURRENT DIAGNOSIS, CLASSIFICATION, AND TREATMENT Frank C. Detterbeck Alden M. Parsons

Key Points ■ Surgery is the mainstay of therapy for thymomas, and a complete

resection needs to be achieved whenever possible. ■ By multivariate analysis, the most important prognostic factors

■

■

■

■ ■ ■ ■

in patients with thymomas are stage and completeness of resection. Multiple methods of histologic classification of thymomas have been proposed but have not been consistently applied and are not of independent prognostic value with the exception of thymic carcinoma, which has a distinctly poor prognosis. The WHO classification system is becoming more widely adopted, but its relevance remains controversial in predicting clinical course and guiding clinical management of each subgroup (as opposed to distinguishing between thymic carcinoma and thymoma). Biopsy of a presumed thymoma is not detrimental and may be indicated particularly in cases where multimodality therapy is being considered. All stages and all histologic subtypes of thymoma have the potential to spread to distant sites. Preoperative chemotherapy for advanced-stage thymoma appears to improve resectability and survival. Adjuvant radiotherapy may be beneficial in patients with incomplete resection of their tumor. Resection of recurrent thymoma is done whenever possible and offers the best chance of prolonged survival.

The thymus gland is a rather mysterious structure. Although it is seated in a central location, its physiologic role is relatively peripheral and to this day is not fully understood. Tumors of the thymus gland, known as thymomas, are also rather enigmatic. Thymomas have many features that are unusual among malignant growths and have long engendered both a great deal of interest and debate. Because these tumors are relatively rare, the accumulation of data regarding thymoma has been slow, and much of the approach to patients with these tumors has been based on speculation or extrapolation from observations in a few patients. However, the number of studies detailing various features of thymomas has increased. In this review we examine what is known about the behavior of thymomas and the results of treatment.

CLASSIFICATION Staging Systems No staging system has been adopted by the official bodies that have defined staging systems for most cancers. The first

staging system, proposed by Bergh and colleagues, classified noninvasive thymomas as stage I, those invading the mediastinal fat as stage II, and those invading surrounding organs or those with metastases as stage III.1 The staging system that has gained widespread acceptance was proposed by Masaoka and associates in 1981 (Masaoka et al, 1981) (Table 131-1).2 As it is currently used, this system takes into account both macroscopic as well as microscopic evidence of tumor invasion into other mediastinal structures. A slight modification of this system has been proposed, namely, to divide stage I into Ia and Ib subclasses (Regnard et al, 1996).3,4 Stage Ia tumors are those without evidence of invasion or adherence into other structures, whereas stage Ib tumors have evidence of adherence to other structures but with no evidence of microscopic invasion when examined under the microscope. Furthermore, some authors suggest that stage III and stage IV tumors need to be divided into a and b subclasses according to whether a complete resection (R0) was performed.3,4 In France, multiple centers have become organized with regard to thymomas and have adopted a staging system known as the GETT (Gruppe d’Étude des Tumeurs Thymiques) system (Table 131-2).5 This staging system bears many similarities to the Masaoka staging system. In fact, one study comparing these two systems found concordance in the numerical stage classification in 88% of 149 patients.6 The distinguishing feature of this system is that it takes into account the extent of surgical resection that has been performed. Although this may be of prognostic value postoperatively, it does not lend itself to clinical staging of patients before treatment to select the optimal approach (which may not involve surgery as the first modality). A staging classification system based on T, N, and M categories has been proposed for thymomas (Tables 131-3 and 131-4).7 This system closely parallels the Masaoka system. The stage is determined primarily by the T classification status, reflecting the fact that thymomas rarely involve lymph nodes. Only one series so far has reported results using this TNM system.8

Histologic Classification Thymomas have attracted the interest of pathologists, in part because there is an exceedingly wide spectrum of morphologic appearances.9-11 Despite the attention received, there is controversy and confusion about how these tumors should be classified and how the types should be defined. Perhaps because of these difficulties, attempts to correlate prognosis with histologic classification have yielded conflicting results, and multivariate analysis has almost invariably shown that the 1589

Ch131-F06861.indd 1589

1/21/2008 4:09:18 PM

1590

Section 7 Mediastinum

TABLE 131-1 Masaoka Staging System

TABLE 131-3 TNM Classification for Staging of Thymomas

Stage

Definition

T1

I

Macroscopically encapsulated tumor, with no microscopic capsular invasion Macroscopic invasion into surrounding fatty tissue or mediastinal pleura Microscopic invasion into the capsule Macroscopic invasion into neighboring organs Pleural or pericardial metastases Lymphogenous or hematogenous metastasis

T2

From Masaoka A, Monden Y, Nakahara K, Tanioka T: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48:2485-2492, 1981.

N3 M0 M1

IIa IIb III IVa IVb

TABLE 131-2 Gruppe d’Étude des Tumeurs Thymiques (GETT) Staging System

Stage

Completeness of Resection

Ia Ib

R0 R0

II IIIa IIIb IVa IVb

R0 R1,2

Definition Encapsulated tumor, totally resected Macroscopically encapsulated, totally resected, but with mediastinal invasion or suspected microscopic capsular invasion Invasive tumor, totally resected Invasive tumor, subtotally resected Invasive tumor, biopsy only Supraclavicular metastasis or distant pleural implant Distant metastasis

From Gamondès JP, Balawi A, Greenland T, et al: Seventeen years of surgical treatment of thymoma: Factors influencing survival. Eur J Cardiothorac Surg 5:124-131, 1991.

histologic type was not of independent prognostic value (see the later section on prognostic factors). However, it must be noted that most of these classification systems have focused primarily on subtyping of the vast majority of thymomas that lack cytologic features of malignancy. The grouping of thymic tumors into three categories— cytologically bland thymoma, well-differentiated thymic carcinoma (WDTC), and thymic carcinoma—is a clinically useful broad classification. More detailed histologic classification systems that have been developed over time have lacked reproducibility and have failed on multivariate analysis to predict prognosis. The most recent classification system was proposed in 1999 by an international committee assembled by the World Health Organization (WHO).12 This system bears some similarities to the Müller-Hermelink system but recognizes six different types of thymic tumors (types A, AB, B1, B2, B3, and C). Type A tumors are composed of neoplastic spindle-shaped epithelial cells without atypia or lymphocytes. Type AB is similar to type A but has foci of lymphocytes. Type B tumors consist of plump epithelioid cells and are subdivided into three subtypes, as defined by an increasing proportion of epithelial cells and increasing atypia. Type B1 tumors resemble normal thymic cortex with areas similar to

Ch131-F06861.indd 1590

T3 T4 N0 N1 N2

Macroscopically completely encapsulated and without microscopic capsular invasion Macroscopic adhesion or invasion into surrounding fatty tissue or pleura or microscopic invasion of the capsule Invasion into neighboring organs such as great vessels, pericardium, lung Pleural or pericardial dissemination No lymph node metastases Metastases to anterior mediastinal lymph nodes Metastases to intrathoracic nodes (other than anterior mediastinal nodes) Metastases to extrathoracic lymph nodes No distant metastases Hematogenous metastases

From Yamakawa Y, Masaoka A, Hashimoto T, et al: A tentative tumornode-metastasis classification of thymoma. Cancer 68:1984-1987, 1991.

TABLE 131-4 Stage Grouping in the TNM Classification System for Staging of Thymomas Stage

T

N

M

I II III IVa IVb

T1 T2 T3 T4 Any Any

N0 N0 N0 N0 N1-3 Any

M0 M0 M0 M0 M0 M1

From Yamakawa Y, Masaoka A, Hashimoto T, et al: A tentative tumornode-metastasis classification of thymoma. Cancer 68:1984-1987, 1991.

thymic medulla. Type B2 have scattered neoplastic epithelial cells with vesicular nuclei. Type B3 are composed predominantly of epithelial cells exhibiting mild atypia, thus resembling what others have described as well-differentiated thymic carcinoma. Thymic carcinomas are designated as type C tumors. The WHO classification system is becoming more widely adopted, but its clinical relevance, both in terms of predicting clinical course and guiding clinical management, is controversial.13 Studies reporting multivariate analysis of the prognostic value of the WHO system generally demonstrate WHO to be of independent prognostic value, although clearly the most important prognostic factor is the stage. When broken down by WHO subgroup, type C clearly exhibits worse survival and type B3 at least suggests intermediate survival; beyond these two subtypes there are few conclusions that can be drawn with regard to prognosis due to inconsistency across studies (Detterbeck, 2006) (Table 131-5).13 The clinical value of WHO in guiding clinical management is also difficult to define. The role of adjuvant radiotherapy is dictated primarily by the completeness of resection (Detterbeck and Parsons, 2004).14-17 The primary management decisions to be made in patients with thymoma primarily relate to surgical resectability and the utility of preoperative chemotherapy.

1/21/2008 4:09:19 PM

Chapter 131 Thymic Tumors

1591

TABLE 131-5 Survival by Histologic Class of Thymoma % 10-Year Survival WHO 1999

No. Patients

A

AB

B1

Okumura et al31 Rieker et al153 Chen et al44 Wright et al154 Ströbel et al37‡ Rea et al55 Nakagawa et al36 Kim et al155 Kondo et al42

311 218 200 179 179 132 130 108 100

(100)* 76 100 (100)† 100 100 (100)* (100)|| 100

(95)* 100 92 (100)† 100 90 (100)* (74)|| 100

Müller-Hermelink

No. Patients

Medullary

Mixed, Medullary Predominant

135 116

37 53 ——— 100 ———

Wilkins et al34 Quintanilla-Martinez et al39 Pan et al25

112

80

69

B2

B3

C

(96)* (90)* 87 82 90 42 (94)† (91)† 100 79 78 33 (86)* (85)* (100)|| (92)|| –————– 94 ––————

(78)* 76 53 (64)† 68 35 (38)* (83)|| 92

— 20 34 (26)† 67§ 0 — (0)|| 58

Mixed, Cortical Predominant

WDTC

UnTC

— 69 ———— 100 ————

— 54

— —

86

43

—

Cortical

78

Verley

No. Patients

Spindle

Lymphocytic

Epithelial

Undifferentiated

Regnard et al4 Verley and Hollman3

307 200

77 75

68 75

65 50

45 0

Bernatz

No. Patients

Lymphocytic

Epithelial

Mixed

Maggi et al32 Nakahara et al24

169 141

88 88

79 66

55 86

Modified Bernatz

No. Patients

Spindle

Lymphocytic

Mixed

Epithelial

Thymic Carcinoma

Wilkins et al34 Blumberg et al49

136 106

81 (95)¶

74 (77)¶

70 (77)¶

33 (59)¶

— (65)¶

Inclusion criteria: studies from 1980-2002 of ≥100 patients. *Thymoma-specific survival (only deaths from thymoma, treatment, or parathymic syndrome counted). † Disease-free survival (any recurrence counted, whether it caused death or not). ‡ Excluding cases of mixed histology. § Only squamous carcinoma. || Cancer-specific survival (only deaths from thymoma or thymic carcinoma counted). ¶ 5-year survival. UnTC, undifferentiated thymic carcinoma; WDTC, well-differentiated thymic carcinoma.

The WHO subtype is generally not available until after resection. Therefore, most management decisions are made by preoperative assessment of tumor stage and by the completeness of resection and not by the WHO type. Histologically, most thymomas are composed of cytologically bland thymic epithelial cells with a variable admixture of lymphocytes.3,18 There is little cellular atypia, pleomorphism, or presence of mitoses. A small percentage of thymic tumors, however, display mitotic figures and other cytologic features of malignancy.19,20 The distinction between these histologic types of thymomas is probably of greatest importance because the latter consistently exhibits a much more aggressive behavior.19,20 This was first defined by Levine and Rosai in 1978,21 who recognized three types of thymoma:

Ch131-F06861.indd 1591

benign thymomas (cytologically bland and without evidence of gross or microscopic invasion), category I malignant thymomas (cytologically bland but with evidence of invasion), and category II malignant thymomas, commonly referred to as thymic carcinoma (cytologically malignant).11 Because of the consistently poorer prognosis of thymic carcinoma, consideration of this group of tumors as a separate group seems justified. Indeed, most large series have done this.6,18,22-25 The first of these three types of thymic tumors, tumors of the thymus that show no cytologic features of malignancy and show no gross evidence of invasion, have sometimes been called benign thymomas.5,21,26,27 However, despite the indolent behavior of such tumors, recurrences and metastases have been reported in all large series after resection,3,4,28-31

1/21/2008 4:09:19 PM

1592

Section 7 Mediastinum

making this is a misleading term. This is true even for stage I thymomas2-4,18,23,24,29-37 and is true for each histologic subtype of thymoma,3,4,18,24,25,36-38 although several authors have noted that they did not observe recurrences among smaller cohorts of patients with medullary thymomas28,39-41 or type A thymomas (Kondo et al, 2004).31,42-44 Thus, even cytologically bland thymomas have the fundamental characteristics of a malignant tumor, despite a relatively indolent course, and the term benign thymoma needs to be discarded. The second group of thymic tumors, the intermediate group for which some authors have used the term welldifferentiated thymic carcinoma, refers to thymomas that have the organotypical features of thymomas but also have areas of atypia and occasional mitoses (usually <2 per 10 high-power field).39,45,46 Myasthenia gravis (MG) was present in major proportion of these patients in all studies (range, 25%-77%).25,45-47 Variability in how such tumors are classified is reflected by wide variations in the reported survival rates as well as in the incidence of thymic carcinomas, with some authors reporting an incidence of about 30% (range, 18%-41%)25,26,38,39,45,47-49 and others reporting rates below 10%.3,4,27,29 This is also underscored by the presence of tumors that exhibit features of both bland thymomas as well as areas of either well-differentiated or undifferentiated carcinoma.10 In fact, several well-documented cases have been reported in which a cytologically bland thymoma appeared to undergo so-called malignant degeneration, developing an aggressive clinical behavior and now exhibiting features of undifferentiated malignancy.10,50 Thus, while it seems reasonable to consider well-differentiated thymic carcinomas as a distinct group, the criteria and prognosis of this group has not yet been well defined. The consistency of this classification among independent review by different pathologists is very high in one study51 but was found to be problematic in others.52 The third group of thymic tumors is thymic carcinoma. These tumors exhibit distinctly more aggressive behavior. Thymic carcinoma accounts for less than 10% of thymic tumors in most series (Table 131-6). A review in 1990 found 99 reported cases that met this definition.19 These tumors occur in patients of all ages with a slight male predominance,19,20,38,47 are typically not associated with MG,20,31,37,38,4245,47,48,52 but are usually symptomatic because of the extent of local invasion that is usually present.20,45,47 Thymic carcinomas have been divided into subtypes, including squamous cell, mucoepidermoid, basaloid, lymphoepithelioma-like, small cell/neuroendocrine, sarcomatoid, clear cell, and undifferentiated/anaplastic.11,20 In conclusion, multiple methods of histologic classification of thymomas have been proposed but have proven difficult to apply consistently and have generally not been of independent prognostic significance. The value of histologic classification of the large majority of thymomas, which are cytologically bland, is questionable at best. However, the small subset of thymic tumors that have abundant cytologic features of malignancy, called thymic carcinomas, do represent a distinct group with a poor prognosis. So-called well-differentiated thymic carcinomas may have an intermediate prognosis, although the definition and prognosis of this group has not

Ch131-F06861.indd 1592

yet been well characterized. The WHO system may be useful as an independent prognostic factor, but its clinical utility has yet to be established.

Clinical Presentation Symptoms Indolent tumors, such as most thymomas, are usually associated with symptoms that are rather vague and subtle and have been present for a long time. The clinical presentation of patients with a thymoma, taken from the larger studies, is shown in Table 131-7. Approximately one third of patients present with symptoms of MG, consistent with the common association of thymomas with this disease. Another one third of patients are asymptomatic. This proportion of asymptomatic patients has been observed fairly consistently, although two studies18,53 found that about 60% were asymptomatic whereas a lower proportion was reported in studies that included primarily patients with more advanced disease.6,27 Approximately 40% of patients with a thymoma present with local symptoms, related to the intrathoracic mass, whereas approximately 30% have systemic symptoms. However, there is a great deal of variability between studies with respect to the actual percentages. This may be related to how symptoms were defined or whether vague symptoms were counted. In addition, dyspnea can be related to local tumor or can be a systemic manifestation of MG. No details of the definitions used are provided in these studies. Nevertheless, several salient observations can be made. It is clear that chest pain, cough, and dyspnea are the most common symptoms. It is also clear that superior vena cava syndrome and weight loss do occur in a small proportion of patients, although such symptoms are generally associated with more aggressive tumors. Finally, a small proportion of patients present with a fever or night sweats, which are more typically associated with lymphoma.

Age and Sex Distribution Thymomas have been found to occur in patients of all ages, having been reported in children as young as 8 months24 and in patients as old as 90 years.18 The age distribution of patients with a thymoma shows a broad peak between approximately age 35 and age 70 (Fig. 131-1). The reported mean age averages approximately 49 years among studies of 100 or more patients (range of reported mean age, 44-54).4,18,23-25,29,36,43,54,55 A large U.S. population–based analysis found a mean age of 56.56 The reported median age averages approximately 53 years among studies of 100 or more patients (range of reported median age, 45-57 years).6,23,34,49,53,57,58 As a group, patients with MG tend to present at a slightly younger age than patients without MG, but there is broad overlap in the age distributions between these two groups (see Fig. 131-1). The ratio of men to women in series of thymomas is approximately equal. An average of 49% of patients are men among series of 100 or more patients (range, 31%-66%).3,4,6,18,2325,29,34,36,43,49,53,55,57,58 An average of 56% of patients were men in six Asian series,23-25,36,43,53 as opposed to 45% in large North American or European series.3,4,6,18,29,34,49,55,57,58 There are

1/21/2008 4:09:19 PM

Chapter 131 Thymic Tumors

1593

TABLE 131-6 Incidence of Histologic Classes of Thymomas % of All Thymomas WHO 1999

No. Patients

A

AB

B1

B2

B3

C

Ströbel et al37 Okumura et al31 Rieker et al153 Chen et al44 Wright et al154† Park et al43 Rea et al55 Nakagawa et al36 Kim et al155 Kondo et al42

545 311 218 200 179 150 132 130 108 100

8 6 20 4 12 5 11 14 6 8

26 25 9 34 29 17 24 43 23 17

6 18 11 9 15 9 15 12 11 27

19 31 38 20 13 30 21 22 30 8

10 8 5 14 29 17 22 9 19 12

13* 11 18 18 2 22 8 Excluded 11 28

Müller-Hermelink

No. Patients

Medullary

Mixed, Medullary Predominant

Mixed, Cortical Predominant

Cortical

WDTC

UnTC

Kirchner et al45 Venuta et al22 Wilkins et al34 Quintanilla-Martinez et al39 Pan et al25 Elert et al26

155 148 135 116

6 14 12 7

20 32 27 29

8 42 17 –——————– 54 –——————– –———– 54 –———– 2 18 19 26

112 102

22 5

20 3

6 22

Verley

No. Patients

Spindle

Lymphocytic

Epithelial

Undifferentiated

Regnard et al4 Maggi et al29 Verley and Hollman3

307 241 200

22 7 30

25 28 30

45 62 33

8 2 7

Bernatz

No. Patients

Lymphocytic

Mixed

Epithelial

Okumura et al23 Nakahara et al24

194 141

27 26

53 55

20 18

Modified Bernatz

No. Patients

Spindle

Lymphocytic

Mixed

Epithelial

Thymic Carcinoma

Kondo and Monden129 Lewis et al18 Wilkins et al34 Blumberg et al49

1089 283 136 106

4 6 4 23

33 25 19 14

42 43 44 18

21 25 28 5

Excluded Excluded 4 41

41 10

8 Excluded 4 2

11 Excluded ————– 26 ————–

Inclusion criteria: studies from 1980-2002 of ≥100 patients. *Squamous carcinomas only. † Only resected patients included. UnTC, undifferentiated thymic carcinoma; WDTC, well-differentiated thymic carcinoma.

slightly more women than men in the older age groups (Fig. 131-2). This appears to be primarily the result of a slight increase in the proportion of women without myasthenia gravis who are found to have a thymoma among the older age groups (Fig. 131-3). In summary, the most important feature of this demographic analysis is that patients with thymoma are relatively evenly distributed among age cohorts, gender, and the presence of absence of MG. Furthermore, these data do not address the important clinical issue of whether these readily available patient characteristics (age, gender, and the pres-

Ch131-F06861.indd 1593

ence of MG) can be used to make a reliable supposition about the less accessible piece of information, namely, the diagnosis of an anterior mediastinal mass. This issue is addressed in the section on differential diagnosis.

Other Associated Diseases Thymomas have been associated with a large variety of associated conditions, often called parathymic syndromes.59,60 The most common of these is clearly myasthenia gravis, which occurs in approximately 45% (range, 10%-67%) among

1/21/2008 4:09:19 PM

1594

Ch131-F06861.indd 1594

Section 7 Mediastinum

TABLE 131-7 Incidence of Symptoms in Patients With a Thymoma

Study Lewis et al18 Park et al43 Cowen et al6* Wilkins et al34 Blumberg et al49 Quintanilla-Martinez et al39 Ogawa et al53 Elert et al26 Chalabreysse et al38 Wilkins et al94 Moore et al92 Wang et al27† Kaiser and Martini68 Average§

MG

Parathymic

Any Systemic Symptom

Weight Loss

60 26 (19) 32 28 31

— 30 (21) — — 40

— — (1) — — 1

18 — — 36 — 10

103 102 90

63 — 37

32 56 36

1 — 6

85 71 61 59

33 25 (12) 32

38 30 (38) 9

37

34

No. Patients

None

283 150 149 136 118 116

Fever

Other Systemic Symptom

Any Local Symptom

Dyspnea

Hoarse ness

SVC Syndrome

Other Local Symptom

8 — — — — 2

3 — — — — 1

10 — (11) — — 8

37 44 — 24 — 18

17 25 12 — — — ———— (22) —–—— — — — 24 24 22 3 9 5

2 — — — — —

2 — (21) — 5 1

3 — — — — —

— 43 —

— 22 3

— 3 —

— 15 —

7 73 —

— 18 8

— 22 4

— 19 —

— 5 —

— 5 3

— 4 —

2 — — —

— — — —

0 — (18) 5

— — (13) 8

— — (1) —

— — — —

4 — (21) 8

12 20 (46) 24

7 18 (36) 20

— — (7) 2

1 — (1) 0

4 — (20)‡ —

3

27

7

4

11

34

12

18

15

3

2

4

Chest Pain

Inclusion criteria: studies from 1980-2002 of >50 patients reporting specific symptoms. *Series of patients referred for radiation therapy, thus probably biased toward patients with more advanced disease or more local symptoms. † Excluded stage I patients, thus probably biased toward patients with more advanced disease or more local symptoms. ‡ Mostly dysphagia, which may have been related to MG rather than a local effect. § Excluding values in parentheses. MG, myasthenia gravis; SVC, superior vera cava.

Cough

1/21/2008 4:09:19 PM

Chapter 131 Thymic Tumors

250 All patients

No. of Patients

200 150

MG

100 No MG

50

>9 0

70 –7 9 80 –8 9

50 –5 9 60 –6 9

40 –4 9

20 –2 9 30 –3 9

10 –1 9

0– 9

0

Age (years) FIGURE 131-1 Age distribution of patients with thymoma, with and without evidence of myasthenia gravis (MG). Data are taken from all studies of 50 or more patients, reporting patient numbers by decades of age. (DATA FOR ALL PATIENTS ARE TAKEN FROM REFERENCES 2, 3, 5, 18, 28, 102, AND 115; DATA FOR PATIENTS WITH MG TAKEN FROM REFERENCES 3, 18, 64, 66, 69, AND 115; AND DATA FOR PATIENTS WITHOUT MG TAKEN FROM REFERENCES 3, 18, AND 115.)

250 All patients

No. of Patients

200 150

Women

100

Men

50

>9 0

70 –7 9 80 –8 9

50 –5 9 60 –6 9

40 –4 9

20 –2 9 30 –3 9

10 –1 9

0– 9

0

Age (years) FIGURE 131-2 Age distribution of patients with thymoma by gender. Data are taken from all studies of 50 or more patients, reporting patient numbers by decades of age. (DATA FOR ALL PATIENTS TAKEN FROM REFERENCES 2, 3, 5, 18, 28, 102, AND 115; DATA FOR PATIENTS BY GENDER TAKEN FROM REFERENCES 3, 5, 18, 102, AND 115.)

60

No. of Patients

With MG Men

40

No MG

Women

Women 20

Men

>9 0

70 –7 9 80 –8 9

50 –5 9 60 –6 9

40 –4 9

20 –2 9 30 –3 9

10 –1 9

0– 9

0

Age (years) FIGURE 131-3 Age distribution of patients with thymoma by gender and with and without evidence of myasthenia gravis (MG). Data are taken from all studies of 50 or more patients, reporting patient numbers by decades of age. (DATA FOR PATIENTS WITH MG TAKEN FROM REFERENCES 3, 64, 69, AND 115; DATA FOR PATIENTS WITHOUT MG TAKEN FROM REFERENCES 3 AND 115.)

Ch131-F06861.indd 1595

1595

larger studies, as shown in Table 131-8. The average proportion is 40% if studies originating from referral centers for MG are excluded.4,23,24,29 Conversely, 10% to 15% of patients with MG are found to have a thymoma,60-62 although among patients with MG who undergo thymectomy, approximately 25% have a thymoma in large series (range, 18%39%).29,33,61,63-66 MG is widely recognized to be an autoimmune disease, characterized in most patients by antibodies that cross react between the thymus and the acetylcholine receptor in the neuromuscular end plate.62 However, it is unclear how a thymoma causes MG or vice versa.62 Most of the conditions other than MG that are associated with thymomas are also widely recognized to be autoimmune processes. Most reports have found such conditions in approximately 6% of patients with thymomas (see Table 131-8). However, one review of 598 patients that focused specifically on parathymic conditions found that 43% of patients had parathymic conditions other than MG (Table 131-9).59 However, this report also included other cancers (occurring in 12%) as an associated condition, as opposed to all other studies. Furthermore, the most common associated conditions besides MG were rather vaguely termed cytopenias. If these are also excluded, the incidence of associated conditions in this review is 13%, which is more in line with all other reports. Nevertheless, the proportion of patients with specific associated conditions in this one report (see Table 131-9) remains approximately twice as high as the proportion listed in other studies.18,25,49,67,68 It is unclear whether this one report represents an overestimation because of overly broad definitions or whether other reports represent an underestimation because other conditions were not carefully sought out and recorded. The truth may well lie somewhere in between. Many studies have noted a higher than expected incidence of second primary malignancies in patients with a thymoma (average, 15%; range, 9%-27%).34,49,56,59,69-73 The consistency of this observation leaves little doubt that the association is real. Furthermore, the observed ratio of other malignancies is higher than what would be predicted for similar populations.69,70 The mechanism behind the association of thymomas and other primary malignancies is unclear.69 Often, the other primary malignancy was present before or at the time of diagnosis of the thymoma.34 Pure red cell aplasia and hypogammaglobulinemia are the conditions other than MG and other primary cancers that are most clearly linked to thymoma.74 They also represent the next most common associated conditions, with pure red cell aplasia occurring in 2% to 5%,18,25,34,38,49,55,60,67 and hypogammaglobulinemia also occurring in 2% to 5%.18,25,38,49,55,59,60 In fact, it has been frequently stated that approximately 50% of patients with pure red cell aplasia are found to have a thymoma whereas only 10% of those with hypogammaglobulinemia have a thymoma.60,74,75 Patients with red cell aplasia and thymoma are a bit older than patients with a thymoma in general (mean age, 60 years), and women are slightly more commonly affected than men.76-78 The average age of patients with hypogammaglobulinemia and thymoma is 50.79 Although the link between thymomas and pure red cell aplasia or hypogammaglobulinemia is well accepted, the mechanism of

1/21/2008 4:09:19 PM

1596

Section 7 Mediastinum

TABLE 131-8 Autoimmune Diseases Associated With Thymoma Incidence (%)

10-Year Survival (%)

Study

No. Patients

MG

Other AI

No AI

Kondo and Monden129 Rosenow et al60* Souadjian et al59* Regnard et al4 Lewis et al18 Levasseur66 Maggi et al29 Rieker et al153 Chen et al44 Verley and Hollman3 Okumura et al23 Wright et al154 Nakahara et al24 Bernatz et al54 Wilkins et al34 Rea et al55 Nakagawa et al36 Blumberg et al49 Quintanilla-Martinez et al39 Ogawa et al53 Curran et al57

1089 960 598 307 283 255 241 218 200 200 194 179 141 138 136 132 130 118 116 103 103

25 35 31 64‡ 46 61 66‡ 26 15 53 56‡ 30 57‡ 46 40 17 12 10 41 32 36

4 5 28† 6 10 6 6 8 — 7 7 1 5 2 3 8 0 10 1 1 6

— — — — — — 62 70 55§ 49§ — — 67§ 82|| — — — — 62 67§ (82)¶ (91)¶ — — — — — — 49§ 70 — — — — ———— 57 ———— — — — — — —

— — — 74 — — 25|| — — — — — — — — — — 24|| — — —

59

—

Average**

38

6.2††

MG

Other AI

68

Inclusion criteria: studies from 1980-2002 of ≥100 patients. *Review of other publications. † 13% if “cytopenias” (not further defined) are excluded. ‡ Referral center for MG. § Includes patients with other autoimmune diseases. || P ≤ .05 versus result with no AI. ¶ Cancer specific survival. **Excluding values in parentheses. †† Average 5.1% if cytopenias are excluded from the Souadjian et al study. AI, autoimmune disease; MG, myasthenia gravis.

TABLE 131-9 Parathymic Syndromes in Patients With a Thymoma Condition

% Incidence*

Condition

% Incidence*

Myasthenia gravis Cytopenias Hypogammaglobulinemia Polymyositis Systemic lupus erythematosus Rheumatoid arthritis Thyroiditis Sjögren’s syndrome Chronic ulcerative colitis Pernicious anemia

31 15 4.5 3.3 1.2 0.8 0.8 0.7 0.3 0.2

Raynaud’s disease Regional enteritis Dermatomyositis Scleroderma Takayasu’s syndrome Cushing’s disease Hyperthyroidism Addison’s disease Macrogenitosomia praecox Panhypopituitarism

0.2 0.2 0.2 0.2 0.2 2 0.8 0.2 0.2 0.2

Inclusion criteria: associated conditions listed in a review of 598 patients with thymoma by Souadjian et al.59 *Percentage of all patients with thymoma.

the association remains an enigma. Other conditions, listed in Table 131-9, are less common in patients with thymoma and are frequently found in patients without thymoma, making the link between these diseases less convincing.74 Approximately one third of patients with a thymoma and a parathymic syndrome (other than MG) will have more than one associated condition.74,76-79

Ch131-F06861.indd 1596

Diagnosis Radiographic Appearance Thymomas are located in the anterior mediastinum. In reviews of patients with myasthenia gravis, the sensitivity of chest radiography in demonstrating these tumors is variable (50%-94%),80,81 whereas CT reliably demonstrates these

1/21/2008 4:09:20 PM

Chapter 131 Thymic Tumors

tumors (sensitivity of 97%).82 They typically appear as a welldefined, round or oval mass.83 They are generally anterior to the great vessels and the heart, but many larger thymomas drape around the great vessels toward either the right or left pulmonary hilum.84 Calcification may be seen in 10% to 20% of patients and is typically curvilinear.80,81,83,85 Extension of the thymoma into the mediastinal fat or lung may be suggested by CT, but the reliability of this finding has not been well studied. The available data suggest that this radiographic observation is not reliable enough to be useful. In a small series of 15 patients with a thymoma in which the fat planes between the tumor and adjacent structures were only partially preserved, the sensitivity of this finding in demonstrating invasion was only 53%.82 Another study found that the impression of invasion into adjacent structures carried a false-positive rate of 20% (1 of 5), and the impression of an absence of invasion had a false-negative rate of 7% (1 of 15).86 Radiographic differentiation between thymoma and thymic carcinoma has been addressed in one study of 53 patients.85 The CT characteristics that were most helpful in predicting that a thymic tumor is not a well-differentiated or undifferentiated thymic carcinoma were the following: ■

■ ■

A smooth or lobulated contour (not irregular; falsepositive rate [FP] 13%, false-negative rate [FN] 41%, sensitivity 89%, specificity 54%) Homogeneous enhancement (FP 6%, FN 51%, sensitivity 74%, specificity 83%) The absence of any areas of low attenuation (FP 13%, FN 65%, sensitivity 63%, specificity 67%)

The characteristics that best predicted the presence of either a routine thymoma or a well-differentiated thymic carcinoma (and not an undifferentiated thymic carcinoma) were the following85: ■ ■ ■ ■ ■

A smooth or lobulated contour (FP 5%, FN 45%, sensitivity 88%, specificity 75%) Homogeneous enhancement (FP 3%, FN 65%, sensitivity 70%, specificity 88%) The absence of any areas of low attenuation (FP 10%, FN 78%, sensitivity 60%, specificity 63%) The absence of a pleural or pericardial effusion (FP 5%, FN 33%, sensitivity 93%, specificity 75%) The absence of any calcification (FP 3%, FN 78%, sensitivity 98%, specificity 45%)

Differential Diagnosis In a series of anterior mediastinal tumors, thymomas make up the largest category, accounting for approximately 50% of anterior mediastinal masses.87-89 Lymphoma accounts for approximately 25% of anterior mediastinal masses, with Hodgkin’s lymphoma being more common than nonHodgkin’s lymphoma.87-89 Approximately 20% of anterior mediastinal masses are classified as germ cell tumors. Most (~80%) of the germ cell tumors are benign teratomas (dermoid cysts are included in this category), with the rest

Ch131-F06861.indd 1597

1597

being either primary mediastinal seminomas or malignant nonseminomatous teratomas (including choriocarcinoma, yolk sac carcinoma, embryonal cell carcinoma, and teratocarcinoma).88 The remainder of mediastinal tumors consist of duplication cysts, thyroid goiters, parathyroid adenomas, and a variety of other tumors.87-89 Many of the tumors that occur in the anterior mediastinum can be easily recognized because of characteristic features. The radiographic appearance of teratomas is often quite characteristic, with cystic areas and mixed areas of calcification and fat.83 Thyroid masses are also generally easily and reliably recognized by a characteristic radiographic appearance (high density), continuity with the thyroid gland, and extension posterior to the great vessels.83 In rare instances, iodine-133 scintigraphy can be useful, although it must be remembered that an 133I scan is likely to have decreased sensitivity when performed within approximately 4 weeks of a CT scan involving iodinated contrast.90 A mediastinal parathyroid adenoma is almost invariably discovered on the basis of an elevated parathyroid hormone (PTH) level. Over 90% of nonseminomatous germ cell tumors have elevated blood levels of αfetoprotein (α-FP), β-human chorionic gonadotropin (β-hCG), or PTH.87 However, this is not true of seminomas, which are seen almost exclusively in young men (ages 20-35 years). The main difficulty in the differential diagnosis of mediastinal masses is in differentiating a thymoma from a lymphoma. Lymphomas are often associated with typical symptoms, such as fevers and night sweats, and there is a rapid progression of symptoms. The presence of an associated autoimmune syndrome such as myasthenia gravis, pure red cell aplasia, or hypogammaglobulinemia reliably implies that an anterior mediastinal mass is a thymoma. However, in the absence of symptoms typical for lymphoma or thymoma it can be difficult to make a reliable presumptive diagnosis. Thymoma accounts for approximately 5% of anterior mediastinal masses in men and women ages 10 to 19, 15% for those aged 20 to 29, 30% for ages 30 to 39, and over 50% for those older than age 40. In contrast, lymphoma accounts for nearly 50% of anterior mediastinal masses in women aged 10 to 39 and only about 5% for those older than age 40. In men, lymphoma and malignant germ cell tumors each account for approximately 25% of anterior mediastinal masses in ages 10 to 39 and for approximately 10% and 2% when older than age 40, respectively. The radiographic presentation of mediastinal lymphomas is usually one of enlargement of multiple lymph nodes, including paratracheal, subcarinal, hilar, and periesophageal nodes, which is not consistent with a diagnosis of thymoma.83 In an asymptomatic patient with an anterior mediastinal mass with ambiguous radiographic features, an open biopsy may be required. Although a needle biopsy may be successful in diagnosing a thymoma, it is usually insufficient to define the subtype of lymphoma. Reports of a high diagnostic yield of needle biopsy for lymphoma have generally involved specific types of lymphoma such as lymphoblastic lymphoma or have involved many patients in whom the needle biopsy was used simply to diagnose recurrence of a lymphoma, when definition of the subtype was not needed.

1/21/2008 4:09:20 PM

1598

Section 7 Mediastinum

Pathologic Diagnosis In many instances, a clinical diagnosis of thymoma is sufficient. For example, if a patient has an anterior mediastinal mass and MG or one of the autoimmune diseases associated with thymoma, a diagnosis of thymoma is quite certain. Furthermore, it is not necessary to establish a preoperative diagnosis of a small, resectable tumor in the anterior mediastinum with a radiographic picture typical of a thymoma. Such a tumor is approached with surgical resection, and the rate of achieving a complete resection is very high (see discussion of resectability rates in the section on surgical treatment). A definitive diagnosis is needed primarily when a presumed thymoma is so extensive that it is thought best treated with a nonoperative approach or with preoperative chemoradiotherapy, or in instances when lymphoma is considered to be a strong possibility. Pathologic confirmation of the diagnosis of thymoma can be achieved from fine-needle aspiration (FNA) or via an open surgical biopsy (anterior parasternal mediastinotomy or, occasionally, thoracoscopy). The success rate of FNA in establishing the diagnosis is reported to be approximately 62% (range, 59%-71%) in four series involving 34, 28, 22, and 19 patients with thymoma who underwent FNA.49,91-93 It appears that in many of these cases, a core biopsy or multiple passes were carried out to have an adequate sample of tissue. In one of the more detailed studies, an FNA had a sensitivity of 71%, a specificity of 94%, a false-positive rate of 23%, and a falsenegative rate of 8%.91 The success rate of an open surgical biopsy in establishing the diagnosis is reported to be approximately 90% (range, 81%-94%) in two series involving 26 and 17 patients.49,93 The reliability of establishing the histologic subtype of thymoma from a limited biopsy may be difficult because of the characteristic variability in morphologic appearance within a thymoma. However, the histologic subtype is of questionable value in determining optimal therapy (see the sections on histologic classification and prognostic factors). There exists a widespread dogma that biopsy of a presumed thymoma should not be undertaken because it risks spreading the tumor into the pleural space or the needle tract or biopsy site.94 However, there are only a few anecdotal cases of recurrence at the site of a needle tract95-97 or at the thoracotomy site used for resection,93,98,99 and generally these recurrences were widespread, involving other sites as well. Investigators of a large series of 136 patients found that there was a trend to better survival in those patients who underwent a pre-resection biopsy by multivariate analysis (P = .056).34 The concern over pleural dissemination presumably stems from the observation that resected thymomas frequently recur as nodules throughout the parietal pleura.100 However, this pattern of spread appears to be characteristic of thymoma itself rather than related to an operative procedure because pleural nodules are also common (68%) in patients who present with advanced tumors and who have never undergone a biopsy.2,7,22,24,29,49,94 Furthermore, it is standard policy to obtain a biopsy in cases of larger tumors suspected to be a thymoma in many centers with extensive experience in thymoma.22,29,41,49,68,92,93

Ch131-F06861.indd 1598

Natural History and Disease Course The prognosis without treatment (i.e., natural history) of patients with a thymoma has not been well studied. Most often, patients present with a localized (albeit often locally invasive) tumor confined to the anterior mediastinum (see section on stage at presentation). The stage distribution among larger series is shown in Table 131-10. It can be seen that at presentation approximately 40% of thymomas are stage I, 25% each are stage II or stage III, 10% are stage IVa, and only 1% to 2% are stage IVb. The clinical progression of disease appears to be rather indolent in most cases. In 31 patients in whom prior films were available, 77% demonstrated a thymoma 1 to 26 years previously (mean, 6 years).101 However, in this series, 23% had no radiographic evidence of tumor 2 to 6 years previously, indicating that, at least in some cases, progression can be more rapid.101 The indolent course is also corroborated by the long interval to recurrence (1-32 years, average 5 years) among treated patients who develop further manifestations of disease (see surgery section) (Table 131-11). Although thymomas are generally indolent tumors that spread most commonly by local extension (including pleural and pericardial implants in 10%), they do have the ability to metastasize to distant sites. Among 383 cases reported in the Japanese literature, 3% had nodal metastases and 6% had distant metastases.7 A study of metastases revealed that 4% of 207 patients referred to a surgery clinic had lymph node or distant metastases at the time of presentation, and another 16% developed lymph node or distant metastases during the course of their disease.7 Of those who developed metastases, nodes were involved in 14% of patients, pleural or pericardial metastases in 56%, and distant sites in 31%.7 The distant sites involved lung (1/3); liver (1/3); bone (1/6); and kidney; brain, or bone marrow (1/6).7 These findings are corroborated by a series of 149 patients undergoing radiotherapy for (higher stage) thymomas, in which 17% developed metastases (including lung, liver, bone, adrenals, kidney, nodes, skin, and central nervous system).6 Among each stage at presentation (including stage I) some patients subsequently developed distant metastases in a classic study of 200 patients by Verley and Hollman,3 and this has been confirmed by others.30 Several small series of patients with distant metastases further confirm that thymomas can exhibit the classic characteristic of malignancies, despite a generally protracted course.18,32,102-104

Treatment Surgery Several large series of surgical resection for thymoma have been reported. In interpreting these data, however, it is important to note that these series all span many decades and many include patients undergoing resection as long ago as the 1950s and earlier.3,4,23,24,26,29,39,49 During this span of time, surgical care and anesthetic management have improved considerably. More extensive resection, such as that of the superior vena cava, became more common in the 1980s and 1990s.4,24,105,106 On the other hand, series that report on patients treated only in recent periods often suffer from short

1/21/2008 4:09:20 PM

Chapter 131 Thymic Tumors

1599

TABLE 131-10 Stage at Presentation Masaoka Stage Study

No. Patients

Years Included

I

II

III

Kondo and Monden129 Regnard et al4 Okumura et al31* Maggi et al29 Rieker et al153 Verley and Hollman3 Chen et al44 Wright et al154† Ströbel et al37 Park et al43 Venuta et al22*† Nakahara et al24* Wilkins et al34 Nakagawa et al36 Monden et al33* Wang et al27 Blumberg et al49 Quintanilla-Martinez et al39 Pan et al25* Myojin et al58 Crucitti et al63*‡ Elert et al26 Kondo et al42

1089 307 273 241 218 200 200 179 179 150 148 141 136 130 127 119 118 116 112 111 103 102 100

90-94 55-93 57-00 59-88 67-98 55-82 69-96 72-03 — 92-02 65-96 57-85 57-97 62-00 — 61-88 49-93 39-90 61-91 75-93 69-89 57-87 73-01

49 44 45 55 43 67 48 36 28 35 28 32 36 31 30 49 21 45 45 30 41 39 36

22 23 26 14 21 18 13 33 41 26 31 23 22 42 25 4 35 28 21 39 48 32 26

19 7 3 27 ——— 6 ——— 23 4 2 22 9 — 16 8 12 ——– 15 ——– 1 32 ——— 7 ——— 25 6 — 23 5 2 13 15 11 26 15 — 34 9 2 31 ——— 4 ——— 19 7 1 35 9 2 34 7 3 36 8 0 24 4 0 24 ——— 11 ——— 29 3 0 9 3 0 24 5 0 17 6 15

40

27

25

Average

IVa

7

IVb

4

Inclusion criteria: studies from 1980-2002 of ≥100 patients with a thymoma seen at an institution. *Thymic carcinoma excluded. † Patients who had biopsy only and patients with stage IVb were excluded. ‡ All patients had myasthenia gravis.

follow-up times (<10 years), which is of particular significance in an indolent tumor such as a thymoma.22,94 Technical Issues. Surgical resection has been the mainstay of treatment of thymomas because these tumors remain localized in the vast majority of cases (90%-95%).7 What has become clear based on the evaluation of prognostic factors for thymomas is that the achievement of a complete resection for thymoma is paramount. Having said this, the resectability rate, defined as the ability to carry out a grossly and microscopically complete resection, varies with the stage of the thymoma, and often with the willingness of the individual surgeon to perform an extended resection (i.e., incorporating mediastinal structures) when needed to achieve a complete resection. Resectability rates are uniformly high in patients with stage I thymomas and high in most reports in patients with stage II thymomas as well (Table 131-12). Approximately half of patients with stage III and only about a fourth of patients with stage IV tumors can be completely resected on average. However, there is wide variation in the reported resectability rates between studies in patients with higherstage thymomas (from 43%-100% for stage II, 0%-89% for stage III, and 0%-78% for stage IV). It is not clear why this is the case. The most likely explanation appears to be differences in philosophy about the role of subtotal resection between different centers and the willingness of surgeons to undertake more extensive operations (e.g., resection of the

Ch131-F06861.indd 1599

superior vena cava). The incidence of involvement of mediastinal structures in recent studies can be seen in Table 131-13. An extended resection including even the aortic arch and main pulmonary artery has been reported.107 Additionally, there are variations in philosophy regarding the necessity of performing a complete thymectomy for thymoma. There is extensive literature espousing complete resection of the entire thymus and perithymic fat in patients undergoing surgery for MG. Many centers with a large experience with thymomas recommend that a complete thymectomy be done even in non-MG patients, and even if only a portion of the thymus is involved with a thymoma.4,24,26,27,29,63,94,108 However, there are little data to either substantiate or refute this. A second small thymoma was found in 3% of 264 patients undergoing thymectomy for thymoma in one large study.4 The occasional occurrence of multicentric thymomas has been corroborated in several other studies.54,66,80,108 In addition, anecdotal cases of occurrence of MG several years after incomplete thymectomy in previously asymptomatic patients have been reported,5,108-111 although it is not clear that this can be prevented by a complete thymectomy. Better survival after complete thymectomy (n = 16) compared with tumor resection alone (n = 18) was suggested in one study that has analyzed this (5-year survival 92% versus 59%, P < .05 at that point in time; 10year survival 47% versus 44%).27 However, another study

1/21/2008 4:09:20 PM

1600

Section 7 Mediastinum

TABLE 131-11 Cause of Death in Patients With a Thymoma % of All Deaths

Study Regnard et al4 Lewis et al18* Maggi et al29 Rieker et al153 Verley and Monden3 Okumura et al23* Maggi et al32 Wright et al154 Park et al43 Cowen et al6*§ Nakahara et al24* Wilkins et al34 Nakagawa et al36 Monden et al33* Kim et al155 QuintanillaMartinez et al39 Ogawa53*

% Stage I

Thymoma

Unknown

Postop

MG

85 83 88 77 —

44 67 55 43 67

35 23 25 53 22

5 7 — 0 0

8 3 13 4 12

—– 25 —– 28 — 27 19 7 1 19 6

57-96 56-84 72-03 92-02 79-90 57-85 57-97 62-00 — 92-02 39-90

89 87 90 69 42 80 68 95 80 82 94

40 64 36 35 3 32 36 31 30 47 45

48 19 21 87 76 58 32 33 56 70 22

— — 18 — 34†‡ † 14 19 33 2 31† — 3 — — 24 0 0 0 0 13 ——————————– 24 –—————————– 0 2 25 8 8 8 ——————— 60 ——————— 6 ——————— 61 ——————— 0 —¶ 25 — 19 ——————————– 30 –—————————– 6 9 16 — 47

79-98

100

17

66

—

—

10

—

24

44

4

7

19

6

27

No. Patients

No. Deaths

Years Included

307 283 241 218 200

92 163 52 70 67

22-93 41-81 59-88 67-98 55-82

194 165 179 150 149 141 136 130 127 108 116

66 42 67 51 62 40 60 33 36 20 32

103

21

% R0

Average

Autoimm Disease

Unrel to Thym 27 37 17 34 40

Inclusion criteria: results of studies from 1980-2002 of ≥100 patients. *Thymic carcinoma excluded. † Includes postoperative deaths. ‡ Includes autoimmune deaths. § Radiotherapy series, including higher proportion of advanced stages. ¶ Postoperative deaths excluded. MG, myasthenia gravis.

TABLE 131-12 Rate of Complete Resection of a Thymoma by Stage Stage Study

No. Patients

I

II

III

IVa

Regnard et al4 Okumura et al23* Nakahara et al24* Blumberg et al49 Kondo et al42 Curran et al57* Masaoka et al2* Gamondès et al5* Kaiser et al68

307 194 141 118 100 99 96 65 59

100 100 100 100 100 100 100 100 100

100 100 100 73 100 100 100 43 63

50 89 73 56 72 20 64 0 21

—– 63 —– 0 0 —— 0 —— 78 — 50 47 — — 0 (0)† —– 13 —– — —

100

87

49

—– 25 —–

Average‡

IVb

Inclusion criteria: studies of ≥50 patients reporting stage-specific resectability rates in patients undergoing primary surgery. *Thymic carcinoma excluded. † <5 patients. ‡ Excluding values in parentheses.

suggested no difference in survival after complete thymectomy (n = 71) compared with tumor resection alone (n = 55).36 Most institutions with experience in this field favor a sternotomy as the optimal incision in patients with a thy-

Ch131-F06861.indd 1600

moma,4,26,27,29,63,92,94,108 with few exceptions.49,55,68 This is consistent with the recommendation for complete thymectomy because it is difficult to perform a complete thymectomy through a thoracotomy or through a minimally invasive video-assisted thorascopic surgical approach.94 Incisions other than a complete median sternotomy are occasionally used, including a transcervical approach61,65,112 or an upper median partial sternotomy.113,114 Operative Mortality. The reported operative mortality in a series of more than 100 patients is an average of 2.2% (range, 0%-4.9%).4,18,24,26,29,32,49,55,63 Several studies have shown that the mortality rates have decreased,63,115 and several series of 50 to 100 patients treated more recently have reported an operative mortality of 0% to 1%.22,55,63,92,94 The incidence of complications after surgery for thymoma has been reported to be approximately 20% (range, 7%-32%).4,18,26,27,55,92 Approximately two thirds of the complications involved pneumonia, respiratory insufficiency, and exacerbation of myasthenia. Other complications included wound infection, atrial arrhythmias, pulmonary embolism, and bleeding.4,26,27,55,92 Survival After Surgical Resection. Overall survival of surgical series of 100 or more patients with thymoma is shown in Table 131-14. The 5-year survival rates are quite good, even for patients with stage III and IV disease. The 10-year survival rates are approximately 90% and 70% for stage I and

1/21/2008 4:09:20 PM

Chapter 131 Thymic Tumors

1601

TABLE 131-13 Incidence of Extension of Thymomas to Adjacent Structures % of Patients With Extension Study

No. (Total)

No. With Extension

Pleura

Pericardium

Lung

Phr N

Inn V

Regnard et al4 Okumura et al23* Blumberg et al49 Wang et al27 Elert et al26 Masaoka et al2* Venuta et al22* Arriagada et al156

307 194 118 119 102 96 65 56

— 113 79 61 32 — 12 56

78 88 61 36 63 — — 75

45 38 57 41 53 22 42 45

30 49 23 39 28 40 58 45

30 — 27 13 19 — 33 5

——– 27 –—— — — ———————– 27 ——————– ———————– 33 ——————– 13 20 17 13 13 3 0 0 ——– 36 ——– — — 17 33 17 17 ———— 51 ———— 6

67

43

39

21

——– 32 ——–

Average

SVC

Ao/PA

Chest Wall

11

9

Inclusion criteria: studies from 1980-2002 of >50 patients reporting on sites of extension to other structures. *Thymic carcinoma excluded. Ao/PA, aorta or pulmonary artery; Inn V, innominate vein; Phr N, phrenic nerve; SVC, superior vena cava.

TABLE 131-14 Overall Survival After Resection of a Thymoma Treatment (%)

5-Year Survival (%)

10-Year Survival (%)

Study

No. Patients

Years Included

R0

Ch

RT

I

II

III

Overall Survival Regnard et al4 Maggi et al29 Verley et al3 Chen et al44 Ströbel et al37 Park et al43 Nakahara et al24* Wilkins et al34 Blumberg et al49 Quintanilla-Martinez et al39 Pan et al25* Ogawa et al53* Elert et al26 Kondo et al42

307 241 200 200 179 150 141 136 118 116 112 103 102 100

55-93 59-88 55-82 69-96 — 92-02 57-85 57-97 49-93 39-90 61-91 79-98 57-87 73-01

85 88 — — 77¶ 69 80 68 73 94 80 100 — 84

6 — Few 4 12 — Few 7 32 1 — — — 28

52 — Most 28 25 — 84 37 58 26 — 100 — 37

89 89 85 97 100 100 100 84 95 100 94 100 83 100

87 71 60 94 100 88 92 66 70 100 85 90 90 100

68 66 72 59 ——— 33 ——— 53 24 87 66 63 23 88 47† 63 40 50 100 70 (70)§ 63 41 56 — 46 —§ 69 57†

91

80

Average|| Disease-Free Survival Okumura et al31* Regnard et al4 Wright et al154 Cowen et al6*†† Quintanilla-Martinez et al39 Kim et al155 Kondo et al42 Average

273 260 179 149 105 108 100

57-00 55-93 72-03 79-90 39-90 92-02 73-01

95 100 90 42 100 82 84

10¶ 6¶ — 50 1 16 28

60¶ 52¶ — 100 26 44 37

99** 99** 87 84 100 100 —— 92‡‡ —— 100 95 100 91 100 94 98

94

65 97** 79 78 75/54‡‡ 70 74 56 73

IVa

59 60** 60 57 48 —§ — 21† 49

I

II

III

80 87 80 90 100 — 100 75 86 100 87 100 — 100

78 60 42 82 91 — 84 50 54 100 69 90 — 100

47 30 64 40 —–— 23 –—— 37 — 84 47 — — 77 47† 44 40 26‡ — 60 (0)§ 58 22 48 — — — 69 —

87

67

99 94 77 76 100 100 — 75‡‡ — 100 90 95 81 94 84 94

88

IVa

54

36

90 49 60 74/38‡‡ 50 46 44

33 42 24¶ 34 —§ — —

56

33

Inclusion criteria: results of ≥100 patients, with results by Masaoka stage. *Thymic carcinoma excluded. † Stage IVa, IVb. ‡ Nine-year survival data. § <5 patients. || Excluding values in parentheses. ¶ Estimated, not specifically reported. **Based on an earlier report.23 †† Radiotherapy series, including higher proportion of advanced stages. ‡‡ Reported by GETT staging; GETT stage Ia, Ib corresponds to Masaoka I, II; GETT stage II, IIIa, IIIb corresponds to Masaoka stage III; GETT stage IVa, IVb corresponds to Masaoka stage IVa, IVb. Ch, chemotherapy; R0, complete resection; RT, radiotherapy.

Ch131-F06861.indd 1601

1/21/2008 4:09:21 PM

Section 7 Mediastinum

II, and 55% and 35% for stage III and IVa. Overall survival rates at 15 years for stage I, II, III, and IV disease are reported as 78%, 73%, 30%, and 8%, respectively.4 Representative survival curves from one of the largest studies are shown in Figures 131-4 and 131-5. It is important to note that not all patients with stage III or IV thymomas underwent a complete resection. These survival rates include patients undergoing a partial resection. Furthermore, it is also likely that those patients with more advanced disease who were included in surgical series represent a selected subset. No data are available regarding the selection criteria or the proportion of all patients with stage III or stage IV disease who underwent surgery.

()

Patients at risk Stage I (n = 135) ] NS Stage II (n = 70) ] P < .001 Stage III (n = 83) ] NS Stage IV (n = 19)

Survival Rate (%)

100 80

80% (62)

78% (11)

78% (16)

73% (30)

60 47% (16) 40

30% (5)

20

30% (6) 8% (2)

0 1

2

3

4

5

6

7

8 9 10 11 12 13 14 15 Years

FIGURE 131-4 Overall survival according to Masaoka stage.4

Stage I (n = 78)

Survival Rate (%)

100 Stage II (n = 44)

80

Significantly better survival has been noted in patients who underwent complete resection by every large study examining this issue.4,18,23,24,29,31,32,34,49,55,58 Only one study has analyzed survival of each stage separately for patients who have had complete and incomplete resection.24 The survival curves are shown in Figure 131-6. These data are corroborated by another study, which analyzed the survival of only those patients who underwent complete resection of the tumor in each stage.4 In this study, the 10-year survival of patients with complete resection was 80%, 78%, 75%, and 42% for stages I, II, III, and IVa, respectively.4 Other studies have also demonstrated good survival after complete resection in patients with a stage III or IV thymoma.106 It is remarkable that the long-term survival of patients with a stage III thymoma is similar to that of those with a stage I thymoma, provided a complete resection was able to be performed. These findings imply that the ability to carry out a complete resection may be the most important factor. This was also noted in a multivariate analysis of 307 patients, in which a complete resection was the only significant prognostic factor (stage was not significant if completeness of resection was included in the model; see section on multivariate analysis).4 Recurrence Rates and Patterns. The rate of recurrence is a better measure of outcome after treatment of thymoma than overall survival, given the indolent behavior of many of these tumors. Recurrence rates from larger series are shown in Table 131-15. Average recurrence rates are low for Masaoka stage I tumors (3%) but increase progressively to 16% and 26% for stage II and III tumors. The recurrence rate for stage IV tumors shows wide variability. This likely reflects variability in which patients are included in the studies as well as the inclusion of only a small number of patients in these reports. In general, recurrence rates are reported only for those patients in whom at least all of the gross tumor was removed. The indolent behavior of thymic tumors is demonstrated by the average time to recurrence of approximately 5 years (range, 3-7 years).4,18,29,30,34,49 The length of time until a recurrence is seen ranges from 3 to 4 months18,30,49 to 10 to 15 years in most studies.4,29,30,34,49 However, recurrences have

Stage III (n = 56)

60

100 40

P < .0001

20 0 0

10

20 Years

30

No. of Patients at Risk Stage I Stage II Stage III Stage IVa

40 24 32 3

15 5 7 1

Ch131-F06861.indd 1602

40

IV, subtotal

50

III, subtotal III, IV biopsy

3 1

FIGURE 131-5 Disease-specific survival according to Masaoka stage.23

I, complete

II, complete

Stage IVa (n = 10)

Stage IVb (n = 6)

III, complete

Survival Rate (%)

1602

0

5

10

15

Years FIGURE 131-6 Overall survival of patients with thymoma by Masaoka stage and by completeness of resection.24

1/21/2008 4:09:21 PM

Chapter 131 Thymic Tumors

1603

TABLE 131-15 Recurrence Rates After Treatment of a Thymoma Treatment

% With Recurrence

Study

No. Patients

% R0

Ch

RT

I

II

III

Kondo and Monden129 Regnard et al4 Maggi et al29 Verley and Hollman3 Wright et al154 Ströbel et al37 Cowen et al6†‡§ Wilkins et al34 Nakagawa et al36§ Monden et al33§ Blumberg et al49 Ruffini et al30 Quintanilla-Martinez et al39 Ogawa et al53†§ Kondo et al42

1089 307 241 200 179 179 149 136 130 127 118 114 105 103 100

(98)# 85 88 — 90 77* 42 68 95 80 73 100 100 100 84

8 6* 7 Few — 12 100 7 4 — 32 — 0 — 28

29 52* 12 Most — 25 50 37 5 74 58 25 24 100 37

1 4 2 6 0 2 (0)¶|| 8 3 3 4 5 0 0 3

4 7 13 36 2 3 7 10 2 13 21 10 13¶ 10 8

27 39†† 16 58 30 25 –—— 38 –—— 31 45 27 — 23 25 24 (0)|| 28 27 27 54 47 80 30 33 13 (0)|| 44 — 50 (67)||

3

11

30

Average**

IVa

43

Inclusion criteria: studies from 1980-2002 of ≥100 patients, with results by Masaoka stage. *Estimated, not specifically reported. † Radiotherapy series, including higher proportion of advanced stages. ‡ Excluding mediastinal only recurrences. § Thymic carcinoma excluded. || <5 patients. ¶ 19% and 6% for IIa and IIb. **Excluding values in parentheses. †† IVa and IVb, R0, 1 resection. # Complete or microscoprcally incomplete resection. Ch, chemotherapy; R0, complete resection; RT, radiotherapy.

been reported up to 32 years after resection of a thymoma.18,116 The mean time to recurrence was 10 years in patients with a stage I thymoma, compared with 3 years in patients with a stage II-IV thymoma.3 A summary of data regarding recurrence patterns is shown in Table 131-16. Local recurrence is by far more common than a distant recurrence. Approximately half of the local recurrences involve the pleural space or the lung, with the typical appearance being a nodule under the parietal pleura. Half of the local recurrences involve the mediastinum (which includes the pericardium, where pericardial nodules are also common). Liver and bone are the two most common sites of distant metastases. Role of Partial Resection. In the event that a complete resection cannot be achieved, do patients benefit from partial resection? Although it is clear that every effort needs to be made to achieve a complete resection, it has been a matter of debate whether there is a benefit to carrying out a subtotal resection (debulking) when a complete resection cannot be accomplished. Some authors argue that a partial resection provides better survival than a simple biopsy in unresectable cases,2,6,24,29,33 whereas others argue that this confers no benefit.4,5,22,27,49,55,117 There are no controlled studies addressing this issue, although data from a number of retrospective series are available (Table 131-17). These results are, of course, subject to selection bias, that is, patients undergoing partial resection may have less advanced disease and fewer

Ch131-F06861.indd 1603

comorbidities. In addition, adjuvant therapy was given to most of the patients who did not undergo complete resection in these series, although the details and impact thereof are unclear. Furthermore, comparison between studies is hampered by potential differences in how aggressive the surgeons were at removal of adjacent structures to achieve a complete resection and in what was considered a partial resection. With regard to this latter issue, the recurrence rate appears to be lower after a resection that is microscopically incomplete (R1) compared with a grossly incomplete resection (R2) in one study of 28 patients, all of whom received adjuvant radiotherapy (overall recurrence rate of 36% versus 71% among patients with a microscopically incomplete resection [R1] versus a subtotal resection or a biopsy; local recurrence rate of 7% versus 86%; mean follow-up 8 years).118 In general, the survival after a partial resection appears to be slightly better than the survival of patients undergoing biopsy only (10-year survival approximately 39% versus 33% as shown in Table 131-17). In most studies the difference has been small, and only 2 studies have shown a substantial difference.24,29 In one of these studies29 only 8-year survival data are available, and the 8-year survival of 72% in patients with partial resection is surprising because the same authors reported a 10-year survival of only 44% in another report 5 years earlier32 that included 76% of the patients reported in the later series. Substituting the data from the earlier study in Table 131-17 changes the averages slightly and makes the

1/21/2008 4:09:21 PM

1604

Ch131-F06861.indd 1604

Section 7 Mediastinum

TABLE 131-16 Recurrence Patterns After Treatment of a Thymoma % of All Recurrence

% of All Recurrence

Study

No. Patients

No. Evaluable

% With Recurrence*

Years to Recurrence

L

L+D

D

Pleura

Regnard et al4 Lewis et al18† Ruffini et al30 Verley and Hollman3 Wright et al154 Maggi et al32 Rea et al55 Nakagawa et al36† Blumberg et al49 Ogawa et al53†

307 287 266 200 179 169 132 130 118 103

260 232 266 181|| 179 165|| 108 124 86 103

9 15‡ 11 16 11 8 15 10 29 17

6 6 7 — — — 3 — — —

96 — (39)§ 81 90 77 81 73 68 82

4 — — 13 — 15 — — 12 18

0 — (61)§ 6 10 8 19 27 20 0

——— 51 ——— 50 — — — — — — — — — ——— 80 ——— — 23 23 62 ————— 63 ————— ——— 55 ——— — 16 60 12 71 — 6

14

5.5

81

12

11

——— 62 ———

Average¶

Inclusion criteria: studies from 1980-2002 with ≥100 patients. *% of all evaluable patients. † Thymic carcinoma excluded. ‡ Local data only reported. § Included any pleural or pericardial recurrences as distant; local included only those confined to the mediastinum. || Included incompletely resected patients. ¶ Excluding values in parentheses. D, distant; L, local (generally defined as within mediastinum or pleura); Peric/Med, pericardium or mediastinum.

Lung

Peric/Med

28

Liver

Bone

Other

4 0 0 — — — — — — — — — 10 — — 0 15 8 13 6 0 — — — 12 16 0 ——–——– 18 ——–——– 7

9

3

1/21/2008 4:09:21 PM

Chapter 131 Thymic Tumors

1605

TABLE 131-17 Survival After Subtotal Resection No. Patients

10-Year Survival (%)

Study

Total

R1,2

Bx

% RT of R1,2/Bx*

Maggi et al29 Park et al43 Nakahara et al24¶ Rea et al55 Blumberg et al49 Mornex et al119¶ Regnard et al4 Gamondès et al5¶ Wang et al27 Kaiser et al68

241 150 141 132 118 90 83§§ 65 61 59

21 5 16 12 18 31 28 15 9 13

9 17 12 12 14 55 12 5 18 7

— — (73)** — — 100 — 96 (85)** 100

Average|| ||

P

R0

R1,2

Bx

R0/R1,2†

R1,2/Bx‡

81 80 (94)†† 71 70 — 75 91 48 82

72§ (0)¶¶ (68)†† 9 28 43 29 32 20 48

27§ 0 (0)†† 25 24 31 35 53 20 44

–———— .001|| –———— –——— <.0001¶¶ –——— <.001 <.01 –———— .001 –———— <.05‡‡ NS — <.02 <.001 NS <.05‡‡ NS — NS — —

75

35

29

Inclusion criteria: studies from 1980-2002 of >50 patients reporting on incomplete resection versus biopsy. *% of patients undergoing incomplete resection or biopsy only who were treated with radiotherapy. † P value for comparison R0 versus R1,2. ‡ P value for comparison R1,2 versus biopsy. § 8-year survival. || P value for comparison of all three groups (R0, R1,2, biopsy). ¶ Thymic carcinoma excluded. **% of all patients in study receiving radiotherapy. †† Disease-free survival ‡‡ P value for R0 versus R1,2 and biopsy groups combined. §§ All stage III patients. || || Excluding values in parentheses ¶¶ R2 only. Bx, biopsy only; NS, not significant; R0, complete resection; R1,2, incomplete resection; RT, radiotherapy.

Ch131-F06861.indd 1605

100 Survival Rate (%)

benefit of partial resection less convincing (10-year survival, 73%, 35%, and 33%). In only one of the four studies in which a statistical analysis was performed was a statistically significant difference in disease-free survival (DFS) found between patients undergoing a partial resection compared with those undergoing biopsy only.24 Only one study has attempted to correct for the stage of patients undergoing partial resection or biopsy (this is one of the studies that reported a substantial difference).24 In this study, significantly better DFS was found for patients with a partially resected stage III thymoma as well as for those with a partially resected stage IVa thymoma compared with those undergoing biopsy (10-year DFS, 80%, 62%, and 0%; P < .01 and P < .05).24 (None of the patients with stage I or II thymomas in this study underwent an incomplete resection.) Two studies have suggested that there may be a transient survival advantage at 5 years among patients who have partial resection compared with those undergoing biopsy only but that this advantage largely disappears at 10 years (Fig. 131-7).6,49 Finally, two studies have reported a lower local recurrence rate after a partial resection compared with a biopsy (16% versus 45% in 86 patients, thymic carcinoma excluded6 and 53% versus 73% recurrence or persistence rate in 26 patients).33 It is difficult to compare the results of patients undergoing partial resection or biopsy only because of the possible influence of other treatments, differences in the stage of thymomas among these patients, and differences in the follow-up periods. In addition, it is unclear how recurrence is defined

75

Gross total resection

50

Subtotal resection

25

Biopsy alone

P < .001, overall 0

0

5

10 Years

FIGURE 131-7 Disease-free survival according to extent of surgery (n = 63, n = 31, and n = 55 for gross total resection, subtotal resection, and biopsy-alone groups, respectively).6

in patients with incompletely resected tumors or how much tumor removal constitutes a partial resection in most of these studies. Among studies reporting stage-specific outcomes and involving patients who were all treated with radiotherapy, there are conflicting data about the benefit of partial resection over biopsy alone. The local failure rate was 14% in patients with partial resection versus 41% in patients who underwent biopsy only in a study of 58 radiated patients with incompletely resected stage III thymomas (median follow-up, 8.5 years).119 In another study involving patients treated with an incomplete resection and radiotherapy, the intrathoracic

1/21/2008 4:09:21 PM

1606

Section 7 Mediastinum

failure rate was 10% versus 80% in 26 patients with a stage III thymoma and 40% versus 100% (3/3) in 18 patients with a stage IVa thymoma (partial resection versus biopsy, respectively).120 In contrast, no difference was found in either the overall or the local recurrence rates between patients who underwent a subtotal resection versus patients who underwent only a biopsy in one study of 28 stage III thymomas (40% versus 50% overall and 20% versus 20% local recurrence rate among radiated patients undergoing subtotal resection versus biopsy only, respectively; median follow-up, 4 years).57 In summary, the data are unclear whether a partial resection is of benefit. In general, the difference in survival appears to be small. It is certainly possible that the difference can be explained entirely by selection of those patients for subtotal resection who are thought to have a better prognosis. On the other hand, especially in the context of adjuvant therapy, it is possible that an incomplete resection that leaves only a minimal amount of residual disease may yield a survival benefit. In addition, local debulking may be of palliative benefit, given the predilection of thymomas to grow locally. However, the indolent nature of thymomas needs to be emphasized, and it is remarkable that even among patients undergoing only a biopsy, the 10-year survival is approximately 25%.

Radiotherapy Adjuvant Radiotherapy. Whether adjuvant radiotherapy should be given after a resection remains controversial. Some authors recommend this for all patients, regardless of stage or completeness of resection,24,33 whereas others recommend it only for stage II and III thymomas4-6,53,68,94,121 or for patients with incomplete resection.5,6,15-17 The fact that the vast majority of recurrences of a thymoma are local provides a logical basis for considering the addition of radiotherapy. However, most of these local recurrences involve pleural or pericardial implants, which are not necessarily contiguous with the original tumor location.58 Examination of data regarding adjuvant radiotherapy is hampered by several factors. A long period of follow-up (i.e., ~10 years) is necessary for an accurate assessment of outcomes because thymomas exhibit rather indolent growth. Because of the relatively low incidence of thymomas, most series span a long period of time and all series involve retrospective reviews rather than an experience with a consistent treatment plan and selection criteria. To minimize the effect of bias in patient selection, the data analysis presented here is limited to studies that reported outcomes separately by stage and completeness of resection. These are the two most consistent prognostic factors (see section on prognostic factors). Table 131-18 shows the results of retrospective series that have compared the outcomes of patients with and without adjuvant radiotherapy. In all of these series the radiation involved megavoltage therapy, although in a few series some of the patients were treated with a cobalt-60 radiation source. There is variability in the doses of radiotherapy given in all series, but the vast majority of patients received a total dose

Ch131-F06861.indd 1606

of 40 to 55 Gy. Examination of the results in patients with complete resection (R0) reveals that the recurrence rates for stage I thymomas is low, even without adjuvant radiotherapy. Although there is a suggestion that radiotherapy may decrease the incidence of recurrences, it must be questioned whether the risk of recurrence is really high enough to warrant routine radiotherapy for patients with stage I disease, considering the potential toxicity and the possibility that a recurrence may be amenable to re-resection (see the section on treatment of recurrence). The results for patients with completely resected stage II and stage III tumors are less clear. Although some series have suggested a trend to a lower incidence of recurrence with adjuvant treatment for stage II thymomas (not statistically significant), the largest series found the opposite result.30 In fact, the higher recurrence rate for stage II thymomas treated with adjuvant radiotherapy in this latter series was statistically significant (P = .02). A higher recurrence rate after adjuvant treatment was also noted for completely resected stage III thymomas in this series,30 whereas three other series have reported no difference in recurrence rates in such patients.17,49,122 Two additional studies, which reported data for patients with completely resected stage II and III tumors combined, have suggested a nonsignificant trend toward a decreased rate of recurrence with adjuvant radiotherapy.4,57 One of these, reported by Curran and coworkers in 1988, is the most detailed study of the effect of radiotherapy on recurrence rates and involved 68 patients who had complete resection (R0).57 The 5-year actuarial recurrence rate for any recurrence was 0% with radiotherapy and 53% without radiotherapy among patients with complete resection of stage II and III tumors combined. The 5-year actuarial recurrence rate for mediastinal recurrence was 0% with radiotherapy and 47% without radiotherapy among patients with completely resected stage II and III tumors combined.57 Several recent studies have found no benefit to postoperative radiotherapy in stage-specific cohorts.15,16 Another detailed study of 80 patients who had complete resection of their tumors found that adjuvant radiotherapy was of benefit in patients with adhesions to the mediastinal pleura without microscopic invasion (recurrence rate 0% with radiotherapy and 18% without radiotherapy, P < .05, stages I, II, III combined).122 There was no difference in the recurrence rates with and without radiotherapy among patients without any pleural involvement or among patients with microscopic or gross pleural involvement, nor was there any difference among patients grouped by Masaoka stage in this study.122 What is meant by “adhesions without microscopic invasion of the mediastinal pleura” by these authors is not entirely clear because some of the categories according to their pleural classification seem to conflict with the stage assignment. In patients with incompletely resected tumors, two studies have suggested a benefit to adjuvant radiotherapy (see Table 131-18), although neither study involved a large number of patients and both are open to bias in terms of patient selection.29,57 A third study, involving both completely resected and incompletely resected stage III thymomas, also found a lower recurrence rate with adjuvant radiotherapy (24% versus

1/21/2008 4:09:22 PM

Chapter 131 Thymic Tumors

1607

TABLE 131-18 Recurrence Rates With and Without Postoperative Radiotherapy by Stage % Recurrence by Stage

P (Obs Versus RT)

n (Obs/RT)* Obs I

RT I

Obs II

RT II

45/13 36/14 –—— 24/90† ——– 0/61 0/25 21/16 8/12 35/14 — 20/20 — 7/25 — –—— 19/5† ——– 9/17 5/19 — 7/29

5 — — 0 — 4 8 0 — —

0 — 0 (0)§ — (0)§ 0 (0)§ — —

4 (22)† — 24 3 0 29 (42)† — —

31 16 64 (13)† ——–—–——–—–– 10 — 44 19 25 25 0 — — 5 — — 8 — — (0)† ————–————– — 52 48 — (25)‡‡ (18)‡‡

3

0

12

12

31

— —

— —

— —

— —

— —

100 67††

Study

% R0

I

II

Ruffini et al30 Regnard et al4 Ogawa et al53 Haniuda et al122‡ Mangi et al16 Singhal et al15 Monden et al33‡ Curran et al57‡ Blumberg et al49 Mangi et al17

100 100 100 100 100 100 100 100 100 100

145/7 — 0/17 20/3 — 27/3 12/26 41/1 — —

— —

III

Average¶ Curran et al57‡ Maggi et al29**

0 0

6/20 6/13

Obs III

RT III

II

III

.02 .02 —– NS† —– — — — — NS — NS — — — —– NS† —– NS NS — NS

45 49 31††

— —

— —

Inclusion criteria: studies of >50 patients by stage and completeness of resection. *Number of patients observed or treated postoperatively with RT per stage. † Stage II, III combined. ‡ Thymic carcinoma excluded. § <5 patients in this category. || Recurrences rates for stage II not explicitly reported but stated to be equal with and without adjuvant RT. ¶ Excluding values in parentheses. **82% of those treated postoperatively received RT, 47% chemotherapy. †† Included some stage II, IV. ‡‡ Disease-specific death rate. NS, not significant; Obs, observed (not treated postoperatively); RT, treated postoperatively with radiotherapy.

40%, no P value given; 44 patients).33 Adjuvant radiotherapy was also found to result in a lower recurrence rate among patients with incompletely resected stage IV thymomas (44% versus 75%; 13 patients).33 Finally, mediastinal recurrences have been found to be lower with radiotherapy among 26 patients with stage III tumors undergoing subtotal resection (5-year actuarial rate 21% versus 100%, no P value given).57 The use of radiotherapy in patients with incomplete resection is supported by several studies that have reported very low rates of mediastinal failure among those patients with gross residual disease treated with adjuvant radiotherapy (21% 5year rate in stage III disease as noted earlier57; 26% among 31 patients, thymic carcinoma excluded, median follow-up 18 years123; and 16% among 44 patients, thymic carcinoma excluded).120 In summary, the role of adjuvant radiotherapy remains poorly defined. The benefit in patients with stage I disease is marginal at best. Given the conflicting results and the potential for bias in patient selection in retrospective series, the role of adjuvant radiotherapy in patients with completely resected stage II and stage III tumors is unclear. Some studies have suggested a benefit in survival or recurrence rates with postoperative radiotherapy, others have found no difference, and others have found a detriment in patients with completely resected stage II and III disease. It appears that radiotherapy does decrease the recurrence rate in patients with incomplete resection.

Ch131-F06861.indd 1607

Preoperative Radiotherapy. Preoperative radiotherapy has been used on a limited basis by some groups in patients thought to have thymomas invading other structures.58,106,124-126 The ability to carry out a complete resection in these patients has been reported to be 53%, 59%, and 75%,124-126 which can perhaps be compared with an average resectability rate in stage III thymomas of 50% (see Table 131-12). The survival is not obviously better than that of other patients with locally advanced thymomas, with 10-year survival rates of 44% to 48% reported in two series (19 and 12 patients).124,125 A comparison of survival in only patients with stage III tumors with and without preoperative radiotherapy, shown in Figure 131-8, also does not suggest a survival benefit.106

Chemotherapy and Combined Chemoradiotherapy Preoperative Chemotherapy. Several series have reported results of preoperative chemotherapy in patients with stage III and IV thymomas (Table 131-19). Approximately 60% of these patients had stage III thymomas. The preoperative regimens have been very well tolerated, and the vast majority of patients went on to surgery. In these studies, thymomas have shown marked chemosensitivity, as demonstrated by a radiographic objective response rate of approximately 90% (23% complete response [CR]) and a pathologic complete response (pCR) of approximately 20%. Downstaging was

1/21/2008 4:09:22 PM

1608

Section 7 Mediastinum

TABLE 131-19 Outcomes After Preoperative Chemotherapy and Resection

Study

No. Patients (Total)

No. Patients With Stage III/IV

Preoperative Chemotherapy

Adjuvant Therapy

% Objective Response

Lucchi et al157 Rea et al55 Venuta et al22* Kim et al158 Rea et al159* Macchiarini et al160*

36 32 25† 22 16 7

25/11 — 12/13 11/11 13/3 7/0

PEEpi × 3 CAPVc × 3 PEEpi × 3 CAPPr × 3 CAPVc × 3 PEEpi × 3

RT RT or Ch RT/Ch RT/Ch RT or Ch RT

Average

% R0

% Pathologic Complete Response

% 5-Year Survival

67 100 — 77 100 100

77 75 80 76§ 69 57

6 — 4 18§ 31 29

77 55 92/68‡ 95 57 —

89

72

18

74

Inclusion criteria: studies of >5 patients with preoperative chemotherapy. *Thymic carcinoma excluded. † Only 21 of 25 patients treated with preoperative chemotherapy. ‡ Data for stage III/stage IV. § Data taken from an earlier full publication.161 Ch, chemotherapy; RT, radiotherapy. Chemotherapy regimens: CAPPr, cyclophosphamide, doxorubicin, cisplatin, prednisone; CAPVc, cyclophosphamide, doxorubicin, cisplatin, vincristine; PEEpi, cisplatin, etoposide, epirubicin.

100 90

Survival Rate (%)

80 70 60 50 40 30 Preoperative RT (+): n = 8 ] ns Preoperative RT (–): n = 26

20 10 0

0

5 Years

10

FIGURE 131-8 Overall survival among patients with stage III thymomas with or without preoperative radiotherapy (RT) and surgery (P = NS).106

noted to have occurred in 16% of the patients in one study.22 The ability to achieve a complete resection is high (72%) compared with studies involving resection alone, in which the resectability of stage III and stage IV thymomas has been approximately 50% and 25%, respectively (although it must be acknowledged that here is variability among studies; see Table 131-12). The 5-year survival (average 78%) also appears to be slightly better than in patients with stage III or IV thymomas who underwent primary surgical resection (average 65% and 62%; see Table 131-14). It appears that the studies of preoperative chemotherapy have excluded cases of thymic carcinoma whereas most of the studies of primary resection in patients with higher-stage disease have included such cases as well. The impact of this difference is unclear. Thus, the available data regarding preoperative chemotherapy for locally advanced (stage III, IV) thymomas suggest that resectability and survival may be improved with this

Ch131-F06861.indd 1608

approach. Although the data are limited in numbers and subject to selection bias, most of these studies were controlled prospective trials and do not appear to have excluded many patients with appropriately staged tumors at these institutions. Longer survival data and wider experience with this approach are likely to become available in the next few years. Chemotherapy Regimens. A number of studies have analyzed the effect of chemotherapy regimens on thymomas. Studies that have involved at least 10 patients treated with a particular regimen are shown in Table 131-20. It is clear from this table that thymomas are sensitive to chemotherapy, with about two thirds of patients showing an objective response and about one third a complete response. These studies have involved patients with measurable disease, which were generally considered to be unresectable but also included a few patients with recurrent disease after a previous resection. In a few series, resection was undertaken after completion of the chemotherapy. In most of the studies, the majority of patients had stage IV tumors. Only a few of the patients included in these studies had thymic carcinomas. Closer examination of the results in Table 131-20 reveals that there is a great deal of variability between studies, with objective response (OR) rates ranging from 10% to 100% and CR rates from 0% to 43%. It is not clear why this is the case. The average OR and CR rates were 69% and 20% for the four studies involving a CAP regimen (cyclophosphamide, doxorubicin, cisplatin ± corticosteroids), 94% and 41% for the three studies involving a CAPVc regimen (cyclophosphamide, doxorubicin, cisplatin, vincristine—also known as ADOC), and 46% and 24% for the remaining three multidrug regimens. The results do not correlate with the inclusion of patients with thymic carcinoma. In general, the studies in which only a minority of patients had stage IV thymomas have reported good response rates, but there remains marked variability among studies involving patients with primarily

1/21/2008 4:09:22 PM

Chapter 131 Thymic Tumors

1609

TABLE 131-20 Results of Treatment of Thymomas With Chemotherapy

Study

No. Patients

% Stage IV

% Thymic Carcinoma

Chemotherapy Regimen

% Objective Response

% Complete Response

Additional Treatment

Response Duration (mo)

Loehrer et al162* Loehrer et al73* Kim et al158† Park et al163 Fornasiero et al164 Rea et al159 Fornasiero et al165 Loehrer et al139 Bonomi et al127* Highley et al128 Giaccone et al166* Göldel et al131

30 23 22 17 37 16 11 25 21 17 16 13

>50 5 50 — 68 16 55 — >52 76 63 —

4 9 0 0 0 0 0 44 0 12 0 0

CAP CAP CAPSt CAP ± St CAPVc CAPVc CAPVc PIE P I EP CAVcSt ± B

50 70 77 64 92 100 90 32 10 46 60 —

10 22 14 35 43 43 36 0 0 39 33 38

— RT ± S S, RT, Ch — ±S S S — — ±RT ±RT, ±S —

12 93 — 90 12 — — — — 57 41 —

63

26

Average

51

Inclusion criteria: studies from 1980-2002 of ≥10 patients. *Multicenter, prospective trial. † Prospective trial. RT, radiotherapy; S, surgery; TC, thymic carcinoma. Chemotherapy agents: A, doxorubicin; B, bleomycin; C, cyclophosphamide; P, cisplatin; St, steroids; Vc, vincristine.

stage IV disease. The results do not seem to correlate with whether the study was a prospective or a multicenter trial as opposed to a retrospective review of an institutional experience. The study with the lowest response rate (OR rate, 10%) was a multicenter trial of single-agent cisplatin, given at 50 mg/m2 every 3 weeks for a maximum of eight doses,127 but marked variability remains even after exclusion of this study and another study involving only a single agent.128 The median duration of response also varies dramatically between studies, ranging from 12 months to 93 months. Again, it is not clear why this is the case. Some of these studies employed radiotherapy after the chemotherapy, but this does not appear to explain the differences. Therefore, although it is clear that a variety of chemotherapy regimens are active in thymomas, no conclusions can be drawn about the duration of the response and further study is obviously needed. In addition, the optimal regimen has not been defined. The impact of chemotherapy on patient survival is difficult to assess. There are no randomized studies of patients treated with and without chemotherapy. In a retrospective analysis, chemotherapy significantly reduced the rate of metastases to the lung, pleura, or distant sites (17% versus 38%, P < .05) among 90 patients with stage III-IV tumors (GETT system) who were treated with radiotherapy and either partial resection (34%) or no resection (61%).6 There was also a trend to better DFS with chemotherapy among these patients (5-year survival 55% versus 32%, 10-year survival 41% versus 24%, P = NS; 59 patients treated with and 31 patients without chemotherapy).119 In a much smaller study, no survival difference was seen whether or not chemotherapy was given in 19 patients with unresectable stage III thymomas (5-year survival 56% versus 58%).49 However, the impact of chemotherapy on survival or recurrence remains undefined because such retrospective analyses are open to selection bias.

Ch131-F06861.indd 1609

Prognostic Factors The presence of MG no longer appears to be a negative prognostic factor. An influential older study reported worse survival in patients with MG, which was due almost exclusively to a higher perioperative mortality and uncontrolled MG.100 A follow-up report from this institution found no difference in the prognosis, and no perioperative deaths occurred in patients with MG because perioperative management of these patients has improved.94 Some recent studies have shown no difference in survival of patients with or without MG,22,33,94 but the majority of studies have suggested either a trend4,23,92,129 or significantly better survival27,29,34 in patients with MG (Kondo and Monden, 2004). Other autoimmune diseases have been found to be associated with slightly better (10-year survival 74% versus 62%, P = NS)4 or significantly worse survival (10-year survival 25% versus 82%, P < .001; and 24% versus 57%, P = .02).29,49 The finding of slightly better survival among patients with MG is likely explained by the fact that most studies have found that more patients with MG have stage I and II tumors than those without MG.2,3,23,24,26 Nevertheless, some studies have reported no difference in stage distribution.29,94 Although one study found lower recurrence rates in patients with MG, stage for stage,33 the fact that multivariate analyses have generally found that MG is not a prognostic factor strongly suggests that the tendency to earlier diagnosis of thymomas in patients presenting with MG explains the trend to better survival. Multivariate analysis of prognostic factors has been carried out in several large studies, as shown in Tables 131-21 and 131-22. Consistent independent prognostic factors are the stage of the tumor and the completeness of the resection. In the largest series, completeness of resection was the only significant prognostic factor when all variables were included

1/21/2008 4:09:22 PM

1610

Ch131-F06861.indd 1610

Factors Predicting Better Survival Treatment (%) Study

No. Patients

R0

Ch

RT

Stage I, II

R0

Hist. Type

Older Age*

Small Size

Male

MG

Adjuvant RT

Adjuvant Chemotherapy

Kondo et al8† Regnard et al4 Lewis et al18 Regnard et al4*** Okumura et al31†a Rieker et al153 Chen et al44 Park et al43 Rea et al55 Cowen et al6† Venuta et al22† Wilkins et al34 Nakagawa et al36†b Blumberg et al49 Pan et al25 Kim et al155b Ogawa et al53† Kondo et al42

1093 307 283 260 273 218 200 150 132 149 148 136 130 118 112 108 103 100

— 85 83 100 95 77 — 69 82 42 — 68 95 73 80 82 100 84

— 6 2 6 10‡ 14 4 — 18 100 33‡ 7 4 32 — 1 — 28

— 52 26 52 60‡ 39 28 — 47 50 — 37 5 58 — 28 100 37

<.001 NS <.05 .00001 <.0001 <.001 <.003 <.001 .003 NS .0001 (NS)¶ <.01 .003 <.05 <.03 .0001 .04

<.001 .00001 <.05 — NS — — — NS 0.003 — <.001 NS .0006 — NS — <.05

NS† NS NS† NS .05†§ <.03§ (NS)§¶¶ <.02§‡‡ .0001§ NS† NS† .02** —§ .004** NS† NS NS† NS§

NS — <.05 — NS NS NS NS NS .013 .001 (.036)†† NS NS — NS NS NS

— — NS — — NS — — — .001¶ — — .01 .0001 — NS NS¶ —

NS — NS — NS NS NS NS NS — — NS NS NS — NS NS NS

NS NS NS NS NS NS NS NS NS NS — .005 NS NS — NS NS NS

— NS — NS — — — — NS — — — — — — — — —

— — — — — — — — — .001 — — — — — — — —

Inclusion criteria: studies from 1980-2002 of ≥100 patients. a Cancer-specific survival (only deaths from thymoma counted). b Thymoma-specific survival (only deaths from thymoma, thymoma-related treatment, and parathymic syndromes counted). *Variously defined as >30 (Lewis, Cowen), >60 (Venuta), >47 (Park), >57 (Wilkins, Kondo), or unspecified. † Thymic carcinoma excluded. ‡ Estimated, not specifically reported. § World Health Organization classification. ¶ Defined as no mediastinal compression. ¶ Stage I versus II-IV. **Spindle, lymphocytic, or mixed types had better survival than the epithelial type or thymic carcinoma. †† In this series older age groups had significantly worse survival. ‡‡ Type C versus all others. ¶¶ Significant only if analysis restricted to stage I, II patients and stage is excluded. ***Restricted to completely resected patients. Hist. histologic; MG, myasthenia gravis; NS, not significant; R0, complete resection; RT, radiotherapy.

Section 7 Mediastinum

TABLE 131-21 Multivariate Analysis of Factors Predicting Better Survival

1/21/2008 4:09:22 PM

Chapter 131 Thymic Tumors

1611

TABLE 131-22 Multivariate Analysis of Factors Predicting Lower Rates of Recurrence Factors Predicting a Lower Recurrence Rate Treatment (%) Study

No. Patients

R0

Ch

RT

Stage I, II

R0

Hist. Type

Older Age

Small Size

Gender

MG

Wright et al154 Wilkins et al34* Blumberg et al49 Quintanilla-Martinez et al39 Kim et al158¶ Ogawa53¶ Kondo42

179 136 118 105 108 103 100

90 68 73 100 82 100 84

— 7 32 0 16 — 28

— 37 58 24 44 100 37

<.0001 (NS)† 0.03 .03 <.03 .0001 .002

NS .003 NS — NS — .051

.003§ NS NS .03‡ NS NS NS§

NS NS NS NS NS NS NS

.001 NS NS NS NS NS** —

NS NS NS NS NS NS NS

NS NS NS NS NS NS NS

Inclusion criteria: studies from 1980-2002 of ≥100 patients. *Factors predicting cause-specific survival. † Stage I versus II-IV. ‡ Medullary, mixed, or cortical thymomas had lower recurrence rates than well-differentiated thymic carcinoma (undifferentiated thymic carcinoma was excluded from the analysis). § WHO classification. ¶ Disease-specific survival. ¶ Thymic carcinoma excluded. **Defined as no mediastinal compression. Ch, chemotherapy; Hist., histologic; MG, myasthenia gravis; NS, not significant; R0, complete resection; RT, radiotherapy.

in the model (Masaoka stage was not of independent significance).4 However, when completeness of resection was excluded from the model, only Masaoka stage was significant.4 In another large series, completeness of resection but not stage was of independent prognostic significance for overall survival, yet stage and not completeness of resection was significant for DFS.6 The histologic tumor classification was not of independent significance in the vast majority of studies, but it must be noted that the majority of these studies excluded patients with thymic carcinomas. There is some suggestion that patients with smaller tumors6,49 and that patients who are younger than the age of 30 to 40 years have a better prognosis.6,18,22 Other factors have generally either been found not to be of value or have not been studied. The presence of involvement of the great vessels by a thymoma deserves mention, although it has not been studied extensively. A recent series of 194 patients found this to be an independent prognostic factor by multivariate analysis, along with tumor stage.23 Involvement of the pleura, pericardium, or lung was not significant by multivariate analysis, although they were significant by univariate analysis. Although vessel involvement was highly correlated with the ability to achieve a complete resection (P = .001), multivariate analysis found vessel involvement to be significant whereas completeness of resection was not. It is unclear whether this finding represents a fluke of the statistical analysis or recognition of a clinically relevant factor (vessel invasion instead of completeness of resection, the latter having been much more widely studied and accepted). The only other study to analyze this involved 43 patients with thymic carcinoma.47 Multivariate analysis in this study also found that innominate vessel invasion was prognostically significant, whereas completeness of resection, stage, and other factors were not. Involvement of other mediastinal structures did not correlate with prognosis, only innominate vessel involvement. Although these

Ch131-F06861.indd 1611

studies are suggestive that great vessel involvement may be prognostically important, further study with careful scrutiny of the statistical methods is necessary before this can be accepted as an established prognostic factor.

Special Considerations Treatment of Recurrence An aggressive approach to recurrence of thymoma has been advocated by several authors.4,29,30,49,94,98,106,108,130 Between half and two thirds of all recurrences were considered to be operable in those series reporting these data.30,49,55,98,130 Of those patients in whom reoperation was undertaken, a complete resection was able to be accomplished in 62% (range, 45%-71%).30,55,98,108,130 Most of the available data show good survival among those who had complete resection (5-year survival 64%, 73%, and 72%; 10-year survival 53% and 72%30,98) as opposed to patients with incomplete resection (5-year survival 17%, 0%, and 25%; 10-year survival 0% and 11%,4,30,55,98 and as seen in Figure 131-9). However, one study has reported a 7-year survival of 79% after incomplete resection and radiotherapy in 6 patients.130 A second recurrence was observed in only 16% to 25% of patients after a complete resection of a first recurrence in two series (mean follow-up of 4 and 5 years after the recurrence).98,108 Other treatments for recurrent thymoma have involved radiotherapy or chemotherapy. Reasonable intermediateterm survival has been reported (5-year survival of 25%-50%) in several studies using various treatment approaches. An actuarial 7-year survival of 65% was observed in 10 patients treated with radiotherapy with curative intent.130 A 5-year survival of 53% and a 10-year survival of 0% were reported in another study of 11 patients treated with radiotherapy alone.30 A 5-year survival of 33% and a median survival time of 10 months were found in 12 patients treated with chemo-

1/21/2008 4:09:22 PM

1612

Section 7 Mediastinum

1.0

1.0

0.8

Proportion Surviving

0.9 Cumulative Proportion Surviving

No recurrence

Total Rad-th Subtotal

0.7 0.6 0.5

0.8

Recur-surg Rx P = .001

0.6

0.4

Recur-no surg

0.4 0.3

0.2 0

0.2 0.1 0.0

0

2

4

6

8

10

Years FIGURE 131-9 Survival by treatment of the recurrence. Total, complete resection (n = 10); Rad-th, exclusive radiotherapy (n = 11); Subtotal, subtotal resection (n = 6).30

therapy for a recurrence.131 In a report of 11 patients treated with either radiotherapy or chemotherapy, a 42% 5-year actuarial survival rate was noted from the time of recurrence.29 A 2-year survival of 30% (from the diagnosis of recurrence) and a 7-year survival of 45% (from the diagnosis of the original thymoma) were reported in another report of 12 patients treated with radiotherapy, chemotherapy, or both.49 Which factors are associated with a favorable prognosis in patients with a recurrent thymoma have not been clearly defined. A mediastinal recurrence was associated with better survival compared with either an intrathoracic or extrathoracic recurrence in one study, but it appears that this is a prognostic factor primarily by being a predictor for a higher likelihood of being able to carry out a complete resection.30 This is corroborated by another series, which noted that there were more patients with a local (i.e., intrathoracic) recurrence among those treated surgically compared with those treated nonsurgically (92% versus 67%).49 The ability to carry out a complete resection of a recurrence is probably an important prognostic factor, as suggested by the observation that good survival has been noted after resection of pleural, pericardial, or pulmonary implants.98 Furthermore, no difference in survival was noted among patients with resected tumors with only mediastinal recurrence, intrathoracic recurrence, or both (5-year survival, 51%, 57%, and 46%).98 No difference in survival was noted in 21 patients treated with curative intent radiotherapy, most of whom did not have their tumor resected in another report (7-year survival of 74%, 77%, and 40% for only mediastinal recurrence, intrathoracic recurrence, or both).130 The original stage of thymoma and the disease-free interval do not appear to be prognostic factors after the appearance of a recurrence,49 although this appears to be somewhat at odds with the observation that local recurrences are seen somewhat more commonly in patients who originally had a stage I or II thymoma and pleural, pericardial, or pulmonary implants are more common in patients who originally had a stage III or IV thymoma.30,98

Ch131-F06861.indd 1612

3 Years

7

FIGURE 131-10 Survival from the original diagnosis of thymoma of patients with no recurrence (n = 61), patients with recurrence treated by resection (n = 13), and patients with recurrences not treated surgically (n = 12).49

The survival of patients with a recurrence appears to be better if surgery is undertaken. In fact, the survival of patients with a recurrence that was resected was the same as the survival of patients without any recurrence in one study (measured from the diagnosis of the original thymoma; Fig. 131-10).49 However, it is also possible that patients undergoing resection for a recurrence have a good prognosis compared with patients whose recurrence is not resected simply because they are selected on the basis of favorable characteristics. It is difficult to determine whether this is the case, in part because prognostic factors have not been defined. In the study just mentioned, there were no differences in terms of the original disease stage or disease-free interval between the patients with recurrence who were treated surgically and those treated nonsurgically.49 Two studies30,49 have suggested that among those treated surgically there were more patients who had a local (i.e., intrathoracic) or mediastinal recurrence, but the prognostic significance of this finding is unclear. The suggestion that the better survival after surgery for a recurrence may be due merely to the location of the recurrence is supported by a study of 21 patients with an intrathoracic recurrence who were treated with curative-intent radiotherapy, which found no difference in survival whether surgery was performed (n = 11) or not (n = 10).130 Therefore, the recurrence of thymoma does not necessarily imply a poor prognosis and an aggressive approach is justified. The key issue appears to be whether a complete resection of the metastases is likely; surgical resection appears to be the best approach if this is the case. Every effort must be made to achieve a complete resection. If it is likely that only an incomplete resection can be accomplished, it is not clear whether surgery is beneficial compared with treatment with radiotherapy or chemotherapy.

Thymic Carcinoma The demographic characteristics of patients with thymic carcinoma are not very different from those of patients with a thymoma. In two collected series of 60 and 99 cases of true thymic carcinoma with obvious histologic features of malignancy, the age distribution was broad (range, 17 days to 81 years) with a broad peak between ages 30 and 60 and an

1/21/2008 4:09:23 PM

Chapter 131 Thymic Tumors

Ch131-F06861.indd 1613

100

Low-grade tumors Overall survival High-grade tumors

80 Percentage

overall average age of 46.19,20 Men outnumber women slightly (1.5 : 1).19,20,37 The clinical presentation, however, is somewhat different in patients with thymic carcinoma compared with patients with a thymoma. Approximately 70% of these patients have symptoms of mediastinal compression due to the tumor, including pain, dyspnea, and superior vena cava syndrome.20,132-134 Constitutional symptoms are also present in some patients, and only a minority of patients are asymptomatic.19,132,134,135 MG is very unusual, and the other parathymic syndromes have not been reported in patients with thymic carcinoma.19,20,31,38,48,132-134 The majority of patients with thymic carcinoma present with advanced disease. In a collected series of 43 patients, the Masaoka stage at diagnosis was stage I in 21%, II in 23%, III in 35%, and IV in 21%.20 Other series have also reported that 50% to 95% of patients have stage III or IV tumors.11,31,37,48,132-136 Thymic carcinomas are divided into several histologic variants. The majority are either squamous carcinoma (42%) or lymphoepithelioma-like (32%).20 The latter are histologically similar to the lymphoepithelioma type of carcinoma of the nasopharynx.20 The squamous carcinomas, however, have histologic features that are different from bronchogenic squamous carcinoma.20 The lymphoepithelioma-like variant occurs in a slightly younger group of patients than the other types of thymic carcinoma.20 Undifferentiated or anaplastic variants account for 10% of thymic carcinomas, and the rest are made up of small cell, basaloid, clear cell, sarcomatoid, mucoepidermoid, and adenocystic variants.20 Some authors have grouped thymic carcinomas into low-grade tumors (squamous cell, basaloid, and mucoepidermoid carcinomas) and high grade tumors (lymphoepithelioma-like, undifferentiated/anaplastic, small cell, sarcomatoid, and clear cell carcinomas).20,134 The prognosis of patients with thymic carcinoma is generally poor. Overall, the median survival is approximately 2 years,19,20,38,133,135 and the 5- and 10-year survival rates are approximately 37% and 32%.19,20,38,47,134 Recurrences are seen in approximately three fourths of patients overall, and distant recurrences occur in about 50%.19,20,38,48,135 A review of 60 patients found that the survival was markedly better in patients with low-grade tumors (primarily squamous) compared with high-grade tumors (primarily lymphoepitheliomalike) (Fig. 131-11).20 Another review, which may have included overlapping patients, found similar results: the 5year survival of resected squamous thymic carcinomas was 57% compared with 13% for lymphoepithelioma-like carcinomas.19 Patients who did not have resection fared poorly, regardless of the subtype of thymic carcinoma. The prognostic difference among subtypes has been corroborated by others.48,132-134 Surgery has been the mainstay of treatment for thymic carcinomas. However, although approximately two thirds of all patients with thymic carcinoma undergo surgery,19,20,135 a complete resection is possible in only about one third of all patients.38,48,134,136,137 Median survival among patients with unresected or partially resected tumors is 12 to 24 months.19,48,134 Chemotherapy (various regimens) has been used in a limited number of patients, with an overall response rate of 20% to 60%,136,138,139 including some complete responses lasting approximately 1 year.138 At least 1 patient

1613

60 40 20 0 0

20

40

60

80

100 120 Months

140 160 180 200

FIGURE 131-11 Overall survival for 60 patients with thymic carcinoma.20

has survived 5 years after treatment with chemotherapy alone.140 Radiation has produced partial response rates of 86%, with local tumor control in 83% of the responders during follow-up periods of 1 to 10 years in one study.136

Carcinoid Thymic carcinoid tumors are rare, with only 150 to 200 cases having been reported.141 They occur in all age groups, from childhood to the elderly, with at least a 3 : 1 male predominance.141-149 About 30% (42/152) of patients present with Cushing’s syndrome.89,134,141,143-145,147,148,150 An association with tumors seen in multiple endocrine neoplasia type 1 syndrome is seen in approximately 15% (27/156).89,141,143-147,149-151 Other paraneoplastic syndromes, including the syndrome of inappropriate secretion of antidiuretic hormone, Eaton-Lambert syndrome, and hypertrophic osteoarthropathy have been reported occasionally, but MG or any of the parathymic conditions associated with thymomas have not been reported in patients with thymic carcinoid tumors.152 Only 2 patients have been reported who exhibited carcinoid syndrome.134 The majority of tumors (72%; 43/60) were of intermediate grade, similar to atypical carcinoids tumors in the lung.89,141,142,147-149 The rest are either high-grade tumors, similar to small cell lung cancer or, less commonly, low-grade tumors similar to typical carcinoid tumors.141 About half of patients have nodal metastases,142,148,150 but this does not appear to predict survival.148 However, even in the presence of a complete resection, distant metastases have developed in the majority of patients.89,141,145,147-150,152 Local recurrence is also frequent, and the disease-free interval is generally short (1-2 years).89,141,143-145,147-150 Nevertheless, intermediate-term survival is fairly good. In a collected series of 81 cases, the 5- and 10-year survival rates were 77% and 30% among patients having complete resection (n = 53), 65% and 19% after partial resection (n = 11), and 28% and 0% in patients whose tumors could not be resected (n = 16).141 Survival curves according to stage are shown in Figure 131-12. Multivariate analysis found only unresectability and advanced stage to be associated with poorer survival, whereas gender, age, Cushing’s syndrome, chemotherapy, radiotherapy, and recurrence had no impact.141 An analysis by histo-

1/21/2008 4:09:23 PM

1614

Section 7 Mediastinum

patients able to undergo a complete resection.38,41,47 Two studies have suggested that the survival rate among WDTC was similar for different Masaoka stages.39,47 However, it is difficult to feel secure about this observation given the small numbers of patients and the fact that the survival rates were reported including patients with complete and incomplete resections and in some cases WDTC as well as poorly differentiated thymic carcinoma. There are no data that specifically address the effectiveness of radiotherapy or chemotherapy in this group of patients.

1.0

Cumulative Survival

0.8 Stages 1 & 2 0.6 0.4 Stage 3 0.2

COMMENTS AND CONTROVERSIES 0.0

Stage 4 0

100 Duration (months)

200

No. of Patients at Risk Stages 1 & 2 8 Stage 3 25 Stage 4 22

5 14 6

2 5 3

1 2 0

0 0 0

FIGURE 131-12 Overall survival of 81 patients with thymic carcinoid tumors according to Masaoka stage.141

logic grade could not be done, owing to varying definitions among published reports. Among smaller series, survival appears to be better the lower the histologic grade (median survival 8.5 years for low-grade tumors, 5 years for intermediate-grade tumors, and 1.5 years for high-grade tumors).141 Resection of recurrences may be of value.143

Well-Differentiated Thymic Carcinoma Several authors have focused on a group of thymic tumors known as well-differentiated thymic carcinoma (WDTC).25,39,45-47 This classification is controversial, with some authors considering these to be part of thymomas (especially the cortical thymomas)25 whereas others consider them part of thymic carcinomas.47 The demographic characteristics of this group of patients are similar to those of others with more typical thymomas, and with patients with classically defined thymic carcinomas as well. There is a wide age range, with an average age at onset about 50 and a relative equal distribution between the sexes.25,31,38,39,45-47 MG was present in major proportion of these patients in all studies (range, 25%-77%),25,31,38,45-47 and other parathymic conditions were seen as well,47 which is in stark contrast to patients with classically defined thymic carcinoma in which these conditions are distinctly absent. The majority (73%; range, 58%83%) of these patients have stage III or IV tumors at presentation.25,31,39,41,45,47 The survival of patients with WDTC has been reported to be variable, with 5-year survival rates ranging from 60% to 80% (average, 75%) and 10-year survival rates ranging from 30% to 78% (average, 61%).25,31,39,41,47 Surgery has been the mainstay of treatment, with approximately two thirds of

Ch131-F06861.indd 1614

Drs. Detterbeck and Parsons have provided a comprehensive discussion on thymic tumors. They have discussed the various aspects in detail including the classification, presentation, and treatment of these tumors. There are several controversies with regard to thymoma that the authors have addressed. These include, first, the utility of needle biopsy in the diagnosis of thymoma. The advantages of a preoperative diagnosis with a needle or open biopsy, particularly in patients who potentially may benefit from neoadjuvant therapy, have been pointed out. Second, what is the role of neoadjuvant therapy in the treatment of thymoma? This issue has been addressed in several series, and, as the authors summarize, it appears that in more advanced lesions (stage III and IV), neoadjuvant therapy may increase the chances of complete resection and survival. This issue is important because complete resection when possible provides the best chance for cure. Third, the indications for adjuvant therapy are again a controversial issue. The authors have discussed the various studies pertaining to this issue and it appears that radiotherapy is beneficial in decreasing local recurrence rates in patients with incomplete resection. The controversies surrounding the use of adjuvant therapy in patients with complete resection of their tumors have been discussed well in this chapter. Finally, partial resection or debulking of the tumor is controversial, and the authors have discussed the controversies surrounding this issue in detail. Prospective studies are required to answer definitively several of these issues. In summary, this chapter serves as an excellent review for thoracic surgeons and oncologists interested in the management of thymomas. J. D. L.

KEY REFERENCES Detterbeck FC, Parsons AM: Thymic tumors. Ann Thorac Surg 77:18601869, 2004. Detterbeck FC: Clinical value of the WHO classification system of thymoma. Ann Thorac Surg 81:2328-2334, 2006. Kondo K, Monden Y: Thymoma and myasthenia gravis: A clinical study of 1089 patients from Japan. Ann Thorac Surg 79:219-224, 2005. Kondo K, Yoshizawa K, Tsuyuguchi M, et al: WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 77:11831188, 2004. Masaoka A, Monden Y, Nakahara K, Tanioka T: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48:2485-2492, 1981. Regnard J-F, Magdeleinat P, Dromer C, et al: Prognostic factors and long-term results after thymoma resection: A series of 307 patients. J Thorac Cardiovasc Surg 112:376-384, 1996.

1/21/2008 4:09:23 PM

chapter

132

GERM CELL TUMORS OF THE MEDIASTINUM Kenneth A. Kesler

Key Points ■ Mature teratomas are the most common mediastinal germ cell

tumor. They are benign, with surgery representing curative therapy. ■ Seminomatous germ cell tumors arising in the mediastinum are malignant but have high cure rates with cisplatin-based chemotherapy alone. ■ Nonseminomatous germ cell tumors of mediastinal origin are malignant and considered poor risk as compared with the more common testicular nonseminomatous germ cell tumors. Cisplatinbased chemotherapy followed by surgical extirpation of residual disease results in 50% to 55% overall long-term survival.

The majority of germ cell tumors originate in the gonads; however, 5% to 10% of all germ cell tumors arise within the anterior mediastinum, which represents the second most common site of origin. Various theories have been proposed to explain the pathogenesis of extragonadal germ cell tumors. The most widely accepted theory involves benign growth or malignant degeneration in primordial germ cells, which are misplaced during embryonic migration through midline structures. Teratoma, one of the so-called four Ts used as a pneumonic for the main differential diagnoses of primary tumors arising in the anterior compartment, actually represents three histology types that demonstrate distinct biologic behaviors, and includes mature teratoma and seminomatous and nonseminomatous germ cell tumors. The focus of this discussion is on the diagnostic and therapeutic algorithms for these three germ cell histology types arising in the anterior mediastinum.

MATURE TERATOMA So-called mature or benign teratomas are the most common germ cell tumor arising in the mediastinum. They represent 60% to 70% of all mediastinal germ cell tumors, but they constitute 5% to 10% of all mediastinal tumors (Nichols, 1991).1 Mature teratomas are usually characterized by the presence of mature tissues derived from all three germinal layers: ectoderm, endoderm, and mesoderm. Histologically, these tumors commonly demonstrate cartilage, bone, fat, and squamous and glandular epithelia. Unlike malignant germ cell tumors, which almost uniformly occur in the male population, mature teratomas occur with equal frequency in both genders. Although reported in all age groups, the vast majority present in infancy or childhood, with chest pain being the

most common symptom, followed by dyspnea and cough.2 Occasionally, a cystic component can become infected, producing local or systemic symptoms. Rarely, cyst contents may rupture into the pleural space or tracheobronchial tree, with the latter resulting in the expectoration of hair or sebum. Asymptomatic or minimally symptomatic tumors can be incidental findings on chest radiographs or CT scans, a finding that is most common in the adult population. The diagnosis of benign teratoma almost uniformly can be made on the basis of CT findings alone (Fig. 132-1). CT usually demonstrates a multilocular but well-circumscribed cystic anterior mediastinal mass containing fluid and fat density (Strollo et al, 1997).3 Approximately half of these tumors radiographically demonstrate calcification, and, on occasion, recognizable bone or teeth are present. Serum tumor markers, α-fetoprotein (AFP) and the β-subunit of human chorionic gonadotropin (β-hCG), are obtained but are usually normal with these radiographic findings. If there is significant elevation of serum tumor markers, the tumor is treated as a primary malignant nonseminomatous germ cell tumor (PMNSGCT) with cisplatin-based chemotherapy followed by surgical extirpation of residual disease. Benign teratomas are not responsive to radiation therapy or chemotherapy. In the usual situation of typical CT findings with normal serum tumor marker levels, complete surgical excision is therefore recommended without biopsy. Because these tumors are usually large, exposure for surgical excision is optimally accomplished through a median sternotomy approach. A posterior lateral thoracotomy approach can be used for smaller tumors, for tumors that are more lateralized, or for better cosmesis in younger patients. Excision using minimally invasive video-assisted thoracoscopic surgery (VATS) has also been reported for smaller tumors.4 Even smaller benign teratomas usually require a large incision to remove the tumor from the chest cavity, which would negate any advantage a minimally invasive approach may offer. Moreover, although benign, surrounding soft tissues are not infrequently adherent to the tumor mass, making mediastinal dissection difficult, particularly through a minimally invasive approach. During surgical extirpation, great care must be taken to avoid injury to the phrenic nerve. If either phrenic nerve is found to be adherent to the tumor, all efforts need to be made to carefully preserve the nerve without resection. Most adherent lung can be freed from the tumor mass without resection as well, although in rare cases of bronchial fistulization, anatomic pulmonary resection in the form of lobectomy is usually necessary. In other rare cases of great vessel involvement, similar to situations in which a phrenic nerve is adher1615

Ch132-F06861.indd 1615

1/21/2008 4:10:10 PM

1616

Section 7 Mediastinum

FIGURE 132-1 Representative CT cut through a mature teratoma originating in the anterior mediastinal compartment. Note the cystic appearance containing fat, fluid, and bone densities.

FIGURE 132-2 Representative CT cut through a seminomatous germ cell tumor arising in the anterior mediastinal compartment. Note the bulky and lobulated but homogeneous appearance.

ent, careful dissection can usually safely preserve any great vein or artery. Where there is dense tumor adherence to a great artery, leaving a thin rim of adherent tumor with radiographic follow-up is probably not an unreasonable option that would spare the morbidity of great artery repair and/or reconstruction. Operative morbidity and mortality would otherwise be anticipated to be low. Final pathologic analysis usually confirms the presence of benign ectoderm, endoderm, and mesodermal tissues. In these typical cases there have been no reports of local or distant recurrence after complete resection. An excellent long-term prognosis is therefore anticipated, and no specific long-term follow-up is necessary. Occasionally, however, elements of undifferentiated fetal tissue are identified on final pathologic examination—a so-called immature teratoma.2,5,6 The overall prognosis remains good, and adjuvant chemotherapy or radiation therapy is not advised in these cases, although clinical and radiographic follow-up is considered because there is some potential for local recurrence or metastases.

Any young adult male presenting with an anterior mediastinal mass needs to have serum tumor markers measured as a standard component of pretreatment evaluation. Patients with a pure PMSGCT usually have normal serum values for tumor markers, but serum β-hCG levels are mildly elevated (<100 ng/mL) in approximately 10% of cases.9 Any elevations in serum AFP above normal levels or significant β-hCG elevations indicate a nonseminomatous germ cell component, and the patient therefore must be treated with cisplatinbased chemotherapy followed by surgical extirpation of residual disease even with the absence of identifiable nonseminomatous elements in biopsy specimens. Because these neoplasms are typically large, percutaneous fine-needle aspiration (FNA) or core-needle sampling under CT guidance can usually be diagnostic without the need for surgery. Either an anterior mediastinotomy (Chamberlain procedure) or VATS approach is utilized for diagnoses of masses not readily accessible to CT-guided biopsy. Although historically radiation therapy has been the treatment of choice for PMSGCTs, radiation does not control systemic metastases, which are frequently present, and additionally subjects these relatively young patients to the longterm morbidity associated with mediastinal radiation. Cisplatin-based combination chemotherapy regimens such as BEP (bleomycin, etoposide, and cisplatin) that have been extensively used in the treatment of nonseminomatous germ cell cancer are now considered the first-line treatment of choice for PMSGCT. Cisplatin-based chemotherapy alone has been reported to result in up to a 100% response rate and a 5-year survival of 85% even in the presence of metastatic disease.10,11 In contrast to PMNSGCT, any residual anterior mediastinal mass after chemotherapy usually represents nonviable germ cell tumor and surgery, therefore, is not indicated. Serial radiographic and clinical follow-up only is recommended. If local growth of a residual mass is demonstrated during long-term follow-up, then second-line cisplatin-based chemotherapy is usually offered with surgery and/or radiation therapy considered only as salvage therapy on rare occasions after failure of second-line chemotherapy. The role of surgery in patients with pure PMSGCT is therefore usually

SEMINOMATOUS GERM CELL CANCER Primary mediastinal seminomas (PMSGCTs) constitute slightly less than half of all malignant primary mediastinal germ cell tumors.7 Similar to PMNSGCTs, PMSGCTs occur almost exclusively in young adult males who are 20 to 40 years of age. Seminomas are typically slow growing and therefore usually become quite large before the symptoms such as chest pain, dyspnea, and cough develop. Chest CT characteristically reveals a bulky, lobulated, but homogeneous mass with only occasional invasion of adjacent structures (Fig. 132-2).3 Sixty to 70 percent of patients will have metastatic disease at the time of diagnosis, most commonly to bone, lungs, liver, spleen, or brain.8 Scrotal examination and ultrasonography along with CT of the abdomen and pelvis are indicated to rule out a testicular primary neoplasm as well as for staging purposes. Additional radiologic studies including positron emission tomography (PET), nuclear scintigraphy, and MRI of the central nervous system are performed on an individual basis.

Ch132-F06861.indd 1616

1/21/2008 4:10:10 PM

Chapter 132 Germ Cell Tumors of the Mediastinum

negligible. Occasionally, resection of a mediastinal mass has been performed for diagnostic and potentially therapeutic purposes when histology provides proof of a pure seminoma. If surgical margins are negative and there is no evidence of metastatic disease, then observation is reasonable with institution of cisplatin-based chemotherapy if the patient develops recurrent disease.

NONSEMINOMATOUS GERM CELL CANCER Diagnosis Nonseminomatous germ cell cancers comprise slightly more than one half of the malignant germ cell tumors arising in the mediastinum. Nonseminomatous germ cell tumors originating in the mediastinum are, however, rare.12 The treatment of testicular nonseminomatous germ cell tumors with cisplatin-based chemotherapy regimens, followed by surgical resection of residual disease, currently represents one of the most successful paradigms of multimodality cancer therapy, with greater than 80% long-term survival anticipated. It has been well established that although histologically and serologically identical to their more commonly occurring testicular counterparts, PMNSGCTs have a distinctly worse prognosis with a similar treatment approach.13 The relatively poorer prognosis is perhaps best attributed to the fact that the histology of residual disease after cisplatin-based chemotherapy is benign in approximately 90% of testicular nonseminomatous germ cell tumors as compared with only 60% of PMNSGCTs. Additionally, up to 10% of patients with PMNSGCTs will unfortunately demonstrate radiographic and serologic progression of malignant disease during chemotherapy, generally rendering the patient inoperable and incurable, which rarely occurs in the treatment of testicular cancer. This distinct biology is also reflected in the findings that up to 20% of PMNSGT patients have Klinefelter’s syndrome and a unique risk for fatal hematologic dyscrasias after treatment that is not observed in patients with nonseminomatous testicular cancer.14,15 The vast majority of PMNSGCTs occur in males 20 to 40 years of age, with extremely rare cases of PMNSGCT occurring in females. At our institution from 1981 to 2005, of 142 PMNSGCT patients presenting for surgery after cisplatinbased chemotherapy, only 2 have been female. Most patients are symptomatic with chest pain, cough, superior vena cava syndrome, and shortness of breath secondary to a rapidly growing anterior mediastinal mass. CT scans usually demonstrate a large heterogeneous mass, with occasional evidence of necrosis and hemorrhage.3 Local invasion into either lung, left brachiocephalic vein, superior vena cava, and pericardium is common, and even direct cardiac chamber/proximal great artery involvement can occasionally be present. Associated pericardial and pleural effusions are also common but typically not malignant. As previously stated, for any young adult male presenting with a mass in the anterior compartment, obtaining serum tumor marker levels is an essential component of clinical evaluation because significant elevation of these values is diagnostic of a PMNSGCT. Cytologic confirmation with CT-

Ch132-F06861.indd 1617

1617

guided FNA is optimal in these cases and necessary in patients with only marginally elevated serum tumor markers before initiating chemotherapy. If CT-guided FNA is not possible, then proceeding directly with chemotherapy, on the basis of significant serum tumor marker elevation alone, is not unreasonable because open biopsy only delays chemotherapy and makes surgery after chemotherapy more difficult. In our institution’s experience, only 5% of PMNSGCT cases will have normal serum tumor markers at the time of presentation. Cytologic or histologic confirmation is also required in these unusual cases before initiating chemotherapy. PMNSGCTs demonstrate at least one of three nonseminomatous histologic subtypes: yolk sac carcinoma, embryonal carcinoma, or choriocarcinoma in order of frequency. Other histologies occasionally found on pretreatment biopsy include mature teratoma, seminomatous germ cell cancer, and degenerative malignancies, such as sarcoma, primitive neuroectodermal tumor (PNET), and adenocarcinoma. Cytogenetic analysis revealing extra segments of chromosome 12 is diagnostic of germ cell cancer in cases in which only degenerative or undifferentiated malignant cells can be identified from biopsy specimens.16 Metastatic disease is present in 20% to 25% of cases before chemotherapy, with lung being the most common site of metastases followed by neck, retroperitoneum, liver, bone, and central nervous system. CT of the chest and abdomen is standard for use in staging, with other radiologic studies including PET, nuclear scintigraphy, and MRI of the central nervous system performed on an individual basis. Gated MRI and/or echocardiography can be helpful to determine the presence of great vessel or cardiac involvement, but subtle invasion may not be apparent until postchemotherapy surgical resection is undertaken. Scrotal examination and ultrasonography are also recommended during evaluation. In our institution’s experience, an isolated metastasis to the anterior mediastinum from a testicular nonseminomatous cancer is distinctly rare, however.

Chemotherapy After diagnosis and staging, primary surgical therapy for PMNSGCT is inappropriate. PMNSGCTs are usually large and infiltrative neoplasms. Surgical resection as initial therapy will therefore rarely achieve local control and does not treat metastatic disease when present. Appropriate therapy begins with four cycles of cisplatin-based chemotherapy, usually BEP, followed by reevaluation of serum tumor markers and CT for consideration of surgical extirpation of residual disease. The BEP regimen is administrated with careful monitoring of pulmonary diffusing capacity. Bleomycin is decreased or discontinued when any reduction of pulmonary function is noted. If pulmonary resection is anticipated after chemotherapy, we have increasingly utilized non–bleomycincontaining regimens such as vinblastine, ifosfamide, and cisplatin (VIP) or withhold bleomycin for the final two cycles to minimize pulmonary toxicity before surgery.17 After chemotherapy there is typically a reduction in tumor dimensions with resolution of pleural and pericardial effusions. Optimally, serum tumor markers levels normalize and surgery is planned after adequate functional and hematologic recovery,

1/21/2008 4:10:11 PM

1618

Section 7 Mediastinum

which usually occurs from 4 to 6 weeks after completion of chemotherapy. Previously, patients with persistently elevated serum tumor marker levels were treated with second-line chemotherapy before considering surgery.18 With relatively poor specificity of mild to moderate elevation in serum tumor markers after chemotherapy for viable residual malignancy and poor sensitivity of these markers to detect degenerative malignancy, as well as the unsatisfactory results of second-line chemotherapy in the treatment of PMNSGCT, it is our current institutional practice that surgery needs to be undertaken if the residual disease is deemed operable after first-line chemotherapy regardless of serum tumor marker status.19,20 Adjuvant cisplatin-based chemotherapy needs to be considered, however, if there is pathologic evidence of viable germ cell cancer in the resected specimen regardless of preoperative serum tumor marker status. Approximately one third of patients referred for surgery at our institution have demonstrated some, but usually minor, serum tumor marker elevation (Fig. 132-3). Occasionally, patients will demonstrate the so-called growing teratoma syndrome, with paradoxical growth of a cystic mass associated with normalization of serum tumor markers during chemotherapy.21 In these cases, chemotherapy is discontinued and surgery undertaken because mature teratoma is not sensitive to chemotherapy.

Surgery In light of the high-risk nature of PMNSGCT, any residual mediastinal mass after chemotherapy needs to be surgically removed. Moreover, there is no role for postchemotherapy PET to determine the need for surgery because residual mature teratoma does not typically demonstrate hypermetabolic PET activity and PET currently lacks sensitivity to identify microscopic foci of viable germ cell or degenerative

FIGURE 132-3 Preoperative serum tumor marker status in 142 PMNSGCT patients presenting for postchemotherapy surgery at Indiana University from 1981 to 2005. The chart on the left shows overall serum tumor marker status, with the two charts on the right specific for αfetoprotein (AFP) and β-human chorionic gonadotropin (β-hCG).

cancer not infrequently identified during pathologic analysis of resected PMNSGCT specimens. The surgical approach is selected to optimize exposure of technically difficult areas of dissection anticipated during removal. Figure 132-4 demonstrates our preferred approach to representative residual postchemotherapy masses based on location. Because the majority of residual masses are located directly behind the sternum without significant lateral extension, a median sternotomy is the most common approach utilized. For residual masses that are more lateralized, a posterior lateral thoracotomy provides optimal exposure to phrenic nerves and pulmonary hilar structures. The so-called clamshell incision (i.e., bilateral thoracosternotomy) offers excellent exposure to both the anterior mediastinum and pulmonary hilum for larger residual masses. We have increasingly been utilizing this approach to remove residual masses referred to our institution after chemotherapy (Fig. 132-5). Surgical removal involves en-bloc dissection of the residual mass, thymus, and surrounding involved structures (Wright and Kesler, 2002).22 Because the majority of postchemotherapy masses pathologically demonstrate only benign residual disease, a balanced surgical approach, sparing critical structures such as phrenic nerves, main pulmonary arteries, great veins, and cardiac chambers where the residual mass abuts but does not invade, with intraoperative frozen section examination of the surgical margin is appropriate. These surgical procedures are challenging from not only decision-making but also technical standpoints because chemotherapy typically results in marked fibrosis at the interface between the residual mass and surrounding mediastinal tissues. Table 132-1 shows the distribution of adjacent structures removed with the residual mass at our institution. Most patients have direct pericardial invasion. En-bloc pericardiectomy including a 1- to 2-cm rim of normal pericardium with

AFP

Normal (77%)

Normal (67%)


100 (5%)

21–100 (18%)

Elevated (33%)

␤-hCG


2 (5%)

Normal (95%)

Ch132-F06861.indd 1618

1/21/2008 4:10:11 PM

Chapter 132 Germ Cell Tumors of the Mediastinum

1619

FIGURE 132-4 The selection of surgical approach to optimize exposure of difficult dissection areas anticipated during removal of representative postchemotherapy residual masses.

“Clamshell”

Median sternotomy

Right thoracotomy

Left thoracotomy

TABLE 132-1 Distribution of Adjacent Structures Removed With the Residual Mass at the Indiana University Hospital

Number of Cases

40 30

Thoracotomy Sternotomy Clamshell

Structure

No. Patients

20

Pericardium

106 (75%)

10

Lung Wedge Lobectomy Pneumonectomy

94 (66%) 48 35 (LUL = 25) 11

Phrenic nerve

50 (35%)

Great vein

42 (29%)

Cardiac chamber*

7 (5%)

Diaphragm

4 (3%)

Separate pulmonary metastasectomy

17 (12%)

0 1981–1986 n  10

1987–1992 n  23

1993–1999 n  51

2000–2005 n  58

FIGURE 132-5 The surgical approach used to remove residual masses after cisplatin-based chemotherapy over 6-year increments at Indiana University. The clamshell incision (bilateral thoracosternotomy) offers excellent exposure to both the anterior mediastinum and pulmonary hilum. We have increasingly been utilizing this approach to remove larger residual masses in patients referred to our institution after chemotherapy.

the residual mass is usually easily accomplished and has no associated morbidity. Pericardial reconstruction with a prosthetic patch, however, needs to be performed if postoperative cardiac herniation through the pericardial defect is a concern. Two thirds of our patients have required some form of en-bloc pulmonary resection, with nearly half of these patients undergoing wedge or shave excision if the residual mass is simply adherent to either lung. Formal anatomic pulmonary resection in the form of lobectomy or pneumonectomy is required with direct parenchyma or hilar invasion. Approximately one third of our patients have required phrenic nerve or great vein resection with the residual mass.

Ch132-F06861.indd 1619

*With cardiopulmonary bypass. LUL, left upper lobe.

Frequently, an anatomic pulmonary resection is also required with phrenic nerve resection; and, in these cases, prophylactic diaphragmatic plication is usually not necessary. Diaphragmatic plication, however, needs to be considered in cases when little or no lung parenchyma has been removed with the phrenic nerve. If only one (usually the left) brachiocephalic vein is removed with the residual mass, venous reconstruction is not necessary. If both brachiocephalic veins and/or superior vena cava are removed, then unilateral brachiocephalic reconstruction, preferably the right, is performed. Although many different autologous and prosthetic grafts have been described for brachiocephalic venous recon-

1/21/2008 4:10:11 PM

Section 7 Mediastinum

struction, we prefer using an externally stented polytetrafluoroethylene vascular prosthesis in these cases. Direct cardiac invasion can also occur. Resection of the atrial wall and even small areas of myocardium with prosthetic patch repair is occasionally required and usually well tolerated in these otherwise young and healthy patients. In this regard, cardiopulmonary bypass support is made available if cardiac or great artery involvement is suggested by preoperative imaging studies. Finally, a separate pulmonary metastasectomy has been performed in 12% of our PMNSGCT cases. Chemotherapy usually resolves extrathoracic metastases when present, but removal of a neck, bone, or central nervous system metastasis has been required as a separate procedure in rare cases. Postoperatively, inspired oxygen concentrations and intravenous fluids are kept to a minimum, particularly in patients who have received a chemotherapy regimen including bleomycin. Otherwise, patients receive routine postoperative care. Overall, operative mortality is 6% in our current institutional series of 142 patients, with all but one death attributed to pulmonary failure. The majority of postoperative deaths have occurred in patients who have undergone large pulmonary resection.17

Long-Term Survival and Pathology Long-term overall survival after surgery has been reported to range between 30% and 60%.10,23-26 We have found that the worst pathology identified in the residual mass after chemotherapy is independently predictive of long-term survival (Kesler et al, 1999).23 In our institutional series, 60% of residual masses have pathologically demonstrated benign residual disease in the form of either necrosis or mature teratoma (Fig. 132-6). Patients who demonstrate complete tumor necrosis with no evidence of viable tumor cells have an excellent long-term prognosis (Fig. 132-7). Patients with pathologic evidence of mature teratoma, with or without necrosis,

Malignant 40%

Persistent germ cell tumor 26%

Benign 60%

Necrosis 27%

demonstrate intermediate survival, with a few late deaths attributed to hematologic dyscrasias in our series. Long-term follow-up in patients pathologically demonstrating a component of teratoma should include not only serial measurements of serum tumor markers but also CT because surgery for early recurrence of teratoma has a high success rate. On the other hand, teratoma has a propensity to degenerate into malignant histology over time, which carries a significantly worse prognosis despite aggressive surgery. Microscopic evidence of persistent germ cell or degenerative cancer has been present in 40% of our institutional cases. Aggressive salvage surgical therapy with consideration of adjuvant cisplatinbased chemotherapy in cases of viable germ cell cancer pathologically identified in the residual mass results in relatively poor but possible long-term survival even in the presence of rising serum tumor marker levels (Schneider et al, 2004).27

DISCUSSION The relative lower rate of benign histology after cisplatinbased chemotherapy for PMNSGCT as compared with testicular nonseminomatous germ cell cancers has prompted exploration of different chemotherapeutic strategies. A recent multi-institutional trial randomized high-risk nonseminomatous germ cell patients, which included a subset of PMNSGCT cases, to either standard BEP chemotherapy as the control arm or high-dose cisplatin-based chemotherapy

1.0 Necrosis P  .01 vs. Rest 0.8

Cumulative Survival

1620

0.6 Teratoma P  .01 vs. GCT and Sarcoma 0.4 Persistent GCT 0.2 Sarcoma

0.0 0

Degenerative cancer 14%

Teratoma 33%

FIGURE 132-6 Postchemotherapy histology of resected masses is not infrequently heterogeneous. Note percentage of worst pathologic diagnoses (necrosis, teratoma, persistent germ cell cancer, degenerative cancer in order of malignant behavior) in surgical specimens of 142 patients.

Ch132-F06861.indd 1620

100 Months

200

FIGURE 132-7 Long-term survival by the worst pathologic diagnosis microscopically identified in the residual mass. Survival curves were generated from two institutional reports. GCT, germ cell tumor. (DATA FROM KESLER KA, RIEGER KM, GANJOO KN, ET AL: PRIMARY MEDIASTINAL NONSEMINOMATOUS GERM CELL TUMORS: THE INFLUENCE OF POSTCHEMOTHERAPY PATHOLOGY ON LONG-TERM SURVIVAL AFTER SURGERY. J THORAC CARDIOVASC SURG 118:692-700, 1999; AND SCHNEIDER BP, KESLER KA, BROOKS JA, ET AL: OUTCOME OF PATIENTS WITH RESIDUAL GERM CELL OR NON–GERM CELL MALIGNANCY AFTER RESECTION OF PRIMARY MEDIASTINAL NONSEMINOMATOUS GERM CELL CANCER. J CLIN ONCOL 22:1195-1200, 2004.)

1/21/2008 4:10:11 PM

Chapter 132 Germ Cell Tumors of the Mediastinum

with stem cell rescue as the experimental arm for first-line therapy.29 Initial results of this prospective randomized trial have found no differences in either treatment arm. Walsh and coworkers from M. D. Anderson Hospital reported on 20 PMNSGCT patients who received a very intensive chemotherapy regimen with two cycles of eight different chemotherapy agents in various combinations.29 There was high chemotherapy-related toxicity, but a 2-year survival rate of 58% in this series, which included patients who had failed first-line therapy, was encouraging. Longer-term follow-up and further evaluation with this aggressive chemotherapy approach is needed. Our institution has begun a phase II study with a four-agent regimen (paclitaxel, gemcitabine, etoposide, and cisplatin). While the search for more effective chemotherapy regimens continues, we have increasingly employed either non–bleomycin- or minimal bleomycincontaining regimens to minimize surgical risks.

SUMMARY Germ cell tumors originating in the anterior mediastinal compartment represent a rare but biologically interesting group of tumors that usually present in children or young adults. Knowledge of the specific biologic behaviors, diagnostic, and therapeutic approaches for the three histologic types—mature teratoma, seminomatous germ cell cancer, and nonseminomatous germ cell cancer—is important to optimize outcome.

COMMENTS AND CONTROVERSIES Dr. Kesler has provided an excellent review of an important group of tumors not commonly seen by thoracic surgeons. There are a number of important points to emphasize. Benign teratomas are usually diagnosed by CT alone. Resection is the appropriate strategy, taking care to avoid injury to the phrenic nerves or great vessels. Inflammatory adherence to mediastinal fat is the norm, making a video-assisted approach less desirable except for small lesions. There is no role for surgical resection of PMSGCT because complete response to cisplatin-based chemotherapy is predictable. Residual mass after chemotherapy need not be resected because this tissue is always benign. For patients with PMNSGCT, surgery does play a role. Residual mass after chemotherapy needs to be resected. This plan is fol-

Ch132-F06861.indd 1621

1621

lowed irrespective of serum tumor marker status or PET findings. This strategy provides superior results than additional chemotherapy. Cystic masses growing while the patient is on chemotherapy are benign teratomas and need to be resected. Patients with microscopic viable germ cell tumor in the resected specimen should receive adjuvant cisplatin chemotherapy. G. A. P.

KEY REFERENCES Kesler KA, Rieger KM, Ganjoo KN, et al: Primary mediastinal nonseminomatous germ cell tumors: The influence of postchemotherapy pathology on long-term survival after surgery. J Thorac Cardiovasc Surg 118:692-700, 1999. ■ Seventy-nine patients with the diagnosis of PMNSGCT underwent 82 thoracic surgical procedures after cisplatin-based chemotherapy. The pathologic finding of either complete tumor necrosis or benign teratoma in 47 of these patients was predictive of excellent to good long-term survival, respectively. Pathologic findings of persistent germ cell cancer or degenerative cancer in the remainder of patients was predictive of poor but possible survival. Nichols CR: Mediastinal germ cell tumors: Clinical features and biologic correlates. Chest 99:472-479, 1991. ■ This review article focuses on the unique biologic and genetic aspects of primary mediastinal nonseminomatous germ cell tumors. Schneider BP, Kesler KA, Brooks JA, et al: Outcome of patients with residual germ cell or non–germ cell malignancy after resection of primary mediastinal nonseminomatous germ cell cancer. J Clin Oncol 22:1195-1200, 2004. ■ Forty-seven patients with PMNSGCT underwent aggressive surgery to remove residual malignant disease in the form of either persistent germ cell cancer or degenerative cancer after chemotherapy. Overall, 16 of these patients were free of disease after last follow-up. This reference includes rationale and indications for “salvage” surgical therapy after first-line cisplatin-based chemotherapy. Strollo DC, Rosado de Christenson ML, Jett JR: Primary mediastinal tumors: I. Tumors of the anterior mediastinum. Chest 112:511-522, 1997. ■ This article is mainly a review of the radiographic findings of all anterior mediastinal neoplasms, including the three germ cell histology types. Wright CD, Kesler KA: Surgical techniques and outcomes for primary nonseminomatous germ cell tumors. Chest Surg Clin N Am 12:707715, 2002. ■ In this review article the authors discuss the surgical approach to PMNSGCTs after cisplatin-based chemotherapy.

1/21/2008 4:10:12 PM

chapter

133

LYMPHOMA OF THE MEDIASTINUM Timothy S. Fenske Nancy L. Bartlett

Key Points ■ Confirm specimen handling with the pathologist prior to the pro-

■

■

■

■

cedure in any patient with suspected intrathoracic lymphoma. Tissue may need to be transported in saline to allow for flow cytometric analysis. Chest tubes are usually unnecessary for management of pleural effusions in patients with newly diagnosed lymphoma. Effusions often resolve rapidly following the initiation of chemotherapy. Nodular sclerosis Hodgkin’s lymphoma and primary mediastinal large B-cell lymphoma are the most common mediastinal lymphomas and are often difficult to distinguish. Both are associated with extensive fibrosis and large biopsies are often required to identify diagnostic malignant cells. Lymphoblastic lymphoma of the mediastinum, seen most commonly in children and young adult men, is a medical emergency requiring urgent initiation of therapy. Most patients with Hodgkin’s lymphoma or large cell lymphoma of the mediastinum have substantial residual masses after successful therapy, and repeat biopsy is not indicated in most cases.

Lymphomas are malignant neoplasms of lymphocytes and their precursor cells, the principal cellular elements of the immune system. Historically, lymphomas were classified merely by their histologic appearance, specifically cell size (e.g., small, large, mixed) and architecture (nodular or diffuse). The current classification system is the World Health Organization (WHO) system, which defines specific subcategories of lymphoma according to the immunologic and molecular characteristics of the lymphoma cells as well as the morphology (Harris et al, 1999).1,2 Although most subtypes of lymphoma can potentially involve the mediastinum or lungs, only a few present as an isolated mediastinal or pulmonary mass. Those with the potential for a primary thoracic presentation are the focus of this chapter, specifically Hodgkin’s lymphoma (HL), large cell lymphoma, lymphoblastic lymphoma, and pulmonary mucosa–associated lymphoid tissue (MALT) lymphoma. We discuss the diagnosis, clinical features, staging, treatment, complications of treatment, and prognosis for each of these subtypes when they present in the mediastinum or lung. The incidence of non-Hodgkin’s lymphoma (NHL) continues to rise, and it is estimated that 63,190 new cases of NHL will be diagnosed in the United States in 2007.3 The cause of this sustained increase is still not understood. The human immunodeficiency virus (HIV) epidemic and the

increase in NHL associated with solid-organ transplantation account for only a minority of these new lymphomas. Primary mediastinal large cell lymphomas represent 2% to 3% of all NHL and 5% of all aggressive lymphomas.4 Lymphoblastic lymphomas account for approximately 30% of pediatric NHL, but they are much less common in adults, representing less than 5% of all NHL.5 More than half of patients with lymphoblastic lymphoma present with mediastinal masses.6 Primary pulmonary lymphomas are quite rare. Most are low grade and originate from the mucosa-associated lymphoid tissue of the bronchus. Primary effusion lymphoma, a rare neoplasm seen primarily in patients with advanced HIV infection, can present in the pleural or pericardial spaces.7 Hodgkin’s lymphoma is much less common than NHL, with an estimated 8,190 new cases of HL diagnosed in the United States in 2007. In contrast to NHL, there has been no change in the rate of occurrence over the past several decades.3 The incidence of HL varies significantly with geography, suggesting either an environmental or a genetic association. HL is very rare in Japan, but, interestingly, the incidence increases in Japanese Americans, suggesting an important environmental component.8,9 HL frequently involves intrathoracic structures, especially mediastinal lymph nodes, but disease limited to intrathoracic sites is uncommon, accounting for approximately 3% of patients diagnosed with HL.10 Presenting symptoms caused by mediastinal adenopathy, such as cough or chest pain, are common. However, during evaluation of these symptoms, a peripheral lymph node is often identified, thereby avoiding the need for a biopsy of mediastinal nodes. The clinical features of all mediastinal lymphomas have significant overlap. However, subtle differences in presenting signs and symptoms and patient characteristics may make one diagnosis more likely and help guide the evaluation. Symptoms attributable to an enlarging mediastinal mass can include chest pain, cough, dyspnea, wheezing, stridor, hoarseness, dysphagia, and superior vena cava (SVC) syndrome with swelling of the face, neck, and upper extremities. SVC syndrome is more common in patients with lymphoblastic lymphoma and large cell lymphoma than in HL. Occasionally, cardiac tamponade may ensue from an associated pericardial effusion. Interestingly, patients with bulky mediastinal lymphoma may have no symptoms related to the adenopathy and come to medical attention during evaluation for an enlarged painless peripheral node. Occasionally, patients with isolated mediastinal lymphoma come to medical attention as a result of an incidental finding on a chest radiograph. An asymptomatic presentation is more likely in patients with HL and large cell lymphoma than in patients with lymphoblastic lym-

1622

Ch133-F06861.indd 1622

1/21/2008 4:11:00 PM

Chapter 133 Lymphoma of the Mediastinum

phoma. Contrasting clinical features of HL, large cell lymphoma, lymphoblastic lymphoma, and pulmonary lymphoma are discussed in more detail subsequently.

BIOPSY TECHNIQUES AND SPECIMEN HANDLING Tissue biopsy is essential in the diagnosis and management of patients with primary mediastinal lymphomas. Recent advances in the immunology and molecular biology of lymphomas, as well as new diagnostic reagents and methods, have resulted in more precise diagnoses.2 The proper handling of specimens for adjunctive diagnostic tests is critical whenever lymphoma is suspected. Do not transport specimens on dry towels or surgical sponges; submit them to the pathologist in saline along with the patient’s clinical history and differential diagnosis. The pathologist usually reserves fresh cells or frozen tissue for immunophenotyping and molecular diagnostics as needed. Immunophenotyping is performed, either by flow cytometry or using immunohistochemical methods on slides prepared from frozen tissue or paraffin-embedded fixed tissue, on nearly all new cases of NHL or HL. Flow cytometry requires a fresh cell suspension, but it offers the advantage of preservation of antigens. Although fewer antigens are preserved in fixed and embedded tissues, immunohistochemical staining of paraffin-embedded specimens allows analysis of archival specimens and offers the benefit of correlation with architectural and cellular details. Application of the WHO classification system requires the integration of clinical, morphologic, cytogenetic, molecular, and immunophenotypical features to accurately characterize lymphoproliferative disorders. Therefore, it is essential that all available clinical and diagnostic information related to a specimen be made available to the hematopathologist.

Needle Aspiration and Biopsy Because of the improved diagnostic methods previously discussed, a less invasive procedure such as transthoracic fineneedle aspiration (FNA) or core-needle biopsy may lead to a precise diagnosis without the need for surgery in some cases of mediastinal lymphoma. In addition, the use of CT has enhanced the accuracy and safety of these techniques in patients with mediastinal lymphoma. Although FNA is a rapid and cost-effective method, it provides only cytologic material. Cytology alone is less useful for the initial diagnosis of lymphomas because the architectural pattern is often necessary for accurate subclassification. In addition, FNA often does not provide adequate tissue for immunophenotyping, especially when the lymphoma is associated with extensive fibrosis (a common finding in HL and NHL of the mediastinum), limiting the ability to aspirate cells. However, if an adequate number of cells can be aspirated, many pathologists agree that FNA may be adequate in the setting of relapsed disease because it is often easier to confirm a previous diagnosis than to render an initial diagnosis on the basis of limited material. Because of the lack of fibrosis and a unique cytologic appearance and immunophenotype, lymphoblastic lymphoma (LL) may represent the one setting in which FNA of a medi-

Ch133-F06861.indd 1623

1623

astinal mass is often diagnostic. This high-grade lymphoma often presents as SVC syndrome or severe dyspnea and progresses extremely rapidly, and the ability of pathologists to provide a preliminary diagnosis within hours on the basis of an FNA may allow earlier initiation of therapy. In one report of eight children with LL, FNA was employed as the initial diagnostic procedure.11 Six of the children presented with an anterior mediastinal mass. Immunophenotyping established the T-cell derivation in all cases, and treatment was initiated based only on FNA results in six cases. Two patients had subsequent surgical biopsies that confirmed the FNA diagnosis of LL. In a separate retrospective study, nine of nine cases of LL were correctly identified based on specimens obtained by FNA.12 In this report, however, the authors did not indicate how many specimens were obtained from the mediastinum. A multi-institutional study evaluated the utility of FNA biopsy for lesions in the mediastinum by analyzing 189 cases of neoplastic and non-neoplastic lesions.13 Of the 189 specimens, 27 were non-neoplastic, 81 were metastatic neoplasms (primarily lung), and 53 were primary mediastinal neoplasms (28 lymphomas, 13 thymomas, 5 germ cell tumors, 3 schwannomas, 1 neuroblastoma, 2 sarcomas, and 2 not otherwise specified). Of the 28 lymphomas, 15 (53%) required surgical biopsies either for confirmation of the diagnosis or subclassification of the lymphoma. Of 16 large cell lymphomas, 2 were misclassified as thymoma and 1 as melanoma on the basis of FNA. In addition, 1 lesion classified as NHL on FNA was a lymphocyte-predominant thymoma on surgical biopsy. The two most common subtypes of isolated mediastinal lymphoma, that is, large cell lymphoma with sclerosis and nodular sclerosing HL, are both composed of dense bands of fibrosis and often have a paucity of malignant cells, which makes establishing a diagnosis by FNA notably difficult. Large cell lymphomas, undifferentiated carcinomas, and melanomas can be difficult to differentiate cytologically, and artifactual cell clustering and elongation can result in a confusing pattern.13 Other series documenting the improved accuracy of peripheral lymph node FNA in establishing an initial diagnosis of lymphoma cannot be generalized to the specific setting of mediastinal lymphomas. For example, Stewart and colleagues reported that FNA of palpable lymph nodes correctly identified 61 of 67 (91%) malignant lymphomas, with 27% of the cases representing recurrent lymphomas.14 However, in a more recent study, Hehn and coworkers found that a specific and complete histologic diagnosis was obtained in only 27 of 93 (29%) of FNA attempts at initial diagnosis, and in only 9 of 22 FNA attempts (41%) done in the setting of recurrent disease (Hehn et al, 2004).15 The use of percutaneous core-needle biopsies (PCNB) can sometimes overcome the limitations of FNA by retaining the architecture of the tissue and providing serial sections for histochemical and immunocytochemical stains. To avoid the risk of pneumothorax, a direct mediastinal approach is chosen over a transthoracic approach; and for patients with anterior mediastinal masses, an anterior parasternal approach is preferred.16,17 If a PCNB is technically feasible, the largest gauge needle possible (i.e., 16-18 Fr) is used and multiple cores

1/21/2008 4:11:00 PM

1624

Section 7 Mediastinum

obtained. In general, the peripheral portion of the mass is sampled to avoid inclusion of necrotic tissue in the biopsy. Only limited data are available on the success rate of PCNB specifically for mediastinal lymphomas. In the largest published series to date, 42 patients ultimately proven to have mediastinal lymphoma underwent image-guided core needle biopsy. There was a 71.5% success rate for the PCNB procedure. No significant difference in success rate was found between NHL and HL cases.18 Four other studies evaluating PCNB for lymphoma diagnosis have been published.19-22 Intrathoracic biopsies constituted a minority (14%-24%) of the biopsies in each of these series. In one of these studies, 241 patients with lymphoma (46 with mediastinal lymphoma) underwent PCNB as their initial biopsy. Overall, an 82.5% success rate of PCNB was observed.19 The other three studies included patients undergoing initial evaluation as well as patients with suspected relapse or progressive disease.20-22 Although the results of the mediastinal biopsies are not specifically reported, in these series between 83% and 93% of the PCNB procedures yielded sufficient material for formulation of a treatment plan.

Open Biopsy When a needle aspiration or biopsy is not feasible or does not yield a diagnosis, additional tissue is obtained by mediastinoscopy or mediastinotomy. Details of these procedures are covered in Chapter 8. Rarely, a thoracoscopy, thoracotomy, or median sternotomy may be needed to establish a diagnosis. When a suspected mediastinal lymphoma is sampled, a large specimen, including the periphery of the tumor, is necessary to distinguish the unique clinical characteristics of the disease. Frozen section biopsy is necessary to ensure that sufficient tissue is obtained and to guide decisions in obtaining special studies. Surgeons often rely on the results of a frozen section biopsy to avoid resection when lymphoma is suspected. De Montpreville and associates analyzed frozen section biopsy specimens from 417 patients with mediastinal tumors, including 46 patients with lymphoma. The pathologists obtained sufficient material for a definitive diagnosis (excluding normal or fibrotic lymph nodes) in 351 of 353 cases. In 45 of the 46 cases with lymphoma, the correct diagnosis was suspected on frozen section, permitting avoidance of resection.23 In a smaller study, 30 patients with mediastinal adenopathy without evidence of a primary lung tumor underwent videoassisted thoracoscopic surgery (VATS). The VATS procedure identified lymphoma in 18 patients, sarcoidosis in 8 patients, and nonspecific lymphoid hyperplasia in 4 patients (Massone et al, 2003).24

nophenotypic analysis of pleural fluid specimens may result in improved accuracy in the diagnosis of lymphoma.26 In one study, 21 of 23 patients (91%) with previously diagnosed NHL had positive effusions and 12 of 23 patients (52%) who were clinically suspected to have lymphoma had positive effusions.26 Pleural fluid cytology is rarely positive in HL. If lymphoma is suspected, a chest tube is not placed before initiating definitive therapy. Most effusions secondary to HL or aggressive NHL will resolve quickly with systemic therapy.

Prebiopsy Corticosteroids Historical teaching dictates that patients with suspected lymphoma do not receive corticosteroids before biopsy because of the theoretical risk of obscured results due to rapid tumor response. In reality, except in the rare case of LL, corticosteroids are unlikely to have a significant detrimental effect if tissue is obtained within 24 to 48 hours of the first dose. In one study of 86 children with mediastinal lymphoma, 23 received prebiopsy corticosteroids. In 5 (22%) an adverse effect on the pathologic diagnosis was observed: 1 patient with HL and 4 with probable LL (Borenstein et al, 2000).27 However, the only indication for prebiopsy corticosteroids is severe, life-threatening airway compromise. Although patients with SVC syndrome can be quite symptomatic, these symptoms are not life threatening over the short term and corticosteroids are not administered until diagnostic tissue is obtained. If LL is suspected, every effort is made to obtain tissue within 1 day of presentation and before administration of corticosteroids.

HODGKIN’S LYMPHOMA Pathology Hodgkin’s lymphoma is a neoplastic proliferation of ReedSternberg (R-S) cells or R-S variants, which are large cells with abundant cytoplasm and multiple or multilobed nuclei. R-S cells are surrounded by host inflammatory cells, including lymphocytes, plasma cells, neutrophils, and eosinophils.2 They are derived, in most cases, from germinal center B cells.28 R-S cells usually express two cell-surface antigens, CD30 (Ki-1, Ber-H2) and CD15 (Leu-M1). HL is classified as either classic HL or nodular lymphocyte predominant HL, with nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted being subtypes of classic HL. Nodular sclerosis HL is the most common subtype of primary mediastinal HL and is characterized by dense fibrotic bands that subdivide the abnormal lymphoid tissue into circumscribed nodules.

Pleural Fluid Cytology Pleural fluid cytology may also provide a diagnosis in patients with large mediastinal masses, especially in patients with LL. Chaignaud and colleagues noted a correlation between pleural effusions and LL: 10 of 14 (71%) patients with LL and only 7 of 60 (12%) patients with HL had pleural effusions at initial presentation.25 Subsequently, three children were diagnosed with LL by performing cytologic and flow cytometric examinations of their pleural fluid. Combined cytologic and immu-

Ch133-F06861.indd 1624

Clinical and Laboratory Features Most patients with HL present with asymptomatic peripheral adenopathy. Lymph node involvement is characterized by contiguous spread with cervical, supraclavicular, and mediastinal nodes being affected most often. There is a bimodal age distribution in most economically developed countries, with a peak at 15 to 40 years of age and a second peak late in life. Severe, generalized pruritus is common in HL, rare in NHL,

1/21/2008 4:11:00 PM

Chapter 133 Lymphoma of the Mediastinum

and often precedes the diagnosis by months. Alcohol-induced pain in involved lymph nodes is rare but pathognomonic of HL. Approximately two thirds of patients with HL have mediastinal involvement at presentation.29 Isolated mediastinal HL occurs most often in young women and usually presents as cough or chest pain. Interestingly, patients who present with cervical or supraclavicular lymphadenopathy are often found to have a bulky asymptomatic mediastinal mass at staging (Fig. 133-1). Systemic symptoms including a temperature of more than 38ºC (100.4ºF) for 3 consecutive days, drenching night sweats, or unexplained weight loss of more than 10% of body weight in the preceding 6 months occur in about 25% of patients with HL, but they are uncommon in early-stage disease, including isolated mediastinal disease.30 Pruritus, systemic symptoms, and many of the laboratory abnormalities seen in HL are probably a result of cytokine production by R-S cells. Nonspecific laboratory abnormalities associated with HL may help in differentiating HL and NHL. Leukocytosis with neutrophilia is common, even in early-stage disease, and is rarely seen in NHL. Thrombocytosis, lymphopenia, eosinophilia, and monocytosis are also seen in a small percentage of patients with HL. An elevated erythrocyte sedimentation rate (ESR) reflects an activated reticuloendothelial system, which, if abnormal at diagnosis, may be useful in following

FIGURE 133-1 Bulky mediastinal mass in a young woman with Hodgkin’s lymphoma presenting with supraclavicular adenopathy and no chest symptoms.

1625

patients after treatment.29 The serum alkaline phosphatase value is elevated in approximately 50% of patients with HL, including those patients without evidence of bony or hepatic involvement. Anemia, low serum albumin, and elevated lactate dehydrogenase (LDH) levels are usually associated with advanced-stage disease.

Staging The Ann Arbor staging system (Table 133-1) is used to classify both HL and NHL and is based on the number and location of involved lymph node regions. The absence or presence of systemic symptoms is noted by an A or B, respectively. The designation E applies to involvement of extranodal tissue contiguous with lymph node disease. Multiple extranodal sites including lung, pericardium, pleura, and chest wall are common in patients with bulky mediastinal HL.31 Pleural fluid cytology is rarely positive in HL. Patients with isolated mediastinal HL have stage I disease if they have no extranodal extension and stage IIE disease if they have one or more sites of contiguous extranodal involvement. Clinical staging includes a thorough history and physical examination, placing particular emphasis on assessing adenopathy, sites of extranodal involvement, and B symptoms. Identification of a peripheral lymph node in a patient with mediastinal adenopathy may prevent the need for a mediastinal biopsy. Laboratory studies include a complete blood cell count (CBC) with differential, an ESR, and determination of LDH, alkaline phosphatase, albumin, total bilirubin, and calcium values. Bone marrow biopsy from at least one site is performed in patients with clinical stage III or IV disease or B symptoms. For patients considered high risk for bone marrow involvement (those older than age 35, those with iliac/inguinal involvement, or those with one or more cytopenias), bilateral bone marrow biopsy may be superior to a unilateral biopsy.32 Patients with stage IA or IIA disease are very low risk (<1%) for bone marrow involvement, and therefore do not require bone marrow biopsy for initial staging.32,33 Imaging studies include a posteroanterior and lateral chest radiograph with calculation of the maximal mediastinal mass ratio (Fig. 133-2) and CT of the chest, abdomen, and pelvis. CT is especially useful in designing radiation therapy portals if radiation therapy is planned. The advent of modern multidetector CT has made bipedal lymphangiography obsolete. Chest MRI is probably more sensitive than chest CT in evaluating chest wall, pericardial, and pleural involvement, but

TABLE 133-1 Ann Arbor Staging System for Lymphoma Stage I

Involvement of a single lymph node region or lymphoid structure, or involvement of a single extralymphatic site (IE).

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm that may be accompanied by localized contiguous involvement of an extralymphatic site or organ (IIE).

Stage III

Involvement of lymph node regions on both sides of the diaphragm that may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of an extralymphatic site or organ (IIIE).

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without lymph node involvement.

Note: The absence or presence of fever (>38°C), unexplained weight loss (>10% body weight), or night sweats should be designated by the suffix letter A or B, respectively.

Ch133-F06861.indd 1625

1/21/2008 4:11:01 PM

1626

Section 7 Mediastinum

Based on a large randomized trial, the use of surgical staging laparotomy and splenectomy for routine staging of patients with early-stage HL is no longer routinely performed.39 In this landmark report, the European Organization for Research and Treatment of Cancer (EORTC) demonstrated no benefit of surgical staging. The 6-year progression-free survival and overall survival rates were similar in clinical- and laparotomystaged patients. Current approaches to the treatment of early-stage HL, most of which incorporate chemotherapy, have also led to a decreased necessity of staging laparotomy. Historical series of laparotomy staging have shown a very low risk (<5%) of infradiaphragmatic disease in patients with clinically isolated mediastinal HL, and staging laparotomy is never indicated in this subset of very favorable HL.10,40

Treatment and Prognosis

FIGURE 133-2 Example of mediastinal mass ratio calculation in a patient with bulky mediastinal Hodgkin’s lymphoma. The mediastinal mass ratio equals the maximal mediastinal width divided by the maximal intrathoracic diameter.

these results have not had an effect on the outcome of therapy, and thus MRI is not part of standard staging. Gallium scans are relatively insensitive to tumor involvement in the abdomen owing to positive uptake in the liver, intestine, and spleen, and they add little to initial staging evaluation of HL. The value of positron emission tomography (PET) for initial staging in HL has been evaluated in several studies, most of which are retrospective series comparing the performance of PET with other imaging modalities. Many include a mixture of NHL and HL patients without a separate analysis for each histologic group. Furthermore, discordant findings between imaging modalities were not typically evaluated with biopsy confirmation. However, despite these limitations, it does appear that PET is at least as accurate as CT in the primary staging of HL, with PET upstaging between 11% and 41% and downstaging between 0% and 28% of patients in several published series.34,35 In one prospective study, patients were staged with both conventional imaging as well as PET. Treatment decisions were based on the conventional imaging; however, it was determined that inclusion of the staging PET in the initial treatment planning would have led to an alteration of therapy in 18% of cases (Naumann et al, 2004).36 Combined PET/CT is now available at many centers. Preliminary studies in lymphoma patients suggest that this imaging modality has significantly increased sensitivity when compared with conventional CT (96% sensitivity versus 61% sensitivity), with enhanced sensitivity when compared with PET alone and a trend toward increased sensitivity when compared with CT and PET scan performed separately but read side by side.37,38 Taken together, it appears that the optimal use of PET scanning in the staging of HL is in combination with CT.

Ch133-F06861.indd 1626

Over the past 30 years there has been great success in the treatment of early-stage HL; however, considerable evolution of treatment strategies has occurred. This has been driven primarily by an increasing incidence of severe, therapy-related late complications occurring more than 10 years after treatment. Historically, after a staging laparotomy, pathologic stage I or II HL, without bulky mediastinal disease, was treated with radiation therapy alone, either subtotal lymphoid irradiation (STLI) or mantle irradiation depending on the extent of disease.41 Recent reports of second malignancies and increased cardiovascular mortality related to radiation therapy have encouraged evaluation of new therapies, with the hope of maintaining or improving efficacy while minimizing late effects. Currently, standard therapy for nonbulky early stage disease is short-course chemotherapy followed by involved field radiation therapy (IFRT) or chemotherapy alone. The ABVD regimen (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) is well tolerated and has emerged as the first-line therapy for patients with either limited- or advanced-stage HL. When compared with older regimens such as MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, prednisone), ABVD has less acute toxicity, as well as a substantially lower risk for therapy-related acute leukemia, myelodysplasia, and infertility.42 An Italian trial for patients with clinical stage I to IIA HL, tested four cycles of ABVD followed either by IFRT or STLI in 136 patients (Bonadonna et al, 2004).43 At 12 years, the progression-free and overall survival rates were 93% and 96% for ABVD plus STLI and were 94% and 94% for ABVD plus IFRT, indicating that, in the setting of combined-modality therapy, the field of radiation therapy could be substantially decreased without compromising outcome. Theoretically, more limited radiation therapy fields significantly reduce the number of radiation-associated second malignancies and cardiovascular events. Preliminary results of a large randomized trial by the German Hodgkin Study Group (GHSG) indicate that two cycles of ABVD chemotherapy and 20 Gy of IFRT may be adequate treatment for patients with favorable early-stage disease; however, longer follow-up is needed.44 Two-year event-free survival and overall survival rates were identical

1/21/2008 4:11:01 PM

Chapter 133 Lymphoma of the Mediastinum

(98%) for patients randomized to two versus four cycles of ABVD followed by 20 versus 30 Gy of IFRT. Previous studies by the GHSG also showed no difference in outcome when 20 Gy, 30 Gy, or 40 Gy was administered to nonbulky sites after chemotherapy.45 As described later, late cardiac toxicities are significantly decreased with mediastinal doses less than 30 Gy (Hancock et al, 1993).46-48 A limited number of studies have also evaluated chemotherapy alone in patients with early-stage disease. In one Spanish series, 80 patients with nonbulky stage I and II HL were treated with six cycles of ABVD alone.49 With a median follow-up of 78 months, the overall and progression-free survival rates at 7 years were 97% and 88%, respectively. In a study from the Memorial Sloan-Kettering Cancer Center, 152 patients with newly diagnosed HL were randomized to six cycles of ABVD versus combined modality therapy (six cycles of ABVD followed by radiation therapy). At 5 years, progression-free survival was 86% for combined modality therapy versus 81% for ABVD (P = .61). Overall survival was 97% for combined modality therapy versus 90% for ABVD (P = .08), approaching statistical significance (Straus et al, 2004).50 In a National Cancer Institute of Canada (NCIC)/ Eastern Cooperative Oncology Group (ECOG) trial, 399 patients with clinical stage I-IIA HL were randomized to receive either four to six cycles of ABVD or a regimen that included STLI. With a median follow-up of 4.2 years, the estimated overall survival was 96% for the ABVD group and 94% for the radiation therapy group. Disease progression occurred in 13% of the ABVD group and 7% of the radiation therapy group. Patients who achieved clinical remission after two cycles of ABVD alone experienced 5-year freedom from progressive disease that was similar to that observed in patients receiving combined-modality therapy (Meyer et al, 2005).51 Many clinicians have therefore adopted an approach in which patients with stage I-IIA disease are treated first with two cycles of ABVD and then have their disease restaged. If the patient attains clinical remission after two cycles of ABVD, he or she is treated with two to four additional cycles of ABVD. If clinical remission is not attained after two cycles of ABVD, a combined-modality approach is preferred. Patients with clinical stage I or II disease and a bulky mediastinal mass, defined as a mediastinal mass ratio greater than one third (see Fig. 133-2), have a worse prognosis compared with other patients with early-stage disease. Because of high relapse rates in this subset of patients when they are treated with either chemotherapy alone or radiation therapy alone, combined-modality therapy is recommended.52 Most patients are treated with four to six cycles of ABVD followed by IFRT. An alternative regimen, designed to minimize both acute- and long-term toxicities, is the Stanford V regimen of 12 weeks of chemotherapy followed by IFRT to sites of bulky (≥5 cm) nodal or macroscopic splenic disease (Horning et al, 2002).53 Cumulative doses of bleomycin and Adriamycin are substantially less with the Stanford V regimen than with ABVD, minimizing the risk of cardiopulmonary toxicity in conjunction with mediastinal radiation therapy. In a phase II study of the Stanford V regimen for bulky mediastinal stage I/II or stage III/IV HL, at 5 years progression-free and overall survival rates were 89% and 96%, respectively.53 The 5-year

Ch133-F06861.indd 1627

1627

progression-free survival rate for the 46 patients with bulky stage I to II disease was 97%. No cases of secondary leukemia were observed, and fertility was maintained.53 On the basis of these results, a large Intergroup (ECOG, Cancer and Leukemia Group B [CALGB], Southwestern Oncology Group [SWOG], and NCIC) phase III trial comparing the Stanford V regimen and ABVD was recently completed and results are pending.

Complications of Treatment Treatment advances have dramatically improved the survival of patients with HL. Unfortunately, long-term survival frequently goes hand in hand with late-term treatment complications. Consideration of latent side effects play an integral role in the choice of treatments for this highly curable malignancy. Investigators at Stanford University performed a retrospective analysis of 2498 patients with HL treated between 1960 and 1995 to determine latent complications of therapy and causes of mortality.54 At 15 years, risk of death from HL was 17%, with only a slight increase thereafter. Risk of death from other causes was also 17% at 15 years; however, there was a sharp increase after 15 years. Similar results have also been reported from other centers, with a consistent association between increased doses of mediastinal radiation and delayed cardiopulmonary toxicities and secondary neoplasms. Hancock and associates reviewed records of 635 children and adolescents with HL to ascertain the risk of cardiac disease after radiation treatment. Overall, a 29.6 relative risk for death from cardiac disease was observed compared with age-, sex-, and race-matched controls from the general U.S. population. Deaths only occurred in patients who received greater than or equal to 40 Gy mediastinal radiation.47 In a similar study of 2232 adult patients, a 3.1 relative risk of death from cardiac disease was observed. No increased risk was seen for patients receiving less than or equal to 30 Gy of mediastinal radiation. The risk of myocardial infarction was significantly increased for patients who were age 20 or younger at the time of treatment.46 Additional series have confirmed the increased risk for long-term cardiovascular complications, with the highest risk again in those patients receiving higher doses of radiation therapy to the mediastinum.48,55,56 Long-term pulmonary toxicities have been modest. In a series of 145 patients treated for HL with ABVD, mediastinal RT, or both, Horning and associates57 reported a decrease in forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLCO) in the first 15 months after treatment followed by recovery within 36 months. In two other studies, decreases in pulmonary function were seen in 20% to 37% of patients treated with ABVD (with or without radiation therapy).50,58 However, it is very rare for chronic symptomatic pulmonary disease to develop in these patients. The increased incidence of second malignancies after treatment for HL has been reported in numerous studies. For patients who have received mediastinal RT, breast and lung carcinomas are of primary concern. In a large study of over

1/21/2008 4:11:01 PM

1628

Section 7 Mediastinum

32,000 patients pooled from 16 cancer registries, a 21.9% risk of solid tumors was observed at 25 years. The relative risk of lung, breast, and gastrointestinal cancers was 2.9, 2.0, and 1.7, respectively (Dores et al, 2002).59 Several other large series have also reported similar findings.60-64 The relative risk of breast carcinoma is significantly higher for women who were younger at the time of diagnosis, with a relative risk of 56 for those aged 19 years and younger, 7.0 for those aged 20 to 29 years, and 0.9 for those aged 30 years and older.64 One study found radiation doses of as low as 4 Gy to increase significantly the risk of breast cancer.65 Taking all of the just-provided data together, it has become evident that consideration of alternative treatments such as reduced radiation doses, chemotherapy alone, or combinedmodality therapy with limited radiation therapy fields is necessary for certain populations of HL patients. This is particularly important for women younger than age 30. However, for patients with personal histories of, or significant risk factors for, breast cancer, lung cancer, or cardiovascular disease, similar alternative treatments need to be given serious consideration as well.

LARGE CELL LYMPHOMA Pathology Primary mediastinal large B-cell lymphoma (PMLBL) derives from medullary thymic B cells and is a distinct form of aggressive lymphoma with characteristic biologic and clinical features. The tumor is composed of large cells with variable nuclear features, often with abundant pale cytoplasm. Importantly, R-S cells may be present, and immunohistochemistry is essential in differentiating nodular sclerosing HL and large cell lymphoma of the mediastinum. Many patients have fine, compartmentalizing sclerosis.4 Occasionally, the tumor cells resemble immunoblasts. Immunohistochemical findings confirm the B-cell phenotype by the expression of the Bcell–associated antigen CD20 and absence of the T-cell– associated antigen CD3. In contrast to other large B-cell lymphomas, the large cells are often surface immunoglobulin negative. PMLBL, like classic HL or anaplastic large cell lymphoma (ALCL), may express CD30, although usually at lower levels than HL or ALCL.4 This feature, in addition to the frequent presence of sclerosis and/or R-S cells, can make differentiating this tumor from classic HL or ALCL challenging. A unique pattern of molecular genetic alterations also supports classifying PMLBL as a distinct subtype of diffuse large B-cell lymphoma (DLBCL). Gains involving chromosome 9p, aberrations of the X chromosome, and amplification of the REL locus on chromosome 2 are commonly observed.4 In gene expression profiling studies, the molecular signatures of PMLBL are more like those of Reed-Sternberg cells than DLBCL (Savage et al, 2003).66,67 Unlike in DLBCL, BCL6 is usually not mutated in PMLBL, indicating a pregerminal center origin.4 These highly characteristic patterns observed at the morphologic, cytogenetic, and molecular levels are evidence that a specific sequence of genetic alterations underlies the neoplastic transformation in PMLBL.

Ch133-F06861.indd 1628

Clinical and Laboratory Features PMLBL presents at a younger age, with a median age in the fourth decade, and is more common in women than men. The tumor originates in the thymus and manifests as a locally invasive upper anterior mediastinal mass. There is frequent contiguous spread to the lung, pleura, pericardium, and chest wall and occasionally to the myocardium or bronchus.4,68 Extrathoracic spread is uncommon at diagnosis; however, at relapse or progression, extranodal involvement is common and tends to involve unusual sites, such as the kidneys, breast, adrenal cortex, ovaries, gastrointestinal tract, and central nervous system.4 Similar to other patients with mediastinal masses, patients with PMLBL frequently present with symptoms attributable to the enlarging mediastinal mass, in some cases including airway compromise and the SVC syndrome. As with other large cell lymphomas, the most common laboratory abnormality is an elevated LDH level.69

Staging The Ann Arbor staging system discussed earlier in the section Staging (see Table 133-1) is also used to classify NHL. As in HL, clinical staging includes a thorough history and physical examination, placing particular emphasis on assessing adenopathy, sites of extranodal involvement, and B symptoms. Laboratory studies include a CBC with differential and LDH, creatinine, calcium, and liver function tests. Bilateral bone marrow biopsy specimens are generally considered part of the routine staging of patients with NHL; however, the low incidence of bone marrow involvement in PMLBL makes the utility of this test questionable. Imaging studies include a chest radiograph and CT of the chest, abdomen, and pelvis.

Treatment and Prognosis The standard approach to stage I or II aggressive NHL, including PMLBL, is combined modality therapy. A recent prospective, randomized, multi-institutional study established the superiority of combined-modality therapy over chemotherapy alone in this setting. Two hundred patients received three cycles of CHOP (cyclophosphamide, Adriamycin, vincristine, and prednisone) chemotherapy followed by IFRT, and 201 received eight cycles of CHOP alone (Miller et al, 1998).70 Radiation therapy doses ranged from 40 to 55 Gy. Patients with bulky mediastinal masses were excluded. Patients treated with combined-modality therapy had significantly better 5-year progression-free and overall survival rates (77% and 82%, respectively) than patients treated with CHOP alone (64% and 72%, respectively). Cardiac toxicities were more pronounced in the group receiving chemotherapy alone. In a recent prospective ECOG trial, 352 patients with stage I/II diffuse aggressive NHL (including some patients with bulky PMLBL) were treated with eight cycles of CHOP and then randomized to observation or IFRT (Horning et al, 2004).71 The patients who received radiation therapy enjoyed prolonged progression-free survival; however, no difference in overall survival was observed between the two groups. In another recent study, 647 patients with stage I/II aggressive NHL (excluding patients with bulky disease) were random-

1/21/2008 4:11:01 PM

Chapter 133 Lymphoma of the Mediastinum

ized to three cycles of CHOP followed by IFRT, versus chemotherapy alone with dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) plus sequential consolidation with methotrexate, ifosfamide, etoposide, and cytarabine.72 The ACVBP group had improved overall survival at 5 years (90%) versus the CHOP + IFRT group (81%). These studies have created controversy regarding the optimal use of radiation therapy in patients with limited-stage DLBCL. It is unclear whether these data can be extrapolated to the setting of bulky mediastinal NHL with similar results. A large randomized trial for patients with bulky stage II or stage III-IV disease comparing CHOP chemotherapy to three different third-generation regimens showed no benefit to the alternate regimens.73 However, several retrospective studies have shown a possible advantage of these regimens in PMLBL. Several series report encouraging results with the 12-week MACOP-B (methotrexate, Adriamycin, cyclophosphamide, vincristine [Oncovin], prednisone, and bleomycin) or VACOP-B (etoposide replaces methotrexate) regimens plus IFRT, with overall survival rates of 70% to 93% at 2 to 10 years.74-76 However, because no prospective randomized studies comparing CHOP with other regimens such as MACOP-B in PMLBL exist, the superiority of one particular chemotherapy regimen in the treatment of PMLBL remains unproven. Consolidative radiation therapy may be an important component in the treatment of PMLBL. The strongest data in support of this comes from an Italian study in which patients underwent gallium scanning after completion of MACOP-B. Many patients converted from a positive to a negative gallium scan after consolidation with 30 to 36 Gy of IFRT, and few of these patients experienced relapse, suggesting a critical role for consolidative RT.76 In other reports, however, similar rates of intrathoracic recurrence were seen regardless of whether patients received radiation therapy, although functional imaging was not utilized as part of restaging in these studies.77,78 In recent years, the anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) has been integrated into primary therapy for CD20-positive large cell lymphoma, including PMLBL. A randomized study performed in France and Belgium demonstrated a survival benefit when patients received R-CHOP versus CHOP as their initial therapy for large cell lymphoma (Feugier et al, 2005).79 Overall survival at 5 years was 58% versus 45%, and the 5-year progressionfree survival was 54% versus 30% for the R-CHOP and CHOP groups, respectively. A population-based study from British Columbia confirmed the benefit of adding rituximab to standard chemotherapy (Sehn et al, 2005).80 The 2-year progression-free survival was 69% in the post-rituximab era and 51% in the pre-rituximab era. Preliminary results have also been reported from two other large randomized studies confirming the benefit of adding rituximab to CHOP in the initial therapy of DLBCL.81,82 In a preliminary report, 62 DLBCL patients with stage I or nonbulky stage II disease were treated with three cycles of R-CHOP followed by IFRT. Two-year progression-free survival was 94%, compared with

Ch133-F06861.indd 1629

1629

85% in a matched historical control population treated with three cycles of CHOP followed by IFRT.83 Although none of these studies specifically report results for PMLBL, the results have been extrapolated such that R-CHOP is now considered the standard chemotherapy regimen for PMLBL. Several retrospective studies have evaluated prognostic features PMLBL. Adverse risk factors that are consistently seen across multiple studies include incomplete response to initial treatment, residual positivity by gallium scan, and poor performance status. Other factors such as increased LDH, involvement of extranodal sites, or pleural effusion have been found to have adverse prognostic value in some studies but not others. The most commonly used prognostic score in aggressive NHL, the international prognostic index (IPI), has been found to be of limited value when applied to PMLBL patients.4

LYMPHOBLASTIC LYMPHOMA Pathology Lymphoblastic lymphomas are highly aggressive neoplasms composed of a diffuse and homogeneous population of immature lymphoblastic cells. They are cytologically, histologically, and immunophenotypically identical to acute lymphoblastic leukemia (ALL). In fact, the distinction between LL and ALL is normally based on marrow involvement, with an arbitrary criterion of greater than 25% blast cells in the bone marrow (with or without a lymphomatous mass lesion) used to define a leukemic process. The biologic basis for these different presentations is not known. Most LLs have a precursor T-cell origin. All LLs express terminal deoxynucleotidyl transferase (TdT), which can be demonstrated in either paraffin or frozen sections or by flow cytometry. TdT expression is unique to LLs.2,6

Clinical and Laboratory Features Lymphoblastic lymphoma is diagnosed twice as often in men than women and has a bimodal age distribution, with peaks in the second and seventh decades of life. The majority of patients (60%-70%) present with a large mediastinal mass. Rapid growth of the tumor occasionally causes acute respiratory compromise due to tracheal compression and SVC syndrome and is the most likely NHL to present as a medical emergency.6 Pleural effusions occur in as many as 70% of patients, and thoracentesis may be the quickest and least morbid diagnostic procedure. Pericardial effusions are also common. The most common extranodal sites of involvement are bone marrow and the central nervous system. In contrast to HL and PMLBL, most patients have a markedly elevated LDH. Up to 60% of patients eventually develop bone marrow infiltration and a subsequent leukemic phase clinically indistinguishable from ALL.84

Staging The Ann Arbor staging system is used for LL (see Table 133-1). Most patients present with stage IV disease. Staging

1/21/2008 4:11:01 PM

1630

Section 7 Mediastinum

evaluation includes posteroanterior and lateral radiographs; CT of chest, abdomen, and pelvis; bone marrow aspirate and biopsy; a lumbar puncture; and laboratory studies, including a CBC and electrolytes, LDH, creatinine, uric acid, and liver function tests.

Treatment and Prognosis Because of the highly aggressive nature of LL, intensive multiagent chemotherapy regimens with central nervous system prophylaxis are required. CHOP-like chemotherapy regimens are not sufficient, yielding long-term survival rates of only 38% to 49%.85,86 Currently, therapy for LL is modeled after treatment for ALL. In adults, the hyperCVAD regimen (fractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone, with alternating cycles of intravenous methotrexate and cytarabine) has been evaluated in LL. Thirty-three patients were treated with eight to nine cycles of hyperCVAD over 5 to 6 months, along with intrathecal prophylaxis, maintenance chemotherapy, and radiation therapy to mediastinal masses. There was a 91% complete response rate, and a 3-year freedom from progression of 66% (Thomas et al, 2004).87 In a separate study from Germany, 45 patients were treated for 6 to 12 months with a multi-agent ALL regimen. In this series there was a 93% clinical response rate and a 7-year disease-free survival of 62% (Hoelzer et al, 2002).88 In two relatively large pediatric series, long-term event-free survivals of 75% to 90% were observed using multiagent chemotherapy regimens.89,90 In one of these studies patients received prophylactic cranial radiation therapy,90 and in the other study patients with bulky disease received IFRT.89 Whether there is a benefit in treating bulky mediastinal disease with IFRT is not clear from the literature.88,91-93 It does appear clear that intrathecal chemotherapy is sufficient for prophylaxis of the central nervous system and that prophylactic cranial radiation therapy does not add further benefit.87,89,94 Autologous stem cell transplantation in first remission may offer a benefit for patients who are believed to be at a high risk of relapse, although this issue remains

A

controversial.95 For patients with relapsed disease, a highdose therapy (stem cell transplant) approach is pursued when feasible, with 15% to 40% of patients achieving long-term progression-free survival, depending on whether their disease is chemosensitive before the transplant.96,97 Tumor responses in lymphoblastic lymphoma are extremely rapid, often with complete normalization of radiographic studies within a few days (Fig. 133-3). Patients are at high risk for tumor lysis syndrome and receive their first dose of chemotherapy as an inpatient with vigorous hydration and prophylactic allopurinol or rasburicase. As discussed previously, patients suspected of having LL on clinical grounds do not receive corticosteroids before a diagnostic biopsy or thoracentesis.

PULMONARY LYMPHOMA Pathology The majority of pulmonary lymphomas are low-grade lymphomas, classified as pulmonary mucosa-associated lymphoid tissue (MALT) or bronchus-associated lymphoid tissue (BALT) lymphomas. Historically, many of these were referred to as pseudolymphomas; however, improved immunocytometric and molecular techniques now identify these as monoclonal B-cell lymphomas. They share common morphologic features with other MALT lymphomas, including lymphoepithelial lesions, follicular colonization, and presence of plasma cells and Dutcher bodies. The lymphoma cells resemble small lymphocytes with round or slightly irregular nuclei that center around reactive follicles with a marginal zone–type distribution. A characteristic phenotype includes the presence of the pan–B-cell antigen CD20 and lack of the CD5 and CD10 antigens, which is unique among low-grade lymphomas.2,98,99 Several groups have reported a translocation involving the anti-apoptotic gene API2 on chromosome 11 and the MALT1 gene on chromosome 18 in pulmonary MALT lymphomas, with the prevalence varying between 7% and 38%.100 A translocation between chromosomes 1 and 14 has

B

FIGURE 133-3 Chest radiograph of a young man with lymphoblastic lymphoma at diagnosis (A) and 4 days later (B) after having received cycle 1 of induction chemotherapy.

Ch133-F06861.indd 1630

1/21/2008 4:11:02 PM

Chapter 133 Lymphoma of the Mediastinum

also been reported in a minority of patients with pulmonary MALT lymphoma.100 Fifteen to 20 percent of patients with pulmonary lymphomas have intermediate- or high-grade histology, usually diffuse large B cell. At least a portion of these aggressive lymphomas probably represent transformation of a previous BALT lymphoma.101

Clinical and Laboratory Features Pulmonary MALT lymphomas arise most commonly in patients between the sixth and seventh decades of life.101 Respiratory symptoms include dyspnea, cough (with or without sputum), hemoptysis, and chest pain. B symptoms occur in approximately 20% of patients. Interestingly, nearly half of patients are asymptomatic and diagnosed after routine chest radiography. In one series, a mean interval of 5.3 years (range, 1.5-21 years) between the abnormal chest film and the definitive pathologic diagnosis was reported.102 Radiographic findings are variable but usually consist of localized masses, pulmonary nodules, or infiltrates.103-106 Lobar consolidations and diffuse bilateral infiltrates are seen in some patients. Associated radiographic findings include groundglass attenuation and air bronchograms.105 Pleural effusions are uncommon, and mediastinal or hilar adenopathy is noted in less than one third of patients. A significant proportion of patients (40%-43%) with pulmonary MALT lymphoma have an associated monoclonal gammopathy.106 The majority of patients with pulmonary MALT lymphomas present with stage IE disease.98 A small number of patients have disseminated disease in other MALT sites such as stomach or salivary glands. Two cases of pulmonary MALT lymphoma in association with mycobacterial infections have been reported.107,108

Staging Disease outside the lung is very uncommon in pulmonary MALT lymphoma.103 Unless a patient has symptoms referable to an extrathoracic site, chest radiography, chest CT, and serum protein electrophoresis are adequate for pretreatment evaluation. Patients with high-grade histology have CT of the chest, abdomen, and pelvis; bone marrow biopsies; and CBC and LDH determinations. PET has a relatively low sensitivity for MALT lymphoma and therefore is not recommended for staging or follow-up evaluation of these patients (Elstrom et al, 2003).109

1631

the median survival had not been reached at 10 years. These excellent survival rates are substantiated in two other small series of pulmonary MALT lymphoma, with overall survival rates of 100% at 3 to 6 years and median progression-free survival between 4 and 6 years.103,104 Single-agent rituximab has significant activity in MALT lymphoma, as reported in a recent series of 34 patients. In this study, 73% of patients responded to four weekly doses of rituximab, with a median response duration of 10.5 months.110 Interestingly, at least one series showed no apparent statistical difference between the survival of these patients and healthy patients of the same age.101 However, in a separate study patients demonstrated a significantly worse overall survival than age- and gender-matched controls.106 Patients who present with high-grade pulmonary MALT lymphoma have a significantly worse prognosis than those with the more common low-grade presentation.

RESIDUAL MEDIASTINAL MASSES Despite improved radiographic techniques over the past 2 decades, evaluation of residual mediastinal masses after treatment for lymphoma remains a common problem (Fig. 133-4). Residual radiographic abnormalities are reported in 64% to 88% of patients with mediastinal HL, and they do not predict for relapse in patients treated with combinedmodality therapy.111,112 Residual radiographic abnormalities are also seen in a significant percentage of patients with NHL.113,114 Historically, residual masses were resected or sampled, with most showing only a mixture of fibrosis and necrotic tissue.115 Because most patients with mediastinal HL and PMLBL are cured with combined-modality therapy, and with the emergence of fluorodeoxyglucose (FDG)-PET scanning, biopsy is limited to patients with FDG-avid masses. Over the past decade, owing to superior resolution and sensitivity, FDG-PET has replaced gallium scintigraphy in the evaluation of lymphoma patients. Because FDG uptake depends on the metabolic status of a lesion, and not on the size of the lesion, FDG-PET is very effective in differentiat-

Treatment and Prognosis Pulmonary MALT lymphoma is generally managed conservatively with limited resection and low-intensity chemotherapy. In one study of 61 cases of low-grade pulmonary MALT lymphoma, 42 (69%) patients underwent surgical excision.102 For 21 patients, surgical excision was the only treatment, while the other 21 received additional therapy; 16 received chemotherapy, 3 received local radiation therapy, and 2 received combined modality therapy. Of 19 patients not undergoing resection, 16 received chemotherapy and 3 patients received no treatment. Chlorambucil alone, used in 11 patients, was the most effective chemotherapy. More aggressive regimens did not prove more effective, and they were more toxic. Overall survival was 94% at 5 years, and

Ch133-F06861.indd 1631

FIGURE 133-4 Residual mediastinal mass in a patient treated with chemotherapy and radiation therapy for bulky mediastinal Hodgkin’s lymphoma.

1/21/2008 4:11:02 PM

1632

Section 7 Mediastinum

ing between active tumor and fibrosis.116 A large number of studies have compared FDG-PET to CT in the restaging of patients with HL and/or NHL. Taken together, this body of literature indicates that FDG-PET has increased sensitivity, specificity, and accuracy when compared with CT (Kumar et al, 2004).117 Several studies have demonstrated that HL and NHL patients who are PET negative at restaging experience significantly longer progression-free survival and overall survival compared with those who are PET positive. When performed after completion of first-line therapy, FDG-PET has a very high positive predictive value (PPV) for impending relapse, with 89% to 100% of PET-positive patients experiencing relapse.117 A recent analysis showed that incorporation of FDG-PET into the International Workshop Criteria for response assessment in aggressive NHL leads to a more accurate response classification.118 In one study of 29 HL patients with residual mediastinal masses after therapy, no relapse was recorded in patients with a negative PET scan, whereas 9/12 (75%) of patients with positive PET scans experienced relapse within 1 year.119 Therefore, FDG-PET is likely to continue to play an important role in the evaluation of patients with residual mediastinal masses after treatment for lymphoma. There is an emerging body of evidence suggesting that the results of FDG-PET obtained early in the course of chemotherapy can identify those patients most at risk for relapse.117 After completion of one to four cycles of chemotherapy, patients with a persistently positive PET scan have a 90% to 100% chance of experiencing relapse whereas those with a negative PET scan have a 67% to 85% chance of remaining disease free.120-122 Future prospective trials, in which FDGPET analysis is incorporated early in the course of chemotherapy, will determine whether application of more intensive therapies to patients who remain PET positive leads to an improved outcome in this high-risk group of patients. A final caveat in evaluating residual mediastinal masses concerns the phenomenon of thymic rebound. Thymic rebound is known to occur in children weeks to months after chemotherapy, but it is also seen in young adults after treatment for HL or NHL. The contour of the mediastinal mass on CT allows differentiation of an enlarged thymus from relapse. Importantly, gallium scans and PET scans may be positive in thymic hyperplasia, which must be ruled out before committing a patient to aggressive treatment for presumed lymphoma relapse.123

SUMMARY An isolated intrathoracic presentation of lymphoma is an unusual but challenging diagnostic and therapeutic problem. Adequate diagnostic material must be obtained for precise subclassification of the lymphoma. Despite frequent residual radiographic abnormalities, most patients with primary mediastinal lymphoma or HL are cured. Future challenges include improving treatments to decrease the long-term side effects associated with radiation therapy to the mediastinum and continuing efforts in identifying the optimal use of FDG-PET and combined PET/CT to identify patients with residual disease, so that tailored therapies can be developed for those patients at high risk of relapse.

Ch133-F06861.indd 1632

COMMENTS AND CONTROVERSIES The thoracic surgeon plays an important role in the management of patients with mediastinal lymphoma, not only in helping to secure an initial diagnosis but also in evaluating the presence of residual disease after therapy. The authors have described recent developments in diagnosis and treatment for those lymphomas with thoracic presentation: Hodgkin’s lymphoma (HL), primary mediastinal large cell lymphoma (PMLCL), lymphoblastic lymphoma (LL), and mucosa- or bronchus-associated lymphoid tissue (MALT or BALT) lymphoma. The classification in current use is the WHO system, based not only on architecture but also on immunologic and molecular characteristics of the lymphoma cells. Fine-needle aspiration is usually insufficient for a diagnosis because architectural pattern is necessary for subclassification. In addition, the cytologic specimen is usually inadequate for immunophenotyping (except in lymphoblastic lymphoma). Combined PET/CT has increased staging sensitivity for lymphoma. Staging laparotomy is no longer in use. In addition, PET/CT is highly sensitive in evaluating residual mass lesions after treatment. Details of treatment are clearly outlined by the authors. Improvements in survival for HL have made treatment-related complications an important consideration. Cardiomyopathy and second tumors within the radiation field are important problems to consider, particularly in young patients. For PMLCL, CHOP chemotherapy has been enhanced by the anti-CD20 chimeric monoclonal antibody rituximab. LL is an aggressive malignancy usually presenting in stage IV. Intensive chemotherapy and radiation protocols with prophylaxis of the central nervous system are required. MALT and BALT are low-grade monoclonal B-cell lymphomas, and limited resection is usually curative. G. A. P.

KEY REFERENCES Bonadonna G, Bonfante V, Viviani S, et al: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: Long-term results. J Clin Oncol 22:2835-2841, 2004. Borenstein SH, Gerstle T, Malkin D, et al: The effects of prebiopsy corticosteroid treatment on the diagnosis of mediastinal lymphoma. J Pediatr Surg 35:973-976, 2000. Dores GM, Metayer C, Curtis RE, et al: Second malignant neoplasms among long-term survivors of Hodgkin’s disease: A population-based evaluation over 25 years. J Clin Oncol 20:3484-3494, 2002. Elstrom R, Guan L, Baker G, et al: Utility of FDG-PET scanning in lymphoma by WHO classification. Blood 101:3875-3876, 2003. Feugier P, Van Hoof A, Sebban C, et al: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 23:4117-4126, 2005. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol 11:1208-1215, 1993. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 17:3835-3849, 1999. Hehn ST, Grogan TM, Miller TP: Utility of fine-needle aspiration as a diagnostic technique in lymphoma. J Clin Oncol 22:3046-3052, 2004.

1/21/2008 4:11:02 PM

Chapter 133 Lymphoma of the Mediastinum

Hoelzer D, Gökbuget N, Digel W, et al: Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 99:4379-4385, 2002. Horning SJ, Weller E, Kim K, et al: Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 22:3032-3038, 2004. Horning SJ, Weller E, Kim K, et al: Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: Mature results of a prospective clinical trial. J Clin Oncol 20:630-637, 2002. Kumar R, Maillard I, Schuster SJ, Alavi A: Utility of fluorodeoxyglucose-PET imaging in the management of patients with Hodgkin’s and non-Hodgkin’s lymphomas. Radiol Clin North Am 42:1083-1100, viii, 2004. Massone PP, Lequaglie C, Magnani B, et al: The real impact and usefulness of video-assisted thoracoscopic surgery in the diagnosis and therapy of clinical lymphadenopathies of the mediastinum. Ann Surg Oncol 10:1197-1202, 2003. Meyer RM, Gospodarowicz MK, Connors JM, et al: Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin’s lymphoma. National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 23:4634-4642, 2005.

Ch133-F06861.indd 1633

1633

Miller TP, Dahlberg S, Cassady JR, et al: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 339:21-26, 1998. Naumann R, Beuthien-Baumann B, Reiss A, et al: Substantial impact of FDG PET imaging on the therapy decision in patients with earlystage Hodgkin’s lymphoma. Br J Cancer 90:620-625, 2004. Savage KJ, Monti S, Kutok JL, et al: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102:3871-3879, 2003. Sehn LH, Donaldson J, Chhanabhai M, et al: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027-5033, 2005. Straus DJ, Portlock CS, Qin J, et al: Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 104:34833489, 2004. Thomas DA, O’Brien S, Cortes J, et al: Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood 104:1624-1630, 2004.

1/21/2008 4:11:03 PM

chapter

134

NEUROGENIC TUMORS OF THE MEDIASTINUM Michael Bousamra, II William Wrightson

Key Points ■ Neurogenic tumors in the adult are commonly of nerve sheath

origin and 98% are benign. ■ Children and young adults are more prone to tumors of the auto-

nomic ganglia, which are frequently malignant. ■ Nerve sheath tumors comprise one fifth of all mediastinal tumors.

■

■

■

■ ■

More than 95% of these are either neurilemmomas (also known as schwannomas) or neurofibromas. Patients with von Recklinghausen’s neurofibromatosis are the lone identified population at risk for benign and malignant neurogenic tumors. Tumors arising from ganglion cells of the sympathetic chain and adrenal medulla are classified into three histologic types: ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. Surgery plays a dominant role in the treatment of early-stage neuroblastoma. In patients with stage I disease, surgical resection alone produces an 89% relapse-free survival at 4 years. Intraspinal extension of neurogenic tumors requires a combined posterior spinal and thoracic approach for safe resection. Benign neurogenic tumors appear to be good candidates for minimally invasive methods of resection whereas malignant lesions are best approached via open transthoracic or transcervical exposures.

Neurogenic tumors of the mediastinum arise from the cells of the nerve sheath, autonomic ganglia, and paraganglionic tissues, all of which trace their embryologic heritage to the neural crest. In turn, neurogenic tumors may exhibit a variety of cytologic products and immunohistochemical markers that aid in pathologic diagnosis. The relative incidence of the various cell types and their corresponding risk of malignancy are strongly correlated with age. Children and young adults are more prone to tumors of the autonomic ganglia, two thirds of which are malignant. In adults, the vast majority of tumors are of nerve sheath origin, and 98% of these are benign (Reeder, 2000).1-4 Although neurogenic tumors may arise from neural elements anywhere within the thorax, the posterior mediastinum along the costovertebral sulcus is the most common location. Intraspinal extension of tumor via the spinal foramen occurs in approximately 10% of cases.5,6 Routine CT is recommended to screen for this phenomenon, and, if it is found, MRI provides the clearest and most useful images. Patients with von Recklinghausen’s neurofibromatosis are the lone identified population at risk for benign and malignant neurogenic tumors.7,8 This disease is an autosomal dominant

hamartomatous disorder of ectoderm and mesoderm resulting in multiple neurogenic tumors. The benign neurofibroma occurs most frequently in this group, and its malignant counterpart, the neurofibrosarcoma, has been found in 2% to 5% of affected individuals.9,10 Lateral meningoceles in the thoracic paravertebral region are also common in patients with neurofibromatosis, and these need to be distinguished from solid tumors. lf there is associated scoliosis with convexity toward the mass, it is almost certainly a meningocele.7

CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS Nerve Sheath Tumors Nerve sheath tumors comprise one fifth of all mediastinal tumors. More than 95% of these are either neurilemmomas (also known as schwannomas) or neurofibromas (Takeda et al, 2004).1-4,11 They behave in a clinically similar fashion, appearing as a smooth, rounded density in the costovertebral sulcus with a greater propensity for the upper posterior mediastinum than for the lower. Most nerve sheath tumors are asymptomatic, presenting as an incidental finding on chest radiography. Nerve sheath tumors may cause intercostal nerve irritation, rib displacement, and bone erosion that leads to pleuritic pain or paraspinal discomfort. Tumors arising within the thoracic inlet often involve the stellate ganglion, producing ptosis or complete Horner’s syndrome. Because of the narrow confines of the thoracic inlet, larger size may also lead to deviation of the trachea and partial airway obstruction. Cough, dysphagia, and symptoms related to brachial plexus compression have been described.1,7,8 With significant intraspinal extension, cord compression and paralysis can occur. Nerve sheath tumors are slow growing. In the adult patient the smooth to multilobulated contour, relative homogeneity, and characteristic position make a presumptive benign diagnosis an accurate one. Nonetheless, most authorities recommend removal to obviate the risk of malignancy. This risk is generally very small in patients who do not have neurofibromatosis or a history of radiation exposure. It is certainly reasonable to follow asymptomatic, small paravertebral tumors in elderly persons or those with tenuous health. In children, ganglioneuroblastoma and neuroblastoma are more common, and a benign diagnosis cannot be assumed; therefore, these tumors must be addressed promptly.

Neurilemmomas Neurilemmomas account for three fourths of nerve sheath tumors. They are encapsulated tumors containing two histo-

1634

Ch134-F06861.indd 1634

1/21/2008 4:11:47 PM

Chapter 134 Neurogenic Tumors of the Mediastinum

FIGURE 134-1 A, Neurilemmoma demonstrating an area of nuclear palisading and elongated nuclei in a compact cellular arrangement consistent with Antoni type A. B, The more haphazard and loose arrangement of cells is characteristic of Antoni type B.

1635

FIGURE 134-2 A 17-year-old woman with neurofibromatosis presented with mild, right-sided chest pain. A large mass is seen in the apex of the right hemothorax that appears to displace both the lung and the mediastinal structures including the trachea. The configuration is suggestive of a pleural or extrapleural mass. Dysplastic changes are noted in the ribs in the area of the lesion. There is also scoliosis, a finding commonly seen in patients with neurofibromatosis.

logic components, Antoni type A and Antoni type B (Fig. 134-1). Antoni type A regions contain compact spindle cells with twisted nuclei and nuclear palisading. Antoni type B regions have loose and myxoid connective tissue harboring a haphazard arrangement of cells. Blood vessel walls tend to be thick, and cystic areas with hyalinization and calcification are noted microscopically.12 Neurilemmomas are S-100 positive. Electron microscopic examination demonstrates long cytoplasmic processes with continuous basal lamina that stain positive for vimentin. Neurilemmomas rarely undergo malignant transformation.

Neurofibromas Neurofibromas account for approximately 25% of nerve sheath tumors. Thirty percent to 45% of patients with mediastinal neurofibromas have von Recklinghausen’s disease. Multiple neurofibromas or a single plexiform neurofibroma (a diffuse tumor of peripheral nerve) is pathognomonic of neurofibromatosis (Figs. 134-2 and 134-3).13 These tumors are radiographically indistinguishable from neurilemmomas. Histologic features include a disorganized proliferation of all nerve elements.13 Interlacing bundles of spindle cells with wavy nuclei and a stroma of mixed collagenous and mucoid types are characteristic (Fig. 134-4). Neurofibromas may or may not be S-100 positive. Neither the neurilemmoma nor

Ch134-F06861.indd 1635

FIGURE 134-3 Multiple neurogenic lesions including intercostal plexiform neuromas are diagnostic of neurofibromatosis.

1/21/2008 4:11:47 PM

1636

Section 7 Mediastinum

tive prognostic factor, whereas adjuvant chemotherapy and radiation therapy appear to offer little survival benefit.

Ganglion Cell Tumors Tumors arising from ganglion cells of the sympathetic chain and adrenal medulla are classified into three histologic types: ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. Together, they occur in infants, children, and young adults. Overlap in their histopathology and clinical behavior forms a continuous spectrum of disease progressing from benign to highly malignant tumors.

Ganglioneuroma FIGURE 134-4 The disorganized arrangement of connective tissue elements and nerve cells is seen on a background of loose myxoid material in this photomicrograph of a neurofibroma.

the neurofibroma secrete significant amounts of bioactive amines.

Melanotic Schwannomas Melanotic schwannomas are a pigmented form of neurogenic tumor with melanin present in melanosomes. They have a higher incidence of intraspinal extension,14,15 and approximately 10% are malignant.16 Microscopically they demonstrate psammomatous calcification. Carney has described a familial disorder consisting of multiple myxomas, patchy pigmentation, and endocrine hyperactivity (acromegaly, Cushing’s syndrome) associated with this entity.17

Neurofibrosarcoma Neurofibrosarcoma (also referred to as neurogenic sarcoma or malignant schwannoma) is a rare malignancy in the general population, but it affects 2% to 5% of patients with neurofibromatosis and arises at an earlier age in these patients.9,10 Neurofibrosarcomas are also associated with radiation exposure. In 60% of cases, a contiguous neurofibroma is identified, implying sarcomatous degeneration from a previously benign lesion.9 The sarcomatous lesion can be differentiated from its benign counterparts by a high level of mitotic activity, lack of encapsulation, and absence of Antoni type A and B areas. CT can demonstrate central areas of low attenuation consistent with necrosis, hemorrhage, or cystic degeneration; these are all signs of malignancy.16 Neurofibrosarcomas may undergo divergent differentiation into other sarcomas. Transformation into regions of rhabdomyosarcoma, chondrosarcoma, and osteosarcoma is most frequently observed.9 Intraneural extension of the tumor within fascicles makes complete resection less probable, and local visceral invasion or hematogenous metastases often prohibits surgical resection. Ducatman and associates reported a 5-year survival for neurofibrosarcoma of 16% in neurofibromatosis patients and 53% in nonneurofibromatosis patients.9 Large tumor size (>5 cm) is associated with poorer survival, but large size is also linked with neurofibromatosis. Complete resection is a strong posi-

Ch134-F06861.indd 1636

Ganglioneuroma is the well-differentiated benign manifestation of this group. It accounts for 42% of thoracic tumors arising from sympathetic ganglia.18,19 Roughly half of affected patients are young adults. Most are asymptomatic, although diarrhea related to secretion of vasoactive intestinal peptide by the tumor is recognized.20 They are usually located in the costovertebral sulcus (Fig. 134-5A and B). This tumor is likely to exhibit intraspinal canal extension (see Fig. 134-5C). Davidson and coworkers reported this histology in seven of eight patients with neurogenic tumors extending through the intervertebral foramen.1 Ganglioneuromas are encapsulated and on cut section have a whorled pattern. They are recognized histologically by well-differentiated ganglion cells on a background of Schwann cells. The ganglion cells contain abundant cytoplasm, are often multinucleated, and are seen to rest within clear lacunae of the stroma (Fig. 134-6). Complete resection is curative, and local recurrence is uncommon.

Ganglioneuroblastomas Ganglioneuroblastomas contain a mixture of mature ganglion cells and malignant neuroblasts; the latter are characteristic of neuroblastoma. The distribution of neuroblasts within the ganglioneuroblastoma is predictive of clinical behavior. A nodular pattern is associated with a high incidence of metastatic disease, whereas the diffuse form rarely has metastases.18 Ganglioneuroblastomas make up approximately one third of autonomic ganglion tumors. Focal calcification is present in regions of the neuroblasts. Grossly, the tumor usually remains encapsulated. Age distribution is similar to neuroblastoma, most arising in infants and children. These tumors are usually resectable, and overall 5-year survival is 88%, as reported by Adam and Hochholzer.18

Neuroblastoma Neuroblastoma occupies the malignant end of the clinical and pathologic spectrum of ganglion cell tumors. It is the most common extracranial solid malignancy in pediatric patients and the most common intrathoracic malignancy of childhood. Prognosis is age dependent, with younger patients (<18 months) having a better prognosis. Certain so-called low-risk patients such as those with diffuse disease (stage 4S) paradoxically have a better prognosis and others will spontaneously regress.26 Staining of neuroblastoma with hematoxylin

1/21/2008 4:11:48 PM

Chapter 134 Neurogenic Tumors of the Mediastinum

1637

A

C

B

FIGURE 134-5 A and B, MR images of a ganglioneuroma at the thoracic apex resected in a 24-year old through a cervical incision. C, MR image of a ganglioneuroma with extension across the spinal foramen and encroachment on the spinal cord.

FIGURE 134-6 Ganglioneuromas are characterized by the large nuclei of ganglion cells resting in clear lacunae and surrounded by fibrovascular connective tissue.

and eosin reveals that it is composed of nests of blue round cells surrounded by fibrovascular stroma. Homer-Wright rosettes may be present (Fig. 134-7).21 The adrenal gland harbors the primary source of neuroblastoma in 38% of all cases; 14% arise within the thorax.22 Extension into the spinal canal and osseous invasion are common. Visceral involvement occurs less commonly in tho-

Ch134-F06861.indd 1637

racic neuroblastoma; in turn, resection is more often feasible. Cervical and mediastinal neuroblastomas are associated with heterochromia iridis and Horner’s syndrome. Hormonal activity may be manifest in any of the tumors of the autonomic ganglia, but it is characteristic of neuroblastomas. Secretion of vasoactive intestinal peptide manifests as diarrhea.23,24 Catecholamine production can be detected by the urinary metabolites vanillylmandelic acid and homovanillic acid. Seeger and colleagues reported that catecholamines were detected in 95% of cases of neuroblastoma.25 Hormone levels fall after tumor resection and can serve as an indicator of complete resection. Recrudescence of elevated hormone levels is a sign of recurrent disease. Patients with neuroblastoma are usually symptomatic, and tumors are often extensive at presentation. Local symptoms of cough, chest pain, dyspnea, and Horner’s syndrome are common. Systemic manifestations include lethargy, fever, and weight loss. Thoracic lesions are more commonly associated with myelopathic symptoms resulting from spinal canal invasion. Cerebellar ataxia and opsoclonus are thought to result from associated autoimmune phenomena. The staging of neuroblastoma has evolved as factors affecting survival have been elucidated. The extent of primary tumor, patient age (<18 months), lymph node involvement, and the presence of residual disease after resection are the dominant variables affecting prognosis.26 The International

1/21/2008 4:11:48 PM

1638

Section 7 Mediastinum

A

B

FIGURE 134-7 A, Pathologic features of neuroblastoma include sheets of small, dark neuroblasts with rosette formation and areas of necrosis. B, CT image of recurrent thoracic neuroblastoma that caused respiratory distress in 3-year-old child who in infancy had stage 4S that had spontaneously resolved. Recurrence was resected, as previously described.29 Patient is well more than 10 years later without ever having received cytotoxic therapy. (FROM KUSHNER BH: NEUROBLASTOMA: A DISEASE REQUIRING A MULTITUDE OF IMAGING STUDIES. J NUCL MED 45:1172-1188, 2004. FIGURE 9.)

TABLE 134-1 International Neuroblastoma Staging System Stage

Tumor Characteristics

Stage 1

Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive).

Stage 2A

Localized tumor with incomplete gross excision: representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.

Stage 2B

Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.

Stage 3

Unresectable unilateral tumor, infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration or lymph node involvement.

Stage 4

Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as defined for stage 4S).

Stage 4S

Localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to liver, skin, and/or bone marrow (limited to infants <1 year of age).

Neuroblastoma Staging System, which reflects these factors, is shown in Table 134-1. Specific genetic and biologic markers also affect survival probability. Levels of neuron-specific enolase greater than 100 ng in patients with stage 3 and 4 disease and serum lactate dehydrogenase greater than 1000 IU for stage 4 are associated with poorer survival.27,28 Having multiple copies of the MYCN gene appears to be an independent predictor of poor survival.26,29,30 The risk of death was 5.48 times greater for patients with MYCN amplification compared with those who did not have amplification.31 The molecular basis underlying the variability in tumor growth, clinical behavior, and responsiveness to therapy remains largely unknown. MYCN amplification occurs in approximately 20% of primary neuroblastoma tumors and is strongly associated with the presence of metastatic disease and poor prognosis.32 Genetic variants involving DNA loss and duplication have been documented in neuroblastoma. The gain of 17q genetic material is associ-

Ch134-F06861.indd 1638

ated with high-risk features and adverse outcome. Loss of chromosomal heterozygosity has been shown at chromosome bands 1p36, 11q23, and 14q23 and also confers a poorer prognosis.26 High tyrosine kinase activity is associated with a favorable prognosis. Surgery plays a dominant role in the treatment of earlystage neuroblastoma. In patients with stage 1 disease, surgical resection alone produces an 89% relapse-free survival at 4 years.33 Radiation therapy in combination with chemotherapy improves survival in patients with residual disease and in resected patients with nodal disease.34 Thoracic tumors are not as recalcitrant to medical and surgical therapies. They more commonly exhibit a single copy of the MYCN protooncogene, and they usually do not invade thoracic viscera. With the common presentation of metastatic disease, thoracotomy may be required for tissue diagnosis; however, less invasive procedures usually yield adequate tissue. Occasionally, resolution of metastatic disease by chemotherapy leaves

1/21/2008 4:11:49 PM

Chapter 134 Neurogenic Tumors of the Mediastinum

the patient with a resectable primary mass. Chemotherapy regimens with increasing toxicity have not altered the natural history of patients with advanced disease. Investigations of autologous bone marrow transplantation have yielded highly variable results, with event-free survival after bone marrow transplantation reported to be 6% to 64%.35-37

Paraganglionic Tumors

sion of the pleural envelope as it reflects over the tumor and blunt dissection generally achieves mobilization and removal. Rough dissection can lead to bleeding from nearby intercostal vessels. As with any open thoracotomy, postoperative pain control is an issue. Pain control is accomplished with intercostal nerve blocks and catheters that deliver local anesthetic to the region of the intercostal nerves. Epidural analgesic is also an option.

Thoracic tumors derived from paraganglionic tissues include the hormonally active pheochromocytoma and the hormonally inactive chemodectoma. Thoracic lesions are usually harbored in the costovertebral sulcus, but they may arise in the visceral compartment being found in the aortic body and within the cardiac atria. Extra-adrenal lesions constitute approximately 10% of pheochromocytomas and, of these, the intrathoracic location is among the rarest. Approximately 10% of intrathoracic pheochromocytomas behave in a malignant fashion, a proportion similar to their retroperitoneal counterparts. Gale and associates noted multicentric tumors in 4 of 23 thoracic cases.2 A paravertebral mass in association with paroxysmal or sustained hypertension, hypermetabolism, or diabetes leads one to suspect pheochromocytoma.15 Confirmation is made by measurement of urinary catecholamines and their metabolites. Identification of middle mediastinal lesions is particularly important because the tumor may be buried in the atria or the great vessels, and failure to remove the catecholamine-producing lesion could lead to life-threatening hemodynamic problems. Localization by 131I metaiodobenzylguanidine scintigraphy and CT has proved to be efficacious.38 Alternatively, taking advantage of the high vascularity of these lesions, Tanaka and associates employed MRI to identify them in the costovertebral sulcus; MRI revealed a flow void in the region of the tumor.39 Preoperative management stresses pharmacologic blockade of α- and β-adrenergic receptors to prevent malignant hypertension and arrhythmias associated with tumor manipulation. The surgeon must also be cognizant that cardiac lesions may derive their blood supply from large vessels arising from the coronary arteries.38 In general, paraganglionic tumors are highly vascular and a cautious, circumspect approach to resection is recommended. Chemodectomas are also highly vascular. Preoperative angioembolization has been advocated, particularly in head and neck regions where vascular control can be problematic.40 Radiation therapy also has an acceptable rate of tumor control and is a rational substitute for surgical resection. Chemodectomas, at the base of the skull, where vascular control is difficult, are prime candidates for radiation therapy.40

Intraspinal extension of neurogenic tumors requires a combined posterior spinal and thoracic approach for safe resection. The procedure is performed in a single stage because thoracic manipulation of the tumor can produce bleeding within the tumor; hemorrhagic expansion of the tumor within the fixed space of the spinal canal can result in cord compression and paralysis.15 Various exposures have been described. Grillo and associates prefer a single incision extending vertically over the spinous processes and continuing laterally beneath the scapular tip.42 Exposure is gained by hemilaminectomy, enlarging the neural foramen, and thoracotomy. Vallieres and colleagues describe a combined video-assisted thoracoscopic (VATS) and microneurosurgical removal of a dumbbell tumor.43

SURGICAL MANAGEMENT

Thoracoscopic Approach

Removal of neurogenic tumors arising in the posterior mediastinum is classically achieved through a posterolateral thoracotomy. Entry into the thoracic cage one to two interspaces above or below the tumor prevents unwanted violation of the tumor capsule. These tumors are usually tucked into the costovertebral sulcus with a broad base. Their lack of mobility can make posterior exposure and separation from the intercostal nerve or sympathetic chain moderately difficult. Inci-

Thoracoscopic resection is now commonly performed for benign neurogenic tumors. Nearly circumferential visualization is provided by the 30-degree thoracoscope. Exposure of the tumor base is facilitated by placing deep sutures within the dense substance of the mass. Retraction on the sutures enables the surgeon to manipulate the position of the tumor. Further advantages of the thoracoscopic approach include less muscle division and small cosmetic incisions. In a retro-

Ch134-F06861.indd 1639

1639

SPECIAL CONSIDERATIONS Approach Tumors of the thoracic inlet present particular technical problems for the surgeon due to close association with vascular and neural structures. Various approaches have been proposed, but none is established as optimal based on tumor location and patient variability. An oblique anterolateral cervical incision combined with a median sternotomy (hockeystick incision) has been in use for the resection of large tumors extending from the neck to the anterior mediastinum. The anterior cervical-transsternal approach provides good exposure of the subclavian vessels and brachial plexus to which the neurogenic tumor may be closely associated.41 Regardless of exposure technique, dissection stays close to the tumor to avoid injury to the subclavian vessels, phrenic nerve, recurrent laryngeal nerve, or stellate ganglia. For more limited lesions, a cervical collar incision can provide adequate exposure to the thoracic inlet. Because these benign tumors are only loosely attached to the surrounding structures, mobilization from above can be performed through the neck with cephalad delivery of the mass.

Intraspinal Extension

1/21/2008 4:11:49 PM

1640

Section 7 Mediastinum

spective series comparing open and thoracoscopic neurogenic tumor resection, shorter hospitalization and return to work times were observed (Kelemen and Naunheim, 2000).44,45 Benign neurogenic tumors appear to be good candidates for minimally invasive methods of resection, but morbidity from standard techniques of removal remains low.1,2,11,46 Less invasive procedures need to match or improve the long-standing acceptable outcomes of minimal blood loss, lack of neurologic deficit, and very low incidence of tumor recurrence before they are considered a standard of care. Some have described the use of the Harmonic scalpel (Ethicon Endosurgical, Cincinatti, OH) with improved hemostasis and ease of dissection.47,48 When malignancy is suspected or documented, the surgeon foregoes thoracoscopy in favor of standard methods of exposure and resection.

COMMENTS AND CONTROVERSIES Drs. Bousamra and Wrightson have provided an excellent revision of the chapter from the previous edition. In adults, the vast majority of these neurogenic tumors are benign and, if asymptomatic, can be followed. Recent developments in VATS technology have made the VATS approach preferable for resection of these benign lesions. Extension into the spinal canal must be ruled out by preoperative

Ch134-F06861.indd 1640

imaging. Intraspinal extension mandates a dual posterior neurosurgical and lateral thoracic approach for resection. In children, these lesions more commonly involve autonomic ganglia and are frequently malignant. The special features of the benign ganglioneuroma and the malignant ganglioneuroblastoma are discussed in detail. Neuroblastoma is the most common intrathoracic malignancy of childhood and commonly associated with increased catecholamine release. The rare paraganglionic tumors pheochromocytoma and chemodectoma are thoroughly covered by the authors. G. A. P.

KEY REFERENCES Kelemen JJ 3rd, Naunheim KS: Minimally invasive approaches to mediastinal neoplasms [Review]. Semin Thorac Cardiovasc Surg 12:301306, 2000. Reeder LB: Neurogenic tumors of the mediastinum. Semin Thorac Cardiovasc Surg 12:261-267, 2000. Takeda S, Miyoshi S, Minami M, Matsuda H: Intrathoracic neurogenic tumors—50 years’ experience in a Japanese institution. Eur J Cardiothorac Surg 26:807-812, 2004. Yamaguchi M, Yoshino I, Fukuyama S, et al: Surgical treatment of neurogenic tumors of the chest. Ann Thorac Cardiovasc Surg 10:148151, 2004.

1/21/2008 4:11:50 PM

chapter

UNUSUAL MEDIASTINAL TUMORS

135

Sudhir R. Sundaresan Ahmad S. Ashrafi

Key Points ■ These rare tumors can be of mesenchymal or epithelial origin. ■ There is no universally accepted classification system. ■ Diagnosis can usually be obtained by computed tomography- or

ultrasound-guided percutaneous needle biopsy. ■ Resection is the treatment of choice. ■ Prognosis is variable and dependent on histology and complete-

ness of resection.

The category of unusual primary tumors of the mediastinum encompasses a group of rare lesions that constitute less than 10% of all mediastinal masses. Both the prevalence and the malignant potential of these tumors appear to be greater in the pediatric population. The majority of these tumors are mesenchymal in origin. Others include extramedullary hematopoiesis, primary carcinoma of the mediastinum, and giant lymph node hyperplasia (Castleman’s disease). Signs and symptoms at presentation are dependent on various factors, including tumor size, location, and histologic status, as well as the age of the patient. Tumors in the pediatric population appear to be symptomatic more often, perhaps due to their higher frequency of being malignant. Accurate diagnosis usually requires tissue biopsy in the form of fine-needle aspiration or core biopsy, although more aggressive measures such as so-called open biopsy are still utilized at some centers. The advantages of percutaneous biopsy include rapid establishment of diagnosis, less morbidity for the patient, and lower cost. The disadvantages include a measurable rate of false-negative biopsies and the very low risk of needle-tract dissemination. Surgical resection remains the most effective treatment, with chemotherapy and radiation therapy typically being reserved for unresectable tumors, recurrences, lesions associated with metastatic disease, or, in rare circumstances, as a neoadjuvant form of therapy. Prognosis is highly variable, depending on tumor histology and extent of disease. Because these lesions are quite rare, even if one pools worldwide experiences, the development of any form of a so-called standard treatment is virtually impossible.

HISTORICAL NOTE Prior to 1963, only scattered case reports existed in the literature documenting the existence of the various mediastinal mesenchymal tumors. However, reviews of the literature were rarely encountered owing to the difficulties inherent in classifying these rare lesions. Case reports were typically

subject to poor documentation and composite nomenclature (e.g., fibroleiomyoma and fibrolipoma). Because of the lack of uniformity of classification, the basis for and results of treatment were sketchy and lacked scientific support. In 1963, Pachter and Lattes from Columbia University College of Physicians and Surgeons published the first paper devoted completely to the review of mediastinal mesenchymal tumors in the journal Cancer.1-3 In their review, they used a classification system previously developed by Stout from the Armed Forces Institute of Pathology in 1953.2 Despite the exhaustive nature of their review, only a total of 39 cases were listed in their paper. Since their report, various authors have proposed a variety of classification systems with greater uniformity. However, owing to the rarity of these lesions, the development of a truly universal system will likely continue to elude us. The classification presented in Table 135-1 is reasonably clear and concise and is a composite of the various classification systems reported in the literature. In 1954, Castleman and Towne reported in the New England Journal of Medicine what was then believed to be a new disease syndrome.4 Two years after this initial case report, Castleman and coworkers described 13 cases of lymph node hyperplasia located within the mediastinum that resembled thymomas both grossly and microscopically.5 In fact, several of these lesions were originally misdiagnosed as thymomas. The authors speculated that these tumors were neither thymic in origin nor neoplastic growths as originally believed. Their speculations were based on various factors, notably the histologic appearance and also the frequent juxtaposition of these lesions to the tracheobronchial tree (as opposed to thymomas, which are typically located in the midline within the superior anterior mediastinum). Since this initial report, the disease syndrome has been expanded to include lesions outside the thorax, multiple histologic varieties, and a multicentric form of the disease associated with generalized lymphadenopathy that appears to have a more virulent clinical course. HISTORICAL READINGS Castleman B, Iverson L, Menendez VP: Localized mediastinal lymph node hyperplasia resembling thymoma. Cancer 9:822, 1956. Castleman B, Towne VW: Case records of the Massachusetts General Hospital, Case No. 40011. N Engl J Med 250:26, 1954. Pachter MR, Lattes R: Mesenchymal tumors of the mediastinum. I: Tumors of fibrous tissue, adipose tissue, smooth muscle and striated muscle. Cancer 16:74, 1963. Pachter MR, Lattes R: Mesenchymal tumors of the mediastinum. II: Tumors of blood vascular origin. Cancer 16:95, 1963. 1641

Ch135-F06861.indd 1641

1/21/2008 4:12:34 PM

1642

Section 7 Mediastinum

TABLE 135-1 Classification of Mesenchymal Tumors of the Mediastinum I.

Adipose Tissue A. Lipoma and lipomatosis B. Lipoblastomas and lipoblastomatosis C. Liposarcoma

II.

Fibrous Tissue A. Fibroma and fibromatosis B. Fibrosarcoma C. Malignant fibrous histiocytoma

III.

Blood Vessels A. Hemangioma B. Hemangiopericytoma, benign and malignant C. Hemangioendothelioma, benign and malignant

IV. Lymphatic Vessels A. Lymphangioma and lymphangiomatosis B. Lymphangiomyomatosis V.

Muscular Origin A. Striated 1. Rhabdomyoma 2. Rhabdomyosarcoma B. Smooth 1. Leiomyoma 2. Leiomyosarcoma

VI. Skeletal Tissue A. Osteogenic sarcoma B. Chondroma C. Chondrosarcoma VII. Mesenchymoma, Benign and Malignant VIII. Others A. Fibrous mesothelioma, without pleural or pericardial involvement B. Myxoma C. Meningioma D. Chordoma E. Histiocytosis X

Pachter MR, Lattes R: Mesenchymal tumors of the mediastinum. III: Tumors of lymph vascular origin. Cancer 16:108, 1963. Stout PA: Tumors of the soft tissues. In Armed Forces Institute of Pathology (eds): Atlas of Tumor Pathology, Section 2, Fascicle 5. Washington, DC, Armed Forces Institute of Pathology, 1953.

MESENCHYMAL TUMORS Mesenchymal tumors arise in virtually all regions of the body. Those that originate in the mediastinum are very rare, but when they occur they typically demonstrate similar histology to mesenchymal tumors in other locations. The clinical features also generally mimic those of mesenchymal tumors in other locations, but local symptoms and signs can arise secondary to their presence within the mediastinum. These tumors can develop from adipose tissue, connective tissue, blood and lymph vessels, striated and smooth muscle, or any combination of these tissues. The majority (>50%) are vascular or lymphatic in origin. Mesenchymal tumors make up 6% to 7% of all mediastinal masses, although this frequency may exceed 10% in the pediatric population. In adults, it is recognized that slightly over

Ch135-F06861.indd 1642

one half are malignant. In children, this incidence can be as high as 85%. As a group there appears to be no difference in incidence between males and females. Although many classifications have been suggested, no consensus is agreed on (see Historical Note). The problem with such an undertaking lies in the inherent difficulty in categorizing tumors that involve more than one anatomic region (e.g., thorax, pericardium, or mediastinum) or are composed of many tissue types. Examples include thymolipomas and thymoliposarcomas, which some authors classify among thymic tumors, whereas others group them with tumors of adipose tissue origin. Table 135-1 contains a classification scheme for mesenchymal tumors of the mediastinum. It is a composite of the various classification systems found in the literature that we have found clear and concise. In the remainder of this section we present and briefly discuss the various lesions as classified in Table 135-1.

Lipomas/Lipomatosis In most large series, lipomas represent the most common mediastinal tumor of mesenchymal origin. Lipomas are wellencapsulated lesions (when nonencapsulated and diffuse, this entity is referred to as lipomatosis) with no apparent gender predilection. The age at diagnosis varies from 2 to 60 years. These tumors are reported to achieve extreme size (up to 30 cm) without causing symptoms. This is most likely due to their complete encapsulation and lack of a significant fixation point. They tend to grow along paths of least resistance and predominate in the anterior mediastinum. Three fourths of patients exhibit symptoms at the time of presentation. These symptoms include chest pain, dyspnea, cough, and rare cases of neurologic deficits due to local extension of the tumor into the spinal canal. Although lipomas rarely compress vascular structures, Del Campo and Mpougas have reported a case of a patient with a mediastinal lipoma who presented with superior vena caval obstruction, requiring urgent surgical decompression.6 Lipomas usually have no documented malignant potential; however, Inaba and colleagues have reported a patient who presented 9 years after resection of a mediastinal lipoma with a mass in the mediastinum extending to the right neck (Inaba et al, 2004).7 Pathologic examination of the resected mass revealed a well-differentiated liposarcoma. Resection of mediastinal lipomas is at times challenging because of their enormous size, but almost all can be excised for cure. Intrathoracic omental herniation through the esophageal hiatus is a rare entity, but sporadic reports indicate that this lesion is often misdiagnosed as a mediastinal lipoma (Kato et al, 1999).8

Lipoblastomas/Lipoblastomatosis Lipoblastoma is a rare type of benign adipose tissue tumor that is found almost exclusively in the pediatric population. Although lipoblastoma is of embryonal fat occurring predominantly in the first 3 years of life, Zarate-Gomez and colleagues (1991) have reported a 14-year-old child with a benign mediastinal lipoblastoma weighing 3.1 kg and measuring 26 × 21 cm.9 Chung and Enzinger have reported the largest series to date, and they have proposed the nomencla-

1/21/2008 4:12:35 PM

Chapter 135 Unusual Mediastinal Tumors

ture for the circumscribed form as benign lipoblastoma and for the diffuse form as benign lipoblastomatosis.10 These lesions can grow to extreme size, similar to lipomas, and also appear to lack any potential for invasion or malignancy. The most common sites of origin of these rare tumors are in the extremities or pelvic region. Their presence in the mediastinum is extremely rare, with only five reported cases in the English literature. These five patients had mediastinal lipoblastomas, and all presented with respiratory signs and symptoms (cough, dyspnea, stridor, and hypoxia) due to compression of adjacent structures. Complete local excision appears to be curative.

two prevailing theories include increased utilization of glucose by the tumor and the formation and release by the tumor of metabolites with insulin-like activity. Histologically, fibrosarcomas resemble fibromatosis, but they have frequent mitotic figures and focal areas of necrosis. The tumors can demonstrate aggressive local invasion, but they rarely metastasize distantly. Despite the lack of distant metastasis, these lesions are rarely resectable for cure. Local recurrence is common, and most patients die within a few years as a result of extensive mediastinal invasion. Surgical resection remains the only chance for cure. The benefits of chemotherapy and radiation therapy are unproved.

Liposarcomas

Malignant Fibrous Histiocytoma

Liposarcomas are very rare in the mediastinum, in contrast to lipomas. Similar to lipomas, there is an equal incidence in men and women. The age at presentation also varies, from young to elderly. However, unlike lipomas, these lesions tend to exhibit extensive local invasion. Almost all patients present with symptoms of severe pain, weight loss, or cough at the time of diagnosis, and these features represent late findings in the course of the disease. Liposarcomas are rarely resectable for cure because of extensive local invasion. Surgery is typically reserved for palliation. Radiation therapy has been used with minimal benefit (Teschner and Lullig, 2003).11,12

Although malignant fibrous histiocytoma is the most frequently encountered soft tissue sarcoma of late adult life, there have been fewer than 20 cases of primary mediastinal malignant fibrous histiocytoma reported in the English literature. Histologically, the tumor tissue consists of spindleshaped fibroblast-like cells and round histiocyte-like cells with bizarre giant cells (Imada et al, 1994).15 Tumors of this tissue origin found in the mediastinum usually represent metastatic disease from the extremity or retroperitoneum. Treatment of this lesion is complete excision when possible. However, local recurrence and metastatic spread typify the course of the disease. Weiss and Enzinger,16 in a review of 200 cases of malignant fibrous histiocytoma found throughout the body, quoted a local recurrence rate of 44% and a distant metastatic incidence of 42%. Although postoperative radiation therapy may have some benefits in reducing local recurrence when resection margins are close or microscopically positive, adjuvant and neoadjuvant therapy have not been shown to improve survival.

Fibroma/Fibromatosis Tumors of this tissue origin are typically found in the fibromatosis form as an ill-defined lesion with indistinct gross margins. Histologically, the tumor is composed of fibroblasts of uniform shape separated by abundant collagen. Because of its ill-defined border, the tumor often infiltrates into adjacent tissue. These are slow-growing tumors, and thus clinical symptoms are present with only rather advanced lesions.1-3,13 They typically manifest as incidental findings on chest radiographs or CT scans. When symptoms arise, they are usually due to compression of adjacent structures such as the vena cava, leading to the development of superior vena cava syndrome. The lesion is benign and does not exhibit metastatic spread. Resection is performed for cure (Fig. 135-1), and if the lesion is incompletely excised, local recurrence occurs. Complete excision is important because these are radioresistant tumors and thus are not amenable to radiation therapy.

Fibrosarcoma Like other sarcomas in the mediastinum, fibrosarcomas are very rare lesions. The last extensive review of the literature by Barua and associates (1979) reported only 36 cases.14 There appears to be equal incidence in men and women, with varying ages (13-79 years) at the time of presentation. They are lesions that often grow to large size and can infiltrate into adjacent structures. Patients are usually symptomatic at the time of diagnosis. Signs and symptoms may include dyspnea, dysphagia, chest pain, and cough due to local compression and invasion by the tumor. The occurrence of hypoglycemia has been associated with very large tumors, and it can be responsible for some of the presenting features. Although the exact basis of this phenomenon has yet to be determined, the

Ch135-F06861.indd 1643

1643

Hemangioma Hemangiomas represent the most common benign vascular tumors of the mediastinum. The majority of patients present with symptoms secondary to local compression of adjacent mediastinal structures by the often extreme size of the tumor. The tumors are most commonly encapsulated, but they may also appear as poorly circumscribed masses that involve adjacent tissues. Although patients can present at varying ages, hemangiomas tend to be diagnosed in childhood. There are three histologic variants that are classified according to the size and type of the predominant vascular component: cavernous, capillary, and venous variants. Cavernous hemangiomas are by far the most common, with the capillary variant second at approximately 15%. The smooth muscle walls of the vascular spaces can sometimes be quite prominent and therefore can be confused with mesenchymal tumors of smooth muscle origin. This again underscores the inherent difficulty in any attempt to accurately classify these tumors. There has been no evidence of any potential for malignant degeneration. Although surgery remains the most effective therapy, and it must be undertaken with great caution due to the extreme size and vascularity of these tumors, there have been reports of induction therapy with the aim of reducing tumor size.

1/21/2008 4:12:35 PM

1644

Section 7 Mediastinum

FIGURE 135-1 A, Posteroanterior and lateral chest radiographs of a middleaged woman who has previously undergone coronary artery bypass grafting. Note the large, ovoid, well-circumscribed mass in the right anterior mediastinal region. B, CT scan of the chest shows that despite its size, the lesion does not appear to deeply invade surrounding structures. C, Surgical exploration was performed through a right anterolateral thoracotomy and revealed a large ovoid mass with a smooth capsule. D, Resected specimen. On histology, the lesion was demonstrated to be a benign fibroma.

Ch135-F06861.indd 1644

1/21/2008 4:12:35 PM

Chapter 135 Unusual Mediastinal Tumors

Kumar and colleagues have reported their success with the use of interferon alfa-2a for shrinkage and subsequent resection of an extensive mediastinal hemangioma in an adult (Kumar et al, 2002).17 Interferon alfa-2a, which is a purified DNA product and a potent angiogenesis inhibitor, blocks the action of basic fibroblast growth factor (Kumar et al, 2002).17 Radiation therapy has not been shown to be effective in relieving symptoms.

1645

must be treated in a manner similar to other high-grade sarcomas, including radical excision with adjuvant chemotherapy or radiation therapy. However, resection for long-term survival is unfortunately rarely possible. Many authors advocate resection of locally recurrent tumors, as well as metastases to liver and lung. Radiation and chemotherapy can also be applied to distant metastases and used to manage local recurrence.

Lymphangioma Hemangiopericytoma Hemangiopericytomas originate from pericytes that are typically found around capillary arterioles. They are generally solitary encapsulated lesions, unless they arise in the malignant form, in which case they can be poorly circumscribed and locally invasive. Differentiation between benign and malignant forms is thus often based on clinical grounds; histologic differentiation is seldom possible because both have a similar appearance. Enzinger and colleagues,18 however, have identified certain histologic findings suggestive of malignancy and therefore a high potential for metastasis. These include four or more mitoses per high-power field, prominent cellular pleomorphism, and areas of hemorrhage and necrosis. Hematogenous and lymphatic spread is the typical course of the malignant form. Treatment is excision, but the prognosis cannot be reliably predicted based on intraoperative findings. Simonton and colleagues reported a fatal outcome as a result of bleeding during attempted resection of a mediastinal hemangiopericytoma in a child (Simonton et al, 1995).19 Morandi and colleagues have reported their experience with a resectable mediastinal hemangiopericytoma treated with preoperative embolization to reduce perioperative blood loss (Morandi et al, 2000).20 Radiation therapy and chemotherapy with doxorubicin (Adriamycin) have been tried without demonstrable benefit.

Epithelioid Hemangioendothelioma Weiss and Enzinger21 originally described epithelioid hemangioendothelioma in 1982. In more recent literature, these tumors are believed to be low-grade malignancies derived from endothelial cells (Fig. 135-2). They have histologic features that are intermediate between those of hemangiomas and angiosarcomas. Similarly, their clinical behavior is also intermediate between that of the benign hemangiomas and the malignant angiosarcomas. They have been divided into two variants depending on their benign versus malignant histology. The majority display a benign histology, but despite these microscopic findings approximately 20% metastasize at 5 years. Twenty-five percent of these tumors display a malignant histology with significant atypia, increased mitotic figures, and necrosis. The malignant variant follows a clinical course that is even more virulent than its benign counterpart. Over one half show evidence of metastasis at 5 years, with an accompanying mortality of approximately 30%. Treatment focuses on wide excision that includes regional lymph nodes. Some authors believe that lesions with malignant histology

Ch135-F06861.indd 1645

Less than 1% of lymphangiomas are confined to the mediastinum. The vast majority that involve the mediastinum are lesions that actually originate in the cervical region and extend into the anterosuperior mediastinum. Most isolated mediastinal lesions are seen in the adult population. Only one fourth are seen in children, and less than 5% are diagnosed in infants younger than 1 year of age. These tumors can be classified into two morphologic types according to the size of the lymphatic spaces. Lesions featuring large cystic lymphatic spaces are called cystic hygromas, whereas lesions with smaller spaces grouped into a spongelike mass are called cavernous lymphangiomas. The pathogenesis involves proliferation of lymphatic vessels that become sequestered from the lymphatic system. Cystic transformation occurs due to accumulation of chyle within the lumen of these vessels, which later fail to communicate with the systemic lymphatic circulation. Differentiation between lymphangiomas and hemangiomas both grossly and microscopically is based on the presence of chyle or blood within the lesions, respectively. However, postsurgical changes can artifactually render lymphangiomas full of blood and mislead the pathologist into misdiagnosing the lesion as a hemangioma. Immunohistochemical staining for intracytoplasmic factor VIII reactivity can aid in the differentiation because this reactivity is a characteristic of vascular endothelium but is absent in lymphatic vessels. Lymphangiomas are benign lesions that have a clinical behavior similar to hemangiomas. They can grow to a very large size and cause symptoms due to compression or erosion into adjacent structures. They can also manifest as associated chylothorax or as an abscess due to secondary infection of the cystic spaces. Treatment is based on surgical resection. Attempts to shrink the lesion with radiation therapy or sclerosing agents are ineffective. In addition, documented cases of malignant transformation by radiation therapy have also been reported, further minimizing the role of this treatment modality. Complete resection is often impossible due to erosion into adjacent structures. However, debulking of the tumor by unroofing the lesion and resection of as much of the cyst walls as possible has been recommended.

Rhabdomyoma Rhabdomyomas are rare lesions that are divided into two variants: cardiac and extracardiac. In the extracardiac group there are three recognized subtypes: adult type, fetal type, and genital type. The most common is the adult type, which usually involves the head and neck region. The fetal and

1/21/2008 4:12:36 PM

1646

Section 7 Mediastinum

FIGURE 135-2 A, Posteroanterior and lateral chest radiographs of a 72-year-old woman with prior history of hyperthyroidism and remote history of ovarian cancer. Note the left anterior mediastinal density. B, Chest CT scan suggests mediastinal infiltration (left side). The lesion shows several areas of low density consistent with necrosis. However, the solid portions of the lesion are brightly enhancing, consistent with significant vascularity. The lesion was resected through a median sternotomy approach, although the left phrenic nerve had to be sacrificed. Pathologic examination showed this to be a hemangioendothelioma.

genital types are morphologically similar and easily distinguished from the adult subtype. They are typically found in the regions of the head and neck in children and in the female genital tract, respectively. They are benign tumors of striated muscle cell origin. As with many of the mesenchymal tumors, their presence in the mediastinum as a primary tumor is extremely rare. The first documented case of an extracardiac rhabdomyoma originating from the mediastinum was by Miller and associates22 in 1978. It is believed that these tumors originate from thymic myoid cells, although the true histogenesis of these tumors is still unknown. Treatment centers around resection, and local recurrence has been reported due to inadequate resection margins.

Ch135-F06861.indd 1646

Rhabdomyosarcoma Similar to their benign counterpart, rhabdomyosarcomas are extremely rare lesions in the mediastinum, with metastasis from extramediastinal origin being the more common source. The first documented cases were by Pachter and Lattes1-3 in 1963. Because of their paucity, our knowledge of their biology, clinical course, and treatment is based primarily on tumors found in soft tissue locations other than the mediastinum. On gross examination rhabdomyosarcomas are rubbery in texture, with a gray-white to pink-tan color on cut sections. Microscopically, there are four subtypes: embryonal, botryoid, alveolar, and pleomorphic. They appear to have a predi-

1/21/2008 4:12:36 PM

Chapter 135 Unusual Mediastinal Tumors

lection for younger patients, and they have an equal gender distribution. Symptoms arise late in the course of the disease and consist of cough, pain, and dyspnea. The cell of origin is thought to be in the thymus gland and has the ability to differentiate toward myoid tissues (Panasuk et al, 2003).23 Because of extensive local invasion, they are rarely resectable for cure. Radiation and chemotherapy appear to have some benefit. Effective chemotherapeutic agents include doxorubicin, cyclophosphamide, dactinomycin, and vincristine.

Leiomyoma Leiomyoma is the least common mesenchymal tumor of the mediastinum. There have been 11 patients with primary mediastinal leiomyomas in the English literature (Baldo et al, 1997).24 They are most commonly found in the 22- to 67year-old age group and are more common in females (Shaffer et al, 1990).25 In an effort to reduce intraoperative blood loss during attempted resection, preoperative embolization has been described by Baldo and colleagues (Baldo et al, 1997).24 Although definitive statements regarding their symptomatology, population dynamics, and clinical course cannot be made because of the paucity of recorded cases, the few case reports have documented well-encapsulated tumors in which curative resection was accomplished.

Leiomyosarcoma Leiomyosarcomas are rare malignant tumors of smooth muscle origin. Most reported cases originate from mediastinal organs such as the superior vena cava, pulmonary vessels, and esophagus. Shields11 argued that tumors originating from mediastinal organs are not true mediastinal tumors and must, in fact, be classified as sarcomas of large vessel origin. True mediastinal leiomyosarcomas not arising from surrounding mediastinal structures are extremely rare. Only 16 cases have been reported to date. The majority are located in the anterosuperior mediastinum, but posterior compartment lesions have also been reported. The origin of these tumors is uncertain, but theories include formation from small vessels within the mediastinum, formation from heterotopic smooth muscle cells derived from splanchnic mesoderm that become displaced during embryologic development, and parasitic tumors from the esophagus that become detached during growth. Clinical presentation appears to be dependent on tumor location. Posterior compartment lesions are typically asymptomatic, whereas anterior compartment lesions often manifest as chest discomfort, cough, or malaise. Treatment centers around surgical resection. In contrast to resection of tumors originating from mediastinal organs (superior vena cava, pulmonary vessels, and esophagus), true mediastinal tumors are more easily resected because of their infrequent involvement of adjacent structures. The need for adjuvant therapy is determined by the histologic grade and clinical stage of the tumor, similar to that for lesions found in other soft tissue locations.

Osteogenic Sarcoma (Extraosseous) The classification of osteogenic sarcomas as extraosseous requires that they be clearly separate from adjacent skeletal

Ch135-F06861.indd 1647

1647

structures. As a primary tumor of the mediastinum, they are extremely rare. There appear to be only seven reported cases of extraskeletal osteosarcoma of the mediastinum in the literature. Except for the case reported by Venuta and associates,26 they have all been located in the anterior mediastinum. The origin of these lesions is uncertain, but the two prevailing theories include metaplasia of the connective tissues and malignant degeneration of embryonal somatic remnants. Suggested predisposing factors have included prior mediastinal radiation therapy, trauma with subsequent development of myositis ossificans, preexisting soft tissue calcifications, and extravasation of thorium dioxide (Thorotrast). Presenting signs and symptoms have included pain (approximately 33% of patients) and areas of calcification on plain radiographs (50% of patients). These tumors are highly malignant and metastasize early, most commonly to the lungs. Treatment options for extraosseous osteosarcomas have centered around radiation therapy only, resection only, and resection followed by adjuvant therapy. Prognosis is very poor, with a 5-year survival of approximately 13%. The rate of local recurrence has been reported to be 56% within 12 months, and for distant metastases it is 62% within 24 months. In this regard, primary mediastinal osteosarcomas fare as poorly as primary osteosarcomas of the bony chest wall; this is in contrast to extremity osteosarcomas, in which an aggressive combination of surgical resection and adjuvant chemotherapy has improved 5-year survival to almost 50%.

Chondroma Most chondromas located in the mediastinum arise from either the cartilaginous rings of the trachea or the major bronchi or from lung parenchyma. They have also been documented to arise from costal cartilage, sternum, vertebral bodies, and joints. However, true soft tissue chondromas of the mediastinum, not attached to the aforementioned structures, are exceedingly rare. Clinical presentation is typically due to airway obstruction by the mass. The benign versus malignant character of these lesions cannot be based on histology alone. Tumors that appear to be malignant histologically can have a benign clinical course, and benign-appearing tumors can recur after resection and even metastasize. Thus, clinical evidence of local tissue invasion despite a benign histology warrants aggressive therapy. Resection remains the only viable method of treatment. Some authors have advocated debulking of malignant tumors that have grown beyond the boundaries of resectability. This is believed to increase the period of disease-free survival.

Chondrosarcoma Primary mediastinal chondrosarcomas (Fig. 135-3) are exceedingly rare. In Burt and associates’ (1998)27 report of the experience at the Memorial Sloan-Kettering Cancer Center of 47 primary mediastinal sarcomas, only one patient had a chondrosarcoma. Ratto and colleagues (2004)28 reported their case of a 36-year-old patient who underwent an en-bloc resection of the tumor, pericardium, mediastinal pleura, and a wedge of the upper and middle lobe of the lung with clear margins. Their patient had two subsequent resections for

1/21/2008 4:12:37 PM

1648

Section 7 Mediastinum

A

B

recurrence but was reported to be well and free of disease 5 years after the initial resection. The exact role of adjuvant or neoadjuvant therapy remains unknown, but the propensity of this tumor to recur in spite of complete resection makes adjuvant chemotherapy or radiation therapy potentially attractive. Primary skeletal chondrosarcomas of the mediastinum are similarly rare, with only three cases documented in the literature. Therapy is very difficult, and radical surgery remains the most effective treatment. Chemotherapy and radiation therapy have been shown to be more effective in extraskeletal chondrosarcomas.

Mesenchymoma Mesenchymomas consist of two or more soft tissue components within the same tumor. They occur in a diverse age range and show no predilection for either gender. Both malignant and benign lesions have been described. The benign type is extraordinarily rare and typically well circumscribed, although not encapsulated. Resection is curative. Ohara and

Ch135-F06861.indd 1648

FIGURE 135-3 A, Posteroanterior and lateral chest radiographs of a 74-year-old woman undergoing evaluation for slowly progressive dyspnea, cough, and dysphagia. B, Computed tomography scan shows a large middle-mediastinal mass containing calcification and exerting significant compression on the bronchial tree bilaterally as well as on the pulmonary arteries. Significant bronchial and esophageal extrinsic compression was confirmed by bronchoscopy and esophagoscopy, respectively. Multiple needle aspirations were nondiagnostic, and thus surgical exploration was required. Open surgical biopsy revealed a low-grade chondrosarcoma. Resection was impossible due to bronchial and vascular invasion by the tumor.

colleagues (1993)29 reported a patient with a giant benign mesenchymoma who presented with superior vena cava syndrome and underwent a complete resection. The benign variety has not been shown to be a precursor of the malignant lesion. Malignant tumors, like benign tumors, can occur at any age. They typically show extensive local invasion at the time of diagnosis and, therefore, are rarely resectable (Fig. 135-4). Despite this, patients often survive for many years after the diagnosis.

PRIMARY CARCINOMA OF THE MEDIASTINUM The diagnosis of primary carcinoma of the mediastinum is applied when a poorly differentiated carcinoma is discovered within the mediastinum such that the pathologic identification of the precise site or tissue of origin is unknown. Unfortunately, this nonspecific diagnosis is at times given because the tissue biopsy specimen is inadequate to allow clear identification. To minimize the overuse of this designation, a close working relationship between the surgeon and pathologist must be established. The use of more sophisticated patho-

1/21/2008 4:12:37 PM

Chapter 135 Unusual Mediastinal Tumors

1649

A

B FIGURE 135-4 A, Anteroposterior and lateral chest radiographs of a 37-year-old woman who presented to the emergency department with complaints of dyspnea, cough, wheeze, and left lateral and posterior chest pain. Radiographs show a large anterior mediastinal mass applied to the left heart border. B, Cephalad CT scan shows some calcification in the lesion, and the more caudal scan shows a heterogeneous soft tissue mass. Core biopsy suggested a diagnosis of stromal tumor. At surgery a successful en-bloc resection was conducted of the mass, the pericardium, a portion of the left hemidiaphragm, and the left phrenic nerve. Pathology showed that the lesion combined areas of fibrosarcoma, osteosarcoma, and spindle cell thymoma.

logic studies such as electron microscopy and immunoperoxidase staining can sometimes help with the identification of the tissue of origin. These tumors occur with equal frequency in men and women. They make up approximately 4% of all primary mediastinal masses in collective series. Most are symptomatic at the time of diagnosis due to local mass effect of the tumor. Symptoms arise from compression or invasion of adjacent mediastinal structures such as the esophagus, trachea, recurrent laryngeal nerves, and superior vena cava. Associated signs and symptoms include dysphagia, hoarseness, cough, hemop-

Ch135-F06861.indd 1649

tysis, dyspnea, superior vena cava syndrome, and chest pain. In the past, these patients were quite often assumed to have metastatic disease with an unknown primary tumor, and treatment was therefore directed at palliative irradiation or even just symptomatic relief. A complete history and physical examination may direct the search for the primary site. Electron microscopy and immunoperoxidase staining can at times help identify more common mediastinal tumors such as lymphomas, thymomas, and neuroendocrine tumors. Serum βhuman chorionic gonadotropin and α-fetoprotein levels,

1/21/2008 4:12:37 PM

1650

Section 7 Mediastinum

when elevated, may suggest the presence of an extragonadal germ cell tumor. Elderly patients with a history of tobacco use undergo panendoscopy, including a diligent bronchoscopy and esophagoscopy, to search for a primary site. CT of the chest and abdomen can aid in localizing abnormal growths. Positron emission tomography may also be useful. In cases in which an identifiable tissue of origin cannot be found, and the tumor appears localized to the mediastinum without extensive invasion of adjacent structures, en-bloc resection is attempted. Unfortunately, the percentage of long-term cures in these patients is small. In cases in which poorly differentiated carcinomas are unresectable, promising results have been achieved with chemotherapy using cisplatin-based regimens.

EXTRAMEDULLARY HEMATOPOIESIS Extramedullary hematopoiesis frequently involves the liver, spleen, and lymph nodes. However, it may also develop in other sites, such as kidneys, mediastinum, and retroperitoneum. Extramedullary hematopoiesis can either be microscopic or lead to formation of masses. They are thought to be a compensatory response to a chronic hemolytic state seen in conditions such as hereditary spherocytosis, thalassemia, hemolytic anemias, leukemias, lymphomas, and myeloproliferative disorders. Alterations in bone marrow function have also been implicated. Intrathoracic extramedullary hematopoiesis is a rare finding, with fewer than 100 cases reported in the literature.30 The diagnosis is sought when a mediastinal mass is found in conjunction with a known history of chronic anemia or disease of the bone marrow. Initial evaluation employs CT (which demonstrates the mass) and 99mTc-labeled sulfur colloid scans (the latter usually demonstrates increased uptake by the mass). Definitive diagnosis requires tissue biopsy for histology. Open biopsy is usually recommended, although there are reports of transthoracic needle biopsy (AlMarzooq et al, 2004).31 Asymptomatic patients are followed clinically without intervention. Symptoms are usually secondary to compression of surrounding mediastinal structures and require treatment in the form of radiation therapy, which can achieve an abrupt reduction in the size of the mass. Surgery alone or in combination with radiation therapy is typically reserved for more aggressive tumors that cause local compression or invasion of adjacent mediastinal structures. Occasionally, a patient presents with a hemorrhagic complication (hemothorax) necessitating urgent surgical intervention (Xiros et al, 2001).32

GIANT LYMPH NODE HYPERPLASIA (CASTLEMAN’S DISEASE) Castleman4 first reported the appearance of giant lymph node hyperplasia in the mediastinum in 1954. Since that time, many descriptive terms have been linked to Castleman’s disease. Among others, these have included angiofollicular lymph node hyperplasia, giant lymph node hyperplasia, lymph node hamartoma, and benign giant lymphoma. The disease can be found wherever lymph nodes are found, but the majority of these tumors originate within the thorax (70%).

Ch135-F06861.indd 1650

The exact etiology is still unclear, but theories include reactive lymphoid hyperplasia, hamartomatous change, benign lymphoid tumor, and inflammatory or infectious reactions of the lymph nodes. Three histologically distinct types of Castleman’s disease have been generally agreed on. They are the hyaline vascular variety, the plasma cell variety, and the transitional (mixed cell) variety. Ninety percent of Castleman tumors are of the hyaline vascular variety. These are characterized by the presence of small hyaline follicles with interfollicular capillary proliferation. They are typically asymptomatic and occur as isolated lesions found on routine chest radiographs (Fig. 135-5). The plasma cell variety is characterized by the presence of large follicles with interposed sheets of plasma cells. These tumors, in contrast to the hyaline vascular type, typically manifest with systemic symptoms of fever and night sweats. Consensus is that the plasma cell variety represents a more aggressive form of the disease. The transitional variant is the least common. It is histologically similar to the hyaline vascular variety with foci of numerous plasma cells and some large, normal-appearing germinal centers. Diagnosis is based on tissue histology, but more comprehensive laboratory evaluation may show anemia, hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate. Although classic Castleman’s disease occurs as a solitary lesion, in recent years a multicentric form has been shown to exist as generalized lymphadenopathy with the morphologic features of giant lymph node hyperplasia. These patients are typically symptomatic at presentation and can exhibit fever, chills, weight loss, hepatosplenomegaly, and altered immunity. This form of the disease has been associated with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Considerable interest has focused on the role of human herpesvirus-8 in this lesion. This virus, previously referred to as Kaposi’s sarcoma–associated herpesvirus, is generally absent in normal control tissues, inflammatory conditions, and various tumors. However, it is present in most Kaposi’s sarcoma lesions (in both HIVpositive and HIV-negative patients); in primary effusion lymphoma (typically an AIDS-related non-Hodgkin’s lymphoma in which neoplastic lymphocytes proliferate in serous body cavities and spare solid organs); and in a significant proportion of cases of multicentric Castleman’s disease (in patients with or without AIDS), in which it may underlie malignant transformation to lymphoma (Fig. 135-6). The multicentric form of the disease is quite virulent compared with the typically benign course of classic Castleman’s disease. Mortality has been reported to be as high as 50%. Although malignant transformation in Castleman’s disease is uncommon, when it occurs it usually originates from the multicentric plasma cell type. Mortality for this variety is most commonly due to overwhelming sepsis. When the diagnosis of Castleman’s disease is secure, observation is a reasonable option. However, if symptoms (e.g., from mass effect) are present and severe or disabling, or if malignancy is suspected, surgical resection is performed and typically offers cure. When resecting a Castleman tumor of the hyaline vascular variety, great care must be taken because of its extreme vascularity. Resection of this variety is often

1/21/2008 4:12:38 PM

Chapter 135 Unusual Mediastinal Tumors

1651

FIGURE 135-5 A, Anteroposterior chest radiograph of a healthy 29-year-old man. Note the rounded left paramediastinal density. B, Chest CT scan from the same patient. The rounded lesion sits apposed to the left pulmonary artery in the subaortic region. It was sampled through a left anterior mediastinotomy, which revealed features of typical Castleman’s disease (hyaline vascular variety).

FIGURE 135-6 A, Posteroanterior and lateral chest radiographs of a 52-year-old woman with a 1-year history of Castleman’s disease (based on biopsy of an upper mediastinal lymph node performed during thyroid cancer resection). She now presents with fever, malaise, and dyspnea. Note the large left pleural effusion. B, Chest CT scans. Thoracentesis revealed a chylothorax. Video-assisted thoracoscopy was performed for further evaluation. Biopsy of an enlarged anterior mediastinal lymph node now revealed B-cell lymphoma. Serologic testing revealed the patient to be positive for human herpesvirus-8. Arrow indicates axillary lymphadenopathy.

Ch135-F06861.indd 1651

1/21/2008 4:12:38 PM

1652

Section 7 Mediastinum

associated with significant intraoperative blood loss. When this tumor is incidentally found during surgery, complete resection is attempted.

COMMENTS AND CONTROVERSIES This chapter thoroughly characterizes and describes an eclectic group of mediastinal tumors, both mesenchymal and epithelial. Consensus regarding management is difficult for some of these lesions because of their rarity. State of the art imaging, usually by CT and occasionally by magnetic resonance, will establish the diagnosis (e.g., for lymphoma, liposarcoma, or osteogenic sarcoma). However, in the majority of patients it is necessary to secure a tissue diagnosis. Fine-needle aspiration or core-needle biopsy will usually suffice. Open biopsy must be considered with caution for vascular lesions. For the majority of these unusual tumors, complete resection is the strategy of choice. The access incision is dictated by the anatomic relationships of the lesion. G. A. P.

KEY REFERENCES Al-Marzooq YM, Al-Bahrani AT, Chopra R, Al-Momatten MI: Fineneedle aspiration biopsy diagnosis of intrathoracic extramedullary hematopoiesis presenting as a posterior mediastinal tumor in a patient with sickle-cell disease: Case report. Diagn Cytopathol 30:119-121, 2004. Baldo X, Sureda C, Gimferrer JM, Belda J: Primary mediastinal leiomyoma: An angiographic study and embolisation of the feeding vessels to improve the surgical approach. Eur J Cardiothorac Surg 11:574576, 1997. Burt M, Ihde JK, Hajdu SI, et al: Primary sarcomas of the mediastinum: Results of therapy. J Thorac Cardiovasc Surg 115:671-680, 1998.

Ch135-F06861.indd 1652

Imada S, Yokota T, Hidaka T, Tamura K: A case of malignant fibrous histiocytoma in the mediastinum. Nihon Kyobu Shikkan Gakkai Zasshi 32:1099-1103, 1994. Inaba H, Furuta Y, Usuda R, et al: Liposarcoma originating in the neck and the mediastinum after removal of mediastinal lipoma. Kyobu Geka 57:935-940, 2004. Kato N, Iwasaki H, Rino Y, et al: Intrathoracic omental herniation through the esophageal hiatus: Report of a case. Surg Today 29:347350, 1999. Kumar P, Judson I, Nicholson AG, Ladas G: Mediastinal hemangioma: Successful treatment by alpha-2a interferon and postchemotherapy resection. J Thorac Cardiovasc Surg 124:404-406, 2002. Morandi U, Stefani A, De Santis M, et al: Preoperative embolization in surgical treatment of mediastinal hemangiopericytoma. Ann Thorac Surg 69:937-939, 2000. Ohara T, Fukushima K, Hasegawa T, et al: Giant benign mesenchymoma of the mediastinum causing superior vena cava syndrome: Report of a case. Surg Today 23:917-919, 1993. Panasuk DB, Bauer TL, Davies AL, et al: Common malignancies with uncommon sites of presentation: Case 1. Anterior mediastinal rhabdomyosarcoma. J Clin Oncol 21:4455-4456, 2003. Ratto GB, Costa R, Alloisio A, et al: Mediastinal chondrosarcoma. Tumori 90:151-153, 2004. Shaffer K, Pugatch RD, Sugarbaker DJ: Primary mediastinal leiomyoma. Ann Thorac Surg 50:301-302, 1990. Simonton SC, Swanson PE, Watterson J, Priest JR: Primary mediastinal hemangiopericytoma with fatal outcome in a child. Arch Pathol Lab Med 119:839-841, 1995. Teschner M, Lullig H: Diagnosis and treatment of primary mediastinal liposarcoma. Pneumologie 57:22-26, 2003. Xiros N, Economopoulos T, Papageorgiou E, et al: Massive hemothorax due to intrathoracic extramedullary hematopoiesis in a patient with hereditary spherocytosis. Ann Hematol 80:38-40, 2001. Zarate-Gomez M, Rodriguez-Montalvo C, Gonzalez-Velasco R, Barbosa-Quintana A: Mediastinal lipoblastoma in a 14-year-old patient. Bol Med Hosp Infant Mex 48:185-188, 1991.

1/21/2008 4:12:39 PM

chapter

136

PEDIATRIC MEDIASTINAL TUMORS Sanjiv K. Gandhi

Key Points ■ The majority of mediastinal masses in children are symptomatic,

often referable to the respiratory system. ■ Chest radiography and CT are the mainstays of diagnostic

modalities. ■ Biopsy or resection of most pediatric mediastinal tumors will be

necessary.

ANATOMY A basic understanding of the anatomy and embryology of the mediastinum is essential to appreciate the location and behavior of mediastinal masses in children. Embryologically, the neck and abdomen communicate by means of an intermediate area; the mediastinum is not yet formed. The mediastinum develops after the craniocaudad migration of organs and the creation of the celomic pleura and pericardial cavities and will separate from the abdomen by means of the diaphragm (Jaggers and Balsara, 2004; Shields, 1987).1,2 When defining the location of specific mediastinal masses, the portion of the thorax defined as the mediastinum extends from the posterior aspect of the sternum to the anterior surface of the vertebral bodies and includes the paravertebral sulci. The mediastinum is limited laterally by the mediastinal parietal pleura, inferiorly by the diaphragm, and superiorly by the thoracic inlet. Descriptive localization of specific lesions is facilitated by division of the mediastinum into three compartments or spaces (i.e., anterior, middle, posterior): 1. The anterior compartment extends from the posterior surface of the sternum to the anterior surface of the pericardium and great vessels. It normally contains the thymus gland, adipose tissue, and lymph nodes. 2. The middle or visceral compartment, or middle mediastinum, is located between the posterior limit of the anterior compartment and the anterior longitudinal spinal ligament. This area contains the heart, pericardium, ascending and transverse portions of the aorta, brachiocephalic vessels, main pulmonary arteries and veins, superior and inferior vena cavae, trachea and mainstem bronchi, numerous lymph nodes, and various neural structures such as the phrenic nerves. Although neoplasms of the middle mediastinum are most commonly of lymphatic origin, neurogenic tumors may rarely occur in this area. Another significant group of masses identified in this compartment are cystic structures associated with a develop-

mental abnormality of the primitive foregut or the precursors of the pericardium or pleura. 3. The posterior mediastinum is the area posterior to the heart and trachea and includes the paravertebral sulci. It contains the descending thoracic aorta and ligamentum arteriosum, esophagus, thoracic duct, azygos vein, and numerous neural structures (including autonomic ganglia and nerves, lymph nodes, and adipose tissue). The majority of tumors of neurogenic origin occupy this posterior portion of the mediastinum (Saenz et al, 2000; Saenz et al, 1993).3,4 Tumors originating from lymphatic, vascular, or mesenchymal tissues can also be found in this compartment.

PRESENTATION Although, in adults, many mediastinal tumors and cysts produce no symptoms and are found incidentally during chest radiographs or other imaging studies of the thorax performed for another reason, approximately two thirds of mediastinal tumors and cysts are symptomatic in the pediatric population; only approximately one third produce symptoms in adults (Azarow et al, 1993).5,6 The signs and symptoms that occur depend on the benignity or malignancy of the lesion, its size, its location, the presence or absence of infection, the elaboration of specific endocrine or other biochemical products, and the presence or absence of associated disease states. In patients younger than 20 years or older than 40 years, approximately one third of mediastinal tumors are malignant, whereas in patients aged 20 to 40 years, roughly one half are malignant. When considering all age groups, nearly 55% of patients with benign mediastinal masses are asymptomatic at presentation, compared with only approximately 15% of those in whom masses are found to be malignant. Symptoms associated with the respiratory tract predominate in pediatric patients because airway compression is more likely. This occurs because of the significant malleability of the airway structures and the small size of the chest cavity in infants and children. Any mediastinal mass in a child, even a small one, is more likely to have a compressive effect on the small, flexible airway structures (Seo et al, 1999).7-10 Symptoms most often observed include persistent cough, dyspnea, and stridor. In addition to compression or obstruction of portions of the airway, an enlarging tumor or cyst in children can also result in a mass effect on the esophagus, the right side of the heart, and the great veins and can result in a number of symptoms. If the location and size of the mass produces partial or complete airway obstruction, obstructive pneumonia can also occur. Infectious symptomatology, and 1653

Ch136-F06861.indd 1653

1/21/2008 4:13:24 PM

1654

Section 7 Mediastinum

even signs of overt sepsis, can occur if a mediastinal cyst becomes infected. Constitutional symptoms, such as weight loss, fever, malaise, and vague chest pain, commonly occur with malignant tumors in pediatric patients. Malignant mediastinal tumors can cause all of the same local effects as those associated with benign lesions but, in addition, are more likely to produce signs and symptoms of obstruction and/or compression because they invade or transfix normal mediastinal structures. Local structures most commonly subject to invasion by malignant tumors include the tracheobronchial tree and lungs, esophagus, superior vena cava, pleura and chest wall, and any adjacent intrathoracic nerves. Clinical findings associated with these malignant properties include cough, hemoptysis, dyspnea, stridor, dysphagia, and even more dramatic findings such as superior vena cava syndrome.11 Invasion of the chest wall or pleura by a malignant neoplasm can produce persistent pleural effusions. Invasion of nearby nerves within the thorax can produce local and referred pain and a variety of other findings such as hoarseness from recurrent nerve paralysis, diaphragmatic paralysis from phrenic nerve paralysis, Horner’s syndrome from autonomic nerve invasion, and even motor paralysis from direct spinal cord involvement. Pain in the shoulder or upper extremity can occur from invasion of the ipsilateral brachial plexus. Systemic pathophysiology can result from certain mediastinal tumors. Many of these manifestations are related to bioactive substances produced by specific neoplasms. Tumors developing from autonomic nerve cells can produce several vasoactive substances. The most common of these is neuroblastoma, which produces excess amounts of the catecholamines epinephrine and norepinephrine. Ganglioneuroma and ganglioneuroblastoma can also produce these substances but do so less often. Neuroblastomas are also thought to produce abnormal antibodies that are responsible for some unusual neurologic manifestations in some children with the tumor. Autonomic nerve tumors are also capable of producing excess amounts of vasoactive intestinal peptide. Some neurosarcomas have been associated with the production of an insulin-like substance that, in turn, can produce hypoglycemia.

DIAGNOSIS The posteroanterior chest radiograph is able to detect about 90% of mediastinal masses in children (Fig. 136-1). A more detailed evaluation is then obtained by CT (Fig. 136-2). This will enable one to evaluate the exact anatomic location of the mass, its consistency, and its relationship to other structures. CT is very accurate in differentiating between fatty tissue, cystic components, vascular components, and soft tissue. MRI is superior to computed tomography (CT) in defining the relationship of mediastinal masses to the spine and possible invasion into surrounding structures.12 Although MRI avoids ionizing radiation, it is limited in children by the prolonged length of the study required. Biochemical markers and elevated hormone levels may be present in patients with various mediastinal tumors. Specific markers and certain hormone levels are obtained in various

Ch136-F06861.indd 1654

FIGURE 136-1 Posteroanterior chest radiograph of large mediastinal mass in an infant, resulting in total collapse of left lung.

FIGURE 136-2 CT scan more clearly delineates anatomic boundaries of the mass seen on the radiograph in Figure 136-1.

clinical settings. For example, all infants and children with a paravertebral mass must be tested for excessive norepinephrine and epinephrine production, which is associated with many neuroblastomas and ganglioneuroblastomas. All patients with a suspected thymoma are evaluated for the presence of anti-acetylcholine receptor antibodies because subclinical myasthenia gravis may be present (Drachman, 1994).13-15 Bronchoscopy, esophagoscopy, or both may be indicated with certain mediastinal masses, depending on symptoms, to evaluate the status and involvement of the tracheobronchial tree and the esophagus. Although nuclear scans and biochemical studies can be used to further characterize a lesion, tissue diagnosis is almost always required. If a mass is likely to be benign after initial evaluation, it can be removed surgically without biopsy (Cohen et al, 1991).16 Otherwise, a diagnostic biopsy specimen can be obtained by transthoracic or transbronchial needle aspiration, mediastinoscopy, anterior mediastinotomy, or video-assisted thoracoscopic surgery (VATS).17-20

1/21/2008 4:13:25 PM

Chapter 136 Pediatric Mediastinal Tumors

1655

ROLE OF THE SURGEON The pediatric cardiothoracic surgeon plays both a diagnostic and a therapeutic role in the management of children with mediastinal tumors. There are many different surgical approaches that may be employed to access the mediastinum (Cohen et al, 1991).16 The upper or superior portion of the visceral compartment of the mediastinum can be approached using mediastinoscopy, which is used for the biopsy of paratracheal or subcarinal masses.21 Suprasternal access to the mediastinum can also be in the form of the transcervical approach to thymic resection. The Chamberlain incision (paramedian anterior thoracotomy) is useful for the biopsy of a variety of masses located in the anterior mediastinum, specifically in the aortopulmonary window.21 Depending on the size, location, and relationship of the mass to surrounding structures, complete resection can be performed using either median sternotomy, partial sternotomy, thoracotomy, a subxiphoid approach, or VATS techniques.22 Median sternotomy affords the best approach to the anterior compartment and most of the visceral compartment of the mediastinum, with the exception of the esophagus. Bilateral thoracosternotomy also may be used for large tumors arising in the anterior mediastinum, extending significantly into either the right or left hemithorax. Thoracotomy is the best approach for paraesophageal lesions and masses of the posterior compartment of the mediastinum and paravertebral sulcus. Of course, accessible structures vary depending on the side of the thoracotomy. On the right, exposure is easily obtained of the esophagus, superior vena cava, thoracic duct, and trachea. On the left, accessible structures include the aorta, superior and inferior portions of the thoracic duct, and lower third of the esophagus.

TYPES OF TUMORS Lymphomas Lymphomas are a very common cause of masses in the pediatric mediastinum (Fig. 136-3). More than 50% of children with lymphoblastic lymphoma present with a mediastinal mass (Glick and La Quaglia, 1999).23 These tumors are of thymocyte origin and are usually difficult to differentiate from lymphoblastic leukemia. These lymphomas have a predilection for the central nervous system and bone marrow, in addition to the mediastinum. More than one third of all patients with non-Hodgkin’s lymphoma have their primary sites in the mediastinum.24 Hodgkin’s disease also frequently involves this anatomic compartment with approximately two thirds of all pediatric cases manifesting mediastinal adenopathy. Lymphomas may involve all components in the mediastinum, but the anterior and middle components are much more frequently involved in children. Although surgical resection generally is not involved in the primary treatment of these diseases, surgeons often play a key role in obtaining adequate tissue for proper diagnostic analysis. Surgical access to the mediastinum is often required in specimen acquisition. Rarely, in situations in which a bulky

Ch136-F06861.indd 1655

FIGURE 136-3 Typical CT appearance of pediatric lymphoma appearing as anterior mediastinal mass.

tumor manifests with life-threatening airway obstruction, surgical debulking may be indicated.

Germ Cell Tumors Germ cell tumors may be either benign or malignant neoplasms (Nichols, 1991).25 They result from abnormal migration of primordial germ cells.26 Germ cell tumors are classified based on cell type into benign teratomas, seminomas, and embryonal tumors. They occur in both gonadal and extragonadal sites, with extragonadal tumors predominating in children younger than 3 years of age and with the gonads being the main location of tumors during and after puberty. They occur more frequently in girls than boys. In the pediatric population, the mediastinum is the fourth most common location for teratomas (the ovary, sacrococcygeal region, and testis being the three most common). The most common location of benign mediastinal teratomas is the anterior compartment (Fig. 136-4), but some occur in the posterior compartment as well. Most mature teratomas are large, well-circumscribed masses that contain a mixture of tissues derived from one or more of the three germinal cell layers (i.e., ectoderm, endoderm, and mesoderm). Skin and skin appendages including hair and cystic spaces lined by stratified squamous epithelium are typical of the ectodermal elements, which usually predominate. Fat, cartilage, smooth muscle, and bone represent mesodermal elements. Examples of endodermal tissue include gastrointestinal and respiratory epithelium, which may also line cystic elements of a teratoma. If the tumor contains any immature or embryonal structures, it is considered an immature teratoma. Neuroepithelial rosettes and disordered foci of immature tissue may be present in only a few fields, thus thorough sampling of the tumor is necessary. Malignant degeneration within a teratoma may occur but is rare. Reports of rhabdomyosarcoma, adenocarcinoma, leukemia, and anaplastic small cell tumors have all been identified as arising from mature or immature teratomas. Other malignant germ cell tumors are relatively uncommon, accounting for approximately 3% of all childhood malig-

1/21/2008 4:13:25 PM

1656

Section 7 Mediastinum

A

B

FIGURE 136-4 A, Intraoperative photograph of an anterior mediastinal teratoma in a teenager. B, Intraoperative photograph of an anterior mediastinal pericardial teratoma in an infant.

nancies. Occurring with an incidence of approximately 4 per million among children younger than 15 years of age, they account for approximately 225 new cases per year in the United States. Primary mediastinal seminomas account for 25% to 50% of malignant mediastinal germ cell tumors, occurring most frequently in men aged 20 to 40 years. Patients present with dyspnea, substernal pain, weakness, cough, fever, gynecomastia, or weight loss. Because of the tumor location, about 10% of patients present with superior vena cava syndrome. Seminomas are uniquely sensitive to radiation therapy. The embryonal tumors, also called nonseminomatous germ cell tumors, are diverse and include choriocarcinomas, yolk sac carcinomas, embryonal cell carcinomas, and teratocarcinomas. These tumors often produce serologic markers such as α-fetoprotein and the β-subunit of human chorionic gonadotropin, which can be useful in the diagnostic evaluation and allow evaluation of the extent of resection and the development of recurrence for many of the tumors.27,28 These tumors are often symptomatic and malignant and predominantly affect young men. In addition, they can be associated with hematologic malignancies, and 20% of patients have Klinefelter’s syndrome. The introduction of cisplatin-based chemotherapy has markedly improved the survival rate for these tumors, as well as the salvage rate for recurrent or metastatic disease.29,30

Thymic Tumors Thymic masses include thymic cysts, thymic hyperplasia, and thymic tumors (Sauter et al, 1991).31 They constitute 2% to 3% of all pediatric mediastinal tumors. Thymic cysts are discussed later in this chapter along with other mediastinal cysts. Thymic hyperplasia consists of two types. In lymphoid, or follicular, hyperplasia, the gland may be abnormal, or normal, in size and weight. There is an association between this type of hyperplasia and autoimmune disease. True thymic hyper-

Ch136-F06861.indd 1656

plasia, although rare, may result in massive enlargement of the gland (Fig. 136-5). Respiratory symptoms are common, and surgical resection is curative. Hyperplasia may also be a rebound phenomenon seen after the treatment of a variety of malignant conditions, including Hodgkin’s disease and Wilms’ tumor.32 It is self-limited and requires no surgical intervention. Thymomas are relatively rare in children, representing less than 1% of all mediastinal tumors.33 They are neoplasms that may originate from the epithelial and lymphoid components of the thymus, which determines their histologic classification.34 Complete surgical resection is the mainstay of therapy for all thymomas. In children, these tumors are typically quite aggressive, with poor outcomes.35,36

Vascular Tumors Mediastinal masses of vascular origin account for 5% to 10% of all mediastinal masses in children. The diagnosis of all may be suggested by plain chest radiography but requires CT, magnetic resonance imaging (MRI), echocardiography, or angiography for confirmation. These lesions can be subdivided based on anatomic origins: 1. Anomalies of the systemic venous system causing a mediastinal mass include aneurysms of the innominate vein and superior vena cava, dilation of the superior vena cava in association with total or partial anomalous pulmonary venous return, persistent left superior vena cava, or azygos or hemiazygos enlargement. 2. Pulmonary arterial anomalies resulting in a mediastinal vascular mass include an enlarged pulmonary artery secondary to a left-to-right shunt (Fig. 136-6), poststenotic dilation of the pulmonary artery, tetralogy of Fallot with absent pulmonary valve, pulmonary embolus, Eisenmenger’s complex, ductus aneurysm, pulmonary artery sling, and aneurysms of the right ventricular outflow tract.

1/21/2008 4:13:25 PM

Chapter 136 Pediatric Mediastinal Tumors

A

1657

B FIGURE 136-5 A, Intraoperative dissection of a massive thymus gland in an infant. B, Resected specimen of a giant thymus.

FIGURE 136-7 Three-dimensional CT reconstructed image of double aortic arch.

FIGURE 136-6 Enlarged pulmonary arteries in a child with intracardiac shunt and resultant pulmonary hypertension.

3. Abnormalities of the pulmonary venous system that may result in a mediastinal mass include pulmonary venous confluence, pulmonary venous varix, and partial and total supracardiac anomalous pulmonary venous connection. 4. Anomalies of the systemic arterial system include diverticula and aneurysms of the left ventricle, coronary artery aneurysms and fistulas, double aortic arch (Fig. 136-7), cervical aortic arch, right aortic arch with Kommerell’s diverticulum, anomalous innominate artery, coarctation of the aorta, and aortic aneurysms. 5. Hemangiomas, hemangiosarcomas, and cystic hygromas are other vascular anomalies that can present as mediastinal masses in children. Hemangiomas are proliferative lesions characterized by increased endothelial cell turn-

Ch136-F06861.indd 1657

over. Angiosarcoma is a malignant vascular tumor that rarely occurs in the mediastinum. Cystic hygromas, or lymphangiomas, are actually lymphatic malformations. They usually are not isolated mediastinal masses but represent an extension of cervical lesions.

Neurogenic Tumors Neurogenic tumors are, by far, the most common neoplasm of the posterior mediastinum (Reeder, 2000; Reynolds and Shields, 2000; Saenz, 1999; Shapiro et al, 2000; Wain, 1992).3,37-40 Although they account for approximately 20% of all adult mediastinal tumors, 35% of pediatric mediastinal tumors are neurogenic in origin. In infants and children, mediastinal neurogenic tumors most commonly occur in the paravertebral sulci and originate from tissues of the autonomic ganglia. Infrequently, they are of nerve sheath origin, and even less commonly they arise from the paraganglionic system.

1/21/2008 4:13:26 PM

1658

Section 7 Mediastinum

Tumors of the autonomic ganglia arise from the primitive neural crest cells. These lesions may be frankly benign, malignant to varying degrees, or frankly and aggressively malignant. The three tumors in this category—ganglioneuroma, ganglioneuroblastoma, and neuroblastoma—are believed to represent a continuum of maturation and differentiation, and treatment varies accordingly. Ganglioneuroma, composed of ganglion cells and nerve fibers, is the most mature and benign form of autonomic nerve tumor. This is also the most common pediatric neurogenic tumor. Although they may be asymptomatic, pressure on the nerve root or spinal cord may elucidate symptoms. They are treated and cured by surgical resection. Ganglioneuroblastomas represent an intermediate degree of differentiation between ganglioneuroma and neuroblastoma. Two categories of these tumors exist: composite and diffuse ganglioneuroblastomas. Identified at an early stage of disease, ganglioneuroblastomas also may be treated with primary resection. Advanced stages are treated primarily with chemotherapy, and surgical resection is rarely indicated. Neuroblastoma is a highly malignant neoplasm most commonly found in children younger than 3 years of age (Suita et al, 2000).41 The tumors represent approximately 50% of pediatric mediastinal neurogenic masses. Intrathoracic lesions occur in about 20% of all neuroblastomas. The clinical presentation of children with a neuroblastoma is quite variable. This tumor has been called the great masquerader because its symptoms mimic so many other diseases. A condition known as opsoclonus-myoclonus syndrome, involving bursts of rapid and involuntary, chaotic eye movement in all directions, can sometimes be a symptom of neuroblastoma. A multitude of paraneoplastic syndromes have been attributed to this disorder. Metastases at the time of presentation are common. Treatment, which may include surgical resection and systemic multimodality therapy, is tailored to the stage of disease at presentation (Suita et al, 2000).41,42 Surgical resection is the treatment of choice for tumors originating from nerve sheath tissue, including neurilemoma, neurofibroma, and neurogenic sarcoma. Neurofibromas are associated with the inheritable condition von Recklinghausen’s disease or neurofibromatosis. Complete resection of the more malignant forms of these tumors may not be possible, and additional treatment modalities may be required. Peripheral neuroectodermal tumors (PNETs), otherwise known as Askin tumors, are rare tumors occurring in the posterior sulcus or chest wall of adolescent and young adult patients. They are believed to develop from intercostal nerve tissue. Standard therapy includes en-bloc resection, with accompanying radiation therapy and chemotherapy if complete resection is not possible. Primary resection is also the treatment of choice for neurogenic tumors of paraganglionic origin, which include paraganglionoma and mediastinal pheochromocytoma.43 Only approximately 2% of pheochromocytomas occur in the chest. Roughly 10% of pheochromocytomas are associated with one of a variety of familial syndromes, the most noted of which are the multiple endocrine neoplasia syndromes. One interesting syndrome specifically associated with multiple extraadrenal pheochromocytomas is the Carney triad, in which these neoplasms occur in association with pulmonary hamar-

Ch136-F06861.indd 1658

tomas and gastric leiomyosarcomas. Functioning mediastinal pheochromocytomas produce an excess of circulating catecholamines. The hallmark clinical finding in individuals with these neoplasms is hypertension. The hypertension may be persistent, paroxysmal, or persistent with paroxysmal episodes. Approximately 10% of these tumors are malignant and may not be entirely resectable. Some, even though benign, may be incompletely resected due to their location and increased vascularity.

Mediastinal Cysts Foregut cysts account for 10% to 18% of mediastinal masses in the pediatric population. Although not actually neoplasms, they represent space-occupying lesions that usually result from abnormal embryologic development (Rescorla and Grosfeld, 2000; Reynolds, 2000; Takeda et al, 2003).44-47 The more common bronchogenic cysts and enteric cysts arise from the primitive foregut in the region of the laryngotracheal groove before its differentiation into the trachea and the esophagus. Other foregut derivatives include neuroenteric cysts, mesothelial cysts, and thymic and thoracic duct cysts. Cysts can also be associated with teratomas within the mediastinum. Bronchogenic cysts likely arise from an abnormality of the normal budding of the ventral foregut, the precursor of the trachea and major bronchial structures (Ribet et al, 1995).48 They are the most common type of intrathoracic foregut cyst (Fig. 136-8). Bronchogenic cysts can be subclassified on the basis of their topography: paratracheal, carinal, hilar, paraesophageal, and miscellaneous. The walls of these cysts are lined by ciliated pseudostratified columnar or cuboidal epithelium and may contain bronchial glands, smooth muscle bundles, and other tissues found in the tracheobronchial tree. Several cases have been reported in which malignant tissue has been found within the wall of a resected bronchogenic cyst. Malignant cell types found include squamous cell carcinoma and adenocarcinoma. Children with a mediastinal bronchogenic cyst may present at any age with nonspecific respiratory symptoms, dysphagia, or often recurrent fever and pneumonia.49 Surgical excision is recommended for all bronchogenic cysts. Enteric cysts (enterogenous cysts, esophageal duplications, dorsal enteric cysts) arise from abnormal development of that portion of the dorsal foregut that becomes the gastrointestinal tract. Most commonly, these cysts are lined with some form of gastrointestinal epithelium. Esophageal duplication cysts are believed to arise in early development, when vacuolization of the solid early esophagus occurs to form the esophageal lumen. If an isolated vacuole fails to merge with the central esophageal lumen, a duplication cyst may occur. Most of these cysts are associated with the esophagus in the lower or middle thirds of the middle mediastinum. Occasionally, a communication between the cyst and the esophagus is present. Infants and children with enteric cysts may not have any symptoms. Conversely, they may also present with evidence of obstruction of the esophagus. If adjacent lung parenchyma is compressed, a pneumonia may result. Gastric mucosa within the cyst may result in peptic ulceration, with bleeding or perforation.

1/21/2008 4:13:28 PM

Chapter 136 Pediatric Mediastinal Tumors

1659

FIGURE 136-8 Bronchogenic cyst appearing as a superior mediastinal bilobed mass in the aortopulmonary window on CT.

Neurenteric cysts develop at a location in which the dorsal foregut and the primitive notochord are in close relationship. Many theories have been offered about the development of these cystic abnormalities; however, the common feature noted in many of them is that an adhesive process of some type appears to cause a vacuole of the foregut to become incorporated into the notochord tissue. The classic cyst is lined with enteric and neural tissue. Most patients present within the first year of life. The signs and symptoms of neurenteric cysts are related most frequently to the compressive effect of the mass on the airway. They are often associated with other defects and anomalies of the vertebral column, such as scoliosis, spina bifida, hemivertebra, and vertebral fusion. Many cases are described in the literature in which the cyst communicates with, or extends into, the spinal canal. Mesothelial cysts are generally made up of a capsule of fibrous tissue with an inner single-cell layer of mesothelial cells. The most common type of mesothelial cyst found in the mediastinum is the pleuropericardial cyst, which is generally located at the anterior cardiophrenic angle (Fig. 136-9). Other mesothelial cysts occurring in the mediastinum are simple mesothelial cysts and lymphogenous cysts. Other primary cysts of the mediastinum include thymic cysts and thoracic duct cysts. Thymic cysts can present as either neck or mediastinal masses in children (De Caluwe et al, 2002; Jaggers and Balsara, 2004).2,50-52 They are generally asymptomatic, found incidentally, and uniformly benign. These cysts may be of congenital origin or may occur as a response to inflammation. True thymic cysts are thin-walled, are unilocular, and have islands of normal thymic tissue in the cyst wall. Hemorrhage into the cyst cavity may result in respiratory symptoms. Thoracic duct cysts are very rare. They may or may not communicate with the duct itself and are composed of the same tissue as normal lymphatic channels.

Other Tumors Primary mesenchymal tumors of the mediastinum are rare. The cell type of origin of these tumors can be quite varied

Ch136-F06861.indd 1659

FIGURE 136-9 Pericardial cyst appearing as a right cardiophrenic soft tissue focus.

FIGURE 136-10 Mediastinal adenopathy in a child with a diagnosis of histoplasmosis.

(Shields, 2000).53 They may originate from adipose tissue, blood vessels, lymphatics, fibrous tissue, smooth or striated muscle, or pluripotential mesenchyme. Mediastinal lymphadenopathy is most commonly seen within the middle mediastinum (Fig. 136-10). The etiology of this adenopathy may be malignancy or benign infectious diseases, such as granulomatous disease from fungi, tuberculosis, or sarcoidosis.

1/21/2008 4:13:28 PM

1660

Section 7 Mediastinum

COMMENTS AND CONTROVERSIES Dr. Gandhi has provided an excellent review of mediastinal tumors in the pediatric population. He points out the important role of imaging in establishing a likely differential diagnosis for these lesions. A variety of approaches are available for surgical access to the mediastinum. In addition to the techniques described, video access techniques, discussed in detail by Dr. Naunheim in Chapter 140, are also available in selected patients. G. A. P.

KEY REFERENCES Azarow KS, Pearl RH, Zurcher R, et al: Primary mediastinal masses: A comparison of adult and pediatric populations. J Thorac Cardiovasc Surg 106:67-72, 1993. Cohen AJ, Thompson L, Edwards FH, Bellamy RF: Primary cysts and tumors of the mediastinum. Ann Thorac Surg 51:378-386, 1991. De Caluwe D, Ahmed M, Puri P: Cervical thymic cysts. Pediatr Surg Int 18:477-479, 2002. Drachman DB: Myasthenia gravis. N Engl J Med 330:1797-1810, 1994. Glick RD, La Quaglia MP: Lymphomas of the anterior mediastinum. Semin Pediatr Surg 8:69-77, 1999. Jaggers J, Balsara K: Mediastinal masses in children. Semin Thorac Cardiovasc Surg 16:201-209, 2004. Nichols CR: Mediastinal germ cell tumors: Clinical features and biologic correlates. Chest 99:472-479, 1991. Reeder LB: Neurogenic tumors of the mediastinum. Semin Thorac Cardiovasc Surg 12:261-267, 2000. Rescorla FJ, Grosfeld JL: Gastroenteric cysts and neurenteric cysts in infants and children. In Shields TW, LoCicero J III, Ponn RB (eds): General Thoracic Surgery, 5th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, vol 2, pp 2415-2422. Reynolds M: Foregut cysts of the mediastinum in infants and children. In Shields TW, LoCicero J III, Ponn RB (eds): General Thoracic

Ch136-F06861.indd 1660

Surgery, 5th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, vol 2, pp 2393-2400. Reynolds M, Shields TW: Benign and malignant mediastinal neurogenic tumors in infants and children. In Shields TW, LoCicero J III, Ponn RB (eds): General Thoracic Surgery, 5th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, vol 2, pp 2313-2328. Ribet ME, Copin MC, Gosselin B: Bronchogenic cysts of the mediastinum. J Thorac Cardiovasc Surg 109:1003-1010, 1995. Saenz NC: Posterior mediastinal neurogenic tumors in infants and children. Semin Pediatr Surg 8:78-84, 1999. Saenz NC, Schnitzer JJ, Eraklis AE, et al: Posterior mediastinal masses. J Pediatr Surg 28:172-176, 1993. Sauter ER, Arensman RM, Falterman KW: Thymic enlargement in children. Am Surg 57:21-23, 1991. Seo T, Ando H, Watanabe Y, et al: Acute respiratory failure associated with intrathoracic masses in neonates. J Pediatr Surg 34:1633-1637, 1999. Shapiro B, Orringer MB, Gross MD: Mediastinal paragangliomas and pheochromocytomas. In Shields TW, LoCicero J III, Ponn RB (eds): General Thoracic Surgery, 5th ed. Philadelphia, Williams & Wilkins, 2000, vol 2, pp 2333-2355. Shields TW: Mediastinal and other less common cysts of the mediastinum. In Shields TW, LoCicero J III, Ponn RB (eds): General Thoracic Surgery, 5th ed. Philadelphia, Williams & Wilkins, 2000, vol 2, pp 2301-2313. Shields TW: The Mediastinum, Its Compartments, and the Mediastinal Lymph Nodes. In Shields TW, LoCicero J III, Ponn RB (eds): General Thoracic Surgery, 5th ed. Philadelphia, Williams & Wilkins, 2000, pp 1983-1987. Suita S, Tajiri T, Sera Y, et al: The characteristics of mediastinal neuroblastoma. Eur J Pediatr Surg 10:353-359, 2000. Takeda S, Miyoshi S, Minami M, et al: Clinical spectrum of mediastinal cysts. Chest 124:125-132, 2003. Wain JC: Neurogenic tumors of the mediastinum. Chest Surg Clin N Am 2:121-136, 1992.

1/21/2008 4:13:29 PM

chapter

MEDIASTINAL THYROID TUMORS

137

Jeffrey Moley Bruce Lee Hall

Key Points ■ Substernal goiters account for less than 10% of all goiters. ■ Almost all substernal goiters are pathologically benign. ■ Almost all substernal goiters arise from orthotopic cervical thyroid

and are supplied by the inferior thyroid artery. ■ Most substernal goiter patients are symptomatic due to mass

effects on trachea or esophagus. ■ Most substernal goiter patients are euthyroid. ■ Most substernal goiters are adequately diagnosed and evaluated ■ ■ ■ ■

by CT. The diagnosis of substernal goiter is an indication for surgery. Almost all substernal goiters can be removed transcervically. Most substernal goiters are anterior or lateral to the trachea, as opposed to posterior. Most substernal goiter patients experience an improvement in symptoms after surgery and can be treated without complications.

overall rate of substernal goiter to be 8.7% of all goiters and divided these goiters into three types20: 1. Small extensions of cervical goiter beneath the sternum (81.9%) 2. Partially intrathoracic goiters where most of the thyroid tissue is intrathoracic (15.3%) 3. Completely intrathoracic masses with no apparent cervical portion or connection to cervical thyroid (2.7%) Most series have since confirmed substernal thyroid masses to be approximately 80% small extensions, 15% partial intrathoracic, and 1% to 4% isolated intrathoracic. Sweet, in 1949, reported most of these masses to be in the anterior mediastinum, versus the retrotracheal or posterior compartments.19 In practice, the small substernal extensions are not usually especially problematic. On the other hand, the partially intrathoracic and totally intrathoracic masses are often challenging. These types, combined, were reported by DeAndrade to represent 1.4% of all goiters, whereas McCort had reported over 3% (DeAndrade, 1977).13,21 HISTORICAL READINGS

The definition of goiter has been debated, and classifications have been proposed based on clinically estimated size or volume, imaging-based estimates of size or volume, and definitive measurements of pathology specimens. Despite this, any thyroid tissue extending significantly behind the sternum or in some cases below the clavicles, or any thyroid tissue found within the confines of the thoracic cavity, can be considered abnormal tissue extension. These situations are all candidates to be classified as substernal goiter. Other terms applied have included retrosternal, subclavicular, infraclavicular, intrathoracic, and mediastinal. More colorful descriptors include aberrant, wandering, spring goiter, goiter mobile, and goiter plongeant.

HISTORICAL NOTE A number of reports of mediastinal or intrathoracic goiters populate the early surgical literature.1-20 Kocher presented his perspectives in 1901. Lilienthal’s 1915 report described a median sternotomy approach to one tumor. Lahey reported his impressive personal experience in the 1930s and 1940s. Higgins, in 1927, classified these goiters based on relative percentage of the mass in the neck or chest, as follows: more than 50% in neck, substernal; more than 50% in chest, partially intrathoracic; and more than 80% in chest, completely intrathoracic.5 Wakely and Mulvaney, in 1940, reported the

Crile G: Intrathoracic goiter. Cleve Clin Q 6:313, 1939. Lahey F: Intrathoracic goiters. Surg Clin North Am 25:609, 1945. McCort J: Intrathoracic goiter: Its incidence, symptomatology, and roentgen diagnosis. Radiology 53:227, 1949. Sweet R: Intrathoracic goiter located in the posterior mediastinum. Surg Gynecol Obstet 89:57, 1949. Wakely C, Mulvaney J: Intrathoracic goiter. Surg Gynecol Obstet 70:702, 1940.

BASIC SCIENCE Pathology Thyroid goiters, whether cervical or extending down into the chest, most often represent benign pathologic diagnoses. The majority are nontoxic multinodular goiters or adenomas, which together appear to account for 90% or more of all cases (Allo and Thompson, 1983; Katlick et al, 1985; Singh et al, 1994).5,22-24 Less common benign diagnoses include toxic hyperplasia and thyroiditis (1%-5% each). The risk of malignancy in substernal goiters is of great concern. Rates of malignancy have been reported between 2% and 40% but based on broad review probably rest at 2% to 12% (Allo and Thompson, 1983; Katlick et al, 1985; Singh et al, 1994).20,22-34 One third to one half, and perhaps more, of the malignancies discovered may be occult and of uncertain clinical significance. Types of malignancy in substernal tissue do not seem to be different than malignancies typical of the thyroid. 1661

Ch137-F06861.indd 1661

1/21/2008 4:14:17 PM

1662

Section 7 Mediastinum

Embryology The thyroid arises from a midline diverticulum of the floor of the pharynx between the first and second pharyngeal pouch levels. In the adult this site is recognized as the foramen cecum of the tongue. The embryologic thyroid develops into a bilobed structure that descends to the level of the developing larynx. The lower poles of the fully developed thyroid usually reach to the first tracheal ring, although abnormal descent farther has been documented. The most common locations for ectopic thyroid tissue are between the upper poles of the gland and the base of the tongue. Tissue from the thyroid lower poles can possibly travel into the anterior compartment of the mediastinum along with the thymus or developing heart.35-38 Ectopic thyroid has been reported at the aortic root, in the pericardium, and within cardiac muscle or esophageal wall.39,40 However, despite these occasional reports, true ectopic thyroid tissue in the anterior mediastinum is thought to be exceedingly rare. This is in noted contrast to the situation for ectopic parathyroids, which often are found in conjunction with thyrothymic or thymic tissue.

Anatomy and Classification From 5% to 6% of apparent mediastinal masses are thyroid tissue.41-43 Of all thyroid goiters, the incidence of substernal goiters ranges from 0.05% to more than 20%, depending on the population examined (Allo and Thompson, 1983; Katlick et al, 1985; Newman and Shaha, 1995; Singh et al, 1994).1,8,13,16,20,22-24,26,29-32,42,44-50 Despite this range, most reports suggest approximately 10% or less have substernal disease. These growths can be partially or totally located within the mediastinum and are easily mistaken for true mediastinal tumors. However, nearly all mediastinal thyroid growths originate from true cervical thyroid tissue or descended from this position and so are not truly primary mediastinal tumors (Torre et al, 1995).51 Negative intrathoracic pressures created by inspiration and swallowing may play a role in gradually pulling thyroid tissue down into the chest. Limitation by strap muscles, trachea, and spine may encourage downward extension of goiter. As noted earlier, a very common classification of substernal or mediastinal goiters divides them into small extensions under the sternum (∼80%), partially intrathoracic extensions (which can be moderate or massive, ∼15%), and truly isolated intrathoracic thyroid tumors (∼0%-1%).3,6,20 A number of classifications have attempted to describe minimal requirements for goiters to be called substernal. Examples include that the greatest diameter substernally must be below the thoracic inlet, the mass must reach the aortic arch, radiographically the mass must reach the fourth thoracic vertebra or lower, 50% of the entire goiter must be intrathoracic, or simply that mediastinal dissection is required for removal (Katlick et al, 1985).1,8,11,23,33 The classification of Higgins based on relative percentages in neck or chest was described previously.5 A more recent refinement defines the amount of goiter present in the chest: grade I substernal goiter is 0% to

Ch137-F06861.indd 1662

25%, grade II is 26% to 50%, grade III is 51% to 75%, and grade IV is more than 75%.52 The category of truly isolated mediastinal tumors is controversial. Terms used to describe this situation have included isolated, ectopic, heterotopic, and aberrant mediastinal/intrathoracic goiter. Whether thyroid ever arises embryologically in the mediastinum in a truly ectopic fashion has been debated for years, as noted earlier. Alternatively, isolated intrathoracic tissue could represent growth from the orthotopic thyroid whose connection became progressively attenuated or could represent implantation at the time of prior intervention.53-55 Most authors state that isolated mediastinal goiter accounts for less than 1% of cases where thyroid is present in the thorax; reports range from 0.2% to 3% (Katlick et al, 1985).2,4,5,17,23,56-58 However, even low percentages might overestimate the truth. Lahey reported no ectopic mediastinal thyroids in more than 24,000 cases.9 The most rigorous criteria for this diagnosis, as set forth by Shields, include the following: the thyroid tissue is completely separated from the gland in the neck, the blood supply must be from vessels arising within the thorax (not the inferior thyroid arteries), the cervical thyroid must be normal or completely absent, no prior surgical removal of any thyroid has been done in the past, there is no current or previous invasive thyroid malignancy, and there is no similar pathologic process in cervical and so-called ectopic thyroid tissue.59,60 Several reports of ectopic mediastinal thyroid have met these rigorous criteria.59,61-63 At the same time, a number have not.53,64,65 The distinction of a true ectopic thyroid mass, if correct, is important precisely because the vascular supply of such masses is dramatically different, arising in the thorax instead of the neck. This information is critical to surgical planning (Katlick et al, 1985).5,13,15,17,23,57 Fortunately, extremely few of these lesions are truly isolated and without cervical origin. Classifying substernal goiters solely by their degree of extension below the thoracic inlet is not, however, the only or even the most informative approach to categorizing these tumors. For instance, there has also been controversy over the true mediastinal compartment location of these tumors. As pointed out by Shields, this controversy stems in part from the existence of different classifications of mediastinal compartments as well as a failure in understanding the location of thyroid tumors.59,60 The thoracic inlet is properly considered the superior aspect of the visceral compartment of the mediastinum. The anterior, or prevascular, compartment begins well below the sternal notch. There is no true posterior compartment. The term superior is used only to modify the words visceral compartment or anterior compartment. Many thoracic goiters that are reported to be in the anterior mediastinum are actually small substernal extensions situated anteriorly or ventrally in the visceral compartment. These tumors may be in contact with the undersurface of the manubrium and lie cephalad to the great vessels, which may in fact be displaced caudad or dorsad. Despite this, the tumor extension remains in the visceral compartment and is prevented from entering the prevascular space by the compartment fascia. This is not to imply that thyroid extensions can

1/21/2008 4:14:17 PM

Chapter 137 Mediastinal Thyroid Tumors

never be found in the prevascular space. Many examples of prevascular extension have been noted in patients with a history of previous thyroid surgery, in whom the fascial planes of the compartments have undoubtedly been violated. Invasive tumors may also invade this compartment. In addition, intrathoracic goiter, particularly on the right, can pass anterior to the trachea and eventually anterior to the ascending aortic arch, thus coming to lie in the anterior compartment below the innominate vessels. The vast majority of substernal thyroid masses, therefore, are located in the superior visceral compartment, behind and cradled by the great vessels. This led McCort to note that substernal goiters were bordered by these vessels in the mediastinum, and this has been repeatedly demonstrated. These vessels, especially the veins, can be displaced and even compressed against the bony confines of the thoracic inlet, mimicking a superior vena cava syndrome.13,60,66,67 Furthermore, nearly all intrathoracic goiters remain approximated to the trachea in some fashion. The majority (85%90%) are located anterior or lateral to the trachea, whereas some (10%-15%) are found posterior to the trachea or esophagus (Katlick et al, 1985).6,13,19,21,23,28,30,31,34,68,69 The term posterior goiter can include both retrotracheal and retroesophageal locations, and growths extending posteriorly can encircle the trachea. These goiters may more frequently be present on the right side, even if originating from the left, apparently due in part to the space-occupying effect of the aorta and arch. In light of the varied relationships that intrathoracic goiters may have to trachea, esophagus, great vessels, and other structures, classification schemes have been proposed based on these relationships and not merely the proportion of the goiter present below the thoracic inlet. To the degree that these detailed classifications can provide useful information to guide surgical intervention, they can be tremendously valuable. Borrelly and colleagues suggested the terms simple form for those goiters located either completely pretracheal or completely retrotracheal and complex form for those occupying a combination of these locations.70 Under such a grouping, approximately 60% of intrathoracic goiters are simple pretracheal, 11% are simple retrotracheal, and 29% are complex.51 A more complex scheme was offered by Shahian (Shahian and Rossi, 1988).42,71 In this scheme, substernal goiter type IA is characterized by isolated anterior mediastinal extension; type IB, by extensive anterior substernal disease; type IIA, by isolated posterior mediastinal goiter; type IIB, by posterior goiter extending ipsilateral to thyroid origin; and type IIC, by posterior goiter extending contralateral to lobe of origin, with IIC1 being retrotracheal and IIC2 retroesophageal. A refinement of such a scheme, which optimizes the information relevant to surgical intervention, was offered by Randolph.72 In this classification, type I represents anterior mediastinal goiters. Type II is posterior mediastinal disease (posterior to trachea, great vessels, and recurrent laryngeal nerve [RLN]), with type IIA representing extension ipsilateral to origin, type IIB contralateral extension, type IIB1 extension behind both trachea and esophagus, and type IIB2 extension between

Ch137-F06861.indd 1663

1663

trachea and esophagus. Type III represents a truly isolated intrathoracic goiter with no connection to cervical gland and probable intrathoracic blood supply. Randolph states the proportions of these types as type I, 85%; type II, 15%; and type III, less than 1%.72 As described previously, the true incidence of type III goiters is controversial. This classification scheme is particularly useful because the anterior (type I) goiters preserve an anterior relationship to the trachea, great vessels, and RLN. This relationship, with the nerve posterior, is the most familiar to the surgeon and probably reflects the situation of least risk to the RLN and other structures. It is also the most common arrangement. In contrast, posterior (type II) goiters can displace the great vessels, trachea, and RLN anteriorly, with the mass resting behind these important structures. This places the RLN ventral to the goiter, in contrast to the normal position dorsal to the thyroid. In these instances in particular the nerves can be splayed thin and difficult to recognize, resulting in frequent injury (Shahian and Rossi, 1988).4,19,42,71,72 At times, the nerve can even apparently be entrapped within goiter tissue that has encircled it. As mentioned earlier, posterior (type II) goiters can extend across the midline from the lobe of origin, crossing either behind both trachea and esophagus (IIB1) or between trachea and esophagus (IIB2). In either case, important structures are at risk of injury, and the surgeon needs to be informed of this situation preoperatively with cross-sectional imaging. The arterial supply of intrathoracic goiters is almost always derived from the cervical inferior thyroid arteries. In fact, as mentioned, the truly isolated intrathoracic thyroid tumor that derives its blood supply from intrathoracic vessels is extremely rare. It is possible that a tumor descending below the mid thorax could compromise the original cervical vascular supply and come to be supplied by replacement vessels, but whether this occurs is uncertain. Certainly, in some patients who have had prior thyroid surgery, implanted, dispersed, or residual thyroid tissue might not be supplied by the inferior thyroid arteries. The important implication for surgical intervention is that nearly all intrathoracic goiters can be vascularly controlled from the neck.

PRESENTATION AND DIAGNOSIS Substernal thyroid masses most commonly come to attention after age 40 years. Some reports state that women are affected two to four times as often as men, whereas others give a more even ratio.25 From 10% to 20% of patients may have a history of prior thyroid surgery (Allo and Thompson, 1983, Katlick et al, 1985; Torre et al, 1995).22,23,26,31,33,34,51 A proportion of patients with substernal goiters will be completely asymptomatic, perhaps with diagnosis by imaging studies performed for other reasons. Most series report 15% to 30% of patients as asymptomatic, but this ranges from 0% to 55% (Allo and Thompson, 1983; Katlick et al, 1985; Reeve et al, 1988; Torre et al, 1995).22,23,25-27,29,31-33,51,73-77 If the substernal portion of a goiter is small, any symptoms or signs might only be those attributable to the cervical portion of the goiter. However, most patients with significant substernal

1/21/2008 4:14:17 PM

1664

Section 7 Mediastinum

components are symptomatic due to these components. Complaints commonly include sensation of a mass (globus), choking sensation or dysphagia (particularly with solids), dyspnea, and cough. Change in voice or hoarseness, possibly due to compression or irritation of the laryngeal nerves, is less common but occurs.78,79 Wheezing or stridor can also be present. Typical reported rates for symptoms are cough, dyspnea, positional or nocturnal breathing trouble, or other manifestation of airway compression in 35% to 96% of patients; dysphagia in 18% to 60%, and hoarseness in 10% to 26% (Allo and Thompson, 1983; Katlick et al, 1985; Rodriguez et al, 1999; Shaha et al, 1992).11,22-24,26,27,29-31,33,51,52,69,76,77,80-84 Although hoarseness may be reported or observed in a fourth of patients, laryngoscopically documented cord dysfunction is found in only 3% to 7% of patients.69 Approximately 25% of patients have severe breathing difficulty. In most cases the course of development of goiters is progressive and gradual enlargement. However, several factors can increase the rate of goiter growth, including pregnancy, iodine deficiency, ingested goitrogens, and treatment with antithyroid medications. The airway can be compromised gradually, by progressive deviation or compression. In addition, 5% or more of surgeries on substernal goiters will be emergent, due to airway compromise, and 1% to 3% of patients with unoperated mediastinal goiters are estimated to die of acute loss of airway (Allo et al, 1983).22,27,34 Upper airway obstruction can occur acutely due to hemorrhage (occasionally due to trauma), superimposed infection, instrumentation, or even swelling after treatment with iodine-131 and can be fatal (Katlick et al, 1985).23,81,85-91 Intubation and emergent surgery, or placement of a surgical airway, are indicated.89,92 The absolute incidence of acute airway compromise in patients with any sign of airway compression, deviation, or narrowing is probably 10% or more (Allo and Thompson, 1983; Katlick et al, 1985; Rodriguez et al, 1999; Shaha et al, 1989; Singh et al, 1994).22-24,27,52,82,83,91-96 A long stable prior history is no guarantee of ongoing stability (Allo and Thompson, 1983).22,52,91 Therefore, early surgical intervention is justified. On physical examination, a cervical mass is usually present but 10% to 30% of patients have no palpable cervical abnormality (Katlick et al, 1985; Rodriguez et al, 1999).11,23,31,82,95,97 Patients with prior cervical thyroid surgery may fall into this group. If palpable, the mass typically moves on swallowing but may show more fixation than simple cervical goiters. Size, consistency, and fixation are documented. The trachea and larynx can be deviated to either side, away from the bulk of the goiter. If the bottom of the thyroid cannot be palpated, the possible presence of a retrosternal extension is suggested and imaging for possible extension is indicated. Note any cervical scar, possibly hinting at prior removal or disruption of thyroid tissue. Adenopathy must also be evaluated. Evaluation of respiration includes rate, pattern, sounds such as stridor, and effort. Signs of hypoxia, such as restlessness or anxiety, and signs of hypercapnia, such as lethargy, may be present. Peripheral signs of decreased oxygenation or cyanosis must be sought. Vocal quality and swallowing are tested during the physical examination to elicit the just-mentioned

Ch137-F06861.indd 1664

findings. Any sense of impending airway compromise leads to immediate preparations for surgery. Venous pseudo-obstruction due to compression of the superior vena cava, causing facial flushing or distended neck or chest wall veins, occurs in 1% to 5% of patients; true obstruction of the superior vena cava is rare.15,30,34,76,77 Symptoms of superior vena cava obstruction can be exacerbated by lifting the arms above the head: Pemberton’s maneuver describes this phenomenon when the patient’s arms are held vertically overhead for 1 minute.15 The sign is insensitive, although it may have better positive predictive value for intrathoracic goiter. Other rare findings include Horner’s syndrome, phrenic nerve palsy, pleural effusion, pulmonary hypertension, heart failure, transient ischemic attacks, or the occurrence of pain (Katlick et al, 1985).23,94,98-101 Biochemically and clinically, most patients are euthyroid. Rarely, hyperthyroidism can be manifest, with reports ranging from 1% to 20% (Allo and Thompson, 1983; Shaha et al, 1989; Torre et al, 1995).22,51,83 Hyperfunction may be due to autonomous nodules or to an increased bulk of functional tissue that does not respond normally to feedback. Signs and symptoms may be typical, including heart failure, arrhythmia, and wasting. With a few exceptions, most series report that evidence of malignant disease is typically absent (Allo and Thompson, 1983).22,33 Most malignancy discovered is occult. Hoarseness certainly raises a concern for malignancy, but because it can occur secondary to benign masses, and because it is not strongly correlated with laryngoscopically documented cord dysfunction, its predictive value for malignancy is poor. If it is present, do laryngoscopy. Evidence of dysfunction of one RLN may affect the approach to the opposite side.

IMAGING STUDIES AND TESTING Images pertaining to five selected patient cases are presented in Figures 137-1 to 137-5. Various panels of these figures illustrate the principles described in the following text. A cross-sectional imaging study such as CT or magnetic resonance imaging (MRI) provides the most important information for the evaluation of, and planning the surgical approach to, substernal goiters. Thyroid function tests are obtained. All other studies have lesser roles, as described below.

Computed Tomography The bulk of diagnostic information, and information needed to inform operative planning, is obtained from cross-sectional imaging, of which CT is the most common. Some form of cross-sectional imaging is strongly recommended.66,67,102,103 The imaging will confirm the location of the tumor in the visceral component of the mediastinum and confirm the relationship to great vessels and other structures. CT characteristics of these tumors have been enumerated66,67: 1. 2. 3. 4. 5.

Continuity of mediastinal mass and cervical gland Well-defined borders Commonly punctate, coarse, or ring-like calcifications Inhomogeneity of the mass Nonenhancing low-density areas

1/21/2008 4:14:18 PM

Chapter 137 Mediastinal Thyroid Tumors

A

B

C

D

E

F

1665

FIGURE 137-1 A patient was observed for more than 2 decades with a goiter that was evident on physical examination in the cervical area. The patient had recently begun having difficulty swallowing certain solid foods but did not report difficulties with breathing. On physical examination, the goiter was evident but its inferior margin could not be discerned. This and the patient’s long history prompted computed tomography, which confirmed extension of the goiter into the mediastinum. A, At approximately the level of the sternal notch, the goiter is evident, with the left side being larger than the right. The left and right sides meet in between the trachea and esophagus, encircling the trachea. At this level the trachea is narrowed to 1.0 cm, whereas it measures 1.8 to 1.9 cm above and below this level. The patient has a left-sided pacemaker and has had shoulder surgery. B and C, As the goiter continues inferiorly (caudad) into the mediastinum, it does so extending from the left thyroid lobe. Thus, it pushes the trachea and esophagus posteriorly (dorsally) and to the right. The goiter is positioned between the trachea posteriorly and the arch and great vessels anteriorly. It extends inferiorly to the level of the right main pulmonary artery. The superior vena cava is compressed and displaced anteriorly. The azygos arch is stretched as it extends to the right. There is an aberrant right subclavian artery. Despite displacing the trachea to the right and extending across the midline to the right, the goiter maintains its relative position on the left side of the trachea; it does not cross behind the trachea or esophagus. The goiter is heterogeneous and contains calcifications. D, The goiter approaches its inferior extent near the level of the carina. Relationships to aorta, carina, and esophagus are clearly demonstrated. E and F, Sagittal and coronal reconstructions show the position of the goiter anterior to the trachea and posterior and superior to the great vessels. This patient was prepared for a thoracotomy if necessary but had a successful transcervical excision. The goiter had a typical cervical blood supply. The recurrent laryngeal nerve on each side was positioned normally (posterior), although on the left it was splayed, but it was preserved. Progressive mobilization and gentle traction, using a spoon to break intrathoracic suction, delivered the goiter intact. Postoperatively, the patient’s voice was normal and there were no complications. The pathology was nodular hyperplasia with degenerative changes.

Ch137-F06861.indd 1665

1/21/2008 4:14:18 PM

1666

Section 7 Mediastinum

A

B

C

D

FIGURE 137-2 A patient presented with a history of problematic cough. On examination, the cervical thyroid was not enlarged, but it was difficult to appreciate the inferior margins, and it was less mobile than expected. Standard chest radiographs and subsequently noncontrast chest CT (due to dye allergy) were performed. A, Chest radiograph showed trachea deviated to the left. Here the borders of the trachea are highlighted for ease of viewing. B, Just above the sternal notch, the thyroid is only moderately enlarged, which was difficult to appreciate on examination owing to the patient’s habitus. C, As the goiter proceeds inferiorly (caudad) beneath the sternum, it enlarges on the right side. D, As the goiter continues into the right side of the mediastinum posteriorly, it remains applied to the side of the trachea and esophagus. The goiter is situated between the spine posteriorly (dorsally) and the great vessels anteriorly. The mass measures 8 cm craniocaudally by 4.6 by 4.3 cm transversely. It impresses on the trachea, but the trachea does not appear significantly narrowed. This patient was prepared for thoracotomy if necessary, but transcervical excision was successful owing to the typical cervical origin of the vascular supply. In this case, the right laryngeal nerve was identified in its normal posterior position and was mildly splayed but was preserved. Progressive mobilization and traction delivered the goiter. Postoperatively the patient’s voice was normal, and there were no complications. Pathology revealed nodular hyperplasia with degenerative changes.

6. Precontrast attenuation greater than adjacent muscle, increased after iodinated contrast 7. Characteristic lateral and anterior displacement of the vessels in the superior visceral compartment with cradling of the mass by right and left brachiocephalic vessels The diagnosis can, however, be less clear for the rare, truly isolated mediastinal goiter. Due to some risk of inducing a hyperthyroid state, CT is safest when performed without

Ch137-F06861.indd 1666

iodine-containing contrast material.102,103 CT will show evidence of airway compromise in up to 60% of patients (see the discussion of pulmonary function testing that follows) (Gittoes et al, 1996).104-107 This airway information can affect the approach to intubation. Adenopathy is also assessed, and the CT scan may provide other clues to the rare malignant case, such as invasion of structures. The revelation of large posterior mediastinal or retrotracheal/retroesophageal tumor Text continued on p 1670.

1/21/2008 4:14:18 PM

Chapter 137 Mediastinal Thyroid Tumors

A

B

C

D

E

F

G

H

1667

FIGURE 137-3 A, In this patient a mediastinal mass was demonstrated on a chest radiograph deviating the trachea to the right. B, Chest CT scout image nicely depicts deviation. C, Cross section at the level of the sternal notch reveals the origin of the goiter in the left thyroid lobe. D, As the goiter travels inferiorly (caudad), it remains applied to the side of the trachea, displacing it to the right, and sits on the front of the spine. E, As the goiter continues inferiorly, it remains applied to the trachea and spine and passes posterior (dorsal) to the great vessels. F, Sagittal reconstruction nicely depicts the position of the goiter between spine and great vessels. G and H, Coronal reconstructions display relationships to trachea, carina, and great vessels. This goiter was easily removed transcervically because it had a typical cervical vascular supply, and in this case the right laryngeal nerve was not displaced anteriorly or splayed. With progressive mobilization and gentle traction, the mass was delivered. Postoperatively there were no complications. Pathology revealed nodular hyperplasia with degenerative changes.

Ch137-F06861.indd 1667

1/21/2008 4:14:19 PM

1668

Section 7 Mediastinum

FIGURE 137-4 A patient presented with hypoxia, shortness of breath, and a mediastinal mass on chest radiograph. CT of the chest with contrast medium enhancement shows there is a mediastinal goiter that originates in the left lobe of the thyroid and extends down into the right chest, measuring 16 × 12 × 8 cm in greatest dimension. It is heterogeneous and enhancing. There are dilated vessels in the region of the goiter, especially inferiorly. The goiter produces a remarkably mild mass effect on the mediastinal structures, including the trachea. A, Scout shows the mass extending significantly to right, but the trachea is minimally deviated. B, The goiter originates in the left thyroid lobe. C, Moving caudad, the goiter expands into the right chest but is technically positioned ventrally in the visceral compartment, applied to the undersurface of the sternum, and pressing the trachea dorsally against the spine. D, As the goiter enlarges caudad, great vessels are also displaced posteriorly. E, As the inferior aspect of the goiter is reached, relation to the heart and vessels is clear. F, Sagittal reconstruction in the midline depicts heart and great vessels displaced inferiorly and posteriorly (dorsally). The anterior position of the goiter is nicely displayed. The trachea is also displaced dorsally. G, Coronal reconstruction shows relation to heart and great vessels. This patient had a median sternotomy because the size of the goiter below the thoracic inlet did not allow delivery of the mass transcervically. Nonetheless, the goiter’s anterior position and the origin from the left thyroid lobe allowed typical vascular control and nerve identification in standard cervical locations. Postoperatively there were no complications. H, The portion of the specimen removed from the mediastinum (the orthotopic thyroid is not pictured). The pathology was benign nodular hyperplasia with degenerative changes.

Ch137-F06861.indd 1668

A

B

C

D

E

F

G

H

1/21/2008 4:14:20 PM

Chapter 137 Mediastinal Thyroid Tumors

A

B

C

D

1669

FIGURE 137-5 A patient with a recurrent thyroid growth in the mediastinum. Imaging suggested this growth had a complex interdigitation with the large vessels and raised concerns for malignancy. Based on this and the reoperative situation, a partial or complete sternotomy was recommended. A, The patient is prepared for upper sternal split. The scar from previous cervical thyroidectomy performed at another institution is visible. The inferior aspect of the skin incision is still well above the xyphoid. B, The sternum is split, and a T is created inferiorly. C, The growth was situated on the right side and probably had originated at the inferior aspect of the orthotopic right thyroid lobe, which had been previously removed. The majority of the mass rested on the anterior aspect of the superior vena cava and brachiocephalic vein and brachiocephalic arterial trunk. The forceps point to the right brachiocephalic arterial trunk just proximal to the origin of the common carotid. However, the mass had two extensions in relation to these large vessels. First, there was a smooth, lobulated portion that traveled anterior to the brachiocephalic vein and ended inferior (caudal) to this vein. This is depicted having been dissected away from the anterior surface of this vein and being lifted up out from its inferior aspect. Second, the mass had an extension in between the brachiocephalic vein and arterial trunk that also extended inferiorly, and this has not yet been dissected from in between these vessels in this photograph. D, The specimen is shown here in relation to the surgical field. The smooth inferior extension (positioned slightly to the right in this photograph) had been anterior to the vein. The other inferior extension (positioned slightly to the left) had been between the artery and vein and had been adherent. The specimen was found to contain papillary carcinoma. Postoperatively there were no complications. The photographs clearly depict the position of the large vessels that can limit access to mediastinal goiters via sternotomy.

Ch137-F06861.indd 1669

1/21/2008 4:14:21 PM

1670

Section 7 Mediastinum

components can have a tremendous influence on surgical planning and approach. Recall that in such cases the RLN might be displaced or even ventrally located. Figures 137-1 to 137-4 display CT images of substernal goiter cases.

Magnetic Resonance Imaging MRI is an acceptable alternative mode of cross-sectional imaging, although it is much less commonly performed than CT. Its coronal and sagittal depictions can be extremely informative. It provides excellent information on relationships to the great vessels and may demonstrate flow voids due to the marked vascularity of most of these tumors.108,109 Many consider it superior at detecting tracheal or esophageal invasion.69,108,110

Plain Radiography Overall correlation between imaging studies and symptoms of substernal goiter is poor. Standard radiographs of the chest or neck can suggest substernal thyroid masses, especially those occupying the superior portion of the chest and extending down from the neck, in 60% to 90% of cases (see Figs. 137-2A, 137-3A, and 137-4A) (Katlick et al, 1985; Rodriguez et al, 1999).6,13,23,80,82,93 Calcifications may be present. Of patients with demonstrable upper airway compromise, 63% will display lateral deviation of the trachea, usually beginning above the thoracic inlet (Gittoes et al, 1996).105 Of patients with an abnormal radiographic finding, only about half appear symptomatic. In the rare, truly isolated mediastinal thyroid lesion, deviation might be absent or visible only on lateral films. Certainly, in many patients with substernal goiters, chest radiographs appear normal. There is significant risk of both overestimating and underestimating disease severity based on plain radiographs alone, and in summary they are not to be relied upon.104 Plain chest radiography is, however, a reasonable part of the general medical preoperative evaluation.

Thyroid Ultrasonography Ultrasonography generally does not provide critical information for patients with substernal goiters. It can help define the cervical extent of disease, but cross-sectional imaging of the chest is clearly the critical priority. If thyroid ultrasonography cannot define the inferior border of a gland, suspicion of a substernal extension needs to be high, and cross-sectional imaging is done. Ultrasonography is essential if a substernal goiter appears to arise from only one side of the cervical gland and the surgeon is considering leaving one cervical thyroid lobe in place and undisturbed. In this case, the lobe that might be left behind must be proved to be normal before surgery.

Scintigraphy This study is perhaps most helpful in determining whether tissue that appears isolated in the chest is, in fact, thyroid tissue (Allo and Thompson, 1983).22,111-113 As discussed, this probably represents 1% or less of all intrathoracic goiters. Even then, the study might correctly diagnose thyroid tissue in 50% or less of cases because many substernal goiters do

Ch137-F06861.indd 1670

not seem to trap iodine.31 General information on so-called cold areas in large goiters is not likely to be reliable or likely to alter management. For these reasons, scintigraphy is rarely necessary. If it is going to be done, it is performed before the use of a contrast agent, such as in a CT scan. Studies performed with technetium are confirmed by radioiodine because technetium can be retained in the esophagus (Allo and Thompson, 1983).22 In addition, technetium may have insufficient energy to penetrate the sternum in some cases.102,103 Technetium scintigraphy before and after administration of potassium perchloride, which will block radioactive accumulation in mediastinal thyroid tissue, can dispel any doubts about the identity of mediastinal tissue.111

Contrast Swallow Studies A contrast swallow study usually easily demonstrates displacement or even compression of the esophagus, particularly when there is retrotracheal or retroesophageal tumor. Nearly all patients with dysphagia have contrast swallow findings.93 This study is not usually necessary, however, to make the diagnosis and would rarely affect operative management. Similarly, a venacavogram might easily reveal displacement or obstruction of veins but is rarely indicated.

Thyroid Function Testing Routine blood testing is performed preoperatively to assess the patient’s functional thyroid status. Typically, 1% to 7% of patients are hyperthyroid (Katlick et al, 1985).23,49 Hyperthyroid patients (with the toxic multinodular goiter of Plummer’s disease or with Graves’ disease) are prepared as would be any other hyperthyroid patient, using antithyroid medications and β-adrenergic blockade. Hypothyroid patients (often due to Hashimoto’s thyroiditis) initiate thyroxine replacement therapy. The goal is always to decrease anesthetic and surgical complications. Patients with Hashimoto’s thyroiditis may also have very firm, fibrotic goiters, which can be exceptionally challenging. In addition, it is very reasonable to check a total serum calcium value preoperatively to rule out hyperparathyroidism, which occurs independently.

Fine-Needle Aspiration Fine-needle aspiration (FNA) is usually unnecessary.31 Regarding the occasional occult tumor, FNA is rarely diagnostic. Sampling error within large goiters is significant. Furthermore, even an FNA result positive for malignancy would be unlikely to alter operative management. Confirmation of hyperplastic or adenomatous tissue is unnecessary. In some cases, the biopsy could be hazardous (Newman and Shaha, 1995).48 Only if a dominant cold nodule requires diagnosis, or if concern of poorly differentiated carcinoma exists, is FNA considered. Again, it must be stressed that it needs to be undertaken only if the results are likely to alter management, and only with extreme caution.

Pulmonary Function Testing Flow-volume loop studies have been recommended by some to demonstrate tracheal obstruction.114 In various series, 30% to 60% of goiter patients have flow-volume evidence of upper

1/21/2008 4:14:23 PM

Chapter 137 Mediastinal Thyroid Tumors

airway obstruction (Gittoes et al, 1996).105,107,115,116 Peak inspiratory flow or FIF50% (forced inspiratory flow at 50% of vital capacity) less than 1.5 L/s has been proposed as an indication for immediate surgery to avoid acute ventilatory failure.90,93,107,117 However, although FIF50% shows some correlation to tracheal caliber, many researchers believe that flow-volume studies overall are both inadequately sensitive to and inadequately predictive of changes in tracheal diameter until the process is well advanced.118 Of patients with airway symptoms, only about 30% have abnormalities on pulmonary function testing.107 In patients with normal flow-volume studies, 57% had airway symptoms, 44% had radiographic tracheal deviation, and 5% had tracheal compression (Gittoes et al, 1996).105 Recognizable changes in lung function did not usually occur until cross section of the airway was reduced by 50% to 75%, or to approximately 5-mm diameter.90,104,106,107,119-122 Conversely, only 23% of patients with demonstrable pulmonary function test changes showed tracheal compression, only 40% to 60% had symptoms, and only 28% reported breathlessness (Gittoes et al, 1996).105,120 Gross goiter size, ultrasound assessment, and plain radiographs are all poor predictors of pulmonary function test abnormalities or airway obstruction. Because a history of a stable airway or lack of symptoms does not preclude acute development of distress, there is little rationale for following airway status with pulmonary function tests or other imaging. In most cases either such obstruction is clinically evident or there is little gained by demonstrating it prior to surgery with pulmonary function tests because these test results are unlikely to significantly affect the surgical approach. For these reasons, pulmonary function tests are not required before the decision for, or performance of, thyroidectomy. Nonetheless, a high level of suspicion for airway compromise accompanies the diagnosis of substernal goiter and is viewed as justification for surgery in these patients. Pulmonary function tests have also been used postoperatively to demonstrate dramatic improvement in airway function after excision of large goiters, with critical peak airway flows improving 100%.117 This clearly justifies surgical intervention.

Indirect Laryngoscopy Indirect laryngoscopy very reliably reveals the condition of the vocal cords and position of the larynx but might be most safely performed at the time of surgery. It is absolutely performed if there is any history of hoarseness or concern for cord function. It is also reasonable to perform this study postoperatively, preferably at the time of extubation, to review cord function, although not all surgeons routinely do so (Reeve et al, 2000).123

MANAGEMENT Radioiodine Therapy Although radioiodine therapy can selectively be applied to cervical goiters, radioiodine treatment of substernal goiters is generally considered suboptimal if not fully contraindicated (Hermus and Huysmans, 1998).22,118,124-130 Larger goiters appear to be less responsive to therapy.131 Therapy might initially create swelling, which could further aggravate compression symptoms. In particular, a marginally compromised

Ch137-F06861.indd 1671

1671

airway could become acutely obstructed (Allo and Thompson, 1983; Hermus and Huysmans, 1998).22,118,128,130,132,133 The full effect of radioiodine treatment is unpredictable and often not evident for 3 to 6 months. Furthermore, radioiodine therapy rarely alleviates airway compression or other mass effects from a large intrathoracic goiter.124 Although some researchers have reported modest success in treating large compressive goiters with radioiodine in patients unwilling or unable to undergo surgery, this is probably more applicable to goiters that are not substernal and not confined to the limits of the thorax (Hermus and Huysmans, 1998).118,12 8,130,131,134-137 Radioiodine also carries risks of thyroiditis (∼5%), need for second treatment (∼20%), hypothyroidism (60%-100%), radiation-induced Graves’ disease (∼10%), and increased risk of malignancy outside of thyroid (lifetime risk increased 1.6%).72 Radioiodine is certainly not first choice of therapy for substernal disease and is considered as a last-ditch option only when surgery is precluded, and only with full appreciation of potential acute complications, including airway compromise (Hermus and Huysmans, 1998).128,129,135

Thyroid Suppression Attempted suppression of a large, space-occupying, intrathoracic goiter with thyroxine is generally ineffective and inappropriate (Hermus and Huysmans, 1998).118,125,127-130 Even for routine cervical goiters, responses to suppression appear modest at best in magnitude, and are delayed, unpredictable, and not durable (Hermus and Huysmans, 1998).128,138,139 Complications of suppressive therapy, including atrial fibrillation and bone loss, are significant. Alleviation of mass effects particularly for goiters within the thorax appears inadequate.

Anesthesia Management Anesthesia and surgical teams must work together to secure the airway for these cases. Joint preoperative reviews of patient history and imaging are a wise practice. Intubation of these patients usually goes well, but difficulties can spell disaster. The trachea may be deviated or compressed, and although this situation usually yields to appropriate transoral intubation, difficulties can arise. Personnel must be ready at all times to perform a surgical airway, through goiter tissue, if necessary. Of course, the emergent tracheotomy can be extremely challenging through overlying goiter with a deviated trachea and can fail. Preoperative laryngoscopy in the operating room is often done, and all information is shared among the surgical and anesthesiology staff. Fiberoptic-assisted intubation is commonly recommended. Awake, upright nasotracheal intubation is often a good option. At times, a large goiter can predispose to congestion of the larynx, which can contribute to laryngeal edema preoperatively after attempts at intubation or postoperatively. This edema can take days to weeks to resolve, necessitating an interval tracheostomy. Although thyroidectomy can be performed under local anesthetic, this is not appropriate for substernal goiters. General anesthesia is unquestionably the safest management option (Reeve et al, 2000).123

1/21/2008 4:14:23 PM

1672

Section 7 Mediastinum

Surgical Intervention All patients with substernal or intrathoracic goiters, whose medical condition permits, deserve consideration for surgical removal of these goiters.25,29,32,127 Surgical resection is the favored, definitive therapy. Eventual local or regional complications due to mass effects are likely. The risk of acute complications is also significant. Surgical relief of mass effects is rapid and reliable. Although the risk of malignancy is not an overwhelming issue, surgical excision is the only therapy that fully addresses this concern. Ongoing FNA evaluations are unlikely to be adequate. Disadvantages include the operative risks of laryngeal nerve compromise and hypoparathyroidism (discussed later), as well as risks of anesthesia for patients who are often elderly or who have serious comorbidities. Surgery is most safely done before the goiter becomes massive. The extent of surgery almost always is bilateral total or near-total thyroidectomy. Tissue can be left as necessary to protect parathyroids or RLNs, but this rarely precludes the conduct of a traditional total or near-total thyroidectomy (we will henceforth use the term total thyroidectomy to refer to the total/near-total approach, whereas the term subtotal thyroidectomy refers to a less extensive surgical approach). Bilateral total thyroidectomy has the lowest recurrence rate and is acceptably safe in experienced hands (see later discussion of complications). In some cases a substernal goiter could arise clearly from just one thyroid lobe. If this is the case and if the opposite thyroid lobe can be documented to be normal (i.e., by ultrasound), then unilateral surgery is an acceptable alternative and will reduce the risks of surgery for the patient. However, this might result in a higher recurrence rate, of which the patient must be aware. Reoperation for recurrence has a higher complication rate, as described later. If one lobe can indeed be left undissected, subsequent surgery on that side is safer. However, unilateral surgery leaving behind a diseased contralateral lobe, or leaving behind significant ipsilateral disease, appears to have an unacceptable recurrence rate (see later) and is not recommended. In patients with bilateral disease, a bilateral subtotal approach is favored by some yet condemned by others—the recurrence rate does seem to be significantly higher than for the total approach. A more aggressive total approach on one side combined with a less aggressive subtotal approach on the other represents a compromise that should have intermediate recurrence and complication rates and has been advocated by some. When considering whether concerns over malignancy drive the extent of surgery, these concerns are usually overshadowed by concerns over recurrence. This is because malignancy rates are low, and most noted malignancies are occult or of uncertain clinical significance. Our belief is that bilateral disease is approached by the experienced surgeon with a total thyroidectomy mindset by default. Starting with this point of view, the surgeon should then feel justified in conservatively leaving tissue where necessary—where the local anatomy, extent of disease, or relationships with parathyroids or nerves modify the default mindset. This is the heuristic we use to balance the risks of recurrence with the risks of complications. This is referred

Ch137-F06861.indd 1672

to by many authors as a selectively aggressive approach and appears to have a very favorable combination of recurrence rate (<10%) and complication rate (Gardiner and Russell, 1995; Rodriguez et al, 1999).82,140-142 Nonetheless, there remains some controversy on this issue, with some surgeons arguing that more aggressive approaches are unnecessary and needlessly risk complications. Nearly all (95%-99%) mediastinal goiters can be removed via cervical exposure through a traditional transverse collar type of incision (Allo and Thompson, 1983; DeAndrade, 1977; Katlick et al, 1985; Newman and Shaha, 1995; Singh et al, 1994).21-26,29,30,32-34,48,77,143 Figures 137-1 to 137-3 portray substernal goiter that were successfully excised via cervical exposure. Transcervical excision is usually possible because of the typical cervical blood supply (via the inferior thyroid artery). This exposure probably also provides the best visualization and protection of the RLNs. With the use of the classification scheme of Randolph, type I substernal goiters are amenable to transcervical removal as long as the maximum diameter is less than that of the thoracic inlet.72 The same is true for type IIA goiters, but type IIB tumors might require additional exposure. Type III isolated goiters can on occasion still be retrieved transcervically but probably require direct exposure. Some have argued that it is important to decompress the negative intrathoracic pressure in attempting to remove substernal goiters, and Kocher was famous for using a special goiter spoon for this purpose.7,144 Foley balloon catheters have also been used.33 Although rarely necessary, additional exposure can be obtained in a number of ways. A partial upper sternotomy is the most commonly reported choice; Figures 137-4 and 1375 show cases in which sternal splits were performed.6,10,19, 25-27,30,41,76,143,145 However, in many cases this reveals the great vessels in front of the goiter mass, with the mass posteriorly positioned (compare Fig. 137-5 with Fig. 137-6). This relationship can limit the utility of the approach. It has been argued that this partial sternal exposure adds little mobilization for the gland that cannot be removed transcervically.87 Nonetheless, it is the most commonly reported additional exposure option. Others have advocated different types of thoracic exposure. Combining anterior thoracic, transclavicular, or video-assisted exposure with cervical exposure is favored by some but remains less common, probably because of unfamiliarity or lack of facility with these approaches.6,21,143,146 Posterolateral thoracotomy exposure alone (without cervical exposure) is probably best avoided. This approach may be problematic with respect to controlling cervical vascular supply and exposure and protection of RLNs.4,19,80,95 An excellent additional exposure option is to simultaneously combine cervical and posterolateral thoracotomy approaches (Shahian et al, 1988).6,12,30,71,76,143,147-149 This allows control of both cervical and thoracic blood supply and provides optimal visualization and protection of RLNs. Beginning with the cervical exposure, the patient is positioned in a typical fashion with an inflatable cushion or other bolster behind the shoulders, moderately extending the neck. The patient may be put into papoose with arms circumferentially padded to protect from ulnar nerve injury and placed in a modified seated position to reduce venous pressure. Hips

1/21/2008 4:14:23 PM

Chapter 137 Mediastinal Thyroid Tumors

1673

Subclavian artery

Subclavian vein Mediastinal goiter Superior vena cava Phrenic nerve

Goiter

Left innominate vein

Azygos vein

Aortic arch

A

Azygos vein

Ascending aorta

Right atrium

B

FIGURE 137-6 Schematic illustrations from the frontal (A) and lateral (B) aspects of a partially intrathoracic goiter lying within the visceral compartment of the mediastinum. The goiter rests on the border of the vertebrae behind the superior vena cava and the innominate vessels above the azygos vein. (ADAPTED FROM JOHNSTON JH JR, TWENTE GE: SURGICAL APPROACH TO INTRATHORACIC (MEDIASTINAL) GOITER. ANN SURG 143:572, 1956.)

and knees are gently flexed to relieve the sciatic nerve. A generous (≥8 cm) collar incision is made above the clavicles, with the lateral borders of the sternocleidomastoids serving as limits. Subplatysmal flaps are developed. It is frequently helpful to transect the strap muscles and reapproximate them later. Selectively sectioning the sternothyroid at its cranial aspect is often sufficient, which helps to preserve the other anatomic planes of the neck, which are often already distorted. Nonetheless, both straps and even the sternocleiodomastoids can be sectioned. Early on, it can be helpful to dissect out the carotid sheath and identify the carotid artery, jugular vein, and vagus nerve. These structures can then be separated from the goiter and traced down the neck. This can clarify the relations between the goiter and these important structures heading down into the mediastinum. Exposure of the vagus can facilitate subsequent identification of the RLN and nerve stimulation, if performed. The procedure proceeds in a typical fashion for extracapsular thyroidectomy, very much as described traditionally (Bliss et al, 2000; Thompson et al, 1973).150,151 The surgeon begins with identification, control, and transection of superior pole vessels. The superior extent of the goiter can travel into the retropharyngeal and tonsillar fossa regions. Dissection requires good exposure with careful control of vessels. Ideally, dissection of this pole is concurrent with or immediately followed by identification of superior parathyroid glands. These glands must be preserved or removed and prepared for reimplantation.152 The approach to the superior glands is critical because they are much more likely to be found in a standard

Ch137-F06861.indd 1673

relationship to the thyroid.23 Their positioning is less variable, and they are probably less vulnerable to displacement by a large goiter extending inferiorly. The inferior parathyroids may be radically displaced and might not be found (of course this is possible for the superior parathyroids as well). Preservation of the inferior parathyroids is maximized by keeping the inferolateral dissection on the thyroid capsule. In all cases, the eventual thyroid specimen should be carefully examined for adherent parathyroid glands, but with a large, multinodular specimen these are notoriously difficult to identify. Dissection can then proceed inferiorly in an extracapsular fashion, and at the mid-lateral and inferolateral regions it is reasonable to control the inferior thyroid artery and accompanying middle vein(s). These are always controlled and transected immediately adjacent to the thyroid capsule. Unfortunately, at times the inferior thyroid artery cannot be identified until the specimen is delivered, but then it is usually controllable. Only the rare case has intrathoracic blood supply, but these can require emergent additional thoracic exposure (Torre et al, 1995).3,6,20,51,97 While dissecting the lateral or inferolateral areas, the surgeon searches for and identifies the RLN. This nerve may be displaced far lateral and posterior to a large goiter, but alternatively it might be displaced anteriorly and splayed by a posterior goiter. There must be a high level of suspicion for this situation. No tissue is sacrificed without certainty that the RLN is not at risk. Nerve stimulation in these instances can be useful.153,154 An option is to identify the RLN near the

1/21/2008 4:14:24 PM

1674

Section 7 Mediastinum

inferomedial border of the carotid, the so-called lateral or back-door approach.155 This is possible with the strap muscles retracted either laterally or medially. In this region, in the presence of a large goiter, the anatomic relationships may be more predictable, making it easier to identify and then trace the nerve superiorly. Another alternative is to identify the nerve in the space between the upper pole of the thyroid and the larynx (the superior approach).155 At times it might be necessary to proceed with mediastinal dissection before controlling the inferior thyroid artery or identifying the RLN. The goiter mass can make these tasks infeasible until it is removed. In this case, work can begin via the thoracic exposure, or cervical dissection can proceed inferiorly into the thorax. Commonly, finger or pledget dissection of the inferiorly extending mass has been recommended, keeping the dissection in or against the thyroid capsule to protect nerves and vessels. In many cases, this blind blunt dissection seems like the only way to make progress in dissection, and many practitioners use this technique. At the same time, however, caution must be exercised. Without identifying the RLN, this type of dissection may carry high complication rates: 17.5% RLN injury has been reported.156 It therefore seems prudent to make all attempts to identify this nerve superiorly, inferiorly, or (traditionally) laterally and trace its course. In addition, any tissue fibers traveling over the surface of the goiter (anteriorly or posteriorly) are tested and/or dissected free and preserved to the maximal possible extent. Exposure of the vagus nerve and its course can be facilitating. As pointed out in the discussion on anatomy presented previously, the retrotracheal (posterior mediastinal—Randolph type II) goiter has the highest likelihood of displacing the RLN anteriorly and causing it to become splayed, putting it at serious risk. In these 10% to 15% of cases the trachea, great vessels, and RLN can all be displaced anteriorly with loss of normal spatial relationships. Obviously, these situations require extreme caution. In these cases in particular there may be benefits to neural monitoring. Both the vagi and the RLNs can be stimulated during surgery.72,157,158 The vagus can be stimulated in the carotid sheath even before identification of the RLN, a maneuver that tests the entire ipsilateral circuit (vagus and RLNs).72 Subsequently, as the goiter is progressively delivered, the nerve can be intermittently tested to make certain that it is not stretched or compromised during dissection. Vagal monitoring can even be used to diagnose a nonrecurrent RLN: vagal stimulation high in the neck (above the branch point) will result in laryngeal electromyographic activity, but stimulation below the larynx (below the branch point) will not.72 Repeated testing appears to be safe when conducted in the 1- to 2-mA range.72,157 If it is decided intraoperatively (or preoperatively based on imaging) that additional exposure is required, posterior thoracotomy (usually right side, fourth to fifth interspace) or median sternotomy can be combined with the cervical approach, as discussed earlier. The goiter is then identified in relation to the superior vena cava, azygos vein, and spine. Opening the overlying pleura via the thoracotomy allows manipulation in combination with the cervical exposure.

Ch137-F06861.indd 1674

Once again, only a minority of cases require this additional exposure. After identification and protection of the RLNs, the goiter can usually be delivered by exerting gradual, continuous traction on the gland from above. The mass will usually incrementally mobilize. This can be combined with thoracic mobilization as described, but that is most often unnecessary. As discussed earlier, a spoon or Foley catheter can help deliver the tissue upward in the face of negative intrathoracic pressure. Although described by Kocher and advocated by Lahey, morcelization as an adjunct to extraction of substernal goiter is generally to be avoided.9 This technique may result in hemorrhage and dispersion of benign or malignant thyroid tissue (Katlick et al, 1985).6,23 Whenever an intrathoracic goiter is removed, drains are routinely used in the mediastinal space. Patients are initiated on oral thyroxine replacement the morning after total thyroidectomy or can be maintained on intravenous (IV) replacement if not sustaining themselves orally. We also routinely begin oral calcium carbonate supplementation until calcium status is known.

RESULTS AND COMPLICATIONS Symptomatic Improvement The majority of patients are effectively treated with surgical removal of the mediastinal goiter. Ninety percent or more of preoperatively symptomatic patients have demonstrably improved symptoms.77 Effects are immediate and reliable.

Mortality Mortality is rare, but it is obviously of concern. Series with mortalities report mortality rates from 0.7% to 6.0% (DeAndrade, 1977; Torre 1995).21,26,28,30,34,51,76 Notably, in many series there have been no deaths (Allo and Thompson, 1983).22,23,25,27,29,32,33,44,52,92

Recurrence Recurrence can manifest after as long as 10 to 30 years. Studies of recurrence are confounded by a lack of standardization of definitions of goiter and of recurrence, as well as variation in surgical techniques. Recurrence might be more likely in the presence of malignancy. Long-term studies report recurrence rates of 15% to 60%.159-164 Recurrence is, of course, highly dependent on the subtotal to total extent of the surgical technique. If total thyroidectomy is performed, and if recurrence is defined as clinically significant disease requiring further intervention, then rates are likely below 10%. If unilateral surgery or significantly subtotal surgery is done for bilateral disease, leaving diseased tissue behind, recurrence seems to be more than 20%, possibly up to 60% (CohenKeren et al, 2000; Reeve and Thompson, 2000).123,160,165,166 At the same time, complication rates may be lower. These contrasting concerns have led some to advocate the subtotal approach but others to condemn it (Cohen-Keren et al, 2000; Delbridge et al, 1999; Pappalardo et al, 1998; Reeve and Thompson, 2000).52,123,160,161,163,165-168 With a selectively

1/21/2008 4:14:24 PM

Chapter 137 Mediastinal Thyroid Tumors

aggressive approach, as described earlier, recurrence is less than 10% (Gardiner and Russell, 1995; Rodriguez et al, 1999).82,140-142 Unilateral surgery for patients with documented unilateral disease is a very reasonable option if the opposite lobe is documented as normal (by ultrasonography) and left undissected during surgery (reducing the risk of future surgery). A lobe that is documented to be normal can be expected to have a reasonably low recurrence rate of less than 10% to 20%. Some investigators believe that recurrence is more common in young females with a family history of this diagnosis and advocate a more aggressive approach in these patients.72,168 Radioactive iodine treatment postoperatively can be considered even without a diagnosis of malignancy if there is particular concern over tissue that was left behind or the possibility of complicated recurrence. Attempted prevention of recurrence using suppressive doses of thyroid hormone is likely ineffective and carries risk of complications: it is not recommended.159,162,164,169,170 Any surgical approach to recurrent disease must be informed by past operative notes and pathology reports. It is essential to acknowledge the increased risk of complications in such cases, as noted later.

Injury to the Recurrent Laryngeal Nerve In skilled hands, total thyroidectomy for goiter is acceptably safe. Permanent RLN injury and vocal cord paralysis rates depend on the surgical exposure used. Rates after removal of substernal goiter have been reported from 0% to 27%, but the higher end of the range might represent cases of lateral thoracotomy or cases where the RLN is not identified, both of which are acknowledged to pose higher risks (Katlick et al, 1985).23,156,165,171-173 Typical permanent injury rates with cervical exposure of substernal goiter, with or without additional exposure, are probably less than 6%, which is still 3 to 12 times higher than accepted rates with other cervical thyroid surgery (Bliss et al, 2000; Delbridge et al, 1999; Reeve and Thompson, 2000; Singh et al, 1994).24-28,30,44,76,123,150,161,166,174,175 Some subpopulations of patients, such as those with massive intrathoracic goiters, might well experience higher rates of injury.176 It is also common to see temporary nerve or cord dysfunction after surgery; reports range from 5% to 30%.25,26,29,30,76,176 Rates of injury to the superior laryngeal nerve in all goiter cases may approximate 1%; for substernal cases the rate is uncertain.177 Cord function is easily examined fiberoptically if there are any concerns postoperatively, and both temporary and permanent medialization options are available. Nonetheless, any dysfunction often improves over the first weeks postoperatively. In patients undergoing reoperative procedures for recurrent disease, overall complication rates are several times higher than in first surgeries. Rates of RLN paralysis range from 3% to 18% (Pappalardo et al, 1998).141,163,165,167,170,178,179

Hypoparathyroidism Compromise of the vascular supply to the parathyroids, or inadvertent excision, can lead to postoperative hypoparathy-

Ch137-F06861.indd 1675

1675

roidism and subsequent hypocalcemia. Dysfunction can be either temporary or permanent and either mild/asymptomatic or severe/symptomatic. Transient postoperative hypocalcemia occurs in up to 40% of these cases but is most commonly reported around 10%; this compares to 5% or more after routine total thyroidectomy for other diagnoses (Delbridge et al, 1999).25-27,29,30,76,161,175 Permanent problematic hypoparathyroidism for all multinodular goiter cases is believed to occur in 1% to 6% of cases, but the largest goiters and substernal goiters might have higher rates (Delbridge et al, 1999; Rodriguez et al, 1999).25-27,44,82,161,175 This compares to less than 2% permanent hypoparathyroidism after routine total thyroidectomy.123,150,175,180 Routine autotransplantation of at least one parathyroid (if identified) is believed by some to reduce the rate of permanent hypoparathyroidism. Some authors report a higher rate of autotransplantation in these cases.30 In patients undergoing reoperative procedures for recurrent disease, overall complication rates are several times higher than in first surgeries. Permanent hypoparathyroidism ranges up to 25% (Pappalardo et al, 1998).141,163,165,167,170,178,179 The parathyroids are typically supplied by fine branches from the inferior thyroid artery. Parathyroid compromise is a particular concern in the management of these large goiters because the parathyroid glands can easily be severely displaced and therefore difficult to find or preserve. As already mentioned, the superior glands might be more reliably located, and thus particular attention needs to be devoted to identifying, preserving, or reimplanting these superior glands. The inferior glands, owing to their typically more superficial (ventral or lateral) location, are more likely to be dramatically displaced by the goiter or compromised during surgical dissection. There is always a low threshold for the reimplantation of potentially compromised parathyroids because merely discovering them in these cases can be an achievement. All patients have a total serum calcium value checked 8 to 18 hours after surgery. Possible symptoms of hypocalcemia might not become apparent for 2 to 5 days. Symptoms include paresthesias of the digits or face, muscle cramps, tetany, or hemodynamic instability. Signs include Chvostek’s and Trousseau’s, but these are of limited reliability. Most patients with hypocalcemia can be supported with oral calcium carbonate alone if asymptomatic, oral calcium and calcitriol if symptomatic, and IV calcium if severely symptomatic or unstable. Most patients recover within 3 to 6 weeks, although they might need supplementation throughout that time. Few patients prove to be permanently affected; these will likely require indefinite supplementation.

Tracheomalacia There has been considerable controversy surrounding the issue of tracheomalacia after removal of goiters, particularly encircling goiters. This condition has been reported and, if present, could lead to collapse of the trachea and acute airway compromise.181-183 In practice, this condition is rarely seen (Allo and Thompson, 1983; McHenry and Piotrowski, 1994; Rodriguez et al, 1999).22,47,72,82,92,181,182,184-186 One review

1/21/2008 4:14:24 PM

1676

Section 7 Mediastinum

of almost 2000 retrosternal goiters uncovered scant evidence of this diagnosis.187 It is possible that acute problems might represent kinking of an elongated or previously displaced trachea. However, it seems most likely that difficulties represent unrecognized RLN injury (Allo and Thompson, 1983).22,72 Examination of the trachea in the operative field is sufficient to rule out tracheomalacia. Nonetheless, if there is concern about airway patency, options include prolonging intubation, tracheal stenting, or tracheostomy placement. More complex operative reconstruction efforts are to be avoided.

Other Complications Other complications with intrathoracic goiters are rare. Intraoperative bleeding occurs in 0.5% to 5.5% of cervical or substernal goiter cases (Torre et al, 1995).33,51,177 Hematoma requiring reoperation after any thyroid surgery is in the range of 1% to 3% (Reeve and Thompson, 2000).25,27,44,77,123,188 Mediastinal hematoma after susbsternal dissection occurs in about 3% (Singh et al, 1994).24 Pneumothorax may occur in 1% to 5%.52,81 Wound infection approximates 2%.177 Other reported complications have included esophageal injury, Horner’s syndrome, air embolism, chyle fistula, and pleural effusion. Tracheostomies are performed in up to 13% of cases for reasons that are varied (Torre et al, 1995).33,51,189,190

COMMENTS AND CONTROVERSIES The investigation and management of mediastinal goiter provide a unique set of challenges. Current imaging techniques, principally CT, provide certain diagnoses in the majority of patients. Surgical resection is the ideal treatment option in symptomatic patients. Preoperative preparation focuses on recurrent laryngeal nerve function and control of the potentially compressed airway. The authors clearly describe the controversy surrounding the optimal degree of resection. Unilateral lobectomy risks recurrence and subtotal thyroidectomy risks increased operative complications, such as recurrent laryngeal nerve injury and hypoparathyroidism. The vast majority of these benign lesions can be extracted utilizing an anterior cervical collar incision. Upper partial median sternotomy or posterolateral thoracotomy is rarely required for exposure. Thoracic surgeons need to have a complete understanding of the management of these lesions. However, the surgical resection and postoperative care need to be in the hands of surgeons (thoracic or endocrine) who are experienced and who have expertise in thyroid disease and its operative management. G. A. P.

Ch137-F06861.indd 1676

KEY REFERENCES Allo M, Thompson N: Rationale for operative management of substernal goiters. Surgery 94:969, 1983. Bliss R, Gauger P, Delbridge L: Surgeon’s approach to the thyroid gland: Surgical anatomy and the importance of technique. World J Surg 24:891, 2000. Cohen-Kerem R, Schachter P, Scheinfeld M, et al: Multinodular goiter: The surgical procedure of choice. Otolaryngol Head Neck Surg 122:848, 2000. DeAndrade M: A review of 128 cases of posterior mediastinal goiter. World J Surg 1:789, 1977. Delbridge L, Guinea A, Reeve T: Total thyroidectomy for bilateral benign multinodular goiter: Effect of changing practice. Arch Surg 134:1389, 1999. Gardiner K, Russell C: Thyroidectomy for large multinodular colloid goitre. J R Coll Surg Edinb 40:367, 1995. Gittoes N, Miller MR, Daykin J, et al: Upper airways obstruction in 153 consecutive patients presenting with thyroid enlargement. BMJ 312:484, 1996. Hermus A, Huysmans D: Treatment of benign nodular thyroid disease. N Engl J Med 338:1438, 1998. Katlick M, Grillo H, Wang C: Substernal goiter: Analysis of 80 patients from Massachusetts General Hospital. Am J Surg 149:283, 1985. McHenry C, Piotrowski J: Thyroidectomy in patients with marked thyroid enlargement: Airway management, morbidity, and outcome. Am Surg 60:586, 1994. Newman E, Shaha A: Substernal goiter. J Surg Oncol 60:207, 1995. Pappalardo G, Guadalaxara A, Frattaroli FM, et al: Total compared with subtotal thyroidectomy in benign nodular disease: Personal series and review of published reports. Eur J Surg 164:501, 1998. Reeve T, Thompson N: Complications of thyroid surgery: How to avoid them, how to manage them, and observations on their possible effect on the whole patient. World J Surg 24:971, 2000. Reeve T, Delbridge L, Brady P, et al: Secondary thyroidectomy: A twenty-year experience. World J Surg 12:449, 1988. Rodriguez J, Hernandez Q, Pinero A, et al: Substernal goiter: Clinical experience of 72 cases. Ann Otol Rhinol Laryngol 108:501, 1999. Shaha A, Alfonso A, Jaffe B: Operative treatment of substernal goiters. Head Neck 11:325, 1989. Shahian D, Rossi R: Posterior mediastinal goiter. Chest 94:599, 1988. Singh B, Lucente F, Shaha A: Substernal goiter: A clinical review. Am J Otolaryngol 15:409, 1994. Thompson N, Olsen W, Hoffman G: The continuing development of the technique of thyroidectomy. Surgery 73:913, 1973. Torre G, Borgonovo G, Amato A, et al: Surgical management of substernal goiter: Analysis of 237 patients. Am Surg 61:826, 1995.

1/21/2008 4:14:24 PM

chapter

MEDIASTINAL PARATHYROID TUMORS

138

Bruce Lee Hall Jeffrey Moley

Key Points ■ Understanding the embryologic origins of the superior and inferior

■

■

■

■

■

parathyroids helps guide exploration, particularly when seeking undiscovered or ectopic glands. Mediastinal parathyroids can be found in 11% to 22% of patients, but only 2% to 4% require sternotomy for removal. Most can be removed via a cervical approach. Imaging studies are indicated for any question of mediastinal or intrathoracic parathyroids: 99mTc-sestamibi and computed tomography (CT) are most commonly employed. Intraoperative parathyroid hormone monitoring is now a critical adjunct in the surgical treatment of parathyroid disease and can limit the extent of surgeries performed. Never discard normal parathyroid tissue, and always treat any parathyroid tissue discovered during reoperations as the patient’s only remaining tissue. Hyperparathyroidism, considering all cases, is cured by surgery 95% to 99% of the time, including 90% of reoperations and 95% of reoperations with successful localization.

HISTORICAL NOTE Parathyroid glands were first identified during autopsy of an Indian rhinoceros by Sir Richard Owen, who published his findings in 1862.1 Sandstrom first described the parathyroid glands in humans in detail in 1875.2 The physiology of the glands was then elucidated over ensuing years. In 1906, Halsted at Johns Hopkins relieved tetany complicating thyroidectomy with supplements of bovine parathyroid.3 MacCallum, around the same time and at the same institution, experimentally demonstrated the role of the parathyroids in calcium homeostasis and showed that tetany after parathyroidectomy was due to hypocalcemia.3 Mandel, in Vienna in 1924, first excised a parathyroid tumor for relief of bone disease.4 Parathyroid hormone (PTH) was isolated by Collip in 1924 at the University of Alberta. Subsequently, Aub at the Massachusetts General Hospital began using PTH to treat the bone disease of lead poisoning and demonstrated the effects of increased serum calcium, decreased phosphate, and increased urinary calcium elimination.4 This experience, in 1926, allowed him to diagnose hyperparathyroidism in Captain Charles Martel, leading to the first operation for hyperparathyroidism in North America, just the first of six unsuccessful neck explorations for this patient. Incited by discussions with Aub, in 1928 Bulger and colleagues at Washington University in Saint Louis diagnosed hyperparathyroid-

ism in a 57-year-old woman, after which Olch performed the first successful removal of a parathyroid adenoma in North America.5 Directed by Churchill at the Massachusetts General Hospital, in 1931 Cope studied the anatomic distribution of parathyroid glands in cadavers. Subsequently, Cope and Churchill systematically developed the surgical approach to the disease. After conducting the last three unsuccessful neck explorations on Captain Martel, on the basis of embryologic studies they explored the mediastinum and found a parathyroid tumor adjacent to the superior vena cava. This represented the first successful removal of a mediastinal parathyroid adenoma.6 Unfortunately, the patient died of renal failure shortly afterward.1 HISTORICAL READINGS Barr D, Bulger H, Dixon H: Hyperparathyroidism. JAMA 29:951, 1929. Cady B, Rossi R (eds): Surgery of the Thyroid and Parathyroid Glands, 3rd ed. Philadelphia, WB Saunders, 1991. Cope O: The story of hyperparathyroidism at the Massachusetts General Hospital. N Engl J Med 274:1171, 1966. Halsted W: Surgical papers. Baltimore, Johns Hopkins Press, 1961, vol 2. Thompson N: The history of hyperparathyroidism. Acta Chir Scand 156:5, 1990.

BASIC SCIENCE Biochemistry Hypercalcemia mediates most effects of primary hyperparathyroidism. This is not different for mediastinal adenomas versus cervical adenomas. Elevated PTH leads to hypercalcemia by stimulating release from bone, increasing reabsorption from renal tubules, and increasing renal conversion of vitamin D (leading to increased gut calcium absorption).4,7-9 PTH also decreases renal tubular reabsorption of phosphorous and bicarbonate and thus can lead to low serum phosphate and metabolic acidosis in advanced cases. Other diseases, however, can also lead to hypercalcemia, including sarcoid and metastatic carcinoma. Of note, squamous cell carcinomas of lung or esophagus can even produce a peptide that mimics the actions of PTH. In the past, this peptide has complicated PTH assays, but current intact PTH assays used by most laboratories no longer cross react with these peptides. PTH levels can now be checked rapidly during surgery at many institutions. After successful removal of overactive glands, PTH falls to normal for most patients within several half-lives (half life: 3.5-4.0 minutes; total 10-12 minutes). 1677

Ch138-F06861.indd 1677

1/21/2008 4:15:09 PM

1678

Section 7 Mediastinum

Pathology Of patients with primary hyperparathyroidism, 85% have a single adenoma, 3% have multiple adenomas, and 12% have diffuse hyperplasia of all glands (Thompson et al, 1982).10,11 Parathyroid carcinoma is rare, representing less than 1% of cases and probably less than 0.1%.10,12 These proportions apply in a similar fashion to cervical as well as mediastinal involved glands (Wang et al, 1986).13,14 The distinction between hyperplasia and adenoma has been difficult, whether cervical or mediastinal.15,16 This led to conservative recommendations for exploring all glands.16 The availability of intraoperative PTH assays, however, has reduced the need for full exploration in many cases. The diagnosis of parathyroid cancer is often based on invasion of adjacent tissues or the presence of metastatic disease, rarely on cellular morphology alone.1,17

Larynx

Parathyroid IV Parathyroid III Thyroid

Thymus

Anatomy The locations of parathyroid glands can vary. This reflects their derivation from the third and fourth branchial pouches around the fifth week of embryogenesis, as depicted in Figure 138-1 (Weller, 1933).18,19 Arising from the third branchial pouch along with the thymic primordia, the inferior parathyroids migrate with the thymus into the lower neck and superior mediastinum. Thus, the inferior parathyroids often rest at the top of the thymus or just below the thyroid’s lower pole. During descent, however, fragments of parathyroid tissue can be dropped anywhere along this course. Because these inferior glands migrate farther during embryogenesis, they are more likely to be abnormally located.1 Figure 138-2 specifically portrays the region of the descent of the thymus, in which ectopic inferior parathyroids are often located. The superior parathyroids, in contrast, arise from the fourth branchial pouch, along with the lateral components of the thyroid. They normally rest along the posterior and lateral aspect of the superior portion of the thyroid, typically above the point where the recurrent laryngeal nerve and inferior thyroid artery cross. Figure 138-3 depicts the regions in which mediastinal ectopic parathyroids, superior or inferior, can be found. There are usually four parathyroids, but there can be more or fewer. A fifth gland can be found in 2% to 22% of subjects, whereas only three glands can be identified in about 3% of subjects (Wang, 1976).1,20,21 As many as 15% of glands can be considered ectopic, that is, not present in a reasonably standard relationship to the thyroid.22 Ectopic glands probably account for more than 50% of initial surgical failure to cure.23 Hyperfunctioning mediastinal glands can be found in 11% to 22% of patients, but only 2% to 4% require thoracotomy (Wang et al, 1986).13,14,24-26 Inferior parathyroid glands are found below the lower border of the thyroid, in a cervical tail of thymus, or in the thyrothymic tract between the thyroid and thymus in about a third of cases (Wang, 1976).20,21,27,28 When an inferior gland is not accounted for, it is often in the thymus. In one series of reoperations, one third of pathologic glands were discovered in the thymus: 40% were cervical and 60% were mediastinal (Wang, 1977).29 When sternotomy is performed, 50%

Ch138-F06861.indd 1678

Aorta Ductus arteriosus Trachea Esophagus FIGURE 138-1 Drawing of a 23-mm embryo, illustrating embryologic relationships of parathyroids, thyroid, and thymus. Parathyroid IV has come to rest on the posterolateral aspect of the thyroid, which was formed by the union of two lateral components with a midline component. Parathyroid III is still contiguous with the cephalad end of the thymus, and both are in the process of descent into the lower neck and superior mediastinum. Parathyroid III anlage may come to rest anywhere in the thymus itself, on the anterior superior pericardium, or adjacent to the aorta and great arteries and veins of the superior mediastinum. See Figure 138-3 for this representation for the adult. (ADAPTED FROM WELLER GL: DEVELOPMENT OF THE THYROID, PARATHYROID AND THYMUS GLANDS IN MAN. CONTRIB EMBRYOL 141:95, 1933.)

to 75% of parathyroids are located within the thymus (Wang et al, 1986).14,24,26,30 In another series, ectopic locations were summarized as follows: paraesophageal, 28%; nonthymic mediastinal, 26%; intrathymic, 24%; intrathyroidal, 11%; carotid sheath, 9%; and high cervical, 2%.23 An ectopic inferior gland in the mediastinum and not associated with thymic or thyrothymic tissues could be present in a number of superior mediastinal locations: ■

■ ■ ■

Near the thymus anteriorly, between posterior thymus and great vessels or pericardium, or on the pericardium below the thymus Near the right or left innominate vein, or on either side of the superior vena cava Adjacent to the ascending aorta, proximal innominate, or either carotid artery In the aortopulmonary window between ascending aorta, left pulmonary artery, and ligamentum arteriosum

Based on embryology, parathyroids are not found within the pericardium.19,27,30

1/21/2008 4:15:09 PM

Chapter 138 Mediastinal Parathyroid Tumors

Right recurrent laryngeal nerve Right vagus nerve

1679

Left recurrent laryngeal nerve Left vagus nerve

Thyroid Thyrothymic tract Thymus

B

A

C

Right pulmonary artery

Cut edge of pericardium

Right phrenic nerve

Left phrenic nerve

Right phrenic nerve

FIGURE 138-3 The three regions in which mediastinal ectopic parathyroids can be found. A, Retroesophageal and paraesophageal, which spans neck and upper mediastinum down to the level of the carina (ectopic superior parathyroid IV). B, Anterior mediastinal, which includes thymus and posteriorly the pericardium, aortic arch, and great vessels of the upper mediastinum (ectopic inferior parathyroid III). C, Middle mediastinal, which includes the areas in front of the carina and mainstem bronchi. This area is in close proximity to the right pulmonary artery and extends along the left main bronchus underneath the aortic arch into the aortopulmonary window.

Thymus Ligamentum arteriosum FIGURE 138-2 The region of the embryologic descent of the thymus, in which ectopic mediastinal inferior parathyroids (III) are often found. The pericardium and vascular structures are important landmarks. Relationships with phrenic, vagus, and recurrent laryngeal nerves are critical. Exposure may be required of the anterior surface of the left pulmonary artery. It may be necessary to divide the ligamentum arteriosum to expose the aortopulmonary window. Middle mediastinal ectopic parathyroids can certainly extend down below the aortic arch on the left.

Parathyroids in the posterior mediastinum usually represent superior glands, possibly enlarged glands that have fallen posteriorly and inferiorly, perhaps related to negative intrathoracic pressures (Wang et al, 1986).14 These glands are found behind the esophagus, laterally along it, or in the tracheoesophageal groove. They can often be removed by a cervical approach. In one review of reoperations, one third of unaccounted-for glands were found behind or around the esophagus, in the neck or mediastinum (Wang, 1977).29 Parathyroids are rarely found in the middle mediastinum but have

Ch138-F06861.indd 1679

been discovered anterior to the carina or right or left main bronchi, posterior to the ascending aorta, or posterior or superior to the right or left pulmonary arteries.31 A supernumerary gland is assumed when four normal parathyroids have been definitively demonstrated without correction of hyperparathyroidism. Two thirds of these are found below the thyroid, usually associated with thymus or thyrothymic tract, whereas most of the rest lie between the normal locations of the superior and inferior glands in the neck.20,32 Parathyroids are normally supplied by the inferior thyroid artery but can also be supplied by the superior, the anastomosis of the two, or other branches. The parathyroid artery is normally terminal, with few anastomoses itself.1

PRESENTATION AND DIAGNOSIS The diagnosis of primary hyperparathyroidism is usually straightforward, relying on an elevated or high-normal serum calcium level (albumin corrected), confirmed at least once, in the presence of elevated or high-normal intact PTH. An elevated 24-hour urine calcium level is confirmatory in about

1/21/2008 4:15:10 PM

1680

Section 7 Mediastinum

40% of patients but not mandatory. A family history is taken to rule out familial causes of hyperparathyroidism, especially for younger patients. When PTH levels are not grossly elevated, the full differential diagnosis for hypercalcemia is considered. Malignancy and hyperparathyroidism together account for more than 90% of all cases of hypercalcemia. Clear elevation of PTH levels narrows the diagnosis considerably. The annual incidence of hyperparathyroidism after age 50 is approximately 1 per 1000 men and 2 to 3 per 1000 women.1 Whether due to cervical or mediastinal parathyroids, confirmed hyperparathyroidism presents a variety of variable, often difficult to objectively quantitate, symptoms and conditions. Traditionally, these included demineralizing bone disease accompanied by bone pain, tenderness, and fractures, as well as renal and ureteral calculi. Psychiatric disturbances, fatigue, and abdominal and other complaints led to the classic complex of so-called bones, stones, moans, and groans. Heightened monitoring and diagnosis today more commonly results in the discovery of asymptomatic decreased bone densitometry readings and early functional renal abnormalities. In symptomatic patients, fatigue remains one of the most common complaints. It can be associated with anorexia, weight loss, and diffuse weakness. Other presenting problems can include subtle psychiatric symptoms, cognitive dysfunction, alterations of mood, proximal muscle weakness, joint complications with possible calcification of articular cartilage, gout or pseudogout, hypertension, phenotype IV lipoproteinemia, and increased cardiac morbidity and mortality.7 Symptoms are more common with higher calcium levels, for instance above 11 mg/dL. Serum calcium levels above 14.5 mg/dL can lead to life-threatening hypercalcemic crisis associated with nausea, vomiting, fatigue, confusion, stupor, and coma.4,8 Emergency treatment includes hydration with isotonic saline and vigorous diuresis to increase urinary excretion of calcium. With calcium levels below 11 mg/dL, many patients are asymptomatic and diagnosis is often made only by routine health maintenance blood testing. There is wide agreement that symptomatic patients need to undergo surgical exploration because this is the only cure and the most effective management. For asymptomatic patients there is some controversy. Recent consensus is that surgery is beneficial for patients with elevation of serum calcium levels greater than 1.0 mg/dL above normal, 24-hour urine calcium value greater than 400 mg, creatinine clearance 30% or more below normal, bone mineral density T score less than −2.5 at any site, or age younger than 50 years.33 Even these patients with mild disease show improvements in bone mineral density, cognitive and musculoskeletal function, reduced nephrolithiasis and nephrocalcinosis, and reversal of lipoproteinemia.7 There is growing support of even more liberal application of surgery because many of the nontraditional symptoms and abnormalities of the disease seem to correct with surgery, and surgical techniques are becoming less invasive, costly, and risky.7 Mediastinal parathyroid disease most commonly manifests either as a hyperparathyroid patient who has had unsuccessful neck exploration leading to consideration or diagnosis of mediastinal disease or as a hyperparathyroid patient not yet

Ch138-F06861.indd 1680

operated on whose preoperative imaging suggests mediastinal disease. It is rare for an abnormal parathyroid to occur as a mediastinal mass not otherwise diagnosed, but 50% to 60% of mediastinal parathyroid cysts can be nonfunctional, and for others the hyperparathyroid state might not be diagnosed until blood tests are then drawn (potentially asymptomatic patients).34,35 In one report, hemorrhage from an adenoma caused chest pain resembling a dissecting aneurysm.36 Whenever a patient believed to have hyperparathyroidism is not cured by neck exploration, the diagnosis is reconfirmed because a variety of conditions other than primary hyperparathyroidism can result in hypercalcemia, including several malignancies (notably breast cancer, multiple myeloma, squamous cell cancer of lung or head and neck, renal cell cancer, prostate cancer, and Hodgkin’s B- and T-cell lymphomas). After exclusion of other diagnoses in the differential diagnosis of hypercalcemia, primary hyperparathyroidism is supported by sustained elevation of serum calcium (albumin corrected) levels and intact PTH levels.4,7-9 Mediastinal exploration has obvious relevance for two groups of patients: those who have imaging suggesting a mediastinal parathyroid (this group might or might not have already had unsuccessful neck exploration) and those who have had unsuccessful neck exploration yet still do not have localizing evidence by any imaging studies. For the latter, mediastinal exploration would most likely be a last resort in the presence of failed localization, unsuccessful neck exploration(s), and persistently problematic hyperparathyroidism.

LOCALIZING IMAGING STUDIES If the diagnosis of primary hyperparathyroidism is certain, either before any surgical intervention has occurred, or after previous surgery has been unsuccessful, then imaging studies are considered. These studies are not considered mandatory before initial surgical exploration, since 96% of patients are cured during a first, full neck exploration (Thompson et al, 1982).11 However, as practice standards have shifted toward minimal exploration, often incorporating intraoperative PTH testing, there has been an accompanying trend toward performing preoperative localization studies. In addition, and in contrast to an initial neck exploration, neck re-exploration can be tedious and exposes the patient to a higher risk of complications, including recurrent nerve injury. Furthermore, mediastinal exploration, if required, can be a lengthy and extensive procedure. Thus, preoperative localization attempts are recommended before reoperative neck exploration.37 Technetium-99m-sestamibi scanning is currently the most useful nuclear imaging study for localizing parathyroid adenomas (McHenry et al, 1996).38-40 Scanning with 99mTc-sestamibi also highlights salivary and thyroid tissues, but delayed images show persistence in parathyroid tissue. Figure 138-4A shows a 99mTc-sestamibi scan localizing a retroesophageal, ectopic, mediastinal parathyroid. Localization success increases with the size of the abnormal parathyroid, and sensitivity ranges from 60% to greater than 90%.41,42 Metaanalysis has claimed 99% specificity.43 Unfortunately, 99mTcsestamibi images are not precise and provide little information

1/21/2008 4:15:11 PM

Chapter 138 Mediastinal Parathyroid Tumors

1681

A

B FIGURE 138-4 Images of a patient with an ectopic parathyroid adenoma behind the esophagus (between the esophagus and spine) in the mediastinum. A, A 99mTc-sestamibi scan shows both lobes of the thyroid and the parathyroid adenoma in question, which is inferior to the thyroid on the right side. The adenoma is visible on both 20-minute and 2-hour delayed images. B, Helical CT scan (5-mm slice, with contrast) of the chest shows the adenoma in question, corresponding to the 99mTc-sestamibi focus. The ectopic gland is approximately 15 mm, is higher in image density than the esophagus, and is sandwiched between esophagus and spine, to the right of the aorta.

on exact landmarks and location. Therefore, for patients who have failed prior exploration, or for patients who appear to have mediastinal foci on 99mTc-sestamibi scanning, a second imaging study is recommended.37 Ultrasound imaging, while useful for thyroid and parathyroid disease in the neck, is of no use for mediastinal tumors.8,9,40 High-resolution CT and magnetic resonance imaging (MRI) are the most common secondary studies. Again, accurate localization improves with the size of the abnormal parathyroid. Success rates for CT and MRI range from 46% to 76%.39 Figure 138-4B shows CT images of the ectopic mediastinal parathyroid imaged by 99m Tc-sestamibi in Figure 138-4A. Highly selective arteriography and selective venous sampling have both been employed to localize parathyroids, but both are seldom used. These tests have lower sensitivity and thus are often reserved for challenging cases. These tests are invasive and have significant complication rates.4,37,44 Despite shortcomings, these are considered when other localization options have failed.

OPERATIVE MANAGEMENT The surgical treatment of hyperparathyroidism consists of removal of the pathologic gland or glands. If all glands are hyperactive, controlled debulking or complete removal with limited reimplantation is performed. In general, and of relevance to mediastinal disease, parathyroid surgery has been revolutionized by the adoption of minimal access approaches and limited explorations. These approaches have become feasible and justifiable with the refinement of more sensitive preoperative imaging studies. Perhaps even more critically,

Ch138-F06861.indd 1681

the development of intraoperative PTH assays has facilitated this evolution by enabling surgeons to assess the adequacy of limited surgical interventions in near-real time (Irvin et al, 1994).7,41,45-48 Initial success rates now approach 99%.49 If a patient has had four normal parathyroids definitively demonstrated, a fifth (supernumerary) gland is assumed. If a patient has had only three glands found, after thorough exploration by an experienced surgeon, then thyroid lobectomy on the side of the missing gland is considered. Rates of intrathyroid parathyroids are variously reported as 1% to 6%.50 Ultrasound information on intrathyroid nodules can help guide the consideration of an intrathyroid parathyroid. Negative predictive value for ultrasound may be as high as 99.5%, although the positive predictive value is probably around 70%. Blind thyroid lobectomy merely on the basis of only demonstrating three glands probably has unacceptably low yield and high risk.50 Any concerns for this possibility need to be laid to rest before nonlocalized mediastinal exploration is undertaken. Mediastinal exploration for a parathyroid adenoma will usually be undertaken on the basis of localizing studies (e.g., 99m Tc-sestamibi and CT), either after a patient has had unsuccessful neck exploration(s) or in a patient who has yet to have neck exploration. Very rarely, such exploration could be undertaken in a patient for whom prior neck exploration was unsuccessful and all localization options have been exhausted without success. Blind mediastinal exploration is, indeed, a rare, last ditch effort, performed only by a specialist. Before a blind exploration is conducted there must be confidence that a rigorously thorough neck exploration has been done or else another must be contemplated.

1/21/2008 4:15:11 PM

1682

Section 7 Mediastinum

Even if a gland is localized in the mediastinum, consideration is given to attempted transcervical removal, based on the realization that most mediastinal glands are approachable in this way.23 Whereas 10% to 22% of patients with primary hyperparathyroidism might have mediastinal parathyroids, only about 4% require thoracotomy or sternotomy (Wang et al, 1986).13,14,24,26,30 Most mediastinal parathyroids, particularly those down through the level of the thymus, can be removed via a cervical approach. In fact, a cervical approach is feasible for glands within or next to the thymus, in the retroesophageal or paraesophageal posterior mediastinum, near the superior aspect of the aortic arch, and possibly even down to the tracheal bifurcation. A thorough cervical exploration approach includes a transcervical thymectomy, exploration of the retroesophageal and esophageal areas, and dissection of tissues down into the superior mediastinum. Removing a mediastinal parathyroid via a cervical incision is analogous to removing intrathoracic goiter via the neck. Recurrent nerves may actually be less vulnerable to injury using a collar incision, versus thoracotomy or sternotomy.11 Even in a re-exploration, most unaccounted-for parathyroids are found in the neck or within reach of a collar incision. Only 20% of reoperations require sternotomy or thoracotomy (Wang, 1977).13,29 In fact, in one series of sternotomies, two thirds of the discovered glands were thought to have been potentially within reach of a cervical approach (Wang, 1977).29 If thorough neck and superior mediastinal exploration are unrevealing, the surgeon must decide whether to proceed immediately with mediastinal exploration or whether to close and return another day. Opinion is divided. Most surgeons would close and return later, likely after further imaging attempts. This has the advantage of limiting the potential draining effect of a tedious and frustrating negative exploration on the surgeon’s physical performance and decision making. On the other hand, a combined collar/sternotomy approach has exposure benefits, and the planes into the mediastinum will never be as clear as at the time of the initial transcervical exposure.30 Unfortunately, these combined incisions have higher complication rates. When transcervical exposure has been exhausted without success (which is a minority of cases), median sternotomy is the default additional exposure of choice. Right lateral thoracotomy puts the recurrent nerve at risk and usually is avoided. Definitive preoperative imaging may convincingly suggest some alternative exposure, such as thoracoscopic removal of a mediastinal gland.51,52 The goal of operative intervention is to remove the hyperfunctioning gland(s). If the patient’s disease is diffuse hyperplasia, and there is involvement of one or more mediastinal glands, the mediastinal gland(s) must be fully removed. It is then at the surgeon’s discretion how to debulk the gland down to a physiologic level of parathyroid tissue activity. This can involve debulking cervical parathyroids down to one half a gland, or down to a normal level of PTH if intraoperative PTH testing is performed. Alternatively, parathyroid tissue can be removed, with some tissue then reimplanted, preferably in the forearm. In either case, at the time of debulking, parathyroid tissue also is cryopreserved. In fact, extensive

Ch138-F06861.indd 1682

and possibly repeated neck explorations create a real risk of compromise of normal parathyroids, resulting in serious or devastating hypoparathyroidism. Thus, ultimate care is always taken in exposing and manipulating normal parathyroids, and there always is a low threshold for cryopreservation of parathyroid tissue or reimplantation of normal glands, preferably in the forearm. Rapid intraoperative intact PTH assay is now often used to confirm that the hyperfunctioning mass has been removed (Irvin et al, 1994).46 It can also be used to guide extent of debulking of diffuse disease. Although there remains some debate over optimal criteria for intraoperative decision making, this practice has revolutionized the surgical approach to this disease. In many cases, preoperative 99mTc-sestamibi injection and use of a hand-held gamma probe during surgery can guide exploration.41,53,54 This technique has been evolving and still evokes controversy over whether it is necessary, but repeated reports have shown high success rates.55-58 Whether or not it is necessary in all cases, there seems less doubt that this may be particularly useful for reoperations and mediastinal cases.59,60 Some patients with persistent or recurrent disease have been approached in innovative, less-invasive ways. Two examples are treating adenomas with angiographic ablation and endoscopic parathyroidectomy techniques. Angiographic embolization of parathyroids has been successfully employed by a number of physicians, including in cases in which mediastinal disease is known but in which surgery is either contraindicated, relatively contraindicated, or refused. With respect to this approach, the following points are to be emphasized61-71: ■ ■

■ ■ ■

■

A skilled interventional radiologist who can localize the adenoma is critical to success. The adenoma has a solitary arterial supply that can be demonstrated and embolized; not all adenomas have this. Not all cases are successful; long-term success rates are unknown. Neurologic complications can occur. Tissue is not obtained for pathology or cryopreservation, which is especially important if the status of the remaining parathyroids is uncertain. Embolization is limited to those symptomatic patients requiring treatment.

Given these limitations, this technique can be extremely valuable and considered for many challenging cases. First reported by Prinz, endoscopic approaches to exploration of the neck itself have been controversial, but the techniques may hold particular appeal for exploration of the mediastinum in skilled hands.25,72-76 Experience with the approach continues to evolve.41,51,52,60,77,78 These approaches may soon be considered standard of care for mediastinal disease and should be carefully considered.

RESULTS Exploration of the mediastinum reveals the missing parathyroid in situations such as described earlier in 66% to 85% of

1/21/2008 4:15:11 PM

Chapter 138 Mediastinal Parathyroid Tumors

cases (Wang et al, 1986).14,24,26,30 However, it must be stressed that in significant fractions of these cases (20%-66%) the abnormal gland was thought to have been potentially within reach of a cervical exploration (Wang, 1977).13,29,30 After failed mediastinal exploration, one third of cases will eventually have an abnormal gland found in the neck.14 In a small proportion, another cause of hypercalcemia will eventually be diagnosed (Thompson et al, 1982; Wang et al, 1986).11,14 Overall cure rates for initial surgery on hyperparathyroidism (all sites) range from more than 95% in experienced hands down to 70% with inexperienced operators.23 As stated previously, the evolving practice of intraoperative PTH monitoring seems to be driving overall cure rates toward 99%.79,80 For reoperations, however, cure rates still fall to about 90%.80,81 For mediastinal disease, results are highly dependent on successful localization by any modality. Successful localization facilitates cure rates of more than 95%.

POSTOPERATIVE ISSUES For cases that have come to require mediastinal exploration there may be a higher prevalence of prior surgical compromise of all normal parathyroids, so vigilance is required. A strategy with a very low threshold for reimplantation of parathyroid tissue, possibly in conjunction with cryopreservation of tissue, is justified. Reimplantation for these patients is preferentially done in the forearm, to simplify further diagnostic and therapeutic management of the neck.30,82 The course after removal of a mediastinal adenoma is not necessarily different from that after other parathyroidectomies. Calcium levels may fall and reach a low 48 to 72 hours after surgery. This will be dependent on the state of the other parathyroid glands, which might have been suppressed by the hyperfunctioning parathyroid, inadvertently damaged or removed in the current or previous surgery, or reimplanted. Suppressed glands may take days to weeks to recover function, and reimplanted tissue may require weeks as well. In addition, in patients with severe bone disease (bone hunger), the bones may aggressively take up calcium and phosphorus, resulting in more rapid postoperative hypocalcemia and hypophosphatemia.4,8 These various issues can take days to weeks to stabilize. For routine parathyroid surgery there may be early or temporary symptomatic hypocalcemia in as many one fourth of patients, but long-term symptomatic hypocalcemia is generally stated to complicate surgery in 1% to 2% of cases per side of the neck explored.83 For reoperation, rates may be 10% to 20%.80,81 For patients with mediastinal disease specifically, many of whom have had previous neck surgery or delayed diagnosis, rates may be this high or higher. Clinical manifestations of hypocalcemia from hypoparathyroidism are not different for mediastinal versus other glands. Hypocalcemia can cause perioral numbness, digital paresthesias, muscle cramps, carpopedal spasm, and possibly laryngospasm. Extreme hypocalcemia may result in tetany or seizure.4,8 Alkalosis from hyperventilation may aggravate the situation by reducing ionized calcium, whereas acidosis such as from renal failure may temporarily mask the issue. Tapping the patient in the preauricular/facial nerve area may elicit twitching of the mouth, known as Chvostek’s sign, but this

Ch138-F06861.indd 1683

1683

is present in 10% or more of normal patients. Application of an arm tourniquet above systolic blood pressure for 3 minutes can elicit carpal spasms, metacarpophalangeal flexion, and interphalangeal extension, known as Trousseau’s sign, but this test is inconvenient and uncomfortable. Hypomagnesemia can also cause or exacerbate spasms; this also is checked. Mild hypocalcemia is usually treated with oral calcium alone: calcium carbonate, 500 to 2000 mg, one to three times a day (total dose up to 6 g). In some resistant cases, vitamin D may also be required. This is usually given orally as its active form, calcitriol (Rocaltrol), 0.25 µg, one or two times per day. Symptomatic or severe hypocalcemia can be treated intravenously with 10 to 20 mL of 10% calcium chloride or 20 to 30 mL of 10% calcium gluconate given over 5 minutes. This is often followed by a slow constant infusion at 1 mg/kg/hr. Rates of injury to recurrent nerves in initial parathyroid and thyroid surgery (all sites) are expected to be about 1% per side of the neck explored. For reoperations these rates may be several times higher. Permanent recurrent laryngeal nerve paralysis after reoperation may approach 4% to 6%.80 For mediastinal disease, alternative surgical exposures such as sternotomy or especially right thoracotomy may contribute to an even higher complication rate.

COMMENTS AND CONTROVERSIES Drs. Hall and Moley have outlined the management strategies for patients with mediastinal parathyroid tumors. Understanding the embryology of the parathyroid gland helps guide exploration because the majority of ectopic glands are in the anterior mediastinum within or in proximity to the thymus. Therefore, most can be reached via a transcervical approach. Para-aortic or within the subaortic window is another common location, requiring a video-assisted thoracoscopic or limited thoracotomy approach for excision. Current imaging with 99mTc-sestamibi or CT will localize most ectopic parathyroid adenomas. The availability of intraoperative PTH monitoring has greatly simplified the operative management and lessened the extent of surgical resection. G. A. P.

KEY REFERENCES Irvin G, Prudhomme DL, Deriso GT, et al: A new approach to parathyroidectomy. Ann Surg 219:574, 1994. McHenry C, Lee K, Saadey J, et al: Parathyroid localization with technetium-99m-sestamibi: A prospective evaluation. J Am Coll Surg 183:25, 1996. Thompson N, Eckhauser F, Harnes J: The anatomy of primary hyperparathyroidism. Surgery 92:814, 1982. Udelsman R, Aruny JE, Donovan PI, et al: Rapid parathyroid hormone analysis during venous localization. Ann Surg 237:714-721, 2003. Wang C: The anatomic basis of parathyroid surgery. Ann Surg 183:271, 1976. Wang C: Parathyroid reexploration: A clinical and pathologic study of 112 cases. Ann Surg 186:140, 1977. Wang C, Gaz R, Moncure A: Mediastinal parathyroid exploration: A clinical and pathologic study of 47 cases. World J Surg 10:687, 1986. Weller G: Development of the thyroid, parathyroid, and thymus glands in man. Contrib Embryol 141:95, 1933.

1/21/2008 4:15:11 PM

chapter

SUPERIOR VENA CAVA OBSTRUCTION

139

Paolo Macchiarini

Key Points ■ Collateral venous flow usually develops rapidly. ■ Endovascular interventions are available. ■ Surgical hypass is often used. ■ Intrathoracic benign and malignant diseases cause SVCO.

HISTORICAL NOTE Superior vena cava (SVC) obstruction (SVCO) was first described by William Hunter in 1757.1 Since then, its etiology has shifted from tuberculosis and syphilitic aneurysms of the ascending aorta to malignant disorders. In effect, of the about 15,000 annual cases of SVCO in the United States, 95% are due to primary intrathoracic (most frequently, small cell lung cancer) or metastatic malignancies in adults. However, the exponential increase in use of indwelling central venous catheters and cardiac pacemakers over the past 2 decades has resulted in more patients with SVCO of benign etiology (Table 139-1). In children, T-cell leukemia and lymphomas are leading causes. Depending on the underlying condition, multiple treatment options are available for SVCO, including radiation therapy, chemotherapy, thrombolytic therapy, anticoagulation, endovascular interventions (e.g., balloon angioplasty [percutaneous transluminal angioplasty, PTA], stents), and open surgery. Initially, endovascular treatments were used in patients unresponsive to radiation therapy and chemotherapy or in whom symptoms recur after traditional therapy. Because of the dramatic technical and clinical results, with symptom relief in more than 90% of patients2 and coupled with the increasing sophistication of endovascular techniques and devices, stent placement has been proposed as first-line treatment in all patients with SVCO due to malignant disease, keeping in mind the short life expectancy of these patients.3-5 However, this tendency has not been supported by data arising from randomized clinical studies, and there still is a role of surgery for very selected patients with locally advanced but completely resectable non–small cell lung cancers (NSCLC) or mediastinal tumors involving or invading the SVC. However, open surgery requires a high level of technical expertise and vigilant attention to patient selection and perioperative management to minimize complications, reported even in highly specialized centers.6 The role of stenting in SVCO of benign etiologies is undecided because its long-term durability remains to be assessed.7-11 By contrast, surgical intervention, with bypass grafting from the innominate vein to the SVC or right atrial

appendage, is still considered the mainstay of treatment of benign SVCO since the first SVC bypass graft with use of an autologous superficial femoral vein half a century ago (Klassen et al, 1951).12 This is because the surgical treatment of benign SVCOs, using a variety of different conduits and type of bypasses, is effective over the long term with excellent patency rates (Dartevelle et al, 1991; Karla et al, 2003).13-16 HISTORICAL READINGS Ahmann FR: A reassessment of the clinical implications of the superior vena caval syndrome. J Clin Oncol 2:961-969, 1984. Dartevelle P, Chapelier AR, Pastorino U, et al: Long-term follow-up after prosthetic replacement of the superior vena cava combined with resection of mediastinal-pulmonary malignant tumors. J Thorac Cardiovasc Surg 102:259-265, 1991. Doty DB: Bypass of superior vena cava: Six years experience with spiral vein graft for obstruction of superior vena cava due to benign and malignant disease. J Thorac Cardiovasc Surg 83:326, 1982. Hunter W: The history of an aneurysm of the aorta with some remarks on aneurysms in general. Med Obs Soc Phys Lond 1:323-357, 1757. Karla M, Gloviczki P, Andrews JC: Open surgical and endovascular treatment of superior vena cava syndrome caused by nonmalignant disease. J Vasc Surg 38:215-223, 2003. Klassen KP, Andrews NC, Curtis GH: Diagnosis and treatment of superior vena cava obstruction. Arch Surg 63:311-325, 1951. McIntire FT, Sykes EM Jr: Obstruction of the superior vena cava: A review of the literature and report of two personal cases. Ann Intern Med 30:925-960, 1949. Ogawa K, Richli W: Stenosis of the vena cava: Preliminary assessment of treatment with expandable metallic stent. Radiology 161:295-298, 1986. Parish J, Marschke RF Jr, Dines DE, Lee RE: Etiologic considerations in superior vena cava syndrome. Mayo Clin Proc 56:407-413, 1981. Tanigawa N, Sawada S, Mishima K: Clinical outcome of stenting in superior vena cava syndrome associated with malignant tumors: Comparison with conventional treatment. Acta Radiol 39:669-674, 1998.

ANATOMY The SVC originates from the confluence of the two innominate veins at the level of the cartilaginous portion of the first right rib. It descends down into the ventral mediastinum and enters the right atrium. Its trunk has an average length of 7 cm and a transverse diameter of 2 cm. It is adjacent to the thymus gland and right pleura and lung ventrally, the right laterotracheal lymphatic chain, pulmonary artery, and superior pulmonary vein dorsally, the ascending aorta medially, and the right pleura, phrenic nerve, and small superior diaphragmatic vessels laterally (Fig. 139-1). The cavoatrial junction is within the pericardium. The serous pericardium envelops the anteroexternal surface of the SVC for a length

1684

Ch139-F06861.indd 1684

1/21/2008 4:15:56 PM

Chapter 139 Superior Vena Cava Obstruction

TABLE 139-1 Etiology of Superior Vena Cava Obstruction Malignancy (95%) Lung cancer (80%) Small cell lung cancer Non–small cell lung cancer Lymphoma (almost invariably non-Hodgkin’s lymphoma) Thymoma Mediastinal germ cell neoplasms Solid tumors with mediastinal metastases (breast cancer most frequently) Others (5%) Iatrogenic: Pacemaker and defibrillator leads, indwelling central venous catheters, postirradiation vascular fibrosis Infectious disease: Fibrosing mediastinitis secondary to tuberculosis, syphilis, histoplasmosis, actinomycosis, aspergillosis, blastomycosis, filariasis, direct spread of nocardiosis Other: fibrosing mediastinitis, sarcoidosis, sclerosing cholangitis, goiter, aortic aneurysm, fibrous mesothelioma, Behçet’s or Hughes-Stovin syndromes

1685

2. The internal thoracic venous system, where the blood pours into the inferior vena cava (IVC) from the internal thoracic vein through the superior and inferior epigastric veins and the external and common iliac veins 3. The vertebral venous system, where the blood from the sinus venosus and bilateral brachiocephalic veins flows into the intercostal, lumbar, and sacral veins and then into the IVC 4. The external thoracic venous system, which is the superficial collateral system where the blood from the subclavian and axillary veins reaches the lateral thoracic vein and then pours into the femoral vein through the thoracoepigastric and superficial epigastric veins.

PATHOPHYSIOLOGY Because of its location in a nondistensible compartment, with thin walls, low hemodynamic pressure, and encirclement by chains of lymph nodes, the SVC is likely obstructed from any pathology of the surrounding structures and/or organs by the following: 1. Compression due to occupying lesions, either malignant or benign 2. Invasion due to malignant tumors 3. Thrombosis due to hypercoagulable states (malignancy and polycythemia), intimal damage (venous lines), and/or stasis (external compression) 4. Constriction, owing to dense scar tissue (e.g., in fibrotic mediastinitis)

FIGURE 139-1 Surgical anatomy of the superior vena cava.

of 2 cm. The sinus node is located along the anterolateral aspect of the SVC to the right atrium junction, and any manipulation of this region jeopardizes atrial conduction. The medial area lying between the intrapericardial SVC and ascending aorta includes an extrapericardial region where the proximal right main bronchus and right retrocaval pulmonary artery are located. There are four main collateral routes of the SVC in humans (McIntire and Sykes, 1949)17: 1. The azygos venous system, which is the only collateral draining directly into the posterior surface of the SVC above the right pulmonary artery and main bronchus

Ch139-F06861.indd 1685

All these mechanisms can increase the venous pressures to as high as 200 to 500 cm H2O in patients with severe SVCO. SVCO results in collateral circulation diverted via the internal mammary, azygos, hemiazygos, lateral thoracic, thoracoepigastric, and vertebral veins, and its severity depends on the rapidity of its onset and location. In acute SVCO, the collateral venous network does not have time to distend to accommodate the increased blood flow, and this causes a marked clinical distress. In patients with long-standing SVCOs, the improvement of venous drainage by the collateral flow that bypasses the obstructed SVC can allow the SVCO to remain unrecognized. These collateral pathways usually include the internal thoracic superior and inferior epigastric veins on the left, lateral thoracic superficial epigastric veins on the right, anterior and posterior intercostal veins, azygos/accessory hemiazygos/hemiazygos veins, jugular veins, vertebral plexus, and small tributaries of the thoracoabdominal wall and the breast.18,19 More rare collateral pathways may involve pulmonary venous collaterals in which systemic veins drain directly into the left side of the heart, resulting in a right-to-left shunt.20 With regard to the site of obstruction, if it is above the entry of the azygos vein, the SVC syndrome is less pronounced because the azygos venous system can readily distend to accommodate the shunted blood with less venous pressure developing in the cephalic and upper extremity territories. If the obstruction is below the entry of the azygos vein, more florid symptoms and signs are seen because the blood flow returns to the heart through the upper abdominal veins and the IVC, and this requires higher venous pressures.

1/21/2008 4:15:56 PM

1686

Section 7 Mediastinum

Left brachiocephalic vein

Tumor Tumor

Accessory hemiazygos vein

Accessory hemiazygos vein

Azygos vein

Azygos vein

Hemiazygos vein

Type II

Type I A

B

FIGURE 139-2 Illustration of the different types of SVC obstruction observable in patients with primary intrathoracic or metastatic malignancies. A, Type I: high-grade SVC stenosis but still normal direction of blood flow through superior SVC and azygos veins. Note increased collateral circulation through hemiazygos and accessory hemiazygos veins. B, Type II: greater than 90% stenosis or occlusion of SVC with normal direction of blood flow through the azygos vein.

The pathophysiology of catheter-related SVC obstruction is not well known but probably involves neointimal hyperplasia from repetitive and prolonged trauma associated with an abnormally high flow state. Early stenosis is associated with thrombosis without a fixed stenotic lesion, whereas late stenosis is postulated to be due to fibrosis, although thrombus formation is still possible.21,22 Moreover, the presence of multiple and/or retention of severed lead(s) and previous lead infection may increase the risk of SVC syndrome.23 On the basis of severity and collateral venous circulation extension, Stanford and Doty24 proposed a classification

Ch139-F06861.indd 1686

scheme for SVCO, in which type I includes stenosis of up to 90% of the SVC, with patency and antegrade flow of the azygos/right atrial pathway; type II, stenosis of more than 90% or occlusion of the SVC with patency and antegrade flow in the azygos/right atrial pathway; type III, stenosis of more than 90% or occlusion of the SVC with reversal of azygos blood flow; and type IV, occlusion of the SVC and one or more of the major caval tributaries, including the azygos systems (Fig. 139-2). However, this classification does not take into account the underlying cause of the SVCO.

1/21/2008 4:15:57 PM

Chapter 139 Superior Vena Cava Obstruction

1687

Tumor

Tumor Internal mammary vein

Accessory hemiazygos vein

Right superior intercostal vein Chest wall collaterals

Superior epigastic veins

Hemiazygos vein

Inferior epigastic veins

C

Type III

D

Type IV

FIGURE 139-2, cont’d C, Type III: occlusion of the SVC with retrograde flow in both azygos and hemiazygos veins. D, Type IV: extensive occlusion of SVC and innominate and azygos veins with chest wall and epigastric venous collaterals.

CLINICAL PRESENTATION The clinical presentation depends on the acuity and degree of the obstruction (Table 139-2). With slowly progressive SVCO, adequate collateral drainage may develop and patients may have no or only mild symptoms. In acute SVC obstruction, collateral pathways do not have time to develop, and patients are more symptomatic. In general, patients with SVCO most often present with complaints of facial edema and erythema, swelling of the neck and/or arms, and visible dilation of the veins in the upper extremity; they may also complain of dyspnea, persistent cough, and orthopnea. As the occlusion progresses, the symptoms may include hoarse-

Ch139-F06861.indd 1687

ness, periorbital edema, dysphagia, headaches, dizziness, syncope, lethargy, and chest pain. Other findings may be confusion and laryngeal and/or glossal edema. In some cases, the nerves that cross the superior mediastinum (i.e., vagus and phrenic nerves) may be affected and can lead to hoarseness and paralysis of the diaphragm. These symptoms may be worsened by positional changes such as bending forward, stooping, or lying down. Patients with SVCO and vagus or phrenic nerve involvement find significant symptom relief when they are in an upright position, and many of these patients sleep in a chair to avoid dyspnea. The venous hypertension associated with SVCO can produce some life-threatening complications, such as cerebral or laryngeal edema and

1/21/2008 4:15:57 PM

1688

Section 7 Mediastinum

TABLE 139-2 Relation of Symptoms and Degree of Stenosis or Obstruction in Patients With Superior Vena Cava Obstruction Initial (Type I)

Intermediate (Type II and III)

Late (Type IV)

Slight facial swelling Slight periorbital conjunctival edema Symptoms at first dissipate within a few hours after rising in the morning

Flushing, increased facial swelling, beefy red color of face (erythema of face) Progressive neck and upper trunk swelling or edema Full feeling in arms, fingers and hands swelling Watery eyes, congested conjunctiva Epistaxis and face erythema

Central venous system: Increased jugular venous distention, tachycardia, decreased blood pressure, periorbital cyanosis, and extremely dilated, prominent chest veins Respiratory: Cough, dyspnea, hoarseness, tachycardia Central nervous system: Headache, confusion, anxiety, vision changes Gastrointestinal: dysphagia

Type I includes stenosis ≤90% of the superior vena cava (SVC) with patency and antegrade flow of the azygos/right atrial pathway; type II, stenosis of >90% or occlusion of the SVC with patency and antegrade flow in the azygos/right atrial pathway; type III, stenosis >90% or occlusion of the SVC with reversal of azygos blood flow, and type IV, occlusion of the SVC and one or more of the major caval tributaries, including the azygos systems.

cerebral vessel thrombosis and hemorrhage, with lethal results. Of note, in patients with long-standing SVCO, the neovenous collateralization can, in rare circumstances, compensate for the obstructed SVC to such extent as to reverse the clinical syndrome, although the main vessel remains totally obstructed.25

DIAGNOSIS Establishing the underlying diagnosis and etiology of SVCO is of outmost importance because of the following26: 1. Certain disorders that cause SVCs may be more amenable to specific treatment regimens 2. Cancer patients with SVCO usually do not die of the syndrome itself but from the extent of their underlying disease 3. Less than 5% of SVCOs are of benign etiology For example, small cell lung carcinoma and lymphoma respond dramatically to chemotherapy and/or irradiation, whereas nonmalignant occlusions may be best first managed with surgical revascularization. SVCO is usually a clinical diagnosis. The initial evaluation of the patient includes a chest radiograph to look for mediastinal masses and associated findings, such as pleural effusion, lobar collapse, or cardiomegaly. Contrast computed tomography (CT) of the thorax yields the most useful diagnostic information and can define the anatomy of the associated etiology and confirm if any collateral venous pathways have developed. However, to make the diagnosis of SVCO based on CT-contrast studies, two criteria need to be met: absent or reduced enhancement of the vein below the level of obstruction and presence of collateral circulation. Venous patency and the presence of thrombi are assessed by using contrast and rapid scanning techniques.27 Contrast or nuclear venography, magnetic resonance imaging, and venous sonography may be valuable in assessing the site, nature, and degree of the obstruction. If bronchogenic carcinoma is suspected, a sputum specimen is obtained. If the sputum specimen is negative, a biopsy specimen is taken from the most accessible site that is clinically involved with disease. The biopsy approach depends on the working diagnosis,

Ch139-F06861.indd 1688

tumor location, patient’s physiologic status, and expertise available at the facility. It may include bronchoscopy; needle biopsy of palpable cervical, supraclavicular, or other nodes; mediastinoscopy; mediastinotomy; median sternotomy; and video-assisted thoracoscopy. Thoracotomy is rarely indicated. A few patients with malignancy have acute and severe SVCO and require urgent treatment. In this situation, the tissue diagnosis can be delayed and endovascular treatment can be performed. Stent placement rapidly relieves the symptoms and does not affect the ability to make a tissue diagnosis at a later date. However, SVCO is usually unlikely to be a life-threatening emergency, and unspecific treatment before definitive diagnosis is not justified.

TREATMENT OPTIONS In the past, radiation and chemotherapy for the underlying malignant obstruction have been the mainstays of treatment for malignant SVCO, especially because of the short life expectancy of the affected patients. However, this consensus opinion has been challenged because not all tumors are radiosensitive, chemotherapy may be of benefit in some cases but requires a finite response time, neither of these two approaches is particularly well suited for the most severe SVC obstruction (type IV), and even in patients who respond to radiation or chemotherapy, there are maximum dosage limits. Recent thinking suggests that angioplasty and self-expandable metallic stents may be used as the first-line therapeutic measure in all malignancies because stenting does not interfere with subsequent antitumor treatments and provides urgently needed relief of symptoms. The response is immediate and spectacular, with the disappearance of symptoms within 24 to 72 hours. Furthermore, stenting eliminates the protracted waiting time of 3 to 4 weeks needed to assess effectiveness when chemotherapy or radiation therapy is the first choice of treatment. Also, the presence of an SVC stent does not preclude surgical bypass,5 and the conclusion that endovascular stenting is preferred to a more invasive surgical procedure seems reasonable. Surgical revascularization has, however, a definitive role in selected patients with locally advanced but completely resectable NSCLC and mediastinal tumors. Moreover, the treat-

1/21/2008 4:15:57 PM

Chapter 139 Superior Vena Cava Obstruction

1689

TABLE 139-3 Surgical Indications and Contraindications in Superior Vena Cava Obstruction Indications

Contraindications

Neoplasms Operable NSCLC Anterior mediastinal tumors Primary SVC tumors

SVCOs due to unresectable tumors NSCLC patients with N2 disease and/or requiring pneumonectomy Type III SVCO

Vascular Primary saccular aneurysms Primary malformations

Abnormal venous walls in the proximal veins

Benign causes

Pacemaker-induced SVCO

NSCLC, non–small cell lung cancer; SVCO, superior vena cava obstruction.

ment of benign SVCO remains surgical because it is more effective over the long term, with secondary endovascular interventions to eventually maintain graft patency (Karla et al, 2003).13-16

SURGICAL MANAGEMENT Indications Several techniques are available for repairing, replacing, or bypassing an obstructed SVC. Indications for surgery as initial treatment are limited to patients with either undiagnosed, asymptomatic or types I to II SVCO due to anterior mediastinal tumors, node-negative right-sided NSCLC,28 and benign SVCOs, which is especially relevant today, with the escalating incidence of iatrogenic SVC thrombosis (Table 139-3). The advantages of surgery are the expeditious tissue diagnosis and definitive removal of the obstruction in malignancies and the superior long-term patency rates compared with endovascular treatments in benign SVCOs. Venous thrombectomy, either mechanical29 or through open surgery, may be indicated in select patients with catheter-induced partial SVC thrombosis to remove the foreign material and obstructing catheter (Fig. 139-3) and reduce the risk of acute pulmonary embolism. In contrast are pacemaker-induced SVCOs in which percutaneous balloon venoplasty with or without self-expandable or balloon-expandable stents has largely replaced surgery.30 From a hemodynamic point of view, primary surgical resection and revascularization is contraindicated when the cephalic venous bed is totally obstructed, when the proximal veins have abnormal venous walls, and in type IIII and IV obstructions because the existing, well-developed collateral venous circulation maximally competes and reduces the blood flow through the graft, exposing it to thrombotic events. In these situations, bypassing the obstructed SVC using either the jugular or axillary veins as proximal implantation sites is the treatment of choice. One must keep in mind, however, that these revascularization procedures are at higher thrombotic risks because of the reduced venous blood flow through the graft (preexisting collateral venous network) and need of

Ch139-F06861.indd 1689

FIGURE 139-3 CT scan showing a partial occlusion of the SVC in a patient with long-term placement of an indwelling central venous catheter.

longer prosthesis, even with the creation of an arteriovenous fistula to enhance flow in the bypass(es).

Preoperative Assessment If surgical resection is planned, the clinical preoperative workup evaluating the extension of the primary disease parallels that made in all intrathoracic malignancies but needs to be as extensive as possible, especially in patients with SVCOs due to NSCLC in which the long-term results are poor.28 All patients have a bilateral arm venogram before operation to anatomically delineate the site, degree, and extension of the venous obstruction, to discern the presence of possible proximal thrombosis, and to anticipate where the proximal graft anastomosis can be made. Systemic venous anatomy is carefully evaluated angiographically to determine the presence of a contralateral SVC (e.g., a persistent left SVC) and an azygos or hemiazygos continuation of the IVC. Ultrasonography of the subclavian veins will show lack of normal collapse of the vein by sudden sniff maneuver, and a barium swallow study may show esophageal varices as a consequence of the collateral blood flow into the IVC. Echocardiography eliminates thrombotic extension into the right atrium and appreciates the patency of the jugular and axillary veins. Because a majority of patients with NSCLC present with a clinically and radiologically silent SVC invasion, key radiologic signs are the invasion of the posterior wall of the terminal SVC on CT and the amputation of the right upper mediastinal artery

1/21/2008 4:15:58 PM

1690

Section 7 Mediastinum

pressure, brain activity by electroencephalography, cerebral oxygenation nonivasively by near-infrared spectroscopy (NIRS), and continuous cardiac output. These monitoring devices serve to control circulation during caval clamping. This anesthetic approach for SVC reconstruction is not evidence based (owing to a lack of data) but is supported by physiologic considerations and based on therapy principles in patients with traumatic head injury.31

Surgical Approach The usual approach includes a right thoracotomy in the fourth or fifth intercostal space for bronchogenic tumors and a median sternotomy for tumors originating from the anterior compartment of the mediastinum, respectively. The right thoracotomy yields the best exposure of the right hilum and excellent visualization of the SVC and right atrium but renders the dissection, control, and revascularization of the left brachiocephalic vein technically demanding. Median sternotomy allows a large exposure of the entire anterior mediastinum, right atrium, both brachiocephalic veins, and the SVC on their entire lengths. This incision can be easily extended to the neck.

Choice of Material

FIGURE 139-4 CT scan showing a right-sided tumor of the proximal right main bronchus infiltrating the dorsal aspect of the terminal SVC and the right upper lobe artery.

on pulmonary angiography (Fig. 139-4). The brain also is investigated to assess its tolerance to SVC cross-clamping.

Intraoperative Monitoring Appropriate invasive and noninvasive monitoring is essential. All patients in whom a tumor resection is planned are ventilated through a double-lumen tube to obtain one-lung ventilation. A capnometer and a pulse oximeter is used to continuously monitor systemic oxygen saturation. A left radial arterial line is inserted transcutaneously for continuous pressure monitoring and arterial blood gas determination. Clamping of the SVC requires venous access via the IVC. Therefore, an indwelling catheter on the dorsal hand is only used for induction of anesthesia; other lines are placed on the dorsal foot and in both femoral veins (one high-flow catheter and a three-lumen central venous catheter). A catheter may be inserted into the cephalic vein in the forearm or more proximally in the antecubital fossa or into the right internal jugular vein retrograde to the jugular bulb to monitor the venous pressure in the cephalic territory. These lines are essential to monitor the physiologic arteriovenous brain parenchymal gradient. At least two venous lines are placed in the lower limbs to achieve volume expansion during venous clamping. Transesophageal echocardiography and nasogastric tube placement are optional. Besides usual monitoring with electrocardiography (ECG) with five leads, continuous arterial blood pressure, pulse oxymetry, and capnometry, we monitor continuous jugular bulb

Ch139-F06861.indd 1690

When the circumference of the involved SVC is less than 30%, a partial resection of the vein is possible and reconstruction can be accomplished with either a primary defect closure or interposition of an autologous pericardial or venous patch (Fig. 139-5). If there is a greater circumferential involvement, complete replacement and revascularization is mandatory, and different materials have been proposed, such as autologous pericardium, which may be fashioned in the shape of a patch or tube,32 saphenous vein grafts that may be split longitudinally and sutured in spiral fashion around a 40-Fr stent, so as to have a diameter of 12 mm (Doty, 1982),33 and synthetic materials, which can take the form of a thin membrane or patch for repairing the SVC or of a tube graft (commonly with external reinforcing rings) for reconstructing or bypassing the vessel.34 Unlike prosthetic materials, autologous pericardium and vein are easy to procure and prepare, involve no risk of infection, and do not necessitate anticoagulation therapy. Autogenous venous grafts represent the nearest approximation of the ideal blood vessel substitute and are acknowledged to provide the best reproducible results of vascular reconstruction. Whatever venous graft—superficial femoral, jugular, or internal saphenous veins—is used, the diameter of these vessels must be at least that of the brachiocephalic vein. One way to construct an adequate-sized autologous venous graft is to make a spiral vein. This requires that the necessary length (l) of the venous graft to be used to replace the length of the resected SVC must be: l=

R ×L r

where R is the radius of the brachiocephalic vein, r is the radius of the autologous venous graft, and L is the length of the resected SVC.

1/21/2008 4:15:58 PM

Chapter 139 Superior Vena Cava Obstruction

A

C

1691

B

D

FIGURE 139-5 Invasions of (A) less than 30% of the SVC can be resected and closed directly using a (B) mechanical or (C) running suture or (D) by autologous pericardial or venous patch interposition.

Ch139-F06861.indd 1691

1/21/2008 4:15:58 PM

1692

Section 7 Mediastinum

Prosthetic grafts in the venous system are far more likely than arterial grafts to occlude because of the relative slow venous flow against a hydrostatic pressure gradient, low intraluminal pressure, and presence of competitive flow from venous collaterals. Not surprisingly, prosthetic replacement of the SVC has usually been regarded as an absolute surgical contraindication because of absence of suitable graft material for reconstruction and technical fear concerning the effects of SVC clamping, graft thrombosis, and infection. However, the feasibility of reconstructing the SVC has been ameliorated by the efficacy of the currently available suitable graft materials. The synthetic nontextile polytetrafluoroethylene (PTFE) vascular graft is the synthetic material of choice for SVC reconstruction. It is the only synthetic material remaining patent at long term. Shortly after its implantation it becomes re-epithelialized with autogenous endothelial cells in humans, and its surgical implantation is associated with a negligible rate of complications. They do not require preclotting, do not leak, are potentially easier to thrombectomize than vein grafts or Dacron conduits if graft thrombosis occurs, are more resistant to infection, have less platelet deposition and less thrombogenicity of the flow surface compared with Dacron grafts, and cause substantially less complement activation and therefore less leukocyte infiltration and release of inflammatory mediators.35 We have used cadaveric ABOincompatible arterial homografts to revascularize the SVC in patients with SVCO due to malignancies. Their advantages are the lack of infection risks, no need for postoperative anticoagulation, and long-term patency. This approach is still in an evaluation phase and is not yet recommended for routine use. Whichever method is used, the overall goals are to relieve symptoms, minimize the risk of complications (e.g., infection, central nervous system sequelae, and upper respiratory edema and stridor), and ensure long-term patency of the SVC, which is usually achievable by providing a high-flow (750-2000 mL/min) conduit for venous return from the upper body, and, whenever possible, performing an anatomic reconstruction, thereby avoiding the need for perioperative and postoperative anticoagulants.

prevents the systemic hypotension that occurs when the clamping of a patent SVC reduces the arteriovenous gradient in the cerebral territory, provides immediate relief of upper body venous hypertension and congestion (resulting in early extubation and a short, smooth postoperative course), and, finally, prevents neurologic complications.

Prevention of the SVC Cross-Clamping Effects

Anticoagulation Therapy

In patients with type I and II SVCO, intraoperative clamping of less than 50% of the circumference of the SVC is usually not associated with a significant hemodynamic imbalance. An intraoperative total clamping is relatively well tolerated for around 35 minutes32,36 but longer periods of clamping of the return venous flow can result in potentially fatal cerebral edema or postoperative neurologic deficits. In such cases, several maneuvers are available to minimize the hemodynamic compromise.

Like other venous replacements, intravenous (IV) sodium heparin (0.5-1 mg/kg) is given before clamping.

Shunt Procedures Placement of an intraluminal or extraluminal shunt between the right internal jugular vein or brachicephalic trunk and the right atrium establishes continuous venous return to the right atrium, eliminates the time constraints posed by cross-clamping of the SVC, facilitates complete repair or reconstruction,

Ch139-F06861.indd 1692

Cardiovascular Management Clamping of the SVC leads to cranial venous hypertension and systemic hypotension owing to an impaired venous return. This reduces cerebral blood flow with possible adverse neurologic consequences. Thus, measures for neuroprotection include the administration of corticosteroids about 30 minutes before clamping and optimization of circulatory parameters during clamping by fluid administration and regulation of mean arterial pressure (MAP) with norepinephrine. To keep cerebral perfusion pressure above 60 mm Hg, MAP is increased at least to 60 mm Hg above jugular bulb pressure (e.g., MAP of 110 mm Hg is achieved if jugular bulb pressure rises to 50 mm Hg). Five-lead ECG is used to detect myocardial ischemia, and cardiac output is kept in a normal range with infusion of crystalloids or colloids or, in case of failure, with epinephrine. The goal is to maintain jugular bulb oxygen saturation above 50%. The patient is moderately hyperventilated to decrease cerebral blood volume. MAP and extent of hyperventilation can be adjusted according to jugular bulb blood gas values.

Shortening the Venous Clamping Time This target can be obtained through a planned surgical strategy. For right NSCLC with carinal or proximal pulmonary artery invasion, it is often easier to perform the vascular step first and then the airway procedure. During the latter, all attention is directed to avoiding bacterial contamination of the prosthesis. For mediastinal tumors involving both upper lobes, operation is made from the left to the right side. This permits a safe and immediate revascularization between the left innominate vein and the right atrium; the remaining excision is then performed.

Types of Prosthetic SVC Reconstruction Trunk Replacement (Fig. 139-6) Trunk replacement requires disease-free confluence of both innominate veins. This procedure, made for malignancies, employs a straight unringed PTFE graft (No. 18 or 20) because the proximal and distal SVC stumps are usually healthy. After proximal (innominate veins confluence) and distal (cavoatrial junction) clamping, the invaded segment of the vein is completely excised. The proximal anastomosis between the SVC stump and the prosthesis is then performed first using a continuous 5-0 polypropylene suture started at the posterior aspect of the prosthesis in an inside to outside fashion. After its completion, the distal anastomosis is then performed in

1/21/2008 4:15:59 PM

Chapter 139 Superior Vena Cava Obstruction

FIGURE 139-6 Trunk SVC revascularization using an unringed synthetic, nontextile polytetrafluoroethylene vascular graft.

1693

FIGURE 139-7 Revascularization between the left innominate vein and the right atrium using a ringed synthetic, nontextile polytetrafluoroethylene vascular graft.

the same way. Before tightening the stretches of the distal suture, the proximal clamp is released and the prosthesis is flushed with heparinized saline solution and extensively deaired. The distal clamp is then released, and the knots are tied. To avoid kinking of the prosthesis, the length of the graft is adapted so that the distal anastomosis rests under tension. At the end of the surgical procedures, the graft is encircled with a vascularized pedicle of parietal pleura.

Revascularization From the Left Innominate Vein (Fig. 139-7) This procedure, always performed through a median sternotomy, requires a ringed PTFE graft (No. 12 or 13). The ringed graft is imperative because after closure of the median sternotomy, the prosthesis may be too long, thus inducing its kinking. Minimal dissection of the left innominate vein is also mandatory to avoid its rotation above the proximal anastomosis. Although the distal anastomosis can be performed either on the right atrium or appendage or on the inferior stump of the SVC, it is preferably performed on the right atrium because of the absence of the pectinate muscles lining the right appendage.

Revascularization From the Right Innominate Vein (Fig. 139-8) Ringed grafts are preferred (No. 12 or 14) to maintain their patency and to avoid their compression by the postoperative fibrosclerosis. The risks of kinking are minimal because the direction of the graft is almost vertical. The proximal ana-

Ch139-F06861.indd 1693

FIGURE 139-8 Revascularization between the right innominate vein and the right atrium using a ringed synthetic, nontextile polytetrafluoroethylene vascular graft.

1/21/2008 4:15:59 PM

1694

Section 7 Mediastinum

stomosis is not always easy to perform because the residual stump of the right innominate vein is often short; it has to be performed first. The distal anastomosis is made on the SVC stump. This architecture results in the straightest and shortest graft and represents the revascularization of choice for mediastinal tumors involving the origin of the SVC.

Revascularization of Both Innominate Veins (Fig. 139-9) This technique is not performed because the blood flow through each graft is lower than that observable after single revascularization.

Postoperative Care Postoperatively, hemodynamics and pulmonary status are monitored closely. The administration of maintenance fluids and blood products is minimized to prevent pulmonary edema, especially in patients requiring pneumonectomy. The head and upper body are elevated to reduce the risk of SVC syndrome by providing a hemodynamic advantage for upper body blood return. IV sodium heparin is continued at a daily dose of 1 to 2 mg/kg as soon as bleeding is controlled to reduce the risk of graft thrombosis and switched to warfarin agents or aspirin at the time of hospital discharge.

Complications of SVC Reconstruction With appropriate patient selection, significant early morbidity and mortality after resection and reconstruction of the SVC can be minimized, but careful vigilance to the intraoperative conduit is paramount.

Graft Anastomosis SVC revascularization requires a perfect technical performance, and a postoperative CT-angiographic control is routinely obtained to correct eventual anastomotic technical failures. Because the vein usually incorporates the graft on its entire transverse diameter, a stenosis at the level of the proximal anastomosis is almost impossible to observe. By contrast, an anastomotic stenosis is more commonly related to an intraoperative excessive dissection of the vein proximal to the anastomosis, which might kink, rotate, or become involved by fibrotic tissue after performance of the prosthetic-venous anastomosis. When excessive venous length or rotation is diagnosed postoperatively, surgical correction is advised. By contrast, a stenosis induced by a fibrosis may be corrected with angioplastic dilation or stent placement.

Graft Thrombosis Most often this is an early postoperative complication associated either with the mechanical obstruction to the flow through the graft or with an inappropriate indication (implantation on a recanalized vein with major pathologic venous wall sequelae, insufficient proximal vein bed, or a chronic SVC syndrome with a very developed venous collateral circulation). The major consequences of graft thrombosis are an acute clinical SVC syndrome leading to reversible brain damage and/or passage and lodgment of thrombotic clot(s) into the pulmonary circulation.

Graft Infection Graft infection is a serious risk inherent in all prosthetic vascular replacements and more likely to develop when the airway is opened, when a bronchial suture and lung parenchymal resection is done, and when surgery is performed after induction chemoradiation therapy. Infection can manifest as a mediastinitis, a thoracic empyema, or septicemia, as in infected thrombophlebitis. Treatment depends on the presence or absence of a systemic septicemia. In the absence of severe septic syndrome, the prosthesis might be conserved by using an omentoplasty covering the graft. However, septicemia and/or severe septic syndrome necessitates graft excision, which may be poorly tolerated in patent grafts.

PROGNOSIS

FIGURE 139-9 Revascularization of both innominate veins with polytetrafluoroethylene grafts implanted independently on the right atrium.

Ch139-F06861.indd 1694

Prognosis of SVCO depends on its underlying cause and histology,25 with the average survival of untreated SVCO patients being only 6 weeks.37 Overall, in patients with NSCLC the median survival with SVCO is 6 months and the overall survival at 1 year is 35% for NSCLC and 18% for SCLC.38 In patients with operable NSCLC, a retrospective, multicenter study reported an overall 5-year survival of 15% (median of 9 months), with survival significantly worse in patients requiring partial SVC resection, with procedures less than a pneumonectomy, in patients with N2 disease, and in patients having a neoadjuvant treatment.28 Similarly, poor results were reported in another retrospective study over a 20-year period in which the 5-year survival rate was 24%, and prognosis was better for patients whose SVC invasion was due to the tumor

1/21/2008 4:16:01 PM

Chapter 139 Superior Vena Cava Obstruction

and not the lymph nodes (36% versus 7%, respectively).39 In both reports, in-hospital mortality was between 10% and 15%. These studies, although retrospective, clearly show that surgical resection of NSCLC is restricted to patients without lymph node involvement and not requiring a pneumonectomy. By contrast, surgery for SVCO due to mediastinal tumors is associated with long-term survival and patency.40 Surgical treatment of benign SVCO is effective over the long term, with secondary endovascular interventions to maintain graft patency. Straight vein grafts remain the conduit of choice for surgical reconstruction, with results superior to bifurcated vein and PTFE grafts (Karla et al, 2003).16 Endovascular treatment is effective in the short term, with frequent need for repeat interventions. It does not adversely affect future open surgical reconstruction and may prove to be a reasonable primary therapeutic intervention in selected patients with suitable anatomy. Patients who are not suitable for or who fail endovascular intervention merit open surgical reconstruction.

SUMMARY The management of SVCO depends on both the acuity and etiology. Options for treating SVCO due to malignant disease include medical therapy with diuretics, corticosteroids, and head elevation followed by chemotherapy or radiation therapy depending on the type of tumor. However, endovascular procedures with angioplasty and stent placement are indicated in SVCO patients with moderate to severe or rapidly worsening symptoms, those who have failed to respond to (or whose disease recurred after) radiation therapy and/or chemotherapy, and those who have reached a dose limit of radiation therapy or chemotherapy. It is currently considered the mainstay of treatment in malignant SVCOs, where therapy is aimed at early relief of the symptoms of obstruction and improving the patients’ quality of life. The life expectancy in cases of malignant SVC syndrome is usually less than 6 months, and results from endovascular therapy have been durable in most cases. However, surgery for malignant SVCO may have a curative role in selected patients with operable anterior mediastinal tumors or in those rare patients whose right-sided NSCLCs invade the SVC directly, do not require a pneumonectomy to accomplish a complete tumor resection, and have minimal hemodynamic venous imbalance. Resection can be accomplished with either a primary defect closure or interposition of an autologous pericardial or venous patch in minimal SVC invasion or by complete replacement and revascularization in major invasion, using different materials, such as autologous pericardium, saphenous vein grafts, and synthetic materials. Unlike prosthetic materials, autologous pericardium and vein are easy to procure and prepare, involve no risk of infection, and do not necessitate anticoagulation therapy. Whichever method is used, the overall goals are to relieve symptoms, minimize the risk of complications (e.g., infection, central nervous system sequelae, and upper respiratory edema and stridor), and ensure long-term patency of the SVC, usually achievable by providing a high-flow (750-2000 mL/min) conduit for venous return from the upper body and, when-

Ch139-F06861.indd 1695

1695

ever possible, by performing an anatomic reconstruction, thereby avoiding the need for perioperative and postoperative anticoagulants. Of utmost importance, complete cross-clamping of the return venous flow for periods of longer than 35 minutes in unobstructed SVC results in potentially fatal cerebral edema or postoperative neurologic deficits, and several maneuvers including intraluminal or extraluminal shunts, adequate cardiovascular management, detailed surgical strategy, and anticoagulation therapy may prevent and reduce this specific morbidity. SVCO caused by nonmalignant disease is typically insidious in onset owing to the development of venous collaterals. Therapy is still aimed at the underlying etiology, and, in some cases, medical therapy with anticoagulation may provide relief. With progression of the SVCO, relief of the congestive symptoms can be accomplished by relieving the stenosis or compression, and this can be accomplished by surgically repairing, replacing, or bypassing an obstructed SVC. Surgery is still considered the first-line treatment for benign SVCO because it is effective over the long term with excellent patency rates, leaving secondary endovascular interventions eventually to maintain graft patency. The role of stenting in SVCO of benign etiology is undecided because its long-term durability remains to be assessed. However, given the increasing sophistication of endovascular techniques and devices, it is not unrealistic to speculate that this approach will gain wider acceptance in the near future, in both benign and malignant SVCOs.

COMMENTS AND CONTROVERSIES Superior vena cava obstruction presents a management dilemma for the thoracic surgeon. Diagnosis of the etiology of obstruction is key. As the author points out, biopsy material must be obtained from the most accessible site. It is important to remember that mediastinoscopy is safe in patients with SVCO. For malignant causes there is rarely a role for surgical intervention The exception to this general rule, of course, are those localized resectable tumors involving the vena cava, most commonly thymoma. Currently available stents provide symptomatic relief while appropriate chemotherapy and radiation protocols are administered. For SVCO of benign etiology, most commonly mediastinal fibrosis, reconstruction is warranted only in those patients who have not developed adequate collateral circulation. Before reconstruction, the surgeon must be assured that there are appropriate proximal and distal venous sites for graft placement. PTFE is the preferred conduit, although autologous or bovine pericardium is also acceptable as a replacement material. G. A. P.

KEY REFERENCES Dartevelle P, Chapelier AR, Pastorino U, et al: Long-term follow-up after prosthetic replacement of the superior vena cava combined with resection of mediastinal-pulmonary malignant tumors. J Thorac Cardiovasc Surg 102:259-265, 1991. ■ The authors discuss the routine employment of synthetic graft materials in patients with malignant superior vena cava due to mediastinal and bronchogenic tumors, with excellent long-term results.

1/21/2008 4:16:01 PM

1696

Section 7 Mediastinum

Doty DB: Bypass of superior vena cava: Six years experience with spiral vein graft for obstruction of superior vena cava due to benign and malignant disease. J Thorac Cardiovasc Surg 83:326, 1982. ■ This landmark paper reports for the first time on the excellent (>90%) long-term patency in superior vena cava obstruction of benign and malignant stenosis using autologous venous grafts. Hunter W: The history of an aneurysm of the aorta with some remarks on aneurysms in general. Med Obs Soc Phys Lond 1:323-357, 1757. ■ This paper is a report of the first description of a superior vena cava obstruction. Karla M, Gloviczki P, Andrews JC: Open surgical and endovascular treatment of superior vena cava syndrome caused by nonmalignant disease. J Vasc Surg 38:215-223, 2003.

Ch139-F06861.indd 1696

■ In this report the authors describe their clinical experience in benign superior vena

cava obstructions using endovascular treatments and open surgery, reinforcing the current superiority of the latter treatment option. Klassen KP, Andrews NC, Curtis GH: Diagnosis and treatment of superior vena cava obstruction. Arch Surg 63:311-325, 1951. ■ In this article the authors describe the successful first surgical bypass of a benign superior vena cava obstruction using autologous superficial femoral vein. McIntire FT, Sykes EM Jr: Obstruction of the superior vena cava: A review of the literature and report of two personal cases. Ann Intern Med 30:925-960, 1949. ■ In this paper the main collaterals of the superior vena cava are carefully and beautifully described.

1/21/2008 4:16:01 PM

Surgical Techniques chapter

140

THORACOSCOPIC MEDIASTINAL SURGERY Keith Naunheim

Key Points ■ The role of video-assisted thoracoscopic surgery (VATS) in the

diagnosis and treatment of mediastinal diseases has evolved during the past decade. ■ During the early portion of the past decade, VATS was used essentially for diagnostic purposes within the mediastinum. ■ With new techniques and operative strategies, VATS is now recognized not only as an invaluable diagnostic modality but also as a promising therapeutic alternative to the open approach and, in selected mediastinal entities, the standard of care.

The role of VATS in the diagnosis and treatment of mediastinal diseases has evolved during the past decade. When VATS was first introduced, it was used for the assessment of disease processes within the pleura and lungs. With advances in instrumentation, and increasing experience, practitioners found that they were also able to apply these minimally invasive techniques to disease processes within the mediastinum. During the early portion of the past decade, VATS was used essentially for diagnostic purposes within the mediastinum.1 However, as expertise developed and instrumentation evolved, surgeons began to perform truly therapeutic procedures within the mediastinum. With these new techniques and operative strategies, VATS is now recognized not only as an invaluable diagnostic modality but also a promising therapeutic alternative to the open approach and, in selected mediastinal entities, the standard of care.

MEDIASTINAL ANATOMY Many arbitrary divisions of the mediastinum have been proposed. The simplest and most commonly used description is one that divides the mediastinum into three compartments bounded anteriorly by the sternum, posteriorly by the spine, inferiorly by the diaphragm, and superiorly by the thoracic inlet. The anterior mediastinum is defined by the sternum anteriorly and pericardium posteriorly. It contains the thymus, innominate vein, aortic arch vessels, internal thoracic vessels, associated lymph nodes, connective tissue, and occasionally thyroid and parathyroid tissue. The middle mediastinum contains the pericardium, heart, great vessels, trachea and hilar bronchi, superior vena cava and proximal azygos vein, proximal esophagus, phrenic nerve, distal thoracic duct, paratracheal/subcarinal lymph nodes, and connective tissue.

The posterior mediastinum is defined anteriorly by the posterior pericardium and posteriorly by the spine. It contains the sympathetic chain, proximal intercostal nerves and vessels, distal esophagus, posterior paraesophageal lymph nodes, proximal thoracic duct, distal azygos vein, and connective tissue. Common tumors, cysts, and other pathologic processes of the mediastinum and their predominance in each compartment vary between adults and children. Anterior mediastinal tumors and thymic masses or lymphomas are more predominant in adults, whereas posterior mediastinal tumors and lymphomas or anterior mediastinal tumors and germ cell neoplasms predominate in children.

OPERATIVE TECHNIQUE: GENERAL CONSIDERATIONS Thoracoscopic mediastinal surgery requires a quiet and clear operative field without infringement by the lungs. Thus, single-lung ventilation using a double-lumen endotracheal tube is relatively standard. The choice for using a left- or right-sided approach depends not only on the mediastinal entity’s location but also, to a relative extent, on surgeon’s preference. Preoperative imaging studies are imperative to determine the accessibility of the lesion and to prepare the surgeon for anatomic structures that can make the approach more complex or potentially increase the morbidity of the procedure. These studies need to be available in the operating room at the time of the procedure. Preoperative computed tomography (CT) or magnetic resonance imaging (MRI) can indicate whether a mediastinal entity extends to the left or the right and therefore help determine which side will provide better operative access to the lesion. Once the operative site has been determined, the patient is placed into the appropriate lateral decubitus position. Overextending the midportion of the chest wall may optimize the accessibility to the operative field by opening up the intercostal spaces and thus providing the potential for superior manipulation of the thoracoscopic instruments with a lesser chance of injury to the intercostal nerves and vessels. Avoid excessive torque of the manipulating instruments against the intercostal neurovascular structures. After initiating single-lung ventilation, the appropriate operative field exposure can be obtained and the area of interest made accessible using positional changes. Rotating the operative table side to side, in Trendelenburg or reverse Trendelenburg position, can be helpful in retracting the lung away from the area of interest in the anterior, middle, or posterior mediastinum. Some surgeons occasionally place the 1697

Ch140-F06861.indd 1697

1/21/2008 4:16:51 PM

1698

Section 7 Mediastinum

patient in a supine position for surgery of anterior mediastinal lesions. This can allow a simultaneous bilateral approach. For posterior mediastinal lesions, some surgeons have used a prone approach, once again allowing bilateral visualization and manipulation. Positioning of the trocar sites can be highly variable and is ideally dependent on the location of the operative lesion. A 0- to 30-degree thoracoscope is ideally placed 15 to 20 cm from the area of interest, often in the midaxillary line. This distance from the operative lesion will allow both for a panoramic viewing and for close-ups when the scope is advanced. Insert the thoracoscope in the same direction that the operating surgeon is looking so that the view is a true one and not a mirror image, which will occur if the scope is placed in a direction opposite to that which the surgeon is standing. It is important to remember that the thoracoscope can be interchanged between different ports as necessary to optimize the operative exposure or viewing. The number and the orientation relative to the thoracoscope of the remaining ports are all determined by the need for additional instruments, the complexity of the operative approach, and the surgeon’s dexterity. Apply the so-called baseball diamond concept for the configuration of the port placement. This implies that the thoracoscope is placed at home plate and that the working ports are placed at the positions of first and third base with the area to be worked on in the second base position. Allow approximately 10 cm between the working ports and the thoracoscope, at any time, for bimanual manipulation of the working instruments (Fig. 140-1). The role of so-called utility thoracotomy (4- to 6-cm incision, often, between the anterior axillary line and the sternum in the same intercostal space that would be used for a thoracotomy if necessary) cannot be overemphasized, especially for lesions in the anterior mediastinum. It is performed anteriorly because the interspaces are wider and there is no bulky musculature to be incised. In female patients, an incision along the inframammary fold can be considered for better cosmetic result. The utility thoracotomy not only permits space for retrieval of a larger specimen but also allows insertion of conventional instruments when necessary. This incision is not mandated in every case but can be a useful adjunct, especially when bulky lesions are approached. If CO2 gas insufflation is considered as an adjunct to singlelung ventilation, limit it to no more than 10 mm Hg at 3 L/min. Higher pressure at the same or higher gas flow can have a deleterious effect on venous return, with the potential for hemodynamic compromise. The thoracoscopic approach to the right mediastinum is similar to that for the left mediastinum, but the access sites may be slightly altered if assessment of the aortopulmonary window is required. Handling the specimen after a diagnostic or a therapeutic thoracoscopic intervention demands some attention. If the benignity of the specimen is in question, use an endoscopic specimen bag for extraction of the lesion. This will help prevent seeding at the trocar sites if the lesion proves to be neoplastic. Occasionally, the size of the retrieving port must be enlarged or a utility thoracotomy can be made, especially for a larger specimen.

Ch140-F06861.indd 1698

Second base

Third base

First base

Home base

FIGURE 140-1 Baseball diamond strategy for trocar placement in thoracoscopy dictates that the target to be operated on rest at second base. The trocar for the viewing scope should be at home plate and ideally is 8 inches or more from the target. Trocars for placement of instrumentation for the right and left hands are placed at first base and third base, respectively. Ideally these instrumentation trocars would each be placed 4 to 6 inches away from the visualization trocar to minimize fencing, that is, the collision/ interference between instruments and scope that occurs frequently if the trocar sites are placed in close proximity.

Not all mediastinal lesions can or should be approached thoracoscopically. The evolution of the thoracoscopic instruments and scopes as well as the increasing expertise of practitioners have substantially increased the number of mediastinal entities amenable to a VATS approach. The potential advantages include decreased morbidity, shorter hospital stay, and superior cosmetic results. In the prospective nonrandomized study by Chetty and colleagues,2 the patients who underwent thoracoscopic resection of mediastinal tumor had similar operating time and duration of chest tube drainage compared with the open approach but enjoyed lower levels of pain and shorter hospital stay. There continue to be, however, limitations to the thoracoscopic approach. Perhaps the greatest risk is the steeper learning curve associated with this type of minimally invasive surgery. Operative times are not infrequently longer with the thoracoscopic approach. Specific limitations include the patient’s inability to tolerate single-lung ventilation, lesions larger than 4 cm (which make dissection and extraction difficult), dense adhesions to the surrounding structures or vital organs, tumor invasion of surrounding structures and limited working space (especially for anterior mediastinal pathologies). It is imperative for the surgeon to remember that conversion to an open approach is not a sign of weakness but rather, in most cases, indicative of good judgment. In a retrospective multi-institutional study by Demmy and coworkers,3 the conversion rate to open thoracotomy was overall

1/21/2008 4:16:51 PM

Chapter 140 Thoracoscopic Mediastinal Surgery

3.5%, but it has been reported as high as 12.3% (Cirino et al, 2000).4

ANTERIOR MEDIASTINAL COMPARTMENT Thymic lesions represent over 40% of the anterior mediastinal masses in adults, followed by lymphomas and germ cell tumors. In children, germ cell tumors and lymphomas predominate (Kelemen and Naunheim, 2000).5

Diagnosis Anterior mediastinal masses most often require that a histologic diagnosis be obtained before the institution of therapy. In specific cases (e.g., anterior mediastinal mass with elevated β-human chorionic gonadotropin and α-fetoprotein), treatment can be instituted without the need for biopsy. However, in the majority of patients, tissue diagnosis is required before therapeutic intervention. CT-guided fine-needle aspiration occasionally provides diagnostic cytology. Many lesions, especially lymphomas, require the acquisition of a piece of tissue for histologic analysis. Those lesions accessible via cervical mediastinoscopy are approached in this fashion because this procedure requires a small incision with no need for violation of the pleural cavity. This obviates the need for single-lung ventilation and chest tube placement. Cervical mediastinoscopy currently is a simple outpatient procedure that is less invasive than thoracoscopy. Anterior mediastinal lesions or para-aortic lymph nodes not accessible to mediastinoscopy can be sampled via either an anterior mediastinotomy (Chamberlain procedure) approach or thoracoscopy.6 Both approaches have the disadvantage of the potential for malignant seeding of the pleural cavity or subcutaneous tissues. For those patients with a mediastinal mass in whom concomitant pleural or pulmonary lesions coexist and require investigation, thoracoscopy is a superior approach that allows the simultaneous inspection and biopsy of the lung, pleural surface, and mediastinum.

Therapy Potential therapeutic indications of VATS in the anterior mediastinum are summarized in Table 140-1. For most thoracic surgeons, therapeutic VATS for anterior mediastinal lesions is applied only for benign entities. The presence of a known malignancy is generally believed by most to be a contraindication to the thoracoscopic approach. However, with emerging technology and the increasing experience of the operating surgeon, there are some experienced thoracoscopic surgeons who disagree with this statement. The majority of thoracic surgeons use an open approach once malignancy has been identified with certainty. Potential tumor seeding of the trocar sites and surrounding tissues with malignant cells and inadequate resection of malignant tumors militates against the thoracoscopic approach or calls for conversion to an open approach. Thoracoscopy has been used for the excision of intrathoracic ectopic parathyroid adenomas not accessible from the neck (∼2% of cases). Preoperative localization is mandatory

Ch140-F06861.indd 1699

1699

TABLE 140-1 Anterior Mediastinum and Therapeutic VATS Applications Myasthenia gravis Thymic neoplasms/cysts Paratracheal cysts Germ cell tumors (benign teratomas)/teratomatous cysts Substernal thyroid tissue Parathyroid adenomas/cysts Mesenchymal tumors/cysts Vascular masses Connective tissue tumors VATS, video-assisted thoracoscopic surgery.

because such lesions may be difficult to locate in the parathymic fat.7 Adenomas smaller than 1 g are difficult to identify intraoperatively without prior localization. Preoperative 99m Tc-sestamibi scanning offers a localization rate as high as 100% for adenomas greater than 2 g to as low as 86% for those less than 1 g (Medrano et al, 2000).8 The strategic value of a combination of preoperative imaging, intraoperative monitoring of intact parathyroid hormone, and intraoperative 99m Tc-sestamibi scanning navigation has been advocated for a successful and expeditious thoracoscopic parathyroid adenoma excision.9-14 Cystic lesions within the thymus or parathyroids can also be excised in this fashion. Controversy remains regarding the issue of resection of anterior mediastinal tumors, which are believed to be benign, such as small thymomas or benign teratomas. Several authors have advocated a thoracoscopic approach to such lesions, citing decreased morbidity and length of hospital stay, improved cosmesis, and optimal exposure. The feasibility of a VATS approach has been demonstrated by a number of authors (Mack, 2001; Yim et al, 1999),15-23 but long-term follow-up on a significant number of patients is not available to demonstrate the safety of this approach. Such procedures need to be undertaken only by an experienced thoracoscopic surgeon who will participate in careful postoperative surveillance. Once again, any clinical or radiologic indication that an anterior tumor is malignant constitutes, at present, a contraindication to the thoracoscopic approach for most of the thoracic community. The optimal operative approach for thymectomy in the treatment of myasthenia gravis in patients without thymoma has been a controversial issue for many years. Both the sternotomy and cervical approaches have been claimed to be optimal by different investigators with different degrees of radicalism suggested regarding resection. The addition of thoracoscopic thymectomy as an alternative surgical approach has done nothing to clarify this controversy. The feasibility of the VATS approach was demonstrated long ago by Mack and Scruggs,17 Yim and associates,18 and Mineo and coworkers.16 Thoracoscopic thymectomy has been described via a leftsided,16 right-sided (Mack, 2001; Yim et al, 1999),18,20 combined transcervical and bilateral,24 combined subxiphoidal and bilateral,23 or combined transcervical/subxiphoidal/right VATS approach.25

1/21/2008 4:16:51 PM

1700

Section 7 Mediastinum

Advocates of the right-sided approach (four-port technique) claim that it allows greater maneuverability within the right pleural cavity with easier identification of the innominate vein because the superior vena cava (SVC) serves as a landmark. The proponents of the left-sided approach (fourport technique) advocate that it provides superior maneuverability and safer dissection because the SVC lies outside the operative field and, furthermore, that extensive removal of the ectopic thymic tissue, particularly from the left pericardiophrenic angle and the aortopulmonary window, is feasible and complete. Proponents of the combined approaches emphasize the superior exposure and extended nature of the dissection. Although the VATS approach is reported to yield less postoperative pain, decreased incidence of perioperative exacerbation of myasthenia, less postoperative pulmonary dysfunction, and better aesthetic outcome, this has been documented in only few instances. Ruckert and colleagues,26 in their prospective randomized study, reported immediate postoperative lung function reduction by 35% after a VATS approach and 65% after a median sternotomy approach. By the third postoperative day, recovery of pulmonary function was complete after thoracoscopic thymectomy and only 55% of baseline after median sternotomy despite the fact that the latter group was maintained on continuous pain administration for 4 days longer. In addition, in experienced hands the reported conversion rate can be as low as 2.6%.21 Finally, Ruckert and associates (Ruckert et al, 2003)27 used a matchedpair prospective comparison of a median sternotomy, anterolateral thoracotomy, and VATS approach for thymectomy in patients with nonthymomatous myasthenia gravis. They demonstrated a statistically significant difference in the overall postoperative morbidity among the groups, with superiority of the VATS approach. There was no difference in mortality or in the frequency of complete remission after 5 years of follow-up. On the other hand, the VATS approach clearly has a steeper learning curve and requires significant advanced thoracoscopic experience; additionally, extended thymectomy is problematic and superiority to standard approaches is yet to be proven. The primary advantage of VATS thymectomy over the alternative approaches appears at this point to be aesthetic because low morbidity, short hospital stay, and minimal analgesic requirements have been reported with these alternative approaches. Continued follow-up is required to ensure long-term efficacy. The use of a VATS approach for thymic neoplasms remains a matter of debate. Advocates of thoracoscopy for Masaoka stage I thymoma (Mack, 2001)19,20,28,29 reported wide local excision of thymic tissue and use of an endoscopic retrieval bag for fully encapsulated thymomas that were sufficiently surrounded by thymic parenchyma. In these series, there was no conversion to an open approach and one recurrence at up to 75 months of follow-up.19 Takeo and colleagues29 used a sternal lifting apparatus to increase the space for operative dissection and suggest that a thoracoscopic extended thymectomy is feasible even for Masaoka stage II and some stage III thymomas. Even in Masaoka stage I fully encapsulated thymomas, the confirmation of whether it really is encapsulated

Ch140-F06861.indd 1700

depends on the pathologist’s expertise. For the vast majority of thoracic surgeons an open approach for all thymomas remains the standard of care. Because the recurrence rate for invasive thymomas appears to be directly related to their complete resectability during the initial excision, the safest approach for most surgeons will be an open one. Cystic lesions within the thymus or adjacent to the pericardium (the so-called springwater cysts) can also be excised safely using thoracoscopy.30 However, it must be remembered that malignant tumors rarely do arise from these cysts.31 Mesenchymal cysts are amenable to VATS. Indications for resection include the presence of symptoms, radiologic evidence of compression of SVC, uncertain diagnosis, or interval increase in size. Nearly 40% are located elsewhere than the pericardiophrenic angle (Mouroux et al, 2003).32 Paratracheal cysts can be approached via cervical mediastinoscopy.33 Although there are reported small series or anecdotal reports for VATS resection of benign teratomas and other germ cell tumors,3,19,34-36 significant controversy exists regarding the applicability of minimally invasive approach for resection of these mediastinal entities.

MIDDLE MEDIASTINAL COMPARTMENT Diagnosis Cervical mediastinoscopy is the time-tested standard approach for the middle mediastinum. VATS has been used for lymph node staging in patients with lung cancer (Massone et al, 2003).37-42 Although nodes at levels II, III, IV, and VII are accessible either via cervical mediastinoscopy or via thoracoscopic approach, cervical mediastinoscopy is generally the preferred approach. It is an outpatient procedure requiring no single-lung ventilation, results in no intercostal pain, and allows access to bilateral paratracheal nodes. However, lymph nodes at levels V and VI that require investigation can be approached either with anterior mediastinotomy (Chamberlain procedure) or with thoracoscopy. The theoretical advantage of a thoracoscopic approach is that one can simultaneously assess for pleural involvement, the presence of pleural effusion, and the involvement or invasion of surrounding structures by a primary lung cancer. Massone and colleagues (2003)41 evaluated the impact of VATS in the diagnosis of clinical (>1 cm in CT scan) mediastinal lymphadenopathies in levels V, VI, and VII. They reported that 60% of enlarged lymph nodes were metastatic, leading to a stage III diagnosis. Only 24% of the tumors were deemed resectable. More than 50% of enlarged nodes without concomitant lung lesions were lymphomas. Sebastian-Quetglas and colleagues40 in their prospective study for preoperative staging in non–small cell lung carcinoma concluded that VATS can be useful for staging T3, T4, and Tx as well as levels IV to IX N2 lymph nodes. Other authors37,39 reported that preoperative imaging results in 27% of primary lung carcinomas being overstaged and 18.9% being understaged. Furthermore, 20% of the centrally located T4 tumors deemed unresectable by preoperative CT were found to be resectable by exploratory VATS, whereas 20% of tumors deemed resectable by preoperative CT were found to be unresectable by

1/21/2008 4:16:51 PM

Chapter 140 Thoracoscopic Mediastinal Surgery

VATS. It was concluded that VATS staging was superior to imaging techniques when detecting tumor extension in the pericardium and to establish resectability of centrally located T4 tumors with pericardial invasion. The staging of esophageal cancer via combined thoracoscopic and laparoscopic approach is feasible and accurate (92%43; 94%44), but with broader application of positron emission tomography (PET) for preoperative staging the indications for thoracoscopic and laparoscopic staging seem to have been lessened. This combined nodal staging approach entails additional expense and inconvenience and is somewhat invasive, requiring indwelling chest tubes and hospital stay for a minimum of 2 days. At present, combined laparoscopic and thoracoscopic staging has only a limited role in specific protocols.

Therapy Potential therapeutic indications for VATS for entities in the middle mediastinum are summarized in Table 140-2. The most common lesion in the middle mediastinum compartment that can be managed thoracoscopically is a bronchogenic cyst. Mediastinal cysts represent 18% to 25% of all primary mediastinal masses. Foregut cysts (bronchogenic, esophageal, neuroenteric) are most common and more frequently found in the middle (especially, bronchogenic cysts) and posterior mediastinum.45,46 Most of the mediastinal cysts are asymptomatic and are incidental findings on routine radiologic examinations. Expectant management with interval CT can be undertaken in young asymptomatic patients with small foregut cysts. If the diagnosis is uncertain, if there is an interval increase in size and radiologic attenuation, or if cysts become symptomatic or infected, then surgical resection is warranted. Thoracoscopic excision of bronchogenic cysts represents an attractive, safe therapeutic approach (Kitami et al, 2004).30,46-51 Improved visualization with controlled decompression of the cyst before excision has been recommended by using intraoperative controlled aspiration technique with a Veress needle47 or double-lumen cannula/balloon.52 When it is difficult or potentially dangerous to dissect the cyst safely from adjacent vital structures, then partial excision or subtotal excision of the cyst is appropriate. Any remaining epitheTABLE 140-2 Middle Mediastinum and Therapeutic VATS Applications Tracheal tumors/cysts Foregut cysts Mesothelial tumors/cysts Metastatic lymphadenopathy Pericardial cysts

1701

lial mucosal lining can be cauterized using either standard electrocautery or argon-beam coagulation (Lin et al, 2000).47,53,54 Kitami and colleagues (2004)51 have suggested that cystic lymphangiomas and thoracic duct cysts should not be approached by VATS owing to their high risk for postoperative chylothorax and high likelihood for recurrence after incomplete resection. Such lesions are resected via an open approach and the thoracic duct ligated concomitantly. Pericardial cysts are usually located in the right pericardiophrenic angle (70%) and, unlike bronchogenic cysts that carry risk for infection or malignant transformation, follow a benign course; VATS excision is recommended only in symptomatic patients or when the diagnosis is not certain.55 Any cyst in which the possibility of concomitant malignancy exists is approached via an open approach rather than by thoracoscopy. Pericardial effusion drainage is technically feasible via VATS approach, but often a subxiphoid approach remains more expeditious. The subxiphoid approach does not require single-lung ventilation or placement of intercostal drainage tubes. It can be performed safely in hemodynamically compromised patients with the use of sedation and local anesthesia. Thoracoscopic pericardiectomy is particularly useful in patients with recurrent or loculated effusions or in those patients who require pericardial drainage and have concomitant pulmonary or pleural pathology that requires concomitant investigation or treatment (i.e., malignant pleural effusion).56

POSTERIOR MEDIASTINUM AND VIDEOASSISTED THORACOSCOPIC SURGERY In adults, the majority of the masses found in the posterior mediastinum are benign. The likelihood of malignancy appears to be greater with decreasing or very advanced age, with lymphomas being fairly common. More than 50% of the mediastinal tumors in children are located in this compartment (Kelemen and Naunheim, 2000).5

Diagnosis Posterior mediastinal masses are easily accessible via CTguided needle biopsy or via endoscopic ultrasound investigation using transesophageal fine-needle aspiration. Compared with the prior two modalities, the thoracoscopic approach for diagnosis alone is less favorable, owing to its more invasive nature. Prior to the wide application of endoscopic ultrasound, VATS was touted as being particularly useful for lymphadenopathy otherwise inaccessible to noninvasive approaches such as mediastinoscopy. Lymph nodes at levels VIII, IX, and X were easily identified using a thoracoscopic approach. However, the evolution of endoscopic ultrasonography with fine-needle aspiration has made the VATS approach unnecessary in the vast majority of cases.

Castleman’s disease Connective tissue tumors Vascular masses VATS, video-assisted thoracoscopic surgery.

Ch140-F06861.indd 1701

Therapy Potential therapeutic indications of VATS for entities in the posterior mediastinum are summarized in Table 140-3. The mainstay of therapy for the posterior mediastinal neoplasms

1/21/2008 4:16:51 PM

1702

Section 7 Mediastinum

TABLE 140-3 Posterior Mediastinum and Therapeutic VATS Applications Neurogenic tumors Sympathetic chain–associated conditions (palmar/axillary hyperhidrosis—vascular disorders) Foregut cysts Mesenchymal tumors/cysts Thoracic duct cysts/lymphangiomas/refractory chylothorax Neuroendocrine tumors Angiomyolipoma/connective tissue tumors Extramedullary hematopoietic masses Esophageal stromal tumors Esophageal and epiphrenic diverticula Paraesophageal hernias Esophageal dysmotility disorders Esophago-/tracheal-/bronchial congenital fistulas Iatrogenic esophageal perforation Esophageal carcinoma Truncal vagotomy Castleman’s disease VATS, video-assisted thoracoscopic surgery.

is resection, and VATS is often the preferred approach. Large size, location at the extremes of the hemithorax, proximity to vital structures, and/or likelihood of malignancy are all relative contraindications to a thoracoscopic approach. Neurogenic tumors extending through vertebral foramina or into the intradural space (so-called dumbbell tumors), neuroendocrine tumors (pheochromocytoma and ganglioneuroblastoma), and large infected cysts should not be approached thoracoscopically as well. An appropriate diagnostic workup often includes chest CT with and without contrast medium enhancement, MRI (to assess potential intraforaminal involvement), and PET. Occasionally, endoscopic ultrasonography and/or selective angiography can be used either to obtain tissue or to identify vascular supply. Any suggestion of a neurogenic tumor with vasoactive component necessitates catecholamine assays and, potentially, scanning with metaiodobenzylguanidine (MIBG). The thoracoscope typically is inserted in the midaxillary line between the sixth and seventh intercostal spaces, and the working ports are placed appropriately to create the best convergence on the mass based on the triangular configuration concept. A utility thoracotomy is, occasionally, necessary. For cystic posterior mediastinal masses, improved visualization with controlled decompression of the cyst before excision has been recommended by using intraoperative controlled aspiration technique with a Veress needle47 or a double-lumen cannula/balloon.52 Again, when it is difficult or potentially dangerous for the cyst to be dissected safely away from adjacent vital

Ch140-F06861.indd 1702

structures, then partial or subtotal excision is appropriate. Any remaining epithelial mucosal lining can be cauterized using either standard electrocautery or argon beam coagulation (Lin et al, 2000).47,53,54 Neurogenic tumors are ideal lesions for a VATS approach because they are nearly all benign. They generally have a relatively sparse vasculature as well. The frequency of malignancy is reported from 1.7% to 14% (Yamaguchi et al, 2004).57 They can be complex, and up to 10% extend through the spinal foramina into the intradural space. These dumbbell neurogenic tumors must be identified preoperatively by highresolution CT or MRI. If such an extension is identified, there is a risk for intraoperative avulsion of the tumor from its intraforaminal extension, leading to intraspinal hemorrhage and cord compression with severe neurologic sequelae. Thus, such dumbbell tumors are generally best managed with a team approach, with thoracic surgeon and neurosurgeon working together. A combined neurosurgical and thoracoscopic approach has been reported by multiple authors (Negri et al, 2001; Venissac et al, 2004).58-63 Thoracoscopic excision of simple neurogenic tumors has become a favored approach with minimal morbidity, shorter length of hospitalization, and substantially faster recovery (Bousamra et al, 1996).64-66 However, some contraindications still exist for posterior mediastinal tumors. Evidence of malignancy is a strong indication for an open approach. Similarly, an extremely large tumor (>6 cm), especially located in the apex, makes thoracoscopy quite difficult and is a relative indication for conversion to an open approach (Kitami et al, 2004; Venissac et al, 2004).51,63,67 One of the rare but feared complications of VATS resection of neurogenic tumors located in the paravertebral sulci (especially from T5-T12) is injury of the segmental arteries supplying the anterior spinal system. To address this issue, Pons and colleagues68 recommended preoperative selective angiography of the referred intercostal arteries and routine use of harmonic scalpel for the dissection. Benign esophageal entities are often amenable to thoracoscopic approach. Esophageal gastrointestinal stromal tumors (GISTs) are infrequent but usually manifest as submucosal masses in the lower third of the esophagus. The presenting symptom is usually dysphagia. Often, the diagnosis is suspected owing to the presenting symptoms and radiographic findings of submucosal mass on CT, MRI, or endoscopic ultrasonography. Unless there is an interval increase in size, significant symptoms, or a complicated course, the mere presence of a GIST is not an absolute indication for intervention. Thoracoscopic resection of GISTs has been reported with favorable outcome, short recovery time, and minimal morbidity (Samphire et al, 2003).69-74 The esophagus can be approached via the left side for a lower-third GIST, but upper or middle esophageal lesions must be approached from the right side of the thorax. An esophageal bougie dilator can be used to make the tumor more prominent, and it has been suggested that this may make the dissection somewhat easier. Although closure of the remaining musculature over the exposed submucosa is not an absolute necessity, it is encouraged to avoid the possible development of pseudodiverticulum.75 After resection, insufflation of air into the esophagus

1/21/2008 4:16:51 PM

Chapter 140 Thoracoscopic Mediastinal Surgery

while submerging the mucosa under saline is suggested to identify any occult mucosal tears (Kelemen and Naunheim, 2000).5 Epiphrenic or pulsion esophageal diverticula have been addressed surgically with thoracoscopy. A combined thoracoscopic and laparoscopic approach has been recommended76 but may not be necessary in all cases. The primary goals are not just excision of the diverticulum but also a longitudinal myotomy of the esophageal musculature distal to the diverticulum. Foregut and duplication esophageal cysts similarly can occur in the posterior mediastinum. Most of the recommendations discussed for GISTs are applicable in this situation as well. Perhaps one of the most common therapeutic interventions undertaken within the posterior mediastinum is thoracoscopic sympathectomy (see Chapter 106). Most commonly it is performed for the management of axillary or palmar hyperhidrosis. Both facial blushing and craniofacial hyperhidrosis have been used as indications for surgery (Claes, 2003).77,78 Additional indications for thoracoscopic sympathectomy include reflex sympathetic dystrophy, Raynaud’s syndrome, upper extremity posttraumatic causalgia, and erythromelalgia (Claes, 2003).78,79 Sympathetic denervation has been accomplished in a number of ways, including direct cauterization of the T2 ganglion,80 division of the main sympathetic trunk above the second thoracic ganglion,81 division of the rami communicantes,82 hemoclip ligation of the trunk,83 and resection of the ganglion with sharp dissection, electrocautery,84 or harmonic scalpel.85 The ultimate goal is ablation of the sympathetic innervation to the upper trunk and/or face. Treatment of palmar hyperhidrosis is successful in 98% of patients after ablation of a T2 sympathetic ganglion. Most surgeons rely on palmar temperature monitoring to guide the extent of the sympathectomy.86,87 Alternatively, laser Doppler digital blood flow imaging can be used.88 However, many surgeons, after obtaining sufficient experience with the procedure and expertise in the anatomy, now no longer use such adjuncts and simply proceed with ablation of the sympathetic chain at the T2 level by any one of the just-mentioned modalities. The success rate for axillary hyperhidrosis ranges between 68% and 90%. Many surgeons ablate from T2 through T4 ganglia or just T2 and T3. However, controversy about the correct level of sympathetic ablation persists. Van’t Riet and colleagues89 recommended limited VATS sympathectomy at the level of T3 only for both palmar and axillary hyperhidrosis. Sympathetic ablation at the level of T2 has been described for the treatment of severe episodic facial blushing, with an alleviation rate of approximately 75%.81 Different approaches for thoracoscopic sympathectomy have been used. Midaxillary and anterior chest approaches use between one90 and three incisions. The parietal pleura overlying the sympathetic chain is divided, and the sympathetic chain is ablated with the method of choice. Attention must be paid to the potential presence of the accessory nerves of Kuntz, which have been reported to be present in up to 68.2% of patients (Chung et al, 2002).91

Ch140-F06861.indd 1703

1703

These branches usually course over the second rib lateral to the ganglion and are divided when present. An indwelling chest tube is really no longer required. Rather, a drainage tube is placed as the lung expands and then is usually removed immediately. The patient can be discharged home the same day. Complications associated with thoracoscopic sympathectomy include standard complications after any thoracoscopic surgery of infection, bleeding, and intercostal neuralgia. However, specific side effects can also occur. These include compensatory hyperhidrosis in the trunk and lower extremities. This has been reported in 25% to 87% of patients but is severe only in less than 2% (Dumont et al, 2004).92,93 Gustatory sweating has been reported in approximately 10% of patients, and Horner’s syndrome can occur in 1% to 2% of patients. The recurrence rate ranges from 1% to 10%, and multiple mechanisms have been hypothesized as responsible for the failure.94 Among the main causes of recurrent palmar hyperhidrosis after a primary thoracoscopic sympathectomy are a possible effect of the T3 ganglion, unidentified Kuntz fibers, nerve regeneration, and incomplete interruption of the T2 ganglion.95 However, the majority of patients remained satisfied and free of relapse in the long term (Zacherl et al, 1998).90,96-98 Sympathectomy for axillary hyperhidrosis has a less favorable long-term outcome (Baumgartner and Toh, 2003).99

MISCELLANEOUS MEDIASTINAL APPLICATIONS OF VIDEO-ASSISTED THORACOSCOPIC SURGERY Mediastinitis/Mediastinal Abscess Descending necrotizing mediastinitis can be a catastrophic condition with significant morbidity and mortality. Treatment with broad-spectrum antibiotics and cervical drainage might not be sufficient, especially for processes extending below the T4 level, below the carina anteriorly, and in the posterior mediastinum.100 The thoracoscopic approach has been described as an alternative approach to conventional surgery with encouraging results, especially in the early stage of the mediastinal infectious process.101-105

Robotic Mediastinal Surgery The introduction of robotic surgical systems opened new horizons in various surgical fields. Recently, thoracoscopic surgery for mediastinal lesions has been described using one of the multiple robotic surgical systems that have been introduced within the past 5 years. The DaVinci system is a computer-enhanced robotic system, and the AESOP is a voice-controlled robotic system. Use of these robotic systems has been described for mediastinal parathyroidectomy,106 AESOP-assisted VATS esophagectomy,107 pericardial cyst excision,108 thymectomy,109 neurogenic tumor excision,110 and posterior mediastinal bronchogenic cyst excision.111 Several theoretical advantages with the computer-enhanced robotic approach include articulating instruments, which provide seven degrees of freedom, allowing the surgeon to be ambidextrous and perform various complex surgical maneuvers (compared with four degrees of freedom by VATS); the

1/21/2008 4:16:51 PM

1704

Section 7 Mediastinum

elimination of tremor by computer technology; the computer-enhanced three-dimensional visualizing system; and the relatively intuitive nature of the robotic system and thus a very short learning curve. However, with the robotic technology there is a significant lack of tactile feedback, and the use of these systems is both time intensive and expensive.108,112 To date, there has been no convincing demonstration of the superiority of the robotic technology in mediastinal surgery, and it remains an option that is under investigation.

SUMMARY Over the past decade, thoracoscopic surgery for the mediastinum has evolved significantly. Thoracoscopy provides an attractive, sophisticated, and minimally invasive approach for the surgical treatment of diseases within the mediastinum but still requires significant expertise with a relatively steep learning curve to achieve mastery. It must be remembered, however, that the goal is always more important than the approach. Thoracoscopy is not used when an easier method can achieve the goal; and, if necessary, conversion to conventional approach is to be advised whenever doubt arises regarding the safety or the efficacy of the minimally invasive technique.

COMMENTS AND CONTROVERSIES The authors have provided a comprehensive overview of thoracoscopy of the mediastinum, and it is clear that the techniques and indications continue to evolve. Some areas remain controversial, for example, the applications of thoracoscopy to malignant lesions of the mediastinum. There is general agreement that the principles of complete resection of malignancies of the mediastinum need to be adhered to. The question remains as to what skills are required and which lesions can indeed be removed with good oncologic technique. More and more reports are being published that describe the thoracoscopic removal of small thymomas and other small potentially malignant lesions with negative margins and apparent good outcomes, but the definitions of small and of detailed outcomes remain indistinct. In my experience it is clear that thymomas that are well surrounded by fat with no evidence of invasion of surrounding structures can be removed thoracoscopically, intact with the entire thymus gland. If one is capable of performing a phrenic-to-phrenic complete resection of the thymus thoracoscopically, it is hard to imagine that splitting the sternum will contribute to any better surgical outcome. However, experience and judgment are the keys and any indication that the principles of a complete oncologic resection are being jeopardized by a thoracoscopic approach in the setting of a potentially malignant lesion should lead to a different approach, open sternotomy, or thoracotomy, depending on the lesion. J. D. L.

Bousamra M II, Hostler GB, Patterson GA, Roper CL: A comparative study of thoracoscopic vs open removal of benign neurogenic mediastinal tumors. Chest 109:1461, 1996. Chung I, Oh C, Hoh K, et al: Anatomic variations of the T2 nerve root (including nerve of Kuntz) and their implications for sympathectomy. J Thorac Cardiovasc Surg 123:498, 2002. Cirino LM, Campos JR, Fernandez A, et al: Diagnosis and treatment of mediastinal tumors by thoracoscopy. Chest 117:1787, 2000. Claes G: Indications for endoscopic thoracic sympathectomy. Clin Auton Res 13(Suppl1):I16, 2003. Demmy TL, Krasna MJ, Detterbeck FC, et al: Multicenter VATS experience with mediastinal tumors. Ann Thorac Surg 66:187, 1998. Dumont P, Denoyer A, Robin P: Long-term results of thoracoscopic sympathectomy for hyperhidrosis. Ann Thorac Surg 78:1801, 2004. Kelemen JJ III, Naunheim KS: Minimally invasive approaches to mediastinal neoplasms. Semin Thorac Cardiovasc Surg 12:301, 2000. Kitami A, Suzuki T, Usuda R, et al: Diagnostic and therapeutic thoracoscopy for mediastinal disease. Ann Thorac Cardiovasc Surg 10:14, 2004. Lin JC, Hazelrigg SR, Landreneau RJ: Video-assisted thoracic surgery for diseases within the mediastinum. Surg Clin North Am 80:1511, 2000. Mack MJ: Video-assisted thoracoscopic thymectomy for myasthenia gravis. Chest Surg Clin N Am 11:389, 2001. Massone PP, Lequaglie C, Magnani B, et al: The real impact and usefulness of video-assisted thoracoscopic surgery in the diagnosis and therapy of clinical lymphadenopathies of the mediastinum. Ann Surg Oncol 10:1197, 2003. Medrano C, Hazelrigg SR, Landreneau RJ, et al: Thoracoscopic resection of ectopic parathyroid glands. Ann Thorac Surg 69:221, 2000. Mouroux J, Venissac N, Leo F, et al: Usual and unusual locations of intrathoracic mesothelial cysts. Is endoscopic resection always possible? Eur J Cardiothorac Surg 24:684, 2003. Negri G, Puglisi A, Gerevini S, et al: Thoracoscopic techniques in the management of benign mediastinal “dumbbell” tumors. Surg Endosc 15:897, 2001. Ruckert JC, Sobel HK, Gohring S, et al: Matched-pair comparison of three different approaches for thymectomy in myasthenia gravis. Surg Endosc 17:711, 2003. Samphire J, Nafteux P, Luketich J: Minimally invasive techniques for resection of benign esophageal tumors. Semin Thorac Cardiovasc Surg 15:35, 2003. Venissac N, Leo F, Hofman P, et al: Mediastinal neurogenic tumors and video-assisted thoracoscopy: Always the right choice? Surg Laparosc Endosc Percutan Tech 14:20, 2004. Yamaguchi M, Yoshino I, Fukuyama S, et al: Surgical treatment of neurogenic tumors of the chest. Ann Thorac Cardiovasc Surg 10:148, 2004. Yim AP, Izzat MB, Lee TW, Wan S: Video-assisted thoracoscopic thymectomy. Ann Thorac Cardiovasc Surg 5:18, 1999. Zacherl J, Huber ER, Imhof M et al: Long-term results of 630 thoracoscopic sympathectomies for primary hyperhidrosis: The Vienna experience. Eur J Surg (580):43, 1998.

KEY REFERENCES Baumgartner F, Toh Y: Severe hyperhidrosis: Clinical features and current thoracoscopic surgical management. Ann Thorac Surg 76:1878, 2003.

Ch140-F06861.indd 1704

1/21/2008 4:16:52 PM

THORACOSCOPIC THYMECTOMY FOR MYASTHENIA GRAVIS

chapter

141

Calvin S. H. Ng Anthony P. C. Yim

Key Points ■ Thoracoscopic thymectomy is a safe and viable alternative tech-

nique for thymectomy in patients with MG. ■ We prefer the right-sided approach, but there is no consensus on

the ideal laterality for VATS thymectomy. ■ Results of VATS thymectomy, in terms of complete stable remis-

sion from MG and symptomatic improvement, are comparable to those of conventional surgical techniques. ■ VATS thymectomy results in less postoperative pain, better preserved early postoperative pulmonary function, and improved cosmesis, which is particularly important to many young, female MG patients who seek early surgical management.

HISTORICAL NOTE Myasthenia gravis (MG) has a history that dates back more than 3 centuries.1 It was first described in 1672 by an Oxford clinician, Sir Thomas Willis, who noted “a woman who temporarily lost her power of speech and became ‘mute as a fish’.” The first thymectomy was performed by Ferdinard Sauerbruch in Zurich in 1911 and reported by Shumacher and Roth the following year. The patient was a 21-year-old woman with hyperthyroidism and MG. Thymectomy was performed in an attempt to treat her hyperthyroidism. The thymus was hyperplastic, and after surgery both conditions were reported to improve temporarily. Mary Walker, a registrar at St. Alfege’s Hospital in Greenwich, London, in 1934, noted the similarity in clinical features between MG and curare poisoning and introduced treatment with the anticholinesterase physostigmine, which produced striking improvement in the muscle strength of a patient with myasthenia. This remarkable discovery, hailed as the “Miracle of St. Alfege’s Hospital,” not only implicated that the pathogenesis of this disease resided in the neuromuscular junction but also provided the most effective treatment available for more than 3 decades. Alfred Blalock (1944) at Johns Hopkins Hospital reported improvement in MG patients after resection of normal thymus and introduced this as a surgical therapy for this condition. Clinical use of edrophonium was introduced around 1950 and was followed a few years later by use of pyridostigmine. John Simpson (1960) first proposed that MG might be an autoimmune disease, which was later confirmed experimentally by Patrick and Lindstrom (1973) at the Salk Institute, who immunized rabbits with purified acetylcholine receptors.

DESCRIPTION It is now common knowledge that MG is an autoimmune disorder of the postsynaptic nicotinic acetylcholine receptor and is characterized by weakness and fatigability of voluntary muscles. The ocular muscles are frequently involved, rendering ptosis and diplopia the most common mode of presentation. Despite the fact that the condition has been recognized for more than 3 centuries, considerable controversies remain over its diagnosis, natural history, and therapy. This chapter is primarily focused on a discussion of surgical therapy. Thymectomy is now an established therapy in the management of generalized MG in conjunction with medical treatment. However, a randomized, prospective study investigating the role of thymectomy has never been undertaken and is unlikely to ever happen. A recent meta-analysis of 28 controlled studies showed MG patients undergoing thymectomy were twice as likely to attain medication-free remission, 1.6 times as likely to become asymptomatic, and 1.7 times as likely to improve. Different demographics and baseline characteristics, however, existed between groups (Grossneth and Barohn, 2000).2 Uncertainties remain over the role of thymectomy for patients with purely ocular symptoms and those with late onset of disease. Several surgical approaches to thymectomy exist. The most commonly adopted surgical approach to thymectomy is via a median sternotomy. Other open thymectomy techniques include the transcervical,3 the combined median sternotomy with a transcervical incision (T incision), and partial sternotomy (involving either the upper4 or lower5 sternum). The thoracoscopic approach to thymectomy was first reported by Sugarbaker from Boston and also the Belgium group in 1993.6,7 Subsequently, several variants have evolved, including video-assisted thoracoscopic surgery (VATS) (unilateral) thymectomy8,9 and the bilateral thoracoscopic approach combined with a cervical incision (video-assisted thoracoscopic extended thymectomy [VATET]).10 More recently, endoscopic robot-assisted thymectomy has also been reported with good immediate results, but long-term data are pending.11 Minimally invasive techniques have become increasingly popular owing to their low procedural morbidity and mortality, improved cosmesis, lesser degree of access trauma and postoperative pain, and equivalent efficacy compared with conventional open techniques. Because of the absence of randomized, controlled trials concerning thymectomy in the treatment of MG, no consensus has been universally adopted with regard to the optimal surgical approach. Furthermore, patient heterogeneity, the fluctuating nature of the disease, and different classification 1705

Ch141-F06861.indd 1705

1/21/2008 4:17:36 PM

1706

Section 7 Mediastinum

systems and practice guidelines make interpretation of outcomes after thymectomy difficult. In this chapter we review our technique regarding VATS thymectomy, discuss the perioperative management in our institution and our criteria for patient selection, and report on our intermediate results.

PATIENT SELECTION For young patients with generalized MG, it is now fairly well accepted that thymectomy needs to be offered. However, uncertainties remain over the role of thymectomy for patients with purely ocular symptoms and those with late onset of disease. Arguments have been put forward not to operate solely because of ocular symptoms because ocular MG is not only less likely to respond to thymectomy but also carries a better prognosis compared with generalized MG. On the other hand, it has been shown that 30% to 70% of patients with initial ocular symptoms eventually develop generalized myasthenia. It is on that basis that we advised some of our young patients to undergo surgery even though their presentation was purely ocular (Figs. 141-1 and 141-2). Although some patients with purely ocular symptoms improve after thymectomy, the patients have to clearly understand that the rationale for surgery here is not based on symptomatic improvement but rather on the expectation of halting disease progression. It is vital that the thoracic surgeons work closely with the neurologists and anesthetists to achieve optimal results.

PREOPERATIVE PREPARATION Myasthenia gravis causes weakness of voluntary muscles, including those involved in respiration, so that patients are at risk of developing postoperative respiratory failure. If bulbar palsy is present, they may also develop aspiration pneumonia. Medical treatment is associated with its own complications. Anticholinesterase treatment increases vagal tone, enhances oral secretion, and potentiates laryngeal spasm. Prolonged

FIGURE 141-1 Large mediastinal mass on chest radiograph.

Ch141-F06861.indd 1706

corticosteroid use could result in electrolyte imbalance and increase the susceptibility to infections. Before elective surgery, it is important that the distribution and severity of muscle weakness are carefully assessed. Respiratory function and nutritional status are also documented and medical treatment optimized. Patients with severe weakness may require preoperative plasmapheresis, together with corticosteroid and anticholinesterase therapy. Admission to the intensive care unit for ventilatory support is indicated for patients who are already in respiratory failure, but it is not necessary to wait until the patient is extubated before surgery can proceed. Intravenous (IV) immunoglobulin is an alternative to plasmapheresis, but there is no clear evidence that one is better than the other. The patient must be warned of the possibility of postoperative mechanical ventilation. The operation is usually arranged as the first case on the elective list. Premedication is prescribed as appropriate, but respiratory depressant drugs are avoided. So-called stress doses of corticosteroids may be required (Yim et al, 1995).12

INDUCTION OF GENERAL ANESTHESIA In our practice, selective one-lung ventilation to the left lung is required to facilitate the operation (Yim et al, 2005).12 Others have reported good results with single-lumen intubation with carbon dioxide insufflation at 6 to 8 mm Hg with excellent exposure. General anesthesia with left-sided double-lumen endobronchial tube is used. Anesthesia is induced with 2 mg/kg of propofol and 2 µg/kg of fentanyl, and intubation can usually be achieved without muscle relaxants. Pretreatment of the tracheobronchial tree with local anesthetics can also facilitate intubation.13 Proper positioning of the endobronchial tube is confirmed with the use of the fiberoptic bronchoscope after intubation and reconfirmed after patient positioning. However, it is generally held that a body weight of at least 30 to 35 kg is necessary for the patient’s airway to accommodate the smallest double-lumen device (28 Fr). This size limitation essentially precludes the use of these devices for patients younger than approximately 8 years of age. Other techniques to achieve one-lung ventila-

FIGURE 141-2 CT scan showing thymic hypertrophy.

1/21/2008 4:17:36 PM

Chapter 141 Thoracoscopic Thymectomy for Myasthenia Gravis

Vi T de V Vi o i mo de m n Li o ag ito gh re e r t s co pri ou rd nte rc er r e

or nit

Ch141-F06861.indd 1707

mo

The team of the principal surgeon, an assistant, a scrub nurse, and the anesthesiologist will remain in the same positions during the whole procedure. The operating room setup consists of the anesthetic unit, video-assisted thoracoscopy unit (TV monitor, video image printer, video recorder, light source), another TV monitor, electrocautery, and instrument trolley (Fig. 141-3). Mostly, conventional instruments are used, such as a sponge-holding forceps (for retraction), a dental pledget mounted on a curved clamp (for dissection), and a rightangled clamp (for dissection of vascular branches). We advocate the use of the conventional thoracic instruments such as

TV

Operating Room Setup

Camera person

y

Under general anesthesia with selective one-lung ventilation, the patient is positioned in the full left lateral decubitus position for the approach to the anterior mediastinum from the right. Some surgeons prefer to place the patient in a 45degree lateral decubitus position to allow greater posterior displacement of the lung. The operating table is flexed to 30 degrees with the fulcrum just inferior to the level of the nipples, to open up the upper intercostal spaces for thoracoscope insertion and instrumentation.16,17

Chief surgeon

Theater nurse

erm

Patient Positioning

Anesthesiologist

ath

POSITIONING

Anesthetic machine

Di

tion such as placement of a bronchial blocker or intentional intubation of a mainstem bronchus with an endotracheal tube are used.14 Hypoxemia during one-lung ventilation is usually caused by shunting of blood. In case of hypoxemia, confirm the position of the double-lumen endobronchial tube and hemodynamic stability. A low level of continuous positive airway pressure (CPAP) applied to the collapsed right lung may improve saturation. Applying positive end-expiratory pressure (PEEP) to the ventilated lung can also raise oxygen saturation during one-lung ventilation. Anesthesia is maintained with isoflurane 1% to 2%, 60% nitrous oxide in oxygen, and a single bolus of 0.1 mg/kg of morphine. Ventilation is controlled to achieve normocarbia. Patients with MG are usually more susceptible to the neuromuscular blocking effect of volatile anesthetics so that nondepolarizing muscle relaxants are usually not required.15 Patients with MG are usually also very sensitive to nondepolarizing muscle relaxants. If muscle relaxation is necessary during the course of anesthesia, use a reduced dose of an intermediate-acting nondepolarizing muscle relaxant followed by a carefully titrated IV infusion. Monitoring neuromuscular transmission is mandatory to adjust the dose of muscle relaxant used and to ensure complete reversal of neuromuscular blockade after the surgery. The electrocardiogram, noninvasive blood pressure, pulse oximetry, end-tidal carbon dioxide, airway pressure, ventilatory volume, inspired oxygen, and neuromuscular transmission are routinely monitored and continuously displayed. Arterial line and central venous catheter for invasive pressure monitoring may be required for coexisting medical conditions.

1707

Instrument trolley

FIGURE 141-3 Operating room setup for VATS thymectomy.

the sponge-holding forceps whenever possible because they are less expensive and are more familiar to the surgeon. However, a few dedicated endoscopic instruments, including endoscissors for incising the mediastinal pleura, endograsper, and endoclip applier for vascular hemostasis (Endoclip, Autosuture, U. S. Surgical, Tyco Health Care, Norwalk, CT), need to be available to aid surgery.

TECHNIQUE Surgical Anatomy The thymus is embryologically derived from the third and fourth branchial pouches. It weighs 10 to 35 g at birth, grows to 20 to 50 g at puberty, and then slowly involutes to 5 to 15 g in the adult. With the process of involution, the thymic parenchyma is gradually replaced by fibroadipose tissue. The fully developed gland is bilobed, but its exact shape is largely molded by the adjacent structures and is highly variable. It occupies the anterior mediastinum, with the superior horns often extending into the neck, lying deep to the sternothyroid muscle. The body of the gland is related anteriorly to the sternum and the upper four costal cartilages; posteriorly to the pericardium, the ascending aorta, the brachiocephalic veins, and superior vena cava; and laterally with the mediastinal pleura. Its relationship with the veins is of great surgical importance. Its fibrous capsule blends in with the pretracheal fascia. The arterial supply is derived laterally from branches of the internal mammary artery and venous drainage through two to three tributaries posteriorly into the left brachiocephalic vein.

1/21/2008 4:17:36 PM

1708

Section 7 Mediastinum

There are two technical considerations regarding thymectomy in the prepubertal population. First, the thymus is relatively large compared with the body weight. Second, the chest is relatively small, and therefore the space for maneuvering of instruments is less. Attention has to be given to achieve selective one-lung ventilation and to use finer instruments (≤5 mm external diameter).

Operative Principles The chest is the most suitable body cavity for the minimal access approach because once the lung is collapsed (with selective one-lung ventilation) there is plenty of room for maneuvering of instruments. Carbon dioxide insufflation and hence the use of valved ports has been reported with success by some groups using single-lumen intubation, double-lung ventilation, and moderate carbon dioxide insufflation pressures of 6 to 8 mm Hg. Some researchers have noted that carbon dioxide insufflation during VATS has an adverse effect on the patient’s hemodynamics compared with selective onelung ventilation. The use of costal or sternal hooks for anterior chest wall lifting during VATS thymectomy may increase the operative space, but we have never found it necessary in our practice.18 There are additional strategies in VATS that can assist in minimizing chest wall trauma, avoiding intercostal nerve compression, and thus minimizing postoperative pain16: ■ ■ ■ ■

Instrument ports Camera port (10 mm)

FIGURE 141-4 Positions of the thoracic ports in VATS thymectomy.

Avoiding the use of trocar ports by introducing instruments directly through the wound Avoiding torquing of the thoracoscope by visualizing with an angled lens (30-degree scope) Using smaller telescopes (5 mm) when clinically allowed Delivering specimens through the anterior port because the anterior intercostal spaces are wider

Cannulae and Port Placement With the patient under general anesthesia, confirm selective one-lung ventilation with the anesthesiologist before port placement. In small children, it may not be feasible to use a double-lumen tube. We advocate a right-sided approach and the three-port technique for the procedure. The thoracoscope port incision should be in front of the tip of the scapula along the posterior axillary line for the insertion of the 10mm port and 0-degree (or 30-degree) telescope.17 The second and third 5-mm instrument ports are inserted by open technique under direct thoracoscopic vision at the third intercostal space midaxillary line and the sixth intercostal space anterior axillary line (Figs. 141-4 and 141-5). Additional ports may be made for lung retraction as necessary. In young female patients, the instrument ports are strategically placed over the submammary fold for better cosmesis.

Exploration The entire hemithorax is carefully examined with particular attention to the mediastinum. Blunt instruments such as sponge-holding forceps may be used to help collapse the lung and for manipulation to complete the exploration. The major structural landmarks are identified, including the superior

Ch141-F06861.indd 1708

FIGURE 141-5 Use of ports during VATS thymectomy.

vena cava, brachiocephalic vein, and right phrenic nerve. It is of paramount importance that the right phrenic nerve is carefully preserved throughout the dissection because phrenic nerve palsy represents a major complication for patients with MG. Pleural adhesions may be present and require adhesiolysis to facilitate complete lung collapse and achieve a good operating field.

Dissection and Vascular Control First, the right inferior horn of the thymus is identified draping over the pericardium. The mediastinal pleura over the free edge of the right inferior thymic horn is then sharply incised anterior to the phrenic nerve. The thymus can then be lifted up and bluntly dissected off the underlying pericardium extending onto the aorta in a cephalad manner until the left brachiocephalic vein is exposed. We have found it useful

1/21/2008 4:17:41 PM

Chapter 141 Thoracoscopic Thymectomy for Myasthenia Gravis

to apply deliberate and gentle traction on the thymus to allow blunt dissection using a pledget. The thymic venous tributaries (usually two or three) draining into the left brachiocephalic vein can then be identified, clipped, and divided. It is important to obtain vascular control before further manipulation of the thymus. Dissection is then carried behind the sternum. With gentle traction on the thymus using a spongeholding forceps, the left inferior horn can be identified and likewise dissected up to the thymus isthmus.

Dissection of Superior Horns The most difficult part of the operation is to dissect the superior horns. The right internal mammary vein is divided in most cases to facilitate exposure. With gentle and deliberate inferior traction on the thymus, the superior horns can be carefully dissected free from their fascial attachments mainly using blunt dissection with the aid of a mounted pledget. The positions of the thoracoscope and inferior instrument port may be exchanged to allow better reach toward the superior parts of the thymus, particularly when conventional instruments are used. In small children with bulky hyperplastic thymus and relatively small thoracic cavity, we have found it useful to retract part of the gland out of an anteriorly placed wound, which creates more room for the instruments to facilitate further dissection. It is noteworthy that the left superior horn occasionally passes behind, instead of in front of, the brachiocephalic vein, and this anatomic variation has to be looked for (we have encountered this in one case and thoracoscopic dissection was successfully accomplished) (Fig. 141-6).

1709

anterior mediastinal soft tissue including the pericardial fat is separately removed. The specimen is inspected for completeness of resection (Fig. 141-7).

Conclusion of Procedure The thymic bed is inspected for hemostasis and completeness of resection. The brachiocephalic veins should have been skeletonized and the junction to form the superior vena cava clearly visualized (Fig. 141-8). The insertion of tube thoracostomy is optional. The lung is then reinflated under direct vision, and layered closure of the stab wounds completes the operation.

Postoperative Care Early extubation is encouraged after surgery. The patient can resume a full diet when fully awake from the general anesthesia, unless impaired by bulbar weakness from MG. A sitting chest radiograph is taken to detect pneumothorax, hemothorax, and any significant atelectasis. Postoperative

Extraction The thymus, as a free specimen, can then be removed in a plastic bag (Endocatch, Autosuture, United States Surgical, Tyco Health Care, Norwalk, CT, or a sterilized plastic sandwich bag) through the most anterior port because the intercostal space is wider anteriorly. After thymectomy, the

FIGURE 141-6 Dissection of left superior horn (LSH) behind the left brachiocephalic vein (LB). RB, right brachiocephalic vein.

Ch141-F06861.indd 1709

FIGURE 141-7 The resected complete thymic specimen.

FIGURE 141-8 Thymic bed after thymectomy clearly demonstrating the venous anatomy. LB, left brachiocephalic vein; LL, left lung; RB, right brachiocephalic vein; SVC, superior vena cava.

1/21/2008 4:17:43 PM

1710

Section 7 Mediastinum

chest physiotherapy and incentive spirometry are provided and encouraged. Regular checks on oxygen saturation and bedside spirometry are performed in the early postoperative period to give warning of respiratory muscle weakness. Patients resume their preoperative medications for the control of MG. Pain can usually be adequately controlled by standard oral analgesics. Tube thoracostomy can be removed on day 1 after confirming no air leak or bleeding.

LIMITATIONS OF VATS THYMECTOMY There are relatively few contraindications to VATS. In addition to the general contraindications such as severe coagulopathy, specific ones include pleural symphysis and patients with severe underlying lung disease or poor lung function who are unable to tolerate the selective one-lung ventilation during general anesthesia. Prior operation in the ipsilateral chest is not regarded as a contraindication. Adhesions can usually be taken down using a combination of sharp and blunt dissection under videoscopic vision. We regard thymic malignancy, or any evidence of invasion of the normal tissue plane, as a contraindication to using the VATS approach for resection.

RESULTS In our institution, we have attempted 49 VATS thymectomies. Two patients required conversion to a small lateral thoracotomy for control of bleeding from a branch of brachiocephalic vein (conversion rate of 4%), which occurred early in our experience. Three thymectomies were not related to MG, and there were six thymomas. Therefore, 38 VATS thymectomies were successfully performed for nonthymomatous MG. Two patients were lost to follow-up, hence complete follow-up data were available in 36 patients (23 females; age range, 9-75 years with a mean age of 33.1) with mean duration of disease of 35.1 months (range, 2-204 months). Before thymectomy, all patients were treated with anticholinesterase and 69.7% of patients were given corticosteroid therapy. Preoperatively, 8 patients were in stage I, 13 in stage IIA, 2 in stage IIB, 4 in stage IIIa, 1 in stage IIIb, 1 in stage IV, and 7 in stage V according to the Myasthenia Gravis Foundation of America (MGFA) classification (Table 141-1).19 Mean operative duration was 107 minutes (range, 60-150 minutes), and there was no surgical mortality. All patients except 2 were extubated within 24 hours. The first patient was a 29-year-old woman with Down syndrome and a history of asthma who experienced postoperative pneumonia and required prolonged ventilation and a tracheostomy. The other one was a 22-year-old woman who was already on mechanical ventilation before surgery for MG. Other potential postoperative complications not encountered in our series include wound infection, hypocalcemia, pneumothorax, surgical emphysema, intercostal neuralgia, and phrenic nerve palsy. The median postoperative hospital stay was 3 days. The final pathology results were hyperplastic thymus, 22 patients; atrophic thymus, 6 patients; and normal thymus, 8 patients.20 After a median follow-up of 69 months (range, 12-139 months), 33 patients (91.6%) experienced some improve-

Ch141-F06861.indd 1710

TABLE 141-1 Myasthenia Gravis Foundation of America Guidelines (2000) I.

Any ocular muscle weakness. May have weakness of eye closure. All other muscle strength is normal.

II. Mild weakness affecting other than ocular muscles. May also have ocular muscle weakness of any severity. A. Predominantly affecting limb or axial muscles or both. May also have lesser involvement of oropharyngeal muscles. B. Predominantly affecting oropharyngeal or respiratory muscles or both. May also have lesser or equal involvement of limb or axial muscles or both. III. Moderate weakness affecting other than ocular muscles. May also have ocular muscle weakness of any severity. A. Predominantly affecting limb or axial muscles or both. May also have lesser involvement of oropharyngeal muscles. B. Predominantly affecting oropharyngeal or respiratory muscles or both. May also have lesser or equal involvement of limb or axial muscles or both. IV. Severe weakness affecting other than ocular muscles. May also have ocular muscle weakness of any severity. A. Predominantly affecting limb and/or axial muscles. May also have lesser involvement of oropharyngeal muscles. B. Predominantly affecting oropharyngeal or respiratory muscles or both. May also have lesser or equal involvement of limb or axial muscles or both. V. Defined by intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVB. From Jaretzki A 3rd, Barohn RJ, Ernstoff RM, et al: Myasthenia gravis: Recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Ann Thorac Surg 70:327-334, 2000.

ment. Complete stable remission (CSR) was found in 8 (22.2%) patients, MM-2 (minimal manifestations) improvement in 9 (25%), and MM-3 improvement in 16 (44.4%) according to the MGFA postintervention status classification (Table 141-2). The status of 2 (5.5%) patients remained unchanged, and 1 (2.7%) died of MG. The death occurred in an elderly man who presented with pure ocular symptoms when he was 73 years old. However, within 1 year, his symptoms progressed to involve the bulbar muscles. At this point, he was referred for surgery. Thoracoscopic thymectomy was performed, and an atrophic thymus was removed without complication. Postoperatively, his symptoms never improved and, after 8 months, he developed acute respiratory failure leading to death within 2 days of admission. This was clearly a case of thymectomy failure, which was not related to any particular surgical approach but to the unpredictable natural history in patients with late-onset MG. The number of patients experiencing postoperative CSR increased tentatively at 13 months after surgery and then rose sharply at 117 months to 75% at 10 years’ follow-up (Fig. 141-9). In view of the delayed response, the true benefits of

1/21/2008 4:17:45 PM

Chapter 141 Thoracoscopic Thymectomy for Myasthenia Gravis

1711

TABLE 141-2 Myasthenia Gravis Foundation of America Postintervention Status Complete Stable Remission (CSR) Pharmacological Remission (PR) Minimal Manifestations (MM)

MM-0 MM-1 MM-2 MM-3 Change in Status Improved (I)

The patient has had no symptoms or signs of MG for at least 1 year and has received no therapy for MG during that time. There is no weakness of any muscle on careful examination by someone skilled in the evaluation of neuromuscular disease. Isolated weakness of eyelid closure is accepted. The same criteria as for CSR, except that the patient continues to take some form of therapy for MG. Patients taking cholinesterase inhibitors are excluded from this category because their use suggests the presence of weakness. The patient has no symptoms of functional limitations from MG but has some weakness on examination of some muscles. This class recognizes that some patients who otherwise meet the definition of CSR or PR do have weakness that is only detectable by careful examination. The patient has received no MG treatment for at least 1 year. The patient continues to receive some form of immunosupression but no cholinesterase inhibitors or other symptomatic therapy. The patient has received only low-dose cholinesterase inhibitors (<120 mg pyridostigmine/day) for at least 1 year. The patient has received cholinesterase inhibitors or other symptomatic therapy and some form of immunosupression during the past year. A substantial decrease in pretreatment clinical manifestations or a sustained substantial reduction in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific decrease in QMG score. No substantial change in pretreatment clinical manifestations or reduction in MG medications as defined in the protocol. In prospective studies, this should be defined in terms of a maximal change in QMG score. A substantial increase in pretreatment clinical manifestations or a substantial increase in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific increase in QMG score. Patients who have fulfilled criteria of CSR, PR, or MM, but subsequently developed clinical findings greater than permitted by these criteria. Patients who died of MG, of complications of MG therapy, or within 30 days after thymectomy.

Unchanged (U) Worse (W) Exacerbation (E) Died of MG (D of MG)

QMG, quantitative myasthenia gravis.

DISCUSSION

1.0 .9 Postoperative Complete Stable Remission

.8 .7 .6 .5 .4 .3 .2 .1 0.0 0

20

40

60

80

100

120

140

Length of Follow-up (months) FIGURE 141-9 Kaplan-Meier cumulative estimate of CSR rate after VATS thymectomy.

thymectomy for MG require prolonged surveillance. With the use of univariate analysis, the only factor associated with a statistically significant probability of CSR was disease duration of 12 months or less. This finding strengthens the argument for surgery to be performed early after the diagnosis of MG.

Ch141-F06861.indd 1711

Considerable uncertainties remain over the optimal treatment of MG. The best surgical approach to thymectomy remains controversial. Regardless of technique, it is generally agreed that thymectomy for MG must be complete. The group from Columbia-Presbyterian Hospital advocated maximal thymectomy,21 involving a combination of median sternotomy with cervical incision to achieve en-bloc thymectomy and anterior mediastinal exenteration, which includes mediastinal pleura from the level of the thoracic inlet to the diaphragm, pericardial fat pad, and all the mediastinal fat. However, despite this radical approach, when compared with sternotomy alone22 or the transcervical approaches,3,23,24 results in terms of clinical improvement did not seem to be significantly different. In addition, a detailed autopsy study identified ectopic thymic tissue in areas (e.g., the retrocarinal fat) that are not accessible via a median sternotomy.25 Although it may seem intuitive to remove as much mediastinal soft tissue as possible to avoid leaving behind ectopic thymus, these remnants have never been conclusively shown to be clinically relevant and even the most radical surgical approach does not result in a remission rate greater than 40%. Furthermore, the majority of ectopic thymus tissue is actually microscopic and may even be missed by radical thymectomy.26 The VATS approach is similar to the transcervical approach in that both are associated with minimal chest wall trauma, low postoperative morbidity, shorter hospital stay, and, perhaps more importantly, improved patient acceptance for

1/21/2008 4:17:45 PM

1712

Section 7 Mediastinum

surgery earlier in the disease compared with the transsternal approach. Only rarely is conversion from VATS to sternotomy required (2.6%-5.5%). However, VATS has additional advantages over the conventional transcervical approach because the visualization is much better and there is no crowding of instruments through a single access site. The thymus, being largely an anterior mediastinal structure, can be more directly approached through the chest than the neck. Video assistance provides a wide, magnified operative field, as well as allowing the other team members to learn and appreciate the progress of the procedure. In addition, VATS may be a helpful approach for completion thymectomy in patients with refractory myasthenia gravis who have already undergone resection by prior transcervical or transsternal approach, with the potential advantage of avoiding previously dissected tissue planes and facilitating the search for residual thymic tissue. Interestingly, it has been shown that in patients who did not benefit initially from a transcervical or transsternal approach, VATS completion thymectomy can be performed to remove residual thymic tissue, resulting in subsequent improvement of symptoms.26 We believe that we are performing the same operation thoracoscopically compared with the transsternal approach by examination of the thymic beds and the resected specimens.17 The cosmetic appearance of the surgical scars is seldom used to argue for a particular surgical approach. However, thymectomy may be a notable exception considering that the majority of patients are young females and the superior cosmetic appearance of VATS needs to be considered. In addition, it has been shown that the pulmonary function is significantly better preserved in the immediate postoperative period followed by a faster recovery after VATS compared with the median sternotomy approach to thymectomy for MG in a small randomized prospective study.27 Such an advantage can contribute toward earlier extubation and potential reduction in the incidence of postoperative pulmonary infections. However, even among the surgeons performing VATS thymectomy there is controversy over the exact technique and, in particular, whether the thymus should be approached from the left or right. Mineo and coworkers (2000)28 from Rome advocated a left-sided approach and the use of pneumomediastinum to facilitate dissection. They believe that the dissection maneuvers are safer from the left because the superior vena cava lies out of the surgical field, thus reducing risk of accidental injury. In addition, the removal of perithymic fatty tissue around the left pericardiophrenic angle and aortopulmonary window can be performed more readily from the left (Mineo et al, 2000).28 On the other hand, we advocate the right-sided approach for the following reasons.29 First, the superior vena cava, easily identified from the right, provides a clear landmark for further dissection of the innominate veins. Second, the confluence of the two innominate veins to form the superior vena cava is an area most difficult to dissect well. This could be more easily accomplished from the right. Third, from the ergonomic standpoint, it is easier for righthanded surgeons performing VATS to start at the inferior poles and work cephalad from the right side. Furthermore, it allows greater maneuverability of instruments in the wider right pleural cavity, particularly in patients with cardiomegaly.

Ch141-F06861.indd 1712

The ultimate surgical goal of thymectomy is to completely remove the gland and the anterior mediastinal tissue. The laterality of approach remains largely the surgeon’s preference, which is ultimately influenced by his or her experience and training. In our institution, we have shown that patients who underwent thoracoscopic thymectomy had significantly less analgesic requirement and shorter hospital stays compared with a historical group who underwent transsternal thymectomy.17 Collective early experience on 33 patients from four centers (Columbia Hospital in Dallas, University of Pittsburgh, Southern Illinois University, and our own) has been previously reported (Mack et al, 1996).30 In this multicenter series, clinical improvement was observed in 88% of patients who underwent thoracoscopic thymectomy after a mean follow-up of 23 months. Subsequently, meta-analysis comparing nine published series performed by other approaches showed no difference in clinical improvement after thymectomy between series (Mack et al, 1996).21,23,30-33 More recent studies on minimally invasive thymectomy for MG with more long-term results are presented in Table 141-3. Our CSR rate of 22.2% is comparable to that in many other studies, particularly those of Savcenko and associates (2002),34 who used the same MGFA criteria and similar operative approach as we did. Nevertheless, the CSR rate is quite varied between series, ranging from 14% to 41%. There are several plausible factors to explain such findings. A review conducted by the American Academy of Neurology reported that the more severe the degree of MG the larger would be the magnitude of improvement after thymectomy (Gronseth and Barohn, 2000).2 In our patient cohort, 36.1% of subjects were MGFA stage III to V, compared with 55.47% in the series by Mantegazza and coworkers.35 Thus, the lower rate of CSR in this series may in part be due to the greater proportion of patients with milder disease (stage I-II). Of note, the percentage of patients on anticholinesterase and immunosuppressive drugs was greater at 100% and 69.7%, respectively, as opposed to 46.5% and 53.5% in the study by Mantegazza and coworkers.35 This perhaps reflects a different medication prescription practice and management strategy among neurologists, the impact on outcome of which is difficult to qualify. A higher percentage of patients on medical therapy also translates into a greater number of patients who need to be weaned off medication before achieving CSR, a factor that clearly has implications on rates of CSR and improvement if an aggressive medication weaning practice was adopted postoperatively. It has been postulated that shorter duration of disease results in better outcomes after surgery; therefore, earlier thymectomy could theoretically lead to improved results. In our patient population, the mean preoperative duration of disease was 35 months compared with 14.8 months in the series reported by Mineo and colleagues (2000)28 and 10 months in the study by de Perrot and associates.36 The timing of surgery in our institution may reflect a delayed surgical referral pattern or prolonged medical treatment, thus accounting for a lower rate of CSR. Undoubtedly, differing methods of disease classification and outcome reporting render comparisons between thymec-

1/21/2008 4:17:45 PM

Chapter 141 Thoracoscopic Thymectomy for Myasthenia Gravis

1713

TABLE 141-3 Results of Minimal Access Thymectomy Approaches for Myasthenia Gravis Author (Year)

Surgical Approach

Yim20 (current)

VATS

34

Savcenko

(2002)

Wright37 (2002) 28

Mineo

(2000) 39

Zielinski

(2004)

Hsu40 (2004) 35

Mantegazza 36

de Perrot

(2003)

(2003)

Shrager24 (2002) 3

Calhoun (1999) 41

Uchiyama

(2001)

No. Patients 36

Mean Follow-up (mo)

Remission (%)

Improvement (%)

69

22.2

91.6

VATS

36

53

14

83

VATS

26

19.5

27

81

VATS

31

40

36

96

TC-Sx-VATS

25

24

32

83.3

SxVATET

15

18.5

37

NA

VATET

159

72

33.3

NA

TC

120

48

41

NA

TC

78

54.6

39.7

NA

TC

100

63.6

35

85

21

15.5

13.3

86.7

Infrasternal mediastinoscopic

NA, not available; SxVATET, subxiphoid video-assisted thoracoscopic extended thymectomy; TC, transcervical thymectomy; TC-Sx-VATS, transcervical subxiphoid videothoracoscopic; VATET, video-assisted thoracoscopic extended thymectomy; VATS, video-assisted thoracoscopic surgery.

tomy studies difficult. The effect of nonstandardized classification systems becomes readily apparent not only when attempting to establish initial disease severity but also when defining a specific outcome such as CSR. For example, duration of CSR according to the MGFA classification is twice as long as the criteria used by de Perrot and associates36 and Shrager and coworkers.24 Of note, other authors did not specify the time interval in their definition of remission (Mineo et al, 2000),28,37 which clearly has implications on the overall rate of CSR because there will be more patients achieving remission given a limited duration. Finally, concerns have been raised regarding using the VATS approach for thymoma with or without associated MG. We are careful in restricting this technique to small, completely encapsulated thymoma (Masaoka stage I38). Clinical judgment is of paramount importance in thymic surgery, and any sign of tissue plane invasion mandates conversion to an open dissection (Yim et al, 1995).12

SUMMARY VATS thymectomy is a safe operation in experienced hands and represents a new, viable alternative approach for patients with MG. We prefer the right-sided approach because visualization of the venous anatomy for dissection is essential. Our own as well as collective experience so far shows that the VATS approach produces results comparable to other conventional surgical techniques for thymectomy. By minimizing chest wall trauma, the thoracoscopic approach causes less postoperative pain, shortens hospital stay, better preserves lung function in the early postoperative period (which may be particularly important for patients with MG), and gives superior cosmesis. Compared with conventional surgery, VATS demands a new set of manual skills and hand-eye coordination. However, for someone who is experienced with open surgery, the learning curve is usually very steep. It is hoped that this patient-friendlier approach will lead to

Ch141-F06861.indd 1713

wider acceptance by MG patients and their neurologists for earlier thymectomies.

COMMENTS AND CONTROVERSIES The authors have provided a comprehensive overview of the results of open thymectomy for MG and the comparison to the VATS approach. Essentially, there is no difference in apparent outcomes for the disease process itself; proponents of the VATS approach point out the less pain and shorter hospital stays and that no one has demonstrated an advantage for open approaches or more radical surgery. The authors present their approach to VATS thymectomy, which includes a right-sided approach, double-lumen intubation, and single-lung ventilation. This reviewer is very familiar with the approach because I had the good fortune to scrub with Dr. Yim during a course in Bangkok in 1995 where he demonstrated very clearly to me that he was a master surgeon and had the rightsided VATS approach very well worked out. After that day I adopted the right-sided VATS approach because it offered a very good access and control of the venous branches from the thymus to the left innominate vein. Our group has made several changes with the influence of Dr. Mack, Dr. Landreneau, and others. Currently, I use the right-sided VATS approach, but this is done with single-lumen intubation and a low pressure insufflation of carbon dioxide (6-8 mm Hg) and we have excellent results with this approach. We now have added a very limited left-sided VATS view at the beginning of the procedure, allowing us to open the pleura along the phrenic nerve up to the mammary vein and then open the mediastinal pleura just at the junction of the mediastinum with the undersurface of the sternal edge and complete a triangle of dissection along the pericardium. In our experience this takes any question away regarding the completeness of a phrenic-to-phrenic dissection of all thymic tissue and makes the completion from the right side much faster, and safer. In the past, when we used only the right-sided VATS approach, I found the dissection toward the right phrenic nerve tedious and had some degree of uncertainty as to being able to remove all of the thymic

1/21/2008 4:17:45 PM

1714

Section 7 Mediastinum

tissues. Thus I changed to this bilateral VATS approach. Also of note, after watching Dr. Mack perform a bilateral sympathectomy in the supine position, with single-lumen intubation, limited lung ventilation, and moderate carbon dioxide insufflation, I was so impressed with the view that we also adopted these additions to our current VATS thymectomy procedure. Thus, to summarize the Pittsburgh approach, we use single-lumen intubation, double-lung ventilation, modest carbon dioxide insufflation, limited initial left-sided VATS followed by completion right-sided VATS, and the supine patient position with a roll under the spine and tilting of the table right to left with a moderate degree of reverse Trendelenburg positioning. In summary, the authors present an excellent overview of the results of VATS thymectomy and their own current approach. The ultimate VATS approach will likely continue to evolve, and I believe it will include a technique including some sternal lift device. However, VATS thymectomy is a technically challenging procedure and most thoracic residents are not receiving this type of advanced minimally invasive training. Also, I have observed the transcervical approach but have found few centers doing this with enough routine to train residents, except for a few specialized centers. Thus, it is clear to me that, at this time, most graduating thoracic residents will not have the skills to perform either the VATS or the transcervical thymectomy and will need to strongly consider either gaining additional specialized training or use the standard open sternotomy, which continues to be a very good approach and is safe for most residents to perform for many diseases of the mediastinum with overall good results. J. D. L.

KEY REFERENCES Gronseth GS, Barohn RJ: Practice parameter: Thymectomy for autoimmune myasthenia gravis (an evidence-base review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 55:7-15, 2000. ■ The authors of this paper describe the latest consensus by the American Academy of Neurology for classifications related to the symptoms of myasthenia gravis and

Ch141-F06861.indd 1714

treatment response, in particular to thymectomy. They systematically review the available controlled but nonrandomized studies describing outcomes in MG patients undergoing and not undergoing thymectomy. Mack MJ, Landreneau RJ, Yim AP, et al: Results of video-assisted thymectomy in patients with myasthenia gravis. J Thorac Cardiovasc Surg 112:1352-1360, 1996. ■ In the first multicenter retrospective series on VATS thymectomy for myasthenia gravis, the right approach was used in 11 patients and the left approach was used in 22 patients. There was one conversion to open and no perioperative mortality or long-term morbidity. Clinical improvement in symptoms of MG was seen in 88% by mean follow-up of 23 months. Meta-analysis comparing the results from this study with those from nine published series using other techniques for thymectomy showed no significant difference in clinical improvement. Mineo TC, Pompeo E, Lerut TE, et al: Thoracoscopic thymectomy in autoimmune myasthenia gravis: Results of left-sided approach. Ann Thorac Surg 69:1537-1541, 2000. ■ This retrospective series of VATS thymectomy for MG between 1993 and 1997 comes from a single center that employs advocates of the left-sided approach. Of the 31 patients, 36% had remission whereas 96% described clinical improvement of their MG at mean follow-up of 39 months. The authors’ arguments for approaching the thymus from the left side are presented. Savcenko M, Wendt GK, Prince SL, Mack MJ: Video-assisted thymectomy for myasthenia gravis: An update of a single institution experience. Eur J Cardiothorac Surg 22:978-983, 2002. ■ This single-center experience occurred over a 10-year period with 38 VATS thymectomies. Overall, clinical improvement at mean follow-up of 53 months was 83%, and 14.0% of patients were in complete stable remission. The data were reported in accordance with the new guidelines by the Myasthenia Gravis Foundation of America Task Force (2000), which allow valid comparison with future studies. Yim APC, Kay RLC, Ho JKS: Video-assisted thoracoscopic thymectomy for myasthenia gravis. Chest 108:1440-1443, 1995. ■ This is the first reported series in the English literature on VATS thymectomy for myasthenia gravis (MG). Of the eight patients, there was no mortality or intraoperative complication. The median postoperative stay was 5 days; and compared with a historical group of transsternal thymectomy patients, the VATS approach was associated with lesser analgesic requirement and shorter hospital stay. All patients have clinical improvement of their MG at median follow-up of 10 months.

1/21/2008 4:17:46 PM

chapter

142

TRANSCERVICAL THYMECTOMY FOR NONTHYMOMATOUS MYASTHENIA GRAVIS John C. Kucharczuk Joel D. Cooper

Key Points ■ All

patients with myasthenia gravis are considered for thymectomy. ■ The goal of thymectomy in myasthenia gravis is long-term remission; surgery is not a treatment option for acute exacerbations. ■ Patients with nonthymomatous myasthenia gravis are considered for transcervical thymectomy, which provides results equivalent to the more aggressive resections but with shorter hospitalization, lower morbidity, and less cost.

Myasthenia gravis (MG) is an autoimmune disorder in which anti–acetylcholine receptor antibodies reduce the number of functionally available acetylcholine receptors at the neuromuscular end plate. Clinically, MG is manifested by muscle weakness and muscle fatigability. The exact role the thymus plays in this disease remains poorly understood. Nevertheless, observations made by Blalock and colleagues1 more than 50 years ago suggest that surgical thymectomy can induce remission of disease in some patients. Unfortunately, precise preoperative selection criteria for patients likely to achieve remission have not been defined. Likewise, the extent of operation required, either radical or simple thymectomy, has not been established. In this chapter we outline the transcervical approach to thymectomy in autoimmune, nonthymomatous MG. Emphasis is placed on patient selection, operative technique, and the advantages of the transcervical technique over more radical transsternal resection.

PATIENT SELECTION The diagnosis of MG is suspected on clinical grounds. The muscle groups involved and their fatigability with repetitive exercise vary greatly from one patient to another. The diagnosis is confirmed by a neurologist on the basis of a positive edrophonium chloride (Tensilon) test, by the presence of acetylcholine receptor antibodies, or by characteristic electromyographic responses. Traditionally, the clinical symptoms and severity of disease are graded according to the Osserman score (Table 142-1). It is important to classify patients on initial surgical evaluation so that standardized measures of outcome are available to compare one operative approach to another. In this regard, a more detailed Myasthenia Gravis Foundation of America (MGFA) Clinical Classification and Score for disease severity has been developed (Jaretski et al, 2000).2 We currently recommend patients be classified

according to the expanded Quantitative MG scheme with the assistance of their neurologist. Patients being considered for thymectomy must be medically optimized. The goal of thymectomy, by any approach, is the long-term induction of remission. Surgical thymectomy is not a treatment for acute exacerbations of MG. In this regard, close collaboration with a neurologist is vital. Preoperative treatments include cholinesterase inhibitors, immunosuppressive agents, plasmapheresis, and intravenous immunoglobulin. Once patients are medically stable, they can be considered for thymectomy. The practice guideline from the American Academy of Neurology states, “For patients with non-thymomatous autoimmune MG, thymectomy is recommended as an option to increase the probability of remission or improvement.”3 Thus, once medically optimized, all patients with MG, regardless of the severity of disease, are considered for thymectomy by a qualified thoracic surgeon. All patients undergo CT of the chest to evaluate for thymoma. In our practice, patients with nonthymomatous autoimmune MG are evaluated for transcervical thymectomy and those with contraindications to this approach, including the presence of thymoma, are considered for transsternal resection. We obtain a preoperative forced vital capacity (FVC) measurement in all patients. This simple test can be invaluable postoperatively in determining respiratory muscle strength in patients who fail the initial extubation attempt in the operating room. Patients undergoing transcervical thymectomy must be able to flex and extend the neck. Those with limited cervical range of motion due either to osteoarthritis or to surgical fusion are not good candidates for transcervical thymectomy. A history of thyroid surgery or a previous tracheostomy is not a contraindication to the transcervical approach, but it does make dissection significantly more difficult, and the conversion rate to a transsternal approach is higher. Prior cardiac surgery through a sternotomy is a contraindication.

OPERATIVE TECHNIQUE The anesthetic plan is reviewed with the anesthesiologists. A list of drugs that exacerbate MG is generated by the pharmacist, reviewed with the anesthesiologist, and made available to all providers caring for the MG patient. Depolarizing muscle relaxants are avoided. Once general anesthesia is induced the patient is intubated with a single-lumen endotracheal tube. The operating table is turned 90 degrees. Patient positioning is vital to successfully performing the transcervical procedure. The head must 1715

Ch142-F06861.indd 1715

1/21/2008 4:18:29 PM

1716

Section 7 Mediastinum

TABLE 142-1 Modified Osserman Scale for Clinical Grading of Symptoms of Myasthenia Gravis Osserman Score

Symptoms

0

No symptoms

1

Ocular signs and symptoms

2

Mild generalized weakness

3

Moderate generalized weakness

4

Severe generalized weakness, respiratory symptoms, or both

From Osserman KE: Clinical aspects. In Osserman KE (ed): Myasthenia Gravis. New York, Grune & Stratton, 1958, pp 79-80.

be positioned at the top edge of the bed. The patient remains in a supine position, and both arms are tucked. An inflatable bag is placed under the shoulders. The bag is inflated to provide maximal neck extension without allowing the head to hang free. The anterior neck, chest, and upper abdomen are prepped and drapped in a sterile fashion. A 5-cm curvilinear incision is made two fingerbreaths above the sternal notch (Fig. 142-1). Electocautery is used to raise subplatysmal flaps to the sternal notch inferiorly and to the level of the thyroid cartilage superiorly. The cleido-cleido ligament is divided at the sternal notch with cautery. Self-retaining Gelpi retractors are placed on each side of the incision to provide exposure. At this point attention is turned toward identification of the cervical poles of the thymus gland. The avascular midline plane is opened with a Metzenbaum scissors. We identify the left pole of the gland first because it usually extends farther into the neck than the right pole. The left sternothyroid strap muscle is identified and elevated with a forceps. A Kistner dissector is used to gently sweep out the left cervical pole of the thymus from underneath the strap muscle. The gland is well encapsulated and differentiated from the surrounding fat by its pink salmon color. The entire dissection is performed in an extracapsular plane, and the entire left cervical pole is defined to its superior margin so that no thymus tissue is left in the neck. A 0 silk ligature is tied to the left cervical pole as a handle. Next, the left pole is dissected down into the sternal notch. At this point the upper body of the gland is identified and used to help locate the right cervical pole. The right pole is dissected free with the Kistner dissector to its most cephalad extent and tagged with a 0 silk ligature as shown in Figure 142-2. The tagging ligatures are retracted anteriorly by the assistant to allow dissection of the thymic veins that drain directly into the innominate vein (Fig. 142-3). This exposes the thymic venous tributaries emptying into the innominate vein. It is important to determine if both thymic lobes descend anterior to the innominate vein. In up to 5% of cases one thymic lobe, usually the left, passes posterior to the innominate vein. We dissect these small branches out completely and ligate them with fine silk before division. Use of hemoclips is avoided because they have a tendency to fall off during blunt dissection, resulting in troublesome bleeding.

Ch142-F06861.indd 1716

FIGURE 142-1 Incision for thymectomy. A 5-cm curvilinear incision is made two fingerbreaths above the sternal notch.

Left lobe of thymus gland Right lobe of thymus gland

Trachea Sternohyoid muscle Sternothyroid muscle

FIGURE 142-2 Identification and dissection of the poles of the thymus (see text for details). (MODIFIED FROM KAISER LR: ATLAS OF GENERAL THORACIC SURGERY. ST. LOUIS, MOSBY, 1997.)

Left lobe of thymus gland Right lobe of thymus gland Tributaries to innominate vein (thymic venous branches)

Innominate vein

FIGURE 142-3 Dissection of the thymic veins that drain into the innominate vein. (MODIFIED FROM KAISER LR: ATLAS OF GENERAL THORACIC SURGERY. ST. LOUIS, MOSBY, 1997.)

1/21/2008 4:18:29 PM

Chapter 142 Transcervical Thymectomy for Nonthymomatous Myasthenia Gravis

FIGURE 142-4 Cooper thymectomy retractor blade.

Next, the tagging ligatures on the thymic lobes are retracted in a cephalad direction and a dissecting finger is used to develop the plane between the sternum and the anterior surface of the gland. Once this plane has been developed, we are ready to suspend the patient for completion of the mediastinal dissection. A Polytrac retractor is assembled and secured to the table. The Cooper thymectomy retractor blade (Pilling Company, Ft. Washington, PA) is the key to providing adequate exposure (Fig. 142-4). This blade is placed under the sternum, and the circulating nurse deflates the bag underneath the patient’s shoulders so that the patient is suspended by the retractor. The head must not be hanging. Parker retractors are used to provide lateral retraction and are secured to the table rails by Penrose drains. Alternatively, if Parker retractors are not available, Army-Navy retractors can be used and secured to the Polytrac retractor bars as shown in Figure 142-5. The surgeon is seated at the patient’s head (Fig. 142-6). A headlight is mandatory to provide illumination.

1717

FIGURE 142-6 Positioning of the surgeon and assistants for thymectomy.

The first maneuver is to continue development of the substernal, prethymic plane. This is done bluntly with the aid of tonsil balls secured by a ring clamp. Next, the gland is mobilized from the pleural reflections laterally and the pericardium posteriorly. This is performed bluntly by using two ring clamps with tonsil ball sponges attached to the ends. One is used for retraction and the other is used for dissection. The pleural reflections are gently swept away from the lateral extent of the gland; care is taken to avoid violation of the capsule. The recognition, identification, and removal of aberrant thymic tissue can also be performed through the transcervical approach. It does not require conversion to a transmanubrial or transsternal approach. Once the entire gland has been mobilized it is brought out through the cervical incision and oriented for the pathologist. A completely resected specimen is shown in Figure 142-7. Mediastinal hemostasis is visually confirmed, and the superior mediastinum is irrigated with saline. The anesthesiologist

Cooper thymectomy retractor

Thymus gland FIGURE 142-5 Army-Navy retractors can be secured to the Polytrac retractor bars. (MODIFIED FROM KAISER LR: ATLAS OF GENERAL THORACIC SURGERY. ST. LOUIS, MOSBY, 1997.)

Ch142-F06861.indd 1717

FIGURE 142-7 Resected specimen to be sent for pathologic analysis.

1/21/2008 4:18:30 PM

1718

Section 7 Mediastinum

TABLE 142-2 Comparison of Selected Published Series of Thymectomy for Myasthenia Gravis Via Transcervical, Video-Assisted Thoracoscopic, and Maximal Combined Transcervical-Transthoracic Approaches Kaplan-Meier Estimates of Complete Remission

Author (Year)

Surgical Approach

No.

Median Follow-Up (mo)

Shrager et al8 (2006)

Transcervical

164

53

43

NR

44% (at 3 yr) 46% (at 6 yr)

Manlulu et al9 (2005)

Video-assisted thoracoscopic

38

69

22

93

75% (at 10 yr)

Transcervical

120

51.6

41

NR

91% (at 10 yr)

10

de Perrot et al (2003) 11

Remission (%)

Improvement (%)

Shrager et al (2002)

Transcervical

78

54.6

40

NR

43% (at 5 yr)

Mineo et al12 (2000)

Video-assisted thoracoscopic

31

39

36

96

NR

Calhoun et al13 (1999)

Transcervical

100

64

35

NR

NR

14

Bril et al (1998)

Transcervical

52

101

44

90

NR

Jaretzki et al15 (1988)

Extended TranscervicalTranssternal “maximal” thymectomy

95

40

38

93

NR

NR, not reported.

is asked to give the patient a large breath and hold it so that the pleura can be inspected. If the pleural membrane has been violated, the pleura is widely opened and the incision is closed over a red rubber catheter to evacuate the pleural space. There is rarely a need for a formal chest tube. The patient is allowed to emerge from anesthesia and is extubated in the operating room under close supervision. If there is any doubt as to the appropriateness of extubation, measurement of FVC is obtained. Patients with an FVC of greater than 1 L can usually be extubated without difficulty. In our current practice, patients are admitted to the shortstay procedure unit on the morning of their procedure. After the procedure a chest radiograph is obtained. If the radiograph is normal, the patients are allowed to recover for 8 hours and then discharged to home. They remain on the preoperative medications without dose change. They return in 3 weeks for the surgeon to inspect the surgical site and at that point are referred back to their neurologist to consider drug weaning. It may take 2 years or more before the benefit of thymectomy is realized, and it is important that patients understand and accept this fact.

EXPECTED OUTCOMES The ideal outcome for thymectomy in MG by any approach is complete remission. This is manifested by resolution of symptoms and discontinuation of medication. There is also an additional cohort of patients who enjoy substantial reduction in symptoms after thymectomy but do not reach complete disease remission. Considerable controversy exists concerning the extent of thymectomy that is required to induce remission. Masaoka and coworkers performed detailed anatomic studies of the distribution of thymic tissue within the anterior mediastinum and discovered a high prevalence of ectopic thymic tissue.4 Jaretzki confirmed this observation by noting a prevalence of ectopic thymus, either microscopic or macroscopic, in the

Ch142-F06861.indd 1718

neck in 32% and in the mediastinum in 98% of specimens resected by his transcervical-transsternal maximum thymectomy.5 Unfortunately, the importance of ectopic thymic deposits and the role it plays in the persistence of symptoms after thymectomy for MG is unknown, although it has fueled heated debates. Opponents of the extended transcervical approach argue that residual extracapsular rests of thymus lead to a failure of remission and suggest performing maximal thymectomy in all patients with MG. Justification for this view consists of citing sporadic cases in which transcervical thymectomy was performed, symptoms persisted, and on transsternal exploration residual thymus was identified and removed.6,7 The weakness in this argument is that if 98% of patients have ectopic mediastinal thymic deposits and these are missed by the transcervical approach, then the procedure should have terrible outcomes, which is not the case. In fact, the complete remission rates between the transcervical approach, transsternal approach, transsternal-transcervical approach, and the thoracoscopic approach appear equivalent (Table 142-2) (Bril et al, 1998; Calhoun et al, 1999).8-15

SUMMARY The operative approach and extent of dissection for thymectomy in MG has remained controversial. In our opinion, the outpatient transcervical thymectomy procedure described in this chapter is less morbid and less costly than transsternal and extended maximal thymectomy procedures but offers similar outcomes. The transcervical thymectomy procedure is our approach of choice in patients with nonthymomatous MG.

COMMENTS AND CONTROVERSIES The authors have presented an excellent overview of the technique of open transcervical thymectomy for MG. One concern is the ease of teaching the technique due to the limited numbers of cases at

1/21/2008 4:18:32 PM

Chapter 142 Transcervical Thymectomy for Nonthymomatous Myasthenia Gravis

any given institution and the limited view between the operator and the assistant. Others have addressed this to some degree by adding a videoscope through the neck incision, but this may be somewhat cumbersome. To the authors’ credit, they have presented a balanced overview of the published results between transcervical, transsternal, and video-assisted thoracoscopic approaches, all of which appear to be equivalent. Thus, it may not be the specific approach that leads to good outcomes but, as with most procedures, the experience of the surgeon with his or her own approach. In our group we have experience with all three approaches and prefer the video-assisted thoracoscopic approach with similar good results. J. D. L.

Ch142-F06861.indd 1719

1719

KEY REFERENCES Bril V, Kojic S, Ilse W, Cooper J: Long-term clinical outcome after transcervical thymectomy for myasthenia gravis. Ann Thorac Surg 65:1520-1522, 1998. Calhoun RF, Ritter JH, Guthrie TJ, et al: Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Ann Surg 230:555-561, 1999. Jaretski A III, Barohn RJ, Ernstoff, RM, et al: Myasthenia gravis: Recommendations for clinical research standards. Ann Thorac Surg 327334, 2000.

1/21/2008 4:18:32 PM

chapter

143

PATHOPHYSIOLOGY AND INITIAL MANAGEMENT OF THORACIC TRAUMA Joshua H. Burack

Key Points ■ Most thoracic trauma patients are managed with a thorough diag-

nostic evaluation and conservative treatment. ■ Patients with major thoracic vascular, cardiac, or airway injury

require operative intervention as soon as possible. ■ Trauma resuscitation corrects shock-related acidosis and avoids

hypothermia, excessive hypertension, and transfusions. ■ CT and ultrasound provide accurate imaging of thoracic vascula-

ture and organs. Endoscopy is superior for the diagnosis of hollow viscus injury. ■ Surgical intervention in the emergency department, chest tube placement, and thoracotomy can be lifesaving.

Successful treatment of injuries to the thorax requires a fundamental base of anatomic and physiologic knowledge, combined with technical skill and creativity. Many milestones in thoracic surgery were first reported on patients with traumatic injury. The Edwin Smith Papyrus, an account of Egyptian surgical practices in 300 BC, records three cases of penetrating chest injury. Two substantial chest wall injuries were treated conservatively, and a third wound to the cervical esophagus was repaired with suture. Homer, in an account of the siege of Troy in 950 BC, described a multitude of chest wounds, including the infamous death of Sarpedon, who exsanguinated after removal of a spear that had penetrated the heart.1 Many current advances and observations essential to the seminal growth of thoracic surgery occurred on the battlefield. Theodoric promoted the surgical débridement and primary closure of chest wounds in the 13th century. The value of an occlusive thoracic dressing and tube drainage, in the setting of open hemopneumothorax, was initially employed by the Napoleonic surgeon Larrey in 1767. The mystique surrounding direct suture of the heart was dispelled by the German surgeon Rehn, who performed the first successful cardiorrhaphy for a penetrating injury in 1896.2 Over the past century, mortality rates from military thoracic injury have steadily declined from 63% in the American Civil War to 9% and 7% in the recent conflicts in Vietnam and Croatia.2-5 The modern advances in surgical technique, early transport and resuscitation, pleural drainage, precise diagnostic tests, and direct operative repair, along with advances in antibiotic therapy, transfusion methods, and anesthesia continue to promote a greater likelihood of survival. In the current Iraqi conflict, the techniques of immediate resuscitation at a forward hospital and abbreviated damage control

surgery have been optimized, resulting in an initial mortality rate of 2% for all combatants. In addition, the prevention of direct thoracic injury with the widespread use of protective thoracoabdominal body armor has reduced the incidence of thoracic injury to 10%, without appreciable mortality among protected combatants.6 Worldwide, it is estimated that all types of traumatic injury result in more than 3 million civilian deaths annually. Automobile accidents and interpersonal violence predominate. In most developed countries, trauma is the most common cause of death in people younger than the age of 44 years.7 In the United States, approximately 150,000 people die each year as a result of trauma. Approximately 25% of the deaths are directly related to thoracic injury.8 In a contemporary series from a major American urban trauma center, the overall mortality rate of civilians admitted with traumatic injury was 4.1%, rising to 7.8% when the admissions met standard trauma registry criteria. The overall mortality for blunt trauma was 5.7%, and for penetrating trauma the mortality rate was 11.5%. The most frequent body region with critical injuries was the head (43%), followed by the chest (28%) and abdomen (19%).9 In the first hour after hospital admission, thoracic vascular and neurologic trauma is the most common cause of death. Three significant risk factors for early death have been observed8,9: 1. A thoracic injury with a chest abbreviated injury score (AIS) greater than 4 2. A neurologic injury with a Glasgow coma scale (GCS) score less than 8 3. Admission systolic blood pressure less than 90 mm Hg Injury has been shown to follow a trimodal death distribution. Immediate death usually occurs at the scene and is secondary to massive central nervous system injury or cardiovascular rupture. These injuries are typically not salvageable and only prevention, as is seen with advanced body armor or automotive technology, can cause significant reduction in mortality. A second group of patients will die in the initial 24 hours after injury, with a cluster of mortality within the first golden hour typically related to major thoracic injury and additional deaths related to brain and abdominal injury occurring within the 6- to 24-hour window. It is this subgroup of patients who will benefit most from rapid resuscitation and treatment of the injury. Lastly, late deaths occur days to weeks after the initial trauma and are due to sepsis and multiple organ failure, which are often a reflection of an imperfect resuscitation and treatment during the initial phases of injury (ACS, 2004).7-11 1723

Ch143-F06861.indd 1723

1/21/2008 4:19:23 PM

1724

Section 8 Trauma

In contrast to those patients who require immediate attention within the initial hour of injury, most patients with thoracic trauma are successfully managed nonoperatively. Thoracic trauma has an approximately 10% mortality rate, and treatment is usually straightforward and successful.12 Most patients survive as a result of a prompt resuscitation, efficient diagnostic testing, and simple therapeutic maneuvers. In a contemporary multicenter experience, urgent operative treatment was required in 0.5% of blunt and 2.8% of penetrating injury (Karmy-Jones et al, 2001).13,14 However, in those who require emergency exploration of the thorax, current operative mortality rates remain significant, with death in 67% of patients with blunt injury and in 17% of patients with penetrating injury (Karmy-Jones et al, 2001).14 It is the initial management, in the golden hour after injury, and the accurate selection of patients for conservative management or prompt exploration that are responsible for the survival of many patients.

ANATOMIC CONSIDERATIONS Precise anatomic knowledge is crucial for the initial assessment of injury. In the diagnostic phase, injury must be considered to affect multiple body cavities if the superior or inferior extent of the thorax has been violated (Fig. 143-1). The diaphragm, at the inferior margin, is frequently injured in truncal trauma. The skin landmarks for the diaphragm extend between the umbilicus and nipple (fourth intercostal space) anteriorly and the inferior tip of the scapula posteriorly. The bony landmarks for the diaphragm extend from T8

to L1. With expiration, the diaphragm rises to the level of the nipple and T5. At the superior margin of the chest lies the thoracic outlet, often referred to as zone 1 of the neck. The zone extends from the cricothyroid membrane to the sternal notch. Particularly in penetrating trauma, injuries at either margin of the chest increase the potential for complex injury. Furthermore, hemothorax may be the result of an extrathoracic injury decompressing into the chest through the diaphragm or from the cervical vasculature. The thorax is divided into separate body cavities defined by the parietal membrane attachments: the pleural spaces, the pericardium, and the posterior mediastinum. These cavities can readily communicate with the peritoneum or the cervical structures as a result of injury. The physiologic response to hemorrhage into the pleura and pericardium is dramatically different. In the adult, each pleural space can accommodate as much as 3 L of blood. This large volume loss will cause rapid progression to class IV hemorrhagic shock and exsanguination (Table 143-1). In contrast, the pericardium can only acutely accommodate an additional 100 to 200 mL of blood before venous return and diastolic filling are impaired, causing cardiac tamponade and shock.15 The integrity of the chest wall and the underlying pleural membrane is essential for respiratory function. Negative intrapleural pressure, the coordinated function of the thoracic musculoskeletal system, and a patent airway are all required for respiration. Airway obstruction or injury, pneumothorax, hemothorax, and a significant flail chest are life-threatening injuries unless quickly treated. An open pneumothorax related to a traumatic chest wall defect will seriously compromise spontaneous respiration. If the defect is larger than two thirds of the cross-sectional area of the trachea, ventilation will preferentially occur across the defect rather than down the trachea (ACS, 2004).8

Cricoid cartilage

PATHOPHYSIOLOGY

Thoracic outlet

T5 Xiphoid Diaphragm

T10

L1

FIGURE 143-1 The boundaries of the thorax: diaphragmatic excursion and the thoracic outlet.

Ch143-F06861.indd 1724

The pathophysiologic response to injury is related to the primary mechanism of injury, which can be classified as blunt or penetrating. Blunt trauma results from vehicular accidents, followed by falls, assaults, sports, crush, or blast injuries. The severity of a blunt injury is proportional to the force or the kinetic energy involved. Newton’s second law of motion describes the relationship as F = ma, where the force (F) of a blunt injury and the resultant gross effects are directly proportional to the mass (m) and acceleration (a) of the impacting object.16 Pulmonary contusion is the most common blunt thoracic injury, and the extent of the alveolar hemorrhage and parenchymal injury is directly related to the magnitude of a blunt chest wall injury.17 Blunt injury can be compounded by dislocated skeletal fracture, which may lacerate underlying viscera with sharp fragments. Substantial blunt injury can also occur without direct impact. Damage from a blast pressure wave preferentially affects gas-containing organs: intestine, eardrum, and lung. Shock and hypoxemia characterize the clinical response to a major blast injury. The lung is particularly susceptible, and barotrauma can cause immediate and life-threatening pulmonary edema.18 In an animal model of blast-induced circulatory

1/21/2008 4:19:23 PM

Chapter 143 Pathophysiology and Initial Management of Thoracic Trauma

1725

TABLE 143-1 Estimated Blood Loss Based on Initial Vital Signs in a 70-kg Man Sign

Class I

Class II

Class III

Class IV

Blood loss (mL)

<750

750-1500

1500-2000

>2000

Blood loss (% blood volume)

<15%

15%-30%

30%-40%

>40%

Pulse rate (bpm)

<100

>100

>120

>140

Blood pressure

Normal

Normal

Decreased

Decreased

Respiratory rate

14-20

20-30

30-40

>35

Urine output (mL/hr)

>30

20-30

5-15

Negligible

Mental status

Anxious

Anxious

Confused

Lethargic

Fluid replacement (3:1 rule*)

Crystalloid

Crystalloid

Crystalloid/blood

Crystalloid/blood

*An empirical resuscitation formula requiring approximately 300 mL of crystalloid solution for each 100 mL of blood loss. Adapted from Committee on Trauma, American College of Surgeons: Advanced Trauma Life Support Program for Doctors, 7th ed. Chicago, American College of Surgeons, 2004.

shock, pulmonary hemorrhage resulted in ventilationperfusion mismatch and a unique type of cardiogenic shock, where myocardial depression without compensatory vasoconstriction were the primary pathophysiologic processes.19 Additional injury can occur as a result of torsion or rotational forces. In response to significant force or deceleration, anatomic structures, fixed in position by membranous attachments, can be avulsed at the point of mediastinal fixation. Injury to the aortic isthmus, main bronchus, diaphragm, or atria is typical. Early survival is related to the integrity and strength of the mediastinal pleura.20 An uncommon injury mechanism may occur when visceral rupture or valvular disruption occurs after blunt trauma. Coincident with blunt impact, intraluminal disruptive forces are intensified when a hollow viscus is a closed space with a fixed volume. Presumably after glottic closure the trachea or the esophagus can rupture, or during coaptation the cardiac valves and subvalvular apparatus can be avulsed.21,22 The host response to equivalent force is also variable. Immature bones are less calcified and more resilient than their adult counterparts. In comparison to adults, children have a much lower incidence of bony injury after major blunt trauma. A rib fracture in a child is usually a marker of a severe injury, and blunt aortic injury almost always occurs without rib fracture.23-25 In adults, after motor vehicle accidents, blunt aortic injury is associated with rib fracture in approximately 50% of cases.26 In the elderly, even isolated rib fractures and relatively innocuous visceral injuries can result in a significant risk of respiratory failure and death, a certain reflection of declining physiologic reserve and comorbid disease.27 In addition, different solid organs, based on their inherent architecture, have different behavior when subjected to equivalent blunt force. In the bovine model, before organ rupture occurs the heart can sustain almost twice the blunt force than the spleen or the liver.28 Penetrating injury causes a laceration of anatomic structures in the trajectory of the weapon. Knife and bullet wounds are the most common injuries. A knife injury is typically limited to the length of the blade and the corresponding depth of the wound, assuming that the entire blade had

Ch143-F06861.indd 1725

penetrated in each instance. Unpredictable missile ricochet can drastically alter the path of a bullet injury. However, in the thorax, large deflections in the missile trajectory are uncommon and are unlikely unless an associated fracture of the impacted bone is present.29 The kinetic energy of a missile is dependent on its weight and velocity. This energy disrupts cells and fragments tissues in an area around the path of the bullet. The actual size of this cavity is determined by the size, rotation, and tumbling of the missile. Close range missile wounds are more destructive because less of the initial energy is dissipated by air friction. As the magnitude of the weapon increases from knife to low-velocity and then high-velocity bullets, the accompanying blast effect to surrounding structures rises. A high-velocity military missile (>3000 ft/s) is 36 times more destructive than a low-velocity missile (<500 ft/s).30

SHOCK AND RESUSCITATION Shock is defined as a syndrome that is precipitated by a global decrease in perfusion that results in inadequate delivery of oxygen to tissues, compromising organ function. Early shock after trauma generally is a result of hemorrhage and subsequent hypovolemia. After cardiac tamponade or tension pneumothorax, compressive shock can occur with mechanical compression of the heart within the confines of the pericardium or thorax. Less common precipitating factors are cardiogenic shock due to myocardial failure and neurogenic shock secondary to loss of sympathetic tone. The physiologic response to hemorrhagic shock is well understood. The magnitude of response is dependent on the volume of hemorrhage (see Table 143-1). A decrease in blood pressure immediately causes an increase in sympathetic activity with tachycardia and vasoconstriction. Within minutes the neuroendocrine response is initiated by the secretion of epinephrine and norepinephrine. Constriction of the microvasculature in the skin, kidneys, viscera, and the capacitance vessels in skeletal muscle and the lungs shifts blood centrally, increasing effective blood volume. This increased central blood volume, tachycardia, and increased myocardial contrac-

1/21/2008 4:19:23 PM

1726

Section 8 Trauma

tility results in increased cardiac output and a state of compensated shock (ACS, 2004).8 Additionally, there is an increase in circulating cortisol in response to a sudden increase in adrenocorticotropic hormone from the anterior pituitary. Cortisol levels are elevated for up to 48 hours and are responsible for tissue catabolism, which provides the necessary substrates for wound healing and hepatic synthesis of glucose and acute phase proteins. The neuroendocrine response to stress also modifies salt and water excretion. Aldosterone and antidiuretic hormone both cause a decrease in urine volume and sodium reabsorption, causing fluid and sodium retention. Glucagon levels increase and insulin levels decrease, signaling hepatic gluconeogenesis. If the patient suffers no complications, this catabolic phase lasts 2 to 6 days and is followed by a prolonged period of anabolism with positive nitrogen balance with normalization of salt and water excretion.31 The cellular response to injury is a consequence of hypoperfusion and reduced oxygen delivery, below the oxygen requirements of the cellular apparatus. The hypoxemic insult initiates anaerobic metabolism and lactate production. With sustained untreated hypoperfusion, precapillary sphincters fail and cellular membrane function becomes impaired. Cellular acidosis and swelling ensue, and the patient becomes more and more resistant to resuscitation. If not rapidly corrected, this uncompensated state results in death. As a result of resuscitation, perfusion is restored to the microvasculature of ischemic tissues, and a reperfusion injury is initiated. Reperfusion injury and activation of the leukocyte-mediated inflammatory cycle is thought to be essential to the development of systemic inflammatory response syndrome (SIRS) and posttraumatic organ failure. The injury is amplified by an interrelated cascade of inflammatory mediators: complement cytokines, coagulation cascade proteins, kinins, and prostaglandins. In addition, free radicals, normally scavenged by healthy cells, persist in the ischemic cell long enough to degrade the lipid cellular membrane. Activated neutrophils subsequently adhere to damaged endothelial cells, resulting in microvascular thrombosis, edema, and further ischemia. SIRS is initiated by injury and appears to be a normal compensatory mechanism for a severe trauma. However, the beneficial effect of SIRS may become exaggerated and dysfunctional, particularly if an additional second injury occurs during the latter phase of management in the emergency department, operating room, or surgical intensive

care unit. The two-hit theory provides an explanation for the generalized inflammatory response and multiorgan dysfunction that is common after major trauma. There is activation of multiple humoral (complement, coagulation, and hormonal) and cellular (neutrophils, macrophages, monocytes, and endothelial cells) components that activate and amplify the production of numerous inflammatory mediators (cytokines, free radicals, proteolytic enzyme, cytokines), which can result in a sustained inflammatory state and multiple organ failure. Ultimately, it is endothelial cell structure and function, manifested by cellular membrane injury and leaky capillaries, that are the initial and final common pathways in organ dysfunction and failure seen after trauma.31-33 Treatment of hemorrhagic shock requires control of hemorrhage and reconstitution of circulating blood volume. After securing the airway and ensuring ventilation, the search for possible sources of hemorrhage and volume resuscitation occur simultaneously. In hypotensive patients, 1 to 2 L of warm lactated Ringer’s solution are infused and the response observed (Table 143-2). In the American College of Surgeons Advanced Trauma Life Support (ATLS) protocols, the traditional 3:1 rule suggests early resuscitation with a volume of crystalloid three times greater than that of the estimated blood loss. If improvement in blood pressure is minimal or transient, then hemorrhage is usually significant and blood transfusion is considered while additional crystalloid is infused. Transfusion is recommended if the blood loss is estimated to be greater than 25% of the total blood volume (ACS, 2004).8 Cross-matched type-specific blood is ideal, but time constraints may require the use of type-specific, type O-negative, or autologous blood. In the unstable patient with substantial hemorrhage and the need for massive transfusion, as defined by a replacement of more than one blood volume in a 24-hour period, a preset massive transfusion protocol can expedite release of red blood cells and required factors. Typically a trauma protocol contains 10 units of blood, along with 4 units of fresh frozen plasma and 6 units of platelets.34 Shed blood, particularly in an anticoagulated pleural collection system, can be autotransfused. However, blood collected from a hemothorax is deficient in platelets, fibrinogen, and the ability to clot.35 Additionally, the transfusion of banked blood has potentially deleterious effects by activating the immune system, provoking neutrophil cytotoxicity, and occluding the microvascula-

TABLE 143-2 Responses to Initial Fluid Resuscitation* Rapid Response

Transient Response

No Response

Vital signs

Normalize

Transient improvement

Remain abnormal

Estimated blood loss

Minimal (<20%)

Moderate and ongoing (20%–40%)

Severe (>40%)

Need for more crystalloid

Low

High

High

Need for blood

Low

Moderate to high

Immediate

Need for operative intervention

Possibly

Likely

Highly likely

*2000 mL Ringer’s lactate solution in adults; 20 mL/kg Ringer’s lactate bolus in children. Adapted from Committee on Trauma, American College of Surgeons: Advanced Trauma Life Support Program for Doctors, 7th ed. Chicago, American College of Surgeons, 2004.

Ch143-F06861.indd 1726

1/21/2008 4:19:23 PM

Chapter 143 Pathophysiology and Initial Management of Thoracic Trauma

ture with abnormal, preserved erythrocytes, all of which may negatively affect oxygen transport and ultimate outcome (Moore et al, 2004).36 In a randomized multicenter trial of resuscitated trauma patients there was no significant difference in outcome when a restrictive transfusion policy (target hemoglobin concentration between 7-9 g/dL) was compared with a liberal transfusion policy (target hemoglobin concentration >10 g/dL).37 Furthermore, in the first 24 hours after injury, it appears that blood transfusion, independent of the severity of injury or shock, is an independent predictor of a worse outcome.38 Despite these observations, which identify new and unforeseen deleterious consequences of blood replacement, in response to active hemorrhage, the prudent approach is to continue to support a relatively liberal transfusion policy (hemoglobin level >7 g/dL in young and healthy patients and hemoglobin level >10 g/dL in the elderly or those with ischemic heart disease).34 The advantage of prompt control of active hemorrhage is undisputed. A prolonged and massive preoperative resuscitation, prior to definitive control of hemorrhage, is avoided. In several randomized trials, an abbreviated resuscitation, to relatively hypotensive endpoints, has been repeatedly shown to provide similar, if not improved, survival in trauma patients.39,40 Furthermore, the lethal triad of coagulopathy, acidosis, and hypothermia is rapidly fatal unless interrupted and is usually a consequence of prolonged resuscitation and delayed hemostasis.36 In the emergency department, after the initial disrobing and physical examination, core body temperature is preserved with various active warming devices: heated blankets, warmed intravenous (IV) fluids, and inspired oxygen.34 Coagulopathy is treated with empirical transfusion of fresh frozen plasma and platelets after transfusion of moderate amounts of banked blood. Additionally, recombinant factor VIIa, which initiates thrombin formation by binding with exposed tissue factor, has been shown to be beneficial in the correction of traumatic coagulopathy.41 Prompt and abbreviated damage control surgery, initially popularized in the setting of major abdominal vascular trauma, emphasizes prompt vascular control of hemorrhage and subsequent resuscitation.42 In the thorax, an emergency department thoracotomy (EDT) and pulmonary tractotomy and nonanatomic resection are established techniques of abbreviated and expeditious surgery.43,44 The presence of a robust distal circulation, with bounding radial or pedal pulses and warm, pink extremities almost certainly excludes hypovolemic shock. However, normalization of blood pressure, pulse rate, and urine output alone are not sensitive indicators of resolution of shock. This is particularly true for patients after class I, II, and III hemorrhage when vital signs are not substantially abnormal but patients remain in shock, albeit compensated shock.45 Shock may be more precisely defined as inadequate tissue perfusion and oxygenation with resultant anaerobic metabolism; therefore, evidence of improved tissue oxygenation or tissue perfusion may provide more precise endpoints of resuscitation. Clinical markers of hypoperfusion and cellular acidosis include serum lactate and base deficit determinations. Serum lactate rises with hypovolemic shock, and increasing levels are associated with increased likelihood of death. In addition,

Ch143-F06861.indd 1727

1727

the longer the time to normalize lactate, the worse the outcome.46 Base deficit, calculated from the arterial blood gas analysis, correlates with severity of injury and risk of death. It generally reflects serum lactate levels as well. It has the advantage that it is readily available, is inexpensive, and can provide important physiologic information about the adequacy of resuscitation.45 In addition to the conventional serum markers for shock, newer techniques of noninvasive monitoring of the circulatory state have potential for application during the initial management of injury. Thoracic electrical bioimpedance monitors for measuring cardiac output, rapid analyzers of serum lactate and mucosal pH, and transcutaneous measurement of tissue oxygen and carbon dioxide tension can all be applied in the emergency department and provide similar information to the conventional pulmonary artery catheter monitor in the surgical intensive care unit.47,48 Once these new technologies become widely available, the clinician will have tools that are more sensitive than the traditional blood pressure, pulse rate, and urine output or the serum indicators of metabolic acidosis and therefore a better ability to detect and avoid the shock state.

HISTORY AND PHYSICAL EXAMINATION An accurate history and physical examination are essential. Obviously, the extent of the initial evaluation may be abbreviated, owing to the severity of injury and the tempo of therapeutic intervention. Furthermore, the initial assessment may be limited by the previous paramedic intervention, and it may be difficult to evaluate an intubated, restrained patient. At the minimum, an AMPLE history is obtained: allergies, medications commonly used, past illnesses or pregnancy, last meal, and the events related to injury (ACS, 2004).8 Re-creation of the injury scene, from the patient’s or paramedical personnel’s accounts, can be rewarding. Certain types of vehicular accidents are associated with different patterns of injury. A frontal impact and the pathognomonic bent steering wheel suggest substantial blunt trauma to the chest wall, lungs, heart, and aortic isthmus. A passenger involved in a side impact accident and a pedestrian struck by an automobile both have the increased possibility of a significant injury to the solid upper abdominal organs on the side of the impact, as well as blunt aortic rupture (ACS, 2004).8,49 Ejection from the vehicle and death of another occupant in the vehicle are associated with a higher incidence of lethal multiple trauma (ACS, 2004).8 Other common blunt injury mechanisms, which are quantified at the time of admission, are falls from heights, crush injuries, assaults, and sports injuries. Blunt impact to the chest during sports activities, particularly baseball in children, can result in commotio cordis and sudden death.50 The history is vital because physical findings are often absent. The specifics of a penetrating injury can also be important. The dimension of the knife, or impaling object, the position of the combatants at the time of the assault, the caliber of the weapon, and the number of shots fired is helpful. Unfortunately, this information is usually vague and unreliable, but occasionally valuable hints about the anatomic extent of injury can be obtained.

1/21/2008 4:19:24 PM

1728

Section 8 Trauma

Physical examination of the trauma patient is straightforward. Vital signs must be obtained on admission to the emergency department and compared with those obtained in the field. The vital signs on presentation will provide an estimate of blood loss (see Table 143-1). As a rule, profound hypotension and a depressed sensorium indicate thoracic or abdominal hemorrhage, rather than neurologic injury and neurogenic shock. The hemodynamic responses of the heart rate and blood pressure to the ongoing resuscitation must be appraised at frequent intervals. Intact peripheral pulses and perfused extremities imply a normovolemic state. The response to early resuscitation has significant implications for the amount of hemorrhage present and the need for operative intervention (see Table 143-2). Evaluation and treatment of the ABCs—airway, breathing, and circulation—compose the initial assessment (ACS, 2004).8 Ventilation is evaluated by observing the respiratory rate and the quality of chest wall and diaphragmatic excursion. If stridor is present, a maxillofacial or tracheal injury is probable. Frank disruption of the airway can be obvious with air escaping from a cervical penetrating injury or subcutaneous emphysema.51 Hemoptysis is usually minor after trauma and suggests a parenchymal lung or tracheobronchial injury. Massive hemoptysis (>500 mL) can occasionally be seen with a major pulmonary vascular injury. A sucking chest wound, and the concomitant open pneumothorax and impaired ventilation, is equally obvious and will cause rapid ventilatory decompensation if large enough. Rarely, traumatic asphyxia can occur as a result of a massive crush injury, causing temporary compression of the superior vena cava or blunt cardiac rupture, and is characterized by upper body plethora, petechiae, and edema (ACS, 2004).8 Both lung fields are auscultated for air entry and the presence of breath sounds. The diagnosis of a pneumothorax or hemothorax is a clinical one. At the accident scene, or if the patient’s condition is unstable, chest tube decompression is often initiated before radiographic confirmation. Despite a noisy emergency department, auscultation to detect hemothorax and pneumothorax is useful when evaluating both blunt and penetrating trauma patients. The absence of breath sounds has a positive predictive value of greater than 95% to detect the presence of abnormal pleural air or blood.52,53 Once and if the patient’s condition is stabilized in the emergency department, a careful secondary survey can proceed. The entire chest wall can be palpated to evaluate for a flail segment, crepitance, soft tissue contusion, or deformity of the ribs, sternum, or clavicle. A flail chest is considered to be present if four or more ribs have fracture or dislocations in at least two places or if an obvious paradox of the chest wall occurs with inspiration. Sternal fractures or dislocations usually manifest as point tenderness or a step off. Fracture or dislocation of the sternoclavicular joint may manifest as prominence of the clavicular head in the case of the more common anterior dislocation or cause compression of the structures of the thoracic inlet along with the hollowed out pocket deformity of a posterior dislocation.54 Hematomas, particularly of the thoracic inlet, can be marked and measured. Peripheral pulses are documented. A pseudocoarctation syndrome can be present after blunt aortic

Ch143-F06861.indd 1728

FIGURE 143-2 Impaled knife in the back. A 25-year-old man sustained a stab wound, with impalement, to the left posterior thorax. Using a VATS technique, the knife was removed under direct vision and the injury to the superior segment of the left lower lobe was resected.

injury or dissection.21 Carotid pulsations and distended neck veins are noted. The heart is auscultated, and sometimes Beck’s triad (muffled heart sounds, distended neck veins, and hypotension) are present, suggesting cardiac tamponade.55 The presence of pulsus paradoxus (>10 mm Hg decline in systolic arterial pressure with inspiration) is also suggestive of cardiac tamponade. However, tension pneumothorax, or any mechanism that causes a rise in intrathoracic pressure, can manifest in a similar fashion. In addition, the axillae and the back must be carefully examined, so that a small penetrating injury is not missed. Lastly, a penetrating object impaled in the chest is left undisturbed, to be removed in the operating room (Fig. 143-2).56

INITIAL EVALUATION Bedside Procedures The airway is secured and respiration is maintained. If ventilation is not adequate, the airway is obtained by orotracheal intubation. Extreme care must be exercised if a cervical spine fracture is suggested, and manual cervical spine alignment must be maintained during intubation. If significant maxillofacial trauma or airway obstruction is present, the airway can be obtained with a cricothyroidotomy (Fig. 143-3). If there is suspicion of a blunt injury to the cervical trachea, orotracheal intubation proceeds over a flexible bronchoscope, with the ability to perform a surgical airway as an option.57 A potential alternative, if an experienced operator and equipment are available, is an emergency percutaneous tracheostomy, particularly if the injury is proximal to the tracheostomy site.58 After a major blast injury, excessive positive pressure ventilation must be avoided to minimize alveolar disruption.18,19 Venous access is secured with large-bore (<16 gauge) peripheral catheters. If a major venous injury is suggested, access must be obtained proximal to an abdominal injury or on the contralateral side of a thoracic venous injury to avoid extravasation of resuscitation fluid into the peritoneum or

1/21/2008 4:19:24 PM

Chapter 143 Pathophysiology and Initial Management of Thoracic Trauma

1729

Tracheal hook

Thyroid cartilage

Cricothyroid membrane

FIGURE 143-3 Technique for cricothyroidotomy. A transverse skin incision is made over the cricothyroid membrane, which is then incised with a scalpel. The incision in the membrane is bluntly spread apart, and a tracheostomy tube is inserted. (FROM MOORE FA, MOORE EE: TRAUMA RESUSCITATION. IN WILMORE DN, BRENNAN MF, HARKEN AH ET AL [EDS]: CARE OF THE SURGICAL PATIENT. NEW YORK, SCIENTIFIC AMERICAN, 1989.)

pleura. A subclavian or internal jugular central venous catheter is desirable, and in the case of a cardiac injury an elevation in the central venous pressure will suggest the diagnosis. The heart rate and rhythm are observed with continuous electrocardiographic (ECG) monitoring. In the case of penetrating cardiac trauma, normal sinus rhythm is a favorable prognostic sign.59 In the context of blunt injury, ECG abnormalities (bundle branch block, ST segment alterations >1 mm, Q waves, abnormal QT interval, and pathologic T waves) or arrhythmia (premature atrial or ventricular contractions) are present in most patients with a cardiac contusion. There is a direct correlation between the severity of the ECG abnormality, the degree of ventricular dysfunction, and the serum troponin-1 level.60 Commotio cordis is heralded by ventricular fibrillation and cardiopulmonary arrest.50 A pulseless agonal idioventricular rhythm or asystole usually implies a prolonged arrest and irretrievable injury. Despite traumatic cardiopulmonary arrest, moribund penetrating trauma victims, but not similar blunt trauma victims, occasionally survive (Hopson et al, 2003).61,62 A Foley catheter is inserted and the urine output is monitored. A urine output greater than 1 mL/kg/hr implies a satisfactory cardiac output and tissue perfusion (see Table 143-1). A nasogastric tube is inserted to provide gastric drainage and avoid pulmonary aspiration, and it may provide information about the integrity of the diaphragm or the presence of a mediastinal hematoma. Drainage of the pleural space with a chest tube may be initiated if the diagnosis of hemothorax or pneumothorax is clinically suggested.52,53 Pleural drainage alone is a simple and definitive treatment in a large number of patients with thoracic trauma (Karmy-Jones et al, 2001).12-14 An open pneumothorax requires an occlusive dressing together with chest tube decompression.

Ch143-F06861.indd 1729

Chest tube insertion is typically performed at the level of the fifth intercostal space, on the lateral aspect of the thorax (Fig. 143-4). The skin is prepared and local anesthetic is administered, particularly to the subdermal region, the periosteum of the rib, and the pleural membrane. A small skin incision (2 cm) is created in the anterior axillary line, just lateral to the pectoralis muscle in males or to the lateral mammary crease in females. With a curved clamp, the intercostal space is bluntly dissected and the pleura is carefully entered over the superior aspect of the rib. A finger is placed in the pleural space to ensure that pulmonary adhesions are not present and then a chest tube (28-32 Fr) is positioned posteriorly and superiorly in the pleural space. A poorly placed tube can cause pulmonary injury, an undrained pneumothorax or hemothorax, a post-removal pneumothorax, or empyema, all of which cause significant morbidity and extended hospitalization. The technique of chest tube insertion is crucial, and thoracic surgeons, and their surgical trainees, have reported a significantly lower complication rate than other physicians involved in trauma care.63 The initial amount of blood drained, along with the degree of air leak, is noted. A massive, continuous air leak or a significant hemorrhage is a prime indication for a formal thoracotomy. In a multicenter study, a direct relationship has been observed between the amount of pleural hemorrhage prior to thoracotomy and the risk of death (Fig. 143-5).14 A prompt video-assisted thoracoscopy and operative evacuation is preferable to a second chest tube for a retained hemothorax (Meyer et al, 1997).64

Diagnostic Tests Routine arterial blood gas analysis, complete blood cell count, and blood chemistry (SMA-18) values can all be obtained

1/21/2008 4:19:24 PM

1730

Section 8 Trauma

Pleural space

R5

Lung

A

Anterior axillary line

B

Insertion of thoracostomy tube

C

D

FIGURE 143-4 Technique for chest tube insertion. A, Chest tube insertion site on the lateral thorax in the fifth intercostal space and the anterior axillary line and lateral to the pectoralis major and the breast. B, A skin incision has been made, and a sharp, curved clamp is used to bluntly spread the intercostal muscles and enter the pleural space over the superior margin of the rib. C, A finger is introduced to explore the wound and to exclude significant pleural adhesions. D, A chest tube is inserted into the pleural space. The tube is guided with a curved clamp in a posterior and cephalad direction. The chest tube is secured to the skin and connected to a pleural drainage system.

from a single puncture of the radial or femoral artery. An indwelling radial arterial line is desirable, particularly in patients who have sustained multiple trauma and who are destined for a multitude of diagnostic tests, or if there is significant suspicion of blunt aortic injury and the patient’s blood pressure must be strictly regulated.65 Arterial blood gas analysis will provide further insight as to the quality of ventilation. The clinical evaluation of respiration remains paramount, and identification of significant hypoxemia or hypercarbia will support the use of mechanical ventilation. The serum pH and base deficit corresponds to the degree of shock and the quality of the resuscitative effort.

Ch143-F06861.indd 1730

A profound or persistent acidosis (pH of <7.20 or base deficit >12 mEq/L) or the inability to normalize the serum lactate level (normal lactate <2 mmol/L) implies decompensated shock and substantial mortality.34,36,45,46 Blood is sent for crossmatch, and routine blood analysis is performed. A complete blood cell count will provide a serum hematocrit, which has a limited role in predicting the amount of acute blood loss or the response to resuscitation. Chemistry analysis is important only to confirm electrolyte balance during volume infusion and to determine serum troponin levels if blunt cardiac trauma is suspected. A normal serum troponin-1 value (<1.05 µg/L) on admission and at 6-hour

1/21/2008 4:19:25 PM

Chapter 143 Pathophysiology and Initial Management of Thoracic Trauma

2000 1600 Operate mL

1200 800 400

Observe 0

15

30 Minutes

0

1000

45

60

2

3 Hours

4

A 50 30

Risk for Death

20 10 5 3 2 1 2000 3000 4000 5000 Total Chest Tube Output (mL)

6000

B FIGURE 143-5 A, Operation versus observation in patients with hemothorax after chest trauma. B, Correlation between mortality and total chest tube output before thoracotomy. The mean (±SD) total output before thoracotomy was 1627 ± 945 mL. The mean (±SD) time was 2.4 ± 5.4 hours. (A FROM MATTOX KL, WALL MJ: NEWER DIAGNOSTIC MEASURES AND EMERGENCY MANAGEMENT. CHEST SURG CLIN N AM 7:213, 1997; B FROM KARMY-JONES R, JURKOVICH GJ, NATHENS AB, ET AL: TIMING OF URGENT THORACOTOMY FOR HEMORRHAGE AFTER TRAUMA. ARCH SURG 136:513, 2001.)

1731

follow-up essentially excludes a cardiac contusion, and an elevated troponin-1 level directly correlates with the severity of arrhythmia and the degree of left ventricular dysfunction.60 An admission chest radiograph is an essential part of the diagnostic workup (Table 143-3). The important exceptions are those moribund patients in whom immediate surgery is required and those patients with an obvious pneumothorax or hemothorax who require urgent chest tube decompression before radiographic confirmation. The plain chest radiograph remains invaluable in the diagnosis of immediately lifethreatening conditions (e.g., tension pneumothorax and hemothorax) and can be diagnostic or suggestive of other potential life-threatening conditions, including diaphragmatic rupture, flail chest, pulmonary contusion, mediastinal hemorrhage, and pneumomediastinum (ACS, 2004).8 Review of the chest radiograph is methodical and includes the pleural spaces, diaphragm, pulmonary parenchyma, mediastinum, bony structures, and indwelling tubes and catheters. A pneumothorax can be subtle and may only be evident hours after the initial injury or may only be apparent on subsequent computed tomography (CT). More commonly, a traumatic pneumothorax is obvious and can progress to a tension pneumothorax with mediastinal shift (Fig. 143-6). A massive pneumothorax, with complete collapse of the lung (fallen lung sign) or abrupt cutoff of the mainstem bronchus (bronchial cut-off sign), both suggest bronchial rupture with complete distal atelectasis (Fig. 143-7) (Mirvis, 2004).66 An upright chest radiograph makes the diagnosis of a hemothorax or hemopneumothorax relatively straightforward, with the loss of the costophrenic sulcus and a fluid meniscus. A supine film may be difficult to interpret, and subtle changes in pleural opacification may be missed, particularly if they are bilateral. A massive hemothorax, with retained intrapleural blood, can trap air next to the mediastinum and cause the medial meniscus sign or a caked hemothorax (Fig. 143-8).67 The radiographic evaluation of the diaphragm can be difficult. Persistent elevation usually suggests an intra-abdominal

TABLE 143-3 Diagnostic Tests Test

Advantages

Disadvantages

Definitive Diagnosis

Chest radiography

Portable, rapid, gold standard for general screening

FAST ultrasound

Portable, extremely rapid

Trained personnel required

Pericardial effusion, hemoperitoneum

Transesophageal echocardiography

Portable

Trained physician required, entire aorta and brachiocephalic vessels not imaged

Pericardial effusion, valvular and wall motion abnormalities, blunt aortic injury

CT/CT angiography

Extensive imaging required in most multiple trauma patients (head and abdomen), emerging standard for general screening

Transport to suite, contrast medium required

Mediastinal hematoma, missile trajectory, fracture, vascular injury

Angiography

Anatomic detail, potential for percutaneous therapeutic intervention

Transport to suite, contrast medium needed, trained radiologist required, slow

Vascular injury

Pleural air or blood, lung parenchyma, fracture?

CT, computed tomography; FAST, focused assessment with sonography for trauma.

Ch143-F06861.indd 1731

1/21/2008 4:19:25 PM

1732

Section 8 Trauma

FIGURE 143-6 Tension pneumothorax. A, Chest radiograph that shows a left-sided tension pneumothorax (arrows) in a 60-year-old man who was involved in a motor vehicle accident. B, Complete lung re-expansion after chest tube drainage.

FIGURE 143-7 Bronchial disruption. Chest radiograph of a 12-yearold boy who was struck by a motor vehicle. A massive left-sided pneumothorax and complete atelectasis of the left lung (fallen lung sign) are shown. Complete disruption of the proximal left mainstem bronchus was repaired primarily at thoracotomy.

Ch143-F06861.indd 1732

FIGURE 143-8 Massive hemothorax. Chest radiograph of an 18year-old man who sustained a close-range, single gunshot wound to the right side of the chest. Brisk pulmonary parenchymal bleeding caused the entrapment of air between the massive hemothorax and the mediastinum (medial meniscus sign) (arrows). A right upper lobe wedge resection was required.

1/21/2008 4:19:26 PM

Chapter 143 Pathophysiology and Initial Management of Thoracic Trauma

process, and flattening or inversion suggests a tension pneumothorax. Traumatic diaphragmatic disruption infrequently presents as an acute eventration of intra-abdominal contents into the pleural space, but it is usually suggested by a subtle loss of diaphragmatic contour or a pleural effusion in the majority of patients (Mirvis, 2004).66,68 Radiographic evaluation of the pulmonary parenchyma may reveal a spectrum of changes seen with contusion. An early contusion can appear as a fluffy, air space–occupying process located in a nonanatomic distribution (geographic distribution) in the periphery of the lung fields and in proximity to bony fracture. However, a large pulmonary contusion, or pulmonary hematoma, can manifest as substantial opacification of the lung fields and can be confused with a hemothorax. Less common are traumatic pseudocysts, which have an appearance similar to bullae or blebs (Mirvis, 2004).17,66 Injury within the mediastinum manifests as extravasated air or blood. Pneumomediastinum is commonly a self-limited radiographic abnormality thought to be related to alveolar barotrauma and subsequent dissection of air beneath the visceral pleura into the mediastinum (Mirvis, 2004).66 Pneumomediastinum may also signal rupture of trachea, bronchus, or esophagus. Particularly after blunt impact, airway injury is more common than esophageal injury, and endoscopic evaluation is warranted.57,69 Mediastinal hematoma can signify blunt aortic injury but is also commonly seen after spinal fracture or inconsequential venous injury.70 Widening of the mediastinum, loss of the contour of the aortic knob or aortic arch, apical pleural cap, depression of the left mainstem bronchus, or deviation of the nasogastric tube or the trachea to the right suggests a blunt aortic injury at the aortic isthmus. The diagnostic value of these radiographic signs is relatively low, with a widened mediastinum being the most common abnormality, but with sensitivity and specificity to detect blunt aortic injury of less than 50% (Mirvis, 2004).66,71 The initial diagnostic efforts to screen for blunt aortic injury are expanded to include aortobrachiocephalic (ABC) injury. Blunt injury of other segments of the thoracic aorta, typically the ascending aorta or major brachiocephalic branches, can occur in up to 20% of all cases of thoracic vascular injury.72,73 Major vascular injury manifests with a normal chest radiograph in up to 44% of cases.65,70-72 The admission chest radiograph must be scrutinized for bony injury. Often, nondisplaced rib fractures, costochondral separations, and vertebral fractures are overlooked on the initial film and further imaging is required. Despite the degree of force required to fracture the first rib, the injury is usually not associated with concomitant vascular injury. The incidence of isolated first rib fracture and associated major vascular injury is approximately 3%. More importantly, multiple trauma and fracture dislocation of the first rib, along with radiographic signs of mediastinal hematoma or suggestive physical findings, are current indications for further evaluation (ACS, 2004).8,74 The radiographic positions of various indwelling catheters can have important therapeutic and diagnostic implications. The endotracheal tube must be in the mid trachea, above the carina. With the nasogastric tube in the stomach, rightward

Ch143-F06861.indd 1733

1733

displacement of the mediastinal path suggests mediastinal hematoma. If the nasogastric tube is coiled above the diaphragm, the diagnosis of blunt rupture of the left diaphragm is confirmed. The chest tube is positioned posteriorly and superiorly, and the last side hole must be in the pleural space. CT of the chest has been applied to chest trauma patients with increasing frequency, reflecting the imaging quality in the current technology and the ability to reconstruct the radiographic image to produce a CT angiogram. Disadvantages include the use of IV contrast medium for vascular imaging and the need to place the injured patient through the CT scanner. However, many patients, particularly patients with blunt multiple trauma, are already being examined in the radiology suite with a head or abdominal CT. CT is invaluable in identifying a mediastinal hematoma and a hematoma in proximity to the great vessels with a much higher degree of accuracy than a chest radiograph (Fig. 143-9) (Mirvis, 2004).65,66,70,75 CT of the chest is an ideal screening test for blunt aortic injury with a negative predictive value of 100% and sensitivity of 100% and a specificity of 83% in one large clinical series.65 Furthermore, CT angiography can be used as the sole diagnostic test before surgery for repair of blunt aortic injury.76 CT angiography provides anatomic detail quite similar to that of a standard aortography, and the diagnostic accuracy is equivalent. The aortogram is held in reserve for equivocal cases, typically those occasional cases with a mediastinal hematoma and a normal aortic contour (Fig. 143-10).76,90 CT can also be widely applied to a large spectrum of patients with thoracic trauma. The majority of patients with a substantial blunt injury (from high-speed motor vehicle accidents or falls from more than 10 feet) or any abnormality on physical examination or chest radiography have had additional injuries identified after CT, which has prompted a change in management in up to 40% of patients. CT is more effective than chest radiography in the detection of skeletal

FIGURE 143-9 Mediastinal hematoma. Contrast medium–enhanced CT scan in a 22-year-old man who was involved in a motorcycle accident shows a small posterior mediastinal hematoma (arrow) near the descending thoracic aorta. Angiography was negative for vascular injury.

1/21/2008 4:19:26 PM

1734

Section 8 Trauma

FIGURE 143-10 Blunt aortic rupture. An aortogram of a 27-year-old woman who fell from the roof of a four-story building. Shown is a blunt aortic rupture with a contained mediastinal hematoma (arrows). A prosthetic interposition aortic graft was necessary at a delayed thoracotomy.

FIGURE 143-11 Focused assessment with sonography for trauma (FAST). Ultrasound transducer positions to examine the pelvis, subdiaphragmatic, pleural, and pericardial spaces for traumatic effusion. (FROM ROZYCKI GS, BALLARD RB, FELICIANO DV: SURGEON-

injury, pulmonary contusion, pneumothorax, hemothorax, and hemopericardium (Mirvis, 2004).66,77,78 Occasionally, CT can identify blunt rupture of the trachea, diaphragm, or heart (Mirvis, 2004).66,79,80 Patients with penetrating transmediastinal injury represent another diagnostic challenge. Gunshot injury traversing the mediastinum precipitates hemodynamic instability related to a thoracic vascular injury in approximately 50% of cases. Unstable patients, in persistent shock, require immediate operative intervention, whereas those patients without obvious hemorrhage and a sustained systolic blood pressure greater than 100 mm Hg may safely undergo further diagnostic evaluation.81 A screening contrast-enhanced CT scan is helpful to define the anatomic extent and trajectory of the missile and the proximity to vascular structures, the trachea, and the esophagus. A negative CT scan can reliably exclude injury, but if the missile is in proximity to these structures, then secondary diagnostic tests are helpful.82,83 Flexible endoscopy, particularly in the agitated or intubated patient, or contrast esophagography, in the awake and cooperative patient, can accurately diagnose esophageal injury.69 Similarly, flexible bronchoscopy provides direct visualization and is highly accurate in the diagnosis of airway injury.57 In complex or diagnostically challenging cases, formal aortography is the

final diagnostic test to identify vascular injury and possibly deliver an endovascular therapeutic intervention.84 Preliminary ultrasound evaluation of the abdomen and thorax, along with formal transthoracic and transesophageal echocardiography, is an important component of the initial evaluation of the trauma patient. Ultrasonography is advantageous owing to the portability of the equipment and the rapidity of the examination. A limited focused assessment with sonography for trauma (FAST) examination can be performed during the secondary survey by trained trauma surgeons or emergency department physicians. In several minutes, four standard ultrasonographic views are obtained: the pelvis, left and right upper quadrants and related pleural spaces, and the subxiphoid pericardial space (Fig. 143-11).85 The diagnosis of a traumatic pericardial effusion can be made by the visualization of an echolucent region between the heart and pericardium, and right ventricular diastolic collapse will confirm tamponade. If a skilled sonographer is present, ultrasonography appears as accurate as traditional subxiphoid pericardial window in making the diagnosis of effusion, with an accuracy, sensitivity, and specificity above 95%.85-87 In a recent multicenter series, most patients (86%) had a true negative ultrasound examination and there were no missed cardiac injuries. Rarely, a false-

Ch143-F06861.indd 1734

PERFORMED ULTRASOUND FOR THE ASSESSMENT OF TRUNCAL INJURIES: LESSONS LEARNED FROM 1540 PATIENTS. ANN SURG 228:557, 1998.)

1/21/2008 4:19:27 PM

Chapter 143 Pathophysiology and Initial Management of Thoracic Trauma

negative result can occur when there is a clotted hemopericardium or if the pericardial effusion is completely decompressed into the pleural space through a pericardial laceration or if a hemothorax is present.87,88 Additionally, the presence of obesity, mechanical ventilation, hyperinflation, and subcutaneous emphysema occasionally does not permit a technically satisfactory examination.87 Despite the advantages of the rapid, accurate, and noninvasive technique of ultrasonography, the subxiphoid pericardial window remains an important diagnostic option for indeterminate or difficult cases. Originally applied to stable patients with penetrating trauma in proximity to the heart, indications for FAST examination may be extended to blunt precordial injury with signs of cardiac tamponade or thoracoabdominal injury with unexplained hypotension. The presence of a hemopericardium implying a cardiac laceration or blunt cardiac rupture can be confirmed. In the unstable patient the choice of the initial incision can be based on the presence of hemoperitoneum or hemopericardium.86,89 A transesophageal echocardiogram can be performed in the emergency department or operating room. The aortic isthmus, the ascending aorta, and the heart can be visualized in great detail. Unsuspected cardiac injuries can be detected, whereas more peripheral vascular injuries to the brachiocephalic branches may be missed (Nagy et al, 2001).90,91 Transesophageal echocardiography can be used to grade the severity of blunt aortic injury, which can be helpful in selecting subsequent treatment options. A grade 1 injury is a limited hematoma or intimal flap, which can be treated conservatively. A grade 2 injury is a subadventitial rupture or modification of the geometric shape of the aorta, which can be repaired at a variable time interval after injury; and a grade 3 injury is an aortic transection with active bleeding or obstruction, which requires immediate surgery.92,93 In experienced hands, transesophageal echocardiography will reliably diagnose a blunt

1735

aortic injury, with a sensitivity of 95% and a specificity of close to 100%, with accuracy similar to that of angiography and CT angiography.90,92,94 With the transition from traditional invasive diagnostic tests (pericardial window, angiography, or endoscopy) to advanced ultrasound and radiographic techniques, it is evident that mediastinal injury, both penetrating and blunt, can be accurately imaged by a number of excellent techniques. The selection of the diagnostic testing typically depends on the location the injury and the stability of the patient, as well as on the expertise of the examiner and institution.

SURGICAL TREATMENT An emergency department thoracotomy (EDT) is the definitive diagnostic and therapeutic option. It is indicated for those patients who present in traumatic arrest or who sustain arrest or near-arrest during the resuscitation. Obviously, exploration in the operating room is preferable if vital signs permit rapid transfer. For an EDT, adequate lighting and surgical equipment, along with anesthesia personnel and banked blood, are made available in the emergency department. Alternatively, in the correct circumstance, a pre-hospital thoracotomy can be performed by trained physicians in the field, allowing survival in a well-selected group of patients.95 Specific guidelines have been developed to facilitate identification of those patients who will potentially benefit from an EDT and, conversely, those patients who will not survive. Patients with a sinus rhythm and a penetrating injury to the precordium, particularly a stab wound, have the highest rate of survival (Hopson et al, 2003).59,61,62 An EDT is performed through a left anterior thoracotomy. The incision is made just below the nipple from the sternum to the midaxillary line, and the chest is entered through the fourth or fifth intercostal space (Fig. 143-12). The descend-

Pericardium

Phrenic nerve

FIGURE 143-12 Emergency department thoracotomy. A left anterior thoracotomy incision is made with the patient in the supine position. The fourth or fifth interspace is entered, and the descending thoracic aorta is cross clamped. Care is taken to avoid injury to the esophagus. The pericardium is opened to initiate cardiac massage. A search for an active source of hemorrhage in the left pleural space and pericardium is performed. The sternum can be transversely divided and the right pleural space can be entered if necessary. (FROM MOORE FA, MOORE EE: TRAUMA RESUSCITATION. IN WILMORE DN, BRENNAN MF, HARKEN AH ET AL [EDS]: CARE OF THE SURGICAL PATIENT. NEW YORK, SCIENTIFIC AMERICAN, 1989.)

Ch143-F06861.indd 1735

1/21/2008 4:19:27 PM

1736

Section 8 Trauma

TABLE 143-4 Early Operative Indications Diagnosis

Comment

Traumatic arrest after penetrating chest trauma

Emergency department thoracotomy

Persistent shock

Failed resuscitation

Suspect or proven cardiac injury

FAST examination if stable

Massive hemothorax (>1500 mL on chest tube insertion) Persistent hemothorax (>500 mL/hr initial hour of drainage or >200 mL/hr for several hours) Retained hemothorax

Initial VATS

Massive air leak or airway injury suspect

Initial endoscopy in operating room

FAST, focused assessment with sonography for trauma; VATS, video-assisted thoracoscopic surgery.

ing thoracic aorta can be cross clamped just superior to the diaphragm, carefully avoiding the esophagus with its indwelling nasogastric tube, in this way potentially improving perfusion to the brain, heart, and upper extremities. A pericardial incision is made anterior to the phrenic nerve, and the heart is exposed. Open cardiac massage can proceed, and the site of injury in the pericardium or left pleural space can be addressed. Cardiac injuries can be managed with digital compression of ventricular injury or occlusive clamping of an atrial or great vessel injury, followed by suture repair. Significant pulmonary injuries will require temporary en mass clamping of the pulmonary hilum to provide proximal control of hemorrhage or air leak. The right pleural space can be entered by bluntly dissecting anterior to the pericardium; and, if need be, the thoracotomy can be carried across the sternum and converted into a clamshell incision. The right atrium is available for the insertion of large IV catheters to facilitate transfusion. The goal of the EDT is to rapidly diagnose the injury and perform direct repair or to temporize the injury to permit restoration of vital signs and rapid transfer to the operating room.43 EDT is most successful in the treatment of penetrating cardiac injuries, particularly knife wounds, in which a reported survival of greater than 50% can be achieved.59 However, the need for aortic cross clamping and an idioventricular rhythm after EDT are predictors of nonsurvival.59 Operative survival after complex penetrating thoracic injuries occasionally occurs, but survival after blunt injury or thoracoabdominal injury is almost nonexistent.43,61 During the course of the initial resuscitation, operative decisions must be made by the trauma or thoracic surgeon. Apparent traumatic cardiac arrest and near-arrest remain the sole indications for an EDT. Indications for prompt transfer to the operating room include a confirmed or highly suspect cardiac injury or persistent hemodynamic instability despite resuscitation. A massive hemothorax (1000-1500 mL of blood on insertion of a chest tube) or persistent hemorrhage (>500 mL of blood in the initial hour or >200 mL of blood/ hour for several hours) mandates exploration, and delay increases the mortality rate in a linear and predictable fashion (see Fig. 143-5) (Karmy-Jones et al, 2001).14 Finally, an airway injury, to the cervical or thoracic trachea or main

Ch143-F06861.indd 1736

bronchus, requires prompt endoscopy and operative repair (Table 143-4).

SUMMARY The treatment of thoracic trauma continues to evolve and improve. Careful examination and resuscitation, together with simple bedside procedures, facilitate a successful outcome in most patients. In addition, important improvements in the management of hemorrhagic shock and technologic advances in diagnostic imaging, combined with prompt operative repair, continue to improve survival in severely injured patients. Subsequent chapters in this section include discussions on the manifestations and specific treatment of injuries to the individual thoracic viscera. The final chapter is a review of the current management of the late sequelae of chest injury.

COMMENTS AND CONTROVERSIES Significant improvements in the management of thoracic trauma can be attributed to experience gained from military combat. Dramatic reductions in combat mortality had been achieved by protective armor, superior initial management, and rapid evacuation. Sadly, such improvements have not occurred in civilian thoracic trauma, particularly in the United States, where mortality rates for thoracic trauma, especially penetrating injury, remain high. In this era of sophisticated subspecialized trauma centers, it is easy for general thoracic surgeons to be excluded from initial management of thoracic trauma. This is a detriment to patient care and thoracic surgical training. In this chapter, the anatomic considerations and pathophysiology of thoracic trauma are reviewed in detail. The management of the lethal triad of coagulopathy, acidosis, and hypothermia is emphasized. Emergent bedside evaluation and management is outlined in detail. Particularly important is the critical interpretation of the initial chest radiograph. Contrast-enhanced CT has replaced angiography for the assessment of most vascular injuries and for the evaluation of penetrating thoracic trauma. Ultrasonography has become standard for the emergency evaluation of the trauma patient. The specific indications for emergency department thoracotomy are clearly stated. There is a limited role for this option in blunt trauma, but for patients with penetrating trauma an occasional salvage can be

1/21/2008 4:19:28 PM

Chapter 143 Pathophysiology and Initial Management of Thoracic Trauma

accomplished. Correct placement of an anterolateral fourth or fifth interspace thoracotomy is key to functional exposure. G. A. P.

KEY REFERENCES American College of Surgeons Subcommittee on Trauma: Advanced Trauma Life Support Program for Doctors, 7th ed. Chicago, American College of Surgeons, 2004. ■ This is the definitive handbook on the basic, initial management of the trauma patient. Hopson LR, Hirsh E, Delgado J, et al: Guidelines for withholding or termination of resuscitation in prehospital traumatic cardiopulmonary arrest: Joint position statement of the National Association of EMS Physicians and the American College of Surgeons Committee on Trauma. J Am Coll Surg 196:106, 2003. ■ Consensus guidelines for the application of emergency department thoracotomy and resuscitation in patients sustaining traumatic cardiopulmonary arrest are provided. Karmy-Jones R, Jurkovich GJ, Nathens AB, et al: Timing of urgent thoracotomy for hemorrhage after trauma. Arch Surg 136:513, 2001. ■ In this multicenter study the authors identify a direct relationship between the amount of post-traumatic hemorrhage and the risk of death. In both penetrating and

Ch143-F06861.indd 1737

1737

blunt trauma, early thoracotomy is recommended to reduce substantial operative mortality. Meyer DM, Jessen ME, Wait MA, et al: Early evacuation of traumatic retained hemothoraces using thoracoscopy: A prospective, randomized trial. Ann Thorac Surg 64:1396, 1997. ■ A prospective clinical trial confirms the value of thoracoscopy, as compared with a second chest tube, in the management of a retained hemothorax. Mirvis SE: Diagnostic imaging of acute thoracic injury. Semin Ultrasound CT MRI 25:156, 2004. ■ A comprehensive and current review is provided of the applications of CT in patients with thoracic trauma. Moore FA, McKinley BA, Moore EE: The next generation in shock resuscitation. Lancet 363:1988, 2004. ■ A well-organized and current summary of the salient issues and controversies in the clinical practice of shock resuscitation from traumatic injury is provided. Nagy K, Fabian T, Rodman G, et al: Guidelines for the diagnosis and management of blunt aortic injury: An EAST Practice Management Guidelines Work Group. J Trauma 48:1128, 2000. ■ Consensus guidelines for the diagnostic evaluation and clinical management for blunt aortic injury are presented.

1/21/2008 4:19:28 PM

chapter

LARYNGEAL TRAUMA

144

Philippe Pasche Florian Lang Philippe Monnier

Key Points ■ The strict adherence to well-established diagnostic and manage-

ment protocols has decreased both the mortality due to airway compromise and the poor outcomes due to delayed diagnosis. ■ When indicated, early surgical intervention in appropriate cases with meticulous repair of the laryngeal framework yields the best functional results.

This chapter addresses external laryngeal trauma and does not deal with internal iatrogenic trauma that is induced by intubation, cricothyrotomy, tracheotomy, and laser. External traumas include blunt and penetrating injuries, inhalation injuries, and injuries from caustic ingestion. Various classifications have been proposed, according to site,1-3 to the tissue injured,4 or to the severity.5 The different injuries are discussed according to the cause of the trauma and to the structure damaged.

HISTORICAL NOTE The first report of a true laryngeal trauma and its treatment dates from as early as Egyptian antiquity (in the Edwin Smith Papyrus), but treatment was not adequate until the extensive anatomic and physiologic works of the Renaissance that allowed the consequences of laryngeal trauma to be fully understood (da Vinci, 1452-1519; Vesalius, 1514-1580; Paré, 1509-1590; Casserius, 1545-1616; Morgagni, 1682-1771).6,7 Tracheotomy then became the standard lifesaving treatment in laryngeal trauma, as reported for the first time in 1620 by Habicot in Paris.6 Some of these patients were also saved by direct tracheal intubation through the wound.8 The first breakthrough in diagnosis and treatment occurred in the second half of the 19th century with a dramatic increase of surgical possibilities because of the development of anesthesiology (inhalation narcosis [Priestly]; chloroform [Simpson]; cocaine [Jelinek]; laryngeal block [Braun]), better hygiene (disinfection of laryngeal instruments [Pasteur]), and laryngoscopy (Garcia, Czernak, Kierstein), which allowed the ultimate in comprehension of laryngeal physiology and pathology. Tracheotomy became part of the treatment only to ensure breathing (prophylactic use [Langenbeck]), and the era of surgical treatments of laryngeal injuries started: laryngotomies for reduction of laryngeal fractures (Eichman, Germany, 1850; Laney, France, during the Napoleonic wars), treatment of laryngotracheal stenoses (Dobleau, 1869), tracheal resec-

tion-anastomosis (Küster, 1885), and laryngeal reconstructions with skin flaps.6,7 In the 20th century, the incidence and the variety of laryngeal traumas that occurred during the world wars and the Korean and Vietnam conflicts forced the further development of adequate diagnostic and treatment procedures. As early as 1918, most of the modern surgical techniques had already been reported.9,10 Enhancement of the prognosis, however, took many additional developments, especially in infection control (penicillin [Fleming, 1928]; sulfonamides [Domagk, 1935]), in radiology (radiography for shrapnel localization [Moure, 1915]; laryngeal tomography [Canuyt, 1939]; computed tomography [CT] scanning), in surgical technology (suspension laryngoscopy [Killian, 1911]; surgical microscope [Albrecht, 1954]; microlaryngoscopy [Kleinsasser, 1963]; CO2 laser [Strong and Jako, 1972]), and in anesthesiology (jet ventilation [Carden, 1973]). More improvements in treatment and prognosis began in the 1960s, at the same time as a change in the epidemiology occurred, with a marked increase of traumas from car and motorcycle accidents. Epidemiology, physiopathology, and laryngeal wound healing were studied systematically.5,11,12 Special care was paid to blunt traumas1 and to laryngotracheal disruptions.13,14 Natural history, classification, and timing of treatment were discussed.15 Hirano became interested in the phoniatric sequelae of laryngeal trauma.16 Diagnosis was refined because of the selective application of CT.17 The specifics of laryngeal traumas in the pediatric age group were reported18,19 as well as surgical novelties such as the miniplate osteosynthesis of the thyroid alae.20 Despite all of this knowledge and the publication of individual and small group studies,2,12,21,22 there was no consensus about the management of such injuries. A significant advance in laryngeal trauma management was made by Gussack and Schaefer, who introduced protocol approaches to this relatively rare injury. Relying on his series of 139 consecutive cases in work over 27 years, Schaefer, in 1992, published a management algorithm of great value (Schaefer, 1992).23 Major surgical advances finally took place in the treatment of laryngotracheal trauma sequelae: enlargement plasties (Réthi, 1956; cricoid split [Cotton, 1992]); resection surgery in the trachea (Grillo, 1965), the larynx (Ogura, 1971; Gerwat and Bryce, 1974; Pearson, 1975), and the pediatric larynx (Savary, 1978); and laser surgery (Duncavage, 1985; Shapshay, 1987). The fact that it took the contributions of so many people and of so many different sciences to understand the larynx and to be able to repair its functional capacity illustrates well the complexity of the organ and the multiplicity of the prob-

1738

Ch144-F06861.indd 1738

1/21/2008 4:20:17 PM

Chapter 144 Laryngeal Trauma

lems that arise when there is a need to restore breathing, swallowing, and voice. HISTORICAL READINGS Barbaix M, Clotuche J, De JP, et al: [Birth and development of otorhinolaryngology in the history of medicine]. Acta Otorhinolaryngol Belg 35:1045-1622, 1981. Guerrier Y, Mounier-Kuhn P: Histoire des Maladies de l’Oreille, du Nez et de la Gorge. Paris, Les Editions DaCosta, 1980. Moure E, Liébault G, Kanuyt G: Pathologie de Guerre du Larynx et de la Trachée. Paris, Librairie Félix Alcan, 1918. Sabatier C: De la Médecine Opératoire ou des Opérations de Chirurgie qui se Pratiquent le plus Fréquemment. Paris, Imprimerie de Didot le Jeune, 1796. Schwab W, Ey W: Verletzungen und Stenosen des Kehlkopfes und der Luftröhre. In Berendes J (ed): Kehlkopf Sprachstörungen. Stuttgart, Thieme, 1963.

ANATOMY Schematically, the larynx is a tubelike structure that is formed by mobile and articulated cartilages that are connected by pliable but resistant fibrous membranes; numerous intrinsic highly differentiated muscles and nerves that may be directly injured; and an internal mucosa that can, in certain places, be easily detached and the integrity of which is critical for normal function of the larynx. The larynx is suspended to the hyoid bone and to the tongue base and is followed caudally by the trachea. Although it lies anteriorly directly subcutaneously on the midline (which can make it vulnerable to anterior penetrating trauma), the larynx enjoys a relatively well-protected position in the neck. It is shielded laterally by the bulk of the sternocleidomastoid muscles, from behind by the cervical spine and the other muscles of the neck, and from above by the overhanging mandible. When the patient is in an upright position, the larynx is shielded from the front and the sides by the mandible and the shoulder girdle because the normal reflexive reaction to impending anterior trauma is to withdraw, lower the head, and raise the shoulders.24,25 Moreover, the vertical and lateral pliability of the laryngeal structures allows a certain degree of avoidance of the trauma. In children, the larynx is situated higher in the neck than is the adult larynx, and its tissue elasticity is increased. Thus, it is afforded even greater protection. Finally, the nasal filter offers the larynx a certain amount of protection against inhalation injuries.

EPIDEMIOLOGY Because of the protected position of the larynx in the neck and along the upper respiratory tract, external laryngeal trauma is uncommon. Previous studies estimate an incidence of 1 per 14,000 to 40,000 emergency visits, with a mortality rate as high as 40% from blunt injuries26 and from 7% to 20% with penetrating injuries.27,28 Mortality is due to immediate asphyxia, hemorrhage from an associated vascular lesion, or simply laryngeal concussion. Because the larynx is a highly innervated organ, a direct blow, even without major laryngeal lesions, can induce a nociceptive reflex to the bulbus, thus provoking a laryngospasm with temporary palsy of one or both recurrent laryngeal nerves, a respiratory arrest lasting up

Ch144-F06861.indd 1739

1739

to several minutes, or a cardiac arrest, which is usually fatal in the absence of cardiopulmonary resuscitation.24 The immediate mortality rate is even higher (as high as 80%) when the thoracic trachea is involved because of the associated vascular injuries and when head and neck or other adjacent sites of the body have injury.29,30 Therefore, external laryngeal trauma has a low overall incidence in trauma centers, accounting for only 1 in 30,000 emergency department visits.31 In their national traffic security report in 1964, Dufflot and Hoffman found craniocerebral traumas in 21.1% of patients injured in a road accident, maxillofacial traumas in 17.7%, and laryngeal traumas in 1.7%. Other data suggest that one laryngeal fracture to every 650 peacetime fractures of the facial bone (0.15%) can be expected.32 The introduction of seat belts and airbags may explain a decrease of the incidence of external laryngeal trauma since the 1980s. In a hospital with a well-established emergency service and trauma center, two to five cases of laryngeal trauma are encountered each year.33 Recently, the incidence of external laryngeal trauma was estimated to be approximately 1 per 137,000 inpatient admissions, with a 2% estimated mortality rate (Jewett et al, 1999).34 Associated injuries included craniocerebral trauma (13%), open neck (9%), cervical spine (8%), and pharyngeal or esophageal (3%) injuries. External laryngeal trauma is caused by motor vehicle accidents in 60% of the cases (car, 37%; motorcycle, 23%), by assault or suicide attempts in 20% (mainly knife wounds or hanging), and by blows to the neck (sport accidents, e.g., karate, soccer; or occupational accidents, e.g., from rotating blades, motor chain saws, or elevator repair) or by falls (ski, mountain bike) in the remaining 20%.12,33 In peacetime, blunt injuries are more common (83%) compared with penetrating injuries (17%).33 The ratio of knife injuries to gunshot injuries depends strongly on geographic factors, and the frequency of gunshot wounds is increasing, especially in the United States.35 In penetrating traumas to the neck, the larynx, with its anterior subcutaneous position, is the most frequently injured organ (10.1% of the cases; pharynx and esophagus, 9.6%; jugular vein, 9%; carotid artery, 6.7%; spinal nerve, 3.0%).36 Supraglottic and transglottic injuries are the most frequent causes. Subglottic injuries are rare, and cricoid cartilage fractures are usually combined with fractures of the thyroid cartilages.29 Because of its high localization in the neck, the pediatric larynx is not commonly injured, and, indeed, in infants who are younger than 18 months of age, trauma is largely the result of impacted foreign bodies, intubation, or hypopharyngeal aspiration. In older children, the activities of childhood play a greater role (falls, sports accidents). Automobilerelated injuries increase in older children, whereas in adolescents they outweigh all other causes in laryngeal trauma incidence.18,19

MECHANISMS OF INJURY Blunt Trauma The basic mechanism for blunt external injury to the laryngotracheal skeleton consists of the compression of the laryn-

1/21/2008 4:20:18 PM

1740

Section 8 Trauma

FIGURE 144-1 Blunt laryngeal trauma due to a car accident. In cases of unfastened or loose seat belts, the body is thrust forward with the neck hyperextended. The unprotected larynx crashes against the steering wheel.

A

B

gotracheal cartilages on the cervical spine. The larynx is particularly exposed to crushing forces in a car accident when no seat belt is worn, when the belt is too loose, or when only a lap belt is used. The occupant of the car is thrust forward during rapid deceleration with the neck hyperextended (Fig. 144-1). This position removes the bony protection that is afforded by the mandible, and the steering wheel, dashboard, and back of the front seats are then ideally positioned for crushing impact.25,35,37 In motorcycle riders, the larynx is usually hit by the handlebar or the brake handle.12 Young and flexible larynges may absorb the impact and spring back into position without fracturing. Only submucosal edema or submucosal hemorrhage may ensue, but these can still result in an airway compromise, especially in children because of the small cross-sectional area of the pediatric airway and because the medical personnel underestimate the situation because of a lack of fractures.35 Indeed, the flexible cartilages potentiate the mechanism of dislocation of the arytenoid cartilages and rupture of the membranous vocal folds. The anterior convex surface of the vertebral bodies acts like a wedge to force the thyroid alae apart when the thyroid cartilage is driven against it (Fig. 144-2). The posterior cricoid lamina is driven anteriorly by its impact on the spine, releasing all tension on the vocal ligaments and simultaneously displacing the arytenoid cartilages anteriorly. If the anterior force of the trauma is then suddenly withdrawn, the larynx springs back instantaneously, massively

C

FIGURE 144-2 Blunt laryngeal trauma: mechanism of injury. A, Larynx in normal position. B, Anterior force (large arrow) driving the cartilage against the vertebral body, spreading the thyroid alae apart. This typically causes vertical median or paramedian fractures of the thyroid cartilage. Note the places (small arrows) where the thyroid alae and the cricoid lamina impact into the pharyngeal mucosa, causing lacerations. C, Sudden withdrawal of the anterior force (large arrow), with a springing back of the larynx. The overextension of the ligaments causes disruption of the vocal folds especially at their anterior insertion (see left vocal fold, small thin arrow) or an anterior arytenoid dislocation (see right vocal fold, small thick arrow).

Ch144-F06861.indd 1740

1/21/2008 4:20:18 PM

Chapter 144 Laryngeal Trauma

1741

strangulation. Typically, both types of injuries cause a marked laryngeal edema with loss of airway in 12 to 24 hours.

Penetrating Trauma

A

B

FIGURE 144-3 Blunt laryngeal trauma: typical lesions. A, Typical hyoid, thyroid, and cricoid fracture lines. Vertical fractures are the most frequent ones. B, Posterior dislocation of the epiglottic petiolus and disruption of the vocal fold at the anterior commissure.

increasing the tension on the vocal ligaments. This may result in rupture of the membranous vocal folds, typically at their insertion at the anterior commissure; dislocation of the arytenoid cartilage that is anterior to the cricoid lamina; or rupture of the thyroepiglottic ligament with posterior dislocation of the petiolus (see Figs. 144-2 and 144-3). Fractures of any or all of the cartilaginous structures occur by the same mechanism, especially in calcified larynges. The fracture pattern corresponds to the point of impact. Associated pharyngeal wounds are common and are due to the impact of the thyroid cornua of the hyoid bone, the posterior margins of the thyroid cartilage, and the cricoid lamina against the vertebral bodies, crushing the lateral and posterior pharyngeal wall between them and causing hematomas, lacerations, or perforations (see Fig. 144-2). Striking the lower neck on a rigid wire or rope (so-called clothesline injury) at high speed while riding a bicycle, a motorcycle, or an all-terrain vehicle exerts a large amount of energy on a small area and results in massive trauma. The elasticity of the supporting structures of the airway tends to pull the larynx cephalad and the trachea caudad, with the point of impact acting as the dividing point.13 Depending on the point of impact, the result is a crushed larynx, a separation of the cricoid from the larynx, or, more commonly, a cricotracheal disruption, which is often followed by immediate death. Two other blunt mechanisms may lead to an acute laryngotracheal disruption: 1. Sudden increase of intratracheal pressure with closed glottis can result in a linear rupture 2. Blow to the chest or an acceleration-deceleration injury produces a sudden movement of the trachea around its fixed points at the cricoid and carina, leading to a shearing force that sometimes results in complete transection In hanging injuries, the hyoid and thyroid are uncommonly fractured, as they may be in ligature or manual strangulation. The cricoid is usually not fractured in either hanging or in

Ch144-F06861.indd 1741

Penetrating trauma is mainly caused by razor or knife cuts, gunshots, or splinters of mines or gun shells. Associated vascular injuries are frequently the cause of death. The larynx may be displaced by knife thrusts without serious injury, and there is no tissue destruction distant to the path of injury. The course of the injury may be estimated from the entrance and exit wounds. Nevertheless, the wound may be narrow, and by its aspect one might be tempted not to suspect deeplying, especially vascular, lesions. Injury from a gunshot depends on the type of weapon used and the range from which it was fired. Shots at close range cause intense energy and are usually fatal, whereas shots from a long range may cause only minimal damage. Low-velocity handguns have a moderate blast effect on soft tissues, but the bullet may be deviated by harder structures such as laryngeal cartilages and may follow an erratic course in the soft tissues. This may be misleading during the initial examination. Military or hunting weapons and, even more so, splinters of mines and shells impart a considerable amount of kinetic energy to the tissues, occasioning necrosis that is far beyond the limits of the obviously nonviable tissues and necessitating a wide débridement of the surrounding tissues.25,35

Inhalation Injuries Inhalation injuries can be thermal or chemical. Thermal injury is the rarest because the regulation system of the nose and oral cavity can dissipate most of the heat; however, if the air is supersaturated with steam, then thermal injury may occur. With hot steam, significant laryngeal edema occurs before any pulmonary injury, whereas with smoke, necrotizing tracheitis, bronchitis, and intra-alveolar hemorrhagic edema may develop first. When it comes in contact with the mucosa, inhaled ammonia gas forms ammonium hydroxide, a strong alkali that causes liquefaction necrosis. The supraglottis is predominantly involved, and edema, ulcerations, and slough cause laryngeal narrowing and spasm. The larynx protects the lower airway. Laryngeal edema often appears briskly but late, sometimes as long as 24 hours after the inhalation. Injuries from caustic ingestion typically occur in children and may result from various household products. In adults, they are usually the result of a suicide attempt. The larynx is injured by direct contact during ingestion or regurgitation of the ingested caustic material. Reflex glottic closure limits these injuries to the supraglottis.25,35,38

SITES OF TRAUMATIC LESIONS TO THE LARYNX AND TRACHEA Hyoid Bone Fractures of the hyoid bone are rare and are mainly caused by strangulation or hanging. They usually do not induce respiratory distress but are very painful, especially during coughing

1/21/2008 4:20:18 PM

1742

Section 8 Trauma

and swallowing. Special care is paid to the diagnosis of associated pharyngeal lacerations.

Epiglottis The most common lesion of the epiglottis is a posterior avulsion of the petiolus due to rupture of the thyroepiglottic ligament (see Fig. 144-3). It is frequently associated with fractures of the thyroid cartilage. It provokes a marked anteroposterior shortening of the supraglottic lumen. Ruptures of the hyoepiglottic ligament are rare and may be associated with a fracture of the hyoid bone. Direct lesions of the epiglottic cartilage are reported only in penetrating traumas.

Thyroid Cartilage The damage to the thyroid cartilage depends on the degree of calcification. In children and young adults, a blunt injury usually results in a vertical, linear, median, or paramedian fracture (see Fig. 144-3). This type of fracture is the most common injury encountered in the larynx. It may be unique or associated with a fracture of the cricoid cartilage. In many cases, it leads to a disruption of the vocal cords. In men and in older patients, the fracture pattern is comminuted. The larynx is shortened in the anteroposterior axis, with airway restriction. The external perichondrium often remains intact, whereas the internal perichondrium is breached by fractured cartilage fragments, resulting in internal soft tissue damage, mucosal lacerations, and exposure of pieces of cartilage.

Cricoid Cartilage An isolated fracture of the cricoid is rare and is typically associated with a fracture of the thyroid cartilage or, less frequently, a cricotracheal disruption. The most likely site of fracture is the anterior arch, but a direct crushing blow to the cricoid generally results in a comminuted type of fracture (see Fig. 144-3). Because the cricoid is a complete ring, there is not much space for expansion of soft tissue, which may result from edema or hemorrhage, and the airway restriction is early and severe. The incidence of concomitant recurrent laryngeal nerve palsy and esophageal injuries is high because of the close anatomic relationship of these structures to the cartilage.

Arytenoids Depending on the mechanism of injury, the arytenoids are either dislocated, subluxated, or completely avulsed.

Soft Endolaryngeal Tissues The mucosa can show edema (peak at 12 hours, gradually subsiding within 2-3 days), hemorrhage, laceration, or complete avulsion of underlying structures, with displacement and contraction of the mucosal flaps and exposure of the submucosal structures. The muscle can show hemorrhage, even in cases of minor trauma, tearing, or separation, the last mainly associated with ligamentous and cricoarytenoid joint lesions. The vocal cords can lack tension and can be shorter than normal in cases of an anteroposterior shortening of the larynx due to a thyroid cartilage fracture (even without other

Ch144-F06861.indd 1742

internal signs) or in cases of an arytenoid cartilage dislocation. With the spring-back mechanism of the larynx in anterior blunt trauma, avulsion of the anterior commissure attachment of one or both vocal cords may occur. Tears of the vocal cords, the false cords, or the aryepiglottic folds result from more severe trauma.

Cricotracheal Ligament A laryngotracheal disruption is one of the most severe laryngeal injuries. It is nearly always associated with a unilateral or bilateral recurrent laryngeal nerve injury. A comminuted fracture of the cricoid cartilage is also reported to be associated.14 Initially, the outward signs may be few, and the respiratory distress may be surprisingly minimal. Breathing is possible for a time, but the collapse of the avulsed soft tissues surrounding the segment of the disruption always results in a sudden airway loss, which is fatal when the condition has not already been diagnosed. The diagnosis is often made only when the condition is suspected with regard to the mechanism of injury.

Trachea The tracheal cartilage is extremely impact well. Severe blunt injury or intratracheal pressure results mainly intercartilaginous membranes, with tracheal cartilage prolapse.

elastic and tolerates injury by increase of in disruption of the varying degrees of

Recurrent Laryngeal Nerves Except for penetrating traumas with transection of the nerve, an injury of the recurrent laryngeal nerve is encountered in cricoid fractures or in laryngotracheal separation. It is caused by distention, complete disruption, or a direct lesion from a displaced cartilaginous fragment. Clinical presentation depends on the type of the laryngeal trauma and the unilaterality or bilaterality of the injury.

DIAGNOSIS Clinical Presentation The challenge in penetrating laryngeal trauma is less of a diagnostic problem than the detection of the associated injuries. The situation differs with blunt trauma, in which diagnosis can be more subtle. The early diagnosis and treatment of blunt laryngeal trauma is crucial to avoid acute complication, and any delay may lead to disastrous late sequelae. The physician is confronted with two situations: a conscious patient who will provide information and will cooperate for the laryngeal examination or an unconscious patient with either an unsecured airway or one that is already intubated or tracheostomized. In the first situation, the diagnosis of laryngeal trauma is evident most of the time but the larynx must be carefully examined after the patient is stable to exclude an insidious delayed development of airway obstruction. In the second situation, delayed diagnosis of laryngotracheal trauma still occurs and becomes only apparent at the time of failed extubation.

1/21/2008 4:20:19 PM

Chapter 144 Laryngeal Trauma

Although the diagnosis is evident in cases of penetrating injuries, many cases of blunt laryngeal trauma may remain asymptomatic at an early stage and can be missed by the physician. Minor symptoms may hide serious underlying injuries; therefore, an aggressive diagnostic investigation must be done, particularly in cases of multiple trauma when preoccupation with the other life-threatening injuries can hide an apparent minor pathology. Knowledge of the mechanisms of the injury may depend on the degree of the wound and the severity of the injury; therefore, witnesses can be helpful when the patient is unconscious. The following symptoms are suggestive of laryngeal trauma: 1. Change of voice. This symptom is constant and ranges from slight dysphonia to hoarseness and aphonia. Hematoma of a vocal cord often causes hoarseness, whereas dislocation of the cricoarytenoid joint, vocal cord paralysis, or avulsion can lead to a weak and breathy voice. Aphonia may be encountered in severe trauma. 2. Dyspnea. This is not constant but represents the most serious symptom of laryngeal trauma. Dyspnea ranges from slight stridor to acute respiratory distress. It may be absent during the early stages of a contusion or nondisplaced fracture, when edema and hematoma are not large enough to create an obstruction, and may only become significant after a few hours when the lesion has enlarged. On the other hand, immediate onset of dyspnea with dramatic acute obstruction may follow a laryngeal crush, an epiglottis avulsion, or a laryngotracheal disruption. 3. Neck pain. This may appear spontaneously or may occur only during swallowing as a result of the mobilization of the injured larynx. 4. Dysphagia and odynodysphagia. These can result from a contusion, a crush, or a laceration of the pharyngeal or esophageal mucosa. 5. Cough. An irritative cough may appear as an initial symptom of a lesion of the larynx. 6. Hemoptysis. Laceration of the pharynx or larynx or disruption of the trachea or bronchi can be followed by hemoptysis, which can be severe enough to cause respiratory distress. 7. Aspiration. This may appear later when the patient begins to eat; it is usually caused by a unilateral or bilateral paralysis of the vocal cord. A discordance may exist between the clinical symptoms and the underlying lesions, and major injuries may be minimally symptomatic initially and suddenly decompensate, as in a laryngotracheal disruption occurring in two stages. Therefore, all patients with suspicion of neck trauma are carefully examined to exclude laryngeal lesions.

Signs Blunt Laryngeal Trauma Observation of the neck may reveal contusion, mild bruising or laceration, loss of the thyroid prominence, or edema or fleshiness of the cervical tissues. A gentle palpation of the neck is performed to discover crepitus of a subcutaneous emphysema, soft tissue swelling and tenderness, or depres-

Ch144-F06861.indd 1743

1743

sion of the thyroid cartilage due to a fracture. Subcutaneous emphysema can diffuse to the face and the thorax. The face is examined to exclude an associated mandibular fracture. The cervical spine is palpated to look for any bony stepoffs.

Penetrating Trauma Clinical findings include subcutaneous crepitus, dyspnea, shock or hemorrhage, expanding neck hematoma, hemoptysis, hematemesis, and neurologic deficit (Grewal et al, 1999).36,39-41 The entrance and exit wounds are carefully examined, and the path of travel of the projectile is estimated to evaluate the potential risk for underlying injuries.

Laryngeal Examination Conscious Patient After the initial evaluation demonstrates a stable airway, examination of the pharynx and the larynx is attempted. Transnasal fiberoptic laryngoscopy has replaced indirect laryngoscopy and allows immediate assessment of airway integrity while maintaining cervical spine immobilization. The risk for laryngospasm during the examination is increased in cases of laryngeal lesion and may precipitate an airway obstruction. Therefore, the medical team is ready for an emergency intubation or tracheostomy. Examination of the larynx assesses vocal cord mobility and the presence of mucosal edema, hematomas, tears, and exposed or avulsed arytenoid cartilages. Arytenoid luxation is suspected in cases of a change of the shape or an unusual position or when there is a disparity between the level of the two vocal cords. In moderate to severe injuries, a detailed examination is performed by direct laryngoscopy under general anesthesia; in most situations, a tracheotomy is performed initially to establish a safe airway.

Intubated Patient Patients are frequently already intubated when transferred to a tertiary center, and transnasal flexible laryngoscopy is thus not possible to check the active mobility of the vocal cords. The larynx is examined by direct laryngoscopy that is performed with an intubation laryngoscope and a 4-mm, 0- or 30-degree telescope. Depending on the severity of the lesions, the endotracheal tube is temporarily removed or a tracheotomy is performed, permitting a precise evaluation of the endolarynx and the subglottis. Passive mobilization of the arytenoids helps differentiate between paralysis and arytenoid dislocation or fixation.

Radiologic Evaluation Radiologic evaluation is performed only after the airway and the hemodynamic parameters are stabilized. It adds diagnostic elements in suspected laryngeal trauma, increases precision in the topography of lesions, and assesses associated injuries of the spine, the vessels, the esophagus, and the chest. Plain radiographs of the cervical spine are taken to exclude vertebral fractures and the presence of deep cervical and prevertebral air. Pneumothorax, pneumomediastinum, pleural effusion, and subcutaneous emphysema are detected by plain chest radiography, which is performed routinely.

1/21/2008 4:20:19 PM

1744

Section 8 Trauma

High-resolution CT has replaced tomography and lateral radiography in the evaluation of the traumatized larynx.17,42 CT shows fractures or dislocations of the cricoid, the hyoid, and the thyroid cartilage and accurately reveals arytenoid luxation, hematoma, and subcutaneous emphysema, but it may fail to demonstrate some forms of cricotracheal separation.43 Controversies are ongoing about the indications for CT examination. According to Schaefer,17 CT of the larynx is not performed routinely but only when the result of the examination will influence the treatment. It is reserved for evaluation of subtle abnormalities to avoid an unnecessary open surgical procedure. Thus, in cases of significant injuries, such as exposed cartilage, evident fracture, de-insertion of the vocal cord, and supraglottic or subglottic disruption, Schaefer states that CT adds no valuable diagnostic element to the external and laryngoscopic examination in patients who require surgical exploration anyway. He limits his indications to two situations:

A

1. For making the decision of an open approach in patients with extensive edema of the laryngeal mucosa that precludes an accurate assessment in direct laryngoscopy 2. In patients with minimal symptoms and a history of trauma important enough to cause a fracture In this second situation CT can exclude an occult thyroid fracture, which may have adverse effects on the quality of the voice. Detection of occult thyroid fractures may have therapeutic consequences. Hirano and coworkers16 reported functional disturbances in only 1-mm displacements. Other authors, however, routinely employ CT regardless of injury severity, arguing that it is valuable in anticipating injuries and planning the operative approach (Butler et al, 2005).44-46 Angiography or color Doppler imaging of the cervical vessels is reserved for cases of penetrating trauma.

B

Associated Injuries Facial and spinal fractures, chest trauma, and closed-head injury are commonly observed in patients with blunt laryngotracheal trauma, whereas injuries to organs that are adjacent to the larynx (vessels, esophagus, spinal cord) and chest injuries are frequently associated with penetrating laryngotracheal trauma.

Pharyngeal and Esophageal Injuries The frequency of associated pharyngeal or esophageal injuries varies from 15% in blunt trauma up to 42% in penetrating trauma (Grewal et al, 1995).30,39,46 Pharyngeal laceration or perforation after blunt trauma is the result of impaction of the cricoid or thyroid cartilage through the mucosa (Fig. 144-4). Odynophagia, hematemesis, and subcutaneous emphysema are the most reliable clinical signs that have motivated some authors to recommend investigations only in symptomatic or unconscious patients (Demetriades et al, 1996).47 However, it is the most commonly missed injury in the neck, and delay in diagnosis may result in severe complication. Thus, other authors recommend aggressive investigation based on the fact that the history and physical examination do not always have diagnostic value. Moreover, a primary

Ch144-F06861.indd 1744

FIGURE 144-4 A, Blunt trauma with horizontal supraglottic disruption and vertical laceration of the posterior pharyngeal wall made by impaction of the cricoid cartilage. The petiolus of the epiglottis has moved backward to the level of the arytenoids. B, CT scan of the same patient shows a fracture of the right thyroid ala and cervical emphysema.

closure within the first 24 hours drastically decreases the mortality rate, which increases to 40% if the treatment is delayed.48 We recommend routine esophagoscopy in all unconscious patients and in patients with symptoms that require laryngeal exploration. The average false-negative rate of 21% for flexible esophagoscopy is similar to that of esophagography. A combination of the two examinations has a 100% rate of sensitivity and specificity, but this falls to 67% for hypopharyngeal perforation.49 For that reason, we strongly advise rigid esophagoscopy, which also checks the hypopharynx. It can be associated with esophagography with a water-soluble contrast agent injected through a catheter to exclude a small occult perforation. In patients at high risk for associated tracheobronchial injuries, the addition of routine tracheobronchoscopy (panendoscopy) is warranted.

1/21/2008 4:20:19 PM

Chapter 144 Laryngeal Trauma

Complication rates of combined esophageal and tracheal injuries reach up to 50%, and fistulas to adjacent structures such as the trachea, skin, and pleura are common. Although the trachea may be closed in one layer, esophageal lacerations are repaired with a two-layer suture and a muscle flap, usually of proximally detached sternohyoid muscle, which is inserted between the esophagus and the trachea to prevent fistula formation.50

Vascular Injuries The incidence of vascular injury is much higher in penetrating trauma (up to 38%) than it is in blunt trauma (<2%), and gunshots are more likely to cause vascular damage than are stab wounds.30,39,41 Routine angiography is recommended by many authors; however, its disadvantages are its high cost and its invasive character. Demetriades and colleagues51 reported, in a series of 176 patients with penetrating trauma to the neck, that 19% of vascular lesions were diagnosed by routine angiography; among them, only 8% required treatment. In another study, these authors showed that the combination of physical examination and color-flow Doppler imaging was a safe and cost-effective method to detect vascular injuries requiring treatment.47

MANAGEMENT Prompt initial diagnosis and management of laryngeal trauma are the keys to success of treatment to avoid both fatal respiratory distress and catastrophic long-term sequelae. Data collected by centers over the years have permitted improvement of the diagnostic strategies and initial management through established protocols and clarification of the indications for conservative and surgical treatments (Butler et al, 2005).45,46,52,53 Grading of the injuries has been established to standardize the reports and to define management options (Table 144-1).

TABLE 144-1 Laryngotracheal Injury Classification Grade

Description

I

Minor endolaryngeal hematoma or laceration without detectable fracture

II

Edema, hematoma, minor mucosal injury without exposed cartilage; nondisplaced fractures noted on a CT scan; absence of dislocation

III

Massive edema or hematoma, mucosal tears with exposed cartilage, cord immobility, displaced fractures

IV

As grade III, with multiple fractures, disruption of the anterior half of the larynx, unstable laryngeal framework or massive trauma to laryngeal mucosa

V

Complete laryngotracheal separation

Data from Schaefer SD: The acute management of external laryngeal trauma: A 27-year experience. Arch Otolaryngol Head Neck Surg 118:598-604, 1992; and Fuhrman GM, Stieg FH III, Buerk CA: Blunt laryngeal trauma: Classification and management protocol. J Trauma 30:87-92, 1990.

Ch144-F06861.indd 1745

1745

Airway Management The emergency department physicians usually manage these patients according to the guidelines of advanced trauma life support. Securing the airway is the most important first step in the management of a victim of laryngeal trauma. Minimal signs and symptoms do not preclude partial obstruction of the airway that can be compromised suddenly. Disagreement exists about the best way to establish the airway. In the past, some authors have advocated orotracheal intubation under the assumption that iatrogenic tracheal injury may result from emergency routine tracheotomy; thus, intubation remains the primary method of airway control but this moves quickly to tracheostomy if intubation is difficult.54 Currently, a consensus has been established and many authors recommend an awake tracheotomy under local anesthesia, arguing that intubation can be hazardous because of potential cervical spine injuries, soft tissue edema, laryngeal laceration, and hemorrhage and may exacerbate mucosal injuries or complete a partial laryngotracheal separation (Schaefer, 1992).15,23,46,53 In agreement with the recent literature,45,45,53,55 oral intubation by an experienced staff can be attempted if the patient’s condition is stable and when flexible fiberoptic examination reveals minimal trauma. The medical staff is prepared to perform a tracheostomy immediately if the patient’s condition becomes unstable. Other patients with mild to moderate lesions and those with severe injuries undergo tracheostomy under local anesthesia. This decisional protocol greatly reduces the risk for loss of or damage to the airway (Fig. 144-5). Tracheotomy is performed lower than usual on the trachea, at the level of the fourth or fifth ring. Exceptionally, cricothyroidotomy may be necessary in urgent situations but in principle is avoided to prevent the airway from sustaining additional trauma. Therefore, it is converted to a formal tracheotomy as soon as possible.44 Care is taken to avoid manipulation of the neck until a cervical spine fracture has been excluded.

Timing Timing of the surgical exploration has been a topic of controversy in the past; however, more recently, it is generally agreed that early treatment yields the best result.45 Delays in operative intervention lead to a higher complication rate (infection, perichondritis, stenosis), more difficult surgery, and poorer voice and airway results (Butler et al, 2005; Schaefer, 1992).23,44,45,53,54 Open exploration is performed within 24 hours of injury to help in the identification of specific damage before the onset of edema.

Conservative Management Conservative management of laryngeal trauma is reserved for cases in which spontaneous healing without alteration of laryngeal function can be expected. The injuries correspond to grade I and II lesions (see Table 144-1): laryngeal edema, hematomas, and small lacerations without exposed cartilage and those not involving the anterior commissure. Single stable and nondisplaced fractures usually require no open exploration because a good functional prognosis is expected.

1/21/2008 4:20:20 PM

1746

Section 8 Trauma

Stable Airway

Airway Obstruction Tracheostomy under local anesthesia

Flexible fiberoptic examination

Flexible fiberoptic examination Normal

Grade I–II

Grade III–IV

CT scan

CT scan (optional)

Grade II

Grade III–IV

CT scan

(CT scan)

Abnormal

Normal

Nondisplaced thyroid cartilage fracture

Tracheotomy or intubation

Normal

Abnormal

Observation

Direct laryngotracheoscopy and esophagoscopy

Direct laryngotracheoscopy and esophagoscopy

Observation

Surgical treatment adapted to lesions

Surgical treatment adapted to lesions

B

A Intubated Patient Direct laryngotracheoscopy and esophagoscopy

Grade III–IV

Grade V

Tracheostomy

Fiberoptic control of the endotracheal tube position

Surgical treatment Surgical treatment

C

Nevertheless, some authors advocate repair of minimally displaced fractures and asymptomatic thyroid cartilage fractures, arguing for the possibility of changes in vocal dynamics.16,56 Conservative management consists of close observation, elevation of the head of the bed, humidification of inspired air, supplemental oxygen, voice rest, prophylactic antibiotics, and daily fiberoptic laryngeal examination until the edema has decreased. Proton pump inhibitors may be helpful, particularly in patients with gastroesophageal reflux, in the pre-

Ch144-F06861.indd 1746

FIGURE 144-5 Decisional protocols for laryngeal trauma. A, Stable airway. B, Airway obstruction. C, Intubated patient.

vention of irritation of the traumatized mucosa. Corticosteroids have been used inconsistently and may be useful if administered early after injury. Tracheotomy is necessary if laryngeal edema is expected to be present for several days. Unrestricted diet is allowed for patients with minor injuries, whereas nasogastric tube feeding is used for patients with more significant mucosal trauma. Functional results after conservative treatment are good in nearly 90% of grade I and II injuries (Butler et al, 2005; Schaefer, 1992).23,44,45

1/21/2008 4:20:20 PM

Chapter 144 Laryngeal Trauma

anterior margin of the true vocal cord to the outer perichondrium of the thyroid cartilage (Schaefer, 1992)23,53; a soft nasogastric feeding tube is used for 1 week in case of esophageal or pharyngeal laceration. Direct laryngotracheoscopy is performed after 10 days and repeated if further treatment is necessary. After 1 week, the tracheostomy cannula is progressively occluded to stimulate phonation.

Surgical Management Open surgical exploration is indicated for more severe laryngeal injuries corresponding to grade III to V injuries (see Table 144-1): large mucosal lacerations, exposed cartilage, multiple or displaced cartilaginous fractures, vocal cord immobility, and laceration of the anterior commissure or of the free margin of the vocal cords. Arytenoid dislocation is preferentially treated endoscopically. Likewise, limited laceration of the posterior pharyngeal mucosa can be sutured by endoscopy using suspension microlaryngoscopy (Fig 144-6). Criteria for neck exploration include the following: progressive subcutaneous emphysema, active bleeding, hematoma of the neck, and neurologic deficit (Grewal et al, 1995).31,39,44,46 The larynx is exposed through a transverse skin incision usually at the level of the cricothyroid membrane. The strap muscles are divided in the midline and retracted laterally. The larynx is explored through a midline thyrotomy. If a vertical fracture exists within 3 mm of the midline, then the larynx is explored through the fracture. The true vocal cords are the first anatomic landmark to be identified. Starting posteriorly, pharyngeal mucosal lacerations are first carefully reapproximated with 4-0 or 5-0 absorbable sutures followed by laryngeal and tracheal repair. Dislocated arytenoids are replaced in their normal position or removed if severely damaged. All exposed cartilages are covered with local mucosal flaps (mainly harvested in the piriform fossae) to prevent scarring and perichondritis. Although skin graft and mucosa graft harvested in the mouth are described in the literature, they are rarely required. Vocal cord injuries are repaired first by the reconstitution of the anterior commissure. This is achieved by suturing the

A

1747

Hyoid Bone Fracture An isolated fracture of the hyoid bone is treated conservatively. Displaced or comminuted fractures are managed by removing the osseous fragments and re-establishing the continuity between the suprahyoid and infrahyoid musculature with large sutures, to facilitate onset of swallowing.

Supraglottic Injury Exploration of the supraglottic area is made through the thyrohyoid membrane. Disruption of the attachment of the epiglottis is treated by anterior fixation of the petiole with resorbable sutures. If anterior anchorage support is not available, then the lower one third of the epiglottis is resected and the remaining cartilage is suspended to the hyoid bone. Significant injuries of the supraglottic area with extensive lacerations are managed with a supraglottic laryngectomy, as performed for oncologic purposes (Fig. 144-7).

Thyroid Cartilage Fracture Minimally displaced or nondisplaced thyroid fractures have an excellent prognosis with conservative treatment, although changes in vocal dynamics have been reported.16 Any single

B

FIGURE 144-6 A, Posterior pharyngeal wall laceration secondary to a coup-contrecoup injury of the thyroid cartilage without fracture. B, The laceration was repaired with sutures placed endoscopically with suspension micropharyngoscopy.

Ch144-F06861.indd 1747

1/21/2008 4:20:21 PM

1748

Section 8 Trauma

A

B

FIGURE 144-7 A, Horizontal supraglottic disruption above the arytenoids with a large communication in the soft tissue of the neck after a blunt trauma during a car accident. B, Result after horizontal laryngectomy; the epiglottis was removed and the base of the tongue was sutured at the anterior commissure.

displaced thyroid fracture is reduced and repaired with No. 24 wire, nonabsorbable sutures, or miniplates. In soft cartilage, 3-0 nonabsorbable sutures are preferred over wire, which can cut through the cartilage. Simple, nondisplaced fractures are fixed by suturing only the outer perichondrium. If the cartilage is ossified, then holes are made with a minidrill to facilitate suture placement. Nevertheless, the forces exerted by the pharyngolaryngeal musculature tend to bend wire and may cause displacement of the cartilaginous fragments.57 For that reason, rigid fixation with miniplates tends to replace nonresorbable or wire sutures. The advantages include better stabilization of multiple unstable segments, a restoration of the exact three-dimensional geometry of the laryngeal framework (mainly the anterior angulation of the thyroid cartilage) and the ability to bridge large defects.57,58 The restoration of a rigid framework can prevent the need for internal stenting. The miniplates are fixed either with screws in ossified cartilage or with permanent sutures in nonossified cartilage (Fig. 144-8). If screws are used, then the holes are drilled with a drill bit that is one size smaller than the appropriate screw size. Resorbable plates offer the advantage of being elongated before resorption and do not restrict skeletal growth in the pediatric population.59

Arytenoid Dislocation Early diagnosis facilitates treatment, and reduction within 3 weeks of injury is associated with good functional results. Open reduction through laryngofissure is performed during the surgical revision of a laryngeal trauma. Avulsed arytenoids are covered with the piriform sinus mucosa or removed if the damage is too extensive. If the arytenoid remains dislocated for an extended period, then fibrotic ankylosis of the joint prevents its reposition; however, it is difficult to predict the upper time limit within which reduction can be attempted. Successful late reductions have been described even after a delay of 1 year. Sataloff and colleagues60 reported a series of 26 cases in which patients with good results had an average

Ch144-F06861.indd 1748

FIGURE 144-8 Fixation of thyroid cartilage fractures with miniplates yields a better stabilization of multiple unstable fragments and restores the exact three-dimensional geometry of the laryngeal framework, mainly, the anterior angulation of the thyroid cartilage. The plates are fixed either with screws in ossified cartilage or with permanent sutures in nonossified cartilage.

time interval of 10 weeks between injury and surgical reduction, whereas the time interval for the group of patients with residual alteration was 29 weeks. Closed reduction remains a difficult procedure. It is performed under general anesthesia and suspension laryngoscopy or with local anesthesia and sedation using the blade of a Miller laryngoscope.60 Pressure is exerted on the lateral

1/21/2008 4:20:22 PM

Chapter 144 Laryngeal Trauma

1749

surface of the vocal process and the body of the arytenoid to push it posteriorly or anteriorly according to the type of luxation. Delicate and thin instruments may lacerate the mucosa; therefore, large and smooth instruments are preferred. Unsuccessful reduction may necessitate delayed endoscopic procedures, such as arytenoidectomy in cases of airway compromise, or intracordal fat or collagen injection in cases of glottic incompetence. Vocal cord medialization through a thyroplasty is another option.

Laryngotracheal Disruption and Cricoid Fractures Laryngotracheal disruption with cricoid fractures is a serious, but rare, injury and has been reported by several authors.1,2,13,14,45,50,55,58,61-63 An immediate low tracheotomy is usually advocated to secure the airway. Although intubation may exacerbate the soft tissue lesions around the dehiscence, it may be the only way to save the patient’s life at the site of the accident (Fig. 144-9). In a series of seven cases, Wu58 reported a successful endotracheal intubation in four patients and an emergency tracheostomy in the remaining three patients after failed intubation. Exposure is obtained through a collar incision positioned 2 to 3 cm above the sternal notch. Exploration can be adequately performed through the cricotracheal dehiscence. Associated injuries of the pharyngolarynx and the esophagus are carefully evaluated and repaired. Meticulous débridement, correct approximation of the laryngeal and tracheal stumps, and tension-free anastomosis are the keys to a successful laryngotracheal reconstruction. If the integrity of the cartilages is preserved, then a circumferential primary anastomosis with absorbable sutures is performed. In case of extensive laryngotracheal damage, a variety of laryngotracheal reconstructions can be applied depending on the extent of local damage and the surgeon’s preference. Resection of broken tracheal rings may be necessary, keeping the posterior wall of the trachea, which can serve as a pedicled mucosal flap to cover a denuded area of the cricoid cartilage, if necessary. If this flap is not available, then it can be replaced by an autograft of buccal mucosa, secured in place with absorbable sutures, fibrin glue, and short-term stenting. Associated cricoid fractures are reduced and fixed with sutures. If the anterior arch of the cricoid is severely damaged, then a partial cricotracheal resection with thyrotracheal anastomosis is preferred (see Chapters 30 and 31). A laryngeal release procedure is rarely necessary to prevent tension on the anastomosis, but it can be performed by cutting the infrahyoid muscle attachments at the hyoid bone and freeing the superior horns of the thyroid cartilage. Other alternatives, such as autografts of the hyoid bone, rib cartilage, or iliac crest, present a higher risk for residual cicatricial stenosis and need to be avoided (Pearson et al, 1986).64,65 Internal stabilization with a Montgomery T tube or a specific laryngotracheal mold may be necessary in extensive damage of the laryngotracheal framework and in fractures of the cricoid plate (Figs. 144-10 and 144-11). Other authors prefer stenting by endotracheal intubation for 1 week.58 Tran-

Ch144-F06861.indd 1749

A

B FIGURE 144-9 A, CT scan of a total cricotracheal disruption; the endotracheal tube is surrounded by air and soft tissues without any visible tracheal rings. B, Periperative view of the dehiscence between the cricoid (right) and the trachea (left). The patient was successfully intubated at the site of the accident.

section or severe damage to the recurrent laryngeal nerves is frequently associated with laryngotracheal disruption, and its management remains controversial. Identification of the recurrent laryngeal nerves may be difficult in swollen tissues and may lead to further damage to a potentially intact nerve in an already tracheostomized patient, without previous information on vocal cord mobility. For that reason, exploration of a hypothetically injured recurrent laryngeal nerve is not advocated. If there is evidence of transection, acute repair of the nerve is more controversial. Some argue that dyskinesia resulting from reanastomosis adversely affects the airway and voice. However, most professionals believe that the improvement in vocal cord tone outweighs the problems associated with dyskinesia. Others advocate performing the anastomosis of the recurrent laryngeal nerve to the ansa cervicalis.66

1/21/2008 4:20:24 PM

1750

Section 8 Trauma

A FIGURE 144-10 A, Laryngeal stents: left, prototype of the Easy LT-Mold that conforms to the inner anatomy of the larynx; right, a Montgomery T tube. B, During the open procedure, the exact distance from the anterior commissure of the larynx to the upper margin of the tracheostoma is measured and recorded on the prosthesis. Then an oval window is cut out and the prosthesis is shortened by cutting off its distal end obliquely. A connecting device is fixed with silicone glue on the prosthesis, which is maintained in place by inserting a cannula through its anterior opening.

For cases in which both recurrent laryngeal nerves are sectioned, various treatments have been proposed. Reanastomosis of the transected nerves is usually followed by poor function and increases the risk for airway compromise.61,67 Direct reimplantation of the nerve into the posterior arytenoid muscle, which acts as the main abductor muscle of the glottis, has been described with inconsistent outcomes.68 Couraud and associates14 resolved the problem of glottic stenosis with enlargement of the posterior commissure by maintaining the posterior hiatus from the fracture with a stent placed for 10 days as described by Réthi.69 However, unilateral laser arytenoidectomy that is performed at a second stage remains the simplest and most effective treatment for symptomatic bilateral vocal cord paralysis.

Missile Injuries to the Larynx After an evaluation of the lesions, the treatment for penetrating injuries of the larynx follows the same general principles as those applied to nonpenetrating traumas, with the addition of extensive infection prevention measures, especially in severe ballistic decay. Surgical exploration focuses on the search for associated injuries (present in up to half of cases) to the vessels, trachea, and particularly the pharynx and esophagus. The extraction of the missile often requires a second incision. Surgical repair includes suturing of the mucosal lacerations with use of piriform fossa mucosal flaps and, rarely, grafts, restoration of the laryngeal architecture, and use of a stent.29 Cutaneous wounds may be left partially open if they are contaminated. Severe soft tissue damage with loss of tissue as a result of high-velocity missiles and military weapons seldom requires partial or total laryngectomy.

Ch144-F06861.indd 1750

B

Box 144-1 Indications for Stenting ■ Disruption of the anterior half of the larynx ■ High instability of the cartilaginous skeleton, which cannot be main-

tained with external fixation of the cartilaginous fractures ■ Severe tracheal ring injury or loss of cricoid structural integrity ■ Massive endolaryngeal laceration and avulsion with a high risk for

cicatricial stenosis ■ Extensive lacerations of the mucosa, preventing the restoration of

a normally shaped anterior commissure

Indications for Stenting The use of laryngeal stents remains controversial, and the indications, type of stent, and timing of removal are still under debate. The main functions of a stent follow: 1. To maintain the lumen of the larynx to prevent web formation and to promote adherence of flaps or grafts to the underlying cartilaginous structures 2. To stabilize an unstable tracheolaryngeal framework by providing internal support as an adjunct to external fixation of cartilages, although the use of miniplates allows the required stability to be achieved alone in many cases 3. To maintain or re-create the anterior commissure by insertion of a keel when the vocal cords are seriously avulsed, which is essential to recovery of a good voice. Indications for stenting are reported in Box 144-1.44,45,52,53,67,70-72 Some professionals argue that laryngeal stents can compromise mucosal perfusion by increasing mucosal pressure, the

1/21/2008 4:20:25 PM

Chapter 144 Laryngeal Trauma

1751

1

2

A

B

C

D

FIGURE 144-11 A, Secondary to a motorcycle accident, grade V injury with displaced fractures of the posterior and anterior arches of the cricoid cartilage and laceration of the trachea with involvement of seven tracheal rings (1, fragments of cricoid cartilage; 2, thyroid cartilage). B, The posterior mucosal lacerations were closed first and the lateral fragments of the cricoid were sutured together. An Easy LT-Mold stent was inserted in the larynx and trachea. C, The anterior laryngotracheal framework was closed by meticulous reduction and suture of the cartilage fragments. The silicone tongue of the prosthesis was fixed with transcutaneous suture through the tracheostomy. D, Endoscopic view of the subglottic area 3 months after the trauma. Note complete restoration of the lumen with good steadiness of the cartilaginous framework. There is some small granulation tissue at the old tracheostomy site. Laryngeal nerves were not injured. The patient has normal voice and breathing.

risk of infection, and formation of granulation tissue. We think that these potential complications are linked to inappropriate stents and that they can be avoided by using stents that conform to the inner contours of the larynx and trachea. The literature is replete with reports of the use of different stents for airway reconstruction. These include rolled Silastic sheet, modified endotracheal Portex tube, Eliachar silicone rubber stent, Aboulker stent, Monnier LT-Mold, and Montgomery T tube. Most authors agree that the stent needs to have the shape of the larynx and needs to be made with soft material to avoid further injuries to the traumatized mucosa. However, there have been few reports of their use (Monnier, 2003).67,72,73 Our experience with long-term stenting in airway reconstructions for complex glottic-subglottic stenoses (see

Ch144-F06861.indd 1751

Chapter 31) and in severe laryngotracheal trauma is very promising (see Figs. 144-10 and 144-11) with the use of the Monnier LT-Mold. Such a stent, made of soft silicone with conformity to the inner laryngeal contours, is extremely well tolerated. The stent is fixed with transcutaneous, nonabsorbable sutures, or it is fixed through the tracheotomy by a connecting device (see Fig. 144-10). Another specific stent is the Silastic keel, which can be used to prevent anterior webbing when the anterior thirds of the true cords are avulsed. Controversies remain among surgeons regarding the duration of stenting of the airway. In acute trauma, our opinion, which is shared by many surgeons, is that a duration of 2 to 3 weeks appears to be sufficient to promote stability of the larynx without further damage to the mucosa (Butler et al,

1/21/2008 4:20:26 PM

1752

Section 8 Trauma

2005; Schaefer, 1992).23,44,45,54,71,74 However, a longer period of up to 6 months of stenting may be required for the treatment of long-term cicatricial sequelae. Fixation of the stent must be handled with caution because death by airway obstruction after displacement of the stent has been reported.52 Broad-spectrum antibiotic coverage is advocated. The stent is removed endoscopically, and follow-up laryngotracheoscopies are performed until complete healing has occurred. Endoscopic adjunctive procedures may be necessary to optimize the final result. Granulations are removed with forceps, and thin webs or synechiae are treated with the CO2 laser.

Inhalation and Caustic Injuries Inhalation injuries of the larynx and the upper airway require endotracheal intubation as soon as slight symptoms such as hoarseness or dysphonia appear, and before the onset of edema, which can quickly lead to a glottic-subglottic obstruction. Extubation is generally possible 2 to 5 days after the laryngeal edema has resolved. Long-term intubation is avoided, and tracheotomy is indicated after 6 days if edema is still present.75 Immediate tracheotomy is advocated by other authors to diminish the risk of subglottic stenosis.76 Conservative treatment with humidification and complete voice rest is seldom complicated by cicatricial stenosis, but sequelae of intubation or tracheotomy increase up to 30% when tracheobronchial burns are associated with laryngeal burns.77 When they occur, laryngeal sequelae consist mainly of posterior glottic stenosis, which may involve one or both cricoarytenoid joints. The consequences are a limitation or an absence of arytenoid abduction, leading to a fixed larynx, which is often associated with complex multiple stenoses of the subglottis and the trachea.75,78,79 The management of laryngeal stenosis by inhalation differs from that of postintubation stenosis because of the longstanding evolution of the lesion. Stenting with a Montgomery T tube for a prolonged period of up to 28 months as soon as the stenosis appears constitutes the first stage of the treatment.77,80 The second stage is accomplished later with the resection of the stenosis by an open surgical procedure when the lesion is stable.75 Nevertheless, Flexon and colleagues79 reported success with an earlier open surgical procedure. The surgery follows the same principles as those applied to laryngeal and subglottic stenoses of other origins but often multiple operations are required. Laryngeal injuries caused by caustic ingestion are mainly located in the supraglottic area and are associated with hypopharyngeal and esophageal burns. Acute management consists of securing the airway by endotracheal intubation or tracheotomy, controlling the hypovolemia with a central venous catheter, and administering broad-spectrum antibiotics and corticosteroids to prevent fibrosis. Feeding jejunostomy or gastrostomy may be necessary in severe cases in which a nasogastric tube for feeding is contraindicated. Cicatricial stenosis of the supraglottis and of the hypopharynx is treated in association with the esophageal stricture in a one-stage procedure. The key to success is to replace the pharyngeal fibrotic tissue with the soft mucosa of the colic transplant such as that used to replace the esophagus. The

Ch144-F06861.indd 1752

pharyngeal stenosis can be resected with the CO2 laser, and the anastomotic zone is well delineated for immediate suture of the transplant up to the arytenoids (Fig. 144-12). Pharyngeal Z-plasty, local mucosal flaps, regional chest flaps, and supraglottic laryngectomy are alternatives that are reported in the literature.81-83

Laryngeal Stenosis Management of laryngeal stenosis after laryngeal trauma does not differ from that of postintubation or congenital stenoses. Subglottic stenoses are best treated with partial cricoid resection and primary anastomosis (see Chapters 30 and 31). Associated glottic stenoses are treated during the same procedure through a laryngofissure. Depending on the severity of the lesion, treatment varies from endoscopic resection to enlargement laryngotracheoplasty. Anterior enlargement is performed by a laryngofissure combined with an anterior cartilage graft interposition and stenting for 4 to 6 weeks or for up to several months in severe cases. Posterior glottic stenosis requires resection of the posterior fibrosis with mobilization of the arytenoids and enlargement of the posterior commissure with the interposition of a costal cartilage graft (Réthi procedure) and stenting for several weeks.69 The LTMold (see Fig. 144-10) is extremely useful in this situation. The development of endoscopic procedures with the CO2 laser, dilation, and stenting has led to overuse without thorough respect for the indications. Endoscopic treatment is only proposed as a first attempt before an eventual open surgical procedure for the following indications: noncircular scar; circular, thin diaphragm without cartilaginous collapse; CO2 arytenoidectomy for bilateral vocal cord paralysis or cricoarytenoid joint ankylosis; and anterior glottic synechia. A keel is often used to restore a sharp anterior commissure. Interventional endoscopy, however, plays an important role as an adjunctive treatment after open procedures to optimize the final results.

RESULTS In the majority of patients treated for external laryngeal trauma, airway patency, voice quality, and swallowing need to be restored to their best possible function. However, the clinical outcome is linked to the severity of the trauma and to the timing of the repair (Box 144-2). Patients treated within 48 hours have better voice and airway outcomes than those in whom repair was delayed.23,44,45,53,70 Butler and associates45 report only 27.7% good results in a delayed-treatment group of patients compared with 78.3% in the early-

Box 144-2 Management of External Laryngeal Trauma: Keys to Success ■ Immediate tracheostomy if the airway is compromised ■ Immediate investigation of the lesions (endoscopy, CT) ■ Meticulous suturing of mucosal lacerations ■ Reconstruction of the laryngeal framework (miniplates) ■ Appropriate stent, if necessary, for a maximum of 10 to 20 days

1/21/2008 4:20:28 PM

Chapter 144 Laryngeal Trauma

1753

FIGURE 144-12 A, Total pharyngolaryngeal stenosis after caustic ingestion in a 5-yearold girl. B, The surgery began with resection of the supraglottic stenosis using the CO2 laser via suspension microlaryngoscopy. The laser cut precisely delineated the mucosal margins in the pharyngolarynx. This was very beneficial in finding the appropriate level of anastomosis for the colic transplant during the open surgical repair. C, Result 1 year after the colic transplant has been sutured to the arytenoids. There is a slight residual supraglottic stenosis without functional impairment.

A

B

C

treatment group. Patients with grade I and II lesions, treated conservatively with or without tracheotomy, most often recover normal laryngeal functions (Butler et al, 2005).16,44,45,50,53,74 Patients with grade III to V injuries have less optimal results. Voice quality is more problematic than airway patency in grade III and IV injuries. The majority of these patients are decannulated with normal airway patency. Butler and associates45 reported decannulation in 100% of his patients with grade III and IV injuries, but 10% of these patients had a limited tolerance to exertion or some aspiration. Voice quality was normal in approximately 70% and altered but intelligible in 30% of the same group. Grade V injuries represent the worst functional prognosis. From 25% to 60% of patients are still tracheotomy dependent, and the majority have poor voice quality (Butler et al, 2005).44,45,58 There is no apparent correlation between the mechanism of injury (blunt versus penetrating) and the clinical outcome (Butler et al, 2005).45 Finally, trauma including recurrent laryngeal nerve injury with unilateral or bilateral vocal cord

Ch144-F06861.indd 1753

paralysis, displaced cricoid fractures, and cricoarytenoid dislocation is difficult to treat and is associated with suboptimal clinical outcome.

COMMENTS AND CONTROVERSIES This chapter provides an excellent review of a devastating injury that is often fatal. The lucid descriptions of laryngeal anatomic relationships and mechanism of injury help the reader understand why cricothyroid separation and coincident pharyngeal injury are frequently seen as a consequence of laryngeal trauma. Initial assessment of this injury is critical. Endoscopic evaluation (rigid and flexible) with high-quality optics provides essential diagnostic information that must be done with control of the airway as the paramount consideration. Familiarity with laryngoscopy, tracheobronchoscopy, and esophagoscopy is essential because associated injury is so common. The authors correctly advocate a controlled awake evaluation of the airway and subsequent intubation to avoid the need for emer-

1/21/2008 4:20:28 PM

1754

Section 8 Trauma

gency tracheostomy. In these patients, emergency tracheostomy quite often augments an injury to an already-damaged airway. The details of the operative repair are comprehensive and worthy of review. G. A. P.

KEY REFERENCES Butler AP, Wood BP, O’Rourke AK, Porusbsky ES: Acute external laryngeal trauma: Experience with 112 patients. Ann Otol Rhinol Laryngol 114:361, 2005. ■ The authors report a series of 112 external laryngeal traumas with an extensive description of diagnosis and management options with reference to the recent literature. Clinical outcomes of airway, voice quality, and deglutition are precisely reported and prognosis factors are identified. Demetriades D, Asensio JA, Velmahos G, Thal E: Complex problems in penetrating neck trauma. Surg Clin North Am 76:661, 1996. ■ The authors provide an excellent review of the diagnostic strategies and management of penetrating trauma of the neck including the larynx and trachea. Investigation and therapeutic protocols are discussed in detail.

Jewett BS, Shockley W, Rutledge R: External laryngeal trauma analysis of 392 patients: Arch Otolaryngol Head Neck Surg 125:877, 1999. ■ This paper, which is based on 11 state trauma databases, analyzes the epidemiology, management, and outcomes of external laryngeal trauma. Monnier PH: A new stent for the management of adult and pediatric laryngotracheal stenosis: Laryngoscope 113:1418, 2003. ■ The author presents a new soft stent for laryngotracheal stenting with technical aspects on the fixation and the modification according to specific indications. Pearson FG, Brito-Filomeno L, Cooper JD: Experience with partial cricoid resection and thyrotracheal anastomosis. Ann Otol Rhinol Laryngol 95:582, 1986. ■ The technique of partial cricoid resection for tracheal and subglottic stenosis and for laryngotracheal disruption is described extensively. Schaefer SD: The acute management of external laryngeal trauma: A 27-year experience. Arch Otolaryngol Head Neck Surg 118:598, 1992. ■ The authors describe the principles of the management of laryngeal trauma, including the diagnostic strategies, criteria for surgical versus medical management, principles of surgical treatment, and indications for stenting. This article is a useful reference for the clinician interested in laryngeal trauma.

Grewal H, Rao PM, Mukerji S, Ivatury RR: Management of penetrating laryngotracheal injuries. Head Neck 17:494, 1995. ■ The authors report on a series of 57 penetrating laryngotracheal injuries, with a focus on airway management, procedure for diagnosing associated lesions, and operative management.

Ch144-F06861.indd 1754

1/21/2008 4:20:30 PM

chapter

TRACHEOBRONCHIAL TRAUMA

145

Douglas E. Wood Riyad Karmy-Jones

Key Points ■ The initial priority is airway stabilization, which may require flexible

or rigid bronchoscopy. ■ Penetrating injury predominantly affects the cervical trachea, and

blunt trauma affects the distal trachea and carina. ■ Diagnosis should be suspected in patients with significant air leak,

subcutaneous emphysema, and/or pneumothorax despite tube thoracostomy. ■ The diagnosis can be missed, resulting in airway stricture, parenchymal necrosis, and/or late-onset asthma. ■ The upper half of the trachea is best exposed via a collar cervical incision, the distal half in most cases by a right fourth intercostal posterolateral thoracotomy. ■ Operative repair involves precise débridement of devitalized tissue, but in most cases simple reconstruction with absorbable interrupted sutures suffices.

Tracheobronchial injury is uncommon but immediately life threatening. The immediate sequelae can include death from asphyxiation, whereas lack of recognition or incorrect management may result in life-threatening or disabling airway stricture. Penetrating injuries can occur with any laceration to the neck or from projectile injuries to the neck or chest. Blunt injuries can occur from a variety of direct and indirect trauma. Laryngotracheal injuries are sometimes classified together, but in this discussion they are separated from laryngeal trauma, including laryngotracheal separation, which is discussed in Chapter 144. In this chapter, we concentrate on injuries that occur between the cricoid cartilage and the right and left main stem bronchial bifurcations.

HISTORICAL NOTE Paré provided the first known attempts of primary suture repair of two penetrating tracheal injuries, which he encountered while he was a young surgeon in the French army in the mid 1500s. Unfortunately, neither of these patients survived.1 Blunt traumatic bronchial rupture was described by Webb in 1848,2 occurring in a pedestrian who was run over by a horse-drawn wagon. The first description of a surviving blunt tracheobronchial injury may be from an 1871 article by Winslow3: The cook was preparing two of them (canvas back ducks) for baking, when she noticed something abnormal in one of them, and called my attention to it. Upon examination, it was evident that at some

previous remote period the left bronchus of the duck had been ruptured upon the outer side, where it joined the trachea at the bifurcation . . . yet, in this wild bird, life and health had apparently existed with the injury for many months, and repair had made good progress until interrupted by the sportsman. In 1927, Krinitzki provided the first report of a patient surviving a blunt bronchial disruption when he described the autopsy of a 31-year-old woman with an occluded right mainstem bronchus from a traumatic stricture due to trauma 20 years earlier.4 Surgical management of tracheobronchial injuries necessitated the development of endotracheal anesthesia and the techniques for pulmonary resection; therefore, the successful management of acute airway injuries is a development that is concurrent with the advent of elective airway surgery developed in the past 4 to 5 decades.5 Successful repair of a penetrating bronchial injury was not reported until 1945,6 and 2 years later Kinsella and Johnsrud7 performed the first successful repair of a bronchial injury from blunt trauma. Late repair of a traumatic stricture was initially performed in 1949 by Griffith,8 who excised the stricture, performed a primary end-to-end anastomosis, and preserved distal pulmonary function.

ANATOMY The trachea is a cervical and mediastinal structure that spans the inferior border of the cricoid cartilage to its bifurcation at the carina. The cervical portion of the trachea spans all of zone 1 in the neck and lies posterior to the strap muscles and thyroid gland and anterior to the esophagus and vertebral bodies. Lateral to the cervical trachea are the jugular veins, the common carotid arteries, and the vagus nerves, whereas the recurrent laryngeal nerves are closely applied to the trachea in the tracheoesophageal groove. As the trachea descends into the mediastinum through the thoracic inlet, it lies posterior to both the innominate vein and the innominate artery. Farther distally, the trachea passes underneath the aortic arch and posterior and to the left of the superior vena cava. The left recurrent laryngeal nerve runs in the left tracheoesophageal groove for nearly the full length of the cervical and thoracic trachea after passing underneath the aortic arch and around the ligamentum arteriosum. The right recurrent nerve is only closely applied to the trachea in its cervical portion. The carina is located at the level of the sternal angle anteriorly and the T4-T5 intervertebral disc posteriorly and lies directly behind the posterior pericardium, the ascending aorta, and the proximal portion of the aortic arch. 1755

Ch145-F06861.indd 1755

1/21/2008 4:21:20 PM

1756

Section 8 Trauma

The left main stem bronchus is 3 to 4 cm long and passes posterior to the posterior pericardium, the aortic arch, and the left atrium and anterior to the esophagus and the proximal descending thoracic aorta. It then passes through the pleural reflection, changing from a mediastinal structure to an intrathoracic structure before bifurcating into the upper and lower lobar bronchi. The right main stem bronchus is 1.5 to 2 cm long and passes medial to the azygos vein and posterior to the azygocaval junction. The right main stem bronchus lies posterior to the right pulmonary artery as it exits the mediastinum through the pleural reflection into the right hemithorax. On average, approximately 50% of the trachea lies within the neck and 50% within the chest. However, this can be markedly influenced by body habitus and neck position. Only 1 to 3 cm of the trachea may lie above the sternal notch in a kyphotic elderly person with a short neck. However, 7 cm or more of the trachea may lie above the sternal notch in a person with a long neck and with marked neck extension. This latter point must be kept in mind, particularly in the presence of penetrating or blunt injuries during neck hyperextension, which may result in an airway injury in an unexpectedly distal location. The anatomic relations of the trachea within the neck and chest are fundamental in evaluating the risk of airway involvement by mechanism and location of injury, as well as in aiding in the consideration and assessment of associated injuries. These anatomic details are also critical to the appropriate choice of surgical incision and exposure for treatment of airway and associated injuries. These decisions may be particularly complex with intrathoracic tracheal or carinal injuries in which optimal airway exposure would be gained through a right posterolateral approach, whereas known or suspected associated injuries may dictate an anterior approach. An intimate understanding of the relational anatomy allows a diversity of approaches to complex intrathoracic trauma that involves the airway.

INCIDENCE The true incidence of tracheal and bronchial rupture is difficult to establish. It is estimated that only 0.5% of all patients with multiple injuries managed in modern trauma centers suffer from tracheobronchial injury.9,10 This estimate is crude, however, because virtually all studies of airway trauma combine penetrating and blunt causes and do not publish a denominator of cervical and thoracic injuries with which to calculate the true incidence of airway involvement. It is therefore even more difficult to establish the incidence of tracheobronchial injury as a percentage of traumatic injuries overall. Penetrating neck injuries have a 3% to 6% incidence of cervical tracheal injury.11,12 Less than 1% (4/666) of patients admitted with penetrating chest trauma had tracheal injury in a series published from the Ben Taub Hospital in Houston.13 Because major urban trauma centers report three to four cases of penetrating tracheal trauma per year,11,14-16 it appears that the incidence of penetrating tracheobronchial trauma constitutes 1% to 2% of thoracic trauma admissions.12

Ch145-F06861.indd 1756

A frequently quoted series by Bertelsen and Howitz17 provides the best information regarding tracheobronchial injuries in blunt trauma. The authors reviewed 1178 autopsy reports of patients dying of blunt trauma and found an incidence of tracheobronchial injury of 2.8%, with over 80% of these patients dying instantly of airway or associated injuries and the rest dying within 2 hours of reaching the hospital. Kemmerer and associates18 reported an incidence of tracheobronchial rupture of under 1% in a study of nearly 600 traffic fatalities. A review of blunt cervical trauma revealed tracheal injury in 1.6%.19 Symbas and colleagues20 reviewed 20 years of English-language literature, spanning from 1970 to 1990, that reported airway injury secondary to blunt trauma. In this time frame, 47 articles described 183 patients, with 6 patients added in the 20-year period from the Grady Memorial Hospital experience in Atlanta. Unfortunately, these data do not provide a meaningful denominator on which to calculate the incidence of airway injury in blunt chest trauma. There is an apparent increase in the incidence of patients with airway injuries reaching the emergency department alive, which may occur as a result of improved prehospital care and development of specialized regional trauma units.21 However, this is difficult to establish, given the inherent inaccuracies in the historical and current data regarding airway injuries. De La Rocha and Kayler22 reported an incidence of tracheobronchial injuries of 1.8% in 327 patients who were discharged from a centralized trauma unit, whereas the authors of another series reported an incidence of 0.5% in a series of 2000 patients requiring admission to an intensive care unit for multiple trauma.23 The best consolidation of these data shows an incidence of tracheobronchial injury occurring in 0.5% to 2% of individuals sustaining blunt trauma, including blunt trauma to the neck. More than 80% of tracheobronchial injuries from blunt trauma are located within 2.5 cm of the carina.24 Most injuries related to blunt trauma involve the intrathoracic trachea and main stem bronchi, with only 4% of these injuries reported in the cervical trachea.20 In this review, 22% of the blunt airway injuries involved the distal thoracic trachea; 27%, the right main stem bronchus; and 17%, the left proximal main stem bronchus. Eight percent were complex injuries involving the trachea and main stem bronchi, and 16% involved the lobar orifices.20 The rate of tracheobronchial injury from penetrating thoracic trauma is also 0.5% to 2%, but, in contrast, penetrating cervical injuries involve the airway 3% to 8% of the time. Penetrating injuries predominantly involve the cervical trachea, with only 25% of the penetrating injuries involving the intrathoracic airways.12

MECHANISM OF INJURY Most tracheobronchial injuries result from blunt or penetrating trauma, although iatrogenic injuries and less common causes such as strangulation, burns, or caustic injury occasionally result in airway injury. Most penetrating trauma is due to stab wounds or gunshot wounds and only uncommonly may occur from impalement or slash injuries. Nearly all stab injuries of the trachea are cervical in origin, owing to the deep location of the intrathoracic trachea. Knife injuries produce

1/21/2008 4:21:20 PM

Chapter 145 Tracheobronchial Trauma

a tearing or shearing effect, resulting in perforation, linear laceration, through-and-through injuries, or transection.12 Gunshot wounds are a more common cause of penetrating airway injury and can affect any portion of the cervical or intrathoracic airways. However, cervical injuries are still more common, being the site of injury in 75% to 80% of penetrating tracheal trauma overall.12,25 This may be, in part, because more distal penetrating injuries of the trachea may have associated fatal injuries of the heart or great vessels, and such patients never arrive at the trauma center for evaluation and management. Knowledge of the missile trajectory based on history and the entrance and exit wounds is very helpful in predicting the path of the bullet and subsequent structures at risk for injury. However, this can be unpredictable, with bullet paths frequently altered by impact with bone or other dense tissue. Therefore, a high index of suspicion for airway injury must be maintained in all cervical and upper thoracic gunshot wounds. Gunshot wounds produce a crush injury and a wound cavity that varies depending on the muzzle velocity, the caliber, and the type of ammunition, with the greatest damage being produced by high-velocity rifles firing hollow-point ammunition. These injuries produce much greater cavitation and soft tissue destruction than do relatively low-velocity injuries from handguns. Blunt injuries of the cervical trachea most commonly result from direct trauma or from sudden hyperextension. Direct cervical trauma produces a crush injury of the trachea because it may be impinged on by the rigid vertebral bodies. This has classically been described as a dashboard injury because unrestrained motor vehicle passengers may hyperextend the neck during head-on collisions, striking the neck on the steering wheel or dashboard and producing a crush injury of the larynx or cervical trachea.26 However, even the restrained passenger may incur a laryngeal or cervical tracheal injury when a highriding shoulder harness applies a compressive and rotational force to the neck in front-impact automobile injuries.27,28 Clothesline injuries may produce similar direct crushing trauma but with the force concentrated across a very narrow band. Other injuries may occur with rapid hyperextension, producing a traction and distraction injury that most commonly results in laryngotracheal separation. This is discussed more thoroughly in Chapter 144. Hyperextension injuries most commonly occur in automobile accidents but can occur in any other situations in which forced rapid cervical hyperextension occurs. The exact mechanism of intrathoracic tracheobronchial disruption from blunt trauma is unknown but, as discussed, 80% of these injuries occur within 2.5 cm of the carina.24 Kirsch and associates29 proposed three potential mechanisms for the cause of blunt intrathoracic tracheobronchial injuries. First, they noted that sudden, forceful anteroposterior compression of the thoracic cage is the most common type of injury associated with tracheobronchial disruption. They postulated that this produces a decrease in the anteroposterior diameter and subsequent widening of the transverse diameter. Because the lung remains in contact with the chest wall because of negative intrapleural pressure, lateral motion pulls the two lungs apart, producing traction on the trachea at the carina. Airway disruption occurs if this lateral force exceeds

Ch145-F06861.indd 1757

1757

tracheobronchial elasticity. A second mechanism may be due to airway rupture as a consequence of high airway pressures. Compression of the lung, trachea, and major bronchi between the sternum and vertebral column during blunt trauma produces a sudden increase in intratracheal airway pressure, and in a patient with a closed glottis at the moment of impact, rupture can occur when the intraluminal pressure exceeds the elasticity of the membranous trachea and bronchi. Rupture in these circumstances occurs most commonly at the junction of the membranous and cartilaginous airway or between cartilaginous rings. The third potential mechanism may be due to a rapid deceleration injury, producing shear forces at points of relative airway fixation such as the cricoid cartilage and the carina, similar to the mechanism of traumatic injuries of the thoracic aorta.

ASSOCIATED INJURIES Because of the adjacent cervical and intrathoracic structures, penetrating airway trauma frequently is associated with other major injuries. Cervical trauma of the airway frequently involves the esophagus, the recurrent laryngeal nerves, the cervical spine and spinal cord, the larynx, and the carotid arteries and jugular veins. Intrathoracic penetrating trauma may involve the esophagus, left recurrent laryngeal nerve, and spinal cord, but it can also involve any of the great vessels, including the ascending arch and descending aorta and the pulmonary arteries, and may involve any of the four heart chambers or the lung parenchyma. Obviously, concomitant great vessel and cardiac injury from penetrating trauma is frequently fatal and may lead to exsanguination or asphyxiation on blood in the airway before presentation in a trauma unit. These associated injuries are common and frequently determine the ultimate outcome in terms of the patient’s survival and morbidity.20 In a series of 100 penetrating tracheobronchial injuries reported by Kelly and colleagues30 in patients with a primary airway injury in the cervical trachea, 28% of the patients had an associated esophageal injury, 24% had a hemopneumothorax, 13% had a major vascular injury, 8% had a recurrent laryngeal nerve injury, and 3% had a spinal cord injury. In contrast, primary injuries of the intrathoracic trachea were associated with an incidence of esophageal injury of 11%; hemopneumothorax, 32%; a major vascular injury, 18%; cardiac injury, 5%; spinal cord injury, 7%; and intra-abdominal injuries, 18%.30 Several other series have shown an overall incidence of associated major injuries with penetrating tracheobronchial trauma to be in the range of 50% to 80%, most of these being esophageal and vascular injuries, followed by spinal cord, pulmonary, and intra-abdominal injuries (Rossbach et al, 1998).11,14-16,31 Because of the magnitude of blunt trauma necessary to produce an airway injury, associated injuries are also common in this group and may be the primary determinant in patient outcome. Any other structure or organ system may be involved as in any patient with multiple trauma. Head, facial, and cervical spine injuries are frequent and important predictors of mortality and morbidity. Blunt intra-abdominal, intrathoracic, and skeletal trauma also occur frequently, as well as

1/21/2008 4:21:21 PM

1758

Section 8 Trauma

specific injuries to the esophagus and great vessels that are adjacent to the major airways. Major associated injuries are present in 40% to 100% of patients suffering blunt airway trauma and are dominated by orthopedic injuries in most patients, with a third to half of the patients having concomitant facial trauma, pulmonary contusions, or intra-abdominal injuries. From 10% to 20% of the patients have major closedhead injuries, and approximately 10% have associated spinal cord injuries (Ramzy et al, 1988; Reece and Shatney, 1988; Rossbach et al, 1998).31-33 In one series, a very high incidence was reported of recurrent nerve injury associated with blunt airway trauma as evidenced by vocal cord dysfunction without evidence of direct laryngeal injury.33 In this series, 49% of patients had recurrent nerve injuries and two thirds of these had bilateral recurrent nerve palsy. In this same series, a 21% incidence of esophageal perforation was reported, clearly suggesting the need for high index of suspicion for associated esophageal injuries, even in the setting of blunt trauma. A high percentage of cervical crush injuries producing tracheal disruption may have associated laryngeal injuries that require careful assessment by an otolaryngologist during the primary assessment phase and before treatment decisions are made regarding repair of the tracheal injury. Associated injuries are extremely common with both blunt and penetrating trauma of the airway and may be the major determinants of both short-term mortality and long-term morbidity. Knowledge of the relational anatomy, mechanism of injury, and incidence of related injuries helps define a prompt but thorough algorithm for diagnosing or excluding important injuries that require immediate or urgent management. Consideration of the known or potentially associated injuries becomes a critical factor in later choices of the surgical approach for addressing the airway injury.

DIAGNOSIS Accurate diagnosis of tracheobronchial injury requires an understanding of the mechanism of injury and a high index of suspicion when these mechanisms or common associated injuries are present. The initial assessment of the patient with potential airway trauma involves the traditional ABCs of resuscitation outlined by the American College of Surgeons in the Advanced Trauma Life Support (ATLS) guidelines.34 Airway injuries become the first priority in trauma, and because of their acuity and critical importance in stabilizing the patient, initial steps in management may proceed simultaneously with the diagnosis of airway pathology and associated injuries. Dyspnea and respiratory distress are frequent symptoms, occurring in 76% to 100% of patients (Kelly et al, 1985; Reece and Shatney, 1988; Rossbach et al, 1998).30,31,33 The other common symptom is hoarseness or dysphonia, which occurred in 46% of the patients in a series published by Reece and Shatney.33 The most common signs of airway injury reported in most series were subcutaneous emphysema (35%-85%), pneumothorax (20%-50%), and hemoptysis (14%-25%) (Kelly et al, 1985; Reece and Shatney, 1988; Rossbach et al, 1998).11,30,31,33,35 Air escaping from a penetrating wound in the neck is a pathognomonic sign of airway laceration and occurs in

Ch145-F06861.indd 1758

approximately 60% of patients with cervical penetrating trauma to the trachea.16 The most useful initial diagnostic studies are those obtained routinely in the initial trauma survey (i.e., chest and cervical spine radiographs). Deep cervical emphysema and pneumomediastinum are seen in 60% and pneumothorax occurs in 70% of patients with tracheobronchial injuries.11,36 The cervical spine or chest radiograph may also show a disruption of the tracheal or bronchial air column on careful examination. Overdistention of the endotracheal tube balloon cuff or displacement of the endotracheal tube may give additional radiologic signs of airway injury.36 An air leak from a penetrating neck wound that disappears after intubation is diagnostic and identifies the injury site as proximal to the cuff. Complete transection of a main stem bronchus may result in the classic signs of atelectasis, absent hilum, or a collapsing of the lung away from the hilus toward the diaphragm, known as the falling lung sign of Kumpe.36-38 A persistent pneumothorax with large air leak from a well-placed chest tube should increase the suspicion of intrathoracic tracheal or bronchial injury. With the chest tube on suction, the patient may experience more respiratory difficulties, and this finding is almost invariably associated with bronchial disruption.39 Although neck and upper chest computed tomogram (CT) has become critical to the accurate diagnosis of traumatic laryngeal injuries,26 the role in more distal tracheobronchial injuries is not well established. Commonly, chest CT may be obtained as a part of the trauma workup and is extremely valuable in detecting the presence of a mediastinal hematoma or the possibility of associated injuries of the great vessels. CT may show mediastinal air, disruption of the tracheobronchial air column, deviation of the airway, or the specific site of airway disruption (Fig. 145-1). Although not specifically indicated for the workup of suggested acute tracheobronchial trauma, preoperative CT can be useful in assessing associated laryngeal injuries or other unsuspected chest injuries that

FIGURE 145-1 CT scan after blunt trauma in a patient with persistent pneumothorax and minimal air leak. Solid arrow indicates area of discontinuity in the right main stem, just proximal to the origin of the right upper lobe bronchus (stippled arrow).

1/21/2008 4:21:21 PM

Chapter 145 Tracheobronchial Trauma

should be dealt with at the time of surgical exploration. CT is contraindicated in the hemodynamically unstable trauma patient or the patient with an unstable airway. A negative CT scan does not obviate the need for bronchoscopy or other diagnostic studies. Other imaging of suspected associated injuries is performed as indicated. Because of the common association of esophageal injuries, particularly after penetrating trauma, a contrast esophagogram is often necessary. Esophageal injuries may be distant from the airway injuries because of the distortion of tissues on traumatic impact.40 Angiography of the aortic arch or cervical vessels is performed for penetrating injuries in a stable patient or in a blunt chest trauma patient when findings on the chest radiograph or CT raise the suspicion for great vessel injury. If the initial diagnosis of airway injury is missed, granulation tissue and stricture of the trachea or bronchus will develop within the first 1 to 4 weeks and will usually lead to symptoms, signs, and radiologic findings of pneumonia, bronchiectasis, atelectasis, and abscess. Stridor and dyspnea are the common signs of late tracheal stenosis, whereas wheezing and postobstructive pneumonia are the common presentations of bronchial stenosis. Chest radiography and CT have been useful in the delayed setting and may directly reveal the site of stenosis and the secondary consequences of airway narrowing. Reconstructing three-dimensional images (CT bronchography) may also be a useful adjunct.41 Bronchoscopy provides the single definitive diagnostic study in a patient with suspected airway injury. Direct or fiberoptic laryngoscopy is an important part of the endoscopic study in patients with cervical trauma and should be performed with the assistance of an experienced otolaryngologist when laryngeal injuries are suggested. Careful examination of the tracheobronchial tree with the fiberoptic bronchoscope will allow determination of the site and extent of injury. Bronchoscopy is the only study that can reliably exclude central airway trauma, although minor lacerations may occasionally be missed. The advantages of fiberoptic bronchoscopy are that it can be performed quickly and easily, even in the setting of concomitant head and neck injuries or cervical spine trauma. If bronchoscopy is being performed for a suspected airway injury in an intubated patient, it is important to carefully withdraw the endotracheal tube during endoscopy to avoid missing proximal tracheal injuries. Bronchoscopy may also prove critical to the initial management of the patient with an injured airway. The flexible bronchoscope can be used as a guide to help intubate across a lacerated or transected trachea or to intubate selectively into a main stem bronchus (Fig. 145-2). With this in mind, many major trauma units have now made a fiberoptic bronchoscope an integral part of their trauma suite equipment to help provide assistance for the establishment of an airway and quick evaluation of potential airway injuries.25 Rigid bronchoscopy is rarely needed and, in fact, has the potential of exacerbating or extending the airway injury and is contraindicated in cervical spine trauma. However, skilled intubation with a ventilating bronchoscope may be lifesaving in cases in which tracheal transection and displacement does not allow identification or intubation of the distal segment with the

Ch145-F06861.indd 1759

1759

FIGURE 145-2 The flexible bronchoscope can be used as a guide and obturator for passing an endotracheal tube distal to the area of injury.

FIGURE 145-3 The rigid bronchoscope may provide airway control and ventilation.

fiberoptic bronchoscope.42 In these cases, the rigid bronchoscope may help realign the displaced airway and allow establishment of emergency ventilation before subsequent surgical repair (Fig. 145-3). In most such cases, proceeding directly to open surgical control of the airway is most expedient and appropriate, as discussed later.

MANAGEMENT Airway Management The initial and most important priority in acute tracheobronchial injury is to secure a satisfactory airway. Patients with respiratory distress and the clinical suspicion of an airway injury should be intubated immediately, preferably with the guidance of a flexible bronchoscope, as described earlier (see Fig. 145-2). Fiberoptic intubation provides several advantages. First, it does not require neck extension for direct laryngoscopy and so can be performed while stabilization of the cervical spine is maintained before the exclusion of cervical spine injuries. Second, fiberoptic intubation can easily be performed in the awake, spontaneously ventilating patient. This prevents the need for sedation and paralysis, which is contraindicated in the patient with an unstable airway, until a satisfactory airway can be established. Sedation and paraly-

1/21/2008 4:21:21 PM

1760

Section 8 Trauma

sis is also contraindicated during the immediate evaluation and stabilization of an injured patient who requires several simultaneous assessments and hemodynamic stabilization. Third, flexible bronchoscopy can act as an obturator for the endotracheal tube and direct the tube past an area of injury under direct vision, allowing accurate placement into the distal trachea or either main stem bronchus as necessary. Lastly, immediate bronchoscopy by an experienced endoscopist allows early evaluation of the location and extent of airway injury. This provides the best early information about the indications and approach for airway repair, allowing this to be calculated into the priority list of possible interventions for the multiply injured patient. In published reports, the incidence of upper airway obstruction or severe distress that requires immediate intubation is variable and dependent on the degree of injuries and the criteria used. Flynn and associates11 reported 8 of 22 patients (36%) requiring an immediate airway and 3 of these patients requiring an emergency tracheostomy or cricothyroidotomy. A series by Gussack and colleagues10 revealed 92% of patients requiring an emergency airway, 73% of these being successfully managed by orotracheal intubation and 3 patients emergently intubated through an open neck wound. Edwards and associates43 and Rossbach and Johnson31 reported that approximately 60% of their patients required prompt control of the airway. In Rossbach and Johnson’s series, 74% of the patients requiring emergency intubation were successfully managed by orotracheal intubation alone, whereas 10% required intubation with fiberoptic guidance, 10% were intubated through an open neck wound, and only one patient (5%) required an emergent surgical airway through tracheostomy or cricothyroidotomy. In the series reported by Edwards and coworkers,43 approximately 60% of the emergency airways were managed by nasotracheal or orotracheal intubation and the other 40% required tracheostomy. Important points are raised concerning the 3 patients in this series who were initially stable but experienced sudden deterioration secondary to the airway injury while they were being evaluated for multiple injuries. Two patients with a transected cervical trachea required emergency tracheostomy with intubation of the distal tracheal segment through the tracheostomy incision. In 1 patient, an attempted emergency cricothyroidotomy produced a significant laryngeal injury that necessitated subsequent delayed repair.43 A high index of suspicion and prompt securing of the injured airway are paramount to both the initial resuscitation and the ultimate outcome. Patients with air emanating from a penetrating cervical injury may be intubated through the neck injury directly into the tracheal lumen. This technique has been used in approximately 25% of airway trauma in reports that include penetrating cervical injuries (Rossbach et al, 1998).10,11,31,43 However, attempts at oral intubation or blind intubation through a cervical wound may be futile and can either precipitate total obstruction or allow the progressive loss of an unstable airway if repeated attempts are unsuccessful. Although intubation guided by a flexible bronchoscope may solve most of these difficulties, delay in obtaining a bronchoscope or successfully traversing the injury may also cause complete obstruction, with the tragic loss of a salvageable patient. In cases in which airway injury is suspected, prepara-

Ch145-F06861.indd 1760

tion for immediate tracheostomy must be made simultaneously with the attempts at intubation. In cases of severe maxillofacial trauma, immediate tracheostomy is the procedure of choice for airway control. Cricothyroidotomy is rarely useful in tracheobronchial trauma because the injury lies distal to the insertion point of the tracheostomy tube, which is placed blindly and with no additional accuracy over oral or nasotracheal intubation alone. If a tracheostomy is performed, the tracheostomy tube should be placed through the area of injury if possible to prevent extension of the tracheal injury by the tracheal stoma. A transected cervical trachea may retract into the mediastinum; in these cases it is best found by inserting a finger into the mediastinum anterior to the esophagus, locating the distal trachea by palpation, and grasping with a clamp to allow retraction into the cervical wound and distal intubation.44 Management of the airway for injuries of the distal trachea, the carina, and the proximal main stem bronchi can be extremely challenging. Use of double-lumen tubes should be avoided because of their rigidity and size, which increases the possibility of injury extension. In these cases, a long endotracheal tube should be positioned beyond the injury or into the appropriate main stem bronchus to provide single-lung ventilation. This can best be performed with the aid of the flexible bronchoscope serving as a guide and to confirm the final position. In almost all cases, standard ventilation can be initiated once distal airway control is ensured. In cases of distal injuries of the left main stem bronchus, the bronchus intermedius, or lobar orifices, a bronchial blocker placed proximal to the injury under endoscopic guidance provides another alternative for stabilizing the airway and allowing ventilation.

Stabilization and Prioritization of Associated Injuries Establishment of a stable airway and assurance of ventilation are the first two priorities as outlined in the ATLS guidelines of the American College of Surgeons.34 Once the airway is secured, the priority shifts to circulation, with the recognition, stabilization, and resuscitation of cardiovascular injuries. Neurologic, intrathoracic and intra-abdominal, vascular, and orthopedic injuries are identified during the primary and secondary trauma surveys. A patient with multiple injuries frequently has several simultaneous, competing priorities for the sequencing of and approach to operative procedures. Fortunately, intubation distal to the injury or into the unaffected proximal main stem bronchus usually allows adequate oxygenation and ventilation for emergency management of associated life-threatening injuries. The sequence of operative procedures must be individualized, but establishment of effective ventilation allows the initial priority to be given to the management of life- or organ-threatening injuries. Subdural hematomas, intra-abdominal bleeding, or major cardiovascular injuries should usually be repaired before definitive repair of the tracheobronchial injury.

Anesthetic Management Close cooperation between the anesthesiologist and surgeon is critical to the successful management of a tracheobronchial injury. In cases in which the airway has not already been

1/21/2008 4:21:22 PM

Chapter 145 Tracheobronchial Trauma

established, the anesthesiologist may provide invaluable assistance in airway control and selective intubation. The choice and timing of anesthetic agents and muscle relaxants, the type of endotracheal tubes used, and the mode of intraoperative ventilation require close communication between the anesthesiologist and surgeon for planning of an efficient and effective operative strategy. If a bronchoscopy has not already been performed, it is necessary at the initiation of the procedure to define the location and extent of injury and to guide the surgeon regarding the operative approach and intended repair. This is best performed with a standard diagnostic bronchoscope through a large single-lumen endotracheal tube. In cases of main stem bronchial or lobar injuries, a contralateral double-lumen endotracheal tube is preferred for the ease of isolated single-lung ventilation. However, in all other injuries involving the trachea or carina, a long, singlelumen tube can traverse and be seated distal to the injury and is preferred because it is less bulky and easier to guide past the torn airway without extending the injury. High-frequency jet ventilation provides an effective option for ventilation with relatively low airway pressures. Its main advantage is during airway reconstruction because it can be delivered through a small catheter with less bulk and rigidity, allowing easier placement of sutures or approximation of the newly reconstructed airway without tension. However, in most cases, it is usually easiest to perform standard ventilation through the oral endotracheal tube or through a sterile endotracheal tube inserted through the operative field into the transected airway. This does not require additional equipment or experience and has the added advantage of a cuffed tube preventing aspiration of blood into the distal airway and less aerosolization of blood around the surgical team.45 Cardiopulmonary bypass (CPB) is virtually never necessary for the intraoperative management of isolated airway injuries. Associated injuries of the heart or great vessels may require CPB. In cases in which CPB is already being used, it may facilitate a concomitant tracheobronchial repair. However, CPB after major trauma can exacerbate intracerebral or intraabdominal hemorrhage and potentiate the systemic inflammatory response that produces acute respiratory distress syndrome, with a very high subsequent mortality. In simple injuries, standard ventilation is straightforward, precluding consideration of CPB. In complex injuries, or those in which associated trauma makes ventilation difficult, the anticoagulation and added trauma of CPB probably results in exacerbation of bleeding and the systemic inflammatory response more than it helps in allowing airway repair. Virtually all patients with isolated tracheobronchial injuries can be easily extubated at the end of the operative procedure and should be managed by the anesthesiologist with this in mind. Patients who require postoperative ventilation because of their associated injuries should finish the procedure with a large-bore, single-lumen endotracheal tube to allow good pulmonary toilet and fiberoptic bronchoscopy if necessary. If possible, this should be placed with the balloon cuff distal to the area of tracheal repair in proximal injuries or should lie proximal and away from the repair for carinal and main stem bronchial injuries. Major laryngeal or maxillofacial injuries with the anticipated need for prolonged ventilation are indications for placement of a tracheostomy at the completion

Ch145-F06861.indd 1761

1761

of the tracheobronchial repair. This tracheostomy should not be placed through the tracheal repair, which will lead to a contamination of the suture line with subsequent dehiscence or stenosis.46

Surgical Management Definitive primary repair of major tracheobronchial injuries is almost always indicated in conjunction with other urgent operative interventions, as discussed earlier. Minor injuries may not be initially apparent or recognized, owing to a lack of clinical suspicion or concealment by prompt distal intubation for stabilization of a patient with multiple injuries. These minor injuries may heal without direct surgical repair with no negative sequelae if they involve less than one third of the circumference of the airway. However, the most reliable short- and long-term result is provided by prompt, definitive repair and should be performed whenever possible when the injury is recognized. In rare circumstances it may be appropriate to perform a delayed repair if it is not possible to perform operative correction because of the instability of the patient with multiple injuries. Figure 145-4 shows the central airways in relation to the anterior skeletal anatomy of the manubrium and sternum and demonstrates the preferred operative approaches for isolated tracheobronchial injuries. The proximal one half to two thirds of the trachea is best approached through a low cervical collar

a

b

c

FIGURE 145-4 Comparative surface anatomy and surgical approaches for repairing tracheobronchial injuries. Proximal tracheal injuries (a) are best approached via a cervical collar incision. The distal half of the trachea, the right main stem bronchus, the carina, and the proximal left main stem bronchus (b) are most easily exposed via right posterolateral thoracotomy. Most of the left main stem bronchus (c) may be exposed via a left posterolateral thoracotomy.

1/21/2008 4:21:22 PM

1762

Section 8 Trauma

incision that also provides excellent exposure to vascular or esophageal injuries in the neck (see Fig. 145-4). Creating a T-shaped incision over the manubrium and splitting the manubrium down to the second interspace opens the thoracic inlet and provides a broader exposure to the middle third of the trachea as well as proximal control of the innominate artery or veins. A full median sternotomy does not provide significant additional airway exposure except in specific circumstances, which are discussed later. The distal third of the trachea, the carina, and the right main stem bronchus are most easily approached through a right thoracotomy, which also provides good exposure to the azygos vein, superior vena cava, and right atrium, as well as all of the intrathoracic esophagus (Fig. 145-5; see Fig. 145-4). Injuries of the left main stem bronchus are most easily approached through a left thoracotomy, which also provides good exposure to the distal portion of the aortic arch, the descending thoracic aorta, and the proximal left subclavian artery (see Fig. 145-4). However, exposure to the proximal left main stem, the carina, the distal trachea, or the right main stem is extremely difficult through a left thoracotomy, owing to the overlying aortic arch (Fig. 145-6A). Adequate proximal exposure may be gained by mobilization of the arch with retraction cephalad and laterally and division of the ligamentum arteriosum (see Fig. 145-6B). These approaches may not be adequate for the management of potential associated injuries. Because of the proximity of the heart and great vessels anterior to the distal trachea, the carina, and the proximal main stem bronchi, penetrating injuries to the chest are likely to have associated lifethreatening cardiovascular injuries (Fig. 145-7). A median sternotomy is often performed to provide optimal access to the heart or great vessels but provides far less satisfactory exposure to the trachea, carina, and bronchi than did respective thoracotomies as described earlier. However, it is possible to obtain exposure to the anterior airway in the vicinity of the carina to allow anterior repair or limited primary resection and reconstruction. This requires mobilization of the

superior vena cava with reflection to the right, retraction of the ascending aorta to the left, and longitudinal division of the posterior pericardium cephalad to the right pulmonary artery and caudal to the innominate vein (Fig. 145-8). Unfortunately, this does not provide any exposure to the posterior airway, where blunt injuries frequently occur. It also does not provide adequate exposure for repair of concomitant esophageal injuries. A bilateral thoracosternotomy or clam shell incision through the fourth interspace provides good exposure to both hemithoraces and the anterior mediastinum and may be considered as an approach because of associated injuries. However, this approach provides little additional

Left lung

Left main stem bronchus Arch of aorta

Trachea Right main stem bronchus

A

Left lung

Left main stem bronchus Arch of aorta

Right lung (retracted)

Trachea

Right main stem bronchus

Esophagus Azygos vein

B FIGURE 145-5 The exposure of the trachea and right main stem bronchus from right posterolateral thoracotomy (via either the fourth interspace or via the bed of the resected fifth rib). The lung is retracted anteriorly.

Ch145-F06861.indd 1762

Right main stem Trachea bronchus

FIGURE 145-6 View of the left main stem bronchus via the left posterolateral thoracotomy. The aortic arch overlies the proximal main stem (A) and must be extensively mobilized to gain adequate proximal exposure (B).

1/21/2008 4:21:22 PM

Chapter 145 Tracheobronchial Trauma

1763

FIGURE 145-7 Major structures close to the tracheobronchial tree are at risk for simultaneous injury.

Thyroid gland Right vagus nerve

Right recurrent nerve

Superior vena cava Azygos vein

Right upper lobe bronchus Right main stem bronchus

Esophagus

Left recurrent nerve Trachea Left vagus nerve Aorta Left recurrent nerve Pulmonary trunk Left main stem bronchus

Thoracic aorta

Azygos vein

airway exposure or airway advantages over those incisions previously described. Simple, clean lacerations without airway devascularization can be repaired primarily with simple interrupted absorbable sutures. We prefer 4-0 Vicryl (Ethicon, Cincinnati, OH), although others have successfully used permanent and absorbable monofilament. In cases in which there is significant tracheobronchial damage, all devitalized tissue should be débrided, with care taken to preserve as much viable airway as possible. In these cases, a circumferential resection and end-to-end anastomosis is almost always preferable to partial wedge resections of traumatized airway with attempted primary repair. The principles of airway resection and reconstruction are similar for tracheal, carinal, or bronchial injuries, although the anatomy of reconstruction is unique to the surgical exposure, the location, and the extent of resection. This is particularly true when a portion of the carina must be resected or reconstructed, because a large variety of techniques may be necessary to achieve reconstruction in this area.47 Dissection of the airway is limited to the region to be resected to preserve tracheobronchial blood supply to the

Ch145-F06861.indd 1763

area of anastomosis. Precise placement of interrupted absorbable suture allows an airtight anastomosis, correction of size discrepancy between the distal and proximal airway, and minimal anastomotic granulations if the anastomosis is brought together without tension. These techniques of tracheobronchial reconstruction have been well described and have been fairly consistently used in most thoracic surgical groups who perform airway reconstruction.48 In most patients, up to half of the trachea can be resected and primarily reconstructed so that the most significant tracheal injuries should be able to allow primary resection and reconstruction without difficulty. Both main stem bronchi can be completely resected with primary reconstruction without tension in all cases. Extensive injuries of the carina are more problematic and should be repaired rather than resected if at all possible. Only 3 to 4 cm of airway involving the carina can be resected and allow for primary reconstruction. A variety of tracheobronchial release maneuvers have been used to allow a tension-free anastomosis. For most limited tracheal resections, blunt development of the anterior avascular pretracheal plane combined with neck flexion is all

1/21/2008 4:21:24 PM

1764

Section 8 Trauma

Azygos vein Trachea

Pulmonary artery

Superior vena cava

Left main stem bronchus

Right pulmonary artery

Right main stem bronchus Right pulmonary veins

Pulmonary veins Aorta

FIGURE 145-8 Transpericardial exposure of the carina. The superior vena cava is retracted to the right, the ascending aorta is retracted to the left, and the pericardium is incised cephalad to the right pulmonary artery.

that is necessary. For more extensive proximal tracheal resections, a suprahyoid laryngeal release can provide 1 to 2 cm of additional proximal mobilization. For resections of the main stem bronchi or carina, division of the pericardium around the inferior aspect of the hilum provides an additional 1 to 2 cm of distal airway mobilization.49 Associated injuries of the esophagus should be repaired in two layers. When working through an anterior cervical exposure, the esophagus may be best exposed by complete tracheal transection through the area of planned tracheal repair. A vascularized flap of muscle or soft tissue should be inter-

Ch145-F06861.indd 1764

posed between the tracheal and esophageal repairs to minimize the risk of postoperative tracheoesophageal fistula. Intrathoracic tracheobronchial suture lines are also preferably wrapped with pedicled pericardial fat, intercostal muscle, or pleura to separate the airway anastomosis from overlying blood vessels. In cases in which a portion of the trachea or carina has been resected and reconstructed, much of the airway mobility is provided by neck flexion. This position is maintained in the postoperative period by placement of a guardian suture between the chin and the sternum.45 As discussed earlier, patients with isolated airway injuries are rou-

1/21/2008 4:21:25 PM

Chapter 145 Tracheobronchial Trauma

tinely extubated in the operating room, even after complex reconstructions.

Postoperative Management Careful airway observation is maintained in the early postoperative period. Aggressive pulmonary toilet, including the liberal use of bedside bronchoscopy, is important because these patients may have difficulty clearing secretions past their anastomosis or area of airway repair. Patients who have an associated vocal cord paralysis may have even more difficulty with pulmonary toilet owing to their inability to produce an effective cough. These patients may benefit from a commercially available minitracheostomy (Minitrach II, Portex, Keene, NH), which is placed through their cricothyroid membrane to allow direct tracheal suctioning. Some patients with tracheal resection have problems with postoperative aspiration because of difficulty in elevating the larynx during deglutition. This is more profound in the patients with associated recurrent nerve injuries or in those who have had a suprahyoid laryngeal release. The remainder of the postoperative management is similar to the routine care after other neck operations or thoracotomy for pulmonary resection. In the trauma setting, management of the associated injuries and their complications may dominate the care of the patient. For the ventilated patient, care should be taken to position the endotracheal balloon distal or proximal to the tracheal suture line and minimize airway pressures in cases in which the endotracheal tube lies above the airway anastomosis by necessity. These patients should be managed at the lowest possible airway pressures that provide satisfactory oxygenation and ventilation and should be extubated as soon as their other injuries allow. Bronchoscopy should usually be performed 7 to 10 days after tracheobronchial repair or before discharge to ensure satisfactory healing without granulation tissue or the early development of anastomotic stenosis.

Complications The complications of tracheobronchial repair are similar to those of airway resection and reconstruction and consist mostly of anastomotic problems. Anastomotic dehiscence or restenosis occurs in 5% to 6% of patients after tracheal reconstruction.50 Initial management involves securing the airway, usually with an endoluminal or tracheal T-tube until healing is complete and the perioperative inflammation has subsided. Most of these patients can be managed with subsequent airway resection and reconstruction 3 to 6 months after the original repair if necessary.51 Anastomotic dehiscence is life threatening if it results in fistula formation to the innominate artery or esophagus. Tracheal–innominate artery fistula is rare but frequently fatal and requires immediate operation for division of the innominate artery and interposition of healthy tissue between the airway and great vessels. Tracheoesophageal fistula can usually be managed initially by establishing gastric drainage, enteral nutrition, and treatment of pneumonia. When the patient is stable and no longer requires ventilatory support, the tracheoesophageal fistula can be divided, with the esophageal and tracheal defects resected or repaired

Ch145-F06861.indd 1765

1765

and healthy soft tissue interposed between the adjacent suture lines. Associated laryngeal complications due to laryngeal injuries or vocal cord dysfunction are discussed in Chapter 144. If vocal cord paralysis is permanent, it can usually be palliated by vocal cord lateralization or medialization procedures.

Late Management Patients may incur delayed treatment after tracheobronchial trauma for three reasons. First, the initial injury may have been subtle and initially missed in the early or intermediate trauma management. Second, severe associated injuries may have prevented early definitive management of recognized airway injury. Third, initial attempts at repair may fail, resulting in dehiscence or late stenosis. In any of these scenarios, the sequelae are similar. Although the airway may be partially or completely disrupted at the time of initial injury, it may be held together by strong peritracheal connective tissue, allowing an airway to be established and ventilation to be maintained. However, as the primary injury or secondary dehiscence heals, granulation tissue and scar contracture result, with subsequent stricture formation that usually develops 1 to 4 weeks after injury. Taskinen and associates51 reported nine patients with blunt tracheobronchial rupture, five of whom had operations purposely delayed from 9 to 89 days because of complete lung expansion with suction drainage. However, in all five patients, dyspnea later developed, with bronchoscopy revealing obstruction and granulation tissue at the site of airway injury. Each of these patients required subsequent airway resection with primary reconstruction. These patients may initially have dyspnea on exertion but may also have wheezing, stridor, cough, difficulty in clearing secretions, or recurrent respiratory infections. Any of these symptoms with a history of trauma or prolonged intubation should raise the suspicion of a late airway stenosis, which should be diagnosed or excluded by bronchoscopy. A 50% reduction in the cross-sectional area of the trachea usually results in dyspnea only with significant exertion, whereas narrowing of the lumen to less than 25% usually produces dyspnea and stridor at rest. Patients may be reasonably compensated in spite of significant stenosis but can have acute life-threatening deterioration with a minor amount of airway edema or secretions. A high index of suspicion in these patients is critical to their subsequent workup and timely diagnosis.52 Once recognized, critical airway stenosis can be evaluated and initially stabilized by bronchoscopy and dilation.53 However, the appropriate, definitive management of most of these patients requires tracheal or bronchial resection with primary reconstruction as for benign airway strictures from other causes.52 Except in cases of distal lung destruction by chronic infection, re-establishment of ventilation to lung parenchyma can be expected to restore significant function, even years after the injury. There may be little or no apparent function by preoperative perfusion scanning; this is likely due to reflexive pulmonary vasoconstriction and is reversible on resumption of ventilation to the lung parenchyma. Airway

1/21/2008 4:21:25 PM

1766

Section 8 Trauma

reconstruction should always be considered first in these instances, with pulmonary resection reserved for patients with unreconstructable lesions or those with destroyed parenchyma from chronic infection or bronchiectasis. An uncommon manifestation is the late presentation of tracheoesophageal fistula that occurs not as a result of surgical complication but rather due to delayed necrosis. This occurs in as few as 0.001% of all blunt trauma admissions, usually involving a history of steering wheel impact or air bag deployment.54 The most common site is at or just above the carina, and presumably as a consequence of hematoma formation between the membranous trachea and anterior wall of the esophagus, in turn leading to delayed necrosis. The most common presentation is new onset of cough or pneumonia, with or without aspiration, that begins 10 days or more after the incident. These fistulas have also been reported after other mechanisms, notably battery ingestion, electrical burns, and falls.55,56 These injuries can occur in an elective setting with choking during drinking, and the diagnosis may be suggested by CT and confirmed by esophagography.57 In a ventilated patient, gastric distention, respiratory distress when the nasogastric tube is on suction, and/or the breathing bag sign of a Foley bag hooked to the nasogastric tube can also prompt the diagnosis.58 Management is usually operative, with a mortality of 10% to 15%. However, medical management has been associated with a mortality approaching 80%, although this may reflect greater associated injury and physiologic derangement.59 In patients whose pulmonary injury is severe enough to prohibit operative intervention, temporary esophageal stenting may permit stabilization until definitive repair can be achieved.60 Alternatively, if the air leak is not so severe, temporization with a gastric tube and feeding jejunostomy can be tried. Usually, repair is performed via a right posterolateral approach and involves resection of the affected airway, esophageal repair and interposition of viable tissue, or gastric pull-up. In some cases, esophageal resection with interval reconstruction is required.

RESULTS Injury to the trachea and proximal bronchi is a lethal injury, with more than 75% of patients with blunt tracheobronchial trauma dying before arrival to the emergency department.17 There are no known series of autopsy studies of penetrating tracheobronchial trauma to give us a similar prehospital mortality denominator. However, in both instances, death is most likely due to associated injuries rather than to the tracheobronchial injury itself. In patients operated on for penetrating injuries, the mortality is 6% to 18%.15,16 Of 17 survivors of penetrating tracheal trauma, 88% had a good result, apparently without symptoms.15 One of 17 patients had permanent hoarseness from concomitant recurrent nerve injury, and a second patient required a permanent tracheostomy because of complications and failed reconstruction of a combined tracheal and esophageal injury. In Rossbach’s series of 32 patients with penetrating (59%) and blunt (41%) tracheobronchial trauma, 78% of patients required postoperative mechanical ventilation. In patients with a penetrating injury, this ranged from 1 to 3

Ch145-F06861.indd 1766

days with a mean of 2 days; and in patients with blunt injury, intubation ranged from 3 to 9 days with a mean of 5 days. The average length of intensive care unit stay was 4 days for patients with penetrating trauma and 9 days for patients with blunt injury, whereas the mean hospitalization was 15 days and 17 days for penetrating and blunt injuries, respectively (Rossbach et al, 1998).31 Nineteen percent of patients in this series sustained postoperative complications, but 93% of patients were ultimately asymptomatic and returned to preinjury function. Only 1 of 32 patients (3%) had a symptomatic late stenosis after repair of complex avulsion injury. The mortality rate in this series was 6% and was related to multiple injuries in the setting of blunt trauma. Results from other series show a mortality of 10% to 25% for patients undergoing repair of tracheobronchial injury in the setting of penetrating or blunt trauma with associated injuries11,20,43 Patients with early definitive airway repair had a long-term good result in over 90% of patients, with poor airway-related outcomes generally being due to associated recurrent nerve injury or failed initial tracheobronchial repair (Reece and Shatney, 1988).10,33 However, in the series by Reece and Shatney,33 good results were only obtained in 67% of patients who had tracheal repair over a stent or with a tracheostomy, leaving the authors to conclude that primary early repair provides the best long-term outcomes. In many series, the ultimate prognosis after airway injury is dependent on the associated injuries, particularly closed-head injuries. Thirteen percent of the patients in a series published by Angood and associates23 were left in a vegetative state in spite of excellent functional airways after definitive tracheobronchial repair.

Thermal Tracheobronchial Injury Inhalational injury represents a combination of local upper, lower, alveolar, and systemic insult. Only the specifics of tracheobronchial thermal injury are discussed here because it represents a unique form of airway trauma and the management of alveolar, cutaneous, and systemic burn injuries would require too extensive a discussion for this text. Inhalational injuries can be the result of direct heat and/or chemical burn. Inhaled heat (flame, gases) tends to result in upper airway injury, whereas toxic byproducts predominantly affect the parenchyma. Heat from dry air dissipates rapidly and affects the upper airway, but steam can affect the entire airway and even injure alveoli, resulting in diffuse severe injury (Fig. 145-9).61 The diagnosis is often suggested by the history (e.g., fire in an enclosed space), evidence of cutaneous injuries around the oropharynx, and/or soot detected in nasal or oral passages or produced by coughing. Fiberoptic laryngoscopy and bronchoscopy has been advocated as a gold standard to make the diagnosis.62 However, its routine use may be guided by clinical correlates. One study evaluated the triad of closed-space fire, carbon monoxide levels more than 10%, and carbonaceous sputum. If three were present, bronchoscopy had a 96% correleation, if two, 70%, and if only one, less than 30%.61 The primary treatment mode is supportive. Any evidence of stridor, hoarseness, or severe upper airway edema should prompt consideration of intubation. The peak edema formation occurs 12 to 36 hours after injury. Cortico-

1/21/2008 4:21:25 PM

Chapter 145 Tracheobronchial Trauma

1767

COMMENTS AND CONTROVERSIES Tracheobronchial trauma constitutes a genuine life-threatening emergency. The authors have discussed this subject in detail. The reader is provided with an interesting historical background. The anatomic considerations for management of these lesions are also discussed. The importance of interaction with the surgery and anesthesia teams is stressed because control of the airway is the paramount consideration in the management of these patients. Expertise in the use of flexible and rigid endoscopic instruments is mandatory, as is an appreciation of the associated injuries often accompanying the major trauma necessary to produce a significant tracheobronchial injury. Definitive repair is always the optimal option. Tracheostomy should be used judiciously. G. A. P. FIGURE 145-9 Autopsy picture of distal trachea and carina after lethal steam inhalation injury. (FROM BAUER GJ, GIBRAN N, HEIMBACH DM: INHALATION INJURIES. IN KARMY-JONES R, NATHENS A, STERN E, [EDS]: THORACIC TRAUMA AND CRITICAL CARE. BOSTON, KLUWER ACADEMIC, 2002, PP 137-150.)

steroids have not been shown to be of benefit acutely.62 Isolated upper airway thermal injuries usually require 3 to 5 days before extubation can be achieved. Patients should be evaluated for possible stricture, and postextubation stridor may require racemic epinephrine and/or heliox. Prolonged intubation increases the risk of vocal cord injury and subglottic stenosis. The current practice at our own burn unit is to consider tracheostomy between 14 and 21 days.

Ch145-F06861.indd 1767

KEY REFERENCES Kelly JP, Webb WR, Moulder PV, et al: Management of airway trauma: I. Tracheobronchial injuries. Ann Thorac Surg 40:551-555, 1985. Kirsch MM, Orringer MB, Behrendt DM, Sloan H: Management of tracheobronchial disruption secondary to non-penetrating trauma. Ann Thorac Surg 22:93-101, 1976. Ramzy AI, Rodriguez A, Turney SZ: Management of major tracheobronchial ruptures in patients with multiple system trauma. J Trauma 28:1353-1356, 1988. Reece GP, Shatney CH: Blunt injuries of the cervical trachea: Review of 51 patients. South Med J 81:1542-1548, 1988. Rossbach MM, Johnson SB, Gomez MA, et al: Management of major tracheobronchial injuries: A 28-year experience. Ann Thorac Surg 54:182-186, 1998.

1/21/2008 4:21:25 PM

MANAGEMENT OF BLUNT CHEST AND DIAPHRAGMATIC INJURIES

chapter

146

Riyad Karmy-Jones Gregory Jurkovich

Key Points ■ Tube thoracostomy can be associated with significant complica-

tions if there is insufficient attention to detail. ■ Pain management is critical. ■ Plain chest radiographs often underestimate the degree of pleural

and/or parenchymal complications. ■ Aggressive and prompt operative management of hemothorax and

ongoing bleeding can reduce complications. ■ Surgeons need to be facile with a wide range of parenchymal

resection techniques, ranging from damage control to formal resection. ■ Diaphragmatic injuries can be missed, especially in patients who present intubated.

Chest injuries are primarily responsible for at least 25% of fatalities after injury and play a major contributing factor in as many as a further 50% of fatal cases.1 Although in the majority of cases the major technical procedure is tube thoracostomy, attention to detail is critical because there are often delayed complications, and interventions are often both hazardous and immediate.

PROCEDURES Tube Thoracostomy Tube thoracostomy is the primary invasive treatment for managing chest injury. In patients at risk of developing tension pneumothorax (e.g., during air transport with chest injuries or those who are requiring significant ventilator support) prophylactic tubes are also indicated. It is critical to recognize that in 20% of cases the physical examination is misleading.2 Patients with chest injuries whose condition is unstable, or those with decreased breath sounds and increased tympany, need to have tubes placed without delay. Stabilized patients without distress are allowed the benefit of a chest radiograph if it is available before tube placement. Computed tomography (CT) is much more sensitive for detecting occult pneumothorax. Even a small pneumothorax in a ventilated patient needs to be drained because the risk of developing tension is significant unless the ventilator support is minimal and extubation is anticipated shortly. In stabilized patients, attention to anesthesia (including local and, if appropriate, conscious sedation) and sterile technique is important. The usual landmark is the anterior to midaxillary line above the inframammary crease. Anterior tubes placed in the same landmark as needle compression are

also appropriate in some settings. If there is a thoracotomy scar, the tube is placed superior to this because the diaphragm usually is scarred to the level of the previous incision. There are two basic methods: the Kelly clamp versus the sharp approach. Using scissors or a scalpel to incise down to the intercostal muscles, rather than blunt dissection, may be quicker, less painful, and associated with less bleeding. Tunneling over one to two ribs higher than the skin incision does not need to be done in most circumstances for the same reason.2 Pain is the most common complication and can lead to splinting, atelectasis, and pneumonia. Laceration of underlying structures can occur due to high airway pressure and/or prior adhesions (present in 15%-20% of patients de novo). Careful determination of intrapleural placement can avoid this, as can controlling the dissection device carefully. Tubes can become displaced (1.7%-5.2% incidence), usually because they are not pushed in far enough, and when the patient sits up and/or lowers his or her arm, tubes are pulled out 1 to 3 cm on average.3 Misplacement at the time of insertion into the extrathoracic space can occur in patients with larger body habitus, thick parietal pleura (e.g., empyema), and/or if there is significant soft tissue edema. Chest radiography may not be clear, but the persistence of pneumothorax with lack of respiratory variation can suggest the diagnosis. The tube is removed and a new one placed through a new incision. Empyema occurs in 2% to 10% of patients who undergo tube thoracostomy in the emergency department. Risk factors include retained hemothorax, poor technique, shock, extrathoracic infectious sites, pain, and pneumonia.4 In the trauma setting, gram-positive organisms are particularly prevalent and there is support for the notion that prophylactic antibiotics for 24 hours or less compared with no antibiotics results in a reduction in empyema.5

Thoracoscopy Thoracoscopy has been described for a variety of diagnostic and therapeutic indications. Rigid thoracoscopy has advantages in that lung isolation is not required, blood and other debris can be evacuated through the larger port, pleural exploration is possible, and in many cases a single port can be used to complete the procedure.6 Video-assisted thoracoscopic surgery (VATS) requires that the lung on the operative side be collapsed, but it offers a more panoramic view and is more flexible in terms of allowing advanced procedures, such as repairing the diaphragm or resecting injured lung parenchyma. VATS has been used acutely to treat ongoing bleeding and large air leak.7 It does

1768

Ch146-F06861.indd 1768

1/21/2008 4:22:14 PM

Chapter 146 Management of Blunt Chest and Diaphragmatic Injuries

require that the patient be hemodynamically stable. The management of empyema and of retained hemothorax is discussed later in this chapter. Resolution of persistent air leak (>3 days) does appear to be shorter with VATS resection compared with placing additional chest tubes.8 Thoracoscopy has also been used successfully to diagnose cardiac and diaphragmatic injuries and in some instances to repair the latter. When entering the chest, it is important to avoid parenchymal injury by bluntly pushing through the intercostal space. Making the initial incision (if there is not a chest tube tract) in a manner that the intercostal muscle can be divided under direct vision reduces this risk. In addition, placing the ports as anteriorly as possible (where the rib spaces are wider) and minimizing the use of ports (which increase nerve trauma) can reduce the incidence of postoperative persistent pain, a complication that occurs in up to 7% of patients. Thoracoscopy, particularly with a mediastinoscope, can be performed without lung isolation and in the supine posture if the primary goal is to drain the pleural space, explore the diaphragm, and/or view the pericardium.

Thoracotomy Although this chapter does not deal specifically with great vessel or cardiac injuries, and tracheobronchial injury has been discussed in the previous chapter, it is not uncommon to have to repair multiple injuries and therefore all aspects of exposure are discussed (see Chapter 145). The choice of operative approach is influenced by injury pattern, patient stability, available equipment, and experience of the surgeon. The initial exposure may prove to be inadequate. Recognizing this and making modifications or closing and repositioning is far better than continuing to struggle. At the same time, particularly in unstable patients, one need not be paralyzed by indecision and trying to choose the perfect approach. The most common urgent incision is the anterolateral thoracotomy. This incision is made in the inframammary crease (not nipple line), with the incision turning superiorly in the medial aspect after crossing over the midclavicular line. This is so that if extension across the sternum is required the incision will not be placed too low. The ribs and costal cartilages change course dramatically at this point also, rising superomedially acutely. If, on entering the chest, high apical bleeding consistent with great vessel injury is encountered, packing the apex and holding pressure while performing an appropriate counterincision can be lifesaving. This can be performed on either side. Patients presenting in shock with isolated stab wounds on the right or major blood loss via right-sided rather than left-sided chest tubes, for example, are better served by a right-sided rather than a left anterolateral thoracotomy. The heart, pulmonary hilum, and ascending aorta are all easily accessible with a median sternotomy. Sternotomy is most likely to provide adequate exposure for penetrating injuries between the nipple lines or anterior axillary lines compared with other approaches.9 The midline is indicated by a line between the suprasternal notch and the root of the xiphoid and is marked by the medial decussations of the pectoralis muscles. There are crossing veins at the supraster-

Ch146-F06861.indd 1769

1769

nal notch and just superior to the sternoxiphoid junction that often need to be ligated. The origin of the great vessels can be controlled through this approach, and dissection starts within the pericardium, particularly if there is extensive superior mediastinal hematoma.10 The innominate vein can be divided or mobilized to expose the innominate artery as it passes beneath it. Sternotomy in conjunction with supraclavicular extension offers equal exposure to the left subclavian as does the trap door approach with less morbidity. On either side, the midportion of the subclavian vessels is best accessed via a supraclavicular incision.11 This incision can be further extended across the mid aspect of the clavicle, curving down toward the deltopectoral groove for access to the distal subclavian and axillary artery junction. Sufficient exposure usually requires division of the sternocleidomastoid muscle attachments to the clavicle, as well as the attachments of the anterior scalenus muscle onto the first rib. In addition, the attachments of the pectoralis major muscle may need to be divided. Great care must be exercised to avoid injury to the phrenic nerve, vagus nerve, and cords of the brachial plexus with this approach. Resection of the medial portion of the clavicle can potentially increase exposure of the subclavian artery. Performing a subperiosteal resection with repair of the periosteum at the conclusion of the case provides adequate cosmetic and functional results without the risk for malunion and persistent pain. Alternatively, if exposure of the midsubclavian vessels is all that is required, a supraclavicular approach, splitting the clavicle in the middle, is often adequate. Plating the clavicle at the end preserves shoulder girdle stability. A dedicated clamshell incision offers many of the advantages of sternotomy, with the additional benefit of providing better posterolateral exposure. Patient positioning is critical. A towel placed longitudinally in the midline with the arms raised above the head will allow the incision to be made across the sternum at the fourth intercostal space (as opposed to the usual extension of anterolateral thoracotomy, which is usually at best at the fifth space). After division of the internal mammary arteries, the sternum is split and the intercostal spaces are opened laterally. Placing bilateral rib spreaders that are sutured in place and dividing the retrosternal areolar tissue provides access to all central structures. The carina and right main pulmonary artery can be reached between the ascending aorta and superior vena cava by incising the posterior pericardium. Posterolateral thoracotomy can be performed using a variety of muscle-sparing techniques. The latissimus can be mobilized if it is anticipated it will be required, but often simply preserving the serratus anterior, by mobilizing it anteriorly, will provide significant support to shoulder function postoperatively. In most cases a fifth intercostal incision is the best, entering the chest at the level of the major fissure. The rib spaces can be counted, but the second rib is most often palpated and recognized by the insertions of the strap muscles posteriorly near the spinous ligament. Resecting the rib at the chosen entry point is helpful if extensive pleural inflammation is expected. This method may be associated with reduced postoperative pain because the pleural edges can be sutured without pericostal sutures that may entrap nerve bundles of

1/21/2008 4:22:14 PM

1770

Section 8 Trauma

the ribs above and below the incision. Shingling the rib posteriorly, removing a small portion to decrease tension and prevent painful friction postoperatively, also helps exposure. As will be noted, fourth intercostal approaches are used for descending aortic injuries (left) or tracheal injuries (right), and seventh or eighth left intercostal approaches are used for lower esophageal injuries. Posterolateral thoracotomy provides dramatically better exposure than anterolateral approaches but obviously prevents exploration across the midline and, except for splenectomy from the left, prevents management of intra-abdominal injuries. Thus, while providing superior exposure it should not be used if there is a question of bilateral or combined injuries that may need simultaneous management. In practice, as far as blunt parenchymal and diaphragmatic injures are concerned, the best thoracic exposure is a posterolateral thoracotomy. If the patient cannot be rotated for reasons of instability and/or associated injuries, an anterolateral thoracotomy, with low threshold for performing a clamshell incision, is the second best approach.

CHEST WALL TRAUMA Rib Fractures and Flail Chest Chest wall trauma is a marker of significant injury, associated with increased likelihood for laparotomy and/or thoracotomy.12 Apart from associated injuries, rib fractures (with or without flail segments) are associated with significant morbidity owing to pain and subsequent atelectasis, as well as underlying pulmonary contusion. The primary therapy for rib injuries is pain control in conjunction with aggressive pulmonary toilet.13 A variety of techniques are available, ranging from rib blocks to epidurals, the latter associated with improvement in functional volumes and reduction in respiratory failure.12 Epidural approaches appear to more reliably improve respiratory function when compared with intravenous (IV) pain medicine, but IV pain therapy is clearly appropriate if other approaches are not possible.14,15 Stabilization of flail segments has been studied extensively. Internal stabilization, using positive-pressure ventilation, has been superseded by pain management because routine intubation has been associated with an increased risk of pneumonia.13,16 The majority of patients will demonstrate some fibrosis and stabilization of the flail segment within 3 weeks, and the presence of a flail segment is not an indication by itself to continue mechanical ventilation. However, occasionally the chest wall instability is so great, or there are other indications for operation, that fixation may be required (Fig. 146-1). The question of whether early rib fixation can lead to improved outcomes has been studied, but only in small series. It appears that patients with no pulmonary contusion may be discharged sooner if fixation is carried out, but the data are sparse at this time. A major problem is the lack of consistently reliable tools for fixation. Options include pericostal sutures around or through the ribs, plates, wires used for orthopedic procedures, and/or Judet staple, which is a form of plate that can wrap around the rib.12 The problems of fixation are that intercostal nerves can be trapped, thus increasing

Ch146-F06861.indd 1770

the pain, the bone is often too thin to hold hardware, and the ribs normally move not only up and down but also outward with respiratory effort, placing a variety of tension forces on any repair site. Flail chest is associated with significant late morbidity, in terms of chronic pain and sensation of decreased ventilatory capacity. Early fixation may reduce the late debility, and this deserves more study.17

Sternal Fractures Because of the force applied, sternal fractures have been associated with an increased incidence of both cardiac and great vessel injury. However, there is debate about how prevalent this injury is. One study found an incidence of cardiac injury in 18%; in another it was 62%.18,19 As with rib fractures, the management is primarily supportive. Most fractures are transverse, involve the sternal-manubrial junction or upper third of the sternum, and stabilize with pain control. Unstable fractures, fractures associated with chronic pain, or those associated with infection (indicated by new sternal click in the setting of fever or erythema) require operative intervention. Options include wires in figure-of-eight fashion, plates, or both. Longitudinal fractures may require closure similar to closing a sternotomy incision. Sternal fractures complicated by mediastinal abscess require débridement. Simple approaches include placement of an irrigation system, but recalcitrant or widespread infection requires closure with muscle and/or omental flaps after widespread débridement.20

Chest Wall Defects Large complex open wounds require a multidisciplinary approach. Initially, aggressive wound débridement, drainage of hemothorax, and simple packing is appropriate.4 Subsequent management depends on which levels are involved as well as location (e.g., ribs, muscle, intrathoracic, skin).21 A dreaded complication of chest wounds is necrotizing infection, characterized by rapidly progressive sepsis with local erythema and, at times, minimal superficial evidence of infection.22 These infectious complications require wide débridement and reconstruction. If sepsis is not a concern, bony stability can be achieved, depending on the size of the defect, with a variety of meshes and/or methylmethacrylate sandwiches. Probably the most important factor is the use of vascularized tissue flaps. Traumatic lung hernia, characterized by protrusion of lung parenchyma outside the ribs, is uncommon but has been described as a complication of chest tubes, thoracotomy, or traumatic defects.23 Most often these occur in patients who require significant levels of positive-pressure ventilation. As long as there is no evidence of incarceration or infarction, immediate repair is not needed. If there is evidence of lung necrosis, early repair (using mesh or other techniques) accompanied by resection of the involved lung will be required.23

PLEURAL SPACE Thoracotomy for Ongoing Hemorrhage In 1970, McNamara and associates described a reduction in mortality when thoracotomy was performed early after pen-

1/21/2008 4:22:14 PM

Chapter 146 Management of Blunt Chest and Diaphragmatic Injuries

A

FIGURE 146-1 A, Chest radiograph after blunt injury in a patient with multiple right-sided injuries, progressive dyspnea, and pain, with clinical evidence of pneumonia. B, CT scan of the same patient, demonstrating the degree of chest wall intrusion. C, Postoperative chest radiograph after rib fixation.

etrating trauma.24 The current Advanced Trauma Life Support (ATLS) guidelines list “initial chest tube output exceeding 1,500 milliliters or a continued hourly output of more than 250 milliliters for three consecutive hours” as criteria for surgical exploration after chest trauma, regardless of hemodynamic stability. Evacuating the hemithorax completely and enabling visceral-parietal pleural apposition provides an opportunity for the lung to tamponade bleeding. Prolonging the interval before this is achieved can result in an insidious cycle of further blood loss, increasing coagulopathy, and metabolic derangement. There tends to be a low threshold for operative management after penetrating injury, but after blunt trauma there can be significant delays before operation. The reasons include distraction by multiple associated injuries, need for complex radiologic tests, and/or dissatisfaction with operating for multiple bleeding vessels of the chest wall. This has led to a tendency to watch hourly outputs or attempt interventional approaches. The risk with monitoring chest tube output is that the tubes can be plugged or not properly monitored or that transient decreases in output can lead to critical delays. A retrospective multicenter study of patients who underwent thoracotomy within 48 hours of injury because of ongoing bleeding noted that, independent of mechanism, each 500 mL of tube output was associated with

Ch146-F06861.indd 1771

1771

B

C a 60% increase in mortality.25 It may be that planning to operate whenever the total output exceeds 1500 mL over a 24-hour period is appropriate. In addition, if patients are stable and not coagulopathic, minithoracotomy with thoracoscopic approaches may be feasible.

Retained Hemothorax Tube thoracostomy fails to completely evacuate hemothorax in approximately 5% of cases.26 Complications that may arise include empyema and/or fibrothorax. Conditions that predispose patients to both include prolonged ventilation, development of pneumonia, break in the pleura with residual blood (as is the case after tube thoracostomy), and/or infection at other sites.27 On the other hand, stable, nonventilated patients with small effusions (less than one-fourth hemothorax) after blunt trauma with no obvious pleural disruption usually recover without sequelae. In these patients the cornerstone of therapy is observation. The use of antibiotics, in particular with gram-positive coverage, in most reviews shows a reduction in the risk of empyema. However, it appears that giving one dose, providing 24 hours of antibiotic administration, and keeping the antibiotic coverage until the drains are removed are all equiv-

1/21/2008 4:22:14 PM

1772

Section 8 Trauma

alent. Thus, our practice is to give one dose only, unless there are other risk factors. Early evacuation of hemothorax has been shown to reduce the incidence of complications preferably within 7 days when loculations begin to complicate pleural débridement.28 In particular, the risk of empyema is reduced. However, recognizing the extent of hemothorax can be difficult. Chest radiography can underestimate both the extent of parenchymal consolidation and the volume of retained blood, particularly in ventilated patients. Chest CT is much more accurate in this setting, but interpretation requires some individualization.29 Moderate effusions in ventilated patients or those with other risk factors are aggressively drained when detected by CT.27,30 When hemothorax is recognized acutely after injury, the simplest and most expeditious treatment is to place a second chest tube. When it is recognized after 1 to 2 days, a chest tube may not be helpful in that it may simply increase pain, splinting, and the risk of pneumonia, with subsequent seeding of the pleural space. Intrapleural streptokinase (250,000 units) or urokinase (40,000 units) has efficacy of 65% to 90%.31 Complications include fever and pain, but the risk of restarting bleeding is negligible. The downside of this approach is that it takes several days longer than more direct operative drainage and will not break down loculations. Thus, it may be more useful after débridement when it is suspected that the clot is relatively soft. Thoracoscopy offers the advantage of complete removal of all clot without the excess morbidity of a formal thoracotomy. Meyer and associates compared placement of a second chest tube versus thoracoscopy for treatment of retained traumatic hemothorax. Patients undergoing thoracoscopy had a shortened length of time requiring chest tube drainage, a shortened hospital stay (2.7 days less), and a decreased total hospital cost ($6000 less) compared with those patients treated with a second chest tube.32 There were no failures and no complications, and no patients required conversion to a formal thoracotomy in the group randomized to early thoracoscopy. In contrast, a second chest tube failed to completely evacuate the retained hemothorax, requiring operative treatment in over 40% of the patients. Thoracotomies through mini approaches are often sufficient to allow removal of soft, gelatinous visceral and pleural rind, permitting full-lung expansion. Irrigation with warm saline facilitates clot removal. The denser the adhesions, the greater the exposure must be, and if a formal decortication of a formed visceral peel is anticipated, a standard approach is required. This can be facilitated by excising a rib subperiosteally to allow safe identification of the pleura. In summary, patients with retained hemothorax who are at risk of empyema are managed aggressively, preferably by early thoracoscopic drainage.27 Occasionally, patients present with delayed effusions, days after blunt injury, presumably partially due to missed small hemothorax and partially secondary to reactive fluid accumulation. If these patients have adequate pain control, have small effusions (less than one fourth of the hemithorax), and have no signs of infection, tube thoracostomy does not need to be performed because the risk of fibrothorax is negligible. Patients who present late

Ch146-F06861.indd 1772

(usually >3 months after injury) with an element of fibrothorax (but with no infection) are managed nonoperatively because at 6 to 9 months in the majority of cases there is some remodeling and adaptation, and if surgery is required there is no increased difficulty if it is undertaken at a later date.

PARENCHYMAL INJURIES Pulmonary Contusion It has been argued that pulmonary contusion is the most common potentially life-threatening chest injury. In essence, transmission of kinetic energy (with or without overlying rib fractures and subsequent laceration) results in bruising of the lung, characterized by interstitial and alveolar edema, hemorrhage, and subsequent alveolar collapse (Fig. 146-2).33 Contrecoup injuries can occur, and the extent of bony injuries depends on the compliance of the chest wall itself. Clinically, hypoxia and ventilatory embarrassment develop within 24 to 48 hours, although changes can occur in a much shorter time depending on the extent of injury and the need for volume replacement that aggravates the process.34 Initial chest radiographs may be normal or at most demonstrate patchy changes, but as resuscitation continues a blossoming is noted with opacification and air bronchograms. If there are significant changes noted on an initial radiograph taken shortly after injury, in general the course will be severe. Chest CT can grade the degree of injury more accurately, and thus may lead to better predictions of clinical course, but other than detecting occult changes (e.g., pneumothorax not appreciated on chest radiography) that can change therapy in up to 30% of patients, this does not lead to significant improvement in outcome.35

FIGURE 146-2 Patient 48 hours after admission following a highspeed motor vehicle accident with chest wall bruising and evidence of blunt cardiac injury (contusion). The patient had a progressive inability to oxygenate and ventilate.

1/21/2008 4:22:15 PM

Chapter 146 Management of Blunt Chest and Diaphragmatic Injuries

The treatment is generally supportive.33 Oxygen (including continuous positive airway pressure [CPAP] mask if needed) is supplied early. If IV volume can be restricted (i.e., in a stable patient), it should be, because the associated capillary leak will lead to a worsening of pulmonary edema. Diuresis may help, particularly if there is evidence of volume overload (pulmonary occlusion pressure >18 mm Hg or end-diastolic volume index >135 mL/m2). Colloid solutions appear to aggravate pulmonary dysfunction because the obligatory leak results in the colloidal agents themselves leaking into the interstitial and alveolar spaces, further promoting edema. Intubation is performed for the usual indications. Flail chest is discussed later, but suffice it to say that an unstable chest wall is not itself an indication for mechanical ventilation.16 Rather, aggressive pain control is attempted first. Once the patient is intubated, lung protective strategies are employed. Corticosteroids have been studied in experimental models, but there is no evidence that the benefits outweigh the risk of immunosuppression in contusion. A significant early complication is pneumonia. This is linked to the need for intubation and mechanical ventilation, increasing from as low as 6% in nonintubated patients to 44% in those who require ventilation.36 There is, however, no role for prophylactic antibiotics. Of all patients admitted with a diagnosis of contusion, nearly 50% develop pneumonia, barotrauma, and/or major atelectasis and one fourth go on to full-blown acute respiratory distress syndrome. Long-term disability can be present as focal fibrosis.37,38 Mortality is dictated by associated injuries, in particular closed-head injury.39 However, there is some correlation with extent of contusion, as defined by chest CT.40 Most reviews report a mortality of 5% to 30%, with contusion being the direct cause of death in 25% to 50% of fatalities.

Parenchymal Injury It has been estimated that 20% to 30% of patients who undergo thoracotomy after trauma require some form of lung resection.41,42 Considering all patients with chest trauma, as few as 2% of all patients with blunt trauma and 6% of those with penetrating trauma require resection. Mortality rates as high as 3% to 50% after lobectomy and 70% to 100% after pneumonectomy reflect the severity of lung and overall injury in patients requiring extensive resection.41,43,44 The use of nonanatomic and stapling techniques has been advocated as a method of both damage control and rapid definitive resection under appropriate circumstances, suggesting the potential for reduced operative time and blood loss, and increased parenchymal salvage.42,45-48 The majority of patients who present with penetrating injuries have peripheral injuries that are simple to manage, whereas extensive blast or blunt trauma often results in combinations of diffuse contusion and lung maceration that are extremely difficult to salvage.49 The most common procedures required are simple suture repair or wedge resection. Tractotomy (as discussed later) is used to either define deep injuries or to manage peripheral injuries that pass through the parenchyma. Lobectomy and pneumonectomy are rarely required and can be performed nonanatomically using sta-

Ch146-F06861.indd 1773

1773

plers (simultaneously stapled lobectomy or pneumonectomy) or anatomically. The latter is usually required in the setting of complete fissures, may take longer, and may be more difficult if there is diffuse edema and bleeding. Minimal peripheral injuries are often encountered when operating for associated injuries.49,50 Typically, the patient is taken to surgery for ongoing hemorrhage secondary to intercostal vessel damage. The intercostal arteries are perfused at systemic pressures and as a result can bleed profusely. Peripheral injuries may spontaneously stop bleeding owing to the relatively low pressure in the pulmonary circuit. To eliminate potential bleeding or air leaks, a wedge resection is performed. Standard stapling devices may be safely used without pledgets or oversewing of the edges.48 Whereas the management of the most severe and the most minor injuries is straightforward, the management of deep lobar injuries is more controversial. Simple oversewing of the entry and exit sites is insufficient because there is invariably continued deep parenchymal hemorrhage that results in aspiration, pneumonia, and unremitting acute respiratory distress syndrome. In general, tractotomy is performed. This can be achieved either with stapler or between clamps. This will expose deep bleeding vessels and may allow definitive control. In those patients with continued instability or associated injuries that need to be addressed, the procedure may be considered definitive.42,46,48 It is not uncommon that after performing tractotomy there is such diffuse bleeding that simple suture ligation is inadequate. Placing large pledgeted mattress sutures, similar to liver stitches, from the depth of the wound to the edge, provides excellent control. After completion of these initial maneuvers, a minority of patients will still have significant air leaks or long tracts of devitalized tissue. If these patients remain stable, they are considered for resection up to and including lobectomy. Tractotomy was initially described as a damage control technique. It may be associated with increased postoperative complications compared with lobectomy, but this is debated. Certainly, if major blood loss continues, or there is obvious extensive lobar destruction, lobectomy must be performed as soon as possible. In patients with complete fissures, a stapled lobectomy, similar to the pneumonectomy procedure described later, may be possible. Otherwise, anatomic lobectomy can be performed by skilled surgeons with almost the same rapidity. Patients with perihilar injuries or extensive lung maceration generally present with severe shock and are taken to the operating room quickly with minimal resuscitation. Survival correlates with the rapidity of control. Thus, on entering the chest, if large central bleeding is encountered, hilar control is the first maneuver performed. The pulmonary ligament is taken down to the level of the inferior pulmonary vein. This allows torsion of the entire lung as a temporizing method. Rarely, very proximal injuries require intrapericardial control of the pulmonary artery. In cases of small injuries to a single structure, a noncrushing vascular clamp may be applied proximally and repair attempted. When both artery and vein are injured or when a significant length of vessel is damaged, the patient will benefit from an early decision to perform a pneumonectomy. A linear

1/21/2008 4:22:15 PM

1774

Section 8 Trauma

stapler is fired across the hilum and a simultaneous stapled pneumonectomy (SSP) is performed.51 Trauma pneumonectomy is generally associated with 50% to 100% mortality, and although it cannot be delayed, it must not be performed without at least quickly assessing whether lesser options are possible. One common cause for acute mortality is sudden rightsided heart failure. If this occurs immediately on clamping, there is usually no hope. However, if it occurs hours or days later, supportive efforts can be tried with diuretics, vasodilators, and occasionally extracorporeal membrane oxygenation. It is preferable in patients with isolated hilar injuries to stop all fluid boluses when the hilum is controlled to avoid aggravating the right-sided heart strain by excessive fluid administration. A second pitfall related to SSP is the potential for increased bronchial stump leak and/or empyema. In fact, animal models have shown that SSP stumps have similar bursting strength when compared with individual ligation and oversewing of the artery, vein, and bronchus. Wagner and associates noted a reduction in stump leak in survivors compared with individual stapling.51 Nevertheless, elective re-exploration, washout, and stump re-enforcement with viable tissue are performed as soon as the patient’s condition can tolerate it. A multicenter review identified 143 patients who underwent emergent lung resection after trauma (28 of which cases were from blunt trauma).49 Lobectomy and pneumonectomy were more often required after blunt trauma, which tended to be associated with significant diffuse parenchymal destruction. The choice of resection was determined by extent of lung injury, and each increment in resection was associated with an 80% relative risk of increased mortality, but the mortality was encouragingly low for this group of extremely unstable patients. Stapled lobectomy was associated with increased mortality, but this was predominantly because it was performed in more critically injured patients.49 Whatever the reason for parenchymal resection, outcome will be significantly affected by the degree of air leak at the time of closing and the residual space that is anticipated. In unstable patients, abbreviated closure must be employed with plans to re-explore and wash out. In patients with extensive contamination or if it is anticipated that there will be significant residual clot, re-exploration or placement of irrigation systems are considered. The smaller the space, the sooner air leak will seal and the lower is the complication risk.

Hematoma, Pneumatocele, and Persistent Air Leak Hematoma and pneumatoceles represent small parenchymal lacerations that are usually clinically insignificant. Hematomas tend to be discrete and usually resolve, although in some instances they may remain and be mistaken for coin lesions. Pneumatoceles also have discrete margins, can be associated with air-fluid levels, and rarely require intervention. These do not require prophylactic antibiotics; but in the rare circumstances in which they appear to have become infected, stan-

Ch146-F06861.indd 1774

dard treatment as for lung abscess, including antibiotics, postural drainage, and/or percutaneous drainage, is usually sufficient. Even more rarely, the pneumatocele can be the source of persistent air leak requiring resection. Persistent air leak requires a workup for airway injury but in the majority of cases represents small parenchymal lacerations that may be exacerbated by high airway pressures (in ventilated patients), incomplete drainage of pneumothorax, and/or parenchymal consolidation. In the majority of cases, adjusting or adding chest drains, weaning from the ventilator, or adjusting settings to reduce peak airway pressure and, most often, the passage of time will allow healing. As mentioned earlier, thoracoscopy can allow quicker resolution if imaging identifies a discrete lesion. Patients with underlying lung disease, particularly emphysema, present additional difficulties. Resection, similar to lung volume reduction surgery with adjunctive use of buttressed staple lines, may be required but needs to be used as a last resort because these patients often have underlying pneumonia and staple lines often fail, resulting in even worse leaks.

DIAPHRAGMATIC INJURIES Injury to the diaphragm accounts for only 3% of the total number of injuries sustained from trauma. Blunt injuries usually occur secondary to high-speed motor vehicle accidents.52 Penetrating injury, such as gunshot wounds and stab wounds, probably occurs more frequently but has been cited less often in the literature. Overall, the associated injury rate has been reported as high as 80% to 100%, particularly after blunt trauma.53 The anatomic location appears to be more often left sided than right sided for two reasons. Most assailants are right handed and therefore will be more likely to injure their victims on the left side. In blunt injury the liver probably affords some degree of protection to lacerations of the diaphragm. The radiographic signs of a left-sided injury are much easier to see and more likely to be detected. All of these reasons probably explain why the reports in the literature document more left-sided than right-sided injury to the diaphragm.52 Bilateral injuries to the diaphragm occur in only 2% of all patients sustaining diaphragmatic trauma. Tears of the central tendon of the diaphragm with herniation of abdominal contents into the pericardium are extremely rare but have been reported.52 Patients may present with symptoms that are abdominal or thoracic or both. They may present with marked hemodynamic instability and require an emergency laparotomy. Chest or abdominal pain, dyspnea, and orthopnea are frequent complaints. Rib fractures, abdominal tenderness, contusions, or wounds of the chest and abdomen are more often associated with injury to other organs and should alert one to the possibility of diaphragmatic injury. Initial chest radiographs are usually normal in 50% of patients and show a pneumothorax or hemothorax in most of the remaining 50% of patients with diaphragmatic injury. Abnormalities that can be detected on a portable chest radiograph that suggest diaphragmatic tears include elevation

1/21/2008 4:22:15 PM

Chapter 146 Management of Blunt Chest and Diaphragmatic Injuries

or obscuration of the diaphragm and visceral herniation. The finding of the nasogastric tube coiling in the left hemithorax is rarely seen but is pathognomonic for diaphragmatic injury.53-55 One scenario in which plain chest radiographs can miss a diaphragmatic injury, even a large left-sided one, is when a patient arrives intubated or is intubated shortly thereafter and requires more than 5 cm H2O of positive end-expiratory pressure. As ventilator support is weaned, abdominal contents progressively herniate.56 This underlines the importance of reviewing chest films in sequence in injured patients. CT has become the primary diagnostic modality in the evaluation of patients sustaining abdominal injury. It is very accurate in detecting intra-abdominal fluid, solid organ injury, fractures, intraperitoneal air, pneumothorax, and retroperitoneal injury. Unfortunately, it has not been consistently able to demonstrate diaphragmatic lacerations in a number of reports in the literature.53 A CT scan obtained in the workup of blunt trauma may reveal herniation of viscera into the pleural space and therefore lead the surgeon to proceed with laparotomy in a patient who might otherwise have been managed nonoperatively (Fig. 146-3). Failure to diagnose diaphragmatic injury by radiographic means has led some surgeons to use newer surgical techniques to improve accuracy. Reports of the use of both diagnostic laparoscopy and VATS have documented high rates of injury identification.6,57,58 An occasional small accessible defect has been successfully repaired by these methods as well. Most acute diaphragmatic injuries are best approached by a laparotomy. A chest tube is often required before operation in those patients with either hemothorax or pneumothorax. It needs to be inserted carefully in those patients with suspected diaphragmatic injury to avoid inadvertent injury to any potentially herniated abdominal viscera. The smaller injuries without tissue loss (class I-III) are best repaired with a continuous monofilament suture of 1-0 or larger.52 The edges of the diaphragm need to be grasped and elevated by long Allis clamps before suturing. This helps prevent inadvertent suturing of the underlying lung and facilitates identification of the full extent of the injury. Class IV injuries can usually

1775

be repaired in the just-described manner as well. The repair may be made more easily by placing some interrupted sutures first to realign the edges before repair with a continuous suture. On occasion, the defect along the lateral chest wall can be extensive and/or there may be combined loss of chest wall integrity. In this setting, resuspending the diaphragm from the ribs at a higher level can allow closure.52

COMMENTS AND CONTROVERSIES The authors have thoroughly stressed the importance of adequate analgesia after blunt chest trauma. Simple rib fracture can be a major injury in the elderly with limited lung function. Local nerve blocks above and below the injury or epidural anesthesia with narcotic or local anesthetic can dramatically improve pain control and pulmonary function. Effective pain control and judicious fluid administration can often avoid the need for mechanical ventilation, even a flail chest injury. We believe that early tracheostomy for patients with major injuries is also important. Early tracheostomy maximizes patient comfort and decreases the likelihood of subsequent laryngeal or subglottic stenosis from prolonged translaryngeal intubation. In their discussion of blunt injury to the lung, the authors stress the importance of conservative therapy and lung preservation techniques if open exploration is required. The lung has a remarkable capability to heal injury of contusion and laceration resulting in functional parenchyma. Resection is avoided even if lobar or segmental pulmonary artery branches must be sacrificed to control bleeding. Although not specifically discussed by the authors, injury to great vessels is of importance. These injuries are currently precisely documented by contrast-enhanced CT. The recent application of endovascular stent therapies for the management of great vessel injuries is exciting and a definite improvement over the previous open procedures requiring cardiopulmonary bypass, clamp-and-suture techniques without bypass, or left-sided heart bypass with aortic cross clamp and repair. Also of importance are the rare esophageal injuries as a result of blunt trauma. Preemptive repair and drainage minimizes the likelihood and consequences of subsequent cervical or mediastinal sepsis that inevitably results after conservative management of esophageal disruption. In severe esophageal injury with tissue loss, placement of a T tube with appropriate drainage has proved to be an effective strategy creating a controlled fistula.1,2 This is a definite improvement in management over the standard diversion techniques. These latter strategies result in subsequent requirement for major surgical intervention to achieve esophageal continuity. 1. Abbott OA, Mansour KA, Logan WD, et al: Traumatic so-called spontaneous rupture of the esophagus: A review of 47 personal cases with comments on a new method of surgical therapy. J Thorac Cardiovasc Surg 59:67-83, 1970. 2. Mansour KA, Wenger RK: T-Tube management of late esophageal perforations. Surg Gynecol Obstet 175:571-572, 1992.

G. A. P.

KEY REFERENCES FIGURE 146-3 CT in the same patient as in Figure 146-1. Lower ribs appear to have punctured the diaphragm, with an abnormal pocket of air. This was confirmed at surgery.

Ch146-F06861.indd 1775

Asensio JA, Demetriades D, Berne JD, et al: Stapled pulmonary tractotomy: A rapid way to control hemorrhage in penetrating pulmonary injuries. J Am Coll Surg 185:486-487, 1997.

1/21/2008 4:22:15 PM

1776

Section 8 Trauma

Cothren C, Moore EE, Biffl WL, et al: Lung-sparing techniques are associated with improved outcome compared with anatomic resection for severe lung injuries. J Trauma 53:483-487, 2002. Karmy-Jones R, Jurkovich GJ, Nathens AB, et al: Timing of urgent thoracotomy for hemorrhage after trauma: A multicenter study. Arch Surg 136:513-518, 2001.

Ch146-F06861.indd 1776

Meyer DM, Jessen ME, Wait MA, Estrera AS: Early evacuation of traumatic retained hemothoraces using thoracoscopy: A prospective, randomized trial. Ann Thorac Surg 64:1396-1400, 1997; discussion 1400-1401. Wall MJ Jr, Soltero E: Damage control for thoracic injuries. Surg Clin North Am 77:863-878, 1997.

1/21/2008 4:22:15 PM

chapter

PENETRATING THORACIC TRAUMA

147

Luis C. Losso Mario C. Ghefter

Key Points ■ Thoracic trauma typically affects the young. It is the leading cause

of death in the first 3 decades of life, and its incidence is increasing. ■ Life-threatening injuries need to be identified and treated immediately, remembering that injuries may develop over time, become life threatening, and require reassessment if the patient’s condition deteriorates. ■ Immediate deaths are usually due to massive hemorrhage from the heart or great vessels, and the earliest deaths are secondary to cardiac tamponade, airway obstruction, and aspiration with severe associated injuries. ■ Optimal treatment requires a through knowledge of the etiology of the trauma and of the pathophysiology of the thorax and expertise in therapeutic interventions.

the point of injury, were one of the first efforts to improve treatment. A Committee on Trauma was formalized by the American College of Surgeons in 1949. Improvements in trauma care were advanced on the battlefields of Korea (with Mobile Army Surgical Hospital [MASH] units), Vietnam, Panama, the Balkans, Somalia, Persian Gulf, and Iraq, with refinement of the concept of forward surgical hospitals for rapid care of the wounded. Significant experience has also been gained from large metropolitan areas as a result of assaults involving firearms and handheld weapons. In 1980, as an educational program, the American College of Surgeons published the first edition of the Advanced Trauma Life Support Manual, which introduces the concepts of trauma assessment and management to medical personnel.

RATIONALE

HISTORICAL NOTE Trauma is perhaps the oldest of humankind’s afflictions, and the history of trauma is as old as medicine itself. One of the earliest writings on thoracic injury was found in the Edwin Smith Papyrus, written in 3000 BC, which describes cases of penetrating thoracic trauma. The word trauma was used for the first time by Hippocrates in the 5th century BC when he described hemoptysis and its relation to severe damage of the lung after rib fractures. Later on, Galen, in 150 BC, reported attempts to treat Romans gladiators with penetrating chest injury with open packing. Romans also developed the first systems of hospitals for the wounded soldiers of the military legions. The science of surgery and of trauma in particular fought its way out of the Middle Ages and continued to advance. In 1535, Cabeza de Vaca first described operative removal of an arrowhead from the chest wall of an American Indian, and Larrey, in 1767, used an occlusive thoracic dressing in the setting of open pneumothorax. Regarding cardiovascular injuries, Rehn performed the first successful cardiorrhaphy for a penetrating cardiac injury in 1896, and in 1922 Dshanelidze performed the first repair of a traumatic injury to the aorta. The military surgery experience through the centuries has been an important determinant of the management of penetrating thoracic trauma. Guidelines for treating thoracic trauma, however, were not established until World War II. The Auxiliary Units, special units to provide care closer to

In the United States the rate of thoracic trauma is 12 per million population per day. From 20% to 25% of deaths due to trauma are attributed to thoracic injury, which still contributes to 25% to 50% of the remaining deaths. That means approximately 16,000 deaths per year in the United States alone are attributable to chest trauma. Thoracic trauma typically affects the young. It is the leading cause of death in the first 3 decades of life, and its incidence is increasing. The increased prevalence of penetrating chest injury and improved prehospital and perioperative care have resulted in an increasing number of critically injured but potentially salvageable patients presenting to emergency centers. Lifethreatening injuries need to be identified and treated immediately, remembering that injuries may develop over time, become life threatening, and require reassessment if the patient’s condition deteriorates. Hypoxia, hypoventilation, and hemorrhage are the primary killers of acute trauma patients.1 Mechanism of injury is important, and a penetrating injury is usually the result of the direct application of a mechanical force to a focal area and depends on the velocity and biomechanics of the projectile. The velocity of the injury may be low, medium, or high. Low-velocity injuries include knife wounds that disrupt only the structures penetrated. Mediumvelocity injuries include bullet wounds from handguns and are characterized by much less primary tissue destruction than wounds caused by high-velocity forces. High-velocity injuries include bullet wounds caused by rifles, which produce injury in adjacent structures in addition to that in the bullet path, tissue cavitation, and shock waves that extend the area of tissue damage. The velocity of the penetrating projectile 1777

Ch147-F06861.indd 1777

1/21/2008 4:23:02 PM

1778

Section 8 Trauma

is the single most important factor that determines the severity of the wound. The degree of injury also depends on the biomechanics of the penetrating projectile, including the efficiency with which energy is transferred from the object to the body tissues. Other factors that dictate the severity of injury include the physical characteristics of the weapon, such as its size of impact force, and the deformability and density of the body tissues penetrated. Penetrating thoracic injuries also occur during diagnostic and therapeutic procedures—iatrogenic trauma—such as percutaneous needle aspiration biopsies, trocar insertion, catheter insertion, and pericardiocentesis. Pneumothorax, pulmonary hemorrhage, systemic air embolism, injury of the superior vena cava and right atrium, coronary vessel injury, and death can occur. Thoracic injury may occur in the chest wall, lungs and pleura, trachea, bronchus, heart, thoracic great vessels, esophagus, and diaphragm. Appropriate early diagnosis and management of rapidly fatal and potentially fatal penetrating thoracic injuries is paramount and also significantly decreases late complications (Feliciano and Rozycki, 1999).2 Immediate deaths are usually due to massive hemorrhage from the heart or great vessels, and the earliest deaths are secondary to cardiac tamponade, airway obstruction, and aspiration with severe associated injuries. Physical examination is the primary tool for diagnosis of acute thoracic trauma, but an initial normal examination does not exclude a significant thoracic trauma, and serial examinations and use of diagnostic adjuncts is important. The examination includes a careful search for penetrating wounds, evaluation of the trachea for deviation, feeling for subcutaneous emphysema, listening for normal, equal breath sounds on both sides, and percussion of both sides of the chest looking for dullness or resonance. Particular attention is paid to the front and back of the patient. The plain anteroposterior chest radiograph remains the standard initial evaluation for chest trauma. For gunshot wounds, all patients with wounds between the neck and the pelvis/buttock area undergo chest radiography. This is especially true if the bullet track is unclear or if there is a missing bullet or an unequal number of entry/exit wounds. The chest radiograph is taken with the patient sitting upright if possible. This will increase the sensitivity for detecting a small hemothorax, pneumothorax, or diaphragm injury. Further investigations include computed tomography (CT), angiography, esophagoscopy, esophagography, and bronchoscopy.3 Optimal treatment requires a through knowledge of the etiology of the trauma and of pathophysiology of the thorax and expertise in therapeutic interventions.

INJURIES OF THE CHEST WALL Chest wall injury accounts for 10% off all penetrating chest trauma. In civilian practice, 85% can be managed with simple procedures and only 15% to 20% require definitive surgical intervention. A penetrating wound of the chest wall creates a communication between the external environment and pleural space. Fracture of a rib also is likely, and a fragment may override

Ch147-F06861.indd 1778

or a pointed fragment may be pushed inward, tearing the pleura and underlying lung, which may be severely injured, causing both pneumothorax and hemothorax.4 In the same way, injuries to the chest wall vessels are frequently found and may cause severe hemorrhage. Due to these reasons the primary survey includes assessment of airway competency for injuries of the base of the neck and the thoracic outlet, visual inspection and palpation of the chest, and observation for enlarging hematomas, crepitus, hemoptysis, and dyspnea. The survey also observes for cyanosis, respiratory movement, intercostal or supraclavicular retractions, tachypnea, deviated trachea, and a change in respiratory pattern. Auscultation of the chest is important to ensure airway exchange in the lungs. Immediate lifethreatening injuries from thoracic trauma include airway obstruction, cardiac tamponade, flail chest, tension pneumothorax, open pneumothorax, and massive hemothorax. Chest radiography is mandatory after a primary survey to identify entrance and exit wounds and also to exclude injury to the thoracic viscera if wounds appear superficial. It is essential after an intervention to document amelioration of injury and serial chest radiographs at least every 6 hours in a patient with penetrating trauma until the patient’s condition stabilizes after 24 hours. In penetrating chest injuries, if the size of the chest wall injury reaches two thirds the size of the tracheal diameter, air passes through the lower resistance injury tract rather than through the normal airways. The consequence is that the ipsilateral lung, exposed to atmospheric pressure, collapses and shifts the mediastinum to the contralateral hemithorax, causing a severe alteration of ventilation and venoarterial shunting, which result in serious ventilation-perfusion imbalance and respiratory distress. This situation is called open pneumothorax. Patients with open pneumothorax must be treated rapidly. In the spontaneously ventilating patient, the treatment of choice is application of a sterile, not totally occlusive dressing, with petrolatum gauze, large enough to cover the wound and entirely taped securely on three sides. Impaled objects must not be removed. Tube thoracostomy is placed in the emergency center. If the chest wall defect is relatively small, the pleura may soon seal and no further intervention is necessary. On the other hand, closure of large, open chest wall defects can be a formidable task. Reconstructive plastic surgery involving closure with autogenous tissue of myocutaneous flaps (trapezius, rectus abdominis, pectoral, or latissimus dorsi muscles) and prosthetic materials (polypropylene mesh, expanded polytetrafluoroethylene and cyanoacrylate) may be required. Another option is to intubate the patient and initiate positive-pressure ventilation. Vascular lesions are also found in chest-penetrating injuries and account for 90% of hemothorax due to injury to intercostal vessels and internal mammary vessels. Subclavian vascular injury is suspected in patients with fractures of the first three ribs, clavicle, and scapula, particularly when associated with significant fracture displacement, extrapleural hematoma, brachial plexus neuropathy, or radiologic evidence of mediastinal hemorrhage. Rarely, hemorrhage results in exsanguination. Bleeding usually stops when the lung is re-

1/21/2008 4:23:02 PM

Chapter 147 Penetrating Thoracic Trauma

expanded. Lacerations of arteries in the chest wall can result in massive hematomas.5 The presence of a fractured sternum and an abnormal mediastinal contour prompts a search for injury to the great vessels. Hemorrhage from mediastinal great vessels and the heart can be life threatening owing to hemodynamic instability consequent to loss of intravascular volume. The chest radiograph, in the erect patient, shows the picture of a fluid level with a meniscus when 400 to 500 mL of blood obliterates the costophrenic angle. It may be difficult to detect small amounts of blood (<200 mL) on the chest radiograph. Emergency department focused assessment with sonography for trauma (FAST) examination can detect smaller hemothoraces, although in the presence of a pneumothorax or subcutaneous air, ultrasonography may be difficult or inaccurate.6,7 Diagnostic thoracentesis is carried out to confirm the diagnosis. For hemothorax, optimal therapy consists of the placement of a large (36 Fr) chest tube. A moderate-sized hemothorax (500-1500 mL) that stops bleeding after thoracostomy can generally be treated by closed drainage alone. However, a hemothorax of greater than 1500 to 2000 mL and continued bleeding of more than 100 to 200 mL/hr are indications for emergency thoracotomy or thoracoscopy. A small percentage of hemothoraces proceed to clot and cannot be evacuated by thoracentesis. Small clots will probably be resorbed and do not require operative removal. Massive clots may lead to respiratory difficulty and infection and must be evacuated surgically.

INJURIES OF THORACIC VISCERA Lung Injuries Penetrating injuries to the lung may extend from the surface of the lung toward the hilum or follow the trajectory of the penetrating object. The vast majority of lung lesions in penetrating trauma are from mechanisms that produce local effects, disrupting alveoli and pulmonary capillaries or small vessels and causing massive hemorrhage and destruction of lung tissue (Mattox et al, 1995).8,9 The lesion’s extent may be minor and localized or extensive and destructive. Lung laceration permits air entry into pleural space—pneumothorax—that results in collapse of the ipsilateral lung.10,11 When air enters the pleural space through the lung wound with a valve-like opening and cannot exit, a progressively increasing intrathoracic pressure in the ipsilateral hemithorax occurs, resulting in a tension pneumothorax. The consequence is impaired central venous return, with mediastinal shift to the opposite side compressing the contralateral lung. This can result in severe alteration of ventilation-perfusion ratio, owing to blood circulation in the nonventilated lung. Because immediate death may follow injury due to tension pneumothorax, any post-traumatic pneumothorax is treated as quickly as possible.12 The emergency management requires immediate thoracostomy with underwater-seal drainage. If the lung does not fully re-expand after tube thoracostomy and there is a large ongoing air leak, the airways need to be evaluated bronchoscopically to exclude a major airway injury.

Ch147-F06861.indd 1779

1779

Lung laceration also permits blood entry into pleural space. Most hemothoraces from injury to lung parenchyma stop bleeding without intervention. These lung lesions may be treated conservatively by using techniques for adequate evacuation of the blood and air from the pleural cavity that allow ventilation and re-expansion of the injured lung, such as chest tube insertion. Although tube thoracostomy is often a lifesaving procedure and is relatively straightforward, it cannot be taken too lightly. There is a complication rate of 21%.13-15 Penetrating injuries, however, are more likely to be associated with arterial (bronchial or pulmonary) hemorrhage requiring surgery. Massive hemothorax, which means more than 1500 mL of blood in the pleural space, requires thoracotomy. The initial volume of blood drained is not as important as the amount and the color of ongoing bleeding. Patients who have continuing drainage with no signs of reduction in chest tube output over 4 to 5 hours need to undergo thoracotomy. The threshold for this is usually stated at 200 to 250 mL of blood per hour. The color of the blood is also important, with dark venous blood being more likely to cease spontaneously than bright-red arterial blood. The operative management of penetrating lung injuries includes oversewing of small lung lacerations (pneumonorrhaphy), wedge resection, and anatomic resection. There are penetrating injuries of the lung for which oversewing of entrance and exit wounds predispose to intrapulmonary hematoma or pulmonary venous systemic air emboli, yet for which formal resection would be time consuming.16 The technique of pulmonary tractotomy with selective vascular ligation was developed in parallel with hepatotomy for liver injuries.17-21 Penetrating trauma from gunshot or knife wounds may be associated with injury to the mediastinum, neck, great vessels, and main bronchi.

Laryngotracheobronchial Injuries Laryngotracheobronchial penetrating injuries can be life threatening if mismanaged. They must be managed quickly and thoroughly. Neck wounds that extend deep to the platysma are considered penetrating injuries. Penetrating injuries of the neck often involve the cervical trachea. Most penetrating injuries in the adult population are related to the violent crime rates of a particular country, as well as to military conflict. Penetrating wounds can cause injury to one or more of the organs of the neck, including the vessels, larynx and trachea, esophagus, and spinal column.22 From 20% to 30% of penetrating neck wounds result in laryngeal, tracheal, or esophageal injuries. The trachea and major bronchi, because of their similar anatomic position, are subject to the same mechanisms of injury for penetrating trauma. Injuries to the main bronchi and intrathoracic trachea are more prevalent than those to the cervical trachea because the latter is protected by the mandible and sternum anteriorly and by vertebrae posteriorly. Penetrating injury to tracheobronchial structures usually causes respiratory distress and inability to ventilate adequately. The signs and symptoms of lesions vary from pain

1/21/2008 4:23:02 PM

1780

Section 8 Trauma

to hoarseness, stridor, respiratory distress, subcutaneous emphysema, pneumothorax, hemoptysis, and mediastinal emphysema and are the most common manifestations, alerting to laryngotracheobronchial injury with large laceration of the structures.23 Imaging findings of bronchial injury include a large pneumothorax (despite adequate placement of one or more chest tubes), massive pneumomediastinum and subcutaneous emphysema, focal peribronchial collections of air, discontinuity or irregularity of the bronchial wall, drooping, or collapsed lung or lobe of the lung. The fallen-lung sign refers to the unusual appearance of a collapsed lung or lobe in the setting of bronchial injury and is thought to be due to disruption of the normal hilar attachments of the lung, causing the collapsed lung to droop peripherally rather than centrally.23 If a laryngotracheal injury is identified with physical examination, laryngoscopy and bronchoscopy are performed. Esophagoscopy also is performed in patients with these injuries because as many as 50% of patients with an airway injury also have a digestive tract injury. All laryngotracheal injuries may result in airway compromise; delayed compromise is possible. Physicians must be aware of the airway status at all times during the evaluation of patients with laryngotracheal injuries, and they must be prepared to secure the airway with tracheotomy if necessary.24 Patients with small injuries without appreciable leaks who do not require positive-pressure ventilation can be treated nonoperatively and with serial examination; however, most patients require urgent repair. The most crucial aspect of tracheal injury is the management of the airway. The first action is to align a transected airway by thrusting the jaw forward to help breathing if the status of the cervical spine is not compromised. Endotracheal intubation can be attempted as a second option, but its repetition is avoided and emergency tracheotomy has to be performed. In the totally separated trachea, the distal end may retract into the mediastinum and may be difficult to locate. It is best found by inserting a finger in the area where the trachea should be, locating it by palpation, and grasping it with a clamp to bring it to the surface of the wound. A tube can then be inserted and the airway secured. However, in a patient with a partially disrupted trachea, a tube inserted through the damaged area is the best alternative under any circumstances. Every attempt is made to conserve a viable trachea while securing or repairing an airway. Anterolateral and posterolateral thoracotomies are the most used operative approaches. The principles of operative repair include ventilatory support using a double-lumen tube and selective bronchial intubation followed by early surgical repair, with débridement with tension-free, end-to-end anastomosis while preserving the blood supply. The suture technique requires an interrupted absorbable monofilament suture. Delay or lack of recognition is common, and subsequent complications of stenosis and obstruction are the rule in missed tracheobronchial injuries.25 Depending on the type and degree of injury, patients with penetrating trauma are likely to require frequent outpatient follow-up care. If an injury to a major organ system is never

Ch147-F06861.indd 1780

identified and if recovery is uncomplicated, long-term followup is not necessary. The intimate anatomic relationship of the trachea to the great vessels, lungs, heart, cervical spine, spinal cord, esophagus, and recurrent laryngeal nerves explains the high incidence of serious associated injuries in penetrating trauma.

Heart and Pericardium Injuries Penetrating cardiac injuries are a leading cause of traumatic death in urban areas, and most of the wounds are from knives or gunshots. It is stated that only 25% of patients with heart wounds survive to reach the hospital. Penetrating chest wounds between the midclavicular line on the right and anterior axillary line on the left are considered to involve the heart and pericardium until proved otherwise. Patients with penetrating wounds of the heart can be classified in the following ways26: 1. Those with small wounds of the heart, caused by ice picks, knives, or other small agents, who, because of the development of cardiac tamponade, reach the hospital alive. 2. Patients who received extensive lacerations or largecaliber gunshot wounds who die almost immediately as a result of rapid and voluminous blood loss. 3. Patients with associated serious injuries in the chest and/ or elsewhere in the body that, in themselves, may contribute to death. The severity of the injury is related to the immediate cause of death, such as hemorrhage, cardiac tamponade, and cardiac lesion. A diagnosis of pericardial tamponade generally is easy. Muffled heart tones are an indication of blood in the pericardium. A systolic-diastolic gradient of less than 30 mm Hg associated with hypotension is consistent with pericardial tamponade. Neck veins are distended. Central venous pressure is elevated. However, the Beck triad is documented in only 10% to 30% of patients who have proven pericardial tamponade. The chest radiograph may demonstrate a widening of the cardiac silhouette. Ultrasonography shows presence of blood in the pericardial space. Echocardiography is a rapid, noninvasive and accurate test for pericardial fluid. It has a sensitivity of at least 95% and is now incorporated into the FAST evaluation. Pericardiocentesis can be both diagnostic and therapeutic and is reserved for patients with significant hemodynamic compromise without another likely etiology. Cardiac lesions may be initially inapparent. Wounds of the ventricle may be self-sealing, and small lacerations may be contained by clot within the pericardium. Traumatic cardiac penetration is highly lethal, with case-fatality rates of 70% to 80%. Patients who reach the hospital before cardiac arrest occurs usually survive.27 Ventricular injuries are more common than atrial injuries, and the right side is involved more often than the left side. Prompt definitive therapy is imperative and based on the patient’s hemodynamic status.28 This includes emergency

1/21/2008 4:23:02 PM

Chapter 147 Penetrating Thoracic Trauma

thoracotomy and suture of the cardiac wound. Emergency department thoracotomy is seldom indicated, being reserved for moribund patients or those whose condition is rapidly deteriorating without time for transfer to the operating room. Left anterolateral thoracotomy is the preferred initial approach because rapid access to the heart can be gained. Distal coronary injuries are usually ligated, whereas proximal injuries may require bypass grafts. Intracardiac shunts or valvular injuries in patients who survive are usually minor and do not require emergent repair. Foreign bodies in the left cardiac chambers must be removed.29 Postoperative deterioration may be due to bleeding or postischemic cardiac myocardial dysfunction. Residual and delayed sequelae include postpericardiotomy syndrome, intracardiac shunts, valvular dysfunction, ventricular aneurysms, and pseudoaneurysms.

Thoracic Vascular Injuries More than 90% of thoracic great vessel injuries are caused by penetrating trauma, and gunshot and stab wounds are the most common source of injury. Thoracic great vessel injuries are almost always nonexistent in patients arriving alive at emergency departments because exsanguinating hemorrhage, massive hemothorax, and pericardial tamponade usually occur, resulting in death. Arterial injuries are more rapidly fatal. The great vessels of the chest include the aorta and its major branches at the arch, the major pulmonary vessels, and the superior and intrathoracic inferior vena cava. The injuries can occur to any of these vessels, both intrapericardial and/or extrapericardial, if the entrance and exit wounds are medial to the nipples anteriorly or to the scapula posteriorly or if the mediastinum has been traversed. Penetrating injuries of the aorta usually are fatal. Lesions of ascending aorta and aortic arch have a mortality rate from 45% to 65% in patients who arrive alive at the hospital in general owing to a contained hematoma. If the lesion is in the descending aorta, then the mortality rate increases up to 85%, and 50% of the initial survivors die during the following 24 hours. If the aorta is noncompletely interrupted and there is an intact adventitial layer, then it is possible to operate on the patient and to repair the lesion. If the injury is not diagnosed and not adequately treated, then the injury will prove fatal in a few hours or days.30 Central pulmonary vessel injury is typically diagnosed only at thoracotomy. Usually, bleeding is profuse; lesions are complex, proximal and distal control is difficult to achieve, and exposure is difficult. Air embolism is a real risk. Pulmonary resection is often necessary to control the situation. The mortality rate is about 30%. Superior and inferior vena cava injuries rarely exist in isolation. Caval injury is often associated with injury to the innominate artery/brachiocephalic vein. The therapeutic approach includes a damage control procedure or a definitive reconstruction because the patient will not tolerate complicated, time-consuming repairs. Injuries in the thoracic outlet are also considered thoracic injuries. Thoracic outlet vascular injuries include lesions of

Ch147-F06861.indd 1781

1781

the innominate artery, carotid, subclavian, intercostals, and internal thoracic vessels. Carotid and subclavian injuries rarely produce death. When these vessels are involved by penetrating trauma, they produce large protective hematomas of the thoracic outlet.31 On the other hand, the innominate artery and intercostal and internal thoracic vessels may produce significant bleeding, resulting in cardiac tamponade, massive hemothorax, and cardiac arrest. The single most important initial evaluative tool is the chest radiograph.32 This may demonstrate suggestive radiologic features, such as widened mediastinum, right tracheal shift, elevation and rightward shift of the right bronchus, depressed left main bronchus, loss of the aortic knob contour, massive hemothorax, fractures, apical hematoma cap, or metal clip marker.33 Helical CT, transesophageal echocardiography, and CT angiography offer several advantages over other diagnostic studies.34,35 CT angiography is the primary method of determining vascular injuries, obviating the much more invasive and operator-dependent conventional angiographic techniques, which were long held to be the standard for assessment of vascular trauma.36,37 Arteriography is useful in the evaluation of the hemodynamically stable patient with suspected vascular lesion.38 The initial approach includes pericardiocentesis and chest tube insertion; if indicated, autotransfusion of hemothorax blood may be lifesaving. Patients who are successfully resuscitated but remain hemodynamically unstable or who demonstrate continued massive blood loss are immediately taken to the operating room.39-41 Median sternotomy with supraclavicular extension for access to the innominate and subclavian vessels is the most useful approach. Left anterolateral thoracotomy is the access for uncontrolled bleeding from an unknown site, and the posterolateral thoracotomy is the incision of choice for access to the descending thoracic aorta. The principles of vascular trauma are to not approach the bleeding directly but rather to obtain proximal and distal control. The repair requires proximal control before entering hematomas in order to avoid exsanguination. Rapid descending aorta cross-clamping and manual control of bleeding may be lifesaving.42 If the injury is small, a primary repair can be accomplished; however, if the lesion is large, the bypass principle is used.43-45 Patients with great vessel injuries have a higher prevalence of associated venous, esophageal, and bronchial injuries compared with patients without great vessel injuries.

Esophageal and Diaphragmatic Injuries The prevalence of injury to the esophagus due to external trauma is less than 1% of patients, and the majority of these injuries are due to penetrating trauma from a variety of instruments. Recognizing injury to the esophagus after trauma is difficult because of the rarity of injuries to this organ, the paucity of clinical signs in the initial 24 hours, and/or the presence of multiple other injuries.46 Dyspnea, cyanosis, sepsis, and shock soon set in and dominate the clinical picture. Prompt investigation including radiography and endoscopy has high diagnostic sensitivity. Emphysema and hydropneu-

1/21/2008 4:23:03 PM

1782

Section 8 Trauma

mothorax in the left mediastinum develop and become visible radiologically. Esophagoscopic visualization of localized blood in the esophagus or a laceration is a diagnostic sign. Thoracoscopy, when warranted, increases the diagnostic sensitivity to almost 100%. With the esophagus exposed, air insufflation through the esophagoscope is occasionally required to precisely identify the site of the injury. The principles in the management of major esophageal injuries are those of early operation, primary repair with adequate tissue buttressing and two-layer surgical closure when possible, and wide mediastinal drainage.47 Extensive tissue destruction or associated major mediastinal contamination are indications to consider a closure with a T-tube to create a controlled fistula or an exclusion technique. Delayed treatment results in the rapid development of sepsis and associated high risk of death. Complications after esophageal repair include esophageal leaks and fistulas, wound infections, lethal mediastinitis, empyema, sepsis, and pneumonia. Long-term complications, such as esophageal stricture, are also possible. The diaphragm is also frequently injured in penetrating thoracoabdominal trauma. Such injury occurs in 15% of stab wounds and in 46% of gunshot wounds. Only 15% of the injuries are more than 2 cm long; therefore, herniation of abdominal contents is rarely immediate.48 Diaphragmatic injury is suspected in any penetrating thoracic wound at or below the fourth intercostal space anteriorly, sixth intercostal space laterally, or eighth intercostal space posteriorly. Stomach and other abdominal viscera may herniate into the left thorax, the left lung may collapse, the mediastinum may be dislocated, the trachea may be deviated to the right, and the right lung may be compressed. Symptoms are related to the quantity of herniated viscera into the thorax.49 Penetrating diaphragmatic injuries are frequently difficult to diagnose. The diagnosis is suspected or confirmed by chest radiography, which may demonstrate atelectasis with silhouetting of the ipsilateral diaphragm, evidence of an air-filled or solid viscus in the thorax, and abnormal curvilinear shadow above the diaphragm. A contrast stomach radiograph may visualize the stomach herniated into thorax.50,51 Ultrasonography, CT, and magnetic resonance imaging will confirm the diagnosis.52 Diagnostic peritoneal lavage appears to be the best procedure, and most centers use 10,000 red blood cells/ mm3, which is a more sensitive criterion than normally used. Sometimes, however, laparoscopy and laparotomy are the unique diagnostic tools.53 Up to 13% of acute lesions are missed, and the patient may present years later when visceral herniation occurs (85% within 3 years), manifesting as decreased cardiopulmonary reserve or obstruction. Bowel strangulation, gangrene, and sepsis are associated with a high mortality rate. Acute injuries are approached with laparoscopy or laparotomy because of possible associated abdominal injuries, and chronic traumas are approached with thoracoscopy or thoracotomy because of dense adhesions that arise between the abdominal contents and the lung.

Ch147-F06861.indd 1782

Associated Injuries The close proximity of base of neck major structures makes their injury highly probable during a chest trauma. They can be assessed by angiography, contrast swallow, endoscopy, or surgical exploration. The surgical approach will vary, but median sternotomy with lateral or superior extension provides the widest exposure. Prosthetic grafts are avoided for vascular repair if the trachea or esophagus is also injured. Cardiopulmonary bypass may be required if the aorta must be cross clamped.

SURGICAL INDICATIONS Immediate Operation The decision to undertake a thoracotomy within 15 minutes of the patient’s arrival in the emergency department presupposes that the main objectives are to relieve cardiac tamponade and control intrathoracic bleeding and/or major air leak so that vital functions such as circulation and respiration can be achieved and maintained, thus improving perfusion to heart and brain. It is a procedure performed solely for resuscitation in patients in cardiac arrest, in those with no blood pressure, and in those whose condition is rapidly deteriorating (Rhee et al, 2000).54-56 The indications for immediate thoracotomy are pericardial tamponade, exsanguinating intrathoracic hemorrhage, massive hemoptysis, massive air leak, cardiac arrest, and intra-abdominal hemorrhage requiring aortic cross clamping. The anterolateral fourth or fifth interspace incision is the standard approach for immediate thoracotomy. The best results occurring with an immediate thoracotomy for trauma are obtained with pericardial tamponade. If the patient’s condition is deteriorating rapidly, an immediate thoracotomy is in order, particularly if neck veins are distended.57 Severe persistent cardiovascular shock despite a rapid intravenous infusion of fluid suggests internal bleeding and also requires an immediate thoracotomy. If a chest is full of blood clinically or has drained more than 1500 mL of blood with a chest tube, immediate thoracotomy is indicated.58 Severe hemoptysis after trauma is life threatening not only because the blood can rapidly flood alveoli and cause severe hypoxemia but also because trauma patients with hemoptysis have a greatly increased chance of developing systemic air emboli. Blood in the tracheobronchial tree rapidly floods alveoli, and only a small fraction is coughed up or can be suctioned through an indwelling endotracheal tube. Blood in the tracheobronchial tree causes the partial pressure of oxygen to fall rapidly with little initial change in partial pressure of carbon dioxide or ventilatory pressures. Performing an immediate thoracotomy is important in patients with posttraumatic hemoptysis to clamp the injured lung and prevent air emboli and further alveolar flooding. Penetrating wounds of the chest can also cause venous or systemic air emboli. Lung positive-pressure ventilation support using airway pressures in excess of 60 mm Hg can force air from injured bronchioles and alveoli into the adjacent pulmonary veins. Systemic air emboli can cause

1/21/2008 4:23:03 PM

Chapter 147 Penetrating Thoracic Trauma

death due to occlusion of coronary or cerebral arteries with less than 1 mL of air. Systemic air emboli need to be anticipated with all lung injuries, especially a gunshot wound of the lung producing hemoptysis. Sudden deterioration in a patient with a lung injury, especially after endotracheal intubation and positive-pressure ventilation, is assumed to be caused by systemic air emboli until proved otherwise. If a systemic air embolism is suspected, the head needs to be lowered and an immediate thoracotomy performed to clamp the injured lung; aspirate air from the left atrium, left ventricle, and aorta; and provide open cardiac massage.59 If adequate cardiac function cannot be restored, the patient needs to be placed on cardiopulmonary bypass to drive the air out of the coronary arteries. The incision for the thoracotomy is anterolateral with the patient supine to minimize flooding of the uninjured lung. A massive air leak due to major bronchial injury or a severe laceration of the lung can occasionally cause a cardiac arrest. However, these patients usually also aspirate blood into their alveoli to further impair oxygenation of the blood. An occasional patient may be saved by immediate thoracotomy and clamping of the involved lung at the hilum. Blood is then removed from the bronchi endoscopically as rapidly as possible, followed by repair or excision of the involved lung. It is almost uniformly agreed that an immediate thoracotomy is of no use in patients who have no vital signs at the scene. However, if the patient with a penetrating wound of the chest had signs of life in the ambulance but arrived at the hospital with an apparent cardiac arrest, it is worthwhile to perform an immediate thoracotomy with 4% to 27% survival.60 On the other hand, if the cardiac arrest occurs in the emergency department, the patient definitely undergoes immediate thoracotomy, which has an 18% to 26% survival rate. Some of the indications for terminating a resuscitative immediate thoracotomy are irreparable heart injury, exsanguination with a persistently empty asystolic heart, and failure to obtain a sustained systolic blood pressure greater than 90 mm Hg after 15 minutes of resuscitation and clamping of the descending thoracic aorta. Patients who have an emergency thoracotomy for penetrating trauma to the heart are followed for 3 to 6 months to rule out the presence of internal cardiac damage that may not be evident at the time of thoracotomy.

Early Operation It is a constant awareness of the possible progression of injuries and their effects that leads to prompt detection of the indications for early thoracotomy in chest trauma. Depending on the instability of the patient and complexity of associated injuries, the selection of diagnostic studies and timing of the operations may be critical. Operation is mandatory and lifesaving for some patients. Some patients also require surgery within a short time of arrival in the emergency department for bleeding, large vessel injury, or other problems. Only 15% of patients sustaining penetrating thoracic injury will require thoracotomy for persistent bleeding control. The

Ch147-F06861.indd 1783

1783

decision to operate is based on the amount of blood lost, which is secondary to systemic artery injury in the vast majority of patients. The timing of the operation can be critical because operating prematurely increases the number of needless operations, whereas waiting too long exposes the patient to increased risk of complication or death. Great differences exist in methods of injury, extent of injury, and war versus civilian environment. Continuing blood loss of more than 150 to 200 mL/hr for than 10 hours or 1500 mL from a tube thoracostomy is considered an indication for surgical exploration.61 Although the majority of patients sustaining a tear of the thoracic aorta will exsanguinate immediately, a small percentage will reach the emergency department with the tear controlled by the adventitia. Symptoms may be either nonspecific or totally absent, and thus attention is diverted to the other obvious sites of injury. The usual anteroposterior semi-erect or supine chest radiograph taken in the emergency department should demonstrate mediastinal widening.62 Obviously, a widened mediastinum, loss of aortic contour, or right-sided deviation of the trachea requires further imaging study. Any major injury to the trachea or a major bronchus is preferably handled by early surgery. Most of these patients do not develop a tension pneumothorax, and few have significant hemorrhage. Many survive the initial injury and develop partial or total stenosis. Delayed repair is possible even years after the injury, with re-expansion of the lung expected.63 One has to highlight the need to be aware of the possibility of multiple organ injury. Because standard protocol requires that all patients be treated as having a cervical fracture until proved negative, in many trauma cases in which the plain chest radiograph is abnormal, with blood, lung contusions, or atelectasis obscuring details, a diaphragmatic lesion may not be suspected or may be only found incidentally during an operation for other injuries.64 In many instances, patients have recovered from acute trauma and months to years later the diaphragmatic injury is discovered incidentally. If the diagnosis is suspected and the patient is stable enough, fluoroscopy and barium studies are useful.

Late Operation There are trauma situations best handled after the patient has been appropriately stabilized and by operations that can be safely delayed. Other conditions are handled surgically as they develop or are recognized at a later stage. The mere presence of a foreign body in the lung, pleural space, or chest wall is not per se an indication for surgical removal. The decision for an operation will depend on the size of the foreign body, the nature of the foreign body, its proximity to a vital structure such as the heart, great vessels, esophagus, or pulmonary hilum, and the development of symptomatic complications. Most are smaller than a centimeter, are smooth surfaced, and produce only a limited local inflammatory response. Almost none of the bullets require removal. Large and irregular fragments of metal, particularly from explosive shells, grenades, and land mines, can cause

1/21/2008 4:23:03 PM

1784

Section 8 Trauma

jagged lacerations and extensive tissue destruction. It is not unusual for them to carry oil, vegetation, bits of clothing, and fragments of a fractured bone, which are often the harbingers of wound infection, empyema, pulmonary abscesses, or osteomyelitis. They can be removed after the patient’s condition has been carefully stabilized. Foreign fragments that lie in proximity to the esophagus, great vessels, or pulmonary hilum or within the heart or great vessels are removed at an early date to prevent progressive erosion with subsequent hemorrhage or infection. Initial treatment is directed toward control of any suppurative process while localization studies are completed.65 CT is of great value not only for localization of the fragment but also for detection of secondary changes. Bullets within the heart and great vessels are notorious for migrating to almost any site within the body, pulmonary or systemic, and are removed early. Because of this tendency, chest radiography is performed at the operating table after the patient has been positioned for surgery. For intravascular (including intrapulmonary) objects, the supine position is preferable to the lateral position, to avoid gravitational effects. During exploratory thoracotomy or video-assisted thoracoscopic surgery for removal of a foreign body, palpation and inspection are not always revealing regardless of how thorough the preoperative localization might have been. When severe or chronic damage has occurred in the lungs as a result of the original trauma or the presence of a foreign body, the segment or lobe with the contained missile can be resected. Many major lacerations of the lung that result from penetrating injuries will seal if handled initially with chest tube drainage. Rarely do these injuries require thoracotomy, except for the unusual massive hemorrhage from hilar vessels. Bronchoscopy would be performed to rule out tracheobronchial injuries, and esophagoscopy is done if the wound has penetrated the mediastinum or if a pneumomediastinum is present.66 Blood within the pleural space clots quickly and must be evacuated early by large thoracostomy tubes. Preferably, any large residual volume of blood is removed to prevent respiratory difficulty and infection. The usual rule is that if the residual clot fills less than one third of the hemithorax, it will be resorbed with restoration of normal pulmonary function, and operation is rarely required. A hemothorax may be lysed by enzymatic débridement with administration of streptokinase or trypsin, using a thoracostomy tube for drainage.67 However, this is often complicated by allergic or pyogenic complications. The action of streptokinase can liquefy an infected hemothorax. An infected hemothorax is evacuated immediately either surgically or enzymatically for re-expansion of the lung and elimination of the infection. A peel quickly forms around the periphery of a clotted hemothorax, with angioblasts and fibroblasts starting ingrowth as early as the seventh day. By the third or fourth week, the entire circumference of the clot has been encased by mature fibrous tissue only loosely connected to parietal or visceral pleura. If inflammation continues, the peel may increase in thickness and ultimately become calcified and extremely

Ch147-F06861.indd 1784

adherent. Usually, however, in 5 to 6 weeks the peel containing the clot can be stripped out totally, leaving essentially normal pleural surfaces. Under most circumstances there is minimal or no air leakage. All experts believe it is better to evacuate any significant volume of clot as soon as the patient is stable rather than wait for a full peel to develop. Decortication, early or late, is usually effective in restoring thoracic cage motion and pulmonary function. Loss of function in such circumstances relates primarily to preexisting damage to the lung parenchyma or chest wall and not to the peel or interval since injury.

Timing of Operation Indications for thoracotomy change from the moment the paramedics “scoop and dash” the patient to the emergency department to the moment of total recovery or death of the patient. Experience has shown that there is no place for openchest resuscitation at the accident site; the mortality rate is 100%. On the other hand, the patient who is transferred to a trauma center after resuscitation during transit or whose condition is rapidly deteriorating poses a different situation.

SURGICAL APPROACHES Several operative approaches are available to access presumed sites of injury. The incision will be selected in agreement with the area to be approached and with the surgeon’s experience and ability in accomplishing that approach. Each technical alternative has advantages and limitations. The anterolateral thoracotomy is the incision of choice in penetrating trauma because it is fast and simple to do. On the right side, it is possible to reach the right atrium, the superior vena cava, the ascending aorta, the right lung, and the pulmonary artery. On the left, the access to left and right ventricles, pulmonary trunk and left branch, and the left lung is guaranteed. The anterolateral thoracotomy provides rapid access to the thoracic cavity in cases of massive intrathoracic hemorrhage, so that an initial evaluation of the injuries and temporary hemostasis can be accomplished. Additional exposure may be obtained by both extending the incision posteriorly or across the sternum and other side (clamshell incision) or by converting it into a thoracoabdominal approach. We usually use the fourth intercostal space to enter the thoracic cavity. The median sternotomy is a very good incision to access the heart, the ascending aorta, the branches of the aortic arch, the superior vena cava, and the pulmonary artery and its main branches. To perform a sternotomy quickly, it is necessary to use appropriate instruments (sternum-splitting instruments). Obviously it is slower when it is performed by a surgeon with little experience with this incision. Injuries to the heart may be accidentally inflicted by the sternum-splitting saw in emergency situations when sufficient care is not taken. The postoperative morbidity of median sternotomy may be high in trauma surgery, mainly owing to osteomyelitis of the sternum. The right posterolateral thoracotomy is a good incision to access the right atrium, the superior vena cava and azygos vein, the right lung, the thoracic esophagus, and the thoracic

1/21/2008 4:23:03 PM

Chapter 147 Penetrating Thoracic Trauma

trachea. It is the best approach to the management of esophageal wounds and for right pulmonary resections. With the left posterolateral thoracotomy it is possible to treat lesions in the left atrium, left ventricle, aorta and its branches, pulmonary trunk, and left pulmonary artery and left lung. The choice of the intercostal space to be entered is based on the region to be accessed. When this information is lacking, the fifth intercostal space is used. The disadvantage of this incision is the position of the patient, which allows contralateral aspiration of blood or pulmonary secretions, and the difficulty of exploration of the neck, abdomen, and opposite thoracic cavity. The use of video-assisted thoracoscopic surgery in penetrating thoracic trauma is controversial, but it can be useful mainly in penetrating wounds in a stable patient to access vascular injuries, evaluate foreign bodies, or explore the diaphragm.68 Other more complex incisions may be chosen, such as cervicothoracic incisions to access the ascending aorta, brachiocephalic arterial trunk, common carotid artery, subclavian vessels, innominate vein, and trachea. Finally, the combination of thoracic and abdominal approaches is very important, owing to the frequency of combined injuries of thoracic and abdominal organs. The thoracoabdominal incision is often the consequence of a thoracic extension of an exploratory laparotomy. The diaphragmatic incision runs peripherally so as to avoid injury to the phrenic nerve and denervation of a large area of the diaphragm. This approach may be useful in cases of splenic lesion in combination with lung or cardiac lesions.

CRITICAL MANEUVERS The operative maneuvers in penetrating thoracic trauma are extremely precise and objective, so that one can offer an increase in survival probability.69 In cases of pericardial tamponade, although pericardiocentesis may be rapidly diagnostic and temporarily lifesaving in some patients with acute severe situation, it rarely provides adequate definitive care because most of the blood present in the pericardium after trauma is clotted. The choice is the performance of a subxiphoid pericardial window unless it is unlikely that a tamponade is present and an immediate thoracotomy is going to be performed anyway. The physician must be prepared to extend the subxiphoid incision immediately into a median sternotomy to definitively manage the cardiac injury if blood is present in the pericardial cavity. However, this anterior approach may be a problem with posterior cardiac injuries unless another incision is made or cardiopulmonary bypass is used. The performance of a subxiphoid pericardial window wastes valuable resuscitative time and may release a tamponade without allowing prompt control of the bleeding site. Chest tube insertion, for pneumothorax and hemothorax, which are life-threatening situations, is the simplest and most important critical lifesaving maneuver in chest trauma. The primary purposes of chest tube insertion are relief of respiratory distress, promotion of lung re-expansion, prevention of pleural complications, and evaluation of bleeding. Early and

Ch147-F06861.indd 1785

1785

complete evacuation of blood and air is the best prophylaxis against complications. All chest tubes placed for trauma are of sufficient caliber to drain hemothoraces without clotting. Uncontrollable bleeding requires immediate exploration. Local pressure control or packing of the bleeding site is a useful immediate step while proximal and distal control is obtained. Local pressure can control the situation while preparations are made for definitive repair.70 Cross-clamping of the descending thoracic aorta is used in patients who remain in severe shock or cardiac arrest. This maneuver improves perfusion of coronary and cerebral blood vessels and reduces blood loss from injuries in the lower torso.71 Organs distal to the clamp will become ischemic, and this includes the spinal cord when the clamp is placed higher, at the aortic isthmus. Clamp time ideally is 30 minutes or less. Safe and effective cross-clamping of the descending thoracic aorta is performed ideally at the level of the diaphragm, to maximize spinal cord perfusion, and under direct vision. External bypass may be useful in a descending aorta lesion, when cross-clamping is expected to require more than 30 minutes. Massive pulmonary lacerations are critical. Pulmonary arterial or hilar clamping is the maneuver of choice to prevent systemic air embolism and control bleeding until a definitive repair can be accomplished. The best way to accomplish main pulmonary artery clamping is from within the pericardium. Extrapericardial clamping is hazardous and time-consuming. Specialized instruments are not always available or may be difficult to use in the pulmonary artery. Another technique is the twisting of the lung at the hilum. It provides rapid vascular control, and in the setting of the emergency department without the special equipment, this procedure can provide an adequate alternative.72 The management of heart wounds and large vessels is extremely delicate and difficult, and the right timing is a decisive factor. Hemorrhage from small cardiac wounds may be controlled by direct digital pressure, but larger wounds may require a trick, such as the use of a balloon-tipped catheter (Foley, Fogarty, or the bronchial blocker) inserted through the wound to stop the bleeding in cases of an atrial lesion. More recently, the use of a cardiac stabilizer has been described for the management of ventricular injuries. The atrial lesions can frequently be clamped with a Satinsky or analogous clamp. In ventricular wounds this approach is avoided. To repair an atrial lesion we use a continuous 4-0 or 5-0 nonabsorbable suture. To repair a ventricular lesion we use a 2-0 absorbable horizontal mattress suture, placed deeply through the myocardium. Then, a definitive suture, continuous or interrupted, of nonabsorbable material is carried out. When the lesion is too close to a coronary vessel, a mattress suture is placed deep enough so as to avoid injury to the coronary vessel. This mattress suture may be removed if hemostasis is obtained with the definitive sutures; otherwise, the mattress suture is left in place. This is the best strategy for gunshot wounds. Large myocardial wounds and injuries to coronary arteries and great vessels may require cardiopulmonary bypass. The repair of an intracardiac defect is not attempted in the acute phase unless satisfactory hemodynamic conditions cannot be maintained. In large wounds,

1/21/2008 4:23:03 PM

1786

Section 8 Trauma

exsanguinations and cardiac arrest may occur before adequate control of the wound, so the surgeon repairs the wound before attempting resuscitative measures. The time in these conditions is critical, being limited to 3 or 4 minutes. In penetrating injury of the superior vena cava, a bypass may be necessary to create conditions to repair it. There are two possibilities, an external bypass or an internal bypass of the superior vena cava. The internal bypass is a complex maneuver but obviates the need for extracorporeal circulation. A tube with lateral holes (arranged such that the intact interval between them will be slightly longer than the distance between two tapes around the superior vena cava) is inserted into the superior vena cava through a right atrial purse-string suture. The outer end is clamped, and the pursestring suture is fastened around the tube. In the external bypass, two purse-string sutures are placed, one in the anterior aspect of the innominate vein and the other in the right atrium. A plastic cannula is inserted through the purse-string sutures, and the tourniquet is fastened around the cannula. The superior vena cava may now be safely cross-clamped and repaired.73 The most challenging and desperate operative maneuver is caval inflow occlusion as an aid in the management of complex cardiac injuries or wounds with difficult access (posterior wall of ventricles). The right atrium is retracted to dissect the superior and inferior vena cava, and a tourniquet is fashioned around them. This maneuver will occlude the inflow to the right atrium, with consequent cardiac arrest and a dry operative field. The time is limited to 3 to 4 minutes. Everything is ready and available for this moment because it is probably the only chance to repair this type of wound.74

COMPLICATIONS The decision to remove a retained foreign body depends on its size, its location, and any specific problems associated with it. Foreign bodies larger than 1.5 cm in diameter, centrally located missiles, irregularly shaped objects, and missiles associated with evidence of contamination are removed. Such removal is best performed 2 to 3 weeks after the acute phase of the injury. Hernia of the chest wall is usually a complication of thoracotomy. A patient with a chest wall hernia presents with pain and an obvious defect, but occasionally a lung may be entrapped and become necrotic. Management includes resection of nonviable tissue and closure with tissue flaps or artificial material. Missed tracheobronchial laceration may result in significant strictures. Patients present with variable degrees of dyspnea. Evaluation with bronchoscopy and CT is followed by treatment with open operative repair. Stenting is a less satisfactory option and is used only when there is a specific contraindication to operative repair. Delayed tracheoesophageal fistula is rare, generally manifesting approximately 10 days after injury, possibly from delayed necrosis following a blast injury. Usually, the airway at or just above the carina is involved. The timing of surgery or intervention is unclear and depends on the degree of ventilatory leak and the overall condition of the patient.

Ch147-F06861.indd 1786

Traumatic air leaks that last longer than 7 days are unlikely to resolve spontaneously, and judicious manipulation of the chest tube to increase or decrease the suction may be appropriate to facilitate healing. Bronchopleural fistulas imply a direct communication between the major airways and the pleural space and usually require some form of intervention for closure. Failure to adequately drain a hemothorax initially results in residual, clotted hemothorax that will not drain via a chest tube. If left untreated, these retained hemothoraces may become infected and lead to empyema formation. Even if they remain uninfected, the clot will organize and fibrose, resulting in a loss of lung volume, which may result in impaired pulmonary function. Failure to adequately drain a hemothorax is due to failure to initially diagnose the hemothorax or inadequate draining of the hemothorax.67 Diagnosis of retained hemothorax is usually made on CT, which shows one or more loculated collections of blood. Surgery is indicated if there is evidence of empyema or if the hemothorax is large enough to cause lung volume loss. Surgery for evacuation is performed early, within the first 3 to 7 days after injury. At this time the clot can be cleared with thoracoscopy.75,76 If clot evacuation is delayed beyond this time, the inflammatory reaction in the pleura requires thoracotomy with removal of the peel and decortication. Traumatic empyema occurs in 2% to 6% of patients, is often loculated, and requires early débridement.77,78 Initial treatment is with tube drainage. Thoracoscopy, particularly if performed within 7 to 10 days, is effective for draining the infection. Embolization to the pulmonary arteries is usually treated with surgical removal or interventional techniques. A chest radiograph taken immediately preceding incision or intraoperative fluoroscopy is mandatory to detect more distal embolization that may occur during positioning. Occasionally, missile emboli may migrate from central parenchymal or vascular injuries to gain access to the left side of the heart and then to the systemic circulation. Most cardiovascular arteriovenous fistulas occur after stab wounds. Virtually all of these fistulas manifest as a machinery murmur after approximately 1 week. Innominate artery-tovein fistulas are the most common. Coronary artery fistulas, usually to the right ventricle, manifest as ischemia, cardiomyopathy, pulmonary hypertension, or bacterial endocarditis. Interventional techniques may be used in a large number of these patients. Chylothorax is often diagnosed as a prolonged leak via a chest drain of clear, turbid, or milky fluid. The thoracic duct injury, if unrecognized, may produce high morbidity due to severe nutritional depletion. Initial management of a delayed chylothorax is always aggressive but nonoperative. Parenteral hyperalimentation of a low-fat diet may result in a significant number of spontaneously sealing thoracic duct injuries. Failure to spontaneously seal after 5 to 7 days indicates the need for surgical intervention for both direct suture control or to ligate the vessel as it traverses the diaphragm. Thoracic duct can be approached thoracoscopically or with video assistance, thus minimizing additional discomfort to the patient. Injury of the phrenic nerve often is noticed as a difficulty in weaning off assisted ventilation. In these circumstances,

1/21/2008 4:23:03 PM

Chapter 147 Penetrating Thoracic Trauma

thoracotomy and plication of diaphragm may provide a better platform against which opposite hemidiaphragm, intercostal muscles, and accessory muscles can act.

SUMMARY The outcome of treating patients with penetrating chest injuries is directly related to the extent of the injuries and the timeliness of initiation of treatments. Patients arriving in a stable condition may expect full recovery, but patients presenting with lesser levels of stability have diminishing probabilities of survival. Traditional approaches and techniques have little competition in the treatment of critically injured patients and those whose condition is unstable. Do not attempt to resuscitate, let alone definitively treat, patients presenting with no vital signs or with injuries from which they could not survive.

COMMENTS AND CONTROVERSIES The evaluation and management of penetrating thoracic trauma requires careful consideration of the mechanism of injury and ana-

Ch147-F06861.indd 1787

1787

tomic structures at risk of injury. This chapter provides a detailed review of mechanisms of injury by gunshot and stab wound. The anatomic zones of injury and required plan of management for each are discussed. Specific organ injuries and their management are discussed in detail. Of particular importance is the discussion on timing of surgical intervention and the surgical approaches available for best exposure. G. A. P.

KEY REFERENCES Feliciano DV, Rozycki GS: Advances in the diagnosis and treatment of thoracic trauma. Surg Clin North Am 79:1417-1429, 1999. Mattox KL, Johnston RH Jr, Wall MR Jr: Penetrating trauma. In Pearson FG, Deslauriers J, Ginsberg RJ, et al (eds): Thoracic Surgery. New York, Churchill Livingstone, 1995, pp 1581-1589. Rhee PM, Acosta J, Bridgeman A, et al: Survival after emergency department thoracotomy: Review of published data from the past 25 years. J Am Coll Surg 190:288-298, 2000.

1/21/2008 4:23:03 PM

chapter

148

LATE SEQUELAE OF THORACIC INJURY Sebastien Gilbert Andrew B. Peitzman Peter Ferson

Key Points ■ Because of associated injuries, delays often occur in the manage-

ment of traumatic chest injuries. ■ Sequelae of hemothorax are the most common. ■ In operative candidates, surgical resection should be the preferred

treatment option for benign airway strictures.

In spite of well-planned management protocols for patients with blunt and penetrating thoracic trauma, delays in the treatment of chest injuries often occur. Prioritization of the treatment of more life-threatening injuries and initial misdiagnosis are common reasons for such delays. Although the initial therapy may palliate such injuries, this temporizing treatment may be insufficient to prevent subsequent sequelae.1,2 Thoracic injuries may also result in significant long-term impairment. Quality-of-life scores remain persistently lower than in the general population up to 18 months after major thoracic trauma.1 The proper management of thoracic injury manifesting in a delayed fashion requires an understanding of the initial mechanism of injury, the development of symptoms and their time frame, the natural history of the injury when left untreated, and the options for therapy. Even when the best available treatment is promptly instituted, long-term sequelae may occur and cause significant problems. Awareness of these issues and judicious surgical intervention should facilitate appropriate therapy, prevent long-term sequelae, and, it is hoped, preserve quality of life.

HEMOTHORAX The most common pleural space problem after chest trauma is hemothorax. This complication may result from seemingly minor chest trauma. In a prospective cohort study of 709 patients who were deemed fit for discharge from the emergency department after blunt chest trauma, 7.4% developed a hemothorax up to 14 days after initial evaluation (Misthos et al, 2004).3 Although hemothoraces can be treated effectively by accurate placement of a chest tube, up to 30% of patients treated in this manner have retained blood clots in the pleural space (Heniford et al, 1997).4-6 The most significant late complications resulting from this type of injury are empyema thoracis and “trapped lung” from fibrothorax. The management of post-traumatic hemothorax has been evaluated in a prospective randomized trial including 39 patients who were initially treated with large-bore (36 Fr)

chest tube drainage (Meyer et al, 1997).7 Early thoracoscopic drainage was found to be superior to tube thoracostomy because of a shorter period of tube drainage, a shorter hospital stay, and decreased costs. In 42% of patients treated with a chest tube, the insertion of a second chest tube failed to drain the residual hemothorax. Although the authors did not provide long-term data, in hemodynamically stable patients initial thoracoscopic drainage may prevent complications related to retained hemothorax by providing definitive treatment at an early stage.

EMPYEMA In patients who sustained a traumatic hemothorax, the likelihood of developing an empyema ranges from 2% to 25% (Heniford et al, 1997).5,8-10 Data from the military experience show a 9% risk of empyema after penetrating chest trauma with hemothorax (Molnar et al, 2004).11 Risk factors for empyema include residual hemothorax after chest tube insertion, delay in chest tube insertion, prolonged chest tube drainage, significant soft tissue injury to the chest wall, pneumonia, and complicated abdominal injuries (Heniford et al, 1997).5 A complete discussion of the management of empyema can be found elsewhere in this textbook. Empyema is a potentially fatal complication of hemothorax. The development of an empyema within a pleural fluid collection increases the mortality of surgical drainage to approximately 9% (Heniford et al, 1997).5 A hemothorax occurs in 5% to 30% of patients with penetrating trauma but can also develop in blunt chest trauma patients, especially those with rib fractures and multiple injuries.12 Prompt thoracoscopic evacuation of retained hemothorax is a safe procedure with minimal risk. Figure 148-1 represents a good example of post-traumatic empyema with trapped lung. This patient had a traumatic hemothorax that was managed with multiple attempts at chest tube drainage. He eventually developed an infected loculated effusion that required operative drainage as well as pulmonary decortication. Fortunately, not all residual hemothoraces or pleural effusions become infected. However, if the hemothorax is left undrained, pleural fluid collections may partially or completely collapse the underlying lung and result in the formation of a fibrothorax.

FIBROTHORAX The end result of the inflammatory response to a chronic pleural effusion is the formation of a fibrotic shell on the pleural surfaces. The underlying lung can no longer fully

1788

Ch148-F06861.indd 1788

1/21/2008 4:23:48 PM

Chapter 148 Late Sequelae of Thoracic Injury

1789

FIGURE 148-1 CT scan showing an empyema resulting from an incompletely drained hemothorax.

expand because of the resulting pulmonary restriction. The chest wall may also contract, leading to narrowed intercostal spaces and even spinal deformities (e.g., scoliosis).13 Any type of pleural effusion can produce lung entrapment if not recognized and treated in a timely fashion. Decortication, by either a thoracoscopic or open approach, is the treatment of choice for operative candidates. A recent prospective analysis of functional outcomes after pulmonary decortication demonstrated a significant gain in forced expiratory volume in 1 second, lung perfusion, and partial pressure of oxygen after surgery.14 These findings are consistent with previously published animal experiments and human retrospective cohort studies of pulmonary decortication.15-18

RIB FRACTURES, FLAIL CHEST, AND PULMONARY CONTUSIONS Rib fractures are a common finding in adults who have sustained blunt chest trauma. However, traumatic rib factures are uncommon in children. In young patients (especially those younger than 5 years old), the ribs are more flexible and can therefore absorb more energy without breaking. Up to 38% of children with pulmonary contusions on CT do not have any rib fractures.19 The most common long-term sequela of chest trauma is chronic pain, which is present in approximately 30% of patients.20 Although the exact cause remains unclear, chronic pain may be related to skeletal trauma and/or intercostal neuroma formation. The management of chronic chest wall pain is best handled through a multidisciplinary approach involving physicians specializing in pain management. Rib and intercostal nerve resection may play a role in the management of selected patients in whom local anesthetic infiltration has demonstrated reproducible pain relief. A flail chest occurs when at least four ribs are fractured in two locations. Five to 13 percent of patients with chest wall injuries present with a flail chest.21 This type of injury may be permanently disabling in up to 25% of patients.22 Other investigators have found that over a period of 12 years, only 40% of patients who developed a flail chest eventually returned to work.23 At a mean follow-up of 5 years, the same

Ch148-F06861.indd 1789

authors reported that 49% of these patients had chronic chest pain, 63% complained of dyspnea, and 57% had abnormal spirometry. Although some patients experience a complete recovery without long-term disability, a significant proportion develop chronic symptoms (Kishikawa et al, 1991).22,24,25 Kishikawa and colleagues attempted to differentiate the long-term effects of flail chest from those of isolated pulmonary contusions.24 The study included a prospective cohort of patients followed for 6 months and a retrospective cohort followed for 1 to 4 years. Data were acquired using spirometry, chest imaging, and arterial blood gas analysis. In the prospective cohort, patients were stratified according to the presence of pulmonary contusions, a flail chest, or both. At 6 months, there was a significant decrease in vital capacity (VC, 12%) and functional residual capacity (FRC, 20%) in the sitting and supine positions. Patients with pulmonary contusions had a higher prevalence of flail chest than patients without contusions (58% versus 33%). Intuitively, one may think that chest wall injuries were largely responsible for the restrictive defect observed in subjects with pulmonary contusions. However, when patients without flail chest were compared with those with a flail chest, there was no difference in spirometric measurements at 6 months. Therefore, the observed decrease in VC and FRC was probably secondary to pulmonary contusions rather than flail chest in this group of patients. At 6 months, computed tomography (CT) scan evaluations revealed changes consistent with pulmonary fibrosis overlying the area of contusion in 83% of patients. These changes were also present in 71% of the long-term follow-up group. In addition, arterial blood gas anomalies were noted in patients with pulmonary contusions at 6 months. Pulmonary contusion patients also had a significant decrease in supine PaO2. This can potentially be explained by the decrease in FRC below the airway closing volume, which results in increased intrapulmonary shunting and decreased oxygenation.

TRACHEOBRONCHIAL INJURY Major injuries of the airways that manifest as uncontrollable pneumothorax and massive air leak may make ventilation of

1/21/2008 4:23:48 PM

1790

Section 8 Trauma

the trauma patient difficult. This clinical scenario should always suggest a tracheobronchial injury to the trauma team. The diagnosis is confirmed by bronchoscopy, and immediate repair is undertaken. However, not all injuries of the trachea or mainstem bronchi have such obvious manifestations. When mechanical ventilation is quickly discontinued, or when low ventilatory pressures are needed, the amount of air leaking into the mediastinum or pleura may be small. In such instances, symptoms are unlikely to develop early after injury. Therefore, unless the degree of clinical suspicion is high enough to perform a bronchoscopy, the injury may not be identified. Also, many injuries to the trachea and main bronchi are associated with other major organ damage. Associated injuries (e.g., great vessel damage) may require emergency treatment and temporarily divert attention away from an airway injury. After the patient recovers from the repair of the associated injury, the airway tear may no longer be clinically obvious (i.e., the tear spontaneously sealed), and it will only become apparent as a stricture develops. Goldfaden and coworkers describe the treatment of a patient with simultaneous injury to the innominate artery and trachea. In this case, both injuries were recognized and repaired.26 Figure 148-2 is a series of CT scans from a patient who had a repair of his innominate artery injury after a motor vehicle accident. A bifurcated graft had been placed from the ascending aorta to the subclavian and carotid arteries. A tracheal stricture is now present at the level of the end of the grafts to the subclavian and carotid arteries. The injury to the

trachea was not recognized at the original hospitalization, and the patient returned 3 months later with significant stridor. Segmental tracheal resection was successful. As in the earlier case, untreated circumferential injuries or partial circumferential tears of the trachea or bronchi will produce a focal area of stricture and possibly a complete airway obstruction. When this occurs in the trachea, the patient develops significant stridor. With obstruction of the main stem bronchus, the symptoms may be less noticeable. Either wheezing or mild dyspnea, suggestive of asthma, or a silent atelectasis or postobstructive pneumonia of the involved lung may result. In young, otherwise healthy trauma patients, a bronchial stricture may cause complete bronchial obstruction without significant symptoms. On the other hand, tracheal strictures uniformly cause severe stridor as they progress. In the acute setting, it is important to differentiate partial or full circumferential tears from linear tears in the posterior wall of the trachea. Such linear tears can occur either from a crush injury against a closed glottis or more commonly from a traumatic intubation (Fig. 148-3). If the patient can be extubated and allowed to breathe spontaneously, or if the endotracheal tube can be advanced beyond the tear, these linear injuries often heal spontaneously.27-29 Mediastinitis has been reported with untreated membranous tears of the airway.30 In the absence of infection, these tears generally heal. When they do heal it is important to be aware that linear tears do not result in stricture. Thus, a patient with a history of a linear tear of the airway would not be expected to return with airway obstruction.

FIGURE 148-2 CT after repair of a traumatic innominate artery injury after a motor vehicle accident. A bifurcated graft had been placed from the ascending aorta to the subclavian and common carotid. Three successive levels in the mid trachea are shown: the first is just above the stricture, the second shows the narrowed trachea, and the third shows the level just below the stricture with the ends of the vascular grafts to previously disrupted great vessels.

A

B

C

FIGURE 148-3 Linear tear of the trachea after intubation. A and B show the tear in the trachea extending to the carina. C shows the same area 6 weeks later after the tear has healed.

Ch148-F06861.indd 1790

1/21/2008 4:23:48 PM

Chapter 148 Late Sequelae of Thoracic Injury

When chronic strictures develop in the trachea, segmental resection is the preferred treatment. The methods and technique of such repair have been well described elsewhere in this book. Careful dissection close to the airway, circumferential dissection only at the site of injury, appropriate tensionreleasing techniques, and end-to-end closure with absorbable sutures are the key elements of a successful repair. Unrepaired acute main stem bronchial strictures can lead to atelectasis of the lung, which may be chronic. Even with long-standing atelectasis, successful repair can be accomplished unless there is infection in the atelectatic lung.31 Caution must be exercised in resecting bronchial stenoses because adjacent structures, such as the pulmonary artery, may be retracted around the fibrotic airway segment. Because operative repair is challenging, there is a natural tendency to search for a less invasive way of dealing with airway strictures. Such search invariably leads to the use of intraluminal stents. Expandable wire stents are seemingly attractive for this purpose because of their ease of insertion. However, when used in chronic fibrotic strictures, wire stents lead to further obstruction from granulation formation and recurrent stricture at the ends of the stent (Gaissert et al, 2003).32 For management of complex tracheal strictures, the silicone T-tube stents give the best long-term results. The T limb holds the stent in place and prevents displacement. It also allows the stent to be smaller than the diameter of the nonstrictured portion of the trachea. This prevents erosion of the airway at the ends of the stent and thus avoids subsequent stricture formation. Patients may be managed successfully with T stents for as long as 10 years. Expandable metal stents (EMS) are becoming popular because they are easier to deploy than silicone-based stents (SBS) and do not require expertise in rigid bronchoscopy. We reviewed our experience with stenting of benign tracheobronchial strictures. Over a period of 8 years, 38 stents were inserted in 34 patients (EMS = 31; SBS = 7). The three most common causes of benign airway structures were following lung transplantation (27%), following tracheostomy (21%), and anastomosis (21%). Eighteen stents (47%) were in the trachea, and the others were placed in the main stem bronchi and/or bronchus intermedius. Re-intervention was necessary in 65% of patients at a mean interval of 6 months after stent insertion. Bronchoscopic laser intervention was needed significantly more often when an EMS was used rather than an SBS (P = .035). Nine patients (24%) had their stent removed because of complications, which included granulation tissue (n = 2), stent collapse or fracture (n = 3), migration (n = 2), and collapsed airway beyond the stent (n = 2). EMS may be difficult to remove. In our experience, thoracotomy was necessary in one third of patients requiring stent removal. After stenting a benign stricture, one should expect to re-intervene (e.g., bronchoscopy, laser, stent removal) in two of three cases. Surgical resection of significant tracheobronchial stenosis should be the standard. When surgical resection is not possible, our data support the use of silicone stents rather than expandable metal stents for benign tracheal strictures. Silicone stents do not work well for long-term stenting of airways distal to the trachea. Except for rare instances where a T-Y silicone stent can be used, bronchial strictures should

Ch148-F06861.indd 1791

1791

be managed by primary repair. If repair cannot be achieved, or if the lung parenchyma has been severely damaged, lobectomy or pneumonectomy is recommended.

STERNAL NONUNION AND MALUNION The standard therapy for transverse fracture of the body of the sternum includes analgesics and limited activity (Velissaris and Tang, 2006).33 The majority of patients respond to this treatment; however, osteomyelitis and mediastinitis can occur.34 Some patients with blunt sternal fracture return with marked overlap of the two parts of the sternum and develop malunion. Sternal injuries may fail to heal because of constant respiratory motion at the fracture site. Presenting symptoms of malunion are pain and/or kyphosis. The kyphosis is most noticeable when there is a combined collapse of the thoracic vertebral body.35 This combination of these bony injuries, when recognized at the initial presentation, requires stabilization of the spine. Without the anterior support of the sternum, the degree of thoracic kyphosis may increase and jeopardize the integrity of the spinal cord. Figure 148-4A is a lateral radiograph of a young man who had suffered a malunion of a sternal fracture and a compression fracture of the upper thoracic vertebral bodies. There is severe kyphosis and accompanying depression of the upper anterior chest. Partial reduction and fixation of the vertebral bodies was performed along with osteotomy and plating of sternum. Figure 148-4B shows the improved postoperative result. Nonunion of the sternum frequently results in symptoms of pain and annoying false motion. Surgical fixation after preparing the opposite ends of the fracture will relieve the symptoms. Fixation with crossed wires is often performed. Alternatively, orthopedic fixation plates can be attached to the adjoining ends with screws.36,37 We prefer the latter method because it seems to result in a more stable immediate result.

DIAPHRAGMATIC RUPTURE Sharp penetration can cause a direct laceration of the diaphragm, whereas blunt injuries may cause a pressure-related rupture of one or both hemidiaphragms. Recognition of the initial injury depends on clinical suspicion and radiographic confirmation. Thus, the diagnosis can be missed when the radiographic findings are subtle and there are no associated symptoms. For instance, the CT scan in Figure 148-5A was obtained when the patient was treated for injuries following a motor vehicle collision. He fractured the 11th and 12th ribs on the left side but did not have any significant clinical or radiographic evidence of a diaphragmatic injury. One month later a left posterior diaphragmatic hernia was incidentally diagnosed (see Fig. 148-5B). The diaphragm had been avulsed from the chest wall, allowing the left kidney to herniate into the pleural space. The defect was successfully repaired using a thoracoscopic approach (see Fig. 148-5C). The symptoms related to late presentation of a diaphragmatic tear may be nonspecific. Dyspnea,38 sepsis from perforation of an incarcerated viscus, vague gastrointestinal complaints, crampy abdominal pain, and other symptoms of intestinal obstruction may be present.39 Conversely, some

1/21/2008 4:23:49 PM

1792

Section 8 Trauma

A

B

FIGURE 148-4 Chest radiographs showing malunion of the sternum combined with compression fracture of the upper thoracic vertebral bodies. A, There is severe deformity of the upper sternum. B, Radiograph taken after osteotomies to realign the sternum and fixation with a plate.

patients may be totally asymptomatic with only radiographic evidence of the diaphragmatic injury. Delayed presentation of a diaphragmatic tear occurs over a wide range of time intervals, often years after injury.40 Figure 148-6A shows the chest radiograph of a man who suffered a jeep rollover during World War II. He had known about the right-sided intrathoracic bowel for many years but he reported that he was instructed never to have the hernia repaired. He had only very mild dyspnea and no intestinal complaints. Serial radiographs showed a density at the apex of the right lung, and a needle biopsy confirmed the diagnosis of lung carcinoma. A lobectomy and repair of the defect were performed. The intestines were surprisingly quite free within the chest with no adhesions to the lung. Figure 148-6B shows the postoperative chest radiograph. Data are scarce concerning the natural history of chronic diaphragmatic herniation. Because patients without diagnosis and treatment of missed diaphragmatic injury survive many years after the initial injury, one might mistakenly assume that the incidental finding is innocent. However, Hegarty and colleagues reported 25 patients treated for diaphragmatic hernia presenting at least 5 months after the initial injury.41 The mortality rate in this group of patients was 20%. We believe that most patients with a symptomatic or an asymptomatic hernia of the diaphragm should have the defect closed and abdominal viscera returned to the abdominal cavity. It is also acceptable to intervene in healthy patients

Ch148-F06861.indd 1792

with incidentally discovered chronic traumatic diaphragmatic hernias. Acutely injured patients with the diagnosis of diaphragmatic rupture should be explored transabdominally because of the high incidence of associated abdominal visceral injury. For delayed diagnosis and treatment of diaphragmatic injury, operation performed through the chest will facilitate lysis of any adhesions and decortication of the lung if necessary. Unfortunately, the presence of adhesions is difficult to predict preoperatively. Both laparoscopic and thoracoscopic repair of diaphragmatic hernias have been reported.42,43 In Hegarty and colleagues’ series of 25 patients with late presentation of diaphragmatic hernia, 9 patients were initially approached through the chest with no problems. However in 6 of 13 (46%) patients approached through the abdomen, the exposure was inadequate.41 Delayed manifestations of thoracic trauma will continue to present interesting problems for the thoracic surgeon. Initial injuries may be overshadowed by other more immediately life-threatening traumatic insults. In most cases, the longterm sequelae of unrecognized thoracic injuries will require surgical evaluation and treatment.

COMMENTS AND CONTROVERSIES The authors have described the salient features in the management of late sequelae of thoracic injury. They have covered a wide range of problems from hemothorax and empyema to tracheobronchial

1/21/2008 4:23:49 PM

Chapter 148 Late Sequelae of Thoracic Injury

1793

A

B

C FIGURE 148-5 Diaphragmatic injury sustained in a motor vehicle accident. The white circles delineate the corresponding areas of diaphragmatic injury on each of the CT images. A, CT scan performed at the time of the initial trauma. There is a small hematoma adjacent to a diaphragm that appears relatively normal. B, Transverse, coronal, and parasagittal views confirmed the separation of the diaphragm from the chest wall and resulting hernia. C, Transverse, coronal, and parasagittal views show restoration of diaphragmatic anatomy after surgical repair.

injuries to diaphragmatic hernias. The advent of thoracoscopy has had an impact in the management of hemothorax, and the authors have referred to a randomized trial favoring thoracoscopy for evacuation of retained hemothorax. They have discussed the management of tracheobronchial stenosis, including the use of stents. We agree that surgical management of benign stenosis should be the standard and stents (preferably silicone) reserved for patients in whom a surgical repair is not feasible. The reader is referred to other chapters in this textbook for the surgical management of tracheal

Ch148-F06861.indd 1793

stenosis. Finally, unlike large asymptomatic paraesophageal hernias, there is less of a controversy as to whether to operate in an asymptomatic patient with a post-traumatic diaphragmatic hernia. Our approach is to repair all post-traumatic diaphragmatic hernias unless medically contraindicated. In view of the complications of a missed diaphragmatic hernia, an area of interest is to determine the optimal investigation in these patients. Some have explored the utility of focused assessment with sonography for trauma (FAST) examination in the diagnosis of these

1/21/2008 4:23:49 PM

1794

Section 8 Trauma

A

B FIGURE 148-6 Delayed presentation of a diaphragmatic tear. A, Chest radiograph of a patient who suffered trauma in a jeep rollover during World War II. The right diaphragm is obliterated, and intestinal shadows are present in the right side of the chest. B, Postoperative radiograph after removal of the right upper lobe for cancer and repair of the right diaphragm.

injuries.1 Because noninvasive testing may not be very sensitive for diaphragmatic injuries, an area of controversy is whether thoracoscopic or laparoscopic exploration should be performed in patients with a high risk of occult injury to the diaphragm. This has been recommended by some authors in a select group of patients. Leppaniemi and coworkers2 did a retrospective analysis of two randomized studies in patients not having indications for immediate surgical exploration. Patients were divided into two groups on the basis of open or laparoscopic exploration versus expectant observation. These authors reported a 7% incidence of occult injuries in the exploration group, 4% incidence of delayed presentation in the observation group, and a 17% incidence of occult diaphragmatic injury in the group with left thoracoabdominal penetrating injury.

Ch148-F06861.indd 1794

They concluded that invasive diagnostic methods, such as laparoscopy or thoracoscopy, should be considered at least in left-sided stab wounds of the lower chest. Whether such invasive diagnostic evaluation should become a standard can only be answered by prospective studies.

1. Blaivas M: Bedside emergency ultrasonographic diagnosis of diaphragmatic rupture in blunt abdominal trauma. Am J Emerg Med 22:601-604, 2004. 2. Leppaniemi A, Haapiainen R: Occult diaphragmatic injuries caused by stab wounds. J Trauma 55:646-650, 2003.

J. D. L. A. P.

1/21/2008 4:23:50 PM

Index

Note: Page numbers followed by b, f, and t indicate boxes, figures, and tables, respectively. A Abciximab, central neuraxial blockade and, 77 Abdomen, scaphoid, in congenital diaphragmatic hernia, 1406 Abdominal binder, in phrenic nerve and diaphragm motor point pacing, 1451, 1451f Abdominal computed tomography scanning, for lung cancer staging, 762 Abdominal disease, diaphragm elevation in, 1398 Abdominal incision, upper midline, 123-125, 124f-125f Ablative therapy with microwave ablation, 802-803 for non–small cell lung cancer, 796-803 with radiofrequency ablation, 796-801, 797f-800f, 799t, 800t with radiofrequency ablation and stereotactic radiosurgery, 802 for solitary brain metastasis, 820 with stereotactic radiosurgery, 801-802, 801f ABO blood compatibility, in lung transplantation, 664 Abscess of chest wall, tuberculous, 517, 518f lung. See Lung, abscess of. mediastinal, 1532, 1578-1579 Absent diaphragm sign, in traumatic diaphragmatic hernia, 1389 Acetylation, in carcinogenesis, 727, 727f Achalasia, video-assisted thoracic surgery for, 116-117 Acid aspiration syndrome, pneumonia in, 491-493, 492f Acid/base status, during one-lung ventilation, 54 Acid-fast tuberculous bacilli, 504, 505f Acidosis metabolic, from fluid therapy, 150 respiratory during one-lung ventilation, 54 in postoperative COPD patients, 608 Acquired immunodeficiency syndrome. See HIV/AIDS. Acquired restrictive thoracic dystrophy (ARTD), 1346, 1348-1349, 1348f-1349f Actinomycosis, 548 pleural, 1086 tracheoesophageal fistula in, 300 Activated protein C (APC) hemorrhage from, 149 for sepsis, 148-149 Acute respiratory distress syndrome (ARDS) in coccidioidomycosis, 543 fluid therapy in, 151, 152 in histoplasmosis, 533 after talc pleurodesis, 1049 A-delta nerve fibers, pain mediated by, 68 Adenocarcinoma fetal, 842 pseudomesotheliomatous, 731, 732, 1123 pulmonary, pathology of, 731-732, 731f scar, 734-735 Adenoid cystic carcinoma, 204 of bronchus, 703-705, 704f, 705t of trachea, 312-320 clinical presentation in, 312-313 diagnostic studies in, 313-314, 313f-314f epidemiology of, 312 histology of, 314, 315t, 316t treatment of, 314-319, 317-319, 317f-319f Adenoma bronchial. See Bronchial gland tumor(s). parathyroid. See Parathyroid tumors.

Adenomatoid cystic malformation, congenital, 466-468, 467f-468f, 1569-1572 clinical presentation in, 1570 diagnosis of, 466, 467f, 1570, 1571f, 1572f incidence of, 1570 management and surgical considerations in, 1570-1572 outcome in, 1572 prenatal treatment of, 467-468 Stocker’s classification of, 466, 466f, 1569 Adenomatous hyperplasia, atypical, 697, 733-734, 734f Adenopathy, mediastinal. See Mediastinal lymphadenopathy. Adenosine deaminase test, in tuberculous pleural effusion, 1074 Adenosquamous carcinoma, 735 Adenovirus encoding β-interferon, for malignant mesothelioma, 1135 Adjuvant medications, for perioperative pain management, 77-78 Adjuvant therapy for non–small cell lung cancer, 785-789, 786t-787t for pulmonary metastasis, 855 for small cell lung cancer, 835, 835t for thymoma, 1606-1607, 1607t Adolescents, tracheal size in, 190t Adrenal metastasis isolated management of, 820 stage IV non–small cell lung cancer with, 779 positron emission tomography specificity for, 436 symptoms of, 753 Adrenocorticotropic hormone, ectopic production of in carcinoid tumors, 702 in small cell lung cancer, 827 Adson test, in thoracic outlet syndrome, 1279, 1280f Advanced care planning, 823 Age interstitial lung disease and, 568 lung cancer and, 710, 710f in preoperative assessment, 9, 43, 43f pulmonary function testing reference values and, 29-30 small cell lung cancer and, 828, 837-838, 838t AIDS. See HIV/AIDS. Air alveologram, 419 Air bronchogram, 418-419, 419f Air leak, 160-161 in bronchopleural fistula, 58, 163 after bullous disease surgery, 650 continuous, 1151 definition of, 1150 expiratory, 1151 forced expiration, 1151 incidence of, 160, 1150 initial evaluation of, 1150-1151 inspiratory, 1151 after lobectomy, 885 after lung volume reduction surgery, 619 management of, 140, 160-161, 1149-1152 persistent, 160, 164 in pneumothorax, 642-643 post-traumatic, 1774, 1786 risk factors for, 1150 treatment of, 1152 without residual cavity, 172 in pneumothorax, 1099, 1100 provocative chest tube clamping in, 1152 RDS classification system for, 1151 recent literature on, 1151-1152

Air leak (Continued) risk factors for, 160 after segmentectomy, 888 size of, 1151 in tracheobronchial trauma, 1758 after video-assisted pulmonary resection, 980 Air pollution, lung cancer and, 715 Airway endobronchial stenting of, 239-240, 239f, 240f fire in, prevention of, 226-227, 227f, 232 inflammatory conditions of, 294-297 late postoperative complications of, 173-176, 174f-177f management of in laryngeal trauma, 1745, 1746f in tracheobronchial trauma, 1759-1760, 1759f in trauma, 1728, 1729f Myer-Cotton grading system for, 366, 366t and pulmonary artery, fistula between, 176 trauma to, 227-228 flexible bronchoscopy in, 91 location of, by mode of injury, 227-228, 227f in mediastinoscopy, 106 in one-lung ventilation with double-lumen tube, 51 tracheobronchial. See Tracheobronchial trauma. upper. See Trachea; Upper airway. Airway bypass, for emphysema, 623-626, 624f-626f Airway obstruction bronchoscopy in, 91, 94, 231-241 central. See Central airway obstruction. localization of, 326, 327b after lung transplantation, 680-682, 681f-682f refractory, after airway surgery, 228 in substernal goiter, 1664 in tuberculous lymph nodes, 514-515 upper flow-volume loops in, 31-32, 32f, 33f variable extrathoracic, 31, 32f variable intrathoracic, 31-32, 33f Airway pressure, reduction in, with intermittent diaphragm pacing, 1455 Airway surgery anesthesia for, 211-229 adjunctive therapies during, 216 agents for, 214-215 in endoscopic procedures, 217-221 historical note on, 211-212 neuromuscular blockers during, 215-216 postoperative complications after, 228 preoperative assessment in, 212-214, 214f ventilation modes during, 216-217, 217f, 217t complications of, 393-398 anastomotic management of, 395-397, 396f outcome after treatment of, 398 risk factors for, 394-395, 395f, 395t historical note on, 393 incidence of, 394, 394t laryngeal, 397-398 management of, 395-397 Albumin, coagulation and, 150 Albuterol, for chronic obstructive pulmonary disease, 606, 609 Alcohol withdrawal, postoperative, 143 Alexander type thoracoplasty, 1166-1168, 1166f-1168f Alfentanil, for airway surgery, 215 Allergic alveolitis, extrinsic, 577 Allergic bronchopulmonary aspergillosis, 534, 535 Allergy, metal, in pectus deformity repair, 1345 Allodynia, 68

1795

Index-F06861.indd 1795

1/25/2008 1:46:10 PM

1796

Index

Alloplastic materials, for chest wall stabilization, 1311 Almitrine, for hypoxemia during one-lung ventilation, 57 Alpha-adrenergic agonists, perioperative, for myocardial infarction prophylaxis, 142 Alpha2-agonists, epidural, for perioperative pain management, 78 Alveolar consolidation in community-acquired pneumonia, 483, 483f radiographic signs of, 418-419, 419f Alveolar pleural fistula. See Air leak. Alveolar pressure, 1004 Alveolar proteinosis, pulmonary, 65-66, 581, 581f Alveolitis, allergic, extrinsic, 577 Alveologram, air, 419 Amebiasis pleural, 1085-1086 pulmonary, 553t, 556t, 563 American Association for Thoracic Surgery, 6 American Board of Thoracic Surgery, 6 Amifostine, as radioprotectant, 807 Amine precursor uptake and decarboxylation (APUD) system, 737 Amiodarone for atrial fibrillation, 142, 153, 161 pulmonary toxicity of, 35 Ammonia gas, inhaled, 1741 Amphotericin B for aspergillosis, 453, 537, 539, 679 for candidal pneumonia, 548 for coccidioidomycosis, 541-542, 1092 for cryptococcosis, 1090 for histoplasmosis, 529, 533 for mucormycosis, 548 for sporotrichosis, 549 Ampicillin, for pleural nocardiosis, 1087 AMPLE history, in trauma, 1727 Amylase, in pleural effusion, 1045 Amyloidosis, tracheobronchial, 210, 210f, 296 Amyotrophic lateral sclerosis, diaphragm motor point pacing in, 1453-1454 Anaerobic pneumonia, 481 Analgesia epidural complications of, 161-162 postoperative somnolence from, 161-162 thoracic, perioperative, 75-77, 76f patient-controlled, for postoperative pain, 71 postoperative, 44 for thoracic surgery, 71-79. See also Pain management, perioperative. Analgesic agents, pain pathway targets of, 69, 69f Anaphylaxis, passive, in hydatid disease, 558 Anastomosis atrial, in sequential bilateral lung transplantation, 670, 671f bronchial. See Bronchial anastomosis. bronchopulmonary, 444 laryngotracheal, in idiopathic laryngotracheal stenosis, 273, 274f pericardial conduit, for pulmonary artery reconstruction, 917 pulmonary artery sling, 254 segmental resection and for high tracheoesophageal fistula, 304-305, 305f for postintubation stenosis, 262-264 for postintubation tracheomalacia, 287 in subglottic region, mini-tracheostomy for, 382 thyrotracheal, subglottic resection with, 355f, 358f, 359, 362f, 369-370, 369f tracheobronchial. See Tracheobronchial anastomosis. Anastomotic complications after airway surgery management of, 395-397, 396f outcome after treatment of, 398 risk factors for, 394-395, 395f, 395t after lung transplantation, 677 Anastomotic dehiscence or stenosis after lung transplantation, 677, 681-682, 681f-682f after sleeve resection and bronchoplasty, 906 after superior vena cava reconstruction, 1694

Index-F06861.indd 1796

Anastomotic dehiscence or stenosis (Continued) after tracheal anastomosis, 380-381, 381t, 394t, 396 after tracheobronchial repair, 1765 Anastomotic failure, after tracheal anastomosis, 394t, 396-397 Anastomotic granulation tissue, after tracheal anastomosis, 380, 381t, 394t, 395-397, 396f Anastomotic leak, esophagogastric, 179, 179f Anastomotic tension, release maneuvers to reduce. See Release maneuvers. Anatomy. See also specific component. of chest wall and sternum, 1197-1208 of diaphragm, 1367-1369, 1368f of lung, 401-414 of mediastinum, 1471-1476, 1472f-1475f of pleura, 1001-1003, 1002f-1003f, 1008, 1121 of upper airway, 189-195, 353, 354f Ancylostomiasis, 552t, 555t, 564 Andres’ thoracomyoplasty, 1163-1164, 1163f, 1164t Anesthesia, 39-66. See also specific procedures and disorders. for airway surgery, 211-229. See also Airway surgery, anesthesia for. for complex operations, 58-59 for esophageal surgery, 60-61 for flexible bronchoscopy, 93, 220, 220f history of, 3, 39-40 intraoperative management of monitoring for, 45-47 positioning and, 47-49, 53 for laryngoscopy, 82, 84-85 for laser surgery, 225-227 and lung separation, 49-57. See also Ventilation, one-lung. for lung transplantation, 62-64 for lung volume reduction surgery, 61-62 for mediastinal mass, 59-60, 59f for mediastinoscopy, 57-58 neuraxial, 77 for one-lung ventilation, 54 for perioperative pain management, 71-75, 72f-75f postoperative analgesia considerations in, 44 premedication considerations in, 44 preoperative assessment for, 40-45, 40t, 41f-43f, 45f of comorbidities, 42-44, 43f, 44t final, 44-45, 45f, 45t principles of, 40-41 of pulmonary function, 41-42, 41f-42f for rigid bronchoscopy, 95, 97, 218-219 technique of, 49 for thymectomy, 60 topical, for indirect laryngoscopy, 81 for tracheal resection, 223 for tracheostomy, 221 for whole lung lavage, 65-66 Anesthetic agents intravenous, 215 opioid, 215 volatile, 214-215 Aneurysm false, of pulmonary artery, 65 mycotic, of ascending aorta, 1478f Rasmussen’s, 512 Aneurysmal bone cyst, of chest wall, 1218 Angiogenesis. See also Antiangiogenic agents. in carcinogenesis, 722-723, 819 Angiography computed tomography, in massive hemoptysis, 447 peripheral, in thoracic outlet syndrome, 1285, 1286f pulmonary in bullous disease, 640 in carinal resection, 384, 384f in chronic thromboembolic pulmonary hypertension, 656, 656f in trauma, 1731t, 1733, 1734f Angiosarcoma, mediastinal, 1657 Angiotensin-converting enzyme (ACE) inhibitors, for bacterial aspiration pneumonia, 493 Ankylosing spondylitis, 1207

Ann Arbor staging system for lymphoma, 1625, 1625t Anorexia, in lung cancer, 752 Anterior commissure laryngoscope, 84f, 85 Antiangiogenic agents for lung cancer, 722 for malignant mesothelioma, 1134-1135 for non–small cell lung cancer, 819 for small cell lung cancer, 839 Antiarrhythmic agents, prophylactic, for postoperative arrhythmias, 15, 44 Antibiotics for acute bronchitis, 488 for acute exacerbation of chronic obstructive pulmonary disease, 489 for acute necrotizing mediastinitis, 1523 for bacterial aspiration pneumonia, 493 for bronchiectasis, 475 for empyema, 1064, 1065t for endocarditis prophylaxis, 140, 140t for hospital-acquired and ventilator-associated pneumonia, 490 for lung abscess, 495-496 for massive hemoptysis, 448 for pleural actinomycosis, 1086 for pleural nocardiosis, 1087 for pneumococcal pneumonia, 480 for pneumonia, 161 for pneumonia in immunocompromised host, 590-591 for poststernotomy mediastinitis, 1269 preoperative, 44 for retained hemothorax, 1771-1772 for sepsis, 146 Anticholinergic agents, for chronic obstructive pulmonary disease, 606 Anticholinesterase agents, for myasthenia gravis, 1550 Anticoagulation in atrial fibrillation, 184 central neuraxial blockade and, 77 in perioperative period, 15, 143 in small cell lung cancer, 838-839 Antifungal agents for blastomycosis, 545 for coccidioidomycosis, 541-542 Anti–interleukin-2 receptor antagonists, after lung transplantation, 676 Antilymphocytes, after lung transplantation, 676 Antimicrobial therapy, for specific pathogens, 587t Antioxidants lung cancer and, 716 in pulmonary flush solution for transplantation, 666 Antireflux precautions, in anesthesia for esophageal surgery, 60-61 Antireflux surgery, thoracoscopic, 117 Antisialagogue, preoperative, 44 Antithrombotic therapy, perioperative planning for patient on, 213 Antithymphocytes, after lung transplantation, 676 α1-Antitrypsin deficiency bullous disease and, 635 chronic obstructive pulmonary disease in, 605 lung volume reduction surgery and, 619 Antituberculous agents, 507, 1075, 1088 Antoni type A or B regions, in neurilemmoma, 1635, 1635f Aorta ascending malposed, 246, 247f mycotic aneurysm of, 1478f circumflex, 249 descending cross-clamping of, for penetrating thoracic trauma, 1785 imaging of, 1482 injury to blunt, 1733, 1734f, 1735 in mediastinoscopy, 106 penetrating, 1781 thoracic, imaging of, 1479f-1480f, 1480 tumor invasion of, extended pulmonary resection for, 946, 950, 950f

1/25/2008 1:46:11 PM

Index

Aortic arch anatomic relationship to trachea, 194, 194f congenital anomalies of, 242-255. See also Vascular rings. development of, 243-244, 243f double, 243f, 244, 244f, 247t, 249-251, 250f, 1657, 1657f imaging of, 1479f, 1480 left, with aberrant right subclavian artery, 245-246, 246f right, with left ligamentum, 244, 244f, 245f, 247t, 248f, 251, 252f and mirror-image branching, 244, 245f and retroesophageal left subclavian artery, 244, 244f Aortic hiatus, 1380 Aortic nipple, 1482 Aortic opening, 1425 Aortobronchial fistula, massive hemoptysis in, 447 Aortopulmonary window, imaging of, 1480f, 1481 Aphonia, in laryngeal trauma, 1743 Apical segmentectomy, 888f-889f, 889 Apical stapling, for pneumothorax, 1101 Apicolysis, in thoracoplasty, 1166, 1168, 1168f Arcuate ligament, 1368-1369 Argon plasma coagulation for airway obstruction, 234-235, 341, 341f probes for, 341f Army-Navy retractors, for thymectomy, 1717, 1717f Arndt wire-guided endobronchial blocker, 51, 52f Arrhythmias, postoperative management of, 153-154 prophylaxis against, 15, 44, 141-142 risk factors for, 14-15 Arterial blood gases in malignant mesothelioma, 1187 postoperative monitoring of, 137 in trauma, 1730-1731 Arterial embolization, for massive hemoptysis, 451-452, 452f Arterial partial pressure of carbon dioxide (PaCO2), preoperative assessment of, 42 Arterial puncture, with internal jugular vein cannulation, 47 Arteriography bronchial, in massive hemoptysis, 448 pulmonary, in fibrosing mediastinitis, 1535 Arteriopexy, innominate, 251, 253, 253f Arteriovenous fistula cardiovascular, post-traumatic, 1786 of internal thoracic vessels, after sternotomy, 1253 massive hemoptysis in, 446 Arteriovenous malformations, pulmonary, 471 Arthritis in interstitial lung disease, 568 rheumatoid, 57-58, 580 septic, of sternoclavicular joint, 1217, 1217f Arytenoid adduction, for vocal fold paralysis, 309-310 Arytenoid cartilages, anatomic relationships of, 257, 258f Arytenoid injury, 1742, 1748-1749 Arytenoidectomy, for vocal fold paralysis, 310, 311f Asbestos exposure lung cancer and, 714-715 malignant mesothelioma and, 1126 Asbestosis, 577, 578f, 1020 Asbestos-related pleural disease benign, 1019-1022, 1020f-1022f, 1123 malignant, 1028-1031, 1029f-1030f Ascariasis, 551t, 554t, 564 Askin’s tumor, 1295, 1658 Aspergilloma, 534, 535-536, 536f Aspergillosis, 534-538 bronchiectasis in, 473 bronchopulmonary, allergic, 534, 535 classification of, 535 clinical features of, 536-537 diagnosis of, 537 epidemiology of, 535, 535f historical note on, 534-535 in immunocompromised host, 593-594 incidence of, 535 infecting lung cavity, 511-512, 511f

Index-F06861.indd 1797

Aspergillosis (Continued) invasive pulmonary, 535, 538-539 after lung transplantation, 679, 680f massive hemoptysis in, 445, 453 pathogenesis of, 535-536, 536f pleural, 539, 1090 pleuropulmonary, 1165, 1165f predisposing factors for, 535 treatment of, 537-538 Aspiration after airway surgery, 228 chronic, tracheostomy in, 346 fine needle. See Fine needle aspiration. gastric acid, pneumonia from, 491-493, 492f in laryngeal trauma, 1743 lung abscess from, 494 needle transbronchial of bronchogenic cyst, 1584 in lung cancer staging, 761 with trocar-suction device, for hydatid disease, 561, 562f-563f percutaneous, for bronchogenic cyst, 1584 postoperative, 162 in vocal fold paralysis, 308 Aspiration pneumonia, 479, 479t bacterial, 493 gastric acid, 491-493, 492f Aspirin preoperative use of, 14, 44 in small cell lung cancer, 839 Asthma bronchoprovocation testing in, 35-36 exercise-induced, testing for, 36 flexible bronchoscopy in patient with, 89 pulmonary function testing pattern in, 34 Atelectasis, 420-423 diaphragm elevation in, 1396, 1397f with lateral position, 48 lobar, 421-422, 421f-422f postoperative, 161, 165 radiographic signs of, 421-422, 421f-422f rounded, 1020-1022, 1022f segmental, 422, 422f after sleeve resection, 905-906 subsegmental (discoid, plate), 422, 422f total, 422-423, 423f Atenolol, during airway surgery, 216 Atlantoaxial subluxation, in rheumatoid arthritis, 57-58 Atracuronium, during airway surgery, 216 Atrial anastomosis, in sequential bilateral lung transplantation, 670, 671f Atrial fibrillation postoperative, 141-142, 153-154, 161, 184 video-assisted thoracic surgery for, 117 Atrial natriuretic peptide, secretion of, in lung cancer, 752 Atrium, left, tumor invasion of, extended pulmonary resection for, 950, 951f Atrostim phrenic nerve pacing system, 1446-1447 Autoimmune diseases, thymoma and, 1595, 1596t Autoimmune response, in myasthenia gravis, 1550 Avery Mark IV Breathing Pacemaker System, 1447 Axillary lymph nodes, imaging of, 1228 Axonotmesis, 1460 Azathioprine, after lung transplantation, 675 Azole antifungal agents, for coccidioidomycosis, 541 Azyesophageal recess, 1480f, 1483 Azygos lobe, 406 Azygos vein anatomic relationship to trachea, 194, 194f anatomy of, 405, 405f imaging of, 1480f, 1482 injury to, in mediastinoscopy, 106 for pulmonary artery reconstruction, 916 Azygos venous system, 1685

B Bacille Calmette-Guérin (BCG) vaccine, 501 Back pain, in lung cancer, 752 Bacterial aspiration pneumonia, 493

1797

Bacterial infection after lung transplantation, 678-679 pulmonary, 478-498 Bacterial pneumonia in immunocompromised host, 589-591 after lung transplantation, 678 Balloon tamponade, for massive hemoptysis, 450 BALT (bronchus-associated lymphoid tissue), pulmonary lymphoma arising from, 848, 1630-1631 Band sign, in traumatic diaphragmatic hernia, 1389 Barbiturates, for airway surgery, 215 Barium esophagogram in substernal goiter, 1670 in tracheoesophageal fistula, 301, 302, 302f in vascular rings, 247-248 Barometric pressure, ambient, 1004 Barotrauma, with jet ventilation, 219 Barrel chest, 604 Barrett’s esophagus, tracheoesophageal fistula in, 301, 301f Base deficit, in hypovolemic shock, 1727 Battery ingestion, tracheoesophageal fistula from, 301 BB-10901, for small cell lung cancer, 839 B-cell lymphoma large, mediastinal, 1628-1629 pulmonary, 694, 848, 1630-1631 Bcl-2 family, in carcinogenesis, 723, 723t BCL2 inhibitors, for small cell lung cancer, 840 Bec2 vaccine, for small cell lung cancer, 838 Beclomethasone, preoperative, for chronic obstructive pulmonary disease, 607 Bedside procedures, in trauma, 1728-1729, 1729f-1731f Belsey-Mark IV fundoplication, thoracoscopic, 117 Benign neoplasms of chest wall, 1231, 1233f bone, 1218, 1219f soft tissue, 1221-1223, 1223f-1226f types of, 1292-1294, 1293f of lung, 691-698 classification of, 691, 692b diagnosis of, 697 historical note on, 691 management of, 698 spectrum and frequency of, 691-692, 692t pleural, 1023-1026, 1023f-1026f, 1121-1123, 1122f of upper airway, 204, 316t Benzodiazepines for airway surgery, 215 for flexible bronchoscopy, 220 Beryllium exposure, 578 Beta blockers, perioperative during airway surgery, 216 for atrial fibrillation, 141, 153-154 for myocardial infarction, 142 in patient with cardiovascular risk factors, 14 Beta-agonists, preoperative, for chronic obstructive pulmonary disease, 606 Beta-carotene, lung cancer and, 716 Bevacizumab with carboplatin and paclitaxel, 789 for lung cancer, 722 for malignant mesothelioma, 1134 for non–small cell lung cancer, 819 for small cell lung cancer, 839 Bilobectomy of middle and lower lobes, 883 for non–small cell lung cancer, 768 of upper and lower lobes, 883 Biochemical tests in empyema, 1061-1062, 1062t in pleural effusion, 1044-1045 Bioimpedance, thoracic, for cardiac output measurement, 158 Biologic implants, for chest wall stabilization, 1310-1312, 1310b, 1311f Biomarkers for lung cancer screening, 749 for lung cancer staging, 762-763 in malignant mesothelioma, 1127 in neuroblastoma, 1638

1/25/2008 1:46:11 PM

1798

Index

Biomarkers (Continued) in non–small cell lung cancer postresection follow-up, 794-795 in small cell lung cancer, 828 Biopsy bone marrow, in small cell lung cancer, 827 of chest wall neoplasms/tumors, 1306-1307 excisional (surgical) of benign lung tumor, 698 of solitary pulmonary nodule, 458-459 fine needle aspiration. See Fine needle aspiration. lung. See Lung biopsy; Transbronchial biopsy. of mediastinal lymphoma, 1623-1624 percutaneous core needle of mediastinal lymphoma, 1623-1624 of mediastinal mass, 1514-1515 pleural in malignant pleural effusion, 1140 in pericardial effusion, 1036-1037 in tuberculous pleural effusion, 1074 Biopsy forceps, 92, 92f, 96f, 100, 332, 334f Bioptome biopsy, 1037 Bisphosphonate therapy, for bone metastasis, 820 Bjõrk thoracoplasty, 1162, 1162f Blast injury, pathophysiology of, 1724-1725 Blastoma, 735-736, 841-842. See also Neuroblastoma. Blastomycosis, 542-545, 543f-544f, 1092 Blebs definition of, 632 radiographic signs of, 427 resection of, 1101 in spontaneous pneumothorax, 1096-1097 surgical management of, anesthesia for, 58-59 Bleeding. See Hemorrhage. Bleomycin pleurodesis, 1049, 1143 Blood fluke infection, 551t, 554t, 564 Blood storage lesion, 153 Blood transfusion after extrapleural pneumonectomy, 1191 hazards of, 153, 153t for hemorrhagic shock, 1726-1727, 1726t leukoreduction in, 153 and minimum acceptable hemoglobin, 152 and outcomes in ICU, 152-153 Bochdalek, foramen of, 1425 Bochdalek hernia, 1382-1383, 1385f chest radiography in, 1406f embryogenesis of, 1402 imaging of, 1499-1500, 1501f pathology of, 1403 Body plethysmography in airway obstruction, 23-24 for lung volume measurements, 22-23, 23f-24f Body temperature during anesthesia, 45 during one-lung ventilation, 57 Bone cyst, aneurysmal, of chest wall, 1218 Bone grafts, for chest wall stabilization, 1310-1311, 1311f Bone islands, 1218, 1219f Bone marrow biopsy, in small cell lung cancer, 827 Bone marrow transplantation, invasive pulmonary aspergillosis after, 538, 539 Bone metastasis bisphosphonate therapy for, 820 palliative care for, 824t positron emission tomography specificity for, 436 scanning for, 762, 827 symptoms of, 753 Bone tumors, of chest wall, 1218-1220 benign, 1218, 1219f malignant, 1218-1220, 1219f-1223f Bortezomib, for lung cancer, 724 Boston Scientific (BOS) electrode, for radiofrequency ablation, 797, 797f Boston suspension device, 86, 86f Botulinum toxin, for vocal fold paralysis, 310 Bougies, esophageal, 332, 333f Bovie pads, for radiofrequency ablation, 796, 797f Boyle’s law, 22 Brachial neuritis, 1230 Brachial plexopathy, poststernotomy, 1254

Index-F06861.indd 1798

Brachial plexus anatomy of, 1202, 1202f compression of, and thoracic outlet syndrome, 1275, 1278f decompression of, 1351-1354, 1352f-1354f dissection of, in superior sulcus tumors, 928-929, 928f-929f, 936-937, 937f imaging of, 1228-1230, 1229f intraoperative injury to, 48 palsy of, phrenic nerve transfer in, 1462-1463 Brachiocephalic artery. See Innominate artery. Brachytherapy endobronchial, 237-239, 238t intraoperative, in sublobar resection, 870f, 872-873, 872f, 873f, 877 palliative, for non–small cell lung cancer, 811 Brain metastasis palliative care for, 824t positron emission tomography specificity for, 437 prophylactic cranial radiotherapy for, 833 scanning for, 762 solitary management of, 819-820 stage IV non–small cell lung cancer with, 779 symptoms of, 753 Breast asymmetry or growth retardation of, after pectus excavatum repair, 1342-1343, 1343f reconstruction of customized prosthesis for, 1313-1314, 1313f for Poland’s syndrome, 1337-1338, 1338f transverse rectus abdominis musculocutaneous flap in, 1320, 1320f-1322f Breast cancer malignant pleural effusion in, 1145 after mediastinal radiotherapy, 1627-1628 pulmonary metastasis of, 859f, 860t, 861-862 Breathing. See also Ventilation. in trauma, 1728 work of, with tracheostomy, 350, 350f, 351f Breathing bag sign, in tracheoesophageal fistula, 302 Bronchial adenoma. See Bronchial gland tumor(s). Bronchial anastomosis anastomotic stenosis with, 906 covering of, 901 preservation techniques for, 680-681 problems with, 680f-682f, 681-682 in sequential bilateral lung transplantation, 669-670, 670f in single-lung transplantation, 669-670, 670f in sleeve lobectomy, 900-901, 900b, 901b Bronchial arteriography, in massive hemoptysis, 448 Bronchial artery(ies) anatomy of, 413-414, 413f, 444, 896-897, 896f of anomalous origin, massive hemoptysis and, 452 embolization of, for massive hemoptysis, 451-452, 452f injury to, in mediastinoscopy, 104-105 patterns of variation of, 192f and tracheal blood supply, 190f, 191-192, 191f Bronchial brushes, 92, 92f Bronchial circulation massive hemoptysis arising from, 444 and pulmonary circulation, anastomotic connections between, 897 Bronchial gland tumor(s), 699-707 adenoid cystic carcinoma as, 703-705, 704f, 705t carcinoid. See Carcinoid tumor, bronchial. historical note on, 699 mucoepidermoid carcinoma as, 705-706, 706f, 706t mucous gland carcinoma as, 706 Bronchial sleeve resection, 903-904 Bronchial stenosis, late, after tracheobronchial trauma, 1759 Bronchial venous drainage, 414, 896-897, 896f Bronchial-associated lymphoid tumors (BALTs), 694-695, 695f Bronchiectasis, 473-477 classification of, 473 clinical presentation in, 474 conservative therapy for, 475 cystic, 427

Bronchiectasis (Continued) definition of, 473 diagnostic studies in, 474-475, 474f-475f etiology of, 473-474 hemodynamic considerations in, 474 massive hemoptysis in, 445, 474, 476-477 pulmonary function testing in, 35 surgical management of, 475-477, 476t in tuberculosis, 514, 515f Bronchiolitis, pulmonary function testing in, 35 Bronchiolitis obliterans, after lung transplantation, 178 Bronchiolitis obliterans organizing pneumonia, 575 Bronchiolitis obliterans syndrome in children, 673 classification of, 685t after heart-lung transplantation, 674 after lung transplantation, 684-686, 685f primary graft dysfunction and, 678, 685 retransplantation for, 674 risk factors for, 685 treatment of, 686 Bronchioloalveolar carcinoma aggressiveness of, 459, 459f nonmucinous, 732, 733f pathology of, 732-733, 732f, 733f relationship to atypical adenomatous hyperplasia, 733-734, 734f with sclerosis, 733 Bronchitis acute, 478-479, 488 chronic, 489, 603. See also Chronic obstructive pulmonary disease (COPD). lymphocytic, bronchiolitis obliterans syndrome and, 685 radiation, from endobronchial brachytherapy, 238 Bronchoalveolar lavage in bacterial aspiration pneumonia, 493 in bronchiolitis obliterans syndrome, 686 in carcinoid tumors, 702 in community-acquired pneumonia, 485 in fungal infections, 526 in interstitial lung disease, 572, 597 after lung transplantation, 676 in pulmonary infections in immunocompromised host, 588 Bronchodilator response, in pulmonary function testing, 32-33 Bronchodilators for bronchiectasis, 475 for chronic obstructive pulmonary disease during exacerbation, 489, 609 postoperative, 609 preoperative, 606, 614 Bronchoesophageal fistula, in tuberculosis, 514 Bronchogenic cyst, 470-471, 470f, 1581-1584 characteristics of, 1511, 1513f clinical presentation in, 1564 diagnosis of, 1582-1583, 1582f, 1583f imaging of, 1495-1496, 1496f-1497f, 1563f, 1564, 1564f infected, 1582 magnetic resonance imaging of, 419f management of, 1564-1565, 1583-1584 open resection of, 1565, 1565f pathology of, 1563-1564, 1564f, 1583 pediatric, 1563-1565, 1563f-1565f, 1563t, 1658, 1659f radiographic signs of, 425, 425f thoracoscopic excision of, 1584, 1701 Bronchogenic tumor, superior sulcus. See Superior sulcus tumors. Bronchogram, air, 418-419, 419f Bronchography, 196, 197f in bronchiectasis, 474f, 475 Broncholithiasis, in histoplasmosis, 532-533, 532f Bronchoplasty. See also Tracheobronchoplasty. flap, 904-905, 904f sleeve. See Sleeve resection, and bronchoplasty. sutures for, 900-901, 901f wedge, 904-905, 904f Bronchopleural fistula. See also Air leak. anesthesia for, 58 clinical presentation in, 1069

1/25/2008 1:46:11 PM

Index

Bronchopleural fistula (Continued) computed tomography in, 1016, 1017f definition of, 1150 diagnosis of, 1069-1070 early, 163 empyema with, 1058, 1059f, 1067-1068, 1069-1071 flexible bronchoscopy in, 91 incidence of, 163, 1069 late postpneumonectomy, 167, 169-171, 169f-171f with residual pleural cavity, 171-172, 171f-173f management of, 171-172, 171f-173f, 1070 pathogenesis of, 1069 post-traumatic, 1786 risk factors for, 163, 171 after tracheobronchial anastomosis, 390 in tuberculosis, 509, 519-520, 524 in tuberculous empyema, 1076, 1076f, 1089, 1090f-1091f Bronchopneumonia, 483, 483f Bronchoprovocation testing, in asthma, 35-36 Bronchopulmonary anastomosis, 444 Bronchopulmonary aspergillosis, allergic, 534, 535 Bronchopulmonary foregut malformation, congenital, 1569-1570 Bronchopulmonary segments, anatomy of, 401-403, 402f Bronchopulmonary sequestration. See Pulmonary sequestration. Bronchopulmonary shunt, in bronchiectasis, 474 Bronchopulmonary stents, for emphysema, 623-626, 624f-626f Bronchoscope flexible, 92, 92f rigid, 96f, 100, 330, 330f, 332, 333f suction ports on, 447, 448f Bronchoscopy for airway bypass in emphysema, 623-626, 624f-626f in airway obstruction, 231-241 in carcinoid tumors, 702 in discriminating benign versus malignant mass, 458 dynamic, in tracheomalacia, 285-286, 287f emergency, in postintubation stenosis, 261 in fibrothorax, 1174 flexible, 89-93 anesthesia for, 220, 220f complications of, 93 for double-lumen endobronchial tube one-lung ventilation, 49-51, 50f-51f endobronchial ultrasound with, 93 equipment for, 92-93, 92f, 93t indications for, 89-92, 90t, 219-220 limitations of, 93 technique of, 93 fluorescence, 749, 761 historical note on, 211-212 in hydatid disease, 559-560 in idiopathic laryngotracheal stenosis, 271, 273f, 276 in interstitial lung disease, 572, 597 in lobectomy, 880 in lung abscess, 495 in lung cancer, 749, 760-761 after lung transplantation, 676 in lung volume reduction surgery, 62 in lung volume reduction with one-way valves, 626-630, 627f-630f, 629t massive hemoptysis during, 446 in pleural disease, 1041 in pleural effusion, 1048 in postintubation stenosis, 261 for postoperative respiratory care, 139 in postpneumonectomy bronchopleural fistula, 169, 169f in pulmonary infections in immunocompromised host, 588 rigid, 94-101 in airway obstruction, 231-232 anesthesia for, 95, 97, 218-219

Index-F06861.indd 1799

Bronchoscopy (Continued) rigid (Continued) in benign endobronchial tumor, 698 in central airway obstruction advantages of, 329 diagnostic, 328, 328b for dilation, 331-335, 333f-334f interventional, 327b, 329-330, 329b, 330f, 330t for recanalization, 336-337 complications of, 100-101, 341 equipment for, 96f, 100, 329-330, 329b, 330f historical note on, 217-218, 218f indications for, 94-95, 94t limitations of, 100 in massive hemoptysis, 447-448, 448f, 449 methods to intubate airway with, 330, 330t patient positioning for, 219 preoperative, 377-378 technique of, 97-100, 98f-99f in tracheal tumors, 314-315 ventilation during, 95-97, 96f, 219 in sarcoidosis, 576 in tracheal pathology, 222 in tracheal tumors, 313, 313f, 314f in tracheobronchial amyloidosis, 296 in tracheobronchial trauma, 1759, 1759f in tracheobronchomegaly syndrome, 279f, 281 in vascular rings, 248-249 virtual, 101, 313, 313f Bronchospasm, exercise-induced, testing for, 36 Bronchostenosis, in tuberculosis, 515, 516f Bronchovascular fistula massive hemoptysis in, 447 after sleeve resection, 906 Bronchus(i). See also Tracheobronchial entries. anatomy of, 1756 blockade of, for one-lung ventilation, 51-52, 52f-53f blood supply of, 896-897, 896b, 896f dissection of, in pneumonectomy, 867-868, 867f endoscopic anatomy of, 233f left anatomy of, 405-406, 405f-406f lower lobe of, 407-408 syndrome of, in tuberculosis, 509, 510f upper lobe of, 407 lymphatic drainage of, 898 management of, in lobectomy, 881 repair of, in postpneumonectomy bronchopleural fistula, 169-170, 170f right anatomy of, 404-405, 404f lower lobe of, 407 middle lobe of, 406-407 upper lobe of, 406 rupture of, traumatic, 1731, 1732f segmental, 407-408 trauma to. See Tracheobronchial trauma. Bronchus intermedius, anatomy of, 895, 895f Bronchus-associated lymphoid tissue (BALT), pulmonary lymphoma arising from, 848, 1630-1631 Brugia malayi, 552t, 555t, 565 Brush/brushing bronchial, 92, 92f pleural, 1037 protected specimen, in community-acquired pneumonia, 485 Bucket handle movement, of rib, 1377 Bullae causes of, 635 classification of, 1097 communicating versus noncommunicating, 642 definition of, 632 giant classification of, 632, 632t-633t definition of, 632 ventilation and perfusion of, 635 infected, 644 pneumothorax versus, 642, 643f in spontaneous pneumothorax, 1097, 1103 Bullectomy, 634-636, 635f-638f by incision and plication, 645, 645f

1799

Bullectomy (Continued) outcomes of open, 650-651 thoracoscopic, 651 reoccurrence after, 651 stapled open, 645, 646f thoracoscopic, 645-646, 647f, 648f thoracoscopic, 645-646, 647f, 648f Bullet injury, 1725 Bulloscopy, 648 Bullous disease, 631-652 definition of terms in, 632-634 natural history of, 636, 636f, 637f pathophysiology of, 634-635 pneumothorax in, 637f, 639, 642-643 preoperative assessment of clinical presentation in, 637-638, 637t, 638t imaging in, 639-640, 640f-641f pulmonary function testing in, 638-639 radiographic signs of, 427, 427f surgical management of air leak after, 650 anesthesia for, 58-59 bullectomy in, 644-646, 645f-648f bulloscopy in, 648 choice of procedure for, 649 contraindications to, 643 endocavitary drainage in, 646, 648, 649f, 651 history of, 631-632 indications for, 636-637, 642 lung cancer and, 644 median sternotomy in, 649 operative outcomes in, 649-651 smoking and, 643-644 Bupivacaine, for paravertebral nerve block, 74-75 Burkholderia cepacia, and lung transplantation in cystic fibrosis, 678 Burns. See Caustic injury. Burrow’s normal reference values, 29

C C nerve fibers, pain mediated by, 68 Cachexia, in lung cancer, 752 Calcification in benign tumors, 697 diffuse, 425 in fibrothorax, 1172, 1173f focal, 425 in hamartoma, 693 in histoplasmosis, 529 in hydatid disease, 557 pericardial, 1541, 1541f pleural, 1019, 1019f types of, in benign versus malignant lesions, 424, 424f Calcineurin inhibitor, after lung transplantation, 675 Calcium, for postoperative hypocalcemia, 1683 Calcium channel blockers for atrial fibrillation, 142, 161 perioperative, for myocardial infarction prophylaxis, 142 Canada, training and accreditation in thoracic surgery in, 6-7 Cancer. See also specific types and sites. extrathoracic, late thoracic complications of, 182 after lung transplantation, 682-683, 683f metastasis of. See Metastatic disease. mortality rates from, 708, 709f, 710f in plombage space, 509 pneumothorax in, 1105 Candidiasis, 548 Capnothorax, 1450 Carbon dioxide pressure end-tidal, during one-lung ventilation, 46 partial, 1005, 1005t Carbon dioxide rebreathing, partial, for cardiac output measurement, 157-158 Carbon monoxide, diffusing capacity for. See Diffusing capacity for carbon monoxide (DLCO).

1/25/2008 1:46:11 PM

1800

Index

Carboplatin in combination therapy, versus cisplatin-containing regimen, 788-789 for malignant mesothelioma, 1130 with paclitaxel, 786, 788, 814, 815-816 with paclitaxel and bevacizumab, 789 for small cell lung cancer, 828, 829 Carboxyhemoglobin adjustment, of diffusing capacity for carbon monoxide (DLCO), 25 Carcinoembryonic antigen (CEA) in pleural effusion, 1045 in small cell lung cancer, 828 Carcinogenesis, 718-727 angiogenesis in, 722-723 Bcl-2 family in, 723, 723t CDKN2A-RB1 pathway in, 720 epidermal growth factor receptor in, 721-722 epigenetics in, 725-727, 726f-727f genomics and proteomics in, 724-725, 724f multistep nature of, 718 Myc family in, 721 nuclear factor KB in, 723-724 Ras family in, 721 TP53 mutations in, 718-720, 719f, 719t, 720t Carcinoid syndrome, 701-702 Carcinoid tumor bronchial, 699-703 atypical, 699-700, 701f, 703, 738, 738f classic, 737-738, 738f clinical presentation in, 701-702, 701t diagnosis of, 702 epidemiology of, 701 pathology of, 699-700, 700f-701f peptide hormones produced by, 699, 700t results of, 703, 703t treatment of, 702-703 massive hemoptysis in, 446 tracheal, 204, 206f-207f Carcinosarcoma, pulmonary pathology of, 735-736, 736f primary, 842-843 Cardiac arrest, emergency thoracotomy for, 1783 Cardiac defects, congenital, associated with ectopia cordis, 1239, 1240-1241, 1241t Cardiac injury pectus deformity repair and, 1340 penetrating, 1780-1781, 1785-1786 Cardiac output decreased, dobutamine for, 148 measurement of, pulmonary artery catheter for alternatives to, 157-158 in critically ill patient, 157 during one-lung ventilation, 54 Cardiac rhythm management device (CRMD), postoperative care in patient with, 142 Cardiac risk factors, perioperative, 142, 142b Cardiac silhouette, enlarged, in pericardial effusion, 1543, 1543f Cardiac surgery complications of, 658 late thoracic complications of, 182, 183f phrenic nerve injury in, 1460-1461 Cardiac symptoms, in diaphragmatic eventration, 1435 Cardiac tamponade acute, 1543, 1543f diagnosis of, 1543-1544, 1543f-1544f, 1780 management of, 1544-1545 regional, 1544 subacute, 1543-1544 Cardiac tuberculosis, 515 Cardiomyopathy, restrictive, versus constrictive pericarditis, 1541-1542, 1542t Cardiophrenic angle mass, Morgagni hernia as, 1384, 1387f Cardiopulmonary arrest, 1729 Cardiopulmonary bypass in anterior mediastinal mass surgery, 60 carinal resection and, 385 disadvantages of, 63 in lung transplantation, 63 in pulmonary artery reconstruction, 913, 919 in pulmonary artery sling anastomosis, 254

Index-F06861.indd 1800

Cardiopulmonary bypass (Continued) in sequential bilateral lung transplantation, 670-671 Cardiopulmonary exercise testing, 26-28 clinical utility of, 36-38, 36f-37f description of, 26-27, 27f in interstitial lung disease, 572 outcome of, exercise protocol and, 27 in preoperative assessment, 42 safety issues in, 28 Cardiorespiratory monitoring, postoperative, 137, 137t Cardiovascular disease massive hemoptysis in, 446-447 after mediastinal radiotherapy, 1627 Cardiovascular status, preoperative assessment of, 13-15, 14b, 15f, 43-44, 43f for airway surgery, 212-213 for lung volume reduction surgery, 617 Cardioversion, perioperative, for atrial fibrillation, 154 Carina anatomy of, 193 injury to, surgical management of, 1763-1764 non–small cell lung cancer tumors proximal to, 775, 777 transpericardial exposure of, 1762, 1764f Carinal pneumonectomy left, 388-390, 389f for non–small cell lung cancer invading trachea, 321, 322 right, 387-388, 387f-388f Carinal resection, 225, 225f, 226f, 383-391 anesthesia for, 225, 225f, 226f, 384-385 contraindications to, 384 historical note on, 383 indications for, 384 with lobar resection, 388, 388f for lung cancer invading trachea, 321-322, 953-954 postoperative care in, 389-390 preoperative evaluation in, 383-384, 384f of primary tumors, 316-317 results of, 390-391, 390t surgical technique for, 385-386 types of, 386-389, 386f-389f without pulmonary resection, 386-387, 386f-387f Carotid artery anatomy of, 1201f, 1202 injury to, 1781 puncture of, with internal jugular vein cannulation, 47 Carpal tunnel syndrome, and thoracic outlet syndrome, 1275, 1278f Caseum, tuberculous, 505 Casoni intradermal test, in hydatid disease, 558 Castleman’s disease, 1641, 1650-1652, 1651f Catamenial pneumothorax, 1105 Catecholamines, in neuroblastoma, 1637 Catheter, superior vena cava obstruction from, 1686, 1689, 1689f Caustic injury laryngeal, 1741, 1752, 1753f tracheobronchial, 1766-1767, 1767f tracheoesophageal fistula from, 301 tracheostomy in, 346 Caval hiatus, 1380 Caval inflow occlusion, for complex cardiac injuries, 1786 Cavernostomy/cavernoplasty, 514 Cavernous hemangioma, of chest wall, 1222-1223 Cavity, 634. See also Pleural cavity; Pulmonary cavity. CD20, monoclonal antibodies against for B-cell lymphoma, 1631 for non-Hodgkin’s lymphoma, 1629 CD56, monoclonal antibodies against, 839 CDKN2A-RB1 pathway, in carcinogenesis, 720 Central airway obstruction, 326-342 benign causes of, 327t, 328 management of, 331-335, 333f-334f clinical presentation in, 326, 327b diagnostic endoscopy in, 328, 328b etiology of, 326-328, 327t

Central airway obstruction (Continued) lesion localization and measurement in, 330, 331f malignant argon plasma coagulation for, 341, 341f causes of, 326-328, 327t electrocautery for, 340-341, 340f laser therapy for, 339-340 recanalization for bronchoscopic, 336-337 microdébrider in, 337-338, 338f urgent treatment of, 335-336, 335f-337f management of anesthetic, 328-329 approaches and algorithms for, 330-331, 332f, 333f general measures for, 328, 328b goals in, 326, 327b postoperative, 341 securing airway in, 329 rigid bronchoscopy in advantages of, 329 diagnostic, 328, 328b for dilation, 331-335, 333f-334f interventional, 327b, 329-330, 329b, 330f, 330t for recanalization, 336-337 types of, treatment options by, 330f Central hypoventilation syndrome, congenital, phrenic nerve and diaphragm motor point pacing in, 1445, 1452-1453 Central nervous system metastasis, 753. See also Brain metastasis. Central nervous system symptoms, in fibrosing mediastinitis, 1535 Central neuraxial blockade anticoagulation and, 77 for perioperative pain management, 75-77, 76f Central sensitization, in nociceptor response, 68, 69 Central venous pressure (CVP), intraoperative monitoring of, 46-47 Cerebellar syndromes, in small cell lung cancer, 827 Cerebrospinal fluid leak, after resection for superior sulcus tumors, 930, 938 Cervical esophagus, exposure of, 121 Cervical fascial anatomy, 1521-1522, 1522f, 15301531, 1530f, 1531f Cervical incision, transverse, 120-122, 120f-122f Cervical intervertebral disc, herniated, 1285, 1287 Cervical mediastinoscopy, 1473, 1474f, 1516-1517 extended, 105, 1473, 1474f, 1517 in lobectomy, 880 technique of, 103-105, 103f-105f Cervical spinal cord injury, phrenic nerve and diaphragm motor point pacing in, 1445, 1451-1452 Cervical spondylosis, 1287 Cervical trachea, exposure of, 121 Cervicothoracic diaphragm of Bourgery, 1002 Cervicothoracic septum, fibrous, 1002 Cervicotomy incision in acute necrotizing mediastinitis, 1522t, 1523 in superior sulcus tumors, 935, 935f Cestode infections, 551t, 554t, 564 Cetacaine, in tracheal resection, 223 Cetuximab, for non–small cell lung cancer, 817-818 Chamberlain procedure, 105, 122f, 1516 Chemodectoma, 1498-1499, 1639 Chemotherapy. See also specific agents, e.g., Cisplatin. for B-cell lymphoma, 1631 for Ewing’s sarcoma of chest wall, 1295, 1309 for Hodgkin’s lymphoma, 1626-1627 intracavitary for malignant mesothelioma, 1134 for malignant pleural effusion, 1050-1051, 1052 late complications of, 182 for lymphoblastic lymphoma, 1630 for malignant mesothelioma, 1130, 1134 for mediastinal nonseminomatous germ cell tumors, 1617-1618, 1620-1621 for mediastinal seminoma, 1616-1617 for multiple-drug-resistant tuberculosis, 511 for non-Hodgkin’s lymphoma, 1628-1629

1/25/2008 1:46:11 PM

Index

Chemotherapy (Continued) for non–small cell lung cancer adjuvant, 785-787, 786t versus best supportive care, 812-813, 813t doublet versus single-agent, 813, 814t neoadjuvant, 781-783, 782f, 782t optimal duration of, 815-816 optimal regimen for, 813-815, 815t palliative, 812-819 second- and third-line agents in, 816 triplet versus doublet, 815 pulmonary infection after, 585t, 594 for pulmonary metastasis, 851, 855 pulmonary toxicity of, 182, 182t with radiotherapy. See Combined modality therapy. for small cell lung cancer adjuvant, 835, 835t advances in, 831 combinations for, 830t dose intensification in, 829-831 duration of, 831 in elderly persons, 837-838, 838t in extensive-stage disease, 828-831 neoadjuvant, 836-837, 836t in relapsed disease, 834 for thymic carcinoma, 1613 for thymoma neoadjuvant, 1607-1608, 1608t regimens in, 1608-1609, 1609t Chest barrel, 604 flail, 1207, 1770, 1771f, 1789 gas-filled intestinal loops in in congenital diaphragmatic hernia, 1406 in Morgagni hernia, 1384, 1388f percussion of, in diaphragmatic function assessment, 1377-1378 Chest pain in bullous disease, 642 in interstitial lung disease, 567-568 in malignant pleural effusion, 1139 in pneumothorax, 1097 Chest physiotherapy for bronchiectasis, 475 for empyema, 1065 postoperative, 138-139 Chest pressure, negative, maintenance of, with phrenic nerve pacing, 1456 Chest radiography in asbestosis, 577, 578f in asbestos-related pleural plaques, 1020, 1020f-1021f in bronchiectasis, 474-475 in bronchogenic cyst, 1582, 1582f, 1583f in bullous disease, 639, 640f, 641f in chronic obstructive pulmonary disease, 605 in chronic thromboembolic pulmonary hypertension, 654, 654f in community-acquired pneumonia, 483-484, 483f-485f in congenital cystic adenomatoid malformation, 466, 467f in congenital diaphragmatic hernia, 1406, 1406f of diaphragm, 1380 in diaphragmatic function assessment, 1378 in diaphragmatic rupture, 1387-1388, 1390f1391f in emphysema, 613, 613f, 615-616 in empyema, 1011, 1013f, 1014f, 1060-1061 in esophageal cyst/duplication, 1566, 1567f in esophageal hiatal hernia, 1499, 1500f in fibrosing mediastinitis, 1535 in fibrous dysplasia, 1209, 1211f in fibrous tumors of pleura, 1023, 1024f-1025f in Hodgkin’s lymphoma, 1625, 1626f in hydatid disease, 559, 560f in interstitial lung disease, 570-571, 570t in lung abscess, 495 for lung cancer screening, 744-746, 745t for lung cancer staging, 757, 759f in massive hemoptysis, 447 in mediastinal hemorrhage, 1504 of mediastinum, 1477 in mucormycosis, 547, 547f

Index-F06861.indd 1801

Chest radiography (Continued) in non–small cell lung cancer postresection follow-up, 792 in pediatric mediastinal tumors, 1654, 1654f in penetrating chest injuries, 1778 in pericardial calcification, 1541, 1541f in pleural effusion, 1008-1010, 1009f-1010f, 1042, 1043f-1045f in pleural hydatid disease, 1083f, 1084 in pleural thickening, 1017, 1017f-1018f in pneumothorax, 1015-1016, 1015f-1017f, 1097, 1097f-1098f in postintubation stenosis, 261 postoperative, 137 in postpneumonectomy bronchopleural fistula, 169, 169f in pulmonary metastasis, 852, 852f in retrosternal goiter, 1666f, 1667f, 1668f, 1670 in sarcoidosis, 575, 576f silhouette sign on, 427 in silicosis, 578, 578f in solitary pulmonary nodule, 456 in sternal dehiscence, 1255, 1255f in superior sulcus tumors, 824 techniques for, 415, 416f in thymolipoma, 1486, 1487f in tracheal tumors, 313 in tracheobronchial trauma, 1758 in tracheomalacia, 284 in trauma, 1731-1733, 1731t, 1732f in tuberculous pleural effusion, 1074, 1074f in vascular rings, 247 Chest tube. See also Tube thoracostomy. air leak from. See Air leak. bedside, 1147-1148, 1148t closed drainage and suction systems for, 1147-1154 connectors in, 1149 history of, 1147, 1148f outpatient, 1152, 1152f three bottle, 1148-1149, 1149f wet versus dry suction in, 1149 high output from, states with, 162 insertion of, in trauma, 1729, 1730f, 1785 management of for air leak, 1149-1152 after lobectomy, 886 provocative clamping of, 1152 removal of, 1153 second, for retained hemothorax, 1772 types of, 1147 Chest wall abscess of, tuberculous, 517, 518f anatomy of, 1197-1208 applied surgical implications of, 1207 superior and inferior apertures in, 1202, 1202f surface, 1197-1200, 1198f-1199f upper extremity musculature in, 1202-1205, 1202t, 1203f-1205f aneurysmal bone cyst of, 1218 anterior, anatomy of, 1203f blood supply to, 1200, 1201f collateral vessels in, 1215, 1216f congenital deformity(ies) of, 1236-1242 imaging of, 1209-1211, 1211f-1212f Jarcho-Levin syndrome as, 1242 Jeune’s syndrome as, 1241-1242, 1241f pectus. See Pectus carinatum; Pectus excavatum. Poland’s syndrome as, 1207, 1210-1211, 1212f, 1239, 1240f, 1337-1338, 1338f defects of, traumatic, 1770 extrathoracic muscles of, 1202-1205, 1202t, 1203f-1205f hernia of, after thoracotomy, 1786 imaging of, 1209-1230 infection of etiology of, 1244-1245 imaging of, 1215-1218, 1217f preoperative evaluation in, 1245-1247 surgical management of, 1245f-1252f, 1245t, 1247-1252 innervation of, 1200

1801

Chest wall (Continued) masses of. See also Chest wall neoplasms/tumors. differential diagnosis of, 1231-1235, 1232t inflammatory, 1231, 1232f metastatic, 1231, 1232f radiological evaluation of, limitations of, 1233-1234, 1234f tissue diagnosis of, 1234 metastasis to, 824t, 1231, 1232f movements of, 1207 neoplasms of. See Chest wall neoplasms/tumors. osteomyelitis of, 1217, 1231, 1232f pain in in lung cancer, 752 after VATS procedure, 1102 physiology of, 1206-1207, 1206f posterior, anatomy of, 1204f postsurgical radiographic changes in, 1212-1215, 1214f-1215f radionecrosis of etiology of, 1244, 1244f, 1245f preoperative evaluation in, 1245-1247 surgical management of, 1245f-1252f, 1245t, 1247-1252 reconstruction of. See Chest wall reconstruction. resection of. See Chest wall resection. sebaceous cyst of, 1223 trauma to blunt, 1770, 1770f imaging of, 1211-1212, 1212f-1213f penetrating, 1778-1779 tumor invasion of. See also Chest wall neoplasms/tumors. computed tomography in, 1219, 1222f extended pulmonary resection for, 941-943, 942f-944f imaging of, 1226-1228, 1228f by non–small cell lung cancer, 773-774, 773f, 773t palliative resection for, 780 Chest wall neoplasms/tumors, 1218-1228, 1291-1301 benign, 1231, 1233f bone, 1218, 1219f soft tissue, 1221-1223, 1223f-1226f types of, 1292-1294, 1293f biopsy of, 1306-1307 bone, 1218-1220 classification of, 1292b clinical features of, 1291 diagnosis of, 1291-1292, 1306-1307 historical note on, 1291 malignant, 1231-1233, 1233f bone, 1218-1220, 1219f-1223f frequency of, 1292t soft tissue, 1223, 1226, 1227f-1228f survival rates for, 1294f types of, 1294-1298, 1294f-1298f soft tissue, 1220-1226 surgery for late results of, 1300-1301, 1301f reconstruction in, 1298-1300, 1299b, 13091327. See also Chest wall reconstruction. resection in, 1298, 1298f, 1306-1309, 1307f-1309f Chest wall reconstruction graft infection after, 178 for pectus excavatum, 1334 for Poland’s syndrome, 1337-1338, 1338f for radionecrosis and infection clinical series on, 1245t, 1247-1248 flaps for, 1245t, 1246f-1252f, 1248-1250 historical note on, 1243-1244 materials for, 1245t, 1248 postoperative care in, 1250 preoperative assessment in, 1245-1247 soft tissue, 1314-1327 for anterior and anterolateral area, 1314, 1314f flaps for, 1315-1327 for lateral area, 1314, 1315f planning of, 1314-1315, 1314f-1315f for posterior area, 1314-1315, 1315f type of, and need for stabilization, 1310

1/25/2008 1:46:11 PM

1802

Index

Chest wall reconstruction (Continued) stabilization in, 1309-1314 alloplastic and synthetic materials for, 13111312, 1312b, 1312f biologic implants for, 1310-1312, 1310b, 1311f implantation methods for, 1312-1314, 1313f indications for, 1309-1310 materials for, 1310-1312 after tumor resection, 942, 943f-944f, 1298-1300, 1299b late results of, 1300-1301, 1301f skeletal, 1299 soft tissue, 1299-1300, 1299b Chest wall resection late complications of, 177-178 for neoplasms/tumors, 1298, 1298f, 1306-1309, 1307f-1309f late results of, 1300-1301, 1301f for radionecrosis and infection clinical series on, 1245t, 1247-1248 historical note on, 1243-1244 postoperative care in, 1250 preoperative assessment in, 1245-1247 for superior sulcus tumors anterior transcervical-thoracic approach to, 937, 937f posterior approach to, 926f-928f, 927-928 Chicago’s disease, 542 Chicken chest. See Pectus carinatum. Chilaiditi syndrome, 1435, 1435f Children bronchogenic cyst in, 1563-1565, 1563f-1565f, 1563t, 1658, 1659f chylothorax in, 1120 congenital diaphragmatic hernia in, 1405-1408, 1418-1419 decortication in, 1175 diaphragmatic eventration in, 1404-1405, 1405f, 1406t consequences of, 1433 etiology of, 1432-1433 treatment of, 1405, 1406t, 1439 diaphragmatic paralysis in etiology of, 1433 treatment of, 1439-1440 diaphragmatic plication in, 1405, 1406t indications for, 1439-1440 results of, 1441-1443, 1442t esophageal cyst/duplication in, 1563t, 1565-1569, 1658 foregut cyst in, 1562-1572, 1573t, 1658 lung transplantation in, 672-673, 682 mediastinal cysts in, 1562-1579, 1658-1659, 1659f mediastinal tumors in, 1653-1660 anatomic considerations in, 1653 clinical presentation in, 1653-1654 cystic, 1579 diagnosis of, 1654, 1654f surgical access in, 1655 types of, 1655-1659 neurenteric cyst in, 1565-1569, 1566f, 1659 pericardial cyst in, 1577-1578, 1659, 1659f post-transplant lymphoproliferative disorders in, 673 rigid bronchoscopy in, 95 subglottic resection in, 363-375. See also Subglottic resection, in children. subglottic stenosis in. See Subglottic stenosis, in children. thymic cyst in, 1576-1577, 1659 tracheal size in, 190t Chlamydia pneumonia, 481-482 Chlorambucil, for B-cell lymphoma, 1631 Cholesterol pleural effusion, 1114-1115 Chondroblastoma, of chest wall, 1218 Chondroma of chest wall, 1292, 1293f mediastinal, 1647 Chondromyxoid fibroma, of chest wall, 1218 Chondrosarcoma of chest wall, 1219, 1223f, 1232, 1294-1295, 1294f surgery for, 1307, 1307f-1309f

Index-F06861.indd 1802

Chondrosarcoma (Continued) mediastinal, 1647-1648, 1648f pulmonary, primary, 845 Choriocarcinoma, pulmonary, primary, 845 Chronic obstructive pulmonary disease (COPD), 603-611 in α1-antitrypsin deficiency, 605 diagnosis of, 30 evaluation of, 603-605 exacerbations of, 489, 609-611, 610t history in, 604 imaging studies in, 605 oxygen assessment in, 605 pathophysiology of, 603 physical examination in, 604 pneumothorax in, 1103-1104 postoperative care in, 607-611 airway, 608 general, 608 oxygen therapy in, 608 pharmacologic, 608-609 physical examination and vital signs in, 608 respiratory, 139 preoperative treatment of, 605-607, 613-614 general, 605-606 oxygen therapy in, 607 pharmacologic, 606-607 pulmonary rehabilitation in, 607 pulmonary function testing in, 604, 604t severity of, classification of, 604, 604t Chyle analysis of, 1114, 1115b composition of, 1112-1113, 1113t flow of, factors influencing, 1110-1111 production of, methods to reduce, 1116-1117 Chylothorax, 1111-1120 in children, 1120 clinical features of, 1113 computed tomography in, 1010, 1012f congenital, 1111 definition of, 1111 diagnostic studies in, 1114, 1114f, 1115b differential diagnosis of, 1114-1115 etiology of, 1111-1112, 1111b historical note on, 1108 history in, 1113 infectious causes of, 1112 late, after esophagectomy, 180 management of conservative, 1115-1117 overall, 1119, 1119f principles and modalities of, 1115t surgical, 1117-1119, 1118f neoplastic, 1112 pathophysiology of, 1113 postoperative, 162-163, 165, 1120 after resection for superior sulcus tumors, 930, 939 traumatic, 1111-1112, 1786 video-assisted thoracic surgery for, 112, 1118 Cicatricial stenosis, post-traumatic, 1752, 1753f Ciliary dysmotility syndromes, bronchiectasis in, 473 Circulation bronchial massive hemoptysis arising from, 444 and pulmonary circulation, anastomotic connections between, 897 pulmonary bronchial circulation and, anastomotic connections between, 897 with lateral position, 48-49 mechanical restriction of, for hypoxemia during one-lung ventilation, 57 in trauma management, 1728 Circumferential bronchoplasty. See Bronchoplasty. Circumflex aorta, 249 Cirrhosis, preoperative risk assessment in patient with, 16 Cisatracuronium, during airway surgery, 216 Cisplatin in combination chemotherapy, 783, 785, 786 versus carboplatin-containing regimen, 788-789 disadvantages of, 815

Cisplatin (Continued) in combination chemotherapy (Continued) optimal regimen for, 813-815, 815t versus single-agent therapy, 813, 814t with cyclophosphamide and etoposide, 781-782 with docetaxel, 814 with etoposide, 783-785, 788 with gemcitabine, 814 with ifosfamide and mitomycin, 782-783 intrapleural, 1050-1051, 1052 for malignant mesothelioma, 1130 with mitomycin and vindesine, 785-786 for small cell lung cancer, 828, 829 with vinorelbine, 786-787 Cisterna chyli, 1109 Clagett procedure for empyema, 1066-1067 postpneumonectomy, 171, 171f, 1156-1157, 1157f, 1158f for tuberculous empyema, 1078 Clamshell incision, 128-129, 129f for chest injury, 1769 hemi-, in superior sulcus tumors, 937-938, 938f-939f Clavicle, 1197, 1198f Clear cell carcinoma, of lung, primary, 735 Clear cell tumor, of lung, 696 Clindamycin, for lung abscess, 496 Clonidine, epidural, for perioperative pain management, 78 Clopidogrel central neuraxial blockade and, 77 preoperative use of, 14, 44 Clothesline injury, 1741, 1757 Clubbing in interstitial lung disease, 568-569 in lung cancer, 752 Coagulation argon plasma for airway obstruction, 234-235, 341, 341f probes for, 341f fluid therapy and, 150-151 selective, for massive hemoptysis, 451 Coagulopathy, traumatic, 1727 Cobb elevator, 927, 928f Cocaine, topical, in indirect laryngoscopy, 81 Coccidioidomycosis, 539-542 clinical features of, 540-541 diagnosis of, 541 disseminated, 541 epidemiology of, 540 historical note on, 539-540 in immunocompromised host, 594 pathophysiology of, 540, 540f persistent, 540-541 pleural, 1092 primary, 540 treatment of, 541-542 Codman’s triangle sign, 1296 Cohen tip-deflecting endobronchial blocker, 51, 52f Colchicine, for pericarditis, 1540 Cold abscess, tuberculous, 517, 518f Collapsotherapy. See also Thoracoplasty. for tuberculosis, 501-502, 503, 504t, 1079 Collar incision for subglottic resection, 356f, 357 for tracheal resection, 378, 379f Collar sign, in traumatic diaphragmatic hernia, 1388, 1390f, 1391f, 1392f Collateral ventilation, in emphysema, 623 Colloid fluid therapy, versus crystalloids, 150. See also Fluid therapy. Colloids, radioactive, pleurodesis with, 1049 Colorectal cancer, pulmonary metastasis of, 859f, 860t, 861 Combined modality therapy. See also Multimodal therapy. for Hodgkin’s lymphoma, 1626-1627 neoadjuvant before extended pulmonary resection, 955, 955f before lobectomy, 885-886 for non–small cell lung cancer, 783-785, 784f-785f for superior sulcus tumors, 931, 939

1/25/2008 1:46:11 PM

Index

Combined modality therapy (Continued) for non-Hodgkin’s lymphoma, 1628-1629 for non–small cell lung cancer adjuvant, 788 definitive, 807-810, 807t-809t neoadjuvant, 783-785, 784f-785f Commotio cordis, 1729 Comorbid conditions and anesthesia for airway surgery, 212-213 preoperative assessment of, 15-16, 42-44, 43f, 44t Complement fixation, in hydatid disease, 558 Compliance, lung with lateral position, 48 measurement of, 26, 26f Computed radiography, 415 Computed tomography (CT) in acute mediastinitis, 1501-1502, 1501f-1502f in acute necrotizing mediastinitis, 1522-1523, 1523f in anterior mediastinal mass, 59, 59f in asbestos-related pleural plaques, 1020, 1021f axial, value of, 201, 202, 203f in Bochdalek hernia, 1500, 1501f of brain, for lung cancer staging, 762 in bronchiectasis, 474f, 475, 475f in bronchogenic cyst, 1495-1496, 1496f, 1582, 1583f in bronchopleural fistula, 1016, 1017f in bullous disease, 637f, 639, 640f in carinal resection, 384, 384f in cervical rib, 1209, 1211f in chest wall invasion, 1219, 1222f in chest wall mass, 1233 in chronic obstructive pulmonary disease, 605 in chronic thromboembolic pulmonary hypertension, 656, 657f in chylothorax, 1010, 1012f in congenital cystic adenomatoid malformation, 466, 467f in congenital lobar emphysema, 465, 465f in desmoid tumors of chest wall, 1223, 1227f of diaphragm, 1380, 1381f in diaphragmatic rupture, 1388-1389, 1390f1393f, 1775, 1775f in emphysema, 616, 616f in empyema, 1011, 1013f, 1014-1015, 1014f, 1061, 1061f in empyema necessitatis, 1216-1217, 1217f in esophageal carcinoma, 1496, 1497f in esophageal cyst, 1498, 1498f, 1567, 1567f, 1585, 1585f in esophageal diverticulum, 1496, 1497f in esophageal hiatal hernia, 1499, 1501f in fibrosing mediastinitis, 1503, 1535 in fibrothorax, 1174 in fibrous tumors of pleura, 1023-1024, 1024f-1025f in focal tracheal narrowing, 203-204, 205f-208f ground-glass opacification on, 420 helical (spiral), 417, 417f in hemothorax, 1010, 1012f high-resolution in interstitial lung disease, 571, 571t, 597, 598f linear opacities on, 420, 421f for lung cancer staging, 757-758, 759f history of, 196-197, 198f in hydatid disease, 559, 561f image acquisition in, 200-201, 201f image reconstruction in, 201-202, 201b minimum intensity projections for, 199f, 202 multiplanar reformatting for, 198f, 201-202, 202f two- and three-dimensional rendering techniques for, 201 volume rendering for, 198f-199f, 202 interpretation hints for, 202, 203f in laryngeal trauma, 1744 in laryngotracheal stenosis, 275 in lobar atelectasis, 422, 422f low-dose for lung cancer screening evaluation of, 746-747, 746t nonsolid and part-solid nodules detected on, 747, 748f

Index-F06861.indd 1803

Computed tomography (CT) (Continued) low-dose (Continued) for lung cancer screening (Continued) in patients with previously resected lung cancer, 747, 748f for postresection follow-up, 792-793, 795 of lung, 415-417, 417f in lung abscess, 495 in lymphangioleiomyomatosis, 580, 580f in malignant mesothelioma, 1028-1029, 1029f1030f, 1126, 1126f, 1186 in malignant pleural effusion, 1139 in massive hemoptysis, 447 in mediastinal hemorrhage, 1504, 1504f of mediastinal lymph nodes, 1483, 1483f in mediastinal lymphadenopathy, 1498, 1499f, 1500f in mediastinal lymphangioma, 1494, 1494f in mediastinal lymphoma, 1490, 1491f, 1492f in mediastinal parathyroid adenoma, 1495, 1681, 1681f in mediastinal seminoma, 1616, 1616f in mediastinal teratoma, 1615, 1616f of mediastinum, 1477, 1478f-1480f in Morgagni hernia, 1495, 1495f multidetector, 197, 417, 417f in neurogenic tumors, 1500, 1501f in nonseminomatous malignant germ cell tumors, 1489-1490, 1490f in non–small cell lung cancer, 766, 767f in paraganglioma, 1499 in pediatric mediastinal tumors, 1654, 1654f in pericardial calcification, 1541 in pericardial cyst, 1492, 1586, 1586f pleural biopsy guided by, 1037 in pleural effusion, 1010, 1011f-1012f, 1042, 1044f-1045f, 1048 in pleural lipoma, 1023, 1023f in pleural thickening, 1017-1018, 1017f-1018f in pneumomediastinum, 1503f, 1504 in pneumothorax, 1016, 1016f-1017f, 1098, 1099f in Poland’s syndrome, 1211, 1212f in postintubation stenosis, 261 in postpneumonectomy space evaluation, 1031, 1032f in poststernotomy mediastinitis, 1264 in pseudochylothorax, 1010 in pulmonary alveolar proteinosis, 581, 581f in pulmonary metastasis, 852-853, 852f, 853f in pulmonary sequestration, 469f, 470 quantitative, in preoperative risk assessment, 12 radiofrequency ablation guided by, 799 in retrosternal goiter, 1493-1494, 1493f, 1664, 1665f-1668f, 1666, 1670 in rounded atelectasis, 1021, 1022f in schwannoma of chest wall, 1221, 1225f in small cell lung cancer, 827 in solitary pulmonary nodule, 113, 423f, 424-425, 424f, 456 in sternal fracture, 1211, 1212f in sternal osteomyelitis, 1215 in sternoclavicular dislocation, 1212, 1213f in sternoclavicular joint septic arthritis, 1217, 1217f in subglottic tracheal stenosis, 198f-199f in superior sulcus tumors, 824, 825f surveillance, for lung cancer screening, 747, 748f in teratoma, 1489, 1489f-1490f in thoracic splenosis, 1026, 1026f in thymic carcinoid, 1485-1486, 1486f in thymic carcinoma, 1485, 1486f in thymic cyst, 1487, 1488f, 1577 in thymolipoma, 1486, 1487f in thymoma, 1484-1485, 1484f-1485f, 1507, 1507f, 1596-1597 of thymus, 1478, 1480, 1481f-1482f of trachea, 202-203 in tracheal masses, 203-204, 205f-207f, 1498 in tracheal tumors, 313, 313f in tracheobronchial amyloidosis, 210, 210f in tracheobronchial stenosis, 198f-199f, 204, 208f in tracheobronchial trauma, 1758-1759, 1758f in tracheoesophageal fistula, 301f, 302

1803

Computed tomography (CT) (Continued) in tracheomalacia, 200, 201f, 204, 208f, 284-285, 285f, 286f in trauma, 1731t, 1733-1734, 1733f in tuberculoma, 512 in tuberculous pleural effusion, 1074 two-dimensional (multiplanar), 197, 198f-199f of upper airway, 196-197, 198f-199f, 200-210, 201f-210f in vascular rings, 248, 248f Congenital anomalies. See also specific disorders, e.g., Tracheomalacia. of aortic arch, 242-255 of chest wall, 1209-1211, 1211f-1212f of lung, 462-471, 463t of pericardium, 1545, 1545f of trachea, 189 Congenital diaphragmatic hernia in adults, 1408, 1408f, 1410-1411 anomalies associated with, 1416 in children, 1405-1408 embryogenesis of, 1402 in fetuses, 1413-1424, 1414b historical note on, 1401 imaging of, 1382-1385, 1385f-1388f incidence of, 1402 isolated, survival rates in, 1413-1414, 1414b laparoscopic repair of, 1410-1411 in neonate diagnosis of, 1406, 1406f treatment of, 1407-1408, 1407t, 1418-1419, 1418b pathology of, 1403 physiologic consequences of, 1403-1404 prenatal counseling and prognosis in, 1416-1418, 1416b, 1416f-1417f, 1417t prenatal diagnosis of, 1405-1406, 1414-1416, 1414b, 1414f-1415f prenatal intervention for, 1407 clinical implementation of, 1419, 1420t conceptual basis of, 1419, 1419b FETO procedure in, 1419-1420, 1420b, 1421f results of, 1420-1422, 1420b, 1422f survival after, predictors of, 1422-1423, 1422b pulmonary hypoplasia in, classification of, 1422-1423 recurrent herniation in, 1407 Connective tissue disease, interstitial lung disease in, 579-580 Constrictive pericarditis, 1540, 1541-1542, 1541f, 1542t Consumption, 499 Contact endoscopy, for vocal cord evaluation, 87 Continuous insufflation, during rigid bronchoscopy, 95, 96f Continuous positive airway pressure (CPAP) for hypoxemia during one-lung ventilation, 56 postoperative, 139 Contralateral resection, after pneumonectomy, 956 Contusion, pulmonary, 1772-1773, 1772f, 1789 Cooper thymectomy retractor, 1550, 1553, 1717, 1717f COPD. See Chronic obstructive pulmonary disease (COPD). Cordotomy, for vocal fold paralysis, 310, 311f Coronary artery bypass graft, preoperative, 14 Coronary artery disease postoperative complications in, preoperative assessment of, 13-14, 14b, 15f, 43-44, 43f preoperative revascularization for, 14 Corticosteroids for chronic obstructive pulmonary disease during exacerbation, 489, 609 postoperative, 609 preoperative, 606, 607, 614 in critically ill patient, 149-150 dose of, lung transplantation eligibility and, 662 for eosinophilic pneumonia, 581 after lung transplantation, 675, 681 for mediastinal lymphoma, prebiopsy, 1624 for organizing pneumonia, 575 for pericarditis, 1540 perioperative use of, 393 for pneumonia in immunocompromised host, 591

1/25/2008 1:46:12 PM

1804

Index

Corticosteroids (Continued) pulmonary infection after, 585t, 594 after sleeve resection, 905 for Wegener’s granulomatosis, 295 Cortisol levels, in sepsis, free versus total, 149-150, 150f Corynebacterium parvum, pleurodesis with, 1050 Costal cartilage resection, in pectus deformity repair, 1330, 1331f-1333f, 1337, 1349, 1349f Costochondritis, of chest wall, 1217-1218 Costoclavicular test, in thoracic outlet syndrome, 1279, 1280f, 1281 Costovertebral articulations, 1199f Cough in bronchiectasis, 474 in interstitial lung disease, 567 in laryngeal trauma, 1743 in lung cancer, 751 in tracheomalacia, 284 Crackles, in interstitial lung disease, 568 Cranial radiotherapy, prophylactic, for brain metastasis, 833 Crapo normal reference values, 28-29 Cricoid cartilage anatomic relationships of, 257, 258f anatomy of, 353, 354f fracture of, 1741f, 1742, 1749-1750, 1749f Cricothyroidotomy definition of, 344 technique for, 349-350 in trauma, 1728, 1729f Cricotracheal ligament, injury to, 1742 Cricotracheal resection, partial. See Subglottic resection. Critically ill patient, 145-158 arrhythmias in, 153-154 blood transfusions in, 152-153, 153t corticosteroids in, 149-150 fluid therapy in, 150-152, 151f. See also Fluid therapy, in critical care. glycemic control in, 156-157 hemodynamic monitoring in, 157-158 intensivist-model ICU for, 145, 146b neuromuscular blockade in, 156 respiratory failure in, 154-156 sedation in, 156 sepsis in, 145-150. See also Sepsis. stress ulcer prophylaxis in, 158 vasopressin in, 147-148, 147t Cryoanalgesia, for perioperative pain management, 72-74 Cryosurgery, for endobronchial obstruction, 237 Cryptococcosis in immunocompromised host, 594 pleural, 1090 pulmonary, 545-546, 546f Cryptogenic organizing pneumonia, 575 Crystalloid fluid therapy, versus colloids, 150. See also Fluid therapy. CT. See Computed tomography (CT). Cubital tunnel syndrome, and thoracic outlet syndrome, 1275, 1278f Culture(s) in aspergillosis, 537 in coccidioidomycosis, 541 in cryptococcosis, 546 in fungal infections, 527 in histoplasmosis, 534 in interstitial lung disease, 597 Cushing’s syndrome in carcinoid tumors, 702 in lung cancer, 752 in small cell lung cancer, 827 Cyanosis, in pulmonary hypoplasia, 464 Cyberknife Stereotactic Radiosurgery System, 801, 801f Cycle ergometry, maximum oxygen consumption values in, 27 Cyclophosphamide with cisplatin and etoposide, 781-782 for small cell lung cancer, 828, 829 for Wegener’s granulomatosis, 295 Cyclosporine, inhaled, after lung transplantation, 675 Cylindroma, of bronchus, 703-705, 704f, 705t

Index-F06861.indd 1804

CYP1A1 and CYP2D6 polymorphisms, lung cancer risk and, 717-718 Cyst(s) bronchogenic. See Bronchogenic cyst. chest wall, 1218, 1223 definition of, 634 esophageal. See Esophageal cyst/duplication. hydatid. See Hydatid disease. in interstitial lung disease, 427 mediastinal. See Mediastinum, cyst of. mesothelial, pediatric, 1659, 1659f neurenteric, 1513 in adults, 1585-1586 pediatric, 1565-1569, 1566f, 1659 parathyroid, 1587 pericardial. See Pericardial cyst. pleural, 1123 pulmonary acquired, 426, 427 congenital, 426 general features of, 425 radiographic signs of, 425, 425f thoracic duct, 1587, 1659 thymic. See Thymus gland, cyst of. Cystectomy, for hydatid disease, 561, 561f Cystic adenomatoid malformation. See Adenomatoid cystic malformation. Cystic bronchiectasis, 427 Cystic fibrosis bronchiectasis in, 473 lung transplantation for, 663, 688-689, 689f massive hemoptysis in, 445 maximum oxygen consumption (VO2max) in, prognosis and, 38 pneumothorax in, 1104 Cystic hygroma. See Lymphatic malformation, cystic. Cysticercosis, 551t, 554t, 564 Cytomegalovirus infection bronchiolitis obliterans syndrome and, 685 pneumonia from in immunocompromised host, 592 after lung transplantation, 679, 679f D Da Vinci robotic system, 989, 990f, 1448 Daclizumab, after lung transplantation, 676 Dart technique, for aspiration of pneumothorax, 1100 Dartevelle approach to superior sulcus tumors, 935-937, 935f-937f Dashboard injury, 1757 Dead space, 27 DeBakey forceps, in video-assisted pulmonary resection, 976 Decontamination, selective digestive, 146 Decortication in children, 1175 contraindications to, 1178-1179, 1178t definition of, 1172 for empyema, 1068-1069 failure of, causes of, 1183-1185, 1183t, 1184f functional results of, 1182-1183 historical note on, 1170-1171, 1174-1185 indications for, 1175-1178, 1175t, 1176f-1179f morbidity and mortality of, 1182 objectives of, 1174 operative technique for, 1179-1181, 1180f-1181f thoracoscopic, 1075, 1181-1182 for tuberculous empyema, 1078, 1078t, 1089 Dedo laryngoscope, 84f, 85 Deep venous thrombosis, postoperative, 143, 143b, 183-184, 183f Dehydration, prevention of, in chylothorax, 1116 Deloculation. See also Decortication. definition of, 1172 indications for, 1175, 1175t, 1176f-1178f Denver shunt, for chylothorax, 1116 Dependent viscera sign, in traumatic diaphragmatic hernia, 1388, 1390f, 1391f Dermatitis, after pectus excavatum repair, 1343, 1343f Dermatomyositis, 580 Desert rheumatism, 540

Desflurane for airway surgery, 214 during one-lung ventilation, 54 Desmoid tumors, of chest wall, 1223, 1227f, 1233, 1293-1294 Detorubicin, for malignant mesothelioma, 1130 Dexamethasone in critically ill patient, 149 for subglottic edema, 341 Dexmedetomidine during airway surgery, 216 epidural, for perioperative pain management, 78 Dexon mesh, for pericardial reconstruction, 1191, 1191f Dextrans, coagulation and, 150-151 Diabetes mellitus preoperative risk assessment in patient with, 15-16 as risk factor for anastomotic complications, 395 Dialysis patients, preoperative risk assessment in, 16 Diaphragm accessory, 1394 anatomy of, 1367-1369, 1368f-1369f, 1374-1375, 1374f-1375f, 1425 apertures of, 1369, 1369f, 1425 blood supply to, 1370, 1370f as boundary for thorax, 1724, 1724f central tendon of, 1367 congenital absence of, 1462 congenital hernias of. See Congenital diaphragmatic hernia. contraction of, pressure during, 1376-1377 costal part of, 1367, 1377 crus (crura) of, 1367-1368, 1377, 1380 depression of, causes of, 1382, 1382t, 1385f elevation of acquired causes of, 1396-1399, 1397t clinical presentation in, 1398 conservative management of, 1398 diaphragmatic, 1396-1398 evaluation of, 1398 infradiaphragmatic, 1398 supradiaphragmatic, 1396, 1396f, 1397f surgical management of, 1398-1399, 1399t bilateral, 1398 causes of, 1381-1382, 1382f-1385f, 1382t embryology of, 1372-1374, 1372f-1374f in emphysema, pathophysiology of, 613, 613f, 1378-1379, 1379f eventration of. See Diaphragmatic eventration. function of, 1375 assessment of, 1377-1378 hernias of acquired, 1385-1389, 1389f-1393f anterior, 1495, 1495f congenital. See Congenital diaphragmatic hernia. diaphragmatic eventration versus, 1432 hiatal, 1385-1386, 1389f, 1499, 1500f, 1501f posterior, 1499-1500, 1500f-1501f traumatic, 1386-1389, 1390f-1393f imaging of, 1380-1394 incisions into, 1374-1375, 1374f-1375f, 14281429, 1429f innervation of, 1371-1372, 1371f, 1373, 1373f lumbar part of, 1367-1369 motion of, assessment of, 1390, 1393-1394 movements of, 1207 muscle fiber composition of, 1376 normal, imaging of, 1380-1381, 1381f paralysis of after cardiac surgery, 1460-1461 causes of, 1389-1390 in children, 1433, 1439-1440 diagnosis of, 1459 diaphragmatic eventration versus, 1404t, 1432 epidemiology of, 1432 imaging of, 1383f, 1390, 1393-1394 in lung cancer, 752 paradoxical movement in, 1396 in phrenic nerve injury, 1396-1397 perfusion of, 1370 physiology of, 1206-1207, 1206f, 1375-1377 plication of, 1398-1399, 1399t, 1431-1443 abdominal approach to, 1436, 1437f “accordion,” 1436

1/25/2008 1:46:12 PM

Index

Diaphragm (Continued) plication of (Continued) in adults, 1409-1410, 1410f, 1411t indications for, 1440-1441, 1441f results of, 1443, 1443t in children, 1405, 1406t indications for, 1439-1440 results of, 1441-1443, 1442t “flag,” 1435-1436, 1436f historical note on, 1431 indications for, 1439-1441, 1439b laparoscopic, 1439 for phrenic nerve injury, 1462, 1462f principles of, 1435 results of, 1441-1443, 1441b, 1442t-1443t techniques of, 1435-1439, 1436b conventional, 1435-1436, 1436f-1437f minimally invasive, 1437-1439, 1438f thoracic approach to, 1435-1436, 1436f video-assisted thoracic surgery for, 1437-1439, 1438f positional abnormalities of, 1381-1382, 1382f1385f, 1382t reconstruction of, after extrapleural pneumonectomy, 1131-1132, 1131f-1133f, 1190-1191, 1191f resection of, in extrapleural pneumonectomy, 1189, 1189f rupture of diagnosis of, 1387-1388, 1390f-1391f traumatic, 1775, 1775f, 1791-1792, 1793f-1794f sternal part of, 1369, 1369f strengthening of, with intermittent diaphragm pacing, 1454-1455 surgical access to diaphragmatic abnormalities and, 1425-1426, 1426t laparoscopy for, 1428, 1429f laparotomy for, 1426, 1427f thoracoabdominal incision for, 1426-1427, 1427f thoracoscopy for, 1427-1428, 1428f thoracotomy for, 1426 surgical anatomy of, 1374-1375, 1374f-1375f, 1425 transplantation of, 1464-1467, 1465f-1467f trauma to, 1731, 1733 blunt, 1774-1775, 1775f penetrating, 1782 tumor invasion of, extended pulmonary resection for, 954 tumors of, imaging of, 1394 weakness of, without paralysis, 1390 zone of apposition of, 1367, 1368f Diaphragm motor point pacing, 1445-1456 in amyotrophic lateral sclerosis, 1453-1454 in congenital central hypoventilation syndrome, 1445, 1452-1453 cost of, 1451 failure of, 1451 future applications of, 1453-1456 history of, 1445-1446 indications for, 1445, 1451-1453 natural orifice transluminal endoscopic surgery and, 1454 postoperative care in, 1450-1451 procedure for, 1446 surgical technique for, 1448-1450, 1449f-1450f system for, 1448 temporary, in intensive care unit, 1454-1456, 1455t in tetraplegia, 1445, 1451-1452 ventilator weaning issues in, 1450-1451 Diaphragm Pacing Stimulation (DPS) System, 1448 Diaphragmatic eventration, 1408-1410 anatomic classification of, 1402b in children, 1404-1405, 1405f, 1406t consequences of, 1433 diagnosis of, 1404-1405, 1405f etiology of, 1432-1433 treatment of, 1405, 1406t, 1439 consequences of, 1404, 1433-1435, 1434f-1435f definition of, 1401, 1432 diagnosis of, 1409, 1409f-1410f, 1411t

Index-F06861.indd 1805

Diaphragmatic eventration (Continued) diaphragm elevation in, 1396 versus diaphragmatic hernia, 1432 versus diaphragmatic paralysis, 1404t, 1432 embryogenesis of, 1402 epidemiology of, 1432 etiology of, 1433 historical note on, 1401 incidence of, 1402-1403 with mediastinal shift, 1432, 1432f natural history of, 1440 pathology of, 1403, 1403f, 1404t with phrenic nerve involvement, 1433 treatment of, 1409-1410, 1410f, 1411t, 14401441, 1441f Diaphragmatic flaps, 1429-1430, 1430f Diaphragmatic hiatus. See Hiatus. Diet in chylothorax, 1116 lung cancer and, 715-717 Diffuse parenchymal disease. See Interstitial lung disease. Diffusing capacity for carbon monoxide (DLCO), 24-25 abnormalities of, disease processes causing, 35 for assessing change over time, 33-34 for assessing severity, 32, 33t hemoglobin and carboxyhemoglobin adjustments of, 25 in interstitial lung disease, 571 normal range for, 29t per unit lung volume, 25 preoperative assessment of, 11t, 12, 42 quality of life and, 13 single-breath, 24-25 tests for, acceptability, repeatability, and number of, 25 Digital x-ray systems, 415 Digoxin, perioperative, for atrial fibrillation, 153 Dilation in central airway obstruction, 331-335, 333f-334f in idiopathic laryngotracheal stenosis, 271 in postintubation stenosis, 261 in sarcoidosis, 297 Diltiazem for atrial fibrillation, 15, 142, 161 after extrapleural pneumonectomy, 1192 Dirofilariasis, 552t, 555t, 563-564 Disability assessment, maximum oxygen consumption (VO2max) in, 38 Disc battery ingestion, tracheoesophageal fistula from, 301 Discrimination, two-point, in thoracic outlet syndrome, 1282, 1283f Dislocation of epiglottic petiolus, 1741f, 1742 of sternoclavicular joint, 1212, 1213f Diuretics, for pulmonary edema, 163 Diverticulum esophageal, 1496, 1497f Kommerell’s, 246, 251, 252f pericardial, 1545, 1545f DNA methylation, in carcinogenesis, 725-727, 726f Dobutamine for cardiac tamponade, 1544 for decreased cardiac output, 148 Docetaxel with cisplatin, 814 disadvantages of, 815 for second-line treatment, 816 for small cell lung cancer, 828 Doppler probe, for airway bypass stent placement, 625, 625f Double wall sign, 637f, 639 Double-diffusion immunoelectrophoresis, in hydatid disease, 559 Double-lumen endobronchial tubes for one-lung ventilation, 49-51, 50f-51f problems with, 51 for pulmonary isolation in massive hemoptysis, 450-451 Double/multiple crush hypothesis, 1275-1276, 1278f

1805

Doxorubicin for Ewing’s sarcoma of chest wall, 1295 pleurodesis with, 1048 for small cell lung cancer, 828, 829 Doxycycline pleurodesis, 1143 Drainage for chylothorax, 1115-1116 closed, 1147-1154. See also Tube thoracostomy. connectors in, 1149 history of, 1147, 1148f outpatient, 1152, 1152f three bottle, 1148-1149, 1149f wet versus dry suction in, 1149 for empyema, 1063-1064, 1063f, 1064t for malignant pleural effusion, 1143-1144, 1144t open for empyema, 1066, 1066f-1068f indications for, 1155 technique for, 1155-1157, 1156f-1158f after pectus excavatum repair, 1343, 1343f percutaneous, of lung abscess, 496-497, 496f postoperative, 139-140, 172, 172f, 173f postpneumonectomy, 868 for poststernotomy mediastinitis, 1265, 1265f for tuberculous empyema, 1076 for tuberculous pleural effusion, 1075 Drug abuse, bullous disease and, 635 Drug-induced interstitial lung disease, 568, 579 Ductus arteriosus division in, in left carinal pneumonectomy, 389, 389f formation of, 401 Dumon stent, 239, 239f Dumon-Harrell bronchoscope, 330, 330f Duplication definition of, 1562 esophageal. See Esophageal cyst/duplication. Duty cycle of diaphragm, 1370 Dying patient, care of. See Palliative care. Dynamic Stent CAG Kernan, 239 Dysphagia in laryngeal trauma, 1743 in vascular rings, 246 in vocal fold paralysis, 308 Dysphagia lusoria, 245 Dysphonia, in tracheobronchial trauma, 1758 Dyspnea exertional in chronic thromboembolic pulmonary hypertension, 653 in postintubation stenosis, 259 in tracheomalacia, 283 grading of, 637, 637t, 638t in interstitial lung disease, 567 in laryngeal trauma, 1743 in lung cancer, 751 in malignant pleural effusion, 1138 in pleural disease, 1033 in pneumothorax, 1097 in tracheobronchial trauma, 1758 unexplained or disproportionate, cardiopulmonary exercise testing in, 36, 36f-37f in vocal fold paralysis, 308

E E-cadherin, in malignant mesothelioma, 1127 Echinococcosis. See Hydatid disease. Echocardiography in cardiac tamponade, 1544, 1544f in chronic thromboembolic pulmonary hypertension, 655, 655f transesophageal during anesthesia, 47 for cardiac output measurement, 158 in trauma, 1731t, 1735 ECOG (Eastern Cooperative Oncology Group) scale, in preoperative assessment, 10, 10t Ectopia cordis of sternum, 1239-1240, 1241t thoracoabdominal, 1240-1241, 1241t

1/25/2008 1:46:12 PM

1806

Index

Edema laryngeal, after tracheal resection, 397 pulmonary. See Pulmonary edema. subglottic, after rigid bronchoscopy, 341 third space fluids and, 151 Effort thrombosis, in thoracic outlet syndrome, 1279, 1288-1289, 1355 Eisenmenger’s syndrome, lung transplantation in, 663, 688, 689f Elastic recoil of lung, 26, 26f Electrocardiography in acute pericarditis, 1539 in pneumothorax, 1098-1099 in trauma, 1729 Electrocautery endobronchial, for airway obstruction, 234-235, 340-341, 340f in extrapleural pneumonectomy, 1189 Electrodes, for phrenic nerve pacing, 1447, 1448f Electrodiagnostic testing, in thoracic outlet syndrome, 1284-1285, 1285f Electrolytes, in chyle, 1112 Electromyography in diaphragmatic function assessment, 1378 laryngeal, in vocal fold paralysis, 308 in nerve conduction studies, 1285, 1285f in phrenic nerve and diaphragm motor point pacing, 1446 Eloesser flap modified, for empyema, 1066, 1066f-1068f, 1155-1157, 1156f-1158f original, 1056, 1056f, 1155, 1156f Embolism, pulmonary. See Pulmonary embolism. Embolization arterial, for massive hemoptysis, 451-452, 452f of thoracic duct, 1116-1117 Embryology of aortic arch, 243-244, 243f of diaphragm, 1372-1374, 1372f-1374f of lung, 401, 462 of parathyroid gland, 1678-1679, 1678f, 1679f of pericardium, 1537, 1538f of pleura, 1001, 1002f of thyroid gland, 1662 of upper airway, 189 Emetine, for pleural amebiasis, 1086 Emphasys endobronchial valve, 626, 627, 627f, 628f Emphysema acinar classification of, 632-633, 633f distal (periacinar; paraseptal), 633f, 634 proximal (centrilobular), 633, 633f airway bypass for, 623-626, 624f-626f bullous, 632. See also Bullous disease. clinical features of, 612-613, 613f collateral ventilation in, 623 definition of, 603, 622, 632 lobar, congenital, 465, 465f lobular classification of, 633, 634f lung volume reduction surgery for, 612-621. See also Lung volume reduction surgery. lung volume reduction with one-way valves for, 626-630, 627f-630f, 629t mediastinal, after lung transplantation, 681, 681f natural history of, 636, 636f, 637f panacinar (panlobular), 633-634, 633f pathophysiology of, 622 diaphragmatic, 1378-1379, 1379f in pneumothorax, 642-643, 1099 pressure-volume curve in, 26, 26f surgery for emerging technologies for, 623-630 history of, 612, 622-623 in tracheobronchial trauma, 1758 tracheomalacia in patient with, 284, 284f Empyema, 1055-1071 acute, 1062-1065, 1062t antibiotics for, 1064, 1065t intrapleural enzymes and talc for, 1064-1065 pleural drainage for, 1063-1064, 1063f, 1064t supportive measures for, 1065 air in, 1014, 1014f bacteriology of, 1060

Index-F06861.indd 1806

Empyema (Continued) with bronchopleural fistula, 1058, 1059f, 1067-1068, 1069-1071 causes of, 1011 chronic, 1015, 1065-1069 decortication and empyemectomy for, 1068-1069, 1175-1176, 1179f muscle transposition for, 1069 rib resection drainage with open thoracic window for, 1066, 1066f-1068f, 1155-1157, 1156f-1158f space sterilization for, 1066-1068 thoracoplasty for, 1069 in chylothorax, 1113 complications of, 1058-1059, 1058b, 1058f-1059f deloculation of, 1175, 1175t, 1176f-1178f diagnosis of, 1060-1062, 1061f, 1062t fibrinopurulent, 1057-1058, 1057f historical note on, 1055-1056, 1056f imaging of, 1011, 1013f-1014f, 1014-1015 in immunocompromised patients, 1070-1071 late recurrence of, 167, 185 after lung transplantation, 680 management of acute, 1062-1065, 1062t chronic, 1065-1069 mixed, 1088 multiloculated, 1058, 1058f parapneumonic (postpneumonic), 1058-1059 pathogenesis of, 1059-1060, 1059b phases of, 112 postoperative, 163-164, 1060 post-traumatic, 1059-1060, 1788, 1789f stages of, 1057-1058, 1057f, 1057t after tube thoracostomy, 1768 tuberculous, 1075-1079 acute, 1076-1077, 1077f with bronchopleural fistula, 1076, 1076f, 1089, 1090f-1091f chronic, 1078-1079 diagnosis of, 1088, 1088f management of, 1088-1089, 1089f-1091f pathology of, 1075-1076 pleural residual space management in, 1077-1078, 1078t video-assisted thoracic surgery for, 112-113 Empyema necessitatis, 167, 168f, 1033, 1034f, 1058, 1058f imaging of, 1216-1217, 1217f Empyemectomy, 1068-1069, 1172 En-bloc resection for pulmonary metastasectomy, 856 for superior sulcus tumors, 929-930 Enchondroma, of chest wall, 1218 Endarterectomy, pulmonary. See Pulmonary thromboendarterectomy. End-expiratory lung volume (EELV), 27, 28f Endobronchial blockers, for one-lung ventilation, 51-52, 52f-53f Endobronchial brachytherapy, 237-239, 238t Endobronchial electrocautery, 234-235, 340-341, 340f Endobronchial hamartoma, 693, 694f Endobronchial laser therapy, 232-234, 233f, 236 Endobronchial stenting, 95, 239-240, 239f, 240f Endobronchial tuberculosis, 515, 516f Endobronchial tubes, double-lumen for one-lung ventilation, 49-51, 50f-51f problems with, 51 for pulmonary isolation in massive hemoptysis, 450-451 Endobronchial ultrasonography, 93 for mediastinal lymph node staging, 107 in tracheal tumors, 314 Endobronchial valve first generation, 626, 627, 627f, 628f second generation, 627-630, 628f-630f Endocarditis prophylaxis, 140, 140t Endocavitary drainage, for bullous disease, 646, 648, 649f, 651 Endocrine large cell carcinoma, 735 Endocrine manifestations, in lung cancer, 752-753 End-of-life care. See Palliative care. Endolaryngeal soft tissue injury, 1742

Endometriosis, pneumothorax in, 1105 Endoscopic laser submucosal resections, multiple, in idiopathic laryngotracheal stenosis, 275 Endoscopic ultrasonography (EUS) fine needle aspiration with in lung cancer staging, 761-762 in mediastinal mass, 1515-1516, 1515f for mediastinal lymph node staging, 107 Endoscopy. See also Bronchoscopy; Fluoroscopy; Laparoscopy; Laryngoscopy; Mediastinoscopy; Video-assisted thoracic surgery (VATS). contact, for vocal cord evaluation, 87 diagnostic, in central airway obstruction, 328, 328b of esophagus in central airway obstruction, 328 in tracheoesophageal fistula, 302, 302f history of, 4 in subglottic resection in infants and children, 364-366, 364b, 365f-366f Endothoracic off-pump coronary artery bypass (OPCAB), chest wall anatomy and, 1207 Endotracheal intubation development of, 3, 39-40 difficult airway surgery and, 213 flexible bronchoscopy for, 90-91 predictors of, 45, 83-84, 213 flexible bronchoscopy and, 90-91 in laryngeal trauma, 1745 for laryngoscopy, 84 late airway complications of, 174f-177f, 176 pneumonia after, 490 postintubation injury after, 256-269. See also Postintubation injury. stenosis after. See Postintubation stenosis. in tracheobronchial trauma, 1759-1760, 1759f tracheoesophageal fistula after. See Postintubation tracheoesophageal fistula. tracheoinnominate artery fistula after, 264-266, 264f, 266f tracheomalacia after, 280f, 281, 281f, 286-287 in trauma, 1728 traumatic, 1790, 1790f Endotracheal tube cuff design for, 256 cuff pressure in, measurement of, 348f size of, for flexible bronchoscopy, 220, 220f End-to-end anastomosis, sleeve resection and, pulmonary artery reconstruction by, 916, 918f, 920 Endurance, muscle strength and, 1375 Entamoeba histolytica, 553t, 556t, 563 Enteric cyst, 1658. See also Esophageal cyst/duplication. Enzyme-linked immunosorbent assay, in hydatid disease, 559 Enzymes, intrapleural, for empyema, 1064-1065 Eosinophilia peripheral blood, in hydatid disease, 558 tropical pulmonary, 552t, 555t, 565 Eosinophilic granuloma, of chest wall, 1218, 1293 Eosinophilic lung disease, 581 Eosinophilic pneumonia, acute versus chronic, 581 Ependymoma, pulmonary, primary, 847 Epicardial pacemaker lead implantation, videoassisted thoracic surgery for, 117 Epidermal growth factor receptor (EGFR; ERBB1) in lung cancer, 721-722 monoclonal antibodies against. See Tyrosine kinase inhibitors. Epidural analgesia complications of, 161-162 postoperative somnolence from, 161-162 thoracic, perioperative, 75-77, 76f Epigenetics, in carcinogenesis, 725-727, 726f-727f Epiglottic petiolus, dislocation of, 1741f, 1742 Epiglottis, visualization of, during rigid bronchoscopy, 97, 98f Epilepsy, laryngeal, 284 Epinephrine for hemostasis during bronchoscopy, 93, 101 for subglottic edema, 341 Epithelioid cells, in fibrosing mediastinitis, 1533

1/25/2008 1:46:12 PM

Index

Epithelioid hemangioendothelioma mediastinal, 1645, 1646f pulmonary, 843-844 Epoprostenol, prophylactic, in lung transplantation, 64 Epstein-Barr virus, post-transplant lymphoproliferative disorders and, 673 Eptifibatide, central neuraxial blockade and, 77 Erlotnik for lung cancer, 722 for non–small cell lung cancer, 817-818, 817t, 818t Erythromycin, for pleural nocardiosis, 1087 Esmolol, during airway surgery, 216 Esophageal carcinoma computed tomography in, 1496, 1497f invading upper airway, 325 palliative care for, 824t staging of, video-assisted thoracic surgery for, 117, 1701 tracheoesophageal fistula from, 325 Esophageal cyst/duplication, 1584-1585 associated findings in, 1566 characteristics of, 1511 clinical presentation in, 1565-1566 diagnosis of, 1585 imaging of, 1497-1498, 1498f, 1566-1567, 1567f, 1585, 1585f incidence of, 1563t, 1565 pathology of, 1585 pediatric, 1563t, 1565-1569, 1658 surgical management of, 1567-1569, 1568f, 1585 Esophageal disease imaging of, 1496-1497, 1497f video-assisted thoracic surgery for, 116-117 Esophageal diversion, for tracheoesophageal fistula, 303 Esophageal diverticulum, 1496, 1497f Esophageal hiatus. See Hiatus. Esophageal stricture, late postresection, 179, 179f Esophageal surgery anesthesia for, 60-61 late complications of, 179-180, 179f-180f Esophageal varices, imaging of, 1496-1497 Esophagectomy late chylothorax after, 180 preoperative pulmonary function testing in, 11, 12 thoracoscopic/laparoscopic, 117 tracheoesophageal fistula after, 301 Esophagogastrectomy, pneumonia in, 61 Esophagogastric anastomosis, leakage after, 179, 179f Esophagogram, barium in substernal goiter, 1670 in tracheoesophageal fistula, 301, 302, 302f in vascular rings, 247-248 Esophagopleural fistula, 185 Esophagoscopy in central airway obstruction, 328 in tracheoesophageal fistula, 302, 302f Esophagus anatomic relationship to trachea, 194, 194f Barrett’s, tracheoesophageal fistula in, 301, 301f cervical, exposure of, 121 dissection of, limited surgical access for, 1474, 1475f imaging of, 1482-1483 injury to laryngeal trauma with, 1744-1745 in mediastinoscopy, 106 penetrating, 1781-1782 tracheobronchial trauma with, 1764-1765 traumatic, 1775 perforation of, mediastinitis in, 1502, 1502f repair of, for high tracheoesophageal fistula, 304, 305f rupture of, diaphragmatic flap for, 1430, 1430f tumor invasion of, extended pulmonary resection for, 954-955 Ethambutol, for tuberculosis, 507 Ethnic differences, in pulmonary function testing reference values, 29 Etilefrine, for chylothorax, 1116 Etomidate, for airway surgery, 215

Index-F06861.indd 1807

Etoposide with cisplatin, 783-785, 788 with cisplatin and cyclophosphamide, 781-782 for small cell lung cancer, 828, 829, 833 Europe, training and accreditation in thoracic surgery in, 7-8 Everolimus, after lung transplantation, 676 Ewing’s sarcoma of chest wall, 1220, 1232, 1233f, 1294f, 1295, 1295f, 1309 pulmonary, primary, 847 Excisional (surgical) biopsy of benign lung tumor, 698 of solitary pulmonary nodule, 458-459 Exercise capacity, assessment of, 12, 26 Exercise testing cardiopulmonary, 26-28 clinical utility of, 36-38, 36f-37f description of, 26-27, 27f impact of exercise protocol on outcome in, 27 in interstitial lung disease, 572 in preoperative assessment, 42 safety issues in, 28 in chronic thromboembolic pulmonary hypertension, 656 in interstitial lung disease, 572 Exercise training, preoperative, in chronic obstructive pulmonary disease, 613-614 Exocrine large cell carcinoma, 735 Expiration, muscles of, 1206-1207, 1206f Expiratory pressure maximum. See Maximal expiratory pressure (MEP). Expiratory reserve volume (ERV), 19, 20f, 22 Extracorporeal membrane oxygenation (ECMO) in anterior mediastinal mass surgery, 60 for congenital diaphragmatic hernia, 1407, 1407t, 1418 in lung transplantation, 63, 64 for primary graft dysfunction after lung transplantation, 677-678 in respiratory failure, 155 Extramedullary hematopoiesis, intrathoracic, 1650 Eyes, protection of, during rigid bronchoscopy, 97

F Falling lung sign of Kumpe, 1758, 1780 False aneurysm, pulmonary artery, 65 Farmer’s lungs, 577 Farnesyl-transferase inhibitors, in lung cancer, 721 Fascia lata compounds, for chest wall stabilization, 1310 Fat, dietary, lung cancer and, 716 FDG-PET for carcinoma staging, 759-760, 759f distant metastasis, 435-437 nodal, 434-435, 435f, 1484 in mediastinal lymphadenopathy, 1498 in mediastinal lymphoma, 1492 in mediastinal lymphoma restaging, 1631-1632 of mediastinum, 1477 principles and technical aspects of, 429-430 radiotherapy planning with, 440 in small cell lung cancer, 827 in solitary pulmonary nodule, 113, 425, 432, 433, 433f-434f standardized uptake value (SUV) in, 430 whole-body imaging protocol in, 430 Fentanyl, for airway surgery, 215 Fetal adenocarcinoma, 842 Fetal endoscopic tracheal occlusion (FETO) clinical implementation of, 1419, 1420t conceptual basis of, 1419, 1419b results of, 1420-1422, 1420b, 1422f survival after, predictors of, 1422-1423, 1422b technique of, 1419-1420, 1420b, 1421f Fetal surgery for congenital cystic adenomatoid malformation, 467-468 for congenital diaphragmatic hernia, 1413-1424. See also Congenital diaphragmatic hernia, prenatal intervention for. for cystic lymphatic malformation, 1574

1807

Fibrinogen-thrombin solution, for massive hemoptysis, 451 Fibroma bronchopulmonary, 695 chondromyxoid, of chest wall, 1218 mediastinal, 1643, 1644f Fibromatosis, mediastinal, 1643 Fibrosarcoma of chest wall, 1297, 1297f, 1307-1308 mediastinal, 1643 Fibroscopy, transnasal, in subglottic resection in infants and children, 364-365, 365f Fibrothorax, 1048, 1048f, 1052, 1144, 1171-1174, 1207 causes of, 1172, 1172t decortication for. See Decortication. diagnosis of, 1173-1174 physiologic consequences of, 1172-1173 post-traumatic, 1788-1789 prevention of, 1174 terminology for, 1171, 1171t Fibrous dysplasia of chest wall, 1292 of ribs, 1209, 1211f Fibrous histiocytoma, malignant of chest wall, 1232, 1297, 1298f mediastinal, 1643 pulmonary, 846 Fick equation, 26 Filariasis, 552t, 555t, 565 Fine needle aspiration endoscopic ultrasonography with in lung cancer staging, 761-762 of mediastinal mass, 1515-1516, 1515f of lung abscess, 495 of mediastinal lymphoma, 1623 of mediastinal mass, 1514 of mediastinal nonseminomatous germ cell tumors, 1617 of substernal goiter, 1670 of thymoma, 1598 transthoracic in discriminating benign versus malignant mass, 458 in lung cancer staging, 761 of tuberculoma, 512 Fire, airway, during laser surgery, prevention of, 226-227, 227f, 232 Fissure(s) accessory, 1008 interlobar imaging of, 1008 pleural fluid in, 1010, 1012f of lung. See Lung, fissure(s) of. management of in lobectomy, 881 in robotic-assisted VATS lobectomy, 993, 996f Fistula between airway and pulmonary artery, 176 arteriovenous cardiovascular, post-traumatic, 1786 of internal thoracic vessels, after sternotomy, 1253 massive hemoptysis in, 446 bronchoesophageal, in tuberculosis, 514 bronchopleural. See Bronchopleural fistula. bronchovascular massive hemoptysis in, 447 after sleeve resection, 906 esophagopleural, 185 subarachnoid pleural, postoperative, 162 tracheoesophageal. See Tracheoesophageal fistula. tracheoinnominate artery. See Tracheoinnominate artery fistula. Fixation rib, 1770, 1771f rigid, of thyroid cartilage fracture, 1748, 1748f sternal, in pectus excavatum repair, 1330-1331, 1334, 1334f, 1336f Flail chest, 1207, 1770, 1771f, 1789 Flap(s). See also specific type, e.g., Pectoralis major flap. bipedicle, mediastinal reconstruction with, 1267, 1267f

1/25/2008 1:46:12 PM

1808

Index

Flap(s) (Continued) bronchoplasty, 904-905, 904f for chest wall reconstruction, 1245t, 1246f-1252f, 1248-1250, 1315-1327 diaphragmatic, 1429-1430, 1430f muscle anterior chest wall muscles used for, 1205, 1205f for chest wall reconstruction, 1299-1300, 1299b for poststernotomy mediastinitis, 1266-1267, 1266f pedicled, of membranous trachea for extended partial cricotracheal resection, 371f, 372 for subglottic resection with synchronous laryngeal reconstruction, 359, 360f for postpneumonectomy bronchopleural fistula, 170 Flavonoids, lung cancer and, 716-717 Flow-volume loop and anesthesia for airway surgery, 213-214, 214f flutter waves in, 32 in idiopathic laryngotracheal stenosis, 271, 273f in spirometry, 20, 20f, 21, 21f in substernal goiter, 1670-1671 in tracheal pathology, 222 in tracheomalacia, 284, 285f in upper airway obstruction, 31-32, 32f, 33f Fluconazole, for cryptococcosis, 546, 1090 Flucytosine, for cryptococcosis, 1090 Fludrocortisone, stress dose of, in critically ill patient, 149 Fluid therapy in critical care, 150-152, 151f after esophageal surgery, 61 for hemorrhagic shock, 1726-1727, 1726t after lung transplantation, 675 during one-lung ventilation, 57 postoperative, 138 reperfusion injury from, 1726 Fluid volume, monitoring of, during anesthesia, 45 Fluke infections, 551t, 554t, 564 F-18 Fluorodeoxyglucose–positron emission tomography. See FDG-PET. Fluoroscopy in bacterial aspiration pneumonia, 493 in diaphragmatic paralysis, 1390, 1393-1394 indications for, 415 5-Fluorouracil, pleurodesis with, 1048 Flush solution, for lung transplantation, 665-666 Fluticasone, for chronic obstructive pulmonary disease, 607 Flutter waves, in flow-volume loops, 32 Fold of Marshall, 403, 403f Foramen of Bochdalek, 1425 Foramen of Morgagni, 1425 Foramen ovale, patent, in chronic thromboembolic pulmonary hypertension, 655 Forced expiratory flow between 25% and 75% of total expiratory flow curve (FEF25%-75%), 29t, 31 Forced expiratory volume in 1 second (FEV1), 19, 20f, 21t, 22 for assessing change over time, 33 for assessing severity, 32, 33t normal range for, 29t in obstructive pattern, 30 in preoperative assessment, 11, 11t, 41-42, 41f Forced expiratory volume in 6 seconds (FEV6), 30-31 Forced vital capacity (FVC), 19, 20f, 21t, 22 normal range for, 29t in preoperative risk assessment, 11 Force-length relationship, 1376 Forceps biopsy, 332, 334f in flexible bronchoscopy, 92, 92f in rigid bronchoscopy, 96f, 100 DeBakey, in video-assisted pulmonary resection, 976 Foregut cyst, pediatric, 1562-1572, 1573t, 1658 Foreign body flexible bronchoscopy in, 91 mediastinal abscess from, 1579

Index-F06861.indd 1808

Foreign body (Continued) removal of, in penetrating trauma, 1783-1784, 1786 rigid bronchoscopy in, 94 tracheoesophageal fistula from, 301 Formoterol, for chronic obstructive pulmonary disease, 606 Foscan, in photodynamic therapy, for malignant mesothelioma, 1135 Four-artery sign, in vascular rings, 248, 248f Fracture of cricoid cartilage, 1741f, 1742, 1749-1750, 1749f of hyoid bone, 1741-1742, 1741f, 1747 of larynx, 1740f-1741f, 1741 of pectus bar, 1344-1345, 1344f of rib, 1733, 1770, 1771f, 1789 of sternum, 1211, 1212f, 1770 of thyroid cartilage, 1741f, 1742, 1747-1748, 1748f “French” incision, 130-131, 130f Functional residual capacity (FRC), 20f, 22 measurement of, 22-24, 23f-24f normal range for, 29t Fundoplication, Belsey-Mark IV, 117 Fungal infection, 525-549. See also specific type, e.g., Histoplasmosis. diagnosis of, 526-527 drug therapy for. See Antifungal agents. historical note on, 525 after lung transplantation, 679, 680f Fungus ball, 535-536, 536f Funnel chest. See Pectus excavatum.

G Ganciclovir, for cytomegalovirus pneumonia, 679 Ganglion cell tumors, 1513, 1636-1639, 1637f-1638f Ganglioneuroblastoma, 1636, 1658 Ganglioneuroma, 1513, 1636, 1637f, 1658 Ganglionoma, 697 Ganglioside vaccines, for small cell lung cancer, 838 Gangrene, lung, from tuberculosis, 509-510 Gardner’s syndrome, desmoid tumors and, 1293 Gas(es) partial pressures of, 1004-1005, 1005t reference, for ventilation-perfusion scintigraphy, 441 Gas dilution techniques, for lung volume measurements, 23 Gas exchange, preoperative assessment of, 42 Gastric acid aspiration, pneumonia from, 491-493, 492f Gastroesophageal reflux disease, bronchiolitis obliterans syndrome and, 685 Gastrointestinal disorders in diaphragmatic eventration, 1404, 1435 in interstitial lung disease, 568 Gastrointestinal stromal tumors (GISTs), thoracoscopic resection of, 1702-1703 Gaucher’s disease, 579 Gefitinib for lung cancer, 722 for non–small cell lung cancer, 817-818, 817t, 818t Gelatin, coagulation and, 151 Gelatin sponge embolization, for massive hemoptysis, 451, 452 Gemcitabine with cisplatin, 814 disadvantages of, 815 for malignant mesothelioma, 1130 for small cell lung cancer, 828 Gender interstitial lung disease and, 568 lung cancer and, 709-710, 710f small cell lung cancer and, 827-828 Gene therapy, for malignant mesothelioma, 1135 General status, preoperative assessment of, 9-10, 10t Genetic factors, in lung cancer, 717-718, 717t Genomics, in carcinogenesis, 724-725, 724f

Geography, lung cancer and, 711 Germ cell tumors. See also Teratoma. mediastinal, 1615-1621 characteristics of, 1508, 1509f-1510f, 1510 imaging of, 1488-1490, 1489f-1490f nonseminomatous, 1489-1490, 1490f, 15091510, 1510f, 1617-1620 chemotherapy for, 1617-1618, 1620-1621 diagnosis of, 1617 pediatric, 1656 postoperative outcome in, 1620, 1620f preoperative serum tumor marker status in, 1618, 1618f surgery for, 1618-1620, 1619f, 1619t pediatric, 1655-1656, 1656f seminomatous, 1616-1617, 1616f, 1656 pulmonary, 697 metastatic, 860t, 861 primary, 844-845 GETT staging system for thymoma, 1589, 1590t Ghon complex, 506 Ghon focus, 505 Giant cell carcinoma, of lung, 735 Giant cell tumor, of chest wall, 1218 Gianturco Z stent, for postintubation stenosis, 262 Gigli saw, for first rib division, 927, 927f Gilchrist’s disease, 542 Glenoid fossa, 1197 Glomus tumor, of chest wall, 1223 Glucose level, in pleural effusion, 1045 Glycemic control in critically ill patient, 156-157 postoperative, 140 Goiter, substernal, 1661-1676 anatomy and classification of, 1662-1663 clinical presentation in, 1663-1664 diagnosis of, 1664 embryology of, 1662 historical note on, 1661 imaging of, 1664-1671, 1665f-1669f pathology of, 1661 radioiodine therapy for, 1671 simple versus complex forms of, 1663 terminology in, 1661 thyroid suppression for, 1671 thyroidectomy for anesthesia in, 1671 complications of, 1675-1676 recurrence after, 1674-1675 results of, 1674-1675 technique of, 1672-1674, 1673f Gore-Tex implant characteristics of, 1311 for medialization laryngoplasty, 309, 309f for superior vena cava reconstruction, 951, 952, 952f Graft(s) autogenous tissue, for postintubation stenosis, 262 autogenous venous, for superior vena cava reconstruction, 1690 bone, for chest wall stabilization, 1310-1311, 1311f costal cartilage, for extended partial cricotracheal resection, 371-372, 371f infection of after chest wall reconstruction, 178 after superior vena cava reconstruction, 1694 primary dysfunction of, after lung transplantation, 677-678, 677t, 678f prosthetic, for superior vena cava reconstruction, 1692-1694, 1693f-1694f rib for chest wall stabilization, 1311, 1311f in Poland’s syndrome repair, 1337-1338, 1338f thrombosis of, after superior vena cava reconstruction, 1694 Granular cell tumor, 693-694 Granulation tissue, after tracheal anastomosis, 380, 381t, 394t, 395-397, 396f Granulocyte colony-stimulating factor (G-CSF) for pneumonia in immunocompromised host, 591 for small cell lung cancer, 830-831

1/25/2008 1:46:12 PM

Index

Granulocyte-macrophage colony-stimulating factor (GM-CSF) for pulmonary alveolar proteinosis, 581 for small cell lung cancer, 830 Granuloma eosinophilic, of chest wall, 1293 immune, in fibrosing mediastinitis, 1533 mediastinal, in histoplasmosis, 529-530, 530f-531f noncaseating, in sarcoidosis, 575 tuberculous, 505, 512 Granulomatosis caseous, 512, 513 cavities associated with, 426 Wegener’s, 210, 294-295 Granulomatous disease mediastinal, 297 pulmonary, 575-577, 576f Graves’ disease, substernal goiter in, 1670 Great vessels injury to pectus deformity repair and, 1340 penetrating, 1779, 1781 traumatic, 1775 tuberculosis of, 515-516 Ground-glass opacification on computed tomography, 420, 459, 459f in interstitial lung disease, 597, 598f in nonsolid pulmonary nodule, 747, 748f, 756 Growing teratoma syndrome, 1489, 1618 GST activity, lung cancer risk and, 718 Gunshot injury laryngeal, 1741 mechanisms of, 1777-1778 tracheobronchial, 1756, 1757 Gynecologic cancer, malignant pleural effusion in, 1145

H Halothane, for airway surgery, 214 Halstead test, in thoracic outlet syndrome, 1279, 1280f, 1281 Hamartoma, 692-693, 692f, 694f Hanging injury, 1741 Hanuman syndrome, 1267-1268, 1267f Hashimoto thyroiditis, substernal goiter in, 1670 Head and neck cancer preoperative risk assessment in patient with, 16 pulmonary metastasis of, 862 Heart. See also Cardiac; Cardiovascular. Heart failure pulmonary function testing findings in, 35 right-sided, after parenchymal injury, 1774 Heart positioning device, in lung transplantation without cardiopulmonary bypass, 671-672, 672f Heart rate, during exercise, 26 Heart sounds in chronic thromboembolic pulmonary hypertension, 654 in congenital diaphragmatic hernia, 1406 Heart transplantation donor organ in, extraction of, 666-667, 667f maximum oxygen consumption (VO2max) and, 38 Heart-lung transplantation history of, 660 technique of, 673-674 Height, and pulmonary function testing reference values, 29 Heimlich valve for outpatient drainage of air leak, 1152, 1152f for pneumothorax, 1100 Heliox, 228 Helium dilution technique, for lung volume measurements, 23 Heller myotomy, thoracoscopic, 117 Helminthic infections diagnosis and treatment of, 554t-555t epidemiology and clinical features of, 551t-552t that do not require surgery, 564-565 that sometimes require surgery, 563-564 Hemagglutination test, in hydatid disease, 559

Index-F06861.indd 1809

Hemangioendothelioma epithelioid mediastinal, 1645, 1646f pulmonary, 843-844 pleural, 1124-1125, 1125f Hemangioma of chest wall, 1218, 1222-1223 of mediastinum, 1643, 1645, 1657 sclerosing, 693, 695f Hemangiopericytoma, 693, 1645 Hematogenous metastasis, in chest wall, 1226, 1228f Hematologic malignancies, malignant pleural effusion in, 1145 Hematoma chronic expanding, after surgery for tuberculosis, 509 epidural, central neuraxial blockade and, 77 mediastinal, in trauma, 1733, 1733f post-traumatic, 1774 wound, after sternotomy, 127 Hematopoiesis, extramedullary, intrathoracic, 1650 Hemiazygos vein accessory, 1482 imaging of, 1482 Hemiclamshell approach, to superior sulcus tumors, 937-938, 938f-939f Hemodynamic monitoring during anesthesia, 46-47 in critically ill patient, 157-158 Hemoglobin, minimum acceptable, 152 Hemoglobin adjustment, of diffusing capacity for carbon monoxide (DLCO), 25 Hemopneumothorax, 1099 Hemoptysis in aspergillosis, 536 in bullous disease, 642 in interstitial lung disease, 567 in laryngeal trauma, 1743 in lung cancer, 751 with malignant etiology, palliative care for, 824t massive, 444-454 arising from bronchial circulation, 444 in arteriovenous fistulas, 446 in bronchiectasis, 474, 476-477 in bronchovascular fistulas, 447 in cardiovascular disease, 446-447 chest radiography in, 447 clinical features of, 447 computed tomography in, 447 definition of, 444 in diffuse parenchymal diseases, 447 after endobronchial brachytherapy, 238 etiology of, 445-447, 445t historical note on, 444 iatrogenic causes of, 446 idiopathic, 447 in inflammatory disease, 445 in lung abscess, 497 in lung cancer, 446 management of, 449-454 algorithm for, 449f arterial embolization in, 451-452, 452f balloon tamponade in, 450 control methods in, 449-453, 449t, 450t ice-cold saline/adrenaline lavage in, 450 intracavitary treatment in, 453 medical therapy in, 448-449 pulmonary isolation in, 450-451 radiotherapy in, 453 selective coagulative treatment in, 451 surgical, 453-454 palliative resection for, 779 in pulmonary embolism, 446 rigid bronchoscopy for, 447-448, 448f, 449 in trauma, 446 in tuberculosis, 512, 513f, 514 in mediastinal granulomatous disease, 297 rigid bronchoscopy for, 94 in tracheobronchial trauma, 1758 Hemorrhage from activated protein C, 149 after airway surgery, 228 control of, in lobectomy, 885

1809

Hemorrhage (Continued) massive, in postintubation tracheoinnominate artery fistula, 265 mediastinal imaging of, 1504, 1504f in mediastinoscopy, 58, 105-106 in poststernotomy mediastinitis, 1268, 1268f postoperative, 164 after lung transplantation, 677 after tracheostomy, 351 pulmonary in bullous disease, 642 major, palliative care for, 824t after rigid bronchoscopy, 100-101 during tracheostomy, 351 in trauma, 1725-1726, 1725t thoracotomy for, 1770-1771 Hemorrhagic malignant pleural effusion, 1138 Hemorrhagic shock physiologic response to, 1725-1726, 1725t treatment of, 1726-1727, 1726t Hemothorax computed tomography in, 1010, 1012f decortication for, 1175 after pectus deformity repair, 1342 postoperative, 167, 168f post-traumatic, 1779, 1788 massive, 1731, 1732f retained, 1771-1772, 1786 surgical indications in, 1729, 1731f after resection for superior sulcus tumors, 930, 939 retained, 1771-1772, 1786 video-assisted thoracic surgery for, 112, 1772 Heparin central neuraxial blockade and, 77 in effort thrombosis, 1289 in pulmonary embolism, 183-184, 183f in small cell lung cancer, 839 before superior vena cava cross-clamping, 1692 Hernia(s) Bochdalek. See Bochdalek hernia. of chest wall, after thoracotomy, 1786 of diaphragm. See Diaphragm, hernias of. hiatal, 1385-1386, 1389f, 1499, 1500f, 1501f Morgagni. See Morgagni hernia. subxiphoid incisional, 1253-1254 ventral, 166 Herpes simplex virus (HSV) infection, in immunocompromised host, 592 Hiatal hernia, 1385-1386, 1389f, 1499, 1500f, 1501f Hiatus, 1369, 1425 exposure of, 125, 125f Hiccups, in lung cancer, 752 Hilum anatomy of, 404-406, 404f-406f clamping of, for penetrating thoracic trauma, 1785 dissection of in robotic-assisted VATS lobectomy, 992-993, 994f-995f in video-assisted pulmonary resection, 975-976, 975b, 977f Histamine H2 receptor antagonists, for stress ulcer prophylaxis, 158 Histiocytoma, malignant fibrous of chest wall, 1232, 1297, 1298f mediastinal, 1643 pulmonary, 846 Histiocytosis, Langerhans cell, pulmonary, 581-582 Histologic studies in cryptococcosis, 546, 546f in histoplasmosis, 533-534, 534f in mucormycosis, 547 Histone acetylation, in carcinogenesis, 727, 727f Histone deacetylase inhibitors, for lung cancer, 727 Histoplasmoma, 529 Histoplasmosis, 297, 527-534 acute pulmonary, 528-529 acute respiratory distress syndrome in, 533 broncholithiasis in, 532-533, 532f chronic cavitary, 533 clinical features of, 528-533 diagnosis of, 533-534, 534f disseminated, 533

1/25/2008 1:46:12 PM

1810

Index

Histoplasmosis (Continued) epidemiology of, 528 fibrosing mediastinitis in, 530, 531f, 532, 1534, 1534f, 1535 historical note on, 527-528 in immunocompromised host, 594 localized pulmonary, 529 mediastinal granuloma in, 529-530, 530f-531f pathophysiology of, 528, 529f pericarditis in, 533 pleural, 1092 rheumatologic symptoms in, 533 tracheoesophageal fistula in, 300 HIV/AIDS bronchiectasis in, 473 bullous disease and, 635 Castleman’s disease in, 1650 empyema in, 1070 and multiple-drug-resistant tuberculosis, 511 pericarditis in, 1540 pneumothorax in, 1104-1105 pulmonary infections in, 585t, 594-595 thymic cyst in, 1577 tuberculosis in, 592 tuberculous pleural effusion in, 1073 Hoarseness in lung cancer, 752 in tracheal tumors, 312-313 in tracheobronchial trauma, 1758 Hodgkin’s lymphoma, 1624-1628 clinical and laboratory features of, 1624-1625, 1625f incidence of, 1622 mediastinal, 1490, 1491f, 1510, 1510f pathology of, 1624 pulmonary, primary, 847-848 staging of, 1625-1626, 1625t, 1626f treatment of, 1626-1627 complications of, 1627-1628 Holinger anterior commissure laryngoscope, 84f, 85 Holinger ventilating bronchoscope, 330, 330f Homer-Wright rosettes, in neuroblastoma, 1637, 1638f Honeycombing in end-stage lung disease, 419, 420, 421f, 427 in interstitial lung disease, 597, 598f Hood stent, 239 Hookworm infection, 552t, 555t, 564 Hoover’s sign, 604, 1378 Hopkins rod-type telescope, 96f, 100 Horner’s syndrome, after resection for superior sulcus tumors, 930, 938 Horseshoe trachea, 204, 207, 209f Hospital-acquired pneumonia, 479, 479t, 489-490 Hospitalized patients, pneumonia in, 486, 487t Human herpesvirus-8, Castleman’s disease and, 1650 Human immunodeficiency virus infection. See HIV/AIDS. Hump sign, in traumatic diaphragmatic hernia, 1388, 1392f, 1393f Hydatid disease, 550, 557-563 complications of, 557-558 diagnosis of, 559-560, 560f-561f epidemiology of, 550 laboratory tests in, 558-559 mediastinal, 1579 parasitic life cycle in, 557, 557f pleural, 1081-1085, 1082f-1085f case study on, 1085, 1085f clinical series in, 1084-1085, 1085f diagnosis of, 1083-1084, 1083f-1084f historical note on, 1081 management of, 1084 pathology of, 1081-1082, 1082f secondary, 558 surgical treatment of, 560-563, 561f-563f Hydrocortisone, stress dose of, in critically ill patient, 149 Hydroxyethyl starches (HES), coagulation and, 151 Hygroma, cystic. See Lymphatic malformation, cystic. Hyoid bone, fracture of, 1741-1742, 1741f, 1747 Hyperabduction test, in thoracic outlet syndrome, 1280f, 1281

Index-F06861.indd 1810

Hypercalcemia causes of, 1677, 1680 in lung cancer, 752 in primary hyperparathyroidism, 1677, 1679-1680 Hypercapnia, permissive, for congenital diaphragmatic hernia, 1407 Hypercarbia in postoperative COPD patients, 608 during rigid bronchoscopy, 219 Hyperhidrosis, sympathicotomy for, 1303-1305, 1304f-1305f Hyperinflation, diaphragmatic consequences of, 1378-1379, 1379f Hypernephroma, pulmonary metastasis of, 860t, 862 Hyperparathyroidism, primary, 1677-1683. See also Parathyroid tumors. Hypersensitivity, delayed-type, in fibrosing mediastinitis, 1533-1534 Hypersensitivity pneumonitis, 577 Hyperthermia, postoperative, 138 Hyperthyroidism postoperative medications in patient with, 140 substernal goiter in, 1670 Hypertrophic pulmonary osteoarthropathy, in lung cancer, 752 Hypocalcemia, after thyroidectomy, 1675 Hypogammaglobulinemia, thymoma and, 1595-1596 Hypoparathyroidism, after thyroidectomy, 1675 Hypothermia, postoperative, 138 Hypothyroidism, postoperative medications in patient with, 140 Hypoventilation, central, congenital, phrenic nerve and diaphragm motor point pacing in, 1445, 1452-1453 Hypovolemic shock, 1727 Hypoxemia during one-lung ventilation, 53-54, 1707 prevention of, 54-55 treatment of, 55-57 in pneumothorax, 1095 refractory after airway surgery, 228 prone ventilation in, 154 during rigid bronchoscopy, 219 during tracheostomy, 351

I Ice slush, for topical hypothermia, phrenic nerve injury from, 1397, 1460-1461 Ice-cold saline/adrenaline lavage, for massive hemoptysis, 450 Idiopathic pulmonary fibrosis, 573-574 Ifosfamide with cisplatin and mitomycin, 782-783 for second-line treatment, 816 for small cell lung cancer, 834 Imaging. See also specific modality, e.g., Computed tomography (CT). of chest wall and sternum, 1209-1230 of diaphragm, 1380-1394 of lung chest radiography for, 415, 416f computed tomography for, 415-417, 417f fluoroscopy for, 415 magnetic resonance imaging for, 417-418, 419f nuclear, 429-442 positron emission tomography for, 417, 418f of mediastinum, 1477-1504 of pleural disease, 1008-1032 of upper airway, 196-210 computed tomography for, 196-197, 198f-199f, 200-210, 201f-210f historical note on, 196, 197f magnetic resonance imaging for, 197, 200, 200f Imatinib mesylate, for small cell lung cancer, 839-840 Immune function fluid therapy and, 150 after video-assisted pulmonary resection, 982 Immune granuloma, in fibrosing mediastinitis, 1533

Immunocompromised host clinical definition of, 583 empyema in, 1070-1071 interstitial lung disease in, 599-600 pneumonia in, 479, 479t, 490-491, 491t bacterial, 589-591 fungal, 593-594 mycobacterial, 592 pneumococcal, 589-590 viral, 592-593 pulmonary infections in, 583-596 algorithms for diagnosis and management of, 585-588, 586t-587t clinical diagnosis of, 583-584, 584f microbial etiology of, 584-585, 584t, 585t, 586, 587t radiographic features of, 585t rapid nucleic acid diagnostic tests for, 586-587 Immunodeficiency bronchiectasis in, 473 inherited, pulmonary infection in patient with, 585t, 594 lung transplantation for, 663, 688-689, 689f Immunoelectrophoresis, in hydatid disease, 559 Immunofluorescence, indirect, in hydatid disease, 559 Immunoglobulin, intravenous for myasthenia gravis, 1551 before thymectomy, 1706 Immunoglobulin E, in hydatid disease, 559 Immunosuppression after lung transplantation, 673, 675-676 for myasthenia gravis, 1550-1551 Immunotherapy for malignant mesothelioma, 1135 for myasthenia gravis, 1551 for pneumonia in immunocompromised host, 591 for small cell lung cancer, 838 Implant(s) biologic, for chest wall stabilization, 1310-1312, 1310b, 1311f for medialization laryngoplasty, 309, 309f for superior vena cava reconstruction, 951, 952, 952f Implantation methods, in chest wall stabilization, 1312-1314, 1313f Incentive spirometry, postoperative, 138 Induction therapy. See Neoadjuvant therapy. Infants. See Children; Neonates. Infection of chest wall etiology of, 1244-1245 imaging of, 1215-1218, 1217f preoperative evaluation in, 1245-1247 surgical management of, 1245f-1252f, 1245t, 1247-1252 cysts and cavities associated with, 426 of graft after chest wall reconstruction, 178 after superior vena cava reconstruction, 1694 after lung transplantation, 678-679, 679f-680f surveillance for, 676 pleural. See Pleural infection. pulmonary bacterial, 478-498 in immunocompromised host, 583-596. See also Immunocompromised host. recent, in discriminating benign versus malignant nodule, 455-456 surgical management of, anesthesia for, 59 respiratory tract bacterial, 478-498 viral bronchiolitis obliterans syndrome and, 685 after lung transplantation, 679 spread of, cervical fascial anatomy and, 1532 tracheobronchial, computed tomography in, 210 wound. See Wound infection. Infectious diseases bronchiectasis in, 473-474 pneumothorax in, 1104 tracheoesophageal fistula in, 300

1/25/2008 1:46:12 PM

Index

Inferior vena cava, 1369 agenesis of, 390, 390f injury to, penetrating, 1781 tumor invasion of, extended pulmonary resection for, 953 Inflammation of airway, 294-297 FDG uptake and, 432 nociceptor activity and, 68 Inflammatory disease, massive hemoptysis in, 445 Inflammatory myofibroblastic tumor, 696, 696f Inhalation injury flexible bronchoscopy in, 91 tracheobronchial, 1766-1767, 1767f Injection augmentation, for vocal fold paralysis, 309 Injury. See Trauma. Innervation density assessment, in thoracic outlet syndrome, 1282, 1283f Innominate artery anatomic relationship to trachea, 194, 194f anatomy of, 1201f, 1202 compression of, during mediastinoscopy, 58 high, tracheostomy and, 348 injury to in mediastinoscopy, 106 penetrating, 1781 Innominate artery compression syndrome, 245, 247, 248, 248f, 251, 253, 253f Innominate vein, superior vena cava reconstruction from, 1693-1694, 1693f-1694f Inspiration, muscles of, 1206-1207, 1206f Inspiratory capacity (IC), 19, 20f, 22, 24, 24f exercise, 27, 28f Inspiratory pressure maximum. See Maximal inspiratory pressure (MIP). Inspiratory reserve volume (IRV), 20f, 22 Insulin therapy intensive, in critically ill patient, 157 lipid levels with, 157 Intensive care unit. See also Critically ill patient. blood transfusion strategies in, 152-153, 153t diaphragm motor point pacing in, 1454-1456, 1455t intensivist-model, 145, 146b pulmonary artery rupture in, 64-65 use of sedation and paralysis in, 156 Intercostal artery(ies) anatomy of, 1200, 1201f injury to, penetrating, 1781 Intercostal nerve(s) anatomy of, 1200, 1373, 1373f blockade of, for perioperative pain management, 71-73, 72f in post-thoracotomy pain, 69-70, 70t transfer of, for phrenic nerve pacing, 1463-1464, 1463f Intercostal vein(s) anatomy of, 1200, 1201f superior, left, imaging of, 1482 Intercostobronchial arteries, 192 Interferon, for small cell lung cancer, 838 Interferon alfa-2a, for mediastinal hemangioma, 1645 Interferon-gamma in delayed-type hypersensitivity, 1534 for malignant mesothelioma, 1135 for pneumonia in immunocompromised host, 591 Interleukin-2 for malignant mesothelioma, 1135 pleurodesis with, 1050 Interleukin-12, for pneumonia in immunocompromised host, 591 Intermittent insufflation, during rigid bronchoscopy, 95, 96f Interstitial lung disease, 566-582 ambulatory diagnostic modalities in, 597-598 bronchoscopy and bronchoalveolar lavage in, 572, 597 characteristic features of, 566 chest radiography in, 570-571, 570t classification of, 566, 567f, 597, 598t clinical presentation in, 597 connective tissue disease–induced, 579-580 cysts in, 427 demographics in, 568

Index-F06861.indd 1811

Interstitial lung disease (Continued) diagnosis of, 567-573, 574f drug-induced, 568, 579 exercise testing in, 572 granulomatous, 575-577, 576f high-resolution computed tomography in, 571, 571t, 597, 598f history in, 567-568 iatrogenic, 579 idiopathic, 573-575, 575f in immunocompromised host, 599-600 incidence and prevalence of, 566-567 inherited, 578-579 laboratory tests in, 569-570, 569t lung biopsy in, 572-573, 597-602 in immunocompromised host, 600 location and number of sites for, 600-601 open versus VATS, 573, 600 role of, 598-599, 599t specimen handling for, 573, 601-602 technique for, 601-602, 601f timing of, 599 massive hemoptysis in, 447 occupational, 568, 577-578, 577t, 578f physical examination in, 568-569 pulmonary function testing in, 571 radiographic signs of, 419-420, 420f-421f signs and symptoms of, 567-568 transbronchial biopsy in, 572-573, 597-598 unique forms of, 580-582, 580f, 581f Interstitial pneumonia community-acquired, 483, 484, 485f idiopathic, 573-575 usual, 573-574 Intubation. See Endotracheal intubation. Ipratropium, for chronic obstructive pulmonary disease, 489, 606, 609 Irinotecan, for small cell lung cancer, 828, 833-834 Irrigation intrapleural, for empyema, 1063 for poststernotomy mediastinitis, 1265, 1265f Ischemia reperfusion injury, after lung transplantation, 63-64, 677 Isoflurane for airway surgery, 214 during one-lung ventilation, 54 Isolation, pulmonary, for massive hemoptysis, 450-451 Isoniazid, for tuberculosis, 504, 507 Isothiocyanates, lung cancer and, 717 Isovolume flow assessment, 33 Itching in Hodgkin’s lymphoma, 1624 in poststernotomy scar, 1254 Itraconazole for cryptococcosis, 546 for histoplasmosis, 529, 532, 533 for sporotrichosis, 549

J Jackson rigid pediatric bronchoscope, for dilation in idiopathic laryngotracheal stenosis, 271 Jarcho-Levin syndrome, 1242 Jet ventilation high-frequency during airway surgery, 216-217, 217t for hypoxemia during one-lung ventilation, 56-57 during laryngoscopy, 85 low-frequency, during airway surgery, 216, 217f, 217t during rigid bronchoscopy, 95, 96f, 219 Jeune’s syndrome, 1241-1242, 1241f acquired, 1346, 1348-1349, 1348f-1349f Jugular vein, internal, cannulation of, arterial puncture with, 47

K Kala-azar, 553t, 556t, 564 Kampmeier foci, 1003-1004

1811

Kantor-Berci video microlaryngoscope, 85, 85f Karnofsky score, in preoperative assessment, 10, 10t Kartagener’s syndrome, 473 Keloid after pectus deformity repair, 1344 after sternotomy, 1254 Kergin thoracoplasty, 1161, 1161f Ketamine, for airway surgery, 215 Kidney. See Renal entries. KIT monoclonal antibodies against, 839-840 overexpression of, in small cell lung cancer, 828 Klinefelter’s syndrome, germ cell tumors and, 1508, 1509 Knife injury, 1725 laryngeal, 1741 mechanisms of, 1777 tracheobronchial, 1756-1757 Knot pusher, in video-assisted pulmonary resection, 976, 978f Koch bacillus, 501 Kommerell’s diverticulum, 246, 251, 252f KRAS mutations, in lung cancer, 721 Krusen-Caldwell technique for nerve conduction studies, 1285 Krypton-81m, for ventilation-perfusion scintigraphy, 441 Kumpe, falling lung sign of, 1758, 1780 Kuntz, accessory nerves of, exposure of, 1303, 1304f Kyphosis, after sternal malunion, 1791, 1792f

L Lactate, serum, in hypovolemic shock, 1727 Lactate dehydrogenase (LDH) in pleural effusion, 1044 in small cell lung cancer, 828 Lady Windermere syndrome, 521 Lambert-Eaton myasthenic syndrome in lung cancer, 753 in small cell lung cancer, 827 Langerhans cell histiocytosis, pulmonary, 581-582 Laparoscopy for diaphragm motor point pacing surgery, 14481450, 1449f-1450f for diaphragmatic access, 1428, 1429f for diaphragmatic plication, 1439 in malignant mesothelioma, 1187 Laparotomy for diaphragmatic access, 1426, 1427f staging, in Hodgkin’s lymphoma, 1626 Laplace’s law, 1376, 1377 Large cell carcinoma with occult neuroendocrine differentiation, 735 Large cell neuroendocrine carcinoma, 735, 739, 739f Large cell undifferentiated carcinoma, 735, 735f Larrey’s gap, 1369, 1425 Laryngeal epilepsy, 284 Laryngeal mask, after direct laryngoscopy, 85 Laryngeal mirror, 81, 82-83, 82f Laryngeal nerve anatomy of, 306 recurrent. See Recurrent laryngeal nerve. superior anatomy of, 306 blockade of, in indirect laryngoscopy, 81 injury to, 306, 307 Laryngeal pacing, for vocal fold paralysis, 311 Laryngeal reconstruction, subglottic resection with, 358f-362f, 359, 362, 371-372, 371f-373f Laryngeal reinnervation, for vocal fold paralysis, 310 Laryngeal surgery, laser, 87-88 Laryngeal trauma, 1738-1754 airway management in, 1745, 1746f associated injuries in, 1744-1745, 1744f blunt, 1739-1741, 1740f-1741f, 1743, 1744, 1744f, 1745 causes of, 1739 caustic, 1741, 1752, 1753f classification of, 1745t clinical presentation in, 1742-1743 conservative management of, 1745-1746 diagnosis of, 1742-1745, 1744f

1/25/2008 1:46:13 PM

1812

Index

Laryngeal trauma (Continued) epidemiology of, 1739 esophageal injury with, 1744-1745 examination of, 1743 mechanisms of, 1739-1741, 1740f-1741f penetrating, 1741, 1743, 1745, 1750 pharyngeal injury with, 1744, 1744f, 1747, 1747f radiologic evaluation in, 1743-1744 signs of, 1743 sites of, 1741-1742, 1741f stents for, 1750-1752, 1750b, 1750f-1751f surgical management of, 1747-1750, 1747f-1751f timing of, 1745 treatment of, 1745-1752, 1746f results of, 1752-1753, 1752b vascular injury with, 1745 Laryngofissure, in subglottic resection with synchronous laryngeal reconstruction, 361, 362f Laryngoplasty, medialization, for unilateral vocal fold paralysis, 309, 309f-310f Laryngoscope for direct laryngoscopy, 84f, 85 flexible, 82, 82f, 83, 83f rigid, 82, 82f, 83 Laryngoscopy, 81-86 direct anesthesia for, 84-85 contraindications to, 83-84 indications for, 83 instruments for, 84f-87f, 85-86 preoperative preparation for, 84 protection of teeth during, 85 technique of, 86-87 indirect anesthesia for, 82 contraindications to, 81 indications for, 81 instruments for, 81-82, 82f in substernal goiter, 1671 technique of, 82-83, 82f-83f transnasal fiberoptic, in laryngeal trauma, 1743 Laryngotracheal disruption, 1742, 1749-1750, 1749f Laryngotracheal resection and reconstruction anastomotic failure rate in, 395 in idiopathic laryngotracheal stenosis, 273, 274f, 275 Laryngotracheal stenosis idiopathic, 270-276 basic science of, 270, 271f clinical features of, 270-271 diagnostic studies in, 271, 272f, 273f differential diagnosis of, 271 historical note on, 270 management of dilation in, 271 principles for, 271 surgical, 273, 274f postoperative care in, 273, 275 results of, 275 in Wegener’s granulomatosis, 295 Laryngotracheal stent, after partial cricotracheal resection, 372, 372f, 373 Laryngotracheal tumors, resection of, 316 Laryngotracheobronchial injuries, penetrating, 1779-1780 Larynx. See also Laryngotracheal entries. anatomy of, 353, 354f, 1739 dysfunction of, after tracheal resection and reconstruction, 381, 381t, 397-398 edema of, after tracheal resection, 397 electromyography of, in vocal fold paralysis, 308 esophageal carcinoma invading, 325 fracture of, 1740f-1741f, 1741 functions of, 306 inhalation injuries to, 1741, 1752 missile injury to, 1750 stenosis of, post-traumatic, 1752 thyroid cancer invading, 322-325 trauma to. See Laryngeal trauma. Laser therapy airway fire during, prevention of, 226-227, 227f, 232

Index-F06861.indd 1812

Laser therapy (Continued) anesthesia for, 225-227 bronchoscopy in flexible, 91 rigid, 94-95 carbon dioxide, for tracheal stenosis, 334 complications of, 226-227 endobronchial for airway obstruction, 232-234, 233f versus photodynamic therapy, 236 laryngeal, 87-88 for malignant central airway obstruction, 339340 Nd:YAG, for tracheal stenosis, 335 photodynamic. See Photodynamic therapy. physics of, 232 for postintubation stenosis, 261-262, 262f for pulmonary metastasectomy, 856, 856f for tracheal stenosis, 334-335 Laser-Flex Tracheal Tube, 227, 227f Lateral position changes to or from, 47-48 neurovascular complications associated with, 48 physiologic changes in, 48-49 Latex agglutination test, in hydatid disease, 559 Latissimus dorsi anatomy of, 1202t, 1203, 1203f-1205f blood supply to, 1323-1324, 1324f chest wall reconstruction with, 1245t, 1246f1248f, 1249, 1299-1300, 1323-1325, 1323f-1324f mediastinal reconstruction with, 1266-1267 as pedicled flap, problems with, 1324, 1324f rotation of, for congenital absence of diaphragm, 1462 Lavage bronchoalveolar. See Bronchoalveolar lavage. ice-cold saline/adrenaline, for massive hemoptysis, 450 lung for pulmonary alveolar proteinosis, 581 whole, 65-66 pleural space, as complement to thoracoscopy, 1040 Legionellosis pneumonia, 481, 589 Leiomyoma mediastinal, 1647 pulmonary, 696 subserosal, 1496 Leiomyosarcoma of chest wall, 1223, 1227f mediastinal, 1647 pleural, 1123 pulmonary, primary, 846 Leishmania donovani, 553t, 556t, 564 Leukocytosis in community-acquired pneumonia, 482-483 in Hodgkin’s lymphoma, 1625 Leukoreduction, in blood transfusion, 153 Lewy suspension device, 85-86, 86f Lidocaine, in tracheal resection, 223 Liebow classification of lung tumors, 691 Life expectancy, pulmonary function and, 13 Ligamentum arteriosus anatomy of, 405, 405f division of, in pneumonectomy, 866, 866f left, right aortic arch with, 244, 244f, 245f, 247t, 248f, 251, 252f Light Induced Fluorescence Endoscopy (LIFE) device, 761 Light’s criteria for exudative pleural effusion, 10351036, 1036b Lindholm laryngoscope, 84f, 85 Lindholm’s self-retaining vocal cord retractor, 365, 365f Linear tomogram, of upper airway, 196, 197f Lingula segmentectomy, 891, 891f-892f Lingular artery, anatomy of, 898, 898f, 910f, 911f, 912 Lipid(s) in chyle, 1112 levels of, with insulin therapy, 157 Lipoblastoma/lipoblastomatosis, mediastinal, 1642-1643

Lipoma bronchopulmonary, 695-696 of chest wall, 1221, 1223f-1224f, 1231, 1233f mediastinal, 1642 pleural, 1023, 1023f Lipomatosis of chest wall, 1221 mediastinal, 1642 Liposarcoma of chest wall, 1221, 1297-1298 mediastinal, 1643 pleural, 1124 Lithium dilution, for cardiac output measurement, 157 Liver disease, preoperative risk assessment in patient with, 16 Liver herniation, in congenital diaphragmatic hernia, 1414, 1414b, 1415f, 1416, 1417, 1417f, 1417t Liver metastasis positron emission tomography specificity for, 436-437 symptoms of, 753 Liver transplantation, phrenic nerve injury after, 1461-1462 Living lobar lung donor transplantation, 664 Living wills, 823 Lobar emphysema, congenital, 465, 465f Lobe(s) anatomy of, 401-402, 402f anomalies of, 402-403 collapse of. See Atelectasis. left lower, 407-408 left upper, 407 right lower, 407 right middle, 406-407 right upper, 406 Lobectomy, 879-886 air leak after, 885 bleeding control in, 885 bronchus management in, 881 carinal resection with, 388, 388f after chemoradiotherapy, 885-886 chest tube management after, 886 exploration and mobilization of lung in, 880-881 fissure management in, 881 hilar dissection management in, 881 history of, 4, 879 incisions for, 880, 880f indications for, 879 left lower, 884-885 left upper, 884, 884f-885f for lung abscess, 497 lymphadenectomy in, 881 of middle and lower lobes, 883 for non–small cell lung cancer, 768 for parenchymal injury, 1773 patient positioning for, 880, 880f preoperative evaluation for, 879-880 prevention of atrial fibrillation and venous thromboembolism after, 886 for pulmonary metastasectomy, 856, 857f right lower, 883 right middle, 882-883, 883f right upper, 881-882, 882f middle lobe torsion after, 885 risk factors for, 11 sleeve. See also Sleeve resection, and bronchoplasty. history of, 4 late airway complications of, 174 left lung, 902-903, 903f after neoadjuvant therapy, 908 versus pneumonectomy, 907, 907t right lung, 901-902, 902f-903f space issues in, 885 sublobar resection versus, appropriate lesions for, 870, 870f-871f of upper and lower lobes, 883 VATS, 113-114 history of, 4 incision for, 134, 134f for non–small cell lung cancer, 769-770, 770t simultaneous stapling technique in, 984-985 technical steps to, 986-987

1/25/2008 1:46:13 PM

Index

Lobectomy (Continued) VATS (robotic-assisted), 989-997 da Vinci Surgical System for, 989, 990f division of fissure in, 993, 996f hilar dissection in, 992-993, 994f-995f historical note on, 989 initial exploration and robot positioning in, 991-992, 991f mediastinal lymph node dissection in, 992, 992f-993f patient selection for, 989 results of, 993, 995-997, 997t robot preparation in, 991 robotic training and technique development for, 989, 991 Local anesthesia for flexible bronchoscopy, 93 for perioperative pain management, 71-75, 72f-75f for rigid bronchoscopy, 97 Loffler’s pneumonia, 581 Lorenz tunneler, in Nuss procedure, 1331, 1334, 1336f Lower extremity amputation of preoperative risk assessment in patient with, 16 and pulmonary function testing reference values, 29 swelling of, in chronic thromboembolic pulmonary hypertension, 654 Lucite-ball plombage, 1162, 1162f delayed complications of, 507-508, 508f Lumbar puncture, in small cell lung cancer, 827 Lung. See also Pulmonary entries. abscess of, 426, 493-497 amebic, 553t, 556t, 563 classification of, 493, 494t clinical presentation in, 495 definition of, 493 diagnosis of, 495 historical note on, 494 after lung transplantation, 678-679 management of, 495-497, 496f microbiology of, 494-495 palliative resection for, 779 pathophysiology of, 494 results of, 496 agenesis of, 462-463, 463f anatomy of, 401-414, 402f-413f aplasia of, 463 benign neoplasms of, 691-698, 692b, 692t bronchopulmonary segments of, 401-403, 402f collapse of. See Atelectasis. compliance of with lateral position, 48 measurement of, 26, 26f congenital anomalies of, 462-471, 463t contusion of, 1772-1773, 1772f, 1789 cyst of. See Pulmonary cyst. drowned, 423 edema of. See Pulmonary edema. embryology of, 401, 462 fissure(s) of anomalies of, 402 confluence of, 408, 408f, 409f left major, 410-411, 411f-412f right major, 408-409, 408f-409f right minor (horizontal), 410, 410f gangrene in, from tuberculosis, 509-510 herniation of imaging of, 1212 as late postoperative complication, 166 traumatic, 1770 hypoplasia of, 463-464, 464f in congenital diaphragmatic hernia, 1422-1423 imaging of chest radiography for, 415, 416f computed tomography for, 415-417, 417f fluoroscopy for, 415 magnetic resonance imaging for, 417-418, 419f nuclear, 12, 429-442 positron emission tomography for, 417, 418f infection of. See Pulmonary infection. injury to, penetrating, 1779 intrapericardial anatomy of, 403-404, 403f

Index-F06861.indd 1813

Lung (Continued) left, anatomy of, 401-402, 402f lobe(s) of anatomy of, 401-402, 402f anomalies of, 402-403 left lower, 407-408 left upper, 407 right lower, 407 right middle, 406-407 right upper, 406 right absent, 462 anatomy of, 401, 402f trapped. See Fibrothorax. Lung allocation score (LAS), for lung transplantation, 661-662, 662t Lung biopsy. See also Transbronchial biopsy. in interstitial lung disease, 597-602. See also Interstitial lung disease, lung biopsy in. open in fungal infections, 526 in interstitial lung disease, 573, 600 in Wegener’s granulomatosis, 294-295 thoracoscopic, 115 in coccidioidomycosis, 543, 543f in interstitial lung disease, 573, 600 technique for, 601, 601f Lung bud anomalies of, 463t, 464-471 failure of development of, 462-464, 463f-464f Lung cancer. See also specific type, e.g., Adenocarcinoma. age and, 710, 710f air pollution and, 715 asbestos exposure and, 714-715 biology of carcinogenesis in, 718-727. See also Carcinogenesis. bullous disease and, 644 and development of thoracic surgery, 3 diagnostic modalities for, 757-762 diet/dietary supplements and, 715-717 epidemiology of analytic, 712-718, 714t, 717t descriptive, 708-712, 709f-710f gender and, 709-710, 710f genetic factors in, 717-718, 717t geography and, 711 histology distribution for, 711-712 historical note on, 708 local recurrence of, late, 176, 177, 178f malignant pleural effusion in, 1144-1145 massive hemoptysis in, 446 after mediastinal radiotherapy, 1627-1628 neuroendocrine features of, 700, 737-739, 738f-739f large cell, 735, 739, 739f nonendocrine, clinicopathologic features of, 729737, 730f-736f non–small cell. See Non–small cell lung cancer. occupational exposure and, 714-715 pathologic features of, 729-740 reports on, 740, 740t suggested ADASP reporting format for, 741b WHO/IASLC classification of, 729, 730t preoperative risk assessment in, 44 primary second, 177, 791, 791t versus secondary, 740 race and, 710f, 711 radiation exposure and, 715 rare forms of, 841-849 screening for, 743-750, 753-756 chest radiography and sputum cytologic examination for, 744-746, 745t current guidelines for, 744 fluorescence bronchoscopy for, 749 historical note on, 743 low-dose computed tomography for evaluation of, 746-747, 746t nonsolid and part-solid nodules detected on, 747, 748f in patients with previously resected lung cancer, 747, 748f, 792

1813

Lung cancer (Continued) screening for (Continued) molecular biologic techniques for, 749 postresection, 792-793 research controversies related to, 743, 745-746, 754, 754f solitary pulmonary nodule and, 755-756, 756t sputum-based investigational approaches to, 747-749 small cell. See Small cell lung cancer. smoking and, 712-714, 714t. See also Smoking. socioeconomic status and, 711 squamous cell. See Squamous cell carcinoma, of lung. stage at presentation for, 712 staging of bronchoscopy for, 760-761 chest radiography for, 757, 759f computed tomography for, 757-758, 759f EUS/EBUS in, 107, 761-762 mediastinoscopy/mediastinotomy for, 102-103, 761 molecular biologic techniques for, 762-763 nodal, evolution of, 958-960, 959f, 960t, 961f organ-specific scanning for distant metastatic disease in, 762 positron emission tomography for, 433-439, 435f-438f, 759-760, 759f regional nodal stations in, 411, 412f, 413, 756-757, 758f sputum cytologic examination for, 760 thoracotomy for, 762 TNM system of, 411, 756, 757t transthoracic fine needle aspiration for, 761 video-assisted thoracic surgery for, 762 surgery for mortality after, 69t planning of, flexible bronchoscopy in, 89-90 symptoms of, 751-753 extrapulmonary thoracic, 751-752 extrathoracic, 752-753 pulmonary, 751 tuberculosis and, 514 Lung disease anatomic distribution of, 428 end-stage, honeycombing in, 419, 420, 421f, 427 granulomatous, 575-577, 576f interstitial. See Interstitial lung disease. localization of, radiographic, 427 obstructive chronic. See Chronic obstructive pulmonary disease (COPD). lung transplantation for, 662-663, 687t, 688, 689f radiographic signs of, 418-428, 419f-427f Lung en cuirasse, 1171 Lung fluke, 551t, 554t, 564 Lung lavage for pulmonary alveolar proteinosis, 581 whole, 65-66 Lung separation, 49-53, 50f-53f, 52t. See also Ventilation, one-lung. Lung tourniquet, introduction of, 4 Lung transplantation, 660-690 anesthesia for, 62-64 in children, 672-673, 682 complications of airway, 680-682, 681f-682f from infection, 678-679, 679f-680f malignancies as, 682-683, 683f pleural space, 680, 680f from primary graft dysfunction, 677-678, 677t, 678f from rejection acute, 683-684, 684f, 684t chronic, 684-686, 685f, 685t from technical error, 676-677 for cystic fibrosis and immunodeficiency disorders, 663, 688-689, 689f donor organ in extraction of, 666-668, 667f-668f living lobar, 664 marginal, 664 non–heart-beating, 664-665

1/25/2008 1:46:13 PM

1814

Index

Lung transplantation (Continued) preservation of, 665-666 standard selection criteria for, 663-664, 664t flexible bronchoscopy in, 91-92 history of, 5, 660-661 invasive pulmonary aspergillosis after, 538, 539 late complications of, 178 for obstructive lung disease, 662-663, 687t, 688, 689f organ allocation considerations in, 661-662, 662t postoperative management of in children, 673 fluid therapy in, 675 immunosuppression in, 673, 675-676 infection and rejection surveillance in, 676 ventilation in, 675 for pulmonary vascular disease, 663, 675, 688, 689f recipient selection for disease-specific considerations in, 662-663 general considerations in, 661-662, 662t for restrictive (fibrotic) lung disease, 663, 689, 689f, 690f results of functional, 687-689, 687t, 688f-690f for late mortality, 687 for operative mortality, 686-687, 687f retransplantation after, 674 sequential bilateral, 668-672 exposure in, 668, 668f, 669f implantation in, 669-672, 670f-672f recipient pneumonectomy in, 668-669 single-lung choice of side in, 672 exposure in, 672 implantation in, 672 ventilation in, 675 survival after, factors that predict, 662t technique of for donor extraction, 666-668, 667f-668f for recipient anesthesia, 668 sequential bilateral, 668-672, 668f-672f single-lung, 672 waitlist for, risk of death while on, 662t Lung volume fetal in congenital diaphragmatic hernia, 1406, 1417-1418 measurement of, 1415f, 1417-1418 observed/expected ratio for, 1418 in interstitial lung disease, 571 loss of diaphragm elevation in, 1396 in diaphragmatic eventration, 1433, 1434 measurement of, 22-25 body plethysmography for, 22-23, 23f-24f carbon monoxide diffusing capacity for, 24-25 definition of, 22 gas dilution for, 23 Lung volume reduction surgery, 612-621 anesthesia for, 61-62 bronchoscopic alternatives to with airway bypass, 623-626, 624f-626f with one-way valves, 626-630, 627f-630f, 629t cardiopulmonary exercise testing after, 36, 38 history of, 5, 612, 622-623 late complications of, 178 median sternotomy for, 617-618 morbidity and mortality of, 618-619 operative approach in, 617-618 postoperative care in, 618 preoperative assessment for, 12, 614-617, 615t, 616f preoperative medical management in, 613-614 rationale for, 612 results of, 619-621, 619f-620f video-assisted thoracic surgery for, 114-115, 618 Lung volume reduction with one-way valves, for emphysema, 626-630, 627f-630f, 629t Lung-to-head ratio (LHR) classification of pulmonary hypoplasia based on, 1422-1423 in congenital diaphragmatic hernia, 1416-1418, 1417f, 1417t

Index-F06861.indd 1814

Lung-to-head ratio (LHR) (Continued) liver herniation and, 1417, 1417f, 1417t prognostic value of, 1405-1406 measurement of, 1415f and survival rate after fetal endoscopic tracheal occlusion, 1422 Lupus erythematosus, systemic, 579 Lupus vulgaris, 499 Lymph node axillary, imaging of, 1228 in cancer staging, evolution of, 958-960, 959f, 960t, 961f giant hyperplasia of, in mediastinum, 1641, 16501652, 1651f interlobar (sump), 408f, 409 mapping of, 959, 959f mediastinal. See Mediastinal lymph node. paratracheal, biopsy of, 1473, 1474f regional, of lung, 411, 412f, 413, 756-757, 758f sampling of definition of, 957 technique of, 963 systematic sampling of, in video-assisted pulmonary resection, 978-979 tuberculosis in, airway obstruction from, 514-515 Lymphadenectomy definitions in, 770b, 957 in lobectomy, 881 mediastinal. See Mediastinal lymphadenectomy. for non–small cell lung cancer, 770-771 Lymphangiogram, in chylothorax, 1114, 1114f Lymphangioleiomyomatosis, 580, 580f Lymphangioma. See Lymphatic malformation, cystic. Lymphatic capillaries, 1110 Lymphatic malformation, cystic, 697 of chest wall, 1223 clinical presentation in, 1573-1574, 1574f imaging of, 1574, 1575f incidence of, 1573 management and surgical considerations in, 1574-1575, 1575f mediastinal, 1494, 1494f, 1572-1576, 1645, 1657 outcome in, 1576 Lymphatic sump of Borrie, 961 Lymphatics of bronchus, 898 of diaphragm, 1370-1371 embryology of, 1109-1110, 1110f of pleura, 1003 pulmonary, 411, 412f, 413, 756-757, 758f patterns of metastatic spread and, 960-962, 962f, 962t of trachea, 194 Lymphoblastic lymphoma, 1623, 1629-1630, 1630f Lymphocytes, in chyle, 1112-1113 Lymphocytic bronchitis, bronchiolitis obliterans syndrome and, 685 Lymphoepithelioma-like carcinoma, pulmonary, primary, 847 Lymphoid thymic hyperplasia, 1488 Lymphoid tumors, bronchial-associated, 694-695, 695f Lymphoma Ann Arbor staging system for, 1625, 1625t of chest wall, 1223, 1226, 1227f Hodgkin’s. See Hodgkin’s lymphoma. large B-cell, primary mediastinal, 1628-1629 lymphoblastic, 1623, 1629-1630, 1630f malignant pleural effusion in, 1145 mediastinal, 1622-1632 biopsy techniques and specimen handling in, 1623-1624 characteristics of, 1510 clinical features of, 1622-1623 corticosteroids for, prebiopsy, 1624 imaging of, 1490-1492, 1491f, 1492f pediatric, 1655, 1655f pleural fluid cytology in, 1624 relapsing, 1491-1492 residual masses after treatment of, 1631-1632, 1631f non-Hodgkin’s incidence of, 1622 mediastinal, 1490, 1492f, 1628-1630

Lymphoma (Continued) non-Hodgkin’s (Continued) pulmonary, 1630-1631 primary, 848-849 pleural, 1027-1028, 1028f versus thymoma, 1597 tumor lysis syndrome in, tracheoesophageal fistula after, 303 Lymphoproliferative disorders, post-transplant, 573, 682-683, 683f Lymphoreticular disorders, malignant, pulmonary, primary, 847-849 Lysozyme test, in tuberculous pleural effusion, 1075 M Magnetic resonance imaging (MRI) in brachial plexopathy, 1228-1230, 1229f in bronchogenic cyst, 1496, 1497f, 1582, 1583f in chest wall invasion, 1227, 1228f in chest wall mass, 1233 in chest wall schwannoma, 1221-1222, 1226f in cystic lymphatic malformation, 1574, 1575f in esophageal cyst, 1498, 1498f in fibrosing mediastinitis, 1503 in fibrous tumors of pleura, 1024 in hydatid disease, 559, 561f in intrathoracic thyroid mass, 1494 of lung, 417-418, 419f of mediastinal lymph nodes, 1483-1484 in mediastinal lymphadenopathy, 1498 in mediastinal lymphangioma, 1494 in mediastinal lymphoma, 1490-1491 in mediastinal parathyroid adenoma, 1495 of mediastinum, 1477 in paraganglioma, 1499 in pericardial calcification, 1541 in pericardial cyst, 1492, 1492f in small cell lung cancer, 827 in substernal goiter, 1670 in superior sulcus tumors, 824, 826f in teratoma, 1489 in thymic carcinoma, 1485 in thymic cyst, 1487, 1488f, 1577 in thymoma, 1484 of thymus, 1478, 1480 in traumatic diaphragmatic hernia, 1389, 1392f of upper airway, 197, 200, 200f in vascular rings, 248 Malacia definition of, 277 tracheal. See Tracheomalacia. Malaria, 553t, 556t, 564 Malignancy. See Cancer. Malignancy-associated changes (MACs), detection of, in sputum-based lung cancer screening, 749 Malignant mesothelioma. See Mesothelioma, malignant. Malnutrition, prevention of, in chylothorax, 1116 MALT (mucus-associated lymphoid tissue) B-cell lymphoma of, 694 pulmonary lymphoma arising from, 848, 1630-1631 Mammary artery, internal dissection of, phrenic nerve injury in, 1461 embolization of, for massive hemoptysis, 451 Mantoux test, 506 Manubrial retractor, for thymectomy, 1550, 1553, 1717, 1717f Manubrium, 1197, 1198f, 1200 Marfan’s syndrome, chest wall deformities in, 1236, 1345 Marimastat, for small cell lung cancer, 839 Marlex mesh characteristics of, 1311 in composite prosthesis, 1312, 1313 for substernal support in pectus deformity repair, 1345, 1346, 1346f, 1347f tracheobronchoplasty with, 291, 292f Masaoka staging system, for thymoma, 1551-1552, 1552t, 1589, 1590t Mask, laryngeal, after direct laryngoscopy, 85 Matrix metalloproteinase inhibitors, for small cell lung cancer, 839

1/25/2008 1:46:13 PM

Index

Matrix metalloproteinases in carcinogenesis, 722 in small cell lung cancer, 826, 828 Maximal expiratory pressure (MEP), 25 Maximal inspiratory pressure (MIP), 25 Maximum oxygen consumption (VO2max) in cardiopulmonary exercise testing, 26 preoperative assessment of, 11t, 12-13, 42 prognosis and, 38 Maximum phonation time (MPT), in vocal fold paralysis, 308 Maximum voluntary ventilation (MVV), 11, 25, 27, 27f Mean arterial pressure, regulation of, during superior vena cava cross-clamping, 1692 Mebendazole, for hydatid disease, 562-563 Mechanical ventilation. See Ventilation, mechanical. Medialization laryngoplasty, for unilateral vocal fold paralysis, 309, 309f-310f Median nerve, compression of, and thoracic outlet syndrome, 1275, 1278f Mediastinal emphysema, after lung transplantation, 681, 681f Mediastinal granuloma, in histoplasmosis, 529-530, 530f-531f Mediastinal granulomatous disease, 297 Mediastinal growing teratoma syndrome, 1489, 1618 Mediastinal hematoma, in trauma, 1733, 1733f Mediastinal hemorrhage imaging of, 1504, 1504f in mediastinoscopy, 58, 105-106 in poststernotomy mediastinitis, 1268, 1268f Mediastinal lymph node dissection of. See Mediastinal lymphadenectomy. giant hyperplasia of, 1641, 1650-1652, 1651f imaging of, 1483-1484, 1483f intraoperative visual evaluation of, 957, 958t patterns of spread to, 960-962, 962f, 962t sentinel, biopsy of, 958 staging of, 958-960, 959f, 960t, 961f chest radiography for, 757 computed tomography for, 758, 1484 endoscopic ultrasound/ fine-needle aspiration for, 761-762 EUS/EBUS for, 107 magnetic resonance imaging for, 1484 mediastinoscopy/mediastinotomy for, 102-103, 761 for non–small cell lung cancer, 766-767, 767f positron emission tomography for, 434-435, 435f-437f, 759f, 760, 1484 video-assisted thoracic surgery for, 115-116, 762, 1700-1701 Mediastinal lymphadenectomy, 957-969 complete definition of, 957 in left hemithorax, 965-966, 966f in right hemithorax, 963-965, 964f-965f complications of, 966-967 future directions in, 969 late complications associated with, 180-181 rationale for, 957-958 robotic-assisted VATS for, 992, 992f-993f survival rate and, 967-968, 968f techniques of, 963 video-assisted thoracic surgery for, 968-969 Mediastinal lymphadenopathy characteristics of, 1511 flexible bronchoscopy in, 91 imaging of, 1483-1484, 1498, 1499f, 1500f pediatric, 1659, 1659f of unknown etiology, 512, 513f Mediastinal mass anterior, anesthesia for, 59-60, 59f characteristics of, according to localization, 1506-1513, 1507f-1513f, 1507t diagnosis of, 1506-1520 compartmental implications in, 1506-1513, 1507f-1513f, 1507t cytohistopathologic, 1513-1519 strategic decisions in, 1519-1520, 1519f fine needle aspiration biopsy of, 1514, 1515-1516, 1515f imaging of, 1484-1501, 1484f-1501f

Index-F06861.indd 1815

Mediastinal mass (Continued) location of, by compartment, 1471, 1472t open procedures for, 1519 percutaneous core needle biopsy of, 1514-1515 residual, after mediastinal lymphoma treatment, 1631-1632, 1631f types of, 115t video-assisted thoracic surgery for, 115, 15171519, 1517f-1519f Mediastinal parathyroid tumors, 1677-1683 Mediastinal seminoma, 1616-1617, 1616f Mediastinal shift in congenital agenesis of lung, 462, 463f in diaphragmatic eventration, 1432, 1432f after pneumonectomy, 1031, 1032f, 1192 Mediastinal structures, anterior projection of, 119, 120f Mediastinal surgery history of, 6 late complications of, 180-182, 181f thoracoscopic, 115-116, 115t, 1697-1704 anatomic considerations in, 1697 in anterior compartment, 1699-1700, 1699t general considerations in, 1697-1699, 1698f in middle compartment, 1700-1701, 1701t in posterior compartment, 1701-1703, 1702t robotic, 1518-1519, 1703-1704 Mediastinal thyroid tumors, 1661-1676. See also Goiter, substernal. Mediastinal tumors germ cell. See Germ cell tumors, mediastinal. mesenchymal, 1641, 1642-1648, 1642t neurogenic. See Neurogenic tumors, of mediastinum. pediatric, 1653-1660 anatomic considerations in, 1653 clinical presentation in, 1653-1654 cystic, 1579 diagnosis of, 1654, 1654f surgical access in, 1655 types of, 1655-1659 unusual, 1641-1652 Mediastinitis acute classification of, 1532 computed tomography in, 1501-1502, 1501f-1502f acute necrotizing, 1521-1528, 1532, 1533f criteria for, 1521, 1522t initial treatment of, 1523 mortality in, 1521, 1522t pathophysiology of, 1521-1522, 1522f radiologic evaluation in, 1522-1523, 1523f surgical treatment of, thoracoscopic, 1703 anatomic considerations in, 1521-1522, 1522f, 1530-1532, 1530f-1532f chronic, 1529-1536 classification of, 1532 cystic, in infants and children, 1578-1579 fibrosing (sclerosing), 297, 1532-1535 clinical manifestations of, 1535 computed tomography in, 207-208 diagnosis of, 1534-1535 etiology of, 1533 in histoplasmosis, 530, 531f, 532 imaging of, 1502-1503 pathogenesis of, 1533-1534 pathology of, 1534, 1534f prognosis in, 1535 radiologic findings in, 1535 treatment of, 1535 historical note on, 1529-1530 phlegmonous, 1532 poststernotomy, 127, 1263-1270. See also Sternomediastinitis, postoperative. Mediastinoscope, for pleuroscopy, 1038, 1038f Mediastinoscopy, 102-108 anesthesia for, 57-58 anterior, 1473, 1473f parasternal, 105, 1516 for bronchogenic cyst, 1584 cervical, 1473, 1474f, 1516-1517 extended, 105, 1473, 1474f, 1517

1815

Mediastinoscopy (Continued) cervical (Continued) in lobectomy, 880 technique of, 103-105, 103f-105f complications of, 105-107 contraindications to, 102 history of, 102 indications for, 102-103 late complications after, 181 for lung cancer staging, 761 in malignant mesothelioma, 1186-1187 in non–small cell lung cancer, 767 in pericardial cyst, 1587 PET/CT versus, 435 in pleural disease, 1041 repeat, 105 results of, 107-108 timing of, 107-108 video-, 105, 106f, 1517 Mediastinotomy anterior, 122-123, 122f for lung cancer staging, 761 Mediastinum abscess of, 1532, 1578-1579 anatomy of, 1471-1476, 1472f-1475f anterior compartment of, 1472, 1472f, 1697 cysts of, pediatric, 1572-1578 imaging of, 1478, 1479f-1482f, 1480 limited surgical access to, 1473, 1473f masses of, 1472t characteristics of, 1506-1511, 1507f-1512f diagnosis of, 1699 differential diagnosis of, 1597 imaging of, 1484-1495, 1484f-1495f video-assisted thoracic surgery in, 1699-1700, 1699t carcinoma of, primary, 1648-1650 chest radiography of, 1477 compartments of, 1471-1472, 1472f, 1472t computed tomography of, 1477, 1478f-1480f cyst of, 1581-1587 embryology of, 1581 pediatric, 1562-1579, 1658-1659, 1659f video-assisted thoracic surgery for, 116, 1701 definitions related to, 1471 drainage of, after pectus excavatum repair, 1343, 1343f extramedullary hematopoiesis in, 1650 FDG-PET of, 1477 four-compartment model of, 1471-1472, 1472f imaging of, 1477-1504 involvement of in lung cancer, symptoms of, 752 in non–small cell lung cancer, 778 magnetic resonance imaging of, 1477 malformations of, congenital subglottic stenosis associated with, 364 masses of. See Mediastinal mass. middle compartment of, 1472, 1472f, 1697 imaging of, 1479f-1480f, 1480-1482, 1482f limited surgical access to, 1473, 1474f, 1475f masses of, 1472t characteristics of, 1511, 1513f diagnosis of, 1700-1701 imaging of, 1495-1499, 1496f-1500f video-assisted thoracic surgery in, 1700-1701, 1701t positron emission tomography/computed tomography of, 1477-1478 posterior compartment of, 1472, 1472f, 1697 imaging of, 1479f-1480f, 1482-1483 limited surgical access to, 1474-1475, 1475f masses of, 1472t characteristics of, 1511-1513, 1513f diagnosis of, 1701 imaging of, 1499-1501, 1500f-1501f video-assisted thoracic surgery in, 1701-1703, 1702t prevascular zone of, 1472 primary carcinoma of, 1648-1650 radiologic anatomy of, normal, 1478-1484, 1479f-1483f radiotherapy to, complications of, 1627-1628

1/25/2008 1:46:13 PM

1816

Index

Mediastinum (Continued) reconstruction of, in poststernotomy mediastinitis, 1266-1267, 1266f retrovisceral zone of, 1472 sclerosing fibrosis of. See Mediastinitis, fibrosing (sclerosing). Shields’ three-zone model of, 1472, 1507f superior compartment of, 1471-1472, 1472f masses of, 1472t surgical access to, 1473-1475, 1473f-1475f in children, 1655 three-compartment model of, 1472 tumors invading, stage II non–small cell lung cancer with, 775 tumors of. See Mediastinal tumors. ultrasonography of, 1478 visceral zone of, 1472 widening of, in fibrosing mediastinitis, 1535 Megaesophagus, 1496 Melanoma, pulmonary metastasis of, 859f, 860t, 862 primary, 844 Meningioma, 697 Meniscus sign, in pleural effusion, 1042, 1043f Mesenchymal tumors, of mediastinum, 1641, 1642-1648, 1642t, 1659 Mesenchymoma, mediastinal, 1648, 1649f Mesentery, dorsal, 1372f, 1373 Mesh for chest wall stabilization, 1311-1312, 1313, 1313f for substernal support in pectus deformity repair, 1345, 1346, 1346f, 1347f tracheobronchoplasty with, 291, 292f Mesothelial cyst, pediatric, 1659, 1659f Mesothelioma, malignant, 1028-1031, 1125-1135 asbestos exposure and, 1126 diagnosis of, 1126, 1126f-1127f diaphragm elevation in, 1396, 1398f histologic classification of, 1126-1127, 1127f imaging of, 1028-1029, 1029f-1030f malignant pleural effusion in, 1145 palliative care for, 824t pericardial, 1545 prognosis in, 1128 simian virus 40 and, 1126 staging of, 1029-1030, 1127-1128, 1128t, 1129t thoracoscopy in, 1039-1040, 1040f treatment of, 1128-1135 chemotherapy in, 1130 extrapleural pneumonectomy in, 1186-1192. See also Pneumonectomy, extrapleural. innovative adjunctive therapies in, 1134-1135 multimodal therapy in, 1133-1134 options in, 1133t radiotherapy in, 1128-1130 surgical, 1130-1133, 1130t, 1131f-1133f, 1186 Metabolic acidosis, from fluid therapy, 150 Metabolic storage diseases, 579 Metabolism, after lung transplantation, 666 Metal allergy, in pectus deformity repair, 1345 Metal plates and struts for chest wall stabilization, 1311, 1312f in pectus excavatum repair, 1330-1331, 1334f Metal rods, dislodgement or fracture of, after pectus deformity repair, 1344-1345, 1344f Metastasectomy in nonseminomatous mediastinal germ cell tumor treatment, 1620 pulmonary. See Pulmonary metastasectomy. Metastatic disease. See also specific site, e.g., Brain metastasis. distant computed tomography in, 758 management of, 819-820 organ-specific scanning for, 762 positron emission tomography in, 435-437, 438f, 759f, 760 symptoms of, 753 nonresectable, criteria for, 793t postresection follow-up for, 793, 793t to upper airway, 204 Methacholine challenge testing, in asthma, 35-36

Index-F06861.indd 1816

Methohexital, for airway surgery, 215 Methotrexate for malignant mesothelioma, 1130 for Wegener’s granulomatosis, 295 Methylmethacrylate in composite prosthesis, 1312, 1313 problems with, 1312 for spinal reconstruction after vertebrectomy, 946, 949f Methylprednisolone for acute exacerbation of chronic obstructive pulmonary disease, 489 after lung transplantation, 675 for subglottic edema, 341 Metoprolol, during airway surgery, 216 Metronidazole, for pleural amebiasis, 1086 Metzenbaum scissors, in video-assisted pulmonary resection, 976 Microdébrider for central airway obstruction, 337-338, 338f for endobronchial obstruction, 235 Microlaryngoscope operating, 86, 87f video, 85, 85f Microwave ablation, 802-803 Midazolam for airway surgery, 215 for sedation in ICU, 156 Middle lobe syndrome, in tuberculosis, 515, 516f Midline approach, for thoracic epidural analgesia, 75, 76f Midsternal stripe sign, 1255 Milky spots, 1003-1004 Miller’s normal reference values, 29 Minithoracotomy with video assistance, 971, 985 Minitracheostomy, 344, 350, 352 for anastomosis in subglottic region, 382 after tracheobronchial trauma, 1765 Minute ventilation, during exercise, 26-27, 27f Mirror, laryngeal, 81, 82-83, 82f Missile injury, 1725 to larynx, 1750 Mitomycin with cisplatin and ifosfamide, 782-783 with cisplatin and vindesine, 785-786 Mitomycin-C–treated stents, for airway bypass, 625, 626f Mivacurium, during airway surgery, 215-216 Mixed obstructive and restrictive defects, pulmonary function testing in, 30f, 31, 34-35 Molecular biologic techniques for lung cancer screening, 749 for lung cancer staging, 762-763 in pleural effusion, 1047 Monnier LT-mold, 1750f, 1751 Monoclonal antibodies against CD20 for B-cell lymphoma, 1631 for non-Hodgkin’s lymphoma, 1629 against CD56, 839 against epidermal growth factor receptor. See Tyrosine kinase inhibitors. against KIT, 839-840 against vascular endothelial growth factor, 819. See also Bevacizumab. Monod’s sign, 537 Montgomery suprahyoid release anastomotic complications and, 394-395 for tracheal anastomosis, 380, 381 Montgomery T tube for laryngeal stenosis, 1752 for postintubation stenosis, 262 after subglottic resection, 362 Morgagni, foramen of, 1425 Morgagni hernia, 1384-1385, 1387f-1388f, 1495, 1495f embryogenesis of, 1402 laparoscopic repair of, 1411 pathology of, 1403 Morgagni’s gap, 1369 Morphine, for airway surgery, 215 Mounier-Kuhn syndrome, 279, 279f, 281, 292 MRI. See Magnetic resonance imaging (MRI). Mucocele, pulmonary, 512

Mucoepidermoid carcinoma, 204, 705-706, 706f, 706t Mucolytics, for bronchiectasis, 475 Mucormycosis, 546-548, 547f, 594 Mucous gland carcinoma, of bronchus, 706 Mucus-associated lymphoid tissue (MALT) B-cell lymphoma of, 694 pulmonary lymphoma arising from, 848, 1630-1631 Mueller maneuver, 25 Multimodal therapy for malignant mesothelioma, 1133-1134 for superior sulcus tumors, 931-932 Multiple crush hypothesis, 1275-1276, 1278f Murmur, in chronic thromboembolic pulmonary hypertension, 654 Muscle flaps anterior chest wall muscles used for, 1205, 1205f for chest wall reconstruction, 1299-1300, 1299b for poststernotomy mediastinitis, 1266-1267, 1266f Muscle strength, endurance and, 1375 Muscle transposition for empyema, 1069, 1156, 1157f-1158f for tracheoesophageal fistula repair, 303-304, 304f Musculophrenic artery, 1370 Musculoskeletal disorders, in interstitial lung disease, 568, 569 Myasthenia gravis classification of MGFA, 1710t Osserman, 1550, 1550t, 1715, 1716t medical treatment of, 1550-1551 versus thymectomy, 1558, 1559t MGFA postintervention status classification in, 1558, 1559t, 1711t ocular, 1550, 1706 overview of, 1550-1551 thymectomy for, 1549-1561 anesthesia for, 60, 1557 historical note on, 1549-1550, 1705 indications for, 1552-1553 perioperative management of, 1557-1558 rationale for, 1549 results of, 1558-1561, 1559t-1560t, 1560f, 1718, 1718t surgical techniques for, 1553-1557, 1556t, 1560t, 1705-1706 thoracoscopic, 1705-1714 transcervical, 1715-1719 thymic hyperplasia in, 1551 thymoma in, 1507, 1551-1552, 1552t, 1592, 1593, 1595, 1596t, 1609 Myasthenic crisis, postoperative, 1557 MYC deregulation, in small cell lung cancer, 828 Myc family, in carcinogenesis, 721 MYCN amplification, in neuroblastoma, 1638 Mycobacterial infection nontuberculous, 520-521, 1089 tuberculous. See Tuberculosis. Mycobacterium abscessus, 521 Mycobacterium avium complex (MAC), 521 Mycobacterium kansasii, 521 Mycobacterium species, 505t Mycobacterium tuberculosis. See Tuberculosis. Mycophenolate mofetil, after lung transplantation, 675-676 Mycoplasmal pneumonia, 481, 589 Mycotic infection. See Fungal infection. Myer-Cotton airway grading system, 366, 366t Myocardial infarction postoperative, 142, 142b, 184 pulmonary resection after, timing of, 44 Myofibroblastic tumor, inflammatory, 696, 696f Myositis ossificans, in chest wall, 1223 Myotomy, Heller, thoracoscopic, 117

N N-901, for small cell lung cancer, 839 Narcan, for somnolence from epidural analgesia, 162

1/25/2008 1:46:13 PM

Index

Natural orifice transluminal endoscopic surgery (NOTES), as facilitator of diaphragm motor point pacing implantation, 1454 Neck. See also Cervical entries. exposure of, 120-122, 120f-122f fascial anatomy of, 1521-1522, 1522f, 1530-1531, 1530f, 1531f pain in, in laryngeal trauma, 1743 Neck surgery, phrenic nerve injury after, 1461 Necrosis aseptic, poststernotomy, 1254 radiation-induced. See Radionecrosis. Necrotizing mediastinitis. See Mediastinitis, acute necrotizing. Needle aspiration. See also Fine needle aspiration. transbronchial of bronchogenic cyst, 1584 in lung cancer staging, 761 with trocar-suction device, for hydatid disease, 561, 562f-563f Needle biopsy, percutaneous core of mediastinal lymphoma, 1623-1624 of mediastinal mass, 1514-1515 Needle holder, double jointed, in video-assisted pulmonary resection, 979, 979f Nematode infections, 551t-552t, 554t-555t, 564 Neoadjuvant therapy carinal resection after, 391 for Ewing’s sarcoma of chest wall, 1309 after lung transplantation, 676 for non–small cell lung cancer, 781-785 for pulmonary metastasis, 855 restaging after, positron emission tomography for, 439-440 for small cell lung cancer, 836-837, 836t for thymoma, 1607, 1608f Neonates Bochdalek hernia in, 1382-1383, 1385f congenital diaphragmatic hernia in diagnosis of, 1406, 1406f treatment of, 1407-1408, 1407t, 1418-1419, 1418b Neostigmine, for myasthenia gravis, 1550 Nerve blocks, peripheral, for perioperative pain management, 71-75, 72f-75f Nerve compression chronic, histopathology of, 1274-1275, 1274f-1278f provocative tests of, 1279, 1280f, 1281 Nerve conduction studies, in thoracic outlet syndrome, 1284-1285, 1285f Nerve deficits, after anterior resection for superior sulcus tumors, 938-939 Nerve injury(ies) classification of, 1459-1460, 1460t intraoperative, with lateral position, 48 mixed, 1460, 1461f Nerve sheath tumors, mediastinal, 1512-1513, 1513f, 1634-1636, 1635f-1636f Nerve transfer phrenic, in brachial plexus palsy, 1462-1463 phrenic nerve pacing and, 1463-1464, 1463f Neural network, for prediction of postoperative complications, 17 Neuralgia acute post-thoracotomy, 78 poststernotomy, 1254 Neurapraxia, 1460 Neuraxial blockade, central, for perioperative pain management, 75-77, 76f Neurenteric cyst, 1513 in adults, 1585-1586 pediatric, 1565-1569, 1566f, 1659 Neurilemmoma, 693-694 of chest wall, 1221-1222, 1225f-1226f malignant, 1636 of mediastinum, 512, 1512, 1513f, 1634-1635, 1635f melanotic, 1636 Neuritis, brachial, 1230 Neuroblastoma, 1513, 1636-1639, 1638f, 1658 Neuroendocrine lung cancer features of, 700, 737-739, 738f-739f large cell, 735, 739, 739f

Index-F06861.indd 1817

Neuroendocrine markers, for small cell lung cancer, 826 Neuroendocrine tumors thymic, 1613-1614 imaging of, 1485-1486, 1486f survival rate for, 1613, 1613f tracheal, 204, 206f-207f Neurofibroma of chest wall, 1222 of mediastinum, 1513, 1635-1636, 1635f-1636f, 1658 Neurofibromatosis, 579, 1634, 1635, 1635f-1636f Neurofibrosarcoma, 1636 Neurogenic tumors of chest wall, 1221-1222, 1225f-1226f of mediastinum, 1634-1640 characteristics of, 1512-1513, 1513f clinical and histopathologic characteristics of, 1634-1639, 1635f-1638f imaging of, 1500-1501, 1501f intraspinal extension of, 1639 pediatric, 1657-1658 surgical approach in, 1639 surgical management of, 1639 video-assisted thoracic surgery in, 1639-1640, 1702 Neurologic disorders in interstitial lung disease, 568, 569 postoperative, 143 Neurologic paraneoplastic syndrome, in lung cancer, 752-753 Neurolysis, in posterior thoracoplasty approach to thoracic outlet syndrome reoperation, 1360, 1362f Neuromuscular blockade during airway surgery, 215-216 in critical care, 156 Neuromuscular disease pulmonary function testing in, 34 tracheostomy in, 346 Neuron-specific enolase, in small cell lung cancer, 828 Neurotmesis, 1460 Neutropenia, and risk for pneumonia, 594 Nicardipine, during airway surgery, 216 Nickel allergy, in pectus deformity repair, 1345 Niemann-Pick disease, 579 Nitric oxide for congenital diaphragmatic hernia, 1407, 1418 for hypoxemia during one-lung ventilation, 57 after lung transplantation, 666 prophylactic, in lung transplantation, 64 for respiratory failure, 155 Nitrogen, partial pressure of, 1005, 1005t Nitrogen mustard, pleurodesis with, 1048 Nitrogen washout technique, for lung volume measurements, 23 Nitrous oxide for airway surgery, 215 as cryogen, 237 Nocardiosis, 548, 1087 Nociception. See also Pain. physiologic basis of, 68-69, 69f post-thoracotomy, 69-70, 70t Nodule, pulmonary. See Pulmonary nodule. Nodulectomy, video-assisted thoracic surgery for, 983-984, 983f, 984b, 984f Non–small cell carcinoma, not further specified, 730 Non–small cell lung cancer ablative therapy for, 796-803 with microwave ablation, 802-803 with radiofrequency ablation, 796-801, 797f800f, 799t, 800t with radiofrequency ablation and stereotactic radiosurgery, 802 with stereotactic radiosurgery, 801-802, 801f chemotherapy for adjuvant, 785-787, 786t versus best supportive care, 812-813, 813t doublet versus single-agent, 813, 814t neoadjuvant, 781-783, 782f, 782t optimal duration of, 815-816 optimal regimen for, 813-815, 815t palliative, 812-819

1817

Non–small cell lung cancer (Continued) chemotherapy for (Continued) second- and third-line agents in, 816 triplet versus doublet, 815 combined modality therapy for adjuvant, 788 definitive, 807-810, 807t-809t neoadjuvant, 783-785, 784f-785f inoperable curative therapy for, 804-810 definition of, 804 palliative therapy for, 810-820 invading upper airway, 321-322 metastasis of. See Metastatic disease. novel therapeutic agents for, 816-819 antiangiogenic agents as, 819 tyrosine kinase inhibitors as, 816-819, 817t-818t positron emission tomography in, 429-440 postresection follow-up for, 790-795 biomarkers in, 794-795 chest radiography in, 792 effectiveness of, 794 guidelines for, 793-794, 793t with metastatic disease, 793, 793t need for, 790-791 physical examination in, 792 routine, 791-792, 791t-792t screening studies in, 792-793 with second primary tumors, 791 survival data from, 790, 791t radiotherapy for adjuvant, 787-788, 787t definitive in early-stage disease, 804-805, 805t in locally advanced disease, 805-807 neoadjuvant, 783 palliative, 810-812, 811t-812t with radioprotectant, 807 stereotactic body, 805, 805t recurrence of molecular predictors of, 794-795 signs and symptoms of, 791, 791t staging of, 766-767, 766f-767f surgical resection of, 765-780 ablative alternatives to. See Non–small cell lung cancer, ablative therapy for. historical note on, 765-766 lobectomy for, 768. See also Lobectomy. lymph node dissection for, 770-771 palliative resection in, 779-780 patterns of failure after, 787t pneumonectomy for, 768-769 preoperative assessment in, 766-767, 766f-767f segmentectomy for, 769. See also Segmentectomy. selection of procedure for, 767-771, 767b for stage I disease (T1 N0, T2 N0), 771-772, 771f for stage II disease T1-2 N1, 772-773, 772f T3 N0 with chest wall invasion, 773-774, 773f, 773t T3 N0 with superior sulcus tumors, 774-775, 774f T3 N0 with tumors in proximity to carina, 775 T3 N0 with tumors invading mediastinum, 775 for stage III disease, 775-778 for stage IIIA disease (N2), 776-777 clinically evident (unresectable), 776-777, 777f clinically undetected (resectable), 776 for stage IIIB disease, 777-778 N3, 778, 778f with organ involvement, 778 with satellite nodules, 778 T4 with carinal involvement, 777 T4 with malignant pleural effusion, 778 for stage IV disease, 779 sublobar, 869-878. See also Sublobar resection. survival rate after, 766, 766t, 790, 791t video-assisted thoracic surgery for, 769-770, 770t wedge resection for, 769

1/25/2008 1:46:13 PM

1818

Index

Nonsteroidal anti-inflammatory drugs (NSAIDs), for perioperative pain management, 77-78 Non-union, sternal, 1255 Normothermia, postoperative maintenance of, 137-138 NPO (nothing by mouth), in chylothorax, 1116 Nuclear factor KB (NF-KB), in carcinogenesis, 723-724 Nuclear imaging. See also Positron emission tomography (PET); Scintigraphy. of lung, 429-442 Numbness of skin, after sternotomy, 1254 Nursing home residents, pneumonia in, 486, 487t Nuss procedure, 1331, 1334, 1335-1336, 1336f, 1336t, 1349, 1350f Nutrition in chylothorax, 1116 postoperative, 138

O Obesity morbid, tracheostomy and, 348 pulmonary function testing pattern in, 34 Oblimersen sodium, for small cell lung cancer, 840 Oblique muscle, external anatomy of, 1202t, 1203, 1203f-1204f chest wall reconstruction with, 1245t, 1248f1251f, 1249-1250, 1300 Obstructive lung disease chronic. See Chronic obstructive pulmonary disease (COPD). lung transplantation for, 662-663, 687t, 688, 689f Obstructive pattern, in pulmonary function testing, 30-31, 30f Obstructive sleep apnea, perioperative management of, 213 Occupational exposure, lung cancer and, 714-715 Occupational interstitial lung disease, 568, 577-578, 577t, 578f Octreotide for carcinoid tumors, 703 for chylothorax, 1116 Ocular myasthenia gravis, 1550, 1706 Odynodysphagia, in laryngeal trauma, 1743 Oligohydramnios, pulmonary hypoplasia in, 464 Omentum blood supply of , 1325f, 1326 chest wall reconstruction with, 1245t, 1250, 1251f-1252f, 1300, 1325f-1326f, 1326-1327 free flap transfers of, 1325 mediastinal reconstruction with, 1266, 1266f as pedicled flap, problems with, 1325-1327 Oncogenesis. See Carcinogenesis. Oncogenic markers. See Biomarkers. One-lung ventilation. See Ventilation, one-lung. Ono’s sign, in tracheoesophageal fistula, 302 Opioids for airway surgery, 215 for flexible bronchoscopy, 220 intravenous, patient-controlled, for postoperative pain, 71 neuraxial, adverse effects of, 77 tolerance to, management of, 79 Opsoclonus-myoclonus syndrome, in neuroblastoma, 1658 Optical coherence tomography, in tracheal tumors, 314 Oral intubation. See Endotracheal intubation. Organ failure, post-traumatic, 1726 Organizing pneumonia, 574-575 Oropharyngeal infections, mediastinitis from. See Mediastinitis. Oropharyngeal spaces, 1531-1532, 1532f Oscillatory ventilation, high-frequency during airway surgery, 217t for congenital diaphragmatic hernia, 1407 for respiratory failure, 154-155 Osserman classification of myasthenia gravis, 1550, 1550t Ossification, 425 Osteochondritis, aseptic, poststernotomy, 1254

Index-F06861.indd 1818

Osteochondroma, of chest wall, 1218, 1292-1293, 1293f Osteochondroplastica, tracheopathia, computed tomography in, 208-209, 209f Osteogenic sarcoma, mediastinal, 1647 Osteomyelitis of chest wall, 1217, 1231, 1232f of sternum, 1215, 1217 Osteosarcoma of chest wall, 1219-1220, 1294f, 1295-1296, 1296f, 1308 pulmonary metastatic, 855, 859f, 860-861, 860t primary, 845-846 Osteotomy, wedge in pectus deformity repair, 1330, 1333f, 1337, 1337f in sternal cleft repair, 1338, 1338f Overdiagnosis issue, in lung cancer screening, 746 Oxygen partial pressure of, 1005, 1005t arterial during one-lung ventilation, 45, 46 preoperative assessment of, 42 saturation of, preoperative assessment of, 10 Oxygen therapy in chronic obstructive pulmonary disease postoperative, 608 preoperative, 607 postoperative, 139 Oxygenation extracorporeal membrane. See Extracorporeal membrane oxygenation (ECMO). for hypoxemia during one-lung ventilation, 55-57

P Pacemaker lead implantation, epicardial, videoassisted thoracic surgery for, 117 Pacing, laryngeal, for vocal fold paralysis, 311 Paclitaxel with carboplatin, 786, 788, 814, 815-816 with carboplatin and bevacizumab, 789 disadvantages of, 815 for small cell lung cancer, 828, 831, 834 Paclitaxel stents, for airway bypass, 625, 626f Paget-Schroetter syndrome, in thoracic outlet syndrome, 1279, 1288-1289, 1355 Pain. See also specific site, e.g., Chest pain. chronic in poststernotomy pain syndrome, 1254 in post-thoracotomy pain syndrome, 78-79 evaluation of, in thoracic outlet syndrome, 1281 intractable, in acute post-thoracotomy neuralgia, 78 pathways of analgesic targeting of, 69, 69f after thoracotomy, 69-70, 70t after thoracic surgery, 166, 185 physiologic basis of, 68-69, 69f physiologic impact of, 69-71, 70t after video-assisted pulmonary resection, 980 Pain management in acute pericarditis, 1539 perioperative, 68-79, 141 adjuvant medications for, 77-78 analgesia strategies for, 71 central neuraxial blockade for, 75-77 multimodal analgesia for, 78 opioid tolerance and, 79 opioids and intravenous patient-controlled analgesia for, 71 peripheral nerve blocks for, 71-75, 72f-75f thoracic epidural analgesia for, 75-77, 76f Palliative care future perspectives on, 822 historical note on, 822 interventional bronchoscopy for, 231-241 thoracic conditions requiring, 823-824, 824t Palliative radiotherapy brachytherapy for, 811 evidence-based approach to, 810-811, 811t-812t indications for, 810

Palliative radiotherapy (Continued) versus other modalities, 811-812 principles of, 810 Palliative resection, indications for, 779-780 Pancoast tumors. See Superior sulcus tumors. Pancoast’s syndrome, 923, 933, 934, 934t Pancoast-Tobias syndrome, 933, 934 Pancreatic pseudocyst, 1587 Paraffin plombage, delayed complications of, 508, 508f Paraganglionic tumors, 1498-1499, 1639, 1658 Paragonimiasis, 551t, 554t, 564 Paramedian approach, for thoracic epidural analgesia, 75, 76f Paraneoplastic syndrome in lung cancer, 752-753 in small cell lung cancer, 827 in thymic carcinoid, 1613 in thymoma, 1507 Parasitic infections, 550-565. See also specific type, e.g., Hydatid disease. helminthic diagnosis and treatment of, 554t-555t epidemiology and clinical features of, 551t-552t that do not require surgery, 564-565 that sometimes require surgery, 563-564 protozoal diagnosis and treatment of, 556t epidemiology and clinical features of, 553t that do not require surgery, 564 that sometimes require surgery, 563 Parasternal weaving suture, 1259, 1260, 1261f, 1262f Parathymic syndromes, in thymoma, 1593, 1595-1596, 1596t Parathyroid cyst, 1587 Parathyroid glands angiographic embolization of, 1682 cancer of, 1678 embryology of, 1678-1679, 1678f, 1679f hyperplasia of, 1678 intrathyroid, 1681 Parathyroid tumors, mediastinal, 1677-1683 anatomic considerations in, 1678-1679, 1678f, 1679f biochemistry of, 1677-1678 diagnosis of, 1679-1680 historical note on, 1677 imaging of, 1494-1495, 1511, 1512f, 1680-1681, 1681f pathology of, 1678 postoperative issues in, 1683 surgery for results of, 1682-1683 techniques in, 1681-1682 thoracoscopic, 1699 Parathyroidectomy hypocalcemia after, 1683 results of, 1682-1683 techniques in, 1681-1682 Paravertebral mass imaging of, 1500-1501, 1501f video-assisted thoracic surgery for, 1475 Paravertebral nerve block, for perioperative pain management, 73-75, 73f-75f Parenchymal disease decortication failure and, 1183-1184, 1184f pulmonary function testing in, 34 video-assisted thoracic surgery for, 113-115, 114t Parenchymal injury, traumatic, 1773-1774 Parenteral nutrition, total, in chylothorax, 1116 Pars costalis, 1367 Pars lumbalis, 1367-1369 Pars sternalis, 1369, 1369f Parsonage-Turner syndrome, 1230 Passy-Muir valve, 1451 Pathology reports, 740, 740t, 741b Patient-controlled analgesia, for postoperative pain, 71 Pectoralis major anatomy of, 1202t, 1203, 1203f-1205f presternal suturing of, in pectus deformity repair, 1346, 1347f vascular supply to, 120, 1315-1316, 1316f

1/25/2008 1:46:13 PM

Index

Pectoralis major flap chest wall reconstruction with, 1245t, 1246f, 1248-1249, 1300, 1315-1318, 1316f-1318f indications for, 1316, 1318 mediastinal reconstruction with, 1266, 1266f padding with, for sternal dehiscence, 1261-1262, 1262f problems with, 1316 Pectus bar dislodgement or fracture of, 1344-1345, 1344f failure of, 1341, 1341f in pectus excavatum repair, 1330-1331, 1334f Pectus carinatum, 1209, 1238-1239, 1238f, 1336-1337 acquired, 1342, 1342f surgical repair of, 1337, 1337f, 1346, 1346f, 1347f types of, 1336 Pectus deformity repair of complications of, 1340-1341 techniques of, 1329-1339 residual, 1340-1341, 1341f true recurrence of, 1345-1346, 1346f-1347f Pectus excavatum, 1207, 1209, 1210f, 1236-1238, 1237f, 1329-1336 background on, 1329-1330 diagnosis of, 1329 musculoskeletal abnormalities associated with, 1329 prosthetic reconstructions for, 1334 surgical repair of acquired restrictive thoracic dystrophy after, 1346, 1348-1349, 1348f-1349f breast asymmetry or growth retardation after, 1342-1343, 1343f historical note on, 1329 indications for, 1329-1330 mediastinal drainage after, 1343, 1343f minimally invasive, 1331, 1334, 1335-1336, 1336f, 1336t, 1349, 1350f open, 1330-1331, 1330f-1335f, 1334-1335 recommended procedure for, 1346, 1346f, 1347f for recurrence, 1346, 1347f results of, 1334-1336, 1336t thoracoscopic, 1334 timing of, 1330 Pectus index, 1236, 1239, 1330 Pemetrexed for malignant mesothelioma, 1130 for salvage therapy, 816 Penicillin for lung abscess, 496 for pleural actinomycosis, 1086 Peptic ulcer, postoperative medications in patient with, 140-141 Peptide hormones, produced by carcinoid tumors, 699, 700t Percussion, in diaphragmatic function assessment, 1377-1378 Percutaneous aspiration, of bronchogenic cyst, 1584 Percutaneous core needle biopsy of mediastinal lymphoma, 1623-1624 of mediastinal mass, 1514-1515 Percutaneous drainage, of lung abscess, 496-497, 496f Perfadex pulmonary flush solution for transplantation, 665 Performance status, preoperative assessment of, 9-10, 10t Peribronchial plexus, 414 Pericardial cyst, 1545, 1545f, 1586-1587 characteristics of, 1511, 1513f clinical presentation in, 1578 imaging of, 1492, 1492f, 1578, 1586-1587, 1586f incidence of, 1578 management of, 1519, 1519f, 1578 pediatric, 1577-1578, 1659, 1659f surgical considerations in, 1578 Pericardial disease, 1537-1548 historical note on, 1537 video-assisted thoracic surgery for, 117

Index-F06861.indd 1819

Pericardial effusion diagnosis of, 1543-1544, 1543f-1544f etiology and pathophysiology of, 1542-1543 in lung cancer, 752 malignant, palliative care for, 824t management of, 1544-1545 in trauma, 1734-1735 Pericardial fluid, characteristics of, 1538 Pericardial patch interposition, autologous, for superior vena cava reconstruction, 1690, 1691f Pericardial window for cardiac tamponade, 1785 late complications after, 181, 181f Pericardiectomy complications of, 1547 indications for, 1547 for pericarditis, 1540, 1542, 1547, 1547f thoracoscopic, 1701 Pericardiocentesis for acute pericarditis, 1539-1540 for cardiac tamponade, 1544-1545 complications of, 1546 indications for, 1546 preoperative and anesthetic considerations in, 1546 technique of, 1546 thoracoscopic, 1547 Pericardiophrenic artery, 1370 Pericardiotomy open drainage through, 1545, 1546 postpericardiotomy syndrome after, 1253, 1546 technique of, 1547 Pericarditis acute, 1539-1540, 1539t constrictive, 1540, 1541-1542, 1541f, 1542t in histoplasmosis, 533 in HIV infection, 1540 infectious, 1540 radiation-induced, 1540 recurrent, 1540 tuberculous, 509, 516-517, 1540 uremic, 1540 Pericarditis-like syndrome, after pectus deformity repair, 1345 Pericardium absence of, 1545 anatomy of, 1538 congenital anomalies of, 1545, 1545f diverticulum of, 1545, 1545f embryology of, 1537, 1538f metastasis to, 1545 neoplasms of, 1545 penetrating injury to, 1780 physiology of, 1538-1539 pressure within, 1539 for pulmonary artery reconstruction autologous, 916, 917 bovine, 916 reconstruction of, after extrapleural pneumonectomy, 1191, 1191f subxiphoid approach to, 124, 124f tumor invasion of, extended pulmonary resection for, 954 Peripheral angiography, in thoracic outlet syndrome, 1285, 1286f Peripheral nerve blocks, for perioperative pain management, 71-75, 72f-75f Peripheral nerve injury, after thoracotomy, 166 Peripheral neuropathy, in lung cancer, 753 Peripheral sensitization, in nociceptor response, 68 Peroneal nerve, intraoperative injury to, 48 PET. See Positron emission tomography (PET). PET/CT. See Positron emission tomography/ computed tomography (PET/CT). pH level, in pleural effusion, 1045 Pharyngeal space, lateral, 1531, 1532, 1532f Pharynx injury to, laryngeal trauma with, 1744, 1744f, 1747, 1747f stenosis of, post-traumatic, 1752, 1753f Pheochromocytoma, 116, 1498-1499, 1639, 1658 Phlebogram, in fibrosing mediastinitis, 1535 Photodynamic therapy disadvantages of, 236 versus endobronchial laser therapy, 236

1819

Photodynamic therapy (Continued) for endobronchial obstruction, 235-236, 235f for malignant mesothelioma, 1135 mechanism of action of, 235 Photofrin, 1135 Photofrin II, 235 Phrenic arteries, 1370, 1370f Phrenic nerve accessory, 1459, 1459f anatomy of, 1371-1372, 1371f, 1458-1459, 1459f development of, 1373 functional assessment of, 1446 injury to diaphragmatic impairment from, 1458 diaphragmatic paralysis in, 1396-1397, 1433, 1439-1440 etiology of, 1460-1462 imaging of, 1383f in mediastinoscopy, 105 pattern of, 1460 prevention of, in mediastinal teratoma surgery, 1615 repair of, 1462 traumatic, 1786-1787 invasion of, imaging of, 1383f involvement of, diaphragmatic eventration with, 1433 left, 1458, 1459f paralysis of. See also Diaphragm, paralysis of. left versus right, 1461 in post-thoracotomy pain, 70, 70t right, 1458-1459, 1459f transfer of, in brachial plexus palsy, 1462-1463 Phrenic nerve pacing, 1445-1456 in congenital central hypoventilation syndrome, 1445, 1452-1453 cost of, 1451 failure of, 1451 future applications of, 1453-1456 history of, 1445-1446 indications for, 1445, 1451-1453 nerve transfers and, 1463-1464, 1463f postoperative care in, 1450-1451 procedure for, 1446 surgical techniques for, 1447-1448, 1448f systems for, 1446-1447, 1447f in tetraplegia, 1445, 1451-1452 ventilator weaning issues in, 1450-1451 Phrenic veins, 1370 Phrenicectomy, for tuberculosis, 502-503, 502f Phrenoesophageal ligament, 1369 Phrenotomy, 1374-1375, 1374f-1375f, 1428-1429, 1429f Phthisis, 499 Physical therapy, for thoracic outlet syndrome, 1287-1288 Physiotherapy, chest for bronchiectasis, 475 for empyema, 1065 postoperative, 138-139 Pigeon breeder’s disease, 577 Pigeon chest. See Pectus carinatum. Pigtail catheters, pleural drainage with, for empyema, 1063 Plasmacytoma of chest wall, 1232, 1296-1297, 1296f pulmonary, primary, 847 Plasmapheresis for myasthenia gravis, 1551 preoperative, in myasthenia gravis, 1557 before thymectomy, 1706 Plasmodium falciparum, 553t, 556t, 564 Plates and struts for chest wall stabilization, 1311, 1312f in pectus excavatum repair, 1330-1331, 1334f Pleomorphic carcinoma, 842 monophasic versus biphasic, 737 pathology of, 735-736, 736f Plethysmography, body in airway obstruction, 23-24 for lung volume measurements, 22-23, 23f-24f Pleura abrasion of, for pneumothorax, 1101 anatomy of, 1001-1003, 1002f-1003f, 1008, 1121

1/25/2008 1:46:14 PM

1820

Index

Pleura (Continued) blood supply to, 1003 calcifying fibrous pseudotumor of, 1025 embryology of, 1001, 1002f innervation of, 1003 lymphatic drainage of, 1003 mechanical properties of, 1004-1005 microscopic anatomy of, 1003-1004 parietal, anatomy of, 1001, 1002f-1003f, 1003 physiology of, 1121 topography of, 1002 visceral, anatomy of, 1001-1002, 1002f-1003f Pleural aspergillosis, 539 Pleural biopsy in malignant pleural effusion, 1140 in pericardial effusion, 1036-1037 in tuberculous pleural effusion, 1074 Pleural calcification, imaging of, 1019, 1019f Pleural catheters for empyema, 1063 indwelling, for malignant pleural effusion, 11431144, 1144t for perioperative pain management, 73 Pleural cavity drainage of, 139-140, 868, 1149 without air leak, 172 Pleural cyst, 1123 Pleural disease asbestos-related benign, 1019-1022, 1020f-1022f malignant, 1028-1031, 1029f-1030f classification of, 1033, 1034t after collapsotherapy, 1079 diagnosis of, 1033-1041 biopsy in, 1036-1037 bronchoscopy in, 1041 history in, 1033 mediastinoscopy in, 1041 physical examination in, 1033-1034, 1034f pleuroscopy and thoracoscopy in, 1037-1040, 1038f-1040f, 1038t, 1040t thoracentesis in, 1033-1036 thoracotomy in, 1040-1041 imaging of, 1008-1032, 1009f-1032f video-assisted thoracic surgery for, 111-113, 111t Pleural effusion, 1042-1053 asbestos-related, 1019-1020 causes of, 1006, 1043-1044, 1046t-1047t cholesterol, 1114-1115 chronic, 1010 chylous. See Chylothorax. clinical presentation in, 1042, 1043f-1045f diagnosis of, 1042-1047, 1043f-1045f biochemical tests in, 1044-1045 biopsy in, 1036-1037 imaging in, 1008-1010, 1009f-1013f, 1042, 1043f-1045f, 1047 molecular biologic techniques in, 1047 thoracentesis in, 1044 thoracoscopy in, 111, 1047 differential diagnosis of, 1046t exudative versus transudative, 1007, 1010, 1011f, 1012f, 1035-1036, 1036b, 1044 incidence of, 1036t late, 173 loculated, 1042, 1044f, 1045f after lung transplantation, 680 malignant, 1137-1145, 1138t in breast cancer, 1145 causes of, 1044, 1046t-1047t, 1138, 1139t clinical presentation in, 1138-1139 cytotoxic agents for, 1050-1051, 1052 diagnosis of, 1138-1140, 1139t in gynecologic malignancies, 1145 in hematologic malignancies, 1145 hemorrhagic, 1138 historical note on, 1137 imaging of, 1139 late complications of, 167 in lung cancer, 1144-1145 in malignant mesothelioma, 1145 management of, 1140-1145 options for, 1140-1144 principles of, 1140 in refractory disease, 1144, 1144t

Index-F06861.indd 1820

Pleural effusion (Continued) malignant (Continued) palliative care for, 824t pleurectomy for, 1052 pleurodesis for, 1048-1050, 1049t-1051t, 10511052, 1141-1144, 1141t-1142t stage IIIB non–small cell lung cancer with, 778 video-assisted thoracic surgery for, 111-112, 111t in malignant mesothelioma, 1028, 1029f management of, 1047-1053, 1053f paramalignant, 1138, 1138t, 1139t pathophysiology of, 1042, 1043t in pulmonary coccidioidomycosis, 1092 subpulmonic, 1010, 1010f with trapped lung, 1048, 1048f, 1052 tuberculous, 509, 518-519, 519f-520f, 1072-1075 clinical presentation in, 1073 complications of, 1075, 1075f diagnosis of, 1073-1075, 1074f, 1074t, 1087-1088 management of, 1075, 1075t, 1088 pathology of, 1072-1073, 1073t pleural cellular response in, 1073 Pleural fistula, alveolar. See Air leak. Pleural fluid composition of, 1005, 1005b cytologic analysis of. See Thoracentesis. tuberculous, 1073-1074, 1074t turnover of, 1005-1007, 1005b, 1006f volume of, 1005-1007, 1005b, 1006f Pleural infection actinomycosis as, 1086 amebiasis as, 1085-1086 aspergillosis as, 539, 1090 blastomycosis as, 1092 coccidioidomycosis as, 1092 cryptococcosis as, 1090 histoplasmosis as, 1092 hydatidosis as, 1081-1085, 1082f-1085f mycobacteriosis as (nontuberculous), 1089 nocardiosis as, 1087 tuberculosis as. See Tuberculosis, pleural disease in. zygomycosis as, 1092 Pleural metastasis, 1026-1027, 1027f, 1123 thoracoscopy in, 1039, 1040f Pleural plaques asbestos-related, 1020, 1020f-1021f, 1123 in malignant mesothelioma, 1028, 1029f Pleural pressure, 1004, 1004f vertical gradient of, 1004 Pleural procedures, late complications of, 167, 168f Pleural sinuses, anatomy of, 1002 Pleural space anatomy and physiology of, 1095, 1121 blunt trauma and, 1770-1772 complications of, after lung transplantation, 680, 680f fixed deficit of, 1150 infection of. See Pleural infection. lavage of, as complement to thoracoscopy, 1040 obliteration of for chylothorax, 1116, 1118 decortication for, 1174. See also Decortication. for pneumothorax, 1101 sterilization of, for empyema, 1066-1068 Pleural tent, for air leak, 650 Pleural thickening asbestos-related, 1020 causes of, 1017 imaging of, 1017-1018, 1017f-1018f in tuberculous pleural effusion, 1075 Pleural tumors, 1022-1031, 1121-1136 benign, 1023-1026, 1023f-1026f, 1121-1123, 1122f fibrous, 1023-1025, 1024f-1025f solitary, 1121-1123, 1122f, 1123t malignant, 1026-1031, 1027f-1030f, 1123-1135, 1124f-1125f uncommon, 1031 Pleurectomy for malignant mesothelioma, 1132, 1134 for malignant pleural effusion, 1052 parietal, for chylothorax, 1118 for pneumothorax, 1101

Pleuritis, 1039, 1039f tuberculous. See Pleural effusion, tuberculous. Pleurodesis. See also specific agent, e.g., Talc pleurodesis. bedside, 1143 chemical, 112 for chylothorax, 1116, 1118 for malignant pleural effusion, 1048-1050, 1049t-1051t, 1051-1052, 1141-1144, 1141t-1142t for pneumothorax, 1102-1103 for postoperative air leak, 140 sclerosing agents for, 1031, 1049-1050, 1050t-1051t thoracoscopic, 1143 video-assisted thoracic surgery for, 112 Pleurolysis, 1180, 1181f Pleuropericardial membranes, 1372f, 1373 Pleuroperitoneal ducts, 1372f, 1373 Pleuroperitoneal shunt for chylothorax, 1116, 1118 for malignant pleural effusion, 1144, 1144t Pleuropneumonectomy, for tuberculous empyema, 1078, 1089, 1091f Pleuroscopy, 1037-1040, 1038f, 1038t Plombage, for tuberculosis, delayed complications of, 507-509, 508f, 508t Plombage thoracoplasty, 1162-1164, 1162f-1163f, 1164t Pneumatocele definition of, 634 infectious, 426 post-traumatic, 426, 1774 Pneumococcal pneumonia, 480 empyema in, 1060 histopathology of, 584f sequential pathogenesis of, 589-590 Pneumocystis jirovecii pneumonia, in immunocompromised host, 593 Pneumomediastinum, 1099 causes of, 1503 imaging of, 1503-1504, 1503f malignant, 1106 spontaneous, primary, 1105-1106 tension, 1106 in trauma, 1733 Pneumonectomy, 864-868 anesthesia for, 865 carinal left, 388-390, 389f for non–small cell lung cancer invading trachea, 321, 322 right, 387-388, 387f-388f closure of postpneumonectomy space in, 868 completion, 769, 955-956 contralateral resection after, 956 controversies in, 868 extrapleural eligibility criteria for, 1130t follow-up care in, 1192 incisions for, 1187f, 1188 for malignant mesothelioma, 1130-1132, 1131f-1133f postoperative care in, 1191-1192 preoperative evaluation for, 1186-1187 preparation for, 1187-1188 reconstruction of diaphragm and pericardium after, 1190-1191, 1191f results of, 1132-1133, 1134 technique of, 1188-1190, 1188f-1190f history of, 4, 401, 864 incisions for, 864-865 indications for, 864 mediastinal shift after, 1031, 1032f for non–small cell lung cancer, 768-769 for parenchymal injury, 1773-1774 pleural cavity drainage after, 139, 868, 1149 pulmonary edema after, 155-156 for pulmonary metastasectomy, 856 recipient, in sequential bilateral lung transplantation, 668-669 risk factors for, 11 sleeve lobectomy versus, 907, 907t technique of, 865-868 bronchus dissection in, 867-868, 867f

1/25/2008 1:46:14 PM

Index

Pneumonectomy (Continued) technique of (Continued) pulmonary artery dissection in, 866-867, 866-867f pulmonary vein dissection in, 865-866, 865f tracheomalacia after. See Postpneumonectomy syndrome. for tuberculosis, 524 for tuberculous empyema, 1078 video-assisted thoracic surgery for, 864-865, 987 Pneumonia, 478-488 anaerobic, 481 aspiration, 479, 479t bacterial, 493 gastric acid, 491-493, 492f candidal, 548 Chlamydia, 481-482 coccidioidomycotic, 540 community-acquired, 479-488, 479t antibiotics for, 485-488 assessment of initial response to, 487 choice of, 485-486, 487t duration of, 487 empiric selection of, 487t failure of initial response to, 488 flow chart for, 482f special considerations in, 486-487 clinical evaluation of, 482-483 host defense mechanism compromise in, 479-480 invasive diagnostic studies in, 485 microbiology of, 480-482, 480t molecular studies in, 485 pathogenesis of, 479 poor outcome in, risk factors for, 486t radiographic evaluation of, 483-484, 483f-485f serologic studies in, 485 sputum examination in, 484-485 vaccine recommendations for, 586t complications of, 488 definition of, 478-479 epidemiologic classification of, 479, 479t in esophagogastrectomy, 61 hospital-acquired, 479, 479t, 489-490 in immunocompromised host, 479, 479t, 490-491, 491t bacterial, 589-591 fungal, 593-594 mycobacterial, 592 pneumococcal, 589-590 viral, 592-593 legionellosis, 481, 589 microbes responsible for most common, 584t treatment recommendations specific to, 587t miliary pattern in, 484, 484f mycoplasmal, 481, 589 organizing, 574-575 postoperative incidence of, 161 risk factors for, 161 treatment of, 161 radiographic clearance of, 488 S. pyogenes (group A streptococcus), 481 Staphylococcus aureus, 481 Streptococcus pneumoniae (pneumococcal), 480 empyema in, 1060 histopathology of, 584f sequential pathogenesis of, 589-590 ventilator-associated, 489-490 Pneumonic symptoms, in lung cancer, 751 Pneumonitis hypersensitivity, 577 postobstructive, 423 Pneumonorrhaphy, for penetrating lung injuries, 1779 Pneumopericardium, after pericardial window, 181, 181f Pneumoperitoneum, 1099 diagnostic, in diaphragm elevation, 1398 Pneumothorax, 1094-1106 in AIDS patients, 1104-1105 after airway surgery, 228 bilateral, 1099 in bullous disease, 637f, 639, 642-643 catamenial, 1105

Index-F06861.indd 1821

Pneumothorax (Continued) causes of, 1015 in chronic obstructive pulmonary disease, 1103-1104 classification of, 1094, 1095t in cystic fibrosis, 1104 duration of, decortication failure and, 1184 emphysema in, 642-643, 1099 after flexible bronchoscopy, 93 gas resorption in, 1096 historical note on, 1094-1095, 1095t iatrogenic, 1094 imaging of, 1015-1016, 1015f-1017f in infectious diseases, 1104 after lung transplantation, 680, 680f in lymphangioleiomyomatosis, 580 in neoplastic disease, 1105 open, 1778 after pectus deformity repair, 1342 physiologic changes secondary to, 1095-1096, 1096f in pulmonary Langerhans cell histiocytosis, 582 in severe acute respiratory distress syndrome (SARS), 1105 size of, 1097-1099, 1099f spontaneous controversies in, 1106 late recurrence of, 167, 168f primary, 1096-1103 aspiration for, 1100 complications of, 1099 diagnosis and staging of, 1097-1099, 1097f-1099f etiology and epidemiology of, 1096-1097 histopathology of, 1097 management of, 1099-1103 observation for, 1099-1100 outcome in, 1103 pleurodesis for, 1102-1103 surgery for, 1100-1102, 1100t tube thoracostomy for, 642-643, 1100 recurrent, 1099, 1101 secondary, 1103-1105, 1103t video-assisted thoracic surgery for, 114, 11011102, 1103 tension, 1096, 1096f, 1097, 1098f, 1099, 1779 therapeutic, pleural effusion after, 509 in tracheobronchial trauma, 1758 during tracheostomy, 351 in trauma, 1094, 1731, 1732f, 1778, 1779 uncomplicated, 1095-1096, 1096f Poland’s syndrome, 1207, 1210-1211, 1212f, 1239, 1240f, 1337-1338, 1338f Polychondritis, relapsing, 295-296 computed tomography in, 209-210 management of, 295-296 tracheomalacia in, 282-283, 283f, 288, 288f PolyFlex stent, 240 Polymerase chain reaction reverse-transcriptase, in pleural effusion, 1048 in sputum-based lung cancer screening, 748 in tuberculous pleural effusion, 1075 Polymyositis, 580 Polypoid tumor, airway obstruction by, 336, 337f Polytetrafluoroethylene (PTFE) prosthetic grafts, for superior vena cava reconstruction, 1692-1694, 1693f-1694f Polyvinyl alcohol embolization, for massive hemoptysis, 453 Porous diaphragm syndromes, 1369 Positive end-expiratory pressure (PEEP) autogenous (auto-PEEP) in emphysema, 613 during one-lung ventilation, 55 for chylothorax, 1116 for hypoxemia during one-lung ventilation, 56 with lateral position, 48 during one-lung ventilation, 54-55 Positive-pressure ventilation for COPD exacerbation, 609-611, 610t high-frequency during airway surgery, 217t two-lung, for hypoxemia during one-lung ventilation, 56

1821

Positive-pressure ventilation (Continued) intermittent, during airway surgery, 217t during laryngoscopy, 84 Positron emission tomography (PET) for carcinoma staging, 433-439 distant metastasis, 435-437, 438f impact of, 437, 439 nodal, 434-435, 435f-437f, 1484 primary tumor, 433-434 F-18 fluorodeoxyglucose–. See FDG-PET. F-18 fluorothymidine–, 432-433 in Hodgkin’s lymphoma, 1626 of lung, 417, 418f for lung cancer staging, 759-760, 759f in malignant pleural effusion, 1139 in mediastinal parathyroid adenoma, 1495 in non–small cell lung cancer, 429-440, 766-767 in poststernotomy mediastinitis, 1264 principles and technical aspects of, 429-430, 431f in pulmonary metastasis, 853, 854t radiotherapy planning with, 440 for restaging after induction therapy, 439-440 in small cell lung cancer, 439 in solitary pulmonary nodule, 432-433, 433f-434f, 456-457 Positron emission tomography/computed tomography (PET/CT) in brachial plexopathy, 1229, 1229f breathing artifact on, 430, 431f for carcinoma staging distant metastasis, 437, 438f nodal, 435, 436f-437f, 1484 primary tumor, 433-434 in chest wall mass, 1234, 1234f in Hodgkin’s lymphoma, 1626 imaging techniques in, 87 in malignant mesothelioma, 1126, 1186 in malignant pleural effusion, 1139 of mediastinum, 1477-1478 principles and technical aspects of, 430-431, 431f radiotherapy planning with, 440 for restaging after induction therapy, 439-440 in superior sulcus tumors, 824 Postintubation injury, 256-269, 348 anatomy of, 257-258, 257f-258f cuff-related, 258-259, 258f glottic, 259 historical note on, 256 pathophysiology of, 258-259, 258f, 260f stomal, 259, 260f subglottic, 259 Postintubation stenosis bronchoscopy in, 261 clinical presentation in, 259, 261 computed tomography in, 198f-199f, 204 pathophysiology of, 258-259, 258f, 260f radiologic findings in, 261 subglottic, 259, 263, 355f, 356, 364 treatment of complications of operations for, 380-381, 381t dilation in, 261 emergency, 261 internal stents in, 262 laser resection in, 261-262, 262f segmental resection and anastomosis in, 262-264 staged reconstruction in, 262 Postintubation tracheoesophageal fistula, 265-269 clinical presentation in, 266-267 etiology of, 299-300, 300f historical note on, 265-266 management of, 267-269, 267f-269f Postintubation tracheoinnominate artery fistula, 264266, 264f, 266f Postintubation tracheomalacia, 280f, 281, 281f, 286-287 Postoperative care, 136-144 arrhythmia prophylaxis in, 141-142 deep venous thrombosis/pulmonary embolism prophylaxis in, 143, 143b fluid management in, 138 maintenance of normothermia in, 137-138 medications in, 140-141, 140t monitoring in, 136-137, 137t myocardial infarction prophylaxis in, 142, 142b neurologic issues in, 143

1/25/2008 1:46:14 PM

1822

Index

Postoperative care (Continued) nutritional management in, 138 pain management in, 141. See also Pain management, perioperative. pleural cavity drainage in, 139-140 preoperative preparation for, 136 respiratory care in, 138-139, 139b Postoperative stress syndrome, 70 Postpericardiotomy syndrome, 1253, 1546 Postpneumonectomy bronchopleural fistula, late, 167, 169-171, 169f-171f Postpneumonectomy space, evaluation of, 1031, 1032f Postpneumonectomy syndrome, 173, 282, 282f Post-tracheostomy stromal strictures, 204 Post-transplant lymphoproliferative disorders, 573, 682-683, 683f Postural abnormalities, in thoracic outlet syndrome, 1281, 1288 Pott’s disease, 499, 517-518, 518t PPD skin test, 506, 1073 Prausnitz-Kustner reaction, in hydatid disease, 558 Precision resection, for pulmonary metastasectomy, 856, 856f Prednisone for airway obstruction in histoplasmosis, 529 for chronic obstructive pulmonary disease, 489, 607 after lung transplantation, 675 Pregnancy, diaphragm elevation in, 1398 Prenatal intervention. See Fetal surgery. Preoperative assessment, 9-18 for anesthesia, 40-45, 40t, 41f-43f, 45f of cardiovascular status, 13-15, 14b, 15f of comorbid conditions, 15-16 decision-making process in, 16-17 of general status, 9-10, 10t of pulmonary function for immediate postoperative risk of morbidity and mortality, 10-13, 11t, 13f for long-term outcome assessment, 13 risk assessment tools in, 16 Preoperative exercise training, in chronic obstructive pulmonary disease, 613-614 Preoperative preparation, 136 Preserved tissues, for chest wall stabilization, 1311 Pressure threshold testing, in thoracic outlet syndrome, 1282, 1282f Pressure-controlled ventilation, one-lung, 55 Pressure-volume curves, 26, 26f Preterm prelabor rupture of the membranes (PPROM), after fetal endoscopic tracheal occlusion, 1419, 1421 Pretracheal fascia, 194 Previsceral fascial cleft/previsceral space, 1530-1531, 1530f, 1531f Primitive neural ectodermal tumor (PNET), 1232, 1295, 1658 Prolene mesh, 1311 Propofol for airway surgery, 215 for sedation in ICU, 156 Propofol infusion syndrome, 156 Prostaglandin E1 for congenital diaphragmatic hernia, 1418 for hypoxemia during one-lung ventilation, 57 in lung transplantation, 665 Prostaglandin I2, inhaled, in respiratory failure, 155 Prosthesis composite, 1312, 1313 customized, 1313-1314, 1313f Prosthetic grafts, for superior vena cava reconstruction, 1692-1694, 1693f-1694f Prosthetic materials for chest wall stabilization, 1245t, 1248, 1299, 1311-1312, 1312b, 1312f for superior vena cava reconstruction, 1692-1694, 1693f-1694f Protein, in chyle, 1112 Protein C, activated, 148-149 Proteomics, in carcinogenesis, 724-725, 724f Protozoal infections diagnosis and treatment of, 556t epidemiology and clinical features of, 553t

Index-F06861.indd 1822

Protozoal infections (Continued) that do not require surgery, 564 that sometimes require surgery, 563 Provocative tests, in thoracic outlet syndrome, 1279, 1280f, 1281 Pruritus in Hodgkin’s lymphoma, 1624 in poststernotomy scar, 1254 Pseudoangina, in thoracic outlet syndrome, 1278 Pseudochylothorax, 509, 1010, 1114-1115 Pseudocyst, pancreatic, 1587 Pseudolymphoma, 694-695, 695f Pseudomeningocele, 1230 Pseudomesotheliomatous adenocarcinoma, 731, 732, 1123 Pseudomesotheliomatous carcinoma, pulmonary, primary, 847 Pseudotumor, calcifying fibrous, of pleura, 1025, 1123 Pulmonary alveolar proteinosis, 65-66, 581, 581f Pulmonary angiography in bullous disease, 640 in carinal resection, 384, 384f in chronic thromboembolic pulmonary hypertension, 656, 656f Pulmonary arteriography, in fibrosing mediastinitis, 1535 Pulmonary arteriovenous malformations, 471 Pulmonary artery(ies) airway and, fistula between, 176 anatomy of, 403-404, 403f anomalies of, 404 catheterization of in critically ill patient alternatives to, 157-158 role of, 157 in lung transplantation, 62 massive hemoptysis during, 446 clamping of, for penetrating thoracic trauma, 1785 development of, 401, 462 dissection of in pneumonectomy, 866-867, 866-867f in video-assisted pulmonary resection, 976, 977f embolization of, for massive hemoptysis, 452 enlarged, 1656, 1657f false aneurysm of, 65 imaging of, 1480-1481, 1480f injury to in mediastinoscopy, 106 penetrating, 1781 interlobar, anatomy of, 910, 910f, 911f, 912 left, anatomy of, 403-404, 403f, 405, 405f-406f, 910f, 911f, 912 reconstruction of. See Pulmonary artery reconstruction. right, anatomy of, 403, 403f, 404, 404f, 909-910, 910f, 911f rupture of, iatrogenic, 64-65 topographic anatomy of, 897-898, 897f-898f Pulmonary artery flush, during lung transplantation, 665-666, 667f Pulmonary artery reconstruction, 909-922 anatomical considerations in, 909-912, 910f911f via cardiopulmonary bypass, resection and, 913, 919 with conduit interposition, sleeve resection and, 916-917, 919f, 920 by end-to-end anastomosis, sleeve resection and, 916, 918f, 920 historical note on, 909 indications for, 912-913, 912f-913f long-term results of, 920-922, 921f-922f, 921t operative techniques in, 913-916 in left lower lobe, 914, 915f in left upper lobe, 913-914, 914f principles of, 913 in right lower lobe, 916 in right upper lobe, 914-915, 915f patch, partial resection and, 916, 916f-917f, 920 pitfalls and complications of, 919-920 techniques of, 910t

Pulmonary artery sling diagnosis of, 247-248, 249 pathology of, 244-245, 246f surgical management of, 253-254, 253f, 254f Pulmonary artery steal, after pulmonary thromboendarterectomy, 659 Pulmonary cavity acquired, 426-427, 426f, 427f coccidioidal, 541 radiographic signs of, 425-427, 426f-427f Pulmonary circulation bronchial circulation and, anastomotic connections between, 897 with lateral position, 48-49 mechanical restriction of, for hypoxemia during one-lung ventilation, 57 Pulmonary contusion, 1772-1773, 1772f, 1789 Pulmonary cyst acquired, 426, 427 congenital, 426 general features of, 425 radiographic signs of, 425, 425f Pulmonary edema from fluid therapy, 151 interstitial, 420f negative-pressure, after airway surgery, 228 noncardiogenic, after carinal resection, 389 postoperative, 163 postpneumonectomy, 155-156 reabsorption of fluids in, 151-152, 152f re-expansion, after thoracentesis, 1036 reperfusion, after pulmonary thromboendarterectomy, 658-659 Pulmonary embolism chronic. See Pulmonary hypertension, chronic thromboembolic. massive hemoptysis in, 446 postoperative, 143, 143b, 183-184, 183f ventilation-perfusion scintigraphy in, 442 Pulmonary fibrosis diaphragm elevation in, 1396, 1397f lung transplantation for, 663, 689, 689f, 690f pressure-volume curve in, 26, 26f Pulmonary function after decortication, 1182-1183 in fibrothorax, 1172-1173 life expectancy and, 13 quality of life and, 13 after thoracotomy, 70, 70t after video-assisted pulmonary resection, 980-981 Pulmonary function testing, 19-38. See also Cardiopulmonary exercise testing. abnormal values for patterns of, 30-32, 30f, 32f-33f severity of, rating of, 32, 33t with specific disease classifications, 34-35 bronchodilator response in, 32-33 bronchoprovocation techniques in, 35-36 in bullous disease, 638-639 cardiac effects on, 35 in chronic obstructive pulmonary disease, 604, 604t in chronic thromboembolic pulmonary hypertension, 654-655 in fibrothorax, 1174 indications for, 19, 20t interpretation of, 28-36 in interstitial lung disease, 571 in malignant mesothelioma, 1187 methods of, 19-26. See also specific method, e.g., Spirometry. normal reference values for, 28-30, 29t in preoperative assessment, 10-13, 11t, 13f, 41-42, 41f-42f repeated measurements in, 33-34 before sublobar resection, 873-874 in substernal goiter, 1670-1671 Pulmonary hemorrhage in bullous disease, 642 major, palliative care for, 824t Pulmonary hypertension chronic thromboembolic, 653-659 clinical presentation in, 653-654 diagnostic evaluation of, 654-656, 654f-657f

1/25/2008 1:46:14 PM

Index

Pulmonary hypertension (Continued) chronic thromboembolic (Continued) thromboendarterectomy for complications of, 658-659, 659f, 659t patient selection for, 656-657 postoperative care in, 658 results of, 659 technique for, 657-658, 658f in interstitial lung disease, 568 lung transplantation in, 663, 688, 689f Pulmonary infarct cavities associated with, 426-427 postoperative, late, 173 septic, 426, 426f Pulmonary infection bacterial, 478-498 in immunocompromised host, 583-596. See also Immunocompromised host. recent, in discriminating benign versus malignant nodule, 455-456 surgical management of, anesthesia for, 59 Pulmonary insufficiency, postoperative, 164 Pulmonary interventions, cardiopulmonary exercise testing after, 36, 38 Pulmonary isolation, for massive hemoptysis, 450-451 Pulmonary ligament inferior, 404, 404f limits of, 1001 release of, in video-assisted pulmonary resection, 976-977 Pulmonary lymphatics, 411, 412f, 413, 756-757, 758f patterns of metastatic spread and, 960-962, 962f, 962t Pulmonary mass(es) in blastomycosis, 544, 544f radiographic signs of, 423-425, 423f, 424f Pulmonary metastasectomy en-bloc resection for, 856 future directions in, 862-863 historical note on, 851 indications for, 114t patient selection for, 854-855, 854t prognostic factors in, 857-858, 858t, 859f rationale of, primary tumor site and, 851, 852t relapse after, and surgical rescue, 860 results of, 857-860, 858t, 859f for specific cancers, 859f, 860-862, 860t surgical approaches to, 855 techniques of, 855-857, 856f-857f video-assisted thoracic surgery for, 114, 856-857 Pulmonary metastasis, 791 basic mechanisms of, 851 chemotherapy for, 851, 855 diagnosis of, 851-854, 852f, 853f versus new primary cancer, probability of, 854t radiotherapy for, 851, 855 resection of. See Pulmonary metastasectomy. staging of, 851-854, 852t, 853f, 854t systemic treatment of, indications for, 855 Pulmonary mucocele, 512 Pulmonary nerves, 414 Pulmonary nodule benign versus malignant, 697 algorithms for, 460-461, 460f bronchoscopy in, 458 characteristics of, 755-756, 756t clinical history in, 455-456, 456t excisional (surgical) biopsy in, 458-459 imaging of, 456-458, 456t positron emission tomography in, 432-433, 433f-434f radiographic signs in, 423-425, 423f, 424f, 459, 459f size on imaging of, 457-458, 457f transthoracic fine needle aspiration of, 458 coccidioidal, 540-541 in community-acquired pneumonia, 483-484, 484f in cryptococcosis, 545 differential diagnosis of, 755t likelihood of malignancy in, recommended imaging based on, 756t multiple, in Wegener’s granulomatosis, 294

Index-F06861.indd 1823

Pulmonary nodule (Continued) nonsolid, on computed tomography, 747, 748f, 756 video-assisted thoracic surgery for, 113 Pulmonary rehabilitation cardiopulmonary exercise testing before, 38 for chronic obstructive pulmonary disease, 136, 607 for lung volume reduction surgery, 613-614 Pulmonary resection. See also Lobectomy; Pneumonectomy. arrhythmias after, 14-15 for aspergillosis, 537-538, 539 for bronchiectasis, 475-477, 476t for carcinoid tumors, 702-703 for coccidioidomycosis, 542 complete versus incomplete, 793 complications of early, 160-165 late, 166-186 extended, 941-956 for aortic invasion, 946, 950, 950f for chest wall invasion, 941-943, 942f-944f for diaphragm invasion, 954 for esophageal invasion, 954-955 historical note on, 941 induction chemoradiotherapy before, 955, 955f for inferior vena cava invasion, 953 for left atrial invasion, 950, 951f for pericardial invasion, 954 for superior vena cava invasion, 951-953, 952f-953f for tracheal carina invasion, 953-954 for vertebral invasion, 943-946, 945f-949f history of, 4 for massive hemoptysis, 453-454 minimally invasive techniques for, variations in, 984-986 morbidity and mortality in, 160 for mucormycosis, 548 palliative, indications for, 779-780 for parenchymal injury, 1773-1774 preoperative anesthetic assessment for, 40-45, 40t, 41f-43f, 45f preoperative assessment for, pulmonary, 12-13, 13f risk factors for, 11 segmented. See Segmentectomy. sublobar. See Sublobar resection. video-assisted. See Video-assisted pulmonary resection. wedge. See Wedge resection. Pulmonary sequestration, 468-470, 468f-469f, 1569-1572 classification of, 1569 clinical presentation in, 1570 extralobar, 468-470, 468f, 469f imaging of, 1570, 1571f, 1573f incidence of, 1570 intralobar, 468f, 470 management and surgical considerations in, 1570-1572 Pulmonary thromboembolism, postoperative prevention of, 143, 143b risk categories for, 143t Pulmonary thromboendarterectomy complications of, 658-659, 659f, 659t patient selection for, 656-657 postoperative care in, 658 results of, 659 technique for, 657-658, 658f Pulmonary toilet flexible bronchoscopy for, 90 postoperative, after tracheobronchial trauma, 1765 Pulmonary torsion, postoperative, late, 173 Pulmonary trunk, 403 Pulmonary vascular disease, lung transplantation for, 663, 675, 688, 689f Pulmonary vasoconstriction, hypoxic, during one-lung ventilation, 53-57 Pulmonary vein(s) abnormalities of, mediastinal mass from, 1657 anatomy of, 403-404, 403f, 404f, 405, 405f, 406f anomalies of, 404

1823

Pulmonary vein(s) (Continued) development of, 462 dissection of, in pneumonectomy, 865-866, 865f Pulse contour analysis, for cardiac output measurement, 158 Pulse oximetry in bacterial aspiration pneumonia, 493 postoperative, 137 Purine synthesis inhibitor, after lung transplantation, 675 Pyopneumothorax, in lung abscess, 497 Pyrazinamide, for tuberculosis, 507 Pyridostigmine, for myasthenia gravis, 1550

Q Quality of life measurement of, 17 pulmonary function and, 13 after sleeve resection, 907 after video-assisted pulmonary resection, 981 Quinacrine, pleurodesis with, 1048

R Race lung cancer and, 710f, 711 pulmonary function testing reference values and, 29 Radiation bronchitis, from endobronchial brachytherapy, 238 Radiation exposure, lung cancer and, 715 Radiation fibrosis, in brachial plexus, 1229 Radiation therapy. See Radiotherapy. Radioactive colloids, pleurodesis with, 1049 Radioaerosols, for ventilation-perfusion scintigraphy, 441 Radiofrequency ablation, 796-801 computed tomography-guided, 799 devices for, 797, 797f, 798f operative approach to, 798-799 patient selection for, 798, 799t plus stereotactic radiosurgery, 802 results of, 800-801 systems for and mechanisms of action of, 796-797, 797f treatment response to, determination of, 799, 800t Radiography chest. See Chest radiography. computed, 415 in laryngeal trauma, 1743 in tracheobronchial trauma, 1758 of upper airway, 196, 197f Radioiodine therapy, for substernal goiter, 1671 Radiologic examination, in tracheal pathology, 222 Radiology setting, pulmonary artery rupture in, 65 Radionecrosis, of chest wall etiology of, 1244, 1244f, 1245f preoperative evaluation in, 1245-1247 surgical management of, 1245f-1252f, 1245t, 1247-1252 Radiopharmaceuticals, for positron emission tomography, 429-430, 432-433 Radiosurgery, stereotactic, 801-802, 801f background and techniques for, 801, 801f patient selection for, 801-802 plus radiofrequency ablation, 802 results of, 802 Radiotherapy for adenoid cystic carcinoma, 704-705 brachytherapy in. See Brachytherapy. for carcinoid tumors, 703 with chemotherapy. See Combined modality therapy. consolidative, for non-Hodgkin’s lymphoma, 1629 involved field for Hodgkin’s lymphoma, 1626-1627 for lymphoblastic lymphoma, 1630 for non-Hodgkin’s lymphoma, 1628-1629 late complications of, 182 for malignant mesothelioma, 1128-1130 for massive hemoptysis, 453

1/25/2008 1:46:14 PM

1824

Index

Radiotherapy (Continued) mediastinal, complications of, 1627-1628 for non–small cell lung cancer adjuvant, 787-788, 787t definitive in early-stage disease, 804-805, 805t in locally advanced disease, 805-807 neoadjuvant, 783 palliative, 810-812, 811t-812t with radioprotectant, 807 stereotactic body, 805, 805t pericarditis from, 1540 planning for, with positron emission tomography, 440 preoperative, avoidance of, 393 for pulmonary metastasis, 851, 855 for small cell lung cancer cranial, prophylactic, 833 dose and fractionation of, 832 in elderly persons, 838 target volume of, 832-833 thoracic, 831-833, 832t timing of, 831-832, 832t after sublobar resection, 872 for thymic carcinoma, 1613 for thymoma adjuvant, 1606-1607, 1607t neoadjuvant, 1607, 1608f for tracheal tumors, 317, 319 Radon exposure, lung cancer and, 715 Ranke complex, 506 Rapamycin, after lung transplantation, 676 Rapid nucleic acid diagnostic tests, for pulmonary infections in immunocompromised host, 586-587 Ras family, in carcinogenesis, 721 Rasmussen’s aneurysm, 512 Raynaud’s phenomenon, in thoracic outlet syndrome, 1279 RB1 mutations, in lung cancer, 720 RECIST criteria for follow-up after radiofrequency ablation, 799, 800t Rectus abdominis anatomy of, 1202t, 1203, 1203f-1205f blood supply to, 1319, 1319f previous incisions and, 1319-1320, 1320f chest wall reconstruction with, 1245t, 1249, 1300, 1318-1323, 1318f-1322f free flap transfers of, 1320, 1323 mediastinal reconstruction with, 1266, 1266f transverse musculocutaneous flap with, 1320, 1320f-1322f Recurrent laryngeal nerve anatomy of, 306, 405, 405f, 1755 course and anatomic relationships of, 194, 194f, 257, 257f injury to laryngotracheal disruption with, 1749-1750 mechanisms of, 307, 310t in mediastinoscopy, 106 in thyroidectomy, 1675 in tracheal resection, 397-398 in tracheobronchial trauma, 1758 traumatic, 1742 vocal fold paralysis and, 306, 307 in pneumonectomy, 866, 866f in sleeve resection and bronchoplasty, 895, 896f trachea and, relationship between, 194, 194f in tracheal resection, 379 Red cell aplasia, pure, thymoma and, 1595-1596 Rehabilitation, pulmonary cardiopulmonary exercise testing before, 38 for chronic obstructive pulmonary disease, 136, 607 for lung volume reduction surgery, 613-614 Rejection after heart-lung transplantation, 674 after lung transplantation acute, 683-684, 684f chronic, 684-686, 685f, 685t classification of, 684t diagnosis of, 683, 684f, 686 surveillance for, 676

Index-F06861.indd 1824

Release maneuvers anastomotic complications and, 394-395 for tracheal anastomosis, 380, 381 for tracheobronchial anastomosis, 385-386 Remifentanil, for airway surgery, 215 Renal cancer, pulmonary metastasis of, 860t, 862 Renal disorders in interstitial lung disease, 568 preoperative risk assessment for, 16, 44, 44t Renal failure postoperative, late, 185 preoperative risk assessment in patient with, 16 Reoperation for postintubation tracheal stenosis, 263-264 as risk factor for anastomotic complications, 395 for thoracic outlet syndrome, 1360, 1362f Reperfusion controlled, after lung transplantation, 666 injury from, after fluid therapy, 1726 Residency programs in thoracic surgery, 6, 7 Residual volume (RV), 20f, 22, 24, 24f, 29t Respiration, muscles of, 1206-1207, 1206f Respiratory acidosis during one-lung ventilation, 54 in postoperative COPD patients, 608 Respiratory care for chylothorax, 1116 for pneumonia prophylaxis, 161 postoperative, 138-139, 139b preoperative, 136 Respiratory distress acute in coccidioidomycosis, 543 fluid therapy in, 151, 152 in histoplasmosis, 533 severe, pneumothorax in, 1105 after talc pleurodesis, 1049 in diaphragmatic eventration, 1433 in tracheobronchial trauma, 1758 Respiratory failure in congenital diaphragmatic hernia, 1404 postoperative late, 184-185, 185f management of, 154-156 after resection for superior sulcus tumors, 930 Respiratory insufficiency chemotherapy-induced, 182, 182t chronic, phrenic nerve and diaphragm motor point pacing for, 1445-1456 Respiratory mechanics, assessment of. See Spirometry. Respiratory rate, in postoperative COPD patients, 608 Respiratory symptoms in diaphragm elevation, 1398 in pediatric mediastinal tumors, 1653-1654 Respiratory syncytial virus infection, in immunocompromised host, 592-593 Respiratory tract infection bacterial, 478-498 viral bronchiolitis obliterans syndrome and, 685 after lung transplantation, 679 Restrictive lung disease in diaphragmatic eventration, 1404, 1434, 1434f lung transplantation for, 663, 689, 689f, 690f pulmonary function testing in, 34 Restrictive pattern, in pulmonary function testing, 30f, 31 Restrictive thoracic dystrophy, acquired, 1346, 13481349, 1348f-1349f Resuscitation goal-directed, for sepsis, 146-147 shock and, 1725-1727, 1725t, 1726t Retransplantation, after lung transplantation, 674 Retropharyngeal fascial cleft, 1530f, 1531, 1531f Retrosternal gap of Larrey, 1425 Retrosternal gas, in poststernotomy mediastinitis, 1264 Retrovisceral space, 1530f, 1531, 1531f Revascularization, coronary, preoperative, 14 Rhabdomyoma, mediastinal, 1645-1646

Rhabdomyosarcoma of chest wall, 1297, 1297f mediastinal, 1646-1647 Rheumatoid arthritis, 57-58, 580 Rhinovirus infection, in immunocompromised host, 593 Rib(s) bucket handle movement of, 1377 cervical excision of supraclavicular approach to, 1351, 1354f transaxillary approach to, 1356 imaging of, 1209, 1211f characteristics of, 1197, 1199f, 1200 false, 1197, 1198f fibrous dysplasia of, 1209, 1211f first anatomy of, 1199f, 1200 compression factors at, 1271, 1272f division of, in chest wall resection, 927, 927f excision of supraclavicular approach to, 1351, 1352f-1354f transaxillary approach to, 1356, 1357f-1358f floating, 1197, 1198f fracture of, traumatic, 1733, 1770, 1771f, 1789 grafts with for chest wall stabilization, 1311, 1311f in Poland’s syndrome repair, 1337-1338, 1338f notching of, 1209-1210 resection of in posterolateral thoracotomy, 131 in thoracoplasty, 1166, 1166f second, anatomy of, 1199f, 1200 sixth, excision of, in extrapleural pneumonectomy, 1188-1189 sternum and, 1199f, 1200 supernumerary, 1209, 1211f true, 1197, 1198f Rib cutter, for first rib division, 927, 927f Rib remnant, excision of, posterior thoracoplasty approach to, 1360, 1361f Rib resection drainage, with open thoracic window, for empyema, 1066, 1066f-1068f Rib spreaders, in lobectomy, 880, 880f Rifampin, for tuberculosis, 507 Ring-sling complex, 245 Risk assessment tools, preoperative, 16 RITA electrode, for radiofrequency ablation, 797, 798f Rituximab for B-cell lymphoma, 1631 for non-Hodgkin’s lymphoma, 1629 RNA analysis, sputum, for lung cancer screening, 749 Robotic system for mediastinal surgery, 1518-1519, 1703-1704 for phrenic nerve pacing surgery, 1448 for thymectomy, 1705 Robotic-assisted VATS lobectomy, 989-997 da Vinci Surgical System for, 989, 990f division of fissure in, 993, 996f hilar dissection in, 992-993, 994f-995f historical note on, 989 initial exploration and robot positioning in, 991992, 991f mediastinal lymph node dissection in, 992, 992f-993f patient selection for, 989 results of, 993, 995-997, 997t robot preparation in, 991 robotic training and technique development for, 989, 991 Rocuronium, during airway surgery, 216 Roos test, in thoracic outlet syndrome, 1280f, 1281 Ropivacaine, for paravertebral nerve block, 74-75 Rounded atelectasis, 1020-1022, 1022f Roundworm infection, 551t, 554t, 564

S Saber-sheath trachea, 204, 207, 209f Salivary gland cancer, pulmonary metastasis of, 862

1/25/2008 1:46:14 PM

Index

Salmeterol, for chronic obstructive pulmonary disease, 606 Sanders ventilating system, 95, 96f Sarcoidosis, 296-297, 575-576, 576f, 635 Sarcoma. See also specific type, e.g., Chondrosarcoma. Ewing’s of chest wall, 1220, 1232, 1233f, 1294f, 1295, 1295f, 1309 pulmonary, primary, 847 neurogenic, 1636 osteogenic (extraosseous), mediastinal, 1647 pleural, 1123-1125, 1124f-1125f pulmonary metastatic, 855, 859f, 860-861, 860t primary, 845-846 soft tissue of chest wall, 1223, 1227f, 1232-1233, 12971298, 1297f-1298f pulmonary metastatic, 859f, 860t, 861 primary, 846 Satellite nodules, stage IIIB non–small cell lung cancer with, 778 Scalene muscles, anatomy of, 1202, 1202f Scalene test, in thoracic outlet syndrome, 1279, 1280f Scalene triangle, 1272 Scalenus anticus, resection of, transaxillary approach to, 1356, 1357f Scalenus anticus syndrome, 1272 Scalenus posterior, division of, in chest wall resection, 926f, 927 Scapula, 1197, 1198f Scar adenocarcinoma, 734-735 Scar carcinoma, 514 Scarring, hypertrophic after pectus deformity repair, 1344 after sternotomy, 127 Schede thoracoplasty, 1160-1161 Schistosomiasis, 551t, 554t, 564 Schwannoma. See Neurilemmoma. Sciatic nerve, intraoperative injury to, 48 Scimitar syndrome, pulmonary hypoplasia in, 464, 464f Scintigraphy in intrathoracic thyroid mass, 1494 in mediastinal lymphoma, 1492 in parathyroid tumors, 1680-1681, 1681f in poststernotomy mediastinitis, 1264 quantitative pulmonary, in preoperative risk assessment, 12 in substernal goiter, 1670 ventilation-perfusion. See Ventilation-perfusion scintigraphy. SCLC. See Small cell lung cancer (SCLC). Sclerosing agents administration of by poudrage, 1051-1052 by tube thoracostomy, 1051 injection of, for cystic lymphatic malformation, 1575 for pleurodesis, 1031, 1049-1050, 1050t-1051t, 1141-1143, 1142t Sclerosing hemangioma, 693, 695f Sclerosing mediastinitis. See Mediastinitis, fibrosing (sclerosing). Sclerosis amyotrophic lateral, diaphragm motor point pacing in, 1453-1454 bronchioloalveolar carcinoma with, 733 systemic, 580 tuberous, 578-579 Scoliosis after pectus deformity repair, 1345 after thoracoplasty, 1169, 1169f Sealant, in decortication, 1180 Secretions aspiration of lung abscess from, 494 pneumonia from, 479, 493 clearance of in postoperative COPD patients, 608 after sleeve resection, 905 in tracheomalacia, 284

Index-F06861.indd 1825

Secretions (Continued) management of, tracheostomy in, 346 tracheobronchial, 284 Sedation in critical care, 156 preoperative, 44 Segmental artery, anatomy of, 898, 898f, 910f, 911f, 912 Segmental bronchoplasty, 904, 904f Segmental exclusion with one-way valves, 626-630, 627f-630f, 629t with sealants, 626 Segmentectomy, 887-893. See also Sublobar resection. air leak after, 888 anterior, 889-890 apical, 888f-889f, 889 basal left, 892 right, 890-891 general considerations in, 887-888 for high tracheoesophageal fistula, 304-305, 305f historical note on, 887 intersegmental plane in, identification and separation of, 887-888 introduction of, 4-5 left lower lobe, 892 left upper lobe, 891 lingula, 891, 891f-892f local recurrence after, 892 for non–small cell lung cancer, 769 posterior, 889 for postintubation stenosis, 262-264 for postintubation tracheomalacia, 287 results of, recent reports on, 893 right lower lobe, 890-891, 890f right upper lobe, 888f-889f, 889 superior left, 892 right, 890, 890f technical considerations in, 889-892 video-assisted thoracic surgery for, 877, 877f, 984 wedge resection versus, 892-893 Selenium, lung cancer and, 716 Seminoma, mediastinal, 1489, 1509, 1509f, 16161617, 1616f Semmes-Weinstein monofilaments, pressure threshold testing with, 1282, 1282f Sensitization, in nociceptor response, 68, 69 Sensory testing, in thoracic outlet syndrome, 12811282, 1282f-1284f Sepsis activated protein C (APC) for, 148-149 antibiotics and source control for, 146 corticosteroids for, 149-150 cortisol levels in, free versus total, 149-150, 150f fluid therapy in, 152 goal-directed resuscitation for, 146-147 pathophysiology of, 148, 148f vasopressors for, 147-148, 147t Septic arthritis, of sternoclavicular joint, 1217, 1217f Septum transversum, 1372-1373, 1372f Septum transversum incision, 1374, 1374f Sequestration, pulmonary, 468-470, 468f-469f Serologic studies in aspergillosis, 537 in coccidioidomycosis, 541 in community-acquired pneumonia, 485 in fungal infections, 527 in histoplasmosis, 534 in hydatid disease, 558-559 postoperative, 137 Seroma after pectus excavatum repair, 1343, 1343f after thoracotomy, 166 Serotonin, carcinoid syndrome and, 702 Serratus anterior anatomy of, 1202t, 1203, 1203f-1205f blood supply to, 1326f, 1327 chest wall reconstruction with, 1245t, 1249, 1300, 1326f, 1327 Severe acute respiratory distress syndrome (SARS), pneumothorax in, 1105 Sevoflurane, for airway surgery, 214

1825

Sheffield palliative care model, 823 Shenstone-Janes lung tourniquet, 4 Shields’ three-zone model of mediastinum, 1472, 1507f Shock definition of, 1725 hemorrhagic physiologic response to, 1725-1726, 1725t treatment of, 1726-1727, 1726t hypovolemic, 1727 markers of, 1727 resuscitation and, 1725-1727, 1725t, 1726t Shoulder function, after video-assisted pulmonary resection, 981 Shoulder pain, referred, in lung cancer, 752 Shunt(s) bronchopulmonary, in bronchiectasis, 474 pleuroperitoneal for chylothorax, 1116, 1118 for malignant pleural effusion, 1144, 1144t during superior vena cava cross-clamping, 1692 Sibson’s fascia, 1200 Silastic implant, for medialization laryngoplasty, 309, 309f Silastic keel stent, 1751 Silhouette sign, on chest radiography, 427 Silicone implant, characteristics of, 1312 Silicone stent, for tracheobronchial strictures, 1791 Silicone Y stent for acquired tracheobronchomalacia, 289, 290f for stricture after lung transplantation, 682, 682f Silicosis, 420f, 578, 578f Simian virus 40, malignant mesothelioma and, 1126 Simon’s foci, 506 Single photon emission computed tomography, 441. See also Ventilation-perfusion scintigraphy. Sirolimus, after lung transplantation, 676 Six-minute walk test in chronic obstructive pulmonary disease, 605 in preoperative assessment, 42 Sjögren’s syndrome, 580 Skeletal muscle weakness, in myasthenia gravis, 1550 Skeletal syndromes, in lung cancer, 752 Skin lesions of, in interstitial lung disease, 568, 569 metastasis to, 753 necrosis of, after sternotomy, 127 numbness of, after sternotomy, 1254 Skin testing in coccidioidomycosis, 541 in fungal infections, 526-527 Sleep apnea, obstructive, perioperative management of, 213 Sleeping position, in thoracic outlet syndrome, 1287, 1288f Sleeve resection and bronchoplasty, 894-908 anatomic considerations in, 895-898, 895b, 895f-898f, 896b complications of, 905-906, 905t covering of anastomosis in, 901 historical note on, 894-895 history of, 4 indications for, 898-899 intraoperative assessment for, 899 late airway complications of, 174 local recurrence after, 906-907, 907t luminal disparity correction techniques in, 900901, 900b, 901f after neoadjuvant therapy, 908 for non–small cell lung cancer, 768 oncologic anatomy of lung cancer applicable to, 898 patient selection for, 899 versus pneumonectomy, 907, 907t postoperative care in, 905 preoperative assessment for, 899 results of, 905-907, 905t-907t surgical techniques for general principles of, 899-901, 900b, 900f-901f in lobes of left lung, 902-903, 903f in lobes of right lung, 901-902, 902f-903f

1/25/2008 1:46:14 PM

1826

Index

Sleeve resection (Continued) and bronchoplasty (Continued) surgical techniques for (Continued) in main stem bronchi, 903-904 in segments, 904, 904f survival rate for, 906, 906t and conduit interposition, pulmonary artery reconstruction with, 916-917, 919f, 920 and end-to-end anastomosis, pulmonary artery reconstruction with, 916, 918f, 920 Slow vital capacity (SVC), 19, 20f Small cell lung cancer (SCLC), 825-840 antiangiogenic agents for, 839 anticoagulation for, 838-839 biomarkers in, 828 chemotherapy for adjuvant, 835, 835t advances in, 831 combinations for, 830t dose intensification in, 829-831 duration of, 831 in elderly persons, 837-838, 838t in extensive-stage disease, 828-831 neoadjuvant, 836-837, 836t in relapsed disease, 834 clinical presentation in, 827 combined, 825 cytogenetics and molecular alterations in, 826 differential diagnosis of, 826 in elderly persons, 837-838, 838t epidemiology of, 825 etiology of, 825 extensive-stage, 826, 833-834 histopathology of, 701f, 738-739, 739f imaging of, 827 immunohistochemistry of, 826 immunotherapy for, 838 limited-stage, 826, 828-833 pathology of, 825-826 positron emission tomography in, 439 prognostic factors in, 827-828 radiotherapy for cranial, prophylactic, 833 dose and fractionation of, 832 in elderly persons, 838 target volume of, 832-833 thoracic, 831-833, 832t timing of, 831-832, 832t relapse of, 834 staging of, 826-827 surgery for, 834-837, 835t-836t treatment of alternative approaches to, 838-840 future directions in, 840 toxicities associated with, 829t very limited-stage, 827 Smoking bullous disease and, 635, 643-644 interstitial lung disease and, 568 lung cancer association with, 712-714, 714t and changing cigarette, 712-713 dose effect in, 712 history of, 712 for second-hand or passive smoking, 713-714 as predictor of malignant pulmonary nodule, 455 prognostic significance of, in non–small cell lung cancer, 767 pulmonary alveolar proteinosis and, 581 pulmonary Langerhans cell histiocytosis and, 581 Smoking cessation in chronic obstructive pulmonary disease, 605 lung cancer risk after, 714, 714t for lung volume reduction surgery, 613 preoperative, 136 Sniff test, in diaphragmatic paralysis, 1393 Socioeconomic status, lung cancer and, 711 Soft tissue metastasis, symptoms of, 753 Soft tissue sarcoma of chest wall, 1223, 1227f, 1232-1233, 1297-1298, 1297f-1298f pulmonary metastatic, 859f, 860t, 861 primary, 846

Index-F06861.indd 1826

Soft tissue tumors, of chest wall, 1220-1226 benign, 1221-1223, 1223f-1226f malignant, 1223, 1226, 1227f-1228f Somatosensory potentials, in thoracic outlet syndrome, 1284 Somatostatin, for chylothorax, 1116 Somnolence, postoperative, from epidural analgesia, 161-162 Sotalol, for atrial fibrillation prophylaxis, 142 Speleoplasty, 514 Spinal canal, tumor invasion of, 945, 948f Spinal cord injury cervical, phrenic nerve and diaphragm motor point pacing in, 1445, 1451-1452 after thoracotomy, 166 Spinal deformity, and pulmonary function testing reference values, 29 Spinal reconstruction, after vertebrectomy, 946, 948f-949f Spinal tuberculosis, 517-518, 518t Spine surgery, thoracoscopic, 117 Spiration umbrella one-way valve, 626, 627f Spirometry, 19-22 acceptability and repeatability criteria for, 21-22, 21t in chronic obstructive pulmonary disease, 604, 604t in diaphragm elevation, 1398 final report data for, 22 flow-volume loop in, 20, 20f, 21, 21f. See also Flow-volume loop. in interstitial lung disease, 571 life expectancy and, 13 measures in, 19, 20f preoperative, 11-12, 11t, 41-42, 41f pseudorestrictive, 34 side-stream, during one-lung ventilation, 46 technique for, 20-22, 20f volume-time curve in, 20, 20f Splanchnicectomy, video-assisted thoracic surgery for, 116 Split pleura sign, 1013f, 1014 Spondylitis, ankylosing, 1207 Spondylosis, cervical, 1287 Spondylothoracic dysplasia, 1242 Spontaneous inhalation ventilation, during rigid bronchoscopy, 96-97 Sporotrichosis, 548-549 Sputum foul, in empyema, 1061 production of, in bronchiectasis, 474 putrid, in lung abscess, 495 Sputum examination in aspergillosis, 537 in community-acquired pneumonia, 484-485 induced, in fungal infections, 526 for lung cancer screening chest radiography combined with, 744-746, 745t investigational approaches to, 747-749 for lung cancer staging, 760 in patients with previously resected lung cancer, 792-793 in tuberculous pleural effusion, 1075 Squamous cell carcinoma cavitary, 426, 427f of lung, pathology of, 729-730, 730f, 731f of trachea, 204, 205f, 312-320 clinical presentation in, 312-313 diagnostic studies in, 313-314, 313f-314f epidemiology of, 312 histology of, 314, 315t, 316t treatment of, 314-319, 317-319, 317f-319f Squeaks, pulmonary, in interstitial lung disease, 568 Stainless steel wire closure for partial sternal split, 128, 128f for sternal split, 127, 127f Staphylococcus aureus pneumonia, 481 empyema in, 1060 Stapled bullectomy open, 645, 646f thoracoscopic, 645-646, 647f, 648f

Staplers/stapling techniques mechanical, specifications of, 976t for segmentectomy, 888 for VATS lobectomy, 984-985 for VATS wedge resection, 984 for video-assisted pulmonary resection, 976, 976t, 977f for wedge resection, 875-876, 875f-876f Starling’s equation, 1005-1006, 1005b Statin therapy, perioperative, for myocardial infarction prophylaxis, 142 Stem cell transplantation for lymphoblastic lymphoma, 1630 pulmonary infection after, 585t, 594 Stent(s) for anastomotic stricture after lung transplantation, 681-682, 682f bronchopulmonary, for emphysema, 623-626, 624f-626f coronary, preoperative, 14, 44 endobronchial, 95, 239-240, 239f, 240f esophageal late complications after, 180, 180f for tracheoesophageal fistula, 303 for laryngeal trauma, 1750-1752, 1750b, 1750f-1751f laryngotracheal, after partial cricotracheal resection, 372, 372f, 373 for malignant tracheoesophageal fistula, 176, 177f metallic, 239f, 240 for postintubation stenosis, 262 for postintubation tracheomalacia, 287 for relapsing polychondritis, 295-296 for sarcoidosis, 297 silicone-based, 239, 239f, 240f for superior vena cava obstruction, 1688 for tracheal stenosis, 174, 174f-175f, 176, 334 for tracheal tumors, 317 for tracheobronchial strictures, 1791 for tracheobronchomalacia, 289, 290f for tracheoesophageal fistula, 303 for tracheomalacia in relapsing polychondritis, 288, 288f Step-down unit, for postoperative care, 136 Stereotactic body radiotherapy, for non–small cell lung cancer, 805, 805t Stereotactic radiosurgery, 801-802, 801f background and techniques for, 801, 801f patient selection for, 801-802 plus radiofrequency ablation, 802 results of, 802 Sterilization, space, for empyema, 1066-1068 Sternal angle, 1200 Sternal fixation, in pectus excavatum repair, 1330-1331, 1334, 1334f, 1336f Sternal spreaders, 126, 126f, 1257-1258, 1258f Sternal wire sutures chronic pain associated with, 1254 types of, 1258-1260, 1259f Sternoclavicular joint dislocation of, 1212, 1213f septic arthritis of, 1217, 1217f Sternocleidomastoid muscle anatomy of, 1202, 1202f mediastinal reconstruction with, 1267 Sternocostal triangles, 1369 Sternomediastinitis, postoperative, 1263-1270 antibiotics for, 1269 diagnosis of, 1264-1265, 1265f general measures for, 1269-1270 Hanuman syndrome in management of, 1267-1268, 1267f late complications of, 1269 muscle flaps for, 1266-1267, 1266f perioperative preventive measures for, 1263-1264 risk factors for, 1263 surgical management of, 1265-1269, 1265f-1269f types of, 1265-1266 vacuum-assisted closure for, 1268-1269, 1269f Sternotomy, 125-128, 126f-128f closure of, 127, 127f, 128f, 1258-1260, 1259f complications of, 127 incisions for, 1254f

1/25/2008 1:46:14 PM

Index

Sternotomy (Continued) late complications of, 166 median, 125-126, 126f for bullous disease surgery, 650 for carinal resection, 385 for chest injury, 1769, 1784 chest wall radiographic changes after, 12121213, 1215, 1215f for pulmonary metastasectomy, 855 tracheostomy and, 348-349 midline general surgical complications of, 1253-1254 infectious complications of, 1262-1270 neurologic complications of, 1254 noninfectious complications of, 1253-1262 sternal instability after factors involved in, 1255-1260, 1256f-1259f with infection. See Sternomediastinitis, postoperative. without infection. See Sternum, dehiscence of. superficial infection after, 1262-1263 partial, 127-128, 128f for tracheal resection, 378, 379f skin-sparing incision for, 126 sternal spreaders for, 126, 126f, 1257-1258, 1258f submammary, 126-127, 127f Sternum. See also Chest wall. anatomy of, 1197, 1198f, 1200 applied surgical implications of, 1207 blood supply to, 1255, 1256f cleft, 1239, 1338-1339, 1338f congenital deformities of, 1239-1241 dehiscence of, 1213, 1215f biomechanical considerations in, 1256-1257, 1257f diagnosis of, 1255, 1255f intraoperative measures to prevent, 1257-1258, 1258f repair of, 1260-1262, 1261f-1262f, 1316, 1317f ectopia cordis of, 1239-1240, 1241t floating, after pectus deformity repair, 1343-1344 fracture of, 1211, 1212f, 1770 malrotation of, pectus deformity repair and, 1341, 1341f-1342f malunion/nonunion of, 1791, 1792f open, for poststernotomy mediastinitis, 12671268, 1267f osteomyelitis of, 1215, 1217 and ribs, 1199f, 1200 sequestration of, after pectus deformity repair, 1344 thoracoabdominal ectopia cordis of, 1240-1241, 1241t Stocker’s classification of congenital cystic adenomatoid malformation, 466, 466f, 1569 Stomal stenosis, 332, 334f Stomata, 1003-1004 Storz bronchoscope, 330, 330f Strangulation injury, 1741 Strap muscle, transposition of, in tracheoesophageal fistula repair, 303-304, 304f Streptococcus pneumoniae, 480 empyema in, 1060 histopathology of, 584f sequential pathogenesis of, 589-590 Streptococcus pyogenes (group A streptococcus) pneumonia, 481 Streptokinase for effort thrombosis, 1289 intrapleural for empyema, 1065 for retained hemothorax, 1772 Streptomycin, for tuberculosis, 504, 507 Stress syndrome, postoperative, 70 Stress test, in malignant mesothelioma, 1187 Stress ulcer postoperative management of, 140-141 prophylaxis against, in critically ill patient, 158 Stridor in lung cancer, 751 in postintubation stenosis, 259 in tracheomalacia, 283 Stromal strictures, post-tracheostomy, 204

Index-F06861.indd 1827

Stromal tumors, gastrointestinal, thoracoscopic resection of, 1702-1703 Strongyloidiasis, 552t, 555t, 564 Struts for chest wall stabilization, 1311, 1312f in pectus excavatum repair, 1330-1331, 1334f SU5416, for malignant mesothelioma, 1135 Subarachnoid pleural fistula, postoperative, 162 Subclavian artery aberrant right, left aortic arch with, 245-246, 246f anatomy of, 1201f, 1202 axillary, decompression of, 1356 dissection of, in superior sulcus tumors, 936, 936f puncture of, with internal jugular vein cannulation, 47 reconstruction of, 936, 936f retroesophageal left, right aortic arch with left ligamentum and, 244, 244f Subclavian revascularization, phrenic nerve injury after, 1461 Subclavian vein anatomy of, 1202, 1202f axillary, decompression of, 1356 dissection of, in superior sulcus tumors, 935-936, 936f Subclavian vessels penetrating injury to, 1778, 1781 superior sulcus tumors with involvement of, 930 Subglottic edema, after rigid bronchoscopy, 341 Subglottic jet ventilation, in laryngoscopy, 85 Subglottic resection in adults, 353-362 anatomic considerations in, 353, 354f anesthesia for, 354, 354f, 356 complications of, 362 historical note on, 353 indications for, 355f, 356 operative technique for, 357-362, 357f-358f postoperative care in, 362 results of, 362 with synchronous laryngeal reconstruction, 358f362f, 359, 362 in children, 363-375 anesthesia for, 367 complications of, 373-374 extended PCTR in, 371-372, 371f-373f future perspectives on, 374-375 historical note on, 363 indications for, 367, 367b international experience with, 374, 374t operative technique for, 367-370, 368f-370f, 370b postoperative care in, 372-373, 372b preoperative assessment for, 364-367, 364b, 365f-366f, 366t single-stage versus double-stage PCTR in, 370-371 Subglottic stenosis in children diagnosis of, 364-367, 364b, 365f-366f, 366t etiology and pathogenesis of, 364 with glottic pathologic processes, 371-372, 371f-373f management of, 367-372 congenital, 364 idiopathic, 270-276. See also Laryngotracheal stenosis, idiopathic. imaging of, 198f-199f postintubation, 259, 263, 355f, 356, 364 Subglottis, anatomy of, 353, 354f Subglottoscope, 85, 85f Sublobar resection, 869-878. See also Segmentectomy; Wedge resection. controversies in, 869-873, 870f-871f, 877-878 future studies on, 873 historical note on, 869 ideal lesions for, in non–small cell lung cancer, 870, 870f intraoperative brachytherapy in, 870f, 872-873, 872f, 873f, 877 lesion identification in, 874-875, 874f local recurrence after, 871-873 minithoracotomy approach to, 876-877, 876f operative considerations for, 874-877

1827

Sublobar resection (Continued) preoperative evaluation before, 873-874 principles of, 877 survival rate for, 870-871 video-assisted thoracic surgery for, 874-875, 874f-876f, 877, 877f Submammary sternotomy, 126-127, 127f Submandibular space, 1532, 1532f Substernal goiter characteristics of, 1510-1511, 1511f imaging of, 1493-1494, 1493f tracheomalacia in, 281f, 282 Substernal pain in acute pericarditis, 1539 in bronchogenic cyst, 1582 Subxiphoid approach to pericardium, 124, 124f Subxiphoid incisional hernia, after sternotomy, 1253-1254 Subxiphoid pericardial window for cardiac tamponade, 1785 late complications of, 181, 181f Succinylcholine, during airway surgery, 215-216 Suction cannula, in rigid bronchoscopy, 96f, 100 Suction device, in mediastinoscopy, 104, 104f, 105f Sufentanil, for airway surgery, 215 Sulfonamides, for pleural nocardiosis, 1087 Sump nodes, in selection of surgical procedure, 768 Superior pericardial recess, imaging of, 1481-1482, 1482f Superior sulcus, anatomy of, 933, 934f Superior sulcus tumors, 923-940 anatomical considerations in, 933, 934f anterior transcervical approach to, 121, 122f anterior transcervical-thoracic (Dartevelle) approach to, 935-937 brachial plexus dissection in, 936-937, 937f chest wall closure in, 937 chest wall resection in, 937, 937f L-shaped cervicotomy incision for, 935, 935f pulmonary resection in, 937 subclavian artery dissection in, 936, 936f subclavian vein dissection in, 935-936, 936f clinical features of, 933-934 diagnosis of, 934 etiology of, 934, 934t hemiclamshell approach to, 937-938, 938f-939f historical note on, 923-924, 933 imaging of, 1229, 1229f induction chemoradiotherapy for, 931, 939 multimodal therapy for, 931-932 non–small cell, management of, 774-775, 774f, 783, 784f posterior resection technique for, 925-932 anesthesia for, 925 assessment of resectability in, 925-926, 926f brachial plexus dissection in, 928-929, 928f-929f chest wall closure in, 930 chest wall resection in, 926f-928f, 927-928 en-bloc resection in, 929-930 patient positioning for, 925 posterolateral thoracotomy incision in, 925, 926f preoperative evaluation of, 924-925, 924f-925f, 935 resection of complications of, 930, 938-939 contraindications to, 924, 925t, 935 staging of, 924-925, 935 with subclavian vessel involvement, 930 with vertebral involvement, 930-931 Superior vena cava anatomy of, 1684-1685, 1685f in carinal resection, 384, 384f collateral routes of, 1685 cross-clamping of cardiovascular management during, 1692 heparin before, 1692 shunt procedures in, 1692 timing of, 1692 imaging of, 1480f, 1482 injury to, penetrating, 1781, 1786 obstruction of, 1684-1695 catheter-related, 1686, 1689, 1689f classification of, 1686, 1686f-1687f

1/25/2008 1:46:15 PM

1828

Index

Superior vena cava (Continued) obstruction of (Continued) clinical presentation in, 1687-1688, 1688t diagnosis of, 1688 etiology of, 1684, 1685t historical note on, 1684 pathophysiology of, 1685-1686 prognosis in, 1694-1695 stenting for, 1688 in substernal goiter, 1664 surgical management of, 1689-1694 treatment options for, 1688-1689 reconstruction of care after, 1694 complications of, 1694 from innominate veins, 1693-1694, 1693f-1694f materials in, 1690-1692, 1691f prosthetic, types of, 1692-1694, 1693f-1694f trunk replacement in, 1692-1693, 1693f resection of approaches to, 1690 assessment before, 1689-1690, 1690f closure materials in, 1690-1692, 1691f contraindications to, 1689, 1689t indications for, 1689, 1689t monitoring during, 1690 in right carinal pneumonectomy, 388 thrombosis of, signs of, 1482 tumor invasion of, extended pulmonary resection for, 951-953, 952f-953f Superior vena cava syndrome in fibrosing mediastinitis, 1535 in lung cancer, 752 in mediastinal lymphoma, 1622 palliative care for, 824t Supraglottic injury, 1747, 1748f Supraglottic jet ventilation, in laryngoscopy, 85 Suprascapular nerve, intraoperative injury to, 48 Suprasternal notch, 1197, 1198f Sutures for anastomoses in lung transplantation, 669-670, 670f for bronchial closure, in pneumonectomy, 867 for bronchoplasty, 900-901, 901f for chest wall stabilization with mesh or screening, 1313, 1313f for diaphragmatic plication, 1436, 1436f, 1437f, 1438, 1438f for diaphragmatic reconstruction, 1131, 1132f for laryngotracheal anastomosis, 273, 274f parasternal weaving, 1259, 1260, 1261f, 1262f pledgeted, for innominate arteriopexy, 253, 253f for sternal cleft repair, 1338, 1338f for sternal malrotation correction, 1341, 1341f sternal wire chronic pain associated with, 1254 types of, 1258-1260, 1259f for superior vena cava reconstruction, 1690, 1691f for tracheal anastomosis, 379-380, 380f, 381-382 for tracheobronchial anastomosis, 385 for tracheobronchoplasty, 291, 291f type of, anastomotic granulation tissue and, 395 in video-assisted pulmonary resection, 979, 979f Swallowing after tracheal resection, 397 with tracheostomy, 350-351 Sympathectomy dorsal with posterior thoracoplasty, 1360, 1362f with transaxillary first rib resection, 1356, 1358f-1359f video-assisted thoracic surgery for, 116, 1703 Sympathetic effusion, high chest tube output from, 162 Sympathetic ganglia, pulmonary branches of, 414 Sympathicotomy for hyperhidrosis, 1303-1305 outcome of, 1305 technique of, 1303-1304, 1304f-1305f terminology for, 1304-1305 Syndrome of inappropriate antidiuretic hormone (SIADH) in lung cancer, 752 in small cell lung cancer, 827

Index-F06861.indd 1828

Synthetic materials, for chest wall stabilization, 1245t, 1248, 1299, 1311-1312, 1312b, 1312f Syphilis, tracheoesophageal fistula in, 300 Systemic inflammatory response syndrome (SIRS), post-traumatic, 1726 Systemic lupus erythematosus, 579 Systemic sclerosis, 580

T T tube Montgomery for laryngeal stenosis, 1752 for postintubation stenosis, 262 after subglottic resection, 362 for tracheobronchial strictures, 1791 for tracheomalacia from chronic tracheal compression, 287 Tachycardia, in postoperative COPD patients, 608 Tacrolimus, after lung transplantation, 675 Taenia echinococcus, 550. See also Hydatid disease. Taenia solium, 551t, 554t, 564 Talc pleurodesis, 112, 1019, 1019f, 1031, 1049, 1050t for bullous disease, 648 for empyema, 1065 for malignant pleural effusion, 1142-1143, 1142t for pneumothorax, 1103 by poudrage, 1051-1052 respiratory complications of, 1143 Tamponade balloon, for massive hemoptysis, 450 cardiac. See Cardiac tamponade. in lung cancer, 752 Tar, from cigarette smoke, 713 Technegas, for ventilation-perfusion scintigraphy, 441 Technetium-99m–sestamibi scanning, in parathyroid tumors, 1680-1681, 1681f Teeth, protection of during direct laryngoscopy, 85 during rigid bronchoscopy, 97 Telescopes, in rigid bronchoscopy, 96f, 100 Tension-time index, of diaphragm, 1370 Teratoma benign (mature) mediastinal, 1489, 1489f-1490f, 1508-1509, 1509f, 1615-1616, 1616f after mediastinal nonseminomatous germ cell tumor treatment, 1618, 1620 pulmonary, 697 malignant mediastinal, 1489, 1509 pulmonary, primary, 844-845 mediastinal, pediatric, 1655, 1656f Tetracycline pleurodesis, 1049, 1049t, 1142 Tetraplegia, phrenic nerve and diaphragm motor point pacing in, 1445, 1451-1452 Thalidomide for malignant mesothelioma, 1134-1135 for small cell lung cancer, 839 Theophylline, for chronic obstructive pulmonary disease, 606-607, 609 Theranostics, 588 Thermal injury. See Caustic injury. Thermal sealing, saline-enhanced, for VATS nodulectomy, 984, 984f Thermography, in poststernotomy mediastinitis, 1264, 1265f Thiamylal, for airway surgery, 215 Thiopental, for airway surgery, 215 Thiotepa, pleurodesis with, 1048 Third space fluids, and edema, 151 Thoracentesis, 1033-1036 in chylothorax, 1115 complications of, 1036 in empyema, 1061-1062, 1062t history of, 1055 in malignant pleural effusion, 1139-1140 repeated, 1140-1141, 1141t in mediastinal lymphoma, 1624 in pleural effusion, 1044 results of, 1034-1035 technique of, 1033-1034

Thoracic arteries, anatomy of, 1200, 1201f Thoracic bioimpedance, for cardiac output measurement, 158 Thoracic cage, upper one third of, 1197, 1198f Thoracic duct anatomy of, 405, 405f, 1109, 1109f cyst of, 1587, 1659 embolization of, 1116-1117 embryology of, 1109-1110, 1110f histology of, 1110 historical note on, 1108 leaking. See Chylothorax. ligation of, for chylothorax, 1118, 1118f physiology of, 1110-1111 Thoracic dystrophy asphyxiating. See Jeune’s syndrome. restrictive, acquired, 1346, 1348-1349, 1348f-1349f Thoracic epidural analgesia, 49 for perioperative pain management, 75-77, 76f Thoracic gas volume (TGV), 20f, 22 Thoracic incisions, 119-135. See also specific incision, e.g., Sternotomy. anterior, 119-129 anatomic considerations in, 119-120, 120f anterior mediastinotomy, 122-123, 122f anterior thoracotomy, 123, 123f partial sternotomy, 127-128, 128f sternotomy, 125-127, 126f-128f thoracosternotomy (clamshell), 128-129, 129f transverse cervical, 120-122, 120f-122f upper midline, 123-125, 124f-125f general considerations in, 119 history of, 119 late complications of, 166-167 lateral, 129-131 axillary thoracotomy, 129-130, 130f lateral (muscle-sparing) thoracotomy, 130-131, 130f long-term sequelae of, 119 posterior, 131-133 muscle-sparing posterolateral thoracotomy, 132, 132f posterior thoracotomy, 132-133, 133f posterolateral thoracotomy, 131-132, 132f thoracoabdominal, 132-133, 133f for video-assisted thoracic surgery, 134, 134f Thoracic inlet, 1200, 1272 anatomy of, 933, 934f as boundary for thorax, 1724, 1724f definition of, 1471 inferior, anatomy of, 1202 injury to, penetrating, 1781 superior, anatomy of, 1202, 1202f Thoracic outlet syndrome, 1271-1289 cervical rib in, 1209, 1211f chronic nerve compression in, histopathology of, 1274-1275, 1274f-1278f clinical evaluation of, 1279-1282, 1280f-1284f compression factors in, 1271, 1272, 1272f, 1273b diagnosis of, 1276-1287 differential diagnosis of, 1285, 1287 double/multiple crush hypothesis about, 12751276, 1278f effort thrombosis in, 1279, 1288-1289, 1355 electrodiagnostic testing in of nerve conduction velocity, 1284-1285, 1285f of somatosensory potentials, 1284 functional anatomy for, 1272 historical note on, 1271, 1355-1356 management of, 1287-1289 pain evaluation in, 1281 after pectus deformity repair, 1345 peripheral angiography in, 1285, 1286f physical therapy for, 1287-1288 provocative tests in, 1279, 1280f, 1281 radiographic findings in, 1282, 1284 recurrent, posterior thoracoplasty approach for, 1360-1363, 1361f-1362f sensory testing in, 1281-1282, 1282f-1284f signs and symptoms of, 1276-1279, 1280f sleeping position in, 1287, 1288f surgical anatomy for, 1271-1272, 1273f

1/25/2008 1:46:15 PM

Index

Thoracic outlet syndrome (Continued) surgical management of, 1289, 1289f supraclavicular approach to, 1351-1354, 1352f-1354f transaxillary first rib resection in, 1355-1359, 1356f-1359f Thoracic scoliosis after pectus deformity repair, 1345 after thoracoplasty, 1169, 1169f Thoracic spine, anatomy of, 76f Thoracic splenosis, 1026, 1026f Thoracic surgery anesthesia for, 39-66 complications of early, 160-165 late, 182-185 perioperative, 41 critical care in, 145-158 development of, impetus for, 3-4 history of, 3-8 anesthesia and control of ventilation in, 3 in Canada, 6-7 endoscopy in, 4 in Europe, 7-8 in United States, 6 as palliative care specialty, 822-824, 824t perioperative pain management in, 68-79, 141 postoperative care in, 136-144 preoperative assessment for, 9-18 recurrent laryngeal nerve injury risk associated with, 310, 310t risk factors for, 11 training and accreditation in, history of, 6-8 Thoracic sympathetic nervous chain, location of, 1303, 1304f Thoracic venous system, 1685 Thoracic vessels, internal, penetrating injury to, 1781 Thoracic window, open, rib resection drainage with, for empyema, 1066, 1066f-1068f Thoracoabdominal ectopia cordis, 1240-1241, 1241t Thoracoabdominal incision, 132-133, 133f for diaphragmatic access, 1426-1427, 1427f late complications of, 166 Thoracomyoplasty, 1163-1164, 1163f, 1164t for tuberculous empyema, 1078 Thoracoplasty, 1159-1169 chest wall radiographic changes after, 1212, 1215f complications of, 1169, 1169f conventional posterolateral (Alexander type), 1166-1168, 1166f-1168f for empyema, 1069 extrapleural, 1161-1162, 1162f historical note on, 1159-1160 incisions and surgical access for, 1165-1166 indications for, 1164-1165, 1164t, 1165f intrapleural, 1160-1161, 1161f limited, 1164 morbidity and mortality of, 1169 plombage, 1162-1164, 1162f-1163f, 1164t principles of, 1160 tailoring, 1164 for tuberculosis, 503, 504t, 524 for tuberculous empyema, 1078, 1089 types of, 1160-1164, 1161t Thoracoscope, for video-assisted pulmonary resection, 973 Thoracoscopy, 109-117. See also Video-assisted pulmonary resection; Video-assisted thoracic surgery (VATS). Thoracosternotomy, 128-129, 129f Thoracostomy open-window chest wall radiographic changes after, 1212, 1214f for empyema, 1066, 1066f for tuberculous empyema, 1077, 1077f, 1089, 1089f tube for chest injury, 1768 for chylothorax, 1115-1116 complications of, 1768 for empyema, 1063, 1063f history of, 1055, 1056f for lung abscess, 497

Index-F06861.indd 1829

Thoracostomy (Continued) tube (Continued) for pneumothorax, 642-643, 1100 sclerosing agent administration by, 1051 Thoracotomy acute detrimental effects of, 11 in acute necrotizing mediastinitis, 1522t, 1523 anterior, 123, 123f anterolateral, 130-131, 130f axillary, 129-130, 130f for carinal resection, 385 for chest injury, 1769-1770, 1782-1783, 1784-1785 chest wall hernia after, 1786 chronic pain after, 78-79 for diaphragmatic access, 1426 emergency indications for, 1782-1783 for trauma, 1735-1736, 1735f, 1736t late complications of, 166 lateral (muscle-sparing), 130-131, 130f left, arterial partial pressure of oxygen during, 45 for lung cancer staging, 762 mini-, with video assistance, 971, 985 muscle-sparing, 132, 132f, 985-986 for ongoing hemorrhage, 1770-1771 open for empyema, 1064, 1066f for malignant pleural effusion, 1144 pain pathways after, 69-70, 70t in pleural disease, 1040-1041 posterior, 132-133, 133f posterolateral, 131-132, 132f preoperative anesthetic assessment for, 40-45, 40t, 41f-43f, 45f pulmonary dysfunction after, 70, 70t utility, in video-assisted thoracic surgery, 1698 video-assisted, 971, 974, 974f, 985 Thorax boundaries of, in trauma, 1724, 1724f reconstruction of, 1245t, 1248, 1299 skeletal framework of, 1197, 1198f trauma to. See Trauma. Thrombin solution, for massive hemoptysis, 451 Thromboembolic pulmonary hypertension, chronic. See Pulmonary hypertension, chronic thromboembolic. Thromboendarterectomy, pulmonary. See Pulmonary thromboendarterectomy. Thrombolytic therapy for effort thrombosis, 1289 intrapleural for empyema, 1065 for retained hemothorax, 1772 Thrombosis deep venous, postoperative, 143, 143b, 183-184, 183f effort, in thoracic outlet syndrome, 1279, 12881289, 1355 graft, after superior vena cava reconstruction, 1694 of superior vena cava, 1482 Thymectomy classification of, 1556, 1556t completion, thoracoscopic, 1712 extended transcervical-transsternal “maximal,” 1718t extent of, 1553 late complications of, 182 for myasthenia gravis anesthesia for, 60, 1557 historical note on, 1549-1550, 1705 indications for, 1552-1553 perioperative management of, 1557-1558 rationale for, 1549 results of, 1558-1561, 1559t-1560t, 1560f, 1718, 1718t surgical techniques for, 1553-1557, 1556t, 1560t, 1705-1706 thoracoscopic, 1705-1714 transcervical, 1715-1719 radical, 1711 thoracoscopic, 116, 1518, 1518f, 1554f, 1555, 1699-1700, 1705-1714 anesthesia for, 1706-1707

1829

Thymectomy (Continued) thoracoscopic (Continued) bilateral, 1555, 1705, 1713-1714 cannulae and port placement for, 1708, 1708f issues in, 1711-1713 limitations of, 1710 operating room setup for, 1707, 1707f operative procedure for, 1708-1709, 1709f patient positioning in, 1707 patient selection for, 1706, 1706f postoperative care in, 1709-1710 preparation for, 1706 principles of, 1708 results of, 1710-1711, 1711f, 1712, 1713t right- versus left-sided approach in, 1712 robot-assisted, 1705 surgical anatomy in, 1707-1708 for thymoma, 1713 versus transcervical approach, 1712 for thymic cyst, 1577 transcervical, 1553, 1554f, 1556, 1560t, 1715-1719 expected outcomes in, 1718, 1718t history of, 1549-1550 operative technique of, 1715-1718, 1716f-1717f patient selection for, 1715, 1716t versus thoracoscopic approach, 1712 transsternal, 1553-1555, 1555f, 1556, 1560t Thymic carcinoma characteristics of, 1507, 1508f, 1592, 1612-1613 imaging of, 1485, 1486f survival rate for, 1613, 1613f versus thymoma, 1597 treatment of, 1613 well-differentiated, 1592, 1614 Thymic rebound, residual mediastinal mass versus, 1632 Thymic veins, dissection of, in transcervical thymectomy, 1716, 1716f Thymolipoma characteristics of, 1508, 1508f imaging of, 1486-1487, 1487f Thymoma, 1589-1614, 1593, 1595, 1596t autoimmune diseases and, 1595, 1596t benign (cytologically bland and without evidence of invasion), 1591-1592 cause of death in, 1600t cellular classification of, 1551, 1589-1592, 1591t characteristics of, 1506-1507, 1507f chemotherapy for neoadjuvant, 1607-1608, 1608t regimens in, 1608-1609, 1609t clinical presentation in, 1592-1596, 1594t, 1595f, 1596t demographic distribution of, 1592-1593, 1595f diagnosis of, 1596-1598 differential diagnosis of, 1597 imaging of, 1484-1485, 1484f-1485f, 1596-1597 metastasis of, 1598 in myasthenia gravis, 1551-1552, 1552t, 1592, 1593, 1595, 1596t, 1609 natural history of, 1598, 1599t, 1600t parathymic syndromes in, 1593, 1595-1596, 1596t pathologic diagnosis of, 1598 pediatric, 1656 pleural, 1123, 1124f, 1484-1485, 1485f prognostic factors in, 1609-1611, 1610t-1611t pulmonary, primary, 843 radiotherapy for adjuvant, 1606-1607, 1607t neoadjuvant, 1607, 1608f recurrent, treatment of, 1611-1612, 1612f staging systems for, 1551-1552, 1552t, 1589, 1590t surgery for, 1598-1606 operative mortality in, 1600 recurrence rates and patterns after, 1602-1603, 1603t, 1604f role of partial resection in, 1603, 1605-1606, 1605f, 1605t survival after, 1600, 1601t, 1602, 1602f technical issues in, 1599-1600, 1600t-1601t thoracoscopic, 1699, 1700 symptoms of, 1592, 1594t

1/25/2008 1:46:15 PM

1830

Index

Thymoma (Continued) thymectomy for thoracoscopic, 1713 transsternal, 1715 treatment of, 1598-1609 Thymus gland carcinoid of, 1613-1614 imaging of, 1485-1486, 1486f survival rate for, 1613, 1613f cyst of, 1587 characteristics of, 1508, 1509f in children, 1576-1577, 1659 clinical presentation in, 1576-1577 imaging of, 1487-1488, 1488f, 1577 incidence of, 1576 management and surgical considerations in, 1577, 1700 embryologic descent of, 1678, 1679f hyperplasia of imaging of, 1488 lymphoid, 1488 in myasthenia gravis, 1551 pediatric, 1656, 1657f measurement of, 1480, 1482f in myasthenia gravis, 1551-1552 normal radiologic appearance of, 1478, 1479f1480f, 1480, 1481f-1482f tumors of. See Thymic carcinoma; Thymoma. Thyroid arteries, and tracheal blood supply, 190f, 191-193, 191f Thyroid cancer intrathoracic extension of, 1494 invading upper airway, 322-325 pulmonary metastasis of, 862 Thyroid cartilage anatomic relationships of, 257, 258f fracture of, 1741f, 1742, 1747-1748, 1748f Thyroid function tests, in substernal goiter, 1670 Thyroid gland anatomic relationship to trachea, 194, 194f embryology of, 1662 parathyroid glands within, 1681 ultrasonography of, in substernal goiter, 1670 Thyroid hormones, abnormalities of postoperative medications in patient with, 140 substernal goiter in, 1670 Thyroid suppression, for substernal goiter, 1671 Thyroid tissue, intrathoracic, 1492-1494, 1493f Thyroid transcription factor-1, in malignant mesothelioma, 1127 Thyroid tumors, mediastinal, 1661-1676. See also Goiter, substernal. Thyroidectomy, for substernal goiter anesthesia in, 1671 complications of, 1675-1676 recurrence after, 1674-1675 results of, 1674-1675 technique of, 1672-1674, 1673f Thyroiditis, Hashimoto, substernal goiter in, 1670 Thyroplasty, type I, for unilateral vocal fold paralysis, 309, 309f-310f Thyrotracheal anastomosis, subglottic resection with, 355f, 358f, 359, 362f, 369-370, 369f Ticlopidine, central neuraxial blockade and, 77 Tidal volume (TV), 20f, 22, 27 during one-lung ventilation, 55 Tietze syndrome, 1218 Tiffeneau index, 30 Tiotropium, for chronic obstructive pulmonary disease, preoperative, 606 Tirofiban, central neuraxial blockade and, 77 TissueLink floating ball device, for VATS nodulectomy, 984, 984f Titanium cage, for spinal reconstruction after vertebrectomy, 946, 949f Tomography computed. See Computed tomography (CT). in idiopathic laryngotracheal stenosis, 271, 272f in postintubation stenosis, 261 in preoperative assessment, 377, 377f in tracheal tumors, 313 Topotecan, for small cell lung cancer, 828, 833-834 Total lung capacity (TLC), 20f, 22, 24, 24f normal range for, 29t in restrictive pattern in, 31

Index-F06861.indd 1830

Total parenteral nutrition, in chylothorax, 1116 Toxicara canis/cati, 552t, 555t, 564-565 Toxoplasmosis, 553t, 556t, 564 TP53 mutations, in carcinogenesis, 718-720, 719f, 719t, 720t Trachea. See also Tracheobronchial entries. anatomic relationships of, 193f-194f, 194-195 anatomy of, 189-195, 190f-194f, 1755-1766 blood supply of macroscopic, 190f-192f, 191-192, 257, 257f microscopic, 192-193, 193f prenatal, 189 carina of. See Carina. cervical, exposure of, 121 cilia of action of, 195 development of, 189 compression of chronic external, tracheomalacia from, 282, 282f, 287-288 computed tomography in, 248, 248f congenital collapse of, without airway compression, 278-279 embryology of, 189 endoscopic anatomy of, 233f esophageal carcinoma invading, 325 length of, 189 lower, blood supply of, 896-897, 896b, 896f lymphatics of, 194 masses of, computed tomography in, 203-204, 205f-207f, 1498 membranous anatomy of, 190 blood supply to, 193 narrowing of diffuse, 204, 207-210, 209f-210f focal, 203-204, 203b, 205f-208f non–small cell lung cancer invading, 321-322 normal, computed tomography of, 202-203 physiology of, 195, 277, 278f rupture of, in one-lung ventilation with doublelumen tube, 51 saber-sheath (horseshoe), 204, 207, 209f segmental cartilaginous defects of, tracheomalacia from, 278 shape of, 189-190 size of in children and adolescents, 190t during respiration, 195 stenosis of. See Tracheal stenosis. submucosal plexus of, 193, 193f thyroid cancer invading, 322-325 trauma to. See Tracheobronchial trauma. tumors of. See Tracheal tumors. Tracheal anastomosis bronchoscopic evaluation of, 396 complications of, 380-381, 381t sutures for, 379-380, 380f, 381-382 Tracheal cartilage shave, for thyroid cancer with airway invasion, 323-324 Tracheal glands, 189, 190 Tracheal occlusion, fetal, for congenital diaphragmatic hernia. See Fetal endoscopic tracheal occlusion (FETO). Tracheal reconstruction staged, in postintubation stenosis, 262 in thyroid cancer with airway invasion, 322-324, 325 Tracheal resection, 221-225, 376-382 anesthesia for, 223, 378 carinal. See Carinal resection. complications of, 380-381, 381t, 393-398 anastomotic management of, 395-397, 396f outcome after treatment of, 398 risk factors for, 394-395, 395f, 395t historical note on, 393 incidence of, 394, 394t laryngeal, 397-398 management of, 395-397 history of, 5-6, 221-222, 376 indications for, 221, 221t, 376 length of, anastomotic failure and, 395, 395f preoperative preparation for, 222-223, 376-378, 377f

Tracheal resection (Continued) of primary tumors, 315-316, 317, 318f-319f, 319, 320 surgical approaches for, 223, 223f surgical technique for, 378-380, 379f-380f for thyroid cancer with airway invasion, 322-324, 325 ventilation during, 224-225, 224f Tracheal rings, anatomy of, 190 Tracheal stenosis benign, emergent management of, 331-335, 333f-334f idiopathic, 270-276. See also Laryngotracheal stenosis, idiopathic. late, 174, 174f-175f, 176 postintubation. See Postintubation stenosis. preexisting, tracheostomy in, 346 pulmonary artery sling with, surgical management of, 254 after tracheobronchial trauma, 1759 after tracheostomy, 352 Tracheal stoma, persistent, after tracheostomy, 352 Tracheal tumors, 312-320 clinical presentation in, 312-313 diagnostic studies in, 313-314, 313f-314f epidemiology of, 312 histology of, 314, 315t, 316t primary, 312-320 secondary, 321-325 treatment of, 314-319 long-term results of, 317-319, 317f-319f for resectable disease, 315-317 for unresectable disease, 317 Tracheitis, tuberculous, 296 Tracheobronchial amyloidosis, 210, 210f, 296 Tracheobronchial anastomosis bronchopleural fistula after, 390 for carinal resection with lobar resection, 388, 388f for carinal resection without pulmonary resection, 386-387, 386f-387f release maneuvers for, 385-386 for right carinal pneumonectomy, 388 technique for, 385 Tracheobronchial imaging, 196-210 computed tomography for, 196-197, 198f-199f, 200-210, 201f-210f historical note on, 196, 197f magnetic resonance imaging for, 197, 200, 200f Tracheobronchial infection, computed tomography in, 210 Tracheobronchial obstruction, palliative care for, 824t Tracheobronchial secretions, 195 Tracheobronchial stenosis acquired, computed tomography in, 198f-199f, 204, 208f post-traumatic, 1790, 1791 Tracheobronchial toilet, rigid bronchoscopy for, 95 Tracheobronchial trauma, 1742, 1755-1767 airway management in, 1759-1760, 1759f anesthesia in, 1760-1761 associated injuries in, 1757-1758 operative approaches for, 1762-1763, 1763f-1764f stabilization and prioritization of, 1760 blunt, 1756, 1757-1758, 1766 diagnosis of, 1758-1759, 1758f-1759f historical note on, 1755 incidence of, 1756 late sequelae of, 1789-1791, 1790f location of, by mode of injury, 227-228, 227f mechanisms of, 1756-1757 penetrating, 1756-1757, 1766, 1779-1780 stricture after, 1786, 1790, 1791 surgical management of, 1761-1765 care after, 1765 carina exposure in, 1762, 1764f complications of, 1765 late, 1765-1766 operative approaches for, 1761-1762, 1761f, 1762f results of, 1766-1767, 1767f

1/25/2008 1:46:15 PM

Index

Tracheobronchial trauma (Continued) thermal, 1766-1767, 1767f ventilation for, 1761 Tracheobronchial tree, topographic anatomy of, 895896, 895b, 895f, 896f Tracheobronchial tuberculous disease, 296 Tracheobronchitis. See Bronchitis. Tracheobronchomalacia acquired, 282, 282f, 289-292, 290f-292f primary congenital, 288-289 Tracheobronchomegaly syndrome, 279, 279f, 281, 292 Tracheobronchoplasty, 291-292, 291f-292f Tracheoesophageal compartment/space, 1530f, 1531, 1531f Tracheoesophageal fistula acquired, 299-305 congenital, 299 delayed, 1786 from delayed necrosis after tracheobronchial trauma, 1766 diagnostic studies in, 301f-302f, 302 from esophageal carcinoma, 325 etiology of, 299-301, 300f-301f high, surgical management of, 304-305, 305f historical note on, 299 inflammatory causes of, 300 as late complication, 176, 177f malignant, 176, 177f, 299 barium esophagogram of, 301, 302f etiology of, 301 medical treatment of, 302-303 postintubation, 265-269 clinical presentation in, 266-267 etiology of, 299-300, 300f historical note on, 265-266 management of, 267-269, 267f-269f post-traumatic, 300-301 presentation in, 302 surgical management of, 303-305, 304f-305f after tracheal resection and reconstruction, 397 after tracheobronchial repair, 1765 after tracheostomy, 352 in tuberculosis, 514 Tracheoinnominate artery fistula, 176 massive hemoptysis in, 447 postintubation, 264-266, 264f, 266f after tracheal resection and reconstruction, 397 after tracheobronchial repair, 1765 after tracheostomy, 352 Tracheomalacia, 277-293 acquired, 280f-282f, 281-282 computed tomography in, 200, 201f, 204, 208f congenital, 277-278, 279f definition of, 277 diagnosis of, 284-286, 285f-287f etiology of, 277-283 inflammatory, 282-283, 282f-283f management of, 286-292, 288f, 290f-292f post-traumatic/postintubation, 280f, 281, 281f, 286-287 signs and symptoms of, 283-284, 284f after thyroidectomy, 1675-1676 tracheobronchoplasty for indications for, 291-292 technique of, 291, 291f-292f Tracheopathia osteochondroplastica, 208-209, 209f Tracheoscope, 334 Tracheostomy, 344-352 in acute necrotizing mediastinitis, 1522t, 1526 anesthesia for, 221 complications of, 351-352 decannulation in, 351 accidental, 351-352 definition of, 344 elective, 221 emergency, 221, 344 historical note on, 344 in idiopathic laryngotracheal stenosis, 276 indications for, 220-221, 344-346 in laryngeal trauma, 1745 mini-, 344, 350, 352 for anastomosis in subglottic region, 382 after tracheobronchial trauma, 1765

Index-F06861.indd 1831

Tracheostomy (Continued) open versus percutaneous, 221, 346-347, 347t technique for, 348-349 percutaneous dilational contraindications to, 349 technique for, 349, 349f, 350f postintubation injury after, 256-269, 348. See also Postintubation injury. for prolonged mechanical ventilation, 345-346, 345t stromal strictures after, 204 surgical technique for, 348-350, 349f, 350f swallowing in patient with, 350-351 work of breathing in patient with, 350, 350f, 351f Tracheostomy tube cuff design for, 256, 347-348 cuff pressure in, measurement of, 348, 348f selection of, 347-348 Tracheotomy definition of, 344 for laryngeal trauma, 1745 for vocal fold paralysis, 310 Tractotomy for parenchymal injury, 1773 for penetrating lung injuries, 1779 Training in thoracic surgery, history of, 6-8 Transbronchial biopsy in acute rejection, 683, 684f of indeterminate pulmonary nodule, 697 in interstitial lung disease, 572-573, 597-598 after lung transplantation, 676 Transdiaphragmatic pressure, 1376-1377, 1378 Transesophageal echocardiography during anesthesia, 47 for cardiac output measurement, 158 Transfer factor (TLCO), 24. See also Diffusing capacity for carbon monoxide (DLCO). Translocation technique, for pulmonary artery sling, 254 Transnasal fibroscopy, in subglottic resection in infants and children, 364-365, 365f Transplantation bone marrow, invasive pulmonary aspergillosis after, 538, 539 empyema after, 1070-1071 heart donor organ in, extraction of, 666-667, 667f maximum oxygen consumption (VO2max) and, 38 heart-lung history of, 660 technique of, 673-674 liver, phrenic nerve injury after, 1461-1462 lung. See Lung transplantation. lymphoproliferative disorders after, 573, 682-683, 683f pulmonary infection after, 490-491, 491t, 585t, 594 stem cell for lymphoblastic lymphoma, 1630 pulmonary infection after, 585t, 594 Transverse cervical incision, 120-122, 120f-122f Transverse process, cervical, excision of, supraclavicular approach to, 1351, 1354f Transverse rectus abdominis musculocutaneous (TRAM) flap, in chest wall reconstruction, 1320, 1320f-1322f Trapezius anatomy of, 1202t, 1203, 1203f-1204f chest wall reconstruction with, 1300, 1327, 1327f Trapped lung, 1048, 1048f, 1052, 1144. See also Fibrothorax. Trauma, 1723-1794 airway in, 1728, 1729f anatomy in, 1724, 1724f angiography in, 1731t, 1733, 1734f arterial blood gas analysis in, 1730-1731 blood loss in, 1725-1726, 1725t blunt, 1768-1775 aortic, 1733, 1734f, 1735 bone injury in, 1725 chest wall, 1770, 1770f diaphragmatic, 1774-1775, 1775f laryngeal, 1739-1741, 1740f-1741f, 1743, 1744, 1744f, 1745

1831

Trauma (Continued) blunt (Continued) mortality in, 1723 parenchymal injury in, 1772-1774, 1772f pathophysiology of, 1724-1725, 1727 pleural space, 1770-1772 thoracoscopy for, 1768-1769 thoracotomy for, 1769-1770 tracheobronchial, 1756, 1757-1758, 1766 tracheoesophageal fistula from, 300 tube thoracostomy for, 1768 visceral rupture after, 1725 to brachial plexus, 1230 breathing in, 1728 bronchial rupture in, 1731, 1732f chest radiography in, 1731-1733, 1731t, 1732f chest tube insertion in, 1729, 1730f, 1785 to chest wall blunt, 1770, 1770f imaging of, 1211-1212, 1212f-1213f penetrating, 1778-1779 circulation in, 1728 computed tomography in, 1731t, 1733-1734, 1733f cricothyroidotomy in, 1728, 1729f and development of thoracic surgery, 3-4, 1723 diaphragmatic, 1731, 1733 echocardiography in, 1731t, 1735 electrocardiography in, 1729 emergency thoracotomy for, 1735-1736, 1735f, 1736t empyema after, 1059-1060, 1788, 1789f endotracheal intubation in, 1728 fibrothorax after, 1788-1789 flail chest after, 1207, 1770, 1771f, 1789 hemothorax in, 1779, 1788 massive, 1731, 1732f retained, 1771-1772, 1786 surgical indications in, 1729, 1731f historical background on, 1723-1724 history in, 1727 incidence of, 1723 initial assessment of ABCs in, 1728 bedside procedures in, 1728-1729, 1729f-1731f diagnostic tests in, 1729-1735, 1731t, 1732f-1734f secondary survey in, 1728 laryngeal, 1738-1754. See also Laryngeal trauma. late sequelae of, 1788-1794 massive hemoptysis in, 446 mediastinal hematoma in, 1733, 1733f mortality in, 1723-1724 pathophysiology of, 1724-1725 penetrating, 1777-1787 associated injuries in, 1782 chest wall, 1778-1779 complications of, 1786-1787 critical operative maneuvers in, 1785-1786 diagnosis of, 1778 foreign body removal in, 1783-1784, 1786 historical note on, 1777 iatrogenic, 1778 laryngeal, 1741, 1743, 1745, 1750 mechanisms of, 1777-1778 mediastinal, 1734 mortality in, 1723 pathophysiology of, 1725, 1727 surgical approaches in, 1784-1785 surgical indications in early, 1783 immediate, 1782-1783 late, 1783-1784 timing of, 1784 tracheobronchial, 1756-1757, 1766, 1779-1780 tracheoesophageal fistula from, 300-301 visceral, 1779-1782 pericardial effusion in, 1734-1735 physical examination in, 1728, 1728f pneumomediastinum in, 1733 pneumothorax in, 1731, 1732f pulmonary contusion in, 1772-1773, 1772f, 1789 rib fracture in, 1733, 1770, 1771f, 1789 shock in, resuscitation and, 1725-1727, 1725t, 1726t

1/25/2008 1:46:15 PM

1832

Index

Trauma (Continued) thoracic boundaries in, 1724, 1724f tracheobronchial, 1755-1767. See also Tracheobronchial trauma. tracheoesophageal fistula from, 300-301 tracheomalacia after, 280f, 281, 281f, 286-287 tracheostomy for, 346 ultrasonography in, FAST, 1731t, 1734-1735, 1734f urine output in, 1725t, 1729 venous access for, 1728-1729 video-assisted thoracic surgery in, 112 Treadmill studies, maximum oxygen consumption values in, 27 Treatment response, oncogenic marker evaluation of, 763 Trematode infections, 551t, 554t, 564 Trichinosis, 552t, 555t, 565 Tricuspid regurgitation, in chronic thromboembolic pulmonary hypertension, 655 Triglyceride, in pleural effusion, 1044-1045 Trigonum sternocostale, 1369 Trocar-suction device, needle aspiration with, for hydatid disease, 561, 562f-563f Troponin-1, serum, after trauma, 1730-1731 Truncus anterior, 407 Tube thoracostomy for chest injury, 1768 for chylothorax, 1115-1116 complications of, 1768 for empyema, 1063, 1063f history of, 1055, 1056f for lung abscess, 497 for pneumothorax, 642-643, 1100 sclerosing agent administration by, 1051 Tuberculoma, 505, 512 Tuberculosis, 499-524 aspergillosis and, 511-512, 511f bronchiectasis in, 473, 514, 515f bronchoesophageal fistula in, 514 bronchopleural fistula in, 509, 519-520, 524 bronchostenosis in, 515, 516f cardiac, 515 cavernoma from, 514 cavity associated with, 426, 426f chest wall abscess from, 517, 518f clinical presentation in, 506-507 collapsotherapy for, 501-502, 503, 504t and development of thoracic surgery, 3 drug-resistant extensively, 499 multiple-, 506, 510-511 empyema in. See Empyema, tuberculous. endobronchial, 515, 516f epidemiology of, 506 extrapulmonary, 507, 515-520, 518f, 518t historical note on, 499-501, 500t, 501f-503f, 504t in immunocompromised host, 592 left bronchus syndrome from, 509, 510f lung cancer and, 514 lung destruction from, 509, 510f lung gangrene from, 509-510 in lymph nodes, airway obstruction from, 514-515 massive hemoptysis in, 445, 449, 512, 513f, 514 medical treatment of, 507 failure of, 509-512, 510f-511f microbiology of, 504-505, 505f, 505t middle lobe syndrome in, 515, 516f pathogenesis of, 505-506 pericarditis in, 509, 516-517, 1540 phrenicectomy for, 502-503, 502f pleural disease in, 509, 518-520, 519f-520f, 10721079. See also Pleural effusion, tuberculous. diagnosis of, 1036, 1037, 1087-1088 historical note on, 1072 management of, 1088-1089, 1089f-1091f plombage for, delayed complications of, 507-509, 508f, 508t Pott’s disease from, 499, 517-518, 518t reactivation, 506 anatomic bias in, 428 screening for, 506 spinal, 517-518, 518t

Index-F06861.indd 1832

Tuberculosis (Continued) surgical treatment of for complications of previous surgery, 507-509 for complications of scarring, 512-515, 513f, 515f-516f for diagnosis, 512, 513f for failure of medical therapy, 509-512 history of, 501-504 indications for, 507, 507t insufficient, complications of, 509 outcome of, 521-524, 522t-523t thoracoplasty for, 503, 504t, 524 tracheobronchial disease in, 296 tracheoesophageal fistula in, 300, 514 transmission of, 505-506 vascular malformations from, 515-516 Tuberculosis complex, 504, 505t Tuberous sclerosis, 578-579 Tumor(s) benign. See Benign neoplasms. malignant. See Cancer. Tumor cells, circulating, molecular detection of, 749 Tumor lysis syndrome, in lymphoma, tracheoesophageal fistula after, 303 Tumor necrosis factor-alpha, antibody against, for pneumonia in immunocompromised host, 591 Tumor-node-metastasis (TNM) system of lung cancer staging, 411, 756, 757t. See also Lung cancer, staging of. of thymoma staging, 1589, 1590t Tumorigenesis. See Carcinogenesis. Tuohy needle, for paravertebral catheter placement, 74, 74f Two-hit theory, in trauma, 1726 Two-point discrimination, in thoracic outlet syndrome, 1282, 1283f Tyrosine kinase inhibitors for lung cancer, 722 for non–small cell lung cancer, 816-819, 817t-818t for small cell lung cancer, 839-840

U Ulcer, stress postoperative management of, 140-141 prophylaxis against, in critically ill patient, 158 Ulnar nerve, compression of, and thoracic outlet syndrome, 1275, 1278f Ulnar nerve conduction velocity normal, 1285 in thoracic outlet syndrome, 1284-1285, 1285f Ultraflex stent, 240, 240f Ultrasonography in congenital diaphragmatic hernia, 1414, 1414f1415f, 1416 of diaphragm, 1380-1381 in empyema, 1061 endobronchial, 93 for mediastinal lymph node staging, 107 in tracheal tumors, 314 endoscopic fine needle aspiration with in lung cancer staging, 761-762 in mediastinal mass, 1515-1516, 1515f for mediastinal lymph node staging, 107 FAST, in trauma, 1731t, 1734-1735, 1734f in malignant pleural effusion, 1139 of mediastinum, 1478 pleural biopsy guided by, 1037 of thyroid, in substernal goiter, 1670 Umbrella Implantable Intrabronchial Valve, 626-627, 627f United States, training and accreditation in thoracic surgery in, 6 United States Preventive Services Task Force (USPSTF) guidelines for lung cancer screening, 744 Univent torque control blocker, 51, 53f Upper airway. See also Trachea. anatomy of, 189-195, 190f-194f, 353, 354f benign neoplasms of, 204, 316t embryology of, 189 esophageal carcinoma invading, 325

Upper airway. See also Trachea (Continued) imaging of, 196-210 computed tomography for, 196-197, 198f-199f, 200-210, 201f-210f historical note on, 196, 197f magnetic resonance imaging for, 197, 200, 200f non–small cell lung cancer invading, 321-322 obstruction of flow-volume loops in, 31-32, 32f, 33f variable extrathoracic, 31, 32f variable intrathoracic, 31-32, 33f physiology of, 195 thyroid cancer invading, 322-325 tumors of primary, 312-320 secondary, 321-325 subglottic resection for, 356-357 Upper extremity musculature, anatomy of, 12021205, 1202t, 1203f-1205f Upper extremity musculoskeletal disorder, workrelated, and thoracic outlet syndrome, 12751276, 1278f Upper midline abdominal incision, 123-125, 124f-125f Uracil-tegafur (UFT), for non–small cell lung cancer, 785 Urchin heart positioning device, in lung transplantation without cardiopulmonary bypass, 671-672, 672f Uremic pericarditis, 1540 Urine output, in trauma, 1725t, 1729 Urinothorax, 1010 Urokinase for effort thrombosis, 1289 intrapleural for empyema, 1065 for retained hemothorax, 1772

V Vaccine bacille Calmette-Guérin (BCG), 501 for community-acquired pneumonia, 586t for small cell lung cancer, 838 Vacuum-assisted closure, for poststernotomy mediastinitis, 1268-1269, 1269f Vagus nerve in post-thoracotomy pain, 70, 70t pulmonary anatomy of, 414 upper, injury to, 306, 307 Valganciclovir, for cytomegalovirus pneumonia, 679 Valley fever, 540 Valley Lab (VL) probe, for radiofrequency ablation, 797, 798f Valvular heart disease, left-sided, with pulmonary carcinoid tumors, 702 Vanishing lung, in bullous disease, 639, 641f Varicella-zoster infection, in immunocompromised host, 592 Vascular closure suture devices, percutaneous, 47 Vascular endothelial growth factor in carcinogenesis, 722 monoclonal antibodies against, 819. See also Bevacizumab. Vascular malformations congenital segmental tracheomalacia in, 278 from tuberculosis, 515-516 Vascular rings, 242-255 cardiac anomalies associated with, 249 classification of, 242, 243t clinical presentation in, 246-247, 247t diagnostic studies in, 247-249, 248f embryology and pathology of, 243-246, 243f-246f historical note on, 242-243 rare, 246, 247f surgical management of, 249-254, 250f, 252f-254f Vascular tumors, pediatric, 1656-1657, 1657f Vasculitis, cavities associated with, 426 Vasoactive agents, for hypoxemia during one-lung ventilation, 57 Vasoactive intestinal peptide, in neuroblastoma, 1637 Vasoconstriction, pulmonary, hypoxic, during onelung ventilation, 53-57

1/25/2008 1:46:15 PM

Index

Vasodilators, pulmonary arterial, selective, in respiratory failure, 155 Vasopressin, in critically ill patient, 147-148, 147t Vecuronium, during airway surgery, 216 Vena cava. See Inferior vena cava; Superior vena cava. Vena cava opening, 1425 Venogram, bilateral arm, in superior vena cava obstruction, 1689 Venous access, for trauma, 1728-1729 Venous grafts, autogenous, for superior vena cava reconstruction, 1690 Venous patch interposition, autologous, for superior vena cava reconstruction, 1690, 1691f Ventilation during airway surgery, 216-217, 217f, 217t during carinal resection, 225, 225f, 226f for chylothorax, 1116 collateral, in emphysema, 623 for congenital diaphragmatic hernia, 1407, 1418 cross-table, during tracheal resection, 224, 224f high-frequency for bronchopleural fistula, 58 during tracheal resection, 224-225 jet high-frequency during airway surgery, 216-217, 217t for hypoxemia during one-lung ventilation, 56-57 during laryngoscopy, 84-85 low-frequency, during airway surgery, 216, 217f, 217t during rigid bronchoscopy, 95, 96f, 219 after lung transplantation, 675 lung-protective, for respiratory failure, 154 maximum voluntary, 11, 25, 27, 27f mechanical introduction of, 3 long-term alternatives to. See Phrenic nerve pacing. problems with, 1445 weaning issues in, 1450-1451 pneumonia associated with, 489-490 prolonged, tracheostomy for, 345-346, 345t minute, during exercise, 26-27, 27f monitoring of, during anesthesia, 46 one-lung, 49-57 anesthetic choice for, 54 body temperature during, 57 bronchial blocker technology for, 51-52, 52f-53f cardiac output during, 54 desaturation during monitoring of, 46 predictors of, 45, 45t in difficult airway, 53 double-lumen tube technology for, 49-51, 50f-51f fluid management during, 57 hypoxemia during, 53-54, 1707 prevention of, 54-55 treatment of, 55-57 increasing collapse of nonventilated lung during, 55 indications for, 49 lung separation for, 49-53, 50f-53f, 52t management of, 53-57 pressure-controlled, 55 ventilation strategies for, 54-55 oscillatory, high-frequency during airway surgery, 217t for congenital diaphragmatic hernia, 1407 for respiratory failure, 154-155 positive end-expiratory pressure. See Positive endexpiratory pressure (PEEP). positive-pressure for COPD exacerbation, 609-611, 610t high-frequency during airway surgery, 217t two-lung, for hypoxemia during one-lung ventilation, 56 intermittent, during airway surgery, 217t during laryngoscopy, 84 posterior lobe, with intermittent diaphragm pacing, 1455 prone, in respiratory failure, 154

Index-F06861.indd 1833

Ventilation (Continued) during rigid bronchoscopy, 95-97, 96f during tracheal resection, 224-225, 224f for tracheobronchial trauma, 1761 Ventilation-perfusion scintigraphy, 440-442 in bronchiectasis, 475 in bullous disease, 640, 640f in chronic thromboembolic pulmonary hypertension, 655 in emphysema, 616, 616f in fibrosing mediastinitis, 530, 531f in malignant mesothelioma, 1187 for prediction of residual pulmonary function after lung surgery, 441-442 in preoperative assessment, 42 in pulmonary embolism, 442 techniques in, 441 Ventricular arrhythmias, postoperative, 154, 184 Venturi jet ventilation, during rigid bronchoscopy, 95, 96f Verapamil for atrial fibrillation prophylaxis, 142 prophylactic, for postoperative arrhythmias, 44 Vertebral artery, in brachial plexus dissection, 929 Vertebral body, tumor invasion of extended pulmonary resection for, 943-946, 945f-948f superior sulcus, 930-931 Vertebral venous system, 1685 Vertebrectomy partial, 945, 945f spinal reconstruction after, 946, 948f-949f technique of, 944-946, 945f-948f total, 945, 946f-947f Vibration testing, in thoracic outlet syndrome, 12811282, 1282f Video display, in rigid bronchoscopy, 100 Video microlaryngoscope, 85, 85f Video-assisted pulmonary resection, 114, 970-987 anesthesia for, 972-973 completion of procedure in, 979, 979f contraindications to, 972, 972b controversies in, 986-987 cost effectiveness of, 982 hilar dissection in, 975-976, 975b, 977f historical perspective on, 970-971 instruments for, 973-974 limited indications for, 982 localization of pathology in, 982-983 operative technique for, 983-984, 983f, 984b long-term survival after, 981-982, 981f major, 971-982 benefits of, 980-982, 981f operative technique for, 972-979, 973f-979f, 975b results of, 979-980, 979t versus muscle-sparing thoracotomy, 986 nonanatomic, 983-984, 983f, 984b patient and surgeon positioning for, 973, 973f patient selection for, 971-972 ports strategy for, 974-975, 974f pulmonary ligament release in, 976-977 simultaneous stapling technique in, 984-985 specimen retrieval in, 977-978, 978f systematic lymph node sampling in, 978-979 training in, 986 VATS exploration before, 975, 975t Video-assisted thoracic surgery (VATS), 109-117, 133-134 advantages of, 970-971, 1698 for benign lung tumor, 698 for bronchogenic cyst, 1584, 1701 for chest injury, 1768-1769, 1785 chest wall anatomy and, 1207 for chylothorax, 1118 complications of, 1040, 1040t contraindications to, 110-111, 111t definition of, 971 for diaphragmatic access, 1427-1428, 1428f for diaphragmatic plication, 1409-1410, 1410f, 1411t, 1437-1439, 1438f for empyema, 1063-1064, 1064t

1833

Video-assisted thoracic surgery (VATS) (Continued) for esophageal cyst/duplication, 1568-1569, 1568f, 1585, 1703 for esophageal disease, 116-117 historical perspective on, 109, 970-971 incisions for, 134, 134f, 1698 indications for, 111, 111t, 1038t limitations of, 1698-1699 for lobectomy. See Lobectomy, VATS. for lung cancer staging, 762 for lung decortication, 1075, 1181-1182 for lung volume reduction, 114-115, 618 for malignant pleural effusion, 1140 for mediastinal disease, 115-116, 115t, 1697-1704 anatomic considerations in, 1697 in anterior compartment, 1699-1700, 1699t general considerations in, 1697-1699, 1698f in middle compartment, 1700-1701, 1701t in posterior compartment, 1701-1703, 1702t robotic, 1518-1519, 1703-1704 for mediastinal lymphadenectomy, 968-969 for mediastinal mass, 1517-1519, 1517f-1519f for mediastinal neurogenic tumors, 1639-1640 for neurenteric cyst, 1586 for nodulectomy, 983-984, 983f, 984b, 984f for non–small cell lung cancer, 769-770, 770t for paravertebral gutter mass, 1475 for pectus excavatum repair, 1334 for pericardial cyst, 1587, 1701 for pericardial disease, 117 for pericardiocentesis, 1547 for phrenic nerve pacing surgery, 1448 for pleural disease, 111-113, 111t, 1037-1040, 1038f-1040f, 1038t, 1040t for pleural effusion, 1047 pleural space lavage as complement to, 1040 for pneumonectomy, 864-865 for pneumothorax, 1101-1102, 1103 port placement in, 1698, 1698f for posterior mediastinal mass, 1474-1475 for posterior subcarinal node biopsy, 1473, 1475f for pulmonary metastasectomy, 856-857 for pulmonary parenchymal disease, 113-115, 114t results of, 1040 for retained hemothorax, 1772 for segmentectomy, 877, 877f, 984 specimen handling in, 1698 for spine surgery, 117 for sublobar resection, 874-875, 874f-876f, 877, 877f for sympathectomy, 116, 1703 for sympathicotomy, 1303-1304, 1304f-1305f technique of, 109-111, 110f, 1038-1040, 1038f-1040f for thymectomy. See Thymectomy, thoracoscopic. for wedge resection, 983-984, 983f, 984b Video-assisted thoracoscopic excisional biopsy, of solitary pulmonary nodule, 459-460 Video-assisted thoracoscopic extended thymectomy (VATET), 1555, 1705, 1713-1714 Videofluoroscopy, in bacterial aspiration pneumonia, 493 Videomediastinoscopy, 105, 106f, 1517 Vienna phrenic pacemaker, 1447 Vincristine, for small cell lung cancer, 828, 829, 831 Vindesine, with cisplatin and mitomycin, 785-786 Vinorelbine with cisplatin, 786-787 disadvantages of, 815 for malignant mesothelioma, 1130 for second-line treatment, 816 Viral infection bronchiolitis obliterans syndrome and, 685 after lung transplantation, 679, 679f Viral pneumonia, in immunocompromised host, 592-593 Virtual bronchoscopy, 101 Visceral compartment/space, 1530f, 1531, 1531f Visceral larva migrans, 552t, 555t, 564-565 Visceral leishmaniasis, 553t, 556t, 564 Vital capacity (VC), 19, 20f, 22 Vital signs, estimated blood loss based on, 17251726, 1725t

1/25/2008 1:46:15 PM

1834

Index

Vitamin A and E, lung cancer and, 716 Vocal cord evaluation of, contact endoscopy for, 87 injury to, 1742, 1747 paralysis of, 306-311 bilateral, 307, 308t treatment of, 310-311, 311f clinical presentation in, 308 diagnosis of, 308, 308t etiology of, 307, 310t incidence of, 307 postoperative, 173 relevant anatomy and physiology in, 306-307 in thyroidectomy, 1675 unilateral, 307, 307f, 308t treatment of, 308-310, 309f-310f Vocal cord retractor, 365, 365f Vocal folds, functions of, 306 Voice alteration in laryngeal trauma, 1743 in lung cancer, 752 in vocal fold paralysis, 308, 308t Volume-time curve, in spirometry, 20, 20f Von Recklinghausen’s disease, 579, 1634, 1635, 1635f-1636f

W Wallstent, for postintubation stenosis, 262 Warfarin central neuraxial blockade and, 77 in small cell lung cancer, 839

Index-F06861.indd 1834

Water seal, chest tube on, for air leak, 160, 650 Wedge bronchoplasty, 904-905, 904f Wedge osteotomy in pectus deformity repair, 1330, 1333f, 1337, 1337f in sternal cleft repair, 1338, 1338f Wedge resection. See also Sublobar resection. of blebs, 1101 of non–small cell lung cancer, 769 versus segmentectomy, 892-893 technique of, 875-876, 875f-876f video-assisted thoracic surgery for, 983-984, 983f, 984b Weerda laryngoscope, 85, 85f Wegener’s granulomatosis, 210, 294-295 Weight loss, in lung cancer, 752 Weinberg reaction, in hydatid disease, 558 Weitlaner retractor, in video-assisted pulmonary resection, 974, 974f Western blot, in hydatid disease, 559 Weston Sanatorium, 6 Wheezing in interstitial lung disease, 568 in lung cancer, 751 Whole-brain irradiation, for solitary brain metastasis, 820 Windup, in nociceptor response, 68, 69 Work of breathing, with tracheostomy, 350, 350f, 351f Work-related upper extremity musculoskeletal disorder, and thoracic outlet syndrome, 12751276, 1278f

World Health Organization (WHO) classification of thymoma, 1590, 1591t World War I/II, and development of thoracic surgery, 3 Wound infection after pectus excavatum repair, 1343, 1343f after sternotomy, 166 after thoracotomy, 166, 182-183 after tracheostomy, 352 Wound problems, superficial noninfectious, after sternotomy, 1253 Wright test, in thoracic outlet syndrome, 1280f, 1281 Wuchereria bancrofti, 552t, 555t, 565

X Xenon-133, for ventilation-perfusion scintigraphy, 441 Xiphoid process, 1197, 1198f, 1200 excision of, in pectus excavatum repair, 1330, 1333f

Z Zephyr endobronchial valve, 627-630, 628f-630f Zoledronic acid, for bone metastasis, 820 Zone of apposition, 1367, 1368f Zygomycosis, 546-548, 547f, 594, 1092

1/25/2008 1:46:15 PM

chapter

1

HISTORY AND DEVELOPMENT OF ESOPHAGEAL SURGERY Earle Wayne Wilkins, Jr. James D. Luketich

The history of oesophageal surgery is the tale of men repeatedly losing to a stronger adversary yet persisting in this unequal struggle until the nature of the problems became apparent and the war was won.

of Billroth’s laboratory operations to a successful resection and anastomosis of the intrathoracic esophagus.

This observation by Professor R. G. Emslie (1988) in his Perspectives in the Development of Oesophageal Surgery is realistically descriptive of the early efforts to manage disorders of the esophagus. Today, more than a century after those earliest ventures, the comment remains all too relevant.

Ultimately, it was the solution of the problem of control of respiration in the open thorax that permitted substantive advances in the technical challenges of esophageal resection. In 1904, Mikulicz in Breslau (now Wroclaw), Poland, initiated research into the development of a differential pressure methodology for control of respiration during surgery. His pupil Ferdinand Sauerbruch (1904) was directly responsible for the negative differential pressure chamber, the complicated system in which the patient and the operating team were closeted in a hermetically sealed space with only the patient’s head outside for control of respiration and administration of anesthetic agents. At the same time, Ludolph Brauer (1904), in Marburg, Germany, was developing the reverse device: a positive-pressure method that enclosed only the patient’s head in a diver’s-like helmet. This permitted administering anesthesia with external positive pressure. A radically different approach came from Samuel Meltzer and John Auer in New York (1909). They devised “continuous respiration without respiratory movements” by means of intratracheal insufflation of a continuous stream of air and anesthetic vapor. Theodore Tuffier, in Paris, had actually reported his development of an intratracheal tube with an inflatable cuff in 1896. It was many years later that this particular technique would become standard. In his Honored Speaker’s Address delivered at the 50th annual meeting of the American Association for Thoracic Surgery in 1970 the scholarly Leo Eloesser considered this development of the methodology of intermittent positivepressure inflation of the lungs “the first milestone in chest surgery.”

ORIGINS Sporadic accounts of surgical procedures on the cervical esophagus are scattered through the millennia dating back to Egyptian times. Brewer (1980) provided a wonderfully detailed reference to the Smith Surgical Papyrus (3000-2500 BC), discovered in 1862 by Edwin Smith and translated and edited in 1930 by J. Henry Breasted. Case No. 28 described the treatment, apparently successful, of “a gaping wound of the throat penetrating the gullet.” Collis (1982) cited a comment made by Ambroise Paré in the 16th century: “when the oesophagus is being sutured great care should be taken.” A marvelous cautionary guideline for the ages! A strong case may be made to credit Theodor Billroth of Vienna with the origins of modern surgery of the esophagus. Rutledge (1995), a Billroth scholar, described him as “probably the most scholarly, productive, and influential surgeon of the 19th century.” In 1871, Billroth demonstrated in dogs that resection of the cervical esophagus with anastomosis was indeed feasible. Vincenz Czerny of Heidelberg, a former assistant of Billroth, performed one of the early resections for carcinoma of the cervical esophagus in 1877. Johann von MikuliczRadecki, likewise a pupil of Billroth, was described by Olch (1960) as “the father of such endoscopy as we know it today” for his 1881 development with Leiter of an esophagoscope with distal illumination. These men provided important stepping stones to ensuing attempts at resection of the thoracic esophagus.

ESOPHAGECTOMY Decades of pioneering surgeons’ struggles with resection of the intrathoracic esophagus form a thread that traces the historical development of surgery of the esophagus. The anatomic remoteness of the thoracic esophagus, along with the physiologic challenge of intraoperative control of respiration, presented double obstacles to the development of successful esophagectomy. It would take some 6 decades from the time

Respiratory Control

Surgical Techniques Meade, the thoracic surgical historian, described “the first successful intrathoracic resection and anastomosis of the esophagus” by Dobromysslow (1901). A 3- to 4-cm segment was resected, the ends united with two rows of silk sutures, and the anastomosis wrapped with a large posteriorly based skin flap. Although “complete union of the suture line” was demonstrated at 3 weeks, Meade (1961) reported that no further follow-up could be discovered. The contemporary development of positive-pressure anesthesia permitted the direct transthoracic approach to esophageal resection. The pioneering operation was that of Franz Torek (1913) in New York. He carried out a left thoracic, 3

4

Section 1 Introduction

subtotal resection of the esophagus for a squamous carcinoma of the middle third in a 67-year-old woman. (Dr. Carl Eggers, later a prominent thoracic surgeon, administered the anesthesia.) The patient survived 13 years and was fed orally via a rubber tube that connected her cervical esophagostomy to her gastrostomy. She refused any attempt at plastic antethoracic skin tube reconstruction. Restoration of alimentary tract continuity after esophageal resection became the principal surgical challenge. Claude Beck (1905), in Cleveland, demonstrated in animal experiments that a tube of greater curvature of the stomach could be used to replace the lower esophagus. Cesar Roux (1907), in Lausanne, developed the technique of esophagojejunoplasty for distal esophageal stricture. Kelling (1911), in Dresden, devised use of the colon for esophageal replacement. In his initial case an isoperistaltic segment of transverse colon was brought up subcutaneously to the midsternal level in preparation for ultimate skin tube connection to the cervical esophagostomy and its distal end anastomosed to stomach. Martin Kirschner (1920), in Leipzig, Germany, originated the now-standard use of a mobilized stomach to replace the esophagus by dividing the left gastric, left gastroepiploic, and short gastric vessels. He planned an antethoracic, subcutaneous placement of the stomach but never succeeded in using it in a patient with carcinoma. In light of this burst of attempts to treat carcinoma of the esophagus, it is surprising that the final accomplishment of a successful esophagectomy with an intrathoracic esophagogastric anastomosis did not come until 1933. Ohsava, in Japan, has rather belatedly been given credit for this pioneering success. In 1938, Samuel Marshall, in Boston, carried out an esophagogastrectomy with re-establishment of continuity by an end-to-side anastomosis. William Adams and Dallas Phemister (1938), in Chicago, followed with a similar successful case, featuring, for the first time, a two-layer anastomosis using interrupted nonabsorbable sutures, in this case linen. Edward Churchill and Richard Sweet (1942), in Boston, presented a classic report of 11 resections emphasizing preservation of gastric blood supply and the meticulous suturing, with two-layer interrupted fine silk, of the anastomosis as the basis for avoiding leakage and/or stricture formation at the anastomosis. Sweet (1945) and the British surgeon Ivor Lewis (1946) extended esophageal resection for any level of carcinoma within the esophagus, Sweet by the strictly left transthoracic double-rib resection approach and Lewis by separate laparotomy and right thoracic incisions. These surgeons created the anastomosis intrathoracically at the apex of the chest. With concerns about the consequences of anastomotic leaks within the thorax, other surgeons preferred carrying out the anastomosis in the neck via a separate cervical incision. K. C. McKeown (1972), in England, advocated this approach, particularly in high carcinoma where total esophagectomy was in order. Eric Nanson (1975), in Auckland, New Zealand, has been a particular advocate of this operation, combining it with a synchronous two-team approach to abdominothoracocervical esophagectomy, a procedure developed while he

was in Bristol, England, with Milnes Walker. He has acknowledged the latter’s role (1988): “Professor Milnes Walker encouraged and helped in the development of this operation.” A totally different tack concerning the route of approach to resection of carcinoma of the thoracic esophagus was initiated by Wolfgang Denk (1913) in Vienna. He demonstrated in cadavers that the esophagus could be removed by blunt dissection through a subcostal transhiatal approach combined with a transcervical dissection. Grey Turner (1933) reported a successful blunt esophagectomy followed by a second-stage completion of an antethoracic skin tube to connect the esophageal and gastric stomas. In his expansive Bradshaw Lecture to the Royal College of Surgeons (1936) he had traced the evolution of his “pull-through” or collo-abdominal technique beginning in 1927. He included a quotation from the English essayist John Ruskin that he found pertinent to his struggles with surgery of the esophagus: There is a time and a way in which all things can be done, none shorter—none smoother. For all noble things, the time is long and the way rude. Ong and Lee (1960), in an innovative approach to esophagopharyngectomy for carcinoma of the hypopharynx or cervical esophagus, utilized blunt dissection for removal of the intrathoracic esophagus before bringing the stomach through the mediastinum to the neck. LeQuesne and Ranger (1966) in their experience with 10 pharyngolaryngectomy operations—3 by triple exposure and 7 by blunt dissection of the intrathoracic esophagus—found the latter technique preferable. It was Orringer and Sloan (1978), in Ann Arbor, however, who deserve credit for the resurrection and continuing perfection of the technique of transhiatal-transcervical esophagectomy without thoracotomy. Progress in the development of thoracoscopic and laparoscopic techniques has added one more facility for this approach. A final controversy in the management of all these techniques has been the safest method of performing the anastomosis. The differences of opinions have revolved principally around the matter of stapled versus hand-sutured anastomosis and, in the latter, one versus two layers. Perhaps the optimum results have been produced by the two-layer sutured anastomosis. Mathisen (1988) reported 104 consecutive esophagogastric anastomoses by this technique without a leak. A later addition to the history of esophageal resection includes the introduction of minimally invasive surgery. One of the first case series of laparoscopic esophagectomy was reported by Lee Swanstrom (1996) in 9 patients. Swanstrom was able to perform these cases totally laparoscopically with no operative mortality and reasonable short-term outcomes. Luketich and colleagues (2003) from the University of Pittsburgh published the first large series of totally minimally invasive esophagectomies, 222 cases performed by a combination of laparoscopy and thoracoscopy with short hospital stays of 7 days, an operative mortality of 1.4%, and oncologic outcomes similar to open series. It is apparent from the literature today that while open esophagectomy remains the standard in most institutions, an explosion in minimally inva-

Chapter 1 History and Development of Esophageal Surgery

sive esophageal surgery is occurring. In addition, esophageal stents are being increasingly used for palliation in patients with malignant esophageal disease (Christie, 2001).

Alternative Reconstruction Techniques Gastric Tube Boerema (1952), in The Netherlands, introduced restoration of continuity after esophageal resection utilizing a gastric tube taken from the greater curvature. Gavriliu (1988), in Romania, has recorded extensive experience with 718 of these procedures, first performed by him in 1951. Heimlich (1961) encouraged use of this technique in North America with his work in replacing the entire esophagus for both malignant and benign stenosis.

Colon Utilization of the right colon to replace or bypass the entire thoracic esophagus was reintroduced by Mahoney and Sherman (1954). Kelling (1911) and Vulliet (1911) independently had reported early experiences with esophagoplasty using segments of colon. Kergin (1953) reported the successful use of the transverse colon to bypass the esophagus in an unusual situation of esophageal obstruction due to a paraffinoma of the mediastinum, the late result of extrapleural collapse therapy for tuberculosis. He was the first surgeon to utilize the intrathoracic route for esophageal bypass with colon. Goligher and Robin (1954) preferred using the left colon, placing the interposed segment in an antiperistaltic fashion. Wilkins (1980), also preferring the left colon but in an isoperistaltic direction, suggested that preoperative mesenteric angiography was an enormous help in making the decision regarding the better portion of colon to use.

Jejunum The greatest experience with use of a long segment of jejunum for replacement of the thoracic esophagus came from the Russian surgeon Yudin (1944). His reconstructions were largely antethoracic. Robertson and Sarjeant (1950) were the first to reconstruct the esophagus with an isoperistaltic segment of jejunum placed in a substernal position through the anterior mediastinum. In general, except for short segment interposition procedures for the distal esophagus, the jejunum has not been a popular replacement of the entire thoracic esophagus, largely because of difficulty in dissecting and preserving its vascular arcades.

Cervical Skin and Other Grafts Early management of localized carcinoma of the cervical esophagus and hypopharynx was provided by Wookey (1942), who utilized a pioneering two-stage procedure. He resected the carcinoma and replaced the operative defect in the esophagus with a quadrilateral full-thickness flap of cervical skin. This technique has given way to free graft replacement of the cervical esophagus, a natural evolution from the development of microvascular anastomotic techniques. The use of a jejunal autograft was pioneered by Seidenberg and colleagues (1959).

An unusual use of a revascularized gastric antrum graft was reported by Hiebert and Cummings (1961).

MANAGEMENT OF ESOPHAGEAL ATRESIA Early mention of this congenital malformation dates back to Thomas Gibson’s The Anatomy of Human Bodies Epitomized (1697), which presents remarkably clear accounts of the particulars of the various forms of the anomaly. Credit for the first realistic surgical approach to both the understanding and management of the complex problem perhaps should be given to Richter (1913). Recognizing the need for gastrostomy for feeding, but also its failure if employed alone, Richter added intrathoracic ligation of the fistula using positive-pressure anesthesia. The literature is replete for another 3 decades with descriptions of attempts to handle the challenges of fistula ligation, proximal pouch drainage, and gastrostomy feedings. Substantive progress finally emerged in the early 1940s, with the not always friendly rivalry between Cameron Haight (1943), in Ann Arbor, and William Ladd (1944), at the Boston Children’s Hospital. Haight is credited with the first successful primary repair, whereas Ladd accomplished his first success with the construction of an antethoracic skin tube. Leven (1940), at the University of Minnesota, had described successful extrapleural ligation of the fistula and cervical esophagostomy. He later (1953) described reestablishment of continuity with jejunal interposition. Swenson (1947), who trained with Ladd, reported a remarkable early 80% success rate with end-to-end anastomosis. The most reliable method of suture of the anastomosis remains a continuing dialogue even today. With improving additions in preoperative preparation, the use of antibiotics, methods of anesthesia, intraoperative techniques, and postoperative care, primary repair has become more reliable. These same advances have also allowed staged repair in unusually premature or sick infants (Koop and Hamilton, 1965). It has been suggested that Richter’s approach 5 decades earlier was the inspiring cornerstone for such staged repairs. Myers (1986) supplied a thorough history of the management of esophageal atresia with and without tracheoesophageal fistula from 1670 to 1984.

SURGERY FOR ACHALASIA Historically known by various names such as cardiospasm, idiopathic dilatation of the esophagus, or megaesophagus, achalasia of the esophagus was first described by Willis (1674), who used a bit of sponge attached to a long strip of whale bone to force impacted food through the narrow distal esophagus. It was Hurst (1927) who gave the condition its present name. He based use of the term achalasia on the failure of the distal esophagus to relax. He also devised the rubber tubes filled with mercury used for esophageal dilation, now recognized as the Hurst dilators, subsequently modified by Maloney with tapering tips. The surgical approach to relief of the nonrelaxing lower esophageal segment originated in the German and Austrian

5

6

Section 1 Introduction

schools of surgery. A variety of procedures were described, all utilizing the transabdominal approach. There were the Marwedel (1903) and Wendel (1910) operations, fullthickness cardioplasties of the Heineke-Mikulicz type. Heyrofsky (1913) used an esophagogastrostomy side-to-side between the dilated esophagus and the gastric fundus, leaving the cardia intact. Grondahl (1916) modified this concept with a U-shaped incision from dilated esophagus across the cardia to gastric fundus with closure in the fashion of a Finney pyloroplasty. All of these procedures failed because of a common physiologic defect; each procedure resulted in destruction of the lower esophageal sphincter and permitted free gastroesophageal reflux, often with ensuing esophagitis and stricture formation. Many years later, Barrett and Franklin (1949) described this complication and, quite belatedly, all of these procedures began to meet with disfavor. One operation from this early German era, however, has survived the tests of time—the Heller (1914) esophagomyotomy. This was a procedure not unlike the extramucosal pyloromyotomy of Ramstedt. Heller also approached the distal esophagus abdominally and performed two myotomies, one anterior and one posterior. Zaaijer (1923) recognized that a single myotomy produced equally good results. It is surprising that this very satisfactory procedure was not widely practiced and universally accepted until well after the conclusion of World War II. Today the modified Heller operation is the standard method for the surgical management of achalasia. Payne (1989) published an interesting report, describing once again Heller’s seminal contribution of esophagomyotomy for achalasia. A common sequela of the Heller myotomy for achalasia has been the development of gastroesophageal reflux. In Europe, Dor and coworkers (1962) and Toupet (1963) developed antireflux repairs with particular application to their use in combination with abdominal Heller myotomies. The Dor hemifundoplication, in turn, became an integral part of the popular laparoscopic approach to achalasia. Richards and colleagues from Vanderbilt University have shown in a randomized trial of laparoscopic myotomy alone versus laparoscopic myotomy with Dor, that the addition of the Dor partial fundoplication was superior in minimizing reflux after myotomy (Richards, 2004). Forceful dilation of the narrow distal segment was the most commonly practiced therapy for achalasia, most often by the pneumatic balloon technique. Okike and colleagues (1979) presented the Mayo Clinic results in 899 patients comparing esophagomyotomy versus forceful dilation, advocating a limited trial of dilation and then, if necessary, esophagomyotomy. In the minimally invasive era, myotomy performed laparoscopically has gained almost universal favor in the United States and many other developed countries (Deb, 2005; Richards, 2004; Rosemurgy, 2005).

SURGERY FOR ESOPHAGEAL DIVERTICULUM The pharyngoesophageal diverticulum was first described by Abraham Ludlow (1767) of Bristol, England, with the

unusually titled paper “A case of obstructed Deglutition, from a preternatural Dilatation of, and Bag formed in, the Pharynx.” Zenker, for whom the diverticulum came to be named, and von Ziemssen (1877) first described the etiology, pathology, and symptoms. They were less sanguine about therapy: “The radical cure of diverticulum of the esophagus by operative procedure from without is . . . one of our vain wishes.” Wheeler (1886) is credited with the first successful resection of the pharyngoesophageal diverticulum. With early concern for postoperative complications, Goldmann (1909) devised a two-stage method of repair. A modification of the two-stage repair was utilized in the extensive experience of Lahey and Warren (1954): diverticulopexy and mediastinal packing in the first stage and resection of the diverticulum in the second. Harrington (1945), from the Mayo Clinic, and Sweet (1947), from the Massachusetts General Hospital, independently developed successful one-stage operations that simplified the management of diverticula. The matter of obstruction at the cricopharyngeus had long been a concern in the management of pharyngoesophageal diverticula. Aubin (1936) was the first to propose cricopharyngeal myotomy combined with diverticulectomy. Payne and Clagett (1965) much later advocated this as one of the two presently favored techniques. The other is diverticulopexy and cricopharyngeal myotomy, pioneered very successfully by Belsey (1966). Barrett (1933) reported the first successful transthoracic resection of a pulsion diverticulum of the distal esophagus. Vinson (1939), in a report of 42 cases of diverticula of the thoracic esophagus, suggested that distal functional or mechanical obstruction could be a factor in the development of these diverticula. Allen and Clagett (1965) showed that a myotomy distal to the excised epiphrenic diverticulum would prevent suture line dehiscence or recurrence of the diverticulum. Endoscopic stapling (Gustchow, 2002) or laser of the septum or the cricopharyngeal muscle has been attempted with good initial reports, but long-term outcomes are not available (Gustchow, 2002).

MANAGEMENT OF ESOPHAGEAL PERFORATION Long before the era of interventional surgery, the entity of postemetic rupture of the esophagus gained renown with the famous case of Baron Jan van Wassenaer, the Grand Admiral of the Dutch fleet. With his stomach overdistended from a hearty meal, he sought relief by inducing vomiting and immediately developed excruciating epigastric pain. It is said that he remarked to his servants that his stomach was torn; if true, this was a remarkable bit of self-diagnosis. The eponym for the condition derives from his physician Hermann Boerhaave, who on that evening (October 29, 1723) was called to see the admiral, who succumbed 18 hours later. The autopsy report, “History of a grievous disease not previously described,” highlighted all of the essentials in the pathology of barogenic trauma.

Chapter 1 History and Development of Esophageal Surgery

Fitz (1877) recorded a very early review of the various causes of rupture of the esophagus, particularly in the otherwise healthy patient. A review by Michel and colleagues (1981) emphasized the important details of operative and nonoperative management. It was more than two centuries after the Boerhaave report that Collis (1944) made the first preoperative diagnosis of postemetic rupture of the esophagus. His patient did not survive the surgical repair. His British colleague Barrett (1947), whose name so often appears in this historical account, achieved the first successful repair of a so-called spontaneous perforation of the esophagus. In the United States in the same year, Olsen and Clagett (1947) reported a successful repair. Mackler (1952), in an experimental and clinical study, concluded that an intraluminal pressure of 5 pounds per square inch was required to cause rupture. He utilized autopsy specimens of the complete esophagus, tied off at either end and subjected to varying pressures, demonstrating that it was the lower extremity of the esophagus that was most likely to rupture. It has become clear that early diagnosis and prompt surgical intervention are the keys to success. As recorded in the Wassenaer case, abdominal physical findings are often not present.

SURGERY FOR GASTROESOPHAGEAL REFLUX DISEASE While early efforts to design esophagectomy for carcinoma were pioneered in the German and Austrian schools, advancements in the understanding and surgical management of gastroesophageal reflux disease (GERD) were blazed by British surgeons. The techniques of esophageal resection and intrathoracic anastomosis had been largely established by the time of World War II, but GERD was not fully understood until early in the decade of the 1950s. Allison (1951) defined clearly that it was not the sliding hiatal hernia itself that was the crucial pathologic process in GERD but, rather, the reflux of acid peptic gastric secretions that resulted in distal esophageal inflammation and ulceration. He described the first logical anatomic repair, although years later, in a remarkable display of critical self-evaluation (1973), he reported a 49% rate of recurrence—certainly and disappointingly unacceptable. Meanwhile, Barrett, long considered the dean of British chest surgeons, was reporting (1950) his experience with columnar-lined esophagus with accompanying esophagitis and ulceration. His interpretation that this was due to congenital shortening of the esophagus was ultimately proved erroneous, largely as the result of pathologic examination of cases by Allison and Johnstone (1953) of resected nondilatable strictures. In these specimens, normal esophageal musculature was found ensheathing the columnar epithelial lining. Nevertheless, Barrett’s name has forever been assigned to this condition. Adler (1963), in a report on the lower esophagus lined with columnar epithelium, noted its association with ulceration,

stricture, and tumor. Years later, Naef and colleagues (1975) reported 12 cases of adenocarcinoma in 140 patients with columnar-lined lower esophagus (9%). The proper role of surgery for Barrett’s esophagus remains unclear. With this background it was clear, certainly to British surgeons, that control of gastroesophageal reflux was the essential requirement in the prevention of GERD. Having spent time working with Barrett, Ronald Belsey spent years studying the nature of reflux, with particular emphasis on his direct esophagoscopic observations. This evaluation was mandatory and always carried out with the patient under topical anesthesia and in the semirecumbent position. By 1952 he had developed a transthoracic technique that restored a 4- to 5-cm segment of intra-abdominal esophagus and created a 270-degree fundoplication of proximal stomach about the distal esophagus. This constituted his Mark IV operation to prevent gastroesophageal reflux. He did not report this until 9 years later with Hiebert (1961). The Mark IV operation remains one of the three basic antireflux surgical repairs. The second of these successful operations was the transabdominal fundoplication procedure of Rudolf Nissen (1961) of Basel. This technique involved suture approximation of anterior and posterior folds of the gastric fundus anterior to the abdominal segment of esophagus. The technique has been modified by a number of surgeons. One of these has been Rosetti’s repair (1977) using only the anterior gastric wall for the wrap. In addition, the fundoplication has now become the primary basis for most laparoscopic operations (Dallemagne et al, 1991) to prevent GERD. The third accepted operation is the transabdominal posterior gastropexy of Hill (1967). In this operation, the posterior aspect of the gastroesophageal junction is anchored to the median arcuate ligament. In 1978, Hill incorporated intraoperative measurement of the lower esophageal sphincteric pressure as his guide to producing the exactly correct sphincteric resistance to reflux. The Hill repair, too, has been adapted to laparoscopic techniques. A major historical contribution to the management of GERD, when reflux-induced, inflammatory, intramural scarring has produced esophageal shortening, has been the work of Collis (1957). His cardioplasty technique provides esophageal lengthening by creation of a proximal gastroplasty tube, sometimes termed neoesophagus, around which is applied a fundoplicating wrap. A popular modern technique has been the combination of a Collis gastroplasty and Belsey fundoplication, described by Pearson and colleagues (1971). This, in turn, has been altered to the modified Collis gastroplasty and Nissen fundoplication (Orringer and Sloan, 1977), primarily because the Nissen fundoplication is surgically easier to carry out. A wave of enthusiasm has been noted for the laparoscopic approach to repair. As the name of their article states, Swanstrom and colleagues (1996) believe that laparoscopic Collis gastroplasty is the treatment of choice for shortened esophagus, and Pierre and colleagues (2002), from Pittsburgh, have now reported a laparoscopic series of 200 cases of repair of giant paraesophageal hernias applying Collis gastroplasty in the majority with good intermediate outcomes.

7

8

Section 1 Introduction

MANAGEMENT OF ESOPHAGEAL STRICTURE Pathology Nissen (1981) quoted that Rokitansky, the Viennese pathologist, demonstrated in 1855 that esophagitis of the lower esophagus could be caused by gastroesophageal reflux. The term peptic esophagitis first appeared in the English literature in the work of Winkelstein (1935). He defined it as a “new clinical entity.” For the surgeon it was Allison (1948) who clearly ascribed it and the peptic stricture, which may result, to gastroesophageal reflux. Acquired shortening of the esophagus resulting from inflammatory scarring and contracture of esophageal musculature was described by Lortat-Jacob (1957). Other forms of esophagitis may result from a variety of causes: ingestion of caustic substances, the columnar-lined esophagus, an inlying nasogastric tube, and perhaps the Schatzki ring. The latter was first reported by Schatzki and Gary (1953), who used the term lower esophageal ring to describe a diaphragm-like narrowing occurring precisely at the squamocolumnar junction, always in the presence of a sliding hiatal hernia. A peculiarity is that biopsies of the ring have not revealed any microscopic evidence of an inflammatory process as seen in true peptic esophagitis.

of continuing reflux but that combining it with a Nissen wrap, the Thal-Nissen procedure, made it their operation of choice. With the introduction of histamine-2 blockers and proton pump inhibitors, the incidence of severe peptic strictures has decreased significantly (Isolauri, 1997; Richter, 1999). In a study of GERD patients treated with medical therapy and followed for 17 to 22 years, no strictures were noted (Isolauri, 1997). Thus, modern medical therapy has made the need for resection or repair with a Thal patch rare except for the most recalcitrant strictures.

DEVELOPMENT OF DIAGNOSTIC AIDS FOR ESOPHAGEAL STUDY

Therapy

The story of the evolution of surgery for disorders of the esophagus would indeed be incomplete without reference to the origins of the diagnostic devices and tests that accompanied, and in a number of instances made possible, the surgical advances. These will be listed approximately in the order of their appearance in esophageal surgical textbooks. That will provide the inquiring student the unusual opportunity of greater understanding and appreciation of just how startling were the various innovations made without the diagnostic aids we have today. In this listing, liberal reference has been made to esophageal surgical texts, particularly that of Jamieson (1988).

Until the greater involvement of the gastroenterologist in the field, management of strictures of the esophagus had historically been the lot of the surgeon and the laryngologist. The basic mode of therapy was esophageal dilation. Hildreth (1821) carried out an early, successful dilation of a stricture. Retrograde dilation via a gastrostomy was successfully accomplished by Woolsey in 1895. Recognizing the potential hazards of blind dilation, Plummer (1910) developed the technique of guided dilation by having the patient first swallow a string with a bead on its tip, over which bougies were passed. As an alternative to these forceful methods of dilation, the gravitational technique with mercury-weighted bougies was introduced by Hurst (1927). The tapered Maloney modification became particularly effective for dilating peptic strictures. In the situation of a transmural nondilatable stricture, surgical intervention may become necessary for relief of dysphagia. Merendino and Dillard (1955) had extensive experience with resection of the strictured area and replacement with jejunal interposition. Their report title is descriptive: “The Concept of Sphincter Substitution by an Interposed Jejunal Segment.” In an effort to avoid resection, Tsukamoto and Thal (1966) developed a technique for widening the scarred distal esophagus by sewing a patch of gastric fundus into a vertical incision through the strictured area, a technique much like the dressmaker’s trick of sewing a gusset into a narrowed sleeve. The Thal patch, as it has become known, is best described in the title of their classic laboratory work, “Correction of Experimental Esophageal Stricture with the Use of the SkinLined Fundic Patch.” Woodward and colleagues (1981) reported that the Thal patch alone was not effective because

1. Rigid esophagoscopy, 1881. Reference has already been made to the quotation of Olch (1960) that MikuliczRadecki was “the father of endoscopy as we know it today.” An earlier reference to “the esophagoscope” was made by Bevan (1868). 2. Esophageal manometry, 1883. In this year Kronecker and Meltzer first described a manometric study of the esophagus using balloons. It would be a remarkable number of years later before Code and his colleagues from the Mayo Clinic (Butin et al, 1953) reported their studies of esophageal pressures in patients with cardiospasm. In the same year, Ingelfinger and colleagues at Boston University (Sanchez et al, 1953) published their work on pressure studies of the distal esophagus. 3. Radiography of the esophagus, 1898. The eminent physiologist W. B. Cannon, while an undergraduate at the Harvard Medical School, reported with Moser their studies of swallowing using the recently discovered Roentgen rays and bismuth capsules. The barium esophagram was a natural sequela. 4. Esophageal pH testing, 1964. DeMeester reports that Miller first described “prolonged esophageal pH monitoring” using an inlying pH probe. This opened the door for improved understanding of gastroesophageal reflux and its pathophysiologic complications. DeMeester and colleagues (1980) described the technique and clinical use of 24-hour esophageal pH monitoring. A new catheterfree device (Bravo Probe, Medtronic, Minneapolis, MN) has been developed. A capsule is placed under endoscopic guidance in the distal esophagus, which in turn measures the pH and transmits to a receiver using radiotelemetry. Early studies are encouraging, but this technology is not

Chapter 1 History and Development of Esophageal Surgery

widely available (Pandolfino, 2003; Richter, 2003; Ward, 2004). 5. Imaging studies, 1972, 1982. Computed tomography (CT) was clinically introduced in 1972 and magnetic resonance imaging (MRI) in 1982. CT provided evidence to assess extraluminal involvement by disease. MRI was of lesser help in evaluating the hollow esophagus itself but was of particular value in detecting distant metastatic disease. 6. Endoscopic ultrasound, 1988. It is difficult to assign a time of origin of the use of ultrasound in studying the esophagus. An early report is that of Silva and colleagues (1988). Its value may lie primarily with determination of the T status in staging of carcinoma. A special ultrasound flexible endoscope is required.

THE ESOPHAGUS AND MOMENTS IN HISTORY There were three critical moments in modern surgical times when events related to the esophagus were to result in monumental changes in our thoracic surgical world. First was the aftermath of the 1913 Torek esophagectomy. Murray (1988) reports “it is not widely appreciated that Dr. Willy Meyer’s description of successful esophageal resection at the annual meeting of the American Medical Association in 1913 was met with indifference” (1914). There was no discussion of this paper. The obvious lack of interest among general physicians for problems dealing with the esophagus was the direct impetus Meyer needed to take the lead, with a small group of “interested” surgeons, in the formation of the American Association for Thoracic Surgery, the founding organization in the clinical specialty of thoracic surgery. “Thus it was lack of enthusiasm that served to ignite the spark which

developed, in time, into the first Society for Thoracic Surgery formed in the world” (Founding of the American Association for Thoracic Surgery, 50th anniversary, 1967). Second was the response to Donald Paulsen’s presidential address to the 61st annual meeting of the American Association for Thoracic Surgery in 1981, “A Time for Assessment.” In this treatise on the imbalances in training of cardiothoracic surgeons Paulsen deplored the decreasing general thoracic experience of residents applying for certification by the American Board of Thoracic Surgery. It was, in particular, the dismally small experience in esophageal surgery that dominated his statistics (only six to nine cases annually for the decade 1971-1980). The creation of a Liaison Committee for Thoracic Surgery has led to a more proper balancing of cardiothoracic training and to the development of general thoracic surgical units in many of the leading teaching and research hospitals. Third was the introduction of laparoscopy by general surgeons, and the report of the first laparoscopic Nissen fundoplication by Dallemagne in 1991 to some degree changed the paradigm of who treated esophageal disorders in many parts of the world, from a primarily thoracic surgeon’s domain to that of the general surgeon with laparoscopic skills. Further, since the introduction of laparoscopic fundoplication there has been a dramatic increase in antireflux procedures (Hunter, 1999; Smith, 2005). In Canada, it should be noted in closing, the Cardiovascular and Thoracic Committee of the Royal College offered a Certificate of Special Competence in Thoracic Surgery. Surgery of the esophagus will always present challenge. With the lessons of history perhaps we are better prepared to face and conquer the challenge. Visit Why History Is Important for Thoracic Surgeons (Wilkins, 2000).

9

chapter

2

CLINICALLY ORIENTED ANATOMY, EMBRYOLOGY, AND HISTOLOGY Dorothea Liebermann-Meffert

ANATOMY Dimensions of Normal Esophagus The esophagus is the musculomembranous tube that serves as a passage for food between the pharynx and the gastrointestinal tract. It is the narrowest tube of the gastrointestinal tract, spanning the interval between the cricopharyngeal constriction and the most voluminous part of the gut, the stomach. Its length, defined as the distance between the cricoid bone and the gastric orifice, ranges from 24 to 34 cm, with an average of 27.6 cm in adult human cadavers.1 To discern the precise localization of the cricoid bone, however, is difficult, and clinicians use the incisors as a landmark; this adds up the esophageal lengths to 39 to 48 cm in clinical examinations (Fig. 2-1).1 Three minor deviations are present. The first one changes from the median position at the pharyngoesophageal junction (Figs. 2-2 and 2-3) toward the left at the base of the neck (see Fig. 2-3). The second deviation is at the level of the seventh thoracic vertebra, where the esophagus shifts slightly to the right of the spine. The third and most prominent angulation occurs after traversing the diaphragmatic crura and above the esophagogastric junction, where the terminal esophagus turns to the left (see Fig. 2-1). As a result, the esophagogastric junction takes position lateral to the xiphoid process of the sternum and to the left of the 12th vertebral body. This means the fundus and the proximal stomach lie anterolateral to the spine, with the greater curvature facing the posterior subdiaphragmatic space and the anterior gastric wall facing the left abdominal wall. This topographic relationship is inadequately shown in standard anatomic or surgical textbooks but is well seen on CT in textbooks of radiology.2 Figures 2-2 and 2-3 demonstrate the intimate contact between the wall of the esophagus and the trachea, possessing no limiting tissue. At rest, the esophageal tube is collapsed. The configuration is flat in the upper and middle regions and rounded in the lower esophageal portion; mean diameters are 2.5 to 1.6 cm and 2.5 to 2.4 cm, respectively.1,3 The esophagus possesses two functional and anatomic narrowings, the one at the entry into the tube and the other at its end. These are called the upper and lower esophageal sphincters (UES and LES).

Surrounding Tissues, Compartments, and Anchors of the Esophagus The esophagus is wrapped in a thin, continuous adventitial sheath, the fibroareolar lamina, that binds together the 10

muscles, vessels, and bony constituents of the neck and chest. Unlike the digestive tube, however, the esophagus has no mesentery and no serosal coating. Its position within the loose, areolar connective tissue of the mediastinum provides transverse and longitudinal mobility to the esophagus. Respiration may induce movement over a few millimeters, and swallowing may cause movement as much as the height of one vertebral body.4 Cranially, the carotid sheath—a portion of the deep cervical fascia—separates to form the pretracheal (previsceral) fascia anteriorly and the prevertebral (retrovisceral) fascia posteriorly. Slit-shaped spaces between the layers of these fasciae form communicating compartments between the neck and chest (Warwick and Williams, 1978).5 The pretracheal space surrounds the vascular structures of the anterior mediastinum but is limited distally by the fibrous tissue of the pericardium. The prevertebral space may extend from the base of the skull down to the diaphragm but is frequently obliterated below the level of the tracheal bifurcation.

Which Structures Stabilize the Esophagus? Insignificant tiny membranes of different extension attach the cranial half of the muscular esophagus to the trachea (Figs. 2-4 and 2-5), the pleura, and the retroperitoneum. The membranes contain elastic and/or collagen fibers (see Fig. 2-4) and occasional, small smooth muscle bundles or striated muscle fibers.3,6 The bundles run toward the posterior end in the retrovisceral fascia or blindly within the connective tissue network of the mediastinum. The membranes are all delicate, ranging from 30 to 1000 µm in thickness and 0.5 to 3 cm in craniocaudal length.6 They are definitely much smaller than the coarse “bronchoesophageal” or “pleuroesophageal” muscle cords depicted by Netter.7 They, however, can be viewed during mediastinoscopic dissection when the esophagus is exposed from the neck. Elastically attached by the phrenoesophageal membrane (PEM), the distal esophagus traverses the diaphragm through the esophageal hiatus (see Fig. 2-5). At the central margin of the diaphragm, the subdiaphragmatic and the endothoracic aponeuroses blend into the PEM (Fig. 2-6). This structure can be recognized by its well-defined lower edge and the slightly yellow color of the enclosed fat pad (see Fig. 2-6). The PEM splits into two sheaths. One sheath extends craniad for 2 to 4 cm through the hiatus, where its fibers

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

Distance in cm

FIGURE 2-1 Classical division of the esophagus and projection to the related organs. The relationships to the cervical and thoracic vertebrae as radiologic landmarks are indicated on the left of the figure. The distances from the incisors and from the cricoid cartilage to the end of the esophagus are also indicated. The curves of the esophagus (arrows 1, 2, 3) are shown. UES, upper esophageal sphincter; LES, lower esophageal sphincter.

Denomination of esophageal sections in regard to

15 cm

Incisors Anatomy Function Cricoid cartilage Vertebrae C8-T1

1

Cervical

UES

Surgery

Proximal Cervical

Incisura jugularis sterni 18–22 cm

Thoracic

Tubular

Thoracic

Distal Thoracic

2

T1-T10 3–6 cm

3

Abdominal

Abdominal

Diaphragm T10-T12 Gastric orifice

LES

Total length 39–48 cm

3 2

5

7 8 1

9

6 C6 4 5 8 2 1

12

12

1 = Esophagus 2 = Trachea 3 = Sternum 4 = Ribs 5 = Musculature 6 = Vertebra 7 = Thyroid gland 8 = Vessels 9 = Musculature 10 = Aorta, cor 11 = Azygos vein = Thoracic duct 12 = Thoracic cavity 13 = Liver 14 = Stomach 15 = Spleen, ligaments

6 Th2

13

14 1 10 6

15

FIGURE 2-2 Diagram (caudal view) of the positional anatomy of the esophagus known from computed tomographic representations at the cervical level (top), upper chest (middle), and esophagogastric junction (bottom).

2

2

1

1

0

3

1

2

3

4

cm FIGURE 2-3 Cross section through the esophagus (1), trachea (2), and thyroid gland (3) in a human at a cervical level. Macroscopic (formaldehyde fixed) specimen (left) and histologic (hematoxylin and eosin stained) specimen (right) are viewed from cranial aspects. The positional close contact between the esophagus and trachea and the lack of a distinct structural partition are recognizable. (SPECIMENS COURTESY OF THE AUTHOR.)

penetrate the esophageal musculature to insert on the submucosa. The second sheath passes down across the cardia and is separated from the muscular wall of the gastroesophageal junction by areolar connective or fat tissue.6 At the level of the gastric fundus, the fibers of the PEM blend into the serosa and the gastric musculature (see Fig. 2-6), the gastrohepatic ligament, and the dorsal gastric mesentery (see Figs. 2-5 and 2-6). The PEM wraps the gastroesophageal junction completely like a loose collar. This guarantees sufficient plasticity for the LES to move in relation to the diaphragm. Stability is provided by the inelastic gastric ligaments that attach the cardia and the posterior fundus wall to the upper retroperitoneal fasciae.

11

12

Section 1 Introduction

Diaphragm

Esophagus

PEM Collar Stomach

FIGURE 2-6 The phrenoesophageal membrane (PEM) of a human autopsy specimen viewed in situ from the anterolateral aspect. This structure also became known as Laimer’s or Allison’s membrane. As shown in the photograph, the lower sheath of the membrane is inserted onto the gastric fundus (3). At the top the diaphragm is held up with a forceps. Diaphragmatic decussating fibers (1) and a submembranous pad of adipose tissue (2) are seen. The diagram shows how the PEM wraps the esophagogastric junction with a wide membranous collar (dotted lines). (FROM DURANCEAU A, LIEBERMANN-MEFFERT D: EMBRYOLOGY, ANATOMY, AND PHYSIOLOGY OF THE ESOPHAGUS. IN ORRINGER MB, ZUIDEMA GD [EDS]: SHACKELFORD’S SURGERY OF THE ALIMENTARY TRACT, VOL 1. THE ESOPHAGUS, 3RD ED. PHILADELPHIA, WB SAUNDERS, 1991, P 3.)

FIGURE 2-4 Histologic cross section through one of the membranes (1) that connect the human esophagus (2) and the trachea (3), viewed from cranial aspect. The finger-shaped insertion of the membrane into the esophageal muscle can be seen. (SPECIMEN COURTESY OF THE AUTHOR.)

1 Cricopharyngeal Area 2 Cricopharyngeal Membrane (Tendon) 3 Bronchoesophageal 4 Pleuroesophageal (strands of fibers and muscles) 5 Phrenoesophageal Membrane 6 Lesser Omentum 7 Diaphragm 8 Gastrosplenic Ligament

Constrictor Raphe 1 UES 2 3 4

5

8

7 6

5 LES

Liebermann-Meffert D. Modified 2005 FIGURE 2-5 Diagram of the anchoring structures of the esophagus viewed from the left. The inferior laryngeal constrictor muscles (1) that insert on the sphenoid bone and the longitudinal muscle of the esophagus that inserts lateral on the cricoid cartilage through the cricopharyngeal tendon (2) are shown. Bundles of elastic, collagen, and muscle fibers connect the esophageal wall with the trachea (3), pleura, and retrovisceral fascia (4). The attachment by the phrenoesophageal membrane (5) is rather mobile, whereas the posterior gastric ligaments (8) and the lesser omentum (6) yield a tight adherence. LES, lower esophageal sphincter; UES, upper esophageal sphincter.

Comments on Surgical Relevance and Consequences The basis for stripping the esophagus is the mobile localization of the esophagus within the mediastinum: the mobility, which is due to the nonexistence of coarse esophagus attaching or supplying fiber structures, is the reason why we can subject the esophagus to a blunt pull-through from the mediastinum, provided that there are no contraindications such as periesophageal tumor invasion.1,8 When the esophagus must be resected, stomach or bowl is used as conduit. The shortest distance between the cricoid cartilage and the celiac axis required for esophageal replacement was found to be the orthotopic route in the posterior mediastinum (= 30 cm). The retrosternal (= 32 cm) and subcutaneous routes (= 34 cm) proved to be longer.9,10 This should allow tension-free construction of a gastroesophageal anastomosis in the neck. Although the whole stomach can serve as conduit to replace the esophagus, it is advisable to use a nonreversed gastric tube so that the blood circulation of the gastric substitute will not be compromised.9,11,12 Inelastic collagenous fiber elements replace the elastic fibers of the PEM with advancing age.13 This loss of elasticity of the PEM in conjunction with a wide hiatus results in herniation, that is, displacement of the gastroesophageal junction and cardia into the thoracic cavity. Eliska suggested that abnormal anchorage of the PEM in youth and pathologic accumulation of adipose tissue in the connective tissue space between the PEM and the cardia musculature may also contribute to the development of a hiatal hernia.13 Mittal14 has attributed sphincter function to the diaphragm and the PEM and its insertions. I could not confirm this claim after creating hernias in cats using long-term experiments.15

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

Dissection of the diaphragmatic membranes and ligaments and positioning of the cardia within the chest by suturing the diaphragm to the middle of the stomach had no long-term effect on either the pressure values or the characteristics of the LES.15 A second peculiarity is the localization of the esophagus within fascial compartments. This feature allows infections to spread from anterior esophageal lesions of the esophagus through the pretracheal space to the pericardium. The cervical region is vulnerable because of the proximity between the esophagus and the trachea (see Fig. 2-3). Special care must be taken not to injure the trachea when developing the plane of dissection between the esophagus and the trachea. The lack of an esophagotracheal partition also paves the way for fistula formation,3 for example, a tracheoesophageal fistula secondary to chemotherapy16 and irradiation. This invariably leads to empyema and often death. The retrovisceral space, however, is clinically more important. For example, oropharyngeal infections can easily descend through spaces within the different sheaths of the deep cervical fascia. Necrotizing mediastinitis resulting from peritonsillar or dental abscesses or even wisdom tooth extraction has been reported and may involve a mortality rate of nearly 40%.17,18 Most instrumental perforations occur in the posterior hypopharynx above the narrowing of the cricopharyngeal sphincter, below which there is no barrier to the spread of infection into the mediastinum. Noninstrumental or spontaneous perforation (Boerhaave’s syndrome) and leakage from an esophageal anastomosis behave in a similar way with rapid and disastrous dissemination of sepsis.

Vascular Structures and Nerves Supplying the Esophagus The history of the arterial supply of the esophagus has been quoted extensively by Siewert and Liebermann-Meffert.19 This publication gives a good review and its reading is recommended. The following description is based on new studies of my group1,11,19 that we performed to answer special questions in regard to foregut surgery.

Arterial Supply Cervical Esophagus. Branches deriving from the right and left superior and inferior thyroid arteries supply the wall of the pharynx, esophagus, and trachea (Fig. 2-7). Compared with the thyroid arteries the vessels to the esophagus are small.1,19 Their equal distribution contrasts to Shapiro and Robillard’s claim in 1950 that a greater number of vessels supply predominantly the right side of the esophagus.20 Thoracic Esophagus. Down to the level of the tracheal bifurcation, the upper thoracic esophagus receives branches from the thyroid arteries, but the majority of the supplying vessels to the esophagus and tracheal bifurcation are derived from the bunch of arteries arising at the inflection of the aorta.1,20 More caudally, most often only one singular artery arises from the anterior aspect of the aorta. Although this vessel clearly supplies the distal part of the trachea and the stem bronchi, small branches also form the esophageal vascularization, as seen in Figures 2-7 and 2-8. In general, these

FIGURE 2-7 Vascular corrosion casts of the arteries of the neck and mouth viewed from the anterior position. Top, Aorta (1), the common carotid artery (2), a network of the thyroid arteries (3), esophageal arteries (4), the left superior thyroid artery (5), and the arteries of the tongue (6). Note that there is not any vascular anastomosis between both sides of the tongue. Bottom, Vascular casts of the aortic arch (1), a bunch of bronchoesophageal arteries (2), and a network of esophageal vessels (3). The stump seen at the lateral aorta had supplied the thoracic wall. (SPECIMENS COURTESY OF THE AUTHOR.)

vessels are straight and short, connecting tightly the aorta, the trachea, and the esophagus.1 At variable localization, one other unpaired artery may arise from the anterior aortic aspect. This vessel, however, courses obliquely down from its origin (Fig. 2-9) to divide—still within the mediastinum— into an ascending and a descending branch.1,19 Abdominal Esophagus. The distal esophagus and the gastric cardia are nourished by up to 11 small arteries that originate at intervals from the left gastric artery.1,19 These vessels travel straight upward alongside the anterior aspect of the cardia (see Fig. 2-9) and follow the wall through the diaphragm in the longitudinal esophageal axis to subdivide into periesophageal tributaries before they dip into the muscular layers. The posterior wall of the terminal esophagus receives several large vessels derived from the splenic artery and/or from vessels of the dorsal fundus, but previous claims that nutritional vessels arise from phrenic arteries have not been substantiated.1 Concerning the vascularization as a whole, the esophagus is an organ of shared vasculature with poor “proper” extrinsic

13

14

Section 1 Introduction

Esophagus A. esoph propr.

Bronchial artery

Branch of tracheobronchial artery

195 2 1

Previous site of diaphragm

10 cm

Cardiac branch of left gastric artery

Bronchial artery + esophageal branches

160

125

Esophageal artery

Aorta FIGURE 2-8 Arterial corrosion cast of thoracoabdominal organs— aorta, esophagus, and stomach—viewed from the anterior aspect. The bronchial artery is shown deriving from the aorta and giving off several smaller branches that form the minute esophageal network. The stump left of the aorta is the residual of the rami intercostalis.

Cardiac branches Left gastric artery

(BERACRYL INJECTION INTO THE AORTA BY THE AUTHOR.)

support. In fact, apart from the few “vasa propria” that derive from the aorta directly, the esophagus receives its blood via vessels feeding mainly other organs, such as the thyroid gland, trachea, and stomach. Even though the vessels are minute within the periesophageal tissue, previous claims of a poor or missing vascularization in the wall of the midesophagus could not be substantiated because connections within and throughout the submucosa and mucosa form a complete and vast intramural network of fine vessels (Fig. 2-10).1,19 And nowhere is the wall of the esophagus avascular. Comments on Surgical Relevance and Consequences. The correctly mobilized esophagus retains an excellent blood supply over a long distance. The vascularization is seldom responsible for a failed anastomosis.21 This circulation is evidently due to the rich and complete network of vessels within the wall. Blunt pull-through esophagectomy without thoracotomy for esophageal cancer is relatively safe and causes a minimum of blood loss.1,22,23 When hemorrhage has occurred after stripping of the esophagus, it was from the site of tumor adhesions rather than from the periesophageal vessels.24 A usually limited bleeding may occur because the major supporting arteries divide into minute branches at some distance from the esophageal wall, and, when torn, benefit from contractile hemostasis.1

0 mm

Aorta

FIGURE 2-9 Diagram of the most common vascular pattern of blood supply to the esophagus and cardia in the human adult. 1, aorta; 2, esophagus.

Venous Drainage Intraesophageal (Intrinsic) Veins. The intraesophageal veins include the subepithelial plexus, which is located in the lamina propria of the tunica mucosa.25 The veins are arranged mainly in the longitudinal axis of the esophagus

FIGURE 2-10 Sample of the submucosal microvascular esophageal blood supply displayed in a scanning electron micrograph. The arteries and veins are small and form a minute polygonal network. (RESIN-INJECTED SPECIMEN BY THE AUTHOR.)

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

and extend through the whole length of the esophageal submucosa.26 The subepithelial plexus receives blood from the adjacent capillaries and drains into the submucous plexus. At the lower end of the esophagus, the systemic and the portal system obviously anastomose; in case of portal venous obstruction the thin-walled superficial veins presumably enlarge to form varices. Vianna and colleagues26 described a specialized longitudinal venous arrangement prevalent in the lower third of the esophagus and in the cardia. This structure consists of perforating veins deriving from the small communicating veins of the submucous plexus that pierce the muscular wall of the esophagus. The intramural veins receive tributaries from the muscle coats and form the veins on the surface of the esophagus. Extraesophageal (Extrinsic) Veins. The extraesophageal veins drain into locally corresponding large vessels. These are the inferior thyroid veins, which empty into the brachiocephalic veins, the azygos and hemiazygos veins, the left gastric vein, and the splenic vein. Comments on Surgical Relevance and Consequences. The azygos vein, because of its vicinity to the root of the lung and its lymph nodes, is one of the initial structures affected by the extramural spread of tumors of the midesophagus. In this situation, the azygos vein can be easily damaged during esophageal resection. In particular during blunt pull-through dissection, this vein represents a high risk factor causing fatal bleeding if the tumor is adherent to the venous wall. Collateral circulation may exist between the azygos vein and the hemiazygos vein. The hemiazygos vein, if not ligated, can be a source of severe hemorrhage when resecting the esophagus through a right thoracotomy.27

Lymphatic Pathways Lymphatic drainage comprises two systems: lymph channels and lymph nodes. The details of these systems, in particular the initial pathways, have recently received special attention because of the lymphatic spread of malignant tumors. Lymph capillaries commence in tissue spaces (Fig. 2-11) as a network of endothelial channels or as blind endothelial sacculations (Partsch, 1988).28 Intraesophageal (Intrinsic) Lymphatics. Because of the considerable technical difficulties to identify by injection or anatomic preparation these slender, normally collapsed structures,29,30 the anatomic knowledge of the esophageal initial lymphatics in healthy individuals is still sparse. Some investigators such as Idanov, in 1959,31 or Rouvière, in 1932,32 emphasized the existence of a rich lymphatic network in the lamina mucosa and tela submucosa of the esophagus. Their claims have never been substantiated by convincing or reproducible documentation. According to recent studies one may assume that tiny precapillary spaces also exist in all the levels of the esophageal lamina mucosa, similar to descriptions of interstitial tissues; other authors have stressed the almost complete absence of true anatomic lymph capillaries in the upper and middle levels of the lamina mucosa of the human stomach29 and esophagus.30 Transmission electron microscopic studies have shown anastomosing lymph capillaries

Terminal lymphatic network

(20–30 µm)

Blind endothelial sacculations (40–60 µm)

Valves with valve leaflets

Collecting lymphatic channel (100–200 µm) FIGURE 2-11 Diagram showing the initial lymphatic network, which is reconstructed from mesentery preparations. The color red indicates the lymphatic channel. Most probably, this pattern equals that of the esophagus. (MODIFIED FROM ZWEIFACH BW, PRATHER JW: MANIPULATION OF PRESSURE IN TERMINAL LYMPHATICS IN THE MESENTERY. AM J PHYSIOL 228:1326, 1975.)

only in the lower mucosal levels and small valve-containing vessels in the tela submucosa of the esophagus. These appeared to form long channels that parallel the organ axis. Extraesophageal (Extrinsic) Lymphatics. The submucosal lymph channels give off occasional branches to the collecting subadventitial and surface trunks. Thoracic Duct. The principal lymphatic vessel of the body is the thoracic duct (Fig. 2-12). It begins with the cisterna chyli at level L1-2, emerges through the aortic hiatus of the diaphragm, and travels in more than half of cases as a single trunk craniad with the aorta on its left and the azygos vein on its right. Then the duct turns at the level of T5-6 behind the left mainstem bronchus toward the left and ascends lateroposteriorly to the trachea and esophagus to end at the angle between the left subclavian and jugular veins by draining the lymph into the bloodstream. Anatomic variations are manifold.31 The close local relationship of the flimsy duct to the esophagus explains its occasional damage during esophageal resection and chylothorax. Normally the thoracic duct is collapsed and then appears, like a string of beads, at preparation, because of numerous strong valves. The thoracic duct is 0.5 to 2.0 mm wide (mean, 1.3 mm) at the distal third, 1.0 to 3.0 mm (mean, 1.7 mm) at the middle, and 1.0 to 4.0 mm (mean, 2.3 mm) at the proximal third (threshold, 4.0 mm) as has been shown in 500 lymphograms of healthy individuals by Wirth and Frommhold.33

15

16

Section 1 Introduction

Compartment

Flow direction Thoracic duct

Cervical esophagus

Neck

Thoracic esophagus

Thorax

Terminal esophagus Abdomen

Celiac lymph nodes Cysterna chyli FIGURE 2-12 Diagram of the lymphatic pathways and lymph node distribution. During human organogenesis, the lymphatic pathways develop from two different sources, the branchiogenic mesenchyme and the body mesenchyme. As a result, lymph drains toward two different directions (arrows) with a zone of bidirectional flow at the tracheal bifurcation. This feature is consistent with clinical observations. The knowledge of lymph flow and the corresponding lymph node distribution is essential in understanding potential spread of malignancy.

Lymph Nodes of the Esophagus. In noncancer autopsy specimens, we found most of the lymph nodes of the thoracic mediastinum piled up around the tracheal bifurcation (see Fig. 2-12). These were rather large, dark nodes. Anatomically, it was impossible to determine whether they drain the esophagus or the lungs or whether they transport proximally or distally. There is an accumulation of small nodes in the neck and cardia region, but few lymph nodes are normally present in the lateral and ventral mediastinum of the upper third and in the dorsal mediastinum in the lower third of the thorax in healthy individuals. We could not identify the classic chain of lymph nodes along and around the esophagus, as described in textbooks and seen in Netter’s7 illustration at routine autopsy. This statement is in accordance with that of Wirth and Frommhold,33 who identified mediastinal lymph nodes in only 5% of 500 normal lymphograms. We found, instead, a greater number of lymph nodes of macroscopic dimensions cranial to the tracheal bifurcation within the tracheoesophageal groove. Considering tumor involvement, the classic lymph node arrangement was elegantly illustrated by Matsubara in 1988.34 Comments on Surgical Relevance and Consequences. The initial (terminal) lymphatics (see Fig. 2-12) take up fluid, colloid material from the tissue, cell debris, microorganisms, and eventually tumor cells.35 The contents are emptied into collecting lymph channels. Paired semilunar valves within the channels determine the direction of flow. They join to form small trunks that convey the fluid and the other absorbed material through the interpositioned lymph nodes. In its passage through the node, noxious material may be filtered

off. It is evident that this system of channels provides easy pathways for tumor spread. Lehnert’s concept that the lymphatics form long channels within the submucosa in which the lymph flows more easily cranially or caudally than through the few channels that pierce the muscular coat supports the clinical observation that the initial submucosal cancer spread follows the longitudinal axis of the organ.29 Consequently, primary esophageal tumors may extend over a long distance within the esophageal wall before obstructing the lumen. The absence of lymphatics from the superficial part of the mucosa and the widely anastomosing plexus within the deep layer of the mucosa and the submucosa may explain why the intramural spread of cancer occurs predominantly in the submucosa. Free tumor cells may follow the lymphatic channels over a considerably long distance before passing through the muscular coat into regional lymph nodes. From the anatomic studies, and the clinical observations, it may be deduced3,22,24,29,34,35 that lymph from areas above the tracheal bifurcation drains mostly craniad toward the thoracic duct whereas lymph from below the carina flows mainly toward the lower mediastinal, left gastric, and celiac lymph nodes. Flow in the area of the tracheal bifurcation normally seems to be bidirectional (see Fig. 2-12), owing to the embryologic development of the two mesenchymal sources.3,36,37 Flow may change under pathologic conditions (tumor invasion). When the lymph vessels become blocked and markedly dilated, either the valves may become incompetent and the flow reversed or a collateral lymphatic circulation may develop; retrograde spread in some malignant tumors may thus be explained. Unfortunately, this possibility also limits the value of establishing normal flow pathways.

Innervation The vegetative (autonomous) nervous system regulates the function of the esophagus. It is subdivided into two parts, the sympathetic and the parasympathetic nervous system. The nerve fascicles may carry parasympathetic and sympathetic components that exert antagonistic influences on the esophagus and control the striated and smooth muscle, glands, and blood vessels.38,39 Sympathetic Nervous System. The sympathetic innervation comes from the cervical and the thoracic sympathetic chain (see Fig. 2-16). The sympathetic pathways are concerned with the movement of the esophageal tract, contraction of the sphincters, relaxation of the muscular wall, increase in glandular and peristaltic activity, and vasoconstriction. The sympathetic trunks are two ganglionated nerve cords that extend from the base of the skull down to the sacrum. They are located lateral to the spine (see Fig. 2-16) and possess 11 to 12 thoracic paravertebral ganglia on each side. The sympathetic innervation of the proximal esophagus is derived from the cervical and upper thoracic ganglia.38 Besides the direct approach to the organ, the fibers form a profuse, delicate network between and around the esophagus.38 Parasympathetic Nervous System. The parasympathetic innervation comes from the vagus nerve (see Fig. 2-16). The

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

FIGURE 2-13 Vagal innervation of the upper esophagus by the inferior (recurrent) laryngeal nerve. Posterior aspect of the muscular wall of the esophagus (1) and pharynx (2) is shown. The left (7) and the right recurrent laryngeal nerves are exposed. Laterally on both sides the turning points around the arch of the aorta (6) and the subclavian artery (5) are displayed. The ramifications of the recurrent laryngeal nerves alternatively enter the lateral wall of the esophagus (1) and trachea. The thyroid gland (3) and the common carotid artery (4) are shown. (FROM LIEBERMANN-MEFFERT D, ET AL: RECURRENT AND SUPERIOR LARYNGEAL NERVES: A NEW LOOK WITH IMPLICATIONS FOR THE ESOPHAGEAL SURGEON. ANN THORAC SURG 67:212, 1999. COPYRIGHT 1999, WITH PERMISSION FROM THE SOCIETY OF THORACIC SURGEONS.)

esophageal branches of the vagus nerve provide motor innervation to the muscular coats and secretomotor innervation to the glands. The vagus nerve is the paired 10th cranial nerve. Its motor fibers arise in the dorsal vagal nucleus, and its sensory fibers derive from the superior and inferior ganglion of the vagus nerve in the neck. The nerve fibers that innervate the upper part of the esophagus and pharyngoesophageal “striped” musculature arise in the nucleus ambiguus.38 Unlike those of the “smooth” muscles, which receive motor input via preganglionic autonomic fibers and synapse on neurons of the myenteric ganglia, the nerve endings of the striped muscle make direct synaptic contacts through motor end plates.40 From their origin in the medulla, the vagus nerves descend as a paired trunk and pass through the corresponding jugular foramen. The branches are shown on Figure 2-16. CERVICAL ESOPHAGUS. By giving off branches to the pharynx, larynx, and trachea (Figs. 2-13, 2-14; see also Fig. 2-16), these fibers form the cervical plexus that also innervates the proximal esophagus.40 The bilateral superior laryn-

FIGURE 2-14 Vagal innervation of the upper half of the esophagus. The specimen obtained from autopsy shows the neck area from the posterior aspect. The meandering left inferior (recurrent) laryngeal nerve (1) wriggles, being loosely adherent to the periesophageal connective tissue from the aorta (2), cranially to dip under the lower lobe of the thyroid gland (4). It will endure some stretching. Common carotid artery (3). (FROM LIEBERMANN-MEFFERT D, ET AL: RECURRENT AND SUPERIOR LARYNGEAL NERVES: A NEW LOOK WITH IMPLICATIONS FOR THE ESOPHAGEAL SURGEON. ANN THORAC SURG 67:212, 1999. COPYRIGHT 1999, WITH PERMISSION FROM THE SOCIETY OF THORACIC SURGEONS.)

geal nerves (SLNs) originate from the vagal trunks of the respective side, that is, from the ganglion nodosum (see Fig. 2-16). Both nerves descend alongside the carotid arteries before dividing into branches that enter the pharynx to innervate the muscles of the pharynx, hypopharynx, and larynx.41,42 Of the inferior (recurrent) laryngeal nerves (RLNs), the right one arises from the vagus nerve in front of the subclavian artery and turns posteriorly around the artery (see Figs. 2-13 and 2-16) before ascending obliquely to the right lateral aspect of the trachea behind the common carotid artery. The left RLN originates from the vagus nerve in front of the aortic arch, surrounds the aorta posteriorly, and ascends, maintaining a meandering course (see Fig. 2-14). Both the RLNs approach the esophagus during their lateral ascent and give off an equal number of nerve branches (6 to 12) to the esophagus as well as to the trachea (see Fig. 2-13). When approaching the pharyngoesophageal junction (see Fig. 2-13), both the right and the left RLNs have obtained an intimate

17

18

Section 1 Introduction

Vagus nerves Right

Left Ganglion nodosum

Sympathetic cervical ganglion Parasympathetic cervical plexus Recurrent laryngeal nerve Sympathetic chain

Parasympathetic esophageal plexus Splanchnic nerve

Anterior (a) and posterior (b) vagal trunks

FIGURE 2-15 Vagal innervation of the midesophagus (1) shown from an anterior aspect. The specimen obtained from autopsy displays elegantly the loosely adherent vagal network of the midesophagus, when pulled up by the forceps (3). Caudad to the tracheal bifurcation (2) large dark lymph nodes are a frequent finding. (SPECIMEN

FIGURE 2-16 Diagram of the topographic relationships between the esophagus and its innervation. This shows the situation from the anterior aspect. The dimensions are out of scale.

COURTESY OF THE AUTHOR.)

proximity with the wall of the esophagus and trachea.41,42 This proximity is particularly pronounced when the proximal RLNs become positioned underneath the medial plane of the thyroid glands. There they entangle the thyroid vessels before they enter the larynx from lateral and caudal to the cricopharyngeal muscle band.41 The terminal branches of the RLNs are most often 1.0 to 1.5 mm thick and divide into several branches to innervate all the laryngeal muscles, including the vocal and epiglottic muscles.41-43 The observation of a nonrecurrent laryngeal nerve is an unfrequent event.44 The situation is almost never found on the right side (31 [0.1%] of 6000 cases of thyroid surgery done by Toniato and associates44 and none on the left). This corresponds to the data presented by Hiebert and colleagues.43 THORACIC ESOPHAGUS. At the level of the tracheal bifurcation, the ongoing main vagal trunks pass posterior to the roots of the lung and divide into multiple small branches to form pulmonary and esophageal plexuses. Caudal to the tracheal bifurcation, the esophageal vagal trunks break up into a network of fascicles (Fig. 2-15). The left vagus builds up mainly the anterior plexus, and the right vagus, the posterior plexus. At a variable distance from the cardia, the fibers of both the anterior plexus and the posterior plexus reorganize into two thick trunks that travel down on the anterior and posterior esophageal wall (Fig. 2-16). Both vagal trunks may now contain fibers from the upper contralateral side.

ABDOMINAL ESOPHAGUS AND STOMACH. Together with the esophagus, the vagus nerves pass through the diaphragmatic hiatus, where they are barely distinguishable under the phrenoesophageal membrane. The posterior vagus nerve often divides into smaller branches that lie 2 to 4 cm distant from the end of the esophagus and to its right. The anterior vagus nerve runs at the left side to the anterosuperior surface of the stomach. Intramural Innervation. Branches from the periesophageal, parasympathetic, and sympathetic plexus enter the wall of the esophagus together with the blood vessels. They form the intrinsic innervation, which is composed of fine nerve fibers and numerous groups of ganglia. The ganglia lie either between the longitudinal and the circular layers of the tunica muscularis, in which case they are called myenteric or Auerbach’s plexus, or in the tela submucosa, in which case they are called the submucous or Meissner plexus. The one regulates the contraction of the muscle coats; the other regulates the peristalsis of the muscularis mucosae and the secretion. Both are interconnected by a meshwork of fibers.45 The number of ganglia is fairly uniform within the esophageal wall.46 Near the junctional zone, however, the nerve fascicles become thicker and ganglia accumulate.45 Comments on Surgical Relevance and Consequences. During esophageal resection and goiter operations, the RLNs are at high risk. Injuries involving the SLNs and RLNs cause clinical pictures of a variety of transient or even lasting motor and sensory disorders of the pharyngolaryngoesophageal junc-

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

4th Week

3rd Week

8th Week

Sagittal 5 7

1

3

3

3

1

1 5

10 9

2

6

4

8

2

7

2

5

FIGURE 2-17 Formation of the developing intestinal tube from the endoderm of the regressing yolk sac cavity (2). The event is due to folding and flexion of the embryo (1) and shows the third, fourth, and eighth weeks of gestation. The portion of the yolk sac that has become included into the embryo forms the foregut, midgut, and hindgut (see Fig. 2-18). The amniotic cavity (3), extraembryonic coelom (4), extraembryonic mesenchyme and cytotrophoblast (5), somatopleure (6), splanchnopleure (7), septum transversum (8), heart (9), and head and neck area (branchial organs) (10) are shown.

Transverse 5 7

3 1

4

3

7

5

1

1 3

2 6 6

2 4

tion area. These may be hoarseness related to vocal cord palsy and respiration and swallowing failure associated with problems of aspiration and dysphagia.41,43

2

5

1

1 4

PRENATAL DEVELOPMENT OF THE ESOPHAGUS AND STOMACH

2 6

General Aspects The first events of human development are best documented in the numerous original publications “Contributions to Embryology” of the Carnegie Institution. The most important descriptions of these publications are reported and updated in the current textbooks of embryology (Moore, 1988).47-49 According to these reports, the human embryo develops during the first 3 weeks after fertilization by going through the following stages: cell division → morula → blastocyst → implantation into the endometrium → formation of the primary yolk sac (from the former blastocyst cavity) and formation of the bilaminar embryonic disc (from the inner cell mass). The embryonic disc is composed of two layers, the ectoderm and the endoderm, which also lines the internal plane of the yolk sac (Fig. 2-17). The endoderm is composed of flattened cells that subsequently become columnar. It gives rise to the epithelial lining of the whole alimentary tract and retains its epithelial character throughout life. The embryo of the third week of gestation consists of an outer protective layer, the ectoderm, and an inner nutritive layer, the endoderm (future mucosa) and has received an intermediate third layer, the mesoderm. The mesoderm provides the material for the mesenchyme, which will differentiate into connective tissues, angioblasts, smooth muscle coats of the gut, and serous coverings. The mesoderm thickens, and by the 21st day of gestation it forms longitudinal masses, the paraxial mesoderm. Until the 31st embryonic day, this material segments progressively from craniad to caudad into cubes of tissue, the somites (Fig. 2-18). This event, together with the growth processes of the heart, brain, and tail that are differently directed and occur at different times, causes the increasing flexion of the primar-

3

7

5

9

S

8

FIGURE 2-18 Left, Formation of the intestinal tube in a human embryo (3 mm long, about 26 days old) with 13 paired somites (S) on scanning electron micrograph. Right, Matching schematic diagram is shown in longitudinal section. Somites are developing from the mesenchymal plate. Shown are the brain (1), foregut (2), buccopharyngeal membrane (3), stomodeum (4), pericardial coelom (5), heart (6), septum transversum (7), hindgut (8). and yolk sac cavity (9). Bar = 100 µm. (MICROGRAPH FROM JIRÁSEK JE: ATLAS OF HUMAN PRENATAL MORPHOGENESIS. NIJHOFF, BOSTON, 1982; DIAGRAM FROM HINRICHSEN KV: HUMAN EMBRYOLOGIE. HEIDELBERG, SPRINGERVERLAG, 1990, WITH KIND PERMISSION OF SPRINGER SCIENCE AND BUSINESS MEDIA.)

ily straight body axis of the embryo (see Figs. 2-17 to 2-19). It is also recognizable on these figures that because of the growth of the heart and head, due to the flexion and formation of the lateral body folds, a part of the yolk sac becomes “incorporated” into the body of the embryo, therewith forming the intestinal tubes. This event occurs during the fourth week (see Fig. 2-17). Successive growth processes and formation of a “body cylinder” until about the 28th day finally divide the yolk sac

19

20

Section 1 Introduction

h

pA S m

2

3

2

6

1 4

8 5

6 8 Ss

7

S

FIGURE 2-19 Progress of the intestinal development of a human embryo (10 mm long, 40 days old); the somite stage (S) and the pharyngeal arches (pA) are completed. The primordia of the limbs (8) are developed. Scanning electron micrograph (left) and schematic illustration (right) show an embryo of the same age with the foregut (1), primordium of the heart (2), lung buds (3), area of the future stomach (4), pancreatic buds (5), umbilical cord (6), and hindgut (7). This period represents the stage of greatest embryologic flexion. h, brain; m, stomodeum. (MICROGRAPH FROM JIRÁSEK JE: ATLAS OF HUMAN PRENATAL MORPHOGENESIS. BOSTON, NIJHOFF, 1983; DIAGRAM MODIFIED FROM HINRICHSEN KV: HUMAN EMBRYOLOGIE. HEIDELBERG, SPRINGER-VERLAG, 1990, WITH KIND PERMISSION OF SPRINGER SCIENCE AND BUSINESS MEDIA.)

into the intraembryonic part, which represents the origin of the aerodigestive tube (Fig. 2-19) and its derivatives, and into the extraembryonic part, which regresses and disappears around the 12th week. At this point, the early digestive system has divided into foregut, midgut, and hindgut (see Fig. 2-18). The upper endodermal tube is separated from the stomodeal cavity by the buccopharyngeal membrane up to a stage of 4-mm crown-rump length (26th day) (see Fig. 2-18). Then the membrane disappears by rupture.

C 10 mm SSL

50 mm SSL

py FIGURE 2-20 Macroscopic aspects of the human stomach at 14 mm (left) and 22 mm (right) crown-rump length (CRL). At 8 mm CRL the greater gastric curvature starts to undergo an asymmetric growth process, which becomes pronounced from 14 mm CRL on and culminates at about 22 to 25 mm CRL by forming the gastric fundus, the cardiac angulation (angle of His), and the esophagogastric junction. Both cardia (C) and pylorus (py) remain tied (arrowheads) by the stalk of the celiac and superior mesenteric vessels. Therefore, growth processes due to mitotic activity occur predominantly at the free mobile margin of the stomach (arrow), which is the greater curvature. (FROM LIEBERMANN-MEFFERT D: FORM UND LAGEENTWICKLUNG DES MENSCHLICHEN MAGENS UND SEINER MESENTERIEN. ACTA ANAT 72:376, 1969.)

Formation of the Esophagus: Development of Tissue Structures and Shape Initially, the foregut is a uniform tube (see Fig. 2-18). Its cranial part, the pharynx, gives rise to its derivatives, the pharyngeal pouches, the trachea, and lungs; the esophagus, the stomach (Figs. 2-19 and 2-20), and duodenum give rise to the choledochal duct, liver, biliary system, and pancreas.37,47,50 The esophagus, the middle segment of the foregut, is initially short; it extends from the tracheal groove (tracheal bud) to the site where the foregut widens to become the stomach (see Fig. 2-19). Increasing growth of the tissues of the esophagus, chiefly of its caudal portion, establishes the definite geographic relationships with the surrounding structures by the end of the seventh week (18 to 22 mm crownrump length).

Developmental Histology of the Musculature and Mucosa Tunica Muscularis The mesenchymal cells, which have derived from the mesoderm, give rise to the foregut musculature. Myoblasts and,

later, short muscle cells appear in the still undifferentiated mesenchyme on the outer aspect of the lumen of the esophageal tube in the form of a ring-shaped condensation of elongated nuclei in an embryo 8 to 10 mm in crown-rump length (Fig. 2-21A). They constitute the circular inner muscle layer of the lamina muscularis of the esophagus before the musculature appears in the gastric wall. In the esophagus of the 12.5-mm long embryo, fibers of the external longitudinal muscle layer become detectable. In the 13.5- and 23.5-mm long embryo the muscle layers have progressed (see Fig. 2-21). In a 23.5-mm embryo, fibers of the muscularis mucosae can be distinguished.

Tunica Mucosa and Esophageal Lumen The differentiation of the mucosa from the endoderm was identified by Johns in 1952 as early as in the 2.5-mm embryo, which is at about the third week of gestation.51 The mucosa is first composed of one single layer of short columnar epithelium in the 5- to 7-mm embryo; shortly thereafter, two

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

3 3 2 1 2

1 3

A

3

B 3

3

2 2

3

C

D

FIGURE 2-21 Cross section through the esophagus of embryos of 8.5 (A), 12.5 (B), 13.0 (C), and 23.5 mm (D) crown-rump length (CRL). The mucosal epithelium (1) is pseudostratified columnar in the 8.5-mm embryo, becomes multilayered by excessive proliferation, is vacuolized between 12.5 and 20.0 mm CRL, and is columnar ciliated at 25.0 to 30.0 mm CRL. The tissue around the mucosal epithelium is predominantly undifferentiated in the 8.5-mm embryo; beginning differentiation of the inner muscle coat is identified by the cell condensation (2). In the 12.5-mm and 20-mm embryos, the inner muscular layer is further advanced; the outer longitudinal layer and muscularis mucosae (arrows) can be identified at 20 to 25 mm CRL. The surrounding mesenchyme contains pale areas of neutral cells exterior to the tube (3) already at the early stage of 8 mm CRL. During this development the extrinsic innervation, in particular the vagus, has become conspicuous (3). The developmental changes of the luminal diameter and shape are due to disappearance of the vacuoles. (A, B, AND D, FROM THE AUTHOR’S COLLECTION; REPRINTED FROM LIEBERMANN-MEFFERT D, DURANCEAU A: ANATOMY AND EMBRYOLOGY. IN ORRINGER MB, ZUIDEMA GD [EDS]: SHACKELFORD’S SURGERY OF THE ALIMENTARY TRACT. THE ESOPHAGUS, VOL I, 4TH ED. PHILADELPHIA, WB SAUNDERS, 1996, P 33; C, FROM ENTERLINE H, THOMPSON J: PATHOLOGY OF THE ESOPHAGUS. NEW YORK, SPRINGER-VERLAG, 1984, BY PERMISSION.)

or three layers of pseudostratified columnar epithelium line the foregut of the 8.5-mm embryo (see Fig. 2-21). Subsequent changes of the mucosal epithelium are shown in Figures 2-21A to D and 2-22 and the events are described in the corresponding legends. Excessive cell proliferation followed by progressive cell autolysis and vacuolization in the 10- to 21-mm embryo alter the initially round or elliptical lumen to a narrow and later asymmetric bizarre lumen (Figs. 2-21D, 2-23, and 2-24). The changes are most distinct at the tracheal bifurcation and in the lower half of the esophagus. Innumerable small to very large confluent vacuoles—many containing debris—occur in

such a manner as to imply solid lumen occlusion. Longitudinal and cross-sectioned histologic series, however, show that the continuity of the lumen remains preserved (see Fig. 2-23).37 One of the first descriptions of the esophageal vacuoles was by Kreuter52 in 1905. He believed that esophageal atresia is the consequence of the closure of the lumen and that “recanalization” of the lumen in certain circumstances does not occur. Even though none of the subsequent investigators confirmed Kreuter’s claim, his ideas are still repeated in surgical and anatomic textbooks today. Because vacuolization of the esophageal mucosa takes place after the trachea and lungs are already fully developed,37 it has also been suggested that atresia of the esophagus may be due to growth defects of the esophagus and the trachea in conjunction with overgrowth of epithelium bulging into the foregut.50 With the disappearance of the vacuoles, the esophageal lumen widens again but retains the definite large longitudinal folds. The embryonic period terminates at the end of the 8th week when the essential structures are present. After the period of vacuolization, the stratified columnar epithelium is about four cell layers deep.51 In the 25-mm embryo, large dark cells appear in the basal epithelial cell layer of the middle third of the esophagus. The cells project toward the lumen to become ciliated columnar (see Fig. 222C) while progressing in a cranial and caudal direction. There is an interesting finding that ciliated cells develop within the stratified epithelium even when the esophagus has been explanted from early human fetuses and maintained in organ culture.53 In the 40- to 60-mm embryo, ciliated cells line the entire mucosa of the esophagus except for the upper and lower ends, where the epithelium is made up of a single layer of large columnar cells.51,54,55 The area of the columnar cells that are in continuity with the gastric mucosa is reduced in the 130-mm fetus, and the continuity with the gastric mucosa is lost at about the 140-mm stage. However, small discrete patches of columnar epithelium occasionally remain proximal to the esophagogastric junction and in the cervical esophagus until birth.54,56 The stratified squamous epithelium appears in the 90- to 130-mm fetus (see Fig. 2-22D). This epithelium also migrates from the middle third of the esophagus, spreading craniad and caudad until it has progressively and almost completely replaced the ciliated columnar epithelium in the 250-mm fetus.54,56 The first superficial acini-containing glands have been described in the 60-mm fetus. They are numerous in the 210-mm fetus and are located chiefly at levels of the cricoid cartilage and terminal esophagus.51,54,55 During the last 3 months of gestation, downgrowth of surface epithelium generates submucosal glands (see Fig. 2-22E). The shape of the esophageal lumen is largely dependent on the level of the position within the chest.

Formation of the Stomach The future stomach is located at the distal segment of the foregut; it appears as a crescent-shaped dilatation at the left

21

22

Section 1 Introduction

FIGURE 2-22 Cross sections through the esophagus at different stages of the developing mucosa. A, Single-layer short columnar epithelium (week 4 to 7). B, Extensive mucosal proliferation, luminal narrowing (center), and onset of vacuolization (upper corner of mucosa) (week 6 to 9). C, Ciliation of columnar cells (week 9 to birth). D, Onset of mucosal transformation into squamous cell tissue with goblet and polygonal cells (week 10 to birth). E, Downgrowth of surface epithelium to generate future submucosal glands (last trimester). (A-D, COURTESY OF THE AUTHOR; E, FROM ENTERLINE H, THOMPSON J: PATHOLOGY OF THE ESOPHAGUS. NEW YORK, SPRINGER-VERLAG, 1984, BY PERMISSION.)

A 50 µm µm

10 µm

B

C

D

E

and lateral (see Fig. 2-20A) and caudad to the septum transversum at the time when the tracheal diverticulum develops (weeks 5 to 6)37,57,58 (see Fig. 2-20B). The stomach is held constantly at this place by adherence to the celiac and pancreatic vessel stalks. They attach the future cardia and the pylorus to the posterior body wall.57,58 To explain the curvatures of the stomach, gastric rotation has been claimed by anatomists since the second half of the 19th century. Regardless of the fact that animals possess a completely different anatomy, the misinterpretation of a rotating stomach also in humans was spread through textbooks of human anatomy since then. In reality, the events are feigned by the asymmetric growth processes within the gastric wall. This feature was proved by the increased asymmetric mitotic activity of the stomach. In human control subjects no evidence has been presented of either esophageal or gastric

mechanical rotation.35,56,59,60 With the extensive growth of the gastric fundus, the esophagogastric junction, which is initially ill defined (see Fig. 2-20), becomes clearly delineated.6,56-58 Individual variations in the height of the fundus and the acuteness of the cardiac angle persist during the fetal period.

ESOPHAGEAL TISSUE ARCHITECTURE AND HISTOLOGY Apart from the lack of a serosal coating, the construction of the esophagus parallels the basic plan of the tissue organization of the digestive tube. It consists of the following four layers: 1. External fibrous layer (adventitia) 2. Intermediate muscular layer (muscularis)

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

6

5 4 7 2

2 1 8 3 1

3

2 2

3

50 µm µm mm 160E so #27 FIGURE 2-23 Developing diaphragm and vacuolization of the esophageal mucosa. Left, The longitudinal section through this 15mm crown-rump length embryo shows the anchoring structures at the esophagogastric junction with developing diaphragmatic musculature (1), the undifferentiated mesenchymal tissue (2), and primitive phrenoesophageal membrane (3). The section also displays the numerous vacuoles (4) located within the mucosa narrowing the esophageal lumen (5), the pleural cavity (6), the developing musculature of the esophagus (7), and the liver (8). The cardia is out of the cutting level and therefore not displayed. Right, Histologic cross section through the esophagus lumen (1) and two vacuoles (2) in the proliferated mucosa (hematoxylin and eosin stain). (LEFT, COURTESY OF

FIGURE 2-25 Arrangement of the muscle fibers at the pharyngoesophageal junction from the posterior and left lateral aspects. Structures seen are the inferior pharyngeal constrictor muscles (1), pharyngeal crossing muscles (2), cricopharyngeal muscles (3), which represent the upper esophageal sphincter (UES), the circular esophageal muscle (4), and thyroid gland (5). (DRY FIBER SPECIMEN COURTESY OF THE AUTHOR.)

FERNANDEZ DE SANTOS, MD, MADRID; RIGHT, SPECIMEN COURTESY OF THE AUTHOR.)

4 1 3

2

FIGURE 2-24 Histologic cross section through the midesophagus (1), trachea (2), and vagus nerve (3) of a human embryo of 23-mm crown-rump length. Both organs lie next to each other within the undifferentiated mesenchyme (4). No firm partition exists. This feature does not change in adulthood. (SPECIMEN COURTESY OF THE AUTHOR.)

3. Intermediate submucous layer (submucosa) 4. Internal mucous layer (mucosa)

Tunica Adventitia Composed of loose connective tissue, the adventitia covers the esophagus and connects it with neighboring structures. The periesophageal tissue contains small vessels, lymphatic channels, and nerve fibers.

Tunica Muscularis The laryngopharynx (Figs. 2-25 and 2-26) is covered posteriorly by the pharyngeal constrictor muscles. The layer is

suspended from the bony structures at the base of the skull, the hyoid bone, and the thyroid and cricoid cartilages. Consisting of the three bilateral constrictors, their muscle bundles spread obliquely upward (see Figs. 2-25 and 2-26). There the muscle bundles of the opposite sides intersect before inserting into the submucosa.42 The most caudal of these muscles, the inferior constrictor muscle, consists of two parts: the first is the bilateral oblique thyropharyngeal muscle, which overlaps the pharyngeal constrictors; the second part, the cricopharyngeal muscle, is a transverse muscle sling. The different arrangement illustrated in Figures 2-25 and 2-26 leaves a triangular area of sparse musculature that is known as Killian’s triangle.61 The cricopharyngeal muscle is suspended between the cricoid processes; it is 3 to 4 mm thick, surrounds the narrowest part of the pharynx, and extends for 1 to 2 cm caudad before blending with the circular muscle of the esophagus (see Figs. 2-25 and 2-26). The cricopharyngeal muscle and up to 2 cm of the cervical esophagus contain predominantly muscle tissue of the striated type.37,62,63 Occasionally, isolated small smooth muscle bundles are found within these muscles. Smooth muscle tissue appears first in the circular muscle layer and in the anterior wall. In a caudal direction, the smooth muscle content in the lamina muscularis increases in the same proportion as the striated muscle decreases (Figs. 2-27 and 2-28). The transition between striated and smooth muscle is neither abrupt nor restricted to individual muscle bundles, and both converge gradually without any distinct anatomic septum. Finally, only isolated striated fibers remain in the midst of smooth muscle units (see Fig. 2-27). The transition is completed in the end of the upper half of the esophagus.62

23

24

Section 1 Introduction

Inferior constrictor muscle Raphe

Cricoid cartilage Cricopharyngeal muscle

V – shaped area of: – Killian – Laimer

Longitudinal muscle of esophagus

Trachea

FIGURE 2-26 Diagram of muscular architecture of the pharyngoesophageal junction, which is the region of the upper esophageal sphincter. The two triangular areas of sparse muscle cover are shown in white. Zenker’s diverticulum arises from the upper weak area from Killian’s triangle.

When the esophageal length is defined as 100%, using the cricoid cartilage as a landmark, the transition between the two muscle types is completed in 40% of the total length (see Fig. 2-28).62 In the neonate and the fetus, we found the transition to be located slightly more caudad. Below the tracheal bifurcation, no striated muscle cell was ever found in the esophageal wall of my specimens of human fetuses and adults.62 The muscularis mucosae of the esophagus is composed entirely of smooth muscle fibers. The tubular esophagus consists of two muscular layers. They support the lumen of the esophagus and are responsible for its propulsive function. The fibers of the external layer parallel the longitudinal axis of the esophagus; those of the inner layer follow a horizontal plane (Fig. 2-29). The longitudinal muscle layer originates bilaterally from the dorsal plane of the cricoid cartilage. Again, this creates the area of sparse musculature described by Laimer in 188364 (see Fig. 2-26). Subsequently, the muscle bundles join and course straight down the entire esophagus before converging in a more oblique plane along the anterior and posterior gastric wall.65 The circular muscle layer begins at the level of the cricoid cartilage (see Figs. 2-25 and 2-26); in descending it forms incomplete circles.65 Both the longitudinal and the circular muscle layers have an equal thickness of only 1 to 1.5 mm throughout the esoph-

FIGURE 2-27 Smooth and striated muscular components at the esophagus. Longitudinal (top) and transverse (bottom) histologic sections through the lower area of the cranial third of the human esophagus. At this level the muscular tissue consists mainly of smooth muscle (1) with interwoven striated muscle fibers and bundles (2). One single striated cell within the smooth muscle tissue is quite common as is shown (hematoxylin and eosin stain). (FROM LIEBERMANNMEFFERT D, GEISSDÖRFER K: IS THE TRANSITION OF STRIATED INTO SMOOTH MUSCLE PRECISELY KNOWN? IN GIULI R, MCCALLUM RW, SKINNER DB [EDS]: PRIMARY MOTILITY DISORDERS OF THE ESOPHAGUS: 450 QUESTIONS—450 ANSWERS. PARIS, LIBBEY EUROTEXT, 1991, P 108).

FIGURE 2-28 Location and proportional content of striated and smooth muscle in the esophagus.

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

Esophagus Fundus

Esophagus

ibe ef

Circular fibers

rs

Circular fibers (middle layer removed)

liqu

Diaphragm

Ob

Semicircular fibers and clasps

Stomach FIGURE 2-29 The muscular structures at the cardia. The arrangement of the muscle fibers at the esophagogastric junction with outer longitudinal (left) and inner circular layer (right) is exposed. The outer longitudinal layer is composed of multiple muscle bundles following a straight downward orientation. The fibers rarely converge but occasionally split as a result of entering vessels or nerves. Beyond the esophagogastric junction the esophageal muscle becomes continuous with the superficial longitudinal bundles of the stomach. Bundles from the right side of the esophagus pass along the lesser curvature; those from the left follow the summit of the fundus along the greater curvature. Bundles from the anterior and posterior esophageal surface, however, fan out and pass to the corresponding gastric surface to blend with the fibers of the underlying luminal muscular layer of the gastric fundus. The inner muscular layer, the semicircular fibers of the esophagus, are found to reorganize to form two components: the short muscle clasps on the lesser curvature side (arrows) and the condensed oblique gastric sling fibers. These hook around the angle of His, then run down the anterior and posterior gastric walls before they turn toward the greater gastric curvature. The clasps and the cranial gastric sling form an oblique muscular ring that accounts for the counterpart of the functional lower esophageal sphincter and is the anatomic lower esophageal sphincter. (FROM DURANCEAU A, LIEBERMANN-MEFFERT D: EMBRYOLOGY, ANATOMY AND PHYSIOLOGY OF THE ESOPHAGUS. IN ORRINGER MB, ZUIDEMA GD [EDS]: SHACKELFORD’S SURGERY OF THE ALIMENTARY TRACT, VOL 1. THE ESOPHAGUS, 3RD ED. PHILADELPHIA, WB SAUNDERS, 1991, P 3.)

agus; no change occurs with age.46 Approximately 3 cm cranial to the junction with the stomach, however, the increasing number of muscle fibers of the inner layer produces a progressive muscular thickening (Figs. 2-30 and 2-31). The fibers at the side of the lesser curvature retain their previous direction to become the short muscle clasps57,65 seen in Figure 2-29; those at the greater gastric curvature side change to become oblique gastric sling fibers.

cricoid cartilage during contraction. This coincides with the fact that the UES, as every endoscopist knows, is not circular.69 Hiebert has reported that the cricopharyngeal muscle may be seen as an indenting band with palpable boundaries during surgery.70 This statement also coincides with the radiologic view of Donner and colleagues71 that the UES is “synonymous with the transverse portion of the cricopharyngeal muscle.”

What Is a Sphincter?

Lower Esophageal Sphincter

Anatomically, a sphincter is understood as “a circular or annular muscle surrounding an opening”66 or “a ringlike band of muscle fibers that constricts a passage.”67 Sphincters divide the gut into functional segments and are characterized by a resting tone that is higher than that in the adjacent segments.

The existence of the LES, an anatomic sphincter between the esophagus and stomach, has been both accepted and denied for a long time.66,72 The dilemma is that no circular structure comparable to that at the pylorus exists. All the same, with the discovery of a high-pressure zone at the esophagogastric junction in 1956 by Fyke and colleagues73 and its establishment almost simultaneously in 1967 by Pope74 and by Winans and Harris,75 the presence of a physiologic sphincter at the lower end of the esophagus became undebatable. In fact, such higher pressures are present in the preterm infant from the 27th week of gestation.76 Approaching the lower end of the esophagus, the inner muscular layer gradually increases in thickness across the junction with the stomach (see Fig. 2-30). It is not an eyecatching thickening, and the soft LES is difficult to palpate.

Upper Esophageal Sphincter The UES refers to a 2- to 3-mm zone of elevated intraluminal pressure existing between the pharynx and the cervical esophagus. Winans, in 1972, described an asymmetric resting pressure both axially and radially.68 This means the higher pressure values are recorded anteriorly and posteriorly on the pressure tracing. Winans attributed this event to a flattening of the cricopharyngeal muscle against the ventral plane of the

25

Section 1 Introduction

MUSCULAR THICKNESS ACROSS THE ESOPHAGOGASTRIC JUNCTION mm 2.1±0.6

2.0±0.6

2.6±1.0 3.4±1.2 3.8±1.3 4.2±1.4 3.4±0.8

2.4±0.9 2.8±1.0 3.4±1.0 3.7±1.3 2.3±0.6

20

GC sm–m mp

mm n = 32

PW

0

50 mm

26

1.9±0.7

0

1.8±0.6

20

20

20

30 20

30 20 mm LC

2.0±0.5

FIGURE 2-30 Longitudinal section through the esophagus, esophagogastric junction, and stomach of a formaldehyde-fixed specimen. The progressive, slow increase and decrease of muscular thicknesses across the esophagogastric junction is shown. Measurement values are given on the scheme. Thickening shows an axial and radial asymmetry with maximum at the greater curvature. The values are averaged from 32 human kidney donor specimens. (MICRODISSECTED AND MEASURED SPECIMENS COURTESY OF THE AUTHOR.)

Nonetheless, it is twice the 2-mm thickness of the esophageal and gastric musculature (see Fig. 2-30). In this context, one may remember that the LES pressures range from 14.5 to 34 mm Hg or less,77 whereas for the thicker UES the range is between 30 and 142 mm Hg.75 A reorganization of the muscle bundles at the terminal esophagus, in particular those of the inner muscle layer that form the “chassis” of the LES (see Fig. 2-29), is consistent with the change of muscle thickness. The semicircular muscle fibers toward the greater curvature augment and are continued by the gastric sling fibers, which extend upward into the esophagus (see Figs. 2-29 and 2-31).65 It has been suggested by Bombeck and coworkers78 that these fibers exert an antireflux effect at the angle of His. On the lesser curvature side, the semicircular bundles of the esophagus continue to become the short muscle clasps,65 which, by their anchorage in the tissue along the medial margin of the oblique gastric sling fibers (see Fig. 2-29), contract in a ring-shaped fashion. The muscular arrangement and the corresponding thickening extend upward for 3 to 4 cm and pass beyond the distal end of the esophagus into the stomach wall for another 1 to 2 cm. This extension of the specialized muscle structure is identical to the length given for the functional sphincter.75,77 Axial and radial asymmetry of the sphincter, as shown when using conventional perfusion manometry techniques75,77 or three-dimensional imaging,79,80 coincides with the circumferential difference in muscle architecture (see Figs. 2-30 and 2-31). The LES has been assumed to be positioned at the level of the diaphragm.14 The muscular structures described earlier are, however, precisely located at the junction to the stomach and at the transition line of the esophagus into gastric folds.65,81,82

0

mm

20

0 AW

2.1±0.7

30

20

FIGURE 2-31 Schematic illustration showing the correlation between radial thickness of the musculature (left) and three-dimensional manometric pressure image (right) at the human esophagogastric junction. The thickness across the junction is given in millimeters at the lesser curvature (LC), anterior wall (AW), greater gastric curvature (GC), and posterior wall (PW). Radial pressures at the junction (in millimeters of mercury) are plotted around an axis representing atmospheric pressure. The left side of the positive-pressure image corresponds with the lesser curvature, the right one with the greater curvature. Asymmetry of the sphincter is apparent. sm-m, (submucosa). mp, (muscularis propria). (FROM STEIN HJ, LIEBERMANNMEFFERT D, DEMEESTER TR, SIEWERT JR: THREE-DIMENSIONAL PRESSURE IMAGE AND MUSCULAR STRUCTURE OF THE HUMAN LOWER ESOPHAGEAL SPHINCTER. SURGERY 117:692, 1995. COPYRIGHT 1995, WITH PERMISSION FROM ELSEVIER.)

Several points favor the functional muscular structure as constituting the LES. Combined radiomorphologic motility studies using wall markers localized the high-pressure zone to the site of muscular thickening.15 Disruption of the junctional musculature by partial or total myotomy or myectomy78,83 significantly reduced or abolished LES pressure values. When muscle of the junction is put into a bath, it maintains tonic contraction, whereas the esophageal muscles from levels just above or below do not.83,84 Enterline54 reported on similar results when he applied electric stimulation to respective muscle strips.

Existence of a Lower Esophageal Sphincter (LES): What Is Indisputable? Why? The LES musculature: ■ ■ ■ ■ ■ ■ ■ ■ ■

Produces a zone of high pressure Is positioned at the esophagus and stomach Acts as a two-way sphincter (forward and retrograde) Does not attract attention Has pressures that are relatively low Is not a muscle structure that is easy to palpate Retracts when cut open in vivo Is not an eye-catching muscle thickening Is of asymmetric pseudocircular muscle architecture

Tela Submucosa The submucosa consists of loose connective tissue and contains elastic and collagen fibers, fine blood vessels, networks

Chapter 2 Clinically Oriented Anatomy, Embryology, and Histology

of lymph channels, nerves, and the deep mucous glands. Esophageal glands are small branching glands of mixed type; their ducts penetrate the muscularis mucosae.

Tunica Mucosa The surface of the esophageal mucosa is reddish in its cranial portion and becomes paler toward the lower third of the esophagus. The smooth esophageal mucosa can be easily distinguished from the dark mammillated gastric mucosa. The mucous layer facing the esophageal lumen consists of the muscularis mucosae, the tunica propria, and the stratified squamous epithelium. The muscularis mucosae is a continuous layer of interlacing smooth muscle bundles. At rest, it folds the lumen into three or four large longitudinal folds. At the lower end, at the last 2 to 3 cm of the terminal esophagus, it has a greater number of small transversely rippled folds.65,85 On distention of the lumen, all these folds disappear. The tunica propria mucosa consists of elastic and collagenous fiber networks and projects into the epithelium to form the papillae. The hypopharynx mucosa contains exclusively alveolar serous glands, whereas the esophageal glands are tubular, small, of mucous type, and lodged exterior to the muscularis mucosae. The hypopharynx mucosa also contains lymph channels, follicles, and esophageal glands of mucous type or, in the terminal esophagus, glands that resemble cardiac glands. Cardiac mucosa is considered to be a small area of specialized columnar cells a few millimeters long between the squamous epithelium and normal oxyntic mucosa.86 Chandrasoma and associates87 stated “cardia mucosa is a histologically defined term used for a mucosa in the gastrointestinal junctional region that contains only mucous cells being devoid of parietal and goblet cells.” Normally located in the vicinity of the gastroesophageal junction, it is not a normal finding when present in the esophagus.87 Whether the cardia mucosa is a normal feature or an acquired condition caused by chronic reflux of gastric content as Chandrasoma87 suggested is still disputed.88 A layer of stratified, nonkeratinizing squamous epithelium,

which is positioned on the lamina propria, covers the inner surface of the esophageal lumen.

Comments on Clinical Relevance and Consequence The mucosal transition at the squamocolumnar junction is an objectively recognizable reference point for endoscopists.69 On fresh anatomic specimens, it is seen as an abrupt demarcation line that shows several small long or short tongues of squamous epithelium toward the esophagus. The transition, known as the Z line, is normally located near the gastric orifice or just above it.69 Endoscopic determination is based on differences in color, transparency of the epithelium, mucosal structures, and the epithelial thickness. Any proximal extension of a stomach-like or intestine-type columnar epithelium is considered pathologic and is attributed to longstanding reflux of gastric content that causes chronic, severe esophageal damage.

COMMENTS AND CONTROVERSIES This chapter on esophageal embryology, anatomy, and histology has its roots in observations by the author on human studies rather than from information taken from standard anatomic textbooks. Text and references are updated from the first edition. Clinically relevant points are emphasized. J. D. L.

KEY REFERENCES Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Philadelphia, WB Saunders, 1988. Partsch H (ed): Progress in Lymphology XI. New York, Excerpta Medica, 1988. Skandalakis JE, Colborn GL, Weidman TA, et al (eds): Surgical Anatomy: The Embryologic and Anatomic Basis of Modern Surgery. Athens, Paschalidis Medical Publications, 2004, vol I. Tilanus HW, Attwood SEA (eds): Barrett’s Esophagus. Boston, Kluwer Academic, 2001. Warwick R, Williams PL (eds): Gray’s Anatomy, 35th ed. Edinburgh, Longman, 1978.

27

chapter

3

PHYSIOLOGY OF THE ESOPHAGUS AND CLASSIFICATION OF ESOPHAGEAL MOTOR ABNORMALITIES André Duranceau

Every voluntary swallow initiates an organized sequence of events that can be divided into three major phases: the oral, pharyngeal, and esophageal phases. During the voluntary oral phase the sweeping action of the tongue pushes the bolus on the hard palate, propelling it backward into the pharynx. The pharyngeal phase of deglutition then becomes involuntary. Tactile receptors in the pharyngeal wall elicit a series of reflex muscle activities controlled by the medullary swallowing centers. These centers stimulate directly the striated muscle motor units of the oropharyngeal musculature. Innervation is carried by the pharyngeal branches of the vagus and the cricopharyngeus branches of the recurrent laryngeal nerves.1,2

PHARYNGEAL PHASE The pharyngeal phase of swallowing is best described by these six events, which occur sequentially: 1. When the bolus is in the oral cavity, the soft palate is apposed to the posterior portion of the tongue, closing the oropharynx. 2. Elevation of the soft palate and of the hyoid bone occurs while the whole pharynx is raised in a piston-like motion. 3. Active compression of the tongue on the bolus pushes it against and along the hard palate toward the entrance of the oropharynx. The soft palate elevates posteriorly and apposes the constrictor wall, closing the nasopharynx. When the bolus passes the limits of the oropharynx, involuntary deglutition occurs and the descending wave of peristalsis begins. 4. The hyoid bone reaches maximal elevation, and the larynx elevates to approach the hyoid. At this point, the laryngeal vestibule closes and the epiglottis tilts downward while pharyngeal peristalsis descends toward the hypopharynx. 5. With pharyngeal contraction, approximation of the pharyngeal wall, soft palate, and posterior tongue creates a closed chamber where the bolus is squeezed into the hypopharynx and through the open cricopharyngeal sphincter. 6. The pharyngeal airway reopens, and the soft palate, tongue, larynx, and hyoid bone return to their resting positions. The epiglottis springs back to a vertical position, and the laryngeal airway reopens when the pharyngoesophageal junction closes and resumes its elevated resting pressure.3 In the hypopharynx, when the pharyngeal wall is collapsed and no air column exists, resting pressures increase progressively to a maximal pressure at the level of the cricopharyn28

geal muscle. On swallowing, pressure recordings show an initial double pressure peak corresponding to the elevation of the laryngopharynx and the simultaneous thrust of the tongue. Peak pharyngeal contraction follows these two initial waves; it is a peristaltic sequence starting radiologically as a stripping wave with closure of the velopharyngeal muscles, and it empties the pharyngeal contents toward the hypopharynx. In the hypopharynx, the same small double peak is identified on swallowing and is attributed to the upward laryngeal movement, the tongue thrust, and the progression of trapped air or the advancing bolus. Accurate recording of pharyngeal motor events is not possible using a water-filled or a water-perfused system. For these reasons, Dodds and associates studied human pharyngeal motor function in 12 recordings using an intraluminal strain gauge system.4 They observed that the pressure was highest in the hypopharynx, with pressure amplitudes on contraction averaging 200 mm Hg. Peak contractions reached 600 mm Hg in one subject. Contraction pressures averaged 100 mm Hg in the oropharynx and 150 mm Hg in the nasopharynx. The wave duration decreased progressively from nasopharynx to hypopharynx from 1.0 to 0.3 second, and the peristaltic wave speed ranged between 9 and 25 cm/sec (Fig. 3-1). Observations by Kahrilas and associates5,6 and Castell and colleagues7 confirm the difficulties in obtaining precise information on pharyngeal function.

ESOPHAGEAL PHASE The esophageal phase consists of the bolus transport from the hypopharynx to the stomach. This phase results from the peristaltic action pushing the bolus through the opened upper esophageal sphincter (UES) along the whole esophagus body and across the opened lower esophageal sphincter (LES).

Upper Esophageal Sphincter The UES is a high-pressure zone that separates the pharynx from the esophagus. Its most important role may be to prevent esophagopharyngeal reflux. Because gastroesophageal reflux does occur in normal individuals, the sphincter may also prevent the regurgitation of gastric contents into the pharynx. The sphincter may also have a role in preventing the entry of air into the esophagus. Sokol and coworkers reported that between the end of the air column of the pharynx and the negative intrathoracic pressure there is a high-pressure zone 2.5 to 4.5 cm in length.8 Within this zone is a shorter high-pressure zone 1 cm long of maximally elevated pressure that corresponds to the location of the cricopharyngeus muscle (Fig. 3-2). The cricopharyn-

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

DS

DS

mm Hg

40

Pharynx

mm Hg

40

20

20

0

0

mm Hg

5 sec FIGURE 3-1 Pharyngeal contraction is short and travels rapidly toward the hypopharynx and the upper esophageal sphincter. DS, dry swallow.

UES

100

50

Upper Esophageal Sphincter Profile 0 2 1

–1 Cricoid cartilage

40

Sokol,1966 Kahrilas, 1988

–2 Cook, 1989 –3 –4

FIGURE 3-2 The cricopharyngeus is the major component of the upper esophageal sphincter. The pressure profile of the sphincter, however, extends more proximally over a 2- to 3-cm width.

geus is a muscle sling attached posteriorly to both laminae of the cricoid cartilage. It exerts its maximal pressure in an anteroposterior direction, closing the pharyngoesophageal junction and forming a crescentic slit seen at rigid esophagoscopy as the upper limit of the esophagus. It is generally agreed that the cricopharyngeus is the major component of the UES. This muscle is approximately 1 cm long, however, and, thus, it cannot account totally for the 2- to 3-cm width of the high-pressure zone of the UES recorded in several studies (see Fig. 3-2).2,8-11 The pressure profile of the UES was studied by Winans when he assessed the pharyngoesophageal high-pressure zone of 18 humans.12 He used a special eight-lumen recording catheter with recording orifices spaced around the circumference of the catheter. He observed significant pressure differences related to the position of the recording port, and this

mm Hg

0

Proximal esophagus

Vocal cords

20

0

5 sec FIGURE 3-3 Function of the normal pharyngoesophageal junction. The pharynx contracts with a single peak lasting 0.2 to 0.5 second. The upper esophageal sphincter (UES) is a high-pressure zone at rest that relaxes to cervical esophageal baseline pressure. Passage of the pharyngeal wave toward the cervical esophagus provides sphincter-closing pressures. Primary peristalsis then appears in the infrasphincteric portion of the proximal esophagus. DS, dry swallow.

led to the concept of sphincter asymmetry. In the UES, the greatest pressures (averaging 100 mm Hg) were recorded from the anterior and posterior orifices. In 1978, Asoh and Goyal13 showed that the UES is a high-pressure zone created mainly by the cricopharyngeus and the inferior pharyngeal constrictor. They observed that its asymmetry is not only radial but also axial (Figs. 3-3 and 3-4; see also Figs. 3-1 and

29

30

Section 1 Introduction

WS

WS

WS

25 cm

40

20

WS

WS

WS

0

35 cm

100

mm Hg

30 cm

40

50

0 20

40 cm

0

50

0

40

100 20 45 cm

35 cm

mm Hg

100

50

0 0

25 sec

A

25 sec

B

FIGURE 3-4 A, Normal peristalsis in the proximal esophageal body, after voluntary deglutition of a water bolus. The wave travels aborally (away from the mouth) and is seen as it passes by each recording port. B, Normal peristalsis in the distal esophagus, just above the lower esophageal sphincter. When interpreting propulsion, the upstroke of the contraction is seen as the onset of the tightening of the esophageal muscle over the proximal part of the swallowed bolus. WS, wet swallow.

3-2). Representative studies reveal great variability in UES pressure values, and even at the present time it is difficult to define normal pressure ranges for the UES.5,6 On swallowing, the UES high-pressure zone falls to resting atmospheric pressure and remains open to accommodate bolus transport through the sphincter area. This relaxation occurs simultaneously with the vertical upward displacement of the larynx, which pulls the upper sphincter anteriorly for about 2 cm. Full sphincter relaxation is observed for 0.5 to 1.2 seconds, and, with the passage of the hypopharyngeal

contraction, the sphincter closes with a contraction that creates a pressure that is often twice as high as the resting pressure in the sphincter (Fig. 3-5). This contraction occurs with progression of the pharyngeal contraction as primary peristalsis into the cervical esophagus. Physiologic evaluation of the UES is problematic. The technical aspect of manometric recordings hampers the sensitivity and specificity of interpreting function at the pharyngoesophageal junction. The single side-hole catheter recording does not take into account the sphincter asymmetry. The

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

FIGURE 3-5 The three types of contractions in the esophagus. The primary wave is the normal response of the esophagus to voluntary swallowing. The secondary wave is a normal peristaltic wave that occurs in response to distention or irritation. The tertiary wave is nonpropulsive. It occurs in response to swallowing or appears spontaneously. WS, wet swallow.

WS

20

20

40

40

40

20

20

mm Hg

0

35 cm

0

mm Hg

0

41 cm

20

0

0

0

40

40

40

20

0

40 cm

mm Hg

20

40 30 cm

36 cm

40

46 cm

46 cm

41 cm

36 cm

40

20

0

20

0

25 sec PRIMARY WAVE

SECONDARY WAVE

eight-lumen circumferential recording catheter does not follow the upward movement of the sphincter when swallowing occurs. Circumferential pressure–sensing transducers can provide direct measures of the circumferential squeeze by the sphincter, but here again the upward movement of the sphincter does not allow for proper assessment of relaxation and coordination. Castell and coworkers proposed positioning the recording sensor above the high-pressure zone of the sphincter for that purpose, allowing the opened sphincter, in its upward excursion, to be studied.14-17 A manometric recording device was proposed by Dent and adapted to the upper sphincter by Kahrilas and colleagues.9,18 This is a sleeve concept that records UES pressures despite its movement during deglutition. They used the sleeve sensor to monitor pressures in the UES for prolonged periods of time. Compared with conventional manometric recordings, the sleeve method showed lower UES pressures and less variability between subjects, thus suggesting that the sleeve method for recording creates less stimulation to the sphincter during recording. The sleeve recording of UES function also showed less susceptibility to axial movement. During these long-term recordings, the basal resting pressures of the UES showed a range of 16 to 118 mm Hg, with an overall mean of 42 mm Hg. Pressures before a meal (45 mm Hg) did not vary from pressures after a meal (43 mm Hg). From these values, resting UES pressures fell to 20 mm Hg during stage 1 sleep and decreased further to 8 mm Hg during deep sleep.

TERTIARY WAVE

Arousal is associated with an abrupt increase in UES resting pressure. Similarly, sleep decreases the swallowing rate from a mean of 1.6/min during wakefulness to 0.24/min during stage 1 sleep and to 0.06/min during deep sleep. The evaluation of UES relaxation and its coordination with pharyngeal contraction remains difficult. When belching is studied, the UES responds to esophageal body distention in two distinct ways: abrupt relaxation occurs when the esophagus is distended with air boluses, and a pressure increase is seen when fluid boluses are used to distend the esophagus. Gerhardt and coworkers showed that the UES responds to the stimulus of intraesophageal volume.19 They also showed that it responds to an intraluminal acid stimulus to a degree greater than can be explained by its volume effect alone. UES pressure is not altered by changes in osmolality of the infused fluids during short-term infusion. Its response to intraesophageal acid infusion is dose dependent: acid delivered at increasing rates into the esophagus evoked incremental increases in the UES resting pressure. Kahrilas reported, however, that acid reflux exerted no influence on UES tone.20

UES Control Mechanisms The high-pressure zone of the UES has been attributed to continuous active muscle contraction and to the elasticity of the surrounding structures. At rest, the cricopharyngeus is a

31

32

Section 1 Introduction

striated muscle that receives its motor nerves from the vagal nuclei through the vagi and without synaptic interruption. The nerve endings come into direct contact with the motor end plates, and a continuous vagal discharge maintains the tonus of the sphincter at rest. On swallowing, a sequence of relaxation involving pharyngoesophageal muscle groups was thought to be caused by disappearance of the action potentials in the muscle fibers. The forward and upward displacement of the larynx is also involved in the opening mechanism of the sphincter. Although there is a general agreement that the cricopharyngeus is the major component of the UES, its wider pressure zone as observed in various reports must be explained by other factors: the passive elastic forces may maintain a closed UES.2 If the nervous supply to the sphincter is removed, residual closing pressures remain. The circular muscle of the pharyngoesophageal junction may also play a role. Recent reassessment of UES function suggests that the tone of the UES may, in fact, be generated by various reflex responses and muscle mechanisms rather than by specific tone-generating circuitry of the brain stem.1

Esophageal Body The muscle layers of the esophagus show a distribution that stems from their embryologic origins: the striated muscle of the upper esophagus is derived from the branchial arches whereas the smooth muscle is derived from the splanchnopleuric mesoderm. In the adult, the most proximal portion of the esophagus shows mostly striated muscle fibers. In the following 6 to 8 cm the muscularis contains progressively more and more smooth muscle fascicles in both layers. Below the tracheal bifurcation only smooth muscle fibers are found in the circular and longitudinal layers. The transition between both types of muscle cells is not abrupt and there is no distinct anatomic separation.21

Neurogenic Control of Esophageal Peristalsis The striated portion of the esophagus is innervated by direct stimulation of the muscle cells by axons emerging from the nucleus ambiguus of the swallowing centers. Motor innervation of the smooth muscle esophagus is different and more complex than that of the striated esophagus, because it is made of extrinsic and intrinsic components. The extrinsic component is located in the dorsal motor nucleus of the vagus. The axons of these nerve cells travel through the vagi and synapse with postganglionic nerve cells in the myenteric plexus, the intrinsic component. The esophageal musculature is not tonically contracted at rest. Swallowing induces vagal stimulation that can either excite or inhibit both the longitudinal and circular esophageal musculature, depending on which myenteric plexus neurons are activated. Inhibition neurons affect predominantly the circular muscle layer via nitric oxide nerves, and this inhibition is prolonged progressively toward the distal esophagus.22,23 Excitation myenteric plexus neurons mediate contraction of both muscle layers via cholinergic receptors. Mittal and associates24 found a fine coordination between the two muscle

layers’ stimulation: the longitudinal muscle contraction provides biomechanical advantages to the circular muscle contraction by increasing its thickness, which in turn increases the force generated by its contraction. Primary peristalsis is triggered voluntarily by swallowing but thereafter is not under voluntary control (see Figs. 3-4 and 3-5). Not all peristaltic waves are complete in normal subjects. In response to dry swallows, complete waves occur on only approximately two thirds of occasions. Specific patterns can be observed, such as the peristaltic “fade out” at the aortic arch level. Tertiary contractions in the distal esophagus can also be recorded in response to swallows. Water swallows produce more complete peristaltic sequences.5,6,25-27 Other factors that may influence primary peristaltic activity are posture and age: a decrease in amplitude is seen in persons older than the age of 80 years, as reported by Hollis and Castell,28 Kaye and Wexler,29 and Grande and associates.30 Electronic topographic esophageal manometry has described unrecognized segments in the normal functioning esophagus by using an increased number of sensors and by displaying three-dimensional representation of peristalsis.31 The esophageal wave travels down the esophageal body at a speed of 2 to 5 cm/sec. The wave of contraction that occurs in response to deglutition progresses slowly in the proximal striated muscle area. It slows further at the striated-smooth muscle junction and then accelerates in the lower one half of the esophagus, except just above the LES where it is seen to slow again (see Fig. 3-4). In similar fashion, peak contraction pressures are weaker in the striated esophagus and stronger in the distal esophagus. The values obtained in recording esophageal body motility vary from author to author, and the influence of different recording techniques is well documented. Peristaltic sequences can also be modified by the rate of swallowing. Swallows at 5-second intervals or less tend to inhibit peristalsis completely; only when swallows are taken at greater than 30-second intervals do completely normal sequences occur.32,33 Secondary peristalsis refers to peristaltic waves that are not controlled by swallowing but usually are in response mostly to esophageal distention or irritation. These secondary waves, which should be seen as an important defense mechanism during sleep or when exposed to irritant material, probably have a “housekeeper” role in clearing refluxed material from the esophagus (see Fig. 3-5).34 Tertiary contractions (Figs. 3-6 and 3-7; see also Fig. 3-5) can be considered abnormal contractions when occurring in response to swallowing (see Fig. 3-6), or they can appear spontaneously between swallows (see Figs. 3-6 and 3-7). Rubin35 suggested a relationship between esophageal motor disorders and the emotional states of patients during recordings. Nonpropulsive contractions and repetitive spontaneous contraction were observed when motor function of the esophageal body was recorded during “affectively charged conversation.” Spontaneous tertiary contractions occur in healthy individuals but are observed more often in patients with a strongly anxious personality (see Fig. 3-20).

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

WS

40

WS

40

40

20

20

0

0

20

0

40 mm Hg

20

40

20

0

0

40

40

20

20

0

0

mm Hg

mm Hg

40

20

0

40 25 sec

25 sec

A

B

FIGURE 3-6 A, Single tertiary contraction in response to a voluntary swallow. B, Repetitive nonpropulsive activity after deglutition. WS, wet swallow.

Lower Esophageal Sphincter It is now accepted that there is both a physiologic LES, as emphasized by Dodds and coworkers36 and an anatomic LES, as documented by Liebermann-Meffert and colleagues.37 The maintenance of a basal tone in the LES is the major mechanism preventing gastroesophageal reflux (Fig. 3-8). Winans38 has pointed out that the pressure profile of the LES shows considerable radial asymmetry, with the highest pressures being recorded in the left posterior orientation. The reasons for this asymmetry are not clear. As with the UES, the LES relaxes to allow passage of luminal contents in either direction, with relaxation occurring with peristaltic activity in the esophageal body or gaseous distention in the fundus of the stomach. With the use of computer imaging, circumferential pressure measurements taken simultaneously can generate a sphincter pressure vector volume. Vector volume assessment of LES pressures is reliable and considered superior to the pullback method used in standard manometry.5,6,39

20

0

25 sec FIGURE 3-7 Spontaneous tertiary activity appearing without swallow.

Control Mechanisms The mechanisms underlying the control of basal tone in the LES are not well understood. Fisher40 and Dodds36 and their coworkers wrote that cholinergic vagal drive seems a likely candidate, at least in part. Circulating hormones, such as gastrin, are considered less likely to contribute to basal tone. Basal tone varies greatly in normal individuals. In the fasting state, the migrating motor cycle may influence LES pressure, which tends to increase during the cycle, as recorded by Dent and associates,41 and can reach high levels during phase III

33

Section 1 Introduction

Jamieson,43 is beginning to favor the involvement of a reflex. Relaxation of the LES occurs with swallowing, with esophageal body distention, and with gastric fundus distention. Transient LES relaxation is a phenomenon of relaxation lasting 5 to 30 seconds described by Dent and colleagues.41 These transient LES relaxations probably arise as a result of gastric distention leading to nonadrenergic, noncholinergic inhibition of the LES tone. As suggested by Dent and colleagues41 and Dodds and associates,44 such transient LES relaxations may be the most important factor in both physiologic and pathologic reflux. These transient LES relaxations are best recorded by the sleeve method. Other factors that should be mentioned as contributing to pressure in the LES region are the extrinsic compression by the diaphragmatic muscle, which is probably most important during straining, and the intra-abdominal position of the LES, which allows for intra-abdominal pressure changes to buttress the LES. Mittal and colleagues45 have reported a number of observations in regard to the synergistic action of the diaphragm muscle in the right crus with that of the LES itself. These authors demonstrated the tonic crural contractions as demonstrated by electromyography and how they increased resistance to gastroesophageal reflux during various physiologic events such as coughing, straining, and breathing. For these reasons these investigators see the crus of the diaphragm as playing a major role in supporting the LES and have suggested the concept of the “extrinsic LES.”

WS

35 cm

100

50

0

mm Hg

40 cm

40

20

0

ESOPHAGEAL MANOMETRIC SYSTEMS

40

45 cm

34

20

0

25 sec FIGURE 3-8 Normal lower esophageal sphincter. Relaxation of the sphincter anticipates the oncoming peristaltic wave. Arrival and passage of the contraction through the sphincter area closes the sphincter before a return to normal baseline pressures. WS, wet swallow.

gastric contractions. Basal tone rises during increases in intraabdominal pressure; it remains controversial whether this change is a reflex rise in pressure or an increased diaphragmatic compression of the LES, as suggested by Boyle and Cohen.42 Perhaps the evidence, as reported by Landers and

Measurement of intraluminal pressures, when performed simultaneously from different points in the esophagus, permits an evaluation of movement. Manometric studies are used to define normal esophageal function as well as motor abnormalities. They provide objective measurements of results with various treatment approaches. During the recent decades three manometric systems have been used clinically: the water-perfused system, the microtransducers system, and, more recently, the topographic axial presentation derived from computerized plotting of data from multiple closely spaced recording sites. The water-perfused system uses water-perfused catheters connected to proximal transducer systems of pressure recording. The intraesophageal pressure exerted on the continuously perfused lateral ports of the catheter are transmitted proximally through the column of water and measured by a pressure transducer located at the proximal end of the catheter. These pressures are then electrically transmitted to the recording physiograph. Faithful recording of proximal and distal sphincter pressures requires the use of perfused sleeve catheters, adapted for each sphincter. Miniaturized pressure transducers integrated in a recording catheter provide side-recording strain gauges for the esophageal body as well as circumferential gel-surrounded transducers for accurate pressure recording of sphincters. The recording sites directly interface with the physiograph eliminating any damping effect. This system provides more accurate pharyngeal pressure recordings.

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

Electronic topographic esophageal manometry utilizes an increased number of pressure sensors to provide a threedimensional display to reveal the pressures of peristalsis. Instead of providing isolated waves in progression, the graphic display represents pressure amplitudes by concentric rings or color gradients with their appropriate scale. This provides a complete dynamic presentation of peristalsis instead of the fragmented data obtained from conventional manometric recordings. The demonstrated advantages of this new technique are the definition of previously unrecognized pressure segments in the esophagus, the segregation of achalasia from other motor disorders, recognition of poor sphincter relaxation, and the detection of pharmacologic effects on esophageal motility. Comparative studies of this technique are needed to define advantages over conventional manometry.6

Variables Affecting the Recording of Esophageal Motility Accurate recording of the physiologic events that occur with swallowing leads to an understanding of the pathophysiologic mechanisms of esophageal disorders. Although initial motility studies were mostly oriented toward research, motor function evaluation is now considered essential in the assessment of normal esophageal function and esophageal dysfunction. Esophageal motility studies record pressures simultaneously at several levels within the esophagus, allowing evaluation of the esophageal body and of the sphincters that close the upper and lower ends of the esophagus. Intraluminal manometry is the method best suited for the study of motility in humans. Technical refinements during the past 2 decades have led to greatly improved capability for accurate measurement with current techniques.

Meticulous attention to the recording method and the numerous factors that may affect it is necessary. For this reason, it is important to have a control population evaluated with the local recording technique. This effort ensures more accuracy and gives a better perspective of what can be interpreted as normal in a patient population. This normal population should include controls from all age categories.30 Most recording systems still use water-perfused catheters because they represent significant cost advantages. The system fluid-filled catheter manometry includes a pneumohydraulic infusion pump and small (0.8-mm internal diameter) polyvinyl tubing. This system reduces the high infusion rate required to record accurately the rapidly changing pressures when using a mechanically driven pump with syringes. Miniature balloon recording disposable catheters have also become available recently. The variables that may affect recording of esophageal physiology and its interpretation are summarized in Table 3-1. Constantly perfused catheters ensure reliability in the pressures recorded. Without perfusion, considerable variability is observed from patient to patient. If mechanical perfusion is used, there is a direct influence of the infusion rate on pressure values (Fig. 3-9). To overcome the inconvenience of infusing high volumes of fluid during a study and to allow more accurate changes in pressure over time (dP/dT) a constant-pressure infusion system was developed by Arndorfer and colleagues.46 It pushes small volumes of water through a noncompliant system and is now used more readily. Intraesophageal microtransducers are accurate and easy to use. Their initial cost, their maintenance, and their repair expenses, however, have proved a major disadvantage to their routine use. The computer system for topographic manometry with the special catheter offering multiple recording

TABLE 3-1 Variables Affecting Esophageal Pressure Recordings Variable

Effects

Variables Associated With Perfused Open-Tipped Catheters Catheter diameter Catheter length Infusion rate Mechanical factor Type of pump

Increase in internal diameter increases pressure Increase length increases drag and decreases pressures High infusion more accurate; low perfusion causes damping and lower-pressure readings

Type of transducers Inherent system drag Elasticity of tubing

Mechanical: High infusion volumes necessary for accuracy Pneumohydraulic: Low infusion volume under pressure Intraluminal microtransducers: Most accurate; high cost Transducers at head level: Pressure changes with position of the esophagus

Other Variables Spatial influence Respiratory Artifacts Dry vs. wet swallows

Irregular configuration of sphincters Inspiration, expiration, respiratory disease Cough, gag, Valsalva maneuver Amplitude of contractions greater with water swallow

Drugs, Food, Hormones

Hypermotility and hypomotility effects

Emotions

Anxiety, stress, and hostility increase nonpropulsive activity

Intraobserver and Interobserver Variation

35

Section 1 Introduction

Pharynx

40

0 100

UES

mm Hg

20

50 0 Perfusion 1.9 mL/min

Perfusion 7.6 mL/min

A 40

100

100

20

50

50

0

0

0

15 sec

15 sec

Perfusion 0 mL/min

Perfusion 1.9 mL/min

15 sec Perfusion 3.6 mL/min

B WS

WS

WS

40

100

100

20

50

50

0

0

0

40

40

40

20

20

20

0

0

0

mm Hg

36

15 sec Perfusion 0 mL/min

15 sec Perfusion 1.9 mL/min

15 sec Perfusion 3.6 mL/min

C FIGURE 3-9 Effect of perfusion on accuracy of pressure recording. A, At upper sphincter level. B, In the esophageal body. C, At lower esophageal sphincter level. A mechanical pump with syringes requires high infusion rates. A pneumohydraulic pump provides constant pressure infusion with low volumes. UES, upper esophageal sphincter; WS, wet swallow.

UES

Pharynx

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

40

40

20

20

0

0

100

100

50

50

0

0

FIGURE 3-10 Irregular configuration of sphincters makes single-port recording inaccurate because of position. Sleeve recording (Dent) or circumferential microtransducers (Castell) offer more accuracy in pressure readings. UES, upper esophageal sphincter.

5 sec Catheter opening in anteroposterior position

5 sec Catheter opening in laterolateral position

sites at every centimeter has significant acquisition and replacement costs. The size of the motility tube influences the recorded pressures, with an increase in size leading to an increase in the pressure recorded. The length of the recording tube may impose a “dragging” effect on the system and result in lower recorded pressures. Both esophageal sphincters have an irregular configuration and exhibit vertical movement during deglutition (Fig. 3-10). Special attention to these areas is required if reliable recordings are to be obtained. Dent and coworkers47 devised a 5cm-long, perfused sleeve that provides reliable LES pressure measurements despite esophageal movement. A similar sleeve catheter was developed by Kahrilas and colleagues48 for the study of the UES. This catheter follows the sleeve principle and permits reliable recording despite movement of the catheter in the sphincter. The result is optimal pressure readings within the sphincter. Despite more accurate recording of pressures in both sphincters, interpretation of relaxation and coordination of these areas remains to be improved (see Fig. 3-3). It is best to leave an interval of at least 30 seconds between swallows; this timing ensures better organization of contractions. Dry swallows may not initiate contractions or may result in weaker contraction, whereas liquid boluses provide longer and stronger contractions. Solids may result in even more prolonged and vigorous waves. A cold bolus can abolish contraction.49,50 Artifacts that frequently modify esophageal motility recordings are coughing, gagging, yawning, eructation, deep inspiration, and the Valsalva maneuver (Fig. 3-11). Just as they are in a clinical interpretation of a manometric

tracing, these artifacts need to be identified and excluded from tracings submitted to automated analysis. The manometric recording technique and the method of scoring motor events should be carefully standardized to retain meaningful observations. Three firm indications exist for the use of esophageal manometry: 1. Documentation of esophageal function in patients with suspected motor disorders, especially those with dysphagia and negative radiographic and endoscopic evaluations 2. Evaluation of patients with chest pain of undetermined origin and in whom coronary artery disease has been ruled out 3. Documentation of physiologic abnormalities in patients with gastroesophageal reflux

INTERPRETATION OF ESOPHAGEAL MOTILITY TRACINGS Careful high quality measurements in a quiet and wellcontrolled environment is essential if meaningful observations and precise diagnosis of esophageal disorders are to be obtained. Interpretation criteria are essential because esophageal motility recordings have so many influence factors. The recorder used to assess esophageal motor function can be a standard physiograph where each recording is then analyzed following pre-established interpretation criteria. New motor function recorders include computerized interpretation programs that follow these same pre-established criteria and deliver the functional results obtained with the recording of both sphincters and of the esophageal body. Automated

37

38

Section 1 Introduction

The interpretation of coordination on motility tracings is less accurate and has to be correlated with videoradiology recordings. The technical limitations associated with UES measurements and their interpretation, especially its coordination, emphasizes the lack of sensitivity or specificity of manometric recordings for the pharyngoesophageal junction. Decisions orienting toward medical or surgical therapy for UES disorders must be based on further investigations, namely, videoradiology and radionuclide pharyngeal emptying studies.

40

20

mm Hg

0

Esophageal Body (see Fig. 3-4)

40

20

0

Normal breathing

Deep breathing

Normal breathing Valsalva

60 sec FIGURE 3-11 Influence of respiration. In the esophagus, normal breathing causes a negative deflection and a positive pressure on expiration. Deep breathing increases the negative pressure, whereas forced expiration or effort against a closed glottis (Valsalva maneuver) increases pressure significantly. These changes may be exaggerated in emphysema and asthma patients. Cough and gag are frequent artifacts that are to be distinguished from spontaneous tertiary activity.

analysis of manometric tracings, however, are not considered accurate to distinguish actual contraction from artifacts, to establish LES relaxation, or to interpret spastic contractions adequately. Manual inspection based on rigid criteria remains the standard for accurate interpretation.6

Upper Esophageal Sphincter (see Fig. 3-3) Due to its marked asymmetry and movement, pressure recordings in the UES can be measured accurately with a circumferential microtransducer or with a UES sleeve catheter. Ten swallows are measured, and all values obtained are averaged. The baseline pressures in the high-pressure zone between the pharynx and the cervical esophagus are recorded. The UES relaxes completely to cervical esophageal baseline pressure. The end relaxation pressure is recorded with the relaxation. The UES closing pressure is seen and recorded as the peak relaxation augmentation. Coordination is seen as normal when the whole phase of the UES relaxation accommodates the whole duration of pharyngeal contraction and the peak pharyngeal pressure.

Physiologic information about the tubular esophagus can only be obtained with standardized interpretation criteria of contractile complexes. A resting period of a least 30 seconds must be respected between each swallow to eliminate deglutitive inhibition with the muscle refractory period. Swallows of 5 mL of water are performed with an electronic swallow marker or manual marking taken with careful observation. Depending on the number of recording ports of the esophageal motility catheter, the whole length of the esophageal body can be recorded in 10 successive swallows. Esophageal body motor function can also be recorded separately in its proximal and distal portions when three or four recording ports are placed under the UES and above the LES. With the new electronic manometry system giving a topographic representation of peristalsis, the whole esophagus with both its proximal and distal sphincters can be assessed in its entirety in a shorter recording time and with less technical difficulties.6,31 The resting pressure in the esophagus is recorded between swallows. The peak contraction pressure is measured, and mean values of the amplitude are obtained from each orifice. When no contraction occurs after a swallow this is called “failed peristalsis.” Contractions or a nontransmitted wave generating less than 30 mm Hg are considered hypotensive and ineffective. They are seen as hypertensive when greater than 180 mm Hg. Averages can be obtained for the proximal and distal esophagus. Duration of the contraction is the length of time between the upstroke of the contraction and where the downstroke comes back to baseline. The velocity measures how fast the wave moves down the esophagus. From the upstroke points between two recording ports 10 cm apart, the distance is divided by the time it takes the wave to reach the distal port giving the distance traveled per second. If the rate of progression is faster than 6.25 cm/sec this is interpreted as a simultaneous contraction. Peristaltic contractions in response to swallowing (primary waves) and spontaneous peristaltic contractions (secondary waves) are recorded separately (see Figs. 3-5 and 3-6). Tertiary contractions are also recorded as occurring in response to swallowing or spontaneously. Simultaneous contractions (tertiary) occurring after voluntary swallows are usually abnormal (see Fig. 3-6). Spontaneous tertiary activity (see Fig. 3-7) between voluntary deglutitions are seen frequently, and their frequency may be affected by a number of influence factors including anxiety and stress (see Table 3-1). When interpreting propulsion, the upstroke of the contraction is seen as the onset of

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

the tightening of the esophageal muscle over the proximal part of the swallowed bolus. Double-peaked contractions are seen as a variant of normal: in these waves the higher peak is used for interpretation of the propulsion. Triple-peak contractions are abnormal and should be numbered separately when tertiary repetitive multipeaked contractile complexes are identified; valleys between the peaks should be at least 10 mm Hg, and there should be at least one second between the peaks.

Lower Esophageal Sphincter (Figs. 3-12 and 3-13; see also Fig. 3-8) When using a continuously perfused open-tipped manometric catheter, measurements in the LES are made either using a rapid pull-through technique or a stationary slower and more progressive method (see Fig. 3-12). Five swallows are recorded at each port, and they are averaged for better accuracy. Resting pressures are considered more accurate when measured with a strain gauge catheter or with a sleeve catheter. High-resolution manometry with topographic data analysis may aid the assessment of the transsphincteric pressure gradient. This can be seen as an advantage of topographic

manometry over the information obtained by current manometric methods. The resting intragastric pressure and the peak resting pressure in the sphincter are recorded at the midpoint of the inspiration-expiration phases. Intragastric pressure is subtracted from the absolute LES resting pressure, providing a gradient between the esophagus and the gastric cavity. The peak closing pressure of the sphincter is recorded. Relaxation of the LES is considered normal with a complete decrease of the LES resting pressure to resting intragastric pressure. This should occur in 100% of the wet swallows. The report of the motor function in any patient should be made with a control population for the laboratory where the recording is analyzed.

CLASSIFICATION AND SPECTRUM OF PHYSIOLOGIC ABNORMALITIES IN THE ESOPHAGUS Esophageal motor disorders can be subdivided into three areas. Oropharyngeal dysphagias result from dysfunction at the pharyngoesophageal junction, the etiology of which is summarized in Table 3-2. Primary idiopathic dysfunction of the esophagus can be classified as hypomotility disorders and

FIGURE 3-12 Pullback method to record the lower esophageal high-pressure zone. A, Stationary pull-through recording. B, Rapid pull-through recording.

40

20

0

Rapid pull-through

Stationary pull-through

A

B

EI

EI

Swallow

EE

EE

40

20

0

20 sec EE Stomach

EE

EI Lower esophageal sphincter

EI Esophagus

FIGURE 3-13 Interpretation of pressure recording at the esophagogastric junction. In the high-pressure zone between stomach and esophagus (lower esophageal sphincter) the respiratory inversion point causes a change in the pressure signal at diaphragmatic level. EE, end-expiratory pressure; EI, end-inspiratory pressure.

39

40

Section 1 Introduction

hypermotility abnormalities. The classification and characteristic of these conditions are found in Table 3-3. Gastroesophageal reflux disease is either idiopathic or secondary to established disease conditions. The abnormalities found in this disorder category are summarized in Table 3-4. TABLE 3-2 Oropharyngeal Dysphagia Neurologic Central Peripheral Neuromuscular Muscle disease Myositis Muscular plate Myasthenia Gravis Metabolic Upper Esophageal Sphincter Dysfunction Idiopathic dysfunction without diverticulum Idiopathic dysfunction with pharyngoesophageal diverticulum Iatrogenic Postsurgical Laryngectomy Cervical dissection Tracheostomy Postirradiation Distal Dysfunction/Obstruction Motor dysfunction Gastroesophageal reflux disease Neoplasia

Oropharyngeal Dysphagia Oropharyngeal dysphagia is a symptom complex characterized by difficulties in initiating swallows, hesitancy in deglutition, and difficulties in propelling food from the oral cavity into the cervical esophagus. In general, three categories of symptoms result from this type of dysphagia: pharyngo-oral regurgitations, when transport cannot be completed from pharynx to esophagus; pharyngonasal regurgitations, when poor control of the velopharyngeal musculature exists; and tracheal aspiration, when laryngeal competence is lost (see Table 3-2). The recorded motor abnormalities in neurologic dysphagia are usually poor pharyngeal contractions with abnormalities in relaxation and coordination of the UES (Fig. 3-14A). Ellis and Crozier51 observed sphincter hypertension in bulbar palsy patients. Bonavina and associates52 reported incomplete relaxation of the UES and poor sphincter opening with pharyngeal contraction. In one of my series, 14 of 21 patients revealed incomplete, absent, or delayed opening of the upper sphincter in response to deglutition. Neurologic dysphagia is the only condition in which we have recorded complete achalasia of the UES (see Fig. 3-14B). Muscular disease may affect the pharynx and striated portion of the esophagus. Oropharyngeal dysphagia is present in 65% of patients with oculopharyngeal muscular dystrophy. Weak and repetitive pharyngeal contractions cannot succeed in pushing a food bolus through the UES area. The UES shows normal resting and contracting pressures (Fig. 3-15). My colleagues and I observed that poor

TABLE 3-3 Primary Idiopathic Motor Disorders Hypomotility

Hypermotility

Nonspecific Esophageal Motility Disorders

Achalasia

Diffuse Esophageal Spasm

Hyperperistalsis (Nutcracker or Super-Squeeze Esophagus)

Hypertensive LES

Totally absent in esophageal body

Repetitive tertiary contractions (triphasic or more) in response to deglutition (30% of wet swallows)

Normal

Normal

Elevated resting pressures

Normal peristalsis between the abnormal contractions

Contraction Amplitude

Weak Mirror-like organization

Duration and amplitude occasionally abnormal

>2 SD above normal Increased mean amplitude in distal esophagus (>180 mm Hg) Increased duration of esophageal contractions (>6 sec)

Normal

Decreased or weak

LES

Elevated resting pressure Incomplete or absent relaxation

LES occasionally hypertensive Occasional incomplete relaxation

Occasional increased LES pressure

Elevated LES resting pressure (>45 mm Hg) Normal LES relaxation

Normal

Peristalsis

LES, lower esophageal sphincter.

Spontaneous tertiary contractions

Tertiary contractions in response to swallowing

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

TABLE 3-4 Motor Disorders and Reflux Disease Idiopathic Gastroesophageal Reflux, Uncomplicated

Idiopathic Gastroesophageal Reflux, Complicated

Esophageal Contraction Amplitude

Normal

Normal Decreased Wall damage Extensive columnar-lined esophagus

Peristalsis

Normal

Normal Decreased Wall damage Extensive columnar-lined esophagus

Rarely present (distal two thirds)

Lower Esophageal Sphincter

Weak (gradient <5 mm Hg)

Weak or absent

Weak or absent

Scleroderma and Reflux

DS

Hypopharynx

100

DS

DS

DS

DS

0

mm Hg

Hypopharynx

40

100

UES

mm Hg

0

UES

Cervical esophageal pressure

40

0 0

5 sec

5 sec

A

B

FIGURE 3-14 A, Normal swallowing. Pharyngeal contraction in response to swallows and relaxation of the upper esophageal sphincter (UES) to cervical esophageal pressure. B, Neurologic dysphagia: pharyngeal contraction is powerless and upper sphincter relaxation in response to voluntary swallowing is absent. DS, dry swallow.

41

42

Section 1 Introduction

DS

WS

40

40

20

Pharynx

Pharynx

WS

20

0

0

mm Hg

UES

200

100

40

UES

0

20

Esophagus

40 Cervical esophageal pressure 20

0

C

0

10 sec

A Normal

OPMD

mm Hg

Pharynx

DS

DS DS DS

40

40

20

20

0

DS

0

5 sec

B relaxation and poor coordination are seen mostly on videoradiology.53 Idiopathic dysfunction of the UES is the diagnosis of choice whenever oropharyngeal dysphagia accompanies significant dysfunction of the UES but without a neurologic, muscular, or other known condition to explain the syndrome.

FIGURE 3-15 A, Normal resting pressure is recorded in the upper esophageal sphincter (UES). Although weak, the pharyngeal contraction results in UES relaxation. B, Muscular disease causing oropharyngeal dysphagia (OPMD) manifests as powerless pharyngeal contraction. C, In a patient with muscular dystrophy, an incomplete relaxation of the upper sphincter to cervical esophageal baseline pressure. DS, dry swallow; WS, wet swallow.

Sutherland54 suggested sphincter hypertension in these patients, but the true dysfunction present in this category of dysphagia still awaits clarification. When idiopathic dysfunction of the UES is accompanied by a pharyngoesophageal diverticulum (Zenker’s), the dysfunction that explains the appearance of the diverticulum

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

Idiopathic Motor Disorders Hypomotility Abnormalities Achalasia. The motor abnormalities of achalasia are the best known and the most easily recognized of the idiopathic motor disorders. The UES functions normally, but the whole esophagus is otherwise abnormal. In the esophageal body, elevated resting pressures suggest poor esophageal emptying. Voluntary swallowing results in an abnormal contraction response over the whole esophagus: the weak tertiary waves are wide and mirror-like at every recording level, and these contractions occur in response to every deglutition (Fig. 3-16). The complete absence of peristalsis is a prerequisite of achalasia. The LES of achalasia reveals normal or elevated sphincter resting pressures with a response of incomplete or absent relaxation with swallowing (Fig. 3-17). When a cholinergic agent (Urecholine) is administered in low dose to achalasic patients, a denervation response is recorded. Increased activity and pressures are then observed in the esophagus, with stronger contractions in response to swallowing.

DS

DS

DS

36 cm

40 20 0

mm Hg

41 cm

40 20 0

40 46 cm

remains to be specified. Poor relaxation of the UES was reported in radiologic studies. Ellis and Crozier51 and Knuff and associates,55 and my colleagues and I56 have reported mostly UES hypotension. Premature closure of the sphincter against the pharyngeal pump action was suggested early to explain the herniated mucosa and submucosa that form a pouch above the UES and through the hypopharyngeal musculature. Cook57 and Jamieson58 and their colleagues, using sophisticated manometric recordings coupled with videoradiology, documented elevated hypopharyngeal intrabolus pressures with restricted compliance of the UES area during swallowing. This resulted from restrictive fibrosis and inflammation in the excised cricopharyngeus muscle. These pressure abnormalities are corrected by UES myotomy with either suspension or resection of the diverticulum. Iatrogenic dysfunction of the UES may be found in patients after extensive neck surgery. Laryngectomy causes symptoms in 40% of treated patients. Incomplete UES relaxation as well as incoordination are seen in this group of patients. We have reported that resting and closing pressures of the UES are significantly lower in patients who have had laryngectomies than in normal subjects.59 It is still unclear whether the UES responds in a specific fashion in patients with gastroesophageal reflux. This UES reactivity may be suggested by oropharyngeal dysphagia symptoms, present in 9% of patients with documented reflux disease, as noted by Bonavina and coworkers.52 Interpretations of all recordings at the UES level must take into account the technical difficulties present when studying this radially asymmetric area. Accurate resting and closing pressures can be obtained with the use of circumferential multiport recordings or of circumferential pressure sensing transducers, as recommended. The use of a long perfused silicone sleeve affords the recording of sphincter pressure along the sleeve, even if the sphincter moves around the sensing device.

20 0

25 sec FIGURE 3-16 Esophageal body in achalasia. Flat, nonperistaltic waves occur in response to all swallows, in both the proximal and the distal esophagus. The elevated resting pressure suggests esophageal retention. DS, dry swallow.

Hypermotility Abnormalities Diffuse Esophageal Spasm. Symptomatic idiopathic diffuse esophageal spasm is a rare condition. Manometric recording of this functional abnormality must be considered in parallel to the clinical presentation to rule out other conditions that may be responsible for this motor pattern. Typically, normal function is found in the proximal esophagus. It is mostly over the smooth muscle portion of the esophagus that abnormal contractions should be expected. When initially described, tertiary contractions that were repetitive and of high amplitude and duration represented the typical abnormalities. Although some normal peristalsis is seen in response to swallowing, most swallows are followed by nonpropulsive, repetitive, and high-pressure waves (Fig. 3-18). Castell60 and Richter and Castell61 suggested that these contraction abnormalities should be present in 10% to 30% of swallows but in less than 100%. Normal peristalsis should be seen occasionally between abnormal contractions. Elevated contraction pressure need not be present, and spontaneous activity is not part of the diffuse spasm pattern. The LES function in patients with diffuse esophageal spasm was considered normal by DiMarino and Cohen.62 As noted by Richter and Castell,61 however, occasional dysfunction can be observed that suggests intermittent abnormalities in the LES with hypertension, incomplete relaxation, or poor coordination (Fig. 3-19).

43

44

Section 1 Introduction

WS

WS

DS

40 26 cm

34 cm

40

20

20

0 0

39 cm

mm Hg

31 cm

40

mm Hg

40

20

0

20

40 36 cm

0

20

40

44 cm

0

60 sec

20 Mean resting pressure

0 Resting intragastric pressure 25 sec FIGURE 3-17 Lower esophageal sphincter (LES) function in achalasia. The LES zone is entered from the gastric cavity recorded on the left. Incomplete or absent relaxation results with swallows. Nonperistaltic contractions in the esophageal body with nonrelaxing LES in response to deglutition. WS, wet swallow.

Idiopathic diffuse spasm of the esophagus does not manifest itself with the clarity of the achalasia motor pattern. Careful recording and correlation with symptoms and radiologic findings should help to narrow down the diagnosis to patients with true dysfunction. Motor disorders secondary to reflux disease or to pathologic infiltration of the esophagus must be ruled out. Hyperperistalsis (Nutcracker, Super-Squeeze Esophagus). Brand and associates,63 after describing high contraction pressures in the esophageal body with prolonged

FIGURE 3-18 Simultaneous contractions with repetitive activity and occasional high-pressure waves in a patient with idiopathic diffuse spasm. DS, dry swallow.

peristaltic waves, suggested the term super-squeeze esophagus. Benjamin64 and Traube65 and their colleagues observed similar abnormalities in patients with noncardiac chest pain. Castell66 suggested the term nutcracker esophagus when mean peristaltic pressures exceeded 2 or 3 standard deviations above normal. Mean contraction pressures above 180 mm Hg after 10 swallows should be recorded in these patients. LES function may show normal function with increased resting pressures. Hypertensive Lower Esophageal Sphincter. Patients showing an LES pressure between 40 and 45 mm Hg are considered to have a hypertensive LES. In these patients, as noted by Code67 and Freidin68 and their associates, LES relaxation is usually normal and esophageal body peristalsis is normal.

Nonspecific Esophageal Motor Disorders The category of nonspecific esophageal motor disorders includes disorders of contraction that cannot be classified as idiopathic hypomotility or hypermotility dysfunction. The

Chapter 3 Physiology of the Esophagus and Classification of Esophageal Motor Abnormalities

WS

WS

WS

40 33 cm

38 cm

400

WS

200

20 0

0 mm Hg

38 cm

40 20

400

40

200 43 cm

43 cm

0

20

0 0 60 sec

48 cm

40

FIGURE 3-20 The hypotensive lower esophageal sphincter of idiopathic reflux disease. Normal contractions and propulsion are retained in the esophageal body. Abundant spontaneous tertiary contractions are recorded in between the voluntary deglutitions. WS, wet swallow.

20

0

30 sec FIGURE 3-19 Very strong antiperistaltic esophageal contractions and nonrelaxing lower esophageal sphincter in patient with hyperdynamic esophagus accompanying an epiphrenic diverticulum. WS, wet swallow.

vast majority of the patients in this category are considered to have inefficient esophageal motility in response to voluntary deglutition.

Motor Disorders of Reflux Disease Idiopathic Reflux Disease (see Table 3-4) Atkinson and colleagues69 initially documented that LES dysfunction was present when significant reflux occurred in the esophagus. Haddad70 emphasized that when LES pressures remained weak, reflux episodes occurred more frequently. Ahtaridis and coworkers71 further documented a correlation between LES pressures and the potential for reflux. They suggested that any increase in the severity of esophagitis leads to weaker LES pressures. Thus, the first and most significant motor abnormality in reflux disease is weak, or virtually absent, LES pressure (Fig. 3-20). Behar and associates72 suggested that, when carefully recorded, this documentation

probably has value as a prognostic factor in the response to treatment. Ransom,73 Iascone,74 and Kahrilas75 and their associates reported that esophageal body dysfunction also tends to increase with increasing damage.

Secondary Reflux Disease Scleroderma is a well-documented disorder in which esophageal function may become significantly affected. Hurwitz and coworkers76 observed that a number of patterns can be identified with this condition, ranging from normal motility and adequate LES to complete absence of esophageal and LES function. Scleroderma patients with absent esophageal defense mechanisms show a higher percentage of severe reflux complications. The typical scleroderma motor dysfunction reveals intact UES and proximal esophagus activity. In the smooth muscle portion, response to swallowing results in poor-quality contractions with loss of peristalsis. These abnormalities, when associated with complete absence of LES resting pressure, result in constant exposure to gastroesophageal reflux and its eventual complications (Fig. 3-21). In a similar fashion, the peripheral neuropathy of both diabetic and alcoholic individuals may reduce normal peristalsis and the quality of the normal LES. Patients with these conditions may present with established complications of reflux disease.

45

46

Section 1 Introduction

WS

WS

DB

WS

WS

28 cm

40 20 0

COMMENTS AND CONTROVERSIES

33 cm

mm Hg

40 20 0

40 38 cm

above, LES pressure recordings show much variability, which limits the sensitivity of the test. When the LES pressure is weaker than 6 mm Hg, however, this becomes specific for abnormal reflux. When the tracing shows no recordable sphincter pressure, the probability of severe reflux is high, with a poor prognosis in response to medical treatment.

20 0

60 sec FIGURE 3-21 Absence of esophageal motor activity in patients with scleroderma. Esophagus and stomach form a single cavity, and severe reflux is seen in these patients. DB, deep breathing; WS, wet swallow.

Motility Studies as a Prognostic Factor in Reflux Disease In one of the early prospective studies looking at the effects of medical and surgical treatment on reflux disease, Behar and associates77 documented that when the tone at the LES level is poor, the sphincter shows no changes over time under medical management. More recently, the use of motility studies has been emphasized as an aspect of esophageal function investigation that carries some prognostic value in the management of patients with gastroesophageal reflux. Lieberman,78 in following patients with reflux esophagitis, found that those who did well with medical management had acceptable values of the LES resting pressures; early relapsers with significant reflux showed low LES pressures. Kahrilas and associates75 reported that patients with increasing reflux damage had significantly weaker LES resting pressure. Progression of mucosal lesions is also accompanied by weaker contractions and by a greater rate of failed peristalsis in the esophageal body. Castell79 proposes that at 10 mm Hg and

Dr. Duranceau has reviewed in detail the physiology of the esophagus and the classification of motor disorders. He describes the physiology of swallowing, the esophageal body, UES and LES physiology, and their mechanisms of control. Esophageal manometric systems and interpretation of normal esophageal motility tracing are explained well. He then describes the classification and manometric diagnostic criteria for primary motility disorders. In addition, he also described the motility abnormalities noted secondary to reflux disease. The role of manometry as an essential component in the diagnosis of esophageal motor disorders is well known and established. However, of further interest is the potential role of manometry as a prognostic factor in benign esophageal disease. Dr. Duranceau describes the role of manometry as a prognostic factor in reflux disease. He refers to a study by Lieberman and colleagues who found that patients who did well after medical treatment for gastroesophageal reflux had acceptable LES pressures, and patients who had an early relapse had lower resting LES pressures. It is, however, controversial whether manometry can predict outcome after antireflux surgery or whether preoperative esophageal peristaltic dysfunction can be a predictor of postoperative dysphagia after antireflux surgery.1 It is also controversial whether preoperative manometric testing will help in tailoring the appropriate antireflux operation. In a recent study, Torquati and colleagues examined the predictors of successful outcome after laparoscopic myotomy for achalasia in 200 patients. These authors found that high preoperative LES pressure was an independent predictor of excellent response in a multivariate logistic regression model. They concluded that elevated LES pressure is the strongest positive predictor of outcome.2 Thus, manometry can be a useful tool not only in the diagnosis but also in selection of therapy and in the prediction of outcome. Recently, there has been an interest in combining manometry with evolving technology such as intraluminal impedance monitoring. Currently, the role of intraluminal impedance monitoring in the evaluation of esophageal motor disorders is not fully evaluated but in the future may play a complementary role to manometric testing. J. D. L. 1. Pandolfino JE, Kahrilas PJ: AGA technical review on the clinical use of esophageal manometry. Gastroenterology 128:209-224, 2005. 2. Torquati A, Richards WO, Holzman MD, Sharp KW: Laparoscopic myotomy for achalasia: Predictors of successful outcome after 200 cases. Ann Surg 243:587-593, 2006.

chapter

4

CLINICAL FEATURES OF ESOPHAGEAL DISEASE Thomas J. Watson Jeffrey H. Peters

Key Points ■ The esophagus has one task, the aboral movement of ingested

food and saliva. ■ Accurate symptom assessment is the first step in diagnosis and

treatment of esophageal disease. ■ Symptom assessment is simplified if the foregut is treated as three

pump-valve-reservoir systems connected in series. ■ Inaccurate localization of esophageal symptoms is a hallmark of

visceral nociception. ■ In Western societies GERD is the most common symptomatic

esophageal disorder.

The esophagus is responsible for only one essential task: the aboral movement of ingested food and saliva from the pharynx to the stomach. As part of this task, prevention of reflux of gastric contents is implicit. Unlike other portions of the gastrointestinal tract, the esophagus has no known digestive, absorptive, immunologic, hormonal, or secretory functions. Despite the apparent simplicity of its responsibilities, the esophagus can exhibit derangements in structure or function that can severely impact the quality of a person’s life. Minor derangements are relatively common, leading to symptoms that are intermittent and easily controlled with dietary and lifestyle modifications. Many patients suffering such symptoms manage them without seeking medical advice. More severe symptoms may require medications designed to modulate foregut function and are more likely to lead to the patient seeking treatment from a physician. Severe symptoms may require intensive medical management or remedial surgery designed to improve foregut structure or function. Finally, in cases of advanced or end-stage benign esophageal disease or foregut malignancy, extirpative surgery may be required with appropriate reconstruction. The art of accurate symptom assessment in the evaluation of esophageal disease is central to the management of this group of patients and has been underemphasized in the surgical literature. Because the symptomatology of patients suffering the manifestations of esophageal disorders is extremely variable and often difficult to ascertain, the ability to obtain a reliable synopsis of symptoms frequently requires perseverance and insight. The clinical history is extremely important, however, in that decisions for or against surgical intervention or other invasive therapies are generally determined by the nature and severity of symptoms, placed in the context of the underlying anatomic or physiologic derangements and the inherent risks of treatment. Symptoms should be categorized

as primary or secondary, for the sake of prioritization of therapy, and the probability of relief of each symptom after a specific intervention is considered. Given the importance of a thorough and reliable symptom assessment when esophageal surgery is planned, the procurement of the clinical history should not be left to the referring primary care physician or gastroenterologist, nor should it be delegated to an inexperienced nurse practitioner, physician assistant, or house officer. The focus of this chapter is on the spectrum of clinical manifestations of esophageal disease. A fundamental tenet of medical practice is that diagnosis should precede treatment. An understanding of the varied presentations of esophageal disorders will enable the physician to better recognize that esophageal pathology is responsible for problems in an individual patient and will help direct subsequent diagnostic and therapeutic measures.

PHYSIOLOGIC MODEL OF THE FOREGUT To understand the clinical manifestations of esophageal and foregut disorders, the physician should possess a knowledge of normal foregut structure and function. The pharynx, esophagus, and stomach have been described by classical anatomists as three distinct structures. Physiologically, the foregut can be viewed in a much different way as three sequential “pump-valve-reservoir” systems. The most commonly discussed of these systems is the esophageal muscular pump consisting of the smooth muscle portion of the esophagus, the lower esophageal sphincter (LES) valve, and the gastric fundic reservoir (Fig. 4-1). In this model, the esophageal pump, like a piston, drives food and saliva from the pharynx toward the stomach. The LES acts as a one-way valve, allowing aboral passage of esophageal content but preventing orad reflux of gastric contents. The fundic reservoir takes in food or liquid for storage, until the gastric antral pump continues the process downstream. The second such “pump-valve-reservoir” system consists of the gastric antral pump, the pyloric valve, and the duodenal reservoir, with each of the components functioning as previously described for the esophagus-LES-fundus. The third such system is the pharynx (pump), the upper esophageal sphincter (UES) valve, and the striated muscle portion of the proximal esophagus (reservoir). Each of these systems has important roles in normal foregut function. Likewise, derangements in any can lead to symptoms or objective findings. Starting from the most distal level, abnormalities in the antropyloroduodenal system may lead to problems with antegrade passage of chyme and manifestations of delayed gastric 49

50

Section 2 Investigation of Esophageal Disease

UES

Esophageal body

“Pump”

LES

“Valve”

Stomach

“Reservoir”

FIGURE 4-1 Physiologic model of the foregut. LES, lower esophageal sphincter; UES, upper esophageal sphincter.

emptying, such as nausea, vomiting, early satiety, or epigastric pain. Duodenogastric reflux may also result, bringing bile and pancreatic enzymes into the gastric lumen and exposing the gastric mucosa to these agents. Because duodenogastric reflux may coexist with gastroesophageal reflux, reflux of gastric contents across the LES into the esophagus may bring not only acid and ingested substances into the esophagus but also the components of the duodenal refluxate. Thus, “acid reflux” is better conceptualized as “duodenogastroesophageal reflux.” Common associated symptoms include heartburn, regurgitation, and chest pain. Dysmotility of the esophageal pump can lead to dysphagia. Finally, because reflux may occur from the esophagus across the UES into the pharynx, gastric and duodenal contents may be brought to the pharyngeal level, leading to regurgitation, sore throat, or water brash. Discoordination of the pharyngeal pump and UES can cause cervical dysphagia or aspiration. Once the refluxate has reached the pharynx, it may continue to pass in any of a number of directions: into the mouth, nasal passages, or laryngotracheobronchial tree. Each of these routes leads to its own potential for symptoms or physical findings. With transoral passage comes the possibility of oral regurgitation, dental caries, tongue pain, or halitosis. With nasal passage comes potential nasal regurgitation or sinus problems. With contact of the refluxate at the larynx or frank aspiration into the tracheobronchial tree comes the potential for cough, asthma, hoarseness, sore throat, pneumonia/ pneumonitis, or the more insidious onset of bronchiectasis or pulmonary fibrosis.

MECHANISMS OF ESOPHAGEAL SYMPTOMS The precise mechanisms by which esophageal symptoms are generated remain unclear. Investigations assessing luminal contents, esophageal distention, smooth muscle function, neural tracts, and brain localization have provided insights into the pathways by which esophageal symptoms are provoked. Evaluations of embryologic development of the foregut, as well as anatomic studies, demonstrate that the visceroneural pathways of the foregut are complexly intertwined with those of the respiratory tract and heart. This fact helps explain the common overlap in clinical presentations of diverse disease processes involving the upper gastrointestinal, pulmonary, and cardiac systems. Not uncommonly, localization of pathology to one organ system or another is difficult.

Early studies into the pathophysiology of esophageal symptomatology focused on intraluminal balloon distention or acid perfusion. A classic study published in 1931 assessed the location of symptoms after balloon distention at 5-cm increments within the esophageal body.1 Patients rarely localized the symptom accurately, consistent with visceral nociception in other parts of the alimentary tract (Fig. 4-2). Symptoms were variously described as heartburn, chest pain, or nausea. Pain located between the shoulder blades, at the base of the neck, or even in the retrobulbar region was also observed. Esophageal perfusion with either acid or bile salts can induce heartburn or angina-like chest pain. Symptom severity correlates with concentration and contact time, although this is also quite variable between individuals. Discomfort tends to be reproducible below a pH of 4, a fact appreciated in the early years of esophageal pH testing. This threshold is partially responsible for selection of pH 4 as the point below which acid reflux into the esophagus is defined on ambulatory pH monitoring. The Bernstein test, now largely of historic interest, relied on the instillation of acid into the esophagus to invoke reflux symptoms as a way to diagnose gastroesophageal reflux disease (GERD). The test, however, lacked both sensitivity and specificity. Similarly, studies assessing bile salt perfusion in the esophagus have shown the ability to invoke symptoms in this manner. Several published studies have evaluated the cortical response to esophageal balloon distention and acid perfusion.2 Responses have been detected via cortical evoked potentials, positron emission tomography (PET), and magnetic resonance imaging (MRI) and have been localized to the posterior cingulate, parietal, and anterior frontal lobes.

GASTROESOPHAGEAL REFLUX: AN OVERSIMPLIFIED CONCEPT GERD is a common disorder afflicting Western societies. Multiple population-based studies have demonstrated that more than one third of adults experience reflux symptoms at least once per month, with 4% to 7% of the population experiencing symptoms on a daily basis.3,4 Klinkenberg-Knol and Castell have popularized the concept of the GERD iceberg (Fig. 4-3).5 Patients presenting to a physician with typical reflux symptoms merely represent “the tip of the iceberg” in terms of the overall population of patients with GERD in the community. The incidence of GERD is likely increasing in Western societies as well as within other parts of the world that are adopting a Western diet and lifestyle. This trend has occurred despite increasingly effective treatment options and stands in stark contrast to the incidence of peptic ulcer disease, which has been dramatically decreasing. Also, the incidence of GERD may be greater than previously appreciated as atypical manifestations of GERD are being increasingly recognized. Whereas the terms gastroesophageal reflux and acid reflux have been widely recognized and applied, clearly more factors are at play in causing symptoms and GERD-related complications than the mere reflux of gastric acid into the esophagus. Reports on the natural history of GERD are rare. The few that do exist typically involve patients undergoing some form

Chapter 4 Clinical Features of Esophageal Disease

Case 36

Case 2

Case 7

Case 21

20

20

20

20

25

25

25

25

30

30

30

30

35

35

35

35

40

40

40

40

Case 34 Lower thoracic spine Angle of left scapula Angle of left scapula

Case 29

20

20

25

25

30

30

35

35

40

40

Pain in back between shoulders

FIGURE 4-2 Localization of symptoms with esophageal balloon distention at various locations within the esophagus. The numbers (20-40) demonstrate the position of the esophageal balloon measured from the incisors, and the circles denote the location of the resultant symptom. (MODIFIED FROM POLLAND WS, BLOOMFIELD AL: EXPERIMENTAL REFERRED PAIN FROM THE GASTROINTESTINAL TRACT: I. THE ESOPHAGUS. J CLIN INVEST 10:435-452, 1931.)

Persistent symptoms and complications

Frequent symptoms, seen by physician

Occasional symptoms, not seen by physician

Asymptomatic Barrett’s esophagus FIGURE 4-3 The GERD iceberg. (FROM KLINKENBERG-KNOL E, CASTELL DO: CLINICAL SPECTRUM AND DIAGNOSIS OF GASTROESOPHAGEAL REFLUX DISEASE. IN CASTELL DO [ED]: THE ESOPHAGUS, 2ND ED. BOSTON, LITTLE, BROWN, 1995, P 437.)

of therapy. A report from Switzerland detailed endoscopic follow-up on 959 patients with GERD over a 30-year period.6 The study involved only patients with endoscopic esophagitis and did not include those with symptoms but without mucosal injury. The study demonstrated that in about 45%

of patients esophagitis developed as an isolated episode that did not return while on acid suppression medication. In the remaining patients, esophagitis occurred intermittently while on medication; and in 42% it progressed on therapy to more severe mucosal injury. This latter group comprises about 23% of the initial population of patients with esophagitis. The study also demonstrated that approximately 16% of patients demonstrated intestinal metaplasia of the esophageal mucosa (Barrett’s esophagus) while on medical therapy. Recent studies suggest that colonization with Helicobacter pylori may have a protective effect against the development of gastroesophageal reflux and that the gradual eradication of H. pylori from the Western population may be an underlying reason for the increasing prevalence of GERD.7 Labenz and associates have shown that patients with duodenal ulcer and successful eradication of H. pylori developed esophagitis significantly more frequently over the ensuing 3 years than those who remained positive for H. pylori.8 The authors suggested that the increased frequency of esophagitis may result from increased gastric acid secretion after eradication therapy. Others have suggested, however, that gastric acid secretion may decrease after H. pylori eradication and questioned the

51

52

Section 2 Investigation of Esophageal Disease

association between eradication therapy and GERD with and without erosive esophagitis. Studying patients in Los Angeles, Oberg and coworkers found the prevalence of H. pylori to be similar in patients with and without erosive esophagitis.9 Furthermore, there was no difference in the prevalence of esophagitis in patients with pH-positive reflux disease when grouped according to the presence or absence of H. pylori infection. Investigations focused on the role of subpopulations of H. pylori have implicated cagA+ strains as particularly relevant to the development of gastroesophageal reflux and its complications.10 Vicari and coworkers demonstrated that in patients with H. pylori infection the prevalence of cagA+ strains progressively decreased with the severity of GERD, including Barrett’s esophagus and esophageal adenocarcinoma.11 Chow and colleagues confirmed an inverse relationship between the presence of cagA positivity and adenocarcinoma of the esophagus and the gastroesophageal junction.12 Both groups postulated that cagA+ strains may protect against the development of adenocarcinoma by inducing more severe mucosal inflammation and atrophic gastritis and thereby decreasing acid reflux. Present data regarding gastric acid secretion are conflicting, however, and further studies are required to test if this hypothesis is true.

CLINICAL PRESENTATIONS OF GERD The Problem With Defining GERD Despite its prevalence and generally understood significance, GERD is difficult to define. GERD is typically diagnosed when a patient suffers from symptoms or mucosal injury associated with excessive or pathologic reflux of gastric contents into the esophagus or to a more proximal level. Thus, GERD can be defined by symptoms, mucosal injury, and/or the amount and character of refluxate. This definition is inherently problematic. Symptoms associated with GERD are not specific for GERD and can be due to any of a number of underlying causes. The severity of symptoms does not necessarily correlate with the amount and composition of the refluxate; large amounts of reflux, as documented on ambulatory esophageal pH monitoring, can cause few symptoms in some individuals, and small amounts of reflux may cause significant symptoms in others. Some symptoms, such as wheezing, coughing, or chest pain, may be thought secondary to other causes in a given individual while, in fact, being due to GERD. GERD-associated symptoms may coexist with other, non–esophageal-related, gastrointestinal and respiratory complaints that will not improve, or may be worsened, by specific GERD-related therapy. Symptoms attributable to irritable bowel syndrome, such as alternating diarrhea and constipation, bloating, or crampy abdominal pain, should be assessed and addressed separately from esophageal pathology. Additionally, symptoms suggestive of gastric disease, such as nausea, early satiety, anorexia, or epigastric pain, should be elicited and distinguished from esophageal symptoms. Esophagitis, the sine qua non of GERD, may or may not be visible on endoscopic assessment and is not specific for acidor bile-induced injury. Metaplastic transformation of the esophageal mucosa, or Barrett’s esophagus, thought to be

secondary to pathologic gastroesophageal reflux, can also occur in the absence of symptoms. Injury can occur to the larynx, tracheobronchial epithelium, or pulmonary parenchyma in the absence of esophageal mucosal injury or typical reflux symptoms. Finally, reflux of acid typically occurs to some extent in normal individuals, so-called physiologic reflux.

Typical Symptoms of GERD The most common symptoms reported by patients with GERD are heartburn, regurgitation, and dysphagia. These symptoms represent the “typical” symptoms of GERD, although none is specific to GERD. Dysphagia, in particular, may represent a sign of more serious underlying esophageal pathology, including esophageal carcinoma. As a result, dysphagia should always be investigated promptly and thoroughly. Heartburn is characterized as a substernal “burning” discomfort often radiating from the epigastrium to the sternal notch. The location of the symptom can be variable with patients reporting discomfort in divergent locations such as the epigastrium, base of the neck, jaw, back, or other areas. Heartburn is typically made worse by citrus juices, chocolate, coffee, alcohol, fatty meals, or “spicy” foods such as tomato sauce. Heartburn generally occurs 1 to 2 hours after eating, often at night or when supine, and typically is relieved by antacids or antisecretory agents such as histamine-2 receptor antagonists or proton pump inhibitors (PPIs). The incidence of nocturnal heartburn and its effect on quality of life have been elucidated in a recent Gallup poll sponsored by the American Gastroenterological Association (Table 4-1). Occasionally patients will refer to “chest pain” rather than heartburn, and the two can be difficult to differentiate. Whereas chest pain is often attributable to cardiac disease, it may be secondary to esophageal pathology. Classic studies by DeMeester and associates demonstrated that approximately 50% of patients with severe chest pain, normal cardiac function, and normal coronary arteriograms had positive 24-hour esophageal pH studies, implicating GERD as an underlying cause.13 In addition, exercise-induced GERD is known to occur in some individuals, leading to exertional chest pain similar to angina. In such circumstances, the differentiation between a cardiac and esophageal etiology may prove difficult. A study by Nevens and coworkers evaluated 248 patients presenting with chest pain, with 185 thought to have typical angina and 63 thought to have atypical symptoms. Twentysix percent of those with classic angina had normal coronary arteriograms, whereas 25% with atypical symptoms had evidence of coronary disease.14 Pope and colleagues evaluated the diagnosis of 10,689 patients presenting to an emergency department with acute chest pain.15 Approximately 45% had a defined cardiac cause, whereas 55% had noncardiac causes. Many of these cases of a noncardiac etiology are likely attributable to esophageal disease. Associated symptoms suggestive of esophageal pathology should be elicited, such as chest pain precipitated by meals, occurring at night or when supine, responsive to acid suppressive therapy, or associated with dysphagia or regurgitation.

Chapter 4 Clinical Features of Esophageal Disease

TABLE 4-1 Nocturnal Heartburn ■

50 million Americans suffer from night-time heartburn at least once per week

■

80% of heartburn sufferers have nocturnal symptoms, 65% both day and night

■

63% report that heartburn affects their ability to sleep and impacts their work the next day

■

72% are on prescription medications

■

45% report that current remedies do not relieve all symptoms

Regurgitation is the spontaneous return of gastric contents proximal to the gastroesophageal junction. The spontaneous nature of regurgitation distinguishes it from vomiting. Regurgitation can be due to an incompetent LES as well as anatomic or functional esophageal obstruction. With obstruction, such as in achalasia, the regurgitant typically is described as bland, undigested food, such as food placed in a blender. When questioned, patients often can distinguish between the regurgitation of gastric versus esophageal contents. The patient will often get a sensation that fluid or food is returning into the esophagus even if it does not reach as high as the pharynx or mouth. Regurgitation is typically worse at night in the recumbent position, when lying down after a meal, or when bending over. Patients commonly compensate by not eating late at night and sleeping partially upright with several pillows, using a wedge to elevate the head of the bed, or sleeping upright in a chair. Nocturnal regurgitation is often less well relieved than heartburn by antacids or antisecretory agents, although it may change in character from acid to a more bland nature, so-called volume reflux. Dysphagia, or difficulty swallowing, is possibly the symptom most specific for foregut disease (Table 4-2). Dysphagia is present in up to 40% of patients with GERD and is typically manifested by a sensation of food hanging up in the lower esophagus (esophageal dysphagia) rather than difficulty transferring the bolus from the mouth to the esophageal inlet (oropharyngeal dysphagia). The latter may be associated with nasal regurgitation or aspiration upon swallowing. Pain (odynophagia) may or may not be associated with difficulty swallowing. Dysphagia limited to only solid foods, with normal passage of liquids, suggests a mechanical disorder such as a large hernia, stricture, or tumor, whereas difficulty with both solids and liquids suggests a functional or motor disorder. Dysphagia often develops slowly enough that the patient may adjust his or her eating habits and not necessarily notice the change. Thus, a thorough esophageal history should include an assessment of the patient’s dietary habits. Illuminating questions include the consistency of food that is eaten; whether the patient requires liquids with meals; the speed of eating and whether the patient typically is last to finish a meal; the occurrence and frequency of choking or vomiting; whether the patient is reluctant to eat in social situations, such as in restaurants, for fear of choking or needing to regurgitate during the meal; and whether he or she has been admitted to the hospital on an emergency basis for food impaction. These assessments, in addition to the ability to maintain nutrition, help to quantify the dysphagia and are

TABLE 4-2 Non-GERD Causes of Esophageal Dysphagia Motility Disorders Primary Achalasia Diffuse esophageal spasm Nutcracker esophagus (hypertensive peristalsis) Hypertensive lower esophageal sphincter Ineffective esophageal motility Secondary Scleroderma Other collagen vascular diseases Chagas’ disease Mechanical Obstruction Intrinsic Peptic, medication-induced, infectious or inflammatory stricture Schatzki’s ring Diverticulum Web Carcinoma Leiomyoma Duplication cyst Other malignant or benign tumors Foreign body Extrinsic Mediastinal masses Vascular compression Cervical osteoarthritis Postoperative pseudoachalasia (e.g., tight Nissen fundoplication)

TABLE 4-3 Extraesophageal Manifestations of GERD Ear, Nose, Throat

Pulmonary

Laryngitis

Cough

Pharyngitis

Asthma

Otitis

Pulmonary fibrosis

Sinusitis

Chronic bronchitis

Hoarseness/voice changes

Bronchiectasis

Throat clearing

Aspiration pneumonitis

Globus sensation Subglottic stenosis Dental erosions

important in determining the indications for surgical therapy.

Atypical Symptoms of GERD Many patients with gastroesophageal reflux manifest “atypical” or “extraesophageal” symptoms, such as cough, wheezing, hoarseness, or sore throat (Table 4-3). Such symptoms may be triggered by laryngopharyngeal reflux (“LPR”). The cause and effect relationship between gastroesophageal reflux and atypical symptoms may be difficult to prove. As previously discussed, typical GERD can be categorized by the presence of typical symptoms, the documentation of esophageal mucosal injury (reflux esophagitis or intestinal metaplasia) and the presence of excessive esophageal acid exposure

53

54

Section 2 Investigation of Esophageal Disease

on ambulatory esophageal pH monitoring. For atypical GERD, on the contrary, symptoms, mucosal injury, and pathologic acid exposure are all unreliable in confirming the diagnosis. Because the atypical symptoms are nonspecific for reflux disease, they may be triggered by causes other than reflux. Many such patients presenting with these complaints do not have typical reflux signs or symptoms. Objective testing for occult reflux is imprecise. There are no pathologic findings on biopsies of the laryngeal or airway mucosa specific for reflux disease.16 The extent of reflux necessary to trigger extraesophageal complaints is poorly defined. Small amounts of acid or non-acid reflux can trigger a cough, sore throat, or any of a variety of pulmonary manifestations and may not be temporally proximate to the onset of symptoms. Finally, any of a variety of these atypical symptoms can coexist with overt GERD but be causally unrelated. Atypical symptoms are thought to be the primary complaint in 20% to 25% of patients with GERD and are secondarily present, in association with heartburn or regurgitation, in many more. The diagnosis of GERD based on symptoms alone is correct in only approximately two thirds of patients (Costantini et al, 1993).17 This disparity is indicative of the fact that GERD-related symptoms are not specific for gastroesophageal reflux and can be caused by other diseases such as achalasia, diffuse esophageal spasm, esophageal carcinoma, pyloric stenosis, cholelithiasis, gastritis, peptic ulcer, non-ulcer dyspepsia, and coronary artery disease. This fact underscores the need for an objective diagnosis before the decision for surgical treatment.

Complications of GERD The complications of gastroesophageal reflux result from the damage inflicted by gastric juice on the esophageal, laryngeal, or respiratory epithelium (Table 4-4). Complications conceptually can be divided into categories: 1. Extraesophageal or respiratory complications such as laryngitis, recurrent pneumonia, and progressive pulmonary fibrosis 2. Mucosal complications such as esophagitis and esophageal stricture 3. Metaplastic and neoplastic complications such as Barrett’s esophagus and esophageal adenocarcinoma The prevalence and severity of complications is related to the degree of loss of the gastroesophageal barrier, defects in esophageal clearance, and the content of refluxed gastric juice.

Respiratory Complications GERD has been increasingly recognized as a cause of respiratory symptoms and complications, either in isolation or associated with typical reflux symptoms or esophageal mucosal injury. Numerous studies have shown that up to 50% of asthmatics have either endoscopic evidence of esophagitis or increased esophageal acid exposure on 24-hour ambulatory pH monitoring.18 This high incidence of correlation suggests that the frequency of dual pathology is higher than would be expected by chance alone.

TABLE 4-4 Complications of GERD Strong Acid Complications (pH < 2) Esophagitis Carditis Ulceration Bleeding Stricture Weak Acid Complications (pH 3-5) Intestinal metaplasia of cardiac mucosa Dysplasia Carcinoma Non–pH-dependent Complications Asthma Bronchitis Laryngitis Aspiration pneumonitis Pulmonary fibrosis

Pathophysiology of Reflux-Induced Respiratory Symptoms. Two mechanisms have been proposed as the pathogenesis of reflux-induced respiratory symptoms (Fig. 4-4). The first, the so-called reflux theory, maintains that respiratory symptoms are the result of micro- or macroaspiration of gastric contents. The second, or reflex theory, maintains that vagally mediated bronchoconstriction follows acidification of the lower esophagus. The evidence supporting a reflux mechanism is fivefold. First, clinical studies have documented a strong correlation between idiopathic pulmonary fibrosis and hiatal hernia. The presence of GERD was shown to be highly associated with several pulmonary diseases, including asthma, in a recent Department of Veterans Affairs study.19 Second, pathologic acid exposure in the proximal esophagus is often identified in patients with respiratory symptoms and reflux disease. Third, scintigraphic studies have shown aspiration of ingested radioisotope in some patients with reflux and respiratory symptoms. Fourth, simultaneous tracheal and esophageal pH monitoring in patients with reflux disease has documented tracheal acidification in concert with esophageal acidification. Finally, animal studies have shown that tracheal instillation of hydrochloric acid profoundly increases airway resistance.20 A reflex mechanism is primarily supported by the fact that bronchoconstriction occurs after the infusion of acid into the lower esophagus.21 This mechanism can be explained first by the common embryologic origin of the trachea and esophagus and their shared vagal innervation. Second, patients with respiratory symptoms and pathologic distal esophageal acid exposure but normal proximal esophageal acid exposure may experience an improvement in their respiratory symptoms after antireflux therapy. The primary challenge in implementing treatment for reflux-associated respiratory symptoms or complications lies in establishing the correct diagnosis. In those patients with predominantly typical reflux symptoms and secondary respiratory complaints, the diagnosis may be straightforward. In a substantial number of patients with reflux-induced respiratory symptoms, however, the respiratory symptoms dominate the clinical scenario (Fig. 4-5). Gastroesophageal reflux

Chapter 4 Clinical Features of Esophageal Disease

ESOPHAGUS

CNS

Reflux

FIGURE 4-4 “Reflux” and “reflex” mechanisms to explain the extraesophageal manifestations of GERD. CNS, central nervous system.

TRACHEOBRONCHIAL TREE

AIRWAY

Microaspiration

Mediator release

Airway vagal afferents

Inflammation Edema

Esophageal vagal afferents

CNS

Airway vagal efferents

Heightened bronchial reactivity

Mucus

Smooth muscle

Extraesophageal and GI symptoms

39% 45%

Extraesophageal symptoms only GI symptoms only

16%

(N = 636)

FIGURE 4-5 Prevalence of extraesophageal symptoms in patients referred for antireflux surgery. GI, gastrointestinal. (FROM SONTAG SJ: IN STEIN M [ED]: GERD AND AIRWAY DISEASE. 1999, PP 115-138.)

in these patients is often silent and is only uncovered when investigation is initiated. A high index of suspicion is required, notably in patients with poorly controlled asthma in spite of appropriate bronchodilator therapy. Supportive evidence for the diagnosis of GERD can be gleaned from endoscopy and stationary esophageal manometry. Endoscopy may show erosive esophagitis or Barrett’s esophagus. Manometry may indicate a hypotensive LES or ineffective body motility, defined by 30% or more contractions in the distal esophagus of less than 30 mm Hg in amplitude. The gold standard for the diagnosis of reflux-induced respiratory complaints has been ambulatory dual-probe pH monitoring. One probe is positioned in the distal esophagus and the other at a more proximal location. Sites for proximal probe placement have included the trachea, pharynx, and proximal esophagus. Most authorities would agree that the proximal esophagus is the preferred site for proximal probe placement. Whereas ambulatory esophageal pH monitoring allows a direct correlation between distal or proximal esophageal acidification and extraesophageal symptoms, this technique has many limitations. The temporal relationship between reflux events and symptoms is complex, in that remote events can trigger symptoms at points well in the future. The threshold for what is considered an abnormal amount of proximal refluxate has not been well established. While evidence would suggest proximal acid exposure more

than 1% to 2% of the total time to be abnormal, this threshold does not reliably discriminate between the presence and absence of symptoms or signs of inflammation. Even minimal reflux events have the potential to trigger extraesophageal symptoms, whereas more extensive proximal reflux does not necessarily trigger symptoms in all individuals. Some authors, therefore, have utilized the “symptom index,” defined as the percent of symptom events associated with reflux episodes, to determine whether reflux is causative of a particular complaint.22 Finally, pH monitoring does not detect non–acid reflux events, which clearly have the potential to trigger symptoms. The technology of combined multichannel intraluminal impedance (MII) and pH monitoring provides better elucidation of reflux episodes and allows classification of reflux into acid, weakly acid, and non-acid events.23 Treatment. Once gastroesophageal reflux is thought to be responsible for laryngeal or pulmonary symptoms, a trial of medical therapy should be initiated. An important principle is that the extraesophageal manifestations of GERD tend to take much longer to resolve than do typical reflux symptoms after GERD-specific therapy, whether it be medical or surgical, is instituted. A common pitfall is that an inadequate trial of therapy, either in terms of intensity of acid suppression or duration of therapy, is undertaken. Patients, therefore, may be deemed to have failed medical therapy, and underlying reflux is ruled out as an underlying cause of symptoms, at times when reflux is, in fact, causative. Current recommendations are for a 3- to 6-month trial of high-dose PPI therapy (with twice or thrice daily dosing) with assessment of symptom resolution. Such a trial of high-dose PPIs is helpful as both a diagnostic and therapeutic maneuver. In those with relief of symptoms, reflux is presumed to be partly or completely responsible. Maintenance therapy, whether it is medical or surgical in the form of an antireflux operation, can then be discussed with the patient. In the presence of atypical symptoms, the outcome of antireflux surgery tends to be better in patients with a good response to medical treatment rather than those who fail to respond. A clinical situation commonly encountered by the esophageal surgeon is the patient referred for antireflux surgery with persistent extraesophageal symptoms despite intensive medical therapy for GERD. The referring clinician may still be suspicious of GERD, even in light of the poor clinical

55

56

Section 2 Investigation of Esophageal Disease

response, owing to the overall symptom complex or objective findings. Many findings, such as laryngeal erythema or edema, while often attributed to GERD, are nonspecific and quite prevalent even in normal subjects.24 Surgery should be recommended cautiously in these patients, because the diagnosis of GERD may be in doubt. The persistence of symptoms despite PPI treatment, however, does not necessarily rule out reflux as being a potential contributor. The algorithm depicted in Figure 4-6, which bases clinical decisions on the results of dual-probe 24-hour pH monitoring, is a useful starting point. One potential problem with such a treatment strategy is that acid reflux can continue despite such a PPI regimen. Also, non-acid reflux may be able to trigger symptoms as well. As stated earlier, MII-pH monitoring may be useful in detecting ongoing acid or non-acid reflux events despite intensive medical therapy. A perhaps better diagnostic and treatment algorithm utilizes such monitoring (Fig. 4-7). Limited data have shown that response to a fundoplication can be predicted by the results of combined MII-pH monitoring performed with the patient on medical therapy.25 Based on the available literature, relief of respiratory symptoms can be anticipated in 25% to 50% of patients with reflux-induced asthma treated with antisecretory medications.26-28 Fewer than 15%, however, can be expected to have objective improvements in their pulmonary function. The reason for this apparent paradox may be that most studies PPI BID × 3 months Improved

Maintenance therapy –PPI –H2RA

Not improved

Antireflux surgery

Not GERDrelated

???

pH monitoring on therapy

FIGURE 4-6 Algorithm for evaluation of extraesophageal symptoms of GERD using ambulatory pH monitoring. PPI, proton pump inhibitor; H2RA, histamine 2–receptor antagonist. Suspected GERD

Trial of PPIs Persistent symptoms

Success

Ambulatory MII-pH monitoring on Rx

Acid GERD

No GERD

Non-acid GERD

FIGURE 4-7 Algorithm for evaluation of extraesophageal symptoms of GERD using combined MII-pH testing. MII, multichannel intraluminal impedance; PPIs, proton pump inhibitors.

employed relatively short courses of antisecretory therapy (<3 months). This time period may have been sufficient for symptomatic improvement but insufficient for recovery of pulmonary function. The chances of success with medical treatment are likely directly related to the extent of reflux elimination. The conflicting findings of reports of antisecretory therapy may well be due to inadequate control of gastroesophageal reflux in some studies. The literature indicates that antireflux surgery improves respiratory symptoms in nearly 90% of children and 70% of adults with asthma and reflux disease (Harding et al, 1993; Sontag et al, 2003).28,29 Improvements in pulmonary function were demonstrated in around one third of patients. Comparison of the results of uncontrolled studies of each form of therapy and the evidence from the two randomized controlled trials of medical versus surgical therapy indicate that fundoplication is the most effective therapy for reflux-induced asthma (Sontag et al, 2003).29 The superiority of the surgical antireflux barrier over medical therapy is probably most noticeable in the supine posture, which corresponds with the period of acid breakthrough with PPI therapy and is the time in the circadian cycle when asthma symptoms and peak expiratory flow rates are at their worst. It is also important to realize that, in asthmatic patients with a non–reflux-induced motility abnormality of the esophageal body, performing an antireflux operation may not prevent the aspiration of orally regurgitated, swallowed liquid or food. This can result in respiratory symptoms and airway irritation that may elicit an asthmatic reaction. This factor may be the explanation why surgical results appear to be better in children than adults, because disturbances of esophageal body motility are more likely in adult patients.

Mucosal Complications Components of the gastric refluxate potentially injurious to the esophagus include gastric secretions, such as acid and pepsin, biliary and pancreatic secretions that regurgitate from the duodenum into the stomach, and toxic compounds generated in the mouth, esophagus, and stomach by the action of bacteria on dietary substances. Our current understanding of the role of the various constituents of gastric juice in the development of esophagitis is based on classic animal studies performed by Lillimoe and associates.30,31 These studies have shown that acid alone does minimal damage to the esophageal mucosa but that the combination of acid and pepsin is highly deleterious. Hydrogen ion injury to the esophageal squamous mucosa occurs only at a pH below 2. With acid refluxate, the enzyme pepsin appears to be the major injurious agent. Similarly, the reflux of duodenal juice alone does little damage to the mucosa, while the combination of duodenal juice and gastric acid is particularly noxious. Reflux of bile and pancreatic enzymes into the stomach can either protect or augment esophageal mucosal injury. For instance, the reflux of duodenal contents into the stomach may prevent the development of peptic esophagitis in a patient whose gastric acid secretion maintains an acid environment, because the bile salts attenuate the injurious effect of pepsin and the acid can inactivate trypsin. Such a

Chapter 4 Clinical Features of Esophageal Disease

patient would have bile-containing acid gastric juice that, when refluxed, would irritate the esophageal mucosa but cause less esophagitis than if it were acid gastric juice containing pepsin. In contrast, the reflux of duodenal contents into the stomach of a patient with limited gastric acid secretion can result in esophagitis, because the alkaline intragastric environment would support optimal trypsin activity and the soluble bile salts with a high pKa potentiate the enzyme’s effect. Hence, duodenogastric reflux and the acid secretory capacity of the stomach interrelate by altering the pH and enzymatic activity of the refluxed gastric juice to modulate the injurious effects of enzymes on the esophageal mucosa. This disparity in injury caused by acid and bile alone as opposed to the gross esophagitis caused by pepsin and trypsin provides an explanation for the poor correlation between the symptom of heartburn and endoscopic esophagitis. The reflux of acid gastric juice contaminated with duodenal contents could break the esophageal mucosal barrier, irritate nerve endings in the papillae close to the luminal surface, and cause severe heartburn. Despite the presence of intense heartburn, the bile salts present would inhibit pepsin, the acid pH would inactivate trypsin, and the patient would have little or no gross evidence of esophagitis. In contrast, the patient who refluxed alkaline gastric juice may have minimal heartburn because of the absence of hydrogen ions in the refluxate but have endoscopic esophagitis because of the bile salt potentiation of trypsin activity on the esophageal mucosa. This possibility is supported by recent clinical studies that indicate that the presence of alkaline reflux is associated with the development of mucosal injury (Kauer et al, 1995).32 Although numerous studies have demonstrated the reflux of duodenal contents into the esophagus in patients with GERD, few have measured this directly. The components of duodenal juice thought to be most damaging to the esophageal mucosa are the bile acids. Accordingly, they have been the most commonly studied. Most reports have indirectly measured the presence of bile acids using pH monitoring. Studies using either prolonged ambulatory aspiration techniques or spectrophotometric bilirubin measurement have shown that, as a group, patients with GERD have greater and more concentrated bile acid exposure to the esophageal mucosa than normal subjects.33,34 This increased exposure occurs most commonly during the supine period while asleep and during the upright period after meals. Most studies have identified the glycine conjugates of cholic, deoxycholic, and chenodeoxycholic acids as the predominant bile acids aspirated from the esophagus of patients with GERD, although appreciable amounts of the taurine conjugates of these bile acids are also found. Other bile acids may be identified in small concentrations. Because glycine conjugates are three times more prevalent than taurine conjugates in normal human bile, these relative ratios are as one would expect. The potentially injurious action of toxic compounds either ingested or formed intraluminally on the mucosa of the distal esophagus and gastroesophageal junction has long been postulated. Until recently, however, few studies have substantiated this effect. Expanding on studies of acid exposure at the gastroesophageal junction, investigators from Glasgow, Scotland, have recently shown that dietary nitrate consumed

in the form of green vegetables or other foods contaminated by nitrate-containing fertilizers results in the generation of nitric oxide at the gastroesophageal junction in concentrations high enough to be potentially mutagenic.35 Previous studies have shown that nitrate ingested in food is reabsorbed in the small bowel, with approximately 25% re-secreted into the mouth via the salivary glands. Oral bacteria chemically transform the relatively innocuous nitrate to the more toxic nitrite, which is swallowed and subsequently converted to nitric oxide and other nitroso compounds by acid and ascorbate in the stomach. Whether this mechanism, in fact, contributes to injury and/or neoplastic transformation in the upper stomach, gastroesophageal junction, and distal esophagus is unknown.

Metaplastic (Barrett’s) and Neoplastic (Adenocarcinoma) Complications The condition whereby the tubular esophagus is lined with columnar epithelium rather than squamous epithelium was first described by Norman Barrett in 1950.36 He incorrectly believed the condition to be congenital. It is now known to be an acquired abnormality, occurring in 7% to 10% of patients with GERD and representing the end stage of the natural history of this disease (Peters et al, 2004).37 The definition of Barrett’s esophagus has evolved considerably over the past decades (Peters et al, 2004).36-38 Traditionally, the term Barrett’s esophagus was used to denote an esophagus with columnar mucosa of any type extending for more than 3 cm above the gastroesophageal junction. More recent data indicating that specialized intestinal-type epithelium is the only tissue predisposed to malignant degeneration, coupled with the finding of a similar risk of malignancy in segments of intestinal metaplasia less than 3 cm long, have resulted in the definition of Barrett’s esophagus as any length of endoscopically visible esophageal columnar mucosa that demonstrates intestinal metaplasia on histologic assessment. The hallmark of intestinal metaplasia is the presence of goblet cells. Recent studies have identified a high prevalence of biopsy-proven intestinal metaplasia at the gastric cardia, not visibly extending onto the esophagus. The significance and natural history of this cardia intestinal metaplasia remains unknown. Factors predisposing to the development of Barrett’s esophagus include early-onset GERD, abnormal LES and esophageal body physiology, and mixed reflux of gastric and duodenal contents into the esophagus.39 Direct measurement of esophageal bilirubin exposure as a marker for duodenal juice has shown that 58% of the patients with GERD have increased esophageal exposure to duodenal juice and that this exposure is most dramatically related to Barrett’s esophagus. The Development of Dysplasia in Barrett’s Esophagus. The prevalence of dysplasia in patients presenting with Barrett’s esophagus ranges from 15% to 25% if low-grade dysplasia is included and 5% to 10% if only highgrade dysplasia is considered. The identification of dysplasia in Barrett’s epithelium rests on histologic examination of biopsy specimens. The cytologic and tissue architectural changes are similar to those described in ulcerative colitis.

57

58

Section 2 Investigation of Esophageal Disease

By convention, Barrett’s metaplasia is currently classified into four broad categories: 1. 2. 3. 4.

No dysplasia Indefinite for dysplasia Low-grade dysplasia High-grade dysplasia

There are few prospective studies documenting the progression of non-dysplastic Barrett’s epithelium to low- or high-grade dysplasia. Those that are available suggest that 5% to 10% per year will progress to dysplasia and 0.5% to 1% per year will progress to adenocarcinoma. Once identified, patients with Barrett’s esophagus complicated by dysplasia should undergo aggressive therapy. Patients whose biopsies are interpreted as indefinite for dysplasia should be treated with a medical regimen consisting of 60 to 80 mg of PPI therapy for 3 months and resampled. Importantly, esophagitis should be healed before interpretation of the presence or absence of dysplasia. The presence of severe inflammation makes the microscopic interpretation of dysplasia difficult. The purpose of acid suppression therapy is to resolve inflammation that may complicate the interpretation of the biopsy specimen. If the diagnosis remains indefinite, the patient should be treated as if low-grade dysplasia were present with continued medical therapy or antireflux surgery and repeat biopsy every 6 months. Patients with low-grade dysplasia are perhaps the most difficult group. This is due to the potential difficulty in surveillance after antireflux surgery. Biopsies within the fundic wrap may be difficult for the inexperienced endoscopist. Either aggressive medical treatment or, given an experienced endoscopist, antireflux surgery is appropriate. High-grade dysplasia should be confirmed by two pathologists knowledgeable in gastrointestinal pathology. Corroboration of dysplasia is important before consideration of esophagectomy. Most authorities would agree that the current standard of care is to proceed with esophagectomy in patients with high-grade dysplasia who are physiologically fit enough to tolerate a major surgical undertaking. Recent less-invasive options, including photodynamic therapy and endoscopic mucosal resection, have been reported with some success40,41 but remain largely investigational or reserved for high-risk surgical candidates. A recent randomized, phase III trial of photodynamic therapy plus omeprazole versus omeprazole alone in the treatment of Barrett’s esophagus with high-grade dysplasia demonstrated a reduction in the development of invasive cancer from 28% in the omeprazole group to 13% in the photodynamic therapy plus omeprazole group during the study period.41 On average, 30% to 40% of patients with the preoperative diagnosis of Barrett’s esophagus with high-grade dysplasia will harbor invasive cancer when the specimen is removed and examined in its entirety. Thus, high-grade dysplasia is a marker for the presence of invasive carcinoma in approximately one third of patients. This fact has been confirmed in studies from the University of Southern California as well as those from the Mayo Clinic, Johns Hopkins University, and many other centers around the world.42-45 It is not possible with present technology, including endoscopic ultrasound, to differentiate the patients who harbor a cancer from those who do not. Furthermore,

esophageal adenocarcinoma associated with high-grade dysplasia, identified by surveillance endoscopy, is generally highly curable. We and others have documented 5-year survival rates of 90% in this setting.

SUMMARY Esophageal disorders are quite prevalent in today’s society. The incidence and recognition of esophageal disease appear to be increasing, without any obvious reversals to this trend being immediately apparent. Because the association between an esophageal problem and the symptoms of a patient may not be immediately identifiable by either the patient or physician, the ability to elicit an accurate history is paramount to starting an appropriate diagnostic workup. An understanding of the underlying pathophysiology of foregut disorders is also important to an appreciation of the various symptoms and complications with which the patient may present. Our ability, as foregut physicians and surgeons, to treat such problems effectively is only as good as our ability to make an accurate assessment and diagnosis. Even the most perfectly executed medical intervention or surgical therapy will lead to a suboptimal outcome if undertaken for the incorrect indication or with a poor understanding of the anticipated benefits. Because the presentations of foregut disorders tend to overlap with those of other disease processes, and because our current testing modalities have clear limitations in certain circumstances, further study is necessary to allow refinements in diagnosis and therapy that will lead to continued improvement in outcomes.

COMMENTS AND CONTROVERSIES The art of careful history taking is a forgotten task in esophageal disease, perhaps because of the simple function of the esophagus. However, the importance of a good history and physical examination cannot be taken too lightly. It will permit clinical diagnosis and direct future testing. Treatment and outcome assessment are not possible without baseline symptom assessment. When eliciting a history it is important to remember (1) the pump-valve-reservoir analogy of the foregut and (2) the three regions from which symptoms may be elicited (pharynx/cricopharyngeus/esophagus, esophagus/lower esophageal sphincter/stomach, and stomach/pylorus/ duodenum). In the Western world GERD is the most common esophageal disorder seen by surgeons. The clinical features and myriad presentations of GERD and its complications must be fully understood to permit a careful patient assessment. Only then can the value of surgical intervention in this interesting and diverse patient population be evaluated. Drs. Watson and Peters have provided an excellent review of the clinical features of esophageal disease with emphasis on the most important clinical problem seen today, GERD. T. W. R.

KEY REFERENCES Costantini M, Crookes PF, Bremner RM, et al: Value of physiologic assessment of foregut symptoms in a surgical practice. Surgery 114:780-786, 1993.

Chapter 4 Clinical Features of Esophageal Disease

■ This manuscript discusses the unreliability of symptom assessment in the evaluation

of GERD and reviews the role of diagnostic testing in confirming the diagnosis. Harding SM, Richter JE, Guzzo MR, et al: Asthma and gastroesophageal reflux: Acid suppressive therapy improves asthma outcome. Am J Med 100:395-405, 1996. ■ This paper contains an excellent discussion of the relationship between GERD and asthma and formulates a rational treatment approach to GERD-induced asthma. Kauer WKH, Peters JH, DeMeester TR, et al: Mixed reflux of gastric juice is more harmful to the esophagus than gastric juice alone: The need for surgical therapy re-emphasized. Ann Surg 222:525-533, 1995. ■ The authors review the pathophysiology of GERD-induced intestinal metaplasia and neoplasia of the esophagus with implications about the potential benefits of antireflux surgery.

Peters JH, Hagen JA, DeMeester SR: Barrett’s esophagus. J Gastrointest Surg 8:1-17, 2004. ■ This manuscript is an excellent synopsis of the recent thoughts regarding all aspects of Barrett’s esophagus. Sontag SJ, O’Connell S, Khandelwal S, et al: Asthmatics with gastroesophageal reflux: Long-term results of a randomized trial of medical and surgical antireflux therapies. Am J Gastroenterol 98:987-999, 2003. ■ This report is of the long-term outcomes of a randomized trial of medical and surgical therapy for GERD-induced asthma that confirms the superiority of surgical therapy.

59

Imaging chapter

5

RADIOLOGY, COMPUTED TOMOGRAPHY, AND MAGNETIC RESONANCE IMAGING Mark E. Baker David M. Einstein

Key Points ■ Using meticulous technique and a tailored approach, the barium

esophagogram is an essential diagnostic examination in patients with esophageal diseases. ■ The barium esophagogram is the single most comprehensive examination in patients with GERD before and after antireflux surgery. ■ CT or MRI is essential to identify and characterize disease extrinsic to the esophagus.

In the new millennium, imaging remains an important aspect in evaluating patients with esophageal diseases. Although the barium esophagogram has fallen into disuse in many institutions, supplanted by endoscopy and manometry, we find that it remains an essential tool in evaluating patients with esophageal symptoms, especially dysphagia. In the past, computed tomography (CT) was used for locoregional and distant staging of esophageal carcinoma. It now is used primarily in conjunction with positron emission tomography (PET), providing attenuation correction data for the PET scan as well as an anatomic road map for precise location of hypermetabolic activity. Lastly, although magnetic resonance imaging (MRI) is rarely used in assessing patients with esophageal disease, when an enhanced CT is contraindicated MRI with gadolinium enhancement is a very reasonable alternative for staging patients with esophageal carcinoma. The purpose of this chapter is to discuss the radiographic techniques used in assessing patients with esophageal diseases. PET/CT and endoscopic ultrasonography are discussed in Chapters 6 and 7 but are referred to when appropriate.

BARIUM ESOPHAGOGRAPHY Because of the ubiquitous use of endoscopy, the barium esophagogram has been relegated to the museum in many institutions. As a result, many recent radiology trainees have not been adequately instructed in the proper performance and interpretation of this examination in patients with esophageal disease. Furthermore, in the past 25 years some gastrointestinal radiologists have stressed the mucosal aspect of the examination in an attempt to compete with endoscopy. This has led to an emphasis on aspects of the examination that are of less importance to the gastroenterologist and esophageal surgeon and a de-emphasis on those aspects of the examination that are helpful. In our institution, nearly every patient with dysphagia has a barium esophagogram regardless of whether an endoscopy has been or will be performed. 60

The barium esophagogram can be divided into seven phases1-3 (Baker et al, 2007): 1. 2. 3. 4. 5. 6. 7.

The timed barium swallow4 The upright, mucosal or double-contrast phase The motility phase The semiprone, distended, single-contrast phase Reflux identification The “solid” food phase The oropharyngeal phase

The oropharyngeal phase of the examination is not discussed in this chapter, but it should be stressed that if an oropharyngeal examination is performed by a trained speech pathologist, and the findings do not explain the patient’s symptoms, a formal esophagogram, termed by us a followthrough examination, must be performed. Many patients have upper esophageal and oropharyngeal symptoms that are caused by nonoropharyngeal problems. We tailor our examination to best evaluate the individual patient. Before the start of any barium examination we take a brief history. The patient is asked about dysphagia, heartburn, chest pain, regurgitation, length and frequency of symptoms, and weight loss. It is important to know if the patient has dysphagia to solids or liquids, because the initial examination will change based on this information. From this history, the radiologist is able to take a rational, stepwise approach toward the examination.

Timed Barium Swallow Phase Most patients with dysphagia to liquids have a severe motility disorder, usually achalasia or diffuse esophageal spasm (DES). Therefore, in our institution any patient with dysphagia to liquids is always first evaluated with a timed barium swallow (Box 5-1),4 which rapidly and accurately quantifies esophageal emptying (Fig. 5-1).5,6 This test is simply performed by asking the patient to ingest a tolerable volume of low-density barium, up to 250 mL, in 45 seconds. Because the ingested volume is self-regulated, there should be no problem with aspiration. The volume of barium ingested is recorded by the technologist. Timed spot films are taken at 1, 2, and 5 minutes. The 2-minute film serves as an intermediate assessment of emptying. A normal patient should easily and rapidly ingest 250 mL of barium, and a normal esophagus should rapidly empty this volume in less than 1 minute. Some patients with achalasia may empty this volume in 2 minutes. Any retained barium in the esophagus is abnormal and strongly suggests a motility disorder. The volume of barium ingested as well as the maximum height and width of the barium

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

Box 5-1 Timed Barium Swallow Technique Initial Pretreatment Examination ■ Patient is upright throughout the entire study. ■ Patient ingests up to 250 mL of low-density barium (68% w/v) over 35 to 40 seconds, with barium volume ingested based on patient tolerance. The volume ingested is documented. ■ Digital spot films are obtained 1, 2, and 5 minutes after ingestion with the patient in a left posterior oblique position. Positioned behind the patient is a ruler with radiopaque markers. The distance of the fluoroscopic carriage from the patient is kept constant for all spot films. The 2-minute film is optional, but fluoroscopy at 2 minutes serves to determine the state of emptying. ■ The degree of emptying is estimated quantitatively by comparing the 1- and 5-minute films, measuring the maximum height and width of the barium column. If there is a barium and food or foam interface, the height of the column is measured at this interface. If no consistent interface is present, a “best guess” is made on both the 1- and 5-minute films. The entire barium column with foam is not measured. Follow-up, Post-Treatment Examinations The same technique as above is done using the same barium volume the patient ingested on the initial examination. If the initial ingested volume was less than 250 mL, and this clears within 5 minutes, a repeat examination is performed with the patient attempting to ingest up to 250 mL of barium. This second ingested volume then becomes the baseline for further evaluations.

column is recorded at 1 and 5 minutes. The effect of any subsequent intervention is compared with this baseline examination. If the timed barium swallow phase shows no emptying problems, we then continue with the standard study. If the emptying is impaired, we move to an assessment of motility, foregoing the air-contrast portion of the examination. Using this technique, we can (1) objectively assess the initial and post-treatment barium column height and diameter and the degree of emptying over time, (2) objectively correlate any change in symptom score with esophageal emptying, and (3) predict the outcome of pneumatic dilation based on the diameter of the pretreatment esophagus. We have found that in most patients the degree of symptom improvement correlates with the degree of esophageal emptying. In a study of 37 patients undergoing 53 pneumatic dilations, 38 of 53 dilations (72%) showed similar improvements in symptom score and esophageal emptying on the timed barium study.5 However, in the 26 patients with a complete resolution of symptoms, 8 showed a less than 50% change in barium height on the 5-minute film when compared with the barium height in the pretreatment study. These patients tended to be older. We also have found that patients with a pretreatment diameter of more than 8 cm do not show much improvement in esophageal emptying using the timed study.

tions this portion of the examination is less important because many patients will have an endoscopy. In other institutions, the barium examination is used as a primary means to detect reflux esophagitis and the potential complications of gastroesophageal reflux disease (GERD).7-9 In our institution, the most important aspect of this phase of the examination is the detection of a fixed hiatal hernia (Baker et al, 2007).3 Many patients with GERD have a hiatal hernia, especially those patients with esophagitis.8-10 The anatomy of hiatal hernias was defined by Allison and by Skinner and Belsey.11,12 Since then, four types have been defined: type I or the common, sliding hiatal hernia (see Fig. 5-2); type II or a true paraesophageal hernia without displacement of the gastroesophageal junction above the diaphragm (a rare hernia) (Fig. 5-3); type III (commonly referred to as a paraesophageal hernia or mixed hernia) with intrathoracic displacement of the gastroesophageal junction (Fig. 5-4); and type IV, which is a type III hernia associated with herniation of other intra-abdominal organs, such as the colon or pancreas (Fig. 5-5). In evaluation of GERD patients, the radiographic identification of the hiatal hernia type is less important in patient care unless there is a type II or large type III or IV hernia, which may become incarcerated. The critical finding in any barium examination is whether the hernia is fixed or persists in the upright position13-15 (Figs. 5-6 and 5-7), which implies esophageal foreshortening. Additionally, foreshortening is assumed when there is a hiatal hernia larger than 5 cm alone or in combination with a stricture or long-segment (>3 cm) Barrett’s esophagus.16-18 Other findings that suggest a foreshortened esophagus include severe, extensive ulcerative esophagitis, straightening or loss of the angle of His, the presence of a stricture alone, and type III mixed or complex paraesophageal hernias.14,19-21 Identification of a scarred, foreshortened esophagus is important because many surgeons believe that a lengthening procedure, such as a Collis gastroplasty or a more extensive esophageal mobilization, is essential to achieve an adequate antireflux operation.13,14,16,22-24 Most antireflux operations are now performed laparoscopically. The pneumoperitoneum created elevates the diaphragm superiorly and spuriously “lengthens” the esophagus. If a laparoscopic procedure is performed without recognition of a foreshortened esophagus, there may be an unrecognized, inadequate length of intraabdominal esophagus at surgery. Furthermore, the surgeon may not be able to assess accurately whether the esophagus has been adequately mobilized for hernia reduction without tension. When the repair is constructed under tension with a foreshortened esophagus, the hernia is reduced below the diaphragm and then retracts up into the chest over time. The fundoplication may or may not remain subdiaphragmatic, or it may disrupt by “slipping” onto the stomach or disrupt completely. We believe that most “slipped” Nissen fundoplications result from the failure to recognize a foreshortened esophagus before surgery.

Upright, Mucosal or Double-Contrast Phase

Motility Phase

The double-contrast portion of the barium esophagogram is designed to evaluate the mucosa (Fig. 5-2). In many institu-

The motility phase is performed with the patient in the horizontal, semiprone, right anterior oblique (RAO) position.

61

62

Section 2 Investigation of Esophageal Disease

250 mL 5 minutes 1 minute

115 pix 105 pix 105 pix

101 pix 112 pix

115 pix

101 pix

112 pix

A

B

FIGURE 5-1 Timed barium swallow in a patient with achalasia. The patient ingested 250 mL of barium over 45 seconds. One-minute (A) and 5-minute (B) films show the amount of barium retention; there is a large amount of foam on both. The height of the barium/foam interface is estimated on both films. A ruler is taped onto the upright table, and the patient is positioned in a fashion to place the barium column in the esophagus just to the left of the ruler. The height and width are measured and compared with the ruler (some digital fluoroscopic units are not calibrated to measure in centimeter units, hence, the use of the ruler).

We ask the patient to ingest a single, small (5-10 mL) mouthful of low-density (45% w/w; 68% w/v) barium. Fluoroscopy should start in the oropharynx and focus on the inverted, V-shaped, proximal end of the barium column. The inverted V corresponds with the start of the upstroke of the primary peristaltic wave25,26 and should rapidly and consistently progress distally to the level of the gastroesophageal junction (a progressive, aboral wave). Generally, we perform five separate swallows separated by 25 to 30 seconds, unless there is a consistent, abnormal pattern after three swallows.26 In a study of simultaneous manometry and barium fluoroscopy, the use of five separate swallows was concordant with manometry in 92% of examinations.25 A videotaped recording of this phase is essential for review. To describe the findings, we use the following subjective terms: normal peristalsis; low amplitude, nonocclusive peristalsis (i.e., significant retrograde escape); nonsegmental tertiary contractions (nonocclusive contractions); segmental tertiary contractions (occlusive contractions); and aperistalsis. The fluoroscopic assessment of esophageal motility is very helpful in evaluating a patient with dysphagia. Dysphagia is a common symptom in esophageal disease, especially GERD. Dysmotility in GERD patients is common27-30 with one recent

report estimating that up to 35% of patients with nonspecific esophageal dysmotility have GERD.30 In our experience, most patients presenting with dysphagia have direct or indirect evidence of reflux disease. Often, the esophagus demonstrates low-amplitude, nonocclusive peristalsis with significant retrograde escape. In some patients, there are vigorous, nonpropulsive tertiary contractions. In all of these patients, a normal lower esophageal sphincter (LES) excludes achalasia. Other important causes of dysphagia include severe motility disorders such as achalasia and DES. Abnormal motility may be the first indication of these diseases in a patient. We use the motility portion of the barium examination to complement the standard manometric study. However, there remain institutions where a surgeon does not perform a preoperative manometry or it is unavailable. Thus, the motility portion of the barium examination may be the only assessment of esophageal motility. In these cases it is essential that a patient with a severe motility disorder (e.g., achalasia) be identified for proper treatment. We have seen several patients with unrecognized achalasia treated with a fundoplication. It is also important to remember that manometry measures luminal pressure change while the motility portion of the

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

R

13 mm

HH

HH

A

B

C

FIGURE 5-2 Type I or sliding hiatal hernia with a distal mucosal ring and gastroesophageal reflux. A, The upright, double-contrast portion of the barium esophagogram shows that the gastroesophageal junction is at the diaphragm (arrows). B, The semiprone, single-contrast portion of the examination shows a small, sliding hiatal hernia (HH) pushed into the mediastinum by the increased intra-abdominal pressure, as well as a 13-mm distal, mucosal ring (arrows). C, With the patient in the supine position there is spontaneous reflux (R) of the barium to the thoracic inlet. The hiatal hernia (HH) and mucosal ring (arrows) are also evident.

esophagogram measures bolus transit. This essential difference between the tests has been elucidated by comparisons of manometry and impedance monitoring (a new technique that assesses bolus transfer in the esophagus).31 In evaluating patients with ineffective esophageal motility (defined by contractions <30 mm Hg) with simultaneous manometry and impedance, Tutian and Castell found that 48% of liquid swallows and 34% of viscous swallows had complete bolus transfer.31 By manometric criteria, these were considered abnormal. This discrepancy between bolus transit and manometry has been confirmed by others.32 In our experience of concurrent video-esophagograms and impedance monitoring, barium studies mimic impedance findings.33,34 Even if impedance is available, the motility portion of the barium examination adds little time and no additional cost to the evaluation, and it can provide helpful information. In general, patients with poor or absent peristalsis can have poor outcomes after a complete, 360-degree Nissen fundoplication, because the low-amplitude pressure wave of the esophagus is inadequate to overcome the pressure gradient created by the Nissen fundoplication. In these

patients, some surgeons would consider a partial wrap, such as a 270-degree Toupet, in an attempt to avoid dysphagia that might occur after a complete 360-degree fundoplication. We perform Nissen fundoplications for all but aperistaltic esophagi. Amplitude is a factor, but the number of nonconducted waves is equally important.

Semiprone, Distended, Single-Contrast Phase As in the motility phase, the distended, single-contrast phase is performed with the patient in the RAO, or semiprone, position and is also videotaped before spot films are taken. During this phase, we can identify a subtle distal mucosal ring or a stricture that can be missed by even skilled endoscopists. We perform fluoroscopy over 3 to 6 seconds while panning down the esophagus, concentrating on the distal esophagus and gastroesophageal junction. Relying on fluoroscopy rather than spot films, we identify more subtle strictures, contour abnormalities, and distal mucosal rings on the videotape (see Fig. 5-2). Spot films are taken after we have thoroughly examined the esophagus fluoroscopically. During this phase,

63

64

Section 2 Investigation of Esophageal Disease

B

F A F

FIGURE 5-3 Type II paraesophageal hernia. The fundus of the stomach (F) has herniated above the diaphragm (arrow) in a paraesophageal fashion. There is a small hiatal hernia (arrowhead), so this is technically a type III, or mixed, hernia, with a predominant paraesophageal component. True type II hernias are very rare.

we also identify most small type I hernias owing to the increased intra-abdominal pressure caused by the semiprone position of the patient (see Fig. 5-2).

FIGURE 5-4 Type III hernia with organoaxial rotation. This is a large hernia, with almost all of the stomach (fundus [F], body [B], and antrum [A]), above the diaphragm. The gastroesophageal junction (arrow) is close to the diaphragm. The stomach has rotated up into the mediastinum along a 180-degree axis, from inferior to superior. Thus, it has rotated in an organoaxial fashion. These large hernias can also twist along the z-axis in a mesoaxial fashion.

S

Reflux Identification Phase For reflux identification, we use provocative maneuvers such as straight-leg raising, cough, Valsalva maneuver, and water siphon test (see Fig. 5-2). After the full-column or distended phase, while the patient is lying in the semiprone position, we fluoroscopically examine the entire esophagus to confirm that all the ingested barium has cleared the esophagus. If it has not after several seconds, we raise the patient into a 45degree, semierect position and fluoroscopically confirm that the barium has cleared the esophagus. If barium remains in the esophagus despite positional change, we have the patient ingest several swallows of water. We then bring the patient to the horizontal, supine position. At this point, any fluoroscopically identified esophageal barium must have resulted from reflux. If none is present, we then proceed with a fluoroscopic assessment provocative maneuvers. Whenever reflux is identified, the maneuver causing the reflux, the height of the reflux, and the clearance time of the reflux are recorded. Clearance time is subjectively divided into less than 30 seconds and more than 30 seconds. The efficacy and importance of reflux identification on the barium esophagogram has been questioned by many authors.35 Many studies have shown that the barium examination is insensitive when compared with 24-hour pH studies.35

FIGURE 5-5 Type IV hiatal hernia containing pancreas. A coronal, multiplanar, reconstruction of a multidetector CT acquisition shows the stomach (S) has herniated into the chest in an organoaxial fashion. Additionally, the pancreas (arrow) has been pulled into the chest.

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

HH

HH HH

A

B

FIGURE 5-6 Distal, peptic esophageal stricture with a fixed hiatal hernia (i.e., foreshortened esophagus). A, Upright, double-contrast portion of the barium esophagogram shows a hiatal hernia (HH) above the diaphragm (arrowheads) and suggests a subtle distal esophageal stricture (arrow). B, Semiprone, single-contrast phase of the examination confirms the presence of a stricture (arrow) and the hiatal hernia (HH).

FIGURE 5-7 Long barrett’s stricture associated with a fixed hiatal hernia (i.e., foreshortened esophagus). Upright, double-contrast portion of the barium esophagogram shows a fixed hiatal hernia (HH) and a long mid- to distal stricture (arrows). A small ulcer is present in the left, anterolateral wall (arrowhead).

However, Thompson, Koehler, and Richter studied 117 patients with clinical findings suggestive of reflux with barium esophagograms and 24-hour pH studies (70 patients had positive 24-hour pH studies and 47 had negative studies).36 These investigators found that with increasing the number of provocative maneuvers (spontaneous, cough/Valsalva maneuver, rolling patient and water siphon test) a 70% sensitivity and 74% specificity could be achieved vis-à-vis 24-hour pH studies. Our experience confirms the findings of Thompson, Koehler, and Richter. In a relatively small number of patients (N = 26), barium had a 65% sensitivity and a 67% specificity relative to 24-hour pH studies (unpublished data). In our practice, the sensitivity of the barium examination in reflux identification is largely irrelevant. As with the motility findings on barium vis-à-vis manometry, the barium assessment of reflux provides the gastroenterologist and surgeon complementary information with 24-hour pH studies. In our practice, the most important part of reflux identification is the volume of reflux (i.e., the height of barium reflux) and the rate of barium clearance from the esophagus. There is no other method available to measure reflux volume. We believe that identifying a large volume (into the proximal esophagus), poorly clearing reflux episode or continuous, spontaneous reflux on barium examinations is more important than a

single, small, rapidly clearing episode (see Fig. 5-2). We do not believe that trace, low-volume reflux that rapidly clears is clinically important.

“Solid” Food Phase The last portion of the examination involves ingesting food or a food surrogate. We use a 13-mm barium sulfate tablet (E-Z-EM Inc., Westbury, NY) whereas others use marshmallows cut into well-defined sizes of increasing diameter.37 In the upright position, the patient swallows the tablet with water. In some patients, this tablet transiently slows or stops at the level of the aortic arch. This is almost always normal and will clear rapidly with another swallow of water. The tablet may also get caught in the valleculae, which may or may not be due to an oropharyngeal problem. The tablet is most useful in detecting or confirming a subtle distal esophageal stricture or the significance of a distal mucosal ring already identified on the previous portions of the examination. Many patients with a subtle stricture have accommodated to that stricture by taking progressively smaller boluses of food or liquid. Despite encouraging efforts, they simply will not rapidly ingest an adequate volume of barium during the single-contrast phase of the examination to demonstrate the stricture. A tablet will confirm the presence of such a

65

66

Section 2 Investigation of Esophageal Disease

stricture. If it is obvious that a ring or stricture will obstruct the tablet, we generally do not use the tablet, although most of our referring physicians prefer that we do use the tablet. Some patients are given a barium paste or pudding, graham cracker, or other solid food mixture to assess the degree of solid emptying. Because there are no standards for solid food passage, we have found interpretation to be very difficult and have largely abandoned this part of the examination. However, there are cases where solid food is helpful in confirming specific complaints in a patient. Some patients may complain of dysphagia only with certain foods, such as chicken or bread. In our practice, when a patient has dysphagia to a specific food, the referring gastroenterologist or surgeon encourages the patient to bring the particular food to the examination so that solid food emptying can be observed. As with pudding, we add barium paste to the food, have the patient chew the mixture, and then have him or her swallow. Sometimes with these patients the symptoms are encountered without any structural or motility abnormality. We find that when the patient views the video and is assured that no abnormality exists, the symptoms often improve. In this way, inappropriate antireflux surgery may be avoided.

COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING Computed tomography and MRI are the two cross-sectional modalities used in esophageal diseases. For the most part, neither is used to detect or characterize primary esophageal disease. They are, however, essential in evaluating neoplastic processes or in cases where extrinsic or metastatic disease may be present. Both are effective. The main advantage of CT is its speed and availability. Currently, with multidetector CT (MDCT) (see Fig. 5-5),38 the chest, abdomen, and pelvis can be scanned in less than 20 seconds. Furthermore, because MDCT produces a volume of information, scans can be reconstructed in multiple planes in addition to the traditional axial or transverse plane.39 For a complete examination, an intravenous injection of iodinated contrast media should be performed. Some patients with significant renal insufficiency or a history of a severe contrast reaction are generally not good candidates for this. Lastly, MDCT uses ionizing radiation. In most instances of adult use, this is not an issue. But for children, exposure to radiation is an issue and MRI is the preferred modality. Because recent technical and software improvements have markedly decreased imaging acquisition time, MRI is increasingly used in the evaluation of non-neurologic and musculoskeletal abnormalities.40 It is generally much more sensitive to disease detection but, as a result, tends to be more nonspecific. It does not use ionizing radiation and can directly scan any body part in unlimited planes. There are MRI techniques that are flow sensitive and, thus, are able to detect blood flow without intravenous contrast agents. However, like CT, intravenous enhancement is often desired to assess soft tissue structures. The preferred agent is gadoliniumDTPA. This agent acts like iodinated contrast media in CT. Although there are rare reactions, they are much less common than with iodinated agents. In the past, gadolinium was

thought to be safe in patients with renal insufficiency or failure; this may not be true.41

RADIOGRAPHIC FINDINGS IN SPECIFIC DISEASES Gastroesophageal Reflux Disease Assessment Before Antireflux Surgery Some patients with GERD symptoms do not have reflux disease but rather a misdiagnosed motility disorder. The classic symptoms of achalasia, including chest pain, regurgitation, dysphagia both solid and especially to liquids, and heartburn may overlap with those of GERD. Therefore, any patient with dysphagia to liquids is always evaluated first with a timed barium swallow to assess esophageal emptying as a manifestation of impaired motility and LES relaxation.4 Any delay in emptying indicates a motility disorder that is often not due to GERD. The barium esophagographic findings in a patient with GERD vary depending on the length and severity of disease (Baker et al, 2007).3,7-9,42 The examination may be completely normal. In general, there is a small, sliding hiatal hernia (hernia absent in the upright position but present during the semiprone, full-column phase of the examination) associated with variable degrees of identifiable reflux. Along with the hernia, there may be a distal mucosal ring or a prominent or persistent cricopharyngeal bar. More significant findings include a fixed hiatal hernia (hernia present in the upright phase of the examination) with or without a distal peptic stricture (Baker et al, 2007).3 The findings of reflux esophagitis include mucosal granularity or nodularity, ulceration, thickened folds, an inflammatory esophagogastric pseudopolyp, distal submucosal ridging or scarring, and a stricture.9 Many of these findings are only seen on the double-contrast portion of the examination. In a review of 37 patients with gastroesophageal reflux symptoms, double-contrast esophagographic examinations and endoscopic findings were compared with biopsy specimens as the reference standard.43 The sensitivity and specificity of barium and endoscopy compared with the biopsy were 35%/79% and 39%/71%, respectively. Most of these patients had mild to moderate esophagitis. In this series, the most common finding on the double-contrast barium study was a granular mucosa with a sensitivity of 35% and a specificity of 93%. At the end of the examination, our radiology report specifically addresses issues pertinent to the care of the patient (Baker et al, 2007).3 These include an emptying assessment in patients with dysphagia to liquids; the presence, type, and reducibility of a hiatal hernia; an assessment of esophageal motility; the presence of reflux, including maneuvers that elicited the reflux as well as the height of the refluxed barium and the time to clear the refluxed barium; and the presence or absence of a stricture or distal mucosal ring.

Assessment After Antireflux Surgery There are five symptom complexes that patients present with after antireflux surgery that may indicate a problem: dysphagia, epigastric pain/gas bloat, nausea and/or early satiety, recurrent reflux, and no improvement in symptoms immedi-

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

ately after surgery.44-48 Before the examination, it is helpful to know the patient’s predominant, currently presenting symptom. It is also important to know the symptom or symptoms that were present before the surgery. In general, GERD is not the cause of the symptoms in those patients who have no symptomatic relief immediately after antireflux surgery. In most instances, these are patients with atypical symptoms who also did not respond to medical treatment before surgery.

Barium Esophagography After Antireflux Surgery The examination after antireflux surgery is basically the same before surgery; however, there are some modifications and a different emphasis. A very tight fundoplication can often cause symptoms that mimic achalasia. Thus, any patient with dysphagia to liquids after antireflux surgery is first evaluated with a timed barium swallow. A normal esophagus should empty 250 mL of low-density barium within 1 minute. Any delay in emptying suggests that the fundoplication is too tight or that peristalsis is inadequate. If there is substantial retention of barium after the emptying study, we discuss the case and the need for further assessment with the referring clinician and may only give a barium tablet to confirm the “tightness of the fundoplication.” If esophageal emptying is normal, we then proceed with the upright, double-contrast portion of the examination. In this phase, we make concerted efforts to distend and coat the fundoplication. We achieve this by laying the patient in the supine position and thus allowing the high-density barium to reflux into the fundoplication. We then have the patient roll several times, attempting to keep the barium in the stomach as well as to coat the fundus and fundoplication. We then place the patient in the right lateral decubitus position and elevate him or her 45 degrees. At this point a spot film is taken of the gastroesophageal junction. In most cases the fundoplication is coated with barium and distended with gas; if not, we repeat the process. We then elevate the patient to the erect position and take spot films in the anteroposterior and right and left posterior oblique positions. Using this technique, we identify the fundoplication, its length, its position vis-à-vis the diaphragm, and what it surrounds (i.e., the stomach or the esophagus). It is important for the radiologist to make every effort not only to distend but also to coat the fundoplication to determine its integrity. After the double-contrast phase of the examination, we perform the motility phase followed by the semiprone drinking or distended phase of the examination. During this last phase, we focus on the distal esophagus and wrap location, fluoroscopically assessing the degree of distal esophageal distention to gauge the relative degree of obstruction caused by the fundoplication. If the wrap was not coated and distended during the mucosal portion of the examination, it usually is adequately distended and coated during this portion of the examination. We also examine the fundoplication location, attempting to assess the length of the fundoplication and what lumen has been encircled by the fundoplication, either the stomach, the distal esophagus, or both. The “tightness”

of the fundoplication is assessed by whether the ingested 13-mm tablet easily traverses the segment of esophagus or stomach surrounded by the wrap. Any delay over a few seconds or obstruction indicates a tight wrap. Lastly, gastric motility and emptying should be subjectively assessed. If there is any delay in emptying, the antrum, pylorus, and duodenum are assessed for a morphologic cause of gastric outlet impairment.

Post-Fundoplication Appearance on the Barium Esophagogram The normal Nissen fundoplication should have the following appearance: the fundoplication should be subdiaphragmatic with no recurrent hernia above it; the fundoplication should be less than 3 cm in length; the fundoplication should surround the distal esophagus with only a small amount of stomach included in the wrap; the fundoplication should not obstruct the ingested 13-mm tablet; there should be no reflux; and the fundoplication should not be twisted (Fig. 5-8). The length of the fundoplication is measured using electronic calipers on digital spot films or grossly estimated by comparing it to the ingested tablet (13 mm) on the videotaped document of the examination. In a normal fundoplication, it is usually very difficult to visualize the anterior blind

FIGURE 5-8 Normal Nissen fundoplication. The area of the wrap is identified on the semiprone, full-column phase of the barium esophagogram. The leaves of the wrap are not well visualized. Only the circumferential impression on the gastroesophageal junction (arrowheads) caused by the wrap is identified. The wrap encircles the gastroesophageal junction, is short (<3 cm), is intact, and is subdiaphragmatic. It did not impair the passage of the ingested 13-mm tablet.

67

68

Section 2 Investigation of Esophageal Disease

ends of the wrap, because it is difficult to reflux barium and gas into this portion of the repair (see Fig. 5-8). It is important to know the fundoplication type, because a Toupet or partial wrap less than 300 degrees can have the appearance of a disrupted fundoplication (Fig. 5-9). Additionally, a Collis-Nissen fundoplication has a characteristic appearance (Fig. 5-10). A variety of radiographic findings can be present in a symptomatic patient. We do not find it helpful to separate abnormal fundoplications into various types, because often they do not fit into discrete categories.49-53 We would rather describe each aspect of the fundoplication. First, it is important to determine the integrity of the fundoplication, whether it is intact or partially or completely disrupted. Then it is important to determine the position of the fundoplication in relation to the diaphragm, whether it is subdiaphragmatic or whether it is partially or completely supradiaphragmatic. Then we determine what lumen is wrapped by the fundoplication, whether it is the distal esophagus, stomach, or both. When the stomach is encircled by the fundoplication, gastric folds surrounded by the wrap are visualized. The length of the fundoplication should be assessed as well. We then determine whether there is a recurrent hernia, which is almost always present when the fundoplication is disrupted. However, a recurrent hernia may be present with an intact fundoplication in cases of a slipped or malpositioned fundoplication, especially when the esophagus is foreshortened.

Pertinent Findings in Post-Fundoplication Dysphagia, Epigastric Pain, and Gas Bloat There are several abnormalities identified in patients with post-fundoplication dysphagia or epigastric pain and gas bloat. In our experience, these patients have one or more of the following findings: a tight fundoplication impairing the passage of a 13-mm tablet (Fig. 5-11); a long fundoplication (>3 cm) usually surrounding the medial fundus, rather than the distal esophagus; a twisted fundoplication identified by a spiral pattern to the wrapped gastric mucosa; or a partially or completely herniated fundoplication, leading to an acquired paraesophageal hernia. On the timed barium swallow there may be substantial retention of barium after 5 minutes, mimicking achalasia. We believe the cause of these long, tight, and sometimes twisted fundoplications is inadequate mobilization of the gastric fundus with incomplete transection of the short gastric vessels unless, that is, the Rosetti modification of the Nissen fundoplication is used. (Currently, most surgeons do not use this modification where the fundoplication is created without dividing the short gastric vessels.) In these cases, the fundoplication is formed by more medially placed portions of the fundus. In so doing the wrap is under torsional forces that may cause a twist. The motility examination is very important in patients with post-fundoplication dysphagia and/or gas bloat syndrome. There are two common motility findings. Some patients show

B

A

FIGURE 5-9 Normal Toupet fundoplication. A, The partial wrap is identified by the nonapposed leaves (arrows) encircling the gastroesophageal junction (arrowhead) on the semiprone, full-column phase of the barium esophagogram. B, The upright double-contrast spot film of the fundoplication shows the nonapposed leaves (arrows).

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

E

A

B

FIGURE 5-10 Collis-Nissen fundoplication. On the semiprone portion of the barium esophagogram (A) and prone spot film of the gastroesophageal junction, with barium still in the esophagus (B), the Collis gastroplasty is identified by gastric folds (arrowheads). In this surgery, the leaves of the Nissen wrap (arrows) are often quite large and do not completely encircle the “lengthened” esophagus.

A

FIGURE 5-11 Long, tight, subdiaphragmatic, obstructing fundoplication encircling the stomach in a patient with dysphagia. A, Semiprone, full-column phase of the barium esophagogram shows the leaves of a long wrap (arrows) surrounding gastric folds (arrowheads). B, The upright spot film was taken after the patient ingested a 13-mm tablet (arrow) and barium. The tablet is obstructed at the proximal portion of the fundoplication (arrowhead).

B

69

70

Section 2 Investigation of Esophageal Disease

FIGURE 5-12 Long, floppy, partially supradiaphragmatic fundoplication encircling the stomach in a patient with recurrent reflux symptoms. The long, floppy wrap (arrows) encircles the stomach and not the esophagus (see gastric folds below the large wrap). A portion of the wrap (arrowhead) has herniated above the diaphragm in a paraesophageal position.

FIGURE 5-13 Disrupted, supradiaphragmatic fundoplication with a small, recurrent hiatal hernia in a patient with recurrent reflux symptoms. The semiprone, full-column portion of the barium esophagogram shows that the prior fundoplication (arrows) has herniated into the mediastinum and has the appearance of a paraesophageal hernia. There is a small, recurrent hiatal hernia (arrowheads).

low-amplitude contractions (substantial retrograde escape at the juncture of the upper and middle third of the esophagus) or aperistalsis. These patients probably had unrecognized, poor esophageal motility before surgery with the subsequent fundoplication causing a relative obstruction. Others show normal primary peristalsis to the level of the distal esophagus. At this point, substantial retrograde escape occurs. In these cases, the presence and amplitude of the primary wave is normal but insufficient to overcome the high LES pressure caused by the tight fundoplication. This finding complements esophageal manometry because manometry will not identify this distal retrograde escape. We have confirmed that this finding on the barium examination correlates with esophageal impedance that measures bolus transit.34 Patients with this finding almost always have a long, tight wrap surrounding the stomach and not the distal esophagus.

the diaphragm without a recurrent hiatal hernia (see Fig. 5-13). In these cases, the fundoplication has the appearance of a paraesophageal hernia. The fundoplication can be malpositioned and/or a “slipped” fundoplication with a recurrent hiatal hernia above the fundoplication and/or diaphragm, with the wrap intact or disrupted (Fig. 5-14). A “slipped” Nissen is classically thought to be caused by retraction of the esophagus into the chest. This causes the sutures passed from the fundoplication to the anterior wall of the esophagus to break down or pull out. Thus, the fundoplication “slips” onto the stomach and the fundus is pulled above the fundoplication. We believe that most “slipped” fundoplications are due to a foreshortened esophagus with inadequate esophageal mobilization during surgery resulting in incomplete reduction of the hernia. After surgery and over time, the esophagus retracts into the mediastinum, resulting in a recurrent hernia. Additionally, the fundoplication may be malpositioned and surround the medial stomach.

Pertinent Findings in Post-Fundoplication Reflux Symptoms In patients with recurrent reflux symptoms, several abnormalities can be identified. First, the fundoplication may be disrupted, either partially or completely; it may be partially or completely herniated above the diaphragm; and there may be a recurrent hiatal hernia (Figs. 5-12 and 5-13). Second, the fundoplication may be partially or completely disrupted with herniation of a portion or all of the fundoplication above

Pertinent Findings in Patients With PostFundoplication Nausea and Early Satiety Patients with post-fundoplication nausea and early satiety may have poor gastric emptying caused by a mechanical obstruction, medication, or gastric aperistalsis from vagus nerve injury. Many of these patients retained gastric secretions and food at the start of the examination. We always ask

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

MR HH

FIGURE 5-14 Slipped, subdiaphragmatic, Nissen fundoplication with a recurrent hiatal hernia in a patient with recurrent reflux symptoms. The semiprone, full-column portion of the barium esophagogram shows that the fundoplication (black arrow) is below the diaphragm (arrowheads) and wraps the stomach (white arrow). There is a recurrent hiatal hernia (HH) because there is a distal mucosal ring (MR).

FIGURE 5-15 Vigorous achalasia with an epiphrenic diverticulum. Upright spot film of the esophagus after ingesting barium shows a left-sided, epiphrenic diverticulum (arrow) and the characteristic beaklike lower esophageal sphincter (arrowhead) seen in achalasia. Proximally, there is an undulating contour of the esophagus seen with the discoordinated, nonocclusive tertiary contractions in these patients.

when the patient last ate and if food is present and document the presence of food and the time of the last meal. A nuclear medicine gastric-emptying study is very helpful in further evaluation if the patient is not on narcotics, has no anatomic cause for gastric outlet impairment, and appears to have depressed gastric motility. At the end of the examination, our radiology report specifically addresses those findings pertinent to the gastroenterologist and surgeon: the emptying assessment in patients with dysphagia to liquids (timed barium swallow); the location of the fundoplication vis-à-vis the diaphragm; the integrity of fundoplication (intact or disrupted); the lumen encircled by fundoplication (either the esophagus, the stomach, or both); the length and “tightness” of the fundoplication; the presence of a recurrent hiatal hernia and its relation to the fundoplication; the state of esophageal motility; and the adequacy of gastric emptying and motility (retained food in the stomach or depressed peristalsis).

studies. Ott and colleagues correlated the radiographic findings with the manometric examinations in 172 patients with dysphagia.25 Manometry was abnormal in 66 of 172 patients (38%) (nonspecific = 26; achalasia = 19; nutcracker = 12; DES = 7; scleroderma = 2). Radiographic sensitivity was 95% (18 of 19) for achalasia, 71% (5 of 7) for DES; and 46% (12 of 26) for nonspecific esophageal motor disorder. Overall sensitivity was 56% (37 of 66) but increased to 89% by excluding nutcracker esophagus and nonspecific disorder. In a later study, these workers also found concordance with synchronous manometry and videofluoroscopy for individual swallows (98%), groups of five swallows (97%), and final diagnosis (90%) in 20 patients (normal = 4; DES = 13; other motility disorders = 3).26 This study suggested that a videofluoroscopic evaluation using at least five separate swallows and careful observation could accurately assess both normal and abnormal motility. A more recent Austrian study of 88 symptomatic patients confirmed these findings.54 In the Austrian study, 44 patients had nonspecific esophageal motility disorder, 15 had achalasia, 9 had scleroderma, and 1 had DES. Radiologic evaluation was 73% sensitive for a nonspecific disorder, 87% sensitive for achalasia, and 100% sensitive for scleroderma.

Motility Disorders Several papers have addressed the sensitivity and specificity of barium motility examinations compared with manometric

71

72

Section 2 Investigation of Esophageal Disease

FIGURE 5-16 Pre- and post-Heller myotomy/dor fundoplication, timed barium swallow examinations in a patient with achalasia. Before treatment there is very little emptying of 250 mL of barium between the 1-minute (A) and 5-minute (B) films. After treatment there is significant improvement in the emptying and caliber of the esophagus on the 1-minute film (C). By 5 minutes (D) there is complete emptying of the esophagus.

5 minutes 1 minute

A

B

1 minute 5 minutes

C

D

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

FIGURE 5-17 Normal pneumatic dilation defect in a patient with achalasia. Upright, single-contrast esophagogram after a pneumatic dilation shows a broad-based, linear collection of barium (arrow) in the region of the lower esophageal sphincter.

FIGURE 5-18 Small, contained perforation after pneumatic dilation in a patient with achalasia. Upright, single-contrast esophagogram after a pneumatic dilation shows a collection of barium outside the lumen of the esophagus (arrow). The collection is focal and round and has a narrow communication with the lumen.

(without or with structural abnormalities such as a significant distal ring or stricture). Various medications and diabetes can also cause abnormal motility.

Dysmotility Associated With Age In the past, many thought that any dysmotility in an older patient could be primarily attributed to the normal aging process. Whereas esophageal function does deteriorate with age,55 we believe that “presbyesophagus” is overdiagnosed in the elderly and that many reasons for dysmotility other than the normal aging process can be identified in this population (i.e., diabetes, medications, GERD). Oropharyngeal dysphagia in this population is relatively common and may be secondary to central nervous system or other neuromuscular disorders. Structural abnormalities such as a larger anterior cervical osteophyte or a persistent cricopharyngeal bar are also causes of dysmotility (although one should be extremely careful not to attribute dysphagia to these findings unless other, more distal abnormalities are excluded, especially dysmotility from GERD or other medical problems). Esophageal dysphagia in this population is caused by many of the same diseases present in younger patients including achalasia, DES, collagen vascular diseases, neoplasms, and reflux disease

Achalasia Achalasia is characterized by progressive esophageal aperistalsis associated with an abnormal LES (normal to elevated resting pressures and incomplete relaxation of the LES with deglutition). As a result, the esophagus progressively dilates from retained secretions and ingested food. Chagas’ disease can have the identical appearance. Furthermore, there are secondary causes of “achalasia” known as pseudoachalasia. The most common cause of pseudoachalasia is an adenocarcinoma of the gastroesophageal junction. In our experience, the best radiographic technique used to demonstrate the pertinent findings in achalasia is the timed barium swallow with a barium motility examination. Any patient with dysphagia to liquids is first assessed with the timed swallow. Even if there is “normal” emptying of the barium column by 1 minute, patients with dysphagia to liquids should then be evaluated with a well-performed, barium motility examination. We have identified a few patients with achalasia who

73

74

Section 2 Investigation of Esophageal Disease

FIGURE 5-20 Diffuse esophageal spasm with an epiphrenic diverticulum. Early (left) and later (right) upright films taken during the double-contrast portion of the barium esophagogram show the characteristic corkscrew appearance of the esophagus (arrowhead) and an epiphrenic diverticulum (arrows).

FIGURE 5-19 Large, contained perforation after pneumatic dilation in a patient with achalasia. Upright, single-contrast esophagogram after a pneumatic dilation shows a large collection of barium outside the lumen of the esophagus (arrows).

empty 250 mL of barium in 1 minute but have aperistalsis on the barium portion of the examination. Lastly, all patients should be given a 13-mm barium tablet or solid food of a known diameter (marshmallow, or cut marshmallow) to determine if the LES is traversed. Early in the course of achalasia, the esophagus is not dilated. In the upright position there is delayed esophageal emptying, best demonstrated with a timed barium swallow.56 The LES mechanism intermittently opens but when closed displays a beaklike appearance (Fig. 5-15). Nonpropulsive tertiary contractions may be present. When present, this condition is often called “vigorous” achalasia. In the motility portion of the barium esophagogram there is little to no propagation of the primary propulsive wave. Additionally, there may be discoordinated, nonocclusive or occlusive, nonpropulsive tertiary waves. In both the upright and semiprone positions the retained barium moves up and down the esophagus. In almost all instances a barium tablet is obstructed at the LES level. As the disease progresses without intervention, the esophagus progressively dilates. The LES becomes more beaklike, and the nonpropulsive tertiary contractions subside. In the “later” stages of the disease the esophagus becomes massively dilated (up to 8-10 cm) and may attain a sigmoid shape. As

previously stated, all achalasia patients treated at our institution with pneumatic dilation or a Heller myotomy are assessed with a timed barium swallow (Fig. 5-16). This post-treatment study helps to objectify any change in symptoms. A luminal examination is almost always performed after pneumatic dilation or a Heller myotomy in a patient with achalasia (Fig. 5-17).57 The normal appearance of the LES after pneumatic dilation characteristically shows a linear to somewhat rectangular collection of barium located at the site of the mucosal tear and rupture of the muscle. This collection of barium broadly communicates with the lumen (see Fig. 5-17). Any barium collection that is round or oval, with a narrow communication with the lumen, indicates a perforation (Fig. 5-18). Most perforations are localized in the adjacent tissues, but they can be larger or more diffuse (Fig. 5-19). We find that both a barium swallow and a CT help to define the size and extent of the leak. However, CT tends to overestimate the extent because there is often abundant mediastinal gas.

Diffuse Esophageal Spasm Diffuse esophageal spasm is a motor disorder of the esophagus characterized by high-amplitude, nonpropulsive contractions. During the motility phase of the examination there may be no demonstrable abnormality. However, most of these patients demonstrate both nonocclusive and/or occlusive tertiary contractions, giving a corkscrew-like appearance (Fig. 5-20).58 The majority of these patients have a normal

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

B

A FIGURE 5-21 Traction diverticulum of the proximal esophagus in a patient with granulomatous disease. A, Left posterior oblique view, with the patient drinking barium, shows the traction diverticulum (arrow) being pulled toward a large, calcified hilar lymph node (arrowhead). B, CT scan through the inferior left hilum shows the large, calcified lymph nodes (arrows).

LES and, thus, can be distinguished from patients with achalasia. Unfortunately, approximately one third have abnormal LES function. Thus, any patient with suspected DES regardless of the radiographic motility findings should have manometry.

Collagen Vascular Diseases Patients with systemic sclerosis or mixed connective tissue disease commonly complain of dysphagia or classic reflux symptoms. The most consistent radiographic finding in the esophagus in this disease is a dilated, atonic esophagus with a patulous gastroesophageal junction. The esophagus may be so distended as to contain an air column on an upright chest radiograph. Because the gastroesophageal junction is widely patent there is free reflux of gastric contents into the esophagus. Because of smooth muscle involvement and the secondary effects of refluxed acid, the refluxed material does not empty or clear rapidly. During the motility phase of the barium esophagogram there is no propagation of the primary wave, especially where the smooth muscle predominates in the mid and distal esophagus. The radiographic motility findings in these patients are similar to those in patients with severe reflux (i.e., poorly propagating, low-amplitude primary

wave, with little to no secondary stripping wave). Peptic strictures occur late.

Midesophageal and Epiphrenic Esophageal Diverticula In the past, most midesophageal diverticula were traction diverticula caused by mediastinal inflammation (e.g., histoplasmosis or tuberculosis) (Fig. 5-21), tumor, or radiation. However, in the Western world most midesophageal diverticula and all epiphrenic diverticula are pulsion diverticula from severe dysmotility. In our practice, any patient with a midesophageal or lower esophageal diverticulum is thought to have achalasia or DES until proven otherwise (see Figs. 5-15 and 5-20). In addition to a barium esophagogram, manometry is essential in these patients. When achalasia is the cause, it is often of the vigorous type, characterized by vigorous, nonpropulsive contractions.

STRUCTURAL CAUSES OF ESOPHAGEAL NARROWING Esophageal Strictures In addition to neoplastic processes and peptic strictures, the esophagus can be narrowed from extrinsic and other intrinsic

75

76

Section 2 Investigation of Esophageal Disease

DK DK

B

A RAA

FIGURE 5-22 Right-sided aortic arch, aberrant left subclavian artery with a diverticulum of Kommerell in a patient with dysphagia lusorum. A, Semiprone, single-contrast phase of a barium esophagogram shows the posterior impression (arrows) on the esophagus by the diverticulum of Kommerell (DK). B, Parasagittal MR image shows the diverticulum (DK) pressing on the esophagus (arrowheads). The trachea (arrows) is anterior to the esophagus. C, Axial MR image shows the right-sided aortic arch (RAA), the diverticulum of Kommerell (DK), the aberrant left subclavian artery (black arrow), and the superior vena cava (white arrow). T, trachea.

T

DK

C

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

FIGURE 5-23 Caustic stricture. Upright, double-contrast phase of the barium esophagogram shows a long, shaggy stricture from lye ingestion as a child.

processes. Extrinsic disease can be due to an enlarged thyroid, any mediastinal mass, such as lymphoma or a germ cell tumor, and vascular variants or anomalies. Whereas barium esophagographic findings of extrinsic compression show the relative degree of narrowing, all extrinsic mediastinal disease is best evaluated with a contrastenhanced, cross-sectional study, either CT or MRI. When a vascular variant or anomaly is suspected, causing dysphagia lusorum, a dedicated cardiac MDCT or MRI is probably the most useful test available to demonstrate fully the vascular ring (Fig. 5-22). One of the most common vascular anomalies causing dysphagia is a right-sided aortic arch, with an aberrant left subclavian artery associated with a diverticulum of Kommerell. A common vascular variant is a left-sided aortic arch with an aberrant right subclavian artery. The impression of the aberrant right subclavian artery on the esophagus is minimal and virtually never causes symptoms. In addition to a peptic stricture, the most common cause of an esophageal stricture, there are other causes, including caustic ingestion (Fig. 5-23), usually lye; a medication stricture; radiation (Fig. 5-24); prolonged nasogastric tube suction; and skin disorders (Fig. 5-25). Lye ingestion causes either a diffuse narrowing or multifocal strictures. Patients with a nasogastric tube stricture always have a history of a relatively long stay in an intensive care unit. A history of irradiation for lung carcinoma or lymphoma is generally available to the

FIGURE 5-24 Radiation stricture from mediastinal radiation for lung carcinoma. Upright, double-contrast phase of the barium esophagogram shows a subtle, proximal esophageal stricture (arrows).

FIGURE 5-25 Cicatricial pemphigoid with multiple, proximal esophageal strictures. Semiprone, single-contrast phase of a barium esophagogram shows multiple strictures (arrows).

77

78

Section 2 Investigation of Esophageal Disease

A

B

FIGURE 5-26 Eosinophilic esophagitis (“ringed esophagus”). A, Upright, double-contrast phase of the barium esophagogram shows multiple, subtle ringlike impressions (arrows) in the proximal esophagus. B, Upright spot film shows that the 13-mm tablet obstructs at the level of the rings.

FIGURE 5-27 Paraesophageal duplication cyst. Axial CT scan through the lower chest shows a water-attenuation, paraesophageal mass (arrow) adjacent to the esophagus (arrowhead).

clinician. When a patient with multiple strictures does not have any prior pertinent history, an unusual skin disorder should be considered. There are several skin disorders that are associated with esophageal strictures: benign mucous membrane cicatricial pemphigoid, lichen planus, and epidermolysis bullosa dystrophica.

FIGURE 5-28 Neurenteric duplication cyst. Axial CT scan through the lower chest shows a soft tissue attenuation, neurenteric cyst (arrow) adjacent to the esophagus (arrowhead). Depending on their contents, not all cysts are water attenuation. Without endoscopic ultrasound correlation, this mass could represent a leiomyoma (see Fig. 5-30).

Over a number of years, many authors have described a “ringed” appearance of the esophagus, more on endoscopy but also with barium esophagograms.59-61 This appearance has been attributed to “congenital” esophageal stenosis, GERD, as well as eosinophilic esophagitis. The growing consensus is that patients with a ringed esophagus have eosinophilic esophagitis (Fig. 5-26). Many, but not all, of these patients have some allergic disorder and have peripheral eosinophilia. On a barium esophagogram, patients with eosinophilic esophagitis often present with a stricture or strictures. The strictures are said to be more often proximal, but we and others have seen distal strictures as well. The esophagus may be diffusely narrowed. In our experience, a diffusely narrowed esophagus is more common. The ringed appearance is often subtle or nonexistent. Endoscopically, the esophagus in these patients has a ringed or ridged appearance when the lumen is insufflated. On a barium examination rings are not generally identified.

Mediastinal Cysts Congenital cysts of the middle and posterior mediastinum may cause intrinsic compression of the esophagus. There are neurenteric and paraesophageal cysts (Figs. 5-27 and 5-28). These can cause variable degrees of smooth extrinsic mass effect on the esophagus. They are best located and characterized by cross-sectional imaging with CT and/or MRI.

Benign Tumors of the Esophagus The most common benign, mucosal tumor of the esophagus is a squamous papilloma. These are small sessile polyps that

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

FIGURE 5-30 Esophageal leiomyoma. Axial CT scan through the lower chest shows a soft tissue attenuation mass (arrow) adjacent to the esophagus (arrowhead). Endoscopic ultrasound showed that this mass was present in the submucosa.

a high signal on both T1- and T2-weighted pulse sequences (see Fig. 5-31). FIGURE 5-29 Esophageal leiomyoma. Upright, double-contrast phase of the barium esophagogram shows a well-defined, submucosal, filling defect (arrow) in the proximal esophagus.

are usually only incidentally identified. Endoscopy is necessary to distinguish these polyps from small carcinomas. The most common benign, submucosal tumor of the esophagus is a leiomyoma, not a gastrointestinal stromal tumor (which expresses c-KIT protein).62,63 Leiomyomas are generally small, smooth, endoenteric, submucosal masses that have characteristic oval shapes protruding into the lumen of the esophagus (Figs. 5-29 and 5-30). They are usually located in the middle to distal esophagus. When detected, their characteristic submucosal location can be easily confirmed with endoscopic ultrasonography. A fibrovascular polyp is a rare, benign mass of the esophagus composed of variable amounts of fibrous, fatty, and vascular tissue, covered by squamous epithelium. These polypoid, intraluminal masses arise from the distal cervical esophagus near the cricopharyngeal muscle.64 By the time they present, their cervical origin is not recognized on barium studies. On barium studies, they present as long, smooth to lobulated, “sausage-shaped,” intraluminal filling defects (Fig. 5-31) that expand the lumen. If there is a sufficient fatty component to the mass, a CT will show a fatty attenuation mass. On MRI, a fibrovascular polyp of sufficient fatty component will have

Barrett’s Esophagus and Esophageal Carcinoma There have been several reports documenting the barium esophagographic findings of Barrett’s esophagus. Chen and Frederick (1994) compiled 309 reported cases documenting the radiographic findings in Barrett’s esophagus (including 52 unpublished cases from Wake Forest Medical Center).8 The most common abnormalities were a hiatal hernia (87%), a stricture (more commonly a lower esophageal stricture) (72%), reflux (60%), distal esophageal dilation (44%), an ulcer (40%), and a reticular pattern (23%). Barrett’s esophagus is more commonly found in patients with moderate to severe esophagitis,8,9,42,65 and radiography has been shown to be 79% to 93% sensitive in moderate esophagitis and 95% to 100% sensitive in severe esophagitis.8 Therefore, some have proposed that patients be stratified as at risk for Barrett’s esophagus on the basis of the barium esophagographic findings.9,42,65 Patients with a midesophageal stricture or ulcer or a reticular pattern on an air-contrast examination are considered at high risk for Barrett’s esophagus. Patients with changes of esophagitis and/or a distal stricture are considered at moderate risk. Patients at low risk are those without any caliber change or esophagitis. But, in a retrospective study of 142 patients with short-segment Barrett’s esophagus, 20 of whom had a double-contrast esophagogram, 14 of the 20 had morphologic findings of reflux disease (esophagitis alone [N = 3], peptic scarring or stricture [N = 7], or both [N = 4]).66 The remaining six patients with Barrett’s esophagus had hiatal

79

80

Section 2 Investigation of Esophageal Disease

B

A

FIGURE 5-31 Fibrovascular polyp. A, Single-contrast, semiprone phase of the barium esophagogram shows a large, lobulated, sausage-shaped polypoid filling defect (arrows) in the proximal and mid esophagus. A thin stalk is present, extending from the upper thoracic esophagus (arrowhead). Axial (B) and sagittal (C), T1weighted MR images through the chest show that this mass (arrows) has high signal, indicative of a predominant fatty component.

C

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

FIGURE 5-32 Ulcerated adenocarcinoma of the esophagus. Semiprone, single-contrast phase of the barium esophagogram shows an ulcerated (arrows) mass in the distal esophagus.

FIGURE 5-33 Varicoid adenocarcinoma of the esophagus. Semiprone, single-contrast phase of the barium esophagogram shows marked, nodular to tubular filling defects (arrows) in the distal esophagus.

hernias or gastroesophageal reflux as the only radiographic finding. Another study of 30 patients with Barrett’s esophagus and 18 control patients, all of which were randomized, masked, and read by two radiologists blinded to the diagnosis, showed that the sensitivity varied from 36% to 83% and the specificity varied from 56% to 100%.67 Unfortunately, there has been no large, prospective study evaluating the efficacy of barium esophagogram vis-à-vis endoscopy in the detection of Barrett’s esophagus in a large number of consecutive patients. All of the published studies are essentially case series and therefore biased. As a result, we do not use radiography as a method to detect Barrett’s esophagus. As in many institutions, endoscopy is the means of detecting and following patients with Barrett’s esophagus.68 However, every patient with a change from moderate to severe esophagitis or a stricture identified on a barium esophagogram should undergo endoscopy. Up until the development of 18F-fluorodeoxyglucose (FDG)-labeled PET, a patient with esophageal carcinoma was evaluated with a barium esophagogram and a CT of the chest, abdomen, and pelvis.69,70 In addition to endoscopy, the results of these tests determined if the patient’s tumor

was radiographically resectable and who was then treated accordingly. This determination was made on the basis of the primary tumor’s relation to adjacent structures, the presence of “enlarged” locoregional lymph nodes, and frank metastatic disease to the liver and other organs. On barium esophagography, esophageal carcinoma has multiple appearances. If the tumor arises in Barrett’s esophagus, there may be no findings other than a peptic stricture. Esophageal carcinoma, both squamous and adenocarcinoma, may be subtly plaquelike or nodular, infiltrative, polypoid, or varicoid, without or with ulceration (Figs. 5-32 and 5-33). When the tumor strictures the lumen there is often an abrupt or shelflike transition between normal caliber and the narrowed portion. Even if a stricture is smoothly and gradually tapering, as in a benign, peptic stricture, most would recommend that endoscopy be performed due to the high prevalence of Barrett’s esophagus in peptic strictures. There is no way to distinguish a squamous cell carcinoma from an adenocarcinoma; however, currently more malignant esophageal tumors are adenocarcinomas. Furthermore, a distal or gastroesophageal junction tumor is almost always an adenocarcinoma.

81

82

Section 2 Investigation of Esophageal Disease

FIGURE 5-34 Submucosal/intramural dissection from endoscopy. Upright, single-contrast esophagogram shows a double-barrel appearance to the esophagus (arrows). The mucosa is identified as a thin line in the barium (arrowheads).

In the modern era, endoscopic ultrasonography is used to evaluate tumor depth as well as to identify and biopsy regional lymph nodes, and PET/CT69,70 is used to evaluate locoregional and distant metastases. Additionally, most patients are now treated with combined preoperative chemotherapy and radiation therapy. Thus, resectability is not necessarily based on the initial imaging findings. In our institution, the barium esophagogram is no longer routinely used in patients with carcinoma. Our current, routine workup for a patient with esophageal carcinoma is endoscopic ultrasonography and PET/CT. Endoscopic ultrasonography is used to stage the tumor locally and regionally, and PET/CT is used to determine whether there are distant metastases. The CT portion of the PET/CT is used both for attenuation correction and anatomic localization.

ESOPHAGEAL PERFORATION The esophagus can rupture due to prolonged or severe retching, as a result of endoscopy, stricture dilation, or pneumatic

dilation of the LES in achalasia (see Figs. 5-18 and 5-19). In cases of suspected perforation we start with a plain radiograph of the chest. This often shows mediastinal and subcutaneous gas and serves as the “scout” film before oral contrast ingestion. The patient then swallows oral contrast media to identify the presence, location, and size of the perforation. Initially, we consider using an iodinated, water-soluble contrast media; however, if there is any risk of aspiration we use low-density barium. We have a very low threshold for the use of barium over iodinated contrast media because aspirated, hyperosmolar iodinated contrast media can cause severe pneumonitis. If iodinated contrast media is used first and no perforation is identified, we then continue the study using low-density barium.71,72 Barium is safe and often detects the location of the perforation when water-soluble, iodinated contrast media does not. Perforation from endoscopy can lead to a submucosal tear and/or intramural dissection rather than a frank perforation. These have a unique “double-barrel” appearance; the contrast agent both fills the esophageal lumen as well as extends into the channel underneath the mucosa (Fig. 5-34). Frank per-

Chapter 5 Radiology, Computed Tomography, and Magnetic Resonance Imaging

B

A

C FIGURE 5-35 Boerhaave’s perforation. A, Upright, single-contrast esophagogram taken after an episode of severe retching. Crepitus was identified on physical examination. Oral contrast medium (arrows) is located in the mediastinum, adjacent to the distal esophagus (arrowhead). B, CT scan through the neck shows extensive gas (arrowheads) in the tissues. The esophagus (arrow) is filled with a small amount of gas. C, CT scan through the lower chest shows an extensive gas collection (arrowheads) in the posterior mediastinum, to the right of the esophagus (arrow).

foration may be contained within the mediastinum (Fig. 5-35) or extend into the pleural space. A CT of the chest may show the extent of perforation.

COMMENTS AND CONTROVERSIES With the advent of more sophisticated tools for esophageal evaluation the wealth of information that is provided by the simple barium esophagogram has been forgotten by many clinicians. Inadequate or incomplete evaluation and reporting further lessen the usefulness of the barium esophagogram. Frequently, the patient brings a jumble of films that are a partial copy of a barium esophagogram performed at another facility with the report either missing or incomplete. It is difficult to reconstruct this examination and uncover all the pertinent information. Many would ignore this test, but it must be repeated.

When viewing a barium esophagogram the clinician must remember it was conducted in a way to evaluate both esophageal form and function. Emptying, mucosa, motility, contour, reflux, and solid-phase and oropharyngeal function are sequentially assessed. The gastrointestinal radiologist’s report should account for each one of these aspects of the esophagogram, and the hard copy record should be illustrative of the findings. Barium esophagography is invaluable in the assessment of benign esophageal disease and crucial for planning treatment. CT and MRI are complementary. T. W. R.

KEY REFERENCES Baker ME, Einstein D, Herts B, et al: Integrating the barium esophagogram in the care of GERD patients before and after anti-reflux surgery. Radiology 243:329-339, 2007.

83

84

Section 2 Investigation of Esophageal Disease

Chen MY, Frederick MG: Barrett’s esophagus and adenocarcinoma. Radiol Clin North Am 32:1167-1181, 1994. de Oliveira JM, Birgisson S, Doinoff C, et al: Timed barium swallow: A simple technique for evaluating esophageal emptying in patients with achalasia. AJR 169:473-479, 1997. Levine MS, Rubesin SE: Diseases of the esophagus: Diagnosis with esophagography. Radiology 237:414-427, 2005. Levine MS: Radiology of esophagitis: A pattern approach. Radiology 179:1-7, 1991. Ott DJ: Gastroesophageal reflux disease. Radiol Clin North Am 32:11471166, 1994. Peters JH, DeMeester TR: Indications, principles of procedure selection, and techniques of laparoscopic Nissen fundoplication. Semin Laparosc Surg 2:27-44, 1995.

Schima W, Stacher G, Pokieser P, et al: Esophageal motor disorders: Videofluoroscopic and manometric evaluation—prospective study of 88 patients. Radiology 185:487-491, 1992. Vaezi MF, Baker ME, Richter JE: Assessment of esophageal emptying post-pneumatic dilation: Use of the timed barium esophagogram. Am J Gastroenterol 94:1802-1807, 1999. Yamamoto AJ, Levine MS, Katzka DA, et al: Short-segment Barrett’s esophagus: Findings on double-contrast esophagography in 20 patients. AJR 176:1173-1176, 2001. Zimmerman SL, Levine MS, Rubesin SE, et al: Idiopathic eosinophilic esophagitis in adults: The ringed esophagus. Radiology 236:159-165, 2005.

chapter

6

NUCLEAR IMAGING Farrokh Dehdashti Barry A. Siegel

Key Points

likely reflects the lack of standardization of both the performance and the interpretation of these methods.

■ Conventional scintigraphy allows for functional assessment of the

■

■

■

■

■

esophagus and provides information that is complementary to clinical and radiologic evaluation. Radionuclide scintigraphy is an alternative to conventional imaging and esophageal function tests in the assessment of functional esophageal disorders. PET with the glucose analogue FDG is more sensitive than CT for detecting locoregional and distant metastasis in patients with esophageal cancer and is now generally accepted as an important method for staging and restaging of this disease. PET is most useful in detection of occult stage IV cancer and identification of local or distant metastatic sites that are most easily accessible for tissue confirmation. Limitations of PET in cancer detection are poor sensitivity for small volume tumors and inability to differentiate inflammation from cancer. The roles of PET in treatment planning, prognostication, and assessment of therapy are being defined.

Several nuclear imaging techniques are available for evaluation of esophageal disorders. These are most conveniently divided into two categories: conventional scintigraphy, predominantly used for imaging of patients with benign diseases, and positron emission tomography (PET), used for imaging of patients with esophageal cancer.

CONVENTIONAL NUCLEAR IMAGING Radionuclide scintigraphy has been long used as an alternative to noninvasive conventional anatomic imaging (e.g., gastrointestinal radiography and ultrasonography) and invasive methods (e.g., endoscopy) for assessment of the functional abnormalities of the esophagus. Radionuclide transit/emptying scintigraphy provides unique information reflecting the physiology of esophageal dysfunction and is easy to perform, inexpensive, and well tolerated by patients. Radionuclide gastroesophageal motor studies have been used for detecting and characterizing esophageal motility disorders, including achalasia, diffuse esophageal spasm, scleroderma, and nutcracker esophagus, and for monitoring the efficacy of therapy for these conditions. Nuclear imaging also has been widely used to confirm the presence of pathologic gastroesophageal reflux, as well as to determine the severity of reflux. However, the frequency of use of these conventional nuclear imaging techniques varies widely from center to center. This variation

Esophageal Transit Scintigraphy In this method, the rate and pattern of movement of a radiolabeled liquid or solid is used to characterize the motor function of the esophagus and to assess for esophageal obstruction. There is no standardized technique for esophageal transit scintigraphy in patients with suspected motility disorders. In general, however, patients should be fasted for at least 3 hours, or preferably overnight, before the examination. Any radiopharmaceutical that is not absorbed via the gastrointestinal tract can be used. The most commonly used radiopharmaceutical is 99mTc-sulfur colloid. A small amount (150-500 µCi) of 99mTc-sulfur colloid is used and is mixed with a small volume (~10 mL) of water or juice. Some have used a semisolid medium.1,2 The patient is instructed to swallow the radioactive liquid with a straw (milk bottle in newborns and small children) in a single bolus (with or without subsequent dry swallows), and then a dynamic study is performed. Typically, a large-field-of-view gamma camera with a high-resolution, low-energy collimator is used with imaging in the anterior or posterior projection (imaging with a dual-head gamma camera allows simultaneous recording of anterior and posterior views and is preferred).3,4 Esophageal scintigraphy can be performed with the patient supine or upright, with the latter being considered more physiologic, but supine positioning may allow for easier demonstration of esophageal motility disorders by removing the effect of gravity.5 Dynamic images are typically acquired at 4 to 10 frames per second for 60 to 120 seconds (Mariani et al, 2004).6 In adult subjects, esophageal transit scintigraphy is typically completed in 120 seconds, and the patient is asked to perform four to five Valsalva maneuvers during imaging to detect gastroesophageal reflux occurring as a result of increased intra-abdominal pressure. The images are viewed in a cine mode to evaluate for reflux. In addition, images can be quantitatively evaluated using time-activity curves over a single region or multiple regions of interest to measure the rate of esophageal transit and to determine retention.

Clinical Uses Esophageal scintigraphy has been studied in patients with atypical chest pain as a method to detect underlying esophageal disease. In particular, nutcracker esophagus, a motility disorder characterized by peristaltic waves in the distal esophagus with mean amplitudes exceeding the normal values by more than 2 standard deviations, can cause chest pain 85

86

Section 2 Investigation of Esophageal Disease

without associated dysphagia. In one recent study, esophageal scintigraphy was reported to be abnormal (showing dysmotility or gastroesophageal reflux) in 89% of patients with atypical chest pain.7 Diffuse esophageal spasm is characterized by uncoordinated esophageal contractions that can interfere with esophageal clearance. In these patients, esophageal scintigraphy should include multiple wet swallows. Visual evaluation of bolus dynamics is important to determine the disordered bolus movements. In addition, evaluation of the time-activity curves is necessary to determine multiple peaks after a single swallow. Achalasia results in incomplete or absent relaxation of the lower esophageal sphincter and loss of body peristalsis. This disease is characterized by degeneration of neurons in the myenteric plexus, neural fibrosis, and some degree of inflammation. This results in impaired esophageal clearance and delayed transit times. Esophageal scintigraphy has been shown to be very sensitive in detecting the delay in transit associated with achalasia.8 Scintigraphic evaluation of esophageal clearance is considered by some investigators to be the method of choice for the follow-up of patients with achalasia to monitor the efficacy of treatment.9-13 Scleroderma is characterized by fibrosis and vascular obliteration of the esophageal muscle and its innervation, resulting in ineffective esophageal motility. Esophageal scintigraphy has a higher sensitivity than manometry and barium swallows in demonstrating dysmotility in both early and advanced disease.14-17 Because it is simple and well tolerated by patients, esophageal scintigraphy is especially well suited for serial studies to monitor the efficacy of treatment of various motility disorders. Esophageal transit scintigraphy is very useful in assessment of the effect of stricture and of dysmotility in a single test and has considerable value after esophagectomy.4,18-22 In addition, esophageal transit scintigraphy can be performed in patients with inoperable esophageal cancer being treated only palliatively, to assess the patency of the esophagus.4

Esophageal Reflux Scintigraphy Gastroesophageal reflux is commonly seen in infants and, in most cases, is self-limiting. However, about one third of affected children have persistent symptoms lasting until approximately 4 years of age; about 5% of these develop esophageal strictures, and up to 5% of patients with severe gastroesophageal reflux succumb if they do not receive adequate treatment (Mariani et al, 2004).6 Most conventional examinations used for diagnosing gastroesophageal reflux in adults are not ideal for use in infants and children, either because significant cooperation from the child is needed or because of the associated radiation dose.23 The scintigraphic method thus appears to be the most suitable. In children, esophageal reflux scintigraphy is typically performed at the time of a scheduled feeding. 99mTc-sulfur colloid (100-500 µCi) is added to milk or formula to label the liquid meal at a concentration of less than 50 µCi/mL.24 Typically, about half of the regular feeding is labeled, leaving the remainder unlabeled for completing the study. If possi-

ble, the scintigraphic study should include the initial swallowing phase and an assessment of esophageal transit. After half of the radiolabeled meal has been given, the remaining unlabeled portion is given to wash radioactivity from the mouth, pharynx, and esophagus. The infant is then burped and placed supine for imaging of the chest and upper abdomen (reflux in infants is more likely to occur in the supine than in the prone position).25 A high-sensitivity collimator is typically used, because the activity during an episode of reflux can be low or in a small volume. Dynamic imaging should be performed continuously at a rate of 6 or more images per minute for at least 60 minutes; about 25% of reflux episodes will be missed if the acquisition is limited to 30 minutes. At the end of the dynamic acquisition, static images of the chest should be obtained to assess for aspiration. If aspiration is suspected, delayed static imaging should be repeated at about 2 and 24 hours. Additionally, the initial dynamic data are used to measure gastric emptying. The images are evaluated in a manner similar to that for esophageal transit scintigraphy, by generating time-activity curves from different regions of the esophagus and by visual inspection of the dynamic imaging set in cine mode. Gastroesophageal reflux is characterized by sharp spikes. In addition, in adults, a simple approach to express esophageal activity (either in selected frames from dynamic recording or in the static images) as a fraction of gastric activity has been used that reliably identifies patients with gastroesophageal reflux (Mariani et al, 2004).6,26 Although gastroesophageal reflux scintigraphy is less often used in adults, the general principle of the method is similar. 99m Tc-sulfur colloid is administered suspended in acidified orange juice, and imaging over the esophagus is performed as an abdominal binder is used to progressively increase intraabdominal pressure, as is done during a conventional barium radiography study. Reflux observed at pressures below 100 mm Hg is considered abnormal.26,27 Clinical studies in patients with suspected esophageal reflux have shown that scintigraphy has a sensitivity of 75% to 100% in detecting gastroesophageal reflux, depending on the protocol used.28 Arasu and associates assessed the diagnostic accuracy of methods (upper gastrointestinal radiography, gastroesophageal scintigraphy, measurement of mean resting lower esophageal sphincter pressure, esophageal intraluminal pH measurement [acid reflux test], and endoscopy) employed for detection of gastroesophageal reflux in 30 infants and children with symptoms of gastroesophageal reflux. They found scintigraphy to be complementary to upper gastrointestinal radiography in the diagnosis of gastroesophageal reflux.28

PET: BASIC PRINCIPLES PET is a functional imaging modality that uses biologically active compounds labeled with positron-emitting radionuclides and produces images reflecting biochemical and physiologic processes in normal and diseased tissues. These functional changes often precede, and may be more specific than, the associated structural changes that are detected by anatomically based imaging techniques. Thus, PET offers the

Chapter 6 Nuclear Imaging

potential to detect disease early and to exclude the presence of disease in an anatomically altered structure. The most useful and widely studied positron-emitting radiopharmaceutical in oncology is the radiolabeled glucose analogue 2(18F)fluoro-2-deoxy-D-glucose (FDG).29 Like glucose, FDG is transported across the cell membrane by glucose transporter proteins and is phosphorylated by hexokinase. However, unlike glucose-6-phosphate, FDG-6-phosphate is not significantly further metabolized via glycolytic or glycogen-synthetic pathways; because it is a charged molecule, it cannot back-diffuse across the cell membrane and remains “metabolically trapped” within the cell. Thus, the cellular level of 18F radioactivity is related to the rate of glucose uptake and utilization by the cell. FDG accumulates in most malignant tumors to a greater extent than in normal tissues and most benign lesions. In 1930, Warburg demonstrated that most malignant tumors have a higher rate of glucose utilization than normal tissues.30 The mechanisms of increased tumor uptake of FDG are not fully understood; however, it has been shown that malignant transformation of several cell lines is associated with a more rapid rate of glucose transfer across cell membranes, increased activities of glycolytic enzymes, or both.31-34 FDG-PET is now widely used for diagnosis, staging, restaging, and assessing or predicting response to therapy for a variety of malignant tumors.35,36 A major shortcoming of PET is its limited resolution and lack of anatomic details. CT is generally the primary imaging method of choice for evaluation of patients with cancer; CT images have high spatial resolution but provide relatively little functional information. With the recent introduction of integrated PET/CT scanners, it is now possible to obtain both functional and anatomic information in a single examination. The PET component affords increased sensitivity and improves on the specificity of the anatomic findings on CT, whereas the CT component provides precise localization of abnormal metabolic activity seen on PET and allows for easier distinction of pathologic and physiologic tracer uptake. There are several advantages of PET/CT by comparison with conventional PET without or with correlation with CT (visual or by the use of software fusion) obtained separately and likely at different times. Although the literature currently contains relatively limited data on the use of PET/CT in specific types of cancers, including esophageal cancer, multiple published reports attest to its generally superior clinical utility for oncologic imaging generally by comparison with conventional PET, which it is rapidly replacing worldwide (Sachelarie et al, 2005).37,38

Imaging Techniques For clinical FDG-PET imaging, patient preparation consists of fasting for at least 4 hours, and preferably overnight, before administration of FDG. Oral water intake or administration of noncaloric intravenous fluids is acceptable. A blood sample is routinely obtained before FDG injection to identify patients with fasting hyperglycemia. The goal of these steps is to ensure a blood glucose concentration within normal range and a serum insulin concentration at the basal level. This is because tumor uptake of FDG is competitively inhibited by

hyperglycemia. Additionally, postprandial hyperinsulinemia further reduces tumor uptake of FDG, because it results in preferential uptake of the tracer in skeletal muscle and adipose tissue. After intravenous injection of FDG (typically 15-20 mCi), imaging is begun 45 to 60 minutes later. With a conventional PET scanner, a typical examination consisting of both emission and transmission images (for attenuation correction) and spanning the region from the skull base to the proximal thighs takes 30 to 60 minutes to perform. In some cancers, 2- or 3-hour delayed imaging has been shown to improve detection of metastatic disease.39,40 Urinary tract preparation, which consists of intravenous hydration, intravenous administration of furosemide, and insertion of a Foley catheter into the urinary bladder, is not commonly used in PET imaging of patients with esophageal cancer. In general, FDG uptake in the gastrointestinal tract is variable and is predominantly intramural rather than intraluminal. Normal FDG uptake in the esophagus is typically mild and is most commonly seen in the distal esophagus and gastroesophageal junction. Because inflammation can result in FDG uptake that can be sufficiently marked to mimic malignant disease, it is important to provide information about any history of esophagitis and whether the patient has had any recent surgical or other therapeutic interventions. With a PET/CT scanner, the CT scans are used for attenuation correction (as well as for anatomic localization of PET findings). This shortens total examination time to 15 to 30 minutes. A disadvantage of PET/CT by comparison with conventional PET is the higher radiation dose; the magnitude of this additional exposure depends on the CT technique used for the study. There are many different imaging protocols for the CT component of PET/CT studies, depending on the type of scanner; whether the CT is intended only for attenuation correction and anatomic localization or will also serve as a diagnostic-quality examination; and whether oral and/or intravenous contrast agents are used. To diminish breathing artifacts, both PET and CT are often performed during normal tidal breathing. PET/CT techniques are continuing to evolve (Sachelarie et al, 2005).37,38,115

FDG-PET in Esophageal Cancer Accurate staging of esophageal cancer is extremely important for both selecting appropriate therapy and predicting prognosis. Patients with distant metastasis or local invasion of adjacent vital structures by the primary tumor need only palliative therapy, whereas patients with no or limited locoregional disease can benefit from surgery with curative intent, with or without chemoradiotherapy. The preoperative noninvasive staging of esophageal cancer has improved over the past decade. CT, which has been the main staging method for many years, has been combined with endoscopic ultrasonography (EUS) and, increasingly, with FDG-PET. Magnetic resonance imaging (MRI) may be useful in selected patients but generally does not provide additional staging information by comparison with CT. Because each of these modalities has advantages and disadvantages, the combined use of several modalities is often needed for initial staging of esophageal cancer in determining curative resectability. FDG-PET has

87

88

Section 2 Investigation of Esophageal Disease

been successfully utilized in evaluating many different malignant tumors, including esophageal cancer.41,42 Based on the published literature, in 2001 Medicare approved reimbursement for FDG-PET for diagnosis, initial staging, and restaging of esophageal cancer. EUS is commonly used to assess the depth of tumor invasion and locoregional spread of tumor and, thus, to determine whether the tumor is localized and can be treated with surgery alone or locally advanced, requiring treatment with chemoradiotherapy with or without surgery. The accuracy of EUS for assessing T and N disease status has been reported to be 85% and 75%, respectively, whereas the sensitivity has been reported to be in the range of 85% to 95% and 70% to 80%, respectively.43,44 The limitations of EUS include its inability to stage distant metastatic disease because of a limited field of view and to stage obstructive esophageal cancer, because passage of the endoscopic probe through high-grade luminal stenosis is not possible. The sensitivity of CT for staging T and N disease has been reported to be 50% to 60% and 60% to 87%, respectively.45,46 Detection of advanced disease (stage IV) is very important. If distant disease is present, locoregional staging has little importance. It is estimated that 30% to 50% of patients have advanced (stage IV) disease at presentation and that this distant disease is missed in 18% to 29% of patients whose disease is staged conventionally.45 In the following sections, the role of PET in diagnosing, staging, and monitoring response to therapy, as well as evaluating recurrent disease, is discussed. In particular, the impact of the addition of FDG-PET and FDG-PET/CT to the current imaging techniques is discussed.

Primary Tumor Staging (T Classification) Esophageal cancer is most often initially detected by endoscopy and biopsy or by double-contrast barium esophagography followed by endoscopy.47 Once the diagnosis of esophageal cancer is established, the depth of tumor invasion, which is an important prognostic factor, needs to be determined. EUS is the best method for evaluation of the depth of primary tumor penetration within the wall and the invasion of periesophageal tissues. Approximately 30% of patients have severe stenosis or obstruction of the esophageal lumen by tumor; complete staging by EUS is not possible in such patients.48 However, a recent report demonstrated that the endoscopic appearance by EUS predicts the stage of tumor; if the tumor caused a luminal stenosis, it is at least a T3 and possibly a T4 tumor on EUS.49 CT is complementary to EUS in detecting gross invasion of mediastinal fat and infiltration into the adjacent organs, particularly the trachea and bronchi. However, CT is less efficient for detection of pericardial invasion because of the frequent absence of a definable fat plane between the esophagus and the pericardium consequent to the significant weight loss typical in patients with esophageal cancer. However, neither EUS nor CT is able to distinguish tumor from inflammation, so that tumor stage may be overestimated in the presence of peritumoral inflammation.

FDG uptake in esophageal cancer is greater than that in the normal esophagus; thus, the primary tumor is usually identified easily.50 FDG-PET has been shown to detect primary esophageal cancers with higher sensitivity than that of CT (95%-100% versus 81%-92%). Detection by PET is directly related to tumor size. A recent study reported an overall sensitivity of 80% for FDG-PET in detecting primary esophageal cancer; 43% of T1, 90% of T2, 98% of T3, and 100% of T4 tumors were seen (Kato et al, 2005).51 In general, falsenegative results are related to small tumor volume or well-differentiated tumor, especially considering the mild to moderate physiologic uptake of FDG seen in the normal esophagus. False-positive results with FDG-PET are typically related to inflammation, such as reflux esophagitis. In addition, radiation-induced esophagitis is commonly seen when the esophagus is included in a radiotherapy portal. However, radiation esophagitis often involves a long segment of the esophagus and usually can be distinguished from esophageal cancer. Himeno and associates demonstrated that FDG-PET has a sensitivity of 100% (n = 15) for detection of primary tumors extending to the submucosa (pT1b) or deeper. However, PET was unable to detect any (n = 7) of the lesions that were confined to the mucosa (Tis or T1a).52 These results likely reflect the limited spatial resolution of PET. There are conflicting results regarding the relationship of the primary tumor FDG uptake assessed by determination of the standardized uptake value (SUV) and the depth of tumor invasion (T classification). Kato and colleagues (2005)51 found a significant relationship between FDG uptake and the depth of tumor invasion within the primary tumor (P < .05), but other investigators have not found any correlation between these two parameters.50,53,54 The FDG uptake in adenocarcinomas and squamous cell carcinomas is generally similarly intense.53 However, Flamen and coworkers reported that adenocarcinoma of the gastroesophageal junction sometimes may not be FDG avid regardless of tumor volume; they found that 20% of their patients belonged in this category and had diffusely growing, poorly differentiated tumors.41 The investigators hypothesized that this may be related to the lack of glucose transporter expression by these tumors or to the presence of large amounts of tumor mucin. The two main limitations of all currently used imaging techniques include poor sensitivity for detecting small volume tumors and the inability to differentiate tumor from active inflammatory disease reliably. Thus, histopathologic examination of the resected specimen remains the criterion standard for determination of T classification.

Nodal Staging (N Classification) The status of regional lymph node is one of the most important prognostic factors in esophageal cancer and has a major impact on treatment selection. Despite the importance of lymph node status in esophageal cancer, available noninvasive methods for lymph node staging are still less than ideal. CT and EUS are commonly used to evaluate for lymph node metastasis; EUS is found to be superior to CT for evaluation of regional nodal disease. However, none of these methods

Chapter 6 Nuclear Imaging

can reliably differentiate benign from malignant lymph nodes. In addition, EUS is operator dependent and is unable to evaluate lymph nodes, other than celiac nodes, that are located distant from the esophageal wall or behind air-filled structures.55,56 The reported accuracy of EUS for detection of mediastinal nodal metastasis is superior to that of CT (64%-88% versus 45%-74%).55,57 However, the combined accuracy of spiral CT and EUS has been reported to be greater than that of each modality alone (70%-90%).63 EUS using fine-needle aspiration of suspicious lymph nodes to obtain histologic proof of disease is increasingly used at initial staging.57 The main limitations of current anatomic imaging techniques are related to their inability to detect tumor involvement in normal-sized lymph nodes and to differentiate metastatic from inflammatory disease in enlarged lymph nodes. Thus, invasive procedures such as thoracoscopy and/or laparoscopy are often used to evaluate for lymph node metastasis to select the best mode of therapy for the individual patient. However, because of their high cost and associated morbidity, the use of these procedures should be limited to those patients in whom a positive finding will have major therapeutic impact. Several studies have compared FDG-PET with CT and/or EUS for assessment of local nodal involvement. The reported sensitivities have ranged from 22% to 92% for PET, compared with 0% to 87% for CT (Kato et al, 2005).51,53,58-63 Specificities ranged from 75% to 100% for PET and from 73% to 100% for CT.51,53,58-63 Kato and colleagues (2005) demonstrated that PET showed incremental value over CT with regard to lymph node status in 14 of 98 patients who received surgery by either demonstrating unsuspected nodal disease or by excluding suspected disease.51 To understand the potential role of PET, comparison should be made to the combined diagnostic performance of CT and EUS, which are the standard preoperative staging methods. Such comparisons have yielded conflicting results. Whereas some studies have shown that the combination of CT and EUS is superior to PET in detecting locoregional lymph nodal metastasis, other studies were in favor of PET being the better method. Flamen and co-workers, in a prospective study of 74 patients with esophageal cancer, demonstrated that CT/EUS was more sensitive (62% versus 33%) but less specific (67% versus 89%) than PET in their patient population.53 Lerut and associates demonstrated that FDG-PET has a lower accuracy than CT/EUS (48% versus 69%).63 More recently, Liberale and colleagues demonstrated that PET is superior to CT/ EUS; the sensitivities, specificities, and accuracy for detection of locoregional lymph node involvement were 25%, 50%, and 42%, respectively, for CT/EUS and were 38%, 81%, and 67%, respectively, for PET.64 Transhiatal esophagectomy is believed to underestimate the extent of lymph node involvement because of its incomplete sampling of mediastinal lymph nodes; thus, histopathologic evaluation of lymph nodes obtained from two- or three-field lymphadenectomy is preferred and considered the “gold standard.” Unfortunately, current published studies are limited in regard to the gold standard. Kim and colleagues compared FDG-PET with CT and histopathologic results

from esophagectomy and extensive, either two-field or three-field, lymph node dissection.65 Forty-seven patients underwent transthoracic esophagectomy and extensive lymphadenectomy, whereas only 3 patients underwent transhiatal esophagectomy. The sensitivity, specificity, and accuracy for detection of metastasis to lymph node groups were 52%, 94%, and 84%, respectively, for FDG-PET and 15%, 97%, and 77%, respectively, for CT. Similarly, Choi and coworkers also studied 48 patients who underwent transthoracic esophagectomy and extensive lymphadenectomy (twoor three-field lymphadenectomy) and demonstrated that for N classification FDG-PET was correct in 83% of the patients, whereas CT and EUS were correct in 60% and 58%, respectively. For assessing metastasis in individual groups, the sensitivity, specificity, and accuracy were 57%, 97%, and 86%, respectively, for FDG-PET and 18%, 99%, and 78%, respectively, for CT.66 These studies demonstrated that, with extensive lymph node dissection, FDG-PET has the same specificity but significantly greater sensitivity and accuracy than CT for assessment of nodal metastasis. A recent metaanalysis of studies reported in the literature by van Westreenen and associates (2004) demonstrated that the overall pooled sensitivity and specificity of FDG-PET for detection of locoregional disease were 51% (95% CI, 34%-69%) and 84% (95% CI, 76%-91%), respectively.67 Co-registered PET and CT images have been shown to improve nodal staging. Yuan and others prospectively studied 45 patients with thoracic esophageal squamous cell cancer and compared the FDGPET/CT images with side-by-side PET and CT images for the diagnosis of locoregional lymph node metastases.116 Lymph node metastasis was found in 32 patients. The investigators found statistically significant differences in diagnostic performance between PET and PET/CT. The sensitivity, specificity, accuracy, positive-predictive value, and negative-predictive value of PET/CT were 93.9%, 92.1%, 92.4%, 75.5%, and 98.3%, respectively, whereas those of PET were 81.71%, 87.30%, 86.15%, 62.62%, and 94.83%, respectively. False-negative results with PET are mainly attributable to small tumor burden (especially nodes <1 cm in diameter) or to close proximity of the involved lymph nodes to the primary tumor (making it difficult to resolve the activity in the nodes as distinct from that in the primary tumor). As with CT and EUS, false-positive results with PET are mainly due to inflammatory disease. In addition, heterogeneous uptake in the primary tumor simulating periesophageal nodal metastasis is another source of false-positive results with PET. Because of the relative insensitivity of FDG-PET and other imaging techniques for detecting regional nodal disease, nodal sampling is routinely used in all patients who are otherwise considered to be surgical candidates. However, the status of adjacent lymph nodes that are typically resected with the primary tumor does not usually alter management.

Distant Metastatic Disease (M Classification) Patients with distant metastasis are beyond cure; thus, a curative surgical approach is not appropriate in these patients. Because of the associated high morbidity and poor outcome

89

90

Section 2 Investigation of Esophageal Disease

of surgical procedures in patients with advanced disease, it is essential to identify patients who can be more safely treated with palliative nonsurgical approaches. Several studies have shown that FDG-PET is superior to CT for detection of distant metastatic disease (Luketich et al, 1999).58-60,64,68,69 FDG-PET detected distant disease unsuspected by conventional methods in 3% to 37% of patients with esophageal cancer.58-60,64,68,69 In a prospective study, Luketich and colleagues (1999) compared PET and CT to minimally invasive staging in 91 patients (100 PET scans) with esophageal cancer.69 In 39 patients, 70 distant metastatic lesions were confirmed clinically or by biopsy. The sensitivity and specificity of FDG-PET for detection of distant disease were 69% and 93%, respectively, for FDG-PET and 46% and 74%, respectively, for CT. Flamen and coworkers, in a recent prospective study of 74 patients with esophageal cancer, found that FDG-PET was superior to CT and EUS in detection of stage IV disease with sensitivity and specificity of 74% and 90%, respectively, for FDG-PET, 41% and 83%, respectively, for CT, and 42% and 94%, respectively, for EUS.53 In this study, FDG-PET upstaged the tumor in 15% by detecting unsuspected metastatic disease and downstaged 7% of the patients. More recently, in a subsequent reanalysis of data in 42 of these 74 patients, these investigators showed that FDG-PET had higher sensitivity (77% versus 46%) and specificity (90% versus 69%) than the combination of CT and EUS, specifically for detection of distant nodal disease.63 In addition, FDG-PET upstaged 12% (5 of the 42) of patients from N1 to M1 disease. Van Westreenen and associates retrospectively evaluated the impact of preoperative staging methods on the number of unnecessary explorations.70 They retrospectively studied 203 patients; resection was aborted in 78 of the 203 patients for the following reasons: distant metastasis in 59, metastatic spread and local nonresectability in 5, and local nonresectability in 14 patients. In a logistic regression model with all preoperative staging modalities and the year of examination as an independent variable, FDGPET was the only modality that predicted intended curative resection and, thus, reduced the rate of unnecessary surgery in the patient population studied (P < .001). The addition of FDG-PET reduced unnecessary surgery from 44% with CT alone and 50% with CT + EUS to 21%. However, the recently reported results of the multicenter American College of Surgeons Oncology Group Z0060 trial showed that confirmed M1b disease was identified by PET in only about 5% of patients who had first been staged by conventional imaging methods.117 The management of additional patients was altered by the PET findings of either unconfirmed evidence of M1 disease or of N1 disease, leading to nonsurgical or neoadjuvant treatment strategies. A recent meta-analysis of 12 studies reported in the literature has demonstrated that the overall pooled sensitivity and specificity of FDG-PET for detection of distant metastatic disease were 67% (95% CI, 58%-76%) and 97% (95% CI, 90%-100%), respectively (van Westreenen et al, 2004).67 FDG-PET is currently accepted as a standard staging technique along with CT and EUS in patients with esophageal cancer. The main impact of PET in these patients is a result of its improved detection of otherwise occult stage IV disease

FIGURE 6-1 FDG-PET for esophageal cancer staging. A 62-year-old man presented with squamous cell carcinoma of the midesophagus. Coronal (top) and transaxial (middle and bottom) CT, PET/CT fusion, and PET images demonstrate intense FDG uptake within the primary tumor mass. In addition, intense FDG uptake was seen in a small superior left paratracheal (single arrow) and small gastrohepatic ligament lymph nodes (paired arrows).

and identification of the local or distant metastatic sites that are the most accessible to confirmation by directed tissue sampling by minimally invasive procedures (Fig. 6-1). This approach not only facilitates staging and avoids extensive unnecessary surgical procedures for staging, but it also prevents ineffective radical therapies that are associated with high cost and morbidity in patients with advanced disease. However, PET is not perfect and false-negative results because of small tumor size and false-positive results because of inflammatory or infectious processes can occur. Thus, histologic confirmation of PET findings is necessary before a patient is denied potentially curative surgery. As noted earlier, the published results to date on the use of PET/CT for imaging of cancer, including esophageal cancer, suggest that PET/CT is significantly more accurate than CT alone, PET alone, and side-by-side PET + CT (Fig. 6-2).71 Presumably this improved accuracy will translate into improved patient management. A PET/CT study of 18 patients with esophageal cancer demonstrated improved detection and characterization of 35% of suspicious lesions in 89% of patients and affected management of 22% of patients.72 In 32 patients with esophageal cancer, Bar-Shalom and coworkers demonstrated that PET/CT had an incremental value over PET for interpretation of 22% (25 of 115) of the lesions, correctly changing the initial characterization of 10 lesions to either malignant (n = 1) or benign (n = 9) and defining the precise anatomic location of 15 lesions.73 PET/ CT had a higher specificity and accuracy than PET reviewed side-by-side with CT (81% and 90% versus 59% and 83%,

Chapter 6 Nuclear Imaging

FIGURE 6-2 FDG-PET for esophageal cancer staging. A 65-year-old man presented with adenocarcinoma of the distal esophagus. Coronal (top) and transaxial (middle and bottom) CT, PET/CT fusion, and PET images demonstrate intense FDG uptake within the thickened distal esophagus, consistent with primary esophageal cancer. Anterior to the abdominal aorta there is mildly increased FDG uptake within an 8mm lymph node (arrow). Endoscopic biopsy of this lymph node was positive for metastatic disease.

respectively, P < .01) but equal sensitivity (96%) for detecting metastatic esophageal cancer. In addition, the investigators reported that image fusion was especially useful for evaluation of cervical and abdominopelvic lesions and disease assessment in locoregional lymph nodes before surgery, as well as in regions of postoperative anatomical distortion. PET/CT had an impact on the further management of 4 patients (10%) by detecting nodal metastases that warranted disease upstaging and by excluding disease in sites of benign uptake after surgery. Another impact of the use of FDG-PET as part of the preoperative workup of patients with esophageal cancer is the incidental detection of synchronous primary tumors. Van Westreenen and associates retrospectively reviewed PET studies in 366 patients with esophageal cancer who underwent PET for initial staging.74 They found 20 synchronous primary neoplasms (5.5%) in the group of patients studied.

Assessment of Prognosis With FDG-PET Because esophageal cancer has an unfavorable prognosis, accurate assessment of prognosis is essential for selection of the mode of therapy. Several tumor characteristics of esophageal cancer at presentation have been found to be predictive of prognosis. Among these is the intensity of FDG uptake in the primary esophageal tumor as measured by the SUV on PET images. Fukunaga and colleagues demonstrated that patients with a tumor SUV greater than 7.0 had a worse

prognosis than did those with lower values.50 These investigators also found a good correlation between hexokinase activity, assessed histochemically in the resected tumor specimens, and preoperative evaluation of tumor FDG uptake by means of SUV and k3, the rate constant for phosphorylation of FDG. In addition, FDG-PET demonstration of local or distant metastatic disease at initial presentation was highly predictive of survival (Luketich et al, 1999).69 Kato and coworkers reported a significant correlation between tumor uptake of FDG and tumor depth (P < .05), occurrence of lymph node metastasis (P < .01), and lymphatic invasion (P < .01).75 The survival rate was significantly lower in patients with tumor SUV greater than 3 than those with SUV less than 3 (P < .05). Luketich and colleagues (1999) reported that the 30-month survival of patients with PET evidence of local disease only was 60%, compared with 20% for patients with PET evidence of distant disease (P = .01). However, no statistically significant correlation was found between CT stage of the tumor and survival in this study: the 30-month survival of patients with CT evidence of local disease only (n = 58) was 52% compared with 38% for patients with CT evidence of distant disease (n = 33).69 Choi and coworkers, in a study of 69 patients with squamous cell esophageal cancer, demonstrated that only the number of PET-positive nodes was an independent significant prognostic predictor for disease-free survival in multivariate analysis (hazard ratio = 1.87, P < .001).76 In univariate survival analysis, the sex, presence of adjuvant therapy, clinical and pathologic stages, number of CT-positive nodes (0, 1, ≥2), maximum SUV of the primary tumor (cutoff: 6.3, 13.7), tumor length on PET (cutoff: 3 cm, 5 cm), number of PET-positive nodes (0, 1, 2, ≥3), and PET stage (N0M0, N1M0, M1) were significant prognostic predictors for overall survival. In contrast, the clinical stage (hazard ratio = 0.53, P < .05), pathologic stage (hazard ratio = 3.14, P < .005), tumor length by PET (hazard ratio = 2.74, P = .01), and number of PET-positive nodes (hazard ratio = 1.71, P < .05) were independent significant prognostic predictors for overall survival in multivariate analysis. Most recently, van Westreenen and associates showed, in a retrospective study of 40 patients, that a high SUV was not an independent predictor of survival but rather was related to resectability, which was the most important prognostic factor in their patients.77 The role in routine clinical practice of the SUV for FDG as a biomarker of prognosis in esophageal cancer remains to be established.

Assessment of Response to Therapy Locally advanced esophageal cancer without systemic spread is amenable to therapy with curative intent. For such patients, neoadjuvant therapy before esophagectomy has shown promising results. The goal of neoadjuvant chemotherapy or chemoradiotherapy is downstaging to achieve resectability. Patients with an objective response to neoadjuvant therapy have a better prognosis and benefit the most from subsequent surgical resection of their tumors while nonresponders are likely to have an unfavorable outcome.78-80 Complete macroscopic and microscopic resection of the primary tumor is a strong independent prognostic factor. Patients with locally

91

92

Section 2 Investigation of Esophageal Disease

advanced disease (T3-4) with complete resection have a 20% to 31% chance of 5-year survival, whereas for those with incomplete resection there is no chance of 5-year survival.55 Response to chemoradiotherapy is not uniform; whereas some tumors respond well to therapy, others progress during therapy. In addition, assessment of response to neoadjuvant therapy is not an easy task. CT and EUS are limited in assessment of response to therapy. These modalities are not reliable in differentiating residual viable tumor from post-therapeutic changes (e.g., inflammation or scar), and no significant correlation has been found between the results of these anatomic imaging modalities and pathologic response. Additionally, a delay of several weeks after completion of therapy is often necessary for evaluating response.81 The use of fine-needle aspiration biopsy in conjunction with EUS has been shown to be more useful than EUS alone. However, a negative fine-needle aspiration biopsy cannot reliably exclude the presence of residual tumor.82 The use of FDG-PET for predicting response shortly after initiation of neoadjuvant therapy or to assess response after completion of such therapy in patients with esophageal cancer has been studied by several investigators. Weber and colleagues studied 40 patients with adenocarcinoma of the gastroesophageal junction by FDG-PET before and 14 days after initiation of neoadjuvant chemotherapy.83 Patients were evaluated for clinical response (defined as reduction in tumor length and wall thickness by more than 50% using endoscopy and conventional imaging) 3 months after completion of therapy, and those patients who underwent surgery were evaluated for histopathologic response. They found that responders had a significantly greater decrease (mean ± standard deviation) in tumor FDG uptake (−54% ± 17%) compared with nonresponders (−15% ± 21%), 14 days after induction therapy. A reduction of FDG uptake of 35% was found to be an accurate cutoff value for distinguishing responders from nonresponders. This cutoff value predicted clinical response with a sensitivity of 93% and specificity of 95%. Eight of the 15 patients (53%) with metabolic response and only one of the 22 (5%) patients without metabolic response had complete or subtotal histopathologic tumor regression. Moreover, patients without a metabolic response had significantly shorter disease-free and overall survival (P = .01 and P = .04, respectively). Thus, the use of FDGPET early during treatment to predict response to neoadjuvant therapy may facilitate identification of patients who will benefit the most from preoperative therapy. For assessing response after completion of neoadjuvant therapy, a decrease in tumor FDG uptake generally indicates effective therapy whereas no significant decrease or even an increase is noted with ineffective therapy. Occasional patients are found to have progression at distant sites during neoadjuvant therapy (Fig. 6-3). Downey and associates studied 24 patients with esophageal cancer who received induction therapy before esophagectomy.84 The investigators demonstrated that the 2-year disease-free survival after induction therapy and esophagectomy was significantly longer in patients with a decrease in tumor FDG uptake, as measured by SUV, by more than 60% than in patients with lesser decreases in FDG uptake (67% versus 38%, P < .05). However, there was

no significant correlation between the 2-year overall survival and changes in tumor FDG uptake after induction therapy (89% versus 63%, P = 0.88). Similar results have been reported by others.85-89 Swisher and colleagues studied 103 patients with advanced locoregional esophageal cancer before and after completion of chemoradiotherapy.42 They showed that after therapy, tumor SUV greater than or equal to 4 had the highest accuracy for pathologic response in comparison with changes in tumor thickness on CT (esophageal wall thickness; 13.3 versus 15.3 mm) and tumor mass size on EUS (0.7 versus 1.7 cm). In addition, using univariate and multivariate Cox regression analysis, a post-therapy tumor SUV greater than or equal to 4 was an independent predictor of survival (hazard ratio 3.5, P = .04). In a prospective study, Cerfolio and colleagues demonstrated that FDG-PET/CT is more accurate than EUS with fine-needle aspiration biopsy (EUS-FNA) and CT for predicting response to neoadjuvant therapy.90 Forty patients with esophageal cancer underwent CT of the chest, abdomen, and pelvis, EUS-FNA, and FDGPET/CT before initiation of neoadjuvant chemoradiotherapy. Patients were restaged with the same three imaging techniques after completion of therapy. They demonstrated that the median percent decrease in FDG uptake, measured by SUVmax, was greater in responders than the nonresponders (47% versus 8%, respectively, P = .03). FDG-PET/CT accurately predicted complete response in 89% compared with 67% for EUS-FNA (P = .045) and 71% for CT (P = .05). In addition, the negative predictive value of FDG-PET/CT was significantly higher than that with EUS-FNA or CT alone (95%, 67%, 73%, respectively; P = .04). The investigators favored PET/CT for evaluation of patients after therapy. Brücher and associates also demonstrated a greater decrease in FDG uptake, as measured by SUV, in responders in comparison to nonresponders (−72% ± 11% versus −42% ± 22%) following chemoradiotherapy of squamous cell carcinomas of the esophagus.91 Nonresponders had a worse prognosis than responders. Using a 52% reduction in tumor FDG uptake as a cutoff value, PET predicted response with a sensitivity of 100% and a specificity of 55%. The poor specificity of FDGPET in this study is likely related to post-therapy inflammation that may persist for several weeks after completion of therapy; patients in this study underwent FDG-PET 3 weeks after completion of therapy (P < .0001). Post-treatment esophagitis is a common finding in patients with esophageal cancer early after completion of radiation therapy (Fig. 6-4). Increased FDG uptake in inflamed tissue makes evaluation of response to cancer therapy by FDG-PET difficult. We were unable to differentiate residual tumor from chemoradiation-induced esophagitis by using a quantitative PET measurement technique in a study of 24 patients with esophageal cancer.92 To avoid this problem, the time interval between chemoradiation therapy and PET follow-up should be carefully selected in future prospective studies. Wieder and associates (2004) studied 38 patients with squamous cell carcinoma of the esophageal to evaluate the time course of therapy-induced changes in tumor FDG uptake during chemoradiotherapy and to correlate the reduction of metabolic activity with histopathologic tumor response and patient survival.93 The patients were studied before, 2

Chapter 6 Nuclear Imaging

Pretherapy Posttherapy

A

B

FIGURE 6-3 FDG-PET for assessing response to therapy. A 52-year-old man presented with poorly differentiated cancer in the midesophagus and distal esophagus. A, Sagittal (top) and transaxial (middle and bottom) CT, PET/CT fusion, and PET images demonstrate markedly increased FDG accumulation within a large lobulated esophageal cancer (arrows). No abnormal uptake is seen in the right proximal humerus (curved arrow). B, Approximately 10 weeks after completion of chemoradiation, similar images show improvement in the degree of FDG uptake within the primary cancer (arrows). However, a small area of increased FDG uptake is seen in the proximal right humerus (curved arrow), consistent with development of distant metastatic disease. Several additional bone metastases also were demonstrated by PET.

weeks after initiation of therapy, and 3 to 4 weeks after chemoradiotherapy (before surgery). In histopathologic responders (<10% viable cells in the resected specimen), the decrease in SUV from baseline to day 14 was 44% ± 15%, whereas nonresponders had a decrease of only 21% ± 14% (P = .005). Metabolic changes at 14 days after therapy also were correlated with patient survival (P = .011). Similarly in the preoperative scan, a significantly greater decrease in tumor FDG uptake was noted in histopathologic responders in comparison to nonresponders (70% ± 11% and 51% ± 21%, respectively) (P = 0.011). A threshold value of 52% decrease in baseline FDG uptake was found to be an optimal cutoff value for differentiation between responders and nonresponders. With this threshold value, the sensitivity and specificity of FDG-PET for predicting response was 89% (95% CI, 67%-99%) and 57% (95% CI, 29%-82%), respectively. In addition, a threshold SUV of 3.8 on the preoperative scan reliably differentiated responders from nonresponders with a sensitivity of 95% (95% CI, 74%-99%) and a specificity of 50% (95% CI, 23%-77%). In a meta-analysis of the literature, van Westreenen and associates compared the diagnostic accuracy of CT, EUS, and

PET in assessing response to therapy in patients with esophageal cancer or cancer of the gastroesophageal junction or gastric cardia. They used summary receiver operating characteristic (ROC) methodology to compare the diagnostic accuracy of the three modalities (based on data from 4 CT, 13 EUS, and 7 FDG-PET studies). They demonstrated that CT had a significantly lower accuracy than FDG-PET (P = .0057) and EUS (P = .0026) for assessment of response to therapy.94 However, the accuracies of FDG-PET and EUS were similar (P = .839). The maximum joint sensitivity and specificity values were 54% for CT, 86% for EUS, and 85% for FDGPET. They found that obtaining CT was always feasible, whereas EUS was not feasible in 6% of patients and FDGPET was not feasible in less than 1% of patients. However, limitations of this meta-analysis include substantial differences in neoadjuvant therapy schemes between studies, differences in technique and data analysis, as well as the differences in the spectrum of disease in patients evaluated by these three modalities. Although patients who were eligible for curative surgery and received neoadjuvant therapy were included, the tumor size range was quite variable (T1 to T3 tumors) in these studies. In addition, measurements of

93

94

Section 2 Investigation of Esophageal Disease

Before Therapy

After Therapy

A

B

FIGURE 6-4. FDG-PET for assessing response to therapy. A 68-year-old man presented with moderately differentiated adenocarcinoma of distal esophagus. A, Sagittal (top) and transaxial (middle and bottom) CT, PET/CT fusion, and PET images demonstrate markedly increased FDG accumulation within the primary tumor mass (curved arrows). B, Approximately 4 weeks after completion of chemoradiation, similar images show significant improvement in the degree of FDG uptake within the primary cancer (curved arrows). At esophagectomy, postirradiation inflammation with no evidence of tumor was found.

changes in tumor volume or FDG uptake may be less accurate in small lesions owing to a larger influence of systematic errors and image noise. Collectively, the studies to date suggest that FDG-PET appears quite promising as a method for response assessment in esophageal carcinoma. Practical clinical application of this approach, however, will depend on the results of future studies to better define the criteria for “metabolic response” and to document that directing therapy decisions based on PET findings is cost effective and leads to improved survival or quality of life.

Detection of Recurrent Disease Despite aggressive therapy for patients with esophageal cancer, long-term survival remains poor. Patients with recurrent disease have a poor prognosis, and the survival benefit of early detection of recurrent disease is uncertain. However, aggressive therapy of local recurrence may prolong diseasefree survival or occasionally be curative. Whereas anatomic imaging modalities are limited in differentiating scar from recurrent disease, FDG-PET has the ability to detect and differentiate recurrent disease from post-therapy changes when disease has altered metabolism without any structural changes. Thus, PET is expected to be more suitable for early detection of recurrent disease. Only a few studies have evaluated the role of FDG-PET in detecting recurrent esophageal cancer. Fukunaga and associates studied 13 patients with suspected recurrent esopha-

geal cancer. Increased FDG uptake was noted in 6 of 7 patients with proven recurrent disease, whereas no significant FDG uptake was seen in the 6 patients who did not have recurrence.95 Flamen and coworkers studied 41 patients with clinical or radiologic suspicion of recurrent disease.96 Recurrent disease was present in 33 patients (80%). Conventional imaging was slightly, but not significantly, better than FDGPET in detecting recurrence around the esophagogastric anastomosis; the sensitivity, specificity, and accuracy were 100%, 57%, and 74%, respectively, for FDG-PET and 100%, 93%, and 96%, respectively, for conventional imaging. However, PET was slightly, but not significantly, better than conventional imaging for detecting recurrent disease in the operative field (regional) and distant recurrence; the sensitivity, specificity, and accuracy were 94%, 82%, and 87%, respectively, for FDG-PET and 81%, 82%, and 81%, respectively, for conventional imaging. On a patient basis, FDG-PET provided additional information in 11 of 41 patients (27%), detected disease in 5 patients with equivocal or negative clinical findings, detected unsuspected distant recurrent disease in 5 patients with documented local disease, and excluded disease in 1 patient. Kato and coworkers (2004) studied 55 patients with thoracic esophageal cancer who had undergone radical esophagectomy.97 They evaluated the accuracy of FDG-PET and CT in detecting recurrence during follow-up. Twenty-seven of the 55 patients had recurrent disease, locoregional and/or distant. The sensitivity, specificity, and accuracy were 96%, 68%, 82%, respectively for PET and 89%, 79%, and 84% for

Chapter 6 Nuclear Imaging

CT. The sensitivity of FDG-PET was higher than that of CT in detecting locoregional recurrence, but its specificity was lower. In distant organs the sensitivity of PET in detecting lung metastasis was lower than that of CT, but its sensitivity for bone metastasis was higher. The investigator predicted that combined PET-CT would appear to be an appropriate modality for the detection of recurrent esophageal cancer. Studies specifically addressing the role of PET/CT for detecting recurrent disease have not yet been reported.

Radiotherapy Planning Radiotherapy plays an important role in the management of patients with esophageal cancer. For curative radiotherapy, distant disease needs to be excluded and locoregional disease needs to be accurately defined. Radiotherapy planning based on CT alone likely misses regions of macroscopic tumor in some patients that may lead to ineffective therapy. FDG-PET has been reported to have an important impact in planning radiotherapy in oncologic patients.98-105 Thus, in patients with locally advanced esophageal cancer, effective therapy requires accurate assessment of lymph node involvement, which is necessary for delineation of the volume to be irradiated. Limited data are available in the literature on the potential use of PET in defining the gross tumor volume (GTV) to be irradiated. Vrieze and associates evaluated the imaging and radiotherapy data from 30 patients with advanced esophageal cancer. The lymph node classification was translated into anatomic volumes on CT.106 Fourteen different regions were scored individually for lymph node involvement on CT, EUS, and FDG-PET. In 14 of the 30 patients, discordances were found in detection of the pathologic lymph nodes between CT/EUS and FDG-PET. In 8 patients, nine metastatic lymph node regions were found on conventional imaging only; in 3 of these patients the influence of FDGPET findings would have led to a decrease in the irradiated volume. In the remaining 6 patients with discordant findings, eight lymph node regions were negative on CT/EUS but positive on FDG-PET; in 3 of these patients (10%) the influence of FDG-PET would have led to enlargement of the irradiated volume. Konski and colleagues evaluated the impact of PET and EUS compared with CT simulation in the planning of radiation fields for patients with esophageal cancer.107 Twenty-five patients underwent PET/CT in the treatment position after conventional CT simulation. Twenty-two patients also underwent EUS. The length of the abnormality was evaluated both on the CT portion of the PET/CT and on PET alone. An SUV threshold of 2.5 was used to delineate the tumor extent on the PET study. The length of GTV and regional adenopathy by PET were also correlated with EUS findings in 18 patients. The mean length of the cancer was 5.4 cm as determined by PET alone, 6.8 cm as determined by CT alone, and 5.1 cm for EUS. The length of the tumor was significantly longer as measured by CT compared with PET (P = .0063), but the length of the cancer determined by FDG-PET correlated better with that determined by endoscopy than did that determined by CT. EUS detected significantly more patients with periesophageal and celiac lymphadenopathy

than did PET or CT. Thus, it was concluded that EUS and PET may add additional information to identify the GTV in patients with esophageal carcinoma. The use of PET/CT in treatment planning of advanced esophageal cancer needs to be further evaluated.

Alternative Radiopharmaceuticals for PET Several investigators have used 11C-choline to study patients with esophageal cancer. Choline is one of the components of phosphatidylcholine, an essential element of phospholipids in the cell membrane. Thus, choline is expected to accumulate to a greater degree in proliferating malignant tumors compared with normal tissues. Kobori and coworkers compared FDG-PET with 11C-choline-PET in 33 patients with biopsyproven esophageal carcinoma.108 Compared with FDG-PET, 11 C-choline-PET was more sensitive in detecting very small mediastinal metastases (88% versus 34%) but was less sensitive in detecting metastases in the upper abdomen (0% versus 79%), because of the normal uptake of 11C-choline in the liver, stomach wall, pancreas, and small intestine. When 11Ccholine-PET and FDG-PET were used in combination, they were very effective in evaluating the lymph node status in both the mediastinum and the upper abdomen and detected 85% of the metastatic lymph nodes. Jager and associates also compared FDG-PET with 11C-choline-PET in 16 patients with esophageal cancer or gastroesophageal junction cancer.109 FDG-PET detected all of the malignant primary lesions (100%), while 11C-choline-PET detected 73%. FDG-PET and 11C-choline-PET were negative in all 12 patients with locoregional metastases (N1). For distant disease, FDG-PET detected 10 of 12 (83%) while 11C-choline-PET detected 5 (42%) lesions. In general, the degree of tumoral uptake of 11 C-choline was lower than FDG. 11C-choline-PET does not appear to have significant advantages compared with FDGPET in esophageal cancer. Several studies have shown that cell proliferation can be measured with the thymidine analogue 3′-deoxy-3′(18F)fluorothymidine (FLT).110-112 Van Westreenen and associates recently compared FDG-PET with FLT-PET in the detection and staging of 10 patients with esophageal or gastroesophageal junction cancer.113 FDG-PET detected all esophageal cancers, whereas FLT-PET detected tumors in 8 of the 10 patients. Both FDG-PET and FLT-PET had low sensitivity for the detection of regional lymph node metastases (2 of 8 patients). Neither FDG nor FLT uptake correlated with tumor Ki-67 expression. The tumor uptake of FDG was significantly higher than FLT. The high physiologic uptake of FLT within the bone marrow and liver limits detection of metastatic disease in these organs. Others have shown similar results.114 Although some data suggest that FLT is a better tracer than FDG for early response assessment during chemotherapy of chemoradiotherapy, no studies have specifically addressed its use for this purpose in esophageal cancer.

COMMENTS AND CONTROVERSIES Nuclear imaging lacks anatomic definition. Its assessment of esophageal function is gross, concentrating on the clearance or reappear-

95

96

Section 2 Investigation of Esophageal Disease

ance of nuclear tracers. Its use in benign disease has been supplanted by better imaging techniques and better measures of esophageal motor and sphincter function. It also has a negative association because this “radioactive” testing is usually proposed for a younger patient with benign disease. Many of these patients have a quiet reluctance to undergo nuclear imaging. For all these reasons nuclear imaging is infrequently used in the assessment of benign esophageal disease. Thus, when the information is really needed, the performance, interpretation, and clinical application of these examinations are suboptimal at most institutions and fail to be of use in patient management. In contrast, nuclear imaging has become an integral component of clinical staging of esophageal cancer. However, hypermetabolism as measured by glucose uptake is a surrogate for malignant growth and examples of false-positive and false-negative FDG-PET examinations abound. The simultaneous performance of FDG-PET and CT has greatly enhanced the value of these two imaging studies. Unfortunately, many patients in a rush to start treatment of their esophageal cancer have CT without consideration of PET/CT. No doubt the computer fusion of the two independent studies after the fact is a poor substitute for the real thing. FDG-PET imaging provides valuable information about M classification. Any positive findings that will be used to influence treatment should be confirmed with pathologic review of fine-needle aspiration or biopsy specimens. The addition of anatomic information of CT has helped clinical N classification, but there is great difficulty separating the primary tumor from closely associated metastatic regional lymph nodes (N1). PET/CT is of no use in T classification. Standardized uptake value (SUV) has become a hot topic. It has been proposed as an independent prognosticator, a predictor of response to preoperative (induction) therapy after the fact, and an indicator of who may respond to induction therapy. The data are questionable. It must be remembered that SUV is a calculated continuous variable that is subject to great variability. There are patient, performance, and interpretation problems. Patient preparation, blood sugar, insulin levels, patient size, obesity, and so on may greatly influence glucose uptake. Amount of fasting, technique of injection, injected dose, and timing of scanning are sources of considerable error. The size, contour, and uniformity of uptake may cause averaging errors in the calculation of SUV. The imaging machinery must be calibrated. There may be considerable variability from study to study in individual patients and definite variability between institutions. SUV may not be the great clinical tool it was hoped to be. T. W. R.

KEY REFERENCES Kato H, Miyazaki T, Nakajima M, et al: The incremental effect of positron emission tomography on diagnostic accuracy in the initial staging of esophageal carcinoma. Cancer 103:148-156, 2005. ■ This paper discusses the additional value of PET when added to CT. The incremental value of PET over CT with regard to lymph node status was seen in 14% of patients by either demonstrating unsuspected nodal disease or by excluding suspected disease. Luketich JD, Friedman DM, Weigel TL, et al: Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans. Ann Thorac Surg 68:1133-1136, 1999; discussion 1136-1137. ■ This paper studied the relationship between the extent of disease on PET and patient survival. The 30-month survival of patients with PET evidence of only local disease was longer than that of patients with PET evidence of distant disease (60% versus 20%). PET findings allowed for significantly better risk stratification than CT. Mariani G, Boni G, Barreca M, et al: Radionuclide gastroesophageal motor studies. J Nucl Med 45:1004-1028, 2004. ■ This paper reviews the use of radionuclide gastroesophageal scintigraphy in management of gastroesophageal motor diseases and discusses the benefits and shortcomings associated with these studies. The main limitation of scintigraphy is the lack of standardization of technique and interpretation criteria. Sachelarie I, Kerr K, Ghesani M, Blum RH: Integrated PET-CT: Evidence-based review of oncology indications. Oncology (Williston Park) 19:481-490, 2005; discussion 490-492, 495-496. ■ By comparison with conventional PET, integrated PET-CT allows for improved characterization of equivocal lesions and decreased intraobserver variability and, thus, it has the potential to significantly affect management of cancer patients. van Westreenen HL, Westerterp M, Bossuyt PM, et al: Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 22:38053812, 2004. ■ This recent meta-analysis documents that FDG-PET may be of limited value for detection of locoregional disease but that its role in detecting unsuspected distant disease is significant. Thus, PET is extremely important in identifying patients who are not candidates for curative surgery. Wieder HA, Brucher BL, Zimmermann F, et al: Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 22:900-908, 2004. ■ This paper evaluates the time course of therapy-induced changes in tumor glucose utilization during chemoradiotherapy of esophageal squamous cell carcinoma and correlated the reduction of metabolic activity with histopathologic tumor response and patient survival. At 14 days after the start of therapy, histopathologically confirmed responders had a significantly greater decrease in tumor FDG uptake than did nonresponders and metabolic changes were correlated with patient survival.

chapter

7

ENDOSCOPIC ULTRASONOGRAPHY Thomas W. Rice Gregory Zuccaro, Jr.

Key Points ■ EUS extends the endoscopic evaluation of the esophageal wall

beyond the mucosa. ■ The principal role of EUS is clinical staging of esophageal cancer. ■ EUS is useful in the diagnosis of benign esophageal tumors. ■ EUS FNA allows sampling and cytologic evaluation of the esophageal wall and surrounding tissues.

The development of endoscopic ultrasonography (EUS) extended the examination of the esophagus beyond the mucosa into the esophageal wall and paraesophageal tissues. Diagnostic capabilities of surface ultrasonography have been expanded by endoscopic placement of ultrasound transducers adjacent to the gastrointestinal mucosa. These transducers, operating at relatively high frequencies, provide detailed examinations of the esophageal wall and surrounding tissues. EUS is the most significant advancement in the diagnosis of esophageal disease since the introduction of flexible fiberoptic endoscopy. These intracorporeal examinations have proven beneficial in the diagnosis and treatment of both benign and malignant diseases of the esophagus and adjacent structures.

FUNDAMENTALS OF ULTRASONOGRAPHY Sound is produced by vibration of a source within a medium. Vibration produces waves, cyclic compression, and rarefaction (expansion) of molecules in the medium, thus transmitting the sound wave through the medium. The number of cycles (compression and rarefaction) of a sound wave occurring in 1 second is the frequency and is measured in hertz (Hz). The frequency of sound waves audible to the human ear is between 20 Hz and 20,000 Hz. Sound waves with frequencies higher than 20,000 Hz are ultrasound waves. Frequencies used in medical ultrasound imaging range from 1 million to 20 million Hz (1-20 MHz). Ultrasound waves may be produced by electrical excitation of a piezoelectric crystal. The application of voltage across a crystal causes it to deform. Alternating electrical energy vibrates the crystal and produces sound waves. Conversely, if a sound wave deforms a crystal, electrical energy is produced. It is this ability to convert electrical energy into sound energy and, conversely, to convert sound energy into electrical energy that allows these crystals to function as both transmitters and receivers (i.e., as transducers). These transducers are responsive to a limited range of frequencies; hence, more than one transducer may be required for an ultrasound examination.

The speed of a sound wave within a medium (tissue) is defined by the following relationship: V = (K/p)1/2

where V is the velocity of the sound wave, K is the bulk modulus of the tissue (a measure of stiffness), and p is the density of the tissue. The resistance to passage of a sound wave through tissue is called the acoustic impedance (Z), which is defined by the following relationship: Z = pV = (pK)1/2

2

Sound waves travel best through dense or elastic tissues. Absorption of some energy of an ultrasound wave occurs as the wave passes through tissue. The amount of absorption is determined by tissue characteristics and the frequency of the sound wave. Higher-frequency waves have greater absorption. Interactions occur as a sound wave encounters different tissues and are critical to the diagnostic capabilities of ultrasound. As a sound wave passes from one tissue to the next, a portion of the wave is transmitted and a portion is reflected. The reflected wave is received by the transducer, providing the diagnostic information of ultrasound. The difference in acoustic impedance between the two tissues and the angle at which the sound wave enters the new medium (angle of incidence) determine the portion of the wave that is reflected and the portion that is transmitted. In the presence of similar acoustic impedances, most of the wave is transmitted. Soft tissue has excellent transmission qualities; the density and velocity vary slightly among different soft tissues. Because acoustic impedance is the product of velocity and density, the product of these small changes results in a somewhat larger difference in the acoustic impedance between fat and muscle. Useless, bright echo images are obtained when an ultrasound wave encounters air or bone. Air is very compressible and of low density, whereas bone, although dense, has low compressibility and high reflectivity. These properties account for the poor transmission of ultrasound waves from tissue to air or tissue to bone. The amount of reflected sound is also related to the angle of incidence; as the angle of incidence increases, less sound is reflected. In addition, sound waves are bent as they travel from one tissue to the next. This process is termed refraction. Absorption, reflection, and refraction are major sources of energy loss. Some ultrasound wave energy is also lost by scattering (diffusion), which occurs when a sound wave encounters heterogeneous tissue. Tiny particles within tissue (e.g., fat in muscle), smaller than the ultrasound wavelength, 97

98

Section 2 Investigation of Esophageal Disease

scatter the ultrasound wave. As a sound wave passes through tissue, a portion of its energy is lost; this is called attenuation. Attenuation increases as more tissues are encountered and as the wave travels farther from the source. If the returning ultrasound wave is not processed, the same tissue would be imaged differently, depending on its distance from the transducer. The intensity of the returning waves must be amplified (gain) to ensure that distant waves are correctly represented. Attenuation increases as ultrasound frequency increases. Resolution is the ability to discriminate among different tissues with ultrasound waves. Depth or axial resolution is the ability to differentiate between two tissues along the path of the ultrasound wave. Lateral resolution is the ability to distinguish between adjacent tissues. Transducer characteristics and focus determine resolution. Higher frequencies allow better resolution but decreased tissue penetration. Pulse-echo technique is used in EUS. Ultrasound waves are emitted for a brief period, followed by a subsequent listening period during which the reflected waves are received. The returning ultrasound waves are displayed so that the brightness is proportional to the amplitude of the returning ultrasound waves. This is known as B-mode ultrasonography. Because the amplitude is presented in a range from white to gray to black, the display is also termed gray-scale ultrasonography. Individual scans are shown at a rate at which the eye cannot detect single images (12/sec). This fast-frame display is called real-time ultrasonography and allows the ultrasonographer to study tissue temporally as well as spatially.

FIGURE 7-1 The Olympus GFUM160 ultrasound endoscope. Upper left, The control section contains the deflection controls and air/water and suction valves similar to those on a standard endoscope. Upper right, The ultrasound transducer is housed in the tip of the endoscope. The forward oblique viewing endoscope and suction channel are proximal to the ultrasound transducer. Lower left, The distal tip of the ultrasound endoscope with the water-inflated contact balloon, which covers the ultrasound transducer.

INSTRUMENTS AND TECHNIQUES Because EUS does not provide adequate endoscopic inspection of the upper gastrointestinal tract, every ultrasonographic study should be preceded by a standard flexible endoscopic upper gastrointestinal examination. This provides precise location and mucosal definition (including biopsy) of the esophageal lesion and provides guidance for the ultrasonographer. Intravenous administration of a narcotic, such as meperidine, and a benzodiazepine, such as midazolam, usually provides adequate sedation. The ultrasound endoscope is generally passed blindly through the oropharynx and hypopharynx. Care must be taken because the distal tip containing the transducer is rigid. For complete examination, the endoscope must be passed beyond the esophagus and into the stomach. Radial ultrasound endosonography is used in the majority of EUS cases (Fig. 7-1) The ultrasound transducer is housed in the tip of the endoscope. It produces up to a 360-degree sector scan perpendicular to the transducer tip. Because the transducer is adjacent to tissues to be examined, higher frequencies than those used in extracorporeal ultrasonography can be employed.1 In the newest models a range of transducer frequencies from 5 to 20 MHz is available. These transducers allow adequate visualization of anatomic structures to a depth of 3 to 12 cm. An acceptable acoustic interface between the transducer and the tissue being examined must be obtained to ensure good quality ultrasound images. This is most commonly accomplished by covering the tip of the endoscope with a latex balloon, which can be filled with water to provide an excellent acoustic interface (see Fig. 7-1). A less commonly employed technique is the rapid insufflation of the esophageal lumen with water. This provides an excellent but transient acoustic interface without the tissue compression that may occur with the latex balloon. Current echoendoscopes also provide a video-endoscopic image, albeit a somewhat limited view in a forward oblique direction. The control section contains the deflection controls and air/water and suction valves similar to those on a standard endoscope (see Fig. 7-1). A water inflation/deflation system for the balloon is incorporated into the air/water and suction valve mechanisms. Current ultrasound endoscopes are totally immersible. The radial mechanical blind probe (Fig. 7-2) is available for the evaluation of esophageal strictures. This echoendoscope

FIGURE 7-2 Olympus MH-908 radial mechanical blind probe. The tip is tapered to allow passage through tight strictures. The radial ultrasound transducer is positioned behind the tapered tip.

Chapter 7 Endoscopic Ultrasonography

B

A

FIGURE 7-3 A higher frequency miniprobe passed through the operating channel of a standard endoscope.

provides images similar to larger-diameter radial mechanical echoendoscopes but has no endoscopic optical capabilities and is less than 8 mm in diameter. More commonly utilized in current practice are higher-frequency miniprobes passed through the operating channel of standard endoscopes (Fig. 7-3); these miniprobes provide radial images from 12 to 30 MHz. These three instruments are used in conjunction with an image processor (Fig. 7-4). The image processor controls allow for adjustment of gain, contrast, and sensitivity time controls. This regulates the strength of the returning echo at different depths. On-screen calibration and labeling can be done with the image processor. The image may be displayed on a video monitor or stored digitally or on videotape. The image processor has been refined and miniaturized with successive generations of EUS equipment.

A

Newer electronic radial endoscopes are also available. These have the advantage of providing color Doppler imaging. They may be less susceptible to breakdown because moving parts are eliminated. In some cases both radial and linear echoendoscopy examination may be possible with one power source and image processor system. The curvilinear electronic echoendoscope (Fig. 7-5) also has video-endoscopic capability, producing up to a 180degree oblique forward field. It allows a range of scanning frequencies from 5 to 10 MHz with depth of penetration of 4 cm or greater. This system can provide color Doppler examination and direct visualization of cytology needles passed into and beyond the esophageal wall. Use of radial and curvilinear endosonography has increased accuracy. However, availability and use of two systems necessarily increases both complexity and cost of EUS examina-

B

FIGURE 7-4 A, The Olympus EUM60 image processor is rack-mounted in a standard cart, which includes the other essential endoscopic equipment. The keyboard can be used to measure and mark ultrasound findings. B, The complete system includes the light source rack, image processor, and ultrasound endoscope.

99

100

Section 2 Investigation of Esophageal Disease

tions. For diagnostic purposes, radial endosonography is preferable because it allows a 360-degree view and is known as the workhorse of EUS. Because the radial scanner does not allow safe directed passage of a needle into the esophageal wall or adjacent tissue, if a tissue sample for cytologic evaluation is required, the curvilinear echoendoscope is employed. It is possible to perform both diagnosis and fine-needle aspiration (FNA) with the linear echoendoscope alone, but the limitation in the viewing field requires significant torque on the insertion tube to image the esophageal wall and adjacent tissues for a 360-degree view. Comparable results, however, for staging examinations have been reported with an electronic curvilinear echoendoscope.2 Both systems must be available for adequate EUS evaluation. As noted earlier, the newest electronic radial echoendoscopes allow for both radial and linear images to be generated from one power source and image processing system, thus increasing unit efficiency and presumably decreasing costs.

A

THE ESOPHAGEAL WALL AND ULTRASOUND ANATOMY

B FIGURE 7-5 Olympus GFUC140P curvilinear electronic endoscope (A) and Aloka Prosound Alpha-5 image processor (B). The optics and operating channel, through which a fine needle is passed, are positioned behind the linear ultrasound transducer. This echoendoscope requires a separate image processor.

FIGURE 7-6 The esophageal wall is composed of mucosa, submucosa, and muscularis propria. The mucosa is composed of epithelium, lamina propria, and muscularis mucosae. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Epithelium Basement membrane Lamina propria Muscularis mucosae Submucosa Muscularis propria

Regional lymphatics Thoracic duct

The esophageal wall is composed of three distinct layers: mucosa, submucosa, and muscularis propria (Fig. 7-6). The mucosa has three elements: epithelium, lamina propria, and muscularis mucosae. The innermost layer is stratified, nonkeratinizing squamous epithelium. It is separated and isolated from the remainder of the esophageal wall by a basement membrane. Immediately beneath is the lamina propria. This loose matrix of collagen and elastic fibers forms a superficial undulating layer; invaginations into the epithelium produce epithelial papillae. Lymphatic channels in the lamina propria are an anatomic feature unique to the esophagus. The muscularis mucosae surrounds the lamina propria. This smooth muscle layer pleats the two inner layers of the mucosa into folds that disappear with distention of the lumen. The submucosa is composed of connective tissues that contain a rich network of blood vessels and lymphatics. The dense submucosal lymphatic plexus facilitates early dissemi-

Submucosal gland

Chapter 7 Endoscopic Ultrasonography

nation of esophageal malignancies. Elastic fibers and collagen combine to make this the strongest esophageal layer. Submucosal glands of mixed type are characteristic of the esophagus. The muscularis propria is the muscular sleeve that provides propulsive force necessary for swallowing. There are two layers of muscle: an inner circular layer and an outer longitudinal layer. The upper cervical esophagus is composed entirely of striated muscle. There is a gradual transition from striated to smooth muscle within muscle bundles until the esophagus is entirely smooth muscle at the junction of the upper and middle third. Lymphatic channels pierce the muscularis propria, draining into the regional lymphatics and/or directly into the thoracic duct. The esophagus has no investing adventitia. Paraesophageal tissue is composed of fibrofatty tissue that lies directly against the outer fibers of the muscularis propria. The normal esophagus is usually viewed as five discrete layers by EUS (Fig. 7-7). These layers are seen as alternating hyperechoic (white) and hypoechoic (black) rings. Studies have demonstrated that the five layers seen by EUS correspond to the balloon-mucosa interface, the mucosa deep to this interface, the submucosa and the acoustic interface between the submucosa and muscularis propria, the muscularis propria minus the acoustic interface between the submucosa and the muscularis propria, and the periesophageal tissue.3,4 For clinical purposes, these layers represent the superficial mucosa, deep mucosa, submucosa, muscularis propria, and periesophageal tissue. In the upper esophagus, with overdistention of the examining balloon, or if the transducer is too close to the esophageal wall, only three layers of the esophageal wall may be apparent: the superficial mucosa, deep mucosa, and submucosa compose one hyperechoic layer. The thickness of each ultrasonographic layer is about equal and does not represent the thickness of the tissue layer but, instead, the time it takes the ultrasound wave to traverse this layer.

ESOPHAGEAL CARCINOMA Stage of an esophageal carcinoma, as defined by its anatomic extent, is the best predictor of outcome for patients with this disease. Recent refinements in the staging of esophageal carcinoma have resulted in the present staging system, which is TNM based (Table 7-1).5 The primary tumor (T) is defined only by depth of invasion; EUS is ideally suited for this determination. T1 tumors are confined to the submucosa or more superficial esophageal layers. T2 tumors invade into but do not breach the muscularis propria. T3 tumors invade beyond the esophageal wall and into the periesophageal tissue but do not invade adjacent structures. T4 tumors directly invade structures in the vicinity of the esophagus. Lymph nodes in the area of the primary tumor, regional lymph nodes (N), are characterized only by the presence (N1) or absence (N0) of metastases. Similarly, distant sites (M) are characterized by the presence (M1) or absence (M0) of metastases. The recent revision of the staging system for esophageal carcinoma subdivides distant metastatic carcinomas (M1) into M1a (distant, nonregional lymph node metastases) and M1b (other distant metastases).5 M1a disease is further classified by tumor location: M1a tumors of the upper thoracic esophagus have metastasized to cervical nodes, and M1a tumors of the lower thoracic esophagus have metastasized to celiac lymph nodes. These TNM descriptors are grouped into stages with similar behaviors and prognoses (see Table 7-1). EUS may be used at two different periods in the course of esophageal carcinoma. The staging examination may be done before (clinical stage) or after (re-treatment stage) treatment.

CLINICAL STAGE (cTNM) Determination of CT Classification Detailed images of the esophageal wall by EUS make it the most accurate modality available for determination of depth

Epithelium Basement membrane Lamina propria Muscularis mucosae Submucosa 1 2 3

4

5

Muscularis propria Paraesophageal tissue

FIGURE 7-7 The esophageal wall is visualized as five alternating layers of differing echogenicity by EUS. The first layer, which is hyperechoic (white), represents the superficial mucosa (epithelium and lamina propria). The second layer, which is hypoechoic (black), represents the deep mucosa (muscularis mucosae). The third layer, which is hyperechoic (white), represents the submucosa. The fourth layer, which is hypoechoic (black), represents the muscularis propria. The fifth layer, which is hyperechoic (white), is the paraesophageal tissue. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

101

102

Section 2 Investigation of Esophageal Disease

TABLE 7-1 Tumor-Node-Metastasis (TNM) Staging of Esophageal Carcinoma T

Primary Tumor TX Tumor cannot be assessed. T0 No evidence of tumor Tis High-grade dysplasia T1 Tumor invades the lamina propria, muscularis mucosae, or submucosa. It does not breach the submucosa. T2 Tumor invades into and not beyond the muscularis propria. T3 Tumor invades the paraesophageal tissue but does not invade adjacent structures. T4 Tumor invades adjacent structures.

N

Regional Lymph Nodes NX Regional lymph nodes cannot be assessed. N0 No regional lymph node metastases N1 Regional lymph node metastases

M

Distant Metastasis MX Distant metastases cannot be assessed. M0 No distant metastases M1a Upper thoracic esophagus metastatic to cervical lymph nodes Lower thoracic esophagus metastatic to celiac lymph nodes M1b Upper thoracic esophagus metastatic to other nonregional lymph nodes or other distant sites Midthoracic esophagus metastatic to either nonregional lymph nodes or other distant sites Lower thoracic esophagus metastatic to other nonregional lymph nodes or other distant sites Stage Groupings Stage 0 Stage I Stage IIA Stage IIB Stage III Stage IVA Stage IVB

Tis T1 T2 T3 T1 T2 T3 T4 Any T Any T

N0 N0 N0 N0 N1 N1 N1 Any N Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b

of tumor invasion (T) before treatment (Figs. 7-8 to 7-11).6-11 The same definition of the esophageal wall is not offered by computed tomography (CT). The thickened esophageal wall, the principal CT finding in esophageal carcinoma, is not specific for esophageal carcinoma and lacks the definition required to distinguish T1, T2, and T3 tumors.12 In the differentiation of T3 from T4 tumors, EUS is superior to CT. The evaluation of fat planes is used to define local invasion at CT examination. The obliteration or lack of fat planes is not sensitive in predicting local invasion, but preservation of these planes is specific for absence of T4 disease.13-20 Compared with CT, EUS provides a more sensitive and reliable determination of vascular involvement.21 Experience with both examination technique and ultrasound interpretation is critical to accurately determine clinical depth of tumor invasion. Seventy-five to 100 examinations are required before competence is obtained.22,23 A review of 21 series reported an 84% accuracy of EUS for T classifica-

FIGURE 7-8 Top, A T1 tumor invades but does not breach the submucosa. Bottom, A T1 tumor as seen on EUS. The hypoechoic (black) tumor invades the hyperechoic (white) third ultrasonographic layer (submucosa) but does not breach the boundary between the third and fourth layers (arrowheads). (TOP, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

tion.24 Accuracy is not constant and varies with T classification. In this meta-analysis, accuracy for T1 carcinomas was 83.5%, with 16.5% of tumors overstaged; accuracy for T2 was 73%, with 10% understaged and 17% overstaged; accuracy for T3 was 89%, with 5% understaged and 6% overstaged; and accuracy for T4 was 89%, with 11% understaged. There is variation in accuracy with T classification: 75% to 82% for T1, 64% to 85% for T2, 89% to 94% for T3, and 88% to 100% for T4.24 The greatest inaccuracy is reported for T2 tumors. EUS anatomy, in part, accounts for this problem. The muscularis propria is vital in defining T1, T2, and T3 tumors. For clinical assessment the fourth ultrasonographic layer is interpreted as the muscularis propria. The fourth ultrasonographic layer, however, does not include the interface between the submucosa and muscularis propria; it is contained in the third ultra-

Chapter 7 Endoscopic Ultrasonography

FIGURE 7-9 Top, A T2 tumor invades but does not breach the muscularis propria. Bottom, A T2 tumor as seen on EUS. The hypoechoic (black) tumor invades the hypoechoic (black) fourth ultrasonographic layer but does not breach the boundary between the fourth and fifth layers (arrowheads). (TOP, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 7-10 Top, A T3 tumor invades the periesophageal tissue but does not involve adjacent structures. Bottom, A T3 tumor as seen on EUS. The hypoechoic (black) tumor breaches the boundary between the fourth and fifth ultrasonographic layers (arrowheads) and invades the hyperechoic (white) fifth ultrasonographic layer (periesophageal tissue). (TOP, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

sonographic layer. Thus, the border necessary to completely differentiate T1 from T2 tumors is contained in the third ultrasonographic layer. Because two boundaries must be assessed in the determination of T2, and errors might occur at each, the inaccuracy is potentially twice that of T1 and T4 tumors. Because invasion beyond the esophageal wall is important in determining therapy, some investigators have examined accuracy of EUS in determining T classification dichotomously. Compared with T classification determined pathologically, EUS was 87% accurate, 82% sensitive, 91% specific, 89% positively predictive, and 86% negatively predictive for tumors confined to the esophageal wall (T2) or invading beyond the esophageal wall (>T2).25 A systematic review of

13 studies also confirmed that EUS was highly effective in differentiating T1/T2 tumors from T3/T4 tumors.26 EUS interpretation is not done in the absence of clinical information; patient history and preceding esophagoscopy and imaging are usually available. This fact was illustrated by Meining and colleagues, who reported that a blinded review of EUS studies was significantly less accurate than a retrospective review of EUS reports: 53% versus 73%, respectively.27 When interpreters were unblinded and given endoscopy tapes, accuracy improved to 62%. Tumor length and luminal obstruction are known at the time of EUS and

103

104

Section 2 Investigation of Esophageal Disease

FIGURE 7-11 Top, A T4 tumor invades the aorta. Bottom, A T4 tumor as seen on EUS. The hypoechoic (black) tumor invades the aorta. The tumor breaches the boundary between the periesophageal tissue and the aorta (arrowheads). (TOP, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

are predictive of T classification.28 In this report, tumor length greater than 5 cm had a sensitivity of 89% and specificity of 92% for diagnosing T3 tumors. Thirteen patients with luminal obstruction had at least T3 tumors. Clinically, EUS examinations are never interpreted in the absence of history and esophagoscopy. A recent series has noted that EUS errors decrease for patients with increasing weight loss and increase for tumors of intermediate length; it is possible that endosonographers are biased by knowledge of the patient’s clinical condition and endoscopic findings and are more accurate when these clues point to a more limited or advanced clinical classification.29 Esophageal obstruction caused by a malignant high-grade stricture prohibits staging in 19% to 63% of examina-

tions.11,30,31 Two studies have reported that EUS may be less reliable in nontransversible esophageal cancers.10,32 Failure to pass an ultrasound probe beyond a malignant stricture has been found to be an accurate predictor of advanced stage. More than 90% of these patients have stage III or IV disease.33 These discordant findings may be reconciled when viewed in the context of a study from Hordijk and colleagues,31 which assessed severity of malignant strictures. In this study, the accuracies for T classification were 87% for nontransversable stricture, 46% for tight strictures that were difficult to pass, and 92% for easily transversable strictures. Options in the case of nontraversable strictures include limited examination of the proximal tumor margin, dilation and subsequent EUS examination, and the use of miniprobes. Limited examination of the tumor above the stricture has variable accuracy but may be useful in staging if T3 or N1 disease is seen. Dilation of malignant strictures followed by EUS examination may be associated with an increased incidence of perforation.33 This allows, however, a complete examination in 42% to 95% of patients with high-grade strictures and is not associated with perforation if careful stepwise dilation is used.34,35 Careful dilation followed by EUS allowed Wallace and colleagues36 to detect advanced disease in 19% of patients, mostly due to the detection of celiac lymph node metastases. This problem may be overcome by the use of miniature ultrasound catheter probes (see Fig. 7-4). Passed through the biopsy channel of the endoscope and advanced through the stricture, these probes accurately determined T classification in 85% to 90% of patients.37-40 Because most of these data are uncontrolled, it is not clear if additional effort and costs provide staging benefits. These 20-MHz probes have limited depth of penetration that may prevent full ultrasound assessment. Because most nontransversable tumors are at least T3, it is crucial to evaluate the outer boundary of the tumor and adjacent structures and regional lymph nodes, which may be outside the range of the miniprobe. Conventional EUS does not image the mucosa well; however, EUS is useful in staging patients suspected of having high-grade dysplasia or intramucosal cancer by detecting unexpected submucosal invasion and/or regional lymph node metastases.41,42 High-resolution EUS has the ability to assess the mucosa and shows promise in staging superficial esophageal cancers.43,44 In treatment of superficial cancer, EUS has been used to decide which patients may be treated with endoscopic mucosal resection, potentially avoiding the risk of esophagectomy.45

Determination of N and M (Nonregional Lymph Node) Classifications Endoscopic ultrasonography is more accurate than CT when used for lymph node classification.46 In addition to size, EUS evaluates nodal shape, border, and internal echo characteristics in lymph node assessment (Fig. 7-12). Large (>1 cm in long axis), round, hypoechoic, nonhomogeneous, sharply bordered lymph nodes are more likely to be malignant; small, oval or angular, hyperechoic, homogeneous lymph nodes with indistinct borders are more likely to be benign.47 In a retrospective review of 100 EUS examinations, EUS determina-

Chapter 7 Endoscopic Ultrasonography

T

FIGURE 7-12 A T3N1 esophageal carcinoma. Top, The T3 tumor (T) obliterates the ultrasound anatomy at this level. At the 1-o’clock position (black arrows), the tumor breaks through the fourth ultrasonographic layer and invades the fifth ultrasonographic layer. An N1 regional lymph node (white arrow), close to the primary tumor, is large (2.2 cm in diameter), round, hypoechoic, and sharply demarcated. Bottom, A T3N1 tumor breaches the muscularis propria to invade the periesophageal tissue and metastasizes to a regional lymph node. (BOTTOM, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

tion of N classification was 89% sensitive, 75% specific, and 84% accurate.48 The positive predictive value of EUS for N1 cancers was 86%; the negative predictive value was 79%. A patient was 24 times more likely to have N1 cancers if EUS detected regional lymph nodes. The single most sensitive predictor in detecting N1 cancers was a hypoechoic internal echo pattern, followed by a sharp border, a round shape, and size greater than 1 cm. When all four factors are present, the accuracy of N1 detection is 80% to 100%.47,48 Unfortunately, all four features are present in only 25% of N1 lymph nodes. In a meta-analysis of 21 series, the overall accuracy of EUS determination of N classification was 77% (69% for N0 and 89% for N1).24 The ability to use EUS to diagnose nodal metastases varies with location. It is better in the assessment of celiac lymph nodes (accuracy, 95%; sensitivity, 83%; spec-

ificity, 98%; positive predictive value, 91%; negative predictive value, 97%) than in mediastinal lymph nodes (accuracy, 73%; sensitivity, 79%; specificity, 63%; positive predictive value, 79%; and negative predictive value, 63%).49 There are associations between the primary tumor and N classification. Close proximity of the regional node to the primary tumor is a predictor of N1 cancers. Comparison of echo characteristic of the tumor and regional lymph nodes is useful for EUS lymph node evaluation. The relationship of T classification to N1 must be considered during EUS examinations. The incidence of N1 cancers increases with deeper tumor invasion: for a patient with a poorly differentiated adenocarcinoma, the probability of N1 is 17% for T1 tumors, 55% for T2, 83% for T3, and 88% for T4.50 For T3 and T4 cancers, an EUS assessment of N0 does not ensure absence of N1 disease. N classification accuracy and overall survival correlates with number of lymph node metastases detected by EUS. Natsugoe and colleagues reported accuracies of 84% with no N1 nodes, 60% with one to three N1 nodes, 43% with four to seven N1 nodes, and 96% with eight or more N1 nodes.51 Five-year survival was 53%, 34%, 17%, and 0% for none, one to three, four to seven, and eight or more N1 lymph nodes, respectively. Endosonography-directed fine-needle aspiration (EUS FNA) further refines clinical staging by adding tissue sampling to endosonography findings (Fig. 7-13).52-56 In a multicenter study, 171 patients had EUS FNA of 192 lymph nodes.57 Values for EUS FNA in determination of N classification were as follows: sensitivity, 92%; specificity, 93%; positive predictive value, 100%; and negative predictive value, 86%. Accuracy of N classification increased from 69% for EUS alone to 92% with EUS FNA. Two to three passes of the needle were made through each node. There was one nonfatal complication: an esophageal perforation at dilation of an esophageal stricture before EUS FNA. Subsequent studies from Vazquez-Sequeiros and colleagues have confirmed and extended these findings.55,56 EUS FNA was more accurate than EUS (87% versus 74%, respectively) when compared with histopathology review of surgical specimens.56 Compared with CT, EUS FNA changed tumor stage in 38% of patients. Complications are extremely rare.58 Unfortunately, some lymph nodes cannot be aspirated because of proximity to the primary tumor. Only nodes in which the needle path avoids the primary tumor are appropriate for EUS FNA because false-positive results might otherwise be obtained. The combination of EUS and EUS FNA of celiac lymph nodes (M1a classification), deemed positive by EUS, had a sensitivity of 77%, a specificity of 85%, a positive predictive value of 89%, and a negative predictive value of 71%.59 EUS FNA confirmed positive M1a classification in 94% of patients and was 98% accurate. EUS detection of M1a disease in the celiac axis and the avoidance of unnecessary surgery make EUS FNA the least costly staging strategy in patients with non-M1b esophageal cancer.60 EUS FNA has been shown to effectively identify lymph node metastases in patients referred for nonoperative endoscopic ablation therapy.61 For preoperative EUS examinations, N classification best predicts patient survival.62 It is a superior predictor of patient

105

106

Section 2 Investigation of Esophageal Disease

survival than EUS determination of T and M1a classifications. Use of EUS FNA is associated with improved recurrence-free and overall survival.63 Therefore, careful EUS N classification with aggressive EUS FNA lymph node sampling is mandatory and critical to treatment planning and prognostication.

Determination of Non-Nodal M1b Classification Endoscopic ultrasonography has limited value in the screening for distant metastases (M1b). The distant organ must be in direct contact with the upper gastrointestinal tract for EUS to be useful. The left lateral segment of the liver and retroperitoneum are two such sites (Fig. 7-14). Positive emission tomography appears to provide superior information to EUS in recognition of distant disease, indicating the complementary nature of these evaluations.64

Re-treatment Stage (yTNM)

FIGURE 7-13 EUS fine-needle aspiration of an N1 regional lymph node. Top, An N1 regional lymph node undergoing fine-needle aspiration under curvilinear electronic endoscopic examination. Bottom, Ultrasound image with needle passed through the esophageal wall and into the N1 node. (TOP, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

After induction therapy, a subset of patients with esophageal cancer will be disease-free. Because significant morbidity and mortality are associated with surgery for esophageal cancer, the ability to detect patients who have no residual cancer (T0 N0) after induction therapy is theoretically desirable. EUS has been applied in multiple clinical series for this purpose. Early series indicated that EUS was very accurate in determining T classification after chemotherapy. In these series, however, the presurgical therapy was largely ineffective in causing pathologic downstaging; therefore, EUS was accurate by merely indicating that no significant change had occurred.65-67 In two earlier series in which radiation therapy was provided along with chemotherapy, accuracy of determination of T classification was again high (72%-78%), but the prevalence of pathologic T0 disease was low or not reported.68,69 Accuracy of T classification can, therefore, be attributed primarily to a lack of tumor response to chemoradiotherapy. Later series incorporate more aggressive regimens of chemoradiotherapy, with higher rates of significant downstaging of tumor and pathologic T0 N0 M0 cancers. In these series, up to 31% of patients had pathologic T0 N0 M0 stage

Liver

Hepatic lesion

3 40 cm Lymph node

FIGURE 7-14 Left, A hepatic metastasis (upper arrowhead) and lymph node (lower arrowhead) in the left lateral segment of the liver. The EUS probe is seen in the gastric cardia. Right, A hepatic metastasis as seen from the gastric cardia by EUS. (FROM RICE TW, BOYCE GA, SIVAK MV, ET AL: ESOPHAGEAL CARCINOMA: ESOPHAGEAL ULTRASOUND ASSESSMENT OF PREOPERATIVE CHEMOTHERAPY. ANN THORAC SURG 1992; 53:972.)

Chapter 7 Endoscopic Ultrasonography

grouping after chemoradiotherapy.70 EUS was poor at accurately determining T classification, with reported rates of 27% to 47%.70-74 The most common mistake made in determining T classification was overstaging because EUS is unable to distinguish tumor from inflammation and fibrosis produced by chemoradiotherapy. Similar difficulties in this differentiation have also been reported with EUS staging of rectal cancers.75 EUS accuracy for N classification after chemoradiotherapy has been reported in only four clinical series. The reported accuracy ranged from 49% to 71%.70,72-74 Accuracy of N classification in patients who undergo chemoradiotherapy is lower than in patients not treated with chemoradiotherapy. Primary reasons for this inaccuracy are alterations in ultrasound appearance of nodes after chemoradiotherapy so that established EUS criteria do not apply and residual foci of cancer within the nodes that are too small for detection by any modality other than pathologic analysis. Change in maximal cross-sectional area before and after chemoradiotherapy appears to be a more useful means of assessing response of esophageal cancer to preoperative therapy.71,76 Chak and colleagues defined a response as 50% or greater reduction of tumor area. Improved survival was reported in responders and responder subgroups who had surgery after chemoradiotherapy, adenocarcinoma, and T3 N1 M0 cancers before treatment.76 Identification of persistent tumor in lymph nodes by EUS FNA has been used to modify treatment of patients receiving preoperative chemoradiotherapy.77 EUS has been useful in the diagnosis and restaging of patients with anastomotic recurrence that is not endoscopically visible.78,79 Integrated positive emission tomography with CT may be superior to EUS or CT alone in predicting N classification or complete response after chemoradiotherapy.80

BENIGN ESOPHAGEAL DISEASES Benign Esophageal Tumors Detailed examination of the esophageal wall with EUS has improved the diagnosis of benign esophageal tumors. EUS identification of intramural masses relies on both the layer from which the tumor arises (Table 7-2) and the ultrasound characteristics of the tumor. Homogeneous lesions that are anechoic, of intermediate echogenicity, or hyperechoic are almost exclusively benign.81 A heterogeneous echo pattern may be seen in benign tumors, but this endosonographic finding, particularly in lesions greater than 3 to 4 cm in largest diameter, may be indicative of malignancy.

Tumors of the Mucosa Fibrovascular polyps are collections of fibrous, vascular, and adipose tissue lined by normal squamous epithelium. Microscopically, fibrovascular polyps are expansions of the lamina propria.82 These polyps usually arise in the cervical esophagus, extend into the esophageal lumen, and may reach into the stomach. Most patients eventually complain of dysphagia and/or respiratory symptoms. Spectacular presenta-

TABLE 7-2 Endoscopic Ultrasound Classification of Esophageal Tumors EUS Layer

Esophageal Tumor

First/second (mucosa/deep mucosa)

Fibrovascular polyp Retention cyst Squamous papilloma Tis esophageal cancer

Third (submucosa)

Lipoma Fibroma Neurofibroma Granular cell tumor T1 esophageal cancer

Fourth

Leiomyoma* T2 esophageal cancer

*Leiomyomas may arise from the second ultrasound layer (muscularis mucosae), but these tumors are much more common from the fourth ultrasound layer. EUS, endoscopic ultrasound.

tions include regurgitation into the hypopharynx and mouth with subsequent aspiration and, occasionally, sudden death by asphyxiation. Barium esophagography and CT best detect these lesions. Because fibrovascular polyps fill the esophageal lumen and have a composition similar to the mucosa, definition by esophagoscopy or EUS may be difficult or impossible.83 Granular cell tumors are the third most common benign esophageal tumor, and the esophagus is the most common gastrointestinal site of these tumors. Most are located in the distal esophagus. Their origin is neural from the Schwann cell. Most patients with granular cell tumors are asymptomatic and rarely require surgery. At endoscopy, these lesions are yellow, firm nodules. Endoscopic biopsy is diagnostic in only 50% of patients.84 EUS evaluation typically demonstrates a tumor less than 2 cm in diameter, with an intermediate or hypoechoic, mildly inhomogeneous solid pattern with smooth borders, that rises from the inner two EUS layers.84,85 Less than 5% originate from the submucosa. Malignant variants are rare and distinguished by size (>4 cm), nuclear pleomorphism, and mitotic activity.86 Atypical EUS findings may predict the rare malignant granular cell tumors.

Tumors of the Submucosa Esophageal stromal tumors are rare and include lipomas, fibromas, and hemangiomas. Lipomas are indirectly detected at esophagoscopy as a bulging of the overlying esophageal mucosa. They have a pale yellow appearance and soft texture when probed with an esophagoscope. Endoscopic biopsies usually produce normal overlying squamous epithelium because these samplings rarely penetrate the submucosa. EUS demonstrates a hyperechoic homogeneous lesion that originates in and is confined to the submucosal layer. Usually asymptomatic and most often found incidentally, lipomas require no EUS follow-up. Fibromas and neurofibromas are very uncommon. At endoscopy, they are firm “to the touch.” These lesions are less hyperechoic than lipomas. Symptomatic

107

108

Section 2 Investigation of Esophageal Disease

submucosal tumors are uncommon and symptoms may be unrelated. These tumors are typically incidental findings of a “shotgun” investigation of atypical symptoms, such as chest pain, cough, and so on. EUS is critical in diagnosis and, thus, in avoiding excision. Hemangiomas may present as dysphagia and bleeding. Most hemangiomas are in the lower esophagus and may be mistaken for esophageal varices. EUS examination reveals a hypoechoic mass with sharp margins arising from the second or third EUS layer.87,88

Tumors of the Muscularis Propria Leiomyomas are benign smooth muscle tumors of the muscularis propria. Symptomatic tumors arising from the muscularis mucosae are rare; the majority arises from the inner circular muscle layer in the distal and midthoracic esophagus.89 EUS examinations reveal that the majority of esophageal leiomyomas are greater than 1 cm in diameter and are most frequently found in the muscularis mucosae.90 Leiomyomas are the most common benign esophageal tumors and account for more than 70% of all benign tumors. There is no gender preponderance, and typically they occur in patients 20 to 50 years old, who are significantly younger than patients with esophageal carcinomas. Although frequently asymptomatic and discovered incidentally, leiomyomas can cause dysphagia, pain, or bleeding. Distal esophageal leiomyomas are often associated with symptoms of gastroesophageal reflux disease. Barium esophagography demonstrates smooth filling defects; esophagoscopy reveals a normal overlying mucosa. EUS displays a hypoechoic, sharply bordered tumor arising in the fourth ultrasonographic layer (Fig. 7-15). Diagnosis of small leiomyomas (<1 cm in diameter) may be enhanced with the use of miniature ultrasound probes.90 Atypical EUS findings are a tumor greater than 4 cm, irregular margins, mixed internal echo characteristics, and associated regional lymphadenopathy. Endoscopic biopsies do not reach the muscularis propria, and EUS FNA is unlikely to provide the cellular architectural characteristics necessary to differentiate leiomyomas from leiomyosarcomas, which are exceedingly rare. Malignant transformation of benign leiomyomas has been infrequently reported. Surgical resection, by minimally invasive techniques if possible, is indicated for symptomatic leiomyomas. In asymptomatic tumors with typical EUS features, expectant therapy and EUS observation are indicated.

Miscellaneous Esophageal Diseases Esophageal Cysts Esophageal cysts are the second most common benign esophageal tumor, accounting for 20% of these lesions. The minority are acquired epithelial cysts arising in the lamina propria. Submucosal glandular inflammation is the suspected cause. The majority of esophageal cysts are congenital foregut cysts. They are lined with squamous, respiratory, or columnar epithelium and may contain smooth muscle, cartilage, or fat. Esophageal duplication is a subtype of foregut cyst; it is lined with squamous epithelium, and its submucosal and muscula-

L

FIGURE 7-15 An esophageal leiomyoma (L). Top, EUS of this most common benign tumor demonstrates a hypoechoic, homogeneous, well-demarcated tumor with no associated lymphadenopathy. EUS balloon overdistention blends the first three ultrasonographic layers into one hyperechoic layer. The tumor arises from, and is confined to, the fourth ultrasonographic layer (arrow). Bottom, A benign leiomyoma arises from, and is confined to, the muscularis propria. (BOTTOM, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

ris elements interdigitate with the muscularis propria of the esophagus. EUS can clearly define the intramural or extraesophageal nature of these tumors and further determine their anechoic, cystic nature (Fig. 7-16).91-94 Transesophageal EUS drainage of a foregut cyst has been reported, but drainage of the cyst without destruction of its lining may result in recurrence.95

Esophageal Varices Esophageal varices have the typical appearance of blood vessels at EUS. Appearing as tubular, round, or serpiginous echo-free structures they may be visualized within submucosa or in tissues adjacent to the esophagus (Fig. 7-17). These EUS patterns change after sclerosis.96 Intravariceal sclerosis fills the varix with echogenic material, representing thrombus. Paravariceal injection leads to obliteration of the varix with hypoechoic extravariceal thickening.

Chapter 7 Endoscopic Ultrasonography

Achalasia The findings of EUS in achalasia are controversial. Some authors have reported a thickened esophageal wall in most patients examined.97,98 This excessive thickening, however, may be artifactual. In a dilated and convoluted esophagus, the ultrasound transducer may orient at an angle oblique to the esophageal wall, giving a false appearance of wall thickening.99 The main role of EUS in achalasia is to exclude other mural abnormalities.100-102

PARAESOPHAGEAL DISEASES Endoscopic ultrasonography has been used to examine mediastinal lymph nodes in patients with bronchogenic carcinoma.103-105 In this setting, EUS has a reported positive predictive value of 77%, a negative predictive value of 93%, and an overall accuracy of 92%, using criteria similar to regional lymph node evaluation in esophageal carcinoma.104 Anatomic constraints limit its usefulness for evaluation of lymph nodes in proximity to the airway. EUS-directed FNA provides cytologic differentiation between benign and malignant lymphadenopathy.106 EUS-directed FNA has successfully diagnosed solid lesions of the mediastinum and lung.81,107-109

SUMMARY

FIGURE 7-16 A foregut cyst. Top, EUS demonstrates a mass (arrowheads) adjacent to the trachea and esophagus. The cyst has two components, one hyperechoic (white) representing proteinaceous material and one hypoechoic (black) representing fluid. Bottom, A foregut cyst in close proximity to the esophagus and trachea. (BOTTOM, REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Both EUS and EUS FNA are essential in determining clinical stage and directing treatment of esophageal cancer. The diagnosis of benign esophageal tumors requires EUS examination, which determines both the layer of origin in the esophageal wall and the ultrasound characteristics of the tumor. Because many of these tumors are asymptomatic, EUS affords simple follow-up and avoids unnecessary excision. EUS is a useful adjuvant for diagnosis and treatment of paraesophageal diseases.

Esophagus VV VV VV

Heart

Wall Aorta VV

A

B

FIGURE 7-17 Paraesophageal varices. A, At endoscopy, small varices are not visible. B, On EUS, the varices (VV) are prominent anechoic, tubular, and rounded structures outside the esophageal wall.

109

110

Section 2 Investigation of Esophageal Disease

COMMENTS AND CONTROVERSIES The authors present a concise review of the current status of esophageal endoscopic ultrasonography. The physics of ultrasound and its applications are explained clearly. Currently available instrumentation is discussed. Endoscopic ultrasonography has become an essential tool for the accurate clinical staging of esophageal cancer. It offers more accurate staging regarding the primary tumor than CT and positron emission tomography scan. As the authors point out, EUS is highly accurate in the important clinical differentiation between T1/T2 lesions, in which primary resection is the treatment of choice, and T3/T4 lesions, in which primary resection is less likely to benefit the patient.

In addition, the status of regional lymph nodes is more accurately assessed by EUS. Echo signal is more accurate than CT in determining benign from malignant lymph nodes. Positron emission tomography is unable to evaluate lymph nodes in the immediate vicinity of the primary tumor. EUS also permits fine-needle aspiration of regional, mediastinal, gastrohepatic ligament, and celiac axis lymph nodes. Of course, EUS has become an important tool in the diagnosis and staging of other thoracic malignancies because primary tumors and lymph nodes in the posterior mediastinum are readily accessible to EUS fine-needle aspiration. G. A. P.

chapter

8

FLEXIBLE ENDOSCOPY John A. Dumot

Key Points ■ Flexible endoscopy has replaced rigid endoscopy due to the ease,

safety, and expanding indications for upper gastrointestinal disease. ■ Proper patient selection with clear indications is a preprocedure quality indicator. ■ Important intraprocedure quality indicators include lesion recognition, proper sampling, and therapeutic interventions in the majority of procedures; only experienced physicians should perform highrisk interventions.

Flexible endoscopes have revolutionized the evaluation of the upper gastrointestinal tract with widespread use of esophagogastroduodenoscopy (EGD), which has become one of the most frequently performed endoscopic procedures. The properties of flexible optic glass fibers conduct visible light into the dark recesses of the lumen. Early forms of the endoscope used the bundles to bring the reflected light waves back to the eyepiece. The current video chip technology at the tip of the insertion tube provides high-definition images. Integration of an accessory channel allows passage of a variety of forceps to take biopsy samples, balloons for dilation of strictures, and a number of devices to ablate or resect large areas of mucosa. Common indications for EGD are listed in Table 8-1. Specifically, the procedure results should have bearing on treatment decisions to justify the risk and cost of the procedure. Flexible endoscopy is well tolerated compared with rigid esophagoscopy, and the risks are low but should not be minimized, especially when undertaking a therapeutic procedure. Quality indicators can be found in the preprocedure, intraprocedure, and postprocedure periods (Cohen et al, 2006).1 Preparation includes a fast from solid food for 8 hours and from clear liquids for 2 hours. Preprocedural issues include informed consent, assessment of the airway and cardiopulmonary status before sedation, and, in some patients, addressing antibiotic prophylaxis and anticoagulation (American Society for Gastrointestinal Endoscopy, 2002b; Hirota et al, 2003) (Table 8-2).17,18 The doctrine of informed consent requires disclosure. Informed consent should include a discussion of the nature of the procedure, benefits, risks, limitations, and alternatives. Informed consent is a process that takes time and effort to establish and cannot be replaced by even the most elegant written forms. Complications include sore throat, bleeding, perforation, infection, adverse reactions to sedation and topical analgesics, missed diagnosis and lesions, chest pain, and aspiration (American Society for

Gastrointestinal Endoscopy, 2002a).2 In general, the risks increase with therapeutic interventions such as dilations and polypectomy compared with diagnostic examinations with routine mucosal biopsies. Exceptions to the rule of informed consent include infrequent emergency situations when there is insufficient time to carry out the process, waiver by the patient knowingly and voluntarily, incompetence when consent should be obtained from a relative or guardian, and, rarely, through therapeutic privilege or legal mandate. Intraprocedure quality indicators include a complete examination of the esophagus and stomach with retroflexion views of the incisura and cardia and the duodenum. Abnormalities should be photographed. Samples should be obtained of all gastric ulcers and other abnormalities such as polyps, masses, and significant mucosal disturbances, such as Barrett’s esophagus or erosive gastritis. Exceptions are considered when the lesion is responsible for acute hemorrhage and a future examination is planned to document healing after medical therapy. Postprocedural quality indicators include accurate detailed reporting so that information can be relayed to other medical providers in a timely fashion. Descriptions of lesions need to be detailed so that a subsequent endoscopist can locate the lesion. Formal training in EGD results in acquisition of skills to complete examinations after 100 cases in more than 90% of training programs.3

PATIENT-CENTERED APPROACH Upper endoscopy requires a team dedicated to a quality procedure. The patients’ concern for comfort should be recognized by the entire team. The quality and safety of the examination are dependent on the patients’ ability to tolerate esophageal intubation and insufflation and on the ability of the physician to visualize the mucosa of the collapsed lumen from the upper esophageal sphincter (UES) to the second portion of the duodenum. Sedation is usually required to perform a thorough EGD. Levels of consciousness may vary from anxiolysis to general anesthesia according to the duration of the examination and patient tolerance. Sedation requires proper cardiopulmonary monitoring with frequent measurement of blood pressure and oxygen saturation. Patients tend to lose control of their airway and require oral suctioning of secretions during deeper levels of sedation. Reversal agents, resuscitation equipment, and oxygen should be readily available. Anesthesiologists are helpful in managing patients with a history of difficulty with sedation, heavy alcohol or substance use (narcotic or benzodiazepine), unusual airways, or altered mental status. Topical anesthesia with Cetacaine or similar spray medications generally adds tolerance to procedures without sedation 111

112

Section 2 Investigation of Esophageal Disease

TABLE 8-1 Diagnostic and Therapeutic Indications for Upper Endoscopy Dysphagia or odynophagia Long-standing or recurrent heartburn, regurgitation, or noncardiac chest pain Dyspepsia with anorexia, weight loss, or age older than 45 years Persistent nausea or vomiting of unknown cause Iron-deficiency anemia or gastrointestinal bleeding Small bowel mucosal biopsy or sampling of duodenal fluid Caustic ingestion evaluation Portal hypertension assessment of esophageal varices

TABLE 8-2 Preparation for Flexible Endoscopy in the Upper Gastrointestinal Tract Antibiotic* prophylaxis is recommended for special subgroups of patients with: Prosthetic heart valves History of endocarditis Synthetic vascular grafts Cirrhosis with acute upper gastrointestinal bleeding Immune compromise When undergoing any of the following: Stricture dilation Sclerotherapy Endoscopic retrograde cholangiopancreatography with biliary obstruction Percutaneous endoscopic gastrostomy†

Familial adenomatous polyposis syndromes Screening for esophageal varices in patients with portal hypertension Treatment of gastrointestinal bleeding and banding esophageal varices Treatment of benign strictures with balloon or rigid dilators Management of achalasia with balloon dilation or botulinum toxin injection Foreign body removal Feeding tube placement or replacement Management of malignant strictures of the esophagus or duodenum with stents or ablation therapy Mucosectomy or ablation therapy for early neoplasia of the esophagus, stomach, or duodenum

and with moderate levels of sedation.4 Rare anaphylactic reactions to topical agents and methemoglobinemia must be recognized and treated aggressively. Methemoglobinemia occurs when levels of oxidized hemoglobin result in the inability to bind and carry oxygen, resulting in cyanosis and cellular hypoxia without a fall in pulse oximetry. In other words, the patient is blue but the pulse oximetry reads more than 90% saturation. Treatment with methylene blue, 1 to 2 mg/kg infusion, with high concentrations of oxygen is required to reverse the effect.

CONSIDERATIONS FOR THE BEGINNING ENDOSCOPIST The endoscope handle is held in the palm of the left hand. The thumb controls the large and small wheels, which pull the tip (via cables) into an up/down or right/left deflection, respectively. The left index and middle finger control the upper air/water and lower suction trumpet valves, respectively. The air/water valve controls insufflation of air just by covering the surface orifice on the top with the tip of the index finger. Depression of the air/water valve causes a small jet of water to clean the lens. The right hand will advance, withdraw, and rotate (also called torque) the insertion tube. Holding the insertion tube between 20 and 25 cm is a good start to begin esophageal intubation. The endoscopy unit should be a calm environment with everyone’s efforts focused on the patient’s care. Talk to your

Anticoagulation medications such as warfarin (Coumadin) and antiplatelet medications should be individualized based on indications for the procedure, indications for the anticoagulation, and urgency of the procedure: Low-risk—no change in anticoagulation necessary Diagnostic esophagogastroduodenoscopy with or without mucosal biopsy Endoscopic retrograde cholangiopancreatography without sphincterotomy Endoscopic ultrasonography without fine-needle aspiration Enteroscopy Endoscopic ultrasonography without fine-needle aspiration High-risk procedures—avoiding anticoagulation is preferred Polypectomy Biliary sphincterotomy Pneumatic or bougie dilation Sclerotherapy and banding of varices Ablation of mucosa or mucosectomy Percutaneous endoscopic gastrostomy *Ampicillin and gentamicin are acceptable choices. † First-generation cephalosporins have been shown to reduce skin infections. From Hirota WK, Peterson K, Baron TH, et al: Guidelines for antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 58:475-482, 2003; and American Society for Gastrointestinal Endoscopy: Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 55:775-779, 2002.

patient even if he or she is sedated. Reassure the patient that he or she will be able to breathe during the procedure. While encouraging the patient with a positive tone, pass the endoscope through the bite block to the base of the tongue. Warn the patient that he or she will feel pressure, which will last only a moment, as the endoscope passes the tongue. Once again, reassure the patient by coaching with the phrase “catch your breath” during and after the esophageal intubation. During intubation of the esophagus, the movement of the tip with the thumb on the large wheel in a “thumb down” motion toward the endoscope handle will bring the tip along the tongue to its base in the pharynx where the epiglottis can be visualized as a dome-shaped covering of the airway (Fig. 8-1). Advance the endoscope in under the epiglottis (or around it) to visualize the vocal cords. Once the vocal cords are visualized, direct the tip to the posterior wall of the hypopharynx with a “thumbs up” movement on the larger wheel (Fig. 8-2). The airway is visualized between these

Chapter 8 Flexible Endoscopy

three fingers at this point to avoid applying excessive pressure. Asking the patient to swallow may relax the UES to allow passage of the endoscope. At times, it helps to momentarily pull the endoscope back away from the cricopharyngeus for it to relax before reapplying gentle pressure. Difficult esophageal intubations may be due to patient intolerance or anatomic abnormalities. Patient intolerance results in tightening of the cricopharyngeus muscle, which becomes a physiologic barrier that can be overcome with deeper levels of sedation and careful passage of the endoscope tip under direct visualization of the lumen. Fixed proximal obstructions due to strictures, webs, or occasionally diverticula (Zenker’s) make intubation of the esophageal lumen extremely difficult. Rarely, a soft-tipped guidewire (0.035 inch) can be used to facilitate esophageal intubation by passing the guidewire through the accessory channel under direct or fluoroscopic visualization. Small-bore endoscopes (<8 mm diameter) are useful for assessing tight strictures, especially in the proximal esophagus.

ESOPHAGOGASTRODUODENOSCOPY FIGURE 8-1 View of the epiglottis from the base of the tongue.

FIGURE 8-2 Vocal cords and location of the esophageal inlet along the posterior wall of the hypopharynx (arrow) and right lateral piriform sinus (arrowhead).

maneuvers and may be cleared of the secretions at the level of the cricopharyngeus, which will help the air exchange and patient comfort. The UES is not a structure that can be visualized but a complex region located between the lateral piriform sinuses, which act as blind pouches that will trap the endoscope tip and result in a perforation if undue pressure is applied. The endoscope should be held with two or

The esophageal lumen is examined as the endoscope is advanced to the stomach with insufflation and suction of oral and gastric secretions (refluxate). Inspection of the esophageal lumen is repeated upon slow withdrawal of the endoscope to identify any subtle lesions missed during insertion. The endoscope should be withdrawn slowly enough to note changes in the most proximal segment of the esophageal lumen. A salmon-colored inlet patch of heterotopic gastric mucosa can be found just below the UES around 18 cm from the incisors in approximately 10% of patients.5 Inlet patches may be associated with Barrett’s esophagus6 and a rare precursor of adenocarcinoma in the proximal esophagus. Esophageal diverticula are uncommon but may be a source of symptoms or complications during insertion of the endoscope or passage of unguided bougie dilators (Fig. 8-3). Attention to the esophagogastric junction (EGJ) is important and may be reported as a separate entity by some physicians. Location of the squamocolumnar junction (SCJ), distal margin of the tubular esophagus, and diaphragmatic hiatus should be recorded in terms of centimeters from the incisors. The SCJ is usually located at or near 40 cm with surprisingly little variation. Barrett’s esophagus, by definition, requires proximal displacement of the SCJ with columnar-lined tubular esophagus containing specialized intestinal metaplasia confirmed by histology. Barrett’s esophagus may vary in length from a tongue of salmon-colored mucosa, which appears as an irregular SCJ, to a very long segment involving almost the entire esophagus. The rising incidence of esophageal and EGJ cancers makes this area particularly important to evaluate in patients with long-standing reflux or dysphagia. Hiatal hernias should be measured by reporting the distance from the teeth to both the end of the tubular esophagus and the diaphragmatic impression on the proximal body of the stomach, which appears as an extrinsic compression of the lumen that moves with inspiration. Complex hernias or paraesophageal hernias can make passage of the endoscope to the antrum and duodenum occasionally very difficult.

113

114

Section 2 Investigation of Esophageal Disease

FIGURE 8-3 Midesophageal diverticulum (arrow).

FIGURE 8-4 Normal esophagogastric junction in the retroflexion view with a portion of the normal squamous mucosa of the esophagus seen adjacent to the insertion tube of the endoscope.

The gastric lumen is inspected after adequate insufflation allows flattening of the gastric folds. The endoscope should be passed into the antrum along the greater curve until the pylorus is inspected. The tip should be deflected upward with the counterclockwise rotation of the large wheel (thumb down) to inspect the lesser curve and incisura. This movement is continued until the tip is retroflexed upon itself with both wheels directed counterclockwise as the endoscope is carefully withdrawn in this position to inspect the body, fundus, and cardia in a retrograde manner, called retroflexion of the endoscope. In a normal EGJ there is little to no space between the endoscope and the gastric cardia, and the squamous mucosa of the esophagus can be seen with careful inspection from the gastric lumen (Fig. 8-4). Biopsy and cytology specimens should be obtained from all esophageal or gastric ulcers. Significant mucosal abnormalities, such as severe esophagitis or gastritis, should also be sampled. Biopsy specimens are routinely obtained from normal-appearing mucosa of the duodenum in patients with diarrhea or unexplained iron deficiency to assess for histologic features of celiac disease.

lung cancer, aortic aneurysm, or aberrant subclavian artery (dysphagia lusoria). Neoplasms of the esophagus usually start as intrinsic strictures as the tumor arises from the epithelium but become predominantly extrinsic once the tumor infiltrates the wall and adventitial space, resulting in mass compression of the lumen. Intrinsic strictures generally respond to dilation therapy, and extrinsic strictures require an endoscopic prosthesis (stent) to maintain an adequate lumen. Treatment of esophageal stricture is quite satisfying to patients and physicians alike when all goes well. Unfortunately, when complications occur or strictures are refractory, endoscopic therapy becomes cumbersome. Setting reasonable goals and patient expectations for improvement can minimize complications based on clinical experience. The “rule of 3” states that no more than three successive dilators should be passed after the first dilator met resistance (Tulman and Boyce, 1981).7 Obviously, this rule is subjective and dates back to an era before through-the-scope balloons. Good clinical judgment is the best rule to follow. For some strictures, due to radiation, neoplasms, or eosinophilic esophagitis, passing three more-successive dilators may be difficult and fraught with complications (pain and/or perforation). Some experts suggest that balloon dilators may be safer than rigid dilators because balloons impart a nearly pure radial force to the esophageal wall whereas rigid dilators impart both radial and linear forces, which may result in shearing the esophageal wall. A comparison of wire-guided bougie dilators (Savary) with through-the-scope balloon dilators failed to find a difference in efficacy or safety.8 Treatment of refractory esophageal strictures should be undertaken with the goal of achieving an objective diameter rather than subjective improvement. In a small randomized

TERMINOLOGY OF FINDINGS Stricture refers to luminal narrowing of any tubular structure and is synonymous with stenosis. An esophageal web is a particularly short stricture that is not usually circumferential compared with a ring, which is circumferential (Fig. 8-5). Strictures can be classified as intrinsic or extrinsic based on the location of the lesion. Intrinsic strictures arise from the esophageal wall and include inflammatory changes due to acid reflux, pill or caustic injury, radiation, or inflammatory conditions of the mucosa or submucosa. Extrinsic strictures are caused by compression from adjacent organs such as

Chapter 8 Flexible Endoscopy

FIGURE 8-5 Esophageal web (left) and ring (right).

controlled trial using barium esophagograms to gauge the diameter of strictures, improvement was more durable when dilations were repeated until a 12-mm barium pill passed the stricture compared with those in which subjective improvement alone was reported.9 Furthermore, the group with objective improvement as a goal (passage of barium pill) required fewer repeat dilation procedures in the follow-up period. Acid suppression with proton pump inhibitors is more effective than histamine receptor antagonists in healing esophagitis and reducing the need for subsequent dilations.10

UPPER GASTROINTESTINAL BLEEDING The utility of EGD in patients with upper gastrointestinal bleeding has been well documented in numerous studies that show accurate diagnosis, predict outcome in terms of rebleeding, and afford endoscopic therapy in the majority of patients.11 Occasionally, bleeding lesions can be obscured by the shear magnitude of blood loss, which is called torrential bleeding. In these situations, localizing the site to a specific organ (esophagus, stomach, or duodenum) can be instrumental in directing further management. The cause of most bleeding lesions can be identified, and peptic ulcers have a characteristic appearance. Peptic ulcers can be classified according to their stigmata of recent hemorrhage: 1. 2. 3. 4. 5.

Clean based Flat spot Adherent clot Nonbleeding visible vessel Active bleeding

A quality examination implies the ability to treat active bleeding with combination therapy using injection of diluted epinephrine (1 : 10,000) followed by thermal therapy or application of a hemostatic clip because injection therapy alone is inferior. Nonbleeding visible vessels appear as pigmented protuberances and should receive endoscopic therapy in the same manner as actively bleeding ulcers.

Endoscopic therapy of stigmata behind adherent clots is challenging but warranted based on randomized controlled trial data.12-14 Flat spots and clean-based ulcers have very low rebleeding rates and require only medical therapy. Esophageal varices from portal hypertension have a characteristic appearance. Endoscopic variceal band ligation is preferred over injection sclerotherapy for safety, availability, and efficacy.15

COMPETENCY IN UPPER ENDOSCOPY Competency in performing EGD is based on training and assessment of skills that ensures a safe and successful procedure that results in accurate observations and meaningful interpretations.16 Competence is ensured through privileging and usually based on formal training programs. Hospital credentialing boards should differentiate routine endoscopy from advanced procedures, which are associated with a higher risk of complications and adverse outcomes. Documentation from the applicant should provide attestation from supervising physicians that he or she is competent to perform the procedures being privileged. New members of a team should be proctored by someone acceptable by the applicant and privileging body. Hospitals and medical organizations can be liable for inappropriate credentialing, and their duty in the process must be made very clear.

COMMENTARY AND CONTROVERSIES Flexible fiberoptic esophagoscopy is the diagnostic workhorse of the esophageal specialist. Its therapeutic role is rapidly expanding. Ever increasing technology has only strengthened this tool and relegated rigid esophagoscopy obsolete. A knowledge and expertise in video-esophagoscopy is essential for the esophageal surgeon. It is a significant disadvantage for esophageal surgeons who do not perform their own flexible fiberoptic esophagoscopy. They are hobbled in the planning of surgery and miss the opportunity to assess outcome of their surgery. T. W. R.

115

116

Section 2 Investigation of Esophageal Disease

KEY REFERENCES American Society for Gastrointestinal Endoscopy: Complications of upper gastrointestinal endoscopy. Gastrointest Endosc 55:784-793, 2002a. American Society for Gastrointestinal Endoscopy: Guidelines on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 55:775-779, 2002b.

Cohen J, Safdi MA, Deal SE, et al: Quality indicators for esophagogastroduodenoscopy. Gastrointest Endosc 63:510-515, 2006. Hirota WK, Peterson K, Baron TH, et al: Guidelines for antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 58:475-482, 2003. Tulman AB, Boyce HW: Complications of esophageal dilation and guidelines for their prevention. Gastrointest Endosc 27:229-234, 1981.

chapter

9

FUNCTION TESTS Tom R. DeMeester Mario Costantini

Key Points ■ Esophageal function tests assess function of the esophageal body

and upper and lower esophageal sphincters, esophageal exposure to gastric juice, and relationships between symptoms and esophageal function. ■ Esophageal manometry and pH and bilirubin monitoring are the principal esophageal function tests. ■ These tests are crucial in planning surgery for benign esophageal diseases and assessing outcome of reparative and reconstructive esophageal surgery.

Esophageal surgery for benign diseases is a most challenging field in that it alters or reconstructs anatomy in an effort to improve function. The outcome is assessed based on the ability of the procedure to provide complete and permanent relief of all symptoms and complications of the esophageal abnormality. Preoperative symptoms are often severe without evidence of anatomic or histologic alterations. Usually, anatomic and histologic changes occur late and represent the end stage of altered function. Furthermore, symptoms of esophageal diseases (i.e., dysphagia, heartburn, regurgitation, belching, and epigastric and retrosternal pain) are often nonspecific and occur in a variety of esophageal as well as gastric and duodenal disorders. On the other hand, atypical symptoms of esophageal diseases (wheezing, choking, coughing, and chest pain) can mimic other organ abnormalities.1 Consequently, a precise diagnosis must be made before any surgical therapy because its purpose is to improve the performance of a malfunctioning organ that will remain in the patient. Achievement of this result depends on an accurate understanding of the pathophysiologic mechanism causing the patient’s abnormality. This understanding requires the use of esophageal function tests, which can be divided into several types (Box 9-1): 1. Tests to evaluate the motor function and clearing ability of the gullet 2. Tests to evaluate upper and lower sphincter function 3. Tests to evaluate exposure of the esophagus to gastric juice 4. Tests to document the relationship between symptoms and esophageal function Because esophageal function is closely related to foregut function, there is, on occasion, a need for tests to evaluate gastroduodenal function.

HISTORICAL NOTE Esophageal function tests were first performed more than a century ago when Kronecker and Meltzer began performing esophageal manometry in 1883, using a large balloon system, and discovered peristalsis.2 This was more than a decade before the discovery by Roentgen, in 1895, of x-rays and the first studies on esophageal peristalsis with radiopaque swallowed substances.3 These early, balloon-based manometric systems were limited in their accuracy. Despite this, they were used for several decades and allowed for important advancements in the understanding of esophageal physiology, namely, the identification of the lower esophageal sphincter.4 The demonstration that the size of the balloon influenced the fidelity of the recordings led to the introduction, in the 1960s, of small, multilumen, nonperfused, fluid-filled catheters with their terminal openings separated from each other, allowing measurement of pressure events at different points along the gullet. Subsequently, it was shown that these nonperfused catheters presented high variability and were still inaccurate. Constant perfusion of the catheters was introduced by means of a mechanical type of infusion pump, but the perfusion rate was shown to heavily influence the fidelity of the recordings. The introduction of the noncompliant pneumohydraulic infusion pump,5 in which a constant, small volume of distilled water is delivered through a capillary system by means of a constant pressure, represents the birth of modern esophageal manometry as it is routinely performed today. Most esophageal laboratories use these low-compliance infused systems, with multilumen catheters in which lateral openings (“side holes”) are located at different levels and are arranged in different directions, to study the entire length of the esophagus and compensate for radial asymmetry of the sphincters. After the first description of peptic esophagitis by Winkelstein in 1935,6 several tests were designed to assess the competency of the gastroesophageal junction (standard acid reflux test7), the esophageal sensitivity to acid (acid perfusion test8), or the ability of the esophagus to clear acid (acid clearance test9). In 1964, however, the concept of pH monitoring was introduced for peptic ulcer disease.10 In 1974, Johnson and DeMeester applied the concept of pH testing to esophageal disease and monitored patients for a 24-hour period.11 This allowed quantitation of esophageal acid exposure and provided direct correlation of a reflux episode with spontaneously occurring symptoms. Today the test has been standardized and forms the basis of the diagnosis of gastroesophageal reflux disease (GERD). This test 117

118

Section 2 Investigation of Esophageal Disease

Box 9-1 Tests to Evaluate Esophageal Motor Disorders and Gastroesophageal Reflux Evaluation of Esophageal Motor Function and Clearance Esophageal manometry (body evaluation) 24-hour motility monitoring Esophageal scintigraphy Acid clearing test Video-radiography with liquid and solid barium Evaluation of Lower Esophageal Sphincteric Function Esophageal manometry Standard acid reflux test

A

Evaluation of Upper Esophageal Sphincteric Function Esophageal manometry Video-radiography with liquid barium

Abdominal mm Hg

RIP 30 20 10

Detection of Abnormal Exposure of Distal Esophagus to Gastric Juice 24-hour pH monitoring Relationship Between Symptoms and Esophageal Dysfunction Pharmacologic provocative test (bethanechol, edrophonium) Balloon distention test Acid perfusion test (Bernstein test) 24-hour pH monitoring 24-hour motility monitoring Evaluation of Gastroduodenal Function 24-hour pH monitoring of the stomach Gastric acid analysis Gastroduodenal manometry Gastric emptying study Cholescintigraphy

opened the era of 24-hour monitoring of a variety of foregut functions in an ambulatory setting. In the late 1980s, development of computer systems and the widespread use of miniaturized pressure transducers allowed monitoring of esophageal motility for a complete circadian cycle. This test can be performed together with 24-hour pH monitoring of the distal esophagus and the stomach, allowing complete foregut monitoring (Stein and DeMeester, 1993).12,13 HISTORICAL READINGS Arndorfer RC, Stef JJ, Dodds WJ, et al: Improved infusion system for intraluminal esophageal manometry. Gastroenterology 73:23, 1977. Bernstein LM, Baker LA: A clinical test for esophagitis. Gastroenterology 34:760, 1958. Booth DJ, Kemmerer WT, Skinner DB: Acid clearing from the distal esophagus. Arch Surg 96:731, 1968. Cannon WB, Moser A: The movements of the food in the oesophagus. Am J Physiol 1:435, 1898. DeMeester TR, Bonavina L, Iascone C, et al: Chronic respiratory symptoms and occult gastroesophageal reflux. Ann Surg 211:337, 1990.

Thor.

Esophageal baseline

Gastric baseline

B

cm

47

46

45

44

43

42

FIGURE 9-1 A, Schematic illustration showing how lower esophageal sphincter (LES) pressure is measured with a perfused catheter system. The outflow of the perfusate through the side holes (white arrows) is restricted by the circular muscle tone of the cardia (dotted line) and the externally applied intra-abdominal pressure (black arrows). B, The length of the abdominal and thoracic portion of the LES can be measured on the pressure record by identifying the point where respiratory excursion changes from positive to negative. This point, the respiratory inversion point (RIP), is the point at which the resting pressure of the LES is measured. DeMeester TR, Wang CI, Wernly JA, et al: Technique, indications and clinical use of 24-hour esophageal pH monitoring. J Thorac Cardiovasc Surg 79:656, 1980. Fyke FE, Code CF, Schlegel JF: The gastroesophageal sphincter in healthy human beings. Gastroenterologia 86:135, 1956. Johnson LF, DeMeester TR: Development of the 24-hour intraesophageal pH monitoring composite scoring system. J Clin Gastroenterol 8:52, 1986. Kronecker H, Meltzer SJ: Der Schluckmechanismus, seine Erregung und seine Hemmung. Arch Ges Anat Physiol (suppl):328, 1883. Miller FA: Utilization of inlying pH-probe for evaluation of acid-peptic diathesis. Arch Surg 89:199, 1964. Stein HJ, DeMeester TR: Indications, technique, and clinical use of ambulatory 24-hour esophageal motility monitoring in a surgical practice. Ann Surg 217:128, 1993. Tuttle SG, Grossman MI: Detection of gastroesophageal reflux by simultaneous measurement of intraluminal pressures and pH. Proc Soc Exp Biol Med 98:225, 1958. Winkelstein A: Peptic esophagitis: A new clinical entity. JAMA 104:906, 1935.

STATIONARY ESOPHAGEAL MANOMETRY Technique In the past 25 years, several technical improvements have allowed esophageal manometry to be more widely used in clinical practice. At present, esophageal manometry is the gold standard for assessment of function of the lower esophageal sphincter (LES) and body of the esophagus. It has

Chapter 9 Function Tests

allowed for the identification of primary esophageal motility disorders (achalasia), diffuse esophageal spasm, nutcracker esophagus, and hypertensive LES as well as of systemic disorders affecting the esophagus, such as scleroderma, dermatomyositis, mixed connective tissue disease, diabetes, and alcoholic neuropathy. In GERD, esophageal manometry is used to identify a defective LES and deterioration of esophageal body function. Esophageal manometry is performed using electronic pressure-sensitive transducers or water-perfused catheters with lateral side holes, connected to external transducers. Electronic microtransducers have become popular because they are small enough to be carried in a 7-Fr catheter, are independent of posture, and can be directly connected to a recording device. For these reasons, they are ideally suited for ambulatory manometry. The major drawbacks are their high cost (~$1500 per transducer, or $5000-$8000 per catheter) and their fragility. Low-compliance, water-perfused catheters constitute the most widely used system for stationary manometry. These catheters are made by combining three to eight capillary tubes of 0.8 mm in inner diameter, with side openings at different levels. Side holes arranged radially at the same level are ideal for measuring circumferential pressures around the LES and upper esophageal sphincter (UES). Side holes spaced 5 cm apart are necessary for studying esophageal peristaltic activity. To obtain maximal information during a single intubation and a minimum number of swallows, most laboratories use an eight-lumen catheter with four side holes at the same level arranged at 90 degrees to each other and the remaining four placed at 5-cm intervals along the length of the catheter. The rate of water infusion must be adjusted to obtain reliable and reproducible pressure tracings. This adjustment is best achieved by a low-compliance pneumohydraulic capillary infusion system, with a constant rate of 0.6 mL/min.5

The study is performed after an overnight fast. The catheter is passed through the nose and esophagus into the stomach, and the gastric pressure pattern is confirmed. To identify the high-pressure zone of the LES, the catheter is withdrawn across the cardia (Fig. 9-1A). As the pressure-sensitive station is brought across the gastroesophageal junction, a rise in pressure on the gastric baseline identifies the beginning of the LES. The respiratory inversion point (RIP) is identified when the positive excursions that occur with breathing in the abdominal cavity change to negative deflections in the thorax. The RIP serves as a reference point at which the amplitude of LES pressure and the length of the sphincter exposed to abdominal pressure are measured. As the pressure-sensitive station is withdrawn into the body of the esophagus, the upper border of the LES is identified by the drop in pressure to the esophageal baseline. From these measurements, the pressure, abdominal length, and overall length of the sphincter are determined (see Fig. 9-1B). To account for the asymmetry of the sphincter,14 the pressure profile is repeated with each transducer and the average values for sphincter pressure above gastric baseline, overall sphincter length, and abdominal length of the sphincter are calculated.15 To improve the station pull-through technique, a new method (the slow motorized pull-through technique) has been introduced to evaluate the LES. The catheter is pulled back at a slow constant rate (1.0 mm/second) using a motor

A mm Hg 20 10 RIP Esoph. baseline

Gastric baseline

B cm

50

49

48

47

46

45

44

43

Respiration FIGURE 9-2 Manometric tracing of lower esophageal sphincter (LES) pressure obtained with four side holes located at the same level and positioned radially at 90 degrees to each other. The slow motorized pull-through technique was used. The asymmetry of the sphincter is evident, in that the sphincter is longer in the lower tracing and the pressure is higher in the upper tracing. RIP, respiratory inversion point.

FIGURE 9-3 Computerized three-dimensional image of the lower esophageal sphincter (LES) in a healthy volunteer (A) and a patient with Barrett’s esophagus (B). A catheter with four to eight radial side holes is withdrawn through the gastroesophageal junction. The radially measured pressures are plotted around an axis representing gastric baseline pressure. The volume inscribed by the three-dimensional image (sphincter vector volume) can be calculated, giving the best estimate of the LES mechanical effectiveness in the prevention of reflux of gastric juice from the stomach into the esophagus. (FROM STEIN HJ, DEMEESTER TR, NASPETTI R, ET AL: THREE-DIMENSIONAL IMAGING OF THE LOWER ESOPHAGEAL SPHINCTER IN GASTROESOPHAGEAL REFLUX DISEASE. ANN SURG 214:374, 1991.)

119

120

Section 2 Investigation of Esophageal Disease

TABLE 9-1 Normal Lower Esophageal Sphincter Parameters in 50 Healthy Volunteers Percentile Parameter

Mean

SEM

Median

5th

95th

Pressure (mm Hg)

13.8

0.7

13.0

8.1

26.5

Overall length (cm)

3.7

0.2

3.6

2.6

5.4

2.2

0.2

2.0

1.1

3.4

Intra-abdominal SVV (mm Hg · mm)

3613.2

531.2

2012.0

684.1

12,918.4

Total SVV (mm Hg2 · mm)

5723.2

843.2

3667.0

1212.1

16,780.4

Abdominal length (cm) 2

SEM, standard error of the mean; SVV, sphincter vector volume.

FIGURE 9-4 Schematic representation of normal esophageal peristalsis initiated by a pharyngeal swallow and coordinated with relaxation of the upper esophageal sphincter (UES) and the lower esophageal sphincter (LES).

mm Hg 80

Pharynx

0 80 UES 0 80 0 Esophageal body

80 0 80

5 sec

0 20 0

and recording pressure from the four radial side holes. This technique is quick, taking about 1 minute for a passage through the sphincter, and is well accepted by the patient. It allows high-fidelity tracings without swallowing artifacts, even in the most difficult patients (Fig. 9-2). Because the pull-through is performed in a continuous mode, it provides an accurate determination of sphincter length without the approximation (+0.5-1.0 cm) given by the station pullthrough technique. Because the patient is allowed to breathe normally, it is possible to locate the RIP, from which the abdominal length can be calculated. Because the technique is independent of the operator, it lends itself to automated computer analysis. Comparison of the technique with the traditional station pull-through in a group of healthy volunteers and patients with different esophageal disorders reveals a good correlation for pressure overall and abdominal length.16 By using the four radially oriented side holes positioned at the same level, one can also construct a three-dimensional pressure image of the sphincter by plotting the pressure values radially around an axis representing the gastric baseline.17 For visual purposes, one can enhance the three-dimen-

LES

sional image by applying a cubic curve-smoothing interpolation, which retains the original data points while adding intermediate ones to give a smoother surface to the three-dimensional sphincter image and improve its readability (Fig. 9-3). The volume circumscribed by the three-dimensional sphincter image, the vector volume,18 integrates pressures exerted over the entire length and circumference of the sphincter into one number, representing sphincter resistance to reflux of gastric contents. This measure can be calculated using standard trigonometric formulas and is expressed in units of mm Hg2 · mm. With the stationary pull-through or the slow motorized pull-through technique, the RIP can be identified and the intrathoracic and intra-abdominal portions of the volume (i.e., the portion of sphincter pressure vector volume located above and below the RIP) can be calculated separately. Validation studies have shown that calculation of the sphincter pressure volume based on four radial transducers is sufficient to reliably evaluate sphincter resistance. Table 9-1 shows the values of LES pressure, overall length, length of the abdominal segment, and sphincter vector volume in 50 asymptomatic subjects with the range of normality in our laboratory.

Chapter 9 Function Tests


10%

E


1 sec Multipeaked contraction

F B

C

Peristaltic sequence

Simultaneous sequence

Interrupted sequence

(prop. speed 20 cm/s)

(prop. speed
20 cm/s)

Repetitive contraction

D Dropped sequence  Amplitude 10 mm Hg

For the evaluation of sphincter relaxation and postrelaxation characteristics, the side holes located 5 cm apart are used; one side hole is positioned within the high-pressure zone, with a distal one located in the stomach and a proximal one within the esophageal body. From 5 to 10 wet swallows (5 mL of water) are performed. In the normal situation, the sphincter pressure drops to the level of gastric pressure during each wet swallow. The function of the esophageal body is assessed with the five recording sites located at various levels in the esophagus. To standardize the procedure, the most proximal pressure transducer is located 1 cm below the well-defined cricopha-

FIGURE 9-6 Computerized printout of an esophageal body motility study. Median patient values are related to the normal range obtained in healthy volunteers. Solid lines, 2.5th and 97.5th percentile; dotted lines, 5th and 95th percentile.

DURATION I

II

II

III

III

IV

IV

V

V 60 80 10 0 12 0 14 0 16 0 18 0 20 0

0 1 2 3 4 5 6 7 8 9

I

sec

mm Hg

V

mm Hg/s



10

V

8

IV

6

IV

4

III

2

III

2

II

10 0 12 0 14 0 16 0 18 0 20 0

II

60 80

I

0

PROPAGATION TIME

I

0 20 40

Esophageal level

SLOPE

12

0 20 40

Esophageal level

AMPLITUDE

ryngeal sphincter, with the distal orifices trailing at 5-cm intervals over the whole length of the esophagus. By this method, a pressure response throughout the whole esophagus can be obtained on swallowing (Fig. 9-4). The response to 10 wet swallows is recorded. Amplitude, duration, and morphology (i.e., number of peaks and repetitive contractions after each swallow) are calculated at all recorded levels of the esophageal body. The delay between the onset or peak of esophageal contractions at the various levels in the esophagus is used to calculate the speed of wave propagation. For computer-read records, the peak of esophageal contraction is used to calculate the speed.

10 11 12

A

FIGURE 9-5 Graphic representation of the classification of esophageal contraction waves on stationary manometry. A, A complete peristaltic sequence is a series of detectable contractions at each esophageal level, with a progression speed slower than 20 cm/second (i.e., the time between the peak axes of two adjacent contractions). B, Simultaneous sequence is a series of detectable contractions at each esophageal level, with a progression speed faster than 20 cm/second. C, An interrupted sequence is a series of detectable contractions in which an initial contraction is followed by no detectable contractions (<10 mm Hg) with a normal contraction subsequently reappearing. D, Dropped sequence is a series of detectable contractions in which an initial contraction is followed by no detectable contractions (<10 mm Hg). The morphology of the contractions is classified as normal, multipeaked, or repetitive. The difference between multipeaked (E) and repetitive (F) contractions is that the pressure between two consecutive peaks returns to the baseline in the latter.

sec

121

122

Section 2 Investigation of Esophageal Disease

TABLE 9-2 Median Values and Range of Normality (5th-95th Percentiles) for Manometric Parameters of Esophageal Body Obtained by Wet and Dry Swallows in 136 Normal Subjects Parameter

Level

Wet Swallows

Dry Swallows

Amplitude (mm Hg)

I II III IV V

88 40 76 93 93

(40-177) (14-94) (30-164) (38-180) (36-190)

74 28 52 61 78

(26-154) (14-74) (26-142) (20-148) (22-172)

Duration (seconds)

I II III IV V

2.3 3.1 3.3 3.6 3.7

(1.5-4.3) (1.8-4.8) (2.4-5.2) (2.6-5.7) (2.4-7.0)

2.3 2.8 3.1 3.4 3.6

(1.5-3.9) (1.0-4.5) (1.8-4.6) (2.0-5.6) (2.4-6.4)

Velocity (cm/second)

I-II II-III III-IV IV-V I-V

2.4 2.8 3.8 2.6 2.9

(1.5-4.6) (1.9-6.2) (1.9-8.3) (1.3-8.3) (2.1-4.0)

2.8 3.1 4.5 3.5 3.5

(1.6-6.2) (1.9-8.3) (1.8-8.3) (1.7-12.5) (2.2-5.0)

% Simultaneous

I-II II-III III-IV IV-V

0 0 0 0

(0-10) (0-10) (0-10) (0-10)

0 0 0 0

(0-10) (0-20) (0-20) (0-40)

% Interrupted

I II III IV V

0 0 0 0 0

(0-0) (0-20) (0-10) (0-10) (0-10)

0 0 0 0 0

(0-10) (0-30) (0-30) (0-30) (0-30)

II III IV

0 (0-10) 0 (0-10) 0 (0-10)

% Dropped

0 (0-20) 0 (0-30) 0 (0-30)

The esophageal contraction waves after a swallow are classified as follows: 1. 2. 3. 4.

Peristaltic Simultaneous Interrupted Dropped (Fig. 9-5)

Modern computer technology allows an objective and quick analysis of these parameters.19 Figure 9-6 shows a report of the esophageal body motility analysis obtained by the computer. Table 9-2 reports manometric values at different esophageal levels obtained in a group of 136 healthy subjects with a wide age range. They form the reference values for our laboratory.20 Recorded manometric pressures are affected by such variables as age, posture, bolus characteristic, catheter diameter, swallowing frequency, and compliance of the perfusion system.21-23 Because these parameters are not necessarily standardized among various laboratories, they must be controlled within the individual laboratory. Each laboratory needs to define its own normal values from volunteers who have no subjective or objective evidence of a foregut disorder; alternatively, one laboratory may adopt the normal values of another laboratory, provided that it employs identical procedures and equipment.

Pharyngeal contraction Bolus pressure

Pharynx Atmospheric baseline pressure

Sphincter

Esophageal baseline pressure

Esophagus Scale:

20 mm Hg

1 sec

FIGURE 9-7 Normal cricopharyngeal recording made with a catheter having side holes spaced 1 cm apart. This technique shows the relation of pharyngeal contractions to the relaxation of the upper esophageal sphincter and response in the cervical esophagus. The typical intrabolus pressure is evident before the upstroke of pharyngeal contractions. (FROM DEMEESTER TR, CROOKES PF: BENIGN AND MALIGNANT DISEASE OF THE ESOPHAGUS. IN LEVINE BA, COPELAND EM III, HOWARD RJ, ET AL [EDS]: CURRENT PRACTICE OF SURGERY. NEW YORK, CHURCHILL LIVINGSTONE, 1993, P 14.)

The position, length, and pressure of the UES are evaluated by a stationary pull-through technique, using 0.5- to 1.0-cm increments, from the cervical esophagus to the pharynx. The rapid pull-through technique needs to be avoided. It gives pressure values consistently higher than the station pull-through technique, probably because of catheter irritation as it is rapidly withdrawn.24 To account for the anatomic asymmetry of the UES,25 the values obtained from the side holes oriented in the different directions must be averaged. One may evaluate the function of the UES on swallowing by placing one side hole of the catheter in the pharynx, one in the sphincter, and one in the upper esophagus. Because of the short duration of the pharyngeal swallowing phase (1.5 seconds), high-speed graphic recordings (50 mm/second) are necessary to evaluate the coordination of cricopharyngeal relaxation with hypopharyngeal contraction. Normally, pharyngeal contractions reach 50 to 60 mm Hg and are coordinated with complete UES relaxation (i.e., a fall in the sphincter pressure to the less-than-atmospheric intraesophageal pressure). Movement of the UES orad during swallowing (2-3 cm) may give a misleading impression of its relaxation, since

Chapter 9 Function Tests

a single side hole, positioned in the center of the UES at rest, may actually lie in the cervical esophagus during a swallow (Kahrilas et al, 1988).26 To obviate this problem, we use a dedicated special catheter assembly consisting of eight side holes located at 1.0-cm intervals, oriented radially around the catheter. Experience has shown this procedure to be useful in evaluating the UES relaxation and the pharyngoesophageal coordination (Fig. 9-7). An alternative approach is the use of a particular type of sleeve sensor27 made especially for the evaluation of UES relaxation over long periods of time. This device is a reliable indicator of UES relaxation. Its disadvantages are its slow response rate to pressure rises and its large caliber. Both must be taken into account in evaluating resting pressure values. Water-perfused catheters, even with low compliance and good pressure rise rate (>200 mm Hg/second), may be inadequate in studying rapid changes in pharyngeal pressure that reach up to 500 mm Hg/second. Therefore, some authors advocate the use of solid-state microtransducers for this purpose.28 Because of their intrinsic construction characteristics, these transducers cannot be assembled closely enough to each other without making the probe rigid and unusable for intubation. Currently, the minimum possible distance between transducers is 3 cm. To overcome this problem, two adjacent probes had been used in some studies.29

Clinical Application Stationary esophageal manometry, performed as described, is indicated when: ■

■ ■

A motility disorder of the esophageal body and/or the LES is suspected from complaints of dysphagia, regurgitation, or chest pain. A comprehensive evaluation of the antireflux mechanism in GERD is desired. A disturbance of the pharyngoesophageal phase of swallowing is suspected.

FUNCTIONAL DISORDERS OF THE ESOPHAGEAL BODY AND LOWER ESOPHAGEAL SPHINCTER Abnormalities occurring in the esophageal body or the LES can give rise to a number of disorders in the esophageal phase of swallowing. These disorders result from either a direct deterioration of esophageal muscle function or a more generalized neural, muscular, or systemic disease such as progressive systemic sclerosis, dermatomyositis, or myasthenia gravis. With the introduction of esophageal manometry, a number of primary esophageal motility disorders have been classified as separate disease entities: 1. Achalasia 2. Diffuse or segmental esophageal spasm 3. High-amplitude peristaltic esophageal contractions, the so-called nutcracker esophagus 4. Hypertensive LES 5. Ineffective esophageal motility (Box 9-2)

Box 9-2 Esophageal Motility Disorders Primary Achalasia, vigorous achalasia Diffuse and segmental esophageal spasm Nutcracker esophagus Hypertensive lower esophageal sphincter Ineffective esophageal motility Nonspecific esophageal motility disorders Secondary Collagen vascular diseases (e.g., progressive systemic sclerosis, polymyositis and dermatomyositis, mixed connective tissue disease, systemic lupus erythematosus) Chronic idiopathic intestinal pseudo-obstruction Neuromuscular diseases Endocrine and metastatic disorders Alcoholic neuropathy

The term nonspecific esophageal motor disorder includes patients whose manometric features are clearly abnormal but defy classification into one of the major groups.

Achalasia The classic pattern includes the loss of progressive peristalsis in the body of the esophagus and failure of the LES to relax on deglutition (Fig. 9-8). The contractions recorded at different esophageal levels are simultaneous and usually of low amplitude. Other features include elevation of intraluminal esophageal pressure and hypertension of the LES. The combination of peristaltic failure and nonrelaxation of the sphincter causes a functional holdup of ingested material in the esophagus and results in dilation of the esophageal body. With time, the functional disorder results in anatomic alterations, which show on radiographic studies as a dilated esophagus with a tapering, beaklike narrowing of the distal end. Usually, the air-fluid level in the esophagus reflects the degree of resistance imposed by the nonrelaxing sphincter. As the disease progresses, the esophagus becomes massively dilated due to pressurization from swallowed air and tortuous due to the inability of the esophagus to support the weight of the retained column of fluid. A subgroup of patients with otherwise typical features of classic achalasia show simultaneous contractions of the esophageal body, which may be of high amplitude. This manometric pattern has been termed vigorous achalasia, and chest pain episodes are a common complaint in these patients.30 In patients with advanced disease, the radiographic study can show a corkscrew deformity of the esophagus due to the helical arrangement of the hypertrophied smooth muscle and diverticulum formation.

Diffuse and Segmental Esophageal Spasm This manometric abnormality occurs relatively infrequently. Its incidence is approximately one-fifth that of achalasia. It may involve the total length of the esophageal smooth muscle but is usually confined to the distal two thirds. In segmental

123

124

Section 2 Investigation of Esophageal Disease

FIGURE 9-8 Esophageal motility in a patient with achalasia, showing the typical features: absence of peristaltic progression in the esophageal body and the inability of the lower esophageal sphincter to completely relax on swallowing. WS, wet swallow.

WS

WS

mm Hg 30 0 30 0 30

0

8 sec

0 30 0 30 0

esophageal spasm, the manometric abnormalities are confined to a short segment of the smooth muscle esophagus. The classic motility finding in these patients is characterized by the frequent occurrence of simultaneous and repetitive esophageal contractions, which may be of abnormally high amplitude or long duration (Fig. 9-9). Key in the diagnosis of diffuse esophageal spasm is that the esophagus usually retains some degree of peristaltic performance, thus distinguishing it from achalasia. A criterion of 20% or more simultaneous contractions in response to wet swallows has been used to justify the diagnosis of esophageal spasm. The LES in patients with the disease usually shows normal resting pressure and relaxation on deglutition. A hypertensive sphincter with poor relaxation may also be present31 and may make differentiation from vigorous achalasia difficult.

FIGURE 9-9 Esophageal body motility in a patient with diffuse esophageal spasm. The motor disorder is characterized by an increased percentage of simultaneous contractions (>20%). The contraction can be repetitive and multipeaked, with high amplitude and long duration. The second level from the top is at the junction of striated and smooth muscle where contractions are normally of low amplitude. WS, wet swallow.

Nutcracker Esophagus Esophageal manometric studies in patients with chest pain of a noncardiac origin have shown that a large proportion of these patients have peristaltic esophageal contractions of exceedingly high amplitude. In the late 1970s, this disorder was termed nutcracker or supersqueezer esophagus. Other terms used to describe this entity are hypertensive peristalsis or high-amplitude peristaltic contractions.32 It is the most frequent of the primary esophageal motility disorders. By definition, nutcracker esophagus is a manometric abnormality in patients with chest pain and/or dysphagia and is characterized by peristaltic esophageal contractions of amplitude that exceeds the 95th percentile of a healthy population (Fig. 9-10). Contraction amplitudes in these patients can

WS

WS

mm Hg 60 30 0 60 30 0 60 30 0 60 30 0 60 30 0

5 sec

Chapter 9 Function Tests

WS

WS

FIGURE 9-10 Esophageal motility in a patient with nutcracker esophagus. Esophageal contractions are always peristaltic, with high amplitude (>180 mm Hg). Relaxation of the lower esophageal sphincter is maintained. WS, wet swallow.

mm Hg 200 160 120 80 40 0 0

8 sec

easily be above 400 mm Hg. Patients with peristaltic waves of excessively long duration are also considered to have nutcracker esophagus. So far, the cause of peristaltic contractions with high amplitude or long duration in the pathogenesis of noncardiac chest pain or dysphagia has not been established.

Hypertensive Lower Esophageal Sphincter An LES of high pressure was first described as a separate entity by Code and colleagues33 in patients with chest pain or dysphagia. The disorder is characterized by elevated basal pressure of the LES with normal relaxation and normal wave progression in the body of the esophagus. About 50% of these patients have associated motility disorders of the esophageal body, particularly nutcracker esophagus and diffuse esophageal spasm, which may account for the symptoms. In the remainder, the disorder exists as an isolated abnormality of the distal esophageal sphincter. Symptoms can be caused by a prolonged post-relaxation contraction of the LES in addition to the hypertensive sphincter. Our criteria for the diagnosis of a hypertensive-hypercontracting LES are listed in Box 9-3.34

Ineffective Esophageal Motility Castell35 has introduced a specific esophageal motility disorder called ineffective esophageal motility. This is defined as a contraction abnormality of the distal esophagus in which the total of the number of low-amplitude contractions (<30 mm Hg) and nontransmitted contractions exceeds 30% of wet swallows. This abnormality is the most common manometric finding in patients with GERD and may be secondary to inflammatory injury of the esophageal body due to increased exposure to gastric juice. When present, the abnormality contributes to increased esophageal acid exposure due to a loss of effective esophageal acid clearance. At present, the process causing the altered motility appears to be irreversible once it has occurred.

Box 9-3 Diagnostic Criteria for a Hypertensive Hypercontracting Lower Esophageal Sphincter 1. Dysphagia and chest pain as the predominant symptoms 2. Lower esophageal mean resting pressure >25 mm Hg 3. Mean duration of post-relaxation contractions >14 seconds 4. Mean slope of post-relaxation contraction pressure rise <25 mm Hg/ second 5. No other primary esophageal motor disorders 6. No endoscopic or radiographic evidence of an organic cause for the symptoms From Eypasch EP, Stein HJ, DeMeester TR, et al: The hypercontractinghypertensive lower esophageal sphincter as a cause of dysphagia and chest pain. In Little AG, Ferguson MK, Skinner DB (eds): Diseases of the Esophagus, Vol II: Benign Diseases. Mount Kisco, NY, Futura Publishing Company, 1990, p 351.

Nonspecific Esophageal Motility Disorders Many patients complaining of dysphagia or chest pain of noncardiac origin demonstrate a variety of esophageal contraction patterns on esophageal manometry that are clearly out of the normal range but do not meet the criteria of a classic primary esophageal motility disorder. Esophageal manometry in these patients frequently shows an increased number of multipeaked or repetitive contractions, contractions of prolonged duration, nontransmitted pharyngeal contractions, interrupted contraction waves, or contractions of low amplitude. These motility abnormalities have been termed nonspecific esophageal motility disorders. The significance of these abnormal contractions in the etiology of chest pain or dysphagia is still unclear. There is considerable overlap in the classification of patients with esophageal motor abnormalities. A clear distinction between the classic primary esophageal motility disorders and so-called nonspecific esophageal motility disorders is often impossible. Patients with a diagnosis of nutcracker esophagus often have only nonspecific esophageal motility

125

126

Section 2 Investigation of Esophageal Disease

abnormalities when studied repeatedly, and progression from a nonspecific esophageal motility disorder to classic diffuse esophageal spasm during the natural course of the disease has been demonstrated.36 Therefore, the finding of a nonspecific esophageal motility disorder may represent a manometric marker of a developing primary esophageal motor abnormality. The boundaries between classic esophageal motility disorders of achalasia, diffuse esophageal spasm, nutcracker esophagus, and hypertensive LES are also vague. Differentiation of vigorous achalasia and diffuse esophageal spasm can be difficult, and intermediate types exist. Progression of diffuse esophageal spasm to achalasia has been observed,37 and peristalsis may return in patients with classic achalasia after a Heller myotomy or balloon dilation.38 These observations support the concept that primary esophageal motility disorders may represent different expressions of a common underlying esophageal pathology.

Secondary Esophageal Motor Disorders The term secondary esophageal motor disorder usually denotes an esophageal motility disorder resulting from a generalized neural, muscular, or systemic metabolic disturbance. The esophagus is particularly affected by almost any of the collagen vascular disorders; the most common are progressive systemic sclerosis, mixed connective tissue disease, and polymyositis or dermatomyositis. Eighty percent of patients with progressive systemic sclerosis have an esophageal motor abnormality. In most cases, the disease follows a prolonged course and usually affects only the smooth muscle in the distal two thirds of the esophagus. Typical findings on esophageal manometry are normal peristalsis in the proximal striated muscle, with weak or absent peristalsis in the distal smooth muscle portion (Fig. 9-11). LES pressure is progressively weakened as the disease advances, resulting in increased esophageal exposure to gastric juice due to a mechanically defective LES and poor clearance function of the esophageal body.39,40 FIGURE 9-11 Esophageal motility in a patient with progressive systemic sclerosis. A weak motor activity is maintained in the upper esophagus; in the distal two thirds (smooth muscle), any detectable activity in response to swallow is virtually absent. WS, wet swallow.

In patients with polymyositis or dermatomyositis, the upper striated muscle portion is the major site of esophageal involvement causing aspiration, nasopharyngeal regurgitation, and cervical dysphagia. Mixed connective tissue disease shows a mixture of the manometric findings of progressive systemic sclerosis and polymyositis.

GASTROESOPHAGEAL REFLUX DISEASE GERD is a common foregut disorder that is complicated by esophagitis, stricture, or Barrett’s esophagus in about 50% of affected patients. The basic pathophysiologic abnormality in this condition is an increased esophageal exposure to gastric juice, for which there are three known causes. The first is a mechanically defective LES, accounting for about 60% of cases of GERD.15 The identification of this cause is important because medical therapy in this situation is plagued by high failure and relapse rates.41 The other two causes are inefficient esophageal clearance of refluxed gastric juice and abnormalities of the gastric reservoir that augment physiologic reflux, such as gastric dilation and persistent gastric reservoir.

Incompetence of the Lower Esophageal Sphincter Failure of the LES is caused by inadequate pressure, overall length, or abdominal length (i.e., of the portion exposed to the positive pressure environment of the abdomen measured on manometry).15,42 The probability of increased exposure to gastric juice is 76% if one component of the sphincter is abnormal, 88% if two components are abnormal, and 92% if all three are abnormal. This finding indicates that the failure of one or two of the components of the sphincter may be compensated for by the clearance of the esophageal body. Failure of all three sphincter components inevitably leads to increased esophageal exposure to gastric juice. The most common cause of a mechanically defective LES is inadequate sphincter pressure, probably related to an WS

WS

mm Hg 30 0 30 0 30 0 30 0 30 0

0

8 sec

Chapter 9 Function Tests

PREVALENCE OF A DEFECTIVE SPHINCTER 100

80 Percentage

abnormality of myogenic function. However, the efficiency of a normal sphincter pressure can be nullified by an inadequate abdominal length or an abnormally short overall resting length of the sphincter. An adequate abdominal length of sphincter is important in preventing reflux caused by increases in intra-abdominal pressure, and an adequate overall length is important in preventing reflux caused by gastric dilation. Therefore, patients with a low sphincter pressure or those with a normal pressure but a short abdominal length are unable to protect against reflux caused by fluctuations of intra-abdominal pressure that occur with daily activities or changes in body position. Patients with a low sphincter pressure or those with a normal pressure and abdominal length but short overall length are unable to protect against reflux related to further shortening of the sphincter caused by gastric dilation from outlet obstruction, aerophagia, or gluttony. Persons with short overall length commonly suffer from reflux caused by further shortening of the sphincter that occurs from gastric distention with eating (i.e., postprandial reflux).43 The overall competency of the LES is well represented by the calculation of the sphincter vector volume that combines pressures exerted over the entire length of the sphincter. When measured in a large number of patients, total and abdominal sphincter vector volumes were found to be markedly lower in patients with increased esophageal acid exposure compared with healthy volunteers, and volume decreased with increased severity of mucosal injury.17 Comparing sphincter vector volume with standard sphincter parameters (i.e., resting pressure, overall and abdominal length), we found that sphincter vector volume had no significant advantage in detection of a defective sphincter in patients with advanced complications of GERD. Sphincter vector volume did have a greater sensitivity than standard manometry in identifying a mechanically defective sphincter in patients with increased esophageal acid exposure but no mucosal damage (Fig. 9-12). Transient loss of the LES can be a functional problem of the gastric reservoir. Ingestion of excessive air or food can result in gastric dilation and, if the active relaxation reflex has been lost, in increased intragastric pressure. When the stomach is distended, the vectors produced by gastric wall tension pull on the gastroesophageal junction with a force that varies according to the geometry of the cardia; that is, the forces are applied more directly when a hiatal hernia exists than when a proper angle of His is present. These forces pull on the terminal esophagus, causing it to be “taken up” into the stretched fundus, thereby reducing the length of the LES. This process continues until a critical sphincter length is reached, usually 1 to 2 cm, when the pressure drops precipitously and reflux occurs. If only the pressure, and not the length, of the high-pressure zone is measured, as with a Dent sleeve, this event appears as a spontaneous dissipation, or “relaxation,” of the LES. The mechanism by which gastric distention contributes to shortening of the LES, so that its pressure drops and reflux occurs, provides a mechanical explanation for transient relaxations of the LES without invoking a neuromuscular reflex. Rather than a transient muscular relaxation, there is a

Standard technique SPVV analysis

60

*

40

20

0 Volunteers n  50

GERD GERD GERD No injury Esophagitis Stricture n  57 n  42 n  20

GERD Barrett’s n  31

FIGURE 9-12 Comparison of standard manometric techniques and sphincter pressure vector volume (SPVV) analysis in the identification of a mechanically defective lower esophageal sphincter. SPVV identifies a significantly higher number of patients with defective sphincter in the group of patients without complications of gastroesophageal reflux disease. Asterisk, P < .05 versus standard manometry. (FROM STEIN HJ, DEMEESTER TR, NASPETTI R, ET AL: THREE-DIMENSIONAL IMAGING OF THE LOWER ESOPHAGEAL SPHINCTER IN GASTROINTESTINAL REFLUX DISEASE. ANN SURG 214:374, 1991.)

mechanical shortening of the LES, secondary to progressive gastric distention, to the point where competence is lost. Consequently, non–swallow-induced relaxations of the LES are inappropriately termed transient lower relaxations; instead, they should be called transient LES shortenings. These transient sphincter shortenings occur in the initial stages of GERD and are the mechanisms responsible for the early complaint of excessive postprandial reflux.

Esophageal Clearance of Refluxed Material A second cause of increased esophageal exposure to gastric juice is inefficient esophageal clearance of refluxed material.44 This problem can result in an abnormal esophageal exposure to gastric juice in individuals who have a mechanically normal LES and normal gastric function by ineffectual clearing of physiologic reflux episodes. This situation is relatively rare, and ineffectual clearance is more likely to be seen in association with a mechanically defective LES, in which case it augments the esophageal exposure to gastric juice by prolonging the duration of each reflux episode. As discussed previously, the motility abnormality that occurs in GERD has been termed by Castell as ineffective esophageal motility disorder.35 Manometry of the esophageal body can detect failure of esophageal clearance by analysis of the pressure amplitude and speed of progression of the peristaltic wave through the esophagus. The work of Kahrilas and colleagues (Kahrilas Dodds, Hogan, 1988)45 has shown that the amplitude of an esophageal contraction required to clear the esophagus of barium varies according to the level. Lower segments require a greater amplitude (30-40 mm Hg) than upper segments.

127

128

Section 2 Investigation of Esophageal Disease

Inadequate amplitude results in ineffective clearance. Increased esophageal clearance as a result of increased swallowing may compensate for a mechanically defective sphincter with an abnormality of one or two of its critical compon-ents but is unlikely to compensate for three abnormal components.

PHARYNGOESOPHAGEAL SWALLOWING DISORDERS Disorders of the pharyngoesophageal phase of swallowing are relatively uncommon. They result from a discoordination of the neuromuscular events during the act of swallowing and the inability to propel the swallowed material from the oropharynx into the cervical esophagus. Zenker’s diverticulum or a cricopharyngeal bar is often, but not always, present. The rapidity of the oropharyngeal phase of swallowing, the movement of the gullet, and the asymmetry of the cricopharyngeus account for the difficulty in assessing abnormalities of esophagopharyngeal swallowing disorders with manometClosed sphincter

Manometrically relaxed sphincter

Catheter 160 120 80 Pharyngeal 40 Crico Esophageal 0

Anatomically relaxed sphincter

Muscle

100

Shoulder pressure 0

FIGURE 9-13 The intrabolus pressure or shoulder pressure in the hypopharynx, in a manometrically relaxed but incomplete anatomically relaxed upper esophageal sphincter (UES). The shoulder on the pharyngeal pressure wave indicates increased resistance to the passage of a bolus through the pharyngoesophageal segment caused by pathology of the cricopharyngeal and cervical esophageal muscle resulting in poor compliance and incomplete anatomic relaxation. (FROM STEIN HJ, DEMEESTER TR, HINDER RA: OUTPATIENT PHYSIOLOGIC TESTING AND SURGICAL MANAGEMENT OF FOREGUT MOTILITY DISORDERS. CURR PROBL SURG 24:441, 1992.)

FIGURE 9-14 Pharyngoesophageal manometric tracing in a patient with Zenker’s diverticulum before and after diverticulectomy and myotomy. A nonrelaxing upper esophageal sphincter and a prominent bolus or shoulder pressure are evident in the preoperative recording. Myotomy increased the compliance of the pharyngoesophageal segment, with complete disappearance of the shoulder pressure in the pharyngeal contractions.

ric techniques. However, carefully performed motility studies may demonstrate incoordination and incomplete relaxation of the UES during swallowing. This pattern is the feature of many neurologic diseases, including cerebrovascular accident and trauma (head injury and iatrogenic nerve injury).49 It may result in failure of the pharynx to empty or cause nasal regurgitation and aspiration. It may, but not always, cause dysphagia. In some patients, particularly those with a history of poliomyelitis, the pressure generated by the pharynx can be subnormal. This condition is important to identify because the presence of a profound loss of pharyngeal pressure may be helped by a cricopharyngeal myotomy. It has been difficult to consistently demonstrate motility abnormalities in patients with cervical dysphagia, cricopharyngeal bar, or Zenker’s diverticulum. Some studies47,48 focused attention on the role of reduced compliance of the UES and cervical esophagus in the pathophysiology of these disorders, making a distinction between a “manometrically relaxed” and “anatomically relaxed” sphincter (Fig. 9-13). Combined radiographic and manometric studies have highlighted the importance of the intrabolus pressure, detected as a “shoulder” or “hump” just before the upstroke of hypopharyngeal pressure wave as an indication of a manometrically relaxed but incompletely anatomically relaxed sphincter. In two separate studies of patients with Zenker’s diverticulum and cricopharyngeal bar,47,48 the intrabolus pressure was found to be elevated despite complete manometric relaxation of the UES. This phenomenon is attributed to decreased compliance of the striated muscle in the cervical esophagus. It allows manometric relaxation but incomplete opening of the sphincter and a higher driving pressure transmitted to the bolus by the tongue and pharyngeal muscles to compensate for the loss of compliance of the upper esophagus. Loss of compliance of the pharyngocervical esophageal segment may be the most common abnormality in patients with pharyngeal dysphagia, with or without Zenker’s diverticulum. Increasing the diameter of this noncompliant segment by a surgical myotomy reduces the resistance it imposes to the bolus transport into the esophagus. Manometrically, this procedure results in the disappearance of the “shoulder” in the pharyngeal contraction (Fig. 9-14). PRE

POST

Bolus pressure Pharyngeal contractions

Pharynx

UES Esophagus

1 sec

20 mm Hg

Chapter 9 Function Tests

With extensive study, Mason and coworkers49 have clarified pharyngeal swallowing disorders and have emphasized that pharyngeal swallowing is a mechanical process. It requires the thyrohyoid muscle groups to elevate the larynx, the glossopharyngeal musculature to propel the bolus, the cricopharyngeus to relax, and the cervical esophageal muscle to be compliant.45,49-54 This equates mechanically to three primary forces: 1. A traction force (Ftraction), due to the contractions of the thyrohyoid muscles, resulting in the anterosuperior movement of the hyoid bone and, in turn, elevation of the larynx. 2. A muscle force (Fmuscle), due to the active and passive tone within the inferior pharyngeal constrictor, cricopharyngeal, and cervical esophageal muscles, which resist sphincter opening. 3. A bolus force (Fbolus) generated by the glossopharyngeal muscles, which propel the bolus into the pharyngoesophageal segment. For opening of the UES to occur, the following must be true: Ftraction − Fmuscle + Fbolus ≥ 0 (atm pressure)

A. Opening pressure

B. Hydrodynamic pressure

C. Contact pressure

Catheter

Bolus

Esophageal wall FIGURE 9-15 Diagrammatic representation of the manometry catheter during the three different physical conditions of the upper esophageal sphincter. Arrows indicate the direction of movement of the esophageal walls relative to the catheter. The esophageal walls are distracted away from the catheter. During this phase, a falling pressure is recorded. A bolus surrounds the pressure transducer on its passage through the pharyngoesophageal segment. During this phase, the pressure reflects the intrabolus pressure. The esophageal or pharyngeal muscles contract and compress the catheter. During this phase of the swallow, a rising pressure is recorded.

or Ftraction + Fbolus ≥ Fmuscle

where atm is atmospheric. Manometry can measure the forces involved in the transfer of a bolus from the hypopharynx into the esophagus and the resistance to flow imposed by a noncompliant cricopharyngeal and cervical esophageal muscle. These measurements provide insight into the mechanical deficiencies of the various steps in the swallowing process and a logical basis for therapy. Surgeons have the ability to substantially alter the Fmuscle and, possibly, the Ftraction forces. Manometry of the pharyngoesophageal segment can identify manometric markers of pharyngeal swallowing that can serve as a guide to the selection of patients who would benefit from a cricopharyngoesophageal myotomy. Manometry of the pharyngoesophageal segment49 can be used to measure pressure associated with three different physical conditions of the UES (Fig. 9-15): 1. Cavity or opening pressure 2. Hydrodynamic or intrabolus pressure 3. Contact or closing pressure The mechanics of pharyngeal swallowing consist of a closed, an opening, an open, and finally a reclosed UES. The pressure sequence during a swallow is from a closing pressure, to an opening pressure, to a hydrodynamic pressure, and finally back to a closing pressure. The cavity or opening pressure reflects the pressure within the UES caused by the walls being pulled open (see Fig. 9-15A). During this phase, the walls of the pharyngoesophageal segment are no longer in contact with the catheter and air fills the space. After the UES is opened, the bolus flows into the pharyngoesophageal segment, producing a hydrodynamic or intrabolus pressure. This pressure reflects the forces applied on the bolus as it

Peak pharyngeal pressure (Tc) Ta

Td

Tb Atmospheric baseline Pressure (B0) Intrabolus pressure FIGURE 9-16 Schematic diagram of a typical pharyngeal pressure tracing. Ta represents arrival of the bolus head; Tb, the bolus tail; Tc, peak pressure of the pharyngeal stripping wave; Td, completion of the pharyngeal pressure wave; and B0, baseline atmospheric pressure.

passes through the UES and into the cervical esophagus (see Fig. 9-15B). The pharyngeal stripping wave closely follows the tail of the bolus, and, as the pharyngeal and cricopharyngeal muscles squeeze down on the catheter, a contact or closing pressure occurs (see Fig. 9-15C). The characteristic feature of the pressure tracing in the proximal pharyngoesophageal segment is that before the swallow the catheter lies freely in the hypopharynx, exposed to atmospheric pressure. After the swallow is completed, the pressure tracing returns to atmospheric pressure (Fig. 9-16). The onset of a swallow (Ta) is identified by a rise in pressure more than 2 mm Hg above the atmospheric baseline pressure (B0). This is caused by the movement of the bolus into the pharyngoesophageal segment. A second steeper slope (Tb) occurs as the tail of the bolus passes the pressure port ahead of the pharyngeal stripping wave. The peak of this slope is

129

130

Section 2 Investigation of Esophageal Disease

the closing pressure of the pharyngeal wall on the pressure port and is the highest amplitude attained during a pharyngeal contraction (Tc). This is followed by a decline back to the resting pressure (Td). The pharyngeal stripping or clearing wave can be assessed by noting the time interval between successive peak pharyngeal pressures recorded by different channels with ports higher in the pharynx. One can measure the total duration of the pharyngeal event by noting the time interval between Ta and Td. The cricoesophageal muscle, or UES, is closed at rest. At the onset of a swallow, the port in the proximal UES exhibits a rise in pressure, reflecting the upward motion of the tonically contracted sphincter on the manometry catheter (T0) (Fig. 9-17). When this occurs, pressure ports in the more distal sphincter may exhibit an immediate pressure fall consistent with the port slipping caudally out of the sphincter into the esophagus as the larynx is elevated. After this rise in pressure in the more proximal portion of the sphincter, a decline in pressure is observed with the relaxation of the sphincter. As the traction forces begin to dominate, the rate of the pressure drop increases and a “checkmark” or kink in the pressure tracing may be generated.55-59 This is due to the traction forces overcoming the muscular forces, causing the sphincter walls to separate with the creation of a gap. The pressure becomes subatmospheric as the walls of the sphincter are pulled apart to create this expanding space (T1). This drop to subatmospheric pressure within the pharyngoesophageal segment implies sphincter opening.51,55-58 As the fluid bolus enters the open sphincter, the pressure rises from the subatmospheric drop to a supra-atmospheric pressure (T2). As the bolus tail leaves the segment, there is again an abrupt rise in pressure (T3), representing closure of the esophageal lumen against the pressure ports. The maximum pressure reached in this rapid ascent is due to the passage of the pharyngeal stripping wave (T4) through the cricopharyngeal muscle and into the cervical esophagus. Sphincter opening is defined as “normal” if the pressure at T1 became subatmospheric and as “impaired” if this does not occur. For a normal subatmospheric intrasphincteric pressure drop to occur, there must be complete sphincter relaxation. The resistance to pharyngoesophageal flow relates to the compliance of the cricopharyngeal and cervical esophageal muscles and the amplitude of the pharyngeal contraction waves. It is assessed by measuring the intrabolus pressure. Intrabolus pressure in the proximal pharyngoesophageal segment is measured at the time of Tb (see Fig. 9-16). Intrabolus pressure in the UES and the more distal pharyngoesophageal segment is measured during the passage of the head (T2) and tail (T3) of the bolus through the open UES (see Fig. 9-17). The highest pressure measured at Tb (see Fig. 9-16), T2, or T3 (see Fig. 9-17) is considered to be the intrabolus pressure for a swallow. The average of five swallows is used to calculate the final intrabolus pressure. A patient is considered to have an elevated intrabolus pressure when the pressure measured with a 5-mL swallow is greater than the 95th percentile for 56 normal subjects (>16.3 mm Hg). A patient is classified as having low pharyngeal contraction

T4 T0

T2 T3

B0

T1 Subatmospheric pressure FIGURE 9-17 Schematic diagram of a typical upper esophageal sphincter pressures tracing illustrating the distal pharyngoesophageal segment. T0 represents the beginning of the swallow; T1, complete opening of the sphincter (with complete opening, pressure is subatmospheric); T2, transition from a subatmospheric to a supraatmospheric pressure as the head of the bolus flows into the sphincter; T3, the bolus tail ahead of the pharyngeal stripping wave; T4, peak pressure following luminal closure by the pharyngeal stripping wave; and B0, baseline atmospheric pressure.

amplitudes when the pressure measured with a 5-mL swallow is below the 5th percentile for 56 normal subjects (<27.7 mm Hg). The UES is normally open and relaxed on arrival of a bolus, and this can be depicted manometrically by a subatmospheric drop in pressure, before any radiologic contrast material can be seen in the UES. Any impairment in UES relaxation and opening is evident by a failure of the intersphincteric pressure to fall during the opening phase of the swallow. In this situation, the intrabolus pressure is elevated as the fluid bolus meets the increased outflow resistance at the level of the UES. If, however, the glossopharyngeal contraction amplitudes are below normal, the intrabolus pressure will be within the normal range. In this situation, a myotomy can still be of benefit by reducing the active and passive tone of the muscles and thereby decreasing the resistance to flow through the pharyngoesophageal segment. As a consequence, it is easier for the weak glossopharyngeal contractions to overcome outflow resistance. For this reason, a poor pharyngeal peak contraction pressure is not a predictor of poor outcome. Selecting which patient will benefit from a myotomy in this situation is difficult because of the absence of an elevated bolus pressure. If pharyngeal contraction pressure is normal, it may help to plot the peak bolus pressure that occurs with progressive increases in the volume of the swallowed bolus (Fig. 9-18). In this situation, the intrabolus pressures at T2 and T3 (see Fig. 9-17) are higher, indicating that the patient’s dysphagia is due to poor compliance in the cricopharyngeal and cervical esophageal muscle. The most important manometric marker in selecting patients for myotomy is the absence of the subatmospheric intrasphincteric pressure drop. When this is combined with an increased intrabolus pressure, the surgeon has the mechanical indicators that myotomy will result in improved swallowing.

Chapter 9 Function Tests

26 Intrabolus pressure (mm Hg)

24 22 20 18 16 14 Dysphagia patients Normal subjects

12 10 5 mL

10 mL Swallowed volume

15 mL

FIGURE 9-18 Relationship of swallow volume to intrabolus pressure in patients who have lost compliance of the cricopharyngeal and cervical esophageal muscle. Higher pressure for increasing swallowed volume indicates that patients have sufficient pharyngeal muscle power to create an intrabolus pressure, and improvement of the compliance with a myotomy of the cricopharyngeal and cervical esophageal muscle should result in clinical improvement.

ESOPHAGEAL PROVOCATIVE TESTS Technique The spontaneous occurrence of symptoms during a standard esophageal motility study is rare, especially in patients with noncardiac chest pain. Consequently, a number of provocative tests have been designed to identify the esophagus as the cause of these symptoms. Of these, the most commonly used follow: 1. Intraesophageal acid perfusion (Bernstein) test 2. Edrophonium (Tensilon) test 3. Intraesophageal balloon distention test

Acid Perfusion Test (Bernstein Test) Introduced more than 40 years ago,8 this simple test aims to determine whether the patient’s symptoms are reproduced by the infusion of acid into the esophagus. If results are positive, the test indicates that the esophagus is sensitive to acid and increased esophageal exposure to acid is assumed. As originally described, the distal esophagus is perfused with 0.1 N HCl at 6 to 8 mL/min, with the patient sitting upright. Ideally, a placebo is also infused; that is, acid or saline is perfused alternately without the patient knowing the identity of the perfusate. The patient is asked to report any symptom that develops during infusion. Consistent reproduction of the patient’s usual symptoms only during acid perfusion and rapid abatement during saline perfusion or after antacid administration indicates a positive test. Development of symptoms during both the saline and acid perfusion or development of symptoms foreign to the patient’s usual experience represents an equivocal test. Failure to develop any symptoms during a 30-minute acid perfusion indicates a normal test finding.

Various investigators have reported that 34% to 100% of patients with typical symptoms of GERD have a positive acid perfusion test result.60-63 Failure to include certain components of gastric juice (pepsin, bile, pancreatic enzymes) in the perfusate may account for some of the normal results. A false-negative result can occur in patients who have an insensitive esophagus and has been exemplified in patients with severe hemorrhagic esophagitis without pain. Falsepositive results are seen in 15% of asymptomatic subjects.61 Of concern is that symptomatic subjects whose pain is not caused by reflux may have a similar incidence of falsepositive findings, resulting in an erroneous diagnosis. Patients with duodenal ulcer may have heartburn as well and often have symptoms during esophageal acid perfusion.64 This condition can cause diagnostic confusion if the ulcer is overlooked.

Edrophonium Test (Tensilon Test) The edrophonium test is used to identify chest pain of esophageal origin in patients in whom cardiac disease has been excluded. The cholinesterase inhibitor edrophonium HCl (Tensilon) is injected intravenously at a dose of 80 µg/kg not to exceed a total dose of 10 mg. A syringe with 1 mg of the antidote atropine always needs to be at hand while the test is performed. The test is ideally placebo controlled. The end point of the test is the patient’s chest pain and the similarity of the pain to that which is spontaneously experienced. A positive result is defined as replication of the patient’s chest pain within 5 minutes of the edrophonium injection but not after the placebo injection. The test is positive in 20% to 30% of patients with noncardiac chest pain but not in asymptomatic volunteers.65,66 In both, edrophonium causes a marked increase in amplitude and duration of esophageal contractions, but the end point of the test is the reproduction of the patient’s typical chest pain rather than a specific change in esophageal motility. The disadvantages of the test are that it is helpful in only a small portion of patients with chest pain, carries a risk of side effects, and reproduces symptoms with an unphysiologic stimulus.67 The test should not be performed in patients with asthma, chronic obstructive airway disease, or cardiac arrhythmias.

Esophageal Balloon Distention Test First described in 1955 as a diagnostic test to distinguish esophageal from cardiac chest pain,68 the balloon distention test has received interest as a useful esophageal provocative test.69-71 An inflatable balloon is positioned 10 cm above the LES and gradually inflated with air in 10-mL increments. The balloon must be completely deflated between two consecutive inflations to avoid esophageal accommodation. Esophageal motility is simultaneously monitored above and below the balloon. The test result is considered positive when typical symptoms are reproduced with distention of the balloon to volumes less than those required to produce pain in normal subjects. One study has indicated that the test reproduces chest pain episodes in up to 48% of patients with noncardiac chest pain

131

132

Section 2 Investigation of Esophageal Disease

but not in volunteers.71 Although the test has a greater diagnostic yield than provocative drug studies, it is relatively invasive and provides no information on spontaneously occurring symptoms.

AMBULATORY 24-HOUR MOTILITY MONITORING OF THE DISTAL ESOPHAGUS Technique The intermittent and unpredictable occurrence of motor abnormalities and symptoms in patients with esophageal motility disorders limits the diagnostic value of standard manometry performed in a laboratory setting over a short time period. The new technique of prolonged esophageal manometry was developed to overcome these shortcomings. Because of the high sampling frequency required to evaluate esophageal motor activity (at least 4 Hz),72,73 prolonged outpatient monitoring of esophageal motility became available only after the introduction of portable digital data recorders with a large storage capacity. Today, ambulatory manometry allows the evaluation of esophageal motor function based on more than 1000 contraction sequences monitored under a variety of physiologic conditions (i.e., upright activity, eating, and sleeping). The technique was introduced in the mid 1980s, and first pioneering recorders stored the data on an analogue basis on a magnetic tape, from which analogue paper tracings were obtained.74 Early solid-state digital dataloggers either had to perform on-line reduction of pressure data75 or only allowed the recording of two pressure signals for a limited period of time (3-4 hours). In this latter situation, an intermittent recording (i.e., 128 seconds, every 17 minutes, or whenever the patient pressed an event marker) was necessary to monitor the patient over a complete circadian period.76 Even though the intermittent recording showed good correlation and reli-

FIGURE 9-19 Prolonged esophageal motility monitoring is performed with three electronic microtransducers positioned 5, 10, and 15 cm above the upper border of the lower esophageal sphincter (LES). An additional microtransducer is located in the pharynx, to detect pharyngeal swallows. Concomitant pH monitoring of the distal esophagus (electrode 5 cm above the LES) and of the stomach (electrode 5 cm below the LES) can be performed. This procedure allows a complete ambulatory foregut physiologic monitoring. UES, upper esophageal sphincter.

ability with the continuous recording, the latter certainly represents a better choice. Furthermore, to characterize the esophageal contraction sequence, the use of only two recording sites may be insufficient. The omission of a pharyngeal transducer prevents the ability to detect pharyngeal swallows because external devices such as microphones are unreliable. Continuous hardware progress has now provided dataloggers with high storage capacity (4.0 megabytes), allowing 24-hour continuous recording of three esophageal and one pharyngeal pressure channels along with contemporary recording of two pH channels for complete foregut physiologic ambulatory monitoring (Fig. 9-19). The test is performed on an outpatient basis. After the standard stationary manometry, a 7-Fr catheter with four electronic microtransducers (Sentron, Amsterdam, The Netherlands) is passed through the nose into the esophagus. The three distal transducers, 5 cm apart from each other, are positioned 5, 10, and 15 cm above the upper border of the LES. The most proximal transducer, 10 cm apart from the others, is located in the cricopharyngeal area, to record pharyngeal swallowing. The transducers are calibrated at 0 and 50 mm Hg by immersion in a water column before and after the test. To ensure test reliability, eventual drifts must not exceed 8 mm Hg. The transducers are connected to a portable digital datalogger (Microdigitrapper 4.0, Medtronic, MN), and data are stored at an 8-Hz sampling rate. After placement of the catheter, patients are sent home and encouraged to perform normal daily activity. They are instructed to keep a detailed diary for the next 24 hours. It needs to indicate the time of meals, when they assume the supine position for sleep, when they arise in the morning, and when symptoms occur. After the test, the raw data are transferred to a computer for further analysis. Approximately 1000 to 1400 contractions are recorded by each pressure transducer over the 24-

Pharyngeal transducer UES 10 cm Proximal 5 cm Middle 5 cm Esophageal pH probe

Distal 5 cm

LES 5 cm Gastric pH probe

Esophageal transducers

Chapter 9 Function Tests

hour period, and a fully automated analysis of such a large amount of data is mandatory. We have developed and validated against manual analysis a software program for automated computer analysis of 24-hour esophageal motility monitoring.77 In brief, the esophageal baseline is reset every 60 seconds according to the mode value for that time period. Contraction recognition is based on an algorithm that defines a contraction as a rise in pressure greater than a threshold value for a specified period of time. An amplitude threshold of 15 mm Hg and a duration threshold of 1 second showed the best sensitivity and specificity for contraction detection. Most of the artifacts (e.g., cough, sneeze) are usually rejected by these thresholds. Algorithms based on contraction slope and morphology are employed to differentiate artifacts and repetitive contractions. Recognized contractions are then related to each other in esophageal sequences or waves and are classified as follows: 1. Peristaltic 2. Simultaneous (if the propagation speed exceeds 20 cm/ second) 3. Interrupted (a sequence lacking a contraction in the proximal or middle esophageal channel but reappearing in the last channel) 4. Dropped (a sequence in which the contractions are present only in the proximal and/or middle channel but absent in the distal one) The esophageal sequences are also related to a pharyngeal swallow and further classified as primary or secondary. The final report graphically displays amplitude, duration, propagation speed, and characteristics of the detected contractions against a background of normal, for the total period of the test and, separately, for predefined periods, that is, meal periods, upright and supine periods, and pain or gastroesophageal reflux–related periods. Furthermore, because to clear the esophagus of a liquid bolus esophageal contractions must be peristaltic and have adequate amplitude (Kahrilas, Dodds, Hogan, 1988),45 a classification of sequences as effective (peristaltic contractions with amplitude >20, 25, and 30 mm Hg, respectively, at 15, 10, and 5 cm above the LES), possibly effective (peristaltic contractions with amplitude less than these values but higher than 15 mm Hg), and ineffective (simultaneous, interrupted, or dropped contractions) can be obtained for the overall and specific periods. The program allows a complete quantitative and qualitative evaluation of the patient’s esophageal motility during an entire circadian cycle.

Clinical Applications Noncardiac Chest Pain Since its introduction in 1985, ambulatory esophageal manometry has been primarily used to identify esophageal motility abnormalities as the cause of noncardiac chest pain.12 Initial experience often showed a direct correlation of esophageal motor abnormalities with spontaneously occurring chest pain episodes.74,78 These patients were, however, highly selected and analysis techniques were inadequate owing to limited experience with normal asymptomatic baseline

recordings.79 Later studies in a larger number of unselected patients showed that many patients do not experience spontaneous chest pain episodes during the 24-hour monitoring period. In those who do, only a small number had motor abnormalities associated with the symptom.80-82 In our experience, 33% of patients with a history of noncardiac chest pain had at least one pain episode during 24hour esophageal motility monitoring.83 When a spontaneous episode of chest pain occurred during the monitored period, motor abnormalities were rarely associated with the symptom in patients with normal motor activity or a nonspecific motor disorder during their symptom-free period. Short episodes of gastroesophageal reflux may have been responsible for the symptom in these patients.84 On the other hand, patients whose motor function during the asymptomatic period was consistent with nutcracker esophagus or diffuse esophageal spasm frequently showed an even more severe esophageal motor abnormality in association with spontaneous chest pain episodes as compared with their own asymptomatic baseline motor activity (Fig. 9-20). Esophageal contractions of abnormal high amplitude or long duration have been suggested to be responsible for esophageal chest pain.85 Contrary to this belief, ambulatory motility monitoring in our patients showed that amplitude and duration of esophageal contractions associated with chest pain episodes were similar to contractions during the asymptomatic recording periods. Rather, it showed that the abnormal motor activity associated with the pain episodes is characterized by an increased frequency of contractions immediately preceding and during the symptom. In contrast to asymptomatic periods, these contractions are mainly simultaneous, double peaked, and triple peaked; they have a high amplitude or are of long duration. These observations suggest that, similar to that of the heart, esophageal blood supply may be interrupted during bursts of abnormal esophageal contractions, especially if the resting blood flow to the esophagus is already compromised, as shown for the hypertropic esophageal muscle in patients with severe esophageal motor disorders.86 A burst of disorganized motor activity in this situation may give rise to ischemic pain. Consequently, chest pain caused by a burst of uncoordinated esophageal motor activity under ischemic conditions has been termed esophageal claudication.87

Primary Esophageal Motor Disorders Current identification and classification of esophageal motor disorders are based on an increased frequency of abnormal contractions after 10 wet swallows on stationary manometry. Ambulatory 24-hour esophageal manometry multiplies the number of esophageal contractions available for analysis and provides an opportunity to assess esophageal motor function in a variety of physiologic situations, such as sleep and awake states and during meal periods. This method should increase the accuracy and dependability of the measurement compared with standard manometry. Studies have been done in large series of consecutive patients that compared the diagnoses obtained by both stationary manometry and ambulatory motility monitoring.

133

Section 2 Investigation of Esophageal Disease

FIGURE 9-20 A, Frequency of patients who experience at least one episode of chest pain during ambulatory 24-hour esophageal manometry and their underlying motor abnormality as diagnosed by 24-hour manometry. B, Number of patients who had abnormal esophageal motor activity associated with noncardiac chest pain that varied statistically outside their underlying motor activity during the symptom-free period. DES, diffuse esophageal spasm; NCE, nutcracker esophagus; NEMD, nonspecific esophageal motor disorder. (FROM STEIN

Normal 23% Achalasia 8% No chest pain during the study. N = 52

NEMD 19%

Spontaneous chest pain N = 26

NCE 19%

DES 31%

A

HJ, DEMEESTER TR, EYPASCH EP, KLINGMAN RR: AMBULATORY 24-HOUR ESOPHAGEAL MANOMETRY IN THE EVALUATION OF ESOPHAGEAL MOTOR DISORDERS AND NONCARDIAC CHEST PAIN. SURGERY 110:753, 1991.)

NUMBER OF PATIENTS WITH CHEST PAIN

10

8

6

4 75% 80%

2 50%

20%

17%

NEMD

Normal

0 Achalasia

DES

NCE

Chest pain associated with abnormal motor activity

B

Chest pain not associated with abnormal motor activity

Surprisingly, there was little agreement between the two tests.83 Ambulatory manometry frequently documented a more severe motor abnormality in patients thought to have normal esophageal motor function, a nonspecific motor disorder, or nutcracker esophagus on standard manometry (Fig. 9-21). This finding appears to be a result of the intermittent expression of esophageal motor abnormalities, which can be missed easily on standard manometry. Yet ambulatory manometry also frequently showed normal or only mildly disordered circadian motor function in patients thought to have a nonspecific disorder or nutcracker esophagus on standard manometry, suggesting that the unphysiologic conditions under which standard manometry is performed may trigger these abnormalities in patients known to have a low anxiety threshold.88 A change in diagnosis was less prevalent in patients who met the criteria for diffuse esophageal spasm or achalasia on standard manometry. This finding would indicate that a failure of peristalsis on standard manometry is a reliable indicator for the presence of a severe motor disorder. These observations also suggest that a more accurate classification of esophageal motor disorders can be made by ambulatory motility monitoring than by standard manometry.

Normal 24-Hour Manometry

134

NEMD NCE DES Achalasia Achalasia

NCE NEMD DES Standard Manometry

Normal

FIGURE 9-21 Classification of esophageal motor disorders in 108 patients with dysphagia and/or noncardiac chest pain according to the findings on standard or ambulatory 24-hour manometry. DES, diffuse esophageal spasm; NCE, nutcracker esophagus; NEMD, nonspecific esophageal motor disorder. (FROM STEIN HJ, DEMEESTER TR, EYPASCH EP, KLINGMAN RR: AMBULATORY 24-HOUR ESOPHAGEAL MANOMETRY IN THE EVALUATION OF ESOPHAGEAL MOTOR DISORDERS AND NONCARDIAC CHEST PAIN. SURGERY 110:753, 1991.)

Chapter 9 Function Tests

In the absence of esophageal obstruction, dysphagia is a common symptom in patients with esophageal motor disorders. The underlying pathophysiologic abnormality responsible for the symptom is not always readily apparent on stationary manometry.89 Ambulatory 24-hour esophageal motility monitoring has shown that amplitude and duration of contractions in the esophageal body are not significantly different among volunteers, patients without dysphagia, and patients who have dysphagia but no evidence of obstruction on endoscopy or barium swallow.90 In all groups, the frequency of esophageal contractions increased from the supine, to upright, to meal periods but was not different among the groups. In volunteers and patients without dysphagia, this increase was caused by an increase in the frequency of peristaltic contractions. This cause was not evident in patients with dysphagia, who had an increase in contraction but a significantly decreased frequency of peristaltic contractions during meals compared with both other groups. Less than 60% of peristaltic contractions during meal periods were associated with a 92% prevalence of dysphagia, suggesting that dysphagia in patients with no esophageal obstruction may result from the inability to organize esophageal motor activity into peristaltic contractions during meal periods. The prevalence of “effective contractions” (peristaltic contractions with an amplitude above 30 mm Hg during meals) during meal periods in normal individuals and patients with and without dysphagia is shown in Figure 9-22; 91% of the patients with dysphagia had 50% or fewer effective contractions during meals, whereas 84% of normal individuals and patients without dysphagia had more than 50% effective contractions during meal periods. When the percentage of effective contractions drops below 50, the patient is likely to experience dysphagia. Such patients may benefit from the use of prokinetic agents. When the esophageal motor activity is severely compromised because of a high prevalence of simultaneous contractions, patients usually receive little

“EFFECTIVE” CONTRACTIONS DURING MEALS 100

Percentage

80

†

benefit from medical therapy. In these patients, a surgical myotomy of the esophageal body can improve the dysphagia, provided that the loss of contraction amplitude of the existing peristaltic waveforms caused by the myotomy has less effect on the swallowing function than the excessive simultaneous contraction had before the myotomy. Experience has shown that this situation is reached when the prevalence of effective contractions during meals drops below 30%.

Gastroesophageal Reflux Disease Esophageal motor activity is the most important factor in the clearance of refluxed gastric contents. Simultaneous manometry and videofluoroscopy have shown that in the distal esophagus peristaltic contractions with a minimum amplitude of 30 mm Hg are required to completely occlude the esophageal lumen and propel a liquid barium bolus.45 This finding is confirmed by studies using combined esophageal pH and motility monitoring, which showed that the duration of a spontaneously occurring reflux episode is directly related to the frequency of peristaltic esophageal contractions with sufficient amplitude after the onset of the reflux episode (Fig. 9-23).91 These studies suggest that ambulatory esophageal motility monitoring allows evaluation of esophageal clearance function by assessing the prevalence of efficient esophageal contractions, that is, peristaltic contractions with an ampli-

12.0

9.6

Frequency (no./min)

Nonobstructive Dysphagia

7.2

4.8

2.4

60 * 40

⎧20 ⎨ ⎩0

0 0 Normal volunteers Pat, no dysphagia Pat, dysphagia

FIGURE 9-22 Prevalence of “effective contractions,” or peristaltic contractions with an amplitude above 30 mm Hg during meal periods in normal individuals, in patients without dysphagia, and in patients with nonobstructive dysphagia. *, experience dysphagia; †, when myotomy likely to be beneficial; Pat, patient.

8

16 24 32 Reflux Duration (min)

40

FIGURE 9-23 Frequency of esophageal contractions per minute versus duration of single reflux episodes derived from seven healthy volunteers. Each square represents one reflux episode. Transformation of frequencies (y axis) into 1/frequency and linear regression of resulting data. (FROM BUMM R, FEUSSNER H, EMDE C: INTERACTION OF GASTROESOPHAGEAL REFLUX AND ESOPHAGEAL MOTILITY IN HEALTHY MEN UNDERGOING COMBINED 24-HOUR MANO/PH-METRY. IN LITTLE AG, FERGUSON MK, SKINNER DB [EDS]: DISEASES OF THE ESOPHAGUS. MOUNT KISCO, NY, FUTURA, 1990, P 101.)

135

Section 2 Investigation of Esophageal Disease

30 sec

7 pH 4

mm Hg mm Hg

1 60

60

mm Hg

COSTANTINI M, DEMEESTER TR, ET AL: SECONDARY PERISTALSIS IS RARE AND IS NOT IMPORTANT IN CLEARING THE ESOPHAGUS OF REFLUXED GASTRIC ACID. GASTROENTEROLOGY 102:A30, 1992.)

ESOPHAGEAL pH

60

mm Hg

FIGURE 9-24 Twenty-four-hour ambulatory esophageal motility and pH record in a normal subject. A gastroesophageal reflux episode (top tracing) was rapidly cleared by two swallows (S, second tracing) that initiated effective contractions (P) in the esophageal body (primary peristalsis). Note that the first contraction sequence (S) after the occurrence of the reflux was not initiated by a swallow and represents a secondary contraction that appeared to be simultaneous. The combined esophageal motility and pH monitoring with swallowing detection revealed that secondary contractions actually play little role in esophageal clearance. (FROM BREMNER RM,

60

S

S

15 cm above LES S

P

P

P

0 10 cm

S

5 cm

S

P

P

P

P

P

0 P

0

tude above 30 mm Hg, over an entire circadian cycle (Figs. 9-24 and 9-25). Application of ambulatory 24-hour esophageal motility monitoring in a series of patients with increased esophageal acid exposure and various degrees of esophageal mucosal injury shows that esophageal contractility deteriorates with increasing severity of esophageal mucosal injury (Fig. 9-26).92 This deterioration appears to occur secondary to persistent reflux across a mechanically defective LES and results in a marked increase in the frequency of inefficient esophageal contractions during the supine, upright, and meal periods, particularly in patients with a stricture or Barrett’s esophagus. In this instance, the compromised clearance activity prolongs esophageal exposure to refluxed gastric juice, as also indicated by the increased frequency of reflux episodes lasting longer than 5 minutes in these patients. Thus, a vicious circle is established. Deteriorated contractility also affects propul-

sion of swallowed food; and once contractility is lost, it is not recovered with treatment, even after a successful antireflux operation (Fig. 9-27). A surgical correction of the underlying defect (i.e., of the mechanically defective LES) early in the course of the disease is indicated. Once effective contractility has been lost, the surgical approach may have to be altered by a repair with minimal outflow obstruction (a partial fundoplication). This appears to be necessary only if the global contraction amplitude drops below 20 mm Hg.

STANDARD ACID REFLUX TEST The acid reflux test attempts to induce reflux by loading the stomach with acid and having the subject perform four maneuvers in four different positions.93 It assesses LES competence rather than the degree of spontaneously occurring reflux.

ESOPHAGEAL pH 1 min. 7 pH 4 1 mm Hg mm Hg

Swallows 30

30

mm Hg

FIGURE 9-25 Twenty-four-hour ambulatory esophageal motility and pH record in a patient with erosive esophagitis showing a gastroesophageal reflux episode (top, drop in pH from 6 to 2), with prolonged clearing time as a result of ineffective body motility. Repetitive swallows (S) elicited esophageal contractions of very low amplitude, which on only a few occasions reached the threshold amplitude of 15 mm Hg to be recognized by the computer. I, isolated contraction; P, peristaltic contractions; S, simultaneous contractions; X, low-amplitude contraction.

S

Swallows

0

30

mm Hg

136

30

S SS

S

S S

S

S

S

S

S

S

0 15 cm above LES S X

X

0 10 cm S

P

I

X

0

0

5 cm

P

P

P

S

S S

Chapter 9 Function Tests

FIGURE 9-26 A, Median contraction amplitude in the distal esophagus in normal volunteers and patient groups during the supine, upright, and meal periods. Stricture or Barrett’s esophagus versus all other groups, P < .01. B, Percentage of nonperistaltic contractions in normal volunteers and patient groups during the supine, upright, and meal periods. Normal volunteers versus all other groups, P < .05; esophagitis or stricture versus no esophagitis, P < .05. GERD, gastroesophageal reflux disease. (FROM STEIN

70

Normal volunteers GERD, no esophagitis GERD, esophagitis

Contraction amplitude (mm Hg)

60 50 40 30

HJ, EYPASCH EP, DEMEESTER TR, ET AL: CIRCADIAN ESOPHAGEAL MOTOR FUNCTION IN PATIENTS WITH GASTROESOPHAGEAL REFLUX DISEASE. SURGERY 108:769, 1990.)

20

GERD, stricture 10

GERD, Barrett’s

0

A

Supine

Upright

Meal

Supine

Upright

Meal

Normal volunteers GERD, no esophagitis GERD, esophagitis GERD, stricture

Nonperistaltic contractions (%)

100

80

60

40

20

GERD, Barrett’s

B

0

After manometry, a pH electrode is placed 5 cm above the upper border of the LES. The manometry catheter is then advanced temporarily into the stomach and 300 mL of 0.1 N HCl is infused. In children, the volume of acid load is reduced accordingly. The pH of the esophagus is monitored while patients rest quietly in the supine position and then while performing four maneuvers: deep breathing, Valsalva, Mueller (inspiration against a closed glottis), and cough. These maneuvers are repeated in the right and left lateral decubitus position and with the head down 20 degrees, giving 16 possibilities for acid reflux to occur. A decrease in esophageal pH to less than 4 is considered evidence of reflux. At the beginning of the test, before the patient is placed in the supine position, the distal esophagus must have a pH greater than 4. This requirement has necessitated that the patient stand erect and swallow repeatedly to clear the esophagus of acid. Patients who cannot clear the esophagus in the erect position after 20 effective swallows, monitored on a motility tracing, are considered to have an abnormal result in all positions and maneuvers and are scored as 16. The algorithm for performing the test is shown in Figure 9-28.

In healthy volunteers, more than two reflux episodes during the test rarely occur. Accordingly, 1 or 2 drops in pH during these 16 challenges to the cardia are considered normal, and 3 or more drops in pH are taken as evidence of mechanical incompetence of the cardia. Patients with severe reflux may be unable to clear acid from the esophagus after reflux has been documented.9 When evaluated in a test population with an equal distribution of normal healthy subjects and patients with classic symptoms of GERD, the standard acid reflux test had a sensitivity (i.e., the ability to detect the disease when known to be present) of 59% and a specificity (i.e., the ability to exclude the disease when known to be absent) of 98%. This finding gave a predictive value of a positive test of 96% and a negative test of 75% with an overall accuracy of 81%.94

AMBULATORY 24-HOUR pH MONITORING OF THE DISTAL ESOPHAGUS Prolonged esophageal pH monitoring was first described by Miller10 in a publication on gastric pH monitoring. Ten years later, it was used to quantitate the actual time the esophageal

137

138

Section 2 Investigation of Esophageal Disease

200 175 150

mm Hg

125 Normal range (5th – 6th percentile)

100 75 50 25 0 Before Fundoplication

After Fundoplication

FIGURE 9-27 Mean amplitude of contractions of the distal 15 cm of the esophagus in patients before and 42 months after Nissen fundoplication. No improvement was noted in patients with a preoperative mean contraction amplitude below the 10th percentile or 35 mm Hg. (FROM STEIN HJ, BREMNER RM, JAMIESON J, DEMEESTER TR: EFFECT OF NISSEN FUNDOPLICATION ON ESOPHAGEAL MOTOR FUNCTION. ARCH SURG 127:788, 1992.)

mucosa is exposed to gastric juice.11 Subsequently, it was shown that the test also assessed the ability of the esophagus to clear the refluxed acid juice and documented the relationship between esophageal exposure to gastric juice and the symptoms experienced by the patient.13 A small pH electrode is passed transnasally and placed 5 cm above the upper border of the LES, previously mea-

FIGURE 9-28 Procedure to be followed after a reflux episode in the performance of the standard acid reflux test. (FROM FUCHS KH,

sured by manometry. Different probes are available, but bipolar glass electrodes are preferred for their greater reliability95 and the elimination of the need for an external reference electrode. The electrode is connected to an external portable solid-state datalogger, and pH values of the distal esophagus are continuously recorded at 4-second intervals for 24 hours, a complete circadian cycle. Precalibration and postcalibration of the system at pH 1 and 7 are important to exclude electrode drift over the period of the study.96 All medications interfering with gastric acid secretion must be discontinued at least 48 hours before the test begins. A washout period of at least 1 week, and in some situations up to 2 weeks, is necessary in patients treated with proton pump inhibitors because of their long-lasting action (Fig. 9-29). The test is performed on an outpatient basis, preferably while the subject is attending normal activities. The patient is requested to remain in the upright position (or sitting) while awake during the day, lying down supine only at night while sleeping, and to ingest two meals at the usual time. The diet is standardized only in the absence of food or beverages with a pH value less than 5.0 and greater than 6.0. Only water is allowed between meals. Patients are also instructed to keep a detailed diary of their symptoms during the study to correlate them with episodes of gastroesophageal reflux. They are asked to record the time when retiring for the night and when rising in the morning. Figure 9-30 shows a typical esophageal pH-monitoring trace in a healthy subject and in a patient with GERD. It is important to emphasize that 24-hour esophageal pH monitoring should not be considered a test for reflux but, instead, a measurement of the esophageal exposure to gastric juice (i.e., of the amount of time the esophageal pH is below a given threshold during the 24-hour period). This expres-

Reflux on positioning or after a maneuver

Unable to clear

DEMEESTER TR, ALBERTUCCI M: SPECIFICITY AND SENSITIVITY OF OBJECTIVE DIAGNOSIS OF GASTROESOPHAGEAL REFLUX DISEASE. SURGERY 102:575, 1987.)

Sit patient upright

Clear

Unable to clear

Replace in position

Stand patient erect

Clear Remain clear Spontaneous reflux Proceed with next maneuver

Count all maneuvers in the position as positive and proceed to clear and move to next position

Cleared by swallows

Proceed with next maneuver

Unable to clear after 20 swallows—consider patient to have free reflux

Chapter 9 Function Tests

sion, however, does not reflect how the exposure has occurred; for example, it may have occurred in a few long or several short reflux episodes. Consequently, two other assessments are necessary: the frequency of the reflux episodes and their duration. For this reason, esophageal exposure to gastric juice is best assessed by the following measurements11:

BAO (mmol/hr)

10

1. Cumulative time the esophageal pH is below a chosen threshold expressed as the percent of the total, upright, and supine monitored time 2. Frequency of reflux episodes below a chosen threshold expressed as number of episodes per 24 hours 3. Duration of the episodes expressed as the number of episodes greater than 5 minutes per 24 hours 4. The time in minutes of the longest episode recorded

Sleep

21:00

00:00

Dinner

3:00

Sleep

9:00

21:00

00:00

3:00

9:00

42

This formula is used to score each of the six components of the 24-hour pH record obtained from the 50 normal subjects. The score for each component is added to obtain a composite score for each of the 50 normal subjects, and the upper level of a normal score is established at the 95th percentile. The upper limits of normal for the composite score for each whole number pH threshold are shown in Table 9-4. The median and 95th percentile for the composite score for each whole number pH threshold can also be expressed graphically (Fig. 9-33). An IBM-compatible program to perform this function is available from Medtronic (Minneapolis, MN). ROC analysis, in which sensitivity is plotted against specificity for a given test, was applied to each of the six parameters and to the composite score, using pH 4 as the threshold. Both the total percentage of time the pH is below 4 and the composite score were found to have optimal specificity and sensitivity.98 However, there was a difference in normal FIGURE 9-30 Twenty-four-hour pH monitoring of the distal esophagus in a healthy subject (top) and in a patient with esophagitis (bottom). Physiologic gastroesophageal reflux episodes occur in a normal subject, mainly in the upright position and after meals. The patient’s record shows the presence of an increased number of reflux episodes, both in the upright and supine positions, some of them with prolonged clearing time. 12:00

Breakfast

6:00

14 21 Days After Cessation of Therapy

Component score = patient value − mean/standard deviation + 1

pH 4

18:00

7

can be awarded points based on whether it is below or above the normal mean value for that component. The formula used for performing the calculation, illustrated in Figure 9-32, is as follows:

7

1

3

GASTROENTEROLOGY SOCIETY, CONGRESS ABSTRACT, 1992.)

Breakfast

6:00

2

FIGURE 9-29 Range and median of basal acid output (BAO) in 10 duodenal ulcer patients after a 4-week course of omeprazole (20 mg/ day). Even after 6 weeks, there were patients with a basic acid output of 0. (FROM MARKS IN, YOUNG GO, WINTER T, ET AL: SOUTH AFRICAN

pH 4

18:00

4

Pre

7

1 15:00

6

0

Normal values for these six components of the 24-hour record at each whole-number pH threshold were derived from 50 asymptomatic control subjects. The upper limits of normal were established initially at the 95th percentile97 and later using percentiles selected by receiver operator characteristic (ROC) analysis.98 Figure 9-31 shows the median and the 95th percentile of the normal values for each component. If the values of symptomatic patients are outside the 95th percentile of normal subjects, they are considered abnormal for the component measured. Most centers use pH 4 as the threshold. With this threshold there is a uniformity of normal values for the six components from centers throughout the world.96,99 This finding indicates that esophageal acid exposure can be quantitated and that normal individuals have similar values despite nationality or dietary habits. The normal values for the six components obtained in 50 healthy volunteers are shown in Table 9-3. To combine the result of the six components into one expression of the overall esophageal acid exposure below a pH threshold, a pH score can be calculated by using the standard deviation (SD) of the mean of each of the six components measured in the 50 normal subjects as a weighting factor.100 By accepting an abstract zero level 2 SDs below the mean, we can treat the data measured in normal subjects as though they have a normal distribution. Thus, any measured patient value can be referenced to this zero point and, in turn, Dinner

8

12:00

139

Time of Upright Monitored Period (%)

80 60 40 20 0

A

100 80 60 40 20 0 0 1 2 3 4 5 6
6
7
8 9 pH Threshold

B 100 No. of Episodes

100 80 60 40 20

80 60 40 20

0

0 0 1 2 3 4 5 6
6
7
8 9 pH Threshold

C

0 1 2 3 4 5 6
6
7
8 9 pH Threshold

D

25

200

20

160 Minutes

TR: PROLONGED OESOPHAGEAL PH MONITORING. IN READ NW [ED]: GASTROINTESTINAL MOTILITY: WHICH TEST? PETERSFIELD, ENGLAND, WRIGHTSON BIOMEDICAL, 1989, P 41.)

100

0 1 2 3 4 5 6
6
7
8 9 pH Threshold Time of Supine Monitored Period (%)

FIGURE 9-31 A-F, Graphic display of the six components of the composite pH score showing the median and 95th percentile levels in 50 normal individuals using whole pH values above and below 6 as thresholds. The blue area represents measurements made in the patient. The dotted line shows the median, and the solid line, the 95th percentile value for the 50 normal subjects. When the blue area exceeds the 95th percentile line for a given pH threshold, the patient has an abnormal value for the component measured. A, Percent cumulative exposure for total time. B, Percent cumulative exposure for upright time. C, Percent cumulative exposure for supine time. D, Number of episodes in 24 hours. E, Number of episodes longer than 5 minutes. F, Duration of longest episode. (FROM DEMEESTER

Time of Total Monitored Period (%)

Section 2 Investigation of Esophageal Disease

No. of Episodes
5 min. in Length

140

15 10 5

120 80 40

0

E

0 0 1 2 3 4 5 6
6
7
8 9 pH Threshold

values between males and females when only the percentage total time the pH is below 4 was used. Consequently, the sex of the subject must be taken into account in borderline situations when the percentage total time that pH below 4 is used to express esophageal acid exposure. The composite score value is applicable to both males and females. The detection of increased esophageal exposure to acid gastric juice is more dependable than that of alkaline gastric juice. The latter is suggested by an alkaline exposure above pH 7 or 8. Increased exposure in this pH range can be caused by any of the following: 1. Abnormal calibration of the pH recorder 2. Presence of a dental infection that increases salivary pH

F

0 1 2 3 4 5 6
6
7
8 9 pH Threshold

3. Presence of esophageal obstruction that results in static pools of saliva with an increase in pH secondary to bacterial overgrowth 4. Presence of regurgitation of alkaline gastric juice into the esophagus (Stein et al, 1992)101 Combined gastric and esophageal pH monitoring in this situation increases the reliability of the test in detecting alkaline reflux. By analyzing the pH data of patients with GERD using the time of exposure to different pH intervals (e.g., pH 0-1, 1-2, 2-3), we have found that increased esophageal exposure to pH 0 to 2 and pH 7 to 8 was associated with mucosal injury (esophagitis, stricture, Barrett’s esophagus) in 89% of

TABLE 9-3 Normal Values for Ambulatory Esophageal pH Monitoring in 50 Healthy Volunteers

Mean

Standard Deviation

Median

Minimum

Maximum

95th Percentile

% Total time with pH < 4

1.5

1.4

1.2

0

6.0

4.5

% Upright time with pH < 4

2.2

2.3

1.6

0

9.3

8.4

% Supine time with pH < 4

0.6

1.0

0.1

0

4.0

3.5

19.0

12.8

16.0

56.0

46.9

Number of episodes >5 min

0.8

1.2

0

0

5.0

3.5

Longest episode (min)

6.7

7.9

4.0

0

46.0

19.8

Composite score

6.0

4.4

5.0

0.4

18.0

14.7

Number of episodes

2.0

Chapter 9 Function Tests

TABLE 9-4 Composite Score for Various pH Thresholds (95th Percentile)

6 5 SD

4.41 4

4 SD 3

3 SD

2

Scoring Units

pH Threshold

95th Percentile

pH < 1

14.2

pH < 2

17.4

pH < 3

14.1

pH < 4

14.7

pH < 5

15.8

pH < 7

14.9

pH < 8

8.5

2 1

SD 1

0 SD

0 Normal Values

Patient Value

FIGURE 9-32 Concept of using the standard deviation (SD) as the unit to score esophageal acid exposure (in this example, the percentage of total time the pH was below 4). Note the establishment of an abstract zero point 2 SD below the mean value for percentage of time the pH was less than 4 in normal volunteers. This method allows scoring the measurement in patients as though the normal values were parametric. By this method, a patient who had a percentage of time with a pH less than 4 of 4.8% would have a score for this component of 4.41. (FROM JAMIESON JR, STEIN HJ, DEMEESTER TR, ET AL: AMBULATORY 24-HOUR ESOPHAGEAL PH MONITORING: NORMAL VALUES, OPTIMAL THRESHOLDS, SPECIFICITY SENSITIVITY, AND REPRODUCIBILITY. AM J GASTROENTEROL 87:1102-1111, 1992.)

patients.102 In a different group of patients,103 the amount of exposure to pH 1.5 to 2.5 in the supine position allowed for discrimination of the severity of the mucosal damage in 75% of the patients. Therefore, 24-hour esophageal pH monitoring is useful not only in diagnosing the presence of GERD but also in predicting the presence of complications of the disease. In patients with symptoms of chronic cough, hoarseness, or aspiration, placement of an additional pH electrode in the proximal part of the esophagus or pharynx can be helpful.104 If reflux episodes reach to the proximal esophagus or pharynx and a temporary relationship between these reflux episodes and the onset of the symptom can be documented, GERD can be assumed to be the cause of the patient’s complaint.

AMBULATORY 24-HOUR ESOPHAGEAL BILIRUBIN MONITORING Reflux of alkaline duodenal contents into the stomach and up into the esophagus is increasingly recognized as an important pathophysiologic factor in GERD. About 25% of patients with GERD develop recurrent progressive disease manifested by advancing complications, from erosive esophagitis to

stricture, ulceration, and/or Barrett’s esophagus, while under medical therapy.105 Evidence is accumulating that the composition of the refluxed gastric juice plays an important role in the development of this progressive mucosal injury.106,107 Animal studies have shown marked augmentation of the acidinduced mucosal injury by the presence of components of duodenal juice.108,109 Clinical observations have shown that the prevalence of complications (e.g., esophagitis, stricture, and Barrett’s esophagus) in patients with GERD is related to an increased esophageal exposure to both acid and alkalinity, and the severity of these complications is greater in patients with acid-alkaline reflux than in patients with acid reflux alone.101 Prolonged esophageal aspiration studies have shown an increase in bile acids in patients with severe esophagitis and Barrett’s esophagus.110 These observations strongly suggest a noxious and synergistic role of components of duodenal juice in the refluxed gastric juice. An ambulatory monitoring system allowing spectrophotometric measurement of luminal bilirubin concentration has been developed.111 With bilirubin used as a marker, the time of esophageal exposure to duodenal contents can be mea20 16 Score

Time pH 4 Total Period (mean %)

5

12 8 4 0 0

1 2 3 4 5 6
6
7
8

9

pH Threshold FIGURE 9-33 Composite pH score used to express the overall results for esophageal pH monitoring for the pH thresholds shown. The dotted line represents median score; the solid line, the 95th percentile of 50 normal subjects. The blue area represents the score of a patient with increased esophageal acid exposure using the various pH thresholds as an indicator of reflux. A score for esophageal acid exposure of less than 4 is abnormal; for less than 3, it is increased but not above the 95th percentile line. (FROM DEMEESTER TR, STEIN HJ: GASTROESOPHAGEAL REFLUX DISEASE. IN MOODY FG, CAREY LC, JONES RC, ET AL [EDS]: SURGICAL TREATMENT OF DIGESTIVE DISEASE, 2ND ED. CHICAGO, YEAR BOOK MEDICAL PUBLISHERS, 1989, P 72.)

141

Section 2 Investigation of Esophageal Disease

sured. In the absence of carotene and serum lipids, the bilirubin concentration in a solution can be measured directly by spectrophotometry on the basis of its specific absorption at a wavelength of 453 nm.112 According to Beer’s law, absorbance (A) is the logarithm of the ratio between the intensity of light transmitted (I°) through a solution containing an absorbing substance and the intensity of light transmitted (I) in the absence of the absorbing substance: A = log(I°/I)

The apparatus used to measure the presence of bilirubin consists of a portable optoelectronic datalogger (80 C196KC, Intel, Santa Clara, CA) (1200 g), which can be strapped to the patient’s side, and a fiberoptic probe, which can be passed transnasally and positioned anywhere in the lumen of the foregut (Bilitec 2000, Medtronic, MN). The spectrophotometric probes are 3 mm in diameter and 140 cm in length, and they contain 36 plastic optical fibers (each 250 µm diameter), which are bonded together and covered with biocompatible polyurethane. Two plugs connect 50% of the optic fibers to the transmitting light-emitting diodes (LEDs) and 50% to the receiving photodiode. The tip of the probe contains a 2-mm space for sampling. Fluids and blenderized solids can flow easily through the space, and their bilirubin concentration can be measured. The probes are flexible, durable, easy to sterilize, and reusable. The optoelectronic unit acts simultaneously as a light signal generator, a data processor, and a data storage device. The unit has two channels, allowing dual measurement with two probes if desired. The light source for each channel is provided by two light-emitting diodes (Fig. 9-34), emitting a 470-nm signal light (blue spectrum) and a 565-nm reference light (green spectrum). Reference and signal light-emitting diodes are stimulated alternatively, for a duration of 0.5 second. To avoid fluctuations in the source, the final 20 ms of each pulse is used for signal processing. Optical signals reflected back from the probe are converted to electrical impulses by a photodiode. This electrical signal is then amplified and processed within the datalogger. Absorbance readings are averaged every two cycles. The system is capable of

FIGURE 9-35 Cumulative descending frequency distribution graph of the prevalence of total study time in which bilirubin was detected above distinct absorbance thresholds in 25 healthy subjects. Data are plotted as medians with the 25th and 75th percentiles. Based on this curve, the threshold absorbance of 0.2 was chosen as an indicator of the presence of bile in the esophageal lumen.

recording 225 individual absorbance values per hour and allows up to 30 hours of continuous monitoring.

AMBULATORY 24-HOUR ESOPHAGEAL PH AND BILIRUBIN MONITORING The fiberoptic probe to detect bilirubin is passed through the nose and positioned 5 cm above the upper border of the LES. Esophageal pH can also be recorded at the same time. Bilirubin absorbance is measured and recorded by the portable optoelectronic datalogger. Figure 9-35 shows the cumulative descending frequency distribution of 24-hour bilirubin exposure at distinct threshold values for absorbance in 25 normal subjects. An absorbance threshold of 0.2 is selected because at this level bilirubin was detected in the esophagus in fewer than 5% of healthy subjects. The fiberoptic probe is calibrated in water before and after monitoring. Records with bilirubin absorbance drift greater than 0.15 are discarded. Medications must be discontinued for 48 hours before testing, except for omeprazole, which must be discontinued at least 2 weeks earlier. With monitors in place, the patient is sent home and instructed to remain in the upright or sitting position until retiring for the night and to follow a special diet, which involves restriction to three meals a day com-

9.5 mm

2 mm FIGURE 9-34 Tip of the fiberoptic probe with a 2-mm space for sampling. Fluid can easily move into and out of the space, and the presence of bilirubin can be detected by its absorbance.

100

80 Total Time (%)

142

60

40

20

0 0

0.04

0.08

0.12

0.16

0.2 0.24 Absorbance

0.28

0.32

0.36

0.4

Chapter 9 Function Tests

FIGURE 9-36 Percentage of time of esophageal bilirubin exposure in 25 normal subjects for the total upright and supine time periods of a 24-hour study. The shaded blue area represents the normal range (95th percentile, upper limit of normal).

Time of Esophageal Bilirubin Exposure
0.2 (%)

14

12

10

8

6 4.0

4 2.9 2

0.4 0 Total Time

1

2

Upright Time

Composition of Refluxed Juice pH 5 6 3 4

Supine Time

8

7

Gastric juice

Prevalence (%)

54

Acid Pepsin

Mixed gastric and duodenal juice 80

Acid + Bile

57 Pepsin

Trypsin Duodenal juice

9

Bile

10

Probability of Mucosal Damage (%)

34

FIGURE 9-37 Prevalence of gastric acid reflux, gastroduodenal reflux, and duodenal reflux into the esophagus and the probability of mucosal injury based on the monitoring of 100 consecutive patients with gastroesophageal reflux disease defined by an increased esophageal exposure to acid and/or bilirubin.

Trypsin

posed of food free of a high bilirubin absorbance.111 The patient keeps a diary of food and fluid intake, symptoms, and the time of the supine and upright positions. The bilirubin absorbance data are analyzed with a commercially available software program (Medtronic, Minneapolis, MN). Esophageal bilirubin exposure in 25 normal subjects, all of whom were asymptomatic and had normal 24-hour ambulatory esophageal pH studies to exclude the presence of pathologic acid reflux, is shown in Figure 9-36. The median percentage time of esophageal bilirubin exposure over a 24-hour period in healthy subjects was 0.1%, and the 95th percentile value was 2.9%. The upright and supine exposure values differed slightly, with a 95th percentile of 4.0% and 0.4%, respectively. Values above the 95th percentile level among healthy subjects for the total 24-hour period are used

to identify increased esophageal exposure to duodenal juice in patients with foregut symptoms.113 Figure 9-37 shows the composition of the reflux juice, gastric, gastroduodenal, or duodenal, seen in 100 consecutive patients with GERD and its relationship to endoscopic evidence of mucosal damage.43 The reflux of duodenal juice is more common in patients with GERD than pH studies alone would suggest. The combined reflux of gastric and duodenal juice causes severe esophageal mucosal damage. The vast majority of duodenal reflux occurs at a pH of 4 to 7, at which bile acids, the major component of duodenal juice, are capable of damaging the esophageal mucosa.113 Consequently, duodenal juice adds a noxious dimension to the refluxed gastric juice and potentiates the injurious effects of gastric juice on the esophageal mucosa.114

143

Section 2 Investigation of Esophageal Disease

obtained by traditional gastric secretion studies (Stein et al, 1992).101 Evaluation of gastric emptying on the basis of the postprandial alkalinization of the gastric pH record is a new concept that evolved from multiple-probe gastric pH monitoring during gastric emptying studies with radiolabeled meals. These studies demonstrated a good correlation between the emptying of oatmeal and the duration of the postprandial plateau and decline phases of the gastric pH record (Stein, DeMeester, Hinder, 1992).119 A prolonged postprandial decline of the pH in the corpus may, however, also be caused by excessive postprandial duodenogastric reflux or a decreased meal-induced stimulation of acid secretion. To assess gastric emptying, the gastric pH record during and after a standardized dinner was assessed. A typical meal resulted in a rapid increase of the gastric pH from the interdigestive pH baseline (pH 1.1-1.6) to a pH between 4 and 7. This pH was maintained for approximately 10 to 20 minutes (plateau period). The plateau period was usually followed by a period of rapid decrease in the pH to approximately 1 pH unit above the baseline.120 This period was followed by a period of slow decline to the interdigestive baseline pH. Gastric emptying studies with a radiolabeled solid and liquid meal have shown that the postprandial pH profile in the corpus correlates closely with emptying of the liquid component of the meal from the stomach (Fig. 9-39). A prolonged postprandial alkalinization of the pH in the corpus may indicate delayed gastric emptying of solids (Fig. 9-40).119

AMBULATORY 24-HOUR GASTRIC PH MONITORING Functional disorders of the esophagus are often not confined to the esophagus alone but are associated with functional disorders of the rest of the foregut (i.e., of the stomach and the duodenum). Abnormalities of the gastric reservoir or increased gastric acid secretion can be responsible for increased esophageal exposure to gastric juice. Reflux of alkaline duodenal juice, including bile salts and pancreatic enzymes, is involved in the pathogenesis of esophagitis and the complication of stricture and Barrett’s esophagus. After the wide acceptance of 24-hour esophageal pH monitoring as the “gold standard” for assessing gastroesophageal reflux, much work has focused on 24-hour gastric pH monitoring as a clinical tool in the evaluation of gastroduodenal disorders. The interpretation of gastric pH recordings, however, is more difficult than that of esophageal recordings. The difficulty is greater because the gastric pH environment is determined by a complex interplay of acid and mucous secretion; ingested food; swallowed saliva; regurgitated duodenal, pancreatic, and biliary secretions; and the effectiveness of the mixing and evacuation of the chyme. Consequently, after its clinical introduction in the 1980s, gastric pH monitoring was used primarily to study the effect, optimal dose, and timing of antisecretory drugs when the calculation of median pH over a given period of time was sufficient.115 Ambulatory 24-hour gastric monitoring can also be used to evaluate the gastric secretory state of the patient. This monitoring is of particular value because the role of gastric acid secretion in the pathogenesis of GERD is well documented,117 and we have shown that 28% of patients with objectively proven GERD had gastric hypersecretion.118 To do so, we plotted the frequency distribution and the cumulative frequency distribution graphs of the pH data of the patient against the range (5th-95th percentiles) obtained in 50 healthy volunteers (Fig. 9-38). In our experience, this approach correlates well with the data

FIGURE 9-38 Cumulative frequency distribution of gastric pH values during the supine period. The shaded area represents the 5th and 95th percentiles of 50 healthy volunteers; the solid line shows the median. Patient M.G. with a duodenal ulcer (DU) had a shift of the median values above the normal range, suggesting gastric acid hypersecretion. Patient B.C. had a shift of the median values below the normal range, indicating hypochlorhydria. (FROM STEIN HJ, DEMEESTER TR, HINDER RA: OUTPATIENT PHYSIOLOGIC TESTING AND SURGICAL MANAGEMENT OF FOREGUT MOTILITY DISORDERS. CURR PROBL SURG 24:418, 1992.)

COMPLETE FOREGUT OUTPATIENT PHYSIOLOGIC MONITORING Many of the classic tests used to evaluate esophageal function described in this chapter have several shortcomings in the face of current technology. Standard manometry and provocative tests are performed in a laboratory environment, are

100 80 Time pH below (%)

144

60 40 20 0 0

0.6

1.2

1.8

2.4

3

3.6

4.2

4.8

5.4

6

6.6

pH Threshold Normal range (5th – 95th percentile) Patient M.G. (hypersecretor, DU) Patient B.C. (hypochlorhydria)

Median

Chapter 9 Function Tests

120

6 Solid emptying

Isotope in Stomach (%)

100

5

Liquid emptying 80

4

pH

60

3 pH

40

2

20

1

0

0

10

20

30

40

50

60

70 80 Minutes

90 100 110 120 130 140 150

0

FIGURE 9-39 Gastric emptying of a radiolabeled solid and liquid meal and simultaneously recorded pH values in the gastric corpus in 15 subjects. There is a close correlation between the emptying curve of the solid and liquid meal and the postprandial drop in pH measured by a pH electrode located 5 cm below the lower esophageal sphincter. (FROM STEIN HJ, DEMEESTER TR, HINDER RA: OUTPATIENT PHYSIOLOGIC TESTING AND SURGICAL MANAGEMENT OF FOREGUT MOTILITY DISORDERS. CURR PROBL SURG 24:418, 1992.)

6 Normal range (5th – 95th percentile)

pH from Baseline (pH units)

5

Patient J.B. (prolonged postprandial alkalinization) Median

4

3

2 1

0 0

15

30

45

60

75 90 Time (minutes)

105

120

135

150

FIGURE 9-40 Graphic report showing the time for the prandial plateau pH to return to preprandial gastric baseline pH measured as the difference in pH units from the preprandial baseline pH. Patient J.B. showed a markedly prolonged recovery time, suggesting delayed gastric emptying. (FROM STEIN HJ, DEMEESTER TR, HINDER RA: OUTPATIENT PHYSIOLOGIC TESTING AND SURGICAL MANAGEMENT OF FOREGUT MOTILITY DISORDERS. CURR PROBL SURG 24:418, 1992.)

unphysiologic, and restrict data sampling to short time periods. Consequently, the results of these tests are often inaccurate and symptoms are frequently misinterpreted as being psychogenic. Overall, the shortcomings of these classic laboratory tests account, at least in part, for the unsatisfactory results of surgical or medical management of patients with complex functional esophageal disorders. The development of miniaturized pH electrodes and electronic pressure transducers plus the introduction of portable digital data recorders with large storage capacity have made possible prolonged monitoring of luminal pH and motor activity of the foregut in an outpatient environment (Fig. 9-41). Ambulatory 24-hour monitoring of foregut pH and motility overcomes the limitations of the standard tests. It allows the recording of foregut function under physiologic

conditions over a complete circadian cycle. This monitoring increases the probability of recording disordered motility and episodes of spontaneous gastroesophageal reflux or duodenogastric reflux. It allows quantitation of the observed abnormalities and their direct correlation with spontaneously occurring symptoms. With the use of modern solid-state recording technology and computerized reading, prolonged foregut monitoring over periods of 24 hours has become safe to perform and easy to analyze. Broad clinical application of this new technology will replace the series of laboratory tests classically required to evaluate thoroughly foregut function. This new technology puts into the surgeons’ hands tools to evaluate complex foregut problems within their own offices and places surgical therapy for functional abnormalities of the foregut on a more scientific basis.

145

146

Section 2 Investigation of Esophageal Disease

FIGURE 9-41 Complete 24-hour foregut ambulatory monitoring in a healthy subject. From top to bottom: esophageal pH record, gastric pH record, compressed pharyngeal swallowing record, and compressed esophageal motility record at 15, 10, and 5 cm above the lower esophageal sphincter (LES). Increase in swallows and esophageal motility with meals is evident, together with the typical rise in gastric pH (prandial plateau), followed by slow return to the baseline (postprandial decline phase). During sleep, a marked reduction in swallowing and esophageal activity is normal.

Esophageal pH 7 4 2 Gastric pH 7 4 2 Swallows

Sleep

Dinner

Breakfast

80 mm Hg 0 15 cm above LES 80 mm Hg 0 10 cm 80 mm Hg 0 5 cm 80 mm Hg 0 14:00

18:00

COMMENTS AND CONTROVERSIES Drs. DeMeester and Costantini have provided an excellent review of esophageal function testing. There also have been recent technologic advances that need to be mentioned.

High-Resolution Manometry High-resolution manometry uses a manometry catheter with pressure sensors placed every 1 cm from the pharynx to the esophagus. The increased data acquisition requires special computerized processing but allows real-time display as either conventional pressure plots or as a spatial-temporal pressure display. This new display allows pattern recognition of normal and abnormal esophageal motility. More importantly, localized motility or sphincter disorders missed with conventional manometry catheters can be identified and studied. Compared to conventional manometry, high-resolution manometry improves diagnostic accuracy.1

Impedance Esophageal multichannel intraluminal impedance (MII) testing is a new technique for the assessment of esophageal function.2-4 Measurement of impedance (resistance) to alternating current between two intraluminal electrodes allows detection of both direction and character of a bolus. During swallowing in normal patients, baseline impedance of the esophageal mucosa rises abruptly as air, which has high impedance, precedes the bolus. As the bolus follows, impedance decreases because food has high ionic content and, thus, high electrical conductivity. Esophageal impedance remains low until the bolus passes out of the segment. There is an overshot of impedance above baseline. This is an artifact, the result

22:00

2:00

6:00

10:00

of baseline mucosal impedance and the decreased esophageal cross-sectional area during peristalsis. The combination of manometry and MII and 24-hour pH monitoring and MII has allowed in-depth evaluation of motility disorders and the characterization of the refluxate in patients with complicated GERD. It is not regularly used in standard esophageal function testing.

Prolonged pH Monitoring The Bravo probe (Medtronic, Shoreview, MN) is a wireless pH monitor. The radiotelemetry pH probe is placed endoscopically and temporarily pinned to the esophageal mucosa 5 cm above the lower esophageal sphincter.5 Every 12 seconds, the probe transmits pH measurements to the receiver that is worn on the patient’s belt. A 48-hour record of pH is provided. This ambulatory system is convenient and comfortable for the patient. Whether it increases diagnostic accuracy over conventional pH monitoring has not been determined. It does increase the cost of this investigation. T. W. R. 1. Clouse RE, Staiano A, Alrakawi A, et al: Application of topographical methods to clinical esophageal manometry. Am J Gastroenterol 95:27202730, 2000. 2. Shay SS, Bomeli S, Richter J: Multichannel intraluminal impedance accurately detects fasting, recumbent reflux events and their clearing. Am J Physiol Gastrointest Liver Physiol 283:G376-383, 2002. 3. Tutuian R, Vela MF, Shay SS: Multichannel intraluminal impedance in esophageal function testing and gastroesophageal reflux monitoring. J Clin Gastroenterol 37:206-215, 2003. 4. Kahrilas PJ: Will impedence testing rewrite the book on GERD? Gastroenterology 120:1862-1864, 2001. 5. Pandolfino JE, Kahrilas PJ: Prolonged pH monitoring: Bravo capsule. Gastrointest Endosc Clin N Am 15:307-318, 2005.

Chapter 9 Function Tests

KEY REFERENCES Kahrilas PJ, Dodds WJ, Dent J, et al: Upper esophageal sphincter function during deglutition. Gastroenterology 95:52, 1988. ■ In this carefully designed study, the function of the upper esophageal sphincter during deglutition has been evaluated with concurrent manometry and videofluorography. Most of the current concepts on pharyngoesophageal function, namely the correlation between the morphoanatomic and the manometric aspects, are based on this paper. Kahrilas PJ, Dodds WJ, Hogan WJ: Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 94:73, 1988. ■ The application of combined manometry and videofluorography to the study of the esophageal body led the authors to relate the efficacy of esophageal peristalsis to the amplitude and propagation characteristics of esophageal contractions. This study gave new and relevant insights on esophageal body function. Stein HJ, Barlow AP, DeMeester TR, et al: Complications of gastroesophageal reflux disease: Role of the lower esophageal sphincter, esophageal acid and acid/alkaline exposure and duodenogastric reflux. Ann Surg 216:35, 1992.

■ In this paper, the authors assessed the importance of manometric evaluation of the

lower esophageal sphincter and of results of the 24-hour pH monitoring of the distal esophagus and the stomach in discriminating patients with GERD of varying severity. The clinical application of these tests is carefully outlined. Stein HJ, DeMeester TR: Indications, technique and clinical use of ambulatory 24-hour esophageal motility monitoring in a surgical practice. Ann Surg 217:128, 1993. ■ This paper represents a comprehensive description of the new technique of 24-hour esophageal motility monitoring, with particular relevance to its application in the diagnostic evaluation of patients with esophageal motor disorders, GERD, noncardiac chest pain, and nonobstructive dysphagia. Stein HJ, DeMeester TR, Hinder RA: Outpatient physiologic testing and surgical management of foregut motility disorders. Curr Probl Surg 24:418, 1992. ■ This monograph describes the pathophysiology and the diagnostic and therapeutic aspects of foregut motility disorders in detail. Particular attention has been paid by the authors to describing the traditional and modern tests available for a careful diagnosis and correct treatment of functional disorders of the esophagus.

147

chapter

10

CONGENITAL ANOMALIES Allan M. Goldstein Daniel P. Doody

Key Points ■ Esophageal atresia with tracheoesophageal fistula is the most

common developmental esophageal anomaly. ■ Esophageal atresia, with or without fistula, is a component of the

VACTERL association.

with one affected sibling have a 0.5% to 2% risk, and the risk rises to 20% when two siblings are affected.7 In addition, a number of chromosomal regions have been identified based on deletions, translocations, and duplications in affected cohorts.8 The recent mouse knockout models described later lend further support to a genetic basis of this condition.9,10

■ Search for associated cardiac and renal anomalies is mandatory

before surgery for esophageal atresia. ■ Most congenital esophageal anomalies can be surgically corrected

with minimal morbidity and mortality. ■ Treatment of long-gap atresia or complex laryngotracheoesophageal clefts is associated with prolonged hospitalization and significant morbidity. ■ Ideal operation for repair of long-gap esophageal atresia has not been established.

ESOPHAGEAL ATRESIA AND TRACHEOESOPHAGEAL FISTULA Historical Note Thomas Gibson1 described a child who, upon swallowing, “was liked to be choked, and what should have gone down returned by the mouth and nose.” In the 250 years since this first description of a patient with esophageal atresia and tracheoesophageal fistula there were multiple failed attempts at operative treatment of this anomaly (Gross, 1953).2,3 The futility encountered led many surgeons to conclude that children affected with this aberration were best left to die. In 1939, Leven4 and Ladd3 performed staged repairs involving gastrostomy and cervical esophagostomy, fistula ligation, and subsequent creation of an antesternal neoesophagus with successful outcomes. In 1941, Haight and Towsley (1943)5 used the left extrapleural approach to ligate the fistula and repair the esophagus primarily. Thus began the modern era of esophageal surgery in infants.

Epidemiology Esophageal atresia occurs in 1 to 2 of every 4000 live births, its incidence being slightly higher in males and in newborns of older or diabetic mothers.6 Various environmental influences have been implicated as causative, including (1) intrauterine exposure to contraceptive pills, progesterone, estrogen, or thalidomide and (2) the unique environment created by diabetes. Although the anomaly is usually sporadic, the occurrence of familial esophageal atresia is well recognized. Children born to an affected parent have a 3% to 4% risk, children

Embryology A thorough understanding of the developmental pathways leading to normal foregut anatomy is essential to comprehend tracheoesophageal anomalies and to improve their management in these infants. Although early development of the human foregut and its separation into intestinal and respiratory components remains poorly understood, meticulous analysis of thin sections of staged human embryos from the Carnegie Embryological Collection has been informative.11,12 On day 26 of human gestation, 6 days after the initial appearance of the foregut, the lung bud can be seen as a ventral outgrowth from the foregut (Fig. 10-1A). As the lung bud grows ventrally and caudally into the surrounding mesenchyme, it descends in front of the esophagus, leaving a mesenchymal layer (the tracheoesophageal septum) between these two epithelial tubes. The most cranial aspect of the septum, the tracheoesophageal sulcus, remains fixed at the level of the first cervical vertebra (between somites 5 and 6) throughout development (see Fig. 10-1B).11,12 In none of these observations of foregut morphogenesis was a common “esophagotrachea” identified. Therefore, the commonly postulated separation of a common channel into digestive and respiratory components by the ingrowth of lateral epithelial ridges may not apply to human embryonic development. Moreover, the tracheoesophageal sulcus, which marks the separation point of trachea from esophagus, does not extend rostrally, as previously thought. Instead, the sulcus remains fixed in position while the tracheal bifurcation descends.13 The aberrations of normal morphogenesis that give rise to esophageal atresia and tracheoesophageal fistula remain uncertain. However, a recently discovered experimental animal model enhances our understanding of this process. Intraperitoneal injection of pregnant rats with doxorubicin (Adriamycin) at 6 to 9 days of gestation (before lung bud formation on day 12) causes development of tracheoesophageal anomalies in 40% to 60% of offspring. Many of the newborn rats also have associated defects commonly seen in humans, including duodenal atresia, anorectal anomalies, and genitourinary defects.14-16 The majority (90%) of affected 151

152

Section 3 Pediatric Disorders

Notochord

Somites Notochord 1

Foregut

2 3 4

Fixed point at 5-6 somite

5 6

Heart

Heart

Lung bud

Liver Liver bud Lungs Midgut

A

B

Midgut

FIGURE 10-1 Lung bud formation during embryogenesis. Human embryos are depicted in the left lateral median plane. A, At Carnegie stage 12 (26-28 days after fertilization), the lung primordium buds from the foregut. B, At stage 13 (28-32 days after fertilization), the lung bud has started its caudal descent. The top of the tracheoesophageal septum is referred to as the tracheoesophageal sulcus. As the lung bud descends, this point remains fixed at the level of the fifth or sixth somite throughout development, corresponding to the level of the first cervical vertebra.

offspring exhibit esophageal atresia with a distal fistula, whereas the remainder have atresia without a fistula or an N-type fistula.14 The embryos with atresia and a distal fistula lack a tracheal bud, and the foregut itself gives rise to both main bronchi, as is observed in the rare cases of tracheal agenesis.17 The abnormal foregut in the affected rats continues caudally to the stomach.15,16 The doxorubicin-induced abnormality also appears similar to the most severe (type IV) laryngotracheoesophageal cleft observed in children.18,19 After treatment with doxorubicin, histologic examination reveals that the upper foregut, proximal to the origin of the bronchi, develops tracheal elements with ciliated pseudostratified columnar epithelium and cartilage, thereby comprising, in essence, a common esophagotrachea. The lower foregut demonstrates a variable transition from tracheobronchial to esophageal histology.15,16 This pattern is similar to that in humans20 and may account for the patient with a tracheoesophageal anomaly and coexisting severe distal esophageal stenosis with associated cartilaginous remnants. The abnormal histopathology in both the upper and lower foregut in the rat model may in some way be associated with the frequent clinical findings of tracheomalacia and esophageal dysmotility in children with esophageal atresia. The additional contribution of abnormal esophageal innervation to the dysmotility characteristic of the syndrome is appreciated but not fully understood.21,22 Doxorubicin-induced failure of lung bud formation may represent a defect in normal interactions between the epithe-

lium of the foregut and its surrounding mesenchyme. Two recent mouse knockout models lend support to this theory. Sonic hedgehog (Shh), expressed in the ventral foregut endoderm and in the early lung bud, is an evolutionarily conserved, secreted molecule that signals via serine/threonine kinase receptors to activate downstream genes essential to proper development and differentiation of numerous structures. Shh protein induces expression of Gli, a gene that encodes a transcription factor expressed in the mesenchyme surrounding the lung bud. Mice with mutations in either the Shh or Gli genes demonstrate foregut malformations strikingly similar to human esophageal atresia with tracheoesophageal fistula.9,10 Thus, these two genes may represent critical components of the epithelial-mesenchymal communication necessary for normal foregut morphogenesis. It would be interesting to investigate whether doxorubicin (an anthracycline anticancer agent that functions via such mechanisms as deoxyribonucleic acid intercalation, inhibition of topoisomerase II, cell membrane binding, and free radical formation) interferes with this pathway. One might then devise pathways for pharmacologic rescue of these defects if they are discovered sufficiently early in gestation. Current experimental data, both genetic and teratogenic, suggest a model for understanding the developmental etiology of esophageal atresia with tracheoesophageal fistula. Endoderm-mesoderm interactions are essential for signaling normal lung bud formation, initiating the development of the tracheobronchial tree from the esophagus. Failure of

Chapter 10 Congenital Anomalies

this critical early event, as occurs in the doxorubicin model, results in trachealization of the proximal foregut, with the main bronchi branching directly from this structure, and the foregut continues caudally to the stomach.9,15,16 Although many questions remain unanswered, these novel experimental models are yielding a new conceptual framework on which to advance our understanding of this fascinating anomaly. A full understanding of the genetics and pathways in which molecular defects occur can lead to improved prenatal and postnatal therapeutic strategies.

Classification Numerous classification schemes describe the anatomic arrangements seen in esophageal atresia, and these are variously referenced in the literature. We prefer to avoid using any classification that simply describes the anatomy of the esophagus and trachea. However, the more commonly used classifications of Ladd3 and Gross (1953)2 are summarized in Table 10-1.

ASSOCIATED CONGENITAL ANOMALIES Because the surgical and perioperative management of the tracheoesophageal disorder has improved dramatically in recent decades, the associated anomalies have become an increasingly important factor in the prognosis of these children. No longer are respiratory failure and sepsis primarily responsible for mortality; instead, the coexistence of severe congenital anomalies, particularly cardiac ones, has emerged as the major cause of death.23 Approximately 50% of all infants born with esophageal atresia, with or without tracheoesophageal fistula, can be expected to have additional anomalies, with a higher likelihood (58%) in infants with isolated atresia, compared with infants with an N-type fistula (27%).24 A careful search for these associated anomalies is crucial to the comprehensive evaluation and ultimate prognosis of these infants as well as to the formulation of a logical approach to their care. The incidence of associated anomalies is severalfold higher among infants weighing less than 2000 g, making the care of these children particularly challenging.

CARDIAC ANOMALIES Although associated defects have been identified in nearly every organ system, the most frequently encountered anomalies involve the heart. From 20% to 30% of infants with

esophageal atresia also have an associated cardiovascular anomaly (Waterston et al, 1962).6,24-26 The most common of the cardiovascular anomalies are listed25: ■ ■ ■ ■

Atrial and ventricular septal defects Patent ductus arteriosus Tetralogy of Fallot Aortic arch anomalies

The presence of coexisting complex congenital heart disease is a major factor accounting for mortality in these patients, reducing the usual survival from nearly 100%22 to 70%.8,25

GASTROINTESTINAL ANOMALIES Associated gastrointestinal anomalies occur in about 25% of patients with esophageal atresia, and most of these are easily repaired at the time of esophageal repair. The most common of these is anal atresia, accounting for 42% of all gastrointestinal anomalies in one series.24 Other defects include duodenal and ileal atresia, malrotation, Meckel’s diverticulum, annular pancreas, and pyloric stenosis.

URINARY TRACT ANOMALIES Abnormalities of the urinary tract have been identified in 24% of patients.23 Early identification of these anomalies in the neonate is essential to prevent potential renal damage. Anomalies frequently encountered include: ■ ■ ■ ■

Unilateral or bilateral renal agenesis or hypoplasia Multicystic kidney Horseshoe kidney Vesicoureteral reflux

NEUROLOGIC AND SKELETAL ANOMALIES Ten percent of patients have neurologic or skeletal anomalies, including neural tube defects, hydrocephalus, scoliosis, and other anomalies affecting the vertebrae and extremities.27

MULTIPLE CONGENITAL ANOMALIES Quan and Smith (1973)28 gave the nonrandom occurrence of multiple congenital anomalies in association with esophageal atresia the acronym VATER to denote vertebral anomalies, anal atresia, tracheoesophageal fistula with esophageal atresia, renal defects, and radial limb dysplasia. The acronym has been expanded to VACTERL to include cardiac and

TABLE 10-1 Types and Relative Frequencies of Tracheoesophageal Anomalies EA + Distal TEF

Isolated EA

“N-Type” TEF

EA With Proximal TEF

EA + Proximal and Distal TEF

Gross Classification

C

A

E

B

D

Ladd Classification

III/IV*

I

II

V

Frequency (%)

86.5

7.7

4.2

0.8

*Type III if fistula enters above tracheal bifurcation; type IV if fistula enters at carina. EA, esophageal atresia; TEF, tracheoesophageal fistula.

0.7

153

154

Section 3 Pediatric Disorders

limb (especially radial ray) defects as well. The VACTERL association (defined as the coexistence of at least three of these anomalies) occurs in approximately 15% of children with esophageal atresia and contributes to an increased mortality rate, particularly as a result of the cardiac anomalies.29,30 A less common and more severe group of anomalies associated with esophageal atresia is known as CHARGE, which includes coloboma, heart disease, atresia choanae, growth and developmental retardation, genital hypoplasia, and ear anomalies (deafness).31 Infrequently, esophageal atresia is present in the Schisis association (omphalocele, neural tube defects, cleft lip/palate, genital hypoplasia) or in other complexes such as trisomy 18 or 21, Potter’s syndrome, polysplenia, or Turner’s syndrome.30,32

E

T

PRESENTATION AND DIAGNOSIS Esophageal Atresia With or Without Tracheoesophageal Fistula Suspicion of esophageal atresia often begins before birth, when a prenatal ultrasound study demonstrates polyhydramnios in association with a small or absent stomach.33 Polyhydramnios presumably results from the inability of the fetus to swallow amniotic fluid through the atretic esophagus. Consequently, pure atresia nearly always leads to maternal polyhydramnios. In those infants with a distal fistula, however, amniotic fluid may pass into the trachea and, via the fistula, reach the stomach, thereby accounting for the absence of polyhydramnios in many of these cases. Prematurity is often associated with esophageal atresia, with 40% of newborns weighing less than 2500 g.30 Within hours after birth, the infant demonstrates excessive drooling of saliva with pooling in the posterior pharynx. This is often followed by aspiration, with choking spells, respiratory distress, and cyanosis with the first feeding. If the aspiration is significant, apnea, bradycardia, and even death may ensue. The presence of a distal fistula often results in more severe respiratory distress as gastric secretions reflux into the tracheobronchial tree, causing pneumonitis and the potential for sepsis. The infant displays excessive salivation from the nose and mouth as well as noisy breathing. The abdomen appears scaphoid in the presence of pure esophageal atresia. If a distal fistula is present, air can enter the stomach via the trachea and may distend the abdomen. A thorough physical examination, including cardiac auscultation, evaluation of the extremities and spine, and digital rectal examination, commonly reveals associated anomalies. A firm 10-Fr catheter passed gently through the mouth of the infant typically meets resistance at about 10 cm. A plain radiograph shows the catheter tip in the proximal esophageal pouch, giving a rough indication of the length of the esophageal gap. The barking cough typical of infants with tracheoesophageal fistula, with or without esophageal atresia, is secondary to associated tracheomalacia. The structure of the trachea can be abnormal, with staple-shaped cartilaginous rings and

FIGURE 10-2 Contrast study demonstrating N-type tracheoesophageal fistula. Contrast swallow in an infant with recurrent pneumonias demonstrates an N-type fistula (arrowhead) between the trachea (T) anteriorly and the esophagus (E) posteriorly. Note that the tracheal end of the fistula is superior to the esophageal end.

a widely redundant membranous mucosa, permitting apposition of the anterior and posterior walls and producing the barking cough.34 Abnormal tracheal development has been attributed to the loss of normal tracheobronchial pressure during lung development as pulmonary amniotic fluid is lost through the fistula into the esophagus.35 Trachealization of the foregut during early development, however (see previous topic), more likely accounts for the abnormal structure and function of the trachea.

Isolated Tracheoesophageal Fistula The rare tracheoesophageal fistula without esophageal atresia (3%-5% of cases) produces subtle symptoms, thus necessitating a high index of suspicion. Isolated tracheoesophageal fistula is also referred to as H-type or, more descriptively, N-type or diagonal fistula to describe the higher insertion of the fistula on the trachea (Fig. 10-2). Coughing and choking occur with feeding, and reflux of gastric fluid into the trachea produces a tracheobronchial pneumonitis that is often bilateral and recurrent.

Chapter 10 Congenital Anomalies

S FIGURE 10-3 Radiograph demonstrating esophageal atresia. Chest radiograph of a newborn with esophageal atresia after attempted placement of a nasogastric tube. Arrowheads mark the air-filled proximal esophageal pouch.

Treatment Preoperative Management Prior to operation for esophageal atresia or tracheoesophageal fistula, the surgeon must carefully delineate the anatomy, search for associated anomalies, and treat comorbid conditions to optimize the infant’s ability to tolerate definitive esophageal repair. A plain radiograph after passage of an esophageal tube can outline the size and shape of the proximal esophageal pouch (Fig. 10-3). In exceptional cases, dilute barium may be used to demonstrate the proximal pouch, but it must be administered with caution and promptly removed to avoid aspiration. The use of water-soluble contrast is contraindicated. Air in the abdomen confirms the presence of a distal fistula, whereas an absence of air suggests pure atresia. Coexisting duodenal atresia may explain air in the stomach and proximal duodenum but not in the remainder of the bowel (Fig. 10-4). Plain films may also reveal the presence of pneumonia, an abnormal cardiac contour suggesting congenital heart disease, or the existence of skeletal abnormalities. It is also mandatory to search for a right-sided aortic arch, the presence of which dictates a left-sided approach to avoid operative catastrophe. The diagnosis of a fistula without esophageal atresia can be more challenging. Chest films may show aspiration pneumonitis with distention of the stomach. The diagnosis can occa-

FIGURE 10-4 Radiograph of coexisting esophageal and duodenal atresia. Plain radiograph of a newborn with esophageal atresia demonstrates the nasogastric tube coiled in the proximal esophageal pouch. The air in the stomach confirms the presence of a tracheoesophageal fistula to the distal esophagus. However, the bowel gas pattern demonstrates a “double bubble” with air in the stomach (S) and proximal duodenum (arrowhead) and no air distally. These findings are consistent with duodenal atresia.

sionally be made with contrast esophagography with the patient in the prone position with the head slightly down. A tube is placed in the distal esophagus, and contrast is injected as the tube is gradually withdrawn. Often, bronchoscopy and esophagoscopy may be required for a definitive diagnosis to be made. The routine search for associated anomalies must include an echocardiogram because of the high incidence of associated heart disease, a renal ultrasound study to detect kidney abnormalities, and a voiding cystourogram to detect vesicoureteral reflux.36 Chromosomal analysis should be obtained in infants with multiple associated anomalies. Infants with esophageal atresia and tracheoesophageal fistula are kept in a semiupright sitting position to minimize reflux of gastric acid through the fistula and into the trachea. A soft sump catheter placed in the atretic esophageal pouch with frequent oropharyngeal suctioning can minimize aspirations. Infants with isolated esophageal atresia can be safely

155

156

Section 3 Pediatric Disorders

placed in the prone position, since their only risk is aspiration of saliva. Systemic antibiotics, usually ampicillin and gentamicin, should be administered empirically. If pneumonitis is present and severe or if the infant has concomitant respiratory distress syndrome, endotracheal intubation and mechanical ventilation may be necessary. In this situation, prompt gastrostomy prevents continued reflux into the trachea and avoids massive gastric distention from passage of air through the fistula and into the stomach. Failure to vent the stomach effectively, as by inadvertent twisting or clamping of the gastrostomy tube, can result in gastric perforation. Unfortunately, the gastrostomy vent may make effective pulmonary ventilation difficult, particularly in infants who require high-pressure ventilation. This situation may force early thoracotomy for ligation of the fistula and, if tolerated, esophageal repair. Definitive repair need be delayed only in the rare infant who is severely unstable.37 Preoperative risk stratification schemes have been developed according to the severity of illness and the expected outcome of infants with esophageal atresia with or without tracheoesophageal fistula (Table 10-2). The risk factors thus identified are useful for assessing an infant’s prognosis and for giving parents realistic expectations. Moreover, these stratification schemes can serve as guidelines for surgical management while also allowing the comparison of outcomes among institutions. The Waterston prognostic classification,26 devised in 1962, is primarily of historical interest. In that era, survival was adversely affected by severe pneumonia, significant associated anomalies, or low birth weight. Fortunately, modern neonatal care has greatly improved the outcome of these infants and rendered these criteria less relevant. As a result, a variety of more appropriate classification schemes have been proposed. Randolph and colleagues38 found that the cardiopulmonary status of the infant, independent of birth weight or coexisting anomalies, was highly predictive of mortality and could serve to select those patients appropriate for early primary repair. All “physiologically stable” infants, defined as those with the absence of a major cardiac anomaly or severe pulmonary compromise, underwent primary esophageal repair with

100% survival. The remaining one third of infants were deemed “physiologically unstable,” requiring initial gastrostomy with delayed primary or staged repair. This group experienced an overall survival of 77%. Their liberalized stratification scheme permitted a greater number of early primary repairs than would have been performed using Waterston’s classification. In a larger and more recent series, 393 infants were grouped on the basis of (1) birth weight greater than or less than 1500 g and (2) the presence or absence of major cardiac anomalies. As shown in Table 10-2, survival was directly related to these two risk factors.8,32,39 On the basis of these findings, further improvements in the survival of children with esophageal atresia will depend largely on additional advances in the treatment of complex congenital heart disease and in the care of very-low-birth-weight infants. The majority of infants can undergo primary esophageal repair with division of the fistula within the first few days of life. Prior to surgery, complete preoperative evaluation is performed while maintaining aggressive pulmonary care, oropharyngeal and proximal pouch suctioning, and systemic antibiotics. A variety of scenarios do not allow for early primary repair. For example, delayed or staged repair is sometimes necessary in the case of long-gap esophageal atresia (see later). Infants with severe pulmonary compromise who require mechanical ventilation may benefit from an initial gastrostomy and, on rare occasions, emergent thoracotomy with fistula ligation, with definitive repair delayed until the pulmonary status improves. Similarly, newborns with severe associated anomalies, profound prematurity, sepsis, or any other significant complicating medical condition may benefit from a period of support, including early gastrostomy to prevent further gastrotracheal reflux. Infants with significant congenital heart disease present a difficult challenge. In deciding how to manage esophageal atresia in these patients, Mee and colleagues25 divided the infants into two groups. For those not dependent on a patent ductus arteriosus for their pulmonary or systemic circulation, early esophageal repair can proceed. In duct-dependent infants, the infusion of prostaglandin E to maintain duct

TABLE 10-2 Risk Stratification Schemes

Classification

Study Years

No. Patients

Waterston et al26

1946-1959

218

Randolph et al38

1982-1988

37

1: physiologically stable 2: physiologically unstable (major cardiac anomaly or severe pulmonary disease)

Poenaru et al30

1969-1989

95

I: patients not in Class II II: life-threatening anomalies or major anomalies with preoperative ventilatory dependence

93 31

Spitz et al8,32

1980-1994

393

I: wt >1500 g II: wt <1500 g or major congenital heart disease III: wt <1500 g and major congenital heart disease

96 60 18

Subgroup Stratification A: wt > 5.5 lb B: wt 4.0-5.5 lb or wt > 5.5 lb with pneumonia or other anomaly C: wt < 4.0 lb or severe pneumonia or significant congenital anomaly

Survival (%) 95 68 6 100 77

Chapter 10 Congenital Anomalies

patency may allow for early esophageal repair. Those infants who do not improve benefit from initial corrective heart surgery. Division of the fistula and gastrostomy placement can be performed at the time of cardiac surgery when indicated. In these severely compromised infants, definitive esophageal repair should be delayed.

Operative Management—Primary Repair The focus here is on repair of long-gap esophageal atresia, because this operation requires multiple maneuvers for successful primary repair, including those maneuvers used when the esophageal gap is much shorter. A bronchoscopic study is routinely performed at the beginning of the procedure in order to do the following: ■ ■ ■ ■

Locate the fistula Identify any undiagnosed upper fistulas Assess the presence and severity of tracheomalacia Position the endotracheal tube, if possible, distal to the fistula yet above the carina

The procedure we describe is the standard open approach. Thoracoscopic repair has been demonstrated to be feasible, with the added advantages of improved cosmesis and avoidance of a thoracotomy.40-42 With the chest, abdomen, neck, and upper arm included in the operative field (Fig. 10-5A), a posterolateral thoracotomy is made 1 cm below the tip of the scapula on the right side, except in the case of a rightsided aortic arch. The incision should stay in the inframammary crease so as not to scar the breast. The chest is entered via the fourth intercostal space, although the third may be better for a high proximal pouch. If necessary, the surgeon can retract the skin incision inferiorly so that the chest can also be entered at the fifth or sixth intercostal space (see Fig. 10-5A) to help when the distal esophagus is being mobilized. We recommend an extrapleural approach, because this limits any esophageal leak to the retropleural space. The surgeon carefully dissects the pleura away from the chest wall using moist cottontipped applicators, from the apex of the chest to several interspaces below the incision and posteriorly to the mediastinum. The azygos vein is divided and the vagus nerve identified and preserved as it courses along the side of the esophageal pouches. The mediastinal pleura is retracted anteriorly until the trachea is exposed (see Fig. 10-5B). The distal esophagus is then identified and circumscribed with a vessel loop to inhibit the air leak through the fistula if this is impairing ventilatory support. Dissection of the upper pouch is facilitated if the anesthetist inserts an oroesophageal tube and pushes the proximal esophagus toward the operator. The surgeon dissects the upper pouch into the neck, taking care to identify any proximal fistula. If the esophageal gap is so large as to preclude approximation of the two segments, circular myotomies can be made in the proximal pouch to increase esophageal length (see Fig. 10-5C). One to three myotomies can be made, each adding up to 1 cm of length to the esophagus.43,44 If a very high pouch is not easily accessible through the chest, the

pouch can be delivered through a neck incision to facilitate performance of the myotomies.45 The fistula is then isolated and divided, and the tracheal side is closed with interrupted fine long-term absorbable suture. The distal esophagus is dissected sufficiently to allow approximation to the upper pouch. Despite the canonical belief that the distal pouch should not be mobilized because of fear of interfering with its segmental blood supply, we find that dissection even through the esophageal hiatus can be done without mishap and may permit an otherwise impossible primary anastomosis, a finding that has been supported by others.46 The proximal pouch is opened, and a single-layer end-toend anastomosis is fashioned with interrupted 5-0 absorbable sutures (see Fig. 10-5C). In the absence of a gastrostomy tube, a feeding tube is carefully passed across the anastomosis into the stomach and fixed at the nose before the anterior closure is completed. If a gastrostomy tube is already present, then a suction tube is left just above the anastomosis. A retropleural drain is placed near the repair and is sutured to the posterior chest wall to prevent direct contact with the anastomosis. Feedings via a gastrostomy tube or a transanastomotic feeding tube can be initiated early postoperatively. A barium swallow is performed on the sixth to seventh postoperative day before initiating oral feedings. If a small leak is present, the infant is not fed orally and a repeat swallow study is performed 1 week later. The drain is removed once the swallow study is normal and oral feedings are initiated. Every attempt should be made to achieve primary repair because esophageal continuity is superior to any substitute yet devised. If the determination is made preoperatively that the esophageal gap is too large to permit early esophageal repair, then delayed primary anastomosis, following an initial gastrostomy tube and continuous upper pouch suctioning, can be performed.47-49 Daily upper pouch bougienage can be used to help augment growth of the proximal atretic segment.50 Delayed primary repair is the preferred approach for many surgeons when dealing with long-gap atresia but has the disadvantage of requiring a prolonged hospitalization before surgery, often up to 3 to 4 months, to permit suctioning of accumulated saliva from the upper pouch. Alternative approaches to primary repair in the setting of long-gap atresias have been proposed. One approach is termed multistage extrathoracic esophageal elongation. This procedure begins with an initial proximal esophagostomy, fistula ligation, and gastrostomy tube. Every 2 to 3 months the esophagostomy is moved further distally along the anterior chest wall to lengthen the proximal pouch. Gaps of up to seven vertebral bodies have been bridged using this approach.51,52 A second technique uses external traction sutures tied to each pouch and exteriorized through the chest wall. Traction on the sutures allows the esophageal ends to be pulled closer together about 1 to 2 mm daily. By using this approach, gaps up to 5 cm have been repaired within 2 weeks.53

Operative Management—Esophageal Replacement In those infants in whom early or delayed primary anastomosis is not possible, esophageal replacement is appropriate.

157

Section 3 Pediatric Disorders

Sternocleidomastoid muscle

4

5

2

Single skin incision adjustable for third or fifth interspace

3

Neck incision if necessary for mobilization of upper esophagus

1

A

Upper body and arm prepped and draped Third interspace

Lift arm

B Long gap High upper pouch

Carina

Through neck incision

C

1, 2, or 3 circular myotomies over upper pouch tube

Lengthen

3rd

2nd

Lung

rib

FIGURE 10-5 Surgical repair of long-gap esophageal atresia. A, A right posterolateral thoracotomy incision is shown. Most esophageal atresias are repaired through the fourth intercostal space. In a longgap atresia, the proximal pouch may be very high, necessitating use of the third interspace, as shown. The surgeon can retract the same skin incision inferiorly to enter the fifth or sixth interspace to dissect the distal segment. Exposure of the trachea and both esophageal segments (B) allows assessment of the gap length. Circular myotomies (C) can be made in the proximal pouch to increase esophageal length. Myotomies extend through the muscular layers without injuring the submucosa, where the blood supply runs. Gentle traction on the esophagus further increases the length obtained. The distal esophagus can be mobilized down through the hiatus in the diaphragm if necessary. The surgeon performs a single one-layer anastomosis using 5-0 absorbable suture, accepting tension to avoid having to resort to interposition grafts.

1st

158

Azygos vein

Lower esophagus

Through chest incision

Fifth interspace

Chapter 10 Congenital Anomalies

Although generally performed for malignancy in adults, esophageal replacement in children is for benign disease, and therefore the conduit must remain functional for a lifetime. Options for esophageal replacement include stomach, small intestine, and colon. Of these, the colon interposition is the most widely used in pediatrics. This operation involves using either the right colon based on the ileocolic vessels and passed retrosternally54 or the left transverse colon based on the left colic vessels and passed through the left chest.55,56 Pyloroplasty is generally added to decrease stasis in the colon. Colonic interposition is associated with several complications, the most common of which are anastomotic leaks and strictures. A recent review of 26 studies on colon interposition found an average rate of 29% and 19%, respectively, for these postoperative complications.57 One of the long-term issues is that the intrathoracic colon has a tendency to become redundant over time, leading to delayed emptying, stasis, and, ultimately, dysphagia.55,58 The stomach can also be used effectively as an esophageal replacement. One approach is the reversed gastric tube, whereby the greater curvature of the stomach is tubularized and, based on the left gastroepiploic artery, passed through the chest in an antiperistaltic fashion.59 The principal advantages of this operation are the use of a well-vascularized conduit that maintains its shape and does not develop the redundancy of the colon interposition. However, the gastric tube procedure is associated with a significant risk for leaks (69%) and strictures (53%), as well as reflux and the development of peptic ulcers.57,60 Gastric transposition offers an alternative technique.61,62 Although frequently used in adults, this procedure is less common in children. One advantage of the gastric pull-up is that it requires only a single anastomosis and avoids the need for the long suture line used to create the gastric tube. Leaks and strictures continue to be a problem, occurring in 21% and 22%, respectively.57 The use of jejunal interposition is mentioned for completeness, although it is infrequently used in infants, primarily because of the precariousness of the blood supply and the relative ease of using alternative conduits. The procedure is performed using a segment of jejunum based on its mesenteric blood supply.63

Complications Although there has been dramatic improvement in the survival of infants born with esophageal atresia, a significant number of complications are associated with tracheoesophageal defects and their repair (Table 10-3). Among the more common early postoperative complications is an esophageal anastomotic leak, which occurs in 15% to 20% of patients.64-66 Anastomotic leaks, which can result in sepsis and are associated with an increased risk for recurrent fistula and esophageal stenosis, should be suspected when frothy saliva appears in the chest tube. The diagnosis may be confirmed by oral administration of methylene blue and the dye’s appearance in the chest tube, while the size and location of the leak are delineated by contrast swallow. Conservative management is appropriate if the leak is small, because the majority of small leaks seal

TABLE 10-3 Complications Associated With Esophageal Atresia and Its Repair Complication

Incidence (%)*

Anastomotic leak

15-20

Recurrent fistula

3-10

Anastomotic stricture

10-35

Gastroesophageal reflux

55-82

Tracheomalacia

10-20

*See text for references.

spontaneously with proximal esophageal suctioning, adequate drainage, antibiotics, and parenteral nutrition. Major disruption of the esophageal or tracheal suture line is uncommon but should be suspected when the chest tube drainage is excessive or when a large air leak is present. In the absence of chest tubes, the presence of uncontrolled sepsis or a new effusion suggests the diagnosis. In these situations, operative intervention is mandatory to prevent or control progression of mediastinitis or empyema. Primary suture repair is feasible if the dehiscence is early (<3 days). In rare instances, if the anastomosis cannot be repaired, closure of the distal esophagus with proximal cervical esophagostomy should be performed, with definitive repair delayed for several months. Recurrent tracheoesophageal fistula occurs in 3% to 10% of infants64-67 and usually presents a few months after repair. Typical symptoms include cyanosis, wheezing, coughing or choking during feeding, and recurrent pneumonias. This spectrum of symptoms is also seen with a variety of other complications, including an unrecognized proximal fistula, anastomotic stricture, tracheomalacia, pharyngoesophageal dyskinesia, and gastroesophageal reflux. An esophagogram can be performed with iso-osmolar contrast injected through a feeding tube in the esophagus while it is slowly withdrawn. This study can identify these potential problems and should therefore be performed in all children with these symptoms. As with congenital fistulas, recurrent or missed fistulas can be difficult to diagnose and are potentially serious and life threatening. Contrast studies often confirm the diagnosis. Bronchoscopy, if necessary, must be done with great care to avoid disruption of the suture line. Operative intervention should follow, because spontaneous closure of these fistulas is unusual. Patients are explored via the neck for high fistulas (T1-T3, by far the most common) or via the chest for lower fistulas. Closure of both ends of the fistula must be accompanied by interposition of tissue flaps to prevent a second recurrence. The most reliable tissue interposition for fistulas that can be reached from the neck is the distal-based medial head of the sternocleidomastoid muscle.18 Other tissue flaps, such as pleural,68 pericardial,69 and intercostal muscle flaps,70 have been used but are less reliable. We have unfurled the parietal pleura if the retropleural approach can be employed.18

159

160

Section 3 Pediatric Disorders

Esophageal anastomotic stricture, which has been reported in up to 35% of patients,64 results from an anastomotic leak, gastroesophageal reflux, or primary repair performed under excessive tension, the latter being accepted in the interest of achieving a primary anastomosis. The symptoms of esophageal stricture include dysphagia, aspiration, and, in later childhood, food impaction, all of which can also be secondary to abnormal motility without an associated stenosis. Once a stenosis is identified by barium study, dilations, using either bougie dilators or balloon catheters, can safely and effectively treat the problem.71,72 Concomitant severe gastroesophageal reflux is often revealed after the stricture is dilated and must be suspected in the setting of recurrent or refractory strictures. Antireflux surgery is required in such cases. Esophageal resection may be necessary for treatment of a refractory stricture, particularly if the original anastomosis was for a long-gap esophageal atresia. Gastroesophageal reflux is a common complication after esophageal atresia repair. The patient presents with heartburn, dysphagia, vomiting, chronic coughing, and recurrent respiratory infections. Esophageal manometry and pH monitoring demonstrate the presence of reflux in 55% to 82% of patients, even decades after the operation.73-76 These tests in the evaluation of esophageal function may show disorganized peristalsis throughout the length of the esophagus, often associated with decreased lower esophageal sphincter tone.74,76 The presence of reflux in the setting of weak and uncoordinated peristalsis leaves these individuals unable to clear secretions effectively from the esophagus and, therefore, at high risk for recurrent aspiration pneumonia. The etiology of the esophageal dysfunction has been attributed to either a congenital defect in the development of esophageal innervation or excessive dissection of the lower esophageal pouch. However, intraoperative manometry shows motor incoordination of the esophagus even before surgical repair, supporting a congenital origin of the esophageal dysfunction.77 The presence of reflux in infants with isolated fistulas, in whom no dissection of an esophageal pouch is necessary, further supports an intrinsic defect in esophageal motility.75 Whether surgical dissection exacerbates this defect or whether traction on the distal pouch alters LES function remains unclear. However, aggressive dissection of the lower esophageal pouch to correct long-gap esophageal atresia does not appear to worsen the outcome of these infants. Given that the native esophagus is the best option for repair, we believe that this extensive dissection of the lower pouch is appropriate if it allows a primary anastomosis. The diagnosis of gastroesophageal reflux is confirmed by contrast study, with careful attention to other potential causes of the patient’s symptoms. Medical treatment, consisting of acid reduction, thickened feedings, and positional measures, is indicated in patients with symptomatic reflux. Unfortunately, 15% to 45% of these patients do not respond to medical therapy and ultimately require an antireflux procedure because of refractory symptoms, repeated pneumonia or pneumonitis, or recurrent esophageal anastomotic strictures.64,73,75,78,79 Traditionally, the Nissen fundoplication has been used as the procedure of choice; however, several groups

have noted a high incidence of severe dysphagia and recurrent reflux after this operation in patients who have undergone prior repair of esophageal atresia,79,80 with a mean failure rate of 30%.81 This high rate may result from esophageal motility that is too weak and disorganized to overcome the high resistance associated with a 360-degree wrap. Therefore, a loose wrap or a partial (Thal) fundoplication is more appropriate in these patients.78,81 Tracheomalacia describes a weakness of the tracheal cartilage that permits easy apposition of the anterior and posterior walls during coughing or expiration. The condition occurs in 15% of patients with esophageal atresia64 (some earlier studies suggest that some tracheomalacia is present in an even higher percentage). Tracheomalacia is a consequence of abnormal foregut development, giving rise to a trachea with diminished structural integrity due to abnormal cartilaginous rings and a redundant posterior membranous wall.82 Moreover, this flaccid trachea is easily compressed between the aorta anteriorly and the dilated upper esophageal pouch posteriorly.35 Symptoms may vary from mild expiratory stridor and a typical barking cough to recurrent pneumonias. Dying spells, characterized by cyanosis, apnea, and bradycardia, are the most serious problems and typically occur within minutes of a feeding. Because the symptoms may mimic those of gastroesophageal reflux, recurrent fistula, or anastomotic leak, bronchoscopy under anesthesia without muscle relaxation, demonstrating collapse of the lumen during spontaneous breathing, is essential for making the diagnosis. Airway fluoroscopy showing tracheal collapse during expiration is suggestive. Esophageal contrast studies also serve to exclude strictures, recurrent fistulas, or leak as the etiologic mechanism. Roughly 50% of patients with severe tracheomalacia require surgery, most commonly for dying spells, inability to extubate, or recurrent pneumonias. Milder symptoms usually improve significantly without surgery after about 1 year of life. The procedure of choice is aortopexy, performed through a left anterior thoracotomy, with suturing of the aortic arch to the posterior surface of the sternum, thereby opening the tracheal lumen.83,84 In the rare instance when aortopexy cannot resolve the tracheal collapse, splinting of the airway is warranted.85 The use of bronchoscopically placed airway stents has been reported in children and may offer an alternative approach.86,87

LARYNGOTRACHEOESOPHAGEAL CLEFT The laryngotracheoesophageal cleft is a rare midline congenital anomaly characterized by an extensive opening between the posterior surface of the larynx and membranous trachea and the anterior surface of the esophagus. The embryologic basis of this anomaly is unknown, although 20% to 50% of cases occur in association with esophageal atresia and tracheoesophageal fistula,88-90 suggesting a common developmental origin. The anomaly may be recapitulated by the doxorubicin rat model.15 A genetic basis is further supported by the description of a spontaneous mutation in the mouse that results in this disorder.91 Unfortunately, the defective gene remains unknown. Children with a cleft should

Chapter 10 Congenital Anomalies

be evaluated thoroughly for cardiovascular, gastrointestinal, and genitourinary anomalies, which accompany this defect and are often severe.89 The clefts are classified into four subtypes according to length of the defect and degree of difficulty of repair and management18,19,92: Type I clefts are limited to the larynx and may extend to the cricoid cartilage. Type II clefts extend through the cricoid to the cervical trachea. Type III clefts extend to the carina. Type IV clefts involve one or both mainstem bronchi. The severity of symptoms may vary with the extent of the cleft and are similar to those encountered in patients with tracheoesophageal fistula. The diagnosis is suspected in infants having immediate and severe symptoms, including choking, respiratory distress, and cyanosis with feeding. Aspiration pneumonia, caused by an incompetent laryngeal mechanism, occurs frequently and may be severe, particularly in those infants with extensive clefts. These infants also have a characteristic toneless cry, a result of the inability of the abnormal larynx to appose the vocal cords sufficiently to generate sound. Delayed diagnosis, which occurs all too often in this syndrome and is attributed to its rarity and subtle differences from the classic tracheoesophageal fistula, often leads to progressive and potentially irreversible respiratory damage. Contrast esophagography may suggest the diagnosis if rapid filling of the tracheobronchial tree is seen following a small dose (1 mL) of oral barium.68 If the bronchoscope falls posteriorly from the larynx into the upper esophagus during endoscopy, the diagnosis is confirmed.19,68 The precise extent of the cleft, as well as accurate measurements of the airway and the extent of tracheal malformation, can be assessed at the first bronchoscopy. For more extensive clefts, the surgeon should design a customized bifurcated endotracheal tube or a short-neck, right-angled tracheostomy tube to be used during and after the repair.19 As with infants with esophageal atresia and an associated fistula, these children should be nursed in an upright position to minimize reflux; to avert aspiration, they require continuous oropharyngeal sump suctioning. At the time of diagnostic bronchoscopy, if the lesion is type IV and the stomach is small, we recommend transecting the stomach with gastrostomy tubes placed proximally and distally to prevent further aspiration of gastric contents and to allow for enteral nutrition.18,19 This drastic step is required because, in our experience, microgastria does not improve with growth of the child, making severe reflux a constant and severe threat to these children.

Operative Management Various techniques are described for repairing the cleft, depending on its distal extent.

Type I and II Clefts Type I defects may be repaired endoscopically,89 whereas type II defects call for posterior or lateral pharyngotomy.

Although some espouse an anterior approach with division of the larynx and trachea in the midline, we avoid this approach because it requires another division of the cricoid, which is essential for stability of the upper airway.

Type III and IV Clefts Surgery for patients with complete laryngotracheoesophageal clefts (types III and IV) is challenging and necessitates careful planning to protect a precarious airway. At the beginning of the operation, the airway may need to be secured by a custom-fitted bifurcated endotracheal tube positioned bronchoscopically from above and suspended anteriorly with a No. 3 ureteral catheter loop placed through the tracheostomy site.18 A combined approach via a right posterolateral thoracotomy through the fourth intercostal space and a right cervical incision may be required. However, infants with the most severe type IV (and occasionally type III) clefts may have a foreshortened trachea, allowing adequate exposure of the full extent of the cleft through the cervical incision alone.19 A partial upper sternotomy can be added if necessary. The incision is made anterior to the right sternocleidomastoid muscle, and the pharynx, trachea, and esophagus are exposed. The surgeon then incises the right tracheoesophageal groove from the thoracic inlet to the carina, taking care to expose and protect the recurrent laryngeal nerve (Fig. 10-6A). From inside the cleft, the surgeon incises the left side of the esophagus 5 to 7 mm below the tracheoesophageal groove (see Fig. 10-6B), pushing aside the left periesophageal tissue to avoid injury to the left recurrent laryngeal nerve. The esophageal flap is rotated to the right (see Fig. 10-6C) to create the neomembranous trachea. The surgeon closes the esophagus and trachea longitudinally, starting at the most distal extent of the defect (see Fig. 10-6D) and continuing to the larynx. The surgeon exposes the laryngeal defect by entering the pharynx laterally and continues the repair cephalad (see Fig. 10-6E). The larynx is commonly more generous than expected. The edges of the membranous posterior defect of the larynx and upper trachea are freshened and then closed in two or three layers (see Fig. 10-6F) from the third tracheal ring to the top of the larynx in interrupted fashion. This step accurately reconstructs the cricoid and larynx. To deter fistula formation, the head of the right sternocleidomastoid muscle is divided cephalad and rotated on its distal base for placement behind the tracheostomy site and between the two suture lines beneath the pharynx.

Complications The postoperative course, particularly of infants with type IV clefts, is often complicated by severe tracheomalacia caused by malformed tracheal rings and a redundant membranous mucosa. The child with tracheomalacia requires prolonged mechanical ventilation to prevent the intermittent collapse of the trachea that occurs in the absence of positive pressure. We have been successful in discharging infants home with bifurcated tracheostomy tubes in place to prevent collapse of these “floppy” airways.19

161

Section 3 Pediatric Disorders

Right bronchus rotated upward

Left bronchus Left

op Es

ha

g

us

us ag h op

Es gus

nchus

Right bro

T

t pha ef eso Cl m o p fr us Fla ag h op es f o e id tf s Le L

F E L C Divide in groove and rotate up and left

B

A

R

Right

Right

Left

fla p

Left

Es op ha ge al

162

C

D

FIGURE 10-6 Surgical repair of a type IV laryngotracheoesophageal cleft. The surgeon begins a type IV cleft repair (A), most often done through the neck, by incising the right tracheoesophageal groove and rotating the trachea to the left. The surgeon incises the left side of the esophagus (B), leaving a U-shaped flap of esophageal wall, which is rotated to the right to close the bronchial and tracheal defects (C). The membranous trachea and the narrowed esophagus are closed in a caudocranial direction, each in a single layer with the suture lines displaced to avoid fistula formation (D).

In addition to tracheomalacia, the major complications encountered by these patients are postoperative tracheoesophageal fistulas and refractory gastroesophageal reflux.93 The interposition of bulky vascularized tissue has helped to decrease the incidence of recurrent fistulas. Microgastria, which is highly associated with type III and IV clefts, complicates the management of reflux, since fundoplication is not feasible. Early division of the stomach, as described earlier, prevents further reflux. Establishment of intestinal continuity can be performed at a later date, often with a Roux-en-Y

gastrojejunostomy using the proximal gastric pouch. Newer techniques of tissue engineering, it is hoped, may be used to enlarge the stomach or to stabilize or reconstruct the abnormal tracheal cartilages to reduce the prolonged morbidity imposed by severe tracheomalacia. The long-term outlook for survivors of the type IV clefts depends largely on early diagnosis and correction of the defect, meticulous perioperative management of the infant, and continued growth and stabilization of the airway. The outlook for infants with type III defects without microgastria

Chapter 10 Congenital Anomalies

Thyroid cartilage Cricoid

Epiglottis Inferior cornu Vocal cords Superior cornu

E Superior cornu

Inferior cornu

Cricoid joined posteriorly

Tracheostomy site anteriorly

Space for interposition of sternocleidomastoid muscle head

Epiglottis Esophagus repaired Pharynx opened 3-layer closure of posterior larynx

F FIGURE 10-6, cont’d With the larynx rotated anteriorly and to the left, the laryngeal cleft (E) is repaired (F) in three layers. The medial head of the sternocleidomastoid muscle is interposed between the repairs and behind the tracheostomy site.

should be good and continues to improve as more experience is garnered.

ESOPHAGEAL CYSTS AND DUPLICATIONS Historical Note An esophageal cyst, or duplication, was first recognized by Blasius in 1674.94 More than a century later, Roth95 described a mediastinal cyst adherent to the vertebral column, now known as a neurenteric cyst. A cyst within the spinal canal itself was first reported in 1928.96 Only one year later, a cyst was successfully removed in a two-stage procedure because

of its large size.97 In 1931, the first one-stage resection of an esophageal cyst was performed.98

Definition Enteric cysts above the diaphragm account for 18% of all intestinal cysts.99 Only 12% of patients from a large series of mediastinal masses were reported to have esophageal cysts.100 However, it has been estimated that in children at least 30% of mediastinal masses are of foregut origin and eventually develop into (1) esophageal, (2) neurenteric, (3) bronchogenic, or (4) isolated cysts.101 Of interest, esophageal cysts have been described in association with esophageal atresia.102

163

164

Section 3 Pediatric Disorders

Although these cysts are commonly considered benign, neoplastic degeneration has been reported.103,104 Because of their appearance, Ladd and Scott105 proposed that all cysts located near the esophagus be known as esophageal duplication. Unfortunately, this term does not allow for explanation of embryologic or pathologic findings. Since 1944, various characteristics of these cysts have been considered in designing an appropriate classification scheme. Esophageal cysts have been described in all locations along the esophagus,106,107 including those that originate below the diaphragm and ascend from the abdomen.108 They are less common in the cervical region.109 Esophageal cysts can be intramural or completely separate from the esophagus. Although they infrequently communicate with the esophageal lumen, common openings between the cyst and the esophagus are reported,110 and in rare instances complete esophageal duplications with entrance and exit openings have been described.94,111 Thoracic cysts originating from the primitive foregut can communicate with hollow abdominal viscera, such as the intestine, biliary tree, or even the pancreatic duct.112,113 Most duplication cysts are solitary, although multiple cysts have been described.114,115 In particular, the posterior esophageal cysts may be multiple.116 Thick, viscous fluid fills most esophageal cysts, although necrotic debris, inflammatory cells, or old blood can accompany ulceration, infection, or hemorrhage. Aside from the likelihood of finding gastric cells in cysts with hemorrhage and ulceration, the contents of a cyst seem to provide little insight into its embryologic derivation.117 Similarly, the variety of mucosa found in an esophageal cyst is less helpful in categorizing the cyst, because the types of epithelial cells that have been reported in these cysts (squamous, columnar, cuboid, pseudostratified, ciliated) are seen at different stages of embryonic esophageal development.118,119 Two exceptions are the presence of cartilage, which usually suggests a tracheobronchial foregut duplication, and gastric mucosa, which occurs more commonly (although not exclusively) in cysts that originate in the abdominal esophagus.120 Because the nomenclature of esophageal cysts and duplications has been confusing, Fallon and associates121 grouped these cysts into categories based on histologic and embryologic features. Intramural esophageal cysts, also termed true duplications of the esophagus or archenteric cysts, are found within the esophageal wall. Lined with squamous or columnar epithelium, they are thought to be aberrations in primitive esophageal vacuolation. Enteric cysts, in contrast, contain epithelia from assorted embryonic tissues and well-developed muscular layers in the cyst wall. Tracheobronchial foregut duplications are anteriorly located cysts that most likely arise from a portion of the primitive lung bud that has incompletely separated from the primitive foregut. These cysts are typically lined with a ciliated columnar or respiratory epithelium. Posterior cysts, commonly adjoined to the spinal column, are believed to arise embryologically from anomalous adhesions between the endoderm of the developing foregut and

the mesoderm of the notochord or the ectoderm of the primitive neural tube. These cysts have been called a variety of names (enterogenous cysts, esophageal duplications, gastrocystomas, neurenteric cysts), although dorsal enteric cysts may be the best terminology to encompass their varied manifestations despite their common embryologic origin. These cysts are usually located in the posterior mediastinum and can be attached to anterior vertebral bodies. They range from simple posterior cysts without vertebral attachments to fistulas from the esophagus to the dorsal thoracic skin through the vertebral column and spinal canal.122 Dorsal enteric cysts may be associated with intra-abdominal intestinal duplication cysts,123 with abnormalities of the vertebral bodies, or with the presence of intraspinal enterogenous cysts. Neurenteric cysts are the subset of dorsal enteric cysts that attach to the dura through a defect in a vertebra.124 At least 50% of dorsal enteric cysts are associated with vertebral anomalies such as spina bifida occulta or anterior hemivertebrae.121 These vertebral defects are typically seen in the cervical or upper thoracic spine as the defect occurs as an early embryologic event, adhering to the ascending notochord while the foregut is forming from the endoderm of the twolayered embryonic disk.

Embryology Kirwan and colleagues122 suggested that errors in vacuolation might contribute to the formation of intramural esophageal cysts. During the 4th week of development, the primordial esophageal lumen is filled with mucosa. Vacuoles within the epithelial cells begin to form in the 6th week, and the lumen is gradually re-established as these vacuoles slowly coalesce. If this process is disrupted, epithelial cells similar to those that line intramural cysts are left within the esophageal wall. Other authors implicate improper budding in the development of certain cysts. Remnants of cells left after ventral tracheobronchial budding from the primitive foregut can cause formation of cysts,125 stenoses of the esophagus, or a combination of stenosis and cystic duplication.126,127 Errors in budding can be as remarkable as a bronchus and a lobe of lung parenchyma arising from the esophagus.128 The development of dorsal enteric cysts has been linked to the endoderm-ectoderm adhesion theory (Fig. 10-7). Adhesions occur at an early embryonic stage between the ectoderm (or mesodermal notochord) and the endoderm as it is forming the primitive foregut. Discordant longitudinal growth of the neural tube and the foregut creates a shear force, which may detach the developing enteric cells.129,130 The split-notochord theory advocates the presence of an abnormal fissure between the endoderm and the ectoderm, allowing the formation of an enterogenous diverticulum in the space created by the notochordal cleft. This diverticulum of endoderm, as the primitive foregut precursor, expands posteriorly to fill this abnormal space.131 The endodermal intrusion leaves the notochord split, can prevent the formation of the anterior vertebral body, and may affect the neural tube as it becomes the spinal cord. Whichever theory is correct, the various clinical manifestations include the following121-123,129:

Chapter 10 Congenital Anomalies

Normal

Abnormal Ectoderm Neural tube Hemivertebra

Vertebral column

Notochord

split Endodermal cyst

Endoderm FIGURE 10-7 Development of dorsal enteric cysts. Persistent attachment of endoderm to ectoderm can lead to a foregut endodermal cyst.

1. Simple intramural esophageal cysts 2. Extraesophageal cysts with or without vertebral anomalies 3. Cysts that extend through vertebral anomalies to the spinal cord 4. Fistulas between the esophagus and the dorsal thoracic skin

neuromas, neuroblastomas, neurofibromas, anterior meningoceles, pulmonary sequestrations, and hemangiomas can also be found posteriorly.110 In addition, cystic hygromas, substernal goiters, and enlarged lymph nodes can present as mediastinal masses, although these are usually found in the superior mediastinum, an uncommon location for esophageal cysts.

Tracts between posterior esophageal cysts and dorsal skin are commonly obliterated but may be found as persistent fibrous strands.

Investigative Techniques

Clinical Presentation One third or more of patients with esophageal cysts remain asymptomatic throughout childhood, and the cyst is incidentally discovered on chest radiographs taken for other reasons. Most other patients present with a minimal to moderate amount of dysphagia, although complete dysphagia is possible. Very large esophageal cysts have been reported to cause superior vena cava syndrome132 or, in the case of large distal cysts, to present as abdominal masses.108 More common, however, would be a symptom attributable to gastric epithelium within the cyst, such as esophageal perforation, hemorrhage, or pain from ulceration.105,129 Some patients with neurenteric cysts can present with neurologic symptoms. Pain is common, and spinal cord compression with associated weakness and even paralysis can be seen with intraspinal lesions.133,134 The most dramatic presentations, however, derive from compromised ventilation in young patients. Symptoms can arise from (1) reduction in ventilatory volume alone, (2) mechanical compression of the trachea,135 or (3) extrinsic pressure of the large bronchi causing emphysema (air trapping and atelectasis) or consolidation (complete collapse).136,137 Respiratory distress is not uncommon in this age group and may be life threatening.138 More common but less dramatic forms of respiratory compromise include stridor, persistent cough, or recurrent pneumonia in patients with smaller esophageal cysts.99

Differential Diagnosis Esophageal cysts are typically located retropleurally in the posterior mediastinum, although bronchogenic cysts, ganglio-

An esophageal cyst should be suspected if a chest film reveals a large mass on one side of the chest. The cyst, typically, is a sharply defined, spherical or tubular mass that commonly displaces the trachea or the esophagus. A propensity for the right hemithorax is presumably a result of changes during intestinal rotation.110,129 Chest radiographs may also occasionally demonstrate vertebral anomalies, such as bifid vertebrae in the lower cervical or upper thoracic spine, suggesting the need for further workup of neurenteric findings, including evaluation with MRI of the spinal canal. A contrast esophagogram may demonstrate a smooth filling defect distorting the lumen or even displacing the esophagus. Filling of cysts with contrast is uncommon because they rarely communicate with the lumen of the esophagus, although large distal cysts have been described in communication with a visceral structure (usually the stomach) below the diaphragm.99 For radiographically obscure lesions, some have advocated transthoracic ultrasonography to confirm the cystic nature of these lesions and to differentiate these lesions from solid tumors of the posterior mediastinum,139 although CT has largely superseded ultrasonography to better delineate posterior mediastinal lesions. Other authors also recommend abdominal ultrasonography to rule out associated intestinal duplications,99 although plain abdominal films may detect the same. Technetium radionuclide scanning in patients who present with symptoms of ulceration, such as anemia or frank hemorrhage, can reveal gastric mucosa in the cysts. Esophagoscopy is of little value in differentiating esophageal cysts from other posterior mediastinal lesions because the esophageal mucosa near the cyst is normal. Esophagoscopy may be of value immediately preoperatively to determine whether a cyst-esophageal connection is present. Although bronchoscopy is a typical modality for evaluating airway

165

166

Section 3 Pediatric Disorders

obstruction, Haller and coworkers138 reported precipitation of ventilation problems by airway instrumentation in the setting of a duplication cyst. CT can clarify obscure masses as well as define their relation to surrounding structures and evaluate for associated vertebral defects.140 When available, however, and especially in the setting of a suspected neurenteric component to the cyst, MRI is the most accurate in detecting vertebral and intraspinal abnormalities and thus is the diagnostic study of choice.141,142 It is important to remember that intraspinal neurenteric cysts can occur, particularly in patients with vertebral anomalies or neurologic abnormalities.116

Operative Management With the propensity for infection, hemorrhage, and possible neoplastic change, prudent management of esophageal cysts must eventually include surgical excision. For most patients, because growth is slow and neoplastic change is rare, surgery can be elective. The rare exception is the patient who presents with severe respiratory compromise from rapid expansion of a cyst that may be initially treated with percutaneous aspiration for decompression until the patient is stable enough for planned surgical excision. When reviewing the radiographic studies and during intraoperative exploration, the surgeon should remember that multiple intramural cysts are not unusual.115 A limited posterolateral thoracotomy, based on the rostrad or caudal location of the cyst, provides adequate exposure. It may be necessary to enter a second separate interspace using the same skin incision for longer or multiple cysts. The use of video-assisted thoracoscopy has been described for small cysts.143 For large distal cysts that extend beyond the diaphragm, an additional abdominal incision may be required. Because it is the gastric mucosa in esophageal cysts that causes most of the associated morbidity, including necrosis, hemorrhage, and ulceration with symptomatic pain and possible perforation, it is essential to remove the cyst mucosa during the surgical excision. Dividing the overlying esophageal musculature and carefully dissecting out the cyst extramucosally can enucleate intramural cysts. If the lumen of the esophagus is not violated surgically, the integrity of the wall and its function should remain intact.144 Although they are uncommon, communications between the cyst and the esophageal lumen can be closed with a fine monofilament suture. The muscular wall should be reapproximated in a manner that does not compromise the lumen. In the rare case that the esophageal mucosa is violated or lumen narrowed, a protective gastrostomy has been used during healing and can be helpful if postoperative esophageal dilations are necessary. Enteric cysts are usually completely separate from the true esophageal wall and most often are connected by a fibrous band with either a free subpleural cyst or one attached to an anterior vertebral body. These cysts can be easier to resect, although adherence to important structures or a rich blood supply can complicate the repair. Again, if necessary, shelling out the mucosa and repairing the subsequent defect would probably accomplish the same ends as excision, alleviating

symptoms and future risks posed by the cyst. If a concomitant intraspinal cyst is found, priority should be given to resection of the spinal component to prevent acute neurologic complications during resection of the intrathoracic component.116

Results Short-term results are excellent in children as well as adults, with appropriate relief of initial symptoms. Although adequate follow-up in children has not been reported, studies in adults teach us that late reflux, esophagitis, and Barrett’s esophagus are more common than previously anticipated,145 thereby stressing the importance of long-term follow-up in all patients after excision of an esophageal cyst.

CONGENITAL STENOSIS AND WEBS Historical Note Early reports of esophageal stenosis of a congenital nature described “webs” (thin membranes) treated by dilation.146,147 The first large series and review of the literature was in 1928 and consisted of 50 cases.148 Tracheobronchial remnants were described in case reports as early as 1936,149 and hypertrophic stenosis was best originally described 23 years later.150 At about that time, Dunbar reported a case of congenital stenosis with tracheoesophageal fistula, an uncommon association.151 Although dilation is the common therapy, resection has been historically described as well.152,153

Definition Congenital esophageal stenosis has been defined as “intrinsic stenosis of the esophagus, present at birth, which is caused by congenital malformation of the esophageal wall architecture.”154 Although easily confused with inflammatory esophageal strictures, such as those from reflux disease, true congenital stenosis is uncommon. The reported incidence is between 1 : 25,000 and 1 : 50,000 births,154,155 with a poorly understood higher incidence in Japan.156 A review in 1995 found only 500 cases described in the world literature.157 A 17% to 33% reported incidence of associated anomalies includes esophageal or intestinal atresia, midgut malrotation, anorectal malformations, cardiac anomalies, hypospadias, chromosomal abnormalities, and malformations of the head, face, and limbs.154,156 Amid a number of confusing classification schemes, NihoulFékété and coworkers154 described three mechanisms representing most clearly the morphologic and possibly embryologic spectrum of this disease: 1. Fibromuscular thickening. Also referred to as idiopathic muscular hypertrophy or fibromuscular stenosis, this is a diffuse fibrosis of the wall in the setting of segmental hypertrophy of the muscularis and submucosa. Most hypertrophic segments are found in the distal esophagus, with the remaining few found in the middle third.158 These lesions are long and tapering, with considerable variation in the degree of stenosis. Of the different types of stenosis, this type is most commonly associated with esophageal atresia.

Chapter 10 Congenital Anomalies

2. Tracheobronchial remnants, or rests, are composed of cartilage, respiratory mucous glands, or ciliated epithelium that produces a rigid, discrete stenosis most commonly in the distal third of the esophagus.149,159 Associated inflammation and fibrosis around very small islands of tissue can produce surprisingly marked obstruction. Tracheobronchial remnants can be associated with esophageal atresia and tracheoesophageal fistula.156,160,161 3. A congenital membranous web (or diaphragm), the rarest type of congenital stenosis, is a thin, diaphragm-like lesion with an eccentric opening that has been reported in all levels of the esophagus.146,147,157,158 The membrane is usually covered on both sides by squamous epithelium. Some have considered these to represent missed variations of esophageal atresia,162 although webs are not commonly associated with congenital lesions, as are the other types of congenital esophageal stenoses.154

Embryology Fibromuscular Thickening Although fibromuscular thickening is the most common cause of congenital stenosis, embryologic or pathogenic factors remain unknown.154 Histologic findings are well described and include normal squamous epithelium overlying fibrous connective tissue and proliferation of smooth muscle fibers in the submucosa. Of interest, but not yet helpful in understanding the embryology, is the recognition that these lesions are histologically quite similar to hypertrophic pyloric stenosis.158

Tracheobronchial Remnants Tracheobronchial remnants are perhaps the best understood type of congenital esophageal stenosis, believed to result from incomplete separation of the primitive foregut from the respiratory tract around the 25th embryonic day.161 The separation of pulmonary and esophageal primordia was originally explained as proliferation of the lateral ridges of the foregut into lung diverticulum and esophagus. Others describe the initial event as induction and growth of a lung bud on the ventral surface of the foregut. Regardless, tracheobronchial tissue can be sequestered in the esophageal wall and then carried caudally by normal development of the esophagus, coming to reside in its typical distal location because of faster growth in the esophagus in comparison to the bronchial tree.161 Although less commonly described, larger rests of cells can even organize into anomalous lobes of lung arising from the esophagus. The syndrome of atresia and remnants can be described by the presence of mesenchyme that induces tracheobronchial differentiation along a short segment of foregut, thereby locally preventing normal esophageal development and narrowing the resulting lumen.

CONGENITAL WEBS Congenital webs are generally thought to occur by failure of complete vacuolization of a mucosa-filled primordial esophageal lumen between the 6th and 10th weeks of development,

as previously described for esophageal cysts.122 Although vacuolization occurs until the 10th week, the separation of the primordial pulmonary and esophageal structures occurs in week 5.163 This timing helps account for the lack of association between webs and other congenital lesions such as atresias as well as the fact that they can occur at any level of the esophagus.154,164

Clinical Presentation Congenital esophageal stenosis usually presents in infancy with progressive dysphagia and vomiting after the introduction of semisolid or solid foods, which typically occurs around the age of 6 months.165 On rare occasion, a patient who presents with a lodged foreign body, after careful examination on removal of the object, may be shown to have an esophageal stenosis.166 The degree of obstruction and location within the esophagus produce an equally varied spectrum of clinical symptoms. Mild stenoses can remain undiagnosed for years; interestingly, a careful history even with presentation in adulthood can retrospectively reveal earlier swallowing difficulties.164 More severe stenoses can present with regurgitation and subsequent respiratory distress in the newborn.154 Almost complete obstruction can resemble esophageal atresia. Proximal stenosis can cause inability to swallow food, whereas more distal lesions can cause regurgitation and, in more serious cases, aspiration with recurrent pneumonias.167

Differential Diagnosis Esophageal stenosis caused by caustic ingestion, esophagitis, chronic foreign body entrapment, and Barrett’s esophagus can resemble congenital lesions. Patients with acquired stenoses, however, usually present with associated signs, symptoms, and a history related to the mechanism of injury. More difficult diagnoses involve distinguishing congenital esophageal stenosis from reflux esophagitis and esophageal narrowing from distal esophageal inflammation168 or distinguishing near-complete web from esophageal atresia. Achalasia and extrinsic compression from mediastinal masses should always be considered as well.

Investigative Techniques Although a congenital cause is occasionally difficult to demonstrate, barium esophagogram and endoscopy provide reliable information regarding the location and the severity of esophageal stenoses. In the distal esophagus, a long and tapered narrowing suggests fibromuscular thickening, whereas a more discrete and abrupt narrowing suggests tracheobronchial remnants, although the latter is commonly interpreted as a reflux-related stricture. Webs or fibromuscular hypertrophy can present as lesions in the middle or even upper third of the esophagus.169 Esophagoscopy demonstrates normal-appearing mucosa overlying a narrow lumen. Esophageal biopsy can confirm the absence of significant esophagitis or gastric metaplasia and help reaffirm the congenital nature of a lesion.166 With both studies, dilation of the esophagus proximal to the stenosis can introduce the question of achalasia, especially with the dys-

167

168

Section 3 Pediatric Disorders

motility that can be caused by dilation itself. Esophageal manometry and pH monitoring can help to distinguish these clinical entities.170

Management The goal of any treatment of congenital esophageal stenosis is twofold: 1. Symptoms should be relieved. 2. The antireflux mechanism should be maintained to avoid long-term complications. Dilation by bougienage, surgical resection, and myotomy has been performed with varying degrees of success in patients with different types of congenital stenosis.

Dilation As early as the first reported series in 1953, therapeutic regimens for esophageal stenosis have begun with dilation (Gross, 1953).2 A series of vigorous antegrade and retrograde dilations with mercury-weighted tapered Maloney or Avaray bougies is usually performed. Use of Gruntzig balloon catheter dilations under fluoroscopic or direct endoscopic guidance has also been reported, with success rates close to 95% in some children.171,172 Most children undergo at least one attempt at nonoperative management before surgical options are explored, and many patients are adequately treated in this fashion periodically, with results meeting both goals of treatment. The ideal candidate for dilation is a patient with a thin esophageal web or mild fibromuscular thickening, although successful treatment of all types of congenital esophageal stenoses has been reported. Success rates after dilation of congenital webs are increased by endoscopic cautery resection, although the addition of cautery resection is associated with a higher morbidity risk.173 Complications of dilation include esophageal leak and failure of therapy. Long-term results are promising, but many patients require an indefinite series of intermittent dilations.166

Resection When dilation fails to provide measurable improvement in symptoms with maintenance of esophageal function, resection and primary anastomosis should be considered with earlier rather than delayed operative treatment.174 Resection is almost always required if tracheobronchial remnants are suspected by tight unyielding strictures that have not responded to repeated dilations.175 It is important to identify clearly the location and severity of the stenosis preoperatively. A right thoracotomy provides adequate access to the middle third of the esophagus, whereas a left thoracotomy is preferred for more distal lesions. Occasionally, laparotomy is needed to access the abdominal portion of the esophagus. Because it can be difficult to define the extent of the stenosis intraoperatively, a balloon catheter passed beyond the point of stenosis and then pulled back against the stenosis with an inflated balloon may assist in this

endeavor.176 Additionally, advancing an esophageal dilator to the point of resistance can aid in identifying the proximal extent of the stenosis. In most cases, segmental resection and end-to-end esophageal anastomosis can be accomplished with careful attention to preserving the vagal nerves. Uncommonly, long fibromuscular stenoses that do not respond to dilation may require resection and subsequent esophageal replacement. Resections of lesions near the gastroesophageal junction cause significant reflux if they are not treated with a concomitant antireflux procedure. Nihoul-Fékété and colleagues154 reported success with a modified Hill gastropexy and a Nissen fundoplication, with or without pyloroplasty. Other authors have recommended Collis gastroplasty with the Nissen fundoplication instead.177 Complications of surgical resection include esophageal leak with mediastinitis and significant reflux, as mentioned earlier.

Myotomy Many long, tapered fibromuscular lesions can be treated with dilation; surgical resection of those lesions that do not respond to dilations would require esophageal replacement for anastomotic reconstruction. As an alternative, some authors have suggested myotomy similar to that used to treat hypertrophic pyloric stenosis or achalasia158 as primary treatment. Given the paucity of follow-up reports, myotomy remains an attractive although untested therapy for these lesions.

ESOPHAGEAL DIVERTICULA Historical Note The relatively uncommon reports of congenital diverticula occurring in the esophagus began in 1908,178 and the clinical picture of congenital esophageal diverticula was described 2 decades later by Jackson and Shallow.179 DeBakey and coworkers180 later successfully repaired a congenital diverticulum with a single-stage operation.

Definition Both forms of acquired diverticula of the esophagus (pulsion and traction) result from herniation of the submucosa and mucosa through a defect in the muscularis. A true congenital diverticulum, in contrast, contains all layers of the esophagus (mucosa, submucosa, muscularis) within the outpouching.181 Congenital occurrences of these diverticula are extremely rare and lack detail in the literature. They occur mostly in the cervical region of the esophagus around the pharyngoesophageal junction, as do most acquired lesions, but have been reported in the mid-esophagus. An anatomic study of these lesions in 1908 proposed an embryologic defect during early foregut formation as the mechanism of diverticula, although the cause of this susceptibility remains unclear.178 Since then, a question has arisen regarding the possible overlap of esophageal cysts with luminal communication and congenital diverticula, although few cysts contain all layers of the esophageal wall, as do true diverticula.

tahir99-VRG vip.persianss.ir

Chapter 10 Congenital Anomalies

Presentation and Diagnosis Newborns with esophageal diverticula typically present with excessive mucous secretions in a pattern that can simulate esophageal atresia. If the diverticulum is large enough and fills while the infant is feeding, respiratory obstruction can be the presenting picture, with a significant danger of aspiration if spillover occurs suddenly. In some cases, foul-smelling breath gives a clue to the diagnosis. A nasogastric tube may not pass, coiling in the diverticulum, but in most cases the tube passes beyond the lesion with surprising ease. A contrast study usually confirms the diagnosis, although it may require the careful injection of contrast agent during withdrawal of an intraesophageal tube. The most superior lesions can be difficult to assess by contrast radiography, and esophagoscopy may be required.

Operative Management Surgical excision is the treatment of choice, although longterm follow-up is unavailable. A three-layer closure is preferred after careful dissection and excision of the diverticulum. Satisfactory mucosal closure in a transverse direction, followed by a multiple layered muscular repair, reduces the risk of recurrence.

COMMENTS AND CONTROVERSIES It is surprising that fetal development of a simple muscular tube can get so messed up. After reading this excellent chapter and reflecting on the complexity of esophageal growth and its close association with the development of the lung, airways, and spinal cord, I find it amazing that congenital esophageal anomalies do not happen more often. The spectrum of abnormalities is staggering; in the extreme, long-gap esophageal atresia and complete laryngotracheoesophageal clefts are the ultimate challenge for the pediatric esophageal surgeon. It is a credit to our pediatric colleagues that esophageal replacement is not required more frequently. However, I am

169

impressed at the lifelong problems that some of these patients encounter. Unfortunately surgical correction of their problem or colonic replacement of the unsalvageable esophagus is not their final procedure that will return the esophagus to “normal” or provide a long-term solution. Esophageal dysmotility is a common problem and significant disability in many patients with esophageal atresia/ tracheoesophageal fistula. The tenet that colon is the best replacement for the unsalvageable esophagus in the pediatric patient ignores late problems with colonic dilation and redundancy.1,2 A complete understanding of fetal esophageal development and congenital esophageal anomalies, which is critical for the pediatric specialist, is equally important for the adult physician. The reasons are threefold. This knowledge facilitates management of (1) the adult who presents with a congenital esophageal abnormality, (2) the adult patient who had a congenital repair as an infant or child, and (3) acquired esophageal disorders in the adult. T. W. R 1. Jeyasingham K, Lerut T, Belsey HRH: Functional and mechanical sequelae of colon interposition for benign oesophageal disease. Eur J Cardiothoracic Surg 15:327, 1999. 2. Jeyasingham K, Lerut T, Belsey HRH: Revisional surgery after colon interposition for benign oesophageal disease. Dis Esophagus 12:7, 1999.

KEY REFERENCES Gross RE: The Surgery of Infancy and Childhood. Philadelphia, WB Saunders, 1953. Haight C, Towsley H: Congenital atresia of the esophagus with tracheoesophageal fistula: Extrapleural ligation of fistula and end-to-end anastomosis of esophageal segments. Surg Gynecol Obstet 76:672-688, 1943. Quan L, Smith DW: The VATER association: Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and renal dysplasia: A spectrum of associated defects. J Pediatr 82:104-107, 1973. Waterston D, Bonham Carter R, Aberdeen E: Oesophageal atresia: Tracheo-oesophageal fistula: A study of survival in 218 infants. Lancet 1:819-822, 1962.

tahir99-VRG vip.persianss.ir

VASCULAR TRACHEOESOPHAGEAL COMPRESSION: VASCULAR RINGS, PULMONARY ARTERY SLING, AND INNOMINATE ARTERY COMPRESSION OF THE TRACHEA

chapter

11

Brian W. Duncan Paul Krakovitz M. Janine Arruda

Key Points ■ The diagnostic approach for vascular tracheoesophageal com-

■

■ ■

■ ■

pressive syndromes usually involves some combination of bronchoscopy, echocardiography, and chest CT or MRI. Respiratory symptoms due to vascular compression range from subclinical to life threatening. A high index of suspicion for the possibility of vascular compression of the airway should be present for asthma that is “atypical” or unresponsive to medical management. More than 90% of all vascular rings are approached surgically via left posterolateral thoracotomy. Pulmonary artery sling is repaired by translocation of the left pulmonary artery to the main pulmonary artery via median sternotomy with cardiopulmonary bypass and concomitant repair of significant tracheal anomalies. Degree of underlying tracheal abnormality is the most important prognostic factor for patients with a pulmonary artery sling. Innominate artery compression of the trachea should be repaired by aortopexy for patients with respiratory symptoms and significant tracheal narrowing demonstrated during bronchoscopic evaluation.

Tracheoesophageal compression syndromes may result from a variety of congenital abnormalities of the great vessels. These vascular anomalies usually have no hemodynamic impact on affected individuals but come to clinical attention due to compression of the trachea and/or the esophagus. The vascular anomalies that give rise to tracheoesophageal compression syndromes include vascular rings arising from abnormalities of the aortic arch and its branches, pulmonary artery slings, and innominate artery compression of the trachea. A standardized nomenclature for these lesions has been produced that accurately categorizes the great majority of these lesions (Table 11-1).1 Although potentially life threatening, TABLE 11-1 Vascular Anomalies Causing Tracheoesophageal Compression Syndromes Double aortic arch Right arch/left ligamentum Pulmonary artery sling Innominate artery compression From Backer CL, Mavroudis C: Congenital Heart Surgery Nomenclature and Database Project: Vascular rings, tracheal stenosis, pectus excavatum. Ann Thorac Surg 69:S308, 2000.

in the absence of advanced underlying structural abnormalities of the trachea that may be associated with these conditions, surgical repair reliably results in definitive treatment for these lesions.

VASCULAR RINGS Embryology The complexity of the structural changes that must occur in a precise sequence during development of the great arteries and their branches makes it perhaps surprising that anatomic abnormalities of these structures do not occur with greater frequency. Clinically significant vascular rings are in fact quite uncommon, comprising no more than 1% to 2% of congenital heart disease.2 During embryonic development, the aorta and its branches develop according to an intricate sequence of steps in which rudimentary structures develop then resorb while adult structures persist and grow. By approximately the 21st day of gestation, a ventral aortic sac and two dorsal aortas are present. A series of six aortic arches subsequently form bilaterally within the branchial pouches that connect the ventral and dorsal aortas.3 The normal development of the aorta and its branches is dependent on the persistence of some of these structures (Table 11-2).4 Vascular rings occur due to alterations in this precise developmental sequence that lead to predictable anatomic pathology that can be described as belonging to one of a limited number of clinical subtypes in the majority of cases. Table 11-3 lists these anatomic subtypes with approximate frequencies of occurrence, as described in a recent large clinical series of more than 200 patients (Backer et al, 2005).5 Although other anatomic sub-

TABLE 11-2 Embryologic Derivation of Normal Great Vessel Anatomy Normal Postnatal Structure

Embryologic Origin

Distal ascending aorta, innominate artery, proximal aortic arch

Aortic sac

Carotid arteries

Third aortic arches

Distal aortic arch and aortic isthmus

Left fourth aortic arch

Right subclavian artery

Right fourth aortic arch

Ductus arteriosus

Left sixth aortic arch

Descending thoracic aorta

Left dorsal aorta

170 tahir99-VRG vip.persianss.ir

Chapter 11 Vascular Tracheoesophageal Compression

171

TABLE 11-3 Anatomic Subtypes of Vascular Rings Anatomic Subtype

Frequency (%)

Double Aortic Arch Right arch dominant Left arch dominant Balanced arches

54 40 10 4

Right Aortic Arch With aberrant left subclavian artery and left ligamentum With mirror-image branching and retroesophageal ligamentum

46 30 16

From Backer CL, Mavroudis C, Rigsby CK, Holinger LD: Trends in vascular ring surgery. J Thorac Cardiovasc Surg 129:1339, 2005.

types of vascular rings occur, they are exceedingly rare; the categories listed in Table 11-3 provide classification for more than 95% of clinically encountered cases of vascular rings.

Double Aortic Arch Double aortic arch is the most commonly encountered form of vascular ring in most series (Backer et al, 2005; Backer et al, 1989; Gross and Neuhauser, 1951).5-12 The embryologic origin of this entity is persistence of the right dorsal aorta with variable regression of the left dorsal aorta. In the majority of cases, perhaps greater than 70%, the right arch is dominant; the left arch is dominant in approximately 20% of cases, whereas the arches are approximately equal in size in 10% (Fig. 11-1) (Backer et al, 2005).5 Rarely, coarctation or interruption of both arches may occur.13-15 The brachiocephalic branching pattern in most cases consists of the right common carotid and right subclavian arteries arising from the right arch, whereas the left common carotid and left subclavian arteries take origin from the left arch. In cases of right dominant arch, the left arch is not uncommonly extremely hypoplastic or atretic at its most posterior aspect between the takeoff of the left subclavian artery and the descending aorta. Occasionally, the left arch is hypoplastic or atretic between the takeoff of the left common carotid and the left subclavian arteries. Although surgical treatment relies on division of the ring at its narrowest point, it is safest to assume that the nondominant arch is patent throughout its extent, and appropriate care with a secure hemostatic closure of each transected end should be performed (see Surgical Management, later).

Right Aortic Arch With Aberrant Left Subclavian Artery and Left Ligamentum A right aortic arch will cause a vascular ring when the left ligamentum passes from a posterior origin near the descending aorta and passes anteriorly to an insertion point on the left pulmonary artery. A right aortic arch with aberrant left subclavian artery and left ligamentum is the most common form of a single right aortic arch that produces a vascular ring, accounting for nearly 70% of these cases (Backer et al, 2005).5 The embryonic origin of this form of vascular ring is persis-

FIGURE 11-1 Double aortic arch with a dominant right arch and a smaller, but patent, left arch. The ligamentum can be seen arising from the undersurface of the left arch inserting into the pulmonary artery. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

tence of the right fourth arch with resorption of the left fourth arch. The sequence of the brachiocephalic branching pattern from the right arch is left common carotid, right common carotid, right subclavian, and left subclavian arteries. The left subclavian artery passes posterior to the esophagus; the ligamentum originates from the descending aorta near the origin of the left subclavian artery and passes anteriorly to the left pulmonary artery, completing the vascular ring (Fig. 11-2).

Right Aortic Arch With Mirror-Image Branching and Retroesophageal Ligamentum This form of vascular ring with a single right aortic arch is less common, occurring in perhaps 30% of these cases (Backer et al, 2005).5 The sequence of brachioecephalic branching in this case is a “mirror image” of normal; the left common carotid and left subclavian arteries arise first off of an innominate artery, then the left common carotid and left subclavian arteries. The ligamentum in these cases arises from the descending aorta, often from a prominent diverticulum of Kommerell that passes anteriorly, inserting into the left pulmonary artery, completing the ring. The embryologic origin of this lesion is also due to persistence of the right fourth arch with regression of the left fourth arch; however, in these cases a segment of the left fourth arch persists as the aortic

tahir99-VRG vip.persianss.ir

172

Section 3 Pediatric Disorders

FIGURE 11-2 Right dominant aortic arch with anomalous left subclavian artery. The ligamentum arises from the undersurface of the aorta opposite the takeoff of the anomalous left subclavian artery.

FIGURE 11-3 Double aortic arch with a dominant left arch and an atretic right arch forming a vascular ring. This rare form is best approached surgically through a right thoracotomy. (REPRINTED WITH

(REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

diverticulum. It is important to note that a right aortic arch with mirror-image branching of the brachiocephalic vessels does not always give rise to a vascular ring. The ligamentum may pass from the innominate artery to the left pulmonary artery, and in these cases no constrictive ring is formed.16

may occur in the newborn period whereas minimal symptoms of dysphagia or even no symptoms may be present through adulthood. Presentation at either extreme of the spectrum is probably rare, with most patients manifesting evidence of airway or esophageal obstruction in childhood. Earlier and more severe airway obstruction is usually more common with double arch anatomy whereas esophageal obstructive symptoms coming to attention later in life suggest the presence of right arch forms with a retroesophageal ligamentum, although a wide range of variability in presentation exists for either type of vascular ring. Airway symptoms that may be present include stridor at rest or that may be induced by exercise and chronic cough and recurrent pneumonias. Rarely, patients present in infancy with significant respiratory distress. Symptoms are often increased, at times dramatically, in the presence of upper respiratory tract infections. Stridor due to large airway obstruction may be mistaken for the much more commonly encountered wheezing due to small airway obstruction in childhood asthma. In fact, these children may undergo prolonged treatment for what is mistakenly thought to be refractory asthma before the correct diagnosis is made. Asthma that is poorly managed medically, especially in the presence of a right aortic arch on chest radiography, should be considered for further workup to exclude the presence of a vascular ring.

Other Forms of Vascular Rings Other forms of vascular rings occur much less frequently than the anatomic subtypes described previously. Important rare forms include those characterized by a dominant left aortic arch. Left dominant aortic arch forms with a right descending aorta may give rise to a ring due to a persistent atretic right arch (Fig. 11-3) or with an aberrant right subclavian artery that gives rise to a ligamentum that inserts onto the right pulmonary artery. Left dominant arch forms probably account for less than 5% of all cases; however, their presence must be ruled out because these forms are best approached through a right thoracotomy.

Clinical Presentation The symptom complex associated with vascular rings is virtually always due to tracheoesophageal compression whereas hemodynamically significant lesions such as coarctation or interrupted aortic arch occur very rarely.13-15,17 Tracheoesophageal obstructive symptoms occur along a spectrum of disease severity: life-threatening airway obstruction

tahir99-VRG vip.persianss.ir

Chapter 11 Vascular Tracheoesophageal Compression

Obstructive symptoms of the esophagus also vary in intensity and may change during the lifetime of the individual. For example, swallowing difficulties may be absent in infancy when the diet consists of breast milk or formula. Symptoms of esophageal obstruction may become apparent for the first time with transition to intake of solid foods. Common esophageal obstructive symptoms related to vascular rings include dysphagia that is worse for solids in older children, whereas vomiting and feeding intolerance may predominate in infants. As is the case for respiratory symptoms due to a vascular ring, esophageal compressive symptoms may be attributed to more common causes such as gastroesophageal reflux disease. To make the diagnosis for these relatively rare anomalies, it is important to maintain a high index of suspicion for the presence of a vascular ring for any patient with respiratory or gastrointestinal complaints that have unusual features or that are refractory to treatment. A devastating clinical presentation is massive gastrointestinal bleeding due to aortoesophageal fistula, which usually occurs in hospitalized patients with a vascular ring due to erosion from a chronic indwelling nasogastric tube. The presence of a vascular ring is usually not suspected in these children, who are often already managed in the intensive care unit setting for an unrelated diagnosis.18,19 In the presence of a right-sided aortic arch, largecaliber, rigid nasogastric tubes should be used cautiously or not at all until the appropriate diagnostic steps have been taken to rule out a vascular ring.

173

Diagnosis A chest radiograph demonstrating a right aortic arch is often the initial diagnostic test that is available to suggest the presence of a vascular ring. This finding is supportive but nonspecific and is not helpful in cases of a vascular ring without a dominant right aortic arch. Historically, barium swallow has been a useful diagnostic tool in these cases, demonstrating a posterior indentation in the esophagus that distinguishes these lesions from a pulmonary artery sling (Fig. 11-4). Despite the ability to infer details regarding the anatomic subtype of vascular ring that is present based on the appearance of the contrast column, barium esophagography does not provide the anatomic detail that CT and MRI provide (Gross and Neuhauser, 1951).8 Echocardiography may be diagnostic of the underlying vascular anatomy, but it is only suggestive of the underlying anatomy in cases in which there is atresia of one limb of a double aortic arch or in the presence of a ligamentum arteriosum.20 Echocardiography is a useful adjunct to rule out significant associated cardiac pathology that may coexist in 10% to 20% of vascular ring cases (Backer et al, 2005).2,5 Contrast CT is perhaps the most useful tool for the diagnosis of a vascular ring; current multidetector techniques for CT provide detailed studies of the underlying anatomy in as little as 10 to 20 seconds but do entail radiation exposure (Figs. 11-5 and 11-6). MRI provides anatomic detail equivalent to CT; however, MRI studies require 30 minutes or more

FIGURE 11-4 A, Barium esophagogram (frontal view) from a symptomatic newborn with a double aortic arch demonstrating midesophageal compression. B, Lateral view of same study demonstrating posterior indentation in barium column typical of vascular ring. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

A

B

tahir99-VRG vip.persianss.ir

174

Section 3 Pediatric Disorders

Ao

MPA

SVC

LV

A

B

FIGURE 11-5 A, Frontal CT scan showing the ascending aorta, the right (large arrowhead) and left (small arrowhead) aortic arches, and the completion of the ring posteriorly by the descending aorta. SVC, superior vena cava; Ao, ascending aorta; MPA, main pulmonary artery; LV, left ventricle. B, Oblique axial 3D reconstruction of CT scans from a patient with a double aortic arch demonstrating a dominant right aortic arch (large arrowhead) and the smaller left aortic arch (small arrowhead) encircling the trachea and the esophagus. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 11-6 Coronal CT scan from a patient with a vascular ring due to a right aortic arch (R arch) with anomalous origin of the left subclavian artery (LSCA) originating from the posterior retroesophageal Kommerell’s diverticulum. Desc Ao, descending aorta. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

to complete under sedation and are subject to artifact from motion and metal (Backer et al, 2005).5,21-25 The ability to obtain detailed anatomic studies in a short time period is especially critical in small children with significant airway compromise. Precise delineation of the underlying anatomy is important to rule out other causes of tracheoesophageal

pathology and to detect rare vascular ring subtypes that require a change in the standard surgical approach, such as dominant left arch forms, which are best approached via right thoracotomy. CT and MRI additionally provide great anatomic detail of the airway to identify associated intrinsic lesions of the trachea and bronchi. Bronchoscopy provides supportive diagnostic information, rules out endobronchial lesions such as foreign bodies, and assesses the degree of accompanying tracheomalacia (Backer et al, 2005).5,26 Although advocated by some centers as part of a routine workup, in most cases, bronchoscopy provides little additional information beyond that obtained by accurate anatomic delineation with contrast CT. Pulmonary function tests are not necessary for most cases; however, characteristic findings of large airway obstruction in a child previously thought to have asthma may be the first indication of the true underlying diagnosis.27 An additional diagnostic test that should be considered in vascular ring patients is screening for 22q11 deletion due to implications for the general health of the child and family members.28-30 McElhinney found microdeletions of chromosome 22q11 in 24% of patients with isolated vascular rings across the spectrum of subtypes encountered.28 Recognizing this prevalence and appreciating the difficulty in making the diagnosis on clinical grounds alone, consideration should be given to obtaining a blood sample for microdeletion detection using fluorescence in-situ hybridization for all children with vascular rings.

Management The presence of a vascular ring in a symptomatic patient is an indication for treatment. Other than optimizing a given

tahir99-VRG vip.persianss.ir

Chapter 11 Vascular Tracheoesophageal Compression

patient’s condition before surgical intervention by treating significant underlying pulmonary infection or adjusting medications for accompanying reactive airway disease, there is no effective medical management for these lesions. The required surgery may be safely performed at any age; and although vascular rings rarely require urgent treatment, proceeding with surgery decreases the likelihood of episodic severe respiratory distress or aspiration. In addition, early removal of physical compression of the trachea and esophagus presumably provides the greatest opportunity for recovery from functional abnormalities of tracheomalacia and esophageal dysmotility induced by long-standing constriction. As stated earlier, the vast majority of these cases are approached through a left lateral thoracotomy. Important anesthetic management issues exist for these patients, especially in the presence of significant airway obstruction. Inhalation anesthesia without muscle relaxation is administered until control of the airway is achieved. In this institution, regional anesthetic techniques are used to supplement general anesthesia: caudal catheters are used in infants up to 1 year of age whereas intrathecal injections are performed in older children. Single-lung ventilation is used for children above 10 kg, with a bronchial blocker in children up to 35 kg, whereas a double-lumen endotracheal tube can be employed in larger children. In that major intrathoracic blood vessels are manipulated during surgery, appropriate monitoring is vital to provide intraoperative confirmation of the underlying anatomy. Pulse oximeters placed on both hands and one foot along with blood pressure cuffs placed on both arms and one leg help ensure the safety of intended vascular division during periods of test occlusion. This monitoring is especially important in cases of double aortic arch with patency of both arches where division of the smaller arch is intended, to detect gradients between the upper and lower extremities before vessel division. A small, laterally placed skin incision over the palpated scapular tip with a muscle-sparing approach provides excellent exposure, although the use of video-assisted techniques through multiple small ports may be used with equally good visualization (Burke et al, 1995).2,31-34 The chest is entered through the fourth intercostal space, and the lung is retracted anteriorly. The vascular ring is usually palpable through the mediastinal pleura and may be visible through the pleura in the smallest infants. It is important to identify the vagus nerve giving off the left recurrent laryngeal nerve, which wraps around the ligamentum. The mediastinal pleura is then opened, exposing the aorta and its branches. It is important to clearly identify the left subclavian artery, left carotid artery, descending aorta, ligamentum arteriosum, and, when present, the left aortic arch. The ligamentum is divided in all cases, which in the case of a right arch and aberrant left subclavian artery is all that is necessary to divide the ring (Fig. 11-7A). If there is a double arch, the nondominant arch is test clamped at its narrowest point. If no gradient is detected, the nondominant arch is divided between clamps and the ends oversewn with a monofilament suture (see Fig. 11-7B). If the narrowest point is truly atretic, ligating and dividing the atretic segment may be performed; however, the safest approach is standard vascular control of the segment using

175

clamps with oversewing of the divided ends (see Fig. 11-7C). Adhesive adventitial bands between the vessels and the trachea and esophagus are taken down as well. A significant diverticulum of Kommerell may continue to produce esophageal compression and should be dealt with at the time of surgery. Use of aortopexy with suture of the diverticulum takeoff to the prevertebral fascia has been used; however, transection and oversewing of the diverticulum with reimplantation of the left subclavian artery should be performed if the diverticulum is significant. This approach has been successful in reoperations for recurrent esophageal compression due to an enlarging diverticulum but should be considered at the time of the initial vascular ring procedure (Backer et al, 2005; Backer et al, 2002).5,35 The mediastinal pleura overlying the great vessels is left open, followed by standard chest closure. Operations for a dominant left arch approached through a right thoracotomy are performed according to the same guiding principles; in these cases, the right recurrent laryngeal nerve wrapping around a right-sided ligamentum serves as an important anatomic landmark.

Outcome Surgery provides immediate and usually definitive relief of the physical compression of the trachea and esophagus; however, functional abnormalities such as tracheomalacia and disturbances of esophageal motility often persist after surgery. While there usually is substantial symptomatic improvement after surgery, some preoperative symptoms may persist. During bouts of viral respiratory infection, edema of the respiratory mucosa may lead to clinically significant airway obstruction after repair, especially in small children, and families should be advised appropriately regarding this possibility. As discussed previously, continued tracheoesophageal compression due to an enlarging Kommerell’s diverticulum may be a source of persistent symptoms after vascular ring surgery. Backer and colleagues described a series of eight children referred for recurrent respiratory symptoms and dysphagia after vascular ring surgery. All patients had a dominant right arch and had previously undergone simple division of a left ligamentum for treatment of their vascular ring without addressing the diverticulum. Resection of the diverticulum with reimplantation of the left subclavian artery into the left carotid artery provided relief of the slinglike effect of the retroesophageal left subclavian artery on the trachea and esophagus. The authors advocate this approach as part of the primary repair in all patients with a retroesophageal subclavian artery and a significant Kommerell diverticulum (Backer et al, 2005; Backer et al, 2002).5,35 Currently, surgery is performed safely and is usually associated with a short postoperative stay. In Backer and colleagues’ report (2005) there were no deaths in more than 150 patients undergoing vascular ring surgery since 1959 with an average hospitalization of less than 3 days over the past 5 years.5 A number of follow-up studies have been performed with fairly consistent findings27,36-40: relief of severe tracheoesophageal obstructive symptoms is usually immediate and permanent. Mild residual symptoms may be found as often as 30% of the time, which may persist for years after repair.36

tahir99-VRG vip.persianss.ir

176

Section 3 Pediatric Disorders

A

B

FIGURE 11-7 Operative sequence for surgical treatment of double aortic arch with a dominant right arch through a left thoracotomy. A, The ligamentum is clamped before division and oversewing. B, The left aortic arch is controlled with vascular clamps at its narrowest point and divided. C, The free ends of the divided left arch are oversewn. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Despite substantial improvement from preoperative studies, some abnormalities may still be detectable in many of these patients postoperatively when evaluated by pulmonary function tests,27,39,40 endoscopy,38 or radiographically.36,40 However, despite residual abnormalities on diagnostic studies that are usually minor, it is important to note that the incidence of reoperation for symptomatic tracheoesophageal compression is less than 5% in several series.11,41,42

PULMONARY ARTERY SLING Anatomy and Physiology Pulmonary artery sling is a rare condition due to a relatively minor congenital abnormality of the pulmonary artery;

C however, affected patients may exhibit a difficult clinical course due to the severity of associated tracheal abnormalities. A pulmonary artery sling occurs when the left pulmonary artery has an anomalous origin from the right pulmonary artery (Fig. 11-8). Typically, the left pulmonary artery, which may be of smaller caliber than usual, then follows an elongated route directly posterior to the trachea and anterior to the esophagus. The presence of a ligamentum arteriosum from the undersurface of the aortic arch inserting onto the main pulmonary artery adjacent to the right pulmonary artery takeoff creates a slinglike compressive mechanism that involves the trachea but not the esophagus. As a result, the symptom complex of a pulmonary artery sling is usually limited to airway obstruction without obstructive esophageal

tahir99-VRG vip.persianss.ir

Chapter 11 Vascular Tracheoesophageal Compression

177

FIGURE 11-9 Bronchoscopic view of distal tracheal compression from a pulmonary artery sling. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 11-8 Pulmonary artery sling due to origin of the left pulmonary artery from the right pulmonary artery. Short-segment tracheal stenosis is also evident. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

symptoms. Airway obstruction due to the anomalous left pulmonary artery alone is variable; the clinical presentation is usually determined by the presence or absence of associated tracheal stenosis (Fig. 11-9). Complete cartilaginous tracheal rings may be present in more than one half of all patients with a left pulmonary artery sling (“ring-sling complex”) (Berdon, 2000)43; however, the presence of complete tracheal rings alone does not ensure that airway obstruction will occur.2,16,44,45 Associated complete tracheal rings with significant stenosis may be limited to the short segment of trachea adjacent to the pulmonary artery sling or may involve variable lengths of the trachea. Rarely, the entire trachea is hypoplastic with important stenosis.

distress, recurrent respiratory infections, and stridor may be present whereas symptoms of esophageal compressive symptoms are notably absent. The diagnosis of pulmonary artery sling can be reliably made with echocardiography, which alone is usually sufficient to adequately define the vascular anatomy without the need for angiography. Barium swallow demonstrates a characteristic appearance with anterior indentation of the contrast column distinguishing it from a vascular ring; however, in current practice, barium swallow is not a necessary component of the diagnostic workup. It is vital to evaluate the trachea in patients with pulmonary artery sling to determine what, if any, additional airway procedure is required. Bronchoscopy should be obtained to provide a preoperative assessment of the luminal diameter and to follow the results of therapy postoperatively. Either CT or MRI should be obtained to evaluate the length of involved trachea (Berdon, 2000).43,46

Surgical Management Clinical Presentation and Diagnosis Symptoms in the setting of pulmonary artery sling usually arise from underlying tracheal stenosis; therefore, the amount of reduction in luminal diameter, most importantly, and the length of tracheal involvement, secondarily, determine the nature and duration of symptoms. At one extreme, longsegment severe tracheal stenosis may present as lifethreatening airway obstruction in infancy. Alternatively, pulmonary artery sling without significant tracheal stenosis may be virtually asymptomatic. Most patients present with some degree of respiratory symptoms due to tracheal obstruction similar to that seen with vascular rings due to abnormalities of the aortic arch and its branches. Respiratory

The diagnosis of pulmonary artery sling is sufficient to proceed with surgical intervention. The surgical approach should be formulated with consideration of the underlying tracheal anatomy as well as the vascular anatomy.44,45,47-50 Repair is performed through a median sternotomy using cardiopulmonary bypass. Aortic and right atrial cannulation with a single venous cannula is performed; however, no aortic cross-clamp is required and the entire procedure is performed with the heart beating and perfused. With the circulation safely supported, the vascular structures are thoroughly dissected out with particular attention to complete mobilization of the left pulmonary artery as well as the main and right pulmonary arteries. If tracheal resection is not performed, the left pul-

tahir99-VRG vip.persianss.ir

178

Section 3 Pediatric Disorders

monary artery and main pulmonary arteries are controlled with clamps, and the left pulmonary artery is divided and oversewn at its origin from the right pulmonary artery and then reimplanted into the main pulmonary artery at a site that approximates where it would normally originate (Fig. 11-10). The left pulmonary artery may have to be shortened to avoid kinking after reimplantation. As previously mentioned, the left pulmonary artery is often hypoplastic, requiring great care in its handling; 6-0 or 7-0 monofilament suture is used for the anastomosis. Tracheal reconstruction has been performed using a variety of techniques (Grillo et al, 2002).44,45,47-49,51,52 For segmental resections, children appear to tolerate tension at the tracheal anastomosis less well than adults with higher incidences of dehiscence, stricture, or other anastomotic complications.52 With this in mind, segmental resection of up to 30% of the tracheal length may be safely performed. Although anterior splitting of the trachea with pericardial patch or rib graft reconstruction has been used effectively in the past for longsegment stenosis, slide tracheoplasty has become a preferred method of repair in many cases (Grillo et al, 2002).51 Slide tracheoplasty uses only native tissue that is completely lined by respiratory epithelium, avoids graft material, and retains the growth potential of the trachea. Using this technique to treat various forms of congenital, long-segment tracheal stenosis, Grillo reported 100% survival with minimal hospital morbidity, rapid extubation, and no need for tracheostomy. All four infants and small children managed with this technique have had documented and satisfactory growth of the reconstructed airway. For tracheal reconstruction that involves transection of the trachea, the left pulmonary artery is most easily managed by anterior translocation to an anatomic location in front of the trachea without reimplantation. Great care must be taken with this approach, however, to avoid recurrent tracheal stenosis due to anterior tracheal compression or kinking of the left pulmonary artery.16,50 If these complications appear likely to occur, the standard approach with left pulmonary artery shortening and reimplantation into the main pulmonary artery should be performed.

INNOMINATE ARTERY COMPRESSION OF THE TRACHEA Clinical Features Although rare, innominate artery compression of the trachea can be a life-threatening cause of airway obstruction in children. Most cases have some degree of underlying tracheomalacia, which may accompany other conditions such as tracheoesophageal fistula or which may present in the absence of other anomalies. So-called late takeoff of the innominate artery arising to the left and posterior from its usual location may be present, although in many cases the vascular anatomy is not clearly abnormal. Affected children usually present in infancy or early childhood with some combination of stridor, cyanosis, and episodic severe respiratory distress. Respiratory difficulties are often characterized by “death spells,” which are dramatic episodes characterized by marked cyanosis and

FIGURE 11-10 Repair of pulmonary artery sling with translocation of left pulmonary artery to anatomically normal position from the main pulmonary artery. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

apnea that may progress to respiratory arrest. A history of these episodes of sufficient severity to require cardiopulmonary resuscitation may be present. Although the esophagus is not compressed by the vascular anomaly, feeding difficulties are often present due to respiratory distress that may be worsened with the effort of feeding. Physical examination usually reveals biphasic stridor that may be absent at birth and that may progress during the first few months of life.

Diagnosis Workup relies on bronchoscopic demonstration of the characteristic appearance of anterior leftward tracheal compression during spontaneous ventilation (Fig. 11-11). The site of compression is typically found at the distal one third of the airway and usually demonstrates arterial pulsation. The right radial pulse may disappear with anterior elevation of the trachea by the tip of the bronchoscope at the point of airway narrowing. The degree of airway compression is usually severe; commonly, the residual airway lumen is reduced to a slitlike aperture. Echocardiography and chest CT or MRI may be performed to rule out the presence of cardiac disease or other causes of airway compression and to provide evaluation of the entire trachea (Jones et al, 1994).53-55 It is important to note that chest CT may not demonstrate tracheal collapse definitively, emphasizing the importance of bronchoscopy evaluation for diagnosis.

tahir99-VRG vip.persianss.ir

Chapter 11 Vascular Tracheoesophageal Compression

179

a late takeoff followed by reimplantation to normalize the vascular anatomy has been described as an effective treatment59; however, this relatively complex procedure seems difficult to justify in light of excellent results obtained with the technically simpler technique of aortopexy.

SUMMARY

FIGURE 11-11 Bronchoscopic view of innominate artery compression of the trachea. Note the triangular shape of the airway due to anterior leftward compression of the trachea. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Surgical Treatment Surgery is indicated for children with significant respiratory events or marked feeding problems in the presence of significant airway narrowing on bronchoscopic examination (Backer et al, 1989; Jones et al, 1994).6,16,54,55 Bronchoscopy usually confirms a lesser degree of airway compression in patients with milder symptoms who may be managed expectantly.54 Surgical repair should be undertaken with anesthetic techniques employed to mitigate risks in patients with airway compromise as described earlier for vascular ring surgery. Aortopexy as originally described by Gross is performed for surgical treatment (Gross and Neuhauser, 1951).8 A small left anterior thoracotomy through the second intercostal space is performed, and the left lobe of the thymus is resected to improve exposure and reduce mediastinal bulk, which provides additional room for the vascular structures away from the airway. Pledgetted mattress sutures are then placed with partial-thickness bites through the aorta and innominate artery. Backer and colleagues (1989) described the placement of these sutures in the ascending aorta in line with the innominate artery, at the base of the innominate artery, and on the anterior surface of the innominate artery a few millimeters beyond its origin.6 The sutures are then passed through the posterior periosteum of the leftward aspect of the sternum. Bronchoscopy should be performed at this time during the procedure to ensure that a normal rounded appearance of the distal trachea has been produced.16,56 Results with aortopexy are uniformly good (Backer et al, 1989; Gross and Neuhauser, 1951; Jones et al, 1994).6,8,16,26,37,54-58 Modifications of this technique include access through a submammary incision with a right thoracotomy performed through the third intercostal space.6 Transection of an innominate artery with

A number of vascular anomalies can produce tracheoesophageal compression. Useful diagnostic tools include a combination of bronchoscopy, echocardiography, and chest CT or MRI. Surgical correction of more than 90% of vascular rings is via left posterolateral thoracotomy. Pulmonary artery slings are repaired by translocation of the left pulmonary artery to the main pulmonary artery with concomitant repair of significant tracheal pathology. The degree of associated tracheal abnormalities is the most important prognostic factor in patients with a pulmonary artery sling. Innominate artery compression of the trachea should be managed with aortopexy if serious respiratory symptoms accompany significant airway compression demonstrated by bronchoscopic examination.

COMMENTS AND CONTROVERSIES Vascular rings are uncommon, but they should be considered whenever unexplained tracheoesophageal compression presents in the pediatric patient or esophageal compression occurs in the adult. Contrast CT with 3D reconstruction has simplified the investigation. The presentation with dysphagia due to a vascular ring is termed dysphagia lusoria, or difficulty swallowing due to a jest or freak of nature. This trick of nature is of course the vascular ring. In the adult population dysphagia lusoria is commonly produced by an aberrant right subclavian artery arising from a normal left-sided aortic arch. The evolution of its treatment provides an interesting review of vascular surgical physiology and history. It was first treated by division of the aberrant artery. In some patients this resulted in subclavian steal syndrome or ischemia and led to reconstruction or reimplantation of the divided artery. Persistence of dysphagia after some of these procedures was the result of a large persistent diverticulum of Kommerell from which the aberrant artery arose. Typically, excision of the diverticulum of Kommerell is now an integral part of this surgery. T. W. R

KEY REFERENCES Backer CL, Hillman N, Mavroudis C, Holinger LD: Resection of Kommerell’s diverticulum and left subclavian artery transfer for recurrent symptoms after vascular ring division. Eur J Cardiothorac Surg 22:64-69, 2002. Backer CL, Ilbawi MN, Idriss FS, DeLeon SY: Vascular anomalies causing tracheoesophageal compression: Review of experience in children. J Thorac Cardiovasc Surg 97:725-731, 1989. Backer CL, Mavroudis C, Rigsby CK, Holinger LD: Trends in vascular ring surgery. J Thorac Cardiovasc Surg 129:1339-1347, 2005. Berdon WE: Rings, slings, and other things: Vascular compression of the infant trachea updated from the midcentury to the millennium—the legacy of Robert E. Gross, MD, and Edward B. D. Neuhauser, MD. Radiology 216:624-632, 2000.

tahir99-VRG vip.persianss.ir

180

Section 3 Pediatric Disorders

Burke RP, Rosenfeld HM, Wernovsky G, Jonas RA: Video-assisted thoracoscopic vascular ring division in infants and children. J Am Coll Cardiol 25:943-947, 1995. Grillo HC, Wright CD, Vlahakes GJ, MacGillivray TE: Management of congenital tracheal stenosis by means of slide tracheoplasty or resection and reconstruction, with long-term follow-up of growth after slide tracheoplasty. J Thorac Cardiovasc Surg 123:145-152, 2002.

Gross RE, Neuhauser B: Compression of the trachea or esophagus by vascular anomalies: Surgical therapy in 40 cases. Pediatrics 7:69-88, 1951. Jones DT, Jonas RA, Healy GB: Innominate artery compression of the trachea in infants. Ann Otol Rhinol Laryngol 103:347-350, 1994.

tahir99-VRG vip.persianss.ir

PATHOPHYSIOLOGY OF GASTROESOPHAGEAL REFLUX DISEASE AND HIATAL HERNIA

chapter

12

Sandro Mattioli

Key Points ■ The LES pressure is the result of the superimposition of the two

branches of the right pillar of the diaphragmatic hiatus to the intrinsic sphincteric area localized in the distal esophagus and proximal stomach. The loss of synergy between the intrinsic and the extrinsic components of the GEJ caused by a hiatal hernia impairs the mechanical properties of the gastroesophageal barrier. In the case of orad migration of the GEJ above the diaphragm, the increase of intra-abdominal pressure does not correspond to equal increase of the pressure of the LES complex because the diaphragmatic pinchcock does not strengthen the intrinsic sphincter and the lower esophagus is influenced by the negative intrathoracic pressure and not by the increased intra-abdominal pressure. ■ Axial hiatal hernias, characterized by the permanent supradiaphragmatic position of the GEJ and not the more common sliding hiatal hernia, are associated with severe GERD. The distance between the GEJ and the diaphragm and not the size of the hernia per se influences the degree of cardiac incontinence and the severity of GERD. ■ When cardiac incontinence is caused by a significant anatomic disorder such as in the case of the permanent axial migration of the GEJ across or above the diaphragm, it is reasonable to add this condition, if it is associated with severe and persistent GERD, to the list of indications for antireflux surgery. ■ The barium swallow is again essential for the preoperative workup: it alerts the patient and surgeon to the possibility of facing a case in which a more complex technique such as the Collis gastroplasty could be required if the radiologic orad migration of the GEJ corresponds to a true short esophagus. This awareness is crucial to illustrate properly to the patient the risks of surgery and the expected results and to plan the operation.

1946)5,6 and Barrett (Barrett, 1952)7 published from the early 1950s to the mid 1970s, surgery was the only option for effectively curing heartburn and esophagitis, which were considered to be strictly related to hiatal hernia. In the 1970s, on the basis of new concepts of the pathophysiology of GERD, the key role of functional mechanisms of the competence of the gastric cardia with respect to anatomic ones was outlined especially by gastroenterologists (Cohen and Harris, 1971).8 The concept that the anatomic disorders of the gastroesophageal junction (GEJ) had little to do with the cardiac competence remained unaltered for the next 20 years. The contemporary introduction of drugs effective in reducing gastric acidity and in enhancing upper gastrointestinal motility, such as histamine-2 blockers and metoclopramide, drastically reduced the indications for surgical therapy of GERD, at least among gastroenterologists. The numerous classifications adopted in the past are mainly based on surgical and radiologic anatomy. It is not surprising that physicians and surgeons could get lost in so many nonhomogeneous concepts and could miss the fact that to different anatomies there could be corresponding different pathophysiologic conditions. The historical perspective of the different classifications of hiatal hernia proposed in the past 100 years may help to understand the causes of the controversies on the relation between hiatal hernia and GERD. The definition of hiatal hernia includes several different anatomic abnormalities (Fig. 12-1). Akerlund (Akerlund, 1926; Akerlund, 1933)9,10 first proposed a classification of hiatal hernias into three types: 1. Type 1, hiatal hernia with congenital short esophagus 2. Type 2, paraesophageal hiatal hernia 3. Type 3, esophagogastric sliding hernia Allison (1951)5 distinguished five different types:

The role of hiatal hernia in the pathophysiology of gastroesophageal reflux has recently been reevaluated (Sloan et al, 1992; Kahrilas et al, 1995; Mattal, 1990).1-3 In particular, the correlation between hiatal hernia and higher degrees of gastroesophageal reflux has been demonstrated.1,4 In this chapter background information and actual data useful for selecting patients for surgical therapy and for choosing and correctly performing antireflux surgery are provided.

1. 2. 3. 4. 5.

Paraesophageal hernia Paraesophageal sliding hernia Sliding hernia Sliding hernia with paraesophageal sac Congenital short esophagus

Barrett (1952)7 described three types:

HISTORICAL NOTE

1. Sliding hernia 2. Paraesophageal hernia 3. Mixed hernia (Zaino et al, 1963)11,12

The history of the relationship between hiatal hernia and gastroesophageal reflux disease (GERD) is in some ways peculiar. After the studies of Allison (Allison, 1951; Allison,

Zaino and Poppel (Zaino et al, 1963)11 introduced new criteria of classification according to pathogenesis, anatomy, and evolution: 183 tahir99-VRG vip.persianss.ir

184

Section 4 Gastroesophageal Reflux and Associated Conditions

the acquired short esophagus phase associated or not with the paraesophageal herniation of the gastric fundus that evolves into the massive incarcerated hiatal hernia. Interestingly, Hiebert and Belsey pointed out that the initial stage of the axial gastric herniation process corresponds with more severe reflux symptomatology than in the case of massive intrathoracic herniation of the stomach.

A

B

C

PATHOPHYSIOLOGY

2

D

G

E

H

F

I

FIGURE 12-1 A, Normal gastroesophageal junction. B, Cardiofundic malformation (hiatal insufficiency). C, Sliding hiatal hernia. D, Paraesophageal hernia. E, Upside-down stomach. F, Mixed hiatal hernia. G, Short esophagus (congenital). H, Short esophagus (acquired). I, Endo-short-esophagus (Barrett’s esophagus).

1. Congenital (brachyesophagus) or acquired 2. True or false depending on the presence or absence of a sac 3. Short, normal, or long (redundant) depending on the length of the esophagus 4. Concentric or eccentric (ampullary or paraesophageal), depending on the site of the protruding stomach 5. Sliding, rolling, or pulsion in type, depending on the underlying mechanical derangements responsible for the hernia 6. Incarcerated or reducible, depending on the fixation of the hernia by adhesions 7. Primary or secondary, depending on the presence or absence of an associated lesion, such as a stricture, esophagitis, or a segmental spasm Zaino and coworkers called the initial stage of a sliding hernia hiatal insufficiency (Zaino et al, 1963),11 which is characterized by the disappearance of the intra-abdominal esophagus (submerged segment) and an obtuse angle of His. This anatomic-radiologic figure does correspond to the Wolf “hiatal herniation without a sac (Wolf, 1970),”13 to the Lortat-Jacob “malposition cardio-tuberositaire,”14 and to the Hiebert and Belsey “patulous cardia.”15 Zaino and Poppel, Wolf, LortatJacob, Hiebert, and Belsey indicated, after the initial one, further steps of axial migration of the GEJ into the chest:

Hiatal hernia impairs esophageal clearing, decreases basal lower esophageal sphincter (LES) pressure and its ability to act as a barrier when intra-abdominal pressure increases, and seems to favor transient LES relaxation. In normal individuals, gastroesophageal reflux is rapidly neutralized by primary and secondary peristalsis and by saliva, which titrates residual acid material adherent to the esophageal wall. Among the population of patients with reflux, those with hiatal hernia have more prolonged acid clearing time in the supine position (Mittal and Balaban, 1997).16-18 Mittal and colleagues19 demonstrated that patients with hiatal hernia, with or without esophagitis, had abnormally prolonged esophageal acid clearance time with respect to a group of patients with esophagitis but without hernia. This study was performed with concurrent esophageal pH recording and scintiscanning that showed repeated episodes of reflux from the hernia into the esophagus during swallowing.19 Using simultaneous videofluoroscopy and manometry, Sloan and Kahrilas17 studied three groups of patients divided according to different radiologic configurations of the esophagogastric junction: 1. Volunteers with a phrenic ampulla less than 2 cm long 2. Patients or volunteers with maximal ampullary or hiatal hernia length greater than 2 cm that reduced between swallows 3. Patients with hernias that did not reduce between swallows Esophageal emptying was recorded after each of 10 barium swallows; this parameter was impaired in both hernia groups but especially in the nonreducible hernia group. Early retrograde flow analogous to that described by Mittal and Balaban (Mittal and Balaban, 1997)18 was seen in almost half the patients in the third group. The LES pressure is the result of the superimposition of the two branches of the right pillar of the diaphragmatic hiatus to the intrinsic sphincteric area (Mittal and Balaban, 1997; Kahrilas et al, 1999)1,18,20 localized in the distal esophagus and proximal stomach. The loss of synergy between the intrinsic and the extrinsic components of the GEJ caused by hiatal hernia (Sloan et al, 1992; Kahrilas et al, 1999)1,20 impairs the mechanical properties of the gastroesophageal barrier. In the case of orad migration of the esophagogastric junction above the diaphragm, the increases of intra-abdominal pressure do not correspond to equal increases of the LES complex pressure because the diaphragmatic pinchcock does not strengthen the intrinsic sphincter and the lower esophagus is influenced by the negative intrathoracic pressure and not by the increased intra-abdominal pressure. This phenom-

tahir99-VRG vip.persianss.ir

Chapter 12 Pathophysiology of Gastroesophageal Reflux Disease and Hiatal Hernia

enon is also particularly evident in the case of nonreducible hernia (Kahrilas et al, 1999).20 To investigate whether intermittent separation of the diaphragm and LES favors the occurrence of gastroesophageal reflux, Bredenoord and associates (Bredenoord et al, 2006)21 performed a clinical study of 16 patients with small hiatal hernias (3 cm) using high-resolution esophageal manometry and pH-impedance monitoring. In all patients, both pressure profiles—single pressure peak profile (reduced hernia) and double-peak profile (unreduced hernia)—were observed. The prevalence of the double-peak profile ranged in individual patients between 11.1% and 91.1% of the total time. The incidence of reflux episodes was significantly lower when the hernia was reduced (12.2 ± 2.4 episodes per hour) than when the LES was spatially separated from the diaphragm (23.1 ± 5.1 episodes per hour). Previously, the same authors had shown that in patients with larger hiatal hernias (5 cm), the double-peak profile occurred more frequently than in patients with small hiatal hernias (3 cm), and the distance between the two pressure zones, when present, was larger.22 Patients affected by complicated and atypical GERD with hiatal hernias do require higher proton pump inhibitor dosages than patients without hernias to obtain an effective intraesophageal acid suppression.23 The relationship between hiatal hernia and transient relaxations of the LES (TLESR) is being debated. Kahrilas and coworkers (Kahrilas et al, 2000)24 divided 23 subjects into three groups: normal controls, and symptomatic GERD patients with and without hiatal hernia. They investigated the mechanisms provoking reflux in the basal condition and after infusion of air in the stomach. A radiopaque clip endoscopically placed at the squamocolumnar junction helped to fluoroscopically define the gastric hernia. In this study, it was concluded that in patients with GERD, hiatal hernia predisposes to an increased TLESR frequency, which is directly proportional to the distance between the squamocolumnar junction and the diaphragm, when TLESRs are elicited by gastric distention. Van Herwaarden and associates (Van Herwaarden et al, 2000)25 used ambulatory manometry to investigate the mechanisms of reflux in patients with sliding hiatal hernias that were identified during upper endoscopy. Gastroesophageal reflux was more severe in the patients with, than in those without, hiatal hernias, but excess reflux in patients with hiatal hernias was prevalently caused by causes other than TLESR. The incidence of reflux episodes related to TLESR was similar in the two groups. Both articles confirm that hiatal hernia predicts severe degrees of reflux and that the anatomic disorder impairs the mechanical properties of the gastroesophageal antireflux barrier, but results regarding the relationship between hiatal hernia and TLESR are contradictory. In the study by Bredenoord and coworkers, the numbers of reflux episodes due to TLESRs were similar in the single pressure peak profile (reduced) and in the double-peak profile (unreduced hernia state). TLESRs were responsible for 51.9% of all reflux episodes during the reduced state, whereas TLESRs were only responsible for 30.3% of the reflux epi-

185

sodes in the unreduced state. The increase in reflux rate during spatial separation of the LES and diaphragm was due to reflux mechanisms other than TLESR, the most important being swallow-associated reflux (Bredenoord et al, 2006).21 The reason why well-designed studies aiming toward the same end point lead to opposite results is probably the same reason why important misunderstandings originated in the past: using the term hiatal hernia to define different anatomic entities that create different pathophysiologic conditions (Mattioli et al, 1998).26 Another major cause of confusion lies in the fact that different diagnostic methods are adopted in research and in clinical practice to assess the presence and type of hiatal hernia. The authors of the two articles mentioned earlier diagnosed the presence of hiatal hernia, one with radiology and the other with endoscopy (Kahrilas et al, 2000; Van Herwaarden et al, 2000).24,25 The morphologic characteristics—size and nonreducibility of the hiatal hernia—have been placed in relation with more severe patterns of reflux disease (Kahrilas et al, 2000).24,27 However, they are not yet accepted as categorizing hiatal hernias. The role of the most frequent hiatal hernia, the sliding or reducible one, in GERD is also far from being defined.28 Surgeons have always been aware of the importance of the permanent infradiaphragmatic or supradiaphragmatic position of the GEJ (nonreducible hernias). This anatomic condition was associated with the most severe manifestations of GERD.29 Since the early 1980s, our group has focused its attention on the anatomic disorders of the GEJ. A radiologic classification currently used in North America30 that described the morphology of the steps of orad migration of the junction in detail (Wolf, 1960)30-32 was modified and adopted for clinical work and research (Fig. 12-2).33 Barium swallow was routinely performed in GERD patients at the diagnostic workup and during follow-up. Subsequently, with a radiologic-manometric study performed on four groups that included healthy volunteers (n = 9), patients with hiatal insufficiency (n = 27), patients with concentric hiatal hernia (n = 17), and patients with short esophagus (n = 11) (Mattioli et al, 1998),26 we showed that in the upright position, when the descent of the GEJ is maximal, the distance between the inferior margin of the LES and the diaphragm is significantly different among the categories considered, thus confirming that each class corresponds to a different degree of migration of the LES toward the chest. In the same article, we considered 132 patients preliminarily studied with the barium swallow: 38 patients with severe symptoms and esophagitis with sliding hiatal hernia with a reducible GEJ in the upright position; 35 patients with hiatal insufficiency; 40 patients with concentric hiatal hernia; and 19 patients with short esophagus. Patients also underwent upper esophagogastric tract endoscopy, stationary manometry, and ambulatory 24-hour threechannel esophagogastric pH monitoring.34 The esophageal acid exposure time was significantly greater in the concentric hiatal hernia and short esophagus groups than in the sliding hiatal hernia group, in spite of the fact that in the latter group symptoms and esophagitis were on average more severe than in the others. It was concluded that permanent esophagogastric junction orad migration axial to the esophagus has greater

tahir99-VRG vip.persianss.ir

186

Section 4 Gastroesophageal Reflux and Associated Conditions

TE

PA D SS EGJ

Angle of HIS

EGJ EGJ HH

a

HH

Z-line EGJ Normal EGJ

Hiatal insufficiency

A

Concentric hiatal hernia

b

Short esophagus

Hiatal Concentric Obvious Normal Reducible sliding insufficiency hiatal short GEJ hiatal hernia esophagus B hernia

Incarcerated hiatal hernia

FIGURE 12-2 A, Graphic representation of the various steps of irreducible intrathoracic migration of the gastroesophageal junction axial to the esophagus compared with the normal position. D, diaphragm; HH, hiatal hernia; PA, phrenic ampulla; TE, tubular esophagus; EGJ, esophagogastric junction; SS, intra-abdominally submerged segment of the esophagus. Black outline is esophageal wall; white outline is gastric wall. B, Radiographic anteroposterior images, with the patient in the upright position, of the various anatomic conditions of the gastroesophageal junction associated with gastroesophageal reflux disease. (FROM MATTIOLI S, D’OVIDIO F, PILOTTI V, ET AL: HIATUS HERNIA AND INTRATHORACIC MIGRATION OF ESOPHAGOGASTRIC JUNCTION IN GASTROESOPHAGEAL REFLUX DISEASE. DIG DIS SCI 48:1823-1831, 2003. WITH KIND PERMISSION OF SPRINGER SCIENCE AND BUSINESS MEDIA.)

pathophysiologic relevance on GERD than sliding hiatal hernia. Axial hiatal hernias, characterized by the permanent supradiaphragmatic position of the GEJ and not the more common sliding hiatal hernia, are associated with severe GERD. The distance between the GEJ and the diaphragm and not the size of the hernia per se influences the degree of cardiac incontinence. The radiologic classification we adopted in 1980 helps to correctly define anatomic disorders that have different pathophysiologic and clinical patterns and to diagnose any possible evolution.

CLINICAL PATTERNS The prevalence of hiatal hernia varies widely from 10% to 80% of the adult population in North America.35 Hiatal hernia is observed in 50% to 94% of patients with GERD and in 13% to 59% of control subjects.28,36-38 In Norway 16.6% of 670 subjects,38 in the United States 22% of 293 subjects,37 and in Sweden 14.5% of 1000 subjects39 undergoing upper endoscopy were found to have a hiatal hernia. The prevalence of hiatal hernia in patients with reflux esophagitis varies in different studies from 13%40 to 84%37 and in patients without reflux esophagitis from 2%40 to 13%.37 In patients with Barrett’s esophagus, a sliding hernia greater than 2 cm in length was detected in 96% of cases.41 Studies by Kaul and colleagues42 and Sontag and associates43 in patients with symptoms strongly suggestive of GERD showed that the prevalence of hiatal hernia in this patient group varied from 50% to 80%. Kasapidis and coworkers44 investigated the prevalence of esophagitis and hiatal hernia in patients with both reflux symptoms and pathologic esophageal acid exposure. A hiatal hernia was observed in 43% of the patients and in none of the asymptomatic subjects. In NERD patients (patients with classic symptoms of GERD and normal esophageal mucosa on upper endoscopy) the prevalence of hiatal hernia is 22% to 29%.41,45 Shapiro and

colleagues45 observed that in patients with functional heartburn, defined as “episodic retrosternal burning in the absence of pathological gastro-esophageal reflux, pathology-based motility disorders, or structural abnormalities,” with an esophageal acid exposure within the physiologic range during 24-hour esophageal pH monitoring, hiatal hernia was found in 20% of cases. Dysphagia in patients with hiatal hernia in the absence of esophagitis is not an uncommon occurrence.46 Kaul and coworkers47 observed 28/54 (55%) patients with hiatal hernia and dysphagia without esophagitis, esophageal stricture, Schatzki’s ring, or motility disorders of the esophagus. Using videoesophagography with barium contrast, they showed that the cause of dysphagia in 60% of these patients is an obstruction to the passage of the swallowed bolus by diaphragmatic impingement on the herniated stomach.47 The prevalence and clinical presentation of reducible and nonreducible hiatal hernia were investigated by our group within a GERD patient population (Mattioli et al, 2003).48 Complete clinical, endoscopic, and radiologic findings were recorded for 791 patients successively observed since 1981. On analysis, 552 patients (70%) had a normal or a reducible esophagogastric junction; in particular, 135 (17%) had a normal esophagogastric junction and no demonstrable hiatal hernia and 417 (53%) had a sliding hiatal hernia with a totally reducible esophagogastric junction. An irreducible esophagogastric junction axial to the esophagus was documented in 183 (23%) patients, of whom 78 (10%) had hiatal insufficiency, 45 (6%) had a concentric hiatal hernia, and 60 (7%) had a short esophagus. A massive incarcerated hiatal hernia was present in 56 (7%) patients. Reflux symptoms, dysphagia, and esophagitis were significantly (P < .001, P < .001, and P = .038, respectively) more severe in patients with irreducible axial esophagogastric junction than in those with a reducible esophagogastric junction. The duration of symptoms from onset to the time of first

tahir99-VRG vip.persianss.ir

Chapter 12 Pathophysiology of Gastroesophageal Reflux Disease and Hiatal Hernia

clinical evaluation was significantly higher (P = .018) in the group with an irreducible esophagogastric junction than in the group with a normal or reducible esophagogastric junction. A multinomial logistic regression analysis performed to predict the dependent radiologic group (reducible esophagogastric junction and irreducible intrathoracic esophagogastric junction axial to the esophagus) using reflux esophagitis, reflux symptoms, and duration of symptoms as factors, showed a significant effect of all the latter on the radiologic groups (P < .0001). The analysis proved a correct classification of 88% for the group with a reducible esophagogastric junction and of 52% for the group with an irreducible intrathoracic esophagogastric junction. In this study it was demonstrated that a sliding hiatal hernia with a reducible esophagogastric junction does not influence the severity of GERD; a nonreducible esophagogastric junction is associated with long-standing severe GERD; and clinical and endoscopic findings may only be indicative of axial esophagogastric junction irreducibility, and thus barium swallow needs to be part of the diagnostic workup of patients affected by GERD.

SURGERY Among the most challenging tasks faced by surgeons is the process of selecting patients, choosing the technique, and deciding on the operation for therapy of GERD and hiatal hernias. After decades of experience, long-term results of open antireflux surgery have been assessed. After Nissen repair, the mortality rate is 0% to 1% and postoperative complications are 10% to 20%; and at 5 years after surgery control of reflux is achieved in more than 90% whereas troublesome dysphagia is present in less than 5%.49 The patient satisfaction rate remains very high even if antacids or antisecretory medications are withdrawn (Spechler et al, 2001).50 Less brilliant results may be obtained after surgical treatment of cases complicated with esophageal motility abnormalities, columnar-lined esophagus, stricture and foreshortened esophagus, or paraesophageal and massive incarcerated hiatal hernia (Pearson et al, 1971; Chen et al, 1999; Swanstrom et al, 1996; Luketich et al, 2000; Johnson et al, 1998),51-63 in which more complex dedicated procedures are required. To reduce an adequate portion (2-3 cm) of distal esophagus in the abdomen without exerting tension on the esophagus itself and on the sutures, full mobilization of the thoracic esophagus and/or a procedure of elongation (Collis technique) associated with an antireflux partial or total fundoplication are necessary.53,54 With regard to complex GERD patients, Belsey observed poor long-term results of surgery in 45% of patients after his repair when an esophageal stenosis was present before the operation51 and when standard antireflux surgery failed in 15% to 21% of patients with Barrett’s esophagus.52 According to past experience, esophageal surgeons must be familiar with several antireflux procedures that have to be tailored to the underlying anatomic and functional abnormalities.64 It has been estimated that about 35% of the patients undergoing surgical therapy require a procedure different from a standard Nissen repair (Kauer et al, 1995).64

187

The experience of minimally invasive surgeons seems to be different. Many thousands of laparoscopic standard antireflux operations have been performed in the world, and numerous articles report satisfactory short- and medium-term functional results in over 90% of cases, but the need for a tailored approach has not emerged.49 The issue of the so-called short esophagus is one of the major points on the management and outcomes of laparoscopic antireflux surgery that deserves reappraisal (Low, 2001).65 Preoperative assessment of the length of the esophagus to decide which surgical technique to adopt is controversial. Yau and colleagues demonstrated that there is an association between esophageal shortening measured by standard manometry and postoperative paraesophageal herniation, but this increased risk is small.66 The most common clinical finding related to esophageal shortening is the presence of an esophageal stricture (Urbach et al, 2001; Mittal et al, 2000; Hoang et al, 2005)67-70; it may occur in 1% to 5%69,71,72 of patients with long-standing severe esophagitis. In this case, the risk of gastroplasty was increased 3.8-fold (95% CI, 1.0-15.0) in the study by Urbach and associates (Urbach et al, 2001)67 and by a factor of 7.5 (95% CI, 3.316.7) according to Gastal and colleagues (Gastal et al, 1999).73 Other predictors of the need for an esophageal lengthening procedure are paraesophageal hernia, Barrett’s esophagus, and failed antireflux surgery (Urbach et al, 2001).67 The presence of a paraesophageal hiatal hernia is considered to be highly predictive of the presence of short esophagus (Urbach et al, 2001).67,70,74 Maziak and associates (Maziak et al, 1998)75 reported that 80% (75/94) of patients with a large paraesophageal hernia required a lengthening procedure. Urbach and coworkers observed an increased risk of gastroplasty of 4.5-fold (95% CI, 1.4-14.6) for paraesophageal hernia, of 4.3-fold for Barrett’s esophagus (95% CI, 1.3-14.3), and of 11.6-fold for “redo” surgery (95% CI, 2.848.4) (Urbach et al, 2001).67 To identify patients in need of an esophageal lengthening procedure, preoperative esophagography, endoscopy, and esophageal manometric length assessment are useful (Urbach et al, 2001; Mittal et al, 2000; Gastal et al, 1999; Awad et al, 2001).67,68,73,76 However, no preoperative assessment can give information on the degree of elasticity or fibrosis of the esophagus (Awad et al, 2001).76 During laparoscopy, the pneumoperitoneum effaces the diaphragmatic hiatus, artificially increasing the length of the intra-abdominal esophagus; and appreciation of tension is difficult through the surgical instruments.77 In a study on the outcomes of the surgical treatment of GERD in 319 patients (Mattioli et al, 2004),78 the multivariate analysis showed the following preoperative factors as predicting the need for a Collis procedure: radiologic classification based on the assessment of the position of the GEJ with respect to the hiatus (P = .005) (odds ratio 20.53) (95% CI, 2.47-170.15); manometry in the upright position, performed after the standard recording in the supine position (P = .038) (odds ratio 5.26) (95% CI, 1.09-25.41); and the presence of peptic stenosis (P = .015) (odds ratio 5.18) (95% CI, 1.38-19.44).

tahir99-VRG vip.persianss.ir

188

Section 4 Gastroesophageal Reflux and Associated Conditions

Horvath and coworkers (Horvath et al, 2000)79 subdivide short esophagus into three groups: 1. True, nonreducible short esophagus 2. True, but reducible short esophagus 3. Apparent short esophagus Preoperatively, radiologic and endoscopic studies in the three groups place the GEJ across or above the hiatus. In the first category, the GEJ cannot be reduced for at least 2.5 to 3 cm below the diaphragm, while in the second category this length of the intra-abdominal esophagus is achieved after wide mobilization of the thoracic esophagus. In the third category, the esophagus has normal length but it is “accordioned” into the distal mediastinum (Horvath et al, 2000).79 To identify the GEJ in relation to the hiatus, intraoperative endoscopy has been proposed (Mittal et al, 2000; Mattioli et al, 2004; Awad et al, 1999).68,78,80 The reference to the gastric folds as an anatomic-endoscopic landmark of the GEJ (Sharma et al, 1998)81-83 helps to eliminate the subjective component of the evaluation in the presence of short and long Barrett’s esophagus (Chen et al, 1999; Awad et al, 2001; Mattioli et al, 2004).54,76,78 This anatomic reference also eliminates the risk of overdiagnosing the condition of short esophagus, as the gastric folds are normally located at or a few millimeters below the Z-line (Mattioli et al, 2004).78 After the endoscopist has placed the tip of the fiberscope at the level of the gastric folds, the point of passage between the tubular esophagus and the stomach is recognized by means of transillumination (Mittal et al, 2000)68 or by palpating the tip of the scope with a grasping forceps. As the length of the open jaws of the same forceps is known, the distance between the hiatus and GEJ can be estimated (Awad et al, 1999).80 The intraoperative esophageal mobilization followed by the measurement of the length of the intra-abdominal esophagus is the gold standard for determination of short esophagus (Mittal et al, 2000).68 As described by Collis,84 there is a large subset of patients who have true but moderate esophageal shortening, which can be treated by an extended mediastinal dissection. O’Rourke and associates (O’Rourke et al, 2003)85 proposed in patients with moderate short esophagus an extended laparoscopic transmediastinal dissection. These authors defined an esophageal dissection less than 5 cm into the mediastinum as type I and an esophageal dissection greater than or equal to 5 cm into the mediastinum as type II. On average, a type II dissection was carried up between 7 and 10 cm into the mediastinum. In cases in which type II dissection failed to release intra-abdominally an adequate segment of tensionfree esophagus, a thoracoscopic-assisted Collis gastroplasty was performed (O’Rourke et al, 2003).85 The lengthening gastroplasty is added to fundoplication if a minimum of 2.5 to 3.0 cm of tension-free intra-abdominal esophagus is not obtained after mobilization (Swanstrom et al, 1996; Luketich et al, 2000; Mittal et al, 2000; Awad et al, 2001; Mattioli et al, 2004; Horvath et al, 2000; O’Rourke et al, 2003).56,57,60,68,76-79,85-87 Surgeons with adequate experience are familiar with the techniques of transthoracic and transabdominal lengthening

gastroplasty, associated with a total or partial fundoplication. The mini-invasive Collis-Nissen procedure became progressively widespread, mainly in tertiary reference centers via a laparoscopic or a combined thoracolaparoscopic approach. In the mid 1990s two techniques of thoracoscopic gastroplasty and laparoscopic fundoplication were proposed (Swanstrom et al, 1996).56,88 Swanstrom performed the lengthening gastroplasty, introducing an endostapler through the right chest (Swanstrom et al, 1996).56 In 1998, Johnson and associates (Johnson et al, 1998)58 performed a laparoscopic technique that reproduced the laparotomic one promoted by Steichen. Instead, Awad and coworkers, in 2000, preferred the left thoracoscopic approach for introducing the articulated endostapler.86 The latter modification of the Collis gastroplasty is the stapled wedge gastroplasty published in 2004 by Terry and coworkers (Terry et al, 2004),89 Lin and associates,62 and, in 2005, by Hoang and colleagues (Hoang et al, 2005).69 This technique is performed laparoscopically; it requires the resection of a slice of gastric fundus to staple vertically the lesser curvature. The wedge gastroplasty was developed because with the fully laparoscopic technique, the apex of the tubularized fundus could become ischemic (Terry et al, 2004).89 A modified laparoscopic/left thoracoscopic technique for the surgical management of foreshortened esophagus was proposed by the Bologna group (Mattioli et al, 2004).78 When a concentric hiatal hernia or short esophagus is diagnosed radiologically, the patient is placed in the 45-degree left lateral position on the operating table with the left chest and arm lifted to perform a thoracostomy in the V-VI space, posterior to the axillary line. The hiatus is opened, and the distal esophagus is widely mobilized. With intraoperative endoscopy, the position of the GEJ in relation to the hiatus is determined to decide whether to perform a standard procedure for reflux or to lengthen the esophagus. In the second case, the short gastric vessels are divided and the gastric fundus is mobilized. An endostapler is introduced into the left chest. The Collis gastroplasty is performed over a No. 46 Maloney bougie. A floppy Nissen and the hiatoplasty complete the procedure (Fig. 12-3) (Mattioli et al, 2004).78 The long-term results of the open Collis procedure associated with antireflux surgery are not homogeneous, and satisfactory results vary from 59% (Chen et al, 1999)54,63 to 80% (Mattioli et al, 2004).78 With regard to the miniinvasive Collis-Nissen procedure, the early results were satisfactory and compared favorably with previous open surgery series. No operative mortalities were reported (Luketich et al, 2000; Johnson et al, 1998; Hoang et al, 2005; Terry et al, 2004).57,58,69,86,89,90 Complications ranged from none to 50% (Luketich et al, 2000; Johnson et al, 1998; Hoang et al, 2005; Terry et al, 2004).57,58,69,86,89,90 Postoperative functional assessment at 12 months for Hunter’s series revealed that 11% of patients complained of reflux symptoms and 11% had dysphagia (Johnson et al, 1998).58 Medium-term follow-up in Jobe and associates’ series revealed 14% of patients with reflux symptoms and 14% with dysphagia (Jobe et al, 1998).91 No wrap failures or mediastinal herniations were observed (Jobe et al, 1998).91 Awad and coworkers reported similar outcome data at a mean follow-up of 17 months: 9% of

tahir99-VRG vip.persianss.ir

Chapter 12 Pathophysiology of Gastroesophageal Reflux Disease and Hiatal Hernia

Gastric folds

189

+ 1 cm

Clip

Endoscopy tip

V-VI sp. 45°

Clips

B

C

A

clips

3 cm

D

E

FIGURE 12-3 A, Position of the patient for the left laparothoracoscopic procedure. Pelvis and chest are turned approximately 45 degrees toward the right side of the patient to allow access to the posterior axillary line. With the right-left rotation of the operative bed, the surgeon always operates comfortably. B, Position of the gastroesophageal junction in relation to the diaphragmatic hiatus is determined with the help of the fibroendoscope; the scope’s tip is positioned at the upper margin of the gastric folds (black arrow). The surgeon localizes the scope by transillumination or palpation mediated by a grasper. C, Measurement with an L-shaped ruler of the distance between the gastroesophageal junction and the apex of the hiatus after completely relaxing the stomach. D, Collis lengthening gastroplasty through a left thoracostomic approach; the neo-esophagus is 3 cm long. E, Antireflux surgery according to Nissen-DeMeester fashioned around the neo-esophagus. The apex of the lengthening gastroplasty according to Collis is completely covered by the fundoplication.

patients complained of reflux symptoms and 9% had dysphagia (Awad et al, 2001).76 They objectively documented a 9% wrap failure rate and a 9% mediastinal herniation rate (Awad et al, 2001).76 The Collis gastroplasty is also a suitable procedure in case of reoperation after a failed antireflux procedure, as performed by Luketich in 52.5%.90 Two specific causes of dysfunction of the lengthening gastroplasty have been focused on. The lack of motility of the neo-esophagus may predispose to dilation of the tube or contribute to postoperative dysphagia (Hoang et al, 2005; Horvath et al, 2000).62,69,79 Of more potential concern is the production of acid secretion within the neo-esophagus–localized esophagitis, as was observed in open Collis procedures (Chen et al, 1999; Hoang et al, 2005; Horvath et al, 2000).54,62,69,79 Jobe and coworkers (Jobe et al, 1998)91 performed an objective follow-up in 15 patients after laparoscopic lengthening gastroplasty and antireflux fundoplication: in 7 of 15 patients, the neo-esophagus above the wrap was found to contain parietal cells that continued to secrete acid. This was indicated by an abnormal postoperative DeMeester score and was confirmed by positive Congo red

testing of the suspected mucosa. Hunter suggests that the highest stitch of the fundoplication be placed on the native esophagus to avoid leaving parietal cells above the fundoplication.62 Although the Collis gastroplasty is conceptually appealing, these problems call into question the liberal application of this technique during antireflux surgery.62

SUMMARY In conclusion, the evidence that anatomic disorders of the GEJ may play a pivotal role in the pathophysiology of GERD has been acquired only a few years ago. The terms hiatal hernia and sliding hiatal hernia are insufficient and imprecise because they include a variety of subtypes. Not the common sliding hiatal hernia characterized by an GEJ that fully descends below the diaphragm in the upright position but the permanent axial migration of the junction across or above the hiatus is associated with the most severe degrees of gastroesophageal reflux caused by the mechanical impairment of the LES and the increase in the time of contact between the reflux and esophageal mucosa. This condition is irreversible,

tahir99-VRG vip.persianss.ir

190

Section 4 Gastroesophageal Reflux and Associated Conditions

it may have a negative evolution (but we do not know when and how), and it can be definitively resolved only by surgery. It is generally agreed that surgery is indicated in patients affected by severe GERD who are not compliant with longterm medical therapy (Cohen and Harris 1971),8 require high dosages of drugs,92 or are too young for lifetime medical treatment (Spechler et al, 2001).50,93-96 Very likely patients who fulfill the current indications for surgery just listed are those with a nonreducible hiatal hernia who require higher drug dosages to control acid reflux in the long term or forever. Because cardiac incontinence is caused by a significant anatomic disorder, it is thus reasonable to add the permanent axial migration of the esophagogastric junction across or above the diaphragm associated with severe and persistent GERD to the list of indications for antireflux surgery already accepted by the medical community. The paraesophageal and the massive incarcerated hiatal hernia are good indications per se for surgical therapy to prevent chronic bleeding and strangulation of the herniated viscus. The barium swallow is essential for providing information that is helpful for the patient and the physician to choose the therapy, whether medical or surgical. The upper gastrointestinal tract imaging associated with other clinical data, such as the duration and severity of symptoms, presence of a peptic stenosis, Barrett’s esophagus, upright esophageal manometry, and large paraesophageal hernia, alert the patient and surgeon to the possibility of facing a case in which a more complex technique such as the Collis gastroplasty could be required. This awareness is crucial to illustrate properly to the patient the risks of surgery and the expected results and to plan the operation.

COMMENTS AND CONTROVERSIES Dr. Mattioli precisely outlines and reviews the “synergy between the intrinsic and extrinsic components of the gastroesophageal junction” in the pathophysiology of GERD. Hiatal hernias cause two important problems: (1) loss of intra-abdominal domain of the distal esophagus and (2) loss of the sphincteric effect of the esophageal hiatus. The intra-abdominal esophagus and functioning esophageal hiatus are crucial elements of the antireflux barrier that have been underappreciated and overlooked in the treatment of GERD. These two elements plus the intrinsic LES must be considered and deficiencies addressed during any surgical treatment of GERD. Unfortunately with the advent of less invasive antireflux surgery, the “synergy” of these three elements has been further overlooked in an attempt to “minimize” the surgery. Failures to (1) restore the intra-abdominal esophagus by posterior mediastinal mobilization or esophageal lengthening and (2) reconstruct the esophageal hiatus are common problems identified at reoperation for failed GERD surgery. Most recently, the practice of mesh reinforcement of the esophageal hiatus has been popularized to minimize failed laparoscopic repairs of large type III (paraesophageal) hernias. This philosophy, that assumes the esophageal hiatus is nothing more than a “hole,” ignores its critical role in the antireflux barrier. For successful control of GERD the three components of the antireflux barrier must be assessed and their function restored. T. W. R.

KEY REFERENCES Akerlund A: Die anatomischen Grundlagen des Röntgenbildes der sogenannten erworbenen Hiatushernie. Acta Radiol 14:523-544, 1933. Akerlund A: Hernia diaphragmatica hernia oesopagei, von anatomischen unt rontgenologischen Gesichtspunct. Acta Radiol 6:3, 1926. Allison PR: Peptic ulcer of the esophagus. J Thorac Surg 15:308-317, 1946. Allison PR: Reflux esophagitis: Sliding hiatal hernia and anatomy of repair. Surg Gynecol Obstet 92:419-431, 1951. Awad ZT, Dickason TJ, Filipi CJ, et al: A combined laparoscopicendoscopic method of assessment to prevent the complications of short esophagus. Surg Endosc 13:626-627, 1999. Awad ZT, Mittal SK, Roth TA, et al: Esophageal shortening during the era of laparoscopic surgery. World J Surg 25:558-561, 2001. Barrett NR: Hiatus hernia. Proc R Soc Med 45:279-286, 1952. Bredenoord AJ, Weusten BL, Timmer R, Smout AJ: Intermittent spatial separation of diaphragm and lower esophageal sphincter favors acidic and weakly acidic reflux. Gastroenterology 130:334-340, 2006. Chen LQ, Nastos D, Hu CY, et al: Results of the Collis-Nissen gastroplasty in patients with Barrett’s esophagus. Ann Thorac Surg 68:10141020, 1999. Cohen S, Harris LD: Does hiatus hernia affect competence of the gastroesophageal sphincter? N Engl J Med 284:1053-1056, 1971. Gastal OL, Hagen JA, Peters JH, et al: Short esophagus: Analysis of predictors and clinical implications. Arch Surg 134:633-638, 1999. Hoang CD, Koh PS, Maddaus MA: Short esophagus and esophageal stricture. Surg Clin North Am 85:433-451, 2005. Horvath KD, Swanstrom LL, Jobe BA: The short esophagus: Pathophysiology, incidence, presentation, and treatment in the era of laparoscopic antireflux surgery. Ann Surg 232:630-640, 2000. Jobe BA, Horvath KD, Swanstrom LL: Postoperative function following laparoscopic Collis gastroplasty for shortened esophagus. Arch Surg 133:867-874, 1998. Johnson AB, Oddsdottir M, Hunter JG: Laparoscopic Collis gastroplasty and Nissen fundoplication: A new technique for the management of esophageal foreshortening. Surg Endosc 12:1055-1060, 1998. Kahrilas PJ, Lin S, Chen J, Manka M: The effect of hiatus hernia on gastro-oesophageal junction pressure. Gut 44:476-482, 1999. Kahrilas PJ, Shi G, Manka M, Joehl RJ: Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology 118:688-695, 2000. Kahrilas PJ, Wu S, Lin S, Puoderoux P: Attenuation of esophageal shortening during peristalsis with hiatus hernia. Gastroenterology 109:1818-1825, 1995. Kauer WK, Peters JH, DeMeester TR, et al: A tailored approach to antireflux surgery. J Thorac Cardiovasc Surg 110:141-146, 1995. Low DE: Surgery for hiatal hernia and GERD: Time for reappraisal and a balanced approach? Surg Endosc 15:913-917, 2001. Luketich JD, Grondin SC, Pearson FG: Minimally invasive approaches to acquired shortening of the esophagus: Laparoscopic Collis-Nissen gastroplasty. Semin Thorac Cardiovasc Surg 12:173-178, 2000. Mattioli S, D’Ovidio F, Di Simone MP, et al: Clinical and surgical relevance of the progressive phases of intrathoracic migration of the gastroesophageal junction in gastroesophageal reflux disease. J Thorac Cardiovasc Surg 116:267-275, 1998. Mattioli S, D’Ovidio F, Pilotti V, et al: Hiatus hernia and intrathoracic migration of esophagogastric junction in gastroesophageal reflux disease. Dig Dis Sci 48:1823-1831, 2003.

tahir99-VRG vip.persianss.ir

Chapter 12 Pathophysiology of Gastroesophageal Reflux Disease and Hiatal Hernia

Mattioli S, Lugaresi ML, Di Simone MP, et al: The surgical treatment of the intrathoracic migration of the gastro-oesophageal junction and of short oesophagus in gastro-oesophageal reflux disease. Eur J Cardiothorac Surg 25:1079-1088, 2004. Maziak DE, Todd RJ, Pearson FG: Massive hiatus hernia: Evaluation and surgical management. J Thorac Cardiovasc Surg 115:53-60, 1998. Mittal KR: Current concepts of antireflux barrier. Gastroenterol Clin North Am 19:501-516, 1990. Mittal RK, Balaban DH: The esophagogastric junction. N Engl J Med 336:924-932, 1997. Mittal SK, Awad ZT, Tasset M, et al: The preoperative predictability of the short esophagus in patients with stricture or paraesophageal hernia. Surg Endosc 14:464-468, 2000. O’Rourke RW, Khajanchee YS, Urbach DR, et al: Extended transmediastinal dissection: An alternative to gastroplasty for short esophagus. Arch Surg 138:735-740, 2003. Pearson FG, Langer B, Henderson MB: Gastroplasty and Belsey hiatal hernia repair: An operation for the management of peptic stricture with acquired short esophagus. J Thorac Cardiovasc Surg 61:50-63, 1971. Pringot J, Ponette E: Radiological examination of the esophagus. In Vantrappen G, Hellemans J (eds): Disease of the Esophagus. Berlin, Springer-Verlag, 1974, pp 154-156. Sharma P, Morales TG, Sampliner RE: Short segment Barrett’s esophagus: The need for standardization of the definition and of endoscopic criteria. Am J Gastroenterol 93:1033-1036, 1998.

191

Sloan S, Rademaker AW, Kahrilas PJ: Determinants of gastroesophageal junction incompetence: Hiatal hernia, lower esophageal sphincter, or both? Ann Intern Med 117:977-982, 1992. Spechler SJ, Lee E, Ahnen D, et al: Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: Follow-up of a randomized controlled trial. JAMA 285:2331-2338, 2001. Swanstrom LL, Marcus DR, Galloway GQ: Laparoscopic Collis gastroplasty is the treatment of choice for the shortened esophagus. Am J Surg 171:477-481, 1996. Terry ML, Vernon A, Hunter JG: Stapled-wedge Collis gastroplasty for the shortened esophagus. Am J Surg 188:195-199, 2004. Urbach DR, Khajanchee YS, Glasgow RE, et al: Preoperative determinants of an esophageal lengthening procedure in laparoscopic antireflux surgery. Surg Endosc 15:1408-1412, 2001. Van Herwaarden MA, Samsom M, Smout AJ: Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 119:1439-1446, 2000. Wolf BS: Roentgen features of the normal and herniated esophagogastric region: Clinical correlations. In Jerzy Glass GB (ed): Progress in Gastroenterology. New York, Grune & Stratton, 1970. vol II, pp 288-315. Wolf BS: Roentgen features of the normal and herniated oesophagogastric region: Problems in terminology. Am J Dig Dis 5:751-758, 1960. Zaino C, Poppel MH, Jacobson HG, Lepow H: The Lower Esophageal Vestibular Complex. Springfield, IL, Charles C Thomas, 1963.

tahir99-VRG vip.persianss.ir

chapter

13

MEDICAL TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE Joel E. Richter

The medical therapy for gastroesophageal reflux disease (GERD) is based on knowledge of the pathophysiology of the disease and a defined set of goals based on symptom presentation and severity of mucosal damage. The ideal medical therapy would augment lower esophageal sphincter (LES) pressure and/or reduce the number of transient LES relaxations, improve esophageal clearance of refluxed gastric contents, accelerate gastric emptying, augment mucosal resistance, and neutralize gastric acidity. Unfortunately, no single drug or drug class addresses all these potential pathogenic mechanisms. In fact, most therapies are directed only at acid control (antacids, H2-receptor antagonists [H2RAs], and proton pump inhibitors [PPIs]) yet result in excellent symptom relief and healing of the esophagitis. The expenditure in the United States alone for these antacid medications exceeds $6 billion per year. The rationale for GERD therapy depends on a careful definition of specific aims. In patients without esophagitis, the therapeutic goals are simply to relieve the acid-related symptoms and to prevent frequent symptomatic relapses. In patients with esophagitis, the goals are to relieve symptoms and to heal the esophagitis while attempting to prevent further relapses and the development of complications (stricture, hemorrhage, or Barrett’s esophagus). These goals are set against a complex background: GERD is a chronic disease that waxes and wanes in intensity, and relapses are common.

NONPRESCRIPTION THERAPY Although GERD is common in the United States, many individuals do not seek medical care for their complaints; instead, they choose to change their lifestyles and self-medicate with over-the-counter antacids and low doses of H2RAs. These observations have led to the “iceberg” model of the GERD population (Fig. 13-1). Most heartburn sufferers selfmedicate and do not seek professional help; only those at the tip of the iceberg, typically patients with severe symptoms or reflux complications, are seen by physicians.1

LIFESTYLE MODIFICATIONS Numerous dietary and lifestyle modifications have been advocated for the treatment of GERD. Before the availability of acid-inhibiting drugs, these interventions formed the backbone of medical therapy for this disease. However, although sound in their intent and sometimes based on solid laboratory research, these lifestyle changes (Table 13-1) can today be considered only adjuncts to pharmacologic therapy. It is important to educate patients about these interventions,

outlining their rationale so that patients can choose for themselves how to integrate these into their treatment plan. In fact, some patients with mild disease will find them extremely helpful whereas others with severe disease will find them of minimal benefit.

Food and Beverages Acidic beverages such as colas and teas, citrus products, and tomato-based foods can exacerbate heartburn symptoms.2 Stimulation of gastric acid or esophageal sensitivity to low pH or hyperosmolar liquid solutions may account for these symptoms.3 The effect of coffee on GERD is controversial, with some studies showing a decrease in LES pressure4; another trial showed no effect of coffee on number of reflux episodes, total reflux time, or LES pressure5; and a third study actually reported an increase in LES pressure.6 Furthermore, there is conflicting evidence that different coffee preparations (caffeinated vs. decaffeinated), roasting methods, and/or processing methods affect GERD parameters.7 A large U.S. epidemiologic study found no association between coffee drinking and GERD.8 Chocolate is frequently implicated as a provoker of GERD because its high xanthine content decreases LES pressure and increases esophageal acid exposure.9 Onions and carminatives (i.e., peppermint) also have been implicated in aggravating heartburn symptoms. However, the data for prohibiting most of these foods in heartburn sufferers are weak. Rather, prohibition of food products should be tailored to those foods or beverages that bring on individual symptoms, so as to promote dietary compliance. The fat content and the timing of meals relevant to bedtime may be more important than the specific foods themselves in promoting GERD. Studies have clearly shown that a highfat meal will decrease LES pressure and increase reflux frequency in both normal and GERD patients9-11; however, it is not clear whether this is based purely on the presence of fat or on meal size. Fat delays gastric emptying, which may also increase the risk of reflux. Although there is reason to recommend a decrease in fat for other health reasons, good outcome studies in GERD patients are again lacking. It is recommended that GERD patients refrain from eating within several hours of bedtime, because a full stomach produces gastric distention and an increase in transient LES relaxation and, therefore, increases gastroesophageal reflux. A recent epidemiologic study, adjusting for smoking and drinking habits and body mass index (BMI), found that a shorter time between dinner and going to bed was significantly associated with an increased risk of GERD. The odds ratio for patients

192 tahir99-VRG vip.persianss.ir

Chapter 13 Medical Treatment of Gastroesophageal Reflux Disease

Persistent symptoms and complications Frequent symptoms seen by MD

Occasional symptoms not seen by MD

Asymptomatic Barrett’s esophagus FIGURE 13-1 The gastroesophageal reflux disease “iceberg” displays the clinical presentations of typical manifestations.

having night-time reflux complaints whose dinner-to-bed time was less than 3 hours was 7.45 (95% CI, 3.38-16.4) compared with patients whose dinner-to-bed time was 4 hours or more.12

Sleeping The recommendation to elevate the head of the bed is based on the theory that stomach contents containing acid will more likely reflux into the esophagus while patients are lying flat without the inhibiting effect of gravity. Studies using prolonged pH monitoring have shown an acceleration of esophageal clearance when the head of the bed is elevated compared with sleeping flat.13 One study found that head of the bed elevation was nearly as effective as ranitidine therapy in healing esophagitis.14 To be effective, the entire upper torso of the body, rather than just the head, should be elevated during sleep by placing 6- to 8-inch blocks under the head of the bed frame, by using a Styrofoam wedge, or by using a mechanical hospital bed and placing the patient in a reversed Trendelenburg position. Sleeping on the left side has also been proposed as being beneficial.15 Specifically, total reflux time, average acid clearance, and LES relaxation are significantly prolonged in patients lying on their right sides compared with the left lateral decubitus position. The reason for this phenomenon is not completely clear but may be related to increased transient LES relaxation in the right position or possibly that the gastroesophageal junction lies above the level of the gastric acid in the stomach in the left lateral position. Unfortunately, there is no currently available commercial device to ensure patients stay on their left side while sleeping. Lifestyle changes during sleep are not recommended for all patients, but only for those with night-time symptoms or laryngeal/pulmonary complaints possibly initiated by acid aspiration while asleep.

Smoking and Alcohol Cigarette smoking decreases LES pressure, prolongs acid clearance, diminishes saliva production, and impairs the pharyngeal/upper esophageal sphincter contractile reflex.16,17 LES pressure falls almost immediately after the start of smoking, with return to normal values within minutes after

193

TABLE 13-1 Lifestyle Modifications in GERD 1. Alter eating habits. ■ Eat smaller meals. ■ Do not lie down after eating. ■ Avoid bedtime snacks. 2. Modify diet. ■ Decrease fatty foods. ■ If symptoms occur, reduce intake of coffee, tea, cola drinks, citrus fruit, and tomato-based products. ■ Limit intake of chocolate, peppermint. 3. Change posture during sleep if nocturnal symptoms are a problem. ■ Elevate head of bed. ■ Sleep on left side. 4. Refrain from smoking and decrease alcohol intake. 5. Avoid refluxogenic medications when possible. ■ Anticholinergics ■ Benzodiazepines ■ β-Agonists ■ Calcium channel blockers ■ Opioids ■ Progesterone-containing medications ■ Xanthines 6. Lose weight, even if not overweight.

the completion of the cigarette.18 Multivariate analysis from a case-control study showed that increased duration of daily smoking was associated with increasing reflux symptom, with the odds ratio (OR) for reflux 1.7 (95% CI, 1.4-2.0) in daily smokers with greater than 20-year tobacco history compared with those who smoked daily for less than a year.19 Despite these physiologic data, three case-controlled studies20-22 have failed to show that smoking cessation for 24 to 48 hours improved acid reflux parameters. Alcohol may precipitate gastroesophageal reflux by reducing LES pressure, increasing spontaneous sphincter relaxation, impairing esophageal and gastric motility, and increasing acid secretion.23 Intraesophageal pH studies in healthy volunteers have demonstrated increased reflux after consumption of both high-proof alcoholic beverages (vodka, whiskey) and low-proof beverages (beer, wine).24 White wine increases the amount of acid reflux more than red wine, and the effect of beer was more pronounced than both types of wine.25 Randomized and cross-sectional studies have suggested an increased prevalence of symptomatic reflux in alcohol users.26,27 No study has assessed the role of alcohol cessation on gastroesophageal reflux or its symptoms.

Medications Certain medications may aggravate heartburn by reducing LES pressure (see Table 13-1).1 This group includes xanthines such as theophylline; anticholinergics including propantheline, dicyclomine, and tricyclic antidepressants; narcotic analgesics; calcium channel blockers such as nifedipine, verapamil, and diltiazem; benzodiazepines; β-adrenergic agonists; and progesterone-containing oral contraceptives. Other medications, including tetracycline and its derivatives, quinidine

tahir99-VRG vip.persianss.ir

Section 4 Gastroesophageal Reflux and Associated Conditions

preparations, aspirin and other nonsteroidal anti-inflammatory drugs, alendronate sodium, both iron and potassium preparations, and ascorbic acid may injure the esophagus directly, producing a “pill esophagitis.” Most patients with pill esophagitis will complain of odynophagia (i.e., painful swallowing) as well as heartburn, chest pain, and dysphagia. Although we commonly recommend avoiding or reducing these medications in our GERD patients, there is a lack of good clinical trials showing improvement in reflux symptoms when these medications are avoided or discontinued.

Obesity Obesity is speculated to cause GERD symptoms due to multiple factors, including increased gastroesophageal sphincter gradient, incidence of hiatal hernia, intra-abdominal pressure, and output of bile and pancreatic enzymes. Although studies were initially conflicting, the majority of data now consistently show that obesity is associated with a statistically significant increase in the risk for GERD symptoms, erosive esophagitis, and esophageal adenocarcinoma.28 For example, a study from the Houston Veterans Administration Hospital found that obese participants were 2.5 times more likely as those with a normal BMI (<25) to have reflux symptoms or esophageal erosions. A dose-response relationship between frequency of heartburn or regurgitation and higher BMI was observed.29 A case-controlled population study from Norway also found a dose-response association between increasing BMI and reflux symptoms in both sexes with a significantly stronger association in women. Compared with those with a BMI less than 25, the risk of reflux was increased significantly among severely obese (BMI >35) men (OR 3.3; 95% CI, 2.4-4.7) and women (OR 6.3; 95% CI, 4.9-9.0).30 Finally, the Nurses Health Study of over 10,000 women reported a dosedependent relationship between increasing BMI and frequent reflux symptoms (Fig. 13-2).31 Even in women with a normal baseline BMI, an increase in BMI of more than 3.5, as com-

FIGURE 13-2 Association between body mass index and the risk of frequent symptoms of gastroesophageal reflux. (FROM JACOBSON BC, SOMERS SC, FUCHS CS, ET AL: BODY MASS INDEX AND SYMPTOMS OF GASTROESOPHAGEAL REFLUX IN WOMEN. N ENGL J MED 354:2340-2348, 2006.)

Multivariate odds ratio

194

4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0

pared with no weight changes, was associated with an increased risk of frequent symptoms of reflux (OR 2.80; 95% CI, 1.63-4.82). Importantly, there was a nearly 40% reduction in the risk of frequent reflux symptoms among women with a decrease in BMI of more than 3.5 as compared with women without a change in BMI (OR 0.64; 95% CI, 0.420.97). These latter observations are consistent with two studies showing reduction in acid reflux parameters in obese patients losing up to 10% of their body weight.32,33 In my own practice, I have found weight loss especially effective when discrete periods of weight gain can be associated with exacerbations of reflux symptoms.

OVER-THE-COUNTER MEDICATIONS Over-the-counter (OTC) antacids, Gaviscon, and H2RAs are very useful in treating mild and infrequent heartburn symptoms, especially when symptoms are brought on by lifestyle indiscretions. Antacids increase LES pressure but work primarily by buffering gastric acid in the esophagus and stomach, albeit for relatively short periods. Heartburn symptoms are rapidly relieved, which is the major reason these drugs are so popular for mild intermittent symptoms. However, patients with more frequent GERD symptoms need to take antacids on a regular basis, usually 1 to 3 hours after meals and at bedtime. In this latter group, chronic use of magnesiumcontaining antacids may cause diarrhea and should be avoided in patients with heart failure, with renal insufficiency, and in late-trimester pregnancy. Aluminum-containing antacids may cause constipation. Gaviscon, containing alginic acid and antacids, mixes with saliva to form a highly viscous solution that floats on the surface of the gastric pool, acting as a mechanical barrier. Both antacids34 and Gaviscon35 are more effective than placebo in relieving symptoms induced by heartburnpromoting meals. However, these agents do not heal esophagitis, and long-term trials suggest effective symptom relief in only 20% of patients using antacids.36

P
.001

2.93 (2.24–3.85) 2.92 (2.35–3.62) 2.43 (1.96–3.01) 2.20 (1.81–2.66)

1.38 (1.13–1.67)

0.67 (0.48–0.93)


20.0

20.0–22.4

22.5–24.9

25.0–27.4

27.5–29.9

30.0–34.9

35.0

Body mass index

tahir99-VRG vip.persianss.ir

Chapter 13 Medical Treatment of Gastroesophageal Reflux Disease

H2RAs are available OTC at doses usually one half of the standard prescription dose. Although their onset of relief is not as rapid as antacids, the OTC H2RAs have a longer duration of action, up to 6 to 10 hours. From a practical standpoint, they are most useful when taken before a potentially refluxogenic activity, such as a heavy meal or exercise. Like antacids, OTC H2RAs are ineffective in healing esophagitis.37 In the summer of 2003, the U.S. Food and Drug Administration (FDA) approved omeprazole (20 mg) as the first OTC proton pump inhibitor (PPI). This was only the second conversion of a prescription drug to an OTC form at its full dose. Drug labeling suggests daily use for only 2 weeks, and recommended physician follow-up for persistent symptoms. Despite initial fears of patients abusing this drug and not seeing a physician, early consumer data support that individuals accurately self-select if OTC omeprazole is appropriate to use, comply with a 2-week regimen, and seek physician care for long-term management of frequent heartburn.38

PRESCRIPTION THERAPY Patients with frequent heartburn, esophagitis, or complications of GERD usually see a physician and receive prescription medications for their disease. Mucosal protective agents potentially bind with acid, pepsin, and bile salts whereas promotility drugs attempt to improve the motility abnormalities associated with GERD. However, the key to controlling symptoms and healing esophagitis is the number of hours each day the intragastric pH is greater than 4.39 This can only be done in the acute and chronic setting with H2RAs or PPIs.

Sucralfate A mucosal protective agent, sucralfate binds to inflamed mucosa protecting the tissue from further injury by acid, pepsin, and bile acids, allowing mucosal healing.40 Currently, sucralfate is rarely used in GERD patients because of the need to administer it four times a day. When compared with H2RAs, equivalent healing rates of erosive esophagitis are demonstrated, although overall healing rates are not as high.41,42 Sucralfate has little systemic absorption and is a safe and effective agent for treating the heartburn of pregnancy when lifestyle modifications fail.43

Promotility Drugs Conceptually, a promotility drug that increases LES pressure, decreases episodes of transient LES relaxation, improves esophageal clearance, and augments gastric emptying, all potential motility abnormalities in GERD, should be an ideal agent for treating this disease. A prokinetic drug might be especially useful when heartburn is associated with no or mild esophagitis or by symptoms suggestive of a diffuse motility disturbance, such as regurgitation, nausea, bloating, or aspiration symptoms. Unfortunately, issues of efficacy, availability, and, most importantly, safety have limited the role of promotility agents to an adjunct role in the treatment of selective patients with GERD.

195

Metoclopramide and bethanechol are the currently available promotility agents, both affordable in generic form, that are being used for treating GERD.44 Metoclopramide blocks dopamine-2 receptors in the esophagus, stomach, and proximal small intestine while augmenting the effect of acetylcholine receptors within the enteric nervous system. Therefore, it increases LES pressure, improves esophageal clearance, decreases gastroesophageal reflux, and accelerates stomach emptying.45 Metoclopramide also blocks dopamine receptors in the chemoreceptor trigger zone of the medulla and the vomiting center within the blood-brain barrier. At a dose of 10 mg 30 minutes before meals and bedtime, metoclopramide improves reflux symptoms better than placebo and as well as the H2RAs cimetidine and ranitidine.46 Healing of esophagitis has not been consistently demonstrated with metoclopramide alone,44 but when it is used in addition to an H2RA, such as cimetidine, accelerated healing rates have been observed.47 The use of metoclopramide has been limited by its safety profile because it crosses the blood-brain barrier. Antidopaminergic side effects are observed in 20% to 40% of patients, especially young or elderly patients with prolonged high-dose regimens. Anxiety, agitation, confusion, motor restlessness, hallucinations, and drowsiness are the most common reversible side effects; depression and tardive dyskinesia (potentially irreversible) are the most serious side effects. To avoid side effects, I prefer to use metoclopramide at a single dose of 10 or 20 mg before the large evening meal or at bedtime, particularly in patients with evening regurgitation or delayed gastric emptying. Bethanechol, a direct-acting cholinergic drug, increases LES pressure and the amplitude of esophageal contractions as well as increasing secretion of saliva that is rich in bicarbonate.44 Studies in children and adults demonstrate improvement in GERD symptoms and healing of esophagitis in patients treated with bethanechol, 25 mg, 30 minutes before meals and at bedtime. Abdominal pain, blurred vision, wheezing, fatigue, and urinary frequency occur in 10% to 15% of patients and are more common in the elderly. Cisapride acts locally by facilitating release of acetylcholine from postganglionic neurons in the myenteric plexus and may potentiate the activity of other mediators of gut function, such as the 5HT4 serotonin receptors. As a result, LES pressure increases, esophageal clearance is improved, and gastric emptying is enhanced.44 Before its removal from the U.S. market in 2001, cisapride was approved for night-time control of GERD50 and clearly was the most widely prescribed and effective promotility drug for the treatment of GERD. It is consistently better than placebo in improving symptoms, promotes the healing of low-grade but not severe esophagitis, and has an overall efficacy similar to that of H2RAs at standard doses.44 Standard cisapride dosing is 10 mg four times a day, before meals and at bedtime. Cisapride was withdrawn from the U.S. market because of increased reports of serious cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation) with associated cardiac arrest and deaths related to possible drug interactions.51

tahir99-VRG vip.persianss.ir

196

Section 4 Gastroesophageal Reflux and Associated Conditions

Dobrilla et al,61 1992

0.39 (0.25, 0.59)

Goy et al,62 1983

0.87 (0.62, 1.15)

Hine et al,63 1984

0.76 (0.51, 1.04)

Lehtola et

al,64

1986

0.73 (0.47, 1.06)

Palmer et al,65 1990

0.62 (0.48, 0.77)

Quik et al,66 1990

0.80 (0.66, 0.96)

Sabesin et al,67 1991

0.70 (0.61, 0.80)

Sherbaniuk et

al,68

1984

0.92 (0.74, 1.12)

Simon et al,69 1994

0.83 (0.70, 0.99)

Sontag et al,70 1987

0.74 (0.53, 1.02)

Kar et al,71 1990

0.62 (0.34, 0.99)

Roufail et al,72 1992

0.70 (0.57, 0.83)

Silver et al,73 1996

0.67 (0.58, 0.76)

Brown et al,75 1979

0.33 (0.09, 1.11)

al,76

1980

0.63 (0.33, 1.24)

Johansson et al,77 1986

0.70 (0.46, 0.96)

Wesdorp et al,78 1978

0.38 (0.18, 0.70)

Combined [random]

0.72 (0.65, 0.79)

Festen et

0.01

0.2 0.1 0.5 Relative risk (95% confidence interval)

1

2

FIGURE 13-3 Forest plot of randomized controlled trials comparing H2RAs with placebo in the treatment of esophagitis over 4 to 8 weeks. (FROM PRESTON C, DONNELLAN C, MOAYYEDI P: MEDICAL TREATMENTS FOR THE SHORT-TERM MANAGEMENT OF REFLUX OESOPHAGITIS. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS [PROTOCOLS]. VOLUME [2], 2006.)

Domperidone, a peripheral dopamine antagonist, stimulates the upper gastrointestinal tract similar to metoclopramide. Trials evaluating the clinical efficacy of domperidone in GERD have produced inconsistent results.44,52 Domperidone does not cross the blood-brain barrier and thus has few central side effects. As with metoclopramide, domperidone can cause hyperprolactinemia with breast engorgement, nipple tenderness, galactorrhea, and amenorrhea in some women. Domperidone is available in Canada and Europe but not in the United States. Tegaserod (Zelnorm; Novartis, Basel, Switzerland), a partial 5-HT4 serotonin receptor agonist, is used to treat women with constipation-predominate irritable bowel syndrome and both genders with chronic constipation. In a recent crossover study of patients with mild-to-moderate reflux disease, tegaserod, 1 mg/day, caused a more than 50% decrease in acid exposure in the postprandial period.53 Its role in the treatment of GERD, either as a sole therapy or combination with PPI, has yet to be determined. The previously discussed promotility agents have no effect on the frequency of transient LES relaxations, the common motility abnormality in all forms of GERD.54 Several agents, including cholecystokinin-A agonists, anticholinergic drugs, nitric oxide synthase inhibitors, and γ-aminobutyric acid (GABA) B agonists have been shown to reduce transient LES

relaxations.58 The only agent available for oral therapy is baclofen, a GABA agonist. Several studies have shown that 10 to 20 mg of baclofen three to four times daily for up to 4 weeks reduces 24-hour esophageal acid and bilirubin reflux, reflux events, and symptoms in healthy subjects and patients with GERD.56-58 Baclofen needs to be titrated upward slowly, beginning at 5 mg four times a day and increased over 10 days to 40 to 60 mg/day. Side effects are common, however, and include drowsiness, nausea, and the lowering of the threshold for seizures. New compounds with more specific and better targeted action will be developed in the future.

Histamine-2 Receptor Antagonists Prior to the availability of PPIs, H2RAs were the mainstay of GERD therapy. The four available agents—cimetidine, ranitidine, famotidine, and nizatidine—derive their efficacy in GERD exclusively by inhibiting acid secretion. They have no effect on LES pressure, transient LES relaxation, esophageal clearance, or gastric emptying. H2RAs only block one receptor on the parietal cell, thus they only reduce postprandial acid secretion by 60% to 70%.59 In contrast, the antisecretory capabilities of H2RAs are best at night, with duration of acid inhibition longer when the drug is taken in the evening or before bedtime. All the H2RAs are equally effective when

tahir99-VRG vip.persianss.ir

Chapter 13 Medical Treatment of Gastroesophageal Reflux Disease

100 PPI H2RA 80 (12)

% Total heartburn free

(17)

60 (13)

(10)

40 (10) (3) 20

0 0

1–2

3–4

6–8

Time in weeks FIGURE 13-4 Symptom relief-time curve expressed as the mean total heartburn relief for PPIs or H2RAs corrected for patients free of heartburn at baseline and over 8 weeks. By week 2, more patients treated with PPIs are asymptomatic compared with patients treated with H2RAs even after a much longer duration of treatment (8 weeks). (FROM CHIBA N, GARA CJ, WILKINSON JM, HUNT RH: SPEED OF HEALING AND SYMPTOM RELIEF IN GRADE II TO IV GASTROESOPHAGEAL REFLUX DISEASE: A META-ANALYSIS. GASTROENTEROLOGY 112:1789-1804, 1997.)

used in proper doses (cimetidine, 600 mg; ranitidine, 150 mg; famotidine, 20 mg; nizatidine, 150 mg), usually given twice a day before meals. H2RAs have been available as OTC agents since 1995. Clinical GERD trials show that heartburn, both day and night, can be significantly decreased by H2RAs compared with placebo, with a number needed to treat (NNT) of five (95% CI, 2-17).60 However, symptoms are rarely abolished on H2RA therapy, even with high doses, and 25% to 60% of patients have persistent heartburn complaints. In a recent Cochrane review,60 H2RAs were found to be effective in healing esophagitis over 4 to 8 weeks, compared with placebo in 18 trials61-78 involving 2134 patients. The relative risk (RR) of esophagitis persisting with H2RAs was 0.72 (95% CI, 0.650.79) (Fig. 13-3) with an NNT of five (95% CI, 3-22). Healing rates in acute studies differ in individual trials, depending primarily on the degree of esophagitis being treated: grade I and II (Los Angeles classification A and B) esophagitis heals in 60% to 90% of patients, whereas grade III and IV (Los Angeles classification C and D) heals in 30% to 50% of patients despite high-dose regimens.79 Reflux symptoms associated with nocturnal gastric acid breakthrough during PPI therapy have been recognized.80 One study reported that the addition of an H2RA at bed time to a twice-daily PPI regimen successfully eliminated this problem, suggesting a new indication for H2RAs in the PPI era.81 However, this study used only a single evening dose, did not mention a washout time, but noted that all four studies (ranitidine, 150 mg or 300 mg at bedtime; omeprazole, 20 mg at bedtime, or placebo) were completed over the following 4 to 21 days. Other groups82,83 attempted to replicate this study, finding identical results after 1 day on a bedtime H2RA added to twice-daily PPI regimen, but by 1 and 4 weeks of bedtime H2RA the night-time gastric acid secretion had returned to values observed with PPIs alone.

Cloud et al,90 1998

0.08 (0.02, 0.27)

Earnest et al,91 1998

0.19 (0.09, 0.41)

Hetzel et al,92 1988

0.23 (0.12, 0.42)

Richter et al,93 2000

0.18 (0.12, 0.28)

Sontag et al,94 1992

0.57 (0.44, 0.73)

Combined [random]

0.23 (0.10, 0.50)

0.01

197

0.1 0.2 Relative Risk (95% confidence interval)

0.5

1

FIGURE 13-5 Forest plot of randomized controlled trials comparing PPIs with placebo in the treatment of esophagitis over 4 to 8 weeks. (FROM PRESTON C, DONNELLAN C, MOAYYEDI P: MEDICAL TREATMENTS FOR THE SHORT-TERM MANAGEMENT OF REFLUX OESOPHAGITIS. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS [PROTOCOLS]. VOLUME [2], 2006.)

tahir99-VRG vip.persianss.ir

198

Section 4 Gastroesophageal Reflux and Associated Conditions

Armbrecht et al,95 1997

0.59 (0.27, 1.13)

Armstrong et

al,96

2001

0.45 (0.26, 0.75)

Bardhan et

al,97

1995

0.29 (0.17, 0.47)

Dehn et

al,98

1990

0.60 (0.36, 0.95)

99

1998

0.54 (0.32, 0.89)

Duvnjak et al,100 2002

0.32 (0.20, 0.49)

Dettmer et al,

101

2000

0.63 (0.50, 0.79)

Feldman et al,102 1993

0.29 (0.16, 0.50)

Farley et al,

Green et

al,103

1995

0.70 (0.60, 0.81)

Havelund et

al,104

1988

0.37 (0.23, 0.57)

Group,105

1991

0.54 (0.39, 0.73)

106

Italian Reflux Oesophagitis Study

1999

0.35 (0.21, 0.57)

Kawano et al,107 2002

0.42 (0.21, 0.79)

Klinkenburg-Knol et al,108 1987

0.33 (0.15, 0.64)

Koop et al,109 1995

0.69 (0.53, 0.92)

Jansen and Van Oene,

Kovacs et

al,110

2002

0.50 (0.35, 0.67)

111

2000

0.22 (0.10, 0.49)

al,112

Menchen et al, Meneghelli et

2002

0.47 (0.36, 0.61)

Pare et al,113 2003

0.35 (0.20, 0.60)

Petite et al,114 1991

0.40 (0.24, 0.63)

Robinson et al,115 1995

0.40 (0.27, 0.60)

al,116

1993

0.45 (0.32, 0.62)

117

1988

0.48 (0.33, 0.68)

118

2000

0.52 (0.36, 0.76)

VanTrappen et al,119 1988

0.46 (0.23, 0.86)

Robinson et

Sandmark et al, Van Zyl et al,

Zeitoun et al,120 1987

0.45 (0.29, 0.67)

Combined [random]

0.47 (0.41, 0.53)

0.01

0.1 0.2 0.5 Relative Risk (95% confidence interval)

1

2

FIGURE 13-6 Forest plot of randomized controlled trials comparing PPIs and H2RAs in the treatment of esophagitis over 4 to 8 weeks. (FROM PRESTON C, DONNELLAN C, MOAYYEDI P: MEDICAL TREATMENTS FOR THE SHORT-TERM MANAGEMENT OF REFLUX OESOPHAGITIS. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS [PROTOCOLS]. VOLUME [2], 2006.)

This is secondary to the phenomenon of tolerance to H2RAs that occurs with continuous usage over weeks to months.84 Placebo controlled studies have not tested the symptomatic efficacy of H2RAs at night for control of nocturnal reflux symptoms. Although not formerly tested, possibly intermittent H2RAs used when patients are exposed to refluxogenic events (i.e., after a large, late fatty meal or night of cocktails) may be the optimal approach to minimizing the chance of drug tolerance. The H2RAs are very safe, with a side effect rate (most are minor and reversible) of about 4%.85 Typical minor gastrointestinal side effects include nausea, abdominal pain, and bloating. There have been some concerns about drug interactions with H2RAs, particularly with drugs metabolized by the cytochrome P450 system. Serum concentrations of pheny-

toin, procainamide, theophylline, and warfarin are altered after the administration of cimetidine and, to a lesser degree, ranitidine, whereas this interaction is not reported with the other two H2RAs. However, the clinical consequences of these drug interactions are minimal and rarely result in a clinically important interaction. The former concern that these agents could alter blood ethanol levels has been discounted.85

Proton Pump Inhibitors Proton pump inhibitors revolutionized the treatment of GERD and currently are the mainstay of both acute and chronic treatment regimens by all groups of physicians. This class of drugs markedly diminishes gastric acid secretion over a 24-hour period, by inhibiting the final common pathway of

tahir99-VRG vip.persianss.ir

Chapter 13 Medical Treatment of Gastroesophageal Reflux Disease

Patients Healed at 8 Weeks (%)

90.0

94.1

100

93.7 86.9

92.6

90

88.8 84.2

80.0 70.0 60.0 50.0 40.0 30.0

Patients Healed at 8 Weeks (%)

100.0

199

91.7 91.3 86.3 86.0

84.6 79.7

80

74.6

70 62.1

60 50 40 30 20 10

20.0 Kahrilas et al, 2000122 Richter et al, 2001123 Castell et al, 2002124 (n  1,304) (n  2,435) (n  5,241)

0 Grade A (n  1878)

Grade B (n  2076)

Grade C (n  959)

Grade D (n  327)

Esomeprazole, 40 mg Omeprazole, 20 mg

Esomeprazole, 40 mg

Lansoprazole, 30 mg

Lansoprazole, 30 mg

FIGURE 13-7 Healing rates of erosive esophagitis at 8 weeks comparing esomeprazole, 40 mg (orange bars) to omeprazole, 20 mg (green bars) or lansoprazole, 30 mg (blue bar) showing statistical superiority of esomeprazole to both the older PPIs. (DATA MODIFIED AND REDRAWN FROM REFERENCES 122 TO 124.)

acid secretion, the H+, K+-ATPase pump. PPIs inhibit daytime, nocturnal, and meal-stimulated acid secretion to a significantly greater degree than H2RAs86 but rarely make patients achlorhydric. Unlike H2RAs, the degree of acid inhibition with PPIs does not correlate with plasma concentration but it is related to the concentration and duration of drug availability (area under the curve). PPIs are weak bases that concentrate in the secretory canaliculi of the parietal cell at pH less than 4. Here the inactive benzimidazole of the PPI is converted to a cationic sulfonamide, which binds to cysteines on the proton pumps, blocking acid production.87 The onset of inhibition after oral ingestion is delayed because PPIs need to accumulate in the secretory canaliculi to bind irreversibly to actively secreting proton pumps.88 Therefore, the slower the PPI is cleared from the plasma, the more of it is available for delivery to the pumps. PPIs are best taken before the first meal, when most pumps are active, blocking 70% to 80% of the active pumps. New H+, K+-ATPase molecules must be synthesized, a process requiring 36 to 96 hours. A second dose, if needed, can be taken before the evening meal. Acid inhibition is never complete because of the continuous synthesis of new pumps, and a steady state is required to maintain continuous acid control.88 The five available PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole, the S-isomer of the racemic omeprazole. Their superior efficacy compared with H2RAs is based on their ability to maintain an intragastric pH greater than 4 for between 15 and 21 hours, compared with approximately 8 hours daily with the H2RAs.89 PPIs are superior to H2RAs in completely relieving heartburn symptoms in

FIGURE 13-8 Healing rates by grade of erosive esophagitis comparing esomeprazole, 40 mg, with lansoprazole, 30 mg, at 8 weeks. The study illustrates the decrement in healing rates as one proceeds from Los Angeles classification grade A through D. This decrement is less for esomeprazole (orange bars) compared with lansoprazole (green bars). (FROM CASTELL DO, KAHRILAS PJ, RICHTER JE, ET AL. ESOMEPRAZOLE [40 MG] COMPARED WITH LANSOPRAZOLE [30 MG] IN THE TREATMENT OF EROSIVE ESOPHAGITIS. AM J GASTROENTEROL 97:573-583, 2002.)

most patients with severe GERD, usually within 1 to 2 weeks (Fig. 13-4).79 In a recent Cochrane review,60 PPIs were more effective than placebo in healing esophagitis (RR = 0.23: 95% CI, 0.01-0.05) (Fig. 13-5) with an NNT of two (95% CI, 1.4-2.5). In these studies, there were five trials that compared PPIs with placebo in 635 patients.90-94 The review also identified 26 trials95-120 involving 4064 patients that compared PPIs with H2RAs. PPIs were superior to H2RAs in healing esophagitis at 4 to 6 weeks (RR = 0.47; 95% CI, 0.410.53) (Fig. 13-6) with an NNT of 3 (95% CI, 2.8-3.6). Another Cochrane systematic review found that PPI therapy was superior to placebo and H2RAs in endoscopynegative GERD and undiagnosed reflux symptoms in primary care, although the effect was not as marked as with esophagitis.121 Until recently, the therapeutic efficacy between PPIs was similar. However, recent large studies (1000-2500 patients) have found the newest PPI esomeprazole, 40 mg, superior to omeprazole, 20 mg, and lansoprazole, 30 mg, in healing esophagitis (Fig. 13-7).122-124 The therapeutic advantage is minimal with mild Los Angeles classification A-B esophagitis (NNT 20-40 patients) and greatest with severe Los Angeles classification C-D esophagitis (NNT 7-10 patients) (Fig. 13-8). This superiority is related to higher systemic bioavailability and less interpatient variability with esomeprazole. All the PPIs are well tolerated, with headaches and diarrhea described as the most common side effects in clinical

tahir99-VRG vip.persianss.ir

200

Section 4 Gastroesophageal Reflux and Associated Conditions

trials. Although increased gastrin levels are reported with all PPIs, the elevations generally do not exceed the normal range for gastrin and return to normal values within 1 week of stopping the drug. Omeprazole may decrease the clearance of diazepam and warfarin because of competition for the cytochrome P450 isoenzyme P2C19.125 The four newer PPIs have minimal or no important drug-to-drug interactions.

SPECIAL TREATMENT SITUATIONS Maintenance Therapy GERD tends to be a chronic relapsing disease, especially in patients with low LES pressure, large hiatal hernia, severe grades of esophagitis, and difficult-to-manage symptoms. Although almost all patients with severe esophagitis can be healed with PPI therapy, recurrence can be anticipated in more than 80% of patients within 6 months of drug discontinuation.92 The chronicity of less severe forms of GERD is less certain, but relapses probably occur in 15% to 30% of patients over 6 months.126 Therefore, maintenance therapy is needed for many patients. One-year maintenance studies always find PPIs superior to H2RAs or prokinetics. A recent systematic review identified 10 randomized trials involving 1583 esophagitis patients that compared the efficacy of PPIs versus H2RAs over 6 to 12 months.127 The relapse rate for esophagitis was 22% on PPIs compared with 58% on H2RAs, with an NNT of 2.5 (95% CI, 2.0-3.4). Similar results were noted when symptom relapse was the end point. This review also identified six trials comparing half dose PPI to H2RA therapy in 1156 patients. With this dosing regimen, 40% of the PPI group had esophagitis relapse versus 66% of the H2RA group (NNT = 3.3; 95% CI, 2.5-5). Therefore, low-dose PPI regimens are also superior to H2RAs but not as effective as standard dose therapy.

Intermittent or On-Demand Therapy Many patients with nonerosive or mild esophagitis can be controlled with intermittent medication because they do not progress to complicated reflux disease. The two approaches are intermittent courses of PPI therapy (e.g., 2 to 4 weeks) or on-demand treatment (e.g., the patient takes a drug for symptoms for as many days as he or she wishes). These trials are difficult to analyze because the end points in trials vary. Nevertheless, a recent systematic review128 identified five trials evaluating on-demand H2RA therapy. All showed superiority to placebo with no difference between the type of H2RA prescribed. Likewise, five on-demand trials of PPIs were identified, all showing statistical superiority to placebo. In these studies, patients took the drug 33% to 50% of the time, and 70% to 93% were willing to continue therapy. There were no studies comparing PPIs with H2RAs, and all placebo-controlled studies were in patients with nonerosive GERD.

Refractory GERD Traditionally, patients with reflux symptoms no longer undergo initial endoscopy but rather are given a 4- to 8-week

TABLE 13-2 FDA Classification of Drugs Used for GERD in Pregnancy Drugs

FDA Classification*

Antacids

None

Sucralfate

B

Histamine-2 receptor antagonists

B

Promotility drugs Cisapride Metoclopramide

C B

Proton pump inhibitors Omeprazole All others including esomeprazole

C B

*FDA Classification: Category A: Well controlled studies in humans show no fetal risk. Category B: Animal studies show no risks. Category C: Animal studies show risk but human studies are inadequate or lacking. Category D: Definite fetal abnormalities in human studies but potential benefits may outweigh the risks. Category X: Contraindicated in pregnancy, fetal abnormalities in animals or humans. Risks outweigh benefits.

trial of a PPI. Failure to improve occurs in 25% to 42% of patients, thus placing them in a more difficult to manage group.129 At this point, the physician should ensure patient compliance and review timing of the PPI dose (30 minutes to 1 hour before a meal). One recent study found that nearly 70% of primary physicians and 20% of gastroenterologists gave the PPI dose at bedtime or did not believe the relationship to meals was important.130 Switching to a second-generation PPI (i.e., pantoprazole, esomeprazole) may be a reasonable alternative. This was recently confirmed in a multicenter study of patients with persistent heartburn symptoms while receiving lansoprazole, 30 mg once daily.131 Switching to a single dose of esomeprazole (40 mg) was as effective as twice-daily lansoprazole in relieving heartburn complaints over 8 weeks of therapy. Most physicians, however, increase the current PPI dosing to twice-daily dosing (before breakfast and dinner), with up to 25% of patients responding.132 Those patients doing no better fall into the “refractory GERD” category.133

Treatment of Elderly or Pregnant Patients Frequently, older patients have less severe reflux symptoms than their younger cohorts, but because of prolonged acid exposure over years the elderly may have more complicated disease.134 Treatment of the older GERD patient follows the same principles as that in other adults, although they may require more aggressive acid suppression therapy.135 Pillinduced esophagitis may complicate their treatment. Metoclopramide must be used with caution because of frequent side effects in the elderly. H2RAs can be associated with mental changes in older patients, and doses need to be decreased in patients with renal insufficiency. Fewer drug interactions are seen with famotidine and nizatidine. Alternative methods of PPI administration may be necessary

tahir99-VRG vip.persianss.ir

Chapter 13 Medical Treatment of Gastroesophageal Reflux Disease

in debilitated patients who cannot swallow intact capsules. PPI capsules can be opened and the granules taken with water, a bicarbonate-based suspension, or apple or orange juice, or the granules can be sprinkled on applesauce or yogurt.136 Teratogenicity or fetal harm from absorption of medications across the placenta is the foremost consideration in the treatment of GERD during pregnancy.137 Lifestyle modifications and antacids or Gaviscon remain the cornerstones of treatment, providing adequate relief to the majority of pregnant women with mild symptoms. Although rarely used in adults, sucralfate was found superior to lifestyle changes in a controlled study in pregnant women.43 Metoclopramide, H2RAs, and most PPIs (except omeprazole) have an FDA category B safety rating for use during pregnancy (Table 13-2), based on animal studies showing no risk, as well as small case series and anecdotal human reports. Ranitidine is the only one of the acid-inhibiting drugs shown to be effective during pregnancy in a clinical trial.138 PPIs are safe for aspiration prophylaxis before anesthesia for cesarean sections. Antacids, sucralfate, and most H2RAs (except nizatidine) are safe to use during breastfeeding, even though the latter group of drugs is excreted in breast milk. PPIs are not recommended during lactation, based on safety concerns in animal studies.137

COMMENTS AND CONTROVERSIES Gastroesophageal reflux disease (GERD) is a very common, chronic relapsing condition. It must be remembered that for the majority of patients the goal of therapy is symptom control. As superbly outlined by Dr. Richter, lifestyle modifications and the careful use of an increasingly effective armamentarium of medicines can successfully control GERD in the majority of patients. Most patients require intermittent or on-demand therapy that can now be provided without supervision by H2RAs or PPIs that are available over the counter. As illustrated in this chapter, only a small subgroup of patients seek physician care and this is the tip of the GERD “iceberg.” With patient education, selection of the appropriate medication, and proper dosing most of these patients will have symptom relief. Failure to control symptoms with appropriate therapy taken correctly should raise the question “Is this GERD?” The patient who has poor symptom control in this setting is likely to have a poor outcome after antireflux surgery. T. W. R.

Acknowledgment The author thanks Liz Koniz for excellent secretarial assistance in the preparation of this chapter.

201

chapter

14

EVALUATION AND SURGICAL TREATMENT OF HIATAL HERNIAS AND GASTROESOPHAGEAL REFLUX Kashif Irshad Arjun Pennathur James D. Luketich Key Points

■ The evaluation of a patient possibly requiring surgical treatment of

hiatal hernia and gastroesophageal reflux begins with a careful history. ■ Essential evaluations are barium esophagography, esophagogastroduodenoscopy with biopsy, esophageal manometry, and 24hour pH monitoring. ■ Principles of antireflux surgery are reduction of the hiatal hernia with restoration of the intra-abdominal esophagus, repair of the esophageal hiatal mechanism, and reinforcement of the lower esophageal sphincter. ■ Choice of the operation and modification will be dictated by patient evaluation.

GASTROESOPHAGEAL REFLUX DISEASE Reflux of gastric contents into the distal esophagus is a physiologic event that is generally associated with minimal to no symptoms and if measured by pH studies of the esophagus occurs up to 4% of the time. The distinction between physiologic gastroesophageal reflux and gastroesophageal reflux disease (GERD), therefore, can be a difficult one. However, patients with daily symptoms, or those whose reflux results in histologic changes in the epithelium of the esophagus, such as esophagitis or intestinal metaplasia (Barrett’s esophagus), can be considered to suffer from GERD. This chapter is designed to provide an overview of this broad subject. We refer the readers to a number of other detailed chapters in this text on related topics such as giant paraesophageal hernia, motor disorders of the esophagus, and details of surgical technique. The most common symptoms of GERD are heartburn and regurgitation of food. However, a significant proportion of patients may have “atypical” symptoms, such as chest pain and wheezing. Although GERD is common, these atypical symptoms may be mistaken for other common diseases, such as coronary artery disease and asthma. For this reason, it is not uncommon for patients with GERD to have symptoms for many years before undergoing appropriate evaluation and treatment. Another reason for a delay in evaluation is that most patients will have some initial symptom relief with widely available over-the-counter medications and may not consider surgery as an option. For the majority of patients with GERD, a combination of appropriate medications and lifestyle modifications will result in adequate control of symptoms. It is estimated that only 10% of patients with GERD will “fail” medical therapy. 202

Because GERD is estimated to affect more than 40 million Americans, this represents a large population of patients who may be considered for surgical intervention. Before surgical consideration it is important that the diagnosis of GERD be firmly established and that appropriate medical therapy has been attempted. For example, a busy surgeon will see patients referred for “fundoplication” who have not had adequate counseling on medical therapy or lifestyle changes or in fact who may suffer from other esophageal diseases, such as achalasia or scleroderma. Patients with atypical symptoms must be carefully scrutinized because it may be more difficult to confirm the diagnosis and the relief of symptoms after fundoplication. A careful evaluation with objective documentation of reflux is required to assure both the patient and the surgeon that a fundoplication will improve these symptoms.

Signs and Symptoms Typical signs and symptoms of GERD include heartburn, regurgitation, and dysphagia. If GERD is not treated, the normal esophagus can progress to erosive esophagitis, Barrett’s esophagus, and esophageal strictures (Fig. 14-1). Up to 15% of patients may present with atypical symptoms, including postprandial fullness, wheezing, chronic cough, hoarseness, choking, belching, vomiting, nocturnal aspiration, odynophagia, and chest pain. As a result, this disease can be confused with a multitude of medical conditions, including achalasia, esophageal spasm, esophageal cancer, cholelithiasis, peptic ulcer disease, pulmonary disease, and coronary artery disease. Interestingly, it has been shown that up to 50% of patients who present with angina-like chest pain and have a negative cardiac workup will be found to have significant gastroesophageal reflux on further evaluation.1

Pathophysiology Several mechanisms contribute to GERD. These can be broadly classified into disorders of the lower esophageal sphincter (LES, the valve), impaired ability of the esophagus (the pump) to clear physiologic reflux, or an impaired capacity of the stomach (the reservoir) to store or transit contents downstream. The most common cause of GERD is an incompetent LES mechanism. Unlike other sphincters such as the pylorus, the LES is not a clearly defined muscle.2 However, it can be characterized manometrically as a zone of elevated intraluminal pressures near the gastroesophageal junction that typically is 4 cm long. The LES valve, ideally, is primarily a one-way mechanism that opens to accept contents delivered by the peristaltic esophagus and then closes. Importantly,

Chapter 14 Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux

FIGURE 14-1 A normal distal esophagus exposed to bile and acid (A) may progress to erosive esophagitis (B), Barrett’s esophagus (C), and esophageal strictures (D).

A

B

C

D

however, backward flow does occur to a limited degree in patients without GERD when physiologic demands are appropriate, for example, when the need to belch or vomit occurs. The crural portion of the diaphragm also aids in the prevention of reflux. Contraction of the crura during a Valsalva maneuver increases LES pressure, thereby preventing gastroesophageal reflux. Loss of this protective mechanism is an important cause of GERD in patients with a hiatal hernia. Not surprisingly, a hiatal hernia is present in up to 70% of patients with GERD.3 Even when a hiatal hernia is not identified on a standard esophagogram, a small sliding hiatal hernia may be present. Any hiatal hernia can displace the LES high-pressure zone proximally, diminish effective esophageal emptying, and widen the diaphragmatic hiatus, all of which contribute to the development of GERD. Failure to see any hiatal hernia at all is of concern when considering an antireflux operation, and clear objective evidence of GERD should be documented. An inability of the peristaltic, pumping mechanism of the esophagus to clear physiologic refluxate may also lead to symptoms of GERD. This is a common contributing factor to GERD symptoms in patients with motility disorders of the esophagus, such as scleroderma. Another contributing factor to GERD symptoms is abnormal salivary function. The alkaline saliva plays an important role in the neutralization and clearance of acid from the distal esophagus. Abnormal salivary function occurs in rare diseases, such as Sjögren’s syndrome. A more common cause is radiation therapy for the treatment of head and neck cancer. Impaired function of the stomach, due to either decreased compliance or poor emptying, also contributes to reflux. This

may occur in patients with a large hiatal hernia in which the stomach assumes an abnormal configuration within the chest and as a consequence does not empty appropriately. Gastric outlet obstruction either from malignancy or peptic ulcer disease, or diabetic gastropathy, may also lead to symptoms of reflux for similar reasons. However, a significant number of patients with GERD will not have an overt anatomic abnormality, such as a large hiatal hernia or gastric outlet obstruction. For these patients, “functional causes” of LES dysfunction are thought to play a primary role. The most important of these is transient lower esophageal sphincter relaxations (TLESRs). In these cases the basal resting pressure of the LES is normal. However, transient decreases in this resting pressure occur that lead to episodes of reflux. It has been estimated that nearly all episodes of reflux are due to TLESR in patients without significant GERD.3a For those with severe esophagitis, an abnormal basal LES pressure plays a more predominant mechanism, although TLESRs also play a significant role.3b The major stimulus for TLESR is gastric distention, which is thought to be mediated by vagal pathways. Other functional causes may contribute to GERD in some patients. For instance, patients with morbid obesity may have significant reflux due to a chronic elevation in intraabdominal pressure that may overcome the resting pressure of a normal LES.4,5 Dietary and social habits may also promote GERD. For example, fatty meals have been demonstrated to promote TLESR. Similarly, smoking and alcohol consumption have both been shown to lead to a decrease in resting pressure of the LES as well an impaired ability of the esophagus to clear reflux.6,7 Other uncommonly discussed disorders

203

204

Section 4 Gastroesophageal Reflux and Associated Conditions

that may contribute to the features of GERD include chronic, severe constipation, for example, secondary to chronic narcotic use or other disorders of colonic motility, and partial small bowel obstruction, leading to impairment of normal gastric emptying and, ultimately, reflux. If these conditions are uncovered in the history, a careful look at total gastrointestinal transit needs to be considered before undertaking antireflux surgery. An additional mechanism that may contribute to problematic GERD is a decrease in esophageal peristalsis. Many patients with GERD may have a decrease in the amplitude of esophageal contractions. The etiology of this is unclear; in some cases this may be the primary event, but in other patients it is likely that it has followed years of pathologic reflux. It is hypothesized that the continuous exposure of the esophageal mucosa to gastric and duodenal reflux leads to transmural fibrosis and shortening of the esophagus. The submucosal neural plexus that plays an important role in esophageal motility may be impaired in this process. As a result, patients with GERD may have a lower than normal contraction amplitude on manometry. It is not always clear in these patients if poor motility is a cause of GERD or the result of long-term reflux. Animal models of reflux have clearly demonstrated that reflux may lead to impaired contractility of the esophagus.8 As one might expect, these motor abnormalities do not consistently resolve with the healing of esophagitis.9 Gastric acid is not the only factor contributing to GERD. Gillison and colleagues10 in 1972 were among the first to suggest that bile acid reflux also plays an important role in the development of complications of reflux, including progression to Barrett’s esophagus and esophageal adenocarcinoma. These early observations were based on animal models in which the esophagus was exposed to varying amounts of gastric and duodenal reflux.11 In these experiments, the development of esophageal adenocarcinoma clearly correlated with increased exposure to duodenal reflux. In clinical studies, exposure of the esophagus to bile reflux can be assessed by the Bilitec system (Fig. 14-2) (Medtronic Functional Diagnostics, Minneapolis, MN), which relies on the detection of bile salts by a fiberoptic system.12 Using this

system it has been demonstrated that patients with Barrett’s esophagus are far more likely to have increased reflux of bile compared with normal controls.11 Clinical application of the Bilitec probe has not gained widespread acceptance. Although a clear link between bile reflux and esophageal cancer has not been established, the available evidence certainly suggests a relationship. Barrett’s esophagus is a known precursor to esophageal cancer and is more prevalent in patients with bile reflux. In addition, patients who have undergone a subtotal gastrectomy have been shown to be at significantly higher risk for the development of so-called gastric remnant cancer, which is thought to be related to exposure of the stomach to excessive bile salts.11

FIGURE 14-2 The Bilitec monitor records frequency and duration of bile exposure in either stomach or esophagus over a 24-hour period.

FIGURE 14-3 Barium esophagogram demonstrating a shortened esophagus and a sliding hiatal hernia.

Diagnostic Studies The proper evaluation of a patient referred for the surgical management of GERD is critical. The purpose of this evaluation is to document that the patient’s symptoms are in fact due to gastroesophageal reflux and to define the aspects of the patient’s disease that may impact on the type of operation required. The four tests that are commonly obtained for the evaluation of GERD patients include barium esophagography, esophagogastroduodenoscopy, esophageal manometry, and 24-hr pH monitoring.

Barium Esophagography The barium esophagram is an inexpensive test that can define the esophageal length (Fig. 14-3) and the presence of a hiatal hernia, gastric ulceration, esophageal shortening, or esopha-

Chapter 14 Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux

geal stricture and, to some degree, evaluate esophageal peristalsis and gastric emptying. These findings will have a significant impact on therapy. For example, a stricture may require repeated dilation before definitive surgical correction is undertaken. Esophageal shortening, often associated with a stricture, may require an esophageal lengthening procedure, such as a Collis gastroplasty. The presence of a giant paraesophageal hernia will also be clearly seen on a barium study (Fig. 14-4) and would require a significantly more complex surgical procedure than simple fundoplication. A barium esophagogram can also demonstrate spontaneous gastroesophageal reflux, and also it may be elicited by provocative maneuvers. The finding of reflux during the barium esophagogram is thought by some to be highly specific for GERD but clearly does not have the sensitivity or symptom correlation that 24-hour pH testing can provide.

Esophagogastroduodenoscopy Upper endoscopy is routinely performed before antireflux surgery. Endoscopy will allow erosive esophagitis and/or Barrett’s metaplasia to be documented. Only 40% to 60% of patients with GERD have endoscopic evidence of esophagitis; thus, the sensitivity of this finding is less than 60%. However, when esophagitis is present, the test has an excellent specificity.12a On occasion, endoscopy may disclose an unexpected finding, such as esophageal cancer, large hiatal hernia, or Zenker’s diverticulum. The presence of erosive esophagitis and esophageal strictures must also be documented. In addition, an assessment of esophageal length can be made with endoscopy. Any stricture or mucosal abnormality is also sampled to exclude an underlying malignancy. Severe stricturing may lead to a decision to delay fundoplica-

tion until serial dilations and aggressive proton pump inhibitor therapy improve the luminal diameter of the esophagus to some degree. Any salmon-colored gastric-like mucosa above the expected squamocolumnar junction is sampled to rule out Barrett’s esophagus and evaluate for possible high-grade dysplasia, which would be considered a relative contraindication to fundoplication. In general in this setting we would recommend esophagectomy, although in some cases mucosal ablation of the dysplastic epithelium may be considered followed by fundoplication if the patient’s symptoms remain difficult to control and the results of serial biopsies show no evidence of dysplasia. All patients with Barrett’s esophagus are followed postoperatively with screening endoscopy, as recommended by the American College of Gastroenterology.12b There is no convincing evidence that antireflux surgery either halts the progression of or leads to a regression of Barrett’s metaplasia. Therefore, it is important to emphasize the need for continued surveillance to these patients, even if their symptoms are well controlled after surgery.

Esophageal Manometry Esophageal manometry provides information on the functional state of the esophagus and is considered to be an essential test in the preoperative evaluation before antireflux surgery.12a,13 It defines the strength of contraction of the esophageal body as well as the percent of swallows that are peristaltic. Manometry will also determine the resting LES pressure and the degree of relaxation in response to swallows. It also defines the location of the LES before performance of pH testing. Absent or diminished peristalsis raises the suspicion of a primary motor disorder (e.g., achalasia). When peristalsis is absent or severely disordered, or if the mean amplitude is low (<30 mm Hg), one may consider a partial fundoplication or a very floppy Nissen procedure. In either case, the patient needs to be educated regarding the possibility of dysphagia after antireflux surgery. The LES pressure is typically low or normal in patients with GERD. Elevated pressures are distinctly unusual and warrant further investigation. In addition, manometry can also be useful in identifying patients with a short esophagus by measuring the distance between the upper esophageal sphincter and the LES. In our practice, we prefer to have manometry performed before antireflux surgery in most cases. Some studies have shown that in the absence of clinical dysphagia, manometry does not influence the planned surgery to a significant degree and may be optional. Most surgeons would agree, however, that manometry is mandatory in any patient with dysphagia in whom antireflux surgery is contemplated. Even in the absence of clinical dysphagia, we have found manometry to be useful in identifying patients with diminished esophageal peristalsis from chronic reflux because this may impact on the operative plan (e.g., choosing the size of the bougie, the length and tightness of the wrap, etc.).

24-Hour pH Monitoring FIGURE 14-4 A giant paraesophageal hernia in a patient with GERD.

Ambulatory intraesophageal pH monitoring is the standard for confirming the diagnosis of pathologic reflux. We perform

205

206

Section 4 Gastroesophageal Reflux and Associated Conditions

this test in most cases, but it is not necessary in all patients. For example, in the patient with a documented hiatal hernia and/or esophagitis and typical GERD symptoms with good initial response to proton pump inhibitors, pH testing is optional. However, the test is quite useful for those in whom the diagnosis of GERD is unclear, for example, in patients with atypical symptoms or poor initial response to proton pump inhibitors. In addition, it is useful in the evaluation of a patient who has symptoms but has normal findings on endoscopy. An abnormal pH score has been shown to be the most important predictor of a successful outcome after a laparoscopic Nissen procedure.14 Results of 24-hour pH monitoring are usually expressed in the form of a DeMeester score. Six variables are calculated to arrive at a composite score: 1. The total number of reflux episodes 2. The percentage of total time spent in an acid environment with a pH less than 4 3. The percentage of upright time spent in an acid environment with a pH less than 4 4. The percentage of supine time spent in an acid environment with a pH less than 4 5. The duration of the longest reflux episode 6. The number of reflux episodes lasting more than 5 minutes. The first four of these factors evaluates the frequency and severity of reflux, and the last two assess the ability of the esophagus to clear acid. The mean values for esophageal acid exposure and 95th percentile results are shown in Table 14-1. The composite score relies on the degree to which each factor deviates from the mean score in healthy volunteers. Each factor is given a different weight. For example, it was observed that very few healthy patients have significant reflux while supine whereas the total number of reflux episodes among healthy volunteers is highly variable. As a consequence, supine reflux is given a greater weight in the composite DeMeester score than the total number of reflux episodes. The major disadvantage of this test is that it is uncomfortable for the patient. Because of this, patients may not engage in their daily activities as they would without the probe, and

so the test may underestimate the amount of reflux that patients routinely experience. A newer wireless system was developed (Bravo pH probe; Medtronics, Minneapolis, MN) that uses miniaturized pH probes that can be deployed endoscopically.15 This system utilizes a small vitamin-sized capsule that contains the pH sensor, a battery, and a transmitter. The device is attached endoscopically to the esophageal mucosa about 6 cm above the normal Z-line. The capsule is painless, does not interfere with normal activities or sleep, and gathers data for 2 days. Over 10 to 14 days, the capsule detaches from the mucosa and passes harmlessly in the stool. The device transmits data to a recorder that is worn on the patient’s belt. Not only is this far more comfortable for the patient, but it also allows for data recording for a period of 48 hours or more (until the device dislodges from the esophageal mucosa) and can potentially be more sensitive to document reflux compared with a standard transnasal probe. Patients who present with atypical symptoms related to pulmonary or laryngeal symptoms present a challenge. In these patients dual-channel pH studies demonstrating the proximal extent of reflux and correlation with extraesophageal symptoms are under investigation. One probe is placed distally, and another probe is positioned in a more proximal location.15a Further evaluation is required to define the role of these dual-channel pH studies.

Alkaline Reflux Alkaline gastroesophageal reflux may play a role in GERD.16 Assessment of alkaline reflux is another area of investigation. Bilirubin has a specific absorption at a wavelength of 453 nm, and bile reflux can be measured using spectrophotometric principles. The study is done similar to placement of a pH probe, and a spectrophotometric probe is placed 5 cm above the LES. The spectrophotometer detects wavelength absorption at 450 nm and at 565 nm every 8 seconds. An integrated microcomputer then detects the differences and a quantitative assessment of the bile exposure is made. This method is independent of pH assessment and considered preferable to measurement of esophageal pH greater than 7.12a Although these considerations are of interest, currently their role in routine evaluation of patients is unclear.

Esophageal Impedance Monitoring TABLE 14-1 Normal Values for Esophageal Exposure to pH < 4 (n = 50) Component

Mean

SD

95th Percentile

Total time pH < 4 (%)

1.51

1.36

4.45

Upright time pH < 4 (%)

2.34

2.34

8.42

Supine time pH < 4 (%)

0.63

1.0

3.45

19.00

12.76

No. of episodes No. of episodes >5 min

0.84

1.18

Longest episode (%)

6.74

7.85

46.9 3.45 19.8

From DeMeester TR, Stein HJ: Gastroesophageal reflux disease. In Moody FG, Carey LC, et al (eds): Surgical Treatment of Digestive Disease. St. Louis, Mosby, 1989.

Esophageal impedance monitoring is a newer modality of investigation that has the potential to make a significant impact in the study of esophageal pathophysiology in the future. Intraluminal electrical impedance is inversely proportional to the electrical conductivity of the luminal contents and the cross-sectional area. A multichannel intraluminal electrical impedance catheter is used to detect intraluminal impedance. Air has a high impedance, whereas saliva has a greater conductivity and a lower impedance. Similarly, luminal contraction results in an increase in impedance. Both esophageal bolus transport and gastroesophageal reflux can be characterized by impedance studies. In addition, combined with pH monitoring, impedance monitoring can detect both acidic and non-acid reflux in the esophagus. Thus reflux can be detected without regard to chemical composition.12a,15a

Chapter 14 Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux

Tamhankar and associates, in normal volunteers, have demonstrated that the use of proton pump inhibitors does not decrease the number of reflux episodes or the duration of reflux episodes but simply converts acid reflux into less acid reflux.17 Recently, Mainie and colleagues, in a multicenter study of 168 patients, evaluated acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy with combined impedance and pH monitoring. They noted a positive correlation with symptoms and reflux in 69 patients of which in 53 patients this was related to non-acid reflux. This study emphasizes the importance of persistent nonacid reflux in patients on proton pump inhibitors and the potential role of impedance monitoring in the evaluation of these patients.18 Thus, intraluminal impedance monitoring, although early in its development, has the potential to play an important role in the evaluation of patients for antireflux surgery.

Other Investigations In some patients, gastric pathology may contribute to the pathogenesis of reflux disease. Radioisotope studies to evaluate gastric emptying may be useful in some patients, particularly in patients who are being evaluated for repeated antireflux procedures. The acid perfusion test of Bernstein to correlate symptoms with acid reflux has essentially been replaced with 24-hour pH monitoring and is rarely performed.

Medical Therapy Treatment of GERD is initially directed at the control of symptoms through education, lifestyle changes, and pharmacotherapy. Lifestyle changes include smoking cessation, dietary modification (decreased fats, caffeine, chocolate, alcohol, and tobacco), and weight loss.19 Patients are advised to refrain from eating within 2 hours of intended sleep. Also, medications known to impair LES function, such as tricyclic antidepressants, nitrates, calcium channel blockers, and theophylline, are discontinued if at all possible. Patients with mild symptoms may respond to lifestyle changes and/or histamine-2 blockers. However, given the wide availability of proton pump inhibitors, these agents are frequently prescribed as first-line therapy for GERD. Proton pump inhibitor therapy does not affect the number of reflux episodes or their duration; rather, it converts acid reflux to less acid reflux. This may explain the persistence of symptoms and the progression of mucosal injury in some patients treated with proton pump inhibitors.17 In the case of refractory signs and symptoms, further evaluation is pursued and consideration given to antireflux surgery.

Antireflux Surgery Antireflux surgery has proven to be an effective means of controlling and restoring LES function, diminishing the reflux of acid and bile into the esophagus, and controlling GERD symptoms. Historically, a number of issues have prevented the widespread acceptance of antireflux surgery in the treatment of GERD. The first problem is the availability of highly effective antacid medical therapy. Other issues are the fre-

quent side effects of surgery, including postoperative dysphagia and gas bloat, conditions that may significantly interfere with quality of life. In the past, another obstacle was the concern of undergoing a major open abdominal procedure and the morbidity associated with laparotomy. Two developments have allowed antireflux surgery to appeal to a greater number of patients. The first is the recognition that a shorter, looser fundoplication reduces the incidence of dysphagia and gas bloat, with equal control of reflux.20 The second was the introduction of laparoscopic Nissen fundoplication, which markedly reduced the length of hospital stay and time off from work required after fundoplication. Historically, antireflux surgery has been reserved for patients with severe esophagitis or stricture or for those refractory to medical therapy. With a greater acceptance of minimally invasive surgery, current indications for surgery also include symptoms refractory to medical therapy, inability or unwillingness to maintain lifelong acid suppression, or the development of complications of GERD, such as stricture or persistent erosive esophagitis.

Principles of Antireflux Surgery The principles of fundoplication are centered on the reconstruction of a functional LES. The degree of LES competence is directly proportional to the length of the intra-abdominal esophagus. Formation of an optimal wrap requires the restoration of 1.5 to 2.0 cm of tension-free intra-abdominal esophagus, which will respond to intra-abdominal pressure changes. The resting LES pressure must be approximately three times the resting gastric pressure to overcome gastric distention. The fundus of the stomach is used to create the wrap, and the vagus nerves must be identified and preserved. These structures are critical in receptive relaxation of the stomach in the setting of deglutition and also play an important role in gastric emptying. It is important that the wrap be neither excessively long or tight, in which case the patient may suffer from significant postoperative dysphagia and excessive gas bloat. Another important step is the closure of the crural defect. In general, if a meticulous dissection of the crura is done and the peritoneal lining remains intact, mesh is not required. We add mesh if the crural integrity is in question or if excessive tension is present during closure (<5% of routine Nissen fundoplication, higher in repair of giant paraesophageal hernias).

Choice of Operation A variety of antireflux procedures have been developed by such innovators as Nissen (1956) (Nissen, 1956),21 Collis (1957) (Collis, 1957),22 Dor (1962),23 Toupet (1963),24 Skinner and Belsey (1967) (Skinner and Belsey, 1967),25 and Hill (1967).26 The Nissen (360-degree) fundoplication is the most commonly performed fundoplication and has been shown to achieve control of GERD symptoms in up to 90% of patients with good durability.27,28 The Dor (partial anterior) and Toupet (partial posterior) fundoplications are wraps that may be appropriate in the setting of impaired esophageal motility (Figs. 14-5 and 14-6). The routine use of partial

207

208

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 14-5 A to F, Dor fundoplication.

C

B

A

E

D

wraps for GERD has been questioned by several groups, including our own. In groups of patients with normal motility, these studies have shown good initial control of GERD symptoms but an unacceptable rate of recurrence at intermediate follow-ups of 18 to 20 months.29,30 The Belsey Mark IV is a transthoracic fundoplication that may be useful for patients who have had a prior transabdominal wrap and require further surgery, but in our initial experience using a thoracoscopic approach yielded similar results to those of other partial wraps, that is, good initial results but a significant recurrence rate by 2 years.30a A transthoracic Belsey fundoplication may also be considered in patients who have a short esophagus and in patients with multiple previous abdominal surgeries. The technical aspects of the various types of fundoplication are discussed in detail in other chapters of this textbook. The following is a summary of some of the important aspects of selected fundoplications. The Toupet technique of posterior fundoplication was described in 1963.24 After the short gastric vessels are divided

F

the fundus is mobilized posterior to the esophagus. Interrupted sutures are placed between the esophagus and the medial aspects of the right and left portion of the posterior fundus wrap. The lateral portions of the wrap are sutured to the respective crura. In the Hill operation, the diaphragmatic crural decussations are dissected to the median arcuate ligament where it crosses the abdominal aorta. Sutures are subsequently placed to approximate the crura. The fundus is then brought posterior to the esophagus, and interrupted sutures are then placed incorporating the median arcuate ligament, the wrapped fundus, and the lateral fundus. The Belsey fundoplication is done through the left chest and is described in more detail in another chapter. Briefly, after placement of a double-lumen tube for anesthesia, the left chest is entered through the seventh intercostal space. The inferior pulmonary ligament is divided, and the esophagus is mobilized up to the inferior pulmonary vein. The phrenoesophageal membrane is divided, and the abdomen is

Chapter 14 Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux

270degree wrap

FIGURE 14-6 Toupet fundoplication.

Wrap sutured to crura of the stomach

Sutured posteriorly to crura of the stomach

entered. The esophagus is dissected circumferentially. The division of Belsey’s artery, which is a communicating artery between the left gastric and inferior phrenic artery, allows the gastroesophageal junction to be mobilized in a circumferential fashion. The stomach is then mobilized into the chest, and the gastric fat pad is removed, defining the esophagogastric junction. Initially, the crural stitches are placed but are left untied. The partial fundoplication is done in two layers with mattress sutures; the first layer is through the esophagus 1 cm proximal to the gastroesophageal junction and the stomach 1 cm distal to the junction. Three sutures are placed for the first layer and tied. The second layer consists of three mattress sutures incorporating the diaphragm, stomach, and the esophagus. The wrap is reduced into the abdomen, and the sutures are tied. The crural sutures are subsequently tied, making sure that it is not too tight, and allows the tip of a finger easily. A nasogastric tube is placed, thoracostomy tube drainage is established, and the chest is then closed (Fig. 14-7).31,32 Worldwide, the Nissen fundoplication remains the most popular procedure in the surgical treatment of GERD. A detailed discussion of partial and complete fundoplication is included in other chapters in this text. In this chapter, we describe our technique of laparoscopic Nissen fundoplication. Bernard Dallemagne published the first description of a laparoscopic Nissen fundoplication in 1991 (Dallemagne et al, 1991).33 Over the past decade, this technique has proven to be safe, effective, and durable and now is considered by many to be the standard surgical approach to GERD. Laparoscopic Nissen fundoplication has been shown to achieve decreased pain, decreased length of hospital stay, and earlier return to work when compared with its open counterpart. However, although it may appear straightforward, the operation is technically challenging. Moreover, seemingly minor errors in the operating room may condemn the patient to a lifetime of dysphagia or recurrent reflux and the prospect of a difficult repeat operation.

C

FIGURE 14-7 Transthoracic Belsey fundoplication.

Technique—Laparoscopic Nissen Fundoplication The patient is placed in a comfortable supine position. We routinely perform on-table endoscopy to evaluate for the presence of esophageal stricture and Barrett’s metaplasia and assess the size of the hiatal hernia. Care is taken to minimize insufflation so as not to overdistend the stomach and small bowel. The scope is used to decompress the stomach and is then withdrawn. Many surgeons prefer either the lithotomy or “inverted-Y” position. We favor the supine position, with the surgeon standing to the patient’s right and the first assistant standing to the patient’s left. Video monitors are positioned on either side of the table. Access to the abdomen is achieved via a direct cutdown technique. We prefer this technique over the Veress needle to minimize the risk of injury to abdominal contents. This approach is particularly useful in patients with

209

210

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 14-8 Port placement for a laparoscopic Nissen fundoplication.

Grasper 5 mm Camera 5 mm

Grasper 5 mm Liver retractor 5 mm Blunt port 10–12 mm

prior abdominal surgery, who may have adhesions and distorted anatomy. Our preferred port placement is demonstrated in Figure 14-8. We begin with placement of a 10-mm blunt port through the right rectus muscle at a level midway between the umbilicus and xiphoid. This port may be positioned somewhat higher in the setting of a large hiatal hernia, where extensive mediastinal dissection is anticipated. The rectus muscle is split in the direction of its fibers. After insufflation to a pressure of 15 mm Hg, a 5-mm 30-degree camera is introduced into the abdomen. Under direct visualization, four additional 5-mm ports are placed: the first in the midclavicular line just inferior to the left costal margin; the second through the left rectus sheath, 4 cm to the left of the initial 10 mm port; the third along the right costal margin toward the right shoulder; and the fourth just inferior to the right costal margin in the midaxillary line where it is used for the liver retractor (Fig. 14-9). The patient is then placed in a steep reverse-Trendelenburg position, allowing gravity to assist in the displacement of the bowel and stomach from the diaphragm. A toothed, noncrushing atraumatic grasper (Snowden-Pencer, Tucker, GA) is used in the surgeon’s left hand, and the autosonic shears (Ultracision, Inc., U.S. Surgical, Norwalk, CT) is used in the right hand. The 30degree camera is positioned in the assistant’s left hand. The gastrohepatic omentum is then opened, and the caudate lobe of the liver is exposed (Fig. 14-10). An aberrant left hepatic artery branch arising from the left gastric artery may be present and, if the surgeon considers this to be a significant contribution to the liver, it can be spared but adds to the technical difficulty of the case. The right crus is exposed, and the peritoneal lining that covers the crus is carefully preserved. This tissue is an important buttress, adding signifi-

cantly to the integrity of the crura. The phrenoesophageal ligament is then divided. During this step it is important that the anterior vagus nerve is identified and preserved. The ligament is divided from right across the crural arch. Dissection is carried on to the left crus, and the areolar attachments between the gastric fundus and the diaphragm are divided. Once the gastroesophageal junction is completely dissected, we then carry our esophageal mobilization into the mediastinum. It is quite easy to inadvertently divide the pleura during this step because the pleura can be densely adherent to the hernial sac. If the pleura is violated on the left side, a floppy diaphragm may ensue. This may impede visualization and lead to problems with hypotension due to tension pneumothorax. If necessary, a small pleural catheter may be placed. At this point, division of the short gastric vessels is performed. Division of the short gastric vessels is a matter of controversy and is not performed by all surgeons. However, a randomized trial by Dalenbak and associates34 has demonstrated that failure to divide the short gastric vessels is associated with an increased risk of postoperative dysphagia. We believe that dividing the short gastric vessels allows the fundus to be completely mobilized. Without this step, the wrap may be under tension, and this could contribute to dysphagia. Also, division of the proximal short gastric vessels will prevent an injury to the splenic capsule as the fundus is being mobilized. Mobilization of the fundus is begun by taking down any remaining attachments of the fundus to the diaphragm at the angle of His. The assistant then grasps the gastrosplenic omentum near the greater curvature and lifts anteriorly, and the surgeon provides countertraction on the stomach. A window is then created into the lesser sac. The surgeon may

Chapter 14 Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux

FIGURE 14-9 Positioning of the liver retractor to expose the esophageal hiatus.

divide several short gastric vessels with a scissors and clips, a bipolar electrosurgical device, or the autosonic shears or harmonic scalpel (Fig. 14-11). Care must be taken as one advances towards the superior pole of the spleen, as the vessel length becomes shorter and the risk of capsular tear greater. Division of the short gastric vessels provides excellent exposure of the inferior portion of the left crus. Further dissection on the left side at this point greatly facilitates the subsequent creation of a retroesophageal window. Careful dissection is then used to develop the window between the crura and the esophagus. The posterior vagus nerve is identified and may be left adjacent to the undersurface of the esophagus with subsequent incorporation in the Nissen wrap, or alternatively it may be dissected further and left outside of the wrap. A window behind the esophagus is created by blunt dissection until the left crus of the diaphragm is identified behind the esophagus. The last step before creating the wrap is to dissect the fat pad off the gastroesophageal junction. Many surgeons omit this step. However, in our opinion, removing the fat pad is the only way to precisely identify the true location of the gastroesophageal junction. It is not uncommon for the fundus to assume a tubularized shape from chronic herniation into the mediastinum. If this is not recognized the wrap will be created on the fundus rather than on the gastroesophageal junction. If the gastroesophageal junction is indeed found to be high after the fat pad has been removed, the surgeon continues dissection as high as possible into the mediastinum. This may be sufficient to deliver 2 to 3 cm of tension-free esophagus into the abdomen. If this is not sufficient, then consider a Collis gastroplasty to lengthen the esophagus and allow the creation of a tension-free segment of neo-esophagus. We then pass a Bougie dilator (50-54 Fr) across the gastroesophageal junction before creating the fundoplication. We generally use a 50- to 52-Fr bougie for smaller patients

FIGURE 14-10 The gastrohepatic omentum is opened, providing exposure to the caudate lobe and the right crus.

FIGURE 14-11 Division of the short gastric vessels facilitates fundic mobilization.

with normal motility and a 54- to 56-Fr for larger patients if motility is diminished. The bougie permits calibration of the wrap, thus preventing excessive narrowing of the esophagus during fundoplication. However, it is certainly possible to make a tight wrap around a relatively large bougie, if the fundus is incompletely mobilized and the wrap is created under tension. To create the wrap a grasper is passed through the retroesophageal window. The fundic tip is then grasped and pulled through the window from a left-to-right direction (Fig. 14-12A). A “shoe-shine” maneuver will ensure the surgeon that the wrap is not twisted or under tension (see Fig. 14-12B). The line of the divided short gastric vessels generally appears on the right side of the esophagus. If

211

212

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 14-12 A, The gastric fundus is wrapped posteriorly at the level of the gastroesophageal junction. B, Assessment of wrap orientation and tension.

adequate mobilization is achieved, the fundic tip remains in place after release of the grasper. If the fundus springs back behind the esophagus, then it is too tight and/or mobilization is incomplete. The fundoplication is then secured using two 2-0 nonabsorbable sutures (Surgidac, U.S. Surgical, Norwalk, CT) (Fig. 14-13A and C). Each stitch incorporates a full-thickness bite of stomach and a partial thickness bite of esophagus to prevent slippage of the wrap around the body of the stomach. Ideally, the wrap is 1.5 to 2 cm in length because longer wraps are associated with a significantly higher risk of postoperative dysphagia. The bougie is then removed, and the crura are approximated behind the esophagus using a heavy nonabsorbable suture (0 Surgidac) (see Fig. 14-13B). Pledgets are not routinely used, although they may be helpful when the crura are thin or when a large defect is present. If the hernia was large and the crura are not easily reapproximated then we generally reinforce the closure with mesh (Surgisis, Cook Biotech, Inc., West Lafayette, IN). The mesh is positioned to close the defect and secured with 2-0 Surgidac sutures or an endoscopic tacking device (Origin Medsystems, Menlo Park, CA). The 5-mm ports are not closed, except at the skin level. Larger ports are generally closed under direct laparoscopic visualization using a suture passer to incorporate fascia and peritoneum. Before closure, we pass a nasogastric tube in complex cases (giant paraesophageal hernia, redo Nissen fundiplication, or Collis-Nissen operation). We believe that this maneuver minimizes early gas bloat and lowers the possibility of retching in the early postoperative period. We routinely perform a barium swallow on the first postoperative day to rule out leaks and use as a “baseline” study should clinical problems develop in the future. A clear liquid diet is started on the morning after surgery. Patients are typically discharged to home on the first or second postoperative day. After dis-

charge the patient is advanced from a soft to a regular diet over a 4- to 6-week period.

Results of Antireflux Surgery The long-term efficacy of surgery to control reflux has been well documented. For example, a Veterans Affairs randomized trial comparing medical therapy (ranitidine, metoclopramide, and sucralfate) with open Nissen fundoplication demonstrated that surgery was more effective in controlling symptoms, preventing the development of esophagitis, and restoring a normal esophageal pH (Spechler, 1992).35 However, with the introduction of laparoscopic antireflux procedures and proton pump inhibitor therapy, both treatment arms of this Veterans Affairs study are now essentially obsolete. A more recent trial of 217 patients compared outcomes after laparoscopic Nissen fundoplication versus proton pump inhibitor therapy.36 In this study and in our own analysis, fundoplication was shown to lead to less acid exposure of the lower esophagus at 3 months and significantly greater improvements in gastrointestinal and general well-being at 12 months compared with proton pump inhibitor treatment.37 If surgeons performing laparoscopic Nissen fundoplication maintain the well-established principles of open antireflux surgery, patients are likely to enjoy the same long-term control of GERD seen with the open Nissen approach. Many retrospective and nonrandomized studies have documented less postoperative pain, shorter hospitalization, and faster recovery with laparoscopic Nissen fundoplication.38 In addition, prospective studies have shown equal control of reflux with a laparoscopic Nissen compared with an open fundoplication. For instance, Laine and coworkers39 compared 55 patients undergoing open Nissen fundoplication with 55 patients undergoing laparoscopic Nissen fundoplication. All of the patients in the laparoscopic group, and 86% of the open group, achieved good-to-excellent control of their reflux

Chapter 14 Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux

A

C

symptoms. The mean hospital stay was 3.2 versus 6.4 days, and the mean sick leave was 15.3 days versus 37.2 days, when comparing the laparoscopic with the open groups. Heikkinen and associates40 demonstrated significant, but equal, improvement in gastrointestinal quality of life indices in both laparoscopic and open patient cohorts. Although operative times were slightly higher (98 versus 74 minutes), the laparoscopic approach has been associated with less pain and a faster return to work. In an economic analysis of laparoscopic versus open fundoplication, total costs were also found to be significantly lower ($7506 versus $13,118) in the laparoscopic group.41 This was due to the decreased length of stay and earlier return to work that can be achieved with minimally invasive surgery. Postoperative complications occur in 8% to 10% of patients after laparoscopic fundoplication and include ileus (6%), pneumothorax (2%), dysphagia (2%), and perforated viscus (0.2%).42 The rate of conversion to an open procedure in most series is 2%. In addition to a shorter hospital stay, a

B

FIGURE 14-13 A, Suture placement for Nissen fundoplication. B, Closure of the crural defect. C, Completed Nissen fundoplication.

decrease in splenic injuries has also been shown after laparoscopic fundoplication (0.1%) compared with open series (2%). This likely reflects the much improved visualization of the left upper quadrant that is possible with laparoscopy compared with a laparotomy. In addition to controlling typical symptoms of reflux, laparoscopic fundoplication has also been shown to improve atypical features of GERD. Interestingly, whereas the otolaryngologic manifestations of GERD (laryngitis, pharyngitis) usually respond to antisecretory medications, reflux-induced asthma responds convincingly only to antireflux surgery.43 In a study of 62 patients with both GERD and asthma followed for up to 19.1 years, patients were randomized to antacids (control, n = 24), ranitidine, 150 mg three times a day (medical, n = 22), or Nissen fundoplication (surgical, n = 16). There was an immediate and sustained reduction in acute nocturnal exacerbations of wheezing, coughing, and dyspnea in the surgical group (but not in the medical or control groups). At 2 years, 75% of the surgical group sustained

213

214

Section 4 Gastroesophageal Reflux and Associated Conditions

improvement in their overall asthma status, compared with 9% in the medical group and 4% in the control group. We have found similar improvements in surgical patients compared with the best medical therapy for patients with pulmonary symptoms.44 Few studies have shown a consistent, significant regression of Barrett’s esophagus after antireflux surgery.45,46 Even more controversial is whether this translates into a reduced risk of esophageal cancer. Although small surgical series did suggest a reduction in the risk, the largest study has shown no such benefit for antireflux surgery.47 In this study of Veterans Affairs patients treated for GERD between 1986 and 1990, 946 patients who had undergone fundoplication were compared with 1892 patients who were managed medically. With a follow-up of more than 11,000 patient-years in the fundoplication group and 20,000 patient-years in the medical arm, no difference in the risk of developing esophageal cancer was demonstrated. Given the results of this study, patients are informed of the benefits of antireflux surgery but also clearly educated that the procedure has no proven benefit in preventing esophageal cancer.

Esophageal Dysmotility and Antireflux Surgery Detailed discussion of surgical approaches to patients with motility is presented in other chapters in this text. In summary, the primary issues in this debate are that partial wraps are associated with less dysphagia and bloat but may lead to less durable control of reflux symptoms. Clinical trials comparing partial and complete wraps have yielded conflicting results. Some prospective series have shown excellent reflux control with partial wraps. For instance, in a randomized study of 110 patients control of heartburn and acid regurgitation was comparable between those who underwent a Nissen or a Toupet procedure, with a median follow-up of 11.5 years.48 No difference in dysphagia was observed, but a significant increase in flatus and postprandial bloating was noted in the Nissen group. In another randomized study of 200 patients,49 cases were stratified by the presence (n = 50) or absence (n = 50) of esophageal dysmotility in both the Nissen (n = 100) and Toupet (n = 100) groups. Symptomatic relief was achieved in 88% of the Nissen group and 90% in the Toupet group, with a notably high incidence of dysphagia in the Nissen group (30 versus 11 patients) that did not correlate with preoperative motility status. However, in some other series a failure rate as high as 20% has been documented at 2 years.50 In a study by Horvath and colleagues,29 a preoperative DeMeester score greater than 50 yielded an 86% sensitivity for predicting failure after a Toupet fundoplication. In our experience, the Toupet procedure appears to result in a higher rate of recurrent symptoms,30 and we do not use it routinely. In the setting of poor motility, however, a partial fundoplication is considered an acceptable alternative to a loose Nissen operation.

Laparoscopic Collis Gastroplasty Acquired Shortening of the Esophagus Acquired shortening of the esophagus and the technique and role of Collis gastroplasty are discussed in other chapters

in this text. In brief, acquired shortening occurs in a small number of patients (<5%) with small hiatal hernias and relatively uncomplicated GERD. However, in the setting of peptic strictures, reoperative antireflux surgery, or giant paraesophageal hernias it is much higher.51,52 Such shortening can prevent adequate esophageal mobilization during fundoplication, ultimately leading to wrap slippage and failure. In a more recent series, Horvath and colleagues29 estimated that esophageal shortening can be demonstrated in 10% of patients undergoing antireflux surgery. Its prevalence is perhaps greatest in the setting of giant paraesophageal hernias, where the gastroesophageal junction is chronically displaced to the mediastinum.53 This esophageal shortening leads to a high rate of recurrence when giant paraesophageal hernias are repaired (up to 40%) compared with a recurrence rate of 3% to 5% in patients undergoing routine antireflux surgery. As discussed earlier, an adequate fundoplication requires at least 2 cm of tension-free intra-abdominal esophagus. Unrecognized esophageal shortening is a major cause of recurrent herniation, which in turn leads to recurrent symptoms of reflux. We also believe that in many cases of a “slipped Nissen” fundoplication the wrap is initially constructed around the tubularized fundus rather than the esophagus. This technical error is easy to make if esophageal shortening is unrecognized. To prevent this, the esophagus is completely mobilized within the mediastinum and the gastroesophageal fat pad routinely removed. Many options have been described for the treatment of esophageal shortening. These include esophagopexy, intrathoracic fundoplication, and a variety of lengthening procedures. Hill26 has long recommended an esophagogastropexy (Hill procedure) as a treatment for all patients with GERD, including those with esophageal shortening. Although the reported results are excellent, this approach has failed to obtain widespread acceptance due to its complexity. Intrathoracic fundoplication can also provide good control of reflux.54 However, there may be significant complications associated with an intrathoracic wrap, most notably dysphagia.55 The Collis gastroplasty, although described much earlier (1957) (Collis, 1957),22 has become the standard technique of esophageal lengthening. In large part this is due to modifications that have allowed the Collis to be performed laparoscopically. The Collis gastroplasty essentially creates a tube of “neo-esophagus” from stomach, allowing a “new” gastroesophageal junction to lie below the diaphragm and restoration of the angle of His. However, a Collis gastroplasty does not achieve control of reflux without a wrap.56 Pearson and colleagues, in 1971, were the first to describe the use of a Collis gastroplasty in conjunction with a transthoracic Belsey fundoplication for patients with a shortened esophagus.56a Using this approach, Pearson and Henderson reported excellent results in 76% of patients followed for 5 to 12 years (Pearson and Henderson, 1976).57 Orringer and Sloan modified the technique further to include a transthoracic CollisNissen fundoplication to improve the durability of the repair (Orringer and Sloan, 1978).58 Excellent long-term results have been reported with this technique (88% reflux control at 10 years), and the Collis-Nissen operation has consequently

Chapter 14 Evaluation and Surgical Treatment of Hiatal Hernias and Gastroesophageal Reflux

become the standard procedure for patients with esophageal shortening.59 Although it is a technically challenging, a Collis gastroplasty can be performed laparoscopically with minimal morbidity in experienced centers.60 The technique is described elsewhere in this text.

Results Excellent long-term results have been achieved with a CollisNissen gastroplasty performed through a laparotomy. Results with the minimally invasive Collis-Nissen have been similar, with greater than 90% control of reflux symptoms. One of the largest reported experiences with laparoscopic CollisNissen was reported from the University of Pittsburgh. In this series of 200 consecutive patients who underwent repair of giant paraesophageal hernia, a total of 112 patients underwent Collis-Nissen fundoplication. The median hospital stay was 3 days, and good to excellent results were reported in 92% of patients. The recurrence rate of hiatal hernia was 2.5%.60 Similarly, we have also reported our experience with the Collis-Nissen fundoplication in patients who underwent minimally invasive repeat anti-reflux surgery.60a Although good results are achievable in dedicated centers, a Collis gastroplasty is not without potential complications. Staple-line leaks have been reported, although the incidence is less than 5% in both open and laparoscopic series. A second concern is the impaired motility of the neo-esophagus. This immotile segment of stomach may predispose to postoperative dysphagia. An additional concern is the creation of a segment of gastric mucosa proximal to a fundoplication. Jobe and associates61 documented that parietal cells could be identified that continued to secrete acid after a Collis-Nissen procedure, as indicated by an abnormal DeMeester score. Although these concerns are somewhat theoretical, a Collis gastroplasty is considered a “last resort” procedure and only performed if complete mediastinal mobilization is not sufficient to create adequate esophageal length.

esophagectomy. We presented our early experience with Roux-en-Y gastric bypass in 2004.63 In that report of 7 patients, the mean excess weight loss among these patients was 70% and 70% of comorbidities were improved or resolved. Heartburn symptoms, as measured by quality-of-life questionnaires, were significantly improved after Roux-en-Y gastric bypass.64 A recent update has been presented in abstract form that confirms these initial promising results.65

SUMMARY A successful outcome after antireflux surgery can be obtained in up to 90% of patients with careful preoperative assessment and operative technique. Improper patient selection, or technical errors associated with fundoplication, may lead to a lifetime of dysphagia or persistent reflux and the possibility of difficult repeat surgery. Some suggestions for avoiding this are as follows: 1. All patients need to have objective data demonstrating GERD. Consider that some patients who present for surgical control of GERD may have other medical problems that mimic GERD symptomatology. 2. While performing an antireflux procedure, ensure adequate length of intra-abdominal esophagus. This can be achieved by extensive mediastinal dissection and, if necessary, a Collis gastroplasty. 3. Always identify and preserve both vagus nerves. A transected vagus nerve may be tolerated but can lead to disabling problems of gastric emptying and dumping. 4. A partial fundoplication can be considered in patients with poor esophageal motility, although a very loose Nissen fundoplication may also be acceptable. 5. A transthoracic approach may be considered in patients with multiple previous abdominal surgeries and in patients with a short esophagus. 6. Roux-en-Y gastric bypass is considered in morbidly obese patients with GERD.

Gastroesophageal Reflux Disease and Roux-en-Y Gastric Bypass

COMMENTS AND CONTROVERSIES

Symptoms of reflux are very common among morbidly obese patients. Roux-en-Y gastric bypass, commonly performed to promote weight loss in these patients, has also been shown to improve symptoms of reflux. For instance, in a study of 239 morbidly obese patients with reflux symptoms, 94% reported improvement in reflux symptoms 9 months after Roux-en-Y.62 Other studies have documented similar findings.63 Roux-en-Y gastric bypass may also be a useful technique in patients undergoing reoperative antireflux surgery, particularly in those who are obese. On occasion the surgeon may find that the fundus is unusable after the previous fundoplication has been taken down. Repeat fundoplication may also been unwise if the surgeon suspects that one or more vagus nerves have been damaged or cannot be identified. In this setting, esophagectomy is typically considered. However, Roux-en-Y gastric bypass is perhaps an acceptable alternative, given the lower morbidity of this operation compared with

Successful outcome after antireflux surgery and hiatal hernia repair requires selecting the right patient and performing the right operation correctly. Drs. Irshad, Pennathur, and Luketich provide an excellent outline for this process. The ideal patient is one with typical symptoms of GERD who experiences relief of heartburn with proton pump inhibitors. The patient should have a small reducible hiatal hernia, a hypotensive lower esophageal sphincter, and otherwise normal esophageal and gastric function. If during the patient evaluation one of these ideal features is not found, the chance of a successful outcome is decreased. To deal with the less-than-ideal patient the standard Nissen fundoplication must be modified to overcome the specific problem. For instance, finding a peptic esophageal stricture or large irreducible hiatal hernia will mandate esophageal lengthening. The third component necessary for successful outcome is the right surgeon. Experience, excellent clinical judgment, and technical excellence are the hallmarks of the right surgeon. T. W. R.

215

216

Section 4 Gastroesophageal Reflux and Associated Conditions

KEY REFERENCES Collis JL: An operation for hiatus hernia with short esophagus. J Thorac Surg 34:768-773, 1957; discussion 774-778. Dallemagne B, Weerts JM, Jehaes C, et al: Laparoscopic Nissen fundoplication: Preliminary report. Surg Laparosc Endosc 1:138-143, 1991. DeMeester TR, Bonavina L, Albertucci M: Nissen fundoplication for gastroesophageal reflux disease: Evaluation of primary repair in 100 consecutive patients. Ann Surg 204:9-20, 1986. Nissen R: Eine einfache Operation zur Beeinflussung der Refluxoesophagitis. Schweiz Med Wochenschr 86:590, 1956. Orringer MB, Sloan H: Combined Collis-Nissen reconstruction of the esophagogastric junction. Ann Thorac Surg 25:16-21, 1978.

Pearson FG, Henderson RD: Long-term follow-up of peptic strictures managed by dilatation, modified Collis gastroplasty, and Belsey hiatus hernia repair. Surgery 80:396-404, 1976. Richter JE: Diagnostic tests for gastroesophageal reflux disease [review]. Am J Med Sci 326:300-308, 2003. Skinner DB, Belsey RH: Surgical management of esophageal reflux and hiatus hernia: Long-term results with 1030 patients. J Thorac Cardiovasc Surg 53:33-54, 1967. Spechler SJ: Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. The Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. N Engl J Med 326:786-792, 1992.

GASTROESOPHAGEAL REFLUX IN INFANTS AND CHILDREN

chapter

15

David A. Partrick

Key Points ■ In infants and children, the signs and symptoms of GERD may be

atypical. ■ Barium esophagogram and esophagoscopy with biopsy are the

mainstay of diagnosis; 24-hour pH monitoring and esophageal manometry are more difficult to perform and interpret in infants and children than in adults. ■ Primary management is nonsurgical and includes lifestyle modifications (e.g., positioning, eating habits, and food composition) and GERD medication. ■ Surgical management of GERD in infants and children is not a miniaturization of the adult procedure.

Gastroesophageal reflux (GER) is a normal physiologic process defined as the retrograde movement of gastric contents through the lower esophageal sphincter (LES) and into the esophagus. GER is very common in infants, usually manifested by recurrent, effortless, nonbilious emesis after feedings.1 At least one episode of GER per day occurs in 50% of neonates up to 3 months of age. It is estimated that the peak incidence of 67% occurs at age 4 months. The majority of these infants have spontaneous resolution of their symptoms by 12 months of age and experience no associated complications (Tolia et al, 2003).2 The incidence of normal physiologic GER continues to decrease after infancy. Twenty-four-hour pH probe studies have demonstrated higher percentages of time pH is less than 4 in those aged birth to 6 years (12%) compared with those aged 6 to 12 years (6%) and finally compared with adults (2%-4%) (Rudolph et al, 2001).3 However, a small number of infants and children develop signs and symptoms of pathologic GER, including poor weight gain, irritability, esophagitis, esophageal stricture, stridor, reactive airway disease, recurrent pneumonia, bronchitis, laryngitis, and life-threatening events.4-7 When GER produces such complications or pathologic consequences it is considered gastroesophageal reflux disease (GERD). GERD in otherwise normal children can persist and is a risk factor for GERD in adolescence and adulthood.8,9

HISTORICAL NOTE Neuhauser and Berenberg originally used the term chalasia in 1950 to describe incompetence of the LES in infants in the absence of a hiatal hernia. In 1951, Allison utilized rigid esophagoscopy and reported the direct effects of reflux on the esophagus and correlated this with the presence of hiatal hernia.10 This was followed in 1960 by the description of a

“partial thoracic stomach” by Carre and Astley in Ireland,11 recognizing the clinical significance of an associated hiatal hernia with GERD in children. Surgical treatment of GERD began to evolve in the mid-20th century with initial emphasis being placed on repair of the associated hiatal hernia.10 However, Hiebert and Belsey emphasized the frequent presence of GER symptoms without a hiatal hernia in 1961.12 Pediatric surgery was not yet developed as a specialty, and the initial surgical descriptions of antireflux procedures were in adults.13 Orringer and Belsey reported a transthoracic anterior fundoplication to control GER in 1955.14 The German surgeon Nissen (who spent most of his professional life in Turkey followed by the United States and finally Switzerland) originally described an anterior gastropexy procedure to correct hiatal hernia in 195615 but soon thereafter added a circumferential gastric fundoplication recognized as a Nissen fundoplication that remains the most common antireflux procedure performed today.13,16 Other types of partial (noncircumferential) fundoplications were also developed within the next decade. Primarily two types of these partial fundoplications have been utilized to correct GERD in infants and children. The French surgeon Toupet published his technique for a transabdominal posterior fundoplication in 1963.17 The other common procedure performed in pediatric patients is the Thal fundoplication, which is a partial anterior fundoplication.18,19 Gross was one of the first pediatric surgeons to report experience with antireflux procedures in infants. In 1964 he and his colleagues published a paper describing a small series of infants treated surgically for GERD, again concentrating on repair of the associated hiatal hernia.20 Since then, techniques have advanced markedly as has understanding of the need for surgical intervention in children with complications of GERD not responsive to medical therapy. More data have also been published concerning the improved safety and efficacy of the various operative procedures. Furthermore, pediatric surgeons have been integral in the development of minimally invasive operative techniques beginning in the 1970s. Gans and Berci described utilizing laparoscopy or “peritoneoscopy” during that time,21 although they were severely limited by the instrumentation and lack of video technology. It was not until 1987 that the first laparoscopic cholecystectomy was described by Mouret22 in France, followed by Reddick and Olsen23 in the United States. After that point, minimally invasive surgery began to be rapidly assimilated into clinical surgical practice throughout the world. Surgery in adults was dominant at first because there was some difficulty adapting the technology to small children. However, with further technologic advancement in 217

218

Section 4 Gastroesophageal Reflux and Associated Conditions

fiberoptics and miniaturization of endoscopes and laparoscopic instruments, minimal access pediatric surgery has experienced an accelerated pace of acceptance and development.24 Soon, large series of laparoscopic fundoplications were being reported (Rothenberg, 1998).25,26 These gradual changes in the approach to GERD and technical advancements help explain why antireflux operations are currently the third most commonly performed operation by pediatric surgeons.27

PATHOPHYSIOLOGY To discuss surgical management of GERD, the underlying pathophysiology must be understood. As mentioned, GER is a normal physiologic event that occurs in patients of all ages to some extent. A series of protective mechanisms prevent damage to the esophagus and airway when GER occurs, whereas failure of these mechanisms accounts for GER-associated disorders.4,28,29 The single most important factor in preventing GER is the physiologic LES. Although not a true anatomic sphincter, the LES arises from the inner circular smooth muscle layer of the esophagus and is asymmetrically thickened in the distal esophagus. This is normally tonically contracted and can be measured as a high-pressure zone manometrically. The phrenoesophageal membrane helps to hold the LES in position, and others have described a “pinchcock” effect exerted by the diaphragmatic crura.30 This functions when the intra-abdominal pressure increases relative to intrathoracic pressure, such as during inspiration and straining, and the diaphragmatic crura contract around the esophagus to prevent GER. The phrenoesophageal membrane and “pinchcock” effect of the diaphragm are likely disrupted to some extent with congenital diaphragmatic hernia and may help explain why those infants are more prone to have problems with GERD.31,32 The properly functioning LES should provide a pressure gradient between the thoracic and abdominal esophagus. Interestingly, the infant’s LES resting tone has been noted to be lower compared with adults and is located 2 cm above the diaphragm for the first 6 months of life.33,34 Normal LES relaxation occurs with esophageal peristalsis initiated by swallowing as well as burping and vomiting. Inappropriate transient LES relaxations have been correlated to GER episodes on pH probe monitoring in children and are likely one contributing factor leading to the development of pathologic GERD.35 In evaluating 193 reflux events in 24 infants, Omari and associates36 determined that 82% of reflux episodes were associated with these transient LES relaxations, compared with 13% that occurred during swallowing and only 2 episodes associated with straining. A second anatomic mechanism for controlling GER is the length of the intra-abdominal segment of the esophagus. Correlation has been made between intra-abdominal esophageal length and LES competency,37 with a length of 3 cm sufficient in preventing GER in 64% of individuals. However, 81% of patients experienced GER when less than 1 cm of intra-abdominal esophageal length was present. These findings have clear surgical implications and point out the importance of obtaining adequate esophageal mobilization when performing fundoplication.29

An appropriate angle of His is a third anatomic mechanism preventing pathologic GER. This is the angle at which the abdominal portion of the esophagus enters the cephalad end of the greater curvature of the stomach. This should be an acute angle, although the functional component of how this contributes to prevent GER is not well understood. What has been demonstrated experimentally is that GER becomes more likely to develop when the angle of His becomes more obtuse. Such an obtuse angle of His can be thought of as converting the upper stomach into a funnel, and with increased intra-abdominal pressure the intragastric contents are directed into the esophagus leading to GER. This concept also has surgical implications when placing a gastrostomy and potentially causing the angle of His to become less acute, thus promoting GER. Effective peristalsis in the distal esophagus is the final physiologic mechanism for controlling GER. The esophagus must be able to clear luminal contents, and both mechanoreceptors and acid receptors mediate esophageal clearance. GER tends to reach the upper esophagus more frequently in infants because they tend to be recumbent. Distention of the upper esophagus from GER in infants leads to vomiting the gastric contents out of the mouth. Delayed gastric emptying, common in neurologically impaired children, can lead to increased gastric pressure and also result in GER. The combination of acid reflux and poor esophageal motility results in prolonged exposure of the esophageal mucosa to the destructive material, potentially leading to esophagitis. Esophagitis can further negatively affect function of the LES mechanism, worsening the problem by decreasing LES tone and impairing peristalsis. Patients with tracheoesophageal fistula tend to have poor esophageal peristalsis along with LES dysfunction and are thus at high risk for pathologic GER.38 In addition, the distal esophageal segment often needs to be extensively mobilized during repair of esophageal atresia to perform the anastomosis with minimal tension. This can change the angle of His and also pull a portion of the stomach through the diaphragmatic hiatus, thereby eliminating the intra-abdominal esophagus. The sequelae of GER in these patients can lead to recurrent esophageal anastomotic stricture and places them at risk for esophagitis.39,40 Multiple interacting elements are thus involved with the pathogenesis of GERD in infants and children. A single event or combination of events can disrupt the delicate balance between physiologic GER and pathologic GERD.4

CLINICAL DIAGNOSIS The diagnosis of GERD can often be made or is at least suspected clinically, with the objective to differentiate those patients with pathologic reflux who are at risk of complications. Signs and symptoms of GERD in infants and children are listed in Table 15-1. Persistent, nonbilious regurgitation of food resulting in failure to thrive remains the most common complication from GERD in infancy (Fonkalsrud et al, 1998).41 However, many children with GERD are now being recognized due to respiratory symptoms6 such as chronic cough, wheezing, stridor, aspiration pneumonitis, apnea, and sudden infant death syndrome. These children are often

Chapter 15 Gastroesophageal Reflux in Infants and Children

TABLE 15-1 Signs and Symptoms of Gastroesophageal Reflux Disease

DIAGNOSTIC STUDIES

Infants

Children

Nonbilious vomiting

Nonbilious vomiting

Sandifer syndrome

Regurgitation/ruminating

Irritability

Heartburn

Anorexia

Dysphagia

Dysphagia

Hematemesis/anemia

Hematemesis/anemia

Cough

Cough

Wheezing

Wheezing

Hoarseness

Stridor

Malnutrition

Choking

Halitosis

Gagging

Recurrent pneumonia

Apnea/cyanotic spells Pneumonitis

referred to as “silent refluxers” because they often have no esophageal symptoms.42 Rudolph and colleagues3 documented that among children with asthma and abnormal esophageal pH probe studies, nearly 50% had minimal or no clinical GER symptoms. Futhermore, in a large population of nearly 2000 neurologically normal children, El-Serag and coworkers43 documented that GER was a significant risk factor for sinusitis, laryngitis, asthma, pneumonia, and bronchiectasis. Asthma that becomes evident after the age of 3 years, reflux symptoms that precede pulmonary symptoms, family history negative for pulmonary disease but positive for GERD, and failure to exhibit pulmonary function improvement after medical therapy may indicate that GERD is a contributing cause of asthma.6 Some degree of esophagitis is also common in infants with GERD,44 but this is not usually the primary manifestation. Sandifer’s syndrome can be confused with torticollis as the infant repetitively turns the head to one side.45 This is associated with neck extension and arching of the back and is presumably secondary to esophagitis-induced pain. Advanced esophagitis can be seen in 10% to 20% of children with GERD and can be complicated further by hematemesis, resulting in anemia as well as esophageal stricture. Barrett’s esophagus is rare in children but if present can be complicated by esophageal stricture and ulceration.46 The association of GER with neurologic abnormalities has been more recently appreciated, and these patients often present with more advanced disease manifested by severe failure to thrive, iron-deficiency anemia, recurrent pneumonia, and esophageal strictures.47 It is also important to distinguish vomiting due to GER from other causes such as hypertrophic pyloric stenosis, urinary tract infection, meningitis, or elevated intracranial pressure. In children undergoing fundoplication, Tovar and colleagues48 reported 81% had regurgitation, 30% had dysphagia, 41% presented with respiratory disease, and 7% had hemorrhage.

Barium upper gastrointestinal radiographic study is used to exclude obstructive lesions of the esophagus, stomach, or duodenum. This can also identify other anatomic abnormalities such as hiatal hernia or malrotation that may be associated with GER. Esophageal ulcerations or strictures can be noted as well as a gross estimation of esophageal motility and clearance. This is not a good method to quantitate GER, but if identified it can be determined how proximal in the esophagus the reflux travels. In addition, an upper gastrointestinal contrast study can be very valuable in evaluation of patients after antireflux surgery. This will determine if recurrent GER is present and if the fundoplication is still intact or if a hiatal hernia has developed. Any difficulty with passage of contrast medium through the area of fundoplication indicating a tight wrap can also be evaluated. Twenty-four-hour pH probe monitoring is considered the gold standard for quantifying GER and establishing the diagnosis in otherwise asymptomatic patients or those with only respiratory symptoms. Although developed in adults, standardization has been documented in children.49,50 Histamine blockers must be stopped 48 hours before the examination, and proton pump inhibitors should be discontinued 5 to 7 days before monitoring. An electrode is transnasally placed 2 to 3 cm proximal to the gastroesophageal junction or at a distance above the LES that is 13% of the entire esophageal length, and its position is documented radiographically.51 An accurate pH study should include awake and sleeping periods, feeding and fasting intervals, and positional changes. A reflux episode is considered to have occurred if the esophageal pH is recorded as less than 4. The final score is calculated according to the percent of the total time that the pH was less than 4, the total number of reflux episodes, the number of episodes lasting longer than 5 minutes, and the longest reflux episode.52 The pH probe study may also show correlation between symptoms and episodes of GER. Intraluminal impedance catheters are a relatively new modality that evaluate the change in esophageal electrical resistance that occurs with the advancement of a bolus, regardless of the pH.53 Combined multichannel intraluminal impedance and pH measurement may become the new gold standard for diagnosis of GER (acidic or nonacidic) and aid in guiding therapy.54 Endoscopic evaluation of the esophagus allows evaluation of mucosal abnormalities both by gross examination as well as by microscopic findings from pathologic biopsy specimens. Evidence of esophagitis can be documented as can other complications of GER, such as ulcer formation, esophageal stricture, or Barrett’s esophagus. However, the absence of esophagitis on upper endoscopy does not rule out significant GERD. More proximally, vocal cord inflammation or edema can also be documented. Bronchoscopy is another study that can be useful in patients with pulmonary symptoms thought secondary to GER. Aspiration of material from the bronchi and analysis for lipid-laden macrophages can help determine if GER is complicated by aspiration.55 Esophageal manometry is utilized in adults and is a wellestablished procedure. However, this is difficult to perform

219

220

Section 4 Gastroesophageal Reflux and Associated Conditions

The primary management of GERD in infants and children involves small, frequent feedings, maintenance of the upright

or prone-elevated posture at all times (head of bed elevation), and thickening of feedings with cereal. Temporary measures can include transpyloric nasoduodenal or nasojejunal feedings. Medications can also be used, the most common being one or a combination of more than one of a histamine-receptor blocker (cimetidine, ranitidine, famotidine), proton pump inhibitor (omeprazole, lansoprazole), and dopamine antagonist (metoclopramide). Medical therapy aims at decreasing the acid content of gastric secretions and improving esophageal and gastric motility. Infants without complications related to their GER are likely to respond well to medical treatment. As time goes on, the LES develops, infants sit up and eventually stand with gravity helping to decrease GER, and solid foods are introduced to replace breast milk or formula liquid diet. All of these combined factors help decrease GER in most infants as they grow. On the other hand, symptomatic GERD in children older than 5 years of age is not usually associated with a similar spontaneous resolution. It is also likely that reflux has been present for a long period of time in these children, although it may have been asymptomatic. Indications for surgical intervention (Table 15-2) include failure of medical management to control symptomatology or intolerable side effects (i.e., extrapyramidal reactions, sedation and diarrhea with metoclopramide). Failure to thrive as a result of caloric deprivation is the most common complication of persistent GERD in infants and children that leads to operative intervention.41 In addition, more urgent surgical treatment should be considered in infants with a history of aspiration associated with GERD, especially when causing either apneic attacks, stridor, or recurrent pneumonitis, and with an ongoing concern of SIDS.59 Older infants and children may also require operative management for poorly controlled esophagitis, esophageal stricture formation, or failure to thrive. It has been estimated that 25% to 75% of children with persistent asthma have increased esophageal acidification documented by pH monitoring, and up to half of these patients will have no symptoms attributable to GER.60 Asthmatic patients should be considered for antireflux surgery

FIGURE 15-1 A view of the retroesophageal window and esophageal hiatus with a clear view of the right and left diaphragmatic crura.

FIGURE 15-2 Suture placed through the left crus and approaching the right crus to close the esophageal hiatus.

TABLE 15-2 Operative Indications for Gastroesophageal Reflux Disease Absolute Indications Apnea/near–sudden infant death syndrome with gastroesophageal reflux Pneumonitis with associated lung changes Esophagitis with ulceration or stricture Relative Indications Failure of medical management Failure to thrive Recurrent pneumonia Atypical asthma Chronic cough Chronic vomiting

in infants and young children and has little clinical value except in children with suspected primary or secondary esophageal motility disorders. Manometry has identified abnormal distal esophageal motility in infants after repair of esophageal atresia with tracheoesophageal fistula.56 A radionuclide scan or scintigraphy of the upper intestinal tract is rarely necessary. This offers no real advantages over the barium upper gastrointestinal study other than quantification of gastric emptying. The study is obtained by administering a technetium-99m–labeled meal. Neurologically impaired children tend to have more problems from delayed gastric emptying compared with neurologically normal children.57 However, fundoplication itself has been demonstrated to improve gastric emptying without performing a concurrent gastric emptying procedure.58 Therefore, obtaining a radionuclide scan preoperatively will rarely alter the surgical plan. If patients continue to have symptoms attributable to delayed gastric emptying after fundoplication is performed, scintigraphy can then be obtained to help determine if a gastric emptying procedure may be indicated.

MANAGEMENT

Chapter 15 Gastroesophageal Reflux in Infants and Children

if pH probe study is abnormal, they are corticosteroid dependent and prone to severe exacerbations, or they have recurrent pneumonia.61 It should also be recognized that pediatric patients with anatomic anomalies that may contribute to GER (i.e., esophageal atresia, congenital diaphragmatic hernia, hiatal hernia) can often be refractory to nonoperative management. Neurologically impaired children have a high incidence of GER,47 and this needs to be investigated when these patients are being evaluated for gastrostomy placement due to failure to thrive or swallowing abnormalities. If GER is identified, fundoplication should also be considered concurrent with gastrostomy placement.62,63

The first laparoscopic fundoplication was reported in 1991.64 This was a Nissen fundoplication performed on an adult patient. Over the past 15 years the number of minimally invasive procedures performed and their associated complexity has increased exponentially, and advanced technology has made minimal access surgery applicable to the pediatric population. The fundamental procedural components of a Nissen fundoplication are the same whether performed open or laparoscopically and have not dramatically changed since first described.16,29 The goals of the operation are to reverse the pathophysiologic causes contributing to GERD as outlined earlier. These include establishing an adequate length of intra-abdominal esophagus, creating a valvelike mechanism or “pinchcock” at the gastroesophageal junction by wrapping a portion of the gastric fundus around the esophagus at that location, re-forming an acute angle of His, and creating a short but sufficiently loose or “floppy” wrap to prevent GER but also avoid complications of dysphagia or gas-bloat syndrome related to gastric distention. The patient is placed in a supine position, usually at the foot of the operating room table in a reverse Trendelenburg position. Access to the abdomen is obtained through a 5-mm umbilical port. Pneumoperitoneum is provided with low-flow carbon dioxide to provide space to operate, usually to a

maximum pressure of 15 mm Hg (lower in infants and those with congenital heart or pulmonary disease). One additional 5-mm port is placed in the left upper quadrant to pass suture needles. This can be placed in an appropriate position for gastrostomy placement if necessary (marked before abdominal insufflation). Two 3-mm ports are placed on the patient’s right, and one additional 3-mm port is placed on the left. A total of five port sites varying between 3 and 5 mm are thus utilized for the entire procedure. The most lateral right-sided port is utilized to pass a retractor for elevation of the left lobe of the liver to allow visualization of the esophageal hiatus. The lesser sac is entered, and short gastric vessels are ligated and divided up to the esophageal hiatus, thereby mobilizing the entire fundus of the stomach. This can be performed with simple hook electrocautery in smaller infants and children or with a harmonic scalpel or LigaSure (Valleylab, Boulder, CO) device in larger children. A retroesophageal window is carefully formed, and the right and left diaphragmatic crura are identified (Fig. 15-1). Limited circumferential dissection of the esophagus is performed, being careful not to damage the anterior or posterior vagus nerves or to form a hiatal hernia. The esophageal hiatus then needs to be closed posterior to the esophagus using interrupted sutures (Fig. 15-2). Any hiatal hernia that is present is closed during this step. The final crural closure is shown in Figure 15-3. An appropriate-sized bougie (Ostlie et al, 2002)65 is then passed down the esophagus and into the stomach by the anesthesiologist. The mobilized fundus of the stomach is then brought through the retroesophageal space around the esophagus. The 360-degree (Nissen) fundoplication is performed over the indwelling bougie to avoid a fundoplication that constricts the esophageal lumen. I typically use three nonabsorbable sutures to form the fundoplication, incorporating the anterior esophageal wall in the most cephalad and caudal locations to anchor the wrap to the esophagus (Fig. 15-4). The most caudal suture should be placed at the gastroesophageal junction (Fig. 15-5). The goal is to form a short and

FIGURE 15-3 Final crural closure posterior to the esophagus, also demonstrating the intra-abdominal length of esophagus obtained.

FIGURE 15-4 Placement of the most cephalad and caudal sutures approximating the two sides of the fundus and incorporating the anterior esophageal wall.

OPERATIVE TECHNIQUE

221

222

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 15-5 Final appearance of a Nissen fundoplication.

floppy fundoplication; usually no more than 2 cm in length is adequate (Ostlie et al, 2002).65 If the second 5-mm site is used for concurrent gastrostomy placement, only four incisions remain at the completion of the procedure. These are closed with absorbable subcuticular sutures, and Steri-Strips are placed for dressings. Alternate partial fundoplications such as those previously described by Toupet (posterior) and Thal (anterior) require a similar dissection to mobilize the esophagus and gastric fundus. However, rather than bringing the fundus of the stomach 360 degrees around the esophagus and suturing it to itself, the stomach is sewn directly to the sides of the esophagus, usually creating a partial fundoplication of 270 degrees. Postoperatively, patients are started on a liquid diet the same day after the procedure is completed. If liquids are tolerated, then the patient is advanced to a soft mechanical diet the day after surgery and discharged home in 1 to 2 days when tolerating this adequately and when reasonable pain control is obtained. They are instructed to remain on the soft diet for approximately 1 week at home and then gradually advanced to a regular diet, being sure to chew food well and avoid swallowing any large pieces that have the potential of getting lodged at the fundoplication site. If a gastrostomy was placed during the original procedure, the patient is kept NPO overnight and a diet is started the following day. This can be taken by mouth or administered via the new gastrostomy. Formula or breast milk feedings are usually started at a small volume and advanced over a 24-hour period.

RESULTS Prior to the laparoscopic era, Fonkalsrud and associates41 reported the largest pediatric series on nearly 7500 patients from combined hospitals in 1998. Of these children undergoing antireflux surgery, they reported good to excellent results in 95% of neurologically normal children and 85% of neurologically impaired children. The most common postoperative

complications were recurrent GER (7%), respiratory problems (4%), gas-bloat symptoms (4%), and intestinal obstruction (3%). With advances in minimally invasive techniques, more series have been reported with relatively large patient numbers, but no randomized controlled trials have been performed comparing laparoscopic and open fundoplication in children. Early retrospective cohort studies documented that the laparoscopic technique results in significantly shorter hospital stays, quicker return to full feedings, and fewer complications.66,67 However, there does remain a concern that laparoscopic Nissen fundoplication may result in a higher recurrence rate and need for reoperation compared with the open procedure.68 Many large retrospective series have been reported in the literature with results of laparoscopic Nissen fundoplication in infants and children (Rothenberg, 1998).25,26,69-71 The results are similar with an operative complication rate of 0% to 7%, open conversion rate of 0% to 3%, and operative times that range from 60 to 105 minutes. The largest postoperative problem seems to be formation of a hiatal hernia and migration of the wrap into the lower mediastinum (slipped Nissen) resulting in recurrent GER symptoms (2% to 6%). To decrease this failure rate, St. Peter and associates have advocated much more limited paraesophageal dissection as well as extra sutures between the crural repair and esophagus as well as the fundoplication itself and the esophagus and diaphragm.72 The previously reported advantage of partial fundoplications is a lower incidence of postoperative dysphagia, but at the cost of higher recurrent GER. Esposito and colleagues reviewed their outcome after at least 5 years of follow-up from laparoscopic Nissen, Toupet, and Thal antireflux procedures in 300 neurologically normal children.73 They found all three procedures resulted in a 5% intraoperative complication rate and 5% postoperative complication rate but no increase in dysphagia. Only 3.7% of children had a recurrence of their symptoms requiring medical therapy. However, all of these positive results need to be balanced against the increased complications and higher recurrence rates (up to 45%) reported in neurologically impaired children.74,75 Lasser and colleagues76 reviewed the national trend in the use of antireflux procedures for children from 1996 to 2003 utilizing a national database. He found that the highest population-based procedure rate was among infants (45% of all procedures were performed in infants) and that neurologic impairment was associated independently with longer lengths of stay and higher mortality rates. However, there was actually a decrease in the proportion of neurologically impaired children undergoing antireflux procedures over this time. This trend appears to be part of the evolution of the procedure during the laparoscopic era because a higher percentage of neurologically normal patients are undergoing antireflux procedures utilizing these minimally invasive techniques. Others have studied the outcome from antireflux operations in terms of the rate of reflux-related hospitalization in these children after surgery. Using a Washington State database containing 1142 patients who underwent antireflux procedures, Goldin and associates77 divided them according to age at the time of operation and whether developmental

Chapter 15 Gastroesophageal Reflux in Infants and Children

delay was present. In those younger than age 4 years undergoing an antireflux operation, the rate of readmission for reflux-related events was lower. However, older children with developmental delay were hospitalized at greater rates afterward, calling into question the subjective and objective indications for surgical treatment in these older patients. There have been additional reports concerning how to manage children who do develop recurrent GERD after Nissen fundoplication. This appears to commonly be due to development of a hiatal hernia postoperatively (up to 75% of redo cases78) or simply loosening of the fundoplication wrap itself. Redo fundoplication can be accomplished laparoscopically the first time up to 89% of the time, but this decreased to 68% for second revisions.78 Conversion to an open procedure was usually due to difficulties with the dissection related to scarring or poor visualization. Others have reported 100% success in completing the redo fundoplication laparoscopically with a 6% wrap failure rate.79 Recognizing that recurrent GERD can be a significant problem after an antireflux procedure, other investigators have proposed performing total esophagogastric dissociation in high-risk patients such as the neurologically impaired. This procedure involves dividing the esophagus from the stomach at the gastroesophageal junction, forming an esophagojejunal anastomosis using a Roux-en-Y configuration, and placing feeding access via gastrostomy. This has been performed as a primary procedure in neurologically impaired patients, and Goyal and colleagues concluded that it is effective compared with fundoplication with a lower failure rate.80 In a 10-year review, Morabito and coworkers81 report that total esophagogastric dissociation resulted in no operative mortality and at follow up between 7 months to 11 years there was no reported recurrence of GER. Another alternative to fundoplication is the Stretta procedure.82 This is an endoluminal antireflux procedure that uses radiofrequency to induce collagen tissue contraction, remodeling, and modulation of the LES physiology. Many reports are available in the adult GERD literature, but the experience is very limited in children. Although the authors agree that longer follow-up is necessary, they report symptomatic relief in six of eight children in the short term.82

COMMENTS AND CONTROVERSIES Diagnosing GERD in the infant is difficult because of the inability to obtain a history and because symptoms of regurgitation of feedings and failure to thrive are not exclusive to GERD. Similarly, respiratory surrogates for GERD are not synonymous with GERD. The problem is further complicated by the natural phenomena of “growing out” of GERD. However, this process of spontaneous resolution with age permits successful medical management of GERD in most infants. In a child, history and diagnostic testing are much more enlightening, but resolution of GERD is less likely without intervention. These difficulties are heightened in the neurologically impaired child. The surgical management of GERD in infants and children is not just a miniaturization of the adult procedure. As pointed out by Dr. Partrick in this excellent review, crural dissection and reconstruction are different from that in the standard adult procedure. The availability of a “laparoscopic” solution to the problem of GERD in infants and children should not lead to the liberalization of the indications for operation. Careful evaluation and meticulous surgery are necessary for a durable life-long solution to GERD. Failed surgery in infants and children may lead to an unsalvageable esophageal problem in the adult. T. W. R.

KEY REFERENCES Fonkalsrud EW, Ashcraft KW, Coran AG, et al: Surgical treatment of gastroesophageal reflux in children: A combined hospital study of 7467 patients. Pediatrics 101:419-422, 1998. Ostlie DJ, Miller KA, Holcomb GW: Effective Nissen fundoplication length and bougie diameter size in young children undergoing laparoscopic Nissen fundoplication. J Pediatr Surg 37:1664-1666, 2002. Rothenberg SS: Experience with 220 consecutive laparoscopic Nissen fundoplications in infants and children. J Pediatr Surg 33:274-278, 1998. Rudolph CD, Mazur LJ, Liptak GS, et al: Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastrenterol Nutr 32:S1S31, 2001. Tolia V, Wuerth A, Thomas R: Gastroesophageal reflux disease: Review of presenting symptoms, evaluation, management, and outcome in infants. Dig Dis Sci 48:1723-1729, 2003.

223

PEPTIC ESOPHAGITIS, PEPTIC STRICTURE, AND SHORT ESOPHAGUS

chapter

16

Rafael S. Andrade Michael A. Maddaus

Key Points Peptic Esophagitis ■ Peptic esophagitis occurs in 40% of patients with GERD. ■ Impaired esophageal acid clearance may play a pivotal role. ■ It may be associated with hiatal hernia. ■ Peptic esophagitis precedes stricture and short esophagus. ■ Proton pump inhibitor therapy resolves 90%. ■ Continuous medical therapy is generally required unless surgery is

performed.

gastroesophageal reflux.6 Short esophagus was first described by Barrett in 1950, and Lortat-Jacob proposed in 1957 that acquired esophageal shortening was a complication of advanced GERD.7,8 In 1956, Nissen published his monumental contribution on fundoplication, and in 1957 Collis published his work on transthoracic gastroplasty as an esophageal lengthening procedure (Collis, 1957).9,10 Skinner (1967) emphasized the importance of the intra-abdominal esophagus as part of the antireflux valve and reported a high hiatal hernia recurrence rate in the presence of a shortened esophagus (Skinner and Belsey, 1967).11

Peptic Stricture ■ It occurs in 8% to 23% of patients with untreated esophagitis.

PEPTIC ESOPHAGITIS

■ Peptic stricture is short (~1 cm), concentric, and immediately prox-

Definition

imal to the squamocolumnar junction. ■ It is associated with short esophagus. ■ Proton pump inhibitor therapy, dilation, and surgery are complementary.

Esophagitis is a general term used to describe mucosal erosions and ulcerations secondary to acid exposure. Esophagitis is classified by severity, and several classification systems have been proposed in an attempt to standardize data. The Los Angeles classification system (Table 16-1; Fig. 16-1) was originally established in 1994 by an international group of endoscopists and was revised in 1999. The current classification system has acceptable interobserver agreement, and the severity of esophagitis is significantly related to the severity of esophageal acid exposure (Lundell et al, 1999).12 Macroscopic esophagitis (grade A) is present in up to 44% of patients with chronic heartburn symptoms.13 Once erosive esophagitis develops, the prevalence of peptic stricture is 10% to 20% and the prevalence of Barrett’s esophagus is 8% to 20%.14-17

Short Esophagus ■ The diagnosis can only be confirmed intraoperatively: the intra-

abdominal esophagus is less than 2.5-cm long. ■ It is associated with a large hiatal hernia. ■ True, reducible short esophagus (requiring mobilization) occurs in

up to 20% of surgically treated GERD patients. ■ True, nonreducible short esophagus (requiring gastroplasty) occurs

in less than 5% of surgically treated GERD patients. ■ Large hiatal hernia repair with gastroplasty and fundoplication has

a recurrence of less than 5% in select, experienced centers.

Pathophysiology Gastroesophageal reflux disease (GERD) is very common: approximately 7% of the U.S. population experience daily heartburn, 14% experience weekly heartburn, and 44% have monthly heartburn (McNally, 2000).1 Although the majority of patients with GERD follow a benign course, a significant percentage of patients (>10%) may develop complications such as esophagitis, peptic esophageal stricture, or acquired short esophagus.2,3

HISTORICAL NOTE Fletcher, in 1831, described esophageal strictures and the dangers associated with blind bougienage.4 In 1935, Winkelstein reported 5 patients with erosive esophagitis and speculated that these changes were secondary to gastroesophageal reflux.5 Allison made his landmark contribution in 1948 by describing the association between erosive esophagitis, hiatal hernia, and peptic stricture and attributing these to 224

The majority of patients with GERD do not develop esophagitis; thus, factors in addition to mere acid reflux must contribute to mucosal injury. Esophageal acid clearance is critical to minimize esophageal acid exposure time, and it depends on peristalsis, salivation, and the anatomy of the gastroesophageal junction (GEJ). Approximately half of patients with GERD have abnormal esophageal acid clearance, and it appears that abnormal esophageal acid clearance is an important factor in the development of esophagitis (Kahrilas and Lee, 2005).18 The squamous epithelium of the esophagus is a poor barrier to gastrointestinal refluxate and permits penetration of hydrogen ions into the deeper layers of the esophageal wall (Gozzetti et al, 1987).19-21 Characteristic findings of early reflux esophagitis include hypertrophy of the basal zone and elongation of papillae; more advanced stages reveal intraepithelial polymorphonuclear cells.1

Chapter 16 Peptic Esophagitis, Peptic Stricture, and Short Esophagus

TABLE 16-1 Los Angeles Classification System Grade A

One (or more) mucosal break no longer than 5 mm that does not extend between the tops of two mucosal folds

Grade B

One (or more) mucosal break more than 5 mm long that does not extend between the tops of two mucosal folds

Grade C

One (or more) mucosal break that is continuous between the tops of two or more mucosal folds but that involves less than 75% of the circumference

Grade D

One (or more) mucosal break that involves at least 75% of the esophageal circumference

From Lundell LR, Dent J, Bennett JR, et al: Endoscopic assessment of oesophagitis: Clinical and functional correlates and further validation of the Los Angeles classification. Gut 45:172-180, 1999.

Clinical Presentation Patients with esophagitis are difficult to distinguish clinically from patients with uncomplicated GERD; the severity of mucosal damage does not correlate well with symptoms.22 However, certain clinical predictors may raise the suspicion of esophagitis: older age, male gender, frequency of heartburn symptoms, and dysphagia.23 Mucosal erosions or ulcerations can occasionally lead to bleeding, but this is an uncommon cause of hospitalization for gastrointestinal hemorrhage (Spechler, 2003).24

Treatment Recommended lifestyle changes should include weight loss, elevation of the head during sleep, an appropriate diet (reduction of alcohol, coffee, chocolate, and avoidance of large meals shortly before bedtime), and smoking cessation. Persistent symptoms or esophagitis should be treated with proton pump inhibitors (PPIs). These drugs are clearly superior to histamine-2 receptor antagonists for the management of GERD symptoms and the regression of esophagitis. Standard-dose PPI therapy will resolve over 90% of esophagitis over a 4- to 8-week period, but grade C or D esophagitis requires a higher PPI dose and the healing rate is lower (80%) (Pohle and Domschke, 2000).25 Esophagitis may relapse after completion of treatment if underlying abnormalities persist (i.e., hiatal hernia, ineffective esophageal clearance), and most patients will require continuous therapy. Recurrence of erosive esophagitis is about 80% within 30 weeks of discontinuation of PPI therapy. Long-term followup (5-11 years) of patients on maintenance omeprazole therapy (20-60 mg/day) keeps esophagitis in remission in up to 100% of patients with GERD. Patients with persistent symptoms and esophagitis despite optimal PPI therapy may have non-acid reflux or simply have developed tachyphylaxis to therapy (Pohle and Domschke, 2000).25 Although PPIs are very effective at neutralizing gastric acid in most patients, medical therapy does not address underlying lower esophageal sphincter dysfunction, impaired esophageal clearance, hiatal hernia, or delayed gastric emptying.26 The addition of esophageal multichannel intraluminal

impedance to 24-hour pH monitoring (MII-pH) has led to the recognition that over 40% of patients with persistent symptoms on PPI have non-acid reflux.27 The effect of nonacid reflux on recurrence or persistence of mucosal abnormalities and the role of surgery in the treatment of non-acid reflux warrant further study.

ESOPHAGEAL STRICTURE Peptic esophageal stricture is the result of chronic esophagitis leading to fibrosis; it is a concentric, distal scar usually less than 1 cm in length (Fig. 16-2), but it may be as long as 8 cm.28,29 Schatzki’s ring is generally not considered to be a true stricture but is a weblike circumferential narrowing at the squamocolumnar junction. Initially reported as a constant morphologic finding by Schatzki and Gary, it was later reported as an organic stricture at the mucosal junction due to reflux.29a These rings are composed of submucosal connective tissue and are approximately 2 to 4 mm thick.30 Schatzki’s ring may be associated with solid food dysphagia, but in many cases it is simply identified in association with a small hiatal hernia and GERD symptomatology. In a long-term follow-up, Schatzki reported that of 332 patients studied, 32% had dysphagia, most having a ring diameter of less than 20 mm. All patients with a ring diameter of less than 12 mm had solid food dysphagia. Most can be managed by simple bougienage; some will require repeated dilations, and these patients may be candidates for sequential dilations followed by laparoscopic antireflux surgery. Schatzki’s rings are often the underlying cause of acute esophageal obstruction secondary to meat impaction (“steakhouse” syndrome).30 The prevalence of a true peptic stricture in patients with untreated reflux esophagitis is 8% to 25%, and it represents 70% to 80% of benign strictures (Richter, 1999; Spechler, 1992; Ferguson, 2005).31-36 Although peptic strictures are less common today primarily due to the introduction of PPI therapy, they still can pose a formidable therapeutic challenge (Richter, 1999).31

Pathophysiology Peptic stricture is a consequence of chronic GERD, and mechanisms that prolong refluxate exposure time, such as ineffective esophageal clearance, are particularly important. This acute process is followed by stages of healing: fibroblasts, which produce collagen, and keratinocytes, which restore epithelial integrity, are recruited. The entire process in chronic GERD may eventually extend transmurally. After repeated cycles of injury and repair, irreversible functional damage, manifesting as scar formation from disorganized collagen deposition and remodeling, ultimately occurs. Repetitive reflux damage leads to progressive tissue destruction that may extend transmurally. The end result is irreversible fibrosis with deposition of type I collagen and maturation into typical scar tissue.37 Esophageal stricture results from circumferential scarring, and short esophagus is the result of longitudinal scar contraction. Therefore, peptic stricture and short esophagus frequently coexist. Stricture formation usually begins at the squamocolumnar junction, which has the highest acid exposure (Hoang et al, 2005).38,39

225

226

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

C

D

FIGURE 16-1 Esophagitis (Los Angeles classification system). A, Grade A. B, Grade B. C, Grade C. D, Grade D. (COURTESY OF DAVID PURDUE, MD, MSPH, ASSISTANT PROFESSOR, DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF MINNESOTA, MINNEAPOLIS.)

Diagnosis Clinical Presentation The most common presenting symptom is dysphagia, initially to solids and eventually to liquids.29,35 Patients with chronic peptic stricture tend to gradually adapt their diet to avoid food items that are difficult to swallow and consequently may no longer complain of significant dysphagia unless specifically

questioned. Additionally, over 75% of patients have a history of heartburn that may actually improve as the stricture progresses and dysphagia becomes the predominant symptom.28 Chest pain due to esophagitis, esophageal spasm, pulsion diverticula (Fig. 16-3), or food impaction can also be a complaint in a patient with peptic stricture. Extraesophageal symptoms include chronic cough and asthma exacerbations secondary to aspiration.35 Weight loss

Chapter 16 Peptic Esophagitis, Peptic Stricture, and Short Esophagus

FIGURE 16-2 Peptic esophageal stricture located at squamocolumnar junction. (COURTESY OF DAVID PURDUE, MD, MSPH,

FIGURE 16-3 Pulsion diverticulum (arrow) associated with peptic stricture. (COURTESY OF DAVID PURDUE, MD, MSPH, ASSISTANT

ASSISTANT PROFESSOR, DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF MINNESOTA, MINNEAPOLIS.)

PROFESSOR, DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF MINNESOTA, MINNEAPOLIS.)

is uncommon, since such patients can adapt by eating softer foods or liquids that pass through the stricture. Significant weight loss, especially in a patient with recent dysphagia onset, suggests malignancy.

esophagitis and decrease the need for repeated peptic stricture dilation.33,42

Diagnostic Tests

The initial management of peptic strictures is guided dilation to relieve dysphagia. Per oral dilation has been performed for centuries, evolving from primitive instruments such as a whale bone to a large variety of dilators and balloons (Lew and Kochman, 2002).43,44 Several randomized controlled studies comparing the efficacy of dilators versus balloons have not shown a significant difference in outcome.45,46 Regardless of technique, the goal is to dilate the esophagus sequentially to a 13-mm to 15-mm diameter (40-45 Fr), the size necessary for a regular diet (Fig. 16-4).29 However, an important note of caution should be added: Strictures may require sequential dilations over a period of time, and it may not be possible to achieve the desired diameter in the first session. Tight, complicated strictures not allowing passage of an endoscope should be dilated either with wire-guided bougies under fluoroscopic guidance, with an optical dilator, or with throughthe-scope balloons to minimize risk of inadvertent esophageal injury.44 A general recommendation for dilation is to choose a dilator size 1 mm larger than the estimated stricture diameter and to dilate sequentially in 1 mm (3 Fr) increments up to three times (“rule of threes”) (Reed, 1997).36,47 Esophageal dilation for peptic stricture relieves dysphagia initially in more than 80% of patients, and most patients require only one or two dilations. Stricture recurrence rates range from 12% to 65% (mean, 45%) after dilation and are

The primary goal of the diagnostic workup is to confirm the etiology of the stricture, to delineate its anatomic characteristics, and to exclude malignancy. A barium esophagogram is a very sensitive, inexpensive study that provides a clear picture of the location, severity, and length of the stricture.40 Esophagoscopy is essential in the evaluation of any patient with dysphagia. Peptic strictures are usually concentric and immediately proximal to the squamocolumnar junction. Esophagoscopy evaluates the esophageal mucosa grossly for esophagitis (50% of patients have associated esophagitis29), intestinal metaplasia, or cancer; provides access for biopsies; and is therapeutic (see later). Any patient suspected of having a malignancy, whether proven by mucosal biopsy or not, should undergo endoscopic ultrasonography.

Treatment Patients with peptic strictures require relief of dysphagia and treatment of the underlying GERD. It is now well recognized that mechanical dilation must be combined with acidsuppression therapy to prevent ongoing esophagitis and therefore frequent stricture recurrence.41 Randomized trials with PPIs established that aggressive acid suppression can heal

Stricture Dilation

227

228

Section 4 Gastroesophageal Reflux and Associated Conditions

known to lead to erosion and even stricture at their ends; for these reasons they should not be left in place for more than 4 weeks. Full-thickness erosions of expandable metal stents have occurred, and perforations may occur on attempted removal if these are left in place for more than 1 to 2 weeks. These recommendations are based on the authors’ experience and the limited available clinical data. Complications of stents include migration, perforation, hemorrhage, stricture, and esophagorespiratory fistula (trachea, bronchus, or parenchyma).36,52-59

Corticosteroids

FIGURE 16-4 Postdilation view of peptic stricture. (COURTESY OF DAVID PURDUE, MD, MSPH, ASSISTANT PROFESSOR, DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF MINNESOTA, MINNEAPOLIS.)

Intralesional corticosteroid injection in addition to stricture dilation has been used as an adjunct in the treatment of patients with recurrent peptic stricture.60-62 Recently, a randomized, controlled, double-blinded study was published, demonstrating a significant advantage to intralesional corticosteroid injection for patients with recalcitrant peptic strictures (Ramage et al, 2005).63 Patients received a one-time injection (sham versus triamcinolone), a single balloon dilation, and PPI therapy (esomeprazole, 40 mg twice a day). At 1 year, 60% of the sham patients and 13% of the corticosteroid patients had required a repeat dilation (P = .011). Local corticosteroid injection should be considered as part of the therapeutic armamentarium for patients with recurrent peptic stricture.

Antireflux Surgery more common in long strictures, in patients with persistent heartburn, and in patients with hiatal hernia.26,36,48-51 Complications of esophageal dilation vary with the severity of the stricture and the experience of the endoscopist and may include perforation (0.1%-0.4%, significantly lower than for radiation-induced strictures), clinically relevant bleeding (0.4%), aspiration, and bacteremia (up to 40%). Antibiotic prophylaxis is recommended for patients at risk for bacterial endocarditis.36,47

Stents Experience with esophageal stenting for benign strictures, in particular for peptic strictures, is very limited. An esophageal stent for peptic stricture should only be considered in a patient with persistent dysphagia on maximal therapy for GERD, after multiple dilations, and for someone who is not a candidate for surgery. Currently, the stent of choice is either a silicone stent that can be left in place for 4 to 12 weeks or an expandable plastic stent. Little published experience exists with the newer expandable plastic stents, but early use suggests a stent migration rate in excess of 50% (personal communication, J. D. Luketich, University of Pittsburgh). Stents are generally left in place for a minimum of 3 to 4 weeks to allow for scar stretching and remodeling. Silicone stents are easy to remove endoscopically and are safe for longer periods of time, but generally we remove them after 3 months and follow the patient with subsequent dietary questionnaires and barium studies if symptoms develop. Metallic stents, even if fully covered, are harder to remove due to tissue ingrowth and a higher radial force, and are

Even with optimal medical therapy, 30% to 40% of patients with peptic strictures require repeat dilation for dysphagia within 1 year.33,42,64 The need for repetitive dilations equates failure of medical therapy and is an indication for antireflux surgery and even esophagectomy in some severe cases. The combination of an antireflux procedure and stricture dilation provides durable treatment of the stenosis and may minimize recurrence by effectively controlling gastroesophageal reflux. Open antireflux surgery for peptic strictures has resulted in good to excellent results in 77% of patients (range, 43%-90%) (Little et al, 1988; Payne, 1984).65-67 Repeat dilations were required in up to 43% of patients postoperatively. Similar outcomes were reported in minimally invasive antireflux surgical series. Spivak and colleagues compared 40 GERD patients with peptic stricture versus 121 GERD patients without stricture who underwent laparoscopic antireflux procedures (Nissen, Toupet, or Collis-Nissen as indicated). At a mean follow-up of 1.5 years, the overall satisfaction rate was 88%, and none of the stricture patients needed esophageal dilations (Spivak et al, 1998).68 Klingler and coworkers reported similar results in a group of 102 patients who underwent laparoscopic antireflux surgery for GERD and peptic stricture (Klingler et al, 1999).69 To date, no randomized controlled trials have compared antireflux surgery versus optimal medical management in the treatment of patients with peptic stricture. Although medical therapy has improved greatly with the advent of PPIs, peptic esophageal stricture is a complication of GERD and, if recalcitrant to dilation and PPI therapy, may warrant surgical correction of the reflux. We recommend that patients with

Chapter 16 Peptic Esophagitis, Peptic Stricture, and Short Esophagus

peptic esophageal stricture initially undergo endoscopic dilation therapy and optimal treatment with PPIs for immediate palliation. The option of laparoscopic antireflux surgery should be offered to patients with persistent GERD symptoms and/or stricture. Recurrent dysphagia warrants more aggressive pursuit of surgical treatment.

Esophageal Resection Patients with end-stage benign recalcitrant strictures or those who have failed multiple antireflux procedures should be considered for esophageal resection and reconstruction (Stirling and Orringer, 1986).70 The most common approach is a gastric pull-up with a cervical or high intrathoracic esophagogastric anastomosis, but a colon interposition may be used as well. Segmental distal esophageal resection with small bowel interposition (Merendino procedure), colonic interposition, or gastro-jejunal-duodenal interposition may be used if the gastric conduit is not available. Recently, interest in these techniques has resurfaced in an attempt to minimize the adverse long-term consequences of esophagectomy.71-73 The stomach is a poor conduit for short-segment distal esophageal resection because it leads to significant reflux problems. Therefore, we generally resect and anastomose up to or above the level of the azygos vein.

SHORT ESOPHAGUS Definition Short esophagus is best defined intraoperatively as an intraabdominal esophageal length of less than 2.5 cm. Mild to moderate degrees of shortening may be addressed by more extensive esophageal dissection well into the mediastinum. If, after extensive dissection, a tension-free segment of intraabdominal length is not attainable, one can assume a short esophagus exists and a lengthening procedure such as a Collis gastroplasty should be performed in addition to an antireflux procedure.39 A short esophagus is the result of longitudinal scarring secondary to severe chronic GERD and is frequently associated with a large hiatal hernia (Fig. 16-5).11 A substantial body of literature supports the concept of acquired short esophagus (Gastal et al, 1999; Jobe et al, 1998).74-81 Its presence can be suggested by barium esophagogram, endoscopy, and manometry, but the definitive diagnosis can only be made intraoperatively. Precise criteria for short esophagus differ slightly between reported surgical series (Gastal et al, 1999).75,77,78,80-83 Horvath and associates have defined three types of esophageal shortening: (1) apparent short esophagus; (2) true, reducible short esophagus; and (3) true, nonreducible short esophagus. Apparent short esophagus is the result of longitudinal compression of the esophagus in the mediastinum but the esophagus is of normal length. True, reducible short esophagus is defined as an esophagus that is indeed shortened but with proper mediastinal mobilization the esophagus has an intra-abdominal length of at least 2.5 cm. True, nonreducible short esophagus does not allow for an intra-abdominal length of greater than or equal to 2.5 cm, despite appropriate mediastinal dissection, and requires a Collis gastroplasty. The relevance of an esophageal intra-abdominal length of greater

FIGURE 16-5 Esophagogram of short esophagus and complete intrathoracic stomach.

than or equal to 2.5 cm is critical to avoid cephalad traction on the completed antireflux wrap and wrap herniation (Horvath et al, 2000).84

Epidemiology The prevalence of short esophagus (defined by the need of extensive mediastinal mobilization and/or a Collis gastroplasty) varies between 1.5% and 19% of patients undergoing surgery for GERD (Gastal et al, 1999; Jobe et al, 1998; Horvath et al, 2000).39,75-78,84-88 The precise prevalence is difficult to ascertain due to selection bias and variability in the definition of short esophagus. Perhaps the most precise measure of the prevalence of true, nonreducible short esophagus is the percentage of patients undergoing surgery for GERD who require a Collis gastroplasty: 1% to 5%.89,90 However, in the setting of giant hiatal hernia, the incidence has been reported to be much higher (Maziak et al, 1998).96,99

Pathogenesis Short esophagus is thought to be the result of similar pathogenic processes as peptic esophageal stricture but may occur in the absence of esophageal stricture and inflammation.39

Preoperative Diagnosis Several preoperative findings may suggest the presence of a shortened esophagus: large (≥5 cm) nonreducing type I hiatal

229

230

Section 4 Gastroesophageal Reflux and Associated Conditions

hernia, a type III hiatal hernia, Los Angeles classification grades C and D esophagitis, peptic stricture, Barrett’s esophagus, and short esophagus by manometric criteria. Awad and associates systematically assessed the efficacy of esophagography, endoscopy, and manometry as predictors of a short esophagus. The combination of radiologic, endoscopic, and manometric preoperative tests yielded 100% specificity, but at the sacrifice of sufficient sensitivity (28%) (Awad et al, 2001).91 No single preoperative test can accurately detect a shortened esophagus; however, these findings, alone or in conjunction, should raise the surgeon’s suspicion for the need of an esophageal lengthening procedure (Gastal et al, 1999; Horvath et al, 2000; Mittal et al, 2000).75,84,92-94

Intraoperative Diagnosis The most accurate method to assess esophageal length is direct, intraoperative visualization of the GEJ. After hernia sac dissection and division of the short gastric vessels and careful dissection of the fat pad, the mediastinal esophagus is mobilized 8 to 10 cm and the relation of the GEJ to the hiatus is determined (O’Rourke et al, 2003).77,95 There must be no tension or traction on the esophagus and stomach; the nasogastric tube or bougie should be removed from the esophagus because they tend to stent or exert downward pressure, artificially displacing the GEJ. The distance from the crura to the GEJ is measured and should be at least 2.5 cm. Frequently, the exact location of the GEJ is difficult to ascertain. In larger hernias, a redundant sac and large amount of fat around the GEJ (“fat pad”) can completely obscure this anatomic landmark and make accurate determination of the true GEJ difficult, if not impossible. In addition, with upward displacement of the esophagus as occurs in hiatal hernias, a phenomenon of “gastric cardia tubularization” is observed, with the stomach just below the GEJ developing a tubular appearance that may be mistaken for the esophagus. The safest way to determine the exact location of the GEJ is by dissection of the fat pad, allowing a clear view of the true angle of His (Fig. 16-6). Pearson used a left thoracotomy approach in 94 patients with giant hiatal hernia and performed extensive esophageal mobilization combined with fat pad dissection of the GEJ (Maziak et al, 1998).96 This meticulous technique led to the diagnosis of true, nonreducible short esophagus in 80% of patients. Intraoperative endoscopy can be a useful tool to aid in the localization of the GEJ; transillumination at the tip of the gastroscope assists with the laparoscopic determination of the GEJ (Mittal et al, 2000).92 However, care should be exerted to avoid excessive insufflation, because it will obscure the simultaneous laparoscopic view of the GEJ and eventually will dilate the small bowel resulting in loss of operative space.

Treatment A gastroplasty is mandatory if extensive esophageal mobilization fails to deliver an intra-abdominal esophagus of 2.5 cm. Failure to recognize the need for a gastroplasty and construction of a fundoplication under cephalad traction may lead to a high hernia recurrence rate (Hashemi et al, 2000).11,97

FIGURE 16-6 Laparoscopic view of true, nonreducible short esophagus after extensive mediastinal mobilization. The gastroesophageal junction (white arrow) is at the level of the hiatus (black arrow). There is no intra-abdominal esophagus. The white line delineates the area previously covered by the fat pad. Note that the vagus nerves have been dissected off the gastroesophageal junction.

Maziak and colleagues published the first study on the systematic use of a Collis gastroplasty for the treatment of true, nonreducible short esophagus. They used a transthoracic approach to reduce the hernia and to extensively mobilize the esophagus; they used a Collis gastroplasty selectively (80%) and performed a Belsey antireflux procedure. At a median follow-up of 6 years using barium esophagography and symptom survey, the anatomic recurrence rate was 2% (2 patients who had not undergone a gastroplasty) and patient satisfaction was 94% (Maziak et al, 1998).96 A second study, published by Patel and associates, reported data on 240 patients with giant hiatal hernias treated with a transthoracic approach using a Collis-Nissen fundoplication in 96% of patients. At an average follow-up of 42 months, the anatomic recurrence rate was 12.4% and patient satisfaction was 86% (Patel et al, 2004).98 These reports represent the gold standard for proper surgical treatment of true, nonreducible short esophagus and giant hiatal hernia, with an anatomic hernia recurrence rate between 2% and 12%. The laparoscopic application of a Collis gastroplasty has led to similar results in experienced hands, with hernia recurrence rates ranging from 0% to 13% (Jobe et al, 1998; O’Rourke et al, 2003; Pierre et al, 2002).76-78,95,99 Luketich and associates published a series of 200 laparoscopic repairs of giant hiatal hernia and used the Collis gastroplasty in combination with fundoplication with a 2.5% recurrence at 18 months of follow-up. At the University of Minnesota, we have repaired 60 giant hiatal hernias using a laparoscopic Collis-Nissen technique. At a median follow-up of 8 months we have had a 4.7% anatomic recurrence rate and a 98% patient satisfaction rate (Whitson et al, 2006).100

SUMMARY Peptic esophagitis, peptic esophageal stricture, and short esophagus are consequences of GERD. Poor esophageal acid

Chapter 16 Peptic Esophagitis, Peptic Stricture, and Short Esophagus

clearance is possibly a triggering factor for the development of esophagitis, and progressive untreated esophagitis eventually leads to circumferential scarring (stricture) and/or longitudinal scarring (short esophagus). Medical therapy (PPIs), endoscopic therapy (dilation), and surgical therapy (fundoplication, Collis gastroplasty) are all essential and complementary in the treatment of these potentially challenging disorders.

Is the mere presence of a peptic esophageal stricture, that is, a complication of GERD, an indication in itself for surgery? The answer is almost universally no. Good medical management with PPI therapy and sequential, serial dilations will be successful in the majority of cases. The need for and the timing of subsequent antireflux surgery will depend on the experience of the patient’s doctors, the severity of the stricture, and the compliance of the patient with medical therapy. If all of these factors are favorable, most strictures can be managed without surgery. On the other hand, if the stricture continues to recur, we have certainly seen cases in which an antireflux operation, often in combination with a Collis gastroplasty, allows good longterm management of the reflux and, in general, in the long run, no need for repeated dilations. This is reminiscent of the concept of “no acid, no ulcer,” that is, no reflux, no stricture. These are complex problems that need complex care by the most experienced surgeons and gastroenterologists in a region, many times requiring referral to a very specialized center. Too aggressive dilations may easily lead to perforations and bad outcomes; too gentle dilations will do little to open the stricture, and, of course, poor medical management will undoubtedly lead to an increase in acid reflux, symptoms of GERD, and rapid return of the inflammation, scar, and stricture process. Gentle, sequential dilations with all of the “tricks of the trade” are required to obtain a good outcome. Poor decisionmaking with respect to antireflux surgery may lead to failure to recognize a shortened esophagus and subsequent failed antireflux surgery or to failure to recognize poor motility and subsequent worsening of dysphagia due to the underlying stricture itself, poor peristaltic activity of the esophagus, and now too tight of a wrap. Regarding the short esophagus, does it exist? Certainly the answer is yes (Fig. 16-7). Some authors have embraced it as a common association with giant hiatal hernia,96,99 and others have denied its existence. The truth likely lies somewhere in between. Also, in the case of giant hiatal hernia, the recurrence rates have been as high as 40% when it is managed laparoscopically without a lengthening procedure, but clearly other factors exist, such as size of the hiatal defect, and so on. The main issue is that one must look for the short esophagus, and, if found, a plan of management must be present to deliver a tension-free segment of the distal esophagus into the abdomen or create a neo-esophagus using a Collis gastroplasty approach. Certainly, until the results of the management of complex patients with reflux disease are solved, all potential considerations that might impact negatively on the long-term outcomes need to be scrutinized and studied as rigorously and scientifically as possible. J. D. L

COMMENTS AND CONTROVERSIES

KEY REFERENCES

The authors present a concise overview of peptic esophagitis, strictures, and the concept of the short esophagus. The topics remain controversial in their diagnosis, management, and in the case of the short esophagus even in its existence. Regarding benign peptic strictures, they are becoming rare enough that most medical residents are not getting adequate experience in their management and will need to rely to a large degree on prior historical series. For the most part, this represents an advance in the medical management of GERD, but to some degree it represents a more generalized awareness of the symptoms of GERD; and patients seem to be seeking and initiating treatment much earlier than in decades past.

Awad ZT, Mittal SK, Roth TA, et al: Esophageal shortening during the era of laparoscopic surgery. World J Surg 25:558-561, 2001. Collis JL: An operation for hiatus hernia with short esophagus. J Thorac Cardiovasc Surg 14:768-788, 1957. Ferguson DD: Evaluation and management of benign esophageal strictures. Dis Esophagus 18:350-359, 2005. Gastal OL, Hagen JA, Peters JH, et al: Short esophagus: Analysis of predictors and clinical implications. Arch Surg 134:633-636, 1999; discussion 637-638. Gozzetti G, Pilotti V, Spangaro M, et al: Pathophysiology and natural history of acquired short esophagus. Surgery 102:507-514, 1987.

FIGURE 16-7 Short esophagus.

231

232

Section 4 Gastroesophageal Reflux and Associated Conditions

Hashemi M, Peters JH, DeMeester TR, et al: Laparoscopic repair of type III hiatal hernia: Objective follow-up reveals high recurrence rate. J Am Coll Surg 190:553-561, 2000. Hoang CD, Koh PS, Maddaus M: Short esophagus and esophageal stricture. Surg Clin North Am 85:433-451, 2005. Horvath KD, Swanstrom LL, Jobe BA: The short esophagus: Pathophysiology, incidence, presentation, and treatment in the era of laparoscopic antireflux surgery. Ann Surg 232:630-640, 2000. Jobe BA, Horvath KD, Swanstrom LL: Postoperative function following laparoscopic Collis gastroplasty for shortened esophagus. Arch Surg 133:867-874, 1998. Kahrilas PJ, Lee TJ: Pathophysiology of gastroesophageal reflux disease. Thorac Surg Clin 15:323-333, 2005. Klingler PJ, Hinder RA, Cina RA, et al: Laparoscopic antireflux surgery for the treatment of esophageal strictures refractory to medical therapy. Am J Gastroenterol 94:632-636, 1999. Lew RJ, Kochman ML: A review of endoscopic methods of esophageal dilation. J Clin Gastroenterol 35:117-126, 2002. Little AG, Naunheim KS, Ferguson MK, et al: Surgical management of esophageal strictures. Ann Thorac Surg 45:144-147, 1988. Lundell LR, Dent J, Bennett JR, et al: Endoscopic assessment of oesophagitis: Clinical and functional correlates and further validation of the Los Angeles classification. Gut 45:172-180, 1999. Mainie I, Tutuian R, Shay S, et al: Acid and non-acid reflux in patients with persistent symptoms despite acid-suppressive therapy: A multicentre study using combined ambulatory impedance-pH monitoring. Gut 55:1398-1402, 2006. Maziak DE, Todd TR, Pearson FG: Massive hiatus hernia: Evaluation and surgical management. J Thorac Cardiovasc Surg 115:53-60, 1998; discussion 61-62. McNally PR: Clinical manifestations, natural history, and differential diagnosis of reflux esophagitis. In Orlando RC (ed): Gastroesophageal Reflux Disease. New York, Marcel Dekker, 2000. Mittal SK, Awad ZT, Tasset M, et al: The preoperative predictability of the short esophagus in patients with stricture or paraesophageal hernia. Surg Endosc 14:464-468, 2000. O’Rourke RW, Khajanchee YS, Urbach DR, et al: Extended transmediastinal dissection: An alternative to gastroplasty for short esophagus. Arch Surg 138:735-740, 2003.

Patel HJ, Tan BB, Yee J, et al: A 25-year experience with open primary transthoracic repair of paraesophageal hiatal hernia. J Thorac Cardiovasc Surg 127:843-849, 2004. Payne WS: Surgical management of reflux-induced oesophageal stenoses: Results in 101 patients. Br J Surg 71:971-973, 1984. Pierre AF, Luketich JD, Fernando HC, et al: Results of laparoscopic repair of giant paraesophageal hernias: 200 consecutive patients. Ann Thorac Surg 74:1909-1916, 2002. Pohle T, Domschke W: Results of short- and long-term medical treatment of gastroesophageal reflux disease (GERD). Langenbeck’s Arch Surg 385:317-323, 2000. Ramage JI, Rumalla A, Baron TH, et al: A prospective, randomized, double-blind, placebo-controlled trial of endoscopic steroid injection therapy for recalcitrant esophageal peptic strictures. Am J Gastroenterol 100:2419-2425, 2005. Reed C: Pitfalls and complications of esophageal prosthesis, laser therapy, and dilation. Chest Surg Clin North Am 7:623-636, 1997. Richter JE: Gastroesophageal reflux disease peptic structures of the esophagus. Gastroenterol Clin North Am 28:875-891, 1999. Skinner DB, Belsey RH: Surgical management of esophageal reflux and hiatal hernia: Long-term results with 1030 patients. J Thorac Cardiovasc Surg 53:33-54, 1967. Spechler SJ: Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. The Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. N Engl J Med 326:786-792, 1992. Spechler SJ: Clinical manifestations and esophageal complications of GERD. Am J Med Sci 326:279-284, 2003. Spivak H, Farrell TM, Trus TL, et al: Laparoscopic fundoplication for dysphagia and peptic esophageal stricture. J Gastrointest Surg 2:555560, 1998. Stirling MC, Orringer MB: Surgical treatment after the failed antireflux operation. J Thorac Cardiovasc Surg 92:667-672, 1986. Whitson BA, Hoang CD, Boettcher AK, et al: Wedge gastroplasty and reinforced crural repair: Important components of laparoscopic giant or recurrent hiatal hernia repair. J Thorac Cardiovasc Surg 132:11961202, 2006.

chapter

MASSIVE (PARAESOPHAGEAL) HIATAL HERNIA

17

Donna E. Maziak F. Griffith Pearson

Key Points ■ Paraesophageal hiatal hernia is a confusing term, and it is used

■ ■ ■ ■

interchangeably and incorrectly for both type II and type III hiatal hernias. Massive (type III and IV) hiatal hernia is the natural progression of a sliding (type I) hiatal hernia. Associated, acquired short esophagus is frequent. Life-threatening emergency complications are rare, and the potential for these complications is not an indication for urgent repair. Regardless of the approach, the principles of repair are identical.

HISTORICAL NOTE Hiatal hernia has been recognized for centuries. As long ago as 1610, Ambrose Paré was credited by Bowditch as having described a patient with the stomach herniated through the esophageal hiatus.1 Potemski was the first to report repair of a hiatal hernia in 1889.2 It was not until 1926 that Akerlund first reported paraesophageal herniation.3 Harrington, in 1938, wrote the first detailed description of hiatal hernia repair in a series of patients.4 Allison, in 1949, was the first physician to attribute the symptoms of gastroesophageal reflux and acid indigestion to hiatal hernia (Allison, 1951).5 Finally, in 1968, with Hill and Tobias’ publication, the anatomy and the clinical implications of paraesophageal hernias were more clearly understood.6

ANATOMY The diaphragm, a muscle that separates the abdominal contents from the chest, consists of two sections: the costal part, arising from the pleuroperitoneal membrane, and a crural section, arising from the esophageal mesentery, which forms the diaphragmatic hiatus. The esophagus lies in the esophageal hiatus between the limbs of the crus of the right diaphragm and includes a sheath of connective tissue—the phrenoesophageal ligament. The lower esophageal sphincter (LES) is a 2.5- to 4.5-cm length of smooth muscle with the upper part lying within the diaphragmatic hiatus and the lower part in the abdomen. The phrenoesophageal ligament, a layer of connective tissue, secures the lower esophagus in an intra-abdominal location. As well, the acute angle between the cardia of the stomach and the esophagus, or the angle of His, acts to some extent as a flap/valve to decrease or prevent gastroesophageal reflux across the gastroesophageal junction (GEJ). A hiatal hernia occurs when a portion of the stomach prolapses into the posterior mediastinum through the diaphragmatic esophageal hiatus.

The classification widely used today lists four types of hiatal hernias: Type I, or sliding hernia, occurs with migration of the GEJ into the posterior mediastinum through the diaphragmatic hiatus. Type II, or paraesophageal hernia, is characterized by an upward migration of the gastric fundus alongside the normally positioned, intra-abdominal GEJ. Type III is a massive or giant paraesophageal hernia and is a combination of types I and II. The stomach herniates cephalad into the thorax in a paraesophageal location, along with mediastinal displacement of the GEJ. Type IV is a massive type III hernia, including additional abdominal organs such as omentum, colon, small bowel, or spleen.

PATHOPHYSIOLOGY Anatomy Sliding hiatal hernia is by far the most common type of hiatal hernia. It occurs when the GEJ, along with a portion of adjacent stomach, migrates into the mediastinum through the esophageal hiatus. A majority of patients with demonstrated hiatal hernias are asymptomatic. When the LES moves into the chest, it is exposed to negative intrathoracic pressure, which reduces the pressure in the LES itself. In addition, widening of the diaphragmatic hiatus and loss of the angle of His may diminish the valvelike “antireflux” function of the LES. As an increasing amount of stomach herniates, the greater curvature side of the fundus “rolls” upward into the posterior mediastinum, on the left side of the lower esophagus, and now lies at a higher level than the displaced GEJ. This rolling variant is a stage in progression from a small to a large sliding hernia. As the hernial defect enlarges and more of the stomach herniates, organoaxial volvulus of the intrathoracic stomach can occur (usually once one half to three fourths or more of the stomach lies in the mediastinum). The lesser curvature side of the stomach remains tethered in the abdomen by the gastrohepatic omentum and the left gastric vessels, and this explains the asymmetrical displacement of the stomach in these large hernias. With organoaxial volvulus, the gastric fundus “folds” anteriorly across the lower esophagus. The uppermost part of the gastric fundus folds anteriorly and comes to lie on the right side of the posterior mediastinum. When volvulus occurs, it may lead to a number of acute and life-threatening complications: partial or complete obstruction at the distal end of the “twisted” GEJ, sometimes 233

234

Section 4 Gastroesophageal Reflux and Associated Conditions

associated with acute dilation of the intrathoracic stomach; impairment of the blood supply to the intrathoracic stomach with necrosis of the gastric wall and perforation into the mediastinum or pleural space; and localized gastric ulceration that may penetrate (pain), perforate (mediastinum, pleura, or pericardial spaces), or bleed massively. When sufficient stomach herniates into the mediastinum it becomes trapped above the narrower diaphragmatic hiatus. This is referred to as an “incarcerated,” irreducible hernia. Less commonly, and with the most extreme degrees of herniation, the intrathoracic contents may include omentum, colon, spleen, and small bowel, resulting in a type IV hernia. Type II, or true paraesophageal, hernias are rare. Here a portion of the stomach, and sometimes part of the peritoneal sac with other organs, migrates into the thorax through the normal esophageal hiatus or through an adjacent defect in the diaphragm. The GEJ remains in its normal intra-abdominal location. When large enough, these type II paraesophageal hernias will also undergo incarceration and become irreducible and proceed to organoaxial volvulus. Since the GEJ remains in a normal intra-abdominal location, however, the “antireflux” valvular function in the lower esophagus is preserved. This is in contrast to type III and IV hernias, in which the LES lies in the thorax and associated pathologic gastroesophageal reflux is common. These large hernias are almost exclusively encountered in an elderly population. With aging, diminished muscle bulk, tone, and elasticity predisposes to thinning and widening of the hiatal margins. Furthermore, some elderly individuals develop a dorsal kyphosis, which may stretch and weaken the muscular margins of the diaphragmatic hiatus. Based on the previous discussion, we propose an alternative categorization of the anatomic types of hiatal hernia. Types III and IV are almost certainly advanced stages of an original sliding, axial hiatal hernia. The type II paraesophageal hernia is the only anatomic variant in which the GEJ remains in its normal intra-abdominal location. We therefore propose the following anatomic categories:

Belsey, 1967).6-12 Nausea and intermittent vomiting may occur. Dyspnea can occur with very large hernias due to compromise of intrathoracic space sufficient for comfortable breathing during exertion. On occasion, pulmonary atelectasis is observed on CT with these larger hernias. Postprandial distress, occult iron-deficiency anemia, or dysphagia are the symptoms most commonly prompting investigations (Maziak et al, 1998).8,10,11 When volvulus occurs patients may experience intermittent obstruction and complain of dysphagia and regurgitation, and on occasion they may have complete obstruction usually at the GEJ. With the stomach trapped in the chest, the venous return is compromised in the hiatus, and the mucous membrane of the incarcerated stomach may become engorged and “weep” blood, which is insufficient to produce either hematemesis or melena. With time, however, this chronic, occult bleeding can result in profound degrees of irondeficiency anemia. Such patients may present with complaints of fatigue and weakness, palpitations, dyspnea, and angina. Reported complications include the ulceration of the herniated stomach, which may lead to painful penetration, perforation, or massive bleeding. Perforation may occur into the mediastinum, pericardium, or pleural space. When the stomach has undergone volvulus this can impair the circulation, and impairment of the circulation can progress to gangrene and necrosis of the incarcerated segment. These patients with giant hernia often give a history of reflux that may be a current problem or only a feature of the remote past (Maziak et al, 1998; Skinner and Belsey, 1967; Allen et al, 1993).8,9,13-22 This range of reported incidence emphasizes the importance of taking a careful and detailed history (Table 17-1).

Type IA: sliding hiatus hernia (GEJ displaced above the diaphragm) Type IB: rolling, paraesophageal hernia, with or without organoaxial volvulus Type IC: paraesophageal hernia including intra-abdominal structures such as omentum, colon, spleen Type II: “pure” paraesophageal hernia (GEJ in the normal, intra-abdominal location), without organoaxial volvulus

TABLE 17-1 Paraesophageal Hernia: Reported Incidence of GERD

DIAGNOSIS AND EVALUATION An adequate chest radiograph will always demonstrate these large hernias, and many incidentally diagnosed hiatal hernias are discovered in this manner (Fig. 17-1). A good quality

Author (Year)

Incidence of GERD (%)

Skinner and Belsey (1967)

Rare

Orringer and Belsey (1972)

—

Ozdemir et al (1973)

—

Wichterman et al (1979)

5

Signs and Symptoms

Pearson et al (1983)

85

Symptoms of large paraesophageal hernias may be the result of incarceration, organoaxial volvulus, mechanical impairment of pulmonary function, and gastroesophageal reflux, and usually are a combination of these factors. Although some patients may initially deny any symptoms, with careful questioning almost all will give a history of some esophagealrelated complaints. Symptoms due to incarceration commonly include some postprandial distress or fullness; intermittent, vague epigastric pain; and early satiety (Maziak et al, 1998; Skinner and

Walther et al (1984)

60

Treacy et al (1987)

72

Menguy (1988)

7

Williamson et al (1993)

33

Allen et al (1993)

16

Fuller et al (1996)

27

Maziak et al (1997)

83

GERD, gastroesophageal reflux disease.

Chapter 17 Massive (Paraesophageal) Hiatal Hernia

FIGURE 17-1 Posteroanterior chest radiograph demonstrates an airfilled cavity in the mediastinum consistent with an intrathoracic stomach.

chest radiograph (posteroanterior and lateral projections) often demonstrates an air-fluid level posterior to the heart in the herniated pouch. An upper gastrointestinal contrast study is the gold standard for evaluating this entity (Figs. 17-2 and 17-3). It delineates the anatomy and relationship of the esophagus and stomach. Typical findings include an outpouching of barium at the lower end of the esophagus and a wide hiatus through which gastric folds and, occasionally, free reflux of barium is observed. Gastric volvulus is very obvious when present (Maziak et al, 1998; Skinner and Belsey, 1967).6,8,9,19 It is important to note if barium freely enters the proximal stomach and duodenum. One can rarely locate the precise position of the GEJ relative to the diaphragmatic hiatus. The barium study is therefore not helpful in distinguishing between a sliding and true paraesophageal hernia. There is no universal agreement on the use of manometric studies in these patients. It may be difficult or impossible to advance the manometry catheter beyond the GEJ in these patients, precluding a complete and meaningful evaluation. In our experience, a complete and useful study can be obtained in about half of these patients and should be done in any patient in whom surgical repair is contemplated. The information obtained may prove useful in the selection of operation and for follow-up evaluation after surgery. Patients with massive paraesophageal hernias frequently have an acquired short esophagus. Maziak and colleagues (1998) showed that in 13 of 13 consecutive patients with paraesophageal hernias in whom a complete manometric study was possible the intersphincteric length was significantly shorter than that recorded in the normal population.8 This measurement is easily and reliably obtained from the manometry tracing. The presence of a shortened esophagus has an important bearing on the selection of the antireflux reconstruction. Manometric studies may also provide valuable information concerning the effectiveness of peristalsis in the body of the esophagus by measuring levels of LES pressure.7,23,24 These

FIGURE 17-2 Intrathoracic stomach shown on an upper gastrointestinal contrast study.

FIGURE 17-3 An intrathoracic stomach with volvulus evident on an upper gastrointestinal contrast study.

patients often have long-standing reflux and suffer diminished peristaltic amplitude in the distal third of the intrathoracic esophagus. Such changes are the result of intramural reflux damage. It has also been shown by 24-hour pH testing that most of these patients have pathologic reflux.17,22 Approximately 20% of patients without preoperative reflux have postoperative reflux if a fundoplication is not completed (Allen et al, 1993).17-22 Esophagogastroduodenoscopy is critically important in the evaluation and assessment of these patients. It is sometimes difficult to find one’s way in the patient with volvulus; it may prove impossible to find the antrum and pylorus because the scope keeps “looping” into the blind sac of distorted gastric pouch. The location of the anatomic GEJ relative to the diaphragmatic hiatus can be accurately determined so long as

235

236

Section 4 Gastroesophageal Reflux and Associated Conditions

the patient is breathing spontaneously. This observation will clearly distinguish a type II hernia from the much commoner combined sliding and paraesophageal types. It is preferable that the operating surgeon performs a preoperative endoscopy if an operation is planned. It is desirable to perform this endoscopy in an awake, spontaneously breathing patient to identify the correct level of the diaphragmatic hiatus (which is easily recognizable with each breath). When the distance between the GEJ and hiatus is greater than 4 to 5 cm, the possibility of acquired short esophagus is strongly suspect. Grossly visible reflux esophagitis and Barrett’s columnar replacement can be identified at endoscopy and are also associated with an increase of acquired short esophagus.

INDICATIONS FOR SURGICAL REPAIR AND OPERATIVE APPROACHES Many surgeons recommend surgical repair of these massive hernias in all patients, even in those with mild or minimal symptoms. Skinner and Belsey (1967) reported that if the hernia is left untreated the rate of fatal complications in such cases was as high as 30%.9 Hill recorded an operative mortality as high as 56% in cases of acute volvulus.25 Hill also reported that incarceration with obstruction developed in 10 of 29 patients with paraesophageal hernia and advocated early repair.25 A review of the literature, however, leads to some uncertainty concerning the incidence of life-threatening complications in patients with mild or minimal symptoms managed without operation. Allen and associates (1993)21 reported on a consecutive series of 147 patients seen at the Mayo Clinic during a 10-year period. Twenty-three of these patients were not operated on, and all were evaluated in medical follow-up for a median of 78 months. No patient developed a life-threatening complication, and symptoms did not progress at all in 19 individuals. Symptom progression in 4 patients resulted in elective operative repairs in 2, refusal of surgery in 1, and a fatal aspiration of barium during a barium swallow for evaluation in the fourth. During the past 40 years, the senior author of this chapter (F.G.P.) has followed a number of unoperated patients with mild or minimal signs and symptoms. Three from among at least 20 of these cases ultimately underwent elective repair because of worsening symptoms. None has presented with a life-threatening emergency complication of the condition. Stylopoulos and coworkers applied a decision analytic model to track a hypothetical cohort of patients with asymptomatic or minimally symptomatic paraesophageal hernias using a pooled analysis of 20 published studies, Healthcare Cost and Utilization Project/National Institute of Science databases, and the literature from 1964-2000.26 They assumed that if the incidence rate of symptom progression is constant, then the lifetime risk is age dependent. Therefore, they calculated the risk of developing life-threatening symptoms to be 18% for a 65-year-old patient, or 1.1% per year. This means if the mortality rate of emergency surgery is 5.4% then the overall lifetime risk of death is approximately 1%. Clearly, since the progression of symptoms is low in this mostly elderly population and rarely progresses to emergency surgery,

patients who are relatively asymptomatic do not require mandatory surgical intervention. Should patients present with symptoms of complications such as incarceration with obstruction, the vast majority can be decompressed with a nasogastric tube. This then allows for appropriate investigation, preoperative assessment, and management before any repair. In the series reported by Maziak and coworkers (1998), only 2 of the 94 surgical patients required an emergency operation. In neither of these 2 could the obstruction be relieved by attempted passage of a nasogastric tube.8

Operative Management Operation is designed to reduce the massive hernia with relief of signs and symptoms secondary to incarceration and volvulus. In other than emergency situations, it is desirable to achieve a complete reduction of the hernia—remove the hernia sac, close the hiatus, restore the GEJ to an intraabdominal location, and add some type of antireflux reconstruction. If acquired short esophagus is present, it is advisable to add a lengthening gastroplasty to reduce the risk of anatomic recurrence and a subsequent predisposition to reflux. The preoperative evaluation for acquired shortening of the esophagus includes observations from the barium swallow, esophageal manometry, and flexible endoscopy, preferable by the operating surgeon. Maziak and colleagues (1998) reported that 80% of 94 operated patients had a gastroplasty added to their repair.8 Good to excellent long-term results were achieved in 94% of patients, with a median follow-up of 9 years. A Belsey repair alone managed the two failures in this series. Both patients developed recurrent herniation and severe reflux and at reoperation were recognized as having esophageal shortening. A lengthening gastroplasty was added to the new repair, and a good result was obtained in both. Pearson, Allen, DeMeester, Altorki, Gastal, and Orringer and their colleagues have described an open transthoracic approach (Allen et al, 1993).16,21,22,27-29 The standard technique involved reduction of the hernia, excision of the sac, repair of the hernia, and fixation (gastropexy) of the stomach. Pearson, Allen, and Gastal and their colleagues frequently added a gastroplasty, following circumferential mobilization of the esophagus to the aortic arch. Altorki and associates maintained that an adequate reduction of the hernia was achieved in the majority of the cases by intrathoracic mobilization alone. Ellis and coworkers favor an open transabdominal repair.30 The addition of a transabdominal gastroplasty has been reported by Henderson (Henderson and Marryatt, 1985) and Moores.31,32 The simple reduction of the hernia and placement of a gastrostomy tube to retain the stomach within the abdomen is reserved for the very high-risk patient. Since the first report on laparoscopic paraesophageal hernia repair in 1992, there has been considerable advancement through lessons learned.33 Early reports favored a laparoscopic Nissen fundoplication, and few removed the hernia sac, leading to fluid collections in the posterior mediastinum, recurrences, and dysphagia. Crural closure was less than ideal, and the use of prosthetic material was advocated, which led to local erosion and infection in some cases. Early

Chapter 17 Massive (Paraesophageal) Hiatal Hernia

reports did not assess esophageal length, and unrecognized shortening of the esophagus led to early recurrences. Laparoscopic surgeons have only recently (2000 to the present) appreciated that acquired short esophagus occurs in a significant proportion of these giant hernias, and the addition of a gastroplasty is increasingly reported. Techniques of minimally invasive gastroplasty have been reported through the right chest or transabdominally.34-38

RESULTS There is a plethora of literature advocating the laparoscopic repair of massive paraesophageal hernia. It is readily apparent that in a skilled surgeon’s hands it is possible to obtain good results. However, follow-up of patients is still early, and this needs to be continued to ensure the recurrence rate is not higher. Some are followed with office visits and others by routine testing such as barium swallow, manometry, 24-hour pH monitoring, and endoscopy. The reported rates of failure vary from 6% to 32%, depending on if it is a radiologic recurrence or symptom recurrence.34,39-44 Most recurrences are asymptomatic and if not, and due to reflux, are often well managed with proton pump inhibitors. The original symptoms of incarceration rarely recur. The longest reported follow-up rate is only 39 months, and continued surveillance is required to ensure good results as with open repair. The recognition of a shortened esophagus and the addition of a laparoscopic gastroplasty performed expertly have decreased the incidence of anatomic recurrence with good outcomes. Continued long-term follow-up is required.

FIGURE 17-4 Forces (blue arrows) acting on the left crus. The left crus is elongated and displaced to the left and posterior. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

COMMENTS AND CONTROVERSIES Massive hiatal hernia is an increasing problem as our population ages. As pointed out by Drs. Maziak and Pearson, the existence of a massive hiatal hernia is no longer a blanket indication for repair, since few patients progress to life-threatening complications. Obstructive symptoms and symptoms of GERD frequently coexist. However in some patients a “natural” fundoplication occurs as the intrathoracic stomach undergoes volvulus, many times reducing or eliminating the symptom of heartburn. The preoperative evaluation is identical for both massive (type III and IV) hiatal hernia and sliding (type I) hiatal hernia. Esophageal motility studies are essential, and they are facilitated by performing esophageal manometry immediately after esophagogastroduodenoscopy and biopsy. At the end of the endoscopic upper gastrointestinal examination a manometry catheter may be placed with the aid of a guidewire. Surgical repair requires reduction of the hernia and restoration of the intra-abdominal esophagus. This necessitates aggressive mobilization of the distal esophagus and herniated stomach and almost always mandates esophageal lengthening. The dissection permits removal of the intrathoracic hernia sac, a frequently overlooked or ignored portion of the surgery. Careful reconstruction of the diaphragmatic hiatus requires understanding of the pathophysiology of hiatal hernia. It is the left crus of the esophageal hiatus that is stretched and displaced posteriorly and leftward toward the retroperitoneum as more and more of the stomach’s greater curve herniates into the mediastinum (Fig. 17-4). Reconstruction requires an unequal suture placement in the left and right crus, in an effort to gather up (shorten) the left crus (Fig. 17-5). In the extreme, the

A

B FIGURE 17-5 A, Simple hiatal reconstruction requires unequal spacing of sutures, normal distance between sutures in the left crus, while slightly smaller distance between sutures in the right crus. This serves to shorten the minimally elongated left crus. B, Simple reconstruction of the esophageal hiatus. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

237

238

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 17-6 A, Complex hiatal reconstruction is required when the left crus is massively elongated. The left crus is plicated, shortening it, so its length is equal to that of the right crus. B, The hiatal reconstruction can then be completed by approximating the now equal length of the right and left crura. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

left crus may need to be plicated to allow a tension-free repair of the diaphragmatic hiatus (Fig. 17-6). Failure of the hiatal reconstruction may result from inadequate exposure of the left crus. If dissection is inadequate, a portion of the hernia sac may remain on the left crus. It may then be mistaken for the left crus and used as the left side of the hiatal reconstruction, ensuring early failure. Long debated, the addition of a fundoplication has become the standard of care in patients with massive hiatal hernia. Gastropexy or tube gastrostomy can be used to stabilize the volvulized stomach in the abdomen. However, these maneuvers should not be added in an attempt to strengthen a faulty repair. In the nonsurgical candidate organoaxial volvulus can be reduced endoscopically. This portion of the stomach can than be fixed to the anterior abdominal wall with a percutaneous endoscopic gastrostomy tube, thus converting a type III hiatal hernia into a type I. T. W. R.

KEY REFERENCES Allen MS, Trastek VF, Deschamps C, et al: Intrathoracic stomach. Presentation and results of operation. J Thorac Cardiovasc Surg 105:253-259, 1993. Allison PR: Reflux esophagitis, sliding hiatal hernia, and the anatomy of repair. Surg Gynecol Obstet 92:419-431, 1951. Henderson RD, Marryatt GV: Total fundoplication gastroplasty (Nissen gastroplasty): Five-year review. Ann Thorac Surg 39:74-79, 1985. Maziak DE, Todd TR, Pearson FG: Massive hiatus hernia: Evaluation and surgical management. J Thorac Cardiovasc Surg 115:53-62, 1998. Skinner DB, Belsey RH: Surgical management of esophageal reflux and hiatus hernia. Long-term results with 1,030 patients. J Thorac Cardiovasc Surg 53:33–54, 1967.

chapter

REFLUX IN THE MORBIDLY OBESE

18

Anita P. Courcoulas

Key Points ■ The surgical therapy for reflux disease in the morbidly obese is an

emerging area of study. ■ There is an increased incidence of reflux disease in severe and

morbidly obese patients. ■ Routine antireflux surgery has a higher failure rate in morbid

obesity. ■ Laparoscopic gastric bypass is an effective antireflux operation

and addresses other common comorbidities.

HISTORICAL NOTE Although the surgical therapy for reflux disease is a development that has occurred during the past 50 years, obesity is a relatively new epidemic. For this reason, the study of reflux in the morbidly obese patient population is an emerging field with data on the pathophysiology, treatment, and long-term outcomes of various available strategies currently evolving. The history of bariatric surgery (surgery for weight loss) dates back to its introduction in the 1950s when Kremen and associates performed a jejunoileal bypass,1 which was subsequently and nearly simultaneously performed by other groups in Sweden and at the University of Minnesota. Several variations of intestinal bypass were developed and used widely in the 1950s and 1960s until the significant complications of these malabsorptive procedures were documented and the procedure was abandoned. In a search for alternate procedures, gastric restrictive procedures and gastric bypass were developed. Gastric bypass was developed by Edward Mason of the University of Iowa based on an observation that patients who had undergone partial gastrectomy for peptic ulcer disease had difficulty gaining weight and tended to remain underweight after the procedure.2 It was Mason who recognized that the lesser curvature of the stomach had the thickest wall and was less likely to stretch, so he used a vertical segment of stomach along the lesser curvature to fashion a small gastric pouch and placed a polypropylene band around the lower end of this vertical pouch to fix the size of the gastric stoma.3 His earlier loop gastric bypass procedure was then subsequently modified to use a Roux-en-Y technique to avoid the loop gastroenterostomy and bile reflux that usually ensues. The Roux-en-Y gastric bypass procedure is now being performed primarily by the laparoscopic approach, and the pure gastroplasty procedures have been abandoned owing to disappointing long-term weight loss results.

A more recent improvement in the jejunoileal bypass is a biliopancreatic diversion (with or without duodenal switch) that combines a limited gastrectomy with a long bypassed intestinal limb. This option is sometimes offered to patients with higher body mass indices, owing to the greatest weight loss results with this procedure, and to those who are unable to tolerate the idea of very limited food intake imposed by gastric bypass. The laparoscopic adjustable band is another alternative procedure offered today in which an adjustable plastic ring is placed just below the gastroesophageal junction to simulate a gastroplasty. Long-term results of this procedure in the United States are not yet available. Laparoscopic gastric bypass is considered the “gold standard” bariatric procedure available in the United States today.

DEFINITIONS AND EPIDEMIOLOGY Obesity is the epidemic of this century, with approximately one third of Americans currently considered overweight or obese (Flegal, 2002).4 Morbid obesity is defined in two ways, either by body mass index (BMI) or by pounds of excess weight over an ideal body weight. Ideal body weights are typically determined from standardized life insurance tables published in 1985 that are specific to gender and frame size. Eighty to 100 pounds of extra weight over the ideal body weight defines morbid obesity. Body mass index, which is defined as weight in kilograms divided by height in meters squared, is more commonly used to define obesity. Current guidelines indicate a BMI of 20 to 25 is healthy, 25 to 30 overweight, 30 to 35 obese, 35 to 40 severely obese, and greater than 40 kg/m2 morbidly obese. Approximately 4% of the U.S. population is morbidly obese, a number that has nearly doubled in the past 10 years according to government survey data. Driving the adult obesity epidemic is the startling rise in childhood and adolescent obesity that is worse among Hispanic and African American children.5 This epidemic has seen a corresponding rise in obesity-related adverse health consequences in both children and adults that include insulin resistance and diabetes, cardiovascular disease, fatty liver disease, orthopedic and degenerative joint problems, sleep apnea syndrome, and pseudotumor cerebri (increased intracranial pressure causing visual symptoms) among many others. In addition, there are serious psychosocial and socioeconomic consequences of obesity in our society that include increased depression rates,6 fewer opportunities for employment and income advancement, and lower marriage rates among the obese.7,8 There is also evolving evidence that obesity contributes to early mortality.9,10 239

240

Section 4 Gastroesophageal Reflux and Associated Conditions

PREVALENCE Several small studies show some conflicting results as to the prevalence of reflux in obesity.11-13 A Swedish populationbased study using information collected by interview failed to correlate BMI with reflux symptoms.14 Two large-scale population-based studies in this country (Locke et al, 1999)15,16 showed that reflux is common in the general population and is especially prevalent among the obese. Locke and colleagues showed that 69% of subjects with a BMI greater than 30 experienced reflux symptoms and that obesity was the strongest risk factor with an odds ratio of 2.8 for reflux symptoms, exceeding the effect of family history, past smoking history, alcohol consumption, and higher psychosomatic symptom scores.15 Ruhl and associates analyzed National Health and Nutrition Examination Survey (NHANES) data from over 12,000 patients for 5 to 22 years and showed that for each rise in BMI of 5 points the hazard ratio for increased reflux disease hospitalization rates was 1.22.16 Recently, Wajed and coworkers showed in a retrospective analysis that there was a strong correlation between BMI and severity of reflux measured by DeMeester score.17 There were no significant differences in manometric findings demonstrated between overweight and normal patients. In a follow-up study in 2003, Nilsson and colleagues showed a dose-response association between increasing body mass index and symptoms of reflux in both sexes, with a stronger association in women, especially those who were premenopausal or using hormone replacement therapy, suggesting an effect-modifying role of estrogen on the association between body mass and reflux.18 Finally, Devesa and colleagues showed that the incidence of adenocarcinoma of the esophagus has risen by over 350% since 1970 among white males. The authors suggest two possible explanations for this dramatic rise: obesity and smoking. Both smoking rates and the percentage of adults who are overweight and obese has grown considerably since the 1970s and suggest these two possible contributing mechanisms for this rise in cancer. The proposed mechanism by which obesity predisposed to esophageal cancer is through the increased risk of reflux and its progression to Barrett’s esophagus and then to adenocarcinoma.19 From the evidence currently available and just summarized, it appears that there is an increased prevalence of reflux in patients who are morbidly obese.

PATHOPHYSIOLOGY The pathophysiology of reflux in obese patients is most certainly multifactorial and differs when comparing obese and lean patients. It makes sense that the normal barrier function would be modulated in the setting of obesity due to anatomic (increased extrinsic fat compression at the gastroesophageal junction), mechanical, chemical, and other factors present in obese patients. In this section the focus is on the unique pathophysiologic mechanisms thought to contribute to the development of reflux in obese patients. A thorough review by Barak and colleagues (2002) on reflux and obesity has helped to identify many of the factors that have been investigated that may or may not contribute to the pathophysiology of reflux in obesity (Table 18-1).20 Esophageal sphincter

TABLE 18-1 Effect of Obesity on the Pathophysiology of Reflux Disease Contributing Mechanism

Obesity Reference

Sphincter length

Not studied

Sphincter pressure

Normal (O’Brien et al21)

Sphincter gradient

Increased (Mercer et al22)

Sphincter location

Increased incidence of hiatal hernia (Stene-Larsen et al23) Increased intra-abdominal pressure causes upward displacement (Sugerman et al24)

Gastric volume

Normal (Wisén et al25)

Gastric motility

Normal (Wisén et al25)

Gastric content composition Acid Pepsin

Bile

Normal (Wisén et al25; Harter et al26) Increased (Wisén et al25) Vagal abnormalities may predispose to changes (Wisén et al27) Increased (Wisén et al27) Vagal abnormalities may predispose to changes (Wisén et al27)

Crural diaphragm function

Normal (Cibella et al29)

Acid sensitivity

Increased (Mercer et al22)

Helicobacter pylori

Increased incidence in obesity (Perdichizzi et al30)

Adapted from Barak N, Ehrenpreis ED, Harrison JR, Sitrin MD: Gastro-oesophageal reflux disease in obesity: Pathophysiological and therapeutic considerations. Obesity Rev 3:9-15, 2002.

length has not been studied in obesity, and lower esophageal sphincter (LES) pressures in the morbidly obese have been shown to be similar to levels reported in nonobese patients.21 Mercer and associates investigated the relationship of the gastroesophageal sphincter gradient to LES in normal and in severely obese subjects. They found no differences in LES but found that the pressure gradient was higher in obese patients during both inspiration and expiration, which could facilitate reflux.22 A prospective study of over 1200 patients referred for endoscopy in Norway found reflux esophagitis in 16% of the patients and hiatal hernia in 20%, with a coexisting hiatal hernia in 68% of those with esophagitis. The degree of overweight was significantly higher (5%), both in patients with hiatal hernia and in patients with reflux esophagitis.23 Their work supports the view that obesity is associated with both hiatal hernia and reflux and that hiatal hernia plays a role in the development of reflux. Hiatal hernia may promote reflux by several mechanisms (Barak et al, 2002)20: 1. Impaired acid clearance from the esophagus 2. The fact that the widened esophageal hiatus impairs the crural diaphragm’s function as a sphincter 3. The intra-abdominal portion of the esophagus lacks the flap-valve mechanism that normally functions as a barrier to esophageal exposure to gastric acid

Chapter 18 Reflux in the Morbidly Obese

In addition, increased intra-abdominal pressure as described by Sugerman and associates (1997) in obese patients with several pressure-related comorbidities such as hypoventilation, urinary incontinence, and abdominal hernia also contributes to reflux by the upward displacement of the esophageal sphincter.24 Gastric volume, motility, and acid content have been shown to be quite similar in lean and morbidly obese subjects.25,26 Wisén and coworkers also showed that obese patients have a higher output of bile and pancreatic enzymes and higher plasma levels of pancreatic polypeptide compared with lean controls. When stimulated with sham feedings to cause vagal stimulation, obese patients failed to respond with an increased secretion of pancreatic and biliary enzymes. In addition, in the obese, exogenous cholecystokinin-stimulated enzyme secretion is significantly reduced. All these impairments of pancreaticobiliary response to vagal stimulation and cholecystokinin in obesity may alter the composition of the reflux fluid, rendering it perhaps more toxic to the mucosa of the esophagus.27,28 Morbid obesity has not been shown to be associated with diaphragmatic dysfunction or fatigue that may have been a factor considered to affect crural function.29 Some evidence also suggests that obese subjects may be more sensitive than lean controls to acid infusion into the esophagus, resulting in the more common development of reflux symptoms after such tests.22 The role of Helicobacter pylori infection in the pathophysiology of reflux in obesity has not been clarified, but one study shows that the incidence of colonization was more common in both diabetic and obese patients than in controls.30 The impact of this finding on reflux symptoms is still unclear. Finally, there is likely an important role of diet in the pathophysiology of reflux in obesity with both fat- and chocolate-containing foodstuffs as important predisposing factors to reflux that are common in the diets of many obese patients.

TREATMENT OPTIONS Lifestyle Modification Although weight loss is advocated as a part of almost all treatment plans for reflux in obese patients, there are little scientific data to support this recommendation. From a theoretical perspective, it makes sense that both decreasing the intraabdominal pressure and changing the diet in a way to eliminate fats should help to ameliorate reflux symptoms. Only two small, prospective studies have investigated the role of weight loss as a treatment for reflux.31,32 Murray and colleagues performed a double-blind clinical trial to evaluate the effect of weight loss and cimetidine in the treatment of reflux. Patients were randomly allocated to placebo/weight loss or cimetidine/weight loss and were evaluated by endoscopy and pH monitoring. After 8 to 12 weeks there was a similar weight loss and improvement in symptoms in both groups but there was no significant change in the frequency or duration of reflux as measured by pH monitoring or scintigraphy.31 In another study, 32 patients were randomized to a very low calorie diet or standard reflux treatment recommendations for 6 months and then allowed for crossover of the control group to the diet group. After 6 months of treat-

ment, with on average 9- to 10-kg weight loss, neither the diet nor the crossover control group experienced any reduction in reflux symptoms (by questionnaire) or improvement in pH measurements.32 The small number of patients in both these studies may account for the lack of findings of improvement, but the role of modest weight loss to treat reflux in obese patients still needs to be investigated further. It may be that the degree of weight loss achieved in these trials was not great enough to see an effect on reflux or that perhaps other unmeasured factors such as weight distribution, presence of hiatal hernia, or baseline severity of clinical reflux symptoms may have affected the outcome observed. Smoking cessation is a necessary component of the medical management of reflux disease in obese patients as well as modification of the diet to limit high fat intake, especially in the form of chocolate.

Medication Therapy Obesity affects the pharmacokinetics of many drugs subject to the lipophilic nature of the drug, the albumin level of the patient, changes in hepatic clearance due to fatty liver disease, and higher glomerular filtration rates, along with many other modifying factors.33 The histamine-2 receptor antagonists have all been shown to decrease gastric volume and raise pH when used in standard doses in morbidly obese patients, preoperatively. Pharmacokinetic studies show that drug dosage should be calculated according to the patient’s ideal body mass and not actual weight.34 Proton pump inhibitors have not been studied in the obese population.

Surgical Therapy Traditional antireflux operations have been carried out in the obese population with variable long-term results. The preponderance of literature shows that obesity adversely affects the outcome after reflux surgery. Only one study by Winslow and associates that looked at the outcomes of laparoscopic antireflux surgery shows no relation of obesity to failure.35 Over 500 patients were stratified by weight (BMI), and the authors found that while operative times were longer in the obese (BMI >30), complication and anatomic failure rates were similar to those in nonobese subjects at long-term (35 months) follow-up. In those reflux operations that are known and seen to fail, the two main reasons for this have been failure of the crural closure and/or malformation of the wrap.36 Both of these factors are particularly stressed in the setting of severe obesity, especially with a significant intraabdominal distribution of adiposity. Horgan and colleagues further classified three main types of failure: type I failure in which the gastroesophageal junction was herniated through the hiatus with or without the wrap, type II failure that involved a paraesophageal component resulting from a redundant wrap, and type III failure that involved a malformation of the wrap due to either defective position or construction.36 Perez and associates (2001) showed that the failure rates of anti-reflux surgery appeared to be influenced by BMI.37 In this retrospective study of 224 patients over 37 months, the total recurrence rate was 11.6% but when stratified by weight category there was a progression of rates from 4.5% to 8.0%

241

242

Section 4 Gastroesophageal Reflux and Associated Conditions

to 31.0% in the normal, overweight, and obese groups, respectively. All groups were similar in age, gender, presence of hiatal hernia, degree of esophagitis, and presence of comorbid medical conditions. Given the recognition of this high failure rate of reflux surgery in obesity and the success of obesity surgery in treating reflux symptoms, bariatric surgical procedures have been applied to patients in the setting of reflux in morbid obesity since the early 1990s (Frezza et al, 2002; Perry et al, 2004).38-42 Bariatric procedures are currently performed on patients with BMIs exceeding 40 kg/m2 and on those with a BMI of 35 kg/m2 or greater in the setting of severe comorbid conditions. Gastric bypass is the dominant bariatric procedure performed in this country and has been shown to have a clinically significant effect on reducing reflux symptoms and pathology. Jones compared 100 gastric bypass patients to 23 historical fundoplication patients and found that the bypass patients were better served, considering their great improvement in reflux symptoms and esophagitis as well as their achievement of sustained weight loss.38 These authors also note the “modified gastropexy” effect with Roux-en-Y gastric bypass because the fixed proximal small bowel mesentery of the Roux limb at the gastrojejunostomy effectively exerts a downward pull on the pouch, holding the stomach within the abdomen (Fig. 18-1). Other groups have since shown that

gastric bypass leads to both symptomatic and clinical improvement in reflux disease and that frequently these changes occur within short-term follow-up (Frezza et al, 2002).39,40 Many centers have now extended offering gastric bypass as an antireflux option in the less than morbidly obese and have shown data that support the efficacy and safety of gastric bypass in this group (Jones, 1998).43 Severe esophagitis is now considered an obesity-related comorbid condition and, in the setting of severe obesity, is reason enough to consider gastric bypass as the preferred surgical approach. Vertical banded gastroplasty (Fig. 18-2) is a historic bariatric procedure that was once thought to help treat reflux by its “Collis effect” in constructing an elongated intraabdominal esophagus by converting part of the lesser curve to a tube, but now it has been shown to be a reflux-inducing procedure that is best converted to a gastric bypass when complicated by severe, refractory reflux.44-47 The malabsorptive bariatric alternatives (biliopancreatic diversion with/ without duodenal switch) have not been studied with a particular focus on their impact on reflux diseases. It would be less likely that the improvements in reflux symptoms would be seen early after these operations because the gastric pouch size is much larger than in a gastric bypass and much of the weight loss effect is based on malabsorption that occurs over a longer period of time. The results of laparoscopic banding in this country are still being evaluated, and the impact of this procedure on reflux has not yet been determined. Early reports show some concern for the potential for increased reflux symptoms in these patients because an inflatable, adjustable, circular obstruction is placed just below the gastroesophageal junction to create a small gastric pouch.48 In summary, the current literature supports that Roux-en-Y gastric bypass is the procedure of choice in severely obese patients with reflux who are considering surgical options. The added health benefits after significant weight loss make a bariatric procedure the preferred treatment choice. A traditional antireflux operation, with its high failure rate, may be contraindicated in the morbidly obese because it may commit

FIGURE 18-1 Roux-en-Y gastric bypass.

FIGURE 18-2 Vertical banded gastroplasty.

Chapter 18 Reflux in the Morbidly Obese

them to future reoperative foregut surgery with its associated higher risks.

Indications and Patient Selection The indications for bariatric surgery to treat reflux (“bariatric reflux surgery”), presurgical evaluation, and patient selection factors for these patients with refractory reflux are listed in Table 18-2. The presurgical evaluation must be thorough to include barium swallow, endoscopy, and other esophageal studies as well as a complete assessment of the obesityrelated comorbid conditions. In addition, all patients preparing to undergo bariatric surgery should have a screening psychological evaluation to rule out untreated depression, substance abuse, or a history of eating disorders as well as educational and supportive nutritional counseling throughout their presurgical and postsurgical course. Patient selection requires a complete understanding of the proposed bariatric reflux operation to include its function as a “tool” for weight loss, the necessity to limit portion size and food types, and the need for postoperative vitamin supplementation (B12, calcium citrate, and multivitamins). In addition, all bariatric reflux operative candidates must commit to long-term, lifelong medical follow-up of the weight and reflux results of their operation as well as for surveillance for marginal ulcers, dumping syndrome, and other vitamin and nutritional deficiencies.

Roux-en-Y Gastric Bypass Technique A traditional Roux-en-Y gastric bypass is shown in Figure 18-1 and consists of a small (15 mL) gastric pouch fashioned along the lesser curvature of the stomach, along with a modest (60-150 cm) intestinal bypass. It is most commonly performed by a minimally invasive approach using approximately six port sites placed in a “modified Nissen” configuration,

slightly caudad from the costal margin with an additional right lower quadrant port for small bowel anastomosis (Fig. 18-3). The Roux and biliopancreatic limb lengths can be varied, with longer limb lengths associated with increased weight loss in the superobese patients (BMI >50 kg/m2).49 The gastrojejunostomy can be constructed after either a retrocolic or antecolic route of small bowel ascent, and the goal is to create a small (5 cm) circumferential stoma. The small bowel–to–small bowel anastomosis from the biliopancreatic limb to the bypassed segment is performed by several different standard techniques, and closure of all the mesenteric defects created is required to prevent internal hernia formation. The appearance of a postoperative barium swallow after gastric bypass is shown in Figure 18-4. Typical weight loss results in morbidly obese patients undergoing gastric bypass show a 60% to 80% excess weight loss over a period of 12 to 18 months. In addition, many comorbid medical conditions improve dramatically, including reflux, diabetes, sleep apnea, stress urinary incontinence, hypertension, and lower extremity venous congestion (Buchwald et al, 2004).50

Mechanisms of Action It is likely that several mechanisms of action after a gastric bypass contribute to the improvement of reflux symptoms in both the short and long term. Initially, the very small gastric pouch size, only containing gastric cardia with no parietal cell mass, limits the amount of acid content that is available to reflux. Bile reflux is also completely eliminated due to the bile diversion to the Roux-en-Y limb and to the long lengths of the biliopancreatic and alimentary Roux-en-Y limbs.

TABLE 18-2 Indications, Evaluation, and Patient Selection for Bariatric Reflux Surgery in Obesity Indications Failure of maximal medical therapy Failure of prior antireflux procedure Refractory reflux after prior gastric (restrictive) procedure for obesity Presurgical Evaluation Barium swallow Upper endoscopy Esophageal manometry 24-Hour pH studies Assessment of other obesity-related comorbid conditions Diabetes Cardiovascular disease Asthma/pulmonary function Sleep apnea Nutritional education and counseling Psychological evaluation Patient Selection Thorough knowledge and understanding of the proposed reflux/ bariatric procedure Willing to participate in long-term follow-up

FIGURE 18-3 Laparoscopic Roux-en-Y gastric bypass port placement.

243

244

Section 4 Gastroesophageal Reflux and Associated Conditions

erative and postoperative education is a critical component to enhance the understanding and success of bariatric procedures.

COMMENTS AND CONTROVERSIES The author has presented a comprehensive overview of the issues that link obesity and reflux. One of the main considerations for today’s esophageal surgeon is the decision as to when to perform a simple Nissen fundoplication for symptomatic gastroesophageal reflux disease (GERD) and when to consider a Roux-en-Y gastric bypass. For patients with GERD and overt comorbidities of obesity and a BMI greater than 40, the decision to perform a Roux-en-Y gastric bypass may be relatively easy. However, in other situations with a presentation of severe GERD, perhaps a lower BMI, and other issues, such as severe esophageal dysmotility, brittle diabetes, and marked knee and hip arthritis, the traditional approach may be to first think of a fundoplication. But is this really the best option for this patient? If one looks closely at the results presented in this chapter, I believe the consideration for Roux-en-Y gastric bypass becomes more compelling in a number of clinical scenarios that most thoracic surgeons have not traditionally been exposed to in their training. The other obvious group of patients are those with multiple failed attempts at Nissen fundoplication who also have an elevated BMI. In this case, further attempts at reconstructing the gastroesophageal junction to redo a Nissen may be doomed to failure, and a Roux-en-Y gastric bypass becomes a very good, if not the best, surgical option. J. D. L.

KEY REFERENCES FIGURE 18-4 Barium swallow after Roux-en-Y gastric bypass.

Finally, the slope of weight loss is most dramatic in the first 3 and then 6 months after bypass surgery, with nearly 30% and then 50% excess weight lost in that time period. This dramatic weight loss contributes to significant reductions in intra-abdominal pressure and improvement in pressurerelated comorbid conditions, including reflux disease (Sugarman et al, 1997).24

SUMMARY Bariatric reflux surgery is a new development in the treatment of both obesity and reflux diseases and shows significant promise as a safe, effective, and perhaps superior approach to traditional antireflux surgery. Much more long-term data with prospective follow-up of outcomes of treatment, including objective measures of durable improvements in reflux disease, are needed. Patients with severe obesity and refractory reflux should be offered a bariatric procedure as an alternative to treat both their reflux and improve their weight control and associated medical problems. Extensive preop-

Barak N, Ehrenpreis ED, Harrison JR, Sitrin MD: Gastro-oesophageal reflux disease in obesity: Pathophysiological and therapeutic considerations. Obesity Rev 3:9-15, 2002. Buchwald H, Avidor Y, Braunwald E, et al: Bariatric surgery: A systematic review and meta-analysis. JAMA 292:1724-1737, 2004. Flegal KM: Prevalence and trends in obesity among US adults, 19992000. JAMA 288:1723-1727, 2002. Frezza EE, Ikramuddin S, Gourash W, et al: Symptomatic improvement in gastroesophageal reflux disease (GERD) following laparoscopic Roux-en-Y gastric bypass. Surg Endosc 16:1027-1031, 2002. Jones KB: Roux-en-Y gastric bypass: An effective antireflux procedure in the less than morbidly obese. Obesity Surg 8:35-38, 1998. Locke GR 3rd, Talley NJ, Fett SL, et al: Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 106:642-649, 1999. Perez AR, Moncure AC, Rattner DW: Obesity adversely affects the outcome of antireflux operations. Surg Endosc 15:986-989, 2001. Perry Y, Courcoulas AP, Fernando HC, et al: Laparoscopic Roux-en-Y gastric bypass for recalcitrant gastroesophageal reflux disease in morbidly obese patients. JSLS 8:19-23, 2004. Sugerman H, Windsor A, Bessos M, Wolfe L: Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity. J Intern Med 241:71-79, 1997.

chapter

19

RINGS AND WEBS Sharon Ong Richard J. Finley

Key Points ■ Esophageal rings and webs are best investigated and seen with

the use of barium radiography. ■ Conservative management can usually treat mild symptoms. ■ Mechanical bougie dilation is the standard treatment for both

esophageal rings and webs. ■ Patients with Plummer-Vinson syndrome must have endoscopic

mucosal surveillance and biopsy, because esophageal webs have malignant potential in this disease entity.

Rings and webs are common structural abnormalities in the esophagus. Yet there is controversy in terminology, pathogenesis, and treatment of these lesions. The terms rings and webs are often used interchangeably. Wilkins and Dreyfuss have established rings and webs as distinct entities—by structure, location, and possibly etiology. In this chapter we will continue to uphold this distinction. As with previous editions, the term ring will refer exclusively to the lower esophageal ring, better known as Schatzki’s ring.1

quent analysis of 64 pathologic cases of lower esophageal rings by Miller and Wichern5 showed that none of the rings had muscle wall involvement except for the one case from Ingelfinger and Kramer. In 1978, Friedland observed and recognized that the ring was found at the mucosal junction due to reflux. This was presented in a progress report that changed the concept of lower esophageal anatomy.6

Morphology The ring is an area of restricted distensibility rather than abnormal contraction. It occurs at the squamocolumnar junction. Histologically, the ring is located exactly at the lower limit of squamous mucosa, lined by squamous epithelium superiorly and columnar epithelium inferiorly. The ring zone reveals chronic inflammatory cellular infiltration of submucosa with little change in overlying mucosa or underlying muscular layers. It consists of a double-backed mucosa, with elements of mucosa and variable amounts of submucosal fibrosis but without any true esophageal muscle (Fig. 19-1). Radiologically, it is consistently associated with a small hiatal hernia (Fig. 19-2).

Causes LOWER ESOPHAGEAL RING Historical Note In 1944, Templeton first described the esophageal ring as an asymptomatic weblike narrowing in the lower esophagus.2 Prior to 1953, all webs were described in infants and children and were believed to be congenital. In 1953, the term ring became popularized because of its association with dysphagia. In the original description of lower esophageal ring, Schatzki and Gary described a radiologic appearance of “a diaphragmlike narrowing in the lower esophagus,”3 a concentric symmetrical narrowing representing an area of decreased or restricted distensibility. Separate reports from Ingelfinger and Kramer4 and Schatzki and Gary3 presented a group of adults older than age 50 years with radiographic findings of a ringlike narrowing of the distal esophagus associated with intermittent dysphagia, especially after swallowing solid foods. Poorly chewed meat would impact at a distal esophageal ring, leading to the term steakhouse syndrome. Schatzki and Gary reported five cases with interesting findings, all of which were associated with a hiatal hernia on radiography.3 Partial excision of one of these rings exhibited involvement of mucosa and submucosa only. In 1968, subse-

Although most published data suggest that reflux esophagitis is not the cause of Schatzki’s ring, considerable evidence suggests that lower esophageal rings, reflux, and hernia are closely linked. The cause of lower esophageal ring remains controversial and unclear. Multiple theories have been formulated and evolved over the years. Skinner and Belsey suggested that lower esophageal ring may be the result of repeated stimulus of acid refluxing into the lower esophagus that causes sustained disordered motor activity and ring of spasm.7 Postlethwait concluded that based on pathologic changes that patients develop a “unique, localized manifestation of reflux esophagitis which produces a Schatzki’s ring.”8 Wilkins stated that overcontractility of circular esophageal musculature at the level of the lower esophageal sphincter, combined with the sliding gastric mucosa of hiatal hernia, results in persisting apposition (buckling) back to back of the two mucosal layers, hence developing a ring.1

Signs and Symptoms Dysphagia is the most common complaint. It is most exclusively confined to solid food and not uncommonly sudden and abrupt. The acuity usually results from an incompletely masticated piece of meat that impacts the nondistensible 245

246

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 19-1 Histologic examination of the ring shows squamous esophageal mucosa (left) and columnar gastric mucosa (right). The juncture lies at the apex of the ring with strands of muscularis mucosae and fibrosis beneath. (FROM WILKINS EW JR: SURGERY FOR SCHATZKI’S RING. IN JAMIESON GG [ED]: SURGERY OF OESOPHAGUS. MELBOURNE, CHURCHILL LIVINGSTONE, 1988, P 365.)

ring. This is frequently accompanied by lower retrosternal distress, pressure, ache, or frank pain, followed by salivation and secretion of copious, thick, tenacious mucus. After impaction, further passage of food or liquid from esophagus to stomach is impossible. Schatzki related obstruction to the size/diameter of the ring and found patients with rings less than 12 mm had dysphagia.9 Postlethwait found that patients with largerdiameter rings (i.e., >13 mm) may have associated symptomatic gastroesophageal reflux.8

Investigation A barium esophagography is the test of choice to make the diagnosis of a lower esophageal ring. The esophagus above and stomach below must be distended with barium to fully appreciate the ring (see Fig. 19-2). The ring can be missed with upright barium swallow but is rarely missed with cineradiographic examination with barium-coated marshmallows, observed by an experienced radiologist. The esophagus must be fully clean, with impacted food dislodged and extracted to fully discern and visualize the ring radiographically. The exact location, diameter, and nature of a Schatzki ring can be visualized directly by flexible fiberoptic esophagogastroscopy (Fig. 19-3). The ring may be sampled if the mucosa looks abnormal.

Management Most esophageal rings are found incidentally, are asymptomatic, and do not require treatment. Patients with mild symptoms are instructed to modify their diet and eating habits by eating soft food, cutting solid food into smaller pieces, and eating slowly. If these conservative measures are not adequate in preventing dysphagia, esophageal dilation with mechanical bougienage is indicated.

FIGURE 19-2 Ring demonstrated by barium radiography with associated hiatal hernia. (COURTESY OF DR. STEPHEN HO, VANCOUVER GENERAL HOSPITAL, VANCOUVER, BRITISH COLUMBIA.)

Two types of mechanical bougies are used for esophageal dilation: Savary dilator and Maloney (mercury-filled) dilator. Both types of bougies are graded in millimeters (mm) and French scale (1 Fr = 3 mm). Both are equally effective, but the Savary dilator is safer because it is introduced over a guidewire through the stricture via the flexible endoscope. An initial endoscopy is performed before esophageal dilation to confirm the diagnosis when using Maloney dilators. With Savary dilators, an endoscopy is a part of each dilation procedure. The goal of dilation is to disrupt the rings rather than stretch them. In most cases, passage of one large bougie is adequate to disrupt the ring. In a prospective study by Eckardt and coworkers, 33 consecutive patients with symptomatic esophageal rings experienced relief of their dysphagia after passage of a single Maloney bougie (46-58 Fr), regardless of ring rupture.10 However, repeat dilation is safe and effective. Fluoroscopic visualization rarely is needed for either procedure but is recommended if the lumen distal to the ring cannot be visualized. For esophageal rings refractory to esophageal dilation, therapeutic success using neodymium:yttrium-aluminumgarnet (Nd:YAG) laser therapy has been reported. In a study of 14 patients by Hubert and associates, Nd:YAG laser incision of lower esophageal rings provided good symptomatic relief.11 Surgery is rarely indicated and is reserved for the occasional patient with associated and intractable reflux. Multiple

Chapter 19 Rings and Webs

FIGURE 19-3 Schatzki’s ring as seen with flexible esophagoscopy. Note the mucosal anatomy of the ring and the absence of esophagitis.

reviews of patients who underwent antireflux surgery for relief of symptoms produced by Schatzki’s ring showed absolute failure.8,12 A true fibrous stricture of the esophagus developed in most patients. In summary, the management of lower esophageal ring is mechanical bougienage. Excision of the ring is never indicated.

MULTIPLE ESOPHAGEAL RINGS Esophageal rings usually exist as a single lesion but can be multiple. Several names have been coined for when multiple rings are found in the esophagus, including multiple esophageal rings or webs, congenital esophageal stenosis, ringed esophagus, corrugated esophagus, and feline esophagus. This is a very rare condition. Unlike lower esophageal rings, multiple esophageal rings are tighter. Dilation should be performed carefully using the smallest size dilator that encounters moderate resistance on initial passage into the esophageal lumen. Only one dilator should be used initially, with serial dilations reserved for later sessions. Starting with a 20- to 30-Fr dilator is not uncommon. Transient chest pain from mucosal tear is common after dilation in this population.31

ESOPHAGEAL WEB Definition An esophageal web is best defined as a thin, less than 2 mm, eccentric membrane of tissue that can occur anywhere in the esophagus but most commonly occurs in the anterior postcricoid area of the proximal esophagus (Fig. 19-4). Postlethwait described it as “a very sharply localized narrowing due to a thin membranous intraluminal extension of the esophageal wall, usually only involving the mucosa and part of the mucosa.”13 The mucosa involved is squamous both above and below the web, thus differentiating this from Schatzki’s ring. An esophageal web is not involved in any esophageal motility disorder. What may appear on barium study as

FIGURE 19-4 Esophageal web: thin weblike indentations in the upper esophagus. (COURTESY OF DR. STEPHEN HO, VANCOUVER GENERAL HOSPITAL, VANCOUVER, BRITISH COLUMBIA.)

weblike structures, such as spiral staircase esophageal peristalsis, have no mucosal abnormalities on endoscopic visualization.

Historical Note The true prevalence of esophageal web is unknown. Most cases are asymptomatic and require specialized tests for identification. Five to 15% of selected patients presenting with dysphagia have been found to have esophageal webs. Most are incidental findings unrelated to their complaints of dysphagia.14,15 In 1919, Brown reported patients with dysphagia, not uncommonly middle-aged women, with “pale, waxy” oropharyngeal mucosa, smooth tongues, and cracking at the corners of the mouth in whom he attributed the accompanying anemia to the “insufficient dietary.” He also observed, on direct inspection, “a circular membranous web . . . reducing the lumen of the entrance to the esophagus to about 5 mm.” Serendipitously, he stumbled on the current therapy when his rigid esophagoscope “slipped onwards into the esophagus,” producing one of the first successful rupture of a web.16 In 1939, Waldenström and Kjellberg were credited with the first report of the actual association of the cervical esophageal web with sideropenic anemia.17 It is now common knowledge that correction of the anemia is basic to permanent control of dysphagia.

Morphology Esophageal web consists only of mucosa, and its thinness is quite transparent. The web is a thin, “diaphanous” partition of the esophagus. The partition may be a shelf-like protrusion of mucosa, usually the anterior aspect, or it may be a circumferential infolding of esophageal mucosa. Histologic study at autopsy (Fig 19-5) demonstrates the transverse fold of normal mucosa and submucosa only, with normal squamous epithelium covering its entire surface with

247

248

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 19-1 Classification of Esophageal Web Congenital Webs Imperforate Perforate Acquired Webs Iron-deficiency Plummer-Vinson/Patterson-Kelly with associated sideropenic anemia Celiac disease Autoimmune Mucous membrane (cicatricial) pemphigoid Epidermolysis bullosa Psoriasis Steven-Johnson syndrome Ulcerative colitis Inflammatory Heterotropic gastric mucosa Graft-versus-host disease Esophageal associated Zenker’s diverticulum Duplication cyst

FIGURE 19-5 Histologic examination of a typical web with squamous mucosa covering both its superior and inferior surfaces. There is little areolar tissue between and slight tenting of the muscularis mucosae at its base. (FROM CHISHOLM M, ARDRAN G, CALLENDER S, WRIGHT R: A FOLLOW-UP STUDY OF PATIENTS WITH POST-CRICOID WEBS. Q J MED 40:409, 1971, WITH PERMISSION.)

occasional chronic inflammatory cells in the subepithelial tissue. There is slight tenting of the muscularis mucosae.

Classification and Etiology Because of confusing terminology and rarity of this disease, classification and adequate study of esophageal web is limited. As well, multiple theories of etiology exist. Several theories have been proposed for the formation of esophageal webs. These include causes related to congenital origin, iron deficiency, development, inflammation, and autoimmunity. As such, simple classification divides esophageal webs into congenital and acquired webs (Table 19-1).

Congenital Webs The only true congenital strictures are the imperforate and perforate webs. They usually occur in the middle or lower third of the esophagus and are commonly believed to be the result of “failure of coalescence of esophageal vacuoles which normally lead to complete luminal patency” during the early embryonic stage.18 Congenital web is more likely to be circumferential with a central or eccentric orifice. It may also be thick and tough rather than thin. If the diagnosis is made later than childhood, or even later in life, symptoms must have been present since the age of eating solid food and causes of acquired webs are absent.

Acquired Webs Acquired web is more common than congenital web and is usually found in the upper portion of the esophagus. Many systemic diseases are associated with this entity.

Symptomatic esophageal webs occur more commonly in females. When associated with iron-deficiency anemia, koilonychia, cheilosis, and glossitis, it is then diagnostic for Plummer-Vinson syndrome or Patterson-Brown-Kelly syndrome. This is characterized by postcricoid or upper esophageal webs eccentrically attached to the anterior wall of the esophagus. Webs are believed to arise in iron-deficiency states. Pharyngeal and cervical esophageal cancers have been associated with Plummer-Vinson syndrome. Periodic screening for esophageal cancer in patients with Plummer-Vinson syndrome is recommended because of its malignant potential. The association between iron deficiency and esophageal webs is controversial. Chisholm and associates supported this association in two case series of 72 and 63 patients.19,20 However, a careful epidemiologic study by Elwood and associates failed to show a correlation between iron deficiency and cervical esophageal webs.21 There is less contention between iron deficiency and dysphagia without webs; iron deficiency clearly can precede dysphagia. Chisholm and associates noted resolution of dysphagia but not webs after iron supplementation.19,22 Celiac disease or gluten-sensitive enteropathy is characterized by small intestinal malabsorption. Because iron is absorbed predominantly in the proximal small intestine, iron absorption is impaired in celiac disease. Dickey and McConnell described two patients with Plummer-Vinson syndrome and chronic iron-deficiency anemia who were found to have celiac disease by histology. They hypothesized that iron deficiency from celiac disease is the primary cause of upper esophageal webs and Plummer-Vinson syndrome.23 In a case study described in 1997, a 55-year-old woman with chronic dysphagia and cervical esophageal web was found to have an inlet patch of gastric mucosa.24 At endoscopy, an inlet patch of gastric mucosa was visualized in proximity to the cervical web. Heterotropic gastric mucosa can occur throughout the esophagus, and it is referred to as an inlet patch if it occurs in the proximal esophagus. The typical

Chapter 19 Rings and Webs

location of an inlet patch is usually right below the cricopharyngeal muscle at 20 to 25 cm from the incisors. It is believed that gastric acid production from the inlet patch led to development of the cervical esophageal web. Upper esophageal webs have also been reported in patients with chronic graft-versus-host disease after bone marrow transplantation. The mechanism is believed to be the “accretion of desquamated esophageal epithelium.”25 Several skin diseases have also been reported in association with esophageal webs, including mucous membrane pemphigoid (cicatricial pemphigoid), epidermolysis bullosa, Stevens-Johnson syndrome, and psoriasis. An autoimmune process is believed to be the cause of these associations. Other esophageal disorders have been reported to be associated with esophageal webs, including Zenker’s diverticulum and esophageal duplication cyst.26 The pathogenesis for these associations is unknown.

the “association of Zenker’s diverticulum and esophageal web is new.”30 In a retrospective reflection of their experience, Wilkins and Dreyfuss described an observation made dating back to 1945 regarding esophageal web associated with pulsion diverticulum: “a web may occur just distal to the inferior aspect of the mouth of a pulsion diverticulum . . . detectable only at time of surgical correction.”1 As with esophageal rings, radiographic techniques are the most sensitive method to find esophageal web. Endoscopy may be used for confirmatory diagnosis (Fig. 19-6). When using a flexible fiberoptic esophagoscope, direct visualization with intubation of the scope is required, because blind passage of a flexible esophagoscope invariably takes the scope past the web. In patients with Plummer-Vinson syndrome and a web, biopsy and screening of mucosa are important owing to its malignant potential.

Management Diagnosis Dysphagia is the principal presenting symptom of esophageal web. The congenital type presents in neonatal or early childhood, whereas the acquired type occurs in later decades of life. Severity of dysphagia is proportional to the narrowing and obstruction caused by the web.

Congenital Webs There are varying presentations of congenital webs depending on the extent of luminal obstruction. Alder, in 1963, reported two cases of “congenital web” in women aged 75 and 76 years who had dysphagia since childhood. No other causes were elicited, such as sideropenic anemia.27 On the other hand, a neonate with major luminal obstruction may have regurgitation of undigested bile-free feeding very early. This may be life threatening, with the possibility of aspiration and consequent airway problems that require prompt treatment. Early diagnosis is accomplished using diatrizoate meglumine (Gastrografin) swallow after tube evacuation of esophageal content.

Treatment of congenital or acquired esophageal webs depends on the physical nature of the web. If it is a thin, membranous, diaphanous web, inadvertent or intentional rupture with the esophagoscope may be all that is required. Recurrence of dysphagia may then be treated by Maloney bougienage. The area of the web should always be inspected on one occasion; bougienage should not be carried out on the basis of radiography alone. Because most esophageal webs are asymptomatic, they do not require treatment. Mild symptoms often can be treated with diet modification and lifestyle changes. If these con-servative measures are unsuccessful, esophageal dilation with mechanical bougienage is the next step in treatment. Esophageal dilation with endoscope, bougie, and an esophageal balloon is effective in disrupting esophageal webs, resulting in long-term relief. Like esophageal rings, postdilation barium study may reveal a persistent esophageal web despite symptom relief. Successful treatment of an esophageal web using Nd:YAG laser has been reported, but this treatment rarely is required.

Acquired Webs Most acquired webs are asymptomatic. Often, they are discovered incidentally during an upper gastrointestinal radiographic study for other reasons. True cervical esophageal web is an anterior, thin, mucosal defect with an eccentric posterior lumen. This must be distinguished from normal folds lying in relation to the pharyngoesophageal juncture, “the post-cricoid impression,” and “cricopharyngeal indentation.” Esophageal webs are quite uncommon. In a random survey of 100 hospitalized patients, Clement and coworkers, in 1974, found eight cervical esophageal webs, with only two causing dysphagia.28 Nosher and associates, in 1975, reviewed 1000 consecutive cinefluoroscopic examinations of the cervical esophagus and pharyngoesophageal junction.29 They defined the incidence of cervical esophageal web as 5.5%, with only 11% related dysphagia. In 1988, 12 patients undergoing diverticulectomy and cricopharyngeal myotomy for Zenker’s diverticulum were found to have cervical esophageal web. Low and Hill reported that

FIGURE 19-6 Esophageal web seen with flexible esophagoscopy. Note the circumferential infolding of the esophageal mucosa.

249

250

Section 4 Gastroesophageal Reflux and Associated Conditions

In patients with associated disorders, such as iron deficiency, inflammatory diseases, or chronic graft-versus-host disease, treating the underlying disorders is warranted. For the unusual thick web that cannot be dilated, transcervical or transthoracic excision may be necessary. This excision is accomplished through longitudinal esophagotomy with circumferential excision of the web and anatomic closure: circumferential of the mucosa from which the web has been excised and longitudinal of the esophagotomy. There is never an indication for esophageal resection in the treatment of true esophageal webs.

COMMENTS AND CONTROVERSIES The esophageal surgeon is unlikely to see many esophageal rings or webs unless diagnostic esophagoscopy is part of his or her practice. This is due to the shift from barium esophagography to flexible fiberoptic esophagoscopy in the diagnosis of most esophageal disorders and because many rings and webs are asymptomatic. Treatment rarely requires more than esophagoscopy and guided dilation. Although a lower esophageal (Schatzki’s) ring is the most common of these entities, the feline or ringed esophagus is being seen with increasing frequency. It is not known whether this is due to an increased awareness and more frequent diagnosis or a true increased incidence. It has a male predominance and occurs both in children and adults. There is an atrophic disposition in up to 80% of children and 60% of adults. There may be a peripheral blood

eosinophilia and increased IgE blood levels. It is also called asthma of the esophagus or allergic eosinophilic esophagitis.1 In the patient with a ringed esophagus, barium esophagography and esophagoscopy are typical and demonstrate a lack of distensibility and multiple concentric rings. Histopathologic review of endoscopic biopsy demonstrates extensive intraepithelial eosinophils. Surface collections of three or more eosinophils are diagnostic of an eosinophilic microabscess, suggestive of allergic eosinophilic esophagitis. Treatment of the ringed esophagus is nonsurgical. Elimination diets have been useful in children in the identification of a food allergen; however, in adults these diets have not been studied. The use of swallowed inhaled fluticasone has become the mainstay of therapy.2 Some studies stress the need for dilation for symptomatic control, but symptoms recur with dilation alone. Medical or surgical treatment of gastroesophageal reflux disease is not indicated. Esophageal webs associated with iron-deficiency anemia are rare and of little more than historical interest. After cervical webs have been dilated, endoscopic inspection of the surrounding mucosa may demonstrate associated gastric mucosa (inlet patch). This should be sampled to confirm etiology and exclude dysplasia. T. W. R. 1. Arora AS, Yamazaki K: Eosinophilic esophagitis: Asthma of the esophagus? Clin Gastroenterol Hepatol 2:523-30, 2004. 2. Noel RJ, Putnam PE, Collins MH, et al: Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin Gastroenterol Hepatol 2:568-75, 2004.

Surgical Techniques chapter

20

DILATION OF PEPTIC ESOPHAGEAL STRICTURES Thomas W. Rice

Key Points ■ Barium esophagography and esophagoscopy with brushing and

■ ■ ■ ■

biopsy must be used to differentiate peptic stricture from other causes of dysphagia. There is no perfect dilator; the most appropriate dilator available must be used. Bougies and balloon dilators are equally effective in the treatment of peptic strictures. Meticulous technique minimizes complications and improves longterm results. Long-term management of GERD and repeat dilation are crucial for successful treatment of peptic esophageal strictures.

A peptic esophageal stricture is the result of excessive and uncontrolled reflux of upper gastrointestinal contents into the esophagus. The amount and composition of refluxed material and the extent of exposure to the esophagus of this material determines the magnitude of damage. Multiple factors control these elements of injury. Patients with peptic esophageal strictures have very disturbed esophageal physiology. Lower esophageal sphincter (LES) pressures are lowest in patients with peptic esophageal strictures. In one study mean LES pressure was 4.9 mm Hg in patients with peptic strictures, 7.5 mm Hg in patients with uncomplicated gastroesophageal reflux disease (GERD), and 20 mm Hg in control subjects.1 There was no overlap of LES pressure between patients with peptic strictures and control subjects. Impaired esophageal motility causes inadequate clearance of the refluxed material, which permits prolonged esophageal exposure and heightens injury. Sixty-four percent of patients with peptic strictures had motility disorders compared with only 32% without strictures.1 Simultaneous or nonpropulsive contractions are most common. In the extreme, aperistalsis has been reported and may be reversible with adequate control of reflux.2 Abnormal distal gastrointestinal motility may result in excessive intragastric pressures and increased volumes of refluxed material. However, there is only indirect evidence that delayed gastric emptying promotes the development of peptic strictures.3,4 Insufficient esophageal mucosal protection may magnify the injury caused by refluxed material. Although these protective mechanisms are poorly understood, the amount and quality of neutralizing saliva and esophageal secretions may be important in preventing reflux injury. The nature and volume of refluxed material are primary determinates of injury. Undoubtedly, acid is the principal agent. Acid combined with alkaline duodenal contents may cause more injury

to the esophageal mucosa than acid alone.5 Although speculation continues regarding alkaline and enzymatic esophageal injury, some experimental data suggest that nonacid injury alone may play a minimal role in peptic esophagitis.6,7 Hiatal hernia is the main structural defect that facilitates reflux and promotes peptic strictures. Prevalence of hiatal hernia increases with severity of GERD. Hiatal hernias have been reported in 42% of patients with reflux, 63% of patients with esophagitis, and 85% of patients with peptic strictures.8,9 At esophagoscopy peptic mucosal injury is easily visualized and graded, but the damage reaches beyond the mucosa. Usually, peptic stricture is the end-stage finding in any rating of esophagitis; however, changes of peptic injury deep to the mucosa are themselves progressive and can be graded.10 Early injury is confined to the submucosa and characterized by edema, inflammation, spasm, and the deposition of immature collagen (type III). The resultant grade 1 stricture is “soft” and dilates easily. A grade 2 stricture occurs with maturation of the collagen (type I) in the submucosa, is hard (firm and annular), and requires significant force to dilate. With continued reflux, inflammation and fibrosis advance to involve the entire esophageal wall and periesophageal tissue. This process generally occurs over a substantial length of the esophagus and produces vertical contracture and significant shortening of the esophagus. The result of panmural scarring and cicatricial contracture is a grade 3 peptic stricture. Dysphagia is the chief complaint of patients with peptic esophageal stricture. However, this symptom is not exclusive to reflux injury. Attempts must be made to exclude all other causes of esophageal stricture. Once confirmed, the mainstay of symptomatic control of peptic esophageal stricture is dilation. Long-term management requires prevention of progressive damage by addressing the multiple factors causing reflux and eliminating further reflux injury. Once reflux is controlled, further dilation is usually needed to treat submucosal, muscular, and periesophageal peptic damage.

HISTORICAL NOTE Esophageal dilation or bougienage was first used to dislodge impacted food and push it distally into the stomach. Bougienage is derived from the Arabic Boujiyah, an Algerian city that was a medieval center of the wax trade. Fabricius ab Acquapendente (1537-1619) is credited with the use of a wax taper to disimpact a foreign body lodged in the esophagus (Earlam and Cunha-Melo, 1981).11 Early esophageal bougies were constructed of various materials that include leather, quills, bone, baleen, iron, and lead. They were used mostly for disimpaction; however, caustic strictures were also dilated with these early instruments. By the early 19th 251

252

Section 4 Gastroesophageal Reflux and Associated Conditions

century shortcomings of blind bougienage of esophageal strictures were recognized.12 In the United States, Hildreth13 performed the first successful dilation of an esophageal stricture. He used a self-designed bougie constructed of iron wire and plaster to repeatedly treat a 61-year-old man with an esophageal stricture. By the late 1800s retrograde dilation of esophageal strictures was a common practice.14 Although this procedure required a gastrostomy, it was thought that the retrograde introduction of a dilator was better tolerated, and the cardia and esophagogastric junction provided a safe funnel for guidance to the stricture. Passage of a string per os and retrieval in a gastrostomy allowed for cutting of the stricture using a sawing motion of the string. This practice was called bow stringing and enhanced by the use of silk thread or piano wire. A dilator could also be tied to the string and then pulled through the stricture. This was the earliest form of guided dilation.15,16 Because it required permanent gastrostomy, retrograde dilation was reserved for severe, recalcitrant strictures, and the technique fell into disfavor. Vinson17 wrote “Gastrostomy is seldom necessary in the management of benign stricture of the esophagus and adds to the risk of treatment.” Although great attention was given to instrument design and the technique of bougienage, the next important breakthrough in dilation came from an entirely unrelated area. Soon after the discovery of x-ray by Roentgen in 1895, contrast materials were being used for x-ray visualization of the esophagus. Dawson18 was the first to radiographically diagnose an esophageal stricture. The importance of x-rays was immediately realized by Dawson, who described his visualization of his first patient’s stricture: “The stricture was evidently a considerable one opposite the fifth dorsal vertebra and the esophagus was dilated above it. The illustration explains why a bougie would sometimes get through the stricture and at other times not, for it would only get through if it happened to hit the aperture in the centre of the sac.” The esophagogram was an important advancement in the treatment of peptic esophageal strictures. Besides aiding in diagnosis, it provided visualization, control, assessment, and long-term follow-up of dilation. The esophagoscope, introduced in the late 19th century, had limited use due to poor illumination. In the early 20th century, rigid esophagoscopy with blind passage of bougies was frequently utilized. The advantages in treatment of peptic stricture with visualization of the upper aspect of the stricture and observation of the entry of the dilator into the stricture outweighed the risk of anesthesia. The introduction of the flexible endoscope in the 1970s provided the full potential of esophagoscopy in the diagnosis and treatment of peptic strictures. Flexible guidewires under endoscopic direction allowed guided dilation in the outpatient setting.19 Plastic guided bougies have now become the mainstay in the dilation of peptic strictures.20,21 Although pneumatic dilation had been used to treat achalasia and strictures, its utility in the treatment of peptic esophageal strictures was not fully appreciated until the introduction of percutaneous transluminal angioplasty. Adoption of this technology advanced the development of

instrumentation that was acceptable for the dilation of peptic strictures. London and colleagues reported the successful balloon dilation of peptic strictures in 1981.22 It has been the impression of many clinicians that the aggressive use of potent antireflux medications such as proton pump inhibitors has decreased the prevalence of peptic esophageal strictures. However, careful record keeping and evaluation does not support this conjecture.23 HISTORICAL READINGS Dawson B: Roentgen rays as an aid to the diagnosis of stricture of the oesophagus. Lancet 2:1144, 1907. Fletcher R: On strictures of the esophagus and the danger of the bougie herein. In Medico-Chirurgical Notes and Illustrations. Part I. London, Longman, 1831. Hildreth CT: Stricture of the esophagus. N Engl J Med Surg 10:235, 1821. Plummer HS: The value of silk thread as a guide in esophageal technique. Surg Gynecol Obstet 10:519, 1910. Tucker G: Cicatricial stenosis of the esophagus, with particular reference to treatment by continuous string, retrograde bougienage with the author’s bougie. Ann Otol Rhinol Laryngol 33:1180, 1924. Vinson PP: Management of benign stricture of the esophagus. JAMA 113:2128, 1939. Woolsey G: The treatment of cicatricial stricture of the oesophagus by retrograde dilatation. Ann Surg 21:253, 1895.

BASIC SCIENCE Types of Dilators There are two basic types of esophageal dilators. The esophageal bougie is a tapered, flexible, yet semi-rigid sound. Esophageal bougies apply both a radial splitting force and a longitudinal stretching force during dilation. The longitudinal force may contribute to perforation during dilation. The second type of esophageal dilator, the balloon dilator, results only in a radial force when applied correctly. This radial force is evenly applied along the length of the stricture and has no longitudinal component. It has therefore been proposed that balloon dilation may result in fewer perforations.24 This theory has not been substantiated by clinical experience.

Physics of Dilation The dilation of a peptic esophageal stricture requires the application of a sufficient force to split the encasing fibrotic tissue in the submucosa and muscularis, allowing expansion of the esophageal lumen while maintaining mucosal integrity. The mucosal contribution to the strength of the esophagus is minimal at small bougie diameters but becomes significant when the outer esophageal diameter is doubled.25 This finding suggests that initial increments of pressure are absorbed by the muscular layers, which eventually split with progressive dilation. At higher pressures the strength of the mucosa must prevent rupture. Excessive force will cause perforation of the esophagus. Cadaver studies showed that the mean pressure required to pneumatically rupture the normal esophagus is approximately 260 mm Hg.26 However, the diseased esophagus with an abnormally thickened and inflamed wall may require pressures much higher than this for successful dila-

Chapter 20 Dilation of Peptic Esophageal Strictures

tion without perforation. For pneumatic dilation of patients with achalasia, Van Trappen and Hellemans27 suggest pressures of 300 to 500 mm Hg, depending on the dilating apparatus. This pressure is known to cause a muscular tear but generally will not rupture the esophagus. Pressures between 25 and 830 mm Hg were measured during dilation of peptic strictures.28 Pressures generated during dilation were considerably higher in untreated patients and generally lower in patients undergoing chronic bougienage. As expected, maximal pressure increased with larger diameter dilators. Pressures generated during dilation in patients with peptic esophageal strictures tended to remain stable or decrease after multiple dilations with the same bougie.

Results of Dilation The maximal diameter of a stricture does not occur immediately after dilation. Over 4 to 7 days after dilation there is an average increase of 1.2 mm in diameter.29 This increase is thought to be secondary to relief of muscular spasm and reabsorption of hematoma and edema. The postdilation diameter of the stricture is always less than the diameter of the last bougie passed. Differences vary from 1 to 11 mm. This variation is caused by spasm and rigidity of the damaged esophageal wall. Peptic strictures generally recur and reach predilation severity by 12 weeks after dilation.30 Dysphagia decreased by 4 days post dilation, remained improved until 6 weeks postdilation, and returned to predilation intensity by 12 weeks. However, stricture diameter was not predictive of dysphagia during this time. In this group, heartburn did not worsen after dilation. No differences in pH monitoring before or after dilation was seen in the group as a whole. However, in one third of the group (3 patients), an increase in reflux after dilation was measured by 24-hour pH monitoring. These patients had absence of lower esophageal sphincter pressure (0-2 mm Hg) and low amplitude pressure waves in the esophageal body (0-36 mm Hg). Heartburn after dilation, regardless of the use of proton pump inhibitors, and the presence of a hiatal hernia were reported to be predictors of early recurrence after dilation.31 An objective outcome rather than relief of dysphagia should be used to define the end point for dilation of peptic strictures. Passage of a 12-mm barium pill as the objective for dilation reduced both stricture recurrence and the need for subsequent dilation.32 After dilation, esophageal transit decreases markedly. This effect lasts for 3 weeks.33 Improvement of esophageal transit was not predictive of outcome; symptomatic relief was predicted by postdilation stricture diameter measured radiographically. After initial dilation, some patients will require further dilation. Composition of the study group, length of followup, and aggressiveness of dilation and reflux control will determine the percentage of dilation failures. Need for repeated dilations ranged from 22% to 65% in various studies.34-37 After two or more dilations the likelihood of further dilation has been reported between 86% to 94% (Glick, 1982).34 In this study the interval between dilations was variable but approximated 1 month after 8 dilations.

Failed dilation is difficult to explain or predict. At least 75% of patients will require more than one dilation if reflux is inadequately managed.38 In these patients, most restricturing occurred during the first 6 months after dilation. Predictors of rapid restricturing were small diameter of stricture at initial endoscopy, a long history of symptomatic GERD, and a short period of dysphagia before dilation. The number or frequency of dilations was not predictive of outcome in patients treated with histamine-2 blockers or surgery.39 Patients without symptoms of heartburn or those reporting weight loss are more likely to require repeat dilation.40 In a study of 195 patients, male gender was predictive of poor outcome (Hands et al, 1989).41 In this study 58% of the patients were women, who were significantly older than the men. Although 54% of both groups required more than one dilation, men required significantly far more dilations over a longer period of time. Both stricture length and diameter are reported as independent predictors of persistent dysphagia after dilation.42 Strictures longer than 2 cm or narrower than 9 mm before dilation had poor long-term outcome with bougienage. Intralesional injection of corticosteroid has been used to improve the outcome of dilation of peptic strictures. Triamcinolone acetonide injection has been reported to decrease the periodic dilation index (number of dilations required per week) from 0.92 ± 0.44 to 0.42 ± 0.2 (P < .001).43 A prospective randomized double-blind trial of intralesional corticosteroid injection of recalcitrant peptic stricture enrolled 30 patients.44 At follow-up, 1 patient in each group died of nonesophageal causes and 2 in each group underwent fundoplication. In 1 year, 2 (13%) patients in the corticosteroid group and 9 (60%) in the sham group (P = .01) required repeat dilation.

DIAGNOSIS Clinical Features Dysphagia is the primary presenting symptom of patients with peptic strictures. Generally, with mechanical obstruction, difficulty swallowing is not perceived until the esophageal lumen is approximately one half of the normal diameter of 20 to 25 mm. Because the obstruction is structural, dysphagia associated with peptic stricture is constant and reproducible. Patients first complain of solid dysphagia with sticky, spongy foods such as beef, chicken, fish, and fresh bread. The onset and progression is insidious; patients learn to avoid these foods before seeking medical advice. Liquids are not a problem until the stricture is advanced or food is impacted. When food impaction occurs, attempts to dislodge the bolus (e.g., dry swallowing or drinking water) are usually unsuccessful. Regurgitation is frequently required before swallowing can resume.

Differential Diagnosis Dysphagia of a peptic stricture must be differentiated from an esophageal motor disorder. With functional disorders, dysphagia is typically intermittent. Liquids are poorly handled in oropharyngeal dysphagia. Signs include drooling, gagging, aspiration, choking, and nasal regurgitation. Motor disorders

253

254

Section 4 Gastroesophageal Reflux and Associated Conditions

of the esophageal body will be equally symptomatic with liquids and solids. Food impaction does not generally require regurgitation, and swallowing water may clear the obstructing bolus. A careful history may elicit other symptoms of reflux in patients with peptic strictures. Most of these patients present de novo with dysphagia. It is not less common to have a patient develop a symptomatic stricture during the treatment and follow-up of GERD. Watson10 reported that 68% of his patients with peptic esophageal strictures had no antecedent diagnosis of GERD. However, on subsequent questioning, 76% had symptoms of reflux. Not all patients with gastroesophageal reflux who complain of dysphagia have a peptic stricture. Of 100 patients with reflux, 53 patients complained of dysphagia; only 2 were found to have peptic stricture.45 In complex cases the association of motility disorder with reflux disease is not predictive of dysphagia. Bombeck and associates46 reported that of 19 patients with reflux, 7 of 14 without motility disorders and 2 of 5 with motility disorders complained of dysphagia. Dysphagia may be multifactorial. In the absence of a peptic stricture or motility disorder, patients with severe reflux may still complain of dysphagia. In a surgical series, Kiroff and colleagues47 reported 12 of 43 patients without strictures and motor disorders had dysphagia. After operative management, 10 of these patients had no further symptoms. Dysphagia is not an exclusive symptom of peptic strictures; other causes, both benign and malignant, must be considered. The epidemic of adenocarcinoma in middle-aged men with columnar-lined esophagus has made the onset of dysphagia in a patient with chronic reflux a worrisome presentation. In this setting, reflux and dysphagia are no longer synonymous with peptic stricture (Table 20-1).

FIGURE 20-1 A, Barium esophagogram of a typical peptic stricture (arrowhead) shows a smooth, short, symmetrical esophageal narrowing with no mucosal destruction, situated immediately above a hiatal hernia. B, Barium esophagogram of a peptic stricture in a columnar-lined esophagus. The stricture occurs at the squamocolumnar junction (upper arrow), well above the esophagogastric junction (lower arrow), which is localized by the hiatal hernia. The intervening columnar epithelium (CLE) is free of mucosal defects.

Investigative Technique Barium esophagography confirms the clinical suspicion of an esophageal stricture and provides a hard copy documentation of the stricture (Fig. 20-1). Both the length and diameter of

TABLE 20-1 Causes of Esophageal Strictures Congenital Esophageal atresia Tracheoesophageal fistula Webs Acquired Infections Fungal Moniliasis Histoplasmosis Viral Herpes Cytomegalovirus Bacterial and mycobacterial Syphilis Tuberculosis Granulomatous Sarcoidosis Crohn’s disease Dermatosis Pemphigoid Behçet’s disease Gastroesophageal reflux Primary Scleroderma

Drug-induced Aspirin Nonsteroidal anti-inflammatory Clinitest Vitamin C Quinidine Progesterone Theophylline Anticholinergics Tetracycline Potassium supplements Caustic ingestion Iatrogenic Sclerotherapy Postoperative (anastomotic) Radiation Post instrumentation Malignant Primary Secondary

Chapter 20 Dilation of Peptic Esophageal Strictures

the stricture are measured. Strictures longer than 2 cm and tighter than 10 mm are considered severe, may be difficult to dilate, and have a tendency to recur. Peptic strictures may be associated with sacculations, fixed transverse folds, or intramural pseudodiverticula.48 Examination may be conducted with barium-soaked marshmallows or a barium pill to detect early strictures, which are difficult to recognize unless there is complete esophageal distention. Video study of solid bolus passage may also demonstrate an unsuspected motility disorder. Double-contrast studies allow assessment of mucosal damage. The presence of a columnar-lined esophagus may be suspected by barium esophagography. Barrett’s mucosa has been reported in 44% of patients with peptic esophageal strictures.49 Because most peptic strictures arise at the squamocolumnar junction, the occurrence of the stricture well above the esophagogastric junction is predictive of a columnar-lined esophagus. Associated abnormalities, such as hiatal hernia, Schatzki’s ring, esophageal ulcer, and so on, may be seen. Finally, barium esophagography allows examination of the stomach and duodenum distal to the stricture. Differentiation of benign from malignant strictures by barium esophagography is possible, but this study lacks both sensitivity and specificity. The accuracy of barium esophagography is reported to be 59% in the diagnosis of malignant strictures and 89% in the diagnosis of benign strictures.50 Most importantly, barium esophagography provides a guide for esophagoscopy, the crucial invasive investigation in the diagnosis of peptic esophageal strictures (Fig. 20-2). Diagnosis can be obtained at endoscopy in 90% to 95% of patients.50,51 Cytologic brushing of the stricture must be added to random biopsy to reach this level of diagnostic accuracy. Endoscopy,

biopsy, and dilation can be safely performed at one sitting (Barkin et al, 1981).52 After dilation, careful endoscopic examination of the stricture and the distal gastrointestinal tract is required. On completion of the dilation, manometric studies of the esophagus should be considered. A peptic esophageal stricture may be associated with motility disorders of the esophagus, most notably scleroderma, which will greatly affect the management of the associated stricture.

MANAGEMENT There is no perfect dilator or dilating procedure for the management of peptic esophageal strictures. Successful dilation requires versatility in technique and instrumentation. Until recently, a common means of dilation was the passage of dilators via the rigid esophagoscope under general anesthesia. Modern equipment has made the routine use of this technique obsolete, and it is reserved for special situations such as uncooperative patients, high cervical esophageal strictures, or dilations that have been unsuccessful under local anesthesia and sedation. The avoidance of general anesthesia and unguided dilations has reduced the morbidity and mortality of esophageal dilation. The majority of dilations may be conducted with an awake patient in the outpatient setting. Preparation is crucial for good outcome. The patient is instructed to take only clear fluids the day before the procedure and nothing after midnight. Dilations performed early in the day allow adequate observation time. In addition, if complications arise, further investigations and management may be optimally performed. The patient should receive complete prior instruction to ensure full cooperation. Fluoroscopy should be available but

FIGURE 20-2 A, The endoscopic appearance of a peptic stricture. The stricture occurs at the squamocolumnar junction. There is associated esophagitis but no other mucosal abnormalities. The stricture is symmetrical and smooth. After brushing and biopsy, the guidewire of the Savary-Gilliard system is passed, under visual control, through the stricture to facilitate the first guided dilation of this peptic stricture. B, The stricture after dilation.

255

256

Section 4 Gastroesophageal Reflux and Associated Conditions

is not crucial for every dilation. Intravenous medication using a narcotic analgesic and a minor tranquilizer (meperidine, 50-100 mg, and midazolam, 2-5 mg, intravenously) provides sufficient sedation, making the patient comfortable and cooperative but not stuporous and combative. Topical anesthesia (4% viscous lidocaine [Xylocaine] gargle or 1% topical lidocaine spray) is optional. If performed at the time of endoscopy, dilation can be conducted in the left lateral decubitus position. Otherwise, the patient may be sitting or in the lateral decubitus position. To minimize complications, the first session of dilation of a peptic stricture should use a guided system. The patient should recover in a monitored setting. Once the sedation has been adequately reversed, the patient should be questioned concerning odynophagia, dysphagia, and chest pain. If these are present, or if they should occur within the next 24 to 48 hours, the physician who performed the dilation should be contacted immediately. Finally, the patient is given an appointment for follow-up and possible repeat dilation, usually within 4 to 6 weeks. However, if the dilation was difficult or if a satisfactory bougie size was not reached, a follow-up visit and possible repeat dilation may be required much sooner, sometimes within 7 to 14 days. The goal of dilation is to increase the diameter of the esophageal lumen sufficient to eliminate dysphagia. In difficult cases this should be confirmed with radiographic passage of a barium pill. For most dilators, the circumference and not the diameter of the dilator is gauged in French units. One French unit is equal to 1 mm of circumference (the circumference of a 40-Fr dilator is 40 mm). Diameter of the dilator is approximately one-third the French size. Most patients with peptic esophageal strictures will be relieved of their symptoms by dilation to 40 Fr or higher. To minimize perforation and other complications, some authors suggest the passage of no more than three dilators after resistance is felt.

The symmetrical, circumferential, and panmural nature of the peptic injury and the associated periesophageal inflammation makes this guideline not as important as in malignant strictures. Most guided bougies have a tip of constant initial diameter, the same for a range of dilators, and expand gradually to the maximal dilator size. In the dilation of peptic strictures, it is acceptable to select a dilator in the range of 40 to 50 Fr and start the dilation by first carefully engaging the tip of the bougie in the stricture. Slow passage of the bougie with constant pressure allows the stricture to be gently and gradually dilated until resistance is felt and dilation is stopped. This technique avoids multiple passes of progressively larger dilators and, if done carefully, is not associated with increased complications. Choice of dilator is dependent on characteristics of the stricture, operator preference, availability, and patient’s dilation history. A facility with a variety of dilators allows for optimum management of peptic strictures.

Nonguided Dilators Gum Elastic Dilators Gum elastic bougies are designed to be passed under direct vision through a rigid esophagoscope. Maximum size of the dilator is therefore limited by the internal diameter of the scope. The gum elastic tip of a Jackson bougie (Fig. 20-3) is mounted on a firm slender wire shaft that does not obstruct the operator’s vision when passed down the dilating esophagoscope. The tip is constructed by coating molded woven silk with vegetable oil. Although rigid, these dilators are flexible, and their flexibility can be increased by warming the dilating tips; heating to the point of sterilization will melt them. These dilators are infrequently used because of limited availability of both the dilators and special dilating esophago-

FIGURE 20-3 The Jackson bougie. Inset, The gum elastic tip of this bougie.

Chapter 20 Dilation of Peptic Esophageal Strictures

scopes (which allow passage of larger dilators) and the problems of unguided dilation in the anesthetized patient.

Guided Dilators Eder-Puestow

Mercury-Weighted Dilators

The Eder-Puestow dilator is a flexible guided system that uses metal olives of progressively larger diameters (Fig. 20-5). After each passage the tip must be disassembled and the next olive fixed in place. The dilator is extremely useful in tight, tortuous strictures where its “positive” feel is cited as a major benefit. However, the necessary manipulation of the tip with each passage (12 different olive sizes), the excessive damage of guidewires, and an increased incidence of oral and pharyngeal trauma are major disadvantages.55 The Key Med dilator was a variation of this system. It had two plastic oblong dilators that replaced the metal olives. These systems are not used today and are mentioned only for complete historical note.

Mercury-weighted bougies are constructed of rubber and filled with mercury. This combination provides stiffness and flexibility. The weight of the mercury does not generally aid in the passage of the dilator. Blunt-tipped Hurst dilators have been replaced by tapered Maloney dilators (Fig. 20-4). These dilators are available in 2-Fr increments from 12 to 60 Fr. Coiling due to their extreme flexibility is a major problem with smaller dilators, but for bougies over 40 Fr coiling is not a problem. Although not useful in tight, long, tortuous, or eccentric strictures, these bougies are excellent for repeat dilations after the initial guided session and for chronic selfbougienage.53,54 Mercury-weighted bougies are cost-effective and least demanding of hospital resources.

FIGURE 20-4 Mercury-weighted bougies. Top, A 48-Fr Hurst bougie. Bottom, A 48-Fr Maloney bougie.

FIGURE 20-5 The Eder-Puestow dilator. Inset, The repeated assembly of the three-piece distal tip allows the passage of progressively larger metal olives.

257

258

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 20-6 The Savary-Gilliard dilator. Left inset, The proximal end of the dilator with the central channel for passage over the guidewire. Right inset, The dilator passed over the flexible guidewire.

Savary-Gilliard Dilators The Savary-Gilliard dilator is a bougie of polyvinyl chloride with a central channel for passage over a guidewire (Fig. 20-6). The spring tip of the guidewire is constructed of wound wire with progressively wider winding as the distal tip is approached. The graduated flexibility of this device prevents acute angulation at the junction of the rigid guide and the flexible tip. This acute angulation was a problem of the Eder-Puestow and other guidewires and responsible for some of the guidewire perforations of the esophagus.56 The SavaryGilliard guidewire is extremely long, which is a prerequisite for passage through the suction channel of a flexible esophagoscope. The dilators are gauged by diameter measured in millimeters and range from 5 to 20 mm. These guided dilators can be used for tight, tortuous strictures, and their plastic construction avoids oropharyngeal injury. Multiple passes of progressively larger dilators may be required. The Celestin system is a similar plastic guided dilator designed to dilate strictures with no more than two passes of bougies. It uses two stepped dilators that increase in diameter by 2-mm increments along the length of the dilator. The first dilator covers the range of 4 to 12 mm; the second, 4 to 18 mm. The Buess dilator is a similar stepped system, designed to pass over a flexible 9-mm esophagoscope.

Balloon Dilators Balloon dilators are guided and may be placed either endoscopically or over a guidewire (Fig. 20-7). The position of the balloon must be confirmed endoscopically or fluoroscopically before or during dilation. These dilators are well tolerated by patients and are useful for narrow strictures. The dilators

tend to migrate out of short strictures. Compared with other dilators, the fragility of the balloon dilator is a major disadvantage of this system.

COMPLICATIONS Esophageal perforation is the most feared complication of esophageal dilation. Despite meticulous technique and correct use of the appropriate dilators perforation is a potential complication. An unguided dilation of a complex stricture is the procedure most likely to be complicated by perforation.57 Perforation is not limited to the difficult dilation and may occur during the routine dilation of a simple peptic stricture with a guided dilator. However, this occurrence is uncommon. Perforation may occur when strictures secondary to disease processes that do not cause panmural and circumferential involvement are mistaken for peptic strictures. This situation is seen in undiagnosed malignancies, nasogastric tube strictures, in which inflammation is limited to superficial esophageal layers (mucosa and submucosa) with minimal muscular or periesophageal inflammation, and caustic strictures that have minimal acute inflammation and dense fibrosis and scarring replacing the esophageal wall. The misdiagnosis of a peptic stricture in any of these three situations may result in unexpected esophageal perforations during dilation. Prompt recognition and treatment of perforation will minimize further morbidity and mortality. It should be suspected in a patient who complains of excessive and prolonged pain after dilation. Subcutaneous emphysema and a pneumothorax may be detected on physical examination. An urgent chest radiograph will demonstrate a hydropneumothorax and possibly mediastinal and subcutaneous emphysema. Early

Chapter 20 Dilation of Peptic Esophageal Strictures

FIGURE 20-7 The balloon dilator. Inset, The balloon dilator passed through the suction channel of the flexible endoscope.

surgical intervention is required with lavage and débridement of the mediastinum and pleural cavity, repair of the perforation, and surgical management of the stricture and its underlying cause. Rarely, there may be a contained leak (intramural dissection) with free, preferential drainage into the esophagus that may be managed nonsurgically. Other less frequent complications of dilation include bacteremia, cerebral abscess, septic arthritis, bacterial endocarditis, bleeding, and equipment failure.58 From 15% to 20% of dilations of benign strictures are complicated by bacteremia.59,60 Oral organisms, most commonly α-hemolytic streptococci, are the frequent pathogens, and antibiotic prophylaxis must be given to patients at risk of endocarditis and those with implanted devices.

ture. The combination of endoscopy, biopsy, brushing, and dilation is safe (Barkin et al, 1981).52 Endoscopic guidance of the initial dilation is the standard of care. Unguided dilation at subsequent dilation is a safe and practical practice. Long-term management of these patients is crucial. Rarely, a patient will require one dilation and no treatment of gastroesophageal reflux. Most patients require aggressive management of the stricture and reflux. Initial medical management is indicated in all patients and allows assessment of the severity of reflux and the tempo of stricturing. Proton pump inhibitors are superior to histamine-2 blockers in preventing restricturing.67-70 Failure of adequate medical management, complications of the disease or treatment, and/or development of precancerous or cancerous changes warrants surgery.

SUMMARY The quest for the perfect dilator continues. Presently, no such instrument exists and the most appropriate dilator available at the time must be used. The patient, the stricture, the operator’s experience, the dilating technique, and the facility are more important in determining outcome than the dilating system. The theoretical advantage of a radial force with no longitudinal component offered by balloon dilation has not reduced complications and may be responsible for potentially inferior results when this system is used.61,62 However, a recent randomized prospective studies found rigid bougies and balloon dilators equally effective in the treatment of benign esophageal strictures.63,64 Meticulous dilating technique will minimize complications and improve long-term results. Guided dilation should be used whenever possible. Fluoroscopy may be helpful in difficult dilations.65 It is a cumbersome and time-consuming procedure and is not necessary for every dilation.66 Endoscopy is a prerequisite in the diagnosis of peptic esophageal stric-

COMMENTS AND CONTROVERSIES Dr. Rice provides a thorough review of the history and status of methods of dilation for peptic esophageal strictures. I would like to add some observations from my experience and understanding of stricture management. Dr. Rice correctly notes that peptic strictures are less easily perforated than are some others, such as mature caustic strictures, in which there is no wall thickening due to active inflammation— only thin, avascular scar. Then, such scar is disrupted by the dilation; it requires little more to breach the full thickness of the esophageal wall, with free perforation into the mediastinum or pleural space. Some postnasogastric tube strictures are similar to those caused by caustic injury: after extubation and recovery there may be no ongoing reflux esophagitis, and the ring of acute peptic injury heals and becomes a pale, avascular scar, without surrounding inflammation. These thin-walled strictures can usually be anticipated on the basis of their appearance at endoscopy: the overlying mucosa is intact, uninflamed, and pale. Such strictures may split and

259

260

Section 4 Gastroesophageal Reflux and Associated Conditions

perforate from the single passage of a mercury-weighted Maloney bougie in the diameter range of 46 to 50 (or greater) French gauge. Chronic but active peptic strictures, with ongoing reflux, can be safely dilated with Maloney bougies in the range of 46 to 50 Fr, when the bougienage is performed with mild sedation and topical anesthesia and the patient is positioned with his or her trunk in a semiupright position. The esophageal wall in these cases is significantly thickened, and even when there is no mucosa, due to active peptic ulceration, the underlying scar does not split through the full thickness of the wall. It is essential, however, to ascertain that one is dealing with an active peptic stricture with preliminary endoscopy before proceeding with this type of indirect dilation. When these principles have been followed, I have not seen a perforation occur due to indirect Maloney bougienage in patients with active peptic stenosis. With new cases after endoscopic evaluation, the surgeon may initiate the dilation with the larger Maloney dilators. If the 46- to 50Fr bougie does not advance fully through the stricture, with the use of gentle forward pressure added to the weight of the bougie when the patient is upright, the surgeon may revert to the use of a smallerdiameter bougie. If the smaller-diameter bougies fail to pass (they are less effective because of reduced weight and undue flexibility), Savary-Gilliard dilators may be used, passed over an endoscopically positioned guidewire. If the stricture cannot be dilated with this method, it may be necessary to undertake direct bougienage with a rigid esophagoscope and with the patient under general anesthesia. This is rarely necessary but does occur in patients with very tight, long fibrous strictures. Small-diameter (12-14 Fr) gum elastic

esophageal dilators may be necessary to initiate the dilation in such cases. As Dr. Rice notes, it is difficult to judge the interval required before bringing the patient back for a repeated dilation. I usually advise the patient to call and schedule a repeated dilation with a significant return or worsening of dysphagia. If reflux can be adequately controlled by medical or surgical therapy, the interval between dilations becomes progressively longer in almost all cases. F. G. P.

KEY REFERENCES Barkin JS, Taub S, Rogers AI: The safety of combined endoscopy, biopsy and dilation in esophageal strictures. Am J Gastroenterol 76:23, 1981. ■ This paper documents the safety of combined endoscopy, biopsy, and dilation, now a standard of practice in the management of peptic esophageal strictures. Earlam R, Cunha-Melo JR: Benign oesophageal strictures: Historical and technical aspects of dilatation. Br J Surg 68:829, 1981. ■ An overview of the history and techniques of dilation. Glick ME: Clinical course of esophageal stricture managed by bougienage. Dig Dis Sci 27:884, 1982. ■ An excellent retrospective study of dilation for the management of peptic esophageal strictures. Hands LJ, Papavramidis S, Bishop H, et al: The natural history of peptic oesophageal strictures treated by dilatation and antireflux therapy alone. Ann R Coll Surg Engl 71:306, 1989. ■ An excellent study of the natural history of dilation and medical treatment of peptic esophageal stricture.

Total Fundoplication chapter

OPEN NISSEN FUNDOPLICATION

21

F. Henry Ellis, Jr.

Key Points ■ There is increasing interest in performing Nissen fundoplication

using a laparoscopic approach. ■ This requires a sound appreciation of the open Nissen fundoplica-

tion technique.

The Nissen fundoplication is the most commonly used operation for the relief of gastroesophageal reflux disease (GERD), particularly by surgeons in North America. Dissatisfaction with long-term results of previous anatomically designed operations led to the realization by surgeons that GERD was the result of a physiologic abnormality secondary to hypotension of the lower esophageal sphincter (LES) and not the result of an anatomic abnormality, such as a sliding esophageal hiatal hernia. Thus, it became clear that the prerequisite of a successful antireflux procedure was to restore normal function rather than to simply restore normal anatomy. In a review of the origins of the Nissen fundoplication and other antireflux procedures, however, it is interesting to note that, with few exceptions, the surgeons responsible for the development of these procedures based their techniques more on anatomic than on physiologic grounds. Belsey’s operation, for example, was designed to reestablish an intraabdominal esophagus, whereas the Hill posterior gastropexy took advantage of what Hill thought were the strongest structures available, namely, the phrenoesophageal ligament along the lesser curvature of the stomach and the arcuate ligament crossing the aorta, just cephalad to the celiac axis. Only later did it become evident that these two operations, as well as the Nissen procedure, owed their effectiveness to varying degrees of esophageal encirclement by the adjacent gastric fundus. Because there are many variations of the Nissen fundoplication, it is hoped that a preliminary discussion of its historical and experimental background provides a better understanding of the surgical procedure, the technique of which is described in this chapter.

HISTORICAL NOTE In December 1955, Rudolph Nissen of Basel, Switzerland, operated on a 49-year-old woman with a long history of GERD without radiographic evidence of a hiatal hernia.1 He used a technique that he had used nearly 20 years earlier to minimize postoperative reflux after resection of a peptic ulcer in the region of the cardia. This technique involved envelopment of the lower esophagus with the gastric fundus by

suture approximation of anterior and posterior fundal folds anterior to the esophagus, within which a large intraesophageal bougie had been positioned. Since this original description, the Nissen fundoplication has been modified in many ways. Nissen combined his operation with anterior gastropexy, only to discontinue that modification.2 Subsequently, Nissen and Rossetti3 suggested that only the anterior wall of the stomach be wrapped around the lower esophagus. In none of these techniques did Nissen recommend division of the short gastric vessels. Other modifications have included narrowing of the esophageal hiatus posterior to the esophagus, anchoring of the fundoplication to the preaortic fascia, and the addition of highly selective vagotomy. The degree of the fundal wrap has been varied to encircle less than 360 degrees of the esophageal tube to avoid the “gas bloat” syndrome, with the anterior portion of the esophagus being wrapped by Dor and associates4 and the posterior portion of the esophagus being wrapped by Toupet5 and Guarner and colleagues.6 For a similar reason, Donahue and associates7 proposed the creation of a loose wrap. The wrap initially performed by Nissen extended over 4 to 6 cm of the esophagus, but a shorter wrap was recommended by DeMeester and associates8 (1986) to avoid some of the potential complications of the operation.

HISTORICAL READINGS DeMeester TR, Bonavina L, Albertucci M: Nissen fundoplication for gastroesophageal reflux disease: Evaluation of primary repair in 100 consecutive patients. Ann Surg 204:9, 1986. Donahue PE, Samuelson S, Nyhus LM, Bombeck CT: The floppy Nissen fundoplication: Effective long-term control of pathologic reflux. Arch Surg 120:663, 1985. Dor J, Humbert P, Dor V, Figarella J: L’intérêt de la technique de Nissen modifée la prevention du reflux après cardiomyotomie extra muquesuse de Heller. Mem Acad Chir 88:877, 1962. Guarner V, Martinez N, Gavino JF: Ten year evaluation of posterior fundoplasty in the treatment of gastroesophageal reflux: Long-term and comparative study of 135 patients. Am J Surg 139:200, 1980. Nissen R: Eine einfache Operation zur Beeinflussung der Refluxoesophagitis. Schweiz Med Wochenschr 86:590, 1956. Nissen R: Gastropexy and “fundoplication” in surgical treatment of hiatal hernia. Am J Dig Dis 6:954, 1961. Nissen R, Rossetti M: Surgery of hiatal and other diaphragmatic hernias. J Int Coll Surg 43:663, 1965. Toupet A: Technique d’oesophago-gastroplastie avec phreno-gastropexie appliquée dans la cure radicale des hernia hiatales et comme complement de l’operation de Heller dans les cardiospasmus. Mem Acad Chir 89:394, 1963. 261

262

Section 4 Gastroesophageal Reflux and Associated Conditions

EXPERIMENTAL BACKGROUND That the Nissen total fundoplication is more effective in the prevention of gastroesophageal reflux than other antireflux procedures is well documented experimentally. The results of Bombeck and associates,9 working with dogs, and of Butterfield,10 working with cadaver specimens, support this view, as do the results of the in vitro studies of Alday and Goldsmith.11 In a series of experiments reported by Leonardi and associates12 that involve in vivo studies in cats, the Nissen procedure proved superior to the Hill and Belsey operations on the basis of postoperative manometry and pH testing. Leonardi and associates13 also showed that a complete wrap was preferable to a partial wrap for the restoration of normal LES function. The superiority of the Nissen 360-degree wrap compared with partial wraps was confirmed in the comparative clinical study of DeMeester and coworkers (1974).14 The precise mechanism by which these antireflux procedures prevent gastroesophageal reflux remains controversial. Siewert and associates (1973)15 postulated that the smooth muscle of the gastric fundus that composes the wrap acts in a manner similar to the smooth muscle of the normal LES, thus accounting for its effectiveness. The anatomic studies of Liebermann-Meffert16 support this concept.

TECHNICAL CONSIDERATIONS Transabdominal Approach FIGURE 21-1 Open Nissen fundoplication. After mobilization, the intrathoracic esophagus is partially delivered into the abdomen and encircled with a Penrose drain. (COPYRIGHT © 1987, LAHEY CLINC.)

A

Details of the surgical technique have been given by Ellis (1990)17,18 and are summarized here. An abdominal approach is preferred, with a thoracic incision used in patients with presumed esophageal shortening and in patients who have previously undergone a left thoracotomy. An upper midline incision is made from the xiphoid to a point just below the

B

FIGURE 21-2 Open Nissen fundoplication. Mobilization of the gastric fundus requires ligation and division of the short gastric vessels. A, The placement of a moist pack behind the spleen relieves tension on these vessels, facilitating their safe division. B, To complete its mobilization so as to permit performance of a loose “floppy” wrap, the posterior gastric artery arising from the splenic artery also usually requires ligation and division. (A COPYRIGHT © 1987, LAHEY CLINIC; B FROM ELLIS FH JR: THE NISSEN FUNDOPLICATION. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 1997, VOL 2, P 37.)

Chapter 21 Open Nissen Fundoplication

umbilicus, skirting to the left of that structure. The incision is continued cephalad on the left side of the xiphoid to provide optimal exposure of the esophageal hiatus. The left lobe of the liver is mobilized by division of the triangular ligament, permitting retraction of the liver to provide exposure of esophageal hiatus. The hernia, if present, is reduced, and the phrenoesophageal membrane is incised to expose the anterior aspect of the distal esophagus and to permit its accurate mobilization. The esophagus is freed from its hiatal attachments, with care taken to preserve the vagus nerves. It then is encircled with a Penrose drain, and esophageal mobilization is continued until 3 to 5 cm of distal esophagus lies free in the abdomen (Fig. 21-1). To provide a loose wrap of gastric fundus around the distal esophagus, the surgeon must mobilize the upper stomach completely. This part of the procedure is initiated by division of the short gastric vessels and is facilitated by the placement of a moist pack behind the spleen, thus relieving tension on the short gastric vessels during their control and division. The importance of this maneuver in the prevention of a wrap that is too tight was emphasized by Hunter and associates,19 who reported a higher incidence of postoperative dysphagia after a Nissen-Rossetti procedure in which these vessels are not divided. The vessels are successively clamped, divided, and tied, starting distally and moving proximally along the greater cur-

A

vature of stomach (Fig. 21-2A). One or two posterior gastric vessels—specifically, the posterior gastric artery arising from the splenic artery and a left inferior phrenic arterial branch— must also be divided to permit complete mobilization of the gastric fundus (see Fig. 21-2B). The importance of recognizing the posterior gastric artery as a branch of the splenic artery in permitting complete mobilization of the gastric fundus has been emphasized by others.20 The gastrohepatic omentum is left undisturbed. Its division with subsequent traction on the stomach may cause incorrect placement of the wrap around the proximal stomach instead of around the distal esophagus. With the right hand, the surgeon passes the freed gastric fundus behind the esophagus, where it is grasped with a Babcock clamp to the right of this organ (Fig. 21-3A). A large-bore indwelling (48-50 Fr) Maloney dilator is introduced transorally by the anesthesiologist and passed into the stomach. All subsequent parts of the wrapping procedure are conducted with this in place as a stent to permit the performance of a loose wrap. Heavy nonabsorbable interrupted sutures are used to approximate the seromuscular walls of adjacent gastric fundus anterior to the esophagus, with a small bite of an esophageal wall caught in one or both sutures. Two sutures of this type are placed, permitting encirclement of the distal 1.0 to 1.5 cm of esophagus with a loose gastric wrap (see Fig. 21-3B).

B

FIGURE 21-3 Open Nissen fundoplication. A, After the short and posterior gastric vessels are divided, the mobilized gastric fundus is passed behind the esophagus and grasped with a Babcock clamp. B, Heavy nonabsorbable sutures are used to approximate the seromuscular walls of the adjacent fundus anterior to the esophagus, with a small bite of esophageal wall caught in the suture. (COPYRIGHT © 1987, LAHEY CLINIC.)

263

264

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 21-4 Open Nissen fundoplication. A, Completed fundoplication with reinforcing sutures of nonabsorbable material that anchor the esophagus; the vagus nerves are carefully preserved. B, The wrapped esophagus with the indwelling probe still in place is elevated to permit approximation of the hiatal crura posteriorly with two or more nonabsorbable sutures. (A COPYRIGHT © 1987, LAHEY CLINIC; B FROM ELLIS FH JR: THE NISSEN FUNDOPLICATION. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 1997, VOL 2, P 37.)

Fine nonabsorbable sutures are then placed between the heavy sutures, and the collar of the wrap is applied to the esophageal wall with similar sutures to complete the fundoplication (Fig. 21-4A). The esophagus is elevated to expose the esophageal hiatus, and the hiatus is narrowed by the placement of two or three loosely tied nonabsorbable interrupted heavy sutures in the diaphragmatic crura posterior to the esophagus (see Fig. 21-4B). Because this maneuver simply prevents migration of the fundoplicated esophagus into the chest, the degree of hiatal narrowing should be slight so as not to compress the esophagus. The abdomen is then closed in the usual manner. Oral feedings are resumed with the recurrence of bowel sounds, and hospitalization rarely exceeds 4 to 5 days.

Transthoracic Approach Although the abdominal approach is preferred when a Nissen fundoplication is performed, under certain circumstances a transthoracic approach is appropriate. I use this approach to effect safe mobilization of the distal esophagus when the patient has previously undergone a left thoracotomy. It should also be the preferred approach if there is radiographic and/or endoscopic evidence of esophageal shortening that might require an esophageal lengthening procedure such as a

Collis gastroplasty to allow intra-abdominal placement of the wrap. A Nissen fundoplication should never be left within the chest because of the complications that may ensue.21 The surgical approach involves a left thoracotomy through the bed of the nonresected eighth rib, the angle of which may be divided for additional exposure. The mediastinal pleura is opened, and the esophagus is encircled with a Penrose drain (Fig. 21-5A). It is important at this point in the procedure to determine whether the length of the esophagus is sufficient to permit a fundoplication around its distal 1 to 2 cm and its placement in an intra-abdominal position. If that cannot be achieved, then an esophageal lengthening procedure, such as a Collis gastroplasty, must be performed before proceeding with the Nissen wrap. The procedure to be described assumes that there is sufficient length of esophagus to allow intra-abdominal positioning of the wrapped distal esophagus. After mobilization of the distal esophagus, the pleura and peritoneum overlying the esophagogastric junctional area are incised to permit access to the peritoneal cavity and to the gastric fundus (see Fig. 21-5B). Mobilization of the gastric fundus is facilitated by tension on a Babcock clamp placed at the apex of the crural sling, followed by ligation and division of several short gastric vessels (Fig. 21-6A). After division of the short gastric vessels, the gastric fundus is elevated to

Chapter 21 Open Nissen Fundoplication

A

B

FIGURE 21-5 Open Nissen fundoplication. A, Transthoracic exposure of esophagus and cardia. B, Opening of hernial sac to provide entry to the abdominal cavity. (FROM ELLIS FH JR: THE NISSEN FUNDOPLICATION. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 1997, VOL 2, P 37.)

A

B

FIGURE 21-6 Open Nissen fundoplication. A, Short gastric arteries are clamped and divided. B, Partial encirclement of distal 1.5 to 2 cm of the esophagus by the completely mobilized gastric fundus. (FROM ELLIS FH JR: THE NISSEN FUNDOPLICATION. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 1997, VOL 2, P 37.)

expose the posterior gastric artery, which is then ligated and divided as described for the transabdominal approach. A large (48-50 Fr) Maloney dilator is positioned across the esophagogastric junction area, and the completely mobilized and redundant gastric fundus is passed behind the esophagus (see Fig. 21-6B). The fundoplication is performed by placing nonabsorbable sutures in the adjacent seromuscular walls of the fundus that

completely surround the distal 1.5 to 2.0 cm of the esophagus, incorporating a superficial bite of the esophageal muscular wall, with care being taken to avoid injury to the vagus nerve. Reinforcing interrupted fine silk sutures are then placed between the esophagus and the encircling gastric fundus (Fig. 21-7A). The wrapped distal esophagus is placed in an intra-abdominal position, and the hiatal orifice is narrowed by the placement of two or more nonabsorbable

265

266

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 21-7 Open Nissen fundoplication. A, Completed fundoplication. B, Wrapped distal esophagus placed intra-abdominally and hiatal crura approximated posteriorly with nonabsorbable sutures. (FROM ELLIS FH JR: THE NISSEN FUNDOPLICATION. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY. PHILADELPHIA, WB SAUNDERS, 1997, VOL 2, P 37.)

sutures in the crura, posterior to the esophagus (see Fig. 21-7B).

DISCUSSION To achieve good results and to avoid complications after the Nissen fundoplication, it is important that patients be properly selected. This selection requires objective confirmation of the presence of gastroesophageal reflux before the initiation of an antireflux operation. Often, in controversial cases, it is necessary to carry out esophageal manometry, and particularly 24-hour pH monitoring, to document the presence of gastroesophageal reflux. The use of esophageal manometry also provides the physician with the information necessary to avoid the pitfall of operating on a patient with a motility disorder of the esophageal body, such as achalasia. Clearly, such a mistaken diagnosis leads to postoperative dysphagia, because a total wrap in the presence of an aperistaltic esophagus may prevent the easy passage of food into the stomach after surgery. Numerous reports have been published regarding the clinical results of open Nissen fundoplication, with hospital mortality rates approaching zero and 80% to 90% of patients experiencing good-to-excellent results overall. Undoubtedly, the largest reported series of Nissen fundoplications is that of Rossetti and Hell (1977).22 Some of these procedures were Rossetti’s modification of the original Nissen operation, which differs from the one described in this chapter. Long-term follow-up of 590 patients with uncomplicated gastroesophageal reflux disclosed that 87.5% were free of symptoms. The report of DeMeester and colleagues (1986)8 is a more objective evaluation of the surgical procedure as described in this chapter and involved 100 consecutive patients with gastroesophageal reflux without stricture or motility abnormalities. The operation was 91% effective in controlling symptoms of reflux during a follow-up period of

up to 10 years. In my experience with 241 fundoplications, of which 157 were of the type described in this chapter, reflux symptoms were relieved permanently in more than 90% of patients.23 One fourth of the procedures were reoperations, and these patients experienced less satisfactory results than did patients after primary procedures. Even more significant is a study of a long-term randomized comparison of the results of medical therapy with patients after a Nissen fundoplication, which disclosed that surgery was significantly more effective than medical therapy in the relief of symptoms and endoscopic signs of esophagitis.24 Although these reports are generally extremely favorable, the procedure is subject to complications if patients are not properly selected and if technical details are not handled in a meticulous manner. Although it is difficult to determine the percentage of patients who require reoperations after a failed Nissen procedure, the rate has been estimated to range from 4% to 6%.25 The major symptoms described by patients with poor results after the Nissen fundoplication are recurrent gastroesophageal reflux, dysphagia, and gas-bloat syndrome. These complications can be avoided or minimized by using a floppy wrap such as that just described. In addition, a number of less frequently observed events have been reported, including paraesophageal hiatal hernia,26 gastric ulceration,27,28 gastric obstruction resulting from a slipped Nissen fundoplication,29 and perforation of the wrap with fistula formation.30 With Gibb and Heatley, I reviewed 101 reoperations performed on my service from 1970 to 199431; only 8 operations involved patients on whom I originally operated. Two thirds of the patients experienced failure for technical reasons. A wrap that was too tight was the most common technical mishap and led to postoperative dysphagia in 11 patients, recurrent reflux in 6, and the gas-bloat syndrome in 4. Seventeen patients had persistent reflux due to an inadequate

Chapter 21 Open Nissen Fundoplication

wrap. A paraesophageal hiatus hernia developed in 13 patients because of failure to narrow the esophageal hiatus posterior to the esophagus after performance of the wrap. A “slipped” Nissen was diagnosed in 12 patients, a complication that, in my opinion, is due to wrapping the stomach rather than the esophagus, usually occurring in a patient with a shortesophagus hiatal hernia, rather than to true slippage of the original wrap. Two patients experienced perforation at the time of the wrap. The remaining third of the operations failed because of an incorrect diagnosis or inappropriate application of the procedure. Regurgitation due to a motility disorder was misinterpreted as gastroesophageal reflux in 22 patients: 16 of these patients had achalasia, 3 had diffuse esophageal spasm, and an additional 3 had scleroderma. Inappropriate use of the wrap in patients with a panmural fibrous stricture or a wrap left in the chest after surgery in patients with a shortened esophagus accounted for 10 additional complications of the Nissen fundoplication. Four antireflux procedures failed for unclassifiable reasons. To avoid the need for a reoperation after a Nissen fundoplication, patients should be selected carefully and certain technical aspects of the operation must be observed. When these recommendations are followed, satisfactory and permanent relief of symptoms of gastroesophageal reflux can be achieved in more than 90% of patients. Postoperative symptoms of persistent or recurrent reflux, dysphagia, and gas-bloat syndrome are extremely rare, and few patients should require a second operation. There is increasing interest in performing the Nissen fundoplication using an endoscopic approach, thus avoiding a laparotomy and/or a thoracotomy. This approach and the results of its use are discussed in detail in Chapter 22.

The Nissen repair requires following a fine line between a repair that obstructs and one that gapes. This is especially true when esophageal peristalsis is less than ideal. Concern for these factors has led surgeons to vary the caliber of the esophageal bougie, to adjust the length and tension of the wrap, to include or exclude tethering sutures into the esophageal muscle, and to experiment with leaving the vagus nerves in or out of the encirclement. As if this were not confusing enough, the performance of “a Nissen” can mean either using the anterior or the posterior wall for the fundoplication or even looping a finger-sized diverticulum of stomach around the neo-esophagus created in the “Collis-Nissen” procedure. Less painful options are available, and it is important for those of us who still place a premium on full exposure to look carefully at the surgical prescription of surgeons like Ellis. F. G. P.

COMMENTS AND CONTROVERSIES

Rossetti M, Hell K: Fundoplication for the treatment of gastroesophageal reflux in hiatal hernia. World J Surg 1:439, 1977. ■ This article from Basel, the site of origin of the Nissen procedure, reviews the largest reported series of patients operated on with Rossetti’s modification of Nissen’s original procedure using only the anterior gastric wall for the wrap.

Surgeons aspiring to duplicate Ellis’ enviable results are advised to select patients carefully, to operate meticulously, and to stifle the temptation, common to residents and established surgeons alike, to improve on the basic design. Inability to belch or vomit, dysphagia, gastric ulcer, impaired gastric emptying, persistent or recurrent symptoms, and slippage of the repair are among the array of problems that may foil even the best of surgeons. The most notorious of these problems is postoperative bloating.

KEY REFERENCES DeMeester TR, Bonavina L, Albertucci M: Nissen fundoplication for gastroesophageal reflux disease: Evaluation of primary repair in 100 consecutive patients. Ann Surg 204:9, 1986. ■ The excellent clinical results after the Nissen procedure with a short 360-degree wrap in 100 consecutive patients are well documented in this article by DeMeester’s group. DeMeester TR, Johnson FF, Kent AH: Evaluation of current operations for the prevention of gastroesophageal reflux. Ann Surg 180:511, 1974. ■ In this article, the superiority of the Nissen procedure over other antireflux operations is clearly demonstrated for the first time. Ellis FH Jr: Nissen fundoplication. In Braasch JW, Sedwick CE, Veidenheimer MC, Ellis FH Jr (eds): Atlas of Abdominal Surgery. Philadelphia, WB Saunders, 1990, p 11. ■ The technique of open Nissen fundoplication is fully described and clearly illustrated in this chapter.

Siewert R, Jennewein HM, Waldeck F, et al: Experimentelle und klinische Untersuchungen zum Wirkungsmechanismus der Fundoplication. Langenbecks Arch Chir 333:5, 1973. ■ This article contains a well-conceived and experimentally documented explanation for the mechanism of action of fundoplication.

267

chapter

22

LAPAROSCOPIC NISSEN FUNDOPLICATION Jonathan F. Finks John G. Hunter

Key Points ■ Upper endoscopy and esophageal manometry should be per-

formed in all patients before antireflux surgery. ■ A 24-hour esophageal pH study is necessary to confirm the diag-

■ ■ ■

■ ■ ■

nosis in patients with nonerosive reflux disease or predominantly extraesophageal symptoms. At least 2.5 to 3.0 cm of distal esophagus must be reduced into the abdomen without tension. Durable closure of diaphragmatic crural defect is mandatory. Complete mobilization of the fundus with division of the short gastric vessels is necessary to reduce tension and torque on the fundoplication. A “floppy” fundoplication 2 cm in length is performed around the distal esophagus over a large esophageal dilator. Care must be taken to avoid injury to the anterior and posterior vagus nerves. Best predictors of good outcome from laparoscopic Nissen fundoplication are a good response to proton pump inhibitors and an abnormal pH study.

Gastroesophageal reflux disease (GERD) is one of the most common chronic diseases of the gastrointestinal tract and has a major impact on health care costs and quality of life in the United States and other Western nations. GERD is estimated to affect nearly 19 million people in the United States, at a yearly cost of almost 10 billion dollars.1 Survey studies have demonstrated that up to 20% of people experience at least weekly heartburn and/or regurgitation symptoms.2 In addition to its financial burden, GERD also has a significant negative influence on quality of life. Several studies have demonstrated significantly impaired healthrelated quality of life in GERD patients when compared with the general population, as well as in people with chronic diseases such as hypertension, diabetes, and congestive heart failure.3-5 The mainstay of therapy for GERD is medical management. Treatment with proton pump inhibitors (PPIs) is highly effective, resulting in relief of symptoms and healing of esophagitis in more than 80% of patients. However, most people require lifelong treatment and up to 50% experience relapsing symptoms despite adequate treatment.6 In addition, medical therapy does not reduce the esophageal damage associated with alkaline reflux,7,8 nor does medical therapy address the mechanical aberrations, such as hiatal hernia and loss of lower esophageal sphincter integrity, that underlie GERD in a substantial number of patients (Fein et al, 1999).9,10 268

By contrast, antireflux surgery restores the functional barrier against reflux of gastric contents and is an effective alternative to medical therapy for some patients with GERD. The operation works by reducing the hiatal hernia and repositioning the distal esophagus and gastroesophageal junction (GEJ) to their normal intra-abdominal location. The fundoplication effectively re-creates the angle of His, restoring its flap-valve function. Studies of esophageal function after antireflux surgery demonstrate normalization of lower esophageal sphincter pressure and esophageal pH exposure (Crookes et al, 1997).11-13 Furthermore, numerous studies with longterm follow-up (5-10 years) after surgery have reported sustained symptom relief and improved quality of life in 80% to 90% of patients (Dallemagne et al, 2006).14-19 Antireflux surgery is an important alternative treatment for carefully selected patients with GERD (Table 22-1). Surgery is indicated for patients who have persistent symptoms despite maximal medical therapy, especially those with continued non-acid reflux or regurgitation. It is also an appealing option for patients who respond well to medical therapy but wish to avoid lifelong medication use. Antireflux surgery should also be considered in patients with primarily extraesophageal symptoms, such as laryngotracheal aspiration, asthma, cough, or hoarseness, as well as those with complications of the disease, such as esophageal strictures or Barrett’s esophagus. Alarm symptoms, including aspiration pneumonia, food impaction, or bleeding ulcer, are additional reasons to consider antireflux surgery. The Nissen fundoplication remains the most commonly performed antireflux procedure in the United States and much of the world. Since Rudolph Nissen’s first report of the operation in 1956, several important modifications to the procedure have been made. To reduce the dysphagia and gas-bloat associated with the operation, Donahue first described the “floppy” Nissen technique, whereby the wrap TABLE 22-1 Indications for Antireflux Surgery ■ Persistent symptoms despite maximal medical therapy,

especially those with non-acid reflux or regurgitation ■ Patients who respond well to medical therapy but wish to avoid

lifelong medication use ■ Complications of GERD, such as esophageal strictures or

Barrett’s esophagus ■ Extraesophageal symptoms of GERD (aspiration, asthma,

cough, hoarseness) ■ Alarm symptoms (food impaction, aspiration pneumonia,

bleeding ulcer)

Chapter 22 Laparoscopic Nissen Fundoplication

Surgeon’s working ports

Liver retractor

Assistant’s port

Camera port

A

FIGURE 22-1 Port placement for laparoscopic Nissen fundoplication.

was performed over an esophageal dilator (Donahue et al, 1985).20 DeMeester further modified the operation by using a larger bougie dilator, limiting the length of the fundoplication and completely mobilizing the fundus by division of the short gastric vessels (DeMeester et al, 1986).21 Perhaps the most significant advance was the introduction of the laparoscopic Nissen fundoplication, first described by Dallemagne and colleagues in 1991.22 Several randomized trials have shown that the laparoscopic approach achieves equivalent results with regard to subjective and objective resolution of GERD, with less postoperative pain, a shorter recovery period, and lower complication rate (Heikkinen et al, 1999; Nilsson et al, 2004).23-25 The laparoscopic approach made surgical therapy a more attractive option for patients and referring physicians alike. Largely due to the introduction of these techniques, the utilization of antireflux surgery in the United States increased dramatically during the 1990s. Between 1990 and 1997, the number of antireflux procedures rose threefold, from 7323 to 23,953 cases.26

DIAGNOSTIC TESTING In a patient with typical symptoms (heartburn, regurgitation), a good response to empirical therapy with PPIs is strongly suggestive of GERD. A more complete assessment of esophageal physiology, however, is necessary when planning surgical intervention. All patients should undergo upper endoscopy before surgery to determine the degree of esophagitis and rule out Barrett’s esophagus and malignancy. In patients with nonerosive reflux disease (NERD) or primarily extraesophageal symptoms, an ambulatory 24-hour pH study is mandatory to confirm the diagnosis. A pH study is arguably unnecessary in patients with typical symptoms, a good response to PPIs, and esophagitis by endoscopy. It is essential to obtain esophageal manometry before antireflux surgery to rule out severe motility disorders such as achalasia or scleroderma. Finally, a gastric emptying study may be indicated in patients with symptoms of delayed gastric emptying, such as early satiety or vomiting.

B FIGURE 22-2 A and B, The lesser omentum is opened beginning with the pars flaccida portion in order to expose the right crus. The hepatic branch of the anterior vagus nerve is preserved.

OPERATIVE TECHNIQUE The principles of laparoscopic Nissen fundoplication are the same as with the open repair. First, mediastinal dissection must be extensive enough to permit reduction of at least 2.5 to 3.0 cm of distal esophagus into the abdomen without tension. Second, closure of the diaphragmatic crural defect must be durable and without tension. Third, we advocate complete mobilization of the fundus with division of the short gastric vessels to reduce postoperative dysphagia. Finally, a 2-cm “floppy” fundoplication is performed around the distal esophagus at the GEJ over a large (56-60 Fr) bougie dilator.

Patient Positioning and Port Placement Before the start of the procedure, a bladder catheter, orogastric tube, and sequential lower extremity compression devices are placed. The patient is positioned supine with the thighs abducted, preferably with a split-leg table, although stirrups are acceptable. Perioperative antibiotics are administered (usually a first- or second-generation cephalosporin). Pneumoperitoneum is established at the umbilicus with a Veress needle, and a 10-mm trocar (camera port) is placed

269

270

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 22-3 Blunt dissection is used to develop a space between the right crus and the esophagus.

through the left rectus muscle, 15 cm from the top of the xiphoid process (Fig. 22-1). An angled laparoscope (30 or 45 degrees) facilitates the retroesophageal and retrogastric dissection. For patients with a large hiatal hernia, a straight-view (0 degree) laparoscope is useful during the mediastinal dissection. A 10-mm trocar, which will function as the surgeon’s right-hand working port, is placed below the left costal margin, 11 cm away from the xiphoid process. A 5-mm assistant’s port is placed farther laterally below the left costal margin. A 5-mm trocar for the liver retractor is inserted just below the right costal margin at the point at which the abdominal wall begins to taper downward. An expandable liver retractor is then used to elevate the left lateral segment of the liver to expose the esophageal hiatus. The retractor is stabilized with a table-mounted mechanical arm. Finally, for the surgeon’s left-hand working port, a 5-mm trocar is inserted through the falciform ligament and angled toward the hiatus. The operative table is then placed in the reverse Trendelenburg position. During port placement, the surgeon stands to the patient’s right side, with the assistant on the patient’s left side and the camera operator between the patient’s legs. Once the ports have been placed, the surgeon and camera operator trade positions. The surgeon then operates through the highest ports. Monitors should be positioned at the head of the table and at eye level to maximize operative ergonomics.

Hiatal Dissection The surgeon begins the dissection with an atraumatic grasper in the left hand and Metzenbaum scissors with electrocautery in the right hand. The assistant uses an atraumatic grasper to retract the gastroesophageal fat pad to the patient’s left. The gastrohepatic omentum is then incised and opened above and below the hepatic branch of the anterior vagus nerve, beginning with the pars flaccida portion (Fig. 22-2). Where possible, the hepatic nerve branch should be preserved to reduce the risk of gallstone formation.27,28 In up to 12% of patients, an accessory left hepatic artery, originating from the left

FIGURE 22-4 Blunt dissection is used to develop a space between the left crus and the esophagus.

FIGURE 22-5 The fundus is mobilized by dividing the short gastric vessels with the ultrasonic dissector.

gastric artery, will accompany the hepatic vagal branch.29 This vessel should be preserved or, when necessary, divided between hemoclips. At this point the caudate lobe of the liver and the right crus of the diaphragm are identified. The ultrasonic dissector is then used to divide the phrenoesophageal ligament anterior to the esophagus. Care must be taken to divide only the superficial peritoneal layers, avoiding injury to the esophagus and anterior vagus nerve. With the gastroesophageal fat pad retracted to the right, the ultrasonic dissector is then used to divide the peritoneal attachments between the diaphragm and the cardia, exposing the left crus. Attention turns once again to the right crus. The ultrasonic dissector is used to open the peritoneum on the anteromedial aspect of the right crus. Blunt dissection using two graspers is performed to develop a space between the right crus and the esophagus (Fig. 22-3). It is important to identify the posterior vagus nerve and ensure that it stays with the esophagus during this dissection. Unlike the anterior vagus, the posterior vagus is not closely approximated to the esophagus and can easily be separated from it, potentially leading to

Chapter 22 Laparoscopic Nissen Fundoplication

FIGURE 22-6 The highest short gastric vessels are divided, taking care not to put these fragile vessels on stretch.

FIGURE 22-7 The retroesophageal dissection is completed from the left side.

injury or transection of the nerve. This hiatal dissection is carried inferiorly until the decussation of the right and left crura is identified. As much of the retroesophageal dissection as can be performed easily is done from this right-sided approach. Some blunt dissection between the left crus and the esophagus can be done at this point (Fig. 22-4). Often the lateral aspect of the left crus can also be bluntly dissected free from the cardia of the stomach. The remainder of the retroesophageal dissection is completed from the left side after mobilization of the fundus.

Mobilization of the Fundus Although the necessity of dividing the short gastric vessels is debated,30,31 our experience and that of others suggests that failure to mobilize the fundus completely predisposes to postoperative dysphagia (Hunter, Swanstrom, Waring, 1996).32,33 Fundic mobilization begins along the greater curvature of the stomach, approximately 10 cm from the angle of His (Fig. 22-5). The surgeon retracts the stomach to the patient’s right, while the assistant retracts the gastrosplenic omentum to the left. The ultrasonic

FIGURE 22-8 The esophagus is retracted with a 1/4-inch Penrose drain to facilitate the mediastinal dissection.

dissector is used to divide the short gastric vessels. Exposure to the more proximal short gastric vessels is optimized by having the assistant push the gastric wall medially (Fig. 22-6). These proximal vessels tear easily and must not be put under excessive tension. To complete the mobilization, the posterior gastric attachments to the pancreas are carefully divided. This dissection proceeds along the greater curvature toward the angle of His. Blunt technique is used to separate the esophagus from left crus, thus completing the retroesophageal dissection (Fig. 22-7). The caudate lobe should then be visible from the left side, with gentle anterior retraction of the esophagus. At this point the surgeon inserts a 4-inch long, 1/4-inch wide Penrose drain behind the esophagus, securing the ends together anterior to the esophagus with a looped suture or clips. The Penrose drain facilitates retraction of the esophagus during the mediastinal dissection (Fig. 22-8).

Mediastinal Dissection With the assistant providing dynamic retraction of the esophagus, the surgeon frees the esophagus circumferentially from its mediastinal attachments (Fig. 22-9). This dissection proceeds until at least 2.5 cm to 3.0 cm of distal esophagus remains within the abdomen after traction on the Penrose drain is released. Most of this dissection can be done bluntly, with the ultrasonic dissector reserved for the larger esophageal aortic branches located predominantly to the left in the mediastinum. Mediastinal bleeding can usually be managed by compression with a gauze sponge. The anterior vagus nerve should be identified and preserved (Fig. 22-10). Care must also be taken to avoid injury to the mediastinal pleura. This is especially important during dissection of the hernia sac in patients with large hiatal hernias. If the pleural cavity is inadvertently entered, tension pneumothorax can be prevented by transabdominal insertion of a 14-Fr red rubber catheter into the affected pleural space. At the end of the procedure the pleural space is evacuated with a Valsalva breath and the catheter is removed.

271

272

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 22-9 Mediastinal dissection proceeds circumferentially.

In patients with long-standing disease, esophageal shortening may prevent reduction of an adequate length of intraabdominal esophagus even after extensive mediastinal dissection. In these cases a lengthening procedure should be performed. We typically perform a stapled-wedge Collis gastroplasty over a 48-Fr esophageal dilator (Terry et al, 2004).34 For this procedure, the assistant retracts the greater curvature of the stomach inferiorly. The surgeon then inserts a 30-mm endoscopic stapler that is maximally reticulated and then fired in series until the esophageal dilator is reached, at a point 3 cm inferior to the angle of His. The stapler is then fired adjacent and parallel to the dilator to excise a small wedge of stomach approximately 15 mL in volume, thereby creating a 3-cm neo-esophagus. The operation then proceeds as detailed below, with placement of the superior portion of the fundoplication at or above the neo-esophagus.

FIGURE 22-10 The anterior vagus nerve is identified and preserved from injury.

FIGURE 22-11 The diaphragmatic crura are closed with interrupted, pledgeted 0 nonabsorbable sutures.

Crural Closure With the esophagus retracted to the left side, the surgeon closes the diaphragmatic crura using interrupted 0 nonabsorbable suture (Fig. 22-11). Closure begins above the crural decussation and usually requires two to four sutures. The sutures are tied using either an intracorporeal or extracorporeal technique. Small (1 cm²) pledgets are routinely used with the crural closure to prevent tearing of the muscle. It is important that the pledgets are placed laterally along the crura and are not in direct contact with the esophagus, because there is a risk of erosion into the esophagus. The closure should be snug, but not tight, around the esophagus.

Creation of the Fundoplication The fundus of the stomach is brought behind the esophagus. By grasping the fundus on either side of the esophagus, a “shoeshine maneuver” is performed to ensure that the stomach is not tethered (Fig. 22-12). The stumps of the short gastric vessels should rest along the right side of the esophagus. At this point, tension on the esophagus is released and the orogastric tube is replaced with a large (56-60 Fr) esophageal dilator. The fundoplication is then performed with the anterior and posterior fundic walls meeting at the

right anterolateral aspect of the esophagus. The fundoplication is secured with three 2-0 nonabsorbable, unpledgeted sutures, placed 1 cm apart and tied intracorporeally (Fig. 22-13). The superior suture is placed first, at approximately 2 cm above the GEJ. Each suture should incorporate full thickness of the stomach and partial thickness of the esophageal wall, with care taken to avoid placement into the anterior vagus nerve. Finally, the wrap is retracted to the right and the fundoplication is anchored to the left posterolateral aspect of the esophagus with a single 2-0 nonabsorbable suture. The dilator is then removed. The completed fundoplication should be about 2 cm in length and floppy, allowing easy passage of a grasper between the esophagus and fundus. At this point, the upper abdomen is irrigated and hemostasis is ensured. The liver retractor and instrument ports are removed, pneumoperitoneum is released, and the skin incisions are closed with absorbable suture or a skin bonding agent.

POSTOPERATIVE CARE The bladder catheter is removed in the recovery room. Clear liquids are begun 3 to 6 hours after surgery, and the patient

Chapter 22 Laparoscopic Nissen Fundoplication

FIGURE 22-12 A “shoeshine maneuver” is performed to ensure that the fundus is freely mobile.

FIGURE 22-13 A 2-cm long, floppy fundoplication is performed just above the gastroesophageal junction, over a large esophageal dilator (56-60 Fr).

is advanced to a soft mechanical diet the following day. A regular diet is delayed until 3 to 4 weeks after the operation. Specifically, patients are advised to avoid tough meat, raw vegetables, cakes, and bread, all of which can get held up at the GEJ in the initial postoperative period. As much as possible, retching must be avoided. To this end, patients receive an aggressive antiemetic protocol, beginning with a dose of ondansetron in the recovery room. Patients are typically discharged on the first or second postoperative day.

There were 7 conversions to laparotomy, 5 of which occurred during the first 100 cases. Major complications occurred in 21 patients, 14 of whom required additional operations. These included 10 esophagogastric perforations, 4 acute paraesophgeal herniations, and 4 splenic injuries. There were 3 deaths in this series, all in patients with paraesophageal hernias. The mean operative time was 177 minutes and the mean length of stay was 2.2 days. Comparison of preoperative and postoperative symptoms in patients who had been followed for at least 1 year revealed that heartburn and regurgitation were resolved or improved in 94% and 95%, respectively. Eighty-one percent of patients reported resolution or improvement in dysphagia, whereas new-onset dysphagia was seen in 3.3% of patients. Resolution or improvement in atypical symptoms was more variable, ranging from 64% for asthma to 80% for cough. Despite some variability in symptom response, 94% of all patients reported that they were satisfied with their surgical outcome at 2 to 5 years postoperatively. These results are similar to those in other large series of laparoscopic antireflux surgery (Table 22-2). In addition, our group and others have also demonstrated significant improvement in quality of life measures after antireflux surgery (Dallemagne et al, 2006; Rattner, 2006).16,36,37 We and others have also assessed objective outcome measures after antireflux surgery. We performed 24-hour esophageal pH studies on 55 patients between 6 and 12 weeks postoperatively. Esophageal pH had normalized in 48 patients (87%). At 1 year after surgery, we performed 54 of these 24-hour pH studies, 7 for symptom evaluation and 49 on a voluntary basis. Forty-nine (91%) of the studies were normal, including 45 (96%) of the volunteers and 4 (63%) of those with recurrent GERD symptoms (Hunter et al, 1996).38 Peters and colleagues examined their results with laparoscopic Nissen fundoplication in 100 patients with abnormal 24-hour pH studies and typical symptoms of GERD.13 Symptom relief was reported in 96% of patients. In 26 (93%) of 28 unselected patients who underwent repeat 24-hour pH studies, esophageal pH exposure had normalized. Upper endoscopy was repeated in 30 of 46 patients with preoperative erosive esoph-

RESULTS We recently reviewed our experience with 1000 consecutive patients undergoing laparoscopic fundoplication for GERD (n = 882) or paraesophageal hernia (n = 118) (Terry et al, 2001).35 Patients with GERD were referred for management of typical reflux symptoms (heartburn, regurgitation, and dysphagia) and/or atypical symptoms (hoarseness, cough, chest pain, and asthma). Upper endoscopy, barium swallow, and esophageal manometry were performed preoperatively on all patients. Ambulatory 24-hour pH monitoring was performed selectively for patients with atypical symptoms and/ or without endoscopic evidence of esophagitis. In most cases (879 patients) a laparoscopic Nissen fundoplication was performed. A 360-degree fundoplication without fundic mobilization (Nissen-Rossetti) was performed in 22 patients. Partial fundoplications were performed in 99 patients with significantly impaired esophageal motility. Outcome measures evaluated in this study were subjective symptom assessment, quality of life (using the SF-36), and global satisfaction. Patients completed symptom surveys preoperatively, 4 to 6 weeks postoperatively, and yearly thereafter. Severity of symptoms (heartburn, regurgitation, and dysphagia) was rated from 0 to 3. Postoperative questionnaires also included questions about overall satisfaction with the surgical outcome, need for medication, and problems arising from the procedure. Of 824 patients who completed preoperative questionnaires, 623 were followed for more than 1 year postoperatively, with a mean follow-up of 26 months.

273

274

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 22-2 Comparative Results of Laparoscopic Antireflux Surgery Series

Author (Year) Dallemagne et al16 (2006) 19

Pessaux et al

(2005)

No.

Median Follow-up (yr)

100

10.3

1340

7.1

Need for Revision/ Reoperation (%)

Relief of Heartburn or Regurgitation (%)

4

89.5

4.4

89.9

Dysphagia (%) 1 5.1

Lafullarde et al18 (2001)

176

6

14.8

87

N/A

Anvari and Allen14 (2003)

181

5

4

88

2.7 27.5

15

Bammer et al

(2001)

Granderath et al41 (2002) 35

Terry et al

(2001)

13

Peters et al

(1998)

171

6.4

1.8

81

103

5

4.8

83.8

4.8

1000

1

3.9

94

3.3

1.8

0

96

1

100

agitis. In 28 patients (93%) the esophagitis had resolved. Finally, lower esophageal sphincter pressure had normalized in all 28 patients who underwent follow-up manometry, increasing from a median of 5.1 mm Hg to 14.9 mm Hg. A common symptom after antireflux surgery is transient dysphagia, reported in 10% to 47% of patients (Terry et al, 2001).13,35,39 In most cases, dysphagia resolves within 3 months of operation. Rarely, endoscopic dilation or surgical revision is required. Bloating and increased flatus are also commonly reported symptoms after fundoplication, although these symptoms are rarely severe and do not typically impact on patient satisfaction with the procedure. Often, these symptoms were present to some degree before surgery and, in some cases, are improved with fundoplication.40 The revision rate for anatomic failure of the fundoplication in our series was 3.9%, which compares favorably to other reports (see Table 22-2).18,19,41 Transdiaphragmatic herniation of the wrap accounted for 29 (74%) of the failures, 4 of which occurred during the initial hospitalization. In four cases (10%), the fundoplication slipped down onto the stomach. In three patients (8%), postoperative dysphagia and luminal narrowing seen on barium swallow did not resolve after 3 to 6 months due to an overtight wrap. These patients were converted to a posterior 270-degree (Toupet) fundoplication. Previously undiagnosed motility disorders accounted for two (5%) of the failures, and disruption of the fundoplication was observed in one patient (3%).

SUMMARY Laparoscopic Nissen fundoplication remains the most common antireflux procedure performed in the United States. The operation is effective and durable, with a low rate of complications. Resolution of heartburn and regurgitation can be expected in up to 95% of patients after antireflux surgery, with long-term recurrence rates of 10% to 20%. Dysphagia is common in the initial postoperative period but in most cases resolves within 3 months from surgery. Other symptoms such as bloating and flatulence are commonly reported but are usually well tolerated. Overall, patient satisfaction is high after laparoscopic Nissen fundoplication and quality of life is measurably improved.

As with most procedures, patient selection is paramount. The presence of GERD should be clearly documented, either by an abnormal 24-hour esophageal pH study or by endoscopic evidence of esophagitis in a patient with an appropriate clinical presentation. The most reliable predictors of a good outcome from surgery are (1) an abnormal 24-hour esophageal pH study, (2) a good response to PPIs, and (3) typical symptoms of GERD (Campos et al, 1999).42 Atypical symptoms, such as cough, hoarseness, asthma, and chest pain do not respond as reliably to fundoplication. For patients with these complaints, it is important to have an honest discussion of expectations from antireflux surgery. Additionally, it is important to rule out other causes for these symptoms before attributing them to GERD. Finally, assessment of esophageal function with manometry is essential to avoid performing a 360-degree wrap in a patient with undiagnosed achalasia or scleroderma.

COMMENTS AND CONTROVERSIES Clearly, laparoscopic Nissen fundoplication is an important alternative to medical therapy for carefully selected patients with GERD. The procedure is well suited to patients with large hiatal hernias, breakthrough symptoms on maximal therapy, and extraesophageal symptoms and those who wish to avoid lifelong medical treatment. Novel endoscopic therapies have also been developed for the treatment of GERD and may be applicable in a subset of patients. What role these emerging therapies will play and how they will impact on the utilization of antireflux surgery remain to be seen. Unless these procedures are capable of correcting the anatomic abnormalities that often underlie GERD, it is unlikely that they will ever replace laparoscopic fundoplication. T. W. R.

KEY REFERENCES Campos GM, Peters JH, DeMeester TR, et al: Multivariate analysis of factors predicting outcome after laparoscopic Nissen fundoplication. J Gastrointest Surg 3:292-300, 1999. Crookes PF, Ritter MP, Johnson WE, et al: Static and dynamic function of the lower esophageal sphincter before and after laparoscopic Nissen fundoplication. J Gastrointest Surg 1:499-504, 1997.

Chapter 22 Laparoscopic Nissen Fundoplication

Dallemagne B, Weerts J, Markiewicz S, et al: Clinical results of laparoscopic fundoplication at ten years after surgery. Surg Endosc 20:159-165, 2006. DeMeester TR, Bonavina L, Albertucci M: Nissen fundoplication for gastroesophageal reflux disease: Evaluation of primary repair in 100 consecutive patients. Ann Surg 204:9-20, 1986. Donahue PE, Samelson S, Nyhus LM, et al: The floppy Nissen fundoplication: Effective long-term control of pathologic reflux. Arch Surg 120:663-668, 1985. Fein M, Ritter MP, DeMeester TR, et al: Role of the lower esophageal sphincter and hiatal hernia in the pathogenesis of gastroesophageal reflux disease. J Gastrointest Surg 3:405-410, 1999. Heikkinen TJ, Haukipuro K, Koivukangas P, et al: Comparison of costs between laparoscopic and open Nissen fundoplication: A prospective randomized study with a 3-month followup. J Am Coll Surg 188:368376, 1999.

Hunter JG, Swanstrom L, Waring JP: Dysphagia after laparoscopic antireflux surgery. The impact of operative technique. Ann Surg 224:51-57, 1996. Hunter JG, Trus TL, Branum GD, et al: A physiologic approach to laparoscopic fundoplication for gastroesophageal reflux disease. Ann Surg 223:673-685, 1996; discussion 685-687. Nilsson G, Wenner J, Larsson S, et al: Randomized clinical trial of laparoscopic versus open fundoplication for gastro-oesophageal reflux. Br J Surg 91:552-559, 2004. Rattner DW: Measuring improved quality of life after laparoscopic Nissen fundoplication. Surgery 127:258-263, 2000. Terry M, Smith CD, Branum GD, et al: Outcomes of laparoscopic fundoplication for gastroesophageal reflux disease and paraesophageal hernia. Surg Endosc 15:691-699, 2001. Terry ML, Vernon A, Hunter JG: Stapled-wedge Collis gastroplasty for the shortened esophagus. Am J Surg 188:195-199, 2004.

275

Partial Fundoplication chapter

23

BELSEY MARK IV REPAIR Toni E. M. R. Lerut Clement A. Hiebert

Key Points ■ The principle of the Belsey Mark IV is the restoration of the distal

esophagus into the high pressure zone below the diaphragm with a posterior buttress for counter pressure. ■ The transthoracic approach allows maximal mobilization of the thoracic esophagus, resulting in maximal gain of length where necessary in order to obtain a tension-free intra-abdominal reduction of the distal esophagus invested by the fundoplication. ■ In contrast to a 360-degree fundoplication, the partial 240-degree fundoplication is less prone to undesired side effects (e.g., dysphagia, gas bloating, and flatulence). ■ In spite of the popularity of laparoscopic antireflux surgery, the Belsey Mark IV procedure remains of added value to the armamentarium of antireflux procedures, in particular, when treating complicated failures after laparoscopic fundoplication or complex giant paraesophageal hernias.

The popularization of laparoscopic surgery in the early 1990s dramatically and forever changed the practice of antireflux surgery since 1991 when Dallemagne introduced the laparoscopic Nissen antireflux procedure to the surgical community. The minimally invasive approach made this rather complex surgical procedure now much more acceptable to not only the patients but also physicians and gastroenterologists, lowering the threshold for referral to the surgeon. Within a few years the incidence of antireflux interventions, now almost exclusively performed through the laparoscope, had at least tripled. The type of intervention almost invariably used nowadays is the Nissen antireflux operation. Indeed it appeared that this technique was the most suitable and most effective one to perform and to be taught. On the contrary, all other accepted interventions used in open surgery (i.e., the Belsey Mark IV, the Hill, and the Toupet procedures) proved to be too difficult for a routine application through the laparoscope or thoracoscope. Although the usefulness and the advantage of the Belsey Mark IV antireflux operation have been well documented, its application has decreased substantially worldwide. It is no longer used as a preferred technique for primary antireflux surgery in the majority of patients, with the laparoscopic Nissen operation being the first choice. Overenthusiasm resulting in ill-devised patient selection, insufficient experience, the tendency to fit all patients into one single type of intervention (i.e., the Nissen operation), and lack of understanding of the physiopathology have recently tempered this enthusiasm as a result of some disastrous complications and bad results. As a result, an increasing 276

number of failures and repeat surgeries have been noted in literature. It appears that the Belsey Mark IV technique is now used more to treat complications of laparoscopic fundoplications. Given the rising incidence of “redo” antireflux surgery, it is of paramount importance to keep the Belsey Mark IV operation within the armamentarium of every surgeon dealing with the different aspects of gastroesophageal reflux disease (GERD). The aim of this chapter is therefore to describe in detail the different technical steps of this particular intervention. As a note of historical interest, all perioperative photographs used for the illustration of this chapter were taken by one author (T. L.) during his training period in Bristol, England, with Ronald Belsey being the surgeon.

HISTORICAL NOTE To appreciate the full significance of Ronald Belsey’s contribution to the surgery of hiatal hernia, it is necessary to revisit the orthodoxy of the first half of the 20th century, a time when surgeons viewed hiatal hernia as a rupture to be repaired, a rim to be snugged, an organ to be tethered. How large the hernia must be to qualify for fixing and whether the approach to it should be through the chest or abdomen were topics of vigorous debate. Philip Allison, at Oxford, ended the era of protrusion surgery by showing that the symptoms of an ordinary sliding hernia derive not from a throttled pouch of stomach but from wrong-way traffic at the lower end of the esophagus (Allison, 1951).1 The culprit was the valve, and symptoms were the lament of esophageal mucosa washed in acid. Allison’s thesis proved correct, even though the operation that bears his name failed the test of his own follow-up clinic.2 It remained for Belsey in Bristol and Nissen in Basel to more or less simultaneously develop reliable operations to curb gastroesophageal reflux. Nissen’s discovery was serendipitous; Belsey’s was the product of a decade of correlating patients’ complaints with the findings on the operating table and in the endoscopy and follow-up clinics (Hiebert, 1991).3-7 Belsey’s preoccupation with developing a physiologic rather than an anatomic repair began in 1942 (Hiebert, 1991).4 Using a rigid 50-cm esophagoscope and examining the minimally sedated patient in the seated position, Belsey came to appreciate that competency of the esophagogastric junction depended on its lying well below the diaphragm. If the junction became displaced to a level at or above the hiatal arch, the esophagogastric opening was seen to gape, allowing a tide of gastric mucus to flow into the terminal esophagus with each deep inspiration. He called the parent condition a “patulous cardia” and set as his operative goal the repositioning

Chapter 23 Belsey Mark IV Repair

of the esophagogastric junction several centimeters below the diaphragm. The Mark I operation was essentially a variant of the anatomic restoration urged by Allison. Mark II and Mark III operations represented degrees of trial and error fundoplication to provide a serosal covered muscular collar more suitable than the naked esophagus for anchoring sutures. A bonus of this crescentic overlay of stomach was its restraining influence on any tendency of the intra-abdominal esophagus to dilate. Belsey waited 6 years before he was sufficiently satisfied with the durability of the operation to publish the results of repair in 71 patients with isolated primary gastroesophageal reflux8 and a full 12 years before collaboration with Skinner in reporting the long-term results on 1030 patients (Skinner and Belsey, 1967).9 Belsey called his intervention the Mark IV operation to remind his students that this statement was neither his first on the subject nor was it necessarily his last.

ADVANTAGES OF THE MARK IV REPAIR

For example, the naked esophagus is unreliable holding ground for sutures that are placed too superficially or are tied too tightly. Baue11 proposed using sutures with pledgets to overcome this concern. 3. The location, depth, and spacing of each suture are crucial to a favorable result (i.e., eliminating abnormal reflux while maintaining agreeable swallowing and ability to belch and vomit when circumstances require). 4. A laparoscopic Mark IV procedure is not possible. 5. Post-thoracotomy wound pain may be a concern but not with the institution of a strict policy of separating ribs not more than 5 to 7 cm.

OBTAINING GOOD RESULTS As with all hiatal hernia repairs, good results with the Mark IV repair depend on the following (Belsey, 1977)12: 1. 2. 3. 4.

Proper selection of patients Optimal preoperative and postoperative care A meticulous operation Relating long-term results to what was done

The advantages of the Mark IV repair are numerous: 1. When correctly done, the operation provides a barrier to reflux but leaves other gullet functions undisturbed. More than 75% of patients retain the capacity for normal swallowing, belching, and vomiting. 2. A tension-free return of the terminal esophagus to the abdomen requires the gullet to be freed up, often to the level of the aortic arch. This requirement is especially important when the esophagus has been shortened by transmural esophagitis. 3. The mediastinum may be approached directly when it is filled with fibrous tissue owing to previous esophageal surgery. 4. Surgery in an obese patient is more easily accomplished through the chest. 5. If primary reduction and repair cannot be done without tension, especially in a child with a stricture, the incision may be extended across the costal arch and the left colon may be substituted for the stenosed esophagus. 6. The transthoracic Mark IV technique is an essential component of Pearson’s ingenious solution to the short esophagus (i.e., the Pearson gastroplasty), incorrectly referred to as to the Collis-Belsey operation. 7. In a patient with scleroderma, or after an esophageal myotomy for achalasia or other motility disorder, the antireflux barrier can be restored and tailored to less than robust esophageal propulsion. 8. A thoracic approach allows the surgeon to manage coexisting disease in the left chest wall, lung, esophagus, or upper abdomen.

DISADVANTAGES OF THE MARK IV REPAIR There are some disadvantages to the Mark IV procedure: 1. The operation is conceptually more complex than a Nissen repair and is more difficult to teach. 2. Orringer and colleagues10 noted that the Mark IV is “a fairly easy operation to do but a difficult one to do well.”

Proper Patient Selection Proper selection of patients means answering a number of questions: ■ ■ ■ ■ ■ ■ ■ ■

Has the diagnosis been confirmed? Is the hernia or patulous cardia the undoubted source of the patient’s complaint? Are there overlapping symptoms of coronary artery disease? How serious is the reflux? Is there evidence for aspiration, esophagitis, columnarlined esophagus, or microcytic anemia? Do the complaints justify the small but significant risk of a less than perfect outcome? Is the patient otherwise fit? What is the cost of long-term medical management vis-àvis operation?

Optimal Preoperative Care Optimal preoperative care includes ensuring that the heart and lungs are at their best: ■ ■ ■

■ ■

Has the chest physiotherapist cleared the airway? Has pulmonary inflammation been controlled? Has the patient been told where the incision will be and instructed in the use of coughing, postural drainage, and breathing exercises? Is the anesthesiologist aware of the potential for regurgitation and aspiration during induction? Is the anesthesiologist adept at inserting a bronchial blocker or double-lumen tube so that, if desired, the lung may be deflated to improve exposure without additional separation of the ribs?

Meticulous Operation The physiologic goal of the Mark IV operation is elimination of gastroesophageal reflux while preserving the other functions of the gullet. The anatomic goal is to return a 4- to 5-cm

277

278

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 23-1 Mobilization of the esophagus. A and B, Adequate mobilization of the esophagus from the diaphragm to the point where the vagus nerves join the esophagus just below the aortic arch is probably the most important single step in the repair of any hiatal hernia. The esophageal artery running from the descending aorta to the junction of the middle and lower thirds is divided, as is the esophageal branch of the lowest bronchial artery. This extensive mobilization of the lower esophagus will not impair its blood supply, which is maintained by the ascending or esophageal branch of the left gastric artery and by the remaining esophageal branches arising from the bronchial arteries in the region of the aortic arch.

Certain points require emphasis.

be directly over the appropriate interspace because the serratus anterior muscle arises from the lower ribs and precludes adjusting exposure via the standard posterolateral thoracotomy employed for rib 5 and above. The Mark IV operation can be done through minimally separated ribs. It is unnecessary to have the (measured) interval between the blades of the retractor greater than 7 cm. By doing so, wound discomfort has virtually ceased to be a problem.

Exposure

Mobilization

The incision is made in the left sixth or seventh interspace; the higher level is used in obese patients. The incision should

With the left lung collapsed or retracted, the inferior pulmonary ligament is ligated and divided and the esophagus

segment of terminal esophagus to the abdomen and to fix it in place (DeMeester et al, 1979).13 The operation has four parts: 1. 2. 3. 4.

Exposure Mobilization Crus approximation Fundoplication

A

B

FIGURE 23-2 Mobilization of the cardia. A and B, The cardia is mobilized by division of the phrenoesophageal ligament. Upward traction on the esophagus brings into view the peritoneal reflection, which is incised to enter the peritoneal cavity. When a hernia sac is present, the peritoneum is entered directly. (A, FROM AELVOET C, CHRISTIAENS MR, CSENDES A, ET AL: EINGRIFFE BEI REFLUXKRANKHEIT. IN SIEWERT JR: OPERATIONSLEHRE BAND IV: CHIRURGIE DES ABDOMENS, 2. GERMANY, URBAN & SCHWARZENBERG, 1989, P 85.)

Chapter 23 Belsey Mark IV Repair

A

B

IPA SG LGA

LGE

C

D Hiatus

SGA

LS IPA

A

E

FIGURE 23-3 Mobilization of the cardia. A and B, The left index finger is now passed around the cardia; the finger can be passed without difficulty through the peritoneum just above the left gastric artery into the lesser sac, which is opened posteriorly onto the tip of this finger. C to E, Above the finger lies a band of peritoneum containing “Belsey’s artery,” a communication between the ascending branch of the left gastric artery (LGA) and one of the inferior phrenic arteries (IPA). This artery must be clamped, divided, and ligated in order to allow full mobilization of the cardia. A, aorta; LGE, left gastroepiploic artery; LS, lesser sac; SG/SGA, short gastric arteries. (SCHEMATIC DRAWINGS BY R. BELSEY.)

279

280

Section 4 Gastroesophageal Reflux and Associated Conditions

Right vagus nerve Left vagus nerve

A

B

FIGURE 23-4 Removal of fat pad. A and B, A vascular pad of fat lies on the front of the esophagogastric junction. This pad must be removed completely to enable firm adhesions to develop between the fundus of the stomach and the anterolateral aspect of the lower esophagus. Any remnants of the hernial sac are removed along with the fat pad. The two vagus nerves are dissected off the esophagus in continuity and allowed to fall back behind the esophagus, out of harm’s way during the fundoplication procedure. The esophagus and cardia have been adequately mobilized and prepared, and the vagi are preserved. Repair can now begin.

first short gastric artery and medially until a thickened band of fibrofatty tissue is encountered (Fig. 23-2). Ligation and division of this band opens the lesser sac and exposes the caudate lobe of the liver posteromedially. Inattention to this step may result in bleeding from an ascending communication of the left gastric and phrenic arteries (Fig. 23-3).14 Near the hiatus, each vagus nerve is gently dissected from the esophagus to provide space for the fundoplicating sutures. Occasionally, one or two of the upper short gastric vessels are taken to achieve full mobilization of the cardia. Finally, the pad of fat in front of the gastroesophageal junction is excised by ligating and dividing its multiple fine vascular attachments (Fig. 23-4). The goal is to promote adhesion between the soon-to-be juxtaposed stomach and esophagus.

together with both vagus nerves is freed of mediastinal connections. Adequate mobilization means carrying the dissection up to the level of the aortic arch (Fig. 23-1). Respect the diaphanous right pleura; it is at the most dependent level of the wound, and opening it allows unseen blood to accumulate in the right chest. The diaphragmatic end of the original longitudinal pleural incision is continued transversely to expose the muscular margin of the hiatus in front and the two halves of the right crus of the diaphragm behind. Peritoneal entry is made at the anteromedial aspect where, upon cutting of the phrenoesophageal ligament, the sudden bulging of extraperitoneal fat may be mistaken for omentum. But the peritoneum is deeper still; after incising it close to the hiatal rim, the surgeon continues the cut laterally to the

A

B

FIGURE 23-5 Restoration of intra-abdominal esophageal segment. A and B, The essential principle underlying the Mark IV repair is restoration of an intra-abdominal segment of esophagus that can be compressed by the positive pressure within the abdomen. A posterior buttress to afford counterpressure is therefore necessary. This support is achieved by approximating the two halves of the right crus behind the esophagus. Three to five posterior approximating sutures are normally required. These sutures are not tied until the final stage of the repair.

Chapter 23 Belsey Mark IV Repair

A

B

FIGURE 23-6 Partial fundoplication. A partial fundoplication is now started, the object being to embrace two thirds of the circumference of the lower 3 to 5 cm of esophagus with gastric fundus so that when the stomach is returned to the abdomen it carries with it and retains this segment of esophagus below the diaphragm. A to C, Three equidistant mattress sutures of 1-0 linen thread are placed. The nontraumatic needle is passed through the seromuscular layer of the stomach at about the level of the original peritoneal reflection. With the esophagus manually shortened to bunch up the muscle layer, the needle is passed vertically through this layer, about 2 cm above the esophagogastric junction, down but not through the submucosa to obtain a good grip on the circular muscle fibers of the esophagus. The correct depth of this suture can be assessed only with experience aided by manual estimation of the thickness of the muscle layer. It is essential to avoid perforating the mucosa. (C, FROM AELVOET C,

C

CHRISTIAENS MR, CSENDES A, ET AL: IN SIEWERT JR: OPERATIONSLEHRE BAND IV: CHIRURGIE DES ABDOMENS, 2. GERMANY, URBAN & SCHWARZENBERG, 1989, P 87.)

281

282

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B Second suture

C

FIGURE 23-7 Partial fundoplication continued. A to E, The suture is then reversed and passed down through the esophageal muscle to embrace a 0.5-cm strip of longitudinal muscle. The suture is then passed back through the seromuscular layer of stomach 0.5 cm anterior to the original point of insertion. This suture is tied very gently to achieve tissue approximation without strangulation. A tight suture will tear out of the fragile esophageal muscle and precipitate failure of the repair.

D

E

Chapter 23 Belsey Mark IV Repair

A

B

Stomach Esophagus Vagus nerves

C

FIGURE 23-8 Completion of third stage of fundoplication. A to C, A third suture is placed over to the right. The importance of gentle suturing cannot be overstressed. At the completion of this stage, two thirds of the circumference of the lower 2 cm of esophagus should be embraced by gastric fundus. The mobilized vagus nerves lie posterior in relation to the area of esophagus not included in the wraparound.

Crus Approximation Crus approximation is an essential component of the Mark IV operation. A firm posterior buttress, not a narrow hiatus, is the goal. The near edge of the right crus is less well defined than its opposite member. Sharp separation of pericardium from the diaphragm gains exposure; however, to locate with certainty the essential pillar through which sutures are to be taken it is helpful to palpate the inner half of the crus while tugging on a Babcock clamp applied to the central tendon of the diaphragm. This maneuver identifies the sturdy inner portion of the right crus and elevates it away from the vena cava. By contrast, the lateral half of the hiatal arch is stout, visible, and ideal for suturing. The spleen lies immediately beneath and is easily palpated. Three to five No. 0 sutures of linen or silk are placed from behind forward at approximately 1 cm (Fig. 23-5). The

sutures are temporarily snugged but are not tied until later. One author (C. A. H.) places the uppermost suture only through the medial half of the crus until after the hernia is reduced. This suture is then passed through posterior esophageal muscle before the final bite of the lateral half of the crus is taken. The strategy is to discourage early herniation at the notch between the esophagus and the reunited halves of the crus.

Fundoplication Fundoplication is started by placing the first of two mattressed rows of 2-0 silk or linen sutures between stomach and adjacent esophagus to create a crescentic fold encompassing an estimated 240 to 270 degrees of the circumference of the esophagus. The previously mobilized lower vagal trunks are gently moved aside if necessary. Proper passage of the atrau-

283

284

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 23-9 Insertion of second layer of mattress sutures. A and B, A second layer of mattress sutures is now inserted to extend the investment 2 cm farther up the esophagus. The sutures of the second layer are first passed through the diaphragm from above downward at the point where the muscle ring of the hiatus joins the central tendon. This maneuver is facilitated by inserting a special spoon-shaped retractor through the hiatus from above; by pressing the diaphragm down into the rim of the spoon, the abdominal viscera are excluded, allowing the needle to be passed with impunity. This technique makes it unnecessary to incise the diaphragm. (A, FROM AELVOET C, CHRISTIAENS MR, CSENDES A, ET AL: IN SIEWERT JR: OPERATIONSLEHRE BAND IV: CHIRURGIE DES ABDOMENS, 2. GERMANY, URBAN & SCHWARZENBERG, 1989, P 88.)

ligation of, the appropriate suture pair. The surgeon achieves reduction of the hernia by gentle downward pressure, using the fingers or a sponge stick (Fig. 23-12). With the hernia reduced, the fundoplicating and posterior crural sutures are tentatively snugged. An index finger in the posteromedial hiatal gap should slip effortlessly to the distal interphalangeal joint (Fig. 23-13). It is better that the hiatal opening be too loose than too tight; if there is any doubt about adequacy of the opening, the uppermost crural suture should be withdrawn or replaced. The esophagus must not be taut. With increasing experience, the surgeon is usually spared the uncomfortable decision whether to mobilize the esophagus still farther, dismantle the repair, and accept a 50/50 risk of a less than ideal result.15 The typical appearance of a properly constructed Mark IV operation is shown in Figure 23-14.

matic needles through the submucosa of the esophagus and stomach is important. Bites that are too superficial predispose to recurrence, and sutures passed through the mucosa invite fistula formation (Figs. 23-6 to 23-8). A critical point of technique is to avoid drawing the first throw of any knot too tight. Suture tension is determined by vision, not feel. Umbilicated tissue is best regarded as strangulated tissue. Use of polytetrafluoroethylene (Teflon) felt washers is suggested by Baue.11 A second row of three mattressed sutures is placed 1.5 to 2 cm from the junction created by the first row and is passed through the diaphragm from below upward. A modified teaspoon serves as a retractor to avoid hapless puncturing of abdominal viscera (Figs. 23-9 to 23-11). Spearing of subserosal gastric vessels happens occasionally, and any resulting hematoma is controlled by traction on, and occasionally by

A

B

FIGURE 23-10 Reintroduction of spoon and needle passage. A and B, The spoon is reintroduced, and the needle is passed through the diaphragm from below upward 0.5 cm from its original point of entry.

Chapter 23 Belsey Mark IV Repair

A

B

FIGURE 23-11 Placement of second row of mattress sutures continued. A and B, The second row of mattress sutures is placed, as with the first row, to invest two thirds of the circumference of the esophagus.

than allow gastric distention to spoil convalescence, it seems prudent to postpone eating and drinking until peristalsis has returned and only then to proceed with limited amounts of water, flat ginger ale, broth, and gelatin dessert. Fruit juices may not be tolerated until later. Discharge instructions to the patient include the advice to remain on a soft diet for 3 weeks and to chew food for twice as long as previously. Patients are urged not to lift children, pets, or objects weighting more than 20 kg because an occasional patient may associate the onset of recurrent symptoms with heavy lifting during the first weeks after surgery.

Optimal Postoperative Care Optimal postoperative care begins in the recovery room, where retching or vomiting can be the undoing of a fresh repair. The surgeon should anticipate possible emetogenic side effects of an analgesic drug by including the proposed postoperative narcotic in the premedication for endoscopy. Postoperative gastric distention is another source of stress on sutured tissues. Although the limited fundoplication of the Mark IV allows belching after tissue swelling subsides, temporary use of a nasogastric tube is advisable. The time to insert it is after fundoplicating sutures are in place but before they are knotted. Safe passage of the well-lubricated tube is facilitated by the surgeon’s fingers guiding the tube from outside of the esophagus. Although many patients tolerate early ingestion of oral fluids, delayed gastric emptying sometimes occurs. Rather

A

RESULTS A summary of results of 1524 standard Mark IV operations reported from Bristol, England, from Leuven, Belgium, and

B

FIGURE 23-12 Return of fundus to abdomen. A and B, The fundus, together with the invested segment of the esophagus, is then returned to the abdomen manually—not by traction on the mattress sutures, whose purpose is to maintain the reduction achieved manually. Any tendency of the stomach to return to the pleural cavity indicates secondary shortening of the esophagus due to severe, chronic esophagitis. A repair under tension will probably fail, and resection and reconstruction of the lower esophagus are indicated. The fundus remains wholly below the hiatus. The three mattress sutures in the second row can be tied gently, “snuggling” the hiatal muscle ring down onto the esophagus.

285

286

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 23-13 Tying of posterior approximating sutures. A and B, Finally, the posterior approximating sutures are tied from behind forward. The object of these sutures is to build up the posterior buttress; narrowing the hiatus plays no part in controlling gastroesophageal reflux. As each suture is tied, a finger is passed through the hiatus posteriorly to ensure no unnecessary narrowing. It is preferable to leave the hiatus too lax than too tight, and the final suture is sometimes omitted. (A, FROM AELVOET C, CHRISTIAENS MR, CSENDES A, ET AL: IN SIEWERT JR: OPERATIONSLEHRE BAND IV: CHIRURGIE DES ABDOMENS, 2. GERMANY, URBAN & SCHWARZENBERG, 1989, P 89.)

in the United States from Atlanta, Georgia, Ann Arbor, Michigan, and Portland, Maine, are given in Table 23-1. Eighty-four percent of patients had good-to-excellent results. The clinical criterion was overall satisfaction—the equivalent of an affirmative response to the question “Would you have had the operation if you had known what to expect?” Not surprisingly, in the updated Bristol series reported by Orringer and coworkers,10 Belsey’s personal operative record of 94% good-to-excellent results in 423 patients remains the 24karat gold standard. In reaching for the elusive goal of perfection, it is important to relate details of patient selection, perioperative care, and technical aspects of the operation to what the patient has to say on follow-up visits. Hiebert and O’Mara16 reviewed 209 patients who had undergone the unmodified Mark IV operation with 95% follow-up to 18 years. Review of original data shows that in only 8 of the group (3.3%) was there less than a 5-year follow-up. Eighty-four percent of patients were sufficiently satisfied with the surgical results that they would go through it again in the light of their experience. Only 5% believed the result to be unsatisfactory. As for specific esophageal functions, 78% found swallowing to be agreeable, 86% could belch, and 78% could vomit when required. Lerut and associates17 (1990) report using the Mark IV operation in 177 patients with 100% follow-up ranging from 1 to 13 years (mean, 4.4 years). Seventeen patients (11.6%) had symptoms suggesting reflux, and two more individuals without symptoms had evidence of recurrence. A total of 13 patients (8.8%) had gas bloat (5), dysphagia (5), or other gastrointestinal side effects (3). Postthoracotomy pain requiring treatment was seen in 13 patients (8.8%).

FIGURE 23-14 Typical postoperative appearance. The distal 4 cm of the esophagus is now below the diaphragm, being wrapped by the gastric fundus.

Chapter 23 Belsey Mark IV Repair

TABLE 23-1 Follow-up and Outcome: 1524 Mark IV Operations at Various Centers No. Patients

Author (Year) Hiebert and Belsey8 (1961) 10

Orringer et al

(1972)

Follow-up (%)

71

95

Period of Follow-up 2 mo-8 yr

Results: Good to Excellent (%) 87

892

86

3-15 yr

84

Hiebert and O’Mara16 (1979) (2nd series)

209

95

1-20 yr

80*

Lerut et al17 (1990)

147

100

1-13 yr

78†

Fenton et al18 (1997)

276

53

2 mo-16 yr

95‡

*10% of failures occurred in 2nd decade of follow-up. † Figure includes complications unrelated to gastroesophageal reflux. ‡ Failure defined in this Atlanta series as the need for reoperation or dilation.

COMMENTS AND CONTROVERSIES Drs. Lerut and Hiebert were fortunate to have trained with Sir Ronald Belsey and learn this most elegant esophageal repair. Although rarely used in the era of laparoscopic hiatal hernia surgery, the principles of esophageal mobilization, hiatal reconstruction, and fundoplication outlined by Dr. Belsey are the foundations of surgical reflux control. Having been taught this operation by Dr. Griff Pearson, I am fortunate to have it in my surgical armamentarium. It is still a useful, functional repair that I employ in the patient with impaired esophageal motility and a hostile abdomen. T. W. R.

KEY REFERENCES Allison PR: Reflux esophagitis, sliding hiatal hernia, and the anatomy of repair. Surg Gynecol Obstet 92:419-431, 1951.

Belsey R: Mark IV repair of hiatal hernia by the transthoracic approach. World J Surg 1:475, 1977. DeMeester TR, Wernly JA, Bryant GH, et al: Clinical and in vitro analysis of determinants of gastroesophageal competence. Am J Surg 137:39, 1979. Ellis FH Jr, Gibb SP, Heatley GJ: Reoperation after failed antireflex surgery: Review of 101 cases. Eur J Cardiothorac Surg 10:225-231, 1996; discussion 231-232. Hiebert CA: Surgical management of esophageal reflux and hiatal hernia: Classics in thoracic surgery. Ann Thorac Surg 52:159, 1991. Pearson FG, Cooper JD, Patterson GA, et al: Gastroplasty and fundoplication for complex reflux problems: Long-term results. Ann Surg 206:473-481, 1987. Skinner DB: Surgical management after failed antireflux operations. World J Surg 16:359-363, 1992. Skinner DB, Belsey RH: Surgical management of esophageal reflux and hiatus hernia: Long-term results with 1,030 patients. J Thorac Cardiovasc Surg 53:33, 1967.

287

chapter

HILL REPAIR

24

Jasmine Huang Donald Low

Key Points ■ The Hill repair is based on re-establishing normal anatomy by

restoration of the gastroesophageal flap valve. Of all the current antireflux procedures, it is the only repair based on firm fixation of the gastroesophageal junction to reliable structures within the abdominal cavity. ■ The fact that the procedure is based on reliable fixation within the abdominal cavity makes the Hill repair the procedure of choice in patients with short esophagus and large paraesophageal hernias. ■ The gastroesophageal flap valve is the key element and works in conjunction with the lower esophageal sphincter and the intraabdominal esophagus in maintaining the antireflux barrier. ■ The Hill repair can be effectively performed open or laparoscopic with documented long-term symptom control.

Gastroesophageal reflux disease (GERD) is the most common upper gastrointestinal problem affecting humans. GERD can be treated medically in the majority of patients. But for a portion of patients who fail medical management or who do not wish to be relegated to a lifetime of medication, surgery can be the treatment of choice. The goal of surgery is to restore the function of the antireflux barrier and control the symptoms and secondary complications of reflux.1,2 The four most popular antireflux operations are the Nissen fundoplication, the Belsey Mark IV, the Toupet, and the Hill procedure. The Hill procedure is the only operation originating in the United States, developed by Dr. Lucius Hill in 1959. The Hill repair has undergone very little modification since its inception. This repair is based on re-establishing normal anatomy by restoration of the gastroesophageal flap valve and firm fixation of the gastroesophageal junction (GEJ) to reliable intra-abdominal structures such as the preaortic fascia and the condensation of the crus.

HISTORICAL NOTE The relationships between peptic esophagitis, hiatal hernia, and gastroesophageal reflux have been evolving for the past two centuries. Bright first provided an anatomic description of the hiatal hernia in 1836.3 Bowditch suggested surgery to correct this abnormality in 1836.4 Scudder was the first to describe the repair of a sliding hiatal hernia in 1912,5 and Winkelstein demonstrated that esophagitis was secondary to GERD in 1935.6 The initial advocate of a surgical approach to the treatment of GERD was Allison; in 1951 he described a repair involving reduction of a hiatal hernia and the distal esophagus into the abdomen with anatomic closure of the 288

enlarged hiatus.7 Unfortunately, success was limited because patients experienced regular recurrence of their acid reflux. Manometric description of the lower esophageal sphincter (LES) in 1956 offered advances in the understanding of the function of the GEJ.8 It became clear that the combination of the hiatal hernia and the hypotensive LES led to the development of GERD. Each of the subsequent antireflux procedures (i.e., Nissen, Hill, Belsey, and Toupet) was based on an understanding of these principles. The Hill repair was first used at Virginia Mason Medical Center in Seattle in 1959. Dr. Lucius Hill then published an early report of his success in a series of 149 patients in 1967 (Hill, 1967).9 Hill initially described the approach involving dissection in close proximity to the celiac axis to clearly identify the median arcuate ligament. This dissection was intimidating to many surgeons and was likely the reason why the Hill procedure did not see wider application in the early years. In 1976, Vansant offered a modification that simplified the dissection of the median arcuate ligament (Vansant et al, 1976).10 We have subsequently adopted a method of using the condensation of the left and right crura to anchor the repair within the abdomen (see our description of the open repair) that obviates the need to dissect the median arcuate ligament. The Hill repair has stood the test of time, and in an era of minimally invasive operations it has seen the application through the laparoscopic approach.

ANTIREFLUX BARRIER The antireflux barrier prevents esophageal injury caused by gastric and biliary secretions. For several decades, the antireflux barrier was thought to primarily consist of the LES (Hill, 1989).1,11-15 It is now clear that the antireflux barrier is composed of many components: 1. Gastroesophageal valve (GEV) 2. LES 3. Posterior attachment of the GEJ (intra-abdominal esophagus) Proper functioning of at least a component of these mechanisms can maintain a competent antireflux barrier.

Gastroesophageal Valve The Hill repair (and in fact, the other antireflux procedures) is predicated on the understanding of the GEV. The GEV is a flat musculomucosal valve created by the angle of His.16,17 The normal intra-abdominal attachments of the GEJ act as a sling, placing tension on the greater curvature and maintaining the angle of His and the one-way flap valve (Fig. 24-1).

Chapter 24 Hill Repair

Thoracic esophagus Superior phrenoesophageal ligament Lower esophageal sphincter Adipose tissue Endoscopic view of the cardiac orifice from below, showing the valve-like fold illustrated.

Diaphragm Inferior phrenoesophageal ligament Gastroesophageal junction Angular valve-like flap

Diagram showing the valve-like structure formed by the cardiac angle wall at the cardiac orifice

Cardiac orifice of stomach

A

B

C

D

FIGURE 24-1 A, The gastroesophageal flap valve is a musculomucosal valve created by the angle of His. It is an important adjunct to the sphincter in preventing reflux. The valve closes against the lesser curve with increased intragastric pressure, which produces a functional barrier against reflux. B, Endoscopic appearance of an incompetent flap valve in a patient before Hill repair. C, Endoscopic appearance of a flap valve immediately after Hill repair. D, Endoscopic appearance of a flap valve 4 weeks after Hill repair. (A, FROM BANNISTER LH: STOMACH. IN BANNISTER LH, BERRY MM, COLLINS P, ET AL [EDS]: GRAY’S ANATOMY, 38TH ED. NEW YORK, CHURCHILL LIVINGSTONE, 1995, P 1757; B TO D, COURTESY OF DONALD E. LOW.)

289

290

Section 4 Gastroesophageal Reflux and Associated Conditions

As the stomach fills, the valve closes against the mucosa of the lesser curvature, thus preventing reflux. We have carried out cadaver dissections that have demonstrated the presence of the valve and the fact that the gradient across the GEJ increases when the valve is lengthened surgically. In addition, it was found that when the normal attachments of the GEJ posteriorly are reinforced, the gradient was raised even further (Hill et al, 1996).18-20 An intact valve allows for free passage of food and liquid into the stomach but creates a barrier against retrograde flow. At our institution, volunteers with documented GERD were examined with retroflexed inspection of the GEJ at the time of upper endoscopy. Comparison of control subjects and those with reflux showed a clear difference in the appearance of the GEJ and the flap valve. These observations have led to the development of a grading system (Fig. 24-2) that has been found to be highly accurate when used in preoperative assessment of patients with GERD.21 Contractor and associates showed that an abnormal GEV was more common in patients with symptomatic GERD than when compared with controls.12

ability to generate the swallow waves necessary to propel a bolus of food or clear acid from the distal esophagus. The re-anchoring of the GEJ in the abdomen along with the accentuation of the GEV are the key aspects to a successful Hill repair.

HILL REPAIR Although it is the least understood, the GEV is the antireflux mechanism most amenable to restoration with antireflux surgery. The angle of His and thus the GEV become distorted as a hiatal hernia widens the crura. All four of the standard antireflux operations do restore this structure. But the Hill repair does so by re-establishing the normal posterior attachments, thereby restoring the GEJ to its intra-abdominal position and re-creating the acute angle of His between the esophagus and the stomach (see Fig. 24-1). This prevents

GRADE II GRADE I

Lower Esophageal Sphincter In 1956, Fyke and associates demonstrated an intraluminal, high-pressure zone in the distal esophagus.8 It is now well established that the presence of a physiologic sphincter maintains a resting pressure higher than in the adjacent body of the esophagus or stomach.22 The LES creates a high-pressure zone that remains tonically closed until the act of swallowing; this sphincter relaxes in response to swallowing and allows for receptive relaxation, belching, and vomiting in response to vagal stimulation. The LES has been evaluated in the presence or absence of reflux. It can generate pressures up to 80 to 90 mm Hg with resting pressures of 12 to 18 mm Hg. A hypotensive LES pressure is a common finding in patients with symptomatic GERD. There is evidence that the LES and the GEV work in conjunction to prevent reflux.

GRADE III

GRADE IV

Posterior Fixation and the Intra-abdominal Esophagus The gastrointestinal tract is suspended by the dorsal mesentery to the posterior body wall. It appears that when this posterior attachment becomes attenuated or lengthened, the GEJ will slide superiorly into the posterior mediastinum, resulting in a hiatal hernia. The occurrence of a hiatal hernia is the most common reason for the loss of the GEV (see Fig. 24-1). Reflux is less likely to occur if the intra-abdominal segment of the esophagus remains intact.1,11,22 The intra-abdominal segment of the esophagus and the gastric cardia are both attached to the posterior abdominal wall. The phrenoesophageal membrane is a plate of fibroelastic tissue that extends from the median arcuate ligament to the aortic arch; this membrane holds the esophagus in place and maintains the intra-abdominal position of the GEJ. When there is loss of the posterior attachment, the GEJ slides into the chest and the GEV is lost. It has been shown that without the normal posterior attachment, the esophagus can demonstrate diminished

FIGURE 24-2 The four grades of the gastroesophageal valve. A grade I valve is a normal musculomucosal valve that stays adherent to the endoscope through all phases of respiration, opens only for swallowing and belching, and closes promptly after opening. The grade II valve is slightly less defined and shorter than the grade I valve, opens with swallowing and belching, closes promptly, and does not allow reflux. A grade III valve is poorly defined, opens frequently without the stimulus of swallowing or belching, stays open, allows reflux, and is often associated with a hiatal hernia. The grade IV valve shows no definition to the musculomucosal fold, stays open constantly, and is associated with a hiatal hernia. (WITH PERMISSION FROM MILLER EA, LOW DE: THE HILL ANTIREFLUX OPERATION. IN: OPERATIVE TECHNIQUES IN GENERAL SURGERY, 2:40, 2000, FIGURE 2.)

Chapter 24 Hill Repair

recurrent herniation and is thought to improve length-tension relationships in the lower esophageal musculature, improving motility in the distal esophagus.23 Comparatively, the Belsey and Nissen operations restore the valve by horizontal or vertical fundoplications, which rely on a more tenuous stabilization of the fundus to the esophagus. When first described by Dr. Lucius Hill, this repair involved the placement of anchoring sutures through the median arcuate ligament. The median arcuate ligament is formed by the condensation of the preaortic fascia, located on the anterior surface of the aorta just superior to the celiac axis. This aspect of the repair involves dissection of the celiac axis and can be intimidating to those unfamiliar with the anatomy. Warshaw24 and Vansant (Vansant et al, 1976)10,25 have described a modified approach to simplify the dissection of the median arcuate ligament. We now advocate an approach using the more easily accessible condensation (or meeting point) of the crural musculature as the anchor for this repair (Fig. 24-3; see also Fig. 24-6).2,26 Previous reports have suggested a higher incidence of dysphagia, gas bloat, and recurrent GERD after the Nissen repair

when compared with the Hill repair.21,27,28 These have been associated with slipped repairs or recurrent hiatal hernia resulting from a lack of reliable intra-abdominal fixation of the GEJ. With the Hill repair, the dependable posterior fixation of the GEJ within the abdominal cavity reduces the tendency of the repair to be pulled up into the chest. This is particularly important in those patients with chronic esophagitis and inflammatory shortening of the esophagus. Some surgeons have advocated the Collis modifications of the Belsey and Nissen operations to avoid a recurrent hernia. In our experience, an adequate length of intra-abdominal esophagus can routinely be maintained by extensive mobilization of the esophagus and firm anchoring without a need for any esophageal lengthening techniques. Thus, the Hill repair has advantages over other repairs, especially when dealing with short esophagus and giant paraesophageal hernias (Low and Unger, 2005).29 Intraoperative manometry has been shown to influence the clinical outcome in the surgical treatment of antireflux disease.21 Intraoperative manometry can provide an objective means of determining the appropriate degree of plication needed to restore the antireflux barrier. The use of manometry minimizes the incidence of postoperative dysphagia and eliminates the need for inserting a bougie when constructing the repair. It also allows for intraoperative modification of the repair. We have found that intraoperative LES pressures between 25 to 55 mm Hg translate to postoperative pressures in the normal range of 15 to 30 mm Hg.

FIGURE 24-3 Modification for isolation of the median arcuate ligament. The surgeon’s finger is inserted between the crus and under the preaortic fascia and is advanced caudad. With the tip of the inserted finger, the ligament can be raised anteriorly to facilitate its dissection away from the celiac axis. (WITH PERMISSION FROM LOW DE, HILL LD: THE HILL REPAIR. IN SABISTON DC JR, SPENCER FC [EDS]: SURGERY OF THE CHEST. PHILADELPHIA, WB SAUNDERS, 1990, P 919.)

FIGURE 24-4 Verticalization of the diaphragm with exposure of the esophageal hiatus. (COURTESY OF DONALD E. LOW.)

291

292

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 24-5 The retraction apparatus used to provide exposure of the esophageal hiatus. This setup facilitates the “verticalization” of the diaphragm so the surgical team can look straight down on the operative field. (USED WITH PERMISSION FROM LOW DE: HILL ANTIREFLUX OPERATION. CHEST SURG CLIN NORTH AM 5:413, 416-421, 1995.)

FIGURE 24-6 Babcock clamp shown grasping the crural muscles and the preaortic fascia through the fibers of the left and right crus. Two heavy sutures have been placed above and below the clamp through the crural fibers and preaortic fascia to facilitate retraction during the remainder of the repair. (USED WITH PERMISSION FROM LOW

Patient Selection

DE: HILL ANTIREFLUX OPERATION. CHEST SURG CLIN NORTH AM 5:413, 416-421, 1995.)

Appropriate patient selection is of the utmost importance. The majority of operative candidates should have typical symptoms that are chronic and refractory to standard medical therapy. The laparoscopic approach to the treatment of GERD has, to a degree, lowered the threshold for recommending surgery for GERD. This has resulted in a rising incidence of surgical treatment for those patients who are asymptomatic but require routine and long-term use of medications. In young patients who wish to avoid lifetime dependence on medications, consideration of antireflux surgery is appropriate. However, if a good outcome is to be achieved in these asymptomatic patients, appropriate attention to patient selection and operative approach is imperative. Factors most commonly associated with successful surgical outcomes include the following: 1. The presence of typical symptoms of GERD 2. Significant improvement of symptoms on proton pump inhibitors 3. An abnormal 24-hour pH test that correlates well with symptoms 4. Normal esophageal motility and the absence of a refractory transmural stricture To this end, all patients being considered for antireflux surgery should undergo preoperative endoscopy and manometry to identify patients with abnormal motility and documented reflux-related problems such as esophagitis, stricture, or Barrett’s esophagus and to assess the size and configuration of any hiatal hernia. We utilize the 24-hour pH studies in the majority of patients to assess the severity of gastroesophageal reflux and more importantly to demonstrate symptom correlation with reflux episodes.

Technique for the Open Repair We currently utilize the open Hill repair in complex revisional operations and in patients with giant paraesophageal hernias or large standard hiatal hernias where esophageal shortening is likely. The Hill repair is aimed at restoring the normal antireflux mechanisms—the GEV, the intraabdominal esophagus, and the LES. The operation is performed using both general and epidural anesthesia. The patient is positioned supine with the right arm tucked and the left arm abducted at 90 degrees. A nasogastric tube should be placed at the start of the case. The Hill repair is performed through an upper midline incision from the xiphisternum to the umbilicus. The upper hand retractor system (V. Mueller, Allegiance, Deerfield, IL) is utilized to “verticalize the diaphragm,” which allows the operating team to work straight down on the GEJ rather than working under the diaphragm (Fig 24-4). If necessary, the xiphoid process may be removed. An additional Balfour retractor is used to enhance exposure of the lower aspect of the incision (Fig. 24-5). The abdomen is explored. The attachment of the left lateral segment is then mobilized, taking down the triangular ligament. Care should be taken to avoid the phrenic vein. The gastrohepatic ligament, including the hepatic branches of the vagus nerve, is incised. The left lobe of the liver is then retracted to the patient’s right (see Fig. 24-5). The dissection proceeds along the anterior aspect of the esophageal hiatus, reducing any hiatal hernia and incising the peritoneal reflection. The esophagus is mobilized and then manually encircled, maintaining close application of the ante-

Chapter 24 Hill Repair

FIGURE 24-7 Left and right crura are closed with two interrupted figure-of-eight sutures. (USED WITH PERMISSION FROM LOW DE: HILL ANTIREFLUX OPERATION. CHEST SURG CLIN NORTH AM 5:413, 416-421, 1995.)

FIGURE 24-9 The nearly completed repair. All five sutures are demonstrated through the anterior bundle, which is held by the forceps. The posterior bundle is being rotated and held by the Babcock clamp. The stitches in the posterior bundle are inserted just posterior to the directly visualized posterior vagus nerve. The sutures are also passed through the crural muscles and preaortic fascia (instead of the median arcuate ligament), which is retracted away from the aorta with the stay sutures (held in the hemostat). (USED WITH PERMISSION FROM LOW DE: HILL ANTIREFLUX OPERATION. CHEST SURG CLIN NORTH AM 5:413, 416-421, 1995.)

FIGURE 24-8 Babcock clamp shown grasping the anterior phrenoesophageal bundle. The first of five sutures is shown passing through the bundle and its underlying serosa. Notice that this stitch is placed lateral to the anterior vagus nerve, which is visualized as each suture is inserted. (USED WITH PERMISSION FROM LOW DE: HILL ANTIREFLUX OPERATION. CHEST SURG CLIN NORTH AM 5:413, 416-421, 1995.)

rior and posterior vagus nerves to the esophagus. A 1-inch Penrose drain is passed around both vagus nerves and the esophagus to facilitate retraction. Dissection is carried out inferiorly along the medial aspect of the right crus to the point where it converges with the left crus. The peritoneal coverings of the left and right crus should be preserved. The fundus is then completely mobilized from the GEJ to the level of the first short gastric vessel. If there is concern for esophageal shortening, the distal esophagus can easily be mobilized over a distance of 8 to 12 cm (and more extensively if necessary) to facilitate a tension-free reduction of the GEJ into the abdomen.

After appropriate mobilization of the esophagus and proximal stomach, the anterior and posterior phrenoesophageal bundles can be visualized at the GEJ. The phrenoesophageal bundles are composed of fibrofatty tissue and form the natural attachments of the GEJ to the diaphragm. The Hill repair uses the positions of these bundles at the base of the angle of His to firmly anchor the repair to posterior attachments, thereby deepening the angle of His and re-establishing the esophageal flap valve. The condensation of the crural muscles is lifted away from the aorta by passing a finger between the right and left crus down to the surface of the aorta as described by Vansant (see Fig. 24-3) (Vansant et al, 1976).10 The crural muscles once lifted up off the aorta are grasped with a Babcock clamp. Two No. 1 silk sutures are placed through the grasped tissue 1 cm apart to act as stay or retraction sutures. These sutures will elevate the crural musculature away from the aorta and are used for retraction purposes when placing the repair sutures (Fig. 24-6). The esophageal hiatus is then closed using figureof-eight 0 silk sutures with Teflon pledgets. Care is taken to assess the tightness of closure by continuing only to a point at which a finger can be inserted along the esophagus through the hiatus (Fig. 24-7). The Hill repair is then initiated by grasping the anterior and posterior phrenoesophageal bundles with Babcock clamps (Fig. 24-8). The anterior and posterior vagus nerves need to be visualized to avoid subsequent damage or inclusion by sutures. The repair is done with five 0 silk sutures. The first is placed laterally on the anterior phrenoesophageal bundle, including a component of the underlying gastric serosa. The same suture is then passed through the superior aspect of the

293

294

Section 4 Gastroesophageal Reflux and Associated Conditions

No.18 Levin tube

Flap valve

Medial arcuate ligament

FIGURE 24-10 Intraoperative assessment of the flap valve by palpating through the anterior wall of the stomach along the indwelling nasogastric tube.

posterior bundle and then down through the condensation of the crus, which is retracted anteriorly with the stay sutures. The next four sutures are placed in a similar fashion with each stitch taken more medial on the anterior bundle and more inferior on the posterior bundle and also passed through the crural fibers (Fig. 24-9). The first three sutures are placed with Teflon pledgets. After all five repair sutures are placed, the first two are tied down to the crural musculature with a single throw and clamped. These first two sutures are key—they deepen the angle of His and produce a palpable flap valve. The valve can be assessed at the point where it encircles the nasogastric tube (Fig. 24-10). Intraoperative manometric testing is carried out to allow preliminary assessment of the repair. We use a standard four-channel manometric tube with side ports located 5 cm apart from the tip of the catheter. Several sequential pull-throughs of the GEJ are performed. Intraoperative pressures of 25 to 55 mm Hg correlated with normal postoperative LES pressures. After measurements are complete, the first two and then remaining sutures are tied. The retraction sutures are removed. Final manometric measurements are then obtained. The repair is completed by placing two interrupted 3-0 silk sutures on the left lateral and anterior aspects of the GEJ from the fundus to the esophageal muscle and then to the rim of the esophageal hiatus (Fig. 24-11). The nasogastric tube is positioned in the stomach, and the abdomen is closed. The GEJ is now fixed in the abdominal cavity, and the GEV mechanism is restored (Figs. 24-12 and 24-13).

Technique for Laparoscopic Hill Repair The Hill repair has been successfully adapted to the laparoscopic approach.30-33 Relative contraindications include morbid obesity, previous extensive upper abdominal surgery, and failed prior antireflux operation. Given the advantages associated with minimally invasive techniques along with

FIGURE 24-11 View of one of the two sutures that is inserted to seal off the anterior hiatus and maximally accentuate the depth of the angle of His and the flap valve. The suture passes from the anterior aspect of the fundus down to the wall of the esophagus and out through the anterior rim of the hiatus. (USED WITH PERMISSION FROM LOW DE: HILL ANTIREFLUX OPERATION. CHEST SURG CLIN NORTH AM 5:413, 416-421, 1995.)

FIGURE 24-12 Relationship of the completed repair and how it deepens the angle of His and produces a very pronounced flap valve (shown highlighted through the anterior gastric wall), which is the major mechanism for controlling reflux postoperatively. (USED WITH PERMISSION FROM LOW DE: HILL ANTIREFLUX OPERATION. CHEST SURG CLIN NORTH AM 5:413, 416-421, 1995.)

improved cosmesis, shorter hospital stay, and faster recovery time, the demand for laparoscopic antireflux surgery will undoubtedly continue to increase.34 The laparoscopic repair is similar to that in the open repair. Standard laparoscopic equipment is utilized—high flow insufflator, five trocars (three 5 mm, two 10 mm), Veress needle, liver retractor, 30-degree 5-mm laparoscope, harmonic scalpel, manometry equipment, and 43-Fr bougie. After induction of general anesthesia, the patient is placed in low dorsal lithotomy position. The right arm is tucked, and the left arm is abducted to 90 degrees. The surgeon stands between the patient’s legs, the first assistant stands at the

Chapter 24 Hill Repair

Esophagus Right crus

Vagus nerve Anterior phrenoesophageal bundle

Left crus

Preaortic fascia Median arcuate ligament Celiac artery Aorta Posterior phrenoesophageal bundle FIGURE 24-15 The anterior and posterior phrenoesophageal bundles are visualized. The diaphragm is closed loosely around the esophagus. (WITH PERMISSION FROM KRAEMER SJ, AYE R, KOZAREK RA, HILL LD: LAPAROSCOPIC HILL REPAIR. GASTROINTEST ENDOSC 40:157, 1994.)

FIGURE 24-13 Esophagogram showing the gastroesophageal flap valve after repair of hiatal hernia. (COURTESY OF DONALD E. LOW.)

Mo

Monitor

or nit

First assistant

Camera assistant 4 5

Manometer

1 3 2

Scrub technician Surgeon

yo Ma nd sta

FIGURE 24-14 Depiction of patient positioning, trocar placement, and room organization with the laparoscopic Hill operation. 1, 10-mm assistant port; 2, 10-mm right-hand work port; 3, 5-mm camera port; 4, 5-mm left-hand work port; 5, 5-mm liver retractor port. (WITH PERMISSION FROM MILLER EA, LOW DE: THE HILL ANTIREFLUX OPERATION. IN: OPERATIVE TECHNIQUES IN GENERAL SURGERY, 2:49, 2000, FIGURE 12.)

left, and the camera operator stands at the patient’s right side. Endoscopy can be performed if the operator chooses. A manometric tube and 43-Fr bougie are placed. Pneumoperitoneum is achieved using a Veress needle and a 10-mm trocar is placed. With direct visualization using a 30degree 5-mm laparoscope, four additional trocars are placed (Fig. 24-14). The abdomen is inspected, and the left lateral segment of the liver is retracted against the abdominal wall with the articulating retractor. The dissection begins by incising the gastrohepatic ligament over the caudate lobe. The phrenoesophageal membrane is opened anteriorly from the patient’s right to left. The dissection continues along each crus with division of the overlying peritoneum. The vagus nerves are kept closely applied to the esophagus. The stomach is retracted caudad and to the right. The retroesophageal and posterior fundal spaces are entered; the posterior fundic attachments are divided. Using the posterior phrenoesophageal bundle to retract the stomach allows for division of any posterior attachments to the level of the first short gastric vessel. The bougie is then pulled back so that the tip is within the thoracic esophagus. The crura are approximated and the hiatus closed with two or three simple nonabsorbable sutures. Pledgets may be used to bolster the repair if the crura are widely separated. All knots are tied extracorporeally. The operator must be aware that if the closure is too tight or the closure is carried too far anteriorly, dysphagia may result. The posterior fundus is then tacked to the left crus with two or three heavy nonabsorbable sutures. This positions the posterior phrenoesophageal bundle for the repair and may add overall strength. The GEV is then re-created and deepened with four simple interrupted nonabsorbable sutures placed through the anterior phrenoesophageal membrane, then the posterior phrenoesophageal membrane, and finally the crural musculature (Fig. 24-15). The laparoscopic Babcock clamp is used to grasp

295

296

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 24-16 The gastroesophageal valve is re-created and deepened with four simple interrupted nonabsorbable sutures placed through the anterior phrenoesophageal membrane, the posterior phrenoesophageal membrane, and then the crural musculature. Pressure measurements are obtained. (WITH PERMISSION FROM KRAEMER SJ, AYE R, KOZAREK RA, HILL LD: LAPAROSCOPIC HILL REPAIR. GASTROINTEST ENDOSC 40:157, 1994.)

the phrenoesophageal bundles before placing the suture. The suture is placed through the anterior phrenoesophageal bundle, lateral to the anterior vagus. It is then passed through the seromuscular layer of the stomach in the posterior bundle, immediately posterior to the posterior vagus nerve. The suture is then passed through the confluence of the crus as inferiorly as possible. The next three sutures are placed in a similar fashion moving laterally on the anterior bundle and superiorly to the posterior bundle and crural musculature (Fig. 24-16). The bougie is replaced into the stomach, and the top two sutures are tied with a single throw and secured with needle holders. The bougie is withdrawn, and manometric testing is performed as described in the open repair. Given the inability to evaluate the valve by palpation, evaluation relies on manometrics and endoscopic appearance. The esophagus should not be pinched or narrowed, and on endoscopy the appearance should be that of a grade I valve (see Figs. 24-1 and 24-2). Two to three additional sutures are placed from the anterior fundus to the hiatus. The instruments and ports are then withdrawn under direct vision. Fascial sutures are used at the two 10-mm port sites. The nasogastric tube and bougie are removed.

RESULTS OF THE HILL OPERATION Multiple reports have shown the Hill repair to be an effective and lasting treatment for patients with GERD. It is associated with few side effects, such as gas bloat and inability to burp and vomit postoperatively. These reports have documented its effectiveness in reflux-associated esophageal stricture, recurrent reflux, and failed previous repairs (Low et al, 1989).30-38 It is a highly effective and safe therapy for primary, recurrent, and complicated reflux problems, including paraesophageal hernias, redo operations, and short esophagus.

In 1989, Low and colleagues published the longest followup study of patients undergoing the Hill repair (Low et al, 1989).37 This review reported on the long-term results (1520 years) in 167 patients after the Hill repair. They found that 88% of patients were still completely satisfied with their results at a mean follow-up of 17.8 years. In addition, the Hill procedure did not appear to be associated with any significant late complications, attesting to the success and durability of this repair. Our group published a large series examining patients undergoing open repair of giant paraesophageal hernias (Low and Unger, 2005).29 This study showed our median length of stay (4.5 days) is comparable to that of recent series for laparoscopic repairs. In addition, when the combined results of laparoscopic reports are compared with our data, operative times are better for the open repair, and the open repair compares favorably with respect to the incidence of visceral injuries and mortality.

SUMMARY The Hill repair is a highly effective and safe therapy for GERD. It is the only repair predicated on firm anchoring within the abdominal cavity and the restoration of the normal anatomy of the GEJ. It re-establishes the acute angle of His between the esophagus and stomach, securing the intraabdominal esophagus via posterior fixation and accentuating the flap valve and is ideally suited for patients with large hiatal and paraesophageal hernias or shortened esophagus. It can be applied with success with either the open or laparoscopic techniques. Described are some minor technical changes from the original description of the Hill repair. The anchoring of the repair to the confluence of the diaphragmatic crus rather than the median arcuate ligament should make the procedure easier to learn and widely applicable. The results obtained with the Hill repair are durable with documented effective long-term symptom control (Low et al, 1989).37

COMMENTS AND CONTROVERSIES The Hill repair is an extremely successful operation when performed by the surgeons of the Virginia Mason Clinic and their trainees. It has failed to gain greater acceptance perhaps because most residents have not been taught this operation, and it is too complex for the practicing surgeon to “pick up” once he or she is comfortable with some variation of a fundoplication. I am certainly one of these surgeons. This chapter is an excellent overview of this repair. Like all antireflux procedures, it follows three principles: (1) restoration of the intra-abdominal esophagus, (2) repair of the esophageal hiatus, and (3) reconstruction of the LES. The first two steps are common to all repairs; however, it is in the third step where the Hill repair differs from the “fundoplications.” Instead of using the gastric fundus to re-form the “angle of His” and reinforce the LES, the Hill repair relies on posterior fixation of the esophagogastric junction. The original operation as proposed by Dr. Hill was based on fixation to the median arcuate ligament. Dissection of the celiac artery was necessary to expose this fibrous periaortic band. Today, this difficult step is avoided by using the technique proposed by

Chapter 24 Hill Repair

Vansant—posterior fixation to the reconstructed hiatus.10 Placement of the fixation sutures requires an understanding and identification of the phrenoesophageal ligament. Again, the “fundoplications” and the Hill repair are similar because they are based on anchoring sutures placed in the esophagogastric wall. Exact placement of these sutures first to the “anterior phrenoesophageal bundle,” second to the “posterior phrenoesophageal bundle,” and finally to the inferior portion of the esophageal hiatus is difficult for the surgeon skilled in fundoplications. However, it is not unlike a fundoplication suture, which is placed first to the fundus, second to the esophageal muscularis, and finally to the fundus. Layering of five successive fixation sutures to reconstruct the angle of His is conceptually difficult for the surgeon inexperienced in this practice. Tying these five fixation sutures, “calibrating” the Hill repair, requires intraoperative manometry. Moreover, it demands a precise knowledge of range and variability of LES pressures in the anesthetized, relaxed patient with an open abdomen or pneumoperitoneum and how these pressures relate to LES pressure in the postoperative patient. This is perhaps the most daunting step for the surgeon unfamiliar with this repair. T. W. R.

KEY REFERENCES Hill LD: Myths of the esophagus. J Thorac Cardiovasc Surg 98:1-10, 1989. ■ This article is a review of “myths” concerning the esophagus, specifically examining understanding of the gastroesophageal junction. Hill LD: An effective operation for hiatal hernia: An eight-year appraisal. Ann Surg 166:681-692, 1967.

■ This article describes the results of the Hill repair after its first 8 years, showing

efficacy of this procedure. Hill LD, Kozarek RA, Kraemer SJ, et al: The gastroesophageal flap valve: In vitro and in vivo observations. Gastrointest Endosc 44:541547, 1996. ■ This study confirms the presence and significance of a gastroesophageal flap valve. Valves were inspected in cadavers and also in patients with and without reflux using endoscopy. Grading of the valve was performed showing correlation with the reflux status of patients. Low D, Anderson R, Ilves R, et al: Fifteen to twenty-year results after the Hill antireflux operation. J Thorac Cardiovasc Surg 98:44-50, 1989. ■ This article describes outcomes and long-term results after the Hill repair. Data show that the Hill repair is effective in managing refractory reflux with minimal morbidity and mortality. Low DE, Unger T: Open repair of paraesophageal hernia: Reassessment of subjective and objective outcomes. Ann Thorac Surg 80:287, 2005. ■ This article compares subjective and objective outcomes after open repair of paraesophageal hernia compared with laparoscopic series. The data indicate that the open approach provides excellent outcomes comparable to the laparoscopic approach. Vansant JH, Baker JW, Ross DG: Modification of the Hill technique for repair of hiatal hernia. Surg Gynecol Obstet 143:637-642, 1976. ■ This paper describes a modification for isolation of the median arcuate ligament. Historically, Dr. Lucius Hill has advocated using the median arcuate ligament to anchor the repair sutures. This requires dissection of the celiac axis, which can be intimidating to surgeons. A simple maneuver to identify the median arcuate ligament and retrocrural fascia is described here.

297

chapter

OPEN TOUPET AND DOR PARTIAL FUNDOPLICATIONS

25

Ahmad S. Ashrafi James D. Luketich Sandro Mattioli

Key Points

as operations for the control of primary gastroesophageal reflux.

■ Partial fundoplications are generally indicated in patients with

impaired esophageal motility.

HISTORICAL READINGS

■ Early results of partial fundoplications are good to excellent, but

several series have shown a higher recurrence rate by 2 years. ■ Partial fundoplications avoid overcompetence and early postop-

erative dysphagia. ■ Dor and Toupet fundoplications aim to achieve an increase of

pressure in the LES region and a long extra-abdominal segment of esophagus. ■ The LES pressure created by the Dor fundoplications are lower than pressures created by the Nissen or Belsey repairs. ■ It remains controversial whether avoiding early postoperative dysphagia (by performing a partial fundoplication) justifies a potentially higher recurrence rate of late postoperative reflux.

Dor J, Humbert P, Dor V, et al: L’intérét de la technique de Nissen modifiée dans la prevention de reflux après cardiomyotomie extramuqueuse de Heller. Mem Acad Chir (Paris) 88:877, 1962. Dor J, Humbert P, Paoli JM, et al: Traitement du reflux par la technique dite de Heller-Nissen modifiée. Presse Med 75:2563, 1967. Nissen R, Rossetti M: Gastropexy and fundoplication in hiatal hernia and reflux oesophagitis. Med World Lond 91:20, 1959. Toupet A: Technique d’oesophagoplastie avec phréno-gastropexie appliquée dans la cure radicale des hernies hiatales et comme complément de l’opération de Heller dans les cardiospasmes. Mem Acad Chir 89:394-399, 1963.

OPERATIVE TECHNIQUE Principles Routine open fundoplication has been abandoned by many surgeons. The indications for the open technique are limited to when a laparoscopic technique is inappropriate or when a laparoscopic approach is converted to an open one because of complications. The Dor and Toupet antireflux procedures consist of partial anterior and posterior gastric fundoplication, respectively. It is generally believed that these partial fundoplications are indicated in patients with impaired esophageal motility. In the past, these techniques were well described in Europe and in the Latin countries and subsequently became more popular among the international surgical community. Most commonly they are described as partial wraps after myotomy for achalasia and other motor disorders of the esophagus.

The principles of the Dor and Toupet operations are listed: 1. Restoration of an abdominal segment of esophagus 2. Accentuation of the angle of His 3. Creation of a long anterior or posterior mucosal valve at the gastroesophageal junction 4. Gastropexy to the right crus Both fundoplications are partial in order to avoid overcompetence and to obviate the complications of dysphagia and the inability to belch and vomit normally when necessary. Some steps are common to both the Dor and the Toupet repairs:

HISTORICAL NOTE

1. The position of the patient on the table 2. The anatomic dissection of the diaphragmatic hiatus 3. The mobilization of the gastroesophageal junction

The partial fundoplication techniques were developed and presented in France in the 1960s by Jacques Dor,1,2 professor of thoracic surgery of the University of Marseilles, and André Toupet,3 surgeon of the City Hospitals of Paris. Dor and Toupet conceived very similar principles almost contemporaneously. Although the two techniques are different, both were developed to avoid the frequent failures reported following the Lortat-Jacob and Allison procedures and to reduce the incidence of dysphagia (10%) reported by Nissen and Rossetti4 using a total 360-degree fundoplication. Interestingly, both Dor and Toupet initially proposed their repair for the prevention of reflux after the Heller myotomy for achalasia. Subsequently, both techniques were utilized

The patient is placed on the operating table in the supine position, and an upper midline, supraumbilical incision is made, beginning at the xiphoid process. The subcostal margins are retracted with a broad-bladed “third-hand” retractor. The left triangular ligament of the liver and the gastrohepatic omentum are divided; the left and the quadrate hepatic lobes are gently displaced. The phrenoesophageal membrane is incised circumferentially for the full 360 degrees. The distal esophagus and diaphragmatic crura are isolated, and the hernial sac is completely resected. Care is taken to avoid injury to the vagal trunks and to the hepatic branch of the vagus. The stomach is gently pulled down by the first assistant to expose at least 5 cm of esoph-

298

Chapter 25 Open Toupet and Dor Partial Fundoplications

agus below the hiatus. Of note, a hiatal repair or closure was not included in the original procedures but may be done if the hiatal opening is excessive.

Dor Gastroplasty The procedure for the Dor gastroplasty is as follows: 1. The right margin of the gastric fundus is sutured to the left margin of the esophagus with five or six interrupted 3-0 nonabsorbable sutures, extending upward from the angle of His for at least 5 cm. After the last two sutures are tied, the ends are not cut, because they will be used to fix the gastroplasty to the left margin of the hiatus (Fig. 25-1A and B). 2. The gastric fundus is folded over the anterior aspect of the esophagus. A suture is positioned between the gastric fundus and the anterior aspect of the esophagus at the superior margin of the gastroplasty. 3. The folded fundus is then secured to the right margin of the esophagus with five or six sutures (see Fig. 25-1C). Two or three sutures, 1 cm apart, are placed below the esophagogastric junction between the lesser gastric curvature and the plicated gastric fundus.

A

B

C

4. The sutures of the fundoplication, beginning with the top two of the first series and all of the second series, are secured with large bites to the diaphragmatic ring, from left to right and top to bottom. 5. At the end of the procedure, the 5-cm-long partial fundoplication is fixed below the diaphragm and the hiatus is closed anteriorly and laterally to the right (see Fig. 25-1D). The restoration of at least 5 cm of esophagus in the abdomen, without tension, and the fixation of the gastric fundus (gastropexy) to the diaphragmatic crura are fundamental features of the Dor repair. If the effort to pull down the esophagus into the abdomen is difficult, as a result of acquired shortening of the esophagus secondary to panmural esophagitis, an alternative antireflux technique should be used. The short gastric vessels need to be divided when the apical suture is under tension. Other surgeons have developed techniques similar to the Dor repair or have modified the original operation. Thal5 proposed a transabdominal anterior fundoplication for hiatal hernia with reflux esophagitis but without stricture. The technique proposed by Schobinger6 differs from the original Dor repair in a few details; that is, two sutures between the lesser gastric curvature and the right diaphragmatic crus fix the gastroesophageal junction in the abdomen. After plication to the anterior aspect of the esophagus, the gastric fundus is fixed to the diaphragm and to the diaphragmatic crura rather than to the right esophageal margin. For achalasia, Pinotti and coworkers7 proposed a modification to the Dor gastroplasty designed to improve the antireflux effectiveness. After the myotomy, the anterior fundoplication is tailored with three series of sutures. The first one is between the posterior aspect of the gastric fundus and the posterior aspect of the esophagus. The remaining two series are sutured as in the Dor technique. The Pinotti technique results in a more extensive fundoplication. Gavriliu8 added a pyloroplasty to the Heller-Dor procedure, and Gallone and colleagues9 added a proximal gastric vagotomy. The Thal technique was adopted in pediatric patients by Ashcraft with a few modifications. The Thal-Ashcraft anterior fundoplication is performed through a transverse upper abdominal incision.10,11 Ashcraft proposed two different running suture techniques for the fundoplication. BoixOchoa12 uses the anterior fundoplication in pediatric patients. His technique differs from the Dor repair in that the gastric fundus is suspended to the diaphragm.

E

Toupet Gastroplasty D

F

FIGURE 25-1 Dor procedure. A and B, The right margin of the gastric fundus is sutured to the left margin of the esophagus. C, The anterior aspect of the fundus is sutured to the right margin of the esophagus. D, The stitches of the second row are sutured to the right crura. Transverse (E) and sagittal (F) sections of the hemifundoplication.

The gastroesophageal junction is circumferentially isolated, and at least 4 cm of tubular esophagus is placed below the diaphragmatic orifice without tension: 1. The gastric fundus is passed behind the esophagus and the posterior vagus nerve; the anterior aspect of the fundus now faces the posterior aspect of the lower esophagus. 2. The right side of the fundus is sutured to the right margin of the esophagus with four 3-0 nonabsorbable sutures; the

299

300

Section 4 Gastroesophageal Reflux and Associated Conditions

A B

A

FIGURE 25-3 Toupet repair according to Ténière. A, Separate closure of the diaphragmatic hiatus and 180-degree gastric wrap around the esophagus. B, Separate closure of the diaphragmatic hiatus and 270-degree gastric wrap around the esophagus.

B FIGURE 25-2 Toupet procedure. A, The right edge of the fundus is sutured to the right margin of the esophagus. The fundus is sutured to the right branch of the diaphragmatic pillar with two stitches. B, A few stitches secure the left posterior gastric fundus to the left branch of the diaphragmatic pillar; the left anterior edge of the gastric fundus is sutured to the left margin of the esophagus.

lowest stitch is applied to the lesser curvature, just below the esophagogastric junction (Fig. 25-2A). 3. The right posterior aspect of the fundus is sutured to the right limb of the diaphragmatic pillar with four to five stitches. The highest suture includes esophagus, fundus, and diaphragmatic ring; the lowest includes the folded fundus and the arcuate ligament. 4. A similar row of stitches secures the left-posterior gastric fundus to the left limb of the diaphragmatic pillar from the bottom to the top. Both rows of sutures should be free of tension. 5. Finally, the left anterior margin of the gastric fundus is symmetrically sutured (four or five sutures) to the left margin of the esophagus (see Fig. 25-2B). If the hiatal orifice is still too wide, one or two stitches can be placed across the hiatus, anterior or posterior to the esophagus. A few variants to the original technique, described here, have been proposed. In the method of Vayre and colleagues,13 the gastric fundus is passed behind the esophagus, and the right posterior fundus is fixed to the right pillar of the diaphragm with four nonabsorbable sutures. The anterior aspect of the fundus is sutured to the left margin of the lower esophagus; the left anterior portion of fundus is sutured to the diaphragmatic dome. The modern version of the Toupet procedure14 differs from the original: Ténière uses separate closure of the diaphragmatic hiatus and increases the gastric wrap around the esophagus to 270 degrees (Fig. 25-3).

These modifications originate from experiences subsequent to the original report of Toupet; it was demonstrated that any fundoplication can slip into the chest when the hiatus is not properly closed14 and that the degree of competence of the fundoplication is related to the extent of envelopment around the esophagus.15

Laparoscopy Today, laparoscopic antireflux procedures are routinely performed in many centers in the world; the detailed description of instrumentation, techniques, and approaches is provided elsewhere in the textbook.

RESULTS It has been repeatedly stated that the ability of the lower esophageal sphincter (LES) to protect the esophageal mucosa from exposure to gastric juice depends on its resting pressure and on its length. Normally, the LES is positioned two thirds below and one third above the diaphragmatic hiatus. Incompetence of the cardia can occur when one or more of these components fail.16 Length and pressure of the distal high-pressure zone (HPZ) are cofactors of cardial competence.15 The aim of both Dor and Toupet repairs is to achieve a competent antireflux barrier by the combination of a moderate increase of pressure in the LES region and a long intra-abdominal segment of esophagus to which the pressure is applied. Table 25-1 is a summary of the long-term manometric characteristics of the Dor and Toupet repairs reported by different authors in patients operated on for gastroesophageal reflux and for cases of achalasia managed by the Heller-Dor operation.16-26 A meaningful comparison between these results is of uncertain validity because the authors do not report normal values for their manometric system. There is no obvious difference in results between the series of cases operated on for gastroesophageal reflux in which the LES is left intact and the series of patients with achalasia managed by a Heller-Dor operation. The Heller-Dor operation is a

Chapter 25 Open Toupet and Dor Partial Fundoplications

301

TABLE 25-1 Dor and Toupet Fundoplications: Distal High-Pressure Zone (HPZ) Pressure and Length After Long-Term Follow-up (>3 Years)

No. Cases

Author (Year)

Distal HPZ Pressure Mean (mm Hg)

Procedure

Distal HPZ Length Mean (cm)

Mussa et al17 (1986)

32

Dor

7.5

*

Mir et al18 (1986)

67

Dor

3.66

3.32

19

(1988)

42

Heller-Dor

20

(1992)

193

Heller-Dor

Csendes et al

Bonavina et al

10.5

2

9.7

2.7

Dor

11.7

2.2

135

Toupet

16

5.4†

Thor and Silander23 (1989)

19

Toupet

16.9

*

Lundell et al16 (1991)

33

Toupet

13

2

Juan et al21 (1992) 22

Guarner et al

24

(1980)

86

(1992)

251

Toupet

17

5†

Michot et al25 (1992)

45

Toupet

23.9‡

4.1†

Ottignon et al26 (1994)

28

Toupet

17.4‡

*

Kabbej et al

‡

*Data not reported. † Total HPZ length. ‡ Data reported in cm H2O.

good model to evaluate the manometric effect of the 180degree anterior fundoplication because the LES is completely abolished by a complete myotomy. The LES pressures created by the Dor fundoplication are relatively low, certainly lower than the pressures created by the Nissen or Belsey repairs.15 The length of the HPZ varies between 2 and 4 cm. According to Mir and coworkers18 and Bonavina and colleagues,20 about 0.5 cm of the superior part of the gastroplasty is positioned above the respiratory inversion point. In their series of 60 patients, distal HPZ mean pressure is 8.00 ± 3.86 mm Hg and length is 5 ± 0.9 cm. The entire fundoplication lies below the diaphragm in 96.7% of these patients. The adaptive response of the Dor fundoplication increases abdominal pressure induced by the Valsalva maneuver, as is shown in Figure 25-4. In 52.2% of fundoplications, the increase of pressure in the fundoplication and in the abdomen is equivalent to a ∆HPZ/ ∆GP ratio of 1. In 47.8% of cases, the increase in intragastric pressure is greater than the increase in pressure in the fundoplication: ∆HPZ/∆GP < 1. There is no relationship between the grade of adaptive response to the intra-abdominal pressure increases and reflux esophagitis (see Fig. 25-4). This observation is consistent with that reported by Behar and associates,27 who observed increases of the HPZ pressure with ratios less than 1 in response to gastric pressure increases in patients undergoing successful operations with a Belsey Mark IV procedure. From manometric study of the Toupet repair, Galmiche and coworkers28 reported postoperative failure of the 180-degree posterior fundoplication when the preoperative LES pressure was below 10 cm H2O. Michot and coworkers25 confirmed these data, suggesting that the Toupet procedure might be insufficient in patients with a low preoperative LES resting pressure. By increasing the intent of fundoplication around the esophagus, an effec-

1.2 1 0.8 ⌬HPZ 0.6 ⌬GP 0.4 0.2 0

2

3

4

5 6 HPZ Length (cm)

7

8

9

FIGURE 25-4 Effect of the Valsalva maneuver on the high-pressure zone (HPZ) in 46 patients undergoing the Heller-Dor procedure obtained by station pull-through technique. ∆HPZ/∆GP, differences between pressures recorded in the HPZ and in the stomach (GP) during the Muller maneuver and in resting condition. Increases in gastric pressure (GP) caused by the Muller maneuver were associated with equal or minor increases in HPZ (∆HPZ/∆GP ≤ 1) of five patients with reflux esophagitis. In three patients, ∆HPZ/∆GP = 1; in two patients, ∆HPZ/∆GP = 0.58 and 0.52.

tive LES pressure can be restored in all patients, with satisfactory early clinical results and no digestive symptoms beyond the postoperative third month. Michot and coworkers suggest that the 180-degree posterior fundoplication is adequate in patients with a preoperative LES pressure above 10 cm H2O. In patients with a preoperative LES pressure below 10 cm H2O, a 270-degree fundoplication results in correction of gastroesophageal reflux without postoperative symptoms.

302

Section 4 Gastroesophageal Reflux and Associated Conditions

The early results of the open Dor and Toupet repairs for primary gastroesophageal reflux disease (GERD) are reported in Table 25-2.11,16-29,21-26,28-36 Mortality and morbidity rates for a Dor repair are low. Postoperative dysphagia and the gas bloat syndrome are infrequent except in one series.21 Some abdominal discomfort, localized below the left costal margin, may appear after larger meals during the first 3 to 4 months after the operation. This symptom is probably the result of the distention of the gastric fundus. With the Toupet repair, mortality in the reported series is nil and morbidity varies from 0 to 28.5%. The highest morbidity (28.5%) was reported by Bensoussan and associates36 in a group of 112 children with a mean age of 39 months (range, 2 months-19 years). Of these patients, 30% were neurologically impaired. Temporary dysphagia is infrequent and disappears spontaneously in most cases in the first postoperative months. Other postoperative symptoms such as abdominal discomfort and gas bloat syndrome are very infrequent in reported case series. Long-term results of Dor and Toupet repairs are shown in Table 25-3.11,17,18,21-24,26,29-38 With the Dor repair, it appears

that the incidence of recurrent hernia or reflux doubles in the presence of reflux complications such as stenosis or severe esophagitis.21 With the Toupet repair, satisfactory results are obtained in 83.3% to 96.5% of cases except in two series when they were 56.5%28 and 56%.26 Early and intermediate-term results of laparoscopic Dor and Toupet procedures are reported in Tables 25-4 and 25-5.39-44 The Dor and Toupet repairs were conceived as additions to the Heller myotomy for the treatment of achalasia. In the aperistaltic patient, an efficient—but not too efficient—fundoplication acts to prevent or diminish postoperative gastroesophageal reflux after myotomy. Compared with total 360-degree fundoplication, relatively weak pressure is applied over a long segment of abdominal esophagus. The Dor antireflux procedure is most frequently used with the Heller myotomy. A few case series regard this as the surgical treatment of primary gastroesophageal reflux. Early results are probably influenced by the learning curve. Clinical results after a mean follow-up of 12 to 22 months appear satisfactory. Overall, early short-term results of partial fundoplications are good to excellent, with patient satisfaction rates exceed-

TABLE 25-2 Dor and Toupet Open Fundoplications: Early Results*

Procedure

Postoperative Deaths (%)

Surgical Complications*† (%)

51§

Dor

3.9

17.6

22

Dor

0

67

Dor

1.5

‡

32

Dor

0

‡

146

Dor

0

‡

‡

‡

‡

37§

Dor

0

16

27

‡

‡

86

Dor

0

8

70

1150§

Dor

0.09

0.7

‡

No. Cases

Author (Year) Dodat et al29 (1978) 30

Anselmetti et al

(1980)

Mir et al18 (1986) Mussa et al17 (1986) Zaragosi Moliner et al

31

(1989)

Lefebvre et al32 (1989) Juan et al21 (1992) Ashcraft and Holder11 (1993)

Dysphagia (%)

Abdominal Discomfort (%)

Gas Bloat Syndrome (%)

‡

‡

‡

4.5

23

‡

3

15

1.5‡

4.5

0

0

0 ‡

0

0 1

Guarner et al22 (1980)

135

Toupet

0

0

Galmiche et al28 (1983)

25

Toupet

0

0

‡

‡

‡

‡

‡

‡

‡

33

Gutierrez et al

(1988)

Thor and Silander23 (1989)

2.9

90

Toupet

0

0

‡

19

Toupet

0

21

‡

0

‡

Segol et al34 (1989)

18

Toupet

0

5.5

Vara-Thorbeck et al35 (1989)

99

Toupet

0

0

‡

‡

‡

Lundell et al16 (1991)

33

Toupet

0

0

10

15

‡

Kabbej et al24 (1992)

251

Toupet

0

15.5

18

Michot et al25 (1992)

45

Toupet

0

0

13.3

112§

Toupet

0

28.5

7

28

Toupet

0

7

38

Bensoussan et al36 (1994) Ottignon et al26 (1994)

0

0

9 ‡

0

0.3 ‡

1.7 15

‡ ‡

*First 30 days after surgical treatment. † Surgical complications included incisional hernia, wound infection, leakage, bowel obstruction, thromboembolism, pleuritis, bronchopneumonia, and splenectomy. ‡ Data not reported. § Pediatric patients.

Chapter 25 Open Toupet and Dor Partial Fundoplications

TABLE 25-3 Dor and Toupet Open Fundoplications: Late Results No. Cases

Author (Year) Dodat et al29 (1978) Anselmetti et al

30

(1980)

Aulagnier et al37 (1980) Maillet

38

Mir et al

(1986)

Mussa et al17 (1986) Zaragosi Moliner et al31 (1989) Lefebvre et al

32

(1989)

Juan et al21 (1992) Ashcraft and Holder11 (1993) 22

Guarner et al

(1980)

Satisfactory Results (%)

Poor Results (%)

†

82.3

7.7

86.3

13.7

Dor

†

89.9

10.1

*

Dor

†

91

51*

Dor

22

Dor

59

(1980) 18

Follow-up (mo)

Procedure

48

9

67

Dor

42

94

32

Dor

38

83.7

146

Dor

†

6 16.3

92

8

37*

Dor

74

88

8

86

Dor

120

95

12

362*

Dor

12-96

90.3

5

135

Toupet

60-120

56.5

Galmiche et al28 (1983)

25

Toupet

21

95

43.5

Gutierrez et al33 (1988)

90

Toupet

12-108

95

5

19

Toupet

60

95

5

23

Thor and Silander 34

Segol et al

(1989)

(1989)

Vara-Thorbeck et al35 (1989) 24

Kabbej et al

(1992) 36

Bensoussan et al

(1994)

Ottignon et al26 (1994)

9.7

18

Toupet

24

83.3

99

Toupet

60

94

16.7 6

251

Toupet

32

96.5

3.5

112*

Toupet

48

90.5

28

Toupet

28

56

9.5 44

*Pediatric patients. Data not reported.

†

TABLE 25-4 Dor and Toupet Laparoscopic Fundoplications: Early Results

No. Cases

Author (Year)

Procedure

Mean Operative Time (hr)

Postoperative Deaths (%)

Laparotomic Conversion (%)

Mean Hospital Surgical Stay Complications* (days)

Kleimann and Halbfass39 (1998)

25

Dor

†

0

†

†

†

Watson et al40 (1999)

54

Dor

1

0

7.4

20.33

3

100

Toupet

3.2

0

0

10

2.8

32

Toupet

2.5

0

0

15.6

3

100

Toupet

†

0

1

4

4

41

Jobe et al

(1997) 42

Wetscher et al

(1997)

Lefebvre et al43 (1998)

Dysphagia (%) 0 1.8 20 3.1 †

Abdominal Discomfort (%) †

†

6 † †

*Esophageal perforation, delayed small bowel perforation, gastric perforation, intra-abdominal hematoma, opening of the pleura, deep venous thrombosis, acute respiratory distress syndrome, delayed gastric emptying, pleural effusion and pneumonia, acute paraesophageal herniation, severe postoperative dysphagia, urinary retention, respiratory atelectasis, and pneumothorax. † Data not reported.

ing 80% in most studies at 5 years. Longer-term follow-up in several studies reveal recurrence of heartburn and volume regurgitation symptoms in 8% to 20% of patients. There have been several studies both in the open and laparoscopic eras directly comparing full and partial fundoplication. The most widely quoted is a study from Lundell and associates45 that randomized 137 patients between mod-

ified Toupet (72 patients) and Nissen-Rosetti (65 patients) procedures using an open technique. Follow-up analysis at a mean of 3 years revealed an incidence of recurrent reflux of 6% versus 5% but a greater rate of dysphagia (39% versus 9%, P = .005) at 3 months, favoring the partial fundoplication. This difference in dysphagia patterns disappeared after further follow-up.

303

304

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 25-5 Dor and Toupet Laparoscopic Fundoplications: Intermediate-Term Results

Author (Year)

No. Cases

Kleimann and Halbfass39 (1998) 40

Watson et al

(1999)

Jobe et al41 (1997) 42

Wetscher et al 44

Lund et al

(1997)

(1997)

Lefebvre et al43 (1998)

25 54

Procedure

Follow-up (mo)

Satisfactory Results (%)

Dor

16.7

94

6

Dor

Poor Results (%)

6

90

10

100

Toupet

22

71

29

32

Toupet

15

96.9

46

Toupet

6

91

9

100

Toupet

12

93

7

Hagedorn and colleagues46 randomized 110 patients to open Nissen-Rosetti versus modified Toupet procedures with a median follow-up of 11.5 years. Control of reflux was similar (88% versus 92%), and there was no significant difference in dysphagia. The total fundoplication group did, however, have a greater prevalence of gas bloat symptoms. Zornig and associates47 prospectively randomized 200 patients into groups based on their preoperative manometry. The postoperative requirement for esophageal dilation and reoperation was not substratified to the groups based on dysmotility, however. Dysphagia was more frequent after Nissen (30%) versus Toupet (11%) procedures. A larger portion of complete fundoplications required reoperation, the vast majority (10/14) for crural disruption. Farrell and associates48 prospectively followed a cohort of patients stratified to complete versus partial fundoplication based on esophageal motility. Heartburn and regurgitation improved in both groups at 6-week follow-up, but dysphagia was greater in Nissen patients (45% versus 25%). At 1-year follow-up, dysphagia rates equilibrated but patients undergoing the Toupet fundoplication developed a higher incidence of heartburn (18% versus 8%) and regurgitation (20% versus 8%) than those who underwent the Nissen repair. Although poor motility was originally thought to be an indication to perform a partial fundoplication, newer data are beginning to dispute this idea. Fernando and coworkers49 also showed an increased incidence of recurrent reflux over a 19.7-month follow-up shown through increased proton pump inhibitor usage (38% versus 20%) and patient dissatisfaction (21% versus 7%) in partial versus total fundoplications. There was a significantly increased incidence of motility disorders in the 44 patients who had the Toupet fundoplication (37%) than in the 163 patients with the Nissen repair (8.6%). However, on subgroup comparison, no difference in preoperative symptoms or medication usage was observed. This late failure with recurrent reflux symptoms in partial fundoplications was also observed by Horvath and associates.50 Chrysos and colleagues51 prospectively randomized 33 patients with documented esophageal dysmotility (lowamplitude contractions <30 mm Hg) into Nissen or modified Toupet groups. Results at 3 months for dysphagia (57% versus 16%) and gas bloat (50% versus 21%) favored the

3.1

partial fundoplications. At 12 months the results were equivalent (16% versus 14%). Oleynikov and coworkers52 found similar results in a prospective evaluation of 96 (39 partial and 57 total) fundoplication patients. They also found an improvement in dysphagia and distal esophageal propulsive amplitudes over time in the total but not in the partial fundoplication groups. Most recently, Patti and associates53 reported on the long-term follow-up of patients tailored to partial or total fundoplication by preoperative manometry versus all patients treated with a loose floppy Nissen fundoplication regardless of manometry. Between 1992 and 2002 they reviewed the pH and manometry data of 235 tailored and 122 nonselective patients. The tailored group showed a higher rate of recurrent reflux (19% versus 4%) and similar dysphagia rates. In general, a properly performed short, loose total fundoplication displays superior long-term results for control of regurgitation and heartburn-related reflux symptoms. Equivalent rates for dysphagia and gas bloat can also be obtained. The need for tailored fundoplications should rarely arise.

COMMENTS AND CONTROVERSIES For most surgeons open partial fundoplication is of historic interest. However, an understanding of its construction and of the indications for its use is necessary even in this period dominated by laparoscopic Nissen fundoplication. Many scenarios can be imagined in which an open partial fundoplication may be necessary. Perhaps its main use is for reoperation in a patient with an aperistaltic esophagus. It is interesting that results of partial fundoplication have been so much better in countries other than the United States. This may be the result of tailoring, that is, selection of partial fundoplication for the poorest candidates for antireflux surgery. However, this is just as likely due to construction of a shorter, less robust fundoplication in North America. Although partial fundoplication can produce similar reflux control with less early dysphagia than a total fundoplication, in most surgeons’ hands control of reflux is suboptimal. The few patients with transient dysphagia or postprandial symptoms after Nissen fundoplication are more than balanced by those with recurrent reflux after partial fundoplication. T. W. R.

chapter

LAPAROSCOPIC TOUPET FUNDOPLICATION

26

Lee L. Swanström

Key Points ■ Laparoscopic Toupet repairs are the second most common anti-

reflux surgery. ■ The main indication for partial fundoplication is for primary motility

repairs. ■ Use of the Toupet repair for primary or severe reflux is

controversial. ■ The original 180-degree repair described by Andre Toupet has

been modified and is usually a 270-degree fundoplication with some crural closure.

as dysphagia, inability to belch or vomit, and gas-bloat syndrome.2 There is certainly evidence from the open experience with the Toupet repair to support such a hypothesis. Both long-term outcome studies and comparative studies with the Nissen repair show that variations of the Toupet procedure, whether done open or laparoscopically, provide excellent symptomatic results with a low incidence of postoperative side effects as long as the patient is appropriately selected.1,3,4 Since the laparoscopic Toupet procedure was first reported by Cuschieri and colleagues (1993), a significant number of cases have been performed worldwide, and it remains the second most commonly performed antireflux procedure after the Nissen procedure. HISTORICAL READINGS

There has been a general trend over the past decade toward the use of the “floppy Nissen” as the primary antireflux surgery for all patients with gastroesophageal reflux. Partial fundoplications, which were thought to be necessary for any degree of esophageal dysmotility or to be a more physiologic alternative to a 360-degree wrap, are generally used less and less. Partial fundoplications such as the Toupet procedure are, however, universally used as an adjunct to Heller myotomy for severe esophageal dysmotility. Even though the “tailored approach” has become less popular there are centers with a long experience in use of the Toupet repair that report excellent long-term results. It is therefore recommended that surgeons with an interest in antireflux surgery be familiar with the laparoscopic Toupet procedure so that they have this “tool” in their armamentarium when it is needed.

HISTORICAL NOTE The introduction of laparoscopic Nissen fundoplication in 1991 by Dallemagne and associates initiated a renaissance in the surgical treatment of reflux disease and other swallowing disorders. After the resulting rapid increase in patient referrals, many investigators began adapting other (non-Nissen) procedures to the laparoscopic approach. These included laparoscopic versions of the Belsey, Hill, Dor, and Toupet procedures. These repairs were chosen either for specific clinical indications or because of traditional institutional bias. Partial fundoplications, most notably modifications of Toupet’s original repair, were particularly attractive to surgeons based on the desire to provide their “minimally accessed” patients with a “minimally morbid” procedure.1 There was a general feeling that the short surgical recovery of laparoscopic repairs would make patients less likely to accept the side effects associated with the Nissen repair, such

Cuschieri A, Hunter J, Wolfe B, et al: Multicenter prospective evaluation of laparoscopic antireflux surgery. Surg Endosc 7:505-510, 1993. Toupet A: Technique d’oesophago-gastroplastie avec phrenogastropexie appliquée dans la cure radicale des hernies hiatales et comme complement de l’operation d’Heller dans les cardiospasmes. Mem Acad Chir 89:394-395, 1963.

GENERAL DESCRIPTION The laparoscopic Toupet repair has become a fairly standardized procedure but is seldom performed exactly as originally described by Andre Toupet in 1963. Adopting the modifications described by Boutelier and Jonsell5 in 1992, the most common current repair is a 270- to 340-degree posterior wrap that is fixed to both the right and left crura. The resulting exposed strip of anterior esophagus creates a “hinge-like” mechanism to reduce bolus transit resistance (Fig. 26-1). A standard 5-port laparoscopic access is used. Traditionally, the hiatus is left open or only loosely closed, although other variations of the wrap, such as that of Lind and colleagues,6 close the hiatus in a standard fashion. The sides of the fundus are sutured to the esophagus at the 10-o’clock and 2-o’clock positions to achieve a partial wrap 3 to 4 cm long (Fig. 26-2).

INDICATIONS AND DIAGNOSIS Indications for the Toupet repair are summarized in Table 26-1. The traditional and most commonly applied indication for the Toupet fundoplication is a transabdominal antireflux procedure for patients with esophageal motility disorders. This can be as an adjunct to the primary surgical treatment of the disorder (e.g., after an esophagomyotomy for a named motility disorder) or as a temporizing, nonobstructive treat305

306

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 26-1 Indications for the Laparoscopic Toupet Fundoplication General Indications Documented gastroesophageal reflux Adequate esophageal length Ability to tolerate general anesthesia Indications for Toupet Versus Nissen Repair Poor esophageal body motility (peristaltic amplitudes <30 mm Hg, >50% dropped or simultaneous waves) Following Heller’s myotomy Severe aerophagia Inadequate gastric fundus for a full wrap Tubular stomach Previous gastric surgery Previous splenorrhaphy

FIGURE 26-1 The most common current modified Toupet repair uses a 270- to 340-degree posterior wrap that is fixed to both the right and left crura. The resulting exposed strip of anterior esophagus creates a “hinge-like” mechanism to reduce bolus transit resistance.

ment for reflux patients with nonspecific peristaltic dysfunction. Use of the Toupet procedure as a routine antireflux procedure for patients with normal motility is practiced at some institutions but remains somewhat controversial because of reports describing a higher rate of breakthrough reflux. In addition to these general indications there are rare specific instances of reflux disease that are perhaps better treated with a Toupet repair. These include patients with psychological issues who would be unlikely to tolerate even the transient side effects of a standard fundoplication or patients with an inadequate amount of fundus to achieve a tensionfree, 360-degree wrap such as might happen after previous gastric resection or splenic surgery.7 Contraindications include the inability to undergo general anesthesia, inability to give informed consent, and any condition that might make laparoscopy dangerous, such as a hostile abdomen from previous upper abdominal surgeries or the inability to tolerate a carbon dioxide pneumoperitoneum due to profound pulmonary carbon dioxide retention. Pregnancy, morbid obesity, and a shortened esophagus represent relative contraindications, and the appropriateness of laparoscopy for such cases should be assessed on an individual basis. Preoperative workup for any patient being considered for a laparoscopic Toupet repair is the same as for any patient being evaluated for antireflux surgery.8 Particular attention should be paid to the preoperative motility test because the procedure is typically done for patients with a motility disorder, and the type and severity of the disorder may be relevant in planning the surgical approach. Motility tracings should, in particular, be looked at to try to differentiate a primary motility disorder versus distal body hypocontractility, which is often simply a result of chronic insult from the refluxate (Fig. 26-3). Increasing evidence indicates that acquired esophageal motility disorders will reverse after

treatment of the reflux.9-11 Upper endoscopy should always be obtained to grade tissue damage, rule out premalignant changes, and assess the lower esophageal valve on retroflexion.12 Any other anatomic factors that might complicate the surgery (e.g., shortened esophagus, esophageal diverticulum, paraesophageal hernia) are well delineated by a barium swallow. Finally, a 24-hour pH study should be obtained in all patients, especially for patients with atypical symptoms, to help arrive at the correct diagnosis.13 Even in patients with typical symptoms, we find that a preoperative 24-hour pH test provides important preoperative information that may alter the surgical approach.14,15 This is particularly true when the preoperative 24-hour pH test documents an extremely high DeMeester score because the partial fundoplication alone is more likely to fail over the long term (Horvath et al, 1999).16 Such patients may, in fact, be candidates for an adjuvant procedure such as a vagotomy or a gastric emptying procedure17 or should at least be counseled before surgery that they may still need to take peptic medications. A final reason to perform 24-hour pH testing in all patients is to obtain a baseline value that will allow future objective followup testing for patients who experience postoperative problems.15

SURGICAL TECHNIQUE After appropriate consent is obtained, the patient is admitted, an intravenous line is started, preoperative antibiotics are given, and deep venous thrombosis prophylaxis is initiated. After the patient is intubated for general anesthesia an oral gastric tube is placed. For the most part these procedures take less than 2 hours so a urinary catheter is not required. The patient is positioned with both arms outstretched on well-padded armboards at less than a 90-degree angle. A split-leg table is used to allow the camera person to sit comfortably between the patient’s legs during the procedure. The surgeon stands on the patient’s left, and the assistant stands on the patient’s right (Fig. 26-4). All port sites are preinfiltrated with bupivacaine. The initial port site, for the laparoscope, is placed 15 cm below the xiphoid process and 2.5 cm to left of the midline. Depending on the diameter of the 45-degree angled laparoscope available, this port will be either 5 mm or 10 mm. A

Chapter 26 Laparoscopic Toupet Fundoplication

270degree wrap

Wrap sutured to crura

Sutured posteriorly to crura

FIGURE 26-2 Current configuration of the modified laparoscopic Toupet repair. Inset, A 270-degree posterior wrap sewn posteriorly to the loosely closed crura. (© CORINNE SANDONE.)

quick visual exploration is made to ensure that no adhesions or other pathologic process would complicate placement of the additional access ports. Because most current laparoscopic instruments are 5 mm, most access ports can also be 5 mm in diameter. Typical port placement is shown in Figure 26-5. The left lobe of the liver is elevated with an atraumatic retractor, which is then secured to a table-mounted instrument holder. The assistant retracts the stomach downward using an atraumatic grasper on the epigastric fat pad, and the surgeon divides the hepatogastric ligament using either bipolar shears or the ultrasonic coagulating shears. Fifteen percent of patients have a left hepatic arterial branch coming from the left gastric artery and running through the hepatogastric ligament. This accessory artery is spared if it is greater than 2 or 3 mm, since in rare instances division can lead to hepatic ischemia. The phrenoesophageal ligament is divided after the right crus has been identified. Both the right and left crural limbs are dissected free anteriorly and posteriorly to the point where they fuse. The mediastinal esophagus is freed with blunt and sharp dissection to obtain 4 cm of tension-free intra-abdominal esophageal length. The short gastric vessels along the upper third of the gastric fundus are divided with the ultrasonic coagulating shears or with clip ligation and division. This allows the fundus to be rotated medially, allowing direct access to the critical retrogastric attachments, which are then divided. The retroesophageal window is created carefully behind the posterior vagus nerve under the direct vision achieved with the angled laparoscope. The posterior wall of the fundus is grasped near the short gastric vessels and brought beneath the esophagus.

Using the fundus as an esophageal retractor, the assistant exposes the posterior hiatus to allow the crural stitches to be placed (Fig. 26-6). Starting caudad, each suture includes both the posterior wrap and crura. Unlike the originally described Toupet repair, which bridged the hiatus with the gastric fundus, we prefer to reapproximate the right and left crura with the posterior sutures to minimize transhiatal migration, which appears to be more common with the laparoscopic approach. The crural closure should be loose in the case of patients with poor body motility, to prevent any crural impingements and resistance to esophageal emptying. Subsequent sutures are placed from the right and left fundal wraps to the corresponding crura. Finally, three or four interrupted sutures are placed from the esophagus to the left and right wrap at the 10-o’clock and 2-o’clock positions to create a wrap between 3 and 4 cm long. This is done with a 56-Fr bougie in place to accurately gauge the 270 to 340 degrees of the fundoplication (see Fig. 26-2). All sutures should be of permanent materials, and intracorporeal tying techniques are preferred because they are less traumatic to the tissues.18 The abdomen is then de-insufflated, and the 10-mm fascial defect is closed. A nasogastric tube is not routinely left in place. Postoperatively, the patient takes nothing by mouth until free of nausea and then is advanced to a pureed diet as tolerated. Antiemetic agents are liberally used to prevent postoperative retching or vomiting, which may cause herniation of the wrap. The patient is typically discharged home on postoperative day 1. Heavy lifting is restricted for 4 weeks after surgery. The patient is told to expect dysphagia for 2 to 4 weeks and to avoid bread and meats during this time.

307

308

Section 4 Gastroesophageal Reflux and Associated Conditions

Swallow # 7

O 200.0 s

19.0

Swallow # 7

443.6s

O

0.0 0.0 200.0

21.0

118.3 0.0 50.0

35.0

0.2 1.1 50.0

39.0

⫺9.8 2.1 50.0

43.0

⫺10.5 2.4

48.0

5.6 0.0

eSleeve

50.0 4.6

54.0

1.4

Gastric

50.0

0.0

5.0 sec

A FIGURE 26-3 Motility tracing.

Chapter 26 Laparoscopic Toupet Fundoplication

We... 19

WS (9) Wet Swallo...

WS (10) Wet Swallo...

WS (11) Wet Swallo...

WS (... Wet... 18

mm Hg

80 60 40 20 0.0 PRESSURE 2 24

23

PRESSURE 3 29

28

PRESSURE 4 34

33

PRESSURE 8 39

38

mm Hg

80 60 40 20 0.0

mm Hg

80 60 40 20 0.0

mm Hg

80 60 40 20 0.0

mm Hg

80 60 40 20 0.0

03:30

03:45

04:00

04:15

B FIGURE 26-3, cont’d

04:30

04:45

05:00

t

309

310

Section 4 Gastroesophageal Reflux and Associated Conditions

Anesthetist

eo Vid nitor mo

eo Vid nitor mo Assistant

Surgeon's ports 5 mm

Liver retractor Surgeon

Babcock clamp 5 mm

Camera 10 mm

FIGURE 26-5 Optimal port placement is crucial for efficient laparoscopic antireflux surgery. Shown are the typical placements for a laparoscopic Toupet fundoplication. (© CORINNE SANDONE.) Scrub nurse

Camera operator

Back table

FIGURE 26-4 Room setup and patient position for the laparoscopic Toupet procedure. (© CORINNE SANDONE.)

RESULTS Since first described by Cuchieri and colleagues in 1993, the laparoscopic Toupet has been shown to be a safe procedure with low operative morbidity. Reported operative complications include esophageal or gastric perforation, vagal nerve injury, and sequelae due to trocar insertion. Large series have reported perioperative morbidity rates between 10% and 15% (Bell et al, 1999).1,19-23 Postoperative success rates vary according to the indications for the surgery. Oddly enough, patients with profound esophageal motility disorders seem to have better success than do those with normal motility. For instance, the Toupet procedure has gained wide popularity as an adjunct antireflux procedure after a laparoscopic Heller myotomy based both on theoretical considerations and on reported good results.24 Whether it is a better antireflux procedure than the traditional Dor

procedure after a Heller myotomy is not known. Similar good results have been reported in series using both types of laparoscopic partial fundoplications after esophagomyotomy.25-27 Only one study has directly compared the two procedures.28 This study showed improved reflux control after myotomy with the Toupet repair compared with the Dor procedure. The study was, however, retrospective and the numbers were barely significant. The ability to perform antireflux surgery laparoscopically has created new expectations among surgeons and their patients. Surgeons are often concerned that their patients and their referral physicians will not tolerate the transient side effects associated with the Nissen procedure. In an effort to minimize postoperative dysphagia and the inability to belch or vomit, these practitioners have advocated routine use of the Toupet procedure as a more physiologic alternative to the Nissen repair in all patients with gastroesophageal reflux disease (GERD).19,29 Early results from these centers have shown encouragingly low rates of postoperative side effects and good control of reflux symptoms. Others, however, have shown unacceptable rates of postoperative reflux, which is frequently asymptomatic. Bell and coworkers,23 in a 1999 report, documented a 50% symptomatic failure rate in 82 laparoscopic Toupet patients operated on for severe GERD at a 30-month follow-up. Farrell likewise showed twice the heartburn recurrence rate with the Toupet repair and no difference in dysphagia rates at 1-year follow-up.30 Fernando and Luketich reviewed their experience with 163 laparoscopic Nissen repairs compared with 43 laparoscopic Toupet repairs and found that whereas short-term

Chapter 26 Laparoscopic Toupet Fundoplication

TABLE 26-2 Results of the Laparoscopic Toupet Procedure in 100 Consecutive Patients Studied Prospectively (Follow-up at 22 Months) Symptom Follow-up Dysphagia 9% (1% dilation) Heartburn 20% (17% on medication, 3% surgery revised to a Nissen) Posterior crural sutures

Objective Follow-up Endoscopy 18% esophagitis Manometry 23 mm Hg mean postoperative pressure (130% increase) 24-hr pH 51% abnormal findings (50% asymptomatic) Data from Jobe BA, Wallace J, Hansen PD, Swanström LL: Evaluation of laparoscopic Toupet fundoplication as a primary repair for all patients with medically resistant gastroesophageal reflux. Surg Endosc 11:1080-1083, 1997.

for laparoscopic fundoplications is the “tailored” approach, which calls for a short floppy Nissen repair for patients with normal motility and a laparoscopic partial fundoplication, most commonly the Toupet repair, for all patients with markedly decreased esophageal body motility.40,41 FIGURE 26-6 Visualization for the placement of the posterior crural sutures is obtained by using the fundal wrap as an esophageal retractor and with a 45-degree angled laparoscope. (© CORINNE SANDONE.)

GERD results were similar, at a median follow-up of 20 months, 38% of the Toupet group were on proton pump inhibitors compared with 20% in the Nissen group.31 Our group has shown a 49% failure rate by 24-hour pH testing at a mean follow-up of 2 years.32 This is in spite of documentation of an adequate Toupet fundoplication in the majority of patients (Horvath et al, 1999) (Table 26-2).16 The weakness of the Toupet repair, at least in patients with normal esophageal motility, seems to be its decreased lower esophageal sphincter augmentation pressures, which result in less reverse flow prevention.33 Most surgeons, therefore, reserve the use of the Toupet fundoplication for patients with GERD and disordered esophageal motility (Erenoglu et al, 2003).34-37 This group of patients presents a particularly difficult therapeutic dilemma. Reflux tends to be particularly severe in patients with delayed esophageal clearance, yet these patients are considered to be less able to tolerate a “heavy-duty” antireflux procedure without unacceptable rates of postoperative dysphagia.38 Many groups, therefore, choose the Toupet fundoplication for patients with poor motility, accepting a higher postoperative reflux rate as the price of an acceptable postoperative dysphagia rate. Some investigators have theorized that a short floppy Nissen fundoplication would be tolerated in patients with poor esophageal motility and report limited clinical data to support that position.39 There are, however, no definitive outcome studies that show acceptable postoperative dysphagia rates with the Nissen repair in this complex patient group, and there exists the possibility that these patients would suffer gradual esophageal failure over the very long term. The current “gold standard”

FUTURE TRENDS The almost universal acceptance of the laparoscopic approach for Heller’s myotomy and fundoplication has created a renewed, and sometimes increased, interest in the Toupet repair. Several clinical questions, however, need to be answered. Although it is generally accepted that a partial fundoplication should accompany a Heller myotomy, it has never been documented whether the Dor or the Toupet fundoplication provides better reflux protection with the least degree of esophageal outflow obstruction. Obviously, this question can be answered only by a well-constructed, prospective clinical study. The true effectiveness of the laparoscopic Toupet procedure as an antireflux surgical procedure also needs to be documented over the long term. Outcome studies with limited short-term follow-up and subjective postoperative assessment are common and frequently favorable in their assessment of the technique. These studies are flawed, because they are weighted toward assessment of the shortterm transient side effects common with any antireflux surgery, such as dysphagia and inability to belch. Because of its unique characteristics, the Toupet repair has always fared well in such assessments. Proof of long-term success in controlling reflux is much more difficult. Objective postoperative testing is needed because as many as 50% of patients with postoperative reflux are asymptomatic.15 It is also difficult to recruit and monitor patients for the 5- to 10-year follow-up that is needed. At least four studies with objective follow-up in the short to intermediate term have indicated higher rates of failure with the laparoscopic Toupet repair when compared with the Nissen (Bell et al, 1999; Horvath et al, 1999).9,30,42,43 These authors concluded that in spite of lower postoperative side effects, laparoscopic Toupet fundoplication should be reserved for patients with significant primary

311

312

Section 4 Gastroesophageal Reflux and Associated Conditions

esophageal motility disorders. However, this dogma is increasingly questioned: Is the Toupet procedure really superior to a complete fundoplication in patients with esophageal motor dysfunction? Several studies have indicated that a short floppy Nissen wrap is well tolerated in these patients.11,44-47 Considering the diminished reflux control of the Toupet repair, this is certainly an outcome study worth initiating.

SUMMARY The laparoscopic Toupet repair was first described in 1993 and has achieved wide acceptance as a procedure in patients with poor esophageal motility and GERD. It has also been widely adopted as an adjuvant procedure after a laparoscopic Heller myotomy. It is certainly associated with a low incidence of annoying postoperative side effects, including dysphagia and the inability to belch, which makes it very suited to patients undergoing a minimally invasive surgical procedure. In addition, there are subsets of patients who should not have a Nissen fundoplication for psychological, anatomic, or physiologic reasons or because of failure of a previous Nissen procedure. It must be realized, however, that the Toupet repair may be associated with lower long-term success rates in controlling reflux. Therefore, surgeons should carefully consider the relative benefits and disadvantages of the laparoscopic Toupet technique before selecting it for their patients (Granderath et al, 2002).48

COMMENTS AND CONTROVERSIES The authors have presented a comprehensive review of the shortand intermediate-term outcomes after the partial laparoscopic Toupet fundoplication. The equivalent results that were reported

in the early short-term analysis of the Toupet partial fundoplication for GERD were overridden by the disappointing longer term results with an unacceptably high rate of pathologic acid reflux. This certainly is a potent reminder for surgeons and gastroenterologists to be cautious when reporting short-term outcomes for any GERD treatment management plan. The Toupet partial fundoplication maintains an important role in the management of reflux in the patient population with significant esophageal motility, but strong consideration should be given to a 360-degree wrap in patients with normal motility. J. D. L.

KEY REFERENCES Bell RCW, Hanna P, Mills MR, Bowrey D: Patterns of success and failure with laparoscopic Toupet fundoplication. Surg Endosc 13:11891194, 1999. Erenoglu C, Miller A, Schirmer B: Laparoscopic Toupet versus Nissen fundoplication for the treatment of gastroesophageal reflux disease. Int Surg 88:219-225, 2003. Granderath FA, Kamolz T, Schweiger UM, et al: Quality of life and symptomatic outcome three to five years after laparoscopic Toupet fundoplication in gastroesophageal reflux disease patients with impaired esophageal motility. Am J Surg 183:110-116, 2002. Horvath KD, Jobe BA, Herron DM, Swanström LL: Laparoscopic Toupet fundoplication is an inadequate procedure for patients with severe reflux disease. J Gastrointest Surg 3:583-591, 1999. Katkhouda N, Khalil MR, Manhas S, et al: Andre Toupet: Surgeon technician par excellence. Ann Surg 235:591-599, 2002. Richardson WS, Trus TL, Thompson S, Hunter J: Nissen and Toupet fundoplications effectively inhibit gastroesophageal reflux irrespective of natural anatomy and function. Surg Endosc 11:261263, 1997.

chapter

OPEN GASTROPLASTY

27

F. Griffith Pearson

Key Points ■ Gastroplasty is an esophageal lengthening technique that reduces

tension on an antireflux repair in patients with “short esophagus.” ■ Diagnosis of short esophagus is made from information gained

through barium esophagography, esophagoscopy, manometry, and intraoperative findings. ■ Removal of the “fat pad” follows the technique used during highly selective vagotomy. ■ A gastric tube of 4 to 5 cm of uniform diameter (48 Fr) is created with a linear cutting stapler.

DEFINITION Gastroplasty is an esophageal “lengthening” technique that is designed to reduce or abolish undue tension on an antireflux repair in patients with acquired esophageal shortening. A tube of stomach is fashioned from the lesser curvature side of the cardia in continuity with the distal esophagus. At completion, the distal end of this “gastroplasty tube” is dealt with as if it were the esophagogastric junction. The distal esophagus has therefore been lengthened, and the potential for tension on any subsequent antireflux repair is avoided. This technique of gastroplasty is not to be confused with the various operations for the management of morbid obesity.

HISTORICAL NOTE The operation of gastroplasty was described by Leigh Collis in 1957 (Fig. 27-1). He combined gastroplasty with his own “Collis” technique of hiatal hernia repair. To quote Collis, the addition of gastroplasty was “designed to help patients with hiatus hernia associated with short esophagus.” In 1961, Collis reported on observations from his experience with 32 patients.1 I visited Mr. Collis in Birmingham in 1960 and observed some of the patients managed by this technique. In Toronto, beginning in 1963, we began to add gastroplasty to the antireflux repair in selected patients, and we reported our initial experience with this technique in 1971.2 We modified Collis’ original operation as follows: exposure was restricted to a left thoracotomy rather than a left thoracoabdominal incision. The gastroplasty tube was fashioned so that the tube diameter remained the same throughout its length, and we added a Belsey Mark IV repair rather than a Collis repair to the reconstruction (Fig. 27-2).2 Subsequent modifications include the techniques of “uncut gastroplasty,” first described by Langer in 19733 and subse-

quently by Demos and colleagues in 1975 and 19844,5; the use of a Nissen type fundoplication rather than a Belsey Mark IV hiatal repair reported by Henderson in 19776 and by Orringer and Sloan in 19777; and an open transabdominal technique requiring the use of the smallest-diameter end-toend anastomosis (EEA) stapler described by Steichen in 1986.8 HISTORICAL REFERENCES Collis JL: Gastroplasty. Thorax 16:197, 1961. Demos NJ, Smith N, Williams D: A gastroplasty for short esophagus and reflux esophagitis. Ann Surg 181:178-181, 1975. Demos NJ: Stapled uncut gastroplasty for hiatal hernia: 12 year followup. Ann Thorac Surg 38:393-398, 1984. Henderson RD: Reflux control following gastroplasty. Ann Thorac Surg 24:206, 1977. Langer B: Modified gastroplasty: A simple operation for reflux esophagitis with moderate degrees of shortening. Can J Surg 16:1, 1973. Orringer MB, Sloan H: Complications and failings of combined Collis-Belsey operation. J Thorac Cardiovasc Surg 74:726, 1977. Pearson FG, Langer R, Henderson RD: Gastroplasty and Belsey hiatus hernia repair. J Thorac Cardiovasc Surg 61:50, 1971. Steichen FM: Abdominal approach to the Collis gastroplasty and Nissen fundoplication. Surg Gynecol Obstet 162:372-374, 1986.

INDICATIONS Gastroplasty is indicated as an addition to any antireflux operation (hiatal hernia repair) when it is anticipated that the repair alone would result in an unacceptable level of tension and an increased risk of failure of the antireflux reconstruction. All of the commonly used standard repairs restore a segment of distal esophagus to an intra-abdominal position (Nissen, Belsey, and Hill). In actual fact, there is little or no esophagus extending beyond the margins of the hiatal canal. In the anatomically normal situation, the esophagogastric junction lies within the channel of the diaphragmatic hiatus (Fig. 27-3). All standard repairs exaggerate the length of the intra-abdominal segment of esophagus and are assumed to be under some degree of tension. An exception may be the Hill repair, in which the reconstruction (posterior gastropexy) begins at the esophagogastric junction and extends distally along the lesser curvature side of the stomach. The primary indication for the addition of gastroplasty is acquired shortening caused by mural scarring, with vertical scar contracture secondary to peptic esophagitis. This complication occurs as a feature of the most advanced stages of reflux esophagitis, which include confluent ulceration, peptic stricture, acquired columnar-lined esophagus, and massive, paraesophageal hernia. 313

314

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 27-1 Diagrammatic representation of the original Collis gastroplasty. (ADAPTED FROM COLLIS JL: GASTROPLASTY. THORAX 16:197, 1961.)

Short esophagus

Position of clamps

Cardia

Hiatal hernia

Broad neck through diaphragmatic hiatus

Gross degrees of shortening are easily recognized in the barium radiograph, at endoscopy, and by the surgeon at the time of the operation. Subtle degrees of shortening, however, may be difficult to appreciate. The diagnosis of acquired short esophagus is made from observations obtained through contrast radiographs, esophagoscopy, specific measurements during esophageal manometry, and intraoperative findings at surgery.

Contrast Radiography As the esophagus shortens, the angle of His is lost and the sliding hernia becomes irreducible, even in the upright position (Fig. 27-4). In patients with extreme esophageal shorten-

ing, the cardia and upper stomach may be pulled well up and fixed in the posterior mediastinum.

Esophagoscopy The distance from the upper teeth, or gum, to the esophagogastric junction can be determined accurately during flexible esophagoscopy. If the esophagogastric junction lies at a high level, in the posterior mediastinum above the diaphragmatic hiatus (≥5 cm), shortening is considered a likely possibility. At esophagoscopy, the finding of severe, gross peptic esophagitis (confluent ulceration, peptic stricture, or acquired columnar-lined esophagus) should alert the surgeon to the possibility of significant acquired

Gastroplasty + Belsey hernia repair

Stricture (dilated)

A

B

FIGURE 27-2 A, Diagrammatic illustration of the Pearson technique of gastroplasty and Belsey partial fundoplication. The peptic stricture has been dilated by a 48-Fr Maloney bougie, and a gastric tube will be created from the lesser curvature side of the stomach in continuity with the distal esophagus and of an approximate esophageal diameter. In this diagram, the stomach will be divided between angulated clamps. In most cases today, the gastrointestinal anastomosis stapler is used. B, Diagram illustrating closure of the esophageal and gastric sides of the divided stomach followed by a Belsey-type partial fundoplication. Most of the gastric tube lies below the diaphragmatic hiatus.

Chapter 27 Open Gastroplasty

shortening caused by transmural inflammation and scar contracture.

Esophageal Manometry The distance between the cricopharyngeal sphincter and the lower esophageal sphincter (LES) can be measured during

LV RV

FIGURE 27-3 Diagram showing the normal anatomy at the esophagogastric junction. The distal esophagus actually lies within the tunnel of the diaphragmatic hiatus. There is no significant length of esophagus that is completely intra-abdominal. LV, left vagus nerve; RV, right vagus nerve.

A

manometry. This distance varies among individuals and depends on height and body configuration. Nevertheless, in most normal adults, the mean distance between these two sphincters is 22 cm: 21.5 cm in women and 22.5 cm in men (measured from the upper border of the LES to the lower border of the cricopharyngeal sphincter). Significantly shorter distances are a further indication of the possibility of acquired shortening.

Intraoperative Findings The presence of acute and chronic panmural esophagitis suggests shortening. Panmural esophagitis is characterized by edema and thickening of the esophageal wall, chronic periesophageal lymphadenopathy, and, in some cases, actual scarring in the periesophageal areolar tissues, which embed the esophagus in the posterior mediastinum. After circumferential mobilization of the distal esophagus, it may become apparent that the location of the esophagogastric junction lies well above the diaphragmatic hiatus. A precise judgment of acquired shortening is gained only with experience. For open repairs, I have used both abdominal and thoracic exposures and feel certain that the recognition of acquired shortening is more easily made from the thoracic exposure than from the abdominal side. In the interval since the previous edition of this textbook, enormous progress has been made in the skills and published experience with minimally invasive laparoscopic management of complex esophageal surgical problems. These advances include widespread and increasingly effective experience with the operation of gastroplasty in the management of short esophagus. Indeed, as I predicted in my editorial commentary for the second edition, laparoscopic techniques of gastroplasty are more commonly employed than open operations. Laparoscopic exposure has resulted in some specific measurements and guidelines for determination of acquired shortening. The reported experience is clearly presented in Chapter

B

FIGURE 27-4 Diagram (A) and photograph (B) illustrating mobilization of the distal esophagus and hiatus. In the diagram, the esophagus has been mobilized circumferentially from the level of the pulmonary hilum above to the diaphragmatic hiatus below. The esophagus is elevated with a Penrose drain, and both vagus nerves are carried with the mobilized esophagus. B, The hiatal margins at the diaphragm have been freed circumferentially and the gastric fundus has been drawn up into the left hemithorax and held with a Babcock clamp.

315

316

Section 4 Gastroesophageal Reflux and Associated Conditions

FP

A

C

B

D

FIGURE 27-5 A, Diagram illustrating the ever-present fat pad (FP) lying at the esophagogastric junction. B, Fat pad (arrow) has been partially freed from the anterior and left lateral aspect of the esophagogastric junction. C, The left vagus nerve is displayed. It has been freed from the esophagogastric junction and courses through the mobilized fat pad (arrow). D, Diagram illustrating mobilization of the esophagogastric fat pad along with the left vagus nerve.

28. There remain, however, instances in which conversion to an open operation becomes necessary, and the open approach should be within the capability of the operating surgeon who is dealing with these relatively complex conditions.

SURGICAL TECHNIQUE Technical details of the open operation of gastroplasty combined with a fundoplication are discussed and illustrated here. I still favor a Belsey-type partial fundoplication, although, today, gastroplasty is much more frequently combined with a 360-degree Nissen-type fundoplication. Creation of the gastroplasty by a transthoracic route is identical for either a complete or partial fundoplication. The addition of a Nissen fundoplication—the Collis-Nissen procedure—is clearly illustrated in a publication by Moores.9

Transthoracic Gastroplasty With Belsey Fundoplication Anesthesia Split-lung ventilation is desirable so that the left lung can be collapsed during the operation. Either a double-lumen tube or a bronchial blocker may be used.

Incision The patient is positioned for a posterolateral thoracotomy. The operating table can be angulated or “broken” at its midpoint, which elevates the left hemithorax for improved exposure. The operating table is tilted with the patient in the reverse Trendelenburg position, which allows the abdominal contents to fall away from the left hemidiaphragm and improves exposure.

Chapter 27 Open Gastroplasty

317

FIGURE 27-6 A 48-Fr Maloney bougie has been passed from above, across the esophagogastric junction, and well down into the stomach. The proposed gastric tube will be created along the dotted line for a distance of approximately 5 cm.

FIGURE 27-7 Diagram illustrating the technique for creating the gastric tube using the gastrointestinal anastomosis (GIA) stapler.

Exposure is obtained with a left posterolateral thoracotomy through the sixth intercostal space. The anterior end of the incision is carried almost to the left costal margin so that it ends within a few centimeters of the diaphragmatic origin. This provides optimal exposure for subsequent dissection at the diaphragmatic hiatus and for application of the gastrointestinal anastomosis (GIA) stapler when the gastric tube is constructed. The ribs are spread as gently as possible and are not separated more than 5 to 7 cm to diminish postoperative incisional pain. The inferior pulmonary ligament is divided, the left lung is retracted anterosuperiorly, and the posterior mediastinum is clearly exposed. The esophagus is then mobilized circumferentially from the inferior pulmonary vein above to the diaphragmatic hiatus below. During mobilization, both vagus nerves are palpated, identified, and carried with the esophagus. The right vagus nerve lies just to the right of the anterior border of the descending aorta and is easily separated from the mobilized esophagus unless the surgeon deliberately seeks it and includes it in the mobilization. Also during mobilization, the mediastinal pleura over the right lung is visualized and the surgeon takes care to avoid opening it. The right mediastinal pleura is displaced by blunt dissection from the margins of the diaphragmatic hiatus below and from the right wall of the esophagus behind the pulmonary hilum above. The mobilized esophagus is then elevated and placed on tension with a Penrose drain (see Fig. 27-4). The hiatal margins are freed circumferentially, and the anterior peritoneal sac of the hernia is opened into the greater sac of the peritoneal cavity. The lesser sac is opened posteriorly. The upper end of the gastrohepatic omentum, which often contains a sizable artery, is identified and divided between clamps. Division of this part of the lesser omentum allows the entire cardia of the stomach to rise freely into the left hemithorax (Fig. 27-5A). Mobilization of the greater

curvature side of the stomach does not require division of any short gastric vessels. There is always a collection of fat between the upper and lower limbs of the phrenoesophageal membrane, which envelops the esophagogastric junction (see Fig. 27-5A and B). This “fat pad” is meticulously dissected from most of the circumference of the esophagogastric junction. During dissection, the left vagus nerve is elevated from the muscular wall of the esophagus and carried with the fat pad (see Fig. 27-5C and D). Fat is cleared from the entire anterior surface of the esophagogastric junction and the adjacent lesser curvature side of the stomach. This dissection is tedious and requires precise coagulation or ligation of the many small vessels between the fat pad and the stomach. The technique is similar to that used during highly selective vagotomy. Removal of this fat pad is a part of the technique of a standard Belsey Mark IV repair and makes it possible to construct the gastric tube through an area of stomach that is free of any fatty covering. However, clearance of a greater circumference of esophagogastric junction is required if gastroplasty is to be added to the repair. At this stage, a 48-Fr Maloney dilator is passed through the mouth by the anesthetist. The bougie is advanced so that the distal end lies well within the stomach. In most instances, a gastric tube 4 to 5 cm in length is sufficient to obviate unwanted tension on the repair. The objective is to create a gastric tube of uniform diameter, from top to bottom, over the indwelling 48-Fr bougie (Fig. 27-6). The stomach is divided with a GIA stapler (Fig. 27-7). The margins of the newly created gastric tube are reinforced and oversewn with a running suture of 3-0 chromic catgut. On the esophageal side of the gastroplasty, the staple line is oversewn, but not inverted, to ensure maintenance of the luminal diameter created by the indwelling 48-Fr Maloney bougie (Fig. 27-8A). The gastric side of the suture line is inverted with a running chromic catgut suture, which will

318

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 27-8 The gastric tube is oversewn. A, The esophageal side of the tube is oversewn with 3-0 chromic catgut, without inversion, which might prejudice the diameter of the lumen. B, The gastric side is oversewn and inverted. This eliminates the “dog ear” of stomach at the distal end of the gastric staple line.

bury the “dog ear” of stomach at the distal end of the gastric suture line (see Fig. 27-8B). A 270-degree (Belsey type) fundoplication is now completed with three tiers of 3-0 silk sutures (Fig. 27-9). Each tier is spaced approximately 1.5 cm apart, which creates a fundoplication that is approximately 4.5 cm in length. The fundoplicating sutures are placed in the identical manner as for a Belsey Mark IV repair. In a Belsey repair, however, only two tiers of fundoplicating sutures are used and a shorter fundoplication is created.

A

Interrupted sutures of 1-0 silk are then placed through the crural margins of the hiatus posteriorly but are not tied at this stage of the operation (Fig. 27-10). The sutures in the right limb of the crus are more widely spaced than are those in the left limb (see Fig. 27-10). The most anterior crural suture on the right side should include a margin of the stout, tendinous diaphragmatic band that is found at the anterior end of the right crus. A spoon is placed through the anterior aspect of the hiatus to facilitate passage of the last tier of fundoplicating sutures

B

FIGURE 27-9 A and B, Diagrams illustrating the sequence of suturing for the 270-degree (partial) fundoplication. In all, three tiers of fundoplicating sutures are placed; each tier is positioned about 1.5 cm above the other.

Chapter 27 Open Gastroplasty

FIGURE 27-10 Diagram showing placement of the sutures for posterior closure of the diaphragmatic hiatus. Interrupted sutures of 1-0 silk are used. The sutures are left untied at this stage in the operation. Three or four sutures usually suffice.

(Fig. 27-11). These sutures are directed through the hiatus to the abdominal side and then passed through the diaphragm and brought out on the thoracic side. In Figure 27-11, both ends of the fundoplicating sutures on the right side have been passed in this fashion but not tied. This suture is passed through the diaphragm just to the right side of the anterior “apex” of the hiatus. The middle suture is in the process of placement just to the left of the apex of the hiatus, and the third suture has yet to be passed (see Fig. 27-17). These three sutures are separated along the diaphragmatic margin by the same distances that separate them on the circumference of the gastric tube or esophageal wall. When the last tier of fundoplicating sutures is pulled taut, the entire fundoplication is reduced below the diaphragm (Fig. 27-12). When these sutures are tied, a length of esophagus (gastric tube) of approximately 5 cm in length is secured in the abdomen below the hiatus. No tension is created on the intrathoracic esophagus or repair. The final step in repair is closure of the diaphragmatic hiatus posteriorly (Fig. 27-13). The hiatus is not closed tightly and should allow passage of the index finger alongside the esophagus and through the hiatus, without an undue sense of constriction (see Fig. 27-13B). The pleural space is drained with a single 28-Fr intercostal tube, and the incision is closed.

Modified Collis Gastroplasty and Nissen Fundoplication Today, a 360-degree Nissen fundoplication is the most frequently used fundoplication that is added to a lengthening gastroplasty. A Nissen reconstruction is conceptually simple and is technically easier to do than the Belsey Mark IV procedure. A complete fundoplication affords more certain

FIGURE 27-11 Diagram illustrating the use of a spoon to facilitate passage of the last tier of fundoplicating sutures through the diaphragmatic hiatus and then back from the abdominal to the thoracic side of the diaphragmatic margin.

FIGURE 27-12 Operative photograph in which the last three fundoplicating sutures have been pulled taut, with reduction of the hernia and a 4- to 5-cm segment of esophagus and gastric tube. These sutures are then tied to secure the fundoplication and intraabdominal segment, without tension on the intrathoracic esophagus.

control of reflux than a partial wrap. However, a 360-degree wrap may be associated with adverse functional side effects from creation of an unphysiologic or “overcorrected” valve, which totally prevents reflux yet may preclude normal belching and vomiting when necessary. These undesirable side effects can be reduced, or avoided, by creation of a short (2 cm or less), loose gastric wrap. The technique of gastroplasty is identical regardless of the extent of the subsequent fundoplication. The illustrations that follow were prepared by Moores for publication in his Operative Techniques in Cardiac and Thoracic Surgery: A

319

320

Section 4 Gastroesophageal Reflux and Associated Conditions

B

A

FIGURE 27-13 Diagram (A) illustrating closure of the diaphragmatic hiatus posteriorly. The sutures are tied at this stage in the operation, without undue compression of the soft crural muscle. The hiatus (B) is closed relatively loosely and should allow easy passage of a finger alongside the esophagus in the newly created hiatus.

Comparative Atlas.9 Once the gastroplasty staple line is oversewn, the crural sutures are placed but not tied. Nonabsorbable 1-0 suture material is used (Fig. 27-14). A 360-degree loose Nissen fundoplication is done using three 0 nonabsorbable sutures, which are placed as illustrated in Figure 27-15A and tied to provide a 2-cm-long fundoplication (see Fig. 27-15B). The crural sutures are then tied, as shown in Figure 27-13.

Transabdominal Gastroplasty and Nissen Fundoplication In 1986, Steichen described a transabdominal approach for gastroplasty using a small-diameter EEA stapler, followed by a linear stapler, to fashion the gastric tube. In this report,8 Steichen clearly illustrated the proposed technique but did not report any clinical experience. Later, Moores9 reported on 44 patients managed by Steichen’s proposed transabdominal approach. Exposure is obtained through a midline upper abdominal incision, extending from the xiphoid process to the umbilicus. The procedure is clearly outlined in Figures 27-16 to 27-25.

PERIOPERATIVE AND POSTOPERATIVE CARE Prophylactic antibiotics are given perioperatively. Cefazolin (Ancef), 1 g intravenously, is administered at the time of induction of anesthesia, and a second dose is given in the recovery room approximately 4 hours later. The intercostal tube is attached to suction drainage and usually can be Text continued on p 324.

FIGURE 27-14 Once the staple line has been oversewn, a large nonabsorbable suture such as No. 1 Ethibond is placed through the crura posterior to the stomach. Good thick bites of the hiatal margin (~2 cm deep) should be obtained. These sutures are left untied at this time. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

Chapter 27 Open Gastroplasty

A

B

FIGURE 27-15 A, Once the crural sutures have been placed, a 360-degree loose Nissen fundoplication is carried out over a 2-cm length with interrupted 0 Ethibond suture from gastric fundus to gastroplasty tube to gastric fundus. B, Three interrupted sutures are placed 1 cm apart, creating a 2-cm-long complete Nissen fundoplication. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

FIGURE 27-16 The intra-abdominal portion of the esophagus is mobilized, and a Penrose drain is placed around the intra-abdominal esophagus incorporating the anterior and posterior vagus nerves within the Penrose drain. Multiple short gastric vessels are then divided in the gastrosplenic omentum all the way down to the bare area of the greater curve, which is the junction point between the blood supply from the left and right gastroepiploic arcades. The esophageal fat pad is then removed as described previously. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

FIGURE 27-17 The Penrose drain is used to retract the esophagus and gastroesophageal junction toward the patient’s left side. At this point the hiatus is repaired with a large nonabsorbable suture such as No. 1 Ethibond. Again, large bites of the crura (~2 cm deep) are taken, incorporating the peritoneum overlying the muscle of the crura. These sutures may be tied or left untied at this time. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

321

322

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 27-18 A 25-mm circular stapler is then used to create a secure buttonhole in the stomach approximately 3 cm distal to the gastroesophageal junction. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

FIGURE 27-20 A 5-cm linear stapler (e.g., gastrointestinal anastomosis [GIA]) is then placed through the buttonhole and applied tight against the Maloney bougie and fired, creating a 5-cm-long Collis gastroplasty. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

FIGURE 27-19 The anesthesiologist then passes a Maloney bougie (52 Fr) through the esophagus into the stomach. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

FIGURE 27-21 Once the gastroplasty has been performed, the esophagus is effectively lengthened by 5 cm (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

Chapter 27 Open Gastroplasty

FIGURE 27-22 The gastroplasty tube is then oversewn with running absorbable suture such as 3-0 polyglactin (Vicryl). Again, the gastroplasty tube is not turned in but is simply oversewn. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

FIGURE 27-23 The gastric fundus is then passed posterior to the gastroplasty tube, and a 2-cm-long loose Nissen is performed with three interrupted 0 Ethibond sutures from gastric fundus to gastroplasty to gastric fundus. These are placed 1 cm apart, leaving a 2-cm-long Nissen fundoplication. The crural sutures, if they have been left untied, are now tied. Again, a finger must pass easily through the hiatus after closure of the crural sutures to avoid obstruction. The Nissen sutures are placed at a 9-o’clock position on the right lateral wall of the esophagus. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

FIGURE 27-24 Once tied, the sutures are passed through the already closed crura to fix the wrap within the abdomen, thereby reducing the possibility of herniation of the wrap into the chest. (FROM MOORES DWO: THE COLLIS-NISSEN PROCEDURE. IN COX JL, SUNDT TS III [EDS]: OPERATIVE TECHNIQUES IN CARDIAC AND THORACIC SURGERY: A COMPARATIVE ATLAS, VOL 2. PHILADELPHIA, WB SAUNDERS, 1997, PP 61-72.)

323

324

Section 4 Gastroesophageal Reflux and Associated Conditions

Top Diaphragm hiatus

Gastroplasty

Bottom

A

B

FIGURE 27-25 A and B, Lateral chest radiograph illustrating small metal clips placed at operation. Single clips mark the top and bottom of the gastroplasty tube; double clips mark the edge of the diaphragmatic hiatus. The position of these clips is easily seen in the follow-up chest radiograph. If their position is unchanged, there is no anatomic recurrence of hiatal hernia.

removed after 24 hours. Nasogastric suction is not used. Ileus has proved to be a very rare complication of this transthoracic repair. Clear fluids are usually begun within 24 hours; if they are well tolerated, the patient’s intake is rapidly advanced to a solid diet. Most patients can manage a soft diet and are discharged by the fourth or fifth postoperative day.

Postoperative Dilation of Peptic Strictures The need for postoperative dilation varies and depends on the severity of the associated stricture. Short, mild strictures are easily dilated by passage of a 50-Fr Maloney bougie before the operation and rarely require dilation after repair. In those patients with moderate degrees of stricture, however, postoperative dilation may be necessary. Interval postoperative dilation is inevitably required in patients with severe, long, fibrous strictures. Dilations usually can be performed with indirect bougienage with Maloney dilators in the outpatient clinic under topical anesthesia. In the most severe cases, interval dilation is necessary for periods up to 1 year while we wait for the resolution of inflammation and scar contracture. A detailed description of the techniques of dilation of peptic strictures is provided in Chapter 20.

Postoperative Follow-up Antireflux surgery is used in patients of all ages for the management of a benign disorder that produces derangements of important and sophisticated physiologic functions, such as the ability to swallow normally, to vent gas from the stomach, to vomit when necessary, and to prevent pathologic reflux of

gastric contents into the esophagus. These functions should be maintained, or restored, without new or additional side effects being created, such as the inability to belch or to vomit when necessary, dysphagia, secondary effects caused by vagal nerve injury, and incisional pain or hernia. Furthermore, surgery should carry a minimal risk of operative death or serious morbidity. With few exceptions, the complications of hiatal hernia and reflux do not influence the patient’s longevity or seriously impair general health. Whenever possible, and within the limits of cost and geography, these patients should be observed for the rest of their lives. Our follow-up protocol consists of the following recommendations: 1. An early postoperative visit is advised at 6 weeks. The patient is then seen at annual intervals for the next 5 years and every 2 years thereafter as long as he or she is able to comply. 2. The visits consist of a personal interview by the surgical staff or resident, completion of a standard questionnaire, and an appropriate examination, including a chest radiograph. 3. A barium swallow is performed to evaluate the repair at 1, 5, 10, and 15 years. 4. Contrast studies of the esophagus and stomach, esophageal manometry, 24-hour pH studies, and endoscopy may be done at any time during follow-up to investigate significant symptoms. The position of the gastric tube and repair may be identified on plain chest radiographs if the reconstruction is marked by the placement of small metal clips at the time of the

Chapter 27 Open Gastroplasty

TABLE 27-1 Long-Term Results of Collis Gastroplasty and Partial Fundoplication by Category Results No. Cases

Good

Short esophagus caused by stricture (138 cases) or esophagitis (77 cases) (excluding reoperations and motor disorders)

215

93% (199)

Reoperations: one or more previous unsuccessful antireflux operations

Fair 4% (10)

Poor 3% (6)

118

80% (93)

12% (15)

Peptic stricture (25 cases) or esophagitis (12 cases) associated with a primary motor disorder

37

54% (19)

24% (10)

22% (8)

Intrathoracic stomach

54

91% (49)

9% (5)

0% (0)

operation. We place a clip at the top and bottom of the gastric tube and two small parallel clips on the top side of the diaphragmatic hiatus. These are easily seen in the posteroanterior and lateral chest films (see Fig. 27-25). As long as there is no change in the position of these clips, we can assume that there has been no anatomic recurrence of the hiatal hernia.

LONG-TERM RESULTS In 1987, we reported long-term results obtained in a consecutive series of 430 patients with complex reflux problems who were managed by a modified Collis gastroplasty and partial fundoplication.10 The results were stratified by category: short esophagus with peptic stricture (138 cases) or gross ulcerative esophagitis (77 cases), reoperation following one or more previous unsuccessful repairs (118 cases), peptic stricture (25 cases) or esophagitis (12 cases) associated with a primary motor disorder, and massive incarcerated hernia or intrathoracic stomach (54 cases). These results are summarized in Table 27-1. It is apparent that gastroplasty and fundoplication provide a high proportion of good results in patients with acquired short esophagus caused by peptic esophagitis. Equally good results were obtained in patients with massive, incarcerated hiatal hernias. The incidence of unsatisfactory results was significantly higher in patients who required reoperation after a previous unsuccessful antireflux repair. The poorest results in this series occurred in patients who presented with peptic stricture and reflux esophagitis associated with an underlying primary motor disorder, such as achalasia, diffuse spasm, or scleroderma. The worst results occurred in patients with achalasia. The long-term results of gastroplasty combined with a complete (Nissen-type) fundoplication were reported in detail by Henderson and Marryatt11 in 1985 and Stirling and Orringer in 1989.12 Both publications reported favorable results. More recent reports have indicated favorable and relatively long-term results after the Collis-Nissen operation for peptic stricture,13,14 for Barrett’s esophagus,15 and for reoperation after failed antireflux surgery.16

8% (10)

In 1999, Demos reported his long-term follow-up in 153 patients managed by his original technique of “uncut gastroplasty and Nissen fundoplication,” again with a series of excellent results.17 Pera and associates,18 in 1995, reported favorable short-term results with the “uncut Collis-Nissen” operation. Jobe and coworkers19 reported the short-term functional results of their technique of laparoscopic Collis gastroplasty. It is difficult, however, to make meaningful comparisons among the results in these reported series. There is variation in the indications for adding gastroplasty, the mix of patients, the length of follow-up, the method of results reporting, and the details of the operative techniques. These problems beset the evaluation of all reports on the outcomes of antireflux surgery.

COMMENTS AND CONTROVERSIES It is a great pleasure to read this chapter written by the pioneering esophageal surgeon who had the insight to add this useful technique to a standard antireflux repair. I was fortunate to be taught how to construct a Collis gastroplasty by Dr. Pearson. An often overlooked but critical portion of this operation is removal of the esophagogastric fat pad. This meticulous dissection prepares the gastroplasty tube for fundoplication. However, more importantly it vagotomizes the gastroplasty tube, so as to minimize the gastric function of this portion of the stomach. The wedge gastroplasty and other open and laparoscopic techniques that try to mimic this open procedure omit this step, accounting for the poor performance of the pseudogastroplasty. T. W. R.

KEY REFERENCES Cooper JD, Gill SS, Nelems JM, Pearson FG: Intraoperative and postoperative manometric findings with Collis gastroplasty and Belsey hiatal hernia repair for gastroesophageal reflux. J Thorac Cardiovasc Surg 74:744-751, 1977. Orringer MG, Sloan H: Complications and failings of the combined Collis-Belsey operation. J Thorac Cardiovasc Surg 74:726-735, 1977.

325

chapter

28

LAPAROSCOPIC GASTROPLASTY James D. Luketich Michael A. Maddaus

Key Points Definitions ■ Hiatal hernia

Type I: sliding Type II: paraesophageal Type III: mixed (sliding and paraesophageal) Type IV: additional abdominal organ herniation (e.g., colon, spleen) Giant hiatal hernia: >50% of stomach is intrathoracic ■ Short esophagus <2.5 cm intra-abdominal esophagus after complete mediastinal mobilization Surgical Principles ■ Complete reduction of hiatal hernia, sac excision, and tension-free

crural repair ■ Evaluation of esophageal length and appropriate use of esopha-

geal lengthening procedures ■ Antireflux procedure

Laparoscopic Steps 1. The hernia sac is incised leaving peritoneal coverage on the crura. 2. Extensive mediastinal esophageal dissection 3. Hernia sac removal from the chest 4. Dissection of fat pad allows identification of the GEJ and evaluation of intra-abdominal esophageal length. 5. Collis-wedge gastroplasty over a 48- to 54-Fr dilator 6. Nissen fundoplication over a 52- to 54-Fr dilator Follow-up ■ Validated symptom review annually for 5 years ■ Anatomic evaluation (barium esophagogram) every year for

5 years ■ Patients with preoperative esophagitis, stricture, or Barrett’s esophagus should be endoscopically evaluated within a year of surgery. ■ Persistent or progressive esophageal mucosal abnormalities without anatomic recurrence should be evaluated further.

The Collis gastroplasty is an esophageal lengthening procedure performed in patients with a giant paraesophageal hernia (GPEH) and a shortened esophagus. The laparoscopic Collis gastroplasty procedure employs principles originally described by Collis (Collis, 1957),1 namely, elongating the 326

esophagus with a tubularized portion of stomach. Selective use of this procedure is critical for the successful laparoscopic repair of a significant number of GPEHs.

HISTORICAL NOTE Bowditch first published a description of a hiatal hernia in 1853. In 1919, Soresi was the first to surgically reduce a hiatal hernia and approximate the crura. During the first half of the 20th century,2 the link between gastroesophageal reflux disease (GERD) and hiatal hernia was gradually established. In 1956, Nissen described fundoplication for the first time,3 and, in 1957, Collis published his work on transthoracic gastroplasty as an esophageal lengthening procedure.1 Skinner and Belsey (1967) emphasized the importance of the intra-abdominal esophagus as part of the antireflux valve and reported a high recurrence rate in the presence of a shortened esophagus.4 Felix Steichen reported a technique in 1987 that gives one of the first descriptions of the Collis gastroplasty using mechanical staplers to complete the entire operation.4a It was not until 1998 that Maziak and colleagues (1998)5 published one of the first meticulous modern reports on the surgical treatment of giant hiatal hernia with routine Collis gastroplasty and fundoplication. Also in 1998, Johnson and associates (1998)6 first described the totally laparoscopic Collis gastroplasty in combination with a Nissen fundoplication. However, Pierre and Luketich published the first large series of GPEHs repaired using the laparoscopic Collis gastroplasty successfully in a routine fashion (Pierre et al, 2002).7

DEFINITION, INCIDENCE, AND PATHOPHYSIOLOGY OF HIATAL HERNIA AND SHORT ESOPHAGUS Definition Hiatal hernia is classified by type as follows: type I indicates sliding hernia; type II, paraesophageal hernia; type III, mixed sliding and paraesophageal hernia (commonly referred to as a GPEH); and type IV, herniation of additional organs (e.g., colon, spleen).8 No consistant definition exists for GPEH; however, any hernia with more than half of the stomach herniated into the chest may be defined as such (Fig. 28-1). The association of GERD and type I hiatal hernia has long been established and is irrefutable, and patients may also have esophagitis or Barrett’s esophagus (Jobe et al, 1998).9,10 However, as a type I hiatal hernia progresses to a type III, often the GERD symptoms are minor compared to mechanical and obstructive symptoms, including postprandial fullness, dysphagia, and regurgitation symptoms.

Chapter 28 Laparoscopic Gastroplasty

FIGURE 28-2 Esophagogram in a patient with a recurrent hiatal hernia (Nissen wrap herniation).

FIGURE 28-1 Esophagogram of complete intrathoracic stomach.

Short esophagus is best defined intraoperatively: after complete mediastinal mobilization of the esophagus, the intra-abdominal esophageal length is less than 2.5 cm. In this setting, one needs to consider that a short esophagus is present and an esophageal lengthening procedure may be indicated (i.e., Collis gastroplasty).11 A short esophagus is the result of longitudinal scarring secondary to severe chronic GERD (Horvath et al, 2000; Skinner and Belsey, 1967).4,12 Ample anatomic, physiologic, and clinical evidence indicates that true esophageal shortening is a distinct entity. Horvath and coworkers (2000)12 defined three types of esophageal shortening: 1. Apparent short esophagus 2. True, reducible short esophagus 3. True, nonreducible short esophagus Apparent short esophagus is the result of longitudinal compression of the esophagus in the mediastinum but the esophagus is of normal length. True, reducible short esophagus is defined as an esophagus that is indeed shortened, but with proper mediastinal mobilization the esophagus has an intraabdominal length of at least 2.5 cm. True, nonreducible short esophagus does not allow for an intra-abdominal length of greater than or equal to 2.5 cm, despite appropriate mediastinal dissection, and requires a Collis gastroplasty. The relevance of an esophageal intra-abdominal length of greater than or equal to 2.5 cm is critical to avoid cephalad traction on the completed antireflux wrap and wrap herniation (Fig. 28-2) (Horvath et al, 2000).12 The successful surgical repair of GPEH can only be accomplished with this concept in mind.

Incidence The prevalence of paraesophageal hernia in patients undergoing a Nissen fundoplication is approximately 9%,13 and GPEH represents from 0.3% to 15% of all hiatal hernias. The prevalence of short esophagus (defined by the need for extensive mediastinal mobilization and/or a Collis gastroplasty) varies between 1.5% and 19% of patients undergoing surgery for GERD (Horvath et al, 2000; Jobe et al, 1998; Johnson et al, 1998; Swanstrom et al, 1996).6,9-17 In the setting of a GPEH (type III), some have suggested the incidence may exceed 80% (Maziak et al, 1998; Patel et al, 2004).5,18 It is not possible to provide more precise estimates of the incidence or prevalence of GPEH, because a consensus on the definitions of GPEH and short esophagus is lacking.

Clinical Evaluation of Patients With Giant Hiatal Hernia Patients with a GPEH generally present with pain, heartburn or a history of heartburn, epigastric pain, dysphagia, vomiting, and anemia (in order of decreasing frequency) (Mattar et al, 2002; Maziak et al, 1998; Patel et al, 2004; Pierre et al, 2002; Skinner and Belsey, 1967).4,5,7,17,18,21 Clinical acuity is necessary for the evaluation of symptoms, because the chronicity of symptoms leads patients to underestimate severity in some cases. The incidence of true incarceration and even strangulation, though a matter of speculation, is low. The workup of a patient with a GPEH should include (1) a barium esophagogram to assess the size of the hernia as well as the presence of axial or longitudinal rotation and strictures and (2) an upper endoscopy to measure the distance from the gastroesophageal junction (GEJ) to the crural impression and to thoroughly examine the mucosa. (Any mucosal abnormalities should be sampled.)

327

328

Section 4 Gastroesophageal Reflux and Associated Conditions

Manometry may help to identify patients with motility disorders requiring tailoring of the fundoplication; however, it is not always technically possible in giant hernias with rotation. Some researchers use manometric length (distance from upper esophageal sphincter to lower esophageal sphincter) as a measure of esophageal shortening (Maziak et al, 1998).5,16 CT can be helpful but is not routinely required. Finally, pH monitoring and gastric emptying studies are unnecessary or unreliable in the setting of a GPEH.

Indications for Surgery Any patient with a symptomatic GPEH should be considered a surgical candidate unless comorbidities are prohibitive. The indication to operate is mainly due to the symptomatic nature of the disease, and on purposeful interrogation the vast majority of patients report symptoms. The potential risk of incarceration and strangulation for GPEH is often quoted as an indication for surgery. Skinner and Belsey (1967)4 found that GPEHs carry a mortality of 29% if treated medically, regardless of symptoms. However, Allen and associates17 reported that 4 of 23 patients (17%) with GPEH (>75% of stomach herniated) treated medically had progressive symptoms without gastric strangulation, and 1 patient (4%) died of an aspiration pneumonia. This discrepancy is likely due to advancements in medical care over the decades. Although the risk of strangulation is a concern, the decision to operate on most hiatal hernias tends to be based on symptoms. Generally, patients who present with an acutely incarcerated hernia have had progressive symptoms for days or weeks, which have been ignored or misdiagnosed.

SURGICAL PRINCIPLES OF GIANT HIATAL HERNIA REPAIR The repair of GPEH mandates the observation of several surgical principles: 1. Complete reduction of hiatal hernia, sac excision, and tension-free crural repair 2. Evaluation of esophageal length and appropriate use of esophageal lengthening procedures 3. An antireflux procedure

The best clinical results are reported in surgical series that adhere to these principles.

Open Surgical Approach Fundoplication under tension due to esophageal shortening leads to a recurrence rate of nearly 40% (Skinner and Belsey, 1967).4 Two large studies of transthoracic repair of GPEH applied the key surgical principles and provided long-term anatomic and symptomatic follow-up data. Maziak and colleagues (1998) published a comprehensive report on repair of GPEH in 94 patients.5 In this study, the authors reduced the hernia, extensively mobilized the esophagus, used a Collis gastroplasty in 80% of cases, and performed a Belsey antireflux procedure. At a median follow-up of 6 years using barium esophagography and symptom survey, the anatomic recurrence rate was 2% (2 patients who had not undergone a gastroplasty) and patient satisfaction was 94%. The second study, published by Patel and coworkers (2004),18 reported data on 240 patients with GPEH treated with a transthoracic approach using a Collis-Nissen fundoplication in 96% of patients. At an average follow-up of 42 months, the anatomic recurrence rate was 12.4% and patient satisfaction was 86%; 4 late recurrences required reoperation 13 to 51 months after the initial repair. These reports represent the gold standard for proper repair and postoperative follow-up of patients with GPEH (Table 28-1). Other large series of transthoracic repair of GPEH do not provide anatomic follow-up; hence, results are difficult to interpret (Altorki et al, 1998).19,20 Mattar and coworkers (2002)21 have reported the importance of hernia sac excision to minimize the potential for postoperative mediastinal seroma. Primary crural closure (with or without pledgets) is a critical component of the operation, and, in our experience, only rarely is a prosthetic patch required. Others have suggested that the routine use of mesh may be important in the repair of GPEH when the hiatal defect exceeds 5 cm in diameter.22 Recently, the shortterm results of a randomized trial of mesh versus primary repair for GPEH were reported.23 Although the mesh arm had a lower hernia recurrence rate (9%) than the non-mesh arm (17%), it is disappointing that the recurrence rates were

TABLE 28-1 Results of Open Transthoracic Repair of Large Hiatal Hernia With Collis Gastroplasty Maziak et al5 (1998)

Patel et al18 (2004)

Technique

Collis-Belsey

Collis-Nissen

No. Patients

94

240

Operating Room Time (min)

—

—

Length of Stay (days)

—

7*

Morbidity (%)

19

22

Mortality (%)

2

2

Mean Follow-up (mo)

94

42

Follow-up Method

Esophagogram, symptoms

Anatomic Recurrence (%) Patient Satisfaction (%) *Median value.

Esophagogram, symptoms

2

12

94

86

Chapter 28 Laparoscopic Gastroplasty

high in both groups at the very short-term analysis of less than 1 year. Probably the important take-home message from this trial is that all steps of the operation are in need of careful attention to detail and that further studies may be needed to determine the optimal surgical approach.

Evolution of Laparoscopic Approaches In an effort to optimize results and to standardize a laparoscopic approach to esophageal shortening, O’Rourke and colleagues (2003)24 emphasized the importance of laparoscopic transhiatal esophageal mobilization as a key step to achieve proper intra-abdominal esophageal length (≥2.5 cm). The researchers defined two types of circumferential transmediastinal esophageal dissection based on length: type I (<5 cm) and type II (≥5 cm). Gradual circumferential blunt and harmonic scalpel esophageal dissection in the mediastinum is carried out with progressive advancement of the laparoscope through the hiatus into the chest. The vagus nerves are identified and protected, but small branches to other mediastinal structures are transected to improve mobilization. By follow-

A

ing these steps, dissection can be safely carried out to the level of the carina (Horvath et al, 2000).12 Swanstrom and colleagues (1996)15 first described a combined thoracoscopic-assisted laparoscopic gastroplasty with the use of a linear right transthoracic stapler (Fig. 28-3A). Formation of the neo-esophagus was accomplished with an endoscopic linear stapler applied parallel to the lesser curve of the stomach with a bougie dilator in place. The stapler was introduced through the right chest and passed into the abdomen through the hiatus. In 2000, Awad and associates (2000)25 described a similar approach using a left-sided thoracoscopic access to perform the esophageal lengthening (see Fig. 28-3B). In our experience, the thoracoscopic approach is suboptimal compared to laparoscopic approaches to the Collis gastroplasty. Johnson and coworkers (1998)6 presented a minimally invasive, totally intra-abdominal Collis gastroplasty following Steichen’s principles (Fig. 28-4).26 The researchers used an endoscopic circular end-to-end (EEA) stapler to create a sealed, transgastric window (see Fig. 28-4A). An endoscopic linear gastrointestinal anastomosis (GIA) stapler was then introduced through the window and fired parallel to an esophageal dilator, forming the neo-esophagus (see Fig. 284B). This method is technically demanding and requires unique expertise. The addition of a circular staple without the use of a purse-string suture may predispose to an incomplete “ring” of the anterior and posterior gastric wall and lead to a staple line leak. This approach has been used successfully by Pierre and Luketich for laparoscopic esophageal lengthening with a staple line leak rate of 3% in their first 50 cases, which decreased to less than 1% in their subsequent series (Pierre et al, 2002).7 Finally, the importance of an antireflux operation is irrefutable after reduction of the GPEH and proper intraoperative management of a shortened esophagus. Persistent GERD will result if an antireflux operation is not performed, because most of the anatomic components of the antireflux valve are compromised as a result of the disease and the extensive dissection (Collis, 1957; Swanstrom et al, 1996).1,15

Laparoscopic Repair: The University of Minnesota Technique

B FIGURE 28-3 A, Right thoracoscopic-assisted laparoscopic Collis gastroplasty. A linear endoscopic GIA stapler is placed through the right chest. B, Left thoracoscopic-assisted laparoscopic Collis gastroplasty. An articulating linear endoscopic GIA stapler is placed through the left chest. (REPRINTED WITH PERMISSION FROM HOANG CD, KOH PS, MADDAUS MA: SHORT ESOPHAGUS AND ESOPHAGEAL STRICTURE. SURG CLIN NORTH AM 85:433-451, 2005.)

The surgical technique used at the University of Minnesota for laparoscopic repair of GPEH, Collis gastroplasty, and fundoplication emphasizes the following points: hernia sac reduction and excision, extensive mediastinal esophageal dissection with vagal preservation, GEJ fat pad dissection and evaluation of intra-abdominal esophageal length, wedge Collis gastroplasty for severely shortened esophagus (<2.5 cm intraabdominal length), reinforced crural repair, and a Nissen fundoplication (Table 28-2 and Figs. 28-5 to 28-13). The wedge gastrectomy technique is based on the original procedure used by Champion for laparoscopic vertical banded gastroplasty.22

RESULTS Laparoscopic Repair Without Collis Gastroplasty Several studies of laparoscopic repair of GPEH without a Collis gastroplasty have been reported. Results have been inconsistent and often disappointing, which can be attributed

329

330

Section 4 Gastroesophageal Reflux and Associated Conditions

B

A

FIGURE 28-4 A, Anvil placement for laparoscopic Collis gastroplasty. B, Longitudinal stapling along an esophageal dilator to complete the laparoscopic Collis gastroplasty. (REPRINTED WITH PERMISSION FROM PIERRE AF, LUKETICH JD, FERNANDO HC, ET AL: RESULTS OF LAPAROSCOPIC REPAIR OF GIANT PARAESOPHAGEAL HERNIAS: 200 CONSECUTIVE PATIENTS. ANN THORAC SURG 74:1909-1916, 2002. COPYRIGHT ELSEVIER 2002.)

TABLE 28-2 Key Procedural Steps to Laparoscopic Repair of Giant Hiatal Hernia: University of Minnesota Technique Step 1 ■ ■ ■ ■

Step 2 ■ ■

Step 3 ■ ■ ■ ■

Step 4 ■

Step 5 ■ ■ ■

Hernia sac reduction and excision (Fig. 28-5) The hernia sac is incised leaving peritoneal coverage on the crura to provide the best possible tissue integrity. Gradual inversion of the sac is done with extensive blunt mediastinal esophageal dissection (≥10 cm). CO2 insufflation aids the blunt dissection of mediastinal tissues. The hernia sac is excised. This maneuver avoids forceful grasping and retracting of the stomach. GEJ fat pad dissection (Fig. 28-6) Careful dissection allows identification of the GEJ and evaluation of intra-abdominal esophageal length. The vagus nerves are dissected off the GEJ and proximal stomach (equivalent to a highly selective vagotomy). Wedge Collis gastroplasty A 48-Fr esophageal dilator is placed along the lesser curvature (Fig. 28-7). The endoscopic GIA stapler is introduced through a left upper quadrant port, and a staple line is started with the fundus retracted inferiorly (Fig. 28-8). A second and (sometimes) third staple line is applied to end snuggly at the edge of the dilator (Fig. 28-9). The wedge is excised with a final staple line from a right upper quadrant port (Fig. 28-10). The Collis segment (neo-esophagus) is approximately 2.5 cm in length (Fig. 28-11). Reinforced crural repair (Fig. 28-12) 0-silk pledgeted sutures are used for maximum strength. Nissen fundoplication A 52-Fr dilator is placed into the neo-esophagus. (This is easily done despite having fashioned the Collis gastroplasty over a 48-Fr dilator.) The wrap is placed within the vagus nerves with the goal to further anchor the wrap. Three-stitch fundoplication is performed (Fig. 28-13).

partially to a steep learning curve for a challenging operation and, more importantly, to failure to consistently address the problem of esophageal shortening. Recurrence rates have ranged from 0% to 42%, and patient satisfaction has ranged from 77% to 100%27; however, anatomic follow-up has generally been incomplete. An alarming report by Hashemi and associates,28 with meticulous symptomatic and anatomic follow-up, revealed a recurrence rate of 42%. In a study published by Weichmann and colleagues,29 60 patients with GPEH were treated laparoscopically with total or partial fundoplication (no Collis gastroplasty). In 44

patients who had a postoperative esophagogram at 6 months there were three recurrences (7% of patients with an objective evaluation).29 Mean operative time was 202 minutes, 6 patients required a conversion to laparotomy, and two intraoperative iatrogenic esophageal perforations occurred. Mortality was 1.7%. Symptomatic improvement was observed in 95% of patients, and an increase in lower esophageal sphincter pressure was documented in patients who underwent a postoperative manometry. However, documentation on esophageal length or hernia size was not provided, and the Text continued on p 334.

Chapter 28 Laparoscopic Gastroplasty

A

C

FIGURE 28-6 Laparoscopic view of short esophagus after extensive mediastinal dissection. The GEJ (white arrow) is at the level of the hiatus (black arrow). There is no intra-abdominal esophagus. The white line delineates the area previously covered by the fat pad. Note that the vagus nerves have been dissected off the GEJ.

B

FIGURE 28-5 A, The laparoscopic grasper reaches into the hernia sac. B, The sac is grasped and inverted. C, The sac is incised and blunt mediastinal dissection started. Note that the sac incision is beyond the edge of the hiatus to preserve peritoneal lining on the crura (arrows).

FIGURE 28-7 Laparoscopic view of placement of a 48-Fr esophageal dilator along the lesser curvature (short white arrows). The fundus has been retracted under tension toward the patient’s right side. Short black arrows indicate fundus; long black arrow, angle of His; long white arrow, hiatus (left crus).

331

332

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

FIGURE 28-8 A, The fundus is now retracted inferiorly and to the patient’s left side (white arrows). B, The black arrow shows the direction of retraction; alignment of the dilator along the lesser curvature is shown. The stapler is introduced through a left upper quadrant port.

A

B

FIGURE 28-9 A and B, The staple line (white arrows) has been completed and brought snuggly to the edge of the dilator (B, dotted line). The yellow arrows point to the wedge of fundus to be resected.

A

B

FIGURE 28-10 A, The gastric wedge (short black arrows) is transected with a stapler from the right upper quadrant. B, The staple line has to be fit snuggly against the dilator (dotted line).

Chapter 28 Laparoscopic Gastroplasty

A

B

Neo-esophagus

FIGURE 28-11 A, The length of the neo-esophagus (Collis segment) is outlined by the arrow. B, Completed Collis gastroplasty (arrow). C, Overview of completed Collis gastroplasty.

C

FIGURE 28-12 Crural repair with 0-silk on an SH needle.

FIGURE 28-13 Completed Nissen fundoplication.

333

334

Section 4 Gastroesophageal Reflux and Associated Conditions

recurrence rate has to be interpreted with caution owing to a short follow-up period. O’Rourke and coworkers (2003)24 carefully evaluated patients undergoing type I and II transmediastinal dissection of the esophagus to achieve an intra-abdominal length of greater than or equal to 2.5 cm, followed by a Nissen fundoplication. Of these patients, 133 underwent type I and 72 underwent type II dissection for short esophagus (mean manometric length, 22.5 cm). Patients requiring gastroplasty were excluded from the study. Follow-up consisted of a symptom questionnaire, and 71% of patients underwent pH testing and/or manometry postoperatively. Failure was defined as an abnormal DeMeester score (>14.7), objective documentation of wrap herniation, or reoperation. Failure rates for type I and II dissection were 11% and 10%, respectively; however, there were only two documented anatomic recurrences (one in each group: 0.8% and 1.4%, respectively). The majority of patients deemed failures were symptomatic postoperatively (68%).

Laparoscopic Repair With Collis Gastroplasty Jobe and colleagues (1998)9 provided the first objective results of laparoscopic repair of GPEH with a thoracoscopic/ laparoscopic Collis gastroplasty and Nissen fundoplication. This study meticulously evaluated 15 patients 14 months after surgery with upper endoscopy and distal esophageal biopsies, manometry, pH study, Congo red staining (to detect acid-producing mucosa), and symptom assessment. Followup was complete in 14 patients (93%). Mean operative time was 252 minutes, and the average length of stay was 2 days. Morbidity was 15%, and no operative deaths were reported. Late follow-up revealed no hernia recurrence and a decrease in esophagitis from 60% to 36%. All 11 patients who underwent biopsy had oxyntic mucosa immediately proximal to the wrap. Preoperatively, 48% of patients had Barrett’s esophagus; no progression of Barrett’s esophagus to dysplastic epithelium was found on follow-up. Manometry revealed an intact reconstruction of the distal high pressure zone in all patients, with an associated 93% increase in resting pressure and a 196% increase in lower esophageal sphincter length. Distal esophageal body function was absent in 43% of patients. The median postoperative DeMeester score was 8.4, pH studies were abnormal in 50% of patients, and all patients with abnormal pH studies had positive Congo red staining. However, only 2 of 7 patients with abnormal pH studies were symptomatic. Notably, all patients considered their surgeries successful. This report emphasizes several important points: esophagitis and Barrett’s esophagus are common in patients with GPEH, a laparoscopic Collis gastroplasty provides excellent symptomatic and anatomic results, abnormal distal esophageal acid exposure is common after a Collis gastroplasty, and symptoms do not correlate well with abnormal DeMeester scores. Lin and coworkers10 reported a total of 68 Collis-Nissen procedures, 56 of which were laparoscopic (operative technique not described). Follow-up averaged 30 months, and symptomatic improvement ranged from 86% to 91% (depending on symptoms). Only 37% of patients had endoscopic and physiologic follow-up, and 4 recurrent herniations were iden-

tified. Importantly, 80% of studied patients had persistent esophagitis or abnormal pH studies, and 2 patients developed new Barrett’s esophagus, despite successful symptom control. These findings underscore that symptoms and persistent or new objective abnormalities do not correlate well. No conclusions can be drawn on recurrence rates because few patients had objective follow-up. At the University of Pittsburgh Medical Center, Pierre and Luketich (2002)7 reported on 203 attempted laparoscopic repairs of giant hiatal hernia (defined as greater than or equal to one third of the stomach in the thorax). Only three conversions were necessary, and a total of 112 patients (56%) had a Collis gastroplasty with a Nissen fundoplication. The use of a laparoscopic Collis gastroplasty increased with experience and was performed in 85% of the latter 100 patients. The median operative time was 3.3 hours, median hospital stay was 3 days, major and minor morbidity was 28%, leak rate was 3%, and mortality was 0.5%. Recurrences were documented in 5 patients, 4 of these were in the first 100 patients, and only 1 in the latter 100 patients. This decrease in recurrence rate is suggestive of the effect of increasing experience and more liberal use of a Collis gastroplasty. Symptoms were evaluated postoperatively by a GERD health-related quality-of-life questionnaire (GERD-HRQOL). Of all patients, GERD-HRQOL results were excellent in 84%, good in 8%, fair in 5%, and poor in 3%. At the University of Minnesota, we have repaired 61 giant hiatal hernias using the previously described laparoscopic Collis-Nissen technique. Median operative time was 274 minutes, median length of stay was 4 days, morbidity was 8.2%, and mortality was 1.7%. Median follow-up was 8 months and included anatomic evaluation in 54 patients (85% upper gastrointestinal series, 15% CT scan [Figs. 28-14 and

FIGURE 28-14 Postoperative esophagogram 24 hours after repair of recurrent hiatal hernia. The arrow points at contrast medium entering the fundoplication.

Chapter 28 Laparoscopic Gastroplasty

28-15]) and symptom evaluation (GERD-QOL questionnaire) in 52 patients (85%). Only two anatomic recurrences were documented (both at 2 years), and patient satisfaction was 98% (excellent = 96%; good = 2%) (Whitson et al, 2006).30 Table 28-3 summarizes the results of laparoscopic Collis-Nissen series.

Follow-up After Collis Gastroplasty and Antireflux Operation No guidelines exist for follow-up of patients after the repair of a GPEH with or without the use of an esophageal lengthening procedure. However, it is clear that many patients have preoperative mucosal abnormalities (esophagitis, stricture, or Barrett’s esophagus), that postoperative symptoms correlate poorly with objective abnormalities, that recurrences tend to occur within the first 2 years after surgery (but may occur several years after the repair), and that mucosal pathology may persist or even progress (Jobe et al, 1998; Mattar et al, 2002; Skinner and Belsey, 1967).4,9,10,13,21 Development of Barrett’s esophagus, high-grade dysplasia, and adenocarcinoma has been reported during the follow-up of patients after GPEH repair with a Collis gastroplasty (Maziak et al, 1998; Patel et al, 2004).5,10,18 In view of these facts, patients should be followed routinely after the surgical repair of GPEH; suggested follow-up protocol includes the following: ■ ■ ■

■

FIGURE 28-15 Postoperative CT scan 1 year after repair of recurrent hiatal hernia. The arrow points at the Collis staple line within the fundoplication.

Validated symptom review annually for 5 years Barium esophagogram annually for 5 years Endoscopic evaluation within a year of surgery for patients with preoperative esophagitis, stricture, or Barrett’s esophagus Evaluation with a pH study for persistent or progressive esophageal mucosal abnormalities without anatomic recurrence

TABLE 28-3 Results of Laparoscopic Repair of Large Hiatal Hernia With Collis Gastroplasty Swanstrom et al15 (1996)

Johnson et al6 (1998)

Jobe et al9 (1998)

Awad et al25 (2000)

Pierre et al7 (2002)

Whitson et al30 (2006)

Technique

Right VATS-assisted Collis-Nissen

Collis-Nissen

Collis-Nissen

Left VATS-assisted Collis-Nissen or Toupet

Nissen, Collis-Nissen

Collis-Nissen

No. Patients

3

9

15

8

202

61

Operating Room Time (min)

257*

297*

252*

—

200†

274†

Length of Stay (days)

2*

3*

2*

3*

3†

4†

Morbidity (%)

0

22

15

50 (minor)

28

8

Mortality (%)

0

0

0

0

0.5

1.7

†

8†

Follow-up (mo)

8*

—

14*

20*

18

Follow-up Method

Endoscopy, pH study, manometry, symptoms

Endoscopy, symptoms

Endoscopy, pH study, manometry, biopsy, symptoms

Symptoms

Symptoms

Esophagogram, symptoms

Anatomic Recurrence (%)

0

11

0

13

2.5

2

Patient Satisfaction (%)

100

89

100

88

92

98

VATS, video-assisted thoracoscopic surgery. *Mean value. † Median value.

335

336

Section 4 Gastroesophageal Reflux and Associated Conditions

It is not clear whether every patient with preoperative mucosal pathology should be treated postoperatively with proton pump inhibitors until a normal postoperative pH study or regression has been documented. Certainly, any patient with a normal anatomic evaluation and an abnormal postoperative pH study who is symptomatic or has esophageal mucosal pathology should be treated with PPIs and followed routinely.

SUMMARY The laparoscopic repair of GPEH mandates the observation of several surgical principles: (1) complete reduction of GPEH, sac excision, and tension-free crural repair; (2) evaluation of esophageal length and appropriate use of esophageal lengthening procedures; and (3) an antireflux procedure. The best clinical results are reported in surgical series that adhere to these principles. Patients should be followed with a regimented protocol for at least 5 years to assess results.

COMMENTS AND CONTROVERSIES This chapter reviews the history and recent literature on laparoscopic Collis gastroplasty. This concept of the short esophagus and the techniques for lengthening remain controversial to some degree regarding the diagnosis, incidence, and indications for treatment in the setting of complex esophageal antireflux surgery. Although most surgeons agree that the shortened esophagus exists, the diagnosis, incidence, and indications for a lengthening procedure remain debatable. However, it does become clear that if the surgeon has no ability to recognize or treat a shortened esophagus, suboptimal results will be obtained if indeed a short esophagus is present. Therefore, the acknowledgment of the possibility of a short esophagus in some cases, the steps to recognition, and the options for treatment make the addition of this type of technique essential to the surgeon who treats complex benign esophageal disorders. Both the laparoscopic stapled gastroplasty approach and the laparoscopic end-to-end anastomotic approach to a Collis gastroplasty have been used now in several series and both can be successful. However, I agree with the authors, that the stapled gastroplasty is a less technically demanding approach and may be a better technique in most hands compared with the laparoscopic end-to-end anastomotic or thoracoscopic approaches. T. W. R.

KEY REFERENCES Altorki NA, Yankelevitz D, Skinner DB: Massive hiatal hernias: The anatomic basis of repair. J Thorac Cardiovasc Surg 115:828-835, 1998. Awad ZT, Filipi CJ, Mittal SK, et al: Left side thoracoscopically assisted gastroplasty: A new technique for managing the shortened esophagus. Surg Endosc 14:508-512, 2000. Collis JL: An operation for hiatus hernia with short esophagus. J Thorac Cardiovasc Surg 14:768-788, 1957. Horvath KD, Swanstrom LL, Jobe BA: The short esophagus: Pathophysiology, incidence, presentation, and treatment in the era of laparoscopic antireflux surgery. Ann Surg 232:630-640, 2000. Jobe BA, Horvath KD, Swanstrom LL: Postoperative function following laparoscopic Collis gastroplasty for shortened esophagus. Arch Surg 133:867-874, 1998. Johnson AB, Oddsdottir M, Hunter JG: Laparoscopic Collis gastroplasty and Nissen fundoplication: A new technique for the management of esophageal foreshortening. Surg Endosc 12:1055-1060, 1998. Mattar SG, Bowers SP, Galloway KD, et al: Long-term outcome of laparoscopic repair of paraesophageal hernia. Surg Endosc 16:745749, 2002. Maziak DE, Todd TR, Pearson FG: Massive hiatus hernia: Evaluation and surgical management. J Thorac Cardiovasc Surg 115:53-62, 1998. O’Rourke RW, Khajanchee YS, Urbach DR, et al: Extended transmediastinal dissection: An alternative to gastroplasty for short esophagus. Arch Surg 138:735-740, 2003. Patel HJ, Tan BB, Yee J, et al: A 25-year experience with open primary transthoracic repair of paraesophageal hiatal hernia. J Thorac Cardiovasc Surg 127:843-849, 2004. Pierre AF, Luketich JD, Fernando HC, et al: Results of laparoscopic repair of giant paraesophageal hernias: 200 consecutive patients. Ann Thorac Surg 74:1909-1916, 2002. Skinner DB, Belsey RH: Surgical management of esophageal reflux and hiatal hernia: Long-term results with 1030 patients. J Thorac Cardiovasc Surg 53:33-54, 1967. Swanstrom LL, Marcus DR, Galloway GQ: Laparoscopic Collis gastroplasty is the treatment of choice for the shortened esophagus. Am J Surg 171:477-481, 1996. Whitson BA, Hoang CD, Boettcher AK, et al: Collis gastroplasty and reinforced crural repair; essential components of laparoscopic giant hiatal hernia repair. Presented before the American Association for Thoracic Surgery 86th annual meeting, Philadelphia, PA, April 29May 3, 2006.

chapter

29

ESOPHAGECTOMY FOR BENIGN DISEASE Mark B. Orringer

Key Points ■ Esophagectomy for benign disease has different considerations

■ ■

■

■

than one for carcinoma: (1) a longer life expectancy for the patient (greater importance of long-term functional results); (2) lack of preoperative chemoradiation therapy; and (3) a greater frequency of prior esophageal operations. Obtaining prior operative records is important in enabling the surgeon to better plan the operation. There has been a decline in the number of esophagectomies being performed for anatomic obstructive pathology (e.g., reflux or caustic strictures) and more for neuromotor disease (achalasia and spasm) after prior unsuccessful operations, failed antireflux/ hiatal hernia operations, and Barrett’s esophagus and its complications. Functional results of esophageal replacement for benign disease should be assessed and reported in terms of the presence and degree of dysphagia, regurgitation, weight loss, post-vagotomy “dumping” symptoms, and patient satisfaction with ability to eat— not only in terms of the flow of barium down the conduit. When a free esophageal perforation occurs in a patient with intrinsic esophageal disease (e.g., carcinoma or a reflux or caustic stricture), esophagectomy is the best treatment option.

Patients with benign esophageal disease requiring esophageal resection and reconstruction differ in several ways from their counterparts with malignant disease: (1) longer life expectancy; (2) lack of neoadjuvant chemoradiation therapy; and (3) a frequent history of prior esophageal operations. Because of their longer life expectancy, those with benign disease serve as a better indicator of the functional results of esophageal substitution. For example, the development of reflux esophagitis is virtually inevitable after performance of a low intrathoracic esophagogastric anastomosis and is inversely related to the level of the anastomosis from the upper incisor teeth. This may have relatively little practical significance when life expectancy is short, but an esophageal reflux stricture causing dysphagia after an esophagectomy for benign disease intended to provide comfortable swallowing represents a dismal outcome. For this reason, a low intrathoracic esophagogastric anastomosis for benign disease should be avoided whenever possible (Fig. 29-1). The long-term results of esophagectomy and esophageal replacement for benign disease must be assessed not only in terms of length of survival after surgery as for the patient with carcinoma but also for the ability to swallow a normal diet comfortably, emptying of the esophageal substitute, posturally related

regurgitation and pulmonary complications resulting from it, and post-vagotomy “dumping” symptoms (postprandial cramping and diarrhea, diaphoresis, and palpitations). The current enthusiasm for neoadjuvant chemoradiation before esophagectomy for cancer places a greater burden on the surgeon to ensure that his or her patient has physiologically recovered from this treatment and is sufficiently strong to withstand an esophagectomy. Whether operating for benign or malignant esophageal disease, the pulmonary and nutritional consequences of impaired swallowing must be treated. Caloric supplementation through a nasogastric or enteric feeding tube is used as necessary, and vigorous preoperative pulmonary physiotherapy is instituted with treatment of pneumonia if present. The patient should use an incentive spirometer, walk 1 to 3 miles a day as tolerated, and absolutely stop smoking cigarettes. Finally, an ever-increasing number of patients requiring esophagectomy for benign disease have undergone one or more prior esophageal operations, often making their esophagectomy a far greater technical challenge that is associated with greater blood loss than in the patient with carcinoma. And because of prior gastric surgery, the options for esophageal reconstruction may be more limited. It is important to obtain prior operative reports that describe whether a crural closure was performed, if the fundoplication was secured to the diaphragm, the length of a previous esophagomyotomy, whether inadvertent entry into the lumen occurred and was repaired, and if a concomitant antireflux operation was performed. In the patient who has had a prior esophagomyotomy for achalasia or diffuse spasm, the exposed esophageal submucosa may become intimately adherent to the descending thoracic aorta, increasing the potential morbidity of esophagectomy. In those who have undergone multiple antireflux/ hiatal hernia operations, takedown of a prior fundoplication without traumatizing the stomach to the point that it cannot be used as an esophageal substitute may be a major challenge. In such patients in whom the stomach may not be a satisfactory esophageal replacement, the colon must be evaluated for its suitability and prepared in the event that it is needed. This chapter reviews the challenges associated with esophagectomy for benign disease.

HISTORICAL NOTE While esophagectomy has been the cornerstone of the surgical treatment of esophageal cancer, the earliest reports of esophageal replacement for benign conditions—esophageal atresia and caustic strictures—involved intrathoracic, substernal, or antethoracic subcutaneous conduits of colon, small 337

338

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 29-1 A, Barium swallow examination in a 74-year-old woman who had undergone a transabdominal distal esophagectomy and low esophagogastric anastomosis (arrow) for esophageal dysmotility. Subsequent gastroesophageal reflux and severe esophagitis resulted in anastomotic and multiple other esophageal strictures causing obstruction, aspiration pneumonia, and impaired nutrition. B, The patient underwent a transhiatal esophagectomy and conversion to a cervical esophagogastric anastomosis (marked with metallic clips). Her symptoms from gastroesophageal reflux and esophagitis were eliminated, bouts of recurrent pneumonia stopped, and her nutrition was restored. A low intrathoracic esophagogastric anastomosis for benign disease is to be avoided.

A

B

intestine, or reversed gastric tubes without resection of the native esophagus. Among the earliest reports of esophageal resection for benign disease were those performed for distal esophageal strictures resulting from gastroesophageal reflux and esophagitis. When reflux esophagitis became recognized as a distinct clinical entity in the 1950s, reflux strictures were generally regarded as representing end-stage irreversible fibrous reaction best treated surgically with resection. An esophagogastrectomy and esophagogastric anastomosis was popular among many surgeons.1-3 Although technically more difficult, others preferred a distal esophagectomy and jejunal interposition.4-11 Additional approaches included colonic interposition (Belsey, 1965)12-14; plastic operations on the distal esophagus15-17; and resection of the stricture with esophagogastrostomy in combination with antrectomy, vagotomy, and Roux-en-Y gastroenterostomy.18,19 In 1961, Hayward suggested that the majority of reflux strictures could be successfully treated with intraoperative dilation in combination with an antireflux operation.20 This approach was first popularized in the United States by Hill in 1970.21 But subsequent reports demonstrated that the presence of a reflux stricture with its inevitable associated esophageal shortening adversely affects long-term reflux control after standard antireflux operations.22,23 Esophageal shortening prevents a tension-free reduction of the distal esophagus well below the diaphragm, and mural inflammation from reflux esophagitis jeopardizes the reliability of the distal esophageal or periesophageal sutures that are used in the standard Belsey, Nissen, and Hill repairs. Because of the unacceptable recurrence rate in patients with strictures and severe reflux esophagitis undergoing an antireflux operation, Belsey advocated a distal esophagectomy and short-segment colon interposition rather than an antireflux procedure in

these patients.23 The case for nonresectional surgical therapy for esophageal reflux strictures was greatly enhanced by Pearson and associates, who in 1971 reported use of the esophageal-lengthening Collis gastroplasty24,25 in combination with the Belsey 240-degree fundoplication in patients with esophageal reflux strictures.26 The rationale was that breakdown of the repair and recurrent reflux in patients undergoing an antireflux operation could be minimized if (1) additional “esophageal” length were gained, thereby reducing tension on the repair, and (2) there were no need to suture to the inflamed distal esophagus. In 1974, Orringer and Sloan reported on the use of the GIA surgical stapler for the Collis procedure, thereby keeping it a “closed” operation.27 Subsequently even better long-term reflux control using a combined Collis-Nissen (360-degree fundoplication) procedure in patients with reflux strictures was demonstrated.28-31 Although esophagectomy for an esophageal reflux stricture may still be required (see later), the operative advances noted earlier, particularly the combination of the esophageallengthening Collis gastroplasty and a Nissen fundoplication and the advent of the H2-receptor antagonists and proton pump inhibitors, have resulted in a sharp curtailment in all operations formerly performed for such strictures. Prior to 1967, alkali (lye) was generally available only in solid form that when ingested would adhere to the mucosa of the oropharynx and upper esophagus where it would produce local burns. In 1967, highly concentrated liquid alkali preparations (Drano, Liquid-Plumr) were introduced in the United States and drastically changed the nature and extent of caustic esophageal injuries. Virtually instantaneous liquefaction necrosis caused by these agents may result in transmural destruction of the esophagus and stomach, requiring emergent operative intervention and the need for an

Chapter 29 Esophagectomy for Benign Disease

FIGURE 29-2 Posteroanterior chest radiograph in a 27-year-old man who underwent a substernal gastric bypass of the excluded esophagus for a caustic stricture 2 years earlier. He presented with chest pain and marked shortness of breath. The right paratracheal mass (arrows) proved to be a large dilated esophageal mucocele that was compressing the tracheobronchial tree. A nasogastric tube is seen in the retrosternal stomach. An endotracheal tube was placed emergently to relieve the airway obstruction. A transthoracic esophagectomy through a right thoracotomy was performed.

FIGURE 29-3 Lateral view from a barium esophagogram in a patient who had undergone a substernal colonic bypass for a caustic esophageal stricture 4 years earlier. She had a 2-year history of severe symptoms of gastroesophageal reflux and presented with upper gastrointestinal bleeding from what proved to be reflux esophagitis. This shows simultaneous opacification of the substernal colon as well as the native esophagus (arrow), which filled as a result of a grossly incompetent lower esophageal sphincter. A transthoracic esophagectomy was required to relieve the reflux esophagitis.

(REPRODUCED WITH PERMISSION FROM ORRINGER MB: COMPLICATIONS OF ESOPHAGEAL SURGERY. IN ZUIDEMA GD, ORRINGER MB [EDS]: SHACKELFORD’S SURGERY OF THE ALIMENTARY TRACT, 4TH ED. PHILADELPHIA, WB SAUNDERS, 1996, P 468.)

(REPRODUCED WITH PERMISSION FROM ORRINGER MB: COMPLICATIONS OF ESOPHAGEAL SURGERY. IN ZUIDEMA GD, ORRINGER MB [EDS]: SHACKELFORD’S SURGERY OF THE ALIMENTARY TRACT, 4TH ED. PHILADELPHIA, WB SAUNDERS, 1996, P 467.)

esophagectomy (see later). If the patient survives the acute injury, the development of both esophageal and gastric stenosis is common. Although historically, an esophageal bypass operation rather than a concomitant esophageal resection and reconstruction was the approach for caustic strictures, this view has changed. The stenotic esophagus due to a caustic injury should be resected whenever possible for the following reasons:

often stored in empty soda bottles and accidental ingestion is common. Packaging and labeling laws in the United States have greatly reduced the incidence of caustic esophageal strictures requiring resection in this country. It is an interesting commentary that an increasing number of esophagectomies for benign disease are being performed in this country not for obstructive pathology associated with reflux or caustic strictures; rather, they are being perfocmed for advanced neuromotor esophageal dysfunction (e.g., megaesophagus or achalasia), recurrent dysphagia after a prior esophagomyotomy or balloon dilation, recurrent gastroesophageal reflux or hiatal hernia after multiple failed prior fundoplications (particularly those done laparoscopically), and Barrett’s mucosa with high-grade dysplasia.

1. A retention cyst or abscess can develop in the retained esophagus (Fig. 29-2). 2. Severe reflux esophagitis in the native retained esophagus may result from the caustic injury and subsequent distortion of the lower esophageal sphincter mechanism (Fig. 29-3). 3. There is a 1000-fold increased risk of developing esophageal carcinoma after a severe caustic injury. 4. Resection of the esophagus allows placement of the esophageal substitute in the native esophageal bed, the shortest and most direct route between the neck and the abdomen. Worldwide, caustic ingestion remains a major cause of esophageal stenosis, particularly in the Middle East where lye is

HISTORICAL READINGS Allison PR, Johnston AS, Royce GB: Short esophagus with simple peptic ulceration. J Thorac Surg 12:432, 1943. Allison PR: Peptic ulcer of the esophagus. J Thorac Surg 15:308, 1946. Allison PR: Reflux esophagitis, sliding hiatal hernia, and anatomy of repair. Surg Gynecol Obstet 92:419, 1951.

339

340

Section 4 Gastroesophageal Reflux and Associated Conditions

Barnes WA, Redo SF: Evaluation of esophago-jejunostomy in the treatment of lesions at the esophagogastric junction. Ann Surg 146:224, 1957. Belsey RH: Reconstruction of the esophagus with left colon. J Thorac Cardiovasc Surg 49:33, 1965. Belsey RHR: Diaphragmatic hernia. In Jones FA (ed): Modern Trends in Gastroenterology. New York, Hoeber, 1952, p 128. Collis JL: An operation for hiatus hernia with short esophagus. Thorax 12:181, 1957. Collis JL: Gastroplasty. Thorax 16:197, 1961. Donnelly RJ, Deverall PB, Watson DA: Hiatus hernia with and without stricture: Experience with the Belsey Mark IV repair. Ann Thorac Surg 16:301, 1973. Dunlop EE: Problems in the treatment of reflux esophagitis. Gastroenterology 86:287, 1956. Ellis FH Jr, Anderson HA, Clagett OT: Treatment of short esophagus with stricture by esophagogastrectomy and antral excision. Ann Surg 148:526, 1958. Girvin GW, Merendino KA: Cardiac sphincter substitution by interpositioned jejunum. Arch Surg 72:241, 1956. Hayward J: The treatment of fibrous stricture of the esophagus associated with hiatus hernias. Thorax 16:45, 1961. Henderson RD, Maryatt GV: Total fundoplication gastroplasty (Nissen gastroplasty): Five-year review. Ann Thorac Surg 39:74, 1985. Henderson RD: Reflux control following gastroplasty. Ann Thorac Surg 24:206, 1977. Hill LD, Gelfand M, Bauermeister D: Simplified management of reflux esophagitis with structure. Ann Surg 172:638, 1970. Merendino KA, Dillard DH: The concept of sphincter substitution by an interposed jejunal segment for anatomic and physiologic abnormalities at the esophagogastric junction. Ann Surg 142:486, 1955. Merendino KA, Thomas GI: The jejunal interposition operation for substitution of the esophagogastric sphincter; present status. Surgery 44:1112, 1958. Neville WF, Clowes GHA Jr: Surgical treatment of the complications resulting from cardioesophageal incompetence. Dis Chest 43:572, 1963. Orringer MB, Orringer JS: The combined Collis-Nissen operation: Early assessment of reflux control. Ann Thorac Surg 33:534, 1982. Orringer MB, Skinner DB, Belsey RHR: Long-term results of the Mark IV operation for hiatal hernia and analyses of recurrences and their treatment. J Thorac Cardivasc Surg 63:25, 1972. Orringer MB, Sloan H: An improved technique for the combined CollisBelsey approach to dilatable esophageal strictures. J Thorac Cardiovasc Surg 68:298, 1974. Orringer MB, Sloan H: Combined Collis-Nissen reconstruction of the esophagogastric junction. Ann Thorac Surg 25:16, 1978. Payne WS: Surgical treatment of reflux esophagitis and stricture associated with permanent incompetence of the cardia. Mayo Clin Proc 45:553, 1970. Pearson FG, Langer B, Henerson RD: Gastroplasty and Belsey hiatal hernia repair. J Thorac Cardiovasc Surg 61:50, 1971. Popov VI: Reconstruction of the esophagus in cases of stricture. Arch Surg 82:226, 1961. Tanner NC, Westerholm P: Partial gastrectomy in the treatment of esophageal stricture after hiatal hernia. Am J Surg 115:449, 1968. Thal AP: A unified approach to surgical problems of the esophagogastric junction. Ann Surg 168:542, 1968. Thal AP, Hatafuku T, Kurtzman R: New operation for distal esophageal stricture. Arch Surg 90:464, 1965. Thomas GI, Merendino KA: Jejunal interposition operation; analysis of 33 clinical cases. JAMA 168:1759, 1958. Woodward ER: Sliding esophageal hiatal hernia and reflux peptic esophagitis. Mayo Clin Proc 50:523, 1975.

ACHALASIA In contrast to South America where the protozoan Trypanosoma cruzi is the offending organism, in North America and Europe, the etiology of achalasia is unknown. Irrespective of the cause, this neuromotor esophageal disease is incurable, and treatment is directed at providing palliation of dysphagia and pulmonary complications of aspiration. Both forceful (pneumatic) dilation and esophagomyotomy are recognized as effective therapy for early achalasia. As facility with video-assisted surgical technique has increased, laparoscopic esophagomyotomy has emerged as the preferred approach, providing more reliable relief of dysphagia with minimal morbidity. However, there are patients with achalasia in whom neither dilation therapy nor esophagomyotomy are the best option, and resection is preferred—those with an end-stage tortuous megaesophagus and those with recurrent obstructive symptoms from a reflux stricture after prior esophageal dilations or esophagomyotomy (Table 29-1). The latter group will often give a history of initially improved swallowing after a previous esophageal balloon dilation or esophagomyotomy without a concomitant antireflux operation but the simultaneous occurrence of posturally related heartburn, the result of converting an incoordinated lower esophageal sphincter into an incompetent one. The development of severe reflux esophagitis, particularly a reflux stricture at the esophagogastric junction in the achalasic patient with an atonic esophagus, is a situation in which a “redo” esophagomyotomy and/or addition of a fundoplication is unlikely to produce a reliably acceptable outcome. The stage of achalasia is a key determinant in recommending esophagectomy. When the diameter of the esophagus is 6 to 8 cm, a “megaesophagus” is present and in my experience is generally best treated by resection. However, if the axis of the esophagus is still straight, after an esophagomyotomy, the megaesophagus may still empty by gravity, so some advocate a myotomy even in these patients with endstage esophageal disease. However, with a sigmoid-shaped lower esophagus of more advanced disease (Fig. 29-4), retention in the “sink trap” supradiaphragmatic segment may occur even after a complete esophagomyotomy. In such cases, the megaesophagus is a functionless organ that is only a source of potential liability for the patient: persistent retention esophagitis, aspiration pneumonia, and the development of carcinoma in 3% to 10%.32,33 Although an esophagomyotomy for advanced achalasia has been recommended by some,34 a transhiatal esophagectomy for a tortuous megaesophagus is

TABLE 29-1 Indications for Esophagectomy for Achalasia ■ Tortuous “sigmoid” megaesophagus with “sink trap”

supradiaphragmatic segment ■ Reflux esophagitis or stricture after prior pneumatic dilation or

esophagomyotomy ■ Recurrent obstruction after prior esophagomyotomy ■ Obstruction from stricture or esophagitis after limited distal

esophagectomy

Chapter 29 Esophagectomy for Benign Disease

A

B

FIGURE 29-4 A and B, Barium esophagograms showing two examples of megaesophagus of advanced achalasia with characteristic “sigmoid”shaped distal end above the obstructing esophagogastric junction (arrows). Because the axis of the body of the esophagus is not aligned with the esophagogastric junction, even after a distal esophagomyotomy food will tend to collect in the dependent supradiaphragmatic pouch and emptying of the esophagus will be impaired. Note that the megaesophagus tends to deviate to the right of the midline, predisposing to entry into the right chest during transhiatal mobilization and the need for a right-sided chest tube.

the approach of others,35 including myself.36 Furthermore, in my experience, multiple prior esophageal operations have been a risk factor for a poorer functional outcome after esophagectomy; those with a history of unsuccessful operations are less satisfied after esophagectomy. For these reasons, I recommend esophagectomy as primary surgical treatment for very advanced achalasia. Recurrent esophageal obstruction after a prior esophagomyotomy or dilation merits careful assessment. If dilation therapy has failed to relieve dysphagia, an esophagomyotomy is reasonable. If dysphagia was initially relieved, but after a variable period of subsequent reflux symptoms dysphagia recurred, then careful endoscopic evaluation for the presence of a reflux stricture is important. Dilation of a reflux stricture and an antireflux operation on an atonic achalasic esophagus seldom relieve dysphagia, and an esophagectomy is simply a better option. Those with persistent or recurrent dysphagia after a prior esophagomyotomy are even more problematic, as the possible causes of the obstructive symptoms are more variable: an inadequate esophagomyotomy, healing of the myotomy, reflux esophagitis or stricture formation, development of a paraesophageal hiatal hernia, or esophageal carcinoma. When dysphagia is experienced virtually immediately after an esophagomyotomy, the likelihood is great that the myotomy was incomplete and failed to divide all circular

muscle fibers at the esophagogastric junction and onto the stomach for 1 to 1.5 cm; a repeat operation to complete the myotomy and perform a nonobstructing partial fundoplication will likely be successful. Reflux strictures occurring years after an esophagomyotomy with or without an antireflux procedure, however, are not well managed with dilation therapy, proton pump inhibitors, or revision or addition of a fundoplication because the achalasic atonic esophagus does not empty well in the presence of a stricture. The relatively large number of reoperations that have been proposed for patients with recurrent obstructive symptoms after a prior esophagomyotomy reflects the variability of results with these operations and lack of consensus that one approach is best: repeat esophagomyotomy; esophagomyotomy with a concomitant antireflux operation; takedown or revision of a prior antireflux operation; addition of a fundoplication; Heineke-Mikulicz–type cardioplasty; Thal-Hatafuku procedure; antrectomy, vagotomy, and Roux-en-Y gastrojejunostomy; distal esophagectomy and intrathoracic esophagogastrostomy; and varying lengths of esophageal resection and reconstruction with stomach or intestine. These reoperations for achalasia are successful, however, in only 45% to 75% of patients.37 It has been reported that a repeat esophagomyotomy is beneficial in only two thirds of patients requiring reoperation and a fundoplication for reflux symptoms in even

341

342

Section 4 Gastroesophageal Reflux and Associated Conditions

fewer.38 It is, therefore, my belief that a total thoracic esophagectomy, placement of the mobilized stomach in the posterior mediastinum in the original esophageal bed, and a cervical esophagogastric anastomosis is a more reliable approach in those patients with achalasia requiring reoperation; and, in most such cases, a transhiatal esophagectomy is feasible. Patients requiring an esophagectomy for achalasia present several unique technical challenges to the surgeon not encountered in others undergoing a transhiatal esophagectomy (Table 29-2). First, the massively dilated esophagus may contain 1 to 2 L of intraesophageal debris, even in the patient who has fasted overnight, thereby increasing the risk of regurgitation and aspiration on induction of general anesthesia (Fig. 29-5). Therefore, before initiating endotracheal anesthesia, TABLE 29-2 Esophagectomy for Achalasia—Unique Considerations ■ Potential for aspiration on induction of anesthesia ■ Predisposition of right pleural entry during transhiatal

esophagectomy ■ Enlarged thoracic aortic esophageal arteries ■ Difficulty encircling dilated cervical esophagus ■ Adherence of myotomized esophageal submucosa to adjacent

thoracic aorta ■ Occasional “parasympathetic dystrophy”—exaggerated post-

vagotomy dumping

FIGURE 29-5 Barium esophagogram showing end-stage achalasia (megaesophagus) with massive dilation of the esophagus and a high air-fluid level indicative of retention of 1 to 2 L of food and fluid and the potential for aspiration on the induction of general anesthesia.

with the patient sitting upright, a nasogastric tube should be introduced into the esophagus and used to evacuate it as much as possible. Either awake endotracheal intubation or a rapid sequence induction with constant cricoid pressure is then carried out and the patient not placed supine until the airway is secured with the inflated cuff of the endotracheal tube. Rigid esophagoscopy with repeated irrigation and suctioning is next performed to complete the evacuation of intraesophageal contents and minimize the degree of mediastinal contamination that may occur if the lumen is entered during esophageal mobilization. Second, due to the tortuosity of the dilated esophagus that typically projects to the right of the midline (see Fig. 29-4) entry into the right pleural cavity is particularly common during a transhiatal esophagectomy and is relatively easily managed with intraoperative placement of a chest tube. Third, the hypertrophied muscle of the achalasic esophageal wall may be nourished by larger than usual thoracic aortic esophageal vessels. Particular care should be exercised exposing the enlarged esophagus through the diaphragmatic hiatus using long narrow retractors placed into the hiatus to facilitate direct mobilization, clamping, and ligation of the lateral esophageal attachments. In Brazil, where Chagas’ disease is common, use of an anterior diaphragmatic incision radiating forward from the hiatus to facilitate exposure of the posterior inferior mediastinum and aid in resecting a megaesophagus has been popularized.35 I, however, have rarely found this to be necessary. Fourth, because dilation of the megaesophagus frequently extends proximally and involves the cervical esophagus, mobilizing and encircling the esophagus in the neck may be more difficult and is potentially complicated by a higher incidence of recurrent laryngeal nerve injury and inadvertent entry into the esophagus. Having a nasogastric tube within the esophagus allows the surgeon to better assess the limits of the esophageal wall. Working through a left cervical incision, by continually retracting the esophagus and contained nasogastric tube toward the patient’s left side with one index finger while progressively dissecting across the anterior surface of the esophagus toward the right side with the other until the prevertebral fascia is felt, mobilization and encirclement of the widened cervical esophagus are achieved. Particular care must be taken to avoid injury to the recurrent laryngeal nerve. Fifth, after a prior esophagomyotomy, the exposed esophageal submucosa may become adherent to the adjacent lung and descending thoracic aorta, increasing the risk of a postoperative air leak or major hemorrhage during esophageal mobilization. For these reasons, some have suggested a transthoracic approach in patients requiring an esophagectomy after a prior esophagomyotomy (Miller et al, 1995).39 In my experience, however, mobilization of the previously myotomized esophagus through the diaphragmatic hiatus is almost always possible. The dissection of the distal esophagus away from the aorta cannot be done “blindly”; direct sharp dissection is the preferred technique. If the esophageal lumen is inadvertently entered, the appropriate plane of dissection may actually become more apparent. If the lumen is entered during the esophageal mobilization, intraesophageal nasogastric tube suction should be instituted, suture closure performed to reduce mediastinal contamination, and the mediastinum copiously irrigated after the

Chapter 29 Esophagectomy for Benign Disease

esophagus has been removed. Stapling of the edge of the lung adherent to the esophageal wall may be performed through the hiatus to avoid a postoperative air leak from this site. I have noted one other peculiarity encountered in some achalasic patients undergoing an esophagectomy—an apparent generalized parasympathetic dystrophy. This may be manifested intraoperatively as a tendency toward excessive salivation during general anesthesia or bradycardia when the peritoneum or mediastinal pleura is stretched as the transhiatal dissection is begun; this is treated with intravenous atropine administration. Postoperatively, these patients may experience exaggerated postvagotomy “dumping” symptoms (postprandial cramping and/or diarrhea, diaphoresis, and prostration). A standard high-fiber “anti-dumping” diet and antidiarrheal medication used to treat “dumping” may be ineffective in these patients. Adoption of an “Asian diet” (predominately rice, vegetables, and fruit), use of atropinelike drugs, and somatostatin injections may be required for control of this problem, which is generally, but not always, self-limited. Whereas such severe “dumping” is uncommon, achalasic patients should be warned preoperatively of this possibility. My associates and I have reported our experience with 98 patients undergoing esophagectomy for achalasia over a 20year period.36 The indications for esophagectomy included a tortuous megaesophagus (64%), failure of a prior esophagomyotomy (63%), and an associated reflux stricture (7%). A transhiatal esophagectomy was performed in 94%, and the stomach was used as the esophageal substitute in 91%. Average intraoperative blood loss was 672 mL. There were two hospital deaths (2%) from respiratory insufficiency and sepsis. Major postoperative complications included anastomotic leak (10%), recurrent laryngeal nerve injury (5%), delayed mediastinal bleeding requiring a thoracotomy for control (2%), and chylothorax (2%). With an average followup of 38 months, 95% eat well; nearly 50% have required an anastomotic dilation; clinically significant regurgitation has been rare; and 4% have refractory postvagotomy dumping (discussed earlier). It was concluded that in appropriately selected patients with end-stage achalasia or achalasia with recurrent obstructive symptoms after esophagomyotomy or dilation, a transhiatal esophagectomy and cervical esophagogastric anastomosis is a safe and reliable approach for definitively dealing with the diseased esophagus.

GASTROESOPHAGEAL REFLUX DISEASE/HIATAL HERNIA A fundoplication—either partial or complete—is the most common surgical approach for controlling abnormal gastroesophageal reflux. Similarly, in most patients currently undergoing repair of a paraesophageal hiatus hernia, there is general consensus that a fundoplication is needed to control associated reflux. Most patients who are operated on for a “paraesophageal” hiatal hernia actually have a combined sliding and paraesophageal (type III) hiatal hernia and frequently give a long history of gastroesophageal reflux disease associated with what began as a sliding hiatal hernia. Over the years, the influence of negative intrathoracic pressure, often combined

with weight gain, results in progressively more stomach being drawn into the chest in a paraesophageal location. Therefore, when these hernias are repaired, the sliding hiatus hernia component warrants an antireflux operation; and in the minority without preexisting reflux, mobilization of the esophagogastric junction and distal esophagus that is required to repair a paraesophageal hiatal hernia results in sufficient disruption of the lower esophageal sphincter mechanism that a fundoplication is justified as a part of the paraesophageal hiatal hernia operation. Antireflux/hiatal hernia operations may fail for a variety of reasons: recurrent reflux symptoms; dysphagia from too tight a fundoplication, an overaggressive crural closure, or unrecognized preexisting neuromotor dysfunction; gas bloat syndrome; intractable postvagotomy dumping; and recurrent hiatal hernia. Because few surgical series of antireflux/hiatal hernia operations provide true long-term (5-10 year) objective follow-up data, the true incidence of poor results after these operations is likely grossly underestimated. Clinical reports based on short-term follow-up and subjective questioning of patients after antireflux operations suggest that reflux is “controlled” in more than 90% of patients, and new symptoms not necessarily related to reflux develop in 10% to 25%. Proper follow-up of these patients, however, not only includes subjective questioning about reflux symptoms, comfortable swallowing, and any adverse symptoms but also periodic distal esophageal pH reflux testing, upper endoscopy if indicated, and a barium swallow at 1-, 3-, and 5-year intervals after a fundoplication to document a continued intra-abdominal location of the wrap and a competent lower esophageal sphincter mechanism. Because such follow-up is seldom obtained, it is likely that poor results after these operations are more common than is currently appreciated. The surgical challenge is to define the key principles that are most critical in minimizing the failure of the initial operation; for with each successive antireflux operation, the likelihood of long-term success is diminished. Every successful antireflux/hiatal hernia operation, regardless of the type, shares certain common features: a 3- to 5-cm length of intraabdominal distal esophagus under the influence of positive intra-abdominal pressure, sutures placed into distal esophageal or paraesophageal tissues, and closure of the crura. Any factors that increase tension on the repair or result in the need to suture to inflamed or fibrotic esophageal or periesophageal tissue potentially jeopardize the long-term success of these operations. Patients being considered for antireflux or hiatal hernia operations should be assessed preoperatively for the presence of “recurrence risk factors,” that is, identifiable factors that predispose them to recurrence after any of the standard repairs: severe esophagitis with transmural inflammation and esophageal shortening that increases tension on the repair and requires suturing to abnormal tissue when performing the fundoplication; marked obesity and chronic obstructive pulmonary disease, both of which increase intraabdominal pressure and tension on the crural closure; a history of hernias at other sites (inguinal, umbilical, incisional) suggesting intrinsic connective tissue weakness; and a recurrent hiatal hernia or prior distal esophageal operation that must be “taken down” and leaves contused lower esoph-

343

344

Section 4 Gastroesophageal Reflux and Associated Conditions

ageal tissue around which to perform a “redo” fundoplication (Stirling and Orringer, 1986).40 Large combined sliding and paraesophageal hiatal hernias present a unique constellation of surgical challenges that increase the risk for recurrent herniation after traditional hiatal hernia repairs: esophageal shortening (less well appreciated through an abdominal approach); an especially widened hiatus, often with attenuated diaphragmatic muscle; particularly “soft tissues”; and, frequently, associated obesity. The current almost universal enthusiasm for “laparoscopic fundoplication” as the surgical approach of choice in any patient with a hiatal hernia or reflux has resulted in a growing number of patients with recurrent reflux or hernias,41 because the presence of “recurrence risk factors” was not acknowledged at the time of the first operation. In acknowledgment of the fact that adequate closure of the hiatus in patients with large paraesophageal hiatus hernias is an inherent weakness of laparoscopic repairs in these patients, use of a mesh “cruroplasty” has been advo-

A

cated.42-44 The potential complications of postoperative dysphagia from distal esophageal obstruction resulting from the mesh and erosion of the mesh into either the esophagus or proximal stomach are substantial, often requiring an esophagectomy for resolution (Fig. 29-6). In patients with reflux and/or hiatal hernias and concomitant “recurrence risk factors” noted earlier, my preference is a combined esophageal-lengthening Collis gastroplasty/Nissen fundoplication procedure that results in a tension-free repair around a resilient neo-esophagus of healthy stomach.31,40 Furthermore, the transthoracic approach in these “high risk for recurrence” patients allows optimal proximal esophageal mobilization and clear delineation of the right and left diaphragmatic crura for suture placement with generous bites back to tendinous diaphragm for reapproximation. By using the transthoracic approach to the hiatus in more than 1200 Collis-Nissen operations, I have never found it necessary to use pledgeted sutures or mesh to achieve approximation of the crura and

B

FIGURE 29-6 A, Barium esophagogram in an obese 71-year-old woman with a large recurrent hiatal hernia (fundoplication in the chest) after a transabdominal Nissen fundoplication 11 years earlier for a paraesophageal hiatal hernia. This patient had “recurrence risk factors”: esophageal shortening, obesity, and a prior failed repair. Yet this recurrence was again approached through the abdomen, the fundoplication reduced back into the peritoneal cavity, and the enlarged hiatus closed with mesh, one side of which was slit and the ends wrapped around the esophagus from opposite sides and sutured to the other side to “anchor” the lower esophagus in the abdomen. B, Barium esophagogram in same patient 9 months after the “mesh repair.” This study was interpreted as showing the fundoplication again herniated into the chest, but this time also obstructed at the level of the diaphragm due to the mesh (arrow). The patient was unable to retain swallowed food. She required a very difficult transabdominal excision of the mesh that was incorporated into the perihiatal tissues. A band of mesh was found to be obstructing the distal esophagus approximately 2 cm superior to the esophagogastric junction. The dilated segment proximal to the stenosis on barium swallow, thought to be a re-herniation of the fundoplication, was actually the severely dilated distal esophagus. Although a colon bowel prep had been performed, it was possible to take down the fundoplication, perform a transhiatal esophagectomy, use the stomach as an esophageal replacement, and construct a cervical esophagogastric anastomosis. Comfortable swallowing was restored. Mesh was not the answer for this recurrent paraesophageal hiatal hernia and resulted in severe esophageal obstruction requiring an esophagectomy. A transthoracic esophageallengthening Collis gastroplasty combined with a Nissen fundoplication would have been the preferred second operation.

Chapter 29 Esophagectomy for Benign Disease

closure of the diaphragmatic hiatus.45 Regardless of the approach, the greater the number of “recurrence risk factors” in a given patient (e.g., a prior failed antireflux operation associated with severe reflux esophagitis and esophageal shortening in an obese patient), the greater the likelihood of failure of an antireflux/hiatal hernia operation. “Redo” antireflux/hiatal hernia operations are a tremendous challenge, often leading to an esophageal resection for benign disease. In my experience, most recurrent hiatus hernias are best approached transthoracically for the reasons cited earlier. If there is primarily an intra-abdominal problem (e.g., too tight a fundoplication causing dysphagia), an abdominal approach to redo the wrap is reasonable. A 40-Fr dilator within the esophagus facilitates its identification and dissection within the mediastinum. In these redo operations, the surgeon must focus on minimizing gastric trauma, “dissecting wide”—at times mobilizing a thin layer of adjacent liver capsule or diaphragm with the stomach—to avoid devascularization of the gastric fundus. If after taking down the prior repair and mobilizing the proximal stomach there is extensive local gastric trauma, esophageal resection and reconstruction is a far safer and more reliable option than repair of the stomach and a “makeshift” hernia repair. Once again, failing to recognize that a recurrent hiatal hernia or reflux after a prior laparoscopic fundoplication is likely explained by the presence of preexisting “recurrence risk factors,” laparoscopic surgeons often tread down the same pathway, approaching the patient with a recurrence with yet another ill-fated laparoscopic repair, justifying this approach on subjective assessments of “sense of well-being” of the patient after fewer than 1 to 2 years of follow-up.46 In patients being operated on for recurrent reflux or hiatal hernia, I routinely evaluate the colon preoperatively with a barium enema and order a colon bowel prep as a “backup” in the event that the “redo” CollisNissen operation is not possible and an esophagectomy and visceral esophageal substitution are required. This possibility is discussed with the patient preoperatively as well. Others also favor the combined Collis-Nissen approach in patients requiring surgery for failed antireflux procedures.47 Unless the patient has a history suggesting a likelihood of abnormal colon blood supply (e.g., a known abdominal aortic aneurysm or history of colon resection), routine mesenteric angiography is not performed. I rely on a palpable pulse in the mobilized colon and intraoperative Doppler determinations of colon blood flow as the best indicators of adequacy of the colon blood supply. When it is determined intraoperatively that a reliable redo hiatus hernia repair is not possible, the surgeon has several options, each with its proponents. It has long been debated whether it is preferable to resect only the distal esophagus and perform either a short-segment left colon interposition (Belsey, 1965)12 or jejunal interposition48 or to remove the entire thoracic esophagus and perform a cervical esophageal anastomosis to avoid the risk of mediastinitis from an intrathoracic anastomotic leak.49 Although “safer” from the standpoint of potential acute postoperative morbidity, a cervical esophageal anastomosis may have a less satisfactory long-term functional result if an anastomotic leak should occur, since 50% of cervical esophageal anastomotic leaks result in forma-

tion of an anastomotic stricture. My use of a side-to-side stapled cervical esophagogastric anastomosis (see Chapter 52) has reduced the incidence of anastomotic leak after esophagectomy to the low single digits, and the need for subsequent anastomotic dilations for dysphagia has similarly fallen (Orringer et al, 2000).50 If after remobilization, the distal esophagus, esophagogastric junction, or proximal stomach is severely contused, another fundoplication may be precluded, but use of the stomach as an esophageal substitute and a cervical esophagogastric anastomosis may still be possible. Because the stapler is applied along the lesser curvature of the stomach in fashioning the gastric tube, much of the unhealthy stomach may be resected, leaving a viable gastric conduit for esophageal replacement. I have also noticed that when the gastric fundus has been operated on previously, submucosal collateral circulation becomes better established (similar to a “delayed” flap), enabling use of the stomach as an esophageal substitute and a cervical esophagogastric anastomosis despite the prior operations on the fundus. Because of the inevitable reflux esophagitis associated with a distal esophagectomy and low intrathoracic esophagogastric anastomosis, this approach should virtually never be used in the patient with benign esophageal disease requiring esophageal replacement and having a reasonable life expectancy (see Fig. 29-1). When performing a transthoracic redo hiatal hernia repair, after mobilizing the stomach and taking down the prior fundoplication, it must be determined if a technically sound repeat fundoplication with a reasonable chance of success can be performed. This is a “judgment call.” If another hiatal hernia repair is not feasible and an esophagectomy is required, so long as the greater curvature of the stomach to its tip appears sufficiently healthy, intrathoracic esophageal mobilization superiorly beneath the aortic arch and into the thoracic inlet is completed. The mobilized thoracic esophagus is left in situ, a chest tube is inserted, and the chest incision is closed in the standard fashion. The wound is dressed, and the patient is positioned supine with the neck extended by a folded rolled sheet beneath the scapulae as for a transhiatal esophagectomy (see Chapter 52). Through an upper midline abdominal incision, gastric mobilization, a Kocher maneuver, pyloromyotomy, and insertion of a feeding jejunostomy tube are completed. Through a left cervical incision, the cervical esophagus is encircled, 8 to 10 cm of the previously mobilized thoracic esophagus is drawn into the neck wound, and the cervical esophagus is divided with a Endo-GIA stapler. The stomach and attached esophagus are drawn out of the abdominal wound, the esophagus separated from the stomach with progressive applications of the stapler, and esophageal replacement using the stomach and a stapled side-to-side anastomosis performed as described in Chapter 52. Judgment and experience play important roles in the selection of patients with gastroesophageal reflux disease and its complications for esophagectomy (Table 29-3). Esophageal resection is indicated in patients with high-grade dysphagia in Barrett’s mucosa, “hard” nondilatable reflux strictures (including those which disrupt as intraoperative dilation is performed); chronic esophageal fistulas complicating prior hiatus hernia repairs; severe ulceration, perforation, or bleed-

345

346

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 29-3 Indications for Esophagectomy for Gastroesophageal Reflux Disease/Hiatal Hernia ■ Recurrent reflux/hiatal hernia with two or more “recurrence risk

factors”: esophageal shortening, stricture, obesity, chronic obstructive pulmonary disease ■ Two prior failed antireflux/hiatal hernia operations ■ Gastric devitalization during remobilization for redo

fundoplication ■ Complications of Barrett’s esophagus: high-grade dysplasia,

bleeding, perforation ■ “Hard” nondilatable reflux stricture ■ Disruption of reflux stricture during attempted intraoperative

dilation

ing from Barrett’s esophagitis; and those in whom it is simply impossible to take down a prior fundoplication or the fundus is severely devascularized in the process of remobilization. Is there an absolute number of prior unsuccessful hiatal hernia repairs that dictate the need for an esophagectomy? Unfortunately there is no reliable “rule of thumb” regarding the need for esophageal resection based on the number of prior operations the patient has had. In my experience, however, long-term success (i.e., no recurrent reflux symptoms, anatomic hiatal hernia, or dysphagia) is achieved in more than 90% of patients after a primary hiatal hernia/antireflux operation. The success rate falls to approximately 75% after a second repair, and those undergoing a third antireflux/ hiatal hernia operation can expect no better than a 50% success rate. I am generally unwilling to do a third antireflux/ hiatal hernia operation and subject the patient to that type of failure rate and will typically recommend an esophagectomy rather than a third antireflux/hiatal hernia operation. It is important that old operative records be obtained and reviewed. “Anatomic” hiatal hernia repairs performed decades ago often consisted of a crural closure and minimal or no periesophageal dissection. The esophagogastric junction in these patients may be relatively “virgin” and readily amenable to an antireflux procedure, particularly a Collis-Nissen repair, which is my choice for recurrent hiatal hernia or reflux. In others, repair or revision surgery is impossible owing to the severity of adhesions, and resection is the only viable option. With the current and growing enthusiasm for laparoscopic fundoplication, the perceived “ease” of this approach has resulted in a laxity of the formerly strict indications for antireflux surgery and a proliferation of laparoscopic fundoplications and their attendant complications. The “knee jerk” reflex to approach all patients with reflux and/or a hiatal hernia with a laparoscopic fundoplication, ignoring the importance of body habitus, the presence of esophageal shortening, or even a history of a prior operation at the hiatus, is predictably associated with a growing number of patients with failed operations. And in the patient who has undergone three or four fundoplications, at times one fundoplication being performed over another without ever fully “taking down” the wrap, an esophagectomy and reconstruction may be the patient’s best chance for comfortable swallowing or relief of esophagitis.

When the need for an esophagectomy has been determined preoperatively, my preferred approach is a transhiatal esophagectomy without thoracotomy and a cervical esophagogastric anastomosis. The colon should be evaluated with a barium enema examination to identify diverticulosis that might preclude use of a particular segment of the colon as an esophageal substitute, and the colon should be prepared in the event that the stomach cannot be utilized. Symptoms of esophagitis are eliminated after an esophagectomy. Troublesome, predominantly nocturnal, positional gastroesophageal reflux is uncommon after a cervical esophagogastric anastomosis and generally responds to elevation of the head of the bed 4 to 6 inches at night and avoiding eating for several hours before retiring. Those who develop a cervical esophagogastric anastomotic stricture, usually after a leak, are a difficult group who require aggressive and initially frequent anastomotic dilations to at least a 46-Fr bougie to achieve comfortable swallowing. Meticulous preparation of the gastric esophageal substitute, minimizing trauma and preserving submucosal collateral circulation, and utilizing the side-to-side stapled cervical esophagogastric anastomosis are rewarded by a lower incidence of anastomotic leak and subsequent stricture formation.

ESOPHAGEAL DISRUPTION Injury to the esophagus may result in a perforation and the development of life-threatening mediastinitis. The focus in this section is on those situations in which esophageal resection for trauma is indicated. Nearly 75% of esophageal perforations are iatrogenic and related to esophageal instrumentation: endoscopy, dilation, intubation, sclerotherapy, and laser therapy. Approximately 25% of esophageal perforations are the result of external, noninstrumental trauma: barogenic trauma such as with Boerhaave’s syndrome, labor, convulsions, defecation, or blunt trauma; penetrating neck, chest, or abdominal trauma; operative injury during vagotomy, pulmonary resection, or esophageal reconstruction; caustic ingestion; or swallowed foreign bodies. Regardless of the etiology, the pathophysiology of an intrathoracic esophageal rupture is constant. As swallowed saliva, oral bacteria, and refluxed gastric contents exit the esophageal tear, respiratory movements and negative intrathoracic pressure increase local contamination. The resulting mediastinal “burn” results in hypovolemic shock, reflex bronchorrhea, and hydropneumothorax as the inflammatory process ruptures through the mediastinal pleura and into a pleural cavity. Early detection of the esophageal tear is the key to reducing morbidity and mortality, ideally allowing repair of the perforation within 6 hours of the injury before mediastinitis can become established. A biplane barium esophagogram is the “gold standard” for diagnosing an esophageal perforation. Water-soluble contrast agents do not provide the same degree of mucosal detail as barium, and a “negative” water-soluble esophagogram should never be regarded as definitive evidence of esophageal integrity in a patient with fever or chest pain after esophageal instrumentation or surgery suspected of having a perforation. Occasionally, contrast medium– enhanced computed tomography may be useful in identifying

Chapter 29 Esophagectomy for Benign Disease

an esophageal perforation in a patient with atypical symptoms or questionable diagnosis; air in the mediastinum, esophageal thickening, or a pleural effusion on computed tomography increases one’s suspicion but does not establish the diagnosis. Conventional wisdom has taught that the earlier an esophageal perforation is diagnosed, the better the chances of a successful repair. As time passes, the edges of the esophageal disruption become progressively more inflamed and less likely to heal after suture repair. Because of the skepticism that late-diagnosed perforations will heal if sutured, a number of procedures to divert, exclude, or achieve a controlled esophagopleural-cutaneous fistula evolved. More modern experience, however, has demonstrated that with meticulous technique, a thoracic esophageal perforation not associated with intrinsic esophageal disease should be managed with a meticulous primary repair and mediastinal drainage, regardless of the duration of the tear. The Endo-GIA surgical stapler, which results in a three-row repair, is ideally suited for this approach.51 Successful healing is achieved in 80% to 90% of those so treated, and of those who develop a recurrent leak, nonoperative management is often adequate for resolution. The patient with an esophageal perforation and intrinsic esophageal disease causing distal obstruction, however, constitutes a far different situation in which primary repair is less likely to be successful and disruption due to elevated

A

intraluminal pressure more common. When treating an esophageal perforation, it is extremely important to elicit from either the patient or his or her family a history of prior dysphagia or treatment of esophageal pathology (Fig. 29-7). Endoscopic assessment of intrinsic esophageal disease at the time of surgery and palpating the esophagus distal to the tear with a finger inserted into the lumen can avoid inadvertently overlooking obstruction distal to the planned repair. If there is mild distal obstruction (e.g., a “soft,” dilatable esophageal reflux stricture), the stenosis should be dilated intraoperatively to a 46-Fr bougie or larger at the time of primary repair of the perforation. In the patient with achalasia who sustains an esophageal perforation during attempted balloon dilation, repair of the perforation, esophagomyotomy, and a partial (Belsey) fundoplication to buttress the repair should be performed. In our group of 42 patients with esophageal perforations, of 25 who underwent a primary repair, one third required further treatment with either esophageal dilation or reconstruction, and all of them had either preexisting esophageal strictures or diffuse motility disorders.52 In those patients with an esophageal perforation and associated intrinsic esophageal disease (tumor, nondilatable stricture) and those with severe, caustic injury, or massive disruption from trauma, esophageal resection is indicated (Table 29-4). Patients with more severe, “hard” reflux strictures that are perforated during dilation may heal after a primary repair, but the fibrosis inherent in the healing process

B

FIGURE 29-7 A, Barium swallow examination in a patient with an epiphrenic diverticulum and associated esophageal dysmotility who was incorrectly treated with balloon dilation of her hypertensive distal esophagus. A perforation (arrow) at the gastroesophageal junction was diagnosed 8 hours later. A transhiatal esophagectomy, transhiatal mediastinal irrigation, and cervical esophagogastric anastomosis was believed to be a better option than repairing the esophageal tear, resecting the diverticulum, and performing an extended esophagomyotomy, thereby leaving two esophageal suture lines in a contaminated posterior mediastinum. B, Posteroanterior (left) and lateral (right) views of the barium swallow after a transhiatal esophagectomy and cervical esophagogastric anastomosis. The patient is alive and well after 8 years. (REPRODUCED WITH PERMISSION FROM ORRRINGER MB: ESOPHAGECTOMY FOR ESOPHAGEAL DISRUPTION. ANN THORAC SURG 49:35, 1990. COPYRIGHT ELSEVIER 1990.)

347

348

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 29-4 Indications for Esophagectomy for Esophageal Disruption ■ Irreparable tear ■ Severe corrosive injury—alkali or acid ■ Perforation with intrinsic disease: “hard” distal stricture,

epiphrenic diverticulum ■ Chronic esophagopleural-cutaneous fistula with sepsis

is only additive and will lead to even worse swallowing than before the perforation. A reflux stricture that disrupts in the surgeon’s hand during attempted intraoperative passage of a dilator is deemed “nondilatable” and is best managed by resection. Severe caustic esophageal perforations and extensive esophageal injuries due to high-velocity gunshot wounds cannot be repaired safely and are best resected. An attempt to salvage a diseased perforated esophagus because of concern that an esophagectomy is too major an undertaking may have disastrous consequences. And when the decision is made to resect the esophagus, a total, not limited, thoracic esophagectomy should be performed. This approach eliminates ongoing mediastinal and pleural contamination and is well tolerated especially in those with perforations diagnosed relatively early. In those otherwise stable patients with “early” free perforations that cannot be managed conservatively but are contained within the mediastinum, a transhiatal esophagectomy, vigorous intraoperative mediastinal irrigation (Fig. 29-8), and a one-stage cervical esophagogastric anastomosis has the advantage of eliminating the esophageal pathology, filling the contaminated posterior mediastinum with wellvascularized stomach, and removing the anastomosis from the contaminated posterior mediastinal field.53 In those patients with pleural contamination, an established empyema, or a chronic esophagopleural-cutaneous fistula (Fig. 29-9), a transthoracic esophagectomy is necessary to mobilize the esophagus from periesophageal inflammatory reaction and decorticate the lung. Every patient with intrinsic esophageal disease and a perforation that warrants esophagectomy may not be physiologically able to withstand a one-stage esophagectomy and reconstruction. Those who are septic and hemodynamically unstable may be better served with an esophagectomy, an end-esophagostomy, and feeding jejunostomy; and once they have recovered from the acute event and regained strength, they can undergo esophageal reconstruction at a later date. When carrying out an end-esophagostomy, the maximum length of viable esophagus proximal to the tear should be preserved. The traditional approach of bringing out the divided esophagus through a neck incision and “tailoring” it to approximate the cervical skin is not a good one. This wastes viable esophageal length as the stoma is created on the side of the neck or in the supraclavicular fossa. It is also difficult to apply a stomal appliance to the supraclavicular fossa, and subsequent salivary drainage is disturbing to the patient. Alternatively, when performing an end-esophagostomy in association with an esophagectomy for a perforation, I divide the mobilized intrathoracic esophagus immediately proximal

FIGURE 29-8 Transmediastinal irrigation after transhiatal esophagectomy for a perforation. When this approach is required, maximum esophageal length to just above the level of the perforation should be preserved and the mobilized intrathoracic esophagus, now nourished by the thyroid vessels and submucosal collateral circulation, delivered out of the neck incision.

to the perforation. Through a left cervical incision, the esophageal remnant, which can be 8 to 10 cm in length, is delivered out of the mediastinum and into the neck wound. The remaining esophagus is nourished by the submucosal collateral circulation now based on the thyroid arteries. A subcutaneous tunnel over the left clavicle and onto the upper anterior chest is made, and the length of the residual esophagus used to estimate where a button of skin should be excised to create the stoma. The esophagus is then passed subcutaneously and the end brought out through the skin opening and sutured to the edges with interrupted absorbable suture (Fig. 29-10). This infraclavicular anterior thoracic esophagostomy constructed on the flat surface of the upper chest is readily contained by a stomal appliance. And ultimately, when a retrosternal esophageal reconstruction is undertaken, the additional remaining esophageal length is more easily apposed to the transposed colon or stomach. As a general rule, esophageal exclusion in a patient with a perforation should be avoided, because these procedures only complicate later esophageal reconstruction. Occluding tapes placed around the esophagogastric junction to prevent reflux of gastric juice out of the perforation must eventually be removed. Dividing the disrupted intrathoracic esophagus

Chapter 29 Esophagectomy for Benign Disease

A

B

FIGURE 29-9 A, Chest radiograph in a 65-year-old woman who underwent a right transthoracic resection of an epiphrenic diverticulum without a concomitant esophagomyotomy. Postoperative disruption of the esophageal diverticulum suture line and mediastinitis were managed with chest tube drainage and antibiotics. Respiratory insufficiency necessitated a tracheostomy and mechanical ventilatory assistance. She was transferred to our hospital in septic shock 4 weeks later. B, Barium esophagogram showing extravasation of swallowed barium into the right chest and no flow of contrast medium distally into the stomach. The day after her arrival and resuscitation she underwent a transthoracic esophagectomy, mediastinal and pleural decortication and irrigation, and anterior thoracic esophagostomy. She was nourished through a feeding jejunostomy tube. Recovery from sepsis followed; and after 2 months, a substernal gastric interposition was performed. The patient is alive and well 18 years later. (REPRODUCED WITH PERMISSION FROM ORRINGER MB, STIRLING MC: ESOPHAGECTOMY FOR ESOPHAGEAL DISRUPTION. ANN THORAC SURG 49:35, 1990. COPYRIGHT ELSEVIER 1990.)

proximal to a perforation and stapling or ligating the distal end below the perforation and resecting the intervening perforated segment leaves an esophageal suture line in the posterior mediastinum in an infected field and can be disastrous when the closure leaks several days later. Dividing the upper esophagus in the neck and constructing a proximal lateral or end-cervical esophagostomy complicates later esophageal reconstruction. When confronted with an intrathoracic esophageal perforation that is believed to be irreparable, thought should always be given to the eventual reconstructive procedure that will be required to re-establish alimentary continuity. The important concept in this discussion is not that every patient with an esophageal disruption should be managed with an esophagectomy. But we have found that often in critically ill patients, particularly those in whom prior attempts to drain, close, or exclude the esophagus have failed to control sepsis, an esophagectomy may be the only means of achieving salvage. Ongoing mediastinal and pleural contamination is stopped, as is continued loss of saliva, gastric, and biliary drainage. Successful conservative nonoperative management of esophageal perforations also has its advocates. With a small

leak contained in the mediastinum in a patient without systemic signs of sepsis, antibiotics and observation may be adequate therapy. In those with larger mediastinal or intrathoracic “free” esophageal perforations of the types referred to earlier, some argue that a thoracotomy to attempt repair in a very ill patient is too aggressive therapy. But the majority of surgeons do not feel comfortable treating such patients with chest tube drainage alone. One caveat, however, is the edentulous elderly patient who may well tolerate a spontaneous intrathoracic esophageal perforation because there are few oral bacteria contaminating the mediastinum. With a chest tube in place, having the patient drink water to flush and cleanse the mediastinum and pleural cavity several times a day and dilating the esophagus over a guidewire to be certain that there is no distal obstruction may eventually result in healing of the perforation without the need for surgical intervention.

TECHNICAL CONSIDERATIONS Management of the Diseased Esophagus Although in the past, a caustic esophageal stricture was often treated by performing a substernal colonic interposition,

349

350

Section 4 Gastroesophageal Reflux and Associated Conditions

ated, chronically inflamed mediastinum in this patient was too great. The best option to stop ongoing aspiration was believed to be a substernal gastric bypass and Roux-en-Y esophagojejunostomy to provide internal drainage of the unresected and nonstrictured native esophagus.

Retrosternal Placement of the Esophageal Conduit

FIGURE 29-10 Construction of an anterior thoracic esophagostomy after transhiatal esophagectomy for a perforation. Left, The mobilized esophagus is placed upon the high anterior chest and its length used as a guide for excision of a “button” of skin for construction of the esophagostomy stoma. Right, A subcutaneous tunnel is developed bluntly over the clavicle, and the end of the esophagus sutured to the skin. The anterior thoracic esophagostomy allows application of a collection bag to the flat surface of the upper chest and is far easier to care for than the traditional esophagostomy in the supraclavicular fossa or neck. At the time of later restoration of alimentary continuity, the esophagus is tailored, but the additional esophageal length available may be very valuable in creation of a tension-free esophageal anastomosis. (REPRODUCED WITH PERMISSION FROM ORRINGER MB: COMPLICATIONS OF ESOPHAGEAL SURGERY AND TRAUMA. IN GREENFIELD LJ [ED]: COMPLICATIONS IN SURGERY AND TRAUMA, 2ND ED. PHILADELPHIA, JB LIPPINCOTT, 1990, P 302.)

leaving the diseased esophagus undisturbed in the posterior mediastinum, I do not advocate this approach. As mentioned previously, when a substernal gastric or colonic bypass of the strictured esophagus is performed, dividing and closing the cervical end with or without dividing the distal end as well, the native esophagus is essentially a blind pouch that may develop into a mucocele that can cause later chest pain and compression of the adjacent airway (see Fig. 29-2). In addition, late distortion of the esophagogastric junction by fibrous contracture, a consequence of the acute caustic injury, may result in severe reflux esophagitis that is difficult, if not impossible, to assess endoscopically (see Fig. 29-3). There is also a reported 1000-fold increased risk of the late development of esophageal carcinoma in patents who have sustained a severe caustic injury. For these reasons, resection of the diseased esophagus, even though for benign disease, is almost always preferable to a bypass procedure. There are exceptions to every rule, however. I have treated a patient who underwent a right pneumonectomy for bronchogenic carcinoma and received postoperative radiation therapy. Within 1 year, she developed a bronchopleural fistula that was managed by open drainage and construction of an Eloesser flap. Four years later, she presented with a bronchoesophageal pleurocutaneous fistula and no evidence of recurrent carcinoma. The risk of resecting the esophagus from the previously radi-

The details of esophagectomy and esophageal replacement by positioning the stomach in the posterior mediastinum in the native esophageal bed are reviewed in Chapter 52. There are situations when dealing with benign esophageal disease in which the posterior mediastinal route is unavailable for use, or placement of the esophageal substitute in an alternative route is preferable. Patients with a severe caustic esophageal stenosis, a radiation stricture, or those who have undergone prior esophageal operations may be found at the time of esophagectomy to have marked periesophageal inflammatory reaction and posterior mediastinal contracture that may predispose to compression and compromise of the stomach placed in the posterior mediastinum. This is a subjective judgment based on the surgeon’s assessment by palpation of the adequacy of the posterior mediastinum to accommodate the stomach. Retrosternal placement of the stomach then becomes the next best option. When it is determined that a retrosternal gastric (or colonic) interposition is needed, it is my practice to resect the medial 4 cm of left clavicle, sternoclavicular joint, and adjacent manubrium with a sternal saw to remove the posterior prominence of the clavicular head and enlarge the anterior opening at the thoracic inlet into the superior mediastinum (Figs. 29-11 and 29-12). This prevents vascular compromise of the retrosternal esophageal conduit as the cervical esophagus veers anteriorly to meet it and later dysphagia due to compression of the anastomosis and conduit at this point (Fig. 29-13). Resection of these bony structures is not a simple task and must be done with care to avoid injury to the adjacent subclavian and internal thoracic vessels. Oozing from the cut edges of the sternum and divided clavicle should be controlled with bone wax and the wound drained with a suction system to prevent accumulation of blood and serum in the subcutaneous space that overlies the enlarged thoracic inlet. The typical cervical esophageal anastomosis in the native esophageal bed is supported by the carotid sheath and its contents laterally, the trachea and thyroid gland medially, the spine posteriorly, and the sternocleidomastoid and strap muscles anteriorly. In contrast, with a retrosternal esophageal conduit, the completed cervical esophageal anastomosis is subcutaneous and unsupported by adjacent structures. In my experience, it is five times more prone to early postoperative disruption resulting from repetitive Valsalva maneuvers with coughing. And a cervical esophagogastric anastomotic leak associated with a retrosternal esophageal conduit has far greater morbidity because the resulting opened neck wound results in a large subcutaneous “pocket” with an exposed esophageal anastomosis at its base. Gentle wound packing is important to prevent further distraction of the anastomosis and the need for later skin flaps to restore alimentary conti-

Chapter 29 Esophagectomy for Benign Disease

1st rib

Trachea Esophagus

1st rib

Oversewn cardia

Posterior prominence of head of clavicle FIGURE 29-11 When replacing the esophagus with a retrosternal conduit, the anterior opening into the superior mediastinum is often compressed by the posterior prominence of the clavicular head (inset). To prevent late obstruction at this point (see Fig. 29-13), the medial 4 to 5 cm of the clavicle, adjacent manubrium, and often the medial first rib should be resected (dotted line). (REPRODUCED WITH PERMISSION FROM ORRINGER MB, SLOAN H: SUBSTERNAL GASTRIC BYPASS OF THE EXCLUDED THORACIC ESOPHAGUS FOR PALLIATION OF ESOPHAGEAL CARCINOMA. J THORAC CARDIOVASC SURG 70:836, 1975.)

nuity. Because the morbidity of an anastomotic leak is so much greater when retrosternal placement of the graft is necessary, prolonged nasogastric tube decompression of the conduit postoperatively for 1 week is advocated to prevent gastric distention and pressure on the anastomosis early after surgery.

Paramediastinal Placement of the Esophageal Substitute At times, the surgeon is confronted with a patient whose posterior mediastinum cannot be utilized for the esophageal replacement for one of the reasons listed earlier and the retrosternal route has been obliterated by prior cardiac surgery. The option of creating a paramediastinal tunnel behind the anterior chest wall and anterior to the hilum of the lung may have to be used. Again, resection of the medial clavicle, sternoclavicular joint, and adjacent manubrium is necessary, but by tunneling downward from the cervical incision lateral to the midline and upward adjacent to the mediastinum against the anterior chest wall through a diaphragmatic opening created lateral to the midline, a space sufficiently large to accommodate the esophageal substitute—either stomach or colon—can be created.

Colonic Interposition Esophageal substitution with colon is a technically demanding but highly effective means for restoring alimentary continuity after esophagectomy. Several technical points about colonic interposition bear emphasis. Because the left colon blood supply is more constant, and its size more closely approxi-

FIGURE 29-12 Retrosternal placement of the stomach after resection of the medial clavicle, sternoclavicular joint, and adjacent manubrium to enlarge the anterior opening into the superior mediastinum. The same enlargement of the thoracic inlet is used for a retrosternal colonic interposition. (REPRODUCED WITH PERMISSION FROM ORRINGER MB, SLOAN H: SUBSTERNAL GASTRIC BYPASS OF THE EXCLUDED THORACIC ESOPHAGUS FOR PALLIATION OF ESOPHAGEAL CARCINOMA. J THORAC CARDIOVASC SURG 70:836, 1975.)

mates the size of the esophagus than other portions of the large intestine, it has been the preferred colon segment for esophageal replacement. However, the surgeon must have the flexibility and technical comfort utilizing any portion of the colon for esophageal replacement if another proves to be unacceptable. The best indicator of an adequate colonic blood supply intraoperatively is a palpable pulse in the mobilized colon segment, not a preoperative mesenteric angiogram, a study I seldom obtain unless there is specific concern about possible mesenteric atherosclerosis (e.g., documented peripheral vascular disease, a known abdominal aortic aneurysm). Intraoperative Doppler confirmation of pulsatile flow in the colon segment being mobilized as each successive vessel in the mesocolon is divided further ensures a viable graft. As broad as possible a mesocolic pedicle containing arterial, venous, and lymphatic drainage of the colon graft must be maintained to avoid overaggressive skeletonizing of the nour-

351

352

Section 4 Gastroesophageal Reflux and Associated Conditions

A

B

ishing artery at the expense of venous drainage. When there is sufficient remaining stomach for construction of a cologastric anastomosis, the vascular pedicle of the colon graft should be positioned posterior to the stomach to avoid late gastric outlet obstruction by the pedicle. When the colon interposition is placed in the posterior mediastinum in the original esophageal bed, the cologastric anastomosis is constructed on the high posterior aspect of the stomach at the junction of the upper and mid thirds of the stomach. With a substernal colonic interposition, the cologastric anastomosis is placed at a similar site on the anterior stomach, not distally near the pylorus. An excessive length of intra-abdominal distal colon graft proximal to the cologastric anastomosis should be avoided to minimize later delayed emptying of the colon. Although the colon interposition is a passive conduit that empties primarily by gravity, isoperistaltic placement of the graft is always preferred. I have treated patients who after an antiperistaltic colon interposition have developed recurrent regurgitation and aspiration pneumonia due to retrograde propulsion of the colon contents by peristalsis. Whereas it was initially thought that the naturally alkaline colonic mucosa resists refluxed gastric juice, ulceration of the distal colonic interposition does occur and late problems with stenosis of the cologastric anastomosis and secondary redundancy of the colon proximal to the obstruction are not uncommon. For this reason, when the remaining gastric remnant is small (<30% of normal gastric size), it is my preference to carry out a completion gastrectomy, oversew the duodenal stump, and then construct a Roux-en-Y jejunal anastomosis to the distal end of the colon graft.

Functional Results of Esophagectomy and Reconstruction for Benign Disease

C FIGURE 29-13 A and B, Low cervical views from barium esophagogram showing compression of a 4-year-old colonic interposition at the level of the unresected left clavicular head (arrows). C, Esophagogram obtained 2 weeks after resection of the medial clavicle and adjacent sternoclavicular joint to enlarge the anterior opening into the superior mediastinum as shown in Figure 29-11, resecting the stricture that had formed at this point and constructing a new anastomosis. Metallic clips mark the new anastomosis. The patient’s severe dysphagia was relieved. (REPRODUCED WITH PERMISSION FROM ORRINGER MB: COMPLICATIONS OF ESOPHAGEAL SURGERY. IN ZUIDEMA GD, ORRINGER MB [EDS]: SHACKELFORD’S SURGERY OF THE ALIMENTARY TRACT, 4TH ED. PHILADELPHIA, WB SAUNDERS, 1996, P 446.)

A number of questions regarding esophageal replacement for benign disease have yet to be resolved: the best organ with which to replace the esophagus; the relative merits of distal versus total thoracic esophagectomy; and the means of minimizing late postoperative morbidity. In the 1960s when colonic interposition was popularized, the prevailing notion was that the stomach was the appropriate organ with which to replace the esophagus in patients undergoing an esophagectomy for cancer. It had the advantage of a single anastomosis, and although gastroesophageal reflux inevitably followed an intrathoracic esophagogastric anastomosis, patients with esophageal carcinoma seldom survived long enough to develop reflux esophagitis. A less technically difficult operation than a colon interposition, a cervical esophagogastric anastomosis was associated with a lower postoperative mortality. Colonic interposition, on the other hand, was touted to be the “best” approach in patients with benign disease. The size of the colon more closely approximated that of the esophagus; the gastric reservoir was preserved; and the normally alkaline colonic mucosa naturally resisted refluxed gastric acid. Over the years, as a cervical esophagogastric anastomosis became a common means of reestablishing alimentary continuity after an esophagectomy, some of the older dogma has given way. Most patients with

Chapter 29 Esophagectomy for Benign Disease

a properly performed cervical esophagogastric anastomosis are not troubled greatly by gastroesophageal reflux. The oblique angle of entry of the cervical esophagus into the anterior gastric wall created by the side-to-side stapled anastomosis (see Chapter 52) apparently contributes to a decreased incidence of later gastroesophageal reflux than may occur if the end of the mobilized stomach is anastomosed directly to the end of the cervical esophagus. Nevertheless, frustratingly, the occasional patient does develop sufficiently severe regurgitation after a “stomach pull-up” procedure to require sleeping upright in a recliner chair at night to avoid aspiration. Therefore, some have championed colonic interposition. In a report of 92 patients with a median follow-up of 5 years after esophagectomy and colonic interposition, 97% were satisfied with their operation; 82% were relieved of their preoperative symptoms; and 18% believed they were significantly improved. Nocturnal regurgitation or gurgling occurred in 29% and diarrhea or dumping occurred in 15%.54 In a review of the results of transhiatal esophagectomy without thoracotomy in 1085 patients, the functional results of esophageal substitution with stomach in 242 hospital survivors of transhiatal esophagectomy and esophageal replacement with stomach for benign disease were reported.55 The patients were followed an average of 47 months. With a liberal policy of passing an esophageal dilator on an outpatient basis in any patient who complains of any degree of cervical dysphagia after a transhiatal esophagectomy and cervical esophagogastric anastomosis, 77% of these patients had at least one postoperative esophageal anastomotic dilation. At the time of their latest follow-up, however, 157 (65%) were eating a regular unrestricted diet without dysphagia, 36 (16%) had occasional mild dysphagia requiring no treatment, 36 (15%) required an occasional dilation but swallowed well between treatments, and 11 (4%) had “severe dysphagia” requiring regular esophageal dilations. There was no regurgitation of gastric contents in 146 (60%), occasional mild regurgitation after a large meal requiring no treatment in 77 (32%), severe nocturnal regurgitation in 18 (7%) requiring them to sleep upright, and 1 patient (<1%) who had experienced pulmonary complications of aspiration. There was no postprandial cramping or diarrhea in 147 (61%) and varying degrees of dumping symptoms generally controlled with antidiarrheal agents in 95 (49%). Based on the most recent follow-up evaluation, overall functional results were scored as excellent (completely asymptomatic) in 71 (29%), good (mild symptoms requiring no treatment) in 93 (39%), fair (symptoms requiring occasional treatment) in 68 (28%), and poor (symptoms requiring ongoing treatment) in 10 (4%). The functional results and quality of life after esophagectomy for benign disease in 255 patients treated at the Mayo Clinic have been reported (Young, Deschamps, and Allen, et al, 2000; Young, Deschamps, and Trastek, et al, 2000).56,57 Stomach was used as the esophageal replacement in 66%, colon in 27%, and small intestine in 7%. Functional results were regarded as excellent in 32%, good in 10%, fair in 35%, and poor in 23%. After their esophagectomy, 51% to 72% experienced varying degrees of dysphagia, heartburn, or

dumping. Only 4% considered themselves as being asymptomatic. Somewhat surprisingly, the organ used as the esophageal substitute did not predict the long-term functional outcome. Teleologically, the colon, a lower gastrointestinal, thinwalled water-absorption chamber, was not intended to transport semisolid chewed food into the stomach. With time, as swallowed solid food is propelled through the colonic interposition, redundancy and tortuosity may develop, and delayed emptying becomes problematic. The mobilized intrathoracic stomach, on the other hand, a thick-walled upper gastrointestinal organ, seldom becomes tortuous or redundant over time. Regardless of which organ is used to replace the esophagus, postvagotomy “dumping” (postprandial cramping, diarrhea, lightheadedness, palpitations) occurs in approximately 20% of patients undergoing a standard esophagectomy, an apparent function of the vagotomy that accompanies this operation. In 1994, Akiyama and colleagues first described vagal-sparing esophagectomy without thoracotomy, preserving the vagus nerves and stomach.58 After removing the esophagus by eversion stripping, a colonic interposition was performed. Reduction in the incidence of postvagotomy dumping symptoms with vagal-sparing esophagectomy was dramatic. More recently, the functional results of vagalsparing esophagectomy in 15 patients were compared to 23 asymptomatic normal subjects.59 There was a physiologic increase in gastric acid output and serum pancreatic polypeptide after sham feedings and normal postoperative gastric emptying in 75% of the patients who underwent vagal-sparing esophagectomy and colonic interposition, and they did not develop dumping symptoms. It remains to be seen if the added morbidity of a colonic interposition can be justified on the basis of prevention of postvagotomy dumping with the vagal-sparing procedure.

“Supercharged” Microvascular LongSegment Jejunal Interposition A final “new” development in esophageal replacement for benign disease is renewed interest in the use of jejunum to achieve a cervical esophageal anastomosis. Reports of the first successful pedicled jejunal interposition date back to 1907.60 Use of this technique was reported in 80 patients in 1944.61 But the technical difficulty of jejunal replacement of the entire thoracic esophagus resulted in its disuse; the variability of jejunal vascular anatomy was too great, and the complications with this procedure numerous. In 1947, Longmire first reported use of microvascular anastomoses between the upper jejunal interposition mesenteric vessels and the internal thoracic vessels to augment flow to the most proximal portion of the intestinal graft.62 Androsov’s series of 11 patients undergoing jejunal bypass and this vascular augmentation technique was reported in 1956.63 Still, the increased complexity of this procedure and its attendant morbidity precluded its widespread acceptance. More recently, on the basis of improvements in microvascular technique, the M. D. Anderson group has reported its use of the “supercharged”

353

354

Section 4 Gastroesophageal Reflux and Associated Conditions

microvascular long-segment jejunal interposition as an alternative to colonic interposition.64 They have used this procedure in 26 patients, most of whom underwent esophageal resection and reconstruction at the same operation, 13 with placement of the jejunal conduit in the posterior mediastinum and 13 retrosternally. When the jejunal graft is placed retrosternally, the proximal mesenteric vessels are generally anastomosed to the internal thoracic vessels; when the graft is in the posterior mediastinum, branches of the external carotid artery and jugular vein are used. There were no hospital deaths, and 24 were ultimately discharged with an intact jejunal graft. The authors also report that there were no reflux symptoms in 95% and no dumping symptoms in 81%. Follow-up is short, but with these impressive results the supercharged microvascular jejunal interposition may become more common in the armamentarium of operations for esophageal replacement after esophagectomy. Whether esophageal replacement with jejunum has distinct functional advantages in patients undergoing an esophagectomy for benign disease remains to be determined.

COMMENTS AND CONTROVERSIES As more and more patients are treated surgically for benign esophageal disease, there is an increasing number who are left in a worse condition and with an irreparable problem. Unlike esophageal cancer patients, most patients with benign esophageal disease have an excellent chance of long-term survival after esophagectomy. Therefore, reconstruction becomes of paramount importance to ensure an improved quality of life. It cannot be stressed enough how necessary a good history is to successful outcome. The severity and timing of symptoms with respect to the initial and subsequent operations is extremely helpful in determining if resection and reconstruction is the optimal therapy. Obtaining old operative reports is

mandatory; however, these reports may not be a true reflection of what is to be found at reoperation. A surgeon specializing in reoperative surgery must be ready for surprises and must be able to deal with them. Preoperative assessment must evaluate both the primary organ of replacement and backup options. This is particularly true if the stomach is the replacement organ of choice and there have been multiple operations. Although this may have produced the equivalent of ischemic reconditioning, the re-mobilization and preparation may render the stomach unusable. Another important step in preoperative planning is the preparation of the patient both physically and psychologically. Unrealistic expectations of the patient and family can turn a reasonable solution to an impossible problem into yet another surgical failure. Dr. Orringer has provided a superb chapter. His understanding of the problems and his logical approach is witness to the fact that he has “been there.” A careful reading of this chapter will reveal an incredible number of clinical “pearls.” T. W. R.

KEY REFERENCES Belsey RH: Reconstruction of the esophagus with left colon. J Thorac Cardiovasc Surg 49:33, 1965. Miller DL, Allen MS, Trastek VF, et al: Esophageal Resection for recurrent achalasia. Ann Thorac Surg 60:922, 1995. Orringer MB, Marshall B, Iannettoni MD: Eliminating the cervical esophagogastric anastomotic leak with a side-to-side stapled anastomosis. J Thorac Cardiovasc Surg 119:277, 2000. Stirling MC, Orringer MB: Surgical treatment after the failed antireflux operation. J Thorac Cardiovasc Surg 92:667, 1986. Young MM, Deschamps C, Allen MS, et al: Esophageal reconstruction for benign disease: Self Assessment of functional outcome and quality of life. Ann Thorac Surg 70:1799, 2000. Young MM, Deschamps C, Trastek VF, et al: Esophageal reconstruction for benign disease: Early morbidity, mortality, and functional results. Ann Thorac Surg 70:1651, 2000.

chapter

ENDOSCOPIC MANAGEMENT OF REFLUX

30

Steven Edmundowicz

Key Points ■ Endoscopic management of gastroesophageal reflux disease has

evolved over the past decade but has not resulted in the development of a durable and effective therapy. ■ New therapies continue to be developed and brought to market. There is no favored therapy at this time.

Gastroesophageal reflux disease (GERD) remains a common problem that can be managed with medical and surgical therapies. Endoscopic therapy for GERD was conceived more than 2 decades ago, before medical management included proton pump inhibitors and when surgical therapy required an open operation. Initial investigators hoped that they could somehow augment the reflux barrier with a simple endoscopic procedure. In the past decade advances in medical and surgical therapy of GERD have been significant. In an attempt to meet the demands of patients who wish to manage GERD without daily medical therapy or extensive surgery, investigators pioneered new devices that would be used to endoscopically modify the reflux barrier in more complex ways. Unfortunately, the experience to date has fallen short of defining a safe, easily administered, durable and effective therapy for GERD. This chapter is a review of the history, pathophysiology, and various mechanisms of endoscopic management of reflux.

HISTORICAL NOTE Endoluminal therapies for GERD have been explored since the 1980s. Initial approaches involved submucosal injection of bovine collagen or scarring of the lower esophageal sphincter (LES) with ethanol to attempt to increase the LES pressure and improve the reflux barrier.1,2 These initial studies were completed before 24-hour pH studies were routinely available. They showed an improvement in reflux symptoms and heartburn scores. Unfortunately, the results were not long lasting and eventually symptoms returned in all patients. The next notable development occurred in 1996 when Dr. Paul Swain presented his initial experience with endoluminal gastroplication.3 This was followed by the rapid evolution of several interesting technologies, including radiofrequency ablation (the Stretta procedure),4 intramural injection of a biopolymer (Enteryx),5 and full-thickness fundoplication.6 This evolution has led to the development of several other interesting technologies for endoscopic management of reflux. Although approval for marketing by the U.S. Food and Drug Administration (FDA) has been obtained for four of the

technologies, one has been withdrawn voluntarily and the others have failed to flourish, largely due to limited clinical acceptance and a lack of effective reimbursement for the procedures. This has led to a general lack of industry support for new developments in endoscopic management of reflux and a significant reduction in new approaches and clinical advancement in this field.

PATHOPHYSIOLOGY OF GERD AS IT RELATES TO ENDOSCOPIC THERAPY The pathophysiology of gastroesophageal reflux is thoroughly reviewed in Chapter 12. There are several pathophysiologic events that contribute to gastroesophageal reflux that could be affected by endoscopic therapies. This topic is discussed extensively in the review by Kahrilas and Pandolfino (Kahrilas et al, 2003).7 In general, endoscopic therapies for gastroesophageal reflux have been evaluated in patients without large hiatal hernias, extensive Barrett’s esophagus, or severe esophageal ulceration. Endoscopic therapies of gastroesophageal reflux focus on changing the compliance of the gastroesophageal junction or reducing the number of transient LES relaxations (tLESRs). If tLESRs have an effect on LES pressure or length it appears to be mild. Both LES region compliance and number of tLESRs can be altered by endoscopic therapies. It has been postulated that these effects lead to the reported symptom improvement and the reduction of acid exposure time during 24-hour pH studies seen in patients who have undergone endoscopic treatments for gastroesophageal reflux. Increased incidence of tLESRs is a common mechanism for the development of gastroesophageal reflux. Changes in the compliance of the LES region can also result in a reduction of the refluxate volume when tLESRs occur. These actions could also lead to a reduction in the symptoms of GERD. In the overall understanding of endoscopic management of reflux it is important to establish a clear pathophysiologic effect of the technology being evaluated.

ENDOSCOPIC THERAPIES FOR GERD Current endoscopic therapies for GERD include gastroplication, radiofrequency therapy, implantation of biopolymers, and full-thickness plication. Each of these techniques has essentially evolved in a similar pattern from proof of principle to human testing, as outlined in Table 30-1. To date none of the endoscopic therapies has been compared with medical or surgical therapy in a randomized trial. Three of the endoscopic therapies are available for use in clinical practice, but Enteryx has been withdrawn from the U.S. market. 355

356

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 30-1 Progression From Model to Clinical Trials for Devices Order of studies and outcome measures to be expected for new endoluminal therapies for GERD: 1. Proof of principle studies (usually in animal or cadaver or before surgical resection of the gastroesophageal junction for other reasons) demonstrating improvement in objective parameters related to GERD and general safety of the technique before use in human subjects. 2. Pilot human studies demonstrating the ability to apply the therapy in a small group of subjects with GERD, evaluating safety and some measure of efficacy. 3. Multicenter prospective open label trials evaluating the therapy in a larger group of subjects followed prospectively with data collection to measure subjective and objective parameters related to GERD. These studies can also be used to establish the durability of the therapy, optimize the technique, and detect adverse events that may not have been seen in earlier pilot studies. 4. Prospective randomized controlled sham studies demonstrating that the new therapy is superior to placebo. The use of a randomized sham study is an acceptable approach to avoid the significant effect of investigator and subject bias when enrolled in an open label study. This level of investigation (or level 5 below) will likely be required to support expanded clinical use and reimbursement of the new technology. 5. Prospective randomized controlled studies comparing the new therapy to an established therapy for GERD. It is only with well-designed and well-executed randomized controlled trials that these new therapies can effectively be evaluated in terms of efficacy, safety, and durability. This level of investigation will ultimately be required for widespread acceptance of the new technology.

Endoluminal Gastroplication EndoCinch System Endoscopic sewing was pioneered by Dr. Paul Swain in the 1980s. He eventually developed the endoscopic suturing system that was utilized to perform endoscopic gastroplication as a treatment for gastrointestinal reflux.3 The procedure utilizes two endoscopes and an overtube. The first endoscope is prepared as the operating scope and includes the suturing attachment with handle and auxiliary suction tubing assembled for the procedure. A second endoscope is used for knot tying (or suture anchoring with the most resent version) and suture cutting. The EndoCinch system (Davol Division, C. R. Bard, Inc., Cranston RI) (Fig. 30-1) is used to place stitches by withdrawing tissue from the cardia of the stomach into the suction chamber of the device (Fig. 30-2). The needle is then advanced through the mucosa, submucosa, and perhaps the muscular wall of the cardia. A tilt tag and suture is then advanced through the needle and captured in the tip of the sewing capsule (see Fig. 30-2A). The endoscope is then withdrawn from the patient and the suture allowed to run through the stitch. Once outside the patient the device is reloaded with the same suture and the process repeated 1 cm adjacent to the first stitch to create a sewn plication in the cardia of the stomach just below the Z line (see Fig. 30-2B). The endoscope is again withdrawn, and the suture is run

through both stitches until both ends of the suture are removed from the patient. The suture is cut from the tilt tag once outside the patient, and the second endoscope with the suture anchor and cutting device is prepared. The suture is inserted through the suture anchor device, and the endoscope is then advanced through the overtube and pushed against the two stitches to form a plication (see Fig. 30-2C). The suture anchor is placed and the suture cut by activating the suture anchor catheter handle. This results in the formation of the first plication, and the entire process can then be repeated for additional plications. The initial clinical experience with EndoCinch has been nicely reviewed in two publications.8,9 A number of openlabel clinical trials reported a short-term improvement in heartburn symptoms, and occasional patients did demonstrate a reduction in esophageal acid exposure. A small randomized trial of 34 patients was completed but did not provide compelling evidence of a superior effect with the EndoCinch system.10 A more recent report of another openlabel treatment of 85 patients at multiple centers appears to show a benefit of the EndoCinch approach that persists for up to 2 years (Chen et al, 2005).11 Unfortunately, this study does not adequately address the objective measures of gastroesophageal reflux improvement nor does it account for the significant placebo effect seen in other open-label studies. Although a longer term benefit was reported in this series many investigators in the field have come to the realization that the mucosa-to-mucosa apposition of tissue as completed in the EndoCinch procedure is not durable and the minimal fibrosis and scarring that may persist after the sutures have passed is not a significant enough force to result in long-term patient improvement. Because of a number of factors the EndoCinch procedure has not been adopted by clinicians as a viable treatment option for gastroesophageal reflux. The complexity of the procedure, long learning curve, limited efficacy, and unproven durability have contributed to this. Although the EndoCinch System is still available, its use as an endoscopic therapy for gastroesophageal reflux has been limited. Work is underway to significantly simplify and improve the EndoCinch procedure. It is also being tested to establish its role in other flexible endoscopic procedures that require suturing.

Radiofrequency Energy Application Stretta System Thermocouple-controlled radiofrequency ablation has had a defined role in many areas of medicine, including management of arrhythmias, sleep apnea, and benign prostatic hypertrophy (Utley, 2003).12 Its application in the management of gastroesophageal reflux has moved from laboratory experiments to clinical trials in the pattern described in Table 30-1. After a number of open-label clinical trials, it was the first endoscopic management of gastroesophageal reflux to be subjected to a randomized sham-controlled clinical trial. The procedure requires the Stretta system (Curon Medical Inc., Sunnyvale, CA), which was cleared by the FDA for marketing in 2001. It consists of two main components, the

Chapter 30 Endoscopic Management of Reflux

B

A

C

FIGURE 30-1 The Endocinch device. A, The assembled EndoCinch device and handle attached to an upper endoscope. B, Attachment of the sewing capsule to the endoscope. C, Needle with pusher catheter visible as the sewing capsule cap has been removed.

A

B

C

FIGURE 30-2 Endoluminal gastroplication with the Endocinch system. A, Endoscope with sewing capsule attached and tissue drawn into the tissue cavity with suction. B, The second stitch is placed. A plication can now be formed with the suture anchor. C, Three plications are formed with suture anchors in place.

radiofrequency treatment catheter and the sophisticated computer control module (Fig. 30-3). The catheter (see Fig. 30-3A) is a flexible 20-Fr device with a soft flexible tip, partial channel for wire guidance, and four 25-gauge needle electrodes that deploy at 90-degree intervals around the center of a basket-balloon assembly. The Stretta catheter

needles have thermocouples at the tip as well as on the surface of the basket-balloon assembly. There are irrigation and aspiration channels in the catheter and a handle with an electrode deployment and withdrawal mechanism, a port for balloon inflation with a syringe, as well as connectors for the generator cable, water infusion, and continuous suction. The

357

358

Section 4 Gastroesophageal Reflux and Associated Conditions

B

1 cm above z-line

A

C

FIGURE 30-3 The Stretta system A, The Stretta catheter with treatment balloon inflated and 4 protruding needle electrodes. B, The Stretta generator. C, Cartoon of treatment balloon in place 1 cm above the Z line with needle electrodes in the esophageal wall.

outside of the catheter is clearly marked in centimeters, starting with the level of the treatment electrodes to allow positioning at the measured Z line without endoscopy or fluoroscopy. The catheters are factory sterilized and tested and sold as single-use devices. The Stretta control module (see Fig. 30-3B) is a computercontrolled, four-channel, radiofrequency generator that has specific control options and display for the procedure. The control module also has automatic safety features that will monitor and discontinue energy flow to a specific electrode in the catheter if parameters of temperature or impedance are violated. The display screen clearly depicts the treatment catheter electrodes as well as the tissue and surface temperature, impedance, and water flow. The foot pedal that activates the unit also starts the infusion of cooled water to maintain the mucosal temperature below 50°C while the needle tip quickly heats to 85°C. This allows delivery of radiofrequency energy to the target tissue without damaging the mucosa of the esophagus. The preclinical testing of the device demonstrated effective delivery of radiofrequency energy to the submucosa of the LES region in animals and humans.12 Nerve ablation, increased wall thickness, and fibrosis were all observed. Physiologic measures included a reduction in tLESRs in a canine model.13

Open-label clinical trials demonstrated safety and efficacy of the device as measured by reported heartburn scores and numerically reduced 24-hour acid exposure time. The physiologic studies were repeated in humans with a documented decrease in the absolute number of tLESRs and a measured increase in LES pressure.14 A randomized sham trial of the Stretta procedure did demonstrate a reduction in heartburn symptoms in the treated subjects versus those on the sham therapy, but there was no change in 24-hour pH time less than 4 or any other objective measure (esophagitis grade, LES pressure, or sphincter length).15 These findings prompted a debate regarding the effect of sensory nerve ablation with the Stretta system and possible esophageal desensitization with the treatment, a discussion that has not been definitively resolved. Although no serious complications were reported with the Stretta system during the initial clinical trials a number of significant problems, including perforations, aspirations, and several deaths, occurred as the device was being initially adopted by the clinical community. Modifications of the treatment duration (fewer levels of treatment around the Z line), combined with physician and patient education, seemed to reduce the incidence of serious complications. Because of the voluntary nature of reporting of complications once the prospective clinical trials are completed, the exact incidence

Chapter 30 Endoscopic Management of Reflux

and nature of complications with this and other endoscopic therapies remain unknown. There are limited durability data for the Stretta system. Results of 1- and 2-year follow-up with symptom reporting have been published. Unfortunately, there is no large, prospectively identified series of patients who have been followed on an intention-to-treat basis. Although anecdotal reports of symptom relief beyond 2 years exist, the true durability of the response with the Stretta procedure remains unknown. A CPT code for radiofrequency therapy for the treatment of GERD has been established by the Centers for Medicare and Medicaid Service and was published to be effective in January 2005. At the time of publication this is the only category 1 CPT code for the endoscopic therapy for GERD. Despite having a CPT code for the procedure, reimbursement remains a struggle, with many insurers electing not to reimburse for the procedure at this time. The impact of the code and the use of the Stretta system as an alternative to medical or surgical therapy for GERD will require further study. Curon Medical Incorporated filed for bankruptcy protection. The future availability of the Stretta system for clinical use is uncertain at the time of publication.

Implantation Therapy The initial attempts at endoscopic therapy for gastroesophageal reflux involved implantation of bovine collagen by endoscopic injection into the submucosa of the esophagus. Additional biopolymers have been developed that can be injected or implanted into the esophageal wall with resultant mechanical effects on the LES region.

Enteryx Endoscopic implantation of Enteryx (8% ethylene vinyl alcohol in DMSO and micronized tantalum powder) was first described as a treatment for GERD in 1999 and published in 2002.16 The biopolymer is implanted into the muscle layer of the LES with a 25-gauge injection needle under fluoroscopic guidance. The technique underwent a successful premarket approval process with the FDA that included an open-label study.17 In addition, a randomized sham study in Europe demonstrated a benefit of therapy with Enteryx.18 The U.S. randomized sham study had completed enrollment and was in follow-up phase when the sponsor became aware of additional complications related to the implant placement. During the clinical use of the product in the United States it became apparent that placement of the implant in structures adjacent to the esophagus could occur despite fluoroscopic monitoring. This has resulted in pericarditis, mediastinitis, unintentional embolization of the kidney, and a patient’s death due to hemorrhage from an Enteryxinduced aortoesophageal fistula.19 The sponsor elected to withdraw the product from the marketplace for concerns regarding the ability of fluoroscopic monitoring to detect implantation of Enteryx in structures adjacent to the esophagus.

Gatekeeper Endoscopic submucosal implantation of hydrophilic material to augment the LES region was described by Fockens and associates as early as 1990.20 Commercialization of this device and technique led to clinical trials in Europe and the United States. The technology was acquired by Medtronic and studied as the “Gatekeeper” antireflux device. It initially held promise as a well-tolerated, reversible therapy for GERD. As clinical trials progressed it was found to have limited efficacy in the treatment of GERD. The U.S. multicenter trial was halted and further studies with the device curtailed by Medtronic at this time.

Polyteflon Feretis and colleagues have described Teflon microsphere injection into the LES to treat GERD in 20 Greek patients.21 Although well tolerated in this pilot study, the use of Teflon microspheres has not progressed in further trials and is not likely to be an acceptable long-term therapy for GERD.

Full-Thickness Plication Several devices have been proposed to create full-thickness plication of the gastric cardia to create a barrier to reflux endoscopically. The concept is similar in all these devices. They create a plication in the region of the cardia that will restrict the relaxation of the LES region and reduce reflux. By creating a full-thickness plication, these devices are less susceptible to the loss of plications seen with submucosal sutures, but they can lead to discomfort and air leaks at the time of the procedure because the device does cross the entire wall of the cardia. In addition, structures adjacent to the serosa of the cardia could be irritated or even entrapped by the process.

NDO Plicator The NDO Plicator (NDO Surgical, Mansfield, MA) has been carefully studied in animal models and humans. The device and action are depicted in Figure 30-4. Essentially the overtube device allows visualization of the full-thickness plication procedure with the use of a standard endoscope. The device is passed over a guidewire and then with the endoscope in place used to perform the plication in retroflexion in the cardia of the stomach. The device incorporates a tissue retractor and polytetrafluoroethylene-pledgeted suture to create the plication. Early human experience was positive in a pilot and an open-label study (Pleskow et al, 2004).6,22 Recent completion of a randomized sham study demonstrated a statistically significant improvement in GERD health-related quality-of-life reporting and 24-hour pH studies at 3 months after placement.23 Further experience with this device is necessary to determine the optimum procedure (one plication or two), efficacy, and durability of the response.

SUMMARY The initial enthusiasm for an endoscopic management of reflux has been replaced by the reality of less than stellar results in clinical trials. The great majority of patients with

359

360

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 30-4 The NDO plicator. A, Components of the plicator system with the gastroscope in place. B, The technique of fullthickness plication with the NDO plicator.

ePTFE pledgets Wall retractor

Standard gastroscope

A

1) Plicator and gastroscope retroflexed.

B

2) Arms opened, tissue retractor advanced to serosa.

4) Single, pre-tied implant is deployed, securing serosa-to-serosa plication.

GERD are satisfied and have their gastroesophageal reflux well controlled with proton pump inhibitor therapy. The safety and cost-effectiveness of medical management for GERD is well established and difficult to surpass with any intervention. Failures of medical management are rare and can usually be easily and effectively managed with minimally invasive laparoscopic surgical techniques with minimal morbidity and excellent efficacy in skilled hands. An effective endoscopic therapy for GERD will need to be extremely safe, easy to apply, effective, and durable. Although there has been a significant evolution of endoscopic therapies, an effective

3) Gastric wall retracted, arms closed.

5) Full-thickness plication restructures normal antireflux barrier.

device that meets all these criteria has yet to be identified. There is a significant debate over the role of endoscopic management of reflux. Some experts have suggested that further clinical use of endoluminal therapies for GERD be curtailed until a specific therapy has been proven to be effective, safe, and durable in well-designed randomized controlled trials.24 Other experts believe that endoluminal therapies for GERD have been demonstrated to be effective for some individuals and should be available and offered to patients as part of a multidisciplinary approach to GERD by physicians who are skilled in their use.25 Perhaps the next decade will

Chapter 30 Endoscopic Management of Reflux

bring forth a new direction in endoscopic therapies that will lead to a more effective, safe, and durable endoscopic management for reflux.

COMMENTS AND CONTROVERSIES The author presents a concise yet comprehensive and objective overview of the history and current status of endoscopic therapies for GERD. It is apparent that the technology is evolving and that current clinical success has been limited. It also needs to be restated that most of these therapies have been tested in patients without significant hiatal hernias or other complex problems and may not be applicable to patients who are currently being referred to specialized surgical centers for recalcitrant GERD. For example, many patients referred to our practice have a significant hiatal hernia, Barrett’s esophagus, Nissen failures, and so on. Thus, endoscopic therapy success for GERD in the patients studied thus far would not preclude the need for surgical intervention. However, it is apparent that investigation into the area of endoscopic therapies for GERD will continue and surgeons should be

actively evaluating these results and, when they are promising, should be open to the design and execution of animal investigation and, ultimately, human clinical trials. Clinical trials need to be carefully designed to assess safety, objective evidence of short-term and long-term efficacy, and a careful comparison to existing minimally invasive therapies for GERD. J. D. L.

KEY REFERENCES Chen Y, Raijman I, Ben-Menachem T, et al: Long-term outcomes of endoluminal gastroplication: A U.S. multicenter trial. Gastrointest Endosc 61:659-667, 2005. Kahrilas P, Pandolfino J: The target of therapies: Pathophysiology of gastroesophageal reflux disease. Gastrointest Endosc Clin North Am 13:1-17, 2003. Pleskow D, Rothstein R, Lo S, et al: Endoscopic full-thickness plication for the treatment of GERD: A multicenter trial. Gastrointest Endosc 59:163-171, 2004. Utley D: The Stretta procedure: Device, technique, and pre-clinical study data. Gastrointest Endosc Clin North Am 13:135-145, 2003.

361

Reoperation for Failed Repairs chapter

OPEN REOPERATIVE ANTIREFLUX SURGERY

31

Sherard Little David P. Mason

Key Points ■ The number of patients requiring reoperation for GERD is

increasing. ■ A careful history and physical examination and thorough objective

studies are critical to optimal outcome. ■ Surgical approach must be tailored to the individual patient. ■ Results of reoperation for GERD are good but inferior to those of

whereas other symptoms developed over time. A detailed history also includes evaluation of all objective studies before the primary surgery and a review of operative notes. The typical patient presents for reoperation with disabling gastrointestinal symptoms that range from dysphagia to severe reflux; most have undergone multiple failed interventions (e.g., esophageal dilation, escalating antacid therapy, and promotility agents) by a gastroenterologist.

primary surgery.

Signs and Symptoms HISTORICAL NOTE In 1951, Allison (1951)1 presented the seminal paper that outlined the relationship of hiatal hernia to gastroesophageal reflux and esophagitis and the principles of surgical repair. Traditionally, repair was performed via laparotomy or thoracotomy. With increased widespread use of laparoscopic surgery over the past decade, more patients are undergoing primary surgery for gastroesophageal reflux. From 1990 to 1997, the number of laparoscopic antireflux procedures performed in the United States increased from 0.02 to 7.8 per 100,000 adults.2 Parallel to the growth in antireflux procedures is the volume of patients who present with surgical failure. Surgical failure rates for antireflux surgery are between 10% and 20% (Skinner, 1992),3-5 although definitions of surgical success and surgical failure vary considerably. Surgical success can be measured by improvement in reflux symptoms as well as improvement in radiologic and physiologic studies; however, reflux symptoms and objective studies may not always demonstrate compatibility.6 Failure is most readily recognized by disabling new or persistent symptoms. The majority of surgical failures can be managed with aggressive medical treatments, which include the use of proton pump inhibitors and motility agents.7 In approximately 4% of failed procedures, however, symptoms are intolerable and patients require reoperative antireflux surgery.3 Patients who require reoperative antireflux surgery present a significant challenge for even the most experienced esophageal surgeon.

CLINICAL PRESENTATION For patients who have undergone previous antireflux surgery, methodical assessment for reoperative surgery is critical for a successful outcome. A careful history and a thorough physical examination are vital first steps. Patient history includes elucidation of the symptoms leading to the original surgery as well as of subsequently developed symptoms. Some symptoms may have been present immediately after surgery 362

Signs and symptoms most commonly present after antireflux surgery are recurrent gastroesophageal reflux, regurgitation, and dysphagia. Patients complain less commonly of abdominal bloating, pain, and diarrhea. Eighty to 90 percent of patients who undergo antireflux surgery have improvement of reflux symptoms.4,5,8 If symptoms persist after surgery, they usually respond well to medical treatment. Of the patients who require reoperative surgery, gastroesophageal reflux is a prominent symptom in 24% to 100%.9,10 Early dysphagia after fundoplication occurs in approximately 20% of patients.11 This is most likely due to edema at the site of the fundoplication. Edema typically resolves with time and, at late follow-up, only 4% of patients reported dysphagia.11 Esophageal dilation is usually the first step in the management of dysphagia and, in most patients, abolishes or controls this symptom.7 Dysphagia, however, can be refractory and debilitating and accounts for 23% to 67% of patients who undergo reoperative surgery.10,12 Abdominal bloating or “gas bloat” is a common symptom after fundoplication because patients with gastroesophageal reflux tend to be chronic gas swallowers. Patients are made aware of this phenomenon because dietary modification and treatment with gas-binding agents or prokinetics may be helpful in improving symptoms and patient comfort.7 Gas bloat is rarely the sole indication for reoperative surgery. Diarrhea is a less frequently seen complication of antireflux surgery and is most likely due to vagal nerve dysfunction. It can usually be managed medically and is rarely an indication for reoperation. Treatment of obesity and chronic obstructive pulmonary disease often includes lifestyle modifications such as smoking cessation and dietary modifications. These are crucial components to controlling gastrointestinal symptoms while improving general well-being.

Esophageal Studies In addition to a thorough history and physical examination, a complete set of esophageal studies is imperative to

Chapter 31 Open Reoperative Antireflux Surgery

delineate the reason(s) for surgical failure and to direct further intervention. These investigations include contrast esophagography, manometry, 24-hour pH monitoring, esophagogastroduodenoscopy, and gastric emptying studies.13 Contrast esophagography is critical in demonstrating esophageal motility, the presence and location of esophageal strictures, the relationship of the fundoplication to the hiatus, and the adequacy of gastric emptying. Of importance is the intrathoracic location of the gastroesophageal junction, which may indicate the presence of a shortened esophagus. Esophageal manometry quantifies esophageal peristalsis and lower esophageal sphincter (LES) pressures and evaluates the coordination of esophageal contractions. Long-standing reflux and esophagitis results in esophageal myopathy and impaired peristalsis. Patients with primary esophageal motor diseases, such as achalasia, or with secondary diseases, such as scleroderma, may be misdiagnosed as having gastroesophageal reflux. The absence of LES relaxation and the presence of low-amplitude peristaltic waves or a large percentage of nonconducted waves may indicate the esophageal motor pump may not be able to overcome the obstructive effects of a complete or partial fundoplication. In this setting, antireflux surgery with wrapping of the LES can catastrophically worsen symptoms. Abnormally low LES pressure may indicate the fundoplication has broken down. Similarly, abnormally high resting LES pressures may indicate a fundoplication or a hiatus that is too tight. The best method to objectively identify gastric acid reflux is with 24-hour pH studies. There are multiple scoring systems, but the most commonly used is the DeMeester score, which uses six components of the pH analysis to calculate a component score.14,15 Although pH studies may not always correlate with patient symptoms they can be used to objectively quantify reflux and serve as a baseline for comparison. Esophagogastroduodenoscopy (EGD) performed by the surgeon is a critical part of the workup for reoperation. EGD identifies the presence, location, and severity of esophageal strictures and the presence of a hiatal hernia. It also allows evaluation of the relationship of the fundoplication to the gastroesophageal junction, which may indicate a telescoped wrap or a dehisced wrap. Failure of the gastroesophageal junction to reduce below the diaphragm suggests the esophagus is shortened. EGD also facilitates identification and biopsy of esophagitis, Barrett’s esophagus, dysplasia, or malignancy. It may also suggest biliary reflux. Gastric emptying studies are routinely performed in the setting of reoperative antireflux surgery. Vagal nerve function or dysfunction are documented. Impaired function may indicate the need for a gastric drainage procedure at the time of reoperation. The critical nature of thorough testing before surgery cannot be overemphasized. In a series of 101 patients reported by Ellis and associates (1996),16 almost 25% of the patients were misdiagnosed with gastroesophageal reflux disease before their initial surgery. This resulted in inappropriate surgical treatment and poor outcome. It is critical not to repeat this error at reoperation.

WHY FUNDOPLICATIONS FAIL Failure of antireflux surgery is almost always multifactorial. Factors may include management of the esophagus, the hiatus, and/or the wrap. Sometimes, it is not possible to discover the reason(s) for failure. Definition, diagnosis, and management of the short esophagus are a matter of considerable debate.14,17 A short esophagus is one in which the gastroesophageal junction cannot be reduced into the abdomen without placing it under tension. A short esophagus is suggested on barium esophagogram by the intrathoracic location of the gastroesophageal junction as well as by an irreducible hiatal hernia on EGD. Severe esophagitis or a peptic stricture may also be present.18-20 Failure to recognize the presence of a short esophagus results in a short length of intra-abdominal esophagus, a repair that is under tension, and an increased tendency for the fundoplication to slip through the hiatus into the chest and cause recurrent symptoms. An esophageal lengthening procedure, preferably a Collis gastroplasty, needs to be considered in the finding of a short esophagus. Another reason for failure may be incorrect closure of the esophageal hiatus. The closure may be too tight, resulting in dysphagia, or too loose or not closed at all, resulting in recurrence of herniation. Additionally, there may be dehiscence of the hiatal closure. This may be due to incorrect identification of the crura, inadequate suture depth, or use of absorbable sutures in the closure. The crura must be carefully identified and dissected out and the hiatus closed with large bites of heavy nonabsorbable suture. The use of prosthetic material that has a tendency to cause stenosis and that may erode into the esophagus over time is discouraged. Failure due to the fundoplication comes in many forms. The fundoplication can be too tight, too long, or too loose. The fundoplication that is too tight and/or too long tends to cause dysphagia. A wrap that is too tight predisposes to dehiscence and may be the result of surgeon misjudgment or inadequate mobilization of the fundus of the stomach with incomplete division of the short gastric vessels. A fundoplication that is too loose tends to telescope or slip so that the wrap is around the fundus of the stomach rather than around the esophagus. This results in a recurrence of reflux symptoms. It is critical to correctly identify the gastroesophageal junction, excise the esophagogastric fat pad, and securely place the fundoplication sutures into the wall of the esophagus to anchor it at the gastroesophageal junction and perform a fundoplication of appropriate length. Dysphagia may also result from wrapping an esophagus with an undiagnosed primary or secondary esophageal motor disorder. In these patients, treatment of the motor disorder combined with a partial fundoplication is more appropriate than a complete fundoplication. Finally, gastric emptying is impaired by injury to the vagus nerve. Every effort is made to identify and preserve the vagal trunks during operations for reflux. Failure to identify impaired gastric emptying will result in symptoms postoperatively.

363

364

Section 4 Gastroesophageal Reflux and Associated Conditions

INDICATIONS FOR REOPERATION Patients with severe reflux symptoms refractory to medical therapy or in whom medical therapy is contraindicated are candidates for antireflux surgery. Similarly, patients with significant dysphagia who do not respond to esophageal dilation are also candidates for surgery. Preoperative studies help identify the etiology of the failed primary operation to assist in guiding the reoperation.

CHOICE OF OPERATION Reoperative surgery for gastroesophageal reflux requires that the surgeon be competent in multiple approaches. No single operative procedure is adequate treatment for all patients. Patience and careful identification of the anatomy of the esophageal hiatus, the gastroesophageal junction, and landmarks of the stomach are vital for a successful outcome. The debate as to the best surgical approach—transabdominal, transthoracic, or thoracoabdominal—is ongoing.

Choice of Approach Currently, the majority of primary antireflux surgeries are performed laparoscopically. Laparoscopic reoperative surgery is performed in a few centers with significant experience in primary antireflux surgery and reoperation. With the presence of extensive adhesions and the increased risk of viscus injury and bleeding, rates of conversion to laparotomy exceed that of primary operations.21 Laparoscopic reoperation is discussed in Chapter 32. Laparoscopic reoperation is not advocated unless the surgeon is extremely skilled and experienced in this type of surgery. An open approach is advocated. Three open approaches commonly performed are laparotomy, thoracotomy, and thoracoabdominal. The choice of approach is individualized to the patient and depends on previous route of operation, the necessity of additional procedures, the patient’s body habitus, and the surgeon’s comfort and preference. Advantages of laparotomy are good visualization of the anatomy of the gastroesophageal junction and of the previous repair if done via laparotomy or laparoscopy. The presence of adhesions is rarely prohibitive in gaining access to the abdomen. Laparotomy seems to be associated with less pain and pulmonary complications when compared with thoracotomy.22 Disadvantages of laparotomy are its challenges of exposure of the gastroesophageal junction and hiatus after multiple reoperations and an increased risk of entry into the stomach or the esophagus, especially if previous myotomy was performed. Exposure may be particularly difficult in the obese patient. One advantage of thoracotomy is a virgin plane of dissection, if a previous transabominal approach was performed, along with excellent access to the esophagus and the ability to easily mobilize it. If a thoracotomy was performed previously, “redo” thoracotomy is usually necessary to adequately remobilize the esophagus. The esophagus can be mobilized all the way to the aortic arch to ensure a tensionfree fundoplication.3,10,23-25 The disadvantage, however, is occurrence of post-thoracotomy syndrome, which can be incapacitating and cause an increased incidence of pulmonary complications.26

A thoracoabdominal approach offers advantages of both laparotomy and thoracotomy and provides the best visualization of the distal esophagus and the gastroesophageal junction. The esophagus can be mobilized adequately in the chest while the abdominal exposure allows mobilization of the stomach with lysis of adhesions and ready access for preparation of the fundoplication. Henderson and Marryatt27 used this approach exclusively in their published series of patients with recurrent hiatal hernia. The main drawbacks are the occurrences of post-thoracotomy pain and pulmonary complications. In one series, 21% of patients had moderate-to-severe post-thoracotomy pain after thoracoabdominal repair.28

Operative Findings Hiatus It is critical that the crura be clearly delineated. If the hiatal closure is too tight, all that may be necessary is the removal of one or more of the crural sutures. If dense scar tissue exists, it will have to be excised and the hiatal closure reconstructed. If there is dehiscence of the hiatal closure with a paraesophageal hernia, it is reduced and the hiatus closed with nonabsorbable interrupted sutures, taking generous bites of the crura.

Esophagus Adequate intra-abdominal esophageal length is essential for a tension-free repair. More extensive mobilization is possible through the thoracic route. Care must be taken to preserve vagal function. In patients with a short esophagus (e.g., those with peptic esophagitis, Barrett’s esophagus, a large hiatal hernia), a Collis gastroplasty is indicated.10,13,22

Fundoplication Examination of the fundoplication may reveal a wrap completely or partially dehisced, a wrap too tight or too long, or one that has telescoped onto the stomach. The wrap is completely taken down. What type of fundoplication to use in the presence of esophageal dysmotility is controversial. Some surgeons advocate a tailored approach, utilizing some form of partial fundoplication, if the patient has dysphagia and/or evidence of dysmotility on manometry.10,22 Alternatively, Rydberg and coworkers,29 in a randomized clinical trial, found no difference in outcome in patients with esophageal motor dysfunction who received a total or partial fundoplication. Our practice utilizes a floppy Nissen fundoplication for the majority of our reoperative cases, regardless of esophageal motor function. We have not noted adverse outcomes in patients with esophageal dysmotility. If the wrap telescoped onto the stomach, it is re-secured at the gastroesophageal junction with nonabsorbable sutures. These are passed into but not through the wall of the esophagus. The fundoplication is then secured to the hiatus with two or three interrupted nonabsorbable sutures.

Esophagectomy Esophagectomy is performed as a last resort for patients with severe esophageal dysmotility or nondilatable strictures.9,24

Chapter 31 Open Reoperative Antireflux Surgery

Little and associates23 suggest esophageal resection and replacement at the second reoperation with gastric pull-up or colonic9 or jejunal30 interposition for reconstruction. In contrast, Deschamps and colleagues10 recommend preservation of the native esophagus when the cause of the reflux appears reversible. Although we do not have a firm rule, we tend to prefer esophagectomy with gastric pull-up at the second antireflux reoperation. An alternative to re-fundoplication or resection is vagotomy, antrectomy, and duodenal diversion. Its selective use has been advocated by several authors, although we rarely employ it.31,32 This approach avoids dissection at the gastroesophageal junction in the reoperative setting where the presence of previous myotomy and/or esophagitis makes dissection treacherous.

RESULTS Most of the published series of patients undergoing reoperative antireflux surgery utilize subjective measures to quantify success. Throughout the literature, postoperative objective testing is greatly lacking. Typically, only patients who remained symptomatic after reoperative surgery were subjected to invasive esophageal testing. Additionally, most series employ varied approaches and techniques tailored toward the individual patient that make comparison difficult. Larger series indicate that although the outcome of reoperative surgery for reflux is inferior to that of primary surgery, good-to-excellent results are achieved in 44% to 94% of patients (Table 31-1). The likelihood of success in surgery for gastroesophageal reflux decreases with subsequent

TABLE 31-1 Reported Series of Open Reoperations With More Than 20 Cases* No. Cases

Author (Year)

Approach

Mortality (%)

Morbidity (%)

Results Excellent/Good (%)

Skinner and Belsey8 (1967)

43

T

4

Orringer et al (1972)

45

T

2.2

75

Hill34 (1971)

63

L

3.3

81

36

L

4

80

121

TA

0

55

T, L

4

61

T, L

4.9

87

30

Polk

(1980) 27

Henderson and Marryatt

(1981)

Maher et al25 (1985) 23

Little et al

(1986) 24

Stirling and Orringer

(1986)

Pearson et al35 (1987) 36

Low et al

(1989)

3

Skinner (1992)

22

Siewert et al 38

Stein et al

(1995)

(1996)

Ellis et al16 (1996) 39

Lim et al

40

Dalla Vecchia et al

(1997)

Deschamps et al10 (1997) 41

Bonavina et al 26

Bais et al

(1998)

(2000)

Braghetto et al42 (2002) Johnsson and Lundell43 (2002) 28

Legare et al

(2002)

Khan et al44 (2004) 45

Ohnmacht et al

(2006)

80 20

72

T, L

2

76

T

0

80

77

L

88

T, L

1.7

21

36

L

0

25

85

89

L

1.5

23

70

71

L

1.4

22.5

86

L, T

1

26

44

31

L

0

16

91

130

L

1.5

30

91

185

T, L, TA

0.5

25.4

60.2

L

0

101

(1996)

94.2

118

117

Ellis and Gibb37 (1994)

5

70

8.5

87

30

T

0

27

104

L

1

12.5

L, T

0

16

84

32

80

31

TA

0

42

93

26

T, L

0

8

92

T, L, TA

0

21.7

71

126

Approach: L, laparotomy; T, thoracotomy; TA thoracoabdominal. *Series reported in English.

365

366

Section 4 Gastroesophageal Reflux and Associated Conditions

reoperations. Little and associates23 demonstrated good-toexcellent results in 85% of patients undergoing a first reoperation compared with 66% in patients undergoing a second reoperation and 45% in patients undergoing three or more reoperations. Similarly, in a series by Skinner (1992),3 85% of patients undergoing a second antireflux procedure had good-to-excellent results compared with two thirds of patients who underwent a third operation. This supports the use of an alternative surgical approach at the second reoperation, such as esophagectomy. Morbidity and mortality rates from reoperative surgery also exceed those of primary surgery. Mortality rates range between 0% and 17%,27,33 and morbidity rates range between 5% and 46%.27,33 Postoperative leaks and fistulas are more common after reoperative surgery. Without question, the best results of antireflux surgery are achieved at the primary operation. Reoperative antireflux surgery provides a challenge whose complexity and volume show no signs of diminishing with the passage of time. For patients who require reoperative antireflux surgery, surgical results can be gratifying for the properly evaluated patient placed in the hands of an experienced surgeon.

COMMENTS AND CONTROVERSIES Reoperative antireflux surgery is a fact of life. It is our responsibility to minimize its occurrence. Once an operation has failed it is imperative that the second operation be successful, otherwise the patient

is well on the path to resection. The reasons for failure must be determined. The patient requiring reoperation presents with either persistent symptoms, new postoperative symptoms, or both. Careful symptom reconstruction before and after the procedures is very helpful in this determination. The prior esophageal evaluations and operative notes must be obtained. Finally, the present state of the esophagus and repair must be determined. With the mode of failure identified a reoperative strategy can be planned. The success of reoperation will not be measured by the approach but by control of symptoms, permanence of the new repair, and avoidance of further surgery. A third operation must be avoided because from then on failures outweigh successes. Reoperation must not be taken lightly. J. D. L.

KEY REFERENCES Allison PR: Reflux esophagitis, sliding hiatal hernia, and the anatomy of repair. Surg Gynecol Obstet 92:419-431, 1951. Ellis FH Jr, Gibb SP, Heatley GJ: Reoperation after failed antireflex surgery: Review of 101 cases. Eur J Cardiothorac Surg 10:225-231, 1996; discussion 231-232. Pearson FG, Cooper JD, Patterson GA, et al: Gastroplasty and fundoplication for complex reflux problems: Long-term results. Ann Surg 206:473-481, 1987. Skinner DB: Surgical management after failed antireflux operations. World J Surg 16:359-363, 1992.

chapter

32

LAPAROSCOPIC TECHNIQUES IN REOPERATION FOR FAILED ANTIREFLUX REPAIRS Christopher R. Morse Arjun Pennathur James D. Luketich

Key Points ■ Reoperative antireflux surgery is becoming more frequent as the

volume of laparoscopic procedures increases. ■ Common indications for reoperative antireflux surgery are medi-

■ ■ ■

■

cally recalcitrant recurrent gastroesophageal reflux disease (GERD) and dysphagia. A thorough and comprehensive preoperative evaluation must take place before reoperative antireflux surgery. Open or laparoscopic reoperative antireflux surgery is complex. Reoperations may include redo-antireflux surgery, Roux-en-Y gastric bypass (especially in the obese population) and esophagectomy. We strongly consider Roux-en-Y or esophagectomy after multiple failed Nissens and/or extensive scarring and obvious vagal injuries. Good to excellent short- and intermediate-term results can be expected from reoperative laparoscopic surgery in experienced centers in up to 85% of carefully selected cases.

ranging between 20% to 40% and mortality rate of 2%.11 However, as experience has increased with minimally invasive antireflux procedures, more reoperative cases are being attempted laparoscopically. The success rate for either open or laparoscopic reoperative surgery does not equal that of the initial antireflux operation. Little and colleagues (1986)12 reported that only 84% of patients undergoing open reoperative antireflux surgery achieved a satisfactory result and only 42% of patients with three or more previous operations had a satisfactory result. In our experience, laparoscopic approaches to reoperative antireflux surgery offers similar results compared with open surgery, the caveat being that these procedures need to be done in centers that have very extensive experience (Luketich et al, 2002).13 In this chapter we discuss the causes of failure, evaluation of patients, choice of operation, the technical aspects of minimally invasive “redo” antireflux surgery, and short- and intermediate-term results.

CAUSES OF FAILURE The application of minimally invasive techniques has led to increasing numbers of antireflux procedures being performed, and reoperation for failed repairs is becoming more frequent. The advantage of laparoscopic antireflux surgery over open approaches has been clearly demonstrated in several studies with over 90% patient satisfaction,1,2 and a recent metaanalysis demonstrated a lower operative morbidity rate, shorter hospital stays, and a quicker return to work. In addition, as compared with open antireflux surgery, there were no significant differences in successful outcomes, recurrence, dysphagia, or bloating.3 Laparoscopic Nissen fundoplication has become the procedure of choice in the surgical management of medically recalcitrant GERD in many centers.4 In 1987, approximately 12,000 antireflux procedures were performed in the United States. This increased threefold to 48,000 cases in 1998, the majority being performed laparoscopically. Well-established failure rates for open fundoplication range from 9% to 30%5-8 whereas laparoscopic failure rates have been reported between 2% to 17%.4,6,9 The laparoscopic failure rate will likely increase with longer follow-up and is thought to be even higher in less experienced hands secondary to a steep learning curve. Although many patients with mild recurrent symptoms can be managed nonoperatively, it is been estimated that between 3% and 6% of all antireflux procedures will require a reoperative intervention, often within 2 years of the original procedure.10 Historically, reoperative antireflux procedures were approached through an open technique with a morbidity rate

The failure of antireflux procedures to relieve symptoms may be secondary to a variety of causes and usually occurs in the first 2 years after the initial procedure. A relatively uncommon cause, but one that needs to be considered, is misdiagnosis of the original problem with an incomplete or misinterpreted primary preoperative evaluation. Immediate failures may occur, that is, obvious problems of severe dysphagia from too tight a wrap or a severe underlying motor disorder that was underestimated. Other immediate problems may occur due to failure to completely reduce the hernia at the initial operation with immediate symptoms. Also early postoperative retching can occur with immediate re-herniation. Technical mistakes may manifest clinically early or late, depending on the severity of the problem, and the patients desire to seek surgical consideration. Alternatively, the wrap may have been constructed appropriately, with good initial results but disruption or transdiaphragmatic herniation may occur in a delayed fashion. Some of these may be due to a sentinel event, such as heavy lifting, in which the patient notes the immediate return of symptoms. Hunter and associates (1999)14 examined the results of laparoscopic fundoplication in 758 patients and found that the mechanism of failure was transdiaphragmatic herniation in 84%, a slipped fundoplication in 32%, and a twisted fundoplication in 30%. In an update of the same series, it was again reported that the majority of failures were secondary to a transdiaphragmatic herniation of the wrap (Smith et al, 2005).15 A series by Hinder and colleagues16 reported the 367

368

Section 4 Gastroesophageal Reflux and Associated Conditions

results of laparoscopic reoperation in 46 patients, with the two most common causes of failure being breakdown of the fundoplication in 35% and breakdown of the crural repair in 22%. A slipped wrap (15%) and a wrap that was too loose (8%) or too tight (8%) were less frequently observed in this series. Also in this series, nearly 70% of patients who required reoperation had recurrent symptoms within 2 years of their original surgery, suggesting that operative techniques play an important contributing role in the failure of antireflux procedures. Although some randomized trials of laparoscopic antireflux surgery indicate that a failure to divide the short gastric vessels does not play a role in recurrent symptoms,17 others, including our group, believe taking down the short gastric vessels is more likely to result in a tension-free wrap. Other complications, such as inadvertent vagal injuries, can lead to significant bloating, delayed gastric emptying, and even recurrent gastroesophageal reflux. In addition, failure to identify a shortened esophagus, either preoperatively or intraoperatively, and the failure to adequately dissect and reduce a hiatal hernia can also lead to herniation of the wrap and symptoms.

Herniation and Crural Disruption Herniation of the fundoplication usually results from disruption of the crural repair or failure to perform the initial wrap over a tension-free segment of intra-abdominal esophagus. There must be at least 2 to 3 cm of tension-free intraabdominal esophagus below the hiatus, and the gastroesophageal junction must be clearly identified. We find the most consistent way to definitively accomplish this is by careful dissection of the gastroesophageal fat pad to allow direct vision of the precise location of the end of striated muscle fibers and the beginning of the serosa of the stomach. The peritoneum overlying the crus is preserved, with the peritoneum acting as a pledget for the crural closure. Failure of the crural repair can result from excessive tension during the primary suture placement or inadequate tissue in which to place the crural sutures. A large esophageal hiatus occasionally requires a relaxing incision in the diaphragm and/or mesh repair. If during a difficult dissection, the crural fibers are clearly visible with no overlying peritoneum, careful apposition with pledgeted sutures and or mesh will likely be necessary. Although many authors have advocated the liberal use of mesh, in the University of Pittsburgh experience with more than 200 paraesophageal hernia repairs, mesh reconstruction of the diaphragm was only required in 11% of cases.18,19 In general, if a tension-free repair of healthy crural tissue is not possible, one should consider some form of buttress or mesh.

Slipped Nissen Fundoplication A slipped Nissen fundoplication occurs when part of the stomach lies both above and below the wrap (Fig. 32-1). This defect may arise from the stomach slipping through the fundoplication or incorrect positioning of the wrap around the stomach at the time of the original surgery.16 Often a chronically tubularized cardia of the stomach will resemble the

FIGURE 32-1 Retroflexed endoscopic view of the appearance of a slipped Nissen fundoplication with the wrap and fundus herniated across the diaphragm.

esophagus and be wrapped during the initial procedure, emphasizing the importance of clearly identifying the gastroesophageal junction. Ruling out the presence of esophageal shortening and ensuring a tension-free wrap around the intraabdominal portion of the esophagus are essential in minimizing the occurrence of this complication.

Fundoplication: Too Loose or Too Tight A fundoplication that is too tight may lead to dysphagia, and a wrap that is too loose may not be therapeutic.20 Preoperative manometric findings, the patient’s body habitus, and intraoperative findings after mobilization of the stomach and distal esophagus must be carefully considered in tailoring the fundoplication. At the University of Pittsburgh, a laparoscopic Nissen fundoplication is generally performed around a Maloney bougie ranging in size from 52 to 54 Fr for the small to average sized (70-kg) patient. In larger patients, the fundoplication is generally wrapped around a 54- to 56-Fr bougie. A “shoe-shine” maneuver is performed at the time of fundoplication to allow careful assessment of the length and to ensure that the fundus is not under tension and slides freely. A recent randomized study of “bougie versus no bougie” use during laparoscopic Nissen fundoplication showed that the bougie group had a lower incidence of clinically significant dysphagia postoperatively.21 In the patient with impaired esophageal motility, our preference is a floppy Nissen wrap over a slightly larger bougie. Some reports have shown good results in patients with impaired esophageal motility using a partial fundoplication such as a Toupet or a Belsey repair. However, our experience and that of other surgeons have shown Toupet fundoplication to be associated with an unacceptable rate of recurrent reflux and need for laparoscopic reoperation.22,23 In a series of 206 patients from the University of Pittsburgh who underwent laparoscopic antireflux opera-

Chapter 32 Laparoscopic Techniques in Reoperation for Failed Antireflux Repairs

Failure to Recognize Esophageal Shortening

FIGURE 32-2 Barium esophagogram demonstrating a shortened esophagus.

tions, the outcomes after laparoscopic Nissen in 163 patients and laparoscopic Toupet fundoplication in 43 patients were evaluated. Short-term results were similar in the two groups; but with longer follow-up, better results were seen with laparoscopic Nissen fundoplication. Even in the setting of moderate decreases of esophageal motility, a 360-degree floppy fundoplication yielded better results.23

Vagal Injury Familiarity with the anatomy and meticulous dissection around the hiatus will minimize the risk of intraoperative injury to the vagus nerves. Injury to even one of the vagus nerves can lead to the exacerbation of usually mild postoperative bloating, often managed with careful dietary counseling and medications such as simethicone. Injury to both vagi frequently results in markedly delayed gastric emptying and dumping symptoms.24 If an injury to both vagus nerves is identified intraoperatively or is suspected preoperatively based on an abnormal gastric emptying test, the addition of a gastric emptying procedure such as a laparoscopic pyloroplasty is considered. In our experience, if this is seen during a reoperation we would generally make a floppier than usual Nissen repair or consider a partial wrap to minimize the inevitable bloating that will be seen. In general, we delay the decision to perform pyloroplasty until a period of “watch and wait” is given.

Although controversial, it is hypothesized that long-standing reflux leads to circumferential esophageal scarring and, in more severe cases, varying degrees of longitudinal scarring and esophageal shortening. Esophageal shortening is suspected in the presence of peptic stricture, Schatzki’s ring, Barrett’s esophagus, and moderate to giant hiatal hernias. Initially, a barium esophagogram may be helpful in detecting patients who have esophageal shortening and in some cases this is very obvious (Fig. 32-2). In addition, a shortened esophagus can be detected preoperatively by a manometric intrathoracic location of the lower esophageal sphincter. Manometry may also reveal a shortened intersphincteric distance between the upper and lower sphincters.25 A careful intraoperative evaluation with dissection of the gastroesophageal fat pad is essential in identifying the true gastroesophageal junction and excluding esophageal shortening. Intraoperative endoscopy may also aid in recognition with borderline cases. Several aspects of antireflux surgery and, in particular, laparoscopic antireflux surgery may contribute to the failure to recognize a shortened esophagus. The placement of a rigid bougie can place downward tension on the gastroesophageal junction, leading to several centimeters of intra-abdominal length that will subsequently retract with removal of the bougie. With laparoscopic procedures, pneumoperitoneum can elevate the diaphragm, again giving the impression of a longer segment of intra-abdominal esophagus. In addition, traction on the gastroesophageal junction (with, for example, a Penrose drain) can also lead to subsequent herniation of the wrap above the diaphragm. In our own observations of redo surgery and observing other cases, one of the most common reasons for failing to recognize the short esophagus is poor preoperative workup and studies and failure to do a thorough examination of the precise location of the gastroesophageal junction after fat pad removal. Adequate laparoscopic mobilization of the mediastinal esophagus is critical in constructing a tension-free, intraabdominal fundoplication. If esophageal shortening is identified and adequate intra-abdominal esophageal length cannot be obtained, a Collis gastroplasty may minimize the incidence of subsequent wrap herniation and ultimate failure. Excellent short-term results have been reported using several minimally invasive approaches to a Collis gastroplasty.18,26,27 The diagnosis and management of the shortened esophagus is more thoroughly discussed in other chapters in this textbook.

Pseudoachalasia or Secondary Achalasia Pseudoachalasia or secondary achalasia is being increasingly recognized as an entity for late-onset dysphagia after antireflux surgery. In many of these patients dysphagia develops after apparent technically successful antireflux surgery. Stylopoulos and colleagues reported a series of 7 patients and defined secondary achalasia by the following criteria23: 1. Preoperative manometry demonstrating normal peristalsis and lower esophageal sphincter relaxation 2. Lack of postoperative peristalsis 3. No mucosal lesions seen on endoscopy 4. Dysphagia refractory to dilation

369

370

Section 4 Gastroesophageal Reflux and Associated Conditions

Pseudoachalasia tended to occur in older patients and was characterized by delayed onset of symptoms. These investigators noted improvement with botulinum toxin injection in 2 patients and myotomy in 1 patient. Esophageal manometry is critical to this diagnosis, and it is important to recognize the development of pseudoachalasia or secondary achalasia as the cause of symptoms. In our experience at the University of Pittsburgh, we reported a series of 80 patients who required redo minimally invasive surgery for antireflux disease; a myotomy with Toupet fundoplication was performed in 1 patient for pseudoachalasia (Luketich et al, 2002).13

EVALUATION OF RECURRENT SYMPTOMS AFTER PRIOR ANTIREFLUX SURGERY Transient symptoms of dysphagia, bloating, and dietary intolerance are not infrequent in the immediate 4- to 6-week period after the initial operation and usually resolve with conservative management. Some patients experience a short course of diarrhea, which is frequently related to gas bloat and often settles with a slower progression of diet and the addition of simethicone. Increased flatus and the inability to vomit or belch are other common complaints, and, again, medications such as simethicone may help symptoms. If diarrhea or gas bloating persists, injury to the vagal nerves is considered; most of these problems can be managed conservatively with an anti-dumping dietary regimen and a significant “tincture of time.” In some cases, a gastric emptying procedure such as a pyloroplasty or pyloromyotomy may be of benefit. For dysphagia, we generally reserve dilation for patients whose symptoms persist beyond 2 to 3 months. Persistent dysphagia despite these measures requires a thorough evaluation and consideration for reoperation. A complaint of foamy salivation or the inability to tolerate liquids immediately postoperatively may be a result of a technical error or a failure to recognize a severe esophageal motility disorder. The postoperative barium esophagogram usually confirms a very tight wrap that is unlikely to improve with time and warrants consideration for early reoperation. The patient with persistent symptoms after an antireflux procedure must have an exhaustive clinical evaluation. The principal symptoms that lead to consultation and potential reoperative surgery are recalcitrant heartburn and dysphagia (Papasavas et al, 2004).28 Gas bloat and gastrointestinal symptoms are seldom an indication for redo surgery. A careful review of the patient’s initial symptoms, previous response to medical therapy, and prior test results can help in recognizing the presence of an esophageal motility disorder (e.g., achalasia) or undiagnosed gastrointestinal disorders (e.g., chronic cholecystitis). This may require the assistance of an experienced and trusted gastroenterologist. The previous workup and the original indication for surgery is carefully reviewed. A careful review of the operative notes and discussion with the original surgeon may provide detail regarding the dissection of the esophagus, short gastric vessels, and the gastroesophageal fat pad. In addition, the positioning and status of the vagal nerves, bougie size, and type of crural repair may assist in recognizing subtle technical errors.

It is also of benefit to calculate a body mass index because conversion of a previous antireflux procedure to a Roux-en-Y gastric bypass may be of benefit in the morbidly obese. Although this is a technically demanding procedure, at the University of Pittsburgh we have demonstrated a significant reduction in gastroesophageal reflux symptoms with the additional advantage of weight loss and improvement of comorbidities.29 In the final analysis, if the surgeon cannot re-establish normal anatomy, or in the setting of vagal injuries or enterotomies, one may consider the Roux-en-Y gastric bypass as a bail-out procedure even in the patient who is not morbidly obese. We recently reported a series of 25 patients with recalcitrant GERD after prior reflux surgery. Forty-four percent of patients had more than one previous reflux surgery, and 40% had previous Collis gastroplasty. At 2-year follow-up 80% reported to be satisfied with the results.30 Alternatively, esophagectomy may be another option, but in most centers it carries a high morbidity and mortality, in excess of Rouxen-Y conversion. At a minimum, our approach to the patient with recurrent symptoms includes a barium videoesophagogram, chest radiograph, upper gastrointestinal endoscopy, esophageal motility testing, 24-hour pH testing, and a nuclear medicine gastric emptying study. The results of these tests are invaluable in determining the cause and possible solution to recurrent or new symptoms after an unsatisfactory result from antireflux surgery. In the setting of an obvious bilateral vagal injury, with marked delay in gastric emptying, our experience has been that reoperative antireflux surgery has a higher failure rate. One may need to consider other options such as Rouxen-Y conversion or esophagectomy.

Barium Esophagography Several radiologic patterns identified on the barium esophagogram can assist the surgeon in determining the cause of a failed wrap (Fig. 32-3): ■

■

■

■

Type I abnormality represents a near complete or complete disruption of the wrap with recurrence of the hiatal hernia. Type II defect occurs from slippage of a portion of the stomach above the diaphragm, usually caused by incorrect positioning of the fundoplication around the upper stomach rather than esophagus. A classic “hourglass” appearance may be observed. Type III defect, commonly referred to as a slipped Nissen, is seen when part of the stomach lies both above and below the wrap. This defect may arise as a result of slippage of the stomach through the fundoplication or incorrect positioning of the wrap around the stomach at the time of the original surgery. Type IV abnormality is seen when the entire fundoplication herniates into the chest, usually as a result of a disrupted crural repair.

Upper Gastrointestinal Endoscopy Upper gastrointestinal endoscopy is performed to assess for esophagitis, stricture, gastritis, ulceration, or tumor and to

Chapter 32 Laparoscopic Techniques in Reoperation for Failed Antireflux Repairs

FIGURE 32-3 Four types of failed wraps.

Complete disruption

Slipped Nissen

Malpositioned wrap

Transhiatal herniation

evaluate the position and integrity of the wrap. This is ideally performed before surgery. An intact fundoplication has the typical “stack of coins” appearance on a retroflexed view with the endoscope (Fig. 32-4). Interpretation of the endoscopic findings to determine the mechanism of the failure requires experience and knowledge. For example, the presence of gastric mucosa above the wrap suggests the possibility of a slipped Nissen fundoplication. Alternatively, a widely patent gastroesophageal junction viewed on retroflexion of the endoscope positioned in the stomach suggests that the cause of recurrent symptoms may be attributed to a loose or disrupted wrap. In addition, other abnormalities such as twisted fundoplication or a two-compartment stomach may be noted (Figs. 32-5 and 32-6). Identifying the squamocolumnar junction and its relation to the diaphragmatic crura can help make an assessment of esophageal length.

Esophageal Manometry Esophageal manometry is essential in the evaluation of a patient with a failed antireflux procedure. The initial manometry may have been improperly performed or interpreted, and subsequent manometry may provide valuable information regarding esophageal motility. Excluding the presence of poor esophageal peristalsis or other esophageal motility abnormalities, such as diffuse esophageal spasm or achalasia, is crucial before proceeding to operation. In addition, manometry allows for an assessment of the lower esophageal sphincter, with a low-pressure reading indi-

cating a fundoplication may have been disrupted or is too loose and a high-pressure reading suggesting a fundoplication that is too tight. The distance from the upper to the lower esophageal sphincter can also be measured and may indicate esophageal shortening.

24-Hour Esophageal pH Studies Twenty-four-hour esophageal pH studies are also necessary in evaluating patients with recurrent symptoms of GERD after surgery.31 In addition to demonstrating recurrent episodes of acid reflux, the presence of an excessively alkaline environment suggests the possibility of duodenogastroesophageal reflux.32 Furthermore, some centers have begun to use biliary probes to test for bile reflux as a cause of recurrent or persistent symptoms. In addition, in the future, impedance studies may potentially be used in preoperative assessment.

SURGICAL THERAPY The principles of reoperative laparoscopic surgery are similar to those of open procedures and are undertaken only by a team of experienced laparoscopic esophageal surgeons. Operative times are frequently prolonged, with difficult cases often requiring several hours or more to complete. These are complex operations and are planned to be the first case of the day. The surgeon needs to be prepared to spend the entire day in performing the redo operation.

371

372

Section 4 Gastroesophageal Reflux and Associated Conditions

Coronal section

Oblique section

Lip

A

B

Scope Ant. groove

Lip

Posterior groove

Body of valve “stacked coins”

C FIGURE 32-4 A to C, Endoscopic view of intact fundoplication with typical stack of coins appearance of wrap on retroflexed view.

FIGURE 32-5 Endoscopic view of a twisted fundoplication.

FIGURE 32-6 Endoscopic view of a two-compartment stomach.

Chapter 32 Laparoscopic Techniques in Reoperation for Failed Antireflux Repairs

After the induction of anesthesia, esophagogastroduodenoscopy is performed. This allows for assessment of Barrett’s esophagus, stricture, the location and integrity of the previous wrap, presence of a twisted fundoplication, and evaluation of esophageal length. The scope is often left in the esophagus for intraoperative evaluation. An arterial line for continuous blood pressure monitoring assists in managing insufflation pressures and monitoring for the development of a tension pneumothorax. This occurs more frequently than in first-time cases, especially when reoperative surgery involves a significant thoracic dissection. We prefer the patient in the supine position, with steep reverseTrendelenburg, and with the surgeon to the right of the patient. Initial port placement is performed with direct peritoneal visualization. A key technical point is that the first laparoscopic port inserted is placed away from any previous incisions. Regardless of location, an open technique is used for placement of the first port. Once a laparoscopic view of the peritoneal cavity is obtained, adhesiolysis is performed in the upper abdomen to allow usual port placement used for laparoscopic antireflux surgery. If dense adhesions are encountered, we generally add a more inferior and lateral port to allow better visualization and assist with the lysis of adhesions. After complete lysis of adhesions, we convert to our standard five (two 10-mm and three 5-mm) access ports (Fig. 32-7). Typically a 10-mm, 30-degree laparoscope is used in reoperative surgery because it provides a wider and more precise view of the operative field. Lower insufflation pressures in the 8- to 10-mm Hg range are often sufficient for the dissection around the hiatus and to minimize the effects of a prolonged pneumoperitoneum during laparoscopic reoperation. After a careful examination of the peritoneal cavity, mobilization of the esophagogastric junction is performed. The density of adhesions around the hiatus and wrap are unpredictable, and often the most severe adhesions are located between the stomach, distal esophagus, and liver. This can

Grasper 5 mm Camera 5 mm Grasper 5 mm Liver retractor 5 mm

Blunt port 10–12 mm

FIGURE 32-7 Standard laparoscopic port placement for initial and reoperative antireflux surgery. (COPYRIGHT JENNIFER DALLAL, JAMES D. LUKETICH, MD.)

make mobilization of the stomach and distal esophagus from the liver and crus extremely difficult. Care is taken during this part of the dissection to avoid perforation of the stomach and esophagus. Careful and meticulous dissection with autosonic shears (U.S. Surgical, Norwalk, CT) or harmonic scalpel (Ethicon, Cincinnati, OH) is helpful and minimizes the risk of injury to surrounding structures and provides a relatively bloodless field. The repair of multiple gastric perforations can lead to difficulty in creating a new fundoplication by changing the anatomy and pliability of the stomach. Every effort is made to identify and protect the vagus nerves. If a patient gives a history suggestive of delayed gastric emptying and has an abnormal nuclear gastric emptying study, a pyloroplasty may be included in the procedure. If hypotension or high ventilatory pressures are detected during the dissection of the hiatus, a pneumothorax is suspected and treated by placement of a chest tube. We prefer a 12-Fr pigtail catheter in the affected hemithorax. Full mobilization of the distal esophagus, the fundus of the stomach, and the gastroesophageal fat pad and identification of the crus are essential in reoperative antireflux surgery. Early identification and complete takedown of the wrap as well as removal of crural sutures will facilitate complete mobilization. A complete takedown of the previous wrap and re-establishing normal anatomy is an essential component of the operation. This may require further division of the short gastric vessels and mobilization of the esophageal fat pad to identify the true gastroesophageal junction if this has not been performed previously. The recognition of a shortened esophagus may require the addition of a Collis gastroplasty to the antireflux repair. The requirement for a Collis gastroplasty may be suspected on the basis of manometric, radiologic, and/or endoscopic findings. However, the final decision is made intraoperatively, after takedown of the previous repair and complete mobilization of the esophagus into the mediastinum. If less than 3 cm of tension-free intra-abdominal esophagus is present, a Collis gastroplasty is included as described previously.33 A Maloney esophageal bougie (typically 50 Fr) is placed by the surgical team across the gastroesophageal junction along the lesser curve. It is critical that the bougie be passed by the surgical team with direct laparoscopic visualization because this is being placed to decrease the chances of perforation. A large tapered needle attached to a No. 2 absorbable suture is straightened and tied to the point of the anvil of the 21-mm EEA stapler (U.S. Surgical), and the needle is passed through the stomach from posterior to anterior adjacent to the bougie (Fig. 32-8) 4 to 5 cm distal to the level of the diaphragmatic hiatus. The anvil is then pulled gently through the posterior and anterior stomach walls adjacent to the bougie. Judicious application of the electrocautery facilitates passage of the anvil tip. The EEA stapler is then inserted into the abdomen, joined to the anvil, and then fired. The fired EEA stapler creates a circular defect in the stomach wall that allows completion of the gastroplasty segment with the Endo GIA II stapler (U.S. Surgical). The Endo GIA II is fired in a cranial direction, snugly against the bougie, to create at least 4 cm of tension-free intra-abdominal neo-esophagus (Fig. 32-9). Alternatively, the laparoscopic Collis gastroplasty can be

373

374

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 32-8 Anvil positioning of EEA stapler. (COPYRIGHT JENNIFER

FIGURE 32-10 Suturing of 360-degree wrap around Collis segment.

DALLAL, JAMES D. LUKETICH, MD.)

(COPYRIGHT JENNIFER DALLAL, JAMES D. LUKETICH, MD.)

FIGURE 32-9 Creation of neo-esophagus with Endo GIA stapler. (COPYRIGHT JENNIFER DALLAL, JAMES D. LUKETICH, MD.)

FIGURE 32-11 Completed crural repair and Collis-Nissen fundoplication. (COPYRIGHT JENNIFER DALLAL, JAMES D. LUKETICH, MD.)

performed as a wedge gastroplasty. In our recent experience, we have noted this technique is easier to perform and much easier to teach. Before performing the wrap, the esophagus and stomach are insufflated with a gastroscope in an attempt to identify unrecognized injuries or leaks. These injuries are recognized and repaired before performing the fundoplication. A floppy 2- to 3-cm 360-degree Nissen wrap is performed over a Bougie (or neo-esophagus if a Collis gastroplasty is included) (Fig. 32-10). The crura are approximated posterior to the wrap (Fig. 32-11). If the crura cannot be reapproximated in a tension-free manner, mesh is used to close the crural defect. Occasionally, a prosthetic patch is required to perform an adequate crural reapproximation. Our current mesh of choice is Surgisis ES (Cook Surgical, Bloomington, IN).

A myotomy and partial fundoplication (Dor or Toupet) is considered in patients with secondary achalasia or pseudoachalasia. A Roux-en-Y gastric bypass is contemplated in morbidly obese patients. It must be emphasized that the wrap is completely taken down before performing the Rouxen-Y gastrojejunostomy. After the procedure a nasogastric tube is placed under direct vision. In the recovery room, a baseline hematocrit is obtained and a chest radiograph is performed to rule out an occult pneumothorax. A barium swallow is typically performed on the first or second postoperative day. If no extravasation of contrast medium is observed on barium swallow, and in the absence of gastric ileus or abdominal distention, the nasogastric tube is subsequently removed and the patient is started on a clear liquid diet. In general, the patient remains on a soft diet for 1 to 2 weeks after surgery.

Chapter 32 Laparoscopic Techniques in Reoperation for Failed Antireflux Repairs

TABLE 32-1 Results of Laparoscopic Repair of Failed Antireflux Surgery Author (Year)

No. Patients

Open (Conversion)

Szwerc et al34 (1999)

15

Watson et al35 (1999)

27

15 (55%)

27

1 (4%)

36

Curet et al

(1999) 37

Horgan et al

0%

Mortality

Good Results

0

0

87%

0

0

93%

7%

0

96%

31

3 (10%)

32%

0

87%

Luketich et al13 (2002)

80

2 (2.5%)

20%

0

82%

Papasavas et al28 (2004)

54

0 (5.6%)

18%

0

82%

14%

0.3%

93%

15

Smith et al

(1999)

Morbidity

(2005)

307

67 (8%)

RESULTS OF LAPAROSCOPIC REOPERATIVE SURGERY Given the increasing worldwide experience with minimally invasive antireflux surgery, reports of the laparoscopic reoperative treatment of failed laparoscopic and open antireflux procedures are becoming more common. Table 32-1 lists selected studies that review the laparoscopic repair of failed antireflux surgery (Luketich et al, 2002; Papasavas et al, 2004; Smith et al, 2005).13,15,28,34-37 Although the series are small, several observations can be made. First, transdiaphragmatic migration of the fundoplication is the most common cause of failure, followed by disruption of the crural repair and the slipped Nissen defect. In most series, a wrap that was too tight accounted for a small proportion of patients presenting with dysphagia and an intact wrap that was too loose was also an uncommon finding. The conversion rate from laparoscopic to open repair ranged from 0% to 55%, and the perioperative morbidity ranged from 0% to 39%. Only a single mortality was reported in any of these series. In shortterm analysis, an overall patient satisfaction score above 80% was obtained in all reports. At the University of Pittsburgh, we reported a series of 80 reoperative laparoscopic antireflux procedures (Luketich et al, 2002).13 On presentation, 42 patients noted recurrent heartburn, 21 complained of dysphagia, and 17 had recalcitrant regurgitation. At the time of surgery, the most common cause of failure was mediastinal migration of the wrap (60%), followed by a wrap constructed over stomach rather than esophagus (13.8%). Other causes included a tight wrap (8.8%), an inadequate (usually partial) wrap (6.3%), and a disrupted wrap (3.8%); and in 6 patients (7.5%) the etiology was unclear. There were two conversions to open procedures. Morbidity included nine minor gastric perforations (repaired at the time of surgery), one pneumothorax, one pulmonary embolus, 2 patients with atrial fibrillation, 1 patient with an ileus, and a single case of Clostridium difficile colitis. Two patients required early reoperation for complications. This included a single patient who developed a leak from his pyloroplasty site and a second who developed a bile leak from the liver parenchyma after extensive adhesiolysis. Both required open repair. There were no operative deaths. Excellent results were reported in 35 (65%) patients, with

satisfactory results in 9 (17%) patients and poor results in 10 (18%) patients; and 10 (18%) patients reported dissatisfaction at follow-up.

SUMMARY As the number of laparoscopic antireflux procedures increases there will certainly be a rise in the number of reoperative procedures. Most failures come in the first 2 years after the initial procedure and are most often done for dysphagia or other recurrent symptoms of gastroesophageal reflux. A thorough and comprehensive evaluation is completed before performing the procedure, and the operative approach depends on the pathophysiology of the underlying cause of failure. It is prudent to work closely with a medical gastroenterologist experienced in the nonoperative management of GERD to confirm that the patient indeed has failed medical therapy. Reoperative laparoscopic antireflux surgery is complex, and advanced training in these techniques is essential for achieving good results. There is no single technique that will work for every patient, and consideration to other approaches such as partial wraps or Roux-en-Y conversions should be made, especially in the obese patient. Esophagectomy may be required in extreme cases, especially in the thin patient. Although the results of reoperative antireflux surgery are not as successful as with the initial procedure, excellent results are possible in 80% to 90% of patients using minimally invasive techniques in the hands of experienced surgeons. KEY REFERENCES Hunter JG, Smith CD, Branum GD, et al: Laparoscopic fundoplication failures: Patterns of failure and response to fundoplication revision. Ann Surg 230:595, 1999. Little AG, Ferguson MK, Skinner DB: Reoperation for failed antireflux operations. J Thorac Cardiovasc Surg 91:511, 1986. Luketich JD, Fernando HC, Christie NA, et al: Outcomes after minimally invasive reoperation for gastroesophageal reflux disease. Ann Thorac Surg 74:328, 2002. Papasavas PK, Yeaney WW, Landreneau RJ, et al: Reoperative laparoscopic fundoplication for the treatment of failed fundoplication. J Thorac Cardiovasc Surg 128:509, 2004. Smith DC, McClusky DA, Rajad MA, et al: When fundoplication fails: Redo? Ann Surg 241:861, 2005.

375

chapter

33

COMPLICATIONS OF SURGERY FOR GASTROESOPHAGEAL REFLUX Bryan F. Meyers Nathaniel J. Soper

Key Points ■ Avoidance of complications begins with a thorough but careful

■

■ ■

■

mobilization of the gastroesophageal junction. Constant attention to the presence and preservation of the spleen and the vagus nerves is essential. Appropriate management of the postoperative patient includes avoidance of narcotics and aggressive management of nausea and vomiting. The wrap is most vulnerable to migration into the mediastinum as a result of early postoperative retching. Conservative management of postoperative delayed gastric emptying is advised because it usually resolves spontaneously. If prosthetic material is used to buttress the closure, it is advisable to use an absorbable bioprosthetic patch that is less likely to migrate into the lumen and cause an esophageal injury that is very difficult to manage. Careful selection and preparation are key elements to a satisfied patient, with emphasis on management of expectations for dysphagia and the eventual likely use of additional medical therapy to control symptoms.

In the past 10 years there has been an increase in the number of antireflux operations being performed. The reasons for this increase include the development and proliferation of laparoscopic techniques, the increase in the fraction of the population that is overweight, and, possibly, the increased willingness of the population to undergo an operation to avoid the necessity of a lifetime of medication or lifestyle changes. There are many who now believe that laparoscopic antireflux surgery is the gold standard of treatment for severe gastroesophageal reflux, a benchmark against which all other therapies must be compared.1 A contrary opinion has also been expressed, challenging the incremental benefits of antireflux surgery over those of a medical regimen based on proton pump inhibitors (Richter, 2003).2-4 Much of the evidence cited by the detractors of surgery for reflux disease is focused on the complications of surgery, both short term and long term. Despite the mixed opinions, the volume of antireflux surgery has grown. Along with the increase in laparoscopic antireflux procedures has been an increase in the number of complications from these procedures. Just as there was a rapid increase in the number of reports of laparoscopic antireflux operations in the late 1990s, there has been in increase in the past few years in the number of published reports on reoperative procedures and complications from the initial operation (Carlson and Frantzides, 2001).5-12 Although each of the case series reports carries with it a local flavor and thus 376

may not convey the “big picture,” there is surprising homogeneity in the types of problems encountered and the frequency with which they are seen. The definition of “complications” of this operation can range from immediate complications that occur at the time of the operation to early postoperative complications that reduce the function of the procedure or introduce unwanted side effects. Complications might also refer to functional failure of the operation, leading to a decision to reoperate and revise the antireflux wrap. For the purposes of organization within this text, we focus on the immediate and acute complications. The long-term and functional complications are covered in greater detail in other chapters.

PROBLEMS WITH INITIAL APPROACH AND MOBILIZATION When a transabdominal approach is used to perform laparoscopic antireflux surgery, laparoscopic trocars should be placed high in the abdomen, in an arc 12 to 15 cm from the xiphoid process. The liver is elevated with a self-retaining retractor to allow for secure exposure of the operative field while minimizing fatigue of the assistant. In patients with an enlarged left lateral section of the liver, this may be challenging. Sometimes more than one retractor needs to be used for adequate exposure. The retractors themselves can cause tearing of the hepatic capsule, leading to hemorrhage, which can obscure the operative field. Furthermore, it is possible that hepatic necrosis can occur during prolonged cases. The surgeon should observe the liver early after placing the hepatic retractor, and if there appears to be significant cyanosis it may be worthwhile to release the retraction intermittently throughout the case to prevent necrosis. Most instances of hepatic capsular tear result in minor bleeding that will resolve spontaneously; however, high-wattage electrocautery or application of Surgicel may be necessary on occasion. Inadvertent enterotomy or gastrotomy may also occur during tissue manipulation. The use of atraumatic grasping devices is critical during these operations to minimize the likelihood of enterotomy or gastrotomy. As a general rule, if muscularis propria can be seen deep to a serosal tear, the tear should be oversewn with absorbable 3-0 sutures. During the operation, the esophagus should never be grasped directly by the surgeon or assistant (Fig. 33-1). The esophagogastric junction may be retracted using a Penrose drain or by grasping the epiphrenic fat pad for manipulation. An alternative approach is to place an umbilical tape or a Penrose drain around the esophagus at the gastroesophageal junction to allow atraumatic retraction. When dissecting the esophagus

Chapter 33 Complications of Surgery for Gastroesophageal Reflux

Crural sutures tied with tying rod

No. 58 Maloney dilator

FIGURE 33-1 Antireflux operation with emphasis on avoidance of perioperative complications. The esophagus is retracted with an atraumatic umbilical tape rather than an instrument. The crural closure and subsequent wrap are calibrated with an appropriately sized bougie. An atraumatic grasper is used to retract the stomach. (FROM

FIGURE 33-2 A transthoracic repair of a hiatal hernia with emphasis on preservation of the vagus nerves. Care is taken to preserve both vagus nerve branches as the fat pad is dissected and prepared for a wrap or a Collis gastroplasty. The same care must be taken from a laparoscopic approach, although visualization and vagus nerve preservation are more challenging with a laparoscopic approach to a large hernia with a shortened esophagus. (FROM ALLEN MA: THE LAPAROSCOPIC NISSEN FUNDOPLICATION. OP TECH CARD THORAC SURG 2:44-51, 1997.)

ALLEN MA: THE LAPAROSCOPIC NISSEN FUNDOPLICATION. OP TECH CARD THORAC SURG 2:44-51, 1997.)

from the mediastinum, the surgeon should place the shaft of the nondominant manipulating instrument adjacent to the esophagus to apply traction, rather than using its tip on the surface of the esophagus or grasping the esophagus directly. Should an esophageal perforation be suspected, this should be ascertained by intraoperative endoscopy with air insufflation under water. If a perforation is visualized, it should be oversewn with fine absorbable sutures and retested on completion. If there are still doubts, leaving a drain is a prudent decision because the periesophageal area will be difficult to drain if a leak becomes apparent later in the course of recovery. Most surgeons advocate dividing the connections to the posterior and lateral borders of the fundus of the stomach to effect a tension-free fundoplication. This maneuver requires traction on the fundus while dividing the short gastric vessels and posterior gastric vessels. Even with prudent traction of the stomach away from the spleen, it is possible to tear the capsule of the spleen. Small capsular tears can generally be treated by placing pressure on the area using a Raytek sponge that is unfolded, placed into the abdominal cavity, and applied to the capsular tear. Sometimes the use of Surgicel, fibrin glue, or other procoagulants will also be of value. Rarely is a splenectomy necessary. In one large series of laparoscopic antireflux operations, a splenectomy was necessary in fewer than 0.5% of cases. Most surgeons use the ultrasonic shears technology to provide hemostasis during division of the gastrosplenic ligament. Occasionally a blood vessel may bleed profusely, obscuring the operative field. Judicious use of suction, pressure with a Raytek sponge, and appropriate retraction will usually allow visualization of the involved blood vessel. Hemostatic control may be achieved using the

ultrasonic shears, a clip, or rapid intracorporeal suturing. Occasionally, if control of the bleeding vessel cannot be obtained, conversion to an open operation under urgent conditions will be necessary. Adequate mobilization of the esophagus from the mediastinum is often required to obtain at least 3 cm of esophagus below the diaphragm without traction being placed on the stomach or esophagus (see Fig. 33-1). The surgeon should use the anterior and posterior vagus nerves as identifying landmarks, dissecting the nerves such that they reside along the esophagus at the conclusion of the dissection (Fig. 33-2). With the use of this approach, inadvertent vagotomy is uncommon. However, in the presence of severe periesophageal inflammation, the location of the vagal trunks may be difficult to ascertain or in an unusual location. Should injury to one of the vagal trunks occur, this should be stated in the operative note, but it is unlikely that any clinically deleterious effects will result. If both vagal trunks are damaged, there is a 20% to 30% chance of subsequent gastric outlet obstruction. The surgeon should maintain a high index of suspicion for this complication and be prepared to perform postoperative pyloric dilation or a second operation with pyloroplasty. During mediastinal dissection, it is not uncommon to create a tear of one or both pleura. This event occurs in approximately 10% of operations around the esophageal hiatus, more commonly with paraesophageal hiatal hernias than for routine laparoscopic antireflux surgery. Some strategies for Collis gastroplasty during a minimally invasive operation include a transpleural approach that requires a communication between the insufflated peritoneum and the pleura. When a pleural tear is recognized by the surgeon

377

378

Section 4 Gastroesophageal Reflux and Associated Conditions

intraoperatively, the anesthetist should be notified. The anesthetist should monitor airway pressure and systemic blood pressure for signs of significant adverse effects of the pleural tear. It must be remembered that under these circumstances there is no underlying pulmonary injury and that the intraoperative pneumothorax is caused by CO2, with the pleural pressure approximating that of the intra-abdominal pressure. If adverse hemodynamic or pulmonary signs develop, the intra-abdominal pressure limit on the insufflator should be decreased and the anesthetist should increase the delivered airway pressure. When using these maneuvers it is exceedingly rare to require any other intervention. It is possible for a “ball-valve” effect to occur with small pleural tears, leading to significant compression of the ipsilateral lung. If this event occurs, the surgeon may choose to simply increase the size of the pleural opening such that there is free communication between the abdominal cavity and pleural space. When a pleural tear has occurred intraoperatively, our routine has been to complete the case and place the tip of the suction wand between the esophagus and closed crura on the ipsilateral side of the esophagus. The anesthetist is instructed to administer several vital capacity breaths in succession while aspirating on the suction wand during evacuation of the CO2 from the abdominal cavity. This maneuver is meant to remove as much of the CO2 as possible without allowing room air to enter the abdominal cavity during trocar removal. We do not routinely obtain postoperative chest radiographs when a pleural tear has occurred. If the patient is hypoxemic or complains of significant pleuritic pain, a chest radiograph may be obtained. We have observed several large pneumothoraces to disappear within a few hours postoperatively, thus supporting the concept of not placing a chest tube or thoracentesis needle on a routine basis. As a sidebar, in approximately 5% of patients, significant subcutaneous emphysema may be evident intraoperatively or postoperatively. This event by itself does not pose a clinical problem, and the CO2 is usually reabsorbed within 24 hours postoperatively. Major vascular injuries occur rarely but may lead to catastrophic situations. The most common injuries are to the left hepatic vein, vena cava, and aorta.13 Because of the potentially life-threatening effects of such an injury, the equipment necessary to perform emergency laparotomy and/or thoracotomy should be immediately available in the operating room. With an enlarged esophageal hiatus, particularly in the presence of a large hiatal hernia, the left hepatic vein may be located in close proximity to the right crus of the diaphragm. An injury may occur during dissection of the diaphragm or suturing of the crura. Management of a hepatic venous injury depends on the physiologic effects and suturing skills of the surgeon. A large venotomy may allow introduction of CO2 into the venous system, leading to a CO2 embolism. If a venotomy is noticed, the initial amount of bleeding may be minimal, given the pressure differential between the insufflated abdomen and the venous lumen. The venotomy should be grasped using atraumatic grasping devices and held closed to minimize the likelihood of a gas embolism. If the surgeon is skilled with intracorporeal suturing, fine sutures of 4-0 Prolene should be used to close the venotomy. If the surgeon

does not possess the requisite skills, a Raytek sponge should be placed over the venotomy and pressure held on the area using a grasping device in the surgeon’s nondominant hand while urgent laparotomy is performed with assistance. The left hepatic vein can usually be suture ligated without sequelae. The incidence of major aortic or caval injury should be minimal in the presence of adequate experience by the surgeon and appropriate anatomic identification. These structures must never be dissected inadvertently (e.g., mistaking the cava or aorta for the esophagus), and neither sharp dissection nor application of surgical energy sources to the surface of the vessels should be utilized. The aorta may also be inadvertently damaged while placing the most posterior suture used to reapproximate the two crura. If on placing this suture there appears to be arterial blood emanating from the site of closure, the suture should be removed and the area examined. Pressure with a Raytek sponge will often allow sealing of the small needle hole resulting from such an injury. If not, appropriate suture placement or urgent conversion to open surgery may be necessary.

EARLY POSTOPERATIVE PROBLEMS Our routine during the performance of laparoscopic antireflux surgery is to administer intraoperative ketorolac (to minimize narcotic use) and ondansetron (to diminish the possibility of postoperative nausea and vomiting). Both of these medications are administered for the first 18 to 24 hours. Some authors have challenged the notion of outpatient antireflux surgery on the basis of the high prevalence of postoperative nausea and vomiting and the implication it might have on wrap migration.14 Patients who retch or vomit in the early postoperative period are at risk for disruption of the crural closure or intrathoracic migration of the fundoplication. Thus, early postoperative vomiting should lead to the performance of a barium swallow to assess the anatomic integrity of the repair and fundoplication. If a disruption is identified, the patient should be taken back to surgery as early as possible. If reoperation is performed within 4 to 10 days, the procedure is usually relatively simple, but if the operation is delayed until after adhesions develop, the anatomy may be very difficult to discern and manage.15 If the early window is missed, it may be prudent to wait several months to allow healing and the dissipation of the perioperative vascularity that comes with early healing.16 Acute postoperative dysphagia may also occur. If the patient is able to consume adequate liquids to maintain hydration, this condition is generally managed expectantly while awaiting resolution of the expected postoperative edema. If, however, the patient is unable to swallow liquids, an anatomic evaluation is warranted. Early dysphagia, although usually caused by perioperative edema, may also be caused by an excessively tight crural closure, angulation of the esophagus at the site of the crural closure, or a tight or twisted fundoplication. Primary prevention of this problem involves the use of an appropriately sized bougie during the calibration of the closure of the hiatus and for the creation of the wrap (see Fig. 33-1). We generally use a 58- to 60-Fr (19-20 mm

Chapter 33 Complications of Surgery for Gastroesophageal Reflux

diameter) bougie for this purpose. Evaluation of severe early postoperative dysphagia should begin with a barium swallow. If this demonstrates a complete cutoff of the barium column at the lower esophagus, the barium should be aspirated with a nasoesophageal tube and upper endoscopy performed. If the endoscope is able to traverse the gastroesophageal junction, an assessment of the wrap in a retroflexed view may be of value to assess for a twisted fundoplication. If an anatomic problem that requires surgical intervention is identified, this should be done in the early postoperative period. If no such anatomic problem is identified, often empirical dilation up to the size of the dilator used intraoperatively may reduce the edema in the region and improve the patient’s symptoms.17 In very rare circumstances, persistent dysphagia without an anatomic explanation will be severe and prolonged enough to merit reoperation. Acute postoperative gastric distention is a rare event but must be considered in a patient who complains of nausea and exhibits epigastric distention. If a plain abdominal radiograph reveals a large gas-filled stomach, a nasogastric tube should be placed for decompression. This is generally a self-limited problem and will resolve spontaneously with expectant observation. Patients should be cautioned to avoid carbonated beverages and to be watchful of any inadvertent air swallowing that they may be doing.18 Many patients swallow small boluses of air to initiate a belch, and this practice may be ineffective and even counterproductive after antireflux surgery. Acute pulmonary problems may be seen in the early postoperative interval. These would include atelectasis, pneumonia, or pulmonary embolism.19 We routinely place sequential compression devices on all patients intraoperatively and early postoperatively and supply incentive spirometers for use in the early postoperative interval. However, pleuritic pain may lead to splinting of the diaphragm and subsequent atelectasis or pneumonia. Patients with severe regurgitation may also suffer from aspiration during intubation. We have encouraged our anesthetist to use rapid sequence induction in all of these patients. In a prolonged case, if the patient has been positioned in reverse Trendelenburg to facilitate operative exposure, it might be of value to intermittently alter the position to Trendelenburg to avoid venous pooling in the lower extremities. Although this practice has no support from published evidence, there is no risk and little delay that is introduced, so it is hard to argue strongly against. By using these safeguards, significant pneumonia and/or pulmonary emboli are quite rare. However, if the patient exhibits hypoxemia or fever, a chest radiograph should be performed. Likewise, if there is a high index of suspicion of pulmonary embolism, a spiral chest CT scan should be obtained. Delayed gastric emptying may be seen in the early postoperative interval. This problem is often attributed to injury to the vagus nerves during the mobilization of the distal esophagus before placement of the antireflux wrap. One study has shown an alteration of vagus nerve function in a substantial fraction of antireflux surgery patients, even in the absence of known vagus nerve injury, although the physiologic testing did not correlate with symptoms observed in the tested patients.20 If the diagnosis is entertained, an upper

gastrointestinal radiograph should be obtained to rule out an anatomic abnormality that may be corrected. If the results of the radiograph are unrevealing, a scintigraphic gastric emptying test should be performed. Gastric outlet obstruction due to bilateral truncal vagotomy is rare but more commonly seen in reoperative situations. When delayed gastric emptying is documented, the options for therapy are either attempted pyloric dilatation (which in our experience is not generally effective) or performance of a laparoscopic pyloromyotomy or pyloroplasty. Other management strategies include the use of prokinetic medications such as metoclopramide, erythromycin, or tegaserod to attempt to improve gastric motility and emptying. There is no good evidence to support such therapy, although the downside is small and it offers a nonsurgical option while time is given to allow improvement.

LATE POSTOPERATIVE PROBLEMS There are a number of problems that have been commonly experienced or intermittently reported in the literature that present as late problems but clearly have their genesis during the operations. If the surgeon is forewarned about the problems, he or she will be able to make the appropriate decisions at the time of the first operation to avoid such problems. Port site hernias have been commonly reported in the medical literature but have become increasingly rare as port technology changes.21 The increasing use of 5-mm or smaller ports has decreased the incidence of such hernias. We generally use 5-mm ports for most access sites, with the exceptions being the left subcostal port and occasionally the use of a Hassan trocar in the periumbilical region in the setting of previous abdominal surgery. When the left subcostal port is a 12-mm port, it has not been necessary to specifically close the fascia and there have been no occurrences of symptomatic hernias in that location. When a Hassan port is placed in a semi-open manner, heavy Vicryl sutures are placed in the fascia at the time of port placement to allow tight closure of the fascia at the time of port removal. Lafullarde and Gys21 describes five cases of herniation of the epiploon through a trocar orifice. A more troublesome problem that presents late after surgery is that of complications caused by the use of prosthetic material at the hiatus.22 There have been several studies looking at the impact of prosthetic bolstering of the diaphragm at the site of hiatal closure, and there is compelling evidence that a prosthetic patch can reduce the risk of subsequent cephalad migration of the wrap and the gastroesophageal junction (Granderath et al, 2005).23,24 When this prosthetic material is permanent and nonabsorbable, its use comes with an added risk of subsequent erosion into the esophagus or stomach. When this occurs, the prosthetic material can find its way into the lumen and thus become contaminated with enteric contents, leading to a situation that can only be dealt with using major reconstruction and repair of the injured viscus.25,26 One method to avoid this problem is to forgo the use of any prosthetic material at the hiatus, although a compromise might be to use only absorbable material in that location. Bovine pericardium, Surgisys,

379

380

Section 4 Gastroesophageal Reflux and Associated Conditions

and Alloderm all provide initial support of the attenuated diaphragmatic crus and provide a structure that allows inflammatory response and ingrowth of connective tissue. The material itself, however, will break down over time and will thus not be as likely to end up in communication with the lumen. The same concerns about permanent prosthetic material have been raised about Teflon pledgets used to bolster suture material at the crural closure.27 They may enhance the strength of the closure but there are reports of these items eroding into the lumen. Late migration of the wrap into the mediastinum is occasionally observed. The frequency of wrap migration and other anatomic problems varies depending on the intensity with which it is sought. One author has suggested an anatomic “failure” rate of 50%, although the majority of such failures are not symptomatic and do not require therapy (Donkervoort et al, 2003).28 Other authors suggest a rate of anatomic failure of 5% to 10%.29 A classification of failures leading to reoperation is depicted in Table 33-1. The most typical situation occurs when there is breakdown of the crural repair sutures, allowing the hiatal opening to be enlarged again. The entire wrap along with the gastroesophageal junction can migrate cephalad, and this will result in an intrathoracic Nissen fundoplication. In the absence of symptoms, this might be safely observed, but these patients typically experience dysphagia and desire intervention. A variation on this problem is the so-called slipped Nissen in which the wrap remains below the diaphragm but the stomach and the gastroesophageal junction slip cephalad to the point that the gastroesophageal junction resides several centimeters above the diaphragm. The wrap now resides on the body of the stomach and typically causes pain and dysphagia. This outcome usually requires a second operation, often with inclusion of an esophageal lengthening procedure such as a Collis gastroplasty. A second variation on this complication is the true paraesophageal hernia. Breakdown of the crural repair sutures only, with an intact wrap and gastroesophageal junction, can result in a gastric volvulus with stomach and small bowel in the chest despite an appropriately placed wrap.16,30,31

including them here will increase the reader’s awareness of them and perhaps lead to early recognition in the event of such a problem.32-39 Chylothorax has been observed on rare occasions after both open and laparoscopic antireflux operations. One must be mindful of the typical location of the thoracic duct when dissecting the mediastinal extent of a hiatal hernia. The usual course of the thoracic duct finds it adjacent to the aorta on the right side as it passes through the aortic hiatus of the diaphragm. It gradually passes from right to left, crossing the midline in the middle of the chest. Care must be taken to avoid dissection lateral and posterior to the aorta. Management of a chylothorax after antireflux surgery is similar to management of the same condition caused by other causes and is covered in detail elsewhere in this text. Internal hernias have been reported after laparoscopic Nissen fundoplication.38,40 In one extreme case, a cecal herniation was reported through the foramen of Winslow immediately after a laparoscopic Nissen procedure. It is not clear how the operation can be performed differently to avoid such a complication, but a level of alertness to the possibility may shorten the time to making the appropriate diagnosis and re-exploration of the patient. Several variations on the theme of local sepsis have been reported.37,41,42 Most likely they are the result of a previously undetected enterotomy at the time of the dissection or repair. These cases include a pleura empyema, septic pericarditis, and cardiac tamponade. In some instances a frank gastropericardial fistula has been demonstrated, whereas in other cases no clear communication was seen between the gastrointestinal lumen and the infected space. In any situation in which a patient presents with signs and symptoms of infection after antireflux surgery, a strong suspicion must be maintained for the possibility of an esophageal leak. Contrast swallow should be considered and endoscopy performed if there is any doubt about the possibility of a leak after contrast swallow. The likelihood of such a leak will be greater when a Collis gastroplasty has been used or in the setting of a “redo” operation.

UNUSUAL COMPLICATIONS

SUMMARY

There are a number of complications that have been reported and deserve inclusion in this chapter for the sake of completeness. None of these has been experienced by us, but because they have been reported there is a possibility that

It is clear that there are innumerable opportunities to introduce complications into the hospital course of patients undergoing antireflux surgery. Like all problems, these complications are best avoided through careful preparation of the patient

TABLE 33-1 Classification of Failure After Antireflux Surgery Requiring Revision Type of Failure

Root Cause

Remedy

Migration of gastroesophageal junction above the crura

Short esophagus, lack of mobilization of esophagus

Better mobilization, consider gastroplasty

Paraesophageal hernia

Inadequate crural closure

Better crural closure, buttress of crura with absorbable mesh

Malformation or failure of the wrap

Technical problem at time of first operation

Revision of wrap

Esophageal dysmotility

Lack of preoperative assessment, too tight of a wrap

Revision to partial wrap, or esophagectomy in severe cases

Chapter 33 Complications of Surgery for Gastroesophageal Reflux

and the surgeon. Preparation of the patient may be through knowledge (e.g., careful and honest counseling regarding risks and benefits) or through interventions such as smoking cessation and weight reduction. One study has shown an association between body mass index and complication rates.43 The uncomplicated antireflux operation in a thin patient with no previous abdominal surgery and no hiatal hernia is a seductively straightforward operation. On the other hand, the patient with an intrathoracic stomach with a shortened esophagus and the “redo” operation in an obese patient are far more complex with much higher stakes with regard to early complications and long-term functional outcomes. These patients usually have a normal life expectancy and will continue to return to the clinic seeking redress of a bad functional outcome. For these reasons, it is important that surgeons have adequate mentoring and assistance during the early portion of their experience with these operations. There is a definite learning curve, and it is important for the patient and the surgeon that the learning curve is shared with a surgeon with greater experience who might have already encountered the pitfalls described in this chapter and thus can help the newer surgeon avoid them.44,45

COMMENTS AND CONTROVERSIES Unfortunately laparoscopic antireflux surgery has been promoted as the gold standard for therapy for gastroesophageal reflux disease. It is hard to believe that an iatrogenic gastric volvulus is a good thing let alone a gold standard. Not until surgeons realize and present these procedures as one of the therapeutic alternatives will our lives be made easier. One way of minimizing long-term complications is to assure that the patient has appropriate expectations and the realization that he or she may be trading one set of problems for another of lesser magnitude. Expectation is everything! Every attempt must be made to avoid complications. Three areas must be examined: the patient, the surgeon, and the procedure. Patient selection is crucial; the slender patient with typical symptoms of gastroesophageal reflux disease, proton pump inhibitor response, abnormal 24-hour pH, normal esophageal motility and gastric emptying, and a reducible hiatal hernia is an ideal patient. Frequently,

the surgeon sets the stage for failure by ignoring obvious patient signals that a long-term complication is inevitable. These include atypical symptoms, failure of symptoms to respond to proton pump inhibitor therapy, normal 24-hour pH studies, a large irreducible hiatal hernia, diabetes and unsuspected gastroparesis, morbid obesity, and so on. Performance of this procedure by an experienced surgeon is necessary to minimize complications. This includes experience in patient selection and preparation, operative technique and skills, and the often-forgotten expertise in postoperative management, which must extend beyond the hospital discharge. Unfortunately there is no experience like experience when it comes to dealing with complications. Finally, adherence to the principles of antireflux surgery will minimize complications. First the surgeon must reduce the hiatal hernia and restore the intra-abdominal length of the esophagus. Next the esophageal hiatus must be reconstructed, remembering that it is not a hole to be patched but a major component of the reflux barrier. Finally, the lower esophageal sphincter must be fortified with the “unnatural” fundoplication. The authors elegantly detail some of the more common complications and how to avoid them. Unfortunately, even with the utmost of care, complications will occur, and it is critical to recognize them early and fix the problem promptly. T. W. R.

KEY REFERENCES Carlson MA, Frantzides CT: Complications and results of primary minimally invasive antireflux procedures: A review of 10,735 reported cases. J Am Coll Surg 193:428-439, 2001. Donkervoort SC, Bais JE, Rijnhart-de Jong H, Gooszen HG: Impact of anatomical wrap position on the outcome of Nissen fundoplication. Br J Surg 90:854-859, 2003. Granderath FA, Schweiger UM, Kamolz T, et al: Laparoscopic Nissen fundoplication with prosthetic hiatal closure reduces postoperative intrathoracic wrap herniation: Preliminary results of a prospective randomized functional and clinical study. Arch Surg 140:40-48, 2005. Richter JE: Let the patient beware: The evolving truth about laparoscopic antireflux surgery. Am J Med 114:71-73, 2003.

381

chapter

34

QUALITY OF LIFE AFTER ANTIREFLUX SURGERY Lars Lundell

Key Points ■ Quality of life has emerged as a valid tool to assess the impact of

a specific disease on the well-being of affected individuals. ■ GERD patients suffer from a significant impairment in their health-

related quality of life. ■ Effective therapy has the capacity to normalize these patients’

quality of life. ■ Antireflux surgery has repeatedly been shown to correct these

deficiencies in well-being, effects that do not subside with time.

Health is often assessed and measured in terms of survival and morbidity, but the concept was further refined in 1948 when the World Health Organization defined it as “not only the absence of infirmity and disease but also a state of physical, mental and social well being.” Thereby a broader, more positive concept of health was introduced that included both physical and mental dimensions. Quality of life (QOL) first emerged on the political agenda in the United States around 1950. Despite these landmark events there is still no consensus as how to define QOL, but it is considered to be a broader concept than just health aspects.1-4 QOL is not a directly observable or measurable entity. To facilitate the operationalistic view of QOL, the concept has been restricted, in a medical sense, to health-related QOL. Even though there is no standard concept for the term, there is agreement that a multidimensional construct should be applied, including physical, social, and emotional functioning as well as disease-related symptoms. Several other factors influence QOL, and additional domains may be incorporated, depending on the research issues, such as sexual functioning, body image, economic impact, cognition, existential issues, and satisfaction with medical care (Patrick and Deyo, 1989; Sullivan, 1992).5-10 For instance, in the area of cancer research QOL has become an important outcome measure in the evaluation of treatment. Knowledge about QOL is considered to be very helpful in the decision-making process in clinical practice concerning both the timing of and the choice between alternative treatments with equal survival rates.11 Furthermore, QOL has been introduced as an end point in cancer trials, which has led to a broadening of the evaluation criteria beyond the traditional ones such as survival, tumor response, and disease-free survival. In disease entities, where the alternative therapeutic approaches may vary considerably, it is of paramount importance to incorporate QOL assessment to obtain a comprehensive view of the pros and cons of respective therapies.12 Gastroesophageal reflux disease (GERD) 382

represents such a therapeutic area where effective medical therapies have to be compared to surgical alternatives, particularly when the long-term management perspective is taken into account. QOL may be assessed by the clinician, the spouse, and/or the patient. There are widespread tools created for clinicians, but they only cover, in a global sense, the physical components relevant to QOL assessment.11,13 The main reason for not using clinicians or spouses to evaluate the QOL of a patient is, however, the discrepancies found between these ratings and those from the patient. Agreement has thus been reached that the patients themselves are the most reliable sources. QOL data may be collected by interviews or through questionnaires. The interview may be structured or semistructured (a combination of open-ended and closed-ended questions). Both methods provide standardization of data collection, but more qualitative information is obtained through the semi-structured interviews. Such interviews are seldom used in a clinical trial because they are time consuming and require extensive resources. The questions for selfassessment are easier to apply to large populations. They are also more reliable tools, because they do not suffer from interviewer bias. During the past decades, several such QOL questionnaires have been developed for use in clinical research.

QUALITY OF LIFE INSTRUMENTS Quality of life instruments can conceptually be categorized into generic or disease specific. Generic instruments are those that are broadly applicable across types and severities of diseases and treatments, whereas disease-specific instruments are those that assess specific diagnostic groups with the intent of measuring clinically important changes (Sullivan, 1992).5,6 The advantages of a generic instrument are that a single instrument can be used in a variety of settings; it can detect different effects and reflect various aspects of health status and comparisons across interventions. The disadvantages are that they may not adequately focus on the area of interest and may not be responsive enough. The advantages of a disease-specific instrument are that they are more clinically oriented and may be more responsive. Their disadvantages are that they may not allow for cross-condition comparisons and may be limited in terms of populations and interventions. A more narrow aspect of QOL is to measure symptom severity. Symptom severity measures only the extent of the patient symptom without addressing other QOL issues such as social interactions or psychological stresses. A symptom

Chapter 34 Quality of Life After Antireflux Surgery

reported is a verbal expression of a subjective experience that summarizes an intergraded stimulant from a variety of aspects.14,15 It is not surprising to find multiple studies that document little or no correlation between patients’ perceived symptoms and the objective measurements such as specific pathophysiologic parameters (Velanovich et al, 1996).16-18 Corresponding observations suggest that an objective surrogate for patients’ perceived symptoms, such as healing of esophagitis or resolution of symptoms of GERD, might represent incomplete end points if symptom relief is the main objective.19-25

Generic Instruments The SF-36 health survey was designed to determine where the variations in patients’ outcomes may be explained by differences in systems of care and clinicians’ specialties and also to offer a practical tool for the routine monitoring of patient outcomes. Population norms with standard deviations have been established and as a result of these efforts, the SF-36 has become one of the most popular and widely used QOL instruments.26-28 The Psychological General Well-Being (PGWB) index was developed to measure subjective wellbeing or distress. Since its introduction it has had a long track record from many clinical studies, in which mostly upper gastrointestinal diseases were addressed. It assesses six dimensions of QOL: anxiety, depressed mood, positive wellbeing, self-control, general health, and vitality. These are then combined also to establish an overall score.6,16,29

Disease-Specific Instruments The Gastrointestinal Symptom Rating Scale (GSRS) was constructed initially to measure symptom severity in peptic ulcer disease and irritable bowel syndrome.30 It is a sevengraded LIKERT scale–based questionnaire, which contains 15 items. It has been extensively used to assess reflux disease and has been found to be very useful both for clinical as well for research purposes. The GERD Health-Related Quality of Life Scale (GERDHRQL) is a disease-specific scale that was designed to address symptom severity in GERD with particular attention to responsiveness. It is a 10-item LIKERT-scale questionnaire in which each response has a descriptive anchor. One of the potential advantages with this instrument is that it is limited to one page.31 Commonly used instruments are a Gastrointestinal Quality of Life Index (GIQLI) and the Quality of Life Reflux and Dyspepsia (QOLRAD). GIQLI offers a general index to which is added gastrointestinal symptoms, emotional status, physical status, social status, and stress of medical treatment. The QOLRAD offers 25 items incorporating emotions, vitality, sleep, eating-drinking, and physical and social functioning (Kamolz, Pointner, 2003).32 A Reflux-Related Visual Analogue Scale has been developed based on the same concept as the Visual Analogue Scale assessment in pain research. Data related to its validity and reliability have yet to be further researched, but it has hitherto been found to be a potentially reliable tool in assessing GERD symptoms preoperatively as well as after antireflux surgery.14

IMPACT OF GERD ON QUALITY OF LIFE Heartburn is the most frequent symptom of GERD. There are, however, a variety of symptom manifestations that may be associated with the disease. For instance, heartburn and acid regurgitation, during the night, may induce sleeping difficulties and readiness to wake the patient from sleep. Regurgitation and pyrosis may lead to acid-induced laryngitis and other respiratory-related symptoms. Relieving these problems is the goal for the clinician. The QOL and symptom severity in GERD have consequently been evaluated using both generic and disease-specific instruments (Kamolz, Pointner, 2003).16,21,31-34 Basically, these instruments have demonstrated that untreated GERD causes a significant and measurable impairment close to what is seen in congestive heart failure, for example.12 When compared with the general population, GERD patients express QOL scores and PGWB indexes as well as SF-36 scores consistently worse than what is considered to be normal, in terms of physical functioning, physical role, bodily pain, general health, vitality, emotions, social functioning, and mental health. As useful as generic QOL instruments are, particularly when comparing different disease manifestations, they poorly assess GERD-related symptom severity.

EFFECT OF THERAPY All trials that are currently available have demonstrated an improved QOL after adequate treatment (primarily diseasespecific instruments). These studies used a variety of instruments. Taken together, different instruments, both generic as well as disease specific, have consistently shown that shortas well as long-term modern medical therapy with a proton pump inhibitor (PPI) normalizes QOL.25,33-36 Furthermore, in erosive disease, PPI-based therapies are more effective even when evaluated by QOL instruments than those based on H2-receptor antagonists (H2RA). Despite the potential of modern antireflux medication to control GERD-like symptoms and improve QOL, an effective long-term management requires the patient’s compliance. Several factors are known to affect patients’ compliance with direct effects on QOL.37

Effect of Surgical Therapy General Aspects A large number of studies exist in the literature covering both the outcome after laparoscopic as well as open surgical treatment of GERD. During recent years, QOL assessments have been added to the conventional outcome measures of these kinds of surgical procedures. As for untreated patients with GERD, patients who are referred for surgical therapy, after failed or incomplete outcome of medical therapy, experience significant impairments in their QOL (Kamolz, Pointner, 2003).15,32,38 In addition to persistent symptoms, which per se exert a corresponding unfavorable effect, these patients are troubled by ineffective treatment and frustrated with growing anxiety

383

Section 4 Gastroesophageal Reflux and Associated Conditions

about their disease. Altogether they are facing difficulties in coping with the effects of the disease on everyday activities, including leisure activities and sexual relationships, to which is added effects on endurance and mental strength. In fact, in 1992 Pope39 emphasized the importance of adding QOL dimensions to the conventional assessments of antireflux surgery, which was later reinforced by others showing that a significant improvement in PGWB and GSRS indexes40-46 could be reached when changing strategy from medical treatment to surgery (Fig. 34-1). Subsequent studies have consistently shown that QOL after successful surgical repair equals that reported in an age- and sex-matched control population, an effect that can be maintained over at least 5 years. It is amazing how close correlation there seems to exist between QOL assessments and the objective and subjective therapeutic response after antireflux repair. The typical report on outcomes of surgical treatment is reflected by the study by Hunter and coworkers,46 showing that 86% of patients with remaining symptoms on conservative treatment improved after surgery, and by use of the SF-36 they demonstrated that surgery improved the QOL scores in all domains measured by this instrument. Several authors have used QOL assessments to compare the results of different surgical procedures. Laparoscopic and open antireflux procedures have been compared, whereupon the conclusion can be reached that laparoscopic surgery is followed by similar symptomatic outcomes as open surgery. However, the immediate postoperative course favors the minimal invasive approach.16,38,42,45,47,48 Furthermore, any additional effects did not follow division of the short gastric vessels to make the wrap more floppy to be picked up by QOL instruments.49 The same instruments have been used to compare the efficacy of laparoscopic Nissen fundoplication and a posterior partial fundoplication (Toupet). In a retrospective of analysis of 162 patients it was demonstrated that both procedures had similar improvement in QOL as measured by the GIQLI.50 Others have confirmed these results and come to the same conclusion.51 It seems, however, debatable whether similar conclusions could have been reached if these instruments were practiced within the framework of a prospective randomized clinical study design. This concern is based on the fact that post-fundoplication complaints are more frequently encountered after a total fundoplication compared with posterior partial Toupet fundoplication,52 differences that by necessity shall translate into QOL differences. A study is in progress focusing on the long-term (>15 years) follow-up of a similar trial that may well reveal corresponding differences. An interesting area for further research is to explore the use of QOL instruments to get a more comprehensive and sensitive description and prediction of those suitable for surgical therapy and in particular those who should be prevented from having a similar operation.37,53,54 Several studies have indicated that stress-related symptomatology in GERD patients and different comorbidities such as psychiatric disorders, dyspepsia, and neuroticism can adversely affect outcomes. Comparable studies may thus reflect the notion that symptom relief in GERD is more complex than just correcting the pathophysiology.

100 PGWB Total Score

384

Normal Value

80 60 40 20 0 Preop

1 Month

6 Months

12 Months

FIGURE 34-1 Quality of life as assessed by Psychological General Well-Being (PGWB) index after laparoscopic fundoplication.

Quality of Life in Patients With Barrett’s Esophagus Barrett’s esophagus is considered to be a manifestation of severe and long-standing reflux and represents the end stage of the disease to which is connected a high risk for malignant transformation. Furthermore, clinical data have consistently demonstrated that Barrett’s esophagus cases are more difficult to treat both with medical therapies as well as by surgical correction (Kamolz, Granderath, 2003; Lundell et al, 2001).55-67 Therefore, it is interesting to specifically assess, by use of QOL instruments, whether the patients with Barrett’s esophagus are more prone to fail on surgical therapy than those GERD patients without Barrett’s esophagus. In a study using HRQOL questionnaires it was not possible to find any significant differences between those with or without Barrett’s esophagus in any subscale of the generic instrument used (SF-36), although the Barrett esophagus cases were associated with more severe GERD symptoms preoperatively.68 Another study using QOL analyses before and after laparoscopic Nissen fundoplication revealed a significantly impaired disease-related QOL in non–Barrett’s as well as Barrett’s GERD patients compared with healthy controls. In general, the preoperative QOL in those with or without Barrett’s esophagus was almost identical, whereas a slight tendency toward somewhat better values was recorded in patients with Barrett’s esophagus. A similar difference was noted in the subscore for gastrointestinal symptoms, which means that GERD-related symptoms may have been experienced less intensively and frequently in Barrett’s cases compared with those without columnar metaplasia.68 These results may again be in accordance with the observations that symptom perceptions and intensity may not correlate well with objective data, such as grading of esophagitis or the amount of acid refluxed.31 One factor, which adds to the complexity, relates to the fact that there may exist a defect in the perception of noxious stimulation of the esophagi of these patients. It has been reported that up to at least 3 years after surgical intervention in patients with Barrett’s esophagus that these patients are doing as well as those GERD patients who do not have Barrett’s esophagus (Fig. 34-2). In fact, a slightly better level of improvement was noted in Barrett’s cases

140

140

120

120 GIQLI General Score

GIQLI General Score

Chapter 34 Quality of Life After Antireflux Surgery

100 80 60 40 20

100 80 60 40 20

0

0 Preop

3 Months Postop

1 Year

3 Years

Controls Barrett’s Non-Barrett’s

Preop

3 Months Postop

1 Year

3 Years

5 Years Postop

Controls Endoscopy+ Endoscopy–

FIGURE 34-2 Quality of life as determined by the gastrointestinal quality of life index (GIQLI) after laparoscopic Nissen fundoplication for Barrett’s esophagus.

FIGURE 34-3 Quality of life as determined by the gastrointestinal quality of life index (GIQLI) after laparoscopic Nissen fundoplication for nonerosive GERD.

compared with non-Barrett’s cases.67 Improvement in GERDrelated symptoms may be the leading expectation of similar patients when embarking on surgical corrections.38,53 Therefore, if treated effectively by an operation, by and large, intensive expectations relevant to disease-related symptoms can, in fact, be improved to a higher level and to a larger extent. In fact, after surgical correction Glise and coworkers38 reported a “supernormal” QOL after antireflux surgery, which may occur as a combination of patients’ high satisfaction after surgery concerning symptomatic improvement and the expectations as referred to earlier.

Data have been presented to show that laparoscopic total fundoplication significantly improved diseased-related QOL in endoscopy-negative reflux disease as well (see Fig 34-3) (Kamolz et al, 2005).71 Long-term follow-up data have shown that these results are durable (5 years). It seems pertinent to conclude that independent of the presence or absence of mucosal damage at endoscopy, GERD patients suffer from an unacceptable low disease-related QOL. In these chronically debilitated patients surgical correction is able to significantly and durably improve QOL to a level comparable to that of healthy individuals.

Quality of Life After Surgical Repair in Nonerosive GERD

COMMENTS AND CONTROVERSIES

Despite the high GERD prevalence in the Western population it is known that at least 50% of the patients with reflux disease will have a normal endoscopy (Kamolz, Pointner, 2003).16,19,22,32 Although these patients demonstrate no signs of esophagitis, they suffer from symptoms as severe as those of patients with endoscopically verified lesions. It has been debated whether medical as well as surgical therapies are equally effective in endoscopy-negative cases compared with those with clear-cut esophagitis.40,69,70 It is well established that the presence or not of erosive esophagitis correlates poorly with the severity of symptoms and the level of QOL impairment. By use of the GIQLI it has been shown that patients with nonerosive reflux disease presented with a slightly worse mean general index compared with those with erosive disease (Fig. 34-3). Similar data may be compatible with the notion that patients without esophagitis may have an abnormal perception of refluxed gastric juice into the esophagus and/or an altered sensitivity of the nociceptors in the organ.

This chapter presents an excellent overview of the importance of assessing surgical outcomes. In particular, the author has succinctly summarized the results of antireflux surgery that have been assessed with detailed analysis of the QOL before and after surgery. This is especially important when analyzing the results of a surgical procedure that indeed is designed to simply improve the QOL from GERD, such as antireflux surgery. The simple reporting of complications and other traditional data may not well represent the full impact of antireflux surgery on the patient’s QOL. From this review, it is clear that GERD significantly affects the patient’s QOL and a well-performed laparoscopic fundoplication leads to an improvement. However, few studies have compared outcomes in patients with GERD who remain on medical therapy to those who choose surgery. In fact, most gastroenterologists regard surgery as a “last resort” and the unknown number out there is how many patients have a diminished QOL on medical therapy but learn to accept this. In one of our own studies,1 we examined the results of medical versus surgical therapy for GERD on the QOL as assessed by the SF-36 and the Heartburn Related Quality of Life (HRQOL) scale. At a median follow-up of 24 months, the HRQOL scores were

385

386

Section 4 Gastroesophageal Reflux and Associated Conditions

significantly better in the surgical group compared with those in the medical group, and a similar advantage was seen after surgery in six of the eight domains of the SF-36 QOL assessment. Future studies of the outcomes of antireflux surgery should include detailed QOL measurements. 1. Fernando HC, Schauer PR, Rosenblatt M, et al: Quality of life after anti-reflux surgery compared with nonoperative management for severe gastroesophageal reflux disease. J Am Coll Surg 194:23-27, 2002.

J. D. L.

KEY REFERENCES Kamolz T, Granderath F, Pointner R: Laparoscopic antireflux surgery: Disease-related quality of life assessment before and after surgery in GERD patients with and without Barrett’s esophagus. Surg Endosc 17:880-885, 2003. Epub March 7, 2003. Kamolz T, Granderath FA, Schweiger UM, Pointner R: Laparoscopic Nissen fundoplication in patients with nonerosive reflux disease:

Long-term quality-of-life assessment and surgical outcome. Surg Endosc 19:494-500, 2005. Epub February 3, 2005. Kamolz T, Pointner R, Velanovich V: The impact of gastroesophageal reflux disease on quality of life. Surg Endosc 17:1193-1199, 2003. Lundell L, Miettinen P, Myrwold ME, et al: Continued (5 year) follow up of a randomised clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll Surg 192:172-179, 2001. Patrick DL, Deyo RA: Generic and disease-specific measures in assessing health status and quality of life. Med Care 27(Suppl):S217-S232, 1989. Pope CE II: The quality of life following antireflux surgery. World J Surg 16:355-358, 1992. Sullivan M: Quality of life assessment in medicine. Nord J Psychiatry 46:79-83, 1992. Velanovich V, Vallance SR, Gusz JR, et al: Quality of life scale for gastroesophageal reflux disease. J Am Coll Surg 183:217-224, 1996.

Columnar-Lined Esophagus COLUMNAR-LINED ESOPHAGUS: EPIDEMIOLOGY AND PATHOPHYSIOLOGY

chapter

35

Manuel Pera

Key Points ■ The presence of columnar mucosa in the esophagus with intestinal

metaplasia defines Barrett’s esophagus. ■ The prevalence of Barrett’s esophagus of any length in reflux

subjects is 10% to 12%. However, a “silent majority” with Barrett’s esophagus remain unrecognized in the general population. ■ Chronic exposure to acid and duodenal-content secretions during reflux causes damage in the esophageal epithelium and the appearance of columnar epithelium in a subset of subjects. ■ Stem cells contained in the proliferative layer of the squamous epithelium or associated glandular ducts may be the cell of origin of Barrett’s epithelium, undergoing an altered transdifferentiation process leading to a glandular phenotype. ■ Cardiac-type epithelium might represent an intermediate step in the acquisition of intestinal-type epithelium.

Columnar-lined esophagus, or Barrett’s esophagus (BE), is an acquired condition secondary to gastroesophageal reflux disease (GERD) in which the normal stratified squamous epithelium lining the distal esophagus is replaced to a variable extent by metaplastic columnar epithelium containing goblet cells, also known as specialized intestinal metaplasia (SIM). The term long-segment BE (LSBE) refers to SIM extending more than 3 cm above the esophagogastric junction. Patients with less than 3 cm of endoscopically evident columnarappearing mucosa, often as tongues, containing SIM are labeled as having short-segment BE (SSBE). This definition distinguishes SSBE from intestinal metaplasia found just below a normally located squamocolumnar junction, which is termed intestinal metaplasia of the cardia.1,2 Investigators recommend maintaining the distinction between endoscopically apparent long segments (>3 cm) and short segments (<3 cm) of SIM because most of our current knowledge of the pathophysiology, incidence, prevalence, and risk of malignant transformation of BE has come from studies of patients with LSBE (Fig. 35-1). Indeed, the definition of BE has changed over time, and earlier definitions had restricted BE to SIM that was 3 cm or more above the esophagogastric junction. BE and GERD are the major recognized risk factors for esophageal adenocarcinoma, a tumor whose frequency has increased profoundly in Western countries over the past several decades.3

HISTORICAL NOTE Columnar lining of the lower esophagus was alluded to in 1906 in Tileston’s review of 44 patients with peptic ulcer-

ation occurring in the lower esophagus, some of whom had “at the edge of the ulcer glands identical with those found in the stomach.”4 However, Barrett’s 1950 article entitled “Chronic Peptic Ulcer of the Oesophagus and Oesophagitis” is considered the first detailed description of this condition. Barrett interpreted this condition as a congenitally short esophagus with an intrathoracic stomach.5 In 1953, Allison and Johnstone,6 with the careful examination of seven esophagectomy specimens, demonstrated that these changes occurred in the esophagus, which was lined by columnar epithelium. They also suggested that the condition might be acquired as a result of gastroesophageal reflux. Finally, in 1957, Barrett accepted the interpretation of Allison and Johnstone and proposed that the term short esophagus be abandoned and that this condition be simply called “lower esophagus lined by columnar epithelium.”7 The association of adenocarcinoma with columnar cell lining of the distal esophagus was first reported by Morson and Belcher in 1952.8 They observed an adenocarcinoma arising in a segment of a “glandular mucous membrane” lining the distal esophagus with chronic inflammation and atrophic changes. In 1976, Paull and associates9 described the results of manometrically guided biopsies at multiple levels throughout the esophagus in 11 patients with a columnar-lined esophagus. Each patient was found to have one or a combination of three types of epithelia lining the distal esophagus: a gastric fundic type composed of mucous cells in the surface and chief and parietal cells in the deeper parts of the glands, a junctional type (cardiac type) composed of mucous glands, and a specialized type with intestinal characteristics including a villiform surface lined by columnar and Alcian blue–staining goblet cells. Further studies confirmed that specialized epithelium was the most common, distinctive, and important of the epithelial phenotypes found in the columnar-lined esophagus. Subsequently, Haggitt and associates suggested and Skinner and colleagues and Reid and Weinstein confirmed that the intestinal-type columnar mucosa was premalignant.10-12 Columnar lining of the esophagus is now known as Barrett’s esophagus. Its importance is underscored by its increasing detection and the clear association between this condition and the development of esophageal adenocarcinoma. HISTORICAL READINGS Allison PR, Johnstone AS: The oesophagus lined with gastric mucous membrane. Thorax 8:87, 1953. Barrett NR: Chronic peptic ulcer of the esophagus and esophagitis. Br J Surg 38:175, 1950. 387

388

Section 4 Gastroesophageal Reflux and Associated Conditions

A

C

Barrett NR: The lower esophagus lined by columnar epithelium. Surgery 41:881, 1957. Haggitt RC, Tryzelaar J, Ellis FH, Colcher H: Adenocarcinoma complicating columnar epithelium-lined (Barrett’s) esophagus. Am J Clin Pathol 70:1, 1978. Paull A, Trier JS, Dalton MD, et al: The histologic spectrum of Barrett’s esophagus. N Engl J Med 295:476, 1976. Skinner DB, Walther BC, Riddell RH, et al: Barrett’s esophagus: Comparison of benign and malignant cases. Ann Surg 198:554, 1983. Tileston W: Peptic ulcer of the esophagus. Am J Med Sci 132:240, 1906.

EPIDEMIOLOGY OF BARRETT’S ESOPHAGUS Epidemiologic studies have assessed the prevalence and incidence of BE in both clinical series of patients with GERD or other digestive symptoms who have undergone endoscopy and population-based studies.

B

FIGURE 35-1 Endoscopic images of columnar epithelium (A) in the distal esophagus extending more than 3 cm above the esophagogastric junction (LSBE) or (B) in the form of a single tongue (SSBE) 1 cm in length. C, Microscopic section of Barrett’s epithelium. Note the villiform surface of Barrett’s epithelium and the characteristic presence of goblet cells (dark blue).

Prevalence of LSBE and SSBE in Patients Undergoing Endoscopy Prospective endoscopic studies of patients with frequent reflux symptoms (at least weekly) showed that 11% to 12% had LSBE.13,14 In subsequent endoscopic studies, however, about 3% of patients (male and female) with reflux symptoms were found to have LSBE.15,16 The inclusion of some patients in former series with columnar-lining epithelium but without SIM may explain their higher prevalence rates of LSBE compared with more recent series, which included only patients with SIM. Various studies have reported SSBE in 9% to 13% of patients with reflux symptoms. In the study by Robinson and coworkers,17 endoscopy was offered to 178 patients with mild GERD symptoms who self-treated with over-the-counter antacids. The prevalence of BE in this group of GERD subjects was 6%. Table 35-1 summarizes the prevalence of both LSBE and SSBE from prospective studies

Chapter 35 Columnar-Lined Esophagus: Epidemiology and Pathophysiology

TABLE 35-1 Prevalence of Long- and Short-Segment Barrett’s Esophagus in Endoscopic Series Author (Year)

No. Patients

Spechler et al21 (1994) 15

Cameron et al*

(1995)

Johnston et al20 (1996) 16

(1997)

18

(1997)

Cameron et al* Chalasani et al

Hirota et al19 (1999)

LSBE

SSBE

142

(1%)

17 (12%)

80

2 (2.5%)

10 (13%)

172

2 (1%)

200

7 (3.5%)

4 (2%) 17 (9%)

87

5 (6%)

7 (8%)

833

13 (1.6%)

50 (6%)

*Series of patients with exclusively reflux symptoms. LSBE, long-segment Barrett’s esophagus; SSBE, short-segment Barrett’s esophagus.

published in the 1990s.18-21 The overall prevalence of BE of any length was 10% to 12% (LSBE, 1%-6%; SSBE, 2%-13%). Over recent years several studies have documented an increase in the diagnosis of SSBE, which probably reflects an increase in the awareness and recognition of this entity, mainly investigated by its clinical importance as a possible precursor of adenocarcinoma of the esophagogastric junction.22-24

Prevalence of Barrett’s Esophagus in the General Population The true prevalence of BE in the general population is not exactly known, but it can be estimated. It seems certain that patients diagnosed by endoscopy and biopsy are only a small fraction of persons with BE in the population. A larger number have undiagnosed BE, for example, adults who have not sought medical attention for their GERD symptoms and adults with BE but no GERD symptoms. Cameron and colleagues (1990)25 estimated the prevalence of LSBE in a population-based study in Olmsted County, Minnesota, using two approaches. First, they looked at clinically diagnosed patients who had undergone endoscopy and biopsy between 1969 and 1986 and had been diagnosed with LSBE and were still alive and residents in Olmsted County. They found 17 such cases, representing an age- and sexadjusted prevalence rate of 22.6 clinically diagnosed cases of BE per 100,000 population. Second, these authors looked for evidence of LSBE in Mayo Clinic autopsies. For 18 months the esophagus was examined by a gastroenterologist at consecutive autopsies looking for visible evidence of LSBE with histologic confirmation. Altogether, 7 cases of BE were found in 733 autopsies, including 4 in 226 autopsies on Olmsted County residents, so that about 1 in 100 older people had LSBE. The estimated age- and sex-specific prevalence of BE based on the autopsy findings was 376 per 100,000 population, about 17 times more than the clinically diagnosed prevalence. It should be noted that in the population-based study in Olmsted County the authors used a definition of BE restricted to segments larger than 3 cm for inclusion. The exclusion of SSBE certainly decreased the number of cases found. Further evidence that BE is underdiagnosed in the

general population comes from more recent studies indicating that 95% of patients with BE who later develop esophageal adenocarcinoma remain unidentified until the cancer is found.26,27 To further understand the prevalence of BE in the community, Gerson and colleagues28 prospectively screened for the presence of BE in subjects with no or negligible GERD symptoms (U.S. veteran population) older than 50 years of age undergoing screening sigmoidoscopy for colorectal cancer. Intestinal metaplasia extending above the esophagogastric junction was detected in 25% of the 119 subjects who underwent upper endoscopy; 8 (7%) had LSBE, and 19 (17%) had SSBE. This number is 66 times higher than the prevalence reported in the Olmsted County autopsy study. In a similar study, Rex and colleagues29 found that lesser, but still substantial, proportions of asymptomatic individuals undergoing upper endoscopy have BE (5.6% BE and 0.36% LSBE). The recent studies and the autopsy study performed by Cameron and colleagues raise issues about the high prevalence of BE in asymptomatic individuals. Cases of diagnosed, symptomatic BE may represent the tip of a Barrett iceberg.30 In the study by Lagergren and associates,31 40% of those with esophageal adenocarcinoma did not have at least weekly symptoms of reflux before development of their cancer; and several other studies have given similar results.32-34 Conio and coworkers (2001)35 discuss another way to estimate the prevalence of BE in the general population. If about 1 in 5 adults have frequent reflux symptoms36 and about 1 in 20 with frequent reflux symptoms has LSBE, then about 1 in 100 adults in the population should have LSBE. This does not take the estimated 40% of BE occurring in asymptomatic persons, or the increasing BE incidence with age, into account. But the 1 in 100 estimate is similar to the autopsy study quoted earlier.

Time Trends in Prevalence and Incidence of Barrett’s Esophagus Epidemiologic data on the incidence of BE in the general population are scarce and conflicting. Only three reports have studied time trends for the incidence of BE at the population level.35,37,38 An increase in the incidence of BE has been reported in all of these three studies, but it is unclear whether this reflects a true rise in occurrence or an increase in the diagnosis because of more upper gastrointestinal endoscopies being performed. Prach and colleagues,37 in Scotland, showed an increase in incidence from 1.4 new cases of BE per 1000 upper gastrointestinal endoscopies in 1980-1981 to 42.7 new cases of BE per 1000 upper gastrointestinal endoscopies in 1992-1993. These authors concluded that a true increase in the prevalence of BE had occurred. Conio and coworkers (2001)35 analyzed changes in the incidence and prevalence of BE (long and short segments) in a defined population (in Olmsted County, Minnesota). The incidence trends of clinically diagnosed LSBE and SSBE are shown in Figure 35-2. The age- and sex-adjusted incidence of clinically diagnosed LSBE increased 28-fold from 0.37/100,000 person-years in 1965-1969 to 10.5/100,000 person-years in 1995-1997. In 1995-1997, the incidence of SSBE was 8.8 cases/100,000

389

12

1600 1400

Endoscopy

1200

BE

1000

10 8

SSBE

800

6

600

4

400 2

200 0 1965 –69

1970 –74

1975 –79

1980 –84

1985 –89

1990 –94

0 1995 –97

New diagnosis Barrett’s/100,000/year

Section 4 Gastroesophageal Reflux and Associated Conditions

Upper endoscopy/100,000/year

390

FIGURE 35-2 Incidence of new diagnosis of BE and SSBE in Olmsted County residents between 1965 and 1997. Also shown is the annual utilization rate for upper gastrointestinal endoscopy in the same population. BE, Barrett’s esophagus; SSBE, short-segment Barrett’s esophagus. (FROM CONIO M, CAMERON AJ, ROMERO Y, ET AL: SECULAR

Barrett’s esophagus, %

TRENDS IN THE EPIDEMIOLOGY AND OUTCOME OF BARRETT’S OESOPHAGUS IN OLMSTED COUNTY, MINNESOTA. GUT 48:304, 2001)

1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0-9

Males Males and females Females

10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 Age, yr

FIGURE 35-3 The prevalence of Barrett’s esophagus at different ages in 51,311 patients having upper gastrointestinal endoscopy. (FROM CAMERON AJ: EPIDEMIOLOGIC STUDIES AND THE DEVELOPMENT OF BARRETT’S ESOPHAGUS. ENDOSCOPY 25:635, 1993.)

person-years. The prevalence of diagnosed LSBE increased from 22.6/100,000 person-years in 1987 to 82.6/100,000 in 1998. The prevalence of SSBE in 1998 was 33.4/100,000. The increased diagnosis rate of BE was similar to the 22-fold increased utilization rate of endoscopy over the same time period. They concluded that the increase in incidence in their study reflected a rise in upper gastrointestinal endoscopies performed instead of a real increase in incidence. A study in 2005 in the Netherlands showed that the incidence of diagnosed BE is increasing, independent of the number of upper gastrointestinal endoscopies that are being performed.38

Prevalence of Barrett’s Esophagus in Relation to Age and Gender In a large series of patients having upper endoscopy for various clinical indications, the prevalence of BE was found to be rare in childhood and to rise progressively with age until reaching a plateau in the seventh decade (Fig. 35-3).39,40

About one fourth of the maximum prevalence was reached by age 30 and one half was reached by age 40, so Cameron and colleagues40 estimated that the probable median age of development of BE is about 40. The mean age of first endoscopic diagnosis of BE without carcinoma was 63 years, suggesting that BE may develop more than 20 years before it is clinically recognized. Data from the U.K. National Barrett’s Oesophagus Registry show that BE is diagnosed at a younger age in males (peak, 60-69 years) compared with females (peak, 70-79 years).41 Unlike the age-related increase in prevalence, however, the length of Barrett’s epithelium did not appear to increase significantly with age. In the series of Cameron and Lomboy,40 the mean length of columnar epithelium was similar in young, middle-aged, and elderly patients. Furthermore, these authors found no significant change in the mean length of columnar epithelium in patients who underwent follow-up endoscopic examinations performed after a mean of 3.2 years. These findings suggest that BE may develop to its fullest extent rapidly, with no subsequent change in length. Although symptoms of gastroesophageal reflux are equally prevalent in men and women, BE is more common in males than in females by a ratio ranging between 2 : 1 and 4 : 1.35,41,42 A recent study from the U.K. National Barrett’s Oesophagus Registry found a slower age-specific rise in the female BE prevalences when younger than the age of 60 years and a 20-year shift between males and females in the prevalence of BE.43 Similarly, the incidence of esophageal adenocarcinoma is also higher in males, with a male-to-female ratio of 4 : 1 or 8 : 1.35,41,44 At present there are no explanations for this observed difference in risk of developing adenocarcinoma of the esophagus between both sexes.

Risk Factors for Barrett’s Esophagus Many risk factors have been evaluated with respect to BE. Several studies have shown that patients with large hiatal hernias, those complaining of nocturnal reflux symptoms, and those who develop symptoms of GERD at an earlier age and experienced them for more than 5 to 10 years are at increased risk for having BE.45-48 Lieberman and associates48 studied patients having endoscopy for reflux symptoms. When compared with GERD patients with symptoms for less than 1 year, the odds ratio for the presence of endoscopic BE in patients with symptoms for more than 10 years was 6.4, and there was a progressive increase in the prevalence as the symptom duration increased.

Familial Predisposition to Barrett’s Esophagus In two studies using questionnaires, the prevalence of reflux symptoms in first-degree relatives of BE patients was shown to be 2.2 and 4.8 times greater than in controls.49,50 Romero and colleagues51 then performed endoscopy in 100 symptomatic BE relatives and in 100 unrelated persons with similar reflux symptoms and found BE in 8% of relatives and in 5% of symptomatic controls, which was deemed not significant. These authors later enlarged the series and found 16/191 (8.4%) relatives versus 12/287 (4.2%) controls had BE, a significant difference (adjusted OR 2.4, P = .039).52 Therefore,

Chapter 35 Columnar-Lined Esophagus: Epidemiology and Pathophysiology

in relatives of BE patients, inherited factors may contribute both to the development of reflux and also to the development of BE in those with reflux.

PATHOPHYSIOLOGY The exact pathophysiology of BE remains to be elucidated, but it is thought that chronic exposure to acid and bile during gastroesophageal reflux causes damage and inflammation in the esophageal squamous mucosa, leading to a metaplastic process in which columnar cells replace squamous ones. On functional assessment, patients with BE compared with patients with GERD without columnar metaplasia and controls have weaker lower esophageal sphincter (LES) pressures, more impaired peristalsis, and more frequent and prolonged episodes of acid reflux, as determined by pH monitoring.53 Studies with the Bilitec probe (designed to monitor reflux of bilirubin) or with direct aspiration of the esophageal refluxate have shown an increase in bile reflux into the esophagus in patients with BE (Oberg et al, 1998).54-58 The clinical and physiologic abnormalities in patients with SSBE are generally intermediate between those found in patients with LSBE and erosive esophagitis (Table 35-2).59 It has been suggested that components present in the reflux material damage the squamous epithelium, promoting its replacement by columnar cells. Experimental studies support the role of chronic duodenal-content reflux in the pathogenesis of BE and esophageal adenocarcinoma.60 It is unclear why some subjects develop severe recurrent erosive esophagitis and never develop BE whereas others with relatively few symptoms and little or no inflammatory disease on upper endoscopy develop long or short segments of intestinal metaplasia. Genetic susceptibility and environmental factors may explain why only a small proportion of people with reflux (approximately 10%) develop BE.61

Development of Barrett’s Metaplasia The development of Barrett’s metaplasia is rarely observed in vivo, and hence it is thought that the columnar-lined mucosa probably develops to its full length over a period of weeks.62 The rapid development hypothesis may explain why the development stage of BE has not been documented.

Cameron and coworkers62 observed a major discrepancy between the length and distribution of erosions in reflux esophagitis and the length and distribution of columnar replacement in BE. They think that long segments of BE are unlikely to arise from columnar re-epithelialization of refluxinduced erosions but that another mechanism involving rapid loss of a long segment of squamous epithelium may be the initiating factor. The etiology of short segments or tongues of BE may be different from that of long segments. The extent of involvement by short BE is often similar to the extent of erosions in reflux esophagitis, and SSBE could arise by direct replacement of erosions.

Origin of Intestinal Metaplasia Although it generally is accepted that BE is an acquired lesion resulting from damage from chronic gastroesophageal reflux, the cell of origin of BE remains controversial. Postulated mechanisms for acquisition of Barrett’s mucosa on the esophagus have evolved over time. Earlier observations favored proximal migration of columnar epithelium from the stomach as a mechanism to re-epithelialize the ulcerated and largely destroyed squamous epithelium. Current theory, however, holds that multipotential stem cells contained in the proliferative layer of the squamous epithelium or associated glandular ducts undergo altered differentiation expressing unique glandular phenotypes.

Migration Hypothesis Bremner and coworkers63 first favored upward cell migration from the junctional cardiac or gastric epithelium after destruction of squamous epithelium. They induced columnar reepithelialization by excising a circular strip of distal esophageal squamous epithelium in dogs that had severe gastroesophageal reflux produced by means of a cardioplasty. In control animals without reflux, the denuded esophageal epithelium was replaced with the downward growth of the esophageal squamous epithelium. However, subsequent observations were not in accord with the migration hypothesis. Using the original model design by Bremner and coworkers in the dog, Gillen and coworkers (1988)64 excised a second circumferential strip of esophageal mucosa more proximally, leaving a

TABLE 35-2 Lower Esophageal Sphincter Function and Esophageal Acid and Bile Exposure in Patients With Intestinal Metaplasia in the Distal Esophagus Control Subjects (n = 20)

SSBE (n = 28)

12.6

7.2*

4.6*

4.8*

Mean esophageal acid exposure time on 24-hr esophageal pH monitoring (%)

2.4

8.6*

17.5*

16.9*

Mean esophageal bile exposure time on 24-hr esophageal Bilitec monitoring (%)

1.2

9.9*

23.4*

25.8*

Mean LES pressure (mm Hg)

LSBE (n = 38)

Barrett’s Cancer (uT1) (n = 17)

*P < .05 versus control. LES, lower esophageal sphincter; LSBE, long-segment Barrett’s esophagus; SSBE, short-segment Barrett’s esophagus; uT1, T1 category on endoscopic ultrasonography. Adapted from Stein HJ, Feith M, Siewert JR: Malignant degeneration of Barrett’s esophagus: Clinical point of view. Recent Results Cancer Res 155:42, 2000.

391

392

Section 4 Gastroesophageal Reflux and Associated Conditions

normal ring of squamous epithelium between the two stripped zones. In this manner, these researchers verified the development of columnar metaplasia in the upper, stripped zone above the squamous epithelial ring, thereby demonstrating that columnar re-epithelialization may occur from cells that are intrinsic to the esophagus and does not depend on proximal migration of gastric columnar epithelium.

Esophageal Stem Cell Hypothesis The source of the columnar epithelium is most likely metaplastic, derived from esophageal multipotential stem cells localized at the basal layer of the squamous epithelium or at the neck of submucosal esophageal glands. Experimental observations and ultrastructural studies support this hypothesis.60,65 Experimental studies using the canine model suggest that severe erosive esophagitis expose the tubuloalveolar submucosal glands containing multipotential stem cells to the action of the luminal reflux and then promotes columnar reepithelialization from the necks of these glands to adjacent ulcerated areas (Gillen et al, 1988).64,66 Li and colleagues66 evaluated healing of experimental esophageal injury in the dog and suggested that the cells repopulating the esophagus after injury arise from multipotential esophageal ductular cells able to differentiate into columnar or squamous cells. Careful examination of the histologic material showed that the deep esophageal gland ducts, which are lined in the proximal two thirds of their length with cuboidal or columnar cells and possibly stem cells, were in direct continuity with the columnar mucosa repairing the defect. In a few animals acid reflux was controlled by an antireflux procedure. On this occasion, however, interspersed with the metaplastic columnar epithelium were small foci of squamous epithelium. Examination of multiple histologic levels of these regenerating squamous islands suggested a direct continuity with the squamous-lined distal portion of the esophageal gland ducts. There has been considerable discussion about whether stem cells in the esophageal squamous epithelium have the capacity to give rise to glandular epithelial cells.67 Duodenalcontent reflux can trigger a glandular transdifferentiation in the esophagus of rats.60 Because rats do not have glandular structures in the esophagus, this indicates that, at least in this species, the differentiation program of keratinocytes can be modified by GERD to induce columnar differentiation. Scanning electron microscopy of the squamospecialized epithelium junction in patients who have BE has demonstrated a distinctive type of multilayered epithelium that shows morphologic and ultrastructural features of squamous and columnar epithelium.65 This epithelium consists of four to eight layers of cells that seem squamous in the basal aspect and columnar in the superficial portion. By immunohistochemical analysis, multilayered epithelium expresses cytokeratin patterns characteristic of stratified squamous and columnar epithelium.68 Further studies have shown the presence of a population of distinctive cells, with morphologic features of squamous and columnar mucosa located at the squamocolumnar junction in about one third of patients who

have Barrett’s esophagus (Fig. 35-4). Sawhney and associates69 suggest that this cell is a morphologic hybrid and that its origin may be the result of transformation of multipotential basal cells of squamous epithelial origin. Another study from the same group demonstrated that multilayered epithelium expresses a pattern of mucin production and cytokeratin expression similar to that of columnar epithelium in BE and shows a high capacity for cellular proliferation and differentiation (transforming growth factor-α, epidermal growth factor receptor, pS2, and villin) (Glickman et al, 2001).70 Of interest, the esophageal mucosal gland duct epithelium showed a similar phenotypic pattern and, in one case, was seen to give rise to multilayered epithelium at the surface of the mucosa. These data provide evidence in support of the hypothesis that multilayered epithelium represents an early or intermediate stage in the development of esophageal columnar metaplasia. Mucosal gland duct epithelium or the basal layer of the squamous epithelium may contain progenitor cells that can give rise to multilayered epithelium.

Cardiac-Type Mucosa as an Intermediate Step to Intestinal Metaplasia Clinical observations strongly support the fact that during the metaplastic process leading to the development of BE, cardiac-type epithelium represents an intermediate step in this process. Some authors support the idea that cardiac mucosa is a native epithelium located in the distal side of the esophagogastric junction. Glickman and colleagues71 evaluated the esophagogastric junctional area in an unselected autopsy population and identified this type of epithelium in 99% of the assessable cases and that it was always present in the distal side of the esophagogastric junction (mean length, 2.7 mm; range, 0.1-12.0 mm). Other authors, however,

FIGURE 35-4 Medium-power view shows a focus of multilayered epithelium at the neosquamous columnar junction in a patient with Barrett’s esophagus. The multilayered epithelium (center) shows squamous cells at the basal aspect of the epithelium and columnar cells in the more luminal aspect of the epithelium. Squamous epithelium is noted on the right, whereas metaplastic columnar epithelium is noted on the left. (COURTESY OF PROFESSOR ROBERT D. ODZE, DEPARTMENT OF PATHOLOGY, BRIGHAM AND WOMEN’S HOSPITAL, BOSTON, MA.)

Chapter 35 Columnar-Lined Esophagus: Epidemiology and Pathophysiology

believe that the finding of cardiac epithelium in the anatomic cardia region represents originally a metaplastic epithelium.72,73 This epithelium may progress into the esophagus and later undergo a phenotypic change leading to an intestinal-type epithelium. The findings that the cardiac mucosa length increases with increasing lower esophageal acid exposure all make it highly likely that cardiac mucosa is an abnormal epithelium caused by reflux. Based on the hypothesis that cardiac mucosa is an abnormal epithelium in the esophagogastric junctional area, these authors suggest that squamous epithelium damaged by reflux undergoes glandular transformation (cardiac-type epithelium) that continues to intestinal metaplasia. Strongly supporting this later hypothesis, cardiac epithelium has been well documented to develop above the fundicsquamous anastomosis created in approximately 50% of patients after esophagogastrectomy and gastric interposition.74-77 In a review of 17 patients who had undergone partial esophagectomy with intrathoracic esophagogastrostomy, Hamilton and Yardley75 noted that columnar mucosa had developed above the esophagogastric anastomosis in 10 of the 17 patients. In each patient the anastomosis had been performed between histologically documented squamous cell–lined esophagus and gastric fundus. They noted that cardiac-type columnar mucosa without goblet cells could be found as early as 2 months after surgery in an area that previously had been shown histologically to be squamous epithelium. In two patients, intestinal metaplasia was found within the cardiac mucosa at the squamous junction at 76 and 106 months after surgery. Taken together, these observations would suggest that cardiac-type mucosa is the precursor of intestinal metaplasia and that the process of intestinalization occurs sequentially over a period of at least 5 years.

Mechanisms Underlying Intestinalization of Cardiac-Type Mucosa There is little understanding of the molecular genetic changes that initiate and promote the transdifferentiation of epithelial cells of the esophagus to an intestinal type in BE, which is associated with the presence of goblet cells and the expression of intestinal markers such as MUC2, alkaline phosphatase, sucrase-isomaltase, villin, and trefoil factor 3. Griffel and colleagues78 have shown that the murine antibody DAS1, which stains specialized columnar mucosa, reacts positively with cardiac-type mucosa and that, on repeat biopsies, histologic evidence of intestinalization later developed in six of seven patients. The presence of DAS-1–positive cells suggests the phenotypic change of the cardiac-type epithelia to a colonic cell type before morphologic changes identified by conventional hematoxylin and eosin staining. It has also been reported that normal cardiac mucosa without evidence of intestinal metaplasia may express MUC2 in glandular epithelium (29%). It is well known that MUC2 is abundantly expressed in intestinal goblet cells but not in columnar cells. Taken together, these findings would suggest that biochemically cardiac-type mucosa and intestinal metaplasia are similar and that cardiac-type mucosa is the precursor of intestinalized columnar epithelium, or Barrett’s esophagus.79

A gene that might induce the initial transdifferentiation to intestinal metaplasia is CDX2, an intestine-specific transcription factor belonging to the caudal-related homeobox gene family.80 It is expressed throughout the small and large intestine, where it plays a role in the regulation of cell proliferation and differentiation. It has been suggested that CDX2 is a master regulator of the intestinal differentiation program and therefore normally not expressed in the stomach and esophagus. Recently, aberrant expression of CDX2 has been identified in areas of the stomach and esophagus containing intestinal metaplasia.81-83 Additionally, CDX2 expression has been detected in 30% of biopsies showing cardiac-type epithelium without histologic features suggestive of intestinal metaplasia and in reflux-exposed squamous epithelium of patients with BE.82,83 A study in 2003 showed that CDX2 expression can be induced in keratinocytes by prolonged exposure to acid.84 Because CDX2 expression is an early event in intestinal differentiation, its presence would indicate that the molecular machinery for intestinal differentiation is in place, even when routine histologic evidence of such differentiation is lacking.

COMMENTS AND CONTROVERSIES Dr. Pera has provided a concise, meticulous review of the epidemiology and pathophysiology of Barrett’s esophagus. The increased awareness of Barrett’s esophagus and the exponential growth of flexible fiberoptic esophagoscopy account in part for its increased prevalence. But, any busy endoscopist with 10 or more years of experience can confirm that there are more patients with Barrett’s esophagus. We have come a long way from the “congenital short esophagus” of Norman Barrett to the pleuripotent squamous stem cell. It has taken almost 60 years to acquire this knowledge; however, this is just the beginning of the unraveling of the mystery of Barrett’s esophagus. T. W. R.

KEY REFERENCES Cameron AJ, Zinsmeister AR, Ballard DJ, Carney JA: Prevalence of columnar-lined (Barrett’s) esophagus: Comparison of populationbased clinical and autopsy findings. Gastroenterology 99:918, 1990. ■ Based on an autopsy series, these authors estimated the prevalence of LSBE in the general population to be 376 cases per 100,000 population, about 17 times more than the clinical diagnosed prevalence. Consequently, they suggested that a large number of persons in the population have undiagnosed BE. Conio M, Cameron AJ, Romero Y, et al: Secular trends in the epidemiology and outcome of Barrett’s oesophagus in Olmsted County, Minnesota. Gut 48:304, 2001. ■ A population based in Olmsted County, Minnesota showed that the incidence of new clinical diagnosis of BE increased 28-fold from less than 1 case per 100,000 per year in 1965 to 11 cases per 100,000 per year in 1997. This may be due to increased detection of BE rather than any real increase in incidence; over the same time interval, the number of upper endoscopic examinations performed in county residents rose to a similar extent from 50 per 100,000 in 1965 to 1400 per 100,000 per year in 1997. Oberg S, Ritter MP, Crookes PF, et al: Gastroesophageal reflux disease and mucosal injury with emphasis on short-segment Barrett’s esophagus and duodenogastroesophageal reflux. J Gastrointest Surg 2:547, 1998.

393

394

Section 4 Gastroesophageal Reflux and Associated Conditions

■ Analysis of the composition of reflux in 281 patients with GERD demonstrated that

the patients with the greatest degree of mucosal injury were more likely to have both gastroduodenal and acid reflux as opposed to pure gastric reflux. Patients with SSBE had elevated esophageal acid and bilirubin exposure and decreased lower esophageal sphincter pressure and length. These abnormalities were similar to those in patients with esophagitis and in general less profound than those found in patients with LSBE. SSBE is a complication of severe GERD and is associated with the reflux of both gastric and duodenal juice similar to that seen in patients with LSBE. Gillen P, Keeling P, Byrne PJ, et al: Experimental columnar metaplasia in the canine oesophagus. Br J Surg 75:113, 1988. ■ Using the original model of severe GERD designed by Bremner and associates in the dog, these authors excised a second circumferential strip of esophageal mucosa more proximally, leaving a normal ring of squamous epithelium between the two stripped zones as a manner of “squamous barrier.” They verified the development of columnar metaplasia in the upper, stripped zone above the squamous

epithelial ring, thereby demonstrating that columnar re-epithelialization may occur from stem cells intrinsic to the esophagus, probably located in esophageal gland ducts. Glickman JN, Chen YY, Wang HH, et al: Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett’s esophagus. Am J Surg Pathol 25:569, 2001. ■ A distinctive type of multilayered epithelium has been described as the neo-squamocolumnar junction and within columnar mucosa in patients with BE and may represent an intermediate step in the development of BE. In this paper the same group showed that the cytokeratin and mucin histochemical properties of multilayered epithelium seem to be a hybrid of BE and squamous epithelium. Their data provide support for the theory that the mucosal gland duct epithelium or the esophageal squamous epithelium may contain stem cells that could give rise to multilayered epithelium.

HISTOPATHOLOGY OF GASTROESOPHAGEAL REFLUX DISEASE AND BARRETT’S ESOPHAGUS

chapter

36

Mary P. Bronner

Key Points ■ The diagnosis of Barrett’s esophagus requires both histologic and

■

■

■

■

endoscopic components, including intestinal metaplasia on histology and endoscopic evidence of glandular mucosa within the tubular esophagus. Gastric mucosa in the region of the lower esophageal sphincter is not Barrett’s esophagus. High-grade dysplasia in Barrett’s esophagus is commonly overdiagnosed. The presence of surface epithelial maturation circumvents most incorrect diagnoses and is the single most important diagnostic criterion for Barrett’s neoplasia. Accurate pathologic diagnosis of the neoplastic spectrum in Barrett’s esophagus depends crucially on the pathologist’s exposure to a high-volume practice of Barrett’s esophagus. Therapy for high-grade dysplasia in Barrett’s esophagus is broadening to include nonsurgical approaches, which makes the distinction on biopsy specimens between high-grade dysplasia and adenocarcinoma very important. Unfortunately, even pathologists expert in the diagnosis of Barrett’s esophagus have poor interobserver and intraobserver variability at this step in the neoplastic spectrum, calling into question such management decisions. An important clinical and histologic mimic of gastroesophageal reflux disease is eosinophilic esophagitis, which is not caused by reflux and is treated medically.

itself and, perhaps even more importantly, (2) the overdiagnosis of high-grade dysplasia (HGD) in Barrett’s esophagus. These two serious problems may result in inappropriate and lifelong cancer surveillance for patients misdiagnosed with Barrett’s esophagus and even unwarranted esophagectomy. Finally, the management options for Barrett’s esophagus with HGD are broadening from surgery alone, given the onset of ablative therapies, endoscopic mucosal resection, and increased knowledge of the natural history of HGD in Barrett’s esophagus. This last point refers to the more indolent behavior of incident HGD diagnosed during surveillance, as opposed to prevalent HGD diagnosed at the patient’s initial endoscopy. Unfortunately, morphologic diagnosis for distinguishing HGD from more advanced neoplasia on mucosal biopsies alone is not reliable, even by the best gastrointestinal pathologists. This is readily apparent to pathologists who struggle mightily with this distinction on tiny mucosal biopsy specimens but is relatively unknown to gastroenterologists and surgeons. This final issue calls into serious question the critical management decisions that clinicians currently base on diagnoses of HGD versus early cancer. In this chapter these evolving issues in the pathology of GERD and Barrett’s esophagus are explored in depth.

NORMAL ESOPHAGEAL HISTOLOGY Mucosa

HISTORICAL NOTE Our understanding of the pathology of gastroesophageal reflux disease (GERD) and particularly Barrett’s esophagus has undergone major changes since the influential British surgeon Dr. Norman Barrett first described this condition over half a century ago. Even as early as 5 years ago, and incredibly still appearing in current editions of surgical pathology textbooks, are the now obsolete references to three types of Barrett’s esophagus, namely, gastric cardiac type, gastric fundic type, and specialized columnar (intestinal) metaplastic type. It is now well-recognized among gastrointestinal pathologists that only the intestinal metaplastic type of Barrett’s esophagus confers an increased cancer risk and therefore is the only type of mucosa in the distal esophagus that should be designated Barrett’s esophagus. The so-called gastric cardiac and gastric fundic types of Barrett’s esophagus are now recognized simply as very common epithelia in the lower esophagus that do not predispose to cancer. Although the definition of Barrett’s esophagus has undergone major advances, continuing diagnostic problems revolve around two important issues: (1) the overdiagnosis of Barrett’s esophagus

The normal tubular esophagus is lined by stratified nonkeratinizing squamous epithelium from its origin in the pharynx to its junction with the stomach. The basal zone of the squamous mucosa, defined as the region where the internuclear distance is less than the nuclear diameter of a basal cell, should occupy only two to three cells in thickness at the base of the epithelium or less than 15% of the total squamous thickness.1 The squamous cells superficial to the basal zone progressively develop more cytoplasm without keratinizing, referred to as normal squamous epithelial maturation. The lamina propria is the fibroconnective, neural, and vascular tissue that projects upward into the epithelium as delicate papillae. These papillae normally occupy no more than two thirds of the total squamous thickness.1 Both the papillae of lamina propria and the basal zone of the squamous epithelium may exceed this thickness in the normal distal 2 to 3 cm of the esophagus, owing to so-called physiologic reflux that occurs to a small extent in normal individuals.2 The squamocolumnar junction (SCJ), also known as the Z line, may be a straight horizontal mucosal junction where the squamous lining of the esophagus intersects with the glandular lining of the stomach, or this junction may demon395

396

Section 4 Gastroesophageal Reflux and Associated Conditions

strate an irregular or jagged circumferential course around the distal esophagus. The SCJ normally lies anywhere within the lower esophageal sphincter (LES) region, which is the increased pressure zone in the distal 2 to 3 cm of the tubular esophagus that is created by two muscles: (1) the intrinsic sphincter made up of the distal esophageal muscularis propria and (2) the extrinsic sphincter made up of the crux of the diaphragm. Normally the external and internal sphincter muscles align and, as mentioned, the LES region occupies the distal 2 to 3 cm of the tubular esophagus. Thus, because the Z line or mucosal junction may lie anywhere within the LES zone, the distal 2 to 3 cm of the normal esophagus may have any of three types of epithelium, namely, squamous, gastric cardiac, or gastric fundic mucosa. There is debate over whether gastric cardiac mucosa is ever truly normal or instead represents an acquired mucosal alteration due to reflux disease. This is further considered later in this chapter. Other than squamous cells, numerous intraepithelial lymphocytes may be observed in the normal esophageal mucosa.3 Less well-appreciated is the fact that normal adults without reflux disease, as documented by normal 24-hour pH monitoring, may also commonly have a few eosinophils within the normal squamous epithelium. There may be upwards of five eosinophils per biopsy fragment in normal adult squamous mucosa.4 Scattered argyrophilic neuroendocrine cells, Langerhan’s cells, and melanocytes are also present in the esophageal mucosa.5

Esophageal Glands The esophagus has mucinous mucosal and submucosal glands. The mucosal glands are also referred to as cardiac glands and are observed in the distal few centimeters of the esophagus as it merges with the proximal stomach. The submucosal glands, on the other hand, are a definitive marker of anatomic esophagus, because they do not exist in the stomach. In combination with the Brunner glands of the duodenum, they are the only submucosal glands of the entire normal gastrointestinal tract. The esophageal glands, in general, exhibit a distinctive lobular architecture and are a caudal extension of the minor salivary glands of the oropharynx. These glands drain to the esophageal lumen by way of ducts lined by cuboidal mucus-secreting or squamous cells. The normal ducts may also be lined by an immature squamous metaplastic or transitional-type epithelium. Both the mucosal and submucosal mucinous glands contain predominantly acid mucin, which stains intensely blue with alcian blue at pH 2.5. This normal finding should not be misconstrued as Barrett’s metaplastic epithelium, which also characteristically stains intensely for acid mucin, as is discussed in detail later in this chapter. Recognition that the entire esophageal gland or multiglandular lobule contains acid mucin allows correct identification of a normal esophageal gland, rather than Barrett’s esophagus. Conversely, Barrett’s epithelium typically contains only individual and scattered alcian blue–positive goblet cells, rather than the continuous complete gland or full lobule staining pattern of normal esophageal glands. Sebaceous glands occur in 2% of adult autopsies.6 Endoscopically, they appear as diminutive round, yellow nodules, which may be multiple. They have no clinical sig-

nificance except that they are occasionally observed endoscopically and sampled.

Esophageal Lamina Propria and Submucosa The normal lamina propria and submucosa of the esophagus have scattered lymphocytes and plasma cells; as such their presence is not indicative of esophagitis. Occasional lymphoid follicles may also be seen in the lamina propria and submucosa of the normal esophagus. Nerves, arteriovenous and lymphatic vessels, and fibroconnective tissues are present in both of these layers of the esophageal wall.7 The rich mucosal lymphatic plexus extends to less extensive submucosal and muscularis propria channels.7 The well-developed network of lymphatics within the lamina propria of the esophagus differs markedly from that of the intestines, which is essentially devoid of lymphatics. This difference is the reason that intramucosal carcinoma is recognized in the esophagus (and stomach for that matter) and has the capacity to metastasize, unlike in the intestines.

Esophageal Muscularis Mucosae, Muscularis Propria, Neural Tissue, and Adventitia The muscularis mucosae of the esophagus, which is composed of smooth muscle, is the thickest in the esophagus of the entire gastrointestinal tract. Normally, it consists of a single band of smooth muscle, but in ulcerating disorders, particularly severe reflux disease and the great majority of Barrett’s esophagus, the muscularis mucosae can split into two or even three layers (unpublished observations by Dr. S. C. Abraham and colleagues, Mayo Clinic, 2006). The muscularis propria of the esophagus has the typical inner circular and outer longitudinal layers, as occur elsewhere in the gut. In contrast to the remaining gut, where the muscularis propria consists entirely of smooth muscle, however, the muscularis propria of the esophagus contains skeletal muscle in the upper esophagus, admixed skeletal and smooth muscle in the midesophagus, and only smooth muscle in the distal esophagus. The esophagus has both submucosal (Meissner) and myenteric (Auerbach) ganglionic plexuses. This mediastinal organ is, however, unlike most of the remaining gastrointestinal tract in that it lacks a true serosa, given its lack of a mesothelial cell lining. The lack of a true serosa for the esophagus is true except for its most distal 2 to 3 cm, where it crosses the diaphragm and enters the abdomen. Above this level and within the mediastinum, it is encompassed only by fibroconnective tissue that is termed the adventitia, which merges with mediastinal soft tissue.

Vascular Supply The esophageal arterial supply derives from the following7: 1. The inferior thyroidal artery for the cervical esophagus 2. The bronchial arteries and branches directly from the aorta and intercostals for the thoracic esophagus 3. The left gastric, left phrenic, and left hepatic accessory arteries in the distal esophagus Venous drainage forms a plexus that is both superficial and deep to the muscularis propria and connects to the inferior

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

thyroid veins proximally, the azygos and hemiazygos veins in the thoracic esophagus, and the short gastric and coronary veins distally.7 The distal venous system connects to the portal venous system, resulting in esophageal varices in patients with portal hypertension. This rich vascular supply to the esophagus explains why esophageal infarction and ischemia are extremely rare.

CONGENITAL VARIATIONS Inlet Patches Embyrologically, the entire esophagus is lined by columnar respiratory mucosa, so it is perhaps of no surprise that ectopic glandular rests may persist into childhood and adulthood. In fact, congenital islands of ectopic gastric mucosa, ciliated respiratory mucosa, or intestinal mucosa do occur in the normal proximal esophagus. These have been termed inlet patches because they are usually recognized as pink patches of glandular mucosa at the inlet of the esophagus. They are relatively common and are found in about 10% of all individuals8 and are separated from the stomach by a large zone of intact squamous epithelium, making the distinction from Barrett’s esophagus obvious. Thus, whereas inlet patches may have intestinal mucosa, they should not be confused with Barrett’s esophagus involving the LES region in continuity with the stomach. Although extremely rare case reports of carcinoma arising in inlet patches have been reported, surveillance is not justified, even in the presence of intestinal mucosa, owing to the extremely low risk of neoplasia in this highly prevalent condition.9

ESOPHAGITIS Gastroesophageal Reflux Disease Reflux esophagitis is caused by the regurgitation of gastric or duodenal contents into the esophagus with resultant esophageal injury.10,11 The causes are multifactorial, but hiatal hernia appears to play a major role, by decreasing the LES pressure and effacing the gastroesophageal mucosal flap valve.12-14 Endoscopic findings include erythema, erosions, ulcers, exudate, and stricture formation. Biopsy of such grossly visible alterations characteristically reveals esophagitis, but the histology of GERD is certainly not specific for reflux. Rather, it represents a nonspecific injury pattern with a differential diagnosis, as discussed later. GERD is, however, by far the most common etiology in the differential diagnosis in developed countries. Nonetheless, as many as 50% to 60% of symptomatic patients with abnormal pH monitoring as evidence of reflux disease will have normal-appearing mucosa or only hyperemia at endoscopy.15 Furthermore, esophageal mucosa that is histologically inflamed may appear normal endoscopically. Hyperemia may reflect histologic esophagitis but also may occur in normal esophageal mucosa. Because of these various endoscopic-pathologic discrepancies, biopsy is warranted in symptomatic patients to both document tissue injury and to exclude the other important entities in the differential diagnosis. This is certainly true in those patients who have failed empirical reflux therapy; however, biopsy is undoubtedly warranted in any diagnostic endoscopy.

Standard forceps biopsies are generally not adequate for evaluating the early changes of reflux because they often do not include the entire thickness of the mucosa and are difficult to orient properly.10,15 For this reason, and certainly for patients with refractory reflux symptoms, an endoscope with a large-caliber biopsy channel to permit “jumbo” biopsy forceps should be used to facilitate the diagnosis. Perhaps no better oxymoron exists than the term jumbo biopsy, but there must be repeated emphasis that the “jumbo” biopsy does not increase the complication rate of endoscopic biopsy16 and yet it greatly improves the histologic specimen obtained. Thus, “jumbo” forceps increase the amount of tissue obtained by up to fivefold relative to regular biopsy forceps. Reflux changes are typically distributed in a patchy fashion over the distal 8 cm of the esophagus, indicating that multiple biopsies are necessary to demonstrate histologic abnormalities consistently.2 Asymptomatic normal subjects may have occasional biopsy specimens from the distal-most 2.5 cm of the esophagus that show microscopic features of GERD.2 Thus, diagnostic biopsy specimens for GERD should be taken more than 2.5 cm above the gastroesophageal junction.2 The value of this approach for the diagnosis of reflux esophagitis has been challenged,17 and, as a practical matter, the gastroenterologist or surgeon managing adult patients rarely obtains biopsy specimens from the esophagus for the purpose of diagnosing GERD. Rather, specimens are taken to exclude infection, other forms of esophagitis such as eosinophilic esophagitis, Barrett’s esophagus, and neoplasms. Esophageal biopsies may be more useful for confirming the diagnosis of reflux disease in infants, however.18

Microscopic Features of GERD Reflux esophagitis produces a characteristic, although nonspecific, microscopic injury pattern. The main features are squamous hyperplasia and variably present inflammatory components. Squamous Hyperplasia. For many years, it was believed that the sole diagnostic criterion for esophagitis was inflammation. However, in 1970, Ismail-Beigi and coworkers demonstrated that some patients with symptomatic reflux, but with normal or minimally abnormal endoscopic appearances, had hyperplasia of the esophageal squamous epithelium. They postulated that hyperplasia reflected an early histologic manifestation of reflux-induced injury.1 Hyperplasia is defined as lengthening of the subepithelial papillae of the lamina propria that exceeds two thirds of, and thickening of, the basal zone to occupy more than 15% of the full thickness of the mucosa. Subsequent confirmatory studies showed a significant positive correlation between length of the papillae and the severity of reflux as measured by the 24-hour pH score, a composite quantitative evaluation of reflux.19 These correlations also exist in infants and children.20 Inflammation. The principal inflammatory cells of reflux esophagitis are the neutrophil, the eosinophil, and the lymphocyte (Table 36-1),4 which are discussed in turn. NEUTROPHILS. Intraepithelial neutrophils within the esophageal squamous epithelium are specific for differentiating normal subjects from those with esophagitis but, unfor-

397

398

Section 4 Gastroesophageal Reflux and Associated Conditions

TABLE 36-1 Inflammatory Cells in Esophageal Epithelium in GERD No. of Biopsies Involved (Total = 91) Neutrophils*

Lymphocytes†

Eosinophils*

Papillary Length (mm)

0

1+

2+

3+

0

1+

2+

3+

1+

2+

3+

0.19 or more (reflux)

44

10

3

3

25

20

7

8

28

22

10

0.18 or less (no reflux, normal)

30

1

0

0

23

8‡

0

0

26‡

5‡

0

*1+ = 1-5 cells per section; 2+ = 6-10 cells per section; 3+ = 10+ cells per section. † 1+ = 1-10 cells per high-power (40×) field; 2+ = 11-20 cells per high-power field; 3+ = 20+ cells per high-power field. ‡ Note that both eosinophils and lymphocytes occur in normal squamous esophageal mucosa. Sensitivity of any neutrophils for esophagitis (long papillae) = 16/60 = 27%. Specificity of any neutrophils for esophagitis (short papillae) = 30/31 = 97%. Sensitivity of 1+, 2+, or 3+ eosinophils for esophagitis (long papillae) = 35/60 = 58%. Specificity of 1+, 2+, or 3+ eosinophils for esophagitis (short papillae) = 23/31 = 74%. From Haggitt RC: Histopathology of reflux induced esophageal and supraesophageal injuries. Am J Med 6(108 Suppl 4a):109S-111S, 2000.

tunately, are an insensitive index of reflux esophagitis. They are present in less than a third of GERD patients with documented reflux (see Table 36-1). However, their presence can be discerned even in improperly oriented specimens. Significant numbers of neutrophils, particularly in the presence of an erosion or ulcer or associated fibrinopurulent exudate, should always prompt the pathologist to search for viral or fungal infection. EOSINOPHILS. Increased numbers of eosinophils are likewise present in reflux esophagitis,21 but since a few eosinophils may be found in the mucosa of normal adults, they are not significant unless 6 or more are present in a biopsy (see Table 36-1).4,22 Eosinophilia in esophageal biopsy specimens may be a particularly valuable diagnostic aid in evaluating reflux esophagitis in children because they are not normally present in a child’s mucosa.20,23 Also, more than one eosinophil in the lamina propria appears to be an even better index of reflux disease in infants.18 Occasionally, large numbers of eosinophils are present in the esophageal biopsy specimens of adult reflux patients.24 When this is the case, other causes of esophageal eosinophilia must be excluded, such as idiopathic eosinophilic esophagitis and eosinophilic gastroenteritis (which may be manifestations of the same disease) and drug reactions including StevensJohnson syndrome and pill-induced esophagitis. Children appearing to have reflux disease with prominent eosinophilia may improve when given elemental diets, suggesting that certain protein sensitivities may lead to reflux-like symptoms.25,26 EOSINOPHILIC ESOPHAGITIS. This is a relatively recently recognized condition that is of importance to the esophageal surgeon because it mimics GERD clinically, endoscopically, and histologically but does not respond to medical or surgical antireflux therapy. Patients with this condition typically present with progressive dysphagia but, by definition, lack evidence for GERD either by having normal pH monitoring or failure to respond to antireflux therapy. A predilection for esophageal rupture complicating dilation procedures has also been reported. Histologically, this condition overlaps

TABLE 36-2 Histology of Eosinophilic Esophagitis Versus GERD

Feature

Eosinophilic Esophagitis

GERD

Proximal esophageal involvement

+

−

Superficial eosinophil layering

+

±

Eosinophil microabscess

+

±

Eosinophil count >20/high-power field

+

±

Squamous hyperplasia

+

+

significantly with reflux disease, particularly if only distal esophageal biopsy samples are examined. Although biopsy specimens of eosinophilic esophagitis tend to contain more marked intraepithelial eosinophilia (in the range of 20 or more per high-power field), severe reflux disease may also produce pronounced eosinophilia, so that this is not a magic number for this differential diagnosis. The entire clinicopathologic picture must be evaluated. Aggregates of eosinophils and their propensity to be located within the superficial layers of the squamous epithelium have also been described for eosinophilic esophagitis, but this, too, is not specific (Table 36-2).26,27 It must be emphasized that these findings are imperfect for discriminating eosinophilic esophagitis from GERD, particularly in distal biopsy specimens. Biopsy involvement of the mid or upper esophageal mucosa has much greater diagnostic significance, because GERD rarely extends this far proximally and proximal involvement is characteristic of eosinophilic esophagitis. Patients with eosinophilic esophagitis tend to be children or young adults; there is a male predominance.25-28 Most have an allergic history, and many have peripheral blood eosinophilia. Eosinophilic gastroenteritis also involving the stomach or intestines is in the differential diagnosis of this esophageal condition. There may be overlap between these entities, and it has been hypothesized that they may represent a spectrum of gastrointestinal tract involvement of a common disorder.

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

The results of esophageal endoscopy may be normal in patients with eosinophilic esophagitis, or there may be esophageal rings, furrows, strictures, or even plaques.28 The plaques may suggest possible Candida esophagitis endoscopically but instead on microscopy are composed of sloughed squamous cells admixed with eosinophils. Endoscopists should actually target these various endoscopic abnormalities for their specimens, because these areas are usually the most diagnostic by virtue of their heavy eosinophil content. Eosinophilic esophagitis often responds to medical therapy with topical or systemic corticosteroids or, in some cases, dietary elimination testing. Herein rests the significance of this disorder for the esophageal surgeon, because it is not a surgical entity. It does, however, significantly mimic reflux esophagitis, as mentioned, and particularly if only distal esophageal biopsy samples are obtained. This could pose a problem if surgical therapy is selected for misdiagnosed reflux disease. The esophageal surgeon would be well advised to consider the possibility of eosinophilic esophagitis before any surgery is performed for reflux disease. Clinical presentation, endoscopic appearance, and particularly involvement of mid to upper esophageal biopsy specimens with numerous eosinophils are the most helpful discriminating features. LYMPHOCYTES. Large numbers of lymphocytes are present within the squamous epithelium of GERD patients.29 As with eosinophils, however, lymphocytes are a normal intraepithelial component of esophageal squamous epithelium, and adult normal controls may have large numbers as well (see Table 36-1).4,29,30 They similarly do not correlate with any other parameters of reflux disease in infants.20 Thus, lymphocytes have no independent diagnostic significance in the diagnosis of GERD. They are largely T cells and have either round or irregular nuclear contours as they become deformed between the squamous epithelial cells. Because of this nuclear deformity, they may resemble granulocytes. This error can be avoided by observing for the cytoplasmic granularity of neutrophils or eosinophils. INFLAMED GASTRIC CARDIAC AND FUNDIC MUCOSA. Chronic and active inflammation of mucosa of both gastric cardiac type and gastric fundic type at the LES region or within a hiatal hernia are common, although nonspecific, features of GERD. The principal differential diagnoses are Helicobacter pylori–induced gastritis versus reflux disease. On its own, and without other more specific findings, such as accompanying antral Helicobacter gastritis or reflux squamous esophagitis, the etiology of inflammation of gastric mucosa in this region cannot be ascertained. Miscellaneous Microscopic Features of GERD. Marked capillary dilation within the mucosa has been described as a characteristic change in reflux esophagitis,31 but it occurs so frequently in normal controls, probably as a traumatic biopsy artifact, that many gastrointestinal pathologists are reluctant to assign diagnostic value to it.32 Other miscellaneous features that may be seen in GERD include ballooning degeneration and multinucleation of squamous cells, which is discussed further in the sections on pill-induced esophagitis. Multinucleation may mimic herpetic esophagitis, but it lacks the nuclear inclusions of herpes with smudged chromatin surrounded by a nuclear halo.

Pathology of Esophageal Erosions/Ulcers The granulation tissue of erosions and ulcers of the esophagus, or from any area of the gastrointestinal tract for that matter, consistently exhibits very large endothelial cells and fibroblasts (Fig. 36-1). In many examples, these cells appear alarmingly atypical or even bizarre.33 They can usually be correctly identified as part of a reparative mesenchymal process by noting their single and scattered distribution within otherwise typical granulation tissue made up of innumerable new blood vessels. Furthermore, these cells typically do not form solid epithelioid clusters and they have a normal or decreased nuclear-to-cytoplasmic ratio. In contrast, carcinoma usually demonstrates epithelioid groups or sheets of cohesive cells with overlapping nuclei and increased nuclearto-cytoplasmic ratios. As a guideline, one should be cautious about diagnosing carcinoma when granulation tissue is present in the biopsy. Rare cases with conflicting features can often be resolved by cytokeratin immunohistochemistry, which is positive in carcinoma and negative in reactive mesenchymal cells. The inflammatory exudates from ulcers or erosions within the esophagus and anywhere else within the gastrointestinal tract characteristically also contain sheets of activated and atypical lymphocytes and macrophages that may simulate lymphoma. As a histologic guideline, these are benign if confined to the surface exudate. They should only raise concern over potential lymphoma if they infiltrate the tissue.

Differential Diagnosis of GERD The differential diagnosis of reflux esophagitis includes infectious esophagitis, inflammation caused by lodging of pills within the esophagus (“pill” esophagitis), esophagitis after the ingestion of corrosive agents such as lye, Barrett’s esophagus plus its neoplastic complications, and squamous neopla-

FIGURE 36-1 Benign mesenchymal cells (either endothelial cells or fibroblasts) within an esophageal ulcer bed may display striking and even bizarre cytologic atypia. These atypical cells can usually be differentiated from carcinoma by their solitary and scattered nature, lack of epithelioid clustering, maintenance of their nuclear-tocytoplasmic ratio, and occurrence within otherwise typical granulation tissue. (Hematoxylin and eosin.)

399

400

Section 4 Gastroesophageal Reflux and Associated Conditions

sia. Esophagitis may also develop in a variety of systemic conditions, such as eosinophilic gastroenteritis, eosinophilic esophagitis, Crohn’s disease, sarcoidosis, graft-versus-host disease, collagen vascular disease, or Stevens-Johnson syndrome. Esophageal stasis syndrome may develop in esophageal dysmotility states such as achalasia or strictures.

Infectious Esophagitis Viruses and fungi cause most forms of acute infectious esophagitis, including most commonly herpes simplex and zoster, cytomegalovirus, and Candida.34 Histoplasmosis is far less common. Bacterial esophagitis occurs in some systemic and upper respiratory tract infections but is rarely seen by the pathologist.

Pill- and Drug-Induced Esophagitis Esophageal injury caused by prolonged direct mucosal contact with tablets or capsules taken in therapeutic doses occurs not infrequently.35-37 Commonly implicated agents include antibiotics (particularly doxycycline), as well as emepronium bromide, potassium chloride, ferrous sulfate,38 quinidine, alendronate,39 and many others.36,37 Symptoms include odynophagia, continuous retrosternal pain, and dysphagia. The patient often gives a history of having taken a pill(s) with little or no fluid just before going to bed and was aware that the pill had “stuck in the chest.” Most affected individuals do not have any apparent abnormality of esophageal transit35-37; however, several patients with quinidine or potassium chloride injury have been described who had preexisting esophageal compression due to either valvular heart disease with left atrial enlargement or esophageal entrapment by fixed mediastinal structures and adhesions after thoracic surgery.37 The histologic appearance of pill-induced esophagitis, ulcer, and stricture is usually nonspecific. Prominent eosinophilic infiltration, spongiosis, and necrosis of squamous epithelium should raise the possibility of pill-induced injury. Polarizable crystalline material may be seen in alendronateinduced injury,39 and crystalline stainable iron can be found in ferrous sulfate–induced disease.38 Esophageal erosions and ulcers have been reported in 20% of arthritis patients taking nonsteroidal anti-inflammatory drugs (NSAIDs).40 NSAID-induced esophageal injury may be caused by both direct and systemic effects, and it may be exacerbated in patients with GERD.40 Esophageal injury by these agents may be less common than injury to other parts of the gastrointestinal tract.41

BARRETT’S ESOPHAGUS Barrett’s esophagus is an acquired condition in which the stratified squamous epithelium normally lining the esophagus becomes replaced by metaplastic, intestinal-type columnar epithelium, defined by the presence of goblet cells. This condition develops as a result of chronic GERD42-44 and predisposes to the development of esophageal adenocarcinoma.42-44 Barrett’s esophagus occurs in both adults and children, in whom it has a similar pathogenesis.45 There are two main sources of error in the pathologic evaluation of Barrett’s esophagus, as outlined in Table 36-3.

TABLE 36-3 Problems in the Pathologic Evaluation of Barrett’s Esophagus Overdiagnosis of Barrett’s Esophagus Definitional problems: Endoscopic and histologic components Three anatomic landmarks to be identified and sampled: Gastroesophageal junction Proximally displaced squamocolumnar junction or Z line Intervening pink mucosa within tubular esophagus of suspected Barrett’s epithelium Not gastric cardiac– or gastric fundic–type mucosa Not a few metaplastic glands in the lower esophageal sphincter region Pseudogoblet cells of gastric cardiac mucosa may mimic Barrett’s mucosa Misinterpretation of alcian blue stain at pH 2.5 Overdiagnosis of High-Grade Dysplasia in Barrett’s Esophagus Not reactive gastric cardiac–type mucosa Not atypia limited to basal glands of Barrett’s intestinal metaplasia Grading accuracy: experience and volume dependent Dysplasia as a morphologic spectrum and for which precise boundaries cannot be defined Obscuring inflammatory change Loss of nuclear polarity as the most objective criterion to differentiate low- and high-grade dysplasia

The first is the overdiagnosis of this serious condition, a problem related to evolving definitions of Barrett’s esophagus, lack of understanding of its histologic mimics, and misinterpretation of alcian blue stains at pH 2.5. The second is the problem of overdiagnosing dysplasia in Barrett’s esophagus, in particular high-grade dysplasia, given its major clinical consequences. Both of these issues exact severe costs for patients and are explored in detail.

Diagnosis of Barrett’s Esophagus Definition A careful definition and diagnosis of Barrett’s esophagus is essential because this cancer-predisposing condition confers untold patient anxiety, serious insurability difficulties, and commitment to lifelong endoscopic cancer surveillance. The current definition of Barrett’s esophagus has two requirements, one endoscopic and one histologic (Fig. 36-2). The diagnosis should not be established unless both are present, as advocated by the American College of Gastroenterology.46 The endoscopic component requires that columnar mucosa, identified endoscopically by its pink color, extends proximally from the gastroesophageal junction (GEJ) into the tubular esophagus (see later discussion of these endoscopic landmarks). The endoscopic component was only more recently added to the definition, owing to the discovery that up to a third of patients with GERD will have a few glands of intestinal metaplasia at an otherwise normal GEJ, as discussed later.47,48 Because of the extremely high prevalence of GERD and the marked comparative rarity of Barrett’s neoplasia, it was then recognized that a few intestinalized junctional glands in GERD could not confer the same increased

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

FIGURE 36-2 Barrett’s esophagus is defined by both endoscopic and histologic components. Endoscopically there must be visible pink columnar epithelium within the tubular esophagus (A) that histologically has intestinalized metaplastic columnar epithelium defined by the presence of true goblet cells (B, arrows) on hematoxylin and eosin staining. Barrett’s esophagus should not be diagnosed without both components.

A

B

cancer risk as an endoscopically defined Barrett’s alteration. This is the reasoning behind the addition of the endoscopic requirement to the definition. The histologic component requires that biopsy specimens taken from the endoscopically identified columnar (pink) mucosa contain metaplastic or intestinalized columnar epithelium with goblet cells.46 This approach still has its difficulties, because the endoscopic anatomy may be problematic to define and, likewise, the minimal amount of metaplastic epithelium required histologically to confer an increased cancer risk remains unknown. However, this two-pronged definition is an important step toward better defining Barrett’s esophagus.

Anatomic Landmarks of Barrett’s Esophagus The literature concerning Barrett’s esophagus is difficult to interpret because of variable and evolving criteria for the diagnosis and imprecise endoscopic definitions of important anatomic landmarks. The following definitions of the various endoscopic anatomic landmarks at the lower esophageal region have helped to refine the endoscopic identification of Barrett’s esophagus (Fig. 36-3). If abnormalities are identified, endoscopists should, at a minimum, separately identify and biopsy these landmarks to enable a correct diagnosis of Barrett’s esophagus.49 The GEJ in normal individuals is the anatomic junction at which the tubular esophagus joins the saccular stomach and is visible at the point where the superiormost gastric folds end.49 However, the SCJ, also known as the “Z line,” is a mucosal junction and it does not always coincide with the gastroesophageal anatomic junction. The SCJ may be irregular; and in as many as half of normal patients, it may be proximally displaced from the GEJ to lie anywhere within the increased pressure region of the LES,

that is, within the distal 2 to 3 cm of the tubular esophagus (see Fig. 36-3A). Thus, for accurate diagnosis of Barrett’s esophagus, separate biopsy samples should be obtained if a proximally displaced SCJ is found, specifying (1) the GEJ, (2) the Z line, and (3) the intervening columnar (pink) mucosa of possible Barrett’s esophagus, whether it is a tongue or a circumferential segment. Single biopsy specimens designated as “rule out Barrett’s” are clearly insufficient. If the intervening mucosa has intestinal metaplasia, this is Barrett’s esophagus, whether it is a long or short segment (see Fig. 36-3B). Despite these anatomic definitions, the endoscopic diagnosis of Barrett’s esophagus may be difficult. This is particularly true when the patient has a large hiatal hernia, and especially if it is combined with a patulous LES. In such a patient, the GEJ may be difficult to identify but its location usually becomes apparent if air is gently insufflated to demarcate the saccular hiatal hernia from the tubular esophagus. Also, the GEJ is located within 1 to 2 cm of the proximal margins of the gastric folds, even when a hiatal hernia is present.50

Lower Esophageal Sphincter Region in Normal Persons and in Patients With Reflux Without Barrett’s Esophagus In normal individuals or in reflux patients without Barrett’s esophagus, endoscopically visible columnar or pink-colored epithelium within the tubular esophagus is composed of gastric cardiac or gastric fundic mucosa (Fig. 36-4). Thus, gastric cardiac–type or gastric fundic–type mucosa within the distal 2 to 3 cm (LES zone) of the esophagus is normal or may reflect reflux disease (see later), but it is not Barrett’s esophagus.42,51 In fact, gastric mucosa occurs in as many as one half of biopsy specimens from the distal esophagus.42,51

401

402

Section 4 Gastroesophageal Reflux and Associated Conditions

Normal esophagus

Barrett’s esophagus

SCJ Esophagus Esophagus

LES

SCJ GEJ

GEJ SCJ >

LES Top of gastric folds

Diaphragm GEJ ~ SCJ

Hiatal hernia

GEJ

Stomach

Stomach Squamous

A

Gastric

Metaplastic

B

FIGURE 36-3 Anatomic landmarks of the normal LES region (A) and of Barrett’s esophagus (B). The squamocolumnar junction (SCJ) is a mucosal junction; the gastroesophageal junction (GEJ) is an anatomic junction located where the saccular stomach joins the tubular esophagus, a point demarcated by the top of the superiormost radiating gastric folds. Note that in many people the SCJ approximates the GEJ (A, left), but that gastric mucosa also occurs very commonly in the LES region (present in about 50% of GERD patients). This latter situation occurs at any time that the SCJ is proximally displaced by gastric mucosa into the tubular esophagus (A, right). Gastric mucosa extending into the distal 2 to 3 cm of the esophagus is not Barrett’s esophagus and does not confer an increased cancer risk. However, it has the same endoscopic salmonpink appearance as Barrett’s metaplastic mucosa, so it must be sampled to ascertain its histology. In true Barrett’s esophagus, the SCJ is not only proximally displaced within the tubular esophagus above the GEJ but the intervening mucosa is composed of intestinalized Barrett’s metaplastic epithelium (B). Barrett’s segments may be short (B, left) or long (B, right), but both confer an increased cancer risk. Hiatal hernia, in which the saccular stomach extends above the diaphragm, is present in the great majority of Barrett’s patients (B).

FIGURE 36-4 Gastric mucosa of cardiac (A) and fundic (B) types in biopsy specimens from endoscopically visible pink columnar mucosa within the LES region. Note the absence of goblet cells, the tall columnar gastric foveolar surface, and the gastric-type mucinous/cardiac (A) or oxyntic/fundic (B) glands. Note also the parietal cell luminal cytoplasmic protrusions in the fundic mucosa (B), a feature commonly caused by proton pump inhibitor therapy of acid reflux in Barrett’s patients. Gastric epithelium of either cardiac or fundic types within the LES region does not represent Barrett’s esophagus and does not confer an increased cancer risk. (Hematoxylin and eosin.)

A

B

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

Gastric cardiac–type and gastric fundic–type mucosa may normally be found within the distal esophagus because the mucosal junction or Z line may be irregular and project into the esophagus, or it may lie entirely within the distal tubular esophagus.49,52 Debate has arisen over whether gastric cardiac–type or gastric fundic–type mucosa in this region is truly “normal” (present congenitally) or alternatively represents an acquired alteration caused by reflux disease.53,54 However, neither gastric cardiac nor gastric fundic epithelia in this region are risk factors for malignancy and they are not diagnostic of Barrett’s esophagus. The previously presented definitional information on Barrett’s esophagus, from both the endoscopic and histologic perspectives, represents a very definite evolution of our understanding over the past several decades. Early on, three types of Barrett’s epithelia were recognized, namely, gastric cardiac type, gastric fundic type, and intestinal type, but we now know that only the intestinal type confers an increased neoplastic risk. It cannot be emphasized strongly enough that the histologic component of Barrett’s esophagus is limited to intestinal metaplasia with true goblet cells.42,51 Lack of understanding on this critical point is one of the major factors generating incorrect diagnoses of Barrett’s esophagus, with the major and unnecessary consequences this poses for patients.

Long Segments of Only Gastric Cardiac–Type Mucosa Virtually all columnar epithelium in adults that extends proximal to the LES (i.e., more than 2-3 cm above the GEJ) is intestinalized.42,51,55 An individual biopsy specimen may contain only gastric cardiac–type or gastric fundic–type mucosa in a patient who has metaplasia in other specimens. In one report, when the diagnosis of Barrett’s esophagus was based on the presence of more than 3 cm of nonmetaplastic or gastric epithelium, the diagnosis could not be confirmed on a second endoscopy in 38% of patients.56 This observation indicates that endoscopic measurement of columnar epithelium alone is an unreliable determinant. An extremely rare patient may, however, have only gastric cardiac–type mucosa without goblet cells extending well above the LES region. The significance of this condition remains unknown.51 This very unusual situation might best be referred to as “columnarlined esophagus of the non-Barrett’s type”55 to distinguish it from Barrett’s esophagus and its known cancer risk. Because of the rarity of the gastric cardiac–only type segment extending above the LES, its neoplastic risk is unknown.51

goblet cell–containing epithelium required to confer an increased cancer risk remains unknown. A few metaplastic glands from an endoscopically normal LES region are quite common and, in fact, have been found in up to a third of patients undergoing upper endoscopy for reflux symptoms (Fig. 36-5).47,48,58 Thus, the very high prevalence of this finding indicates that it cannot possibly have the same neoplastic risk as Barrett’s esophagus that is endoscopically visible. Thus, it seems ill advised to diagnose Barrett’s esophagus on predominantly gastric cardiac–type mucosa with only a few metaplastic glands with true goblet cells. A few metaplastic glands is defined as fewer than five as a practical matter and is one of personal opinion. In such cases, a diagnosis of “focal intestinal metaplasia; negative for dysplasia” rather than Barrett’s esophagus is reported, along with an explanatory comment regarding the high prevalence of this finding in GERD and the need for endoscopic correlation to define a definitive diagnosis of Barrett’s esophagus. There are no data that such minute foci of metaplastic epithelium confer an increased cancer risk, nor are such data likely to become available in the near future or ever. The requisite trial size to investigate the neoplastic risk of a few metaplastic glands would be enormous and the follow-up extensive, dooming such a study to economic failure. Nonetheless, based on current knowledge that a few intestinalized glands in a patient with GERD is a highly prevalent finding, it seems unwise to give such a patient a diagnosis of Barrett’s esophagus. If the endoscopist has additional concerns about the endoscopic alterations and the possibility of Barrett’s esophagus, then additional biopsy samples should be obtained. Finally, the clinical practice of taking biopsy samples from an otherwise endoscopically normal GEJ should be discouraged, because there is no known clinical significance to the histologic findings in this setting and the practice leads to the overdiagnosis of Barrett’s esophagus.

Characteristics of Barrett’s Epithelium and Its Mimics GERD or Helicobacter Gastritis? An ongoing debate exists over whether metaplastic columnar epithelium in biopsy samples taken from the GEJ is due to reflux disease– induced Barrett’s esophagus or Helicobacter pylori–induced

Minimal Histologic Requirements for Barrett’s Esophagus or “How Many Goblet Cells Are Enough?” Metaplastic epithelium is defined histologically by the presence of acid mucin–containing goblet cells. When it is identified in a biopsy specimen taken from endoscopically visible columnar epithelium within the tubular esophagus (above the GEJ) it is abnormal, regardless of whether it occupies a 1- or a 10-cm segment.42,46,51,55 This is true Barrett’s esophagus. Short segment Barrett’s esophagus is defined arbitrarily by the presence of 3 cm or less of metaplastic epithelium within the esophagus.50,57 However, the minimal amount of

FIGURE 36-5 Rare metaplastic glands with goblet cells (arrows) at the gastroesophageal junction are insufficient to establish a diagnosis of Barrett’s esophagus. (Alcian blue at pH 2.5.)

403

404

Section 4 Gastroesophageal Reflux and Associated Conditions

intestinalized pangastritis.59-61 Voutilainen and associates found that complete intestinal metaplasia at the junction was related to Helicobacter infection in the stomach but that the incomplete type was related to reflux disease.61 Ormsby and colleagues have demonstrated differences in the cytokeratin-7 and cytokeratin-20 staining patterns for these different causes.62 To date, the clinical significance of these distinctions is unknown because long-term prospective follow-up data are lacking. Such natural history studies will be necessary before such distinctions are incorporated into clinical practice. As a practical matter at present, if metaplastic glands at the GEJ are accompanied by Barrett’s esophagus of the tubular esophagus as defined earlier, they should be considered part of reflux disease. In the absence of esophageal involvement, they then should be considered as part of H. pylori gastritis if there is also evidence of active or past infection as determined by antral biopsy or Helicobacter serologic study, respectively. Pancreatic Acinar Metaplasia. Biopsy specimens obtained from the region of the GEJ not infrequently have foci of pancreatic acinar metaplasia.63 This is an incidental finding that has no known clinical importance.63 Barrett’s Esophagus in Children. As mentioned earlier, gastric cardiac– or gastric fundic–type epithelium may normally reside within the distal 2 to 3 cm of the tubular esophagus. Children with a columnar-lined esophagus have been reported to have gastric fundic– or gastric cardiac–type epithelium above the LES region, but the validity of this observation has been challenged.45 Children with reflux disease who do not initially have metaplastic epithelium may eventually develop it.52 Of the children with reflux disease reported by Qualman and colleagues who had metaplastic epithelium, the youngest was 5 years of age.52 Metaplastic Epithelium With True Goblet Cells and Interpretation of the Alcian Blue Stain at pH 2.5. Barrett’s metaplastic epithelium is histologically identical to intestinal metaplasia of the incomplete type (type II or III) or less commonly the complete type (type I).42 Subtyping of intestinal metaplasia, however, has no practical clinical significance, because neoplastic change may develop in all types. The epithelium covering the mucosal surface and pits, or the villiform projections of Barrett’s mucosa, has two major cell types—goblet cells and columnar cells (Fig. 36-6). Paneth cells may also be seen occasionally in complete-type intestinal metaplasia. True goblet cells not only have the rounded goblet shape but also contain acidic mucin that stains intensely blue with alcian blue–pH 2.5. Histochemical analyses show that this acidic mucin most often contains a mixture of sialomucins and sulfomucins but the sialomucins generally predominate.64 Demonstration of acid mucin subtype, similar to the subtyping of intestinal metaplasia itself, also has no clinical or prognostic significance. Neither aspect need be analyzed or reported for practical diagnostic purposes. Routine alcian blue–pH 2.5 staining of potential Barrett’s mucosa is expensive and not necessary, because it can be readily recognized in most cases on staining with hematoxylin and eosin alone. This is especially true if the hematoxylin being used is optimized to stain the goblet cells blue on its own. Alcian blue staining or the lack thereof can, however, be very helpful

FIGURE 36-6 Metaplastic or intestinalized epithelium in Barrett’s esophagus with true barrel-shaped goblet cells that tend to be singly dispersed within the epithelium. (Hematoxylin and eosin.)

in the setting of gastric cardiac–type mucosa with gobletshaped cells (so-called pseudo–goblet cells). The columnar cells between the goblet cells may resemble normal gastric foveolar cells or intestinal-type absorptive cells, but they do not have all the typical features of either. The brush border, if present, is only partially developed, in contrast to the fully developed, refractile brush border of the mature intestinal absorptive cell. The columnar cells differ from normal gastric surface cells because they frequently contain alcian blue–pH 2.5–positive mucin in variable quantities (so-called tall columnar blues).51 Sialomucins usually predominate over sulfomucins, just as they do in the goblet cells, but again this has no known diagnostic significance. Pseudo–Goblet Cells. Not uncommonly, gastric cardiac– type mucosa may contain foveolar cells with barrel-shaped or distended cytoplasm. These distended gastric foveolar cells have been termed pseudo–goblet cells (Fig. 36-7) and are a large source of error in the false-positive diagnosis of Barrett’s esophagus. Fortunately, these mimickers usually stain less intensely than true goblet cells with alcian blue–pH 2.5, if positive at all. Of additional importance, pseudo–goblet cells are not generally singly admixed with the columnar absorptive and gastric foveolar-type cells of true Barrett’s mucosa. Rather, pseudo–goblet cells are characteristically arranged in linear continuous stretches without intervening columnar cells, as opposed to the singly dispersed pattern of true goblet cells. The columnar cells of gastric cardiac–type mucosa, including the barrel-shaped pseudo–goblet cells, may show positive alcian blue–pH 2.5 staining. This is usually weak but occasionally may be intense and should not be mistaken for

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

ally scattered intensely blue true goblet cells of Barrett’s metaplastic mucosa. The ducts draining these glands may have a mucinous or transitional-type epithelium (similar to immature squamous metaplasia in the uterine cervix), and these also may contain alcian blue–positive cells or surface mucin caps. The contiguous alcian blue–positive cells within a ductlike structure and/or coexistent transitional-type epithelium and/or identification of the actual esophageal gland being drained by the duct usually permits distinction from Barrett’s metaplastic epithelium.

Summary of Establishing a Diagnosis of Barrett’s Esophagus

FIGURE 36-7 Pseudo–goblet cells arranged in a diffuse, contiguous pattern that are also negative for alcian blue staining at pH 2.5 or faintly positive, as opposed to the singly dispersed pattern and intense blue positivity of true goblet cells. (Alcian blue–pH 2.5.)

Barrett’s metaplastic epithelium. In the majority of cases, the pattern and types of cells present will permit this distinction, as discussed earlier. When these alcian blue–positive columnar cells are present in the absence of true goblet cells, the diagnosis of Barrett’s esophagus should not be made,42,51 because this type of alcian blue staining is common in reactive gastric foveolar mucosa that may well be present in reflux disease alone. Distinguishing reactive, inflamed gastric cardiac–type mucosa from dysplastic Barrett’s epithelium is another difficulty that may be considerable (Fig. 36-8). In both of these epithelial types, there is a strong tendency for loss of cytoplasmic mucin (whether it is loss of foveolar gastric mucin on the one hand or goblet cell mucin on the other), and both also show cytologic atypia. In neoplastic Barrett’s epithelium, the loss of cytoplasmic mucin may be a feature of dedifferentiation, whereas in reactive gastric cardiac–type mucosa the mucin loss may reflect cell injury. Either way, these epithelia may appear remarkably similar and, of course, have an entirely different significance. Differential diagnostic features between these epithelia are further discussed later in the section on problems in the diagnosis of dysplasia. Esophageal Glands. Other sources of confusion about alcian blue–positive cells derive from the normal esophageal mucosal and submucosal glands and their corresponding ducts. They are located within the deeper portions of the biopsy specimen but may be either within the lamina propria or the submucosa. They are characteristically intensely alcian blue positive but are differentiated from Barrett’s epithelium by their rounded and grouped or lobular configuration, similar to minor salivary glands, and their diffuse alcian blue staining pattern. Specifically, the entire esophageal glandular lobule stains intensely blue, which contrasts sharply to the individu-

The consequences of a diagnosis of Barrett’s esophagus are high, with its attendant predisposition to cancer, lifelong surveillance implications, major insurability issues, and psychological burden to the patient. Accordingly, the diagnosis should not be established when the data on an individual patient are ill defined and without proven significance. Endoscopic landmarks, including (1) the GEJ, (2) the proximally displaced SCJ (Z line), and (3) the intervening pink columnar mucosa endoscopically suspected of being Barrett’s esophagus should each be separately sampled and identified for the pathologist. The intervening mucosa must contain metaplastic intestinalized epithelium with true goblet cells. Careful histologic attention should be paid to potential mimics of Barrett’s mucosa, particularly pseudo–goblet cells and inflamed gastric cardiac–type mucosa. The interpretation of alcian blue–pH 2.5 staining may also be challenging as well as the fact that several cell types within the esophagus may be alcian blue positive at pH 2.5 that are not Barrett’s epithelium. Finally, a few metaplastic glands from an endoscopically normal-appearing LES region should not be diagnosed as Barrett’s esophagus but rather as only a scant focus of intestinal metaplasia, because this is a very common phenomenon in patients with reflux.47,48,58

Neoplastic Progression in Barrett’s Esophagus Barrett’s esophagus predisposes to the development of esophageal adenocarcinoma,42,44 but the frequency with which it does so is somewhat controversial. Part of the difficulty in defining the cancer risk is that the prevalence of Barrett’s esophagus itself, and thus the denominator in the equation, is not well documented. Barrett’s esophagus is present in 10% to 12% of patients with symptomatic GERD who undergo endoscopy,42 but an autopsy study has suggested that its true frequency may be as much as 20 times higher.65 The reported prevalence of adenocarcinoma in Barrett’s esophagus averages about 10%; that is, at the time the initial diagnosis of Barrett’s esophagus is made, about 10% of patients will have adenocarcinoma.42 The estimated incidence of adenocarcinoma in Barrett’s esophagus ranges from 1 in 52 to 1 in 441 patientyears, representing an increased risk of 30- to 125-fold.42 Adenocarcinoma of the esophagus appears to be limited to patients who have metaplastic epithelium. The length of the endoscopically visible columnar-lined segment does not seem to have a significant influence on cancer risk, because patients with even very short segments may develop cancer.50,57

405

406

Section 4 Gastroesophageal Reflux and Associated Conditions

A

C

B FIGURE 36-8 Similarities between reactive gastric cardiac mucosa (A, B) and dysplastic Barrett’s mucosa (C) may lead not only to the overdiagnosis of Barrett’s esophagus itself but also to the diagnosis of dysplastic Barrett’s mucosa. The similarities include mucin loss and sometimes marked nuclear atypia, as seen in A (at higher magnification) and B. The differences include the often more bland gastric mucinous glands at the base of the mucosa (B) relative to the more atypical surface (A, black arrow) (so-called top-heavy atypia of reactive gastric mucosa) in comparison to the opposite pattern in Barrett’s esophagus, when the atypia is characteristically most severe in the deep glands (C) (so-called bottom-heavy atypia). Mitotic figures may also be helpful, because the mitotic or regenerative zone of gastric mucosa resides in the central or neck region of the gastric crypt (A, white arrowhead), whereas in Barrett’s esophagus and in any intestinal-type epithelium the regenerative zone emanates from the deepest part of the crypt. The locations of the regenerative zones (neck or mid mucosa in gastric and deep in intestinal) explains the “top”- or “bottom”-heavy patterns of atypia characteristic of these two different epithelia. Finally, reactive gastric foveolar cells commonly retain a well-developed linear array of small apical foveolar mucin caps along the mucosal surface (A, black arrow), which is not as common in dysplastic Barrett’s epithelium. (Hematoxylin and eosin.)

Cancer probably arises in Barrett’s esophagus through a multistep sequence of events that is initiated by chronic gastroesophageal reflux, leading to metaplasia, then dysplasia, and, finally, adenocarcinoma.

Definitions and Characteristics of Dysplasia Dysplasia is defined as neoplastic epithelium that remains confined within the basement membrane of the epithelium within which it arises.66 When the dysplastic epithelium proliferates to form a mass, the term adenoma may be applied, but this is uncommon in Barrett’s esophagus.67 Dysplasia in Barrett’s esophagus is recognized histologically by a combination of architectural and cytologic abnormalities. Dysplastic

glands may retain their normal configuration but more often have irregular, crowded, or even markedly distorted architecture. The glands are usually lined by cells with enlarged, irregular, hyperchromatic, crowded, and stratified nuclei. In other examples, the nuclei are large and hyperchromatic, contain large nucleoli, and have lost their polarity, but they lack the crowding and stratification mentioned earlier. In all cases, the cytologic features extend from the glands onto the epithelial surface, and this surface extension is perhaps the single most important criterion in the diagnosis of dysplasia in gastrointestinal epithelium. Additionally, we allow for slightly more cytoarchitectural atypia directly at the squamocolumnar junction, because this site is prone to somewhat more cytologic atypia at its baseline than away from the

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

FIGURE 36-9 Low-grade dysplasia example (arrow) directly adjacent to mucosa that is negative for dysplasia (arrowhead). Note in the lowgrade dysplastic nuclei the nuclear enlargement, stratification, hyperchromasia, and maintenance of nuclear polarity (long axis of the nucleus remains perpendicular to the basement membrane). (Hematoxylin and eosin.)

FIGURE 36-10 Example of high-grade dysplasia in Barrett’s esophagus; note the loss of nuclear polarity, wherein the nuclei are no longer perpendicular to the basement membrane nor are they oriented to each other. (Hematoxylin and eosin.)

junctional mucosa in Barrett’s esophagus. For purposes of clinical utility, dysplasia in Barrett’s esophagus has been subdivided into low- and high-grade categories in a manner analogous to that for dysplasia complicating idiopathic inflammatory bowel disease.42,66,68 The criteria for grading dysplasia are as follows:

staining characteristics. Goblet cell mucin is usually diminished or absent, and dystrophic goblet cells may be present. The cytologic changes extend from the base of the crypts onto the surface epithelium. When there is a discrepancy between the architectural and cytologic features, then cytologic features take precedence. However, owing to the major consequences at the present time of a diagnosis of HGD, it should not be established without 100% certainty.

Low-Grade Dysplasia (Fig. 36-9) The crypt architecture tends to be preserved, and distortion, if present, is mild. The nuclei are usually stratified and are enlarged, hyperchromatic, and crowded. Abnormal mitotic figures may be present in the upper portion of the crypt. Goblet cell mucin is often diminished and may be absent, or goblet cells in which the vacuole of mucin lies on the basal rather than luminal side of the nucleus may be seen (so-called dystrophic goblet cells). The changes extend from the base of the crypts onto the surface epithelium, and nuclear polarity is preserved (the nuclear long axis remains perpendicular to the basement membrane).

High-Grade Dysplasia (Fig. 36-10) Distortion of crypt architecture is usually present and may be marked. Such glandular architectural distortion is composed of branching and lateral budding of crypts, marked glandular crowding, a villiform configuration of the mucosal surface, or intraglandular bridging of epithelium to form a cribriform pattern or “back-to-back” glands. Nuclear abnormalities are present as in low-grade dysplasia, but, in addition, there is greater nuclear enlargement, more irregularity of nuclear membranes, and loss of nuclear polarity, where the long axis of the nucleus no longer remains perpendicular to the basement membrane and the nuclei are no longer orderly in their arrangement or orientation to one another. Loss of nuclear polarity is the most objective criterion for distinguishing low- and high-grade dysplasia, and as such we place heavy emphasis on it. The nuclei vary markedly in size, shape, and

Problems in the Diagnosis of Dysplasia Sampling Error Mapping studies of esophagectomy specimens containing adenocarcinoma that was not endoscopically visible show that dysplasia involves a highly variable amount of esophageal mucosa surrounding the invasive carcinoma.69 The dysplastic mucosa may occupy most or the entire esophagus, or it may be quite limited in extent. Thus, the endoscopist must thoroughly sample the mucosa to avoid missing small areas of dysplasia or carcinoma. Four-quadrant, well-oriented jumbo biopsies taken at 2-cm intervals or less throughout the length of the Barrett’s segment are recommended, combined with additional biopsies of any endoscopic lesions.69 Shortening of the interval to every 1 cm, based on a computerized modeling approach, has been recommended for patients with HGD who are maintained in endoscopic surveillance.70 Adherence to this or similar protocols is reported to produce excellent correlation between the preoperative endoscopic diagnosis and the final diagnosis in the resected specimen.69,70

Baseline Glandular Atypia of Barrett’s Metaplastic Epithelium Metaplastic Barrett’s epithelium that is negative for dysplasia consistently shows nuclear atypia when viewed in contrast to the normal columnar or gastric epithelium. This is particularly true of the deepest metaplastic glands adjacent to the muscularis mucosae. This deep glandular nuclear atypia includes enlargement, hyperchromatism, crowding, irregular

407

408

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 36-11 Baseline glandular atypia in Barrett’s metaplasia that is negative for dysplasia. The most crucial criterion to differentiate this deep glandular atypia (arrows) from dysplasia is maturation of the atypia onto the surface of the mucosa. (Hematoxylin and eosin.)

nuclear contours, prominence of nucleoli, and stratification. These changes may be marked; and, because of this, these abnormalities may be confused with dysplasia (Fig. 36-11). However, they are usually separable from dysplasia because they are confined to the deep glands while the upper portions show less abnormality or are normal; this feature is best recognized in well-oriented biopsy specimens and is referred to as maturation to the surface. Thus, the diagnosis of dysplasia should be made with great caution, if ever, when the changes do not extend onto the mucosal surface.

Distinction From Reactive Change and “Indefinite for Dysplasia” The differentiation of Barrett’s dysplasia from reactive or regenerative change caused by inflammation is difficult, and at times impossible. Reactive changes in biopsy specimens from the edges of ulcers may be indistinguishable from dysplasia or even carcinoma. When there is doubt as to the significance of epithelial abnormalities in a sample, the diagnosis of indefinite for dysplasia should be made with the request for more samples. Specimens obtained from repeated biopsies after intensified medical antireflux therapy will often show resolution of the abnormalities. Another category of change that may be classified as indefinite for dysplasia is that of cytoarchitectural abnormalities in uninflamed Barrett’s epithelium that are not negative for dysplasia but yet are not sufficient for a diagnosis of low-grade dysplasia. A common issue is that the alterations mature partially but not completely as the cells extend onto the biopsy surface (Fig. 36-12). These are alterations that presumably are on the pathway of neoplastic progression but have not yet crossed the threshold for low-grade dysplasia. All types of indefinite for dysplasia are fraught with interobserver and intraobserver diagnostic variability.68

Variability in the Diagnosis of Dysplasia As the epithelial abnormalities in dysplasia form a continuous spectrum, from relatively mild atypism to overt dysplasia, the

FIGURE 36-12 Indefinite for dysplasia in Barrett’s esophagus with cytologic atypia that partially but incompletely matures onto the biopsy surface. As such, these changes do not yet cross the threshold for unequivocal low-grade dysplasia. (Hematoxylin and eosin.)

boundaries between the grades cannot be sharply defined. Thus, observer variation exists in the diagnosis and grading of dysplasia, particularly at the indefinite/low-grade interface.68 For this reason, the categories of indefinite and low-grade are combined in most endoscopic protocols for practical clinical management purposes. Fortunately, at the high end of the spectrum of abnormalities (HGD and intramucosal carcinoma), where the diagnosis may lead to invasive therapy, there is excellent agreement by gastrointestinal pathologists within and between observers. Similarly, there is good reliability for the diagnosis of negative for dysplasia as well.68 As part of an ongoing trial of photodynamic therapy in patients with HGD in Barrett’s esophagus, an interobserver variability investigation of the three study pathologists was conducted, including the late Dr. Rodger Haggitt, Dr. Shari Taylor, and Dr. Mary Bronner. Overall interobserver percent agreement was 85% or greater for all outcomes on a per endoscopy basis and 90% or greater on a per biopsy basis. Interobserver agreement per endoscopy for HGD was 92% (κ 0.85). Intraobserver agreement per endoscopy was very high for all outcomes. When the findings of all three pathologists were averaged, intraobserver agreement on the outcomes of HGD, carcinoma, HGD or carcinoma, and Barrett’s esophagus negative for dysplasia was 94%, 99%, 96%, and 99%, respectively (unpublished data). These data demonstrate that the problem of observer variability in histologic diagnosis is less of a problem for gastrointestinal pathology specialists than often stated.69 Both from another study of 12 gastrointestinal pathologists all from different institutions across the United States,68 and from the discussed group of three gastrointestinal pathologists at the

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

same institution, interobserver and intraobserver diagnostic concordance can be excellent to outstanding. The caveat, of course, is that these pathologists see a high volume of Barrett’s esophageal biopsy material. This is an important and probably critical factor in the accuracy of dysplasia grading in Barrett’s esophagus. Nonetheless, histopathologic diagnosis can be highly reliable and accurate, especially at the lowest and highest ends of the spectrum.

Overdiagnosis of High-Grade Dysplasia in Barrett’s Esophagus Barrett’s esophagus with HGD is a serious condition prone to overdiagnosis by pathologists. As already mentioned, the accuracy of this important diagnosis, with all of its attendant major clinical consequences, is highly dependent on the pathologist’s experience and continued exposure to a high volume of Barrett’s material. Documentation of the magnitude of the problem of the overdiagnosis of HGD is also provided by the previously mentioned multi-institutional international trial of photodynamic therapy in over 200 patients with Barrett’s HGD. Prior to study enrollment, all potential patients carried a biopsy diagnosis from their local hospital of Barrett’s esophagus with HGD. To identify the 208 patients with Barrett’s esophagus with HGD who were ultimately randomized into the trial, a total of 485 patients had to be screened (Table 36-4). There was an incredible number of 237 (49%) patients who were thought to have HGD but ultimately did not. This was uncovered by a rigorous endoscopic and pathologic screening biopsy protocol. The screening included review of the original pathology thought to have HGD by the referring pathologists and a new protocol endoscopy by one of the trial investigators. This included four-quadrant jumbo biopsies every 2 cm, beginning in the proximal gastric fundus, through the LES region and the entire visible columnar pink mucosa within the tubular esophagus to the proximally displaced Z line and squamous mucosa. The 237 patients who did not qualify for the trial had a variety of pathologic processes (see Table 36-4), as interpreted by the three study pathologists at the University of Washington (unpublished data by the late Dr. Rodger Haggitt, Dr. Mary Bronner, and Dr. Shari Taylor). As shown in Table 36-4, many patients (18, or 4% in total) who failed to qualify for the trial did not even have Barrett’s

TABLE 36-4 Re-interpretation of High-Grade Dysplasia in Barrett’s Esophagus in 237 of 485 Patients Re-interpreted Diagnoses Gastric only Other, not Barrett’s

No. Patients

%

18

4

1

<1

Barrett’s negative

35

7

Barrett’s, indefinite for dysplasia

61

12

Barrett’s, low-grade dysplasia

79

16

Barrett’s, carcinoma Total

43

9

237

49

esophagus, much less Barrett’s esophagus with HGD! These and the rest of a total of 194 patients who had less than Barrett’s esophagus with HGD were all facing esophagectomy. This underscores the problem of the overdiagnosis not only of Barrett’s esophagus itself but also of Barrett’s esophagus with HGD.

Avoidance of the Overdiagnosis of Barrett’s Esophagus and High-Grade Dysplasia Reactive Gastric Mucosa One of the more frequent errors in the overdiagnosis of HGD in Barrett’s esophagus is the misinterpretation of gastric cardiac–type mucosa with reactive change (see Fig. 36-8). Such reactive change frequently develops in gastric mucosa in response to gastroesophageal reflux and gastritis involving the LES region and hiatal hernias. It is a particularly unfortunate misinterpretation, because it not only renders a falsepositive diagnosis of Barrett’s esophagus, with all of its attendant problems as discussed earlier, but it may also cause the patient to undergo an unnecessary esophagectomy. The reasons for this error are at least twofold. First, damaged gastric cardiac–type mucosa tends to develop reactive mucin depletion. Mucin depletion is also common in dysplastic Barrett’s epithelium (see Fig. 36-8C). Thus, both tend to lack goblet cells or much mucin in the remaining epithelial cells, so that this potential differentiating cytoplasmic feature is commonly lacking. Second, reactive gastric mucosa may have marked cytologic atypia. This is witnessed by the notoriously atypical reactive entities in gastric pathology, such as reactive gastropathy caused by NSAIDs or bile reflux. The atypia of benign reactive gastric mucosa may in fact be worse than the atypia of dysplasia or even of cancer. Based on these issues, it is no surprise that reactive gastric cardiac–type mucosa may be histologically treacherous and difficult to differentiate from Barrett’s dysplastic epithelium. A useful criterion to distinguish reactive gastric cardiac– type mucosa (see Fig. 36-8A and B) from Barrett’s dysplasia (see Fig. 36-8C) concerns the deeper glands. The deeper glands in reactive gastric cardiac–type mucosa tend to retain most and commonly all of their mucin (see Fig. 36-8B). Furthermore, the mucinous cells within the deep glands (and the surface for that matter) involve the entire gland or crypt in a linear continuous fashion, rather than as scattered goblet cells typical of metaplastic mucosa. Note that on staining with alcian blue at pH 2.5, reactive gastric cardiac–type mucosa may have intensely blue positive cells, but again full gland or continuous linear involvement is characteristic, rather than the scattered blue goblet cells of metaplastic epithelium. Furthermore, the basal glands of gastric cardiac mucosa are characteristically not mitotically active. This is because the regenerative zone of gastric cardiac mucosa resides in the more superficial foveolar neck region, generally located in the upper mid region of gastric cardiac mucosa (see Fig. 36-8A, white arrowhead), rather than within the deep glandular compartment as is typical of intestinal epithelium. Another diagnostic gastric feature is the presence of parietal cells. Reactive gastric cardiac–type mucosa may also retain some surface mucin in the form of markedly shortened but

409

410

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 36-13 High-grade dysplasia with marked distortion of glandular architecture such that adenocarcinoma cannot be excluded. Note the severe crowding, making this biopsy worse than simple highgrade dysplasia and something of more concern. Definite features of invasion are not observed, however. (Hematoxylin and eosin.)

FIGURE 36-14 Intramucosal adenocarcinoma in Barrett’s esophagus, showing a never-ending gland pattern of lamina propria invasion. (Hematoxylin and eosin.)

back-to-back foveolar mucin caps covering the surface of the biopsy (see Fig. 36-8A, black arrow). These features in combination with bland mitotically inactive mucinous glands, often diffusely positive for alcian blue at pH 2.5, are the best criteria for recognizing reactive gastric cardiac–type mucosa rather than Barrett’s esophagus or Barrett’s esophagus with dysplasia (see Fig. 36-8C). Dysplastic Barrett’s epithelium typically also shows loss of goblet cell mucin and other features of cytoplasmic differentiation, but the glandular compartment is characteristically more atypical than the surface. This is in sharp contrast to the opposite pattern in reactive gastric mucosa, where the glands tend to be very bland and the surface markedly atypical. Mitotic activity is also highest in the regenerative glandular compartment of Barrett’s metaplastic epithelium, similar to the regenerative compartment of intestinal epithelium elsewhere in the gastrointestinal tract. This is quite different from the regenerative mitotic region of gastric cardiac–type mucosa, located in the mid or neck region of gastric mucosa, as discussed earlier. The cytologic atypia in reactive gastric cardiac–type mucosa tends to be uniform across all of the affected nuclei, whereas dysplastic Barrett’s nuclei tend to show much more pleomorphism. Reactive gastric nuclei usually are not as hyperchromatic as dysplastic Barrett’s epithelium, but this often depends on the type of fixative and processing used and is therefore a somewhat less reliable criterion. As in all areas of diagnostic pathology, it is not always possible to differentiate reactive gastric cardiac–type mucosa from Barrett’s esophagus with dysplasia or even HGD. In this case, a diagnosis of “atypical glandular epithelium of uncertain origin (gastric versus Barrett’s) with alterations indefinite for dysplasia” can be made, along with the request for additional biopsy specimens after aggressive medical management to attempt to eliminate the obscuring reactive inflammatory change.

Baseline Atypia in Barrett’s Regenerative Glands Another issue of great importance in the overdiagnosis of dysplasia in Barrett’s esophagus is that Barrett’s metaplastic epithelium has a baseline and characteristic glandular atypia that is negative for dysplasia.42 This is especially true when the metaplastic glands are viewed in comparison with the frequently admixed nonmetaplastic gastric cardiac or gastric fundic glands (see Fig. 36-5). The pathologist needs to see enough cases of metaplastic Barrett’s epithelium to gain an appreciation for the spectrum of this baseline glandular atypia that is negative for dysplasia. The major distinguishing factor between this and dysplastic or indefinite Barrett’s epithelium is maturation to the surface. This feature cannot be overemphasized.

High-Grade Dysplasia Versus Carcinoma When HGD develops, architectural distortion may reach a point at which the diagnosis of carcinoma is impossible to exclude with certainty on the basis of a superficial biopsy. This occurs when glands grow in a cribriform or dense “backto-back” pattern, when they are closely packed together, or when dilated glands with luminal necrotic debris are present. HGD in the setting of an ulcer is another very serious risk factor for carcinoma. In such cases, a diagnosis introduced by the late Dr. Rodger Haggitt, and now in wide use, is appropriate, namely, “high-grade dysplasia with marked distortion of glandular architecture; invasive adenocarcinoma cannot be excluded” (Fig. 36-13). When numerous individual invasive cells, or sheets of malignant-appearing cells, or angulated infiltrative and abortive glands infiltrate the lamina propria, or a never-ending gland pattern is observed, adenocarcinoma that is at least intramucosal may be diagnosed (Fig. 36-14). If a well-defined desmoplastic stroma can be identified separate from inflammatory or ulcer stroma, the diagnosis of invasive adeno-

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

Squamous Overgrowth

FIGURE 36-15 Barrett’s adenocarcinoma that has at least submucosal invasion, as indicated by the surrounding desmoplastic stroma. (Hematoxylin and eosin.)

carcinoma that is at least submucosal can be established (Fig. 36-15). Although these last two diagnostic categories (HGD and intramucosal adenocarcinoma) are easily defined on the printed page, application of these criteria can be quite challenging. Now that ablative therapies are entering the therapeutic armamentarium for Barrett’s neoplasia, and that a few groups have published natural history data on dysplasia in Barrett’s esophagus showing that continued endoscopic surveillance can be a safe option for HGD, especially incident HGD (see later), the precise distinction between HGD and intramucosal, or at least submucosal, invasive adenocarcinoma is becoming ever more important. Prior to ablative options or the natural history data, esophagectomy was the standard of care for diagnoses of HGD or worse. This is now changing with the advent of less invasive therapies and the knowledge that HGD may not inexorably progress to adenocarcinoma. Despite the increasing importance of distinguishing HGD from adenocarcinoma on biopsy specimens, only limited interobserver and intraobserver variability data exist on this distinction.68 In our experience, this interface in the morphologic spectrum of neoplastic progression in Barrett’s esophagus is among the most challenging, and serious additional study is warranted. Preliminary data from seven experienced gastrointestinal subspecialty pathologists at the Cleveland Clinic, including myself, indicate that the histologic distinction between HGD and worse disorders on biopsy samples is very unreliable.71 This calls into serious question any management decisions based on this distinction. Occasionally, adenocarcinoma in Barrett’s esophagus may be so well differentiated that invasion cannot be diagnosed histologically in biopsy specimens. This type of cancer can only be recognized by the presence of invasion below the muscularis mucosae on resection specimens. Because biopsy specimens are superficial and usually include only the mucosa and a small amount of submucosa, if any, a diagnosis of carcinoma on biopsy may not be possible in such cases. However, if multiple samples are taken according to a standard protocol, one or more will usually reveal the correct diagnosis.

Successful antireflux therapy can eliminate or reduce the intensity of reactive changes secondary to inflammation that may be misinterpreted as dysplasia. Successful medical or surgical antireflux therapy may also be associated with some downward migration of the squamocolumnar junction and with the development of squamous “islands” within the Barrett’s segment. Complete regression of all Barrett’s epithelium rarely occurs. Prior biopsy sites, proton pump inhibitor therapy, and ablative therapies are also associated with squamous islands. Such squamous overgrowth may cause an underestimation of the endoscopic extent of Barrett’s mucosa, because metaplastic epithelium may persist beneath squamous re-epithelialized areas in Barrett’s esophagus.72,73 The magnitude of this problem is beginning to emerge and does not appear to represent a serious concern. Unpublished data from a large randomized trial of photodynamic therapy (138 patients and >23,000 biopsies) versus an omeprazole-only plus continued surveillance control arm (70 patients and >10,000 biopsies) indicate no differences in squamous overgrowth between cases and controls. This was true on either a per-biopsy (31% versus 33%) or a per-patient (1.2% versus 2.2%) basis. Furthermore, the most advanced histologic diagnosis was never found to be concealed beneath squamous overgrowth but rather was always identified on surface Barrett’s mucosa, using four-quadrant biopsies every 2 cm throughout the Barrett’s segment. The grading of dysplasia in metaplastic epithelium with squamous overgrowth remains uncharted territory. I approach the issue as follows: bland metaplastic epithelium beneath squamous mucosa can be classified as negative for dysplasia, and severely crowded and cytologically severely atypical glands with loss of nuclear polarity can be recognized as HGD or invasive carcinoma. However, the squamous overgrowth obscures the identification of surface maturation, so that the distinction between low-grade dysplasia and indefinite for dysplasia cannot be reliably made. My colleagues and I classify biopsy specimens in this indefinite to low-grade dysplasia part of the spectrum beneath squamous mucosa all as indefinite for dysplasia. In addition to the squamous overgrowth phenomenon, most patients taking proton pump inhibitors develop parietal cell protrusions, or peculiar tongue-like projections or blebs of parietal cell cytoplasm into fundic gland lumina, and a few will develop fundic gland polyps.74,75

Flow Cytometry DNA content flow cytometry has been extensively evaluated in the study of neoplastic progression in patients with Barrett’s esophagus. The prevalence of DNA aneuploidy and increased 4N (G2/tetraploid) and S-phase fractions increases with increasing histologic grade.70,76 DNA aneuploidy can be detected in paraffin-embedded mucosal biopsy specimens and may help determine the significance of epithelial alterations in negative, indefinite, and even possibly the low-grade dysplastic biopsy categories.76 It appears to be adjunctive, but experts in this field do not recommend that it replace histology.80 Once the histologic diagnosis of HGD has been made, DNA flow cytometry adds no additional prognostic informa-

411

412

Section 4 Gastroesophageal Reflux and Associated Conditions

tion. The late Dr. Rodger Haggitt noted additional insights into neoplastic progression that are afforded by DNA flow cytometry in his excellent review on Barrett’s esophagus.42 Of historical note, Dr. Haggitt provided 15 years of detailed and exacting histologic data for the Seattle Barrett’s project,69,70,76,80 during which time he single-handedly provided the histologic gold standard diagnoses for these studies on well over 54,000 biopsy specimens.

Specific Genetic Abnormalities in Barrett’s Esophagus Although many genetic abnormalities have been documented in Barrett’s esophagus, these tend to correlate with advancing histologic grades of neoplastic progression (i.e., the more advanced the histology, the more numerous and frequent the genetic abnormalities). However, to date, long-term, prospective studies are virtually nonexistent to determine the potential clinical utility of these markers. No genetic marker has ever been shown to be a better predictor of cancer than histologic neoplastic progression, and, in particular, HGD.42 Despite research that genetic alterations in TP53 may be predictive of cancer risk, neither this nor any other genetic alteration to date has been documented to be more powerful or more cost effective than histologic detection of dysplasia, which parenthetically is also routinely available. Despite intensive studies investigating the diagnostic reproducibility of histologic diagnoses in Barrett’s esophagus,68 no reproducibility studies exist regarding genetic biomarkers of cancer risk. There has never been to my knowledge a single patient who was referred for esophagectomy or any other high-risk therapy for anything other than a pathologic diagnosis of HGD or cancer in Barrett’s esophagus. This may change, but the current standard of care continues to rely on morphology.

Significance and Management of Dysplasia Management of the patient with dysplasia complicating Barrett’s esophagus presents a difficult task. The options for HGD are the most controversial and have recently broadened from esophagectomy alone to also include ablative therapies, endoscopic mucosal resection, and continued intensive biopsy surveillance. Published clinical management guidelines exist,46 which are partially data driven but still largely empirical.

Focal High-Grade Dysplasia Two studies with significant patient numbers and length of follow-up have investigated the significance of focal versus extensive HGD, hypothesizing that focal disease may have a lower risk of progression to carcinoma and thus may be followed conservatively with continued intensive biopsy surveillance. Focal HGD was arbitrarily defined but in essence consists of a limited extent of disease (five or fewer glands of HGD in one biopsy sample)77,78 from adequately sampled Barrett’s esophagus segments according to the Seattle protocol. The results and conclusions are conflicting. The Mayo Clinic group found that diffuse HGD had a 3.7-fold increased cancer risk in comparison with focal HGD (P = .02). On the other hand, the Cleveland Clinic group, who followed all of

these patients to esophagectomy as an added strength of that study, found no difference in cancer risk using the same definition of focal HGD. In the Cleveland Clinic series, adenocarcinoma was present in 5 of 7 (72%) patients with focal disease compared with 19 of 34 (54%) with diffuse disease (P = .68). The presence of incident or prevalent disease was not addressed by these studies and may explain some of the discrepancies (see later). However, the answer on the issue of focal HGD remains uncertain at the present time but may predict a more favorable outcome.

Natural History of High-Grade Dysplasia and Continued Surveillance Until very recently, insufficient numbers of patients with dysplasia had been followed for a long enough period and using adequate numbers of biopsy specimens to achieve a high enough degree of diagnostic confidence to determine the natural history of dysplasia in Barrett’s esophagus. Pertinent questions with direct impact on patient management include whether all dysplasia inevitably progresses to cancer and over what time period. To begin to answer these critical questions, two large cohorts of patients with Barrett’s esophagus have now been followed extensively using similar rigorous highdensity surveillance biopsy protocols. One program is at the Hines Veterans Administration Hospital in Chicago,79 and the other is at the University of Washington in Seattle.80 Based on these important data, we are now beginning to understand the natural history of neoplastic progression in Barrett’s esophagus, on which to base data-driven management decisions. At the Hines VA Hospital program,79 a total of 1099 patients were diagnosed with Barrett’s esophagus over a 20year period. A total of 79 (7.2%) patients in the cohort had HGD, of which 34 had prevalent HGD (present at the first endoscopy) and 45 had incident HGD (detected during surveillance and therefore probably earlier in its natural history). Of the 75 who remained without detectable cancer during the first year of intensive biopsy surveillance, called “the hunt,” only 12 patients (16%) developed cancer over a mean of 7.3 years of surveillance. Furthermore, 11 of the 12 who were compliant with the surveillance protocol were considered cured of their early cancers by surgical or ablative therapy. In the 15-year prospective longitudinal study at the University of Washington,80 a total of 327 patients were evaluated by rigorous surveillance endoscopy for progression from their baseline alterations. Median surveillance intervals were 24.4 months for baseline negative histology, 18.2 months for indefinite histology, 15.7 months for low-grade dysplasia, and 4.6 months for HGD. Mean and medium follow-up periods were 3.9 and 2.4 years, respectively. Overall, a total of 42 patients developed cancer and 35 of these cancers developed within 5 years of the first endoscopy. No patient with negative, indefinite, or low-grade dysplasia with normal flow cytometric studies developed cancer within 5 years; this patient subset made up two thirds of the entire cohort. This indicates that surveillance intervals could be lengthened to 5 years for this majority subset, using the

Chapter 36 Histopathology of Gastroesophageal Reflux Disease and Barrett’s Esophagus

Seattle protocol, including baseline intensive biopsies and flow cytometry with expert preparation and interpretation of both. The benefits of extension of the surveillance interval are multiple. No biomarkers were more powerful or diagnostically significant than the histologic detection of neoplastic progression and HGD in particular, which had a 5-year cancer incidence of 59%. Detailed information on the cancers and their curability was not provided by Reid and colleagues.

Incident Versus Prevalent High-Grade Dysplasia The data from the Seattle cohort, like the Hines VA data, show that lesions with less than HGD (metaplasia, indefinite, and low-grade dysplasia) have a very low rate of progression over even greater than 10 years of follow-up, if they do so at all. These data further document that HGD itself does not inexorably progress to cancer. In fact, the data demonstrate that one can increase the margin of safety if continued surveillance is performed for incident rather than prevalent HGD. Specifically, incident HGD is discovered after the patient has been under surveillance with adequate biopsy sampling for some period of time. The Seattle group showed that this type of HGD has only about a 20% progression rate to cancer after 6 years of follow-up.80 An even lower rate was observed in the Hines VA trial.79 This is undoubtedly because incident HGD is diagnosed closer to the time at which it actually begins and is therefore much more likely to be early in its natural history, which probably takes many years to decades to progress to cancer if it does so at all. Prevalent HGD, on the other hand, is diagnosed at the patient’s first endoscopy, when the patient is symptomatic in some way. As such, prevalent HGD has therefore been present for an unknown and likely much longer period of time than incident HGD. Prevalent HGD would thus be expected to have a higher rate of progression to cancer, because it is further along in its neoplastic pathway than incident disease. Such was indeed the case in both the Seattle and Hines VA cohorts.79,80 Based on these natural history data, we finally are beginning to form a rational basis for patient management. Especially in the setting of patients who may be poor surgical candidates, or in those who have incident HGD, continued intensive surveillance is now an option with growing acceptance, albeit one that must be pursued with great vigilance and care. The reproducibility of the discussed Seattle and Chicago data and the nontrivial issue of the transportability of this type of intensive surveillance from the research setting into private practice both remain serious and important caveats at this time.

High-Grade Dysplasia as a Marker for Unsampled Carcinoma When HGD is detected for the first time in a patient with Barrett’s esophagus, early re-endoscopy with multiple biopsies should be done to rule out a coexisting early carcinoma.79,80 Extensive sampling of the mucosa is essential, because early carcinomas may not be recognizable to the endoscopist. Accordingly, it has been suggested that sampling should be increased to four samples taken every 1 cm (as

opposed to every 2 cm) in the Barrett’s segment in patients with HGD.70 Because HGD is rare in unselected patients with Barrett’s esophagus, and because most pathologists therefore do not have the opportunity to study many examples of it, the general pathologist would be wise to seek a second opinion regarding the diagnosis of HGD before surgery is undertaken. The patient with early carcinoma invading the lamina propria (intramucosal) or submucosa and who has a reasonable estimated operative risk is a candidate for esophagectomy because these lesions have a low, but significant, potential to metastasize (~5% with positive nodes).81 Resection of these early carcinomas provides the opportunity for cure.82,83 In patients with an endoscopic biopsy diagnosis of HGD, but not carcinoma, and who undergo esophagectomy, a relatively high prevalence of carcinoma in resected specimens has been reported.83 This has led to the conclusion that HGD is a “marker” for coexisting adenocarcinoma, but this conclusion has been based on very small numbers of patients with limited numbers of biopsy specimens obtained, many of whom already had advanced disease because they had symptoms or endoscopic findings suggestive of carcinoma. When thorough endoscopic biopsy sampling is carried out by experienced gastroenterologists and pathologists according to the protocol outlined earlier, specimens appear to accurately determine whether a clinically unsuspected carcinoma accompanies the dysplasia.77,79,80 Following a policy of continued surveillance for HGD has produced a high cure rate for early adenocarcinoma in Barrett’s esophagus but at the same time has avoided esophagectomy in patients with HGD who may never develop carcinoma (as many as 41%-84%).79,80

Endoscopic Ablative Therapy Nonsurgical methods for the treatment of patients with HGD are being explored, and with very promising results. These include photodynamic therapy (PDT), multipolar electrocoagulation, argon plasma coagulation, laser ablation, cryotherapy, and endoscopic mucosal resection.84-93 PDT has received approval by the U. S. Food and Drug Administration after completion of a phase III prospective randomized placebo-controlled trial of 208 patients treated for Barrett’s esophagus with HGD.89 Results demonstrate that after a mean follow-up of more than 2 years (of a total of 5 years soon to be published), 77% of those randomized to PDT had complete ablation of their HGD (versus 39% in the control arm of patients with HGD treated only with acid suppression and intensive surveillance, P < .0001). Furthermore, the PDT patients in this trial had a greater than twofold reduction in cancer development (13% of the PDT group developed intramucosal cancer and underwent esophagectomy versus 28% of the control arm, P < .006).89 A high, albeit treatable, stricture rate was the most significant complication of PDT ablation therapy.89

BARRETT’S ADENOCARCINOMA More than 75% of esophageal adenocarcinomas are located in the distal esophagus, as a consequence of their development from GERD and Barrett’s esophagus.94 At the time of

413

414

Section 4 Gastroesophageal Reflux and Associated Conditions

diagnosis, approximately half of Barrett’s adenocarcinoma patients have nonresectable or distant metastatic disease.94 The pathologist must diligently stage Barrett’s adenocarcinoma for the greatest depth of invasion, nodal, and margin status (proximal, distal, and radial/adventitial). A new aspect of the depth invasion involves the recent recognition that the muscularis mucosae splits into two or more layers in the great majority of resected Barrett’s esophagus specimens (unpublished data by S. C. Abraham and colleagues). The significance of invasion into these acquired layers beneath the original muscularis mucosae is unknown. Angiolymphatic invasion must also be reported, as should tumor grade. Welldifferentiated tumors are gland forming in their entirety and exhibit only low to moderate nuclear pleomorphism and atypia. Moderately differentiated tumors consist of admixed gland-forming and invasive single cells, cell clusters, and abortive glands, with moderate to marked cytologic pleomorphism. Poorly differentiated tumors lack gland formation and have moderate to marked nuclear abnormalities. Finally, the surgical pathology report for a resected Barrett’s adenocarcinoma should include the completeness of resection of not only the neoplasm but also the predisposing Barrett’s segment, because complete resection of both is the curative goal of this surgery.95

DIFFERENTIAL DIAGNOSIS OF BARRETT’S ESOPHAGUS The differential diagnosis of Barrett’s esophagus and its neoplastic complications of dysplasia and adenocarcinoma includes intestinal metaplasia and neoplasia of the gastric cardia extending into the esophagus.96,97 The causes of intestinal metaplasia of the cardia include GERD, as in Barrett’s

esophagus, but also intestinalized gastritis, most commonly caused by Helicobacter pylori gastritis. Biopsies of the gastric body and antrum, along with serologic and other assays of H. pylori infection, are necessary to determine the etiology in a given patient. Identification of specialized metaplastic epithelium within the tubular esophagus proximal to a neoplastic lesion serves to document its association with Barrett’s esophagus. Adenocarcinoma arising in ectopic gastric mucosa within the upper esophagus (inlet patch) is extremely rare and can be differentiated from adenocarcinoma arising in Barrett’s esophagus, because ectopic mucosa is separated from the stomach by a large zone of intact squamous mucosa and Barrett’s mucosa is in the distal esophagus and characteristically is contiguous with the stomach.

COMMENTS AND CONTROVERSIES This extensive review of the histopathology of GERD and Barrett’s esophagus is invaluable to the clinician. We depend on the eye and experience of our colleagues in pathology to direct therapy for our patients with GERD and its complications. I have the good fortune of working with Dr. Bronner and six other pathologists who are experts in esophageal diseases. I have learned most at the microscope, reviewing difficult cases. The treating physicians must understand what the pathologist is “really saying,” and they must be aware that each pathologist has his or her threshold for diagnosis. A close working relationship and frequent communication between the clinician and pathologist are necessary for excellent patient care. There is no substitute for seeing the histopathology for yourself, guided by your esophageal pathologist. T. W. R.

chapter

MEDICAL THERAPY FOR BARRETT’S ESOPHAGUS

37

Richard E. Sampliner

Key Points ■ Keystone of medical therapy is proton pump inhibition for control

of reflux symptoms. ■ Interval surveillance endoscopy is performed to detect high-grade

dysplasia and early adenocarcinoma. ■ Staging of early adenocarcinoma with endoscopic ultrasound

(nodal involvement) and endoscopic resection (T classification) determines if a patient is a candidate for endoscopic therapy. ■ Endoscopic therapy includes endoscopic resection and ablation for high-grade dysplasia and early adenocarcinoma.

HISTORICAL NOTE Although described more than 50 years ago by a British surgeon, the definition of Barrett’s esophagus has evolved over the decades from “extensive columnar lining”1 to an abnormal columnar-appearing lining with intestinal metaplasia by biopsy2 (Fig. 37-1). This definition means that the contemporary diagnosis of Barrett’s esophagus requires an endoscopy with biopsies. Intestinal metaplasia is a change in the lining of the distal esophagus that looks like the intestine, that is, with goblet cells. Intestinal metaplasia is the precursor lesion for adenocarcinoma of the esophagus, the most rapidly rising incidence cancer in the United States and Western Europe.3 The medical therapy for Barrett’s esophagus is aimed at controlling the underlying gastroesophageal reflux symptoms and preventing or detecting early esophageal adenocarcinoma (EAC). In this chapter a review is presented of the pharmacologic therapy of reflux, the role of surveillance endoscopy for detection of high-grade dysplasia (HGD) and early EAC, the staging of early EAC, and endoscopic therapy for HGD and early EAC.

PROTON PUMP INHIBITOR THERAPY The foundation of the medical therapy for Barrett’s esophagus is the use of proton pump inhibitors (PPIs) to eliminate reflux symptoms. Symptom control usually results in endoscopic healing of erosive esophagitis. It is well documented that the control of symptoms does not mean normalization of interesophageal pH.4 Even high-dose twice-daily PPI therapy does not control esophageal acid exposure in 25% of patients with Barrett’s esophagus.5 Even though heartburn symptoms can usually be well controlled, the same is not true of volume reflux, that is, regurgitation.6 A recent, interesting, and important finding is the reduction in the development of dysplasia by PPI therapy. This has

been documented in two prospective cohorts analyzed retrospectively. An Australian cohort of 350 patients was followed for 1145 patient-years; 15% had low-grade dysplasia (LGD) at baseline and 71% were men.7 A U.S. series had 236 veterans with 1170 patient-years of follow-up. None had dysplasia at baseline, and 98% were men (El-Serag et al, 2004).8 In the former study, patients not using a PPI for 2 or more years after the diagnosis of Barrett’s esophagus had 5.6-fold risk of developing LGD (95% CI 2.0-5.7). In the latter study, the use of PPI after the diagnosis of Barrett’s esophagus was independently associated with a reduced risk of developing dysplasia, with a hazard ratio of 0.25 (95% CI, 0.13-0.47). These data provide an indication for PPI treatment of all patients with Barrett’s esophagus.

ENDOSCOPIC SURVEILLANCE Although lacking an evidence base of randomized trials, endoscopic surveillance is the current standard practice in the United States. The goal is the prevention of cancer or early case detection of EAC and appropriate therapy to improve on the poor global survival of EAC (5-year all-case survival in 1997 of 13%).9 Currently, endoscopic surveillance is driven by the grade of dysplasia2 (Table 37-1)—an unequivocal neoplastic change in the cytology and architecture of the glandular tissue. If no dysplasia is present in the first two endoscopies, then repeat endoscopy every 3 to 5 years is sufficient. If low-grade dysplasia is found, it should be reconfirmed as the worst lesion; then annual endoscopy is sufficient. The management of HGD is controversial and needs to be individualized based on the patient’s risk aversion to cancer and to operative mortality, comorbidity, the stage of the lesion, and the local institutional expertise. The options include intensive surveillance (every 3 months), endoscopic therapy (see later), and esophagectomy. Endoscopic surveillance assumes that erosive esophagitis is healed to reduce the impact of inflammation on the reading of dysplasia. This is best achieved with PPI therapy. Any mucosal irregularity should be sampled first and placed in a separate container. The biopsy protocol is four-quadrant every 2 cm for no dysplasia and for LGD. For HGD, four-quadrant biopsies should be performed every 1 cm. A survival advantage of endoscopic surveillance has been documented in a community-based population and in a Surveillance Epidemiology and End Results (SEER)/ Medicare database (Corley et al, 2002).10,11 The leading edge of technologic research in Barrett’s esophagus is the real-time optical recognition of dysplasia for 415

416

Section 4 Gastroesophageal Reflux and Associated Conditions

FIGURE 37-2 Autofluorescence imaging using a prototype endoscope demonstrates high-grade dysplasia in purplish area at left. (FROM KARA MA, 2005. AVAILABLE AT WWW.GASTROHEP.COM. BLACKWELL PUBLISHING.)

FIGURE 37-1 Endoscopic image of Barrett’s esophagus.

TABLE 37-1 Barrett’s Surveillance Dysplasia

Documentation

Follow-up EGD

None

2 EGDs with biopsy

3-5 years

LGD

Highest grade on repeat endoscopy

1 year until no dysplasia

HGD

Repeat EGD with biopsy to rule out cancer/document HGD Obtain expert pathologist’s confirmation

Mucosal irregularity—endoscopic resection Individualize intervention

EGD, esophagogastroduodenoscopy; HGD, high-grade dysplasia; LGD, low-grade dysplasia. Adapted from Sampliner RE, Practice Parameters Committee of the ACG: Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 97:1888-1895, 2002.

better biopsy targeting or ultimately endoscopic resection or ablation. Technologies with available prototypes include high-resolution endoscopy, narrow band imaging, confocal microscopy, and autofluorescence (Fig. 37-2). More developmental techniques include Raman spectroscopy, optical coherence tomography, and combinations of different imaging techniques. All of these tools to optically recognize dysplasia require validation, and some require further development before clinical use. They will provide a much easier recognition and localization of dysplasia than an arbitrary random, although systematic, biopsy protocol.

STAGING OF EARLY ESOPHAGEAL ADENOCARCINOMA Accurate staging is essential to determine if the lesion is appropriate for endoscopic therapy, that is, superficial and without regional lymph nodes. Staging is currently best achieved with endoscopic resection for the depth of wall invasion (T classification) and endoscopic ultrasonography

(EUS) for lymph node involvement. Endoscopic resection was developed by Japanese investigators for the treatment of early gastric cancer and has been adapted to lesions in the esophagus, including EAC and Barrett’s esophagus (Ell et al, 2000).12 The large tissue sample obtained by endoscopic resection enables more accurate and direct tumor classification than EUS.13 Both the depth of the specimen and the margin can be evaluated for the presence of neoplasia. A T1b lesion, with cancer extending through the muscularis mucosae to the submucosa, has a 25% chance of positive nodes, whereas a lesser-invading lesion has less than a 5% chance. EUS with fine-needle biopsy is the most accurate method to establish nodal status. A patient with a T1b or N1 lesion is a candidate for esophagectomy, not endoscopic therapy. The disease is already likely to be systemic.

ENDOSCOPIC THERAPY The largest reported therapeutic trial in Barrett’s esophagus is the multicenter randomized photodynamic therapy (PDT)

Chapter 37 Medical Therapy for Barrett’s Esophagus

SUMMARY The medical therapy for Barrett’s esophagus is rapidly evolving. Potent acid reduction medications, PPIs, have been documented to reduce dysplasia. The detection of dysplasia and early EAC is improving with more thorough biopsy surveillance protocols. Techniques are emerging for the optical detection of dysplasia. High-volume centers are demonstrating the usefulness of endoscopic therapy in staging (endoscopic resection) and therapy (endoscopic resection, photodynamic therapy) of HGD and early EAC. The medical therapy for Barrett’s esophagus has progressed from symptom relief and surveillance endoscopy to more accurate staging and endoscopic intervention. Future endeavors are sure to refine these approaches and improve patient outcome.

COMMENTS AND CONTROVERSIES

FIGURE 37-3 Endoscopic appearance of endoscopic resection site done with a cap-assisted device. (REPRINTED FROM LARGHI A, LIGHTDALE CJ, MEMEO L, ET AL: EUS FOLLOWED BY EUR FOR STAGING OF HIGH-GRADE DYSPLASIA AND EARLY CANCER IN BARRETT’S ESOPHAGUS. GASTROINTEST ENDOSC 62:16-23, 2005, WITH PERMISSION FROM THE AMERICAN SOCIETY FOR GASTROINTESTINAL ENDOSCOPY.)

trial using porfimer sodium as a photosensitizer in 208 patients with HGD and Barrett’s esophagus.14 HGD was centrally read by expert pathologists. PDT eliminated HGD in 77% of patients versus 35% without PDT (P < .001). In 2 years, EAC developed in 13% of the PDT arm versus 28% in the control arm (P = .006). Thirty percent of patients developed strictures, and photosensitivity reactions were common. This is the only form of therapy other than esophagectomy documented to reduce the development of EAC. Unfortunately, a 5-year follow-up is not available. Argon plasma coagulation for HGD has also demonstrated a reduction in the development of EAC compared with historical controls. PDT using the oral photosensitizer 5-aminolevulinic acid is another modality that can maintain long-term (median, 37 months) disease control (cancer free). This was accomplished in 66 patients with HGD or early EAC, and none of the patients died of Barrett’s esophagus neoplasia (Pech et al, 2005).15 Endoscopic resection has also been used for “disease control” (Fig. 37-3). Criteria have been established for lesions favorable for endoscopic resection: less than 2 cm in greatest diameter, moderately to well differentiated, and lacking lymphatic and vascular invasion (Ell et al, 2000).12 The EUS role in staging has already been discussed. Although never directly compared with esophagectomy and lacking as long a follow-up, favorable intermediate-term results have been accomplished with endoscopic therapy for HGD and early EAC. This has been accomplished without operative morbidity and mortality.

Medical therapy for Barrett’s esophagus is important for symptom control in three fourths of patients who experience symptoms. More importantly, medical therapy with PPIs treats esophagitis, permitting more accurate interpretation of surveillance biopsies. Distinguishing the inflammatory and reparative changes in the acutely injured columnar-lined esophagus from early neoplastic changes (lowgrade dysplasia) is most difficult for the pathologist. Maintenance of an uninflamed esophageal mucosa as well as symptom control should be the goals of medical therapy. The ability of any antireflux therapy to reverse dysplasia is debatable. This is a reflection of many problems with sampling at esophagoscopy and histopathologic differentiation of regeneration from dysplasia. Unlike esophageal EUS, which provides clinical classifications of T and N (cT, cN), the combination of endoscopic mucosal resection of superficial cancers and esophageal EUS-directed fine-needle aspiration (EUS-FNA) of regional and nonregional lymph nodes produces pathologic T and N classifications (pT, pN). This is an excellent combination of invasive evaluations for superficial cancer before definitive therapy. The addition of fused computed tomography and positron emission tomography (CT/PET) for clinical assessment of distant metastases (cM) provides superb staging information for treatment decisions. However, this practice is not applicable for all patients. Endoscopic mucosal resection by present techniques in the setting of “long-segment” Barrett’s esophagus is challenging. Mucosal ablation, although theoretically appealing, cannot presently offer total ablation of the Barrett segment and destroys the ability to pathologically classify tumors. Therefore, endoscopic mucosal resection and mucosal ablation are therapeutic alternatives in those patients who are not candidates or do not want surgery or continued surveillance. My hope is that we will develop better therapies than endoscopic mucosal resection, ablation, fundoplication, or esophagectomy for patients with Barrett’s esophagus. T. W. R

KEY REFERENCES Corley DA, Levin TR, Habel LA, et al: Surveillance and survival in Barrett’s adenocarcinomas: A population-based study. Gastroenterology 122:633-640, 2002. ■ A small cohort with surveillance-detected Barrett’s esophagus–associated esophageal adenocarcinoma had lower-stage disease and improved survival compared with patients with cancers not surveyed in a population-based study.

417

418

Section 4 Gastroesophageal Reflux and Associated Conditions

Ell C, May A, Gossner L, et al: Endoscopic mucosal resection of early cancer and high grade dysplasia in Barrett’s esophagus. Gastroenterology 118:670-677, 2000. ■ The technique of endoscopic resection is described as well as the criteria for a favorable lesion identified in a prospective series of 64 patients. El-Serag HB, Aguirre TV, Davis S, et al: Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett’s esophagus. Am J Gastroenterol 99:1877-1883, 2004. ■ This study of 236 veterans with Barrett’s esophagus and no dysplasia at baseline, followed for 1170 patient-years, demonstrated a 75% reduction in the development of dysplasia in proton pump inhibitor users versus nonusers.

Pech O, Gossner L, May A, et al: Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett’s cancer and high-grade intraepithelial neoplasia. Gastrointest Endosc 62:24-30, 2005. ■ Sixty-six patients with high-grade dysplasia and early esophageal adenocarcinoma were treated with photodynamic therapy with 5-aminolevulinic acid. All but 1 patient achieved a complete response with a median follow-up of 37 months. None died of cancer.

chapter

38

SURGICAL THERAPY FOR THE COLUMNAR-LINED ESOPHAGUS

NON-NEOPLASTIC BARRETT’S ESOPHAGUS Thomas W. Rice Key Points ■ Esophageal physiology and hiatal anatomy are most severely

impaired in patients with columnar-lined esophagus. ■ Surgery in these patients is more complex and less successful than

in patients with uncomplicated GERD. ■ Antireflux surgery is indicated in patients with symptoms or com-

plications not controlled by aggressive medical therapy. ■ Regression of columnar lining or prevention of carcinoma is not

assured by repair. ■ Resection is indicated in the patient with an end-stage esophagus,

a perforated ulcer, an undilatable stricture, high-grade dysplasia, or invasive carcinoma.

The columnar-lined or Barrett esophagus is an extremely advanced and difficult-to-manage form of gastroesophageal reflux disease (GERD). Treatment of GERD in patients with columnar-lined esophagus does not reliably or completely restore normal squamous epithelium, may not eliminate or prevent complications, and does not do away with the need for continued endoscopic surveillance for cancer. Patients with columnar lining of the esophagus have very disturbed esophageal physiology. Lower esophageal sphincter (LES) pressures are lowest in these patients. Mean LES pressure was 5 mm Hg in patients with a columnar-lined esophagus, 9 mm Hg in those with uncomplicated GERD, and 17 mm Hg in controls.1 LES pressure is similarly significantly disturbed in patients with severe esophagitis and columnarlined esophagus.2-4 Patients with columnar-lined esophagus frequently have low amplitude and nonperistaltic esophageal contractions.5,6 As a result of inflammation, patients with columnar-lined esophagus and severe esophagitis have a higher incidence of failed peristalsis than both control subjects and patients with mild esophagitis.3 Similarly, mean peristaltic amplitude is lower than in control subjects or those with mild esophagitis.4,7 Slow esophageal transit results in poor clearance of refluxed gastric contents.8 Radionuclide esophageal emptying was reported to be impaired in 50% to 80% of patients with columnar-lined esophagus.7,8 Acid and bile reflux is most severe in patients with a columnar-lined esophagus. The proportion of time esophageal pH was less than 4 was 28% for patients with columnarlining, 14% for those with uncomplicated GERD, and 3% for controls.1 Similar 24-hour pH monitoring abnormalities were

reported by Gillen and associates,2 Robertson and associates,9 and Fiorucci and associates.10 Reflux patterns are different, and nocturnal reflux occurs more frequently in patients with columnar lining.9 Twenty-four-hour bile monitoring, using the Bilitec 2000 probe, detected esophageal bile during 43% of the recording period in patients with columnar-lined esophagus, 12% in patients with uncomplicated GERD, and 2% in controls.11 Patients with columnar lining have the most aberrant anatomy of the esophagogastric junction. Hiatal hernia of 2 cm or greater was detected in 96% of patients with columnar lining and in 42% of controls with or without esophagitis.12 The diaphragmatic hiatus is larger in patients with columnar lining than in patients with hiatal hernia alone: 3.5 cm versus 2.2 cm.12 Esophageal injury sufficient to cause replacement of the mucosal lining of the esophagus also results in edema, spasm, and eventual fibrosis of the mucosa, submucosa, and muscularis propria. A columnar-lined esophagus is frequently associated with peptic esophageal stricture and esophageal shortening. Columnar lining has been reported in 44% of patients with esophageal strictures.13 The prevalence of columnar lining was reported to be nearly equal in patients with and without strictures: 25% of patients with strictures and 24% of patients without.14 Long segment (>3 cm) columnar lining is predictive of a short esophagus.15 A short esophagus is strongly suspected by a history of peptic stricture or dilation and a large or irreducible hiatal hernia. All of these factors are often reported in patients with a columnar-lined esophagus. The patient with a columnar-lined esophagus represents the utmost challenge to the esophageal surgeon. Standard repairs are subject to extremely high late failure rates (up to 64% at 100 months) when physiologic assessment is used instead of symptom control.16 A 15% to 21% failure rate of antireflux operations has prompted some surgeons to consider esophageal lengthening (Collis gastroplasty) and total fundoplication (Nissen) as mandatory in all patients with a columnar-lined esophagus.17 Thoughtful consideration of the indications for surgical management of the columnar esophagus is important for successful surgical treatment in these most demanding of GERD patients. Presence of a columnarlined esophagus is not in itself an indication for surgery.

INDICATIONS FOR ESOPHAGEAL REPAIR Symptom Control The principal objective of medical treatment for GERD is control of acid reflux and regurgitation. Potent acid suppression with proton pump inhibitors also decreases the volume 419

420

Section 4 Gastroesophageal Reflux and Associated Conditions

of gastric secretion, reducing these typical symptoms in many patients. However, the relief of symptoms does not ensure the normalization of physiologic testing and does not eliminate reflux.18-20 To further complicate this treatment strategy, the patient with a columnar-lined esophagus may be relatively asymptomatic.21,22 Reconstructing the esophageal hiatus, reinforcing the LES, and restoring the intra-abdominal length of the esophagus eliminates reflux and relieves typical symptoms. One of the few predictors of successful surgical outcome is the control of typical symptoms with proton pump inhibitors.23,24 Inability to control acid reflux with adequate medication suggests that GERD may not be the primary source of symptoms. The surgeon must be cautious of the patient with unmanageable acid reflux who seeks urgent surgery because symptoms are refractory to all medical therapy. In the patient with columnar-lined esophagus, control with medical therapy alone is more difficult for regurgitation than for acid reflux.25 An excellent indication for surgery is persistent regurgitation despite good control of acid reflux with proton pump inhibitors. For these patients, an effective LES is needed to control volume regurgitation. Another important indication for surgery develops when patients who have had good symptom control with proton pump inhibitors require escalating doses or multiple changes of these drugs because symptoms become intractable. Some patients experience disabling side effects with these medications and may require surgery for symptom relief. The young patient whose symptoms are well controlled with medication but who has a life-long requirement for proton pump inhibitor therapy may be a candidate for surgery. The cost of longterm medical therapy for severe esophagitis will eventually equal the cost of surgery. Although extremely variable, the time when these costs are equal has been estimated to be between 1.4 years to 10 years of medical therapy.26,27 In the patient with the columnar-lined esophagus, the frequent need for complex surgical repairs, higher failure rates of surgery, and the need for more aggressive medical therapy may greatly alter the break-even point and thus the indication for surgery. Laparoscopic antireflux surgery has been aggressively applied to patients with columnar-lined esophagus. It has been reported that short-term results have been excellent with no deterioration in extended follow-up (2-5 years).28 Parilla and colleagues29 reported excellent or good symptom control with laparoscopic antireflux surgery in 91% of patients with columnar-lined esophagus at a median follow-up of 5 years. However, difficulty in obtaining complete relief of typical symptoms in patients with a columnar-lined esophagus with antireflux surgery is evident in the report of Oelschlager and colleagues.30 Resolution of typical symptoms of heartburn, regurgitation, and dysphagia was reported in 70% (heartburn), 75% (regurgitation), and 64% (dysphagia), respectively; improvement in 26%, 9%, and 18%, respectively; and no improvement in 4%, 16%, and 18%, respectively, at a median of 40 months’ follow-up. Surgical results for atypical symptoms, such as chest pain, chronic cough, asthma, hoarseness, globus sensation, halitosis, laryngitis, sore throat, or enamel loss, cannot be predicted, and patients have about a 50% chance of relief.23

These symptoms alone, particularly if they do not respond to proton pump inhibitor therapy, are not indications for surgery.

Complications Ulcer Barrett’s initial description in 1950 of the entity that bears his name focused on peptic ulceration arising in the columnar-lined esophagus (Barrett, 1950).31 He noted that these ulcers were large, deeply penetrating, often circumferential, and difficult to treat. During surveillance, 46% of patients acquired an esophageal ulcer complicating a columnar-lined esophagus and 24% had an episode of gastrointestinal bleeding.32 However, only 2% of acute gastrointestinal bleeding is due to esophageal ulcers and a minority of patients, 40%, have esophagitis.33 In surgical series, true Barrett’s ulcers are seen in less than 15% of patients with columnar-lined esophagus.34 The addition of proton pump inhibitors to medical therapy has improved treatment of esophageal ulcers that complicate a columnar-lined esophagus; however, healing is slow and not always complete.35 In patients not responding to therapy, gastroplasty and fundoplication have successfully healed recalcitrant ulcers and arrested acute bleeding.34,36 Primary suture repair and fundoplication is not advised for perforation complicating Barrett’s esophagus.37

Stricture The complaint of dysphagia in a patient with a columnarlined esophagus necessitates a comprehensive endoscopic examination and vigorous biopsy protocol to exclude malignant degeneration. Peptic strictures are a common complication and have been reported in one third to one half of patients with a columnar-lined esophagus.34,38 Medical therapy that includes a proton pump inhibitor and aggressive and repeated dilation is the treatment of choice for strictures complicating benign columnar-lined esophagus. If therapy fails, aggravating factors such as pill-induced injury, scleroderma, motility disorders, and so on must be excluded. Surgery is indicated for failure of medical therapy, inability to heal esophagitis, and recurrence of strictures after adequate dilation and medical therapy and in those patients who are not candidates for chronic medical therapy. A shortened esophagus is a certainty in these patients, necessitating a complex repair with both gastroplasty and fundoplication. Surgical outcome is significantly poorer than in the uncomplicated patient.

Metaplasia-Dysplasia-Carcinoma Sequence Length of columnar lining minimally increases during surveillance (Cameron and Lomboy, 1992).39 An early report suggested that in some patients columnar lining was completely reversible with surgery.40 However, antireflux therapy rarely produces significant regression and in 75% of patients the length of columnar lining is unchanged after surgery.41 In endoscopic follow-up of 33 (66%) patients who had laparoscopic antireflux surgery, 3 (9%) had a decrease in columnar lining by more than 2 cm.42 The variability of repeated endoscopic length measurements is significant and in the range of

Chapter 38 Surgical Therapy for the Columnar-Lined Esophagus

many reported length regressions of columnar-lined esophagus. For every 1 cm of columnar-lined esophagus there was a reported 0.15-cm increase in absolute difference between first and second endoscopies (Dekel et al, 2003).43 The range of variability in the endoscopic measurement of length was ±1.4 to 1.6 cm. Using a life-sized esophageal model with 10 inserts of varying length, 240 measurements were made by 12 endoscopists (Guda et al, 2004).44 The reported mean difference (SD) between measured and actual was 1.1 cm (±1.7 cm). Length was overestimated by 47% and underestimated by 37%. Intra-observer variability was 0.5 cm, for only fair agreement (κ = 0.40 [fair]). The authors concluded “Accurate measurement of length at endoscopy is difficult even under ideal conditions. Intra-observer agreement is fair, but results obtained by different endoscopists are widely divergent. Small improvements in the length of Barrett’s epithelium observed in some clinical trials could be because of chance of therapeutic effect.” Because surgery does not significantly reduce the length of columnar lining, the possibility for regression of the length of columnar lining is not an indication for surgery. Regression of low-grade dysplasia to columnar metaplasia has been reported.30,42,45-47 Differentiation of acute inflammatory and regenerative changes from low-grade dysplasia is most difficult (Skacel et al, 2000).48 Reported regression of low-grade dysplasia can also be explained by elimination of inflammation and promotion of repair by effective surgical treatment of GERD. In the selective follow-up of 23% of patients with columnar-lined esophagus who had antireflux surgery, 36% were reported to have some histologic regression at follow-up esophagoscopy compared with preoperative histology.47 Surprisingly, the authors report complete regression to normal squamous lining in 1 (7%) medically treated patient. In analysis of any histologic regression there was a significant difference between surgical and medical therapy (P < .03). However, surgical and medical groups had a similar prevalence of regression from intestinal metaplasia to normal squamous epithelium—14% versus 7%, respectively (P = .7). The 7% regression seen in medically treated patients may be an indication of the range of error in endoscopic assessment, tissue sampling, and pathologic interpretation. In endoscopic follow-up after antireflux surgery histologic regression was reported to occur in 56% (30 of 54) of patients with shortsegment columnar lining but no patient with long-segment columnar lining.30 However, no sampling protocol was reported, there were no criterion for number or interval of endoscopies, outside gastroenterologists performed endoscopy and biopsy, and only “equivocal” biopsy specimens were reviewed at the study institute. The reported regression may be due to lackadaisical endoscopic assessment. In endoscopic follow-up of 33 (66%) patients who had laparoscopic antireflux surgery, 9 (27%) had regression and 4 (12%) had progression to high-grade dysplasia.42 Reported regression is rarely complete, and reported prevalence of histologic regression is within the range of errors in detection and diagnosis. Some surgeons believe the rate of progression of metaplasia to dysplasia and carcinoma is less for surgery than for medical therapy. The projected dysplasia- and cancer-free survival at 9 years was 100% for 15 surgical patients compared with 58% for 82 medical patients.49 However, Ortiz

and associates20 reported similar rates of malignancy regardless of therapy. For patients receiving medical therapy, cancer was projected for one patient for each 127 patient-years of follow-up and 1 in 160 patient-years after surgery. In this report, the study populations were small, there were few events, and the only surgical patient who progressed had a failed operation. Late occurrence of cancer after surgery is usually associated with recurrence of GERD and confirmed by 24-hour pH monitoring.41 Early development of highgrade dysplasia or cancer after successful surgery may be the result of irreversible activation of the dysplasia-carcinoma process just before surgery. Of 113 patients, 2 patients developed adenocarcinoma and 1 had high-grade dysplasia within 39 months of surgery, suggesting undetected dysplasia or carcinoma at the time of operation (McDonald et al, 1996).50 A meta-analysis of 34 reports found a similar incidence of malignant degeneration in Barrett’s patients (P = .3) treated surgically with fundoplication (3.8 cancers/1000 patientyears) and medically (5.3 cancers/1000 patient-years) (Corey et al, 2003).51 The incidence of esophageal adenocarcinoma in GERD patients with fundoplication (0.72 cancers/1000 patient-years) was not different from that of GERD patients treated medically (0.4 cancers/1000 patient-years) in the analysis of the Veterans Affairs cohort study.52 The adjusted hazard ratio for cancer in the fundoplication patients was 1.88 (95% CI, 0.7-5.03). In 59,439 years of follow-up of control patients no esophageal cancer developed. When comparing these data with that of Corey and colleagues51 the rate of progression to cancer is 10-fold less for GERD patients than for patients with a columnar-lined esophagus. The evidence that successful surgery induces quiescence in the columnar-lined esophagus is lacking. Prevention of dysplasia and carcinoma, albeit a potential benefit of surgery, is not presently an indication for surgery.

INDICATIONS FOR RESECTION Penetrating ulcers and undilatable strictures are principal indications for resection of the nonmalignant columnar-lined esophagus.53 Multiple failed operations that result in an endstage, nonfunctioning esophagus require resection and reconstruction. The need for long-term surveillance in the young patient is never an indication for resection unless periodic endoscopy and biopsy are not available. High-grade dysplasia is intraepithelial carcinoma where cytologically malignant cells are present in the epithelium without invasion of the basement membrane. The difficulty in differentiating high-grade dysplasia from intramucosal carcinoma and the occurrence of intramucosal carcinoma or more invasive cancers in 50% of patients undergoing resection for high-grade dysplasia has caused many surgeons to consider the detection of high-grade dysplasia an indication for resection. Surgery must be accomplished with an operative mortality less than 1% and a low morbidity.54,55 Once invasion of the basement membrane is confirmed, there is no controversy that resection is indicated.

SUMMARY Development of a columnar-lined esophagus is an irreversible complication of GERD in the vast majority of patients. Patients are at increased risk of complications and develop-

421

422

Section 4 Gastroesophageal Reflux and Associated Conditions

ment of carcinoma. Surgery in these patients is more complex and less successful than in patients with uncomplicated GERD. Antireflux surgery is indicated in patients with symptoms or complications not controlled by aggressive medical therapy. Regression of columnar lining or prevention of carcinoma is not assured by repair. Resection is indicated in the patient with an end-stage esophagus, a perforated ulcer, an undilatable stricture, high-grade dysplasia, or invasive carcinoma. KEY REFERENCES Barrett NR: Chronic peptic ulcer of the oesophagus and “oesophagitis.” Br J Surg 38:175, 1950. Cameron AJ, Lomboy C: Barrett’s esophagus: Age, prevalence and extent of columnar epithelium. Gastroenterology 103:1241, 1992.

BARRETT’S CARCINOMA Toni E. M. R. Lerut Key Points ■ Intestinal metaplasia is the hallmark of Barrett’s metaplasia. ■ Progression from low-grade to high-grade dysplasia and carci-

■

■

■ ■

noma is the result of a number of genetic and epigenetic events leading to loss of stability. However, the eventual progression to Barrett’s carcinoma through this sequence of events remains unpredictable. Endomucosal resection has become the treatment of choice for high-grade dysplasia/T1a carcinoma in short-segment Barrett’s metaplasia, provided complete resection is possible. The value of such treatment for high-grade dysplasia/T1a cancer in longsegment Barrett’s metaplasia is under evaluation. In T1b carcinoma, because of the distinct tendency of lymph node involvement, esophagectomy combined with a proper lymphadenectomy remains the standard therapy. In advanced (stage III and non-distant metastatic stage IV) carcinoma surgery remains the mainstay of treatment. The benefit of combined therapeutic regimens (induction or adjuvant chemotherapy and/or radiotherapy) remains to be proven.

Historically, the diagnosis of Barrett’s esophagus or columnar-lined esophagus required the presence of metaplastic mucosa more than 3 cm into the tubular esophagus (i.e., above the gastroesophageal junction [GEJ]). Beside the fact that such a segment is not easy to correctly identify, it has become clear that the hallmark of Barrett’s esophagus is the intestinal type of metaplasia. Indeed, of the three histologic subtypes of Barrett’s metaplasia—cardiac, fundic, and intestinal—only the last has a significant premalignant potential, owing to its higher rate of cellular proliferation. Histologically, the specialized intestinal metaplasia is confirmed by the presence of the characteristic goblet cells. Short-segment (<3 cm) Barrett’s metaplasia is more common than the long-segment type.1 It is now well documented that intestinal metaplasia in Barrett’s esophagus progresses to low-grade dysplasia (low-

Corey KE, Schmitz SM, Shaheen NJ: Does a surgical antireflux procedure decrease the incidence of esophageal adenocarcinoma in Barrett’s esophagus? A meta-analysis. Am J Gastroenterol 98:2390, 2003. Dekel R, Wakelin DE, Wendel C, et al: Progression or regression of Barrett’s esophagus—is it all in the eye of the beholder? Am J Gastroenterol 98:2612, 2003. Guda NM, Partington S, Vakil N: Inter- and intra-observer variability in the measurement of length at endoscopy: Implications for the measurement of Barrett’s esophagus. Gastrointest Endosc 59:655, 2004. McDonald ML, Trastek VF, Allen MS, et al: Barrett’s esophagus: Does an antireflux procedure reduce the need for endoscopic surveillance. J Thorac Cardiovasc Surg 111:1135, 1996. Skacel M, Petras RE, Gramlich TL, et al: The diagnosis of low-grade dysplasia in Barrett’s esophagus and its implications for disease progression. Am J Gastroenterol 95:3383, 2000.

grade intraepithelial neoplasia), high-grade dysplasia (highgrade intraepithelial neoplasia), intramucosal carcinoma, and, finally, more invasive cancer. This sequence is driven by a number of genetic and epigenetic events leading to a loss of genetic stability. These events are believed to be triggered by reflux of acid and gastroduodenal contents. Prolonged reflux results in tissue damage initially affecting the superficial layers of the squamous epithelium that are replaced by immature squamous cells. The mechanism whereby focal areas of squamous epithelium are replaced by metaplastic epithelium is not well understood, but this metaplastic columnar epithelium is seen as an end stage of reflux disease and its intestinal component as a precursor of malignant degeneration. The progression of Barrett’s esophagus to cancer remains unpredictable. In fact, most patients with Barrett’s metaplasia will not develop dysplasia; and if the dysplasia appears, it does not necessarily progress into a high-grade dysplasia or eventually become a true carcinoma. It is therefore difficult to estimate the real incidence of patients with Barrett’s metaplasia who will develop cancer. More than a substantial number of those patients will remain asymptomatic, a particular feature of Barrett’s metaplasia.2 Nevertheless, it is well accepted that the incidence of esophageal adenocarcinoma is on the rise, increasing 5% to 10% each year, a phenomenon noted since the 1970s particularly in the Western hemisphere. This rate of increase is greater than that of any type of cancer and has been linked to the increase of gastroesophageal reflux, the aging population, and the decline of Helicobacter pylori infection, which is believed to be a protective factor in the Western world (Pera et al, 2005).3 Most high-volume centers today report a shift from squamous cell cancer to adenocarcinoma, with the latter reaching up to 80% of the overall number of cases seen. As a result of these events much interest has been generated in setting up screening programs, mostly by using upper gastrointestinal endoscopy. It has become clear that the at-risk population for Barrett’s metaplasia in general is too broad. Too many cancers occur outside of this population because many patients with Barrett’s metaplasia will never seek medical attention because they are asymptomatic. To make a screening program practical and not too expensive it needs to focus on the highest risk groups (i.e., white men older than age 50

Chapter 38 Surgical Therapy for the Columnar-Lined Esophagus

years). In patients with no dysplasia, endoscopy is performed every 2 to 3 years after two negative endoscopies. If lowgrade dysplasia is detected, endoscopy is performed on a 6month basis for 1 year and thereafter yearly.4 In the case of high-grade dysplasia the strategy is more controversial, given the highly variable natural history of the disease. Although the overall risk of developing a cancer is estimated to be 50 to 350 times higher,5 other studies reported that over a period of several years of follow-up only a few patients will develop an invasive carcinoma. One such study indicated that only 16% of the patients with high-grade dysplasia progressed to cancer over a mean period of 7.3 years of follow-up.6 As a result, the Practice Parameters Committee of the American College of Gastroenterology recommend intensified follow-up. In any case, the diagnosis of high-grade dysplasia needs to be reconfirmed by an expert pathologist. A further surveillance every 3 months is proposed (Sampliner, 2002).4 Biopsy recommendations are for four-quadrant biopsy at 2-cm intervals and at all sites of mucosal abnormalities after reflux esophagitis is medically controlled with proton pump inhibitors. In the presence of high-grade dysplasia the protocol changes into four-quadrant biopsy every 1 cm.6,7 The diagnostic accuracy can be improved by using chromoendoscopy (i.e., with toluidine blue), which allows more precise identification of areas of high-grade dysplasia. Further improvement is expected from the development of optical techniques (e.g., high-resolution endoscopy, fluorescence spectroscopy, optical coherence tomography, lightscattering spectroscopy) that are being tested for their ability to distinguish between benign and malignant disease.7 Much is expected from future developments of biomarkers, which may identify patients with Barrett’s metaplasia who are at risk for development of adenocarcinoma because of genetic or other risk factors.8,9

TREATMENT Over the past 10 to 15 years a number of new therapeutic approaches have been developed and used in patients with early tumors detected in the course of surveillance for Barrett’s metaplasia. For patients with more advanced tumors combined modality therapy has been widely used, and in some centers there is a tendency to treat such patients with definitive chemoradiotherapy as primary treatment. As to the surgical therapy, controversy persists in regard to the extent of resection and the extent of lymph node dissection.

Early Carcinoma Better diagnostic and interventional endoscopic techniques have led to a search to develop methods to endoscopically remove areas of Barrett’s metaplasia and thus avoid surgery. Several techniques have been developed (e.g., photodynamic therapy, argon plasma coagulation, endoscopic mucosal resection). Photodynamic ablation therapy is becoming increasingly used, particularly in North America. This method uses laser activation of light-sensitive drugs that concentrate in preneoplastic tissue. The drug most commonly used is porfimer

sodium (Photofrin), which is injected intravenously and then activated by a neodymium : yttrium-aluminum-garnet (Nd : YAG) laser, which causes it to release damaging oxygen free radicals. Overholt and Panjehpour10 reported their results on 103 patients presenting with low-grade metaplasia, high-grade metaplasia, or early cancer treated with this method. Mean follow-up on 82 patients was 58.5 months. Of the 65 patients with high-grade dysplasia, 94% were cured. Three patients developed subsquamous carcinoma. Subsquamous metaplastic but nondysplastic epithelium was found in another 4.9%. For the whole series, strictures occurred in 18% of the patients treated with one session and in 50% with two treatments of photodynamic therapy, for an overall incidence of 30%. Overall intention to treat success rates were 92.9%, 77.5%, and 44.4%, respectively, for lowgrade dysplasia, high-grade dysplasia, and early cancer. The high rate of post-treatment stenosis can be reduced by decreasing the amount of light used. This is at the price of more (up to 30%) residual high-grade dysplasia or T1 carcinoma in Barrett’s metaplasia.11 The use of 5-aminolevulinic acid as a photosensitizer in photodynamic therapy may increase the efficacy of the treatment. Pech and colleagues12 reported a 90% long-term remission of high-grade dysplasia. In patients with mucosal cancer the disease-free survival was 68% over a median follow-up period of 37 months. Beside the risks of recurrence and the high incidence of stenosis another major criticism is the lack of pathologic staging because this method provides no histologic material for study. This may lead to undertreatment of those patients who have submucosal invasion that was clinically understaged.13 Perhaps photodynamic therapy may play a role as an adjunct of endomucosal resection in removing residual zones of metaplastic tissue.14 An argon plasma coagulator is a noncontact electrocoagulation device that provides high-frequency monopolar current to the tissue by a flow of ionized argon gas. Argon plasma coagulation usually is performed by coagulating linear strips of tissue by moving the tip of the probe from the gastroesophageal junction to the upper segment of the metaplasia. Several successive sessions are required, especially when dealing with circumferential Barrett’s esophagus, based on the rationale that leaving intervening bridges of untreated mucosa will reduce the likelihood of stricturing. In a study by Van Laethem and coworkers15 involving a series of 10 patients (7 with high-grade dysplasia, 3 with adenocarcinomas), 8 showed complete regression. One patient progressed to cancer, and 1 had persistent high-grade dysplasia. Perforation and death have been reported.16 Attwood and associates17 reported a series of 29 patients with high-grade dysplasia who were treated with argon plasma coagulation. Twenty-two had complete regression, and 4 developed cancer at a mean follow-up of 37 months. Besides the persistent risk of progression and the risk of perforation the major drawback of this method again is the nonavailability to provide histologic material as well as the development of buried Barrett’s epithelium underneath the regenerated squamous epithelium.

423

424

Section 4 Gastroesophageal Reflux and Associated Conditions

As a result, today more attention is directed toward endomucosal resection (Fig. 38-1). Endoscopic mucosal resection techniques are done with or without suction. The lesion can be removed in a single piece or in several fragments (piecemeal). Removal of high-grade dysplasia or early cancer in one single specimen is ideal to improve the completeness of the resection and to allow a better assessment of the depth and resection margins at pathologic examination.18 As a result, the risk of missing an invasive cancer (i.e., invading the submucosa [T1b]) in patients with pathologically proven high-grade dysplasia or T1a carcinoma after endomucosal resection decreases substantially. A study by Vieth and coworkers19 dealing with 742 endoscopic resection specimens obtained from 326 patients showed complete resection in 74.5% of patients. In 26.8% this was obtained after one attempt, and in 47.8% after repeated sessions. Most of the lesions (84%) contained lowto high-grade dysplasia or T1a tumor. Carcinoma infiltrating the submucosal layer was found in the remaining 16%. After a mean follow-up of 21 months, data on outcome in 64 patients treated with endomucosal resection showed recurrence or metachronous carcinomas in 14% of the cases. These lesions were again successfully treated by repeat endomucosal resection. The same group reported complete remission in 43 of 44 patients for patients presenting with high-grade dysplasia/early cancer in short-segment Barrett’s esophagus using a combination of endomucosal resection and photodynamic therapy or argon plasma coagulation.20

A

B

D

E

As mentioned earlier, the addition of photodynamic therapy to endomucosal resection seems to be useful to prevent further recurrence. Nijahwan and Wang21 reported their results using this combined approach in a series of 24 patients, obtaining a R0 resection in all patients, who remained free of disease at 12 months’ follow-up. Nevertheless, a recurrence rate of 25% to 30% during the first 3 years has to be expected after endomucosal resection for high-grade dysplasia or early esophageal cancer. Another important conclusion from literature data is that to obtain optimal results, referral of patients to centers with appropriate infrastructure and technical expertise is of paramount importance (Ell et al, 2007).22 The highest quality endoscopic equipment (e.g., magnification endoscopy, chromendoscopy) is required for optimal detection of subtle mucosal abnormalities. Technical expertise and familiarity with the different available technologies for endoscopic ablation of tissue is equally important, as well as reliable histologic evaluation of biopsy and resection specimens. Despite these advances in endoscopic techniques and technologies the debate between those who advocate esophagectomy versus those who advocate endoscopic ablation is ongoing. This debate is fueled not only by the fact that recurrence or metachronous lesions are to be expected in over 25% of the cases but also by the risk of underestimating depth of tumor and, consequently, the increasing risk of lymph node involvement.23,24 Several studies comparing the pathologic staging after esophagectomy for clinically staged high-

C

FIGURE 38-1 Endoscopic mucosal resection of early adenocarcinoma in Barrett’s esophagus. A, Endoscopic image of the target lesion (arrow) using white light endoscopy. B, Computed virtual endoscopy (FICE) image of the lesion. The target lesion (red circle) can clearly be demarked from the surrounding mucosa and contains dense neovascularization. Notice the increased irregular capillary network proximal to the lesion (arrow) that showed high-grade dysplasia on biopsy. C, Methylene blue (0.5%) staining in the same esophagus, showing minimal uptake beside the lesion (arrow) but absence of uptake in the lesion and in the area of the irregular capillary network. D, Endoscopic image after mucosal resection of the target lesion and surrounding area. The underlying submucosa and muscular layer is blue after submucosal injection of saline containing 0.01% methylene blue. E, Pathology specimen of the target lesion. Pathology showed an m3 mucosal adenocarcinoma with negative lateral and deep section margins. (COURTESY OF DR. R. BISSCHOPS, UNIVERSITY HOSPITAL, LEUVEN.)

Chapter 38 Surgical Therapy for the Columnar-Lined Esophagus

metastasis and micrometastasis in patients with tumors limited to the mucosa (i.e., high-grade dysplasia and T1a intramucosal carcinomas). Mainly three approaches have been developed over the recent years. The first consists of a more limited partial esophagectomy and resection of the cardia followed by an interposition of a pedicled jejunal segment to restore continuity (Merendino operation). Results of the largest series using this technique have been published by Stein and associates.32 Seventy patients staged as uT1 by endoscopic ultrasonography and with no evidence of lymphatic spread underwent surgery. There was no evidence of lymphatic spread into surrounding lymph nodes on pathologic examination. At a median follow-up of 69 months, 5-year survival was 83.4%. Quality of life assessment showed no evidence of gastroesophageal reflux and good-to-excellent swallowing function in 92% of the patients. A second approach for high-grade dysplasia or intramucosal cancer with no visible lesions consists of vagal nerve–sparing subtotal esophagectomy and reconstruction with a longsegment coloplasty. The aim of the vagal nerve–sparing esophagectomy and the use of colon instead of stomach is to preserve the alimentary track function and innervation. This operation is performed through a transhiatal approach. Banki and colleagues,35 in a series of 15 patients, reported a complete absence of diarrhea and a statistically significantly lower incidence of dumping (6.6%) as compared with the standard resection followed by either colon interposition (30% and 60%) or gastric pull-up. Gastric emptying was normal in 70% of the patients. A third approach has been described by Luketich and colleagues36 consisting of a totally thoracoscopic and laparoscopic subtotal esophagectomy followed by a gastric tubularization and cervical anastomosis. In a large series of 222 patients treated by this technique the 30-day operative mortality was 1.4%. Survival at 40 months in a group of 45 patients with high-grade dysplasia was 96%, and for stage I tumors it was 70%. The major criticism in relation to these different minimally invasive techniques is the absence of

grade dysplasia have indicated the presence of unforeseen T1a or T1b carcinoma in up to 50% of the cases (Rice et al, 1998).25-28 Another critical issue in this respect is whether intramucosal carcinoma (T1a) can be correctly discriminated from submucosal cancer (T1b) before surgery. Certainly, 20-mHz echo endoscopies can be helpful to solve this problem,23 but these endoscopic ultrasonographic systems are not readily available in most centers. The importance of the (in)ability to discriminate T1a from T1b tumors25-27 relates to the reported incidence of 25% to 30% lymph node involvement in T1b tumors. The incidence of lymph node involvement increases with the depth of invasion into the three different layers of the submucosa (sm1, sm2, sm3). An analysis from the Leuven database showed lymph node involvement in 12% of sm1, 25% of sm2, and 57% in sm3 tumors. Mostly, the number of lymph nodes is limited; thus, most surgeons will argue that this group benefits most from surgery with curative intent. At this point the results of esophagectomy for high-grade dysplasia and early Barrett’s cancer are to be considered as the gold standard against which all other therapeutic modalities have to be compared. Data from the literature show a very high 5-year survival. Several studies show a 5-year cancer-free survival for high-grade dysplasia and T1a of over 90% (Rice, 2006),27,29-32 and these results are also confirmed by our data (Fig. 38-2). Outcome after esophagectomy for T1b is very much dependent on the absence or presence of involved lymph nodes. Again, in the absence of lymph node involvement 5year survival curves may exceed 90%. In case of lymph node involvement the 5-year survival curves are between 40% and 60%.31-33 Despite these excellent oncologic results the major drawback is the high morbidity rate (20%-45%) and a small but significant mortality rate (1%-5%).34 In an effort to further decrease these mortality and morbidity figures as well as to match the challenge posed by endoscopic ablation techniques, recent attention has been paid to develop less-invasive surgical interventions. The rationale for this is based on the virtual absence of lymph node

1 0.9 0.8

97.8%

90.3%

87.7%

87.7%

Survival

0.7 0.6 0.5

46.4%

0.4 0.3

pT1a (n
47)

0.2

pT1b-LN Neg. (n
23)

0.1

pT1b-LN Pos. (n
9)

22.2%

0 0

12

24

36

48

60 72 Months

84

96

108

120

FIGURE 38-2 Early (T1) adenocarcinoma in Barrett’s esophagus. Cancer specific survival in T1a and T1b. (DATA FROM THE LEUVEN DATABASE 1990-2003.)

425

426

Section 4 Gastroesophageal Reflux and Associated Conditions

thorough lymphadenectomy and the resulting lack of precise staging and the potentially higher incidence of recurrent disease affecting the final outcome. A study by Westerterp and associates29 on 120 patients presenting with high-grade dysplasia or early T1 tumors and operated on by a transhiatal approach showed a mean number of resected nodes of 8.6. Locoregional recurrence was 5.8%, distant metastasis was 6.7%, and a combination of both in another was 2.5%. A matched group of 120 patients from the Leuven database but operated on with a transthoracic approach showed a mean number of resected nodes of 17.8. Locoregional recurrence occurred in 2.3%, distant metastasis in 3.9%, and a combination of both in 1.6%. Recurrence-free 5-year survival in node-positive patients was 33% and 46%, respectively, in these two studies. The recently introduced concept of sentinel node detection may possibly contribute to assess whether there may be a need to perform more extended lymphadenectomy. The mapping of sentinel nodes is optimal when using blue dye and a radiocolloid. Preliminary results seem to indicate reliable detection in early cancer with a detection rate, and a correct prediction of, nodal status in up to 90% of the patients.37 The technique, however, has a steep learning curve, and further experience is needed before drawing conclusions.

Advanced Carcinoma As the tumor penetrates deeper into or through the muscular wall of the esophagus the incidence of lymph node involvement will increase.28 For T3 tumors the incidence of node involvement is up to 80%. Lymph node involvement is considered to be the most important prognostic factor. From these findings, however, different attitudes toward therapeutic strategies have emerged, resulting in controversy about the optimal access route and extent of resection and lymphadenectomy for adenocarcinoma of the distal third and GEJ. This controversy is mainly fueled by different opinions regarding lymph node involvement. Some consider lymph node involvement equal to systemic disease; therefore, outcome of treatment is determined at the time of diagnosis.38 Removal of the primary tumor, aiming at relief of symptoms, is the primary goal of resection, with systematic removal of involved lymph nodes being judged of no benefit. The operation typically is performed by transhiatal resection, which restores continuity by gastric pull-up and cervical esophagogastrostomy. Such operations today can be performed equally effectively using video-assisted thoracoscopic surgery.36 Many authors, however, believe that the natural course of the disease can be influenced by a wide peritumoral or an en bloc dissection combined with meticulous lymphadenectomy of the upper abdominal compartment (so-called D2 lymphadenectomy).39-41 According to Feith and associates,42 lymph flow in carcinoma of the distal esophagus and GEJ is mainly directed downward toward the lymphatic nodes around the celiac

axis. In their analysis, lymph node metastases were rarely found in the paratracheal, subcarinal, or midthoracic paraesophageal lymph nodes. As a result this group favors a “radical” transhiatal lymphadenectomy and en bloc lymphadenectomy of the distal posterior mediastinum and upper abdominal compartment. The evaluation of the results on mortality and morbidity and outcome after esophagectomy for Barrett’s carcinoma is difficult because often information on selection, indication, and characteristics of the treated population are missing. Several studies, however, indicate an overall 5-year survival that ranges between 23% and 59%.42-46 A recent analysis on the results of esophagectomy in 184 patients with Barrett’s carcinoma treated in Leuven between 1990 and 1999 showed an overall 5-year survival of 53.6%. According to the lymph node status, a highly significant difference of 75.1% 5-year survival for node-negative versus 27.8% for node-positive disease was noticed (Fig. 38-3A). Tumors located in the distal esophagus did better than tumors located at the GEJ, mainly as a result of a higher percentage of stage III and IV tumors in the latter group. Five-year survival in Barrett’s carcinoma according to the TNM classification was 27% for stage III and 22% for stage IV) (see Fig. 38-3B). Because obviously the majority of patients presenting with advanced stage of the disease will die of metastatic disease even after an intervention with curative intent, efforts are now directed to multimodality regimens in the hope to improve outcome. Today most published phase II trials dealing with adenocarcinoma are without specification in relation to the presence of Barrett’s carcinoma. Neoadjuvant chemotherapy is generally well tolerated but does not improve the results in terms of local control nor survival when compared with surgery alone. Chemoradiation showed a survival benefit in only one trial, but in this trial the surgical arm had unusually low survival.47 From the available data only patients showing a complete response seem to benefit from neoadjuvant therapy.48,49 Unfortunately, it remains impossible to predict which patients will respond. The introduction of positron emission tomography may help differentiate early response from nonresponse after a first cycle of chemotherapy.50 Based on such a protocol, Siewert and associates51 compared the outcome of 154 patients with T3/T4 Barrett’s carcinomas responding to induction therapy to the outcome in a historical series of 138 patients after primary resection of T3/T4 Barrett’s carcinoma. Whereas the first group had a 5-year survival of approximately 50%, the second group had a 5-year survival of only 25%. These results seem to confirm the results obtained for treatment of adenocarcinoma in general. More recently, attention has been directed to postoperative adjuvant therapy in cancer of the esophagus and GEJ, particularly the combination of chemotherapy and radiation therapy. Rice and associates52 published their data on a series of 31 patients with locally advanced esophageal carcinoma of the esophagus who received postoperative chemoradiotherapy. Of these 31 patients, 26 had an adenocarcinoma. The results were compared with those of an historical group of 52 patients treated with surgery alone. Four-year survival was

Chapter 38 Surgical Therapy for the Columnar-Lined Esophagus

FIGURE 38-3 Advanced adenocarcinoma in Barrett’s esophagus. A, Cancer-specific survival according to lymph node status. B, Cancer-specific survival in stage III and IV disease. (DATA FROM THE LEUVEN DATABASE 1990-1999.)

1 0.9

75.1%

0.8 0.7

72.8%

Survival

0.6 0.5 0.4

27.8%

0.3 0.2

Barrett LN () (n
91) Barrett LN () (n
93)

0.1

12.1%

0 0

12

24

36

48

60

72

84

96

108

120

Months

A 1 0.9

Stage III (n
45) Stage IV (n
31)

0.8

Survival

0.7 0.6 0.5 0.4 26.0%

0.3

10.8%

23.3%

0.2 0.1

8.7%

0 0

12

B

24

36

48

60

72

84

96

108

120

Months

44% versus 17%, favoring the combined therapy. Obviously further confirmation by randomized controlled trials is mandatory.

SUMMARY The treatment of high-grade dysplasia and carcinoma in patients with Barrett’s metaplasia remains an extremely complex and challenging topic. The rapidly evolving diagnostic tools as well as the introduction of endoscopic ablation techniques may have a dramatic impact on the therapeutic strategy. Further experience will indeed show whether endoscopic ablation techniques will become the gold standard in high-grade dysplasia and T1a tumors, especially when new imaging technology will allow more precise discrimination between T1a and T1b tumors. Whether so-called minimally invasive surgery, in particular vagal nerve–sparing resection without lymphadenectomy, will become a valid alternative awaits further proof. Perhaps sentinel node detection may become an important tool in this respect. In more advanced cancer, surgery remains the mainstay of the treatment, but it appears that multimodality treatment

regimens, especially chemoradiotherapy, may be beneficial in particular in the subset of responders receiving induction therapy. Adjuvant chemoradiation may become a valuable tool in patients who after primary surgery appear to have more advanced disease at pathologic examination.

COMMENTS AND CONTROVERSIES The columnar-lined esophagus and the metaplasia-dysplasiacarcinoma sequence is a complicated topic. Serious controversy abounds across the entire spectrum of this subject. Because of its importance, Dr. Rice addresses the subject of Barrett’s metaplasia without carcinoma and Dr. Lerut covers the subject of adenocarcinoma in the columnar-lined esophagus. Dr. Rice makes clear the importance of a full investigation in patients with Barrett’s esophagus before embarking on antireflux surgery. He emphasizes that results of repair are not as reliable as in patients without Barrett’s esophagus. The need for continued surveillance is stressed because fundoplication does not facilitate regression of Barrett’s esophagus or prevent subsequent development of adenocarcinoma in the lining of the esophagus.

427

428

Section 4 Gastroesophageal Reflux and Associated Conditions

Dr. Lerut extensively reviews the endoscopic resectional strategies currently available. I believe these are not good options for patients with long-segment Barrett’s esophagus or for those patients with known mucosal cancers. Strictures and perforation are known complications. There is also a risk of squamous mucosa overgrowing a residual submucosal cancer. The various resectional strategies are reviewed. Each has advantages and disadvantages but provide excellent results in the hands of experienced surgeons. Dr. Lerut stresses the importance of appropriate lymph node staging in patients with known cancer. Good nodal staging can be accomplished by the minimally invasive thoracoscopic technique described by Luketich as well as by transhiatal and transthoracic resections. Implicit in both sections of this chapter is the need to have these patients evaluated and treated in centers with the necessary expertise and technology for their proper management. J. D. L.

KEY REFERENCES Ell C, May A, Pech O, et al: Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc 65:3-10, 2007. Pera M, Manterola C, Vidal O, Grande L: Epidemiology of esophageal adenocarcinoma. J Surg Oncol 92:151-159, 2005. Rice TW: Esophagectomy is the treatment of choice for high-grade dysplasia in Barrett’s esophagus. Am J Gastroenterol 101:21772184, 2006. Rice TW, Zuccaro G, Adelstein DJ, et al: Esophageal carcinoma: Depth of tumour invasion is predictive of regional lymph node status. Ann Thorac Surg 65:787-792, 1998. Sampliner RE: Practice Parameters Committee of the American College of Gastroenterology: Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 97:1888-1895, 2002.

chapter

39

BENIGN ESOPHAGEAL TUMORS Andrew F. Pierre

Key Points ■ Benign esophageal tumors are rare. ■ Most are asymptomatic and probably do not require any treatment

other than observation and follow-up. ■ Accurate diagnosis is the key to effective management of benign

tumors. ■ If removal of the tumor is required, then extramucosal resection by

enucleation is usually sufficient.

Benign esophageal tumors are rare, and many are asymptomatic. They will be found with increasing frequency as radiologic and endoscopic investigations become more commonplace, and they may result in significant morbidity if untreated or treated inappropriately. The exact incidence is difficult to determine because so many of these tumors are asymptomatic. In one autopsy series only 90 cases of a benign esophageal tumor were found in nearly 20,000 autopsies over a 50-year period.1 From 11,000 patients complaining of dysphagia, only 15 cases were found in another series.2 Benign tumors probably account for less than 1% of all esophageal tumors and account for less than 10% of all surgically resected esophageal tumors (Seremetis et al, 1976).3 Benign esophageal tumors are probably best classified according to their location within the wall of the esophagus (i.e., intraluminal, submucosal, intramural, or extraesophageal) (Table 39-1). They may also be classified according to their histologic type (i.e., epithelial, nonepithelial, or heterotopic). The smooth muscle leiomyoma is by far the most common benign tumor of the esophagus and is almost always intramural. Extraesophageal congenital cysts and duplications are the second most common lesions, but these are not true neoplasms. Intraluminal esophageal polyps are the next most common tumor overall. All other types are quite rare. Gastrointestinal stromal tumors (GISTs) are well-defined mesenchymal tumors of the gastrointestinal tract that are quite distinct from esophageal leiomyoma and are not discussed extensively here.4 The majority of these benign tumors are located in the middle and lower thirds of the thoracic esophagus. Tumors arising from the cervical esophagus are less common except for the fibrovascular polyps, which are more common in the cervical esophagus.

CLINICAL FEATURES Benign tumors of the esophagus may grow very slowly. The majority are probably asymptomatic. As a tumor enlarges it

may obstruct the esophageal lumen or compress surrounding tissue. There may be spontaneous cessation of growth, and the tumor may not increase in size for many years.5 If it is symptomatic, dysphagia is the most common symptom. It may also be symptomatic because of ulceration and bleeding, pressure effects on surrounding mediastinal structures, or, very rarely, regurgitation of a tumor on a long stalk, potentially leading to airway obstruction.6,7 Fatal asphyxia has been reported from the dramatic regurgitation of a giant fibrovascular polyp. Significant esophageal obstruction is produced only by tumors greater than 5 cm.8 Occasionally, the intramural tumor may completely encircle the esophagus, causing obstruction, and may mimic a cancer or peptic stricture.3 Benign tumors may coexist with other esophageal pathologic processes, such as reflux, achalasia, diverticulum, or cancer. These other findings are more likely to result in symptoms, and the benign tumor is likely an incidental finding.

DIAGNOSTIC TESTS Barium swallow is perhaps the best initial test to evaluate the symptomatic patient (Fig. 39-1). Many benign tumors may be missed by other investigations, such as endoscopy, chest TABLE 39-1 Classification of Benign Esophageal Tumors* Intraluminal Polyps Adenoma Lipoma Fibrovascular polyp Inflammatory polyp Squamous cell papilloma Inflammatory pseudotumor Submucosal Hemangioma Granular cell tumor Neurofibroma, neurinoma Intramural Leiomyoma Gastrointestinal stromal tumor Schwannoma Rhabdomyoma Extraesophageal Cysts and duplications *Many histologic tumor types may occur in multiple layers of the esophageal wall. 431

432

Section 5 Neoplasms

FIGURE 39-1 Barium swallow of an intramural leiomyoma (arrow). Note the smooth surface and clear sharp angles at the upper and lower ends of the tumor.

radiography, or CT. Certain intraluminal tumors may demonstrate altered peristalsis at the level of the tumor or may be interpreted as an ingested foreign body. The mobile nature of the tumor may become apparent on the cineradiographic swallow. Very small tumors are easy to miss on endoscopy, especially when located near the cricopharyngeus muscle, and a good barium swallow is the best way to find these lesions. CT will help define the relationship between the tumor and surrounding structures. Oral contrast agent administration will help to identify smaller lesions, but these may be easily missed with this technique. Other mediastinal, extraesophageal pathology that might lead to dysphagia could be identified by CT (e.g., vascular rings, mediastinal adenopathy, aneurysms, and congenital cysts and duplications) (Fig. 39-2). Chest radiography is of limited value in the era of CT. Endoscopy is essential in ruling out cancer and can help to confirm the diagnosis of a benign lesion. The degree of obstruction can also be assessed at this time. Intramural tumors, such as the leiomyoma, appear as a bulge into the lumen with a completely normal overlying mucosa (Fig. 39-3). Biopsy of intraluminal and submucosal lesions is usually uncomplicated, although hemangiomas may bleed briskly. However, biopsy of intramural tumors (e.g., leiomyoma) is contraindicated because adequate pathologic material to exclude malignancy is impossible to obtain and violation of the mucosal layer may complicate subsequent surgical resection.

FIGURE 39-2 A, Barium swallow in a patient with mild dysphagia: well-defined smooth filling defect with intact mucosa (arrow) at the level of the carina. B, CT scan confirms the presence of extrinsic calcified subcarinal lymph nodes (arrow) as the cause of the abnormal barium swallow.

Chapter 39 Benign Esophageal Tumors

FIGURE 39-3 Endoscopic appearance of esophageal leiomyoma.

Esophageal endoscopic ultrasonography (EUS) may further help in the diagnosis, planning of surgery, and follow-up of these tumors.9 EUS clearly delineates the layers of the esophageal wall involved with the tumor (Fig. 39-4). Ultrasound characteristics of certain tumors are more likely to represent a benign versus a malignant lesion. EUS can help to determine whether an endoscopic approach to resection is feasible or whether the tumor, because of depth of invasion, should be approached in a transthoracic fashion (Dorais and Marcon, 1997).10

LEIOMYOMA Leiomyoma is a benign tumor of smooth muscle that occurs at all levels in the esophagus but more commonly in the mid lower third. It is the most common benign tumor of the esophagus. It can occur at any age but is quite rare in children. Only 2.6% of documented cases have been in children.11 Seremetis and associates reported on 838 collected cases of esophageal leiomyomas (Seremetis et al, 1976).3 Mutrie and colleagues from the Massachusetts General Hospital group reported on 53 patients operated on at their institution over a 40-year period (Mutrie et al, 2005).12 Only 31 of those patients had surgery solely for the resection of their symptomatic leiomyoma. The true incidence is difficult to determine. Shields found 11 cases in 700 autopsies, but none was found in 4000 autopsies done by Daniel and Williams.13,14 Clearly, even the busy esophageal surgeon will only operate on a few of these cases over his or her career. Leiomyoma should be distinguished from leiomyosarcoma and GISTs. The term GIST refers to all mesenchymal tumors of the gastrointestinal tract, including those of smooth muscle cell origin, but recent evidence indicates that most GISTs comprise a group of neoplasms distinct from true leiomyoma and leiomyosarcoma based on immunohistochemical, ultrastructural, and molecular genetic markers.4,15 Pathologists currently classify leiomyoma and GIST as two separate, discrete types of tumors. Leiomyoma is the most common

FIGURE 39-4 An esophageal leiomyoma. Top, EUS of this tumor demonstrates a hypoechoic, homogeneous, well-demarcated tumor with no associated lymphadenopathy. The tumor (L) arises from, and is confined to, the fourth ultrasound layer (arrow). Bottom, A benign leiomyoma arises from, and is confined to, the muscularis propria. EUS, endoscopic ultrasonography. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

mesenchymal tumor of the esophagus but is very rare in other parts of the gastrointestinal tract. In contrast, GIST is common in the stomach and intestines but are rarely found in the esophagus. Leiomyomas commonly arise from the muscularis propria layer of the esophagus and much less commonly from the muscularis mucosae. Very rarely would they present as an extraesophageal lesion. In the review by Seremetis and associates, 97% were intramural, 1% were polypoid intraluminal, and 2% were extraesophageal (Seremetis et al, 1976).3 It is controversial whether leiomyoma can undergo malignant transformation—if it does it is exceedingly rare. However, it can be very difficult to differentiate histologically between a leiomyoma and a leiomyosarcoma. Leiomyomas appear histologically as smooth muscle fibers arranged in whorls of long spindle cells with eosinophilic cytoplasm surrounded by hypovascular connective tissue. Leiomyosarcomas show increased mitotic rate, cellular atypia, pleomorphism, and hyperchromatic nuclei.

433

434

Section 5 Neoplasms

Box 39-1 Indications for Surgical Resection of Leiomyoma ■ Unremitting symptoms ■ Increasing size of tumor during follow-up ■ Need to obtain histologic diagnosis (i.e., clinical diagnosis in

doubt) ■ Facilitation of other esophageal procedures

Most leiomyomas are asymptomatic (Seremetis et al, 1976).3 Symptoms are uncommon until the tumor is larger than 5 cm. Dysphagia and retrosternal discomfort are the most common symptoms. Respiratory complaints such as cough, dyspnea, or wheezing may result from large tumors causing local compression of the tracheobronchial tree. Aspiration pneumonia may occur from vomiting or regurgitation due to esophageal obstruction but is rare in most cases. With the normal overlying mucosa, gastrointestinal bleeding is also very rare. The diagnosis of leiomyoma can be made confidently with a careful history, physical examination, barium swallow, CT, and endoscopy. Tissue diagnosis is not necessary, and as discussed earlier, the distinction from leiomyosarcoma can be very difficult even with the entire resected specimen. EUS can further aid in the diagnosis. Homogeneous anechoic or hyperechoic lesions are almost exclusively benign.16 A heterogeneous echo pattern may be seen in benign tumors, but this EUS finding in lesions greater than 4 cm is somewhat suggestive of malignancy. There is general consensus in the literature that esophageal leiomyoma should be surgically removed in symptomatic patients; however, treatment of asymptomatic patients continues to be debated. Many advocate for the resection of these tumors in asymptomatic patients because of the possibility of malignant transformation, the possibility of symptom development in the future, the desire to obtain a definitive histologic diagnosis, and the exclusion of malignancy only by complete removal. However, literature and experience have shown that asymptomatic patients do not develop complications from their leiomyomas if untreated, and the risk of malignancy or malignant degeneration is extremely low. Therefore, it seems that asymptomatic patients with a tumor less than 4 cm can be managed with clinical and radiographic/endoscopic follow-up. EUS would be the ideal way to follow these tumors with a scan every 1 to 2 years initially. Indications for surgical resection of a leiomyoma include unremitting symptoms, increasing size of tumor, need to obtain histologic diagnosis (i.e., diagnosis is in doubt), and facilitation of other esophageal procedures (Box 39-1). Enucleation (shelling out) of the intramural leiomyoma is the preferred surgical treatment. There are now a variety of surgical approaches, including thoracotomy and thoracoscopic (video-assisted thoracic surgery [VATS]) and endoscopic resections. Rarely, the tumor will require esophageal resection with reconstruction. The principles of the operation include resection of the lesion without injury to the underly-

FIGURE 39-5 Enucleation of a leiomyoma: the mediastinal pleura has been incised and the esophagus has been exposed. Note the bulging tumor above the azygos vein (arrow).

FIGURE 39-6 Enucleation. Myotomy of the outer longitudinal muscle over the tumor mass and a plane of dissection developed between the tumor and the muscle layer.

ing mucosa and closure of the muscularis propria to prevent mucosal bulging. There is some disagreement as to whether the myotomy should be sutured closed after enucleation; however, most experts recommend reapproximation of the muscular wall to prevent mucosal bulging with subsequent diverticulum formation.17,18 Resection can usually be achieved by extramucosal enucleation via thoracotomy or VATS. Considerable experience with the VATS resection has been gained over the past 10 years, and this technique seems to be safe and to have an equivalent outcome (Samphire et al, 2003).17-20 Tumors in the upper or middle third of the thoracic esophagus are best approached via the right chest, and distal third tumors are best approached via the left chest. Occasionally, a laparotomy or laparoscopic approach may be better for tumors very near the gastroesophageal junction (Samphire et al, 2003),20 especially if other pathologic processes in that area need to be addressed (e.g., hiatal hernia or achalasia). When the outer longitudinal muscle over the tumor is divided, the leiomyoma appears as an avascular encapsulated mass underneath (Figs. 39-5 to 39-8). It is usually easily

Chapter 39 Benign Esophageal Tumors

FIGURE 39-9 This intramural leiomyoma, elongated and spiral, has been removed by enucleation. FIGURE 39-7 The tumor has been enucleated without damaging the mucosa.

FIGURE 39-8 Gross appearance of a typical intramural leiomyoma after enucleation.

enucleated using blunt dissection away from the surrounding muscle fibers and the mucosa unless there is inflammation or mucosal damage caused by preoperative endoscopic biopsy. If the mucosa is perforated during the dissection, it should be repaired with absorbable suture and the muscularis closed over top with interrupted silk suture. Small tears in the mucosa can be checked for by insufflating air through a gastroscope with the myotomy covered with saline looking for bubbling through the perforation. If there is no perforation in the mucosa then the muscularis should be simply closed with interrupted silk suture. I do not routinely leave a nasogastric tube. Enteral nutrition can be started the following day. Enucleation is safe and effective, with a mortality rate of 0% to 1%, and the majority of patients experience complete resolution of symptoms. Long-term results are also excellent, with more than 90% of patients being asymptomatic 5 years later (Mutrie et al, 2005).12,17-19 Recurrence after enucleation is extremely rare, with only two such cases reported in the literature.21 Careful long-term follow-up is still necessary. Postoperatively, patients may develop significant gastroesophageal reflux that may require medication or antireflux repair. Theoretically, enucleation of a large leiomyoma may result in an esophagus that functionally resembles achalasia. However, tumors up to 10-cm long (Fig. 39-9) can generally

be removed by enucleation without significant postoperative dysphagia as long as the mucosa is intact and the myotomy is reapproximated.17-19 Tumors larger than 10 cm may ultimately require esophagectomy, but functional outcomes should be assessed after enucleation to determine the extent of postoperative dysphagia, because esophagectomy may not be a significant improvement and comes at considerable risk. Difficulty in performing the enucleation may be a sign of leiomyosarcoma, which typically infiltrates the surrounding muscle. Frozen section of the enucleated tumor may suggest leiomyosarcoma if it is very cellular with a large number of mitotic figures, nuclear atypia, hemorrhage, and necrosis. However, as mentioned earlier, histologic distinction of benign from malignant can be very difficult and may require waiting for permanent sections. Ultimately, if leiomyosarcoma is strongly suspected, or proved, then esophagectomy with clear margins is the treatment of choice. An endoscopic approach may be considered for a leiomyoma that originates in the muscularis mucosae, which often grows in an intraluminal or polypoid fashion. The tumor should ideally be less than 2 cm. After separation of the tumor from the submucosal layer by injection of saline or other solutions, it is resected with a polypectomy electrocautery snare (Dorais and Marcon, 1997).10,22 Experience with this technique is considerable in Japan but limited in the West. Few truly symptomatic tumors will be amenable to this technique. In summary, a leiomyoma is the most common benign tumor of the esophagus. At least half of identified cases will be asymptomatic. Symptoms when present include dysphagia and vague chest pain. Diagnosis is best made with barium swallow, endoscopy, CT, and EUS. Depending on the details of each particular case, treatment may include observation alone, or removal of the tumor via open, VATS, or endoscopic techniques. Prognosis is excellent after enucleation, but patients should continue to be followed long term.

ESOPHAGEAL CYSTS AND DUPLICATIONS Congenital cysts and duplications arise from the primitive foregut and are usually found in close proximity to the esophageal wall or within it. They are not true neoplasms but generally present as similar clinical findings to other benign

435

436

Section 5 Neoplasms

FIGURE 39-10 CT scan of upper esophagus showing a well-defined fluid-containing cavity to the left of the esophagus that at surgery was found to be an esophageal duplication.

esophageal tumors. They are the second most common tumor-like condition of the esophagus.23,24 They may have a distinct CT scan appearance with a completely fluid-filled interior (Fig. 39-10), but because of hemorrhage or secondary infection the contents of the cyst may be more complex. Differentiation from a solid tumor may be more difficult in the latter case. EUS can further help distinguish cystic lesions from solid tumors. Cysts and duplications usually present in early childhood with dysphagia, dyspnea, stridor, wheezing, or as a mass. If not diagnosed in childhood, then they are generally found as incidental asymptomatic lesions in adults. The general recommendation has been to remove even asymptomatic lesions in adults. Esophageal cysts should be removed by extramucosal resection whenever possible, as is done for leiomyoma. The majority of the cyst is apart from the esophagus, and resection is quite straightforward by either thoracotomy or VATS in most cases. Prognosis is excellent in resected patients. Esophageal cysts are discussed more completely in Chapter 10.

FIBROVASCULAR POLYPS Fibrovascular polyps are the most common intraluminal benign tumors of the esophagus.7,25-28 The majority (85%) are found in the upper esophagus.28 They may start as very small polypoid mucosal tumors and with time become elongated and pedunculated due to peristalsis in the cervical esophagus.26 Seventy-five percent of these polyps are larger than 7 cm at the time of clinical presentation.7,25-28 Tumors of 20 cm length have been reported (Fig. 39-11). However, even large tumors often remain asymptomatic. Dysphagia is the most frequent complaint in symptomatic patients. Respiratory symptoms are the next most common clinical finding. Ulceration leading to occult bleeding has been reported but is very rare. The pedicle of these polyps may be fairly thick and may contain blood vessels of considerable size. The polyp has a gross appearance of a fleshy cylindrical mass (Fig. 39-12). Even when large, these tumors may be missed on endoscopy, and a good barium swallow can help alert the clinician to the

FIGURE 39-11 Barium swallow of a giant fibrovascular polyp of the esophagus. Note the large, elongated filling defect, which also enlarges the esophagus. Ripples of barium across the esophagus represent tertiary contractions.

presence of this tumor. At the time of endoscopy the exact point of origin of the pedicle should be determined if possible. Care should be taken at the time the endoscope is removed because the tumor may be drawn into the pharynx, causing acute laryngeal obstruction.29 Once the diagnosis of fibrovascular polyp is made, resection is indicated to prevent fatal asphyxiation from acute airway obstruction.6,7 The method of resection depends on the size of the tumor, the location of the pedicle, and the vascularity of the pedicle. Small tumors less than 2 cm in diameter with a thin pedicle may be removed by endoscopic mucosal resection (EMR) techniques (Dorais and Marcon, 1997).10,22,29 Larger tumors (>8 cm) or those with a thick, likely very vascular, pedicle should be removed by open surgical techniques. The approach depends on the site of the origin of the pedicle. A polyp that originates near the upper esophageal sphincter is removed via a neck incision. The incision is made on the side opposite the origin of the tumor. A longitudinal esophagotomy is then performed to expose the tumor and its pedicle base. The pedicle is best visualized by first delivering the tumor out of the esophagotomy incision. The mucosal origin of the pedicle is then securely ligated and divided, and the specimen is removed. The esophagotomy is closed in two layers with absorbable suture for the mucosa and silk for the muscle. Local excision is curative.

SQUAMOUS CELL PAPILLOMA Squamous cell papillomas are very rare, with an autopsy incidence of about 0.01%.30 They occur more often in older

Chapter 39 Benign Esophageal Tumors

FIGURE 39-12 Gross appearance of a large pedunculated fibrovascular polyp.

patients as “warty” 1- to 2-cm lesions located in the lower third of the esophagus (Fig. 39-13). These tumors should be sampled to rule out squamous cell carcinoma, which may have a similar gross appearance. Esophageal papillomas, like their airway counterparts, have been associated with human papillomavirus. A single case of malignant degeneration has been reported.31 Indications for resection include esophageal obstruction and inability to exclude malignancy. Endoscopic resection (i.e., EMR) should be attempted first for both indications. If cancer is still suspected after endoscopic resection, or if endoscopic resection is not possible, surgical removal will be required. At the time of surgery, esophagotomy with local resection of the papilloma is performed followed by frozen section to rule out malignancy.

GRANULAR CELL TUMOR Like other benign esophageal tumors, granular cell tumor is very rare. Coutinho and colleagues’ review of the literature revealed only 119 cases (Coutinho et al, 1985).32 Patients are usually asymptomatic, and most of the tumors were in the distal esophagus. The tumors are located in the submucosa and have a distinct appearance of a submucosal pale yellow polypoid lesion with an intact mucosa. These tumors range from 0.5 to 2.0 cm. The cell of origin is believed to be a perineural (Schwann) cell. Diagnosis may be difficult because of the submucosal position, but multiple deep biopsies will help rule out carcinoma. EUS may also help define this benign lesion from carcinomas. Some granular cell tumors have been observed to remain stable in size over a long period of follow-up.33,34 Malignancy was found in only 4 of 119 cases (3.4%) (Coutinho et al, 1985),32 but malignant transformation in previously benign lesions has not been reported. The indications for surgery include large (>2 cm) symptomatic tumors, growth during follow-up, and those in which malignancy cannot be excluded. There are now several reports of successful endoscopic resection of granular cell tumors with EMR.35-37 Esophagotomy and local surgical excision by thoracotomy is the other option but should rarely have to be resorted to.

FIGURE 39-13 Squamous papilloma of the esophagus. Note the warty surface. (COURTESY OF DR. R. INCULET.)

INFLAMMATORY PSEUDOTUMORS Inflammatory pseudotumors are localized masses that usually occur in the lower third of the esophagus.38 They arise from the mucosal layer and show marked inflammatory changes that make them difficult to distinguish from esophageal carcinoma grossly. They may originate from previous mucosal ulceration. These tumors are important only because they may be mistaken for carcinoma. Multiple biopsies, perhaps on repeated occasions, will help to rule out carcinoma. They require no specific treatment. Gastroesophageal reflux, if present, should be treated.

INFLAMMATORY POLYPS Inflammatory polyps are a result of gastroesophageal reflux and are composed of inflamed gastric folds at the gastroesophageal junction. Biopsy of the polyp shows only nonspecific inflammation in otherwise unremarkable gastric mucosa. The pathology is quite distinct from inflammatory pseudotumor. Treatment is directed toward lessening the reflux.

ADENOMATOUS POLYPS Adenomatous polyps usually arise in columnar-lined epithelium in the distal esophagus. Benign neoplastic proliferation occurs in the dysplastic epithelium forming the adenomatous polyps. These adenomas have the same dysplastic features as adenomas in the colon. They should be aggressively sampled in addition to the surveillance biopsies of the columnar-lined epithelium of the esophagus. The finding of high-grade dysplasia in one of these adenomatous polyps is an indication for esophagectomy. The large area of dysplastic epithelium is not well treated by EMR in this case.

HEMANGIOMA Hemangiomas arise from the submucosal layer and represent a localized malformation of blood vessels. They account for only 3% of all benign esophageal tumors and are usually found in the distal esophagus.39,40 Grossly, they appear as a solitary bluish nodular submucosal lesion. They may be mistaken for esophageal varices. They can occur as multiple esophageal

437

438

Section 5 Neoplasms

hemangiomas in association with Osler-Weber-Rendu syndrome. Patients are usually asymptomatic, and these lesions are most commonly incidental findings on endoscopy. Upper gastrointestinal bleeding and dysphagia are the most common symptoms if the patient is symptomatic. Bleeding is a result of ulceration of the overlying mucosa or from endoscopic trauma or biopsy. Massive hemorrhage has been reported from biopsy. Diagnosis may be suspected from the endoscopic appearance and confirmed with CT and/or radionuclide angiography.40 Endoscopic biopsy carries with it a significant risk of bleeding and should be avoided. EUS shows a hypoechoic mass with sharp margins arising from the submucosa.41,42 Observation alone is an option for asymptomatic patients with no evidence of occult blood loss. A variety of treatments are available for the symptomatic lesion: fulguration, sclerotherapy, radiation therapy, surgical excision, and EMR.43,44 Significant bleeding is the obvious complication from endoscopic treatments.

SUMMARY Benign esophageal tumors are rare. Few symptomatic tumors will be encountered in clinical practice. Leiomyomas are the most common benign tumor, followed by congenital cysts. With the knowledge and experience gained over the past few decades, and improved diagnostic tests, such as EUS, we should be able to confidently observe many of these tumors if asymptomatic. For the symptomatic patient treatment may come in the form of EMR or other minimally invasive techniques. Outcomes have been excellent with surgically treated lesions in the past, and minimally invasive approaches are likely to show equally good results in the future.

COMMENTS AND CONTROVERSIES Benign esophageal tumors are rarely encountered in clinical practice, accounting for less than 1% of all esophageal neoplasms. As a result, the individual surgeon’s experience is often anecdotal. Given the lack of large series there are no specific guidelines. This chapter provides a fine overview of the different types of benign

diseases and their diagnostic and therapeutic features. Leiomyoma is the most frequent benign tumor of the esophagus. In a substantial number of patients the diagnosis is a coincidental finding, the patient being asymptomatic. Although the differential diagnosis between leiomyoma and gastrointestinal stromal tumor is of importance in clinical practice, I agree that asymptomatic patients in general do not require surgical treatment, given the low risk of malignant degeneration. Patients presenting with leiomyoma located in the distal third of the esophagus frequently have associated gastroesophageal reflux disease. In my experience with patients presenting with a symptomatic distal third leiomyoma, further diagnostic workup, including 24-hour pH studies, documented gastroesophageal reflux in a third of the cases. It is assumed that the mechanical component of the tumor may be a contributive factor. In such a case it seems reasonable to add an antireflux procedure at the time of the enucleation of the leiomyoma, in particular when choosing a laparoscopic approach. If a transthoracic route is used, the combination of an enucleation and antireflux procedure precludes a VATS approach. The introduction of videoscopic technology has resulted in a tendency to perform the enucleation of a leiomyoma through a VATS approach. As a result, some surgeons are omitting to close the muscular breach after enucleation of the lesion. This may result in the subsequent formation of a pseudodiverticulum, causing gradually increasing symptoms. T. L.

KEY REFERENCES Coutinho DS, Soga J, Yoshikawa T, et al: Granular cell tumors of the esophagus: A report of two cases and review of the literature. Am J Gastroenterol 80:758-762, 1985. Dorais J, Marcon N: Endoscopic resection of gastrointestinal tumors: How far can the endoscopist go? Endoscopy 29:192, 1997. Mutrie CJ, Donahue DM, Wain JC, et al: Esophageal leiomyoma: A 40-year experience. Ann Thorac Surg 79:1122-1125, 2005. Samphire J, Nafteux P, Luketich J: Minimally invasive techniques for resection of benign esophageal tumors. Semin Thorac Cardiovasc Surg 15:35-43, 2003. Seremetis M, Lyons W, DeGuzman V: Leiomyomata of the esophagus: An analysis of 838 cases. Cancer 38:2166, 1976.

chapter

40

BIOLOGY AND EPIDEMIOLOGY OF MALIGNANT ESOPHAGEAL CARCINOMA Alan G. Casson David S. Schrump

Key Points ■ Squamous cell carcinoma of the esophagus is one of the 10 most

frequent malignancies worldwide, with a characteristic geographic variation in incidence and with well-established environmental risk factors. ■ Over the past 3 decades, a marked change in the epidemiology of esophageal malignancy in North America and Europe has been reported, with an increasing frequency of esophageal adenocarcinoma. ■ Although a strong statistical association between gastroesophageal reflux disease, Barrett’s esophagus, and risk for primary esophageal adenocarcinoma is reported, sociodemographic, dietary, and lifestyle risk factors are less defined for this tumor subtype. ■ Identification of molecular alterations associated with Barrett’s metaplasia-dysplasia-adenocarcinoma progression may provide further insight into the molecular pathogenesis of esophageal adenocarcinoma.

Carcinoma of the esophagus is one of the most frequent malignancies wordwide.1 The epidemiology of this disease is characterized by a striking geographic variation in incidence, not only between countries but also within distinct geographic regions and among ethnic groups. These observations distinguish esophageal cancer from many other human solid tumors. Although squamous cell carcinoma remains the most frequent histologic subtype of esophageal cancer globally, there has been a marked change in the epidemiology of this disease in North America and Europe, where, over the past 3 decades, the incidence of adenocarcinoma of the esophagus and esophagogastric junction (cardia) has increased at a rate exceeding that of any other human solid tumor (Blot and McLaughlin, 1999).2-5 The cause of this is not known with certainty. Although epidemiologic studies from high-incidence geographic areas have reported strong statistical associations between various environmental risk factors and the development of esophageal squamous cell carcinoma, it is unlikely that a single etiologic factor could account for the marked global variation in the frequency of this disease. However, such well-established sociodemographic, dietary, and lifestyle risk factors are less well defined for adenocarcinomas of primary esophageal origin (Lagergren, 2005; Wong and Fitzgerald, 2005).6,7 Esophageal adenocarcinomas are thought to arise from Barrett’s esophagus, an acquired condition in which the normal esophageal squamous epithelium is replaced by a

specialized metaplastic columnar cell–lined epithelium.8,9 Progression of Barrett’s esophagus to invasive adenocarcinoma is reflected histologically by the metaplasia-dysplasiacarcinoma sequence.10 Because gastroesophageal reflux disease (GERD) is a risk factor for Barrett’s esophagus, there is a plausible link between GERD, Barrett’s esophagus, and esophageal adenocarcinoma.11 The recent identification of molecular markers associated with Barrett’s metaplasia-dysplasia-adenocarcinoma progression may provide further insight into the molecular pathogenesis of this disease (McManus et al, 2004; Reid et al, 2003).12-14 However, because GERD and Barrett’s esophagus are relatively common in the general population, and only a fraction of individuals progress to invasive adenocarcinoma, it is more likely that environmental risk factors interact with molecular genetic alterations to modulate individual susceptibility for progression to invasive esophageal adenocarcinoma. Despite recent advances in multimodality therapy, esophageal cancers are highly lethal neoplasms, with generally poor outcome.15 Although it is anticipated that improved survival may be achieved with early detection, endoscopic surveillance programs, and chemoprevention strategies, it is likely that substantive long-term progress with this disease will only be made with an improved understanding of its etiology and tumor biology. Therefore, in this chapter we present a summary of recent clinically relevant advances in the biology and epidemiology of esophageal malignancy. Because the premalignant lesion Barrett’s esophagus appears central to our understanding of the molecular pathogenesis of esophageal adenocarcinoma, attention is focused on molecular alterations and environmental risk factors associated with the metaplasia-dysplasia-adenocarcinoma progression.

HISTORICAL NOTE Cancer of the esophagus was apparently first described over 2000 years ago in high-incidence regions of China.16,17 However, few accurate reports of esophageal malignancy were forthcoming until the late 1800s, when improved pathologic descriptions paralleled initial attempts at surgical resection of cervical esophageal tumors. The remarkable variation in incidence of esophageal cancer worldwide led to numerous epidemiologic studies to delineate risk factors for the disease. Careful analysis of patients with esophageal squamous cell carcinoma suggested that tobacco carcinogens and alcohol might play an important role in the development of this malignancy. Such epidemiologic observations stimulated laboratory studies of experimental esophageal carcinogenesis from the 1950s onward. 439

440

Section 5 Neoplasms

Advances in molecular biology have changed our understanding of the pathogenesis of human cancer. Huebner and Todaro (1969) initially reported oncogenes in RNA tumor viruses, proposing that they were derived from protooncogene sequences contained in normal eukaryotic cells.18 Following technical advances in tumor virology, Stehlin and colleagues (1976) reported the first transforming viral gene, the SRC oncogene.19 Rapid progress followed, and in 1981 DNA from human tumor cells was found to transform murine fibroblasts. In 1982, a transforming gene, HRAS, was isolated from a human bladder carcinoma cell line and sequenced.20,21 A point mutation in the first exon of the HRAS gene was found: the nucleotide guanine (G) replaced by thymidine (T) at codon 12. As a consequence of this genetic mutation, the protein product encoded by this gene was changed and the amino acid glycine (normal) was replaced by the amino acid valine. It is thought that the normal function of cell membrane–associated CDKN1A (formerly p21) RAS proteins is to modulate cellular differentiation through signal transduction, with mutation conferring transforming potential. The 1990s saw an exponential rate of development and application of molecular biology technology in cancer research, in particular with interest in another class of cancer regulatory gene, the tumor suppressor gene,22,23 and with the development and first clinical application of gene therapy strategies.24-26 In particular, the TP53 tumor suppressor gene appears to have a central role in human neoplasia and has been implicated in control of the cell cycle, regulation of cellular differentiation, DNA repair and synthesis, and apoptosis.27-31 It is the most frequently altered gene in human cancer, including esophageal squamous cell carcinoma,32 esophageal adenocarcinoma, and associated Barrett’s epithelium33 and has been proposed as a clinically relevant molecular target.29,30 However, the relative importance of individual oncogenes and tumor suppressor genes, of the sequence of gene activation and interactions, and of pathways by which genes mediate their effect or potential for modulation by gene therapy is not yet known for esophageal cancer. The history of premalignant esophageal lesions is also relevant to the understanding of esophageal adenocarcinogenesis. Peptic ulceration of the lower esophagus, presumed secondary to “insufficiency of the cardia,” was described in detail almost a century ago by Tileston (1906), who alluded to the presence of an abnormal glandular epithelium.34 The modern concept of a columnar epithelium–lined esophagus arose from the observations of Barrett,35,36 Bosher and Taylor,37 and Allison and Johnstone,38 50 years later. Morson and Belcher39 reported that esophageal adenocarcinomas arose from “ectopic gastric mucosa,” crediting Carrie (1950) with this original observation.40 Until the 1970s, esophageal adenocarcinomas were considered uncommon, accounting for less than 5% of all esophageal cancers, until the publication of a number of landmark studies from North America and Europe that confirmed clinical suspicions that esophageal adenocarcinomas were being seen more frequently (Blot and McLaughlin, 1999).2-5

HISTORICAL READINGS Allison PR, Johnstone AS: The esophagus lined with gastric mucous membrane. Thorax 8:87, 1953. Huebner RJ, Todaro GJ: Oncogenes of RNA tumor viruses as determinants of cancer. Proc Natl Acad Sci U S A 64:1087, 1969. Krontris TG, Cooper GM: Transforming activity of human tumor DNAs. Proc Natl Acad Sci U S A 78:1181, 1981. Stehlin D, et al: DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170, 1976. Tileston W: Peptic ulcer of the esophagus. Am J Med Sci 132:240, 1906. Wynder EL, Bross IJ: A study of etiologic factors in cancer of the esophagus. Cancer 14:389, 1961.

BIOLOGY Over the past decade, and certainly since the first edition of this text, there has been an exponential increase in our knowledge and understanding of the molecular pathogenesis of human malignancy (Macdonald et al, 2004).41 With the completion of the human genome project, numerous molecular lesions have been reported throughout the genome, and many somatic sequence alterations (mutations) have been described in various tumor types. Indeed, several molecular alterations have been reported in esophageal cancer, including premalignant Barrett’s esophagus, and the reader is referred to several recent reviews describing the spectrum of molecular alterations in esophageal malignancy.12-14,42-48 It is increasingly recognized that molecular alterations, including loss of heterozygosity (LOH) at multiple tumor suppressor gene loci, frequent chromosomal gain or loss, aberrant splicing, and epigenetic alterations, contribute to malignant transformation.41 For instance, acquired genomic instability in Barrett’s esophagus is thought to predispose to clonal outgrowth of cells exhibiting cumulative molecular alterations, resulting in progression to invasive esophageal adenocarcinoma.49-51 As with other human solid tumors, the accumulation of molecular genetic alterations may correlate with defined histologic stages of tumor progression and is associated with increased risk of malignancy (Fig. 40-1). However, despite such increasing knowledge, the temporal sequence of molecular events, regulatory pathways, and interactions that mediate esophageal carcinogenesis are still not known with certainty. Numerous molecular alterations have been proposed to have potential clinical application regarding risk assessment and early detection in endoscopic surveillance programs, staging, and prognosis of patients with locally advanced disease, prediction of chemosensitivity, as well as intermediate biomarkers for chemoprevention studies and as novel targets for anticancer therapies. To facilitate the translation of recent advances in basic science into clinical practice, the National Cancer Institute Early Detection Research Network proposed five phases to validate molecular biomarkers used in screening and surveillance for the early detection of cancer.52 The aim of phase I (preclinical exploratory) studies is to identify novel molecular biomarkers in tumor tissues, using

Chapter 40 Biology and Epidemiology of Malignant Esophageal Carcinoma

Index case histologically

Division of surface cells

Goblet cells

OF DR. W. DINJENS, ERASMUS UNIVERSITY, ROTTERDAM, THE NETHERLANDS.)

Glands

Normal lining

Metaplasia

FIGURE 40-1 Barrett’s metaplasia-dysplasia-carcinoma sequence. Histologically, although the index case is at low risk for malignant progression, the accumulation of molecular genetic alterations increases the risk for progression to invasive esophageal adenocarcinoma. LGD, low-grade dysplasia; HGD, high-grade dysplasia. (COURTESY

LGD

HGD

Invasive carcinoma

Genetic alterations

Low risk

High risk Index case molecularly

matched histologically normal tissues for comparison. Phase II studies are primarily to validate molecular biomarker assays, to estimate true- and false-positive rates, to optimize assay conditions, to compare assay techniques, and to explore associations between a biomarker and selected clinicopathologic factors in patients with cancer (e.g., tumor histology, grade) and normal controls (e.g., gender, age, smoking history). Phase III (retrospective longitudinal repository) studies utilize banked tissues to evaluate the capacity of a biomarker to detect preclinical disease and to define criteria for a positive screening test. The ability of a biomarker to predict disease is determined by prospective screening studies (phase IV), which also consider potential benefits of early detection, including the feasibility and costs of implementing a screening program. Phase V (cancer control studies) addresses whether biomarker-based screening will reduce cancer mortality. To date, no molecular biomarker associated with esophageal malignancy has been evaluated in a phase V study. Rather than catalogue all molecular alterations reported in esophageal malignancy (phase I and II studies), in the following sections we summarize the results of a limited number of phase III and IV studies that have evaluated selected molecular biomarkers that may have potential clinical application.

Inflammation and Carcinogenesis It is generally accepted that Barrett’s esophagus is an acquired condition resulting from GERD.8,9,11 Reflux of duodenal contents has been suggested as an important contributing factor in the pathogenesis of esophagitis and Barrett’s esophagus, an

observation supported by clinical53 and experimental animal models of duodenoesophageal reflux.54 Although pure alkaline reflux is thought to be rare, a mixed refluxate comprising acid, bile, lysolecithin, and pancreatic enzymes (trypsin, lipase, carbopeptidase) may cause more esophageal mucosal damage than acid alone. It is suggested that bile acids alter the ionic permeability of mucous membranes, with back-diffusion of hydrogen (H+) ions and intracellular acidification.55 It is hypothesized that GERD results in acute mucosal injury (esophagitis), promotes cellular proliferation, and induces specialized columnar metaplasia (Barrett’s epithelium) of the normal squamous epithelium lining the esophagus. Although the precise biologic mechanisms are still unknown, oxidative stress resulting in the local overproduction of reactive oxygen species in response to inflammation has been suggested as a critical early event in the molecular pathogenesis of this disease.56,57 Reactive oxygen and nitrogen species have been implicated in endogenous mutagenic processes, including deamination of DNA bases, inactivation of DNA repair, inhibition of apoptosis, and signature G:C to A: T mutations in the TP53 tumor suppressor gene, which are characteristic of esophageal adenocarcinoma.58 Peroxynitrate, the reaction product of nitric oxide with superoxide (another free radical generated during inflammation), oxidizes thiols and initiates lipid peroxidation as well as cleavage of DNA. Peroxynitrate reacts with the amino acid tyrosine to produce a stable reaction product, nitrotyrosine, a marker of cellular protein damage that has been detected in esophageal squamous cell carcinoma,59 esophageal adenocarcinoma, Barrett’s esophagus, and GERD-induced esophagitis.60

441

442

Section 5 Neoplasms

The role of inflammation in carcinogenesis is further supported by clinical observations that anti-inflammatory drugs are protective against progression to invasive esophageal malignancy.61 The enzyme cyclooxygenase-2 (COX-2), which may be induced by a variety of inflammatory mediators, controls the rate-limiting step in the conversion of arachidonic acid to prostaglandin; COX-2–mediated production of prostaglandin E2 inhibits apoptosis, increases cellular proliferation, and stimulates angiogenesis. Increased levels of COX-2 have been observed in Barrett’s esophagus with and without dysplasia and in esophageal adenocarcinoma62-64; increased COX-2 protein expression correlates with reduced postoperative survival.65 In experimental models, COX-2 expression is induced by exposure to acid and bile, and COX2 inhibitors reduce cellular proliferation of cultured esophageal epithelial cells.66

Cell Proliferation and Apoptosis Normal tissue growth results from the balance between cellular proliferation and loss (apoptosis).67 Esophageal epithelium damaged from GERD, including Barrett’s esophagus, has been shown to be hyperproliferative, reflected by an increased S-phase fraction on flow cytometry68 and immunohistochemically using monoclonal antibodies to proliferating cell nuclear antigen (PCNA)69 and Ki67,70 a cell nuclear proliferation– associated antigen. Whereas PCNA immunostaining is normally seen in the basal layer of metaplastic Barrett’s epithelia, in high-grade dysplasia it is seen to extend to more superficial layers.71 Similar patterns of staining were seen for Ki-67, suggesting a functional instability of Barrett’s mucosa.70 Apoptosis, or programmed cell death, is a protective mechanism to eliminate injured or DNA-damaged cells. The role of apoptosis in the progression to invasive esophageal adenocarcinoma remains controversial, although reports suggest that Barrett’s esophagus is relatively resistant to apoptosis.72,73 Similarly, telomerase, a ribonucleoprotein enzyme complex that prevents telomere shortening (which limits the number of times a cell can divide), is overexpressed coincident with progression from low- to high-grade dysplasia and may be an alternative mechanism by which premalignant cells escape apoptosis.74,75

DNA Repair Maintenance of genomic integrity by DNA repair genes is an essential component of normal cellular growth and differentiation.76,77 Rapid repair of damaged DNA, a consequence of exposure to exogenous (environmental) agents or endogenous mutagens, may be achieved through several mechanisms, including nucleotide excision repair (NER), base excision repair (BER), homologous recombination, telomerase activation, and mismatch repair (MMR). Loss of MMR is manifested by microsatellite instability (MSI); presently, the role of MSI in the molecular pathogenesis of esophageal cancer is unclear. Low levels of MSI (MSI-L), which characterize esophageal malignancy, may result either from subtle overloading of the MMR system or as a consequence of intrinsic susceptibility of progenitor cells to replication error.78 Although MSI-L suggests an inherent baseline genomic

instability, with potentially increased susceptibility to mutations during tumor progression, the target genes remain unknown. Considerable research efforts have focused on the evaluation of common polymorphisms involving DNA repair genes in patients with esophageal cancer. For example, individuals with a polymorphism involving a poly (AT) insertion/deletion in intron 9 of the xeroderma pigmentosum group C gene (XPC) appear to be at increased risk for developing esophageal adenocarcinoma.79 XPC is an integral component of the NER pathway, which repairs genetic damage induced by tobacco carcinogens, a significant risk factor for esophageal malignancy. Interestingly, a protective effect of the homozygous variant (Arg399Gln) of the x-ray repair crosscomplementing 1 gene (XRCC1) was found in patients with GERD and Barrett’s esophagus. These data suggest that BER alterations occur early in the molecular pathogenesis of esophageal adenocarcinoma and that polymorphisms involving genes regulating BER pathways may explain why only a fraction of individuals with Barrett’s esophagus progress to malignancy.

DNA Content and Chromosome Alterations DNA Content (Ploidy). Several phase I to phase III studies have now clearly demonstrated that abnormal cell nuclear DNA content (aneuploidy) in Barrett’s esophagus is associated with risk of progression to malignancy and that the prevalence of aneuploidy appears to increase with the degree of dysplasia detected by standard histologic criteria.68,80-83 Compelling evidence for utilizing flow cytometry to determine tissue ploidy was demonstrated in an ongoing phase IV study, involving prospective evaluation of more than 300 patients over a 15-year interval, using a well-established endoscopic biopsy protocol.84 Briefly, patients with Barrett’s esophagus whose baseline biopsy demonstrated no, indefinite, or low-grade dysplasia with a diploid cell population (without aneuploidy or increased 4N fraction) appeared to be at low risk for malignant progression.85 Endoscopic surveillance at intervals up to 5 years was proposed for this group of patients. More frequent surveillance was recommended for individuals whose baseline biopsies exhibited aneuploidy, tetraploidy (4N), or high-grade dysplasia, because these patients had 5-year cancer incidences of 43%, 56%, and 59%, respectively. All patients who did not have flow cytometric evidence of aneuploidy or tetraploidy in endoscopic biopsies, yet progressed to invasive esophageal adenocarcinoma, had high-grade dysplasia at baseline. Specific ploidy variables determined by flow cytometry (aneuploid DNA content >2.7N; 4N fraction >6%) were even more highly predictive of progression to cancer in this surveillance program.86 Anatomic mapping studies have demonstrated that most aneuploid cell populations are localized to isolated regions of esophageal mucosa, suggesting clonal expansion of single progenitor cells. Whereas multiple distinct aneuploid cell populations are encountered occasionally in Barrett’s esophagus, only one aneuploid population is typically found in the primary tumor.10,51,87,88 Although tumor ploidy in esophageal adenocarcinoma has been reported to be associated with

Chapter 40 Biology and Epidemiology of Malignant Esophageal Carcinoma

443

copy number, structure, and expression of genes and DNA sequences. Nonrandom chromosomal abnormalities are frequently observed in esophageal cancer specimens as well as their precursor lesions, suggesting that these events are causally related to malignant transformation.93-98 Cytogenetic and molecular analyses have consistently revealed evidence of allelic loss involving 2q, 3p, 5q, 9p, 11p, 12q, 13q, 17q, 17p, 18q, and Xq; interestingly, loss of Y chromosome is an extremely common and early event. Although allelic loss involving 3p, 5q, 9p, and 17p may disrupt known tumor suppressor genes, the genes specifically targeted by the remaining allelic losses have not been identified. Tumor Suppressor Genes. Tumor suppressor genes regulate several normal cellular functions, including response to mitogens, cell cycle progression, cellular differentiation, repair of DNA damage, and angiogenesis.22,23,99 Loss of an allele or portion of a chromosome suggests the presence of a tumor suppressor gene at or near that locus. The remaining allele is often inactivated by mutation or promoter hypermethylation. TP53. The TP53 tumor suppressor gene, located on chromosome 17p13, encodes a 53-kd polypeptide (TP53) that has many cellular functions, including regulation of cell cycle progression, DNA repair, apoptosis, and neovascularization in normal and malignant cells via highly complex DNA and protein interactions (Fig. 40-3).27-31,100-103 TP53 mediates cell

advanced stage of disease, lymph node metastasis, and reduced survival, data have been inconsistent.89-91 Flow cytometry has also been used to study cell cycle kinetics, including S-phase fraction, in esophageal premalignancy in a number of phase I and II studies.68,81,86,92 In the only substantive phase IV study of Barrett’s esophagus performed to date, the S-phase fraction was shown to be a twofold predictor of cancer risk by univariate analysis but was not a significant independent risk factor in a multivariate analysis incorporating ploidy and dysplasia.86 Chromosome Alterations. Conventional cytogenetic techniques are limited by both the size of chromosome to be visualized (at least 5 megabases of DNA) and the requirement that cells be cultured and stimulated into mitosis for banding. Recent molecular cytogenetic techniques, such as fluorescence in-situ hybridization (FISH), will resolve smaller structural chromosomal changes (less than 1 kilobase of DNA) and may be applied to detect multiple chromosomal changes in heterogeneous cell populations and to follow cytogenetic changes at various stages of tumor development. Over the past decade, comparative genomic hybridization (CGH) has become the most popular molecular cytogenetic tool to analyze the entire genome (Fig. 40-2). These recent cytogenic techniques are complemented by molecular genetic techniques, such as restriction-landmark genomic scanning, differential display, serial analysis of gene expression (SAGE), and microarray techniques for genome-wide screening of

ALL ADENOCARCINOMAS Gain Barrett’s adenocarcinoma Loss Barrett’s adenocarcinoma Loss cardia adenocarcinoma Gain cardia adenocarcinoma

1

2

3

4

6

7

8

9

10

13

14

15

16

17

19

20

21

22

5

11

12

18

X

FIGURE 40-2 Comparative genomic hybridization showing chromosomal gains and losses in adenocarcinomas of the esophagus and esophagogastric junction. (COURTESY OF DR. W. DINJENS, ERASMUS UNIVERSITY, ROTTERDAM, THE NETHERLANDS.)

Y

444

Section 5 Neoplasms

FIGURE 40-3 Mode of action of TP53. Activation of the TP53 network after stress results in activation of kinases that phosphorylate TP53, resulting in release of MDM2 with concomitant stabilization of TP53. TP53 binds to CDKN1A, resulting in its transcription. CDKN1A then interacts with the cyclin-dependent kinases (CDKs), which prevent RB phosphorylation and thereby prevent cell cycle progression until damage is repaired. (REPRODUCED WITH PERMISSION FROM MACDONALD F, FORD CHJ, CASSON AG: MOLECULAR BIOLOGY OF CANCER, 2ND ED. ABINGDON, OXFORDSHIRE, ENGLAND, TAYLOR & FRANCIS/GARLAND SCIENCE/BIOS SCIENTIFIC PUBLISHERS, 2004.)

Ultraviolet or chemotherapeutic drug damage

DNA breaks

ATM kinase

TP53

DNA-dependent kinase

ATR kinase

MDM2

Casein kinase

TP53 Stabilization

TP53 CDKN1A

CDKN1A

CDKs

CDKN1A

Cell cycle blocked

DNA repair

FIGURE 40-4 Structure of TP53 protein showing the five highly conserved regions. The regions at which protein partners bind to TP53 are also indicated. (REPRODUCED WITH PERMISSION FROM MACDONALD F, FORD CHJ, CASSON AG: MOLECULAR BIOLOGY OF CANCER, 2ND ED. ABINGDON, OXFORDSHIRE, ENGLAND, TAYLOR & FRANCIS/GARLAND SCIENCE/BIOS SCIENTIFIC PUBLISHERS, 2004.)

Transactivation domain

Sequence-specific DNA binding domain

Oligomerization domain

MDM2 binding Nuclear export signal Nuclear localization signals Proline-rich region

cycle arrest in part by inducing the expression of CDKN1A (formerly p21, WAF-1), which sequesters a variety of cyclindependent kinases (CDKs), facilitating G1 as well as G2/M arrest. Loss of TP53 function by point mutation is a common mechanism of inactivation, and over 90% of TP53 mutations occur in the conserved DNA binding domain (exons 5 to 8) (Fig. 40-4). TP53 appears to have a central role in human malignancy and has been characterized extensively over the past decade. TP53 gene mutations were initially reported over a decade ago in esophageal squamous cell carcinomas,32 primary

esophageal adenocarcinomas, and associated Barrett’s epithelium.33 These findings were subsequently confirmed in several phase I and II studies, and the spectrum of TP53 alterations in esophageal malignancy has been characterized in detail.58, 91,104-116 In surgically resected esophageal adenocarcinomas, TP53 mutations were associated with poor tumor differentiation and reduced disease-free as well as overall survival after surgical resection.58 Of particular biologic interest was the observation that patterns of TP53 mutations in esophageal adenocarcinomas were predominantly G:C to A:T transitions at CpG dinucleotides,58,91 suggesting that

Chapter 40 Biology and Epidemiology of Malignant Esophageal Carcinoma

TP53 mutations result from endogenous mechanisms, likely involving spontaneous deamination of 5′-methylcytosine to thymidine, typically at CpG dinucleotides.58 These patterns of mutations appear unique to esophageal adenocarcinoma, suggesting these tumors are biologically distinct from esophageal squamous cell carcinoma.110 The finding of TP53 mutations in nondysplastic Barrett’s epithelia suggests that TP53 may be altered early in the metaplasia-dysplasia-carcinoma sequence and may therefore be a useful biomarker in endoscopic surveillance programs. Although no phase IV studies have evaluated TP53 mutations or protein overexpression in Barrett’s epithelia as predictors of malignant progression, LOH of 17p (inclusive of TP53) was evaluated in one phase IV study in conjunction with flow cytometry.117 The prevalence of 17p LOH ranged from 6% in nondysplastic Barrett’s epithelia, to 57% in high-grade dysplasia, and was a significant independent predictor of progression to esophageal adenocarcinoma, with a relative risk of 16. In this study of 325 patients with Barrett’s esophagus, only 6 of 26 patients who progressed to malignancy did not have 17p LOH in biopsy specimens. 17p LOH was also associated with increased risk for aneuploidy, tetraploidy, and high-grade dysplasia, with relative risks of 7.5, 6.1, and 3.6, respectively. CDKN2A. The CDKN2A gene (formerly p16), localized to chromosome 9p21, encodes a protein that belongs to a family of CDK inhibitors. CDKN2A binds to and inhibits CDK4/6, resulting in reduced phosphorylation of RB and inhibition of cell cycle progression through G1. An alternative transcript, CDK2AP2, functions to sequester MDM2, thereby stabilizing TP53. Alterations of CDKN2A are reported frequently in various human malignancies, but mechanisms of CDKN2A inactivation appear to differ among tumor types.118 Although point mutations in Barrett’s esophagus and esophageal adenocarcinoma are relatively uncommon, 9p LOH and promoter hypermethylation appear to be frequent mechanisms of CDKN2A inactivation in esophageal malignancy.119-121 In several studies, hypermethylation of CDKN2A has been the most frequent and earliest molecular event in premalignant Barrett’s epithelia. In addition, CDKN2A hypermethylation has been detected in histologically normal epithelia adjacent to esophageal cancers.122 The subject of phase I and II studies only, CDKN2A alterations are increasingly recognized as critical molecular lesions associated with esophageal carcinogenesis.123 MISCELLANEOUS TUMOR SUPPRESSOR GENES. Several other tumor suppressor genes have been implicated in esophageal malignancy. These include the fragile histidine triad (FHIT),124,125 von Hippel-Lindau (VHL), and peroxisome proliferator activated receptor-gamma (PPARG) genes on chromosome 3p126; the mutated in colorectal cancer (MCC) and adenomatous polyposis coli (APC) genes on chromosome 5p127-130; the retinoblastoma (RB) gene on chromosome 13q131,132; as well as the deleted in colorectal cancer (DCC) and deleted in pancreatic cancer (DPC4) genes on chromosome 18q.133 Further candidate (as yet unidentified) tumor suppressor genes have been suggested on chromosomes 5p, 7q, and 14q based on data derived from phase I LOH studies.134,135

Oncogenes Various oncogenes have also been implicated in esophageal carcinogenesis, although data are generally limited to phase I and II studies. In contrast to other gastrointestinal tumors, the RAS oncogene is rarely mutated in human esophageal malignancy.136-138 However, recent studies suggest that overexpression of RAS-regulated genes (osteopontin, cathepsin L) occurs in more than 50% of primary esophageal adenocarcinomas.137 Similarly, MYC amplification has been reported in about half of all esophageal adenocarcinomas studied; it has been suggested that MYC is the target gene of chromosome 8 amplification.139

Growth Factors and Receptors The epidermal growth factor receptor (EGFR) is a 170-kd tyrosine kinase glycoprotein that is overexpressed in approximately 80% and 30% of esophageal squamous cell cancers and adenocarcinomas, respectively. Gene amplification appears to be the most common mechanism of EGFR overexpression in esophageal cancer; interestingly, in contrast to EGFR mutations in lung cancers that enhance response to tyrosine kinase inhibitors, no mutations have been observed in the tyrosine kinase domain of EGFR in esophageal carcinomas.140-142 EGFR overexpression appears to correlate with the degree of dysplasia. Similarly, transforming growth factoralpha (TGF-α), which is structurally and functionally related to EGF and binds to the EGFR to stimulate growth via autocrine mechanisms, is also overexpressed in dysplastic esophageal epithelium.141,143 Several recent studies have suggested that EGF/EGFR overexpression may have prognostic significance after surgical resection of esophageal cancer, associated with both regional nodal and distant metastasis.144 The ERBB2 (formerly HER-2/NEU) gene encodes a 185kd tyrosine kinase receptor molecule that is structurally related to EGFR; heregulin is the putative ligand for this receptor. The prevalence of ERBB2 protein overexpression/ amplification in esophageal cancers varies considerably (10% to 70%) depending on tumor histology and methodology used to examine this proto-oncogene product and may correlate with tumor invasion, lymph node metastasis, tumor stage, and survival.140,145-147 Basic fibroblast growth factor (FGF-2) is the prototypic member of a family of related genes encoding heparin-binding proteins with growth-, antiapoptotic-, and differentiation promoting activity. FGF-2 is expressed in esophageal squamous cell carcinoma cell lines148 and is elevated in esophageal adenocarcinoma, suggesting an autocrine or paracrine role in esophageal tumorigenesis.149 The FGF2 gene maps to chromosome 4q26, a site of frequent gain or loss in esophageal adenocarcinoma and Barrett’s esophagus.150 FGF2 is bidirectionally transcribed to generate overlapping sense and antisense (FGF-AS) mRNAs. FGF-AS has been implicated in the post-transcriptional regulation of FGF2 expression. Overexpression of FGF2 mRNA has been reported to be associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer.151 Because these risks were reduced in tumors coexpressing the FGF-AS mRNA, it was suggested that FGF-AS is a novel tumor suppressor that

445

446

Section 5 Neoplasms

INK4

RB – E2F

RAS Cyclin A + B + CDC2

Cyclin D + CDK4 and 6

M

RB + E2F

cdk4 and cdk6 Cyclin D

Cyclin D/cdk4 and cdk6 CDKN1A

CDKN2A G1

G2

Restriction point

S Cyclin A1 + CDK2

CDKN1A, CDKN1B, and CDKN1C

TP53

ARF

Cyclin E + CDK2

CDKN1A, CDKN1B, and CDKN1C

FIGURE 40-5 The stages of the cell cycle and expression of the cyclins, CDKs, and their inhibitors, the CKIs. (REPRODUCED WITH PERMISSION FROM MACDONALD F, FORD CHJ, CASSON AG: MOLECULAR BIOLOGY OF CANCER, 2ND ED. ABINGDON, OXFORDSHIRE, ENGLAND, TAYLOR & FRANCIS/GARLAND SCIENCE/BIOS SCIENTIFIC PUBLISHERS, 2004.)

modulates the effect of FGF-2 expression. Studies also suggest that FGF-2 modulates sensitivity of esophageal cancer cell lines to cisplatin and 5-fluorouracil, two anticancer agents widely used in clinical practice.

Cell Cycle Regulation In normal esophageal epithelia, progression through the cell cycle is governed by complex interactions between stimulatory and inhibitory signals mediated by proto-oncogenes and tumor suppressor genes, respectively (Fig. 40-5). Growth factor stimulation induces quiescent (G0) cells to enter the G1 phase; progression through G1 requires continuous external mitogenic stimulation until the restriction point is traversed, whereby the cell becomes committed to divide irrespective of exogenous growth factor support. After G1, cells progress into S phase, where DNA replication occurs, and then proceed through G2 to undergo mitosis (M phase). Checkpoints at the G1/S and G2/M transitions ensure genomic integrity before DNA replication and entry into mitosis, respectively.41,152,153 Progression through the cell cycle occurs after the sequential formation, activation, and degradation of specific CDK complexes that interact with regulatory proteins involved in cell proliferation. Cyclin D1/CDK-4 (and 6) primarily regulate progression through early and mid-G1, whereas cyclin E/CDK-2 controls the transition from G1 into S phase. Cyclins A and B together with CDK-2 (and 1) govern progression through S, G2, and M phases.154 A variety of oncogene and tumor suppressor gene mutations (described in preceding sections) frequently observed in esophageal cancers and their precursor lesions disrupt cell

FIGURE 40-6 Regulation of the G1 restriction point.

cycle regulation by perturbing the G1 restriction point (Fig. 40-6). The RB protein governs the restriction point by sequestering E2F transcription factors. During mid-G1, RB is phosphorylated by cyclin D/CDK-4 or 6 complexes, thereby liberating E2F, which activates transcription of genes required for DNA synthesis in S phase. The CDKN2A tumor suppressor gene product inhibits the association of CDK-4 and CDK6 with cyclin D1. Overexpression of growth factor receptors such as EGFR or ERBB2 enhance signal transduction via RASregulated pathways and upregulate cyclin D1. Aberrant activation of oncogenes induces expression of CDK2AP2, which functions to stabilize the TP53 tumor suppressor gene product. TP53 mediates apoptosis in response to activated oncogenes or genotoxic stress and induces cell cycle arrest, in part, by enhancing the expression of CDKN1A, which sequesters a variety of CDKs, including CDK-4 and CDK-6. Hence, G1 restriction point control can be circumvented by the loss of RB, CDKN2A, or TP53 tumor suppressor gene expression or by overexpression of RAS or cyclin D, resulting in aberrant cell cycle progression.41 A reciprocal relationship between RB, cyclin D, and CDKN2A expression has been observed in esophageal cancers. In general, esophageal cancers that lack RB expression tend to have normal cyclin D1 and CDKN2A expression; in contrast, cancers that retain RB expression typically exhibit overexpression of cyclin D1, CDKN2A inactivation, or both.155,156 In the majority of esophageal cancers, restriction point control is circumvented via overexpression of cyclin D1 and/or inactivation of CDKN2A—often in the context of TP53 mutations. Cyclin D1. As previously mentioned, cyclin D1 is a key regulator of cell cycle progression, particularly the transition from G1 to S phase.154,157 Cyclin D1 is encoded by the CCND1 gene located on chromosome 11q13. Several phase I and II studies have implicated cyclin D1 in esophageal malignancy.158,159 Overexpression of cyclin D1 protein has been observed in up to 64% of adenocarcinomas and associated Barrett’s epithelia. In a phase III case-control study, immunohistochemical overexpression of cyclin D1 in patients with Barrett’s esophagus was associated with a sixfold increased risk of progression to esophageal adenocarcinoma.159 Recently, a common polymorphism (G870A) in exon 4 of CCND1 that creates an alternative splice site encoding a truncated protein isoform with an altered C-terminal domain, has been implicated in neoplastic transformation. In a prospective case-control (phase IV) study, individuals with the CCND1 A/A genotype were found to be at increased risk

Chapter 40 Biology and Epidemiology of Malignant Esophageal Carcinoma

TABLE 40-1 Summary of the Phases of Biomarker Evaluation for Barrett’s Esophagus Phase

Description

Biomarkers (and selected references)

1

Preclinical exploratory

Ploidy,68,80-92 S-phase,68,92 TP53,32,33 cyclin D1,158 CDKN2A,120-123 FHIT,124,125 APC,127-130 RB,131,132 and many others (reviewed in references 10, 12-14, and 42-48)

2

Clinical assay and validation

Ploidy,81-92 S-phase,68,81,86,92 TP53,58,91,104-116 cyclin D1,158,159 CDKN2A,120-123 and many others (reviewed in references 10, 12-14, and 42-48)

3

Retrospective longitudinal

Ploidy,81-92 S-phase,68,81,86,92 TP53,109 cyclin D1159

4

Prospective screening

Ploidy,85,86 17p LOH (TP53)117

5

Cancer control

Modified from the National Cancer Institute Early Detection Research Network Guidelines. Pepe MS et al: Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 93:1054, 2001.

for GERD, Barrett’s esophagus, and esophageal adenocarcinoma; these data suggest that this polymorphism modulates susceptibility to esophageal adenocarcinoma.160

Summary Over the past decade, numerous molecular alterations associated with esophageal malignancy have been described. However, it is anticipated that relatively few will have clinical application. Based on current levels of evidence, molecular alterations associated with Barrett’s metaplasiadysplasia-adenocarcinoma progression that may predict individuals with Barrett’s esophagus at risk for malignant progression are summarized in Table 40-1. Confirmation of these results will, however, require the incorporation of biomarkers in ongoing and future prospective endoscopic surveillance studies.

anticipate that future trials will investigate therapies that employ agents targeted to specific molecular alterations. Selective COX-2 inhibition has gained considerable attention as a chemoprevention strategy in Barrett’s metaplasia. Currently there is an ongoing trial (ASPECT) in the United Kingdom investigating the effect of aspirin in addition to proton pump inhibitor therapy on neoplastic progression in patients presenting with Barrett’s metaplasia. And, finally, perhaps molecular events may become indicators of aggressiveness in patients who present with early cancer, helping to decide between endomucosal ablative techniques and more aggressive resectional surgery. T. L.

EPIDEMIOLOGY

COMMENTS AND CONTROVERSIES

Squamous Cell Carcinoma Demographic and Geographic Variations

This chapter describes in a very concise and clear way the actual knowledge and understanding of the molecular pathogenesis of esophageal cancer with special emphasis on Barrett’s esophagus. Indeed, the metaplasia-dysplasia-carcinoma sequence offers a unique model to study the sequences of genetic events that eventually result in the occurrence of an invasive carcinoma. As rightfully stressed by the authors, the genetic alterations and molecular interactions among the different actors (e.g., oncogenes, suppressor genes, growth factor, signaling pathways) only represent a fraction of events that ultimately turn a benign metaplasia into a high-grade dysplasia containing the cancer hallmarks. As a result, the relative importance of these different actors, their interactions, and the pathways by which they mediate their effect is not yet sufficiently understood. Nevertheless, today a number of biomarkers are clearly emerging as potentially useful (e.g., TP53 mutations), and DNA aneuploidy may become routine in endoscopic surveillance programs. Clearly, large-scale studies will be needed to evaluate if the use of such biomarkers will eventually reduce Barrett’s cancer–related mortality. The ongoing unraveling of these molecular events undoubtedly will result in an increase of eventually validated biomarkers, consequently followed by their introduction into clinical practice, the ultimate goal of translational research. In the same way, one may

Recent estimates of the incidence, prevalence, and mortality of common human cancers have documented squamous cell carcinoma of the esophagus to be 1 of the 10 most frequent malignancies worldwide, with a similarly high mortality rate.1 Esophageal cancers exhibit a marked geographic variation in incidence, perhaps greater than for any other tumor, likely reflecting exposure to environmental risk factors (Fig. 40-7). Whereas age-standardized incidence rates in Western countries are generally below 5 per 100,000 population (for males), high-incidence regions with rates above 100 per 100,000 population include China and northern Iran.161 Other well-defined high-risk areas (with rates up to 50 per 100,000 population) include South Africa, Northwest France, and temperate South America, especially Uruguay and northern Argentina. Low-incidence regions (with rates below 10 per 100,000 population) include northern Europe; Japan; the former Soviet Union; middle, western, and northern Africa; central America; western Asia; and Polynesia. However, within each of these broad geographic areas are identifiable smaller regions in which the incidence and mortality rates for esophageal squamous cell carcinoma may be at least 10 to 50 times higher. For example, within three central/northern Chinese provinces (Henan, Hebei, Shanxi), the crude ageadjusted mortality rates vary from 140 per 100,000 in Hebei

447

448

Section 5 Neoplasms

FIGURE 40-7 World map showing geographic regions of high incidence of esophageal cancer.

County to 1.5 per 100,000 in Hunyuan County.162,163 In Henan Province, where a registry was started in 1959, average incidence and prevalence rates for esophageal squamous cell carcinoma were reported as 109 per 100,000 and 379 per 100,000, respectively, and this disease is currently a leading cause of cancer deaths among adult men in this region. Similar regional trends are found in other high-incidence geographic areas. In other countries of the Far East in which accurate registries are kept, esophageal squamous cell carcinoma is most frequent in southern Thailand,164 mountainous regions of Japan,165 and along the southern coast of China.163 In certain regions of Iran bordering the Caspian Sea, the incidence of esophageal cancer is reported to be greater than 100 per 100,000.166 In southern Africa, squamous cell carcinoma of the esophagus is one of the most common cancers among black males in the southern Transkei, central Kenya, and southern Zimbabwe. In contrast to areas in which esophageal cancer has been endemic for centuries, the increasing incidence of this tumor in southern Africa appears to be relatively recent. A marked subregional variation in incidence is also seen within countries of Europe and North America.167 High-incidence clusters of this malignancy are reported in the French provinces of Brittany, Normandy, and Pays de Loire161; northeastern Italy168; and certain industrial cities of central England.169 In the United States further regional variation is seen, with high-incidence areas reported around Washington, DC, and along coastal regions of the southeastern states.170 Age, Gender, and Race. In general, esophageal squamous cell carcinoma is seen infrequently in early adulthood and rising incidence parallels increasing age. In high-incidence regions of China, the incidence of esophageal malignancy increases gradually from age 25 years, with the highest mortality rates for men seen between 60 and 70 years of age. In

the United States, squamous cell carcinoma of the esophagus has been reported infrequently in those younger than age 40 years, beyond which the incidence continues to rise with each successive decade (Fig. 40-8).170 Worldwide, males of all ages are more frequently affected than females. In France, the male-to-female ratio approximates 9:1, whereas in the United States the male-to-female ratio for squamous cell carcinoma ranges from 2.1 : 1 to 3.7 : 1 for all age groups.161 In northern China the male-to-female ratio ranges from 2.6:1 in low-incidence regions to 1.4:1 in regions of high incidence.16,162,163 In high-incidence regions of the Caspian littoral of Iran, the sex ratio is reversed and esophageal cancers are reported more frequently in females.171 As a general rule, the sex ratio narrows in high-incidence regions. Racial or ethnic differences have been reported from highincidence areas of the world, although the significance of these observations is unclear. In western China an increased incidence of esophageal cancer is seen in peoples of the Kazak ethnic group but not in the neighboring Uygurs. The black populations of South Africa and North America appear to be at increased risk for developing esophageal squamous cell tumors, especially if younger than age 55 years, where such a high black/white ratio is seen for no other cancer. Tobacco and Alcohol. Several retrospective as well as prospective studies have consistently demonstrated at least a fivefold to sixfold increased risk of esophageal squamous cell carcinoma among cigarette smokers.168,172-175 Furthermore, smokers of cigars and pipes also appear to be at increased risk. In high-incidence areas, where tobacco smoking is uncommon, other local habits are associated with the development of esophageal cancers, such as chewing opium residue in Iran,171 betel nuts and leaves in India and southern

Chapter 40 Biology and Epidemiology of Malignant Esophageal Carcinoma

20

Rate per 100,000 Person-Years

10

1

9 198

6 198

3 198

0 198

197

7

0.2

Year Squamous cell carcinoma, black men Squamous cell carcinoma, white men Adenocarcinoma, black men Adenocarcinoma, white men FIGURE 40-8 Trends in age-adjusted incidence rates of squamous cell carcinomas and adenocarcinomas of the esophagus among American men by race. (COURTESY OF DR. W. J. BLOT.)

Thailand,164,176 and pipe tobacco residue in southern Africa.177 Clinical observations as well as formal epidemiologic studies indicate that heavy alcohol intake is an independent risk factor in the etiology of esophageal squamous cell carcinoma.168 Alcohol consumption has also been evaluated in cohort studies, which have demonstrated a progressively higher risk of developing squamous cell esophageal cancer among heavy drinkers of hard liquor.175 Cohort studies of beer drinkers demonstrated an increased risk of esophageal cancer among brewery workers in Denmark178 but not in Ireland.179 In certain high-incidence regions of the world such as Iran, where alcohol is forbidden for religious reasons, other environmental factors probably assume greater importance in the pathogenesis of esophageal cancer. One of the most interesting epidemiologic observations is the increased relative risk (exceeding 100-fold) of developing esophageal squamous cell carcinoma when cigarette smoking is combined with heavy alcohol consumption.168,172 Although this observation would imply synergy between chemical mutagens that frequently contaminate tobacco and alcoholic drinks, the precise contribution of each agent to human esophageal carcinogenesis is still undefined. Alcohol, particularly when consumed hot, appears to be a significant risk factor, and may function in part as a promoter by enhancing proliferation of epithelial cells, thereby increasing vulnerabil-

ity to tobacco carcinogens, as well as increasing permeation of carcinogens to the premitotic cells within the mucosa.180 Diet and Nutrition. Perhaps more than for any other malignancy, dietary and nutritional factors have been consistently implicated in the pathogenesis of esophageal cancer.16,161-167 In general, populations living in high-incidence areas of the world have frequently been shown to have poor diets, often with specific nutritional deficiencies, or to be exposed to common dietary carcinogens. Epidemiologic observations have been reproduced in animal models, providing additional compelling evidence for diet in the pathogenesis of esophageal cancer. In the future, dietary supplementation and improved nutritional status may reduce the frequency of esophageal cancer in high-risk populations. Several nutritional surveys of high-incidence regions worldwide have suggested that diets rich in carbohydrate and low in animal protein, green vegetables, and fruit were associated with the development of esophageal cancer.183,184 Cholesterol consumption in the form of butter may contribute to a large proportion of esophageal cancers in high risk areas in France.185 Although overt clinical malnutrition was uncommon, most diets were also deficient in vitamins, trace elements, or minerals. For example, deficiency of vitamin A has been associated with esophageal tumorigenesis in humans and laboratory animals.186,187 Dietary supplementation with vitamin A was found to prevent carcinogen-induced esophageal tumors in animals.188 Prospective dietary intervention studies, supplementing high-risk populations in China with multiple vitamins and minerals, are ongoing to assess the efficacy of this approach to cancer prevention. Epidemiologic studies have also supported a role for direct ingestion of dietary carcinogens in esophageal cancer, because the esophagus is frequently the first mucosal site to contact potentially harmful dietary components. Specifically, exposure to nitrosamines and their precursors (nitrates and nitrites) has been shown to be common in high-incidence regions of northern China for both humans and domestic animals sharing common water and food sources.189 Similarly, increased exposure to nitrosamines has been reported in Iran,166 southern Africa,167 India,190 and southern Thailand.164 Nitrosamines induce esophageal tumors in laboratory animals. Carcinogenic N-nitroso compounds are formed endogenously by reaction of nitrates with secondary or tertiary amines. Major sources of ingested nitrates are pickled vegetables, cured meats or fish, and alcoholic drinks. Fungal contamination of such foods may further increase levels of dietary amines and promote increased nitrosamine formation. In addition, high levels of carcinogenic polycyclic aromatic hydrocarbons in food may contribute to the high incidence of esophageal cancer in certain provinces of China.191

Adenocarcinomas Demographic and Geographic Variations Over the past 3 decades, a marked change in the epidemiology of esophageal malignancy in North America and Europe has been reported.2-5 While the frequency of esophageal squamous cell carcinoma has remained steady, an increasing incidence of esophageal adenocarcinoma has been observed, a

449

450

Section 5 Neoplasms

trend confirmed by several population-based studies. Although still a relatively uncommon malignancy in the United States, the incidence of esophageal adenocarcinoma in males increased from 0.72 per 100,000 population in the mid 1970s to 3.7 per 100,000 population over 2 decades later, an increase of greater than 400%, a rate of increase exceeding any other solid tumor over the same time interval.2,170,193 Indeed, by 1990, esophageal adenocarcinoma surpassed squamous cell carcinoma as the most common histologic subtype of esophageal cancer, accounting for more than half of all esophageal tumors. Similar trends were reported from Europe, where the incidence rates for esophageal adenocarcinoma are highest in Scotland (9 per 100,000 population).3 Age, Gender, and Race. Esophageal adenocarcinomas are generally reported to be most frequent in the 55- to 60-year age range. Although most frequent in white males, a similar increase in incidence from the mid 1970s has been seen in African American males from 0.35 per 100,000 to 0.81 per 100,000, and in white females from 0.11 per 100,000 to 0.47 per 100,000 in the United States.170,192

Barrett’s Esophagus and Gastroesophageal Reflux Disease Most primary esophageal adenocarcinomas are thought to arise from Barrett’s esophagus; progression of Barrett’s esophagus to invasive adenocarcinoma is reflected histologically by the metaplasia-dysplasia-carcinoma sequence.10 Dysplasia is widely regarded as the precursor of invasive cancer, and high-grade dysplasia in Barrett’s epithelium is frequently associated with esophageal adenocarcinoma.193,194 The risk for malignant progression has been estimated to vary from 1 in 50 to 1 in 400 patient-years, with a mean risk of about 1 in 100 patient-years.195,196 Studies of the epidemiology of Barrett’s esophagus have generally reported incidence and prevalence rates for classic long-segment disease and have varied between populations.197 However, several trends are apparent; Barrett’s esophagus appears to be more frequent in males, with prevalence rising with age and a mean age at diagnosis of 63 years.198,199 For patients who undergo endoscopy for upper gastrointestinal symptoms (predominantly reflux-related), current estimates suggest a prevalence for Barrett’s esophagus of 3% to 8%, compared with patients who undergo endoscopy for any clinical indication, where a prevalence of around 1% is reported.200-202 However, based on autopsy series, the prevalence of Barrett’s esophagus may actually be much higher (approximately 20 times) in the general population.203 Although families with Barrett’s esophagus have been occasionally reported, this is quite uncommon, and a genetic locus for familial GERD and/or Barrett’s esophagus has not been identified.204 Earlier reports described associations between Barrett’s esophagus and use of anticancer chemotherapy,205 in addition to various intrinsic esophageal diseases including scleroderma,206 after lye ingestion,207 post gastrectomy,208 and after myotomy for achalasia.209 It is currently unclear whether the prevalence of Barrett’s esophagus is increasing or whether this diagnosis is being made more frequently because of widespread use of endos-

copy.210,211 Preliminary data from the United Kingdom, adjusting for increasing numbers of endoscopic procedures, suggests a real increase in prevalence of Barrett’s esophagus.212 These trends have also been confirmed in The Netherlands.213 Other studies have reported that while the prevalence of long-segment Barrett’s esophagus remains unchanged, it is the prevalence of short-segment Barrett’s esophagus that is increasing, a phenomenon related in part to increased recognition and awareness of this condition.214 Estimates of the prevalence of short-segment Barrett’s esophagus in unselected patients currently range from 2% to 13%.215,216 Although several studies have addressed the epidemiology of Barrett’s esophagus and esophageal adenocarcinoma, relatively few have investigated the prevalence of dysplasia within Barrett’s epithelia. Based on careful pathologic examination of resected esophageal adenocarcinomas, dysplastic changes are present in a relatively high percentage of associated Barrett’s epithelia.193,194,217,218 However, the prevalence of dysplasia in patients with Barrett’s esophagus who undergo endoscopy for any reason is estimated to be below 10%.198, 216,219,220 Recent population-based studies have reported strong statistical associations between chronic GERD and risk for esophageal adenocarcinoma but not for esophageal squamous cell carcinoma.221 However, GERD is highly prevalent in the general population, and it is estimated that up to 20% of adults have reflux symptoms on a weekly basis; the cancer risk for an individual with GERD is low.11 It is more likely that obesity and lifestyle risk factors (see later) interact with molecular genetic alterations to modulate individual susceptibility for progression to esophageal adenocarcinoma.

Tobacco, Alcohol, Diet, and Obesity Although strong statistical associations between GERD, Barrett’s esophagus, and risk for esophageal adenocarcinoma have now been reported, lifestyle risk factors are less well defined and remain controversial. In particular, the contribution of smoking, alcohol consumption, and diet to the pathogenesis of esophageal adenocarcinoma is controversial. To date, most studies have reported only a moderate increased risk for esophageal adenocarcinoma among smokers.184,222-224 One recent study clearly established that smoking is associated with high rates of DNA damage in esophageal squamous (and columnar) epithelium, increasing the likelihood of genetic change in esophageal epithelium, providing a sound biologic basis for malignant progression.225 The role of alcohol consumption as a risk factor for esophageal adenocarcinoma is also unclear, with only about half of all published studies reporting a positive, but generally weak, association.223,224,226,227 In contrast to data pertaining to esophageal squamous cell carcinoma, relatively few studies have critically evaluated dietary risk factors for esophageal adenocarcinoma. Increased dietary fat and low intake of fruit, raw vegetables, fiber, and vitamins, particularly vitamin C, have been associated with increased risk of esophageal adenocarcinoma.228-230 Similar dietary risk factors have also been reported for GERD and

Chapter 40 Biology and Epidemiology of Malignant Esophageal Carcinoma

Barrett’s esophagus. Increased consumption of dietary nitrate, principally derived from green leafy vegetables, has recently been implicated in esophageal adenocarcinogenesis.231 It was proposed that increased use of nitrate-based fertilizers since the 1950s may account for recent epidemiologic trends and that ingested nitrate is converted into nitric oxide at the esophagogastric junction, the first point of contact with ascorbic acid in the stomach. As prevalence rates for obesity have increased dramatically, and in parallel with reported epidemiologic changes for many human cancers, obesity was proposed as a major risk factor for esophageal adenocarcinoma, an observation now supported by a number of case-control studies.232-238 However, relatively few studies have evaluated the effects of excess weight on the precursor lesion, Barrett’s esophagus, and clinically symptomatic GERD, a well-recognized risk factor for both Barrett’s esophagus and esophageal adenocarcinoma. One study reported obesity as a risk factor for Barrett’s esophagus for patients younger than age 50 years only, whereas a second study found no association between body mass index (BMI) and Barrett’s esophagus and selected biomarkers (flow cytometry, allelic loss of chromosome 9p or 17p). However, the latter study did demonstrate increasing risk between cell cycle and genetic abnormalities (aneuploidy and 17p loss, respectively) in Barrett’s esophagus and increasing waist-to-hip ratio, supporting the notion that distribution of body fat (male-pattern obesity) may be more important than BMI.239 Similarly, the association between BMI and GERD has been controversial, with a number of wellperformed studies reporting no clear relationship.240-242 However, more recent reports have demonstrated obesity to be a significant risk factor for GERD,243-246 with a clear association between increasing BMI and the severity and frequency of GERD symptoms and objective measurement of distal esophageal acid exposure.247 The observation that the strongest association between obesity and GERD was reported in females (especially those who were premenopausal or using hormone replacements) suggests that female sex hormones may play an important role in the pathogenesis of GERD.245,246 It has been hypothesized that estrogens may modulate nitric oxide–mediated reduction of smooth muscle tone in the lower esophageal sphincter (LES), which is an important barrier to reflux.246 The precise mechanism(s) underlying the reported association between body mass and GERD or Barrett’s esophagus, both of which are important risk factors for progression to esophageal adenocarcinoma, have not yet been defined. It has been suggested that overweight/obese individuals may have associated esophageal dysmotility, resulting in reduced esophageal clearance or increased intra-abdominal pressure and hiatal hernia, with consequent mechanical disruption of LES function. LES function may also be altered by smoking, dietary factors including high fat, increased alcohol consumption, and a variety of medications that relax the LES and predispose to GERD. Indeed, an increased risk for esophageal adenocarcinoma has been observed in individuals taking various LES-relaxing drugs, including long-term use of theophylline and β-agonists.248,249 Finally, several metabolic consequences of obesity may play a role in carcinogen-

esis, possibly mediated by leptin and insulin, as well as insulin-like growth factor, which has been shown to stimulate cell proliferation and inhibit apoptosis, although these would not be specific to esophageal malignancy.250-252 Adenocarcinomas of the Esophagogastric Junction. In parallel with the rising incidence of primary esophageal adenocarcinomas described in preceding sections, adenocarcinomas arising at the esophagogastric junction (cardia) have also been reported with increasing frequency over the past 3 decades. To date, many epidemiologic and clinical studies have classified adenocarcinomas of the lower esophagus and esophagogastric junction as a single entity. However, there is increasing evidence from clinical, pathologic, epidemiologic, and molecular studies to support the hypothesis that such tumors are of primary gastric (vs. esophageal) origin and should therefore be considered as a distinct tumor type. Although not the focus of this chapter, the reader is referred to recent work related to these interesting, and controversial, tumors.253

Miscellaneous Associations and Risk Factors Various intrinsic diseases of the esophagus have been reported to be associated with the development of esophageal malignancy, particularly squamous cell carcinoma, although patient numbers are inevitably small and statistical correlation is difficult. Plummer-Vinson (Patterson-Kelly) Syndrome. Atrophy of the oropharyngeal and esophageal mucosa secondary to iron and vitamin (nicotinamide and lactoflavin) deficiency was found to be associated with increased risk for developing squamous cell carcinoma of the cervical esophagus and hypopharynx.254 This Scandinavian study also reported that correction of iron-deficiency anemia reduced the incidence of these tumors. Esophageal Mucosal Injury and Stricture. Esophageal mucosal injury from chronic ingestion of hot liquids or foods has been associated with cancer development in high-risk regions of France,255 China,16,256 Iran,257 Japan,258 Thailand,164 Brazil,259 Paraguay,260 and Uruguay.261 Occasional case reports suggest that esophageal malignancy may develop as a late complication of acid- or lye-induced esophageal strictures.262 Experimental studies in rats with surgically induced esophageal strictures demonstrated increased numbers of carcinogen-induced esophageal tumors at the site of esophageal narrowing as compared with control rats without stenosis.263 Achalasia. Squamous cell carcinoma has been reported to develop as a late complication of achalasia. The observation of only 13 tumors in more than 1300 patients with achalasia suggested this complication occurs infrequently.264 A population-based study from Sweden documented a 16-fold increased risk of esophageal cancer from 1 to 24 years after the diagnosis of achalasia.265 Although the precise etiology of this functional esophageal disorder is unknown, prolonged mucosal exposure to ingested carcinogens secondary to stasis is proposed as a possible factor predisposing to malignancy. Diverticula. Esophageal diverticula are rare and are frequently associated with functional esophageal disorders. A

451

452

Section 5 Neoplasms

few case reports have documented an association between esophageal cancer and pharyngoesophageal,266 midesophageal,267 and epiphrenic diverticula.268 Infectious Causes. Evidence suggesting infectious agents in the pathogenesis of esophageal squamous cell carcinoma was extrapolated from associations between human papillomavirus and herpes simplex virus infection and oral cancer, Epstein-Barr virus and nasopharyngeal cancer, and Helicobacter pylori infection and gastric cancer. However, subsequent epidemiologic studies have not conclusively linked infection with esophageal malignancy, although this is an area of ongoing research. The association with H. pylori is particularly interesting, because gastric infection with cag-A–positive strains appears to be inversely associated with the development of esophageal adenocarcinoma.269 Multiple Primary Tumors of the Upper Aerodigestive Tract. Patients with cancers of the upper aerodigestive tract (oropharynx, lung, and esophagus) exhibit an increased risk for developing second, or multiple, primary tumors. The finding of discordant TP53 gene mutations in multiple primary cancers of the upper aerodigestive tract suggests that such tumors may arise as independent events.270 Occupational Exposure. Reports of increased risk secondary to occupational exposure to asbestos, silica, and rubber are infrequent.271,272 Familial Clusterings. Observations of familial clusterings of esophageal cancer raise the question of whether such individuals were at increased risk because of underlying genetic factors or because of exposure to a common environmental factor, such as a dietary carcinogen.273,274 Earlier reports of esophageal cancer families from Iran and China initially suggested no apparent genetic predisposition. Slight associations were reported of esophageal cancers with blood group A, HLA-A2, and HLA-B40 and with cytogenetic aneuploidy in high-risk families in Linxian, China.275 However, the first formal genetic segregation analysis of 221 high-risk families in Linxian suggested an autosomal recessive mendelian inheritance, with the putative gene present at a frequency of 19% in this subpopulation.276 Tylosis, a rare autosomal dominant disorder, is an uncommon familial syndrome characterized by thickening, or hyperkeratosis, of the skin of the soles of the feet and the palms of the hands. In the largest series of four families with tylosis, almost 40% of family members developed squamous cell carcinoma of the esophagus by their mid 40s.277 It was estimated that members of these four families would have a 95% risk of developing esophageal cancer by age 65 years. Similarly, members of the first American family recently described with this condition were also estimated to have at least a 90% risk of developing esophageal malignancy by age 65 years.278 Using linkage analysis on U.K. and U.S. family members, the tylosis esophageal cancer gene was localized to a small region on chromosome 17q25; recent LOH studies have further implicated this gene in sporadic esophageal tumors.279

Summary Cancer of the esophagus remains a leading cause of morbidity and mortality throughout the world. During recent years,

considerable insight has been achieved regarding the molecular pathogenesis of esophageal malignancy. Presently, however, no molecular biomarker is sufficiently robust to use as a surrogate endpoint for clinical trials involving early detection or chemoprevention of esophageal cancer, or for assessing prognosis or treatment response in patients with advanced disease. Further studies involving the epidemiology of esophageal cancer as well as evaluation of molecular alterations associated with esophageal carcinogenesis may facilitate further advances regarding the early detection, staging, and treatment of this highly lethal disease.

COMMENTS AND CONTROVERSIES The most important and fascinating aspect in the epidemiology of cancer of the esophagus is the dramatic increase of adenocarcinoma of the esophagus and gastroesophageal junction. This phenomenon is thought to be related to a real increase, at least in some countries, in the occurrence of gastroesophageal reflux–induced Barrett’s metaplasia and its well-known relation with adenocarcinoma through the metaplasia-dysplasia-carcinoma sequence. Besides the correlation between reflux, Barrett’s metaplasia, and risk for adenocarcinoma, obesity and lifestyle factors such as alcohol and tobacco use are thought to interact with molecular alterations that eventually may result in a progression into development of adenocarcinoma. Dietary risk factors are intensely studied. The nitrate-nitrite hypothesis with high nitric oxide concentration from chemical reactions within the lumen may damage the surrounding epithelium with an increased carcinogenic effect. Further studies may reveal new pathways in chemoprevention by reduction in dietary nitrates. The association between mixed bile and acid reflux and Barrett’s metaplasia is well accepted. In this respect the role of proton pump inhibitor therapy and its resulting change in pH profile is questioned. Acid suppression results in deconjugation of bile acids that appear to be toxic to the esophageal mucosa, nearing a pH of 7. The decreased volume of acid as induced by proton pump inhibitor therapy results in an increased concentration of bile acids exercising their noxious effect on the esophageal mucosa. This phenomenon may perhaps in part explain the increased diagnosis of short and ultra-short esophagus. The latter may be the consequence of mixed acid-bile–induced carditis. This supports the idea that both adenocarcinoma of distal esophagus and gastroesophageal junction at least in part have a common denominator, that is, intestinal metaplasia. Such similar oncologic behavior differentiates them as a separate entity from cancer of gastric origin. Barrett’s metaplasia and its rising incidence are an ideal model to refine recognition, diagnosis of intestinal metaplasia, and subsequent evolution toward dysplasia and early carcinoma. Highresolution and magnification endoscopy, narrow band imaging, chromoendoscopy, and confocal endoscopic microscopy are all being introduced in clinical practice, all of course resulting in an increase of the health care economics. So the debate continues regarding screening and surveillance, particularly since a substantial number of patients with Barrett’s metaplasia are asymptomatic. Perhaps lessons can be learned from the successful application of brush cytology obtained by swallowing a capsule as a simple and inexpensive screening tool so efficiently demonstrated in China for screening of squamous cell carcinoma in a high-risk population. T. L.

Chapter 40 Biology and Epidemiology of Malignant Esophageal Carcinoma

KEY REFERENCES Blot WJ, McLaughlin JK: The changing epidemiology of esophageal cancer. Semin Oncol 26:2, 1999. Lagergren J: Adenocarcinoma of oesophagus: What exactly is the size of the problem and who is at risk? Gut 54:1, 2005. Macdonald F, Ford CHJ, Casson AG: Molecular Biology of Cancer, 2nd ed. Abingdon, Oxfordshire, England, Taylor & Francis/Garland Science/Bios Scientific Publishers, 2004.

McManus DT, Olaru A, Meltzer SJ: Biomarkers of esophageal adenocarcinoma and Barrett’s esophagus. Cancer Res 64:1561, 2004. Reid BJ, Blount PL, Rabinovitch PS: Biomarkers in Barrett’s esophagus. Gastrointest Clin North Am 13:369, 2003. Wong A, Fitzgerald RC: Epidemiologic risk factors for Barrett’s esophagus and associated adenocarcinoma. Clin Gastroenterol Hepatol 3:1, 2005.

453

Management chapter

41

DIAGNOSIS AND STAGING OF ESOPHAGEAL CANCER Thomas W. Rice

Key Points ■ cTNM is clinical classification and it is best determined by the

■ ■

■ ■

combination of endoscopic ultrasonography (EUS), endoscopic ultrasonography with fine-needle aspiration (EUS-FNA), and fused positron emission tomography and computed tomography (PET/CT). pTNM is pathologic classification and it supplements cTMN with information acquired during or from surgery. ycTNM is the clinical classification obtained during multimodality therapy, and ypTNM is the pathologic classification after multimodality therapy. rTNM is recurrent classification and is determined after a diseasefree interval. aTNM is autopsy classification, and it is determined at autopsy.

(>99%) (Figs. 41-3 and 41-4). Pathologic analysis of these specimens provides both histologic type and grade of the esophageal cancer. In the exceptional case of a patient whose esophagoscopy and biopsy fail to confirm the clinical diagnosis, endoscopic ultrasonography (EUS) and fine-needle aspiration (EUS-FNA) of the abnormal esophageal wall are useful in the diagnosis of malignant strictures that are not endoscopically accessible.2 FNA or open biopsy of distant metastases provides a pathologic diagnosis and crucial staging. Surveillance of high-risk groups allows diagnosis of earlystage cancer in asymptomatic patients. This process is costeffective compared with other cancer surveillance programs.3,4 Patients with a columnar-lined esophagus without dysplasia on two endoscopic examinations should have esophagoscopy and biopsy (4-quadrant biopsies every 2 cm) every 3 years after two negative examinations.5

STAGING DIAGNOSIS Clinical diagnosis of esophageal cancer is obtained from history, physical examination, and barium esophagography. In the Western world, the classic presentation is dysphagia to solid foods in a middle-aged to elderly white male with a long-standing history of reflux and a known hiatal hernia. This is treated as an esophageal adenocarcinoma until proven otherwise. Physical examination typically reveals a robust male without weight loss, with potential comorbidities, and without clinically detectable metastases to nonregional lymph nodes (supraclavicular) or distant sites (e.g., liver, pleura). In contradistinction, a patient with squamous cell carcinoma is usually from an endemic area and a lower socioeconomic class, with a history of dysphagia, weight loss, heavy smoking and drinking, and an advanced-stage carcinoma. Barium esophagography, the first investigation in the evaluation of dysphagia and the clinical diagnosis of esophageal cancer (Fig. 41-1), has been replaced by flexible fiberoptic videoesophagoscopy in many centers (Fig. 41-2). However, in patients with esophageal cancer, modern barium esophagography has been reported to detect a lesion in 98% of barium studies, was suggestive or diagnostic of esophageal carcinoma in 96%, and had an estimated positive predictive value of 42%.1 For many physicians barium esophagography remains the principal test for the clinical diagnosis of esophageal cancer. Clinical diagnosis of esophageal cancer requires tissue confirmation. Flexible esophagoscopy is the procedure of choice for the pathologic diagnosis of esophageal cancer. Cytology brushings and multiple biopsies are diagnostic in most patients 454

Staging of esophageal cancer using the TNM classification is obtained by evaluation of the primary tumor (T), regional lymph nodes (N), and distant sites (M) (Table 41-1) (Greene et al, 2002).6 The primary esophageal tumor (T) is defined only by the depth of invasion (Fig. 41-5). Tis tumors are intraepithelial malignancies, confined to the epithelium without invasion of the basement membrane (high-grade dysplasia). T1 cancers breach the basement membrane to invade the lamina propria, muscularis mucosae, or the submucosa but do not invade beyond the submucosa. T2 cancers invade into, but not beyond, the muscularis propria. T3 cancers invade beyond the esophageal wall into the paraesophageal tissue but do not invade adjacent structures. T4 cancers directly invade structures in the vicinity of the esophagus. The broad definition of T1 cancers has prompted the clinically accepted practical subdivision of this subset into T1 intramucosal cancers (T1a), which invade the lamina propria or muscularis mucosae, and T1 submucosal cancers (T1b) (see Fig. 41-5). Multiple primary cancers are denoted by the suffix “m” recorded in parentheses as pT(m)NM. Regional lymph nodes (N) are characterized only by the absence (N0) or presence (N1) of metastases in lymph nodes in the area of the primary cancer (see Table 41-1 and Fig. 41-5). Distinction of a regional lymph node from a nonregional lymph node may be problematic despite the broad definition in the staging manual (Greene et al, 2002).6 The regional lymph node map is crucial for clinical staging and lymph node sampling (Fig. 41-6). Lack of subclassification of N1 is a shortcoming of the present staging system. N1 lymph node burden is a prognosticator, and many physicians

Chapter 41 Diagnosis and Staging of Esophageal Cancer

FIGURE 41-3 Adenocarcinoma cells obtained from brushing of Barrett’s esophagus. Clusters of neoplastic cells are seen with hyperchromatic, pleomorphic nuclei and loss of polarity but with retained columnar configuration and cytoplasmic mucin.

FIGURE 41-1 Barium esophagogram of a malignant esophageal stricture. This long, irregular stricture has mucosal destruction and irregular filling defects obstructing the esophageal lumen.

substage N1 depending on the total number of N1 nodes and percent of resected lymph nodes that are N1.7-10 Similarly, distant sites (M) are characterized by the presence (M1) or absence (M0) of metastases (see Table 41-1). The 1997 revision of the staging system for esophageal cancer subdivided distant metastatic carcinomas (M1) into M1a (distant, nonregional lymph node metastases) and M1b (other distant metastases).11 M1a disease is classified further by tumor location: M1a cancers of the upper thoracic esophagus metastasized to cervical nodes and M1a cancers of the lower thoracic esophagus metastasized to celiac lymph nodes. No M1a subdivision for midthoracic esophageal cancers exists because these tumors’ metastatic to nonregional lymph nodes are assumed to have an equivalent prognosis to those metastatic to other distant sites. Although this subclassification has anatomic and statistical significance, the clinical relevance is questionable and should probably be eliminated.9,12 TNM descriptors are grouped into stages to assemble subgroups with similar behavior and prognosis (see Table 41-1). Despite shortcomings,7-10 the present staging system is an essential tool in the evaluation and treatment of esophageal cancer.

Clinical Staging All information obtained before definitive treatment establishes clinical classification (cTNM). Evidence is derived from physical examination, imaging, esophagoscopy, laparoscopy, thoracoscopy, biopsy, and needle aspiration. Clinical classification is assigned before any treatment and is not changed by subsequent information. Every patient must be clinically staged to permit rational treatment decisions. Clinical classification is also used when treatments are evaluated.

Determination of cT Classification FIGURE 41-2 Esophagoscopy and biopsy, following brush cytology, of a malignant esophageal stricture.

Esophageal EUS is the only clinical tool that provides detailed examination of the esophageal wall. It is the procedure of choice for determining cT. The muscularis propria (fourth

455

456

Section 5 Neoplasms

FIGURE 41-4 A, Superficial mucosal biopsy specimen shows malignant glands undermining intact squamous mucosa. This is at least intramucosal cancer. No goblet cells are seen. B, Higher magnification demonstrates malignant glands infiltrating the lamina propria below the squamous epithelium. TABLE 41-1 TNM Classification for Staging of Esophageal Carcinomas T TX T0 Tis T1

T4

Primary Tumor Tumor cannot be assessed. No evidence of tumor High-grade dysplasia Tumor invades the lamina propria, muscularis mucosae, or submucosa. It does not breach the submucosa. Tumor invades into, but not beyond, the muscularis propria. Tumor invades the paraesophageal tissue but does not invade adjacent structures. Tumor invades adjacent structures.

N NX NO N1

Regional Lymph Nodes Regional lymph nodes cannot be assessed. No regional lymph node metastases Regional lymph node metastases

M MX M1a:

Distant Metastasis Distant metastases cannot be assessed. Upper thoracic esophagus metastatic to cervical lymph nodes Lower thoracic esophagus metastatic to celiac lymph nodes Upper thoracic esophagus metastatic to other nonregional lymph nodes or other distant sites Midthoracic esophagus metastatic to either nonregional lymph nodes or other distant sites Lower thoracic esophagus metastatic to other nonregional lymph nodes or other distant sites

T2 T3

M1b

Stage Groupings Stage 0 Stage I Stage IIA Stage IIB Stage III Stage IVA Stage IVB

Tis T1 T2 T3 T1 T2 T3 T4 Any T Any T

N0 N0 N0 N0 N1 N1 N1 Any N Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b

From Greene FL, Page DL, Fleming ID, et al (eds): Digestive system: Esophagus. In AJCC Cancer Staging Manual, 6th ed. New York, Springer, 2002, pp 91-98.

ultrasound layer) is critical in differentiating T1, T2, and T3 cancers. EUS also evaluates the interface between the primary cancers and adjacent structures. Cancers are defined as follows: cTis: Cytologically malignant cells contained by the basement membrane cT1: Invasion not beyond the submucosa (first to third ultrasound layers) cT2: Invasion confined to the muscularis propria (fourth ultrasound layer) cT3: Invasion beyond the muscularis propria (fifth ultrasound layer) cT4: Invasion of adjacent structures In a review of 21 series, accuracy of EUS for determination of T classification was 84%.13 Accuracy is not constant and varies with T classification. In this meta-analysis, accuracy for T1 cancers was 83.5%, with 16.5% of tumors overstaged; accuracy for T2 was 73% with 10% understaged and 17% overstaged; accuracy for T3 was 89% with 5% understaged and 6% overstaged; and accuracy for T4 was 89% with 11% understaged. A review of the literature shows variation in accuracy with T classification: 75% to 82% for T1, 64% to 85% for T2, 89% to 94% for T3, and 88% to 100% for T4.14 The most unreliable of EUS determinations is for T2.15 Despite significant clinical staging error, cT2 N0 M0 may be useful in clinical decisions, because the majority of patients have overstaged T1b cancers.16 Exclusion of cT4 cancers, demonstrated by preservation of fat planes between an esophageal cancer and adjacent structures, is the only role of CT in the determination of cT (Fig. 41-7). Contiguous soft tissues provide radiographic contrast necessary to define the esophagus; however, these planes may be absent in cachectic patients. In some “normal” patients fat between an esophageal cancer and aorta, trachea, left main bronchus, or pericardium may be absent. This physiologic absence of fat planes complicates the assessment of invasion of adjacent structures. Alternate CT findings have been devised to predict T4 cancers. Aortic invasion is suggested by

Chapter 41 Diagnosis and Staging of Esophageal Cancer

T1 Submucosal HGD

Epithelium

T2 T1 intramucosal T3

T4

Basement membrane Lamina propria Muscularis mucosae Submucosa Muscularis propria Periesophageal tissue

N0 N1

Aorta

FIGURE 41-5 Primary tumor classification (T) is defined by depth of tumor invasion. Regional lymph node classification (N) is defined by the absence (N0) or presence (N1) of regional nodal metastases. HGD, high-grade dysplasia (Tis). (COPYRIGHT © 2000, CLEVELAND CLINIC FOUNDATION.)

an arc of contact between the tumor and the aorta that is more than 90 degrees. This finding is not an absolute confirmation of a T4 cancer. Thickening or indentation of the normally flat or slightly convex posterior membranous wall of the intrathoracic trachea or left main bronchus is suggestive of airway invasion. On occasion, cancers invading the airway lumen or a fistula between the esophagus and airway may be visualized by CT; however, confirmatory bronchoscopy with biopsy is necessary. Pericardial invasion is suspected if pericardial thickening, pericardial effusion, or indentation of the heart with loss of the pericardial fat plane at the level of the cancer is demonstrated. MRI offers no significant advantage over CT. Theoretically, thoracoscopy or laparoscopy could exclude cT4 cancers but requires dissection of the primary cancer and adjacent structure thought to be invaded. Although mentioned as a possible staging tool for cT4 classification,17,18 the only documentation of T classification has been the detection of cT4 disease in 14% of patients undergoing thoracoscopy and laparoscopy for regional lymph node staging.19 Using positron emission tomography, 2-[18F]fluoro-2deoxy-D-glucose (FDG-PET) has been reported to accumulate in 92% to 100% of esophageal cancers.20,21 However, FDG-PET and other imaging modalities do not provide definition of the esophageal wall or paraesophageal tissue and,

therefore, have no value in the determination of cT. FDGPET has been reported to be useful in detecting multiple primary cancer, pT(m).22 PET/CT has been used to differentiate benign from malignant esophageal disease. Esophageal cancers have eccentric, focal uptake in the esophageal wall, whereas benign disease is associated with luminal uptake or concentric, diffuse, homogeneous mural uptake.23

Determination of cN (Regional) and cM1 (Nonregional) Lymph Node Classifications Endoscopic ultrasonography is used to evaluate nodal size, shape, border, and internal echo characteristics in regional lymph node assessment. In a retrospective review of 100 EUS examinations, EUS classification of lymph node status was 89% sensitive, 75% specific, and 84% accurate.24 The positive predictive value of EUS for N1 disease was 86%; the negative predictive value was 79%. In a meta-analysis of 21 series, the accuracy of EUS classification of lymph node status was 77%, of N0, 69%, and of N1, 89%.13 EUS-FNA further refines clinical staging by adding tissue sampling to EUS findings. In a multicenter study, 171 patients had EUS FNA of 192 lymph nodes.25 The accuracy of EUS-FNA in determination of lymph node status was sensitivity, 92%; specificity, 93%; positive predictive value, 100%; and

457

458

Section 5 Neoplasms

1

2L

2R

4L 4R 10R

6 2L

5

3P

6

10L

5

7

4L

8M 9 9 8L

8M 9

15

8L 16

15

16 17

18

20

19

17 18

20 19

A

B

2R 4R 4R

8M

9 8R

17

19 20 18

C FIGURE 41-6 Lymph node map for esophageal cancer. A, Anterior view. B, Left lateral view. C, Right lateral view. Lymph node stations: 1, supraclavicular; 2R, right paratracheal; 2L, left paratracheal; 3P, posterior mediastinal; 4R, right tracheobronchial angle; 4L, left tracheobronchial; 5, aortopulmonary; 6, anterior mediastinal; 7, subcarinal; 8M, middle paraesophageal; 8L, lower paraesophageal; 9, inferior pulmonary ligament; 10, hilar; 15, diaphragmatic; 16, paracardial; 17, left gastric; 18, common hepatic; 19, splenic; 20, celiac. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Chapter 41 Diagnosis and Staging of Esophageal Cancer

FIGURE 41-7 A, Nonspecific CT finding of esophageal cancer is thickening of the esophageal wall. CT does not discriminate between cTis, cT1, cT2, and cT3 cancers. Preservation of periesophageal fat excludes cT4 cancer. In this study, preservation of the posterior fat plane (arrow) excludes invasion of the prevertebral fascia. Although suggestive of aortic invasion, the absence of a fat plane between the tumor and aorta (arrowhead) is not diagnostic. B, Esophageal cancer (T) is surrounded by fat. An enlarged thoracic lymph node (arrow) is seen.

negative predictive value, 86%. The combination of EUS and EUS-FNA of celiac lymph nodes deemed positive by EUS had a sensitivity of 72%, a specificity of 97%, a positive predictive value of 95%, and a negative predictive value of 82%.26 FNA confirmed positive EUS M1a disease in 88% of patients. Surface ultrasound examination of cervical lymph nodes has been reported to detect nonpalpable metastasis in patients with squamous cell carcinoma.27,28 Thoracoscopic and laparoscopic staging has been used to evaluate cN and cM1 lymph node status. A combination of thoracoscopic and laparoscopic staging was reported 94% accurate in detecting lymph node metastases.19 For thoracic lymph nodes, sensitivity, specificity, and positive predictive value were 63%, 100%, and 100%, respectively. For abdominal lymph nodes, sensitivity, specificity, and positive predictive value were 85%, 100%, and 100%, respectively. Of 88 patients entered into the study, thoracoscopy was performed in 82 (93%), laparoscopy in 55 (63%), and both in 49 (57%). Induction chemoradiotherapy was administered to 34 (39%) patients. Only 47 (53%) patients underwent resection, making comparative pathologic stage available in only 13 (15%) patients. The best operative time and hospital stay reported are 3.6 hours and 1.8 days, respectively.29 These procedures are not without serious morbidity.30 An enlarged lymph node by CT suggests nodal metastasis (see Fig. 41-7). The short axis of these nodes is easily measured; intrathoracic and abdominal lymph nodes larger than 1 cm are enlarged. Supraclavicular lymph nodes with a short axis greater than 0.5 cm and retrocrural lymph nodes greater than 0.6 cm are pathologic.31 The probability that cN status can be determined by lymph node size alone is small.32 Normal-sized nodes may contain metastatic deposits, and metastatic nodes in direct contact with the tumor may be indistinguishable from the primary tumor. These situations result in false-negative examinations and influence the sensi-

tivity and negative predictive value. All enlarged lymph nodes may not be malignant. Inflammatory nodes are the most common cause of a false-positive examination, lower specificity, and positive predictive value. CT assessment of lymph nodes varies with anatomic site; accuracies of 61% to 96%, sensitivities of 8% to 75%, and specificities of 60% to 98% were reported for cervical, mediastinal, and abdominal nodes.33 Again, MRI offers no important advantage over CT. The physiologic evaluation of esophageal cancer provided by FDG-PET relies not only on size of the metastatic deposit but also on the intensity of FDG uptake and decay. Theoretically, it is possible to identify microscopic metastases if glucose metabolism is sufficient to concentrate large quantities of FDG. FDG-PET may not be able to differentiate adjacent N1 from the primary cancer (Fig. 41-8).20 The accuracy of FDG-PET in the detection of lymph node metastases from esophageal cancer is highly variable, ranging from 37% to 90%.21,34-36 Compared with detection of lymph node metastases in lung cancer, FDG-PET is much less accurate in esophageal cancer.37 Because of its high sensitivity, the main role of FDG-PET is confirmation of cN0 classification.38 The addition of [Methyl-(11)C]choline PET to FDG-PET has been reported to increase the accuracy of PET cN1 staging,39 but it has not gained clinical acceptance. Co-registered PET and CT examinations and fused PET/ CT studies have improved observer confidence and diagnostic performance by combining anatomic and metabolic information.40 PET/CT has been reported to improve the classification of cN. Referent values for PET/CT versus PET alone for cN1 in squamous cell cancer of the esophagus were accuracy, 92% versus 86% (P = .006); sensitivity, 94% versus 82% (P = .03); specificity, 92% versus 87% (P = .07); positive predictive value, 75% versus 63% (P = .06), and negative predictive value 98% versus 95% (P = .04).41

459

460

Section 5 Neoplasms

FIGURE 41-9 On CT hepatic metastases appear as ill-defined, low-density lesions of variable size.

FIGURE 41-8 PET scan of a T3 N1 M1b esophageal cancer. Primary tumor and regional lymph nodes cannot be differentiated and appear as one large mass. There are two hepatic metastases (arrows). The kidneys excrete and the bladder stores fluorodeoxyglucose.

Determination of Non-Nodal cM1b Classification In patients with recently diagnosed esophageal cancer, metastases are found in the liver in 35% of patients, in the lung in 20%, in the bone in 9%, in the adrenal in 2%, and in the brain in 2%, with 1% each in the pericardium, pleura, soft tissues, stomach, pancreas, and spleen.42 Except for the brain, CT of the esophagus includes all or a portion of these sites. Contrastenhanced CT with imaging during the portal venous phases of contrast distribution provides both screening for and diagnosis of masses in these areas. Hepatic metastases appear as ill-defined, low-density lesions of variable sizes (Fig. 41-9). Conventional CT (dynamic incremental scanning with intravenous-bolus contrast enhancement) is excellent in the detection of hepatic metastases larger than 2 cm.43 Sensitivity is 70% to 80%.31 Although no study is available for esophageal cancer, spiral CT produced similar results to conventional CT in the detection of colorectal liver metastases; sensitivity of 76% and a positive predictive value of 90% have been reported.44 Subcentimeter metastases are frequently not recognized by CT; they are the main cause of false-negative examinations and the low sensitivity of CT in the detection of liver metastases. To distinguish benign from malignant nodules, ultrasound is used for diagnosis of benign cysts and MRI for hemangiomas. Adrenal metastases cause heterogeneous, focal enlargement of the adrenal gland. Contrast-enhanced CT is a sensitive but nonspecific screening tool for adrenal masses.

Noncontrast CT, MRI, percutaneous FNA, or laparoscopy may be required to confirm the nature of these nodules. In a cohort of patients with predominate squamous cell cancer of the esophagus, solitary lung metastases were rare at diagnosis of the primary cancer and were probably a benign nodule or synchronous primary lung cancer.45 Although multiple lung metastases were uncommon at diagnosis, they became increasingly more common during the late stages of the disease. Many were not visualized by chest radiography. CT is very sensitive in the detection of pulmonary nodules; however, histologic confirmation of these abnormalities is required if their presence alone will determine therapy. The presence of ascites, pleural effusion, or nodules in the omentum or pleura is suggestive of metastases to these mesothelial-lined surfaces. Laparoscopy and/or thoracoscopy can confirm these findings. Brain metastases are reported in 2% to 4% of patients presenting with esophageal carcinoma.42,46 They tend to occur in patients with large adenocarcinomas of the esophagogastric junction that have invaded locally and/or metastasized to lymph nodes. A pretreatment CT of the brain may be reasonable in these patients. Despite improved technology, CT has a sensitivity of 37% to 66% in screening for distant metastases in patients with esophageal cancer.34,35,37,47 FDG-PET is superior to CT in detecting M1b disease. In 91 patients undergoing 100 FDGPET studies, distant metastatic disease was detected in 39 scans at 51 sites.37 Seventy distant metastases were confirmed by biopsy or at resection. The sensitivity of FDG-PET was 69%, specificity was 93%, and overall accuracy was 84%. In this series the sensitivity of CT was 46%, specificity was 74%, and accuracy was 63%. FDG-PET failed to diagnose distant metastases in the liver in 10 patients, pleura in 4, lung in 2, and peritoneum in 1. All metastases were smaller than 1 cm in diameter. Of 21 false-negative CT scans, FDG-PET identified distant metastases in 11 (62%); of 12 false-negative FDG-PET scans, CT was accurate in 4 (33%). These mature results are less favorable than in an earlier report by the same group in which sensitivity of FDG-PET in detection of distant

Chapter 41 Diagnosis and Staging of Esophageal Cancer

metastases was 88%, specificity was 93%, and accuracy was 91%.36 Five (71%) of 7 patients with distant metastatic disease were diagnosed by FDG-PET.20 A liver metastasis that was less than 1 cm in diameter was not visualized, and a pancreatic metastasis was misinterpreted as a left gastric lymph node metastasis. There were no false-positive results in 36 patients. Over a similar time period, the same group reported 17 distant metastases in 59 patients with FDG-PET. There were no false-negative findings, but transhiatal esophagectomy was commonly used to obtain pathologic stage.34 FDG-PET detects radiographically occult distant metastatic disease in 10% to 20% of patients with esophageal cancer.34-37 The combination of FDG-PET and CT had a diagnostic accuracy of 80% to 92%34,35 and avoided unnecessary surgery in 90%.35 FDG-PET provided additional staging information in 22% of patients, upstaging 15% and downstaging 7%.38 PET/CT provides incremental value over PET alone in cM classification. In 32 patients, PET/CT changed the classification of 25 of 115 metastatic sites (22%).48 The initial characterization of 10 sites (9%) was changed to malignant in 1 and benign in 9, and the anatomic location was more precisely defined in 15 sites (13%). Laparoscopy has been reported to change therapy in 10% of patients, allowing resection in 2% who were overstaged and avoiding resection in 8% with undetected M1b disease.49 The sensitivities of laparoscopy in detecting peritoneal and liver metastases were 71% and 86%, respectively. Laparoscopic ultrasonography does not improve staging by laparoscopy alone.50,51 EUS has limited value in the screening for distant metastases (M1b). The distant organ must be in direct contact with the upper gastrointestinal tract for EUS to be useful (e.g., the left lateral segment of the liver and retroperitoneum).

Pathologic Staging Pathologic classification (pTNM) is clinical classification modified by additional information acquired from surgery and pathologic examination of the resection specimen and biopsies of distant sites. Pathologic assessment of the primary tumor (pT) requires resection (primary tumor mobilization and biopsy in the case of pT4 tumors) sufficient in extent to evaluate the highest pT category.6 Pathologic assessment of regional lymph nodes (pN) also entails removal of a sufficient number of lymph nodes to evaluate the highest pN category (Greene et al, 2002).6 At least 12 regional lymph nodes must be sampled to accurately define pN.52 Biopsy of distant metastasis without removal of the primary tumor is necessary to confirm pM1b. Although recommendations are available for the handling of esophageal resection specimens, no uniform criteria for the examination of the resection specimen exist.53-55 An acceptable method of sectioning requires that only 8 to 11 sections be evaluated (Fig. 41-10). Lymphadenectomy specimens and lymph nodes removed from the resection specimen are evaluated by single representative sections of each individual

FIGURE 41-10 Pathologic evaluation of an esophagectomy specimen. Sections are taken at proximal resection margin, distal resection margin, esophagus proximal to the tumor, esophagus distal to the tumor, and esophagogastric junction. The tumor should have its soft tissue margin inked and be sectioned at its largest point. The superior and inferior boundaries of the tumor should be sectioned. All lymph nodes should be dissected from the resection specimen and be evaluated with the lymphadenectomy specimen. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

lymph node. The histologic determination of pT and pN is subject to sampling error.

Staging During or After Multimodality Therapy Classification during (ycTNM) or after (ypTNM) multimodality therapy is clinical classification modified by additional information acquired from clinical staging or surgery and pathologic examination of the resection specimen and biopsies of distant sites. EUS is not accurate in the determination of ycTN status after effective chemoradiotherapy. It is unable to distinguish tumor from inflammation and fibrosis produced by chemoradiotherapy, and it cannot detect microscopic residual disease. From the experience of restaging after induction chemoradiotherapy, EUS was reported inaccurate in determining ycT status, 27% to 59%.56-60 The most common mistake made in determining ycT status was overstaging. Similar difficulties in distinguishing tumor from post-chemoradiotherapy inflammation and fibrosis have also been reported with EUS staging of rectal cancers.61 EUS accuracy for ycN status after chemoradiotherapy has been reported as 58% to 71%.56,57,59,60 The accuracy of ycN determination after chemoradiotherapy is lower than that of cN. This is due to alteration in ultrasound appearance of nodes after chemoradiotherapy to the extent that established EUS criteria do not apply and residual foci of cancer within the nodes are too small for detection by any modality other than pathologic analysis.

461

462

Section 5 Neoplasms

CT is inaccurate in ycT and ycN determination after chemoradiotherapy.62 After induction therapy FDG-PET has been reported to not add to the estimation of locoregional resectability or detection of new sites of metastases.63

Recurrent Cancer Staging The staging of a recurrent cancer after primary treatment and a disease-free interval is termed recurrent cancer classification (rTNM). Biopsy or FNA cytology will determine recurrent tumor stage. Local recurrence (rT) can usually be established by endoscopy and biopsy. Determination of rN and rM may require mediastinoscopy, thoracoscopy, or laparoscopy. Open biopsy may sometimes be necessary. Imaging, although less accurate in the recurrent cancer staging, directs these biopsy procedures. EUS has been useful in restaging disease in patients with anastomotic recurrences that are not endoscopically visible.64,65 The role of FDG-PET in recurrent cancer staging is still being defined. It may not differentiate anastomosis recurrence from stricture. However, it is valuable in detecting regional and distant recurrences.66,67 CT detection of a mass in the field of resection or a distant metastasis is helpful in determining recurrent cancer stage.

Autopsy Staging Every effort should be made to obtain a postmortem examination to determine autopsy classification (aTNM). Therapeutic assessment in treated patients and natural history in untreated patients is valuable information.68-71

SUMMARY Stage, defined by anatomic extent (TNM), is invaluable in the treatment and study of esophageal cancer. Potentially, stage may be determined at four intervals in patients treated with surgery alone 1. 2. 3. 4.

Prior to treatment, clinical stage (cTNM) After resection, pathologic stage (pTNM) At time of recurrence, recurrent cancer stage (rTNM) At death, autopsy stage (aTNM)

In patients receiving multimodality therapy there are potentially five intervals when stage may be determined: 1. 2. 3. 4. 5.

Prior to treatment, clinical stage (cTNM) During multimodality therapy (ycTNM) After resection (ypTNM) At time of recurrence, recurrent cancer stage (rTNM) At death, autopsy stage (aTNM)

Clinical stage of an esophageal carcinoma has prognostic and therapeutic importance. CT is readily available to all patients. It is relatively inexpensive and usually reimbursed. It provides exquisite anatomic detail of the chest and abdomen in patients with esophageal cancer. The only reliable use of CT in the determination of T is the exclusion of T4 tumors, suggested by the preservation of fat planes. Enlarged lymph nodes are suggestive of metastatic disease but require further study or tissue sampling if nodal metastases will determine treatment. The major use of CT is in the detection of distant

metastatic disease, but 30% to 60% of distant metastases may be radiographically occult. FDG-PET represents advancement over CT in the screening for distant metastases. Major problems with FDG-PET staging of esophageal cancer are failure to detect metastatic deposits less than 1 cm in diameter and lack of anatomic definition. It is unable to determine T classification and has been inaccurate in the detection of lymph node metastases. This test is readily available but is expensive and may not be reimbursed. The combination of CT and PET, either as coregistered examinations or fused studies, is better than either alone. PET/CT has become the clinical staging modality of choice for cM. EUS is the mainstay in the clinical determination of cT and cN. Because there is a significant learning curve for EUS in clinical staging of esophageal cancer, this study should be performed at an institution where there is a dedicated, experienced endoscopic ultrasonographer with adequate instrumentation to allow specialty imaging and EUS-FNA. EUS is the best means of clinically determining cT. The addition of EUS-FNA to routine EUS evaluation of lymph nodes allows accuracy similar to the EUS determination of cT. EUS has no role in assessment of non-nodal distant metastatic disease. The serendipitous finding of distant metastases in adjacent structures visualized during the evaluation of the primary tumor and lymph nodes has, on occasion, detected M1b disease. Results of EUS, EUS-FNA, and PET/CT should determine the necessity for invasive staging techniques such as thoracoscopy and laparoscopy and direct their use. Complete resection of the primary cancer, adequate sampling/resection of regional lymph nodes, and meticulous handling and analysis of the resection specimen are necessary for accurate pathologic staging. Because pathologic stage is built on clinical stage, precise pathologic stage requires a precise clinical stage. The tools of clinical staging are all that are available to determine stage during or after induction therapy and recurrent cancer stages. However, imaging in treated patients is less accurate. Results of these studies should determine the necessity for invasive staging and direct its uses. Responsibility to our patients with esophageal carcinoma extends beyond death. Autopsy stage is invaluable to the study of the disease and its treatment. A postmortem examination should be obtained in every patient.

COMMENTS AND CONTROVERSIES During the past decade, strategies for the diagnosis and clinical staging of esophageal cancer have progressed remarkably. The single biggest change in the management of esophageal cancer has been the widespread acceptance and application of current modalities necessary for the accurate clinical staging of esophageal cancer. Clinical staging, although still not perfect, has become much more accurate, enabling more appropriate allocation of patients into various treatment protocols, specifically primary resection, induction therapy followed by resection, definitive chemotherapy, and radiation or palliative care. No one has made a bigger contribution in this field than Dr. Rice, who authors this outstanding chapter. His detailed analysis of acute clinical staging and its implications in

Chapter 41 Diagnosis and Staging of Esophageal Cancer

management have moved the field of esophageal cancer forward significantly. Although standard barium esophagogram remains an informative investigation, it has been replaced by flexible fiberoptic videoesophagoscopy in many institutions. Esophageal ultrasound, critical for accurate determination of clinical T status and EUS-guided fine needle aspiration, should be available in every institution treating esophageal cancer. Current CT imaging technology does not help very much in accurately evaluating T and N status. FDG-PET is of no value in determinating T status or identifying disease in nodes in immediate proximity to the primary tumor. However, it is of value in identification of distant nodal disease and hematogenous metastases. Laparoscopic and thoracoscopic staging does provide greater accuracy for determination of N and M status. However, in view of obligatory costs in equipment and operative time as well as associ-

ated morbidity, neither modality has reached the stage of routine application. Another important consideration is staging during (ycTNM) and after (ypTNM) induction or definitive chemotherapy and radiation. Post-treatment inflammatory change and fibrosis make EUS, CT, and PET much less reliable. Finally, accurate pathologic staging depends on complete resection of the primary tumor and regional lymph nodes as well as appropriate labeling and analysis of all specimens. G. A. P.

KEY REFERENCE Greene FL, Page DL, Fleming ID, et al (eds): Digestive system: Esophagus. In AJCC Cancer Staging Manual, 6th ed. New York, Springer, 2002, pp 91-98.

463

SURGICAL MANAGEMENT OF SQUAMOUS CELL CARCINOMA

chapter

42

Simon Law John Wong

Key Points ■ Patients with squamous cell cancers pose different problems than

patients with adenocarcinomas of the esophagus. ■ Staging methods have become more sophisticated, accurate, and

refined. This is likely to impact on future treatment strategies. ■ Versatility is required in the choice of surgical procedures. ■ Low mortality rates after esophagectomy can be achieved in spe-

cialized centers, and a volume-outcome relationship is evident, although the complication rate remains substantial. ■ Main controversies remain the appropriate extent of lymphadenectomy and the relative roles of multimodality treatment strategies, such as chemoradiotherapy and surgery, in the management of esophageal cancer. ■ Excellent long-term results are obtained in patients with early cancer, although diagnosis at this stage is unlikely except in highincidence areas such as China, where selected screenings are carried out.

HISTORICAL NOTE One of the earliest descriptions of esophageal cancer was in the second century AD when Galen described a fleshy obstructing growth in the esophagus that led to emaciation and death. In early Chinese literature, a patient who had esophageal cancer was described as “one suffers in autumn, and does not live to see the coming summer.” Unfortunately this description of the natural course of the disease is still true for many in modern times. In 1877, Czerny was the first to successfully resect a cervical esophageal cancer and the patient lived for 15 months. Torek, in 1913, performed the first successful transthoracic resection.1 A 67-year-old woman had a squamous cell cancer of the midesophagus. Through a left thoracotomy, the esophagus was resected. The proximal cervical esophagus was brought out through an incision anterior to the sternocleidomastoid muscle and tunneled subcutaneously along the anterior chest wall, where a cutaneous esophagostomy was fashioned. The patient was fed via a rubber tube connecting the esophagostomy with a gastrostomy. The patient lived for 17 years. The high mortality rates of transthoracic resection led to attempts at different techniques of esophagectomy. The transhiatal approach to esophageal resection was introduced by Denk2 in 1913 and later refined by Turner in 1933.3 The technique became more popular in the 1960s when Ong and Lee,4 in 1960, and Le Quesne,5 in 1966, described it for cancer of the hypopharynx and cervical esophagus. During the 1920s and 1930s re-establishment of feeding, with or without esophageal resection, was mostly by gastros464

tomy, with interposition of a plastic tube, skin tubes, or flaps. Kirschner, in 1920, detailed in experimental animals the use of stomach, which was brought up subcutaneously to anastomose to the cervical esophagus.6 The first successful resection of a thoracic esophageal cancer with reconstruction using the stomach was performed by Ohsawa, a Japanese surgeon in Kyoto, who reported the technique in 18 patients in 1933.7 In 1946, Ivor Lewis described esophageal resection using a two-phase approach via a right thoracotomy and laparotomy.8 Tanner independently also described the procedure in 1947.9 Since then, other methods of reconstruction, including the use of colon and small bowel, have been described. The first surgeon to use free jejunal graft for reconstruction was Seidenberg, reporting his experience with that of his colleagues in 1959.10 Free jejunal graft transfers to replace the cervical esophagus have gained popularity after advances in microvascular surgery. Although surgical resection has remained the main treatment for esophageal cancer, recent years have seen a proliferation of treatment options especially with regard to different combinations of chemotherapeutic agents, radiation therapy, and surgery. There has also been a divergence in the epidemiologic pattern between Western and Eastern countries. The predominant esophageal cancer cell type in the West has become adenocarcinomas related to Barrett’s esophagus and gastroesophageal reflux disease. In the East, squamous cell cancers remain the most common form of esophageal tumor, and one should be mindful of this difference when treatments and results from East and West are compared. HISTORICAL READINGS Akiyama H: History, epidemiology, and related factors. In Gardner N (ed): Surgery for Cancer of the Esophagus. Baltimore, Williams & Wilkins, 1990. Breasted JH: The Edwin Smith Surgical Papyrus. Chicago, University of Chicago Press, 1930, p 312. Brewer LA: History of surgery of the esophagus. Am J Surg 139:730, 1980. Denk W: Zur Radikaloperation des Oesophaguskarzinoms. Zentralbl Chir 40:1065, 1913. Kirschner MB: Ein neues Verfahren der Oesophagoplastik. Langenbecks Arch Chir 114:606-610, 1920. LeQuesne L: Pharyngolaryngectomy, with immediate pharyngogastric anastomosis. Br J Surg 53:105-109, 1966. Lewis I: The surgical treatment of carcinoma of the esophagus with special reference to a new operation for growths of the middle third. Br J Surg 34:18, 1946. Ohsawa T: Esophageal surgery. J Jpn Surg Soc 34:1318-1950, 1933.

Chapter 42 Surgical Management of Squamous Cell Carcinoma

Ong GB, Lee Y: Pharyngogastric anastomosis after oesophagopharyngectomy for carcinoma of the hypopharynx and cervical oesophagus. Br J Surg 48:193-200, 1960. Seidenberg B, Rosenak S, Hurwitt E, Som L: Immediate reconstruction of the cervical esophagus by a revascularized isolated jejunal segment. Ann Surg 149:162, 1959. Tanner NC: The present position of carcinoma of the esophagus. Postgrad Med J 23:109, 1947. Torek F: The first successful case of resection of the thoracic portion of the esophagus for carcinoma. Surg Gynecol Obstet 16:614, 1913. Turner G: Excision of thoracic esophagus for carcinoma with construction of extrathoracic gullet. Lancet 2:1315, 1933.

CLINICAL PATHOLOGY In Asia, more than 80% of esophageal cancer is of squamous cell in origin. From a clinical standpoint, the most important pathologic information that is relevant in management decision making is (1) the relationship between depth of tumor infiltration and lymphatic spread and (2) the propensity for intramural and widespread longitudinal lymphatic spread of esophageal cancer to the mediastinal, cervical, as well as abdominal nodes. It is well recognized that patients who have early-stage cancers have a much better prognosis than patients with more advanced cancers. Superficial cancer is usually defined as tumors limited to the mucosa or submucosa, whereas tumors in which invasion is thought to extend to the muscularis propria or beyond are classified as advanced type. Mucosal lesions can be divided into m1 to m3. Intraepithelial cancer or cancer that barely breaks the basement membrane is defined as m1, cancer that is close to or infiltrates the lamina muscularis mucosae as m3, and lesions between these two as m2. In a national survey in Japan, the incidence of lymph node involvement in m1, m2, and m3 tumors was 0%, 3.3%, and 12.2%, respectively. Submucosal lesions can be similarly divided into sm1, sm2, and sm3 cases. The incidence of lymph node involvement was 26.5%, 35.8%, and 45.9%, respectively.11 For mucosal cancers, the 5-year survival rate is 80% to 100%, and for submucosal cancers it is 50% to 65%.12 The Japanese Society for Esophageal Diseases (JSED) has classified the morphologic appearance at endoscopy of superficial cancer into different types13: Type 0: Superficial type 0-I: Superficial protruding type 0-Ip: Polypoid type, including papillary type 0-Ipl: Plateau type 0-Isep: Predominantly subepithelial type 0-II: Superficial and flat type 0-IIa: Superficial elevated type 0-IIb: Flat type 0-IIc: Slightly depressed type 0-III: Superficial and distinctly depressed type Similarly for more advanced lesions, they are divided into types I to V (also with subtypes): Type I: Protruding type Type II: Ulcerative and localized type Type III: Ulcerative and infiltrative type

Type IV: Diffusely infiltrative type Type V: Miscellaneous type There is some correlation between endoscopic appearance and pathologic depth of infiltration. In most areas of Asia, esophageal cancers are often at an advanced stage at presentation and early cancers are uncommon, with the exception of high-incidence areas in China, such as Hebei and Henan provinces, where population screening is carried out, and in Japan, where frequent screening endoscopy (mostly indicated for gastric cancers) frequently diagnoses early tumors. According to the Comprehensive Registry of Esophageal Cancer of 1999 in Japan, cTis and cT1 disease was found in as many as 27% of patients, and in 20% of patients clinical stage I disease was diagnosed.14 Spread of squamous cell carcinoma is by direct infiltration, intramural extension, and lymphatic and bloodborne metastasis. The esophageal wall has a rich network of submucosal lymphatics and thus is prone to longitudinal spread of tumor. Intramural metastases may present microscopically as subepithelial spread, skip lesions, or satellite nodules, all of which may be found some distance away from the main tumor. The incidence of intramural metastasis and multiple tumors is up to 30%.15 Because subepithelial spread is not uncommon, surgical resection, especially the extent of axial resection margin required, must take this into consideration. Another important pathologic behavior of esophageal cancer is the potential for widespread lymph node metastases, not uncommonly involving the mediastinum, abdomen, as well as the cervical regions. When preoperative endoscopic injection of technetium-labeled rhenium colloid into the esophageal wall is performed, radioactivity can be detected in lymph nodes. It was shown that lymphatic flow of the upper and middle thirds of the esophagus drains mainly to the neck and upper mediastinum and that from the lower third drains mainly into the abdomen. Lymphatics of the thoracic esophagus can therefore drain to all three fields, but there is usually one predominant area of drainage, depending on the location of the tumor.16 From a therapeutic viewpoint, the most important group of lymph nodes lies along the recurrent laryngeal nerves, which transgresses the thoracic inlet. This widespread lymphatic spread forms the basis of three-field lymphadenectomy, where lymphatic dissection of all three fields is carried out, though its value remains unproved.

DIAGNOSIS Early Cancers Diagnosis of symptomatic esophageal cancer is usually straightforward because most are advanced at presentation. Diagnosing the disease at the asymptomatic or early stage is crucial in improving prognosis, although at present this is only possible in the minority of patients. Abrasive cytology is selectively used for population screening in high-incidence areas in China. Two principal types of samplers have been used: an inflatable balloon developed in China17 and an encapsulated sponge sampler developed in

465

466

Section 5 Neoplasms

Japan.18 The balloon is made of rubber covered with a cotton tube, which the patient is asked to swallow. Once inside the stomach, it is inflated with 20 to 30 mL of air and then gradually pulled back. After removal, the cotton tube is smeared onto glass slides for examination. The sponge sampler is made of a sphere of polyurethane mesh compressed inside a gelatin capsule and attached to a thin, solid plastic stylet. The sponge is swallowed and is left in the stomach for 5 minutes to allow the gelatin capsule to dissolve and the sponge to expand, after which it is pulled back into the esophagus. The sponge is shaken in fluid, centrifuged; the “cell pellet” is then resuspended for making slides for examination. Cytology screening in China was started in the late 1950s; in a 30-year period balloon cytologic screening has been carried out over 150,000 times in mass survey. Esophageal cancer was found with an overall frequency of 2%, of which early cancers were found in 84% and esophageal dysplasia in 26% of subjects.19 Thus, cytology contributed significantly to early diagnosis of esophageal cancer. The specificity of balloon cytology screening seems high, although it lacks in sensitivity. One study showed that the sensitivity and specificity of balloon cytology in detecting biopsy-proven squamous cell cancers were 44% and 99%, respectively, and were 47% and 81% for identifying squamous dysplasia or carcinoma.20 On long-term follow-up studies, a consistent progression of risk for developing esophageal cancer with increasing severity of initial cytologic diagnosis of hyperplasia, dysplasia, and “nearcancer” can be shown.21 When early-stage cancers are diagnosed by this method, excellent long-term results after esophagectomy with a 5-year survival rate approaching 90% and a 25-year survival rate of 50% can be achieved (Wang et al, 2004).22 In recent years, endoscopic screening with chromoendoscopy is replacing balloon cytology in screening high-risk populations.19,23,24 Chromoendoscopy is a useful adjunct in the diagnosis of early esophageal cancer. For squamous cell cancers, the most commonly used stain is Lugol’s iodine solution. This solution stains nonkeratinized squamous cell epithelium dark brown to black because of the glycogen content. Inflammatory, dysplastic, and malignant tissues remain unstained. In endoscopic examinations of more than 20,000 high-risk adults older than 40, there were 766 early cancers, including 498 (65%) carcinoma in situ and 49 (6.4%) minute cancer foci less than 0.5 cm in diameter.19 Like cytologic grading, increasing severity of dysplasia on endoscopy with targeted biopsies can be shown to lead to increasing risk of subsequent esophageal cancer.25 In addition to esophagectomy, endoscopic mucosal resection (EMR) is also increasingly performed. Endoscopy is more sensitive than cytology in screening for dysplasia and early cancers but involves more technical expertise and cost. Based on the effective and successful methods for early detection and early treatment, a strategy named “Taihang Anti-Cancer Campaign” is under study in China. It is so called because of the Taihang mountain range, which includes the high-incidence areas such as Linchou (formerly called Linxian) in Henan province and Cixian in Hebei province.

Among a general population of 600,000, two groups will be formed. One group will be assigned for endoscopic screening, the other as control. A high-risk group of subjects older than age 40 will be recruited in endoscopic screening of an estimated 67,000 individuals (~22.5% of the general population). Individuals identified to have mild or moderate dysplasia will be followed up by interval endoscopy with possibly drugs for chemoprevention,26 and those with severe dysplasia or frank carcinoma in situ or invasive cancers will be treated as appropriate. In a pilot study in 2,213 high-risk adults, 61 (3.5%) cases of esophageal cancer, 15 (0.9%) cases of gastric cardia cancer, and 147 (8.3%) cases of severe dysplasia were found. Ninety percent of the cancers identified were regarded as early tumors.19 It is hoped that with this strategy, mortality from esophageal cancer can be reduced significantly in these high-incidence areas. Advances in endoscopic methods, such as magnification endoscopy with instruments that provide 35× to 115× enlargement, light-induced fluorescence endoscopy, light-scattering spectroscopy, optical coherence tomography, and confocal laser scanning microscopy, are promising but are still in the research phase of their development.27,28

Advanced Cancers In patients with advanced cancers the most common presenting symptom is dysphagia (80%-95%), which initially is for solids and later for liquids as the obstruction becomes complete. However, dysphagia may not be apparent until two thirds of the esophageal lumen has been obliterated, and, furthermore, many patients may delay seeking medical attention until severe dysphagia and weight loss have occurred. Regurgitation is common. Fluid regurgitation, especially at night, can lead to bouts of coughing, aspiration, and even chest infection. Odynophagia (retrosternal pain associated with swallowing) is not uncommon. Hoarseness is the result of recurrent laryngeal nerve involvement either by the primary tumor or from metastatic nodal disease. Left vocal cord palsy can be related to nerve compression anywhere from the neck to the aortic arch because of its long intrathoracic course, whereas right recurrent laryngeal nerve palsy indicates a proximal tumor or metastatic lymph node to the right paratracheal area from the neck to the level of the subclavian artery. Tumor invasion of the tracheobronchial tree may present as an incessant cough or, when the tracheobronchial mucosa is breached, as hemoptysis. A frank tracheoesophageal fistula leads to coughing and choking on drinking and is characteristic. Paradoxically, the symptom is less when more solid food is taken, because of the relative ease of liquid to flow through the fistula compared with more solid food. General examination may reveal evidence of weight loss, muscle wasting, and dehydration. Patients are often heavy smokers, and thus signs of chronic obstructive airway disease may be present. The most likely site of a positive physical finding is the neck, especially the paratracheal area and supraclavicular fossae, where metastatic lymph nodes should be searched for. In advanced cancers, endoscopic biopsies usually confirm the diagnosis.

Chapter 42 Surgical Management of Squamous Cell Carcinoma

STAGING INVESTIGATIONS The clinical staging system follows the American Joint Committee on Cancer Staging (AJCC) TNM classification system29 or the Japanese Society for Esophageal Diseases (Fig. 42-1).13 The nodal stations are classified differently in the two systems; the latter also takes into account the number of lymph node involvement in categorizing the N classification. There is no universal agreement, but the AJCC system is less complicated. Apart from physical examination and simple chest radiography, specific methods in clinical staging involve barium contrast studies, bronchoscopy, CT, percutaneous ultrasonography of cervical lymph nodes with or without fine-needle aspiration (FNA) cytology, endoscopic ultrasonography (EUS) with or without FNA, 2-(18F)fluoro2-deoxy-D-glucose (FDG) positron emission tomography (PET), and laparoscopy and/or thoracoscopy. From the point of view of surgical management, accurate staging ensures a high probability of achieving an R0 resection.

Barium Contrast Study With the availability of other more sophisticated investigative modalities, a barium contrast study may not be essential in the workup of a patient with esophageal cancer; nevertheless, it gives a longitudinal graphical view of the tumor in relation to other mediastinal structures, especially the trachea and main bronchi, and is a useful guide to the endoscopist. It is also sensitive in depicting a tracheoesophageal fistula. Typical

features include mucosal irregularity and shouldering, narrowing of the lumen, and proximal dilation of the esophagus. Tortuosity, angulation, axis deviation from the midline, sinus formation, and fistulation to the bronchial tree are signs indicative of advanced tumor that has traversed the adventitia and involved the neighboring fixed organs.30

Bronchoscopy Flexible fiberoptic bronchoscopy is essential for middle or upper third tumors to look for tracheobronchial involvement. Signs of involvement include a widened carina, external compression, tumor infiltration, and fistulization. The last two signs contraindicate resection.31 Gross macroscopic bronchoscopic appearance, however, may not be accurate, and biopsy and brush cytology of suspicious areas are recommended. In one study on patients with supracarinal cancers, endoluminal tumor mass, protrusion of the posterior tracheal wall, and signs of mucosal invasion were visible in 5.9%, 28.6%, and 4.1% of bronchoscopies, respectively. However, in only 8.6% of 220 bronchoscopies, cancer invasion was proved by biopsy or cytology. Bronchoscopic examination excluded patients from surgery because of airway invasion in 18.1% of otherwise potentially operable patients, with an overall accuracy of 93.3%.32 Bronchoscopic ultrasound has been investigated as a staging tool. The presence of tracheobronchial invasion was diagnosed based on an interruption in the most external hyper-

FIGURE 42-1 A, Lymph node stations according to the American Joint Committee on Cancer classification. B, Lymph node stations according to the Japanese Society for Esophageal Diseases.

467

468

Section 5 Neoplasms

echoic layer of the tracheobronchus (corresponding to its adventitia). In one study, of 26 patients diagnosed as being invasion-free by bronchoscopic ultrasonography, only 2 had invasion, compared with 7 of 22 patients who had invasion after CT had suggested they did not. The examination had no complication.33 The technique, however, is not commonly performed.

Computed Tomography For T classification, the main use of CT lies with the diagnosis of T4 disease, since it is unreliable in distinguishing the earlier T classifications. Obliteration of the fat plane between the esophagus and the aorta, trachea and bronchi, and pericardium is suggestive of invasion, but the paucity of fat in cachectic patients makes this criterion unreliable. Thickening or distortion of the normally flat membranous trachea and left main bronchus is also suggestive of invasion but should always be confirmed by bronchoscopic examination. When the area of contact between the esophagus and the aorta extends for more than 90 degrees of the circumference, an 80% accuracy of infiltration was reported,34 but this is by no means absolute and the accuracy is inferior to that of EUS. The main value of CT in staging of esophageal cancer lies with its ability to detect distant nodal or visceral metastases, such as liver metastases. Solitary lung metastases are rare in patients presenting with esophageal carcinoma35 and thus when seen on CT are more likely to be primary lung cancers or benign nodules and should be investigated as such. The sensitivity of detecting mediastinal and abdominal nodal involvement is suboptimal with CT because only size alone can be used as diagnostic criterion. False-positive and false-negative results in the diagnosis of malignant nodes may be related to the fact that normal-sized lymph nodes may contain metastatic deposits, and enlargement of lymph nodes may be due to reactive and inflammatory hyperplasia. Intrathoracic and abdominal nodes of more than 1 cm and supraclavicular nodes with a short axis greater than 0.5 cm and retrocrural nodes greater than 0.6 cm are generally regarded as pathologic.36 Recent studies using high-resolution helical CT scanning have demonstrated sensitivities of 11% to 77% as well as specificities of 71% to 95% for detection of regional nodal disease.37,38 CT is relatively insensitive in detecting celiac axis lymphadenopathy.

Percutaneous and Endoscopic Ultrasonography Percutaneous ultrasonography has a specific role in diagnosing cervical lymph nodes, especially for squamous cell cancers because the incidence of lymph node metastases in the neck is high. It can aid therapeutic decision in performing cervical lymph node dissection. In one large study in 519 patients, cervical lymph node metastasis was detected in 30.8% of patients (160 of 519). The sensitivity, specificity, and accuracy of ultrasound diagnosis in patients who underwent subsequent cervical lymphadenectomy were 74.5%, 94.1%, and 87.6%, respectively. In those who did not undergo neck dissection, the chance of cervical nodal recurrence was less than 5%.39

EUS is the only imaging modality able to distinguish the various layers of the esophageal wall, usually seen as five alternating hyperechoic and hypoechoic layers. The accuracy of EUS in locoregional staging is not questioned. The accuracy of EUS for T and N classification staging averages 85% and 75%, respectively, compared with 58% and 54% for CT.40 A review of the literature shows variations in accuracy for T classification, as follows: 75% to 82% for T1, 64% to 82% for T2, 89% to 94% for T3, and 88% to 100% for T4.41 One main limitation of EUS is the inability to pass the endoscope through the tumor stricture, which occurs in about one third of patients.42,43 It has been shown that dilation will result in up to 25% chance of perforation without much gain in diagnostic information, since high-grade nontraversable tumors usually indicate T3 or T4 disease with lymph node metastases anyway.44,45 More recent results suggest that dilation can be performed safely, and the success rate of complete examination depends on the size of dilation: 36% for 11 to 12.8 mm and 87% for 14 to 16 mm.46 An alternative is to use miniaturized ultrasound catheter probes passed through the working channel of a conventional endoscope, which can achieve comparable accuracy to conventional EUS. With the use of a 6-Fr, 12.5-MHz mini probe, the overall accuracy in the assessment of tumor infiltration depth is 90%, and it is 78% for nodal disease.47 Higher-frequency echo-ultrasound (15-20 MHz) allows fine distinction of early mucosal and submucosal esophageal cancers into mucosal (m1-m3) and submucosal cancers (sm1sm3). The esophageal wall is seen as a series of seven or nine layers. Diagnostic accuracies for superficial cancers vary from 65% to 100%.48 The diagnostic accuracy was 80% when the muscularis mucosae was seen.49 Such information is of particular importance when endoscopic mucosal resection is a treatment option for early cancers. Echo-ultrasound features of lymph nodes that suggest malignant involvement include echo-poor (hypoechoic) structure, sharply demarcated borders, rounded contour, and size greater than 10 mm, in increasing order of importance.50 When all four features are present, the accuracy reaches 80%. However, one study showed that all four features were present in only 25% of malignant nodes.51 A collective review showed that the overall accuracy of staging nodal disease was 77%.40 Accuracies may differ for different lymph node locations. Its sensitivity is highest for cervical and upper thoracic paraesophageal, infracarinal, left paratracheal, and recurrent laryngeal nodes. It is best with paraesophageal nodes and varies inversely with the axial distance of the nodes from the esophageal axis52; this is related to the limited depth of penetration of EUS (~3 cm). When EUS-FNA is available, the diagnostic accuracy of nodal disease is much improved, ranging from 86% to 100%.48 Because of the limited penetration of ultrasound, EUS is insufficient to diagnose distant disease, with perhaps the exception of celiac lymph nodes. Because having an involved celiac node is regarded as stage IV disease and some would consider this a contraindication for surgery, accurate diagnosis is important. Even helical CT is suboptimal in picking up celiac nodes.53 EUS is more accurate and, in addition, EUS-

Chapter 42 Surgical Management of Squamous Cell Carcinoma

FNA allows direct puncture and aspiration of cells for cytologic examination.54 In one large series of 102 patients, the sensitivity of EUS in detecting celiac lymph nodes was 77%, specificity was 85%, negative predictive value was 71%, and positive predictive value was 89%. When EUS-FNA is compared with CT, the former is clearly superior. Of 20 patients who satisfied the criteria for EUS-FNA directed toward the celiac nodes, 18 (90%) were positive for malignancy. CT was able to detect only 6 (30%) of the 20 cases of suspicious celiac lymph nodes, of which 5 (83%) were positive for malignancy by FNA.55 One limitation of EUS is the inability to distinguish between postradiation fibrosis, inflammation, and tumor after neoadjuvant therapy, with corresponding reduction in accuracy. To assess T and N classification stage after such treatments, EUS was only 27% to 48% and 38% to 71% accurate, respectively.56,57 Reduction in cross-sectional area of the primary tumor by more than 50% and reduction in tumor thickness were also parameters investigated to assess response.58,59 Combining cervical ultrasound and EUS is highly accurate. In 329 patients who underwent esophagectomy, one-to-one comparisons between preoperative ultrasonography, EUS, and histologic diagnosis were compared. The accuracy of combined ultrasonography was 80.2% for regional lymph nodes, 91.5% for distant lymph nodes, and 74.4% in overall stage grouping. When the number of metastatic nodes was classified into subdivisions of 0, 1-3, 4-7, and 8 or more, accuracy rates were 83.8%, 59.7%, 43.3%, and 96%, respectively. More importantly, the preoperative combined ultrasound separation into the number of involved lymph node showed prognostic stratification close to the histologic diagnosis (Natsugoe et al, 2001).60 This type of examination on both the location and number of nodes with one-to-one comparisons with histologic findings does require experience and meticulous attention to detail.

H

PET/CT Syngo 3D Postprocessing VB10B SL75-fcsP97

FDG-Positron Emission Tomography FDG-PET, by utilizing the differential glucose metabolism of cancer, provides a functional assessment of tumor metastases. PET is gaining popularity in esophageal cancer staging61,62; as more data are accumulated, the role of PET is becoming clearer (Fig. 42-2). For the detection of the primary tumor, the sensitivity of PET ranges from 78% to 95%, with most false-negative tests occurring in patients with T1 or small T2 tumors,37,63 suggesting that limitations in spatial resolution of the PET imaging device, currently 5 to 8 mm, are the cause for nonvisualization. PET does not provide enough definition of the esophageal wall and thus has no value in T classification staging. For locoregional nodal metastases, its spatial resolution is also insufficient to separate the primary tumor with juxtatumoral lymph nodes because of interference from the primary tumor, and thus most studies demonstrate poor sensitivity.63,64 This is especially true for nodes in the middle and lower mediastinum, where most primary tumors are found. In one study, the sensitivities of PET for detecting cervical, upper thoracic, and abdominal nodes were 78%, 82%, and 60%, respectively but only 38% and 0%, respectively, for the middle and lower mediastinum.37 Specificity of PET in detecting regional nodes is usually much better, reaching 95% to 100%,63,64 indicating that false-positive findings are uncommon. A recent meta-analysis of 12 publications on PET in esophageal cancer showed that the pooled sensitivity and specificity for the detection of locoregional metastases were 0.51 (95% CI, 0.34-0.69) and 0.84 (95% CI, 0.76-0.91), respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 0.60 and 0.46, respectively. For distant metastases, pooled sensitivity and specificity were 0.67 (95% CI, 0.58-0.76) and 0.97 (95% CI, 0.90-1.0), respectively. The corresponding PPV and NPV were 0.92 and 0.83. When 2 studies (of 11) that had particularly low sen-

H

PET/CT Syngo 3D Postprocessing VB10B SL75-fcsP97 HFS

Distal Oesophagus Tumour Maxsuv 14

RP

2 Distance 3.20 cm 1 Distance 4.71 cm 2 1 10cm

kV 130 512•512

GT 00

W 350 C 35

FIGURE 42-2 PET/CT scan showing a distal esophageal tumor. The standard uptake value of the tumor is 14. The PET image can be superimposed on the CT image.

469

470

Section 5 Neoplasms

sitivities for detection of distant metastases were excluded (probably because they included more early tumors), the pooled sensitivity improved to 0.72 and specificity to 0.95 (van Westreenen et al, 2004).65 Specifically for celiac nodes, sensitivity, specificity, PPV, and NPV range from 53% to 98%, 77% to 200%, 79% to 100%, and 82% to 100%, respectively. This study highlights that the accuracy of PET in locoregional nodes is only moderate. EUS-FNA may be better in this regard. PET is, however, more useful for picking up distant nodal and visceral metastases. Specificity is especially high. The diagnostic yield of PET for detection of unsuspected metastases in early-stage disease (Tis, T1) may be low because the chance of lymph node metastases increases with increasing T classification. Cost-effectiveness in this setting is uncertain. It seems that PET should be performed in patients in whom standard staging methods (CT and EUS) demonstrate no distant metastatic disease. In such cases, PET may improve the detection of metastatic disease and thus change management strategies.

Thoracoscopy and Laparoscopy Thoracoscopy and laparoscopy have their advocates. Thoracoscopic staging usually involves a right-sided approach, with opening of the mediastinal pleura from below the subclavian vessels to the inferior pulmonary vein; lymph node sampling is then performed. Sometimes left-sided thoracoscopy is also performed to sample lymph nodes at the aortopulmonary window. Laparoscopic staging can include celiac lymph node biopsy, collection of peritoneal fluid for cytologic examination, and the use of laparoscopic ultrasound for detecting liver metastases. In a study of 53 patients whose staging included conventional CT and EUS, minimally invasive staging reassigned a lower stage in 10 patients and a more advanced stage in 7 patients (32.1%).66 The multi-institutional study (CALGB 9380) reported on combined thoracoscopy and laparoscopy staging in 113 patients, and the strategy was feasible in 73% of patients. Thoracoscopy and laparoscopy identified nodes or metastatic disease missed by CT in 50% of patients, by MRI in 40%, and by EUS in 30%. Although no deaths or major complications occured, it did involve a general anesthesia, one-lung anesthesia, a median operating time of 210 minutes, and a hospital stay of 3 days.67 Given the increasingly improved accuracies of staging methods such as PET, the invasiveness of thoracoscopy is unlikely to invite widespread use. Laparoscopy is generally of little use in the staging of squamous cell cancers, whereas the chance of metastases in the abdomen is considerably more with adenocarcinomas of the lower esophagus and gastric cardia.68

MANAGEMENT In the past, surgical resection or radical radiotherapy were the only two treatment options. Advances in chemotherapy and radiotherapy, and various endoscopic treatments, have increased the choice of therapy. Accurate staging allows stage-directed therapies to be carried out, although many treatment strategies remain controversial. Modifications of

the present AJCC staging system are also likely in the future and will drive further refinements in selecting the most appropriate methods of treatment.

Endoscopic Treatment of Early Cancers Superficial cancers, as already described, are defined as tumors that are limited to the mucosa or submucosa. The fine distinction of these cancers into m1 to m3 and sm1 to sm3 is important because the more superficial lesions are readily amenable to endoscopic mucosal resection (EMR). The recommended indication for EMR in esophageal cancer is well- and/or moderately differentiated squamous cell cancers of m1 or m2 infiltration with no evidence of nodal metastases. There is no consensus on the maximal size, although circumferential lesions are usually avoided because of potential for stricture formation.69 For sm2 and sm3 tumors the high incidence of nodal metastases makes esophagectomy with lymphadenectomy more suitable. For m3 and sm1 tumors, indications for EMR are relative because of the fairly frequent nodal metastases. It is well suited for patients who are not fit for or who refuse surgery. High-frequency EUS (up to 30 MHz) with chromoendoscopy and even magnification endoscopy can aid in selecting patients for EMR.70 There are many techniques of EMR, but the most commonly performed is perhaps the EMR-cap method (EMRC). With the use of a cap-fitted forward-viewing endoscope, saline is injected into the submucosal layer to raise the lesion from the deeper wall layer. The lesion is sucked into the cap, and a snare wire that has been pre-looped is used to snare the lesion. The strangulated mucosa is cut by blend-current electrocautery. In a series of 250 patients, 72% had absolute indications when EMR was performed for m1 to m2 lesions. In these patients, no local or distant metastases occurred during follow-up. The 5-year survival rate was 95%. All those who died within 5 years did so of non–cancer-related causes.71 Complications of EMR include bleeding (which is usually minor), perforation (which can be prevented by adequate submucosal saline injection and can be treated sometimes with hemoclipping), and stenosis (which tends to occur when the lesion is large). All these should be rare events.

Surgical Management Surgical resection remains the mainstay treatment for patients with localized esophageal cancer. It is justified only when acceptably low morbidity and mortality rates can be achieved; otherwise the benefits gained by those who survive the operation are offset by the deaths of others.72 A volume-outcome relationship is evident in complex surgery like esophagectomy; in dedicated high-volume centers a resection mortality rate of 2% to 3% can be achieved (Ando et al, 2000; Law et al, 2003).73-79 It is also true that the overall mortality rate still approximates 10% when results from multicenter trials and national figures are included.80-82 In Japan, where low mortality rates are commonly reported in the surgical literature, a Comprehensive Registry of Esophageal Cancer revealed a postoperative death rate of 12%.14 In high-incidence areas in China, mortality rates from resection have consistently

Chapter 42 Surgical Management of Squamous Cell Carcinoma

been low,83 but this could be related to patient selection and surgical experience. This difference between figures from specialized centers and national figures is consistent and also considerable in other parts of the world. The results of surgical resection are dependent on many factors and are mainly related to the following: 1. Selection of appropriate patients for resection and optimization of the patients’ physiologic status before surgery 2. Choice of surgical techniques and their execution 3. Perioperative care

Patient Selection for Esophagectomy Appropriate patient selection is important to achieve the best results. Overaggressive surgery in elderly patients with advanced cancer will likely lead to more postoperative deaths, whereas very conservative patient selection will deny treatment to those who would benefit from surgical resection. Resection rates depend on many factors, including the following: 1. 2. 3. 4.

The referral pattern of individual centers The prevailing treatment philosophy The availability of alternative therapies The possible mortality that the surgeon and patient are prepared to accept

Thus, reported resection rates may vary from 21%84 to 70% to 80%.77,85,86 Patients with squamous cell cancers are also reported to have significantly lower resection rates compared with those who have adenocarcinomas.74 In studies that report on improvement of surgical results over time, more stringent patient selection often comes into play, either by excluding high-risk patients or by treating advanced disease with nonoperative means, such as chemoradiotherapy.87 Patients with squamous cell cancers are likely to be malnourished, have high alcohol intake, are smokers, and thus have impairment of pulmonary and hepatic functions. Advanced age does imply more postoperative complications (Law et al, 2004),88 although equally low mortality rates can be achieved compared with younger patients.89 Diseasespecific long-term survival was also not inferior. Thus, selection based on age alone is not adequate; rather, more objective evaluation is warranted.89,90 The “general” condition of the patient is often regarded as important, although it is hard to quantify. A patient with a Karnofsky score of less than 80 is more likely to have a complicated or lethal postoperative course.87 Significant proteinenergy malnutrition has been found in 50% of esophageal cancer patients at presentation, and those with abnormal nutritional status have higher mortality rates.91 One problem of nutritional assessment is that there is no reliable and easily available method for quantification that has been shown to be related to esophagectomy outcome, whether by anthropometric, biochemical, or immunologic data. Clinically, recent weight loss of 10% or more of the usual body weight is commonly regarded as significant. Definite evidence that preoperative hyperalimentation can improve surgical results after esophagectomy is lacking.92

Pulmonary complications are common after esophagectomy, and the heavy smokers who suffer from squamous cell cancers are particularly vulnerable. Advanced age and supracarinal tumor are additional risk factors.88 Patients should have a history taken and signs of chronic lung disease carefully evaluated. An abnormal chest radiograph is a risk factor and should prompt further detailed investigations.93 An obstructive pattern on spirometric tests and clinical and spirometric improvement with bronchodilators should prompt optimal treatment before surgery. Other poor prognostic parameters include a low preoperative PaO294 and a low FEV1.93 Incentive spirometry, a form of maximum inspiratory technique to prevent atelectasis that also reflects the patient’s respiratory muscle strength, coordination, and mental cooperation, was also predictive of outcome.93 Liver cirrhosis is associated with a marked increase in postoperative mortality. Ruol and colleagues observed a 21% mortality rate, 23% anastomotic leakage rate, and 4% necrosis of the esophageal substitute even in Child’s class A cirrhosis.95 In many centers, patients with cirrhosis are excluded from esophagectomy. Assessing a patient’s fitness is often based on surgeons’ experience and intuition, rather than an exact science. Objective scores to assess operative risk have been generated using various statistical methods to help patient selection.87,93 One series of studies identified a compromised general status and poor cardiac, hepatic, and respiratory function as independent predictors of postoperative death. The different parameters were rated and weighted to give a composite risk score from 11 to 33. Scores greater than 21 were predictive of excessive mortality; 30% of patients with otherwise resectable tumors were excluded from surgery when this scoring system was used. When this was applied in prospective patient selection, it led to a decrease of the postoperative mortality rate from 9.4% to 1.6%.87 Objective risk scores like this have their practical drawbacks. These scores require a suitably large patient database to generate and another group of patients for validation before they can be applied clinically. Problems arise when changes in surgical experience and management protocols take place with time. Thus the factors derived may become less relevant by the time they are put into clinical decisionmaking protocols. Scores that are applicable at one institution or population may not be useful at another. It is uncertain if patient selection based on a “strict” mathematical scoring system is better than that of the assessments of surgeons and anesthesiologists. They are more likely to be complementary.

Choice of Surgical Procedure and Approaches Versatility is required in esophagectomy; no single operation can cope with cancers at all levels of the esophagus, of different disease stages, and in patients with variable physiologic reserve.

Cervical Esophageal Cancer In 1960, Ong and Lee first described the procedure of pharyngolaryngoesophagectomy (PLE) as a one-stage, three-

471

472

Section 5 Neoplasms

phase operation that involved cervical and abdominal incisions and a thoracotomy.4 Tumors involving the hypopharyngeal and upper cervical esophageal region were resected together with the whole esophagus, and the stomach was delivered via the posterior mediastinum to the neck for pharyngogastric anastomosis. A terminal tracheostome was constructed. The thoracotomy was later replaced by transhiatal esophageal mobilization. Thoracoscopic esophageal mobilization has become another, and our preferred, alternative.96 PLE is associated with significant morbidity and mortality, partly related to the fact that the procedure is often performed as a last resort for salvage, when no other means of palliation exists.96 At our institution, of 317 PLEs performed from 1966 to 1995, the mortality rate decreased from 31% to 9%.97 For tumors confined to the proximal portion of the cervical esophagus, with sufficient distal margin, free jejunal interposition grafts and deltopectoral or pectoralis major myocutaneous flaps are options for reconstruction after resection. The use of a free jejunal graft is advantageous because it avoids mediastinal dissection, although expertise in performing microvascular anastomosis is essential. Graft necrosis, fistula formation, and late graft strictures are specific problems. When compared with gastric pull-up, graft survival and leak rates are similar. Stricture was the most common late complication for free jejunal transfers, whereas reflux was most common in gastric pull-ups, both occurring in approximately 20% of patients.98 Functional study showed satisfactory swallowing mechanism in all patients.99 The jejunal graft is also tolerant to postoperative radiotherapy.100 When primary surgical resection is performed, adjuvant radiotherapy is usually given. The need to sacrifice the larynx does make surgical resection an unattractive option, and upfront chemoradiotherapy is preferred by many, with surgery reserved for salvage.101

Intrathoracic Esophageal Cancer and Abdominal Esophageal Cancer For tumors in the upper thoracic esophagus, obtaining a sufficient proximal resection margin dictates an anastomosis placed in the neck. For this reason resection is best carried out by a three-phase esophagectomy or the McKeown approach.102 In this procedure a right thoracotomy is first carried out to mobilize the thoracic esophagus together with lymphadenectomy. This is followed by abdominal and neck incisions for the mobilization of the esophageal substitute placing the anastomosis in the neck. The split-sternum approach is an alternative, especially for tumors close to the thoracic inlet.103,104 Squamous cell esophageal cancers are mostly located in the middle and lower esophagus. The most widely used approach was that described independently by Lewis (1946)8 and Tanner (1947).9 The operation begins with an abdominal phase, in which the stomach is prepared; a right thoracotomy and resection of the tumor, together with lymphadenectomy, follow. The stomach is then brought up into the chest for anastomosis with the proximal esophagus at the apex of the pleural cavity. An alternate approach involves a single left thoracotomy incision. Through a left thoracotomy and incision in the dia-

phragm, both the esophagus and stomach could be mobilized and resection carried out; the stomach is then delivered into the chest for anastomosis, either below or above the aortic arch. Proximally, the aortic arch does hinder surgical access, making mobilization of the proximal esophagus and subsequent anastomosis difficult, although a left cervical esophageal anastomosis is also possible without position change. The left thoracotomy approach is generally more suitable for cancer of the distal esophagus where an adequate resection margin is obtained below the aortic arch. This method is most popular in China (Liu et al, 2004).105 For squamous cell cancers that are limited to the abdominal esophagus or that have invaded the gastric cardia or proximal stomach, an abdominal–right thoracic approach as in a Lewis-Tanner esophagectomy is one option, with the proximal stomach also resected to gain an adequate distal resection margin. A left thoracoabdominal incision through the seventh or eighth rib space also gives good exposure of the low mediastinum and upper abdomen. However, we do not prefer to use this incision. A transhiatal approach, in which the thoracic part of the esophagus is mobilized by blunt and often blind dissection through the enlarged esophageal hiatus and the mobilized stomach is then delivered to the neck and anastomosed to the cervical esophagus, is advocated especially for distal esophageal tumor or early-stage tumors of other parts of the esophagus. For most patients with symptomatic squamous cell cancers, which are usually advanced and more proximally located, this method is not ideal. Randomized trials have not provided evidence of superiority of the transhiatal approach over the transthoracic method.106,107 The largest randomized trial to date involved 220 patients. Postoperative morbidity rates were less for the transhiatal group, but mortality rates were similar. There was also a trend toward better long-term survival in the transthoracic group. This study, however, only included patients with adenocarcinomas of the middle or lower esophagus.108

Minimally Invasive Surgery Various minimally invasive approaches to esophagectomy have been studied in recent years, which include thoracoscopy, laparoscopy, mediastinoscopy, hand-assisted laparoscopy, and open laparotomy and thoracotomy in different combinations (Law and Wong, 2002).109 The most popular is thoracoscopic esophagectomy with gastric mobilization via a laparotomy and cervical esophagogastrostomy.96,110 Combining laparoscopy and thoracoscopy has its advocates,111-113 as does a totally laparoscopic approach.114-116 The myriad of surgical methods implies a lack of consensus on which is superior. Potentially serious intraoperative complications can occur. These include bleeding from the azygos vein117 and from intercostal vessels118 and injury to the aorta,119,120 tracheobronchial tree,121-123 and recurrent laryngeal nerve.124 The lack of tactile control is probably a contributory factor. On the contrary, the increased magnification and excellent visualization offered by thoracoscopy might, in fact, help lessen complications. Less blood loss110 and reduction in transient recurrent laryngeal nerve palsy from 80% to 18% was reported.125 tahir99-VRG vip.persianss.ir

Chapter 42 Surgical Management of Squamous Cell Carcinoma

For postoperative complications, similar anastomotic leak and respiratory complication rates, but shortened intensive care and hospital stay compared with historical controls, were shown in one study.112 Another report showed that the incidence of pulmonary complications was reduced from 33% to 20%.125 Osugi and colleagues experienced longer operation duration, but reduction of vital capacity and performance status was less for the thoracoscopy group, with the number of retrieved lymph nodes, blood loss, and morbidity being similar.126,127 When thoracoscopic esophagectomy was selectively applied to patients with elevated risk, similar outcome was obtained compared with those who underwent open thoracotomy, implying a benefit in high-risk patients.110 Except in the few studies mentioned, clear advantages of the minimal access methods could not be demonstrated, partly because most reports are underpowered to detect a statistical difference. There are also other reasons why benefits are difficult to confirm. With modern analgesic methods such as epidural analgesia, postoperative pain control is less critical a problem.128 The genesis of cardiopulmonary complications is multifactorial and does not depend solely on the size of the incision. Surgical trauma of mediastinal dissection is also independent of the incision size. The benefit of smaller port sites compared with open thoracotomy may be offset by the lengthened time of single-lung anesthesia. A learning curve obviously exists for such complicated procedures.125,129 The duration of the thoracoscopic procedure, the blood loss, and the incidences of postoperative pulmonary infection were all less, and the number of mediastinal nodes retrieved was more, in the latter half of a group of 80 patients who had thoracoscopic esophagectomy.129 Most reports to date studied only limited numbers of patients. Only three reports had patient number close to or over 100, with each using different techniques.111,126,130 Thus, for most series the full technical potential may not have been realized. The appropriate indications for minimally invasive techniques remain controversial. Some surgeons select patients with good pulmonary reserve so that the lengthened time of anesthesia is better tolerated.126 Others believe that it should be performed in patients with elevated risk.110 Concerning cancer stage, in some series, selection of patients with early disease is evident: two thirds of patients had cancer of stage II and below in two studies111,113; and in the report from Pittsburgh, 21% of patients had only high-grade dysplasia.111 Yet others have suggested that these methods are appropriate for stage IV disease, given that palliation is the aim, lymph node dissection is of secondary importance, and laparoscopic or thoracoscopic approaches may be particularly beneficial (e.g., shorter hospital stay, less pain, rapid recovery).115 The most important test will be long-term survival, which many studies have not addressed. In those that have there is no reported difference compared with historical controls. Another concern is port site recurrence.110

Extent of Resection Axial and Lateral Margin. One of the most controversial aspects of treating gastrointestinal malignancies is the appropriate extent of resection, and this debate is exemplified by esophageal cancer.131 An R0 resection results in total removal

473

of the tumor mass (primary and lymph nodes) with clear proximal, distal, and lateral margins and is consistently identified as the most important prognostic factor for long-term survival. The propensity of esophageal cancer to have intramural spread and multicentric lesions has been discussed. The chance of a histologic positive margin reduces with increasing distance at which the esophagus is transected away from the tumor edge, and the frequency of anastomotic recurrence is a function of the length of proximal resection margin attained. Taking into account shrinkage of the specimen after resection as a guide to surgery, an in-situ margin of 10 cm (fresh contracted specimen of ~5 cm) should be aimed for, to allow a less than 5% chance of anastomotic recurrence.132 Intraoperative frozen section is one method to ensure a negative margin. However, a negative margin does not preclude anastomotic recurrence. The occurrence of skip lesions or submucosal spread can be missed even by a conscientious pathologist, and thus margins may be falsely negative. Extramural recurrence with infiltration back to the anastomosis may also be indistinguishable from true anastomotic recurrence. In our study, a positive histologic margin (diagnosed with definitive histology and not with frozen section) occurred in 7.5% of patients who had esophagectomy, which had an anastomotic recurrence rate of 10.3% compared with 4.9% in those with a negative margin. The difference, however, did not reach statistical significance.132 Microscopic involvement of the lateral margin (macroscopically clear) results in increased chance of local recurrence as well as worse survival. This effect seems especially important in patients with low nodal disease burden.133 Obtaining a clear lateral margin is difficult with esophageal cancer because of its anatomic position and adjacent indispensable structures. Some Western centers advocate the concept of en-bloc resection, which in addition to lymphadenectomy, removes the primary tumor together with the pericardium, thoracic duct, azygos vein, intercostal vessels, and bilateral pleurae overlying the primary tumor and a surrounding cuff of crura (where the primary tumor is abutting) to enhance lateral clearance.75,134 Obviously this type of resection is less suitable for upper and middle esophageal cancers in close proximity to the trachea and bronchi. The concept of en-bloc resection is thus more applicable for Western patients, in whom most tumors are adenocarcinomas of the lower esophagus. Lymphadenectomy. For early cancers (m1-m2 tumors), the prevalence of lymphatic spread is negligible and thus lymph node dissection is not indicated. Instead these are readily treated by EMR. For m3 tumors, and cancers that have infiltrated farther into the esophagus, the chance of lymphatic spread increases substantially and lymphadenectomy is indicated. The optimal extent of lymphadenectomy is controversial. The ability to perform lymphadenectomy is closely related to the surgical approach utilized and an open transthoracic approach is necessary, unless a limited lower mediastinal dissection is planned. Surgeons who perform transhiatal esophagectomy mostly disregard the benefits of lymph node dissection.135 Conventional transthoracic resection usually involves a “standard two-field” lymphadenectomy, which entails removing the nodes and periesophageal tissue below the level of the tahir99-VRG vip.persianss.ir

474

A

Section 5 Neoplasms

B

C

FIGURE 42-3 The extent of mediastinal lymphadenectomy. A, Standard mediastinal lymph node dissection includes removing the paraesophageal nodes and subcarinal and right and left bronchial nodes below the tracheal bifurcation. B, Extended mediastinal lymphadenectomy involves standard lymphadenectomy plus the right apical nodes, right recurrent nerve nodes, and right paratracheal nodes. C, Total mediastinal lymphadenectomy includes an extended mediastinal lymphadenectomy plus the left recurrent laryngeal and paratracheal nodes. For the abdominal field, lymph nodes around the celiac trifurcation should be resected. For the cervical field, the cranial landmark is the cricoid cartilage and the caudal border is the upper margin of the clavicle. The most important nodes are the paratracheal nodes along the recurrent laryngeal nerves.

carina and the lymph node stations around the celiac trifurcation. When superior mediastinal lymph node dissection is performed, it is sometimes known as extended or total twofield lymphadenectomy. “Three-field” lymphadenectomy involves additional bilateral cervical lymph node clearance. The definitions of the nodal stations within the “fields” vary among surgeons. A consensus conference held in 1994 for the extent of lymphadenectomy recommended standardized definitions, especially of the mediastinal dissection (Figs. 42-3 to 42-7).136 A more complicated system akin to that for gastric cancer surgery is used by the Japanese Society for Esophageal Disease, which stratifies nodal stations into four tiers and denotes D0-3 dissection according to the nodal stations.13 The rationale for extensive lymphadenectomy is that lymph node spread occurs widely for esophageal cancer. The overall rate of cervical lymph node metastases has been documented by three-field lymphadenectomy in Japan and is approximately 30%. In relation to the level of primary tumor, cervical lymph nodes are involved in 60%, 20%, and 12.5%

FIGURE 42-4 Infracarinal mediastinal dissection. Ao, descending aorta; CL, carinal lymph node on esophagus; E, esophagus; LB, left main bronchus; P, pericardium; RB, right main bronchus; Tr, trachea.

tahir99-VRG vip.persianss.ir

Chapter 42 Surgical Management of Squamous Cell Carcinoma

475

FIGURE 42-7 Cervical lymph node dissection on the left side. C, carotid artery; E, esophagus; IJV, internal jugular vein; LRLN, left recurrent laryngeal nerve; Tr, trachea.

FIGURE 42-5 Superior mediastinal dissection. Ao, aorta; ES, esophageal stump; LB, left main bronchus; LRLN, left recurrent laryngeal nerve; RB, right main bronchus; RBA, right bronchial artery; Tr, trachea.

FIGURE 42-6 Right recurrent laryngeal nerve (RRLN) node dissection. E, esophagus; N, lymph node; S, subclavian artery; Tr, trachea.

of upper, middle, and lower third tumors, respectively.85 In selected centers in the United States and Europe, three-field lymphadenectomy has been tested also in patients with adenocarcinomas and, interestingly, also demonstrates similar incidences of positive cervical lymph nodes of around 30%.76,137 With the apparent high incidence of cervical nodal metastases, routine cervical lymphadenectomy seems justified. However, some studies of recurrence pattern after esophagectomy suggest a limited role of neck dissection. In a study of 108 patients who underwent esophagectomy without cervical nodal dissection, 11% of patients developed recurrent disease in the neck but only 4% had isolated cervical nodal recurrence. The higher incidences of mediastinal recurrence (25%) and systemic organ metastases (26%) further limited the role of additional neck dissection.138 A very similar study on 176 patients also documented a 6% incidence of cervical nodal recurrence, dwarfed by a local mediastinal recurrence rate of 21% and a systemic recurrence rate of 18%. Only 2 patients had isolated cervical nodal recurrence and underwent further neck dissection.139 The relatively low incidence of cervical nodal recurrence was also found for patients undergoing transhiatal resection; of 149 patients with middle and lower third tumors, cervical recurrence was found in 8.5% of patients. Again, the addition of a cervical lymphadenectomy was questioned.140 Perhaps the importance of cervical lymphadenectomy does not lie within the neck alone. It is realized that the most important group of lymph nodes lies along the recurrent laryngeal nerves, which transgress the thoracic inlet. Reports on recurrence patterns rarely segregate the upper (when often no lymphadenectomy is carried out around the recurrent laryngeal nerves) from the lower mediastinum (where lymph node dissection is usually adequate). When nodes along the recurrent laryngeal nerves from the superior medi-

tahir99-VRG vip.persianss.ir

476

Section 5 Neoplasms

astinum are considered together with the cervical nodes as one entity, this “cervicothoracic” group is involved in up to 63.4% of proximal-third, 45.2% of middle-third, and 42.0% of lower-third cancers in patients undergoing three-field lymphadenectomy.85 Thus, the value of three-field lymphadenectomy may not lie with the addition of a cervical phase but with the completeness of the superior mediastinal dissection along the recurrent laryngeal nerves. It is observed that complete two-field dissection of the superior mediastinum performed from the thorax can, in fact, remove most of the relevant nodes in the neck. The added value of a separate approach to the neck in these patients is therefore questioned.141,142 The addition of a cervical phase certainly eases dissection of the nodes at the thoracic inlet, especially around the paratracheal area. It has the advantage of additional dissection of more laterally located nodes, such as those in the supraclavicular fossae. The argument of an additional cervical incision is thus less important, especially because it does not add much morbidity to an otherwise thorough upper mediastinal dissection. A review of three-field lymphadenectomy as practiced in Japan showed an overall hospital mortality rate of 4% (Tachibana et al, 2003).143 Although this very low mortality rate is achieved, most of these results come from experienced and specialized institutions and such extensive surgery is expected to carry with it a more unfavorable outcome if more widely and unselectively applied. Morbidity rates can also be substantial; an overall complication rate of 44.8%, septic complications of 26.8%, and pulmonary morbidities of 21.3% may be expected (Tachibana et al, 2003).143 The major criticism of three-field dissection is that the prognostic superiority over conventional resection has never been proven by randomized controlled trials; and although retrospective studies provide evidence for benefits of threefield dissection (Udagawa and Akiyama, 2001),144,145 it is only a result of stage migration. Only two small randomized trials have been published. The first showed a higher postoperative mortality rate for two-field dissection and a survival advantage for three-field dissection; in the second, 5-year survival rates were not statistically different for three-field (66.2%) and two-field dissection (48%). In both studies, the patient groups appeared highly selected and not well matched and adjuvant therapies were not controlled.146,147 Perhaps realizing such an extensive operation carries with it substantial morbidity, and that not all patients could benefit, recent focus of research in this area is to further refine the indication of extended lymphadenectomy. A survival advantage was demonstrable only for upper- and middlethird cancers by various investigators.85,86,148 Other poor prognostic factors include the following: 1. When all three fields have metastatic nodes 2. When a lower-third tumor has positive cervical nodes 3. When five or more lymph nodes are involved These situations indicate advanced metastatic disease, and three-field lymphadenectomy may not be justified.149 Other suggested strategies include using intraoperative polymerase chain reaction to examine recurrent laryngeal nerve lymph nodes to predict the need for cervical dissection,150 similar to

the sentinel lymph node metastases concept.151 Some advocate a two-stage operative approach to select patients suitable for cervical lymphadenectomy at a separate procedure.152 Replacing three-field lymphadenectomy by neoadjuvant, adjuvant, or intraoperative radiotherapy153 is an alternative but remains controversial. Reconstruction After Esophagectomy. The reconstruction phase of an esophagectomy determines to a significant extent the postoperative morbidity and long-term quality-oflife. The ideal esophageal substitute should replicate esophageal function, but unfortunately none exists. The most commonly used conduit is the gastric tube, and, of the many configurations, a tailored isoperistaltic tube based on the greater curvature with preservation of the right gastric and right gastroepiploic vessels is most reliable. Disadvantages of the gastric conduit are that patients who have an intrathoracic stomach often experience postprandial discomfort and early satiety related to loss of normal gastric function such as receptive relaxation. Patients could also suffer from acid reflux, possible gastric ulceration, and dysfunctional propulsion.154 The level of the esophagogastric anastomosis has a bearing on the severity of reflux. Patients who have a low intrathoracic anastomosis tend to have more severe reflux and esophagitis compared with the high intrathoracic or cervical anastomosis. Preserving a longer length of esophagus may enhance swallowing function, although no conclusive data are available. The vagotomy that is an integral part of an esophagectomy may lead to poor gastric emptying in the absence of a pyloric drainage procedure. In a randomized trial, 13% of patients who did not have a pyloroplasty had problems with gastric emptying.155 When a drainage procedure is done, a one-layer technique is comparable to a two-layer method156 and a pyloromyotomy is as effective as a pyloroplasty.157 A metaanalysis suggests that a drainage procedure lessens the chance of early postoperative gastric stasis, but long-term function is not affected.158 A drainage procedure, however, is not universally accepted. Some surgeons perform intraoperative digital dilation of the pylorus or carry out endoscopic dilation only when evidence of poor gastric emptying exists after esophagectomy. The controversy is in part related to the other factors that may contribute to emptying of the intrathoracic gastric conduit. A smaller stomach enhances postoperative emptying.159 The straighter position of the stomach when delivered to the neck via the orthotopic (posterior mediastinal) or the retrosternal route may make the stomach empty more efficiently compared with one placed in the right pleural cavity. The angulation at the diaphragmatic hiatus as the stomach emerges from the right paravertebral gutter into the abdomen may hinder food passage. This problem is not present when a left thoracic approach is used with the gastric conduit delivered to the left thoracic cavity for anastomosis. With a gastric conduit, diet modifications and the use of acid-suppressive and prokinetic drugs such as erythromycin may be useful.160,161 Another potential drawback of a gastric conduit is that columnar epithelium as well as specialized intestinal metaplasia could develop in the esophageal remnant above the anastomosis.162 One study showed that 24 (50%) of 48

tahir99-VRG vip.persianss.ir

Chapter 42 Surgical Management of Squamous Cell Carcinoma

patients developed columnar mucosa, and of these 13 had specialized intestinal metaplasia at a median follow-up time of 61 months. In another study, 15 (46.9%) of 32 patients developed columnar mucosa within their cervical esophagus, 3 of whom had intestinal metaplasia; and they had been observed for 8.5, 9.5, and 10.4 years after esophagectomy.163 Thus, there is at least a theoretical risk of Barrett’s cancer in the esophageal remnant, although both studies suggest that a substantial time of exposure is required for intestinal metaplasia to develop. In our experience we have never encountered Barrett’s cancer arising in the esophageal remnant. Whether patients with squamous cell cancers are different from patients with Barrett’s cancer who have resections in this regard is unknown. The simplicity of preparation, adequate length, and robust blood supply makes the gastric conduit the first choice as an esophageal substitute. There are instances when the stomach cannot be used, such as after previous gastric resection and when tumor involvement of a substantial part of the stomach dictates its removal. In these situations use of the colon is preferred. Whether the right, left, or transverse colon is used very much depends on the surgeon’s experience and preference. For most, colonic interposition remains an infrequently performed procedure and has the potential for more complications.164 Mobilization of the colonic loop is more complex; its blood supply is less reliable than that of the gastric conduit, three anastomoses are required, and when the colon becomes ischemic, the choice of alternative conduit is restricted. In our experience, use of a colon loop is associated with more blood loss, a longer operating time, and a higher anastomotic leak rate. Colon ischemia occurs in 1 in 42 patients (2.4%), which compares favorably to a rate of 3% to 10% reported in the literature.165 It has been suggested that a colon conduit is more durable, and the supposed long-term functional benefits of colon interposition make it the preferred esophageal substitute, especially in those with benign disease and also in patients whose cancer disease stage predicts long survival. A colonic conduit provides good long-term swallowing function, and normal oral intake is restored in 65% to 88% of patients.166,167 Colonic conduit seems to have active peristalsis, and this is presented as an explanation for their superior function as an esophageal substitute compared with a passive gastric conduit.168,169 Although peristalsis can be demonstrated immediately after surgery,170 long-term emptying likely relies on gravity.171 When the distal stomach is retained in the abdomen after a colon interposition with a cologastric anastomosis, the latter provides additional reservoir function.166 Unique to the colonic conduit is the risk of redundancy, which can manifest years later.172 Redundancy can cause obstructive symptoms such as dysphagia and regurgitation, and correction can be a complex undertaking. Very few cases of revision are reported in the literature, and in our patients only 1 of 42 patients required a revision of a redundant loop in the neck. In another series of 69 patients with long colonic loops, 10% required anastomotic revision and 25% developed significant colonic redundancy.173 The jejunum is used most frequently after distal esophagectomy and total gastrectomy for cancer of the lower esophagus and gastric cardia. A Roux-en-Y configuration seems best

477

because it prevents bile reflux to the esophagus. A jejunal loop used in a modified Merendino procedure to interpose between the esophagus and proximal stomach after limited resection of the distal esophagus and gastroesophageal junction has also been advocated.174 Excellent postoperative quality of life and function is claimed. A long jejunal loop is sometimes used to reach the neck, but preparation is tedious and the vasculature may not be reliable.175 A free jejunal graft is used for reconstructing the defect after resection of the pharyngoesophageal segment in the neck.100 The route of reconstruction is, in part, related to the surgical approach for resection. When a cervical anastomosis is chosen, a choice exists for placing the conduit in the orthotopic, retrosternal, or subcutaneous route. The subcutaneous route is rarely used because it is cosmetically unsightly. The retrosternal route has variably been shown to be associated with increased or similar cardiopulmonary morbidity and mortality rates.176-178 The retrosternal route is 2 to 3 cm longer compared with the orthotopic route179 but is rarely of relevance because the esophageal replacement conduit is usually of sufficient length. Some suggest that the tight space at the thoracic inlet in the neck could cause potential constriction on the conduit and recommend partial manubrium, clavicular head, and first rib resection.135 We have found this unnecessary. The angulation at the inlet to the retrosternal tunnel from the neck may result in some hold-up sensation during food intake. In addition, the same angulation makes endoscopic bougie dilation more difficult should it be required for benign or malignant anastomotic strictures. Functionally, although it was shown that there was a higher rate of gastric retention when the retrosternal route was used, quality of life was not adversely affected.177,180 When palliative resection is carried out for advanced tumor, recurrent tumor could infiltrate into the conduit placed in the posterior mediastinum. In a retrospective study of 209 patients who had undergone curative resection and orthotopic reconstruction, of 73 patients (35%) who had locoregional tumor recurrence, 46 (22%) had secondary dysphagia as a result. The authors concluded that in 27 patients (13%), dysphagia would likely have been prevented by using a retrosternal reconstruction route.181 However, the site of the obstruction that produced dysphagia was not clearly stated. The stomach is usually spacious, and tumor infiltration will not readily result in dysphagia. Only at the thoracic inlet and in the cervical region where there is limited space can tumor involvement lead to obstruction and dysphagia. Using the retrosternal route will eliminate tumor involvement in the posterior mediastinum, but infiltration from tumors in the neck cannot be avoided. The effect of choosing the retrosternal route in reducing “secondary” dysphagia from recurrent tumor infiltration may therefore be overemphasized. In our own study, only 4 of 28 patients (14%) developed tumor infiltration into the gastric conduit in the posterior mediastinum. The main symptom was bleeding in 2 patients, and none had dysphagia.182 It is our policy therefore to use the retrosternal route for reconstruction when resection is palliative, especially when postoperative radiation therapy is planned, or when the reconstructive phase of the operation precedes tumor resection.

tahir99-VRG vip.persianss.ir

478

Section 5 Neoplasms

Perioperative Care and Postoperative Morbidity and Mortality. With adequate preoperative workup, serious cardiac events such as myocardial infarction should be rare. Atrial arrhythmia is common, affecting about 20% of patients. In itself, atrial fibrillation is benign; rather, it serves as a marker for more serious underlying pulmonary and septic surgical complications.183 Occurrence of atrial arrhythmia should prompt thorough search for a more ominous underlying cause. Pulmonary complications remain the most common and serious postoperative morbidity. Most report a respiratory morbidity rate of about 20%.81 Pneumonia and respiratory failure occurs in 15.9% of our patients and is responsible for 55% of hospital deaths. Predictive factors include advanced age, supracarinal tumor location, and lengthened operating time. The increased chance of pulmonary complications associated with supracarinal tumors is, in part, related to the prevalence of recurrent laryngeal nerve injury, which reduces the effectiveness of glottic closure on coughing, diminishes airway protection, and predisposes to aspiration. Long-term quality of life is also impaired.184 Neoadjuvant therapy did not lead to increased morbidity.88 Measures to improve respiratory outcome include cessation of smoking preoperatively, chest physiotherapy, avoidance of recurrent laryngeal nerve injury, cautious fluid administration to avoid fluid overload, use of smaller chest tube,185 early ambulation, regular bronchoscopy, and early tracheostomy to provide easy access should there be sputum retention despite regular bronchoscopic clearance.186 Epidural analgesia is invaluable in postoperative pain relief and should be the standard of care after esophagectomy.128 The most common surgical complication after esophagectomy is still anastomotic leak and can reach 30%,187 although in experienced centers leak rates of below 5% can be achieved. Most leaks are probably related to technical faults (Whooley et al, 2001),93,188 such as tension between the conduit and the esophageal stump, ischemia of the conduit because of rough handling and poor preparation, and suboptimal anastomotic technique. The actual method of anastomosis is perhaps less important than its proper application. Stapled anastomosis is popular for intrathoracic anastomosis whereas the handsewn technique is preferred in the neck. There is no evidence from randomized trials that leak rates differ between stapled and hand-sewn anastomoses, but the circular stapler may give rise to more strictures.189 The linear stapler has also been advocated for use in the neck. One group reduced their cervical leak rate from 10% to 15% using a hand-sewn technique to 2.7% using linear staples with a side-to-side anastomosis.190 With experience, however, the hand-sewn method is as safe, if not more so, and certainly less expensive. Leak rate was 3% in our patients who had an intrathoracic anastomosis, 35% of whom died, resulting in an overall leak-related morality of 1% of all patients who had esophagectomy (Whooley et al, 2001).188,191 Early detection of anastomotic leaks is important so that timely intervention can be instituted; sometimes a high index of suspicion is important when other seemingly unrelated complications develop, such as atrial fibrillation.183 Treatment principles dictate adequate drainage, whether by radiologic,

endoscopic, or surgical means. Maintenance of nutritional status is important, preferably via the enteral route, either by a fine-bore nasoduodenal tube placed endoscopically or by feeding jejunostomy. The mortality of leaks remains high, in spite of the improvement in perioperative care and intensive care support. Improvements in the management of leakrelated sepsis would likely lead to a decrease in morbidity and mortality. Other surgical complications such as chylothorax and herniation of bowel through the diaphragmatic hiatus are rare but should be recognized early, and both are corrected by surgical re-exploration. Surgery for Palliation. In the presence of locally advanced or metastatic disease, palliation is the goal of treatment. “Quality of life” (QOL) issues assume more importance than long-term prognosis. Major symptoms of dysphagia, pain, and tumor bleeding are obvious symptoms to eliminate, but the patient’s attitude, anxiety, and other aspects of QOL should be taken into account when treatment is planned. QOL may deteriorate significantly after surgical resection. One study showed that in patients who survived at least 2 years, QOL scores returned to preoperative levels within 9 months but patients who died within 2 years of surgery never regained their former QOL. The improvement in dysphagia was maintained until death.192 Although this cautions against performing palliative resections, there has been no study which directly compares QOL in equivalent patients undergoing surgical resection or other palliative therapies. Patients undergoing nonoperative palliative treatment naturally would also report gradual deterioration in most aspects of QOL until death.192 The ability of esophagectomy to restore swallowing function is superior to that of other forms of treatment. Our own study showed that both curative and palliative esophagectomy resulted in significant improvement in the type and quantity of food intake and other diet-related symptoms for at least 1 year after surgery. More importantly, these symptom improvements were equally well maintained in the curative and palliative groups. After 3 months, more than 90% of patients were asymptomatic with regard to swallowing or had only occasional difficulty with solid food. Pain status and global QOL score were worse for the palliative group at 9 months after resection.193 Surgical resection also palliates other symptoms, such as pain due to tumor and bleeding. It also prevents the development of esophageal airway fistula formation and airway obstruction by the primary tumor. Surgical bypass using stomach, colon, and jejunal loops, if successful, offers durable good and rapid palliation in dysphagia.166,194,195 The most commonly employed bypass is the Kirschner operation, in which the stomach is brought up to the neck by the retrosternal or subcutaneous route to anastomose with the cervical esophagus. The thoracic esophagus is drained by a Roux-en-Y jejunal loop anastomosed to the divided abdominal esophagus.6,196,197 There is no doubt that successful surgical resection or bypass provides excellent relief of dysphagia, but the operative magnitude, short life expectancy, and the availability of low-risk alternatives make them less attractive. Thus, planned palliative resections or bypass are uncommonly performed. When unanticipated unresectable disease is encountered at

tahir99-VRG vip.persianss.ir

Chapter 42 Surgical Management of Squamous Cell Carcinoma

attempted resection, a bypass procedure is justified. In this situation, a lesser procedure is performed for a patient judged fit to undergo tumor extirpation and in whom surgical exploration is already being undertaken.198

Combined Multimodal Treatment Strategies The past 2 decades have seen a proliferation of additional treatments of esophageal cancer. The rationale is based on the suboptimal long-term results of surgery or radiation therapy. Both the spatial and synergistic actions of chemotherapeutic agents and radiotherapy are explored in multimodality treatments. How surgical resection and these new combinations should be integrated into treatment programs is an active area of research. Trials on neoadjuvant radiotherapy have failed to show increased resection rate or improved survival compared with surgery alone.199-203 A Cochrane meta-analysis showed that if preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in 5-year survival of around 3% to 4%.204 This treatment strategy is not commonly used anymore. Postoperative radiotherapy demonstrated improved local disease control.205-207 The largest study published to date randomized 495 patients with intrathoracic squamous cell cancers. Postoperative radiotherapy of 50 to 60 Gy was given to 220 patients to the entire mediastinum and bilateral supraclavicular fossae. Per protocol analysis showed no overall difference in 5-year survival at 31.7% for the surgery alone group and 41.3% for the radiotherapy group. A benefit in the radiotherapy group was observed in stage III patients only; 5-year survival rates were 13.1% and 35.1%, respectively. The chance of mediastinal, cervical lymph node and anastomotic recurrences was also reduced (Xiao et al, 2003).207 It seems reasonable to give postoperative radiotherapy to subgroups of patients, especially those who had palliative resections, to enhance local disease control.206 Suitable metaanalysis should be carried out to further test the statistical validity of the conclusions. Two large randomized trials on neoadjuvant chemotherapy were contradictory in their results. The Intergroup trial (INT 0113) randomized patients into a group that was to undergo surgery alone, one that was to have three cycles of cisplatin and 5-fluorouracil before surgery, and one with stable or responsive disease in which two additional postoperative courses were performed.208 Of 440 eligible patients, 213 were assigned to the neoadjuvant group. The median survival was 14.9 months for the chemotherapy group compared with 16.1 months for the surgery group. Two-year survival rates were no different at 35% and 37%, respectively. The MRC trial (OE02) involved 802 patients and similar preoperative regimens with two courses of cisplatin and 5-fluorouracil.80 Overall survival was better in the chemotherapy group. Median survival was 16.8 months versus 13.3 months, and 2-year survival rates were 43% and 34%. The differences in findings in these two studies are difficult to resolve. There are many differences, including the chemotherapy regimen, the number of patients who underwent resection, the time to resection, the type of surgery per-

479

formed, and the number of patients who also had radiotherapy. Interestingly, the median survival of the surgery alone arm in the Intergroup trial (16.1 months) was equivalent to that in the chemotherapy arm in the MRC trial (16.8 months). A Cochrane meta-analysis on neoadjuvant chemotherapy analyzed 2051 patients (Malthaner and Fenlon, 2004).209 The rates of resection, complete resection, and postoperative complications were not influenced. The pooled clinical response was 36%, and pathologic complete response was only 3%. There appears to be a significant survival advantage for chemotherapy, only reaching statistical significance at 5 years. The overall benefit was modest; it required 11 treated patients to benefit one extra survivor. It is also worth noting that all trials evaluated patients with squamous cell cancers except the Intergroup and MRC trial, where most patients suffered from adenocarcinomas. Subgroup analysis in these two trials, however, could not show a difference between the two cell types in terms of response to chemotherapy. Studies on purely postoperative chemotherapy are limited. One report compared surgical resection with the addition of postoperative cisplatin and 5-fluorouracil in 242 patients with squamous cell cancers.210 The 5-year disease-free survival rate was significantly different at 45% with surgery alone and 55% with surgery plus chemotherapy. The overall 5-year survival rates were not significantly different at 52% and 61%, respectively. This type of approach seems more popular in Japan, usually given after extended resection, and where poor prognostic factors on pathologic examination are present. Chemoradiotherapy, either as neoadjuvant or definitive treatment, is currently most intensely studied. Several groups have explored chemoradiotherapy as neoadjuvant therapy. In five randomized trials, only squamous cell cancers were recruited.203,211-214 In two other studies, mostly adenocarcinomas were studied,215,216 and one included only adenocarcinomas.217 A survival advantage with neoadjuvant chemoradiotherapy over surgery alone was demonstrated only in the trial with adenocarcinomas only.217 This trial was mainly criticized for its exceptionally poor 3-year survival rate of 6% in the surgery alone group. In a French study that included stage I and II squamous cell cancers only, the chemoradiotherapy group had longer disease-free survival, a longer interval free of local disease, a lower rate of cancerrelated deaths, and a higher frequency of curative resection, but overall survival was not different.213 The results from these studies are inconclusive. The Patterns of Care studies in North America showed that preoperative chemoradiotherapy increased from 10.4% during 1992-1994, to 26.6% in 1996-1999. Interestingly, trimodal therapy was three times more common in patients with adenocarcinomas compared with those with squamous cell cancers.218 Notwithstanding the lack of concrete data supporting such regimens, its use is commonplace. The Radiation Therapy Oncology Group (RTOG 85-01) trial of chemoradiotherapy versus radiotherapy provided convincing evidence of the superiority of chemoradiotherapy.32,33,34 The 5-year survival rate reported for the combined therapy group was 26% compared with 0% after radiotherapy (median survival, 14 months versus 9 months). Data on

tahir99-VRG vip.persianss.ir

480

Section 5 Neoplasms

recurrence patterns showed that both local and distant disease control were superior with combined treatment. Local persistence of disease and recurrence was 47% compared with 65%. Intensification of radiation dose to beyond 50.4 Gy, whether by external beam219 or by brachytherapy,220 did not yield further advantage but had potential added complications. A recent Cochrane meta-analysis on 13 randomized trials that compared chemoradiotherapy with radiation confirmed the superiority of chemoradiotherapy. Concurrent chemoradiotherapy provides significant overall reduction in mortality at 1 to 2 years, an absolute reduction of death by 7%, and reduction of local persistence/recurrence rate by 12%. The downside is a 17% increase in grade 3 and 4 toxicities. Sequential chemoradiotherapy provides no benefit, perhaps demonstrating the need to maximize the radiosensitizing properties of chemotherapy (Wong and Malthaner, 2004).221

The esophageal tumor is intensely hypermetabolic, long segment 7.5 cm length

Upper border of esophageal tumor at T6 level (28.5 cm from upper incisor) Lower margin of tumor reaches upper T9 level (36 cm from upper incisor)

A

Role of Surgical Resection The RTOG 85-01 trial suggested that in patients with T1-3 N0-1 M0 disease, a 14% to 26% 5-year survival can be expected. It has been suggested that surgery may be of no additional value to chemoradiotherapy and should be relegated as an “adjuvant” treatment. Two clinical trials attempted to examine whether surgical resection was necessary after chemoradiotherapy. A French study (FFCD 9102) was an equivalence trial that treated 455 patients with both squamous cell cancers and adenocarcinomas of stage T3-4 N0-1 M0 with two cycles of 5-fluorouracil, cisplatin, and concurrent radiation (46 Gy at 2 Gy/day or split course 15 Gy weeks 1 and 3). Only 259 patients who had at least a partial response were randomized to undergo immediate surgery or to have three more cycles of chemotherapy with 20 Gy at 2 Gy/day or split course 15 Gy). The death rate within 3 months after starting induction treatment was 9% for surgery group compared with 1% in the chemoradiotherapy group. Two-year survival rates were not different at 34% and 40%, so were median survival at 17.7 months and 19.3 months for surgical and nonsurgical groups, respectively. Patients in the surgical arm, however, required stenting less often (13% versus 27%) or dilations (22% versus 32%).222 There was no difference in the long-term quality of life, but the surgery arm had transient deterioration in the immediate postoperative period.223 A German multicenter equivalence trial recruited 177 patients with squamous cell cancers (T3-4 N0-1 M0). Three cycles of 5-fluorouracil/leucovorin/etoposide/cisplatin were given, followed by chemoradiotherapy (cisplatin/etoposide + 40 Gy). Resection was then performed. This was compared with a control group with the same chemotherapy, followed by definitive chemoradiotherapy (cisplatin/etoposide + >60 Gy). Treatment-related mortality rates were 10% in the surgical arm versus 3.5% in the nonsurgical arm. Local tumor control was worse in the nonsurgical arm, but median survival time and 3-year survival rates were not different at 16 months and 28% (surgical arm) versus 15 months and 20% (nonsurgical arm). Three-year survival rate was 35% in nonresponders

B FIGURE 42-8 PET scan showing reduction of glucose uptake (standardized uptake value) by the tumor after chemoradiotherapy. In A there is intense uptake by the tumor; in B, arrows indicate the primary tumor showing marked response with much less intense uptake. The standardized uptake value was reduced from 11 to 3.8.

undergoing complete tumor resection compared with 11% in nonresponders who did not undergo resection (Stahl et al, 2005).224 Both studies concluded that surgical resection may not be necessary after chemoradiotherapy. It may be premature to negate the value of surgical resection. First, chemoradiotherapy is by no means harmless, and surgical resection may not be as morbid as described. Treatment duration of chemoradiotherapy is often long, and compliance is problematic. Only 68% of the patients in the RTOG-8501 trial could complete the planned treatment.225 Acute grade 3 and 4 toxicity was reported in 43% and 26% of patients, respectively, and long-term grade 3 and 4 toxicity occurred in 24% and 13% of patients.219 Treatment-related mortality can be as high as 5% to 9%.219,226 In studies that showed a benefit for chemoradiotherapy or questioned the value of surgical resection, the results of the surgical arm were often suboptimal. In the FFCD 9102 trial, death rate within 3 months in the surgical arm was 9% compared with 1% in the nonsurgical arm222; in the German trial again the mortality rates were 10% and 3.5%, respectively (Stahl et al, 2005).224 The early surgical deaths likely biased the long-term survival results. The Irish study of an unusually poor 6% 3year survival was cited earlier.217 Comparisons with nonoperative treatments will only be valid when better results from high-volume centers are integrated into clinical trials.

tahir99-VRG vip.persianss.ir

Chapter 42 Surgical Management of Squamous Cell Carcinoma

481

PATIENT WITH CANCER OF ESOPHAGUS

Staging (Endoscopy/Bronchoscopy, PET/CT, EUS, Ultrasound neck)

T4 disease Tracheoesophageal fistula

Stage IVb with visceral metastases

Resectable disease

R0 resection probable

R0 resection improbable

Risk assessment

Chemoradiation

Good risk

Poor risk

Poor response

Good response

Palliation

Endoscopic methods Radical resection Selected patients with chemotherapy
radiotherapy

Definitive Study protocol chemoradiation / radiotherapy neoadjuvant / adjuvant radiotherapy
chemotherapy

Palliation

FIGURE 42-9 Management protocol for squamous cell cancer of the esophagus at The University of Hong Kong.

Second, local disease control with chemoradiotherapy alone is less than satisfactory. It can be shown with increasing extent of lymphadenectomy that better local control is achieved with surgery; by comparison, nonoperative chemoradiotherapy has a much higher local persistence/recurrence rate of over 50%.219,227 The relief of dysphagia, the main symptom requiring palliation, is much more certain with surgical resection; and the need to treat dysphagia with a stent was twice that in the nonsurgical group in the FFCD 9102 trial.222 Third, for the majority of patients treated by chemoradiotherapy, residual disease exists. The pathologic complete response rate for most trials is about 25%. It may be assumed that surgical resection is not useful in these patients. However, ascertaining true complete response is difficult, whether by endoscopy, EUS, or CT.57,228 Recent studies using FDG-PET showed promise,63,229 but although PET can more reliably distinguish responders and nonresponders, it is not accurate enough to pinpoint the complete pathologic responders.230 With improved technology to detect small amount of residual tumor in the esophagus or in lymph nodes (micrometastases), such as immunohistochemistry or polymerase chain reaction, the “true” rate of complete responders is even lower.231 In the 75% of patients who do not show a complete response, surgical resection may enhance cure. In the German trial, the 3-year survival of nonresponding patients who underwent resection was 35% compared with 11% in those who did not (Stahl et al, 2005).224 Reliable predictors for response to chemoradiotherapy would be useful, because multimodality treatments are toxic,

time consuming, and costly. Various markers have been explored, such as simple histology,232 TP53, proliferative cell nuclear antigen (PCNA), epithelial growth factor receptor (EGFR), Ki-67, cyclin D1, thymidylate synthase, and microvessel density, both in tissue and serum. None is reliable nor can help in clinical decision-making.233 Metabolic imaging with PET may be useful, with its ability to predict response early in the course of treatment (Fig. 42-8).230 How all this information should be used requires more studies. It seems that cisplatin and 5-fluorouracil–based chemoradiotherapy has reached its therapeutic limit in treating esophageal cancer. More novel chemotherapeutic agents are being explored, including paclitaxel, docetaxel, the topoisomerase I inhibitor irinotecan (CPT-11), vinorelbine, gemcitabine, Herceptin, oxiliplatin, and biomodulators such as interferon.234 This remains a very active area of research. In addition, advances in techniques in radiation delivery, such as intensity-modulated radiotherapy, may further reduce radiation toxicity.235

TREATMENT STRATEGIES AT THE UNIVERSITY OF HONG KONG Treatment strategies for squamous cell cancers are based on a patient’s disease stage and physical fitness (Fig. 42-9). Measures are employed to maximize the chance of an R0 resection because this is the one factor that is unequivocally shown to achieve a good prognosis. For tumors on preoperative investigations that suggest a high likelihood of R0 resection, surgical resection with two-field lymphadenectomy is performed. For patients with tumors that are locally advanced

tahir99-VRG vip.persianss.ir

482

Section 5 Neoplasms

100

pCR Stage I Stage II T0N1 Stage III Stage IV

80

N 37 26 103 15 117 33

Median (Months) 86.8 81.3 28.1 21.1 13.4 13.2

5 yr 61.7% 58.4% 37.7% 25.9% 10.5% 12.1%

60 % 40

20

P  .01 0 0

1

2

3

4

5 Years

6

7

8

9

10

FIGURE 42-10 Survival curves according to pathologic disease stage. pCR, pathologic complete response after chemoradiotherapy; T0N1, patients with sterilization of the primary tumor but positive nodal disease.

or have cervical and celiac lymph node metastases, upfront chemoradiotherapy is given. Surgical resection is offered when good response is obtained. Patients with obvious incurable disease or who are not fit for surgical intervention are treated by chemoradiotherapy or stent insertion. Studies on the benefit of superior mediastinal and cervical lymphadenectomy are ongoing. Survival curves with respect to disease stage and R-category of resections are shown in Figures 42-10 and 42-11.

THE FUTURE Advances have been made in the management of esophageal cancer; the onus is to select the most appropriate treatment for individual patients. Surgeons play a central role in directing management of this disease by advising on how best to integrate surgical therapy with nonoperative programs. Surgeons should aim at improving their results further, so that the best results of surgery are used to compare with seemingly “safer” nonsurgical therapies. Low death rates have been achieved in specialized centers, but there is still much room for improvement in terms of morbidity rates. The indications for surgery and nonoperative treatments are going to evolve when more information is made available and should vary with patients and disease stage. Staging for esophageal cancer is likely to undergo major changes. Already the designation of cervical and celiac lymph nodes as stage IV disease is being questioned, because the prognosis seems better than in those patients with visceral metastases.236 The number of lymph nodes has already been incorporated into

the Japanese staging system, and the AJCC system may likewise do the same. Staging investigations such as PET and EUS are becoming more sophisticated and accurate, which serves to further refine our therapy selection. Chemoradiotherapy has made an important impact on current management strategies,73 but perhaps its overenthusiastic adoption and its presumed benefit has to be balanced against the lack of clear evidence of superiority over surgery.237 Distant failure remains a hurdle to improving survival, and search for more effective systemic drugs as well as our ability to predict responders with precision must be a therapeutic target. Management strategies are going to evolve further, with improvements in molecular techniques, imaging methods, and introduction of more novel tumoricidal agents. The challenge for the future is for us to critically test our strategies in a scientific, unbiased manner and to explore other innovative treatments.

COMMENTS AND CONTROVERSIES This chapter by Drs. Law and Wong is a very complete description of all aspects related to the diagnosis and management of squamous cell carcinoma of the esophagus. As a result it offers the reader a wealth of data and useful information. Especially of interest are a number of features typically for the Asiatic presentation and therapeutic approach of squamous cell carcinoma of the esophagus, a condition that in a number of Western countries has lost its relative importance compared with the still-increasing incidence of mainly Barrett’s esophagus–related cancer of distal esophagus and gastroesophageal junction.

Chapter 42 Surgical Management of Squamous Cell Carcinoma

100 N 266 25 40

R0 R1 R2

80

Median (Months) 30.7 13.8 8.4

5 yr 35.0% 8.3% 3.8%

P  .01 60 % 40

20

0

0

1

2

3

4

5 Years

6

7

8

9

10

FIGURE 42-11 Survival curves according to R category of resection. R0, macroscopic and microscopic disease clearance; R1, microscopic residual disease; R2, macroscopic residual disease.

In this respect I refer to the use of cytology screening started in China in the 1950s. Balloon cytology screening is a very simple and inexpensive tool that obviously contributed significantly to the early diagnosis of esophageal cancer in a mass survey of a population living in a high-risk area of China. It is only surprising that such a technique never has been used in the Western world where Barrett’s metaplasia has reached almost endemic proportions. It would be relatively easy to identify among the population with Barrett’s esophagus a high-risk group consisting of patients presenting with a long-segment intestinal-lined Barrett’s esophagus who perhaps could benefit from such a simple inexpensive screening test. The authors rightfully underscore the high incidence of intramural metastasis, multifocal lesions, and the chaotic pattern of lymph node involvement that has been traditionally a focus of research coming from the Far East, in particular from the work of Japanese authors. In this context the difficulties of precise staging are well explained. Despite refinements in EUS technology, overall accuracy of staging nodal disease remains suboptimal, which clearly has consequences in relation to neoadjuvant multimodal treatment strategies. Also T classification staging, particularly in thin patients, which is often the case in Asiatic patients, may be difficult owing to a decreased or absent fat plane between the aorta, trachea/bronchi, and pericardium, erroneously suggesting invasion by the tumor. A helpful maneuver to better assess such tumor invasion is by performing CT in both supine and prone positions, taking benefit of the gravitational movement of the intrathoracic organs. This maneuver results in a marked decrease of the number of patients falsely diagnosed as having unresectable disease and therefore denied potentially curative operations.

Besides adequate clinical staging, assessment of medical operability is of paramount importance. In particular in squamous cell carcinoma as opposed to adenocarcinoma in patients with Barrett’s esophagus, many patients have a history of heavy tobacco and alcohol abuse. As stressed by the authors, risk assessment is difficult and often based on the surgeon’s and anesthesiologist’s experience rather than an exact science, a statement I fully endorse. Several scoring systems (e.g., Possum, P-Possum) have been established in an effort to predict postoperative morbidity and mortality. It appears that none of them really fulfills the expectations, with the surgeon’s feeling based on experience being superior. In this respect, in particular when assessing pulmonary status, the old-fashioned way of assessing whether a patient can climb two flights of stairs, in my experience, remains a very valuable test. As to the surgery, it must be clear that surgeons dealing with esophagectomy for cancer need to master different access routes and techniques as well as the different options to restore continuity. In this context the recent enthusiasm favoring minimally invasive surgery requires a note of caution. Such novel techniques before widespread application first have to be validated in particular on their oncologic value. It is not clear at this point whether video-assisted thoracic surgery (VATS)/laparoscopic esophagectomy, although feasible, will allow for a proper oncologic intervention. Increased manipulation of the esophagus and the tumor at the time of esophageal dissection, the feasibility of en-bloc resection, and proper lymphadenectomy as well as a steep learning curve and some doubts about the real advantage are some of the concerns that I share with the authors.

483

484

Section 5 Neoplasms

Nevertheless, it appears to me that VATS/laparoscopic esophagectomy is a valuable option in the surgical treatment of early (T1 m1-sm3) cancers. In such patients, the risk of incomplete R1 resection is nonexistent, a proper thoracic lymphadenectomy being feasible as well. A substantial part of the manuscript is dedicated to the discussion of the extent of lymphadenectomy, which traditionally was a focus of interest in the Far East and mainly Japan. The main message here is the high incidence of cervical lymph node involvement irrespective of the tumor location. This has been proven to be true also in the West for patients presenting with adenocarcinoma, underscoring again the chaotic character of lymphatic spread in both squamous and adenocarcinoma. Refinement in clinical staging in particular from PET as well as refinement of surgical techniques, in particular sampling of lymph nodes at the base of the neck during the thoracic part of the operation, may eventually result in a decrease of three-field lymphadenectomy, given the rightful concerns about an increased morbidity. Postoperative care as described is an integral part of the surgeon’s responsibility and may be very demanding, requiring meticulous attention to a number of factors that may influence sometimes dramatically postoperative outcome. Familiarity with the integral spectrum of diagnosis, staging, multidisciplinary approach, surgery, and postoperative care of this complex oncologic problem requires a dedicated specialist surgical team practicing in high-volume centers as reflected in many publications dealing with volumeoutcome relationships. Finally, the number of long-term survivors has increased substantially over the past 2 decades. As a result, quality of life issues are becoming increasingly important. Focusing on functional outcome is therefore mandatory to assess and to improve not only the oncologic value but also, and equally important, the functional outcome of a particular surgical technique and to compare it with nonsurgical treatment modalities. T. L.

■ In specialized centers, a very low mortality rate can be achieved after esophagec-

KEY REFERENCES

Udagawa H, Akiyama H: Surgical treatment of esophageal cancer: Tokyo experience of the three-field technique. Dis Esophagus 14:110114, 2001. ■ The results from Akiyama, a surgeon who dedicated his whole professional career to the study of esophageal cancer, are summarized.

Ando N, Ozawa S, Kitagawa Y, et al: Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg 232:225-232, 2000. ■ Progress of surgical results over a 15-year period in a specialized center in Japan; reasons for improvement were analyzed. Law S, Kwong DL, Kwok KF, et al: Improvement in treatment results and long-term survival of patients with esophageal cancer: Impact of chemoradiation and change in treatment strategy. Ann Surg 238:339348, 2003. ■ The availability of chemoradiotherapy provided impetus for change in treatment strategies for patients with esophageal cancer. Using chemoradiotherapy to treat patients with very advanced disease, and its incorporation into clinical trials as neoadjuvant treatment, led to reduction in palliative surgical procedures and improvement in overall patient prognosis. Law S, Wong J: Use of minimally invasive oesophagectomy for cancer of the oesophagus. Lancet Oncol 3:215-222, 2002. ■ Current status of the various minimally invasive approaches in esophagectomy is summarized. Law S, Wong KH, Kwok KF, et al: Predictive factors for postoperative pulmonary complications and mortality after esophagectomy for cancer. Ann Surg 240:791-800, 2004.

tomy but morbidity, especially related to pulmonary complications, remains significant. Advanced age, supracarinal tumor location, and increased operating time were related to respiratory complications, whereas advanced age and blood loss were related to death after esophagectomy. Liu JF, Wang QZ, Hou J: Surgical treatment for cancer of the oesophagus and gastric cardia in Hebei, China. Br J Surg 91:90-98, 2004. ■ Results in the treatment of 15,653 patients with esophageal and cardia cancers from 1952-2000 in a very high incidence area in China are summarized. Of interest is the left thoracic approach to many patients, popularized by Chinese surgeons. Malthaner R, Fenlon D: Preoperative chemotherapy for resectable thoracic esophageal cancer (Cochrane Review). In The Cochrane Library. Chichester, UK, John Wiley & Sons, 2004. ■ A systematic review of chemotherapy used in the neoadjuvant setting indicates that the potential benefits seem limited. Natsugoe S, Yoshinaka H, Shimada M, et al: Number of lymph node metastases determined by presurgical ultrasound and endoscopic ultrasound is related to prognosis in patients with esophageal carcinoma. Ann Surg 234:613-618, 2001. ■ The authors describe their results in using percutaneous and endoscopic ultrasound in the staging of patients with esophageal cancer. Very accurate staging information can be obtained by these examinations, provided they are meticulously performed. Patients’ prognosis could be stratified by the number of metastatic lymph nodes using ultrasound, which is as good as post surgical pathological staging. Stahl M, Stuschke M, Lehmann N, et al: Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23:2310-2317, 2005. ■ In this first large published multicenter trial of neoadjuvant chemoradiotherapy with surgical resection versus chemoradiotherapy alone in the treatment of locally advanced squamous cell esophageal cancer, no difference in overall survival was found. Mortality from surgery remains high. Tachibana M, Kinugasa S, Yoshimura H, et al: Extended esophagectomy with 3-field lymph node dissection for esophageal cancer. Arch Surg 138:1383-1389, 2003. ■ The results of three-field lymphadenectomy for esophageal cancer as practiced in Japan are summarized. Low mortality rate is achieved; morbidity rates remain substantial.

van Westreenen HL, Westerterp M, Bossuyt PM, et al: Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 22:38053812, 2004. ■ A systemic review of the use of FDG-PET scan in staging of esophageal cancer, a modality whose use is becoming standard practice. Wang GQ, Jiao GG, Chang FB, et al: Long-term results of operation for 420 patients with early squamous cell esophageal carcinoma discovered by screening. Ann Thorac Surg 77:1740-1744, 2004. ■ This paper describes the long-term results in a large number of patients who were diagnosed to have esophageal cancer by a population screening program in a highincidence area in China. It shows the excellent surgical results that can be obtained in patients with early cancer. Whooley BP, Law S, Alexandrou A, et al: Critical appraisal of the significance of intrathoracic anastomotic leakage after esophagectomy for cancer. Am J Surg 181:198-203, 2001. ■ The significance and management of intrathoracic anastomotic leaks are described. A 1% leak-related mortality after esophagectomy is achieved.

Chapter 42 Surgical Management of Squamous Cell Carcinoma

Wong R, Malthaner R: Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus (Cochrane Review). In The Cochrane Library. Chichester, UK, John Wiley & Sons, 2004:CD002092. ■ This systematic review of chemoradiotherapy versus radiotherapy alone in treating esophageal cancer confirms the RTOG-8501 trial that chemoradiotherapy is superior to radiation alone. This has become the standard nonoperative treatment of esophageal cancer.

Xiao ZF, Yang ZY, Liang J, et al: Value of radiotherapy after radical surgery for esophageal carcinoma: A report of 495 patients. Ann Thorac Surg 75:331-336, 2003. ■ Results from the largest single center randomized trial using postoperative radiotherapy are presented. Radiotherapy benefits subsets of patients.

485

chapter

43

PRIMARY SURGERY FOR ADENOCARCINOMA OF THE ESOPHAGUS Nasser K. Altorki

The treatment of choice for patients with esophageal adenocarcinoma is controversial. Although esophagectomy remains the standard of care, its role has been challenged owing to the generally poor outcomes after surgical resection alone.1,2 A survey of the patterns of care for esophageal cancer in the community using the American College of Surgeons National Cancer Database examined the modalities of treatment offered to more than 5000 patients in over 820 hospitals across the United States in 1994.3 This study, reported in 2000 by Daly and colleagues, showed that surgical resection as a primary modality of therapy was offered to only 43% of patients with esophageal adenocarcinoma clinically staged as stages I, II, and III. The majority of the remaining patients underwent definitive chemotherapy or chemoradiation therapy followed by a planned surgical resection.3 A more recent pattern of care survey showed that 56% of over 11,000 patients with esophageal cancer received chemoradiation therapy with curative intent (Suntharalingam et al, 2005).4 In an additional 33% of patients, chemoradiation therapy was given prior to a planned esophagectomy. These findings suggest that treatment options offered in the community to patients with esophageal cancer have, to a large extent, at least in the United States, discounted primary surgical resection in favor of combined modality therapy with or without a subsequent esophagectomy. The use of such measures, often outside the realm of controlled clinical trials, is not supported by the results of most randomized trials that have yet to show a survival advantage for preoperative chemoradiation therapy followed by esophagectomy over esophagectomy alone, particularly in patients with adenocarcinoma of the esophagus.5,6 Additionally, there is considerable controversy within the surgical literature as to what represents the appropriate operation for patients with esophageal cancer, regardless of cell type. The debate focuses primarily on the need for, and the extent of, lymph node dissection during the conduct of esophagectomy for cancer. In the following discussion I attempt to outline the various surgical strategies and their impact on survival and disease recurrence, focusing on patients with adenocarcinoma.

TRANSHIATAL ESOPHAGECTOMY Transhiatal esophagectomy is one of the more common techniques for esophagectomy in North America and Europe. In the previously mentioned survey by the American College of Surgeons, transhiatal esophagectomy was performed in 25% of patients with carcinoma of the distal third of the esophagus.3 As described elsewhere in this textbook, the procedure entails extirpation of the intrathoracic esophagus without a 486

thoracotomy and advancement of the esophageal substitute, usually a greater curvature gastric tube, to the neck for reconstruction. The extent of nodal dissection with this operation is essentially limited to the periesophageal nodes and those perigastric nodes along the cardia and lesser gastric curve. The largest single experience with transhiatal esophagectomy is that of Orringer and associates, who reported on 800 patients with cancer of the intrathoracic esophagus and cardia (Orringer et al, 1999).7 Adenocarcinoma was present in 69% of the patients, while 28% had epidermoid cancer. Hospital mortality was 4.5%, and morbidity was 27%. Major complications included anastomotic leaks (13%), recurrent laryngeal nerve injury (7%), wound infection (3%), pulmonary complication (2%), bleeding, and chylothorax (1% each). Overall survival at the 2-, 3-, and 5-year marks was 47%, 34%, and 23%, respectively. Five-year survival was 59% for patients with stage I disease and 22% for patients with stage IIA disease. Patients with stage III disease had 2- and 5-year survival rates of 32% and 10%, respectively. There was an overall statistically significant survival advantage for patients with adenocarcinoma (24% versus 17%). This study by the University of Michigan group is considered the benchmark for transhiatal esophagectomy and represents the best expected outcome after transhiatal resections for carcinoma. However, it is clear from reviewing the literature that these survival rates are quite consistent with the experience of most surgeons who practice a similar approach. Gelfand and coworkers reported on 160 patients who underwent transhiatal esophagectomy for carcinoma of the lower esophagus and cardia.8 Most tumors were adenocarcinoma, and most were in earlier stages. Survival rates at 2 years and 5 years were 40% and 21%, respectively. Gertsch and associates reported on 100 patients with esophageal carcinoma who were uniformly treated with transhiatal esophagectomy without adjuvant therapy over a 10year period.9 Hospital mortality was 3%, and morbidity was 68%. The median survival was 18 months, and the overall 5-year survival was 23%. There was no difference in survival between patients with adenocarcinoma compared with those with squamous histology. Survival was better for T1 and T2 tumors (63% 5-year survival). Vigneswaran and colleagues reported on the results after transhiatal esophagectomy in 131 patients, the majority of whom had adenocarcinoma. Operative mortality was 2%. Overall 5-year survival was 21%. Patients with stage I disease had a 47.5% 5-year survival compared with patients with stage III disease, whose 5-year survival was 5.8%. Patients with adenocarcinoma had a 5-year survival of 27%, whereas not a single patient with squamous cell cancer was alive at the 5-year mark.10

Chapter 43 Primary Surgery for Adenocarcinoma of the Esophagus

A few studies reported the local recurrence rates after transhiatal resection. Urba and coworkers reported the results of a randomized trial comparing transhiatal esophagectomy alone to transhiatal esophagectomy after induction chemoradiotherapy.5 More than 75% of patients in both study arms had adenocarcinoma. From a statistical point of view, overall survival and disease-free survival were not significantly different within the two arms of the study. Overall survival and disease-free survival were both 16% for the transhiatal esophagectomy alone. Overall survival and disease-free survival were 30% and 28%, respectively, for transhiatal esophagectomy after induction chemoradiation therapy. Local recurrence as a component of treatment failure occurred in 42% of patients in the surgery alone arm versus 19% in the combined modality arm. This figure is almost identical to the local failure rate reported by Barbier and colleagues, who used serial CT to evaluate prospectively the recurrence rate in 50 patients who underwent transhiatal resection for cancer.11 Local recurrence was detected in 39% of patients. More recently, Hulscher and associates reported a locoregional recurrence rate of 37% among 137 patients, 95 of whom had adenocarcinoma, treated by transhiatal esophagectomy without preoperative therapy.12 In summary, it appears that for patients with esophageal adenocarcinoma, transhiatal esophagectomy can usually be performed with an operative mortality of 5% or less in the hands of experienced esophageal surgeons. Five-year survival rates are generally in the 20% to 25% range. Survival for patients with stage I tumors is in the 60% to 70% range, whereas patients with stage III disease have a 5% to 10% 5year survival. Finally, the procedure is associated with failure to control or eradicate local disease in nearly 40% of patients.

STANDARD TRANSTHORACIC ESOPHAGECTOMY Transthoracic esophagectomy is probably the most widely performed operation for cancer of the esophagus worldwide. In the United States, nearly 60% of all surgically treated tumors of the lower third of the esophagus are performed using a transthoracic approach.3 The procedure can be carried out through a right or left thoracotomy, depending on the preference of the surgeon and the location of the tumor within the esophagus. Generally, a right thoracotomy is required for adequate exposure of tumors in the middle or upper thirds that are anatomically intimately related to the membranous trachea or the arch of the aorta. Tumors located at the gastroesophageal junction or in the lower third of the esophagus can usually be approached through a left thoracotomy incision combined with a left phrenotomy or, alternatively, with a left thoracoabdominal incision. Regardless of the side of the thoracotomy, the extent of lymph node dissection is usually limited to the immediate periesophageal, cardial, and perigastric nodes. One of the largest experiences in North America with this approach is that of Ellis and coworkers (Ellis, 1999).13 These authors reported their experiences with nearly 500 patients who received a transthoracic esophagectomy employing

standard surgical techniques. One third had squamous cell carcinoma, whereas the majority had adenocarcinoma of the esophagus or gastroesophageal junction. Hospital mortality was 3.3%. Complications occurred in 34% of patients. Overall 5-year survival including operative mortality and non–cancerrelated deaths was 24.7%. Patients who had a complete (R0) resection had a 5-year survival of 29%, whereas no patients with either residual microscopic (R1) or macroscopic disease (R2) survived 5 years. Median and 5-year survival for patients with adenocarcinoma was 18 months and 25%, respectively. The corresponding figures for squamous cell cancers were 18 months and 20%, respectively, and were not statistically different from those for adenocarcinoma. Five-year survival was 79% for patients with stage I disease, 38% for those with stage IIA, and 27% for those with stage IIB. Patients with stage III disease had a 3- and 5-year survival of 20% and 13.7%, respectively. This series by Ellis is generally representative of the results achievable using this surgical technique in many esophageal centers across the United States. For example, a recent study from the Mayo Clinic reported on the results after transthoracic esophagectomy in 220 patients, of whom 188 had adenocarcinoma.14 Notwithstanding, an impressively low hospital mortality and morbidity (1.4% and 37%, respectively), the survival rates remained essentially similar to those reported by Ellis nearly a decade previously. Overall 5-year survival was 25% and survival at 5 years for stages I, IIa, IIb, and III was 94%, 36%, 14%, and 10%, respectively. A review of some of the surgical series reported within the past decade from North America and Europe is shown in Table 43-1 (Ellis, 1999; Putnam et al, 1994).13-21 Resectability rates ranged from 60% to 90% and hospital mortality rates ranged from 3.2% to 23%. Five-year survival rates varied between 9% and 24%. The variability in rates of resectability, hospital mortality, and 5-year survival more than likely represents inherent differences in patient selection, surgical expertise, and the retrospective nature of nearly all of these studies. More instructive to review are the survival results achieved by the surgical arms of randomized trials comparing various preoperative regimens to surgical resection alone. The most recent of these trials was the North American Intergroup trial that compared chemotherapy followed by surgery with surgery alone (Kelsen et al, 1998).22 There were 467 eligible patients, of whom 227 underwent primary surgical resection. The majority of resections were through a transthoracic approach. One hundred six patients had squamous cell cancer (47%), and 121 had adenocarcinoma (53%). Hospital mortality was 6%. Major complications occurred in 26% of patients. Overall survival at 1, 2, and 3 years was 60%, 37%, and 26%, respectively. Actuarial 5-year survival was 20%. There was no difference in outcome between patients with adenocarcinoma and those with epidermal cancer. In the trial by Walsh and associates, 113 patients, all of who had adenocarcinoma, were randomized to receive either surgery alone or chemoradiation therapy followed by transthoracic esophagectomy.6 Hospital mortality in the control arm was 2%, and 3-year survival was 6%. In 2002, the Medical Research Council Oesophageal Cancer Working Group reported the results of a large multicenter controlled

487

488

Section 5 Neoplasms

TABLE 43-1 Transthoracic Esophagectomy for Esophageal Cancer

Author (Year)

No. Patients

Cell Type

Hospital Mortality (%)

5-Year Survival (%)

Median Survival

Hofstetter et al20 (2002)

994

A/S

7

34 (3 yr)

20 mo

14

Visbal et al

220

A/S

1.4

25.2

1.9 yr

Karl et al16 (2000)

(2001)

143

A/S

2.1

29.6 (3 yr)

1.6 yr

Ellis13 (1999)

455

A/S

3.3

24.7

18 mo—A 18 mo—S

Kelsen et al22 (1998)

227

A/S

6

26 (3 yr)

16.1 mo

597

A/S

6.9

16.3

NS

18

21

Adam et al

(1996) 19

Sharpe and Moghissi

562

A/S

9

Walsh et al6 (1996)

113

A

2

Lieberman et al17 (1995)

258

A/S

5

27

27 mo

134

A/S

8.2

19

22 mo

A

2

15

Putnam et al

(1994)

Wright et al18 (1994)

(1996)

91

6 (3 yr)

8

NS 11 mo

NS

A, adenocarcinoma; NS, not stated; S, squamous carcinoma.

randomized trial of preoperative chemotherapy followed by esophagectomy versus esophagectomy alone (Medical Research Council Oesophageal Cancer Working Party, 2002).23 Although the details of the operative procedures were not described, the assumption may be made that the majority of cases had been done using a transthoracic approach, a common surgical strategy in most European centers. Survival in the surgery-alone arm was 34% at 2 years and 15% at 5 years, with no difference in survival between adenocarcinoma and squamous cell cancer. Local recurrences after standard transthoracic resections have been reported in 30% to 60% of patients. Most of the data regarding local recurrences are obtained from the surgical control arms of the various randomized trials. In the previously mentioned Intergroup trial comparing esophagectomy alone with chemotherapy followed by esophagectomy, the local recurrence rate in the control arm was 31% among 135 patients who received a complete (R0) resection. An additional 68 patients had an R1 or R2 resection. The overall local failure rate (persistent or recurrent disease) in all 227 patients in the control arm was 61%.

anastomotic leaks (16% versus 10%), anastomotic strictures (28% vs. 16%), and recurrent laryngeal nerve injury (11% vs. 5%). Overall 5-year survival was 24% after transhiatal esophagectomy and 26% after transthoracic resection. More recently, Hulscher and colleagues reported a meta-analysis of the results of all comparative studies of transhiatal and transthoracic esophagectomy (Hulscher et al, 2001).25 Their analysis included data abstracted from 50 articles published in the English literature between 1990 and 1999, with a total of 7500 patients. Although the influence of cell type on survival was not specifically examined there was no statistically significant difference in overall 3-year and 5-year survival between the two procedures. In summary, it is clear that there is no important difference in survival based on the surgical approach for esophageal resection. However, it is important to note that in none of these series was a radical lymph node dissection performed; thus, the results reflect the impact of the choice of the surgical incision rather than the extent of lymph node dissection performed.

EN-BLOC ESOPHAGECTOMY COMPARISON OF TRANSHIATAL AND TRANSTHORACIC ESOPHAGECTOMY Several retrospective studies have shown little difference in the operative mortality and morbidity between transhiatal and transthoracic esophagectomy. Rindani reviewed the results from 44 series published between 1986 and 1996.24 Thirty-three articles reported results on 2675 patients who underwent transhiatal resection, whereas 29 articles reported results of transthoracic resections done in 2808 patients. Thirty-day mortality was 6.3% after transhiatal and 9.5% after transthoracic esophagectomy. Major pulmonary and cardiovascular morbidity was similar in both groups. Transhiatal esophagectomy was associated with a higher incidence of

The deep location of the esophagus within the narrow confines of the mediastinum and the lack of a well-defined mesentery have generally precluded the application of en-bloc resection principles, practiced in most gastrointestinal malignancies, to patients with esophageal carcinoma. Logan introduced the en-bloc concept in 1963,26 and it was reintroduced by Skinner in 1979.27 The basic premise of the en-bloc operation is to maximize local tumor control by resection of the tumor-bearing esophagus within a wide envelope of adjoining tissues that includes both pleural surfaces laterally and the pericardium anteriorly where these structures are intimately related to the esophagus. Posteriorly, the lymphatics wedged dorsally between the esophagus and the aorta, including the

Chapter 43 Primary Surgery for Adenocarcinoma of the Esophagus

thoracic duct throughout its mediastinal course, are resected en bloc with the specimen. This posterior mediastinectomy necessarily results in a complete mediastinal node dissection from the tracheal bifurcation to the esophageal hiatus. Additionally, an upper abdominal lymphadenectomy is performed, including the common hepatic, celiac, left gastric, lesser curvature, parahiatal, and retroperitoneal nodes. Local recurrence rates reported by proponents of this approach have been in the 2% to 10% range.28,29 This is a strikingly low local failure rate when compared with local recurrences reported after either transhiatal esophagectomy or standard transthoracic resections or those reported after chemoradiation delivered with curative intent.6,30 Critics have argued that the procedure is associated with a high operative mortality and morbidity, without an apparent survival advantage. In fact, in the earliest report by Skinner, the operative mortality for 80 patients with cancer of the cardia treated by an en-bloc resection was 11% and the 5-year survival only 18%.27 However, the past decade has witnessed a significant reduction in hospital mortality to the 2% through 7% range.31-33 Several investigators have also reported survival rates exceeding those achievable by standard resection. Lerut and colleagues reported his experience with 195 patients who had an R0 (curative) resection for adenocarcinoma of the distal esophagus and gastroesophageal junction.31 All patients had transmural disease (T3), and none received preoperative therapy. Five-year survival was 57% for node-negative patients and 26% for patients with nodal metastases. Altorki and Skinner reported on 111 patients who had an en-bloc resection, the majority of whom had adenocarcinoma and stage III disease (Altorki and Skinner, 2001).32 These patients had a hospital mortality rate of 3.6%. Overall 5-year survival was 40%. Stage-specific survival was 78%, 72%, and 39%, respectively, for stages I, IIa, and III disease. Hagen and associates reported similar results in a smaller group of patients with adenocarcinoma of the distal esophagus and gastroesophageal junction.33 En-bloc resection was performed in 30 patients, and transhiatal resection was done in 16 patients. Overall survival was significantly better after en-bloc resection (41% versus 14%, P = .001). A survival advantage was observed in patients with early lesions (T1 and T2), in whom 5-year survival was 75% versus 21%, in favor of en-bloc resection. Similarly, patients with transmural tumors (T3) associated with five or fewer positive nodes had a significantly better survival after en-bloc resection (27% versus 9%). An important criticism of most of these studies is the failure to clearly define the criteria for patient selection for one procedure versus another. For example, in the study by Hagen and coworkers, the patients receiving a transhiatal resection were either significantly older than the en-bloc group or had a worse performance status with respect to cardiopulmonary function. Additionally, a selection bias toward inclusion of patients with early-stage disease in the en-bloc groups may have unfavorably biased survival outcome. One may argue that such patients would have had a similarly favorable outcome after a more limited resection technique.

The only randomized trial reported to date comparing transthoracic en-bloc resection with transhiatal esophagectomy was reported by Hulscher and associates in 2002 (Hulscher et al, 2002).34 The authors randomly assigned 220 patients with adenocarcinoma of the mid to distal esophagus, or adenocarcinoma of the cardia, to either a transhiatal resection or a transthoracic esophagectomy with extended en-bloc lymphadenectomy. This study was powered to detect a 50% relative improvement in survival in favor of the en-bloc procedure. Although there was an important trend favoring the transthoracic group in both overall (39% versus 29%) and disease-free survival (39% versus 27%) at 5 years, the resultant 25% relative improvement in survival did not achieve statistical significance. A subsequent report by the same group suggested that with continued follow-up the difference achieved statistical significance for adenocarcinoma of the esophagus, but not that of the cardia.35 Interestingly, in this randomized trial there was no difference in either the rate of locoregional recurrence or the time to recurrence between the two arms of the study.

THREE-FIELD LYMPHADENECTOMY The concept of three-field lymph node dissection for esophageal cancer was developed by Japanese surgeons in the 1980s in response to the observation that as many as 40% of patients with resected squamous cell esophageal cancer developed isolated cervical lymph node metastases.36 A nationwide retrospective study was subsequently reported describing the findings and potential benefits of esophagectomy with threefield dissection.37 The additional third field of dissection included excision of the nodes along both recurrent nerves as they course through the mediastinum and neck, as well as a modified cervical node dissection. Previously, unsuspected cervical nodal metastases, primarily in the recurrent nodes, were seen in approximately one third of patients. Furthermore, the authors reported a significantly higher overall 5-year survival after three-field dissection in comparison to two-field dissection. The relevance of these findings to a Western population afflicted primarily by esophageal adenocarcinoma remains unknown. The only experience in North America with this technique was reported by Altorki and associates in 2002.38 The procedure was performed in 80 patients, 60% of which had adenocarcinoma of the esophagus. Hospital mortality was 5%, and morbidity was 47%. Recurrent nerve injury occurred in 6% of patients. An average of 60 nodes were resected per patient. The prevalence of cervical nodal metastases was 37% in patients with adenocarcinoma. Overall and disease-free survival was 50% and 46%, respectively, and was not influenced by cell types. Patients with adenocarcinoma who had metastases to the recurrent laryngeal lymph nodes had a 3- and 5-year survival of 30% and 15%, respectively. Lerut and associates reported the only European experience with esophagectomy and three-field lymph node dissection (Lerut et al, 2004).39 One hundred and seventy-four patients had an R0 three-field esophagectomy, with a hospital mortality of 1.4% and morbidity of 57%. Fifty-five percent of patients had

489

490

Section 5 Neoplasms

adenocarcinoma of the esophagus or cardia. Overall and disease-free survival at 5 years was 42% and 46%, respectively. There was no difference in survival between patients with adenocarcinoma compared with those with squamous carcinoma (35% versus 44%, P = .5). The incidence of positive cervical nodes in patients with adenocarcinoma was 23% and was slightly higher for those with esophageal versus cardial tumors (26% versus 18%). Four- and 5-year survival rates for patients with adenocarcinoma and positive cervical nodes were 35% and 11%, respectively.

PERSPECTIVE Since the early 1980s, there have been seven randomized trials of preoperative chemotherapy and eight trials that compared preoperative chemoradiation therapy to surgery alone. Only two of the preoperative chemotherapy trials and two of the preoperative chemoradiation therapy trials included patients with esophageal adenocarcinoma. The results of the Medical Research Council trial of preoperative chemotherapy reported a significant survival advantage in favor of preoperative chemotherapy, a result that contradicted the North American Intergroup trial using the same chemotherapy regimen (Medical Research Council Oesophageal Cancer Working Party, 2002).22,23 Similarly, the results of the two preoperative chemoradiation therapy trials were contradictory.5,6 Given these conflicting results and the reports from two recent, well-conducted meta-analyses, primary surgical resection should still be considered the standard of care for esophageal adenocarcinoma.40,41 The previous discussion about the results of the various surgical approaches suggests that there is no substantive difference in mortality, morbidity, or survival between transhiatal and conventional transthoracic esophagectomy. The single randomized trial of en-bloc esophagectomy suggests that there may well be a small but significant survival benefit of this approach in patients with adenocarcinoma of the middle and distal esophageal thirds. These results may have to be confirmed by other similar trials. The role of three-field lymph node dissection will also need to be further evaluated and more precisely defined. It seems that, even in the best circumstances, survival after primary surgery may be in the 40% to 45% range; thus, the majority of patients will continue to succumb to recurrent disease. It is hoped that with refinements in molecular staging techniques and the introduction of targeted therapies more innovative adjuvant and neoadjuvant strategies can be pursued.

COMMENTS AND CONTROVERSIES Primary surgery traditionally has been considered as the mainstay in the treatment of adenocarcinoma of the esophagus. Progress of the surgical outcome has been well illustrated by three consecutive compilation studies of the literature by Earlam, Muller, and Jamieson, respectively. From these three studies a constant decline in postoperative mortality was noticed in the most recent study by Jamieson, being 8.8% and a steady increase in 5-year survival up to 27.9%. This improvement in long-term outcome is not only the result of decreased surgical mortality but also the result of better surgical

techniques, in particular the introduction of more extensive lymphadenectomy as well as better selection. The results of these efforts are well highlighted in this chapter. The effort to perform more extensive lymphadenectomy indeed seems to result not only in a more precise staging but more importantly in a substantial decrease in locoregional recurrences. Whether more radical surgery results in a proven increase in long-term survival remains controversial. The only randomized trial in this respect could not show a statistically significant difference, but a strong trend in favor of more radical surgery in particular for adenocarcinoma of the distal esophagus cannot be denied. In fact, 8 years of survival after radical surgery doubles that of simple esophagectomy. Whatever the controversy today in centers of experience, overall 5-year survival after radical surgery for adenocarcinoma of the esophagus and gastroesophageal junction often exceeds 40%. In stage III disease, 5-year survival figures of 25% or more can be obtained after primary radical surgery. Such figures should be considered as the gold standard to which all other treatment modalities, in particular neoadjuvant or adjuvant regimens, should be compared. Unfortunately, the nonsurgical literature keeps quoting the Earlam paper with a dismal overall postresectional 5-year survival of 5% as the reference point to justify other treatment modalities. Moreover, in none of the existing trials comparing surgery versus combined modality treatment with or without surgery has quality criteria for the surgical arm been worked out. This lack of surgical quality, of course, makes the interpretation of such trials difficult, if not worthless. Although surgery definitely cannot cure all cancers it must be accepted that even in the presence of lymph node involvement, provided the involvement is limited in number and locoregional, primary surgery is able to influence the natural course of the disease. Therefore, to propose combined modality treatment for every single patient with suspicion of lymph node involvement is to be seen as overtreatment if not denying a substantial number of patients a chance for cure by radical primary surgery because they might develop resistance to chemotherapeutic drugs, compromising the immune responsiveness and losing precious time. Perhaps a more efficient approach seems to first perform radical surgery for locally advanced tumors with limited node involvement and to administer adjuvant chemoradiation therapy based on a more precise staging and prognostic assessment as provided by the final pathologic report. T. L.

KEY REFERENCES Altorki N, Kent M, Ferrara C, Port J: Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg 236:177-183, 2002. Altorki N, Skinner D: Should en bloc esophagectomy be the standard of care for esophageal carcinoma? Ann Surg 234:581-587, 2001. Ellis FH Jr: Standard resection for cancer of the esophagus and cardia. Surg Oncol Clin North Am 8:279-294, 1999. Hulscher JB, Tijssen JG, Obertop H, van Lanschot JJ: Transthoracic versus transhiatal resection for carcinoma of the esophagus: A meta-analysis. Ann Thorac Surg 72:306-313, 2001. Hulscher JB, van Sandick JW, de Boer AG, et al: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 21;347:1662-1669, 2002.

Chapter 43 Primary Surgery for Adenocarcinoma of the Esophagus

Kelsen DP, Ginsberg R, Pajak TF, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979-1984, 1998. Lerut T, Nafteux P, Moons J, et al: Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: Impact on staging, disease-free survival, and outcome: A plea for adaptation of TNM classification in upper-half esophageal carcinoma. Ann Surg 240:962-972, 2004. Medical Research Council Oesophageal Cancer Working Party: Surgical resection with or without preoperative chemotherapy in oesophageal cancer: A randomized controlled trial. Lancet 359:17271733, 2002.

Orringer, MB, Marshall B, Iannettoni MD: Transhiatal esophagectomy: Clinical experience and refinements. Ann Surg 230:392-403, 1999. Putnam JB Jr, Suell DM, McMurtrey MJ, et al: Comparison of three techniques of esophagectomy within a residency training program. Ann Thorac Surg 57:319-325, 1994. Suntharalingam M, Moughan J, Coia LR, et al: Outcome results of the 1996-1999 patterns of care survey of the national practice for patients receiving radiation therapy for carcinoma of the esophagus. J Clin Oncol 23:2325-2331, 2005.

491

chapter

44

ADENOCARCINOMA OF THE CARDIA Arnulf H. Hölscher

Key Points ■ ACs of the esophagogastric junction should be subclassified as

AC of the distal esophagus (type I), AC of the cardia (type II), and subcardiac gastric AC (type III). ■ These three types are different in epidemiologic terms and patterns of lymph node metastases. ■ The suggested extent of surgical resection is transthoracic en-bloc esophagectomy and gatric pull-up for type I and transhiatal extended total D2 gastrectomy with distal esophageal resection for types II and III.

In contrast to the decreasing frequency of gastric cancer and squamous cell carcinomas of the esophagus, investigators in various Western countries have reported an increasing incidence of adenocarcinomas of the esophagus as well as of the cardia.1-9 The reason for the shift of gastric cancer topography from distal to proximal is unknown. The definition and classification of adenocarcinomas of the esophagogastric junction is not standardized, and the choice of surgical procedures still causes controversial discussion.10 However, because of the increasing frequency, a precise classification of carcinomas of the esophagogastric junction and a definition of the surgical extent of resection becomes more important for daily surgical routine.

DEFINITION AND CLASSIFICATION In the literature the term adenocarcinoma of the esophagogastric junction summarizes different tumor entities. To compare different treatment modalities my colleagues and I introduced a classification for carcinomas of the esophagogastric junction in 1987 (Siewert et al, 1987).11,12 This classification was based on a morphometric analysis of a large series of junctional adenocarcinomas in a cooperative study of surgeons and pathologists. The aim was a surgical classification to plan the extent of resection concerning primary tumor and lymphadenectomy. Furthermore, it could serve as a basis for scientific comparison of series from different institutions. In the meantime, this classification has been generally accepted by many groups working in this field (Kodera et al, 1999; Sasako et al, 2006).13-20 Adenocarcinomas of the esophagogastric junction are designated as those with a tumor center 5 cm oral and aboral of the lower esophageal sphincter. Adenocarcinomas of the distal esophagus and subcardial gastric carcinomas are only included if they infiltrate the 492

cardia. Following this definition, carcinomas of the esophagogastric junction can be classified according to their location into three different types (Fig. 44-1): Type I: Adenocarcinoma of the distal esophagus infiltrating the gastroesophageal junction and mostly developing in Barrett’s esophagus (Fig. 44-2) Type II: True carcinoma of the cardia arising from the cardiac mucosa (Fig. 44-3) Type III: Subcardial gastric carcinoma infiltrating the cardia from below (Fig. 44-4). The assignment of these tumors to the three different types is based on the anatomic localization of the center of the tumor in relation to the three different areas given in Figure 44-1. This topographic anatomic classification is supported by histologic analysis of the junctional mucosa differentiating also three types of epithelia as origin of adenocarcinomas (Misumi et al, 1989).21-25 Further epidemiologic data especially concerning the male-to-female ratio have shown clear differences between the three types of adenocarcinomas of the esophagogastric junction (Table 44-1) (Siewert et al, 2000).12,26

DIAGNOSIS AND STAGING The best way to assign the adenocarcinomas of the esophagogastric junction to the three different types is by radiologic and endoscopic examination. A thoracic survey radiograph in two planes with contrast visualization of the esophagus and stomach is taken to localize the tumor topographically and anatomically, particularly in relation to the sphincter and to the diaphragm. Esophagogastroscopy must be performed in prograde as well as retrograde view of the cardia to define the lower esophageal sphincter and the localization of the major part and center of the tumor. Furthermore, Barrett’s esophagus has to be detected. Endosonography is essential for the T classification staging but can also contribute especially to the question of oral and aboral extent of the carcinoma. Computed tomography (CT) of the thorax and abdomen is helpful for the assignment of the tumor. This examination also reveals important information on the infiltration of adjacent structures such as the diaphragm and pancreas and the presence of possible distant metastases. Because of the connection to the retroperitoneum, carcinomas of the esophagogastric junction can metastasize via

Chapter 44 Adenocarcinoma of the Cardia

direct retroperitoneal lymphatics along the posterior gastric wall to the hilus of the spleen and to the region of the left renal hilus.27-29 The preoperative nodal status is evaluated by endosonography and CT. However, the evaluation of metastatic lymph nodes is based only on lymph node size.30

+ 5 cm

Morphologic studies of gastric cancer were able to show a lack of correlation between lymph node size and metastatic infiltration.30,31 Therefore, an accurate preoperative evaluation of the N classification stage is not possible. After the staging, it has to be clarified whether an R0 resection can be achieved. If a complete resection seems to be questionable, neoadjuvant treatment has to be discussed. The final matching to one of the three different types has to be reconfirmed intraoperatively and on the resected specimen. In some cases the preoperative assessment has to be revised.

Type I

Type II

+ 1 cm – 2 cm

Type III

– 5 cm

SURGICAL TREATMENT The aim of surgical therapy is the complete resection of the primary tumor and the regional lymph nodes. The three different types of adenocarcinoma of the esophagogastric junction require different surgical strategies especially concerning type I compared with types II and III (Fig. 44-5).

Type I Because the adenocarcinoma in Barrett’s esophagus represents an esophageal carcinoma a radical esophagectomy is necessary. This has two reasons: FIGURE 44-1 Classification of adenocarcinomas of the esophagogastric junction according to the localization of the center of the tumor by Siewert and colleagues (1987).11

1. Although this represents a distal tumor, clearance of the oral resection line is usually not achievable by a transhia-

FIGURE 44-2 Type I: adenocarcinoma in Barrett’s esophagus infiltrating the cardia from above.

FIGURE 44-3 Type II: true adenocarcinoma of the cardia.

493

494

Section 5 Neoplasms: Management

FIGURE 44-4 Type III: subcardiac gastric adenocarcinoma infiltrating the cardia from below.

TABLE 44-1 Epidemiologic Data of Patients With Adenocarcinoma of the Esophagogastric Junction n = 270

Type I

Type II

Type III

No. Patients

184

53

33

66.0

62.8

NS

4:1

1.5 : 1

.001

Age x¯ (y)

61.9

M:F –x, mean.

12 : 1

Type I

II

P

III

FIGURE 44-5 Suggested extent of resection for the three different types of adenocarcinomas of the esophagogastric junction.

tal approach. An adequate safety margin is at least 3 to 4 cm. Furthermore, the whole columnar cell–lined lower esophagus has to be removed because of possible multifocal carcinoma and later malignant degeneration of persisting Barrett’s epithelium. The safety margin to the stomach mostly is not a problem of these tumors originating from the esophagus. 2. Lymph node metastases of Barrett’s carcinoma can develop in both directions of the tumor: orad into the mediastinum and to the lesser gastric curvature, the left gastric artery, and the celiac trunk (Schröder et al, 2002).32,33 Therefore, adequate resection of potentially

infiltrated lymph nodes can only be achieved by transthoracic en-bloc esophagectomy combined with resection of the upper part of the stomach and lesser gastric curvature (lymph nodes [LN] 1, 2, 3) including the origin of the left gastric artery (LN 7) and lymphadenectomy along the common hepatic and splenic artery (LN 8, 9, 11) (Lerut et al, 2004, Siewert et al, 2000).26,33-36 The surgical technique of transthoracic en-bloc esophagectomy is described elsewhere in this text. This strategy is supported by the results of the Dutch prospective randomized trial comparing transthoracic en-bloc esophagectomy to transhiatal esophagectomy in adenocarcinoma of the esophagus and cardia (Hulscher and van Lanschots, 2005).37,38 In a special analysis of this series, carcinomas of the gastric cardia were extracted from the total group, and the long-term data only for adenocarcinomas of the esophagus showed prognostic advantages at least for a subgroup of the patients with radical esophagectomy (Hulscher and van Lanschot, 2005).38 Transhiatal esophagectomy, therefore, has less importance in the treatment of esophageal cancer today.39 The reconstruction after transthoracic esophagectomy is performed with gastric pull-up and high intrathoracic esophagectomy.35,36 In cases of advanced distal adenocarcinoma of the esophagus the concomitant resection of parts of the diaphragmatic crura is advocated to ensure local R0 resection (Alderson et al, 1994).40

Type II For true carcinoma of the cardia, transhiatal extended total gastrectomy with resection of the distal esophagus is recommended in addition to D2 lymphadenectomy (Table 44-2) (Sasako et al, 2006; Siewert et al, 2000).12,18,26,41 Most carcinomas of the cardia can be completely resected by this approach with an adequate oral resection margin. The en-bloc excision of both crura is recommended especially in advanced tumors.40 The transhiatal approach after anterior incision of the diaphragm to enlarge the hiatus is preferred compared with the left thoracoabdominal approach. This recommendation is based on the results of the Japanese prospective ran-

Chapter 44 Adenocarcinoma of the Cardia

TABLE 44-2 Results of Surgical Therapy of Type II Adenocarcinomas of the Esophagogastric Junction

Author (Year) Siewert et al26 (2000) Hulscher et al

37

(2002)

de Manzoni et al63 (2002) Ito et al

64

Time Span

No. Patients

Type of Surgery

pT1

R0 Resection

Postoperative Mortality

1982-1999

271

THG

14%

76%

2.9%

1994-2000

40

TH or TT

15%

71%

3%

1988-2000

34

Mixed

21%

91%

Postoperative Morbidity

5-Year Survival (R0)

Country

42%

Germany

30%

35%

The Netherlands

6.7%

28%

24%

Italy

(2004)

1991-2001

59

THG

14%

69%

2.4%

20%

32%

USA

Bai et al20 (2006)

1995-1999

80

Mixed

15%

69%

4%

16%

34%

China

Cologne (2007)

1997-2005

53

THG

23%

96%

2.6%

31%

44%

Germany

TH, transhiatal esophagectomy; THG, transhiatal extended total gastrectomy; TT, transthoracic esophagectomy.

TABLE 44-3 Results of Surgical Therapy of Type III Adenocarcinomas of the Esophagogastric Junction

Author (Year) Siewert et al26 (2000) 63

de Manzoni et al Ito et al

64

(2002)

Time Span

No. Patients

Type of Surgery

1982-1999

370

THG

1988-2000

41

THG

(2004)

1991-2001

23

THG

Bai et al20 (2006)

1995-1999

94

THG or DE + proximal gastrectomy

Sasako et al18 (2006)

1995-2003

Cologne (2007)

1997-2005

167* II = 95 III = 63 II + III = 7 33

R0 Resection

Postoperative Mortality

7%

69%

2.9%

2%

78%

4.2%

21%

pT1

Postoperative Morbidity

5-Year Survival (R0)

Country

35%

Germany

24%

Italy

9%

52%

2.4%

20%

25%

USA

11%

61%

6%

20%

33%

China

THG = 82 LTA = 85

2% 1%

93% 88%

0 4%

34% 49%

52% 38%

Japan

THG

0

97%

5.6%

31%

21%

Germany

*Types II and III analyzed together. DE, distal esophageal resection; LTA, left thoracoabdominal approach for distal esophageal resection and total gastrectomy.

domized trial of Sasako and associates, which showed lesser postoperative morbidity and mortality and better long-term survival after transhiatal instead of thoracoabdominal resection (Table 44-3) (Sasako et al, 2006).18 Total gastrectomy with D2 lymphadenectomy follows the rules of gastric cancer surgery (Sasako et al, 2006).18,42-45 The long-term results of the prospective randomized Dutch trial have shown prognostic advantages for a subgroup of patients with radical D2 lymphadenectomy compared with D1 lymph node dissection.46 The spleen is preserved because several randomized trials have not documented an impact of splenectomy on survival in patients with cardia or proximal gastric cancer (Mönig et al, 2001).47,48 Splenectomy in accordance with a gastrectomy even leads to more postoperative morbidity and mortality according to the Dutch trial.44,45 The reconstruction is performed by jejunal Roux-en-Y loop with end-to-side esophagojejunostomy in the lower mediastinum. In advanced carcinomas of the cardia neoadjuvant treatment either by chemotherapy or chemoradiation is applied. This usually leads to a downsizing of the tumor to facilitate complete

resection. However, if the tumor is still not completely resectable by a transhiatal approach a total esophagogastrectomy with colon interposition has to be considered. The other possibility is transthoracic esophagectomy and reconstruction by a narrow gastric tube that allows an extended resection of the cardia tumor on the stomach side. However, for usual type II cardia carcinoma the extension of lymphadenectomy into the middle and upper mediastinum by transthoracic esophagectomy has not led to a better prognosis compared with transhiatal esophagectomy with lymphadenectomy of the lower mediastinum.38 Therefore, it can be concluded that the transhiatal approach with distal esophageal resection and lymphadenectomy of the lower mediastinum, together with D2 total gastrectomy, is sufficient for type II cancer.

Type III Similar to type II carcinomas, subcardial adenocarcinoma of type III is treated by transhiatally extended total gastrectomy with distal esophageal resection and D2 lymphadenectomy

495

496

Section 5 Neoplasms: Management

(see Table 44-3). To achieve a tumor-free oral resection margin is even easier than in type II cancer because the infiltration of the cardia mostly does not extend too high into the distal esophagus. The spleen is preserved as mentioned earlier except if a direct infiltration is present or in case of gross lymph node metastases in the splenic hilus. In this case a splenectomy with a pancreas-preserving zone is recommended.43,47

Early Adenocarcinoma of the Esophagogastric Junction In mucosal adenocarcinoma of the esophagogastric junction endoscopic mucosectomy is an established procedure because lymph node metastases are very rare.49,50 The results are good if the procedure is performed in high-volume centers, especially if a complete resection with one mucosal specimen avoiding piecemeal resection is achieved. However, if the carcinoma is penetrating the lamina muscularis mucosae the rate of lymphatic infiltration increases in clear correlation with the depth of infiltration to the submucosa (Bollschweiler et al, 2006).49,50 Therefore, submucosal adenocarcinomas of the esophagogastric junction are treated in the same radical manner as T2 or T3 tumors. The chance for cure of patients with these small carcinomas with possible limited regional lymph node metastases is high by radical surgery.51 In early gastric cancer it has been shown that an effect of radical lymph node dissection is reproducible also in pN0 patients.52 In a recent Italian multicenter study of 652 resected T1 gastric carcinomas a clear correlation was demonstrated between the number of resected lymph nodes and the risk of recurrence for 10 years for the total group as well as the 560 pN0 cases.53 Limited resection of the esophagogastric junction in early cancer can be performed by the Merendino operation. This was primarily designed for peptic stenosis in severe reflux disease but is now also applied for esophagogastric junction tumors (Katai et al, 2003).54-57 The approach is transhiatal, and the distal esophagus is resected together with the cardia and the subcardial part of the stomach. The best technique is the vagus nerve–preserving Merendino operation to preserve the gastric acid secretion and the antral and pyloric function.57 The reconstruction is performed with an isoperistaltic interposition of a jejunal loop of about 15 cm in length (Fig. 44-6). Up to now only limited series of Merendino operations for early Barrett’s carcinomas or cardia carcinomas are available, but the early oncologic results seem to be good (Katai et al, 2003).55,56 A comparison to more radical procedures is lacking. However, the long-term functional outcome is jeopardized in some patients by reflux, restenoses, or gastric emptying disorders, especially if the vagus nerve is not preserved.56,57 Larger experience and long-term results are necessary for definitive judgment of this technique. The mentioned symptoms that may occur after the Merendino operation are even worse if a direct esophagogastrostomy is performed after limited resection of the cardia region.58-62 Therefore, this simple technique of reconstruction cannot be recommended.

Vascular connection of jejunum segment

FIGURE 44-6 Merendino operation: transhiatal resection of the esophagogastric junction and reconstruction by end-to-side esophagojejunostomy and end-to-side jejunogastrostomy.

SURGICAL RESULTS Results after surgical treatment of carcinomas of the esophagogastric junction from the literature are only partly comparable because a uniform classification has been not used. Many studies do not even differentiate between adenocarcinomas of the distal esophagus and esophageal squamous cell carcinomas. The results after surgical therapy of esophageal adenocarcinoma type I are described elsewhere in this text. The surgical results of patients with type II carcinoma are given in Table 44-2. In Table 44-3 the surgical results of series of type III carcinomas are presented. Different surgical strategies have been applied in the several series. However, mostly transhiatal extended total gastrectomy with distal esophageal resection has been performed for type II as well as for type III carcinoma. The rate of early carcinomas was very low in type III patients, as has been described before (Siewert et al, 2000).10,26 This is because carcinomas of the cardia in the narrow sphincter region cause dysphagia much earlier than subcardial tumors. The rate of R0 resection is comparable between the series of type II and III carcinomas as well as postoperative morbidity and mortality. Some investigators have reported a significantly worse prognosis of patients with type II carcinoma compared with those with type III carcinoma.19 This cannot be confirmed by the results mentioned in Tables 44-2 and 44-3, which show comparable overall 5-year survival rates between 25% and 40%.

Chapter 44 Adenocarcinoma of the Cardia

SUMMARY The surgical classification of types I, II, and III adenocarcinoma of the esophagogastric junction has proven to be of value for planning the extent of resection and for comparing epidemiologic data and therapeutic results of different series. The preoperative assignment is especially achieved by contrast radiography and endoscopy and enables the surgeon to plan preoperatively the adequate extent of the resection. The type I adenocarcinoma represents a distal esophageal cancer and consequently is treated by transthoracic en-bloc esophagectomy. The type II and type III adenocarcinomas are treated by total gastrectomy and distal esophageal resection with D2 lymphadenectomy, preserving the spleen via an abdominal and transhiatal approach. The significance of limited resection of the esophagogastric junction for early carcinomas is not yet clear. In case of an advanced carcinoma with high risk of incomplete resection, neoadjuvant chemotherapy needs to be taken into consideration.

COMMENTS AND CONTROVERSIES The definition of adenocarcinoma of the esophagogastric junction remains a difficult issue. Dr. Hölscher is a coauthor of the classification that was introduced in 1987 to be able to compare different treatment modalities. The classification, now commonly referred to as the Siewert classification, was based on morphometric analysis of a large series of resected specimens. It must be noted, however, that a substantial difference exists between the clinical (i.e., mainly endoscopic) classification and the final pathologic classification on the resection specimen. In general, endoscopists tend to classify tumors at the gastroesophageal junction as distal third esophageal cancers (type I) whereas pathologists are more inclined to classify them as type II junction tumors. Because the purpose of the Siewert classification aims at planning the extent of resection and related surgical access route, its real value in clinical practice and therapeutic planning is debatable. Based on this classification, the author recommends for the true carcinoma of the cardia (type II) a total gastrectomy with resection of the distal esophagus and lymphadenectomy via a laparotomy and a transhiatal mobilization of the distal esophagus. Given the difficulties in distinguishing between type I and type II tumors at clinical staging one may question the oncologic safety of such an approach that combines limited distal esophagectomy as well as a lack of lymph node clearing in the posterior mediastinum. In early carcinoma, in particular T1a tumors in Barrett’s esophagus, lymph node involvement is a rare event. In such a case a limited vagus nerve–sparing resection with jejunal loop interposition (Merendino operation) is proposed. Such an operation can be done

only in the case of rather limited length (<5 cm) of Barrett’s metaplasia. However, in such an event, endoluminal therapeutic procedures, in particular endomucosal resection, provided a tumor diameter of 1.5 cm or more can be achieved, seem to offer excellent long-term outcome without, of course, the risks of the surgeryrelated mortality, albeit small, and morbidity. Further experience within the framework of carefully designed prospective studies will determine the value of endoluminal therapeutic procedures versus limited surgical procedures. T. L.

KEY REFERENCES Alderson D, Courtney SP, Kennedy RH: Radical transhiatal oesophagectomy under direct vision. Br J Surg 81:404, 1994. Bollschweiler E, Baldus SE, Schröder W, et al: High rate of lymph node metastasis in submucosal esophageal squamous cell carcinomas and adenocarcinomas. Endoscopy 38:144-151, 2006. Hulscher JBR, van Lanschot JJB: Individualised surgical treatment of patients with adenocarcinoma of the distal esophagus or gastrooesophageal junction. Dig Surg 22:130-134, 2005. Katai H, Sano T, Fukagawa T, et al: Prospective study of proximal gastrectomy for early gastric cancer in the upper third of the stomach. Br J Surg 90:850-853, 2003. Kodera Y, Yamamura Y, Shimizu Y, et al: Adenocarcinoma of the gastroesophageal junction in Japan: Relevance of Siewert’s classification applied to 177 cases resected at a single institution. J Am Coll Surg 189:594-601, 1999. Lerut T, Nafteux P, Moons J, et al: Three-field lymphadenectomy dissection for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: Impact on staging, disease-free survival and outcome. Ann Surg 240:962-974, 2004. Misumi A, Murakami A, Harada K, et al: Definition of carcinoma of the gastric cardia. Langenbecks Arch Chir 374:221-226, 1989. Mönig SP, Collet PH, Baldus SE, et al: Splenectomy in proximal gastric cancer: Frequency of lymph node metastasis to the splenic hilus. J Surg Oncol 76:89-92, 2001. Sasako M, Sano T, Yamamoto S, et al: Left thoracoabdominal approach versus abdominal transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial. Lancet Oncol 7:644-651, 2006. Schröder W, Mönig SP, Baldus SE, et al: Frequency of nodal metastases to the upper mediastinum in Barrett’s cancer. Ann Surg Oncol 9:807-811, 2002. Siewert JR, Feith M, Werner M, Stein HJ: Adenocarcinoma of the esophagogastric junction: Results of surgical therapy based on anatomic-topographic classification in 1002 consecutive patients. Ann Surg 232:353-361, 2000. Siewert JR, Hölscher AH, Becker K, Gössner W: Kardiakarzinom: Versuch einer therapeutisch relevanten Klassifikation. Chirurg 58:2534, 1987.

497

chapter

45

INDUCTION AND ADJUVANT THERAPY FOR CANCER OF THE ESOPHAGUS Ziv Gamliel Mark J. Krasna

Key Points ■ Surgery alone is curative for stage I disease. ■ The data on neoadjuvant chemotherapy or radiation therapy alone

is contradictory. ■ Combination chemoradiation is superior to radiotherapy alone as

alone with complete resection of all grossly apparent disease is associated with median survival ranging between 12 and 18 months in most centers and 5-year survival rarely exceeding 20%. Because of the low cure rates associated with the treatment of esophageal cancer by surgery alone, other modalities have been added to the treatment regimen.

definitive therapy but has a high local recurrence rate. ■ There is compelling data, though not definitive, that neoadjuvant

chemoradiation followed by surgery has a survival benefit.

SURGERY FOR ESOPHAGEAL CANCER Patients with esophageal cancer rarely present at an early stage of the disease. Symptoms do not usually arise until the tumor becomes large enough to cause obstruction or invasion of adjacent structures. The lack of an esophageal serosal layer may allow early tumor invasion into adjacent structures, such as the trachea, aorta, and spine. The most common symptom associated with esophageal cancer is dysphagia. The goal of surgical resection in esophageal cancer is both curative and palliative. Esophageal cancer can metastasize to virtually any organ in the body. Widespread distant metastases are almost always present at the time of death. The extensive lymphatic drainage pathways in the esophagus and the long time interval during which tumors typically remain asymptomatic may contribute to the high incidence of lymph node metastases. As many as 30% of patients with early (T1) lesions may have lymph node metastases. The success rate for treatment of esophageal cancer with surgery alone is related to the disease stage. If the depth of tumor invasion is limited to the submucosa without regional lymph node involvement or distant metastases (T1 N0 M0), the majority of patients undergoing complete resection will survive 5 years. In most cases of esophageal cancer presenting with dysphagia, however, management is complicated by the prevalence of locally advanced disease (T3 or T4), involvement of regional lymph nodes (N1), or distant (often occult) metastases (M1). Curative treatment of esophageal cancer must address local control of the primary lesion as well as the control and/or prevention of metastases. For most patients with localized esophageal cancer, surgical resection affords the best chance for local control and the best means of palliation of dysphagia. In all but the earliest stages of esophageal cancer (T1 N0 M0 or T2 N0 M0), however, both local and systemic recurrence of disease is common when surgical resection is performed as the sole treatment modality. For all but the earliest lesions, surgery 498

NEOADJUVANT RADIOTHERAPY The rationale for using preoperative radiotherapy is to reduce marginally resectable tumors to a more resectable size, to reduce the risk of tumor spread during surgical manipulation, and to treat extension of tumor beyond the surgical specimen. Surgery then removes the central, more radioresistant tumor mass. It does not appear that preoperative radiotherapy has an adverse effect on resectability or surgical morbidity. Preoperative radiation doses of 30 to 45 Gy have been reported to result in a complete pathologic response rate of 15% to 30%. Precise reporting of the rates of tumor sterilization is not possible because not all patients who are irradiated undergo surgery and not all those operated on have resectable disease. Some clinical trials have suggested that survival after preoperative radiotherapy is correlated with the extent of tumor destruction seen in the resected specimen. A multicenter, randomized, controlled trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) involved the administration of 33 Gy in 10 fractions in the treatment arm, followed by esophagectomy within 8 days. There were no significant differences in resectability or operative mortality between the study arms. Locoregional failure was significantly decreased in the radiotherapy arm from 67% to 46%. This was not associated with a survival benefit. A subsequent randomized trial of 206 patients compared preoperative radiotherapy using 40 Gy versus surgery alone. There was no significant difference in resectability rates, but local failure was significantly reduced in the radiotherapy arm from 41% to 34%. Although there was no significant difference in overall survival, 5-year survival was 50% in the subgroup of patients in whom preoperative radiotherapy achieved complete tumor sterilization. A prospective, randomized, controlled Norwegian trial of 186 patients studied patients with esophageal squamous cell carcinoma whose disease was deemed resectable at the time of enrollment. Patients in the preoperative radiotherapy arm received 35 Gy. In contrast to some other studies, this trial found significantly improved 3-year survival in the treatment arm.

Chapter 45 Induction and Adjuvant Therapy for Cancer of the Esophagus

Comparison of the results of different trials of preoperative radiotherapy is made difficult by variations in pretreatment staging methods, doses and fractionation of radiation, and interval to surgery. Preoperative radiotherapy can reduce tumor bulk and may sterilize some tumors and does not appear to increase perioperative morbidity or mortality or to adversely affect resectability. The available data suggest that preoperative radiotherapy for esophageal cancer results in improved local control but does not necessarily improve survival.

NEOADJUVANT CHEMOTHERAPY Patients with esophageal cancer who appear to have locoregional disease often have unrecognized systemic metastases. This is reflected in the poor results of radiotherapy alone or surgical resection alone in the management of esophageal cancer. The potential benefits of preoperative chemotherapy include downstaging the disease to facilitate surgical resection, improvement of local control, and eradication of micrometastatic disease. Surgical resection subsequently provides an opportunity to assess the tumor response to chemotherapy and to evaluate the patient for possible postoperative adjuvant therapy. In patients with localized, resectable tumors, chemotherapy-related toxicity can occasionally result in prolonged delay or even cancellation of planned surgical resection, risking further spread of disease. The resulting need for careful patient selection for participation in clinical trials of preoperative chemotherapy can bias treatment results. An American multi-institutional randomized trial of 440 patients compared surgery alone versus neoadjuvant chemotherapy followed by surgery. Preoperative chemotherapy consisted of three cycles of 5-fluorouracil and cisplatin. Surgical resection followed 2 to 4 weeks later. Patients received two additional cycles of chemotherapy postoperatively. There was no significant difference in perioperative morbidity and mortality between the two groups. There was no significant difference in 1-year survival (60%), in 2-year survival (35%), or in local or distant recurrence rates. Survival did not differ between patients with squamous cell carcinoma and adenocarcinoma. Median survival time was 15 to 16 months in both treatment arms. A similar Italian trial of 96 patients with esophageal squamous cell carcinoma reported a 40% response rate to preoperative chemotherapy and comparable rates of microscopically complete resection (74% versus 79%) in both treatment arms. The rate of complete pathologic response in patients receiving preoperative chemotherapy was 12.8%. Treatmentrelated mortality was 4.2% in each arm. Responders to chemotherapy had significantly better 3-year and 5-year survival rates (74% and 60%) compared with nonresponders (24% and 12%) and patients undergoing surgery alone (46% and 26%). Survival was significantly improved for patients achieving a complete pathologic response but not for those achieving a partial response. A British randomized, controlled trial of 802 patients also studied the use of preoperative 5-fluorouracil and cisplatin. The rate of microscopically complete resection was significantly higher for patients undergoing preoperative chemo-

therapy than for those undergoing surgery alone (60% versus 54%). Postoperative complication rates were similar in both groups (41% versus 42%). Patients undergoing preoperative chemotherapy achieved significantly improved median survival (16.8 versus 13.3 months) and 2-year survival (43% versus 34%). The results of this trial, however, are potentially confounded by the fact that clinicians were allowed the option to give preoperative radiotherapy to their patients, irrespective of randomization. As with preoperative radiotherapy, comparison of the results of different trials of preoperative chemotherapy is made difficult by variations in pretreatment staging methods, doses, and timing of administration of chemotherapy, interval to surgery, and the inconsistent use of adjunctive preoperative radiotherapy. Preoperative chemotherapy can potentially increase the likelihood of microscopically complete resection. In published trials of carefully selected patients, preoperative chemotherapy does not appear to increase perioperative morbidity or mortality. There are conflicting results surrounding the potential survival benefit of preoperative chemotherapy. There are data to suggest that survival benefit from preoperative chemotherapy for esophageal cancer might depend on the achievement of a complete pathologic response. The use of neoadjuvant chemotherapy must still be considered investigational at this time.

NEOADJUVANT CHEMORADIATION THERAPY Both chemotherapy and radiotherapy have been reported to improve survival in patients with esophageal cancer when administered preoperatively. The notion of “downstaging” esophageal cancer before surgical resection is appealing. In an attempt to improve resectability of and survival from esophageal cancer, chemotherapy has been combined with radiotherapy in the neoadjuvant setting. Most reports of so-called trimodality therapy for esophageal carcinoma describe concurrent neoadjuvant chemoradiation therapy using combinations of cisplatin and 5-fluorouracil while administering 30 to 45 Gy of radiation. Some studies have used additional postoperative chemotherapy. The results appear comparable at most experienced centers. A randomized, prospective French study of 86 patients with squamous cell carcinoma of the esophagus compared surgery alone versus concurrent neoadjuvant chemoradiation therapy using 5-fluoruracil/cisplatin and 20 Gy followed by surgical resection. There was no significant difference in operative mortality (7% versus 8.5%), hospital stay (27 days), or 1-year survival (47%). Five-year survival data have not been reported. In an Irish study of 113 patients who had esophageal adenocarcinoma, patients were randomly allocated to surgery alone versus trimodality therapy with neoadjuvant chemoradiation therapy. Patients randomized to the trimodality arm received two cycles of 5-fluorouracil and cisplatin given concurrently with 40 Gy, followed by surgery. Neoadjuvant chemoradiation therapy was associated with a pathologic complete response rate of 25%. Trimodality therapy was associated with significantly increased median survival (16 months versus 11 months) and 3-year survival (32% versus

499

500

Section 5 Neoplasms

6%). It should be noted that the incidence of lymph node involvement was significantly higher in the group undergoing surgery alone. Survival with surgery alone was lower than that reported in most other series. A French randomized trial of 282 patients compared surgery alone versus two cycles of cisplatin chemotherapy and concurrent radiotherapy (total 37 Gy) followed 2 to 4 weeks later by surgery. Neoadjuvant chemoradiation was associated with a pathologic complete response rate of 26% but with significantly increased operative mortality (12.3% versus 3.6%). Despite a significantly increased rate of microscopically complete resection, longer local disease-free survival time, longer overall disease-free survival time, and fewer cancer-related deaths in the trimodality arm, overall survival time was 18.6 months in both treatment arms. A randomized trial of 100 patients at the University of Michigan compared transhiatal esophagectomy alone versus preoperative chemoradiation with 5-fluorouracil/cisplatin/ vinblastine and concurrent hyperfractionated (twice daily) radiotherapy (total 45 Gy), followed by transhiatal esophagectomy 3 weeks later. There was no significant difference in median survival (17.6 months versus 16.9 months). A trend to increased 3-year survival in the trimodality arm (30% versus 16%) was not statistically significant. The study was designed with 80% power to detect a median survival increase from 1 year to 2.2 years. Meta-analyses of randomized trials of trimodality therapy versus surgery alone for esophageal carcinoma have revealed a trend to increased treatment-related mortality and slightly increased overall survival. Among patients treated with trimodality therapy for esophageal carcinoma, the best predictor of survival appears to be the finding of a pathologic complete response at the time of surgical resection. To date, there is no completely reliable preoperative method to identify pathologic complete response after neoadjuvant chemoradiation.

ADJUVANT RADIOTHERAPY Radiotherapy is commonly used postoperatively to “sterilize” residual microscopic disease and to control gross residual locoregional tumor. As an advantage, reserving radiotherapy for postoperative use avoids necessarily subjecting all patients with completely resectable disease to the damaging effects of radiation. As a disadvantage, the use of postoperative radiation in patients who have undergone gastric pull-up or colonic interposition exposes large volumes of normal tissue to harm and is a potential cause of late morbidity. A French randomized trial of 221 patients with squamous cell carcinoma arising in the distal two thirds of the esophagus compared surgical resection alone versus surgery followed by postoperative radiotherapy doses of 45 to 55 Gy in daily fractions of 1.8 Gy. Among patients with negative lymph nodes, local recurrence rates were lower in the group that received postoperative radiotherapy. There was no significant difference in survival between the two groups. A randomized trial from Hong Kong studied 130 patients undergoing either palliative or curative resection for esopha-

geal cancer. Patients randomized to the postoperative radiotherapy arm of the study received doses of 49 to 52.5 Gy in daily fractions of 3.5 Gy. The very high daily radiation dose used in this study was associated with a significantly decreased median survival when compared with surgery alone (8.7 versus 15.2 months). In patients undergoing curative resection, postoperative radiotherapy was not associated with any improvement in local control. Although postoperative radiotherapy was associated with improved local control in patients undergoing palliative resection with gross residual disease, there was no survival benefit. A prospective Chinese study of 495 patients who had undergone surgical resection of esophageal cancer randomized patients to a postoperative radiotherapy group or a control group. A midplane dose of 50 to 60 Gy was administered in daily fractions of 2 Gy. A trend to improved 5-year survival in patients who received postoperative radiotherapy (41.3% versus 31.7%) was not statistically significant. This trend was somewhat stronger in patients with positive lymph nodes (29.2% versus 14.7%, P = .07). Postoperative radiotherapy was associated with a statistically significant improvement in 5-year survival only among patients with stage III disease (35.1% versus 13.1%).

ADJUVANT CHEMOTHERAPY A multi-institutional Japanese randomized controlled trial of 242 patients who had undergone complete surgical resection for esophageal squamous cell carcinoma studied the effects of adjuvant chemotherapy with two cycles of cisplatin/5fluorouracil. Adjuvant chemotherapy was associated with significantly improved 5-year disease-free survival in patients with lymph node involvement (52% versus 38%). Despite improved disease-free survival, there was no significant improvement in overall survival. Among node-negative patients receiving adjuvant chemotherapy, a trend to improved 5-year disease-free survival (76% versus 70%) was not statistically significant. To date, there are no published North American data suggesting that postoperative chemotherapy in the absence of documented metastatic disease is associated with prolonged survival.

SUMMARY Although surgical resection affords the best chance for local control and the best means of palliation of dysphagia for most patients with localized esophageal cancer, both local and systemic recurrence of disease are common when surgery is the sole treatment modality. Because of the low cure rates associated with the treatment of esophageal cancer by surgery alone, other modalities have been added to the treatment regimen. After esophagectomy with gastric pull-up or colonic interposition, adjuvant radiotherapy exposes a large volume of normal tissue to harm and is a potential cause of late morbidity. After complete surgical resection and in the absence of documented metastatic disease, there are little data to suggest that adjuvant radiotherapy or adjuvant chemotherapy can afford a survival advantage. Both chemotherapy and radiotherapy have been reported to improve survival in patients with esophageal cancer when

Chapter 45 Induction and Adjuvant Therapy for Cancer of the Esophagus

administered preoperatively. Current data on trimodality therapy for esophageal carcinoma have revealed a trend to increased treatment-related mortality with only slightly increased overall survival. The best predictor of survival after neoadjuvant chemoradiation therapy is a complete pathologic response. To date, there is no completely reliable preoperative method to restage a patient’s tumor after neoadjuvant chemoradiation therapy to identify pathologic complete response. Novel restaging techniques as well as further study of the risks and benefits of neoadjuvant chemoradiation therapy are needed.

COMMENTS AND CONTROVERSIES Over the past decade the use of neoadjuvant protocols aiming at downsizing and/or downstaging the disease have been widely tested in the hope of improving survival through better local and systemic control. The literature displays a large number of phase II and phase III trials that often have conflicting results. Several Cochrane meta-analyses on the results of multimodality treatment have been published, offering the reader a balanced perspective on the real value of these therapeutic strategies.1-3 Preoperative radiotherapy has failed to improve outcome as compared with surgery alone. Neoadjuvant chemotherapy may offer some survival advantage, but, because two major studies have conflicting results, data are not conclusive. Meta-analysis on the results of 8 randomized controlled trials comparing induction chemoradiation therapy plus surgery versus surgery alone favor the combined-modality arm. However, when adding two very recently published randomized controlled trials to the metaanalysis,4 in only 1 of the total of 10 trials was significant benefit shown in favor of the multimodality arm. This trial, known as the Irish trial, has been strongly criticized because of the very poor, belowstandard results of the surgical arm, with a 3-year survival of only 6%. Furthermore, as revealed by these meta-analyses, postoperative mortality and morbidity remain a source of concern in the multimodality arm. Another source of concern is the fact that in all trials quality criteria for surgery were lacking, casting a shadow over the results, particularly in the surgery-only arm. This is well illustrated by the overall survival figures at 3 years, mostly not exceeding 25% at 3 years in all of these trials and being well below the 5-year survival figures of 35% to 40% obtained after radical primary surgery and extensive lymphadenectomy. The only constant finding is the better outcome in patients having a complete response at final pathologic staging, but nonresponders seemingly pay the price because of loss of precious time and development of resistant tumor lines. In this context, response assessment by fluorodeoxyglucose-labeled positron emission tomography in an early phase of induction therapy may provide easy discrimination between responders and nonresponders, thus allowing a more individualized and tailored therapy

(i.e., continuation of induction therapy versus immediate surgery or palliation). 1. Arnott S, Duncan W, Gignoux M, et al: Preoperative radiotherapy in esophageal carcinoma: A meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group). Int J Radiat Oncol Biol Phys 41:579-583, 1998. 2. Malthaner R, Colin S, Fenlon D: Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 3:CD001556, 2006. 3. Malthaner R, Wong RK, Rumble RB, Zuraw I, and the Gastrointestinal Disease Group of Cancer Care Ontario’s Program in Evidence-Based Care: Neoadjuvant or adjuvant therapy for respectable esophageal cancer: A clinical practice guideline. BMC Cancer 4:67, 2004. 4. Burmeister BH, Smithers BM, Gebski V, et al, for the Trans-Tasman Radiation Oncology Group (TROG) and the Australasian Gastro-Intestinal Trials Group (AGTIG): Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: A randomised controlled phase III trial. Lancet Oncol 6:659-668, 2005.

T. L.

KEY REFERENCES Bossett JF, Gignoux M, Triboulet JP, et al: Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 337:161-167, 1997. ■ This French trial reported that trimodality therapy for esophageal squamous cell carcinoma was associated with improved disease-free survival. Overall survival, however, was not improved. Gignoux M, Roussel A, Paillot B, et al: The value of preoperative radiotherapy in esophageal cancer: Results of a study by the EORTC. World J Surg 11:426-432, 1987. ■ This study demonstrates that preoperative radiotherapy in esophageal cancer is associated with improved local control but not with improved survival. Herskovic A, Martz K, al-Sarraf M, et al: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326:1593-1598, 1992. ■ This RTOG trial demonstrated that the addition of chemotherapy to radiotherapy was associated with significantly increased survival and decreased local recurrence. The study also indicated that morbidity and mortality rates were higher with combined chemoradiotherapy. Kelsen DP, Ginsberg R, Pajak TF, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979-1984, 1998. ■ This large trial demonstrated convincingly that preoperative chemotherapy for localized esophageal cancer is not associated with improved outcome as compared with surgery alone. Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462-467, 1996. ■ This Irish trial reported that trimodality therapy for esophageal adenocarcinoma was associated with improved median survival. Criticisms of this study have included that patients randomized to treatment with surgery alone had a higher incidence of lymph node metastases than patients in the trimodality group and had lower survival rates than other series of patients treated with surgery alone.

501

chapter

46

PRINCIPLES OF RADIOTHERAPY Karin Haustermans H. Rodney Withers

Key Points ■ Normal cells and tumor cells show a radiation response at a rate

proportional to their rate of proliferative turnover. ■ A series of fractionated doses amplifies the therapeutic difference

between normal tissues and tumor. ■ The four R’s—repair of cellular injury, redistribution within the divi-

■ ■ ■

■

sion cycle, repopulation by surviving cells, and reoxygenation of the tumor—are the major players in determining the response to radiation. The rate of tumor regression during and after radiation is not, in general, prognostic. Surgery and radiotherapy are mutually beneficial. Chemotherapy can consolidate the cytotoxic achievements of radiation. The clinical target volume for radiation in esophageal cancer should encompass the tumor and the lymph nodes at risk. Due to the anatomy of the esophagus and its draining lymph nodes, this will lead to large radiation volumes. The use of shrinking volumes is a logical approach to eliminate distant potentially microscopically invaded lymph nodes while limiting toxicity.

X-rays produce breaks in the DNA. Single-strand breaks are of little consequence because the cell has efficient mechanisms to repair them. These mechanisms evolved to protect us against injury from environmental radiation and other toxins. However, if the dose of x-rays is high enough, two single-strand breaks will be close enough to one another to cause a double-strand break. Without intact templates for their mutual repair, double-strand breaks may be misrepaired and disrupt the integrity of the chromosome. Chromosomal aberrations do not normally affect survival or function of the cells between the time they are irradiated and the time they attempt to replicate. Thus, normal tissues and tumors show a radiation response at a rate proportional to their rate of proliferative turnover. The mucosa of the esophagus, which is actively proliferative, develops a detectable reaction within 2 or 3 weeks of first exposure in a course of radiation treatment. Slowly proliferating tissues such as lung, bones, and spinal cord respond slowly to x-irradiation with signs of damage only months or years after exposure. X-rays also induce a variety of stress responses leading quickly to apoptosis. With notable exceptions (e.g., lymphocytes, serous cells in parotid), apoptosis occurs more frequently in proliferating than in nonproliferating cell populations and therefore contributes to the early development of a response. 502

BIOLOGIC BASIS OF RADIOTHERAPY Basic knowledge of cell survival after radiation, biologic effective dose, and fractionation is essential for daily radiotherapy practice and for all radiation oncologists and other specialists involved in the combined modality treatment of esophageal cancer. Early radiation treatments were given as large, but poorly measured, doses of soft (low energy) x-rays. In 1914 in Vienna, Schwartz treated a girl with a lymphoma with 6 fractions instead of a single dose with the aim of exposing more tumor cells while they were in mitosis, the first mention of exploiting cell cycle redistribution during an interfraction interval to enhance the response of a tumor.1 Two major advances emerged in 1922. Regaud published his famous experiments that showed that, unlike with single doses, several small daily doses to the testis could sterilize animals without a severe response in the dose-limiting skin of the scrotum.2 The testis response to irradiation was equated with that of a tumor. Also, Coutard reported the first cures of surgically inoperable laryngeal cancers using a multifraction regimen.3 Dose fractionation in this case was not an initiative based on radiation biology. Rather, it resulted from the necessity to deliver the treatment over many days because of the low dose rates resulting from an attempt to minimize the adverse effect of the poor depth dose distribution associated with low-energy beams (by “hardening” the beams with filters and exploiting the inverse square effect by increasing the distance between the tumor and the source of x-rays). By the advent of World War II, fractionation over 2 to 4 weeks was common.4,5 Baclesse pioneered the protraction of treatment to overall times of greater than 6 weeks on the basis of reduced skin responses from treatment of cancer of the breast.6 Until the 1960s the fractionation response was quantified in terms of the overall treatment duration. With the demonstration of repair of sublethal injury in 1959 it became clear that the number of fractions was also important.7,8 This led to the development by Ellis of the Nominal Standard Dose (NSD) concept, which embodied both the number of fractions and overall time, albeit empirically.9 The NSD formula was widely used to calculate how to modify the total dose when the number of fractions was reduced with a view to increasing cost-effectiveness in both industrialized and developing nations. But unknown at that time, there is a differential in the fractionation response between early- and late-reacting normal tissues such that large dose fractions increase preferentially the severity of responses in slowly responding tissues. This difference between the responses of early- and late-reacting tissues was illustrated by

Chapter 46 Principles of Radiotherapy

1

Late S 0.1

SF

0.01 G1

SF 0.001 G2-M 0.0001

Dose (Gy) FIGURE 46-1 Increase in cell survival (SF [surviving fraction] plotted on a log scale) by splitting the radiation dose (Dose) in fractions.

the “spaghetti isoeffect” curves and quantified in terms of the alpha-beta ratio (Thames et al, 1982).10,11 In 1959, Hermens and Barendsen demonstrated accelerated regrowth of tumor clonogens in a rat sarcoma after subcurative doses of x-rays.12 A similar phenomenon in human tumors was reported by Maciejewski and associates in 1983 and later quantified in terms of increase in dose per day needed to compensate for rapid regrowth (Withers et al, 1988)13-15 or by the percentage of decline in tumor control probability with extension of overall treatment time.16

THE FOUR R’S A series of fractionated doses amplifies the therapeutic differential between normal tissues and tumor for several reasons, easily remembered as the four R’s: repair of cellular injury, repopulation by surviving viable cells, redistribution within the division cycle, and reoxygenation of the tumor.

Repair Sublethal damage repair is the operational term for the increase in cell survival that is observed when a given dose of radiation is split into two fractions separated by a time interval, or, alternatively, the increase in dose necessary to achieve an isoeffect (Fig. 46-1).

Redistribution Cells vary in radiosensitivity as they progress through the cell cycle, being most radioresistant in late S phase (Fig. 46-2). Cells that survive a first dose of radiation are more radioresistant than the average. With time these survivors progress through the mitotic cycle and, as a result, during a fractionated course of radiation, there will be a relative selfsensitization in a proliferative population that does not occur in the nonproliferating cell population characteristic of lateresponding tissues.

0

3

6 9 Dose (Gy)

12

15

FIGURE 46-2 Cells vary in radiosensitivity as they progress through the cell cycle from G1 through S, G2, and M. (SF [surviving fraction] plotted on a log scale).

Repopulation The importance of repopulation is implicit in the history of radiation therapy. The current standard protracted overall treatment times confer a benefit by allowing regeneration of acutely responding normal tissues during treatment, which reduces toxicity. Conversely, when attempts are made to deliver curative treatment more quickly than is now standard, acute responses become more severe and dose limiting. The concept of accelerated repopulation by human tumor clonogens during and after a course of fractionated irradiation is supported by several observations and is of particular concern when treatment is prolonged. The rate of regeneration in human tumors can be assessed by the increase in dose required for tumor control as treatment duration is increased.15 Scattergram analysis of time versus total dose in the cure of squamous cell carcinoma of the oropharynx indicates that, for treatment durations of 30 to 55 days, each day of extension required the total dose to be increased by an average of about 0.6 Gy to achieve a constant rate of tumor control.14 Assuming that a dose of 2 Gy is required to reduce cell survival by 50%, an increase of 0.6 Gy per day is consistent with a 3 to 4 days’ doubling time of the surviving clonogenic cells. This is a dramatic change from the average doubling time of about 60 days for tumor cells before the start of treatment. This change occurs at some time after the start, but within the duration of a protracted treatment, and is not detected by clinical examination because it occurs in microscopic foci scattered throughout the shrinking tumor. Based on the results of several accelerated randomized phase III studies in head and neck cancer we can conclude that protraction may worsen the results more than acceleration may benefit them; therefore, avoidance of protraction during a conventional multifraction regimen is more important than introducing some acceleration.

Reoxygenation When solid tumors grow, they often outstrip their blood supply and acquire areas of hypoxia and necrosis. Hypoxic

503

504

Section 5 Neoplasms

cells are two to three times as radioresistant as normoxic cells for radiochemical reasons. When multiple small fractions of radiation are given over a period of weeks, the normoxic cells, being more radiosensitive, are selectively killed and the previously hypoxic cells gain better access to oxygen. This process is called reoxygenation. In summary, dividing a dose into a number of fractions spares normal tissues because of repair of sublethal damage between fractions while at the same time increasing damage to the tumor because, during the interfraction intervals, tumor cells are sensitized by reoxygenation of hypoxic cells and redistribution of surviving, relatively radioresistant cells into more radiosensitive phases of the mitotic cycle. Furthermore, cells in acutely responding normal tissues can repopulate sooner and faster than tumor cells.

TUMOR REGRESSION AFTER IRRADIATION The rate of tumor regression is determined by cell cycle kinetics and, more importantly, by the “normal” (preradiation) rate of cell loss. Rapid regression can occur in tumors that are slow growing because the cell loss factor is high and is to be expected in a rapidly growing tumor. Such tumors may regrow rapidly; and rapid regression is not, of itself, necessarily a favorable prognostic sign. Conversely, slow regression is not an indication of treatment failure, and the rate of regression is not, in general, prognostic.

ALTERED FRACTIONATION Hyperfractionation Reduction of dose per fraction allows preferential sparing of late-responding tissues relative to squamous carcinomas and acutely responding normal tissues. Theoretically it also enhances tumor radiosensitization through redistribution in the cell cycle. In randomized clinical trials of hyperfractionation for carcinomas of the head and neck, two fractions of 1.15 to 1.2 Gray (Gy) per day were given instead of one fraction of 2 Gy, to deliver a total dose 15% to 20% higher in the same overall treatment time period. The rates of tumor control were increased by about 10% without worsening of late effects in normal tissues.

Accelerated Fractionation It is possible that tumor cell proliferation during treatment may reduce the effectiveness of radiotherapy, and this is the rationale for accelerated radiotherapy. With an accelerated fractionation schedule the overall treatment time is reduced. The total dose delivered exceeds the equivalent of 10 Gy per week in 2-Gy fractions. More important than shortening the conventional treatment duration is the avoidance of prolonging it.

BIOLOGIC RATIONALE OF COMBINED MODALITY TREATMENT Each daily fraction of 2 Gy reduces tumor cell survival to about 50%. The larger the tumor the more tumor cells to be killed and, thus, the higher the total dose required and the higher the risk of complications. Radiotherapy can eliminate

large tumors, but it is better at eradicating small tumors and subclinical tumor deposits. Conversely, surgery is excellent for removing masses, but its therapeutic ratio in subclinical disease is usually low. Surgery and radiotherapy are therefore mutually beneficial in that less radical treatments with each achieve equivalent or better tumor control rates and fewer side effects. In many settings chemotherapy and radiotherapy can consolidate the cytotoxic achievements of one another; this is well established for esophageal tumors.

CLINICAL TARGET VOLUME FOR RADIOTHERAPY When radiation is used with curative intent in the treatment for esophageal cancer, either alone or in combination with surgery and/or chemotherapy, the radiation volume should encompass the detectable tumor and the anatomic areas at risk for metastatic spread. In esophageal cancer it is hard to determine these areas for the individual tumor. Moreover, the areas at risk are very large, and this implies that if all areas at risk need to be covered, large radiation volumes are necessary. Esophageal cancer can spread longitudinally and radially. The esophagus is characterized by a rich network of submucosal lymphatics, which allows easy tumor spread along its length to lymph nodes far from the primary tumor. Longitudinal spread occurs in both distal and proximal directions along the intramural lymphatic network and perineural spaces, with intramural localizations up to 5 to 6 cm from the primary tumor. Intramural localizations are defined as being clearly separated from the primary tumor, located in the esophageal or gastric wall, not surrounded by endothelium, and not accompanied by intraepithelial cancerous extension. Thus they are presumably metastatic deposits that have extravasated from the submucosal lymphatics. Of 393 patients with squamous cell carcinoma in the thoracic esophagus, 60 were found by histologic examination to have intramural metastasis.17 Fifty of these were identified by gross inspection. A strong correlation was found between intramural metastasis and lymph node involvement. Because the esophagus has no serosa, radial spread and direct invasion into the adjacent anatomic structures such as the pleura, tracheobronchial tree, lung, and recurrent laryngeal nerves occur early. The esophagus has a dual longitudinal interconnecting system of lymphatics in the lamina propria and the other in the muscularis mucosae. This is in contrast with other parts of the gastrointestinal tract where lymphatics are located below the submucosa. As a result of this system, lymph fluid can travel over the entire length of the esophagus before draining into the lymph nodes. Lymphatics enter the mucosa to lie just below the basement membrane of the epithelium and drain the lamina propria and muscularis mucosae and then pierce the muscularis propria to drain into regional lymph nodes or directly into the thoracic duct.

Lymph Node Mapping Early studies18,19 of lymphatic drainage of the esophagus showed three major draining areas, namely, the neck,

Chapter 46 Principles of Radiotherapy

mediastinum, and abdomen. The pattern of drainage tends to follow longitudinal pathways.20 Although upper esophageal tumors spread mainly to the cervical and supraclavicular regions, involvement of the celiac nodes can occur in 10% to 30% of these tumors. The opposite is also true: involvement of the supraclavicular nodes can occur in 10% to 30% of patients with lower esophageal tumors (Akiyama et al, 1994).19,21-23 The N classification, the number of metastatic lymph nodes, and the location of these nodes are important to predict prognosis, to select the appropriate treatment, and to delineate the radiation volume. Therefore, extensive and precise lymph node mapping is necessary in patients with esophageal carcinoma. Several lymph node classifications and nomenclatures have been devised to facilitate the identification and dissection of lymph nodes during radical surgery for carcinoma of the

esophagus (e.g., RTOG lymph node map23 or the classification of Akiyama24). However, for radiotherapy planning we need to correlate the anatomic volume on imaging modalities with the different lymph node regions described from surgical experience. Therefore, we modified the classification of Akiyama with the help of an experienced surgeon and radiologist to be able to identify the different regions on a CT in treatment position (Table 46-1). Several techniques have been used to diagnose pathologic lymph nodes. CT has been the imaging modality of choice in the past decades. Lymph nodes larger than 10 mm are considered to be involved. This implies that tumor involvement in normal-sized nodes cannot be detected and results in false-negative findings. The sensitivity of CT is low (11%75%). The specificity is higher (43%-100%), although falsepositive findings can occur in enlarged inflammatory lymph nodes.22,25-35

TABLE 46-1 Lymph Node Mapping Lymph Node Mapping According to Akiyama

Lymph Node Mapping for Radiotherapy

Location

1

Deep lateral cervical nodes

1

Cervical nodes

Along the course of the internal jugular vein, above the sternoclavicular joint

2

Deep external cervical nodes

2

Supraclavicular nodes

Along the course of the subclavian artery, above the sternoclavicular joint

3

Deep internal cervical nodes

4

Recurrent nerve lymphatic chain

3

Recurrent nerve lymphatic chain

Along the course of the right recurrent laryngeal nerve where it hooks around the subclavian artery

5

Brachiocephalic artery nodes

4

Brachiocephalic artery nodes

Anterior and medial to the right vagus nerve where it crosses the brachiocephalic artery

6

Paratracheal nodes

5

Paratracheal nodes

On the left (including the left recurrent laryngeal nerve nodes) and the right of the trachea from the sternoclavicular joint to the carina

7

Infra-aortic arch nodes

6

Infra-aortic arch nodes

Beneath the aortic arch

8

Paraesophageal nodes above the carina

7

Paraesophageal nodes above the carina

On the left and right of the esophagus from the sternoclavicular joint to the carina

9

Tracheal bifurcation nodes

9

Tracheal bifurcation nodes

Located beneath the carina

10

Pulmonary hilar nodes

8

Pulmonary hilar nodes

Along the right and left terminal portions of the main bronchi or pulmonary pedicles

11

Paraesophageal nodes in the middle mediastinum

Paraesophageal nodes below the carina

On the left and right of the esophagus from the carina to the cardia

12

Paraesophageal nodes in the lower mediastinum

13

Diaphragmatic nodes

14

Paracardiac nodes

15

Lesser curvature nodes

16

Left gastric artery nodes

17

Celiac trunk nodes

18

Common hepatic artery nodes

Cervical nodes

10

Paraesophageal nodes below the carina 11

Diaphragmatic nodes

12

Superior gastric lymph nodes

At the diaphragmatic level of the lower esophagus, to the left and right of the cardia

Diaphragmatic nodes Along the course of the left gastric artery

Superior gastric lymph nodes 13

Celiac trunk nodes

Around the celiac trunk and at the root of the common hepatic and splenic arteries

Celiac trunk nodes 14

Retroperitoneal nodes

Along the course of the abdominal aorta distal to the celiac trunk

505

506

Section 5 Neoplasms

Most of the studies that investigated the sensitivity and specificity of CT and fluorodeoxyglucose-positron emission tomography (FDG-PET) for diagnosis of pathologic lymph nodes compared with the gold standard of pathology reported a higher accuracy for FDG-PET (59%-92%) than for CT (45%-88%).22,25-35 Meltzer and colleagues33 reported a very low sensitivity for FDG-PET, but these data are reported with a low sensitivity interpretation (e.g., assigning equivocal findings as negative) and are based on nonattenuation corrected images. The somewhat lower sensitivity of FDG-PET in recent studies25-30,34,35 can be explained in several ways. The sensitivity was calculated for each separate lymph node group instead of overall N classification, except in the study of Wren and associates.34 Second, five of these studies were prospective, thus preventing overestimation of sensitivity. Moreover, most patients were treated with a transthoracic esophagectomy with extensive lymph node dissection, which also results in a lower sensitivity as well, because lymph nodes with microscopic tumor involvement were also included in the sensitivity calculation. In the earlier studies22,31,33 most patients underwent a transhiatal esophagectomy or lymph node sampling, resulting in less precise lymph node dissection and underestimation of lymph node involvement. FDG-PET can detect metastasis in normal-sized lymph nodes because metabolic changes often precede structural changes,22 but, nevertheless, micrometastasis will result in false-negative findings on the FDG-PET.28,32 False-negative findings are also due to difficulties detecting local lymph nodes adjacent to the primary tumor because of the intense activity in the primary tumor.26 Because the sensitivity of the FDG-PET is still relatively low (6%-92%),22,25-35 the incidence of false-negative findings is not negligible. However, if the primary tumor is FDG positive and the suspect lymph nodes seen on conventional modalities are not localized adjacent to the primary tumor, the negative predictive value of the FDG-PET increases (Lerut et al, 2000).26,36 FDG-PET has a high specificity (82%-100%).22,25-35 False-positive results can be caused by inflammatory lymph nodes.28 The specificity decreases in patients with active pulmonary inflammatory disease or tuberculosis.29 Endoscopic ultrasonography (EUS) can contribute to detection of periesophageal and peritumoral lymph nodes. However, the accuracy varies inversely with the axial distance of the nodes from the esophageal wall,37 and distinguishing nodal metastasis from inflammatory lymph nodes is difficult.25,26,38,39 Also in our study the probe could not pass the tumor in 60% of the patients. Therefore, the contribution of this investigation to detection of pathologic lymph nodes was inferior to that of CT. Recent reports suggest more specific lymph node staging with trans-EUS–guided lymph node biopsies. This technique has a limited availability and seems to have a steep learning curve.40-42

Guidelines for Selection of Target Volumes and Radiation Field Design When delineating the clinical target volume for esophageal cancer the radiation oncologist should make sure that the volume treated adequately encompasses the tumor and lymph

nodes at risk. Due to the anatomy of the esophagus this will lead to large radiation volumes. Many of these more distant nodes are only microscopically invaded, and the total dose given to these regions at risk does not need to be as high as the dose needed to treat macroscopic disease. The use of shrinking volumes is a logical approach to eliminate distant microscopically invaded lymphatics and nodes while limiting toxicity. Nevertheless, the toxicity and morbidity of such treatment is substantial because irradiation needs to be combined with chemotherapy. Esophageal cancer is notorious for its ability to spread intramurally distant from the main lesion.17 Some surgeons advocate the removal of at least 5 cm of normal esophagus to ensure a safe surgical margin. Not infrequently, 5 cm may not be sufficient for primary tumors with multicentric lesions and spread. However, with new advances in endoscopic and radiologic techniques, the tumor extent and spread, together with synchronous lesions, are frequently accurately detected. It is generally accepted that lymph node regions with a probability of 10% or more to be microscopically invaded should be included in the clinical treatment volume. This would mean that the celiac trunk nodes do not need to be included in the clinical treatment volume for tumors of the upper and middle esophagus. However, most cases referred for radiation have an advanced stage at diagnosis and are referred for preoperative neoadjuvant treatment. So the estimated percentage of involved nodes deduced from the surgical series is probably lower than the probability among those patients referred for radiotherapy.

Influence of FDG-PET on the Irradiated Volume We studied the additional value of performing FDG-PET scans to delineate the clinical treatment volume. Thirty patients with advanced esophageal cancer were studied prospectively. All patients underwent CT of the chest and the abdomen, EUS, and FDG-PET before the start of the preoperative chemoradiotherapy. Fourteen different lymph node regions were defined on the basis of surgical series. All these regions (n = 1260) were scored individually for lymph node involvement with the help of an experienced radiologist and nuclear medicine physician. Radiation volumes were defined on the basis of conventional imaging modalities. The supraclavicular nodes were included in the treatment volume for primary tumors located above the carina. When FDG uptake was found in a lymph node region without pathologic nodes on CT and/or EUS, the influence of this finding on the radiation fields was assessed. In 14 of the 30 patients discordances were found in diagnoses of pathologic lymph nodes between the conventional imaging modalities (CT/EUS) and FDG-PET (Table 46-2). In 8 patients, nine pathologic lymph node regions were detected on conventional imaging only (see Table 46-2). The irradiated volumes based on the FDG-PET would have been smaller than the irradiated volumes based on the conventional imaging modalities in 3 of these patients. Thus, the chance of a false-negative result is not negligible owing to the low sensitivity of FDG-PET. On the other hand, the specific-

Chapter 46 Principles of Radiotherapy

TABLE 46-2 Potential Influence of FDG-PET on Irradiated Volume When Discordant Findings Were Found Location of Tumor

Imaging: FDG-PET (−)/CT-EUS (+)

Influence of FDG-PET on Irradiated Volume

1

Upper

Celiac trunk nodes

Decreased

2

Upper

Cervical

No

3

Middle

Pulmonary nodes

Decreased

4

Middle

Infra-aortic arch nodes

No

5

Middle

Retroperitoneal

Decreased

6

Lower

Paratracheal nodes

No

7

Lower

Tracheal bifurcation nodes

No

8

Lower

Tracheal bifurcation nodes Lower paraesophageal nodes

No

8/30 (27%) patients

9/420 regions

3/30 (10%) smaller volume

Location of Tumor

Imaging: FDG-PET (+)/CT-EUS (−)

Influence of FDG-PET on Irradiated Volume

1

Middle

Supraclavicular nodes Paratracheal nodes

No

2

Middle

Cervical nodes

No

3

Lower

Celiac trunk nodes Paracardiac nodes

Enlarged

4

Lower

Supraclavicular nodes

Enlarged

5

Lower

Supraclavicular nodes

Enlarged

6

Lower

Supraclavicular nodes

No

6/30 (20%) patients

8/420 regions

3/30 (10%) larger volume

Total

14/30 (47%) patients

17/420 regions

6/30 (20%) volume change

ity of the CT is rather high. Therefore, the irradiated volume should not be decreased based on a negative FDG-PET. In the other 5 patients the lymph node regions with discordant findings could not be excluded from the radiation volume owing to the margin around the primary tumor and the other (concordant) pathologic lymph nodes. In 6 patients, 8 pathologic lymph node regions (see Table 46-2) were detected on FDG-PET without detection on conventional imaging. In 3 of these patients (10% of total) the influence of the FDGPET would have led to enlargement of the irradiated volume. The specificity of FDG-PET is very high, and the prevalence of false-positive results is low. Moreover, the sensitivity of the CT scan is rather low. Therefore, enlarging the irradiated volume based on a positive FDG-PET in a region with no suspect lymph nodes on CT and/or EUS should be considered. In the other 3 patients the discordances were found in the supraclavicular or cervical nodes, but these nodes were already included in the irradiated volume because of the presence of other pathologic lymph nodes or the location of the primary tumor above the carina. This study indicates a role for FDG-PET in radiotherapy planning for esophageal cancer. However, enlarging the radiation volume can lead to an increase of the complication rate, and further studies are needed to evaluate whether FDGPET can lead to therapeutic gain.

DOSE-VOLUME HISTOGRAMS Dose-volume histograms (DVHs) provide more data for predicting tumor control and side effects than has been available historically. Most of the DVH is irrelevant, and the relevant regions are different for different tissues. A relatively low dose to a large volume of tissue such as lung, liver, and kidney (parallel organs) can lead to serious sequelae, but, by contrast, a high dose to a small volume may have little effect on the functioning of the organ as a whole. The vulnerability of organs such as the spinal cord and the nerves in which functional subunits are aligned in series (serial organs) is quite different in that severe injury to a small volume is effective in compromising function of the whole structure, whereas a low dose to a large volume may be well tolerated.21 In considering a tumor DVH, the magnitude of a dose reduction in the tumor is the major determinant of decline in tumor control probability. A large dose reduction to even a small volume of tumor can profoundly decrease tumor control probability. If it were possible to identify areas of increased clonogen volumes, such volumes could be painted with an extra dose, but there is a high risk of geographic inaccuracy with current imaging and immobilization devices. Escalation of dose to hypoxic foci may be beneficial if such foci are large enough and persist throughout treatment. In

507

508

Section 5 Neoplasms

such a case, the dose required for tumor control may be much higher than usually prescribed,21 and other treatment approaches such as surgery or the use of drugs to sensitize or kill hypoxic cells should be considered.

SUMMARY Radiation therapy has made major progress, not only in the complexity of the treatment machines and treatmentplanning computers but also in the understanding of the biologic processes that underlie radiation responses. The manipulation of these characteristics to increase the therapeutic differential between normal tissues and tumor to provide safer, more comfortable, and more effective cancer treatment is the goal of further research.

COMMENTS AND CONTROVERSIES In this chapter the authors provide the reader with a more in-depth sight into the biologic basis of radiotherapy. It is clear that not only knowledge of anatomy and of macroscopically visible aspects of tumor behavior (e.g., lymphatic spread) but also, in particular, understanding the mechanism controlling cell kinetics as a basis of radiobiology are of paramount importance in modern radiotherapy. Quantifying response on tumoral and normal tissue, concepts of therapeutic ratio including hyperfractionation, accelerated fractionation, combined radiotherapy and chemotherapy and their mutual interactions (e.g., hypoxia) are all factors important in treating esophageal cancer and cancer of the gastroesophageal junction and obviously are areas where further research is needed. The chaotic pattern of lymph node involvement as well as the longitudinal intramural spread over a long distance well away from the primary tumor distinguishes cancer of the esophagus and gastroesophageal junction from other solid organ tumors. These findings resulting from meticulous mapping of lymph node involvement after extensive lymphadenectomy and detailed pathologic examination of resection specimens after subtotal esophagectomy have substantially influenced the definition and delineation of clinical target volume in these cancers. The recent introduction of FDG-PET also has confirmed the need for enlarging the irradiated volume in these cancers. But especially the combination of chemotherapy and enlarged radiation volume may result in an increase of complication rate. From my own experience it appears that performing radical surgery with extensive lymphadenectomy after induction chemoradiotherapy indeed sharply increases postoperative morbidity and, to a certain extent, postoperative mortality especially when performing three-field lymphadenectomy.1 This risk for increased morbidity and mortality is therefore used as an argument by some surgeons to restrict the irradiated field to

the tumor area to better guarantee an R0 resection, with lymph nodes being cleared anyway at the time of operation. This view, however, is opposed by the findings that chemotherapy, besides its presumed but not proven systemic effect, is functioning as a sensitizer for radiotherapy. Thus, including more distant lymph node in the irradiated field indeed increases the chances to complete T0 N0 M0 (i.e., sterilization of all tumor and lymph node areas). Whether such policy eventually improves the long-term survival as compared with a more limited target volume is not known and requires further research. Another interesting area of research in the field of radiation oncology is the effect of hypoxia on tumor behavior. Hypoxic tumor cells appear to be two to three times more resistant. Ongoing research indicates that hypoxic-cell radiosensitizers such as nimorazole and hypoxic cytotoxins such as tirapazamine may have a significant beneficial impact on long-term survival through better targeting hypoxic cells within the primary tumor mass. Hypoxia is used as an argument favoring induction radiotherapy rather than postsurgery radiotherapy because it is believed that postsurgery fibrosis with its less-ordered vasculature enhances hypoxia in remaining tumor cells, making them more resistant to postoperative radiotherapy. However, within the context of the recent interest for postoperative adjuvant chemoradiotherapy, further research in this area may open interesting perspectives. 1. Hagry O, Coosemans W, De Leyn P, et al: Effects of preoperative chemoradiotherapy on postsurgical morbidity and mortality in cT3-4 +/− cM1 lymph cancer of the esophagus and gastroesophageal junction. Eur J Cardiothorac Surg 24:179-186, 2003; discussion 186.

T. L.

KEY REFERENCES Akiyama H, Tsurumaru M, Udagawa H, Kajiyama Y: Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 220:364-373, 1994. Lerut T, Flamen P, Ectors N, et al: Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esophagus and gastroesophageal junction. Ann Surg 232:743-752, 2000. Thames HD, Withers HR, Peters LJ, Fletcher GH: Changes in early and late radiation responses with altered dose fractionation: Implications for dose-survival relationships. Int J Radiat Oncol Biol Phys 8:219-226, 1982. Vrieze O, Haustermans K, De Wever W, et al: Is there a role for FDGPET in radiotherapy planning in esophageal carcinoma? Radiother Oncol 73:269-275, 2004. Withers HR, Taylor JMG, Maciejwski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncologica 27:131-146, 1988.

chapter

47

CHEMOTHERAPY AND RADIOTHERAPY AS PRIMARY TREATMENT OF ESOPHAGEAL CANCER David H. Ilson Bruce D. Minsky

Key Points ■ In esophageal cancer, single agent chemotherapy achieves

■

■

■

■

■

■

responses in 10% to 20% of patients and combination chemotherapy in 35% to 45% of patients, with a median survival of 7 to 9 months. The addition of a third chemotherapy agent to cisplatin and fluorouracil, either epirubicin in the ECF regimen or docetaxel in the DCF regimen, increases antitumor response rates by 10% and improves survival by only 1 to 2 months. In locally advanced esophageal cancer, primary concurrent chemoradiotherapy achieves curative potential in patients with squamous cell carcinoma, and long-term disease control is also achieved with chemoradiotherapy in a minority of patients with adenocarcinoma. The addition of surgery to primary chemoradiotherapy reduces local recurrence without a clear impact on survival in squamous cell cancer of the esophagus. Because of lower pathologic complete response to chemoradiotherapy in adenocarcinoma of the esophagus, surgery is more often considered as part of primary management. Controversy remains about the preferred preoperative therapy in esophageal cancer, with current approaches using either preoperative chemotherapy or combined preoperative chemotherapy and radiation therapy, followed by surgery. Higher radiation therapy doses above conventional 5040 cGy, or the addition of induction chemotherapy before radiation therapy, do not appear to improve treatment outcome. Newer therapies, including molecular targeted agents, and new technologies such as PET scan, are under active investigation in esophageal cancer.

Esophageal cancer, an uncommon but highly virulent malignancy in the United States, will have been responsible for 15,560 deaths in 2007.1 The majority of patients who have esophageal cancer die of the disease, which represents the sixth leading cause of cancer death in American men. Although esophageal cancer remains relatively uncommon in the United States, it is a major cause of cancer worldwide. Particularly high incidences are observed in northern China, the Caspian littoral, and the Transkei province of South Africa.2-4 The epidemiologic factors responsible for the geographic variability in incidence of esophageal cancer, including potential dietary and environmental carcinogens, are under active investigation. In Western countries, an association with abuse of tobacco and alcohol and the development of squamous cell carcinoma of the esophagus is generally accepted.5

Although the incidence of squamous cell carcinoma of the esophagus has remained relatively constant in the United States, adenocarcinoma of the esophagus is increasing at an epidemic proportion in this and other Western countries. Esophageal adenocarcinoma now exceeds squamous cell carcinoma in incidence in white men, and esophageal adenocarcinoma has shown the most rapid rate of increase of any solid tumor malignancy in the past 20 years.6 Epidemiologic studies have implicated tobacco use and obesity as potential risk factors.7,8 One prospective study identified chronic symptoms of esophageal reflux as substantially raising the risk of esophageal adenocarcinoma independently of other factors.9 The prognosis for patients with esophageal cancer treated with the standard approaches of surgery or radiotherapy is suboptimal. The largest retrospective series of patients treated with either surgery alone or radiotherapy alone, reviewed by Earlam and Cunha-Melo,10,11 reported equally poor 2-year survivals of 6% to 8% and 5-year survivals of 4% to 6%. The operative mortality for surgically treated patients in this review was 29%. However, this 1980 report is out of date and at variance with current results. Later surgical series from single institutions have reported operative mortality rates of 5% to 15%. Muller and associates12 reported an overall operative mortality rate of 12.5% in a review of the surgical literature, with 10% of patients achieving a 5-year survival. More recent surgical series have indicated long-term survival in up to 30% to 40% of patients treated with surgery for squamous cell carcinoma13,14 and adenocarcinoma,15 which is likely a reflection of improved patient staging and selection of patients for primary surgical management. Ultimately, most patients treated with either surgery or radiotherapy alone are destined to die of their disease. The failure of standard surgery or radiotherapy in patients with disease clinically limited to the locoregional area before treatment is due both to a high incidence of locoregional failure of treatment and to early systemic dissemination of disease. Autopsy series bear out the frequent systemic nature of squamous cell carcinoma, even at the time of or shortly after initial presentation.16-19 Despite the brief duration of illness in these patients, most were found to have evidence of distant metastatic disease at autopsy whether or not residual local disease was present. Adenocarcinoma of the distal esophagus or gastroesophageal junction appears to have a natural history of disease similar to that of esophageal squamous cell carcinoma, with equally poor survival after surgical therapy due to a combination of local and systemic recurrence of disease.20 The clear need to address the early systemic spread of esophageal carcinoma with systemic treatment has led to the development 509

510

Section 5 Neoplasms

of combined-modality therapy with the incorporation of chemotherapy. Concurrent use of chemotherapy and radiotherapy is now a standard of care in the nonsurgical management of locally advanced esophageal cancer. Preoperative chemotherapy and combined preoperative chemoradiotherapy are the subjects of ongoing investigation. Approximately 50% of patients with a diagnosis of esophageal cancer present with overt metastatic disease, and chemotherapy is the mainstay of palliation in this setting. With the high likelihood of the development of metastatic disease in patients with initial locoregional cancer, systemic chemotherapy is ultimately required in the majority of patients. This chapter focuses on the use of systemic chemotherapy in the treatment of esophageal cancer and of radiation-based therapy in the primary management of locally advanced esophageal cancer.

SINGLE-AGENT CHEMOTHERAPY The antitumor activity for single-agent chemotherapy in esophageal carcinoma is summarized in Table 47-1. Early

studies evaluated only squamous cell carcinoma. Modest antitumor activity for a broad range of chemotherapy drugs is seen in esophageal carcinoma, but the duration of response to single-agent chemotherapy is generally brief and on the order of 4 to 6 months. Early chemotherapy trials, such as the studies of bleomycin, were performed on small numbers of patients, often in the context of broad phase I or II trials in diverse solid tumors. Such trials also included patients with prior, often extensive chemotherapy treatment. More modern trials, however, have been larger phase II trials and have generally limited new drug evaluation to patients without prior chemotherapy exposure. Later studies have also employed a population size large enough to quantify a major antitumor response with some degree of statistical significance. These trials have included patients with adenocarcinoma, reflecting the rising incidence of this disease. For some single agents, variable response proportions in different trials have been reported. In general, higher response rates for single agents have been observed in patients with locoregional disease (often before definitive local surgery or radiotherapy) than in patients with distant metastatic disease.

TABLE 47-1 Activity of Single-Agent Chemotherapy Agent

Cell Type

Antibiotics Bleomycin Mitomycin Doxorubicin

S S S

No. Responses

Response Rate (%)

Reference

80 58 38

12 15 7

15 26 18

21, 24, 159-163 22, 164, 165 23, 24

Methotrexate

S A+S S

26 13 65

4 11 23

15 85 35

23, 25 25 23, 166

Plant Alkaloids Vindesine Navelbine (vinorelbine)

S S

86 30

19 6

22 20

28-31 32

S A S A

152 12 59 11

42 1 3 1

28 8 5 9

33, 167-169 170 35, 36, 38 37

S A A+S A+S A A S

18 32 14 58 8 22 49

5 11 0 9 2 4 10

28 34 — 15 25 18 20

39 39 40 41 37 43 44

Irinotecan

A+S S A

27 26 55

0 5 8

— 19 15

46, 42 48 49, 50

Other Drugs Ifosfamide Lomustine Mitoguazone

S S S

22 19 45

2 3 9

8 16 20

171 172, 174 173

Antimetabolites 5-Fluorouracil

Heavy Metals Cisplatin Carboplatin Taxanes Paclitaxel Paclitaxel (96-hour) Paclitaxel (1-hour) Docetaxel

Topoisomerase Inhibitors Etoposide

A, adenocarcinoma; S, squamous cell carcinoma.

No. Patients

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

Greater response rates have also been seen in trials treating chemotherapy-naive patients rather than pretreated patients. In trials employing higher drug doses, higher response rates have also been observed. Despite the disparate response rates for some single agents, the confidence limits of response overlap among different trials in most cases.

Antibiotics, Antimetabolites, and Plant Alkaloids Antitumor antibiotics have been evaluated only in squamous cell carcinoma. Bleomycin has demonstrated a pooled response rate of 15%. The largest of these trials, conducted by Tancini and colleagues,21 achieved a 14% response rate in 29 patients. However, 41% of patients suffered severe pulmonary toxicity, 2 of whom died. High-dose mitomycin C, 20 mg/m2, every 4 weeks and then every 6 weeks was used in an Eastern Cooperative Oncology Group (ECOG) trial evaluating this agent.22 Of 24 previously untreated patients, 42% had a major response. Cumulative grade III/IV hematologic toxicity was, however, noted in 42% of patients. Lower doses of mitomycin C have shown lower response rates but more acceptable levels. The anthracycline doxorubicin has also been evaluated in phase II trials, with an overall response rate in only 18% in 38 patients treated in two phase II trials.23,24 The ECOG has also evaluated single-agent methotrexate and bolus single-agent 5-fluorouracil (5-FU) in patients with previously untreated, metastatic, or unresectable squamous cell carcinoma.23 Major responses were noted in 12% of patients treated with methotrexate and in 15% of patients treated with 5-FU. In a small study by Lokich and coworkers,25 continuous infusion 5-FU had a higher response rate. Patients in this study had localized disease only, however, and this higher response rate has not been confirmed in other, similar studies. Oral 5-FU prodrugs, which may potentially mimic a continuous infusion 5-FU schedule by daily exposure, have also undergone evaluation in metastatic gastric cancer. Capecitabine is an oral fluoropyrimidine carbamate that requires several enzymatic steps to achieve activation to 5-FU, including the enzyme thymidine phosphorylase. Because thymidine phosphorylase is found at higher levels in tumor tissue compared with normal tissue, activation of capecitabine to 5-FU may occur to a greater degree in tumor sites as opposed to nontumor sites. Response rates of 26% to 34% have been reported for metastatic gastric adenocarcinoma in Japanese and Korean trials, and these data may be relevant to the potential activity of capecitabine in adenocarcinoma of the distal esophageal and gastroesophageal junction.26,27 The Vinca alkaloid vindesine has shown consistent antitumor activity in squamous cell carcinoma.28-31 One study by Kelsen and associates29 showed a 17% response rate in 23 mostly pretreated patients. Toxicity, however, was significant, with peripheral neuropathy in 50% of patients and one treatment-related death. A newer plant alkaloid, vinorelbine, has shown less toxicity with a similar response rate. In a trial by the European Organization for Research and Treatment of Cancer (EORTC), vinorelbine, 25 mg/m2, was given weekly to 46

patients with measurable squamous cell carcinoma.32 Six of 30 previously untreated patients (20%) and 1 of 16 previously treated patients (6%) showed a major response. The median duration of response in the untreated group was 21 weeks. The entire group had a median survival of 6 months. Grade III/IV granulocytopenia was seen in 59% of patients, yet there was no significant peripheral neuropathy and no treatment-related deaths occurred.

Platinum Analogues Since its introduction in 1980, cisplatin has become the cornerstone of combination chemotherapy in esophageal cancer. As a single agent, cisplatin has a pooled response rate of 20%. The largest trial, conducted by the Southwest Oncology Group, treated patients with squamous cell carcinoma with cisplatin, 50 mg/m2, on days 1 and 8 every 28 days.33 Nine of 35 evaluable patients (26%) had a major response. A second study by ECOG gave a relatively low dose of cisplatin (50 mg/m2) once every 3 weeks.22 This group reported a 25% response rate in 24 previously untreated patients. Treatment was well tolerated in both trials, with no treatment-related deaths. Carboplatin, by contrast, has shown a lower 0% to 9% response rate in both squamous cell carcinoma34-36 and adenocarcinoma.37 Oxaliplatin is a promising new platinum analogue that, in combination with 5-FU, can salvage patients with colorectal cancer refractory to 5-FU.38 Oxaliplatin as a single agent has not been evaluated in esophageal cancer, but 5-FU and capecitabine combinations with oxaliplatin have been evaluated in phase II and III trials (see later in the discussion of 5-FU and cisplatin combination therapy).

Taxanes Paclitaxel is one of the most active single agents in esophageal cancer and has also been evaluated in combination chemotherapy trials. Initial results were reported by Ajani and colleagues39 in a joint Memorial Sloan-Kettering Cancer Center (MSKCC) and M. D. Anderson Cancer Center trial. In this study, paclitaxel was given as a 250-mg/m2 infusion over 24 hours with granulocyte colony-stimulating factor (G-CSF) support every 21 days. Of 32 patients with adenocarcinoma, 11 patients (34%) showed a complete or partial response. Similarly, 5 of 18 patients with squamous cell carcinoma (28%) had a major response. The median duration of response was 17 weeks, and the median survival was 13.2 months. Therapy was generally well tolerated. Although 86% of patients had grade III and IV neutropenia, only 18% were hospitalized for neutropenic fever. Based on earlier work in breast and ovarian cancer, other infusion schedules for paclitaxel have been studied. Threehour paclitaxel is the most commonly used schedule, but it has not been tested as a single agent in esophageal cancer. On the basis of a successful salvage regimen for metastatic breast cancer, esophageal cancer patients who experienced progression of disease while receiving a shorter infusion schedule of paclitaxel were treated with 96-hour paclitaxel at a dose of 35 mg/m2/day every 21 days at MSKCC.40 There were no responses in 14 patients.

511

512

Section 5 Neoplasms

In breast and ovarian cancer, 1-hour weekly paclitaxel has shown significant antitumor activity with greater total dose and lower neutropenia than with the original, more protracted infusions. Weekly paclitaxel by 1-hour infusion had a response rate of 15% in 58 patients treated in a multicenter phase II trial in squamous cell and adenocarcinoma of the esophagus.41 Docetaxel has been evaluated in an ECOG study of 33 patients with gastric cancer and 8 patients with esophageal adenocarcinoma.42 Previously untreated patients received 1hour docetaxel, 100 mg/m2, every 3 weeks. Two of the eight patients with esophageal adenocarcinoma (25%) had a major response. Overall, grade IV neutropenia occurred in 88% of patients and neutropenic fever in 46%. A larger single institution trial of docetaxel administered at a dose of 75 mg/m2 in 22 patients with esophageal adenocarcinoma reported a response rate of 18% in chemotherapy naïve patients and no responses in previously treated patients.43 Febrile neutropenia occurred in 32% of patients. A recent trial evaluated a schedule of 70 mg/m2 every 3 weeks in 49 patients with squamous cell carcinoma, of whom 36 had received prior platinum-containing chemotherapy.44 A response rate of 20% was observed. Neutropenic toxicity was also significant in this trial, with 88% of patients experiencing grade 3 or 4 neutropenia and 18% febrile neutropenia. There are no comparative studies of docetaxel and paclitaxel. In vitro, however, docetaxel has been more active than paclitaxel in 10 esophageal cancer cell lines (histology not given by the authors).45

Topoisomerase Inhibitors The topoisomerase I inhibitor etoposide (formerly VP-16) has been studied in both adenocarcinoma and squamous cell carcinoma.46,47 In mostly pretreated patients, Kelsen and associates47 reported no activity in 7 patients with adenocarcinoma and no major responses in 20 patients with squamous cell carcinoma. In a later study of previously untreated patients with squamous cell carcinoma, however, Harstrick and colleagues48 observed five partial responses in 26 patients (19%) treated with a higher dose of etoposide. The topoisomerase II inhibitor irinotecan has shown promising activity in gastric cancer, and reports of the use of irinotecan in combination with cisplatin and 5-FU in both esophageal and gastric cancer also indicate significant activity. As a single agent, irinotecan has been evaluated in two recent phase II trials in adenocarcinoma of the stomach and gastroesophageal junction, with a response rate of 15%.49,50

COMBINATION CHEMOTHERAPY With modest activity demonstrated for several single chemotherapy agents, combination chemotherapy has also been extensively studied (Table 47-2). In earlier trials, patients with both locoregional and metastatic disease were treated with the same protocols, although patients with locoregional disease usually underwent subsequent definitive surgery or radiotherapy. Virtually all studies used cisplatin. Cisplatinbased combination chemotherapy has yielded antitumor activity in metastatic squamous cell carcinoma of the esophagus in the range of 25% to 35% of patients. The response

rate observed in locoregional disease has been consistently higher, on the order of 45% to 75%. Despite higher response rates seen with combination therapy than with single-agent chemotherapy, the duration of response to combination therapy has also been relatively brief (4 to 6 months). Unfortunately, the higher response rates achieved with cisplatin combinations have not translated into significantly longer response duration or improved survival. In this primarily palliative setting, the potentially greater response rate for combination chemotherapy must be balanced with a frequently higher toxicity and an increasingly complex and timeconsuming schedule. Early trials combined bleomycin with cisplatin and other agents. Coonley and associates51 reported activity of bleomycin and cisplatin in 61 patients with squamous cell carcinoma, only 15% of whom showed a major response. Comparable response proportions were seen in patients with locoregional disease treated preoperatively (given only one cycle of preoperative chemotherapy) and in patients with advanced or metastatic disease. Duration of response in metastatic disease ranged from 5 to 9.5 months. Three other smaller trials showed similar antitumor activity for the combination of bleomycin and cisplatin.52-54 Overall, a response proportion of 25.5% has been observed. The three-drug combination of cisplatin, vindesine, and bleomycin has been studied in three phase II trials and two phase III trials. In the largest phase II trial, reported by Kelsen and coworkers,55 major responses were seen in 28 of 44 patients with locoregional disease (63%) after one or two cycles of preoperative therapy and in 8 of 24 patients (33%) with advanced or metastatic disease. Schlag and associates56 reported major responses in 45% of patients with squamous cell carcinoma treated preoperatively, 2 of whom had pathologically confirmed complete responses (5%). Dinwoodie and colleagues57 reported major responses in 7 of 27 patients (29%) with advanced or metastatic disease. In phase III trials, preoperative cisplatin, vindesine, and bleomycin were compared with either surgery alone58 or preoperative radiotherapy,59 with major responses seen in 47% to 55% of patients and pathologically confirmed complete responses in 6% to 8%. Of a total of 192 patients treated with cisplatin, vindesine, and bleomycin, 91 patients (47%) responded, with consistently different response proportions seen in patients with locoregional disease (54%) and metastatic disease (29%). Bleomycin-induced pulmonary toxicity was substantial in many of these trials. Cisplatin in combination with mitoguazone and vindesine or vinblastine was studied in three separate phase II trials, with one trial treating both adenocarcinoma and squamous cell carcinoma.60-62 Overall, 15 of 30 patients with locoregional squamous cell carcinoma had a major response (50%) with two pathologically confirmed complete responses (7%), and 14 of 60 patients with advanced or metastatic disease had a major response (23%). Duration of response in metastatic disease was brief, lasting a median of 3 to 4 months. Other cisplatin-based combinations have been reported, including combinations with methotrexate and other agents, with response proportions of 20% to 76% in pooled series of patients with metastatic or locoregional disease (see Table

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

TABLE 47-2 Activity of Combination Chemotherapy Cell Type

No. Patients

Response Rate (%)

Reference

Cisplatin/bleomycin/vincristine/5-fluorouracil (5-FU) Cisplatin/bleomycin/etoposide

S S S A S S

110 191 90 16 10 16

28 91 29 5 6 5

26 47 32 33 60 31

51-54 55-59 60-62 61 175 176

Cisplatin/Methotrexate Cisplatin/methotrexate Cisplatin/methotrexate/bleomycin Cisplatin/methotrexate/vincristine Cisplatin/methotrexate/bleomycin/mitoguazone

S S S S

43 41 28 14

32 13 17 9

76 32 61 64

166 177, 178 179 180

Cisplatin/etoposide/doxorubicin

S S A A

15 65 27 25

3 31 13 13

20 48 48 52

181 63 64 65

Cisplatin/5-FU Cisplatin vs. cisplatin/5-FU

S

89

Cisplatin/5-FU/bleomycin Cisplatin/5-FU/vindesine Epirubicin/cisplatin/5-FU vs. 5-FU/doxorubicin/methotrexate Epirubicin/cisplatin/5-FU vs. mitomycin/cisplatin/5-FU Cisplatin/5-FU vs. docetaxel/cisplatin/5-FU Cisplatin/5-FU vs. irinotecan/5-FU Oxaliplatin/5-FU

238 33 21 24 20 35 43 32 274 580 445 333 34

11 36 49 61 33 71 65 49 53 53 21 44 36 32 40

84

S S S S S A S S A A A A A

NS NS 116 20 7 17 13 17 23 16 45 42 26 26 14

78-83 85 86 87 146 88 182 183 91 92 93 94 96

Biomodulation 5-FU/leucovorin Cisplatin/5-FU/leucovorin Cisplatin/5-FU/leucovorin-etoposide 5-FU/interferon 5-FU/interferon/cisplatin 5-FU/interferon/cisplatin 13-cis-Retinoic acid/interferon

S S S A+S A+S S A+S

35 56 38 57 26 45 41

6 27 22 15 13 34 0

17 48.2 58 26 50 76 —

99 100, 102 147 103, 104 105 107, 106 108-110

Cisplatin/Paclitaxel Cisplatin/paclitaxel/5-FU Cisplatin/paclitaxel/5-FU Cisplatin/paclitaxel Cisplatin/paclitaxel Cisplatin/paclitaxel

A S A A A

+S

60 17 32 20 59

29 12 15 11 31

48 71 44 55 52

111 113 114 115 116

40 35 16 15 35 46 10 24 24 20 24 38 115

22 20 3 2 9 12 3 7 3 12 11 11

117 119 66 67 68 69 70 71 72 73 74 75 76

37 26

17 15

54 57 19 13 27 26 30 29 13 60 46 29 34 42 46 58

Agent Bleomycin Cisplatin/bleomycin Cisplatin/vindesine/bleomycin Cisplatin/vindesine/vinblastine/mitoguazone

Cisplatin/Etoposide Cisplatin/etoposide

Cisplatin/5-FU Cisplatin/5-FU/mitomycin Cisplatin/5-FU/doxorubicin Cisplatin/5-FU/doxorubicin/etoposide Cisplatin/5-FU/etoposide

Other Combinations Carboplatin/paclitaxel Cisplatin/irinotecan Bleomycin/doxorubicin Mitomycin/etoposide Paclitaxel/irinotecan Docetaxel/irinotecan (every 3 weeks) Docetaxel/irinotecan (day 1, day 8) Docetaxel/vinorelbine Docetaxel/capecitabine Irinotecan/5-FU Irinotecan/cisplatin versus Irinotecan/5-FU Irinotecan/mitomycin Docetaxel/irinotecan/cisplatin A, adenocarcinoma; NS, not stated; S, squamous cell carcinoma.

A A S A A A A A A S A A A A A

+S +S +S

+S

+S +S +S

No. Responses

77 123

513

514

Section 5 Neoplasms

47-2). One reported preoperative trial of etoposide, doxorubicin (Adriamycin), and cisplatin in esophageal adenocarcinoma reported a response in 52% of patients.63 The combination of cisplatin and etoposide achieved a 48% response rate in 27 patients with advanced adenocarcinoma64 and in 65 patients with advanced squamous cell carcinoma.65 Toxicity was primarily neutropenia.

Non–Cisplatin-Based Combination Chemotherapy There are few combination chemotherapy regimens in esophageal cancer that do not incorporate cisplatin. An early trial of bleomycin in combination with doxorubicin showed relatively modest activity.66 Braybrooke and associates67 investigated the combination of mitomycin C and oral etoposide in patients with advanced adenocarcinoma of the upper gastrointestinal tract. Of 28 evaluable patients, 15 had esophageal or gastroesophageal junction cancers. In this group, only 2 patients (13%) had a major response. More recent non–cisplatin-containing combination trials have explored regimens employing the taxanes and irinotecan. Although these trials have indicated encouraging response rates in the phase II setting, substantial hematologic and diarrheal toxicities of these regimens may not offer an advantage over the older cisplatin-containing regimens. A preliminary report of the combination of paclitaxel at a dose of 225 mg/ m,2 and irinotecan, 100 mg/m,2 administered once very 3 weeks, indicated a response rate of 27% in patients with adenocarcinoma of the gastroesophageal junction.68 Docetaxel has been evaluated in combination with irinotecan in four recent phase II trials. Two trials evaluated irinotecan doses of 100 to 160 mg/m2 and docetaxel, 50 to 60 mg/m2, administered once every 3 weeks; two trials evaluated a day 1 and day 8 schedule of irinotecan, 50 to 55 mg/m2, and docetaxel, 25 to 35 mg/m2, cycled every 3 weeks. The trial with the once-every-3-week schedule, which treated predominantly patients with adenocarcinoma, had response rates ranging from 26% to 30%.69,70 The day 1 and day 8 schedule studies reported a response rate of 29% in 24 patients with previously untreated squamous cell or adenocarcinoma71 and only a 13% response rate in 24 patients with prior therapy for esophageal squamous or adenocarcinoma.72 Hematologic toxicity, which exceeded 50% in patients treated on the once-every-3-week schedule, seemed to be less using the day 1 and day 8 schedule compared with the once-every-3-week schedule, and grade 3 and 4 diarrheal toxicity on both schedules ranged from 13% to 31%. Docetaxel and vinorelbine were evaluated in a phase II trial in 20 patients with squamous cell carcinoma mainly with locally recurrent disease, and a response rate of 60% was reported.73 Docetaxel, 75 mg/m2, every 3 weeks and capecitabine, 1000 mg/m2, twice daily for 14 days were evaluated in a phase II trial of 24 patients with predominantly squamous cell carcinoma of the esophagus. A response rate of 46% was observed.74 Toxicity was mainly hematologic, with 42% of patients experiencing grade 3 or 4 neutropenia. In addition to the irinotecan combination trials with docetaxel described earlier, irinotecan has also been evalu-

ated in combination with continuous infusion 5-FU in recent single-arm and randomized phase II trials in esophageal and gastric cancer. One recent trial evaluated the combination of irinotecan, 180 mg/m2, every 2 weeks combined with bolus 5-FU, 400 mg/m2, leucovorin, 125 mg/m2, and a 48-hour continuous infusion of 5-FU dosed at 1200 mg/m2/day, cycled every 2 weeks.75 The regimen was well tolerated, and a response rate of 29% was reported in patients with esophageal and gastric cancer who had progressed on at least one prior chemotherapy regimen. The tolerability and activity of irinotecan and continuous infusion 5-FU was also reported in a randomized phase II trial in gastric cancer, where the 5-FU combination was compared with irinotecan and cisplatin.76 One hundred fifteen patients with adenocarcinoma of the stomach or gastroesophageal cancer were randomized to receive irinotecan, 80 mg/m2, in combination with leucovorin, 500 mg/m2, and a 22-hour infusion of 5-FU at a dose of 2000 mg/m2, cycled weekly for 6 weeks with a 1-week rest, or to irinotecan, 200 mg/m2, and cisplatin, 60 mg/m2, once every 3 weeks. The irinotecan plus 5-FU arm had a superior toxicity profile, with less hematologic toxicity but slightly more diarrheal toxicity than the irinotecan/cisplatin arm. Response rates were comparable for the 5-FU arm (42%) and cisplatin arm (34%), but the time to progression (6.5 versus 4.2 months) and median survival (10.7 versus 6.9 months) favored the irinotecan and 5-FU combination. Based on these phase II results, a phase III trial (discussed later) compared irinotecan and 5-FU to the combination of cisplatin and 5-FU in gastroesophageal junction and gastric adenocarcinoma. Irinotecan in combination with mitomycin has been reported in a recent phase II trial in esophageal cancer.77 Irinotecan administered at a dose of 125 mg/m2 day 1 and day 8 every 3 weeks was combined with one of two dose schedules of mitomycin: mitomycin, 6 mg/m2, on day 2 or mitomycin, 3 mg/m2, on days 2 and 9, cycled every 3 weeks. Patients with both locally advanced and metastatic disease were treated, and 17 responses were reported in 37 patients (46%).

Cisplatin and 5-Fluorouracil The combination of cisplatin and 5-FU given by continuous infusion for 4 to 5 days has been studied extensively, primarily on the basis of the activity of this regimen in squamous cell carcinoma of the head and neck and with interest waning in the use of bleomycin-containing regimens because of the pulmonary toxicity observed in surgical and radiotherapy protocols. Toxicity observed for the combination of cisplatin and 5-FU, mainly mucositis and myelosuppression, has been substantial but tolerable. Kies and associates78 reported the first use of 5-FU and cisplatin in locoregional squamous cell carcinoma of the esophagus, with 11 major responses observed in 26 patients treated preoperatively with three cycles (42%). The duration of response was indeterminate because most of the patients underwent surgical resection or later received radiotherapy. Subsequent reports have noted similar response proportions in patients predominantly with locoregional disease.79-83 Of a total of 238 patients treated with squamous carcinoma,

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

the majority of whom had locoregional disease and were treated preoperatively or prior to local radiotherapy, 116 (48.7%) showed a major response. Occasionally, pathologically confirmed complete responses have been observed in patients treated preoperatively (14 patients, 7.0%). In the trials of patients with metastatic or unresectable disease, the response to cisplatin and 5-FU has been lower, ranging from 35% to 40%.84,81 Efforts have been made to improve on this regimen by adding other agents. In one study, mitomycin C (6 mg/m2) was added to the cisplatin/5-FU regimen in 33 mostly untreated patients with unresectable or metastatic squamous cell carcinoma and yielded a 61% major response rate.85 Toxicity was reported as mild, yet 46% of patients required a treatment delay. The addition of doxorubicin,86 doxorubicin and etoposide,87 or allopurinol81 to 5-FU and cisplatin in squamous cell carcinoma has shown no significant improvement over cisplatin and 5-FU alone. Similarly, in adenocarcinoma, the addition of etoposide88 or leucovorin with etoposide89 has shown no advantage. Despite the common use in the community of the combination of 5-FU and cisplatin for the treatment of esophageal carcinoma, only one trial has directly addressed the issue of the comparative efficacy of single-agent cisplatin and the combination of 5-FU and cisplatin.84 This phase II study in locally advanced or metastatic squamous cell carcinoma randomly assigned patients to receive either cisplatin (100 mg/ m2) plus continuous infusion 5-FU (1000 mg/m2/day, days 1-5) or cisplatin (100 mg/m2) alone, with both regimens repeated every 3 weeks. The patients in the cisplatin/5-FU arm had a higher response rate (35%) and better median survival (33 weeks) than those in the cisplatin arm (19% and 28 weeks, respectively), but these findings were not statistically significant. Cisplatin/5-FU was also more toxic, with 16% treatment-related deaths for the combination, compared with no such deaths for cisplatin alone. Cisplatin in combination with UFT (an oral 5-FU prodrug combining tegafur with uracil, an inhibitor of the enzyme dihydropyrimidine dehydrogenase which degrades 5-FU) has also been evaluated in esophageal cancer. A response rate of 46% was reported.90 Overall, cisplatin-based combination chemotherapy has significant antitumor activity in esophageal cancer. Most studies have evaluated patients with locally advanced disease with squamous cell carcinoma, with response proportions for metastatic disease consistently lower than for locoregional disease. Activity for cisplatin-based chemotherapy is also noted for adenocarcinoma; however, the trials conducted in this disease have mainly been of preoperative chemotherapy for locoregional, resectable disease. Recent phase III trials have compared the addition of a third agent to cisplatin/5-FU versus cisplatin/5-FU alone or have compared alternative non–cisplatin-containing regimens to cisplatin/5-FU. The Royal Marsden group developed the ECF regimen, a combination of epirubicin, 50 mg/m2, and cisplatin, 60 mg/m2, every 3 weeks in combination with daily protracted continuous infusion 5-FU, 200 mg/m2/day, in gastric cancer. The ECF regimen was compared in a phase III trial in gastric and gastroesophageal junction adenocarcinoma to a bolus regimen of 5-FU, doxorubicin, and metho-

trexate (FAMTX).91 The ECF regimen resulted in a superior response rate (45% versus 21%), failure-free survival (7.4 versus 3.4 months), and median survival (8.9 versus 5.7 months) in comparison with FAMTX. The ECF regimen had a tolerable toxicity profile, with less than 10% rates of grade 3 or 4 diarrhea or stomatitis. A more recent trial treating nearly 600 patients with advanced esophageal squamous and adenocarcinoma and gastric adenocarcinoma compared the ECF regimen with a similar regimen substituting mitomycin, 7 mg/m2, every 6 weeks for epirubicin (Ross et al, 2002).92 This trial validated the previously reported response rate and median survival for the ECF regimen (42%, 9.4 months), but the response rate and median survival observed for the mitomycin combination regimen (44%, 8.7 months) were identical to that of the ECF regimen. Given that there was no difference in efficacy for the epirubicin-containing versus mitomycin-containing arms, this study raises the question of whether the addition of a third agent makes a difference in outcome when combined with cisplatin and protracted-infusion 5-FU. Another concern about the ECF trials is the large percentage of patients treated with locally unresectable, nonmetastatic disease, accounting for 40% of patients treated on both ECF trials. The inclusion of patients with locally advanced disease may lead to inflation of both antitumor response rates and survival, and results from these trials may not be entirely comparable to studies treating only patients with distant metastatic disease. The addition of docetaxel as a third agent added to 5-FU and cisplatin has also recently been reported in a phase III trial of gastroesophageal junction and gastric cancer. 5-FU dosed at 1000 mg/m2 by continuous infusion over 5 days combined with cisplatin, 100 mg/m2, was compared with cisplatin, 75 mg/m2, 5-FU, 750 mg/m2 by continuous infusion over 5 days, and docetaxel, 75 mg/m2 (DCF), in 445 patients with metastatic gastric or gastroesophageal junction adenocarcinoma (Moiseyenko et al, 2005).93 DCF resulted in a higher response rate and time to progression (36%, 5.6 months) compared with 5-FU and cisplatin (26%, 3.7 months), but only a marginal median survival improvement (0.6 month) was noted for three-drug therapy. Toxicity was substantial in both treatment arms, including hematologic and gastrointestinal toxicity, with 82% of patients receiving the three-drug combination experiencing grade 3 or 4 neutropenia. The potential superiority for DCF was underscored by a recent randomized phase II trial comparing the ECF regimen with DCF in gastric and gastroesophageal junction cancer. DCF appeared to result in a superior response rate and time to tumor progression when compared with ECF, but the toxicity, particularly rates of neutropenia and neutropenic fever, was substantial.94 The combination of irinotecan and infusional 5-FU was compared head to head to conventional 5-FU and cisplatin in a recent phase III trial in gastric and gastroesophageal junction cancers,95 based on previous phase II data for the irinotecan combination.76 Irinotecan, 80 mg/m2, in combination with 5-FU, 2 g/m2, over a 24-hour infusion and leucovorin, 500 mg/m2, administered weekly for 6 weeks on and 1 week off, was compared with cisplatin, 100 mg/m2, and 5-FU, 1000 mg/m2 continuous infusion for 5 days, administered

515

516

Section 5 Neoplasms

every 4 weeks, in 333 patients. There was no difference in response rate (26%-32%), time to progression (4.2-5.0 months), or median survival (8.7-9.0 months). However, the toxicity profile significantly favored the irinotecan/5-FU combination, with less neutropenia, neutropenic fever, stomatitis, and nausea. Only the rate of grade 3 or 4 diarrhea was greater in the irinotecan arm. This trial suggests that the regimen of irinotecan and 5-FU may represent a comparably active but potentially better tolerated alternative to 5-FU/ cisplatin. Oxaliplatin as a potential substitute for cisplatin has been explored in single-arm and randomized phase II trials in esophageal and gastric adenocarcinoma. Mauer and colleagues combined oxaliplatin, 85 mg/m2, on day 1, with boluses of 5-FU, 400 mg/m2, and leucovorin, 500 mg/m2, and a 22-hour continuous infusion of 5-FU administered on days 1 and 2, cycled every 2 weeks.96 A response rate of 40% was observed in 34 patients with metastatic squamous cell or adenocarcinoma of the esophagus. The Royal Marsden group has undertaken a 1000-patient phase III trial in esophageal squamous cell and adenocarcinoma and gastric cancer, evaluating the front-line use of oxaliplatin. This trial compares conventional ECF with the substitution of capecitabine for infusional 5-FU and that of oxaliplatin for cisplatin. The trial employs a twoby-two design, with the control arm ECF and the experimental arms including capecitabine, 625 mg/m2 twice daily, substituted for infusional 5-FU, oxaliplatin, 130 mg/m2, substituted for cisplatin, and a fourth arm with a substitution of both capecitabine and oxaliplatin. An interim analysis of the trial results in the first 204 patients treated revealed comparable rates of 5-FU–related toxicities in all the treatment arms and comparable response rates of 31% to 48% across treatment arms.97 Full reporting of the trial after the planned full patient accrual is pending. The recent trials of 5-FU infusion combination chemotherapy indicate improved therapy tolerance and potentially enhanced antitumor activity, employing either a more protracted low-dose infusion of 5-FU as in the ECF regimen or weekly infusions of 5-FU as in the irinotecan/5-FU regimen. The addition of a third agent, including epirubicin or docetaxel, to 5-FU and cisplatin may modestly increase response rates and survival but, in the case of docetaxel combination therapy, result in substantial therapy-related toxicity. The use of relatively high and relatively toxic doses of cisplatin (75-100 mg/m2) is also called into question, given data from the British phase III ECF trials indicating potential better therapy tolerance for 60 mg/m2 without evident compromising of treatment efficacy.

Biomodulation Combination Chemotherapy On the basis of results first reported in colorectal cancer, efforts were made to improve response rates in esophageal cancer with biomodulation therapy. Leucovorin, which enhances the cytotoxic activity of 5-FU by potentiating the inhibition of the enzyme thymidylate synthase, enhances the clinical antitumor response of 5-FU in patients with colorectal carcinoma.98 Alberts and colleagues99 studied leucovorin as a potential biomodulator of 5-FU antitumor activity in

patients with esophageal squamous cell carcinoma who received the Mayo Clinic regimen. Of 35 patients with metastatic or locally advanced squamous cell carcinoma, 6 showed a major response (17%), with a median duration of response of 32 weeks. No improvement was seen in antitumor response compared with the reported experience with single-agent 5-FU. Cisplatin in combination with infusional 5-FU and leucovorin was studied in 56 patients with locally advanced disease who were treated preoperatively or had metastatic disease.100-102 Twenty-seven (48.2%) patients experienced a major response, no different from the results achieved without leucovorin (48.7%). Interferon, another potential biomodulator of 5-FU, has also been evaluated in the metastatic disease setting. Kelsen and associates103 first tested the combination of interferon and 5-FU in patients with locally advanced or metastatic disease. Ten of 37 evaluable patients (27%) had a major response. The response rate was somewhat better in adenocarcinoma (38%) than in squamous cell carcinoma (21%); however, the patient numbers were small. A confirmatory study by Wadler and colleagues104 showed similar results. To improve the response rate, Ilson and coworkers105 added cisplatin to the interferon/5-FU combination in patients with previously untreated metastatic or unresectable esophageal carcinoma. Thirteen of 26 evaluable patients (50%) had a major response. A higher response rate was noted in squamous cell carcinoma (73%) than in adenocarcinoma (33%), although only a small number of patients in this trial12 had squamous cell carcinoma. Toxicity was significant, and two treatment-related deaths occurred. Similar response rates, toxicities, and deaths with this combination were reported by Wadler and associates106 and Pai and colleagues107 in patients with previously untreated squamous cell carcinoma of the esophagus. Others have investigated biomodulation therapy in esophageal cancer with 13-cis-retinoic acid and interferon alfa. Unfortunately, no major responses were seen in a total of 28 patients in three phase II studies of squamous cell carcinoma or in a separate trial of 13 patients with adenocarcinoma.108-110

Taxane-Platinum Combination Therapy Paclitaxel, which had shown significant promise as a single agent, was added to the cisplatin/5-FU regimen in a phase II multicenter study.111 Paclitaxel (175 mg/m2/3 hr, day 1), cisplatin (20 mg/m2, days 1-5), and continuous-infusion 5-FU (750 mg/m2, days 1-5) were given to patients with metastatic or recurrent esophageal cancer on a 28-day treatment cycle without G-CSF support. A 3-hour schedule of paclitaxel was selected on the basis of results of a prior phase I trial reported by Bhalla and associates,112 who had used the regimen in an attempt to reduce myelosuppression and permit the delivery of full doses of 5-FU and cisplatin. Of 60 patients evaluable for response in the multicenter study, 29 patients (48%) had major responses. Similar response rates were seen in patients with adenocarcinoma (46%) and patients with squamous cell carcinoma (50%). The median duration of response was 5.7 months, and the median survival was 10.8 months. As with the DCF trial discussed earlier, toxicity was also severe for

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

the combination of paclitaxel, 5-FU, and cisplatin. Fortyeight percent of patients required a dose attenuation. Half the patients were hospitalized for toxicity, yet there were no treatment-related deaths. An alternative schedule of cisplatin, 5-FU, and paclitaxel has been given to patients with unresectable or metastatic squamous cell carcinoma.113 In this phase I study reported from Spain, paclitaxel was given on day 14 instead of day 1. Paclitaxel dosage was escalated from 135 mg/m2 to 225 mg/ m2, at which point one toxicity-related death occurred. The maximum tolerated dose for paclitaxel was 200 mg/m2. Complete responses were noted in 24% of patients, and partial responses occurred in 47%. Because of the severe toxicity seen with the cisplatin, 5FU, and paclitaxel combination, a U.S. multicenter group initiated a trial of paclitaxel, 200 mg/m2 over 24 hours, and cisplatin, 75 mg/m2, without 5-FU but with G-CSF support.114 Patients with predominantly metastatic disease were treated. In 32 patients, an overall response rate of 44% was seen. Gastrointestinal toxicity was less severe with the elimination of 5-FU from the regimen, but myelosuppression remained significant, with grade 4 neutropenia in 47% of patients and treatment-related deaths in 11%. Two European groups have evaluated a biweekly schedule of paclitaxel and cisplatin. Petrasch and coworkers115 gave 3-hour paclitaxel (90 mg/m2) with cisplatin (50 mg/m2) every 14 days in a phase II trial to patients with unresectable or metastatic disease. Of 20 patients with either adenocarcinoma or squamous cell carcinoma, 40% had a major response, and the complete response rate was 15%. Grade III to IV toxicity was limited to neutropenia (10%) and neurotoxicity (5%). Kok and associates116 reported a phase I trial of cisplatin, 60 mg/m2, and escalating doses of 3-hour paclitaxel without G-CSF support in 31 patients with adenocarcinoma and 28 patients with squamous cell carcinoma. Paclitaxel was increased from 100 mg/m2 to 200 mg/m2. Grade III to IV granulocytopenia was the predominant toxicity, yet sensory neuropathy was dose limiting, with a maximal tolerated paclitaxel dose of 180 mg/m2. Of 58 evaluable patients, 30 (52%) had an objective response, the rates being 53% in those with adenocarcinoma and 50% in those with squamous cell carcinoma. No treatment-related deaths were reported in either trial. Paclitaxel has had limited evaluation in combination with carboplatin in metastatic esophageal cancer. A phase I trial of weekly carboplatin dosed from an AUC of 2 to 5 was combined with a 1-hour infusion of paclitaxel, 100 mg/m2, in 40 patients with advanced esophageal and gastroesophageal junction cancer, with an overall response rate of 54% observed.117 The trial suggests comparable activity for the substitution of carboplatin for cisplatin in paclitaxel combination therapy. The phase III trial of docetaxel added to 5-FU and cisplatin, compared with 5-FU and cisplatin alone, in the treatment of gastroesophageal junction adenocarcinoma and gastric cancer was described previously. Despite a higher response rate and superior time to progression for the addition of docetaxel to 5-FU and cisplatin compared with 5-FU and cisplatin alone, the improvement in median survival was mar-

ginal (0.6 month) and came at the cost of substantial hematologic and nonhematologic toxicity. Alternative dosing and scheduling of these agents, including every-2-week dosing of docetaxel and a shorter infusion schedule of 5-FU, are the subjects of ongoing investigation.

Irinotecan-Cisplatin Combination Therapy On the basis of the promising results observed in lung, colon, and gastric cancer by Japanese investigators, Saltz and colleagues118 developed a regimen of irinotecan, 65 mg/m2, and cisplatin, 30 mg/m2, given weekly for 4 weeks followed by a 2-week rest period. A phase II trial of this regimen was then initiated in patients with previously untreated, metastatic esophageal cancer.119 A 57% response rate in 35 evaluable patients has been observed. Response rates for patients with adenocarcinoma (52%) and with squamous cell carcinoma (66%) were similar. Toxicity was relatively mild, with tolerable myelosuppression and rare grade III diarrhea. On the basis of the favorable experience with the combination of weekly irinotecan and cisplatin, recent trials have evaluated the addition of paclitaxel, docetaxel, 5-FU, and capecitabine in phase I and II trials.120-123 In a recent phase II trial, docetaxel, 30 mg/m2, was combined with irinotecan, 50 to 65 mg/m2, and cisplatin, 25 mg/m2, on a day 1 and day 8 schedule every 3 weeks.123 A response rate of 58% was observed in 26 patients with esophageal and gastric cancer.

Response Rates in Adenocarcinoma and Squamous Cell Carcinoma Generally, it appears that adenocarcinoma and squamous cell carcinoma have overlapping response rates to combination chemotherapy, similar to the experience with non–small cell lung cancer. Few single agents have been tested in both cell types, and the number of patients treated in such studies has been small. Combination chemotherapy trials, incorporating such agents as cisplatin, 5-FU, and paclitaxel, have mostly shown overlapping response rates that are slightly higher in squamous cell carcinoma. An interesting exception is the combination of cisplatin, 5-FU, and interferon. Three trials have shown a remarkably high pooled response rate of 70% (42 of 60 patients) for use of this combination in squamous cell carcinoma but only a modest 33% response rate (5 of 15 patients) in one trial of its use in adenocarcinoma.

TARGETED AGENTS Of great interest is the identification of biochemical markers in tumors that may be predictive of chemotherapy response and resistance. Thymidylate synthase, the enzyme targeted by 5-FU, appears to be a potential marker of chemotherapy response: an increase in expression of thymidylate synthase may lead to resistance to 5-FU in gastroesophageal cancers.124 It is hoped that advances in pharmacogenomics, which is the study of individual patient metabolism of chemotherapy agents, and pharmacogenetics, the germ-line variation of tumor target expression in each patient, will lead to better tailoring of therapy to the individual patient.

517

518

Section 5 Neoplasms

The search for effective antitumor agents in the treatment of esophageal cancer continues, given the modest activity of currently available agents and brief duration of antitumor responses observed. Future strategies in the treatment of esophageal carcinoma will undoubtedly be based on advances in the understanding of the molecular biology of the disease. Ongoing studies indicate a role for numerous oncogenes and tumor suppressor genes in the mechanism of tumorigenesis, and these factors may be important biologic prognostic factors as well as potential targets for the development of new antitumor drugs. Over the past decade, the field of drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. For esophageal squamous cell carcinoma and gastroesophageal adenocarcinoma, potential tumor targets/markers have been described, including those related to growth regulation (epidermal growth factor receptors [EGFR, ERBB2, and Ki67]), angiogenesis (vascular endothelial growth factor [VEGF]), inflammation (COX-2 pathway), cell cycle control (CDKN1A, CDKN2A, cyclin D1), apoptosis (TP53, BAX, and BCL2), metastatic potential (tissue inhibitor of metalloproteinase, E-cadherin) and sensitivity to chemotherapy (p-glycoprotein, thymidylate synthase, glutathione Stransferase, metallothionine, ERCC-1). Most have been studied solely as markers to predict clinical outcomes such as pathologic response after preoperative chemotherapy or chemoradiotherapy.125-130 Multiple targeted therapies for esophageal cancer are in various phase I/II clinical trials, including monoclonal antibodies and signal transduction/tyrosine kinase inhibitors for EGFR, monoclonal antibodies to the ERBB2 receptor and VEGF ligand, oral COX-2 inhibitors, and other novel drugs. Overexpression of EGFR via immunohistochemistry occurs in 30% to 90% of esophageal cancer and correlates with a poor prognosis.125,131-135 Cooperative group and singleinstitution clinical trials exploring the role of cetuximab, ABX-EGF, and EMD7200, recombinant monoclonal antibodies targeting the EGFR, in esophageal cancer included trials in advanced disease and with combined chemoradiotherapy. Tyrosine kinase inhibitors are a class of oral, small molecules that inhibit the adenosine triphosphate binding within the TK domain, which completely inhibits EGFR autophosphorylation and signal transduction.136 Phase II trials with the tyrosine kinase inhibitors erlotinib and gefitinib in esophageal and gastroesophageal junction cancers have been described in abstract form and indicate a 10% rate of response for esophageal adenocarcinoma and squamous cancer.137-140 Of the identified angiogenic factors, VEGF is the most potent and specific and has been identified as a crucial regulator of both normal and pathologic angiogenesis. In particular, bevacizumab combined with combination chemotherapy in advanced colorectal cancer improved overall survival compared to placebo.141 VEGF is overexpressed in 30% to 60% of patients with esophageal cancers, and multiple studies have demonstrated a correlation between high levels of VEGF expression, advanced stage, and poor overall survival in patients undergoing a potentially curative esophagectomy.142-145 Trials combining VEGF-targeted therapy, including bevaci-

zumab, are ongoing or planned in the treatment of both metastatic and locally advanced esophageal cancer.

PALLIATION Most chemotherapy trials in metastatic esophageal cancer report on the response rate of single-agent or combination therapy. Secondary end points in these trials include median patient survival and toxicity of therapy. Few trials reported on either the symptom palliation or the quality of life achieved on these trials. Later studies, however, have included symptomatic relief in response assessment, and, increasingly, quality of life measures are being included in patient assessment of palliative chemotherapy programs. Recent chemotherapy trials have reported significant palliation of patient dysphagia with chemotherapy alone.64,92,114,119 Spiridonidis and colleagues64 treated patients who had unresectable or metastatic esophageal cancer with cisplatin and etoposide. Of 18 evaluable patients with dysphagia, 89% experienced relief of dysphagia within 3 weeks of initiating chemotherapy. Of 25 patients with dysphagia before therapy with cisplatin and paclitaxel, 18 showed complete resolution (72%) and 2 had partial resolution of dysphagia (8%) with chemotherapy. In a trial using a combination of weekly irinotecan and cisplatin, 20 patients had evaluable dysphagia; 14 patients (70%) had complete resolution; and 4 patients (20%) experienced improvement of dysphagia, with improvement occurring after a median of one treatment cycle.119 Quality of life was assessed in this trial as well, with responding patients showing a statistically significant improvement in quality of life as measured by two quality-of-life scales. In a recent phase III trial, Ross and colleagues treated nearly 600 patients with esophageal or gastric cancer with either the ECF regimen or mitomycin combined with cisplatin and 5FU infusion.92 In patients evaluable for dysphagia, in both treatment arms 77% of patients reported improvement in dysphagia symptoms. The rate of dysphagia relief reported in these trials correlated with antitumor response rates, ranging from 40% to 50%. Given the often substantial toxicity of combination chemotherapy used to palliate metastatic disease, symptom relief and quality of life assessment of patients will play an increasing role in the future assessment of the clinical benefit of systemic chemotherapy programs.

NEOADJUVANT CHEMOTHERAPY The use of preoperative chemotherapy in locally advanced esophageal carcinoma has been the subject of numerous trials. Most of these trials were single-arm phase II studies evaluating preoperative chemotherapy given from one to six cycles, followed by a definitive surgical procedure. Later trials, however, have given chemotherapy both preoperatively and postoperatively. Virtually all preoperative chemotherapy trials in esophageal cancer have employed cisplatin-based combination chemotherapy. Earlier trials involved predominantly squamous cell carcinoma but, with the higher incidence of adenocarcinoma, both cell types have been treated with the same preoperative protocols. Preoperative chemotherapy has many potential benefits. These include downstaging of the primary tumor, thereby

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

improving resectability and local control, early treatment of occult micrometastases, and pathologic assessment of response to treatment, which may enable better selection of postoperative therapy. The risks are potential selection of drug-resistant clones and delay in definitive treatment. Early trials combined bleomycin with cisplatin and other agents. Because of the marginal antitumor activity observed for cisplatin and bleomycin, vindesine was added to cisplatin and bleomycin in subsequent trials in squamous cell carcinoma.55,56,58,59 Given the pulmonary toxicity associated with bleomycin, and the limited antitumor activity observed for the combination of bleomycin and cisplatin in preoperative therapy and in metastatic disease, other cisplatin-based combinations were studied in phase II preoperative chemotherapy trials. Cisplatin in combination with mitoguazone and vindesine or vinblastine was studied in two phase II trials.61,62 The combination of cisplatin and 5-FU given by continuous infusion for 4 to 5 days has also been extensively studied in preoperative chemotherapy trials.78,79,82,83 Subsequent trials combined etoposide with cisplatin and 5-FU88 or cisplatin, doxorubicin (Adriamycin), and etoposide63 in adenocarcinoma of the gastroesophageal junction or of the distal esophagus. Other reported series of patients have been treated with preoperative 5-FU and cisplatin in combination with doxorubicin,86 doxorubicin and etoposide,87 etoposide,146 leucovorin,101 leucovorin and etoposide,147 and carboplatin.148 Toxicity observed for these trials (mainly mucositis, myelosuppression, and nephrotoxicity) has been substantial but tolerable. Overall, preoperative chemotherapy with cisplatin-based combination chemotherapy has achieved a major response in 17% to 66% of patients, with pathologically confirmed complete responses in 3% to 10% of patients. Rate of operability after chemotherapy has ranged from 50% to 100%, and the rate of resectability of operated tumors has ranged from 40% to 90%, with the operative mortality after preoperative chemotherapy comparable to that of surgical series alone. These results indicate that the administration of preoperative chemotherapy is safe and without a demonstrably adverse effect on surgical outcome. The overall survival of patients treated with preoperative chemotherapy has been disappointing, however, with a median survival ranging from 10 to 26 months in larger series. An improvement in the percentage of patients achieving long-term survival has been suggested in preoperative chemotherapy trials, with a trend toward better survival in patients manifesting a major objective response to chemotherapy. Whether response to chemotherapy is independent of other favorable prognostic factors is unclear. The duration of chemotherapy delivered in preoperative chemotherapy trials has also undergone evolution. Whereas earlier trials administered only one or two cycles of chemotherapy preoperatively without subsequent postoperative therapy, more recent trials have given up to three or more cycles of preoperative therapy and two or three cycles of postoperative chemotherapy. The treatment outcomes of the earlier and late trials may not be directly comparable, particularly in regard to the impact of additional cycles of systemic therapy on systemic recurrence of disease. Postoperative

radiotherapy was also delivered in some trials, but later trials have not routinely included postoperative radiotherapy. The role of preoperative chemotherapy in the treatment of locoregional esophageal carcinoma can be clearly defined only in the context of random assignment trials with a surgery-only control arm (Table 47-3). Four small randomized trials have compared surgery alone with preoperative chemotherapy and surgery, and a fifth trial compared preoperative chemotherapy with preoperative radiotherapy. Roth and colleagues58 randomly assigned patients to receive preoperative chemotherapy with cisplatin, bleomycin, and vindesine or to undergo surgery alone. Schlag149 randomly assigned patients to undergo surgery alone or to receive three cycles of preoperative chemotherapy with 5-FU and cisplatin. Nygaard and coworkers150 randomly assigned patients to receive either surgery alone, preoperative chemotherapy with cisplatin and bleomycin, preoperative radiotherapy, or preoperative treatment with sequential chemotherapy and radiotherapy. Kok and associates151 randomly assigned patients to two cycles of preoperative etoposide plus cisplatin, with responding patients receiving a total of four cycles. Kelsen and colleagues59 randomly assigned patients to treatment either with preoperative high-dose radiotherapy, 5500 cGy delivered over 5.5 to 6 weeks by a multi-field technique, or with preoperative chemotherapy consisting of cisplatin, vindesine, and bleomycin. Of these four small randomized trials, only one trial demonstrated a survival advantage for preoperative chemotherapy, with Kok and associates151 reporting a median survival advantage for chemotherapy (18.5 months) over surgery alone (11 months). Schlag149 reported no difference in survival between patients receiving 5-FU and cisplatin and those undergoing surgery alone. No survival benefit was conveyed by preoperative chemotherapy in the study reported by Nygaard and coworkers,150 and the patients with the poorest survival at 3 years (5%) had received preoperative chemotherapy. The use of a probably suboptimal chemotherapy regimen may have diminished the effect of chemotherapy in this study. In the trial reported by Kelsen and colleagues,59 a survival comparison between the two treatment groups could not be made because the trial design permitted a postoperative crossover to the other treatment modality and most patients received both chemotherapy and radiotherapy. The actuarial survival rate observed for all patients was 20% at 5 years, superior to that for historical controls, with the subgroup of patients with responses to either chemotherapy or radiotherapy showing a trend toward improved survival. The large American Intergroup Trial (INT) 0113, reported by Kelsen and associates,152 is the most definitive trial to date of preoperative chemotherapy in esophageal cancer. In this landmark trial, 227 patients were randomly assigned to undergo immediate surgery and 213 patients to receive three preoperative cycles of cisplatin and 5-FU, surgery, and two postoperative cycles of cisplatin and 5-FU. The trial showed no benefit for neoadjuvant chemotherapy over surgery alone. Pathologic complete responses to preoperative chemotherapy were rare and occurred in only 2.5% of patients treated. Median survival for patients undergoing surgery alone was

519

520

Section 5 Neoplasms

TABLE 47-3 Esophageal Cancer Preoperative Chemotherapy Phase III Trials

Regimen

Cell Type

Cisplatin/bleomycin/vindesine

S

No. Patients

Resectable Tumors (%)

Operative Mortality (%)

Median Survival (Months)

Survival (%)

Reference

17

35

12

9

25 (3 yr)

19

21

0

9

5 (3 yr)

S

29

71

21

8

—

40

77

12

9

—

S

50

58

15

NS

3 (3 yr)

Surgery

41

69

13

NS

9 (3 yr)

RT 3500 cGy

48

54

11

NS

21 (3 yr)

RT/cisplatin/bleomycin

47

66

24

NS

17 (3 yr)

48

58

11

10

20+

59

12 152

Surgery Cisplatin/5-fluorouracil Surgery Cisplatin/bleomycin

Cisplatin/bleomycin/vindesine

S

RT Cisplatin/5-FU

A+S

Surgery Cisplatin/etoposide

S

Surgery Cisplatin/5-FU Surgery

A+S

48

65

14

213

62

7

14.9

20

227

59

6

16.1

20

74

63

NS

18.5

74

63

NS

11

400

10

10

16.8

43 (2 yr)

402

54

10

13.3

34 (2 yr)

58

149

150

151

153

A, adenocarcinoma; RT, radiation therapy; S, squamous cell carcinoma.

16.1 months compared with 14.9 months for patients receiving chemotherapy, not a significant difference. Overall survival at 2 years (37% for surgery alone versus 35% for chemotherapy) and 5 years (20% for both treatment groups) was also not significantly different for the two patient groups, and there was also no difference in 2-year disease-free survival for either group (20%). Curative resections with negative surgical margins (R0 resection) were equivalent in the two groups (59% for surgery alone and 62% for preoperative chemotherapy), and surgical mortality was also comparable (6% operative mortality for surgery alone and a 7% operative mortality for preoperative chemotherapy). Two percent of patients died of chemotherapy-related complications. A potential renewed interest in the use of preoperative chemotherapy in esophageal cancer has been stimulated by a trial from the Medical Research Council (MRC) in the United Kingdom.153 Larger than the Intergroup trial with nearly twice as many patients entered, the MRC trial compared surgery alone to treatment with two cycles of preoperative 5-FU and cisplatin followed by surgery. A modest improvement in median survival (16.8 versus 13.3 months) and an increase in 2-year overall survival of 9% was observed with the use of preoperative chemotherapy. The larger sample size on this trial may have made possible the detection of a small survival improvement achieved with chemotherapy. Differences in the surgical outcome of the MRC trial and American trials are notable. The MRC trial reported a 10% postoperative mortality rate for both treatment arms compared with only 5% to 6% postoperative mortality in the American trial. In contrast to the U.S. trial, in which there

was no improvement in resection rate after preoperative chemotherapy, the MRC trial reported a 5% improvement in curative resection rate with the delivery of preoperative chemotherapy. Differences in surgical outcome may partly explain the different outcomes between the two trials. The median follow-up on the MRC trial is only 37 months, and more mature follow-up on this trial is required before this therapy can be considered as a standard treatment option. Results of a recent gastric cancer trial also may be relevant. In a trial by Cunningham,154 503 patients were assigned to three cycles of preoperative and three cycles of postoperative epirubicin/cisplatin/5-FU (ECF) or surgery alone. Preoperative chemotherapy resulted in significant improvement in patient survival, with a 6-month improvement in progression-free survival, a 4-month improvement in median survival, and a 13% improvement if 5-year overall survival, all statistically significant. Despite the survival improvement with preoperative and postoperative chemotherapy, there was no improvement in rate of curative resection in patients treated with preoperative chemotherapy compared with surgery alone, and there were no cases of pathologic complete response to preoperative chemotherapy. Because 26% of patients had tumors in the gastroesophageal junction and lower esophagus, the results may apply to locally advanced esophageal cancer. In summary, randomized trials, including a large Intergroup trial, have failed to show a consistent benefit for preoperative chemotherapy. Although early results of a large esophageal and a large gastric trial are encouraging, and the use of pre-

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

operative chemotherapy may confer some survival benefit, the absence of pathologic complete responses to chemotherapy alone and the limited to no improvement in resection rates have engendered more interest in the role of combined chemotherapy and radiotherapy (see later discussion in this chapter). Postoperative chemotherapy allows administration of systemic treatment while avoiding undesired delays in definitive surgery. Delivering it to patients who have already received preoperative therapy is difficult. For example, in INT 0113, only 38% of patients were able to receive the two cycles of postoperative cisplatin/5-FU.152 Postoperative chemotherapy, without preoperative therapy, was studied in three Japanese randomized trials. In these trials, two cycles of chemotherapy, cisplatin/vindesine155,156 or cisplatin/5-FU,157 were given to patients with squamous cell carcinoma. Chemotherapy was well tolerated. Two of the studies showed no benefit for postoperative chemotherapy, but early results of the third trial showed an improvement in improved 5-year disease-free survival for patients receiving two cycles of postoperative cisplatin/5-FU (55% versus 45%, P = .037). The greatest benefit in 5-year disease-free survival favoring adjuvant chemotherapy was in node-positive patients compared with patients with node-positive disease undergoing surgery alone (52% versus 38%, P = .041). The Eastern Cooperative Oncology Group (ECOG) performed a phase II trial of four cycles of postoperative cisplatin/paclitaxel in patients with T3-4 N+ adenocarcinomas of the esophagus, gastroesophageal junction, and cardia.158 The results confirmed the feasibility of the approach. Comparison with historical control suggested an improved survival (60% versus 38% 2-year survival, P = .0008).

PRIMARY RADIOTHERAPY Primary therapy for esophageal cancer is either surgical or nonsurgical. Although the overall results of these approaches are similar, the patient population selected for treatment with each modality is usually different, resulting in a selection bias against nonsurgical therapy.

Radiotherapy Alone Many historical series have reported results of external-beam radiotherapy alone. Most include patients with unfavorable features such as unresectable T4 disease. In the series by De-Ren, 184 of the 678 patients had stage IV disease.184 Overall, the 5-year survival rate for patients treated with radiotherapy alone is 0% to 10%.184-186 Even in the radiotherapy alone arm of the RTOG 85-01 trial where patients received 64 Gy with modern techniques all patients were all dead of disease by 3 years.187,188 There are limited reports of radiotherapy alone for patients with clinical early-stage disease. The trial by Sykes and associates was limited to 101 patients (90% squamous cell carcinoma) with tumors less than 5 cm who received 45 to 52.5 Gy in 15 to 16 fractions. The 5-year survival was 20%.189 Sai and colleagues reported more favorable results in 34 patients with clinical stage I squamous cell cancers treated with external-beam radiotherapy alone (median 64 Gy) or

external-beam radiotherapy (median 52 Gy) plus brachytherapy.190 The 5-year survival was 59%. In summary, radiotherapy alone should be reserved for palliation or for patients who are medically unable to receive chemotherapy. As discussed next, the results of combined modality therapy (CMT) are more favorable and it has become the standard of care.

COMBINED MODALITY THERAPY Standard Approaches There are six randomized trials comparing radiotherapy alone with CMT.187,191-195 Of the six trials, five used suboptimal doses of radiation and three have used inadequate doses of systemic chemotherapy. The only trial designed to deliver adequate doses of systemic chemotherapy with concurrent radiotherapy was the RTOG 85-01 trial (Fig. 47-1).187,193,196 This Intergroup trial primarily included patients with squamous cell carcinoma. Patients received four cycles of 5-FU/ cisplatin. Radiotherapy (50 Gy) was given concurrently beginning day 1 of chemotherapy. The control arm was radiotherapy alone, albeit using a higher dose (64 Gy) than the CMT arm. Patients who received CMT had a significant improvement in median survival (14 months versus 9 months) and 5-year survival (27% versus 0%, P < .0001). With a minimal followup of 5 years, the 8-year survival was 22% (Cooper et al, 1999).196 Histology did not significantly influence the results with 21% of patients with squamous cell carcinomas (N = 107) alive at 5 years compared with 13% of patients with adenocarcinoma (N = 23; P = NS). Although African Americans had larger primary tumors and all were squamous cell carcinomas, there was no difference in survival compared with whites.197 The incidence of local failure as the first site of failure (defined as local persistence or recurrence) was also decreased in the combined modality arm (47% versus 65%). The protocol was closed early due to the positive results; however, following this early closure, an additional 69 eligible patients were treated with the same CMT regimen. In this nonrandomized combined modality group the 5-year survival was 14% and local failure was 52%. The addition of chemotherapy is associated with a higher incidence of toxicity. In the 1997 report of the RTOG 85-01 trial, patients who received CMT had a higher incidence of acute grade 3 (44% versus 25%) and grade 4 toxicity (20% versus 3%) compared with radiotherapy alone. Including the one treatment-related death (2%), the incidence of total acute grade 3+ toxicity was 66%.193 The 1999 report examined late toxicity. The incidence of late grade 3+ toxicity was

RTOG 85-01

5-fluorouracil/cisplatin + 50 Gy

64 Gy

FIGURE 47-1 RTOG 85-01.

521

522

Section 5 Neoplasms

similar in the CMT arm compared with the radiation alone arm (29% versus 23%).196 However, grade 4+ toxicity remained higher (10% versus 2%, respectively). Interestingly, the nonrandomized CMT group experienced a similar incidence of late grade 3+ toxicity (28%) but a lower incidence of grade 4+ toxicity (4%) and there were no treatmentrelated deaths. Based on the positive results from the RTOG 85-01 trial, the conventional nonsurgical treatment for esophageal carcinoma is CMT. This change is reflected in the 1996-1999 U.S. Patterns of Care survey in which only 11% of patients who were treated with radiation as a component of their initial therapy received radiotherapy without chemotherapy.198 In contrast, the 1995-1997 Japanese Patterns of Care survey reported that 60% received radiation without chemotherapy.199 Because the local failure rate in the RTOG 85-01 CMT arm was 47% and the 8-year survival was only 22%, new approaches such as intensification of CMT and escalation of the radiation dose were developed in an attempt to help improve these results.

Intensification of Combined Modality Therapy Neoadjuvant Chemotherapy Phase I/II trials have tested the use of neoadjuvant chemotherapy before CMT using non–5-FU-containing regimens such as paclitaxel/cisplatin200,201 or CPT-11/cisplatin.202 The majority of patients in these trials had adenocarcinoma, and, although optional, most underwent surgery. Bains and associates reported that of 38 patients who presented with dysphagia, 92% had relief after the completion of two cycles of neoadjuvant paclitaxel and cisplatin.200 Similar results have been reported by Ilson and coworkers in 19 patients who received two cycles of neoadjuvant CPT-11 plus cisplatin on weeks 1, 2, 4, and 5 before the start of CMT.202 Treatment was well tolerated with no grade 3+ nonhematologic toxicity, and only 5% of patients required a feeding tube. Of the 16 patients who presented with dysphagia, 81% had dysphagia relief after the completion of neoadjuvant chemotherapy. Another potential advantage of neoadjuvant chemotherapy is the early identification of those patients who may or may not respond to treatment. Ott and colleagues found that the response (as measured by a decrease in standardized uptake volume [SUV]) by fluorodeoxyglucose-labeled positron emission tomography (FDG-PET) 2 weeks after the start of preoperative cisplatin/5-FU/leucovorin in 35 patients with adenocarcinoma of the gastroesophageal junction or stomach was able to predict patients who responded, based on the surgical specimens, to the full course of chemotherapy.203 Weider and associates reported similar findings in 38 patients with squamous cell cancers.204 Although investigational, if the nonresponders can be identified early, changing the chemotherapeutic regimen may be helpful. Although the early trials primarily using 5-FU/cisplatinbased neoadjuvant regimens did not suggest a benefit,59 more recent trials using paclitaxel and CPT-11–based regimens reveal more favorable response rates and rapid improvement of dysphagia.

Intensification of the Radiation Dose Another approach to the dose intensification of CMT is increasing the radiation dose either by intraluminal brachytherapy and/or external-beam radiotherapy. Intraluminal Brachytherapy. Intraluminal brachytherapy has been used both as primary therapy (usually as a palliative modality)205 as well as boost after external-beam radiotherapy or CMT.206 Although there are technical and radiobiologic differences between high dose and low dose rates, there are no clear therapeutic advantages. Trials in which the dose is escalated by combining brachytherapy with either external beam or CMT report similar results to those series without brachytherapy. Calais and colleagues reported a local failure rate of 43% and a 5-year actuarial survival of 18%.207 Even with the more favorable subset of patients with clinical T1-2 disease, Yorozu and associates reported a local failure rate of 44% and a 5-year survival of 26%.208 In the RTOG 92-07 trial, 75 patients (92% with squamous cell cancers) received the RTOG 85-01 combined modality regimen (5-FU/cisplatin/50 Gy) followed by a boost during cycle 3 of chemotherapy with either low dose rate or high dose rate brachytherapy.209 Although the complete response rate was 73%, with a median follow-up of only 11 months, local failure as the first site of failure was 27%. Acute toxicity included 58% grade 3, 26% grade 4, and 8% treatmentrelated deaths. The cumulative incidence of fistula was 18% per year, and the crude incidence was 14%. Of the six treatment-related fistulas, three were fatal. Given the significant toxicity, this treatment approach should be used with caution. Based on this experience, the American Brachytherapy Society has developed guidelines for esophageal brachytherapy.210 For patients treated in the curative setting, brachytherapy should be limited to tumors less than 10 cm with no evidence of distant metastasis. Contraindications include tracheal or bronchial involvement, cervical esophagus location, or stenosis that cannot be bypassed. The applicator should have an external diameter of 6 to 10 cm. If CMT is used, the recommended doses of brachytherapy are 10 Gy in two weekly fractions of 5 Gy each for high dose rate and 20 Gy in a single fraction at 4 to 10 Gy/hr for low dose rate. The doses should be prescribed to 1 cm from the source. Lastly, brachytherapy should be delivered after the completion of external-beam therapy and not concurrently with chemotherapy. In patients treated in the curative setting, the addition of brachytherapy does not appear to improve the results compared with radiotherapy or CMT alone. Therefore, the additional benefit of adding intraluminal brachytherapy to radiation or CMT, although reasonable, remains unclear. External-Beam Radiotherapy CONVENTIONAL FRACTIONATION. Some investigators have advocated CMT regimens using higher external-beam radiotherapy doses. Data from retrospective series suggest improved locoregional control with higher radiation doses.211 Calais and coworkers212 and the INT 0122 trial213 reported that doses of 64.8 to 65 Gy are tolerable. Based on the toler-

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

RTOG 94-05

5-fluorouracil/cisplatin + 50.4 Gy

5-fluorouracil/cisplatin + 64.8 Gy

FIGURE 47-2 RTOG 94-05.

ability of 64.8 Gy in the INT 0122 trial, this higher dose of radiation was used in the experimental arm of the Intergroup esophageal trial INT 0123 (RTOG 94-05). INT 0123 was the follow-up trial to RTOG 85-01. In this trial, patients with either squamous cell carcinomas (85%) or adenocarcinomas (15%) who were selected for a nonsurgical approach were randomized to a slightly modified RTOG 85-01 combined modality regimen with 50.4 Gy versus the same chemotherapy with 64.8 Gy (Fig. 47-2). The INT 0123 was closed to accrual in 1999 when an interim analysis revealed that it was unlikely that the highdose arm would achieve a superior survival compared with the standard-dose arm. For the 218 eligible patients there was no significant difference in median survival (13.0 months versus 18.1 months) or 2-year survival (31% versus 40%) in the high-dose versus standard-dose arm (Minsky et al, 2002).214 Although 11 treatment-related deaths occurred in the high-dose arm compared with 2 in the standard-dose arm, 7 of the 11 occurred in patients who had received less than 50.4 Gy. To help determine if the unexplained increase in treatment-related deaths in the high-dose arm was the factor responsible for the inferior survival rate, a separate survival analysis was performed that included only patients who received the assigned dose of radiation. Despite this biased analysis, there was still no survival advantage with the highdose arm. Although the crude incidence of local failure and/or persistence of local disease (50% versus 55%) and distant failure (9% versus 16%) was lower in the high-dose versus the standard-dose arm this did not reach statistical significance. At 2 years, the cumulative incidence of local failure was 56% for the high-dose arm versus 52% for the standard-dose arm (P = .71). Therefore, based on the INT 123 trial, the standard dose of external-beam radiation remains 50.4 Gy. ALTERED FRACTIONATION. In addition to increasing the total dose, radiation can be intensified by accelerated hyperfractionation. Wang and colleagues randomized 101 patients with squamous cell carcinoma to continuous accelerated hyperfractionated radiation (66 Gy) versus late-course accelerated hyperfractionated radiation (68.4 Gy).215 Compared with patients who received late-course accelerated hyperfractionated radiation, those treated with continuous accelerated hyperfractionated radiation had a significantly higher incidence of grade 3+ esophagitis (61% versus 10%, P < .001) but had no benefit in local control or survival. Zhao and associates treated 201 patients with squamous cell carcinoma using 41.4 Gy followed by late-course accelerated hyperfrac-

tionation to 68.4 Gy.216 The results were similar to those of the RTOG 85-01 (38% local failure and 26% 5-year survival). Choi and associates treated 46 patients with 5-FU/cisplatin and twice-daily radiotherapy using a concurrent boost technique and reported a 37% 5-year survival.217 Although these approaches are reasonable, most series report an increase in acute toxicity without any clear therapeutic benefit. These regimens remain investigational. Split-course radiotherapy is inferior to continuous-course radiotherapy. In a randomized trial from France, 95 patients with squamous cell carcinomas who received continuous course therapy had a significantly higher local control rate (57% vs. 29%), 2-year event-free survival (33% versus 23%), and a borderline significant 2-year survival rate (37% versus 23%).218 NOVEL RADIATION APPROACHES. Based on the more favorable dose distribution of protons, Sugahara and colleagues treated 46 patients (45 with squamous cell) with a combination of protons or combined protons/photons to a median dose of 82 Gy or 76 Gy, respectively.219 Although 23 of 46 patients had T1 disease, the local failure was still 35% and 5-year survival was only 13%. Nutting and colleagues compared two-phase conformal radiotherapy with intensity-modulated radiotherapy (IMRT) in 5 patients who received 55 Gy plus concurrent chemotherapy.220 Treatment plans using both techniques were performed and were compared using dose-volume histograms and normal tissue complication probabilities. The IMRT field using nine equally spaced fields provided no improvement over conformal radiotherapy because the larger number of fields in the IMRT plan distributed a low dose over the entire lung. In contrast, IMRT using four fields equal to the conformal fields offered an improvement in lung sparing. Radiation Field Design and Treatment Techniques. Radiation field design for esophageal cancer requires careful techniques.221 There are a number of sensitive organs that, depending on the location of the primary tumor, will be in the radiation field. These include, but are not limited to, skin, spinal cord, lung, heart, intestine, stomach, kidney, and liver. Minimizing the dose to these structures while delivering an adequate dose to the primary tumor and locoregional lymph nodes requires patient immobilization and CT-based treatment planning for organ identification, lung correction, and development of dose-volume histograms. The integration of other imaging modalities in radiation treatment planning such as esophageal ultrasonography222 and PET223,224 are under active investigation. Comparing PET, ultrasonography, and CT for treatment planning, Konski and associates reported that PET underestimated the tumor length compared with CT and ultrasonography identified more nodes versus both PET and CT.222 Recent studies have examined the effectiveness of PET in the staging of esophageal cancer.223 Following standard staging for esophageal cancer, which included CT and endoscopy, undetected metastatic disease was detected by PET in 15% of patients in the series by Flamen and colleagues225 and 20% in the series by Downey and associates.226 Given the potential for CT to understage metastatic disease, PET should be part of the standard workup for patients receiving CMT.

523

524

Section 5 Neoplasms

As with surgery, the success of radiation treatment is also related, in part, to patient volume. The 1996-1999 U.S. Patterns of Care study of 414 patients (49% with squamous cell carcinomas) treated with a component of radiotherapy at 59 institutions reported that, by multivariate analysis, there was a significant improvement in survival in those patients treated at centers where more than 500 versus fewer than 500 new cancer patients were seen each year.198

New Chemotherapeutic Agents Because 75% to 80% of patients die of metastatic disease, advances in systemic therapies are necessary. The most widely used regimen combined with radiation has been 5-FU and cisplatin. There are new chemotherapeutic agents in both current practice and development. Most are being developed as preoperative regimens and are combined with radiation doses of 45 to 50.4 Gy. These include both cytotoxic and targeted small molecules. Paclitaxel-200,201,227 and docetaxel-228 based CMT regimens have shown encouraging results. The RTOG randomized phase II trial E-0113 compares paclitaxel plus cisplatin, with/or without 5-FU. Other agents such as irinotecan,202,229,230 trastuzumab (Herceptin),231 and oxaliplatin,232,233 are being used as platforms for new regimens. Ongoing trials are testing the combination of radiotherapy, irinotecan/cisplatin, plus bevacizumab or cetuximab. Whether these investigational approaches will offer improved results compared with conventional 5-FU/cisplatin-based CMT regimens is not known. The development of the ideal regimens and schedules remains an active area of clinical investigation.

Predictors of Response to Combined Modality Therapy Berger and colleagues reported that in patients receiving preoperative CMT, a complete response was associated with a significant improvement in survival.234 Therefore, it would be helpful to predict those tumors that have a higher likelihood of responding to CMT. Unfortunately, most studies have limited numbers of patients and the results are conflicting. Markers such as BCL2L1,235 TP53,236 membrane phospholipids,237 CDC25B,238 Ki-67, EGFR, cyclin D1, VEGF, MVD, thymidylate synthase, dihydropyrimidine dehydrogenase and glutathione S-transferase,239,240 lymphocytic infiltration,241 and ERBB2242 have been correlated with response and/or outcome. With the further discovery and understanding of various tumor suppressor genes, in the future, molecular markers may be helpful in selecting treatment. There are conflicting data regarding the ability of imaging to predict response or outcome. Kalha and colleagues found that post-treatment endoscopic ultrasonography did not accurately predict the pathologic response after CMT,243 whereas Lim and coworkers reported that response was the most significant predictive factor for survival.244 Brink and colleagues reported that the change in SUV from pretreatment to post-treatment FDG-PET did not correlate with the pathologic response after preoperative CMT.245 Weider and associates found that changes in metabolic activity measured by PET 14 days after starting CMT in patients

with squamous cell cancers correlated with tumor response and patient survival.204

Is Surgery Necessary After Combined Modality Therapy? Most phase II trials reveal that patients who respond to preoperative CMT have a corresponding improvement in outcome.234,246 However, whether surgery is necessary after CMT has been examined in two randomized trials. In the FFCD 9102 trial, 445 patients with clinically resectable T34 N0-1 M0 squamous cell or adenocarcinoma of the esophagus received CMT. The randomization was limited to patients who responded to initial CMT. Patients initially received two cycles of 5-FU, cisplatin, and concurrent radiation (either 46 Gy at 2 Gy/day or split course 15 Gy weeks 1 and 3) (Bedenne et al, 2002).247 The 259 patients who had at least a partial response were then randomized to surgery versus additional CMT, which included three cycles of 5-FU, cisplatin, and concurrent radiation (either 20 Gy at 2 Gy/day or split course 15 Gy). There was no significant difference in 2-year survival (34% versus 40%, P = .56) or median survival (18 months versus 19 months) in patients who underwent surgery versus additional CMT. The data suggest that for patients who initially respond to CMT, patients should complete CMT rather than stop and undergo surgery. Using the Spitzer index, there was no difference in global quality of life, but a significantly greater decrease in quality of life was observed in the postoperative period in the surgery arm (7.52 versus 8.45, P < .01, respectively).248 The German Oesophageal Cancer Study Group compared preoperative CMT followed by surgery versus CMT alone (Stahl et al, 2005).249 In this trial, 172 eligible patients younger than age 70 years with uT3-4 N0-1 M0 squamous cell cancers of the esophagus were randomized to preoperative therapy (three cycles of 5-FU, leucovorin, etoposide, and cisplatin, followed by concurrent etoposide, cisplatin, plus 40 Gy) followed by surgery versus CMT alone (the same chemotherapy but the radiation dose was increased to 60 to 65 Gy ± brachytherapy). Despite a decrease in local failure for those who were randomized to preoperative therapy followed by surgery versus CMT alone (36% versus 58%, P = .003) there was no significant difference in 3-year survival (31% versus 24%).

Palliation of Dysphagia Dysphagia is a common problem in patients with esophageal cancer. Not only is it the most frequently presenting symptom, but it can remain a problem up to the time of the patient’s death. Coia and colleagues reported that within 2 weeks after the start of CMT 45% had improvement in dysphagia and by the completion of the 6th week, 83% had improvement.250 Overall, 88% had an improvement in dysphagia with a median time to maximum improvement of 4 weeks. Histology and stage had no impact of the rate of palliation. Harvey and colleagues treated 106 patients and reported that 51% maintained improved swallowing until the time of last follow-up or death.251 Intraluminal brachytherapy is also an effective, albeit more limited, method of achieving

Chapter 47 Chemotherapy and Radiotherapy as Primary Treatment of Esophageal Cancer

palliation of dysphagia in 40% to 90% of patients.252,253 In a randomized trial from the Dutch SIREC Study Group of stent versus one 12-Gy fraction of brachytherapy, dysphagia, as measured by a variety of quality of life scales, improved more rapidly after stent placement; however, long-term relief was superior after brachytherapy.205 Median survivals were similar (145 versus 155 days).

Acute and Long-Term Toxicity of Radiotherapy There are limited toxicity data in patients who received conventional doses of radiotherapy. Patients will experience lethargy and esophagitis beginning 2 to 3 weeks after the start of radiation; these symptoms usually resolve 1 to 2 weeks after the completion of therapy. The most carefully documented acute toxicity data in patients receiving CMT were reported in the RTOG 8501187,188 and 94-05 trials and were previously discussed.214 The effect of radiation on pulmonary function was examined by Gergel and associates.254 Patients received 39.6 Gy with anteroposterior fields followed by oblique fields to a total dose of 50.4 Gy plus concurrent oxaliplatin and 5-FU. Pulmonary function tests performed both before radiotherapy and a median of 16 days after radiotherapy revealed significant declines in DLCO and total lung capacity. Lee and associates reported that 18% of 61 patients treated with preoperative CMT had pulmonary complications.255 The incidence was significantly increased in patients with V10 greater than 40% versus less than 40% (35% versus 8%, P = .014) and V15 greater than 30% versus less than 30% (33% versus 10%, P = .036).

Radiation Treatment in the Setting of a Tracheoesophageal Fistula The presence of a malignant tracheoesophageal fistula is an unfavorable prognostic feature. Although the experience is very limited, data from the Mayo Clinic suggest that radiation does not necessarily increase the severity of a malignant tracheoesophageal fistula and it may be administered safely. A total of 10 patients with a malignant tracheoesophageal fistula received 30 to 66 Gy of external-beam radiation; the median survival was 5 months, and none experienced an enlarging or more debilitating fistula after radiotherapy.256

SMALL CELL CARCINOMA Small cell carcinoma of the esophagus is an uncommon histologic subtype of esophageal carcinoma, with fewer than 100 cases reported in the literature. The incidence ranges from less than 1% to 3% of cases of esophageal cancer diagnosed.257-259 Staging of small cell carcinoma of the esophagus is similar to that of small cell carcinoma of the lung, with limited-stage disease defined as locoregional disease with or without local regional lymph node involvement. Extensivestage disease is defined as distant metastatic disease outside the locoregional area. As in small cell carcinoma in the lung, there is a clear association between development of the disease in the esophagus with tobacco use, and distant metastatic disease is frequently present at diagnosis. Also, like small cell cancer of the lung, esophageal small cell carcinoma

appears to be highly responsive to radiotherapy and to a broad spectrum of chemotherapeutic agents.257,260 The almost universal development of metastatic disease in small cell carcinoma of the esophagus has led to the general acceptance of chemotherapy as part of CMT in the treatment of small cell carcinoma of the esophagus. However, despite treatment of limited-stage disease with a combination of chemotherapy and surgery and/or radiotherapy, reports of long-term survivors with small cell carcinoma of the esophagus are anecdotal. Median survival of patients with small cell carcinoma of the esophagus ranges from 3 months to 7.5 months. For local control of disease, it seems more logical to use radiotherapy rather than to subject the patient to the risks associated with esophagectomy. However, the appropriate role of surgery or radiotherapy for control of the primary tumor remains to be established.

COMMENTS AND CONTROVERSIES This chapter provides an exhaustive and very detailed overview of the numerous existing pilot studies, trials, and protocols to treat cancer of the esophagus. It is the reflection of the difficult, painstaking, often frustrating pursuit to improve the results of the treatment of cancer of the esophagus and gastroesophageal junction. The common denominator is the search to improve the dose-responsetoxicity relationships. The variety of available drugs used in monotherapy or by combining different drugs, the dose variations, the modalities of administering the drugs, and the combinations of drugs with different radiotherapy regimens result in an almost insurmountable difficulty in interpreting the real value of all those data. However, whatever regimen is used, the higher the administered dose, the higher the response, be it often, if not always, at the price of higher toxicity and thus higher risk for treatment-related morbidity and mortality. Another source of concern relates to the definition of response, in particular, complete response. It is well known from final pathology reports after esophagectomy following induction therapy that a substantial number of clinically complete responders still have viable tumors in the resected specimen. This, of course, questions the actual enthusiasm to use FDG-PET as a predictor of complete response in trials aiming at definitive chemoradiotherapy without subsequent surgery. This is well illustrated by high incidence of locoregional relapse as seen in the trial by the German Oesophageal Cancer study group. So-called rescue or salvage surgery in such cases only adds up to the frustrations for both the patient and the surgeon because often the resection will be incomplete if not impossible. For patients who have an oncologically incurable cancer or who are medically unfit for a treatment with curative intent, palliation of symptoms, offering, if possible, a prolonged survival is the first goal. Physicians who are responsible for the care of such patients must accept the obligation to ensure that palliation occurs early and effectively, to guarantee the best quality of life for the remaining limited lifespan. In such a setting cost-benefit considerations may play an important role. Relief of dysphagia, odynophagia, and malnutrition and, if possible, prolonged survival with good quality of life are the essentials of any program of palliation. Depending on the physical condition as well as the available expertise, as described in this chapter, a wide range of therapeutic modalities can be utilized

525

526

Section 5 Neoplasms

to deal with this often extremely complex and difficult aspect of the terminal phase of obstructive esophageal cancer. T. L.

KEY REFERENCES Bedenne L, Michel P, Bouche O, et al: Randomized phase III trial in locally advanced esophageal cancer: Radiochemotherapy followed by surgery versus radiochemotherapy alone (FFCD 9102). Proc Am Soc Clin Oncol 21:130a, 2002. Cooper JS, Guo MD, Herskovic A, et al: Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA 281:1623-1627, 1999. Minsky BD, Pajak T, Ginsberg RJ, et al: INT 0123 (RTOG 94-05) phase III trial of combined modality therapy for esophageal cancer:

High dose (64.8 Gy) vs. standard dose (50.4 Gy) radiation therapy. J Clin Oncol 20:1167-1174, 2002. Moiseyenko VM, Ajani J, Tjulandin SA, et al: Final results of randomized controlled phase III trial (TAX 325) comparing docetaxel combined with cisplatin and 5-fluorouracil to CF in patients with metastatic gastric adenocarcinoma [Abstract 4002]. Proc Am Soc Clin Oncol 23:308, 2005. Ross P, Nicolson M, Cunningham D, et al: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996-2004, 2002. Stahl M, Stuschke M, Lehmann N, et al: Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23:2310-2317, 2005.

chapter

48

PALLIATION OF ESOPHAGEAL CANCER Virginia R. Litle Neil A. Christie

Key Points ■ Self-expanding metal stents provide rapid relief from dysphagia. ■ Lasers

control bleeding and relieve proximal esophageal obstruction. ■ Thermal Nd:YAG laser provides rapid palliation. ■ PDT laser provides the best hemostasis. ■ All endoscopic therapies are complementary.

The incidence of esophageal adenocarcinoma has been increasing during the past two decades, and about 15,560 new cases will be diagnosed in the United States in 2007.1 The overall survival from esophageal cancer is dismal at 5% to 10%, and less than half of the patients will be eligible for potentially curative resection at time of presentation. Most often patients present with dysphagia and weight loss; thus, the majority of patients may be candidates for palliative interventions to improve their swallowing, allow adequate oral intake, and reduce the risk of aspiration pneumonia. The goals of palliation are a return to oral intake, ease of treatment, and short hospital stay. Not all patients presenting with malignant dysphagia need palliative interventions; for example, patients with dysphagia but minimal nutritional deficits and operable disease may be candidates for immediate surgical resection. Patients with malignant dysphagia who are candidates for chemotherapy or chemoradiation therapy frequently respond to therapy and will not need initial interventions for dysphagia. However, depending on the degree of dysphagia, the presenting limitations in oral intake, and the performance status of the patient, a significant number of patients may need endoscopic interventions designed to improve oral intake and nutritional status as the first step in their treatment algorithm. Most endoscopic therapies vary considerably in their durability but share in common a fairly brisk initial improvement in dysphagia. After improvement in oral nutrition, performance may improve and other therapies may be tolerated. In this chapter we review all the commonly employed methods for endoscopic palliation of malignant dysphagia. In general, these methods deliver rapid relief and allow intake of a soft to regular diet with some modifications depending on the individual. Some limitations in oral diet will still be required, but most patients will be able to avoid the need for enteral nutrition. The durability of the relief of dysphagia is variable, depending on the method used and the progression of the disease at the locoregional level. Many patients who live longer than a few months will need some form of rein-

tervention to maintain relief. On occasion, in a patient with very good performance status with incurable disease, esophagectomy may be indicated for palliation when other interventions fail. In our practice, advances in endoscopic palliative modalities have made this unusual.

ESOPHAGEAL DILATION Malignant esophageal dysphagia can be relieved immediately to some degree with dilation by a bougie or a balloon. If this is the only therapy, recurrent dysphagia will occur in almost all patients within 1 or 2 weeks. However, it is apparent that some temporary relief is obtained and may allow improvement of oral intake for a short period of time while other therapies are initiated. Bougies produce both radial and longitudinal forces to the esophagus, whereas a balloon dilator produces only a radial force. In either case, we perform endoscopy with fluoroscopy and a guidewire to confirm safe placement of the balloon or bougie across the tumor. When dilation is followed by rapid initiation of externalbeam radiation therapy, up to 75% of patients in a small series showed improvement in dysphagia, and approximately 50% needed no additional therapy for dysphagia.2 When the esophageal lumen is very narrow, expandable metal stent placement without initial dilation may lead to stent infolding and an initial dilation may be indicated. Similarly, after expandable metal stent placement, careful balloon dilation may facilitate immediate expansion. Overzealous dilation, however, may lead to a less snug fit of the stent and early migration. Pneumatic dilation or bougienage is often used before and after laser therapy. For neodymium:yttrium-aluminum-garnet (Nd:YAG) laser therapy the esophagus is dilated to allow passage of the endoscope and laser fiber. Dilation may also be performed before photodynamic therapy (PDT) to allow better visualization of the distal extent of tumor and after PDT treatment to aid in the débridement of necrotic tumor. Complications after esophageal dilation range from minor (pain and fever) to major (risk of perforation). Although risk of perforation is uncommon in experienced hands, the endoscopist should have a low threshold for further diagnostic studies, such as barium esophagography, to rule this out, in particular in the patient with excessive pain or pneumomediastinum, pneumoperitoneum, or a pneumothorax after dilation. If there is no leak, the patient should be started on clear liquids for 24 hours, followed by a soft diet as tolerated. In some cases, if the perforation is minor and contrast agent shows no or minimal extravasation, with good drainage into 527

528

Section 5 Neoplasms

the esophageal lumen, patients can be conservatively managed and treated with antibiotics and nothing by mouth for a short period of observation. In some cases, immediate deployment of a covered, expandable metal stent will seal more substantial leaks. It is imperative that an experienced thoracic surgeon evaluates these patients, because, even in the era of covered expandable stents, surgical intervention may be indicated for perforations.

STENTS Esophageal intubation to relieve malignant dysphagia historically involved placing a plastic tube via either a per oral pulsion or an open traction technique, which required a laparotomy and gastrotomy. General anesthesia was necessary for both approaches. In a large series of 400 patients, esophageal intubation improved dysphagia in 80% of patients but was associated with a 3% mortality rate. Complications included food impaction, migration, and perforation in up to 10% of patients.3 With the advent of the self-expanding metal stent (SEMS) during the past decade, endoscopic palliation is now easier and associated with fewer complications, such as perforation and migration. A SEMS can be placed via upper endoscopy with fluoroscopic guidance and does not require general anesthesia. Aspiration precautions should be followed. One of the earlier reports on the SEMS involved placing a Wallstent, which was originally designed for vascular stenosis. In this small series, the endoluminal tumor was partially obliterated with laser and then the SEMS was placed with safe and effective results.4 In a small randomized trial comparing plastic stents to expandable metal stents the improvement in dysphagia scores were similar; however, there were no early complications in the metal stent group versus 20% early morbidity and 16% mortality in the plastic stent group.5 After this early experience with expandable metal stents for the relief of malignant dysphagia, multiple large series have been reported and are summarized in Table 48-1 (Christie et al, 2001).6-10 Immediate palliation of dysphagia occurs in greater than 85% of patients when evaluated with a standard dysphagia scoring system.6 Over 80% of the patients in these series who required enteral or parenteral nutritional support were able to discontinue this after stent placement. Failure of the stent to immediately relieve dysphagia typically results from poor stent expansion or malpo-

sition and, in larger series, in experienced hands occurs in less than 10% of cases. If this occurs, depending on the design of the expandable metal stent, the stent may be removed and replaced with a more appropriate size or the patient may be offered another endoscopic option such as PDT. The risk of perforation occurring during removal of a SEMS depends on the type of stent, the duration it has been in place, the severity of endoscopic obstruction, and the experience of the endoscopist. There are several types of expandable metal stents, and all share many features but have minor design modifications, which may offer advantages of one over the other. The Wallstent (Boston Scientific, Boston, MA) and Z-stent (Cook, Bloomington, IN) are composed of stainless steel in either a mesh or zigzag design. Both are released with a sheath and pusher rod mechanism. The Ultraflex SEMS (Boston Scientific, Boston, MA) is a knitted nitinol stent deployed with the removal of a suture. After deployment, typical stent diameter ranges from 18 to 23 mm and stent length is 7 to 15 cm. The high radial force of SEMS may result in postoperative pain, which is usually mild and transient. In unusual cases it may persist and require removal. A SEMS is available covered or uncovered. The covered stents reduce tumor ingrowth except at the ends, which are uncovered to reduce stent migration. When tumor ingrowth of the stent occurs or overgrowth at the end of the stent occurs, additional stents can be applied or Nd:YAG laser or PDT laser can be used to ablate the tumor. Thermal laser may be limited in these situations because the laser can damage the stent itself. Some of the newer designs of expandable metal stents (Alveolus Inc., Charlotte, NC) offer fulllength coverage with options for more stable esophageal wall contact that may minimize migration yet allow full-length coverage. In our practice, we use a combination of endoscopic and fluoroscopic guidance to measure the length of esophageal obstruction before deploying the expandable metal stents. After adequate seating in the esophagus, the intrinsic radial force of the most expandable metal stents leads to continued expansion to its maximal diameter, depending on the severity of the obstruction. Thus, if a stent appears patent but not open completely on initial placement, the clinician can re-endoscope the patient the next day or obtain a barium esophagogram to see if the stent has expanded fully. Poor initial stent deployment, especially with significant infolding, may indicate an improper stent diameter

TABLE 48-1 Self-Expanding Metal Stents for Malignant Esophageal Obstruction: Outcome From Several Series Author (Year)

No. Patients

Christie et al6 (2001)

100

85

47

100

17

216

NA

29

Xinopoulos et al (2004)

78

100

11-14

Yang et al10 (2005)

66

100

3-18

Tomaselli et al7 (2004) Homs et al8 (2004) 9

NA, not available.

Immediate Relief of Dysphagia (% of Patients)

Complications (% of Patients) 0-33

Chapter 48 Palliation of Esophageal Cancer

TABLE 48-2 Complications of Self-Expanding Metal Stents Major

Frequency (%)

Minor Complications

Frequency (%)

Death

0

Tumor ingrowth or overgrowth

4-33

Perforation

1-3

Migration

0-10

Airway compression

<1

Food impaction Bleeding Reflux Chest pain

8 0-6 11 <2

Data from Therasse E, Oliva VL, Lafontaine E, et al: Balloon dilation and stent placement for esophageal lesions: Indications, methods, and results. Radiographics 23:89, 2003; and Christie NA, Buenaventura PO, Fernando HC, et al: Results of expandable metal stents for malignant esophageal obstruction in 100 patients: Short-term and long-term follow-up. Ann Thorac Surg 71:1797, 2001.

or length. Immediate intervention, such as gentle dilation, or even stent removal may be necessary if an obvious failure is observed. Complications from stent placement can occur early or late. The early complications include aspiration pneumonia during the procedure, esophageal perforation, malpositioned stent, airway compression and compromise with mid to upper esophageal stents, persistent obstruction, and pain. Late complications include intractable reflux, stent obstruction, or migration. The risk of delayed perforation or erosion into adjacent structures is rare but has been described (Christie et al, 2001).6 The major and minor complications of SEMS are outlined in Table 48-2. Delayed removal or repositioning of expandable esophageal stents is generally avoided but in experienced hands has been done. The obvious risk is esophageal trauma with the potential for esophageal perforation. In summary, expandable metal stents provide rapid improvement in malignant dysphagia, allowing patients a short or no hospital stay and improved quality of life. The need for reintervention is common in patients who live longer than a few months. In these cases, a careful investigation of the causes for stent failure should be made to determine if additional dilation, stent placement, or laser therapy may be indicated to provide continued relief of obstruction.

NEODYMIUM:YTTRIUM-ALUMINUMGARNET LASER TREATMENT Thermal laser therapy for esophageal cancer was initially described in 1982 and involved use of argon or Nd:YAG lasers (Overholt, 1992).12 The Nd:YAG laser has since been proven to be more effective than the argon laser but suffers from some technical limitations and a perforation rate as high as 7% to 10%. PDT was approved by the U.S. Food and Drug Administration in 1996 for the treatment of malignant dysphagia and has a low perforation rate (1%) and is more durable than Nd:YAG laser ablation. Thermal laser remains a useful tool for ablating the unusual bleeding esophageal tumor acutely. The Nd:YAG laser uses a wavelength of 1064 nm. For both bleeding and obstructing esophageal lesions, 50 to 90 W is used with a pulse duration of 0.3 to 1.0 second. The greatest risk with thermal laser use

TABLE 48-3 Thermal (Nd:YAG) Laser Treatment for Relief of Malignant Esophageal Obstruction

No. Patients

Author (Year)

Immediate Relief of Dysphagia (%)

Average Survival After Treatment (mo)

Loizou et al13 (1991)

43

95

6.1

Angelini et al14 (1991)

34

89

NA

20

90

5.3

118

48

4.6

15

Carter et al

(1992) 16

Lightdale et al

(1995)

NA, not available.

is esophageal perforation, which can occur directly from the laser or with concurrent dilation. The laser treatment often begins with esophageal dilation either with a pneumatic balloon or Savary dilator with a guidewire and fluoroscopic guidance. The general concept is to work off the luminal surface of the tumor to minimize the risk of perforation. The tumor is then circumferentially ablated with the endoscopically placed Nd:YAG laser in a point-by-point method. Depending on the length of the endoluminal tumor, Nd:YAG can be more time consuming than PDT as the nonthermal laser diffuser probe allows administration of light over a greater surface area. Tumors with a significant component of extraluminal mass may fail laser therapy due to extrinsic compression and may be better palliated with an expandable metal stent. Several series comparing Nd:YAG laser with other palliative therapies are summarized in Table 48-3 (Lightdale et al, 1995).13-16 One study comparing thermal laser to esophageal stenting found similar relief in dysphagia and survival, but the dysphagia relief lasted significantly longer in the lasertreated group in whom the patients had significant gastric involvement.13 The main complication of Nd:YAG laser therapy is esophageal perforation, which occurred in 7% of 118 patients in a randomized multicenter trial of patients undergoing PDT versus Nd:YAG therapy for palliation of esophageal cancer. Esophageal dilation had accompanied laser therapy in half of the perforation cases. Fever, nausea, and postoperative

529

530

Section 5 Neoplasms

respiratory insufficiency are all potential perioperative morbidities of the laser treatment (Lightdale et al, 1995).16 Fistulas and strictures occur as late complications in 10% of patients.17 Thermal laser therapy may be valuable in cases where a stent cannot be placed easily such as in the cervical esophagus where proximal airway compression or obstruction may result from the stent. Distal esophageal stents placed across the gastroesophageal junction can result in significant reflux, and laser therapy may minimize this problem. In some patients PDT is also an excellent option but has its own set of limitations.

PHOTODYNAMIC THERAPY Photodynamic therapy is a nonthermal laser process using selective endoscopic delivery of light with a specific wavelength to activate a photosensitizing agent that results in tumor ablation and restores endoluminal patency. Currently, PDT is primarily performed with Photofrin, a hematoporphyrin derivative with a light activation wavelength of 630 nm. The depth of penetration and tumor necrosis after PDT is limited to 5 mm. This provides a safety factor in minimizing risk of esophageal perforation but also can limit its effectiveness for large bulky tumors, especially when significant extrinsic compression is present. Full-thickness perforation can occur, but in our series of 215 patients from the University of Pittsburgh, esophageal perforation occurred in only 5 patients (1.5%) (Litle et al, 2003).18 Balloon dilation was performed before PDT to allow passage of the endoscope through the obstructing tumor. It was unclear whether the mechanical dilation of the esophagus, the use of PDT, or a combination of the two factors contributed to this complication. In the same series of 215 patients, esophageal stricture after PDT occurred in only 1.5% of patients. This rate of stricture formation is low compared with that seen when PDT is used as curative treatment, where the stricture rate may be as high as 50%, probably due to a significant degree of light exposure to normal surrounding esophageal mucosa when treating high-grade dysplasia or small mucosal tumors (Overholt 1992).12 This low rate of stricture after PDT for palliation may be explained by the fact that less normal esophagus is exposed to the laser light when a bulky tumor is present, and most of our patients underwent dilation as part of the post-PDT débriding session on the second day of PDT treatment. The combination of radiation therapy, chemotherapy, and PDT typically increases the risk of stricture formation. Whether a true PDT-induced stricture or tumor progression resulting in luminal narrowing occurs is sometimes difficult to ascertain. Ideal candidates for palliative PDT have locally advanced esophageal carcinoma with primarily endoluminal disease and minimal stricture or extrinsic compression. The overall advantages of PDT for treating locally advanced esophageal cancer include improvement in malignant dysphagia within days of treatment, minimal pain, and, in some cases of gastroesophageal junction tumors, less reflux; and in cases of high cervical esophageal obstruction, there is less concern over tracheal compression resulting from stent expansion of

the cervical esophagus. The main disadvantages include the skin photosensitivity in patients with a limited life expectancy, the costs of specialized equipment and the photosensitizing agent, and limitations in efficacy when significant, bulky, extrinsic compression is present. In our experience, if the patient survives longer than 2 months after PDT, there is a 20% reintervention rate with PDT, SEMS, or Nd:YAG to relieve recurrent obstruction.

BRACHYTHERAPY Endoluminal brachytherapy with high dose rate radiation is another modality to locally ablate obstructing esophageal cancer. The benefits are good tumor response, but the risks include stricture and fistula formation. Patients typically return for several treatment fractions over 2 to 3 weeks to obtain the full treatment dose. In addition, brachytherapy requires specialized staff and expensive delivery equipment with limited availability. For each treatment the patient undergoes esophageal dilation and placement of the after-loading catheter. Afterward they are transported to the brachytherapy delivery room, where the catheter is loaded and approximately 500 cGy is administered, which penetrates to a depth of 0.5 to 1 cm. The patient must be able to sit alone in the brachytherapy unit while the radiation is administered. Contraindications to the procedure include the presence of an esophageal fistula because this is a known potential complication of the procedure. Other complications include perforation and stricture formation, the latter of which can be treated successfully with dilation. In a prospective randomized trial comparing brachytherapy and laser ablation for palliation of esophageal cancer by Low and colleagues (1992) (Low and Pagliero, 1992),19 overall dysphagia scores improved in 83% of patients and were maintained in 75% of patients at 2-month follow-up. Thirty percent of the brachytherapy patients had transient post-treatment dysphagia, for which the authors recommended inpatient observation after treatment. Temporary chest pain and fever occurred in approximately 16% of patients treated with brachytherapy or Nd:YAG laser. Both brachytherapy and laser treatment had a low rate of complications while improving dysphagia significantly. The only perforation was small and contained and occurred in the laser group.

CHEMORADIATION THERAPY Palliation of malignant dysphagia with radiation therapy alone requires 4 to 6 weeks for improvement in swallowing (Siersema et al, 1998).20 The addition of chemotherapy to a 3-week course of external-beam radiation (35-40 Gy) results in significant improvement in malignant dysphagia, as demonstrated in a large recent study by Harvey and colleagues (Harvey et al, 2004).21 Treatment regimens included a combination of 5-fluorouracil, cisplatin, and paclitaxel. Of 102 patients available for dysphagia scoring after treatment, 78% had an improvement in at least one grade of the dysphagia scoring system. The minor complication rate was low and included radiation pneumonitis and infections. There was a

Chapter 48 Palliation of Esophageal Cancer

6% treatment-related mortality rate. The median time to improvement was 6 weeks after the start of chemoradiation therapy. Part of the delay to clinical improvement is undoubtedly related to the significant incidence of esophagitis secondary to the treatment. Thus, while tumor may be shrinking, esophagitis may contribute to the delay to satisfactory oral intake. Patients who could not tolerate chemoradiation therapy were offered a palliative stent. In summary, patients with malignant dysphagia from obstructing esophageal cancer are best palliated by clinicians who are familiar with a variety of endoluminal techniques. This allows a tailoring of therapy best suited to the individual patient and tumor characteristics. Endoscopic options including SEMS, Nd:YAG, and PDT laser all provide immediate relief. Chemoradiation therapy can take longer than a month to see a benefit but may be a good choice for cervical esophageal lesions. For distal esophageal cancers, SEMS can produce significant reflux when placed across the gastroesophageal junction, and PDT may be a better endoscopic choice in some patients. A combination of therapies may be required in good performance patients with extended survival beyond several months due to recurrent dysphagia. The overall goals of palliation are improving oral intake, minimizing hospital stay, and maximizing quality of life.

COMMENTS AND CONTROVERSIES This chapter reviews the palliative approaches to the patient with dysphagia who has inoperable disease. There is no single palliative therapy that works well for all patients, and, indeed, not all patients with mild degrees of dysphagia need palliation. On the other hand, it is critical that we recognize that the ability to restore oral nutrition is a valuable aspect of allowing the patient to regain an important

component of his or her quality of life, which is far superior and more cost effective than feeding tubes or parenteral nutrition. Ideally, the clinician dealing with esophageal cancer patients should be well versed in all endoscopic interventions and the palliative aspects and limitations of chemotherapy and radiation therapy. Finally, it is the surgeon interventionalist who may represent the last opportunity to reconsider the operative indications so that operable patients are recognized and not just assumed to be palliative candidates. J. D. L.

KEY REFERENCES Christie NA, Buenaventura PO, Fernando HC, et al: Results of expandable metal stents for malignant esophageal obstruction in 100 patients: Short-term and long-term follow-up. Ann Thorac Surg 71:1797, 2001. Harvey JA, Bessell JR, Beller E, et al: Chemoradiation therapy is effective for the palliative treatment of malignant dysphagia. Dis Esophagus 17:260, 2004. Lightdale CJ, Heier SK, Marcon NE, et al: Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: A multicenter randomized trial. Gastrointest Endosc 42:507, 1995. Litle VR, Luketich JD, Christie NA, et al: Photodynamic therapy as palliation for esophageal cancer: Experience in 215 patients. Ann Thorac Surg 76:1687, 2003. Low DE, Pagliero KM: Prospective randomized clinical trial comparing brachytherapy and laser photoablation for palliation of esophageal cancer. J Thorac Cardiovasc Surg 104:173, 1992. Overholt BF: Photodynamic therapy and thermal treatment of esophageal cancer. Gastrointest Endosc Clin North Am 2:433, 1992. Siersema PD, Dees J, van Blankenstein M: Palliation of malignant dysphagia from oesophageal cancer. Rotterdam Oesophageal Tumor Study Group. Scand J Gastroenterol Suppl 225:75, 1998.

531

chapter

49

UNUSUAL MALIGNANCIES Nabil Rizk Majit Bains

Key Points ■ Tumors of the esophagus other than adenocarcinoma or squa-

mous cell carcinoma represent only about 2% of esophageal tumors. ■ Leiomyomas are by far the most common unusual esophageal malignancy. ■ Management of these tumors usually involves surgical resection.

Esophageal neoplasms are dominated by the predominance of malignant adenocarcinoma and squamous cell carcinoma. This has not always been the case, and it is interesting to note, for instance, that in some early reviews of esophageal neoplasms, adenocarcinoma was nearly as rare as some of the tumors that are discussed in this chapter, at that time only representing 2.3% of cases.1 Several important caveats should be kept in mind when reading this review. Foremost, although the discussion in this chapter summarizes the information presented in some exhaustive reviews of world experiences of these various tumors, it must be recalled that because the tumors discussed are rare, most of the reviews used are based on compilations of case reports and small retrospective case series from single institution experiences assembled over extended periods of time. In many of these series, management is not uniform and follow-up is poor. Older reports that include operative management often have unacceptably high morbidity and mortality rates by today’s standards, thereby skewing the potential outcome from surgical management of some of the tumors. Likewise, the relative benefits of chemotherapy and radiation therapy are difficult to assess because many regimens used would not be considered as current standards of care. As such, it is difficult to draw any firm conclusions about the management and outcome of these rare lesions. Another factor complicating a review of these neoplasms is the fact that, over time, there have been various names assigned to some of the tumors and that more recent literature has sometimes recognized that some of these tumors should be unified under a single name. A good example of this is pseudosarcoma and carcinosarcoma, two tumors previously believed to be separate entities but that more recently have been understood to be variations of the same tumor. Conversely, some of the tumors that were previously combined under unified subsets more recently have been recognized by immunohistochemical analysis to be completely distinct lesions. The most evident example of this is the prior equating of most spindle cell tumors with benign and malignant smooth muscle tumors (leiomyoma and leiomyosar532

coma, respectively). There has been recent appreciation of the fact that within the previous broad category of spindle cell tumors, gastrointestinal stromal tumors (GISTs) represent a completely separate category from smooth muscle tumors, arising from a different cell of origin altogether. This misidentification possibly explains some of the disparate behaviors assigned to leiomyomas and leiomyosarcomas in the past. Other tumors, too, were previously lumped into the broad spindle cell/smooth muscle tumor category, including schwannomas and granular cell tumors. Unusual tumors of the esophagus can be broadly outlined into three categories, namely, epithelial, mesenchymal, and lymphoid (Table 49-1), with subcategories of benign and malignant. Only those occurring with some amount of frequency are discussed in detail. Reference is made throughout this review to the Memorial Sloan-Kettering (MSKCC) esophageal surgery database as a contemporary source of information. As a means to underscore the rarity of these tumors, there are only 20 such tumors within the database of 867 patients who underwent an esophagectomy since 1996 (2.3% of the total).

LYMPHOID Although rare, the most common site of gastrointestinal tract involvement with primary lymphoma is the stomach. The esophagus is rarely the site of primary lymphoma. Several case series2-6 indicate that primary esophageal lymphoma represents less than 1% of all primary gastrointestinal lymphomas and that these tumors represent less than 1% of all esophageal malignancies.7 This number may, in fact, even be an overestimate because of the likely contribution of proximal extension of the more common gastric lymphomas to this number.8 In addition, using the criteria of Dawson,9 the literature does not always distinguish primary esophageal lymphoma from secondary involvement with disseminated lymphoma, a much more common occurrence. Dawson’s criteria propose that primary gastrointestinal lymphoma should only be assigned if there is predominant involvement of the esophagus and its regional nodes and if there is absence of peripheral and mediastinal nodal disease as well as lack of splenic and liver involvement. An additional confounder in the literature is focal lymphoid hyperplasia (pseudolymphoma), which can be confused for lymphoma.10 This entity is believed to result from chronic irritation and injury. Gupta and colleagues11 list 17 reported cases of primary esophageal lymphoma. All but 1 case are non-Hodgkin’s lymphomas. A more recent review (Coppens et al, 2003)12 indicates 5 reported cases of primary Hodgkin’s lymphoma of the esophagus in the English literature. Even more rare tumors include

Chapter 49 Unusual Malignancies

TABLE 49-1 Unusual Primary Malignancies of the Esophagus Lymphoid Origin Malignant Non-Hodgkin’s lymphoma Hodgkin’s lymphoma Mucosa-associated lymphoid tissue (MALT) lymphoma Plasmacytoma Epithelial Origin (other than squamous cell and adenocarcinoma) Malignant Adenosquamous Basaloid cell carcinoma Melanoma Small cell carcinoma Verrucous carcinoma Carcinoid Carcinosarcoma Lymphoepithelioma Adenoacanthoma Pseudosarcoma Benign Adenoma Papilloma Mesenchymal Origin Malignant Gastrointestinal stromal tumor (GIST) Schwannoma Leiomyosarcoma Liposarcoma Rhabdomyosarcoma Malignant fibrous histiocytoma Synovial sarcoma Kaposi’s sarcoma Osteosarcoma Ewing’s sarcoma Myxofibrosarcoma Benign Leiomyoma Granular cell tumor Fibrovascular polyps Papilloma

MALT lymphoma, with 2 case reports,13,14 and primary extramedullary plasmacytoma, with 4 reported cases.15 Esophageal lymphoid tissue is located in the lamina propria and submucosa, and the incidence of lymphoma is directly associated with the amount of lymphoid tissue normally present.2 Median age at presentation is 57.9, with a male-tofemale ratio of 15:9.16 Presenting symptoms of the lymphomas are dominated by dysphagia. Endoscopic appearances include a polypoid mass, diffuse nodularity, ulcerated lesions, or strictures. There are case reports of an initial presentation with esophageal perforation17 and fistula. Diagnosis of these tumors can be made on biopsy, although on occasion this is unsuccessful because of their submucosal site of origin.18 The radiographic appearance typically is of an irregular luminal narrowing, with an ulcerated or polypoid mass being less common.19 The location of the disease is similarly variable, with reported sites most frequently occurring in the midesophagus but with others being found in the proximal or distal esophagus. The etiologic factors responsible for the

development of primary esophageal lymphoma are unclear, but some researchers speculate that immunosuppression may be a component, including chronic use of immunosuppressive agents20 and infection with human immunodeficiency virus.21 The type of treatment for these lesions is anecdotal, and follow-up is not well documented. Chemotherapy, radiotherapy, surgery, or a combination of these modalities has been used to treat primary esophageal lymphoma. Survival is difficult to assess from the literature. However, there are two reports that list 2-year survival after surgical resection combined with chemotherapy and chemoradiotherapy.11,18

EPITHELIAL TUMORS Fibrovascular Polyp These benign tumors of the esophagus are rare. First described in 1895,22 these lesions have in the past been called fibrolipomas, lipomas, fibromas, and angiolipomas (Levine et al, 1996).23 Fibrovascular polyps occur with equal frequency in men and women and can occur in any age group, with a reported age range of 24 to 89 years. The tumor consists of mixtures of fibrous tissue, adipose tissue, and vascular structures with a normal overlying squamous mucosa.24 There have been no reports of malignant degeneration. They usually arise in the proximal esophagus adjacent to the cricopharyngeal muscle25 and can attain a remarkably large size (giant fibrovascular polyp). In Levine’s series of 16 patients, the average length of the polyp was 15 cm, with the largest being 25 cm. Their large size is thought to be due to chronic traction during peristalsis.26 The most common presenting symptom is dysphagia, although respiratory symptoms or the more dramatic asphyxiation27,28 due to retrograde prolapse are also possible. The radiographic appearance of this lesion by barium esophagography is of a smooth, elongated, endoluminal polypoid mass. Esophagoscopy reveals a large endoluminal mass, albeit the finding of normal mucosa can lead to a missed diagnosis.29 Once a diagnosis is made, the recommended treatment is excision, especially because of the potential for airway compromise. The surgical approach most commonly reported is a cervical esophagotomy with transection of the stalk. Transthoracic approaches are also described. Although endoscopic excisions have also been reported,30 concern over hemorrhage from a stalk vessel has limited the use of this approach.29

Verrucous Carcinoma This rare tumor is a squamous cell carcinoma variant that was first identified as a distinct morphologic entity in the oral cavity in 194831 and first reported in the esophagus in 1967.32 There have been a total of 20 cases reported since, including the 5 from the first report. These have been summarized by Osborn and colleagues (Osborn et al, 2003).33 Verrucous carcinoma is thought to result from chronic mucosal irritation, and most patients have a documented potential irritant, including esophagitis, achalasia, and previous caustic injury (Osborn et al, 2003).32-36 A history of smoking and alcohol abuse is also common. Mean age at presentation is 61, with a male-to-female ratio of about 2:1. These tumors are

533

534

Section 5 Neoplasms

characterized by being slow growing and well differentiated with proliferation of the mucosal surface.37 The feature that distinguishes verrucous carcinoma from benign squamous cell papillomas is areas of tumor infiltration.38 Metastases at presentation are rare. Dysphagia is the most common presenting symptom. However, symptoms are frequently present for months to years prior to making the diagnosis owing to the difficulty in obtaining a histologic confirmation of a malignancy, and endoscopies are more often nondiagnostic than diagnostic. Misdiagnoses include hyperkeratosis and acanthosis. This tumor should be suspected in patients with these pathologic findings and a long history of dysphagia.39 Endoscopically, the tumor is described as a white, wart-like mass. The use of endoscopic ultrasonography has only been reported in one case, but it was believed to be influential in making the diagnosis in the presence of negative biopsy results (Osborn et al, 2003).33 The tumor is located most often in the distal esophagus, followed in frequency by the proximal esophagus. It has been described only once in the midesophagus. Treatment of this tumor is surgical resection when possible. Successful endoscopic resection has also been reported.37 When resected early in its course, long-term survival should be expected,40 with 3 years being the longest reported follow-up. However, because of frequent delay in diagnosis, the tumors are often not resectable due to local invasion and the resulting survival in these patients is poor.38

Melanoma First described in 1906,41 the existence of primary esophageal melanoma remained controversial until two crucial pieces of evidence came to light. The first was the discovery of benign melanocytes within the normal esophagus in 4% to 8% of patients,42,43 present primarily in the distal esophagus where tumors are known to occur most frequently44; the other was the realization that metastatic melanoma to the esophagus was a distinctly rare event, present in only 4% of patients with visceral melanoma involvement.45-48 In stark contrast, the rest of the gastrointestinal tract has a much greater predilection to be involved with metastases, with tumor deposits evident in over 50% of patients with metastatic melanoma.49 Primary esophageal melanoma represents 0.1% to 0.5% of all malignant esophageal tumors50 and 0.5% of all noncutaneous melanomas.51 In 1995, Joob and associates (Joob et al, 1995)52 reported 180 cases in the literature. The commonly accepted criteria used to establish the esophagus as the primary site of disease are the presence and typical histologic pattern of a melanoma and the presence of junctional changes in the adjacent mucosa.53 The overlying mucosa is typically normal. Three reviews (Joob et al, 1995)52-55 have summarized the literature on primary esophageal melanoma. They occur in any age group but appear most often in sixth and seventh decades, with twice the incidence in men than in women. The most consistent presenting symptom is dysphagia. The tumors are mostly single, pigmented, polypoid lesions of variable sizes located in the middle to distal esophagus, although less commonly they can be multiple (12%) and not contain any pigment (10%-25%). Up to 40% of patients have evidence of nodal or distant disease at the time of presentation.

Endoscopic biopsy is reported to be diagnostic in 54% of cases, and electron microscopy and immunohistochemistry are helpful at distinguishing primary versus metastatic disease.56 On a contrast esophagogram, these tumors appear as bulky polypoid masses that expand the esophagus without obstructing it.57,58 Positron emission tomography has been shown to be highly sensitive at detecting metastatic disease in cutaneous melanoma59 and has been reported in one study on esophageal melanoma.60 Therapy for primary malignant melanoma of the esophagus has included surgical resection, radiotherapy, chemotherapy, and immunotherapy, or some combination of these. The median survival in the literature is 14.4 months from the time of diagnosis, with a 5-year survival of 4.2%.54 The value of nonsurgical treatment is unclear, but there are some longterm survivors after esophagectomy (mean 14.2 months), and it is the recommended primary management.55 Limited surgical resection is thought to be a poor choice because of potential submucosal spread, and no survivors were noted after 12 months. At MSKCC, since 1996 there have been 4 patients with primary esophageal melanoma who have undergone surgical resection (0.46%). There were 3 men and 1 woman, and the age range was 41.3 to 83.2. All patients had a preoperative diagnosis of melanoma, and the surgical approach was an Ivor Lewis esophagectomy. All patients experienced recurrence (median time 7.8 months), and median survival was 16.8 months, with the longest survivor living 34.3 months (Fig. 49-1).

Basaloid Squamous Cell Carcinoma This is a rare variant of squamous cell carcinoma that is more commonly found in the upper aerodigestive tract, where it is associated with poor survival.61 It was previously misdiagnosed as adenoid cystic carcinoma and small cell carcinoma, as well as frequently grouped together with squamous cell carcinoma. Wain and associates62 defined the diagnostic criteria in 1984, distinguishing them histologically from pure squamous cell carcinomas, albeit these tumors frequently contain a mixture of these two histologies (Sarbia et al, 1997).61 Histologically, basaloid squamous cell carcinomas are noteworthy for their poor differentiation and a high proliferative activity (Sarbia et al, 1997).61,63 Reviews of patients previously identified with squamous cell carcinoma indicate that about 4% to 11% should be recategorized as basaloid cell carcinoma (Sarbia et al, 1997).61,63,64 In a large singleinstitution review of 30 basaloid cancers,63 Lam and coworkers noted a mean age at presentation of 67, with a 5:1 male-to-female ratio. Dysphagia was the most common presenting symptom. All patients underwent surgical resection. Survival of these patients was statistically equivalent to squamous cell carcinoma (median 26 months). Review of the MSKCC surgical database identified 8 patients with basaloid cell carcinoma compared with 178 patients with squamous cell carcinoma, representing 4.3% of these patients. There were 5 women and 3 men, and the mean age at presentation was higher than in patients with squamous cell carcinoma (71.3 versus 62.9, respectively). The tumor was evenly distributed in location (2 proximal, 2

Chapter 49 Unusual Malignancies

A

B

C

D

FIGURE 49-1 A, CT scan in a patient with a distant esophageal melanoma. B, Endoscopic appearance of a distal esophageal melanoma. C, Gross resected specimen of a distal esophageal melanoma, showing a pigmented polypoid mass. D, Histopathology of an invasive and in situ melanoma arising in squamous epithelium of the esophagus.

middle, 4 distal). Survival was the same for basaloid squamous cell carcinoma and squamous cell carcinoma, with a median survival of 34.2 months and 42.1 months, respectively. Sarbia and associates showed similar results (Fig. 49-2) (Sarbia et al, 1997).61

Small Cell Carcinoma First described by McKeown in 1952,65 over 230 cases of small cell carcinoma of the esophagus have since been reported in the literature.66 This tumor has been known under several different names in the past, including anaplastic carcinoma,

oat cell carcinoma, and APUDoma.67 The esophagus represents 53% of all small cell carcinomas of the gastrointestinal tract, with the stomach and colon representing 11% and 13%, respectively.68 It represents 0.15% to 2.4% of all esophageal tumors,69-71 albeit the incidence seems to vary by geography, with a higher incidence (9%-15%) reported in Japanese studies for instance.72-75 These aggressive tumors are believed to arise from a pluripotential cell of the basal layer that is a precursor to squamous cell carcinoma, adenocarcinoma, and small cell carcinoma.76 Although not standardized, staging is similar to pulmonary small cell carcinomas; namely, limited stage is assigned to disease isolated within one anatomic

535

536

Section 5 Neoplasms

A

B

C

region (with or without regional adenopathy), and extensive stage is assigned to disease outside the locoregional area. From 31% to 90% of patients present with extensive-stage disease.69,70,77 Casas and colleagues’ review (Casas et al, 1994)78 indicates a mean age at presentation of 63.8 with a male-to-female ratio of 1.57:1. There is no consistent predisposing factor (Casas et al, 1994),78 but smoking seems to be common in many studies.70 Most tumors are located in the middle to distal esophagus, with only about 5% reported in the proximal esophagus. The average size at presentation is 6.1 cm. Dysphagia is the most common presenting symptom, and by endoscopy the appearance is described as indistinguishable from that of squamous cell carcinoma, appearing either as a hard mucosal mass or as a polypoid mass.77,79 Treatment of limited-stage disease is based on small retrospective series and is driven largely by evidence of their early local and distant recurrences as well as experience from the treatment of small cell carcinoma of

FIGURE 49-2 A, Endoscopic view of a basaloid carcinoma. B, Gross specimen from a resected distal esophageal basaloid carcinoma. C, Histopathology of a basaloid carcinoma undermining squamous epithelium. The tumor exhibits a solid growth pattern and the small gland-like spaces are filled with bluish basaloid material.

the lung. Since the first successful reported use of chemotherapy alone in 1980 to treat this disease,80 most series (47%) include chemotherapy either as the sole treatment modality or in some combination with surgery and radiotherapy for treatment of limited disease (Casas et al, 1994).78 About 36% of reported patients only received local therapy. A multivariate analysis showed that use of chemotherapy increased survival (Casas et al, 1994).78 The prognosis from small cell carcinoma of the esophagus remains poor, with median survival ranging from 4.2 to 18.5 months.69 While the role of surgery remains undefined, the few long-term survivors in the literature (>5 years) have been in patients who have undergone surgical resection.76,81

Pseudosarcoma and Carcinosarcoma These two entities have been described as separate tumors until more recently, when a unified diagnosis has been advocated. These tumors have also been known as polypoid

Chapter 49 Unusual Malignancies

squamous carcinoma82-84 and spindle cell carcinoma85 and fibrosarcoma.1 They are rare and represent less than 3% of esophageal tumors.86,87 These polypoid tumors are composed of both epithelial and mesenchymal components,88 and previous confusion over nomenclature stems from various opinions as to which of the two cellular components had a malignant potential,89-91 as well as what the cell of origin of each component was.92 Stout88 believed that the sarcomatous component was due to reactive proliferation next to the malignant epithelial component, whereas Hughes and Cruickshank93 noted that the sarcomatous component was the only one that recurred after resection. These tumors have also previously been thought to be less aggressive, with a lower likelihood of nodal and distant metastases.94 In a review of the literature (Iascone and Barreca, 1999),95 Iascone and colleagues summarized all reported cases of pseudosarcoma (n = 56) and carcinosarcoma (n = 127) and compared their clinical behavior. They noted that, in fact, the clinical behavior of these two entities was identical and that, in support of their similar immunohistochemical appearance, these tumors should be considered as a single entity. Furthermore, the consensus now appears to support a common cellular origin of the two components of these tumors.88 The presenting symptom is most often dysphagia (83%-92%), and the age distribution is centered between 50 and 70 years of age. Most tumors are polypoid (82%-97%) and are located in the mid to distal esophagus (89%-94%). Half of patients had nodal metastases at presentation. Treatment consists of surgical resection, and 3-year survival is 55% to 65%. The role of local excision is unclear, with some reported long-term survivors after this procedure.

Carcinoid First reported in the esophagus in 1968,96 and most commonly found in the small bowel and appendix, there are approximately 32 cases reported in the literature of primary esophageal carcinoid.97 This represents 0.002% of all reported carcinoids. The average age at presentation is 60, with a range of 30 to 82.97 There is a 6:1 male to female ratio. Dysphagia is the most common presenting symptom, and only 1 patient had symptoms of carcinoid syndrome.97 Lindberg and coworkers reviewed the literature in 1997.98 The tumors presented as either ulcerated masses or polypoid lesions, mostly in the distal esophagus.98 The endocrine cell precursors of carcinoid tumors arise in the lamina propria and basal cells of the epithelium. There are two situations in which carcinoids arise—either as an isolated polypoid mass or in association with Barrett’s esophagus and adenocarcinoma.99,100 Half of patients have lymph node involvement at the time of diagnosis.97 Most patients underwent esophagectomy, whereas some only had a limited excision. Survival seems to be directly related to stage of disease; and, after excluding operative deaths and potentially misdiagnosed patients from the literature, prognosis appears to be favorable.99

Lymphoepithelioma Of the 13 reported cases of this rare neoplasm in the esophagus, 12 have been in the Japanese population101 and 1 in a

patient of Arabic descent.102 These tumors are epithelial in origin with surrounding T lymphocytes.103 They are most commonly found in the pharynx. There is a strong association between lymphoepitheliomas and the Epstein-Barr virus.104 The mean age of patients is 67, with 9 males and 4 females. All patients underwent surgical resection, and some received additional preoperative or postoperative treatment. Survival in these patients appears to be favorable, with 8 of 9 (88%) patients reported to be alive at 2 years.

MESENCHYMAL TUMORS Leiomyoma Although rare in the rest of the gastrointestinal tract, leiomyomas are the most common benign tumor of the esophagus, accounting for 60% to 70% of all benign tumors.105,106 Nonetheless, these remain rare tumors, with an incidence under 0.1% in autopsy series,107 and an incidence estimated at 1/50th that of esophageal carcinoma (Seremetis et al, 1976).108 In the MSKCC surgical database, there were a total of 5 incidental and 1 symptomatic leiomyomas detected in 869 patients undergoing esophagectomy for cancer (0.7%). The male-to-female ratio is 2:1. The typical age at presentation is between 20 and 59.109 These tumors primarily arise in the muscularis propria (80%) and are located mostly in the middle (40%) and distal (50%) esophagus.110 They are intramural and solitary in 97% of cases (Seremetis et al, 1976).108 Their average size is between 2 and 5 cm (Seremetis et al, 1976).108 The majority of patients are asymptomatic, but about 47.5% complain of dysphagia and odynophagia (Seremetis et al, 1976).108 Bleeding is rare. Evaluation by contrast esophagography shows a smooth, rounded submucosal mass. On CT, leiomyomas appear as nonspecific homogeneous soft tissue masses. By endoscopy, there is evidence of a mobile submucosal mass with a normal overlying mucosa. Biopsy of a suspected leiomyoma is not recommended because of the increased likelihood of a mucosal tear at the time of surgery. The recommended treatment of symptomatic leiomyomas is surgical removal. There is no consensus on the management of incidentally identified asymptomatic masses that clinically appear to be leiomyomas. Some advocate following these presumed leiomyomas clinically, because these are benign lesions that can easily be evaluated for worrisome changes. The concern over malignant degeneration as a reason to resect asymptomatic lesions appears to be unfounded, since there are only 4 case reports of such an event (Seremetis et al, 1976)108,111-113; furthermore, some have even questioned the validity of the original diagnosis of leiomyoma in these cases and point to the possibility that they may in fact have been GISTs.114 Other arguments for resecting asymptomatic tumors include the fact that some patients will become symptomatic and the fact that it may be difficult to ascertain if one is dealing with a benign or a malignant process.115,116 Surgical treatment of leiomyomas consists of extramucosal enucleation, via thoracotomy, laparotomy, or video-assisted means. Although not universally advocated,117 most reports recommend reapproximating the muscle edges after the myotomy to avoid mucosal

537

538

Section 5 Neoplasms

bulging and possible motility problems.118 Special mention needs to be made about giant leiomyomas, defined as tumors more than 10 cm in diameter and representing about 5% of leiomyomas.119 From a technical standpoint there is concern that resection of these large masses via enucleation might defunctionalize the esophagus, albeit there are reports documenting safe enucleation of these large tumors (Fig. 49-3).120

Leiomyosarcoma Review of the esophageal leiomyosarcoma literature should be viewed with caution given the revisions in nomenclature, especially in relation to recent recognition of GIST tumors as separate entities.114 Leiomyosarcoma of the esophagus was first described in 1902 by Howard,121 and first resected by Harrington in 1945.122 Although reported to represent 5% of all gastrointestinal leiomyosarcomas,123 redefinition of these tumors likely will increase significantly the proportion of these tumors represented by the esophagus because of the preponderance of GISTs in the remaining gastrointestinal tract. Nonetheless, leiomyosarcomas represent less than 1% of all esophageal tumors124,125 and occur at 1/10th the incidence of leiomyomas.126 At MSKCC, there was only one leiomyosarcoma identified in the surgical database (0.1%). The pathogenesis of this tumor is unclear, but malignant degeneration from a leiomyoma is not believed to be a likely cause, because there are only 4 case reports of this in the literature (see Leiomyoma). A review of the 55 reported cases of leiomyosarcoma in 1995127 shows a mean age at presentation of 58.9 and an equal distribution in the upper and middle esophagus, with more tumors found in the distal esophagus (45%). Most tumors are polypoid (55%), and the mean size was 9.2 cm. Presenting symptoms include dysphagia (75%), weight loss (50%), and chest pain (45%).128 Endoscopic biopsy is helpful for diagnosis, but in the case of intramural leiomyosarcomas, especially in well-differentiated tumors, a diagnosis can be difficult to make.124 The principal confounder in this instance is leiomyomas. In the more common polypoid tumors, the potential endoscopic differential diagnosis includes verrucous squamous cell carcinoma, pseudosarcoma/carcinosarcoma, or melanoma.128 Primary therapy for these tumors is surgical resection. Hatch and associates reported 82 documented cases of surgically treated leiomyosarcomas in the literature.109 Forty-eight patients underwent esophageal resection, and 16 underwent local excision or enucleation. In a well-documented series, Rocco and colleagues125 provideed their single-institution experience on 17 patients over 66 years. Resections included enucleation, polypectomy, and esophagectomy. Five-year survival was 77.9% in patients who had complete resections and 0% in those with incomplete resections. Factors affecting survival included completeness of resection, stage, grade, growth pattern, and location. The suitability of a lesser resection is not established. One patient in their series who underwent an enucleation for an intramural tumor had adequate followup with no recurrence at 108 months, whereas 2 patients died of recurrence. Two additional reports of limited resec-

tion (wedge resection) showed one local recurrence in 1 patient and the other patient without recurrence at 14 months.129,130 It is not possible to comment on the relative benefits of chemotherapy and radiotherapy utilized in the few reported cases. The 1 patient in the MSKCC database with a leiomyosarcoma underwent an Ivor Lewis esophagectomy for a 4 × 2 × 1-cm tumor that had been noted 2 years previously and followed at an outside hospital with several nondiagnostic biopsies. The patient is alive and without recurrence at 44 months (Fig. 49-4).

Gastrointestinal Stromal Tumors Gastrointestinal stromal tumors are biologically distinct mesenchymal tumors. They are the most common mesenchymal tumors of the gastrointestinal tract but are relatively rare in the esophagus,131 where leiomyomas predominate. In the past, most spindle cell tumors were classified as smooth muscle tumors, principally as leiomyomas when benign and leiomyosarcomas when malignant, but also as cellular leiomyomas, epithelioid leiomyosarcomas, and leiomyoblastomas (Miettinen et al, 1999).132 Recent work, however, has refined the understanding of these tumors and has led to the reclassification of some of these lesions.114 In a review of 68 patients diagnosed previously with leiomyomas, leiomyosarcomas, smooth muscle tumor, and stromal tumor of the esophagus, 17 patients (25%) were believed to have had GISTs, 48 to have had leiomyomas, and only 3 to have had leiomyosarcomas. At MSKCC, there were two GISTS identified in a surgical database of 869 patients (0.23%). The cell of origin of GISTs is thought to be the precursor cell of the interstitial cell of Cajal (intestinal pacemaker cell) located within the muscularis propria.133 GISTs are composed predominantly of spindle cells in 70% of patients and epithelioid cells in 30% of patients.134 The hallmark of GISTs is their expression of the KIT polyclonal antibody CD117 (97%)131 and of CD34 (70%-80%).135 The biologic behavior of GISTs is difficult to predict, and thus assigning a malignant potential to these tumors can be problematic.135 In Miettinen and associates’ study, all patients with tumors larger than 10 cm died of their disease.114 In some studies, mutation of the KIT protein (exon 11 gain of function mutation) is prognostic of poor outcome.136 On the other hand, mitotic activity does not consistently appear to correlate with a worse outcome.137 In Miettinen’s series,114 the median age at presentation was 63. The dominant presenting symptom was dysphagia. Preoperative biopsy was most frequently diagnostic of carcinoma. The median size of the tumor was 8 cm, and 8 of 11 evaluable tumors were intramural, of which 2 tumors also had intraluminal extension. Ten patients underwent extramucosal resection, whereas 7 patients underwent esophageal resection. Median survival in these patients was 27 months. Of the 2 MSKCC patients with an esophageal GIST, 1 underwent an extramucosal resection at our institution for a presumed leiomyoma and the second patient had an extramucosal resection at an outside hospital for a presumed leiomyoma and presented at MSKCC due to positive margins.

Chapter 49 Unusual Malignancies

A

C

B

D

E

F

FIGURE 49-3 A, CT scan in a patient with a leiomyoma. B, Contrast esophagogram of a leiomyoma. C, MR image of giant leiomyoma. D, Gross specimen of a “giant” (13 cm) and multinodular leiomyoma resected by an Ivor Lewis esophagectomy. The left lower corner reveals the attached small fragment of gastric mucosa. E, Cross section of an esophageal leiomyoma in a patient who underwent an extramucosal resection. F, Histopathology of a leiomyoma involving the submucosa of the distal esophagus. The tumor reveals a hypocellular spindle cell neoplasm with smooth muscle differentiation.

539

540

Section 5 Neoplasms

A

B

C FIGURE 49-4 A, CT scan shows a distal esophageal leiomyosarcoma. B, Esophagographic appearance of a leiomyosarcoma. C, Histopathology of a leiomyosarcoma showing a hypercellular malignant spindle cell neoplasm with frequent mitoses.

Pathology review in this patient confirmed the tumor as a GIST, and the patient subsequently underwent an Ivor Lewis esophagectomy with evidence of residual disease. Neither patient has experienced a recurrence with more than 4-year follow-up. The role of the KIT inhibitor drug (imatinib [Gleevec]) in the treatment of primary esophageal GISTs is unclear (Fig. 49-5).

Other Mesenchymal Tumors Synovial sarcoma has been reported five times in the literature.138-142 Although these tumors usually form in the extremities, about 10% occur in soft tissues. In the esophagus, they are polypoid and present as dysphagia. Treatment has

been by surgical resection. Five-year survival is reported to be between 25% and 65%.142 Liposarcoma has been reported 13 times in the literature. A review by Garcia and coworkers143 indicated that these tumors occurred at a mean age of 58.7, with an equal proportion of men and women affected. Tumors mostly occurred in the proximal esophagus as polypoid masses and presented as dysphagia. Nine of the 13 tumors were resected by polypectomy and 4 with an esophagectomy. Documented follow-up is short, but there are 2 patients who have a survival of more than 5 years but who had documented recurrences.144,145 Rhabdomyosarcoma has been reported 14 times in the literature.146 The mean age is 61, with a male-to-female ratio

Chapter 49 Unusual Malignancies

A

D

B

C

E

FIGURE 49-5 A, CT scan shows a distal esophageal GIST. B, Contrast esophagogram of a distal esophageal GIST. C, Incisional view of the gross specimen of a resected GIST. The tumor is submucosal (arrow). D, Positive immunoreactivity of KIT in a GIST. E, Histopathology of a GIST showing a hypercellular spindle cell neoplasm.

541

542

Section 5 Neoplasms

FIGURE 49-6 Gross appearance of a distal esophageal rhabdomyosarcoma.

of 3:1. It presents either as a polypoid or an ulcerative mass, most commonly in the middle to distal esophagus. This obviously raises questions as to its histogenic origins.147 Management has been typically with surgical resection, and outcome is documented as poor. The MSKCC database contains 1 patient with rhabdomyosarcoma who underwent surgical resection. The patient died 4.9 months after resection without documented disease recurrence (Fig. 49-6). Granular cell tumors, originally called myoblastomas, are now thought to originate from Schwann cells in the submucosa.148-150 These occur mostly as incidental findings in the dermis of the upper extremities and trunk as well as the tongue, but there are 200 reported cases in the literature of them occurring in the esophagus (representing one third of all gastrointestinal cases).150 These are mostly benign tumors, but there are 3 reported cases of malignant granular cell tumors of the esophagus.148 One half of these tumors present in the distal esophagus, usually as an asymptomatic, small (<2 cm) polypoid lesion. Histologic differentiation from GISTs is difficult. With the low malignant potential, local excision is recommended. Local recurrence after resection is indicative of potential malignancy.

Schwannoma was initially reported in 1967,151 and there are approximately 19 reported cases of esophageal schwannomas in the literature, 16 of which were reported as benign and 3 as malignant.152 Seito and associates reviewed the literature through 1999153 and noted in 15 patients a median age of 54, with a 6:9 male-to-female ratio. The tumors were evenly distributed throughout the esophagus, and the average size was 6.8 cm. Presentation is most commonly due to dysphagia. These tumors originate in the submucosa. Most tumors were treated by surgical enucleation, although there is a report of endoscopic removal.154 Prognosis appears to be good.155 The MSKCC database contains 1 patient with an esophageal schwannoma. The patient presented with a large intramural mass that was causing dysphagia. Preoperative biopsy indicated a spindle cell neoplasm, with the differential diagnosis including a possible schwannoma. An Ivor Lewis esophagectomy was performed, and a 15-cm schwannoma was reported. The patient is alive without disease recurrence 1 year after surgery (Fig. 49-7). Other sarcomas that have been documented in the esophagus include Ewing’s sarcoma,156 myxofibrosarcoma,157 inflammatory fibrosarcoma,158 osteosarcoma,159 and Kaposi’s sarcoma.160

Chapter 49 Unusual Malignancies

A

B

C

E

D

FIGURE 49-7 A, Endoscopic view of a schwannoma. B, CT scan image of a schwannoma. C, Intraoperative image of a schwannoma. D, Contrast esophagogram of a schwannoma. E, Histopathology of a submucosal esophageal schwannoma revealing a compact spindle cell neoplasm with whorling of the cells and a vague fascicular pattern.

543

544

Section 5 Neoplasms

KEY REFERENCES Casas F, Ferrer F, Farrus B, et al: Primary small cell carcinoma of the esophagus: A review of the literature with emphasis on therapy and prognosis. Cancer 80:1366-1372, 1994. Coppens E, El Nakadi I, Nagy N, Zalcman M: Primary Hodgkin’s lymphoma of the esophagus. AJR Am J Roentgenol 180:1335-1337, 2003. Iascone C, Barreca M: Carcinosarcoma and pseudosarcoma of the esophagus: Two names, one disease—comprehensive review of the literature. World J Surg 23:153-157, 1999. Joob AW, Haines GK, Kies MS, Shields TW: Primary malignant melanoma of the esophagus. Ann Thorac Surg 60:217-222, 1995. Levine MS, Buck JL, Pantongrag-Brown L, et al: Fibrovascular polyps of the esophagus: Clinical, Radiographic, and pathologic findings in 16 patients. AJR Am J Roentgenol 166:781-787, 1996.

Miettinen M, Sarlomo-Rikala M, Lasota J: Gastrointestinal stromal tumors: Recent advances in understanding of their biology. Hum Pathol 30:1213-1220, 1999. Osborn NK, Keate RF, Trasteck VF, Nguyen C: Verrucous carcinoma of the esophagus: Clinicopathophysiological features and treatment of a rare entity. Dig Dis Sci 48:465-474, 2003. Sarbia M, Verreet P, Bittinger F, et al: Basaloid squamous cell carcinoma of the esophagus: Diagnosis and prognosis. Cancer 79:1871-1878, 1997. Seremetis MG, Lyons WS, DeGuzman VC, Peabody JW: Leiomyomata of the esophagus: An analysis of 838 cases. Cancer 38:2166-2177, 1976.

chapter

50

COMPLICATIONS OF ESOPHAGEAL RESECTION Richard J. Battafarano G. Alexander Patterson

Key Points ■ The morbidity and mortality associated with esophageal resection

can be significantly decreased by taking aggressive steps to anticipate and treat complications associated with this procedure. ■ The esophagogastric anastomosis must be placed along the greater curvature of the stomach as close to the gastroepliploic arcade as possible. Gastrotomies between the lesser curvature staple line and the anastomotic site (sometimes used for passage of the EEA stapling device) need to be avoided to prevent ischemic necrosis of the intervening gastric tissue. ■ Recurrent laryngeal nerve injuries need to be identified promptly and treated with vocal cord medialization to facilitate the mobilization of pulmonary secretions and to prevent aspiration and subsequent pneumonia.

Esophageal surgery is now commonly performed for both benign and malignant disorders of the esophagus. Hospital mortality for esophageal resection has dramatically decreased over the past 2 decades and is currently well below 10% in most esophageal centers. However, the procedure is still associated with substantial morbidity.1-3 Because of the frequency and severity of complications associated with esophagectomy, surgeons must become familiar with each of the potential complications and take aggressive steps to anticipate and treat any problems that might arise in the postoperative period.

HOSPITAL MORTALITY The importance of preventing and appropriately managing postoperative complications after esophagectomy cannot be overstated. Operative mortality has been shown to be inversely related to surgeon experience4,5 and hospital volume (Begg et al, 1998).6 In a retrospective review of esophagectomies performed for cancer, 42 patients were operated on by surgeons who performed 6 or more esophagectomies per year, and 32 patients were operated on by surgeons who performed 5 or fewer esophagectomies per year. In the 42 patients operated on by surgeons who performed this operation frequently there were 3 (7%) anastomotic leaks and no operative deaths. In 32 patients operated on by surgeons who performed this operation occasionally there were 7 (22%) anastomotic leaks and 7 (22%) operative deaths. Although the difference in anastomotic leak rates did not approach statistical significance (7% versus 22%, P < .07), surgeons experienced in performing this operation had a significantly lower operative mortality (0% versus 7%, P < .001).5

The impact of technical complications on survival has been reported from the group at Memorial Sloan-Kettering Cancer Center (Rizk et al, 2004).7 Of the 510 patients studied, 138 (27%) had complications directly attributable to surgical technique, such as anastomotic leak, paralyzed vocal cord, or chylothorax. Technical complications were associated with increased length of stay (median 23 days versus 11 days, P < .001), increased in-hospital mortality (12.3% versus 3.8%, P < .001), and higher rate of medical complications (77.5% versus 47.3%, P < .001). Importantly, only 43 of 138 patients (31%) with technical complications were alive at 3 years, whereas 179 of 372 patients (48%) without technical complications were alive. After controlling for age, medical comorbidities, use of induction therapy, tumor stage, histology, location, and completeness of resection, the presence of a technical complication remained highly predictive of poorer overall survival (hazard ratio = 1.41, P = .008). A retrospective study attempted to determine if increased hospital volume for selected surgical oncology procedures is associated with a decreased operative mortality. Over 5000 patients were identified in the Surveillance, Epidemiology, and End Results (SEER)/Medicare-linked database who underwent esophagectomy, pneumonectomy, pancreatectomy, liver resection, or pelvic exenteration for cancers of the esophagus, lung, colon and rectum, and various genitourinary cancers diagnosed between 1984 and 1993. Higher hospital volume was linked with lower operative mortality for esophagectomy (P < .001), pancreatectomy (P = .004), liver resection (P = .04), or pelvic exenteration (P = .04), but not for pneumonectomy (P = .32). The most striking results were for esophagectomy, in which the operative mortality was 17.3% in low-volume hospitals compared with 3.4% in highvolume hospitals (Begg et al, 1998).6

PATIENT SELECTION Although individual surgical expertise and familiarity of all hospital personnel with the management of patients after esophagectomy is important, the selection of patients who have the adequate physiologic reserve to withstand an extended operation and a potentially complicated postoperative course remains an important responsibility of the surgeon. In an attempt to define objective criteria that might help to identify those patients unable to tolerate esophagectomy, a three-phase study was undertaken by Bartels and coworkers.8 In phase I, the records of 432 patients who underwent esophagectomy from 1982 to 1991 were retrospectively reviewed. From this analysis, four parameters were identified that correlated with morbidity and mortality after esophagectomy: 545

546

Section 5 Neoplasms

1. 2. 3. 4.

Karnofsky index less than 80% Aminopyrine breath test less than 0.4 Vital capacity less than 90% PaO2 less than 70 mm Hg

Using this information, a composite risk score was devised that incorporated a multiplier factor based on the relative risk associated with each individual factor: general status ×4, cardiac function ×3, pulmonary function ×2, and hepatic function ×2. Summation of the results creates a single composite score ranging from 11 points in those patients without any risk factors to 33 points for a patient with the highest risk in all categories. In phase II, prospective evaluation of this composite scoring system in 121 consecutive patients undergoing esophagectomy for esophageal cancer confirmed the ability of the scoring system in predicting postoperative course. Postoperative mortality was 2% in 46 patients classified as low risk (11-15 points), 5% in 55 patients classified as moderate risk (16-21 points), and 25% in the 20 patients classified as high risk (22-33 points). Operative mortality was significantly higher in patients categorized as high risk compared with moderate risk (P < .05) and low risk (P < .01). Importantly, of the 9 patients who died postoperatively, 5 had a score of 22 points or greater. In phase III of this study the authors used the scoring system to determine how to manage these patients with esophageal cancer. Use of the two-stage esophageal reconstruction (resection and delayed reconstruction 4 weeks later) in moderate- and high-risk patients or complete exclusion of these patients from esophageal resection resulted in a marked reduction in the 30-day postoperative mortality rate from 7.4% to 1.6% in 252 patients who underwent esophagectomy. Although rigid adherence to this system may exclude some patients from esophagectomy who might otherwise survive operation, it does provide an objective means to identify those patients at greatest risk for death after esophagectomy.

GENERAL COMPLICATIONS Cardiac Complications The most common cardiac complications after esophagectomy are supraventricular tachydysrhythmia (SVT) and myocardial infarction. After obtaining a careful history identifying a patient’s functional capacity and risk factors for atherosclerotic cardiovascular disease, the need for further cardiovascular investigation is individualized based on one’s risk for developing perioperative cardiac events.9,10 Identification of cardiac ischemia on preoperative stress electrocardiography or thallium studies mandates a complete evaluation before proceeding with esophagectomy. In an effort to identify the incidence of cardiac complications after esophagectomy, 100 consecutive patients who underwent transhiatal esophagectomy without a prior history of cardiac arrhythmias were prospectively studied. The incidence of SVT was 13%, and the incidence of acute myocardial infarction was 1%. SVT was associated with hemodynamic compromise in 9 of 13 (69%) patients and with myocardial

ischemia in 4 of 13 (31%) patients. One patient required immediate cardioversion for a systolic arterial pressure less than 70 mm Hg. After controlling the ventricular rate with diltiazem, no patient had evidence of ongoing myocardial ischemia or infarction. The one myocardial infarction in the study resulted in the patient’s death.11 The median time to development of SVT was 72 hours (range, 16-576 hours), suggesting that availability of cardiac telemetry in the early postoperative period is advisable. Two episodes of SVT developed late in the postoperative period (days 10 and 28) and were associated with sepsis.

Deep Venous Thrombosis/Pulmonary Embolus Deep venous thrombosis (DVT) and pulmonary embolism (PE) represent serious complications in surgical patients. Although the exact incidence is unknown in patients undergoing esophagectomy, the overall incidence of DVT and PE in general surgical patients has been calculated by pooling data from control patients in published trials examining the effectiveness of prophylactic methods.12 The overall incidence of DVT using fibrinogen uptake tests and phlebography confirmation was 19%. In surgical patients with malignant disease, the incidence of DVT was 29%. In this analysis, the incidence of clinically recognized PE and fatal PE was 1.6% and 0.9%, respectively. Because patients undergoing esophagectomy are considered at highest risk for developing a DVT or fatal PE (major surgery in patients >40 years plus malignant disease), all patients should receive preoperative prophylaxis. Successful preventive strategies include low-molecular-weight heparin, low-dose unfractionated heparin, intermittent pneumatic compression stockings, or oral anticoagulation. In a prospective randomized study of 2551 patients who had cardiac surgery, the combination of low-dose unfractionated heparin with intermittent pneumatic compression stockings resulted in a lower incidence of PE compared with patients receiving low-dose unfractionated heparin alone (1.5% versus 4%, P < .001).13 Based on this information, all patients should have pneumatic compression stockings placed before the induction of anesthesia and used throughout the postoperative period until the patient is ambulating on his or her own. In addition, subcutaneous low-dose unfractionated heparin is given every 12 hours until the time of discharge from the hospital.

COMPLICATIONS ASSOCIATED WITH ESOPHAGEAL RESECTION Anastomotic Leaks Anastomotic dehiscence is the most serious complication associated with esophageal resection. The rate of anastomotic leak and its associated morbidity and mortality vary depending on the location of the esophagogastric anastomosis. In a meta-analysis of the literature of the surgical treatment of patients with esophageal carcinoma by Muller and associates,14 the anastomotic leak rate for intrathoracic anastomoses was significantly lower compared with cervical anastomoses (11% ± 6% versus 19% ± 15%). However, the

Chapter 50 Complications of Esophageal Resection

tion as long as the just-listed principles are adhered to. Because, the mortality associated with intrathoracic anastomotic dehiscence approaches 60%,14,17,18 an aggressive approach to this problem is required. The third group consists of clinically apparent cervical leaks. These patients often develop wound erythema and crepitus associated with fever and an elevated white blood cell count. Initial management requires reopening the wound at the bedside. In the majority of patients, the leak will be contained in the neck by the surrounding tissues and frequent dressing changes are all that is required. However, a small subset of patients with esophagogastric anastomoses constructed via a cervical approach will leak into the mediastinum or pleural space and will require the aggressive approach described earlier for clinically apparent thoracic leaks. The overall mortality associated with these leaks has been reported to be 20%,14 indicating the importance of managing these patients appropriately. Clinically silent leaks are found incidentally during routine postoperative contrast studies in patients with no systemic signs of infection. The leak identified is contained by surrounding structures and often drains back into the lumen through the anastomotic defect. Management of these leaks is dictated by their location and the patient’s clinical course. Contained leaks close to the aorta and the trachea should be drained because of the risk of developing fistulas to these vital structures.19-21 Free extravasation of contrast into the pleural space or clinical deterioration of the patient mandates immediate drainage of the leak (Fig. 50-1).

mortality associated with an intrathoracic leak was three times higher (69% ± 16% versus 20% ± 11%). In contrast, a single group compared its experience with cervical anastomoses and thoracic anastomoses and found no statistical difference in anastomotic leak rate (4.3% versus 3.7%) or mortality associated with anastomotic leak (40% versus 36%).15 Urschel categorized esophagogastric anastomotic leaks into four groups according to their clinical presentation and subsequent outcome.16 Group 1 constitutes early fulminant leaks that present within the first 48 hours and are usually caused by gastric (or colonic) necrosis. These patients present with purulent chest tube drainage and septic shock and require immediate thoracotomy, resection of nonviable portions of the stomach, cervical end esophagostomy, and abdominal gastrostomy. This complication occurs infrequently but is often fatal even with prompt aggressive treatment. Group 2 includes clinically apparent thoracic leaks. These leaks are often identified by the development of a pneumothorax or pleural effusion associated with septic deterioration. The three critical principles in the management of this problem are (1) complete drainage of the pleural space, (2) adequate control of the esophagogastric fistula, and (3) re-expansion of the lung. Small anastomotic leaks will often heal if the lung is completely expanded because the visceral pleura functions to buttress the leak. Chest tube drainage alone, thoracoscopic drainage and repair, and reoperative thoracotomy with direct repair and muscle flap reinforcement of the leak can all be successfully used to treat this complica-

A

B

FIGURE 50-1 A contrast-medium swallow demonstrated what initially appeared to be a contained anastomotic leak (A). However, a postswallow CT scan showed free extravasation of contrast medium into the right pleural space (B).

547

548

Section 5 Neoplasms

Anastomotic Stricture Dysphagia after esophageal resection as a result of narrowing at the anastomosis occurs frequently in the postoperative period. The need for anastomotic dilation ranges from 5% to 44%, but the incidence of true anastomotic stricture is much lower.22-25 Creation of a side-to-side esophagogastric anastomosis using an endoscopic gastrointestinal anastomosis (Endo GIA) stapler appears to decrease the incidence of anastomotic stricture.26,27 Stricture formation in the immediate postoperative period is likely related to inflammatory changes associated with wound healing. In support of this hypothesis, the incidence of postoperative stricture has been shown to increase if there is a postoperative anastomotic leak.25 The treatment of early strictures consists of dilation with either the mercury-tipped Maloney dilators (46-50 Fr) or with the Savary dilators (1260 Fr) over a guidewire under fluoroscopic control. Most anastomoses require only a single dilation, but up to 10% will persist and require repeated dilations. Delayed stricture formation most commonly is a result of recurrent carcinoma or reflux esophagitis. An aggressive search for anastomotic recurrence including barium swallow, contrast-enhanced CT of the chest, and esophagoscopy with biopsy is necessary before initiating anastomotic dilation. In the absence of recurrent cancer, most strictures can be easily dilated. Persistent strictures can be resected, and new cervicogastric anastomoses can be constructed.

spective, randomized trial studying the effect of pyloroplasty versus no drainage in a group of patients undergoing IvorLewis esophagogastrectomy found that pyloroplasty decreased the amount of nasogastric aspirate, the gastric emptying time by radioisotope study, and long-term symptoms of gastric outlet obstruction.28 A pyloroplasty or a pyloromyotomy should be performed in all patients during reconstruction after esophagogastrectomy. In addition, the diaphragmatic hiatus should comfortably admit three or four fingers alongside the stomach at the completion of the operation to allow free flow of gastric contents into the duodenum. Delayed gastric emptying early in the postoperative period often is caused by mucosal edema at the level of the pyloromyotomy or pyloroplasty and generally resolves within 10 to 14 days (Fig. 50-2). During this interval it is important to keep the stomach decompressed to prevent aspiration and to decrease tension on the esophagogastric anastomosis. In those patients with persistent delayed gastric emptying after 14 days, erythromycin has been shown to improve emptying.29,30

Respiratory Complications Pulmonary complications including atelectasis, pneumonia, and respiratory insufficiency result in significant morbidity and mortality after esophagectomy regardless of technique used. The incidence of pulmonary complications ranges from

Dumping Syndrome Sweating, palpitations, tachycardia, nausea, and epigastric distention after meals in patients undergoing esophagogastrectomy represent signs and symptoms of the dumping syndrome. These intestinal vasomotor symptoms are thought to occur because of the rapid transit of hyperosmolar gastric contents into the jejunum, resulting in rapid hyperglycemia followed by reactive hypoglycemia. Although most patients will report some symptoms attributable to the dumping syndrome early in the postoperative period, dietary modifications including multiple small meals, avoidance of fluids during meals, avoidance of milk products and highcarbohydrate meals, and the occasional use of antidiarrheal medications allow the patient to overcome these symptoms within the first year after esophageal resection.

Gastric Outlet Obstruction Delayed gastric emptying occurs in a minority of patients after esophagogastrectomy and has been attributed to any of a number of factors. Vagotomy, torsion of the stomach into the posterolateral gutter of the right chest, the size of the gastric conduit, the pressure gradient between the intrathoracic stomach and the abdominal duodenum, compression of the distal stomach at the level of the diaphragmatic hiatus, and the lack of a drainage procedure all have been associated with this complication. Those patients with delayed gastric emptying are at increased risk for aspiration pneumonia and, ultimately, impaired oral alimentation. Gastric outlet obstruction at the level of the pylorus should be addressed at the time of the original operation. One pro-

FIGURE 50-2 A contrast-medium swallow demonstrated minimal passage of contrast medium through the pylorus despite pyloromyotomy at the time of esophagogastrectomy. Balloon dilation was performed 2 weeks postoperatively with resolution of the gastric outlet obstruction.

Chapter 50 Complications of Esophageal Resection

25% to 47%, and these complications are responsible for many of the deaths that occur after esophagectomy.1,2 Cessation of smoking combined with an exercise program including the use of incentive spirometry for at least 2 weeks is an important part of the patient’s preoperative preparation. Adequate perioperative and postoperative analgesia using epidural catheters and patient-controlled analgesia has been shown to decrease the incidence of pulmonary complications especially in patients who underwent a transthoracic esophagectomy.31 These should be routinely incorporated into the postoperative care of these patients. The use of postoperative ventilatory assistance the night of operation was used previously. However, extubation can safely be performed as soon as the patient is maintaining satisfactory ventilation and has a good gag reflex.32 Prevention of aspiration and the control of pulmonary secretions are the two most important factors in decreasing the incidence of postoperative respiratory complications. Elevation of the head of the patient and decompression of the gastric tube or colon interposition graft using a nasogastric tube are required in the postoperative period until the return of gastrointestinal function. Ambulation and chest physiotherapy are initiated on the first postoperative day and continued until the time of discharge. In those patients with significant bronchorrhea after esophagectomy, daily therapeutic bronchoscopy at the bedside is performed until the patient is independently able to mobilize his secretions on his own. This is especially important in those patients who have sustained a recurrent laryngeal nerve injury.

Chylothorax Chylothorax after esophagectomy has an incidence ranging from 0.4% to 2.7%.33,34 However, this complication is poorly tolerated in nutritional depleted patients with esophageal cancer, and mortality rates as high as 50% have been reported. Postoperative chylothorax presents as persistently elevated chest tube output that increases with the initiation of oral intake. As the patient’s diet is advanced to include a higher fat content, the chest tube output becomes milky white. Definitive diagnosis can be confirmed by determining the triglyceride content of the output, but this is often unnecessary. In equivocal cases, a triglyceride level in the pleural fluid of greater than 110 mg/dL is associated with a 99% chance of a chylous leak, whereas a triglyceride level of less than 50 mg/dL has less than a 5% chance of a chylous effusion.35 Prevention of unrecognized thoracic duct injuries and subsequent chylothorax requires careful dissection along the course of the thoracic duct during esophagectomy. The thoracic duct begins at the confluence of the cisterna chyli and enters the thorax through the aortic hiatus posterior to the aorta and anterior to the vertebral bodies of T10-L2. It then ascends just to the right of the anterior surface of the vertebral bodies between the aorta and the azygos vein in the right hemithorax. At the level of the T4 and T5 vertebral bodies, the duct crosses over to the left side of the spine and passes behind the aortic arch and into the neck. In the neck, the duct passes posteriorly to the carotid sheath and drains into the junction of the left jugular and subclavian veins. Any

injury to the thoracic duct identified preoperatively should be managed with ligation of all tissues lying between the azygos vein and the descending aorta. Careful inspection of the thorax along the course of the duct should be performed to identify chylous leaks before closure of the thorax. The management of chylothorax after esophagectomy remains controversial, with advocates for both conservative therapy and immediate surgical intervention. Conservative management usually includes total parenteral nutrition, alone or in combination with medium-chain triglyceride enteral formulas. Surgical intervention is usually performed via a right thoracotomy with ligation of the thoracic duct as it enters the thorax. Early surgical ligation of the thoracic duct after recognition of a chylous leak effectively controls this complication36 but requires right thoracotomy and anterior retraction of the gastric or colonic conduit in the early postoperative period. Conservative management of this complication results in closure of the chylous fistula in approximately 80% of patients within 14 to 35 days but has associated nutritional and septic complications.37,38 In an effort to identify those patients who will spontaneously seal their chylous fistula without surgical intervention, Dugue and colleagues34 retrospectively examined their experience in 23 patients who developed chylothorax after IvorLewis esophagectomy. Initial management included unilateral or bilateral chest drainage and total parenteral nutrition as soon as the diagnosis of chylothorax was established. Conservative treatment was continued for at least 12 days, after which reoperation through the previous right thoracotomy was attempted if daily chest tube output was greater than 500 mL per day or the lung was not re-expanded. Just before reoperation, a cream-rich diet was administered via the nasogastric tube or feeding enterostomy to facilitate identification of the chylous leak. Conservative management resulted in successful recovery in 14 of 23 (61%) patients. In these patients, chest drainage was stopped after a mean of 9 days (range, 3-17) and initiation of enteral nutrition within 12 days (range, 7-21) without the recurrence of the chylous effusion. Conservative therapy was complicated in 1 patient who developed sepsis from his central venous catheter. In 9 patients, conservative therapy did not result in closure of the chylous leak. These patients underwent reoperation after a mean of 18 days (range, 12-27). Reoperation with identification and ligation of the chylous fistula was successful in all 9 patients. However, 2 patients died of sepsis associated with anastomotic dehiscence. Retrospective analysis of the data identified one variable that was reliable for differentiating those patients in whom conservative therapy succeeded from those who required operation. Chylous drainage from the chest tube on postoperative day 5 was below 10 mL/ kg in 12 of 14 patients (mean 6.7 ± 5.5 mL/kg) who did not require reoperation and greater than 10 mL/kg in all patients (mean 23.5 ± 16.6 mL/kg) who underwent reoperation. Thus, any patient with a chylous output of greater than 10 mL/kg on postoperative day 5 should be returned to the operating room for transthoracic ligation of the thoracic duct. Administration of heavy cream containing methylene blue via the feeding jejunostomy for 4 hours before surgery facilitates

549

550

Section 5 Neoplasms

risk of pneumonia is increased. In addition, cricopharyngeal motor dysfunction and its associated dysphagia combined with an inability to completely appose the vocal cords markedly increase the risk of aspiration in these patients. The reported incidence of recurrent laryngeal nerve injury after esophagectomy ranges from 3% to 45% (Swanson et al, 2001).1,25,39-42 Higher vocal cord palsy rates have been reported in those series utilizing the extended radical esophagectomy technique; however, this is not a universal finding. Baba and associates and Nishimaki and coworkers reported vocal cord palsy rates of 33% and 45%, respectively, whereas Altorki and associates and Swanson and colleagues reported rates of 6% and 9%, respectively. Although the majority of patients only suffer transient vocal cord paralysis, its impact on postoperative pulmonary care is significant. Vocal cord paralysis may not become apparent until the third postoperative day or later when patients are noted to have difficulty generating a vigorous cough. This delay in presentation is thought to be caused by a gradual decrease in vocal cord edema in the postoperative period resulting in abduction of the paralyzed cord and an inability to generate pressure against a closed glottis. The diagnosis is often confirmed at the time of therapeutic bronchoscopy for retained secretions and bronchorrhea. Optimal management

identification of the leak and should be utilized in all patients. In addition to identification and ligation of the leak, supradiaphragmatic ligation of all tissues between the azygos vein and the aorta is performed during reoperation. In patients with a persistent chylous fistula despite thoracic duct ligation, lymphangiography with placement of a drainage catheter adjacent to the leak facilitates the subsequent use of sclerosing agents to seal the leak and achieve pleurodesis (Fig. 50-3).

Recurrent Laryngeal Nerve Injury Injury to the recurrent laryngeal nerve during esophagectomy results in significant postoperative morbidity. The recurrent laryngeal nerve supplies motor function to the intrinsic muscles of the larynx (except for the cricothyroid muscle which is supplied by the external laryngeal nerve) and supplies sensory fibers to the mucous membrane of the larynx below the vocal folds. Although hoarseness is often the initial presenting sign in patients with this injury, the risk of aspiration and the development of pneumonia represent its most serious consequences. Because recurrent laryngeal nerve injury results in inability to generate a vigorous cough, postoperative pulmonary toilet is severely compromised and the

A

B

FIGURE 50-3 Lymphangiography identified a collection of extravasated contrast medium (horizontal arrows) that collected in the mediastinum at the level of the hiatus (A). Placement of a drainage catheter adjacent to the leak (B) facilitated the subsequent administration of sclerosis agents through the catheter and the right pleural tubes.

Chapter 50 Complications of Esophageal Resection

of these patients includes therapeutic bronchoscopy and prompt medialization of the paralyzed vocal cord to improve the patient’s ability to cough and to prevent aspiration.

COMMENTS AND CONTROVERSIES Esophagectomy is a major undertaking and even today is associated with a hospital mortality of around 5% as well as a substantial morbidity. Despite all efforts to define objective criteria for risk assessment much depends on surgical, anesthesiologic, and postoperative care expertise. Over the past decades substantial progress has been made in both oncologic and medical patient selection as well as per- and perioperative management. As a result, age itself, provided adequate selection, is no longer an obstacle to perform this kind of major surgery. Even in very old patients (>75 years) the hospital mortality nowadays has come down to acceptable levels of around 5%. The incidence of both medical and surgical complications has decreased over the past decade and complications have been more efficiently managed when they have occurred. Nevertheless, surgeryrelated complications, in particular anastomotic leakage and stricture, gastric outlet obstruction and dumping, and weight loss, although rarely fatal nowadays, remain a cause of considerable morbidity and sometimes are very difficult to manage. Except for the extremely rare occasion of a necrosis of a gastric conduit, re-intervention for an anastomotic leak has virtually disappeared in my practice. Conservative therapy, including CT-guided drainage of fluid collection when necessary, suffices to solve such a complication. For intrathoracic anastomotic leaks, successful treatment by introducing stents until closure of the fistula has been reported. Gastric outlet obstruction in case of the use of a rather narrow tube is, in accordance with the law of Laplace, rarely a serious problem but more commonly occurs when using whole stomach. In such circumstances, pyloromyotomy or pyloroplasty may be a helpful adjunct to prevent this disturbing problem. However, pylo-

romyotomy/plasty in itself may aggravate the occurrence of dumping-like symptoms and above all exposes the patient to duodenogastric bile reflux. As more patients become long-term survivors the number of reports is increasing of the appearance of intestinal metaplasia in the remainder of the esophagus after esophagectomy followed by gastroplasty. Therefore, I am not in favor of adding a pyloromyotomy/plasty at the time of surgery. If gastric outlet obstruction becomes apparent in the follow-up it usually can be treated adequately by performing a balloon dilation of the pylorus in combination with the temporary administration of a potent prokinectic drug (e.g., erythromycin). In particular, dysphagia and the resulting weight loss and fatigue seem to be determining factors in the patient’s perception of quality of life as well as the occurrence of postoperative morbidity in general and the related length of hospital stay. Quality of life aspects have become an important focus of attention in particular in relation to the recent tendency toward treatment of cancer of the esophagus by definitive chemoradiotherapy. Surgeons, therefore, should continue to make all efforts to offer to their patients an intervention that, despite its magnitude, can be performed with the lowest possible mortality and morbidity and length of hospital stay. T. L.

KEY REFERENCES Begg CB, Cramer LD, Hoskins WJ, Brennan MF: Impact of hospital volume on operative mortality for major cancer surgery. JAMA 280:1747-1751, 1998. Rizk NP, Bach PB, Schrag D, et al: The impact of complications on outcomes after resection for esophageal and gastroesophageal junction carcinoma. J Am Coll Surg 198:42-50, 2004. Swanson SJ, Batirel HF, Bueno R, et al: Transthoracic esophagectomy with radical mediastinal and abdominal lymph node dissection and cervical esophagogastrostomy for esophageal carcinoma. Ann Thorac Surg 72:1918-1924, 2001.

551

chapter

51

SELECTION AND PLACEMENT OF CONDUITS Carl E. Bredenberg Clement A. Hiebert

Key Points ■ Subtotal esophagectomy with anastomosis of the cervical esoph-

agus to stomach brought to the neck through the posterior mediastinal bed of the resected esophagus has become the “workhorse” for treatment of both malignant and end-stage benign disease. ■ Long-segment isoperistaltic colon interposition from cervical esophagus to gastric antrum is an excellent alternative when adequate healthy stomach is not available and is the preferred reconstruction in a few centers because of perceived long-term functional advantages. ■ Intrathoracic esophagogastric anastomoses cause significant reflux problems, and their use today is limited to patients with esophageal cancer for whom short-term palliation is the most likely outcome. ■ Transfer of free flaps of abdominal viscera or skin with microsurgical anastomosis of its axial blood supply to cervical or superior mediastinal vessels is a useful alternative for bridging defects of the pharynx and cervical esophagus.

Except for excision of the second portion of the duodenum there is no greater surgical challenge in the digestive tract than resection and replacement of the esophagus. The permutations created by the variety of surgical exposures, levels of anastomosis, conduit choices, and routes for passage of the replacement organ create a large number of alternatives for reconstruction of the resected gullet. In rare instances a very short defect in continuity may permit end-to-end esophageal anastomosis. More often, reconstruction requires use of an intra-abdominal viscus, stomach, small bowel, or colon, most often used as pedicled grafts but also available as free flaps using microsurgical vascular anastomosis. Free flaps of skin from a variety of sites whose axial blood supply can also be anastomosed to cervical vessels are another source of conduit for one-stage reconstruction of cervical esophagus and pharynx. The site of proximal anastomosis can be abdominal, thoracic, or cervical; and the route of passage can use the esophageal bed in the posterior mediastinum or a substernal tunnel, traverse a pleural space, or, more rarely, lie subcutaneously. The general absence of large, well-controlled randomized trials combined with the natural enthusiasm common to the experienced practitioners and advocates of each alternative can make objective selection difficult. There is no single solution that solves all the problems that can be encountered in replacing the esophagus, and differences of opinion and practice are common. While acknowledging the wide variations

in practice, in this chapter we try to offer a perspective for assessing the usefulness of the major alternatives in esophageal reconstruction and under what circumstances each may be appropriately used.

CRITERIA FOR EVALUATION No esophageal replacement functions as well as a normal esophagus contained by well-coordinated sphincters at each extremity. For the patient, the consequence of esophageal replacement is inevitably something less than absolutely normal gastrointestinal function. In evaluating methods of esophageal reconstruction, the acute morbidity must first be considered. In addition to the potential complications attendant upon any large and complex operation, anastomotic leak and ischemic necrosis of the reconstructed conduit are specific complications, dangerous in their own right, but also having long-term sequelae, including anastomotic stricture and reoperations for salvage. Over the long term, the ability to swallow, eat a relatively normal diet, maintain a satisfactory weight, be free from severe reflux symptoms, and avoid the need for reoperation are all important criteria in evaluating the success of esophageal replacement (see Chapter 63 for a discussion of long-term quality of life after esophagectomy). For the patient with esophageal cancer, freedom from recurrence, particularly local recurrence with luminal obstruction, is a critical requirement for success. The location of the primary tumor, axial extent of resection, and sites chosen for proximal and distal anastomosis obviously help determine which reconstructive options might apply. If preoperative radiation therapy is given as part of multimodality treatment, a preference for anastomosis to unirradiated esophagus may also influence the choice. Does the disease for which operation is proposed promise the likelihood of long-term survival, or is short-term palliation the most frequent outcome? In most patients with esophageal cancer, palliation over a finite interval is still the most realistic goal and the ability of the patient to withstand major surgical onslaught may be reduced. In these patients, the primary goal is a safe operation that allows the patient to swallow and avoid aspiration. A relatively straightforward, reliable operation familiar by frequent practice to the surgeon may be preferred in this setting, even if it restores less than optimal function. For the patient with benign disease or very early and limited cancer where a long life expectancy can be anticipated, success for the patient requires a higher threshold of satisfactory gastrointestinal function that is durable for many years. 555

556

Section 6 Operative Techniques

OPTIONS Primary Anastomosis Simple end-to-end esophageal anastomosis is rarely an option in reconstruction except for infants with tracheoesophageal fistula. In adults, it can be occasionally utilized when little or no esophagus needs to be resected. When closing a cervical esophageal diversion previously performed to encourage healing of distal perforation or, more rarely, after resection of a very small tumor, the span may be sufficiently short to allow direct reanastomosis.1,2

Stomach Most esophageal resections are performed for cancer, and the stomach is by far the most frequently used esophageal replacement. Mobilized and released from its short gastric and left gastric vascular tethers, the fundus can be detached from the esophagus and readily advanced to the cervical esophagus if desired (Orringer et al, 2001).3,4 Relocating the stomach requires but one anastomosis. It can be mobilized from the abdomen, through a thoracoabdominal incision, or even through the undivided diaphragmatic hiatus, as reported by Belsey and Hiebert,5 who described esophagogastrectomy with intrathoracic anastomosis using an exclusive right thoracic approach. It is the conduit with which most thoracic surgeons have the most experience. Transposing the stomach has both short- and long-term risks. For decades, it has been taken as common knowledge that the stomach has a robust blood supply fully capable of tolerating minor abuse from clamps, forceps, or fingers. Liebermann-Meffert and colleagues6 showed with corrosion cast studies that robustness of blood supply trails off at the upper end of the gastroepiploic arcade. After left and short gastric vessels are divided, survival of the fundus depends on less than robust submucosal microvascular channels (Liebermann-Meffert et al, 1992).6,7 The consequent vulnerability of the mobilized stomach to ischemia and anastomotic leak appears to be greater when it is delivered to the neck, and most series show a higher incidence of anastomotic leaks for cervical esophagogastric reconstructions than for intrathoracic reattachments. Care in handling the stomach and newer anastomotic techniques using an endoscopic linear cutting stapler have reduced the frequency of cervical leaks.8-10 Gastroesophageal reflux with associated esophagitis, stricture, and aspiration can be a severe long-term problem deriving from the valveless joining of esophagus to stomach (Watson et al, 1997).11-13 The level at which the esophagus is rejoined to the stomach is a critical variable in determining the severity of the reflux symptoms. As noted by Sweet14 over 60 years ago, in general, the higher the anastomosis, the less severe the problem with reflux. Esophagogastric anastomoses performed in the abdomen or low in the left chest are particularly vulnerable to this complication. Anastomoses constructed high in the right side of the chest have less reflux,14-16 but even there they are subject to the gradient between positive intra-abdominal and negative intrathoracic pressures that is the putative mechanism for aggravating reflux in the absence of a lower esophageal sphincter.16,17

Anastomosis in the neck substantially improves the functional results of esophagogastrostomy primarily by reducing the frequency of severe reflux symptoms.18-21 The stomach can be brought to the neck by a variety of techniques. Most frequently it is brought up after transhiatal esophagectomy. Cervical esophagogastric anastomosis is also used with a three-incision abdomen/right chest/cervical approach and least frequently as part of an extended left thoracoabdominal subtotal esophagectomy. Reflux symptoms can be further minimized by having the patient exercise prudence in avoiding overeating at a single meal, delay an hour after a meal before assuming the recumbent position, and, for some, sleeping with two pillows or elevating the thorax on a wedge when in bed. With these usually easily followed practices, complaints of frequent or severe reflux with cervical esophagogastric anastomosis are uncommon.20,21 These excellent functional results are with the stomach in the posterior mediastinal bed of the resected esophagus. Substernal placement of the stomach results in far less satisfactory results and generally should be avoided.22 The leak rates for cervical esophagogastric anastomoses are generally higher than with intrathoracic reconstructions.19 Uncontained intrathoracic leak is a major complication that has traditionally carried a high mortality rate. However, with improved surgical management, the high mortality rate from intrathoracic leaks has been substantially reduced.15,23,24 Cervical leaks are generally less morbid and can usually be managed by reopening the cervical wound for drainage. Rarely, devastating complications can occur after even a cervical leak.25 Both intrathoracic and cervical anastomoses will not infrequently require dilations during long-term follow-up, particularly if there has been an anastomotic leak. Modern techniques of dilation using the flexible endoscope have made dilation less of a problem, providing the patient is cautioned to return at the slightest symptom of dysphagia.15,26,27 Dilation of an early, mild narrowing is easily performed, whereas tight strictures or long lengths of scar from ischemia are difficult and may require multiple and frequent dilations. Using an endoscopic linear cutting stapler to construct the cervical anastomosis reduces the need for anastomotic dilation.8-10 This improvement is in part because of the reported reduction in anastomotic leaks. Also, this technique creates a long biased end-to-side anastomosis with a substantially larger circumference than the usual hand-sewn or circular intraluminal stapled anastomosis.8 With the enlarged circumference, any long-term contraction of anastomotic scar will be less likely to critically narrow the opening. The long-term functional results of cervical anastomosis to the stomach brought to the neck through the posterior mediastinal bed of the resected esophagus have been excellent, encouraging use of this technique in patients with both benign and malignant disease.4,28,29 In contrast, the intrathoracic esophagogastric anastomosis at whatever level has enough problems with reflux to avoid using this approach when longterm survival is expected.11-13,21 Stomach is not a universal esophageal replacement. Colon interposition or free jejunal grafts are better functioning con-

Chapter 51 Selection and Placement of Conduits

duits when the proximal extent of resection includes all or part of the pharynx.29-31 More frequently, prior gastric surgery or disease, or the extent of gastric resection required at the time of esophagectomy, may leave stomach unavailable as an esophageal substitute, requiring use of an alternative conduit.

Gastric Tubes The most common gastric tube used today is made simply by resecting more of the lesser curve and a greater portion of the width of the stomach to narrow the conduit during esophagogastrectomy. Although reported by some to improve gastric emptying, resecting this additional stomach reduces collateral flow in the stomach wall at the point where it is most tenuous6,7 and vulnerable to ischemic leak. If not needed for oncologic margins, transferring a generous width of whole stomach is safer and functionally effective.7,20 Replacement of the entire esophagus with a reversed greater curvature tube was rediscovered by Gavriliu,32 and for a while championed by a variety of surgeons.33-35 Detaching a greater curve tube, either proximally or distally based, from the body and fundus of the stomach creates a long, vulnerable suture line where microcirculatory collaterals are at their most tenuous and has been associated with high rates of leaks and strictures. Because whole stomach works well and easily reaches the neck, there is infrequent need for these gastric tubes. If one wishes to preserve the gastric reservoir, it is preferable to use colon or jejunum for the conduit.

Jejunum Jejunum may replace the lower esophagus as (1) a Rouxen-Y reconstruction, (2) a pedicled interposition between abdominal or intrathoracic esophagus and stomach, or (3) a free tissue graft transposed to the neck, where its artery and vein are anastomosed with microvascular techniques to suitable vessels in the cervical area (Cooper and Miller, 1999).36 Jejunum is readily available, and its peristalsis may help transport of the food bolus. It does not require a bowel preparation, and its diameter is a convenient match for the esophagus. As a pedicled graft, it is an excellent replacement for the distal esophagus.37 As an interposed isoperistaltic conduit the jejunum becomes an effective barrier against gastroesophageal reflux, especially if its overall length is at least 15 cm and if the intra-abdominal portion is sufficient to allow anastomosis well down on the posterior wall of the stomach.12,37,38 Although constructing an interposed segment of jejunum is usually performed using both thoracic and abdominal exposures, some surgeons use a transabdominal approach, enlarging the esophageal hiatus for exposure of the lower mediastinum.39 The limiting factor with jejunum is the tight radius of the looping branches of the superior mesenteric artery, which resembles parachute shrouds pulling down from the edge of the canopy. What limits the level to which the jejunum can be elevated is not the length of the viscus but the configurations of these vascular arcades.40 In children with good arteries and generally fat-free mesentery, careful division of the secondary vascular arches with preservation of the marginal

arcades has allowed staged reconstruction to the neck.41 Supercharging the marginal distal blood supply with microvascular anastomosis to cervical or internal mammary vessels42 has also allowed extension to the neck, even allowing interruption of the entire marginal vascular arcade to uncoil the mesenteric tether.43 Other than in a few reported series, however, pedicled grafts of jejunum are limited to the level of the pulmonary hilum or lower. Interposed in this position, it has generally performed well as a substitute for the distal esophagus and can be considered as an alternative to short-segment colon interposition (Cooper and Miller, 1999).36,37 A Roux-en-Y jejunal segment has become the standard reconstruction after total gastrectomy and distal esophagectomy. There is still varying opinion as to whether adding a pouch to the loop improves long-term function. Two recent reviews acknowledge the lack of conclusive data but suggest that current evidence favors creating a pouch.44,45 A discussion of the use of the Roux-en-Y reconstruction as an alkaline diversion procedure for severe alkaline reflux can be found in Chapter 57.

Colon A pedicled segment of isoperistaltic left colon is a versatile substitute for excised esophagus in the treatment of a wide variety of maladies, benign and malignant, in patients from infancy to old age. Colon is the organ to which the surgeon likely turns when the stomach has been truncated by caustic burn, scar, ulceration, or previous operation. It has been a successful esophageal substitute for a wide variety of conditions, including long-segment esophageal atresia, malignant tracheoesophageal fistula, benign stricture, lye burns, perforation, and failed gastric pull-up as well as after unsuccessful operations for achalasia (Watson et al, 1997).13,29,46,47 Although stomach can usually reach the pharynx, the improved functional results of colon interposition at that level make colon the conduit of choice for combined esophagopharyngeal replacement.29-31 The most successful technique uses the left and transverse colon based on the ascending branch of the left colic artery (Watson et al, 1997).13,29,46,47 The marginal artery is more consistent than on the right. The marginal vessels of the colon lie straight and close to the viscus, allowing a direct path to thorax or neck by any anatomic pathway. The caliber of its lumen matches that of the esophagus. Disadvantages of using an isoperistaltic segment of left colon are few. A bowel prep is desirable, making it difficult to use as an ad hoc maneuver in the event of an unexpected intraoperative disappointment with another organ. Requiring extensive and careful mobilization to define and preserve its vascular pedicle and three anastomoses, it is a long operation, even with two teams working synchronously. Its complexity particularly rewards the surgeon with extensive experience in its use. However, given the general popularity and usefulness of stomach as a conduit in the most common setting of resection for cancer, colon interposition is a procedure infrequently used by most surgeons, except those who have adopted it as one of their primary reconstructions of choice

557

558

Section 6 Operative Techniques

for both malignant and benign disease (Watson et al, 1997).13,47 Acute complications include a low rate of anastomotic leak, but the frequency of ischemia preventing or complicating long-segment colon interposition approaches 10%.29,47 Reflux is usually not a problem. Anastomotic strictures occur infrequently. Redundancy of the transposed colon segment can slow passage of the food bolus, requiring later surgical shortening.47,48 Contraindications to the use of large intestine as an esophageal substitute include atherosclerosis involving the visceral arterial trunks, abdominal aortic aneurysm that threatens the inferior mesenteric artery, and anatomic discontinuity of the marginal artery. Belsey46 has observed that mild diverticulosis does not seem to impede its use, but episodes of diverticulitis prohibit its use. If circulation through the marginal artery to a long segment of colon appears inadequate, threatening success of interposition to the neck, the middle colic vessels supplying the cervical extent of the transplant can be anastomosed to suitable artery and vein in the neck, a so-called “supercharged” graft.29,49-52 Isoperistaltic right colon can also be used as an esophageal substitute. However, its marginal blood supply is less reliable than that of the left and transverse colon. Moreover, the bulky cecum can be awkward to position in the mediastinum. Although it has had greater popularity in the past, right colon is now best regarded as an option when stomach or left colon is unavailable (Watson et al, 1997).13 Whatever segment is used, colon functions best as an esophageal substitute when placed in isoperistaltic orientation. Antiperistaltic colon segments should be avoided (Watson et al, 1997).12,13,29,46 Good long-term functional results can be obtained with colon interposition either as a short segment into the chest or as a long segment to the neck.29,47 For patients with long life expectancy, the absence of severe reflux problems makes it much preferred to intrathoracic esophagogastrectomy even if the latter has a role as a relatively short-term palliative operation for cancer. The good functional results of longsegment colon interposition to the neck along with the ability to extend the distal extent of gastric resection and preserve the distal stomach as a reservoir make it the conduit of choice in a few centers for patients with end-stage benign disease or those with early cancers in whom long-term survival is likely (Watson et al, 1997).13,47 Short-segment colon interposition is an alternative after resection of an undilatable distal benign esophageal stricture. It preserves a generous length of normal thoracic esophagus. Short-segment colon interposition has generally been performed through a left thoracoabdominal incision that provides excellent exposure but often leaves the patient with significant long-term incisional complaints. Separate abdominal and thoracic incisions should be considered in this case. However, surgical resection of reflux-induced stricture at the esophagogastric junction is performed infrequently in this era of more effective medical acid suppression and more frequent antireflux surgery. More often, the extent of benign disease or high-grade dysplasia calls for subtotal esophagectomy with reconstruction to the neck.28

In many instances in which excellent long-term functional results are demanded, colon interposition and gastric pull-up with cervical anastomosis are alternative reconstructive choices. Each has its advocates who have become expert with consistent practice.4,13 Our own experience has been similar to that of the majority of surgeons. The good long-term functional results of bringing stomach through the posterior mediastinum to the cervical esophagus make this a simpler, widely applicable, and more frequently used procedure preferable to colon interposition when adequate healthy stomach is available (Orringer et al, 2001).4,28,29 If adequate stomach is not available because of disease or extent of resection, long-segment colon interposition to the neck is the preferred alternative.

Revascularized Free Grafts of Abdominal Viscera Use of flaps with defined axial blood supply and applying microsurgical techniques for anastomosing very small arteries and veins have broadly advanced the practice of free tissue transfer in reconstructive surgery in a wide range of anatomic locations.53 Free visceral grafts are an option for replacement of the cervical esophagus and pharynx when the thoracic esophagus is normal. Early use of abdominal viscera as a free graft for segmental esophageal replacement includes Seidenberg and associates’ use of jejunum54 and Hiebert and Cummings’55 use of revascularized gastric antrum. Colon segments have also been used as free grafts (Chen and Tang, 2000).56,57 Currently, jejunum is the abdominal organ most frequently used as a free tissue transfer for cervical esophageal or pharyngoesophageal reconstruction (Chen and Tang, 2000).53,56-60 Free visceral transfers allow wide proximal resection of the pharynx for malignant disease or extensive caustic stricture (Chen and Tang, 2000).56,61 Their use can preserve normal distal esophagus and an intact lower esophageal sphincter as long as the extent of distal cervical resection leaves sufficient exposure for a safe anastomosis in the lower neck or thoracic inlet. If required, this exposure can be improved by midline division of the manubrium and upper few centimeters of sternum.62 If less than the full circumference of the original organ needs repair, the jejunal transplant may be opened longitudinally and applied as a gusset (Chen and Tang, 2000).53,56 Like other esophageal replacements, complications include ischemia, anastomotic leak, and stenosis. For pharyngeal and cervical esophageal resections, free visceral transfers are alternatives to transhiatal resection of the entire esophagus and pharynx and reconstruction with longsegment colon interposition. Free grafts are complex, timeconsuming operations requiring specialized training and continued experience with microsurgical techniques. Most reports of their success come from head and neck or plastic and reconstructive surgical services. In addition to their applicability to major pharyngeal-cervical esophageal resections, they have particular usefulness in replacing an ischemic or failed cervical segment of a conventionally transposed viscus (Chen and Tang, 2000).56,63

Chapter 51 Selection and Placement of Conduits

Supercharged Pedicle Flaps 64

Longmire was the first to apply the then newly emerging techniques of vascular anastomosis to use the internal mammary vessels to augment blood flow to pedicled longsegment jejunal limbs extended to the neck. Microvascular anastomoses of distal (relative to arterial flow) visceral vessels to cervical or upper mediastinal vessels can prevent ischemia of conventionally pedicled visceral grafts such as colon or jejunum if blood flow to the cervical segment is tenuous (Chen and Tang, 2000).29,42,49,50,56,65 This technique can be used with jejunal grafts in which the marginal arcade is deliberately interrupted to uncoil the mesentery to allow the small bowel to reach the neck.41,43 In this case, the circulation of the proximal segment of the jejunal graft is entirely dependent on the microvascular cervical anastomoses.

Skin or Myocutaneous Flaps Skin or myocutaneous flaps are another alternative, particularly in pharyngeal-cervical esophageal reconstructions. These can be pedicled, or, more often, used as free transfers. Bulky myocutaneous flaps from the chest wall (pectoralis major or deltopectoral) are now used only if more soft tissue is needed to cover a lateral cervical defect especially after neck dissection and/or radiation therapy.53 Thinner, more pliable free flaps of skin, most frequently from the forearm based on the radial artery, are currently used.58 They are most useful as an onlay patch for lateral pharyngeal defects and salivary fistulas. They can also be rolled into a tube as a last ditch effort to replace a short circumferential defect of pharynx and cervical esophagus (Chen and Tang, 2000).56,57 Like free visceral transfers, these are highly specialized plastic and reconstructive techniques utilized primarily by head and neck tumor services and applied primarily to pharyngeal defects with associated loss of a short segment of cervical esophagus. They are also useful as yet another fallback option for repair of secondary leaks or salivary fistulas in the neck.

External Bypass With a Prosthesis An external prosthesis was used to intermittently connect the cervical esophagus and stomach after the first successful esophagectomy by Thorek.66 There is limited contemporary experience with this technique.12,67 If the esophagus cannot be definitively reconstructed with biologic tissue, most patients today will survive with a cervical salivary fistula and a feeding gastrostomy or jejunostomy. If a portion of proximal thoracic esophagus can be preserved, the proximal esophagostomy can be placed over the upper sternum rather than on the side of the neck. The midline position is much more conveniently contoured for an ostomy bag to collect salivary secretions.

POSITIONING OF THE CONDUIT Posterior Mediastinum Route The route used to position the esophageal substitute is often determined by the extent of visceral resection and the incisions and exposures required by the resection. There is con-

sensus that removal of the esophagus is preferable to bypassing and leaving it in situ even with benign conditions (Orringer et al, 2001; Watson et al, 1997).4,13,22 The posterior mediastinal bed of the resected esophagus is the route of choice for reaching the neck. It has the advantage of being the most direct and free of angles and turns. It can be used from the abdomen, the abdomen and neck, or via a thoracotomy on either side. It is 5 to 10 cm shorter than the substernal route.68 The vagal-sparing technique of transhiatal esophagectomy described by Akiyama and associates69 and further elaborated by DeMeester and colleagues70 is a variant of the posterior mediastinal route. A vein stripper is passed through the esophageal lumen from abdomen to neck, where it is secured to the distal end of the divided cervical esophagus. As the vein stripper is then withdrawn back into the abdomen, the thoracic esophagus is progressively inverted and stripped from the mediastinum, sparing the adjacent vagal plexus and nerves. An isoperistaltic long segment of left colon is passed to the neck through the limited posterior mediastinal tunnel within the vagi to connect cervical esophagus to stomach. In patients with end-stage achalasia, the dilated muscular tube of esophagus remains as the tunnel for the colon interposition. Compared with conventional reconstructions that sacrifice both vagi, the reported results of this technique have noted fewer gastrointestinal complications such as dumping, delayed gastric emptying, and diarrhea.70 This technique has been applied mainly to patients with benign disease, including Barrett’s esophagus with high-grade dysplasia, but it has also been applied to selected patients with intramucosal carcinoma. Further experience will better define the indications and benefits of this interesting alternative.

Substernal Route The retrosternal route created by blunt dissection is most useful when the posterior mediastinum is frozen or when extensive adhesions block safe crossing of the pleural space. It can be used for both stomach and colon, although experience with substernal stomach as a bypass has been less than satisfactory.22 In addition to being a somewhat longer route than through the posterior mediastinum, the substernal route creates two angles in its course. One is where the interposed visceral segment comes forward from its posterior position in the neck to reach the substernal tunnel. Distally, the conduit must then usually angle posteriorly from the xiphoid to reach stomach or duodenum. Previous cardiac or great vessel operations through a sternotomy may prevent using this route, and, in turn, a substernal viscus will interfere with any future operation requiring sternotomy. It is important to ensure an adequate space at the upper mediastinal entrance, and, for this, resection of a portion of manubrium and head of clavicle is a useful technique. The substernal route has had wider usage in the past. The current preference for resecting esophagus rather than bypassing it and better functional results make the posterior mediastinal route preferable, if it is technically feasible.

559

560

Section 6 Operative Techniques

The subcutaneous presternal route is a tunnel of last resort. It has obvious cosmetic disadvantages and functionally may require manual milking of the food bolus to propel it through.

is used to avoid the reflux complications inherent in a direct low esophagogastric anastomosis. As should be clear from the previous brief descriptions, these are complex procedures performed by expert and experienced esophageal surgeons. Although the surgical approach is from the abdomen, the enlarged hiatus allows extensive dissection and construction of stapled anastomosis in the lower mediastinum. Attempting a limited esophagogastrectomy through the normal esophageal hiatus, on the other hand, provides the potential for all the complications of dangerously limited visualization for anastomosis, inadequate axial tumor margins, and severe reflux problems postoperatively. Even with small tumors, this limited transabdominal esophagogastrectomy should be avoided.

Endoesophageal Route

SPECIFIC SITUATIONS

The esophagus itself may be used as a tunnel for routing stomach or colon to the neck. The mucosa and submucosa are stripped from within the esophagus, leaving a distensible muscle sleeve through which the transposed viscus is passed to the neck. Described by Saidi and associates,71 it avoids the potential hazards of mediastinal dissection by conventional transhiatal esophagectomy. It is only useful for limited lesions at the esophagogastric junction or cervical esophagus. There is very little reported experience with this technique, and experienced surgeons have made conventional dissection during transhiatal esophagectomy remarkably safe, reducing the need for an intraesophageal route.

We conclude this chapter with a summary addressing the more common situations requiring a new esophageal conduit.

Transpleural Route The transpleural route is used by pediatric surgeons and may be useful in the adult when neither the posterior mediastinal nor substernal routes are available. Compression of the lung by the transposed viscus is of some concern.46 It has been a route used for palliative bypass of unresectable, obstructing carcinoma.

Subcutaneous Route

Transabdominal Anastomosis The short intra-abdominal length of esophagus allows for anastomosis of esophagus to stomach or other abdominal viscus from an exclusively abdominal approach. This is most frequently used for a Roux-en-Y jejunal reconstruction after total gastrectomy for gastric cancer where a limited extent of distal esophagus is resected for satisfactory oncologic margins. Widening the esophageal hiatus by incising it anteriorly improves the exposure of the lower mediastinum, allowing for wide resection under direct vision of both pleura as well as the lower mediastinal lymph nodes.72 Siewert and Stein73 have successfully used this enlarged transhiatal exposure of the mediastinum to perform an extended total gastrectomy, distal esophagectomy, and wide en-bloc abdominal lymph node resections for tumors of the esophagogastric junction and proximal stomach (Siewert types II and III). A Roux-enY loop of jejunum is used for reconstruction. With this expanded transhiatal exposure, the anastomosis is not in the abdomen but in the lower mediastinum, constructed using the circular endoluminal stapling devices.72 They have recently used this same extended transabdominal exposure to resect distal esophagus and proximal stomach for early (T1) adenocarcinomas located just above the esophagogastric junction (Siewert type I). This resection also includes extended en-bloc nodal clearance, and gastrointestinal continuity is restored with pedicled jejunal interposition from mediastinal esophagus to the residual stomach.39 The jejunal interposition

Cancer For most patients with esophageal cancer even without evident metastatic disease, palliation for a finite interval is still more likely than cure. Reconstruction with stomach, either to the neck or high in the right side of the chest, remains the most common procedure. These operations are the most straightforward, requiring only a single anastomosis, and provide adequate function. Our preference is to bring stomach to the neck whenever possible. Colon or, less frequently, jejunum is used primarily when stomach is not available.

Long-Term Life Expectancy For patients with benign disease, Barrett’s esophagus with high-grade dysplasia, or early invasive cancer (T1 N0), longterm survival is likely and there is greater concern for longterm function. Intrathoracic esophagogastric anastomoses are too prone to reflux even when performed high in chest to be recommended here. Functional results with cervical esophagogastric anastomosis using the posterior mediastinal route have been good enough that this is now, for most surgeons, the preferred choice for reconstruction when long-term survival is expected. Colon interposition is the alternative conduit that is most useful when stomach is not available. It must be noted, however, that a small number of leading esophageal surgeons use the left colon as the conduit of choice for good long-term functional results (Watson et al, 1997).13,47

Pharyngoesophageal Resections For radical cervical resections for cancer or corrosive injury that require total or partial laryngectomy, the preferred alternatives are subtotal transhiatal esophagectomy with colon interposition or free visceral graft, most often jejunum. The latter alternative requires that the distal extent of disease and cervical resection permit exposure for safe anastomosis at the

Chapter 51 Selection and Placement of Conduits

thoracic inlet. Extensive corrosive injury can damage the pharynx and stomach as well as the entire esophagus, requiring long-segment colon to open the scarred pharynx and replace the entire esophagus.

Total Gastrectomy After total gastrectomy with distal esophagectomy, Rouxen-Y esophagojejunostomy is the reconstruction of choice with or without using a redundant loop to create a pouch to enlarge the reservoir. There appears to be no advantage to interposition to duodenum in this setting.44,45 After total or subtotal esophagectomy and total gastrectomy, colon interposition from neck to duodenum is the preferred reconstruction.

Reoperation and Salvage Reoperations for failed prior visceral reconstruction can severely tax the surgeon’s creativity and the patient’s stamina. Failure is usually in the cervical segment. Although located proximal in the gastrointestinal tract, this represents the distal blood supply and thus is most vulnerable to ischemia. If identified at the primary operation, ischemic failure can be prevented by “supercharging” the visceral pedicle flap. Anticipation of this problem and having appropriate surgical expertise available for microvascular anastomosis is necessary. For established ischemic loss of cervical conduit, surgical management by free graft of viscera (usually jejunum) or skin (currently a forearm flap based on the radial artery is preferred) can be utilized. For partial circumferential defects and salivary fistulas, onlay jejunum or forearm skin flaps are the first choices. Myocutaneous flaps based on axial blood supply from the chest wall are reserved for situations requiring additional soft tissue for coverage.

LIMITS OF SURGICAL PALLIATION A generation ago, surgical resection or bypass was regularly performed to relieve luminal obstruction in patients with metastatic esophageal cancer.18 The goal of this often desperate attempt was to allow the patient to swallow at least a modest diet and to avoid the cesspool of a totally obstructed esophagus with a patient unable to swallow even his or her own saliva. However, the brevity of survival coupled with the very high mortality and morbidity of performing major operative procedures in this subgroup has led to a general shift away from resection or bypass in patients with far advanced cancer. Today, most experienced esophageal surgeons avoid either resection or bypass in the presence of significant metastatic disease. Modern techniques of radiation therapy and chemotherapy have provided more sustained relief of obstructive symptoms. When obstruction persists or recurs, newer endoluminal stents placed endoscopically will frequently palliate for the limited life expectancy remaining.27 In short, with advanced cancer the best conduit may be to preserve the patient’s own esophagus with its lumen maintained by stents and adjuvant treatment.

COMMENTS AND CONTROVERSIES From this chapter it becomes clear that reconstruction, be it after resection or as a bypass procedure, is a complex difficult task. Meticulous attention to even the smallest details is of paramount importance, as indeed the slightest technical failure may have dramatic consequences (e.g., anastomotic leaks as a result of undue traumatization of the gastric fundus, redundancy, and kinking of a colon interposition causing malabsorption, and dysphagia). Gastroplasty, because of its relative technical simplicity and its good to excellent functional outcome, has become the “workhorse” covering the needs of the vast majority of reconstructions. Other reconstruction modalities, therefore, are less frequently used and, if so, often in more difficult and particular circumstances (e.g., after major gastric surgery). As a result, these reconstruction modalities are more challenging and the outcome perhaps less satisfactory if they are not properly performed. Here, mastery of the full spectrum of reconstruction techniques is the key to success, and it seems logical to confer such complex interventions to surgeons and centers familiar with all these different operations. The recent introduction of nonsurgical treatment of early carcinoma by endomucosal resection or other endoscopic techniques has challenged the surgeons to improve both the short-term and long-term (i.e., functional) outcome of their surgery. Quality of life has become a major topic of interest. Vagal-sparing esophagectomy followed by colon interposition or gastroplasty after denervation of the lesser curvature has been described seemingly with superior functional outcome. Others have reintroduced the Merendino-type jejunal interposition after vagal-sparing partial esophagectomy more specifically in the surgical treatment of early cancer in short Barrett’s esophagus, again claiming superior functional outcome as compared with the classic subtotal esophagectomy with cervical esophagogastrostomy. And, finally, the total thoracoscopic laparoscopic subtotal esophagectomy and gastroplasty is another attempt to minimize the surgical trauma and to improve quality of life. Most of these operations as mentioned are used in the treatment of early esophageal cancer. However, it is well known that once the tumor reaches the submucosa (T1b) the incidence of lymph node involvement increases sharply, up to 30% to 50%. It remains, therefore, to be seen if less aggressive surgery is resulting in equal oncologic outcome as compared with more radical surgery. These are situations in which a correct balance between following sound surgical oncologic principles must be balanced against the concerns about improving functional outcome and quality-of-life considerations. T. L.

KEY REFERENCES Chen H, Tang Y: Microsurgical reconstruction of the esophagus. Semin Surg Oncol 19:235, 2000. ■ The authors describe the variety of visceral and skin flaps currently used for reconstruction of the cervical esophagus and pharynx. Free jejunal flap is their first choice. The wider lumen of colon makes it useful for large oropharyngeal defects. Free skin grafts with anastomoses to their axial blood supply have largely replaced pedicled myocutaneous flaps from the chest wall. Cooper WA, Miller JI: Jejunal interposition for esophageal replacement. Oper Tech Thorac Cardiovasc Surg 4:239, 1999.

561

562

Section 6 Operative Techniques

■ A succinct and clearly illustrated description of techniques for using jejunum in all

three alternatives: as a Roux-en-Y limb, as a pedicled interposed segment, and as a free graft to the neck. As a pedicled interposition, they rank jejunum as the third choice for esophageal replacement after stomach and colon. Liebermann-Meffert DMI, Meier R, Siewert JR: Vascular anatomy of the gastric tube used for esophageal reconstruction. Ann Thorac Surg 54:1110, 1992. ■ In this elegant study of the anatomy of gastric blood and the intragastric collaterals, emphasis is placed on the blood supply to the greater curvature used for construction of a gastric tube. The study demonstrates that the critical part of the greater curve aspect of the fundus on which the reversed gastric tube is based has the poorest collateral supply, depending entirely on the submucosal and mucosal microvascular network. It is nicely confirmed by the work of Collard and colleagues.7 Orringer MB, Marshall B, Iannettoni MD: Transhiatal esophagectomy for treatment of benign and malignant esophageal disease. World J Surg 25:196, 2001. ■ Dr. Orringer introduced the modern operation of transhiatal esophagectomy to a skeptical world in 1978. Since then, it has become one of the most frequently used methods for resecting the esophagus. This article summarizes the results of 1085 transhiatal esophagectomies performed by Dr. Orringer and his colleagues. They

emphasize the good long-term functional results of the cervical esophagogastric anastomosis using the posterior mediastinal bed of the resected esophagus. With benign disease, good or excellent functional results were achieved in 68% of patients. Three fourths of the patients in long-term follow-up underwent at least one anastomotic dilation, although strictures requiring continued dilation developed in only 4%. The incidence of anastomotic leak and the need for dilation have substantially dropped after introducing the partially stapled anastomosis using the endoscopic linear cutting stapler. Nocturnal reflux requiring elevation of the head of the bed occurred in 7%. The authors conclude that transhiatal esophagectomy is applicable to most patients requiring esophageal resection for either benign or malignant disease. Watson TJ, Peters JH, DeMeester TR: Esophageal replacement for end-stage benign esophageal disease. Surg Clin North Am 77:1099, 1997. ■ This reference summarizes the experience and preference for long-segment colon interposition by a well-recognized group of outstanding foregut surgeons. Their operation now includes a proximal gastrectomy to prevent gastric stasis. Their clear preference is for a cervical esophagocolon anastomosis and the posterior mediastinal route. They have abandoned intrathoracic esophagogastric anastomoses because of complications of severe reflux. The technique of vagal sparing esophagectomy is also outlined and referenced.

chapter

TRANSHIATAL ESOPHAGECTOMY

52

Mark B. Orringer

Key Points ■ A successful transhiatal esophagectomy involves an orderly series

■

■

■

■

of steps in the abdominal, cervical, and mediastinal phases of the operation. A surgeon’s assessment of esophageal mobility on manual palpation through the diaphragmatic hiatus is the most important determinant of the appropriateness of a transhiatal esophagectomy. A surgeon performing a transhiatal esophagectomy is not absolved of the responsibility of having a firm knowledge of thoracic anatomy and the complications of esophagectomy and their management. A properly mobilized stomach should be as pink in the neck prior to the esophagogastric anastomosis as it was in the abdomen when the operation began. A cervical esophagogastric anastomotic leak translates to a stricture in 50% of cases; a meticulous side-to-side stapled anastomosis minimizes the risk of this complication.

HISTORICAL NOTE In 1913, using a vein stripper to avulse the esophagus from the posterior mediastinum, Denk1 first reported the performance of blunt transmediastinal esophagectomy without thoracotomy in cadavers and experimental animals. In 1933, Turner2 carried out the first successful transhiatal esophagectomy for carcinoma and re-established continuity of the alimentary tract using an antethoracic skin tube at a second operation. As endotracheal anesthesia became established, thus permitting transthoracic esophagectomy under direct vision, transhiatal esophagectomy was essentially forgotten, being used only occasionally as a concomitant procedure with laryngopharyngectomy for pharyngeal or cervical esophageal carcinomas when the stomach was employed to restore continuity of the alimentary tract. In the 1960s, Ong and Lee3 and LeQuesne and Ranger4 reported the first successful primary pharyngogastric anastomoses after laryngopharyngectomy and transhiatal esophagectomy. In these cases and in a case reported by Akiyama and associates in 1971,5 an essentially normal thoracic esophagus was being resected. Kirk6 used the transhiatal approach for palliation of incurable esophageal carcinoma in five patients in 1974. In 1977, Thomas and Dedo7 treated four patients with severe chronic pharyngoesophageal caustic strictures with transhiatal esophagectomy, mobilizing the stomach through the posterior mediastinum and performing a pharyngogastric anastomosis. Historically, however, throughout the world the most widely used technique for

esophageal resection and reconstruction was a transthoracic approach with an intrathoracic esophagogastric anastomosis. The notion long prevailed that the mobilized stomach would not easily reach to the neck. In the early 1970s, in an attempt to lessen the morbidity and mortality of traditional esophageal resection and reconstruction, my colleagues and I adopted a policy of avoiding an intrathoracic esophagogastric anastomosis whenever possible. Based on autopsy room measurements of the mobilized stomach, we were convinced that the properly mobilized stomach could virtually always reach to the neck. Regardless of the level of esophageal pathology, the entire thoracic esophagus was resected and a cervical esophageal anastomosis performed. Although this approach necessitated three incisions (cervical, thoracic, and abdominal), death from anastomotic disruption after esophagectomy virtually disappeared on our service. In 1974, while mobilizing the stomach transabdominally in a patient with a sliding hernia and a small distal third esophageal adenocarcinoma in preparation for a standard transthoracic esophageal resection and esophageal reconstruction, I mobilized nearly 4 inches of esophagus out of the posterior mediastinum and into the abdomen through the diaphragmatic hiatus. My experience with mediastinoscopy for the evaluation of patients with carcinoma of the lung had taught me that the index finger could reach through a cervical incision into the mediastinum to the level of the carina. Therefore, in this particularly obese patient, who was regarded as a high risk for thoracotomy, a cervical incision was made and, with one hand in the abdomen through the diaphragmatic hiatus and in the posterior mediastinum and the other hand in the superior mediastinum through the cervical incision, a “blunt” esophageal mobilization was performed and the esophagus extracted. The mobilized stomach was positioned in the posterior mediastinum in the original esophageal bed, and a cervical esophagogastric anastomosis was constructed. The successful outcome of this initial experience with transhiatal esophagectomy without thoracotomy was the basis for our initial report in 1978 of the procedure in 28 patients, of whom 4 had benign disease of the intrathoracic esophagus and 22 had carcinomas involving various levels of the esophagus (Orringer and Sloan, 1978).8 Additional reports of experience with transhiatal esophagectomy quickly followed in the late 1970s and 1980s, some supportive,9-15 others not.16-19 Since its initial description, critics of transhiatal esophagectomy warned that the operation violates basic surgical principles of adequate hemostasis and exposure and falls short as a “cancer operation” because it precludes a complete en-bloc mediastinal lymph node dissection. Published experience of 563

564

Section 6 Operative Techniques

my group20-26 and of others27-30 has now amply addressed these criticisms with objective data. Katariya and colleagues,31 in their 1994 collective review of the complications of transhiatal esophagectomy in 1353 reported patients, cited an overall 30-day mortality of 7.1%; a 1.3% incidence of massive intraoperative bleeding, necessitating conversion to a transthoracic procedure; an 11.3% incidence of recurrent laryngeal nerve injury; a 50% incidence of “thoracic or pulmonary complications”; and a 15.1% anastomotic leak rate. Seventy percent of the referenced papers, however, were series of 50 patients or fewer and therefore represented the initial phase of the “learning curve” with this procedure. In 1997, a review of 1192 patients by Gandhi and Naunheim32 cited an average mortality rate of 6.7%, a 3% incidence of mediastinal hemorrhage, a 9% incidence of recurrent laryngeal nerve injury, a 12% incidence of respiratory complications, a 12% incidence of anastomotic leak, and a 15% incidence of cardiac complications. Fifty percent of the referenced papers were series of 100 or more patients. The 1999 University of Michigan report by my colleagues and I on 1085 transhiatal esophagectomies for diseases of the intrathoracic esophagus represents the largest published experience with this operation and provides a benchmark standard (Orringer et al, 1999).33 Transhiatal esophagectomy has emerged as a widely accepted alternative operative approach that may be associated with substantially less risk and morbidity. Transhiatal esophagectomy avoids the morbidity of a thoracotomy, and the routine cervical esophageal anastomosis minimizes the potential for mediastinitis resulting from anastomotic disruption as a cause of postoperative death. Furthermore, the abdominal approach used for the esophagectomy provides optimal access to all portions of the gastrointestinal tract used for esophageal substitution. My group’s experience with more than 2000 transhiatal esophagectomies has justified our current belief that there is seldom an indication for opening the thorax in the majority of our patients requiring esophageal resection for either benign or malignant disease. HISTORICAL READINGS Akiyama H, Sato Y, Takahashi F: Immediate pharyngogastrostomy following total esophagectomy by blunt dissection. Jpn J Surg 1:225, 1971. Bains MS, Spiro RH: Pharyngolaryngectomy, total extrathoracic esophagectomy and gastric transposition. Surg Gynecol Obstet 149:693, 1979. Cordiano C, Fracastoro G, Mosciaro O, Mozzo W: Esophagectomy and esophageal replacement by gastric pull-through procedure. Int Surg 64:17, 1979. Denk W: Zur Radikaloperation des Osophaguskarfzentralbl. Chirurg 40:1065, 1913. Kirk RM: Palliative resection of esophageal carcinoma without formal thoracotomy. Br J Surg 61:689, 1974. LeQuesne LP, Ranger D: Pharyngogastrectomy with immediate pharyngogastric anastomosis. Br J Surg 53:105, 1966. Ong GB, Lee TC: Pharyngogastric anastomosis after oesophagopharyngectomy for carcinoma of the hypopharynx and cervical esophagus. Br J Surg 48:193, 1960. Orringer MB: Partial median sternotomy: Anterior approach to the upper thoracic esophagus. J Thorac Cardiovasc Surg 87:124, 1984.

Orringer MB: Technical aids in performing transhiatal esophagectomy without thoracotomy. Ann Thorac Surg 38:128, 1984. Orringer MB: Transhiatal esophagectomy without thoracotomy for carcinoma of the thoracic esophagus. Ann Surg 200:282, 1984. Orringer MB: Transhiatal esophagectomy for benign disease. J Thorac Cardiovasc Surg 90:649, 1985. Orringer MB: Transhiatal esophagectomy for benign and malignant disease. J Jpn Assoc Thorac Surg 36:656, 1988. Orringer MB, Marshall B, Stirling MC: Transhiatal esophagectomy for benign and malignant disease. J Thorac Cardiovasc Surg 105:265, 1993. Orringer MB, Sloan H: Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg 76:643, 1978. Szentpetery S, Wolfgang T, Lower RR: Pull-through esophagectomy without thoracotomy for esophageal carcinoma. Ann Thorac Surg 27:399, 1979. Thomas AN, Dedo HH: Pharyngogastrostomy for treatment of severe caustic stricture of the pharynx and esophagus. J Thorac Cardiovasc Surg 73:817, 1977. Turner GG: Excision of thoracic esophagus for carcinoma with construction of extrathoracic gullet. Lancet 2:1315, 1933.

PATIENT SELECTION I regard virtually every patient in need of an esophagectomy for either benign or malignant disease as a potential candidate for transhiatal esophagectomy. Age per se is not a contraindicating factor, with an increasing number of octogenarians and nonagenarians requiring esophageal resection for a variety of esophageal pathologic processes. Physiologic, not chronologic, age is more important in this decision, and the determination of the patient to have the operation is often one of the best indicators of the likelihood of success. Bronchoscopy is a routine part of the evaluation of every patient with an upper or middle third thoracic esophageal carcinoma, and endoscopic evidence of tracheobronchial invasion by the esophageal tumor is an absolute contraindication to transhiatal esophagectomy. In patients with malignant cervicothoracic tumors of the esophagus, larynx, or thyroid gland in whom a cervical exenteration (laryngopharyngoesophagectomy) and an anterior mediastinal tracheostomy are being contemplated, at least a 5-cm length of uninvolved trachea proximal to the carina after the resection is optimal, and accurate bronchoscopic measurement of the distance between the tumor and the carina is a routine part of preoperative assessment of resectability.34 With the exception of some patients with limited celiac lymph node metastases (M1a stage IVa esophageal carcinoma), patients with stage IV esophageal carcinoma have an extremely poor prognosis and are not regarded as candidates for esophagectomy. Careful preoperative staging of esophageal carcinoma with CT of the chest and abdomen, positron emission tomography (PET), and esophageal endoscopic ultrasonography (EUS) is now routine. Although convincing evidence of stage IV disease can be surmised on the basis of a widely positive PET scan, patients with “solitary metastases” on PET generally warrant tissue diagnosis proof of incurability (e.g., with a fine-needle aspiration biopsy of the liver or a supraclavicular node biopsy). Patients with a history of hypertension or coronary artery disease should undergo preoperative cardiology clearance for

Chapter 52 Transhiatal Esophagectomy

general anesthesia with objective tests of myocardial perfusion and ventricular function to exclude contraindicating cardiac risk factors. Periesophageal fibrosis from prior esophageal operations, caustic injuries, or radiation therapy does not preclude a transhiatal esophagectomy. In patients with such a history, however, the surgeon must have a relatively low threshold for converting to a transthoracic esophageal resection if significant intrathoracic periesophageal adhesions are encountered upon assessment of the esophagus through the diaphragmatic hiatus. This is of particular importance in patients who have undergone a previous esophagomyotomy for either achalasia or esophageal spasm and in whom fusion between the exposed esophageal submucosa and the adjacent aorta may predispose to disastrous intraoperative bleeding at the time of esophagectomy. In every transhiatal esophagectomy, the surgeon’s assessment of esophageal mobility on manual palpation through the diaphragmatic hiatus is the most important factor in determining whether it is appropriate to proceed or whether it is better to abandon the transhiatal route for a transthoracic resection under direct vision.

Preoperative Preparation An aggressive 2- to 3-week preoperative outpatient program of pulmonary physiotherapy using an incentive inspirometer and physical conditioning by walking between 1 and 3 miles a day when possible is initiated in patients requiring an esophagectomy. Complete abstinence from cigarette smoking for a minimum of 2 to 3 weeks is mandatory. Baseline pulmonary function tests with arterial blood gas values are obtained in those with suspected or documented chronic lung disease. When the esophageal obstruction is high grade and precludes an adequate oral calorie intake of even liquid diet supplements, a nasogastric feeding tube is inserted through the tumor and into the stomach and enteral feedings providing 2000 to 3000 calories/day are administered. In patients with a history of previous gastric disease or surgery that might preclude use of the stomach for esophageal replacement, a barium enema study is obtained to evaluate the suitability of the colon as an esophageal substitute, and the colon is prepared in the event that colonic interposition is required. This is not routine, however, because in patients with a normal stomach the gastric fundus readily reaches above the level of the clavicles for a cervical anastomosis. Patients who have undergone neoadjuvant chemoradiation therapy have often sustained a physiologic insult greater than the impact of the proposed esophagectomy. Although ideally esophageal resection is generally performed within 3 to 5 weeks of completion of chemotherapy and radiation therapy, some patients are far too weak and dehydrated for a major operative undertaking at that point. Careful assessment by the surgical team and the patient and his or her family of the readiness for surgery is extremely important. The operation should be delayed as necessary to improve the state of hydration and nutrition, wean the patient from narcotics used to treat radiation esophagitis, and reinstitute use of the incentive inspirometer and regular walking, which may have stopped during neoadjuvant therapy. It is far better to delay

the esophagectomy for 4 to 6 weeks after completion of neoadjuvant therapy than to proceed in a debilitated highrisk patient.

Anesthetic Considerations Two large-bore peripheral intravenous catheters, a radial artery catheter to monitor blood pressure during the esophagectomy and a thoracic epidural catheter for postoperative analgesia, are inserted before induction of anesthesia. The arterial catheter is well secured and padded, because the patient’s arms are kept at the sides during the operation to allow the surgeon access to the neck, chest, and abdomen. It is generally unnecessary to monitor central venous pressure; when this is required, however, it should be done through a right neck vein, away from the operative field on the left neck. An unshortened standard endotracheal tube is generally used so that in the rare event of a posterior membranous tracheal tear during the transhiatal dissection, the end of the tube can be advanced until the balloon is beyond the tear and direct repair can then be performed. A double-lumen endotracheal tube is rarely used. Inhalation anesthetic agents are reduced, and inspired oxygen concentration is increased as the actual transhiatal dissection is performed to minimize the adverse affects of transient hypotension that may occur during the esophagectomy and mediastinal dissection through the hiatus. The operation requires close cooperation between the anesthetist and the surgeon to minimize prolonged hypotension.

Operative Technique The patient is positioned supine with pressure points padded and a small folded sheet beneath the scapulae to extend the neck. The head is turned toward the right and stabilized with a head ring beneath the occiput. The arms are carefully padded to protect the intravenous and arterial catheters and are placed at the patient’s sides. If a prior feeding gastrostomy or jejunostomy tube has been inserted, it is removed and the skin opening sutured closed. The skin of the neck, anterior chest, and abdomen is prepared and draped from the mandible to the pubis and anterior to both midaxillary lines. Even when there is concern that a transthoracic esophagectomy may be required (e.g., with upper or middle third esophageal tumors or with a history of a previous long esophagomyotomy), I prefer the patient to be supine. If a transthoracic approach is needed, the abdomen is closed and the patient is repositioned for a standard posterolateral thoracic incision. Use of a table-mounted, self-retaining (upper hand) retractor greatly facilitates exposure. Transhiatal esophagectomy has four separate phases: 1. 2. 3. 4.

Abdominal Cervical Mediastinal The anastomosis

Abdominal Phase The entire abdominal portion of the operation is performed through a supraumbilical incision (Fig. 52-1, inset). The tri-

565

566

Section 6 Operative Techniques

FIGURE 52-1 Standard mobilization of the stomach for esophageal replacement after transhiatal esophagectomy. The mobilized stomach is based on the right gastric and right gastroepiploic vascular arcades after division of the left gastric artery and left gastroepiploic vessels. A pyloromyotomy and Kocher maneuver are performed routinely. Inset, standard left cervical incision paralleling the anterior border of the sternocleidomastoid muscle and the supraumbilical midline abdominal incision used for transhiatal esophagectomy and esophageal replacement with the stomach in the posterior mediastinum. (FROM ORRINGER MB: TRANSHIATAL

Ligated short gastric vessels

ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

Dividend left gastric artery

Pyloromyotomy Kocher maneuver

Right gastroepiploic artery

angular ligament of the liver is divided, and the left hepatic lobe is retracted to the right. It is quickly ascertained that the stomach is sufficiently free of disease and that it is a suitable esophageal replacement, and the right gastroepiploic artery is identified early and protected. This is particularly important in patients with a history of previous abdominal surgery in whom the need to divide adhesions may jeopardize the gastric blood supply. Mobilization of the greater omentum away from the stomach is begun high on the greater curvature, and the lesser sac is entered through an avascular portion of omentum. Separation of the omentum from the stomach superiorly is carried out by sequential clamping, dividing, and ligating several of the high short gastric vessels 1.0 to 1.5 cm away from the gastric wall. The right gastroepiploic artery is identified and the greater omentum separated from this vessel at least 1.5 to 2 cm inferior to the artery to minimize the chance of injuring it. This omental mobilization away from the stomach ends at the level of the pylorus, avoiding injury to the origin of the right gastroepiploic artery from the gastroduodenal artery. With the lesser sac now widely opened, retraction of the stomach to the right exposes the remaining high left gastroepiploic and short gastric vessels, which are divided and ligated along the high greater curvature of the stomach, avoiding injury to the spleen as well as gastric necrosis from ligation of these vessels too near the gastric wall. Once the greater curvature of the stomach is mobilized, the peritoneum overlying the esophageal hiatus is incised and the distal esophagus is encircled with a 1-inch Penrose drain.

Proceeding downward now along the lesser curvature of the stomach, the surgeon incises the gastrohepatic omentum along the high lesser curvature; and the left gastric artery and vein are isolated, ligated, and divided. As the gastrohepatic omentum is being divided, any aberrant left hepatic artery should be identified and preserved if substantial. Enlarged gastrohepatic ligament nodes are mobilized for resection with the stomach. When the esophagectomy is being performed for carcinoma, the celiac axis lymph nodes are resected and submitted separately to the pathologist for staging purposes. When possible, the left gastric artery is divided near its origin from the celiac axis and any adjacent lymph nodes are swept laterally along with the stomach. The right gastric artery is protected as the remainder of the gastrohepatic omentum is divided inferiorly along the lesser curvature. After the stomach has been mobilized, a generous Kocher maneuver is performed to provide sufficient duodenal mobility for the pylorus to be lifted from its usual position in the right upper quadrant of the abdomen to the level of the xiphoid process in the midline. A pyloromyotomy is then performed to avoid the possibility of delayed gastric emptying after the vagotomy that accompanies the esophagectomy. The pyloromyotomy begins with a 1.5-cm incision through gastric muscle and is carried through the pylorus and onto the duodenum for 0.5 to 1 cm (see Fig. 52-1). This is carried out with the cutting current of a needle-tipped electrocautery and a fine-tipped vascular mosquito clamp to dissect the gastric and duodenal muscle away from the underlying submucosa. Silver clip markers are placed at the level of the

Chapter 52 Transhiatal Esophagectomy

Recurrent laryngeal nerve

Esophagus Sternocleidomastoid muscle

FIGURE 52-3 The index finger is placed over the tracheoesophageal groove at the level of the cricoid cartilage, and, with gentle traction superiorly, the upper esophagus is elevated out of the superior mediastinum. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

FIGURE 52-2 The initial phase of the distal transhiatal esophageal mobilization is carried out posterior to the esophagus along the prevertebral fascia with the volar aspects of the fingers kept against the esophagus. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

pyloromyotomy for future radiographic assessment of gastric emptying. Back at the level of the diaphragmatic hiatus and the previously incised phrenoesophageal attachments, a narrow Deaver retractor is placed into the hiatus. The soft tissue and lymph nodes on either side of the esophagogastric junction and distal esophagus are sequentially mobilized toward the midline sharply with a long right-angled clamp and a long needle-tipped electrocautery. Entry into one or both pleural cavities may occur at this point and signal the need for a later chest tube. Aortic esophageal branches are champed, divided, and ligated. In this fashion, the distal 10 cm of the esophagus is mobilized from the posterior mediastinum into the abdomen by retracting the esophagogastric junction downward with the encircling Penrose drain while dissecting upward along the esophagus into the mediastinum (Fig. 52-2). As experience is gained with transhiatal esophagectomy, less of the dissection of the distal half of the esophagus is done “bluntly.” Rather, with narrow deep (Deaver) retractors inserted into the hiatus, the lateral periesophageal attachments are visually clamped with long 13-inch right-angle clamps, divided, and ligated. This direct esophageal mobilization is generally possible to at least the level of the carina. When operating for carcinoma, the surgeon assesses the mobility of the esophagus within the posterior mediastinum by grasping the tumor and “rocking” the esophagus from side

Esophagus Prevertebral fascia Carotid sheath Sternocleidomastoid muscle

FIGURE 52-4 The paraesophageal soft tissue is incised posterolaterally to the tracheoesophageal groove (dotted line), avoiding injury to the recurrent laryngeal nerve. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

567

568

Section 6 Operative Techniques

FIGURE 52-5 Elevation of the esophagus out of the superior mediastinum is maintained by the finger near the cricoid cartilage as a right-angled clamp is passed behind the esophagus from lateral to medial, thereby completing circumferential mobilization of the esophagus. The cervical esophagus is encircled with a 1-inch rubber drain. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

to side to ascertain that it is not fixed to the prevertebral fascia, the aorta, or adjacent mediastinal structures. If there is no marked fixation of the esophagus, which would preclude a transhiatal resection, the mediastinal dissection is temporarily discontinued at this point. A 14-Fr rubber jejunostomy feeding tube is inserted 4 to 6 inches beyond the ligament of Treitz and is secured in place with a Weitzel maneuver. The jejunostomy tube is not brought out through the abdominal wall until the transhiatal esophagectomy is completed.

Cervical Phase The cervical phase of the operation is performed through an oblique 6- to 7-cm incision that parallels the anterior border of the left sternocleidomastoid muscle and extends from the suprasternal notch to the level of the cricoid cartilage (see Fig. 52-1, inset). The platysma and omohyoid fascial layer are incised, the sternocleidomastoid muscle and carotid sheath and its contents are retracted laterally, and the larynx and trachea are retracted medially. No retractor should be placed against the recurrent laryngeal nerve in the tracheoesophageal groove during the entire cervical portions of this operation. The middle thyroid vein and the inferior thyroid artery are usually ligated and divided. In patients with a “bull neck”

FIGURE 52-6 The encircled cervical esophagus is retracted anteriorly and to the patient’s right as a half sponge on a stick is inserted through the cervical incision posterior to the esophagus and advanced down through the superior mediastinum along the prevertebral fascia. The esophagus is progressively mobilized away from the prevertebral fascia until the sponge stick inserted from above meets the hand inserted through the diaphragmatic hiatus. During this and subsequent steps of the transhiatal mobilization, care is taken to deliberately keep the dissecting hand as close to the spine as possible, thereby avoiding pressure against the heart and the potential for prolonged hypotension from cardiac displacement. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

habitus or those in whom cervical osteoarthritis prevents extension of the neck, an adequate length of cervical esophagus may not be available for the anastomosis. In such cases, addition of a partial upper sternal split provides the prerequisite access to the high retrosternal esophagus35; however, this is not usually required. The dissection proceeds directly posteriorly to the prevertebral fascia, which is followed by blunt finger dissection into the superior mediastinum. The cervical esophagus is elevated out of the superior mediastinum by gentle finger retraction superiorly in the tracheoesophageal groove (Fig. 52-3), and the paraesophageal tissue posterolateral to the tracheoesophageal groove is incised, avoiding injury to the recurrent laryngeal nerve (Fig. 52-4). By gentle blunt dissection anteriorly and along the right lateral esophageal wall, the cervical esophagus is gradually encircled with a Penrose drain (Fig. 52-5). This drain is retracted superiorly as blunt dissection of the

Chapter 52 Transhiatal Esophagectomy

FIGURE 52-7 After completion of the dissection posterior to the esophagus, the anterior esophageal dissection is next performed. The esophagogastric junction is gently retracted inferiorly by the rubber drain encircling the esophagogastric junction, and the surgeon’s hand is inserted against the anterior wall of the esophagus palm downward and is advanced upward into the mediastinum. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

upper thoracic esophagus from the superior mediastinum is carried out (see Fig. 52-2). The volar aspects of the fingers are kept against the esophagus in the midline, and care is taken not to tear the posterior membranous trachea. With this technique, the upper thoracic esophagus is mobilized almost to the level of the carina through the neck incision.

Mediastinal (Transhiatal) Dissection The transhiatal dissection of the esophagus is carried out in an orderly, sequential fashion. One hand in the abdomen is inserted through the diaphragmatic hiatus posterior to the esophagus as a “half sponge on a stick” is inserted into the superior mediastinum through the cervical incision along the prevertebral fascia. The surgeon carries out the posterior esophageal dissection by sweeping the esophagus away from the prevertebral fascia from above until the sponge stick makes contact with the hand inserted through the diaphragmatic hiatus (Fig. 52-6). Intra-arterial blood pressure is monitored continually during the esophageal dissection to avoid prolonged hypotension. Blood is evacuated from the posterior mediastinum by means of a 28-Fr Argyle Saratoga sump catheter inserted from the cervical incision downward into the mediastinum. After the posterior esophageal dissection is completed, the anterior dissection is begun. The Penrose drain encircling the

FIGURE 52-8 A mirror-image dissection of the anterior esophagus away from the posterior aspect of the pericardium and the carina is now performed. At the cervical incision, the encircled esophagus is now retracted superiorly and toward the patient’s left shoulder as two fingers with their volar aspects against the anterior wall of the esophagus are advanced downward into the superior mediastinum. Care must be taken to continually dissect posteriorly away from the posterior membranous trachea above and the pericardium below. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

esophagogastric junction is retracted inferiorly as the surgeon’s hand is inserted palm down against the anterior esophagus and is advanced into the mediastinum (Fig. 52-7). The esophagus is progressively mobilized away from the posterior aspect of the pericardium and the carina. The hand must be kept flattened and posterior to minimize cardiac displacement and hypotension. Simultaneous dissection through the abdominal and cervical incisions along the anterior surface of the esophagus avulses the typically filmy attachments to the posterior trachea (Fig. 52-8). If the fingers inadvertently stray anteriorly during this portion of the mediastinal dissection, injury to the membranous trachea may occur. With the anterior and posterior esophageal dissection complete, the remaining lateral esophageal attachments must now be divided. The surgeon elevates the cervical and upper thoracic esophagus out of the superior mediastinum with one encircling finger. The lateral upper esophageal attachments are gently dissected away from the esophagus as it is delivered progressively into the neck wound (Fig. 52-9). In this

569

570

Section 6 Operative Techniques

FIGURE 52-9 After completing mobilization of the anterior and posterior intrathoracic esophagus, the cervical esophagus is “hooked” by the surgeon’s left index finger and the upper esophagus elevated out of the superior mediastinum as the lateral attachments are progressively dissected away from the esophagus as it is delivered into the neck wound. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

FIGURE 52-10 Once the anterior and posterior esophageal attachments have been dissected, the hand inserted through the diaphragmatic hiatus is advanced superiorly into the mediastinum until the undivided lateral esophageal attachments at the thoracic inlet can be palpated. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

Chapter 52 Transhiatal Esophagectomy

Vagus nerve

Diaphragmatic hiatus

FIGURE 52-11 The index and middle fingers are used to “trap” the esophagus against the prevertebral fascia, and, with a gentle but firm downward raking motion of the hand, the lateral esophageal attachments are gradually avulsed. Larger, more tough fibers may be delivered downward closer to the diaphragmatic hiatus and either clamped, divided, and ligated or divided with a long electrocautery (inset). (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT

FIGURE 52-12 In patients in whom exposure of the cervical esophagus is limited by cervical osteoarthritis that prevents extension of the neck or a “bull neck” habitus, an extension of the cervical incision onto the upper anterior thorax (inset) is used to carry out a partial upper sternal split across the sternomanubrial junction. A partial upper sternal split provides exposure of the cervicothoracic esophagus almost to the level of the carina (main illustration). (FROM

THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

fashion, 5 to 8 cm of upper thoracic esophagus is circumferentially mobilized. With downward traction on the Penrose drain encircling the esophagogastric junction, one hand is inserted palm downward through the diaphragmatic hiatus anterior to the esophagus and is advanced into the superior mediastinum behind the trachea until the completely circumferentially mobilized upper esophagus and its intact lateral attachments are palpated (Fig. 52-10). The esophagus is “trapped” against the prevertebral fascia between the index and middle fingers, and a downward raking motion of the hand gently avulses the remaining periesophageal attachments and smaller vagal nerve branches (Fig. 52-11). Larger vagal branches are frequently palpated along the middle and distal esophagus, and their identification, division, and ligation under direct vision are facilitated by means of narrow, deep retractors again placed into the diaphragmatic hiatus (see Fig. 52-11, inset) At times, subcarinal or subaortic periesophageal adhesions or fibrosis prevent complete mobilization of a 1- to 2-cm segment of midesophagus. It may then be necessary to compress this tissue firmly between the index finger and thumb, thereby fracturing it. Alternatively, as originally described by Waddell and Scannell in 195736 and later by Orringer (1984),35 access to the upper thoracic esophagus to the level of the carina may be achieved by means of a partial upper sternal

split, so that the remaining periesophageal attachments can be divided under direct vision (Fig. 52-12). When the entire intrathoracic esophagus is mobile, an 8- to 10-cm length is delivered into the cervical wound, and the esophagus is divided with a gastrointestinal anastomosis (GIA) surgical stapler (Fig. 52-13). Whenever possible, the esophagus should be divided in the neck so as to leave a generous length of cervical and upper thoracic esophagus. If there is any difficulty with the stomach reaching to the neck, a partial upper sternal split can be made and the extra remaining length of upper esophagus can then easily reach to the gastric fundus. After the surgeon divides the esophagus with the GIA stapler, the stomach and lower thoracic esophagus are drawn out of the abdomen and placed upon the anterior thorax. Once the esophagus has been removed from the mediastinum, and before attention is focused on the specimen, narrow deep Harrington “sweetheart” retractors are placed in the diaphragmatic hiatus to allow direct inspection of the posterior mediastinum for bleeding and the mediastinal pleura for a tear. Blood is evacuated from the posterior mediastinum by means of the 28-Fr Argyle Saratoga sump catheter inserted from above through the cervical wound. Any bleeding aortic esophageal artery is identified, clamped, and ligated. If entry into either chest cavity has occurred during the esophageal

571

572

Section 6 Operative Techniques

4–6

cm

FIGURE 52-13 With the intrathoracic esophagus completely mobilized, 8 to 10 cm of esophagus is delivered into the cervical incision. The nasogastric tube is removed, and the esophagus is divided obliquely with a GIA surgical stapler applied from front to back with the anterior tip slightly longer than the posterior corner. (FROM

FIGURE 52-14 With the stomach and attached esophagus placed on the anterior abdominal and thoracic wall, the point on the gastric fundus along the greater curvature that will reach most superiorly to the neck is identified, gently grasped with a moist pack, and drawn toward the neck. An area along the high lesser curvature of the stomach at approximately level to the second vascular arcade (“crow’s foot”) from the cardia is cleared of fat and blood vessels between clamps and ties. The upper stomach is then divided progressively by an average of three applications of the GIA 60 surgical stapler, beginning from the lesser curvature and proceeding toward the fundus. (FROM ORRINGER MB: TRANSHIATAL

ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

dissection as determined by direct inspection and palpation through the hiatus, a 28-Fr chest tube is inserted into the appropriate chest in the midaxillary line, secured to the skin, and connected to underwater chest tube suction. One or two large abdominal packs are pushed up through the hiatus into the posterior mediastinum, and two narrow “thoracic packs” are pushed into the superior mediastinum through the cervical incision and left there for hemostasis as preparation of the stomach continues. The gastric fundus is retracted superiorly, and the lesser curvature of the stomach is cleaned of adjacent fat by dividing the vessels and fat at the level of the second vascular arcade (“crow’s foot”) from the cardia. The GIA stapler is used to divide the stomach beginning at this point (Fig. 52-14). When the partial proximal gastrectomy has been completed, the esophagus and attached upper stomach are removed from the field. The gastric staple suture line is oversewn with a running 4-0 polypropylene Lembert stitch. The point along the greater curvature of the stomach that reaches most cephalad is identified (Fig. 52-15). Traction sutures in the tip of the stomach and suction devices to pull the stomach through the posterior mediastinum are intentionally avoided to minimize trauma to the gastric tip in the region where the anastomosis will be constructed. Instead,

after removing the posterior mediastinal packs and checking again for hemostasis, the mobilized stomach is gently pushed upward through the diaphragmatic hiatus and beneath the aortic arch into the superior mediastinum by one hand until the tip of the gastric fundus can be palpated by the fingers of the other hand placed through the cervical incision. The gastric fundus is then carefully grasped with a Babcock clamp (which is not completely ratcheted closed) and gently pulled upward while the other hand, inserted into the mediastinum from the abdomen, continually pushes the stomach upward (Fig. 52-16). Care must be taken to avoid torsion of the stomach during its positioning in the posterior mediastinum. When the stomach is properly oriented, the oversewn gastric staple suture line is seen along the most medial aspect of the stomach in the neck wound toward the patient’s right side and the greater curvature is toward the patient’s left side (see Fig. 52-16, inset). The anterior surface of the stomach is also gently palpated through the hiatus and from the neck incision to ensure that no inadvertent twist of the stomach has occurred. In most patients, after the gastric fundus is mobilized so that its apex is several centimeters above the level of the clavicles, the pylorus comes to rest within 1 to 3 cm of the diaphragmatic hiatus in the abdomen.

Chapter 52 Transhiatal Esophagectomy

FIGURE 52-15 The surgeon identifies the site along the high greater curvature of the stomach that will reach most cephalad to the neck by placing the mobilized stomach on the anterior chest. The staple suture line along the lesser curvature has been oversewn. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

At times, dense periesophageal fibrosis with inflammatory narrowing of the posterior mediastinum is encountered, for example, in association with long-standing reflux esophagitis or after radiation therapy. If after removal of the esophagus the posterior mediastinum does not readily accept the surgeon’s forearm, there should be concern that gastric circulation may be compromised because of insufficient room for the stomach. It may then be necessary to position the stomach in the anterior mediastinal retrosternal space. Although this is an acceptable option, it is certainly not preferred. When the retrosternal route is used for esophageal replacement, the medial clavicle and sternoclavicular joint should be resected to enlarge the anterior opening into the superior mediastinum.37 Furthermore, the incidence of anastomotic leak is much higher when the cervical esophagogastric anastomosis is essentially subcutaneous and unsupported in contrast to the normal esophageal bed, where it is buttressed by the spine, the carotid sheath, the trachea and thyroid, and the overlying strap muscles. When a typical cervical esophagogastric anastomosis is performed in the normal esophageal bed, once the tip of the stomach has been mobilized into the neck wound, it generally remains there, although retraction back into the chest as the abdomen is being closed can be prevented by placing a moistened gauze pad posterior to the stomach along the prevertebral fascia at the thoracic inlet. Ideally, if the stomach has not been excessively traumatized during its mobilization or

FIGURE 52-16 The surgeon gently manipulates the mobilized stomach through the posterior mediastinum in the original esophageal bed by placing one hand through the diaphragmatic hiatus. This hand gently pushes the stomach upward against the spine and underneath the aortic arch until the tip of the gastric fundus can be felt by the fingers of the other hand inserted through the cervical incision. The tip of the gastric fundus is then grasped with a Babcock clamp inserted through the cervical incision, and the stomach is gently delivered into the neck wound until it can be grasped by the fingertips (inset). The upper stomach is delivered into the neck wound by pushing from below through the diaphragmatic hiatus rather than by traction on the stomach in the neck. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

subsequent positioning in the posterior mediastinum, the gastric tip visible in the neck wound should be as pink and viable as it appeared in the abdomen before repositioning of the stomach. Before the cervical anastomosis is performed, the abdominal phase of the operation is concluded. The diaphragmatic hiatus is narrowed with one to three interrupted 1-0 silk sutures so that it easily admits three fingers alongside the stomach. The edges of the diaphragmatic hiatus are tacked to the anterior gastric wall with one or two 3-0 silk sutures to prevent subsequent herniation of intra-abdominal viscera into the chest. The left lobe of the liver is repositioned, and the previously divided triangular ligament is reattached to provide further closure of the hiatus. The pyloromyotomy is covered by adjacent omentum and by the previously retracted left hepatic lobe. The feeding jejunostomy tube is brought out through a separate left upper quadrant stab wound, and the jejunum is fixed to the anterior abdominal wall with several interrupted sutures placed around the circumference of the tube site. The surgeon closes and excludes the abdominal incision from the field by covering it with a sterile towel and sheet. The last major portion of the operation, the cervical esophagogastric anastomosis, is now performed.

573

574

Section 6 Operative Techniques

FIGURE 52-18 The site of the subsequent anastomosis on the stomach is carefully selected, with some planned redundancy in the length of the remaining cervical esophagus. A 1.5-cm vertical gastrotomy (dotted line) is performed with a needle-tip electrocautery. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

FIGURE 52-17 The mobilized stomach generally reaches 4 to 5 cm above the level of the left clavicle. The end of the divided cervical esophagus is retracted superiorly with an Allis clamp. The gastric staple suture line is toward the patient’s right. A Babcock clamp is used to deliver the anterior surface of the stomach upward from the thoracic inlet and to rotate the gastric staple suture line even more medially. A 3-0 cardiovascular traction suture is placed distal to the clamp and is used to elevate the stomach to the surface of the wound for subsequent construction of the anastomosis (inset). (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

Cervical Esophagogastric Anastomosis Attention returns to the neck incision, where the end of the divided esophagus is grasped with an Allis clamp and retracted superiorly. As my associates and I have described (Orringer et al, 2000),38 use of a side-to-side stapled cervical esophagogastric anastomosis, rather than a hand-sewn one, has dramatically reduced the anastomotic leak rate and is therefore now the preferred technique. When the stomach has been properly mobilized through the posterior mediastinum, a 4to 5-cm length of gastric fundus is visible above the level of the clavicles (Fig. 52-17). A 3-0 silk traction suture is used to elevate the anterior gastric wall to the surface of the skin (see Fig. 52-17, inset). After carefully judging the point at which the esophagus will comfortably reach the stomach once the traction suture has been removed, the surgeon makes a 1.5-cm vertical gastrotomy on the anterior gastric wall (Fig. 52-18). The gastrotomy must be positioned far enough inferiorly from the tip of the stomach to allow the

full insertion of the 3-cm-long staple cartridge. The cervical esophageal staple suture line is amputated obliquely, with the anterior tip of the divided esophagus being left slightly longer than the posterior corner (Fig. 52-19). Two anastomotic stay sutures are placed (Fig. 52-20), and with downward traction on these stay sutures, a GIA stapler loaded with a 30-3.5 staple cartridge is inserted into the stomach and the esophagus (Fig. 52-21). The midpoint of the posterior wall of the cervical esophagus must be carefully aligned with the anterior wall of the stomach as the staple cartridge is advanced completely into the esophagus and stomach. After the jaws of the stapler are approximated, two “suspension sutures” between the stomach and esophagus are placed on either side (Fig. 52-22). Firing the stapler results in a 3-cm-long side-to-side anastomosis (Fig. 52-23). After placement of a 16-Fr nasogastric tube into the intrathoracic stomach by the anesthetist, the gastrotomy and remaining open esophagus are approximated in two layers (Figs. 52-24 and 52-25). Silver clip markers are placed on either side of the anastomosis for future radiographic assessment, and the wound is closed loosely with interrupted sutures over a small Penrose drain. A portable chest radiograph is obtained in the operating room to ensure that no unrecognized hemothorax or pneumothorax or large mediastinal hematoma is present and that the nasogastric, chest, and endotracheal tubes are in proper position.

Transhiatal Esophagectomy for Carcinoma of the Esophagogastric Junction The technique of transhiatal esophagectomy just described is applicable in most patients with carcinoma localized to the cardia and proximal stomach (Fig. 52-26). The traditional

Chapter 52 Transhiatal Esophagectomy

FIGURE 52-19 The staple suture line is amputated with an atraumatic vascular forceps as a straight edge to ensure a clean cut. The anterior tip of the end of the divided esophagus is longer than the posterior tip. The amputated staple suture line is submitted to the pathology department as “the proximal esophageal margin.” (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

FIGURE 52-20 Two full-thickness 4-0 anastomotic stay sutures are placed, one from the anterior tip of the cut cervical esophagus and one from the midpoint of the upper edge of the vertical gastrotomy and the posterior “corner” of the esophagus. The previously placed anterior gastric wall traction suture elevates the stomach from the depths of the cervical incision and helps to achieve apposition of the posterior wall of the cervical esophagus and the anterior wall of the stomach. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

proximal hemigastrectomy performed for such tumors “wastes” valuable stomach that can be used for esophageal replacement, contributes little to the patient’s longevity, and commits the surgeon to an intrathoracic esophageal anastomosis. In most cases it is possible to divide the stomach 4 to 6 cm distal to palpable tumor, thereby preserving the entire greater curvature of the gastric fundus. The narrowed remaining gastric tube functions well as an esophageal substitute. In this situation, with a narrower gastric tube, during construction of the cervical esophagogastric anastomosis care must be taken to avoid placement of the stapler too close to the lesser curvature gastric staple line to avoid intervening ischemia of the anterior gastric wall. The cervical esophagus should not be divided until the surgeon is satisfied that there will be sufficient remaining stomach to reach to the neck. After the cervical esophagus is divided and the thoracic esophagus is removed, if the esophagogastric junction tumor is found to involve so much stomach that a proximal hemigastrectomy is required to remove it, there will be insufficient remaining gastric length to reach to the neck. Moreover, if the colon is not prepared, the patient will be left with a cervical esophagostomy and a feeding tube, which is a dismal outcome of an esophageal operation intended to relieve dysphagia.

POSTOPERATIVE CARE The average operative time required for transhiatal esophagectomy is 3 to 5 hours, depending on the patient’s size, the esophageal pathology, and the need for a partial upper sternal split. Although early in my experience with transhiatal esoph-

3 cm

A

B

FIGURE 52-21 As the two anastomotic stay sutures are retracted inferiorly, the Endo GIA 30-3.5 staple cartridge is inserted with the thinner “anvil” portion in the stomach and the thicker, staple-bearing portion in the esophagus. A and B, As the staple cartridge is advanced into the esophagus and stomach, the tip of the cartridge is gradually angulated toward the patient’s right ear. The alignment of the esophagus and stomach must be parallel, and the gastric staple suture line should be well away from the anastomosis to avoid intervening ischemia between the gastric staple suture line and the anastomosis. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

575

576

Section 6 Operative Techniques

FIGURE 52-22 The surgeon approximates the jaws of the staple cartridge by squeezing the handle of the stapler. Before it is fired, however, the stapler is rolled from side to side as two seromuscular sutures between the adjacent esophagus and stomach are placed on either side. These four sutures are now used to support the anastomosis in the neck instead of the initially advocated “suspension” sutures between the tip of the gastric fundus and the prevertebral fascia. (FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT

FIGURE 52-23 Advancing the knife assembly of the stapler fires the cartridge and creates a 3-cm-long side-to-side anastomosis as the opposing walls of the esophagus and stomach are stapled and cut. The stapler is removed, the anastomosis inspected for bleeding, and a nasogastric tube inserted by the anesthetist and guided into the intrathoracic stomach. “Corner” sutures are placed in preparation for completion of the anastomosis. (FROM ORRINGER MB: TRANSHIATAL

THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

FIGURE 52-24 The edges of the opened esophagus and stomach are approximated in two layers, the first being a full-thickness inverting running inner layer of 4-0 monofilament absorbable suture.

FIGURE 52-25 The anastomosis is completed with an outer interrupted layer that incorporates the anterior wall of the upper esophagus and the adjacent stomach. (FROM ORRINGER MB:

(FROM ORRINGER MB: TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

TRANSHIATAL ESOPHAGECTOMY WITHOUT THORACOTOMY. OPER TECH THORAC CARDIOVASC SURG 10:63, 2005.)

agectomy, mechanical ventilation was maintained overnight until the morning of postoperative day 1, my current practice is to extubate the patient in the operating room and to avoid an intensive care unit stay entirely. This is a function of better preoperative preparation but, equally, of the availability of epidural anesthesia to reduce postoperative pain and to facilitate optimal respiratory function and early ambulation.

Because the patient has been taught preoperatively the desirability and necessity of early postoperative ambulation and pulmonary hygiene, use of the incentive spirometer is resumed immediately after surgery and continued as it was preoperatively. Walking is begun on postoperative day 1. Postoperative ileus seldom lasts longer than 48 to 72 hours. Therefore, feedings of 5% dextrose and water through the jejunostomy tube at a rate of 30 mL/hr are usually

Chapter 52 Transhiatal Esophagectomy

Within 3 to 5 days of operation, intravenous lines, the arterial catheter, the cervical wound drain, the Foley urethral catheter, and the nasogastric tube typically have been removed so that the patient can ambulate freely and practice unrestrained deep breathing. Within 24 hours of removal of the nasogastric tube, oral liquids are begun. Oral intake is progressively advanced, and depending on the patient’s appetite and ability to take in adequate oral nutrition, the jejunostomy tube feedings are concomitantly decreased and then discontinued. On postoperative day 7, a barium swallow examination is performed to document the following: 1. The anastomosis is intact. 2. Gastric emptying through the pyloromyotomy is adequate (both areas having been marked intraoperatively with silver clips). 3. There is no significant obstruction at the site of the jejunostomy tube.

*

4–6 cm

FIGURE 52-26 Transhiatal esophagectomy and a cervical esophagogastric anastomosis is applicable for localized tumors of the cardia and distal esophagus. The gastrointestinal anastomosis stapler is used to divide the high lesser curvature of the stomach 4 to 6 cm distal to palpable tumor. The asterisk indicates that point along the greater curvature that reaches most cephalad to the neck for the anastomosis. The stippled area represents the portion of stomach that traditionally has been resected when a standard hemigastrectomy is carried out for distal esophageal carcinoma, thereby precluding the possibility of a cervical esophagogastric anastomosis. (FROM ORRINGER MB, SLOAN H: ESOPHAGECTOMY WITHOUT THORACOTOMY. J THORAC CARDIOVASC SURG 76:643, 1978.)

begun on postoperative day 3. If this is tolerated for 12 hours, jejunostomy tube feedings are begun and the volume is gradually increased. Usually by postoperative day 3, the nasogastric tube drainage is less than 100 mL per 8-hr nursing shift, and the nasogastric tube is removed. Postoperative postprandial diarrhea (“dumping”) may occur in response either to tube feedings or to the vagotomy that accompanies transhiatal esophagectomy. This is controlled with diphenoxylate (Lomotil) or tincture of opium (paregoric).

If this study is satisfactory, the patient is discharged. The need for continuing jejunostomy tube feedings at home is individualized. There is little justification for withholding oral intake until after a postoperative barium swallow on the 7th to 10th postoperative day. Because the patient is swallowing saliva from the moment of awaking from the operation, oral contents are crossing the anastomosis despite the fact that food is not being swallowed. Furthermore, at least 1 week is typically required for the patient to adjust to the initial retrosternal fullness, early satiety, or postvagotomy cramping and diarrhea (“dumping”) that may occur; if one waits until after the barium swallow on the 7th to 10th postoperative day to feed the patient, another week of unnecessary hospitalization may be required as this adjustment to eating is made. Currently, the patient is typically discharged after a satisfactory barium swallow on the postoperative day 7. The jejunostomy feeding tube is removed at an outpatient visit 2 to 4 weeks later. At times, if the patient is anorectic immediately after surgery, supplemental caloric intake with jejunostomy tube feedings at night may be continued for the first several weeks at home. Most patients, however, leave the hospital able to eat satisfactorily without the need for supplemental jejunostomy tube feedings.

COMPLICATIONS AND THEIR MANAGEMENT The complications of transhiatal esophagectomy without thoracotomy occur in two broad categories: 1. Intraoperative, including pneumothorax, tracheal tear, and hemorrhage 2. Postoperative, occurring in the first “critical” 10 days after operation and including hoarseness or impaired swallowing from recurrent laryngeal nerve injury, anastomotic disruption, chylothorax, supraventricular tachyarrhythmias, and sympathetic pleural effusion Entry into one or both pleural cavities during the mediastinal dissection occurs in nearly three fourths of patients undergoing transhiatal esophagectomy. Once the esophagectomy has been completed and before the stomach is posi-

577

578

Section 6 Operative Techniques

tioned in the posterior mediastinum in the original esophageal bed, the pleura should be carefully inspected both manually and by palpation through the diaphragmatic hiatus to be certain that no tear has occurred. If the pleurae have been violated, insertion of a 28-Fr chest tube or tubes is indicated.

Tracheal Tear There are few more devastating experiences during transhiatal esophagectomy than the rush of air from the ventilator felt through a tear in the posterior membranous trachea. Tracheal tears occurring during this operation may vary from small, linear, and relatively easily sutured to these that are irreparable, as when the surgeon has wrongly attempted to resect a tumor that is densely adherent to or invading the trachea and major tracheobronchial disruption occurs. If a tracheal tear occurs during esophagectomy, the endotracheal tube cuff should be deflated by the anesthetist and the tube should then be advanced as the surgeon’s hand, inserted through the hiatus and anterior to the esophagus to the level of the carina, guides it into the distal trachea or left mainstem bronchus so that the endotracheal tube cuff is distal to the tear. With control of the airway now reestablished, the tear can be repaired in a more controlled fashion. A partial upper sternal split (see Fig. 52-12) provides ample exposure of the membranous trachea for most direct repairs. If possible, it is best to complete the transhiatal esophagectomy before attempting the tracheal repair, since exposure of the posterior trachea is better once the esophagus is removed. If the tracheal tear is too extensive or involves the carina or mainstem bronchus, an anterior approach through a partial upper sternal split will not be adequate. In such a situation, one-lung anesthesia, administered through the endotracheal tube inserted into the left mainstem bronchus should be continued as the abdomen is quickly and temporarily closed and the incision covered with an adherent plastic surgical drape. The patient is then repositioned for a right thoracotomy, completion esophagectomy, and closure of the tracheal injury. With the airway repaired, the patient is turned supine again, the stomach carefully mobilized through the posterior mediastinum, and the cervical anastomosis completed as described previously.

Bleeding Average intraoperative blood loss for transhiatal esophagectomy is less than 500 mL, and major intraoperative bleeding is the exception rather than the rule. As shown in the elegant anatomic studies by Liebermann-Meffert and associates,39 the aortic esophageal arteries branch into very small capillaries before they reach the wall of the esophagus; and when these smaller vessels are avulsed from the esophagus during transhiatal esophagectomy, natural hemostatic mechanisms of thrombosis and arterial contraction control bleeding. As one gains experience with the technique of transhiatal esophagectomy, progressively more of the dissection is performed under direct vision.

For example, with narrow retractors in the diaphragmatic hiatus, the lateral esophageal attachments can be clamped, divided, and ligated, often to the level of the carina, by use of long, right-angled clamps. Major uncontrolled bleeding should occur rarely with this operation. When palpation of the esophagus through the diaphragmatic hiatus indicates dense fixation to the aorta or periesophageal tissues, the transhiatal approach should be abandoned. If major intraoperative bleeding occurs during the transhiatal dissection, the 28-Fr Argyle Saratoga sump catheter should be inserted through the cervical incision to help evacuate bleeding from above, and narrow deep retractors within the diaphragmatic hiatus should be used to facilitate inspection of the mediastinum in an effort to identify and control the point of bleeding. If hemostasis cannot be achieved, there is little alternative but to tamponade the mediastinum with large abdominal packs inserted through the diaphragmatic hiatus. The abdomen should be closed quickly with several large throughand-through heavy sutures, the wound covered with a plastic adhesive surgical film, and the patient turned to the appropriate side for a thoracotomy. If bleeding has been encountered during dissection of the lower third of the esophagus, a left thoracotomy should be undertaken. Alternatively, if dissection of the mid or upper thoracic esophagus has resulted in bleeding, a right thoracotomy is more appropriate for control.

Recurrent Laryngeal Nerve Palsy Recurrent laryngeal nerve injury during transhiatal esophagectomy and a cervical esophagogastric anastomosis is a serious complication that may have far greater consequences than simply a hoarse voice. Impaired cricopharyngeal motor function with resulting cervical dysphagia and aspiration may cause life-threatening aspiration pneumonia. In my group’s early experience with this operation, transient recurrent laryngeal nerve injury occurred frequently. The injury was initially attributed to “unavoidable” intraoperative stretching of the left recurrent laryngeal nerve beneath the aortic arch in the chest. However, it is now apparent that such a mechanism of injury to the recurrent laryngeal nerve seldom occurs. Rather, almost inevitably, recurrent laryngeal nerve paresis or paralysis is the result of direct injury to the nerve during the cervical portions of the operation. It is therefore a preventable complication that can be avoided by not placing any metal retractor against the tracheoesophageal groove. Since adopting a policy of using only finger retraction against the tracheoesophageal groove during the cervical portions of the operation, we have rarely encountered this complication.

Cervical Anastomotic Leak Cervical esophageal anastomotic leaks seldom occur after the 10th postoperative day, are typically associated with very little early postoperative morbidity, and are rarely fatal. If a temperature of 38.3°C (101°F) or more develops 48 hours after transhiatal esophagectomy, it is assumed that an anastomotic leak is present until proven otherwise, and an imme-

Chapter 52 Transhiatal Esophagectomy

diate contrast study of the esophagus is indicated. We prefer the use of dilute barium sulfate for this study, because it better defines mucosal detail then water-soluble contrast (Gastrografin) and is not associated with the potential for chemical pneumonitis if aspiration occurs. Alternatively, drainage of swallowed liquid or food from the cervical incision establishes the diagnosis of a leak on clinical grounds alone without the need for a contrast study. If such an anastomotic leak is diagnosed, the cervical wound is gently opened in its entirety at the bedside down to the prevertebral fascia and the patient is asked to swallow water while a suction catheter is used to evacuate the fluid that issues from the neck wound, thereby flushing away associated debris. The neck wound is loosely packed with slightly moistened gauze several times a day, and nutrition is maintained with jejunostomy tube feedings. Leaks that occur between 7 and 10 days after operation are generally quite small. Within 2 to 3 days of opening the neck wound, the patient is allowed to drink water after the wound has been unpacked. Observing the amount of water that exits through the wound gives an estimate of the size of the remaining fistula. As the fistula closes, the patient may swallow soft food while applying direct pressure over the packed cervical wound. A 46-Fr tapered Maloney esophageal dilator is carefully passed through the anastomosis at the bedside at least once after the cervical wound is opened and before the patient is discharged to ensure that there is no element of distal obstruction (e.g., from local edema or fibrosis) associated with the fistula and to minimize the chance of anastomotic stricture development. Passage of an esophageal dilator before the fistula has completely closed does not further damage the anastomosis and in fact is usually followed by total closure of the fistula in 2 to 5 days.40 In less than 2% of patients with cervical esophagogastric anastomotic leaks, as reported by Iannettoni and colleagues (Iannettoni et al, 1995),41 catastrophic complications occur: gastric tip necrosis necessitating anastomotic takedown and cervical esophagostomy, vertebral body osteomyelitis, epidural abscess with neurologic impairment, internal jugular vein abscess, and tracheoesophagogastric anastomotic fistula. Patients who remain ill after bedside drainage of a cervical esophagogastric anastomotic leak should undergo cervical reexploration in the operating room. Major gastric tip ischemia or necrosis, or both, may warrant takedown of the anastomosis, return of the intrathoracic stomach to the abdomen, resection of nonviable stomach, and construction of a cervical esophagostomy. Esophageal reconstruction can be performed later if the patient survives this disastrous event. But if the esophagectomy was performed for carcinoma, 6 to 12 months should be allowed to pass and then the tumor restaged with CT and PET to be certain that metastases have not developed, thereby contraindicating a major esophageal reconstruction.

Chylothorax When chest tube drainage after transhiatal esophagectomy is excessive or prolonged, the diagnosis of chylothorax due to an injured thoracic duct should be considered. This diagnosis

may not be apparent early after surgery when there is no oral intake of fat, because the fluid draining from the chest tube is not “milky.” However, if chest tube drainage exceeds 200 to 400 mL per 8-hr shift more than 48 hours after transhiatal esophagectomy, one should consider the possibility of a thoracic duct injury. The diagnosis is established by observing a change in the character of the chest tube drainage from serous to milky fluid after administration of 60 to 90 mL/hr of cream through the jejunostomy tube for 3 to 6 hours. This is not a subtle diagnosis, and rarely is it necessary to determine cholesterol, triglyceride, chylomicron, or lymphocyte levels in the fluid to prove that a chylothorax has occurred. There is little place for conservative management of chylothorax in the nutritionally compromised patient who has undergone an esophagectomy for esophageal obstruction, because the loss of protein and lymphocyte-rich chyle is poorly tolerated.42 Unless the chylous drainage decreases dramatically within 3 to 5 days of instituting elemental jejunostomy tube feedings, thoracotomy and ligation of the injured thoracic duct most effectively manages the problem and minimizes morbidity. After 60 to 90 mL/hr of cream has been administered through the jejunostomy tube for 6 hours and there is a sustained flow of milky fluid draining from the chest tube, a thoracotomy on the side of the leak is performed. A double-lumen endotracheal tube permits one-lung anesthesia and exposure of the mediastinum through a limited thoracotomy. The brisk flow of chyle from the injured thoracic duct makes identification of the tear and direct suture ligation a relatively simple undertaking. This direct approach often constitutes less of a physiologic insult to the patient than weeks of conservative management with intravenous hyperalimentation and chest tube suction.

Pleural Effusion When the pleural cavity is not violated during transhiatal esophagectomy and no chest tube is therefore required, a sympathetic pleural effusion related to the mediastinal dissection may occur during the first postoperative week. If the effusion is asymptomatic and does not continue to enlarge, no treatment is necessary and spontaneous resolution follows. Alternatively, if significant dyspnea results from a large effusion, an occasional thoracentesis may be required. A recurrent pleural effusion must be differentiated from a chylothorax and treated accordingly.

RESULTS My colleagues and I have reported the largest single-institution experience with transhiatal esophagectomy in 1085 patients, 285 (26%) of whom had benign disease necessitating esophageal replacement and 800 (74%) of whom had carcinoma33 (Table 52-1). Transhiatal esophagectomy was possible in 98.6% of patients in whom it was attempted over a 22-year period. Fifteen patients required conversion to a transthoracic esophagectomy as a result of intrathoracic esophageal fixation or bleeding. Neither a history of prior radiation therapy nor chronic periesophageal fibrosis from prior esophageal operations has precluded transhiatal esophagectomy. Of the

579

580

Section 6 Operative Techniques

TABLE 52-1 Indications for Transhiatal Esophagectomy (1085 Patients) No. (%) Benign Conditions Neuromotor dysfunction Achalasia Spasm/dysmotility Scleroderma Stricture Gastroesophageal reflux Caustic ingestion Radiation Other Barrett’s mucosa with high-grade dysplasia Recurrent gastroesophageal reflux Recurrent hiatal hernia Acute perforation Acute caustic injury Other

285 (26.0) 93 (33.0) 70 22 1 75 (26.0) 42 19 4 10 54 (19.0) 21 (7.0) 14 (5.0) 14 (5.0) 6 8

Carcinoma of Intrathoracic Esophagus Upper third Middle third Lower third thoracic and/or cardia

800 (74.0) 36 (4.5) 177 (22.0) 587 (73.5)

From Orringer MB, Marshall B, Iannettoni MD: Transhiatal esophagectomy: Clinical experience and refinements. Ann Surg 230:392, 1999.

patients with carcinoma, 234 (29%) had a history of prior radiation therapy. Of the patients with benign disease, 146 (52%) had undergone one or more esophageal or periesophageal operations. Stomach was used as the esophageal substitute in 96% of patients, with a colon interposition being required in 39 patients who had either caustic gastric burns or a history of a prior gastric resection for peptic ulcer disease precluding cephalad reach of the stomach to the neck for construction of a cervical anastomosis. The posterior mediastinal esophageal bed was used for esophageal replacement in all but 20 patients with gross residual tumor or radiation fibrosis of the posterior mediastinum.

Morbidity Three intraoperative deaths occurred as a result of mediastinal hemorrhage that occurred during esophageal mobilization. Six other patients experienced inordinate intraoperative blood loss ranging from 5850 to 18,440 mL. In three, the bleeding was from a torn azygos vein during mobilization of a mid-third carcinoma; in three others, the bleeding was intra-abdominal: in two associated with portal hypertension from cirrhosis and one from splenic injury. If these latter six patients are excluded, the measured intraoperative blood loss averaged 689 mL (652 mL in the patients with carcinoma and 795 mL in those with benign disease).

Intraoperative Complications After removal of the esophagus from the mediastinum in 831 patients (77%), direct inspection through the diaphragmatic

hiatus revealed entry into one or both pleural cavities, which was managed by placement of one or more chest tubes. Intraoperative membranous tracheal lacerations occurred in 4 patients; three of the lacerations involved the high membranous trachea and were exposed and successfully repaired through a partial upper sternal split. In the fourth patient, the tear involved the membranous carina. Management involved guiding the endotracheal tube into the left mainstem bronchus through the diaphragmatic hiatus, providing onelung ventilation and performing a transthoracic repair of the tracheal tear. A splenectomy was required in 34 patients (3%) because of intraoperative injury. The duodenal or gastric mucosa was entered during the pyloromyotomy in fewer than 2% of patients. Management consisted of suturing the hole with 5-0 polypropylene and buttressing the repair with adjacent omentum.

Postoperative Complications Five patients (<1%), 3 with carcinoma and 2 with megaesophagus of achalasia, experienced mediastinal hemorrhage, requiring a thoracotomy for control of bleeding within 24 hours of transhiatal esophagectomy. Recurrent laryngeal nerve injury occurred in 74 patients (7%) and resolved spontaneously in 50 patients within 2 to 12 weeks. Hoarseness persisted in 24 patients (<1%), and 7 of these required vocal cord medialization procedures. Since compulsively avoiding placement of metal retractors against the tracheoesophageal groove during the cervical portions of the operation, the incidence of postoperative hoarseness was less than 3%. Chylothorax occurred in 18 patients (<1%), 12 with carcinoma and 6 with benign disease, and was managed successfully, as described previously,42 with transthoracic ligation of the injured thoracic duct. Abdominal wound infection or dehiscence occurred in 29 patients (3%). Clinically significant atelectasis or pneumonia prolonging the hospitalization beyond 10 days occurred in 17 patients (2%). The overall anastomotic leak rate after a cervical esophagogastric anastomosis was 13% (146 patients). All but nine of these anastomotic leaks were managed successfully by opening the cervical wound at the bedside, local wound packing, and early esophageal bougienage to prevent late stenosis, as described previously.40 As indicated earlier, since initiation of the stapled side-to-side cervical esophagogastric anastomosis, the anastomotic leak rate has fallen to below 3%.38 Necrosis of the upper stomach, necessitating takedown of the intrathoracic stomach, resection of devitalized stomach, and a cervical esophagostomy, occurred in 9 patients.

Mortality The total hospital mortality among the 1085 patients was 4% (44 deaths). Among the 285 patients with benign disease, there were 8 deaths (2.8%); these were due to sepsis (5), myocardial infarction (1), respiratory insufficiency (1), and portal vein thrombosis (1). There were 36 deaths (4.5%) among the 800 patients with carcinoma; these resulted from hepatic failure (6), respiratory insufficiency (5), myocardial

Chapter 52 Transhiatal Esophagectomy

infarction (4), intraoperative hemorrhage (3), pneumonia (3), sepsis (3), intestinal ischemia (3), sudden death/cardiac arrest (3), pulmonary embolus (2), and posterior mediastinal abscess, peritoneal abscess, unrecognized brain metastasis, and delayed pyloromyotomy leak (1 each). In a 2001 meta-analysis of 7527 patients undergoing either transhiatal or transthoracic esophagectomy between 1990 and 1999, the relative advantages of transhiatal esophagectomy have been demonstrated (Table 52-2) (Hulscher et al, 2001).43 Of note, the 13.6% average anastomotic leak rate with a cervical esophagogastric anastomosis after transhiatal esophagectomy is reminiscent of the 14% leak rate reported by the author before initiation of the stapled side-to-side cervical esophagogastric anastomosis. The 9.5% incidence of vocal cord paralysis reflects poor technique in applying traction directly to the recurrent laryngeal nerve in the tracheoesophageal groove. Five-year survival was approximately 20% after both types of esophageal resection.

ADDITIONAL COMMENTS In my experience, transhiatal esophagectomy has been applicable in virtually every situation requiring an esophagectomy for either benign or malignant disease. For example, this technique is being used increasingly in patients with failed esophagomyotomies for achalasia or those presenting with megaesophagus.44,45 Whereas some have advocated routine enlargement of the diaphragmatic hiatus by means of an incision from the anterior hiatus toward the xiphoid to facilitate transhiatal esophagectomy in patients with megaesophagus of achalasia, we have rarely found this necessary. Gradual dilation of the hiatus until it will accept the surgeon’s hand (size 7 glove) generally provides ample exposure for the operation. The placement of narrow, deep retractors into the diaphragmatic hiatus facilitates dissection of the esophagus under direct vision, often to the level of the carina. When the esophagus is found to be fixed to the aorta or to the tracheobronchial tree by invasive carcinoma or by fibrosis due to benign disease or multiple prior operations, the surgeon must be prepared to abandon the transhiatal route and convert to a transthoracic resection. Inflexible persistence with a transhiatal esophagectomy may have catastrophic consequences. In the end, it is the surgeon’s judgment on palpation of the esophagus and assessment of its mobility that is the single most important factor in determining whether the transhiatal approach is appropriate for the esophagectomy. This point having been made, however, increased experience leads to progressive facility with the operation. And recent data convincingly relate the outcome after esophagectomy to the surgical volume, that is, to experience of those performing the operation.46-48 In my colleagues and my cumulative current experience with more than 2000 transhiatal esophagectomies, the procedure has been possible in 98.6% of all patients in whom it has been attempted in the past 30 years. Another important technical aid is the partial upper sternal split used to obtain access to the upper esophagus in patients with little or no length of cervical esophagus, for

TABLE 52-2 Transthoracic Esophagectomy Versus Transhiatal Esophagectomy for Carcinoma—a Meta-Analysis (7527 Patients) Statistically Significant Differences Transthoracic

Transhiatal

In-hospital mortality

9.2%

5.7%

Blood loss (mL)

1001

728

Pulmonary complications

18.7%

12.7%

Chylothorax

2.4%

1.4%

Intensive care unit stay (days)

11.2

9.1

Hospital stay (days)

21.0

17.8

Anastomotic leak

7.2%

13.6%

Vocal cord paralysis

3.5%

9.5%

Survival 3 yr 5 yr

26.7% 23.0%

25.0% (ns) 21.7% (ns)

From Hulscher JB, Tijssen JG, Obertop H, van Lanschot JJ: Transthoracic versus transhiatal resection for carcinoma of the esophagus: A meta-analysis. Ann Thorac Surg 72:306, 2001.

instance, elderly patients with cervical osteoarthritis who cannot extend their neck or the so-called bull neck (“no neck”) obese individual in whom the cricoid cartilage (the level of the upper esophageal sphincter) rests essentially at the level of the suprasternal notch. The maneuver has been required in approximately 5% of my colleagues and my patients. From a functional standpoint, the stomach has emerged as the organ of choice for esophageal replacement for both benign and malignant disease. Gastroesophageal reflux and esophagitis, virtually inherent with an intrathoracic esophagogastric anastomosis, are rarely clinically significant after a properly performed cervical anastomosis. The end-to-side cervical esophagogastric anastomotic construction appears at least in part to provide more of a “flap-valve” protection against regurgitation than does an end-to-end anastomosis between the tip of the gastric fundus and the cervical esophagus. Long-term functional problems with colonic interpositions (redundancy of the graft, delayed emptying, nocturnal regurgitation, aspiration) that have been well documented are far less frequent when the stomach is used as the esophageal substitute. As is the case after a partial gastric resection for peptic ulcer disease, gastric capacity after a cervical esophagogastric anastomosis is generally less, and patients experience early satiety and frequently stabilize at a new lower weight after an initial period of weight loss. It is important that patients be warned preoperatively about the possibility of postvagotomy dumping symptoms (postprandial cramping, diarrhea) that occur to varying degrees in approximately 20%. In most cases, these symp-

581

582

Section 6 Operative Techniques

toms can be controlled with (1) dietary modifications (avoidance of high-carbohydrate intake and dairy products and not stretching the stomach by drinking liquid with meals) or (2) medication (diphenoxylate for diarrhea, tincture of opium for spasm).

COMMENTS AND CONTROVERSIES Dr. Orringer’s precise description of each of the steps during the different phases of the operation offers the reader a detailed manual on how to successfully perform a transhiatal esophagectomy. But in doing so he rightfully emphasizes the need of “a firm knowledge of thoracic anatomy and the implications of esophagectomy and their management.” Indeed, although this technique may seem less complex and therefore more attractive as compared with the open transthoracic approach, it must be emphasized that, as in any other major surgery, mastery of a particular technique involves a learning curve. A minimum of volume is essential and a tutorial by an experienced colleague is highly recommended to overcome such a learning curve, to become familiar with a number of pitfalls, and to bring to the attention the important details of this operation. Over the years Dr. Orringer has constantly improved the technique, thus reducing postoperative mortality and morbidity after esophagectomy for both benign and malignant conditions. His superb results have been instrumental in popularizing this technique in particular in the Western world over the past 2 decades. An “Achilles heel” of this operation has been the rather high incidence of both anastomotic leaks and the resulting anastomotic strictures. The more recent introduction by Dr. Orringer of the sideto-side semi-mechanical stapled anastomosis has obviously resulted in a substantial decrease of these anastomotic leaks. This technique has also the advantage of increasing the diameter and thus the surface of anastomosis, which in itself has resulted in an important decrease of the need of postsurgical dilatation for anastomotic strictures. With an increasing number of long-term survivors these improvements have resulted in a major beneficial impact on quality of life. The drawback of this particular anastomotic technique is the need for a longer segment of cervical esophagus to construct the anastomosis. Therefore, this semi-mechanical anastomosis may be less suitable for carcinomas of the middle to upper third of the esophagus. The vocal cord paralysis remains another complication seemingly more specifically related to the transhiatal esophagectomy. Although temporary in a substantial number of patients, this complication will affect the quality of life and may induce an increased risk of aspiration and subsequent pulmonary infection in the early weeks or months after the operation. So, here again is an example of one of those steps of the operation that requires meticulous attention. During the dissection of the cervical esophagus the recurrent nerve should be identified to avoid any injury from the dissection itself or from an inadvertent placement of any retractor against the tracheoesophageal groove. Focusing on these aspects resulted eventually in an incidence of postoperative hoarseness of less than 3%. Dr. Orringer claims a superiority of transhiatal esophagectomy as compared with the transthoracic approach in relation to the post-

operative outcome. To support this statement he refers not only to his own data but also to a meta-analysis by Hulsher and coworkers dealing with more than 7000 patients. This meta-analysis did show significant advantages favoring transhiatal esophagectomy for blood loss, intensive care unit stay, hospital stay, and hospital mortality. This meta-analysis, however, deals with reported experience spanning more than 3 decades. Certainly over the past decade major improvements in the short-term postoperative outcome have been reported by many authors when using a transthoracic access route. Median blood loss today in many centers including my own is around or below 500 mL. Overall complication rate and median hospital stay, most recently 8.2 days for my own center, have also decreased substantially. Such improvements are perhaps best illustrated in a publication by Cerfolio and coworkers looking into the possibility of fast tracking after Ivor Lewis esophagectomy in 90 patients, showing a mortality of 4.4%, no anastomotic leaks, and a median hospital stay of 7 days, with intensive care unit stay being avoided in most patients.1 From such data it appears that transhiatal esophagectomy, admittedly having superior results in the past, may well be losing these advantages nowadays. Another challenge to transhiatal esophagectomy is the introduction of video-assisted thoracic surgery/laparoscopic esophagectomy. This videoscopic technique may have the advantage of allowing more precise dissection and thoracic lymphadenectomy yet be as competitive on the short-term postoperative outcome as the transhiatal esophagectomy. The final perhaps most important question to be answered is the value of transhiatal esophagectomy on long-term oncologic outcome. The previously mentioned meta-analysis by Hulscher and coworkers did not show any difference in oncologic outcome, but the same authors later on published the results of a randomized controlled trial for adenocarcinoma of the esophagus and gastroesophageal junction comparing transthoracic radical versus transhiatal nonradical esophagectomies.2 Although statistical significance was not reached, there was a clear tendency favoring transthoracic esophagectomy with estimated 5-year survival of 39% versus 29% for transhiatal resections. This trend is supported by many other publications both from the West and the East. Perhaps by splitting the diaphragm to provide a wider access to the inferior part of the mediastinum may offer a better possibility for a more radical resection and more extensive lymph node clearing. Most importantly, however, Dr. Orringer has clearly shown that in a high-volume center and with growing experience a complex major intervention can be refined in such a way that it merits a definite place in the armamentarium of surgical techniques. 1. Cerfolio RJ, Bryant AS, Bass CS, et al: Fast tracking after Ivor Lewis esophagectomy. Chest 126:1187-1194, 2004. 2. Hulscher JB, van Sandick JW, de Boer AG, et al: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1662-1669, 2002.

T. L.

KEY REFERENCES Hulscher JB, Tijssen JG, Obertop H, van Lanschot JJ: Transthoracic versus transhiatal resection for carcinoma of the esophagus: A metaanalysis. Ann Thorac Surg 72:306, 2001.

Chapter 52 Transhiatal Esophagectomy

■ This meta-analysis of relatively contemporary published reports from 1990-1999

includes 7527 patients undergoing either transthoracic or transhiatal esophagectomy. Statistically significant differences in favor of transhiatal esophagectomy were found for in-hospital mortality, blood loss, pulmonary complications, chylothorax, intensive care unit stay, and hospital stay. Anastomotic leak and vocal cord paralysis were more common after transhiatal esophagectomy. The 5-year survival after both operations was approximately 20%. Iannettoni MD, Whyte RI, Orringer MB: Catastrophic complications of the cervical esophagogastric anastomosis. J Thorac Cardiovasc Surg 110:1493, 1995. ■ Fewer than 2% of 856 patients undergoing transhiatal esophagectomy and cervical esophagogastric anastomosis experienced catastrophic cervical infectious complications. These 11 complications included vertebral body osteomyelitis (1), epidural abscess with neurologic impairment (2), pulmonary microabscesses from internal jugular vein abscess (1), tracheogastric anastomotic fistula (1), and major dehiscence necessitating anastomotic takedown (6). Although the generally low morbidity associated with a cervical esophagogastric anastomosis is emphasized, this sobering report of the prevention, presentation, and management of the serious complications that can occur merits review by those undertaking these operations. Orringer MB, Marshall B, Iannettoni MD: Eliminating the cervical esophagogastric anastomotic leak with a side-to-side stapled anastomosis. J Thorac Cardiovasc Surg 119:277, 2000. ■ This report describes the authors’ technique of constructing the cervical esophagogastric anastomosis after transhiatal esophagectomy utilizing the GIA II stapler

applied directly through the cervical wound. The anastomotic leak rate has been reduced to less than 3% using this technique, and this has contributed to reduction in the average length of stay after an uncomplicated transhiatal esophagectomy to 7 days. Swallowing has been more comfortable, and ease of subsequent esophageal dilation, if required, has been greater. Orringer MB, Marshall B, Iannettoni MD: Transhiatal esophagectomy: Clinical experience and refinements. Ann Surg 230:392, 1999. ■ This report summarizes the authors’ cumulative 22-year experience with 1085 transhiatal esophagectomies, the largest such reported series. Of these operations 800 were performed for carcinoma and 285 for benign disease. Stomach was used as the esophageal substitute in 96%. Overall hospital mortality rate was 4%. Blood loss averaged 689 mL. Major complications included anastomotic leak (13%), atelectasis/pneumonia (2%), intrathoracic hemorrhage, recurrent laryngeal nerve injury, chylothorax, and tracheal tear (<1% each). Late functional results have been excellent or good in 70%. Actuarial survival for patients with cancer equals or exceeds that reported after transthoracic esophagectomy. Orringer MB, Sloan H: Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg 76:643, 1978. ■ This preliminary report from the University of Michigan summarized the results of transhiatal esophagectomy in 26 patients (4 with benign disease and 22 with carcinomas involving various levels of the esophagus). It aroused renewed interest in a technique that had been virtually abandoned as the availability of endotracheal anesthesia permitted safe thoracotomy and esophagectomy under direct vision.

583

chapter

53

LEFT THORACOABDOMINAL ESOPHAGECTOMY Sudish C. Murthy

Key Points ■ The left thoracoabdominal approach is an excellent option for

locally advanced gastroesophageal junction malignancies. ■ The flexibility of the approach allows for Roux-en-Y reconstruction

after total gastrectomy and distal esophagectomy as well. ■ Meticulous closure is essential in order to prevent costochrondral-

related wound complications. ■ Familiarity with the anatomy viewed from a lateral approach is

essential.

Esophagectomy through a left thoracotomy approach was described more than 60 years ago.1 It ushered in the new era of transpleural and transmediastinal placement of the gastric conduit and confirmed the safety of the intrathoracic anastomosis. Prior to this, an extrathoracic passage (subcutaneous) was used to facilitate the cephalad transfer of the mobilized gastric conduit to the neck for the esophagogastric anastomosis.2 Initially, this was favored because of the trepidation of performing an intrapleural anastomosis. Esophagectomy through a left thoracotomy remained a common approach for the ensuing 30 years. Ultimately, it was largely supplanted by other techniques,3-5 although none of the more commonly performed procedures for esophageal resection truly replaced the left thoracotomy approach. By the late 1970s, Ivor Lewis and McKeown procedures seemed more appropriate for midesophageal squamous cell carcinoma, and transhiatal (blunt) esophagectomy appeared to be the best approach for the then, less common, adenocarcinoma of the distal esophagus. Current trends suggest the overall incidence of esophageal cancer has not appreciably changed; however, a marked shift in the frequencies of histologic subtypes in the United States has occurred. Adenocarcinoma of the distal esophagus and gastroesophageal junction is now the predominant cancer. Thus, when considering an operation for esophageal cancer, optimal exposure to the distal esophagus and gastric cardia is critical, because this will be the location of the cancer in the majority of patients. Moreover, since N1 lymph node involvement is a likely early characteristic, exposure of the esophageal hiatus and distal posterior mediastinum for lymphadenectomy (or relevant sampling) must be considered a critical component of any operation for adenocarcinoma of the esophagus. To achieve optimal exposure of the hiatus and posterior mediastinum for resection of esophageal cancer, there is no better procedure than the left thoracoabdominal approach (Ginsberg, 2002).6 584

To date, no randomized studies exist that advocate which of several esophageal resection techniques provides the most complete resection for cancer, nor do any propose what technique may have the greatest potential for a highly successful outcome. Attempts were made retrospectively to compare outcomes of different procedures performed at the same institution. Unfortunately, no consensus was elicited among these (Goldfaden et al, 1983; Hagen et al, 1993).7,8 Little question remains, however, that the lesser operation (transhiatal esophagectomy) has less morbidity compared with any approach utilizing a thoracotomy. Yet, this must be balanced by the nearly 40% locoregional cancer recurrence rate after transhiatal resection (Hulscher et al, 2000).9 If one simply abides by the basic tenets of cancer surgery— (1) optimal exposure of the cancer field, (2) complete resection that includes radial margins, and (3) extensive locoregional lymphadenectomy (or sampling) for accurate staging—the best operative approach for esophageal cancer in the 21st century may very well be the left thoracoabdominal esophagectomy with cervical esophagogastric anastomosis (Fig. 53-1). Morbidity of the approach can be reduced by careful preoperative patient selection, meticulous surgical technique, and early recognition and management of evolving postoperative problems.

INDICATIONS AND PREPARATION Numerous surgical approaches to the distal esophagus and stomach allow the surgeon to select the most appropriate operation for a given set of conditions and pathologic processes. This decision relies greatly on the experience and wisdom of the esophageal surgeon, who must be familiar with all techniques, as well as their distinct advantages, disadvantages, and specific complications. The left thoracoabdominal/left neck approach for esophagectomy is principally a cancer operation. Occasionally, this approach is useful as a salvage procedure for a patient who has experienced multiple failed abdominal hiatal hernia repairs. For the morbidly obese patient with resectable esophageal cancer, the left thoracoabdominal/left neck approach may be technically easier than one requiring laparotomy. This procedure should be reserved for patients with locally advanced adenocarcinoma of the distal esophagus, gastroesophageal junction, or gastric cardia where some justification for exchanging increasing morbidity (compared with a transhiatal approach) for improved tumor and lymphatic basin clearance is possible. Because of the location of the aortic arch, a high left-sided intrathoracic anastomosis cannot be

Chapter 53 Left Thoracoabdominal Esophagectomy

created, as in the Ivor Lewis approach. Consequently, a cervical anastomosis is favored for this technique. A left thoracoabdominal/left neck approach for distal esophageal and gastroesophageal junction adenocarcinoma provides excellent exposure to the tumor bed, allows en-bloc resection of regional lymph nodes (N1) and celiac trunk disease (M1a), and permits the entire procedure to be completed with a single sterile preparation and draping. In addition, it affords the surgeon the opportunity to assess curability before a commitment to open the left thorax. Finally, significant splenic capsular injury is extremely rare because of the superior access to the short gastric arcade. Because the left thoracoabdominal/left neck procedure is performed infrequently, orientation of abdominal, thoracic, and cervical structures is less familiar, and an appreciation of the anatomic relationships from the left lateral view must be exercised. Structures close or to the right of the midline (i.e., duodenum and thoracic duct) are more difficult to access. Protracted ipsilateral lung collapse is required to complete the mediastinectomy. Of importance is the morbidity associated with division of the costal arch and circumferential dissection of the left diaphragm. This morbidity can be significant, and, accordingly, specific attention to incision closure is mandated. Standard workup for a patient with documented adenocarcinoma of the esophagus includes a thorough assessment of cardiopulmonary fitness and determination of surgical candidacy. Radiographic (chest CT, positron emission tomography) and endoscopic ultrasound staging is obtained for all patients. Operative candidates with stage I disease are offered transhiatal esophagectomy. The left thoracoabdominal/left neck approach is reserved for patients who present with clinical stages II to IVA. Induction chemoradiotherapy is given to patients with T3 N0, Tx N1, and Tx Nx M1a tumors. Patients receiving induction therapy undergo complete restaging before resection to rule out disease progression, which would contraindicate esophagectomy. All patients undergo a bowel prep the day before surgery. An epidural catheter is placed before induction of anesthesia. Standard support lines include left-sided double-lumen endotracheal tube, nasogastric tube, right internal jugular central venous access, right radial arterial line, and bladder catheter. Patients are positioned in a modified right lateral decubitus position with the abdomen and pelvis rotated back (corkscrewed) toward the table (Fig. 53-2). The sterile prep is extended beyond the midline anteriorly from neck to groin and posteriorly to the spine. The entire left arm is included within the field. Until cervical exposure is needed, the arm is draped across the patient’s body and supported on an armboard. Important musculoskeletal landmarks are the left sternocleidomastoid muscle, scapular tip, costal margin, umbilicus, and anterior iliac spine.

THORACOABDOMINAL INCISION The thoracoabdominal incision generally extends from two fingerbreadths below the scapula tip along the seventh interspace, across the costal margin, and obliquely toward the umbilicus (Fig. 53-3). The oblique abdominal incision, begin-

FIGURE 53-1 Overview of area to be resected. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 53-2 Patient positioned for the left thoracoabdominal approach. The left arm is prepped into the operative field. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

ning at the costal arch is made first. External and internal oblique muscles are divided, and the lateral aspect of the rectus muscle and sheath is incised. The left inferior epigastric vascular pedicle is seldom encountered and approximates the most medial extent of the abdominal incision in large patients. Manual palpation of abdominal viscera is used to determine resectability. Specifically, peritoneal carcinomatosis, as well as liver, porta hepatis, duodenum, pancreatic, and gross celiac involvement, would end the procedure after enteral feeding access (J tube) was placed. If, however, only localized, resectable disease were encountered, the entire incision is created with posterior extension along the seventh interspace as deemed appropriate. Lower slips of serratus muscle are generally divided in the direction of their fibers, and the anterior aspect of the latissimus dorsi muscle is

585

586

Section 6 Operative Techniques

FIGURE 53-4 The celiac axis is dissected easily from the lateral approach. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 53-3 Exposure of the gastroesophageal junction is ideal. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

incised depending on the posterior and superior extent of the incision. To connect the thoracotomy and oblique laparotomy, the costal margin and the diaphragm must be divided. The costal arch is cut sharply, usually between the seventh and eighth ribs. Beginning at this location, the diaphragm is circumferentially divided posteriorly for 8 to 10 cm (see Fig. 53-3). A 2-cm margin of diaphragm should be left attached to the chest wall to facilitate diaphragm closure at the conclusion of the case. The ribs are distracted in the standard fashion, and an abdominal retractor is placed. With ipsilateral lung deflation, the gastroesophageal junction should be in the center of the operative field and either the abdominal or mediastinal dissection performed first. From this exposure, mobilization of the proximal stomach is much easier because the short gastric arcade is more superficial. Moreover, because the celiac trunk is approached from a more lateral vantage point, the regional abdominal lymphadenectomy is far more complete (Fig. 53-4). As the greater omentum is separated from the right gastroepiploic arcade, transillumination simplifies the dissection. Complete mobilization of the duodenum (Kocher maneuver) is slightly more awkward but can, nonetheless, be fully completed. Similarly, gastric conduit drainage (pyloromyotomy or pyloroplasty) can be performed. Despite the use of preoperative chemoradiotherapy in most cases, dense fibrosis at the hiatus is rarely problematic,

even in obese patients. A circumferential cuff of diaphragm can easily be included en bloc. For cancers of the gastric cardia or fundus, where a distal esophagectomy and total gastrectomy would be preferred, this exposure is ideal. The Roux-en-Y limb is easily harvested, passed retrocolic, brought up through the hiatus, and anastomosed to the distal esophagus without much fanfare. The mediastinal portion of the procedure begins by widely opening the left mediastinal pleura and fully dividing the inferior pulmonary ligament. Posteriorly, the dissection continues on the aortic adventitia to the right, toward the spine and azygos vein. The right pleural space is frequently opened. Anteriorly, the mediastinal tissues are dissected off the inferior aspect of the pericardium. After these two tissue planes have been established, the en-bloc dissection continues cephalad toward the subcarinal region (Fig. 53-5). A Penrose drain can be used to encircle the specimen and provide countertraction. Because of its right-sided location, it may be difficult to identify the thoracic duct. Inclusion of the duct during the resection is often by chance, and attention must be taken to carefully clip or ligate any tissues remaining along the right side of the aorta to prevent postoperative chylothorax. Some care must also be taken to avoid injury of the azygos vein because repair from the left side is exceptionally difficult. The mediastinectomy is terminated after evacuation of the subcarinal lymph node packet. Cautery injury of the left mainstem bronchus and left pulmonary artery are risks during this aspect of the procedure. Several aortoesophageal collaterals are typically encountered and require surgical control. Above the level of the carina, the esophagus is bluntly dissected off the airway and spine toward the neck. At this point, the dissection plane is on the areolar tissues of the esophageal adventitia. The arm is then rotated laterally and distracted inferiorly to expose the left lateral neck.

Chapter 53 Left Thoracoabdominal Esophagectomy

FIGURE 53-6 The cervical esophagus is exposed through a counter incision along the left sternocleidomastoid muscle. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 53-5 En bloc posterior mediastinal lymphadectomy is demonstrated. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

Exposure of the cervical esophagus is more challenging than from a standard supine approach. Both lateral and posterior distraction of the sternocleidomastoid muscle is required. The orientation makes it difficult to use self-retaining retractors so assistants are relied on to manually expose the region. A standard oblique incision is made along the anterior border of the sternocleidomastoid muscle (Fig. 53-6). The platysma is incised sharply, and the sternocleidomastoid muscle is mobilized anteriorly and medially and displaced primarily posteriorly. The omohyoid muscle is then divided and the carotid sheath structures carefully mobilized laterally. A useful anatomic landmark is the middle thyroid vein, which is often bowstrung across the field and requires division. Once this is done, access to the cervical spine is facilitated. It is easy to mistakenly dissect into the tracheoesophageal groove because of the lateral orientation. To prevent this, the spine must be first identified and the cervical esophagus initially approached posteriorly. The trachea will be relatively immobile because of the double-lumen endotracheal tube within. Isolating the cervical esophagus from the trachea is left as the final maneuver. Circumferentially controlling the esophagus in the superior mediastinum (working back up to the cervical esophagus) reduces the frequency of both right and left recurrent laryngeal nerve injury. With the cervical esophagus encircled, blunt esophagectomy techniques are used to fully dissect the thoracic esophagus above the aortic arch. When completely mobilized and with the nasogastric tube drawn back proximally, the proxi-

mal esophagus is delivered into the neck and divided and the entire en-bloc specimen is returned to the abdomen. There it is separated from the proximal stomach using a linear stapler-cutter without significantly tubularizing the conduit. This seems to improve venous drainage to the tip and results in fewer anastomotic complications. A greater than 5-cm distal (gastric) margin is essential. For adenocarcinoma of the esophagus, the proximal margin is rarely an issue. Occasionally, for patients with extensive intestinal metaplasia, it is preferred to resect Barrett’s mucosa back to normal stratified squamous epithelium. The lesser curve staple line is imbricated with fine, absorbable, monofilament suture. The conduit is carefully passed orthotopically to the neck to ensure the conduit is not twisted and proper orientation is maintained. While the gastric and esophageal margins are being examined pathologically, a feeding jejunostomy can be placed. A modified Collard anastomosis (Figs. 53-7 and 53-8) is used to re-establish alimentary tract continuity.10 Once again, more lateral exposure can be slightly disorienting, but the anastomosis is constructed identically to that performed with the patient supine. When finished, the anastomosis is returned orthotopically and repositioned in the superior mediastinum (Fig. 53-9). The nasogastric tube is passed into the stomach and advanced to the pylorus before closing the anterior aspect of the esophagogastrostomy. Gentle traction on the conduit at the hiatus will aid in straightening the stomach out, delivering the anastomosis to the superior mediastinum, and identifying any tension of the conduit.

INCISION CLOSURE The ideal time to inspect the mediastinum for lymph leak and hemostasis is just before the pull-up of the gastric conduit. Unless frank chyle is present from an occult lymph leak, it is difficult to identify an uncontrolled main or accessory thoracic duct disruption intraoperatively. Suture ligatures and metal clips can be placed across the presumed course of

587

588

Section 6 Operative Techniques

FIGURE 53-7 A modified stapled anastomotic technique is used. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

FIGURE 53-8 The anterior aspect of the anastomosis is completed using a hand-sewn technique. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

the thoracic duct, along the right side of the spine and medial to the inferior azygos vein, as prophylaxis. Nonetheless, some degree of chylothorax will be present in 5% to 10% of patients; of these, one half will require intervention (usually percutaneous). After the pull-through, the conduit should be loosely secured to the remaining hiatus to prevent gross herniation of abdominal contents into the left chest. Drains are placed in the superior mediastinum (from the neck) and left and right hemithoraces. An abdominal drain is optional. After the neck incision is generously lavaged with warm saline, a two-layer, interrupted, suture closure is preferred for the cervical incision. The platysma and dermis are closed separately with absorbable suture. The interrupted technique allows for partial opening of the cervical incision for leak or infection (5%-10%). As described earlier, a Silastic closed suction drain is placed into the superior mediastinum through the cervical incision. Closure of the thoracoabdominal incision begins with repair of the diaphragm. This is routinely conducted with interrupted, large-gauge (No. 1) Polyglactin suture. The repair is made significantly easier if 2 cm of diaphragm is left on the chest wall as the sewing cuff. Interrupted No. 2 Polyglactin suture is used to coapt the thoracotomy with a figure-of-eight suture placed across the costal margin defect (into the cartilage edges) for realignment purposes. The diaphragm is tacked at the costal margin repair site to fortify the closure. Occasionally, the cartilage ends at the costal arch may need to be trimmed if they cannot be accurately realigned. Chest and abdominal wall muscles, as well as abdominal fascia, are repaired in layers with continuous absorbable suturing technique. The skin and subcutaneous closure is routine. After application of sterile dressings, the nasogastric tube is securely fastened and the double-lumen endotracheal tube is switched to single lumen. It is not policy to extubate patients in the operating room for several reasons. First, the en-bloc resection technique is simply a larger operation and, consequently, more fluid resuscitation is required intraoperatively. Second, since most patients are preoperatively debilitated by induction chemoradiation therapy, response to the large surgical stress is more difficult to predict. Third, excellent pain control must be ensured before extubation. This is best assessed after the patient completely emerges from anesthesia.

POSTOPERATIVE COURSE

FIGURE 53-9 Orthotopic repositioning of the gastric conduit. (REPRINTED WITH THE PERMISSION OF THE CLEVELAND CLINIC FOUNDATION.)

There is no question the magnitude of the procedure leads to a more complicated postoperative course. It should be remembered that this procedure, in combination with induction chemoradiation therapy, is principally reserved for fit patients with locally advanced malignancy and with limited, if any, other effective treatment options. Clearly, there is a benefit for responders.11 These results encourage us to keep this procedure a routine part of our practice. Cervical infection, with or without anastomotic leak, occurs in 5% to 10% of patients. Early identification reduces its impact. Treatment usually requires only reopening the cervical incision and widely draining the space. The majority

Chapter 53 Left Thoracoabdominal Esophagectomy

of anastomotic fistulas heal within 2 weeks. A short course of broad-spectrum antibiotics is useful to treat the accompanying cellulitis. Approximately 5% of patients will develop chylothorax requiring a re-intervention. These are defined by early highvolume output (>1000 mL/day) or chylothorax that fails to resolve after 2 weeks, despite complete bowel rest and total parenteral nutrition. Percutaneous identification and embolization of chylous leak is the standard therapy. Reoperation and thoracic duct ligation, performed through the right chest, is reserved for a minority of patients on whom other therapies fail. Costal arch dehiscence usually occurs in the setting of a deep surgical site infection. Although the prevalence is rare, operative débridement, wide drainage, and postoperative vacuum dressings are indicated. Uncomplicated costal margin “clicks” are managed expectantly. To reduce the chance of early gastric distention and herniation of the conduit into the left chest, patients are maintained solely on tube feeding for 4 weeks. Oral intake is gradually advanced, and separation from tube feeding occurs at between 6 to 8 weeks.

SUMMARY The left thoracoabdominal/left neck approach provides exceptional exposure for operations centered at the esophageal hiatus. A complete two-field lymph node dissection is easy to complete; en-bloc esophagectomy can be performed without patient repositioning. The orientation may initially seem awkward but rapidly becomes appreciated and embraced.

COMMENTS AND CONTROVERSIES Although many surgeons prefer the right Ivor Lewis or McKeown approach, I fully agree with Dr. Murthy that the left thoracoabdominal approach is to be preferred for distal third and gastroesophageal tumors. This approach undoubtedly offers an exposure of the mediastinum and upper abdominal compartment that is superior to any other approach. The criticism to this approach mainly relates to the partial division of the diaphragm with subsequent dysfunction as well as the painful consequences of interrupting the costal arch. However, by dividing the diaphragm at its periphery the phrenic innervation and muscular function remain intact without any impairment on the pulmonary function. Provided that the incision is made in the sixth intercostal space and not lower, post-thoracotomy pain is seldom an issue of

importance. Occasionally non-union of the costal arch may occur, but this is absolutely without any relevant functional consequence. I usually mobilize the spleen and pancreatic tail by incising the peritoneum behind the spleen. This maneuver results in an unparalleled exposure of the left upper abdomen facilitating not only the mobilization of the greater curvature but, in particular, facilitating as radical as possible lymphadenectomy around the celiac axis and its trifurcation. Such an approach might be of particular interest in the very obese patient—nowadays increasingly seen especially in the Barrett’s population. In the chest a radical en-bloc resection and lymphadenectomy is, of course, easily feasible. I definitely find an en-bloc dissection in the lower mediastinum easier to perform as compared with a right-sided approach from the fifth intercostal space, the latter obscuring the sight in the most distal part of the posterior mediastinum. To avoid chylothorax and also to improve the completeness of resection it is my practice to routinely resect and ligate the thoracic duct. The esophagus is dissected high up behind the aortic arch up into the base of the neck so that during the cervical part of the operation there is no need for further dissection and less risk for damaging the recurrent nerve. Lymphadenectomy can easily be performed up to the aortopulmonary window and behind the aortic arch on the left side. Lymph node clearance high up in the right paratracheal side is less obvious. Nodes around the brachiocephalic trunk, however, can be palpated easily; and when deemed necessary they can be cleared by performing a three-field lymphadenectomy. I do not perform pyloromyotomy/plasty in order to avoid bile reflux. When a gastric tube of less than 5 cm width is placed, gastric outlet obstruction is rare and in such an event is usually easily managed by administering prokinetics and, if necessary, by using balloon dilatation. T. L.

KEY REFERENCES Ginsberg R: Left thoracoabdominal cervical approach. In Pearson FG (ed): Esophageal Surgery, 2nd ed. Philadelphia, Churchill Livingstone, 2002, pp 809-817. Goldfaden D, et al: Adenocarcinoma of the distal esophagus and gastric cardia: Comparison of results of transhiatal esophagectomy and thoracoabdominal esophagogastrectomy. J Thorac Cardiovasc Surg 91:242-247, 1983. Hagen J, Peters J, DeMeester T: Superiority of extended en bloc esophagogastrectomy for carcinoma of the lower esophagus and cardia. J Thorac Cardiovasc Surg 106:850-858, 1993. Hulscher JB, van Sandick JW, Tijssen JG, et al: The recurrence pattern of esophageal carcinoma after transhiatal resection. J Am Coll Surg 191:143-148, 2000.

589

chapter

ESOPHAGECTOMY VIA RIGHT THORACOTOMY

54

Philip A. Linden David J. Sugarbaker

Key Points ■ Esophagectomy carries a mortality rate of 10% that can be reduced

■ ■

■ ■

to 2% to 3% in high-volume centers with careful patient selection, meticulous technique, and intensive perioperative care. Method of resection is determined by the location of the tumor, extent of local spread, and need for complete lymphadenectomy. Tri-incisional esophagectomy affords dissection of the difficult esophagus under direct vision, allows for the greatest longitudinal and radial margins, allows for complete lymphadenectomy, minimizes the risk of intrathoracic leak, and ensures the anastomosis will be out of the radiated field for lower- and middle-third tumors. Trend toward improved survival observed with transthoracic versus transhiatal esophagectomy. Pulmonary complications are the main risk after any type of esophagectomy and may be minimized by the use of an epidural catheter, less invasive thoracic incisions, early ambulation, specialized care in a dedicated thoracic unit, and early cord medialization in cases of recurrent nerve injury.

CONSIDERATIONS AND CHOICE OF OPERATION Choice of operation depends on several factors, including nature of esophageal disease (benign versus malignant), need for adequate longitudinal and radial margins, surgeon preference, patient factors, and neoadjuvant treatment. We prefer the tri-incisional esophagectomy in almost all circumstances because it does the following (Swanson et al, 2001)6: 1. Affords dissection of the difficult esophagus under direct vision 2. Allows for the greatest longitudinal and radial margins 3. Permits complete lymphadenectomy 4. Minimizes the risk of intrathoracic leak 5. Ensures that the anastomosis will be out of the radiated field for lower- and middle-third tumors Individual series have shown, however, that even difficult middle-third esophageal tumors can be managed via the transhiatal technique (Orringer et al, 1999)7 and intrathoracic anastomoses can be performed with an extremely low rate of leak (Mathisen et al, 1988).8

Nature of Esophageal Disease

HISTORICAL NOTE Torek is credited with the first esophageal resection via thoracotomy in 1913.1 This was performed without reconstruction; an extracorporeal rubber tube was used to connect a cervical esophagostomy with an abdominal gastrostomy for feeding. Transthoracic esophagectomy with reconstruction is commonly credited to Adams and Phemister in 1938,2 although Ohsawa, in Japan, had described esophagectomy via a left thoracoabdominal incision with reconstruction as early as 1933.3 Nonetheless, esophagectomy via thoracotomy, even for middle-third tumors, was a rare event before being described and popularized by a London surgeon, Ivor Lewis, in 1946.4 His initial reports described a two-stage approach involving a laparotomy and mobilization of the stomach, followed 1 to 2 weeks later by right thoracotomy, esophageal resection, and intrathoracic anastomosis. As the operation became popular, it evolved into a two-stage operation performed in a single setting. In an effort to improve proximal margins, McKeown first described a tri-incisional, or “threehole,” technique of esophagectomy.5 These two techniques are today the most popular methods of right-sided transthoracic esophageal resection. 590

Any esophagectomy technique should allow for adequate removal of the esophagus whether for benign disease or neoplasia limited to the mucosa. In end-stage achalasia, the esophagus is commonly dilated, tortuous, and fed by relatively large vessels. Although esophagectomy for this disease can be performed using the transhiatal approach, right thoracotomy or thoracoscopy yields a safer dissection. Resection of the esophagus with high-grade dysplasia may be performed using either the transthoracic or transhiatal technique, because the incidence of lymph node metastasis is low.

LONGITUDINAL AND RADIAL MARGINS The distance of the cancer from the incisors and the need to obtain adequate proximal and distal margins are two of the most important determinants of esophagectomy technique. Tam and associates examined the relationship between intraoperative margins and local recurrence in patients with squamous cell carcinoma of the esophagus. Local recurrence occurred in 20% of patients with margins less than 5 cm, in 8% of patients with margins between 5 and 10 cm, and in no patients with margins greater than 10 cm.9 Thus, esophagectomy margins in squamous cell cancer should be at least 5 cm and, ideally, 10 cm. For gastroesophageal junction tumors, any approach will achieve adequate longitudinal margins

Chapter 54 Esophagectomy via Right Thoracotomy

(assuming that there is not extensive spread onto the cardia). For upper-third esophageal tumors, a cervical incision and anastomosis is required, and sometimes laryngectomy. Tumors with proximal extent greater than 25 cm from the incisors are best approached with a cervical incision and anastomosis. Tumors with proximal extent below thus can be approached either with a cervical incision or an Ivor Lewis approach. The average added margin obtained with a cervical incision has been estimated to be only 3 cm. However, if the frozen section on the proximal margin returns positive, it is far easier to redo the anastomosis more proximally via a cervical incision than with an Ivor Lewis incision. Achieving adequate radial clearance for tumors invading through the esophageal wall (T3) and into involved lymph nodes is a more complicated issue. Two (Goldminc et al, 1993; Hulscher et al, 2002)10,11 of three (Chu et al, 1997)12 prospective, randomized trials comparing the transthoracic versus transhiatal approach showed a trend toward improved long-term survival with a transthoracic approach, although statistical significance was not reached. A lower esophageal lymph node dissection can be performed with the transhiatal technique; however, almost twice the number of lymph nodes are harvested using the transthoracic approach (Hulscher et al, 2002).11 En-bloc removal of the thoracic duct, pericardium, and pleura may provide even better radial clearance.13 This issue is further discussed in the sections on en-bloc resection and three-field lymph node dissection.

Patient Factors Esophagectomy is potentially one of the most lethal and morbid resections. Proper selection and preparation of patients undergoing esophagectomy is essential. Significant associated cardiac, pulmonary, or renal disease likely increases the risk of serious complications. Pulmonary function testing should be performed. An FEV1 of less than 1 L (approximately 40% predicted for an average man) would suggest a higher likelihood of serious pulmonary complications, and a thoracoscopic approach should be considered. If a patient suffers from significant coronary or valvular disease but is still a candidate for resection, a transthoracic approach should be considered. Transthoracic resection is associated with less hypotension than the transhiatal method, which requires insertion of the surgeon’s hand behind the left atrium (Chu et al, 1997).12 Prior scarring from either thoracic or abdominal incisions should not affect the risk or difficulty of operation. Severe scarring of the pleural space (pleural symphysis) as observed after pleurodesis would increase significantly the difficulty of a transthoracic approach. Scarring around the esophagus as seen after prior esophageal surgery would favor esophagectomy under direct vision (i.e., via thoracotomy for all lesions above the gastroesophageal junction).

Neoadjuvant Treatment In the United States, many patients with locally advanced cancer (i.e., T2 or greater or N1 or greater, M0) are treated with preoperative chemoradiation, which causes scarring of nearby vital structures often not seen in patients not receiving

such treatment. In general, dissection of such tumors via transthoracic approach is safer, although Orringer and colleagues have reported a large series of patients undergoing preoperative radiation followed by transhiatal resection (Orringer et al, 1999).7 In general, randomized studies of transthoracic versus transhiatal dissection have excluded these patients from randomization (Chu et al, 1997; Hulscher et al, 2002).11,12 Surgery is generally performed at least 4 weeks after completion of chemoradiation therapy.

PREPARATION Severely malnourished patients or those with significant obstruction or dysphagia who require preoperative chemoradiation should have a jejunal feeding tube placed in advance. Smoking cessation should be encouraged as far in advance of surgery as possible. Mechanical bowel preparation is given the day before surgery, in case the stomach is not a suitable substitute and colon is required. Antibiotics can be administered orally the day before surgery or parenterally the morning of surgery. A thoracic epidural catheter is placed before operation to aid in postoperative pain control and pulmonary toilet. Bronchoscopy and esophagogastroduodenoscopy are performed by the surgeon before incision. Bronchoscopy is used to rule out invasion of the trachea or left main bronchus, and it permits suctioning of secretions before institution of single-lung ventilation. Esophagogastroduodenoscopy confirms the location of the tumor and rules out associated disease in the gastric conduit.

TECHNIQUE: TRI-INCISIONAL APPROACH Thoracic Stage After the double-lumen endotracheal tube has been placed and its position verified, the patient is placed in the left lateral decubitus position. A serratus-sparing posterolateral thoracotomy is made approximately 10 cm in length (Fig. 54-1). The chest is entered in either the fifth or sixth intercostal space, and an additional rib is shingled posteriorly. The lung is carefully palpated and inspected for any metastatic nodules. The inferior pulmonary ligament is divided with electrocautery, and the lung is retracted anteriorly. The initial dissection of the esophagus is performed in an area of normal anatomy, away from scarring or invasion. The pleura is incised, and the esophagus is encircled with a Penrose drain. The drain is used to retract the esophagus, displacing it anteriorly for dissection posterior to the esophagus and to the right for dissection on the left side of the esophagus. All lymphatic tissue between the pericardium, aorta, and spine is removed en bloc with the specimen. If pleura or pericardium is densely adherent to the tumor, it is removed en bloc with the specimen. Cautery dissection is used, taking care to clip larger arterial branches originating from the aorta. If the tumor is at the gastroesophageal junction, a rim of diaphragm should be incorporated into the specimen (Fig. 54-2). The Penrose drain is then knotted to itself and passed into the abdomen for later retrieval. The dissection proceeds toward the cervical esophagus. The carina lies just below the azygos vein. All cautery dissec-

591

592

Section 6 Operative Techniques

FIGURE 54-1 A limited, serratus-sparing posterolateral thoracotomy is performed for the first phase of the tri-incisional esophagectomy.

FIGURE 54-2 A rim of diaphragm is left attached to the esophagus in tumors of the gastroesophageal junction. (REPRODUCED WITH PERMISSION FROM THE MCGRAW-HILL COMPANIES FROM SUGARBAKER DJ, DECAMP MM, LIPTAY MJ: SURGICAL PROCEDURES TO RESECT AND REPLACE THE ESOPHAGUS. IN ZINNER MJ [ED]: MAINGOT’S ABDOMINAL PROCEDURES, 10TH ED. STAMFORD, CT, APPLETON & LANGE, 1997, PP 885-910.)

tion from this point cephalad should be done at low cautery settings to avoid thermal tracheal injury. The vagus nerves are identified and divided at this level. All cephalad dissection should be performed inside these nerves to avoid injury to the recurrent vagus nerves. The azygos vein is typically divided with an endovascular stapler, although this is not absolutely necessary. At the apex of the chest, further dissection is performed bluntly with the surgeon’s finger reaching into the neck (Fig. 54-3). The Penrose drain is knotted and placed with the vagus nerves in the neck along the spine for easy isolation of the esophagus during the cervical phase (Fig. 54-4). A final inspection is made for hemostasis as well as any chyle leaks. In the unfed patient, a chyle leak may appear as a clear fluid collecting in the space between the aorta and spine. If a leak is identified, the duct should be repaired with a 4-0 pledgeted Prolene suture. Some surgeons choose to perform prophylactic ligation of the duct at the hiatus. With this technique, all tissue between the aorta and spine is isolated with a large right-angle clamp and ligated with a heavy 0-silk suture at the level of the hiatus. A 28-Fr chest tube is placed via a separate stab incision to the apex of the chest. The ribs are approximated with 2-0 Vicryl stitches. The latissimus fascia is closed with running 0 Vicryl suture. The subdermal layer is closed with running 2-0 Vicryl suture, and the skin is closed with running 3-0 Vicryl or Monocryl suture.

FIGURE 54-3 Dissection at the apex of the chest is generally performed bluntly as the surgeon’s finger reaches through the thoracic inlet. (REPRODUCED WITH PERMISSION FROM THE MCGRAW-HILL COMPANIES FROM SUGARBAKER DJ, DECAMP MM, LIPTAY MJ: SURGICAL PROCEDURES TO RESECT AND REPLACE THE ESOPHAGUS. IN ZINNER MJ [ED]: MAINGOT’S ABDOMINAL PROCEDURES, 10TH ED. STAMFORD, CT, APPLETON & LANGE, 1997, PP 885-910.)

Chapter 54 Esophagectomy via Right Thoracotomy

FIGURE 54-5 After sweeping all nodal tissue onto the specimen, the left gastric artery is clamped with an endovascular stapler. (REPRODUCED WITH PERMISSION FROM THE MCGRAW-HILL COMPANIES FROM SUGARBAKER DJ, DECAMP MM, LIPTAY MJ: SURGICAL PROCEDURES TO RESECT AND REPLACE THE ESOPHAGUS. IN ZINNER MJ [ED]: MAINGOT’S ABDOMINAL PROCEDURES, 10TH ED. STAMFORD, CT, APPLETON & LANGE, 1997, PP 885-910.)

FIGURE 54-4 A knotted Penrose drain is placed into the neck during the initial phase of the operation for retrieval during the cervical phase. Placement within the vagus nerves helps to avoid injury to the recurrent vagus nerves. (REPRODUCED WITH PERMISSION FROM THE MCGRAW-HILL COMPANIES FROM SUGARBAKER DJ, DECAMP MM, LIPTAY MJ: SURGICAL PROCEDURES TO RESECT AND REPLACE THE ESOPHAGUS. IN ZINNER MJ [ED]: MAINGOT’S ABDOMINAL PROCEDURES, 10TH ED. STAMFORD, CT, APPLETON & LANGE, 1997, PP 885-910.)

Abdominal/Cervical Stage The patient is repositioned in the supine position and reintubated with a single-lumen endotracheal tube. A transverse roll is placed under the shoulder blades and the neck is turned 45 degrees to the right. An upper midline laparotomy is performed from the umbilicus to the xyphoid. The abdomen is explored for metastatic disease, paying close attention to the liver. The knotted Penrose drain at the gastroesophageal junction is grasped and retracted with a Kelley clamp. The stomach is inspected, and the right gastroepiploic pulse is palpated. Dissection begins along the greater curvature at least 2 cm away from the right gastroepiploic artery. The lesser omentum is entered. Dissection proceeds up along the greater curvature. The stomach should be grasped and retracted with care not to retract or grasp the gastroepiploic vessel. Tissue may be divided with an ultrasonic scalpel, ligated between clamps, or divided with a tissue vascular stapler. Large short gastric vessels are best individually ligated. Dissection proceeds cephalad until the drain surrounding the gastroesophageal junction is reached. Additional dissection proceeds caudad on the greater curvature of the stomach to the pylorus. Care should be taken at this point as the artery wanders away from the gastric wall.

The gastrohepatic ligament is divided by cautery, taking care to avoid any replaced left hepatic artery. The stomach is then retracted anteriorly. Adhesions between the pancreas and posterior aspect of the stomach are divided with electrocautery. The left gastric artery is identified. The artery is skeletonized, and all lymph nodes are swept up onto the specimen. The artery is clamped with an endovascular stapler (Fig. 54-5). Before the stapler is fired, the right gastroepiploic artery is palpated to ensure that the celiac axis has not been compromised. A Kocher maneuver is performed using a combination of cautery and blunt dissection. After this maneuver has been performed, the pylorus should reach the midline. A pyloromyotomy or Heineke-Mikulicz pyloroplasty is then performed to aid in drainage. The pyloroplasty should be closed with a single layer of 3-0 silk interrupted sutures, carefully incorporating mucosa and muscular wall. Attention shifts to the left neck where an incision is made extending along the sternocleidomastoid muscle 6 cm cephalad from the sternal notch through the platysma. Dissection proceeds medial to the carotid sheath but lateral to the strap muscles. The middle thyroid vein and omohyoid muscles may be divided. Blunt dissection can then be used to palpate the Penrose knot against the spine. The Penrose is grasped, and the proximal esophagus is gently and bluntly mobilized. The nasogastric tube is withdrawn just proximal to the proposed line of division and a 75-mm thin tissue linear cutter stapler is closed along the proposed line of division. A 2-0 silk suture is sutured to the most proximal portion of the esophagus that is to be excised, and the stapler is fired. The esophagus is drawn into the abdomen along with the silk suture

593

594

Section 6 Operative Techniques

FIGURE 54-7 After the stomach has been completely mobilized, the gastric conduit is constructed by repeated firings of a thick-tissue GIA 75-mm stapler parallel to the greater curvature of the stomach.

FIGURE 54-6 After division of the esophagus in the neck, the specimen is drawn into the abdomen. A long, heavy silk suture is attached to the esophagus and drawn into the abdomen. (REPRODUCED WITH PERMISSION FROM THE MCGRAW-HILL COMPANIES FROM SUGARBAKER DJ, DECAMP MM, LIPTAY MJ: SURGICAL PROCEDURES TO RESECT AND REPLACE THE ESOPHAGUS. IN ZINNER MJ [ED]: MAINGOT’S ABDOMINAL PROCEDURES, 10TH ED. STAMFORD, CT, APPLETON & LANGE, 1997, PP 885-910.)

(Fig. 54-6). A clamp is placed on the other end of the suture in the neck. Attention is then turned to creation of the gastric tube conduit. A series of linear cutting thick-tissue 75-mm staplers are applied along the lesser curvature leaving a conduit diameter of approximately 5 cm. The end point is the crow’s foot of veins on the lesser curve (Fig. 54-7). The right gastric artery is divided at this point to permit maximal length of the conduit and to avoid a “bowstringing” effect. Some surgeons choose to oversew the staple line with 2-0 silk suture. A final inspection is made for hemostasis in the abdomen before drawing the conduit up into the neck. One ampule of glucagon is administered intravenously to provide maximal relaxation and length of the gastric conduit. An atraumatic method of bringing the conduit up into the neck involves placing the conduit in an endoscopic camera bag (Fig. 54-8). The long 2-0 silk suture traversing the mediastinum is tied to the valved end of a three-way 30-mL Foley catheter. An endoscopic camera bag is placed over the Foley balloon and secured to the Foley catheter. A small amount of saline is placed in the bag, and the conduit is placed in the

FIGURE 54-8 The gastric conduit is drawn up to the neck atraumatically in an endoscopic camera bag attached to a Foley catheter. The catheter is placed on suction and pulled into the neck, while the assistant guides the conduit through the hiatus. (REPRODUCED WITH PERMISSION FROM THE MCGRAW-HILL COMPANIES FROM SUGARBAKER DJ, DECAMP MM, LIPTAY MJ: SURGICAL PROCEDURES TO RESECT AND REPLACE THE ESOPHAGUS. IN ZINNER MJ [ED]: MAINGOT’S ABDOMINAL PROCEDURES, 10TH ED. STAMFORD, CT, APPLETON & LANGE, 1997, PP 885-910.)

bag with proper orientation and without twisting. The valved end of the Foley catheter is brought out into the neck and suction is applied. The surgeon guides the conduit up into the chest until the pylorus is sitting at the hiatus. It is critical to ensure proper orientation of the conduit at all times. The staples on the lesser curve should appear on the right side of

Chapter 54 Esophagectomy via Right Thoracotomy

the conduit in the neck. The bag is cut away, and the anastomosis may be hand sewn or stapled. A stapled anastomosis is typically performed in side-to-side, functional end-to-end fashion using a linear thin-tissue 75-mm stapler for the initial posterior aspect of the anastomosis (Fig. 54-9), followed by additional fires of an endoscopic 30-mm stapler to achieve a wider orifice. The nasogastric tube is then passed through the anastomosis, and the anterior wall is closed with either a TA30 or 60-mm stapler. A hand-sewn anastomosis may be performed using interrupted 3-0 silk sutures. A Penrose or bulb suction drain is placed behind the anastomosis anterior to the spine. The platysma is closed using a running 2-0 Vicryl suture, and the skin is closed using staples. A jejunal tube is created 40 cm distal to the ligament of Treitz if one has not been placed preoperatively. The abdominal fascia is closed using two separate PDS or Prolene sutures, and the skin is closed with staples.

TECHNIQUE: IVOR LEWIS APPROACH The abdominal phase of the Ivor Lewis approach is performed identically to that described in the tri-incisional approach. As much dissection of the lower esophagus should be performed as possible through the hiatus, because it may be difficult to visualize this area through a fourth interspace Ivor Lewis thoracotomy. The conduit is passed into the chest before closure of the abdomen. A double-lumen endotracheal tube is placed, and the patient is repositioned in the left lateral decubitus position. A serratus-sparing right posterolateral thoracotomy is performed, and the chest is entered through the fourth intercostal space. The lung is inspected for metastatic disease. The esophagus is dissected as described in the prior section with the exception that the esophagus is only mobilized about 2 cm cephalad to the proposed line of division (usually just above the azygos vein for lower-third tumors). An appropriate amount of gastric conduit should be advanced into the chest. While redundant gastric conduit in the chest is unusual after a cervical anastomosis, it may exist after an intrathoracic

anastomosis, folding over itself at the hiatus and resulting in obstructive symptoms. The anastomosis may be performed either via stapled technique or hand-sewn method. The hand-sewn method most frequently described is that of Churchill and Sweet and is taken from the prior edition of this publication.14 Key tenets of this technique are atraumatic handling of tissues, division of the esophagus and stomach with a scalpel, preservation of blood supply to the divided ends, and meticulous placement of interrupted sutures. After appropriate positioning of the gastric conduit in the chest, a circle of serosa 2 cm in diameter is scored on the conduit at least 2 cm away from the stapled margin. Submucosal vessels are individually ligated with silk sutures. The anastomosis is constructed in two layers. The posterior layer is constructed with interrupted horizontal mattress 4-0 silk sutures, placing the corner stitches first. The esophageal sutures include longitudinal and circular muscle, while the gastric stitches are seromuscular. The sutures are tied firmly but without causing tissue necrosis. The esophagus is divided sharply with a scalpel after the posterior outer layer is performed (Fig. 54-10). The circular gastric button is excised, and the posterior aspect of the inner

FIGURE 54-10 Ivor Lewis esophagectomy with reconstruction. The anastomosis is typically performed at the level of the azygos vein.

FIGURE 54-9 The initial portion of the side-to-side anastomosis is constructed with a GIA 75-mm stapler.

(REPRODUCED WITH PERMISSION FROM THE MCGRAW-HILL COMPANIES FROM SUGARBAKER DJ, DECAMP MM, LIPTAY MJ: SURGICAL PROCEDURES TO RESECT AND REPLACE THE ESOPHAGUS. IN ZINNER MJ [ED]: MAINGOT’S ABDOMINAL PROCEDURES, 10TH ED. STAMFORD, CT, APPLETON & LANGE, 1997, PP 885-910.)

595

596

Section 6 Operative Techniques

anastomosis is performed with interrupted simple sutures incorporating the mucosa of the esophagus and full thickness of the stomach. The esophagus is transected. The nasogastric tube is advanced across the anastomosis, and the inner anastomosis is completed, with knots tied on the inside. The anterior outer row is completed with interrupted horizontal mattress sutures. The outer row must be tied without tension on the esophagus, since the esophagus lacks a serosal surface and can easily tear. Omentum is used to buttress the anastomosis. Additional sutures may be placed between the gastric conduit and parietal pleura as well as the conduit and diaphragmatic hiatus.

POSTOPERATIVE CARE Patients are admitted to the intensive care unit. Maintenance intravenous fluids at a rate of 125 to 150 mL/hr are administered for at least 24 hours. Patients are kept in reverse Trendelenburg position to minimize the possibility of aspiration with free reflux. The nasogastric tube is flushed with small amounts of saline at each nursing shift to ensure patency. A metabolic acidosis is not uncommon on admission to the intensive care unit but usually resolves within 12 hours with appropriate resuscitation. Low urine output or low blood pressure is treated with intravenous fluids not vasopressors. Ambulation begins on postoperative day 1. The quality of the voice and effectiveness of cough should be examined on the first postoperative day. A soft, hoarse voice and ineffective cough are signs of recurrent laryngeal nerve injury and should prompt immediate evaluation by the ear, nose, and throat specialist and cord medialization. Early intervention improves mobilization of pulmonary secretions and reduces the risk of perioperative pneumonia. In some cases the voice may be normal soon after the operation only to diminish several days later as the cord swelling produced by the double-lumen endotracheal tube recedes. Diuresis usually begins on postoperative day 2 or 3. Patients with compromised cardiac or renal function may require active diuresis at this stage to avert pulmonary edema. The nasogastric tube is kept in place by some surgeons until the barium swallow study on postoperative day 7 but is removed by other surgeons when the patient’s postoperative ileus resolves. Some choose to remove the nasogastric tube the day after the operation. A swallow study is performed on postoperative day 7. A small amount of Gastrografin is used first, followed by barium if no leak is seen. The anastomosis is inspected for leak or stricture, and the entire conduit is inspected for leak as well as emptying. Provided the study is negative, the results should be confirmed by giving the patient purple grape juice to drink, while the surgeon observes the first few swallows for any evidence of cervical leak or any possible signs of aspiration. Ten percent of cervical leaks are missed on postoperative barium swallow. If purple fluid is not seen in the cervical drain, the drain is removed. The patient is advanced to a clear liquid diet and to a full liquid

diet on the following day. Patients are discharged on a full liquid diet.

COMMENTS AND CONTROVERSIES Today a majority of surgeons prefer the right-sided approach over the left-sided approach when performing a transthoracic esophagectomy irrespective of the location of the tumor. For infracarinal tumors I prefer a left-sided approach. For supracarinal tumors, however, a right-sided approach is mandatory. Indeed, supracarinal tumors (i.e., mostly squamous cell cancers) have a higher tendency to spread along the paratracheal and brachiocephalic lymph nodes. A right-sided approach obviously allows a more precise dissection of these lymph node chains from a right-sided approach. Dissection of the tumor of the tracheal wall can be performed more precisely from the right. The down side of this approach is a less obvious accessibility to the lower part of the mediastinum from a fifth intercostal space thoracotomy. Another disadvantage is the higher tendency of the gastric tube to become dilated in its proximal part by accumulation of air and the subsequent compression atelectasis of the right upper lobe, which sometimes can be important. This is never seen when using the left-sided approach because the gastric tube is kept in place by an intact mediastinal pleura and between the azygos vein and aortic arch, thus preventing such dilation. Especially when using whole stomach the gastric conduit has the tendency over time to roll over to the right, sometimes filling up almost entirely the right hemithorax. This may eventually cause delayed gastric emptying, which may be very difficult to overcome with prokinetics and/or pyloric balloon dilation. The choice of the location of the anastomosis (i.e., high in the chest or cervical) is often related to the surgeon’s personal preference. I believe that a cervical anastomosis exposes the patient to less reflux-related problems and that there is less risk of an anastomotic leak. T. L.

KEY REFERENCES Chu K, Law SY, Fok M, et al: A prospective randomized comparison of transhiatal and transthoracic resection for lower-third esophageal carcinoma. Am J Surg 174:320-324, 1997. Goldminc M, Maddern G, Le Prise E, et al: Oesophagectomy by a trans-hiatal approach or thoracotomy: A prospective randomized trial. Br J Surg 80:367-376, 1993. Hulscher JB, van Sandick J, de Boer AG: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1662-1669, 2002. Mathisen DJ, Grillo HC, Wilkins EW Jr, et al: Transthoracic esophagectomy: A safe approach to carcinoma of the esophagus. Ann Thorac Surg 45:137, 1988. Orringer MB, Marshall B, Iannettoni MD: Transhiatal esophagectomy: Clinical experience and refinements. Ann Surg 230:392-403, 1999. Swanson S, Batirel HF, Bueno R, et al: Transthoracic esophagectomy with radical mediastinal and abdominal lymph node dissection and cervical esophagogastrostomy for esophageal carcinoma. Ann Thorac Surg 72:1918-1925, 2001.

chapter

55

EN-BLOC RESECTION OF THE ESOPHAGUS Jeffrey A. Hagen Brendan Boland

Key Points ■ Outcome of primary surgical resections for carcinoma of the

esophagus are better than commonly quoted, with recent series reporting 5-year survival rates in excess of 50%. ■ Because of the high false-positive rates of preoperative staging by EUS and PET/CT, caution must be exercised in denying a patient potentially curative resection without confirmation of the presence of metastatic disease. ■ The en-bloc resection has been reported to result in improved long-term survival and a lower risk of local recurrence compared to standard resection techniques.

The central role of surgical resection for esophageal cancer is being challenged as proponents of alternatives to primary resection cite as justification high surgical mortality rates of 10% to 15% and low 5-year survival rates of 20% to 25% after surgery. These statements, based largely on past experience with squamous cell carcinoma, give the perception that surgery is not curative in most patients with esophageal carcinoma and suggest that the survival benefits of surgery are outweighed by the risks of resection. Dissatisfaction with the results of surgery alone in patients with locally advanced tumors has led many centers to routinely administer neoadjuvant therapy, despite the lack of clear evidence of benefit to this approach.1-6 In some centers, the need for any resection at all is being questioned, with definitive chemoradiotherapy offered as primary therapy.7 Observations suggest that the results of surgical resection are much better than commonly quoted, in the present era of improvements in perioperative care, with increasing numbers of patients with tumors diagnosed at an earlier stage. Modern series including large numbers of patients treated at specialty centers report overall survival rates approaching 50% with operative mortality rates of less than 5% (Portale et al, 2006; Stein and Siewert, 2004).8,9 Data such as these argue strongly that surgical resection should remain the primary mode of therapy for patients with cancer of the esophagus in the absence of systemic metastases. It offers the highest likelihood of cure for patients with localized disease and can offer quality palliation for patients with more advanced disease. When surgical resection is performed, controversy persists with regard to the extent of surgery necessary to achieve cure,10-14 with much of the debate centered on the benefits of a systematic lymph node dissection. In this chapter we review our current approach to the management of esophageal cancer, with an emphasis on data to support the application of an en-bloc

resection. The important technical aspects of this challenging operation are also described in detail.

HISTORICAL NOTE The first resection of the intrathoracic esophagus followed by reconstruction with esophagogastrostomy was performed in Japan by Ohsawa in 1932,15 and it was popularized in the United States by Adams and Phemister at the University of Chicago in 1938.16 It was not until 1963, however, that Logan17 first reported the application of the principles of surgical oncology to esophageal cancer. In his classic paper, he emphasized the need for adequate proximal and distal resection margins and the importance of a systematic en-bloc resection of the adjacent tissues in an attempt to achieve cure. The mortality associated with the procedure was high, but the survival rate reported remains one of the best reported to date. This approach was adopted by Skinner and associates in 1965,18 and, after gaining experience in 80 patients, they demonstrated that the operation could be performed safely with survival rates higher than those reported at the time. Over the next decade, the operation was evaluated in centers around the world with similar results.19-21 During this same time period, there was a revival of interest in the technique of esophagectomy without thoracotomy beginning with the report of Akiyama and associates in 197122 and later by Orringer and Sloan in 1978.23 This set the stage for a debate that has persisted until today regarding the role of different surgical strategies in the management of this disease. HISTORICAL READINGS Adams W, Phemister D: Carcinoma of the lower esophagus. J Thorac Surg 7:621, 1939. Akiyama H: Cardinals in the regional lymph node dissection in surgery of thoracic esophageal cancer. In Siewert JR, Holscher AH (eds): Disease of the Esophagus. Berlin, Springer-Verlag 1988, p 416. Akiyama H, Sato Y, Takahashi F: Immediate pharyngogastrostomy following total esophagectomy by blunt dissection. Jpn J Surg 1:225, 1971. DeMeester TR, Zaninotto G, Johansson KE: Selective therapeutic approach to cancer of the lower esophagus and cardia. J Thorac Cardiovasc Surg 95:42, 1988. Logan A: The surgical treatment of carcinoma of the esophagus and cardia. J Thorac Cardiovasc Surg 46:150, 1963. Orringer MB, Sloan H: Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg 76:643, 1978. Ohsawa T: The surgery of the esophagus. Arch Jpn Chir 10:605, 1933. Siewert JR, Holscher AH, Roder JD, Bartels H: En bloc resektion der speiserohre beim Oesophaguscarcinom. Langenbecks Arch Chir 373:367, 1988. 597

598

Section 6 Operative Techniques

Skinner DB: En bloc resection for neoplasm of the esophagus and cardia. J Thorac Cardiovasc Surg 85:59, 1983.

MANAGEMENT OF LOCALLY ADVANCED ESOPHAGEAL CANCER Patient Assessment Esophageal cancer is a disease that occurs predominately in the sixth and seventh decades of life, with many patients presenting after the age of 70. Although the risk of morbidity and mortality appear to be higher in elderly patients, this increased risk is due to the higher frequency of medical comorbidities such as heart, liver, and kidney disease rather than age per se.24 Consequently, advanced age alone should not be considered a contraindication to esophagectomy, and patients can be considered candidates for potentially curative resection even into their 80s and 90s, if particular attention is paid to their preoperative assessment. Because of the strong etiologic ties between cancer of the esophagus and alcohol and tobacco use, it is imperative that patients be carefully screened for the presence of cardiovascular, pulmonary, and hepatic dysfunction regardless of their age. It has been estimated that between 20% and 30% of patients with esophageal cancer will have evidence of cardiovascular disease if carefully screened.25 The preoperative evaluation should also include pulmonary function testing and arterial blood gas analysis. Patients with significant impairment in the forced expiratory volume at 1 second (FEV1 <1 L) and

those with chronic bronchitis are at increased risk of respiratory complications after surgery.26,27 The presence of hypercarbia (PaCO2 >45 mm Hg) or hypoxemia (PaO2 <55 mm Hg) is also associated with an increased risk of complications. Finally, cirrhosis of the liver is not uncommon in patients with esophageal cancer, particularly those with squamous cell carcinoma. Well-compensated cirrhosis (Child’s classification A) is not a contraindication to resection of an otherwise curable cancer, but care should be exercised in considering resection in the setting of more advanced stages of cirrhosis.

Tumor Location Selection of the most appropriate therapy for an individual patient also depends on the location of the tumor. Tumors located in the cervical esophagus and the upper third of the thoracic esophagus are less amenable to complete en-bloc resection due to the comparatively close proximity of these tumors to the airway and important vascular structures. As a result, these tumors are preferentially treated by either definitive chemoradiotherapy or chemoradiation therapy followed by resection of any residual disease. In contrast, tumors of the lower esophagus and gastroesophageal junction are more amenable to an en-bloc resection owing to the wider margin of surrounding fibroadipose tissue. In these patients, selection of the type of operation should be based on the results of a complete clinical staging evaluation. The selective therapeutic approach that we have used is summarized in Figure 55-1.

Known or suspected esophageal cancer

Upper intestinal endoscopy/ Endoscopic ultrasound

Early esophageal cancer

Locally advanced tumor ⬎5 cm length High-grade stenosis Transmural invasion (⫹) Locoregional nodes

Visible lesion

No

Yes

Vagal-sparing esophagectomy

PET/CT

EMR

Metastases

Definitive chemoradiotherapy

Intramucosal cancer No metastases Yes Vagal-sparing esophagectomy

No En-bloc esophagectomy

En-bloc esophagectomy (Consider neoadjuvant therapy if extensive nodal disease)

FIGURE 55-1 Patient management algorithm used to select the type of operation performed based on the extent of disease present and the physiologic status of the patient. EMR, endoscopic mucosal resection.

Chapter 55 En-Bloc Resection of the Esophagus

Preoperative Staging Evaluation Upper Gastrointestinal Endoscopy and Endoscopic Ultrasonography Evaluation of patients with esophageal cancer should include an upper intestinal endoscopy. The length of the tumor on endoscopy can provide useful information regarding the likelihood of lymph node involvement and/or systemic spread. Tumors less than 5 cm in length are more likely to be T1 or T2 tumors, whereas tumors longer than 5 cm are more likely to be T3 or greater.28 In addition, it has been shown that tumor length is also predictive of survival in the absence of nodal disease, with longer tumors having poorer survival.29 Patients found to have a high-grade luminal stenosis that precludes passage of the adult endoscope also have a greater likelihood of having locally advanced tumor invasion.30 When the endoscope can be passed beyond the tumor, the stomach and duodenum should be examined. This evaluation should include a retroflexion maneuver to assess the fundus and cardia region of the stomach, which can be involved in a patient with a distal-third cancer and may impact on the type of reconstruction performed. Endoscopic ultrasonography (EUS) should also be performed because it remains the best diagnostic tool available to assess the locoregional extent of disease. Introduced in the 1980s in Japan and the Netherlands for squamous cell carcinoma of the esophagus, it has recently grown in popularity in the United States for staging esophageal adenocarcinoma. The depth of tumor penetration of the esophageal wall and the presence of lymph node involvement can be assessed using this flexible endoscope with an ultrasound probe attached to the tip. The accuracy of EUS in staging esophageal cancer has been reviewed.31 EUS is 75% to 82% accurate in detecting T1 tumors, 64% to 85% accurate for T2 tumors, and 87% to 94% accurate for T3 disease. The accuracy of detecting invasion of adjacent structures approaches 100%. However, EUS is less accurate in assessing the depth of invasion for earlier stage tumors, owing to difficulty in distinguishing between intramucosal (T1a) and submucosal (T1b) invasion. When locoregional nodes are assessed by EUS before esophagectomy and lymphadenectomy, the accuracy of identifying a malignant node ranges from 70% to 85%. Sensitivity of EUS in detecting node involvement ranges from 80% to 89%, but the specificity is only 50% to 75%. Fine-needle aspiration biopsy may improve these results. Given the relatively high false-positive rate of EUS assessment of lymph node involvement, caution should be exercised in denying a patient potentially curative resection on the basis of EUS alone.

Positron Emission Tomography Several recent reports indicate that PET has the ability to detect otherwise occult metastatic disease that can result in alteration in the clinical staging in as many as 20% of patients with esophageal cancer.32,33 As with other staging modalities, false-positive results can occur with PET and confirmatory biopsies should always be obtained. PET can also be used to identify regional lymph node involvement, although the intense hypermetabolism present in the primary tumor often obscures activity in the nodes in close proximity to the tumor mass. These are, of course, the nodes most likely to be involved. In addition, there are size limitations in the identification of lymph nodes with PET, with an increasing falsenegative rate for nodes smaller than 8 mm. The use of combined PET/CT appears to improve the accuracy of detecting node involvement, but false-positive and falsenegative test results remain a problem.

Surgical Approach for Esophageal Cancer The indications for an en-bloc resection for esophageal cancer are best understood in the context of a broader-tailored approach to the management of this condition. In our experience, this approach depends heavily on the depth of tumor invasion. When endoscopic ultrasound suggests the presence of a superficial T1 tumor, we recommend an endoscopic mucosal resection to determine the depth of invasion with accuracy.34 If the tumor is limited to the lamina propria or if invasion into but not through the muscularis mucosae is present, recent data suggest that fewer than 4% of patients will have lymph node involvement.35 In these patients, an en-bloc resection and systematic lymph node dissection are not necessary to achieve cure. A more limited surgical approach, such as the vagal-sparing esophagectomy, can be performed with less perioperative morbidity and improved alimentary function.36 Tumors that penetrate into the submucosal layer or beyond have a high frequency of lymph node involvement that demands that consideration be given to performing an en-bloc resection with a systematic lymph node dissection. Approximately one half of patients with a submucosal tumor will have node metastases, with a frequency of lymph node involvement of more than 80% when muscular invasion is present.37 Transmural tumors are associated with lymph node involvement in over 85%, and the median number of involved nodes and the proportion of patients with more than 4 involved nodes increases significantly (Table 55-1) (Hagen et al, 2001).38 Because of the high frequency of lymph node involvement, any patient with a tumor that extends into the submucosa or beyond should be considered for an en-bloc resection based on the time-honored principles of surgical oncology, which emphasize the importance of a complete resection.

Computed Tomography of the Chest and Abdomen CT scans of the chest and abdomen should be performed as part of the staging evaluation before consideration of curative en-bloc resection. It not only provides important information regarding the size of the primary tumor and the status of the mediastinal lymph nodes, but it also allows for assessment of the lungs, liver, and adrenal glands for metastases.

Technique of En-Bloc Esophagectomy The en-bloc procedure is performed through an initial right thoracotomy followed by a midline laparotomy and an incision in the left neck. The resection includes removal of the tumor-bearing esophagus surrounded by a wide envelope of adjacent tissues. In the chest this includes the removal of the

599

600

Section 6 Operative Techniques

TABLE 55-1 Relationship Between Tumor Depth and Lymph Node Status

Tumor Depth Intramucosal

Prevalence of Node Metastases* 1/16 (6.25%)

No. of Involved Nodes (median [IQR])†

No. With 1-4 Involved Nodes‡

2 (n/a)

1/16 (6.25%)

No. With >4 Involved Nodes§ 0/16 (0)

Submucosal

5/16 (31.25%)

1 (n/a)

4/16 (25%)

1/16 (6.25%)

Intramuscular

10/13 (76.92%)

2 (1-4)

9/13 (69.1%)

1/13 (7.69%)

Transmural

47/55 (85.45%)

5 (3-13.5)

2

*X † 2 X ‡ 2 X § 2 X

= = = =

22/55 (40%)

25/55 (45.45%)

42.0, P < .0001 (Chi square test for trend). 11.02, P = .0116 (Kruskal-Wallis) includes only patients with involved nodes. 13.64, P = .0035 (Chi square test for trend). 21.38, P < .0001 (Chi square test for trend).

FIGURE 55-2 Division of the intercostal veins as they drain into the azygos vein. Dotted line indicates the anterior and posterior limits of the thoracic dissection.

Arch of azygos vein Divided intercostal vein

azygos vein with its associated nodes, the thoracic duct, and the low paratracheal, subcarinal, paraesophageal, and parahiatal nodes in continuity with the resected esophagus. The block of tissue removed is bounded laterally on each side by the excised mediastinal pleura, anteriorly by the pericardium and membranous trachea, and posteriorly by the aorta and vertebral bodies. The abdominal dissection includes the systematic removal of the lymph nodes at the porta hepatis, along the hepatic artery, and the retroperitoneal tissue above the pancreas overlying the diaphragmatic crura. The musculature of the diaphragmatic hiatus is also excised in continuity with the esophagus.

Thoracic Dissection The procedure begins with the patient in the left lateral decubitus position, with a posterolateral thoracotomy performed entering the chest through the seventh or eighth intercostal space for tumors of the distal esophagus and in the fifth or sixth intercostal space for tumors arising in the middle or upper thirds of the esophagus. Selective ventilation

of the lung using a double-lumen endotracheal tube greatly facilitates this portion of the operation. The posterior mediastinal dissection is performed by incising the pleura overlying the lateral aspect of the vertebral bodies from the level of the azygos arch to the diaphragm. The intercostal veins are divided between ligatures as they enter the azygos vein (Fig. 55-2). A dissection plane is then created following each intercostal artery to reach the adventitial plane of the aorta. Blunt dissection continues across the anterior surface of the aorta, until the left mediastinal pleura is reached. In this dissection, one or more hemiazygos communicating veins need to be ligated as they pass behind the aorta (Fig. 55-3). The anterior dissection plane is developed along the posterior aspect of the pericardium, which is not removed unless the tumor is adherent. Once the left mediastinal pleura is reached, a vertical incision is made in the pleura just behind the pericardium. A hand can then be inserted between the esophagus and the pericardium into the left chest with the fingers directed posteriorly. With upward and anterior traction, the left-sided mediastinal pleura can be exposed anterior to the aorta and it can also be incised vertically to

Chapter 55 En-Bloc Resection of the Esophagus

Esophagus Azygos vein Aorta Hemiazygos vein

Aorta

Azygos vein

Intercostal artery FIGURE 55-3 Dissection along the intercostal arteries and anterior surface of the aorta (inset) exposes hemiazygos communicating veins that pass behind the aorta.

FIGURE 55-4 Anterior retraction on a Penrose drain allows dissection along the anterior aspect of the aorta to reach the contralateral pleura. The dissection is transitioned to the wall of the esophagus just above the level of the azygos arch, which marks the superior limit of the en-bloc dissection.

incorporate a strip of left mediastinal pleura in the resection specimen. Once the left mediastinal pleura has been incised both anteriorly and posteriorly, the thoracic esophagus can be encircled with a Penrose drain for traction. The dissection plane along the anterior aspect of the aorta is continued cephalad to a point just above the azygos arch, where the

dissection is transitioned to the wall of the esophagus (Fig. 55-4). In this transition, the right vagus nerve and the bronchial artery are divided after ligation. By retracting the Penrose drain posteriorly, the dissection plane along the posterior pericardium can be continued cephalad until the subcarinal nodes are encountered. Careful dissection along the

601

602

Section 6 Operative Techniques

FIGURE 55-5 The anterior dissection follows the pericardium proximally to the subcarinal region where the lymph node tissue is dissected off of the right bronchus upward to the carina and downward along the left bronchus.

The en-bloc dissection is continued caudally both anteriorly and posteriorly until the thoracic surface of the diaphragm is reached. The crural musculature should be partially incised circumferentially to incorporate a portion of the esophageal hiatus with the specimen. The mediastinal tissue that remains posteriorly just above the diaphragm includes the thoracic duct, which must be ligated carefully to prevent the development of a chylothorax (Fig. 55-6). A heavy silk ligature should be placed that incorporates all of the tissue anterior to the vertebral body and lateral to the aorta and esophagus. This ligature will also contain the azygos vein as it traverses the diaphragm. After the azygos vein is ligated near the diaphragm, the upper end of this vein is ligated flush with its confluence with the superior vena cava using an articulating laparoscopic stapler with a vascular load. The chest is closed after placement of a suction drain.

Abdominal Dissection FIGURE 55-6 Retraction on the diaphragm exposes the thoracic duct and azygos vein as they traverse the diaphragm. Mass ligation should be performed to include all tissue anterior to the vertebral body and aorta and lateral to the esophagus.

right main bronchus up to the carina and then distally along the left main bronchus allows removal of the entire subcarinal node packet in continuity with the resected esophagus (Fig. 55-5). At this point, the anterior dissection is also transitioned to the wall of the esophagus by dividing the left vagus nerve. This bundle of tissue often contains a bronchial artery branch, which should be ligated. Blunt dissection should be performed from this point proximally as far as possible into the base of the neck to facilitate delivery of the esophagus into the neck later in the operation.

The abdominal portion of the operation is performed through a midline laparotomy. This portion of the operation is greatly facilitated by the use of a sturdy retractor fixed to the bed (Upper Hand Retractor, Pilling, Inc., Kansas City, MO). This allows steady upward and lateral retraction on both costal margins. A third blade can be used to retract the left lateral segment of the liver. The abdominal portion of the en-bloc resection begins at the porta hepatis where all of the lymph node–bearing tissue overlying the hepatic arterial trunk and the portal vein is removed. This dissection is continued proximally along the hepatic artery to its origin from the celiac axis (Fig. 55-7). The retroperitoneal tissue above the pancreas overlying the right crus of the diaphragm is dissected medially and superiorly to remain attached to the esophagectomy specimen. Attention is then turned to the greater curvature of the

Chapter 55 En-Bloc Resection of the Esophagus

Lung Caudate lobe of liver

Collar of diaphragmatic muscle

Gallbladder

Proper hepatic artery Common hepatic artery FIGURE 55-7 The abdominal lymphadenectomy begins at the porta hepatis where all of the lymph node–bearing tissue overlying the hepatic arterial trunk and the portal vein is removed. This dissection is continued proximally along the hepatic artery to its origin from the celiac axis.

stomach where the gastrocolic omentum is divided, preserving the gastroepiploic arcade. This dissection should begin distally at the level of the pylorus, continuing proximally to include division of the short gastric vessels. Use of a Harmonic Scalpel (Ethicon Endosurgery, Cincinnati, OH) greatly facilitates this dissection. The short gastric vessels should be divided as close as possible to the spleen to preserve as many collateral vessels to the fundus as possible. After the short gastric vessels have been divided, the gastric fundus can be rotated to the right to expose the retroperitoneum. All of the lymph node–bearing tissue above the splenic artery and overlying the left crus of the diaphragm can be dissected upward with the esophagectomy specimen. Because of the increased propensity for abdominal lymph node involvement, we recommend resection of the proximal two thirds of the stomach along with the spleen in patients with bulky tumors of the gastroesophageal junction. With the spleen and stomach rotated to the right, the splenic artery and its associated lymph node–bearing tissue can be dissected off of the superior margin of the pancreas, with the splenic artery and vein ligated proximally (Fig. 55-8). The musculature of the diaphragmatic hiatus is then incised to meet the incision made in the diaphragm during the thoracic dissection. By retracting the stomach anteriorly, ample exposure of the celiac axis can be achieved to allow ligation of the coronary vein and the left gastric artery at its origin (Fig. 55-9). A Kocher maneuver should be performed to allow maximum mobility of the stomach. A pyloromyotomy is then performed to aid in drainage from the vagotomized stomach.

Restoration of Gastrointestinal Continuity—Gastric Pull-up Reconstruction is performed either by creating a gastric tube after a wide resection of the gastric cardia down to the

FIGURE 55-8 For bulky tumors at the gastroesophageal junction, the spleen and the proximal two thirds of the stomach should be removed. The lymph node–bearing tissue along the superior margin of the pancreas is removed by rotating the spleen and stomach to the right and dissecting the splenic artery and its associated lymph node– bearing tissue off of the superior margin of the pancreas. The splenic artery and vein are ligated proximally.

Splenic artery and vein

Left gastric artery

FIGURE 55-9 By rotating the specimen anteriorly and to the right, the left gastric artery and vein can be exposed for proximal ligation.

fourth vein on the lesser curvature of the stomach or using an isoperistaltic colon interposition based on the left colic artery. The colon interposition is used for reconstruction when the tumor involves a significant portion of the upper stomach or if the collateral circulation along the greater

603

604

Section 6 Operative Techniques

curvature is insufficient to support the gastric tube. When a colon interposition is to be performed, the abdominal dissection also includes the removal of the proximal two thirds of the stomach, the omentum, and the lymph nodes along the proximal two thirds of the greater curvature of the stomach. In most patients undergoing resection for esophageal cancer, reconstruction is performed using a gastric conduit. The blood supply is very dependable, and only a single anastomosis is required. The proximal anastomosis is performed in the neck. This avoids the troublesome reflux associated with a low intrathoracic anastomosis and the significant morbidity associated with an anastomotic leak in the posterior mediastinum. Exposure of the cervical esophagus is accomplished through an oblique left neck incision placed along the anterior border of the sternocleidomastoid muscle. This incision should extend from the sternal notch to a point halfway to the ear lobe. The omohyoid, sternohyoid, and sternothyroid muscles are divided laterally. A dissection plane is created between the contents of the carotid sheath and the trachea and esophagus to reach the prevertebral fascia. The inferior thyroid artery is divided between ligatures. Dissection is then continued posterior to the esophagus down into the thoracic inlet where the dissection plane created during the thoracotomy is reached. The esophagus is encircled bluntly, and a Penrose drain is passed for traction. The upper thoracic esophagus can be delivered up into the neck where it is transected using a linear stapling device. In patients with distal tumors, the esophagus should be divided as low as possible in the neck to preserve length for performing the anastomosis. For tumors of the middle and upper thirds, the goal should be to achieve a 10-cm margin above the tumor whenever possible. Once the esophagus has been divided in the neck, the specimen is removed through the abdomen by gentle traction applied to the stomach. The gastric tube is created using successive applications of a linear stapling device. The stomach should be gently straightened after each application of the mechanical stapler to obtain the maximal length of the gastric tube. This staple line begins on the upper fundus at least 5 cm from the distal limit of the tumor and should continue to a point along the lesser curvature corresponding to the fourth or fifth branch of the left gastric artery. Controversy persists regarding the optimal width of this gastric tube. The principle advantage of a wide gastric tube is the potential for better submucosal collateral blood flow to the tip of the stomach, while the main disadvantage is related to a higher propensity for gastric stasis. We prefer a narrow tube (approximately 6 cm across), which in our experience empties better. This staple line should be oversewn with a running absorbable suture to minimize the risk of a leak. The gastric tube is passed through the posterior mediastinum to lie in the bed of the resected esophagus. Trauma to the gastric pull-up can be minimized by wrapping the gastric tube in a bowel bag, which is attached to a chest tube or to the funnel of a Mousseau-Barbin tube to pull it gently up into the neck. Care should be exercised to avoid excessive tension on the stomach or its gastroepiploic arcade during this maneuver, and twisting of the stomach must be avoided.

The anastomosis is performed between the remaining cervical esophagus and the anterior wall of the gastric pull-up. We prefer to use a single-layer technique and place 4-0 monofilament absorbable sutures with the knots tied in the lumen. The last three or four sutures are placed in a modified Gambee fashion to achieve mucosal inversion. Gentle retraction on the gastric conduit from within the abdomen will remove redundancy in the gastric pull-up. Several nonabsorbable sutures should be placed between the stomach and the left diaphragmatic crus to prevent herniation of the stomach back into the thorax. A nasogastric tube is then carefully passed, a drain is placed in the neck, and the cervical wound is closed.

Restoration of Gastrointestinal Continuity—Colon Interposition When a colon interposition is to be performed, the proximal stomach is removed with the esophagectomy specimen by dividing the stomach at the level of the antrum. Leaving more denervated stomach can result in gastric stasis and does not result in improved gastrointestinal function. The ascending and descending colon are mobilized completely. The segment of colon to be interposed derives its arterial supply from the ascending branch of the left colic artery and usually corresponds to the segment extending from the middle of the transverse colon to the proximal descending colon. This segment is prepared by tracing the middle colic artery back to its origin from the superior mesenteric artery, where it arises as a single trunk in most patients. After the middle colic artery and vein are temporarily occluded to ensure adequate collateral flow through the marginal artery at the splenic flexure, the middle colic artery and vein are then ligated and divided. The colon is then lifted upward toward the patient’s head. The apex of the arc portended by the vascular pedicle is then marked with a suture. The colon usually reaches a point at or slightly above the xiphoid. The distance from this point to the mid-neck level is measured with an umbilical tape. This tape is used to measure proximally from the previously placed marking stitch to determine the point of transection of the proximal colon. The divided colon is then passed through the bed of the resected esophagus by suturing it to the funnel of a Mousseau-Barbin tube and wrapping it in a bowel bag (Fig. 55-10). A single-layer monofilament anastomosis is performed to the remaining cervical esophagus. Traction is gently applied to the colon from within the abdomen to eliminate redundancy, and the colon is secured to the left crus of the diaphragm with a nonabsorbable suture. The colon is then divided with a linear stapler 5 to 10 cm below the point where it enters the abdomen. Care should be exercised not to leave too long of an intra-abdominal segment of colon because this will result in food retention. The mesentery should be divided immediately adjacent to the wall of the colon to avoid injury to the vascular pedicle. A two-layered anastomosis is performed between the proximal divided colon and the antrum, and colon continuity is restored by a standard colocolostomy.

Chapter 55 En-Bloc Resection of the Esophagus

TABLE 55-2 Perioperative Complications Occurring in 263 Consecutive Resections for Esophageal Adenocarcinoma

Inverted Mousseau-Barbin tube Suture Bowel bag FIGURE 55-10 The colon graft to be interposed is prepared for passage to the neck by suturing the end of the colon to the funnel of a Mousseau-Barbin tube. The graft is wrapped in a bowel bag to facilitate atraumatic passage.

Complication

No.

Respiratory Pneumonia Prolonged intubation Empyema Pleural effusion

61 (23%) 25 15 5 16

Cardiovascular Arrhythmias Myocardial infarction

44 (17%) 42 2

Anastomotic Leak Graft ischemia

36 (14%) 31 5

Chylothorax

8 (3%)

Deep vein thrombosis/Pulmonary embolism

9 (3%)

Gastrointestinal bleeding

1 (<1%)

Jejunostomy Catheter Insertion

Sepsis

4 (2%)

We routinely perform a catheter jejunostomy to provide for early postoperative feeding and to avoid the need for parenteral nutrition in the event of postoperative complications such as an anastomotic leak. The jejunostomy catheter is removed when the patient is able to maintain his or her weight by oral feedings, usually 3 to 4 weeks postoperatively.

Urinary tract infection

Postoperative Care Patients are routinely extubated at the completion of the operation, and they are admitted directly to the intensive care unit where they are observed for 2 to 3 days after surgery. During the first 72 hours after surgery, patients are supported with a minimal amount of intravenous crystalloid and dextrose solutions. When fluid boluses are necessary, colloid-containing fluids are preferred because the extensive mediastinal dissection tends to favor the development of pulmonary edema. Continuous infusions of dopamine (3 µg/ kg/min) and nitroglycerin (5-20 mg/min) are used to aid graft perfusion. A thoracic epidural catheter placed before the operation is used for postoperative pain management. This encourages early ambulation and assists in pulmonary toilet. Broad-spectrum antibiotics are continued for 24 hours after the operation. Jejunal feedings are initiated at 15 mL/hr on the third postoperative day when the dopamine and nitroglycerin are discontinued, and the patient is transferred to the ward. The nasogastric tube is removed when the drainage is minimal and bowel function has returned. We routinely obtain a contrast esophagogram 6 or 7 days after surgery to check for anastomotic leak and delayed conduit emptying. An oral diet, beginning with clear liquids and advanced to a soft diet over 2 to 3 days, is gradually instituted with the patient sitting during and for 90 minutes after the meal. During this transition and after discharge, jejunal feedings are delivered at night to provide approximately 1000 calories until the patient is able to maintain hydration, weight, and nutrition with oral intake.

3 (1%)

Wound infection

10 (4%)

Reoperation Abdominal bleeding Anastomotic leak/graft necrosis Sepsis/bowel infarction Thoracic duct ligation Empyema or continuous thoracic drainage Fascial rupture/wound infection Others

30 (11%) 5 6 3 3 6 7 4

Complications Despite recent improvements in perioperative management, postoperative morbidity and mortality after esophagectomy for cancer remain significant. These are large technically demanding operations that are often performed on patients with compromised cardiopulmonary function. Nutritional disturbances are also common, owing to the combined effects of the cancer itself and the obstructing effects of the mass in the esophagus. Complications occurring in a recent series of resections performed for esophageal adenocarcinoma are summarized in Table 55-2.9 Overall, 62% experienced at least one complication. Pulmonary complications including pneumonia, acute respiratory distress syndrome requiring prolonged intubation, pleural effusion, and empyema are among the most common complications, occurring in 23%. These complications can be minimized by early ambulation and careful attention to adequate pain control. Prevention of aspiration can be achieved by keeping the patient in the semi-upright position at all times and by meticulous attention to maintaining a functioning nasogastric tube. When necessary, a mini-tracheostomy can provide invaluable assistance in clearing retained secretions. Cardiac complications occur in approximately 17% of patients, with the development of atrial fibrillation accounting for the majority of these complications. Although these

605

606

Section 6 Operative Techniques

are generally self-limiting, they do require cardiac monitoring and treatment, which can prolong the stay in the intensive care unit. There is no evidence that prophylactic administration of antiarrhythmic drugs reduces the development of atrial fibrillation, although these drugs are commonly employed. Anastomotic complications occur in 10% to 30% of patients depending on the type of reconstruction performed. They appear to be more common after the use of neoadjuvant therapy, and in patients with diabetes, with hypertension, and who are obese.39 Most of these leaks can be managed with local drainage and antibiotic administration as long as the vascular supply to the reconstruction is adequate. We recommend early endoscopy in any patient who is known or suspected to have a leak to exclude potentially lifethreatening conduit ischemia, which can be present in as many as 14% of patients with an anastomotic leak.

Long-Term Results Comparison of Survival The goals of operation in patients with esophageal cancer include elimination of dysphagia and improvement in longterm survival. Esophageal resection and reconstruction successfully achieves palliation of dysphagia in 80% to 90%, but strictures do occur in 10% to 15%, which may require intermittent dilation. Weight loss, which is present in the vast majority of patients before operation, is reversed in the majority, and most patients are able to return to work. Other potential complications of untreated esophageal cancer such as tumor pain, hemorrhage, and the development of an esophagorespiratory fistula can also be prevented. Long-term survival after esophagectomy depends on a number of factors, such as the depth of tumor invasion, the number of involved lymph nodes, and the location of the tumor in the esophagus. The prognosis is better for tumors of the cervical esophagus and for those located at the gastroesophageal junction than for tumors located in the thoracic esophagus. The impact of the type of resection performed on long-term survival remains the subject of debate. Whereas the results of single institutional series would seem to indicate improved survival after an en-bloc resection, to date no prospective randomized trial has been reported with sufficient sample size to answer this question definitively. We have reviewed our experience with 100 consecutive en-bloc resections performed for esophageal adenocarcinoma.38 Despite the fact that 55% had transmural invasion, and node metastases were present in 63%, overall survival at 5 years was 52%. Survival after en-bloc resection was over 94% for stage I disease with survival in stage II disease of approximately 80%. Even when stage III or IV disease was present, en-bloc resection achieved long-term survival in approximately 25%. Similar results have been reported in several other relatively large single institution series. Altorki and Skinner have reported a 5-year survival of 40% in a series of 111 patients in which 60% had lymph node involvement and 59% had T3 or T4 disease.40 Survival in patients with stage III disease was 39%. Collard and colleagues41 have also reported a large experience with en-bloc resection in a series

of 235 patients, half of whom had N1 disease and over 62% had T3 or T4 disease. Survival at 5 years was 49%, with 30% of the 98 patients with stage III disease surviving 5 years or more. In comparison, recent series reporting survival after the transhiatal esophagectomy indicate overall 5-year survival of 18% to 27% (Orringer et al, 1993)42,43 with 10% to 15% survival in stage III disease. In addition to these case series, four retrospective cohort studies have been published that compare survival after transhiatal and en-bloc resections at a single institution.13,43-45 Three of these report improved survival after en-bloc resection. Proponents of the transhiatal esophagectomy argue that the apparent benefit in overall survival associated with the en-bloc resection can be explained by selection of patients with more favorable tumors for en-bloc resection. They also explain differences in survival by stage that have been consistently reported as being due to stage migration, which results from the more thorough lymph node sampling that undoubtedly occurs during an en-bloc procedure. To address this question, Altorki and colleagues13 have reported outcome after en-bloc and transhiatal resections performed in patients with T3 N1 (stage III) disease. In this group of patients, stage migration cannot explain differences in survival observed because all patients have locally advanced tumors with lymph node involvement. They reported 4-year survival of 35% after en-bloc resection, which was significantly better than the 11% survival observed after transhiatal esophagectomy. Ultimately, this debate can only be resolved by the completion of a large randomized controlled trial. To date, only one such trial has been reported.46 In this moderate-sized trial of 220 patients, survival after en-bloc resection was 39%, compared with 27% survival after a transhiatal esophagectomy. This difference, which amounted to a 44% improvement in survival after en-bloc resection, was of borderline statistical significance (P = .08), suggesting that the study may have been underpowered.

Comparison of Local Recurrence Rates Although controversy persists regarding the impact of a more extensive resection on survival, available data suggest that local disease control is superior after an en-bloc resection. Table 55-3 compares the reported rates of local recurrence TABLE 55-3 Comparison of the Reported Rates of Local Recurrence After Standard Transhiatal Esophagectomy and an En-Bloc Resection Author (Year)

No. Subjects

Local Recurrence

En-Bloc Esophagectomy Matsubara et al (1994) Altorki et al (2001) Hagen et al (2001) Collard et al (2001) Swanson et al (2001)

171 111 100 324 250

10% 8% 1% 4% 5.6%

Transhiatal Esophagectomy Hulscher et al (2000) 137 Becker et al (1987) 35 Gignoux et al (1987) 125 Nygaard et al (1992) 186 *Included preoperative radiation therapy.

23% 31% 47%* 35%*

Chapter 55 En-Bloc Resection of the Esophagus

after a standard transhiatal esophagectomy and after an en-bloc resection. Local recurrence after an en-bloc resection is uncommon, reported in 1% to 10% of patients. In contrast, 23% to 47% of patients treated by transhiatal esophagectomy will develop local recurrence, even when radiation therapy is added.

SUMMARY There can be little doubt that the en-bloc esophagectomy is a technically demanding operation that requires considerably more time to complete than a standard esophagectomy. A dedicated team of specialists is necessary to perform the procedure and to care for the patient after the operation to achieve acceptable morbidity and mortality rates. The technical expertise required to perform the surgery is demanding, and the learning curve is steep. Care after the operation is constant and complex for 10 to 14 days but can on occasion be much longer. Recognizing these issues, it is doubtful that the procedure will gain widespread acceptance until a prospective randomized trial is accomplished to show the benefit of the en-bloc procedure. If such a study were to show the superiority of the en-bloc resection, it should be only done in a few select centers capable of organizing a team to perform the procedure and committed to providing the care after the procedure. With the type of tailored approach to patients with esophageal cancer outlined in this chapter— using the en-bloc resection in patients with locally advanced disease—an overall 5-year survival of greater than 50% can be achieved,9 which is a dramatic improvement compared with the dismal results reported in the past.

COMMENTS AND CONTROVERSIES I fully underscore the statement made by the authors in that the results of primary esophagectomy for patients presenting without evidence of systemic metastasis are much better than commonly quoted, in particular in the nonsurgical literature. Indeed over the past 2 decades the 5-year survival figures in high-volume centers have almost doubled, with 5-year survival of 35% to 40% now being the gold standard with which all other therapeutic modalities should be compared. These improvements are in part due to better patient selection and improved preoperative and perioperative care, resulting in a decrease in postoperative mortality rates now generally accepted to be less than 5%. But there is also a growing body of evidence in the literature that improvement in long-term outcome is also related to the radicalness of resection and extent of lymphadenectomy. Although the only properly randomized and controlled trial1 could not substantiate a significant survival benefit by more radical and extensive surgery as compared with standard surgery, the trial did notice a strong trend in particular for adenocarcinoma of the distal third of the esophagus with a survival benefit of 17% at 5 years.2 A substantial number of publications dealing with retrospective and/or prospective studies indicate the same trend. As rightfully highlighted by the authors, an en-bloc resection is a major undertaking. Careful risk assessment is of paramount impor-

tance and the presumed survival should clearly outweigh the risk estimation of postoperative mortality. Given the frequent presence of comorbidities, en-bloc esophagectomy will therefore be applicable in only a restricted number of patients. The technique of en-bloc dissection is well described in this chapter. It differs from its original description by Logan and later on by Skinner, in that the pericardium is not systematically resected en bloc with the esophagus, which, except in case of adherence, is not always easy to assess even at the time of surgery. As stated by the authors I, too, prefer to construct a rather narrow gastric tube both for oncologic and functional reasons. From a functional point of view, using a narrow gastric tube admittedly results in a higher incidence of early satiety as compared with use of the whole stomach. Using the whole stomach, as stated by the authors, clearly results in more gastric stasis unless a pyloroplasty is performed. The latter, however, induces biliary reflux with all its related problems, in particular, the potential to induce Barrett’s metaplasia in the remaining cervical esophagus. This problem is increasingly reported, given the increasing fraction of long-term survivors. Moreover, use of whole stomach, especially after using a right transthoracic approach, often results in gastric dilation and subsequent compression atelectasis of the right lung, in particular, when transecting the azygos vein. As expected, postoperative complications are frequent, some of them complex and life threatening, which is again an argument that such an intervention should be performed as stated by the authors only in those centers “capable of organizing a team to perform the procedure and committed to providing the care after the procedure.” In this respect the surgeon remains the responsible actor, but obviously the whole undertaking requires more than just a surgeon. 1. Hulscher JB, Sandick JW, de Boer AG, et al: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1662-1669, 2002. 2. Hulscher JB, van Lanschot JJ: Individualised surgical treatment of patients with an adenocarcinoma of the distal oesophagus or gastro-oesophageal junction. Dig Surg 22:130-134, 2005.

T. L.

KEY REFERENCES Hagen JA, DeMeester SR, Peters JH, et al: Curative resection for esophageal adenocarcinoma: Analysis of 100 en bloc esophagectomies. Ann Surg 234:520-530, 2001; discussion 530-531. Hulscher JB, van Sandick JW, de Boer AG, et al: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus [see comment]. N Engl J Med 347:1662-1669, 2002. Orringer MB, Marshall B, Stirling MC: Transhiatal esophagectomy for benign and malignant disease. J Thorac Cardiovasc Surg 105:265-276, 1993; discussion 276-277. Portale G, Hagen JA, Peters JH, et al: Modern 5-year survival in resectable esophageal adenocarcinoma: Single institution experience with 263 patients. J Am Coll Surg 202:588-596, 2006. Stein HJ, Siewert JR: Improved prognosis of resected esophageal cancer. World J Surg 28:520-525, 2004.

607

chapter

56

THREE-FIELD LYMPH NODE DISSECTION FOR CANCER OF THE ESOPHAGUS Nasser K. Altorki Toni E. M. R. Lerut

Key Points ■ Three-field lymph node dissection for squamous cell cancer of the

esophagus was pioneered by Japanese surgeons and clearly shows that 25% to 40% of patients have occult metastases to the recurrent laryngeal and/or deep cervical nodes. ■ Western experience with this technique is limited to fewer than a handful of centers where adenocarcinoma is the predominant cell type. The prevalence of occult nodal metastases to the recurrent laryngeal and/or cervical nodes in esophageal adenocarcinoma is 20% to 30%. ■ In experienced hands, the procedure can be performed safely with a hospital mortality of less than 5% but morbidity in the 30% to 50% range. ■ In the absence of adequately powered randomized trials comparing two- and three-field dissection, the existing retrospective data suggest that dissection of the “third field” may improve survival of patients with squamous cell carcinoma. In patients with adenocarcinoma, the procedure results in the most precise staging information; however, its impact on survival is unclear.

GENERAL ASPECTS The concept of three-field lymph node dissection for carcinoma of the esophagus was introduced and has been practiced by Japanese surgeons since the early 1980s. This development was prompted by studies showing that the cervical lymph nodes were the site of tumor recurrence in 30% to 40% of patients in whom a curative resection had been performed.1 The extended procedure included dissection of the cervical, mediastinal, and upper abdominal nodes in patients with carcinoma of the thoracic and abdominal esophagus. In 1991, Isono and coworkers reported the results of a nationwide study on three-field dissection performed at 35 institutions throughout Japan.2 Nearly 1800 patients underwent esophagectomy with three-field lymph node dissection, whereas 2800 underwent two-field dissection. The following important observations were made: 1. Approximately one third of patients had previously unsuspected metastasis to the cervical lymph nodes. The prevalence of cervical nodal metastases was highest for upper-third tumors (40%), but even patients with lowerthird cancers had a 20% probability of metastatic carcinoma involving the cervical lymph nodes. 2. The frequency of nodal metastases increased with increasing depth of tumor penetration through the esophageal wall. Patients with intramucosal carcinoma had a 30% 608

probability of nodal metastasis, whereas invasion into the submucosa, muscularis propria, and adventitia signaled a 50%, 60%, and 80% probability of nodal disease, respectively. The high prevalence of nodal metastases in patients with submucosal tumors (T1b) should cast some doubt on the logic of “limited disease = limited operation.” 3. The cervical lymph nodes most frequently involved with metastatic carcinoma include the nodal chains along both recurrent nerves as well as the deep cervical nodes located along the posterior aspect of the internal jugular vein. Supraclavicular nodal disease was infrequent and carried a distinctly poor outcome. In light of these observations, it is clear that a considerable number of patients will be inaccurately staged after en-bloc resection with isolated mediastinal and abdominal lymphadenectomy. From 15% to 30% of patients will have their tumor-node-metastasis (TNM) classification upstaged as a result of the extended procedure. Although most surgeons readily concede the impact of the extended lymphadenectomy on tumor staging, its impact on survival is fervently disputed. Nonetheless, Japanese surgeons have provided a compelling argument for a positive impact from this procedure on survival. In 1984, Akiyama and colleagues reported their experience with 717 patients in whom a complete (R0) resection was performed using either a two-field (n = 393) or a three-field technique (n = 324) (Akiyama et al, 1994).3 Five-year survival in node-negative patients was 84% after the three-field procedure compared with 55% after two-field lymphadenectomy (P = .004). Patients with node-positive disease also fared better after three-field dissection, with a 5-year survival rate of 43% compared with a 28% 5-year survival rate after two-field dissection (P = .0008). The superior 5-year survival in node-positive patients clearly disposes of the argument that the improved survival rates are a function of simple stage migration. Similar results have been reported by a number of Japanese surgeons.4-9 Significantly, most Japanese studies report a 5-year survival of 25% to 30% in patients with metastatic carcinoma to the cervical lymph nodes. These impressive survival rates seem to argue that the recurrent laryngeal nodes should be considered as regional (N1) rather than distant sites of disease for tumors of the intrathoracic and abdominal esophagus. Support for this notion is also suggested by data obtained from lymphoscintigraphy studies in which radiolabeled colloid was injected in the midthoracic esophagus.10,11 Uptake was routinely detected by scintillation counting in the upper mediastinum and cervical nodes as well as in the left gastric nodes.

Chapter 56 Three-Field Lymph Node Dissection for Cancer of the Esophagus

Despite these intriguing results reported by Japanese surgeons, most European and North American centers have greeted three-field dissection with skepticism. Several reasons might explain the lack of enthusiasm for the procedure: 1. A prevailing concept among Western surgeons is that patients with carcinoma of the esophagus have systemic disease at the time of presentation. Cure after resection has often been considered a “chance phenomenon” that is dependent more on the biologic behavior of the tumor than on the surgical strategy pursued. 2. Three-field lymph node dissection has been associated with a definite, albeit statistically insignificant, increase in hospital morbidity. Foremost among the potential complications is injury to one or both recurrent nerves. Recurrent nerve injury has been reported in as many as 70% of patients and in at least some patients has resulted in tracheostomy and prolonged mechanical ventilation. Furthermore, at least one study12 examined the quality of life after esophagectomy with three-field lymph node dissection with particular emphasis on the effect of vocal cord paralysis. Twenty percent of patients reported severe hoarseness, restricted food intake, and reduced exercise tolerance up to 60 months postoperatively. 3. Notwithstanding the compelling data from Japan, nearly all were the result of retrospective studies that compared surgical therapy delivered over two different decades. Two prospective studies have been reported.8,13 The study by Nishihira and colleagues was a prospective randomized trial that showed a survival advantage for three-field over two-field lymph node dissection (65% versus 48%); however, the difference was not statistically significant.11 The study from the National Cancer Hospital in Tokyo was a prospective nonrandomized case-matched study that showed that 5-year survival was significantly better after three-field dissection (48% versus 33%; P = .03). Five-year survival in the group of patients with cervical nodal disease was an impressive 30%.

WESTERN EXPERIENCE Esophagectomy with three-field lymph node dissection has been practiced at the Weill Cornell Medical College in New York since 1994 and at the University of Leuven since 1991. A prospective database was established at both institutions to assess the feasibility of the procedure as well as to study the patterns of nodal metastasis and survival in a European and a North American patient population. Particular emphasis was placed on assessment of these criteria in adenocarcinoma of the esophagus, a disease rapidly increasing in incidence on both continents. At the Weill Cornell Medical College, patients were considered eligible for the procedure if the entire tumor was located within the tubular esophagus and there was no preoperative or intraoperative evidence of distant organ metastasis or confirmation of T4 disease. Additionally, the group at the University of Leuven evaluated the role of the procedure in patients with tumors of the gastroesophageal junction that extended aborally into the gastric cardia. Patients were carefully evaluated to assess their ability to undergo esopha-

geal resection, including a full pulmonary and cardiologic evaluation. Advanced age by itself was not a contraindication to operation, although patients older than 75 years of age were often treated by en-bloc two-field dissection. CT, endoscopic ultrasonography, and, more recently, positron emission tomography were used to assess the extent of disease.

Surgical Procedure The surgical approach is generally determined by the preference of the surgeon. A fifth interspace right thoracotomy is preferred by one of us (N.A.) for all tumors regardless of location. An alternative approach used at the University of Leuven (T.L.) is to perform an extended left thoracotomy for all tumors below the carina and tumors of the gastroesophageal junction and a right thoracotomy for more proximal tumors. For distal esophageal and gastroesophageal junction tumors, a sixth interspace thoracotomy provides excellent access to the middle and lower mediastinum and is always combined with a semilunar peripheral diaphragmatic incision to provide exposure of the upper abdomen. The peritoneum is incised, and the spleen, tail, and body of the pancreas are reflected medially. Dissection of the upper abdominal compartment begins at the level of the descending thoracic aorta and proceeds toward the celiac axis; to the superior mesenteric artery; and, in cases of gastroesophageal junction tumors, to the left renal vein and artery. This dissection clears all the lymphatics in the upper abdomen and extends medially to the nodal tissue along the common hepatic and splenic arteries. In the chest, a posterior mediastinectomy is performed, including the thoracic duct and the nodes in the subcarinal region, in the aortopulmonary window, and along the mainstem bronchi. After resection of the specimen and advancement of the gastric tube to the neck, the thoracotomy is closed and the patient is repositioned. A U-shaped incision is made in the neck combined with a manubrial split, if necessary, to access the lower neck and superior mediastinum. This third field of dissection includes the nodes lateral and posterior to the carotid sheath, the brachiocephalic nodes, and the supraclavicular nodes, as well as dissection of the nodes along both recurrent nerves (Fig. 56-1). This dissection can be carried down well into the chest along the trachea and left recurrent nerve to the level of the aortic arch, as is done in Leuven when using the left thoracoabdominal approach. When the operation is done through a right thoracotomy (routine at Weill Cornell and for supracarinal lesions at Leuven), the previously described posterior mediastinectomy is initially performed up to the level of the arch of the azygos vein (Fig. 56-2). In the superior mediastinum the prevertebral and retrotracheal attachments of the esophagus are divided and the organ is mobilized to the neck. The left recurrent nerve is exposed near its origin at the level of the aortic arch and dissected to the thoracic inlet, thus allowing a left paratracheal node dissection. Finally, the right recurrent nerve is exposed as it loops around the right subclavian artery and the adjoining chain of nodes dissected well into the neck. The right paratracheal nodes are not dissected.

609

610

Section 6 Operative Techniques

FIGURE 56-1 Schematic representation of a view from a cervical incision combined with a partial sternal split for a three-field dissection.

Vagus nerve Common carotid artery Internal jugular vein Deep external cervical nodes and Supraclavicular nodes

Deep internal cervical nodes Right recurrent nodes

Although the recurrent laryngeal nodes are thought to have a cervical and superior mediastinal component, we believe that such distinction is arbitrary because the nodes form a contiguous group extending from the mediastinum to the neck. In fact, it is often possible to complete the dissection of these nodal groups well into the neck through the thoracotomy incision. However, for staging purposes, along with the Union Internationale Contre Cancer (UICC) TNM classification principles, the Leuven group did not include upper mediastinal nodes along the recurrent nerve. The thoracotomy is closed, and a cervical and abdominal incision accomplishes the abdominal and cervical nodal dissections previously described.

Postoperative Care Patients are routinely admitted to the intensive care unit or recovery room (Leuven) where they are mechanically ventilated overnight and are generally extubated the next morning. After extubation, close attention is paid to bronchopulmonary hygiene, including bronchoscopy, if necessary, because bronchorrhea is commonly encountered. Patients are generally able to clear their own secretions by the third or fourth postoperative days in the absence of vocal cord palsy. Oral intake of liquids is usually begun on the fifth postoperative day and advanced to a general diet when the integrity of the anastomosis has been ascertained by a barium study. Hospital morbidity and mortality rates are shown in Table 56-1.

Left recurrent nodes

Patterns of Nodal Spread Eighty patients with carcinoma of the esophagus at the Weill Cornell Medical College (Altorki et al, 2002)14 and 194 patients at the University of Leuven (Lerut et al, 2004)15 were treated with esophagectomy and three-field dissection. An average of 50 nodes were resected per case. Nodal metastases were found in 70% of patients at both institutions. The most commonly affected nodal groups were, in order of frequency, the lesser curvature nodes, the parahiatal nodes, and the recurrent nodes (Table 56-2). The prevalence of cervical nodal metastasis was 36% in the Weill Cornell series and 24% in the series from Leuven. This difference in prevalence is probably within the range of statistical chance and is likely explained by the relatively smaller number of patients in the Weill Cornell series and the variability in the inclusion criteria at each site. For example, the series from Weill Cornell excluded patients with gastroesophageal junction tumors. In the Weill Cornell series nodes along the recurrent nerve in the neck and the chest were grouped together, whereas in the Leuven series, along with the TNM classification, only nodes in the neck were classified as cervical nodes. However, in general, these results are not dissimilar from those previously reported by Japanese surgeons. In both series there was no difference in the frequency of cervical nodal disease by either cell type (adenocarcinoma versus squamous cell carcinoma) or tumor location within the tubular esophagus (distal versus proximal). Interestingly,

Chapter 56 Three-Field Lymph Node Dissection for Cancer of the Esophagus

TABLE 56-1 Morbidity and Mortality of Three-Field Lymph Node Dissection

Left recurrent laryngeal nerve and nodes

Right recurrent laryngeal nerve and nodes

Left vagus nerve Thoracic duct Azygos vein (ligated)

Weill Cornell Medical College (n = 80) Operative mortality

University of Leuven (n = 192)

4%

1%

Morbidity

51%

58%

Pulmonary complications

25%

33%

Cardiac complications

15%

11%

Anastomotic leaks

11%

4.2%

Recurrent nerve injury

4%

2.6%

Infection complications

10%

8%

Subcarinal and hilar nodes Pericardium

TABLE 56-2 Patterns of Nodal Spread Periesophageal nodes

Weill Cornell Medical College

University of Leuven

Resected nodes per patient

60

59

Patients with positive nodes (%)

70

78

Common sites of spread Left gastric nodes Parahiatal nodes Recurrent nodes

57% 42% 30%

58% 67% 28%

Squamous cell carcinoma with positive neck nodes

40% (6/15)

22% (5/22)

Adenocarcinoma with positive neck nodes

26% (4/15)

35% (6/17)

Left lung Thoracic duct (ligated) Parahiatal nodes Left gastric nodes Lesser curvature nodes Celiac trunk Splenic nodes Common hepatic nodes

FIGURE 56-2 The various nodal stations dissected through a right thoracotomy and laparotomy for a three-field node dissection. Further dissection is performed through a cervical incision.

although both groups reported an increased prevalence of nodal disease with increased depth of tumor penetration into the esophageal wall, the frequency of cervical nodal spread remained relatively constant. For example, Lerut and associates reported that cervical nodal involvement occurred in 21% of T1b tumors, 16% of T2 tumors, and 26% of T3 tumors. Similarly, Altorki and colleagues reported that cervical nodal disease occurred in 30% to 50% of patients regardless of T stage. These observations suggest that cervical nodal spread may be a relatively early event in the metastatic evolution of esophageal carcinoma. Overall, in 15% of patients in the Leuven series and 30% of patients in the Weill Cornell

series the stage of the disease was changed to a higher level as a result of addition of the third field of dissection. These findings raise serious concerns about the validity of the current clinical staging modalities as well as the criteria used for inclusion of patients into induction therapy trials. From a therapeutic point of view the data derived from three-field dissection indicate that 25% to 30% of patients who undergo an en-bloc two-field lymph node dissection would not be rendered disease-free at the conclusion of the operative procedure. Although the impact of three-field lymph node dissection on survival remains unproven, it seems difficult to construct a rational argument for an isolated twofield dissection that relegates 25% to 30% of the patients to an incomplete resection. The impact of such incomplete resections on survival is not clearly established, but there is general agreement that R1 or R2 resections are associated with a dismal prognosis and little chance of survival beyond 2 years. Furthermore, these findings shed some doubt on the significance of results obtained from various preoperative therapy trials. Indeed, the lack of a survival benefit in the combined therapy arms, reported by most of these studies, may be a function of an incomplete surgical resection rather than the result of an ineffective preoperative regimen.

611

612

Section 6 Operative Techniques

SURVIVAL Weill Cornell Medical College Eighty patients were treated with an esophagectomy and three-field lymph node dissection between August 1994 and April 2000. After a median follow-up of nearly 4 years, the overall and disease-free 5-year survivals were 50% and 46%, respectively. Overall 5-year survival was not influenced by cell type, but, predictably, disease stage was an important determinant of survival. The survival for node-negative patients was 88%, whereas 33% of node-positive patients were alive at 5 years without evidence of disease recurrence. Patients with metastasis to the cervical nodes had an overall 3- and 5-year survival of 33% and 25%, respectively. Patients with squamous cell carcinoma and positive cervical nodes generally had better 3- and 5-year survival than those with adenocarcinoma with cervical nodal disease (40% versus 30% and 15%, respectively). Among 72 patients evaluable for recurrence, 37% had distant metastasis, 4% had locoregional recurrence, and 5.5% had both. The overall locoregional failure rate was 9.5%. Locoregional failure occurred in the mediastinum in 5.5% and in the dissected recurrent laryngeal bed in 4% of patients.

University of Leuven Esophagectomy with three-field lymph node dissection was performed in 192 patients between 1991 and 1999, of whom 174 patients had a primary R0 resection.15 In contrast to the Weill Cornell experience, this series included 36 patients with carcinoma of the gastroesophageal junction. Overall and disease-free 5-year survivals were 42% and 46%, respectively. Patients without nodal metastasis had a 5-year survival of 80% compared with a 5-year survival of 25% for nodepositive patients. Patients with middle-third squamous cell carcinoma and positive cervical nodes had a 5-year survival of 27%. In contrast, patients with distal-third adenocarcinoma and positive cervical nodes had a 5-year survival of 12% but a 4-year survival of 36%. In patients presenting with an adenocarcinoma of the gastroesophageal junction and positive

cervical nodes there was no 5-year survival, indicating that adding the third field does not contribute to long-term survival. Distant recurrence developed in 28.6% of 171 patients evaluable for recurrence. Locoregional recurrence occurred in isolation in 5% and along with distant disease in 10% of patients; the latter included 3 patients with associated anastomotic cervical recurrence. In no patient was recurrence confined to the cervical nodes only. Thus, overall locoregional failure occurred in 15% of patients treated with curative intent.

SUMMARY Our combined experience suggests that three-field lymph node dissection of carcinoma of the esophagus can be performed with reasonably low mortality and morbidity. The procedure is technically demanding, and the surgeon must take great care in dissection of the recurrent nerves to avoid injury to these vulnerable structures. Our data regarding nodal metastasis are essentially identical to those reported by Japanese surgeons. The eventual impact on survival of this extended procedure remains to be determined, but our longterm results seem encouraging. From our data at both the Weill Cornell Medical College and the University of Leuven it is evident that positive cervical nodes in squamous cell carcinoma of the esophagus should be considered as regional (N1) rather than distant (M1Ly) metastasis. KEY REFERENCES Akiyama H, Tsurumaru M, Udagawa H, Kajiyama Y: Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 220:364-373, 1994. Altorki N, Kent M, Ferrara C, Port J: Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg 236:177-183, 2002. Lerut T, Nafteux P, Moons J, et al: Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: Impact on staging, disease-free survival, and outcome: A plea for adaptation of TNM classification in upper-half esophageal carcinoma. Ann Surg 240:962-974, 2004.

chapter

57

TOTAL GASTRECTOMY AND ROUX-EN-Y RECONSTRUCTION Alberto Peracchia Riccardo Rosati

Key Points ■ Indications to the procedure are based on the Siewert classification

of the disease. ■ High intrathoracic esophagojejunal anastomosis is made through

either the hiatus or the right chest. ■ Extended nodal dissection is performed. ■ Mechanical or semi-mechanical anastomosis is done.

The esophageal surgeon generally performs total gastrectomy and Roux-en-Y reconstruction to treat a selected group of patients affected by cancer of the esophagogastric junction. Indication for the procedure is based on the preoperative workup according to the Siewert classification of tumors of this area. Total gastrectomy for cancer of the esophagogastric junction differs from total gastrectomy performed to treat gastric tumors, mainly in the extent of esophageal resection and, as a consequence, in the extent of lymphadenectomy. Different techniques to accomplish this procedure are available. Hereafter, we describe our favored approaches: the “open” total gastrectomy and Roux-en-Y reconstruction, either totally abdominal or through an abdominothoracic approach, is the standard of surgical care. In high-volume centers, selected patients may be treated within investigational protocols with a “minimally invasive” approach.

INDICATIONS AND PATIENT SELECTION The indications for total gastrectomy are complex. In case of purely gastric cancer, total removal of the stomach is generally indicated in cancer of the upper third. However, the choice of this procedure may be dependent also on the extension of the cancer in the stomach, on the need to resect adjacent organs such as the spleen, the body and tail of the pancreas, and the transverse colon, on the extent of lymphadenectomy, and also on the concurrent presence of another gastric disease such as ulcer. Age and general condition of the patients are the other major determinants of indication for the procedure. In case of cancer of the esophagogastric junction we base our choice on the Siewert classification of the disease (Fig. 57-1) (Siewert et al, 1987).1 In particular our preferred indications are as follows: Type I: Esophagogastric resection and esophagogastroplasty via laparotomy (laparoscopy) and posterolateral thoracotomy in the fifth interspace. Type II: Esophagogastric resection and esophagogastroplasty via laparotomy (laparoscopy) and posterolateral thoracot-

omy in the fifth interspace; total gastrectomy and distal esophagectomy with Roux-en-Y esophagojejunal anastomosis via laparotomy (laparoscopy) and anterior thoracotomy in the fifth interspace may be considered in some patients. Type III: Total gastrectomy with distal esophagectomy with Roux-en-Y esophagojejunal anastomosis either via laparotomy and anterior thoracotomy in the fifth interspace or via laparotomy and anterior phrenotomy (Pinotti approach) (Pinotti et al, 1981).2 In the past for cancers classified as type III we have also used a left thoracophrenolaparotomy (Akiyama, 1995).3 We have abandoned this approach in favor of the abdominothoracic (right) approach and the total abdominal approach with anterior phrenotomy, which, in our opinion, give better results. Selection of patients for operation is based both on tumor staging and evaluation of patients’ general conditions and operative risk. Standard clinical staging of the tumor is obtained through double-contrast barium swallow, endoscopy with proven histology, endoscopic ultrasonography, abdominal and thoracic CT, and tumor markers. Other examinations that can be useful in selected cases or within research protocols are positron emission tomography, endoscopic ultrasonography with high-frequency mini-probes, and optical coherence tomography (Peracchia and Bonavina, 2000).4,5 The screening of patients’ general conditions includes cardiologic, respiratory, and anesthesiologic evaluation: patients in ASA classes I to III are generally considered suitable for surgery. Patients who pass the initial screening and are clinically staged as T1-2(3) N0 M0 undergo primary surgical treatment. If peritoneal carcinomatosis is suspected preoperatively, this should indicate an explorative laparoscopy as a first stage of the procedure. Patients staged as T3-4 N0 M0 or any T N1 M1 (lymph) undergo a protocol of neoadjuvant chemotherapy or chemoradiation.6 Because of the poor prognosis of advanced disease, only responders should then undergo surgery, whereas nonresponders might benefit more from nonsurgical palliation (Maruyama et al, 1995).7

TECHNIQUE Abdominal Approach Patient Position and Surgical Incision The patient is placed on the table supine with a roll just below the scapula to elevate the supramesocolic region. General anesthesia is obtained, and mechanical ventilation is 613

614

Section 6 Operative Techniques

Type Type I: Adenocarcinoma of the distal esophagus Type II: Adenocarcinoma centered on the esophagogastric junction Type III: Subcardial adenocarcinoma that infiltrates the cardia and distal esophagus

cm 5

I 1 0

II

2 III

5

FIGURE 57-1 Siewert classification of cancer of the esophagogastric junction.

FIGURE 57-3 Anterior phrenotomy to gain access to the inferior mediastinal esophagus (Pinotti’s approach).

FIGURE 57-2 Patient position on the operating table and schema of an upper midline laparotomy.

the liver is then mobilized by division of the left triangular ligament and retracted. An anterior phrenotomy is started, cutting the diaphragm between two interrupted sutures placed on the muscle at the middle of the hiatal circumference to secure the diaphragmatic veins: the resection is driven anteriorly by cutting the central tendon of the diaphragm, whose cut edge can be progressively sutured and retracted (Fig. 57-3). Attention should be paid to ligate the diaphragmatic veins that are encountered during the muscular section that can be prolonged anterosuperiorly until the xiphoid process is reached.

Dissection of the Esophagus and Stomach guaranteed through a single-lumen orotracheal tube. A nasogastric tube is in place. Our favored incision is an upper midline laparotomy with resection of the xiphoid process (Fig. 57-2). Either a bilateral subcostal incision or a combined midline and transverse incision on a reversed T shape might be preferred in case of particular anatomic morphology of the rib cage. Exploration of the peritoneal cavity (Douglas pouch included), visceral serosa, liver surface, omentum and omental bursa, and inframesocolic area is performed in a search for signs of carcinomatosis. Opening of the lesser sac allows assessment of resectability at the level of the celiac trunk.

Anterior Phrenotomy Dissection starts at the hiatal region: the gastrohepatic ligament is severed until the right crus is encountered. At this level the hepatic branch of the vagus nerve is found sometimes with an accessory left hepatic artery (that can be ligated and divided). The phrenoesophageal membrane is divided, and dissection is prolonged on the left side up to the left crus and to the gastrophrenic ligament to mobilize the posteromedial part of the gastric fundus. The esophagus is encircled and taped with a Penrose drain, and digital exploration of the inferior mediastinum confirms resectability. The left lobe of

The inferior esophagus is mobilized en bloc with all the lymphatic and the fatty mediastinal tissue from the level of the inferior pulmonary veins to the cardia with the following limits of dissection: the aorta posteriorly, the right pleura on one side, and the left pleura and the pericardium contralaterally. Care should be taken not to damage the thoracic duct at this level. If seen, it must be ligated. The surgeon must be careful to obtain at least 4 to 5 cm of normal esophagus above the upper margin of the tumor. Dissection of the stomach starts with separation of the greater omentum from the transverse colon and hepatic and splenic flexures, dividing its attachments with the mesocolon. The origin of the right gastroepiploic arcade is dissected, and the artery and vein are ligated and divided separately. The infrapyloric nodes that are found at this level are dissected and removed. The pyloric artery (right gastric artery) is dissected, ligated, and divided at its origin from the hepatic artery. The duodenum is encircled and transected with a linear stapler just below the pylorus. Buttressing the mechanical suture may be added even though this has not been proved useful. The peritoneum covering the lesser sac is severed at its insertion on the left lobe of the liver, joining the previously made opening of the phrenoesophageal membrane.

Chapter 57 Total Gastrectomy and Roux-en-y Reconstruction

Retraction of the transected stomach medially and upward allows removal of the lymph nodes of the suprapancreatic area. The fatty tissue medial to the common bile duct is dissected, freeing the duct, the hepatic artery, and the portal vein. Dissection is extended to the level of the celiac trunk. The greater curvature of the stomach is then freed from its vascular attachments to the great omentum and the spleen: the left gastroepiploic artery and vein and the short gastric vessels are ligated and divided until all the gastric fundus is totally freed. Extremely useful in this part of the procedure are the radiofrequency dissector (Ligasure, Valleylab Tyco Healthcare, Boulder, CO) or the harmonic scalpel (Ultracision, Ethicon Inc., Somerville, NJ): their use allows a safe coagulation/section of the vessels, minimizing the risk of splenic tears and splenectomy even in obese patients. Once the gastric fundus is completely freed, the only remaining attachment of the stomach is the left vascular pedicle. The stomach is lifted upward, and the pancreas is pushed downward: this maneuver puts the celiac axis under tension and allows dissection of the left gastric artery and vein, which are separately ligated and divided at their takeoff. The

peritoneal reflection along the splenic artery is dissected as well, and the lymphatic tissue is removed up to the hilum of the spleen. Clearing of all the tissue along and within the diaphragmatic crura completes the dissection.

Lymphadenectomy Even if there is no definite evidence of the therapeutic effect of extended lymphadenectomy, the high prevalence of metastatic nodes in cancer of the cardia requires a radical operation to obtain an R0 resection. Carrying out the dissection of the stomach in the proper plan following the arterial walls as described earlier means having performed a wide nodal dissection. All the abdominal nodes of stations 1 through 11 (field 1 lymphadenectomy) and the inferior mediastinal stations 108 and 110 through 112 (field 2 lymphadenectomy) are included in the volume of resection, defining this as a D2 abdominal nodal dissection combined with a standard nodal dissection of the lower mediastinum (Fig. 57-4). The nodes of the station 16 should also be removed to include the extraperitoneal lymphatic drainage from the cardia into the

FIGURE 57-4 Abdominal lymphatic stations to achieve a D2 lymphadenectomy; inferior mediastinal lymphadenectomy (standard).

108

112 110 111 20

19

2

Ao 7

LG

1

4sa

9

10 Ce 11

H

Sp

RG 8 CH

GD

4sb 3

5

LGE 4d 6 RGE

615

616

Section 6 Operative Techniques

nodes of the left renal hilum.8,9 In the chest, within investigational protocols, standard lymphadenectomy may be extended for type I cancer to the right upper mediastinal nodes (field 2—one) or even to the left ones (field 2—two): this procedure gives a better staging of the disease but without a proven better survival and may be associated with increased morbidity (Lerut et al, 2004).10-12 For this reason, to reduce the morbidity related to unnecessary extended lymphadenectomy, protocols of sentinel node biopsy are now under investigation in mucosal adenocarcinoma of the distal esophagus and esophagogastric junction.13-15

Pancreaticosplenectomy If the tail of the pancreas and the spleen have to be included in the volume of resection, the splenic artery is ligated and divided at its takeoff from the celiac trunk. The splenic vein is identified at the posterior aspect of the gland. It is also dissected, ligated, and divided. The superior and inferior longitudinal pancreatic arcades are ligated and divided along the pancreatic borders. The pancreas is transected: this can be done either with a linear stapler or by sharp dissection and subsequent suture of the pancreatic remnant. In both cases the pancreatic duct is preferably identified and ligated separately to prevent a postoperative pancreatic fistula that, even if generally benign, can increase morbidity and delay discharge from the hospital. The pancreatic tail is dissected from the avascular posterior plane with the adrenal gland and is removed en bloc with the stomach and spleen after section of the splenophrenic and splenocolic ligaments.

Roux-en-Y Jejunal Loop Transillumination allows the identification of the mesenteric vascular arcades. To prepare the Roux-en-Y jejunal limb, the second jejunal arcade is ligated and divided at its takeoff from the superior mesenteric vessels, the mesenterium is separated, and the jejunum is sharply divided. The proximal stump is anastomosed on the antimesenteric border of the jejunum approximately 60 cm distally: a hand-sewn technique is generally used with two running extramucosal sutures with a long-lasting reabsorbable material. The jejunal loop is then transposed in the mediastinum in a transmesocolic fashion to accomplish the esophagojejunal anastomosis.

the tissue doughnuts transected by the stapler blade, the jejunal stump is closed using a linear stapler (Fig. 57-5). The jejunal loop is suspended to the diaphragmatic crura with two stay sutures to avoid tension on the anastomosis. Semi-mechanical Anastomosis. More rarely employed, especially in case of a small diameter of the esophagus, is a technique that is partially mechanical and partially manual. The stapled end of the Roux-en-Y jejunal loop is transposed in the mediastinum. Two stay sutures are placed between the stapled line of the jejunum and the posterior wall of the esophagus 4 cm craniad to the opened esophageal end. A small incision is made in the anterior wall of the jejunum at the level of the esophageal end, and a 35-mm linear stapler with parenchymal cartridge (Endo-GIA 30, 3.5 mm, Autosuture, Tyco Healthcare, Norwack, CT) is inserted and fired, creating a wide suture between the posterior wall of the esophagus and the anterior wall of the jejunum (Fig. 57-6A). This is the mechanical part of the anastomosis (posterior anastomotic wall). The anterior circumference of the esophageal end and the opening made on the jejunal wall are then sutured in a single or double layer, either in a running or interrupted suture, realizing the manual part of the anastomosis (anterior anastomotic wall; see Fig. 57-6B). This technique, popularized by Orringer for cervical esophageal anastomosis (Orringer et al, 2000),16 can be successfully employed also in this region.

Abdominothoracic Approach Patient Position and Surgical Incision Our favored patient position for this operation allows contemporary access to the abdominal cavity and to the chest. A double-lumen orotracheal tube for a one-lung ventilation and the nasogastric tube are in place. The patient lies on the operating table in an oblique position between the supine and the left lateral decubitus. A rolled sponge elevates the right chest, and a second one is placed transversely to elevate the supramesocolic region. The right arm is elevated and abducted (Fig. 57-7). The access to the abdomen is obtained through an upper midline laparotomy; the access to the right chest is

Techniques of Esophagojejunal Anastomosis The favored anastomotic techniques are the mechanical and the semi-mechanical. Mechanical Anastomosis. A purse-string suture is placed in the esophageal stump either with a manual suture (overand-over technique using a 2-0 monofilament including muscular and mucosal layers) or using an automatic purse-string device. The anvil of a circular stapler (the most used size is the 25) is then inserted into the esophageal stump and the purse-string is tied on the central rod of the anvil. The stapler with the trocar inserted into the gun central rod is introduced in the jejunal stump and perforates the antimesenteric border of the loop 5 cm distal to the stump. The anvil is reassembled on the gun, which is then closed, fired, opened, and extracted from the anastomosis. After checking the completeness of

FIGURE 57-5 Mechanical end-to-side esophagojejunal anastomosis.

Chapter 57 Total Gastrectomy and Roux-en-y Reconstruction

FIGURE 57-6 Semi-mechanical anastomosis. A, The linear stapler introduced into a jejunal opening and into the severed esophageal stump creates the posterior wall. B, The anterior wall is completed by manual suture.

A

B

A

B

FIGURE 57-7 Patient positioned on the operating table for the combined abdominothoracic incision through upper midline laparotomy and anterior right thoracotomy in the fifth interspace.

obtained through an anterior thoracotomy in the fifth interspace. Lateral tilting of the table makes it possible to obtain a fully supine position for the abdominal part and a fully lateral position for the thoracic part. The advantage of this position is to obtain full access to the esophagus in the right chest, even above the arch of the azygos vein, and to have complete control of the jejunal loop during its transposition to the chest.

Dissection of the Stomach After a full exploration of the abdominal cavity has excluded tumor spread, division of the phrenoesophageal membrane, encirclement of the abdominal esophagus, and digital exploration of the lower mediastinal esophagus confirm local resectability. The subsequent dissection of the stomach parallels that described earlier in the case of a totally abdominal procedure.

617

618

Section 6 Operative Techniques

Dissection of the Esophagus The volume of the esophagus to be resected en bloc with the mediastinal tissue is established according to the level of the tumor. With the operating table tilted toward the left, the anterior thoracotomy in the fifth interspace after rib retraction gives full access to the esophagus. According to the level of the tumor, dissection of the esophagus is made en bloc with all the mediastinal tissue, with or without division of the azygos vein, starting craniad and reaching the diaphragmatic area. We ligate en bloc the tissue lying between the vertebral body, the azygos vein, and the aorta just above the diaphragmatic level, in order to tie the thoracic duct and prevent the occurrence of postoperative chylothorax. Once the esophagus is completely dissected, it is divided and the proximal stump is prepared to accomplish the anastomosis, either in a mechanical or semi-mechanical method as described earlier. The specimen is protected, pushed below the hiatus, and retracted from the laparotomy side while the operating table is tilted backward to place the patient back in the supine position and complete the abdominal dissection.

Roux-en-Y Jejunal Loop The jejunal loop is prepared as described earlier. It is placed in a transmesocolic fashion and is brought into the chest through the hiatus. The contemporary abdominal and thoracic accesses allow visual inspection of the position of the loop, thus avoiding inadvertent torsion along the vascular pedicle.

Techniques of Esophagojejunal Anastomosis The same techniques described for the abdominal parts are also used in the abdominothoracic approach. We perform both the mechanical and the semi-mechanical techniques mainly according to the dimension of the esophagus and to the mobility of the jejunal loop. As the anastomosis is accomplished it is suspended with some interrupted sutures to the pleura to avoid tension.

Minimally Invasive Approach In selected cases within investigational protocols, in some centers with high-volume esophageal surgery and experience in advanced laparoscopic procedures, a minimally invasive total gastrectomy with Roux-en-Y reconstruction has been performed that accomplishes all the abdominal surgery through laparoscopy. With this access the procedure can be performed both totally laparoscopically with anterior phrenotomy and as a hybrid procedure, through laparoscopy and anterior right thoracotomy. Patient position on the operating table is comparable to that of the open approaches except that the patient lies on the table with opened legs to allow the surgeon to stand between them. An open laparoscopy is made at the level of the umbilicus with a Hasson trocar. Two other 12-mm trocars are placed on the right and left flanks, and a fourth one is placed below the xiphoid in the typical baseball field pattern. The use of either the Ligasure or the Ultracision is mandatory in the minimally invasive approach for this operation.

The laparoscopic technique exactly mimics all the steps of the open technique: coloepiploic division; ligature and division of the right gastroepiploic artery and vein and of the right gastric artery; stapled transection of the duodenum; and full mobilization of the stomach with ligature and division of the left gastric artery and vein, the left gastroepiploic arcade, and the short gastric vessels. Abdominal lymphadenectomy is carried out following the same principles and plans of open surgery. The abdominal and mediastinal esophagus is dissected and mobilized along with the surrounding lymphatic tissue, thus achieving a lower mediastinal nodal dissection (periesophageal and pericardial nodes) after anterior phrenotomy. The Roux-en-Y limb is then prepared: the jejunum is transected with a linear stapler with a vascular (white) cartridge and the loop mesenterium is divided using either Ligasure or Ultracision. The proximal jejunal stump is then anastomosed with the jejunal antimesenteric border approximately 60 cm distally to the jejunal cut edge. A small enterotomy is made in both the loops, and an endoscopic linear stapler with vascular cartridge is inserted and fired. A running suture of the enterotomy completes the anastomosis. The jejunal loop is then transposed in a transmesocolic fashion. In the totally laparoscopic technique, the esophagus is transected sharply (and the whole specimen is placed in a specimen bag) in two different ways according to the favored technique of esophagojejunal anastomosis. In the mechanical technique a purse-string instrument (Storz) is placed through the subxiphoid trocar and a 2-0 monofilament suture is advanced. The anvil of a 25 circular stapler is forcefully inserted into the abdomen from the umbilical incision; it is brought inside the esophageal stump and the purse-string suture is tied. An incision is then made in the stapled closure of the jejunal loop, and the circular stapler is inserted through the umbilical port; the scope is moved to the left port, and the surgeon uses the right and the subxiphoid ones to proceed with the operation. The stapler is inserted into the opening in the jejunum, and its trocar perforates the antimesenteric border of the loop almost 5 cm distally. The anvil is reassembled on the gun, and the instrument is closed and fired. As the end-to-side esophagojejunal anastomosis is performed, the circular stapler is removed and the trocars are repositioned. The opened jejunal stump is transected with a linear stapler close to the esophageal anastomosis, and the jejunal loop is sutured to the diaphragmatic crura to avoid tension. If the semi-mechanical anastomotic technique is chosen, the stapled end of the Roux-en-Y loop is sutured to the posterior esophageal wall 4 cm above its cut edge, a small incision is made in the anterior jejunal wall, and a linear stapler with a 30-mm parenchymal cartridge (blue) is introduced into the jejunal lumen and into the esophagus. The jaws are closed, and the gun is fired, forming the posterior wall of the esophagojejunal anastomosis. The anterior circumference of the esophagus and the opening on the jejunal wall are then sutured with either running or interrupted stitches to manually complete the anastomosis. This is a difficult technique that requires advanced laparoscopic skills. The specimen that was placed in the specimen bag is then extracted through a Pfannenstiel incision.

Chapter 57 Total Gastrectomy and Roux-en-y Reconstruction

If the abdominothoracic approach is preferred, once the jejunojejunal anastomosis at the feet of the Roux-en-Y limb is completed and the limb is advanced in a transmesocolic fashion, its stapled end is secured to the stomach at the stapled closure of the duodenum. The specimen and the loop will be retrieved through the hiatus via the anterior thoracotomy in the fifth interspace made to complete the thoracic dissection of the esophagus, and the intrathoracic esophagojejunal anastomosis is performed according to the previously described technique.

POSTOPERATIVE MANAGEMENT Wide-spectrum antibiotic prophylaxis is administered in all cases. Patients with total gastrectomy and Roux-en-Y reconstruction made via an abdominothoracic approach have a pleural drainage whereas those with a totally transabdominal procedure have a perianastomotic soft Penrose drain. Total parenteral nutrition is maintained for 5 days postoperatively when a liquid contrast (Gastrografin) swallow ensures the absence of leaks. This allows removal of drains and resumption of liquids and then a soft diet. Malnourished patients may benefit from enteral nutrition administered via a nasogastric tube placed during surgery that is advanced along the jejunal loop in the early postoperative period. Enteral nutrition can be maintained for several days even if oral feeding has already begun to give a higher calorie intake to the patient. Postoperative hospitalization in the uncomplicated patient normally lasts between 7 and 10 days. Small anastomotic leaks, if well drained, are generally benign and heal conservatively with good nutritional support.

COMMENTS AND CONTROVERSIES The decision to perform a total gastrectomy can be taken before starting the operation based on the results of clinical investigation indicating tumoral spread extending downward on the lesser curvature and gastric fundus. However, occasionally at the time of surgery a more than expected spread into the serosal layer of the stomach can be encountered. In such cases the surgeon has to be prepared to react in an appropriate way and be ready to perform a total gastrectomy to be combined with either a partial esophagectomy and, in such a case, a Roux-en-Y jejunal reconstruction or with a subtotal esophagectomy followed by a long-segment coloplasty. There are basically three surgical access routes to approach a subcardiac tumor with invasion of the Z line and distal esophagus—laparotomy, left thoracotomy abdominal approach, and laparotomy and right thoracotomy, the latter in case of more upward extension of the tumor into the distal esophagus. The obvious preference of the authors is laparotomy with anterior split of the diaphragm. It is claimed that such approach allows for

an adequate periesophageal dissection and lymphadenectomy of the posterior mediastinum up to the level of the pulmonary veins as well as a proper D2 lymphadenectomy in the upper abdomen. My own preference still is to approach these tumors by a left thoracoabdominal incision because it provides a superb access to both the posterior mediastinum and left upper abdominal quadrant. This is of particular help when the patient presents with a more bulky tumor with possible invasion into surrounding structures. Wide peritumoral dissection possibly in combination with splenectomy and partial pancreatectomy is sometimes easier to perform through this approach as well as an extensive lymphadenectomy. In case of extension into the trifurcation at the celiac axis an approach from above allows sometimes better possibilities to dissect out the celiac axis and its trifurcation, increasing resectability and R0 resection rate. The authors describe a total laparoscopic or a hybrid laparoscopic and right thoracotomy as an alternative technique. It is clear that such total gastrectomy and Roux-en-Y jejunal reconstruction through the laparoscope is feasible but requires, as stated by the authors, exquisite advanced laparoscopic skills. No data at this point are available to judge whether such laparoscopically performed intervention is offering the same oncologic results as compared with open surgery. Therefore, the use of such technology should be strictly reserved to high-volume centers where such advanced laparoscopic skills are available until the proof of equal oncologic outcome has been established. T. L.

KEY REFERENCES Akiyama H: Total gastrectomy with Roux-en-Y reconstruction. In Pearson G, et al (eds): Esophageal Surgery. London, Churchill Livingstone, 1995, pp 729-738. Lerut T, Nafteux P, Moons J, et al: Three-fields lymphadenectomy for carcinoma of the esophagus and esophagogastric junction in 174 R0 resections: Impact on staging, disease-free survival and outcome: A plea for adaptation of TNM classification in upper-half esophageal carcinoma. Ann Surg 92:60-67, 2004. Maruyama K, Sasako M, Kinoshita T, et al: Pancreas-preserving total gastrectomy for proximal gastric cancer. World J Surg 19:532-536, 1995. Orringer M, Marshall N, Iannettoni M: Eliminating the cervical esophagogastric anastomotic leak with a side-to-side stapled anastomosis. J Thorac Cardiovasc Surg 119:277-288, 2000. Peracchia A, Bonavina L: Adenocarcinoma of the Esophagogastric Junction: Current Concepts and Management. Milan, Edra Medical Publishing, 2000, pp 71-90. Pinotti HW, Zilberstein B, Pollara W, Raia A: Esophagectomy without thoracotomy. Surg Gynecol Obstet 152:344-346, 1981. Siewert R, Holscher A, Becker K, Gossner W: Kardiacarzinom: Versuch einer therapeutisch relevanten Klassifikation. Chirurg 58:25-32, 1987.

619

chapter

MINIMALLY INVASIVE ESOPHAGECTOMY

58

Ninh T. Nguyen James D. Luketich

Key Points ■ Minimally invasive esophagectomy is safe, and its outcome is

equivalent to that of open esophagectomy. ■ The two most frequently performed procedures are (1) the 3-hole

thoracoscopic and laparoscopic esophagectomy with a cervical anastomosis and (2) the thoracoscopic/laparoscopic Ivor Lewis esophagogastrectomy. ■ Minimally invasive esophagectomy should be performed by surgeons with extensive experience with laparoscopic esophageal surgery and at institutions performing a high volume of esophageal resections.

Blunt transhiatal esophagectomy and Ivor Lewis esophagogastrectomy are the two most commonly performed operations for esophageal resection. Blunt transhiatal esophagectomy is performed through a midline abdominal incision with blunt dissection of the thoracic esophagus through the esophageal hiatus, gastric pull-up, and a cervical esophagogastric anastomosis. The Ivor Lewis esophagectomy is performed through an upper, midline abdominal incision with construction of the gastric conduit and followed by a right thoracotomy with dissection and removal of the thoracic esophagus and construction of an intrathoracic esophagogastric anastomosis. Both blunt transhiatal and Ivor Lewis esophagectomy are complex operations that can be associated with high morbidity and mortality.1 Esophagectomy is often performed in elderly patients who have many coexisting medical comorbidities, including respiratory and cardiovascular disease. In an effort to limit the physiologic stress and possibly reduce the morbidity associated with open esophagectomy, minimally invasive surgical approaches to esophagectomy were developed. Similar to other minimally invasive operations, minimally invasive esophagectomy emphasizes the techniques that reduce the size and hence the surgical insult of the access incision. With minimally invasive approaches to esophagectomy, the abdominal laparotomy is replaced with laparoscopy and the invasive thoracotomy is replaced with thoracoscopy.

HISTORICAL NOTE The initial minimally invasive approach to esophagectomy began as a hybrid operation consisting of thoracoscopy with esophageal mobilization to reduce the respiratory morbidity associated with a right thoracotomy.2 Table 58-1 describes the results of thoracoscopic esophageal mobilization performed over the past decade.3-10 Thoracoscopic esophageal 620

mobilization, however, still required a standard midline laparotomy for construction of the gastric conduit in combination with gastric pull-up and construction of a cervical esophagogastric anastomosis. Alternatively, another hybrid technique for esophagectomy was described with laparoscopic construction of the gastric conduit followed by a right thoracotomy for removal of the thoracic esophagus and construction of an intrathoracic esophagogastrostomy (Table 58-2).11,12 These two hybrid approaches to esophagectomy utilize minimally invasive techniques in one of the two body cavities (chest or abdomen) but continue to require either a thoracotomy or a laparotomy. In 1995, DePaula and colleagues13 were the first group to report a small series of laparoscopic transhiatal esophagectomies performed totally via laparoscopy. Their approach consisted of laparoscopic construction of the gastric conduit followed by laparoscopic mobilization of the mediastinal esophagus through the esophageal hiatus. A neck incision was performed for construction of an esophagogastric anastomosis. Subsequently, in 1998, Luketich and coworkers14 reported the combined thoracoscopic and laparoscopic approach to esophagectomy. Their technique consisted of thoracoscopic esophageal mobilization followed by laparoscopic construction of the gastric conduit, gastric pull-up, and a neck anastomosis. A minimally invasive Ivor Lewis technique was later reported by Watson and associates15 in 1999, who described laparoscopic construction of the gastric conduit followed by thoracoscopic esophagectomy with construction of an intrathoracic esophagogastric anastomosis. The techniques and outcomes of minimally invasive approaches to esophagectomy are described in this chapter.

TOTAL LAPAROSCOPIC TRANSHIATAL ESOPHAGECTOMY Laparoscopic transhiatal esophagectomy was the first total minimally invasive approach to esophagectomy that did not include a thoracotomy or laparotomy. This technique is similar to that of blunt transhiatal esophagectomy except that the blunt mediastinal esophageal dissection is replaced by a laparoscopic transhiatal dissection of the mediastinal esophagus. The indications for a total laparoscopic transhiatal esophagectomy are similar to those of transhiatal esophagectomy, and the procedure is particularly useful for patients who have lower- or middle-third tumors with significant proximal involvement or in conjunction with long-segment Barrett’s esophagus. The anastomosis is performed in the neck and allows the surgeon to maximize the proximal margin. The main limitations of this technique include a limited view of

Chapter 58 Minimally Invasive Esophagectomy

TABLE 58-1 Outcome for Selected Series of Thoracoscopic Esophageal Mobilization for Esophagectomy

No. Patients

Author (Year) McAnena et al3 (1994)

Total Blood Loss (mL)

OR Time for Thoracoscopy (min)

Mean Hospital Stay (d)

30-Day Mortality (%)

Leak (%)

Conversion (%)

9

—

128

21.5

0

11.1

11.1

24

—

184

18*

12.5

9

8.3

Akaishi et al (1996)

39

767

200

—

0

5.1

0

6

Dexter et al4 (1996) 5

Law et al (1997)

22

450*

110

—

4.5

0

18.1

Peracchia et al7 (1997)

18

213

114

—

5.5

11.1

11.1

Kawahara et al8 (1999)

23

—

111

26

0

9

Smithers et al (2001)

153

Osugi et al10 (2002)

77

—

104

14*

5.2

284

226

—

0†

†

4.3

—

4

11

1.3

0

Dissected Lymph Nodes (n)

33.9

*Median value. † In-hospital mortality. OR, operating room; —, data not available.

TABLE 58-2 Outcome for Selected Series of Laparoscopic Gastric Mobilization With a Right Thoracotomy No. Patients

Author (Year) Jagot et al11 (1996) 12

Bonavina et al

(2004)

Total Blood Loss (mL)

Mean OR Time (min)

Mean Hospital Stay (d)

30-Day Mortality (%)

Leak (%)

Conversion (%)

Dissected Lymph Nodes (n)

6

—

504

10.3

0

0

0

8.1

27

—

260

11

0

3.7

7.4

—

OR, operating room; —, data not available.

the middle and upper third of the mediastinum, leading to technical difficulty in performing the mediastinal mobilization and mediastinal lymphadenectomy; surgeon inexperience in extended laparoscopic dissection into the mediastinum; and other standard limitations of this approach, including gastric extension of tumor, limiting the length of the gastric conduit, and the potential for recurrent laryngeal nerve dysfunction. Advantages of this technique include repositioning of the patient is not required, the pain of thoracotomy or thoracoscopy and its associated complications is not a factor, and double-lumen intubation is not required.

Surgical Technique Laparoscopic transhiatal esophagectomy is performed in two stages. In the first stage, the patient is positioned in the supine position for laparoscopic construction of the gastric conduit and transhiatal mobilization of the thoracic esophagus. In the second stage, the cervical esophagus is mobilized through a neck incision with removal of the esophageal specimen and gastric pull-up. An esophagogastric anastomosis is performed in the neck.

Stage 1: Laparoscopic Mobilization of the Esophagus With the patient in a supine position, the surgeon stands on the patient’s right side and the assistant stands on the left; alternatively, some surgeons prefer to place the patient in a lithotomy position and position themselves between the

patient’s legs. Abdominal insufflation is achieved using the Veress needle, and pneumoperitoneum is maintained at 15 mm Hg. Five abdominal trocars are placed. The first trocar (11-mm) is placed at the left midclavicular line at the level of the umbilicus. A 5-mm trocar is placed at the left anterior axillary line below the costal margin to be used by the assistant surgeon. A 5-mm trocar is placed at the right anterior axillary line below the costal margin and used for retraction of the left lobe of the liver. Another 5-mm trocar is placed at the right midclavicular line below the costal margin. The fifth trocar (12-mm) is placed close to the midline above the umbilicus for use by the surgeon. Once all trocars are placed, a thorough staging procedure is performed to determine if occult metastases are present, if the gastric conduit is acceptable, and if resectable disease is present. If the staging procedure is satisfactory, a needle-catheter jejunostomy is inserted in the proximal jejunum. The patient is then placed in a reverse Trendelenburg position to help with exposure by displacing the stomach and colon caudad. The greater curvature of the stomach is mobilized carefully to avoid injury to the right gastroepiploic vessels. The gastric fundus is mobilized by dividing the short gastric vessels. The hepatogastric ligament is divided to enter the lesser sac. The left gastric vessels are isolated and divided with a vascular linear stapler. If indicated, a celiac lymphadenectomy is performed to remain en bloc with the surgical specimen. Multiple linear staplers are used to construct the gastric conduit, starting at

621

622

Section 6 Operative Techniques

TABLE 58-3 Outcome for Selected Series of Total Laparoscopic Transhiatal Esophagectomy

Author (Year) DePaula et al13 (1995) 16

Swanstrom et al

(1997)

No. Patients

Total Blood Loss (mL)

Mean OR Time (min)

12

—

256

Mean Hospital Stay (d) 7.6

30-Day Mortality (%) 0

Leak (%) 8.3

Conversion (%)

Dissected Lymph Nodes (n)

8.3

—

9

290

390

6.4

0

0

0

—

22

400

160

12.1

13.6

4.5

0

8

Bonavina et al (2004)

12

—

270

10

0

8.3

16.6

13

19

22

220

380

8*

4.5

4.5

4.5

Del Genio et al17 (2004) 18

Avital et al

(2005)

14.3

*Median value. OR, operating room; —, data not available.

the distal aspect of the lesser curvature of the stomach. A gastric conduit (4-5 cm in diameter) is constructed based on the greater curvature of the stomach and separated from the surgical specimen at the angle of His. In the last step of the abdominal phase of this procedure the esophagus is mobilized through the esophageal hiatus circumferentially as high as possible in an effort to reach the cervical esophageal dissection plane. If needed, a portion of the crus of the diaphragm is divided to enlarge the esophageal hiatus to facilitate exposure and transhiatal delivery of the surgical specimen. The tip of the gastric conduit is sutured to the surgical specimen. The abdominal operation is now stopped, and the neck procedure is initiated.

Stage 2: Cervical Anastomosis A horizontal left neck incision is performed, and the platysma muscle is divided. The sternocleidomastoid muscle is retracted laterally. The inferior thyroidal vessels and the omohyoid muscle are divided. The cervical esophagus is encircled with a Penrose drain, and blunt dissection is carried inferiorly to join the dissection plane achieved by the laparoscopic mediastinal dissection. Once the entire esophagus is circumferentially mobilized, the esophageal specimen is removed through the cervical incision, pulling along with it the gastric conduit. The laparoscope is now placed back into the abdomen to allow direct visualization of the gastric tube to note the orientation and avoid trauma or spiraling of the conduit. The esophagus is divided at 4 cm distal to the upper esophageal sphincter. The specimen margin is sent to pathology for frozen section. On confirmation of a negative margin for carcinoma or Barrett’s esophagus, an esophagogastric anastomosis is performed in the neck using either a two-layer hand-sewn or stapled technique.

Surgical Results The results of laparoscopic transhiatal esophagectomy are listed in Table 58-3.13,16-19 The mean operative time ranged from 160 to 390 minutes. The mean blood loss ranged from 220 to 400 mL. The conversion rate was 0% to 16.6%. Anastomotic leak ranged from 0% to 8.3%. The mean hospital stay ranged between 6.4 to 12.1 days. Thirty-day mortality ranged from 0% to 13.6%. The mean number of lymph

10 mm 10 mm 10 mm 5 mm FIGURE 58-1 Thoracoscopic ports for minimally invasive esophagectomy.

nodes retrieved was 8 to 14. Surgical margin data were satisfactory when stated but were not commented on in detail, and long-term oncologic outcomes are not reported.

THORACOSCOPIC AND LAPAROSCOPIC ESOPHAGECTOMY WITH A CERVICAL ANASTOMOSIS Thoracoscopic and laparoscopic esophagectomy was originally developed to overcome one of the major limitations of laparoscopic transhiatal esophagectomy, which includes the poor visualization and technical complexity of laparoscopic transhiatal mediastinal dissection of the esophagus. Unlike total laparoscopic transhiatal esophagectomy, the intrathoracic segment of the esophagus is first mobilized using thoracoscopy. Thoracoscopic esophageal mobilization enables the surgeon to also perform a mediastinal lymphadenectomy under direct visualization. Thoracoscopic and laparoscopic esophagectomy is indicated for patients requiring total esophagectomy. The esophagogastric anastomosis is performed in the neck. If the cervical anastomosis leaks, it can be drained readily through the cervical incision. This technique may be more difficult in patients with a prior right thoracotomy because thoracoscopy would be technically difficult.

Chapter 58 Minimally Invasive Esophagectomy

FIGURE 58-2 Thoracoscopic esophageal mobilization with en-bloc lymphadenectomy.

FIGURE 58-3 Laparoscopic ports for minimally invasive esophagectomy.

Surgical Technique

intercostal space at the anterior axillary line. Carbon dioxide insufflation is not used during thoracoscopy. The 30-degree laparoscope is used to inspect the pleural cavity and the surface of the lung for any metastatic deposit. The lung lobes are retracted medially to expose the esophagus. The inferior pulmonary ligament is divided, with the ultrasonic dissector taking care to avoid injury to the inferior pulmonary vein. The pleura overlying the esophagus is divided to expose the intrathoracic esophagus. The azygos vein is isolated and divided with the linear stapler. The esophags is circumferentially mobilized at a portion below the azygos vein, and a Penrose drain is placed around the esophagus to facilitate esophageal retraction (Fig. 58-2). The esophagus is circumferentially mobilized from the esophageal hiatus up to the thoracic inlet. Above the level of the azygos vein, the dissection is maintained directly on the esophagus to avoid potential injury to the airway or the recurrent nerves. A lymph node dissection is also performed to remain en bloc with the surgical specimen. At the completion of the thoracoscopy, a Penrose drain is left in the thoracic inlet around the cervical esophagus. This Penrose drain will be retrieved during the cervical dissection of the esophagus. A 28-Fr chest tube is inserted through the camera port for postoperative chest drainage.

Thoracoscopic and laparoscopic esophagectomy is performed in three stages. In the first stage, the patient is positioned in the left lateral decubitus position for thoracoscopic mobilization of the intrathoracic esophagus. In the second stage, the patient is placed in a supine position for construction of the gastric conduit. The third stage consists of mobilization of the cervical esophagus via the left neck, removal of the surgical specimen and gastric pull-up, and construction of an esophagogastric anastomosis. If indicated, laparoscopic staging is performed as the first step.

Stage 1: Thoracoscopic Mobilization of the Esophagus The patient is positioned in a left lateral decubitus position with single-lung ventilation. The surgeon stands posterior to the patient. Four thoracic trocars are introduced into the right chest (Fig. 58-1). The first trocar (5-mm) is placed at the eighth intercostal space anteriorly and is used for the camera. A 5-mm port is placed immediately posterior to the scapula, for use by the surgeon. A 12-mm trocar is placed at the ninth intercostal space and 2 cm behind the posterior axillary line. The last trocar (5-mm) is placed at the sixth

623

624

Section 6 Operative Techniques

FIGURE 58-4 Laparoscopic gastric mobilization with division of short gastric vessels.

FIGURE 58-5 Laparoscopic pyloroplasty.

A recently described modification of this technique utilizes the prone position for the thoracoscopic dissection.20 The advantages of the prone position are that gravity assists in allowing the esophagus to be more easily delivered from the mediastinum and small amounts of bleeding do not pool in the surgical area contributing to a poor view. The main disadvantage is the technical aspects of the prone position and the learning curve to this unfamiliar approach to the mediastinum. We have observed the detailed video of this procedure and have performed this now in a small number of cases with good results, and it does appear to offer some considerable potential.

Stage 2: Laparoscopic Construction of the Gastric Conduit The patient is positioned in the supine position and prepped and draped from the neck to the pubic symphysis. Five abdominal trocars are placed as previously described (Fig. 58-3). The gastric fundus is mobilized by dividing the short gastric vessels (Fig. 58-4). Currently, a pyloroplasty is considered optional based on surgeon’s preference (Fig. 58-5). One of us (JDL) performs a pyloroplasty routinely, whereas the other (NTN) has reported good results without it. A gastric conduit (4-5 cm in diameter) is constructed based on the right gastroepiploic arcade of the greater curvature of the stomach (Fig. 58-6). The gastric conduit is sutured to the surgical specimen. The last step of the abdominal dissection is mobilization of the esophageal hiatus to connect with the thoracic dissection. Once the phrenoesophageal ligament is opened from the abdomen, the surgical dissection must be performed expeditiously to limit the amount of loss of carbon dioxide insufflation, poor abdominal view, and potential tension pneumothorax.

FIGURE 58-6 Laparoscopic construction of gastric conduit.

Stage 3: Cervical Anastomosis A horizontal neck incision is performed above the suprasternal notch. The cervical esophagus is mobilized until the dissection plane in the neck is connected with the dissection plane achieved in the right chest. The Penrose drain left during thoracoscopic esophageal mobilization is retrieved through the neck incision. Under laparoscopic guidance, the surgical specimen is removed through the neck incision and the gastric conduit is pulled up to the neck, with care taken to prevent trauma to the ascending gastroepiploic arcade and to avoid spiraling of the conduit (Fig. 58-7). The cervical esophagus is divided, and an esophagogastric anastomosis is performed, hand sewn or with endomechanical staplers (Fig. 58-8). The nasogastric tube is passed through the anastomosis. Next, the antral area is grasped carefully and gentle caudal retraction is applied to remove any redundant gastric tube

Chapter 58 Minimally Invasive Esophagectomy

FIGURE 58-7 Retrieval of surgical specimen through a neck incision and gastric pull-up.

FIGURE 58-8 Completed schematic view of thoracoscopic and laparoscopic esophagectomy with cervical anastomosis.

that may have been pulled up above the diaphragm during the mobilization to perform the neck anastomosis. The gastric conduit is sutured to the right and left crura in proper orientation and to the diaphragmatic hiatus anteriorly to prevent delayed hiatal herniation. The neck is irrigated with antibiotic solution, and the wound is closed loosely. The laparoscope is reinserted to inspect the abdominal cavity for adequate hemostasis.

complications was 32% and that for minor complications was 24%. The most common minor complications were atrial fibrillation and pleural effusions requiring thoracostomy tube placement. The anastomotic leak rate was 11.7%, but in the latter half of their series this dropped to 6%. At a median follow-up of 24 months, the stage-specific survival was comparable to that of previously published open series.

Results

LAPAROSCOPIC AND THORACOSCOPIC IVOR LEWIS RESECTION

The outcomes of laparoscopic and thoracoscopic esophagectomy are listed in Table 58-4.21-25 The mean operative time ranged from 265 to 350 minutes. The mean blood loss ranged from 200 to 300 mL. The conversion rate was 2.2% to 14.3%. Anastomotic leak ranged from 8% to 28.5%. The median hospital stay ranged between 7 to 12 days. Thirty-day mortality ranged from 0% to 4.3%. The mean number of lymph nodes retrieved was 9 to 17. Luketich and colleagues21 reported the largest series of minimally invasive esophagectomies (n = 222 cases). The median intensive care unit stay was 1 day, and the median length of hospital stay was 7 days. The 30-day operative mortality was 1.4%. The rate for major

Laparoscopic and thoracoscopic Ivor Lewis resection is indicated for cancer of the distal esophagus when there is concern over gastric cardia involvement. In this scenario, a wide resection of the proximal gastric cardia is required to obtain a negative distal margin. The resulting shortened length of the gastric conduit precludes construction of a neck anastomosis, and an intrathoracic anastomosis is necessary to create a tension-free esophagogastric anastomosis. Alternatively, some prefer this approach to all patients with distal esophageal cancer as well. Laparoscopic and thoracoscopic Ivor Lewis resection should not be performed for upper-third esophageal cancers because of concern over proximal margins.

625

626

Section 6 Operative Techniques

TABLE 58-4 Outcome for Selected Series of Thoracoscopic and Laparoscopic Esophagectomy With Cervical Anastomosis No. Patients

Author (Year) Watson et al22 (2000) 23

Nguyen et al

(2003)

Luketich et al21 (2003) 24

Collins et al

Total Blood Loss (mL)

Mean OR Time (min)

Median Hospital Stay (d)

30-Day Mortality (%)

Leak (%)

Conversion (%)

Dissected Lymph Nodes (n)

7

200*

265*

12

0

28.5

14.3

—

46

279

350

8

4.3

4.3

2.2

10.3

—

—

7

1.4

11.7

7.2

—

222

(2006)

25

200

350

9

4

12

8

9

25

25

300*

330*

11

0

8

8

17*

Leibman et al

(2006)

*Median value. OR, operating room; —, data not available.

Tumors located endoscopically proximal to the lower third to midesophagus are best managed by total esophagectomy with a neck anastomosis to ensure a negative proximal margin of resection.

Surgical Technique Laparoscopic and thoracoscopic Ivor Lewis resection is performed in two stages. In the first stage, a supine position is used for laparoscopic construction of the gastric conduit and other parts of the abdominal phase described in earlier sections of this chapter. In the second stage, the patient is repositioned to a left lateral decubitus position for mobilization of the thoracic esophagus, removal of the esophageal surgical specimen, gastric pull-up, and construction of an intrathoracic esophagogastric anastomosis.

Stage 1: Laparoscopic Construction of the Gastric Conduit The patient is positioned in a supine position. The stomach is mobilized by dividing the short gastric and left gastric vessels. The gastric conduit is constructed with multiple applications of the linear staplers starting at the distal aspect on the lesser curvature of the stomach and completed at the angle of His. The tip of the gastric conduit is sutured to the surgical specimen. The distal esophagus is circumferentially mobilized. At the completion of the esophageal mobilization, a Penrose drain is left around the distal esophagus for retrieval in the thoracic phase of the procedure.

Stage 2: Thoracoscopic Construction of an Intrathoracic Anastomosis After the patient is positioned in a left lateral decubitus position, four thoracic trocars are introduced in the right chest. The lung lobes are retracted laterally to expose the mediastinal esophagus. The mediastinal pleura overlying the esophagus is divided to expose the intrathoracic esophagus. The Penrose drain left around the distal esophagus is retrieved and used for retraction of the esophagus. The azygos vein is isolated and divided with a vascular linear stapler. The esophagus is circumferentially mobilized from the esophageal hiatus to a level above the azygos vein. A lymph node dissection is also performed to remain en bloc with the surgical specimen. The esophagus is divided immediately above the level of the

azygos vein. The esophageal surgical specimen is pulled into the thoracic cavity, pulling along with it the preconstructed gastric conduit. The esophageal surgical specimen is detached from the gastric conduit and removed through a limited thoracotomy incision (4 cm), which is protected with a plastic wound protector. A 25- or 28-mm anvil is placed transthoracically into the esophageal stump and secured with a purse-string suture. A gastrotomy is performed either along the staple line of the gastric conduit or at the apex of the gastric conduit for placement of the circular stapler. The circular stapler is inserted transthoracically through the limited thoracotomy incision and advanced through the gastric conduit until its tip exits through the wall of the gastric conduit. The cartridge on the circular stapler is attached to the anvil placed in the esophageal stump, and a circular stapled anastomosis is created. A nasogastric tube is positioned through the anastomosis under direct visualization. The gastrotomy is either closed with a running suture or a linear stapler. The anastomosis is oversewn with interrupted sutures; one of us (N.T.N.) has found fibrin sealant applied over the anastomosis to be useful. A 28-Fr chest tube is inserted through the camera port for postoperative chest drainage.

Results The results of two published case reports, a 15-patient case series of laparoscopic and thoracoscopic Ivor Lewis esophagectomy and a recent 50-patient series, are listed in Table 58-5.15,26-28 In Watson and colleagues’ report of two cases15 there were neither leaks nor conversions. Kunisaki and associates27 reported a small series of laparoscopic and thoracoscopic Ivor Lewis esophagectomy (n = 15 cases); however, the rate of anastomotic leak was somewhat high (13.3%) and a long hospital stay was observed (30 days). In the largest series to date (JDL), the median stay in the intensive care unit was 1 day, the median hospital stay was 7 days, the mortality rate was 6%, the surgical margins were negative in 98% of cases, and anastomotic leak occurred in 6%. Longterm oncologic outcomes are not available.28

HAND-ASSISTED LAPAROSCOPIC TRANSHIATAL ESOPHAGECTOMY The technique of hand-assisted laparoscopic transhiatal esophagectomy is similar to the technique of blunt transhia-

Chapter 58 Minimally Invasive Esophagectomy

TABLE 58-5 Outcome for Selected Case Reports and Case Series of Laparoscopic and Thoracoscopic Ivor Lewis Esophagectomy No. Patients

Author (Year) Watson et al15 (1999) 26

Nguyen et al

2

Total Blood Loss (mL)

Mean OR Time (min)

Mean Hospital Stay (d)

30-Day Mortality (%)

175

255

10

0

Leak (%) 0

Conversion (%)

Dissected Lymph Nodes (n)

0

—

(2001)

1

200

450

8

0

0

0

11

Kunisaki et al27 (2004)

15

448

544

30

0

13.3

—

24.5

35

250

—

7

6

6

2

16

28

*Bizekis et al

(2006)

Note: 15 patients had a mini-thoracotomy and results were analyzed separately. OR, operating room; —, data not available.

TABLE 58-6 Outcome for Selected Series of Laparoscopic Hand-Assisted Transhiatal Esophagectomy With Cervical Anastomosis

Author (Year)

No. Patients

Total Blood Loss (mL)

Mean OR Time (min)

Mean Hospital Stay (d)

30-Day Mortality (%)

Leak (%)

Conversion (%)

Dissected Lymph Nodes (n)

Van den Broek et al30 (2004)

25

600

300

16*

0†

8

36

7

31

17

331

336

0

—

0

Bernabe et al

(2005)

9.1

8.7

*Median value. † In-hospital mortality. OR, operating room; —, data not available.

tal esophagectomy as described by Orringer and colleagues.29 The entire intra-abdominal phase of the procedure is performed laparoscopically, including construction of the gastric conduit, mobilization of the distal esophagus, and placement of the needle-catheter jejunostomy. Subsequently, an upper midline incision (8 cm) is made sufficient for insertion of the surgeon’s left hand to perform a blunt dissection of the thoracic esophagus, and the anastomosis is performed in the neck. Hand-assisted laparoscopic transhiatal esophagectomy may play a role in patients with prior right thoracotomy, patients who would not tolerate single-lung ventilation, and in morbidly obese patients in whom thoracoscopy would be technically difficult.

Surgical Technique The technique of hand-assisted laparoscopic transhiatal esophagectomy is similar to the technique of blunt transhiatal esophagectomy except that the gastric mobilization portion of the procedure is performed laparoscopically and the midline incision is limited to 8 cm or less. Hand-assisted laparoscopic transhiatal esophagectomy is performed in three stages. In the first stage, laparoscopic construction of the gastric conduit is performed. The second stage consists of transhiatal blunt dissection of the thoracic esophagus through an 8-cm subxiphoid incision. In the third stage, mobilization of the cervical esophagus is performed with completion of a neck esophagogastric anastomosis.

lized as previously described. The linear staplers are used to create the gastric conduit starting at the distal aspect of the lesser curvature of the stomach and completed at the angle of His. The completed gastric conduit is sutured to the surgical specimen.

Stage 2: Hand-Assisted Blunt Transhiatal Dissection An 8-cm subxiphoid midline incision is performed. The surgeon stands on the patient’s left side and the assistant stands on the patient’s right. The surgeon performs a blunt dissection of the mediastinal esophagus using his or her left hand placed through the esophageal hiatus. The blunt esophageal dissection is performed up to the level of the cervical esophagus.

Stage 3: Cervical Anastomosis A horizontal neck incision is performed. The cervical esophagus is mobilized as previously described. A blunt finger dissection of the upper mediastinal esophagus is performed until the dissection plane from the neck meets the dissection plane created through the mediastinum. Once the entire esophagus is completely mobilized, the esophageal specimen is removed through the cervical incision. The gastric conduit is pulled along with the surgical specimen transhiatally until the tip of the gastric conduit is delivered into the neck. The esophagus is transected approximately 4 cm distal to the upper esophageal sphincter, and an esophagogastric anastomosis is performed.

Stage 1: Laparoscopic Gastric Mobilization The patient is positioned in a supine position. The left lobe of the liver is retracted laterally to expose the gastroesophageal junction. The greater curvature of the stomach is mobi-

Results The results of two series of laparoscopic hand-assisted transhiatal esophagectomy are listed in Table 58-6.30,31 Van den

627

628

Section 6 Operative Techniques

Broek and colleagues30 reported the largest series of 25 handassisted laparoscopic esophagectomy; however, their conversion rate was high at 36%. The high conversion rate reflects the difficulty of this complex laparoscopic operation. In a small series of 17 laparoscopic hand-assisted esophagectomies, Bernabe and coworkers31 reported no conversion and no mortality.

LAPAROSCOPIC VERSUS OPEN ESOPHAGECTOMY Nguyen and colleagues32 compared outcomes of patients who underwent thoracoscopic and laparoscopic esophagectomy with patients who underwent transhiatal or transthoracic esophagectomy. In this retrospective analysis, thoracoscopic and laparoscopic esophagectomy was associated with shorter operative times, less blood loss, fewer blood transfusions, and shortened intensive care unit and hospital stays than transthoracic or blunt transhiatal esophagectomy. In a case-control study of laparoscopic hand-assisted transhiatal esophagectomy versus open transhiatal esophagectomy, Bernabe and associates31 found that laparoscopic hand-assisted transhiatal esophagectomy was associated with a shorter operative time, less blood loss, and a shorter hospital stay compared with open esophagectomy.

WHICH OPERATION? The decision to use one of the previously discussed minimally invasive esophagectomy options is based on the location and extension of the tumor and experience of the surgeon with a particular technique. It is important for the surgeon to be knowledgeable in more than one surgical option because factors such as tumor characteristics and its extension, the patient’s body habitus (obesity), and history of prior surgery (thoracic or gastric surgery) may dictate the type of surgical option. The following are some examples of scenarios that may dictate a certain type of procedure. ■

■

■

■

Distal esophagus cancer with involvement of gastric cardia may require a laparoscopic and thoracoscopic Ivor Lewis esophagectomy to allow a negative gastric margin. Mid- to upper-third esophagus cancer may require a thoracoscopic and laparoscopic esophagectomy with a cervical anastomosis or a hand-assisted laparoscopic transhiatal esophagectomy. Distal esophagus cancer in a patient with previous right thoracotomy requires either a laparoscopic transhiatal esophagectomy or a hand-assisted laparoscopic transhiatal esophagectomy. Distal-third esophagus cancer can be treated using either the laparoscopic transhiatal esophagectomy, thoracoscopic and laparoscopic esophagectomy with neck anastomosis, or laparoscopic and thoracoscopic Ivor Lewis esophagogastrectomy technique.

SUMMARY Minimally invasive esophagectomy is technically feasible and can be performed as safely as conventional esophagectomy

by surgeons experienced in open and advanced minimally invasive techniques. Minimally invasive esophagectomy employs the use of thoracoscopy and laparoscopy instead of thoracotomy and laparotomy and therefore reduces operative trauma to the patient. It may be prudent that minimally invasive esophagectomy should be performed in centers with significant experience in open esophagectomy and esophageal surgery and ideally by surgeons who have experience in both open esophagectomy and advanced laparoscopic and thoracoscopic procedures.

COMMENTS AND CONTROVERSIES This chapter is written by two pioneers and recognized world experts in this field. The information is very clearly presented, yet concise, complete, and well illustrated. They describe experience and operative details of five variations of the minimally invasive esophagectomy approach, including clinical features pertinent to the application of each modification. In 2003, Luketich and colleagues21 reported outcomes in 222 consecutive cases managed by thoracoscopic and laparoscopic minimally invasive esophagectomy. The morbidity and mortality in this series compare favorably with those in the very best reported results after traditional “open esophagectomy”: a median hospital stay of 7 days and a 30-day operative mortality of 1.4%. Minimally invasive esophagectomy is currently a pinnacle of achievement with this relatively recent, video-assisted technology. At present, Drs. Luketich and Nguyen are among a small number of experts in the world who have successfully advanced this surgery to a remarkable and enviable level of proficiency, in a relatively short period of time. De Paula and colleagues,13 Swanstrom and Hansen,16 and Luketich and colleagues14 pioneered the development of this surgery beginning less than 10 years ago. They have achieved results defined by morbidity, mortality, and much reduced hospital stay. I believe this approach will almost certainly become a desirable standard for the future management of resectable esophageal cancer. At present, there are very few centers capable of these achievements. In their conclusions, the authors state “It may be prudent that minimally invasive esophagectomy should be performed in centers with significant experience in open esophagectomy and esophageal surgery, and ideally by surgeons who have experience with both open esophagectomy and advanced laparoscopic and thoracoscopic procedures.” This is a mild caution! The “learning curve” for this difficult surgery is long and arduous, effective training programs are scarce, and the necessary technology is complex and expensive. Nevertheless, minimally invasive esophagectomy should evolve, and I would predict the advent of relatively widespread application of this surgery within the next decade. T. L.

KEY REFERENCES Luketich JD, Alvelo-Rivera M, Buenaventura PO, et al: Minimally invasive esophagectomy: Outcomes in 222 patients. Ann Thorac Surg 238:486-495, 2003. Nguyen NT, Follette DM, Lemoine PH, et al: Minimally invasive Ivor Lewis esophagectomy. Ann Thorac Surg 72:593-596, 2001.

Chapter 58 Minimally Invasive Esophagectomy

Nguyen NT, Follette DM, Wolfe BM, et al: Comparison of minimally invasive esophagectomy with transthoracic and transhiatal esophagectomy. Arch Surg 135:920-925, 2000. Nguyen NT, Roberts P, Follette DM, et al: Thoracoscopic and laparoscopic esophagectomy for benign and malignant disease: Lessons learned from 46 consecutive procedures. J Am Coll Surg 197:902913, 2003.

Orringer MB, Marshall B, Iannettoni MD: Transhiatal esophagectomy: Clinical experience and refinements. Ann Surg 230:392-400, 1999. Swanstrom L, Hansen P: Laparoscopic total esophagectomy. Arch Surg 132:943-947, 1997.

629

chapter

COLON INTERPOSITION

59

Brian E. Louie Steven R. DeMeester

Key Points ■ Colon interposition is an alternative to gastric conduit that offers

long length, acid resistance, consistent and robust blood supply, and potential for wide gastric margins for cancers of the esophagogastric junction. ■ Reconstruction with a colon interposition is technically demanding and often used only in specialized centers. ■ Technical details such as intraoperative arterial and venous assessment to determine colon viability, and straightening and anchoring the colon interposition to the diaphragm to prevent graft redundancy are crucial for successful outcome. ■ Long-term function is excellent particularly after vagal-sparing esophagectomy with colon interposition.

A variety of methods have been used to re-establish gastrointestinal continuity after esophageal resection. Currently, the most common esophageal substitutes are stomach, colon, and small intestine. Although the most common replacement organ is the stomach, the colon is an excellent option for reconstruction because of its consistent blood supply, long length, and acid resistance. However, esophageal reconstruction with a colon interposition is a technically demanding operation, and minute details can have a major impact on graft survival and long-term function. In this chapter we outline the principles of colon interposition and focus on the technical details of the procedure. In addition, the postoperative management of these patients is discussed and the functional results of esophageal replacement with a colon graft are reviewed.

HISTORICAL NOTE Tumors of the esophagus were recognized as far back as the 12th century. Early surgical experience was limited to operations on the cervical or intra-abdominal esophagus because of the risk of fatal pneumothorax associated with operations in the chest. The stomach or jejunum were the primary reconstructive conduits and were situated subcutaneously or retrosternally. Kelling1 and Vulliet2 introduced the use of colon to bypass benign or malignant processes separately in 1911 two years before the first successful resection of an intrathoracic esophageal cancer was performed in the United States by Torek3 in 1913. Kelling, in the first of two stages, used an isoperistaltic transverse colon segment to bypass an esophageal carcinoma by placing the conduit subcutaneously. Unfortunately, the patient died before re-establishment of continuity. Vuilliet, using cadaveric dissections, proposed using an antiperistaltic right colon interposition. 630

It was not until 1914 that the first successful colon bypass was performed by von Hacker.4 In 1934, Ochsner and Owens5 reviewed the worldwide experience of 20 cases of anterothoracic colon bypass of the esophagus. Mortality was 22%. The operation was completed in over 60% of patients and, of these, about half had fair to excellent results. After advancements in surgical and anesthetic techniques, most notably the availability of intratracheal administration of anesthetic gases, intrathoracic resection of the esophagus became possible and led to increased interest in the options for esophageal reconstruction. Over time, the complexity of colon interposition has given way to the relative ease of gastric tube reconstruction. Presently, a gastric pull-up is the preferred graft for esophageal reconstruction in most centers, and colon interposition is used only in limited circumstances at select esophageal centers. However, a gastric pull-up may not be ideal in all circumstances; therefore, it is worthwhile to consider the advantages and disadvantages of both the stomach and the colon as esophageal substitutes.

COMPARISON OF ESOPHAGEAL SUBSTITUTES Stomach The primary advantage of the stomach as an esophageal substitute is the relative ease of mobilization and the need for only a single anastomosis. In most patients, the stomach has sufficient length to reach the neck for a cervical esophagogastric anastomosis, and typically it is quite hardy. However, the disadvantages include an increased potential for aspiration of a noxious mixture of acid and bile when compared with a colon interposition. Furthermore, prolonged contact of the residual squamous esophageal epithelium to reflux of gastric contents after esophagectomy and gastric pull-up has led to recurrent Barrett’s esophagus and even adenocarcinoma in the esophageal remnant.6 The vascular supply of the stomach is also somewhat less reliable than a good colon graft. Rarely is there a Doppler signal at the tip of the gastric fundus because the gastroepiploic arcade stops approximately two thirds of the way along the greater curvature, leaving the fundus supplied primarily by intramural vessels. Another concern is that the stomach, and particularly the fundus, is often within the field of radiation when definitive or neoadjuvant therapy for distal esophageal cancers is delivered. This likely impacts the healing and stricture rate for an esophagogastric anastomosis. Lastly, large tumors near the gastroesophageal junction often force a compromise between a wide excision margin along the lesser curve and preserving sufficient stomach to enable it to serve as the esophageal replacement.

Chapter 59 Colon Interposition

Colon The colon has a number of attributes that make it an excellent option for esophageal replacement. It has several key advantages, including long length, acid resistance, typically excellent blood supply, and the potential for a wide gastric resection margin for patients with cancers of the gastroesophageal junction. In patients with esophageal or cardia tumors who undergo neoadjuvant chemoradiotherapy an added advantage is that it is outside the radiation field. Two minor disadvantages of colon interposition are that the colon requires preoperative evaluation with colonoscopy or barium enema ± angiography to evaluate for arterial abnormalities that might preclude safe use of the colon and the need for preoperative cleansing. Additional operative time is also required compared with a gastric pull-up. The added time is, in part, related to the need to mobilize the colon and to complete three anastomoses when using the colon (esophagus to colon, colon to stomach, and colon to colon) rather than the one anastomosis required with a gastric pull-up. Perhaps the most significant disadvantage, though, are the reports indicating the relative frequency of late redundancy in colon grafts. In some cases the redundancy is troublesome enough to require revision of the graft.

ANATOMY The intra-abdominal colon can be divided into segments: ascending, transverse, descending, and sigmoid (Fig. 59-1). The right and transverse colon are supplied by branches arising from the superior mesenteric artery. The ileocolic and

right colic arteries supply blood to the ascending colon, whereas the middle colic artery supplies the transverse colon. The splenic flexure and proximal descending colon are supplied by the inferior mesenteric artery via the ascending branch of the left colic artery. Anatomic variants of the colonic arteries have been well described. Despite a relatively consistent appearance to the arterial supply of the colon, Sonneland and associates7 described 24 different arterial patterns to the superior mesenteric system that could be classified into seven types. Sixtyeight percent of patients exhibited the “textbook” arterial supply with three separate arteries (middle, right, and ileocolic) supplying the right and transverse colon. The right colic artery was absent in 12.4% of cases, and the middle colic was absent in 3.6% of cases. In 87.8% of patients a single, middle colic trunk was found, whereas 7% had two separate middle colic vessels and 1.6% had three separate vessels. In contrast, only 0.03% of patients had a variation in the left colic artery. Paracolic arterial anastomoses are found 1 to 3 cm from the mesenteric side of the bowel, creating a continuous arterial arcade from the ascending branch of the ileocolic artery to the descending limb of the final sigmoid artery (Sonneland et al, 1958).7,8 Within the mesentery of the colon, there are often secondary and tertiary arcades found at the branch points of the colic arteries (Sonneland et al, 1958).7 Steward and Rankin9 showed that 5% of patients did not have a paracolic anastomosis between the ileocolic and right colic artery. Comparatively, the paracolic anastomosis between the left branch of the middle colic and the ascending branch of the

Superior mesentery artery, vein

Paracolic anastomosis Inferior mesentery artery, vein

Middle colic artery, vein Right colic artery, vein

Marginal artery of Drummond

Ileocolic artery, vein

Ascending branch of left colic artery

Ileal artery, vein Hemorrhoidal artery, vein

Marginal artery, vein Sigmoid artery, vein

FIGURE 59-1 Usual vascular anatomy of the colon.

631

632

Section 6 Operative Techniques

left colic (i.e., marginal artery of Drummond) is virtually always present. Venous drainage of the colon parallels the arterial system (see Fig. 59-1). The left colon has more than sufficient venous drainage via the left colic vein that joins the splenic and portal system. In addition, the marginal vein also provides colonic venous drainage via the hemorrhoidal vein and inferior vena cava if it is left in continuity when the colon graft is divided. This differs from the right colic system where there is greater variation and often no dominant vein. Nicks10 suggested that the inadequate venous drainage is in part responsible for the higher infarction and anastomotic leak rate associated with using the right colon.

MANAGEMENT Indications for Colon Interposition Colon interposition is generally indicated for reconstruction of the resected esophagus when the stomach is unavailable for reconstruction or when it is desirable to maintain a gastric reservoir. Under these broad categories, the colon, either long or short segment, is used for varying conditions in children and adults (Table 59-1). Often the use of a colon interposition in the setting of gastroesophageal reflux is with a short segment for a destroyed gastroesophageal junction after multiple surgical repairs. Use of the colon is generally contraindicated when primary colonic pathology exists or an inadequate vascular supply has been identified.

Preoperative Evaluation Preoperative evaluation of a patient for colon interposition must take into consideration not only the primary esophageal pathology but also the patient, the status of the colon, and the planned route of reconstruction. Evaluation of the patient begins with a careful history and physical examination. Specific questions regarding the patient’s history should include a review of any chronic colonic symptoms, diverticulitis, inflammatory conditions such as Crohn’s or ulcerative colitis, polyps, or malignancy. In addition, the patient should

TABLE 59-1 Indications for Colon Interposition Desire to maintain gastric reservoir ■ Tracheoesophageal fistula (congenital or acquired) ■ Congenital esophageal atresia ■ Achalasia ■ Intramucosal esophageal carcinoma ■ Caustic stricture Prior gastric surgery ■ Antrectomy ■ Previous antireflux surgery Enable complete resection ■ Locally advanced gastric tumor ■ Extensive esophageal tumor ■ Cervical esophageal cancer Desire for antireflux barrier (gastroesophageal reflux disease) ■ Peptic stricture ■ Destroyed gastroesophageal junction

be questioned about prior colonic resection or abdominal aortic aneurysm repair or stenting. Particular attention is also paid to the patient’s physiologic cardiopulmonary status. Often, a good overall assessment of function can be quickly obtained by having the patient climb stairs with an oxygen saturation monitor. Routine esophageal investigations such as esophagography, computed tomography, gastroscopy, endoscopic ultrasound, and positron emission scanning are applied as appropriate. Investigations such as pulmonary function testing and dobutamine stress echocardiography are useful when considering a long and complex surgery such as colon interposition. In patients who have not had a recent colonoscopy, the colonic mucosa should be examined before use of the colon for esophageal replacement. An air-contrast barium enema is considered to be the minimal investigation, but colonoscopy is preferred because it allows direct examination of the colonic mucosa and biopsy or removal of polyps or lesions. The role of virtual colonoscopy with a CT scan remains to be determined but likely would be acceptable. The colon should be prepared before surgery, and our preference is to admit the patient into the hospital the day before surgery and cleanse the colon with 4 L of GoLITELY and oral neomycin and metronidazole. We avoid using enemas to minimize the potential for mucosal edema in the colon. The routine use of angiography to examine the colonic vasculature is controversial. However, most esophageal surgeons use angiography particularly in patients with a history of atherosclerosis, abdominal aortic aneurysm, or major prior abdominal surgery to evaluate the integrity of the vessels supplying the planned colonic interposition. Peters and colleagues11 have outlined angiographic criteria that suggest adequate vascularity for a standard transverse colon interposition based on the ascending branch of the left colic artery. These findings include a patent inferior mesenteric artery, an intact marginal artery connecting the left and middle colic circulation, the presence of a single middle colic trunk, and a separate origin of the right colic artery. A patent inferior mesenteric artery and marginal artery are considered absolute requirements for an isoperistaltic left colon interposition. In most patients the graft is placed in the posterior mediastinum in the bed of the native esophagus, and this route tends to produce the best functional result. However, this route is unavailable in patients presenting for delayed reconstruction. In addition, consideration should be given to an alternate route in patients with extensive nodal disease or incomplete resection because local recurrence could lead to obstruction of the graft when placed back into the posterior mediastinum. In these instances a substernal location is favored. Prior coronary artery bypass surgery makes creation of a substernal window hazardous and is a relative contraindication. Other rarely used options include the transthoracic or subcutaneous route on the anterior chest.

Operative Technique for Left Colon Interposition The isoperistaltic left colon interposition is performed through an upper midline incision and a left neck incision and is based on the ascending branch of the left colic artery via

Chapter 59 Colon Interposition

the marginal artery communicating with the divided middle colic circulation (DeMeester et al, 1988).12,13 Reconstruction with a colon graft can immediately follow esophagectomy or be performed in a delayed fashion. If the plan is for a singlestage resection and reconstruction, the colon graft is often mobilized and prepared before esophageal resection to give it time to demonstrate any perfusion problems before beginning the reconstruction. The first step is to dissect the omentum off the transverse colon and mobilize both the splenic and hepatic flexures from their retroperitoneal attachments. The mesentery is transilluminated to identify the origins of the middle colic artery and the ascending branch of the left colic artery. The ascending branch and left colic artery can be identified when the mesentery is stretched in a cephalad direction by its tendency to form a natural pedicle ascending in the direction of the splenic flexure. To determine the approximate length of colon necessary for reconstruction, we measure from the bottom of the left earlobe to the xiphoid with an umbilical tape and cut the tape to this distance. The left colon/splenic flexure region is brought up to the xiphoid until limited by the tethering effect of the left colic artery, and the antimesenteric border is marked at that location with a silk stitch (Fig. 59-2). The

previously prepared umbilical tape is then used to measure the necessary length of colon starting from the site of the first stitch near the splenic flexure and extending proximally toward the cecum. A second silk marking stitch is then placed at the proximal limit of the umbilical tape, typically near the hepatic flexure or ascending colon just distal to the cecum (Fig. 59-3). This portion of the colon will be brought up to the residual esophagus for the proximal anastomosis after division of the middle colic vessels, and the graft is based on the left colic vessels and the marginal arcade. A reversed or retroperistaltic graft would use a similar portion of the colon, but the region of the splenic flexure would become the proximal portion of the graft with the vascular supply based on the middle colic vessels. Isoperistaltic grafts are preferred whenever possible. Once the necessary length of colon for esophageal replacement is marked out, the vascular supply of the colon graft is assessed. The middle colic vessels can be identified within the mesentery of the transverse colon after opening the omentum into the lesser sac. The middle colic vessels should be dissected down to their origin from the superior mesenteric artery and vein. It is critical to maintain communication between the right and left branches of the middle colic artery to provide adequate perfusion to the proximal portion of the

FIGURE 59-2 Traction of the ascending branch of the left colic artery and placement of the first marking suture at the xiphoid. Determining the proposed length of colon is done by using an umbilical tape to measure from ear lobe to xiphoid. Umbilical tape

Xiphoid

1st marking stitch

Marginal artery and vein

Ascending left colic artery, vein

633

634

Section 6 Operative Techniques

FIGURE 59-3 Colon interposition placed on top of sternum to demonstrate length of colon as measured by the umbilical tape.

Second stitch

Middle colic vessels

Umbilical tape

First stitch Left colic artery Ascending Left colic artery vein

proposed colon graft (near the hepatic flexure). In some cases the bifurcation of the right and left branches of the middle colic artery is so close to the superior mesenteric artery that a side-biting vascular clamp must be applied to the superior mesenteric artery to ligate the middle colic artery proximal to this bifurcation (DeMeester et al, 1988).12 When there are completely separate origins of the right and left branches of the middle colic artery from the superior mesenteric artery use of the transverse colon is risky without supercharging the graft via a microvascular anastomosis between the middle colic vessels and suitable vessels in the neck. In most cases the need to divide more than two arteries or veins should prompt consideration of an alternate graft or to use the colon based on the middle colic circulation. Similarly, every effort should be made to maintain communication between the right and left branches of the middle colic vein. Venous anomalies are common and must be anticipated, and one that is seen with some frequency is a common trunk for the middle colic and gastroepiploic veins into the superior mesenteric vein. The gastroepiploic vein must be preserved, and thus the middle colic vein in this situation is ligated distal to this junction. Once the anatomy of the middle colic vessels has been found to be acceptable, the artery is temporarily occluded with a fine bulldog vascular clamp. Vascular isolation of the

proposed graft is completed by temporarily clamping the collateral circulation from the right and ileocolic vessels coursing within the mesentery between the cecum or ascending colon and the proximal extent of the proposed graft. At this point the vascular supply to the graft should be exclusively from the left colic vessels, and the adequacy can be assessed using palpation, inspection, and Doppler signal. Regardless of preoperative angiographic findings, the final decision regarding use of the colon as a graft is always made in the operating room after a careful inspection of the isolated graft. In a good graft, within several minutes of clamping, the small vessels adjacent to the wall of the colon in the proximal portion of the proposed graft will be visibly pulsatile. In the absence of visible pulsations in the vessels along the mesenteric border of the graft, Doppler evaluation should demonstrate a strong signal. If a strong signal is not present, consideration should be given to supercharging the graft or staging the reconstruction and leaving the colon in the abdomen to be inspected again in 48 hours. The adequacy of venous outflow should also be assessed, since venous hypertension can ultimately lead to arterial compromise and loss of the graft. If the vascular supply is adequate, the middle colic vessels are divided, and the colon is transected with a gastrointestinal anastomosis stapler at the site of the proximal stitch. The remaining avascular por-

Chapter 59 Colon Interposition

End cervical esophagus Trachea Recurrent laryngeal nerve Esophageal plexus

Anterior vagus nerve

Highly selective vagotomy

Spleen

Vein stripper

A FIGURE 59-4 A, Technique of vagal preservation showing passage of a vein stripper via a gastrotomy to the proximal esophagus and secured. Note the highly selective vagotomy along the lesser curve. Continued

tions of the transverse mesocolon are divided so that the colon graft can be straightened out as much as possible. We bring the colon interposition up through the posterior mediastinum into the neck by suturing it to the funnel of an inverted 14-mm Mousseau-Barbin tube (Porges Catheter Corporation, New York) and wrapping the graft in a camera bag. This allows atraumatic transfer of the graft because tension is transferred to the bag, and the bag also protects the mesentery during passage through the mediastinum. It is critical to avoid twisting of the graft, and the mesenteric vessels should be located to the right and inferior to the graft. We prefer to anastomose the esophagus to the colon in an end-to-end fashion using a single layer of interrupted 4-0 monofilament sutures, although a stapled technique works for this anastomosis, particularly when there is a significant size discrepancy between the esophagus and colon. All knots are placed on the inside with the exception of the final three or four modified Gambee sutures used to complete the anastomosis on the anterior surface. At the completion of the proximal anastomosis the camera bag is pulled down from the abdomen and removed, and in

the process it pulls the graft straight and reduces the anastomosis into the thoracic inlet to minimize redundancy. It is important to pull the colon graft straight and secure it to the left crus with several 2-0 silk sutures to prevent late redundancy and to avoid herniation of abdominal viscera into the mediastinum through the hiatus. The distal end of the colon graft is transected approximately 10 cm distal to the hiatus in preparation for the cologastric anastomosis. Care should be taken to transect the colon immediately adjacent to the bowel wall to avoid injury to the mesenteric vascular pedicle of the graft. The distal colon is mobilized just sufficiently to allow it to be reanastomosed to the remaining ascending colon in an end-to-end fashion.

Vagal-Sparing Esophagectomy With Colon Interposition In the vagal-sparing procedure, the esophagus is stripped from the mediastinum using a vein stripper, allowing the vagal plexus in the mediastinum to be preserved (Fig. 59-4A and B). Since no mediastinal dissection is necessary it is an

635

636

Section 6 Operative Techniques

End cervical esophagus

Vessel loop around anterior vagus nerve

Esophageal plexus

Spleen

Inverted esophagus

Vein stripper

B FIGURE 59-4, cont’d B, Stripping the esophagus with the vein stripper.

easier procedure than a transhiatal resection. A highly selective vagotomy is included along the lesser curve of the stomach both to free the vagal trunks away from the distal esophagus and upper stomach in preparation for stripping out the esophagus and also to reduce gastric acidity to minimize the potential for the development of ulcers in the colon near the cologastric anastomosis. Although it is relatively acid resistant, we have found that the intact, innervated stomach in the vagal-sparing procedure can generate sufficient acid to lead to colonic ulcers. The routine addition of a highly selective vagotomy and use of acid suppression medication when necessary have largely eliminated this problem. Because the esophagus is stripped out with the vagalsparing procedure the mediastinum is typically not large enough to accommodate a colon graft and needs to be dilated, the exception being when the esophagus is removed for endstage achalasia. Thus, to prevent compression of the graft and the potential for vascular compromise we dilate the mediastinal tract before bringing up the colon graft by pulling a 90-mL Foley catheter from the abdomen up to the neck through the posterior mediastinum several times, each time with more saline in the balloon. The colon graft is then

wrapped in a camera bag for protection, brought posterior to the intact stomach via a window created by division of the proximal one to two short gastric and posterior pancreaticogastric vessels, and pulled up into the neck. A hand-sewn, single-layer esophagocolic anastomosis is performed, and the colon is pulled back into the abdomen by pulling on the camera bag and removing it from the abdomen. A stapled cologastric anastomosis is then performed to the posterior fundus of the intact, innervated stomach. No pyloroplasty is necessary because the antral innervation has been preserved (see Fig. 59-4C)

Non–Vagal-Sparing Esophagectomy If the vagus nerves have been divided or there is preoperative evidence of poor gastric emptying, then the colon should not be anastomosed to the intact stomach because significant problems with regurgitation are likely to develop. Instead, removing the proximal two thirds of the stomach and anastomosing the colon to the antrum works very well. Over time the antrum regains a degree of function and acts as a pump to move material to the duodenum, while the colon graft

Chapter 59 Colon Interposition

Left vagus nerve Esophagus

Colon Recurrent laryngeal nerve Anterior vagus nerve

Spleen

Stomach

C FIGURE 59-4, cont’d C, Colon interposition placed in the native esophageal position among the vagal plexus with end-to-end proximal anastomosis and end-to-posterior gastric wall anastomosis.

takes on the former role of the stomach and acts as a reservoir. The longer the colon graft is in place the better the function tends to be, so patience is warranted on the part of the patient and physician if there are troubling symptoms in the first 6 to 12 months after the procedure. We prefer an end-to-end hand-sewn anastomosis between the distal colon and antrum utilizing the full length of the antral staple line after gastric transection. In this fashion, colonic emptying is maximized and the potential for an anastomotic stricture is minimized. In patients in whom the whole stomach has been removed the colon can be connected to a Roux-en-Y limb of jejunum.

Operative Technique for Right Colon Interposition The approach to the isoperistaltic right colon interposition is started similarly to the left colon but is based on the middle colic vessels. After mobilization of the omentum, the entire right colon and terminal ileum are mobilized from the retroperitoneum. The graft will be based on the middle colic vessels, and the first step is to stretch the transverse colon at the site of the middle colic vessels cephalad to the xiphoid

and place a marking stitch in the antimesenteric border of the bowel at that point. The length of colon required is estimated in the same fashion using an umbilical tape cut to the distance between the left ear and the xiphoid. The site on the proximal colon where the umbilical tape reaches is also marked with a silk stitch. The ileocolic, right colic, and ileal (if required) arteries are isolated and clamped with atraumatic clamps. The vascular supply based on the middle colic artery can now be assessed. In select circumstances a reversed right colon graft can be used based on the right and/or ileocolic vessels with division of the middle colic vessels using the region of the splenic flexure or proximal descending colon for the proximal anastomosis. Once the adequacy of the vascular supply has been confirmed, the appropriate vessels are divided and the graft is brought up to the neck as described previously.

Routes for Reconstruction Once the conduit has been prepared, the route of reconstruction must be selected and readied for the graft. There are two primary routes and two alternate, although seldom used, routes. In most cases the colon graft is positioned in the

637

638

Section 6 Operative Techniques

posterior mediastinum, in the bed of the excised esophagus. If the posterior mediastinum is unavailable or unwise to use because of residual disease in the chest, the graft is brought up substernally in the anterior mediastinum. When the colon is to be placed substernally it is important to enlarge the thoracic inlet and minimize the acute angle created when the esophagus deviates from its normal course into the posterior mediastinum and turns superficially to pass under the sternum. We enlarge the thoracic inlet by removing the medial aspect of the left clavicle, the left half of the manubrium, and the medial portion of the first rib. Likewise the exit from the substernal tunnel should be inspected. If there is a very large left lateral segment of the liver it may be necessary to remove this to prevent interference with the graft as it descends posteriorly to join the gastric remnant. The diaphragm should be resected back several centimeters on each side of the substernal window to prevent diaphragmatic obstruction of the graft. After obtaining hemostasis the substernal tunnel is ready for the graft. One seldom-used option available when the posterior and anterior mediastinal routes are not available is the intrathorcic or pleural route. The left pleural space can be accessed either through the esophageal hiatus or through a small phrenotomy in the anterior aspect of the left diaphragm. The conduit can be brought up to the neck either anterior or posterior to the pulmonary hilum and then through the enlarged thoracic inlet after partial manubriectomy and claviculectomy. A last option is the subcutaneous route. This is a potential space created above the sternum in the subcutaneous tissue. At the xiphoid, dissection with electrocautery is used to create a tunnel on the anterior aspect of the sternum. Similarly, at the sternal notch, the subcutaneous tissue is dissected free of the sternum. A tunnel three fingerbreadths wide is necessary to create enough space for the colon interposition. By necessity, a ventral hernia is created at the level of xiphoid to allow the colon to exit the abdominal cavity and lie on top of the sternum. The graft is brought up via the subcutaneous tunnel into the neck.

Postoperative Care Patients are routinely extubated at the completion of the operation and admitted directly to the intensive care unit. Continuous infusions of dopamine (3 µg/kg/min) and nitroglycerin (5-20 mg/min) are used to aid graft perfusion for 72 hours. Intravenous fluids and 5% albumin infusions are administered as needed to maintain intravascular volume. A thoracic epidural catheter placed before the operation is used for postoperative pain management and facilitates pulmonary toilet. Antibiotics are discontinued after routine perioperative coverage. Nasogastric suction is maintained until the drainage is minimal and bowel function has returned. We routinely obtain a videoesophagogram before starting a diet to check for anastomotic integrity and assess conduit emptying. If this is satisfactory, an oral diet, beginning with clear liquids and advanced to a soft diet over 2 to 3 days, is started. Patients are given strict instructions to eat or drink only when upright and to stay upright for a minimum of 60 minutes

afterward to allow the graft to empty and to minimize the potential for aspiration. Starting at 72 hours after surgery and continuing until the patient is taking an adequate oral diet, supplemental jejunal feedings are delivered, initially sufficient to provide full caloric support and then tapered to provide 1000 calories overnight once the patient is taking oral nutrition.

RESULTS OF COLON INTERPOSITION Despite recent improvements in perioperative management, postoperative morbidity and mortality after colon interposition remains significant (Table 59-2). Although use of the colon for esophageal replacement is a longer and more complex operation that entails three anastomoses, several reviews (Briel et al, 2004; Hagen et al, 2001)14,15 have shown that there are no significant differences in morbidity or mortality compared with reconstruction with a gastric pull-up procedure.

Operative Mortality and Morbidity Operative mortality with esophageal surgery is very dependent on surgeon and center volume.16 Mortality in most experienced centers is under 5%, and most deaths result from septic or cardiopulmonary complications. One of the most feared complications in esophageal surgery is graft ischemia and necrosis. In several series, graft necrosis accounted for 50% of the postoperative deaths (DeMeester et al, 1988).12,17,18 Several reports have suggested that right colon interposition had a greater necrosis rate compared with left colon interposition, potentially related to a less reliable arcade with the right compared with the left colon graft.17,19 Preservation of an adequate vascular supply, both arterial and venous, is critical for a successful outcome with colon interposition. We utilize several strategies to optimize the arterial supply: (1) patient selection is based on angiographic features such as a patent and disease-free inferior mesenteric artery and an intact marginal artery that communicates with the middle colic artery; (2) perioperatively, we use dopamine and nitroglycerin infusions to support adequate splanchnic circulation and strictly forbid the administration of any vasopressors; and (3) the adequacy of vascular flow is tested by temporarily occluding all vessels except the vessels upon

TABLE 59-2 Summary of Modern Operative Results for Long-Segment Colon Interposition in Several Series

Author (Year)

Patients (No.)

Wilkins17 (1980)

Mortality (%)

Morbidity (%)

Graft Loss (%)

100

9.0

40

7.0

Curet-Scott et al18 (1987)

53

3.8

30

7.5

DeMeester et al12 (1988)

100

5.4

24

3.4

19

Cerfolio et al

(1995)

32

9.4

24

6.3

Thomas et al21 (1997)

60

8.3

65

5.0

Wain et al26 (1999)

52

4.0

6.7

5.8

Chapter 59 Colon Interposition

which the graft is to be based. Because venous outflow obstruction and thrombosis can lead to arterial insufficiency and graft necrosis, we maximize venous outflow by maintaining an intact mesentery to the descending colon. This keeps the marginal vein in continuity with the hemorrhoidal plexus, allowing drainage to the inferior vena cava as well as to the inferior mesenteric vein. When necrosis of the conduit is suspected, it should be promptly diagnosed and aggressively treated to prevent the development of multiorgan failure and death. Immediate endoscopy is the most valuable test to assess graft viability and can suggest an alternate etiology for the clinical deterioration if the graft appears healthy and the anastomosis intact.20 If the graft is necrotic, immediate resection of the ischemic portions with creation of an esophagostomy must be done to salvage the patient. Although an early and aggressive surgical approach can salvage many of these patients, delay in diagnosis and therapy is usually fatal.21 Common complications that occur with colon interposition are summarized in Table 59-3. Pulmonary complications including pneumonia, acute respiratory distress syndrome requiring prolonged intubation, pleural effusion, and empyema are among the most common complications, occurring in more than 20% to 25% of patients. These complications can be minimized by early ambulation and careful attention to adequate pain control. Prevention of aspiration can be

TABLE 59-3 Perioperative Complications Occurring in 263 Consecutive Resections for Esophageal Adenocarcinoma Complication

No.

Respiratory Pneumonia Prolonged intubation Empyema Pleural effusion

61 (23%) 25 15 5 16

Cardiovascular Arrhythmias Myocardial infarction

44 (17%) 42 2

Anastomotic Leak Graft ischemia

36 (14%) 31 5

Chylothorax

8 (3%)

Deep vein thrombosis/pulmonary embolism

9 (3%)

Gastrointestinal bleeding

1 (<1%)

Sepsis

4 (2%)

Urinary tract infection

3 (1%)

Wound infection

10 (4%)

Reoperation Abdominal bleeding Anastomotic leak/graft necrosis Sepsis/bowel infarction Thoracic duct ligation Empyema or continuous thoracic drainage Fascial rupture/wound infection Others

30 (11%) 5 6 3 3 6 7 4

achieved by keeping the patient in the semi-upright position at all times and by meticulous attention to maintaining a functioning nasogastric tube until gastrointestinal function has returned. When necessary, a mini-tracheostomy can provide invaluable assistance in clearing retained secretions. Cardiac complications occur in approximately 17% of patients, with the development of atrial fibrillation accounting for the majority of these complications. While these are generally self-limiting they do require cardiac monitoring and treatment that can prolong the stay in the intensive care unit. There is no consistent evidence that prophylactic administration of antiarrhythmic drugs reduces the development of atrial fibrillation although they are commonly employed. Anastomotic complications occur in 3% to 46% of patients undergoing esophagectomy, depending on the type of reconstruction performed, and are most common at the esophageal anastomosis (Briel et al, 2004).13,15 The factors leading to anastomotic breakdown are multifactorial, but one must be ever vigilant to exclude potentially life-threatening conduit ischemia that can be present in up to 14% of patients with an anastomotic leak (Briel et al, 2004).15 When anastomotic complications of colon interposition are compared with gastric pull-up there is a significantly higher incidence of ischemia and leak and both a higher rate of and more severe stricture formation in patients with the gastric pull-up procedure (Table 59-4) (Briel et al, 2004).15 Treatment of most anastomotic strictures is simple dilation. Minor disruptions in the cervical anastomosis can be managed with local drainage and antibiotic administration as long as the vascular supply to the graft is adequate.

Long-Term Complications and Function Long-term problems with colon interposition are reported to occur in approximately one third of patients.17-19 The majority of these consist of graft redundancy, aspiration, and bile reflux/peptic complications (Table 59-5). The need for revisional surgery has been estimated in many series to range from 15% to 30%. Of the patients requiring revision of their colon interposition, 75% will be for redundancy of the interposition and anastomotic-related problems.18 These complications appear to be related to failure to pull the colon graft firmly into the abdomen and secure it with stitches to the left crus at the time of the original operation. However, the natural tortuosity of the colon and its thin wall render it susceptible to dilation along its course from extrinsic obstruction. Most commonly, redundancy is

TABLE 59-4 Anastomotic Complications in Colon and Gastric Interpositions Colon Interposition

Gastric Interposition

Mortality

4.7

4.3

Morbidity Ischemia Leak Stricture Severe stricture

7.4 6.1 8.7 2.0

10.4 14.3 31.3 11.2

639

Section 6 Operative Techniques

TABLE 59-5 Late Postoperative Complications for Colon Interposition

Author (Year)

Bile Aspiration Reflux Reoperation Redundancy (%) (%) (%) (%)

Wilkins17 (1980)

NR

1.0

Curet-Scott et al18 (1987)

NR

NR

37

DeMeester et al12 (1988)

NR

2.3

15.2

Cerfolio et al19 (1995)

NR

NR

NR

24

Thomas et al21 (1997)

8

NR

NR

NR

Wain et al26 (1999)

6

2

15.4

4

8.0

1.0 12.5 3.4

NR, Not reported. FIGURE 59-5 Barium swallow showing a redundant colon interposition.

other bile-binding agents and prokinetics including bisacodyl (Dulcolax) should be tried before considering revisional surgery.

seen just above the hiatus (Fig. 59-5). Redundancy is the most challenging long-term complication of colon interposition. Although rarely seen in short-segment interposition, redundancy has been reported to occur in 3% to 25% of longsegment colon interpositions. Redundancy leads to retention of food and liquid in the graft with regurgitation and an increased risk of aspiration. Reoperation with excision of the redundant portion and end-to-end colocolostomy corrects the problem and is well tolerated because over time the vascular supply of the graft becomes quite hardy as long as the mesenteric pedicle is preserved. Rarely patients will have severe bile reflux and aspiration events unrelated to a redundant graft, and for these patients reoperation with Roux-en-Y colojejunostomy or duodenal switch procedure may ultimately be required. However, medical therapy with sucralfate (Carafate) and

Functional Status of Colon Interposition The interposed colon appears to have none of the functions it provides the body in the abdomen. It is merely a conduit for food and liquid to be transported from the mouth to the intestine. Movement of material is by gravity, and manometry of the colon interposition has shown an absence of peristaltic activity. Contractions are infrequent but, if present, are associated with wet swallows and increasing colonic distention or volume within the colon.22 In addition to distention, acidification of colonic contents promotes contraction, shortening, and reduction in redundancy, leading to better transit times.23

100 90 80 Meal consumed (%)

640

70 60

P = .003

50 40 30

Normal (n = 23) Vagal sparing (n = 15) Colon (n = 10) Gastric (n = 10)

20 10 FIGURE 59-6 Percentage of standard meal consumed by vagal-sparing colon interposition, colon interposition, and gastric interposition.

0

10

20

P = .003

30 40 50 60 70 Percentage of the population

80

90

100

Chapter 59 Colon Interposition

Calorie consumption rate (cal/min)

110 Normal (n = 23) Vagal sparing (n = 15) Colon (n = 10) Gastric (n = 10)

100 90 80 70 60 50 40

P < .001

esophagectomy with colon interposition, standard esophagectomy with colon interposition, and standard esophagectomy with gastric pull-up (Banki et al, 2002).25,26 The results of this study are shown in Figures 59-6 to 59-8. The ability of patients to consume a meal and maintain their body-mass index was significantly better after a vagal-sparing esophagectomy and colon interposition compared with the other procedures.

30 20

SUMMARY

P < .001

10

P < .001

0

10

20

30 40 50 60 70 80 Percentage of the population

90 100

FIGURE 59-7 Comparison of calories consumed per minute with vagal-sparing colon interposition, colon interposition, and gastric interposition.

Compared with the normal esophagus, transit through the colon interposition is markedly delayed when measured by nuclear medicine and barium swallow (DeMeester et al, 1988).12,24 Furthermore, the intra-abdominal portion of the colon interposition appears to act as a reservoir.24 Fluoroscopy has also shown regurgitation from the stomach into the colon interposition.24 This makes patients prone to aspiration after eating and forms the basis for the recommendation that patients remain upright for a minimum of 1 hour after meals. Early postoperative evaluation of swallowing is deceptive, and it often takes several months for patients to eat well enough that the feeding tube can be removed. Over time, eating with a colon interposition becomes very natural, although many patients will require liquids with meals and will have a sensation of a “hold up” while swallowing. Pregnancy in patients with a colon interposition has not led to difficulties with eating or appropriate weight gain in our experience. We recently compared a randomly selected group of patients who underwent one of three operations: vagal-sparing 40

P = .433

P = .009

Colon interposition is a challenging operation but remains an excellent option when a gastric pull-up is not available or would be an oncologic compromise. Long-term function is excellent provided strict attention to operative detail is maintained. A colon interposition may offer benefits over a gastric pull-up procedure in young patients who require esophageal replacement, particularly when performed as a vagal-sparing procedure to the intact, innervated stomach. Because of the complexity, its use is perhaps best restricted to specialized centers that perform a high volume of esophageal surgery.

COMMENTS AND CONTROVERSIES Specific advantages for reconstruction with colon are: ■ Adequate length of viscus freely available for replacement of the entire esophagus up to and including the pharynx. ■ The blood supply from the left colic artery is robust and the proximity of the marginal artery to the bowel permits, as opposed to jejunum, a linear interposition procedure without mechanical kinking. ■ Colonic interposition is applicable to reconstruction in infants and children. The procedure itself, however, is complex. The surgeon needs to be aware of the anatomic variations of the vascularization, and to achieve a successful surgical and functional outcome the many different steps of the operation require extreme surgical precision.

P = .021

Body mass index (kg/m2)

35

30

25

20

15 Preop BMI Follow-up BMI 10 n = 15 Vagal sparing

n = 10 Colon

n = 10 Gastric

FIGURE 59-8 Body-mass index (BMI) before and after vagal-sparing colon interposition, colon interposition, and gastric interposition.

641

642

Section 6 Operative Techniques

Because of its complexity in every phase of its use, as compared with gastroplasty, the latter requiring only one anastomosis and offering excellent functional long-term results, most surgeons today prefer stomach as the primary esophageal substitute not only in malignant disease but also in benign disease. As a consequence the successful execution of a colonic interposition becomes even more challenging because it is no longer taught in training programs (with the exception of large-volume centers), with poor surgical and functional outcome being often an inevitable consequence. In this chapter the different steps and pitfalls are clearly described. The authors correctly emphasize that one of the crucial aspects of the operation is to avoid venous congestion, which is perhaps the main reason of necrosis and loss of the graft. A simple and helpful measure in this respect is not to transect the marginal blood vessels when transecting the distal end of the coloplasty at the splenic flexure. Dividing a couple of branches taking off toward the colon off from this marginal vessel provides ample space to transect the colon, and because of its flexibility there is no traction on this arcade when performing both the colocolic and gastrocolic anastomosis. Angiography can be used to detect vascular anomalies, but radiographic findings are rarely useful because in practice it is only during the operation that the vasculature will be fully displayed, thus allowing the surgeon to adequately assess if colon interposition is or is not feasible. I have never used angiography. Reflux of gastric contents into the colon graft may not only cause anastomotic ulceration but also regurgitation and aspiration of acid, bile, and food into the throat. To overcome this problem the cologastric anastomosis is to be designed in such a way that it creates an effective antireflux mechanism. The anastomosis is to be performed in the posterior aspect of the stomach near to the greater curvature at a point one third of the fundopyloric distance distal to the cardia. As a result, approximately 10 cm of graft is retained within the infradiaphragmatic pressure zone, with the fundus falling on this segment and functioning as a flap valve. There is ongoing controversy as to interposition of the colon in an antiperistaltic way, which is especially favored by a number of surgeons when using the right colon. Although a similar functional outcome as compared with isoperistaltic interposition is claimed, painful spasms, dysphagia, and, in particular, regurgitations have

been reported, findings that are endorsed from my own experience. One of the merits of this chapter is that the authors are reporting their experience with colonic interposition performed by principle, rather than by necessity, in a group of patients with benign disease and early cancer, and this in combination with the preservation of the vagal innervation. It appears that the ability to consume a full meal and to maintain body-mass index was superior to non– vagal-sparing colon interposition and gastric interposition, opening an interesting avenue for this subset of patients. However, these results are medium-term results, the final assessment requiring at least 25 years’ follow-up. This need has been clearly illustrated by Jeyasingham and colleagues, who analyzed the Frenchay Hospital experience including Belsey’s experience who championed this operation.1,2 From this report it appears that over the years there is a slow but increasing tendency of developing supradiaphragmatic or infradiaphragmatic redundancy requiring late revision surgery in a substantial number of patients. 1. Jeyasingham K, Lerut T, Belsey RH: Revisional surgery after colon interposition for benign oesophageal disease. Dis Esophagus 12:7-9, 1999. 2. Jeyasingham K, Lerut T, Belsey RH: Functional and mechanical sequelae of colon interposition for benign oesophageal disease. Eur J Cardiothorac Surg 15:327-331, 1999.

T. L.

KEY REFERENCES Banki F, Mason RJ, DeMeester SR, et al: Vagal-sparing esophagectomy: A more physiologic alternative. Ann Surg 236:324-335, 2002; discussion 335-336. Briel JW, Tamhankar AP, Hagen JA, et al: Prevalence and risk factors for ischemia, leak, and stricture of esophageal anastomosis: Gastric pull-up versus colon interposition. J Am Coll Surg 198:536-541, 2004; discussion 541-542. DeMeester TR, Johansson KE, Franze I, et al: Indications, surgical technique, and long-term functional results of colon interposition or bypass. Ann Surg 208:460-474, 1988. Hagen JA, DeMeester SR, Peters JH, et al: Curative resection for esophageal adenocarcinoma: Analysis of 100 en bloc esophagectomies. Ann Surg 234:520-530, 2001; discussion 530-531. Sonneland J, Anson BJ, Beaton LE: Surgical anatomy of the arterial supply to the colon from the superior mesenteric artery based upon a study of 600 specimens. Surg Gynecol Obstet 106:385-398, 1958.

chapter

60

RECONSTRUCTION AFTER PHARYNGOLARYNGECTOMY Lorenzo E. Ferri Shaf Keshavjee

Key Points

tions that may impair or limit the length of the conduit, preventing it from reaching the hypopharynx.

■ Surgery for tumors of the hypopharynx and cervical esophagus is

complicated not only by the difficult resection but also by the reconstruction. ■ Numerous options are available to the surgeon for the reconstruction after pharyngolaryngectomy, including pedicled and free enteric grafts as well as pedicled and free myo/fasciocutaneous flaps. ■ Each of the approaches is associated with differing rates of success and complications. ■ The optimal method of reconstruction is individualized to the patient and depends on distal extent of the tumor, availability of donor sites, and surgeon preference.

Locally advanced squamous cell carcinoma of the hypopharynx and cervical esophagus represent the most common indications for pharyngolaryngectomy. Not only is this procedure technically difficult and often in a previously irradiated field, but the restoration of intestinal continuity also can present an imposing challenge. The goal for reconstruction is to balance the surgical morbidity of the procedure with the functional result with respect to swallowing and voice. Thus the ideal mode of reconstruction is associated with the lowest surgical morbidity, lowest stricture and fistula rate, and most rapid restoration of deglutition and speech. The options for reconstruction after pharyngolaryngectomy are numerous; the most common are presented in this chapter under the following headings: pedicled enteric conduits (stomach and colon); enteric free grafts (jejunal, gastro-omental); pedicled myocutaneous flaps (pectoralis major); and myocutaneous free grafts (radial forearm and anterolateral thigh). The optimal method of reconstruction is dependent on many factors, including extent of disease, unavailability of various conduits due to previous treatment, and surgeon experience and preference. We review the technical aspects and discuss the benefits and disadvantages of each of these methods.

Gastric Conduit The gastric conduit (or “pull-up”) is the reconstructive method most commonly used and with which esophageal surgeons are most familiar. The benefits of this conduit are the ease of preparation and the requirement of a single, pharyngogastric anastomosis. Disadvantages include the necessity of an abdominal incision and the potential for physiologic derangements of digestion, such as dumping syndrome and early satiety. Preparation of the gastric conduit is well described elsewhere in this volume and is not discussed here in detail. After pharyngolaryngoesophagectomy, in which a long defect results, there are several maneuvers that may be employed to ensure adequate length of the conduit. These include complete mobilization of the duodenum with a generous Kocher maneuver, avoidance of a pyloroplasty (by use of a pyloromyotomy or the absence of a drainage procedure), and generation of a long narrow conduit with multiple serial firings of a linear stapling device along the greater curvature of the stomach. In addition, the posterior mediastinal, orthotopic route of reconstruction, if available, is the most direct, maximizing the cephalad reach of the conduit. These procedures may not be necessary but can be very helpful in obtaining additional length in certain patients with less than favorable anatomy.

Colon Interposition When considering a pedicled enteric graft, the stomach is usually the preferred choice for the reasons just stated. However, owing to previous surgery or disease, a gastric conduit may not be available or may result in a graft of inadequate length. In these circumstances, a colonic interposition should be entertained. The colon provides a long conduit with a reasonable blood supply, but several anastomoses are required and because of the vascular arcades, redundancy of the intestine often results. This operative technique is extensively covered in Chapter 59.

PEDICLED ENTERIC CONDUITS Tumors extending to the cervical esophagus may require complete resection of the esophagus to ensure clear margins. In this circumstance, a pedicled enteric conduit is required to replace the entire esophagus. However, this does not preclude the use of this method of reconstruction in patients with tumors that are limited to the hypopharynx. Relative contraindications include previous gastric or colonic resec-

ENTERIC FREE GRAFTS In patients who do not require resection of the esophagus distal to the thoracic inlet, the resulting defect after pharyngolaryngectomy may be reconstructed by a shorter enteric segment with a microvascular anastomosis to the local vasculature. Although many enteric donor sites have been historically employed, free jejunal grafts and gastro-omental flaps 643

644

Section 6 Operative Techniques

are presently the most commonly used. Relative contraindications to pedicled enteric grafts include ascites, extensive prior abdominal surgery, and diffuse inflammatory bowel disease such as Crohn’s disease.

Free Jejunal Graft The free jejunal graft was first used in 1959 and represented the earliest reported free tissue transfer in humans.1 Since that initial attempt, the free jejunal graft has been used routinely to restore intestinal continuity of the proximal esophagus and pharynx. The caliber of the jejunal lumen approximates that of the replaced esophagus, facilitating the enteric anastomosis of this graft. The secretory surface of the small intestine reduces the symptoms from radiation-induced xerostomia, allowing for a good functional result, with most patients able to resume an oral diet within 2 weeks.2 However, an abdominal procedure is required to harvest the graft, and, as with all free tissue transfers, a microvascular anastomosis is required.

Technique The harvest of the jejunal segment may often be undertaken concurrent to the resection of the tumor by a second team. With the patient supine, a periumbilical midline abdominal incision is used to gain access to the peritoneum. A jejunal segment of 20 to 25 cm in length is usually required to restore intestinal continuity. Free jejunal segments have been successfully harvested from the proximal jejunum up to 150 cm distal to the ligament of Treitz. The exact location is confirmed after identifying the optimal vascular arcade by transilluminating the mesentery. Once identified, the mesentery is divided down to the feeding vessel (Fig. 60-1A). To minimize ischemia time, the recipient vessels are prepared in

the neck before dividing the feeding mesenteric vessels. The recipient vessels vary depending on what is available among the cervical vasculature. Although the superior thyroid or facial artery and vein are usually a good size match for an end-to-end anastomosis, we prefer to perform the anastomosis directly to the jugular vein and carotid artery in an endto-side manner. To optimize the functional outcome, care must be taken to insert the graft in an isoperistaltic orientation (see Fig. 60-1B), and the proximal and distal enteric anastomoses complete the procedure. We prefer a twolayered hand-sewn anastomosis with continuous absorbable sutures internally and interrupted silk sutures externally. Although some authors advocate the routine addition of an exteriorized monitoring segment of jejunum based on the same vascular pedicle,3 we have not found this additional procedure necessary.

Gastro-omental Flap The gastro-omental flap was first reported by Baudet in 19794 and popularized by Panje and others more recently.5 The use of this graft has increased exponentially since then owing to its multiple benefits. The large size and pliability of the gastric wall allow it to be molded to a variety of defects. In addition, the flap is harvested with an apron of omentum, enabling the surgeon to fill the surgical resection space and cover often irradiated vessels and the anastomosis with a vascularized bulk of tissue. The gastro-omental flap enjoys the same advantage as the free jejunal graft, in that mucus secretion aids in deglutition. As with free jejunal grafts, enthusiasm for gastro-omental flaps is hampered by the requirement of an abdominal incision and a gastric staple line. A problem unique to this free enteric flap is the potential for acid secretion by the gastric mucosa. Mucosal ulceration of the adjacent pha-

A FIGURE 60-1 Jejunal free flap. A, A jejunal free flap is raised based on a transilluminated feeding mesenteric vessel. B, The jejunal segment is then brought up to fill the pharyngolaryngectomy defect, and microvascular anastomoses to recipient vessels in the neck are performed. (COURTESY OF DR. RALPH GILBERT, TORONTO GENERAL HOSPITAL, TORONTO, CANADA.)

B

Chapter 60 Reconstruction After Pharyngolaryngectomy

ryngeal or esophageal mucosa has been well described, but this complication usually responds to acid suppression with proton pump inhibitors (Gallagher et al, 2002).6

defect and cover both the enteric anastomoses and vessels (see Fig. 60-2C). As with the jejunal graft, an exteriorized monitoring segment of omentum may be placed.

Technique

PEDICLED MYOCUTANEOUS FLAPS

To harvest the gastro-omental flap, access to the peritoneum is gained via an upper midline incision. The lesser sac is entered immediately superior to the transverse colon. This maneuver effectively liberates the omentum from the colonic attachments. The flap is usually based on the right gastroepiploic artery, because this vessel has a slightly larger diameter (1.5-3 mm) than the left gastroepiploic artery (1.22.9 mm) (Gallagher et al, 2002).6 Depending on the surgical defect, a segment of up to 20 to 25 cm of greater curvature is resected with the omentum using serial firings of a linear stapler (Fig. 60-2A). To ensure a tubular configuration of an adequate diameter, we recommend stapling along two, sideby-side, large-bore chest tubes placed in the eventual flap through a proximal and distal gastrotomy. As with all free tissue transfers, the recipient vessels are prepared before dividing the right gastroepiploic vessels. The flap is then brought up to the neck and placed to bridge the defect (see Fig. 60-2B). The accompanying omentum is used to fill the

Pedicled local and myocutaneous flaps have a long history in reconstruction of head and neck resections. Von Hacker, in 1908, described a multistaged reconstruction of a complete pharyngeal defect using tubularized cervical skin.7 Wookey expanded on this and reported on a staged reconstruction using laterally based cervical skin flaps in 1942.8 Although innovative for that era, the results were disappointing, with high rates of fistula formation and distal stenosis. The advent of regional myocutaneous flaps represented an advance over these local cervical skin flaps. Commonly employed pedicled myocutaneous flaps include pectoralis major, latissimus dorsi, and deltopectoral. These pedicled flaps enjoy a reliable blood supply and ease of harvest. Although some authors describe successful use of a pectoralis myocutaneous flap in complete, circumferential, pharyngeal defects,9 most advocate limiting their use to partial pharyngeal defects, because they are usually too bulky to fashion a suitable tubularized conduit. To address this issue, coverage may be obtained by suturing

A

C

B

FIGURE 60-2 Gastro-omental free flap. A, Gastro-omental free flaps are based on the right gastroepiploic artery and are harvested by stapling along the greater curvature of the stomach with a linear stapling device. B, The flap is brought up to the neck, and the accompanying omental apron can be used as bulk to fill the void left by extensive resections as well as cover irradiated vessels and the enteric anastomoses (C). (COURTESY OF DR. RALPH GILBERT, TORONTO GENERAL HOSPITAL, TORONTO, CANADA.)

645

646

Section 6 Operative Techniques

the pedicled myocutaneous flap directly to the prevertebral fascia, obviating the need for complete tubularization of the graft.10 Given the limited use in reconstruction of complete defects after pharyngolaryngectomy, in this chapter we only discuss the most common pedicled myocutaneous flap: the pectoralis major.

Technique The pectoralis major myocutaneous flap is based on the long axis of the pectoralis branch of the thoracoacromial artery. Depending on the defect, an appropriately sized graft is outlined on the chest wall (Fig. 60-3A); usually a width of 6 to 8 cm suffices. The skin, subcutaneous tissue, and muscle are then incised down to the chest wall. Care is then taken to mobilize this graft based on the feeding pectoralis branch of

A

D

B

the thoracoacromial artery (see Fig. 60-3B). The raised flap is tunneled up to the defect either over or under the clavicle (see Fig. 60-3C). The cutaneous surface of the pectoralis major flap is then sutured to the mucosal surfaces of a partial defect (more common) (see Fig. 60-3D) or directly to the prevertebral fascia or tubularized for complete defects. The exterior muscular surface is then covered with a splitthickness skin graft (see Fig. 60-3E).

MYOCUTANEOUS/FASCIOCUTANEOUS FREE FLAPS Myocutaneous or fasciocutaneous free flaps have the benefit of minimal morbidity, obviating the need for an abdominal operation, and a long and reliable vascular pedicle (Makitie et al, 2003).11 In addition, excellent functional results have

C

E

FIGURE 60-3 Pectoralis major myocutaneous flap. A pectoralis major myocutaneous flap is used primarily to cover a partial defect. A, The flap is first mapped out on the anterior chest wall. B, The graft is elevated based on the pectoralis branch of the thoracoacromial artery and tunneled up to the neck (C). The cutaneous surface of the flap is then sutured to the mucosal edges of the defect (D), and a skin graft is harvested to cover the exposed muscle (E). (COURTESY OF DRS. SIMON LAW AND JOHN WONG, UNIVERSITY OF HONG KONG, HONG KONG, SAR.)

Chapter 60 Reconstruction After Pharyngolaryngectomy

this flap has been associated with high fistula and stenosis rates, prompting some to advocate routine use of a salivary stent (Varvares et al, 2000).15 In addition, the radial forearm free flap may not provide adequate length for reconstruction of large defects.

been observed with respect to speech should a tracheoesophageal puncture be performed.12 However, high stricture rates associated with these types of reconstructive procedures have prompted some to routinely stent the repair with salivary tubes. The most promising and commonly performed myocutaneous/fasciocutaneous free flaps are radial forearm and anterolateral thigh flaps.

Technique Before elevating the flap on the patient’s nondominant arm, an Allen test is required to ensure that adequate blood supply will be maintained to the hand after excising the radial artery. A rectangular skin paddle is then marked and incised over the distal volar aspect of the arm. This flap is then elevated on the radial artery for a variable length, depending on the defect. The radial artery may then be dissected more proximally to allow for a long donor artery (Fig. 60-4), expanding the pool of potential recipient vessels in the neck. The donor vessel is then divided and the flap may be tubularized either ex vivo or in situ in the neck after the microvascular anastomosis. Some authors advocate tubularization after the microvascular anastomosis so as to limit ischemia time.16

Radial Forearm Free Flap Although first described in 1981 in the Chinese literature by Yang and colleagues,13 it was Harii and associates, in 1985, who popularized the radial forearm free flap as a method of the reconstruction after pharyngolaryngectomy.14 The benefits of the radial forearm free flap include a reliable, largecaliber, supplying vessel (radial artery), technical ease of elevation, avoidance of an abdominal incision, and excellent functional results with tracheoesophageal speech. However,

Anterolateral Thigh Free Flap This free flap may be raised as a cutaneous, fasciocutaneous, or myocutaneous graft. The anterolateral thigh flap is based on the musculocutaneous or septocutaneous perforators of the descending branch of the lateral circumflex femoral artery. The specific benefits of this free flap compared with the radial forearm are that it allows for a longer defect to be repaired. However, the technical difficulty in elevating the anterolateral thigh graft and its variable blood supply have limited general acceptance of this flap.

Technique The skin perforating vessels are mapped out with a hand-held Doppler probe. These vessels are usually located half the distance between the anterior superior iliac spine and the upper lateral aspect of the patella (Fig. 60-5A). The pedicle

FIGURE 60-4 Radial forearm free flap. The radial forearm free flap is elevated on the radial artery, allowing for a long, reliable, and largecaliber donor vessel. (COURTESY OF DR. RALPH GILBERT, TORONTO GENERAL HOSPITAL , TORONTO, CANADA.)

A

B

FIGURE 60-5 Anterolateral thigh flap. A, The skin perforators of the anterolateral thigh flap are mapped out with a hand-held Doppler probe. B, The flap is elevated on the musculocutaneous or septocutaneous perforating branches of the descending branch of the lateral circumflex femoral artery. (COURTESY OF DR. RALPH GILBERT, TORONTO GENERAL HOSPITAL, TORONTO, CANADA.)

647

648

Section 6 Operative Techniques

TABLE 60-1 Methods of Reconstruction After Pharyngolaryngectomy Method

Advantages

Disadvantages

Pedicled Enteric Graft Gastric “pull-up” Single anastomosis, excellent for total esophagectomy Colon interposition Enteric Free Flap Jejunum Gastro-omentum

Excellent for total esophagectomy

Surgical morbidity, multiple anastomoses, redundancy may result in dysphagia

Good size match, mucus secretion aids in swallowing, early restoration of swallowing

Requires abdominal incision, variable speech, requires microvascular anastomosis

Wide tube diameter possible, mucus secretion aids in swallowing, omentum may cover vascular and enteric anastomosis

Requires abdominal incision, “wet” sounding speech, requires microvascular anastomosis

Pedicled Myocutaneous Flap Pectoralis major Minimal morbidity, ease of preparation

Bulky flap, difficult to tubularize for circumferential defects

Myocutaneous Free Flap Radial forearm Excellent speech, large-caliber vascular supply, minimal donor site morbidity, ease of preparation Anterolateral thigh

Surgical morbidity, poor speech, dumping syndrome, reflux

Excellent speech, minimal donor site morbidity, longer length than radial forearm flap

is raised by first incising the skin at the medial border of the planned flap. This incision is taken down through the deep fascia, and the flap is dissected laterally until the skin perforators are identified. If a musculocutaneous branch is the dominant vascular supply, a cuff of vastus lateralis is usually included, as the vessel courses through this muscle. This maneuver is not required in flaps supplied primarily by septocutaneous branches. With the skin perforators identified and protected, the remaining skin and fascial incisions are performed, raising the entire pedicle (see Fig. 60-5B). As with all free tissue transfers, the recipient vessels are prepared before dividing the donor vessels. The anterolateral thigh flap may then be tubularized and anastomosed to the neck vessels.

SUMMARY In this chapter we have discussed the technical aspects of the many options available to the surgeon in the reconstruction after pharyngolaryngectomy: pedicled enteric grafts (gastric pull-up and colon interposition), free enteric flaps (jejunum and gastro-omental grafts), pedicled regional musculocutaneous flaps (pectoralis major), and myo/fasciocutaneous free flaps (radial forearm free flap and anterolateral thigh). All of these techniques have the ability to restore intestinal continuity and are associated with various benefits and differing rates of morbidity (Table 60-1). The specific method of reconstruction used depends on several factors, including patient comorbidity, unavailability of donor sites due to previous or concurrent disease and surgery, and surgeon preference.

COMMENTS AND CONTROVERSIES In this chapter the authors provide an excellent overview of the different reconstructive techniques available today when dealing with

High stenosis and leak rate (minimized with salivary stent), limited length, requires microvascular anastomosis Variable blood supply, technically difficult preparation, requires microvascular anastomosis

cancers of the hypopharynx. For a tumor confined to the hypopharynx there is usually no need to perform a total esophagectomy and a wide variety of reconstructive techniques are available. The authors describe accurately the pros and cons of each of these techniques. In case of downward extension over the cricopharyngeal muscle into the cervical esophagus a total esophagectomy becomes inevitable. The gastric pull-up either with whole stomach or a gastric tube is the preferred mode of reconstruction. The anastomosis is performed at the base of the tongue after a pharyngolaryngectomy. This operation is a major undertaking. Often these patients have been treated before by high-dose radiotherapy and/or chemotherapy. As a result, morbidity (e.g., anastomotic leaks) is frequent and revalidation of both swallowing and speech is a difficult and longstanding process. And last, the psychologic impact of the mutilation caused by the laryngectomy and subsequent loss of speech is an enormous burden for the patient. Because of this mutilation attention over the past decade has been directed toward nonsurgical treatment (i.e., definitive chemoradiotherapy), which is now considered as the standard of care for the majority of these patients. Surgery is reserved in case of relapse but, as already mentioned, has an increased risk of complications because of the chemoradiation. It is important to stress the use of a multidisciplinary approach as well as the need for an experienced team approach involving ear, nose, and throat surgeons, plastic surgeons, medical oncologists, radiation oncologists, and thoracic surgeons to offer the patients the best option for cure and at the same time guaranteeing the least possible postsurgical morbidity and mortality. T. L.

KEY REFERENCES Gallagher J, Webb A, Ilankovan V: Gastro-omental free flaps in oral and oro-pharyngeal reconstruction: Surgical anatomy, complications, and outcomes. Br J Oral Maxillofac Surg 40:32-36, 2002.

Chapter 60 Reconstruction After Pharyngolaryngectomy

Lorenz R, et al: The increasing use of enteral flaps in reconstruction for the upper aerodigestive tract. Curr Opin Otol Head Neck Surg 11:230-235, 2003. Makitie A, Beasley NK, Neligan PC, et al: Head and neck reconstruction with anterolateral thigh flap. Otolaryngol Head Neck Surg 129:547-555, 2003.

Varvares MA, Cheney ML, Gliklich RE, et al: Use of the radial forearm fasciocutaneous free flap and the Montgomery salivary bypass tube for pharyngoesophageal reconstruction. Head Neck 22:463-468, 2000.

649

chapter

61

FREE VASCULARIZED GRAFTS IN ESOPHAGEAL RECONSTRUCTION Bruce H. Haughey Andy T. A. Chung

Key Points ■ Multiple donor sites are available for free flaps. ■ The “workhorse” flap is the tubed radial forearm. ■ Superior functional outcomes (e.g., swallowing, voice) are achieved

by free tissue transfer.

Reconstruction of the circumferential pharyngoesophageal or cervical esophageal defect has as its primary goal the reconnection of the pharynx to the esophagus with an epitheliallined conduit. With a healed, well-vascularized, and pliable tissue tube in place, patients will predictably swallow by mouth after a single reconstructive procedure and then rehabilitate their voice if the larynx has been removed. The various techniques of pharyngoesophageal and cervical esophageal reconstruction have used a hierarchy of tissues from all levels of the “reconstructive ladder,” with skin grafts and local, regional, and distant tissues employed to form a tubular connection between the pharynx and the esophagus. The focus of this chapter is microvascular free tissue transfer reconstruction of the pharyngoesophageal and cervical esophageal circumferential defect. Total esophagectomy and thoracic esophageal defects are probably better reconstructed with gastric pull-up or colonic interposition procedures, discussed elsewhere in this text. Construction of the neopharynx and cervical esophagus will improve a patient’s quality of life. Immediate reconstruction of a circumferential defect facilitates early oral alimentation and allows oral speech after a tracheoesophageal puncture.1 Connection of the pharynx with the esophagus prevents soiling of the neck and chest with saliva and food and eliminates maceration of the skin. Aspiration of saliva into the tracheostoma with pneumonia is also avoided. Elimination of a pharyngostome avoids the requisite packing and dressing, with their costs and social stigmata.

PREOPERATIVE EVALUATION Generally, patients who require a total or partial laryngopharyngectomy and cervical esophagectomy have one or more major systemic illnesses. Derangement of the pulmonary, cardiovascular, endocrine, renal, hepatic, or hematopoietic systems carries inherent perioperative risk. Tobacco and ethanol abuse, the usual etiologic factors for head and neck cancer, are commonly coupled with long-standing malnutrition. Timely general medical clearance is mandatory before surgery for risk assessment, intervention, and anesthetic 650

treatment planning. A percutaneous gastrostomy (PEG) tube may be placed several weeks ahead of the anticipated procedure to fortify a patient’s nutritional status. Dental evaluation is also a requisite, especially if the dentate oral cavity is within the intended radiation portal. Social service input is helpful for postoperative home care. Site-specific problems of the neck are usually related to prior surgery and/or radiotherapy, but these problems may have systemic implications. Up to 15% of head and neck cancer patients have occult hypothyroidism, which if untreated could precipitate a perioperative cardiopulmonary event or result in delayed or failed wound healing. Radiationinduced atherosclerosis may cause subtotal occlusion of the carotid vasculature, with possible cerebral ischemia after manipulation. External carotid donor vessels may be similarly diseased and require an alternate donor vessel for flap viability. A neck previously dissected on both sides should be considered for a carotid and/or aortic angiogram to aid in the search for appropriate donor vessels.

DONOR SITES Surgeons typically select the donor site based on defect size, body habitus, hair growth pattern of the skin, patient age, gender, occupation, and both patient and surgeon preference (Fig. 61-1). The preferred donor site is the radial forearm, and a reasonable secondary alternative is the anterolateral thigh (Fig. 61-2). Other free flaps that have been used for this purpose include the lateral arm, lateral thigh, jejunum, and gastro-omental complex. The radial forearm free flap (RFFF) allows a two-team approach, leaves few donor site problems, and imports new skin for the neopharynx and/or neck closure via a single flap (Fig. 61-3), but this flap requires a skin graft for donor site closure (Taylor and Haughey, 2002).2 Some reports recommend harvest within the subcutaneous plane to maximize tendon and sensory nerve function.3 The anterolateral thigh free flap (ALTFF) has now replaced the lateral thigh flap as the preferred flap harvested from the thigh. This flap is usually closed primarily for defects measuring less than 8 to 9 cm in width. Larger defects require skin grafting. The ALTFF can potentially provide a large skin paddle measuring up to 20 cm in width and 30 cm in length.4 In contrast to the RFFF, the ALTFF does not have the same concern with adequacy of vascular perfusion of the extremity (Hayden, 1993).5 As with any flaps harvested from the thigh, the ALTFF may be relatively contraindicated in an obese patient because this donor site is a usual location for the accumulation of fatty “saddle bags,” especially in women. If

Chapter 61 Free Vascularized Grafts in Esophageal Reconstruction

CIRCUMFERENTIAL PHARYNGOESOPHAGEAL DEFECT

Esophageal anastomosis in neck

Gastric pull-up procedure

Allen’s test

Unfavorable

“Saddle bags” of fat

Present

Esophageal anastomosis in chest

Favorable

Absent

Elective laparotomy not contraindicated

Tubed radial forearm free flap

Tubed anterolateral thigh free flap

Free jejunal transfer

FIGURE 61-1 Reconstructive options for the circumferential pharyngoesophageal defect are shown in the algorithm. The preferred reconstruction (shown in bold type) is the tubed radial forearm free flap.

FIGURE 61-3 Reconstruction of neck skin and pre segment with a single radial forearm free flap.

such is the case, then free jejunal transfer is a reasonable option at the expense of an open laparotomy. Newer techniques of laparoscopic jejunal free flap (JFF) harvests are now used successfully and reduce the morbidity previously associated with traditional laparotomy harvest techniques.6 Vascular compromise of the extremity should be a rare occurrence with the RFFF, provided that favorable results of a preoperative Allen test are obtained and an intraoperative evaluation of vascular perfusion of the hand is performed after division of the radial artery (Brown et al, 1996).7 A compartment syndrome caused by an expanding hematoma, tight dressing, or splint is also possible. In contrast, without a laparotomy, there is no risk of a donor site–related ileus, abdominal abscess, enteric anastomotic leak, abdominal bleeding, or peritonitis.

RADIAL FOREARM FREE FLAP

FIGURE 61-2 The preferred donor sites for pharyngoesophageal reconstruction are depicted. The radial forearm free flap has been tubed while perfusion continues by the native radial vessels before transfers to the neck.

The radial forearm fasciocutaneous flap was first introduced by Yang and associates in 1981.8 The flap is based on the radial artery and two venae comitantes; additionally, the cephalic vein is also routinely incorporated with the flap. The usual proximal connection between the venae comitantes and the cephalic vein form the basis for using either or both venous systems to drain the flap. For pharyngoesophageal reconstruction, the RFFF skin paddle typically measures 8 × 12 cm and is centered longitudinally over the radial artery,9 although reports of skin paddles measuring 15 × 35 cm have been described.8 In designing the skin paddle, we routinely preserve a 3- to 4-cm segment of normal volar forearm skin measured from the flexor crease of the wrist to the distal extent of the flap. This allows for cosmetic coverage of the

651

652

Section 6 Operative Techniques

skin graft site with a long sleeve shirt and for a watch or jewelry to be worn comfortably over native wrist skin. Under tourniquet control for no more than 1.5 hours, the flap is elevated medially and laterally; the surgeon takes care to preserve the paratenon and epimysium for subsequent skin grafting to the donor site. The superficial radial (sensory) nerve is preserved to maintain sensation to the snuffbox area and dorsum of the wrist. The radial artery is temporarily occluded on the distal end of the skin paddle with two microvascular clamps, and then the artery is divided. Following the harvest and after release of the tourniquet, the hand and thumb are examined to confirm adequate vascular perfusion and the distal radial artery backflow is assessed. This final intraoperative assessment of collateral arterial blood flow through the deep and superficial palmer arches confirms adequate perfusion of the hand. Only then is the distal radial arterial stump suture ligated. If perfusion is inadequate, the radial artery can be reanastomosed, the hand is reperfused, and an alternate donor site is used. The vascular pedicle is elevated from between the tendons and muscle bellies of the brachioradialis and flexor carpi radialis, with careful preservation of the fascial attachments to the flap. The flap then remains attached to the arm only by the radial artery and veins, while the initial flap contouring is being done and perfusion continues in situ. The skin paddle is tubed lengthwise upon itself, skin inside, thus forming an epithelial-lined conduit on the forearm (Fig. 61-4); 3-0 Polyglactin sutures placed in an interrupted vertical mattress fashion, spaced no more than 0.5 cm apart, are used in this closure. Recipient vessels are chosen and prepared in the neck in anticipation of the microvascular free tissue transfer. Branches of the external carotid artery are evaluated for diameter, length, patency, pulsatile flow, and lie of the vessel, including its relationship to any potential recipient vein. Typically, the linguofacial trunk or superior thyroid artery is chosen. The former vessel is turned beneath and then superficial to

FIGURE 61-4 The pharyngoesophageal tube is formed at the donor site before being inset.

the hypoglossal nerve to help set up an unencumbered arterial anastomosis. A suitable recipient vein such as the external jugular or tributary into the internal jugular is selected and left in situ. After flap harvest, the yet-to-be revascularized skin tube is transferred and oriented lengthwise in the pharynx. Usually, the proximal part of the skin paddle can be made 2 to 3 cm wider than the distal paddle, which allows a wide open inlet to the prefabricated skin tube at the tongue base. The whole skin tube is then tacked to local tissue, and the vascular pedicle is properly draped. Attention is then directed to the microvascular anastomoses. An interrupted or running continuous 9-0 nylon suture is used to perform an end-to-end anastomosis of the artery, and a mechanical coupling device (e.g., the 3M Precise System, 3M, St. Paul, MN) is used to perform the venous anastomoses. Primary ischemia time is routinely less than 1.5 hours. The proximal and distal flap anastomoses to the pharynx and esophagus are performed usually over a Montgomery salivary stent. The longitudinal suture line uniting the sides of the flap into a tube is carefully positioned against the prevertebral fascia to ensure a relatively immobile base (Fig. 61-5). The repair is then insufflated via the nostril with saline or hydrogen peroxide, and the integrity of the suture lines is assessed for leakage. Additional sutures are placed as necessary. The neck flaps are reapposed over drains, and a marking suture is placed in the skin overlying the distal portion of the reanastomosed vascular pedicle where the Doppler signal is easily heard for postoperative monitoring.

FIGURE 61-5 The prefabricated fasciocutaneous tube has been inset to reconnect the pharynx and esophagus. Note that the vertical suture line is overlying the prevertebral fascia. The inset shows a tubed flap, a de-epithelialized skin segment, and an attached skin paddle. This technique allows pharyngoesophageal reconstruction along with resurfacing of deficient neck skin by a single free tissue transfer.

Chapter 61 Free Vascularized Grafts in Esophageal Reconstruction

ANTEROLATERAL THIGH FREE FLAP The anterolateral thigh flap was first introduced in the 1980s10 and has since been used successfully for circumferential pharyngoesophageal reconstruction. The flap is supplied by perforators of the descending branch of the lateral circumflex femoral artery (DLCFA) and its two venae comitantes. The length of the vascular pedicle ranges from 8 to 16 cm with an arterial vessel diameter greater than 2 mm. The cutaneous territory of the flap overlies a segment of skin that is centered along a vertical line drawn from the anterior superior iliac spine and lateral patella. This line approximately marks on the skin surface the area of the septum between the rectus femoris and vastus lateralis muscles. The cutaneous perforators are identified by Doppler within 3 cm on either side of the midpoint of this line, with the majority of the perforators located in the inferolateral quadrant of this circle. There are typically one to three identifiable perforators in this location. The perforators exit the DLCFA pedicle and usually traverse within the substance of the vastus lateralis muscle as they travel toward the subcutis and dermis. The cutaneous paddle may measure up to 20 × 30 cm. Flap elevation is performed initially with an anterior incision followed by subfascial dissection in a posterolateral direction until the perforating vessels that were previously located by transcutaneous Doppler localization are encountered entering the subcutaneous layer. At this point the perforators are dissected toward the DLCFA, usually through the vastus lateralis muscle and then proximally to their branching points. The DLCFA is then dissected proximally to its branching from the profunda femoris artery. During dissection of the perforators, it may be necessary to perform intramuscular dissection through the vastus lateralis if musculocutaneous perforators are encountered. Intramuscular dissection may lengthen flap harvest time as well necessitate transection of the nerve to the vastus lateralis muscle. Despite intramuscular dissection, the majority of patients are able to perform activities of daily living normally and without limitations.11 A portion of muscle may also be included in the flap. Tube formation can be performed at the donor site, as for the RFFF. The microvascular technique and insetting of the cutaneous portion of the ALTFF follow the same principles described for the RFFF. Once the flap has been harvested and transferred to the head and neck, closure of the leg defect is carried out by a minimum of undermining and primary closure for defects measuring less than 9 cm in width, resulting in a linear scar. The skin is pliable and frequently hairless, especially in women. As such, the flap can easily be tubed to provide an epithelium-lined conduit for pharyngoesophageal and cervical esophageal repair. The distant location of this flap from the head and neck also allows for synchronous double-team surgery. In patients with thick thigh skin and subcutis or with a large muscle component, this flap cannot be tubed adequately, so an alternate donor site is used.

LATERAL THIGH FREE FLAP The lateral thigh flap was introduced by Baek in 198312 and was described for reconstruction of pharyngoesophageal

defects by Hayden in 1984.13 The skin of the lateral thigh receives its arterial blood supply via direct cutaneous perforators of the profunda femoris artery, exiting posterior to the femur. The principal arterial supply to the lateral thigh flap is the third perforator, although in a very small minority of patients the fourth cutaneous perforator is the dominant pedicle. Venous drainage from the lateral thigh is through venae comitantes that accompany each of the arterial perforators. There are almost always two venae comitantes traveling with the arterial perforator, but, more proximally, they join to become one large vein that ultimately accompanies the profunda femoris artery. The third cutaneous perforator of the profunda femoris artery is arborized deep to the superficial fascia and the fat of the lateral thigh. It supplies an elliptical distribution in the lateral thigh, allowing for flaps of at least 27 × 14 cm to be harvested without any peripheral necrosis. The LTFF also allows a double-surgical team approach but is also contraindicated in obese patients. The major drawback of the LTFF in comparison to the ALTFF is ergonomic relative to dissection of the vascular pedicle and the remote risk of sciatic nerve injury.

JEJUNAL FREE FLAP Autotransplantation of a segment of the jejunum was first described by Seidenberg and colleagues in 1959 (Seidenberg et al, 1959).14 This procedure was first done in dogs, and thereafter the transfer was successfully performed in a human, although the patient died in the early postoperative period. The procedure requires harvest of a segment of the second loop of jejunum with its mesenteric arcade of vessels, transplantation to the neck region, and microsurgical revascularization. It is an appropriate choice for pharyngoesophageal replacement, because the jejunum is yet another mucosa-lined conduit from the alimentary tract, the caliber of which closely approximates that of the pharyngoesophagus. Digestion is not disturbed by sacrifice of the small segment of jejunum; primary reanastomosis in the abdomen is fairly straightforward. It is a reliable flap that, once revascularized, has an excellent blood supply. However, most head and neck reconstructive surgeons have relegated it to a second-tier option because of the risks of a laparotomy, the dysphagia associated with uncoordinated graft contraction, and a “wet” voice quality if tracheoesophageal puncture speech is achieved. Much has been written about placement of the jejunum in the neck in an isoperistaltic versus nonisoperistaltic direction; some authors believe that the latter direction causes problems with swallowing. It has been difficult to validate this premise, because peristalsis of the jejunal segment, once it has been transplanted, is not consistently coordinated with the oral or esophageal phase of swallowing.15 Nonetheless, it is easy enough to mark the jejunal segment before harvest and to place it in the neck in its anatomic orientation. In all large head and neck operations in which the pharynx is entered, perioperative systemic antibiotics should be administered. Preparation of the bowel for its sterilization, however, is more controversial. In 1959, Lillehei and associ-

653

654

Section 6 Operative Techniques

ates demonstrated that bowel sterilization did not increase survival in dogs that had their superior mesenteric arteries clamped for 5 hours.16 McGill and coworkers also showed that intraluminal antisepsis of isolated dog jejunum clamped for 90 minutes did not decrease the extent of the resulting mucosal injury.17 Despite this, Wang and colleagues as recently as 1986 recommended irrigation of the isolated jejunal lumen with germanium bromide and neomycin (Wang et al, 1986).18 Although a few authors have advocated preoperative bowel preparation, the majority do not consider it necessary for small intestinal transfers.19 A two-team approach generally is used in autografting, with one group harvesting the segment of jejunum while the other performs the cancer ablation procedure. As always, it is imperative that the ablative team be sensitive to the needs of the microvascular surgeon in preserving a suitable recipient artery and vein. The segment of jejunum to be harvested should be supplied by a single vascular arcade of adequate dimensions. Some authors identify the appropriate arcade by transilluminating the mesentery.20 Considerable controversy exists regarding the best segment of jejunum to be harvested. Jejunal segments have been isolated from just distal to the ligament of Treitz, from the fourth jejunal arcade, and from 20 cm, 28 cm, 45 to 60 cm, and even 100 to 150 cm distal to the ligament of Treitz.21 After the jejunal segment is isolated, the vascular pedicle is dissected proximally to a point close to the origin from the superior mesenteric vessels. This yields the largest vessel diameter and length to provide flexibility and ease of vascular anastomoses. The jejunal segment is divided and left vascularized by its arcade until the recipient site has been prepared. After the donor and recipient vessels have been placed in approximating clamps, the head should be manipulated to assess the effect that any changes in position may have on the vessels. This should be performed again after the anastomoses have been completed. If the vessels approximate with tension, an interpositional vein graft may be needed. The proximal pharyngeal anastomosis is usually hand sewn in an end-to-end fashion with interrupted sutures. If the circumference of the hypopharynx is greater than that of the jejunal graft, the cephalad jejunum can be opened along its antimesenteric border to improve the size match.22 Although enteric stapling of the pharyngojejunal anastomosis has been reported, in most cases this is a difficult undertaking because of problems in inserting the stapling device through the oral cavity and in obtaining a watertight seal because of discrepancies in the size of the apposing pharyngeal and enteric lumens. The distal suture line can be stapled or hand sewn with interrupted sutures. After the vascular and enteric anastomoses are performed, any redundant mesentery should be wrapped around the esophageal end of the anastomosis. This has been shown to decrease the incidence of postoperative fistulas.23 After the reconstruction is completed the wounds are closed and drained in standard fashion. Monitoring of the JFF can be accomplished with transcutaneous Doppler ultrasound as previously described. In addition, direct monitoring can be performed by exteriorizing a segment of jejunum based on its own mesenteric vessels. The exteriorized jejunum can be excised on postoperative day 5

to 7 with the use of local anesthesia once flap viability is confirmed.

POSTOPERATIVE CARE After microvascular free tissue transfer reconstruction, the patient is managed in an intensive care unit for 3 days. Low doses of intravenous heparin (50 units/hr), aspirin per rectum (600 mg/day), hetastarch (500 mL/day), and dexamethasone (6 mg every 6 hours) are given for 3 days. The flap is checked hourly for clinical evidence of arteriovenous insufficiency by assessing the adequacy of the Doppler signal and by inspection, capillary refill, and needle prick testing of any visible paddle on the neck. The neopharyngoesophageal reconstruction is also evaluated by daily inspection of the pharyngoesophageal lumen using fiberoptic nasopharyngoscopy. The donor site is also evaluated to ensure adequacy of distal limb perfusion in the case of RFFF reconstruction and to monitor for wound infection. Patients are begun on oral feeding with clear liquids at 10 days after their reconstruction or at 14 days if there is a history of prior irradiation. If no fever or neck tenderness develops, then the diet is advanced steadily. Consultation with a swallowing therapist may be necessary for swallowing instruction.

FUNCTIONAL OUTCOMES As reconstructive surgeons, our goal with pharyngoesophageal and cervical esophageal free flap reconstruction is not just measured by flap survival, fistula rates, or neck wound complications. We must also evaluate critically the function of these tube conduits in respect to speech and swallowing outcomes. We have reviewed our results of 45 patients who have undergone free flap reconstruction of pharyngoesophageal defects at Washington University’s Department of Otolaryngology. With the use of the Salassa swallowing scale, 33 of 45 patients achieved compensated and stable swallowing (either a 1 or 2 of 5) usually within 2 months of their original surgery.24 In addition, of the 31 patients who also required a total laryngopharyngectomy, 15 achieved a useful fluent voice via tracheoesophageal puncture after free flap pharyngoesophageal reconstruction. These reconstructions were with both jejunal and fasciocutaneous flaps. We found no correlation between functional outcomes and flap type but did note that patient comorbidity and use of an indwelling esophageal stent led to significantly poorer swallowing scores on multivariate analysis. When using wound complications as an end point, more complications were associated with surgery in an already treated neck field and when the wider surgical field was developed with simultaneous neck dissections or when reconstruction was combined with resection in a single procedure. Lewin and colleagues confirm that the ALTFF resulted in better speech and swallowing outcomes when compared with JFF reconstructions.25

COMPLICATIONS The most common major complication of any type of pharyngoesophageal and cervical esophageal reconstruction is the pharyngocutaneous fistula. A fistula low in the neck carries

Chapter 61 Free Vascularized Grafts in Esophageal Reconstruction

risks of aspiration, mediastinitis, and erosion of the vessels of the neck and chest. Fistulas develop because of prior irradiation, residual tumor, nonhealing recipient tissue, flap tissue loss, or poor surgical technique. Tissue trauma, wound tension, mucosal inversion, hematoma formation, and infection contribute to development of a fistula. Once recognized, most fistulas will respond to conservative treatment. This requires protecting the airway with a cuffed tracheotomy tube, administration of culture-directed intravenous antibiotics, and possible biopsy to rule out recurrent disease. The fistula should be diverted away from the great vessels and tracheostomy by packing, wound revision, and pressure dressings. A suction drain, salivary bypass tube, or T tube may be helpful to reduce the amount of soilage of the neck tissues. If the fistula is persistent, relatively small, and not exposed to prior irradiation, local turn-in flaps may have value. For larger lesions, the time-honored technique is to create a controlled pharyngostomy or esophagostomy, which when matured can be closed with another free flap or regional myofascial tissue such as the pectoralis major flap. Other possible complications, common to neck surgery, are hematoma, deep neck abscess, and wound breakdown/ skin loss, the latter being a greater risk after radiotherapy. Hematomas require drainage and hemostasis; abscesses necessitate drainage, culture, and antibiotic administration; and neck skin loss or breakdown may require flap reconstruction. Of late complications, stricture is a problem that can often be solved by endoscopy and balloon dilation, although in recurrent cases it may necessitate flap reconstruction.

COMMENTS AND CONTROVERSIES Over the past decades the indications for surgery and the type of surgery for cancer of the hypopharynx have changed dramatically. To avoid the mutilating consequences of laryngectomy much attention has been directed toward nonsurgical treatment, that is, definitive radiochemotherapy, which is now considered as the standard of care for the majority of these patients.

Moreover, if surgery is performed, larynx-sparing surgery is the rule. This has been made possible through the impressive progress and now virtually unlimited possibilities since the introduction of microvascular free tissue transfer. As a result, total pharyngolaryngectomy with or without esophagectomy and gastric pull-up has become rare. But, as rightfully pointed out by the authors, owing to the increasing use of definitive chemoradiation therapy, surgery has become the last resort for a number of patients presenting with persistent or recurrent disease. In such cases, the often poor general conditions of the patient, the radiochemotherapy-related damage to the operative field, and the technical aspects of microvascular free tissue transfer are turning this surgery into a major undertaking. In some cases the irradiated skin of the cervical regions may be of such poor quality that its resection and reconstruction (e.g., with deltoideopectoral skin muscle flap) may be necessary to protect the underlying structures. Therefore, such interventions should be done only in expert centers familiar with such complex pathology. Multidisciplinary and team approach are the keys to success. T. L.

KEY REFERENCES Brown MT, Cheney ML, Gliklich RL, et al: Assessment of functional morbidity in the radial forearm free flap donor site. Arch Otolaryngol Head Neck Surg 122:991, 1996. Hayden RE: Reconstruction of the hypopharynx. In Cummings C, Fredrickson JM, Harker LA, et al (eds): Otolaryngology—Head and Neck Surgery, 2nd ed. St. Louis, Mosby-Year Book, 1993, p 2178. Seidenberg B, Hurwitt ES, Som ML: Immediate reconstruction of the cervical esophagus by a revascularized isolated jejunal segment. Ann Surg 149:162, 1959. Taylor SM, Haughey BH: Combined pharyngoesophageal and cervical skin reconstruction using a single radial forearm flap. Laryngoscope 112:1315, 2002. Wang ID, Sun YE, Chen Y: Free jejunal grafts for reconstruction of the pharynx and cervical esophagus. Ann Otol Rhinol Laryngol 95:348, 1986.

655

chapter

GASTRIC TUBES: REVERSED AND NONREVERSED

62

Stanley C. Fell Manoel Ximenes-Netto

Key Points ■ For anatomic and physiologic reasons, the ideal esophageal

replacement may be a tube constructed from the greater curvature of the stomach and vascularized by the gastroepiploic arcade. ■ In adults, either preexisting colonic disease or prior colon resection prohibits the use of a colon conduit. Infants with esophageal atresia may have an associated high imperforate anus and require reconstructive colon surgery. Anomalous arterial patterns or a poor marginal artery make colon interposition hazardous. In contrast, the stomach has an excellent arterial supply in a predictable pattern (Fig. 62-1). The gastroepiploic arcade, which is situated peripheral to the greater curvature of the stomach and thus has a greater arc, lengthens when the gastric tube is created and straightened and does not limit the length of the conduit. The colon and jejunum, with their fan-shaped mesenteries, are longer than their vascular arcades and therefore tend to be redundant when interposed between the esophagus and stomach. In contrast to the gastroepiploic vessels, which are closely applied to the stomach, these mesenteries are subject to tension and torsion. ■ Colon interposition, even if not redundant when first performed, dilates and becomes redundant years later, with attendant problems of stasis and poor emptying. This phenomenon has been noted only rarely with the gastric tube.1 ■ An earlier gastrostomy is not a contraindication to the construction of a gastric tube. In fact, it is a great advantage, because the stomach may be dilated when a large amount (1000 to 1500 mL) of a liquid diet is offered every 3 or 4 hours during waking hours. In 2 to 3 months, the stomach is so enlarged that there is abundant stomach available for esophageal replacement. If this form of reconstruction is anticipated and prior gastrostomy is required, preferably it should be performed toward the lesser curvature of the stomach. The location of the gastrostomy is of little consequence, provided that the stomach is dilated as described. Prior gastric resection or outlet obstruction is usually but not an absolute contraindication to the application of the gastric tube for esophageal reconstruction.

HISTORICAL NOTE In experiments on cadaver dogs, Beck and Carrel in 19052 demonstrated that a tube constructed from the greater curvature of the stomach based on the left gastroepiploic artery could reach the cervical esophagus. Jianu, in 1912,3 successfully performed reversed gastric tube (RGT) esophagoplasty in living dogs, but his two attempts in humans in 1914 failed. In 1951, Gavriliu and Georgescu4 performed the first suc656

cessful RGT in a human; since then, Gavriliu has performed 718 of these procedures. Independently, Heimlich and Winfield, in 1955,5 in the United States, repeated the experimental work of Jianu and subsequently reported their experience in humans.6 Sanders, in 1962,7 was the first to use the RGT for esophageal replacement in a child. Anderson and Randolph, in 1978,8 reported excellent results in pediatric cases. Postlethwait, in 1979 (Postlethwait, 1979),9 developed and popularized the use of the nonreversed gastric tube (NRGT) based on the work of Mes.10 A comprehensive review of the history of the RGT was published by O’Connor.11 HISTORICAL READINGS Anderson KD, Randolph JG: Gastric tube interposition: A satisfactory alternative to the colon for esophageal replacement in children. Ann Thorac Surg 25:521, 1978. Beck C, Carrel A: Demonstration of specimens illustrating a method of formation of a prethoracic esophagus. Ill Med J 7:463, 1905. Gavriliu D: The replacement of the esophagus by a gastric tube. In Jamieson G (ed): Surgery of the Oesophagus. New York, Churchill Livingstone, 1988, p 765. Heimlich HJ: Replacement of the entire esophagus for malignant or benign stenosis. Am J Gastroenterol 35:311, 1961. Jianu A: Gastrostomie und Oesophagoplastik. Dtsch Z Chir 118:383, 1912. Mes G: New method of esophagoplasty. J Int Coll Surg 11:270, 1948. O’Connor TW: A historical review of reversed gastric tube esophagoplasty. Surg Gynecol Obstet 156:371, 1983. Postlethwait RW: Technique for isoperistaltic gastric tube for esophageal bypass. Ann Surg 189:673, 1979. Sanders GB: Esophageal replacement with reversed gastric tube. Utilization for bleeding esophageal varices in a 4-year-old child. JAMA 181:944, 1962.

MANAGEMENT: OPERATIVE TECHNIQUE The patient is positioned supine with a footboard on the table. During the course of mobilization of the stomach, it is helpful to tilt the patient 30 degrees, feet down, to facilitate access to the proximal portion of the stomach. Laparotomy is performed through a midline incision that extends from the xiphoid to below the umbilicus. A selfretaining retractor is inserted, and the stomach and omentum are drawn into the operative field. The vascular arcade and the greater curvature are inspected and palpated. A decision is made in regard to which gastroepiploic artery will vascularize the tube. The RGT is based on the left gastroepiploic artery, and the NRGT is based on the right gastroepiploic artery. The

Chapter 62 Gastric Tubes: Reversed and Nonreversed

657

Line of division of lesser omentum

Common Left gastric artery hepatic artery

Spleen

Splenic artery

Short gastric arteries

Right gastroepiploic artery

Left gastroepiploic artery

Right gastric artery Transverse colon

Right gastroepiploic artery

A

B FIGURE 62-1 A, Arterial supply of the stomach. B, The greater omentum is mobilized.

gastrohepatic ligament is opened, and a hand is placed in the lesser sac, passing superficial to the pancreas, with the fingers exiting the omentum on the greater curvature inferior to the vascular arcade. The greater omentum is dissected from the transverse colon and both hepatic and splenic flexures, with care taken to avoid injury to the middle colic artery. The resultant omental flap is left attached to the gastric tube, to be elevated into the neck and wrapped about the cervical anastomosis to protect against anastomotic leak (Figs. 62-2 and 62-3). The spleen is retracted medially, and a large, moist pad is placed between it and the posterior abdominal wall, thus relieving tension on the vasa brevia. At the level of the spleen, the gastroepiploic artery is no longer present on the greater curvature and only the short gastric arteries must be isolated individually and divided. This may not be necessary in children. The vessels are divided close to the spleen with clips for the splenic end and silk ties for the gastric end of the vessels. Although splenectomy was an integral part of the surgical procedure, as originally described, it is not required unless there is an irreparable splenic laceration or strong adhesions. Once the stomach is dilated by means of a previous gastrostomy, the greater curvature does not come near the hilum of the spleen, thus making splenectomy unnecessary. If possible, the abdominal esophagus is mobilized and encircled with a Penrose drain. When the drain is retracted to the right, the ligation and division of the vasa brevia is

FIGURE 62-2 The reversed gastric tube is constructed over the catheter beginning 4 cm proximal to the pylorus.

658

Section 6 Operative Techniques

Omentum wrapped around gastric tube FIGURE 62-3 The omentum, preserved to buttress the cervical anastomosis, is wrapped about the gastric tube to facilitate its transposition to the neck.

facilitated. The gastrophrenic attachments are divided, and the stomach is freed from its avascular adhesions to the pancreas. This mobilizes the entire greater curvature and fundus. To prepare the RGT, the right gastroepiploic artery is ligated and divided approximately 4 cm from the pylorus (see Fig. 62-2). This area of the antrum must be sufficiently wide to allow emptying of the gastric remnant. A linear stapling instrument is placed at that point at a right angle to the greater curvature. In adults, a 2.5-cm double row of staples is inserted. The distal staple line is oversewn with a continuous 3-0 polypropylene suture. Several of the staples are removed from the proximal staple line to allow for the insertion of a 40-Fr rubber catheter, which is advanced proximally to the fundus to facilitate the firing of the staples. In children, a 20- to 26-Fr catheter is used, depending on the child’s age. The RGT is constructed with multiple applications by a linear stapling instrument in loose proximity to the catheter to avoid tension on the staple line. A 2.5-cm-diameter tube long enough to reach the cervical esophagus or pharynx is thus created. Usually, four or five applications of the stapling device are required to construct the tube. The staple line of the newly formed greater curvature of the stomach is oversewn with a continuous 3-0 polypropylene suture. The staple line of the RGT is similarly oversewn (see Fig. 62-3). Interrupted sutures are used at the angle where the tube joins the stomach. Keeping the tube stretched to its full length on the catheter ensures that it is not shortened by

the application of the suture. The continuous suture is completed 5 cm from the end of the tube. At this point, interrupted sutures are used again; this allows the excision of redundant tube if necessary. The tube may be placed on the anterior chest wall to verify that its length is sufficient for the cervical anastomosis. If additional length is required to reconstruct the entire esophagus or pharynx, other variations of the technique are available. Presently, we have five different types of the RGT (Fig. 62-4). The gastroesophageal junction may be closed and an extra 30% tube length may be used (the Gavriliu 2 variation). In case of antrum pyloric stenosis, a partial gastrectomy is performed and the tube constructed (the Gavriliu 3 variation). In the Gavriliu 4 variation the pylorus is included in the construction of the tube. In that case a Kocher maneuver is performed and the right gastric artery is divided. A terminal branch of the right gastroepiploic artery in the pyloric area also requires division before transection of the duodenum 2 cm distal to the pylorus. The 40-Fr catheter is then inserted through the duodenum, and the RGT is constructed, as previously described. A Billroth I gastroduodenostomy is then performed to the gastric remnant. In the Gavriliu 5 variation the tube includes the pylorus and the gastroesophageal junction is divided. In the experience of Ximenes-Netto and associates (Ximenes-Netto et al, 1998),12 decompression of the distal esophagus via external tube drainage or anastomosis to the jejunum has not been necessary because the esophageal mucosa has been effectively destroyed by the initial injury. The omentum is inspected. Any devascularization should be excised. The remaining omentum is wrapped about the tube to facilitate its transposition to the neck. This is accomplished by shielding the tube and catheter in a plastic sleeve. The tube may be transposed via the substernal, transthoracic, or transhiatal route as circumstances dictate. Three possibilities exist regarding the cervical anastomosis of the RGT, depending on the extent of fibrosis that results from the caustic injury. The anastomosis may be performed above the hyoid bone, through it after its removal, or below it (Fig. 62-5). When the anastomosis is made to the pharynx, Ximenes-Netto and associates (Ximenes-Netto et al, 1998)12 use the Montgomery T tube to stent the anastomosis; the tube is left in place for at least 3 months. The same procedure has been used by others.13 The higher the anastomosis, the more difficulties are encountered and, therefore, the more frequent findings of leaks and strictures. The cervical anastomosis is wrapped with omentum. Closed suction drainage of the cervical incision is advisable, and the wound is loosely closed. A feeding jejunostomy is constructed, and feedings are begun on the third postoperative day. An oral contrast study is performed on the seventh postoperative day. If the results of the study are satisfactory, a soft diet is begun. To prepare the NRGT, an extensive Kocher maneuver is performed to free the duodenum and the head of the pancreas so that the pylorus approaches the midline. The greater omentum and vasa brevia are managed, as previously described, and the gastric fundus is freed from its diaphrag-

Chapter 62 Gastric Tubes: Reversed and Nonreversed

FIGURE 62-4 Five variations of the reversed gastric tube (RGT). The heavy line represents the part of the stomach that is going to be severed and become the RGT. A, Gavriliu 1, the greater curvature is stapled and elevated into the neck. B, Gavriliu 2, the gastroesophageal junction is also severed in order to gain more length. C, Gavriliu 3, when there is an outlet obstruction, a partial gastrectomy is performed and the RGT is constructed from the proximal gastric remnant; the distal part is anastomosed to the duodenum. D, Gavriliu 4 includes the pylorus, which is elevated into the neck. E, Gavriliu 5 is similar to D but severs the gastroesophageal junction.

A

B

C

D

E

659

660

Section 6 Operative Techniques

A

I

C

B II

III

A Short gastric arteries Left gastroepiploic artery

FIGURE 62-5 The cervical anastomosis may be performed either above the hyoid bone (I), through it after its removal (II), or laterally (III). Also demonstrated are the lingual (A), hypoglossal (B), and superior laryngeal (C) nerves. (REDRAWN FROM POPOVICI Z: ASPECTS PARTICULLERES DE LA COLO-OESOPHAGOPLASTIE DANS LES STENOSES OESOPHAGENNES POST CAUSTIQUES. J CHIR (PARIS) 113:269, 1977.)

matic attachments and the pancreas. The prepyloric region is examined for an area that is sufficiently wide to allow the construction of a tube 2.5 cm in diameter, with at least an equal amount for the remaining antrum. At that point, the anterior and posterior walls of the stomach are opened with cautery to allow the insertion of a linear stapling instrument. Alternatively, a 25-mm circular stapling instrument is inserted with the anvil applied to the posterior wall of the stomach (Fig. 62-6A). The linear stapler is inserted through the defect created by the circular stapler. The tube is not constructed over a catheter; therefore, its width must be carefully appraised before each application of the stapling device. It is helpful to mark the line of staple application on the anterior wall of the stomach with needle tip cautery at the low power setting. The final application of the stapling instrument is oblique in the fundic area. The staple closure of the stomach and the tube are reinforced with a continuous polypropylene suture, as previously described (see Fig. 62-6B). Interrupted sutures are used at the fundic end so that any excess tube may be excised if necessary.

RESULTS Anastomotic leak and stricture have been common occurrences in cases of gastric tube esophagoplasty, just as they are after transhiatal interposition of the entire stomach to the

Omentum wrapped around gastric tube

B FIGURE 62-6 A, Preparation of the nonreversed gastric tube. The circular stapler creates the defect required for insertion of the linear stapler. B, Omental wrap of the nonreversed gastric tube before cervical transposition.

neck. Orringer and Iannettoni14 reported a 10% to 15% leak rate in more than 1000 patients undergoing transhiatal esophagectomy. Leaks do not necessarily result in stricture, and the reverse is also true. Gavriliu (Gavriliu, 1975)15 reported a 20% incidence of cervical fistulas in his early cases. This rate decreased to 6% in his last 300 cases, but he stated that “the leaks are not included in these statistics.” Heimlich reported eight leaks in 53 cases of RGT and nine strictures, of which four occurred after leaks.5 Ximenes-Netto and associates (Ximenes-Netto et al, 1998)12 reported a 10% (8 cases) fistula rate in 80 cases of RGT, but only three required reoperation. The esophageal transit time, when measured with technetium-99m pertechnetate in 16 patients, averaged 15.6 seconds (normal, 8.8 ±

Chapter 62 Gastric Tubes: Reversed and Nonreversed

and the NRGT as “peristaltic”; both tubes serve only as conduits. The RGT has a theoretical advantage. It has mucussecreting antral mucosa anastomosed to the esophagus and acid-secreting fundic tissue at the suture line. Nevertheless, no long-term clinical differences between the two procedures have been found. Reflux is common, especially in children, who may require elevation of the head of the bed during sleep. Lindahl and colleagues17 performed upper gastrointestinal endoscopy on 14 children who had undergone gastric tube esophagoplasty for esophageal atresia performed more than 2 years earlier. Ten patients were noted in biopsy specimens to have Barrett’s metaplasia. In no case was there severe dysplasia or intestinal metaplasia. It was concluded that the vagotomized tube secretes acid in response to the influence of the residual stomach, which has normal vagal innervation and secretes gastrin, thus stimulating acid production by the parietal cells of the tube. Therefore, cervical esophagitis and gastric metaplasia may occur in the absence of gastrotubal reflux. The long-term risk of this finding has not yet been determined. Barrett’s epithelium has also been noted in 8% of patients with esophageal atresia treated by conventional repair.

SUMMARY

FIGURE 62-7 Lateral view of the reversed gastric tube, demonstrating its intra-abdominal portion (arrow).

6 seconds) with partial retention in the distal third. No reflux was seen in this group of individuals on whom these studies were performed (Fig. 62-7). Postlethwait (Postlethwait, 1979)9 reported 13 leaks in 30 cases of NRGT interposition; the leaks closed in 1 to 4 weeks. Anastomotic leaks are also common in pediatric cases. Ein and colleagues, in 1987, noted 24 leaks (66%) and 15 strictures (41%) in 36 cases (Ein et al, 1987).16 All but one leak closed within 3 months; however, nine children required surgery. Nine cases of stricture required surgical revision. In 29 of the 36 cases, gastric tube interposition was performed in two stages. The gastric tube was constructed in the first stage, and the cervical anastomosis was performed 2 weeks to 2 months later. This protocol allows the mediastinum to seal and obviates the risk of cervical leak, which results in mediastinal sepsis. In the interval between stages, the child is fed through a gastrostomy. Anderson and Randolph8 reported an incidence of leaks in five patients in their series of 15 RGTs (33.3%), but only one leak required surgical closure. Regardless of how the gastric tube is constructed, it is a vagotomized structure. Peristalsis has not been noted in the gastric tube. It is erroneous to term the RGT “antiperistaltic”

Given that no substitute performs as well as a healthy native esophagus, the gastric tube has advantages over other conduits in addition to the anatomic reasons previously mentioned. The diameter of the tube is similar to that of the esophagus and occupies less space in the thorax and neck than does the colon or whole stomach. Reflux may occur in all conduits, but it is better tolerated in the gastric tube than in the colon, which may develop ulceration. Colon interposition requires three enteric suture lines; the gastric tube has only one. Gastric tube interposition is technically easier to perform, takes less operating time, and does not require bowel preparation. The major deficiency of the gastric tube esophagoplasty is the frequent occurrence of anastomotic leak or stricture. These complications, reported by all who use this method of reconstruction, imply that the impaired vascularity of the gastric tube is the cause, whether the tube is reversed or nonreversed. Gavriliu, in 1975, and Heimlich, in 1972, suggested that splenectomy augments flow to the left gastroepiploic artery. There is no physiologic evidence that this occurs, nor has splenectomy reduced the incidence of anastomotic failure. Splenectomy has its own risks, not the least of which is impaired resistance to infection by encapsulated organisms, such as pneumococci. Accordingly, it is rarely performed in pediatric cases. It is not indicated in the preparation of the NRGT and is not a requirement for a successful RGT. The anatomic studies of Liebermann-Meffert and associates (1992) are a notable contribution to the understanding of the vascular deficiencies of the gastric tube. By means of corrosion casts, the authors demonstrated that the right gastroepiploic artery is the exclusive conduit of blood to the tube and that the right gastric artery makes an inconsequential contribution. The branches of the left

661

662

Section 6 Operative Techniques

gastroepiploic artery vascularize the midportion of the tube, and there is only a weak connection between the right and left gastroepiploic arteries. The arterial supply of the upper 20% of the gastric tube (fundus) is through arterioles and capillaries. Arterial communication between the right and left gastroepiploic arteries thus occurs via retrograde flow if either of these vessels is divided. The arterial supply of the fundus is also retrograde after division of the vasa brevia. LiebermannMeffert and associates (1992) further demonstrated that the right gastroepiploic artery, besides receiving flow from the gastroduodenal artery, receives equal inflow from the pancreatic branches of the superior mesentery artery. This anatomic study suggests that the right gastroepiploic artery, the vascular pedicle of the NRGT, provides better arterial inflow and more efficient retrograde perfusion of the left gastroepiploic artery than would occur in the reverse situation. Furthermore, division of the right gastric artery allows for a more extensive Kocher maneuver and brings the pylorus to the midline, making elevation of the tube easier and tension free. After this step, the fundic area of the tube (the upper 20%), which has the poorest blood supply, can be shortened. If the gastric tube is to be placed substernally, the thoracic inlet should be widened by a resection of the sternal attachments of the strap muscles and the sternomastoid muscle if necessary. This maneuver prevents compression of the arterial supply and venous drainage of the tube. It is hoped that the techniques described might improve the vascularity of the gastric tube and decrease the incidence of anastomotic leak or stricture.

mally, allows the gastric tube to more easily reach the neck. Another advantage of the RGT is that the ingested material empties into the antrum well away from the esophagogastric junction, and this may be of special importance in reducing reflux of gastric contents up into the esophagus. The authors note the uniformly high rate of anastomotic leakage at the esophagogastric junction after use of either the RGT or the NRGT. For this reason, a two-stage operation in which the gastric tube is brought to the neck in the first stage and the esophagogastric anastomosis is performed 7 to 10 days later should be strongly considered. This is particularly appropriate if there is a preexisting cervical esophagostomy. J. D. C.

COMMENTS AND CONTROVERSIES

Liebermann-Meffert D, Meier R, Siewert J: Vascular anatomy of the gastric tube used for esophageal reconstruction. Ann Thorac Surg 54:1110, 1992. ■ An elegant laboratory study of the blood supply of the stomach when it is used as an esophageal substitute.

This chapter and its beautiful illustrations demonstrate a little-used, but nonetheless very important, option for esophageal bypass. This option has the major advantage of retaining the esophagogastric junction for drainage of the excluded or bypassed esophagus. The authors describe its use mainly for benign conditions such as lye stricture or esophageal atresia, but one of its appropriate applications is for bypass of malignant tracheoesophageal fistula. The authors note the anatomic studies of gastric vasculature by Liebermann-Meffert and colleagues (1992), indicating that based on an intact right gastroepiploic artery, the NRGT is more likely to result in a well-vascularized gastric tube. In fact, this is borne out by experience, and it is generally accepted that the NRGT is by far a better option than the RGT. As noted by the authors, mobilization of the duodenum, which allows the antrum to be reflected proxi-

KEY REFERENCES Ein SH: Gastric tube. In Rob & Smith´s Pediatric Surgery, 5th ed. London, Chapman & Hall Medical, 1998, pp 143-151. ■ This article deals with 40 patients operated on for esophageal replacement for more than 30 years and reports the principles of the operation, preoperative and postoperative care, and complications. Ein SH, Shandling B, Stephens CA: Twenty-one year experience with the pediatric gastric tube. J Pediatr Surg 22:77, 1987. ■ This report presents the technique, complications, and results of gastric tube esophagoplasty in pediatric cases. Gavriliu D: Aspects of esophageal surgery. Curr Probl Surg 12:36, 1975. ■ This paper is of historical interest yet furnishes important details of the operative technique for the creation of the RGT. Some aspects of the technique are controversial, and the complications are not well described.

Postlethwait RW: Technique for isoperistaltic gastric tube for esophageal bypass. Ann Surg 189:673, 1979. ■ This is the first article to describe the technique of the NRGT gastric tube in adults. Ximenes-Netto M, Silva RO, Vieira LF, Gregorcic A: The reversed gastric tube revisited: A useful replacement for benign disease. South Am J Thorac Surg 5:22, 1998. ■ This article describes the results in 80 cases of RGT for replacement of the esophagus and pharynx for benign diseases. The hospital mortality rate was 3.7% (three cases), and excellent to good results were obtained in 85.2% of the surviving patients.

chapter

63

QUALITY OF LIFE IN ESOPHAGEAL CANCER PATIENTS Mark I. van Berge Henegouwen Mirjam Locadia Mirjam A. G. Sprangers Jan J. B. van Lanschot

Key Points ■ Quality of life is a multidimensional construct incorporating three

■ ■ ■ ■ ■

broad domains—physical, psychological, and social functioning— that are affected by a patient’s disease and treatment. Various validated generic and esophageal cancer–specific questionnaires exist to describe patients’ quality of life. With a utility measure, patients can numerically express their valuation of quality-of-life outcomes. Most disease-free patients after esophageal resection show return to baseline quality-of-life levels. Gastric tube reconstruction gives superior quality of life compared with other reconstructive techniques. Palliation for incurable esophageal cancer with best long-term results with respect to quality-of-life outcome is best achieved by single-dose brachytherapy.

This chapter addresses quality of life in esophageal cancer patients. First, a brief introduction to the concept of quality of life and its measurement tools is provided. Subsequently, studies addressing quality of life in esophageal cancer patients are described. The effect of various surgical procedures on quality of life in patients with potentially curable esophageal cancer will be assessed, followed by an evaluation of quality of life in patients with nonresectable esophageal cancer and a discussion of various follow-up strategies in patients with Barrett’s esophagus. To conclude, the results of the studies that are described are discussed, and some of the challenges faced when assessing quality of life in esophageal cancer patients are elucidated. In addition, future aspects of the assessment of quality of life in esophageal cancer patients are addressed.

CONCEPT OF QUALITY OF LIFE In the 1950s and 1960s the concept of “quality of life” became popular as a consequence of increasing prosperity.1 In this period, health care budgets became available not only to cure patients but also to pay for their well-being. Because the demand for health care was almost endless and as technology expanded further, it became necessary to investigate the extent to which interventions affected patients’ health in addition to cure or survival. Originally, quality-of-life research aimed to describe the impact of disease and treatment to enhance insight into patients’ lives. As a result, patient information could be made more accurate and care could be improved. As health care budgets became limited, the effectiveness or cost-effectiveness of medical interventions had to be evaluated. At the same time, patients have become more conscious consumers of health care. They often want to participate in medical decision making by weighing the advantages and disadvantages of the available treatment options. Thus, quality-of-life data have become important in the support of the medical decision-making process. Research on quality of life is particularly important in the field of oncology. Despite survival improvements in specific areas, many patients cannot be cured. In addition, the adverse effects of cancer treatment such as fatigue, hair loss, and severe nausea and vomiting can have a major impact on patients’ lives. As a result, decision making in oncology is complex. Possible negative effects of treatment on quality of life need to be weighed against benefits in survival or cure.

Quality of life is a multidimensional construct incorporating at least three broad domains: physical, psychological, and social functioning (Testa and Simonson, 1996).2 The selection of these components is in line with the 1948 World Health Organization’s definition of health.3 Physical functioning refers to physical symptoms resulting either from disease or from treatment and to the ability to perform activities of daily living. Psychological functioning ranges from severe psychological distress to well-being and may also encompass cognitive functioning. Social functioning refers to quantitative and qualitative aspects of social relationship and interaction and of societal integration. Beyond this core set of domains, additional issues may be relevant for specific groups of patients depending on the functional domains affected by the disease or treatment (e.g., body image in patients undergoing mutilating surgery). There is consensus that quality-oflife assessment should also encompass an overall judgment of health and/or quality of life. Moreover, the patient is considered to be the primary source of information regarding his or her quality of life.

INSTRUMENTS TO ASSESS QUALITY OF LIFE Multidimensional quality-of-life instruments are available that provide an adequate description of the basic quality-oflife domains. The most common instruments in quality-oflife research are generic and disease-specific questionnaires. Generic instruments are intended to be used across a wide range of disease populations. The major advantage of these instruments is that they allow for comparison of results 663

664

Section 6 Operative Techniques

across different patient populations. In contrast to generic instruments, disease-specific instruments address issues relevant to a specific patient population. Disease-specific instruments are more likely to be responsive to disease-related changes in quality of life than generic instruments.

Generic Instruments Examples of generic quality-of-life instruments that have well-established levels of reliability and validity include the Sickness Impact Profile (SIP),4 the Nottingham Health Profile (NHP),5 the Medical Outcome Short Form Health Survey (MOS SF-36),6 and the EuroQol (EQ-5D).7 The MOS SF-36 has become the most widely used generic instrument. Its 36 items are combined to form eight subscales: general health, physical functioning, role limitations due to physical problems, bodily pain, vitality, social functioning, role limitations due to emotional problems, and general mental health. A physical component score and a mental component score can be calculated from these subscales. The MOS SF-36 has been evaluated in large population studies.8 Subscale scores and the component scores obtained in a patient population can be compared with reference scores from the general population of different countries as well as with those from a wide range of disease groups.

Cancer-Specific Instruments Examples of questionnaires that have been specifically designed for the assessment of quality of life in cancer patients

include the Rotterdam Symptom Checklist (RSCL),9 the EORTC Quality of Life Questionnaire (EORTC QLQC30),10 and the Functional Assessment of Cancer TherapyGeneral (FACT-G).11 The reliability and validity of these measures have been well documented. The RSCL measures the symptoms reported by cancer patients and covers four domains: physical symptom distress, psychological distress, activity level, and overall global quality of life. The EORTC QLQ-C30 and the FACT-G have been developed according to the so-called modular approach to quality-of-life assessment. In this approach a generic or “core” instrument, applicable to a broad range of cancer patients, is combined with a specific questionnaire (“module”) that assesses topics of relevance to specific cancer patient subgroups in more detail.

Esophageal Cancer–Specific Instruments To assess quality of life in patients with esophageal cancer, the EORTC esophageal module QLQ-OES24 was developed to be used in combination with the generic EORTC QLQC30.12,13 This esophageal module was refined to the EORTC QLQ-OES18, comprising four scales (dysphagia, eating, reflux, and pain) and six single items: swallowing saliva, choking when swallowing, dry mouth, taste problems, coughing, and speech problems (the complete esophageal module is depicted in Table 63-1). A large international study has demonstrated that the EORTC QLQ-OES18 has good psychometric properties (Blazeby et al, 2003).14 The only

TABLE 63-1 Esophageal Cancer Module Measuring Quality of Life Developed by the European Organization for the Research and Treatment of Cancer (EORTC): EORTC QLQ-OES18 Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you have experienced these symptoms or problems during the past week. Please answer by circling the number that best applies to you. During the Past Week

Not at All

A Little

Quite a Bit

Very Much

1. Could you eat solid foods?

1

2

3

4

2. Could you eat liquidized or soft foods?

1

2

3

4

3. Could you drink liquids?

1

2

3

4

4. Have you had trouble swallowing your saliva?

1

2

3

4

5. Have you choked when swallowing?

1

2

3

4

6. Have you had trouble enjoying your meals?

1

2

3

4

7. Have you felt full up too quickly?

1

2

3

4

8. Have you had trouble with eating?

1

2

3

4

9. Have you had trouble with eating in front of other people?

1

2

3

4

10. Have you had a dry mouth?

1

2

3

4

11. Have you had problems with your sense of taste?

1

2

3

4

12. Have you had trouble with coughing?

1

2

3

4

13. Have you had trouble with talking?

1

2

3

4

14. Have you had acid indigestion or heartburn?

1

2

3

4

15. Have you had trouble with acid or bile coming into your mouth?

1

2

3

4

16. Have you had pain when you eat?

1

2

3

4

17. Have you had pain in your chest?

1

2

3

4

18. Have you had pain in your stomach?

1

2

3

4

© EORTC QLQ-OES18 Copyright 2002 EORTC Quality of Life Group. All rights reserved.

Chapter 63 Quality of Life in Esophageal Cancer Patients

other disease-specific measure that has been developed for patients with esophageal cancer is the FACT esophageal module (FACT-E) to accompany the FACT-G.15 The EORTC QLQ-OES18 and FACT-E focus on similar symptoms and common problems related to esophageal cancer. The main difference between the two approaches is their scoring system. A recent study has shown that FACT esophageal scales relate poorly to EORTC esophageal symptom scores, except for swallowing.16

gamble between perfect health and immediate death (choice B) (Fig. 63-1).17 In the gamble there is a probability of living in perfect health (p), and a probability of immediate death (1-p). These probabilities are systematically varied, until the patient reports indifference between the two options (choice A versus choice B). The utility of the health state under evaluation then equals the value of p at which the patient reports indifference.

METHODS TO ASSESS UTILITIES FOR HEALTH OUTCOMES

Time Trade-Off The time trade-off method was developed as a less complicated, conceptually different alternative to the standard gamble.20 It is based on trade-offs similar to those of the standard gamble, but the concept of probability is replaced by time. In the time trade-off, the patient is asked to choose between a fixed duration of time (t) in the health state under evaluation and a variable amount of time (x) in perfect health; both health states are followed by death (Fig. 63-2). The amount of time in perfect health is varied until the patient reports indifference between the two options. The utility of the health state under consideration is then calculated by dividing x by t.

Generic and disease-specific instruments have been developed to describe patients’ quality of life. For (cost-) effectiveness analyses, however, a valuation of quality-of-life outcomes is needed. With a utility measure, patients can numerically express their valuation of (potential) outcomes of disease and treatment. The most commonly used utility measures are the standard gamble, the time trade-off, and the Visual Analogue Scale (VAS).17 Utilities range from 0, representing death, to 1, representing perfect health. They can be obtained for an actual health state as well as for hypothetical health states. By combining utilities for different outcomes with length of survival, the expected value of a treatment strategy can be expressed in terms of overall survival corrected for quality of life, the so-called qualityadjusted life years (QALYs).18 QALYs reflect the level of desirability of treatment strategies with respect to quality and length of life.19

Visual Analogue Scale The VAS is a 10-cm line anchored by death and perfect health. The patient is asked to place a mark on the line between these two extremes to indicate the valuation of the health state under evaluation. The distance between the mark and the anchor death is measured (in millimeters and divided by 100), resulting in the utility for the particular health state.17 Theoretically, only the standard gamble method produces scores that can truly be termed utilities, because they are elicited under conditions of risk and uncertainty. However, scores obtained with the time trade-off and the VAS are often also termed utilities for convenience, a convention that is followed throughout this chapter.

Standard Gamble In the standard gamble, the patient is asked to choose between a certain—but imperfect—health state (choice A), and a Choice A: no gamble Health state under evaluation p

Choice B: gamble

Perfect health

Immediate death

1-p

CLINICAL STUDIES ASSESSING QUALITY OF LIFE IN ESOPHAGEAL CANCER PATIENTS

FIGURE 63-1 Standard gamble. In the standard gamble the patient is asked between a certain health state (choice A), and a gamble between perfect health (p) and a probability (1-p) of immediate death (choice B). The probabilities are systematically varied until the patient reports indifference between choice A and choice B.

For the purpose of this chapter a Medline search was performed (until July 2005) to identify studies assessing quality of life or quality-adjusted survival after esophageal resection.

Health state under evaluation

1

2

3

4

5

Perfect health Utility
x/t
0.80

6

7

t

8

9

10

x

FIGURE 63-2 Time trade-off. In the time trade-off, the patient is asked to choose between a fixed duration of time (t) in the health state under evaluation and a variable amount of time (x) in perfect health. The amount of time in perfect health (x) is varied until the patient reports indifference between the options.

665

666

Section 6 Operative Techniques

Studies were selected with the following key and text words: “esophagectomy”; “esophageal” or “esophagus” and “resection,” combined with “quality of life” or “quality-adjusted life” or “utility” or “utilities” or “health state values.” Studies were limited to the English language. A total of 224 articles were identified. Only studies in patients with esophageal cancer or Barrett’s esophagus using validated quality-of-life questionnaires or incorporating utilities were selected. Reviews and case reports were discarded from further analysis. Additionally, references from selected studies were cross checked for studies missed in the initial search. Eleven studies were found to adequately assess quality of life or qualityadjusted life survival after specific surgical techniques. To give a comprehensive overview of esophageal cancer patients’ quality of life, we also discuss six studies evaluating quality of life during palliative treatment for esophageal cancer, previously summarized by Homs and associates (Homs et al, 2005).21 Moreover, seven studies evaluating quality-adjusted survival or utilities for a variety of surveillance protocols in patients with Barrett’s esophagus are discussed.

QUALITY OF LIFE AFTER RESECTION OF ESOPHAGEAL CANCER A great variety in operative techniques is applied to treat esophageal cancer. To acquire surgical access a transthoracic or transhiatal approach can be used. For the reconstruction of the alimentary tract after resection, different procedures are available, including a gastric tube, a colonic interposition, or a jejunal loop. These reconstructions can be performed through different anatomic routes (i.e., the prevertebral route, the retrosternal route, and the presternal, subcutaneous route). Recently, minimally invasive esophagectomy has been introduced. Esophageal resection can be performed thoracoscopically, while the laparoscopic approach can be applied to construct the gastric tube. In this section we address studies that have evaluated a variety of surgical procedures with respect to quality of life or utility measures. Studies using validated quality-of-life questionnaires or utility measures in patients undergoing esophageal resection are listed in Table 63-2. Most studies evaluated one specific type of procedure with respect to quality of life, but a number studied multiple parameters.

Heterogeneous Groups of Patients In several studies assessing quality of life after esophageal resection, surgical access, type of reconstruction, and route of reconstruction were not specified. In general, these studies show a return to baseline levels of quality of life for long-term (>2 years) disease-free survivors (de Boer et al, 2004; Hulscher et al, 2002).22-24 When compared with healthy individuals a number of symptoms may persist (i.e., dysphagia) but, in general, quality of life after esophageal resection is similar to the quality of life of healthy individuals.25-27 A randomized study comparing adjuvant postoperative radiation therapy to surgery alone found that postoperative irradiation causes delayed recovery of patients’ quality of life.28

Surgical Access Transthoracic resection of the esophagus aims to improve long-term survival by radical resection of the tumor and adjacent structures in combination with an extended lymph node dissection, which is not performed during the transhiatal approach. In a recent study, Olsen and associates studied quality of life using the EORTC QLQ-C30 and the EORTC QLQ OES18 in a small (n = 18) and heterogeneous group.29 Physical performance was diminished after transthoracic resection, as was respiratory function (forced vital capacity and forced expiratory volume in 1 second). Moreover, patients reported more dysphagia, fullness, diarrhea, and fatigue in comparison with age-matched controls. In a recent randomized trial comparing limited transhiatal and extended transthoracic resection, quality of life was measured using the MOS SF-20 (a derivative of the MOS SF-36) and a modified version of the RSCL during a 3-year follow-up period (de Boer et al, 2004; Hulscher et al, 2002).22,23 Physical symptoms, activity level, physical functioning, social functioning, and energy were significantly reduced at 3 months postoperatively for both procedures. Although recovery was slower for patients after transthoracic resection, scores for patients in both groups returned to preoperative values within 6 to 9 months (Fig. 63-3). Quality-adjusted life years were calculated by multiplying survival of a certain health state with the utility of that state. Utilities for 7 health states were elicited using the standard gamble method.30 Quality-adjusted survival did not differ significantly for the two groups (Hulscher et al, 2002).23

Type of Neo-esophagus Quality of life after gastric tube reconstruction has been evaluated in several studies (de Boer et al, 2004).22,25,31 The randomized study, mentioned earlier, comparing the transhiatal and transthoracic approach, used a gastric tube reconstruction in 206 of 220 patients. As mentioned earlier, quality-of-life scores returned to baseline levels within 1 year after surgery (de Boer et al, 2004).22 In another study, de Boer and coworkers examined 35 patients who were disease free for at least 2 years after esophagectomy and gastric tube reconstruction for esophageal cancer. Although some residual symptoms persisted (mainly dysphagia), general quality of life in these patients was similar to that in healthy individuals.25 Gawad and colleagues used the EORTC QLQ-C30 to compare different anatomic routes in patients who underwent a gastric tube reconstruction.31 All groups in this study showed quality-of-life values for physical status, working ability, and social functioning comparable to the normal population. Cense and colleagues described a small group of long-term disease-free patients (n = 14) who underwent colonic interposition for malignant disease.32 These patients were compared with patients with gastric tube reconstruction from an earlier report of the same research group using the MOS SF36 and an adapted version of the RSCL.25 Colonic interposition was shown to have an impaired quality of life as compared

Chapter 63 Quality of Life in Esophageal Cancer Patients

TABLE 63-2 Studies Using Validated Quality-of-Life Questionnaires or Utility Measures in Patients With Esophageal Cancer Undergoing Surgery No. Patients

Patient Specifics

Heterogeneous Groups of Patients RCT Zieren et al28 (1995)

68

Esophageal cancer; postoperative RT (n = 33), no postoperative RT (n = 35)

Transhiatal resection; gastric tube (“as preferred reconstruction”; numbers not stated)

EORTC QLQC30

Postoperative RT causes delayed recovery of QOL

McLarty et al27 (1997)

Prospective cohort

64

Esophageal cancer, >5-yr disease-free survival

Transhiatal or transthoracic dissection; gastric tube reconstruction

MOS SF-36

Physical functioning and energy worse than healthy controls; mental health better than healthy control

Blazeby et al24 (2001)

Prospective cohort

92

Esophageal cancer (n = 55 resection)

Not stated

EORTC QLQC30; QLQOES24

Improvement in emotional function is related to longer survival

Headrick et al26 (2002)

Retrospective cohort

54

HGD/esophageal cancer

Lewis esophagogastrectomy (n = 34), transhiatal esophagectomy (n = 10), transthoracic esophagectomy (n = 8), other (n = 2)

MOS SF-36

Acceptable function and quality of life; worse scores on health perception for patients with cancer

RCT (HIVEX trial)

220*

Esophageal cancer

Transhiatal resection (n = 106); transthoracic resection (n = 114); all gastric tube

Standard gamble; quality-adjusted life years

No significant difference in quality-adjusted life years

de Boer et al22 (2004)

RCT (HIVEX trial)

220*

Esophageal cancer

Transhiatal resection (n = 106); transthoracic resection (n = 114); all gastric tube

MOS SF-20 RSCL

QOL returned to baseline levels in both groups <1 yr. Faster improvement after transhiatal compared with transthoracic approach

Olsen et al29 (2005)

Prospective cohort

18

Esophageal cancer (n = 14); benign disease (n = 3); missing data (n = 1)

Transthoracic resection; gastric tube (n = 13), colon (n = 4), small bowel (n = 1)

EORTC QLQC30; QLQ-OES18

In comparison to age-matched controls more dysphagia, fullness, diarrhea, and fatigue

Type of Neo-esophagus de Boer et al25 (2000) Prospective cohort

35

Esophageal cancer; 2 years cancer-free survivors

Transhiatal resection; gastric tube

MOS SF-36

Some residual symptoms persist, but general QOL is similar to healthy individuals

Cense et al32 (2004)

14

HGD/esophageal cancer

Colonic interposition

MOS SF-36 RSCL

Poorer QOL after colonic interposition compared with gastric tube reconstruction

Author (Year)

Surgical Access Hulscher et al23 (2002)

Study Design

Prospective cohort

Surgery

QOL Measurement

Outcome

Continued

667

668

Section 6 Operative Techniques

TABLE 63-2 Studies Using Validated Quality-of-Life Questionnaires or Utility Measures in Patients With Esophageal Cancer Undergoing Surgery—cont’d

Author (Year)

Study Design

Route of Reconstruction RCT Gawad et al31 (1999)

Minimally Invasive Esophagectomy Luketich et al34 (2003) Prospective cohort

No. Patients

Patient Specifics

26

Esophageal cancer

Gastric tube (n = 14 retrosternal; n = 12 posterior mediastinal)

EORTC QLQC30

No significant differences between groups

222

HGD/esophageal cancer

Gastric tube (n = 8 transhiatal; n = 214 transthoracic); laparoscopic and/or thoracoscopic

MOS SF-36

QOL returned to baseline levels. Low postoperative reflux scores

Surgery

QOL Measurement

Outcome

*Same patient groups EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire; HGD, high-grade dysplasia; MOS SF-36, Medical Outcomes Study Short Form-36; QLQ-OES18, esophageal module of the EORTC QLQ-C30; QOL, quality of life; RCT, randomized controlled trial; RSCL, Rotterdam symptom check list; RT, radiotherapy.

with gastric tube reconstruction. Patients with a colonic interposition also showed worse subscale scores for general health, physical role, vitality, social functioning, and mental health.

Route of Reconstruction There have not been many comparative studies addressing quality of life in relation to the route of reconstruction after esophagectomy. Gawad and colleagues performed a study in which patients were randomly allocated to either retrosternal or prevertebral positioning of the gastric tube after esophagectomy.31 Patients after retrosternal positioning had a higher morbidity and mortality rate than after prevertebral positioning (mortality 14% versus 8%); furthermore, emptying of the gastric tube was significantly hampered in the group that underwent retrosternal positioning, as measured scintigraphically by means of a liquid tracer. It has to be noted, however, that in the retrosternal group a higher number of transthoracic procedures were performed. Patients’ quality of life was measured using the EORTC QLQ-C30. In this small study, no significant differences between both routes of reconstruction were found.

Minimally Invasive Esophagectomy Since the report by Cuschieri and coworkers in 1992 on thoracoscopic esophagectomy,33 this technique has been used in a number of centers as an alternative to open esophagectomy. Only a few studies on minimally invasive esophagectomy have assessed aspects of quality of life through validated questionnaires. To assess quality of life after laparoscopic and thoracoscopic esophagectomy with gastric tube reconstruction the MOS SF-36 was used in a study comprising 222 patients.34 Results showed conservation of quality of life postoperatively, with scores comparable to age-matched controls.

QUALITY OF LIFE DURING PALLIATIVE TREATMENT OF ESOPHAGEAL CANCER A number of studies have assessed quality of life in patients with incurable esophageal cancer. Various treatment modalities have been investigated, including laser therapy, plastic or metal stent placement, chemotherapy, chemoradiotherapy, brachytherapy, or a combination of these treatments (Table 63-3) (Homs et al, 2005).21 In a study by Dallal and associates comparing laser and metal stent treatment, no improvement was found after either treatment, with short-term results even worsening 1 month after stent placement.35 Another study showed improvement of dysphagia measured by the RSCL after treatment with a combination of radiotherapy and plastic tube placement compared with baseline values.36 In other studies, the effect of different chemotherapeutic regimens was assessed by means of the EORTC QLQ-C30.37,38 Most scale scores remained stable during follow-up, although some minor changes were found between different chemotherapeutic protocols. A recent randomized controlled trial by Homs and associates comparing metal stent placement and single-dose brachytherapy showed improvement in both treatment strategies as measured by EORTC QLQ-C30 and dysphagia scores (Homs et al, 2004).39 There were, however, fewer dysphagia-related complaints after single-dose brachytherapy (Fig. 63-4). Scores on the EORTC QLQ-C30 questionnaire deteriorated in both groups, but more so after stent placement.

QUALITY OF LIFE DURING SURVEILLANCE FOR PATIENTS WITH BARRETT’S ESOPHAGUS Studies assessing quality-adjusted life expectancy and/or utilities for various surveillance protocols in patients with Barrett’s esophagus with or without dysplasia are listed in Table 63-4.

100 90 80 70 60 50 40 30 20 10 0

Transhiatal Transthoracic

s hs ths nths ear ears ears ars ears ek nt n y e y we mo mo mo 1 .5 y 2 y .5 y 3 5 9 1 3 6 2 Measurement Point

e in

el

s Ba

A

Transhiatal

Physical Functioning Score

Mental Health Score

Transhiatal Transthoracic

s e rs ars ars ars hs ear hs hs ek lin ea ye nt ont ont y e e ye ye y o s w 1 2 3 5 5 m m 9m . . 5 Ba 2 1 3 6 Measurement Point

5

3

s

th

on

m

6

Transhiatal Transthoracic

100 90 80 70 60 50 40 30 20 10 0

s

th

on

1

m

m

Transhiatal Transthoracic

e 5

B

s s s s r s ar ears ear ar th nth ea y on mo 1 y 5 ye 2 ye y 3 m m 9 5 1. 3 6 2. Measurement Point

ks

e we

D

s

th

on

100 90 80 70 60 50 40 30 20 10 0

Transhiatal Transthoracic

e

in

l se

F

s s s s ar ar ar ear ar ye ye ye y ye 3 5 2 5 9 1. 2. Measurement Point

s

th

on

100 90 80 70 60 50 40 30 20 10 0

lin

s r s s s s e ks ar ars ears ear th nth yea in th el wee on on ye ye y o y s 1 5 3 m m m 2 5 5 Ba 1. 6 3 9 2. Measurement Point Role Functioning Score

ek

we

e as

Pain Score

Social Functioning Score

100 90 80 70 60 50 40 30 20 10 0

E

s

e

lin

e as

B

100 90 80 70 60 50 40 30 20 10 0

669

Transthoracic

B

C

G

100 90 80 70 60 50 40 30 20 10 0

Energy Score

Health Perceptions Score

Chapter 63 Quality of Life in Esophageal Cancer Patients

Ba

5

ks

e we

3

s

m

6

s

th

th

on

m

on

9

m

1

s

s

ar

s

th

on

ye

5

1.

ye

ar

2

ye

ar

s

ar

rs

5

2.

a ye

3

ye

Measurement Point

Transhiatal Transthoracic

s s e rs hs ths nths ear ears ears ear lin ek ea nt n y se we mo mo mo 1 .5 y 2 y .5 y 3 y a 5 B 2 1 9 3 6 Measurement Point

FIGURE 63-3 Health perceptions (A), energy (B), mental health (C), physical functioning (D), social functioning (E), pain (F), and role functioning (G) measured with the MOS SF-20 during 3 years for patients randomly assigned to transhiatal esophagectomy or transthoracic esophagectomy with extended en-bloc lymphadenectomy. *, statistically significant, P = .01. (REPRINTED FROM DE BOER AG, VAN LANSCHOT JJ, VAN SANDICK JW, ET AL: QUALITY OF LIFE AFTER TRANSHIATAL COMPARED WITH EXTENDED TRANSTHORACIC RESECTION FOR ADENOCARCINOMA OF THE ESOPHAGUS. J CLIN ONCOL 22:4202-4208, 2004.)

670

Section 6 Operative Techniques

TABLE 63-3 Studies Using Validated Quality-of-Life Questionnaires in Patients With Esophageal Cancer Undergoing Palliative Treatment Study Design

No. Patients

Patient Specifics

Palliative Therapy

QOL Measurement

O’Hanlon et al36 (1995)

Prospective cohort

43

Inoperable, Radiotherapy proven esophageal cancer

Plastic tube

RSCL

Dysphagia improved; other parameters remained stable or deteriorated.

Webb et al37 (1997)

RCT

111

Inoperable, histologically proven esophageal cancer

Chemotherapy with epirubicin, cisplatin, 5-FU (n = 54) vs chemotherapy with doxorubicin, methotrexate, 5-FU (n = 57)

EORTC QLQ-C30

Global QOL scale was maintained with epirubicin but declined with doxorubicin.

Blazeby et al70 (2000)

Prospective cohort

37

Histologically proven esophageal cancer. Patients either unfit for surgery or had metastatic disease or T4 tumor

Stent (n = 30); chemoradiotherapy (n = 7)

EORTC QLQ-C30; QLQ-OES24

Most aspects of QOL measurement remained stable during follow-up.

Dallal et al35 (2001)

RCT

65

Inoperable, histologically proven esophageal cancer

Metal stent (n = 31) vs laser (n = 34)

EORTC QLQ-C30; QLQ-OES24

Dysphagia scores were not improved after both treatments. In laser group scores were stable. In stent group scores deteriorated.

Ross et al38 (2002)

RCT

313

Inoperable, histologically proven esophageal cancer

Chemotherapy with epirubicin, cisplatin, 5-FU (n = 156) vs chemotherapy with mitomycin, cisplatin, 5-FU (n = 157)

EORTC QLQ-C30

Global, physical, and emotional QOL scores maintained with epirubicin but declined with mitomycin-based chemotherapy.

Homs et al39 (2004)

RCT

209

Inoperable, histologically proven cancer of esophagus or gastroesophageal junction

Self-expanding metal stent (n = 108) vs single-dose brachytherapy (n = 101)

EORTC QLQ-C30; QLQ-OES23

Brachytherapy had better long-term relief of dysphagia and fewer complications. Brachytherapy had later onset of dysphagia relief.

Author (Year)

Outcome

EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life core questionnaire; MOS SF-36, Medical Outcomes Study Short Form-36; QLQ-OES23-24, esophageal module of the EORTC QLQ-C30; RCT, randomized controlled trial; RSCL, Rotterdam symptom check list. Adapted from Homs MY, Kuipers EJ, Siersema PD: Palliative therapy. J Surg Oncol 92:246-256, 2005.

Studies Assessing Quality-Adjusted Life Expectancy for Patients With Barrett’s Esophagus Provenzale and colleagues compared 12 different surveillance protocols in patients with Barrett’s metaplasia without evidence of dysplasia (no surveillance: esophagectomy for cancer/high-grade dysplasia versus surveillance every 1 to 5 years: esophagectomy for cancer/high-grade dysplasia).40 Utilities were based on expert estimates. Annual surveillance plus esophagectomy for high-grade dysplasia would be the treatment of first choice when only length of life is considered. Yet surveillance with endoscopy every 2 to 3 years, followed by esophagectomy in case of high-grade dysplasia provided greatest quality-adjusted life expectancy. Provenzale and colleagues performed a second study, comparing 6 sur-

veillance strategies (no surveillance and surveillance every 1 to 5 years) again in patients with Barrett’s metaplasia without evidence of dysplasia. In this study, more recent cancer risk estimates were incorporated and utilities elicited from patients with Barrett’s disease were used. Surveillance every 5 years with esophagectomy in case of high-grade dysplasia increased both length and quality of life and would be most cost effective.41

Studies Assessing Quality-Adjusted Life Expectancy for Patients With Barrett’s Esophagus and High-Grade Dysplasia Hur and coworkers calculated quality-adjusted life expectancy in patients with Barrett’s esophagus with high-grade dysplasia treated with esophagectomy, endoscopic surveil-

Chapter 63 Quality of Life in Esophageal Cancer Patients

FIGURE 63-4 Mean dysphagia scores measured using EORTC QLQC30 and QLQ OES-23 in esophageal cancer patients treated by single-dose brachytherapy or stenting. (REPRINTED

3.0 Mean dysphagia score, stent Mean dysphagia score, brachytherapy Spline function with 95% Cls, stent Spline function with 95% Cls, brachythrapy

Dysphagia score

2.5

FROM HOMS MY, STEYERBERG EW, EIJKENBOOM WM, ET AL: SINGLE-DOSE BRACHYTHERAPY VERSUS METAL STENT PLACEMENT FOR THE PALLIATION OF DYSPHAGIA FROM OESOPHAGEAL CANCER: MULTICENTRE RANDOMISED TRIAL. LANCET 364:14971504, 2004.)

2.0

1.5

1.0

0.5 0

50

100

150

200

250

300

350

400

Time (days)

lance, and photodynamic therapy.42 Utilities were based on the literature and expert estimates. Photodynamic therapy increased quality-adjusted life expectancy and was most costeffective when compared with esophagectomy or endoscopic surveillance. In a study by Shaheen and associates comparing esophagectomy and photodynamic therapy, the latter therapy also provided the longest quality-adjusted life expectancy.43 Vij and coworkers studied four different strategies (esophagectomy, endoscopic surveillance, and photodynamic therapy followed by either esophagectomy or intensive surveillance) and used utilities from the literature.44 Results showed that photodynamic therapy followed by endoscopic surveillance had the greatest quality-adjusted life expectancy.

Studies Assessing Utilities in Patients With Barrett’s Esophagus Most studies comparing esophagectomy, endoscopic surveillance, and photodynamic therapy have used utilities based on expert estimates. In 1999, Provenzale and colleagues measured the utility for “esophagectomy” in patients with Barrett’s esophagus, resulting in a median score of 0.97.41 In 2005, Hur and coworkers measured utilities for these states in patients with Barrett’s esophagus and high-grade dysplasia using VAS, which resulted in a mean score of 0.46 for “esophagectomy,” 0.79 for “surveillance,” and 0.60 for “photodynamic therapy.”45 Fisher and associates examined utilities for 16 different scenarios related to surveillance with scores varying from 0 for “esophagectomy followed by fatal postoperative complications,” to 0.80 for “endoscopic surveillance every 2 years without the need for invasive therapy.”46

CONCLUSIONS, CHALLENGES, AND FUTURE ASPECTS Conclusions Only a small number of studies assessing quality of life in esophageal cancer patients are currently available. The number of studies using validated quality-of-life questionnaires in patients treated with curative intent and in patients undergoing palliative treatment are limited. There are, however, a number of conclusions that can be drawn from these studies. In general, there is a return to baseline levels in quality-oflife measurements for long-term disease-free survivors. Moreover, in some studies, esophageal cancer patients report similar or even higher levels of quality of life than healthy individuals. This outcome might be explained by a phenomenon called “response shift.” Surgical access does not seem to have an important impact on quality of life. Although patients after transhiatal resection seem to recover faster, compared with patients undergoing transthoracic resection, scores for patients in both groups returned to baseline levels after 6 to 9 months in a randomized study (Hulscher et al, 2002).23 Although there are no randomized trials available on the type of neo-esophagus used, it can be concluded from the present data that gastric tube reconstruction is the preferred type of reconstruction. Most studies showing return to baseline quality-of-life levels have used gastric tube reconstruction as the procedure of choice. Furthermore, in a small cohort of patients with a colonic interposition, quality of life was shown to be impaired as compared with patients with a gastric tube reconstruction.32

671

672

Section 6 Operative Techniques

TABLE 63-4 Studies Assessing Quality-Adjusted Life Expectancy (QALE) and/or Utilities for Various Surveillance Protocols in Patients With Barrett’s Esophagus

Author (Year)

Study Design

Surveillance Protocols

Health States

Studies Assessing QALE for Patients With Barrett’s Esophagus Decision No surveillance: Short-term Provenzale et al40 (1994) analysis esophagectomy morbidity after (Markov for cancer/HGD endoscopy and model) Surveillance surgery every 1-5 yr: Long-term esophagectomy morbidity after for cancer/HGD esophagectomy Provenzale et al41 (1999)

Decision analysis (Markov model)

Studies Assessing QALE for Patients With Hur et al42 (2003) Decision analysis (MarkovMonte Carlo model)

No surveillance Surveillance every 1-5 yr

Short-term morbidity after endoscopy and surgery Long-term morbidity after esophagectomy

Barrett’s Esophagus and HGD PDT Endoscopy ± Esophagectomy complications, Endoscopic (post-)PDT, surveillance (post-) esophagectomy

Utility Measure

Source

Outcome

No utility measure used

Expert opinion and literature

Endoscopic surveillance every 2-3 yr provides longest QALE.

No utility measure used Time trade-off

Expert opinion and literature Patients with HGD or cancer (n = unknown)

Endoscopic surveillance every 5 yr provides longest QALE.

No utility measure used

Expert opinion and literature

PDT increases QALE by 1.8 yr relative to surveillance and by 1.65 yr relative to esophagectomy.

Shaheen et al43 (2004)

Decision analysis (Markov model)

PDT Esophagectomy Endoscopic surveillance

Post esophagectomy Endoscopic surveillance

No utility measure used VAS

Literature 55 patients with Barrett’s esophagus

PDT provides the longest QALE.

Vij et al44 (2004)

Decision analysis (Markov model)

PDT Esophagectomy Endoscopic surveillance

Perfect health, metaplasia, HGD, esophagectomy and early and late cancer

No utility measure used

Author consensus/ literature

PDT provides the longest QALE, followed by endoscopic surveillance.

VAS

Twenty patients with Barrett’s esophagus

Endoscopic surveillance has patients’ preference (70%).

VAS

Fifteen patients with Barrett’s esophagus

The median utility for individual scenarios ranges from 0 to 0.8.

Studies Assessing Utilities in Patients With Barrett’s Esophagus Hur et al45 (2005) Questionnaire PDT PDT study Esophagectomy Esophagectomy Endoscopic Endoscopic surveillance surveillance Fisher et al46 (2002)

Questionnaire study

16 outcomes of endoscopic surveillance

16 scenarios describing surveillance outcomes

HGD, high-grade dysplasia; PDT, photodynamic therapy; VAS, Visual Analogue Scale.

Only one quality-of-life study randomized the route of reconstruction after esophageal resection.31 Retrosternal reconstruction showed an impaired quality of life as compared with prevertebral reconstruction. This might be caused by a significantly higher morbidity in the retrosternal group. There are only a few studies evaluating quality of life in patients undergoing minimally invasive esophagectomy. In only one study, quality of life was assessed using a validated

questionnaire.34 Patients showed levels of quality of life comparable to that of age-matched controls. Additional studies will be necessary to further elucidate the effect of this form of esophageal surgery on quality of life. Options for palliative treatment of esophageal cancer are numerous, and results of studies assessing quality of life after palliative treatment vary. The best option for palliation of esophageal cancer is not yet known. Palliative chemoradiotherapy in combination with brachytherapy or stent place-

Chapter 63 Quality of Life in Esophageal Cancer Patients

ment might be most promising. Further studies will have to test a combination of existing treatment modalities. In three studies, a decision model was used to compare photodynamic therapy, endoscopic surveillance, and esophagectomy for Barrett’s esophagus with or without highgrade dysplasia in terms of quality-adjusted survival.42-44 Photodynamic therapy provided the highest quality-adjusted life expectancy in each of these studies, suggesting that photodynamic therapy (or other organ-preserving techniques) might be the strategy of first choice for patients with Barrett’s esophagus and high-grade dysplasia.

Challenges As shown by the results of our literature search, few studies assessing quality of life after esophageal cancer surgery are available. This might be caused by a number of challenges with which quality-of-life research in esophageal cancer patients is faced. A first challenge of longitudinal research in esophageal cancer patients is patient loss to follow-up. Because survival for esophageal cancer is poor and rarely exceeds 30% after extensive surgery (Hulscher et al, 2002),23,47,48 patient attrition does not appear to be a random event but is often related to declining health status. Yet, it is precisely at the point of disease progression or acute symptom experience that one might be most interested in assessing changes in quality of life. When patients are severely ill, relatives, friends, and/or health care providers might be employed as an alternative source of information on patients’ quality of life. It is recommended that such “proxy informants” are included from the beginning of the study, if patient loss to follow-up is anticipated. The agreement level between patient and proxy responses can be calculated, as long as the patient’s quality of life is being studied directly. The results can then be based on the proxy responses adjusted for this agreement level. Such calibrated proxy scores have been successfully used in a study among stroke survivors.49 A second challenge of quality-of-life research in esophageal cancer patients is “response shift.” Studies assessing quality of life in patients surviving esophageal cancer have found that patients report similar or even better levels of quality of life than healthy people.25,27 In other studies, cancer patients under active treatment were also found to report levels of quality of life not inferior to those of healthy individuals.50,51 The recurrent finding that cancer patients report higher levels of quality of life compared with those observed by their relatives/friends and health care providers is another source of puzzlement. When such findings are the result of changes in patients’ internal standards, values, and/or the conceptualization of quality of life over the course of the disease, they are referred to as response shift. Schwartz and Sprangers have described various procedures to detect response shift, including individualized approaches, qualitative methods, preference-based techniques, design approaches, and statistical approaches.52 Several studies in cancer patients have shown that quality of life can be measured more validly by taking response shift into account.53-59 A third challenge of quality-of-life research in general is interpreting the clinical relevance of the results. Lydick and

Epstein distinguished two approaches to establish clinical meaningfulness: distribution-based and anchor-based approaches.59 The distribution-based approach relates the results to some measure of variability. Cohen,60 for example, proposed to use standardized mean scores or effect sizes, defined as the mean change score divided by the standard deviation of stable subjects (e.g., as obtained at baseline). His guidelines to interpret effect sizes in the range of 0.2 SD units as small, 0.5 as moderate, and 0.8 as large have been widely adopted. The anchor-based approach incorporates a meaningful, external measure that is more clearly understood than quality-of-life scores. The “minimal clinically important difference” approach, for example, correlates change in quality-of-life scores over time with patients’ overall evaluations regarding the extent to which they improved, remained stable, or deteriorated.61,62 Recent research has attempted to empirically test the relationship between the distributionand anchor-based approaches. It has been shown that 0.5 effect size roughly equals the minimal clinically important difference.63 The convergence of the different methods, however, requires further validation. It is hoped that studies incorporating multiple sources of evidence of clinical meaningfulness as well as clinicians’ day-to-day use of quality-oflife measures will ultimately lead to clear interpretability of quality-of-life results.

Future Aspects Despite increasing recognition of the importance of cancer patients’ quality of life, the amount of patient-physician communication devoted to such issues is limited.64 To identify quality-of-life issues of concern to individual patients and to facilitate communication between health care providers and patients, quality-of-life questionnaires can be used in daily practice.65 Most typically, a patient is asked to complete a quality-of-life questionnaire while waiting to see his or her physician. A computer immediately processes the patient’s responses, producing a summary highlighting the most prevalent problems. In some instances, responses provided at a previous visit are also included in the overview, allowing detection of changes over time. This synopsis can then be used by the doctor and his or her patient during the subsequent consultation. Two reviews addressing the effectiveness of such interventions, conducted in noncancer health care settings, have shown that feedback to clinicians enhances the identification of psychological and, to a lesser extent, functional problems.66,67 Studies in an oncologic setting have shown that the use of quality-of-life questionnaires in daily practice is time effective and leads to an increase in the frequency with which quality-of-life issues are discussed.64,68,69 Velikova and colleagues have shown that quality-of-life assessments in clinical practice can be beneficial for some cancer patients, with improvement in their overall and emotional well-being.69 Routine quality-of-life assessments in individual patients facilitates patient-physician communication. Given that effective communication is an important part of the cancer patients’ care process, physicians should consider using quality-of-life measures in their daily practice.70

673

674

Section 6 Operative Techniques

COMMENTS AND CONTROVERSIES This third edition as opposed to the previous edition incorporates a chapter on quality of life in esophageal cancer patients, reflecting the increasing importance attributed to this issue over recent years. These concerns are in part driven by health economics, ethical reflections, perceptions of changes in lifestyle in today’s society, as well as an increasing competition between surgical and nonsurgical treatment modalities for cancer of the esophagus and gastroesophageal junction. Endoluminal therapeutic modalities such as endomucosal resection or photodynamic therapy are indeed increasingly accepted within the medical community. As shown in this chapter the qualityadjusted life expectancy is superior in patients treated, for example, with photodynamic therapy as compared with surgery. Obviously, quality-of-life considerations should not jeopardize the oncologic principles of treatment but for sure will play an increasing role in the overall approach toward high-grade dysplasia and early cancer. In this setting, quality-of-life aspects require an increasing amount of attention and time in the communication between the physician and patient. As a result of the minimally invasive videoscopic technology, a wide range of different surgical options can now be considered to solve a particular cancer problem. Besides oncologic issues and risk factors, expectations on quality of life add to the complexity of the decision-making process. Given the parallel increasing awareness from the patient’s side, a multidisciplinary, team approach toward the patient’s problem is becoming increasingly mandatory. The growing tendency toward definitive chemoradiotherapy without surgery for locally advanced cancers is another area where quality-of-life issues may challenge the traditional statement that surgery is still a cornerstone in the treatment of these cancers. The results of the Amsterdam group indicate a recovery to baseline quality of life within 6 to 9 months after surgery (and it appears that the access route [i.e., transhiatal versus transthoracic] and extent of lymphadenectomy are not likely to have a major impact in this respect). Unfortunately, at this point there are no comparative results on quality of life after definitive

chemoradiotherapy. Obviously if such therapeutic modalities would eventually indicate similar oncologic results (albeit doubtful for the time being), quality-of-life issues will become a very important parameter. Recent data on improvement of surgical techniques and the resulting decrease in perioperative morbidity and the recovery to baseline quality after 6 to 9 months may indicate that today the risk of dropout when starting up adjuvant therapy is perhaps no longer of the same magnitude as in the past. This may stimulate a renewed interest for adjuvant regimens as compared with neoadjuvant regimens. The advantage of adjuvant regimens is that a more precise staging and thus prognostic assessment is provided by the final pathologic staging. Here, too, measurement of quality-of-life parameters may become an important guide in the decision-making algorithm. T. L.

KEY REFERENCES Blazeby JM, Conroy T, Hammerlid E, et al: Clinical and psychometric validation of an EORTC questionnaire module, the EORTC QLQOES18, to assess quality of life in patients with oesophageal cancer. Eur J Cancer 39:1384-1394, 2003. de Boer AG, van Lanschot JJ, van Sandick JW, et al: Quality of life after transhiatal compared with extended transthoracic resection for adenocarcinoma of the esophagus. J Clin Oncol 22:4202-4208, 2004. Homs MY, Kuipers EJ, Siersema PD: Palliative therapy. J Surg Oncol 92:246-256, 2005. Homs MY, Steyerberg EW, Eijkenboom WM, et al: Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: Multicentre randomised trial. Lancet 364:1497-1504, 2004. Hulscher JB, van Sandick JW, de Boer AG, et al: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1662-1669, 2002. Testa MA, Simonson DC: Assessment of quality-of-life outcomes. N Engl J Med 334:835-840, 1996.

chapter

64

PHARYNGEAL AND CRICOPHARYNGEAL DISORDERS André Duranceau Pasquale Ferraro

Key Points ■ Regardless of the definition of oropharyngeal dysphagia, the

investigation approach is systematic. of cricopharyngeal disorders directs their management. ■ Detailed technique of cricopharyngeal myotomy is essential. It is the only surgical option in these patients. ■ Results of surgical treatment are disease dependent. ■ Classification

OROPHARYNGEAL DYSPHAGIA Definition Oropharyngeal dysphagia refers to difficulties in swallowing at the pharyngoesophageal level. This high, or proximal, dysphagia causes three categories of symptoms because the oropharynx is involved in the functions of swallowing, speech, and respiration (Figs. 64-1 and 64-2): 1. Difficulty exists in propelling food or liquid from the oral cavity to the cervical esophagus. Whether the difficulty is with initiating swallows, with moving the bolus from mouth to pharynx, or with food incarceration at the cricopharyngeus level, the result is difficulty in swallowing. 2. When mechanical or functional obstruction occurs to food or liquid transit, the bolus is misdirected back toward the mouth as pharyngo-oral regurgitation or through the nasopharynx as pharyngonasal regurgitation.

3. The last category of symptoms relates to the larynx and its role in phonation and respiration. Poor coordination with hypopharyngeal stasis results in laryngeal and tracheal aspiration. Oropharyngeal dysphagia and its symptom-complex is usually related to neurologic and neuromuscular diseases. Idiopathic dysfunction of the upper esophageal sphincter (UES) is a frequent cause of oropharyngeal dysphagia. Previous treatment at the oropharyngeal level, either surgery or radiation therapy, may result in proximal dysphagia. Gastroesophageal reflux or transit abnormalities at the gastroesophageal junction may result in symptoms referred to the oropharyngeal level. The causes of oropharyngeal dysphagia are summarized in Figure 64-3 and Box 64-1. Patients with oropharyngeal dysphagia are difficult to assess. However, patients affected by these symptoms, when carefully selected, can experience great improvement after surgery on the UES. The role of surgery in managing patients with oropharyngeal symptoms is reviewed in this chapter.

Approach to the Patient Regardless of etiology, patients with oropharyngeal dysphagia must be assessed in a systematic fashion. Clinical assessment of symptoms remains the most important step in classifying the disorder. Although the assessment is subjective, it helps to obtain the patient’s previous history. FIGURE 64-1 Lateral view of pharynx and larynx. The upper esophageal sphincter and its relationship to the cricoid cartilage are shown.

Nasopharynx Oropharynx

Hypopharynx

Larynx

Hypopharynx

677

678

Section 7 Neuromuscular Disorders

FIGURE 64-2 Lateral and frontal views of the hypopharynx and larynx. The interrelation of swallowing, speech, and respiration is responsible for oropharyngeal dysphagia symptoms.

Oropharynx

Valleculae

Hypopharynx

Piriform sinuses

Box 64-1 Oropharyngeal Dysphagia: Etiology and Classification NEUROGENIC • Central

V

V VII

• Peripheral

VII IX X

IX X

Myogenic End-plate disease Muscular disease Idiopathic Dysfunction of Upper Esophageal Sphincter Isolated upper esophageal sphincter dysfunction Upper esophageal sphincter dysfunction and pharyngoesophageal diverticulum

XI XII

NEUROMUSCULAR • End-plate diseases • Muscular

IATROGENIC • Surgery • Radiotherapy

Neurogenic Central Peripheral

Iatrogenic Surgery Radiation therapy Distal Esophagus Dysfunction Gastroesophageal reflux Motor disorder Obstruction

STRUCTURAL • Idiopathic dysfunction of UES

MECHANICAL • Intraluminal • Extraluminal

Mechanical Intrinsic Extrinsic Psychogenic

GASTROESOPHAGEAL REFLUX FIGURE 64-3 Etiology of oropharyngeal dysphagia. UES, upper esophageal sphincter.

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

TABLE 64-1 Symptom Scoring Applied to Oropharyngeal Dysphagia* 1 Point

2 Points

3 Points

4 Points

I: Frequency

Occasional (less than once a month)

More often than once a month but less than once a week

More often than once a week but not as often as daily

Daily

II: Duration

Less than 6 months

More than 6 months, less than 24 months

More than 24 months, less than 60 months

More than 60 months

III: Severity

Mild, nuisance value

Moderate, spoils enjoyment of life

Marked, interferes with living normal life

Severe, terrible experience

*To calculate: add frequency to duration, multiply by severity. 1-7, mild symptoms; 8-15, moderate symptoms; 16-23, marked symptoms; 24-32, severe symptoms.

B A FIGURE 64-5 Anatomy of the pharyngoesophageal junction with contribution of the inferior constrictor to the cricopharyngeus. A, Posterior closed view. B, Posterior open view.

FIGURE 64-4 Pharyngoesophageal junction, with the imprint of the cricopharyngeus between C6 and C7.

The genealogy of transmitted disease can be clarified. For more objectivity, symptoms can be quantified as has been suggested for reflux disease.1 This method is summarized in Table 64-1. The routine use of video-esophagography to delineate anatomic and functional abnormalities of the pharyngoesophageal junction is most important (Fig. 64-4). Conventional studies are inadequate because of the rapidity of events during the early phase of swallowing. The importance of this type of radiologic assessment is emphasized by the fact that abnormal function is sometimes confined to one or two frames projected each second.2 The description of specific

muscle group abnormalities also requires the assistance of video technology.3,4 Manometric evaluation of the whole esophagus must be performed. Assessment of the esophageal body and the lower esophageal sphincter (LES) will rule out motor disorders and document the tone of the LES. Specific manometric assessment of the UES is difficult to obtain. The radial asymmetry of the sphincter requires multiple port recordings to summate the action of the sphincter5 or a circumferential pressuresensing transducer (Figs. 64-5 to 64-7).6,7 The Dent sleeve is a 6-cm perfused silicone membrane that also has the advantage of recording accurate resting pressures in the UES area.8 It can record the sphincter pressure at any level along the length of the membrane even if movement displaces the sphincter. Assessment of sphincter relaxation and coordination with pharyngeal contraction is limited in its accuracy by the upward movement of the larynx during the recording (see Fig. 64-7). Castell and associates6,7 propose to position the recording sensor above the high-pressure zone of the sphincter for that purpose. Despite the sophistication of more recent manometric recordings there is

679

Pharynx

Section 7 Neuromuscular Disorders

UES

40

40

20

20

0

0

100

100

50

50

0

0

Box 64-2 Dysphagia of Neurogenic Origin

5 sec

5 sec

A

B

FIGURE 64-6 Accurate manometric recording of the upper esophageal sphincter (UES) is difficult to obtain because of its radial asymmetry. Catheter opening in anteroposterior (A) and laterolateral (B) position. DS

mm Hg

Pharynx

40

100

UES

50

0

40

mm Hg

Central Nervous System Disease Neurologic disorders Vascular disease Cerebrovascular accident Basilar artery thrombosis Aneurysm and brain stem compression Amyotrophic lateral sclerosis and multiple sclerosis Bulbar disease Poliomyelitis Pseudobulbar palsy Progressive bulbar palsy Syringobulbia Degenerative disease Parkinson’s disease Tumors Brain stem Base of the skull Trauma Peripheral Nerve Involvement Neuropathy Alcohol Diabetes Tumor Trauma

20

0

Proximal esophagus

680

20

0

FIGURE 64-7 Normal function and coordination between the pharynx, upper esophageal sphincter (UES), and cervical esophagus. The recorded UES relaxation may be partly caused by the upward excursion of the sphincter during swallowing. DS, dry swallow.

undoubtedly an underestimation of true functional abnormalities present in patients with pharyngoesophageal function disorders. Radionuclide pharyngoesophageal transit studies are performed routinely in our assessment of patients with oropharyngeal dysphagia. These observations add quantitation to symptoms and radiologic and manometric abnormalities (Fig. 64-8). The end result of oropharyngeal dysfunction is poor emptying with solids, liquids, or both. Quantification of this end result when transit abnormalities are present should enhance objectivity, especially when any type of therapy is considered. Endoscopic assessment of the patient with oropharyngeal dysphagia must be undertaken with great care. Anatomic abnormalities must be delineated clearly before any attempt at endoscopic evaluation is made. Flexible endoscopy can be used if no distortion is present. Any resistance to passage of the instrument should lead to assessment with the patient under general anesthesia. Examination under direct vision using the laryngoscope and the short rigid esophagoscope provides detailed visualization of the larynx, pharynx, hypopharynx, and esophageal inlet. If resistance or abnormalities are present, no forceful effort should be made to pass the instrument beyond the cervical esophagus. A total assessment of the esophageal body and cardia must be obtained in patients with oropharyngeal dysphagia. If any risk is entailed in the evaluation procedures, however, therapy for the proximal condition should prevail before the investigation of the distal esophagus is completed.

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

FIGURE 64-8 Quantification of bolus retention above the upper esophageal sphincter using radionuclide scintiscan.

FIGURE 64-9 A, Pseudotumor effect of the pharyngeal wall caused by paralysis of right half of the pharynx. B, Cricopharyngeal bar and hypopharyngeal stasis seen with paralysis of the right hemipharynx.

NEUROGENIC DYSPHAGIA Almost any disease of the central nervous system can cause oropharyngeal dysphagia. Damage to the peripheral neurologic system may also result in significant symptoms. Tongue, soft palate, larynx and epiglottis, pharynx, and UES all must be exquisitely controlled with well-integrated mechanisms to achieve proper phonation and deglutition. Independent of the cause, loss of control of this integrated process may result in dysfunction with resultant dysphagia symptoms.

A general classification of the etiology of neurologic dysphagia is given in Box 64-2. Rarer conditions are not discussed.

Historical Note Reports on investigation and surgical management of neurologic dysphagia have mostly appeared since the 1960s. However, the first account of cricopharyngeal myotomy to appear in the English literature for a neurologic condition was

681

Section 7 Neuromuscular Disorders

WS DS

DS

DS DS DS DS DS DS

DS

40

20

mm Hg

Pharynx

15 cm

mm Hg

40

0 0

40

UES

20

mm Hg

20 cm

mm Hg

40

0 0

40

20

0

mm Hg

Cervical esophagus

25 cm

40 mm Hg

682

0 5 sec FIGURE 64-10 Absent coordination between pharyngeal contraction and upper esophageal sphincter (UES) relaxation. Incomplete UES relaxation. WS, wet swallow.

FIGURE 64-11 Poor relaxation and coordination of the upper esophageal sphincter (UES) with repeated attempts at swallowing. DS, dry swallow.

the report of the operation of Kaplan in 1951.9 The operation was carried out for dysphagia in a patient with bulbar poliomyelitis. Eight more cases treated by myotomy were subsequently reported by the same author. The justification for performing a myotomy in these patients came from the demonstration that even if the cricopharyngeus seemed to be functionally normal, it could “get in the way” when the patient’s pharynx was unable to mount a proper pharyngeal contraction. Further reports followed, recommending cricopharyngeal myotomy as treatment of dysphagia of neurologic origin: Bofenkamp (1958),10 Mills (1964),11 Wilkins (1964),12 and Lund (1968)13 all treated patients with cerebrovascular accidents and bulbar poliomyelitis. The low morbidity of the operation encouraged a more liberal approach, and additional reports appeared during the 1970s and the 1980s.

HISTORICAL READINGS Bofenkamp B: The surgical correction of aphagia following bulbar poliomyelitis. Arch Otolaryngol 68:165, 1958. Kaplan S: Paralysis of deglutition: A post-poliomyelitis complication treated by section of the cricopharyngeus muscle. Ann Surg 133:572, 1951. Lund SW: The cricopharyngeal sphincter: Its relationship to the relief of pharyngeal paralysis and the surgical treatment of the early pharyngeal pouch. J Laryngol Otol 82:353, 1968. Mills CP: Dysphagia in progressive bulbar palsy relieved by division of the cricopharyngeus. J Laryngol Otol 78:963, 1964. Wilkins SA: Indications for section of the cricopharyngeus muscle. Am J Surg 108:533, 1964.

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

DS

DS

DS

40 mm Hg

mm Hg

Pharynx

40

DS

Hypopharynx

DS DS

0

UES

mm Hg

40 0

0 40

mm Hg

UES

5 sec FIGURE 64-13 Achalasia of the upper esophageal sphincter (UES) recorded by sleeve manometry in a patient who suffered a cerebrovascular accident. DS, dry swallow.

0

mm Hg

Cervical esophagus

40

0

FIGURE 64-12 Achalasia of the upper esophageal sphincter (UES) in a patient who suffered a basilar artery thrombosis. DS, dry swallow.

Diagnosis Clinical Features Damage from cerebrovascular accidents may be diffuse or localized. Reduced lingual control and loss of initiation of the swallowing reflex usually cause delayed swallowing a nd reduced pharyngeal peristalsis.14 Bilateral involvement results in more severe symptoms, whereas dysphagia from lesions confined to one cerebral hemisphere occurs more rarely. When infarcts affect the control mechanisms for the nucleus ambiguus, unilateral paralysis of the pharyngeal and laryngeal musculature occurs.15 Poor closure of the larynx coupled with hypopharyngeal stasis results in aspiration (Fig. 64-9). Pain on swallowing is rare in these patients and is usually associated with inflammatory lesions or neoplasia.16 Of patients with bulbar poliomyelitis, 60% have significant oro-

pharyngeal dysphagia for more than 1 year after the initial damage. In the condition known as amyotrophic lateral sclerosis, degeneration of motor neurons in the brain, brain stem, and spinal cord occurs. Dysphagia occurs when nerves are damaged, with resulting aspiration. Weakness, atrophy, and fasciculation of the musculature lead to poor handling of the food bolus with defective swallowing. Patients with Parkinson’s disease have difficulty with the formation and preparation of the food or liquid bolus.17 Lack of UES opening with pulmonary aspiration may result when a delay in triggering the swallowing response occurs. Vagal lesions and selective trauma or malignant invasion of the recurrent laryngeal nerves can cause significant dysphagia. When it occurs, spontaneous improvement of dysphagia is usually observed within a few months after onset.

Radiology During the oral phase of swallowing, cine- and videoradiologic studies reveal the adequacy of tongue movement and propulsion, the tone of the floor of the mouth, and the adequacy of bolus formation. Some patients with more diffuse neurologic damage may keep the bolus in the mouth without any attempt at initiating swallows. Hesitancy in deglutition, tremors, poor bolus formation, and back-andforth movements of the bolus are seen in patients with Parkinson’s disease and amyotrophic lateral sclerosis. During the pharyngeal phase of swallowing, the symmetry or asymmetry of the pharyngeal wall velopharyngeal muscles and laryngeal structures can be observed. Unilateral paralysis may be the only manifestation of a cerebrovascular accident. This condition is easily misdiagnosed as a pharyngeal tumor (see Fig. 64-9). Patients with brain stem damage exhibit reduced laryngeal closure. Pooling and stasis may be observed in valleculae and pyriform sinuses, but residual barium in the hypopharynx is considered a more reliable sign of abnormal function.18

683

684

Section 7 Neuromuscular Disorders

A D

B E

C FIGURE 64-14 A-I, Technique of pharyngoesophageal myotomy for upper esophageal sphincter dysfunction after neurologic damage. See text.

F

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

Assessment of the third phase of swallowing, UES function, is properly assessed with video-radiology. Curtis and Hudson3 observed cricopharyngeal abnormalities in 77 patients, or 10.8% of their study group; 15% of these patients had dysphagia. Functional obstruction caused by poor opening of the UES against the contracting pharynx may cause pharyngo-oral or pharyngonasal regurgitation with laryngotracheal aspiration. Poor relaxation of the UES is a striking abnormality in patients with brain stem lesions, especially in patients with thrombosis of the posterior cerebellar artery or with bulbar paralysis. Delayed opening of the UES is seen in 30% of central degenerative disease patients.19 In our series of radiologic evaluations for neurologic dysphagia, 14 of 21 patients showed incomplete, absent, or delayed opening of the UES.

Motility Studies Manometric tracings recorded in oropharyngeal dysphagia of neurologic origin reveal abnormalities in resting pressure, coordination, and relaxation. Bonavina and colleagues20 reported normal pharyngeal pressures but incomplete UES relaxation and poor opening coordination of the sphincter with the pharyngeal contraction (Fig. 64-10). Ellis and Crozier21 reported UES hypertension in bulbar palsy patients after cerebrovascular accidents. Delayed relaxation and poor coordination of the UES as well as spontaneous and repetitive activity were observed in patients with amyotrophic lateral sclerosis (Fig. 64-11).22 In our interpretation of motility patterns in neurologic patients, resting pressures were within normal range. Relaxation was abnormal in 7 of 20 patients (35%), 4 of whom showed abnormality in over 70% of swallows. Only 20% of all patients showed normal coordination of sphincter opening with pharyngeal contraction. Only in patients with central neurologic disease have we recorded complete absence of relaxation (achalasia) of the UES: once in a patient with basilar artery thrombosis and once in a patient who had sustained a cerebrovascular accident (Figs. 64-12 and 64-13).

G

H

Radionuclide Studies The specific use of radionuclide studies in assessing pharyngeal and hypopharyngeal emptying in neurologic dysphagia is not implemented regularly and has not been reported frequently. Our patients were assessed with upright and supine times and activity curves, and they were compared with normal subjects. When standing, 4 of 11 patients (36%) could not clear 90% of the radioactive bolus in 2 minutes. When supine, 50% of the group was unable to clear the pharynx of 90% of its content at 2 minutes. When compared with normal subjects, neurologic patients show nearly a 90% bolus retention at 20 seconds after swallowing. Preliminary results show improved emptying after cricopharyngeal myotomy when voluntary deglutition is preserved.

I FIGURE 64-14, cont’d

Management Operation Myotomy of the pharyngoesophageal junction is the operation of choice in patients with dysfunction of the UES

685

686

Section 7 Neuromuscular Disorders

after neurologic damage. Our technique is depicted in Figure 64-14.23 The patient is placed supine with a small pillow under the shoulders. The head is in hyperextension and turned to the right. The thyroid and the cricoid cartilages are easily located, especially if the patient has a thin neck. The incision is made along the anteromedial border of the left sternomastoid muscle, covering two thirds of the distance between the ear lobe and the sternal notch (see Fig. 64-14A). The subcutaneous tissues and the platysma are divided. A branch of the cervical cutaneous nerve may be seen in the upper third of the field. It is protected, if feasible, because its division causes hypesthesia and dysesthesia in the submandibular skin (see Fig. 64-14B). The sternomastoid muscle is dissected from the underlying musculature. The omohyoid muscle and the pre-thyroid muscles are cut to expose the jugular vein, the carotid artery, and the thyroid gland (see Fig. 64-14C). The middle thyroid vein, if present, is ligated and divided. The thyroid gland, pharynx, and larynx are then retracted contralaterally, putting the deep cervical fascia under tension. The fascia is opened along the line of the incision, with care taken to identify the inferior thyroid artery immediately deep to this layer. The inferior thyroid artery is ligated as far laterally as possible where it disappears behind the carotid sheath. The recurrent laryngeal nerve, which is in the groove between the trachea and the esophagus, passes behind the branches of this inferior thyroid artery while it travels along the posterior part of the gland (see Fig. 64-14D). Figure 64-14E is a cross section of the neck as seen from below. The plane of access to the superior mediastinum and to the posterior pharyngoesophageal junction is depicted. Once the inferior thyroid artery is ligated and divided, the pharynx and esophagus are dissected free from the prevertebral fascia. The recurrent laryngeal nerve is easily palpated and visualized in this groove. It is not dissected. A 36-Fr mercury bougie is passed into the esophagus and used as a stent. Identification of the cricoid cartilage locates the pharyngoesophageal junction. The assistant retracts toward the contralateral side while pushing the right side of the junction toward the left. This procedure usually affords complete exposure of the posterior pharyngoesophageal wall. Using low-intensity diathermy, the surgeon coagulates the superficial tissues over the pharynx, cricopharyngeus, and cervical esophagus, along the course of the planned myotomy. While the first assistant maintains optimal exposure, the myotomy is begun on the esophageal muscle lateral to the midline and progresses proximally. If right-handed, the surgeon holds a dissector swab in the left hand and produces lateral traction on muscle while cutting with the scalpel in the right hand. The surgeon can maintain perfect hemostasis using diathermy. The mucosa is recognized by its bluish coloration with the submucous venous plexus that overlies it. The muscle of the cricopharyngeal area, when cut, retracts in a more pronounced fashion toward its insertion. The muscular wall of the hypopharynx is thicker. The submucous venous plexus is occasionally impressive with large tortuous veins that are easily

FIGURE 64-15 Persistent aspiration with pulmonary soilage requires laryngeal excision or exclusion. Exclusion, as illustrated here (arrows), permits eventual reconstruction if there is potential for full laryngeal activity recuperation.

opened, requiring a fine absorbable suture for transfixion proximally and distally. The completed myotomy extends approximately 6 cm across the posterior pharyngoesophageal junction (see Fig. 64-14G). The muscularis along the myotomy line is dissected free from the mucosa along the discrete areolar plane that separates both layers. The proximal and distal limits of the myotomy are cut transversely, raising a muscle flap that is thicker on the pharyngeal side and thinner at the esophageal level. Retraction of the cricopharyngeus becomes more evident at this point. This flap of muscle is resected for histologic assessment (see Fig. 64-14H). The bougie is removed from the esophageal cavity, and a nasogastric tube is passed gently toward the stomach. As the gastric tube is passed in the area of the myotomized zone, 20 to 50 mL of air is injected through the tube while the myotomy is submerged under saline. This procedure ensures the integrity of the mucosa. Two small Penrose drains are left in the mediastinum for 24 hours, one at the thoracic inlet and another behind the myotomized area (see Fig. 64-14I).

Postoperative Care The nasogastric tube is left in place, primarily to avoid the need to insert it blindly through a freshly myotomized pharyngoesophageal junction in an emergency situation. It is

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

usually removed the following morning after normal peristalsis is present. The patient is given a liquid diet, and the soft drains are removed after 24 hours. A hospital stay of 48 to 72 hours is considered reasonable after this operation. Complications specific to this operation are recurrent laryngeal nerve trauma, hematoma formation, and infection with salivary fistula. Meticulous technique should prevent all of these complications. If retropharyngeal hematoma occurs, it should be evacuated because of the prolonged resorption period in patients with poor swallowing function. When aspiration persists, with absent phonation and disappearance of all protective mechanisms, pulmonary aspiration and sepsis are to be expected. In these extreme situations, we have resorted to permanent tracheostomy with laryngeal excision or exclusion (Fig. 64-15).

TABLE 64-2 Causes of Neurologic Dysphagia: Results With Cricopharyngeal Myotomy Result* Excellent

Moderate

Poor

Cerebrovascular disease

71

20

24

10

Amyotrophic lateral sclerosis

54

25

14

10

Bulbar and pseudobulbar palsy

21

1

7

5

Miscellaneous central causes

24

6

—

3

Etiology

Results When our own observations are added to a review of the literature, more than 201 myotomies have been reported in the treatment of pharyngeal dysphagia of exclusively neurologic origin (Table 64-2). It is difficult to extract clear results from many of these reports. Consequently, numbers are incomplete and results often inconclusive. Dysphagia caused by cerebrovascular accidents may be improved significantly by myotomy, depending on damage location; lesions in the brain stem with localized damage and basilar artery thrombosis are associated with excellent results. The same is true for dysphagia from brain stem compression by tumor or aneurysm. One third of patients in this category show excellent results, a second third show moderate improvement, and the last third remain unimproved. Mortality occurs in 12% of these victims of cerebrovascular accidents, mostly from pulmonary and cardiovascular causes. Morbidity results from persistent aspirations. In a summary of our results for cricopharyngeal myotomy in neurogenic dysphagia,24,25 we found an operative mortality of 2.5% in 40 patients. Patients were significantly improved with regard to dysphagia and aspiration in 75% of cases. Patients with amyotrophic lateral sclerosis or motor neuron disease may show initial improvement; however, the complete loss of voluntary deglutition results in poor improvement over time. Loizou and associates26 and Lebo and coworkers27 reported their respective experience with 25 and 35 patients. The mortality in Loizou and associates’ experience was 20%, and Lebo and colleagues saw swallowing improvement in 50% of patients 6 months after the operation. Most of the patients with bulbar poliomyelitis and bulbar and pseudobulbar palsy showed moderate improvement after cricopharyngeal myotomy. Six of 10 patients with Parkinson’s disease showed clinical improvement immediately after myotomy. The improvement in syringomyelia and in miscellaneous central lesions is comparable. When trauma, invasion, or nerve resection resulted in oropharyngeal dysphagia, Henderson and coworkers28 and Mills29 reported excellent results with UES myotomy. All three patients treated by Akl and Blakely30 showed poor results.

No. Patients

Trauma

10

3

—

4

Peripheral nervous system dysfunction

21

7

3

—

*As discussed in the text, results from the literature are often partial, inconclusive, and difficult to clarify.

It is an error to refuse consideration of myotomy and a potential return to comfortable swallowing in patients with central and peripheral neurologic damage. Overall, cricopharyngeal myotomy for oropharyngeal dysphagia of neurologic origin gives satisfactory to excellent results in more than 75% of treated patients. The recognized prognostic factors for improvement in these patients are as follows31: ■ ■ ■ ■

Intact voluntary deglutition Adequate antepulsion and retropulsion of the tongue Normal phonation Absence of dysarthria

Appropriate selection of patients for cricopharyngeal myotomy in this patient category should improve those results.

MYOGENIC DYSPHAGIA Patients with muscular dystrophy are frequently affected with dysphagia at the oropharyngeal level. This is even more the case if they have the oculopharyngeal muscular variety of the disease. This disorder is hereditary and transmitted in an autosomal dominant fashion. It is characterized by late onset and in North America shows a high prevalence in families of French Canadian origin. A study by Brais and colleagues32 on the genetics of oculopharyngeal muscular dystrophy (OPMD) has demonstrated the locus of the OPMD gene to be on chromosome 14 in the region of the α and β cardiac myosin heavy-chain genes. This condition is now well documented in families of multiethnic origins, and it is present on five continents.32 Symptoms occur in these patients because of poor propulsive forces in the pharynx. The UES may also respond poorly, either because of a decreased stimulation response or as a result of a restrictive myopathy with diminished compliance of the pharyngoesophageal junction. This hypothesis, already well documented for the pathogenesis of pharyngoesophageal

687

688

Section 7 Neuromuscular Disorders

diverticulum, has not been substantiated for muscle disease dysphagia.

Historical Note The initial reports on cricopharyngeal myotomy as a treatment of dysphagia in patients with muscular disease appeared in the early 1960s. Peterman and colleagues (1964)33 reported the history of a French Canadian patient living in California. He had bilateral ptosis and complained of significant dysphagia, which became markedly improved by cricopharyngeal myotomy. Previous reports on this condition had focused mostly on bilateral ptosis.23 In 1966 in Montreal, using as a starting point patients of French-Canadian origin whose cases were published in the literature, a neurologist completed a genealogical study.34 This study concluded that the same two persons, Zacharie Cloutier and Xainte Dupont, who immigrated to Quebec from Perche, France, in 1634, were the progenitors of a form of muscular dystrophy that they transmitted in an autosomal dominant fashion to 11 generations of French Canadians (Fig. 64-16). Although well documented in families of French Canadian descent, oculopharyngeal muscular dystrophy has also been documented in families of other origin.23 These observations served as a basis to improve knowledge on clinical manifestations and evolution in these dystrophy patients. Blakeley and associates35 and Melgar36 were followed by Montgomery and Lynch,37 and Taillefer and Duranceau38 (Taillefer and Duranceau, 1988) who subsequently contributed their surgical experience with this disease process.

HISTORICAL READINGS Barbeau A: The syndrome of hereditary late onset ptosis and dysphagia in French Canada. In Kuhn E: Symposium uber Progressive Musker Dystrophie. Berlin, Springer-Verlag, 1966, p 102. Blakeley WR, Gerety EJ, Smith DE: Section of the cricopharyngeus muscle for dysphagia. Arch Surg 96:745, 1968. Montgomery WW, Lynch JP: Oculopharyngeal muscular dystrophy treated by inferior constrictor myotomy. Trans Am Acad Ophthalmol Otolaryngol 75:986, 1971. Peterman AF, Lillington GA, Jamplis RW: Progressive muscular dystrophy with ptosis and dysphagia. Arch Neurol 10:38, 1964. Taillefer R, Duranceau A: Manometric and radionuclide assessment of pharyngeal emptying before and after cricopharyngeal myotomy in patients with oculopharyngeal muscular dystrophy. J Thorac Cardiovasc Surg 95:868, 1988.

Diagnosis Clinical Presentation Barbeau39 observed that oculopharyngeal muscular dystrophy is usually manifested by symmetrical bilateral ptosis. Although dysphagia usually appears subsequently, it may on occasion become manifest simultaneously or even precede the ptosis. Both the ptosis and the dysphagia appear late and are slowly progressive. During the evolution of the disease, two categories of symptoms have been described in patient groups assessed before surgery on the UES: (1) those that are oropharyngeal in origin and (2) those that affect the tracheobronchial tree.31,40,41 Dysphagia located at the oropharyngeal level is present in 65% of patients seen initially with ptosis. Frequent

FIGURE 64-16 Oculopharyngeal muscular dystrophy is traceable in French-Canadian families to the same two ancestors who emigrated from France to Canada 11 generations ago. PROVINCE DE QUÉBEC

Québec 1648

Château-Richer 1672

Isle d’Orléans

Fleuve Saint-Laurent

Montmagny 1721 Cap St-Ignace 1713

Comté Montmagny

Islet 1705

St-Roch 1743

Comté l’Islet

Rivière Quelle 1714

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

food incarceration followed by pharyngo-oral regurgitation is the result of a powerless pharynx that is incapable of pushing the food bolus through the UES area. Pharyngonasal regurgitation occurs frequently and is increased by the use of liquids to facilitate the swallowing of solids. Dystrophic velopharyngeal muscles account for the poor occlusion of the nasopharynx. In these patients, the time required to eat a normal meal increases significantly, such that some will eat alone, away from their families. Moreover, social embarrassment brought on by these symptoms removes the enjoyment of eating out. Tracheobronchial symptoms result from poor control of laryngeal muscles and parallel pharyngeal weakness and hypopharyngeal stasis. Penetration in the aditus of the larynx and tracheal aspiration may occur occasionally initially and may be present at every meal during late evolution. Repetitive aspiration leads to bronchorrhea. During the day these patients may frequently aspirate saliva, food, and liquids. At night, pooling and aspiration of salivary secretions create an abundant, thick, and viscous bronchorrheic mucus, which patients have to expectorate. As long as adequate muscular strength and cough reflexes are retained, tracheobronchial toilet is maintained. Aspiration pneumonia eventually supervenes in 25% of patients during late evolution. Voice changes are present in most symptomatic patients, secondary to disease affecting tensors of the vocal cords. Dystrophy of the scapular and lower limb muscles causes weakness and gait problems in 20% of all patients affected by this condition.

FIGURE 64-17 Pseudotumor effect by a tightly closed pharyngoesophageal junction in a patient with dystrophy.

Radiology Cineradiographic findings in patients with dystrophy show impaired clearance of the radiopaque material from the pharynx. The initiation of the swallow and the voluntary phase of swallowing are usually normal. Bender42 reported puddling of contrast material and tracheal aspiration in 5 of 17 patients. In a report on 16 severely symptomatic patients assessed before cricopharyngeal myotomy, Duranceau and associates40,41 reported weak or absent pharyngeal contraction in 14 of the patients. Pooling in the hypopharynx is seen in all patients, and pharyngonasal regurgitation was documented in 3 of the 16 patients. When assessing the UES, the radiologist suggested a smaller luminal diameter on opening, with a relaxation occurring incompletely or late in 12 patients. A cricopharyngeal bar is described in 12 patients (see Fig. 644). The radiologic appearance had a pseudotumor effect in 2 patients (Fig. 64-17). Tracheal aspiration was documented in more than 50% of the group (Fig. 64-18).

Motility Studies Motor function of the pharynx and proximal esophageal sphincter in muscle disease patients has been reported in a number of studies. All these reports have to be analyzed with consideration of the known difficulties in recording function of the pharyngoesophageal junction. In our initial report,40 pharyngoesophageal function showed a pharyngeal contraction that was significantly weaker and

FIGURE 64-18 Tracheal aspiration in a dystrophic patient. Twentyfive percent of such patients may suffer from aspiration pneumonia in the late evolution of the disease.

longer than in controls. Efforts at swallowing resulted in repetitive weak pharyngeal contractions (Figs. 64-19 and 6420). The UES showed normal resting and contracting pressures (Fig. 64-21). Time to relaxation to a cervical esophageal resting pressure and coordination did not vary significantly from the normal. These observations are in contrast to the findings at radiology, which show significant dysfunction at the UES level. A more definitive observation was possible when Castell and colleagues43 used a motility catheter with three solidstate transducers spaced at 3-cm intervals, the distal trans-

689

690

Section 7 Neuromuscular Disorders

DS

DS DS 40

20

20

0

DS

DS 40

Pharynx

40

DS

20

0

A

0

B

FIGURE 64-19 Manometry. A, Normal pharynx. B, Repetitive efforts at swallowing in patient with dystrophy has resulted in powerless pharyngeal contractions. DS, dry swallow. 200 DS

DS UES

DS

Pharynx

40

20

100

0

0 40 5 sec FIGURE 64-20 Weak, long, and repetitive contractions seen in oculopharyngeal muscular dystrophy. DS, dry swallow.

ducer being a circumferential sphincter transducer. Eleven patients with dystrophy were compared with 14 healthy controls. Abnormalities in the dystrophy group were characterized by low pharyngeal pressures and correspondingly low pharyngeal contractions. Prolonged pharyngeal contractions and associated incoordination between pharyngeal and UES relaxation were documented. Abnormal UES relaxation was found in 4 of 11 patients, with 3 showing increased residual pressures and all 4 showing an abnormal duration of relaxation. Patients with severe symptoms had a markedly abnormal manometric profile, whereas patients with mild symptoms showed a normal manometric profile. Interestingly, esophageal body dysfunction was documented as well. Four patients showed nontransmitted contractions in the proximal esophagus, whereas 9 patients in this group revealed simultaneous contractions in 20% to 100% of all swallows in the distal esophagus. The LES was considered abnormal in 9 patients, showing incomplete relaxation in 33% to 100% of the swallows and being hypertensive in one case. From these observations, abnormal transport in the esophagus may well exist even if the disease is considered to affect the striated muscle predominantly.

20

0

5 sec FIGURE 64-21 Despite the weak pressure signal from the pharynx, the upper esophageal sphincter (UES) shows appropriate relaxation. DS, dry swallow.

Radionuclide Emptying Studies Pharyngoesophageal emptying studies have been obtained in dystrophy patients to assess pooling and emptying before and after myotomy of the pharyngoesophageal junction.38 The weakness of the pharynx in these patients results in poor pharyngeal transit. On average, only 20% of the liquid tracer is cleared within 1 second of voluntary swallowing. Significant retention occurs in valleculae and piriform sinuses (see Fig. 64-8). After cricopharyngeal myotomy, significant improve-

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

14 cm mm Hg 19 cm mm Hg 24 cm mm Hg

Esophagus

UES

Pharynx

DS

DS

DS

20

20

10

10

0

0

100

40

50

20

0

0

40

40

20

20

0

0

ment in clearance at 1 second, in both the upright and the supine positions, is recorded. This finding correlates well with the substantial symptomatic improvement. Emptying studies are noninvasive. They can be used with a bolus of variable consistency. Liquid, soft food, or solid boluses can help quantitate the capacity of the pharynx to accomplish effectively the initial phase of deglutition.

Management Operation Cricopharyngeal myotomy for muscle disorders is identical to the operation described in the section on neurogenic dysphagia (see Fig. 64-14).

Results No medical treatment has been shown to be of any use in helping dysphagia in patients with muscular dystrophy. However, to conclude that no proven rationale exists for surgical intervention in patients with swallowing difficulties from any form of muscular dystrophy is overly pessimistic. Cricopharyngeal myotomy decreases significantly both the resting pressure and the opening time of the UES (Figs. 6422 and 64-23) and improves pharyngoesophageal transit (Figs. 64-24 and 64-25). Since the initial report by Peterman and associates (1964),33 a number of authors have reported the results of a cricopharyngeal myotomy for dysphagia in dystrophy patients. The results in 42 patients reported in a 1988 review are summarized in Table 64-3. There was one death in this series, from a gastrointestinal hemorrhage. Excellent results were reported

FIGURE 64-22 Effects of cricopharyngeal myotomy on the upper esophageal sphincter (UES) before (left) and after (right) surgery. DS, dry swallow.

12 sec

UES resting pressure (mm Hg)

12 sec

DS

100 80 60 40 20 0 Before myotomy

P < .002

After myotomy

FIGURE 64-23 Resting pressures of the upper esophageal sphincter (UES) are reduced significantly in oculopharyngeal muscular dystrophy. The opening phase of the UES is reduced in a similar way.

in 75% of the group. We have reported that 8 of 11 of our initial patients have shown excellent symptomatic improvement in early follow-up.40 Sustained relief for 2 to 4 years has been reported by Montgomery and Lynch.37 Peterman and associates33 observed a valuable improvement during the initial year after the myotomy. However, new aspiration episodes occurred when hoarseness appeared as a symptom. A repeated myotomy at this point did not improve the aspiration episodes.

691

692

Section 7 Neuromuscular Disorders

TABLE 64-3 Myogenic Dysphagia: Results With Cricopharyngeal Myotomy

Author (Year)

No. Patients Result

Peterman et al36 (1964)

1

Melgar34 (1968)

1

Considerable improvement

Blakeley et al35 (1968)

2

Excellent

Weitzner (1969)

1

Poor, died of gastrointestinal hemorrhage

Leonard (1970)

1

Complete relief

Montgomery and Lynch37 (1971)

8

7 excellent, 1 poor

Nanson (1974)

2

Marked improvement

30

Akl and Blakeley

7 marked relief, 2 satisfactory

1

Spectacular improvement

Hurwitz (1975)

2

Unspecified

Mitchell (1975)

1

Excellent

Dayal (1976)

1

Excellent

1

Excellent

11

8 excellent, 3 moderate improvement

Bender

(1976) 40

Duranceau et al

FIGURE 64-25 Enlarged pharyngoesophageal opening after myotomy.

(1974) 9

Desaulty (1975)

42

FIGURE 64-24 Constricted pharyngoesophageal junction before operation.

Excellent for 1 year, poor after appearance of hoarseness

(1978)

Adapted from Duranceau A, Lafontaine ER, Taillefer JR, Jamieson GG: Oropharyngeal dysphagia and operations on the upper esophageal sphincter. Surg Annu 19:317, 1987.

In a more recent report concentrating on the morbidity of the operation, our results were summarized for 89 operated patients.44 Inadvertent mucosal opening occurred in 6 patients and was repaired with fine absorbable suture without subsequent infection or fistula. One severe infection of the floor of the mouth occurred. Systemic complications were more frequent, with pulmonary infection from aspiration being the most common. Three patients went on to develop an acute respiratory distress syndrome and died of this complication. Cardiac problems, mostly arrhythmias, occurred in 6 patients, urinary retention occurred in 3 patients, and metabolic abnormalities were noted in 2. The 75% excellent results reported in the literature is a constant observation at early follow-up. In our long-term assessment, symptoms reappear mostly in association with new manifestations of muscular disease in other muscle groups. Voice changes and upper and lower limb muscle weakness are witness to the progression of the disease. Reappearance of oropharyngeal symptoms may also become manifest. In our experience, hoarseness and total dysphonia are ominous prognostic signs. Absent muscular activity in the larynx encourages aspiration episodes in these patients. Four of our patients underwent permanent tracheostomy with laryngeal exclusion in 2 and excision in 2. Similar improvement in symptoms is reported for patients with dermatomyositis and polymyositis treated by cricopha-

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

ryngeal myotomy. In these patients, the classification of their condition and the differential diagnosis from other myopathies may be difficult. Analysis of the muscle flap resected at the time of cricopharyngeal myotomy provides an objective diagnosis. In all reported cases of myositis, moderate to excellent results are obtained even after progression of the underlying disease.

IDIOPATHIC DYSFUNCTION OF THE UPPER ESOPHAGEAL SPHINCTER Cricopharyngeal Dysfunction Without Diverticulum Occasionally, no neurologic condition and no muscular pathology are present to explain oropharyngeal dysphagia accompanying dysfunction of the UES. The dysphagia is then classified as idiopathic or structural, suggesting primary dysfunction of the UES (Fig. 64-26). In the absence of a diverticulum, prominence of the cricopharyngeus muscle with failure of relaxation has led to the confusing term achalasia of the upper sphincter. This condition was seen by Belsey45 as an intrinsic

abnormality of the cricopharyngeus manifesting itself “as recurrent attacks of obstruction aggravated by generalized nervous tension.” Such suggestion of a neuropsychogenic cause for this condition has never been substantiated. However, it remains an attractive hypothesis with the observation that such patients are often high-strung individuals like those with other types of primary motor dysfunction of the esophagus. Patients with idiopathic dysfunction of the UES present mainly with symptoms of dysphagia, pharyngo-oral regurgitation, and aspiration. Functional assessment of the pharynx and UES are anecdotal at most. Sutherland46 has suggested sphincteric hypertension in these patients with recognizable muscle hypertrophy at operation. A strong pharyngeal contraction should be present, and the proximal esophageal sphincter acts as a poorly relaxing functional obstruction. Whether such a hypothesis will be confirmed with true functional abnormalities of the sphincter or with abnormalities secondary to a restrictive myopathy with decreased compliance of the cricopharyngeus remains to be demonstrated. If true, development of a pharyngoesophageal diverticulum might be anticipated as a further step in the evolution of this condition. Results after cricopharyngeal myotomy for idiopathic dysfunction of the UES, without any diverticulum present, have been reported for more than 80 patients (Table 64-4). Seven

TABLE 64-4 Idiopathic Dysfunction of the Upper Esophageal Sphincter: Results With Cricopharyngeal Myotomy Author (Year)

No. of Patients Result

Sutherland46 (1962)

8

7 excellent, 1 moderate

Bingham (1963)

1

Excellent

Belsey45 (1966)

32

Excellent

Parrish (1968)

1

Good

36

Melgar

FIGURE 64-26 Idiopathic dysfunction of the upper esophageal sphincter causing tracheal aspiration.

(1968)

1

Improved

Leonard (1970)

1

Excellent

Calcaterra et al (1975)

3

Excellent

Desaulty (1975)

2

Poor (fistula and stricture)

Chodosh (1975)

1

Excellent

Mitchell (1975)

1

Excellent

Hiebert (1976)

6

6 of 15 patients: 13 excellent, 2 improved

West (1977)

7

6 excellent, 1 good

Cruse (1979)

6

Unspecified

Orringer (1980)

7

6 excellent, 1 poor

Gagiz (1983)

4

3 excellent

Gay (1984)

1

Good

Adapted from Duranceau A, Lafontaine ER, Taillefer JR, Jamieson GG: Oropharyngeal dysphagia and operations on the upper esophageal sphincter. Surg Annu 19:317, 1987

693

694

Section 7 Neuromuscular Disorders

FIGURE 64-27 The pharyngoesophageal diverticulum is a midline protrusion above the upper esophageal sphincter.

of eight treated patients have shown excellent results, and morbidity is minimal. The frequent association of a strong psychological overlay in these patients warrants the use of objective quantification of abnormalities before proceeding with cricopharyngeal myotomy. The correlation of symptoms with radiologic dysfunction, manometric abnormalities, and poor pharyngeal clearance favors a good prognosis after myotomy.

Pharyngoesophageal (Zenker’s) Diverticulum Historical Note Among conditions that cause oropharyngeal dysphagia and related symptoms, a pharyngoesophageal (Zenker’s) diverticulum has the longest past history. Ludlow (1769)47 published the first description of a pharyngoesophageal diverticulum in a patient with “obstructed deglutition.” Zenker and Von Ziemssen, more than 100 years later (1878),48 reported 22 cases with five patients of their own. They proposed that this diverticulum was the result of “pulsion” within the esophagus rather than distortion occurring by traction on the esophagus. Early attempts at treatment failed because leakage and mediastinitis followed resection of the pouch. These problems were enough to stimulate creativity among surgeons. Wheeler (1886)49 described a successful excision, and Kocher

FIGURE 64-28 The diverticulum descends in the mediastinum to lie between the spine and the posterior esophageal wall.

(1892)50 subsequently performed a diverticulectomy with primary closure. With the lack of antibiotics at a time when anastomotic leakage and acute mediastinitis remained the most important problems, Schmid (1912)51 proposed suspension of the diverticulum to obtain better emptying while reducing morbidity and mortality. Lahey and Warren (1954)52 emphasized the safety of the procedure (diverticulopexy) and the importance of freeing the diverticulum from the fibers of the cricopharyngeus muscle. They anchored the pouch mucosa to the proximal edge of the sternohyoid muscle well above the level of its junction with the esophagus. Care was taken not to transfix the diverticular wall with sutures to avoid leak and contamination. Cigarette drains were packed in the mediastinum to wall off any eventual infection from the subsequent resection. Re-exploration was carried out a week later to dissect free and resect the diverticulum. This approach significantly reduced morbidity and mortality. These authors recorded two deaths and a recurrence rate of 4.8%, with no incidence of cervical abscess or mediastinitis. Harrington (1945)53 and Sweet (1956)54 challenged the concept of this staged approach. This led to the single-stage diverticulum resection used by Payne and Clagett (1965).55 The concept of adding cricopharyngeal myotomy in treating the pharyngoesophageal diverticulum appeared in 1958 with the work of Harrison.56 After that report, Jamieson and col-

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

FIGURE 64-29 Minute diverticulum in a patient with intermittent dysphagia.

leagues57 considered the cricopharyngeus to be the number one problem and the diverticulum to be the complication of the dysfunction. Others continued to view the diverticulum itself as the main problem, maintaining diverticulectomy as the main line of treatment. An increasing number of surgeons now treat the dysfunction by myotomy and the diverticulum by either suspension or resection. HISTORICAL READINGS Jamieson GG, Cook IJ, Show D: The pathogenesis of Zenker’s diverticulum and its normalization by cricopharyngeal myotomy [Abstract]. ISDE World Congress Aug:242, 1992. Lahey FH, Warren KW: Esophageal diverticula. Surg Gynecol Obstet 98:1, 1954. Ludlow A: A case of obstructed deglutition from a preternatural dilatation of a bag formed in the pharynx: Observations and inquiries. Soc Physicians (Lond) 3:85, 1769. Sweet RH: Excision of diverticulum of the pharyngo-esophageal junction and lower esophagus by means of the one stage procedure. Ann Surg 143:433, 1956.

Diagnosis Clinical Presentation Symptoms of a pharyngoesophageal diverticulum may vary with the stage of development and range from a lump sensation at the oropharyngeal level with swallowing to complete esophageal obstruction. Duranceau and Jamieson58 reported a series of 120 patients treated over a 32-year period, between 1950 and 1982. The mean age was 62.9 years. Forty-eight percent of the patients were symptomatic for an average of

FIGURE 64-30 Appearance of diverticulum 10 years later in same patient as in Figure 64-29. The diverticulum has increased in size with progression of oropharyngeal symptoms.

just under 2 years. Dysphagia and food regurgitation were present in all patients regardless of the size of the diverticulum. Oropharyngeal dysphagia (98%), fresh food regurgitation (85%), episodes of aspiration on swallowing (61%), cervical bruit or noise on swallowing (26%), halitosis (25%), respiratory complications (17%), and voice changes (13%) were the other symptoms recorded. Thirty-six percent of all patients reported losing weight. In contrast, Lerut and coworkers59 reviewed 95 patients of their own and 390 patients from 15 different European centers. Even with the smallest form of diverticula, they observed that all patients had oropharyngeal dysphagia symptoms. Of their patients, 66% presented with severe pulmonary infections and 39 of the 95 patients had significant cachexia, suggesting a later presentation stage. In a collected series, Postlethwait60 reported that 90% of the patient population was older than 40 years of age, no patient was younger than 30, and the highest incidence was seen between 60 and 70 years of age.

Radiology On radiologic evaluation, the pharyngoesophageal diverticulum is seen as a midline protrusion at the level of the posterior hypopharyngeal wall, just above the cricopharyngeus muscle (Figs. 64-27 and 64-28). In our patient group, the diverticulum was less than 1 cm in diameter in 4% of patients, 1 to 2 cm in 20% of patients, and larger than 2 cm in 76% of the patient population. In 22% of the patients, the diverticulum protruded toward the left; in 10%, it was positioned more toward the right side of the neck.

695

Section 7 Neuromuscular Disorders

DS

Pharynx mm Hg

40

20

0

40 FIGURE 64-31 Bilateral diverticula at the pharyngoesophageal junction.

The incidence of asymptomatic diverticula varies from 0.11% to 2%.61,62 Small diverticula may be transient: they have been reported in 4% to 5% of the population. It is not clear whether these transient diverticula develop into permanent pouches. Once the diverticulum is present, however, it progresses in size over time (Figs. 64-29 to 64-31). Associated hiatal hernias have been described, with an incidence ranging from 22%63 to 90%.64 No causative relationship has been established between reflux disease and the formation of a pharyngoesophageal diverticulum.

Motility Studies It is mostly from cineradiographic studies that the presumed pathogenesis of pharyngoesophageal diverticulum formation has been proposed. Holmgren61 observed the appearance of small diverticula with significant impressions of the cricopharyngeus on the hypopharynx. This finding was interpreted later as a lack of relaxation of the cricopharyngeus in advance of the oncoming pharyngeal contractions. These radiologic observations were never clearly recorded on motility studies. Function of the UES was reported by various authors to be either abnormal or normal. Kodicek and Creamer65 and Pedersen and associates66 reported normal function. Hunt and coworkers67 observed a hypertensive UES, whereas Ellis and associates,21,63 Duranceau and colleagues,68 and Knuff and associates69 found low resting pressures in the sphincter. Coordination abnormalities of the sphincter with the oncoming pharyngeal contraction were suggested by Ellis63 and Duranceau (Fig. 64-32).68 Cook and colleagues70,71 and Jamieson and associates,72 using sophisticated manometric equipment in conjunction with videoradiology of the pharyngoesophageal junction, have clarified the pathophysiology of Zenker’s diverticulum formation. They computed the sphincter surface area, demonstrating that it is significantly restricted. When studied under the microscope, the excised cricopharyngeus muscle is

UES mm Hg

696

20

0

3 sec FIGURE 64-32 Incoordination between pharyngeal contraction and closure of the upper esophageal sphincter (UES). DS, dry swallow.

infiltrated by fibrosis and inflammation (Cook et al, 1992).73,74 This constrictive pathology, causing decreased sphincter compliance, results in elevated pharyngeal and hypopharyngeal intrabolus pressures with each deglutition (Fig. 64-33A and B). Both the radiologic abnormalities and the elevated intrabolus pressures are corrected by cricopharyngeal myotomy, followed by either resection or suspension of the diverticulum.57

Endoscopy Although rigid esophagoscopy was used in the past in the diagnosis of a pharyngoesophageal diverticulum, rigid endoscopy today would be considered dangerous and unnecessary. One of the main arguments for using endoscopy is to rule out a carcinoma in the diverticulum, a very rare finding. Reporting on endoscopic examinations in 58 patients who eventually underwent myotomy and diverticulopexy, Lerut and associates59 found no lesions in any of the patients. In this setting, the risks may well outweigh the advantages. If there is reasonable suspicion of malignancy on radiologic assessment, it is ruled out by direct laryngoscopy and by using the short rigid esophagoscope. Distal esophageal problems associated with a pharyngoesophageal diverticulum are common and may require complete endoscopic assessment. Full evaluation of the esophagus is completed only after operation on the pharyngoesophageal diverticulum, when easy transit from pharynx to esophagus has resumed.

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

80

1

mm Hg

mm Hg

Retrograde escape

3

5 mL 2

0

80

20 mL

0 0.5 sec

0.5 sec

A

B

Intrabolus pressure (mm Hg)

40 Controls Zenker’s 30

20

10

0

0

10 Bolus volume (mL)

20

C

Radionuclide Studies The use of tracers in pharyngoesophageal diverticulum patients is not optimal for anatomic evaluation of the condition. Quantification of retention and improved clearance analysis after treatment are theoretical advantages of this technique.

Management The therapy for pharyngoesophageal diverticulum is surgical, and all patients with this condition should be considered for surgery.

Cricopharyngeal Myotomy for Small Diverticula Lahey and Warren52 viewed the smallest form of pharyngoesophageal diverticulum as relatively asymptomatic. They considered that any surgical operation on these small pouches was improper. Patients were advised to await the development of a larger diverticulum. Surgeons have used cricopharyngeal myotomy alone for this condition since the late 1950s. The number of patients

FIGURE 64-33 A, Sleeve recording and measurement of intrabolus pressure in a normal patient. B, Manometric recording in a patient with Zenker’s diverticulum. Hyperpressure is noted in the hypopharynx, whereas an incomplete relaxation of the sphincter is observed radiologically; this is due to restrictive disease in the sphincter. The end result over time is probably diverticulum formation. C, Significantly greater intrabolus pressures exist in the hypopharynx of patients with Zenker’s diverticulum when compared with normal subjects. (FROM COOK IJ, GABB M, PANAGOPOULOS V, ET AL: PHARYNGEAL [ZENKER’S] DIVERTICULUM IS A DISORDER OF UPPER ESOPHAGEAL SPHINCTER OPENING. GASTROENTEROLOGY 103:1229-1235, 1992.)

undergoing myotomy has increased significantly during the past 30 years. Of all patients presenting with a diverticulum, 4% have a pouch smaller than 1 cm that is amenable to simple cricopharyngeal myotomy.58 When performing a myotomy for Zenker’s diverticulum, Lerut and associates59 left the pouch untouched when it was smaller than 2 cm. They observed no complication from this operation, and 82% of their entire group is totally asymptomatic and 95% show very good to excellent results. Payne and King75 reported that cricopharyngeal myotomy alone, without attention to the diverticulum, brought permanent control of symptoms in only 78% of patients. Ellis and associates21,63 reported two failures after this operation, both in patients with small, dependent pouches. In patients with those small or minute pouches, the myotomy must extend 2 to 3 cm over the hypopharyngeal musculature and 3 to 4 cm toward the cervical esophagus. When this procedure is done, the smallest pouches simply disappear. Whenever a visible diverticulum persists after myotomy, it is important to suspend it with enough tension to eliminate any drooping of the pouch below the neck of the sac.

697

698

Section 7 Neuromuscular Disorders

FIGURE 64-34 With a 36-Fr mercury bougie serving as an intraesophageal stent, the myotomy is started on the cervical esophagus, progresses over the cricopharyngeus, and is extended 2 to 3 cm on the hypopharynx.

Cricopharyngeal Myotomy and Diverticulum Suspension A popular option today is to treat the abnormal cricopharyngeus by myotomy and to suspend the diverticulum behind the pharynx by suturing it either to the pharyngeal musculature or to the prevertebral fascia. Initially proposed by Aubin in 193676 and first reported in the English literature by Harrison in 1958,56 this operation has gained a wider acceptance over the past 40 years, and reported results are uniformly good to excellent. The results of these reports have been summarized in a recent review (Sideris et al, 1999).77 The technique that we use is as follows (Figs. 64-34 to 64-36). The approach is similar to that described for cricopharyngeal myotomy for oropharyngeal dysphagia (see Fig. 64-14). After dissection and elevation of the diverticulum, a 36-Fr Maloney bougie is placed within the esophageal lumen. It serves as a stent, precisely locates the neck of the diverticulum, and protects the integrity of the esophageal lumen if a resection of the diverticulum is considered necessary. The myotomy is begun on the cervical esophagus (see Fig. 64-34). The cricopharyngeus is transected, and the muscularis around the neck of the diverticulum is freed. The myotomy is then extended proximally on the hypopharynx for a distance of 2 to 3 cm. Meticulous hemostasis is maintained. Once the myotomy is completed, the muscularis is freed from the mucosa over the posterior aspect of the pharyngoesophageal junction. The diverticulum is then suspended with four or five silk stitches, which anchor the lower end of the pouch to the posterior wall of the pharynx or, if small enough, to the muscular sides of the cleft created by the hypopharyngeal muscle transection (see Figs. 64-35 and 64-36). We have avoided tying the diverticulum on the prevertebral fascia after treating two infections without fistula that were attributed to contamination from the sutured pouch. If a diverticulectomy is considered necessary because of the size of the diverticulum, a linear stapler is used and the mucosa

FIGURE 64-35 The diverticulum is suspended and fixed by four or five stitches to the posterior pharyngeal wall.

transected above the neck of the diverticulum. The remaining collar is then suspended behind the pharynx as for a smaller diverticulum. Even if a diverticulectomy is performed, the myotomy is left wide open under the resection line. Wound management is comparable to that for the simple cricopharyngeal myotomy. The rationale behind this operation is to treat the cricopharyngeal abnormality. Jamieson and colleagues72 have shown that the elevated intrapharyngeal pressures that occur as a result of the restrictive myopathy in the UES are normalized by cricopharyngeal myotomy. The second argument behind the operation is to avoid opening the esophageal lumen and to prevent the complications of infections and fistula. Lerut and associates59 observed that the incidence of these complications was doubled when a resection of the diverticulum was performed without a myotomy, presuming an obstructive role for the cricopharyngeus. Myotomy with suspension of the diverticulum does not prevent the possibility of infection and fistula formation, however. In Lerut and associates’ review of 55 patients in the European community, no infection was reported but one recurrent nerve paralysis and two hematomas were noted. Orringer78 has reported one fistula and one vocal cord paralysis. We have now seen two fistulas after myotomy with or without diverticulum suspension. From one review of more than 130 esophageal myotomies combined with a diverticulum suspension, good to excellent results were obtained in 95% of all patients. The exact recurrence rate for symptomatic pouches is yet to be clarified (see Fig. 64-36).

Diverticulectomy With Cricopharyngeal Myotomy Diverticulectomy is a one-stage operation for simplified management of the pharyngoesophageal diverticulum. Sweet54 reported 77 patients without mortality, with a single fistula and with a 4.8% recurrence rate. Payne and King75 reviewed the diverticulectomy results at the Mayo Clinic in 888 patients treated between 1944 and 1978. The mortality rate was 1.2%. The most frequent complications observed were wound infection in 3% of all cases, accompanied by a fistula in 1.8% of the group. Thirty-two patients presented with a recurrence (3.6%).

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

B A

C

D

E

F

FIGURE 64-36 The up-ended diverticulum should leave no prolapse of the pouch below the neck of the sac.

Long-term follow-up of the patient after diverticulectomy, however, raises some questions. The formation of a diverticulum is a long-term process, and, as in many other esophageal problems, it is the long-term assessment of results that may clarify the underlying problems. Holinger and Schild79 reported on a patient presenting with a recurrent diverticulum 26 years after diverticulectomy. Nicholson80 followed 20 patients, and 13 showed recurrent pouches. Hansen and coworkers81 reported that 3 of 19 patients had a radiologic recurrence. The series by Bertelsen and Aasted82 showed 14 of 68 patients with a recurrence, whereas that of Einharssen83 revealed 17 of 20 cases with pouches. Despite these recurrences, symptoms did not seem as prominent as those recorded before operation. It is probably for these reasons that surgeons who initially treated the pharyngoesophageal diverticulum by removal of the sac are only now adding a myotomy to the diverticulectomy (Fig. 64-37). Payne and King75 suggested that myotomy adds little time and morbidity to diverticulectomy. These authors were especially encouraged that no leaks occurred after their use of this operation, and symptoms of anatomic recurrence were often less severe. The later documentation by Cook and colleagues70,71 and Jamieson and coworkers72 of the restrictive pathology in the cricopharyngeus now solidly justifies adding a myotomy whenever the pharyngoesophageal diverticulum is either removed or suspended. The technique may vary for closure of the resection line after diverticulectomy. Payne and associates84 have described closure with either a hand suture technique or a linear stapler. They then re-cover the muscularis of the cervical esophagus with the hypopharyngeal wall above the mucosa at the base

FIGURE 64-37 A-F, Technique of myotomy and diverticulectomy proposed by the Mayo group. The muscularis is closed over the diverticulectomy site.

of the resected diverticulum, as for a two-layer anastomosis. Like Orringer,78 we perform the diverticulectomy by leaving the myotomy wide open below the resection line. We tack the redundant mucosa posterior to the staple line to the proximal pharyngeal wall, suspending the neck of the diverticulum to avoid dependency, and add protection to the mucosal closure. This procedure has not yet resulted in fistula formation. In summary, the results of diverticulectomy for the pharyngoesophageal diverticulum are uniformly good. Because of the known long-term recurrences and symptoms and because of the present evidence suggesting UES dysfunction, cricopharyngeal myotomy should be added to diverticulectomy.

OTHER CONDITIONS CAUSING OROPHARYNGEAL DYSPHAGIA Iatrogenic Causes Any type of surgical procedure at the cervical level can result in oropharyngeal dysphagia symptoms. A good example is tracheostomy. Direct limitation to the normal laryngeal excursion is responsible for these symptoms.85 Time and rehabilitation usually alleviate the problem.

699

700

Section 7 Neuromuscular Disorders

WS

WS

WS

WS

WS

WS

11 cm

15 cm

13 cm mm Hg

Pharynx

40 20 0

20

16 cm

20 cm

UES

18 cm mm Hg

40

20

21 cm

25 cm

40 23 cm mm Hg

Prox. esophagus

0

0

A

B

5 sec

C

FIGURE 64-38 Incoordination between pharyngeal contraction and upper esophageal sphincter (UES) closure (A and B) and opening (C) after laryngectomy. WS, wet swallow. FIGURE 64-39 A and B, Incomplete relaxation of the upper esophageal sphincter (UES) after laryngectomy. WS, wet swallow.

WS

WS

WS

WS

12 cm

14 cm mm Hg

Pharynx

40 20 0

19 cm

UES

19 cm mm Hg

40 20

22 cm

40 24 cm mm Hg

Prox. esophagus

0

20 0

5 sec

A Extensive neck surgery and laryngectomy may distort innervation and muscular function at the pharyngoesophageal level (Figs. 64-38 and 64-39). A decrease in resting pressures with loss of the radial asymmetry of the sphincter has been recorded.86,87 Spastic contractions of the cricopharyngeus are

B

observed in 25% of this patient category.88 Mladick and coworkers89 emphasized that 40% of patients after laryngectomy present with symptoms of oropharyngeal dysphagia. Cricopharyngeal myotomy may help in this setting, after objective documentation of the condition.

Chapter 64 Pharyngeal and Cricopharyngeal Disorders

Gastroesophageal Reflux Belsey45 has reported “spasmodic contraction” of the cricopharyngeus in 3.5% of 829 patients treated for hiatal hernia and reflux. Henderson and colleagues90 suggested that oropharyngeal symptoms occurred in 51% of his evaluated cases. Bonavina and associates20 reported that 9% of their 103 patients with well-documented gastroesophageal reflux had dysphagia referred at the cervical level. The evidence that favors interaction between UES dysfunction and reflux disease is speculative at best. Oropharyngeal dysphagia, asthma, and chest pain of undetermined origin represent three categories of symptoms that require, in our opinion, unequivocal proof of association with reflux episodes (by 24-hour pH monitoring), of mucosal damage (by endoscopy and biopsies), and of the physiologic dysfunction present with reflux disease (by careful motility studies), before concluding that they are related to reflux. Oropharyngeal dysphagia should be investigated and treated as such. Any association with reflux disease should also be investigated on its own. The indications for treatment in both conditions should be considered separately and independently.

Summary At this writing, medication and dilation have shown no proven benefit in managing permanent dysfunction of the cricopharyngeus. Removing the resting pressure effects of the UES in these conditions should provide significant clinical benefit. Diminished resistance to bolus transit is probably the mechanism by which this improvement occurs (Pera et al, 1997).91 Selection of patients remains the first step toward successful surgery in the surgical management of oropharyngeal dysphagia. Intact voluntary deglutition, normal movements of phonation and deglutition musculature, and correlation with radiologic and manometric abnormalities constitute the most objective prognostic criteria for improvement.

COMMENTS AND CONTROVERSIES Because patients with disorders affecting the pharynx and cricopharyngeus rarely seek or require surgical intervention, many surgeons are inexperienced and unequipped to deal with these problems.

Even if an esophageal surgeon is not planning to treat these patients it is critical that he or she have an excellent understanding of the physiology and pathophysiology of this area. Adequate oropharyngeal function is necessary if distal disease is to be effectively managed by surgery. Drs. Duranceau and Ferraro have provided an excellent and systematic approach to problems of the pharynx and cricopharyngeus. The division of pharyngeal and cricopharyngeal disorders into neurologic, muscular, iatrogenic, and idiopathic allows the clinical scenarios to be appreciated. Unfortunately, the early phases of swallowing are difficult to study and investigative techniques are limited. Both manometry and endoscopy in this area are tricky to perform and may be problematic in evaluation and interpretation. Perhaps these tests are most important in assessing the esophagus distal to these problems. Radionuclide studies of the pharynx and cricopharyngeus are infrequently performed at most institutions and therefore of questionable value. This leaves the videoesophagogram; its importance in pharyngeal assessment cannot be overemphasized. Regrettably, the only surgical option available is destructive—the cricopharyngeal myotomy. For surgery to be successful proximal function must be preserved. As outlined by the authors, the patient must have intact voluntary glutition, adequate function of the tongue, normal phonation, and no dysarthria. Successful surgical outcome begins with careful patient selection. T. W. R.

KEY REFERENCES Cook IJ, Blumbergs P, Cash K, et al: Structural abnormalities of the cricopharyngeus muscle in patients with pharyngeal (Zenker’s) diverticulum. J Gastroenterol Hepatol 7:556-562, 1992. Cook IJ, Kahrilas PJ: AGA Technical review on management of oropharyngeal dysphagia. Gastroenterology 116:455-478, 1999. Pera M, Yamada A, Hiebert CA, Duranceau A: Sleeve recording of upper esophageal sphincter resting pressures during cricopharyngeal myotomy. Ann Surg 225:229, 1997. Sideris L, Chen LQ, Ferraro P, Duranceau A: The treatment of Zenker’s diverticula: A review. Semin Thorac Cardiovasc Surg 11:337, 1999. Sivarao DV, Goyal RJ: Functional anatomy and physiology of the upper esophageal sphincter. Am J Med 108:27s-37s, 2000. Taillefer R, Duranceau A: Manometric and radionuclide assessment of pharyngeal emptying before and after cricopharyngeal myotomy in patients with oculopharyngeal muscular dystrophy. J Thorac Cardiovasc Surg 95:868, 1988.

701

chapter

65

ESOPHAGEAL DIVERTICULA Toni E. M. R. Lerut James D. Luketich Costas Bizekis

Key Points ■ Esophageal diverticula may be classified by presumed pathophys-

■ ■ ■ ■ ■

iology (traction versus pulsion), type (true versus false), or esophageal location. Zenker’s diverticulum is seen most often in the elderly, and other esophageal pathologic processes are common. Association between gastroesophageal reflux disease and Zenker’s diverticulum is well known but may not be a cause-and-effect. Diverticula of the esophageal body are infrequent and are found most often in an epiphrenic location. Principle of treatment is relief of distal obstruction by myotomy. The diverticulum then must be excised or suspended. Treatment may be by “classic” open surgery or by endoscopic or minimally invasive techniques.

Diverticula of the esophagus can be located at any level. Generally they are classified as either traction or pulsion diverticula. Traction diverticula are true diverticula caused by a mediastinal inflammatory process (e.g., tuberculosis). They are rare, often asymptomatic, and not associated with any motility disorders. Specific treatment is usually not necessary. Pulsion diverticula are false diverticula, because only mucosa and submucosa protrude. It is now accepted that they are the expression of an underlying motility disorder. Pulsion diverticula are seen at the level of pharyngoesophageal junction (Zenker’s diverticulum) and in the middle and distal (epiphrenic) portions of the esophagus. The clinical presentation and the treatment of these pulsion diverticula are reviewed here.

ZENKER’S DIVERTICULUM Pharyngoesophageal diverticulum was described for the first time as a pathologic entity by Ludlow in 1679.1 However, it was Zenker who gave his name to this condition through his publication in 1877 in which he reported a series of 27 patients.2 Already at that time Zenker presumed that the pouch was the consequence of “forces within the lumen acting against a restriction,” a hypothesis that is close to the modern understanding of the pathogenesis and remarkable because both endoscopy and radiography had yet to be invented. However, the mechanistic compression theory as a cause of symptoms would prevail until far into the 20th century. This would influence the therapeutic strategy because the primary treatment would be diverticulectomy. During the last decade of the 20th century, thanks to the 702

new developments in imaging, endoscopy, manometry, and manofluorography, better insights into the pathogenesis of Zenker’s diverticulum were developed, resulting in fundamental changes in the therapeutic strategy (myotomy of the cricopharyngeal muscle).

Clinical Presentation (Table 65-1) Zenker’s diverticulum is defined as a blowout of the mucosa through a so-called locus minoris resistentiae on the posterior wall at the transition zone between the hypopharynx and the esophagus (Killian’s triangle).3 The proximal and lateral borders of this zone are the horizontal cricopharyngeal muscle distally and the oblique fibers of the thyropharyngeal muscle, which is part of the constrictor pharyngeus inferior muscle. The exact cause of the development of a Zenker diverticulum remains unclear, and several hypotheses have been developed over time. However, with the significant improvements in imaging techniques, endoscopy, manometry, and manofluorography,4 the concept that Zenker’s diverticulum is to be considered as a pulsion diverticulum secondary to an underlying disturbance in the function of the cricopharyngeal muscle and a so-called proximal upper esophageal sphincter has grown. In particular, the work of Cook and coworkers (Cook et al, 1992)5 has indicated a decreased compliance (i.e., inadequate opening of the cricopharyngeal muscle) as the most important pathologic finding. This inadequate opening at the time of passage of the alimentary bolus results in an increased intrabolus pressure in the hypopharynx during swallowing, eventually resulting in the formation of a pulsion diverticulum. The manometric finding of decreased compliance of the upper esophageal sphincter may be the result of changes in both the cricopharyngeal and proximal esophageal muscle that have been demonstrated by enzymatic and immunohistochemical experiments (Lerut et al, 1992).6 Gastroesophageal reflux has been implicated by some authors because of the high prevalence of pathologic reflux in the population with Zenker’s diverticulum. The chronic reflux of gastric acid content is thought over time to cause damage to the cricopharyngeal muscle, but validation of this hypothesis is lacking.7 In the presentation of symptoms, the dysfunction of the cricopharyngeal muscle is playing a primary role (albeit that of the presence of the pouch, especially a larger one) contributing to the symptomatology. The lack of compliance by the cricopharyngeal muscle and the upper esophageal sphincter causes dysphagia (intrinsic dysphagia), which is the cardinal symptom along with choking. The distention of the pouch by the incoming bolus and the

Chapter 65 Esophageal Diverticula

TABLE 65-1 Zenker’s Diverticulum: Clinical Presentation and Symptoms: Leuven Experience (n = 319) Clinical Presentation 50% > age 70 yr 20% > age 80 yr

Mean age: 68 yr (range: 38-92 yr)

Symptoms Dysphagia Regurgitation Choking Coughing Globus sensation Weight loss Others

Mean duration: 37.4 mo 80% 58% 20% 18% 21% 23% 14%

Associated Pathology Pulmonary infection Upper gastrointestinal pathology Documented reflux Other comorbidity

37% 60% 44% 52%

cation. Nevertheless, data from the literature indicate an incidence of salivary fistula varying between 1% and 25%.8,9 Moreover, because of a bare staple line on a fragile structure such as the mucosa, there is a tendency to wait somewhat longer before starting oral feeding. This, of course, will have a clear impact on hospital stay, which in itself may increase the risk for comorbidity, especially in geriatric patients, resulting in a longer hospital stay and possibly mortality. To decrease the risk for postoperative leakage with possible fatal outcome, a technique has been developed by which the pouch after dissection is turned upside down and suspended on the prevertebral fascia of the cervical spine. This is called diverticulopexy.10 The main advantage of this method is the fact that the esophageal lumen will not be opened, allowing the patients to resume oral feeding the very same day or the day after the operation and thus resulting in a substantial decrease of hospital stay and a virtually inexistent incidence of salivary fistula.

Importance of Myotomy

accumulation of food particles in the pouch may aggravate the sensation of dysphagia (extrinsic dysphagia). Regurgitation of undigested food particles, abnormal noise during swallowing, halitosis, the rare event of a visible swelling in the neck, and ear, nose, and throat symptoms are all manifestations of Zenker’s diverticulum. Spontaneous evolution may result in life-threatening complications, in particular cachexia and/or recurrent pulmonary infection and progression into end-stage respiratory insufficiency as a result of chronic aspiration. These complications are even more life threatening because Zenker’s diverticulum is seen as a condition of the elderly, with over 50% of the patients being older than age 70 years and more than 20% older than age 80 years at the time of diagnosis. More than 50% of patients present with synchronous or metachronous complaints and/or documented pathology of the upper gastrointestinal tract. Especially, the high association between hiatal hernia and gastroesophageal reflux has to be looked for. From our own material it appeared that 44% of the patients presented with pathologic reflux on 24-hour pH study and/or with grade II esophagitis or more at endoscopy.7 These figures indicate that a full investigation of the upper gastrointestinal tract is mandatory in every patient presenting with Zenker’s diverticulum, and, if present, such associated pathology (e.g., gastroesophageal reflux) has to be treated accordingly.

Several authors noticed a recurrence of symptoms and pouch recurrence in a number of patients treated by simple diverticulectomy or diverticulopexy. Depending on the intensity of the follow-up and technical examinations applied, recurrence rate after simple resection/pexy is reported between 2.5% and 20%.8,9 It appears that development of recurrence is a slow process requiring several years before occurring. As a result, in very elderly patients symptomatic recurrence most likely will not become apparent. In our experience it appeared that after simple diverticulectomy (which was the preferred method between 1953 and 1975), over time a rising incidence of symptomatic recurrence occurred.11 As a result of the better understanding of the physiopathology, an increasing number of authors have underlined the importance of adding a myotomy of the cricopharyngeal muscle and proximal cervical striated muscle when performing either a diverticulectomy or a diverticulopexy (Figs. 65-1 and 65-2) (Belsey, 1966; Lerut et al, 1992).6,12 Although a randomized study has never been performed, today there seems to be a consensus that the myotomy is to be seen as an essential step in the treatment of Zenker’s diverticulum. In small diverticula (<2 cm) it even suffices to simply perform a myotomy to completely relieve symptoms that in themselves seem to confirm the importance of the myotomy.

Treatment

Endoscopic Techniques

Treatment is indicated for any symptomatic Zenker diverticulum. Today, a variety of techniques are available and are discussed briefly.

The concept of an endoscopic approach dates back to the beginning of the 20th century. In 1917, Moscher described the technique by which through an endoscopic approach the common wall between the esophagus and the pouch (the so-called cricopharyngeal bar) could be divided.13 Initially, the method resulted in high postoperative mortality. In 1960, Dohlman and colleagues substantially improved this technique14 by using a fixed rigid esophageal scope that allowed better visualization of the cricopharyngeal bar and the use of electrocoagulation. More recently, further refinement was obtained, replacing electrocoagulation by laser and by using

Diverticulectomy—Diverticulopexy Through a cervicotomy, preferably left sided, the diverticulum is identified and, after dissection of the pouch down to its neck, resected (diverticulectomy). The development of stapling devices that allow resection after firing staplers has resulted in a clear decrease in the incidence of postoperative salivary fistula, which is the most important surgical compli-

703

704

Section 7 Neuromuscular Disorders

A

B

FIGURE 65-1 Myotomy and diverticulopexy in Zenker’s diverticulum. A, The diverticulum is clearly visible. The forceps points toward the proximal border of the cricopharyngeal muscle. B, Appearance in same patient after performance of a longitudinal myotomy of the cricopharyngeal muscle and the proximal striated cervical muscle. C, Schema of the operation illustrating the diverticulopexy fixed to the prevertebral fascia.

C

A

B

FIGURE 65-2 A, Contrast study shows preoperative appearance of Zenker’s diverticulum. B, Appearance in same patient after myotomy and diverticulopexy. Note free passage of the contrast material. The suspended diverticulum is visible as a small line of contrast agent (arrow).

Chapter 65 Esophageal Diverticula

magnifying devices.15 The advantages of the endoscopic approach are evident: no open external approach and therefore less surgical trauma, shorter length of narcosis, and resumption of earlier feeding. The downside of the method is the fact that the cricopharyngeal bar can only be incised over a short distance because of the risk of perforation with subsequent mediastinitis. As a result, in a substantial number of patients, several sessions are required to eventually obtain complete symptomatic relief but this comes at the risk of higher morbidity. With the introduction of videoscopic surgery, a method was developed by which, through an endoscopic approach, a stapler is introduced and an esophagodiverticulostomy is performed. Besides a sufficiently long myotomy of the cricopharyngeal bar and proximal cervical esophageal muscle, the anterior wall of the pouch and the posterior wall of the cervical esophagus are stapled alongside the line of transection (Fig. 65-3).16-18 In addition to the myotomy this method also

enlarges the base of the pouch. This technique clearly is much more in alignment with the concept of a sufficiently long myotomy but without increasing the risk for salivary fistula. Negative aspects of the technique are the already documented risks of instrumental perforation and occasional leakage. Another disadvantage is that the pouch remains in its place and despite enlargement of its base a so-called culde-sac persists. This may result in an accumulation of alimentary particles at the bottom of the pouch, potentially causing regurgitation, coughing, or aspiration. Furthermore, it is evident that in a number of patients—10% to 15%—the method is not applicable (e.g., ankylosis of the jaw, prominent dental arch, or cervical kyphosis making hyperextension impossible). Finally, the procedure is difficult, if not impossible, in patients presenting with a diverticulum less than 3 cm because of the difficulty of introducing the stapler into the small pouch, resulting in an inadequate myotomy.

A

B

C

D

FIGURE 65-3 Endoscopic approach. A, Cricopharyngeal bar. The sac of the diverticulum is shown at the bottom of the photograph. The entrance of the esophagus and the nasal gastric tube in place in the esophagus are evident at the top. B, Placement of stay suture in common wall between esophagus and diverticulum. C, Stapling of the diverticulum. D, Esophagodiverticulostomy in same patient after firing the endostapler. Note the “V” shape aspect caused by the retraction of the cricopharyngeal muscle.

705

706

Section 7 Neuromuscular Disorders

Conversely, in the presence of very large diverticula (>6 cm) several staplers need to be fired, resulting in a too long transection of the dorsal cervical esophageal wall, which eventually may result in a creation of a cloaca. More recently, the technique of endoscopic approach has been further refined, allowing its application via flexible endoscopy. This opens up the perspective of treatment on an ambulatory basis.19,20

Results Leuven Experience Initially the treatment of choice consisted of a simple diverticulectomy. Between 1955 and 1975, 30 patients were treated in such a way. There was no postoperative mortality. In the long-term follow-up 7 surviving patients were studied. One patient had a symptomatic stenosis. One patient had a symptomatic recurrence 16 years after surgery.11 Between 1975 and until December 2003, surgery was performed on 289 patients. Postoperative mortality was 0%. Overall morbidity in this series was 8.5% but gradually decreased over the years, being 5.8% in 138 patients treated during the past 10 years. In the entire series of 289 patients, 3 had fistulas (0.1%) and 3 had recurrent nerve injuries (0.1%) with temporary vocal cord paralysis (Table 65-2). Also, the mean hospital stay sharply decreased over the years from 8.3 days during the 1970s and mid 1980s to 2.6 days during the past 10 years. Typically, the day after operation a contrast study is performed; if there is no evidence of leakage, normal oral alimentation is resumed and the patient is discharged. The treatment of choice is the myotomy of the cricopharyngeal muscle and proximal cervical striated muscle combined with diverticulopexy. This type of operation has been performed in 265 patients. In 9 patients a simple myotomy was performed, the diverticulum itself being too small for a diverticulopexy. In 4 patients a myotomy was combined with a diverticulectomy because of residual impaction of barium contrast material in the diverticulum. Finally, in 11 patients a videoendoscopic esophagodiverticulostomy was performed. As to the results, over the years an extended follow-up study was performed twice. In a first analysis, 178 patients were

studied who were operated on between 1975 and 1996 and in whom a myotomy and a diverticulopexy was performed. Excellent to very good results were obtained in 90.6%, and 85% of the patients considered themselves totally asymptomatic. A fair to poor result was noticed in 3.4%. One patient had to undergo reoperation. In this patient the diagnosis of a primary muscular disorder was considered as the likely cause of recurrent symptoms. In these series a group of 28 patients operated on over more than 10 years was analyzed: 27 patients were completely asymptomatic. Between 1993 and August 2003, surgery was performed on 138 patients and results were studied by a detailed questionnaire and/or outpatient clinic follow-up. Excellent to very good results were obtained in 94% of the patients. Five patients (3.8%) had a fair result, 3 of them because of persistent symptoms of gastroesophageal reflux disease. This group of 138 patients contained 12 patients (8.7%) referred after previous endoscopic or open intervention. Redo intervention consisted 11 times in a myotomy and diverticulopexy and, in 1 patient, in a videoendoscopic esophagodiverticulostomy. Excellent to very good results were obtained in 87% of this subgroup of patients. In this series of 138 patients, 11 patients were, within the framework of a prospective study, treated by videoendoscopic esophagodiverticulostomy. There were no postoperative complications, but in the further follow-up 2 patients developed recurrence of dysphagia and choking. This appeared to be the consequence of a fibrotic tissue bar hampering the passage of the solid bolus (Fig. 65-4). A “redo” intervention was performed, again via an endoscopic approach. Both patients remained asymptomatic afterward. Because of these complications the prospective study was interrupted and the treatment of choice today remains the open approach with a myotomy and diverticulopexy because in both methods resumption of oral alimentation can be started the day after the operation and in both techniques mean hospital stay is equally short. In other words, it appears that a videoendoscopic technique had no extra advantage with respect to resumption of oral alimentation and hospital stay.

Pittsburgh Experience TABLE 65-2 Zenker’s Diverticulum: Postoperative Complications Complication

No.

Temporary phonetic symptoms

6

Infection/abscess

4

Pneumonia

3

Recurrent nerve paralysis

3

Hematoma

2

Fistula

3

Respiratory insufficiency

1

Thoracic duct leak

1

Other

3

Postoperative mortality

0

A retrospective 6-year review identified 29 patients undergoing endoscopic stapling or open surgery for Zenker’s diverticulum. Endoscopic stapling was attempted in 11 and open surgery was performed in 18. The only absolute requirement for endoscopic stapling was a diverticulum of at least 3 cm. Endoscopic surgery was performed transorally using a Weerdascope (extended laryngoscope) (Storz) to identify the septum between the esophagus and diverticulum. An Endostitch to the septum provides cephalad traction during division by a transorally placed Endo GIA stapler (U.S. Surgical, Norwalk, CT). Open surgery included myotomy alone (n = 2), with diverticulopexy (n = 12) or diverticulectomy (n = 4). Outcomes studied included dysphagia severity using a scale from 1 (no dysphagia) to 5 (severe dysphagia). The review included 20 men and 9 women. Median age was 72 years (range: 52-85). Endoscopic stapling was com-

Chapter 65 Esophageal Diverticula

A

B

FIGURE 65-4 Endoscopic approach. A, Preoperative appearance of Zenker’s diverticulum. B, Appearance in same patient postoperatively: contrast study with solid bolus indicates hampering of the passage by a fibrotic tissue indentation into the lumen (arrow).

pleted in 10 of 11 patients. One conversion was necessary because of inadequate exposure of the diverticulum. Comparison was made between the 10 successful endoscopic staplings and the 18 open surgery patients. There were no deaths and only one complication (i.e., Clostridium difficile colitis) in an open surgery patient. Mean operative time (1.6 versus 2.4 hours) and length of stay (2 versus 2.5 days) were less (P < .01) in patients having endoscopic stapling. Median follow-up was 7.5 months. Preoperative and postoperative dysphagia scores significantly improved (P < .01) for both endoscopic stapling (2.8 versus 1.1) and open surgery (2.8 versus 1.0) patients.

Literature Review Review of the literature is difficult because of poor definitions of outcome measures and incomplete reporting (e.g., seriousness of complications, definition of improvement as compared with preoperative symptoms). In addition, the definition of recurrence when using the videoendoscopic approach is lacking precision because the diverticulum remains in place. Moreover, it is often unclear whether redo surgery was incorporated as a recurrence in the results section when describing the final outcome. When studying the literature, one has also to take into consideration the date of publication, especially when studying the results of the open approach. Indeed, over the years undoubtedly progress of surgery in general and improvement of perioperative management has resulted in a substantial decrease of surgical complications, as reflected by more recent publications over the past decade. Tables 65-3 to 65-5 represent an overview of the most relevant and larger series in the more recent literature dealing with Zenker’s diverticulum (Chang et al, 2003; Peracchia et al, 1998).21-48 The results of this overview indicate the consistent progress in relation to postoperative mortality during the past 2 decades. Mortality today is indeed very low. Morbidity seems

to be similar for the different therapeutic approaches and is generally to be considered as rather minor. It appears, however, that a videoendoscopic approach results more frequently in a need for re-intervention and in a clear and higher incidence of recurrence or insufficient control of symptoms. The incidence of patients being totally asymptomatic is clearly higher when using an open approach incorporating a myotomy, as compared with the videoendoscopic approach, in particular endoscopic stapling. This is also reflected by two available comparative studies described in Table 65-5.9,48

Which Treatment? Nowadays, Zenker’s diverticulum can be treated safely with a very low postoperative mortality rate irrespective of the treatment modality. Equally irrespective to the treatment modality, oral alimentation can be started the day after (possibly the same day) surgery with a very short mean hospital stay. In fact, the hospital stay is determined by the patient’s comorbidity. This comorbidity can be serious and life threatening because Zenker’s diverticulum is indeed a condition of the elderly. As a result, the goal of the treatment of Zenker’s diverticulum is to provide a definitive solution with a single intervention for this often serious medical and social problem. Therefore, the treatment of choice is an approach and/or technique that in the long run offers an optimal guarantee for an excellent (totally asymptomatic) result. Cosmetic considerations related to scar visibility are obsolete. The scar is limited and, in fact, barely visible after complete healing. Data from the literature and in particular our own data seem to favor an open approach with a myotomy of the cricopharyngeal muscle and the proximal cervical striated muscle combined with a diverticulopexy as the technique of choice. In those occasional patients who present with contraindications for general anesthesia or open surgery an endoscopic treatment modality may be preferred. Evidently, experience and mastering of the different available

707

708

Section 7 Neuromuscular Disorders

TABLE 65-3 Open Approach Results (%) Complications Mortality Asymptomatic Partial Recurrence (%) (%) to Very Good Improvement (%)

Author (Year)

Time Period Method

n

Payne21 (1992)

1944-1978

888

Laing et al

22

D, DM, M

(1995)

1979-1988

DM

Lerut et al23 (1996)

1960-1982

D 184 DM 121 PM 55 M 26 P4

Bonafede et al24 (1997) Zbaren et al

25

M, DM, PM

2

82

NA

92.5

7.5

94

4.9

67

16.4

390

21 10 12.7 0 0

1.5

87

24

3.5

66

15

NA

77

11

6

D, DM PM, DM

140

4.2

1

>90

Leporrier et al27 (2001)

1988-1998

DM, PM

40

17.5

0

92

0.8 8

1987-2000

DM

73

4

0

99

1

Colombo-Benkmann et al29 (2003)

1985-1995

D, DM

79

15

0

76

19

Lerut (2004)

1975-2003

PM, M, MD

0

94.2

Total

289

8.5

2119

10.5

3

13

1982-1998

(2003)

3.6

78

1987-1997

Jougon et al

1.5

11

4.9 1.8 NA 7.6

Feussner and Siewert26 (1999)

28

(1999)

1976-1993

}

7.9

3.8

1.40

0 0 2.5 0.03 3.50

D, diverticulectomy; M, myotomy; NA, not announced; P, diverticulopexy.

TABLE 65-4 Endoscopic Approach Results (%)

Author (Year)

Time Period

n

Complication (%)

Mortality (%)

Asymptomatic to Very Good

Partial Improvement

Recurrence (%)

Electrocauterization With CO2 Laser Van Overbeek15 (1994) Ishioka et al19 (1995) Von Doersten and Byl30 (1997) Hashiba et al31 (1999) Lippert et al32 (2000) Nyrop et al33 (2000) Mattinger and Hormann34 (2002) Krespi et al35 (2002)

1964-1992 1982-1992 1985-1994 since 1978 1984-1996 1989-1999 1974-1998 1989-2001

545 42 40 47 60 61 52 83

6.7 4.8 25 14.9 10 13.3 13.5 4.8

1 0 0 0 0 0 1 0

90.6 92.9 92.5 96 73 70 84.6 85.5

8.6 7.1 0 4.3 21 22 15.4 11

NA 7.1

930

8.7

95 18 74 14 23 44 32 30 31 25 150 39

0 5.9 5 0 4.3 4.5 3.7 27 9.7 8 12.7 10

575

7.8

Total Endoscopic Stapler Diverticulostomy Peracchia et al36 (1998) Van Eeden et al37 (1999) Cook et al38 (2000) Philippsen et al39 (2000) Luscher and Johansen40 (2000) Sood and Newbegin41 (2000) Jaramillo et al42 (2001) Stoeckli and Schmid43 (2001) Counter et al44 (2002) Raut and Primrose45 (2002) Chang et al46 (2003) Chiari et al47 (2003) Total

1992-1996 1996-1997 1995-1999 1996-1996 1997-1998 1992-1999 1996-1999 1997-2000 1993-1997 1994-1998 1995-2001 1997-2001

0.02 0 0 0 0 0 1 0 0 0 0 0 0 0.02

10 13 7.5 7.2

92.2 53 71 57 76 70 80 96 50 48 73.3 71

7.8 35 24 21 14 24 7.4 NA 44 32 22 20

5.4 NA 8.7 NA 4.3 9

22 11.8 10.9 10.9

Chapter 65 Esophageal Diverticula

TABLE 65-5 Comparative Studies on Long-Term Results Excellent Results

Excellent to Good Results

Open

Endoscopic

Open

Endoscopic

Gutschow et al9 (2002) (1984-2002) Diverticulum <3 cm Diverticulum ≥3 cm

n = 47 85% 86%

n = 28 25% (P < .003) 56% (P < .004)

n = 84 98% 97%

n = 79 57% (P < .001) 88% (P < .04)

Zaninotto et al48 2003 (1993-2001)

n = 34 100%

n = 24 87.5% (P < .05)

techniques are of paramount importance in determining the indication, type of treatment, and overall outcome.

DIVERTICULA OF THE ESOPHAGEAL BODY Clinical Presentation Pulsion diverticula are seen in the midthoracic and distal (epiphrenic) esophagus. Dysphagia, regurgitation, and aspiration are the most common and potentially life-threatening symptoms; associated chest pain is mainly caused by the underlying disorder. Diverticula of the esophageal body comprises 10% to 15% of all esophageal diverticula. Manometric studies in patients with midesophageal diverticula frequently show the classic features of diffuse esophageal spasm or nonspecific motor disorders. Lower esophageal sphincter pressure in these cases is usually normal, although sphincter relaxation abnormalities are frequently seen.49,50 From these data it is clear that a correct diagnosis of a possible underlying motor disorder should be made before any surgical treatment is attempted. The natural history of midesophageal diverticula may lead to severe complications, such as erosions of the esophageal wall, causing hemorrhage or perforation. Fistulization into the pericardium has been described,51 and occasional neoplastic transformation has been reported.

A

B

Treatment The necessity for, and method of, treatment of esophageal diverticula depends on the presence of symptoms and the size of the diverticula. Asymptomatic diverticula, which are usually small, normally require no treatment. In general terms, treatment should be directed toward the cause of the symptoms, that is, the underlying motor disorder. Conservative treatment will usually be unsuccessful. The objective of the operative technique is the elimination of the underlying functional disorder by a long myotomy. The myotomy must be extended proximally above the level of the diverticulum, or above the highest diverticulum when multiple diverticula are present. Distally, the myotomy may or may not be extended onto the stomach, according to the manometric features of lower esophageal sphincter function.52 If the myotomy is extended onto the stomach, consideration needs to be given to the risk of subsequent gastroesophageal reflux and thus the necessity of performing a concomitant antireflux procedure (Figs. 65-5 and 65-6). Small diverticula that are unlikely to cause food retention do not usually require any further spe-

C FIGURE 65-5 Diverticulum of the esophageal body. Principles of diverticulum removal (open or video-assisted thoracoscopic surgery) include the following: A, The diverticulum is identified and grasped. B, The neck of the diverticulum is dissected and the surrounding muscle wall identified. C, A large Maloney bougie is passed through the mouth, and an endostapler is used to complete the resection.

cific treatment because they tend to regress in size after the myotomy. For larger diverticula, which are likely to result in food retention, treatment also must be directed to the diverticulum itself. The choice of treatment lies between diverticulo-

709

710

Section 7 Neuromuscular Disorders

A 1-5 cm

10-15 cm

B FIGURE 65-7 Placement of thoracic ports for video-assisted thoracic surgery.

C FIGURE 65-6 Diverticulum of the esophageal body. A-C, Muscle closure over the resection site and contralateral myotomy. A partial Belsey Mark IV fundoplication was performed.

pexy or diverticulectomy. The introduction of stapling devices has greatly facilitated diverticulectomy, substantially decreasing the risk of suture line leaks. As a result of this, large diverticula or diverticula with a very narrow communication between the sac and esophageal lumen are indications for resection of the diverticulum.53 In the latter circumstances, diverticulopexy would result in inadequate drainage of the diverticulum. An additional argument in favor of diverticulectomy is the possible risk, albeit small, of malignant change within the diverticulum due to chronic stasis. Epiphrenic diverticula comprise approximately 20% of all esophageal body diverticula.53 They are frequently alluded to as separate pathologic entities from other pulsion diverticula. There is, however, sufficient evidence to show that the same underlying mechanisms as in midthoracic pulsion diverticula are present. Hypertensive lower esophageal sphincter and increased tone within the esophagus create a high-pressure area above the sphincter, resulting in outpouching of the mucosa through what is thought to be a weak area of muscle.54 Epiphrenic diverticula are often seen in association with acha-

lasia as well as with diffuse esophageal spasm. The natural history, complications, and principles of treatment are, therefore, the same as for midesophageal diverticula, and a concomitant nonobstructing partial fundoplication is therefore advised. The importance of performing myotomy is well illustrated by a study, performed at the Mayo Clinic by Allen and Clagett,55 in which two series of patients were compared. In a first series of 21 patients, only a diverticulectomy was performed. Five patients suffered from suture line leakage, and 4 had a documented recurrence of the diverticulum. In a subsequent series, myotomy was added to the diverticulectomy in 10 patients. No leakage was observed. At the site of the resected diverticulum the breach in the muscle is closed to protect the suture line.

Minimally Invasive Management of Diverticula The use of video-assisted thoracic surgery (VATS) for resection of a diverticulum of the esophageal body was reported in 1996 by Stuart and associates.56 Later, Saw and coworkers57 described the VATS resection combined with a myotomy and partial fundoplication. The access for VATS treatment depends on the location of the diverticula. The approach is left sided for distal diverticula and right sided for more proximal diverticula. In these cases division of the azygos vein may be necessary using an endostapler (Fig. 65-7). A diverticulum is usually easy to identify and is grasped by an endoscopic Babcock retractor or an Endograsp. With upward traction the sac can be freed from surrounding structures circumferentially. At the level of the neck, the surrounding muscle fibers are gently pushed away to free the entire base of the neck. The diverticulum can be removed

Chapter 65 Esophageal Diverticula

TABLE 65-6 Diverticula of the Esophageal Body: Morphologic Characteristics No. Localization Distal third—epiphrenic Middle third Multiple diverticula

A

Associated hiatal hernia and/or reflux Gastric prolapse in diverticulum with strangulation

B FIGURE 65-8 Principles of VATS treatment of esophageal diverticula. A, Diverticulum is identified and grasped. A Maloney bougie or endoscope is passed endoluminally. B, resection of the diverticulum is done with the endostapler. Closure of the myotomy is done above the resected diverticulum and contralateral myotomy of the esophageal body.

with either a standard linear stapler introduced through a widened intercostal port or with a linear endostapler. Use of a linear endostapler requires the introduction of the instrument through the lowest posterior thoracic port in such a way that the stapler is parallel to the neck of the diverticulum. This maneuver can be cumbersome and difficult to perform. When the neck of the diverticulum is small, the application of one 35-mm stapler suffices. If the diverticulum has a broad base, two or more applications or the use of a 60-mm endostapler is needed. To avoid narrowing of the esophageal lumen, it is advisable to introduce either an esophagoscope or a 50-Fr Maloney bougie into the esophagus before the diverticulum is stapled. After the diverticulum is resected, the surgeon begins the myotomy by marking the area of the muscle to be divided with electrocautery. The longitudinal fibers are incised in an area at least 90 degrees away from the diverticular staple line. The underlying circular muscle layer is incised with the electrocautery hook. Great care is taken to lift the fibers during coagulation to avoid injury to the mucosa. The myotomy is extended up to the aortic arch, with great care to preserve the vagal nerves and its branches. Usually, an oblique vagal branch connects the right and left vagus nerve. This branch is elevated off the muscle to facilitate the myotomy. The muscle layer is dissected off the underlying mucosa in the submucosal plane for about half the surface of the esophagus to prevent reconstitution of the muscle layer by healing of the myotomy incision (Fig. 65-8). The muscle breach over the resection site is closed. Rosati and colleagues58 described the technique of diverticulectomy, myotomy, and fundoplication through laparoscopy as an alternative to treat epiphrenic diverticula. The myotomy is continued caudally to or across the gastroesophageal junction according to the manometric findings. The myotomy is taken cephalad to a level proximal to the neck of the diverticulum. After an adequate myotomy, the mucosa should bulge fully between the cut edges of the

13 11 5 11 1

TABLE 65-7 Diverticula of Esophageal Body: Manometric Characteristics No. Diffuse spasm

8

Achalasia

3

Vigorous achalasia

1

Nutcracker

2

Aspecific motor disorder

5

Normal

2

Unknown

3

muscular wall. Insufflation of air through a nasogastric tube rules out mucosal perforation. In the event of mucosal perforation, the defect can usually be closed with a simple fine needle suture. The procedure ends with approximation of the two edges of the muscular wall to cover the diverticular staple line.

Results Leuven Experience Our own experience deals with 24 cases (Table 65-6). Diffuse esophageal spasm as an underlying motor disorder was documented in 8 patients, achalasia in 3, vigorous achalasia in 1, nutcracker esophagus in 2, and aspecific motor disorders in 5 other patients. Only 2 patients had a normal manometry. In 3, manometry was not performed or the result was unknown (Table 65-7). Five patients had multiple diverticula extending up to the level of the aortic arch. In 1 patient the stomach was prolapsing in a giant epiphrenic diverticulum causing symptoms of strangulation (Fig. 65-9). Eleven patients had an associated hiatal hernia and/or documented reflux. Surgical treatment consisted in a simple diverticulectomy in 1 patient. In all other patients a myotomy was performed. Diverticulopexy was performed in 4 patients and resection in 19. One patient presenting with a giant diverticulum showed an intense peridiverticulitis in the entire mediastinum at the time of surgery. In this patient the operation consisted of a long myotomy only. This resulted in complete symptomatic relief until the patient died of lung cancer 12 years later. In 10 patients the operation was completed with

711

712

Section 7 Neuromuscular Disorders

FIGURE 65-9 A, Preoperative barium swallow: large epiphrenic diverticulum with large filling defect caused by gastric intussusception. The patient had documented achalasia as the underlying motor disorder. B, Postoperative barium study after diverticulectomy-myotomy and Belsey Mark IV antireflux procedure. Note the staple line alongside the left side of the distal esophagus.

A

B TABLE 65-9 Diverticula of the Esophageal Body: Complications and Follow-up

TABLE 65-8 Diverticula of the Esophageal Body: Surgery Characteristics Left side

16

Right side

8

Without resection Myotomy Myotomy and pexy Myotomy and pexy and Belsey Mark IV

1 1 2

With resection Diverticulectomy Diverticulectomy + myotomy Diverticulectomy + myotomy + Belsey Mark IV + Dor VATS Attempted Completed

1 10 8 1 6 4

VATS, video-assisted thoracic surgery.

an antireflux intervention. In 9 patients this was a Belsey Mark IV; in 1, a Dor antireflux valve was created laparoscopically (Table 65-8). There was no postoperative mortality. Early and transient dysphagia was seen in 3 patients. Persistent dysphagia occurred in 2 others, with 1 requiring a re-intervention consisting of a laparoscopic myotomy and Dor antireflux valve and 1 requiring a pneumatic dilation. One patient was treated for an episode of food impaction requiring endoscopic extraction, and, finally, 1 patient suf-

Mortality

0

Major complications

0

Fistula (contained)

2

Early dysphagia

3

Persistent dysphagia 1 pneumatic dilation 1 re-intervention: myotomy + Dor

2

Food impaction

1

Vomiting–aspiration

1

Final results Excellent Very good Good Bad 1 re-intervention 1 vomiting–aspiration

14 4 2 2

fered from persistent vomiting and aspiration (Table 65-9). The final result was judged excellent in 14 patients, very good in 4, good in 2, and poor in 2 (1 requiring a re-intervention, 1 suffering from persistent vomiting and aspiration). In 6 patients a thoracoscopic ± laparoscopic approach was attempted. The intervention was completed successfully in 4 patients. In the 2 other patients the VATS approach had to be converted into an open approach, with each case due

Chapter 65 Esophageal Diverticula

to severe peridiverticular inflammatory reaction. In 2 patients a small contained leak was noticed, but otherwise there were no other complications.

Pittsburgh Experience A retrospective analysis was performed of 20 consecutive patients who underwent minimally invasive repair of midesophageal or epiphrenic diverticula between January 1997 and September 2002.59 There were 16 epiphrenic and 4 midesophageal diverticula with a median size of 7.5 cm (range: 2-11 cm). Symptoms included dysphagia (14), regurgitation (12), weight loss (8), heartburn (4), aspiration pneumonia (3), chest pain (2), and vomiting (2). The surgical approaches utilized were laparoscopy (10), VATS (7), laparoscopic/VATS (2), and laparoscopic/thoracotomy (1). The most common operation performed was a diverticulectomy, myotomy, and partial fundoplication (12). Four patients had a diverticulectomy and myotomy using a right VATS approach, and 2 patients had a VATS diverticulectomy alone. Two patients with recurrent hiatal hernias after previous antireflux surgery, and normal esophageal motility, underwent laparoscopic diverticulectomy with a Collis gastroplasty and Nissen fundoplication. Complications occurred in 9 (45%) patients (Table 65-10). There were no differences in complications between laparoscopic, VATS, or combined approaches, location of diverticulum, or associated motility disorder. There were four

TABLE 65-10 Postoperative Complications Complication

No.

Postoperative esophageal leak

4

Intraoperative perforation

1

Respiratory Pneumonia Pulmonary embolism Empyema Pneumothorax (requiring chest tube)

2 1 2 1

Cardiac Myocardial infarction Atrial fibrillation Congestive heart failure

1 1 1

Neurologic Cerebrovascular accident Seizure

1 1

Port site hernia

1

Wound seroma (requiring drainage)

1

Renal failure Total

1 19

postoperative esophageal leaks (20%), of which three were successfully managed with good outcomes. The fourth patient died 61 days after operation. Median hospital stay was 5.0 (1 to 61) days. Detailed follow-up was available in 18 patients at a median of 15 (1 to 70) months. Dysphagia scores improved significantly (P < .001) from 2.3 to 1.3 postoperatively. Symptomatic improvement was excellent in 13 (72%), good in 2 (11%), fair in 1 (6%), and poor in 2 (11%) patients. The surgical management of esophageal diverticula is challenging, even when utilizing open techniques. Minimally invasive operations for esophageal diverticula are feasible when performed in an experienced center. In our series, good to excellent results were achieved in 83% of patients. Whether a minimally invasive or open technique is chosen, these patients should be evaluated and selected carefully before repair is undertaken. We favor the inclusion of a myotomy extending onto the stomach for epiphrenic diverticula, even in those with normal manometry findings.

COMMENTS AND CONTROVERSIES Esophageal diverticula are uncommon, and our knowledge of pathophysiology is incomplete. In the Western world, diverticula are exclusively false, pulsion diverticula. Treatment is indicated only in the symptomatic patient. The physiologic principles of treatment are conceptual, but experience has taught that relief of distal obstruction is the key to successful therapy, and this must be accomplished to avoid recurrent diverticula. Management of the diverticulum has become of secondary importance. Unfortunately there are no options in therapy, and treatment is limited to destruction of esophageal sphincters and esophageal/gastric musculature by myotomy. Endoscopic stapling of Zenker’s diverticulum is an attractive approach but incorporates the diverticulum into the pharyngoesophageal wall. Minimally invasive treatment of diverticula of the esophageal body must avoid intrathoracic leakage at the sites of diverticulectomy and myotomy. T. W. R.

KEY REFERENCES Belsey R: Functional diseases of the esophagus. J Thorac Cardiovasc Surg 52:164-188, 1966. Chang C, Payyapilli R, Scher R: Endoscopic staple diverticulostomy for Zenker’s diverticulum: Review of literature and experience in 159 consecutive cases. Laryngoscope 113:957-965, 2003. Cook IJ, Gabb M, Panagopoulos V, et al: Pharyngeal (Zenker’s) diverticulum is a disorder of upper esophageal sphincter opening. Gastroenterology 103:1229-1235, 1992. Lerut T, Van Raemdonck D, Guelinckx P, et al: Zenker’s diverticulum: Is a myotomy of the cricopharyngeus useful? How long should it be? Hepatogastroenterology 39:127-131, 1992. Peracchia A, Bonavina L, Narne S, et al: Minimally invasive surgery for Zenker’s diverticulum: Analysis of results in 95 consecutive patients. Arch Surg 133:695-700, 1998.

713

chapter

66

ESOPHAGEAL MOTILITY DISORDERS Mohammed A. Qadeer Michael F. Vaezi

Key Points ■ Being a hollow muscular organ with an extensive intrinsic innerva-

tion, the esophagus has characteristic motility patterns during rest and swallowing that can be recorded on the motility studies. ■ The motility studies usually record the resting and relaxation pressures of the sphincters and the amplitude and frequency of the peristalsis in the esophageal body. ■ Disorders of esophageal motility typically manifest as dysphagia or noncardiac chest pain. However, neither the symptoms nor endoscopy or radiology is specific for various motility disorders. Therefore, these disorders are classified on the basis of motility studies.

The esophagus, a hollow muscular organ, displays characteristic wave patterns during rest and swallowing that can be recorded on the motility studies typically performed for the evaluation of noncardiac chest pain or dysphagia.1 Normally, these motility studies record the resting and relaxation pressures of the sphincters and amplitude and frequency of the peristalsis in the esophageal body (Richter, 2001; Spechler and Castell, 2001).1-3 Esophageal motility disorders are classified on the basis of differential pattern of the manometric recordings because other modalities of diagnosis, such as clinical examination or radiology, may be nonspecific. All the motility disorders can be broadly classified into primary esophageal motility disorders (PEMD) (Table 66-1) and secondary disorders (Table 66-2) depending on whether the cause of the disorder is idiopathic or secondary to a known condition. Among the PEMDs, achalasia is the most common and most studied disorder. The clinical significance of other motility disorders is still a conundrum owing to the lack of understanding of the etiology and pathogenesis of these disorders. As a result, some suggest that these motility disorders might be epiphenomena and not related to underlying disorders (Spechler and Castell, 2001).3 Nevertheless, the most described PEMDs include achalasia, diffuse esophageal spasm (DES), nutcracker esophagus (NE), hypertensive lower esophageal sphincter (HLES), and ineffective esophageal motility (IEM). In this chapter we discuss each of these conditions with special emphasis on their clinical significance.

ACHALASIA Achalasia, the most common PEMD, is characterized manometrically by aperistalsis of esophageal body and incomplete relaxation of the lower esophageal sphincter (LES). Its prevalence in the general population is low—about 10 cases per 714

100,000 individuals and with an annual incidence of 0.5 cases per 100,000.1 There is no gender predilection, but there are marked racial differences; whites are much more likely to have achalasia than nonwhites with an annual incidence of 0.6 to 1.0/100,000 compared with 0.3/100,000, respectively.4 In subjects referred for the motility studies, the prevalence of achalasia and other motility disorders is reported to be in the range of 25% to 33%.5

Historical Note Sir Thomas Willis, an English anatomist, first described a case of achalasia in 1674 and successfully treated the patient with a whalebone dilator.1 Von Mikulicz suggested in 1881 that esophageal spasm might be causal in achalasia and named this disorder as “cardiospasm.”1 However, this spasm theory was questioned by Hurst and Rake in 1915; instead, they propounded that the pathology was due to a failure of relaxation rather than spasm and, therefore, termed this disorder achalasia (from the Greek terms meaning “lack of relaxation”).1 Russel, in 1898, performed the first successful pneumatic dilation of the esophagus,1 whereas Ernst Heller performed the first successful cardiomyotomy in 1914.1

Etiology and Pathogenesis Normally, there is a dynamic balance between excitatory and inhibitory activity in the esophagus leading to well-choreographed movements of the esophageal smooth muscle and sphincter during deglutition. A successful deglutition requires active inhibition of the smooth muscles and sphincters as the esophagus is in a state of minimal contraction during the resting state. The primary abnormality observed in achalasia is the loss of inhibitory activity with relatively intact excitatory activity resulting in the failure of smooth muscle relaxation.6 The loss of inhibitory activity is further supported by immunohistochemical studies. Nerve fibers containing vasoactive intestinal peptide (VIP) as well as nitric oxide (NO)— known inhibitory neurotransmitters—were decreased or absent in patients with achalasia compared with normal controls.7-9 Because nitrinergic neurons and peptidergic neurons coexist in the myenteric plexus,10 their combined loss appears to be the primary reason for the loss of inhibitory activity in patients with achalasia. There is also evidence to suggest that an inflammatory process of unknown cause may be responsible for damaging the myenteric plexus cells in achalasia. Goldblum and coworkers (Goldblum et al, 1996),11 as well as others,12,13 observed that there was a high concentration of inflammatory cells in

Chapter 66 Esophageal Motility Disorders

TABLE 66-1 Classification of Primary Esophageal Motility Abnormalities

TABLE 66-3 Signs and Symptoms of Achalasia Sign/Symptom No. Patients Studied Mean (%) Mean Range (%)

Inadequate LES Relaxation Classic achalasia Atypical disorders of LES relaxation Uncoordinated contraction Diffuse esophageal spasm Hypercontraction Hypertensive esophagus (nutcracker esophagus) Hypertensive LES Hypocontraction Ineffective esophageal motility Hypotensive LES LES, lower esophageal sphincter. Adapted from Spechler SJ, Castell DO: Classification of esophageal motility abnormalities. Gut 49:145-151, 2001.

TABLE 66-2 Secondary Causes of Achalasia and Other Primary Esophageal Motility Disorders Malignancies (Pseudoachalasias) Involving gastroesophageal junction Adenocarcinoma (breast, gastric, prostate, and lung) Esophageal squamous cell carcinoma Lymphoma (gastric, esophageal) Esophageal lymphangioma Remote From the Gastroesophageal Junction Brainstem metastasis Hodgkin’s disease Hepatocellular carcinoma Gastric adenocarcinoma Poorly differentiated lung cancer Reticular cell sarcoma Peritoneal mesothelioma Nonmalignant Esophageal Infiltrative Disorders Amyloidosis Leiomyomatosis Eosinophilic esophagitis Sarcoidosis Sphingolipidosis Miscellaneous Chagas’ disease Congenital lower esophageal diaphragmatic web Diabetes mellitus Familial adrenal insufficiency with alacrima Multiple endocrine neoplasia (type IIB) Pancreatic pseudocysts Postvagotomy From Birgisson S, Richter JE: Achalasia: What’s new in diagnosis and treatment. Dig Dis 15(Suppl):1-27, 1997.

the early stages of the disease while later stages were characterized by collagen deposition and fibrosis.

Clinical Features Almost all the symptoms seen in patients with achalasia are nonspecific, and many of them have insidious onset with a mean duration of 4.6 years before presentation.1 Many times, several other causes such as gastroesophageal reflux disease

Dysphagia

1930

97

82-100

Regurgitation

1892

75

56-97

Weight loss

1675

58

30-9

Chest pain

1894

43

17-95

Heartburn

127

36

27-42

Cough

732

30

11-46

From Birgisson S, Richter JE: Achalasia: What’s new in diagnosis and treatment. Dig Dis 15(Suppl):1-27, 1997.

(GERD), peptic stricture, esophageal spasm, presbyesophagus, allergies, or eating disorders are considered before a correct diagnosis of achalasia is made.14 Dysphagia is the most common symptom of achalasia, occurring in up to 97% of the patients (Table 66-3). Patients have dysphagia to solids and liquids.15 Regurgitation of undigested food occurs in 75% of patients with achalasia.1 The regurgitated food is usually nonbilious and nonacidic. However, in advanced achalasia, it might become acidic owing to the fermentation of intraesophageal contents. Regurgitation might manifest as nocturnal aspiration, causing aspiration pneumonia and lung abscess.16 Chest pain is rarely a major complaint and reported in fewer than half of patients with achalasia.15 Sometimes, it mimics angina pectoris, typically in young people. Pain may suggest that the esophagus is still narrow because it disappears once the esophagus starts dilating.17 The exact cause of pain in achalasia is not known but has been attributed to the fermentation of food causing acid irritation in the esophageal wall, pill-induced esophagitis, candidal esophagitis, or impairment of belch reflex. Heartburn occurs not uncommonly in patients with achalasia, even though the LES is tight. It is characterized by a lack of postprandial nature and has a poor response to proton pump inhibitors.18 Weight loss is insidious over a period of several years. A marked decrease in weight over a short period of time should raise the suspicion of secondary achalasia (pseudoachalasia).19,20 Sometimes, the initial presentation may be with one of the several complications of achalasia (Table 66-4). About 10% of patients with achalasia have significant bronchopulmonary complications.21

Diagnosis The diagnosis of achalasia may be suspected based on patients’ presentations and formally established by radiography, manometry (Table 66-5), and, occasionally, endoscopy. Plain chest radiographs may show absent gastric bubble in the upright position in 50% of patients.22 Sometimes, an airfluid level in the posterior mediastinum, widened mediastinum, chronic parenchymal lung changes, and abscesses can also be visualized.23 A barium esophagogram (Fig. 66-1) may show dilated esophagus, aperistalsis of the body, impaired esophageal emptying in the upright position, and symmetrical tapering at the gastroesophageal junction known as a bird’s

715

716

Section 7 Neuromuscular Disorders

TABLE 66-4 Complications of Achalasia Esophageal Complications Megaesophagus Bezoar of the esophagus Distal esophageal diverticulum (epiphrenic diverticulum) Esophageal hemorrhage Esophageal foreign body Esophageal perforation Esophageal squamous cell carcinoma Esophageal varices Gastroesophageal intussusception Postmyotomy Barrett’s esophagus Extraesophageal Complications Aspiration pneumonia Bronchitis Lung abscess Small cell carcinoma Esophagocardiac fistula Esophagobronchial fistula Hiccups Neck mass (bull frog neck) Pneumopericardium Pulmonary Mycobacterium fortuitum infection Stridor with upper airway obstruction Sudden death Suppurative pericarditis Modified from Wong RKH, Maydonovitch CL: Achalasia. In Castell DO, Richter JE (ed): The Esophagus, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 1999, pp 185-404.

TABLE 66-5 Radiographic and Manometric Features of Achalasia Barium Esophagogram Essential features Bird’s beak appearance of the LES with incomplete opening Loss of primary peristalsis Delayed esophageal emptying Supportive features Dilated or sigmoid esophagus Epiphrenic diverticulum

FIGURE 66-1 Esophagographic findings in classic achalasia. Impaired esophageal emptying in the upright position, and symmetrical tapering at the gastroesophageal junction known as bird’s beak appearance.

Manometry Essential features Aperistalsis in the distal two thirds of the esophagus Abnormal LES relaxation Supportive features Hypertensive LES pressure Low-amplitude esophageal contractions LES, lower esophageal sphincter. Adapted from Vaezi MF, Richter JE: Diagnosis and management of achalasia. Am J Gastroenterol 94:3406-3412, 1999.

beak appearance.24 The rate of esophageal emptying is significantly delayed in achalasia; for example, 250 mL of barium is emptied within 1 minute in healthy persons compared with about 5 minutes in achalasia (Fig. 66-2). Other noticeable findings during barium study include the height of the barium column, which is inversely correlated to the chest pain, but directly to the regurgitation,25 and the presence of epiphrenic diverticum.26 However, tumor as a cause of pseudoachalasia is detected in only 28% (10/36) of patients (Kahrilas et al, 1987).27,28

FIGURE 66-2 Timed barium swallow in achalasia. Upright films taken at 1, 2, and 5 minutes post ingestion of 250 mL of barium show delayed emptying up to 5 minutes after ingestion.

Chapter 66 Esophageal Motility Disorders

Esophageal manometry is the gold standard for the diagnosis of achalasia. It shows aperistalsis in the smooth muscle portion of the esophagus, manifested by simultaneous contractions (mirror-image or isobaric contractions) (Fig. 66-3). The contractile pressures are typically low (10 to 40 mm Hg), and repetitive prolonged waves are frequently observed.29 Vigorous achalasia is used to describe aperistalsis with higher than normal amplitude (>40 mm Hg).30 Sometimes, pressures up to 120 mm Hg are reached and may occur in about a third of the patients with achalasia.30 Elevated resting pressure is not necessary for diagnosis since up to 40% of patients have normal resting pressure (10-45 mm Hg).30 Seventy to 80 percent of patients have absent or incomplete LES relaxation with wet swallows. The LES relaxes by more than 90% in normal individuals but barely reaches 40% in achalasia.31 Sometimes, complete relaxations can be seen, but they are artifactual.

Endoscopy is important to exclude pseudoachalasia and evaluate esophageal mucosa before any intervention. It can be performed at the time of dilation unless there is a strong suspicion for cancer. The esophagus appears dilated, atonic, and tortuous with usually a normal mucosa, although mucosa can sometimes be red and friable as well. The LES appears puckered (Fig. 66-4) with air insufflations, but an endoscope would traverse it with gentle pressure. Sometimes, a “pop” is felt, but that is rare. The most important maneuver is the retroflexed vision of the gastroesophageal junction to rule out any masses, but it could be missed in up to 35% of patients.19,20 Endoscopic ultrasonography enhances our ability to detect achalasia; the LES is about 31 mm thick in achalasia compared with 22 mm seen in normal persons.32 Furthermore, it adds an in-depth view of the esophageal wall to detect malignancies by showing thickening in the mucosal and submucosal layers and lymph nodes and is proven to be better than CT for detecting submucosal disease.33

Differential Diagnosis The differential diagnosis is quite extensive and listed in Table 66-2. The most important differential diagnosis is to separate it from pseudoachalasia, which represents 3% of all achalasia cases and 9% of all achalasia cases in persons older than age 60 years.14,19,20 Curiously, pseudoachalasia can be caused not only by direct tumoral invasion but also by the paraneoplastic syndromes and often successful treatment of the primary tumor causes regression of the signs and symptoms of achalasia. Before the advent of endoscopic ultraso-

FIGURE 66-3 Manometric findings in achalasia. Top panel shows the lack of relaxation of the lower esophageal sphincter (LES) with swallows, and the bottom four panels show the isobaric simultaneous contractions classic in patients with achalasia.

FIGURE 66-4 Endoscopic view of the lower esophageal sphincter in achalasia. Note the typical rosette appearance.

717

718

Section 7 Neuromuscular Disorders

nography, differentiation of achalasia from pseudoachalasia was sometimes difficult. In such a situation, pseudoachalasia was considered if patients had a clinical triad consisting of age older than 50 years, duration of symptoms less than a year, and weight loss of greater than 6.8 kg.19 However, this triad was later evaluated and found to have a positive predictive value of only 18%.22 Another observation was the presence of the classic barium esophagographic finding of shoulder segment, but, again, it was present in only 40% of cancer patients. Other findings seen in pseudoachalasia were a narrowed distal segment of more than 3.5 cm and esophageal dilation of less than 4 cm.34

Nonsurgical Treatment of Achalasia The primary treatment of achalasia is palliation because loss of the myenteric neurons is usually irreversible. Palliation is achieved by procedures that reduce LES pressure, which facilitates swallowing by utilizing gravity. On the other hand, peristalsis rarely, if ever, returns to normal.35 Three different therapeutic modalities are used to decrease the LES pressure: pharmacologic therapy, dilation of the LES, and surgical myotomy.

Pharmacologic Agents The most commonly used medications to decrease LES pressure are nitrates and calcium channel blockers. Nitrates increase the nitric oxide levels in smooth muscle cells leading to increased cyclic guanosine monophosphate (cGMP) levels, which cause muscle relaxation. Similarly, calcium channel blockers decrease effective calcium levels in the muscle cells, leading to relaxation. Both these medications reduce LES pressure and temporarily decrease dysphagia. To be effective, these medications should be used 15 to 45 minutes before meals. The sublingual nitrates resulted in symptom improvement in 53% to 87% of patients with achalasia,36,37 whereas calcium channel blockers improved symptoms in 53% to 77%.37,38 As far as the efficacy of these medications is concerned, it is shown that sublingual isosorbide dinitrate is more effective than sublingual nifedipine, which, in turn, is more effective than diltiazem and verapamil.39 The disadvantages of these medications are the short duration of effectiveness, lack of complete relief, and tachyphylaxis.40 Several other medications have been tried with the intention to either decrease cholinergic activity or to increase the inhibitory activity. Some of these medications include anticholinergics (cimetropium), β-adrenergic agonists (terbutaline and carbuterol), and peripheral opioid agonists (loperamide).41-44 But none of these drugs results in sustained improvement. Recently, sildenafil (Viagra), which blocks phosphodiesterase-5, a principal degrading enzyme for cGMP, was evaluated in patients with achalasia and showed significant decrease in the LES pressure starting from 15 minutes and lasting up to 1 hour.45 However, further studies are needed before this medication is used routinely. Other techniques evaluated to correct the neuronal imbalance include transcutaneous electric nerve stimulation, which stimulates nonadrenergic and noncholinergic activity and thus improves the level of VIP, which causes smooth muscle relaxation.46

Behavior pain management was shown to decrease chest pain in patients with vigorous achalasia.47 However, none of these techniques is routinely prescribed for achalasia because of the lack of well-designed studies.

Botulinum Toxin Continuing with the same theme to promote neurohumoral balance in the esophageal myenteric plexus, botulinum toxin (Botox), a potent inhibitor of acetylcholine release from nerve endings and thus a strong anticholinergic agent, initially appeared as a possible treatment of achalasia.48 However, it was observed in several studies that up to 50% of treated patients had recurrence of symptoms, possibly owing to regeneration of the affected receptors, and required reinjection.49 Patients with vigorous achalasia and those older than age 60 years may respond better and have more long-lasting response (Pasricha et al, 1996).50 Nevertheless, the response rate seemed to diminish with each additional injection. For example, only about 75% of those patients who respond to initial therapy respond to second injection,49 possibly owing to the development of antibodies to Botox, but only 20% of those patients who did not respond to initial therapy would respond to second injection.51 Another concern with Botox injections is the reported difficulty with submucosal dissection in patients undergoing subsequent myotomy, possibly owing to submucosal fibrosis.52

Pneumatic Dilation Dilation of the LES is the oldest known therapy for achalasia. Indeed, Sir Thomas Willis was the first to successfully use this technique by using a whalebone dilator.1 Even though several types of dilators are available now, the underlying principle has stayed the same—forceful stretching of the LES circular smooth muscle. Indeed, dilation is the most effective nonsurgical method of treating achalasia. Older dilators used expanding bags and balloons; balloons were filled with either water or air—Plummer hydrostatic dilators, BrowneMcHardy dilators, Hurst-Tucker dilators, and Rider-Mueller dilators. Experience with the older dilators reported a mean symptom improvement of 85% with a mean follow-up of 3 years; the overall perforation rate was 2%.53 The major disadvantage of these dilators was the compulsory use of fluoroscopy for deployment. The later models include Witzel dilator (US Endoscopy, Mentor, OH) that has the significant advantage of visualizing the site of deployment but comes only in size 4.0 cm, which is not routinely used as the first step.54 Hence, these dilators are not very popular. Over the past 2 decades, Rigiflex dilators (Boston Scientific Corp., Boston, MA) have become the most commonly used dilators.55 They are made of polyethylene polymer mounted on a flexible catheter. They are 10 cm long and come in three sizes: 3.0, 3.5, and 4.0 cm (Fig. 66-5). The technique of esophageal dilation with Rigiflex dilators is described in Table 66-6; about 74% to 93% of patients (mean, 82%) report good response with a mean follow-up of 17 months in several studies (Table 66-7) (Vaezi and Richter, 1999).56 The overall perforation rate in these studies was 2%. It was observed that the increasing balloon size resulted in

Chapter 66 Esophageal Motility Disorders

TABLE 66-6 Recommended Technique for Pneumatic Dilation Using Graded Balloons 1. Fasting for at least 12 hours before procedure 2. Esophageal lavage with large-bore tube (if needed) 3. Sedation and endoscopy in left lateral position 4. Guidewire positioned in stomach and balloon passed over the guidewire 5. Initial dilation with 3-cm diameter balloon; subsequent progression to 3.5-cm and 4-cm balloons may be required at separate sessions. 6. Accurate placement of balloon across the gastroesophageal junction fluoroscopically 7. Balloon distention to obliterate the waist, which usually requires 7-10 psi (this is the key to a successful dilation) 8. Gastrografin study followed by barium swallow to exclude esophageal perforation 9. Observation for 4 hours for chest pain and fever 10. Discharge with follow-up in 1 month Note: Before proceeding with pneumatic dilation, it is important to ensure that a thoracic surgeon is available in case of an esophageal perforation.

FIGURE 66-5 Three sizes of the Rigiflex balloon dilators used in achalasia. From left to right: 3.0 cm, 3.5 cm, and 4.0 cm.

TABLE 66-7 Cumulative Effectiveness of the Graded Pneumatic Dilators in Achalasia

% Symptom Improvement (Excellent/Good)

Follow-up (yr) Mean (Range)

Perforation

86

0.8 (0.5-1.0)

0

Study Design

Dilator (size/cm)

7

Prospective

3.0

Gelfand

24

Prospective

3.0, 4.0

Barkin

50

Prospective

3.5

90

1.3 (0.1-3.4)

0

Stark

10

Prospective

3.5

74

0.5

0

Makela

17

Retrospective

3.0, 3.5, 4.0

50, 75, 75

0.5

5.9

0

Author Cox

No. Patients

Objective Assessment (% Decrease LES Pressure)

60, 68

70, 93

0

Levine

62

Retrospective

3.0, 3.5

Kadakia

29

Prospective

3.0, 3.5, 4.0

67

62, 79, 93

4 (0.3-6.0)

Kim

14

Prospective

3.0, 3.5

39

75

0.3

88, 89

2.3 (1-4)

6.6

89

2-5

2.5

Lee

28

Prospective

3.0, 3.5, 4.0

Abid

36

Retrospective

3.5, 4.0

Wehrmann

40

Retrospective

3.0, 3.5

85, 88

0

7

42

Lambroza

27

Retrospective

3.0

67

1.8 (0.1-4.8)

0

Bhatnagar

15

Prospective

3.0, 3.5

73, 93

1.2 (0.3-3)

0

Size 3 Size 3.5 Size 4.0

125/168 = 74% 184/214 = 86% 90/100 = 90%

1.6 (0.1-6)

7/345 = 2%

Total

359

LES, lower esophageal sphincter. Adapted from Vaezi MF, Richter JE: Diagnosis and management of achalasia. Am J Gastroenterol 94:3406-3412, 1999.

719

720

Section 7 Neuromuscular Disorders

increasingly better symptomatic improvement. Katz and colleagues reported a follow-up of 72 patients for a period of 6.5 years and found 85% success rate with dilation.5 Csendes and coworkers57 followed up 54 patients for a median period of 58 months and reported overall success of 65% for pneumatic dilation. Thirty percent of patients initially dilated required subsequent myotomy. However, long-term followup of these patients suggests that the response diminishes with time. For example, the Amsterdam group58 followed 125 patients for a period of more than 30 years with the mean follow-up being 12 years and reported that the success rate was only 50% after a mean of four dilations. This suggests that patients with achalasia should regularly follow up with their physician particularly if the symptoms recur. Because dilation is not a panacea for patients with achalasia, many investigators have attempted to decipher potential predictors of success. One of the known pre-dilation predictors is age: older patients (age >40 years) seem to respond better to dilation than younger patients (Farhoomand et al, 2004).59,60 Gender also plays significant roles because young women do better than young men (Farhoomand et al, 2004).59 Long duration of symptoms is another predictor; patients with dysphagia of more than 8.2 years fare better than those with a 2.5-year duration.61 Other predictors include a moderately dilated esophagus of 5 to 8 cm.61 There are several post-dilation predictors of success as well. Most of these predictors are objective because subjective improvement of patients after dilation—even though very important—could be misleading if not accompanied by objective evaluation. Absence of objective evaluation in symptomatically improved patients leads to earlier recurrences of symptoms and sometimes to complications such as megaesophagus.62-64 On manometric examination, the reduction of LES pressure by 40% to 50% from pre-dilation values or to less than 10 mm Hg results in good outcomes for up to 2 years.60 Because it can be cumbersome to perform repeat manometry, some investigators used radionuclide emptying studies and reported significant correlation with symptoms, but its expense precludes routine use. Finally, the most widely accepted and the most useful physiologic study is the timed barium esophagogram in an upright position at 1 month.63 Normalization of the barium column was associated with symptom-free period of 3 years compared with only symptom improvement without timed barium improvement (Vaezi et al, 2002).64 This technique was also shown to have excellent reproducibility.65 For example, studying 61 esophagograms in 37 achalasia patients, Vaezi and colleagues reported significant association (r = .61; P < .001) between symptom improvement and barium emptying (Vaezi et al, 2002).64

Complications About 33% of patients may report adverse events—most of them minor.66 These include prolonged post-dilation chest pain in 15% of patients, aspiration pneumonia, hematemesis, fever, esophageal mucosal tear, esophageal hematoma, and angina.66 The most significant complication is perforation (mean perforation rate was 2.3% in several studies). Graded

dilations seemed to be better than starting dilations with 3.5 cm.67 The incidence of GERD after dilation is not known, but some series have suggested that it could be 25% to 35%.68

DIFFUSE ESOPHAGEAL SPASM Historical Note In 1889, Osgood69 described a group of six patients with attacks of sudden and intense constriction in the epigastrium and attributed them to esophageal spasm. The term diffuse esophageal spasm was first described by Moersch and Camp69 based on the appearance of the esophagus on contrast radiography. In 1958, Creamer and colleagues69 were the first to describe the manometric abnormalities of this disorder, and it was further delineated by Fleshler in 1967.69

Prevalence In the beginning, DES was considered a common disorder and the diagnosis was applied to any patient with dysphagia and chest pain. The reported range of DES is 15% to 18% in patients referred for motility studies.70 However, with the better definition of this disorder, recent studies found a prevalence of 4% to 10% in the referred population.5,71

Etiology and Pathogenesis As with achalasia, the exact etiology of this disorder is unknown, and similar mechanisms as for achalasia are considered responsible for this disorder. Some studies have identified familial clustering of this disorder.69 The primary pathology is also deemed to be identical to achalasia, which is the loss of nitrinergic neurons and/or VIPergic neurons, which secrete nitric oxide and VIP, respectively.

Clinical Features The hallmark of this disorder is recurrent chest pain and dysphagia. Indeed, the chest pain mimics the cardiac chest pain by virtue of favorable response to nitroglycerin and sometimes being postprandial, but, unlike cardiac chest pain, it is rarely exertional.71,72 Dysphagia is typically intermittent, nonprogressive, and for both solids and liquids. Often it seems to be precipitated by hot and cold liquids, rapid eating, and stress.72 Rare cases of swallow syncope have also been described. Rarely, there is a tendency for food impaction and patients may develop fear of eating73 due to spasm.

Diagnosis Radiology The most common radiographic features seen in DES include disruption of normal activity and severe tertiary activity. Tertiary activity produces a “rosary bead” appearance of esophagus (Fig. 66-6). However, the LES itself is usually normal. Radiographic findings are not very sensitive to diagnose DES. For example, in a study of 17 manometrically confirmed patients with DES,74 only 6 patients had characteristic radiologic signs of DES whereas 4 patients had completely normal radiographic findings. Remaining patients

Chapter 66 Esophageal Motility Disorders

had nonspecific radiologic signs, with one of them having a typical achalasia-like picture. Thus, it can be concluded that DES is a dynamic disease and a normal radiographic activity does not rule out diagnosis.

Manometry

FIGURE 66-6 Classic barium esophagographic findings in diffuse esophageal spasm. Note the “corkscrew” appearance to the esophagus due to uncoordinated esophageal contractions.

The primary motility abnormality noted in DES patients is incoordinated motility (Fig. 66-7). Usually, there are simultaneous contractions in 20% or more wet swallows intermixed with normal peristalsis. If all contractions are simultaneous, then the diagnosis is achalasia. The criteria for diagnosis are based on a study on normal volunteers conducted by Richter and coworkers75 in which simultaneous contractions were rarely seen in normal subjects (4/95) and none of the patients had simultaneous contractions in more than 10% of wet swallows. A number of other disorders mimic DES on manometric examination. Diabetes mellitus, scleroderma, amyloidosis, idiopathic pseudo-obstruction, alcoholic neuropathies, and GERD69 are all associated with simultaneous contractions and hence are indistinguishable from symptomatic DES. Sometimes, the frequency and amplitude of contractions predict the symptomatology. For example, in a study of DES patients, it was noted that the group with highest simultaneous contraction amplitude of 100 mm Hg or more had more

FIGURE 66-7 Manometric findings in diffuse esophageal spasm. The left side of the tracing shows the typical multiple simultaneous uncoordinated contractions, while on the right hand side there is normal peristalsis with swallows.

721

722

Section 7 Neuromuscular Disorders

complants of chest pain than the group in which the highest simultaneous contractions were 74 mm Hg or lower.76 Another significant manometric finding in DES patients is the presence of repetitive waves (three peaks), which are seen in 0.1% of wet swallows in healthy volunteers75 but in about 21% of wet swallows (12/56) in DES patients.77 Spontaneous contraction, once considered a common finding in DES, is actually seen in up to 50% of healthy subjects.75 LES pressure could be either normal or abnormal.77

Long-Term Course The prognosis of patients with DES is excellent. Longitudinal follow-up studies have shown that up to 3% to 5% of patients transition to achalasia within 4 years of diagnosis.21,78 Otherwise, symptoms remain stable and may improve spontaneously. There have been no known associations between DES and malignancy.

NUTCRACKER ESOPHAGUS The NE is the most enigmatic esophageal motility disorder characterized by extremely high amplitude of peristaltic contractions, poor correlation with symptoms, and even poorer response to standard therapeutic measures utilized successfully in other motility disorders.

Historical Note The characteristic manometric abnormality of NE was first described in patients with noncardiac chest pain (NCCP) in 1977.79 In this study, up to 41% of patients with NCCP had high-amplitude peristaltic contractions (HAPCs). The term nutcracker esophagus was first coined by Benjamin and other in 197980 based on the presence of extremely high contraction amplitudes (>400 mm Hg) in some of the patients with NCCP.80 Subsequent investigators have reported that the prevalence of NE was in the range of 27% to 48% in patients undergoing manometry for NCCP.5,79

reproduced in the laboratory when high pressures are generated and even in the presence of HAPCs on manometric examination. Furthermore, reduction of pressure with therapy or time does not correlate with symptom improvement. Therefore, it has been suggested that NE may not be a true disorder but a manometric curiosity.85 However, chest pain is more frequently produced in NE than in other motility disorders with the use of edrophonium, acid, or balloon provocation, implying that there may be an element of visceral hypersensitivity.5 Sometimes, NE is sometimes used as a marker of chest pain syndrome. Other disorders commonly seen in these patients include depression, anxiety, and somatization.

Diagnosis Radiology All patients have normal peristalsis and barium studies are usually normal; radionuclide emptying studies are nondiagnostic and may give conflicting results.86

Manometry The essential criteria to diagnose NE requires contraction amplitude to be greater than 2 SD above normal with all the contractions being peristaltic (Fig. 66-8). Prolonged duration contraction and increased LES pressure are seen occasionally but are not required for the diagnosis.87 The location of HAPCs has varied in different studies. One author reported

Etiology and Pathogenesis As with other motility disorders, the etiology of NE remains unknown. Occasional transition of NE patients to classical achalasia has led to the speculation that NE might be part of the spectrum of motility disorders in which achalasia is the end result.81,82 Of all the motility disorders, NE is most strongly correlated with psychological symptoms. It has been shown to have significant symptom overlap with irritable bowel syndrome.83 In this study, the Million Behavior Inventory was given to patients with NE, IBS, and structural esophageal disease and to normal controls. The most striking similarity was seen in NE and IBS patients. In another study, Clouse and Lustman84 reported psychiatric abnormalities in about 30% of patients with NE and suggested that it may be a part of irritable bowel syndrome.

Clinical Features About 90% of the patients diagnosed with NE have chest pain as their primary symptom, with a significantly lower percentage reporting dysphagia.5 However, the chest pain is not

FIGURE 66-8 Manometric findings in nutcracker esophagus. Normal high-amplitude peristaltic contractions are seen.

Chapter 66 Esophageal Motility Disorders

finding HAPCs at multiple levels every 2 cm,79 whereas others found isolated distal esophageal smooth muscle HAPCs. Most experts use two levels of HAPCs as significant: 3 cm and 8 cm from LES.87

Long-Term Follow-up The manometric findings of NE may change with time. Dalton and colleagues,88 in an interesting study of 24 patients with NE, found that only 54% of them with initial NE findings had retained similar findings over a 32-month followup. Other studies documented changes of manometric findings from NE to DES, non-specific esophageal motility disorder (NEMD), or normal tracings81 and to achalasia.84

HYPERTENSIVE LOWER ESOPHAGEAL SPHINCTER This disorder was first described in 1960.69 However, this is an uncommon abnormality, characterized by increased LES pressure that is 2 SD above normal (>45 mm Hg). Often it seems to overlap with NE and also is commonly seen in patients with NCCP. Unlike NE, occasional dysphagia is reported.5 The prevalence of this disorder varies from 0.5% to 2.8% in various series.5,89 Contrary to the expectations, this disorder is also seen with GERD.89 In a study of 349 patients with GERD, 18 (5.2%) were characterized as having HLES.89 In patients with GERD diagnosed with abnormal pH, the prevalence was as high as 10%.89 This might seem contrary because patients with GERD have hypotensive LES. Fairly common overlap with NE is seen. Manometric evaluation shows functional abnormality with impaired relaxation and increases in residual pressure.89 Fifty percent of patients also have HAPCs in the distal esophagus. Long-term studies with HLES are not available. Radiologic examinations are usually normal, but up to 50% of patients might have hiatal hernia. Radionuclide studies are also normal.

studies of patients with IEM were compared with those in 153 patients with other manometric abnormalities, it was observed that the pH values of less than 4 were much higher and acid clearance was much slower in the recumbent posture in IEM patients compared with all other groups except patients with scleroderma.

TREATMENT OF NONACHALASIA MOTILITY DISORDERS The treatment of these disorders should be tailored individually to the patients. Emphasis should be placed on symptom relief and improving the quality of life because most of them are not reversible, but excellent palliation can be achieved. Nonpharmacologic treatment has shown to be very effective for these disorders. Studies have clearly demonstrated that reassurance on the part of the physician and knowledge about the disorders are very helpful in symptom reduction. Richter and colleagues92 found that awareness of esophageal etiology of the symptoms and reassurance was as good as nifedipine in patients with NE. Significant benefits with psychotherapy have also been noted. The pharmacologic therapeutic measures include nitrates, calcium channel blockers, and sedatives/tranquilizers. Attempts at mechanical dilation have also been made, particularly in patients with the predominant symptom of dysphagia.

Nitrates Nitrates have been used in the treatment of DES since 1940s because they cause smooth muscle relaxation but have no effect on peristalsis on normal subjects. Some case studies reported that amyl nitrate decreased radiographic abnormality and reduced chest pain associated with DES. But the effect was short lived and disappeared as soon as the drug was withdrawn. Many case series also described improvement of symptoms with nitrates.93,94

INEFFECTIVE ESOPHAGEAL MOTILITY Previously, abnormal manometric patterns that did not fit into any of the named esophageal motility disorders were known as nonspecific esophageal motility disorders. They typically included low-amplitude peristalsis (<30 mm Hg), nontransmitted contractions (>20% of wet swallows), spontaneous contractions, prolonged duration contractions (>6 seconds), isolated incomplete LES relaxation, retrograde contractions, or triple-peaked contractions.90 These findings were commonly seen in patients with chest pain, dysphagia, and GERD. In fact, this was the second most common finding in patients with unexplained chest pain.5,79 Leite and associates,91 in a classic study of 600 consecutive patients over a period of 2.5 years, found that almost all the patients who had the diagnosis of nonspecific motility disorder (60/61, 98%) had contraction amplitudes of less than 30 mm Hg in 30% or more of wet swallows. Hence, they renamed this disorder as ineffective esophageal motility disorder (IEM). This type of disorder was later shown to occur very commonly in patients with GERD and atypical GERD. For example, in the above series,91 GERD was found in 35 of the 60 (58%) patients. In another study in which pH

Calcium Channel Blockers/Vasodilators Calcium channel blockers have become the most popular medical therapy for patients with these disorders because they decrease the amplitude of contractions in the body and reduce LES pressure in healthy controls.95 Blackwell96 demonstrated that sublingual nifedipine could abort acute chest pain and decrease the frequency and severity of chest pain at 20 mg taken thrice daily. Another study97 showed decreased frequency of chest pain attacks but no overall decrease in frequency or severity of chest pain over a 12-week trial period. A 14-week crossover study in 20 patients with NE showed decreased esophageal amplitude, duration of contractions, and LES pressure, but there was no difference in symptom relief.92 Diltiazem has also been tried in these patients and is shown to decrease the amplitude and duration of esophageal contractions in patients with NE. There was significant symptom improvement in chest pain in one open-label trial.98 A placebocontrolled study of diltiazem in patients with NE compared 60 mg to 90 mg QID dosing with placebo in a randomized double-blind crossover trial in 14 patients99 in which diltia-

723

724

Section 7 Neuromuscular Disorders

zem fared better. However, the results are somewhat confusing because another study100 described no change in symptom improvement with diltiazem, 60 mg TID, in a 10-week crossover placebo trial. Hydralazine, an arterial smooth muscle relaxant,101 was also shown to improve symptoms in 3 patients with DES at oral doses of 75 and 200 mg/day. But nifedipine is the only commonly used medication.

Sedatives/Tranquilizers Because there is a high incidence of depression and panic disorders102 in these patients, sedatives and tranquilizers have been used successfully. In a 6-week double-blind placebocontrolled trial, low doses of trazodone (100-150 mg/day) fared significantly better than placebo.103 However, there were no changes in motility patterns. Alprazolam was also shown to be occasionally useful in patients with NCCP without motility changes. Tricyclic antidepressants also improved symptoms in NCCP patients compared with placebo.104 Symptom improvement was irrespective of motility abnormalities. Botulinum toxin was initially tried in 15 patients with DES, NE, and HLES who were unresponsive to other therapies.105 All patients received toxin injections in the LES and were followed for 270 days. Initial response was good in 11 patients. However, at 120 days after injection, there were no significant differences in pretreatment and post-treatment scores.

Pneumatic Dilation The effectiveness of pneumatic dilation was tested in 9 patients with DES and HLES who had dysphagia and chest pain unresponsive to medical therapy and bougienage; pressures of 8 to 12 psi for 15 seconds were applied.106 Symptomatic improvement for dysphagia occurred in 8 of 9 patients. Some case reports of improvement of symptoms in HLES have also been described with dilation. In another study, Rigiflex dilators107 were used for treating 20 patients with DES and symptoms of chest pain and dysphagia in whom conventional therapy had failed. Second balloon dilation was performed if the first procedure failed. Complete relief of symptoms was seen in 8 patients, 6 additional patients had some relief, and 2 patients had a second dilation. Overall, the dilation was unsuccessful in 5 patients and caused

perforation in 1 patient. The incidence of reflux in successfully treated patients was 10%. Mercury bougienage dilation was attempted in patients with NE in a double-blind crossover study of 9 patients using placebo dilator (24 Fr) and a therapeutic dilator (54 Fr).108 Only temporary subjective improvement was seen in both groups without any change in motility.

COMMENTS AND CONTROVERSIES Esophageal motility disorders are defined, measured, and quantified by esophageal manometry. Symptoms may be nonspecific, misleading, and misinterpreted. Therefore, diagnosis and treatment must be based on esophageal manometry supplement by radiography and esophagoscopy. The best defined and most common abnormality is achalasia. Treatment of achalasia is well established, and results of the various treatment options are fairly well documented. Other motility disorders are uncommon and may be transient, related to other esophageal pathologic processes such as GERD, achalasia in evolution, or an epiphenomena. Therefore, patience of both the patient and physician is required in diagnosis and treatment. Management of many motility disorders should initially be temporizing, because time may allow further definition of the abnormality and better direct therapy. T. W. R.

KEY REFERENCES Farhoomand KS, Connor JT, Richter JE, et al: Predictors of outcome of pneumatic dilation in achalasia. Clin Gastroenterol Hepatol 2:389394, 2004. Goldblum JR, Rice TW, Richter JE: Histopathologic features in esophagomyotomy specimens from patients with achalasia. Gastroenterology 111:648-654, 1996. Kahrilas PJ, Kishk SM, Helm JF, et al: Comparison of pseudoachalasia and achalasia. Am J Med 82:439-446, 1987. Pasricha PJ, Rai R, Ravich WJ, et al: Botulinum toxin for achalasia: Long term outcome and predictor of response. Gastroenterology 110:1410-1415, 1996. Richter JE: Esophageal motility disorders. Lancet 358:823-828, 2001. Spechler SJ, Castell DO: Classification of esophageal motility abnormalities. Gut 49:145-151, 2001. Vaezi MF, Baker ME, Achkar E, et al: Timed barium esophagram: Better predictor of long term success after pneumatic dilation than symptom assessment. Gut 50:765-770, 2002. Vaezi MF, Richter JE: Diagnosis and management of achalasia. Am J Gastroenterol 94:3406-3412, 1999.

chapter

67

SECONDARY ESOPHAGEAL MOTOR DISORDERS Sudish C. Murthy

Key Points ■ Secondary esophageal motor disorders are observed in multiple

distinct disease states. ■ Although rarely life-threatening, they are an important source of

morbidity. ■ Treatment strategies are often complicated, which is attributable

to the underlying systemic illness.

Esophageal motility dysfunction classically presents as some variable combination of dysphagia, regurgitation, and atypical chest pain. When this symptom-complex occurs in the setting of a systemic disease or is not directly attributable to one of a number of well-characterized isolated esophageal disorders,1,2 it is then considered a secondary esophageal motor disorder. The spectrum of diseases associated with secondary esophageal motor disorders can be broadly separated into six categories: rheumatologic (collagen vascular), infectious, other inflammatory, neuropathic, iatrogenic, and cryptogenic. The involvement of the esophagus with each condition is slightly different and clearly warrants independent consideration. Regardless, esophageal motility is affected and, rarely, can become the most important clinical manifestation of the disease.

CLINICAL MANIFESTATIONS Rheumatologic Systemic Sclerosis Systemic sclerosis (SS) is a progressive, generalized connective tissue disorder characterized by fibrosis and degenerative changes of skin and visceral structures, including the esophagus. Sometimes termed scleroderma, this label only represents the cutaneous manifestations of the disease and, consequently, underestimates the generalized nature of the condition.3 Involvement of the gastrointestinal tract, particularly the esophagus, is extremely common in systemic sclerosis because up to 90% of patients will ultimately demonstrate dysmotility and dysfunction of the esophageal body or gastroesophageal junction.4,5 Many patients will also present with the complete CREST syndrome (Calcinosis, Raynaud’s phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasia) and can be identified by the presence of anticentromere antibody in their serum. The disease is rare (<2/100,000 persons), has a female predominance, and affects younger people.6

Esophageal injury and dysfunction associated with systemic sclerosis is hypothesized to begin with neuropathy, progress through myopathy, and culminate with fibrosis.4,7 Esophageal electromyography demonstrates disorganized conduction hyperactivity with early esophageal involvement and scant or no activity with end-stage disease.8 The mechanism is thought to involve a regional devascularization of tissues with perhaps the investing capillary bed serving as the site of initial injury.9 Ischemic neural dysfunction is presumed to be secondary to evident changes within the vasa nervorum, and this likely begins the cascade of events terminating in fibrosis.10 Histologic examination of gastrointestinal tract specimens from patients with systemic sclerosis demonstrates heterogeneous fibrosis and muscular atrophy targeting the circular smooth muscle layer.11 Within the esophagus, this process is classically confined to the distal body and gastroesophageal junction. An amotile distal esophagus with an incompetent lower sphincter represents the end stage of disease. No peristaltic waves are conducted, and free-flowing recumbent gastroesophageal reflux can be observed. Aboral passage of food in this setting occurs purely by gravity. It is debated as to how much gastroesophageal reflux contributes to the perpetuation of the esophageal injury and the development of the endstage esophagus. Clinical Features. Esophageal dysfunction is an early and frequent complication of systemic sclerosis and may precede by years the development of hallmark skin changes.12 Up to 80% of patients will complain of dysphagia or heartburn.13 Moreover, many patients will have abnormal esophageal motor function when investigated even in the absence of complaints.14-17 Lack of organized peristalsis and esophageal clearance, diminished lower esophageal sphincter tone, and gastroparesis all contribute to the development of gastroesophageal reflux and its complications. Not surprisingly, erosive esophagitis is encountered in up to 60% of patients with systemic sclerosis.18 Other complications such as peptic stricture, perforation, Barrett’s esophagus, and even carcinoma are also predisposed.19 Heartburn is presumed due to reflux of gastric acid across the lower esophageal sphincter, and functional dysphagia follows stricture development or disturbed peristalsis.20 Finally, the increased prevalence of lung disease (chronic cough, dyspnea) in patients with systemic sclerosis may be attributable, in part, to gastroesophageal reflux from esophageal involvement.21 Interestingly, lung dynamic compliance is significantly reduced in patients with severe esophageal involvement22 and esophageal hypomotility is associated 725

726

Section 7 Neuromuscular Disorders

FIGURE 67-1 Esophagogram of a patient with systemic sclerosis showing a distal stricture and mildly dilated esophagus. The distal esophagus was noted to be aperistaltic on the cine portion of the study.

with a reduction of forced vital capacity and diffusion capacity.23 Diagnosis. Videoradiology, manometry, 24-hour pH determination, and endoscopy are routinely used in the evaluation of esophageal function in patients with systemic sclerosis. Each provides important information and, collectively, they help define the magnitude of esophageal involvement and, ultimately, direct therapy. Videoradiography or cineradiography (esophagography) has long been considered the initial study to evaluate the esophagus in patients with systemic sclerosis. It provides useful anatomic detail and, often, relevant functional information. The proximal esophagus is usually normal, but there is marked reduction in peristalsis by mid body and, frequently, dilation without peristalsis in the distal third and stricture (Fig. 67-1). In contradistinction to achalasia, the gastroesophageal junction is often patulous, and free reflux of contrast agent can be observed from stomach back into esophagus.24 Roughly 10% of patients will have an incidental hiatal hernia discovered,25 and the severity of this problem can easily be gauged by an esophagogram. Finally, esophageal emptying scintigraphy,26 often used for assessment and grading of esophageal dysmotility in patients with systemic sclerosis, may be replaced by the timed barium esophagogram, which appears to provide equivalent information and seems more specific and less operator dependent.10,27 Manometry is considered the most sensitive test to detect esophageal dysmotility in patients with systemic sclero-

sis,4,28,29 although abnormal motility does not necessarily translate into symptoms.17 Manometric results are, unfortunately, highly variable among systemic sclerosis patients with esophageal dysmotility but generally correlate with the magnitude of esophageal involvement.25 Usually consistent among examinations is a sparing of the proximal esophagus (Fig. 67-2). Findings range from preserved peristalsis with a hypotensive lower sphincter to complete absence of both peristalsis and lower esophageal sphincter tone.30 Gastroesophageal reflux is an important sequela of systemic sclerosis. Twenty-four-hour pH monitoring provides the most accurate assessment of this problem. Patients are at risk for gastroesophageal reflux because of the loss of lower sphincter tone, ineffective clearance of the distal esophagus, and some degree of gastroparesis. Given this, it is not surprising that gastroesophageal reflux can be documented in up to 80% of patients with systemic sclerosis.5,31 A 24-hour assessment will objectively demonstrate the duration of reflux, as well as symptom correlation. This is important because not all patient symptoms will correlate with pathologic reflux.32 Perhaps the most important roles of pH monitoring may be to confirm adequacy of acid suppression for those patients on therapy and to identify treatment failures in patients with systemic sclerosis. Endoscopy is an important adjunct because of the high incidence of erosive esophagitis and associated distal stricture in patients with systemic sclerosis. Because not all patients with esophagitis are symptomatic, early endoscopy may be a reasonable option once esophageal involvement in systemic sclerosis can be documented. Up to 40% of patients will have a stricture identified at endoscopy,33-35 and up to one third of patients will present with concomitant esophagitis and stricture.36 Moreover, prevalence of Barrett’s esophagus is as high, if not higher, than that in the general population,36-38 and there is no reason to believe that progression to adenocarcinoma would not occur in this setting of chronic reflux injury.

Other Rheumatologic Disorders Secondary esophageal motor disorders are salient features of several other autoimmune/rheumatologic disorders. Esophageal involvement is slightly different in each. Mixed connective tissue disease presents as an amalgam of a variety of connective tissue disorders. The dominant manifestations resemble either systemic sclerosis or a lupus-like disease.10 The diagnosis is primarily clinical and supported by identification of serum antinuclear and anti-ribonucleoprotein antibodies. Esophageal involvement is considered less severe than in systemic sclerosis, and manometry often demonstrates a more proximal esophageal involvement of the striated muscle.39 In more than 50% of patients manometry will be abnormal.10 Raynaud’s phenomenon is thought to represent episodic peripheral vasospasm, which is considered biphasic. It has been postulated that when upper alimentary tract vasculature becomes involved, esophageal dysfunction can result.40 Raynaud’s disease represents this vasospasm syndrome occurring as a singular, primary event, whereas Raynaud’s phenom-

Chapter 67 Secondary Esophageal Motor Disorders

FIGURE 67-2 Manometric tracings from several areas along the length of the esophagus in a patient with systemic sclerosis demonstrating some preservation of peristalsis in the proximal esophagus but minimal progression of contractile waves through the distal portion.

enon connotes its presence as part of another systemic connective tissue disorder (e.g., systemic sclerosis, lupus, Sjögren’s syndrome, polymyositis, mixed connective tissue disease). An association with esophageal dysmotility has not been shown for Raynaud’s disease.41 The secondary esophageal motor disorder observed in patients with Raynaud’s phenomenon is characteristic of the underlying connective tissue disease and not the phenomenon itself. Sjögren’s syndrome is a chronic autoimmune inflammatory disorder of unclear etiology. The spectrum of disease ranges from an organ-specific process (salivary gland) to a systemic illness with variable musculoskeletal, pulmonary, gastric, hematologic, dermatologic, renal, and nervous system involvement.42 The disease may occur as a primary syndrome or in combination with other connective tissue disorders, particularly rheumatoid arthritis. Although xerostomia is the most frequent complaint, dysphagia is reported in at least one third of patients.43 Diagnostic manometric findings are not consistent among studies,42,43 although it has been postulated that dysphagia may be related to gastroesophageal reflux in the setting of poor acid clearance because of lack of saliva43 (Fig. 67-3). Dysphagia affects 2% to 25% of patients with systemic lupus erythematosus and is primarily attributable to reflux.44 It has been suggested that Raynaud’s phenomenon coexists in patients with systemic lupus erythematosus with dysphagia and may be important in the development of esophageal dysmotility.45 Rarely, bullous mucous disease can develop within the esophagus and lead to dysphagia.46 Polymyositis and other inflammatory myopathies are systemic connective tissue disorders principally targeting skeletal muscle. Although proximal striated muscle of the esophageal and pharynx are typically involved, the midbody and distal esophagus smooth muscle can be affected in a

FIGURE 67-3 Reflux-related stricture in the distal esophagus in a patient with Sjögren’s syndrome.

similar fashion to scleroderma.47,48 Video swallowing studies frequently reveal pharyngeal pooling and impaired oropharyngeal and cricopharyngeal function,49 resulting in a syndrome presenting as cricopharyngeal achalasia.48 Not surprisingly, cricopharyngeal myotomy can be a useful intervention for relief of dysphagia in these patients.49 Nonetheless, the presence of dysphagia in the setting of an inflammatory myopathy, especially dermatomyositis, portends an ominous outcome, with serious respiratory complications secondary to aspiration commonly observed.49

727

728

Section 7 Neuromuscular Disorders

Infectious

Cryptogenic

Patients infected with the human immunodeficiency virus frequently have symptoms of dysphagia and odynophagia. These symptoms have been thought to be secondary to opportunistic infections (Candida, cytomegalovirus, and herpes simplex virus) yet often persist after appropriate therapy and endoscopic resolution of disease.50-52 Interestingly, esophageal dysmotility is a common finding in patients infected with this virus independent of both symptoms and mucosal injury.53 The spectrum of motility disorders includes a hypertensive lower sphincter with incomplete relaxation, a nutcracker esophagus, hypocontraction, and a nonspecific motility disorder.53

When examining causal relationships between esophageal dysfunction and various disease entities, the presence of gastroesophageal reflux is an important confound of proposed associations. Gastroesophageal reflux is a significant component of most of the systemic and local diseases thus far discussed, and there is little doubt that it has a sizeable impact on esophageal motor dysfunction.65 This is highlighted by the finding that almost 50% of patients with gastroesophageal disease will have ineffective esophageal motility.65 Another confounding variable is the presence of obesity, although this may be a surrogate for gastroesophageal reflux. Despite this, in a survey of patients with esophageal aperistalsis and clinical dysphagia, one third of patients age 65 years and older had no known disease process that could account for the esophageal dysfunction.66 In contrast, a contemporary series of patients 40 years and younger had only 6% of patients with cryptogenic esophageal dysfunction and, consequently, the aging process itself has been implicated as a cause of secondary esophageal motor dysfunction.66

Inflammatory Eosinophilic esophagitis is a rare pediatric and adult inflammatory condition characterized by a dense eosinophilic polymorphonuclear leukocyte infiltrate of the esophageal mucosa, without involvement of other segments of the alimentary tract, gastroesophageal reflux, parasitosis, or disseminated malignancy.54 Clinical manifestations include subacute onset of intermittent dysphagia with episodic food impaction as well as chest pain, heartburn, and vomiting.55,56 Almost 60% of patients will have manometric abnormalities, most of which involve spastic or hypercontractility findings. There is still some debate as to whether eosinophilic esophagitis represents a primary or a secondary motor disorder.55

Neuropathic Esophageal dysfunction associated with diabetic neuropathy is well documented,57 as up to 60% of diabetic patients report esophageal symptoms.58 Curiously, symptoms are primarily restricted to patients with peripheral neuropathy. Although dysautonomia may be an important contributor,48,59 there does appear to be a correlation between esophageal dysmotility and diabetic motor neuropathy.60 Both upper and lower sphincter pressures can be reduced in diabetics and amplitudes of peristaltic waves diminished.58 The velocity of peristaltic waves and duration of contractions are also often decreased. There is also delayed esophageal transit time secondary to either peristaltic failure or lowamplitude pressure waves.48,61

Iatrogenic Although not usually considered a contributing cause of secondary esophageal motor disorders, iatrogenic induction of esophageal dysfunction is being increasingly recognized. Gastric banding procedures seem particularly prone.62 Pseudoachalasia has been observed after laparoscopic adjustable gastric banding procedures.63 This syndrome results in gastric pouch dilation and esophageal decompensation and, ultimately, failure of the procedure. A predisposing factor for this problem appears to be preexisting lower sphincter insufficiency.63 Aberrant motility and esophageal dilatation occurs in 30% to 50% of patients after gastric banding.64

TREATMENT Therapy for secondary motor disorders of the esophagus has less to do with the underlying systemic diseases but, rather, is directed more toward the actual resulting functional problem of the esophagus. To this end, severe intractable reflux in a patient with systemic sclerosis would very likely be managed similarly to reflux in a patient with Sjögren’s syndrome. Selection of the ideal therapy depends on a keen understanding of the anatomic and motor deficiencies, assessment of comorbid diseases, and reasonable expectations for outcome because treatment is largely considered palliative.

Management of Gastroesophageal Reflux Medical Treatment The most treatable condition in these patients is gastroesophageal reflux. As outlined for systemic sclerosis, the workup of this problem, regardless of systemic disease, includes esophagography, manometry, 24-hour pH monitoring, and endoscopy. These studies will clarify the severity of the condition and the function of the esophagus (including competency of the lower sphincter) and whether a stricture or hiatal hernia exists. Additional details such as corticosteroid and antimetabolite use, blood sugar control, concurrent infections, and cardiopulmonary fitness may become relevant if a surgical intervention is being considered. Daily administration of proton pump inhibitors has been shown to facilitate healing of esophagitis and possibly decrease the rate of stricture.67 Some researchers have argued to begin all patients with systemic sclerosis with documented esophagitis, regardless of presence of symptoms, on long-term proton pump inhibition.68 Patients with documented dysmotility but without esophagitis are counseled to adopt antireflux lifestyle changes and have regular endoscopy.33 Bile salt–binding agents may be of some use. Endoscopic antireflux procedures are in their infancy and cannot be commented on at this time.

Chapter 67 Secondary Esophageal Motor Disorders

Because many patients will also have delayed esophageal and gastric emptying, prokinetic agents can be tried. In the esophagus, these agents act at the level of the myenteric plexus and facilitate release of acetylcholine. They might be transiently useful to increase lower sphincter tone and promote gastric emptying in some patients, but where esophageal smooth muscle has largely been replaced by fibrosis (as occurs in advanced systemic sclerosis), they are of limited use.48

Surgical Treatment Indications for surgical intervention in patients with secondary esophageal motor disorders are similar to those without systemic disease because surgery is primarily utilized as salvage therapy for failed medical treatments. Clearly, the persistence of erosive esophagitis and development of refluxrelated complications (e.g., strictures and perhaps Barrett’s esophagus) after extended medical therapy would be considered the major indications. Intractable pain on optimal medical therapy, particularly if symptoms correlate with reflux on 24-hour pH monitoring, might also lead to consideration for surgery. Mobilization of the distal esophagus, posterior hiatal repair, and fundoplication (either 180 or 360 degrees) are the critical elements of antireflux operations. Disorders such as associated aperistalsis, distal esophageal fibrosis, shortened esophagus, megaesophagus, Barrett’s metaplasia, impaired gastric emptying, and bile reflux must be considered during operative planning. As might be expected, given these multiple variables, selecting the most appropriate operation can be quite challenging and requires a multidisciplinary team approach. It is becoming increasingly clear that laparoscopic fundoplication is a reasonable approach for most patients with medically unmanageable gastroesophageal reflux, who are otherwise fit for surgery.69-71 What is less clear is whether this approach can be utilized for patients with associated disorders of peristalsis, delayed gastric emptying, and large hiatal hernia, all of which complicate gastroesophageal reflux in patients with secondary esophageal motor disorders. Surprisingly, recent data, with lengthy follow-up, do suggest a role for laparoscopic fundoplication in patients with gastroesophageal reflux and aperistaltic esophagus.72 Whether a partial fundoplication is more prudent in these patients has been questioned. The long-term outcome of patients with 180-degree anterior fundoplication appears satisfactory, with the expected sacrifice of higher risk of reflux recurrence balanced by a lower rate of adverse side effects (e.g., gas bloat and dysphagia) when compared with a full 360-degree wrap.73 However, acceptable outcomes have been obtained with a complete wrap as well; patients who appear to benefit the greatest from a 360-degree fundoplication are able to clear a food bolus during contrast esophagography performed preoperatively.74 There is some evidence to suggest that a conventional Nissen fundoplication is more durable than the laparoscopic equivalent. To this end, esophageal lengthening in combination with fundoplication was demonstrated to be a useful

strategy for systemic sclerosis–related reflux over 30 years.75 Yet, for patients with an end-stage, dilated, amotile esophagus and severe reflux, from an operative standpoint, the compromise between control of reflux and postoperative dysphagia must be appreciated. Unfortunately, for these patients, regardless of operation, it is exceptionally difficult to predict when a fundoplication is too loose (inadequate reflux control) or when it is too tight (worsening dysphagia). When gastroplasty is combined with either partial or complete fundoplication, at least one fourth of patients with systemic sclerosis still have persistent acid reflux and 40% complain of postoperative swallowing problems.34 I prefer a lengthening procedure (Collis gastroplasty) with a 270-degree posterior fundoplication (Toupet) for these challenging situations (Fig. 67-4). Gastric emptying is assessed preoperatively because if significantly prolonged, a pyloromyotomy may be a reasonable adjunct, especially in patients with systemic sclerosis. Although there is little written about this approach, it seems to appease the constraints imposed by the delicate balance between reflux and dysphagia. Two other more radical approaches, esophagectomy and biliary diversion, need to be considered as salvage surgeries when other more conventional approaches have failed.

SUMMARY Secondary esophageal motor disorders are found within a heterogeneous spectrum of medical diseases. A thorough workup is mandated to define the specific functional prob-

FIGURE 67-4 Esophagogram obtained 1 year after Collis gastroplasty and Toupet fundoplication for severe reflux in a patient with systemic sclerosis. No acid reflux was present on a 24-hour pH study and the patient had no swallowing complaints.

729

730

Section 7 Neuromuscular Disorders

lems. Treatment strategies are considered palliative, but durable, because many patients may live lengthy and productive lives.

COMMENTS AND CONTROVERSIES Secondary esophageal motor disorders are an extreme challenge for the gastroenterologist and esophageal surgeon. The underlying

disorder targets the esophagus, but it is not treated by therapies directed at the problems of the esophagus. Medical therapy is usually limited to aggressive control of gastroesophageal reflux. Reparative surgery is hampered by destruction of the esophageal body and lower esophageal sphincter. Palliation may require resection. T. W. R.

chapter

68

CHAGAS’ DISEASE Manoel Ximenes-Netto

Key Points ■ Chagas’ disease is caused by the protozoa Trypanosoma cruzi;

the vector is the insect species Triatoma. ■ Myocarditis, pulmonary complications, and esophageal cancer

reduce survival. ■ Serologic tests are diagnostic in 95% of chronically infected

patients, and contrast radiography reliably documents esophageal involvement. ■ In the acute phase of the disease antiparasitic therapy is curative, but for established megaesophagus it is ineffective. ■ Effective palliation of dysphagia and regurgitation is best accomplished by myotomy. ■ Chagas’ megaesophagus is not routinely resected but palliated with a gastric onlay (Thal) patch.

American trypanosomiasis (Chagas’ disease) is a chronic disease caused by the flagellate protozoa Trypanosoma cruzi, discovered by Carlos Chagas in 1909. Passage to humans and animals results from contamination with feces of a bloodsucking Triatoma insect deposited close to the bite wound. Congenital transmission is also possible, as is transmission through blood or organs received from a contaminated donor. Oral transmission is due to ingestion of food contaminated by feces of infected Triatominae. A nursing mother may infect her infant. Although lesions caused by the parasite may be found in any organ, the most commonly affected are the nervous, cardiovascular, and digestive systems. Because of better housing conditions in recent years in Latin America there has been a decreasing number of cases of Chagas’ disease. It is estimated that 16 to 18 million people are infected and, of these, 6% to 9% may have chagasic achalasia. In the United States, native cases are rare, despite the occurrence of a sylvatic cycle, but, owing to a great number of immigrants from Mexico and South and Central America, this infection may be present in 100,000 to 675,000 immigrants from these countries. More than 100 mammalian species have been contaminated with T. cruzi, and several patterns of parasitemia may occur with predilections for different organs. There is a wide distribution of the Triatoma organisms, ranging from 41°N latitude, where Triatoma protracta has been found in Salt Lake City, Utah, to 46°S, where Triatoma patagonica has been described in Patagonia in South America. There are six major vectors of Chagas’ disease, namely, Triatoma dimidiata, Rhodnius prolixus, Triatoma infestans, Triatoma sordida, Panstrongylus megistus, and Triatoma brasiliensis.

Chronic cardiac disease resulting from Chagas’ disease is found in 50% of patients with megaesophagus. Stomach involvement in this disease is characterized by diminished chloride-peptic secretion, delay in gastric emptying time, and pyloric hypertrophy. The duodenum is the third most frequently affected part of the digestive tract, after the esophagus and the colon. The small intestine, gallbladder, and salivary glands are less commonly involved in Chagas’ disease. Chagas’ disease results in 45,000 to 50,000 deaths per year, mainly due to chagasic cardiomyopathy, with 60% of these cases caused by ventricular fibrillation.1

HISTORICAL NOTE Chagas’ disease is perhaps the only disease in the history of medicine for which the discoverer described simultaneously the causative agent (T. cruzi), the vector (Triatoma), and the clinical manifestations. The patient in whom all these aspects were studied was 2 years old at the time (1909) and lived to be 82. The first references in the Brazilian medical literature to what may have been a case of megaesophagus were by Pimenta in 1707 and by Ferreira in 1735. The term then used was tropical dysphagia, and the association with constipation was also noted. The association between esophageal dilation and Chagas’ disease was postulated by the scientist himself in 1916. Amorim and Correa Neto in 19322 described the lesions of the myenteric parasympathetic plexus, but it remained for Koeberle in 19563,4 to demonstrate the depopulation of ganglion cells not only in the esophagus but also in the entire digestive tract, heart, and bronchi. The link between the “mega” syndromes and the chagasic etiology was clearly demonstrated by Freitas in 1946 and Laranja and colleagues in 1948.5,6 Both authors verified that complement fixation tests performed in patients with either megaesophagus or megacolon showed 91.2% and 97% positive serologic results, respectively. In addition to possible variations in organ vulnerability, the likelihood of human infection depends on the habits of the more than 100 strains of the parasite.7 For example, T. protracta, T. rubida uhleri, and T. gestraecheri are found in the Midwest, Arizona, and New Mexico; however, because these organisms live in the woods and do not defecate after their blood meal, human infection is rare. HISTORICAL READINGS Andrade ZA: Patologia da doença de Chagas. In Brener Z, Andrade ZA, Barral-Netto M (eds): Trypanosoma cruzi e Doença de Chagas. Rio de Janeiro, Guanabara Koogan, 2000, pp 201-230. 731

732

Section 7 Neuromuscular Disorders

Chagas C: Tripanosomiase americana: Forma aguda da moléstia. Mem Inst Oswaldo Cruz 8:37, 1916. de Rezende JM, Moreira H: Chagasic megaesophagus and megacolon: Historical review and present concepts. Arq Gastroenterol 25:32, 1988. Koeberle F: Chagas Krankheit: Eine Erkrankung der neurovegetative Peripherie. Wien Klin Wochenshr 68:333, 1956. Laranja FS, Dias E, Nóbrega G: Estudo eletrocardiográfico de 81 casos de megaesôfago. Mem Inst Oswaldo Cruz 46:473, 1948.

C B

D

BASIC SCIENCE Chagas’ disease was initially a malady of forest inhabitants. Human migration and destruction of the jungle have brought the disease to a more rural environment. Most of the triatomines are prevalent in mud houses, in the thatched or straw roofs, and in cracks, especially at the upper level. Humans, cats, dogs, and birds are the most common source of blood for the triatomines. Rodents may play a role not only as vectors but also as predators. Once infected with the Trypanosoma organisms, an insect becomes a carrier for the rest of its life. The life cycle of the T. cruzi begins after the triatomine takes a blood meal from a contaminated human or animal who has circulating parasites, trypomastigotes. The ingested parasites become epimastigotes and multiply in the gut of the vector insect; later, they transform once again into metacyclic trypomastigotes in the hindgut of the bug. After a subsequent blood meal, the infected insect frequently deposits the infective metacyclic form of the parasite. Once in the human organism, Trypanosoma organisms multiply in the cytoplasm of the blood cells, transform into motile trypomastigotes, and rupture, liberating organisms that penetrate new cells, are carried into the bloodstream to begin further cycles of multiplication, or are ingested by other vectors and initiate a new cycle (Fig. 68-1). Two basic pathogenic mechanisms explain the lesions caused by T. cruzi. The first is a local mechanism, consisting of an inflammatory reaction with necrosis, tissue destruction with healing, and fibrosis. The second involves an immune reaction and is not yet completely understood. Koeberle and Alcantara3,4 noted an acute inflammatory process followed by a chronic phase with severe symptoms related to the cardiovascular, digestive, respiratory, and nervous systems. Koeberle believed that after the disintegration of the leishmania forms of T. cruzi in the acute phase there would be release of a neurolytic substance capable of destroying the nerve cells of the parasympathetic system. He postulated that lysis of the ganglion cells would occur in the acute phase and that the chronic phase was a consequence of the denervation of the affected system. In light of these principles, Koeberle studied the ganglion cell population of the heart, colon, bronchi, and esophagus in normal and chagasic individuals and found that the threshold for the appearance of symptoms in this disease was 25% destruction of the ganglion cells in the heart, 55% in the colon, 75% in the bronchi, and 90% in the esophagus (Fig. 68-2). Autoimmune mechanisms in the pathogenesis of the chagasic syndromes have also been investigated but remain

A

Vertebrate E Invertebrate

F J

G I

H FIGURE 68-1 Life cycle of Trypanosoma cruzi. A, The metacyclic T. cruzi penetrates into the cells. B, It becomes the leishmanial form. C, Binary multiplication fills the cytoplasm. D, It has transformed into metacyclic Trypanosoma. E, Rupturing into blood, Trypanosoma goes into other cells. F, It is digested by the triatomine (dotted arrow). G and H, In the duodenum of the insect, it multiplies by binary division. I and J, Differentiation of metacyclic Trypanosoma occurs in the rectum of the triatomine. (ADAPTED FROM CHAGAS C JR: DOENÇA DE CHAGAS. IN CANCADO JR: [ED]: DOENÇA DE CHAGAS. BELO HORIZONTE, MG, BRAZIL, 1968.)

contradictory. Antibodies that are anti-EVI (endocardium, vessels, and interstitium), anti-nerves, anti-muscle, and antimyocardium have been demonstrated both experimentally and in human infection. Still in the investigative phase are labeled deoxyribonucleic acid (DNA) probes and isolation of different strains by means of isoenzymes and gel electrophoresis. A consensus has been reached in order to put together the previously described clones of the Trypanosoma into two groups, namely, T. cruzi I and T. cruzi II, and both may cause the human disease, but the first is associated with the domestic cycle and the latter with the sylvatic cycle.

DIAGNOSIS Clinical Features The diagnosis of Chagas’ megaesophagus is quite simple on clinical grounds alone. The most common symptoms are dysphagia, regurgitation, singultus, salivation with hypertrophy

Chapter 68 Chagas’ Disease

100 NORMAL NERVE CELLS 80 60 40 20 % 20 H 40 60 80

FIGURE 68-3 Chronic hypertrophy of the parotid gland in a patient with Chagas’ disease.

S B DESTROYED NERVE CELLS

E

100 FIGURE 68-2 Threshold between the number of lost ganglion cells and the appearances of symptoms in Chagas’ disease. H, heart; S, sigmoid; B, bronchi; E, esophagus. (FROM KOEBERLE F: CHAGAS KRANKHEIT: EINE ERKRANKUN DER NEUROVEGETATIVE PERIPHERIE. WIEN KLIN WOCHENSCHR 68:333, 1956.)

of the salivary glands, cough, constipation, weight loss, and pain. A history of contact with the triatomine is almost always described by the patient. The acute phase is found in but 1% to 2% of patients, usually in children. After an incubation period lasting approximately 1 week, induration and erythema—a so-called chagoma—can be seen at the bite site. The chagoma is frequently followed by regional adenopathy, fever, and splenomegaly. There may be periorbital swelling (Romaña’s sign). One third of patients already show electrocardiographic changes, but 2% to 3% mortality in the acute phase is usually attributed to infection of the child’s central nervous system. Eight to 10 weeks after the acute stage, the patient is symptom free but remains an important reservoir of infection. Only one third of the patients infected with Chagas’ disease experience the classic cardiac, digestive, or neurologic symptoms.8 The time interval between infection and the symptomatic period may vary from 10 to 20 years. Any part of the digestive tract may become symptomatic, but the esophagus and colon are most commonly affected. Dysphagia is the main symptom in megaesophagus and at the time of treatment is present in nearly all patients. It may be intermittent, depending on the type of meal ingested, and in time is present for either solid or liquid food. Sudden onset is usually associated with emotional stress and has no relation to the size of dilation. The patient, becoming aware of this difficulty, develops characteristic maneuvers to encourage passage of food: drinking large amounts of water, taking deep

breaths, deliberately swallowing air, or holding the breath. Valsalva’s maneuver or arching backward is also tried in a futile attempt to empty the esophagus. Dysphagia is a result of the functional obstruction caused by loss of innervation of the body of the esophagus and consequent loss of peristalsis plus the inability of the stolid lower esophageal sphincter (LES) to open when presented with swallowed food. Regurgitation is seen in 55% to 91% of cases of Chagas’ achalasia. It is necessary to distinguish regurgitation from vomiting, the latter being unusual. Regurgitation is the effortless flow of an undigested meal back into the pharynx. The patient at times may provoke it in order to relieve the pain or discomfort. It usually occurs at night or when lying down. Aspiration pneumonia, lung abscess, and bronchiectasis are common sequelae. Weight loss is seen in almost 50% of patients with Chagas’ esophagopathy. It is due to either inability to empty the esophagus or fear of eating because of odynophagia. When it is associated with anemia and weight loss, carcinoma should be excluded. Retrosternal pain or discomfort is a frequent complaint. In the early stages of the disease or with vigorous achalasia, severe spontaneous substernal pain with radiation to the jaws, shoulder, and arm, lasting from a few minutes to hours, has been described. It does not seem to be related to gastroesophageal reflux or esophagitis and is frequently relieved after surgical treatment or administration of sublingual nitrates. The denervation test, which involves administration of Mecholyl (Cannon’s law), produces similar symptoms.8 When the lower esophagus is impacted by food, pain is the predominant symptom and endoscopic removal of the food is necessary. Heartburn after inadequate surgical treatment that results in reflux is infrequent. Singultus (hiccup) may be an early sign of megaesophagus. It can be of short duration or may last for hours or days; sometimes surgical treatment is required. Hypertrophy of the salivary glands with excessive salivation is a frequent finding in Chagas’ megaesophagus. Indeed, it is characteristic of the infection (Fig. 68-3). Constipation

733

734

Section 7 Neuromuscular Disorders

TABLE 68-1 Radiologic Classification of Megaesophagus Stasis

FIGURE 68-4 Chest radiograph of a patient with stage IV megaesophagus. Note the air-fluid level and the absent gastric bubble.

in chagasic patients is common and results from two mechanisms: (1) the loss of ganglion cells and consequent megacolon (found in 22% of cases) and (2) swallowing of less bulky food. For these reasons, when megaesophagus and megacolon are found in the same patient, the former should be treated first.

Natural History The long-term prognosis in patients with Chagas’ megaesophagus does not seem to be influenced by the dilation of the organ; it is associated with myocarditis, pulmonary complications, and carcinoma, which influence survival. In a review of 450 cases of Chagas’ megaesophagus, my colleagues and I, in 1987,9 found symptomatic associated disease in the following order and frequency: megacolon, 100 cases (22%); cholelithiasis, 40 (8.8%); heart disease, 8 (5.5%); and carcinoma, 10 (2.2%). Biliary tract disease is found in a higher proportion of patients, probably because of the parasympathetic denervation, and on account of this it justifies an abdominal approach.

Complications In the chronic stage, 30% of infected patients manifest one of the forms of the disease, such as cardiac, pulmonary, digestive, or neurologic conditions. The pulmonary problems are caused by aspiration of regurgitated food material, which

Group

Transverse Diameter (cm)

10 sec

5 min

30 min

I

4

Yes

No

No

II

4-7

Yes

Yes

Eventually

III

7-10

Yes

Yes

Yes

IV

>10

Yes

Yes

Yes

occurs particularly at night when the patient is lying down. Manifestations include cough, wheezing, and shortness of breath. Pneumonia, lung abscess, bronchiectasis, empyema, and pulmonary embolization are frequently found. Fistula between the trachea and the esophagus is a rare finding. One such case has been described.10 There seems to be a difference between idiopathic achalasia and Chagas’ megaesophagus regarding the incidence of carcinoma, which is less common in the latter. The incidence in carefully studied series should not exceed 3%.11 The diagnosis is usually delayed because of the preexisting dysphagia. One should suspect carcinoma in patients with worsening of the symptoms, weight loss, regurgitation of blood-stained material, melena, and anemia. Previous surgery does not seem to prevent the appearance of cancer. The outlook in cases of megaesophagus and malignancy is poor. There are at least two reasons for delayed therapy: (1) the patient is rather accustomed to some degree of dysphagia; and (2) because of the large caliber of the gullet, a bulkier tumor must be present before obstruction occurs.

Differential Diagnosis Several methods are available for establishing a definite and correct diagnosis of Chagas’ disease. An easy and accurate method consists of collecting blood in a capillary tube, centrifuging it, and examining the interphase between the leukocyte buffy coat and the red blood cell. The chance of confirming a diagnosis of Chagas’ disease in the acute phase varies from 60% to 100%; in the chronic stage, it is below 10%. The indirect methods are xenodiagnosis and blood culture, with 100% sensitivity in the acute stage dropping to less than 50% in the chronic stage. Several serologic tests can be used to diagnose Chagas’ disease. The most commonly used are the complement fixation test (Machado-Guerreiro test), the indirect hemagglutination test, the indirect immunofluorescence test, the enzyme-linked immunosorbent assay (ELISA), and the direct agglutination test. In patients with proven parasitemia and in the chronic phase, 95% accuracy is expected. Other conditions that may appear as megaesophagus syndrome are pseudointestinal obstruction, familial adrenal insufficiency, and postvagotomy achalasia. Pseudointestinal obstruction affects primarily the small intestine and involves the myenteric plexus and smooth muscles. It may occasionally appear as an esophageal motility disorder with spontaneous and simultaneous contractions

Chapter 68 Chagas’ Disease

FIGURE 68-5 Radiologic staging of megaesophagus in four groups based on a series of 450 surgically treated cases. A, Stage I, 11 patients (2.4%). B, Stage II, 136 patients (30.2%). C, Stage III, 163 patients (36.2%). D, Stage IV, 140 patients (31.1%).

and abnormal function of the lower esophageal sphincter manometrically. Familial adrenal insufficiency with achalasia was described by Allgrove and colleagues in 1978.12 It is characterized by early recurrent hypoglycemia, increased pigmentation secondary to hypercorticism, and deficient tear production and is of unknown etiology. It is an autosomal recessive trait. Postvagotomy achalasia is extremely rare after dissection of the cardia and is usually caused by trauma with resulting edema and hematoma. If both vagus nerves are interrupted at the cervical or thoracic level, an achalasia-like syndrome may appear, caused by the loss of the preganglionic nerves that supply the LES.

Investigative Techniques Radiologic studies with or without contrast material are the most important tools in the diagnosis of Chagas’ achalasia. A simple chest radiograph may demonstrate several features capable of distinguishing this disorder from other organic obstructions of the esophagus. At times, the enlarged mediastinum in cases of advanced disease may be confused with a mediastinal tumor (Fig. 68-4). Other signs are absence of the gastric air bubble and lung alterations caused by the inflammatory changes, such as pneumonia, lung abscess, and “tumor-like shadow.” On the lateral view, an air-fluid level is seen in advanced cases with displacement of the trachea. Contrast studies of the esophagus should be preceded by lavage with a large-bore tube in order to remove residual food

and facilitate examination of the patient in both lying and standing positions. With the horizontal position, the effect of gravity is eliminated, and some features of the megaesophagus may be appreciated, including the lack of esophageal emptying, discoordinated peristalsis, and lack of relaxation of the lower esophageal sphincter. On the basis of retention of contrast material, caliber of the esophagus, contractility tonicity of the lower segment, and lengthening of the organ as well as the transverse diameter, four groups of megaesophagus have been described by Rezende (Table 68-1).13 A group “0” was added for cases featuring no dilation but diminished peristalsis, and the diagnosis was established by biologic and manometric criteria. The corresponding radiologic and anatomic findings are shown in Figures 68-5 and 68-6. Treatment decisions are based on this classification; the simpler myotomy is useful in less advanced cases (groups I and II), and cardioplasty or occasionally esophageal resection is required for groups III and IV.

Endoscopy Endoscopic examination is mandatory in the patient with megaesophagus before any surgical procedure. The organ should be emptied thoroughly to facilitate complete visualization of the esophagus and stomach as well as to rule out the presence of an associated carcinoma. The flexible fiberscope has the advantage of good maneuverability and superior optics. The examination is more hazardous, and the findings of dilation, tortuosity, and friability increase the risk of

735

736

Section 7 Neuromuscular Disorders

FIGURE 68-6 Transverse diameter of normal esophagus (upper left) and the degrees of dilation ranging from progressive hypertrophy to almost complete loss of the muscle wall and thinning. (FROM KOEBERLE F: CHAGAS KRANKHEIT: EINE ERKRANKUNG DER NEUROVEGETATIVE PERIPHERRE. WIEN KLIN WOCHENSCHR 68:333, 1956.)

perforation. The dilation is proportionate to the stage of the disease. Other findings include reflux esophagitis (6.4%), stasis esophagitis (3.1%), esophageal stenosis (1.3%), carcinoma (0.8%), hiatal hernia (0.7%), leukoplasia and ulcerations (0.4%), and varices (0.3%).14

Scintigraphy Radioisotope scintigraphy has been used in esophageal disease to verify the transit time and dysfunction and to assess the therapeutic response to treatment. In this technique, in both the supine and sitting positions, the patient swallows a liquid or solid labeled with 99mTc sulfur colloid in an amount varying from 100 to 300 mCi of labeled material. Counts in the area of interest are made at fixed intervals (0.25 and 40 seconds) between the upper, middle, and lower thirds of the esophagus and stomach. Rezende15 studied 13 healthy persons and 52 individuals with Chagas’ disease to evaluate the esophageal transit time. He found an average esophageal transit time of 8.3 ± 2.2 seconds in the sitting position to be normal. When the esophageal transit time was longer than 40 seconds, he found two patterns, partial and total retention. In the cases with shuttling of material between the proximal and distal esophagus, the incoordination was classified as adynamic. Manometry confirmed the radioisotope studies in 88.5% of the cases. Absence of peristalsis was tantamount to retention in both sitting and supine positions, regardless of the motor status of the sphincter. However, when peristalsis was present in the upper third, partial retention was the rule.

Manometry Pressure studies in patients with Chagas’ megaesophagus are particularly helpful in the initial stage of the disease and in the differential diagnosis regarding other esophageal motility

disorders. Before the examination, it is important to evacuate the esophageal contents, including retained water, which may interfere with the interpretation of the results. The basic findings in both non-Chagas’ and Chagas’ achalasia are lack of peristalsis, achalasia of the LES, elevation of its resting pressure, and heightened response to stimulation of the esophageal smooth muscle with cholinergic drugs. Upon deglutition in the normal individual, there are repetitive coordinated waves of contraction and opening of the LES (Fig. 68-7). In the patient with Chagas’ disease, the coordinated movement of peristalsis disappears and is replaced by synchronous movement in all levels of the esophagus. The upper esophageal sphincter (UES) is not altered in the patient with Chagas’ esophagus. The LES demonstrates lack of relaxation in about 50% of patients in whom the esophagus is not dilated. In the more advanced cases with dilation, the LES does not relax in more than 80% of patients (Godoy, 1972; Pinotti, 1968).8 Total aperistalsis is seen only in advanced cases. The spontaneous motor activity of the esophagus is then caused by the stimulus produced by retained fluid; and once the esophagus is emptied, no peristalsis is seen. According to Paula-Costa and Rezende,17 the normal resting pressure of the LES varies between 7 and 17 mm Hg (average, 12.7 ± 4.2); in an individual with Chagas’ disease with grade II, it was between 8 and 32 mm Hg (average, 19.9 ± 6.3), and in an individual with grade III, it varied between 13 and 37 mm Hg (average, 23.4 ± 6.5).17 Under normal circumstances, the LES relaxes completely with deglutition and no pressure gradient exists. In patients with Chagas’ disease, a residual pressure between the stomach and esophagus effectively obstructs the cardia and contributes to stasis and dilation. With surgery in the early stages of the disease, normal peristaltic waves may return in 10% to 30% of patients. The denervated esophagus becomes hypertensive to cholinergic drugs such as bethanechol, pentagastrin, and chole-

Chapter 68 Chagas’ Disease

C1 1 C2 2 C1 3

A

50

↑ Mecholyl

A 0 mm Hg

C1 C1 C2 C2 C3 C3

B FIGURE 68-7 Manometric tracings in a healthy individual (A) and in a patient with Chagas’ disease (B). The catheters were placed in the esophageal body and at the cardia. Note the peristaltic waves and lower esophageal sphincter opening in the normal person and in the chagasic nonperistaltic contraction. (FROM MENEGHELLI VG: O ESÔFAGO NA DONEÇA DE CHAGAS: ESTUDOS FISIOLÓGICOS, FARMACOLÓGICOS E CLÍNICOS. ARQ GASTROENTEROL 24:177, 1987.)

cystokinin (Cannon’s law). This motor response may not be seen in the more advanced stages (groups III and IV) but is intense in earlier stages (Fig. 68-8).

MANAGEMENT Chagas’ megaesophagus is a benign disease that affects young people, and the treatment should be simple, straightforward, and capable of restoring the ability to eat as normally as possible. Morbidity and mortality rates should be close to zero. In the acute phase of the disease, medical treatment is not only feasible but curative; in the intermediate and chronic stages, medical treatment is not advisable. A nitrofuran derivative and a nitroimidazole are both effective drugs against trypomastigotes and amastigotes. The first is given daily in a dosage of 10 mg/kg to adults and 15 mg/kg to children for 60 or 90 days, and benznidazole is used in a daily dosage of 5 to 10 mg/kg for 30 to 60 days. Allopurinol in a high dosage of 600 mg daily is being tried with promising results. For the established form of megaesophagus, pharmacologic therapy has been tried but found wanting. Botulinum toxin injection in high-risk achalasia patients has been tried in several centers. Gordon and Eaker18 used 20 units of this substance in the four quadrants of the LES in 16 patients. Recurrent symptoms were noted in 32% of the patients, and within 6 months, 1 developed reflux and 2 were

B

↑ Mecholyl 2.0 mg

1 min.

FIGURE 68-8 Mecholyl test. In healthy people (A), there is no response; in individuals with Chagas’ disease (B), there is hyperactivity. (FROM MENEGHELLI VG: O ESÔFAGO NA DONEÇA DE CHAGAS: ESTUDOS FISIOLÓGICOS, FARMACOLÓGICOS E CLINICOS. ARQ GASTROENTEROL 24:177, 1987.)

found to have esophageal wall inflammation. Loss of tissue planes and mediastinal adhesions were found at subsequent myotomy. In Chagas’ megaesophagus, this drug has been used by Brant and coworkers19 but the short duration of response and untoward side effects suggest caution.

Bougienage and Dilation Bougienage should not be undertaken as a primary form of treatment of megaesophagus because relief, if any, is of very short duration. Better results can be expected after pneumatic or hydrostatic balloon dilation of the LES. Seventy-one percent of patients so treated improve, but 16% of them require more than one stretching. A good account of dilation techniques is given by Earlam and Cunha-Mello.17 The complications of forceful dilation include intense pain, perforation, bleeding, aspiration, and gastroesophageal reflux leading to esophagitis and eventually stenosis as a late sequela.

Surgical Treatment The question of forceful dilation versus surgery as the initial treatment of megaesophagus has been debated for years. In many institutions, including ours, surgery is the primary form of treatment, with dilation performed only rarely. There are few prospective randomized studies comparing both methods. Csendes and colleagues20 treated 39 patients by dilation and 42 by operation. The results were considered good in 65% after dilation compared with 95% after myotomy.

737

738

Section 7 Neuromuscular Disorders

Felix and associates21 randomly assigned 40 patients for treatment: 20 by forceful dilation and 20 by myotomy. In their analysis, patients treated by surgery had a significantly greater reduction of the LES pressure and less reflux compared with those treated by dilation. Anselmino and coworkers22 also found Heller’s myotomy superior to dilation in the treatment of achalasia in a group of 61 patients, 16 of whom had undergone surgical treatment. As a rule, surgery should be performed in the following circumstances: ■

■

■ ■ ■ ■

In advanced cases of megaesophagus associated with marked dilation and tortuosity of the organ and difficult and hazardous positioning of the instrument In patients with associated disease, such as epiphrenic diverticulum, hiatal hernia, suspected carcinoma, cholelithiasis, or any other intra-abdominal pathologic process In patients with severe esophagitis and an esophageal wall that is friable and likely to split and perforate When previous surgery performed at the gastroesophageal junction has been unsuccessful In children and adolescents When patients prefer surgical therapy to dilation and its complications

Heller’s Myotomy Surgery for megaesophagus was first described by the German surgeon E. Heller, who performed the operation on April 14, 1913.23 The procedure was similar to a Ramstedt pyloromyotomy, with an anterior and posterior incision, and was later modified to a single incision by Groenvedeldt in 191824 and Zaaijer in 1923.25 Several procedures were added to the myotomy, namely, antireflux maneuvers with the gastric fundus, which also keep the edges of the myotomy apart and cover the esophageal mucosa as a protection in case of perforation. The most commonly used of these techniques are those described by Nissen in 1951,26 Collis and colleagues in 1954,27 Lortat-Jacob and coworkers in 1956,28 Lind and associates in 1965,29 Belsey in 1966,30 Hill in 1967,31 and Dor and coworkers in 1967.32 Not all agree on the use of these added procedures, and there is even disagreement on the same procedure with different terms used, such as “loose,” “floppy,” or “two-stitch” fundoplication. The critical point in all these ancillary procedures is the amount of gastric tissue that is placed around the gastroesophageal junction as a wrap. Andreollo and Earlam33 addressed this question, analyzing 5002 cases of achalasia, and found no difference in the incidence of postoperative reflux when an antireflux procedure was done through either a laparotomy (7.4%) or a thoracic approach (7.3%). The 360degree plication, as described by Nissen originally, should never be applied because it creates a barrier that contradicts the basic principle of lowering LES pressure.34 Thoracoscopic or laparoscopic myotomy has been used by several groups to treat esophageal achalasia. Results of both approaches have been published by Abir and associates.35 These results are summarized in Box 68-1.

Box 68-1 Results of Laparoscopic and Thoracoscopic Surgery for Achalasia Laparoscopic approach (Heller) No. cases: 499 Improvement (%): 94 ± 6 Follow-up (in years): 1 ± 0.4 Gastroesophageal reflux disease (%): 13 ± 10 Mortality (%): 0 Thoracoscopic approach No. cases: 294 Improvement (%): 76 ± 13 Follow-up (in years): 2.3 ± 1.8 Gastroesophageal reflux disease (%): 35 ± 18 Mortality (%): 0

Box 68-2 Important Steps for a Successful Cardiomyotomy 1. Empty the stomach just before surgery with a large-bore gastric tube. 2. Avoid a long incision on the gastric wall. Stop at the first gastric vessels. 3. Avoid a short proximal incision, which may result in incomplete myotomy; up to 6 to 8 cm is sufficient. 4. Dissect the hypertrophied esophageal muscle around 50% of its circumference. 5. Never use a complete wrap around the esophagogastric junction, such as a Nissen fundoplication. It defeats the purpose of lowering the pressure in the lower esophageal sphincter. 6. Place a loose, 180-degree fundoplication anteriorly to keep the esophagus intra-abdominally (at least 4 cm), to keep the edges of the myotomy apart, and to seal any perforation. 7. Look for an associated hiatal hernia and repair it. 8. Do not place a nasogastric tube. 9. Offer a liquid diet on the day of surgery, and allow the patient to be discharged within 24 to 48 hours.

When comparing the two groups, in relation to operating room time, length of stay, abnormal 24-hour pH study, dysphagia, and heartburn, the laparoscopic technique has great advantage. On the other hand, Vogt and colleagues in 199736 reported 20 patients treated laparoscopically, 18 of whom also had undergone a Toupet fundoplication. Morbidity (35%) included five mucosal injuries, one bile leak, one splenic tear, and 20% reflux. The hospital stay ranged from 2 to 20 days, with an average of 5 days. With increasing knowledge and technology, a laparoscopic Heller myotomy will become the method of choice. The points that we consider important for a successful cardiomyotomy are listed in Box 68-2. In advanced megaesophagus (stages III and IV), the Heller myotomy does not offer as good results as in less advanced cases. For this reason, we have used the principles of the

Chapter 68 Chagas’ Disease

onlay gastric patch as described by Thal and Hatafuku.37 After the original description of the cardioplasty by Wendel in 1910, many modifications were made by several surgeons. The main drawback of these procedures is the reflux that follows if no other measures are taken to prevent it. After experimental work, Thal and associates demonstrated that a peptic stricture at the gastroesophageal junction could be incised and a fold of gastric fundus could be placed in such a manner that it would cover the defect. The operation was later applied to the treatment of megaesophagus electively, in case of rupture of the gastroesophageal junction, or as a remedial operation after unsuccessful treatment of megaesophagus.38-43 The ingenious part of this procedure is the insertion of a gusset of adjacent gastric wall in such a manner that the serosa faces into the lumen, creating an endoluminal valve.

The technique consists of full mobilization of the esophagogastric junction followed by a longitudinal full-thickness incision through the narrow segment, 6 to 8 cm in the proximal esophagus and 1 to 2 cm into the stomach (Fig. 68-9). If necessary, a few stitches are placed transversely to widen the posterior wall of the gastroesophageal junction. The next step is the formation of an antireflux valve, which is performed with three initial stitches placed parallel between the gastroesophageal junction and the gastric wall, at a point 4 cm on the angles and 2 cm in the middle. Additional suturing completes the valve. The gastric onlay is then performed with the gastric fundus, which is sutured to the esophageal opening with interrupted nonabsorbable sutures. A few short gastric vessels may be ligated to better mobilize the gastric fundus. The completed procedure is shown in Figure 68-10.

FIGURE 68-9 Technique of cardioplasty with an endoluminal valve (Thal procedure). A, Midline laparotomy and section of the left triangular liver ligament. B, Exposure of the gastroesophageal junction. C, Opening of the gastroesophageal junction 6 to 8 cm above and 2 cm below. (COURTESY OF H. BARRETO, MD.)

A

B

C

739

740

Section 7 Neuromuscular Disorders

FIGURE 68-10 Cardioplasty and endoluminal valve (Thal procedure). A, Endoluminal valve with sutures placed at the ends (4 cm) and in the middle (2 cm). B, Completion of the valve. C, Closure of the gastroesophageal junction opening with the gastric fundus and ventral surface of the stomach in a “V” shape. D, The procedure is completed. (COURTESY OF H. BARRETO, MD.)

A

B

C

D

The antireflux valve has been demonstrated both in experimental animals and in humans to be competent and capable of avoiding gastroesophageal reflux. The results of the Thal procedure have been well documented in the Brazilian literature, especially in cases of advanced megaesophagus. The results are shown in Table 68-2. Manometric studies by Barichello and coworkers44 after the fundic patch operation showed the disappearance of vigorous achalasia (contractions) in more than half of the cases. One may assume an improvement of smooth muscle function because of the relief of obstruction and the absence of food stasis in the esophageal lumen after the operation. Radiologic studies performed 3 years after the cardioplasty with an endoluminal valve (Thal) demonstrated decreases of the caliber of the esophagus to half its original size and of esophageal emptying time to less than 30 minutes in advanced disease (Fig. 68-11).

TABLE 68-2 Results of the Thal Operation in Chagas’ Megaesophagus (Brazilian Literature)

Author (Year)

No. Cases

Mortality (%)

Results Morbidity (%) (Good/ (%) Excellent)

Barbosa et al (1989)

351

1.4

7.4

100

Ximenes-Netto et al (1991)

210

0.9

4.6

97

Malafaia et al (1981)

111

0

4.5

99

Sader et al (1975)

28

0

0

85.6

Guarino (1975)

20

0

10

92

Brandalise et al (1979)

20

0

0

70.3

Nakadaira et al (1977)

15

0

6.6

93.3

0.32

4.7

91.02

Total

755

180

180

150

150

120

120

90

90

60

60

30

30

no avail, thus justifying the removal of the organ. In our experience, the risk of malignant change is quite low, 2.2% in a series of 450 surgically treated patients.11 Other experienced surgeons discount the value of esophagectomy, whether to prevent cancer, to correct stasis, or because other operations have failed. Hiebert, in 1989,51 questioned the logic of substituting one nonperistalsing bag for another. The Thal procedure or other lesser operations have been favored by my coworkers and me,43 Mendelsohn and colleagues,52 and Ellis.53,54 Minutes

Minutes

Chapter 68 Chagas’ Disease

2

2 NORMAL 0

0 Preoperative

Postoperative

FIGURE 68-11 Esophageal emptying time measured with a standard barium meal preoperatively and postoperatively, demonstrating that after surgery the time is reduced to less than 30 minutes 3 years later.

The esophageal emptying time determined with a 99mTcdiethylenetriaminepentaacetic acid (DPTA) meal also revealed a diminished curve. My colleagues and I were also unable to demonstrate the presence of reflux after ingestion of a 10-mL bolus of water containing 300 mCi of 99mTc sulfur colloid.41 This test is performed after the patient swallows substances through the mouth, pharynx, and esophagus into the stomach with recording by a gamma camera. A single dry swallow is completed 30 seconds later. The procedure is repeated with another radionuclide bolus, and the radioactivity counts are averaged to obtain the final transit pattern. The data from the gamma camera are transferred to a microprocessor, where they are converted into a graphic display of radioactivity plotted against time for each area of interest.

Esophagectomy Total removal of the thoracic esophagus in patients with Chagas’ disease was first proposed in Brazil by Camara-Lopes and Ferreira-Santos in 1958 and 1964, respectively.45,46 The esophagectomy with or without deliberate opening of the pleural cavities has been performed for advanced Chagas’ megaesophagus or as a remedial operation by several groups and championed by Ferreira,47 Pinotti and colleagues,48 Orringer and Stirling,49 and Miller and associates.50 These authors claim that there is a potential risk of malignancy in the dilated esophagus or that other lesser procedures are of

Other Procedures Excision of the gastroesophageal junction and replacement by a piece of jejunum or the ileocecal valve has been proposed as a form of definitive treatment of megaesophagus. Reporting on 170 patients with a jejunal interposition, DaSilva and coworkers55 found a mortality rate of 5.9% and complications in 31.8%. Rezende,56 in a series of 113 patients, reported two early deaths (1.7%) and two late ones. Complications included infection, intestinal obstruction, invagination of the transposed jejunum, fistula, duodenal obstruction, and obstruction of the transplanted bowel. Barbosa57 transplanted the ileocecal valve in 23 patients with Chagas’ megaesophagus. Three of the patients died in the postoperative period (13%), and 7 had good results (73.9%). Esophagectomy and replacement of the esophagus with the transverse colon have been used by Rassi58 in advanced stages of the disease in a two-stage operation. Among 48 cases that were followed, he reported three postoperative deaths (2.6%) and many complications: fistula (28%), pulmonary infection (10.9%), wound infection (23.6%), and hemothorax (9%). Because of the large number of complications and high death rate, these procedures have not had many followers. In cases of recurrence, antrectomy and Roux-en-Y diversion and resection of the stenotic gastroesophageal junction or esophageal gastric anastomosis has been used with much success by Ellis53 and Serra Dória as described by Ponciano and colleagues.59

COMMENTS AND CONTROVERSIES Despite globalization, Chagas’ disease is rarely seen in North America. Although improved living conditions in endemic areas have reduced its prevalence, it is unlikely that patients presenting in North America have been exposed to this parasite. Although a travel history in patients with achalasia is mandatory, I have yet to see an achalasia patient with potential contact with Trypanosoma cruzi have positive serology. In North America, Chagas’ disease is an interesting geographic curiosity that has some similarities to, but many differences from, achalasia. The differences are most remarkable. Chagas’ disease is a systemic disease of known etiology, whereas achalasia is of unknown cause but limited to the esophagus. There is curative treatment for acute exposure to T. cruzi. There is no cure for achalasia. Successful palliation of dysphagia by myotomy is achieved with diametrically opposed techniques. Dr. Ximenes-Netto suggests a long esophageal myotomy and a limited gastric myotomy to avoid incomplete myotomy. In achalasia an incomplete myotomy is avoided by

741

742

Section 7 Neuromuscular Disorders

extending the myotomy onto the stomach and limiting the esophageal component. End-stage Chagas’ disease is treated with an onlay gastric patch, whereas esophagectomy is reserved for endstage achalasia. What at first seem to be similar diseases are in reality quite different, and comparisons are probably not helpful. T. W. R.

KEY REFERENCES Ferguson MK: Achalasia: Current evaluation and therapy. Ann Thorac Surg 52:336, 1991. ■ This article reviews current treatment of achalasia, with an analysis of large series, and indicates the various forms of treatment of this condition over the past 20 years. Rezende JM: The digestive tract in Chagas disease. Mem Inst Oswaldo Cruz 79:106, 1984.

■ The author, who has one of the largest experiences in the world with Chagas’

disease, analyzes all the aspects of this entity when it affects the digestive tract. The radiologic findings as well as the basic concepts regarding the electromanometry are described in detail. World Health Organization (WHO): Chagas disease, Brazil: Interruption of transmission. Wkly Epidemiolog Rep 75:153, 2000. ■ This technical report demonstrates epidemiologic and entomologic data showing a diminishing curve of vectorial transmission of Chagas’ disease in Brazil as a result of the national control program. This represents one insect per 10,000 houses, an infestation rate far below the minimum required for effective transmission of the parasite to new patients. Ximenes-Netto M: Megaesophagus: Current review of techniques and results. Rev Saude DF 2:209, 1991. ■ All aspects of the treatment of Chagas’ megaesophagus are analyzed, including the newest techniques that are available for the surgical treatment of this condition. Analysis of the results in large collected series is reported. An account of the oldest techniques is also given in a historical perspective.

chapter

69

SURGICAL APPROACHES FOR PRIMARY MOTOR DISORDERS OF THE ESOPHAGUS Richard J. Finley

Key Points ■ The introduction of minimally invasive surgical techniques in 1992

has revolutionized the treatment of motor disorders of the esophagus. ■ Laparoscopic Heller esophageal myotomy reverses the symptoms of achalasia with minimal morbidity. ■ Treatment of other esophageal motor syndromes has been less rewarding because of the poor understanding of the disease processes.

Motility disorders of the esophagus are usually classified as primary when unrelated to systemic disease and secondary when they occur in association with another condition. Spechler and Castell (2001)1 have proposed a classification of primary disorders of motility based on the four major patterns of esophageal manometric abnormalities: inadequate lower esophageal sphincter (LES) relaxation, uncoordinated contraction, hypercontraction, and hypocontraction (Table 69-1). Diseases that affect the inhibitory innervation of the LES such as achalasia can interfere with LES relaxation, resulting in delayed esophageal clearance. In the body of the esophagus, abnormal motility is characterized by uncoordinated contraction, hypercontraction, and hypocontraction. Uncoordinated aperistaltic esophageal contractions can delay esophageal clearance. These uncoordinated contractions are seen in achalasia and diffuse esophageal spasm. Hypercontraction abnormalities of high amplitude and/or long duration are seen in nutcracker esophagus or isolated hypertensive LES. Hypocontraction abnormalities, which result from weak low-amplitude contractions of the esophageal body, can cause delayed esophageal clearance and LES hypotension, which can result in gastroesophageal reflux. Inadequate LES relaxation or an isolated hypertensive LES may be treated with a myotomy of the lower 5 to 6 cm of the esophagus and extending onto the stomach for 2 to 3 cm done through a left thoracotomy, left thoracoscopy, or laparotomy or done laparoscopically. A partial fundoplication may be added if gastroesophageal disease is present or anticipated. Hypercontraction abnormalities of high amplitude and/or long duration, seen in nutcracker esophagus or diffuse esophageal spasm, which cause significant dysphagia and weight loss, may be treated with an extended long esophageal myotomy done either through a thoracotomy or thoracoscopically.

ACHALASIA Definition Achalasia is a motility disorder of the esophagus characterized manometrically by incomplete relaxation of the LES upon swallowing and aperistalsis of the esophageal body. Classic primary achalasia is characterized by low-amplitude, nonperistaltic, tertiary contractions of the body of the esophagus. Vigorous achalasia is characterized by high-amplitude, nonperistaltic contractions.2 Primary achalasia is most commonly seen in North America and Europe. The underlying pathophysiology appears to be loss of ganglion cells in the myenteric plexus of the esophagus, resulting in absence of peristalsis of the esophageal body, failure of the LES to relax with swallowing, and normal or elevated LES pressures. The estimated incidence of primary achalasia is about one case per 200,000 population.3,4 The disorder is most commonly diagnosed in patients between the ages of 20 and 40 years. Achalasia secondary to ganglion cell destruction by Trypanosoma cruzi infection (Chagas’ disease) is seen primarily in South and Central America. In the endemic areas, Chagas’ megaesophagus develops in one patient per 1000 population (see Chapter 68).

Historical Note Surgical therapy for achalasia has been directed at obliterating the dysfunctional LES. A myotomy of the muscles of the lower esophagus and gastroesophageal junction using both anterior and posterior incisions was first performed by the German surgeon E. Heller on April 14, 1913 (1914).5 The procedure was later modified to a single incision by Groenvedeldt6 and Zaaijer.7 The surgical approach, transabdominal or transthoracic, and the need for an antireflux procedure remain controversial issues. In 1962, Professor Jacques Dor and associates at the University of Marseilles described fixing the myotomized lower esophagus in the abdomen and wrapping it using a partial anterior gastric fundoplication to compress the esophagus during elevated intragastric pressure, at which time gastroesophageal reflux usually occurs (Dor et al, 1962).8 Partial fundoplication is preferred to 360-degree fundoplication because a total fundoplication defeats the principle of lowering the high-pressure zone at the bottom of the aperistaltic esophagus. Long-term symptomatic improvement has been reported after an esophageal myotomy was performed through a left thoracotomy with (Malthaner et al, 1994)9 and without10 a partial fundoplication. 743

744

Section 7 Neuromuscular Disorders

TABLE 69-1 Classification of Esophageal Motility Abnormalities Inadequate relaxation of lower esophageal sphincter Classic achalasia Atypical disorders of lower esophageal sphincter relaxation Uncoordinated contraction Diffuse esophageal spasm Hypercontraction Nutcracker esophagus Isolated hypertensive lower esophageal sphincter Hypocontraction Ineffective esophageal motility

After the popularization of minimally invasive surgery, Pellegrini and coworkers (Pellegrini et al, 1992)11 reported the first use of thoracoscopic esophagomyotomy for achalasia. Rosati and colleagues (Rosati et al, 1995)12 first reported excellent relief of symptoms after a laparoscopic myotomy and anterior partial fundoplication for achalasia.

Diagnosis Clinical Features The functional obstruction at the esophagogastric junction results in symptoms of progressive dysphagia for liquids and solids. The disease usually follows an indolent course with several years of progressive dysphagia for liquids and solids, leading eventually to regurgitation of undigested food, weight loss, wheezing, and coughing. Patients with vigorous achalasia may have intermittent bouts of crushing retrosternal chest pain. Patients present for medical care with an average duration of symptoms of 6 years.4 Over time, the esophagus slowly dilates and eventually assumes a sigmoid appearance on the barium radiograph. Burning retrosternal discomfort, secondary to acidic fermentation products of retained food, may occur at this stage.

FIGURE 69-1 Barium swallow showing the “bird’s beak” appearance typical of classic achalasia.

Investigative Techniques Early in the disease process, the chest radiograph may be normal. Later, however, manifestations of achalasia may include a widened mediastinum, an air-fluid level, absence of a gastric air bubble, and even aspiration pneumonitis. A barium swallow shows absence of peristalsis in the body of the esophagus with distal esophageal narrowing to form a “bird’s beak” configuration (Fig. 69-1). A sigmoid appearance of the esophagus, retention of food, and an esophageal diameter greater than 6 cm are signs of long-standing achalasia (Fig. 69-2). Upper gastrointestinal endoscopy is used to examine the esophageal mucosa for signs of esophageal cancer and the esophagogastric junction to determine whether there is any structural cause of the obstruction such as cancer or peptic stricture, which may mimic achalasia. The endoscopist should be able to pass the tube through the esophagogastric junction with minimal pressure in classic achalasia. For biopsy of the esophagogastric junction, the instrument should be directed posteriorly if possible, to avoid mucosal perforation in the line of the future anterior esophageal myotomy.

FIGURE 69-2 Barium swallow showing a dilated “sigmoid shaped” megaesophagus secondary to end-stage achalasia.

Chapter 69 Surgical Approaches for Primary Motor Disorders of the Esophagus

Timed barium or radionuclide swallows to assess esophageal transit are useful in the diagnosis and follow-up of patients with achalasia.13,14 Studies with liquid radionuclide swallows are more reproducible than solid scintigraphic studies, which have decreased reliability because of poor mixing of the radionuclide. The esophageal transit time for both liquids and solids should be decreased in patients with achalasia in the supine and upright positions.13,14 Esophageal manometry is the procedure of choice for the diagnosis of achalasia. Classic esophageal manometric findings include (1) an elevated LES pressure; (2) failure of the LES to relax upon swallowing; and (3) aperistalsis of the body of the esophagus. Absence of peristalsis of the body must be documented to confirm the diagnosis of primary achalasia (Spechler and Castell, 2001).1,2 Patients with vigorous achalasia have high-amplitude, nonperistaltic contractions in the body of the esophagus in response to swallowing and complain more often of chest pain.2 In our center, the patient’s quality of life is assessed by standardized questionnaires administered in the preoperative period and at 3, 6, and 12 months, and then yearly after surgery. Postoperative dysphagia is subdivided into four classes, as described by Vantrappen and Hellemans:15 Class Class Class Class

I: No dysphagia II: Dysphagia occurring less than once weekly III: Dysphagia occurring more than once weekly IV: Persistent dysphagia

With the same classification system, patients are questioned to determine the presence of heartburn or regurgitation; patients are also asked to state whether they are very satisfied, somewhat satisfied, or not satisfied. Recently, Urbach has introduced a patient-derived quality-of-life tool to assess the impact of achalasia and its treatments on qualityof-life outcomes.16

Management Principles of Management The primary goal of therapy is palliation of symptoms, because the esophageal motor abnormality remains unchanged after all forms of intervention. At present, all treatment techniques are directed at relieving the functional obstruction at the level of the LES by disruption or paralysis of the esophageal muscle constituting the LES. Destruction of the LES function also places the patient at risk for pathologic gastroesophageal reflux disease (GERD). Therefore, the treatment of patients with achalasia must strike a balance between the relief of dysphagia and the potential creation of pathologic gastroesophageal reflux.

Medical Therapy Treatment approaches have involved both surgical and nonsurgical techniques. The nonsurgical techniques have consisted of passive esophageal bougienage or pneumatic dilation of the esophagogastric junction and injection of botulinum toxin into the LES muscles. Pneumatic dilation forcibly disrupts the muscular fibers of the LES while preserving the esophageal mucosa. This

procedure resulted in esophageal perforation in up to 4% of patients in one series17 and other significant complications in more than 30% in another series.18 With experienced clinicians, long-term symptomatic relief of dysphagia and regurgitation is obtainable in 60% to 75% of patients after the first dilation and in up to 85% after an additional procedure.19 In a prospective randomized trial, however, Csendes and colleagues20 demonstrated that esophagomyotomy of the muscles constituting the LES via laparotomy controlled dysphagia better than pneumatic dilation. Endoscopic botulinum toxin injections relaxed the smooth muscle fibers of the pathologic LES, but these effects lasted less than 6 months in most patients. Repeated injections were required for consistent long-term relief.21 Many of these patients require other forms of treatment, and the technique is now limited to poor candidates for either pneumatic dilation or a surgical procedure.22 In a randomized controlled trial, Zaninotto and colleagues23 showed superior long-term symptom relief with myotomy versus botulinum toxin injection. Patients who have undergone botulinum injection may develop submucosal fibrosis, which may lead to a more difficult esophageal myotomy and occasional mucosal perforation.24 Urbach and associates (2001)25 have recommended a decision analysis of the optimal initial approach to achalasia combining all of these treatment modalities.

Surgical Therapy The primary goal of surgical therapy is to relieve the functional obstruction at the level of the LES by division of the esophageal muscles constituting the LES without placing the patient at risk for pathologic GERD. Esophagocardiomyotomy has been the surgical procedure of choice for the treatment of achalasia since the initial description by Heller (1914).5 The myotomy extends from the lower 5 to 6 cm of the esophagus and onto the stomach for 2 to 3 cm done either through a left thoracotomy, left thoracoscopy, laparotomy, or laparoscopically. The surgical approach—transthoracic (Malthaner et al, 1994),9,10 thoracoscopic (Pellegrini et al, 1992),11 laparotomy (Bonavina et al, 1992),26 or laparoscopically (Rosati et al, 1995)12—and the need for concomitant fundoplication (Dor et al, 1962)8,27 remain controversial. Prior to 1995, the most common transthoracic operation was a transthoracic cardiomyotomy with or without fundoplication. Ellis10 claimed that minimal dissection of the cardia with a short myotomy of the stomach relieved the outflow obstruction of achalasia without the need for a fundoplication to prevent reflux. Furthermore, it has been suggested that the addition of a fundoplication may increase resistance to esophageal emptying, leading to progressive dilation of the esophagus and eventually esophageal failure. On the other hand, Malthaner and colleagues (1994)9 suggest that a complete gastric myotomy of at least 2 cm in length, along with the esophageal myotomy, completely obliterates the dysfunctional LES but requires a fundoplication to avoid gastroesophageal reflux. A partial fundoplication is preferred because a true 360-degree Nissen fundoplication appears to produce dysphagia in patients with myotomy for achalasia.27

745

746

Section 7 Neuromuscular Disorders

Pellegrini and colleagues (1992)11 reported the first use of thoracoscopic esophagomyotomy for achalasia. A follow-up of these thoracoscopic esophagomyotomies showed a high incidence of dysphagia and reflux.28 In our center, two of the first seven patients treated with this technique had an inadequate thoracoscopic myotomy because of inability to carry the myotomy onto the stomach.13 Stewart and colleagues29 have shown that laparoscopic myotomy results in less mucosal perforations and postoperative dysphagia and gastroesophageal reflux than the thoracoscopic approach. The incidence of inadequate myotomy and gastroesophageal reflux has led us to favor laparoscopic Heller’s myotomy for the primary surgical therapy of achalasia. Preoperative Preparation. Patients with achalasia usually present for surgical consideration with signs and symptoms of dysphagia for liquids and solids, regurgitation, weight loss, and aspiration. Severe malnutrition is treated with at least 10 days of enteral feeding before surgical intervention. Cardiopulmonary function is maximized and pulmonary sepsis is cleared before surgery. Patients who have received a previous botulinum injection are warned about the increased frequency of mucosal perforation related to submucosal fibrosis.26 However, previous botulinum injection should not be a contraindication to endoscopic Heller myotomy.23 Patients undergoing endoscopic esophageal myotomy should understand the risks and benefits of both laparoscopic and thoracoscopic approaches. The laparoscopic approach is preferred because of the superior long-term results (Urbach et al, 2001)25,29 but may not be possible if the patient has significant obesity that decreases the chance of accurate visualization of the esophagogastric junction with the laparoscopic technique; has undergone previous upper abdominal surgery or a previous transabdominal esophageal myotomy; or requires an additional long esophageal myotomy for symptomatic esophageal spasm. In these situations the thoracoscopic approach may be necessary. Conversely, thoracoscopic surgery may be contraindicated in patients with decreased pulmonary function that prevents the use of one-lung ventilation, which is necessary for accurate visualization of the esophagus. Operative Technique. All patients receive a liquid diet for 2 days before the operation and fast for 12 hours before surgery. At the time of the operation, the esophagus and the stomach are cleaned out with endoscopy before intubation and ventilation to avoid aspiration. TRANSTHORACIC ESOPHAGOMYOTOMY. The objective of this operation is to perform a myotomy of the lower 6 cm of the esophagus, the esophagogastric junction, and the proximal 2 cm of the stomach. The operation is done through a left thoracotomy with a nasogastric tube in place and the patient in a reverse Trendelenburg position. The chest is entered through the sixth intercostal space after deflating the left lung using a double-lumen tube or bronchial blocker. The inferior pulmonary ligament is divided, and the lung is retracted superiorly. The mediastinal pleura over the esophagus is divided, and a tape is placed around the esophagus and vagi nerves. A myotomy with no fundoplication as described by Ellis10 may be done without mobilization of the fundus. (See technique

described under thoracoscopic myotomy.) If a fundoplication is contemplated, the phrenoesophageal ligament is divided circumferentially and the peritoneal cavity is entered. The fundus of the stomach is mobilized into the chest by dividing two to three short gastric vessels. The phrenoesophageal fat pad is excised with care taken not to injure the vagus nerves. A myotomy through the longitudinal and circular muscles of the esophagus is started 6 to 8 cm above the phrenoesophageal junction and extended onto the stomach for at least 2 cm to divide the sling fibers of the esophagogastric junction (Fig. 69-3). The myotomy may be facilitated by exchanging the nasogastric tube with a 30-Fr Maloney bougie or a flexible gastroscope. Using the endoscope as a stent, the surgeon then dissects the muscles away from the mucosa for 180 degrees to prevent rehealing of the myotomy (Fig. 69-4). The gastroscope may also be used to check the adequacy of the myotomy or the presence of mucosal tears by insufflating the esophagus and stomach with air while the chest is

Fundus FIGURE 69-3 With straight Mayo scissors, a myotomy of the circular muscle fibers is performed and carried onto the stomach for approximately 2 cm.

Mucosa

FIGURE 69-4 With straight Mayo scissors, a circumferential dissection is performed in both directions of circular muscle off the mucosa to allow it to protrude.

Chapter 69 Surgical Approaches for Primary Motor Disorders of the Esophagus

full of warm saline. It is important to remove the air from the stomach before removal of the gastroscope to facilitate the fundoplication and avoid the use of a nasogastric tube in the postoperative period. At this stage, a modified Belsey fundoplication is used to decrease the chance of reflux without impeding esophageal transit (Fig. 69-5). Ideally the fundoplication should cover the whole length of the myotomy to avoid a pseudodiverticulum of the esophagus above the wrap. If a mucosal perforation occurs during the myotomy, the hole should be closed with a stapler or sutures and covered with the fundoplication. In the presence of an epiphrenic diverticulum, mobilization of the esophagus is the same except that the diverticulum is

A

747

excised before the myotomy. The neck is dissected free and stapled in the longitudinal direction with a gastroscope or bougie placed in the esophagus to avoid stenosis. The muscles are closed over the staple line, the esophagus is rotated 180 degrees, and the esophagogastric myotomy is performed as described earlier. THORACOSCOPIC ESOPHAGOMYOTOMY. The objective of this operation is to perform a myotomy of the lower 6 cm of the esophagus, the esophagogastric junction, and the proximal 2 cm of the stomach using thoracoscopic techniques. With the thoracoscopic technique, the left side of the chest allows the best visualization of the lower esophagus and cardioesophageal junction. After careful endoscopic cleansing of the esophagus and stomach before anesthesia, the trachea is intubated with a double-lumen tube, avoiding aspiration. The flexible gastroscope is then reinserted into the esophagus. Pneumatic stockings are used to avoid thromboembolic disease, and the patient is placed in the right lateral decubitus position with the head of the bed elevated 30 degrees to allow the abdominal contents and diaphragm to fall away from the operative area. The left sixth intercostal space is marked for a posterolateral thoracotomy if this is required for an open operation (Fig. 69-6). After collapse of the left lung, the first 10-mm port (see A on Fig. 69-6) is introduced through a small incision in the third intercostal space in the anterior axillary line, avoiding injury to the lung. No valves are used in the ports to avoid tension pneumothorax or an air embolus. A 30degree telescope is then introduced through the port to ensure that there are no pleural adhesions preventing the lung from collapsing and to examine the pleural space and diaphragm. Under direct vision, a second 10-mm trocar (see B on Fig. 69-6) is introduced in the sixth intercostal space 5 cm posterior to the posterior axillary line, with care taken to avoid injury to the intercostal vessels or nerve. This port site is used for the 5-mm 30-degree telescope for most of the operation.

B

C D A E B

C FIGURE 69-5 A, The modified Belsey repair is carried out via vertical mattress sutures in the first layer. B, A second layer of sutures is placed 1 cm above the first on the esophagus, which secures the wrap to the diaphragm. C, The wrap is reduced into the abdomen, and the second layer of sutures is secured.

FIGURE 69-6 Diagram of the left sixth intercostal space (broken line) and the positions of the port sites (A through E) for thoracoscopic esophagomyotomy.

tahir99-VRG vip.persianss.ir

748

Section 7 Neuromuscular Disorders

E

C

B D

A

FIGURE 69-7 The esophagomyotomy is started 6 to 7 cm above the diaphragmatic hiatus with a hooked cautery tip or sharp scissors dissection and brought through the phrenoesophageal ligament and onto the stomach for 1 cm.

A third 5-mm port (see C on Fig. 69-6) is then placed in the sixth intercostal space in the anterior axillary line to be used for dissection or retraction of the diaphragm, and a lung retractor is then placed through port A. Once the esophagus has been well visualized, the center of the operating diamond is established and an additional two 5-mm ports (D and E on Fig. 69-6) are placed about 15 cm apart to allow introduction of the left-hand and right-hand instruments of the operating surgeon. The left lung is retracted upward, and the inferior pulmonary ligament is divided with electrocautery up to the level of the inferior pulmonary vein. The mediastinal pleura is opened with care taken to avoid injury to the esophagus or the vagus nerve. The flexible endoscope is brought down to the lower esophagus and pointed up into the left chest to allow visualization of the esophagus. If the esophagus is not easily visualized at this time, a vascular tape is placed around the esophagus and brought out through one of the skin incisions beside the operating ports. The esophageal myotomy is started 6 to 7 cm above the diaphragmatic hiatus and brought through the phrenoesophageal ligament and onto the stomach for 1 cm (Fig. 69-7). After the longitudinal muscle of the esophagus has been identified and marked, the incision is deepened until the circular muscle fibers are evident. The circular muscle fibers are carefully hooked away from the mucosa and divided by means of low-power electrocautery or sharp scissors dissection. The surgeon introduces the flexible endoscope into the stomach, taking care not to distend the stomach with air. The myotomy is carried distally. As the diaphragm is approached, the assistant pulls on the muscular wall of the esophagus, bringing the esophagogastric junction into the chest while the instrument through port C pushes down on the diaphragm. As the incision is carried through the esophagogastric junction, care must be taken not to injure the mucosa, which is thinner in this area and may be more difficult to separate from the muscularis than in the thoracic esophagus.

FIGURE 69-8 Port placement for laparoscopic Heller myotomy and anterior fundoplication.

The branch of the left gastric vein running across the phrenoesophageal ligament marks the esophagogastric junction, and the myotomy should be carried onto the stomach for at least 1 cm distal to this landmark to divide the sling fibers of the stomach. An adequate myotomy is evident to the endoscopist as the lumen of the gastroesophageal junction suddenly becomes widely patent (open). When the lower part of the esophageal myotomy has been completed, the proximal end of the myotomy is carried toward the inferior pulmonary vein for 6 cm proximal to the esophagogastric junction. Using the endoscope as a stent, the surgeon then dissects the muscles away from the mucosa for 180 degrees. The chest is filled with warm saline and the esophagus is distended with air to check for mucosal perforations. If the mucosa is perforated, thoracoscopic suturing may be used to close the defect. Unless the surgeon is well versed in thoracoscopic suturing, however, the esophageal defect is more safely closed with absorbable sutures through a left thoracotomy and covered, if possible, with a partial fundoplication or an intercostal muscle flap. Port sites are then injected with 0.25% lidocaine and closed except for the anterior port, through which a 28-Fr angled chest tube is placed into the pleural cavity and attached to underwater drainage. This tube is removed 24 hours after surgery following completion of a successful esophagogram obtained by the use of water-soluble contrast material. Patients are given a “dental” soft diet for 3 weeks, after which they may resume a normal diet. Nocturnal proton pump inhibitors are given to patients with symptoms of heartburn.

tahir99-VRG vip.persianss.ir

Chapter 69 Surgical Approaches for Primary Motor Disorders of the Esophagus

FIGURE 69-9 The left lobe of the liver is retracted, exposing the diaphragmatic hiatus. The Babcock grasper is used for caudal retraction on the esophagogastric junction. Division of the gastrohepatic ligament and peritoneum overlying the abdominal esophagus begins superior to the hepatic branch of the vagus nerve and proceeds to the patient’s left to the left crus of the diaphragm with care taken not to injure the anterior vagus nerve.

LAPAROSCOPIC MODIFIED HELLER ESOPHAGOGASTRIC MYOTOMY WITH ANTERIOR FUNDOPLICATION. The objective of the modified Heller procedure is to carry out a myotomy of the lower 6 cm of the esophagus, the esophagogastric junction, and the proximal 2 cm of the stomach, obliterating the dysfunctional LES. The antireflux barrier is augmented by fixing the lower 6 cm of myotomized esophagus below the diaphragm under the influence of positive intra-abdominal pressure and wrapping it with a partial anterior gastric fundoplication. The fundoplication results in compression of the esophagus when intragastric pressure is elevated, reducing the propensity for reflux. All procedures are accomplished with the patient under general anesthesia after preoperative endoscopic cleaning of the esophagus and stomach to avoid aspiration during induction of anesthesia. Pneumatic stockings are used, and the patient is placed on the operating table in the lithotomy position with the head of the bed elevated 30 degrees. A flexible endoscope is reinserted into the midesophagus under direct vision. After preparing and draping of the patient’s abdomen, the surgeon stands between the patient’s legs with the camera operator on the patient’s right side. The

749

FIGURE 69-10 The left crus of the diaphragm is exposed completely.

video screen is placed at the head of the patient. The costal margin and the base of the xiphoid are marked. A pneumoperitoneum is produced using either a Veress needle in the left upper quadrant or the Hasson technique if the patient has had previous upper abdominal surgery. Port positions are illustrated in Figure 69-8. A 10-mm port (see A in Fig. 69-8) is placed 15 cm below the base of the xiphoid through the left rectus sheath medial to the epigastric vessels. A 30-degree telescope is introduced through port A, and a second 10-mm port (see B in Fig. 69-8) is placed using direct vision under the left costal margin 10 cm from the base of the xiphoid. A 5-mm trocar (see C in Fig. 69-8) is placed beneath the right costal margin 10 cm from the xiphoid. Through this port, the surgeon holds an atraumatic grasper with the left hand. A 5-mm trocar (see D in Fig. 698) is placed 15 cm from the base of the xiphoid through the right rectus sheath. Finally, the liver retractor is placed through a 5-mm port (see E in Fig. 69-8) placed in the midline just below the tip of the xiphoid. The left lobe of the liver is retracted, exposing the diaphragmatic hiatus (Fig. 69-9). A 5-mm Babcock grasper placed on the upper stomach through port D is used to retract the esophagogastric junction caudad. Division of the gastrohepatic ligament and the peritoneum overlying the abdominal esophagus begins superior to the hepatic branch of the vagus nerve and proceeds to the patient’s left to the left limb of the crus of the diaphragm, with care taken not to injure the anterior vagus nerve. The

tahir99-VRG vip.persianss.ir

750

Section 7 Neuromuscular Disorders

FIGURE 69-11 The retroesophageal space is opened from the right side of the esophagus. The esophagus is encircled with a vascular tape. The gastroscope is placed into the stomach under direct vision.

left crus of the diaphragm is exposed completely (Fig. 69-10). The surgeon opens the retroesophageal space from the right side of the esophagus and encircles the esophagus with vascular tape, taking care not to injure the posterior vagus nerve or the esophagus (Fig. 69-11). With careful hemostasis maintained, 6 cm of esophagus is mobilized into the abdominal cavity. A flexible endoscope is then placed into the stomach under direct vision. The phrenoesophageal ligament is divided between clips along the line of myotomy, with care taken to avoid injury to the anterior vagus nerve. The esophageal myotomy is started with a hook using low-power cautery in the thickened esophagus 6 to 8 cm proximal to the phrenoesophageal ligament and carried under the anterior vagus nerve, through the esophagogastric junction, and onto the stomach for at least 2 cm (Fig. 69-12). This allows division of the sling fibers of the esophagogastric junction. The esophageal muscle is swept off the mucosa for 180 degrees. The surgeon removes the gastroscope, checking the esophagogastric junction for patency and the mucosa for perforations. The myotomized esophagus is anchored in the abdomen by placement of three 2-0 silk sutures between the medial side of the fundus, the left crus of the diaphragm, and the left myotomized esophageal muscle (Fig. 69-13). The vascular tape is removed. If no anterior fundoplication is done, the right myotomized esophageal muscle is sewn to the right limb of the crus. If an anterior fundoplication is indicated, the apex of the fundus of the stomach is anchored to the anterior aspect of the right crus. The rest of the fundus is rolled loosely over the lower esophagus and anchored in place with three sutures between the fundus, the right side of the myotomized muscle, and the right limb of the crus of the

FIGURE 69-12 The esophagomyotomy is started in the thickened esophagus 6 cm proximal to the phrenoesophageal ligament and carried under the anterior vagus nerve and onto the stomach for at least 2 cm via a hooked cautery.

FIGURE 69-13 The myotomized esophagus is anchored in the abdomen by placement of three sutures between the medial side of the fundus, the left limb of the crus of the diaphragm, and the left edge of the myotomized esophageal muscle.

tahir99-VRG vip.persianss.ir

Chapter 69 Surgical Approaches for Primary Motor Disorders of the Esophagus

FIGURE 69-14 The fundus is rolled loosely over the esophagus and anchored to the right myotomized esophagus and right crus with three or four sutures.

FIGURE 69-15 The short gastric vessels are divided if the fundoplication is under tension.

diaphragm (Fig. 69-14). The short gastric vessels are divided if the fundoplication is under tension (Fig. 69-15). If the mucosa is perforated during the course of the procedure, the surgeon uses a laparoscopic suturing technique employing interrupted absorbable sutures to close the perforation. The perforation is then covered with the anterior fundoplication.

Thoracoscopic Esophageal Myotomy

Postoperative Care An esophagogram with water-soluble contrast material is obtained on the first postoperative day to rule out mucosal perforations. A clear fluid diet is started, and the patient is discharged to home, usually within 24 to 48 hours. Patients are given a dental soft diet for 3 weeks postoperatively, after which a normal diet is resumed.

Results Transthoracic Esophagomyotomy Long-term symptomatic improvement has been reported after an esophageal myotomy performed through a left thoracotomy with and without an antireflux procedure. Ellis10 reported that 74% of his patients had no or minimal dysphagia 9 years after a left thoracotomy and myotomy without an antireflux procedure. Malthaner and associates9 (1994) reported that 67% of their patients had minimal dysphagia 19 years after a left thoracotomy with partial fundoplication. The major late complications of transthoracic myotomy appear to be related to gastroesophageal reflux (esophagitis, columnar-lined esophagus, and peptic strictures), megaesophagus, or carcinoma. Ideally, the patient should either undergo postoperative 24-hour pH studies to rule out reflux or be placed on proton pump inhibitors to reduce the longterm sequelae of the reflux.

751

In 1993, Pellegrini and colleagues28 reported the results for 24 patients who had undergone esophageal myotomy. Dysphagia was completely relieved in 17 of these patients and substantially, but not completely, relieved in 4 of the 24. Five of 8 patients who had undergone a 24-hour pH study exhibited abnormal esophageal reflux, although they were asymptomatic. These investigators recommended that these patients be treated with night-time proton pump inhibitors to decrease the amount of acid reflux and that they be monitored with periodic endoscopic monitoring to make sure that mucosal damage caused by reflux was not occurring. Pellegrini’s group observed that 3 of the 24 patients had residual dysphagia and concluded that the myotomy was not carried down far enough onto the stomach. Stewart and Finley29 analyzed the short-term and longterm results of thoracoscopic esophageal myotomy in 24 patients in two centers. In 5 patients the procedure was switched to open thoracotomy; 3 of the 5 patients had intraoperative esophageal perforations. These were recognized intraoperatively and, after conversion to thoracotomy, the perforations were closed and wrapped by means of a partial fundoplication using a Belsey technique. There were no postoperative leaks. The mean postoperative length of stay was 6 days as a result of prolonged hospitalization for the 3 patients with esophageal perforations. After a median follow-up of 42 months, 31% of the patients had no to minimal dysphagia, 67% had no or minimal heartburn, and 77% were satisfied with the surgical results. Patti and colleagues24 reviewed the results for 35 patients who had undergone thoracoscopic esophagomyotomy in two centers. In 2 patients, the procedure was switched to open thoracotomy. Four mucosal perforations occurred; one was repaired thoracoscopically, two were repaired by thoracot-

tahir99-VRG vip.persianss.ir

752

Section 7 Neuromuscular Disorders

omy, and one required an esophagectomy because of endstage disease. Excellent or good relief was observed in 73% of the patients. Symptoms of regurgitation, heartburn, and chest pain were also significantly relieved. Nine patients had persistent dysphagia secondary to an incomplete myotomy. Four of them subsequently underwent laparoscopic completion myotomies with good results. These authors have now recommended that the laparoscopic approach to a modified Heller myotomy is the best primary surgical therapy for achalasia unless the patient has significant obesity that decreases the chance of accurate visualization of the esophagogastric junction with the laparoscopic technique, has undergone previous upper abdominal surgery or a previous transabdominal esophageal myotomy, or requires an additional long esophageal myotomy for symptomatic esophageal spasm.

Laparoscopic Esophageal Myotomy and Fundoplication Using a laparoscopic myotomy and anterior fundoplication, Rosati and colleagues (1995)12 reported that 96% of their patients had absent or mild dysphagia postoperatively. Finley and colleagues30 reviewed 69 consecutive patients with achalasia who had undergone a laparoscopic Heller myotomy and anterior fundoplication by one surgeon. The median operative time was 1.9 hours, and there were no conversions to laparotomy. Operative complications included 1 patient with a mucosal perforation closed laparoscopically without sequelae and 3 patients with pneumothoraces that resolved spontaneously. Of the 64 patients available for follow-up (mean, 1 year), 96% were satisfied with their surgery. Symptoms were reported more than once a week for dysphagia in 4 patients, for regurgitation in 3 patients, and for heartburn in 6 patients. Liquid-phase esophageal transit studies revealed significant improvement. During a 10-minute period, esophageal clearance in the supine position improved from 28% before the operation to 49% after the operation and in the upright position from 55% to 81%. One patient had persistent postoperative dysphagia secondary to a tight anterior fundoplication. The dysphagia disappeared after a laparoscopic reversal of the fundoplication. A recent review of 217 consecutive patients with classic achalasia treated in our center with laparoscopic myotomy between 1994 and 2005 showed that the operation decreased the frequency of any dysphagia from 99% to 14%, any heartburn from 62% to 20%, and any regurgitation from 95% to 5%. Intraoperative complications included one pneumothorax requiring a chest tube and three mucosal perforations that were closed laparoscopically and did not leak. No patients required conversion to an open procedure. Postoperative complications included 12 patients with subcutaneous emphysema, 8 patients with atelectasis, 8 patients with asymptomatic pneumothoraces, 2 patients with wound infections, 2 patients with pleural effusions, 2 patients with pneumonia, and 1 patient with delayed gastric emptying. There were no perioperative deaths. Persistent postoperative dysphagia was influenced by preoperative botulinum toxin injection. Two patients have required reoperation for dysphagia.

Patti and associates24 studied 133 patients who had undergone a laparoscopic myotomy in addition to a partial fundoplication. Mucosal perforations, which occurred in 6 patients, were closed laparoscopically. Eleven percent of the patients had persistent dysphagia initially, and 1% developed recurrent dysphagia after 1 year. Four of these patients had imperfectly formed Dor fundoplications, 5 had fibrotic transmural strictures, and 2 had incomplete myotomies. The incidence of preventable technical failure dropped from 23% during the early period of the study to 3% in the later experience. New gastroesophageal reflux developed in 17% of patients after laparoscopic myotomy. However, preoperative reflux was corrected in 5 of 7 patients. The authors also reported excellent swallowing after a laparoscopic Heller myotomy, even in patients with an esophageal diameter greater than 6 cm. The ability to mobilize and straighten a sigmoid-shaped esophagus during laparoscopic myotomy may improve esophageal emptying. An adequate myotomy that obliterates the entire LES is most likely to improve esophageal emptying in patients with achalasia. Oelschlager and colleagues31 showed that an extended gastric myotomy (3 cm) more effectively disrupts the LES, thus improving the results of surgical therapy for achalasia for dysphagia without increasing the rate of abnormal gastroesophageal reflux, provided that a Toupet fundoplication is added. Surgical treatment of achalasia with myotomy of the LES requires a fine balance between an improvement in esophageal emptying and the possible development of GERD. In a prospective, randomized, double-blind, controlled clinical trial, Richards and associates32 showed that Heller myotomy plus Dor anterior fundoplication was superior to Heller myotomy alone in regard to the incidence of postoperative gastroesophageal reflux as measured by 24-hour pH studies. In a retrospective study of 149 patients, Rice and colleagues14 showed that gastroesophageal reflux measured by 24-hour pH studies was significantly less in both the upright and supine positions with the addition of a Dor fundoplication to laparoscopic Heller myotomy. Lower premyotomy LES pressure was associated with increased reflux. In both of these studies the abnormal 24-hour pH studies seen in the patient groups without fundoplication are just above the upper limits of normal. Although the long-term effects of this low exposure to acid are unknown, these patients should probably be treated with proton pump inhibitors to reduce the long-term sequelae of peptic strictures or columnar-lined esophagus. The addition of a fundoplication to prevent reflux may adversely affect esophageal emptying after esophageal myotomy. The addition of a Nissen fundoplication to Heller myotomy failed to improve esophageal emptying immediately post myotomy. Furthermore, esophageal emptying worsened over time, with 29% of patients requiring takedown of the Nissen fundoplication.27 Finley and coworkers33 showed that patients with an anterior fundoplication after myotomy had decreased esophageal clearance and less improvement in dysphagia and regurgitation scores compared with patients without fundoplication. Other studies showed that the addition of fundoplication increased resting and residual LES pressures compared with no fundoplication, but

tahir99-VRG vip.persianss.ir

Chapter 69 Surgical Approaches for Primary Motor Disorders of the Esophagus

it did not significantly affect esophageal emptying, as assessed by timed barium studies,14 or increase the incidence of dysphagia. Pending long-term follow-up, the present evidence suggests that the optimal laparoscopic operation involves complete obliteration of the LES with an extended gastric myotomy followed by a loose anterior or posterior partial fundoplication. For primary surgical therapy of achalasia, the laparoscopic approach to esophagomyotomy is favored over the thoracoscopic technique because the most difficult part of the dissection at the gastroesophageal junction is easiest to see laparoscopically and mucosal lacerations can be avoided. Furthermore, the laparoscopic technique avoids one-lung anesthesia and the need for chest tubes, allowing the surgeon to carry out an adequate myotomy and an antireflux procedure.

ISOLATED HYPERTENSIVE LOWER ESOPHAGEAL SPHINCTER Definition Hypertensive LES is an uncommon manometric abnormality characterized by a normally relaxing, but hypertensive, LES (>26 mm Hg). Function of the body of the esophagus is normal.

Diagnosis Clinical Features Patients present with dysphagia and chest pain. The chest pain is usually epigastric in location, but cardiac disease must be ruled out. The dysphagia may occur with solids or liquids. The pain or dysphagia may be initiated by episodes of emotional stress, ingestion of cold liquids, or rapid eating. Many patients will have a sliding hiatus hernia and symptoms of GERD such as heartburn or acid regurgitation.

In patients identified as having gastroesophageal reflux the use of a fundoplication to decrease GERD raises concerns about inducing or increasing dysphagia. The role of myotomy in isolated hypertensive LES is also unclear.

Medical Therapy Medical therapy is aimed at providing maximum gastric acid control with proton pump inhibitors and decreasing reflux with weight loss and elevation of the head of the bed and reduction of stimuli that initiate the symptoms. Prokinetic agents appear to be ineffective and sometimes make the symptoms worse.34

Surgical Therapy Surgical therapy is generally reserved for patients with recurrent, incapacitating episodes of dysphagia with or without chest pain who do not respond to medical treatment. Tamhankar and colleagues35 used two approaches for patients with this syndrome. Patients with hypertensive LES and GERD or type III hiatal hernia had a Nissen fundoplication, and those with isolated hypertensive LES had a myotomy of the LES with partial fundoplication. Dysphagia and chest pain were relieved in all patients at long-term follow-up. Outcome was excellent in 10, good in 3, and fair in 3 of 16 patients.

DIFFUSE ESOPHAGEAL SPASM Definition Diffuse esophageal spasm is a motility disorder of the esophagus characterized by ineffective simultaneous contractions in the distal esophagus but normal peristaltic waves intermixed with the normal contractions (Spechler and Castell, 2001).1

Investigative Techniques

Diagnosis

Cardiac disease should be ruled out as a cause of the chest pain. Cine barium swallow may show an intermittent narrowing at the lower esophagus and the presence of a hiatal hernia. Endoscopy may show evidence of a hiatal hernia or reflux esophagitis. A Schatzki ring or peptic stricture should be ruled out. Twenty-four-hour pH studies may show evidence of gastroesophageal reflux. Esophageal manometry shows normal propulsive waves in the body of the esophagus with a hypertensive LES (>26 mm Hg; i.e., >95th percentile of the control population) that relaxes normally with swallowing (Spechler and Castell, 2001).1 Results of nuclear medicine esophageal transit studies are normal, as opposed to the decreased transit seen in patients with achalasia.

Clinical Features

Management Principles of Management The primary goal of therapy is the relief of the chest pain and dysphagia. Achalasia and diffuse esophageal spasm need to be excluded from the differential diagnosis by esophageal manometry. Anatomic abnormalities such as a hiatal hernia or stricture are identified by endoscopy or barium swallow.

753

Diffuse esophageal spasm is a clinical syndrome characterized by symptoms of substernal distress, dysphagia, or both occurring equally in males and females at an average of age 50 years. The chest pain is indistinguishable from cardiac angina and may be relieved by nitrates. The pain or dysphagia may be initiated by episodes of emotional stress, ingestion of cold liquids, or rapid eating.

Investigative Techniques When cardiac disease has been eliminated as a cause of the symptoms, the patients should undergo endoscopy and radiographic studies to rule out anatomic disease. The endoscopy identifies nonpropulsive waves, the presence of achalasia, and GERD. The radiographic appearance by cine barium swallow shows localized nonprogressive waves and intermittent nonperistaltic contractions or tertiary contractions. The segmentation of the barium column by tertiary contractions has been described as pseudodiverticula, curling, or corkscrew changes. Manometric evidence of diffuse esophageal spasm includes the presence after wet swallows of more than 20% simultane-

tahir99-VRG vip.persianss.ir

754

Section 7 Neuromuscular Disorders

ous contractions that must be intermixed with normal peristaltic waves. If all contractions are simultaneous, then a diagnosis of achalasia is made (Spechler and Castell, 2001).1 Gastroesophageal reflux is excluded by the use of 24-hour pH studies.

Management Principles of Management The primary goal of therapy is palliation of symptoms since the esophageal motor abnormality remains unchanged after all forms of intervention. At present, all treatment techniques are directed at relieving pain and dysphagia.

Medical Therapy Medical therapy for diffuse esophageal spasm include oral medications, dilation, botulinum injection, and treatment of gastrointestinal reflux. Anticholinergic medications decrease the amplitude of the contractions but have significant side effects. Nitrates relieve chest pain by deceasing the amplitude and duration of the contractions. Calcium channel blockers also decrease the amplitude and duration of contractions but have no effect on the frequency and duration of chest pain.36,37 Finally, the medications used to treat diffuse esophageal spasm lower LES pressure, resulting in reflux and emphasizing the need for 24-hour pH studies and aggressive antireflux therapy in these patients. Pneumatic dilation has shown an improvement in 70% to 89% of cases but has the risk of esophageal perforation. Short-term relief with botulinum injection has also been observed.38

Surgical Therapy Surgical therapy is generally reserved for patients with recurrent, incapacitating episodes of dysphagia with or without chest pain who do not respond to medical treatment. A long esophageal myotomy in these patients abolishes (1) all contractile activity, eliminating the functional obstruction resulting from simultaneous contractions and decreased muscle compliance, and (2) any remaining propulsive contractions. Therefore, for a long esophageal myotomy to be of benefit, the degree of functional obstruction causing dysphagia must outweigh the existing propulsive activity in the esophagus. Ambulatory manometry has been proposed as a means of identifying candidates for myotomy.39 These authors found that when the percentage of effective contractions fell below 50% during meals, dysphagia was common. When the percentage of effective contractions fell below 30%, surgery was beneficial. The important technical aspects of a long esophageal myotomy include the following: ■ ■ ■

Determination of the proximal and distal extent of the myotomy Need for an antireflux procedure The ideal operative approach

Esophageal manometry is a useful guide to the extent of myotomy required. The proximal extent of the myotomy should be high enough to encompass the entire length of

disordered motility. Henderson and associates40 recommended extending the myotomy to the level of the thoracic inlet in all patients on the basis of the observation that smooth muscle can account for up to 30% of the upper thoracic esophagus muscles. Most authors recommend the addition of an antireflux procedure when the myotomy is carried through the LES, but there is no uniform agreement about the need to carry the myotomy onto the stomach. The esophageal myotomy may be carried out via the left chest either using an open thoracotomy or thoracoscopic approach as described earlier or through a right thoracoscopic approach. The myotomy should be extended to the level of the aortic arch or ideally to the thoracic inlet because the upper esophagus has smooth muscle involvement in 30% of cases. The arguments regarding the distal extent of the myotomy in diffuse esophageal spasm depend on the presence of abnormalities in the function of the LES. If the patient has evidence of significant gastroesophageal reflux documented by 24-hour pH studies and endoscopy, then an antireflux procedure is indicated after maximum medical management. A left posterolateral thoracotomy allows easy access to the gastroesophageal junction for a complete myotomy and the addition of an antireflux procedure. The myotomy is usually carried proximally to the level of the aortic arch but may be extended proximally under the arch to the thoracic inlet if necessary. The ideal antireflux procedure is a modified Belsey fundoplication. After completion of the myotomy, a fundoplication is performed by suturing a tongue of gastric fundus to the margins of the myotomy for a distance of 4 cm. This procedure helps to prevent rehealing of the myotomy site and provides reflux protection. The flap of gastric fundus is allowed to retract into the abdomen and is secured in place by passing the tails of the tied apical sutures of the fundoplication through the diaphragm. If no antireflux procedure is indicated and there are no LES abnormalities then a thoracoscopic myotomy may be done using the technique described in Figure 69-7. In this case the myotomy is only carried to the level of the diaphragm. The advantage of a right thoracoscopic approach is the ease with which the myotomy can be carried to the thoracic inlet versus the left thoracoscopic approach in which the myotomy must be extended proximally under the arch of the aorta to the thoracic inlet.

Late Results The results of long esophageal myotomy in the patient with diffuse esophageal spasm have been variable. Henderson and associates40 reported good results in 88% of cases with a myotomy to the level of the thoracic inlet combined with a short Nissen fundoplication. A myotomy to the level of the aortic arch combined with a Dor partial fundoplication has been reported to be successful in 80%.39 In a retrospective review comparing medical therapy with thoracoscopic long myotomy, Patti and associates34 reported success in only 26% in the medical group compared with good to excellent results in 80% after surgery. In summary, the role of long esophagomyotomy for patients with diffuse esophageal spasm and related motor disorders remains controversial. The results are

tahir99-VRG vip.persianss.ir

Chapter 69 Surgical Approaches for Primary Motor Disorders of the Esophagus

poorer than those after esophagomyotomy for achalasia, and long-term postoperative follow-up of these patients is essential because early good results may be misleading.41 Two methods are considered equally effective in avoiding postmyotomy reflux: a short, floppy wrap of the LES or a sphinctersparing myotomy when manometry indicates normal functioning of the sphincter (Ellis, 1998).42

NUTCRACKER ESOPHAGUS Definition Nutcracker esophagus is a motility disorder of the esophagus characterized by high-amplitude peristaltic contractions in the distal esophagus.

Diagnosis Clinical Features The most common symptom is chest pain. Many patients have symptoms of anxiety, depression, and irritable bowel syndrome, but, unlike patients with diffuse esophageal spasm, these patients usually do not have dysphagia or weight loss.

Investigative Techniques The presence of chest pain mandates a cardiac evaluation. Radiographic and endoscopic examinations of patients with nutcracker esophagus are usually normal. To establish a diagnosis of nutcracker esophagus, manometry must show peristaltic waves and contraction amplitudes at levels 2 SD above the mean (180 mm Hg) in the distal esophagus.

Management Medical Therapy Calcium channel blockers are the only drugs to show symptom improvement and decrease in contraction amplitude in this syndrome.36 Bougienage and pneumatic dilation are not effective.

Surgical Therapy Because dysphagia and weight loss are not features of this syndrome, myotomy is not usually indicated for pain alone. Myotomy has the added complication of obliterating any peristaltic contractions, increasing the risk of adding dysphagia to the patient’s symptoms.

COMMENTS AND CONTROVERSIES Achalasia is the only motility disorder that is commonly treated surgically. It is a well-defined entity with a large literature detailing treatment outcome. This disease is well suited to laparoscopic palliation. The patient must be informed that the esophagus is not being repaired but converted into a passive conduit. With realistic expectations for palliation of dysphagia and regurgitation, achalasia

755

patients are one of the most satisfied patient groups undergoing esophageal surgery. Persistent obstruction from an incomplete myotomy or peptic stricture from excessive reflux is to be avoided with careful surgical technique. The myotomy must not be too excessive on the esophagus (limited to the intra-abdominal esophagus) and must extend onto the stomach for 2 to 3 cm. Any myotomy of this extent must be accompanied by a partial fundoplication. Reflux should be assessed postoperatively by 24-hour pH monitoring, and any nocturnal reflux should be treated with nighttime proton pump inhibitor therapy. Follow-up must be lifelong to ensure adequate esophageal emptying with minimal or no reflux. This approach of early and complete myotomy of the LES and prevention of reflux is most likely to preserve the esophagus as a passive one-way conduit and avoid esophagectomy for the endstage sigmoid esophagus. Unfortunately the other esophageal motility disorders are not as well understood. This is in part because they are very uncommon, and patients so afflicted rarely proceed to surgery. Treatment is sometimes paradoxical, as in fundoplication for hypertensive esophageal sphincter, or excessive, as in long myotomy for diffuse esophageal spasm. As previously stated, these disorders may be transient, related to other esophageal pathologic processes such as GERD, achalasia in evolution, or epiphenomena. Therefore, patience of both the patient and physician is required in diagnosis and treatment. Management of many motility disorders should initially be temporizing, because time may allow further definition of the abnormality and better direct therapy. T. W. R.

KEY REFERENCES Bonavina L, Nosadini A, Bardini R, et al: Primary treatment of esophageal achalasia: Long-term results of myotomy and Dor fundoplication. Arch Surg 127:222, 1992. Dor J, Humbert P, Dor V, et al: L’intérêt de la technique de Nissen modifiée dans la prevention de reflux après cardiomyotomie extramuqueuse de Heller. Mem Acad Chir (Paris) 88:877, 1962. Ellis FH Jr: Long esophagomyotomy for diffuse esophageal spasm and related disorders: An historical overview. Dis Esophagus 11:210-214, 1998. Heller E: Extra Mukose cardiaplatik beim chronisher Cardiospasmus mit Dilation Oesophagus. Mitt Grenzgeb Med Chir 27:141, 1914. Malthaner RA, Todd TR, Miller L, et al: Long-term results in surgically managed esophageal achalasia. Ann Thorac Surg 58:1343, 1994. Pellegrini C, Wetter LA, Leichter R, et al: Thoracoscopic esophagomyotomy: Initial experience with a new approach for the treatment of achalasia. Ann Surg 216:291, 1992. Rosati F, Fumagalli U, Bonavina L: Laparoscopic approach to esophageal achalasia. Am J Surg 169:424, 1995. Spechler SJ, Castell DO: Classification of oesophageal motility abnormalities. Gut 49:145, 2001. Urbach DR, Hansen PD, Khajanchee YS, et al: A decision analysis of the optimal initial approach to achalasia: Laparoscopic Heller myotomy with partial fundoplication, thoracoscopic Heller myotomy, pneumatic dilatation, or botulinum toxin injection. J Gastrointest Surg 5:192-205, 2001.

tahir99-VRG vip.persianss.ir

chapter

70

CAUSTIC INJURIES TO THE ESOPHAGUS Kashif Irshad Michael S. Kent James D. Luketich

Key Points ■ Corrosive injuries are challenging problems that require experience

and judgment in management. ■ During initial evaluation, equipment for endotracheal intubation and

■ ■

■ ■

■ ■

■

■

■

■

cricothyroidotomy needs to be available in case of severe upper airway edema. If intubation is required, orotracheal intubation or fiberoptic-assisted intubation is preferred over blind nasotracheal intubation. Endoscopy is performed early; it is most safely performed using a pediatric endoscope with minimal air insufflation and advancement only until the area of the injury is seen. An experienced esophageal surgeon may advance the endoscope farther in an adult, with extreme caution. Randomized trials have shown that corticosteroids do not appear to decrease the incidence of strictures. For second- and third-degree burns, early dilation starting at 3 to 4 weeks may help decrease the incidence of strictures; dilations can be performed in a retrograde fashion through a gastrostomy or antegrade over a guidewire using fluoroscopic guidance. Initial management is guided on endoscopic estimation of the extent of injury. Key to successful management decisions is constant reassessment of the clinical status of the patient. A deteriorating clinical course may indicate the need for surgical exploration and possible resection, diversion, and drainage. If immediate surgery is indicated, almost all patients need to undergo an abdominal exploration with placement of a feeding tube and placement of a gastrostomy tube for potential future retrograde dilation. When not requiring urgent resection, a nonabsorbable suture placed across the esophagus and exiting via the gastrostomy tube may facilitate later endoscopy and safe dilations. If resection is being considered, consult with experienced members of the surgical team. Immediate resection of obviously necrotic tissue may be lifesaving. In some patients, drainage and secondlook operation within 12 to 24 hours may be necessary. If an esophagectomy is performed, preserve as much proximal esophagus as possible. Reconstruction is delayed for several months until the patient has recovered from the initial injury. If a stricture does not respond to repeated dilations for a minimum of 6 months, resection may be considered; in this circumstance, remove the native esophagus to prevent the development of a future carcinoma. In cases of severe burns and a severe fibrosing reaction, the esophagus is excluded and a substernal gastric pullup or colon interposition is performed.

At the beginning of the 20th century, lye products became available for domestic use. This led to a dramatic increase in cases of accidental ingestion of these compounds. Unfortunately the majority of patients were children. In response, Chevalier Jackson, a leading endoscopist from the University of Pennsylvania, began a campaign that led to the Federal Caustic Act (1927), which mandated proper labeling of these harmful substances. The rate and severity of corrosive injuries again increased dramatically in the 1960s with the introduction of household cleaners with high alkali concentrations. Subsequently, the Poison Prevention Act of 1970 and the Federal Hazardous Substance Act of 1972 have enforced proper labeling, antidote instructions, concentration restriction, and child-resistant packaging. Nonetheless, corrosive esophageal injuries still remain a significant health hazard, particularly for children. The controversies that confronted physicians who treated some of the first patients with caustic esophageal injuries remain largely unresolved today. These include the risk and benefit of early endoscopy, methods for preventing and treating esophageal strictures, and the timing and techniques of esophageal resection and replacement. The best treatment remains elusive owing to the relative rarity of this problem, the variable severity of the injury, and the difficulty in objectively assessing a variety of treatment options.

EPIDEMIOLOGY Caustic injuries result from the ingestion of either a strong base or acid. Alkali ingestion constitutes the vast majority of injuries because they are the main ingredient in common household cleaners. These products accounted for almost 230,000 exposures reported to the U.S. Poison Control Center in 1998 alone, making it the most common type of harmful exposure. Approximately 80% of caustic injuries occur in children younger than 5 years of age. The severe injuries that may result could be easily prevented by proper storage of these cleaners in a location inaccessible to children. Foreign bodies may also cause caustic injury if lodged within the esophagus. Most commonly, this results from the ingestion of disc batteries found in electronic devices. A significant percentage of battery ingestions occur among children who are hearing impaired and ingest the batteries from their own hearing aids. Severe injury results within 1 hour of ingestion from the extravasation of highly toxic potassium or sodium hydroxide contained in the battery.1 759 tahir99-VRG vip.persianss.ir

760

Section 8 Trauma

Ingestion of cosmetic agents such as hair relaxers have also been a cause of caustic esophageal injury in children.2 These compounds typically contain sodium or calcium hydroxide. Unfortunately, childproof packaging is not required for these products, despite their clear potential for injury. In the adult population, most ingestions result from suicide attempts. As opposed to children who do not ingest more than a mouthful of a noxious substance, adults may intentionally ingest a greater amount. Consequently their injuries tend to be more extensive. In adults, another cause of caustic injury is the ingestion of prescribed drugs. There are several studies that document that aspirin (acetylsalicylic acid) and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with severe esophagitis or esophageal stricture.3 Nearly 100 other oral medications have been reported to produce esophageal injury.4 Nearly any pill that remains in contact with the esophagus for a sufficient amount of time can cause mucosal injury. For some medications the mechanism of injury has been fairly well elucidated: acidic burn (ascorbic acid, ferrous sulfate, tetracyclines, and emepronium), alkaline burn (phenytoin), local hyperosmolarity (ferrous sulfate), and intracellular poisoning after mucosal uptake (NSAIDs). However, the exact cause of injury is unknown for many other medications known to be caustic to the esophagus.

PATHOPHYSIOLOGY The severity of injury to the esophagus depends on the following factors5: 1. 2. 3. 4.

pH of the ingested substance Whether the substance is solid or liquid Duration of exposure Quantity ingested

The exposure of the esophagus to the two extremes of the pH scale results in very different patterns of injury. Alkaline substances tend to penetrate the oropharynx and esophagus to a much greater degree than acid. This leads to a more severe injury than ingestion of an equivalent amount of acid. This deeper burn may lead to perforation in the immediate postingestion period. For patients who survive the initial injury, severe stricture and motor dysfunction (from injury to the smooth muscle or myenteric plexus) may develop.6 Another reason that alkaline injuries are more severe is that bases are often odorless and tasteless, and so a greater quantity can be ingested. In contrast, acids tend to taste bitter and cause immediate pain on ingestion. As a consequence the patient will often spit out the compound before there is significant exposure to the esophagus. Even with more prolonged exposure, acid burns are more likely to produce a superficial eschar that protects the deeper layers from significant damage. In part, this may be due to the squamous mucosa, which protects the esophagus from daily reflux of gastric acid. Whether the substance is solid or liquid will also dictate the severity and location of the injury. Solid alkaline compounds tend to adhere to the mucosa of the oropharynx, limiting the area of injury. A liquid base is more rapidly swallowed, causing less oropharyngeal damage but much more

TABLE 70-1 Commonly Ingested Caustic Substances Acid-Containing Substances Toilet bowl cleaning products Automotive battery liquid Rust removal products Metal cleaning products Cement cleaning products Drain cleaning products Alkali-Containing Substances Ammonia-containing products Oven cleaning products Swimming pool cleaning products Automatic dishwasher detergent Hair relaxers Bleaches

severe esophageal and gastric injury. Esophageal injury also tends to be most severe at areas where the lumen is smaller, and consequently the transit speed is lower. These areas are as follows: 1. The cricopharyngeus 2. The midesophagus at the level of the aortic arch and left main stem bronchus 3. The distal esophagus just above the lower esophageal sphincter Esophageal and gastric injury may be further aggravated by pylorospasm, which leads to gastric retention and regurgitation of the caustic agent back into the esophagus. The initial injury results in an intense inflammatory reaction causing erythema and edema of the superficial layers. Vascular thrombosis, bacterial infiltration, cell death, and fatty saponification (after alkaline injuries) may occur subsequently, depending on the depth of penetration. During the first hours after ingestion, the injured area is usually not well demarcated. However in the ensuing 24 to 48 hours the damaged layers begin to degenerate and become infiltrated with lymphocytes. Angiogenesis and migration of fibroblasts begin between the second and fourth day after injury. By 1 week, the necrotic tissue has sloughed off and ingrowth of granulation tissue begins. The wound is clearly demarcated by this time, and the risk of perforation is probably the highest owing to the low tensile strength of the collagen deposited in the wound. By the end of the second week, the injured areas are filled with granulation tissue and the contractile phase of healing begins. This phase is the target of many medications that aim to limit stricture formation. The contractile process continues for months and can result in debilitating strictures.

DIAGNOSIS AND MANAGEMENT History and Physical Examination It is helpful to identify the nature of the ingested material (Table 70-1). Household ammonia is commonly ingested, although the concentration is usually not high enough to cause severe mucosal injury. Other household disinfectant cleaners (e.g., Lysol) contain phenol, a strong alkali that

tahir99-VRG vip.persianss.ir

Chapter 70 Caustic Injuries to the Esophagus

761

FIGURE 70-1 A patient presented who had ingested lye, resulting in severe airway edema requiring bronchoscopic-guided endotracheal intubation. Note on this CT scan that the airway edema has completely enveloped the endotracheal tube. Also, the esophageal lumen is obliterated by edema.

can result in severe injuries even when ingested in small quantities. Symptoms of caustic ingestion include oral pain, hematemesis, drooling, and the inability to swallow. Hoarseness, stridor, and dyspnea suggest laryngeal edema or epiglottic injury, which will likely require endotracheal intubation. Fullthickness injury with perforation may present as retrosternal pain or neck crepitus. Even with severe injury, patients may have very few signs and symptoms in the early period. For example, a recent study has shown that 20% of children with caustic ingestion are asymptomatic on presentation, and at least half of these patients will have injuries that require treatment.7

Initial Evaluation When a patient with a suspected caustic ingestion is being evaluated, equipment for endotracheal intubation and cricothyroidotomy needs to be available in case of severe upper airway edema. Orotracheal intubation or fiberoptic-assisted intubation is preferred over blind nasotracheal intubation because of the risk of accidental perforation (Fig. 70-1). It is important not to administer emetics because this will reexpose the esophagus to the caustic agent. Gastric lavage is also contraindicated, owing to the risk of esophageal perforation and aspiration of gastric contents. Radiographic evaluation of the patient begins with a standard chest radiograph. Findings may include pneumomediastinum, pleural effusion, pneumoperitoneum, and aspiration pneumonitis. A more sensitive study to detect early perforation is CT of the chest and abdomen with enhancement with an oral contrast agent. A common finding on CT is severe edema of the esophageal wall that can cause near obliteration of the lumen (Fig. 70-2).

Endoscopy The definitive study to determine the severity of injury is flexible endoscopy. If endoscopy is to be used, it is performed early because the risk of iatrogenic perforation is much higher

FIGURE 70-2 CT of the chest shows severe esophageal wall edema. The lumen remained patent, and the patient was able to tolerate his own saliva.

48 to 72 hours after ingestion. The procedure is most safely performed using a pediatric endoscope with minimal air insufflation.8 The endoscope is passed until the first area of injury is noted. From this point on, extreme caution must be exercised to avoid mucosal injury, creating a false lumen and the possibility of a full-thickness injury. On the other hand, in our experience, one can frequently navigate through areas of moderate injury to allow a full assessment of the entire esophagus, stomach, and proximal duodenum. However, if any concerns on the safety of the procedure are encountered, one may need to consider terminating the examination. Burns may be classified according to the depth of injury seen on endoscopy (Table 70-2). This simple classification system is very useful in predicting the severity of injury and likelihood of stricture formation. The use of endoscopic ultrasonography in this setting remains of uncertain value. Safety and potential perforation is one issue, the other is validation and interpretation of results in the setting of severe mucosal edema. In one study endoscopic ultrasonography did not increase the accuracy for prediction of early or late complications above that of standard endoscopy, and it is not used in most centers.9 We do not use endoscopic ultrasonography in our center to evaluate caustic ingestions.

Hospital Management All patients suspected of having a caustic esophageal injury are admitted to the hospital for observation. Patients are routinely started on broad-spectrum antibiotics and antifungal agents and given nothing by mouth. Although no controlled studies in humans have been done, animal studies have shown that the early administration of antibiotics can

tahir99-VRG vip.persianss.ir

762

Section 8 Trauma

TABLE 70-2 Classification of Burns by Depth of Injury Grade

Depth

Endoscopy

First degree

Mucosal

Mucosal hyperemia and edema

Second degree

Transmucosal, with or without involvement of muscularis. No extension to periesophageal tissue.

Hemorrhagic, exudative, ulcerative pseudomembranes

Third degree

Full-thickness injury with extension into periesophageal tissue. May involve mediastinal or intraperitoneal organs.

Complete obliteration of esophageal lumen by massive edema; charring and eschar; full-thickness necrosis with perforation.

decrease the local infection that occurs after corrosive injury. These infections may lead to an increased inflammatory response with subsequent fibrosis and stricture formation.10 Subsequent management decisions are guided by the severity of injury documented on endoscopy, but the key to successful management is a constant hourly reassessment of the patient’s clinical status. A severe injury may go unrecognized on initial endoscopy, and a perforation may develop on the second or third hospital day. Frequent physical examinations, radiographs, and even CT scans are considered to reassure the physician that the patient’s injury is not progressing. A deteriorating clinical course may require surgical exploration and possible resection, diversion, and drainage. Assuming that a perforation has not occurred and the clinical course is stabilized, the major controversies in the early postinjury period are the benefits of corticosteroids and early dilation, two measures that one hopes will prevent or minimize the development of esophageal stricture.

Corticosteroids The benefit of administering corticosteroids to patients who have a high risk for developing local and systemic infection is unproven. This practice was justified by retrospective studies that suggested corticosteroids may minimize the development of esophageal strictures.11,12 However, two large studies have since documented the minimal impact that corticosteroids have on preventing stricture formation.13,14 The first is a randomized controlled trial of 131 children with esophageal injury, in whom half received corticosteroids.13 Among these children, 45% had significant injury documented on endoscopy and 50% developed strictures. Almost all of the patients who developed strictures had thirddegree burns. There was no difference between those treated with corticosteroids and the control group. The conclusion of this study was that the depth of injury alone determines the development of strictures. The second study was a meta-analysis of the European literature on corticosteroids in corrosive esophageal injury.14 This analysis comprised 20 studies that included 572 patients. In the 305 patients treated with corticosteroids, 35% developed strictures, compared with 33% of those not treated with corticosteroids. Given the results of these studies the use of corticosteroids to prevent strictures has been largely abandoned. Newer medications are being investigated for their ability to prevent strictures. Mitomycin C has been shown to inhibit

fibroblast proliferation and lower the rate of stricture formation in animal studies.15 Halofuginone, an inhibitor of type 1 collagen synthesis, has also shown similar benefits.16 There is no indication for their use outside a well-designed clinical trial.

Early Dilation and Stenting Patients with second- or third-degree burns are at high risk for developing esophageal stricture. The concern is that once the contractile phase of healing has begun the lumen of the esophagus may become obliterated, making future dilation unsafe if not impossible. To prevent this, some recommend early dilation. During the initial endoscopy a nonabsorbable suture may be placed across the esophageal lumen to guide future dilations. This practice is especially common in children. The proximal end of the string is brought out through the nose, and the distal end is brought out through a gastrostomy. The gastrostomy is used not only for nutrition but also for access to perform retrograde dilation. Dilation through the gastrostomy can be performed as soon as 3 weeks after its creation. The suture is exchanged for a guidewire over which a dilator is passed. Retrograde dilation using this suture technique is safer in the setting of severe injury and avoids repeated, blind endoscopic attempts in the setting of severe structuring and lumen obliteration. In addition, these patients may have significant oropharyngeal injuries that make endoscopy difficult. The technique of dilation is extremely important because perforation may occur easily. This complication could convert a potentially salvageable situation to one of high mortality and very poor functional outcome. We believe that to minimize this risk, dilation is performed in either an endoscopy unit or the operating room using fluoroscopic guidance. Dilation occurs over a guidewire whose position has been confirmed by fluoroscopy. Dilation is begun by using a small size bougie and increased until either moderate resistance is met or blood is seen. Repeated dilations after the appearance of blood will increase the likelihood that the stricture will be torn, resulting in a more severe stricture after this tear heals. Balloon dilation of a stricture is another option and can be performed through a retrograde approach over a guidewire.17 The balloon may be filled with contrast material to assess proper placement across the stricture under fluoroscopy. We prefer using the Savary dilator over a guidewire because the endoscopist has a better feel for the forces exerted on the wall of the esophagus compared with a balloon. Also, caustic

tahir99-VRG vip.persianss.ir

Chapter 70 Caustic Injuries to the Esophagus

injury typically leads to several areas of long stricture that may be better treated with a bougie. However, good results have been reported with balloon dilation with a perforation rate as low as 1.5%.18

Stents Stenting an injured esophagus has the advantage of maintaining patency of the lumen with a single procedure until the fibrotic phase of healing has subsided. This would be a clear advantage compared with performing multiple dilations, each of which carries a risk of perforation. The disadvantages of stents include migration and potential erosion through the esophageal wall into adjacent structures. Interest in the use of stents to manage corrosive esophageal strictures has increased with the development of a removable, self-expanding plastic design (Polyflex stent, Boston Scientific, Natick, MA). With this design the stent is maintained in position by the radial force of the stent itself. A significant advantage over conventional metal stents is that these plastic stents can be easily removed. To date, the majority of experience with this device has been in adults for the management of peptic strictures or anastomotic complications after esophagectomy.19 However, in one recent paper it was shown that stents may also be useful in patients with caustic injury. In a review of 149 patients with caustic injury from China, 28 patients were treated by stenting. The stent used in this series was custom made because the commercially available stents were prohibitively expensive. Among these 28 patients, 23 were successfully managed by stent alone.20 Of the 5 patients who failed stenting, 4 ultimately required surgical reconstruction. The authors concluded that stenting could prevent esophageal stricture in a large number of patients with corrosive esophageal injury. Whether these results will be confirmed in other centers remains to be determined. In our experience in using the Polyflex stent for benign strictures, the migration rate was over 50%, leading to a consideration that to be effective a redesigning of these stents will ultimately be necessary if they are to be used routinely in this setting.21

ROLE OF SURGERY IN CAUSTIC INJURIES Surgery in the Early Postinjury Period The majority of patients with corrosive esophageal injury can be managed nonoperatively. Pneumoperitoneum, peritonitis, and clinical deterioration indicate perforation and mandate surgery (Table 70-3). Small paraesophageal leaks that spontaneously drain back into the esophageal lumen may not need surgery. In the acute setting, surgery may be indicated to control mediastinitis and/or peritonitis. Although each case may present unique issues, some guiding principles can be emphasized. The first is that if surgery is indicated, almost all patients need to undergo an abdominal exploration, even if the thoracic esophagus is the site of injury on endoscopy. The reason is that all patients with severe injury will require enteral access (usually a jejunostomy) for nutrition, even if esophagectomy can be avoided. In addition, a gastrostomy can be used for access for later retrograde dilation.

TABLE 70-3 Indications for Surgery in Caustic Injuries to the Esophagus Early Indications Esophageal perforation Transmural necrosis Grade 2 or 3 injury Late Indications Complete stenosis in which all attempts have failed to establish a lumen Perforation after dilation Fistula formation Inability to dilate or maintain the lumen above a 40-Fr bougie Patients who are unwilling or unable to undergo prolonged periods of dilation Esophageal carcinoma

FIGURE 70-3 A 42-year-old patient presented after a suicide attempt with lye ingestion. A portable chest radiography showed free air under the diaphragm. The initial view at laparotomy demonstrates a necrotic distal esophagus, stomach, and duodenum. (COURTESY OF DR. JON WEE AND DR. PETER FERSON, PITTSBURGH, PA.)

If resection is being considered, consultation with experienced members of the surgical team is recommended because significant clinical judgment is required in determining the extent of resection. On the one hand, drainage and secondlook operation within 12 to 24 hours may be necessary and avoid unnecessary radical resection of potentially viable tissue. On the other hand, immediate resection of obviously necrotic tissue may be lifesaving. If an esophagectomy or gastrectomy is performed, it is usually wise to delay reconstruction for several months until the patient has recovered from the initial injury (Figs. 70-3 and 70-4). In the case of esophagectomy, as much proximal esophagus as possible is preserved. If possible, place the esophagostomy exit site well down onto the anterior chest wall. This length may be helpful during future reconstruction. Extensive injuries may also require débridement of periesophageal tissue and partial or complete gastrectomy. Again, consideration for drainage and second-look re-exploration is given if potentially viable tissue is present. A pancreaticoduodenectomy may be indicated for

763

764

Section 8 Trauma

FIGURE 70-4 Final specimen from the patient in Figure 70-3 demonstrating complete necrosis of the distal esophagus, stomach, and first part of the duodenum. The patient underwent a cervical esophagostomy and a feeding jejunostomy.

patients with significant injury distal to the pylorus. In these complex cases primary anastomosis of the pancreatic and common bile ducts to a Roux-en-Y loop is the preferred method of reconstruction.22 Some centers advocate an exploratory laparotomy for all patients with second- or third-degree burns.23 If fullthickness esophageal wall necrosis is seen, then an esophagectomy with a cervical esophagostomy and a feeding jejunostomy are performed. If the injury is partial thickness, then an esophageal stent may be considered. In our center we often will perform a diagnostic laparoscopy for seconddegree burns. This procedure has minimal morbidity and allows for thorough evaluation of the distal esophagus, stomach, and duodenum; and a feeding jejunostomy may be placed during the same procedure. In any case, consideration for repeated endoscopy, laparoscopy, and/or open reexploration is given if marginally viable tissue is encountered or changes in the clinical course occur.

Surgery for Late Complications Indications The two primary indications for surgery after a corrosive esophageal injury are (1) a stricture that is refractory to repeated dilation or (2) the development of esophageal cancer (see Table 70-3). Fortunately, many patients with caustic injuries will not require radical surgical intervention. However, some patients with second- or third-degree burns will develop significant strictures that lead to dysphagia and weight loss. The strong association between caustic injury of the esophagus and squamous cell carcinoma must also be kept in mind. The development of such a cancer can occur several years or even decades after the initial injury. It has been estimated that up to 13% of patients with a caustic injury will develop a squamous carcinoma.24 For this reason any stricture that persists is repeatedly sampled to rule out an occult cancer.

FIGURE 70-5 A significant esophageal stricture after lye ingestion in a 36-year-old man. Repeated attempts at maintaining an adequate lumen with gentle bougienage were unsuccessful. (COURTESY OF DR. PAUL CHIASSON, SIR WILLIAM OSLER HEALTH CENTRE, ONTARIO, CANADA.)

Furthermore, patients need to be informed of this risk and recommended to undergo annual screening endoscopy. A less common indication for surgery is antral stenosis. Unlike a stricture, this complication may not be clinically evident until several years after the initial ingestion. Patients present with the typical symptoms of gastric outlet obstruction. These patients may also be treated with dilation. Should this fail, options for reconstruction include either a loop or Roux-en-Y gastrojejunostomy or a pyloroplasty if the injury to the pylorus is minimal. Gastric resection may be required if a significant portion of the stomach has been injured by the initial exposure to the corrosive agent.25

Surgical Reconstruction Most patients with undilatable strictures will undergo esophagectomy (Figs. 70-5 and 70-6). The reason for this is that the native esophagus of these patients is diffusely diseased, with long-segment strictures and severe dysmotility. However, the esophagus may be retained for patients with a relatively short-segment stricture. One technique that allows the majority of the esophagus to be preserved is the platysma myocutaneous flap. This technique was developed in a region of China where lye is often used for the preparation of food. Accidental ingestion of lye is frequent, particularly because lye is stored in the same bottles that are used to stock alcohol and syrup. The platysma flap is only appropriate for patients who have a short-segment stricture of the cervical esophagus. In this reconstruction, an incision is made along the anterior border

Chapter 70 Caustic Injuries to the Esophagus

of the sternocleidomastoid muscle. The esophageal stricture is then split longitudinally, and the lumen is augmented using a rectangular flap of platysma muscle. The flap includes both the skin as well as muscle, and the flap is rotated such that the skin faces the lumen. The largest series reported 25 patients who underwent this operation.26 There were no operative deaths, and the rate of anastomotic leak and restenosis after reconstruction was 11% and 7%, respectively. Alternatively, a short-segment free jejunal interposition may work well. The majority of patients with an undilatable stricture will require an esophagectomy. In some cases the esophagus may be so adherent to the mediastinum after a deep burn that an

esophagectomy is not possible. Attempted esophagectomy in this setting may carry a high mortality. In some centers, esophagectomy is only attempted if the stricture is located distal to the carina.20 Patients with significant adhesions between the esophagus and the mediastinum may undergo bipolar exclusion of the thoracic esophagus and subsequent substernal gastric or colon pull-up. The advantages and disadvantages of each approach are discussed thoroughly in other chapters of this text. Our preference has been to use a gastric conduit if there is minimal injury here. However, there are some patients with severe corrosive injury to both the stomach and the esophagus and in this instance colon is the only conduit available (Table 70-4).

SUMMARY Injury from lye ingestion can result in superficial damage or a devastating life-threatening emergency. It is crucial for the clinician to promptly assess the degree of injury by careful history of the ingested agent, the physical examination, laboratory studies, CT, and endoscopy. Any evidence of transmural necrosis or perforation with sepsis or clinical deterioration mandates surgical exploration and possible esophageal, gastric, and potentially duodenal resection. In more superficial burns, or completely stable clinical course, medical management may be appropriate and includes intravenous fluids and antibiotics. For second- or third-degree burns serial dilation or placement of a long esophageal stent may be of benefit in preventing stricture. In our experience, with moderate to severe burns not requiring urgent resection, a nonabsorbable suture placed through the nose and across the esophagus and exiting via a gastrostomy tube may greatly facilitate later endoscopy and safe dilations. In general, corticosteroids are not administered. If a cervical stricture does not respond to dilation, options include plastic stents, jejunal interpositions, and platysma flaps. Longer-segment strictures may require esophagectomy. If possible, we remove the native esophagus to prevent the development of a future carcinoma, although this may not be possible in cases of severe burns and fibrosis between the remaining esophagus and the airway, aorta, or other important structures. In these situations, the esophagus is excluded and a substernal gastric pull-up or a colon interposition is performed. FIGURE 70-6 The patient shown in Figure 70-5 underwent esophagectomy and esophageal replacement with left colon. The esophageal stricture could not be dilated. (COURTESY OF DR. PAUL CHIASSON, SIR WILLIAM OSLER HEALTH CENTRE, ONTARIO, CANADA.)

COMMENTS AND CONTROVERSIES Be it an accidental injury in a child or a suicide attempt in an adult, the sequelae of caustic ingestion and resultant gastrointestinal injury

TABLE 70-4 Options for Esophageal Replacement Advantages

Disadvantages

Reverse gastric tube

Useful when right gastroepiploic supply poor or disrupted

Technically difficult

Gastric pull-up

Single anastomosis, reliable blood supply

Acid reflux, bulky

Colon interposition

Maintains propulsion

Three anastomoses required; development of redundancy

Jejunal interposition

Maintains peristalsis, diameter match with esophagus Less gastroesophageal reflux

Often requires free vascular anastomosis Variable vascular anatomy Redundancy develops

765

766

Section 8 Trauma

are lifelong and never correctable. Tragically, these episodes are preventable by careful control and storage of caustic and corrosive agents. Acute management of these injuries is supportive. Catastrophic damage necessitates urgent resection. No treatment strategy has been proven to limit damage. Chronic management starts early after the injury and is sadly limited to repeated dilation in an attempt to control or limit the fibrous repair of these horrific injuries. Resection is required for nondilatable strictures and those complicated by perforation or malignant degeneration. Transhiatal esophageal resection may be difficult or impossible because of significant surrounding fibrosis and scarring of the

resection planes. The reconstruction is always difficult and suboptimal because the remaining upper gastrointestinal tract has suffered sublethal injury to the mucosa and wall. Similarly, the stomach may be subclinically injured and not be ideal for reconstruction, leaving the colon or small bowel as the best organs for esophageal replacement. Lifelong follow-up of these patients is required—overtly to survey for carcinomatous degeneration in the injured organs and covertly to prevent a second injury. T. W. R.

chapter

ESOPHAGEAL FOREIGN BODIES IN ADULTS

71

Florian Lang Philippe Pasche Jean-Baptiste Ollyo Philippe Monnier Marcel Savary

Key Points ■ Esophageal foreign bodies in adults are mostly solid foods. ■ Esophageal foreign bodies in children are extremely varied. ■ In healthy patients, the most frequent site of impaction is the

cervical esophagus.

bodies, with a 2% mortality rate.5 Currently, removal of esophageal foreign bodies by a rigid esophagoscope maintains a 99% success rate, and the mortality rate has continued to drop to less than 0.2%.6-9 To sustain these results, precise knowledge and an adequate practical attitude must be preserved in this field.

■ Impaction at a more distal site should raise suspicion of intrinsic

esophageal disease.

HISTORICAL READINGS

■ Diagnosis requires a careful history, physical examination, radiog-

raphy, and esophagoscopy. ■ Esophagoscopy is the first line of therapy, but surgical removal

may be required.

Foreign bodies, as well as food boluses, pills, and corrosive agents, are objects that can induce swallowing injuries to the esophagus.

HISTORICAL NOTE Until Samuel Gross published his treatise on foreign bodies in 1854, it was common to use some form of bougie to push the offending object down into the stomach. Gross devised and advocated the use of various instruments to extract the foreign body (e.g., curved forceps, blunt metallic hooks, a piece of wire formed into a noose, a gum elastic catheter outfitted with a stylet or a piece of sponge attached to its extremity).1 The overall prognosis for patients with incarcerated esophageal foreign bodies remained poor; and according to Terracol2 the mortality rate was still more than 50% at the end of the 19th century. The prognosis improved with the progress in surgery but only for foreign bodies impacted in the proximal esophagus. In 1904 in a series of 326 patients with external cervical esophagotomies, Balacescu and Kohn3 reported a mortality rate of 26.5% in the pre-antiseptic era before 1880 and of 12.6% in the aseptic era after 1900. Real progress came with the development of rigid esophagoscopy. Bonzini was the first to visualize the upper end of the esophagus around 1795, Mackenzie used a skeleton type of esophagoscope in 1890, and Einhorn definitely improved the technique in 1902 with the introduction of the auxiliary tube in the wall of the esophagoscope as the light carrier.1 With distally illuminated tubes, the overall fatality rate dropped rapidly to 12.5% in 200 cases.4 In 1957, Jackson reported a 98% success rate for endoscopic removal of foreign

Balacescu and Kohn: Die äussere cervicale Oesophagotomie zur Extraction von Fremdkörperm im Oesophagus. Arch Klin Chir, Berl lxxii:347-414, 1904. Clerf LH: Historical aspects of foreign bodies in the air and food passages. Ann Otol Rhinol Laryngol 61:5, 1952. Jackson CL: Foreign bodies in the esophagus. Am J Surg 93:308, 1957. Lerche W: The esophagoscope in removing sharp foreign bodies from the esophagus. JAMA 56:634, 1911. Terracol J: Les Maladies de l’Oesophage. Paris, Masson et Cie., 1959.

EPIDEMIOLOGY Around 1950, swallowing injuries represented the main source of esophageal trauma, being much more common than instrumental lesions. Today, they are proportionately less frequent than esophageal instrumental injuries (as a result of esophagoscopy, dilation, malignant tumor intubation, laser application, surgery, endotracheal intubation, or tracheostomy tubes), which have increased during the past decades. However, the incidence of esophageal swallowing injuries has not decreased in absolute number.10 Foreign body ingestion remains a relatively common problem, with an estimated incidence of 120 ingestions per million population, resulting in approximately 1500 deaths each year in the United States.11 The following discussion is in large part based on a clinical series of 2018 patients (age >16 years) with a history of foreign body or food impaction who underwent esophagoscopy, which revealed a foreign body, food impaction, or a swallowing injury in 69% of cases (Table 71-1).

AGE AND SEX DISTRIBUTION Incarcerated esophageal foreign bodies can occur at any age, but two frequency peaks appear in most published series— one in children through the age of 10 years and one in adults older than 50 years. Both sexes are equally affected (Table 71-2). During their early learning and developmental years, 767

768

Section 8 Trauma

TABLE 71-1 Outcome of Endoscopy in 2018 Adults With a History of Foreign Body or Food Impaction

TABLE 71-3 Risk Factors for Foreign Body Ingestion Childhood

Endoscopy Outcome

No. (%)

Foreign body or food impaction With esophageal injury

949 (47) 392 (19)

No foreign body but esophageal injury

447 (22)

No foreign body or esophageal injury

622 (31)

From a clinical series of patients of the ENT and Head and Neck Surgery Clinic, University of Lausanne, January 1, 1963, through December 31, 1998.

Psychiatric disease Altered level of consciousness Drug use Alcohol use Dementia Structural abnormalities Poor vision Wearing of dentures Pathologic conditions of esophagus Consumption of high-risk foods Chicken bones Fish bones

TABLE 71-2 Age and Sex Distribution for 949 Adults With Endoscopically Confirmed Foreign Body or Food Impaction

Professional activities Upholsterer Dressmaker

Total

Foreign Bodies

Nonedible Alimentary Foreign Bodies

No. of patients

949

133

390

416

Male-to-female ratio (%)

52 : 48

60 : 40

38 : 62

62 : 38

Mean age (yr)

56.9

49.3

56.6

65.1

Food Impaction

From a clinical series of patients of the ENT and Head and Neck Surgery Clinic, University of Lausanne, January 1, 1963, through December 31, 1998.

children are likely to place nondigestible objects in their mouths, with subsequent accidental swallowing. Impaired vision, incomplete food mastication due to poor dentition or ill-fitting dentures, and diminished mucosal sensitivity of the palate due to dental plates account for foreign body ingestion in older adults.11,12

RISK FACTORS Besides those at risk just mentioned, other high-risk groups include certain professionals who tend to keep items such as pins in their mouths while working (upholsterers, dressmakers), psychotic patients, drug smugglers, prisoners, and persons with preexisting esophageal lesions (Table 71-3) (Webb, 1988).2,5,13-16

TYPES OF FOREIGN BODIES Most of the foreign bodies found in adults originate from food, consisting of either a soft bolus, usually a piece of meat, or a nonedible item, such as a piece of bone or a fruit pit (Table 71-4). In contrast to children, who swallow a wide variety of smooth objects (primarily toys and coins), sharp foreign bodies are predominant in adults. Bone splinters, fish bones, and dentures are among the most commonly swallowed objects. Because of the sharpness, their incarceration may produce more severe damage; injuries of the esophageal wall are common (see Table 71-1). The nature of accidentally swallowed esophageal foreign bodies has changed. Fortunately, safety pins, hairpins, and

Illicit activities Drug smuggling Voluntary ingestion of foreign bodies by prisoners Concealment of forbidden objects by prisoners From a clinical series of patients of the ENT and Head and Neck Surgery Clinic, University of Lausanne, January 1, 1963, through December 31, 1998.

TABLE 71-4 Types of Esophageal Foreign Bodies Found in 949 Adults Food Impaction Meat Vegetables, miscellaneous food

426 (45%) 239 187

Alimentary Nonedible Foreign Bodies Bones (e.g., chicken, mutton) Fish bones, mussel shells Pits, nutshells, bay leaves

390 (41%) 299 64 27

True Foreign Bodies Dentures, teeth Pills (with or without wrapping) Metal objects (e.g., pins, clips, can openers) Mucilages Plastic objects Toothpicks Coins Miscellaneous (e.g., disc batteries, coin bags)

133 (14%) 34 23 21 16 12 6 5 16

From a clinical series of patients of the ENT and Head and Neck Surgery Clinic, University of Lausanne, January 1, 1963, through December 31, 1998.

defective dentures, which were known to produce severe esophageal injuries and to cause major mechanical difficulties during manipulation for removal, have become less common; however, objects such as disc or button-type batteries, beverage can openers, plastic pieces, and cocaine packages have become more prevalent (Webb, 1988).13,16-18 The frequency of encountered foreign bodies also depends on geographic factors (different alimentary habits); in a series by Nandi and Ong of 2394 foreign bodies in a Chinese population, 84% of the objects were fish bones.19

Chapter 71 Esophageal Foreign Bodies in Adults

The type of foreign bodies reported in the literature varies according to the medical specialty of the authors. Certain treatment techniques, especially the nonendoscopic methods, imply a selection of type or localization of the foreign bodies, and the series published by ear, nose, and throat surgeons, gastroenterologists, and radiologists differ considerably.

BASIC SCIENCE Natural History From 80% to 90% of swallowed foreign bodies reach the stomach without difficulty, but 10% to 20% must be removed.17 When the passage is difficult, damage to the esophagus can be produced in the absence of incarceration (see Table 71-1). When the foreign body is incarcerated, no mucosal damage or superficial laceration is observed on endoscopic removal in about 87% of adult patients. Deep laceration is present in 9%, whereas esophageal perforation can be diagnosed in 4% (Table 71-5). Incarcerated esophageal foreign bodies can be removed endoscopically in more than 99% of patients.5,7,8 In 1% or 2% of patients, the extraction must be performed with surgery.6 Once in the stomach, most foreign bodies, even when sharp or pointed, pass the distal digestive tract without problems. However, large objects, with dimensions of greater than 2 × 5 cm, are unlikely to pass the stomach and duodenum, and endoscopic removal is recommended.13 Sometimes even small but relatively heavy metallic foreign bodies, such as coins and disc batteries, do not pass the stomach. Their position is monitored radiographically, and if they do not move uneventfully within 7 to 10 days, endoscopic extraction is mandatory.11 Patients with a sharp or pointed object in the stomach are observed clinically and radiographically until natural evacuation of the foreign body has occurred; about 12% of these patients require laparotomy because of perforation.11

Prognosis In contrast to the situation in children, prolonged sojourn of an esophageal foreign body is exceptional in adults. Rare cases

Foreign Body Present (n = 949)

No Foreign Body (n = 1069)

Type of Injury

No. (%)

No. (%)

Superficial mucosal tear

262 (28)

384 (36)

Deep laceration with or without hematoma

88 (9)

54 (5)

Total

Pathophysiology Ingested foreign objects can lodge at any level of the gastrointestinal tract, but most often they become impacted in regions that are physiologically or pathologically narrowed. The normal esophagus has three anatomic sites of narrowing: the upper sphincter (cricopharyngeus muscle), the level of the aortic arch, and the lower sphincter. Indeed, 84% of true or nonedible foreign bodies lodge just above, immediately at, or just below the upper sphincter and 42% of food impactions occur above the lower sphincter (Table 71-6). However, the presence of an anatomic narrowing cannot account for 22% of foreign bodies and 29% of food impactions in the cervical esophagus, just below the cricopharyngeus muscle. In fact, the typical incarcerated foreign body in the cervical esophagus is located just below the posterior lip of the cricopharyngeal muscle. The chutelike effect due to the posterior lip of the cricopharyngeal muscle, which is the chief factor in overriding a foreign body during esophagoscopy, may be of some importance. As early as 1950, Jackson suspected a weakness of the peristaltic musculature in the upper cervical esophagus, which is sufficient to carry a bolus of well-masticated and unsalivated food downward but is not strong enough to carry down a physically different foreign body. Manometric studies have confirmed the presence of a segment of weak contraction amplitude in the normal proximal esophagus commonly believed to represent the area of transition from striated to smooth muscle. Particularly low in subjects with a history of foreign body, the amplitude of contraction in this area is,

TABLE 71-6 Localization of Esophageal Foreign Bodies in 949 Adults

TABLE 71-5 Esophageal Injury Due to Foreign Body Ingestion in 2018 Adults

Perforation

have been reported in which a foreign body incarcerated during childhood was discovered during adulthood (Jackson and Jackson, 1950).20 The prognosis for a patient with an untreated esophageal foreign body can be estimated only on the basis of the natural history to overlooked incarcerated foreign bodies; patients with an overlooked foreign body in the esophagus do not survive longer than 5 to 6 years and usually die within 1 year.20 The prognosis thus appears catastrophic owing to perforation and its subsequent complications (see later).

42 (4)

9 (1)

392 (41)

447 (42)

From a clinical series of patients of the ENT and Head and Neck Surgery Clinic, University of Lausanne, January 1, 1963, through December 31, 1998.

Location

No. of Foreign Bodies (True and Alimentary Nonedible) (%) (n = 523)

No. of Food Impactions (%) (n = 426)

Hypopharynx

116 (22)

21 (5)

Upper esophageal sphincter

209 (40)

44 (10)

Cervical esophagus

113 (22)

122 (29)

Midthoracic esophagus

46 (9)

60 (14)

Lower esophagus

39 (7)

179 (42)

From a clinical series of patients of the ENT and Head and Neck Surgery Clinic, University of Lausanne, January 1, 1963 through December 31, 1998.

769

770

Section 8 Trauma

even in healthy volunteers, occasionally not adequate for the propulsion of an object.21,22 Once the foreign body has harmlessly passed through the Killian sphincter and the cervical esophagus, it usually reaches the stomach without difficulty. When incarceration occurs in the thoracic or lower esophagus, which is a much less common occurrence, an underlying esophageal disease must be suspected (see later). In contrast to the ingestion of a foreign body, esophageal food impaction occurs more frequently in the mid and lower esophagus and is related to a preexisting esophageal lesion or to a motor disorder in 65% of patients.

Underlying Esophageal Disease Most foreign bodies that are accidentally incarcerated in the esophagus of a healthy person are found in its cervical portion. In the minority of cases in which the foreign body is located lower down, an esophageal disease must be suspected and is found in nearly 80%. In such cases, the patient’s history often reveals previous or repeated episodes of foreign body incarceration.14 In our series, the following pathologic esophageal conditions were found (in order of frequency): reflux esophagitis with strictures, postoperative stenoses, webs, Schatzki rings, hiatal hernia, cardioachalasia, carcinoma, diverticula, and motor disorders. Consequently, a thorough postprocedural evaluation of the esophagus, including radiology and manometry at a minimum, takes place in the following situations: ■ ■ ■

A foreign body incarcerated below the cervical esophagus (Fig. 71-1) Repeated episodes of foreign body impaction Meat or food impaction (see Fig. 71-1)

Complications Esophageal injuries either are due to the sharpness of the foreign body or are secondary to pressure necrosis, as in the case of a prolonged incarceration, which is rare in adults. Regardless of whether the foreign body has spontaneously reached the stomach despite a difficult esophageal passage or has remained incarcerated, an injury is found at endoscopy in about 40% of patients with either situation (see Table 715). The injury is mainly a superficial mucosal tear, located in the cervical esophagus. When the foreign body has been incarcerated, severe injuries are more frequent and are detected endoscopically in 13% of the patients, with perforations occurring in 4%. Bones and fish bones cause the highest rate of injury (76%) and account for the most severe injuries (8% perforations), whereas nonalimentary foreign bodies, even sharp metallic objects (injury rate, 38%; perforation rate, 2%) and, of course, food impactions (injury rate, 11%; perforation rate, 2%) are far less dangerous. The main complications of esophageal foreign bodies are related to esophageal perforation, either primary or secondary. The overall mortality rate coincident with perforation is substantial at 22%.23 The more severe esophageal lesions, including perforations, are found in the upper and mid esophagus. The prognosis for patients with an esophageal perforation depends on the cause (acute perforation by sharp foreign body or slow perforation by pressure necrosis), size, location, and early recognition. Acute perforations are followed by the passage of air, saliva, or even food particles into the surrounding soft tissues with a very quick bacterial spread, resulting in the development of mediastinitis and potentially lethal septic shock (Atkins et al, 1985).24 Leaks that result from slow erosion are more likely to be contained by the subacute local inflammatory reaction, which thus limits the spread of

FIGURE 71-1 A, Meat impaction in the cervical esophagus (chicken with bone). B, Underlying esophageal webs secondary to epidermolysis bullosa detected during the postextraction endoscopic follow-up evaluation.

Chapter 71 Esophageal Foreign Bodies in Adults

infection, resulting more often in a local cervical or mediastinal abscess, sometimes with migration of the foreign body into the surrounding tissues or even with a complete secondary healing of the esophageal wall (Atkins et al, 1985).2,24-26 In small puncture-like perforations, the bacterial seeding is of less importance, and the reaction of the surrounding tissues is most often only local. Thoracic perforations are more feared than are cervical perforations because of the possible mediastinitis and the possible formation of fistulas between esophagus and trachea, main stem bronchi, pleura, pericardium, and major arteries (aorta, subclavian, carotid), with the arterial fistulas being lethal most of the time (Hollander and Quick, 1991).27 Early recognition of a perforation is vital for a good prognosis.28,29 Normally, a perforation is diagnosed during postextraction control endoscopy (see later). If there is no initial suspicion, progressive occurrence of fever, retrosternal pain, and dysphagia during the postoperative period alerts the physician. Endoscopic recognition is easy when the laceration is large and clearly opens the mediastinum. Long, sharp, transversely incarcerated foreign bodies can also be easily recognized as transfixing the esophageal wall when they are removed. In contrast, deep, localized lacerations that extend to the muscular layer always make the endoscopist uncomfortable, arousing only a suspicion of perforation. Especially in these cases, cervical and chest radiographs are obtained to detect cervical or mediastinal emphysema. In addition, a contrast study of the esophagus with diatrizoate meglumine (Gastrografin) is performed. The management of perforation needs to be aggressive. There are very few indications for conservative treatment: small puncture-like perforations, especially in the cervical esophagus, with no leakage of contrast medium, can be treated conservatively with IV fluids and antibiotics, nothing by mouth, and close monitoring; slow perforations due to pressure necrosis, when small, can also be closely monitored after extraction of the foreign body.30 If the evidence of response is not rapid, as measured by a reduction in fever, normalization of white blood cell count and radiographic appearance, and abatement of symptoms, there is a definite need for surgery. If the perforation is evident, early surgical drainage is started within 1 to 3 hours (Atkins et al, 1985).10,24 Aortoesophageal fistula is very rare (1 case in 2018 consecutive endoscopies for suspicion of foreign body in adults during a 35-year period) but is an especially serious complication, with only 9 survivors in about 500 patients reported in the literature (Hollander and Quick, 1991).27,31-33 Clinically, aortoesophageal fistula is characterized by Chiari’s triad (midthoracic pain, sentinel hemorrhage of bright red arterial blood, and exsanguination after a symptom-free interval). Most fatalities reported follow time-consuming diagnostic procedures after the sentinel hemorrhage or endoscopic extraction of the foreign body (one case in our series). Surgery at the time of exsanguination is too late. In the presence of a history of ingestion of a foreign body and an arterial sentinel hematemesis, immediate diagnostic endoscopy is undertaken at the time of surgery, in the presence of a thoracic surgeon. As soon as the foreign body or fistula is localized, a

thoracotomy for foreign body extraction and excision of the fistula with aortic and esophageal repair is necessary. Placement of a Sengstaken-Blakemore tube has demonstrated some benefit as a temporizing measure in the control of unrelenting hemorrhage (Hollander and Quick, 1991).27 Esophageal strictures and tumor-like lesions are rare complications of long-standing foreign bodies in adults.34,35

DIAGNOSIS The diagnostic procedure includes the patient history, physical examination, radiology, and endoscopy.

History The penetration syndrome is almost always present in adults; exceptions include some psychiatric patients and drug smugglers. This condition is described as a difficult swallowing episode with painful pharyngoesophageal passage and occasionally is associated with coughing, choking, vomiting, and, in rare instances, hematemesis. When this syndrome is absent in the adult, a strong suspicion of another abnormal pharyngoesophageal condition is aroused but a complete diagnostic investigation nevertheless must be undertaken. Incarceration of a foreign body results in a painful sensation that is usually felt in the lower jugular notch and is constantly exacerbated by swallowing movements, at times associated with a true dysphagia. The same symptoms may be present even if the foreign body has spontaneously reached the stomach after a difficult pharyngoesophageal passage, resulting in an esophageal injury. Total aphagia with sialorrhea may occur when the esophageal lumen is completely obstructed, such as by meat impaction. A coughing or choking attack followed by persistent dyspnea can be the result of a large foreign body, such as a piece of meat, impacted at the pharyngoesophageal junction (pseudo-café coronary). The critical differentiating symptom is that in esophageal blockage the main laryngeal functions—respiration and speech—albeit painful and impaired, always remain possible; in the true café coronary, the intralaryngeal impaction of meat induces a complete respiratory obstruction.24 Localization of the foreign body sensation by the patient does not always correspond to its actual position in the esophagus. The higher the object, the better subjective localization seems to be. When the symptoms are well lateralized within the cervical region, the object is likely to be above the cricopharyngeus muscle and on the side indicated.36 Items that are impacted below this level are poorly localized, and pain and discomfort are often felt higher up than at the effective site of incarceration. Pharyngeal innervation by the vagus and glossopharyngeal nerves seems to provide better sensation than the less-dense esophageal innervation by the vagus and cervical sympathetic nerves.36 In taking the patient’s history, the clinician must inquire about repeated episodes of foreign body or food impaction and preexisting swallowing disorders or upper digestive diseases. The time and circumstances of the incident, the type of suspected foreign body, previous treatment trials, food and drink consumption after the time of ingestion, and the development of symptoms must be noted.

771

772

Section 8 Trauma

FIGURE 71-2 A, Soft tissue lateral radiograph of the cervical region shows a thumbtack in the hypopharynx. B, Anteroposterior chest radiograph shows a coin at the lower esophageal sphincter.

Physical Examination The physical examination includes indirect pharyngolaryngoscopy (visible hypopharyngeal foreign body, salivary retention, edema of the arytenoid region), cervical palpation (subcutaneous emphysema, tenderness of the jugular region, painful active or passive mobilization of larynx), cardiopulmonary auscultation, abdominal palpation, and temperature determination.

Radiologic Examination Any suspicion of an esophageal foreign body requires a lateral soft tissue radiograph of the cervical region and a chest radiograph to confirm and locate a possible radiopaque foreign body and to detect cervical or mediastinal emphysema secondary to an esophageal perforation (Fig. 71-2). An early radiologic sign of cervical emphysema is detected on the lateral cervical view, dorsal to the cricopharyngeal muscle, in the retrovisceral space in front of the sixth cervical body (sign of Minnegerode) (Fig. 71-3). In adults, it is sometimes difficult to differentiate an ingested bone splinter from calcifications of thyroid or cricoid cartilages. Contrast studies with barium are contraindicated for the following reasons13-15,37: 1. They obscure the endoscopic view, masking the foreign body or mucosal lacerations. 2. There is a risk associated with mediastinal penetration of barium in cases of a perforation. 3. There is a hazard of barium aspiration Gastrografin contrast studies do not provide any additional useful information within the classic endoscopic management of foreign bodies. Highly radiopaque foreign bodies such as coins, nails, and disc batteries are easily recognized. Slightly radiopaque foreign bodies are of a physical density somewhat greater

than that of body tissues and form a subtler image. These substances include glass, aluminum, chicken bones, and some plastic materials. Most common commercial glass is radiopaque. Aluminum (can tops), although a metal, is of low physical density. Both glass and aluminum are visible on a properly exposed radiograph but are difficult to visualize on radiographs with a number of superimposed structures, such as the standard chest radiograph. Foreign bodies that have the same density as that of the body (thorns, spines, some plastics, wood in situ for longer than 48 hours) are virtually impossible to detect. Radiolucent foreign bodies, which are of lower density than body tissues, contain mostly air (wood within a short period of injury, some plastics) and may be visualized but with difficulty. Wood (toothpicks) begins to absorb fluids immediately and within a few hours becomes equivalent in density to body tissues and thus invisible.38

Endoscopy Any suspicion of an esophageal foreign body warrants esophagoscopy even when the results of physical and radiologic examinations have been negative (see Table 71-1). When the suspicion is based exclusively on the patient’s history and no physical symptoms or radiologic signs are present, the patient is evaluated again on the next day and released if still asymptomatic. In the presence of the slightest symptom, even when physical and radiologic findings are negative, esophagoscopy is recommended. However, esophagoscopy is not carried out with the sole purpose of making a preliminary diagnosis; it is directly scheduled as an extraction procedure, and everything needed for removal needs to be at hand (Jackson and Jackson, 1950).20 In patients with severe hematemesis, indicating a possible fistula with a major vessel, and in patients with cervical or mediastinal emphysema, disclosing a perforation, endoscopy takes place in the surgical unit, where surgical

Chapter 71 Esophageal Foreign Bodies in Adults

FIGURE 71-3 A, Cervical emphysema is first detected by a soft tissue lateral radiograph of the cervical region, in the retrovisceral space in front of the sixth vertebral body (sign of Minnegerode). B, Cervical emphysema in the retrovisceral space.

extraction and further treatment can be performed without delay.

ENDOSCOPIC MANAGEMENT Indication Endoscopic extraction is the therapy of choice for incarcerated esophageal foreign bodies.5,6,8,37 An absolute contraindication to endoscopic extraction is the presence of severe hematemesis, indicating a possible fistula with a major vessel due to a perforating foreign body.6,39 Any evidence of perforation requires foreign body extraction as well as surgical revision for drainage and closure of the perforation. If the foreign body can be endoscopically extracted without further damage to the esophagus, the procedure may be combined (endoscopic extraction and surgical revision in the same procedure); in other cases, the entire procedure is exclusively surgical.

Timing A foreign body that is lodged in the esophagus, regardless of its nature, must be removed under direct visualization as soon as possible; however, an emergency situation in which a complete diagnostic investigation is not possible is rare. Disc batteries must be removed without any delay because leakage of the corrosive content can rapidly perforate the esophageal wall (see later). Sharp foreign bodies can induce immediate perforations, but this event is rather unusual. We recommend extraction within the first 6 hours. Nandi and Ong19 report

that most perforations due to sharp items occurred 24 hours after impaction; perforation occurred later in cases of smooth foreign bodies (pressure necrosis). If a perforation is evident, extraction and surgical revision procedures need to take place within 1 to 3 hours. The only true surgical emergency is a fistula with a major vessel (see earlier). If the foreign body ingestion has been followed by a sentinel hematemesis, only emergency thoracotomy can save the patient (Hollander and Quick, 1991).6,10,27,33,40,41 Even the presence of a large piece of meat at the pharyngoesophageal junction (pseudo-café coronary) (see earlier) is not a critical emergency because the respiratory tract is not blocked. Nevertheless, rapid endoscopic removal is required because of the dyspnea and because of the possibility of associated compression-induced weakening or rupture of the pharyngoesophageal wall. Indeed, a number of these patients have been subjected to one or more applications of the Heimlich maneuver; in contrast to intralaryngeal meat impaction, this maneuver does not resolve the problem because the flexibility and elasticity of the esophageal wall militate against compression-induced expulsion. Moreover, if the esophageal wall is weakened or if bits of hard material are contained in the lodged bolus, there is a chance of induced perforation with use of this maneuver (Atkins et al, 1985).24

Requirements The endoscopic procedure needs to be carried out in a hospital with an endoscopy suite or operating room completely

773

774

Section 8 Trauma

equipped with facilities for general anesthesia, resuscitation, and upper aerodigestive endoscopies (laryngoscopy, bronchoscopy, esophagoscopy). General anesthesia with tracheal intubation provides the best conditions because it prevents bronchoaspiration and provides the time and stability necessary for the extraction maneuver by ensuring respiratory function and full relaxation of the patient.14,37,42 If the patient’s stomach is not empty, appropriate precautions must be taken. Under no circumstances must the stomach be washed out or evacuated before examination. Usually, the extraction can be scheduled by the anesthetist within the time limits reported here. A rigid instrument, which allows procedures with an open tube, is preferred, and either a full-lumen open tube of the Haslinger or Jackson type or a Storz Universal optical endoscope may be used (Fig. 71-4). The diameter and length of the instrument are chosen according to the location of the foreign body and the patient’s age. The rigid instrument allows the various instrumental maneuvers to be carried out under conditions of perfect stability. When present above the foreign body, food particles can be properly removed. The distal lip of the rigid tube is very helpful in unfolding the mucosa and disengaging an incarcerated foreign body.

Technique The following three steps must always be carried out: 1. Endoscopic evaluation 2. Extraction 3. Postprocedural endoscopy

Endoscopic Evaluation Any retained saliva or food particles are removed with a suction tube or spoon-shaped fenestrated forceps. The foreign body is brought into view, approached, and located. By shifting the instrument laterally and using the lip of the esophagoscope, the operator can identify the foreign body on the basis of its shape, size, consistency, and surface appearance.

Its position is precisely determined with regard to the esophageal walls. In cases of a large and deeply perforating foreign body or in cases of severe bleeding, we refrain from any endoscopic extraction and switch to open surgery. If there are no contraindications, the method and suitable instruments are chosen and the endoscopic maneuvers (e.g., disengaging, detaching, turning, cutting) are determined.

Extraction The procedure for extraction includes the following: 1. Stabilizing the endoscope and the corresponding esophageal segment (suspension of respiratory activity) 2. Contacting the foreign body with the distal end of the instrument (the lip of the endoscope is set accordingly) 3. Gripping the chosen portion of the foreign body firmly in a single movement 4. Drawing the foreign body into the endoscope. A foreign body is seldom retracted completely into the esophagoscope. It is not necessary to draw out that part of the foreign body that seems the most dangerous because every sharp point creates a possible hazard when being withdrawn. It is important to respect Jackson’s key concept that “advancing points perforate, trailing points do not.”20 5. Maintaining complete stability of endoscope, forceps, and foreign body 6. Using a slow, regular, and continuous movement for removal, ensuring that the axis of the endoscope corresponds to that of the esophagus and pharynx, with awareness of any abnormal resistance caused by friction or impaction of the foreign body

Postextraction Endoscopy With an optical esophagoscope, the area of entrapment is carefully explored to evaluate a possible laceration. Furthermore, the esophagus below the site of impaction is

FIGURE 71-4 A, Full-lumen open-tube esophagoscope of the Haslinger type with interchangeable tubes of various diameters and lengths, foreign body forceps, and suction tube with distal opening. B, Storz Universal optical endoscope.

Chapter 71 Esophageal Foreign Bodies in Adults

screened down to the stomach for any preexisting esophageal disease that may have caused the impaction. During removal of the endoscope, the esophagus above the site of incarceration is examined to detect any injury due to the extraction maneuver. Postoperative management depends on these findings.

Postextraction Management When the extraction has been difficult and when deep laceration extending to the muscular layer has been detected without endoscopic and radiologic evidence of a true perforation, postoperative management is conservative, with close clinical and radiologic monitoring (see “Complications” earlier). When a puncture perforation is diagnosed endoscopically (pin or sharp bone puncture) and no mediastinal or cervical emphysema is present, management is the same, including the use of broad-spectrum antibiotics. In cases of an endoscopically or a radiologically evident perforation, surgical repair of the perforation with covering and drainage is performed within the first 3 hours, followed by the same close monitoring, which is maintained for 10 days. In all of these situations, a Gastrografin contrast study is performed before oral food intake is resumed and the patient is discharged.

SPECIAL SITUATIONS Meat Impaction Esophageal soft food impaction is common in adults, with large pieces of meat involved in 56% of cases (see Table 714). Impaction usually occurs when alcohol consumption is also involved. The patient talks while chewing food that consists of thick pieces of overcooked meat that are too hard to be effectively masticated (“backyard barbecue syndrome”43). Food impaction may also be related to insufficient chewing by elderly, edentulous patients.14,44-46 Two preferential sites of obstruction are encountered with equal frequency—the upper portion of the esophagus and the lower esophagus. In 65% of these cases, but especially in cases that involve lower esophageal impactions, an underlying disease is revealed (see “Underlying Esophageal Disease”).47 Impactions of food other than meat are far more common in the lower esophagus. The clinical diagnosis is evident. Swallowing of food or liquid is impossible. The patient regurgitates and may complain of retrosternal pain. There is no need for complementary radiologic investigation. The symptoms and management of food impactions at the pharyngoesophageal junction (pseudo-café coronary) have been described. The only suitable therapy is rapid endoscopic removal. Complications such as tracheobronchial aspiration or perforation are reported primarily after more than 12 hours of impaction.13 Preoperative management is carried out with rehydration in mind. Cautious aspiration of the fluid retained above the impacted bolus can be performed with a Levin tube.43 General anesthesia with tracheal intubation is necessary to ensure safe and adequate respiratory function, with the procedure often being laborious and time consuming. Open-tube endoscopes such as the Haslinger esophagoscope with interchangeable

tubes of varying diameters and lengths, a large fenestrated spoon forceps, and a powerful suction tube with only one distal opening are the instruments especially suitable for this kind of procedure (see Fig. 71-4). Whenever possible, the main portion of the procedure is performed with rigid open esophagoscopes to avoid repeated removal and reinsertion of the instrument, as is necessary with fiberscopes. In patients with severe stiffness of the cervical spine or in kyphotic patients, a fiberscope is helpful to complete the extraction in the distal esophagus. An “overtube” can be used to avoid lesions associated with repeated reinsertion of the instrument, but it must be used with care because the mucosa can become caught between the overtube and the fiberscope, sometimes inducing perforations of the esophagus.48 Taking into account the high percentage of underlying esophageal diseases (65%), thorough postextraction endoscopy with an optical esophagoscope is mandatory. Of a total of 21 patients with “steakhouse syndrome,” Stadler and associates49 found 38% with malignant disease. When esophagoscopy results are negative, a swallowing disorder must be ruled out with radiology and manometry. The endoscopic removal of a massive food impaction in an older patient in poor general condition may represent a difficult and lengthy procedure and probably is why various alternative treatments have been proposed. Enzymatic digestion of the impacted food with papain (e.g., some meat tenderizers) has been proposed,44-46 but it cannot be recommended. The procedure is indicated only for meat impactions. The success rate is low, and in their in vitro study, Goldner and Danley50 could not demonstrate any capacity of the most commonly used solutions to digest or reduce the size of an impacted meat bolus. Papain solutions have even proved to be dangerous because of underlying mucosal lesions that allow in-depth penetration of the enzymatic agent, thus significantly increasing the risk of perforation. Underlying esophageal diseases, especially esophagitis, can be worsened by the use of enzymatic solutions. Tracheobronchial aspiration of papain can cause serious pulmonary edema; and because of their high sodium content, some papain solutions have been reported to cause hyperosmolar coma when administered in large quantities (Webb, 1988).16,17,46,49,50-52 Glucagon, nitroglycerin, nifedipine, and diazepam have been described to induce spontaneous passage of the impacted bolus by relaxing the lower esophageal sphincter without altering the esophageal peristalsis.53-57 The reported success rates, around 37%, are low.57 These drugs are contraindicated in a number of situations. Glucagon can cause vomiting16 and serious tracheobronchial aspiration. Moreover, in a prospective placebo-controlled double-blind study, there was no significant difference in the use of glucagon, diazepam, or placebo to treat patients with impacted food boluses.58 Carbonated beverages, such as cola and champagne, have also been used. The rationale is to distend the esophagus with carbon dioxide, in turn causing relaxation of the lower esophageal sphincter and free passage of the impacted bolus into the stomach.59-61 The success rate is mediocre, about 70% in four published series of a total of 87 patients, with a 3.4% rate of serious complications, including perforation.62 The

775

776

Section 8 Trauma

method is not suitable for impactions that have been present for longer than 24 hours because of the increased risk of serious perforation.62 This method also may induce regurgitation, vomiting, and tracheobronchial aspiration, especially in elderly patients. All of these treatments are very unpleasant to patients already enduring a total esophageal obstruction because they force the patient to retain solutions that induce belching, regurgitation, and vomiting: these remedies cannot be compared with the security and comfort of endoscopic removal under general anesthesia. None of these treatments, even if successful, can spare the practitioner a mandatory postdisimpaction endoscopic examination. Finally, in consideration of the high percentage of underlying diseases, the relative inefficiency of these treatments is apparent.

Coins Accidental coin ingestion is rare in adults (see Table 71-4) but occurs frequently during games in which a person drinks a glass containing an alcoholic beverage with a coin in the bottom and attempts to catch the coin between the teeth. Coins are the simplest and safest foreign bodies to remove endoscopically and are removed that way. Nevertheless, alternate blind extraction procedures with a Foley catheter under fluoroscopic control with the patient in the Trendelenburg position are still performed63-68 but only by specialists with no specific training in the care of foreign bodies in the upper aerodigestive tract.69 Success rates of around 80% (71%-98%) have been reported, with complication rates that range between 0.4% and 1.7% (Berggreen et al, 1993).64,65,67,68,70 However, these seemingly good results have been obtained in a group of highly selected patients (blunt foreign body in upper or midesophagus present for less than 24 hours in patients with no history of underlying disease), precisely that group of patients expected to have the lowest complication rate regardless of the method used. The method provides no control of the foreign body as it is removed. There is no airway protection. The discomfort for the patient is great; the Trendelenburg position can be associated with vomiting, especially when the stomach is not empty. The underlying pathology, if present, cannot be assessed and can give rise to complications. Cases of unrecognized (thus unextracted) foreign bodies have been described with use of this technique.71 If edema is evident radiologically or if the foreign body is present for longer than 24 hours, this technique is not used. We do not use the Foley catheter technique, and we do not recommend it. It may be a treatment option only if endoscopy is not available.

Disc Batteries Although the ingestion of disc batteries has become more frequent because of the advances in electronic miniaturization, it remains a rare event in adults (see Table 71-4). Ingestion occurs during the replacement of used cells, after the person places the new battery on the tongue to test its potency, after mistaking the battery for a tablet, or during suicide attempts.11 As with coins, the larger disc batteries (>21 mm in diameter) cause problems. The most common

battery systems contain an alkaline electrolyte (26%-45% potassium or sodium hydroxide) that is strong enough to cause rapid liquefaction necrosis of tissue. Zinc hearing aid and mercury oxide batteries are those most often ingested. Esophageal injury is caused through direct corrosive action, low-voltage burns, or pressure necrosis. The low-voltage current generated by the battery in gastrointestinal fluid often causes disruption of the seal and leakage of the strong alkaline content. Perforations can result, especially in the esophagus, and are rapidly complicated by esophagotracheal or esophagoaortic fistula formation.17 Because of the rapid action of the alkaline substance on the esophageal wall, disc batteries must be removed without delay. Radiologically, they are easily identified by a doubledensity shadow in the anterior projection with rounded edges, with a step-off at the junction of the cathode and anode in the lateral projection. Endoscopic removal may be difficult because the smooth edges of the battery are difficult to grasp with a forceps17; the procedure is less problematic with the use of larger forceps with rigid endoscopes. The physician can also remove the battery with a through-the-scope balloon, drawing it under direct vision, at least partially, into the rigid endoscope, and removing the balloon, battery, and endoscope as a unit. Sometimes the reaction of the adjacent tissues makes it necessary to dissect the battery free. Thorough postextraction endoscopic examination and a Gastrografin contrast study are vital for adequate further management. If endoscopic extraction is not possible, surgical removal is considered. Under no circumstances can the battery be left in the esophagus. Once a battery reaches the stomach, chances are excellent that it will pass distally and be evacuated. Problems in the distal digestive tract are rare. Nevertheless, clinical and radiological monitoring are required.

Drug Packages A “body-packer” or “body-bagger” is a person who ingests packets of illicit drugs, usually cocaine, to conceal them. The condom is a favorite packet, with 3 to 5 g of cocaine usually put into a single condom. The ingestion of 1 to 3 g of cocaine in a powdered form can be fatal, and the rupture of even one package carries the risk of death.17 The packets can be identified on radiography in 70% to 90% of cases.17 Esophageal impaction is rare. In the single case in our series, the ingested package was relatively large, with a significant amount of drug being wrapped in paper inside the condom, and the symptoms were those of total esophageal obstruction. Endoscopic removal can be dangerous, and packet rupture has been described.72 The security of the procedure must be thoroughly evaluated depending on the type of package. Even in cases of esophageal impaction in which the body-bagger is willing to cooperate, general anesthesia with airway protection is mandatory and the use of the rigid endoscope is more secure. However, the safest means of removal remains surgery. In the management of these cases, the high probability of the presence of other packages in the lower digestive tract, with the attendant risk of toxicity, must always be considered.

Chapter 71 Esophageal Foreign Bodies in Adults

SURGICAL MANAGEMENT Surgical management is indicated: 1. When the foreign body cannot be endoscopically removed without further damage or cannot be removed at all (Fig. 71-5)

2. In the presence of an evident esophageal perforation, either for closure and drainage purposes after an endoscopic extraction or for extraction as well (Fig. 71-6) 3. As an emergency procedure in cases of associated hematemesis

FIGURE 71-5 A, Accidental ingestion of a whole dental drill, deeply impacted in the esophageal wall above the lower sphincter. B, Surgical removal through left thoracotomy. The drill was too heavy and too deeply impacted and had no place to be firmly gripped by a forceps to allow an endoscopic removal. Shown are the foreign body (single arrow), retracted lung tissue (double arrows), and the diaphragm (triple arrows). C, Foreign body: dental drill.

777

778

Section 8 Trauma

FIGURE 71-6 A, Denture deeply impacted in the hypopharynx with evident perforation (massive cervicomediastinal emphysema). B, The deeply impacted, sharp-pointed hooks prevented endoscopic removal without further laceration of the esophageal wall.

TABLE 71-7 Esophageal Foreign Bodies in 949 Adults: Treatment and Final Outcome

Outcome

No. (%)

Patients With Nonperforating Foreign Body (n = 907)

Endoscopic extraction

926 (97.6)

887

Endoscope pushing into stomach

15 (1.6)

15

Surgical extraction

8 (0.8)

5

3

Recovery

947 (99.8)

906

41

1

1

Overall (n = 949)

Death

2 (0.2)

Patients With Perforating Foreign Body (n = 42) 39

From a clinical series of patients of the ENT and Head and Neck Surgery Clinic, University of Lausanne, January 1, 1963, through December 31, 1998.

The need for primary surgical extraction of an esophageal foreign body is rare (0.8%) (Table 71-7). The earlier the intervention, the better the overall prognosis; therefore, diagnostic endoscopic or radiologic procedures to locate and evaluate the foreign body and perforation must be undertaken without delay. Immediate IV treatment with a broadspectrum antibiotic that covers anaerobic bacteria is started as well. For cervical lesions, left-sided cervicotomy along the anterior border of the sternocleidomastoid is preferred, with closure of the tear in two layers and drainage of the site of perforation and the mediastinum. For upper thoracic esophageal lesions and for lesions associated with a right pleural effusion, a right posterolateral thoracotomy is required, with

a large pleural drainage tube. Lesions of the distal thoracic esophagus are explored through the left side of the chest24 or through an upper median laparotomy.15 When possible, repair is made in two layers. Covering of the esophageal repair, with a strap muscle flap, pleura, or pericardium, may be helpful. If inflammatory changes in tissues or the size of the perforation makes the closure impossible, alternative methods must be considered, such as partial esophagectomy, T-tube drainage, esophageal exclusion with secondary reconstruction, or transesophageal drainage and stenting (Atkins et al, 1985).10,24,29

RESULTS In our series, 2018 patients older than 16 years underwent endoscopy, with the confirmation of an impacted foreign body in 949 cases (47%) and the presence of an esophageal injury after spontaneous passage of a foreign body in 447 cases (22%) (see Table 71-1). The endoscopic management of these esophageal foreign bodies and food impactions with rigid esophagoscopy in the patient under general anesthesia (with no exclusions as to the type or location of the foreign body and with the use of practitioners in training) was successful in 941 (99.2%) patients (see Table 71-7). In 8 (0.8%) patients, the extraction was performed surgically, either because of the presence of a large perforation (3 patients) or because of the danger of endoscopic removal of a very large foreign body that was already associated with deep esophageal laceration (in 5 patients). Two (0.2%) patients died after endoscopic extraction. One patient died of a massive hemorrhage after the endoscopic removal of a chicken bone lodged in the vicinity of the aortic arch, and the other patient, an elderly woman with massive food impaction, died after vigorous endoscopic maneuvers that caused esophageal perforation (see Table 71-7).

Chapter 71 Esophageal Foreign Bodies in Adults

DISCUSSION Endoscopic removal with rigid esophagoscopes in patients under general anesthesia appears to be efficient and safe, and the prognosis for patients with incarcerated foreign bodies of the esophagus is excellent. Nonendoscopic treatments for blunt foreign bodies of the cervical and thoracic esophagus (extraction with a balloon catheter) and for food impaction (enzymatic digestion, spasmolytic drugs, gas-forming agents) do not offer the success rate, security, innocuousness, and comfort of rigid endoscopic removal performed with general anesthesia and cannot be recommended. Fiberoptic endoscopy has great popularity, mainly because its use does not necessitate prolonged technical training. Numerous publications have proposed the fiberoptic extraction of esophageal foreign bodies in adults and children.42,73-78 Flexible endoscopy allows the extraction of foreign bodies from the stomach and duodenum and avoids the need for general anesthesia in the adult. The absence of protection of the respiratory tract, however, exposes patients to the risk of displacement of the foreign body with potentially severe consequences (Webb, 1988).16 Even with sedation, a long and difficult extraction using local anesthesia not only is unpleasant for the patient but also may create greater stress in cases of preexisting cardiorespiratory diseases than would the use of short-acting general anesthesia. The average foreign body extraction lasts approximately half as long with the rigid endoscope as with the flexible endoscope.79 This is understandable because in the esophagus, especially in the upper sphincter and the cervical portions, despite numerous technical improvements, the efficiency of instrumental maneuvers with the fiberscope is still inferior to that of the rigid esophagoscope because of its lack of stability and the configuration of its tip.74,80 The success rate of fiberoptic esophageal foreign body removal appears to be significantly lower (76%78 and 85.5%81) than that with the use of rigid instruments (99%,5 96%,7 and 98%6). Moreover, most published reports on the fiberoptic removal of esophageal foreign bodies include patients selected according to the nature, shape, size, or location of the foreign body. Sharp and pointed foreign bodies, impacted in the upper sphincter or in the cervical or upper thoracic esophagus, which are the most frequently encountered foreign bodies in adults and the most likely to produce severe esophageal injury, are almost always managed with rigid esophagoscopes by otorhinolaryngologists or thoracic surgeons.6-8,15,82 The mortality and morbidity rates for both procedures are basically the same,17 with this selection of foreign bodies not taken into account. The general anesthesia required for rigid endoscopy has also been considered by many to be a significant disadvantage that reduces the cost-effectiveness of the procedure,16 but this is no longer true. Most of the rigid endoscopies of this series were performed on an outpatient basis, and since the introduction of the anesthetic agent propofol, postprocedural discomfort is extremely low and the postoperative surveillance (3-4 hours) is almost the same as that after intravenous (IV) sedation. Hospitalization, which is indicated only for a suspected complication, is not dependent on the type of procedure. In our institution, there are only minor differ-

ences in charges for the two procedures. In 2008, the cost of rigid endoscopic removal is about $750 ($262 for endoscopist and anesthetist fees, $487 for use of the endoscopy unit), and for fiberoptic removal with local anesthesia and sedation it is $664 ($194 endoscopist fee, $470 for use of the endoscopy unit). These differences are not sufficient to choose fiberoptic removal—an overall less effective procedure—on the basis of cost alone. Although the popularity of the fiberscope has led, increasingly, to the management of upper digestive foreign bodies with the flexible endoscope (Webb, 1988),16 one must keep in mind that in the field of esophageal foreign body removal, only rigid esophagoscopy with the patient under general anesthesia allowed a success rate of 99% with a 0.2% mortality to be reached in a comprehensive series of patients. Moreover, this occurred under conditions in which endoscopists were being trained. Novelty does not necessarily mean progress. It must first be demonstrated that basic technical innovations maintain the current level of efficiency and safety before being accepted for convenience, comfort, or economic reasons. In the future, it will still be the otorhinolaryngologist or the thoracic surgeon who is called on in difficult situations. In our experience, the need to train these specialists in rigid esophagoscopy for removal of pharyngoesophageal foreign bodies has not vanished despite the technical development of fiberoptic upper gastrointestinal panendoscopes. Optimally, the physician in charge of this field masters both rigid and fiberoptic endoscopy as well as laryngoscopy and bronchoscopy.

COMMENTS AND CONTROVERSIES Although the objects removed from the esophagus are interesting, the stories of how they got there are generally much more interesting. Dr. Lang and his coauthors have provided an excellent and comprehensive chapter of a topic that on the surface appears to be a mundane and simple problem. However, the removal of a foreign body from the esophagus can be anything but simple. Although increasingly possible using advanced flexible fiberoptic equipment and specialized instrumentation, the need for an experienced surgeon with rigid esophagoscopy skills still occurs. In the extreme, open removal at thoracotomy may be necessary. T. W. R.

KEY REFERENCES Atkins JP, Keane WM, Rowe LD: Foreign bodies in the esophagus: Esophageal perforation. In Berk JE (ed): Gastroenterology, 2nd ed. Philadelphia, WB Saunders, 1985. ■ This review article includes the clinical presentation and the treatment of “pseudocafé coronary,” rules for rigid endoscopic extraction, and the diagnosis and management of esophageal perforation. Berggreen PJ, Harrison E, Sanowski R, et al: Techniques and complications of esophageal foreign body extraction in children and adults. Gastrointest Endosc 39:626, 1993. ■ This discussion of rigid, fiberoptic, and alternate extraction procedures, especially with Foley catheters, is from personal experience with 76 adult and 116 pediatric cases. Hollander JE, Quick G: Aorto-esophageal fistula: A comprehensive review of the literature. Am J Med 91:279, 1991.

779

780

Section 8 Trauma

■ The epidemiology, etiology, clinical presentation, and management of aortoesopha-

geal fistulas, including the place of endoscopic procedures, are provided on the basis of 106 references. Jackson C, Jackson CL: Bronchoesophagology. Philadelphia, WB Saunders, 1950. ■ The first and largest experience in esophageal foreign body management describes all of the basic rules of rigid endoscopic extraction.

Webb WA: Management of foreign bodies of the upper gastrointestinal tract. Gastroenterology 94:204, 1988. ■ Management of the different types of foreign bodies, including historical considerations, and an analysis of morbidity/mortality and cost-effectiveness, based on 118 references, are described.

ESOPHAGEAL FOREIGN BODIES IN INFANTS AND CHILDREN

chapter

72

Blake C. Papsin Evan J. Propst

Key Points ■ Most esophageal foreign bodies occur in children younger than 5

years of age. ■ Impactions occur at anatomic narrowings (e.g., the cricopharyn-

geus) or strictures. ■ Coins are the most common esophageal foreign body. ■ Disc or button batteries can lead to stricture, perforation, and

death. ■ Radiography of the neck, chest, and abdomen is essential. ■ Esophagoscopy is the safest method of removal of a foreign

body.

The ingestion of foreign bodies into the aerodigestive tract is a relatively common phenomenon in children younger than 3 years of age because children explore their environment through oral and tactile means, have sparse dentition, and lack the cognitive ability to distinguish food from inedible objects. Approximately 75% of ingested foreign bodies are lodged in the esophagus, and the remainder are found in the laryngotracheobronchial tree.1 The resulting symptoms depend on the site and level of impaction, the size of the object, and whether the object is corrosive or sharp. Smaller, smooth objects such as coins may remain in situ for days or weeks with minimal consequence, whereas foreign bodies that can penetrate the mucosa can rapidly cause death from hemorrhage or mediastinitis.

HISTORICAL NOTE Even though death due to foreign body ingestion has been known to occur for centuries, the complex presentation of an occult indwelling foreign object was only first recognized in 1838 by Ryland, who wrote: “The diagnosis of the foreign body accident claims the most minute attention.”2 In 1896, G. Killan performed the first removal of a foreign body using an endoscopic technique. Nevertheless, it was not until the 1930s that rigid, well-illuminated, endoscopy became recognized as a safe procedure.3 HISTORICAL READINGS Clerf LH: Historical notes on foreign bodies in the air and food passages. Am Med Hist 8:547, 1936. Jackson C, Jackson CL: Diseases of the Air and Food Passages of Foreign Body Origin. Philadelphia, WB Saunders, 1936.

BACKGROUND Incidence and Risk Factors Approximately 84% of esophageal foreign body ingestions occur in children younger than 5 years of age, and 73% occur in children younger than age 3 years.1 Factors that increase the risk of foreign body impaction include cerebral palsy, achalasia of the cardia, and neuromuscular disorders. Anatomic narrowing of the esophagus (Fig. 72-1) can cause retention of foreign bodies. From 63% to 84% of foreign bodies are retained at the level of the cricopharyngeus muscle, 10% to 17% at the level where the aorta crosses the esophagus, and 5% to 20% at the lower esophageal sphincter.4 Acquired stenoses secondary to a repaired tracheoesophageal fistula or esophageal atresia, stricture that forms after a caustic burn, or prolonged gastroesophageal reflux can also increase the propensity for objects to lodge at the level of the narrowing (Fig. 72-2). Inadequate parental care or abuse has also been found to be a risk factor for aerodigestive foreign body ingestion.5

Type of Foreign Body The type of foreign body ingested by children has evolved over time. Previously common metallic objects such as diaper pins are now rarely seen, and plastic toy parts are becoming more frequent occurrences. Because plastic toy parts are often not visible on radiography, toy makers are being encouraged to incorporate radiopaque substances into toys to remedy this situation.6 Coins. Coins remain the most common esophageal foreign body found in children.7 Owing to their size, quarters usually lodge at the cricopharyngeus whereas smaller dimes and pennies may appear more distally. Food. In the older child and adolescent, fish and chicken bones often become impacted in the tonsils, vallecula, or hypopharynx. Poorly chewed meat tends to lodge lower at the gastroesophageal junction or at the site of previous surgery (tracheoesophageal fistula repair). If food lodges at the cricopharyngeus or midesophagus, bulbar palsy may be suspected. In the adolescent, mental retardation, seizure disorders, and alcohol intoxication can also predispose to accidental ingestion of large objects such as bottle tops.8 Batteries. The increased availability of disc or button-type batteries for use in electronic devices such as hearing aids, watches, and calculators has led to an increase in disc or button-type battery ingestion in children.9 Litovitz and Schmitz10 reviewed 2382 cases of button battery ingestion reported to the National Button Battery Ingestion Hotline 781

782

Section 8 Trauma

A

B

C

FIGURE 72-2 Foreign objects are likely to become impacted proximal to a stenotic segment.

FIGURE 72-1 Anatomic narrowings of the esophagus where foreign bodies are likely to become impacted: A, cricopharyngeus; B, indentation of the esophagus caused by the aortic arch; C, cardioesophageal sphincter.

and Registry over a 7-year period. Risk factors for battery ingestion included male sex and age younger than 5 years, with a peak incidence in 1- and 2-year-olds. Multiple batteries were ingested in 8.5% of cases. Most batteries were ingested immediately after removal from a product rather than from the battery packaging. The majority of ingested batteries were intended for use in hearing aids: 33% of these were removed by the child from his or her own hearing aid. Batteries measuring less than 15 mm in diameter were implicated in 97% of ingestions, as compared with larger button cells measuring 15 to 23 mm that were implicated in the remaining 3% of ingestions. When the chemical system of the ingested button cell was known, 29.6% were manganese dioxide, 28.6% were zinc/air, 24.7% were mercuric oxide, 16.6% were silver oxide, and 0.4% were lithium. Sodium

hydroxide, potassium hydroxide, and mercury can leak from an ingested battery, leading to local caustic injury, stricture formation, perforation, and death.11 On May 13, 1996, a U.S. federal law was passed banning the sale, promotion, or use of button cell mercuric-oxide batteries.12 Because mercury prevents the build-up of gases in button cells that would otherwise lead to leakage or rupture, many states allow mercury to be added to other types of button cells.13 The average mercury levels are 11 mg in alkaline manganese cells, 8 mg in zinc/air cells, and 3 mg in silver oxide cells.13 Lithium button batteries do not contain any mercury.13 Although disc batteries can resemble coins on radiography (Fig. 72-3), management of ingested batteries is quite different, because they require emergency removal. It is for this reason that all pediatric patients with esophageal foreign bodies should be referred to an endoscopist who has the experience to recognize the object on radiography as being unusual and the ability to remove the battery and assess for esophageal damage (Fig. 72-4).

DIAGNOSIS History Approximately 75% of esophageal foreign body ingestions are witnessed.14 Parents or guardians may observe the actual

Chapter 72 Esophageal Foreign Bodies in Infants and Children

FIGURE 72-3 Radiograph of coins and button batteries. 1-4, Zinc/air hearing aid batteries (10A, 13A, 312A, 675A). Note the crescentshaped double rim. 5-7, Silver oxide batteries (386, 389, 391) used for watches/electronics and 8, silver oxide battery (76S) for use in a camera. Note their uniform appearance. 9, Canadian 10¢ coin. 10, US 10¢ coin. 11-13, Lithium batteries (1216, 1616, 1620) used for watches/electronics and 14, lithium battery (1/3N) for use in a camera. 15, Canadian 1¢ coin. 16, US 1¢ coin. 17, Canadian 1¢ coin with 12sides. 18, Alkaline battery (625A) for use in a camera. 19, Canadian 5¢ coin. 20, US 5¢ coin. 21-23, 26, 27, Lithium batteries (2016, 2025, 2032, 2430, 2450) for use in watches/electronics. 24, Canadian 25¢ coin. 25, US 25¢ coin. 28, Canadian $1 coin. 29, Canadian $2 coin.

ingestion or witness the relatively constant brief spell of choking or gagging that occurs immediately after ingestion. Information regarding the type of foreign material ingested (including type of battery and imprint code), the time of ingestion, increased salivation, coughing or gagging, airway compromise, dysphagia, vomiting, hematemesis, abdominal pain, fever, anorexia, constipation, or unusual stools is critical. It is important to remember that parents or guardians may mistakenly or deliberately deny having witnessed their child ingest a foreign body, and a high index of suspicion must be maintained at all times.

Presentation Acute Symptoms and Signs Symptoms associated with esophageal foreign body vary and can be missed if not placed in context by a witness. In the absence of “classic” symptoms or signs, a high level of suspicion is helpful in the diagnosis of esophageal foreign bodies because symptoms resemble those of general upper respiratory tract illness in children. Vomiting, dysphagia, and drool-

ing are the most common symptoms of esophageal foreign body impaction in children.7 There is often an asymptomatic interval after the foreign body has become lodged, which can result in a significant delay in diagnosis. An undiagnosed foreign body will, however, eventually cause symptoms that redirect attention to its presence such as when dysphagia, failure to thrive, or erosion into potentially dangerous structures occurs.15 Large objects caught in the hypopharynx or esophagus can compress the larynx and trachea, causing airway compromise and biphasic stridor. Initially, coughing, choking, and cyanosis may be seen, which progress to an inability to produce sound or speech if the airway becomes completely obstructed. This circumstance is best treated by immediately applying the Heimlich maneuver.16 The child should not be turned upside down and slapped between the scapulae because of the risk of further lodging of the foreign body.17 When the object has passed the laryngeal inlet, choking noises cease and the object (typically a coin) may lodge silently at the cricopharyngeus (Fig. 72-5), the crossing of the aortic arch at midesophagus (Fig. 72-6), or distally at the cardioesophageal sphincter. If the object totally obstructs the lumen, there is marked drooling, dysphagia, substernal discomfort, and occasionally repeated gagging (Fig. 72-7). Spillover of secretions into the larynx of the very young or debilitated patient can lead to coughing and aspiration (Fig. 72-8). Disc or button batteries can damage the mucosa of the esophagus within 1 hour, erode into muscle in 2 to 4 hours, and perforate the esophageal wall within 8 to 12 hours. Perforation of the esophageal mucosa and muscular wall causes pneumomediastinum and mediastinitis with associated back pain, shortness of breath, tachycardia, and spiking fever (Fig. 72-9). Sharp objects can perforate the stomach and cause peritonitis.

Chronic Symptoms and Signs Esophageal foreign bodies that have been impacted for some time can lead to progressive dysphagia, anorexia, and weight loss, presenting as failure to thrive in infants. Long-standing foreign bodies may present as hematemesis because they become embedded in granulation tissue, which can be friable and bleed. Late sequelae of esophageal foreign bodies are stricture formation, recurrent pneumonia (due to fistula into the trachea), massive hematemesis (due to fistula into a blood vessel), and perforation.18

Physical Examination Patients with severe airway obstruction must be taken to the operating room immediately and anesthetized with a nonparalytic inhalation technique. The foreign body should be identified with the use of a lit curved-blade laryngoscope and removed with Magill forceps. In patients without airway compromise, physical examination may identify fish and chicken bones impacted in the tonsils, vallecula, or hypopharynx. Auscultation of the chest may reveal decreased air entry. Abdominal tenderness suggests gastrointestinal injury. A lack

783

784

Section 8 Trauma

FIGURE 72-4 Battery from a pocket organizer ingested by a 9-month-old the day after her father thought he had thrown it out. A, Radiograph showing foreign body. The foreign body’s abnormal appearance was thought to be Japanese money that had been lying around the house. Although the battery was removed immediately on arrival at our institution, 5 hours had elapsed since ingestion and a considerable amount of damage had already occurred. B, One week after ingestion, after maintaining the child on nothing-by-mouth status with a nasogastric tube, a diatrizoate meglumine (Gastrografin) swallow shows perforation of the cervical esophagus. This was managed conservatively.

of findings on physical examination does not preclude the possibility of an esophageal foreign body, and appropriate imaging must always be performed.

Imaging Plain radiographs should be obtained of the neck and chest (anteroposterior and lateral views), and of the abdomen (anteroposterior view). The lateral view is essential to allow the identification of multiple foreign bodies, because 3% to 5% of patients have an initially unsuspected second foreign body.19 Hematemesis warrants an arteriogram before endoscopic removal of a foreign body in case a major artery has been eroded and thoracotomy is required.18 Coins. In a retrospective review of 80 children with a history of coin ingestion, 31% had a radiographically demonstrated esophageal coin, including 44% of patients who were asymptomatic at the time.20 All symptomatic patients were found to have coins in the esophagus. Foreign bodies rotate to the greatest diameter of the lumen, and flat objects in the esoph-

agus are usually oriented in the coronal plane.21 Coins that do not orient to the coronal plane are unusual but may be difficult to diagnose due to their abnormal appearance on radiography (Fig. 72-10). Quarters are usually located at the cricopharyngeus, whereas dimes and pennies appear more distally. Trying to identify the type of coin by holding it up to a plain radiograph is misleading because the x-ray beams diverge due to the distance between the coin and the film, leading to a larger image on the radiograph. As a result, small coins can easily be mistaken for larger ones. Knowing the type of coin before esophagoscopy may benefit the surgeon who wishes to select the proper forceps or practice ahead of time. The following are some tips to help identify the type of coin on radiography (see Fig. 72-3). 1. American and Canadian coins are approximately the same size22,23: • Penny (19 mm) (1¢) • Nickel (21 mm) (5¢) • Dime (18 mm) (10¢)

Chapter 72 Esophageal Foreign Bodies in Infants and Children

FIGURE 72-7 Total obstruction, seen on barium swallow.

FIGURE 72-5 Safety pin at the cricopharyngeus.

FIGURE 72-6 Coin (a quarter) lodged in the esophagus at the level of the aortic arch.

FIGURE 72-8 Repeated aspiration pneumonia from spillover from an obstructed esophagus.

785

786

Section 8 Trauma

FIGURE 72-9 Mediastinitis from esophageal perforation.

A

B

C

FIGURE 72-10 A-C, Radiographs of a 25-cent coin at different orientations. Coins that are not oriented in the coronal plane can be difficult to recognize.

• Quarter (24 mm) (25¢) • Dollar coin (26 mm) ($1) • Canadian 2-dollar coin (28 mm) (Can$2) 2. Canadian 1¢ coins minted from 1982 to 1996 had 12 sides and were created fully round thereafter.22 Canadian 5¢ coins minted from 1942 to 1963 also had 12 sides and were created fully round thereafter.22 Canadian $1 coins have been 11-sided since their inception in 1987.22 The Canadian $2 coin has a distinctive bimetallic coin locking mechanism with the outer ring made almost exclusively from nickel and the inner piece made mostly from copper.22 This may appear as two densities on radiography.

FIGURE 72-11 Barium swallow can locate radiolucent foreign bodies, which in this case is a Styrofoam ball.

Radiolucent Foreign Bodies. These can be demonstrated by means of barium or iohexol (Omnipaque) swallow.6 If complete obstruction is suspected, a small amount of these suspensions should be administered initially to prevent overflow aspiration (Fig. 72-11). Small, sharp, radiolucent objects such as fish bones can be identified by dipping a cotton ball or marshmallow in barium, which then may stick on the sharp process of the foreign body. Suspected perforation from a sharp foreign object or by the presence of cervical emphysema may be confirmed by administering a small-volume barium swallow (Fig. 72-12). Batteries. Early detection and timely removal of button batteries is essential. Because button batteries are often misdiagnosed as coins on plain radiograph, a high level of suspicion must be maintained with every esophageal foreign body. The classic radiographic appearance of a button battery includes a double ring around its contour (see Fig. 72-3).24 This double contour is clearly evident in lithium and alkaline batteries but is not evident in silver oxide batteries. Zinc/air hearing aid batteries appear to have a crescent-shaped double contour. On lateral view, thick batteries have a stepped appearance that usually has a rounded edge, whereas multiple coins stacked in an off-center fashion may have a more squarely stepped appearance (Fig. 72-13). Metallic Foreign Bodies. When a metallic foreign body has been demonstrated radiographically, a commercially available metal detector can confirm its location and whether it has spontaneously passed.25 Although this technique cannot obviate the need for initial radiographs (because it cannot

Chapter 72 Esophageal Foreign Bodies in Infants and Children

FIGURE 72-12 A, Mucosal perforation at the right piriform fossa. B, Mucosal perforation at the right piriform fossa demonstrated by barium swallow (arrowhead).

differentiate a coin from a battery), it can eliminate the need for follow-up radiographs if time has elapsed between initial diagnosis and arrival at the treatment facility.

MANAGEMENT The primary objective is to protect the airway from the foreign body. Large objects in the hypopharynx (dentures, plastic caps) should be removed immediately using Magill forceps and a distally lit laryngoscope while the patient is under deep inhalation anesthesia. For objects located at or distal to the cricopharyngeus, the patient should be intubated before manipulation of the foreign body. The use of a cuffed endotracheal tube is optimal in adolescents and adults to diminish the chance of spillover of secretions into the airway. Once the airway is protected, any method of retrieving the object is acceptable. However, for the surgeon, controlled esophagoscopy under direct visualization is optimal.

Esophagoscopy Esophagoscope Endoscopic foreign body retrieval is a frequently performed and safe procedure. Age-appropriate equipment is selected before the patient is brought to the operating room (Table 72-1).26 Rigid esophagoscopes are more versatile than flexible ones because they allow for the passage of various different grasping forceps. The superior fiberoptic illumination and

A

B

FIGURE 72-13 A, Lateral view of two coins stacked together demonstrates a square-shaped step. The two coins are the same size but are off center. B, Lateral view of a button battery demonstrating the rounded, stepped appearance.

internal Hopkins rod-lens telescope and forceps of the Storz esophagoscope (Fig. 72-14) have revolutionized the visibility and accessibility of foreign bodies, making it far superior to the previously popular Hollinger and Jesberg endoscopes. The Storz endoscope lacks a separate suction channel, but a flexible suction catheter can be used through a side port.

Positioning Damage to the cervical spine and trauma to the cricopharyngeus can be avoided by correctly positioning the patient with

787

788

Section 8 Trauma

TABLE 72-1 Age-Appropriate Esophagoscope Size Chart Mean Age

Range

Premature infant

Esophagoscope Size 4

Term newborn

0-3 mo

4 to 5

6 mo

3-18 mo

5 to 6

18 mo

1-3 yr

6

3 yr

2-6 yr

6 to 7

7 yr

5-10 yr

7

10 yr

10-18 yr

8

Data from Barretto RL, Holinger LD: Foreign bodies of the airway and esophagus. In Cummings CW, Flint PW, Harker LA, et al (eds): Cummings Otolaryngology Head and Neck Surgery, 4th ed. Philadelphia, Elsevier, 2005, p 4349.

ROLL

A

B FIGURE 72-15 Correct (A) and incorrect (B) positioning for rigid endoscopy.

FIGURE 72-14 Storz esophagoscope. A, Light source; B, optical forceps; C, light source; D, prism; E, esophagoscope; F, suction tubing; G, rigid suction.

a roll under the shoulders and the head extended obliquely to one side to create a straight line from the mouth to the gastroesophageal junction (Fig. 72-15). Extreme care must be taken to evaluate the status of the teeth before endoscopy and to protect the teeth during the procedure.

Special Considerations Coins. Coins lost in the stomach during attempted removal can safely be left to pass naturally through the gastrointestinal tract. In a large study of button battery ingestions where gastrointestinal transit time was known, passage occurred within 24 hours in 22.6% of cases, within 48 hours in 61.3% of cases, within 72 hours in 78% of cases, and within 96 hours 86.4% of cases.10 Passage required more than 1 week in 4.5% of cases and more than 2 weeks in 1.1% of cases. Battery transit time increased with increasing age. Coins impacted at a narrowed pylorus secondary to an ulcer or surgical procedure may require gastroscopic or surgical removal.

Batteries. Litovitz and Schmitz suggested a management protocol for battery ingestions based on their review of 2382 cases.10 1. Batteries lodged in the esophagus should be removed emergently via esophagoscopy because burns may occur as early as 4 hours after ingestion and perforation can occur after only 6 hours. 2. The battery diameter and chemical system should be determined by locating the imprint code of a duplicate battery, checking battery packaging, or measuring the battery compartment from the object where the battery was intended to be inserted (see Fig. 72-3). Because most button cells are 7.9 to 11.6 mm in diameter, identification of the chemical system is not necessary unless fragmentation or free radiopaque material is documented on a radiograph. For batteries larger than 15 mm in diameter, the battery’s chemical system information must be determined because cells containing mercuric oxide are more likely to fragment and release mercuric oxide into the child’s system. Information regarding a battery’s chemical system can be obtained from the battery’s imprint by calling the National Button Battery Ingestion Hotline at 202-625-3333.

Chapter 72 Esophageal Foreign Bodies in Infants and Children

FIGURE 72-16 Sharp foreign body (circular razor blade from shaver) embedded in the esophagus. A, Anteroposterior view. B, Lateral view.

3. Batteries that have passed beyond the esophagus need to be retrieved only if the patient manifests signs or symptoms indicating gastrointestinal tract injury (abdominal pain or tenderness), or if a large battery fails to pass through the pylorus. Otherwise, patients can resume normal activity and diet without observation. 4. In the asymptomatic child, follow-up radiographs are required only to confirm battery passage. Passage is best confirmed by inspection of stools. Ingestion of a 15.6-mm mercuric oxide cell may warrant once- or twice-weekly follow-up radiographs owing to the greater likelihood that these cells may split and require removal. Ingestion of a battery greater than 15 mm by a child younger than 6 years of age requires radiography if it does not pass within 48 hours, since it is not likely to pass at this point and the child may benefit from early endoscopic retrieval. 5. Ingestion of mercuric oxide cells that demonstrate radiographic evidence of splitting or expelling radiopaque droplets in the gut requires monitoring of blood and urine mercury levels. Chelation therapy should be initiated in symptomatic patients or in asymptomatic patients demonstrating toxic mercury levels. Sharp Foreign Bodies. Sharp foreign bodies, such as open safety pins, should be drawn into the esophagoscope as far as possible and removed with the sharp tip trailing. Sharp-

tipped objects that are pointed toward the endoscopist may be covered and withdrawn using point-sheathing forceps. Alternatively, the endoscopist may use a safety pin–closing forceps or may turn the safety pin around by using a ring forceps to grasp the ring of the safety pin,27 push it distally through the gastroesophageal sphincter, reverse its direction in the stomach (known as endogastric version), and pull the ring into the esophagoscope. Large Foreign Bodies. Foreign bodies that are too large to be withdrawn through the esophagoscope should be withdrawn against its distal end, and both should be removed as a unit. The forceps must be held firmly at the level of the cricopharyngeus because it is at the laryngeal inlet that the object is most likely to be stripped out of the forceps’ grasp. Unusually Shaped Foreign Bodies. Unusually shaped objects are occasionally encountered that are not amenable to removal by any of the available forceps. Figure 72-16 shows a circular blade from a shaving razor in midesophagus. The upward-pointed edges of the blade rendered it impossible to withdraw directly because of the risk of ripping mucosa. The blade was too large to be covered by an instrument or pulled into the lumen of the esophagoscope. Therefore, a small alligator-jaw forceps was used to grasp each blade tip in turn and gently roll the blade up the esophagus without causing a perforation. The Gordon bead forceps can be used to remove oval or globular objects such as marbles.

789

790

Section 8 Trauma

Multiple Foreign Bodies. Five percent of patients have an initially unsuspected second foreign body (Fig. 72-17).19 To avoid missing a second foreign body, it is helpful to repeatedly reinsert the esophagoscope to the level of the gastric junction and then withdraw it slowly in a side-to-side sweeping motion to distend and examine every mucosal fold.19 Hidden Foreign Bodies. Occasionally, an object can be seen in the esophagus on radiography but not at esophagoscopy. This may occur when a small, flat object is hidden by the rugae of the esophageal mucosa. These folds can be distended by insufflation of a large volume of air to expose the object or by inflation of a Fogarty balloon catheter beyond the object to hold the mucosa in a distended position.28 This technique can be adapted to facilitate the safe removal of irregularly shaped, sharp foreign bodies such as partial dental plates or bridges. Granulation Tissue. Foreign objects that have been indwelling for some time can become embedded in granulation tissue. Neuropads soaked in 1:1000 epinephrine can be applied with forceps to shrink the tissue to obtain a better view of the object and to provide hemostasis if bleeding occurs. Significant bleeding after removal of such an object is treated by tamponading the area with a pack on a forceps or with a Foley catheter. In rare instances when bleeding is

brisk, an arteriogram with embolization may be necessary for hemostasis. Deeply embedded, sharp, irregularly shaped, or excessively large foreign bodies that cannot be removed safely by esophagoscopy may be better removed by thoracotomy, esophagotomy, and primary closure. Lastly, child abuse must always be suspected when foreign bodies are found in infants younger than 8 months (i.e., too young to crawl or grasp efficiently) or if multiple foreign bodies are identified (see Fig. 72-17). In the teenager or adult, multiple foreign body ingestion should lead the medical professional to question psychological disturbances,29 suicide attempts, or Munchausen syndrome.

CONTROVERSIAL METHODS OF ESOPHAGEAL FOREIGN BODY REMOVAL These methods of removing esophageal foreign bodies are usually proposed by physicians who are not able to gain access to operating room facilities or who do not have surgical colleagues who are willing to routinely accept such cases. Esophageal foreign body removal is best undertaken by an endoscopist who can safely and directly visualize foreign bodies and remove them gently and who is fully prepared to intervene more aggressively should the need arise.

Foley Catheter The Foley catheter method of esophageal foreign body removal involves passing a balloon catheter beyond an impacted foreign body under fluoroscopic guidance, inflating the balloon, and withdrawing the catheter to disimpact and remove the foreign body from the esophagus. Debate regarding the use of the Foley catheter to remove esophageal foreign bodies is largely fueled by economic considerations. Proponents of this method cite the significant reduction in cost required for “safe” removal without the need for general anesthesia.30 Although there have been reports of serious complications with this method, opponents argue that the airway is not protected during removal of the foreign body and that there is an uncontrolled opportunity for the object to become lodged in the larynx or nasopharynx.31 Balloon catheter removal also assumes that the object visualized fluoroscopically is the only one present. In addition, the status of the esophageal wall cannot be assessed during removal, which may be important if the object has been present for a long period of time and has caused ulceration. Most importantly, the removal procedure involves restraining an awake child in the Trendelenburg position, which is likely much more traumatic for the child as compared with a properly administered general anesthetic.

Papain

FIGURE 72-17 Multiple safety pins in the esophagus (murder attempt/child abuse).

The use of papain to “digest” impacted vegetable matter and of meat tenderizer to soften impacted meat is not advisable, because it may also erode the mucosal wall, causing florid granulation and possibly esophageal or stomach perforation.32

Chapter 72 Esophageal Foreign Bodies in Infants and Children

Drugs Use of intramuscular diazepam, morphine, glucagon, and propantheline bromide (Pro-Banthine) has been described to relax the lower esophageal sphincter. Even though these methods have realized limited success, they can be used under observation to assist the passage of smooth objects caught at the lower esophageal sphincter. Emetics such as ipecac syrup are ineffective and unsafe because they can lead to retrograde movement of foreign bodies from the stomach into the esophagus and foreign body aspiration during induced emesis.10

Blind Bougienage Blind bougienage has been described30 to dilate a stricture or sphincter so as to assist the passage of a foreign body. The authors strongly discourage the use of blind bougienage, because it may result in perforation of the gastrointestinal tract.

SUMMARY The ingestion of foreign bodies is quite common in infants and children. Careful history, physical examination, and radiography are required to determine the type of esophageal foreign body to provide appropriate management. A high index of suspicion must be maintained at all times so as not to miss disc or button batteries, multiple foreign body ingestions, and child abuse. Endoscopic foreign body retrieval is the safest method available for retrieval of esophageal foreign bodies.

COMMENTS AND CONTROVERSIES Drs. Papsin and Propst have provided an excellent chapter reviewing pediatric ingestions. Diagnosis and removal of an ingested

foreign body in a child seems to be a simple task; however, in an infant or toddler it may be extremely difficult. The ingestion may be unwitnessed and thus the history is unavailable, the presentation may be late, the symptoms are nonspecific respiratory or upper gastrointestinal complaints, and the offending object may be radiopaque. A high index of suspicion and a familiarity with the types of objects ingested are critical to diagnosis. Treatment should be taken seriously and no shortcut or unorthodox techniques used. General anesthesia and a skilled and dexterous endoscopist are always required. The ingestion of a button or disc battery is a serious event with dire consequences for the child if it is not removed promptly and carefully. T. W. R

KEY REFERENCES Holinger LD: Foreign bodies of the airway and esophagus. In Holinger LD, Lusk RP, Green CG (eds): Laryngology and Bronchoesophagology. Philadelphia, Lippincott-Raven, 1997, p 234. ■ The author provides a comprehensive review of the topic of foreign bodies in the airway and esophagus. Litovitz T, Schmitz BF: Ingestion of cylindrical and button batteries: An analysis of 2382 cases. Pediatrics 89:747, 1992. ■ This paper is a detailed review of 2382 cases of battery ingestion reported to the National Button Battery Ingestion and Registry at Georgetown University Hospital’s National Capital Poison Center. Cases are analyzed with respect to type of battery ingested, management, and natural history. Therapeutic recommendations are offered as well as strategies for prevention and intervention. McGahren ED: Esophageal foreign bodies. Pediatr Rev 20:129, 1999. ■ A comprehensive review of esophageal foreign bodies is presented.

Muntz HR: Management of foreign bodies. In Wetmore RF, Muntz HR, McGill TJ (eds): Pediatric Otolaryngology. New York, Thieme Medical, 2000. ■ The author presents a comprehensive review of the management of esophageal foreign bodies.

791

chapter

73

ESOPHAGEAL PERFORATION Stanley C. Fell

Key Points ■ In the clinical setting of an esophageal perforation, performance of

■ ■

■

■

a negative water-soluble esophagogram should be immediately followed by that of a thin-barium esophagogram. Prompt diagnosis and early treatment is critical to a good outcome. Cervical esophageal perforations are managed by surgical drainage, débridement, and drainage. Repair of the perforation may not be possible. Thoracic and abdominal esophageal perforations require esophageal repair, lavage, and débridement of the surrounding tissue and drainage. An expandable covered metal stent may palliate an esophageal perforation in an otherwise terminal patient.

The esophagus, strategically situated in the neck, mediastinum, and abdomen, is subject to irreparable injury; the consequences of perforation are grave and commonly result from technical misadventure. Despite advances in diagnostic methods and supportive therapy—including ventilatory support, antibiotics, and nutrition therapy—mortality rates for esophageal perforation are 13% in patients undergoing surgery less than 24 hours after injury and 55% for those in whom therapy is delayed.1 Factors influencing mortality are (1) the age and general condition of the patient, (2) the location and cause of the perforation, and (3) the presence or absence of intrinsic esophageal disease. The common causes of esophageal perforation are discussed later. Anastomotic leaks and caustic esophageal injuries are discussed elsewhere in this volume. In a review of 511 esophageal perforations (Jones and Ginsberg, 1992),2 43% were caused by instruments, 19% were caused by trauma, 16% were spontaneous, 7% were caused by foreign bodies, 8% were caused by operative injury, and 7% were caused by tumor and miscellaneous causes. Endoscopy alone accounted for 35% of perforations by instruments, pneumatic dilation caused 25%, and bougienage caused 20%. Faulty endotracheal intubation, SengstakenBlakemore tubes, nasogastric tubes, sclerotherapy, and endoesophageal prostheses caused 20% of iatrogenic perforations. In a 1974 survey of endoscopic esophageal injury, the incidence of esophageal perforation was 0.03%.3 Although endoscopic procedures are performed in increasing numbers, the more frequent use of flexible endoscopy, coupled with video imaging, has probably decreased the incidence of perfora792

tions. However, the increased use of intraoperative transesophageal echocardiography for cardiac surgery has contributed another source of perforation by instruments. Sixty percent of cervical perforations are the result of endoscopy; the remainder are caused by penetrating trauma or foreign bodies. Injury most commonly occurs during passage of the endoscope through the cricopharyngeal sphincter, the narrowest zone of the esophagus. Older people, in whom neck extension may be limited and who often have osteoarthritic spurs juxtaposed to the posterior esophageal wall, are especially at risk. The second site of esophageal narrowing, the region of the aortic arch and the left main bronchus, is more likely to be perforated by ingested foreign bodies than by instruments. The gastroesophageal junction, the third zone of esophageal narrowing, is likely to be perforated during biopsy or dilation of both benign and malignant strictures or achalasia. Because the clinical manifestations, radiographic findings, treatment, and prognosis of cervical perforation differ from those of thoracic and abdominal perforations, cervical perforation is best discussed as a separate entity.

CERVICAL PERFORATIONS Historical Note Early in the 20th century, the morbidity and mortality of cervical esophageal perforation and nasopharyngeal infections stimulated the interest of anatomists and surgeons who were studying the fascial planes of the neck and mediastinum. Pearse4,5 realized that the cervical drainage procedure described by Marschik in 1909 did not address the problem of infection that descended into the posterior superior mediastinum. He must be credited with describing the drainage procedure that is currently used and discussed in this chapter. Pearse’s 1938 paper contains superb discussions by Churchill, Alexander, Lilienthal, and Wangensteen. Lilienthal6 described posterior inferior mediastinotomy for abscesses that occur below the level of the tracheal bifurcation, a procedure that was used by Seybold and colleagues.7 Neuhof and Jemerin8,9 described the pathology and compared the clinical course in patients who were treated nonoperatively with the clinical course in patients undergoing a drainage procedure.

Overview Technical errors or omissions leading to cervical esophageal perforation include (1) inadequate sedation or anesthesia, (2) improper passage of the esophagoscope through the cricopharyngeus, (3) failure to use a rubber-tipped lumen finder and thus becoming lost in the piriform fossa, (4) failure to deflate

Chapter 73 Esophageal Perforation

TABLE 73-1 Causes of Esophageal Perforation Endoesophageal Instrumentation Esophagoscopy Transesophageal echocardiography Bougienage Pneumatic dilation Sclerosis of esophageal varices Placement of intraesophageal tubes (nasogastric, SengstakenBlakemore, prostheses) Traumatic endotracheal intubation Periesophageal Surgery Mediastinoscopy Thyroid surgery Anterior spinal surgery Vagotomy Pulmonary resection Antireflux surgery Thoracic aneurysm resection Trauma Penetrating Foreign body Caustic ingestion

C6 T1 Pretracheal space Aorta

Retrovisceral space T6

Anterior mediastinum Posterior mediastinum

Diaphragm

Barotrauma Postemetic Blunt trauma—neck, thorax, abdomen Compressed air ingestion Miscellaneous—seizure, childbirth, defecation, brain disease Tumor Esophagus Lung Mediastinal Infection Tuberculosis Histoplasmosis Syphilis Acquired immunodeficiency syndrome

the cuff of the endotracheal tube during insertion of the esophagoscope, and (5) failure to elevate the instrument anteriorly away from the cervical spine (Table 73-1). Failure to obtain an esophagogram before endoscopy increases the risk of perforation in areas of unsuspected disease.

Pathology A perforation occurs either as an immediate total breach of the esophageal wall or as a mucosal laceration that is followed by intraluminal abscess formation and subsequent mural rupture. Thus, there may be an interval of many hours between the endoscopy and the appearance of signs and symptoms of overt perforation. Sharp foreign bodies may perforate immediately, but blunt foreign bodies sometimes cause pressure necrosis and delayed perforation. The thin buccopharyngeal fascia is adherent to the posterior wall of the pharynx and esophagus. Thus, the perforation can enter the retrovisceral space, allowing infection to descend into the posterior mediastinum (Fig. 73-1). The retrovisceral space becomes obliterated by fibrous tissue in the region of the tracheal bifurcation at the level of the sixth thoracic vertebra. Below this point, the space continues to the dia-

FIGURE 73-1 Diagram showing pathways for spread of infection to the mediastinum and pleural cavities after cervical or thoracic esophageal perforation.

phragm. If the pharyngoesophagus is perforated anteriorly or laterally via the piriform fossa, infection occurs in the pretracheal space and may then descend substernally.

Clinical Features Virtually all patients with cervical perforations complain of neck pain made worse with swallowing and neck flexion. Dysphagia and odynophagia are common. The neck is tender, and crepitation may be noted on palpation or auscultation. A cervical perforation is suggested if severe pain is elicited when the examiner grasps the thyroid cartilage between the thumb and index fingers and moves it from side to side. Fever and leukocytosis develop promptly. Lateral cervical radiographs usually demonstrate loss of the normal lordosis, anterior displacement of the trachea and esophagus, and widening of the retrovisceral space. Streaks of air in the soft tissue planes are best seen in the sagittal view. Chest radiographs may demonstrate pneumomediastinum and posterosuperior mediastinal pleural fluid collections (Fig. 73-2). If surgery is not immediate, pleural effusion, usually right sided, commonly develops after 24 hours. Esophagograms that are performed with water-soluble contrast material confirm perforation in approximately 80% of cases.10 The 20% incidence of false-negative results is twice that found in thoracic esophageal perforations. If findings are normal, a thin-barium swallow may demonstrate the perforation. Given

793

794

Section 8 Trauma

the clinical and radiographic findings previously described, a negative esophagogram should not deter appropriate surgical therapy. Esophagoscopy is especially valuable in cases of foreign-body perforation or penetrating trauma.

Treatment Once cervical esophageal perforation is suspected, oral intake must cease, nasogastric suction should be begun, and antibiotics should be given intravenously that are effective against oral bacterial flora. Prompt surgical drainage is the basic requirement for successful management, thus reducing length of hospital stay, morbidity, and mortality. No patient is too

sick for surgery. Cervical drainage may be performed with the patient under general or local anesthesia if necessary, supplemented by sedation and ventilatory support via endotracheal intubation.8 The operative approach to cervical esophageal perforation and associated mediastinal sepsis is as follows (Fig. 73-3). An incision is made along the lower third of the anterior border of the sternocleidomastoid muscle on the side of the neck where contrast agent can be seen to extravasate or where significant accumulation appears in the mediastinum. Otherwise, the left-sided approach is generally preferred by right-handed surgeons. The surgeon retracts the carotid sheath and internal jugular vein laterally and divides the middle thyroid vein, if necessary, allowing the trachea and esophagus to be retracted medially. Blunt dissection leads to the retrovisceral space and the prevertebral fascia directly posterior to the esophagus. The dissection is facilitated by the edema and fluid accumulation caused by the perforation. The perforation is sought and, if found, is closed with several absorbable sutures. This step is not a requirement for successful treatment because cervical esophageal perforations heal with adequate drainage in the absence of distal obstruction. Finger dissection is carried down into the posterior mediastinum, allowing the insertion of a suction tip. The area is copiously irrigated, and a soft suction drain is inserted into the mediastinum. Suction drainage is preferable to a Penrose drain because the drainage is uphill against gravity. The drain exits the neck through the lower angle of the incision, which is loosely closed. Perforations resulting from external trauma generally require buttressing with a pedicled flap of strap muscle or omohyoid. In cases of missile or stab wounds that cause contiguous tracheal and esophageal perforation, it is essential to interpose a pedicled muscle flap between the separate repairs.

A

Superficial cervical fascia Sternocleidomastoid muscle

Strap muscles

Thyroid gland

Middle cervical fascia Esophagus Omohyoid muscle

FIGURE 73-2 Cervical perforation after traumatic endotracheal intubation. Treatment was delayed for 24 hours. A, Chest film demonstrating cervical emphysema and mediastinal (open arrows) and right mediastinal collection and pleural effusion (solid arrows). B, CT scan 24 hours after inadequate cervical drainage demonstrates right upper mediastinal fluid collection (arrow) and right pleural effusion. Thoracic drainage of mediastinal abscess and empyema was required.

Retrovisceral space

Internal jugular vein Carotid sheath

A FIGURE 73-3 A-E, Operative technique for cervical mediastinal drainage. See text for details.

Chapter 73 Esophageal Perforation

Middle cervical fascia Omohyoid muscle Sternohyoid muscle Superficial cervical fascia

Sternocleidomastoid muscle

Sternocleidomastoid muscle

C

B

Middle cervical fascia Prevertebral fascia (retrovisceral space) Thyroid gland Esophagus

Internal jugular vein

Middle thyroid vein

D

Esophagus

E FIGURE 73-3, cont’d

Fingertip in retrovisceral space

795

796

Section 8 Trauma

Oral feedings are withheld, and nasogastric suction and intravenous antibiotics are continued until cervical drainage ceases, approximately 1 week later. An esophagogram with aqueous contrast is then obtained. After esophageal integrity is demonstrated, the drain is removed and oral feeding is gradually resumed.

THORACIC AND ABDOMINAL PERFORATIONS In contrast to cervical perforations that are instrumental or traumatic and managed by the simple operative procedure described in the preceding section, thoracic esophageal perforations have multiple causes, including injury by instrument (Fig. 73-4), barotrauma (Fig. 73-5), caustic ingestion, carcinoma, and penetrating wounds. The management and outcome of the perforations depend on the cause, the associated esophageal disease, and the condition of the patient at the time of therapy. Risk factors for endoscopic and instrument perforation of the thoracic esophagus include: ■ ■ ■ ■

Poor sedation or anesthesia Attempts to dilate strictures using inappropriate means Failure to recognize a stricture that is not suitable for peroral dilation Biopsy performed without proper visualization

Dilation of strictures and pneumatic dilation for achalasia together are responsible for 45% of esophageal per-

forations. Dilation of strictures over a guidewire under fluoroscopic control should reduce the incidence of perforation. Barogenic trauma (Boerhaave’s syndrome) accounts for 10% to 15% of thoracic perforations. Less commonly, perforations result from endoscopic removal of foreign bodies or gunshot wounds. Operative injuries include perforations after the performance of transthoracic or abdominal antireflux operations and unrecognized mucosal injury during esophagocardiomyotomy for achalasia. The incidence of esophageal perforation after transabdominal vagotomy is 0.54%.11 The advent of laparoscopic Nissen antireflux procedures has added a new source of intraoperative esophageal injury, although with increasing experience the rate of occurrence of this complication appears to be diminishing. Esophagopleural fistula, an uncommon complication of pleuropneumonectomy for pulmonary tuberculosis,12 has also occurred after radical resections for lung cancer. Mediastinal perforation of the esophagus, a rare manifestation of pulmonary tuberculosis13 or histoplasmosis, has been reported in association with the tuberculosis that is seen in patients with acquired immunodeficiency syndrome in whom the esophagus is invaded by mycobacteria from adjacent mediastinal lymph nodes.14 Approximately 8% of middle-third esophageal carcinomas develop fistulas to the tracheobronchial tree, and occasionally esophageal carcinoma perforates into the mediastinum with abscess formation.

Clinical Features Perforation of the thoracic esophagus is clinically manifested by substernal or epigastric pain. Cervical subcutaneous air is noted in only 20% of cases of thoracic perforations (Sawyers, 1990),15 but mediastinal emphysema and pleural effusion are common. Because plain chest and abdominal radiographs are nondiagnostic in at least 12% of cases,16 esophagograms with water-soluble agents, followed by thin-barium examination if necessary, have become routine practice after the performance of pneumatic dilation in some institutions. Abdominal esophageal perforations that are not diagnosed and treated at the time of laparotomy cause epigastric tenderness, muscle spasm, and epigastric pain often radiating to the back or left shoulder. A history of endoscopy or periesophageal surgery makes esophageal perforation suspect. Pleural effusion, often bilateral, and subdiaphragmatic air are commonly noted radiographically. Oral contrast study confirms the diagnosis.

BOERHAAVE’S SYNDROME Historical Note

FIGURE 73-4 Perforation of a normal esophagus (arrow) during rigid endoscopy, ineptly performed. Gastrografin esophagography had been performed because the chest radiograph revealed a right pneumothorax. Repair was performed 8 hours after injury.

Shortly before midnight, on October 29, 1723, Hermann Boerhaave, professor of medicine at Leyden University, was summoned to attend Baron Jan van Wassenaer, grand admiral of the Holland fleet, a prodigious gourmand who often relieved his postprandial discomfort by self-induced vomiting. Having feasted richly on duck and beer early in the day, the Baron vomited and gave forth a horrifying cry, complaining to his servants that something near the upper part of his stomach was torn. Thereafter, he continued to experience

Chapter 73 Esophageal Perforation

FIGURE 73-5 A, Esophageal rupture (curved arrow) caused by blunt trauma (motor vehicle accident), diagnosed 3 days after laparotomy for liver laceration. Extravasation of contrast agent into mediastinum (straight arrows). A left chest tube had been inserted for pneumothorax. B, Esophagogram after repair with intercostal musculopleural flap. Gastrostomy and jejunostomy were also performed.

severe pain. Boerhaave’s examination of the Baron disclosed no abdominal findings. Death occurred 18 hours after onset of illness. At autopsy, Boerhaave noted emphysema of the chest wall and abdomen and a rupture of the left posterolateral wall of the esophagus, 3 inches above the diaphragm, without evidence of esophageal ulcer. He was struck by the strong odor of roasted duck and observed the olive oil, which the Baron had taken as an emetic, floating in the left pleural cavity. His 70-page autopsy protocol, “History of a Grievous Disease Not Previously Described,” published in 1724,17 achieved wide acclaim; thus the eponym “Boerhaave’s syndrome” has been applied to postemetic rupture of the normal esophagus. Using cadavers, MacKenzie18 reproduced the Boerhaave lesion, and Mackler19 confirmed these findings using intraluminal pressure of 5 psi. In 1944, Collis and colleagues20 made the preoperative diagnosis of postemetic esophageal rupture and performed thoracotomy and repair, but the patient died of shock 20 hours later. In 1947, Barrett,21,22 having made the correct preoperative diagnosis, reported the first successful repair

(performed 10 hours after the rupture). Olsen and Clagett23 reported a successful result in the same year.

Pathophysiology Similar findings are noted in cases of esophageal rupture that are unassociated with emesis, such as blunt thoracic or abdominal trauma, compressed air hose injury, epileptic seizures, defecation, and childbirth, all of which may be associated with a sudden increase in intra-abdominal pressure. All cases of barotrauma resulting in esophageal rupture may be considered to be variants of Boerhaave’s syndrome, because the pathologic process and clinical course are similar. The term spontaneous rupture of the esophagus is inappropriate because the rupture invariably follows barotrauma. Although several reports of cases have been alleged to have been truly spontaneous,24 these ruptures have usually been associated with motility disorders, lower esophageal ring, or food impaction. During the normal vomiting reflex, there is coordination between the increased intra-abdominal pressure caused by

797

798

Section 8 Trauma

rapid diaphragmatic descent and abdominal wall contraction and the relaxation of the esophagus sphincters. Alcohol ingestion, sedatives, general anesthesia, and repetitive vomiting adversely affect the reflex. Failure of the upper esophageal sphincter to relax results in an increase in intraesophageal pressure and esophageal rupture. The Mallory-Weiss syndrome (massive hematemesis with or without melena) also occurs after persistent retching or vomiting but is unassociated with pain. The process consists of single or several mucosal tears at the esophagogastric junction. The pathogenesis is thought to be related to the effect of vomiting or retching when the inferior esophageal sphincter cannot relax. The pathologic lesion in Boerhaave’s syndrome is a longitudinal rent with well-defined edges, varying in length from 0.5 to 20 cm, located on the left posterolateral wall of the esophagus, 2 to 6 cm above the diaphragm in 80% of cases. The rent may involve the posterior wall or the right posterolateral wall in 8% of cases each. The anterior wall or the midesophagus is a rare site of esophageal rupture.25 The predilection for the left posterolateral wall of the esophagus to be the site of rupture is thought to result from local anatomic factors, such as splaying of muscle fibers in that region or the entrance of blood vessels and nerves into the esophageal wall at that site. In rare instances, the laceration has been noted to be transverse, as it was in Boerhaave’s case, or intra-abdominal.

Clinical Features Typically, Boerhaave’s syndrome occurs in men (85% of cases) in the fourth to sixth decades, who vomit, often after overindulgence in food and drink. Eight cases have been reported in infants who were younger than 1 year of age, including three in neonates.26 Hematemesis is rare. Typically the onset of pain occurs immediately after a vomiting episode. Patients complain of a tearing substernal or epigastric pain, which may radiate to the left chest, shoulder, or back. The pain is accentuated by swallowing or bodily motion. Initially, the physical findings are minimal, perhaps only epigastric tenderness, in marked contrast to the severity of the symptoms. The differential diagnoses include perforated ulcer, acute pancreatitis, renal colic, myocardial infarction, dissecting aortic aneurysm, or incarcerated paraesophageal hernia. All these diagnoses may be excluded by careful history taking, physical examination, and appropriate routine laboratory tests. Flooding of the mediastinum with gastric content and mixed oral flora leads to a fulminant mediastinitis with hemorrhagic necrosis. The mediastinal pleura usually ruptures soon thereafter, with resultant massive pleural effusion, leading to ventilatory insufficiency, hypovolemia, and shock. In some cases, the mediastinal pleura does not rupture and the perforation is contained within the mediastinum. In such cases, the pain may be especially intense and the mediastinal phlegmon may dissect up and down the mediastinum for a considerable distance. As a result, the diagnosis may be considerably delayed because of the initial absence of a pleural effusion. Rupture into the pleural space may occur from days to weeks later.

Cervical subcutaneous emphysema is noted in 65% of cases but may not be appreciated early in the course of the disease. Plain chest radiography is the most valuable laboratory examination; mediastinal widening and cervical or mediastinal air are frequently noted, as is pleural effusion or hydropneumothorax. The effusion is most often left sided but may be right sided or bilateral. Pneumothorax alone is rare. Subdiaphragmatic air has been reported in only one case.27 Initially, thoracentesis yields serous fluid; after rupture of the mediastinal pleura, however, gastric content and food particles may be aspirated. These findings and a pleural fluid pH below 6 make the diagnosis indisputable. Nevertheless, an esophagogram using water-soluble contrast medium should be obtained (Fig. 73-6). An esophagogram may demonstrate the less common right-sided rupture. Occasionally, the watersoluble agents do not reveal the esophageal fistula, in which case thin-barium swallow is recommended. In late or complicated cases, CT scans with contrast medium may be valuable in demonstrating the site of esophageal perforation or periesophageal air.28 Esophagoscopy is useful if it is not possible to obtain an esophagogram or if the study results are equivocal. Despite the dramatic symptoms and signs of Boerhaave’s syndrome, the diagnosis is frequently missed because of the rarity of the disease. Mackler18 stated succinctly that given an acutely ill patient exhibiting signs of collapse, the elicitation of a history of sudden thoracic pain occurring during or after the act of vomiting, followed by the appearance of interstitial emphysema at the base of the neck, constitutes sufficient evidence to warrant a left thoracotomy. Unfortunately, the Mackler triad is not always present in Boerhaave’s syndrome; at least 40% of cases have an atypical presentation, as exemplified by the following case: An alcoholic man who had vomited was admitted to the medical service and treated with intravenous antibiotics for left lower lobe pneumonia and pleural effusion. Closed thoracostomy was performed, resulting in only partial clearing of the pleural effusion, which was considered to be empyema. Decortication was performed 1 week later, and the left lung was successfully re-expanded. Persistent copious drainage from the chest tube led to further analysis of the chest drainage. Amylase and anaerobic enterococci were detected, suggesting an esophageal fistula. A CT scan with oral contrast material clearly demonstrated the esophageal rupture. Healing of the esophageal rent and recovery occurred after a draining gastrostomy and feeding jejunostomy were performed. Two lessons were learned from this case: Lesson 1: Had the patient come to the emergency department wearing a naval admiral’s uniform, voicing his complaints in Dutch, the diagnosis would still have been missed: “What one knows, one sees” (Goethe). Lesson 2: Drainage of intrapleural sepsis, pulmonary decortication to obliterate the empyema space, gastrostomy to prevent reflux, and maintenance of nutrition by means of jejunostomy may be sufficient to allow healing of the esophageal rupture in rare cases, diagnosed late, without overwhelming sepsis.

Chapter 73 Esophageal Perforation

FIGURE 73-6 Boerhaave rupture of the esophagus. A, Mediastinal air (open arrows) and intrapleural extravasation (solid arrows) noted on Gastrografin esophagogram. B, Esophagogram after primary repair and musculopleural flap.

Treatment of Thoracic Perforation Once the diagnosis of thoracic perforation is established, there should be no delay in bringing the patient to surgery. Preoperative measures, including hydration, intravenous antibiotics, and nasogastric intubation, must be expeditious. Prolonged attempts at resuscitation are not productive. The “golden” period for closure of esophageal perforations is the first 12 hours; after 24 hours the likelihood of a post-repair leak increases. Nevertheless, healing and survival may be achieved. Upper-third and middle-third thoracic perforations are best approached by right thoracotomy through the fourth or fifth intercostal space. Lower esophageal perforations are best approached through the left sixth or seventh intercostal spaces. In cases of instrument perforation that is diagnosed early, the surgeon is often afforded the luxury of operating on a fasting patient with an uncontaminated pleura. Nevertheless, the presence of preexisting esophageal disease requires definitive management that is concomitant with esophageal repair. Perforations resulting from pneumatic or hydrostatic dilation for achalasia (usually longitudinal and, like postemetic rupture, situated on the left posterolateral wall of the esophagus) are managed by two-layer closure (see next section) and performance of esophagomyotomy 180 degrees away on the opposite wall of the esophagus (Fig. 73-7).29 Perforation of benign strictures may often be further dilated intraoperatively and then closed and buttressed with a fundoplication such as that for an antireflux procedure. If there is esophageal

shortening, a Collis gastroplasty distal to the dilated stricture may be possible. If these options are not technically feasible, esophagectomy should be considered, because healing of perforation proximal to a stricture is unlikely. In cases of carcinoma or known irreparable stricture with endoscopic perforations, either transthoracic or transhiatal esophagectomy should be considered in patients who are otherwise good surgical candidates.30 Reconstruction may be either immediate or delayed, depending on the patient’s condition.31 Esophageal perforations caused by woven bougies or biopsy forceps are the easiest to repair because of their clean edges but are often difficult to find because of the obliquity of their transit through the esophageal wall. Instilling methylene blue via a nasoesophageal tube to localize the site of perforation is not advised. The dye stains the tissues so intensely that it is difficult to perform an accurate repair. Milk instilled in the same way is easily visualized and does not stain the tissues. Milk taken orally is also readily visible in chest tube drainage. Whatever the cause, once the perforation is visualized, it is essential to incise the muscular coat of the esophagus to ensure that the entire length of the mucosal defect is visualized before a two-layer closure is accomplished. Failure to do so results in inadequate repair and fistula recurrence. The patient with a malignant esophagorespiratory fistula or perforated carcinoma with mediastinal abscess is a candidate for an endoesophageal prosthesis (Fig. 73-8),32 because 80% of these patients succumb within 3 months, 9% live an additional month, and only 11% survive more than 6 months.33 Palliative bypass procedures carry significant morbidity and

799

800

Section 8 Trauma

FIGURE 73-7 A, Rupture of the terminal esophagus following pneumatic dilation for achalasia. Note mediastinal air on the abdominal film (arrows). Esophagography was not performed before surgery. B, Esophagogram after repair 3 hours after injury. Myotomy was performed on the opposite wall of the esophagus.

mortality and usually deprive patients of the opportunity to spend their remaining days at home with their family. Successful management of thoracic perforations is predicated on the following:

4. Thoracic drainage and irrigation 5. Intraluminal stents 6. Resection

1. Débridement and drainage of the mediastinum and pleural spaces 2. Control of the esophageal leak 3. Re-expansion of the lung 4. Prevention of gastric reflux 5. Nutrition and ventilatory support 6. Appropriate antibiotics 7. Postoperative localization and drainage of residual septic foci

Technique of Closure

The methods used have been: 1. Closure with buttress or patch 2. Exclusion and diversion 3. T-tube fistula

Left posterolateral thoracotomy is performed through the bed of the subperiosteally resected seventh rib. I prefer this method, rather than intercostal incision, because it facilitates the later construction of a pedicled, vascularized, intercostal musculopleural flap to buttress the esophageal suture line. Preparation and application of the flap are described in the next section. The chest is evacuated of debris and gastric content and is copiously irrigated. The mediastinal pleura bulges and often appears as if burned by gastric secretions; it is incised from the diaphragm to the aortic arch and widely débrided of necrotic tissue (Fig. 73-9). The esophagus is then gently elevated on a silicone-like (Silastic) loop exposing the right

Chapter 73 Esophageal Perforation

FIGURE 73-8 Carcinoma of the midthoracic esophagus with tracheoesophageal fistula (A) treated by endoesophageal prosthesis (B).

pleural surface. This area must also be débrided to prevent the late development of a right posterior mediastinal abscess. Right pleural effusion, if present, may often be drained by passage of the suction tip into the right pleural space. Conventional closed right chest drainage is established later, after completion of the left thoracotomy if a right pleural space collection is present. Attention is next directed to the esophageal rent. It is essential to incise the muscle layer longitudinally to ensure that the entire length of the mucosal defect is visualized. Edematous mucosal edges are trimmed, the mucosa and submucosa are closed with interrupted silk or polyglactin sutures, and the knots are placed intraluminally. The muscle coat is closed with interrupted silk. In cases diagnosed after 48 hours, the muscular closure may not be possible. Buttressed closure is then essential. A nasogastric tube is positioned above the suture line, the chest is flooded with saline, and air is gently injected into the tube. Lack of air bubbles in the chest indicates an intact suture line. The lung is then decorticated, thus ensuring full re-expansion. At this point, consideration must be given to buttressing the repair. Despite repair within 24 hours after the injury,

there is still the risk of suture line disruption and an esophagopleural fistula. Parietal pleura,34 pedicled intercostal muscle,35 diaphragm,36 pericardium,37 and omentum and gastric fundus38 have all been used. Use of the last four tissues runs the risk of infecting the peritoneal or pericardial cavities. Gastric fundus transposed to the chest may in effect create a paraesophageal hernia, with the attendant risks of late stasis ulceration and gastric mural necrosis. In early cases, the parietal pleura is thin and does not make a suitable buttress and a pedicled intercostal musculopleural flap is preferred.34 Wright and colleagues39 confirmed the value of buttressing the primary repair of thoracic esophageal perforations with the pedicled intercostal muscle flap. They achieved primary healing in 89% of the 28 patients, 13 of whom were treated more than 24 hours after perforation. In the 7 patients with postoperative leaks, only one required reoperation. Finley and associates reported successful management with primary closure and drainage in seven cases with delayed (>48 hours) recognition of esophageal perforation. None of the patients required reoperation.40 When only mucosal repair could be accomplished, the intercostal flap was applied to the esophagus using fibrin glue; primary healing resulted.41

801

802

Section 8 Trauma

Diaphragm

Mediastinal pleura

Pericardium

Aorta

Esophagus

A

Right mediastinal pleura

B

Mucosa

Muscularis

C FIGURE 73-9 A, Necrotic mediastinal pleura has been excised, and the esophageal tear has been débrided. B, Elevation of the esophagus on a rubber drain allows for débridement of the right mediastinal pleura if indicated. C, Débridement of the esophageal rupture. Muscularis is incised superiorly and inferiorly to allow visualization of the extent of mucosal defect before two-layer closure of the perforation if possible.

Chapter 73 Esophageal Perforation

Preparation of the Pedicled Intercostal Musculopleural Flap After thoracic débridement and esophageal repair, the rib spreader is removed and the ribs are partially distracted manually if necessary. The surgeon uses a length of umbilical tape to estimate the flap length required, measuring from the posterior end of the segment of rib (usually the seventh) resected at thoracotomy to the esophageal suture line. The periosteum of the next lower rib is incised and stripped from the upper border of that rib (Fig. 73-10A and B). The

Intercostal muscle

8th rib

Periosteum

A

8th rib

Periosteum

periosteum, the pleura, and the intervening intercostal muscle bundle, with its associated neurovascular components, are then mobilized to the full extent of the thoracotomy incision, with a marked tape used to ensure adequate length. It is desirable to have the flap terminate in a spatulate fashion, so that a generous width of pleura is created anteriorly. The flap is transected anteriorly, and the intercostal artery and vein should bleed profusely; they are then ligated. The flap is then applied to the site of esophageal repair or defect and meticulously sutured to the muscle closure or muscle remnants (see Fig. 73-10C and D). Neurovascular bundle

7th rib

Pleura

Fascia

Pleura

B

FIGURE 73-10 Construction of intercostal musculopleural flap. A, Periosteum of the rib inferior to thoracotomy incision is incised, and the subjacent pleura is mobilized. B, The neurovascular bundle is divided anteriorly, and the flap is created. Continued

803

804

Section 8 Trauma

Intercostal musculopleural flap

C

D

FIGURE 73-10, cont’d C, Two-layer closure of the esophagus is performed if possible. D, The musculopleural flap is applied as a buttress or a patch if closure of the perforation is not possible.

The excess pleura is fixed to whatever mediastinal tissue is available to maintain the flap in position. The flap should not be wrapped circumferentially about the esophagus, because periosteal new bone formation may cause a “napkin ring” constriction. Flaps constructed from the rhomboideus major,42 pectoralis major,43 and latissimus dorsi (Richardson et al, 1985)44 muscles have been used to close upper thoracic esophageal perforations. The chest is drained with two largebore catheters, one of which is juxtaposed to the esophageal repair. After closure of the chest, the patient is placed in the supine position, and, with a fresh surgical armamentarium, draining gastrostomy and feeding jejunostomy are performed. Gastrostomy prevents acid reflux, and jejunostomy is essential to maintain nutrition and facilitate healing. Postoperative mechanical ventilation is mandatory for these patients with sepsis who have compromised pulmonary function. Mechanical ventilation ensures that the lung will remain fully expanded and will adhere to the esophageal repair, possibly affording additional support. Elective use of mechanical ventilation and positive end-expiratory pressure may be helpful in maintaining lung expansion.40 Experimentally, the lung is able to seal esophageal defects.45 If a leak develops postoperatively, a contrast esophagogram is helpful in determining the possible need for further intervention. With good drainage, nutrition support, appropriate antibiotics, and the absence of distal obstruction, the leak should eventually heal. During early convalescence, it is not uncommon for the patient to take a turn for the worse with fever and leukocytosis associated with an unremarkable chest radiograph. A CT

scan may demonstrate a residual septic focus. On occasion, this infection may be drained by catheters placed with ultrasound or CT guidance. Limited mediastinotomy may be required.

Esophageal Exclusion The concept of esophageal exclusion for the management of thoracic perforations was advanced by Johnson and colleagues,46 who divided and sutured the esophagogastric junction and created an end-cervical esophagostomy. Subsequently, jejunal interposition was used for reconstruction,47 with neartotal esophageal exclusion by means of lateral cervical esophagostomy and tube gastrostomy. Urschel and associates48 modified the technique of total esophageal exclusion in continuity, initially tying an umbilical tape over a polytetrafluoroethylene (Teflon) band at the esophagogastric junction and performing tube gastrostomy and lateral cervical esophagostomy. Urschel49 later modified the esophagogastric occlusion by use of a polypropylene suture snared over a Silastic band, exteriorizing the snare to obviate the need for a second laparotomy to relieve the induced esophagogastric obstruction. Because of difficulties in the later reconstruction of the cervical esophagus after lateral or terminal esophagostomy, proximal esophageal diversion has been accomplished by means of a mushroom catheter50 or T tube with closed distal limb51 and a Silastic occluding band applied about the esophagus and distal T-tube limb. After the esophageal perforation has healed, the band and catheter are removed. The cervical salivary fistula heals within several days.

Chapter 73 Esophageal Perforation

Stapling of intestinal segments in continuity may result in restoration of the lumen.52 Ladin and colleagues53 closed a postemetic esophageal rupture and stapled the esophagus proximal and distal to the suture line, also performing cervical esophagostomy and tube gastrostomy. Six weeks later, the esophageal lumen was found to be reconstituted without stricture. Because luminal restoration after stapling with stainless steel staples is not predictable, esophageal exclusion with absorbable staples (Lactomer) has been introduced, with esophageal recanalization reported after 2 weeks.54 Nasoesophageal suction was used for decompression of the proximal staple line, and nutrition was maintained via jejunostomy.

T-Tube Fistula and Drainage Abbott and associates55 constructed a large-bore Silastic T tube that was inserted through the perforation. The distal portion of the short limb traversed the gastroesophageal junction, and the large limb exited from the chest. A nasogastric tube that was passed through the T-tube lumen into the stomach aided in maintaining the T tube in position. Pleural drainage was also instituted. In a subsequent report from this group56 the authors recommended that the T tube should be brought out through a lateral incision and sutured to the diaphragm in a position that would avoid aortic erosion. Eventual healing of the control esophageal fistula is predicated on full expansion of the lung to patch the perforation. Therefore, thorough mediastinal débridement and pulmonary decortication are required for the successful application of this technique.

Mediastinal Irrigation and Drainage Brewer and coworkers57 used mediastinal antibiotic irrigation and drainage, as well as transesophageal irrigation and thoracic drainage, in selected cases. Santos and Frater58 used peroral, transesophageal mediastinal irrigation with drainage of the irrigant via chest tubes as a method for evacuating mediastinal sepsis. This technique requires thoracotomy for thorough débridement and well-positioned chest tubes for effective drainage.

Intraluminal Stents The various intraluminal stents that have been used for the palliation of nonresectable esophageal carcinoma have also been used to seal instrument perforations in poor-risk patients.32 An expanding mesh stent placed under fluoroscopic control has been successful in the management of a Boerhaave rupture in an aging patient who could not tolerate thoracotomy.59 In this situation, the transabdominal route was used to drain and irrigate both the pleural cavity and the mediastinum. As with esophageal exclusion and diversion, T-tube drainage, mediastinal irrigation, and intraluminal stents have been reserved for situations in which the condition of the patient and the size and age of the perforation indicate that optimal treatment of buttressed repair is not feasible.

Resection Esophagectomy for the management of perforations should be considered in patients with instrument perforation, esophageal carcinoma, irremediable stricture, late diagnosed cases of Boerhaave rupture, severe traumatic disruption, and overwhelming sepsis in which successful surgical management by other means is considered unlikely to succeed or has failed. Esophagectomy may be performed via the transthoracic or transhiatal route, but mediastinal and pleural débridement are essential. The patient is left with an end-cervical esophagostomy and gastrostomy. Reconstruction by means of colon or gastric interposition via the substernal route is often best deferred for several months when mediastinitis has been controlled and the patient is in stable and satisfactory condition.

Treatment of Abdominal Perforations Abdominal esophageal perforations are associated with an excellent prognosis if they are recognized at the time of injury. They are best managed by closure and partial fundic wrap as a buttress or patch. If it is not possible to use gastric fundus, an omental wrap should be performed. Complementary gastrostomy and jejunostomy are usually indicated. Berne and colleagues60 treated five cases of Boerhaave rupture by transabdominal repair, gastric fundoplication, and transabdominal drainage of the mediastinum. Empyemas were treated by closed thoracostomy.

RESULTS Jones and Ginsberg2 analyzed the results of 13 series of esophageal perforation, totaling 598 patients, reported between 1980 and 1990. The overall mortality was 22%. Instrument and iatrogenic injuries carried a mortality rate of 19%; for Boerhaave ruptures, the rate was 39%. In their analysis of 439 patients, the mortality rate for cervical perforations was 6%; for thoracic perforations, 34%; and for abdominal perforations, 29%. All series demonstrate that early diagnosis and surgical management favorably affected the outcome; after 24 hours, both morbidity and mortality rates increased. In Attar’s series,1 the survival in patients undergoing surgery in less than 24 hours after perforation was 87% and decreased to 55% in patients undergoing operation later. Sawyers (1990)15 reported no deaths in 115 patients who were managed by operation within 24 hours of perforation in the years between 1980 and 1990. Other factors that adversely influence mortality rate are preexisting esophageal disease, perforation in a thoracic site, and anastomotic leak.44 Buttressing the thoracic esophageal suture line appears to decrease the incidence of recurrent esophagopleural fistula and mortality. Gouge and associates (1989)61 reviewed the results of 10 series of primary suture of thoracic perforations: fistulas developed in 39% of 158 patients, with a 25% mortality rate. This group included patients operated on both before and after 24 hours after perforation. In those operated on after 24 hours after perforation, the esophageal repair leaked in 50% of cases. In contrast, in 99 patients who had a buttress repair, the leakage rate was 13% and the mor-

805

806

Section 8 Trauma

tality rate was 6%. These data lend credence to the concept that suture repairs of thoracic esophageal perforations should be buttressed; if suture repair is not possible, the defect should be patched, preferably with a muscle flap.

Results of Alternative Procedures Analysis of reported series of other methods (Gouge et al, 1989)61 revealed mortality rates to be 36% for T-tube drainage, 35% for exclusion-diversion, and 26% for resection. Orringer and Stirling31 used transhiatal or transthoracic resection with either immediate or delayed reconstruction and noted a mortality rate of 13%. Preexisting esophageal disease was present in most patients in this group.

DISCUSSION Pearse’s landmark contribution in 1933 defined the operative approach to cervical esophageal perforation and had a profound effect on survival in the preantibiotic era. In Jemerin’s report, only 50% of patients with cervical perforations before 1936 had undergone any form of operative drainage; 70% of the entire group died. In the decade following 1936, 90% of patients underwent cervical drainage, as recommended by Pearse, and the mortality rate decreased to 17%. The availability of potent intravenous antibiotics has led some physicians to advocate nonoperative treatment for small esophageal perforations. The vexing question is: How small is small? Pearse asked, “Should the esophagus be exempt from the rules, which experience has dictated, for early surgical intervention in case of perforation of other organs?” In the absence of the radiographic findings detailed in this chapter, it is tempting to give the patient intravenous antibiotics and parenteral alimentation and to operate if the patient’s condition deteriorates, as demonstrated by increase in fever, tachycardia, tachypnea, leukocytosis, and evidence of mediastinal and pleural fluid collections on subsequent chest films. This approach puts the patient at risk for the development of massive mediastinal sepsis; thus, the alternatives: Should one wait for mediastinal sepsis to develop and thus increase the risk of a fatal outcome, or should one operate to prevent the development of sepsis? Again, to quote Pearse, “the patient does not die of the perforated cervical esophagus per se nor does he necessarily die from the infection in the neck, but usually dies from mediastinitis, the indirect result of the perforation.” To paraphrase Groves,62 esophageal perforation is an accepted hazard of esophageal instrumentation, yet it is difficult for endoscopists to conquer their pride and accept that perforation has occurred, and it is even more difficult to explain what happened to the patient and to the family. It is easy to succumb to the temptation to inform the patient that the esophagus has been “scratched” and to keep the patient hospitalized on an antibiotic regimen and parenteral alimentation. The standard for management of thoracic esophageal perforations in the absence of preexisting esophageal disease is, as detailed in this chapter, buttressed closure preceded by evacuation of mediastinal sepsis, followed by decortication of the lung, thoracic drainage tubes, gastrostomy, and jejunos-

tomy. The reported results with gastric fundus flap for perforations at the esophagogastric junction have been excellent, provided that total fundoplication is not left above the diaphragm. The hiatus should be widened to avoid constriction of the fundus, which should be sutured circumferentially to the margins of the diaphragm. The fundus flap is ideally suited for buttressing intra-abdominal perforations. The parietal pleura, if thin, is fragile and not a satisfactory buttress. The intercostal musculopleural flap or diaphragm flap is preferred. Excellent results have been achieved with either flap without the late sequelae that occasionally occur when a portion of the stomach is transposed into the left hemithorax. The latissimus, rhomboid, and pectoralis major muscle flaps are useful in the management of middle and upper thoracic perforations. Discussions of the merits of nonoperative management of thoracic esophageal perforation invariably refer to a report by Cameron and associates.63 Their criteria for not performing thoracotomy are (1) contained mediastinal disruption that drains back into the esophagus and (2) minimal systemic signs and symptoms. Of the eight cases treated, five were postsurgical, including one closure of an esophageal perforation, and seven of the eight were detected from 2 to 9 days after onset and demonstrated minimal systemic findings. Although some patients with periesophageal and mediastinal fibrosis resulting from preexisting esophageal disease do not develop fulminating mediastinitis after thoracic esophageal perforation, they are the exception rather than the rule (Fig. 73-11).

FIGURE 73-11 Esophagogram after endoscopic removal of a chicken bone that perforated the thoracic esophagus (arrow) 2 days previously. Contained mediastinal perforation without sepsis was managed with intravenous antibiotics and parenteral alimentation.

Chapter 73 Esophageal Perforation

Decision making may be difficult when esophageal perforation occurs in the presence of benign lower esophageal obstruction. Achalasia is well managed by closure of the perforation and complementary esophagomyotomy. The management of perforation of strictures associated with reflux esophagitis requires good judgment and an experienced surgeon. If left thoracotomy is required to treat intrathoracic sepsis, intraoperative dilation of the stricture before closure and buttress may allow healing. These strictures are frequently associated with a degree of esophageal shortening that does not allow the creation of a competent esophagogastric junction that may be repositioned beneath the diaphragm. If the esophageal stricture is considered to be irremediable, esophagectomy—either transthoracic or transhiatal—is indicated. The experience of the surgeon and anticipated technical difficulties weigh heavily in this decision. Restoration of continuity may be immediate or delayed, depending on the patient’s condition (Fig. 73-12). Decision making in cases of perforation from esophageal carcinoma is easier. If the patient is otherwise a candidate for esophagectomy, the surgeon should proceed promptly. If not, because of the extent of the disease or because of associated medical conditions, transoral insertion of an esophageal prosthesis may be a logical solution. The grave prognosis limits surgical options. The best results in cases of Boerhaave rupture have been achieved by the operative procedure described. The necrotiz-

ing mediastinitis caused by synergistic oral bacteria and gastric content must be débrided and drained if the patient is to survive. Otherwise, the statistics are grim: Of 71 cases in the historic series of Derbes and Mitchell,64 only 35% survived for 24 hours, 11% lived for 48 hours, and none lived longer than 1 week. Thus, closed thoracostomy, antibiotics, and ventilatory care have resulted in prolonged survival in patients with a late diagnosis, making them candidates for repair and drainage. The mortality rates of T-tube diversion and exclusion and diversion reflect the severity of illness in this group of patients, rather than the magnitude of the procedures. For example, a patient with cirrhosis who has hepatic failure and esophageal perforation that has been caused by a SengstakenBlakemore tube may not be a candidate for repair but might possibly survive following T-tube drainage or diversion and exclusion. The objections to diversion-exclusion are that the creation of end-cervical esophagostomy presents an insurmountable problem in the restoration of esophageal continuity and that the distal cervical esophagus retracts into the mediastinum and is not retrievable. Lateral cervical esophagostomy with T-tube insertion is more acceptable; but whether it is truly more diverting than a sump nasoesophageal tube, which eliminates the need for subsequent cervical esophageal repair, is questionable. Furthermore, the sump tube allows for transesophageal instillation of antibiotic solution as an irrigant. Is band occlusion of the esophagogastric junction significantly more efficient than a gastrostomy tube that is placed on suction? Does not the surgically created distal obstruction impede healing of the thoracic perforation, and is the band not likely to cause stricture or pressure necrosis of the esophageal wall, no matter how carefully applied? Diversionexclusion should be used when thoracotomy is not a reasonable alternative or when attempted repair has not controlled sepsis. Although some encouraging results have been reported for esophageal stapling in continuity, the surgeon should beware of stapling and division of the esophagus. The distal staple line is subject to dissolution, and leaving the esophagus in situ in this circumstance virtually guarantees that intrathoracic sepsis will not be controlled. If thoracotomy is being considered with this option in mind or has already been performed, esophagectomy and cervical esophagostomy are better options, with substernal gastric or colonic interposition scheduled at a later date. Advances in technology may produce more sophisticated stapling devices, lasers, or biologic adhesives for the management of perforations, but esophageal perforations will continue to pose formidable obstacles to successful management, testing the mettle of surgeons for the foreseeable future.

COMMENTS AND CONTROVERSIES FIGURE 73-12 Barium swallow obtained postoperatively in a cardiac surgical patient after intraoperative transesophageal echocardiography. The two parallel columns of contrast agent without extraluminal extravasation are virtually diagnostic of intramural perforation.

Immediate diagnosis, rapid resuscitation, and prompt treatment are necessary to successfully manage esophageal perforations. Presentation and treatment options are determined by esophageal location, cause of the perforation, and underlying esophageal

807

808

Section 8 Trauma

pathology. The optimal treatment of a thoracic perforation in an otherwise normal esophagus is repair with buttressing, mediastinal and pleural débridement, lavage and drainage of the pleural space and mediastinum, temporary gastrointestinal decompression, and placement of a feeding tube. In patients with significant underlying esophageal pathology, resection with immediate or staged reconstruction may be necessary. Malignant perforations or perforations in terminal patients may best be palliated by an expandable, covered metallic stent blocking the perforation and percutaneous drainage of the surrounding space. Cervical esophageal perforations are surgically drained and frequently are not or cannot be repaired. Abdominal esophageal perforations may be difficult to diagnose or are misdiagnosed. Nonstandard therapies and conservative management are required only in the most uncommon situations. T. W. R.

Acknowledgment Supported by the Feldesman Fund for Thoracic Surgery at the Montefiore Medical Center. KEY REFERENCES Gouge TH, Depan HJ, Spencer FC: Experience with the Grillo pleural wrap procedure in 18 patients with perforation of thoracic esophagus. Ann Surg 209:612, 1989. Jones WG, Ginsberg R: Esophageal perforation: A continuing challenge. Ann Thorac Surg 53:534, 1992. Richardson JD, Martin LF, Borzotta AP, Polk HC: Unifying concepts in the treatment of esophageal leaks. Am J Surg 149:157, 1985. Sawyers J: Discussion of Attar S, Hankins J: Esophageal perforation: A therapeutic challenge. Ann Thorac Surg 50:45, 1990.

Index

Note: Page numbers followed by b, f, and t indicate boxes, figures, and tables, respectively. A Abdomen, dissection of in en-bloc resection of esophageal carcinoma, 602-603, 603f in laparoscopic gastric conduit construction, 623f-624f, 624 in transhiatal esophagectomy, 565-568, 566f-567f Abdominal approach, in total gastrectomy with Roux-en-Y reconstruction, 613-616, 614f-617f Abdominal esophagus anatomy of, 11f arteries supplying, 13-14, 14f carcinoma of, surgical management of, 472 perforation of, 796, 805 vagal innervation of, 18 Abdominal viscera, revascularized free grafts of, for esophageal replacement, 558 Abdominothoracic approach, in total gastrectomy with Roux-en-Y reconstruction, 616-618, 617f Abdominothoracocervical esophagectomy, origins of, 4 Ablative therapy, endoscopic for early Barrett’s adenocarcinoma, 423-425, 424f for high-grade Barrett’s dysplasia, 413, 416-417, 417f Achalasia, 714-720 barium esophagogram in, 62f, 71f-74f, 73-74, 715-716, 716f, 744-745, 744f in Chagas’ disease, 736-737, 737f, 738, 738b, 743 chest radiography in, 715, 716t, 744 clinical features of, 715, 715t, 744 complications of, 716t computed tomography in, 74 definition of, 743 diagnosis of, 715-717, 716f-717f, 716t, 744-745 differential diagnosis of, 715t, 717-718 endoscopy in, 109, 717, 717f epidemiology of, 714 esophageal transit scintigraphy in, 86 etiology and pathogenesis of, 714-715 historical note on, 714 manometry in ambulatory 24-hour, 134, 134f stationary, 123, 124f, 716t, 717, 717f, 745 medical treatment of botulinum toxin in, 718, 745 pharmaceuticals in, 718 pneumatic dilation in, 5, 6, 253, 718-720, 719f, 719t, 745 motor abnormalities of, 43, 43f, 44f radiologic findings in, 71f-74f, 73-74, 715-716, 716f, 744-745, 744f secondary, 73-74, 369-370, 715t, 717-718 squamous cell carcinoma in, 451 surgical management of, 745-751 choice of operation in, 745-746 esophagectomy in, 340-343 indications for, 340-342, 340t, 341f technical considerations in, 341f, 342-343, 342t esophagomyotomy in laparoscopic, 6, 746, 748f-751f, 749-751, 752-753 thoracoscopic, 745-746, 746f-748f, 747-748, 751-752 transthoracic, 745, 746-747, 746f-747f, 751 evolution of, 5-6 historical note on, 743-744 operative technique for, 746-751, 746f-751f preparation for, 746 results of, 751-753 ultrasonography in, 109, 717 “vigorous,” 71f, 74, 123, 717

Acid clearance, abnormal, in peptic esophagitis, 224 Acid mucin in esophageal glands, 396 in goblet cells, 404, 404f in pseudo-goblet cells, 404-405, 405f Acid perfusion test, 50, 131 Acid reflux gastroesophageal. See Gastroesophageal reflux disease. mucosal complications associated with, 56-57 Acid reflux test, standard, 136-137, 138f Acid-containing substances, ingestion of, caustic injury from, 760, 760t Acidic beverages, gastroesophageal reflux disease and, 192 Acini-containing glands, embryology of, 22, 22f Acoustic impedance, in endoscopic ultrasonography, 97 Adenocarcinoma Barrett’s. See Barrett’s adenocarcinoma. epidemiology of, 449-451 of esophagogastric junction, 451, 492-497 classification of, 492, 493f-494f, 497, 614f definition of, 492 diagnosis and staging of, 492-493 esophagectomy for, 493-494, 574-575, 574f gender and, 492, 494t metastasis of, 492-493 surgical therapy for for early stage, 496, 496f results of, 495t, 496 by type, 493-497, 494f, 613, 614f total gastrectomy and Roux-en-Y reconstruction for, 613, 614f geographic variations in, 449-450 Helicobacter pylori cagA+ strains and, 52 incidence of, 509 primary surgery for, 486-490 radiologic findings in, 81, 81f ulcerated, 81f varicoid, 81f Adenomatous polyps, 437 Adjuvant therapy for Barrett’s adenocarcinoma, 426-427 results of, 500 for squamous cell carcinoma, 479 Adventitia, 396 Aerodigestive tract, upper, tumors of, multiple primary, 452 Aerodigestive tube, origin of, 20, 20f Age adenocarcinoma and, 450 Barrett’s esophagus and, 390, 390f esophageal motor disorders and, 728 motility disorders and, 73 squamous cell carcinoma and, 448, 449f Airway obstruction of from foreign body, 783, 787 in innominate artery compression of trachea, 178 in pulmonary artery sling, 177 in vascular rings, 172, 175 stenting of, for tracheomalacia, 160 Alcohol consumption adenocarcinoma and, 450 gastroesophageal reflux disease and, 193, 203 squamous cell carcinoma and, 449 Alkali-containing substances, ingestion of, caustic injury from, 759-760, 760t Alkaline reflux, detection of, 140, 141t, 142f, 206

Allergic eosinophilic esophagitis. See Ringed esophagus. Allopurinol, for Chagas’ disease, 737 Alprazolam, for nonachalasia motility disorders, 724 Aluminum, antacids containing, for gastroesophageal reflux disease, 194 American trypanosomiasis. See Chagas’ disease. Amyotrophic lateral sclerosis, dysphagia in, 683, 687 Anal atresia, esophageal atresia with, 153 Anastomosis. See also specific anatomy or technique. cervical colon interposition and gastric pull-up with, 558 for reversed gastric tube placement, 658, 660f cervical esophagogastric. See Cervical esophagogastric anastomosis. for colon interposition, 635, 636-637 complications of, in colon versus gastric interpositions, 639, 639t end-to-end, 556 for esophageal atresia repair, 157 for esophageal web repair, 168 esophagogastric. See Esophagogastric anastomosis. esophagojejunal, in total gastrectomy with Rouxen-Y reconstruction, 616, 616f, 617f, 618 intrathoracic esophagogastric. See Intrathoracic esophagogastric anastomosis. for Ivor Lewis esophagectomy, 595-596, 595f leaks of. See Anastomotic leaks. for left thoracoabdominal esophagectomy, 587, 588f paracolic arterial, 631-632, 631f for pharyngoesophageal reconstruction, 652, 654 for pharyngolaryngeal reconstruction, 644 staplers for. See Staplers/stapling techniques. strictures of. See Anastomotic strictures. transabdominal, for Roux-en-Y jejunal reconstruction, 560 for tri-incisional esophagectomy, 595, 595f Anastomotic leaks, 547, 556 with en-bloc resection of esophageal carcinoma, 606 with esophageal atresia repair, 159 with esophagectomy, 546-547, 547f with esophagogastric anastomosis, 547, 547f, 556 with gastric tube esophagectomy, 660-661 thoracic, 547, 556 with transhiatal esophagectomy, 578-579, 580 Anastomotic strictures with esophageal atresia repair, 160 with esophagectomy, 548 with esophagogastric anastomosis, 660 postoperative, 548 Anatomy. See also specific component. of arteries, 13-14, 13f-14f course deviations in, 10, 11f of esophageal wall, 100-101, 100f general features of, 10, 11f-12f of lymphatics, 15-16, 15f-16f of nerves, 16-19, 17f-18f surgical relevance of, 12-13 surrounding tissues, compartments, and anchors in, 10-11, 12f of veins, 14-15 Anchoring structures, anatomy of, 10-11, 12f Anemia, iron deficiency esophageal web and, 248 in paraesophageal hernia, 234 Anesthesia topical in esophageal dilation, 256 in esophagogastroduodenoscopy, 111-112 for transhiatal esophagectomy, 565

809

810

Index

Aneuploidy, DNA in Barrett’s esophagus, 411-412 in esophageal carcinogenesis, 442-443 Angiography, preoperative, in colon interposition, 632 Antacids for gastroesophageal reflux disease, 194 in pregnant patients, 200t, 201 Anterolateral thigh free flap for pharyngoesophageal reconstruction, 650-651, 653 for pharyngolaryngeal reconstruction, 647-648, 647f Antibiotics for caustic injury, 761-762 for esophageal carcinoma, 510t, 511 for esophageal perforation, 796, 806 prophylactic, for esophagogastroduodenoscopy, 112t Anticholinergic agents, for diffuse esophageal spasm, 754 Anticoagulation, for esophagogastroduodenoscopy, 112t Antidepressants, tricyclic, for nonachalasia motility disorders, 724 Antimetabolites, for esophageal carcinoma, 510t, 511 Antireflux barrier anatomy of, 288-290, 289-290 in infants and children, 218 surgical restoration of all components of, need for, 190 Antireflux surgery, 207-214. See also Fundoplication; specific technique. after esophageal atresia repair, 160 barium esophagogram after, 67-71, 67f-71f in Barrett’s esophagus, 419-422 for peptic strictures/ulcers, 420 rate of progression after, 421 for symptom control, 419-420 Barrett’s esophagus after, 214 in Chagas’ disease, 738-740, 739f-740f, 740t choice of operation in, 207-209 complications of early postoperative, 378-379 immediate, 376-378, 377f late postoperative, 379-380, 380t unusual, 380 diagnostic studies prior to, 204-207 esophageal carcinoma and, 214 esophageal lengthening procedure with, 187-189, 189f failure of. See Failed repairs. for hiatal hernia and GERD, 187-189, 189f Hill repair as. See Hill repair. indications for, 190, 207, 268, 268t in infants and children historical perspective on, 217-218 indications for, 220-221, 220t results of, 222-223 surgical alternatives to, 223 technique for, 220f-222f, 221-222 laparoscopic for hiatal hernia and GERD, 187-189, 189f for peptic stricture, 228, 229 for reflux in obese patients, 241-242 for peptic stricture, 228-229 principles of, 207 radiography and, 66-67 for reflux-induced respiratory symptoms, 56, 213-214 for Schatzki ring, 246-247 for secondary esophageal motor disorders, 729 signs and symptoms after, 362 successful, common features of, 343 Antral stenosis, after caustic injury, 764 Antrectomy, vagotomy and duodenal diversion with, for failed repairs, 365 Antropyloroduodenal system, in physiologic model of foregut, 49-50, 50f Aorta esophageal branches of, 13, 13f, 14f injury to, intraoperative, 378

Aortic arch development of, 170, 171t double, 170-171, 171f, 173f, 175, 176f left, dominant, 172, 172f right with aberrant left subclavian artery and left ligamentum, 171, 172f, 174f in dysphagia lusorum, 76f, 77 with mirror-image branching and retroesophageal ligamentum, 171-172 Aortoesophageal fistula from foreign body, 771 in vascular rings, 173 Aortopexy for innominate artery compression of trachea, 179 for tracheomalacia, 160 Apoptosis, in esophageal carcinogenesis, 442 Archenteric cysts, 164 Arcuate ligament, median, isolation of, in modified Hill repair, 288, 291, 291f Argon plasma coagulation for early Barrett’s adenocarcinoma, 423 for high-grade Barrett’s dysplasia, 417 Arrhythmias, after en-bloc resection of esophageal carcinoma, 605-606 Arteries anatomy of, 13-14, 13f-14f, 396 of colon, 631-632, 631f of stomach, 656, 657f surgical consideration of, 13-14, 13f-14f Aspiration after colon interposition, 640, 640t fine needle, endoscopic ultrasonography with for carcinoma staging, 105, 106f, 416, 457, 459, 468-469 in paraesophageal disease, 109 pulmonary, persistent, after cricopharyngeal myotomy, 686f, 687 tracheal in cricopharyngeal dysfunction without diverticulum, 693, 693f in oculopharyngeal muscular dystrophy, 689, 689f in oropharyngeal dysphagia, 40 Aspiration pneumonia in foreign body impaction, 783, 785f in laryngotracheoesophageal cleft, 161 in oculopharyngeal muscular dystrophy, 689 Aspirin, caustic injury from, 760 Asthma of esophagus. See Ringed esophagus. reflux-induced antireflux surgery for, 213-214 diagnosis of, 55 in infants and children, 218-219, 220-221 pathophysiology of, 54-55, 55f rate of, 54, 55, 55f treatment of, 55-56, 56f Atelectasis after transhiatal esophagectomy, 580 early postoperative, 379 Atrial fibrillation, after en-bloc resection of esophageal carcinoma, 605-606 Attenuation, in endoscopic ultrasonography, 98 Auerbach’s plexus, 18, 396 Autofluorescence imaging, in Barrett’s esophagus, 416, 416f Autonomic nervous system, esophageal distribution of, 16-18, 17f-18f Autopsy carcinoma staging, 462 Azygos nerve, division of, in right-sided transthoracic esophagectomy, 592 Azygos vein, surgical relevance of, 15

B Babcock clamps, in Hill repair, 292f, 293, 293f, 295 Baclofen, for gastroesophageal reflux disease, 196 Balloon dilation. See Pneumatic dilation. Balloon distention test, 131

Bariatric surgery history of, 239 for reflux in obese patients indications and patient selection in, 243, 243t mechanisms of action of, 243-244 techniques in, 242-243, 242f, 243f Barium enema, for colon interposition, 632 Barium esophagogram, 60-66 in achalasia, 62f, 71f-74f, 73-74, 715-716, 716f, 744-745, 744f after Roux-en-Y gastric bypass, 243, 244f in Barrett’s esophagus, 79, 81 in benign neoplasms, 431, 432f in Boerhaave’s syndrome, 798, 799f in collagen vascular diseases, 75 in diffuse esophageal spasm, 74-75, 74f, 720-721, 721f double-contrast (upright, mucosal) phase of, 61, 63f-65f in esophageal carcinoma, 81, 81f, 454, 455f in esophageal cysts, 165 in esophageal perforation, 82, 82f, 83f in esophageal stricture, 77f, 78, 78f in esophageal webs, 167 in fibrovascular polyp, 79, 436, 436f in foreign body ingestion, 785f, 786, 786f, 787f in gastroesophageal reflux disease, 66-67, 204-205, 204f, 205f in infants and children, 219 in leiomyoma, 79, 79f in midesophageal and epiphrenic esophageal diverticulum, 75, 75f in motility disorders, 71 motility phase of, 61-63 oropharyngeal phase of, 60 in peptic stricture, 227, 254-255, 254f post-fundoplication, 67-71 normal appearance of, 67-68, 67f in patient with dysphagia and/or gas bloat syndrome, 68, 69f, 70 in patient with dysphagia to liquids, 67 in patient with nausea and early satiety, 70-71 in patient with reflux symptoms, 70, 70f, 71f reflux identification phase of, 64-65 in ringed esophagus, 78, 78f in Schatzki ring, 246, 246f in short esophagus, 314, 369, 369f single-contrast (semiprone, distended) phase of, 63-64, 63f “solid” food phase of, 65-66 in squamous cell carcinoma staging, 467 in systemic sclerosis, 726, 726f timed barium swallow phase of, 60-61, 61b, 62f in vascular rings, 173, 173f in workup for reoperation, 363, 370, 371f Barotrauma, esophageal perforation from, 796, 797f. See also Boerhaave’s syndrome. Barrett’s adenocarcinoma advanced, treatment of adjuvant chemotherapy and radiotherapy in, 426-427 esophagectomy in, 426, 427f lymphadenectomy and en-bloc resection in, 426 neoadjuvant chemotherapy in, 426 dysplasia progression to, 58, 387, 405-406 early staging of, 416 treatment of, 423-426 endoscopic ablative therapy in, 423-425, 424f esophagectomy in, 425-426, 425f histopathology of, 413-414 infiltrating gastroesophageal junction, 492, 493-494, 493f, 494f screening for, 422-423 Barrett’s epithelium baseline glandular atypia of, 407-408, 408f characteristics of, 403-405 versus esophageal glands, 405 versus Helicobacter pylori gastritis, 403-404 versus inflamed gastric cardiac-type mucosa, 405, 406f versus pancreatic acinar metaplasia, 404

tahir99-VRG vip.persianss.ir

Index

Barrett’s epithelium (Continued) versus pseudo-goblet cells, 404-405, 405f with true goblet cells and Alcian blue staining, 404, 404f Barrett’s esophagus, 387-393 after antireflux surgery, 214 anatomic landmarks of, 401, 402f antireflux surgery in, 419-422 for peptic strictures/ulcers, 420 rate of progression after, 421 for symptom control, 419-420 biomarker evaluation for, 440-447, 447t. See also Esophageal carcinogenesis. cell of origin of, 391 in children, 404 definition of, 57, 400-401, 401f development stage of, 391 diagnosis of, problems with, 395, 400-405, 400t, 401f-405f differential diagnosis of, 414 dysplastic versus baseline glandular atypia, 407-408, 408f, 410 definitions of, 406-407 development of, 57-58 diagnosis of, 407-409, 408f high-grade, 407, 407f versus carcinoma, 410-411, 410f-411f diagnosis of, 395 endoscopic ablative therapy for, 58, 413, 416-417, 417f esophagectomy for, 58 focal, 412 incident versus prevalent, 413 as indication for resection, 421 as marker for unsampled carcinoma, 413 natural history of, 412-413 overdiagnosis of, 400t, 409, 409t quality-adjusted life expectancy in, 670-671, 672t surveillance of, 412-413 low-grade, 407, 407f regression of, after antireflux surgery, 421 management of, 412-413 versus reactive change and “indefinite for dysplasia,” 408, 408f versus reactive gastric mucosa, 409-410 endoscopic identification of, 400-401, 402f epidemiology of, 388-391, 449 esophageal physiologic disturbances in, 419 factors predisposing to, 57 familial predisposition to, 390-391 flow cytometry in, 411-412 genetic factors in, 412 histologic requirements for, 401, 401f minimal, 403, 403f historical note on, 387 long-segment, 387, 388-389, 388f, 389t short esophagus and, 419 medical therapy for, 415-417 metaplasia-dysplasia-carcinoma sequence in, 420-421, 439, 440, 441f neoplastic progression in, 405-406, 422 obesity and, 451 overdiagnosis of, 400t avoidance of, 409-411, 410f-411f pathophysiology of, 391-393, 391t, 392f, 393f prevalence and incidence of age and, 390, 390f gender and, 390, 390f in general population, 389 in patients undergoing endoscopy, 388-389, 389t time trends in, 389-390, 390f progression to, from GERD, 202, 203f proton pump inhibitors for, 58, 415, 419-420 quality of life in patient with, 384-385, 385f quality-adjusted life expectancy in, 670-671, 672t radiologic findings in, 79, 81 resection indications in, 421 risk factors for, 390 short-segment, 387, 388-389, 389t

Barrett’s esophagus (Continued) squamous overgrowth in, 411 surveillance in endoscopic, 415-416, 416f, 416t, 423 quality of life during, 668, 670-671, 672t utility measures in, 671, 672t Barrett’s stricture, long, with fixed hiatal hernia, on barium esophagogram, 65f Basaloid squamous cell carcinoma, 534-535, 536f Base excision repair (BER), in esophageal carcinogenesis, 442 Battery ingestion in adults, 768, 768t, 773, 776 caustic injury from, 759 in infants and children, 781-782, 783f, 784f, 786, 787f, 788-789 mercury exposure with, 782, 788 Behavior pain management, for achalasia, 718 Belsey fundoplication Collis gastroplasty with, 214, 230 for gastroesophageal reflux disease, 7, 208-209, 209f transthoracic esophagomyotomy with, 747, 747f Belsey Mark I repair, 277 Belsey Mark II repair, 277 Belsey Mark III repair, 277 Belsey Mark IV repair, 276-287 advantages of, 277 Collis gastroplasty with, 313, 314f, 315f-320f, 316-319, 325, 325t, 328, 328t current indications for, 276 disadvantages of, 277 for gastroesophageal reflux disease, 208-209, 209f goals of, 277-278 historical note on, 276-277 patient selection for, 277 Pearson gastroplasty with, 313, 314f, 315f-320f, 316-319 postoperative care in, 285 preoperative care in, 277 results of, 285-286, 287t technique for, 277-285 crus approximation, 280f, 283 exposure, 278 fundoplication, 281f-286f, 283-284 mobilization, 278-280, 278f-279f Benign disease, esophagectomy for, 337-354 functional results of, 352-353 historical note on, 337-339 technical considerations in, 349-354 Benign neoplasms, 431-438. See also specific disorders, e.g., Leiomyoma. classification of, 431, 431t clinical features of, 431 diagnostic tests in, 431-432, 432f-434f endoscopic ultrasonography in, 107-108, 107t, 108f incidence of, 431 radiologic findings in, 78-79, 79f Benznidazole, for Chagas’ disease, 737 Bernstein test, 50, 131 Bethanechol, for gastroesophageal reflux disease, 195 Bile acid exposure, proton pump inhibitors and, 452 Bile reflux after colon interposition, 640, 640t after Roux-en-Y gastric bypass, 243 assessment of, 204, 204f in Barrett’s esophagus, 391, 391t esophageal carcinoma and, 204 gastroesophageal reflux disease and, 204 mucosal complications associated with, 56-57 Biliopancreatic diversion, for weight loss, 239 Bilirubin monitoring, ambulatory 24-hour, 141-142, 142f pH monitoring with, 142-143, 142f-143f Biomarker evaluation for Barrett’s esophagus, 440-447, 447t in chemotherapy, 517-518 Biomodulation combination chemotherapy, 513t, 516 Biopsy in Barrett’s esophagus, 407, 415, 423 esophageal perforation from, 799 in gastroesophageal reflux disease, 397 in squamous cell carcinoma, 465-466, 483

811

Bird’s beak, in achalasia, 715-716, 744, 745f Bleeding with blunt pull-through esophagectomy, 14, 15 gastrointestinal “torrential,” 115 upper, esophagogastroduodenoscopy in patient with, 115 in paraesophageal hernia, 234 with transhiatal esophagectomy, 571-572, 578, 580 Bleomycin with cisplatin, 512, 513t with cisplatin and vindesine, 512, 513t with doxorubicin, 513t, 514 for esophageal carcinoma, 510t, 511 Bloating. See Gas bloat syndrome. Body mass index antireflux surgery complications and, 381 gastroesophageal reflux disease and, 194, 194f, 240 Boerhaave’s syndrome, 83f, 796-798 clinical features of, 798, 798f historical note on, 796-797 pathophysiology of, 797-798 treatment of, 799-805, 800f-804f, 806, 807 Boix-Ochoa anterior fundoplication, 299 Botulinum toxin for achalasia, 718, 745 for Chagas’ disease, 737 for diffuse esophageal spasm, 754 for nonachalasia motility disorders, 724 Bougienage. See also Esophageal dilation. for caustic injury, 762-763 for Chagas’ megaesophagus, 737 dilators for, 252, 256-258, 256f-258f, 260 esophageal perforation from, 799 for foreign body passage, 791 during laparoscopic Nissen fundoplication, 368-369 for nonachalasia motility disorders, 724 for Schatzki ring, 246-247 Bowel bag, in colon interposition, 604, 605f Brachytherapy after combined modality therapy, 522 esophageal, guidelines for, 522 for palliation of esophageal carcinoma, 530, 668, 670t, 671f Brain stem compression, dysphagia in, 687 Bronchogenic carcinoma, 109 Bronchorrhea, in oculopharyngeal muscular dystrophy, 689 Bronchoscopy in esophageal cysts, 165-166 in gastroesophageal reflux disease, 219 in innominate artery compression of trachea, 178, 179f in pulmonary artery sling, 177, 177f before right-sided transthoracic esophagectomy, 591 in squamous cell carcinoma staging, 467-468 in vascular rings, 174 Buccopharyngeal membrane, 19f, 20 Budding, errors in, in esophageal cysts, 164 Buess dilator, for peptic stricture, 258 Bull neck, transhiatal esophagectomy and, 581 Burns. See also Caustic injury. endoscopic classification of, 762t Bypass external, with prosthesis, for esophageal replacement, 559 gastric. See Gastric bypass. jejunoileal, 239 palliative, for squamous cell carcinoma, 478

C Café coronary, in foreign body ingestion, 771 Calcium channel blockers for achalasia, 718 for diffuse esophageal spasm, 754 for nonachalasia motility disorders, 723-724 Cancer. See also specific types and sites. quality of life instruments specific to, 664 staging of. See Carcinoma staging. unusual types of, 532-542, 533t

tahir99-VRG vip.persianss.ir

812

Index

Capecitabine with docetaxel, 513t, 514 for esophageal carcinoma, 510t, 511 Carbonated beverage, for meat impaction, 775-776 Carboplatin for esophageal carcinoma, 510t, 511 with paclitaxel, 513t, 517 Carcinoid, 537 Carcinoma. See also Adenocarcinoma; Squamous cell carcinoma. of esophagus. See Esophageal carcinoma. gastric, infiltrating cardia from below, 492, 494f, 495-496, 495t Carcinoma staging, 454-462 autopsy, 462 clinical, 455-461 non-nodal (cM1b) distant metastasis in, 460-461, 460f nonregional (cM1) lymph node status in, 457, 459, 459f-460f regional (cN) lymph node status in, 457, 459, 459f-460f tumor (cT) stage in, 455-457, 459f computed tomography for distant metastasis, 460, 460f nodal, 88-89, 459, 459f, 505 during or after multimodality therapy (ycTNM or ypTNM), 461 primary tumor, 88, 456-457, 459f recurrent cancer, 462 endoscopic ultrasonography for distant metastasis, 461 M1a, 105-106 nodal, 88-89, 104-106, 105f-106f, 457, 459, 506 non-nodal M1b, 106 during or after multimodality therapy (ycTNM or ypTNM), 461 primary tumor, 88, 101-104, 102f-104f, 455-456 recurrent cancer, 462 FDG-PET for distant metastasis, 89-91, 90f, 91f, 460-461 nodal, 88-89, 459, 460f, 506 primary tumor, 88, 457 recurrent cancer, 462 lymph node stations in, 454, 458f, 467, 467f during or after multimodality therapy (ycTNM or ypTNM), 461-462 pathologic (pTNM), 461, 461f positron emission tomography/computed tomography for distant metastasis, 90-91, 91f, 461 nodal, 89, 459 primary tumor, 457 preoperative, 599 recurrent, 462 summary of, 462 TNM system of, 101, 102t, 454-455, 456t, 457-458 validity of, cervical nodal metastasis and, 610-611 Carcinosarcoma, 536-537 Cardia gastric, full-thickness plication of, for gastroesophageal reflux disease, 359, 360f intestinal metaplasia of, 387 mobilization of, in Belsey Mark IV repair, 278f-279f, 280 true carcinoma of, 492, 493f, 494-495, 494f, 495t Cardiac anomalies, with esophageal atresia, 153 Cardiac glands, histology of, 396 Cardiac mucosa, 27 Cardiac-type mucosa gastric long segments of, 403 reactive, versus Barrett’s dysplasia, 409-410 intestinalization of, mechanisms underlying, 393 as precursor to intestinal metaplasia, 392-393 Cardioplasty, Thal, for Chagas’ disease, 738-740, 739f-740f, 740t Cardiothoracic training, 9 Cardiovascular complications, after en-bloc resection of esophageal carcinoma, 605-606

Carminatives, gastroesophageal reflux disease and, 192 Carotid sheath, 10 Caustic injury, 759-766 burns from, classification of, 762t common substances causing, 760t corticosteroids for, 762 early dilation for, 762-763 endoscopy in, 761, 762t epidemiology of, 759-760 esophageal perforation from, 763 esophageal stricture from, 77, 77f, 259, 339, 339f, 764, 764f esophagectomy for, 339, 339f, 763, 765, 765t history and physical examination in, 760-761 hospital management of, 761-762 initial evaluation of, 761, 761f pancreaticoduodenectomy for, 763-764 pathophysiology of, 760 platysma myocutaneous flap for, 764-765 squamous cell carcinoma after, 764 stents for, 763 surgery for early, 763-764, 763f-764f, 763t late, 763t, 764-765, 764f-765f symptoms of, 761 CDKN2A gene, in esophageal carcinogenesis, 445, 446, 446f CDX2 gene, in intestinalization of cardiac-type mucosa, 393 Celestin dilator, for peptic stricture, 258 Celiac axis, dissection of, in left thoracoabdominal esophagectomy, 586, 586f Celiac disease, esophageal web and, 248 Cell cycle regulation, in esophageal carcinogenesis, 446-447, 446f Cell proliferation, in esophageal carcinogenesis, 442 Cell survival, radiation dose and, 503, 503f Cerebrovascular accident, dysphagia in, 681f, 683, 687 Cervical anastomosis colon interposition and gastric pull-up with, 558 for reversed gastric tube placement, 658, 660f Cervical cutaneous nerve, in cricopharyngeal myotomy, 686 Cervical emphysema in Boerhaave’s syndrome, 798 in cervical esophageal perforation, 794f in foreign body ingestion, 772, 773f Cervical esophagogastric anastomosis colon interposition versus, 352-353 for laparoscopic transhiatal esophagectomy, 622 overview of, 556 in patient with long-term life expectancy, 560 for thoracoscopic and laparoscopic esophagectomy, 624-625, 625f for transhiatal esophagectomy, 574, 574f-576f Cervical esophagus anatomy of, 11f arteries supplying, 13, 13f carcinoma of, surgical management of, 471-472 elevation of, in transhiatal esophagectomy, 567f, 568 encircling of, in transhiatal esophagectomy, 568-569, 568f exposure of, in left thoracoabdominal esophagectomy, 587, 587f foreign body incarcerated below, 769, 769t, 770, 770f perforation of, 792-796 clinical features of, 793-794, 794f historical note on, 792 iatrogenic causes of, 792-793 pathology of, 793, 793f treatment of, 794-796, 794f-795f surgery on, evolution of, 3, 4 vagal innervation of, 17-18, 17f-18f Cervical incision, for transhiatal esophagectomy, 567f, 568 Cervical infection, after left thoracoabdominal esophagectomy, 588-589

Cervical lymph nodes metastasis to, and validity of carcinoma staging, 610-611 squamous cell carcinoma metastasis to detection of, 468, 469 rate of, 473-474 surgical resection of, 473-476, 474f-475f Cervical plexus, 17 Cervical radiography, in foreign body ingestion, 772, 772f, 773f Cervical skin, for esophageal reconstruction, 5 Chagas’ disease, 731-742 achalasia in, 736-737, 737f, 738, 738b, 743 basic science of, 732, 732f, 733f bougienage and dilation for, 737 chest radiography in, 734f, 735 clinical features of, 732-734, 733f complications of, 734 diagnostic studies in, 735-737 differential diagnosis of, 734-735 endoscopy in, 735 historical note on, 731 manometry in, 736-737, 737f medical treatment of, 736-737, 737f natural history of, 734 radiologic studies in, 734f-736f, 734t, 735 scintigraphy in, 736 surgical treatment of, 737-741 esophageal emptying time after, 740-741, 741f esophagectomy in, 741 Heller’s myotomy in, 738, 738b indications for, 738 miscellaneous procedures for, 741 Thal cardioplasty in, 738-740, 739f-740f, 740t Chagoma, 732 CHARGE association, esophageal atresia in, 154 Chemotherapy. See also specific agents, e.g., Cisplatin. adjuvant, 521 for Barrett’s adenocarcinoma, 426-427 results of, 500 in squamous cell carcinoma, 479 biochemical markers of response to, 517-518 combination, 512-517, 513t biomodulation, 513t, 516 cisplatin-based, 512, 513t, 514-516 irinotecan-cisplatin, 513t, 517 non–cisplatin-based, 513t, 514 response rates in adenocarcinoma and squamous cell carcinoma with, 517 taxane-platinum, 513t, 516-517 neoadjuvant for Barrett’s adenocarcinoma, 426 in combination chemotherapy, 518-521, 520t before combined modality therapy, 522 results of, 499 in squamous cell carcinoma, 479 versus surgery alone, 490 for palliation of esophageal carcinoma, 518 with radiotherapy. See Combined modality therapy. single-agent, 510-512, 510t Chest drainage for chylothorax, 549 in transhiatal esophagectomy, 572 Chest pain in achalasia, 715 in diffuse esophageal spasm, 722 esophageal, provocative tests for, 131 in gastroesophageal reflux disease, 52 noncardiac, ambulatory 24-hour manometry in, 133, 134f in nutcracker esophagus, 722 in peptic stricture, 226 Chest radiography in achalasia, 715, 716t, 744 in adenocarcinoma of esophagogastric junction, 492 in caustic injury, 761 in cervical esophageal perforation, 793, 794f in Chagas’ disease, 734f, 735 in esophageal cysts, 165 in esophageal perforation, 82 in foreign body ingestion, 772, 772f in paraesophageal hernia, 234-235, 235f

tahir99-VRG vip.persianss.ir

Index

Chest tube, in esophagectomy for achalasia, 341f, 342 Children antireflux surgery in historical perspective on, 217-218 indications for, 220-221, 220t results of, 222-223 surgical alternatives to, 223 technique for, 220f-222f, 221-222 congenital anomalies in, 151-169 foreign bodies in, 781-791. See also Foreign body, in infants and children. gastric tube esophagectomy in, 661 gastroesophageal reflux disease in, 217-223 diagnosis of, 218-219, 219t diagnostic studies in, 219-220 historical note on, 217-218 management of, 220-221 pathophysiology of, 218 scintigraphy in, 86 obesity in, 239 Chocolate, gastroesophageal reflux disease and, 192 C-11 choline positron emission tomography, 95 Chromosome alterations, in esophageal carcinogenesis, 443, 443f Chromosome 22q11 deletion, in vascular rings, 174 Chyle leak, in right-sided transthoracic esophagectomy, 592 Chylothorax after antireflux surgery, 380 after esophagectomy, 549-550, 550f after left thoracoabdominal esophagectomy, 589 after transhiatal esophagectomy, 579, 580 Cicatricial pemphigoid, with multiple esophageal strictures, 78, 78f Cigarette smoking. See Tobacco. Ciliated cells, embryology of, 22, 22f Cimetidine, for gastroesophageal reflux disease, 196-198 Circular muscle layer, 23f, 24 Circumflex femoral artery, lateral, descending branch of, anterolateral thigh free flap with, 653 Cirrhosis en-bloc resection and, 598 esophagectomy and, 471 Cisapride, for gastroesophageal reflux disease, 195 Cisplatin with bleomycin, 512, 513t with bleomycin and vindesine, 512, 513t in combination chemotherapy, 512, 513t, 514 with docetaxel and 5-fluorouracil, 517 for esophageal carcinoma, 510t, 511 with 5-fluorouracil, 513t, 514-516 with 5-fluorouracil and docetaxel, 513t, 515 with 5-fluorouracil and epirubicin, 513t, 515 with 5-fluorouracil and mitomycin C, 513t, 515 with 5-fluorouracil and paclitaxel, 513t, 516-517 with irinotecan, 517 with irinotecan and docetaxel, 517 with mitoguazone and vindesine, 512, 513t with paclitaxel, 513t, 517 in palliation chemotherapy, 518 with UFT, 513t, 515 Cleaning products, ingestion of. See Caustic injury. Coagulation, argon plasma for early Barrett’s adenocarcinoma, 423 for high-grade Barrett’s dysplasia, 417 Coffee, gastroesophageal reflux disease and, 192 Coin ingestion in adults, 768, 768t, 776 in infants and children, 781, 783f, 784, 786, 786f, 788 Colic artery anatomy of, 631-632, 631f left, colon interposition based on, 632-633, 633f middle, right colon interposition based on, 637 Colic vessels, middle, dissection of, in colon interposition, 633-634 Collagen vascular diseases, barium esophagogram in, 75 Collard anastomosis, modified, for left thoracoabdominal esophagectomy, 587, 588f

Collis gastroplasty for gastroesophageal reflux disease, 7 historical note on, 313, 314f laparoscopic in antireflux repair, 373-374, 374f with Belsey fundoplication, 214 evolution of approaches to, 329, 329f-330f for gastroesophageal reflux disease, 7 for paraesophageal hernia, 334-335, 334f-335f, 335t for short esophagus, 187-189, 189f, 214-215, 230 with Nissen fundoplication. See Collis-Nissen fundoplication. open, with Belsey Mark IV repair, 214, 313, 315f-320f, 316-319, 325, 325t, 328, 328t for short esophagus, 230 with Toupet fundoplication, in secondary esophageal motor disorders, 729, 729f wedge, 330t, 331f-333f Collis-Nissen fundoplication complications in, 215 for gastroesophageal reflux disease, 214-215 for hiatal hernia and GERD, 188, 230 laparoscopic, 272 follow-up after, 335-336 for giant hiatal hernia, 230 results of, 215, 334-335, 334f-335f, 335t University of Minnesota technique for, 329, 330t, 331f-333f normal appearance of, on barium esophagogram, 68, 69f open results of, 325, 328, 328t technique for, 319-320, 320f-321f results of, 215 Colloid fluids, after en-bloc resection of esophageal carcinoma, 605 Coloantral anastomosis, 636-637 Cologastric anastomosis, 635, 636, 637f Colojejunal anastomosis, 637 Colon arteries of, 631-632, 631f enlarged, in Chagas’ disease, 734 venous drainage of, 631f, 632 Colon interposition, 5, 557-558, 630-642 advantages of, 631 anastomoses with, 635, 636-637 anatomic considerations with, 631-632, 631f in antiperistaltic way, 642 in caustic injury, 765t versus cervical esophagogastric anastomosis, 352-353 complications of, 558, 639-640, 639t-640t contraindications to, 558 disadvantages of, 631, 656 in en-bloc esophagectomy, 604, 605f in esophageal atresia, 159 functional status of, 640-641, 640f-641f gastric pull-up versus, 630 and gastric pull-up with cervical anastomosis, 558 graft necrosis with, 638, 639 graft redundancy with, 639-640, 640f, 640t, 642 historical note on, 630 indications for, 632, 632t left, 557-558, 632-635, 633f-634f long-segment, 558 management of, 632-638 non–vagal-sparing esophagectomy with, 636-637 for pharyngolaryngeal reconstruction, 643 postoperative care in, 638 preoperative evaluation for, 632, 632t quality of life after, 666, 667t, 668 results of, 353, 638-641 functional, 640-641, 640f-641f long-term, 639-640, 640t operative, 638-639, 638t-639t right, 558, 637 routes for, 632, 637-638 short-segment, 558 technical considerations in, 351-352 transverse, 557 vagal-sparing esophagectomy with, 635-636, 635f-637f, 640-641, 640f, 641f

813

Colon interposition (Continued) vascular supply considerations with, 631-632, 631f, 634, 638-639 Colonoscopy, for colon interposition, 632 Columnar-lined esophagus of Barrett’s type. See Barrett’s esophagus. of non-Barrett’s type, 403 Combination chemotherapy, 512-517, 513t biomodulation, 513t, 516 cisplatin-based, 512, 513t, 514-516 irinotecan-cisplatin, 513t, 517 neoadjuvant, 518-521, 520t non–cisplatin-based, 513t, 514 response rates in adenocarcinoma and squamous cell carcinoma with, 517 taxane-platinum, 513t, 516-517 Combined modality therapy biologic rationale for, 504 brachytherapy after, 522 carcinoma staging during or after, 461-462 intensification of, 522-524 neoadjuvant results of, 499-500 versus surgery alone, 490 neoadjuvant chemotherapy before, 522 new chemotherapeutic agents in, 524 for palliation of esophageal carcinoma, 524-525, 530-531 radiation dose intensification in, 522-524, 523f response predictors in, 524 in squamous cell carcinoma, 479-481, 480f standard approaches to, 521-522, 521f surgery after, 524 Comparative genomic hybridization, 443, 443f Computed tomography (CT) in achalasia, 74 in benign neoplasms, 431, 432f for carcinoma staging distant metastasis, 460, 460f nodal, 88-89, 459, 459f, 505 during or after multimodality therapy (ycTNM or ypTNM), 461 preoperative, 599 primary tumor, 88, 456-457, 459f recurrent cancer, 462 in caustic injury, 761, 761f development of, 9 in esophageal carcinoma, 88, 93 in esophageal cysts, 166, 436, 436f in esophageal perforation, 83, 83f in fibrovascular polyp, 79 in leiomyoma, 79, 79f in mediastinal cysts, 78, 78f in midesophageal and epiphrenic esophageal diverticulum, 75, 75f multidetector, in esophageal disease, 64f, 66 positron emission tomography with. See Positron emission tomography/computed tomography (PET/CT). in squamous cell carcinoma staging, 468 in vascular rings, 173-174, 174f Conduits. See also specific types, e.g., Colon interposition. criteria for evaluation of, 555 options for cervical skin as, 5 colon as, 5, 557-558. See also Colon interposition. external bypass with prosthesis as, 559 free grafts as, 558 gastric, 4, 5, 12, 556-557, 557. See also Gastric pull-up; Gastric tube. jejunum as, 5, 557. See also Jejunum interposition. skin or myocutaneous flaps as, 559 supercharged pedicle flaps as, 559 positioning route for endoesophageal, 560 paramediastinal, 351 posterior mediastinal, 559 quality of life and, 667t, 668 retrosternal, 350-351, 351f-352f, 573 subcutaneous, 560 substernal, 559

tahir99-VRG vip.persianss.ir

814

Index

Conduits (Continued) positioning route for (Continued) transabdominal, 560 transpleural, 560 Congenital anomalies, 151-169. See also specific disorders, e.g., Esophageal atresia. Congenital esophageal diverticulum, 168-169 Congenital esophageal stenosis, 166-167 Congenital esophageal webs, 167-168 Connective tissue disorders, mixed, esophageal motor disorder in barium esophagogram in, 74, 75 clinical manifestations of, 726 manometry in, 126, 126f Constipation, in Chagas’ disease, 732-733 Constrictor muscles, histology of, 23, 23f, 24f Coronary vein, ligation of, in en-bloc resection of esophageal carcinoma, 603 Corrosive injury. See Caustic injury. Corrugated esophagus. See Ringed esophagus. Corticosteroids for caustic injury, 762 injection of, for peptic stricture, 228, 253 for ringed esophagus, 399 Cosmetic agents, ingestion of, caustic injury from, 760 Costal arch dehiscence, after left thoracoabdominal esophagectomy, 589 Costal margin, division of, in left thoracoabdominal esophagectomy, 586, 586f Cough, barking, in tracheoesophageal fistula, 154 CREST syndrome, 725 Cricopharyngeal bar, 128, 705, 705f Cricopharyngeal myotomy for cricopharyngeal dysfunction without diverticulum, 693-694, 693t with diverticulectomy, 6 with diverticulopexy, 6 for iatrogenic oropharyngeal dysphagia, 700 for myogenic dysphagia, 691-693, 691f-692f, 692t for neurogenic dysphagia, 684f-686f, 685-687, 687t postoperative care in, 686-687, 686f results of, 687, 687t surgical technique for, 684f-685f, 685-686 for pharyngoesophageal diverticulum, 6, 697-698, 698f-699f, 703, 704f. See also Pharyngoesophageal diverticulum, surgical management of. Cricopharyngeus foreign body impaction at, 781, 781f, 783, 785f histology of, 23, 23f, 24f swallowing functions of, 28-29, 29f, 31-32 manometry of, 128-130, 128f-131f transverse portion of, upper esophageal sphincter as, 25 Crura closure of in Hill repair, 293, 293f, 295 in laparoscopic Nissen fundoplication, 220f, 221, 272, 272f in laparoscopic Toupet fundoplication, 307 Teflon pledgets in, complications caused by, 380 support of lower esophageal sphincter by, 34, 203 Crural approximation in antireflux repair, 374, 374f in Belsey Mark IV repair, 280f, 283 in laparoscopic Collis-Nissen fundoplication, 330t, 333f Cruroplasty, mesh in antireflux repair, 374, 374f complications of, 344, 344f requirements for, 368 CT. See Computed tomography (CT). Cyclin CDKs, in esophageal carcinogenesis, 445, 446, 446f Cyclin D, in esophageal carcinogenesis, 446-447, 446f Cyclooxygenase-2 (COX-2), in esophageal carcinogenesis, 441 Cyclooxygenase-2 (COX-2) inhibition, as chemoprevention strategy, 447

Cyst(s) enteric, 163, 164, 165f, 166 esophageal. See Esophageal cysts. foregut, 108, 109f mediastinal, 78, 78f neurenteric, 78, 78f, 164, 165 paraesophageal, 78, 78f Cytology screening, for squamous cell carcinoma, 465-466, 483

D Deaver retractor, in transhiatal esophagectomy, 567, 567f Deglutition. See Swallowing. DeMeester score, 206 Dermatomyositis dysphagia in, 692-693 motility disorder associated with, manometry in, 126, 126f Diabetic neuropathy, esophageal motor disorder in, 728 Diaphragm crus of. See Crura. division of, in left thoracoabdominal esophagectomy, 586, 586f in laparoscopic modified Heller myotomy with anterior fundoplication, 749-750, 749f repair of, in left thoracoabdominal esophagectomy, 588 in right-sided transthoracic esophagectomy, 591, 592f verticalization of, in Hill repair, 291f, 292 Diaphragmatic hiatus. See Hiatus. Diarrhea, after antireflux surgery, 362 Diazepam for foreign body passage, 791 for meat impaction, 775 Diet. See Nutrition. Diffuse esophageal spasm. See Esophageal spasm, diffuse. Dilation balloon. See Pneumatic dilation. esophageal. See Esophageal dilation. Dilators for achalasia, 718-720, 719f, 719t balloon type. See Pneumatic dilation. bougie type, 252, 256-258, 256f-258f, 260. See also Bougienage. for caustic injury, 762-763 in laparoscopic Nissen fundoplication, 211 in open Nissen fundoplication, 263, 265 for peptic stricture guided, 257-258, 257f-258f, 260 nonguided, 256-257, 256f-257f for Schatzki ring, 246-247 in transthoracic gastroplasty with Belsey fundoplication, 317, 317f Diltiazem, for nonachalasia motility disorders, 723-724 Disk battery ingestion in adults, 768, 768t, 773, 776 caustic injury from, 759 in infants and children, 781-782, 783f, 784f, 786, 787f, 788-789 mercury exposure with, 782, 788 Distal esophagus adenocarcinoma of, infiltrating gastroesophageal junction, 492, 493-494, 493f, 494f ambulatory 24-hour manometry of clinical applications of, 133-137 technique for, 132-133, 132f ambulatory 24-hour pH monitoring of, 137-141 composite scoring of, 139-140, 140f, 141f, 141t normal values for, 139, 139f, 140t receiver operator characteristic analysis of, 139-140 technique for, 137-139 intestinal metaplasia in, 387. See also Barrett’s esophagus. cardiac-type mucosa as intermediate step to, 392-393 origin of, 391

Diverticulectomy cricopharyngeal myotomy with, 6 for midesophageal and epiphrenic esophageal diverticula, 709-710, 710f-711f, 711 for pharyngoesophageal diverticulum, 698-699, 699f, 703, 704f Diverticulopexy cricopharyngeal myotomy with, 6 and mediastinal packing, 6 for pharyngoesophageal diverticulum, 698-699, 699f, 703, 704f Diverticulostomy, endoscopic stapler, for pharyngoesophageal diverticulum, 705-706, 705f, 706-707, 707, 707f, 708t Diverticulum esophageal. See Esophageal diverticulum. Kommerell in dysphagia lusorum, 75, 76f in vascular rings, 175 pharyngoesophageal. See Pharyngoesophageal diverticulum. Diverticulum suspension, for pharyngoesophageal diverticulum, 697-698, 698f-699f, 703, 704f DNA aneuploidy in Barrett’s esophagus, 411-412 in esophageal carcinogenesis, 442-443 DNA repair, in esophageal carcinogenesis, 442 Docetaxel with capecitabine, 513t, 514 with cisplatin and 5-fluorouracil, 513t, 515, 517 with cisplatin and irinotecan, 517 in combined modality therapy, 524 for esophageal carcinoma, 510t, 512 with vinorelbine, 513t, 514 Domperidone, for gastroesophageal reflux disease, 196 Dopamine, infusion of after colon interposition, 638 after en-bloc resection of esophageal carcinoma, 605 Dor fundoplication, 207-208 for achalasia, 6 with Heller myotomy, 300-301, 301t historical note on, 298 laparoscopic, results of, 302, 303t-304t open lower esophageal sphincter pressures created by, 300-301, 301t modifications of, 299 principles of, 298-299 results of, 300-304, 301t-303t technique for, 299, 299f results of, versus full fundoplication, 303-304 Dose volume histograms, in radiotherapy, 507-508 Doxorubicin with bleomycin, 513t, 514 esophageal atresia induction by, 151-152 for esophageal carcinoma, 510t, 511 Drainage chest for chylothorax, 549 in transhiatal esophagectomy, 572 for esophageal perforation, 794, 794f-795f, 805, 807 Drooling, in foreign body impaction, 783 Drug(s) esophagitis from, 400 gastroesophageal reflux disease aggravated by, 193-194 Drug package ingestion, 776 Dumping syndrome after esophagectomy, 353, 548 after transhiatal esophagectomy, 577 Duodenal atresia, esophageal atresia with, 155, 155f Duodenal diversion, vagotomy and antrectomy with, for failed repairs, 365 Duodenectomy, for caustic injury, 763-764 Duodenogastroesophageal reflux, 50 ambulatory 24-hour pH monitoring of, 144f, 145f bilirubin monitoring with, 142-143, 142f-143f Barrett’s esophagus and, 441 mucosal complications associated with, 56, 57 Duodenoscopy. See Esophagogastroduodenoscopy. Duplications, esophageal. See Esophageal cysts.

tahir99-VRG vip.persianss.ir

Index

Dyspepsia. See Heartburn. Dysphagia in achalasia, 715, 744 after antireflux surgery, 362 after enucleation of leiomyoma, 435 after laparoscopic Nissen fundoplication, 274 age and, 73 causes of, 62 in Chagas’ disease, 732 differential diagnosis of, 253-254, 254t in diffuse esophageal spasm, 722 early postoperative, prevention of, 378-379 in esophageal cysts, 165 in esophageal web, 249 in foreign body impaction, 783 in gastroesophageal reflux disease, 53, 53t, 202 in hiatal hernia, 186 to liquids, timed barium swallow for, 60-61, 61b, 62f malignant, palliation of. See Palliation of esophageal carcinoma. nonobstructive, ambulatory 24-hour manometry in, 135, 135f in peptic stricture, 226, 251, 253 in Schatzki ring, 245-246 in squamous cell carcinoma, 466 Dysphagia lusorum, 76f, 77, 179 Dysplasia Barrett’s. See Barrett’s esophagus, dysplastic. definition of, 406 in metaplasia-dysplasia-carcinoma sequence, 420-421, 439, 440, 441f

E Echoendoscope, for endoscopic ultrasonography, 98-99, 98f, 100f Ectoderm, 19 Eder-Puestow dilator, for peptic stricture, 257, 257f Edrophonium test, 131 Elderly patients esophageal motor disorders in, 728 gastroesophageal reflux disease in, 200-201 Electrocauterization for diverticula, 708t, 711 for pharyngoesophageal diverticulum, 708t Embryology of esophageal atresia, 151-153, 152f of esophageal cysts, 164-165, 165f of esophagus, 20-22, 20f-23f of foregut, 20, 20f of intestines, 19-20, 19f-20f of laryngotracheoesophageal cleft, 160-161 of stomach, 20f, 21-22 of vascular rings, 170-172, 171f-172f, 171t Emesis. See Vomiting. Emetics, for foreign body passage, 791 Emphysema, cervical in Boerhaave’s syndrome, 798 in cervical esophageal perforation, 794f in foreign body ingestion, 772, 773f En-bloc resection of esophageal carcinoma, 597-607 abdominal lymphadenectomy with, 602-603, 603f in Barrett’s adenocarcinoma, 426 colon interposition with, 604, 605f complications of, 605-606, 605t extended lymphadenectomy with, 489 gastric pull-up with, 603-604 historical note on, 597 indications for, 599 jejunostomy tube in, 605 postoperative care in, 605 preoperative evaluation for, 598-599, 598f results of, 488-489, 597, 606-607, 606t in squamous cell carcinoma, 473 technique for, 599-605 abdominal dissection, 602-603, 603f thoracic dissection, 600-602, 600f-602f thoracoscopic esophageal mobilization with, 622f-623f, 623 three-field lymphadenectomy with, 608-612 EndoCinch system, for gastroesophageal reflux disease, 356, 357f

Endoderm, 19 Endoderm-ectoderm adhesion theory of dorsal enteric cysts, 164, 165f Endoesophageal prosthesis, for perforated carcinoma, 799, 801f Endoesophageal route for esophageal replacement, 560 Endoscopes for endoscopic ultrasonography, 98, 98f, 99, 100f rigid for foreign body removal, 774, 774f, 787, 788f, 788t for meat impaction, 775 Endoscopic ablative therapy for early Barrett’s adenocarcinoma, 423-425, 424f for high-grade Barrett’s dysplasia, 413, 416-417, 417f Endoscopic mucosal resection for fibrovascular polyp, 436 for mucosal adenocarcinoma of esophagogastric junction, 496 for squamous cell carcinoma, 466, 470 Endoscopic stapler diverticulostomy, for pharyngoesophageal diverticulum, 705-706, 705f, 706-707, 707f, 708t Endoscopic ultrasonography (EUS), 97-110 in achalasia, 109, 717 anatomy considerations in, 100-101, 100f, 101f in benign esophageal disease, 107-109, 107t, 108f-109f, 433, 433f for carcinoma staging distant metastasis, 461 M1a, 105-106 nodal, 88-89, 104-106, 105f-106f, 457, 459, 506 non-nodal M1b, 106 during or after multimodality therapy (ycTNM or ypTNM), 461 preoperative, 599 primary tumor, 88, 101-104, 102f-104f, 455-456 recurrent cancer, 462 TNM system of, 101-107, 102t in caustic injury, 761 development of, 9 in esophageal carcinoma, 88 assessment of response to therapy with, 93, 106-107 radiotherapy planning with, 95 in esophageal cysts, 165 with fine needle aspiration for carcinoma staging, 105, 106f, 416, 457, 459, 468-469 in paraesophageal disease, 109 fundamentals of, 97-98 instruments and techniques for, 98-100, 98f-100f nontraversable strictures during, 104 in paraesophageal disease, 109 pulse-echo technique in, 98 in squamous cell carcinoma staging, 468-469 Endoscopy. See also Laparoscopy; Thoracoscopy. of esophagus. See Esophagoscopy. of larynx, in oropharyngeal dysphagia, 680 of upper gastrointestinal tract. See Esophagogastroduodenoscopy. Endotracheal intubation in caustic injury, 761, 761f in transhiatal esophagectomy, 565 Enema, barium, for colon interposition, 632 Enteric conduits, pedicled, for pharyngolaryngeal reconstruction, 643 Enteric cysts, 163, 164, 165f, 166 Enteric free grafts, for pharyngolaryngeal reconstruction, 643-645, 644f-645f Enterotomy, inadvertent, 376 Enteryx, endoscopic implantation of, for gastroesophageal reflux disease, 359 Enucleation, for leiomyoma, 434-435, 434f-435f EORTC esophageal cancer module, 664, 664t EORTC Quality of Life Questionnaire, 664 Eosinophilic esophagitis, allergic. See Ringed esophagus. Eosinophils, in gastroesophageal reflux disease, 398, 398t

815

Epidermal growth factor receptor in esophageal carcinogenesis, 445 monoclonal antibodies targeting, 518 Epidermolysis bullosa dystrophica, esophageal stricture associated with, 78 Epigastric pain in abdominal esophageal perforation, 796 in Boerhaave’s syndrome, 798 in thoracic esophageal perforation, 796 Epirubicin, with cisplatin and 5-fluorouracil, 513t, 515 Epithelial tumors, 532t, 533-537, 535f-536f Epithelium Barrett’s. See Barrett’s epithelium. metaplastic histologic definition of, 403, 403f minute foci of, 403 pseudostratified columnar, embryology of, 21f, 22 stratified squamous embryology of, 22, 22f nonkeratinizing, 27 ERBB2 gene, in esophageal carcinogenesis, 445 Erythromycin, for gastric outlet obstruction, 548, 548f Esomeprazole for gastroesophageal reflux disease, 199, 199f for refractory gastroesophageal reflux disease, 200 Esophageal atresia, 151-160 classification of, 153, 153t congenital anomalies associated with, 153-154 diagnosis of, 154 in duct-dependent infant, 156-157 embryology of, 151-153, 152f epidemiology of, 151 genetics of, 152 historical note on, 151 long gap, surgical repair of, 157, 158f risk stratification schemes for, 156, 156t surgical management of complications of, 159-160, 159t esophageal replacement in, 157, 159 evolution of, 5 preoperative, 155-157, 155f, 156t primary repair in, 157, 158f symptoms of, 154 Esophageal body in achalasia, 43, 43f diverticula of, 709-713. See also Esophageal diverticulum, midesophageal and epiphrenic. manometry of in functional disorders, 123-126, 124f-126f in gastroesophageal reflux disease, 127 interpretation of, 38-39 normal parameters for, 121f, 121t stationary, 121-122, 121f, 122t muscle layers of, 32 in nutcracker esophagus, 44 in physiologic model of foregut, 49, 50f Esophageal carcinogenesis, 440-447 cell cycle regulation in, 446-447, 446f cell proliferation and apoptosis in, 442 chromosome alterations in, 443, 443f DNA content (aneuploidy) in, 442-443 DNA repair in, 442 growth factors and receptors in, 445-446 inflammation in, 441-442 oncogenes in, 445 tumor suppressor genes in, 443-445, 444f Esophageal carcinoma, 439-463. See also Adenocarcinoma; Squamous cell carcinoma. antireflux surgery and, 214 bile reflux and, 204 biology of, 440-447. See also Esophageal carcinogenesis. chemotherapy for. See Chemotherapy. combined modality therapy for. See Combined modality therapy. computed tomography in, 88, 93 diagnosis of, 454, 455f-456f endoscopic ultrasonography in, 88 assessment of response to therapy with, 93, 106-107 radiotherapy planning with, 95

tahir99-VRG vip.persianss.ir

816

Index

Esophageal carcinoma (Continued) epidemiology of, 439, 447-452 familial clusterings of, 452 FDG-PET in, 87-88 assessment of prognosis with, 91 assessment of response to therapy with, 91-94, 93f, 94f detection of recurrent disease with, 94-95 postradiation esophagitis and, 92, 94f radiotherapy planning with, 95 geographic variations in, 447-448, 448f, 449-450 historical note on, 439-440 induction and adjuvant therapy for, 498-501 inoperable, esophageal transit scintigraphy in, 86 management of, recent patterns of care in, 486 palliation of, 527-531. See also Palliation of esophageal carcinoma. perforated, treatment of, 799, 801f, 807 positron emission tomography/computed tomography in, 92, 93f, 95 prognosis in, 509 quality of life in, 663-674. See also Quality of life, for esophageal carcinoma patients. radiologic findings in, 81-82, 81f radiotherapy for. See Radiotherapy. recurrent, imaging of, 94-95 risk factors for, 448-449, 449f, 450-452 small cell, 525 surgical therapy for choice of procedure in, 598-599, 598f en-bloc resection as. See En-bloc resection of esophageal carcinoma. esophageal replacement as. See Conduits; specific organ. esophagectomy in. See Esophagectomy. primary, 486-490, 498 Esophageal cysts, 163-166, 435-436 clinical presentation in, 165 definition of, 163-164 diagnosis of, 165-166, 436f differential diagnosis of, 165 embryology of, 164-165, 165f endoscopic ultrasonography in, 108, 109f esophageal web in, 249 historical note on, 163 intramural, 164 multiple, 164 surgical management of, 166, 436 Esophageal dilation for achalasia, 5, 6, 718-720, 719f, 719t, 745 balloon. See Pneumatic dilation. for caustic injury, early, 762-763 for Chagas’ megaesophagus, 737 complications after, 527-528 for diffuse esophageal spasm, 754 dilators for. See Dilators. esophageal perforation from, 258-259, 527-528, 796, 799 for esophageal stricture, 8 for esophageal webs, 168, 249 failed, 253 for nonachalasia motility disorders, 724 for palliation of esophageal carcinoma, 527-528 for peptic stricture, 227-228, 228f, 251-260 complications of, 258-259 guided, 257-258, 257f-258f historical note on, 251-252 long-term management in, 259 nonguided, 256-257, 256f-257f preparation for, 255-256 results of, 253 physics of, 252-253 recurrent obstruction after, as indication for esophagectomy, 341 retrograde, 252 for Schatzki ring, 246-247 Esophageal diverticulum, 702-713. See also Pharyngoesophageal diverticulum. congenital, 168-169 esophageal carcinoma in, 451 esophagogastroduodenoscopy complicated by, 113, 114f

Esophageal diverticulum (Continued) midesophageal and epiphrenic, 709-713 clinical presentation in, 709 radiologic findings in, 75, 75f treatment of minimally invasive techniques for, 710-711, 710f-711f myotomy and diverticulectomy in, 709-710, 709f-710f results of, 711-713, 711t-712t, 712f in peptic stricture, 226, 227f pulsion, 702 surgical management of, evolution of, 6 traction, 702 Esophageal duplications. See Esophageal cysts. Esophageal exclusion, for thoracic esophageal perforation, 804-805, 807 Esophageal glands, 27, 396 Esophageal hiatus. See Hiatus. Esophageal intubation, for palliation of esophageal carcinoma, 528 Esophageal lengthening multistage extrathoracic, for esophageal atresia repair, 157 for short esophagus, 187-189, 189f, 214-215, 230. See also Gastroplasty. Esophageal lumen, embryology of, 20-21, 21f-23f Esophageal motor disorders. See also specific disorders, e.g., Oropharyngeal dysphagia. barium esophagogram in, 71f-75f, 73, 74 classification and spectrum of, 39-46, 40t-41t nonspecific, 44-45 primary idiopathic, 39-40, 40t, 43-44, 43f-45f. See also Motility disorders. with reflux disease, 40, 41t, 45-46, 45f, 46f secondary, 126, 725-730 clinical manifestations of, 725-728, 726f-727f treatment of, 728-729 undiagnosed, failure due to, 363 Esophageal mucosa anatomy of, 100, 100f complications of, in gastroesophageal reflux disease, 56-57 embryology of, 20-21, 21f-23f evaluation of, barium esophagogram for, 61, 63f-65f histology of, 27, 395-396 injury to, carcinogenesis and, 451 tumors of, endoscopic ultrasonography in, 107 on ultrasound, 101, 101f Esophageal obstruction in benign neoplasms, 431 esophageal perforation in, esophagectomy for, 347-349, 347f-350f, 348t in paraesophageal hernia, 234 in vascular rings, 173 Esophageal perforation, 792-808. See also Boerhaave’s syndrome. abdominal, 796, 805 after caustic injury, 763 after endoscopy, 82-83, 82f, 792-793, 796, 796f after esophageal dilation, 258-259, 527-528, 796, 799 after foreign body ingestion in adults, 770-771, 773, 775, 777, 778f, 778t in infants and children, 783, 786f after laser therapy, 529-530 after photodynamic therapy, 530 after pneumatic dilation, 73f, 74, 74f, 796, 799, 800f alternative procedures for, results of, 806 antibiotics for, 796, 806 from barotrauma, 796, 797f causes of, 792, 793t cervical, 792-796 clinical features of, 793-794, 794f historical note on, 792 iatrogenic causes of, 792-793 pathology of, 793, 793f treatment of, 794-796, 794f-795f decision-making discussion for, 806-807 diagnosis of, 346-347 from esophageal carcinoma, 799, 801f, 807

Esophageal perforation (Continued) in esophageal obstructive disease, esophagectomy for, 347-349, 347f-350f, 348t nonoperative management of, 349, 806, 806f radiologic findings in, 82-83, 82f, 83f repair of, 347 results of, 805-806 sepsis with, 13 of strictures, 807, 807f surgical management of, evolution of, 6-7 thoracic in Boerhaave’s syndrome, 83f, 796-798 causes of, 796, 796f, 797f clinical features of, 796 treatment of, 799-805, 800f-804f, 806 closure technique in, 800-801, 802f decision-making discussion for, 806-807 drainage for, 794, 794f-795f, 805, 807 esophageal exclusion in, 804-805, 807 esophagectomy in, 805 intraluminal stents in, 805 nonoperative, 806, 806f pedicled intercostal musculopleural flap in, 803-804, 803f-804f Esophageal phase of swallowing, 28-34, 29f-34f Esophageal reconstruction. See also specific approach or procedure. for adenocarcinoma of esophagogastric junction, 494, 496, 496f after pharyngoesophageal resection, 560-561 after total gastrectomy, 561 anastomosis techniques for. See Anastomosis. for benign disease, 337-354 functional results of, 352-353 historical note on, 337-339 technical considerations in, 349-354 for caustic injury, 763, 765, 765t conduits for. See Conduits. criteria for evaluation of, 555 for early Barrett’s adenocarcinoma, 425-426 for esophageal atresia, 157, 159 for esophageal carcinoma, 560 leaks with. See Anastomotic leaks. in patient with long-term life expectancy, 560 for reoperation and salvage, 561 for squamous cell carcinoma, 476-477 techniques for, evolution of, 5 Esophageal reflux scintigraphy, 86 Esophageal replacement. See Conduits; Esophageal reconstruction. Esophageal ring in esophagogastroduodenoscopy, 114, 114f lower. See Schatzki ring. multiple. See Ringed esophagus. Esophageal rupture, barotrauma-induced. See Boerhaave’s syndrome. Esophageal shortening. See Short esophagus. Esophageal spasm, diffuse barium esophagogram in, 74-75, 74f, 720-721, 721f clinical features of, 720 definition of, 753 diagnosis of, 753-754 esophageal transit scintigraphy in, 86 etiology and pathogenesis of, 720 historical note on, 720 manometry in, 721-722, 721f ambulatory 24-hour, 134, 134f stationary, 123-124, 124f motor abnormalities in, 43-44, 44f-45f prevalence of, 720 prognosis in, 722 treatment of, 723-724, 754-755 Esophageal sphincters. See Lower esophageal sphincter (LES); Upper esophageal sphincter (UES). Esophageal stem cell hypothesis, for pathophysiology of Barrett’s esophagus, 392, 392f Esophageal stenting. See Stent(s). Esophageal strictures after photodynamic therapy, 423, 530 anastomotic. See Anastomotic strictures. carcinogenesis and, 451 causes of, 254, 254t

tahir99-VRG vip.persianss.ir

Index

Esophageal strictures (Continued) from caustic injury, 77, 77f, 259, 339, 339f, 764, 764f congenital, 166-167 dilation of. See Esophageal dilation. with dysphagia lusorum, 76f, 77 esophagectomy for, 337-339, 338f-339f in esophagogastroduodenoscopy, 114-115 extrinsic, 114 foreign body impaction at level of, 781, 781f intrinsic, 114 nontraversable, endoscopic ultrasonographic options in, 104 pathology of, 8 peptic. See Peptic strictures. perforation of, 807, 807f postnasogastric tube, 259-260 progression to, from GERD, 202, 203f radiation-induced, 77, 77f radiologic findings in, 75-78, 76f-78f skin disorders associated with, 78, 78f Esophageal submucosa, 396 anatomy of, 100-101, 100f tumors of, endoscopic ultrasonography in, 107-108 on ultrasound, 101, 101f Esophageal surgery. See also specific procedures. anatomy for, 10-27 diagnostic aids for, development of, 8-9 history and development of, 3-9 modern turning points for, 9 origins of, 3 Esophageal symptoms, mechanisms of, 50, 51f Esophageal tear, débridement of, 800-801, 802f Esophageal transit scintigraphy. See also Pharyngoesophageal transit scintigraphy. clinical uses of, 85-86 technique for, 85 Esophageal varices, endoscopic ultrasonography in, 108, 109f Esophageal vascularization, 13, 13f, 14f Esophageal wall, 100-101, 100f, 101f Esophageal webs classification of, 248, 248t congenital, 167-168, 248, 249 definition of, 247, 247f diagnosis of, 249, 249f in esophagogastroduodenoscopy, 114, 115f etiology of, 248-249, 248t historical note on, 247 management of, 249-250 morphologic features of, 247-248, 248f Esophagectomy abdominothoracocervical, origins of, 4 for achalasia, 340-343, 590 indications for, 340-342, 340t, 341f technical considerations in, 341f, 342-343, 342t for adenocarcinoma of esophagogastric junction, 493-494, 574-575, 574f anastomotic stricture after, 548 for Barrett’s adenocarcinoma, 425-426, 425f, 427f for Barrett’s esophagus with high-grade dysplasia, 58 for benign disease, 337-354 functional results of, 352-353 historical note on, 337-339 technical considerations in, 349-354 blunt pull-through, bleeding considerations in, 14, 15 cardiac complications after, 546 for caustic injury, 339, 339f, 763, 765, 765t for Chagas’ disease, 741 chylothorax after, 549-550, 550f complications of, 545-551 deep vein thrombosis/pulmonary embolism after, 546 dumping syndrome after, 548 for esophageal perforation, 347-349, 347f-350f, 348t, 805 for esophageal strictures, 337-339, 338f-339f for esophageal webs, 168 for failed repairs, 364-365. See also Failed repairs, reoperation for. gastric outlet obstruction after, 548, 548f, 551

Esophagectomy (Continued) for gastroesophageal reflux disease/hiatal hernia, 343-346, 344f, 346t hospital mortality in, 545 intrathoracic, 3-4, 472 Ivor Lewis laparoscopic and thoracoscopic, 625-626, 627t open, 590, 595-596, 595f laparoscopic, introduction of, 4-5 laparoscopic and thoracoscopic, 622-625 results of, 625, 626t surgical technique for cervical esophagogastric anastomosis in, 624-625, 625f laparoscopic gastric conduit construction in, 623f-624f, 624 thoracoscopic esophageal mobilization in, 622f-623f, 623-624 for leiomyosarcoma, 435 management of diseased esophagus in, 349-350 minimally invasive, 620-628. See also Minimally invasive esophagectomy. nonobstructive indications for, 339 palliative, 478-479, 561 pathologic staging after, 461, 461f patient selection for, 471, 545-546 for peptic stricture, 229 prior, in achalasia patient, technical considerations with, 342-343 quality of life after, 666-668, 667t-668t, 669f recurrent laryngeal nerve injury during, 550-551 respiratory complications after, 548-549 respiratory control during, 3 risk scoring for, 546 route of, quality of life and, 667t, 668 for squamous cell carcinoma abdominal, 472 cervical, 471-472 complications of, 478 extent of, 473 intrathoracic, 472 minimally invasive approaches to, 472-473, 483-484 reconstruction after, 476-477 subtotal, for early Barrett’s adenocarcinoma, 425-426 technical complications during, survival and, 545 techniques for considerations in selecting, 590-591 evolution of, 3-5 for thoracic esophageal perforation, 805 thoracoabdominal, 584-589. See also Thoracoabdominal esophagectomy. Torek, 9 transhiatal. See also Transhiatal esophagectomy. blunt, 563-583 laparoscopic, 620-622 quality of life after, 666, 667t, 669f transhiatal-transcervical, without thoracotomy, 4 transthoracic. See Transthoracic esophagectomy. for traumatic injuries, 346-349, 347f-350f, 348t tri-incisional, 591-596. See also Tri-incisional esophagectomy. vagal-sparing, 353 with colon interposition, 635-636, 635f-637f, 640-641, 640f, 641f Esophagitis allergic eosinophilic. See Ringed esophagus. causes of, 8 classification of, 224, 225t, 226f eosinophilic. See Ringed esophagus. erosive pathology of, 399, 399f progression to, from GERD, 202, 203f in hiatal hernia, 186-187 infectious, 400 panmural, 315 peptic. See Peptic esophagitis. pill- and drug-induced, 400 postradiation, FDG-PET in, 92, 94f reflux. See Peptic esophagitis. Esophagocolostomy, 635, 636

817

Esophagodiverticulostomy, for pharyngoesophageal diverticulum, 705-706, 705f, 706-707, 707f, 708t Esophagogastric anastomosis anastomotic leaks with, 547, 547f, 556, 660-661 anastomotic strictures with, 660 cervical colon interposition versus, 352-353 for laparoscopic transhiatal esophagectomy, 622 overview of, 556 in patient with long-term life expectancy, 560 for thoracoscopic and laparoscopic esophagectomy, 624-625, 625f for transhiatal esophagectomy, 574, 574f-576f evolution of, 4 intrathoracic for benign disease, avoidance of, 337, 338f reflux associated with, 556 thoracoscopic construction of, 626 Esophagogastric dissociation, total, for gastroesophageal reflux disease, 223 Esophagogastric junction. See Gastroesophageal junction. Esophagogastroduodenoscopy, 111-115 for carcinoma staging, preoperative, 599 competency in, 115 complications of, 111 considerations for beginning endoscopist in, 112-113, 113f in esophageal web, 249, 249f in gastroesophageal reflux disease, 205 indications for, 111, 112t in oropharyngeal dysphagia, 680 in paraesophageal hernia, 235-236 in patient with upper gastrointestinal bleeding, 115 patient-centered approach in, 111-112 preparation for, 111, 112t quality indicators for, 111 before right-sided transthoracic esophagectomy, 591 techniques for, 113-114, 114f-115f terminology in, 114-115 in workup for reoperation, 363, 370-371, 372f Esophagogram, barium. See Barium esophagogram. Esophagojejunal anastomosis, in total gastrectomy with Roux-en-Y reconstruction, 616, 616f, 617f, 618 Esophagojejunoplasty, 4 for adenocarcinoma of esophagogastric junction, 496, 496f Esophagomyotomy for achalasia laparoscopic, 6, 746, 748f-751f, 749-751, 752-753 thoracoscopic, 745-746, 746f-748f, 747-748, 751-752 transthoracic, 745, 746-747, 746f-747f, 751 for diffuse esophageal spasm, 754-755 recurrent obstruction after, as indication for esophagectomy, 341-342 Esophagopharyngectomy, 4 Esophagorespiratory fistula. See Tracheoesophageal fistula. Esophagoscopes for foreign body removal, 774, 774f, 787, 788f, 788t for meat impaction, 775 Esophagoscopy in achalasia, 717, 717f in adenocarcinoma of esophagogastric junction, 492 in Barrett’s adenocarcinoma, 416, 424, 424f for Barrett’s dysplasia surveillance, 412-413 for Barrett’s esophagus disease control, 417, 417f for Barrett’s esophagus surveillance, 415-416, 416f, 416t, 423 in benign neoplasms, 431-432, 433f in caustic injury, 761, 762t in Chagas’ disease, 735 in esophageal carcinoma, 454, 455f, 456f in esophageal cysts, 165 esophageal perforation from, 82-83, 82f, 792-793, 796, 796f

tahir99-VRG vip.persianss.ir

818

Index

Esophagoscopy (Continued) in esophageal webs, 167-168 in gastroesophageal reflux disease, 355-361 endoluminal gastroplication as, 356, 357f evolution of techniques for, 355, 356t full-thickness plication of gastric cardia as, 359, 360f historical note on, 355 implantation therapy as, 359 in infants and children, 219 issues in, 359-361 pathophysiologic considerations in, 355 radiofrequency energy application as, 356-359, 358f in peptic stricture, 227, 255, 255f in pharyngoesophageal diverticulum, 696 preoperative, in laparoscopic Toupet fundoplication, 306 rigid development of, 8 in oropharyngeal dysphagia, 680 in Schatzki ring, 246, 247f in short esophagus, 314-315 for squamous cell carcinoma screening, 466 in systemic sclerosis, 726 Esophagostomy, anterior thoracic, after esophagectomy for perforation, 348, 350f Esophagus. See also specific segment, e.g., Cervical esophagus. anatomic narrowing of esophageal perforation and, 805 as risk factor for foreign body impaction, 781, 781f structural causes of, 74-82 embryology of, 20-22, 20f-23f endoscopy of. See Esophagoscopy. enlarged. See Megaesophagus. mobilization of in Belsey Mark IV repair, 278-280, 278f problems with, 376-377, 377f in transthoracic gastroplasty with Belsey fundoplication, 315f, 316 physiology of, 28-39 reoperative evaluation of, 364 short. See Short esophagus. stripping of, in vagal-sparing esophagectomy, 635-636, 635f-636f substitutes for. See Conduits. Etoposide for esophageal carcinoma, 510t, 512 with mitomycin C, 513t, 514 in palliation chemotherapy, 518 EuroQol, 664 EUS. See Endoscopic ultrasonography (EUS).

F Failed repairs causes of, 343, 363, 367-370 classification of, 380, 380t clinical evaluation in, 370 clinical presentation in, 362-363 esophageal studies in, 362-363, 370-371, 371f-372f historical note on, 362 reoperation for choice of approach in, 364 esophageal reconstruction for, 561 indications for, 345-346, 346t, 364 laparoscopic techniques for, 364, 371, 373-374, 373f-374f, 375t open techniques for, 364-366, 365t results of, 365-366, 365t, 367 success rate for, 367 technical considerations in, 345 types of, 370, 371f Famotidine, for gastroesophageal reflux disease, 196-198 Fasciocutaneous free flaps, for pharyngolaryngeal reconstruction, 646-648, 647f Fat, dietary, gastroesophageal reflux disease and, 192

Fat pad dissection, 230, 230f in Belsey Mark IV repair, 280, 280f in laparoscopic Collis-Nissen fundoplication, 330t, 331f in laparoscopic Nissen fundoplication, 211 in transthoracic gastroplasty with Belsey fundoplication, 316, 316f FDG-PET for carcinoma staging distant metastasis, 89-91, 90f, 91f, 460-461 nodal, 88-89, 459, 460f, 506 primary tumor, 88, 457 recurrent cancer, 462 in esophageal carcinoma, 87-88 assessment of prognosis with, 91 assessment of response to therapy with, 91-94, 93f, 94f detection of recurrent disease with, 94-95 postradiation esophagitis and, 92, 94f radiotherapy planning with, 95 radiotherapy planning with, 506-507, 507t in squamous cell carcinoma staging, 469-470, 469f standardized uptake value (SUV) in, 91, 96 Feline esophagus. See Ringed esophagus. Fibrin sealant, over intrathoracic anastomosis, 626 Fibroareolar lamina, 10 Fibroblast growth factor 2, in esophageal carcinogenesis, 445-446 Fibroma, endoscopic ultrasonography in, 107-108 Fibromuscular thickening, congenital esophageal stenosis from, 166, 167 Fibrovascular polyps, 436-437, 533 barium esophagogram in, 436, 436f endoscopic ultrasonography in, 107 gross appearance of, 436, 437f radiologic findings in, 79, 80f resection of, 436 Fine needle aspiration, endoscopic ultrasonography with for carcinoma staging, 105, 106f, 416, 457, 459, 468-469 in paraesophageal disease, 109 FISH (fluorescence in situ hybridization), 443 Fistula aortoesophageal from foreign body, 771 in vascular rings, 173 pharyngocutaneous, after pharyngoesophageal reconstruction, 654-655 salivary, after diverticulectomy, 703 tracheoesophageal. See Tracheoesophageal fistula. T-tube, for thoracic esophageal perforation, 805, 807 Flap(s) for esophageal replacement, 5, 559 free. See Free graft(s). myocutaneous for caustic injury, 764-765 for esophageal replacement, 559 for pharyngolaryngeal reconstruction free, 646-648, 647f pedicled, 645-646, 646f pedicled for pharyngolaryngeal reconstruction, 645-646, 646f for thoracic esophageal perforation, 803-804, 803f-804f tissue, for tracheoesophageal fistula repair, 159 Flow cytometry in Barrett’s esophagus, 411-412 in esophageal carcinogenesis, 442-443 Fluid boluses, after en-bloc resection of esophageal carcinoma, 605 Fluorescence in situ hybridization (FISH), 443 F-18 Fluorodeoxyglucose–positron emission tomography. See FDG-PET. F-18 Fluorothymidine–positron emission tomography, 95 5-Fluorouracil biomodulators of, 513t, 516 with cisplatin, 513t, 514-516 with cisplatin and docetaxel, 513t, 515, 517 with cisplatin and epirubicin, 513t, 515 with cisplatin and mitomycin C, 513t, 515

5-Fluorouracil (Continued) with cisplatin and paclitaxel, 513t, 516-517 for esophageal carcinoma, 510t, 511 with irinotecan, 513t, 514, 515-516 with oxaliplatin, 513t, 516 Foley catheter, for foreign body extraction, 776, 790 Food impaction in adults, 768, 768t, 770, 770f, 775-776 in infants and children, 781 Food ingestion gastroesophageal reflux disease and, 192-193 solid, during barium esophagogram, 65-66 timing of, gastroesophageal reflux disease and, 192-193 Foregut complete outpatient physiologic monitoring of, 144-145, 146f cysts of, 108, 109f embryology of, 20, 20f morphogenesis of, 151, 152f physiologic model of, 49-50, 50f Foreign body, 767-791. See also Food impaction. age and sex distribution for, 767-768, 768t alkaline, caustic injury from, 759 aortoesophageal fistula from, 771 complications of, 769f, 770-771 diagnosis of, 771-773 endoscopic diagnosis of, 772-773 endoscopic management of, 773-776 indications for, 773 postextraction, 775 requirements for, 773-774, 774f rigid versus flexible, 779 for special situations, 775-776 technique for, 774-775 timing for, 773 epidemiology of, 767-768, 768t esophageal injury from, 769, 769t, 770 esophageal perforation from, 770-771, 773, 775, 777, 778f, 778t Foley catheter extraction of, 776, 790 in granulation tissue, 790 Heimlich maneuver for, 773, 783 hematemesis from, 773 hidden, 790 historical note on, 767 history in, 771 incarcerated below cervical esophagus, 769, 769t, 770, 770f in infants and children, 781-791 airway obstruction with, 783, 787 blind extraction of, 791 controversial methods for removal of, 790-791 diagnosis of, 782-787 endoscopic management of, 787-790 patient positioning for, 787-788, 788f requirements for, 788f, 788t for special situations, 788-790, 789f-790f esophageal perforation from, 783, 786f historical note on, 781 history in, 782-783 imaging of, 784, 784f-787f, 786-787 incidence of, 781 laryngoscopic removal of, 783, 786f metallic, 786-787 physical examination in, 783-784 radiolucent, 786, 786f risk factors for, 781, 782f signs and symptoms of, 783, 785f, 786f types of, 781-782, 783f, 784f large, 789 localization of, 769-770, 769t multiple, 790, 790f natural history of, 769, 769t pathophysiology of, 769-770, 769t physical examination in, 772 postextraction management of, 775 prognosis in, 769 radiography in, 772, 772f-773f results of, 778, 778t risk factors for, 768, 768t sharp, 789 surgical management of, 777-778, 777f-778f types of, 768-769, 768t

tahir99-VRG vip.persianss.ir

Index

Foreign body (Continued) underlying esophageal disease associated with, 770, 770f unusually shaped, 789, 789f Fractionation, in radiotherapy altered, 504, 523 conventional, 522-523, 523f Free graft(s) anterolateral thigh for pharyngoesophageal reconstruction, 650-651, 653 for pharyngolaryngeal reconstruction, 647-648, 647f jejunal for esophageal reconstruction, 5, 558 for pharyngoesophageal reconstruction, 651, 653-654 for pharyngolaryngeal reconstruction, 644, 644f lateral thigh, for pharyngoesophageal reconstruction, 653 for pharyngoesophageal reconstruction, 650-655 for pharyngolaryngeal reconstruction enteric, 643-645, 644f-645f myocutaneous/fasciocutaneous, 646-648, 647f radial forearm for pharyngoesophageal reconstruction, 650, 651-652, 652f for pharyngolaryngeal reconstruction, 647, 647f Function tests, 117-146 historical note on, 117-118 technologic advances in, 146 types of, 117, 118b Functional Assessment of Cancer Therapy-General (FACT-G), 664 esophageal module of, 664-665 Fundoplication. See also Antireflux surgery. anterior Boix-Ochoa, 299 laparoscopic modified Heller myotomy, 746, 748f-751f, 749-751, 752-753 Thal-Ash craft, 299 barium esophagogram after, 67-71, 67f-71f Belsey. See Belsey entries. Collis-Nissen. See Collis-Nissen fundoplication. failure of. See Failed repairs. Galloon, 299 for gastroesophageal reflux disease choice of operation in, 207-209, 209 in infants and children, 220f-222f, 221-222 Gavriliu, 299 herniation of, 368 Hill repair versus, 296-297. See also Hill repair. intrathoracic, for gastroesophageal reflux disease, 214 laparoscopic failed, causes of, 367-368 introduction of, 9 in secondary esophageal motor disorders, 729 long, 68 loose, 160, 368 Nissen. See Nissen fundoplication. partial, 298-304 Dor. See Dor fundoplication. versus full fundoplication, 303-304 for gastroesophageal reflux disease, 207-208, 208f-209f late failure of, 304 motility disorders and, 214 Toupet. See Toupet fundoplication. Pinto, 299 principles of, 207 recurrent hiatal hernia after, 70, 70f, 71f for reflux-induced asthma, 56 reoperative evaluation and management of, 364 slipped, 70, 71f Thal. See Thal fundoplication. tight, 68, 69f, 368 transabdominal. See Nissen fundoplication. twisted, 68, 372f

G Gadolinium-DTPA, 66 Galloon fundoplication, 299

Ganglia, esophageal, 18 Ganglion cells, destruction of in achalasia, 743 in Chagas’ disease, 732, 733f Gas bloat syndrome after antireflux surgery, 362 barium esophagogram in, 68, 69f, 70 early postoperative, 379 Gastrectomy for adenocarcinoma of esophagogastric junction, 494-496, 495t in en-bloc resection of esophageal carcinoma, 603, 603f total, with Roux-en-Y reconstruction, 561, 613-619 abdominal approach to, 613-616, 614f-617f anterior phrenotomy in, 614, 614f dissection of esophagus and stomach in, 614-615 lymphadenectomy in, 615-616, 615f pancreaticosplenectomy in, 616 patient positioning in, 613-614 surgical incision in, 614, 614f abdominothoracic approach to, 616-618, 617f dissection of esophagus and stomach in, 617-618 patient positioning in, 616-617, 617f surgical incision in, 617, 617f esophagojejunal anastomosis in, 616, 618 mechanical, 616, 616f semimechanical, 616, 617f indications for, 613 jejunal loop in, 616, 618 minimally invasive approach to, 618-619 patient selection for, 613 postoperative care in, 619 techniques for, 613-619, 614f-617f Gastric. See also Stomach entries. Gastric antrum graft, for esophageal reconstruction, 5 Gastric arteries esophageal distribution of, 13, 13f left in en-bloc resection of esophageal carcinoma, 603, 603f in right-sided transthoracic esophagectomy, 593 posterior, in open Nissen fundoplication, 262f, 263 short, in gastric tube placement, 657, 657f Gastric banding, laparoscopic esophageal motor disorder after, 728 for reflux in obese patients, 242-243 for weight loss, 239 Gastric bypass development of, 239 for reflux in obese patients, 242 Roux-en-Y as bail-out procedure, 370 barium esophagogram after, 243, 244f development of, 239 gastroesophageal reflux disease and, 215 laparoscopic, 243, 243f mechanisms of action after, 243-244 for reflux in obese patients, 242, 242f technique for, 243, 243f Gastric carcinoma, infiltrating cardia from below, 492, 494f, 495-496, 495t Gastric cardia, full-thickness plication of, for gastroesophageal reflux disease, 359, 360f Gastric emptying ambulatory 24-hour pH monitoring of, 144, 145f delayed early postoperative, 379, 548, 548f in gastroesophageal reflux disease, 203 in gastroesophageal reflux disease, 207 in workup for reoperation, 363 Gastric fundus fixation of, in Dor fundoplication, 299 mobilization of in laparoscopic Nissen fundoplication, 210-212, 212f, 270f-271f, 271 in open Nissen fundoplication, 262f, 263, 264265, 265f Gastric juice, constituents of, mucosal complications associated with, 56-57

819

Gastric mucosa cardiac-type long segments of, 403 reactive, versus Barrett’s dysplasia, 409-410 inflammation of, in gastroesophageal reflux disease, 399 inlet patch of, 113 esophageal web and, 248-249 in lower esophageal sphincter region, 401, 402f, 403 Gastric outlet obstruction after esophagectomy, 548, 548f, 551 in gastroesophageal reflux disease, 203 postoperative, 379 Gastric pH, ambulatory 24-hour monitoring of, 140, 140t, 144, 144f, 145f Gastric pull-up advantages of, 630 anastomotic complications with, 639, 639t in caustic injury, 765t colon interposition and, cervical anastomosis with, 558 colon interposition versus, 631, 640-641, 640f-641f disadvantages of, 630 in en-bloc esophagectomy, 603-604 in esophageal atresia, 159 laparoscopic construction of, 624, 624f Gastric sling fibers, 26, 26f Gastric tube, 656-662 advantages of, 661 arterial supply for, 656, 657f, 661-662, 662 disadvantages of, 661 for esophageal replacement, 5, 12, 557 in caustic injury, 765t quality of life after, 666, 667t historical note on, 656 nonreversed development of, 656 preparation of, 658, 660, 660f results of, 661 superiority of, 662 operative technique for, 656-660, 657f-660f for pharyngolaryngeal reconstruction, 643 results of, 660-661, 661f reversed anastomosis of, 658, 660f development of, 656 preparation of, 657f, 658 results of, 660-661, 661f variations of, 658, 659f in right-sided transthoracic esophagectomy, 594-595, 594f-595f Gastric vessels, short, division of in laparoscopic modified Heller myotomy with anterior fundoplication, 751, 751f in laparoscopic Nissen fundoplication, 210, 211f, 271, 271f in open Nissen fundoplication, 263 Gastroenteritis, eosinophilic, 398 Gastroepiploic arcade, 656, 657f Gastroepiploic artery in transhiatal esophagectomy, 566 for vascularization of gastric tube, 656, 657f, 661-662 Gastroesophageal junction, 10, 11f adenocarcinoma of, 451, 492-497 classification of, 492, 493f-494f, 497, 614f definition of, 492 diagnosis and staging of, 492-493 esophagectomy for, 493-494, 574-575, 574f gender and, 492, 494t metastasis of, 492-493 surgical therapy for for early stage, 496, 496f results of, 495t, 496 by type, 493-497, 494f, 613, 614f total gastrectomy and Roux-en-Y reconstruction for, 613, 614f anatomy of, 315f embryology of, 20f, 22 in esophagogastroduodenoscopy, 113, 114f exposure of, in left thoracoabdominal esophagectomy, 585, 585f

tahir99-VRG vip.persianss.ir

820

Index

Gastroesophageal junction (Continued) fat pad dissection of, 230, 230f in Belsey Mark IV repair, 280, 280f in laparoscopic Collis-Nissen fundoplication, 330t, 331f in laparoscopic Nissen fundoplication, 210 in transthoracic gastroplasty with Belsey fundoplication, 316, 316f interposition procedures on, for Chagas’ disease, 739, 740f, 741 intraoperative visualization of, 230, 230f migration of after antireflux surgery, 380 in hiatal hernia and GERD, 185, 186f permanent axial, as indication for antireflux surgery, 190 posterior fixation of, in Hill repair, 289f, 290-291, 294, 294f, 295-296, 296f pressure recording at, interpretation of, 38f, 39, 39f resections of lesions near, 168 Gastroesophageal reflux disease acid perfusion test in, 131 after esophageal atresia repair, 160 after gastric tube esophagectomy, 661 after laryngotracheoesophageal cleft repair, 162 alkaline reflux assessment in, 206 ambulatory 24-hour pH monitoring in, 135-136, 136f, 138, 139f, 140-141, 205-206 with bilirubin monitoring, 143, 143f gastric, 144 antireflux surgery for. See Antireflux surgery. atypical (extraesophageal) symptoms of, 53-54, 53t prevalence of, 55, 55f barium esophagogram in, 66-67, 204-205, 204f, 205f clinical presentations of, 52-58 complications of, 54-58, 54t definition of, problems with, 52 diagnostic studies in, 204-207 differential diagnosis of, 399-400 endoscopic therapy for, 355-361. See also Esophagoscopy, in gastroesophageal reflux disease. esophageal impedance testing in, 206-207 esophageal motor disorders with, 40, 41t, 45-46, 45f, 46f, 62 esophagectomy for, 343-346, 344f, 346t esophagogastroduodenoscopy in, 205 versus Helicobacter pylori infection, 403-404 Helicobacter pylori infection and, 51-52, 241 hiatal hernia in, 183-190. See also Hiatal hernia. histopathology of, 397-400 “iceberg” model of, 50, 51f, 192, 193f ineffective esophageal motility in, 125, 127-128, 723-724 in infants and children, 217-223 diagnosis of, 218-219, 219t diagnostic studies in, 219-220 historical note on, 217-218 management of, 220-221 pathophysiology of, 218 scintigraphy in, 86 surgical management of historical perspective on, 217-218 indications for, 220-221, 220t results of, 222-223 techniques for, 220f-222f, 221-222 inflammation in, 397-399, 398t lower esophageal sphincter incompetence in, 126-127, 127f, 202-203 manometry in ambulatory 24-hour, 135f-138f preoperative, 205 stationary, 126-128, 127f medical treatment of, 192-201, 207 in elderly patients, 200-201 failure to improve with, 200 intermittent or on-demand therapy in, 200 lifestyle modifications in, 192-194, 193t, 194f maintenance therapy in, 200 nonprescription therapy in, 194-195

Gastroesophageal reflux disease (Continued) in pregnant patients, 200t, 201 prescription therapy in, 195-200 metaplastic and neoplastic complications of, 57-58. See also Barrett’s esophagus. microscopic features of, 397-399, 398t motility studies as prognostic factor in, 46 mucosal complications of, 56-57 natural history of, 50-51 nonerosive, quality of life in patient with, 385, 385f oropharyngeal dysphagia and, 701 as oversimplified concept, 50-52, 51f in paraesophageal hernia, 234, 234t pathology of erosions/ulcers in, 399, 399f pathophysiology of, 202-204, 218 quality of life in patient with, 383 radiologic findings in, 66-67 recurrent after antireflux surgery, 362 after fundoplication in infants and children, 222, 223 risk factors for, 343-344 refractory, 200 respiratory complications of antireflux surgery for, 213-214 diagnosis of, 55 in infants and children, 218-219 pathophysiology of, 54-55, 55f rate of, 54, 55, 55f treatment of, 55-56, 56f Roux-en-Y gastric bypass and, 215 scintigraphy in, 86 signs and symptoms of, 202, 203f squamous hyperplasia in, 397 surgical management of. See Antireflux surgery. in systemic sclerosis, 725-726 typical symptoms of, 52-53, 53t Gastroesophageal valve anatomy and physiology of, 288-290, 289-290 grades of, 290, 290 loss of, in hiatal hernia, 290, 290 Gastrohepatic ligament, in right-sided transthoracic esophagectomy, 593 Gastrohepatic omentum, in laparoscopic Nissen fundoplication, 210, 211f Gastrointestinal anomalies, with esophageal atresia, 153 Gastrointestinal bleeding “torrential,” 115 upper, esophagogastroduodenoscopy in patient with, 115 Gastrointestinal Quality of Life Index (GIQLI), 383 Gastrointestinal stromal tumors (GISTs), 433, 538, 540, 541f Gastrointestinal Symptom Rating Scale (GSRS), 383 Gastrojejunostomy, in Roux-en-Y gastric bypass, 243 Gastro-omental flap, for pharyngolaryngeal reconstruction, 644-645, 645f Gastropexy, Hill posterior, for gastroesophageal reflux disease, 7, 208, 214 Gastroplasty Collis. See Collis gastroplasty. definition of, 313 laparoscopic, 326-336. See also Collis gastroplasty, laparoscopic. open, 313-325 historical note on, 313, 314f indications for, 313-314 long-term results of, 325, 325t peptic stricture dilation with, 324 perioperative care in, 320, 324 postoperative follow-up in, 324-325, 324f for short esophagus, 313-316 transabdominal, with Nissen fundoplication, 7, 320, 321f-323f transthoracic, for giant hiatal hernia, 328, 328t Pearson, with Belsey Mark IV repair, 313, 315f320f, 316-319 stapled wedge laparoscopic Nissen fundoplication with, 272 for short esophagus, 188 vertical banded, for reflux in obese patients, 242, 242f

Gastroplication, endoluminal, for gastroesophageal reflux disease, 356, 357f Gastrostomy in caustic injury, 762 in esophageal atresia repair, 156, 157 in esophageal perforation, 804 gastric tube creation after, 656 in laryngotracheoesophageal cleft, 161 Gastrotomy inadvertent, 376 in transhiatal esophagectomy, 574, 574f Gatekeeper antireflux device, 359 Gaviscon, for gastroesophageal reflux disease, 194 Gavriliu fundoplication, 299 Gavriliu variations of reversed gastric tube, 658, 659f Gender adenocarcinoma and, 450, 492, 494t Barrett’s esophagus and, 390, 390f squamous cell carcinoma and, 448, 449f Geographic variations in adenocarcinoma, 449-450 in squamous cell carcinoma, 447-448, 448f GERD. See Gastroesophageal reflux disease. GERD Health-Related Quality of Life Scale (GERDHRQL), 383 Glucagon for foreign body passage, 791 for meat impaction, 775 Gluten-sensitive enteropathy, esophageal web and, 248 Goblet cells, dystrophic, 403, 403f, 407, 407f Graft(s) free. See Free graft(s). necrosis of, with colon interposition, 638, 639 redundancy of, with colon interposition, 639-640, 640f, 640t, 642 Graft-versus-host-disease, esophageal web in, 249 Granular cell tumor, 107, 437, 542 Granulation tissue, foreign body in, 790 Great vessels, embryology of, 170, 171t Greater curvature of stomach, in esophageal reconstruction, 5, 557 Growth factors and receptors, in esophageal carcinogenesis, 445-446 Gum elastic dilators, for peptic stricture, 256-257, 256f

H Halofuginone, for caustic injury, 762 Hand-assisted laparoscopic transhiatal esophagectomy, 626-628, 627t Harmonic scalpel in en-bloc resection of esophageal carcinoma, 603 in total gastrectomy with Roux-en-Y reconstruction, 615 Haslinger open tube esophagoscope for foreign body removal, 774, 774f for meat impaction, 775 Health outcomes, utility measures of, 665, 665f Heartburn in achalasia, 715 after dilation, 253 in gastroesophageal reflux disease, 52, 53t, 202 in peptic stricture, 226 Heimlich maneuver, for foreign body, 773, 783 Helicobacter pylori cagA+ strains, esophageal adenocarcinoma and, 52 Helicobacter pylori infection intestinal metaplasia and, 403-404 reflux and, 51-52, 241 squamous cell carcinoma and, 452 Heller myotomy for achalasia, 745 barium esophagogram after, 72f, 74 for Chagas’ disease, 738, 738b with Dor fundoplication, 300-301, 301t historical note on, 743 laparoscopic modified, with anterior fundoplication, 746, 748f-751f, 749-751, 752-753 laparoscopic Toupet after, 310

tahir99-VRG vip.persianss.ir

Index

Hemangioma, 108, 437-438 Hematemesis from foreign body, 773 in Mallory-Weiss syndrome, 798 Hematoma, retropharyngeal, after cricopharyngeal myotomy, 687 Hemiazygos vein division of, in en-bloc resection of esophageal carcinoma, 600, 601f surgical relevance of, 15 Hemorrhage. See Bleeding. Hemostasis, with transhiatal esophagectomy, 572, 578, 580 Heparin, for pulmonary embolism prophylaxis, 546 Hepatic vein, injury to, intraoperative, 378 Hernia hiatal. See Hiatal hernia. internal, after laparoscopic Nissen fundoplication, 380 port site, 379 Hernia sac intrathoracic, removal of, in paraesophageal hernia repair, 237 reduction of, in laparoscopic Collis-Nissen fundoplication, 330t, 331f Hiatal hernia after fundoplication in infants and children, 222, 223 anatomic types of, 233-234 barium esophagogram in, 61, 63f-65f definition of, 183-184, 184f development of, 12 esophagectomy for, 343-346, 344f, 346t fixed, 61, 65f. See also Short esophagus. in gastroesophageal reflux disease, 183-190 clinical patterns of, 186-187 frequency of, 203 historical note on, 183-184, 184f pathophysiology of, 184-186, 186f surgical management of, 187-189, 189f massive. See Paraesophageal hernia. mixed, 61, 64f obesity and, 240 paraesophageal. See Paraesophageal hernia. in peptic stricture, 251 pharyngoesophageal diverticulum and, 696 recurrent, after fundoplication, 70, 70f, 71f Schatzki ring associated with, 245, 246f sliding, 61, 63f, 233, 234 Hiatus closure of incorrect, failed repair from, 363 in transthoracic gastroplasty with Belsey fundoplication, 319, 320f critical role of, in antireflux barrier, 190 dissection of, in laparoscopic Nissen fundoplication, 269f-270f, 270-271 exposure of, in laparoscopic modified Heller myotomy with anterior fundoplication, 749-750, 749f insufficiency of, 184 reconstruction of, in paraesophageal hernia repair, 237-238, 237f-238f reoperative evaluation of, 364 use of prosthetic material at, complications caused by, 379-380 Hill posterior gastropexy, for gastroesophageal reflux disease, 7, 208, 214 Hill repair, 288-297 advantages of, 291 anatomy and physiology for, 288-290, 289-290 gastroesophageal junction in, posterior fixation of, 289f, 290-291, 294, 294f, 295-296, 296f historical note on, 288 manometry during, 291, 294, 296 modification of, for isolation of median arcuate ligament, 288, 291, 291f patient selection for, 292 results of, 296 technique for laparoscopic, 294-296, 295f-296f open, 291f-295f, 292-294

Histamine H2 receptor antagonists in elderly patients, 200 for gastroesophageal reflux disease, 195, 196-198 for maintenance therapy, 200 nocturnal breakthrough of reflux symptoms with, 197 for on-demand therapy, 200 in pregnant patients, 200t, 201 for reflux in obese patients, 241 Histology, esophageal congenital variations in, 397 normal, 23-27, 23f-26f, 395-397 pathologic. See specific anatomy or disorder. Hodgkin’s lymphoma, 532 Hospital volume, esophagectomy hospital mortality and, 545 Human immunodeficiency virus (HIV) infection, esophageal motor disorder in, 728 Hurst dilators, for achalasia, 5 Hydralazine, for nonachalasia motility disorders, 724 Hyperfractionation, in radiotherapy, 504, 523 Hypermotility disorders, primary, 43-44, 44f-45f Hyperperistalsis. See Nutcracker esophagus. Hypomotility disorders, primary, 43, 43f-44f Hypopharynx anatomy of, 677f, 678f cancer of nonsurgical treatment of, 648 pharyngolaryngeal reconstruction in. See Pharyngolaryngeal reconstruction. foreign body impaction at, 769, 769t, 787 mucosa of, 27 during swallowing, 28 Hypoxia, tumor behavior and, 503-504, 508

I “Iceberg” model of gastroesophageal reflux disease, 50, 51f, 192, 193f Image processor, for endoscopic ultrasonography, 99, 99f Imaging. See specific modality, e.g., Computed tomography (CT). Impedance, acoustic, in endoscopic ultrasonography, 97 Impedance testing, esophageal multichannel intraluminal, 97 in gastroesophageal reflux disease, 206-207 Implantation therapy, for gastroesophageal reflux disease, 359 Induction therapy. See Neoadjuvant therapy. Ineffective esophageal motility, in gastroesophageal reflux disease, 125, 127-128, 723-724 Infants. See Children. Infection after antireflux surgery, 380 cervical, after left thoracoabdominal esophagectomy, 588-589 mediastinal with Boerhaave’s syndrome, 798 with esophageal perforation, 13, 793, 793f, 794f surgical drainage of, 794, 794f-795f, 805 surgical consideration of, 13 Infectious esophagitis, 400 Inflammation in esophageal carcinogenesis, 441-442 in gastroesophageal reflux disease, 397-399, 398t Inflammatory polyps, 437 Inflammatory pseudotumors, 437 Inlet patch esophageal, 397 gastric mucosal, 113, 248-249 Innominate artery compression of trachea, 178-179, 179f Intercostal musculopleural flap, pedicled, for thoracic esophageal perforation, 803-804, 803f-804f Intercostal veins, division of, in en-bloc resection of esophageal carcinoma, 600, 600f Interferon, as biomodulator, 513t, 516 Intestinal metaplasia of cardia, 387 in distal esophagus, 387. See also Barrett’s esophagus.

821

Intestinal metaplasia (Continued) in distal esophagus (Continued) cardiac-type mucosa as intermediate step to, 392-393 origin of, 391 Helicobacter pylori infection and, 403-404 Intestines, embryology of, 19-20, 19f-20f Intra-abdominal esophagus, Hill repair and, 290 Intrabolus pressure, for swallowing, 129f-131f, 130 Intraluminal stents, for thoracic esophageal perforation, 805 Intramural esophageal cysts, 164 Intrathoracic esophagectomy evolution of, 3-4 for squamous cell carcinoma, 472 Intrathoracic esophagogastric anastomosis for benign disease, avoidance of, 337, 338f reflux associated with, 556 thoracoscopic construction of, 626 Intrathoracic fundoplication, for gastroesophageal reflux disease, 214 Intrathoracic hernia sac, removal of, in paraesophageal hernia repair, 237 Intubation endotracheal in caustic injury, 761, 761f in transhiatal esophagectomy, 565 esophageal, for palliation of esophageal carcinoma, 528 nasogastric after Belsey Mark IV repair, 285 esophageal stricture associated with, 77, 259-260 in laparoscopic Nissen fundoplication, 212 Irinotecan with cisplatin, 517 with cisplatin and docetaxel, 517 for esophageal carcinoma, 510t, 512 with 5-fluorouracil, 513t, 514, 515-516 with mitomycin, 513t, 514 with paclitaxel, 513t, 514 in palliation chemotherapy, 518 Iron deficiency anemia esophageal web and, 248 in paraesophageal hernia, 234 Ivor Lewis esophagectomy laparoscopic and thoracoscopic, 625-626, 627t open, 590, 595-596, 595f Ivor Lewis-McKeown esophagectomy. See Transthoracic esophagectomy, right, tri-incisional approach.

J Jackson bougie, for peptic stricture, 256-257, 256f Jackson open tube esophagoscope, for foreign body removal, 774, 774f Jejunogastrostomy, for adenocarcinoma of esophagogastric junction, 496, 496f Jejunoileal bypass, 239 Jejunostomy tube after gastric tube placement, 658 in caustic injury, 764 in en-bloc resection of esophageal carcinoma, 605 in esophageal perforation, 804 in transhiatal esophagectomy, 568, 577 Jejunum interposition, 5, 557 in caustic injury, 765t in esophageal atresia, 159 for esophageal reconstruction, 5, 558 for pharyngoesophageal reconstruction, 651, 653-654 for pharyngolaryngeal reconstruction, 644, 644f “supercharged” microvascular long-segment, 353-354, 559 in total gastrectomy with Roux-en-Y reconstruction, 616, 618 in transabdominal Roux-en-Y jejunal reconstruction, 560

K Ketorolac, during laparoscopic antireflux surgery, 378 Key Med dilator, for peptic stricture, 257

tahir99-VRG vip.persianss.ir

822

Index

Killian’s triangle, 23, 24f diverticulum at, 702 KIT protein, in gastrointestinal stromal tumors, 538 Kocher maneuver in gastric tube placement, 658 in left thoracoabdominal esophagectomy, 586 in right-sided transthoracic esophagectomy, 593 in transhiatal esophagectomy, 566

L Lamina, fibroareolar, 10 Lamina propria, esophageal, 396 Lansoprazole, for gastroesophageal reflux disease, 199, 199f Laparoscopy. See also under specific procedure. as carcinoma staging tool, 457, 459, 461, 470 introduction of, 9 Laparotomy for gastric tube creation, 656 midline, in en-bloc resection of esophageal carcinoma, 602 for reoperation, 364 in right-sided transthoracic esophagectomy, 593 in total gastrectomy with Roux-en-Y reconstruction, 614, 614f Laryngeal exclusion, after cricopharyngeal myotomy, 686f, 687 Laryngeal nerve(s) esophageal distribution of, 17-18, 17f-18f recurrent in cricopharyngeal myotomy, 686 dissection along, for squamous cell carcinoma, 475-476, 475f injury to dysphagia in, 683 during esophagectomy, 550-551 during three-field lymphadenectomy, 609 during transhiatal esophagectomy, 578-579, 580 surgical relevance of, 18-19 Laryngectomy, oropharyngeal dysphagia after, 700, 700f Laryngopharyngeal reflux, in gastroesophageal reflux disease, 53 Laryngopharynx, 23, 23f, 24f Laryngoscope, for foreign body removal, 783, 786f Laryngoscopy, in oropharyngeal dysphagia, 680 Laryngotracheoesophageal cleft, 160-163, 162f-163f Larynx anatomy of, 677f reconstruction of. See Pharyngolaryngeal reconstruction. Laser therapy, Nd:YAG for esophageal web, 249 for palliation of esophageal carcinoma, 529-530, 529t for Schatzki ring, 246 Lateral thigh free flap, for pharyngoesophageal reconstruction, 653 Leiomyoma, 433-435, 537-538, 539f asymptomatic, treatment of, 434 diagnosis of, 434 diagnostic tests in, 431-432, 432f-434f endoscopic ultrasonography in, 108, 108f versus GIST, 433 versus leiomyosarcoma, 433 radiologic findings in, 79, 79f surgical resection of, 434-435, 434b, 434f-435f, 438 symptoms of, 434 Leiomyosarcoma, 538, 540f esophagectomy for, 435 leiomyoma versus, 433 LES. See Lower esophageal sphincter (LES). Lesser curvature of stomach, in esophageal reconstruction, 557 Leucovorin, as biomodulator, 513t, 516 Leuven University pharyngoesophageal diverticulum surgery results at, 706, 706t, 707f three-field lymphadenectomy results at, 612

Lichen planus, esophageal stricture associated with, 78 Lifestyle modifications for gastroesophageal reflux disease, 192-194, 193t, 194f, 241 for peptic esophagitis, 225 Ligamentum left, aberrant left subclavian artery and, right aortic arch with, 171, 172f, 174f retroesophageal, right aortic arch with mirrorimage branching and, 171-172 Lipoma, 107 Liposarcoma, 540 Liver retractor complications related to, 376 in laparoscopic Nissen fundoplication, 210, 210f Longitudinal muscle layer, 24, 24f Los Angeles classification system of esophagitis, 224, 225t, 226f Lower esophageal ring. See Schatzki ring. Lower esophageal sphincter (LES). See also Gastroesophageal junction. in achalasia, 43, 44f, 717, 717f anatomy of, 10, 11f, 12f in antireflux barrier, 290 basal tone of, 33-34 in Chagas’ disease, 736-737, 737f computerized three-dimensional image of, 120, 120f control mechanisms of, 33-34 diaphragmatic support of, 34 in diffuse esophageal spasm, 43, 45f existence of, facts concerning, 26 foreign body impaction at, 769, 769t, 781, 781f histology of, 25-26, 26f in normal person or patients with reflux without Barrett’s esophagus, 401, 402f, 403 hypertensive, 44, 723 definition of, 753 diagnosis of, 753 diagnostic criteria for, 125b in gastroesophageal reflux disease, 45, 45f, 723 manometry in, 125 treatment of, 723-724, 753 incompetence of, in gastroesophageal reflux disease, 126-127, 127f manometry of in functional disorders, 123-126, 124f-126f in gastroesophageal reflux disease, 126-128, 127f interpretation of, 38f, 39, 39f sleeve catheter for, 37 versus sphincter pressure vector volume analysis, 127, 127f stationary, 118f, 119-121, 119f, 120f, 120t respiratory inversion point in, 118f, 119, 119f vector volume in, 119-120 myogenic dysfunction of, 690 in physiologic model of foregut, 49, 50f pressure of, 33, 34f, 119, 119f in Barrett’s esophagus, 391, 391t in hiatal hernia, 184-185 with partial fundoplication, 300-301, 301t in peptic stricture, 251 relaxation of, manometric evaluation of, 121 transient relaxations of, 34 baclofen for, 196 in children, 218 in gastroesophageal reflux disease, 203 in hiatal hernia, 185 Lung. See also Pulmonary entries. Lung bud, 151, 152f Lupus erythematosus, esophageal motor disorder in, 727 Lymph nodes anatomy of, 16, 16f in carcinoma staging, 454, 457, 458f-460f, 459, 467, 467f cervical, metastasis to, and validity of carcinoma staging, 610-611 esophageal carcinoma metastasis to, 498 esophagogastric junction adenocarcinoma metastasis to, 492-493 mapping of, for radiotherapy planning, 504-506, 505t

Lymph nodes (Contineud) patterns of spread to, in three-field lymphadenectomy results, 610-611, 611t regional map of, 454, 458f, 467, 467f pathologic assessment of, 461, 505-506 recurrent laryngeal nodes as, 608 squamous cell carcinoma metastasis to detection of, 468, 469 rate of, 473-474 surgical resection of, 473-476, 474f-475f subcarinal, removal of, in en-bloc resection of esophageal carcinoma, 602, 602f Lymphadenectomy abdominal, in en-bloc resection of esophageal carcinoma, 602-603, 603f for adenocarcinoma of esophagogastric junction, 494, 495-496 in en-bloc resection of Barrett’s adenocarcinoma, 426 in left thoracoabdominal esophagectomy, 586, 586f mediastinal, extent of, 474, 474f pathologic staging after, 461 for squamous cell carcinoma, 473-476, 474f-475f thoracoscopic esophageal mobilization with, 623, 623f three-field. See Three-field lymphadenectomy. in total gastrectomy with Roux-en-Y reconstruction, 615-616, 615f Lymphadenopathy, endoscopic ultrasonography in, 109 Lymphangiography, in chylothorax, 550, 550f Lymphatics, 396 anatomy of, 15-16, 15f-16f surgical relevance of, 16 Lymphocytes, in gastroesophageal reflux disease, 398t, 399 Lymphoepithelioma, 537 Lymphoma, tumor characteristics of, 532-533, 532t

M Mackler triad, in Boerhaave’s syndrome, 798 Magnesium, antacids containing, for gastroesophageal reflux disease, 194 Magnetic resonance imaging (MRI) development of, 9 in dysphagia lusorum, 76f, 77 in esophageal cysts, 166 in esophageal disease, 66 in fibrovascular polyp, 79, 80f in vascular rings, 173-174 Malignancy. See Cancer. Mallory-Weiss syndrome, 798 Maloney dilator in open Nissen fundoplication, 263, 265 for peptic stricture, 257, 257f, 260 for Schatzki ring, 246-247 in transthoracic gastroplasty with Belsey fundoplication, 316, 317f Manometry in achalasia, 716t, 717, 717f, 745 ambulatory 24-hour of complete foregut physiology, 144-145, 146f of distal esophagus clinical applications of, 133-137 technique for, 132-133, 132f in gastroesophageal reflux disease, 135-136, 135f-138f in noncardiac chest pain, 133, 134f in nonobstructive dysphagia, 135, 135f in primary motility disorders, 134, 134f in Chagas’ disease, 736-737, 737f development of, 8, 117 in diffuse esophageal spasm, 721-722, 721f of esophageal body. See Esophageal body, manometry of. in gastroesophageal reflux disease, 126-128, 127f in infants and children, 219-220 preoperative, 205 high-resolution, 146 during Hill repair, 291, 294, 296

tahir99-VRG vip.persianss.ir

Index

Manometry (Continued) indications for, 37 interpretation of, 37-39, 38f, 39f of lower esophageal sphincter. See Lower esophageal sphincter (LES), manometry of. in neurogenic dysphagia, 682f-683f, 685 in nutcracker esophagus, 722-723, 722f in oculopharyngeal muscular dystrophy, 689-690, 690f in oropharyngeal dysphagia, 679-680, 680f in paraesophageal hernia, 235 perfusion effects on, 35, 36f in pharyngoesophageal diverticulum, 696, 696f-697f preoperative, in laparoscopic Toupet fundoplication, 306, 308f-309f as prognostic factor in gastroesophageal reflux disease, 46 pull-through technique for, stationary versus slow motorized, 119-120, 119f respiration effects on, 38f in short esophagus, 315 sleeve catheters in, 37, 37f stationary clinical applications of, 123 in functional disorders of esophageal body and LES, 123-126, 124f-126f in gastroesophageal reflux disease, 126-128, 127f normal parameters for, 120t, 121f, 122t in pharyngoesophageal swallowing disorders, 128-130, 128f-131f technique for, 118-123, 118f-121f in systemic sclerosis, 726, 727f systems for electronic topographic, 35 microtransducer, 34, 119 water-perfused, 34, 35, 118f, 119 of upper esophageal sphincter. See Upper esophageal sphincter (UES), manometry of. variables affecting, 35-37, 35t, 36f-38f in workup for reoperation, 363, 371 Mark IV repair. See Belsey Mark IV repair. Mayo scissors, for transthoracic esophagomyotomy, 746, 746f McKeown approach, for intrathoracic esophageal carcinoma, 472 Meat impaction, in adults, 768, 768t, 770, 770f, 775-776 Mechanical ventilation in esophageal atresia, 156 postoperative, in esophageal perforation, 804 during surgery, 3 Mecholyl test, in Chagas’ disease, 737f Median arcuate ligament, isolation of, in modified Hill repair, 288, 291, 291f Mediastinal lymphadenectomy extent of, 474, 474f for squamous cell carcinoma, 473-476, 474f-475f Mediastinal pleura débridement of, for esophageal perforation, 800, 802f rupture of, in Boerhaave’s syndrome, 798 Mediastinal route, posterior, for esophageal replacement, 559 Mediastinal tract, dilation of, in vagal-sparing esophagectomy, 636 Mediastinitis in Boerhaave’s syndrome, 798 from esophageal perforation, 783, 786f Mediastinum anterior, colon interposition in, 638 cysts of, 78, 78f dissection of in en-bloc resection of esophageal carcinoma, 600-601, 600f-601f in laparoscopic Nissen fundoplication, 271-272, 272f in left thoracoabdominal esophagectomy, 586, 586f in total gastrectomy with Roux-en-Y reconstruction, 615-616, 615f in transhiatal esophagectomy, 568f-573f, 569-573

Mediastinum (Continued) infection of with Boerhaave’s syndrome, 798 with esophageal perforation, 13, 793, 793f, 794f surgical drainage of, 794, 794f-795f, 805 irrigation of after esophagectomy for perforation, 348, 348f for thoracic esophageal perforation, 805 posterior, colon interposition in, 637-638 Medical Outcome Short Form Health Survey (MOS SF-36), 383, 664 Megacolon, in Chagas’ disease, 734 Megaesophagus in achalasia, 744, 744f in Chagas’ disease, 731. See also Chagas’ disease. bougienage and dilation for, 737 clinical features of, 732-733 radiologic classification of, 734t, 735, 735f-736f surgical treatment of, 737-741 intraesophageal debris in, evacuation of, 342, 342f tortuous, as indication for esophagectomy, 340341, 341f Meissner plexus, 18, 396 Melanoma, 534, 535f Mercury exposure, with battery ingestion, 782, 788 Mercury-weighted dilators, for peptic stricture, 257, 257f Merendino operation for early adenocarcinoma of esophagogastric junction, 496, 496f for early Barrett’s adenocarcinoma, 425 Mesenchymal tumors, 532t, 537-542, 539f-543f Mesoderm, 19 Metallic foreign body, 786-787 Metallic stents for peptic stricture, 228 self-expanding complications of, 529, 529t for palliation of esophageal carcinoma, 528-529, 528t, 529t, 668, 671f Metaplasia intestinal. See Intestinal metaplasia. pancreatic acinar, 404 Metaplasia-dysplasia-carcinoma sequence, in Barrett’s esophagus, 420-421, 439, 440, 441f Metaplastic epithelium histologic definition of, 403, 403f minute foci of, 403 Methemoglobinemia, in esophagogastroduodenoscopy, 112 Methotrexate, for esophageal carcinoma, 510t, 511 Metoclopramide in elderly patients, 200 for gastroesophageal reflux disease, 195 Microgastria, after laryngotracheoesophageal cleft repair, 162 Microsatellite instability, in esophageal carcinogenesis, 442 Microvascular free tissue transfer reconstruction. See Free graft(s). Migration hypothesis, for pathophysiology of Barrett’s esophagus, 391-392 Minimally invasive esophagectomy, 620-628 choice of operation in, 628 historical note on, 620, 621t hybrid techniques for, 620, 621t laparoscopic transhiatal esophagectomy as, 620622, 622t, 626-628, 627t versus open esophagectomy, 628 quality of life after, 667t, 668 for squamous cell carcinoma, 472-473, 483-484 thoracoscopic and laparoscopic esophagectomy with cervical anastomosis as, 622-625, 622f625f, 626t thoracoscopic and laparoscopic Ivor Lewis esophagectomy as, 625-626, 627t Minnegerode sign, in foreign body ingestion, 772, 773f Mitoguazone, 512, 513t Mitomycin C for caustic injury, 762 with cisplatin and 5-fluorouracil, 513t, 515 for esophageal carcinoma, 510t, 511

823

Mitomycin C (Continued) with etoposide, 513t, 514 with irinotecan, 513t, 514 in palliation chemotherapy, 518 Montgomery salivary stent, in pharyngoesophageal reconstruction, 652 Montgomery T tube, for cervical anastomosis to pharynx, 658 Morphine, for foreign body passage, 791 Motility. See Peristalsis. Motility disorders. See also specific disorders, e.g., Achalasia. age and, 73 barium fluoroscopic assessment of, 71 esophageal transit scintigraphy in, 85-86 in gastroesophageal reflux disease, 203, 204 nonspecific, 44-45, 125-126, 134, 134f partial fundoplication and, 214 in peptic stricture, 251 primary, 39-40, 40t, 43-44, 43f-45f, 123-126, 123b, 714-724 classification of, 714, 715t, 743, 744t manometry in ambulatory 24-hour, 134, 134f stationary, 123-126, 124f-126f nonachalasia, treatment of, 723-724 surgical approaches for, 743-755 Toupet fundoplication for, 305-306, 311 Motor neuron disease, dysphagia in, 687 Mousseau-Barbin tube, in colon interposition, 604, 605f, 635 MRI. See Magnetic resonance imaging (MRI). Mucosa cardiac, 27 cardiac-type. See Cardiac-type mucosa. esophageal. See Esophageal mucosa. gastric. See Gastric mucosa. hypopharyngeal, 27 tunica, 20-21, 21f-23f tunica propria, 27 Mucosa-associated lymphoid tissue (MALT) lymphoma, 532-533 Mucosal glands, histology of, 396 Mucosal resection, endoscopic. See Endoscopic mucosal resection. Muscle disease, oropharyngeal dysphagia in, 40, 42, 42f Muscles histology of, 23-25, 23f-26f peristalsis coordination by, 28-32, 29f-31f thickening of, 25, 26f Muscular dystrophy, oculopharyngeal. See Oculopharyngeal muscular dystrophy. Muscularis mucosae, 24, 27, 396 Muscularis propria anatomy of, 100, 100f, 396 tumors of, endoscopic ultrasonography in, 108, 108f on ultrasound, 101, 101f Musculopleural flap, pedicled intercostal, for thoracic esophageal perforation, 803-804, 803f-804f MYC amplification, in esophageal carcinogenesis, 445 Myenteric plexus, 18, 396 Myocardial infarction, after esophagectomy, 546 Myocutaneous flaps for esophageal replacement, 559 for pharyngolaryngeal reconstruction free, 646-648, 647f pedicled, 645-646, 646f platysma, for caustic injury, 764-765 Myogenic dysphagia, 687-693 clinical presentation in, 688-689 diagnosis of, 688-691, 689f-690f genetics of, 687-688, 688, 688f historical note on, 688, 688f motility studies of, 689-690, 690f myotomy management of, 691-693, 691f-692f, 692t radiologic assessment of, 689, 689f radionuclide studies of, 690-691 Myotomy. See also Pyloromyotomy. circular, in esophageal atresia repair, 157 cricopharyngeal. See Cricopharyngeal myotomy. esophageal. See Esophagomyotomy.

tahir99-VRG vip.persianss.ir

824

Index

Myotomy (Continued) for esophageal webs, 168 Heller. See Heller myotomy. manometric marker for, 130, 130f for midesophageal and epiphrenic esophageal diverticula, 709, 709f, 710, 711 for nonobstructive dysphagia, 135

N Nasogastric intubation after Belsey Mark IV repair, 285 esophageal stricture associated with, 77, 259-260 in laparoscopic Nissen fundoplication, 212 Nasopharynx, anatomy of, 677f, 678f NDO Plicator, for gastroesophageal reflux disease, 359, 360f Neck pain, in cervical esophageal perforation, 793 Neoadjuvant therapy assessment of response to with computed tomography, 92 with endoscopic ultrasound, 92, 106-107 with FDG-PET, 91-94, 93f, 94f for Barrett’s adenocarcinoma, 426 in combination chemotherapy, 518-521, 520t before combined modality therapy, 522 esophagectomy technique and, 591 results of, 498-500 for squamous cell carcinoma, 479 versus surgery alone, 490 Neoplasm. See Tumor(s). Nerves anatomy of, 16-19, 17f-18f anomalies of, with esophageal atresia, 153 peristalsis coordination by, 32 swallowing coordination by, 30f, 31f, 32, 33f Nervous system, autonomic, esophageal distribution of, 16-18, 17f-18f Neurenteric cysts, 78, 78f, 164, 165 Neurofibroma, endoscopic ultrasonography in, 107-108 Neurogenic dysphagia, 681-687 clinical features of, 681f, 683 diagnosis of, 681f-683f, 683-685 etiology of, 680b historical note on, 681-682 motility studies in, 682f-683f, 685 motor abnormalities in, 40, 41f myotomy management of postoperative care in, 686-687, 686f results of, 687, 687t surgical technique for, 684f-685f, 685-686 radiologic assessment of, 681f, 683-685 radionuclide studies in, 685 Neuromuscular disease, of pharynx and cricopharynx. See Oropharyngeal dysphagia. Neuropathy diabetic, esophageal motor disorder in, 728 peripheral, reflux disease in, esophageal motor disorders with, 45 Neutrophils, in gastroesophageal reflux disease, 397-398, 398t Nifedipine for meat impaction, 775 for nonachalasia motility disorders, 723 Nissen fundoplication after esophageal atresia repair, 160 Collis gastroplasty with. See Collis-Nissen fundoplication. evolution of, 268-269 foreshortened esophagus and, 61 for gastroesophageal reflux disease, 7, 207 laparoscopic, 268-274 bougie versus no bougie during, 368-369 complications in, 213, 273 creation of fundoplication in, 272, 273f crural closure in, 272, 272f current status of, 209 diagnostic studies in, 269 failure of, 274 gastric fundus mobilization in, 270f-271f, 271 hiatal dissection in, 269f-270f, 270-271 indications for, 268, 268t

Nissen fundoplication (Continued) laparoscopic (Continued) in infants and children, 220f-222f, 221-222 internal hernia after, 380 introduction of, 269 versus laparoscopic Toupet repair, 310-311 mediastinal dissection in, 271-272, 272f patient positioning for, 269 port placement for, 210, 210f, 269-270, 269f postoperative care in, 272-273 results of, 212-214, 273-274, 274t suture placement for, 212, 213f, 272, 273f technique for, 209-212, 210f-213f, 269-272, 269f-273f normal appearance of, on barium esophagogram, 67-68, 67f open, 261-267 experimental background on, 262 failure of, 266-267 historical note on, 261 patient selection for, 266 Penrose drain in, 262f, 263, 264 results of, 266-267 transabdominal approach in, 262-264, 262f-264f transthoracic approach in, 264-266, 265f-266f Rosetti procedure with, partial fundoplication versus, 303-304 in secondary esophageal motor disorders, 729 slipped, 70, 71f, 267, 368, 368f in infants and children, 222, 223 technique for, 330t, 333f transabdominal open gastroplasty with, 320, 321f-323f Nitrate, dietary, mucosal complications associated with, 57 Nitrates for achalasia, 718 for diffuse esophageal spasm, 754 for nonachalasia motility disorders, 723 Nitrimidazole, for Chagas’ disease, 737 Nitrofuran, for Chagas’ disease, 737 Nitroglycerin infusion of after colon interposition, 638 after en-bloc resection of esophageal carcinoma, 605 for meat impaction, 775 Nitrosamine exposure, squamous cell carcinoma and, 449 Nizatidine, for gastroesophageal reflux disease, 196-198 Nocturnal heartburn, 52, 53t Nocturnal regurgitation, 53 Nominal Standard Dose (NSD) formula, in radiotherapy, 502 Nonsteroidal anti-inflammatory drugs (NSAIDs), caustic injury from, 760 Nottingham Health Profile, 664 Nuclear imaging, 85-96. See also Positron emission tomography (PET); Scintigraphy. Nuclear polarity, loss of, in high-grade dysplasia, 407, 407f Nutcracker esophagus clinical features of, 722 definition of, 755 diagnosis of, 755 esophageal transit scintigraphy in, 85-86 etiology and pathogenesis of, 722 historical note on, 722 long-term follow-up in, 723 manometry in ambulatory 24-hour, 134, 134f stationary, 124-125, 125f, 722-723, 722f motor abnormalities in, 44 treatment of, 723-724, 755 Nutrition adenocarcinoma and, 450-451 gastroesophageal reflux disease and, 192-193, 203 postoperative, for total gastrectomy with Roux-enY reconstruction, 619 squamous cell carcinoma and, 449 total parenteral, for chylothorax, 549

O Obesity antireflux surgery complications and, 381 Barrett’s esophagus and, 451 epidemiology of, 239 morbid, definition of, 239 reflux in, 194, 194f, 203, 239-244 antireflux surgery for, 241-242 bariatric surgery for indications and patient selection in, 243, 243t mechanisms of action of, 243-244 techniques in, 242-243, 242f, 243f lifestyle modifications for, 241 medical treatment of, 241 pathophysiology of, 240-241, 240t prevalence of, 240, 451 surgical management of, 241-244 Occupational exposure, esophageal carcinoma and, 452 Oculopharyngeal muscular dystrophy, 687-693 diagnosis of, 688-691, 689f-690f historical note on, 688, 688f management of, 691-693, 691f-692f, 692t oropharyngeal dysphagia in, 40, 42, 42f Omentum gastric tubes and, 657, 657f, 658, 658f gastrohepatic, in laparoscopic Nissen fundoplication, 210, 211f mobilization of, in transhiatal esophagectomy, 566 Omeprazole for Barrett’s esophagus with high-grade dysplasia, 58 for gastroesophageal reflux disease, 195, 199, 199f for peptic esophagitis, 225 Oncogenes, in esophageal carcinogenesis, 445 Ondansetron, during laparoscopic antireflux surgery, 378 Oral phase of swallowing, 28 Organoaxial rotation, hiatal hernia with, on barium esophagogram, 64f Oropharyngeal dysphagia, 677-680 age and, 73 assessment approaches in, 677-680, 679f-681f causes of, 40-43, 40t, 41f-42f, 677, 678b, 678f classification of, 678b, 678f definition of, 677 with diverticulum, 694-699, 694f-699f gastroesophageal reflux and, 701 iatrogenic, 700, 700f manometry in, 128-130, 128f-131f myogenic, 687-693 diagnosis of, 688-691, 689f-690f historical note on, 688, 688f management of, 691-693, 691f-692f, 692t neurogenic, 681-687 diagnosis of, 681f-683f, 683-685 etiology of, 680b historical note on, 681-682 management of, 684f-686f, 685-687, 687t motor abnormalities in, 40, 41f in pharyngoesophageal diverticulum, 702 surgical treatment of. See Cricopharyngeal myotomy. symptom scoring in, 679t symptoms of, 40 without diverticulum, 693-694, 693f, 693t Oropharynx anatomy of, 677f, 678f functions of, 677, 678f Oxaliplatin for esophageal carcinoma, 510t, 511 with 5-fluorouracil, 513t, 516

P Paclitaxel with carboplatin, 513t, 517 with cisplatin, 513t, 517 with cisplatin and 5-fluorouracil, 513t, 516-517 in combined modality therapy, 524 for esophageal carcinoma, 510t, 511-512 with irinotecan, 513t, 514

tahir99-VRG vip.persianss.ir

Index

Pain behavioral management of, in achalasia, 718 chest. See Chest pain. epigastric in abdominal esophageal perforation, 796 in Boerhaave’s syndrome, 798 in thoracic esophageal perforation, 796 neck, in cervical esophageal perforation, 793 retrosternal in achalasia, 744 in Chagas’ disease, 732 substernal in Boerhaave’s syndrome, 798 in thoracic esophageal perforation, 796 Palliation of esophageal carcinoma, 527-531 brachytherapy for, 530 bypass surgery for, 478 chemotherapy for, 518 combined modality therapy for, 524-525, 530-531 esophageal dilation for, 527-528 esophageal intubation for, 528 laser therapy for, 529-530, 529t photodynamic therapy for, 530 quality of life during, 668, 670t, 671f stents for, 528-529, 528t, 529t, 668, 671f surgical, 478-479, 561 Pancreas, hiatal hernia containing, on barium esophagogram, 64f Pancreatic acinar metaplasia, 404 Pancreaticoduodenectomy, for caustic injury, 763-764 Pancreaticosplenectomy, in total gastrectomy with Roux-en-Y reconstruction, 616 Papain, for meat impaction, 775, 790 Papilloma, squamous cell, 78-79, 436-437, 437f Paracolic arterial anastomoses, 631-632, 631f Paraesophageal cysts, 78, 78f Paraesophageal disease, endoscopic ultrasonography in, 109 Paraesophageal hernia, 233-238 anatomy of, 233 asymptomatic, natural history of, 236 diagnosis and evaluation of, 234-236, 235f giant, 205, 205f definition of, 326, 327f incidence of, 327 historical note on, 233 including intra-abdominal structures, 233 laparoscopic repair of, 236-237 with Collis gastroplasty, 334-335, 334f-335f, 335t without Collis gastroplasty, 329-330, 334 pathophysiology of, 233-234 pure, 233 rolling, with or without organoaxial volvulus, 233 short esophagus and, 187, 235 signs and symptoms of, 234, 234t surgical management of esophagectomy indications in, 345-346, 346t follow-up after, 335-336 indications for, 236, 328 laparoscopic, 329-336, 330f-335f, 335t open, 328-329, 328t principles of, 328 reoperation in, 345 results of, 236-237, 237f-238f techniques for, 236-237, 237f-238f, 238 true, 61, 64f, 234 Paraesophageal tissue, 101, 101f incision of, in transhiatal esophagectomy, 567f, 568 Paramediastinal route for esophageal replacement, 351 Parasympathetic dystrophy, in achalasia patient requiring esophagectomy, 343 Parasympathetic nervous system, esophageal distribution of, 16-18, 17f-18f Parkinson’s disease, dysphagia in, 683, 687 Patterson-Brown-Kelly syndrome, esophageal web in, 248 Pearson gastroplasty, with Belsey Mark IV repair, 313, 315f-320f, 316-319 Pectoralis major myocutaneous flap, for pharyngolaryngeal reconstruction, 646, 646f

Pediatric disorders. See Children. Pedicled flaps for pharyngolaryngeal reconstruction, 643, 645646, 646f for thoracic esophageal perforation, 803-804, 803f-804f Pemphigoid, cicatricial, with multiple esophageal strictures, 78, 78f Penetration syndrome, in foreign body ingestion, 771 Penrose drain in en-bloc resection of esophageal carcinoma, 601, 601f in laparoscopic Nissen fundoplication, 271, 271f in open Nissen fundoplication, 262f, 263, 264 in right-sided transthoracic esophagectomy, 591, 592, 592f, 593f in transhiatal esophagectomy, 567, 567f, 568 Pepsin, reflux of, mucosal complications associated with, 56-57 Peptic esophagitis, 8, 397-400 clinical presentation in, 225 definition of, 224, 225t, 226f differential diagnosis of, 399-400 in infants and children, 219 microscopic features of, 397-399, 398t non-acid, 225 pathology of erosions/ulcers in, 399, 399f pathophysiology of, 224 strictures from. See Peptic strictures. treatment of, 225 Peptic strictures, 225-229 antireflux surgery for, 228-229, 420 corticosteroid injection for, 228, 253 diagnosis of, 226-227, 227f, 253-254 diagnostic studies in, 254-255, 254f-255f differential diagnosis of, 253-254, 254t dilation of, 227-228, 228f, 251-260, 324 balloon, 252, 258, 259f complications of, 258-259 guided, 255-258, 257f-258f historical note on, 251-252 long-term management in, 259 nonguided, 256-257, 256f preparation for, 255-256 results of, 253 retrograde, 252 esophageal resection for, 229 with fixed hiatal hernia, 65f pathophysiology of, 225 prevalence of, 225 Schatzki ring versus, 225 short esophagus from. See Short esophagus. stenting of, 228 treatment of, 227-229 Peptic ulcer, 115, 399, 399f Percutaneous ultrasonography, in squamous cell carcinoma staging, 468 Peripheral neuropathy, reflux disease in, esophageal motor disorders with, 45 Peristalsis barium fluoroscopic assessment of, 61-63 failed, 38 manometry of, 34-37. See also Manometry. ambulatory 24-hour, 132-133, 132f bolus transit versus, 63-64 interpretation of, 38-39 stationary, 121f, 122, 122t muscle control of, 28-32, 29f-31f neurogenic control of, 32 primary, 30f, 31f, 32, 38 prolonged. See Nutcracker esophagus. secondary, 31f, 32, 38 tertiary, 31f, 32, 33f, 38, 45f PET. See Positron emission tomography (PET). PET/CT. See Positron emission tomography/ computed tomography (PET/CT). pH monitoring ambulatory 24-hour in Barrett’s esophagus, 391, 391t bilirubin monitoring with, 142-143, 142f-143f of complete foregut physiology, 144-145, 146f of distal esophagus, 137-141 composite scoring of, 139-140, 140f, 141f, 141t

825

pH monitoring (Continued) ambulatory 24-hour (Continued) of distal esophagus (Continued) normal values for, 139, 139f, 140t receiver operator characteristic analysis of, 139-140 technique for, 137-139 dual-probe, for reflux-induced respiratory symptoms, 55, 56 gastric, 144, 144f, 145f in gastroesophageal reflux disease, 135-136, 136f, 138, 139f, 140-141, 205-206 in infants and children, 219 in laparoscopic Toupet fundoplication, 306 normal values for, 206, 206t probes for, 132, 132f in systemic sclerosis, 726 in workup for reoperation, 363, 371 ambulatory 48-hour, 146, 206 development of, 8-9, 117-118 in standard acid reflux test, 137, 138f Pharyngeal phase of swallowing, 28, 29f Pharyngeal pump, in physiologic model of foregut, 50 Pharyngocutaneous fistula, after pharyngoesophageal reconstruction, 654-655 Pharyngoesophageal diverticulum, 694-699, 694f-699f, 702-709 clinical presentation in, 694, 702-703, 703t definition of, 702 diagnosis of, 694f-697f, 695-697 endoscopy in, 696 esophageal web in, 249 gastroesophageal reflux disease and, 702, 703 historical note on, 694 manometry in, 128, 128f motility studies in, 696, 696f-697f radiologic assessment of, 694f-695f, 695-696 radionuclide studies in, 697 surgical management of cricopharyngeal myotomy in, 6, 697-698, 698f-699f, 703, 704f diverticulectomy/diverticulopexy in, 698-699, 699f, 703, 704f diverticulum suspension in, 697-698, 698f-699f, 703, 704f endoscopic techniques for, 703, 705-706, 705f evolution of, 6 preferred technique for, 707, 709 results of in Leuven experience, 706, 706t, 707f literature review on, 707, 708t-709t in Pittsburgh experience, 706-707 for small diverticula, 697 Pharyngoesophageal junction. See also Upper esophageal sphincter (UES). anatomy of, 679f function of, 29f neuromuscular dysfunction of, 677, 679f-681f. See also Dysphagia. video-esophagography of, 679, 679f Pharyngoesophageal myotomy. See Cricopharyngeal myotomy. Pharyngoesophageal reconstruction, 650-655 anterolateral thigh free flap for, 653 complications of, 654-655 donor sites for, 650-651, 651f functional outcomes in, 654 jejunal free flap for, 653-654 lateral thigh free flap for, 653 postoperative care in, 654 preoperative evaluation for, 650 radial forearm free flap for, 651-652, 652f Pharyngoesophageal resection, esophageal reconstruction after, 560-561 Pharyngoesophageal segment, manometry of, 129, 129f Pharyngoesophageal transit scintigraphy in oculopharyngeal muscular dystrophy, 690-691 in oropharyngeal dysphagia, 680, 681f Pharyngolaryngeal reconstruction, 643-648 anterolateral thigh free flap for, 647-648, 647f colon interposition for, 643 comparison of methods for, 648, 648t enteric free grafts for, 643-645, 644f-645f

tahir99-VRG vip.persianss.ir

826

Index

Pharyngolaryngeal reconstruction (Continued) free jejunal graft for, 644, 644f gastric conduit for, 643 gastro-omental flap for, 644-645, 645f myocutaneous/fasciocutaneous free flaps for, 646-648, 647f pedicled enteric conduits for, 643 pedicled myocutaneous flaps for, 645-646, 646f radial forearm free flap for, 647, 647f Pharyngolaryngoesophagectomy for cervical esophageal carcinoma, 471-472 reconstruction after, 643 Pharyngonasal regurgitation, in oropharyngeal dysphagia, 40 Pharyngo-oral regurgitation, in oropharyngeal dysphagia, 40 Pharyngotomy, for laryngotracheoesophageal cleft, 161 Pharynx anatomy of, 677f disorders of. See Oropharyngeal dysphagia. paralysis of, pseudotumor effect of, 681f, 683 during swallowing, 28, 29f Photodynamic therapy for early Barrett’s adenocarcinoma, 423 for high-grade Barrett’s dysplasia, 58, 413, 416-417, 417f for palliation of esophageal carcinoma, 530 quality-adjusted life expectancy with, 671, 672t Phrenoesophageal bundle, in Hill repair, 293, 293f, 295, 295f Phrenoesophageal membrane anatomy of, 10-11, 12f loss of elasticity of, 12 Phrenotomy, anterior, in total gastrectomy with Roux-en-Y reconstruction, 614, 614f Physical functioning, quality of life and, 663 Pill-induced esophagitis, 400 Pinotti fundoplication, 299 Pinotti’s approach to total gastrectomy with Roux-en-Y reconstruction, 614, 614f Piriform sinuses, 678f Plant alkaloids, for esophageal carcinoma, 510t, 511 Plasmacytoma, 533 Plastic stents, self-expanding, for caustic injury, 763 Platinum analogues for esophageal carcinoma, 510t, 511 with taxanes, 513t, 516-517 Platysma myocutaneous flaps, for caustic injury, 764-765 Pleura intraoperative tear of, 377-378 mediastinal débridement of, for esophageal perforation, 800, 802f rupture of, in Boerhaave’s syndrome, 798 Pleural effusion with esophageal perforation, 793, 793f, 794f with transhiatal esophagectomy, 579 Pleural route for esophageal replacement, 638 Plication, full-thickness, of gastric cardia, for gastroesophageal reflux disease, 359, 360f Plummer-Vinson syndrome esophageal web in, 248 squamous cell carcinoma in, 451 Pneumatic compression stockings, for pulmonary embolism prophylaxis, 546 Pneumatic dilation for achalasia, 5, 6, 253, 718-720, 719f, 719t, 745 barium esophagogram after, 73f, 74, 74f for diffuse esophageal spasm, 754 esophageal perforation after, 73f, 74, 74f, 796, 799, 800f for localization of esophageal symptoms, 50, 51f for nonachalasia motility disorders, 724 for peptic stricture, 252, 258, 259f Pneumomediastinum, in cervical esophageal perforation, 793, 794f Pneumonia after transhiatal esophagectomy, 580 aspiration in foreign body impaction, 783, 785f in laryngotracheoesophageal cleft, 161 in oculopharyngeal muscular dystrophy, 689 early postoperative, 379

Pneumothorax, intraoperative, 378 Poliomyelitis, dysphagia in, 683, 687 Polyhydramnios, in esophageal atresia, 154 Polymyositis dysphagia in, 692-693 esophageal motor disorder in, 727 manometry in, 126, 126f Polyps adenomatous, 437 fibrovascular. See Fibrovascular polyps. inflammatory, 437 Polyteflon, endoscopic injection of, for gastroesophageal reflux disease, 359 Positron emission tomography (PET), 86-95 basic principles of, 86-87 C-11 choline–, 95 for carcinoma staging, 599 F-18 fluorodeoxyglucose–. See FDG-PET. F-18 fluorothymidine–, 95 imaging techniques in, 87 radiopharmaceuticals for, 87, 95 Positron emission tomography/computed tomography (PET/CT) advantages of, 87 for carcinoma staging distant metastasis, 90-91, 91f, 461 nodal, 89, 459 primary tumor, 457 in esophageal carcinoma assessment of response to therapy with, 92, 93f detection of recurrent disease with, 95 radiotherapy planning with, 95 imaging techniques in, 87 Pregnant patients, gastroesophageal reflux disease in, 200t, 201 Pretracheal (previsceral) fascia, 10 Pretracheal space, 10 Prevertebral (retrovisceral) fascia, 10 Prevertebral space, 10 Prokinetic agents for nonobstructive dysphagia, 135 in secondary esophageal motor disorders, 729 Promotility drugs, for gastroesophageal reflux disease, 195-196 Propantheline bromide, for foreign body passage, 791 Prosthesis endoesophageal, for perforated carcinoma, 799, 801f with external bypass, for esophageal replacement, 559 Prosthetic material, at hiatus, complications caused by, 379-380 Proton pump inhibitors for Barrett’s esophagus, 58, 415, 419-420 bile acid exposure and, 452 efficacy of, comparison of, 199, 199f in elderly patients, 200-201 for gastroesophageal reflux disease, 195, 196f-199f, 198-200 for hypertensive lower esophageal sphincter, 753 for maintenance therapy, 200 for on-demand therapy, 200 for peptic esophagitis, 225 for peptic stricture, 228-229 in pregnant patients, 200t, 201 for reflux-induced respiratory symptoms, 55 for secondary esophageal motor disorders, 728 Provocative maneuvers, during reflux identification phase of barium esophagogram, 64, 65 Provocative tests, techniques for, 131 Pseudoachalasia, 73-74, 369-370, 715t, 717-718 Pseudobulbar palsy, dysphagia in, 687 Pseudo-café coronary, in foreign body ingestion, 771, 773 Pseudodiverticulum, after enucleation of leiomyoma, 438 Pseudo-goblet cells, versus Barrett’s epithelium, 404-405, 405f Pseudolymphoma, 532 Pseudosarcoma, 536-537 Pseudotumor effect in oculopharyngeal muscular dystrophy, 681f, 683 in pharyngeal paralysis, 681f, 683 Pseudotumors, inflammatory, 437

Psychological functioning, quality of life and, 663 Psychological General Well-Being Index, 383 Ptosis, in oculopharyngeal muscular dystrophy, 688 Pulmonary artery sling, 176-178, 177f-178f Pulmonary aspiration, persistent, after cricopharyngeal myotomy, 686f, 687 Pulmonary dysfunction after en-bloc resection of esophageal carcinoma, 605 after esophagectomy, 548-549 after radiotherapy, 525 after transhiatal esophagectomy, 580 reflux-induced antireflux surgery for, 213-214 diagnosis of, 55 in infants and children, 218-219 pathophysiology of, 54-55, 55f rate of, 54, 55, 55f treatment of, 55-56, 56f in systemic sclerosis, 725-726 Pulmonary embolism after esophagectomy, 546 early postoperative, 379 Pulse-echo technique, in endoscopic ultrasonography, 98 “Pump-valve-reservoir” model of foregut, 49-50, 50f Pyloromyotomy in left thoracoabdominal esophagectomy, 586 in right-sided transthoracic esophagectomy, 593 in transhiatal esophagectomy, 566-567, 566f Pyloroplasty laparoscopic, 624, 624f in left thoracoabdominal esophagectomy, 586 in right-sided transthoracic esophagectomy, 593 Pylorospasm, in caustic injury, 760

Q Quality of life, 382-385 concept of, 663 for esophageal carcinoma patients, 663-674 after esophagectomy, 666-668, 667t-668t, 669f challenges related to, 673 conclusions about, 671-673 future aspects of, 673 measurement of, 664-665, 664t during palliative treatment, 668, 670t, 671f impact of GERD on, 383 measurement of, 382-383, 663-665 with cancer-specific instruments, 664 with disease-specific instruments, 383 with esophageal cancer-specific instruments, 664-665, 664t with generic instruments, 383, 664 postoperative, 383-385 in Barrett’s esophagus, 384-385, 385f in esophageal carcinoma, 666-668, 667t-668t, 669f general aspects of, 383-384, 384f in nonerosive GERD, 385, 385f during surveillance in patients with Barrett’s esophagus, 668, 670-671, 672t utility measures and, 665, 665f Quality of Life Reflux and Dyspepsia (QOLRAD), 383 Quality-adjusted life years (QALYs), 665

R Race adenocarcinoma and, 450 squamous cell carcinoma and, 448, 449f Radial forearm free flap for pharyngoesophageal reconstruction, 650, 651-652, 652f for pharyngolaryngeal reconstruction, 647, 647f Radiation therapy. See Radiotherapy. Radiofrequency dissector, in total gastrectomy with Roux-en-Y reconstruction, 615 Radiofrequency energy application, for gastroesophageal reflux disease, 356-359, 358f

tahir99-VRG vip.persianss.ir

Index

Radiography barium. See Barium esophagogram. cervical, in foreign body ingestion, 772, 772f, 773f chest. See Chest radiography. in foreign body ingestion, 783f-786f, 784, 786 Radiology. See also Computed tomography (CT); Magnetic resonance imaging (MRI). in achalasia, 71f-74f, 73-74 barium. See Barium esophagogram. in Barrett’s esophagus, 79, 81 in benign neoplasms, 78-79, 79f in esophageal carcinoma, 81-82, 81f in esophageal perforation, 82-83, 82f, 83f in esophageal stricture, 75-78, 76f-78f of esophagus, development of, 8 in gastroesophageal reflux disease, 66-67 in leiomyoma, 79, 79f in mediastinal cysts, 78, 78f in midesophageal and epiphrenic esophageal diverticulum, 75, 75f in squamous papilloma, 78-79 Radiolucent foreign body, 786, 786f Radionuclide studies. See Scintigraphy. Radiopharmaceuticals for esophageal transit scintigraphy, 85 for positron emission tomography, 87, 95 Radiosensitivity, cell, 503, 503f Radiotherapy adjuvant for Barrett’s adenocarcinoma, 426-427 results of, 500 for squamous cell carcinoma, 479 alone, versus combined modality therapy, 521-522, 521f altered fractionation in, 504, 523 biologic basis of, 502-503 with chemotherapy. See Combined modality therapy. clinical target volume for, 504-507 FDG-PET and, 506-507, 507t guidelines for selection of, 506 lymph node mapping and, 504-506, 505t conventional fractionation in, 522-523, 523f dose volume histograms in, 507-508 esophageal stricture from, 77, 77f four R’s of, 503-504, 503f intensity-modulated, 523 neoadjuvant, results of, 498-499 Nominal Standard Dose (NSD) formula in, 502 for palliation of esophageal carcinoma, 530 in patient with tracheoesophageal fistula, 525 planning for with computed tomography, 505 with endoscopic ultrasonography, 95, 506 with FDG-PET, 95, 506-507, 507t with positron emission tomography/computed tomography, 95 radiation field design in, 523-524 primary, 521 principles of, 502-508 surgery with, biologic rationale for, 504 toxicity of, 525 tumor regression after, 504 Ranitidine for gastroesophageal reflux disease, 196-198 in pregnant patients, 201 RAS-regulated genes, in esophageal carcinogenesis, 445 Raynaud’s phenomenon, esophageal motor disorder in, 726-727 RB protein, in esophageal carcinogenesis, 446, 446f Recurrent laryngeal nerve. See Laryngeal nerve(s), recurrent. Reflex theory of reflux-induced respiratory symptoms, 54, 55, 55f Reflux disease. See Gastroesophageal reflux disease. Reflux esophagitis. See Peptic esophagitis. Reflux identification, on barium esophagogram, 64-65 Reflux volume, measurement of, 65 Reflux-Related Visual Analogue Scale, 383 Refraction, in endoscopic ultrasonography, 97 Regional (cN) lymph node status, in carcinoma staging, 457, 459, 459f-460f

Regurgitation. See also Vomiting. in achalasia, 715 in Chagas’ disease, 732 in gastroesophageal reflux disease, 53, 202 in infants and children, 218 in oropharyngeal dysphagia, 40 in pharyngoesophageal diverticulum, 695 in squamous cell carcinoma, 466 Reoperation. See Failed repairs, reoperation for. Reoxygenation, in radiotherapy, 503-504, 503f Respiration manometry and, 38f oropharyngeal dysphagia and, 677, 678f Respiratory control, during esophagectomy, 3 Respiratory distress, in esophageal cysts, 165 Respiratory inversion point, in stationary manometry of LES, 118f, 119, 119f Respiratory symptoms. See Pulmonary dysfunction. Retching, persistent, Mallory-Weiss syndrome after, 798 Retinoic acid, as biomodulator, 513t, 516 Retroesophageal space, in laparoscopic modified Heller myotomy with anterior fundoplication, 750, 750f Retroesophageal window, in laparoscopic Nissen fundoplication, 220f, 221 Retroflexion, in esophagogastroduodenoscopy, 114 Retropharyngeal hematoma, after cricopharyngeal myotomy, 687 Retrosternal pain in achalasia, 744 in Chagas’ disease, 732 Retrosternal route for esophageal replacement, 350351, 351f-352f, 573 Retrovisceral space, clinical importance of, 13 Rhabdomyosarcoma, 540, 542, 542f Rheumatologic disorders, esophageal motor disorder in clinical manifestations of, 725-727 treatment of, 728-729 Rigiflex dilators, for achalasia, 718-720, 719f, 719t Ringed esophagus, 250 dilation for, 247 esophageal motor disorder in, 728 histology of, 398-399, 398t medical treatment of, 399 radiologic findings in, 78, 78f terminology for, 247 Rosetti’s repair for gastroesophageal reflux disease, 7 Nissen fundoplication with, partial fundoplication versus, 303-304 Rotterdam Symptom Checklist, 664 Roux-en-Y gastric bypass as bail-out procedure, 370 barium esophagogram after, 243, 244f development of, 239 gastroesophageal reflux disease and, 215 laparoscopic, 243, 243f mechanisms of action after, 243-244 for reflux in obese patients, 242, 242f technique for, 243, 243f Roux-en-Y reconstruction jejunal, transabdominal anastomosis in, 560 total gastrectomy with, 561, 613-619. See also Gastrectomy, total, with Roux-en-Y reconstruction.

S Salivary fistula, after diverticulectomy, 703 Salivary gland, hypertrophy of, in Chagas’ disease, 732, 733f Sarcomas. See also Carcinosarcoma; Leiomyosarcoma. unusual, 540, 542, 542f Savary dilator, for Schatzki ring, 246-247 Savary-Gilliard dilator, for peptic stricture, 258, 258f Schatzki ring, 8 causes of, 245 diagnostic studies in, 246, 246f-247f historical note on, 245 management of, 246-247

827

Schatzki ring (Continued) morphologic features of, 245, 246f versus peptic stricture, 225 signs and symptoms of, 245-246 Schisis association, esophageal atresia in, 154 Schobinger repair, 299 Schwannoma, 542, 543f Scintigraphy in Chagas’ disease, 736 esophageal reflux, 86 esophageal transit, 85-86 in myogenic dysphagia, 690-691 in neurogenic dysphagia, 685 in pediatric gastroesophageal reflux disease, 220 in pharyngoesophageal diverticulum, 697 pharyngoesophageal transit in oculopharyngeal muscular dystrophy, 690-691 in oropharyngeal dysphagia, 680, 681f Sclerosis amyotrophic lateral, dysphagia in, 683, 687 systemic, esophageal motor disorder in, 725-726 barium esophagogram in, 75 clinical features of, 725-726 diagnosis of, 726, 726f-727f esophageal transit scintigraphy in, 86 manometry in, 126, 126f reflux disease in, 45, 46f treatment of, 728-729 Sebaceous glands, 396 Sedation in esophageal dilation, 256 in esophagogastroduodenoscopy, 111 Sedatives, for nonachalasia motility disorders, 724 Semicircular muscle fibers, 26 Sepsis. See also Infection. after antireflux surgery, 380 with esophageal perforation, 13 SF-36 health survey, 383, 664 Shoeshine maneuver, in laparoscopic Nissen fundoplication, 272, 273f Short esophagus, 61, 65f, 313-316 apparent, definition of, 327 clinical evaluation of, 327-328 conditions associated with, 369 contrast radiography in, 314 definition of, 326-327 esophagoscopy in, 314-315 failure to recognize, 363, 369, 369f in hiatal hernia and GERD, 187-189, 189f incidence of, 327 intraoperative findings in, 315-316 long-segment Barrett’s esophagus and, 419 manometry in, 315 Nissen fundoplication and, 61 nonreducible definition of, 229, 229f, 327 diagnosis of intraoperative, 230, 230f preoperative, 229-230 epidemiology of, 229 pathogenesis of, 229 treatment of, 230 paraesophageal hernia and, 187, 235 reducible, definition of, 327 subgroups in, 188 surgical management of, 187-189, 189f, 214-215, 230. See also Gastroplasty. Sickness Impact Profile, 664 Siewert classification of adenocarcinoma of esophagogastric junction, 492, 493f-494f, 497, 614 Sildenafil, for achalasia, 718 Silicone stents, for peptic stricture, 228 Silk marking stitch, in colon interposition, 633, 633f, 634f Sjögren’s syndrome, esophageal motor disorder in, 727, 727f Skeletal anomalies, with esophageal atresia, 153 Skin disorders esophageal stricture in, 78, 78f esophageal web in, 249 Skin flaps. See Flap(s). Sleeping position, gastroesophageal reflux disease and, 193

tahir99-VRG vip.persianss.ir

828

Index

Slide tracheoplasty, in pulmonary artery sling repair, 178 Small cell esophageal carcinoma, 525, 535-536 Smoking adenocarcinoma and, 450 gastroesophageal reflux disease and, 193, 203 squamous cell carcinoma and, 448-449 Smooth muscle esophagus, 23, 24f, 32 Somites, 19, 19f Sonic hedgehog (Shh) gene, in esophageal atresia, 152 Spasm, esophageal. See Esophageal spasm, diffuse. Speech, oropharyngeal dysphagia and, 677, 678f Sphincter definition of, 25 esophageal. See Lower esophageal sphincter (LES); Upper esophageal sphincter (UES). Sphincter pressure vector volume analysis, of lower esophageal sphincter, 127, 127f Spleen in gastric tube placement, 657, 657f tear of, intraoperative, 377 Splenectomy in en-bloc resection of esophageal carcinoma, 603, 603f gastric tube esophagectomy and, 661 Splenic artery, esophageal distribution of, 13 Split-notochord theory of esophageal cysts, 164 Squamocolumnar junction in Barrett’s esophagus, 401, 402f clinical relevance of, 27 histology of, 395-396 Squamous cell carcinoma, 464-484 advanced, diagnosis of, 466 after caustic injury, 764 basaloid, 534-535, 536f clinical pathology of, 465 cytology screening for, 465-466, 483 diagnosis of, 465-466 early, 465-466, 470 endoscopic appearance of, classification of, 465 endoscopic screening for, 466 epidemiology of, 447-449, 448f-449f geographic variations in, 447-448, 448f Helicobacter pylori infection and, 452 historical note on, 464 management of, 470-481 combined modality therapy in, 479-481 for early cancer, 470 future directions in, 482 surgical, 470-479 at University of Hong Kong, 481-482, 481f-483f in Plummer-Vinson syndrome, 451 radiologic findings in, 81 staging of, 467-470, 467f accuracy in, 483 barium esophagogram in, 467 bronchoscopy in, 467-468 computed tomography in, 468 endoscopic ultrasonography in, 468-469 FDG-PET in, 469-470, 469f percutaneous ultrasonography in, 468 surgical management of, 470-479, 483-484 after chemoradiotherapy, 480-481, 480f approaches to, 471-473 complications of, 478 extent of, 473-476, 474f-475f palliative, 478-479 patient selection for, 471 perioperative care in, 478 reconstruction in, 476-477 survival curves for, 482f, 483f Squamous cell papilloma, 78-79, 436-437, 437f Squamous hyperplasia, in gastroesophageal reflux disease, 397 Stabilizing structures, anatomy of, 10-11, 12f Standard gamble utility measure, 665, 665f Standardized uptake value (SUV), in FDG-PET, 91, 96 Stapled wedge gastroplasty laparoscopic Nissen fundoplication with, 272 for short esophagus, 188 Staplers/stapling techniques in cervical esophagogastric anastomosis, 556 in colon interposition, 604

Staplers/stapling techniques (Continued) in diverticulectomy, 711 in diverticulostomy, 705-706, 705f, 707, 707f, 708t in esophageal perforation repair, 805, 807 in esophagectomy for squamous cell carcinoma, 478 in gastric tube creation, 316, 317f, 604, 658, 660, 660f in laparoscopic Collis gastroplasty, 374, 374f in left thoracoabdominal esophagectomy, 587 postoperative anastomotic stricture and, 548 in right-sided transthoracic esophagectomy, 593, 593f in side-to-side anastomosis after right-sided transthoracic esophagectomy, 595, 595f in thoracoscopic construction of intrathoracic anastomosis, 626 in total gastrectomy with Roux-en-Y reconstruction, 616, 616f, 617f in transhiatal esophagectomy, 571, 572, 572f, 574, 576f Steakhouse syndrome, 245, 775 Stent(s) for caustic injury, 763 intraluminal, for thoracic esophageal perforation, 805 metallic for peptic stricture, 228 self-expanding complications of, 529, 529t for palliation of esophageal carcinoma, 528529, 528t, 529t, 668, 671f Montgomery salivary, in pharyngoesophageal reconstruction, 652 for peptic stricture, 228 plastic, self-expanding, for caustic injury, 763 for tracheomalacia, 160 Sternocleidomastoid muscle, incision along in left thoracoabdominal esophagectomy, 587, 587f in right-sided transthoracic esophagectomy, 593 Sternum, partial upper split of, in transhiatal esophagectomy, 571, 571f, 578, 581 Steroids. See Corticosteroids. Stomach. See also Gastric entries. arterial supply of, 656, 657f dilation of, for gastric tube creation after gastrostomy, 656 dissection of in right-sided transthoracic esophagectomy, 593, 593f in total gastrectomy with Roux-en-Y reconstruction, 614-615, 617 embryology of, 20f, 21-22 for esophageal replacement, 556-557. See also Gastric pull-up; Gastric tube. greater curvature of, in esophageal reconstruction, 5, 557 lesser curvature of, in esophageal reconstruction, 557 mobilization of in hybrid esophagectomy procedures, 620, 621t in laparoscopic Nissen fundoplication, 210-212, 212f, 270f, 271 in open Nissen fundoplication, 262f, 263, 264-265, 265f in transhiatal esophagectomy, 565-566, 566f necrosis of, after transhiatal esophagectomy, 580 in physiologic model of foregut, 49, 50f resection of. See Gastrectomy. two-compartment, 372f vagal innervation of, 18 Storz optical endoscope, for foreign body removal, 774, 774f, 787, 788f Stretta system, for gastroesophageal reflux disease, 223, 356-359, 358f Striated muscle, 23, 24f Strictures anastomotic. See Anastomotic strictures. esophageal. See Esophageal strictures. peptic. See Peptic strictures. Stridor, in vascular rings, 172 Stromal tumors, gastrointestinal, 433, 538, 540, 541f

Subclavian artery, aberrant left in dysphagia lusorum, 76f, 77 and left ligamentum, right aortic arch with, 171, 172f, 174f Subcutaneous route for esophageal replacement, 560, 638 Subepithelial plexus, 14-15 Submucosa esophageal. See Esophageal submucosa. histology of, 26-27 Submucosal glands embryology of, 22, 22f histology of, 396 Submucous plexus, 18, 396 Substernal pain in Boerhaave’s syndrome, 798 in thoracic esophageal perforation, 796 Substernal route for esophageal replacement, 559, 638 Sucralfate for gastroesophageal reflux disease, 195 in pregnant patients, 200t, 201 Suicide attempt, caustic ingestion from, 760 Supercharged pedicle flaps, for esophageal replacement, 559 Super-squeeze esophagus. See Nutcracker esophagus. Supraumbilical incision, in transhiatal esophagectomy, 565, 566f Supraventricular tachycardia, after esophagectomy, 546 Surgeon experience esophagectomy hospital mortality and, 545 transhiatal esophagectomy outcome and, 581 Sutures in Belsey Mark IV repair, 281f-286f, 284 in colon interposition, 635 in Hill repair, 293f, 294, 294f, 295-296, 296f in laparoscopic Nissen fundoplication, 212, 213f, 272, 272f, 273f in laparoscopic Toupet fundoplication, 306f, 307 in left thoracoabdominal esophagectomy, 588, 588f in open Nissen fundoplication, 263, 263f, 264, 264f, 265-266, 266f in right-sided transthoracic esophagectomy, 592, 593-594, 594f in total gastrectomy with Roux-en-Y reconstruction, 616, 617f in transhiatal esophagectomy, 574, 575f-576f in transthoracic gastroplasty with Belsey fundoplication, 316, 318f, 319, 319f Swallowing after pharyngoesophageal reconstruction, 653 intrabolus pressure for, 129f-131f, 130 lower esophageal sphincter in, 33-34, 34f manometry of, 31, 34-37, 128-130, 128f-131f oropharyngeal dysphagia and, 677, 678f pharyngeal response in, 28, 29f physiology of, 28-34 neurogenic control of, 30f, 31f, 32, 33f response phases in, 28-31, 29f-31f primary forces in, 129 upper esophageal sphincter in, 28-31, 29f-31f Sympathetic nervous system, esophageal distribution of, 16, 18f Synovial sarcoma, 540 Systemic lupus erythematosus, esophageal motor disorder in, 727 Systemic sclerosis, 725-726. See also Sclerosis, systemic.

T Tachycardia, supraventricular, after esophagectomy, 546 Taxanes for esophageal carcinoma, 510t, 511-512 with platinum analogues, 513t, 516-517 Teflon pledgets, in crural closure, complications caused by, 380 Tegaserod, for gastroesophageal reflux disease, 196 Tela submucosa, histology of, 26-27 Ténière modification of Toupet repair, 300, 300f Tensilon test, 131 Thal cardioplasty, for Chagas’ disease, 738-740, 739f-740f, 740t

tahir99-VRG vip.persianss.ir

Index

Thal fundoplication, 299 after esophageal atresia repair, 160 for esophageal stricture, 8 for gastroesophageal reflux, in infants and children, 222 Thal-Ashcraft anterior fundoplication, 299 Thal-Nissen procedure, 8 Thigh free flap anterolateral for pharyngoesophageal reconstruction, 653 for pharyngolaryngeal reconstruction, 647-648, 647f lateral, for pharyngoesophageal reconstruction, 653 Thoracic anastomotic leaks, 547, 556 Thoracic duct anatomy of, 15, 16f ligation of for chylothorax, 549-550, 579 in en-bloc resection of esophageal carcinoma, 602, 602f Thoracic esophagostomy, anterior, after esophagectomy for perforation, 348, 350f Thoracic esophagus anatomy of, 11f arteries supplying, 13, 13f, 14f perforation of in Boerhaave’s syndrome, 796-798 causes of, 796, 796f, 797f clinical features of, 796 treatment of, 799-805, 800f-804f, 806 closure technique in, 800-801, 802f decision-making discussion for, 806-807 drainage in, 794, 794f-795f, 805, 807 esophageal exclusion in, 804-805, 807 esophagectomy in, 805 intraluminal stents in, 805 nonoperative, 806, 806f pedicled intercostal musculopleural flap in, 803-804, 803f-804f surgery on, evolution of, 3-5 vagal innervation of, 18, 18f Thoracic inlet, enlargement of, for substernal placement of colon interposition, 638 Thoracic surgery training in, history of, 9 video-assisted for leiomyoma, 434, 438 for midesophageal and epiphrenic esophageal diverticula, 710-711, 710f-711f for squamous cell carcinoma, 483-484 Thoracoabdominal approach, for reoperation, 364 Thoracoabdominal esophagectomy, left, 584-589 anastomosis for, 587, 588f historical note on, 584 incision closure in, 587-588 incisions in, 585-587, 585f-587f indications for, 584-585 postoperative course after, 588-589 preparation for, 585, 585f Thoracoscopy. See also Video-assisted thoracic surgery (VATS). as carcinoma staging tool, 457, 459, 470 in hybrid esophagectomy procedures, 620, 621t Thoracotomy for achalasia, 746 for en-bloc resection of esophageal carcinoma, 600-602, 600f-602f for Ivor Lewis esophagectomy, 595 for reoperation, 364 for thoracic esophageal perforation repair, 799, 800 for three-field lymphadenectomy, 609 for tri-incisional esophagectomy, 591, 592f Three-field lymphadenectomy, 608-612 general aspects of, 608-609 morbidity and mortality of, 611t patterns of nodal spread results in, 610-611, 611t postoperative care in, 610 results of, 489-490 in Japanese studies, 608 at University of Leuven, 612 at Weill Cornell Medical College, 612 for squamous cell carcinoma, 473-476, 474f-475f surgical procedure for, 609-610, 610f-611f Western experience with, 609-612 Western skepticism about, reasons for, 608

Thymidylate synthase, as potential marker of chemotherapy response, 517 Thyroid artery esophageal distribution of, 13, 13f in transhiatal esophagectomy, 568 Thyroid gland, esophagus relation to, 11f Thyroid vein esophageal distribution of, 15 in transhiatal esophagectomy, 568 Thyropharyngeal muscle, histology of, 23, 23f Time trade-off utility measure, 665, 665f Tissue architecture, 22-27 of lower esophageal sphincter, 25-26, 25f, 26f of tela submucosa, 26-27 of tunica adventitia, 23 of tunica muscularis, 23-25, 23f-26f of tunica submucosa, 27 of upper esophageal sphincter, 25 Tissue flaps, for tracheoesophageal fistula repair, 159 Tobacco adenocarcinoma and, 450 gastroesophageal reflux disease and, 193, 203 squamous cell carcinoma and, 448-449 Topoisomerase inhibitors, for esophageal carcinoma, 510t, 512 Torek esophagectomy, 9 Total parenteral nutrition, for chylothorax, 549 Toupet fundoplication Collis gastroplasty with, in secondary esophageal motor disorders, 729, 729f for gastroesophageal reflux, 207-208, 208, 209f in infants and children, 222 historical note on, 298 indications for, 214 laparoscopic, 305-312 contraindications to, 306 future trends in, 311-312 historical note on, 305 indications for, 305-306, 306t modifications of, 305, 306f preoperative care in, 306 preoperative workup for, 306, 308f-309f results of, 302, 303t-304t, 310-311, 311t technique for, 306f-307f, 307, 310f-311f normal appearance of, on barium esophagogram, 68, 68f open lower esophageal sphincter pressures created by, 300-301, 301t modifications of, 300, 300f principles of, 298-299 results of, 300-304, 301t-303t technique for, 299-300, 300f results of, versus full fundoplication, 303-304, 368-369 Toxic ingestions, mucosal complications associated with, 57 TP53 gene, in esophageal carcinogenesis, 443-445, 444f Trachea bifurcation of, vagal innervation of, 18, 18f esophagus relation to, 10, 11f, 12f, 13 innominate artery compression of, 178-179, 179f reconstruction of, in pulmonary artery sling repair, 178 stenosis of, in pulmonary artery sling, 177, 177f tear of, with transhiatal esophagectomy, 578 vagal innervation of, 17-18, 17f-18f Tracheal aspiration in cricopharyngeal dysfunction without diverticulum, 693, 693f in oculopharyngeal muscular dystrophy, 689, 689f in oropharyngeal dysphagia, 40 Tracheal diverticulum, embryology of, 20f, 22 Tracheal rings, in pulmonary artery sling, 177 Tracheobronchial foregut duplications, 164, 165f Tracheobronchial remnants, congenital esophageal stenosis from, 167 Tracheobronchial symptoms, in oculopharyngeal muscular dystrophy, 689 Tracheoesophageal compression syndromes, vascular anomalies causing, 170-179, 171t Tracheoesophageal fistula, 151-160 after laryngotracheoesophageal cleft repair, 162 classification of, 153, 153t

829

Tracheoesophageal fistula (Continued) congenital anomalies associated with, 153 diagnosis of, 154 embryology of, 151-153, 152f epidemiology of, 151 genetics of, 152 historical note on, 151 malignant, endoesophageal prosthesis for, 799 N-type, 154, 154f, 155 radiotherapy in patient with, 525 recurrent, 159 risk stratification schemes for, 156, 156t surgical management of complications of, 159-160, 159t esophageal replacement in, 157, 159 preoperative, 155-157, 155f, 156t primary repair in, 157, 158f tissue flaps in, 159 symptoms of, 154 Tracheoesophageal puncture, voice via, after pharyngoesophageal reconstruction, 653 Tracheoesophageal sulcus, 151, 152f Tracheomalacia after esophageal atresia repair, 160 after laryngotracheoesophageal cleft repair, 161 Tracheoplasty, slide, in pulmonary artery sling repair, 178 Tracheostomy mini-, after colon interposition, 639 permanent, after cricopharyngeal myotomy, 686f, 687 Tracheostomy tube, in laryngotracheoesophageal cleft, 161 Traction diverticulum, barium esophagogram in, 75, 75f Tranquilizers, for nonachalasia motility disorders, 724 Transabdominal anastomosis, for Roux-en-Y jejunal reconstruction, 560 Transabdominal approach in open Nissen fundoplication, 262-264, 262f-264f Transabdominal fundoplication. See Nissen fundoplication. Transabdominal open gastroplasty with Nissen fundoplication, 7, 320, 321f-323f Transcutaneous electrical nerve stimulation, for achalasia, 718 Transforming growth factor-alpha, in esophageal carcinogenesis, 445 Transhiatal esophagectomy blunt, 563-583 anesthesia for, 565 complication(s) of, 564, 577-579 bleeding as, 572, 578, 580 cervical anastomotic leak as, 578-579, 580 chylothorax as, 579, 580 intraoperative, 580 pleural effusion as, 579 postoperative, 580 recurrent laryngeal nerve palsy as, 578 tracheal tear as, 578 contraindications to, 564-565 hemostasis with, 572, 578, 580 historical note on, 563-564 hospital mortality with, 580-581 morbidity with, 580 operative technique for, 565-575 abdominal phase in, 565-568, 566f-567f for carcinoma of esophagogastric junction, 574-575, 577f cervical esophagogastric anastomosis in, 574, 574f-576f cervical phase in, 567f-568f, 568-569 mediastinal dissection in, 568f-573f, 569-573 patient selection for, 564-565 postoperative care in, 575-578 preoperative preparation for, 565 recurrence rate after, 584 results of, 486-487, 579-581, 580t versus en-bloc esophagectomy, 606-607, 606t versus transthoracic esophagectomy, 488, 581, 581t as variant of posterior mediastinal route, 559 laparoscopic, 620-622 hand-assisted, 626-628, 627t surgical results of, 622, 622t

tahir99-VRG vip.persianss.ir

830

Index

Transhiatal esophagectomy (Continued) laparoscopic (Continued) surgical technique for cervical esophagogastric anastomosis in, 622 laparoscopic esophageal mobilization in, 621-622 quality of life after, 666, 667t, 669f Transpleural route for esophageal replacement, 560 Transthoracic approach, in open Nissen fundoplication, 264-266, 265f-266f Transthoracic esophagectomy en-bloc, versus transhiatal esophagectomy, 489 evolution of, 3-4 quality of life after, 666, 667t, 669f results of, 487-488, 488t versus transhiatal esophagectomy, 488, 581, 581t right, 590-596 choice of operation and, 590-591 historical note on, 590 Ivor Lewis approach for, 595-596, 595f patient selection for, 591 postoperative care in, 596 preparation for, 591 tri-incisional approach for, 591-596, 592f-595f Transthoracic esophagomyotomy, for achalasia, 745, 746-747, 746f-747f, 751 Transthoracic gastroplasty, open, for giant hiatal hernia, 328, 328t Traumatic injuries, esophagectomy for, 346-349, 347f-350f, 348t Trazodone, for nonachalasia motility disorders, 724 Tricyclic antidepressants, for nonachalasia motility disorders, 724 Tri-incisional esophagectomy, 591-596 abdominal/cervical stage in, 593-595, 593f-595f advantages of, 590-591 anastomosis for, 595, 595f thoracic stage in, 591-592, 592f-593f Trypanosoma cruzi, 731, 732, 732f. See also Chagas’ disease. T-tube fistula, for thoracic esophageal perforation, 805, 807 Tubular esophagus, 24, 25f Tumor(s) behavior of, hypoxia and, 503-504, 508 benign. See Benign neoplasms. depth of in carcinoma staging, 455-457, 459f lymph node status and, 600t epithelial, 532t, 533-537, 535f-536f granular cell, 107, 437, 542 location of, en-bloc resection and, 598 malignant. See Cancer; Carcinoma. mesenchymal, 532t, 537-542, 539f-543f stromal, gastrointestinal, 433, 538, 540, 541f of upper aerodigestive tract, multiple primary, 452 Tumor suppressor genes, in esophageal carcinogenesis, 443-445, 444f Tumor-node-metastasis (TNM) system of carcinoma staging, 101, 102t, 454-455, 456t, 457-458. See also Carcinoma staging. Tunica adventitia, 23 Tunica mucosa, 20-21, 21f-23f Tunica muscularis embryology of, 20, 21f histology of, 23-25, 23f-26f Tunica propria mucosa, 27 Tunica submucosa, 27 Tylosis esophageal cancer gene, 452

U UES. See Upper esophageal sphincter (UES). UFT, with cisplatin, 513t, 515 Ulcer, peptic, 115, 399, 399f Ultraflex SEMS, 528 Ultrasonography B-mode, 98 bronchoscopic, in squamous cell carcinoma staging, 467-468 endoscopic. See Endoscopic ultrasonography (EUS). fundamentals of, 97-98

Ultrasonography (Continued) gray-scale, 98 real-time, 98 Umbilical tape, for measurement of colon graft, 633, 633f, 634f University of Hong Kong, squamous cell carcinoma management at, 481-482, 481f-483f Upper aerodigestive tract, tumors of, multiple primary, 452 Upper esophageal sphincter (UES) anatomy of, 10, 11f, 12f during belching, 31 control mechanisms of, 31-32 dysfunction of in gastroesophageal reflux, 43 iatrogenic, 43 idiopathic, 42 with diverticulum, 42-43, 694-699, 694f-699f without diverticulum, 693-694, 693f, 693t myogenic, 689-690, 690f myotomy management of, 691-693, 691f692f, 692t neurogenic, 682f-683f, 685 myotomy management of, 684f-686f, 685-687, 687t foreign body impaction at, 769, 769t histology of, 25 manometry of interpretation of, 38 in oropharyngeal dysphagia, 679-680, 680f sleeve catheter for, 37, 37f, 123, 679, 680f stationary, 122-123, 122f during swallowing, 31 in swallowing disorders, 128-130, 128f-131f physiologic evaluation of, problems associated with, 30-31 in physiologic model of foregut, 50, 50f pressure of, during swallowing, 28-30, 29f, 30f relaxation of, anatomical versus manometric, 128, 128f role of, 28 swallowing coordination of, 28-31, 29f-31f manometric studies of, 128-130, 128f-131f Upper gastrointestinal bleeding, esophagogastroduodenoscopy in patient with, 115 Upper gastrointestinal contrast study, in paraesophageal hernia, 235, 235f Upper gastrointestinal tract, flexible endoscopy of. See Esophagogastroduodenoscopy. Urinary tract anomalies, with esophageal atresia, 153 Utility measures in Barrett’s esophagus, 671, 672t description of, 665, 665f

V VACTER/VACTERL association, esophageal atresia in, 153-154 Vacuolization errors in in esophageal cysts, 164 in esophageal webs, 167 of esophageal mucosa, 21, 23f Vagal injury dysphagia in, 683 failure due to, 363, 369 intraoperative, 377 Vagal innervation, 17-18, 17f-18f Vagal-sparing esophagectomy, 353 with colon interposition, 635-636, 635f-637f, 640-641, 640f, 641f Vagotomy antrectomy and duodenal diversion with, for failed repairs, 365 dumping syndrome after, 353, 548 highly selective, in vagal-sparing esophagectomy, 636 Vagus nerve division of, in right-sided transthoracic esophagectomy, 591-592 esophageal routes of, 16-17, 17f-18f, 18 Valleculae, 678f Vascular endothelial growth factor, monoclonal antibodies targeting, 518

Vascular injuries, intraoperative, 378 Vascular rings anatomic subtypes of, 170, 171t clinical presentation in, 172-173 diagnosis of, 173-174, 173f, 174f dysphagia lusorum, 76f, 77, 179 embryology of, 170-172, 171f-172f, 171t in pulmonary artery sling, 177 surgical management of, 174-176, 176f Vasodilators, for nonachalasia motility disorders, 723-724 Vayre modification of Toupet repair, 300 Vector volume, in stationary manometry of LES, 119-120 Vein stripper, in vagal-sparing esophagectomy, 635-636, 635f-636f Veins of colon, 631f, 632 of esophagus, 396-397 extraesophageal versus intraesophageal, 14-15 Vena cava, injury to, intraoperative, 378 Venotomy, intraoperative, 378 Venous thrombosis, deep, after esophagectomy, 546 Ventilation, mechanical in esophageal atresia, 156 postoperative, in esophageal perforation, 804 during surgery, 3 Verrucous carcinoma, 533-534 Vertical banded gastroplasty, for reflux in obese patients, 242, 242f Video fluoroscopy, in motility disorders, 71 Video-assisted thoracic surgery (VATS). See also Thoracoscopy. for leiomyoma, 434, 438 for midesophageal and epiphrenic esophageal diverticula, 710-711, 710f-711f for squamous cell carcinoma, 483-484 Videoendoscopic esophagodiverticulostomy, for pharyngoesophageal diverticulum, 705-706, 705f, 706-707, 707f, 708t Video-esophagography, of pharyngoesophageal junction, 679, 679f Vindesine with cisplatin and bleomycin, 512, 513t with cisplatin and mitoguazone, 512, 513t for esophageal carcinoma, 510t, 511 Vinorelbine with docetaxel, 513t, 514 for esophageal carcinoma, 510t, 511 Visual analogue scale, 665 Visual Analogue Scale, Reflux-Related, 383 Vitamin A deficiency, squamous cell carcinoma and, 449 Vocal cord paralysis after esophagectomy, 550-551 after transhiatal esophagectomy, 582 Volvulus, paraesophageal hernia with, 234 Vomiting. See also Regurgitation. early postoperative, 378 esophageal rupture with. See Boerhaave’s syndrome. in foreign body impaction, 783 persistent, Mallory-Weiss syndrome after, 798

W Wallstent, 528 Weight loss in achalasia, 715 after Roux-en-Y gastric bypass, 244 in Chagas’ disease, 732 for reflux in obese patients, 241

Z Z line in Barrett’s esophagus, 401, 402f clinical relevance of, 27 histology of, 395-396 Zenker’s diverticulum. See Pharyngoesophageal diverticulum. Z-stent, 528

tahir99-VRG vip.persianss.ir